MXPA06006820A

MXPA06006820A - Methods for treating retinoid responsive disorders using selective inhibitors of cyp26a and cyp26b

Info

Publication number: MXPA06006820A
Application number: MXPA/A/2006/006820A
Authority: MX
Inventors: A Chandraratna Roshantha; L Beard Richard; Wang Liming; Liu Xiaoxia; Vasudevan Jayasree; Yin Tsang Kwok; Li Ling; A Takeuchi Janet; Vu Thong; Bhat Smita; Yang Rong
Original assignee: Allergan Inc; L Beard Richard; Bhat Smita; A Chandraratna Roshantha; Li Ling; Liu Xiaoxia; A Takeuchi Janet; Yin Tsang Kwok; Vasudevan Jayasree; Vu Thong; Wang Liming; Yang Rong
Priority date: 2003-12-17
Filing date: 2006-06-15
Publication date: 2006-12-13

Abstract

The invention provides methods for treating an individual having a retinoid responsive disorder. In one embodiment, a method involves administering to the individual an effective amount of a selective CYP26B inhibitor, the selective CYP26B inhibitor having at least 10-fold selectivity for CYP26B relative to CYP26A. In another embodiment, a method involves administering to the individual an effective amount of a selective CYP26A inhibitor, the selective CYP26A inhibitor having a chemical formula set forth in the specification. The invention further provides screening methods for identifying a selective CYP26A inhibitor or selective CYP26B inhibitor.

Description

METHODS TO TREAT RETINOID SENSITIVE DISORDERS USING SELECTIVE CYP26A AND CYP26B INHIBITORS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates generally to the treatment of disorders sensitive to retinoids and, in particular, to the therapeutic use of compounds that selectively inhibit CYP26A (P450RAI-1) or CYP26B (P450RAI-2). Retinoids, such as retinoic acid ("RA"), are important modulators of division and differentiation, immune response and embryonic development. These molecules work in cells binding and activating the retinoic acid (RAR) receptors, which successively bind to certain DNA sequences and regulate the target gene expression. Retinoid drugs can be used to beneficially modulate the expression of certain target genes by improving or avoiding disease conditions. For this reason, more than 30 analogs of natural and synthetic origin of retinoic acid have been developed for their use as therapeutic agents. Current therapies with retinoids include the differentiation of acute promyelocytic leukemia (APL); the treatment of nodulocystic acne, a severe form of inflammatory acne; the treatment of psoriasis; the prevention of secondary head and neck cancers; topical therapy of acne vulgaris; and reversal of photolesion as measured by UV / Thacher et al., Current Pharm. Design 6:25:58 (2000)). Unfortunately, retinoids can be highly toxic at therapeutic doses. Therefore, the dosage of retinoids that can be administered to patients is limited by the significant side effects, which include irritation and inflammation of the skin and mucous membranes, elevation of serum triglycerides, dysregulation of bone formation and resorption, headaches, hypothyroidism, and fetal malformation. Another disadvantage of retinoid therapy is that patients, particularly cancer patients, often become resistant to therapy over time. Thus, there is a need to identify new methods to therapeutically increase or maintain the beneficial levels of retinoic acid and other retinoids in the body to treat the disease. The present invention satisfies this need and also provides the advantages described.

SUMMARY OF THE INVENTION The invention provides methods for treating an individual who has a retinoid responsive disorder. In one embodiment, a method involves administering to the individual an effective amount of an inhibitor of CYP26B (P450RAI-2), the selective CYP26B inhibitor having a selectivity of at least 10-fold for CYP26B relative to CYP26A. A selective CYP26B inhibitor used in a method of the invention can have a selectivity of at least 20 times for CYP26B relative to CYP26A (P450RAI-1), for example, a selectivity of at least 100 times, at least 500 times and at at least 1,000 times for CYP26B in relation to CYP26A. Exemplary selective CYP26B inhibitors which can be used in a method of the invention are shown below in the form of Formulas 5, 15 and 30 to 32. In another embodiment, a method for treating an individual having a sensitive disorder the retinoids involve administering to the individual an effective amount of a selective CYP26A inhibitor, the selective CYP26A inhibitor having a selectivity of at least 10-fold for CYP26A relative to CYP26B and having a formula selected from Formulas 1 to 4,6. to 14, 16, 17 and 18 to 29, as shown here below. A selective CYP26A inhibitor used in a method of the invention can have a selectivity of at least 20 times for CYP26A relative to CYP26B, for example a selectivity of at least 100 times, at least 500 times and at least 1, 000 times for CYP26A in relation to CYP26B. Exemplary retinoid responsive disorders that can be treated using a method of the invention include a skin disorder, such as acne, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and an eye disorder. pulmonary disorder. In different embodiments, a selective CYP26A inhibitor or a selective CYP26B inhibitor can be administered, for example, peripherally or orally. In one embodiment, a method of the invention can be used to treat a human having a retinoid sensitive disorder. The invention further provides a screening method for identifying a selective CYP26A inhibitor having a selectivity of at least 10-fold for CYP26A relative to CYP26B. The method involves connecting a CYP26A with one or more candidate compounds; selecting from the candidate compounds a compound that inhibits CYP26A activity; determining the ability of the compound selected to inhibit CYP26B: activity and to identify a compound having a selectivity of at least 10-fold for CYP26A relative to CYP26B. The invention also provides screening for identifying a selective CYP26B inhibitor having a selectivity of at least 10-fold for CYP26B relative to CYP26A.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows that 13-cis retinoic acid is effective in reducing the differentiation of the sebaceous gland into the hamster's side organ. Fig. 2 shows that the activity of 13-cis retinoic acid on differentiation of the sebaceous gland can be blocked by a retinoic acid receptor antagonist. Fig. 3 shows that a synthetic RAR pan-antagonist (TTMBB) is effective in reducing the differentiation of the sebaceous gland into the hamster's side organ. Fig. 4 shows that both the selective CYP26A inhibitor and the selective CYP26B are effective in reducing the differentiation of the sebaceous gland into the hamster's side organ.

DETAILED DESCRIPTION OF THE INVENTION Retinoids play important roles in the regulation of gene expression during embryonic development and in the maintenance of adult epithelial tissues. The amount of a retinoid, such as retinoic acid (RA), present in the body at any given time is regulated, in part, by cellular metabolism. Cytochrome P450 molecules CYP26A and CYP26B, also known as P450RAI-1 and P450RAI-2, respectively, metabolize RA into more polarized hydroxylated and oxidized derivatives, thereby reducing the level of this retinoid in the body. By blocking the RA shredding activity of CYP26A or CYP26B, the amount of natural RA or administered in a cell can be maintained at a beneficial level. Accordingly, an inhibitor of CYP26A or CYP26B can be used to maintain or beneficially increase a retinoid level in an individual, either alone or in conjunction with a retinoid treatment. It has been observed that the administration of certain CYP26A inhibitors to mammals causes a significant increase in the levels of endogenous retinoic acid (see, for example, U.S. Patent Nos. 6. 531,599 and 6,495,552). For example, the treatment of human patients with the CYP26A inhibitor liarozole produces beneficial effects similar to those observed after treatment with retinoids, such as the improvement of psoriasis (Kuijpers, et al., Bri tish Journa.1 of Dermatology 139: 380-389 (1998)). Below, selective inhibitors of CYP26A having a selectivity of at least 10-fold for CYP26A relative to CYP26B have been identified and are referenced as Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. In Table 4 A variety of selective CYP26A inhibitors and selective CYP26B inhibitors are shown below. The selective CYP26A inhibitors shown in Table 4 have a selectivity ranging from at least 10-fold to at least 888-fold selectivity for CYP26A relative to CYP26B. The selective CYP26B inhibitors shown in Table 4 have a selectivity ranging from at least 10-fold to a selectivity at least 83-fold for CYP26B relative to CYP26A. While the selective CYP26A inhibitors described herein are not structurally related to the above-described CYP26A inhibitors, these compounds can provide similar beneficial effects by reducing the destruction of endogenous or administered retinoids, including, without limitation, retinoic acid and acid analogs. retinoic Based on the identification of the selective inhibitors of CYP26A and CYP26B, the present invention provides therapeutic methods involving the selective inhibition of CYP26A or CYP26B. The methods are useful for beneficially treating an individual having any of a variety of retinoid sensitive disorders described herein below or otherwise known in the art. As described herein in Example I, compounds that selectively inhibit the activity of CYP26A or CYP26B were shown to be effective in reducing sebocyte differentiation in an animal model of acne development. In this animal model, which involves the observation of the differentiation of the sebaceous gland in the organ of the hamster side, retinoid receptor and retinoic acid agonists block differentiation, which is analogous to blocking the development of acne in a mammal such as a human. On the other hand, treatment with a selective CYP26A inhibitor or a selective CYP26B inhibitor reduced sebocyte differentiation as effectively as ACCUTANE, one of the most widely used commercially available acne medications with commercially available retinoic acid. Thus, in one embodiment, the present invention provides a method for treating a retinoid responsive disorder by administering an effective amount of a selective CYP26A inhibitor having any of Formulas 1 through 4, 6 through 14, 16, 17 and 18 a 29 or a selective CYP26B inhibitor having a selectivity of at least 10-fold for CYP26B relative to CYP26A. As used herein, the term "retinoid responsive disorder" means a condition or disease that normally has a symptom that is improved, alleviated, delayed at onset, or prevented following the administration of retinoic acid (RA) or a retinoid synthetic that has RA activity. A variety of disorders responsive to retinoids are known in the art and include, without limitation, cancers such as skin cancer, mouth cancer and Kaposi's sarcoma.; skin disorders such as acne, psoriasis and eczema; and other multiple disorders of diverse etiology, including but not limited to emphysema and Alzheimer's disease. The ability of the RA or a synthetic retinoid having the activity of the RA to improve, alleviate, delay the onset of, or prevent at least one symptom of a condition or disease, if not known, can be determined using well-known methods, including those described here below. A synthetic retinoid used for such a determination can be any of a variety of retinoids used experimentally or clinically. Among the exemplary synthetic retinoids in clinical use today are acitretin, isotretinoin, tretinoin, tazarotene, and adapalene. A variety of retinoid sensitive disorders can be treated according to a method of the invention. Such skin disorders include, without limitation, inflammatory and noninflammatory acne, psoriasis, eczema, atopic dermatitis, pityriasis rubra pilaris, multiple-cell carcinomas-actinic keratosis, arsenic keratosis, ichthyosis, and other disorders of the skin. keratinization and cutaneous hyperproliferatives, Darriers disease, lichen planus, glucocorticoid injury (steroid atrophy), cutaneous microbial affection, excessive skin pigmentation, and cutaneous photo-deterioration. In various embodiments, the invention provides methods for treating acne that involve the administration of a selective CYP26A inhibitor or a selective CYP26B inhibitor. Acne is a common disease of the pilosebaceous glands, and is characterized by comedones, papules, pustules, inflamed nodules, cysts filled with superficial pus, and (in extreme cases) sacs that are channeled and deep, inflamed, sometimes purulent. In the art, multiple categories or types of acne have been defined based on the severity of the condition. For example, "superficial acne" is characterized by black spots (open comedones) or white spots (closed comedones), inflamed papules, pustules, and superficial cysts, occasionally producing large cysts. As another example, "deep acne" is similarly characterized except with deep inflamed nodules and cysts filled with pus, which often rupture and become abscesses. Other acne categories include "acne vulgaris", which is the most common form of acne; the "acne conglobata," which is an acne that covers the back, chest, and buttocks with pustules that often connect under the skin; "acne fulminans", which is an extreme form of acne conglobata that involves the sudden outbreak of pustules and nodules, infected nodules, fever, joint pain, and possible weight loss or appetite; "Medicated acne", which is caused by a drug; "comedonal acne", which is acne characterized by blackheads and whiteheads without other forms of skin lesions, and "cystic acne," which occurs when the infected content of a pustule or pimple bursts beneath the skin, instead of on the surface. It is understood that the method of the invention can be used to beneficially treat an individual having any form of mild, moderate or severe acne including, but not limited to, those discussed above. In a further embodiment, the invention provides a method for treating an individual having a proliferative disorder which involves administering to the individual an effective amount of a selective CYP26B inhibitor having a selectivity of at least 10 times for CYP26B relative to CYP26A, or an effective amount of a CYP26A inhibitor, which is represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. As used herein, the term "proliferative disorder" means a disease or abnormal condition. that produces unwanted or anomalous cell growth, viability or proliferation. Among the proliferative disorders include diseases such as cancer, in which the cells are transformed neoplastic, and diseases resulting from the overgrowth of normal cells. For example, cellular proliferative disorders include diseases related to connective tissue overgrowth, such as various fibrotic diseases, including scleroderma, arthritis, alcoholic liver cirrhosis, keloid, and hypertrophic scarring.; vascular proliferative disorders, such as atherosclerosis; benign tumors, and the abnormal proliferation of cells that mediate autoimmune diseases. As used herein, the term "cancer" means a class of diseases characterized by uncontrolled growth of aberrant cells, including all known cancers, and neoplastic conditions, whether characterized as malignant, benign, soft tissue or solid tumor. Specific cancers that can be treated using the method of the invention include, without limitation, cancers of the skin, breast, eye, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leucoplasias, papillomas of the mucous membranes and Kaposi's sarcoma. A compound that maintains or beneficially increases the level of a retinoid in the body can be used by selectively inhibiting CYP26A or CYP26B to treat a variety of cancers. For example, the increase in the amount of retinoid in the body of cancer patients has been a successful strategy to treat a variety of cancers. For example, retinoids have been used to reduce or prevent cancers of the mouth, skin, and head and neck in individuals at risk of these tumors (see, for example, Bollag et al., Ann. Oncol. 3: 513-526 ( 1992), Chiesa et al., Eur. J. Cancer B. Oral Oncol. 28: 97-102 (1992), Costa et al., Cancer Res. 54: Supp. 7, 2032-2037 (1994)). Retinoids have also been used to treat squamous cell carcinoma of the cervix and skin (see, for example, Verma, Cancer Res. 47: 5097-5101 (1987); Lippman et al., "Nati Cancer Inst. : 235-241 (1992), Lippman et al., J. Nati Cancer Inst. 84: 241-245 (1992)) and Kaposi's sarcoma (see, for example, Bonhomme, et al., Ann. Oncol. : 234-235 (1991)), and have found significant use in the therapy of acute promyelocytic leukemia (see, for example, Huang et al., Blood 72: 567-572 (1988); Castaigne et al., Blood 76: 1704-1709 (1990), Lo Coco et al., Blood 77: 1657-1659 (1991), Warrell et al., N. Engl. J. Med 324: 1385-1393 (1991), and Chomienne et al. ., FASEB J. 10: 1025-1030 (1996)). Accordingly, a compound which maintains or beneficially increases the level of a retinoid in the organism can be used by selective inhibition of CYP26A or CYP26B to treat a variety of cancers using a method of the invention.

In another embodiment, the invention provides a method for treating an individual having a neurological disorder responsive to retinoids which involves administering to an individual an effective amount of a selective CYP26B inhibitor having a selectivity of at least 10 times for CYP26B relative to CYP26A, or an effective amount of a selective CYP26A inhibitor represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. As a selective CYP26A inhibitor or a selective CYP26B inhibitor can beneficially maintain or increase the level of a retinoid in a tissue of the nervous system of an individual, such an inhibitor can be used to treat a variety of neurological disorders that respond beneficially to retinoids. Both CYP26A and CYP26B are highly expressed in the brain, and multiple lines of evidence indicate that retinoids such as RA play important roles in normal neurological function and in neurological diseases. For example, retinaldehyde dehydrogenase, the enzyme that forms retinoic acid from retinaldehyde, has 1.5 to 2 times higher activity in the hippocampus and parietal cortex of brains with Alzheimer's disease than in normal controls.

(Conner and Sidell, Mol Chem. Neuropathol 30 (3): 239-52 (1997)). In addition, it has been indicated that retinoid hypofunction and impaired retinoid transport are factors that contribute to Alzheimer's disease (Goodman and Pardee, Proc. Nati, Acad. Sci. USA 4; 100 (5): 2901 -5 (2003)). Exemplary retinoid sensitive neurological disorders that can be treated with a selective CYP26A inhibitor or a selective CYP26B inhibitor according to a method of the invention include, but are not limited to, Alzheimer's Disease, schizophrenia, disease of Parkinson's disease, anxiety, depression, drug addiction, cognitive disorders, emesis, eating disorders, attention deficit hyperactivity disorder, Tourette's syndrome, Huntington's disease, tardive dyskinesia , Lesch-Nyhan disease, Rett syndrome and any neurological disorder that is sensitive to retinoids. In a further embodiment, the invention provides a method for treating an individual having an inflammatory disorder or autoimmune disorder responsive to retinoids or by administering to the individual an effective amount of a selective CYP26B inhibitor having a selectivity of at least 10 times for CYP26B relative to CYP26A, or an effective amount of a selective CYP26A inhibitor represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. A method of the invention can be used to treat any of a variety of inflammatory disorders, including, without limitation, those resulting from injuries; infection by a bacterium, virus, fungus or other pathogen; autoimmune disorders; and other anomalous conditions. Examples of inflammatory disorders responsive to exemplary retinoids that can be treated using a method of the invention include, for example, without limitation, inflammatory skin disorders, e.g., psoriasis; inflammatory gastrointestinal disorders, for example, ileitis, irritable bowel syndrome, ulcerative colitis and Crohn's disease; autoimmune disorders such as rheumatoid arthritis and other forms of arthritis; the rejection of organ transplantation; and any other inflammatory or autoimmune disorder responsive to retinoids. In another embodiment, the invention provides a method for treating an individual having an ocular disorder responsive to retinoids which involves administering to the individual an effective amount of a selective CYP26B inhibitor having a selectivity of at least 10 times for CYP26B relative to CYP26A, or an effective amount of a selective CYP26A inhibitor represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. A method of the invention can be used to treat a variety of ocular disorders, including , without limitation, diabetic retinopathy; macular edema such as macular edema associated with diabetes mellitus or other conditions; degeneration of the retina such as macular degeneration related to age or retinitis pigmentosa; inflammatory disorders of the retina; vascular occlusive conditions of the retina such as retinal vein occlusions or occlusions of the secondary or central retinal artery; retinopathy of premature babies; retinopathy associated with blood disorders such as sickle cell anemia; the lesion that follows the retinal detachment; the injury or attack due to vitrectomy surgery or retinal surgery; and other retinal lesions including therapeutic lesions such as those resulting from laser treatment of the retina, for example, pan-retinal photocoagulation for diabetic retinopathy or photodynamic therapy of the retina, for example, for age-related macular degeneration.; genetic and acquired optic neuropathies such as optic neuropathies characterized primarily by the loss of central vision, for example, hereditary optic neuropathy of Leber (LHON), autosomal dominant optic atrophy (Kjer's disease) and other optic neuropathies such as those involving mitochondrial effects, aberrant dynamin-related proteins or inappropriate apoptosis, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye, as well as any ocular disorder that is sensitive to retinoids. Referring to ocular disorders see, for example, Carelli et al., Neurochem. Intl. 40: 573-584 (202); and Olichon et al. , J. Biol. Chem. 278: 7743-7746 (2003). In still another embodiment, the invention provides a method for treating an individual having a pulmonary disorder involving the administration to the individual of an effective amount of a selective CYP26B inhibitor having a selectivity of at least 10-fold for CYP26B relative to CYP26A, or an effective amount of a selective CYP26A inhibitor represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. Retinoid treatment has been used to successfully treat, for example, emphysema , which is a pulmonary disorder resulting from the progressive destruction of the alveolar septa that was considered irreversible until it was shown that the administration of retinoic acid can reverse the anatomical and physiological signs of emphysema in a rat model (Massaro and Massaro, Nature Medicine 3: 675-7 (1997)). A method of the invention can be used to treat emphysema or another pulmonary disorder that is responsive to retinoids. Non-limiting examples of pulmonary disorders include, but are not limited to, obstructive lung disorders such as emphysema, chronic bronchitis, bronchial asthma, bronchiectasis, and cystic fibrosis; and restrictive pulmonary disorders such as interstitial fibrosis, pulmonary edema, respiratory fatigue syndrome in adults, rheumatoid spondylitis and pleural effusion. It is understood that increasing the level of a retinoid in a tissue of an individual may have beneficial effects in individuals having a variety of other retinoid responsive disorders, including cardiovascular disorders such as, without limitation, diseases associated with metabolism of lipids including dyslipidemias and post-angioplasty restenosis; and diabetes. In that case, the methods may be useful for treating a variety of retinoid sensitive disorders including, but not limited to, skin disorders, autoimmune disorders, inflammatory disorders, proliferative disorders, neurological disorders, eye disorders and pulmonary disorders.

By specifically mentioning the above categories of retinoid sensitive disorders, those skilled in the art will understand that all cases and types of these disorders are included in such terms. For example, it is desired that the term "skin disorder" includes any skin disorder having a symptom that is improved, alleviated, delayed in its onset or prevented after administration of the RA or a synthetic retinoid having the activity of the RA. Accordingly, the methods of the invention are applicable to disorders responsive to known retinoids as well as to disorders that have been determined to be responsive to retinoids, for example, in an animal model corresponding to a particular disorder. As described here below, CYP26A and CYP26B have different expression levels in different tissues in humans and other mammals. Thus, a selective CYP26A inhibitor or a selective CYP26B inhibitor can be used to inhibit the activity of a particular CYP26, such as CYP26A, for example, in a selected tissue without substantially altering CYP26B activity in that tissue, and vice versa. A selective CYP26A inhibitor or a selective CYP26B inhibitor can also be used to direct the inhibition of a CYP26 in a particular tissue, if desired. It is also understood that a selective CYP26A inhibitor or a selective CYP26B inhibitor can be used without targeting specific proteins for the inhibition of CYP26. In humans, CYP26A expression has been observed in the liver, brain and placenta (Ray et al J. Biol. Chem. 272: 18702-18708 (1997)); the expression of CYP26B has been observed in the brain (White et al Proc. Nati.

Acad. Sci. USA 97: 6403-6408 (2000) as well as in the kidney, the lung, the spleen, the fetal spleen, the skeletal muscle, the thymus, the peripheral blood leukocytes, the lymph nodes, the bones, the stomach, the placenta , the duodenum, the small intestine, and the pituitary gland (PCT / CA00 / 01493). It is understood that either CYP26A and CYP26B or both may be present in other tissues in humans or other mammals. For example, as shown in Example 1, both CYP26A and CYP26B are expressed in hamster skin. It is understood that a selective CYP26A or selective CYP26B inhibitor can be used to treat a retinoid sensitive disorder associated with a tissue in which either CYP26A or CYP26B is expressed. For example, an individual having cancer in a tissue in which CYP26A is expressed can be treated using a selective CYP26A inhibitor, while an individual having cancer in a tissue in which CYP26B is expressed can be treated using an inhibitor of CYP26A. Selective CYP26B. Thus, the expression of CYP26A or CYP26B in a particular tissue can be used to evaluate whether a treatment of a particular retinoid sensitive disorder with a selective CYP26A inhibitor or selective CYP26B inhibitor is appropriate. It is understood that a selective CYP26A or selective CYP26B inhibitor may be useful for treating a retinoid sensitive disorder even when the target tissue contains a low level of expression of both CYP26A and CYP26B. Methods for determining the expression levels of CYP26A or CYP26B mRNA or protein are well known to those skilled in the art and are described, for example, by Sambrook et al., In Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory , New York (1992) and by Ausubel et al., In Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1998).

Selective CYP26A and CYP26B inhibitors A. Functional characteristics The methods of the invention involve the administration of a selective CYP26A inhibitor or of selective CYP26B. As used herein, the term "selective CYP26A inhibitor" means a compound that reduces the expression or activity of CYP26A at least 10 times more than any reduction made by the inhibitor on the expression or activity of CYP26B. A selective CYP26A inhibitor can have, for example, a selectivity of at least 10 times for CYP26A relative to CYP26B, a selectivity of at least 20 times, at least 40 times, at least 80 times, at least 100 times, at least 500 times, at least 800 times, or at least 1,000 times for CYP26A in relation to CYP26B. As used herein, a "CYP26B inhibitor" means that it reduces the expression or activity of CYP26B at least 10 times more than any reduction made by the inhibitor on the expression or activity of CYP26A. A selective CYP26B inhibitor can have, for example, a selectivity of at least 10 times for CYP26A relative to CYP26B, a selectivity of at least 20 times, at least 40 times, at least 80 times, at least 100 times, at least 500 times, at least 800 times, or at least 1,000 times for CYP26B in relation to CYP26A. Exemplary small molecule selective CYP26A inhibitors are described herein as Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29; the exemplary small molecule selective CYP26B inhibitors are described herein as Formulas 5, 15 and 30 to 32. A selective CYP26A or selective CYP26B inhibitor may also be, for example, a protein, a peptide, a peptidomimetic, a ribozyme , a nucleic acid molecule or oligonucleotide, an oligosaccharide, or a small molecule or combination thereof. A selective CYP26A inhibitor or a selective CYP26B inhibitor useful in a method of the invention can act by any mechanism, and can, for example, alter the catalytic action of the specified enzyme and consequently reduce, or in some cases, stop the catalysis. A selective CYP26A inhibitor or a selective CYP26B inhibitor may therefore be a competitive, uncompetitive, or concurrent inhibitor of CYP26A or CYP26B, respectively, and may additionally function in a reversible or irreversible manner. It is understood that a selective CYP26A inhibitor or a selective CYP26B inhibitor can also act indirectly, for example by reducing or down-regulating the expression of CYP26A or CYP26B mRNA or protein, respectively. A selective CYP26A or selective CYP26B inhibitor useful in a method of the invention does not bind to a retinoic acid receptor (RAR), or subunit thereof.

B. Structural characteristics As described herein, a variety of structurally unrelated compounds that have a selectivity of at least 10-fold for CYP26A relative to CYP26B may be selective CYP26A inhibitors; and a variety of structurally unrelated compounds that have a selectivity of at least 10-fold for CYP26B relative to CYP26A, may be selective CYP26B inhibitors and therefore may be useful in a method of the invention. A selective CYP26A inhibitor can be, for example, an organic molecule represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29, or a salt, ester, amide, stereoisomer or racemic mixture of the pharmaceutically acceptable A selective CYP26B can be, for example, an organic molecule represented by any of Formulas 5, 15 and 30 to 32, below, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof. As described herein in Table 4, the identified CYP26A inhibitors have selectivities of about 10 times, about 40 times, about 60 times, about 80 times, about 200 times, about 300 times, and about 900 times; the identified CYP26B inhibitors have selectivities of about 10 times, for example about 25 times, about 50 times and about 80 times. It is understood that these and other selective CYP26A inhibitors and selective CYP26B inhibitors may be useful for treating a retinoid responsive disorder according to a method of the invention. The compounds useful in the methods of the invention are shown in two sections below. In the first section, Formulas 18 to 32 are described, which are encompassed by the generic Formulas 1 to 17. In the second section, Formulas 1 to 17 are described.

I. Formulas 18 to 32 Formula 18: where, R3 = H or lower alkyl; Y R1 = R2 = H, Me or Et; X = O or S; Y = CH2N (Me) (cyc-Pr), H, halo, OH, lower alkoxy, lower alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; or R? = Me; R2 = H; X = H (C) CH2N (Me) (cyc-Pr);, Y = H, halo, lower alkoxy, lower alkyl, cycloalkyl or haloalkyl; or R? = Me, R2 = H; X = C = 0, Y = H, lower alkyl, haloalkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl.

Formula 19: where, R3 = H or lower alkyl; and Rx = R2 = H, Me or Et; X = O or S; and Y = CH2N (Me) (cyc-Pr), H, halo, OH, lower alkoxy, lower alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; or R3 = H or lower alkyl; and R? = Me; R2 = H; X = H (C) CH2N (Me) (cyc-Pr); and Y = H, halo, lower alkoxy, lower alkyl, cycloalkyl or haloalkyl; or R3 = H or lower alkyl; and Rx = Me; R2 = H; X = C = 0; and Y = H, lower alkyl, haloalkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl.

Formula 20 where, R? = R2 = Me; X = O or S; and Y = CH2N (Me) (cyc-Pr), OR or COOR, where R = lower alkyl or cycloalkyl; or Rx = Me; 2 = H; X = H (C) CH2N (Me) (cyc-Pr); and Y = OR, COOR where R = lower alkyl, or cycloalkyl; or R? = Me; R2 = H; X = C = 0; and Y = alkenyl.

Formula 21: where, R? = R2 = Me; X = O or S; and Y = lower alkyl, haloalkyl, cycloalkyl, CH2N (Me) (cyc-Pr), OR, COOR, where R = lower alkyl, cycloalkyl; or R? = Me; R2 = H; X = H (C) CH2N (Me) (cyc-Pr); and Y = lower alkyl, haloalkyl, cycloalkyl, OR, COOR, where R = lower alkyl, or cycloalkyl; or R? = Me; R2 = H; ? = C = 0; and Y = alkenyl, lower alkyl, or cycloalkyl.

Formula 22 where, R3 = lower alkyl; Y R1 = R2 = H or Me; or R? = Me; and R2 = H.

Formula 23: where, R3 = lower alkyl; Y R? = H and R2 = H; and Y = alkenyl, or alkynyl; or R? = Me and R2 = H or Me; and Y = lower alkyl, alkenyl, or alkynyl; or R? = H or Me and R2 = Me; and Y = lower alkyl, alkenyl, or alkynyl.

Formula 24 where, R3 = H or lower alkyl; Y R? = H, Me or Et; X = 0 or S; and Y = CH2N (Me) (cyc-Pr), H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl, or alkynyl; or R? = Me; X = H (C) CH2N (Me) (cyc-Pr); and Y = H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl or alkynyl; or Ri = Me; X = c = 0; and Y = H, lower alkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl.

Formula 25 where, R3 = H or lower alkyl; Y Rx = H, Me or Et; X = O or S; and Y = CH2N (Me) (cyc-Pr), H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl or alkynyl; or R? = Me; X = H (C) CH2N (Me) (cyc-Pr); and Y = H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl or alkynyl; or R? = Me; ? = c = O; and Y = H, lower alkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl.

Formula 26 where, Rx = H, Me or Et; X = O or S; and Y = CH2N (Me) (cyc-Pr), OR, or COOR, where R = lower alkyl or cycloalkyl; or R? = Me, X = H (C) CH2N (Me) (cyc-Pr); and Y = alkenyl, OR, COOR, where R = lower alkyl or cycloalkyl; or R? = Me; X = C = 0; and Y = alkenyl.

Formula 27: where, Z = H, Me or Cl; Y R? = H, Me or Et; X = O or S; and Y = lower alkyl, cycloalkyl, CH2N (Me) (cyc-Pr), OR, or COOR, where R lower alkyl or cycloalkyl; or R? = Me, X = H (C) CH2N (Me) (cyc-Pr); and Y = lower alkyl, cycloalkyl, OR, or COOR, where R = lower alkyl, or cycloalkyl; or R? = Me; ? = c = 0; and Y = alkenyl, lower alkyl, or cycloalkyl Formula 28 where, R = lower alkyl; and R? = H; and R2 = Me; or R1 = R2 = Me or H.

Formula 29; where, X = COOR, C (CH3) 2COOR, CH2N (CH3) (cyc-Pr), where R = lower alkyl; Y = H, lower alkyl, haloalkyl, alkenyl or alkynyl; Y Ri = H and R2 = Me; or R1 = R2 = Me or H.

A CYP26A inhibitor having a selectivity of at least 10-fold for CYP26B relative to CYP26A may have a chemical formula shown as any of Formulas 30 to 32 described below. Formula 30: wherein, R = t-Butyl, CH2N (Me) (cyc-Pr), or N (Me) (cyc-Pr); and X = H or Me.

Formula 31 wherein, R = t-Butyl, CH2N (Me) (cyc-Pr), or N (Me) (cyc-Pr); and X = H or Me Formula 32: where, n = 0 or 1; Y Ri = R2 = Me; X = O, S, where R = lower alkyl; and Y = cycloalkyl, alkenyl, alkynyl, lower alkoxy, halo, or haloalkyl; or R? = Me; R2 = -CH2CH2-; X = O or S; and Y = cycloalkyl, alkenyl, alkynyl, lower alkoxy, halo, or haloalkyl; or Ra = Me; R2 = H; X = -CHCH2N (Me) (cyc-Pr); and Y = H, lower alkyl, cycloalkyl, alkenyl, lower alkoxy, halo or haloalkyl; or R? = Me; R2 = H; X = CMe2; and Y = H, lower alkyl, cycloalkyl, alkenyl, alkynyl, lower alkoxy, halo or haloalkyl. II. Formulas 1 to 17 Formula 1 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, C 1 -C 6 alkyl or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with alkyl C? _C6, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I or alkoxy of 1 to 6 carbons; Z is -C = C-, - (CR? = CR?) N ', where n' is an integer having the value 1-5, -CO-NRi-, NRi-CO-; -CO-O-, -0-CO-, -CS-NR-, NRi-CS-, -CO-S-, -S-CO-, -N = N-; or -NRx-CO-NR? -; Ri is independently H or alkyl of 1 to 6 carbons; p is an integer that has the values of 0 to 4; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 2; R4 is independently H, alkyl of 1 to 6 carbons, or F, alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 2; W is -C (R5) 2- or -CR5 = CR5-; R5 is independently H, halogen, or alkyl of 1 to 3 carbons with the proviso that when W is -C (R5) 2- a.1 minus one R5 is alkyl of 1 to 3 carbons, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (alkyl Ca-Ce ), CH2OCO (C? -C6 alkyl) or a pharmaceutically acceptable base cation.

Formula 2 Formula 2 where the dashed line represents a link or the absence of a link; A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups; X is alkyl of 1 to 6 carbons, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl , Br, or I, OR, SR, NRR7, -CO-OR where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, C 1 -C 6 alkyl or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with alkyl C? -C6, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I , COOR8 or alkoxy of 1 to 6 carbons; Z is -C = C-, - (CR? = CR?) N ', where n' is an integer having the value 1-5, -CO-NRi-, NRi-CO-; -CO-O-, -0-CO-, -CS-NRX-, NRi-CS-, -CO-S-, -S-CO-, -N = N-; or -NRx-CO-NR? -; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 2; R4 is independently H, alkyl of 1 to 6 carbons, or alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 4; W is ~ C (R5) 2- or -CR5 = CR5-; R5 is independently H, halogen, or alkyl of 1 to 3 carbons with the proviso that when W is -C (R5) 2- at least one R5 is alkyl of 1 to 3 carbons; R7 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with lower alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C6-C6 alkyl), CH2OCO (alkyl) Ci-Cß) or a cation of a pharmaceutically acceptable base.

Formula 3 Formula 3 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; X is O, S or NR where R is H, alkyl of 1 to 6 carbons, trialkyl (C-C6) silyl or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, alkyl Cx-C6 or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with C? -C6 alkyl, alkenyl of 2 to 6 carbons and having 1? or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, or I; Z is -CE = C-, - (CR? = CR?) N '/ where n' is an integer that has the value 1-5, -CO-NRx-, NRi-CO-; -CO-O-, -O-CO-, -CS-NR-, NRi-CS-, -CO-S-, -S-CO-, -N = N-; or -NRx-CO-NRi-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; W is -C (R5) 2- or -CR5 = CR5-; R5 is independently H, halogen, or alkyl of 1 to 3 carbons with the proviso that when W is -C (R5) 2- at least one R5 is alkyl of 1 to 3 carbons; R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C6 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C alkyl? -C6), CH2OCO (Ca-C6 alkyl) or a pharmaceutically acceptable base cation.

Formula 4 Formula 4 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; X is OR7, SR7 or NRR7 where R is H, alkyl of 1 to 6 carbons or benzyl; Y is H, alkyl of 1 to 10 carbons, benzyl, C 1 -C 6 alkyl, benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with alkyl C6-C6, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I , or -COORi; Z is -G = C-, - (CR? = CR?) N ', where n1 is an integer having the value 1-5, -CO-NRi-, NRi-CO-; -C0-0-, -0-C0-, -CS-NRi-, NRi-CS-, -CO-S-, -S-CO-, -N = N-; or -NRi-CO-NRi-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; W is -C (R5) 2- or -CR5 = CR5-; R5 is independently H, halogen, or alkyl of 1 to 3 carbons with the proviso that when W is -C (RS) 2- at least one R5 is alkyl of 1 to 3 carbons; R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C3 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C alkyl? -Ce), CH2OCO (Ca-C6 alkyl) or a pharmaceutically acceptable base cation.

Formula 5 COORe Formula 5 wherein: A is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Y is H, alkyl of 1 to 10 carbons, benzyl, alkyl C? -C6 or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with C? -C6 alkyl, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, or -COORi; Z is -C = -C-, - (CR = CR?) N ', where n' is an integer having the value 1-5, -CO-NR-, NRx-C0-; -CO-O-, -O-CO-, -CS-NR-, NRi-CS-, -CO-S-, -S-CO-, -N = N-; or -NRi-CO-NRi-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has values from 0 to 3, n is an integer that has the values of 0 or 1, p is an integer that has the values of 0 or 1, W is -C (R5) 2- or - CR5 = CR5-; R5 is independently H, halogen, or alkyl of 1 to 3 carbons with the proviso that when W is -C (R5) 2- at least one R5 is alkyl of 1 to 3 carbons, and R8 independently is H, alkyl of 1 at 6 carbons, -CH20 (C? -C6 alkyl), CH2OCO (C? _6 alkyl) or a pharmaceutically acceptable base cation.

Formula 6 Formula 6 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R groups; X is O, S, NR or CO where R is H or alkyl of 1 to 6 carbons; Y is H, alkyl of 1 to 10 carbons, benzyl, C 1 -C 6 alkyl or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with alkyl C? -C6, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I , OR7, CH2-NRR7 or -COORi; Z is -C = C-, - (CR? = CR?) N ', where n1 is an integer having the value 1-5, -CO-NRx-, NRi-CO-; -CO-O-, -0-CO-, -CS-NR-, NRi-CS-, -CO-S-, -S-CO-, -N = N-; or -NRi-CO-NRi-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 4; W is -C (R5) 2- or -CR5 = CR5-; R5 is independently H, halogen, or alkyl of 1 to 3 carbons with the proviso that when W is -C (R5) 2- at least one R5 is alkyl of 1 to 3 carbons, and R is H, alkyl of 1 to 6 carbons, 3 to 6 carbon cycloalkyl or 1 to 6 carbon cycloalkyl substituted with L-C6 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C? -C3 alkyl), CH2OCO (C? Alkyl? -C6) or a cation of a pharmaceutically acceptable base.

Formula 7 Formula 7 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Y is alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, OR7, CH2-NRR7 or -COORi; Z is -C = C-, -CO-0-, or -NR1-CO-NR1-; R is independently H or alkyl of 1 to 6 carbons; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R 4 is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 4; R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C3 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C alkyl? -C6), CH2OCO (C? -C3 alkyl) or a pharmaceutically acceptable base cation.

Formula 8 Formula 8 where; A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups; Y is alkenyl of 2 to 6 carbons, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons; Z is -C = C-, -CO-O-, or - Ri-CO-NR-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values of 0 to 3, - R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C6 alkyl, and R8 is H , alkyl of 1 to 6 carbons, -CH20 (C?-C6 alkyl), CH 2 OCO (L-CS alkyl) or a pharmaceutically acceptable base cation.

Formula 9 Formula 9 wherein A is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Z is -C = C-, -CO-0-, or -NR1-CO-NR1-; R is H or alkyl of 1 to 6 carbons; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkyltium of 1 to 6 carbons or benzyl; m is an integer having the values of 0 to 3, - R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C6 alkyl, and R8 independently is H, alkyl of 1 to 6 carbons, -CH20 (C? -C6 alkyl), CH2OCO (C? -C3 alkyl) or a pharmaceutically acceptable base cation.

Formula 10 Formula 10 where the broken line represents a link or the absence of a link; A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups; X is NRR7, or C00R8; Y is H, alkenyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, OR7 or -COORi; Z is -C = C-, -CO-O-, or -NRi-CO-NRi-; R is independently H or alkyl of 1 to 6 carbons; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R 4 is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 4; R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C6 alkyl, and R8 independently is H, alkyl of 1 to 6 carbons, -CH20 (Ci alkyl) -Cg), CH2OCO (C? -C6 alkyl) or a pharmaceutically acceptable base cation.

Formula 11 Formula 11 wherein A is a phenyl or naphthyl group, or heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Y is, alkenyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, or alkynyl-alkenyl of 4 to 6 carbons; Z is -C = C-, -C0-0-, or -NRa-CO-NRi-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer having the values of 0 to 4, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C? -C6 alkyl), CH2OCO (C? -C6 alkyl) or a cation of a pharmaceutically base acceptable.

Formula 12 Formula 12 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazole and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Z is -C = C-, -CO-O-, or -NR1-CO-NR1-; R is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values of 0 to 3, and R8 independently is H, is alkyl of 1 to 6 carbons, -CH20 (C? -C6 alkyl), CH2OCO (C? -C6 alkyl) or a cation of a pharmaceutically acceptable base.

Formula 13 Formula 13 wherein A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Z is -C = C-, -C0-0-, or -NRi-CO-NRi-; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values of 0 to 3, and R8 independently is H, alkyl of 1 to 6 carbons, -CH20 (C? -C6 alkyl), CH2OCO (C -C6 alkyl) or a pharmaceutically-based cation of a base acceptable Formula 14 COOR8 Formula 14 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; Y is H, alkyl of 1 to 10 carbons, benzyl, alkyl C? -C6 or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with C? -C6 alkyl, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, OR7, CH2-NRR7 or -COORi; R is independently H or alkyl of 1 to 6 carbons; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen, -o is an integer having the values of 0 to 4; R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C! -C6 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (alkyl) C6), CH2OCO (C? -C6 alkyl) or a pharmaceutically acceptable base cation.

Formula 15 Formula 15 where; is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R 2 groups; X is O or S; Y is H, alkyl of 1 to 10 carbons, benzyl, Ci-Cg alkyl or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with alkyl C -C6, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I, 0R7, CH2-NRR7 or -COORi; Ri is independently H or alkyl of 1 to 6 carbons; p is an integer that has the values of 0 to 4; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R 4 is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 4; R is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C6 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C alkyl? -C6), CH2OCO (C? -C6 alkyl) or a pharmaceutically acceptable base cation.

Formula 16 Formula 16 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two groups R2; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer having the values of 0 to 3, and R8 independently is H, alkyl of 1 to 6 carbons, -CH20 (C? -C6 alkyl), CHOCO (C? -C6 alkyl) or a cation of a base pharmaceutically acceptable.

Formula 17 Formula 17 wherein: A is a phenyl or naphthyl, or heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups; X is O or S; Y is H, alkyl of 1 to 10 carbons, benzyl, C? -6 alkyl or benzyl substituted with halogen, alkyl of 1 to 10 carbons substituted with fluorine, cycloalkyl of 3 to 6 carbons, cycloalkyl of 3 to 6 carbons substituted with alkyl C? -C3, alkenyl of 2 to 6 carbons and having 1 or 2 double bonds, alkynyl of 2 to 6 carbons, alkenyl-alkynyl of 4 to 6 carbons, alkynyl-alkenyl of 4 to 6 carbons, Cl, Br, I , OR7, CH2-NRR7 or -COOR ?; Ri is independently H or alkyl of 1 to 6 carbons; R 2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF 3, alkyl substituted with fluorine of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons; R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, alkyl substituted with fluorine of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl; m is an integer that has the values of 0 to 3; R 4 is independently H, alkyl of 1 to 6 carbons, or F; alkyl substituted with fluorine of 1 to 6 carbons, or halogen; or is an integer that has the values of 0 to 4; R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl of 1 to 6 carbons substituted with C? -C6 alkyl, and R8 is H, alkyl of 1 to 6 carbons, -CH20 (C alkyl? -C6), CH2OCO (C? -C6 alkyl) or a pharmaceutically acceptable base cation.

The term alkyl refers to and covers each and every one of the groups that are known as normal alkyl and branched chain alkyl. Unless otherwise specified, lower alkyl means the defined broad definition before alkyl groups having from 1 to 6 carbons in the case of normal lower alkyl, and from 3 to 6 carbons for the lower branched chain alkyl groups. A pharmaceutically acceptable salt can be prepared for any compound used according to the invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not confer any adverse or adverse effect on the subject to which it is administered and in the context in which it is administered.

The pharmaceutically acceptable salts can be derived from organic or inorganic bases. The salt can be a mono or polyvalent ion. Inorganic ions are sodium, potassium, calcium, and magnesium. Organic salts can be made with amines, namely ammonium salts such as mono-, di- and trialkylamines or ethanolamines. The salts can be formed with caffeine, tromethamine and similar molecules. When there is a sufficiently alkaline nitrogen to be capable of forming acid addition salts, these can be formed with any inorganic or organic acid or alkylating agent such as methyl iodide. Preferred salts are those formed with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Likewise, any number of simple organic acids such as mono-, di- or triacids can be used.

Some compounds used according to the present invention may have trans and cis (E and Z) isomers. Unless the specific orientation of the substituents in relation to a double bond or a ring is indicated in the name of the respective compound, and / or specifically showing in the structural formula the orientation of the substituents in relation to the double bond or ring the invention encompasses the trans isomers as well as cis.

Some of the compounds used according to the present invention may contain one or more chiral centers and therefore may exist in enatiomeric and diastereomeric forms. It is intended that the scope of the present invention encompass all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and also racemic mixtures of enantiomers (optical isomers).

The novel compounds used according to the invention are encompassed by the general formulas 1 to 17 given above. In each of these formulas a linker or a linking group designated Z covalently connects an aromatic or heteroaromatic radical designated A (R2) -W-COOR8, A (R2) -CH2-COOR8 or A (R2) -COOR8 and another radical cyclic which according to these formulas is a substituted phenyl radical, substituted tetrahydronaphthalene, substituted dihydronaphthalene, substituted chroman, substituted thiochroman or substituted tetrahydroquinoline. In general terms compounds such as XA (R2) -W-COOR8, X4-A (R2) -CH2-COOR8 and X4-A (R2) -COOR8 are commercially available, or can be made according to the chemical literature, or a modification of known chemical procedures, or chemical procedures described herein that are within the practical knowledge of the organic chemist. The group X4 represents a reactive group, which is suitable for coupling the compounds XA (R2) -W-COOR8, XA (R2) -CH2-COOR8 and X4-A (R2) -COOR8 to a derivative of the substituted phenylene radical, tetrahydronaphthalene substituted, substituted dihydronaphthalene, substituted chroman, substituted thiochroman, or substituted tetrahydroquinoline so that as a result of the coupling the linker or the linking radical is formed. In many cases the X4 group is a removable group such as halogen, or trifluoromethanesulfonyloxy, or a group capable of participating in a Wittig or Horner Emmons reaction. In some cases the group X is an ethynyl group capable of undergoing a coupling reaction with a leaving group (such as a halogen or a trifluoromethanesulfonyloxy group) attached to the substituted phenyl radical, substituted tetrahydronaphthalene, substituted dehydronaphthalene, substituted chroman, substituted thiochroman, or substituted tetrahydroquinoline. The group X may also represent an OH or NH2 group that forms an ester linker (COO) or amide (CONH), respectively, when reactions with an activated carboxyl derivative of the substituted phenyl radical, substituted tetrahydronaphthalene, substituted dihydronaphthalene, substituted chroman, substituted thiochroman , or substituted tetrahydroquinoline. Compounds of formulas X4-A (R2) -W-COOR8, X4-A (R2) -CH2-COOR8 and X4-A (R2) -COOR8 are generally referred to herein as "coupling reagents" or only "reactants" "and the preparation of various examples of these coupling reagents is described below in the specific examples. Additional examples are pyridyl, thienyl furyl, pyridazine, pyrazine and other heteroaryl analogs of the coupling reagents described in the specific examples. These reagents can be obtained according to the chemical literature, or modifications of known chemical methods, or of chemical methods described herein that are within the practical knowledge of the practicing organic chemist.

Still further, according to the general synthetic methodology for providing the compounds of Formulas 1 to 17, a substituted phenyl radical, substituted tetrahydronaphthalene, substituted dihydronaphthalene, substituted chroman, substituted thiochroman, or substituted tetrahydroquinoline having a covalently anchored group X5 is first synthesized.

The group X5 reacts with the group X4 of the reagents X4-A (R2) -W-COOR8, X4-A (R2) -CH2-COOR8 and X4-A (R2) -COOR8 to form the linker designated Z in the formulas The group X5 is that which is capable of participating in a coupling reaction, (such as an ethynyl group when X4 is a deletable group), or a deletable group (such as halogen or trifluoromethanesulfonyloxy when X4 is an ethynyl group) ), or an activated carboxylic acid functionality (when X4 is OH or NH2). The group X5 can also be an OH, SH or NH2 group when the group X4 is an activated carboxylic acid functionality. Specific examples of the intermediates substituted phenyl, substituted tetrahydronaphthalene, substituted dihydronaphthalene, substituted chroman, substituted thiochroman, or substituted tetrahydroquinoline having an X5 functionality are provided below, and are also available in the scientific and patent chemical literature. In general terms, for reactants and reactions that covalently link a substituted tetrahydronaphthalene intermediate, substituted dihydronaphthalene, substituted chroman, substituted thiochroman, or substituted tetrahydroquinoline with an aryl or substituted heteroaryl group, of Formulas A (R2) -W-COOR8, A (R2) -CH2-COOR8 and A (R2) COOR8 to form a compound including the linker designated Z, reference is made to U.S. Patent Nos. 5,648,503; 5,723,666, 5,952,345, 6,252,090 and 6,313,107 each of which memoir is hereby expressly incorporated by reference.

The substituted phenyl radical, substituted tetrahydronaphthalene, substituted dihydronaphthalene, substituted chroman, substituted thiochroman, or substituted tetrahydroquinoline of the novel compounds used according to the invention are transformed so as to include specific substituents (such as for example cycloalkyl substituents) encompassed in the scope of the invention, either before or after the radical A (R2) -W-COOR8, A (R2) -CH2-COOR8 or A (R2) -COOR8 has been anchored and the Z linker has formed, as it is illustrated by the specific examples described below. The radical W-COOR8, CH2-COOR8 or COOR8 of the compounds of Formulas 1 to 17 can be modified in order to obtain even more novel compounds. One such modification is the saponification of the compounds in which R8 is an alkyl group, CH20 (C? -C6 alkyl) or CH2OCO (L-C6 alkyl). Another modification is the esterification of the carboxylic acid functionality when the R8 group is H or a cation. Such saponification and esterification reactions are well known in the art and within the practical knowledge of the practicing organic chemist.

With reference to the symbol A in Formulas 1 to 17, the preferred novel compounds used according to the present invention are those in which A is phenyl, naphthyl, pyridyl, thienyl or furyl. Even more preferred compounds are those compounds wherein A is phenyl. As regards the substitutions of groups A (phenyl) and A (pyridyl), compounds in which the phenyl group is substituted in the 1,4-position (para) and in which the pyridine ring is substituted in the 2,5-position are usually preferred. (The substitution in positions 2,5 in the nomenclature of "pyridine" correspond to the substitution in position 6 in the nomenclature of "nicotinic acid"). In the currently preferred novel compounds used according to the invention there is no substituent R2 in group A, or alternatively the substituent R2 is preferably a fluoro group which is preferably located in the aromatic carbon adjacent (ortho) to the carbon carrying the group W -COOR8, CH2-COOR8 or COOR8.

As regards the radical W-COOR8, the variable W preferably represents -CH = CH-, -CR5 = CH-, CH = CR5- (cinnamic acid derivatives) C (R5) 2 or CHR5 where R5 is preferably methyl . For the group R8, the groups H, lower alkyl of 1 to 3 carbons, -CH20 (alkyl) are preferred.

C? -C3) and -CH2OCO (CX-C3 alkyl), as well as the pharmaceutically acceptable salts of the free acids when R8 is H. Among the lower alkyl groups, -CH20 (CX-C3 alkyl) and -CH2OCO (C-alkyl) ? -C3), methyl, ethyl, CH2OCH3 and CH2OCOCH3 respectively are very preferred at present.

The linker group Z in all the novel compounds used according to the invention is preferably ethinyl, (-CC-), ester (CO-O), or ureido (NHCONH). On the other hand for the chroman, thiochroman and tetrahydroquinoline derivatives the linker Z is preferably anchored to position 6 (e.g., see Formula 1). For the tetrahydronaphthalene and dihydronaphthalene derivatives the linker Z is preferably anchored to the 6-position as such positions are numbered in Formulas 2 and 11.

The group Ri is preferably methyl when it serves as a substituent attached to a carbon of the nucleus of chroman, thiochroman, tetrahydroquinoline, tetrahydronaphthalene or dihydronaphthalene and is preferably hydrogen when it forms part of the linker Z.

The aromatic portion of the chroman, thiochroman, tetrahydroquinoline, tetrahydronaphthalene or dihydronaphthalene nuclei of the compounds of the present invention is preferably either not substituted with a group R3 (the variable m is zero (0)), or R3 is alkyl or halogen The non-aromatic portion of the chroman, thiochroman, tetrahydroquinoline, tetrahydronaphthalene or dihydronaphthalene nuclei of the compounds of the present invention is preferably either unsubstituted with a group R4 (the variable is zero (0)), or (R4) or represents methyl groups, even more preferably gemomethyl dimethyl or gemyl diethyl groups attached to the 2-position of the chroman core.

The structures of the most preferred compounds of the invention are shown in Table 1. While most of the compounds shown in Table 1 are carboxylic acids, it should be understood that the Cx-C3 alkyl esters, the esters are also preferred. CH2OCH3 and CH2OCOCH3 and the pharmaceutically acceptable salts of these compounds.

Table 1 NA1 = Not Active; DA2 = Weakly Active The compounds of the invention can be synthesized by applying the general synthetic methodology described above, and by similar modifications of the specific synthetic routes described below that will be readily apparent to chemists practicing synthetic organic chemistry in light of the description and in view of general knowledge available in the art. The specific reaction schemes described below are directed to the synthesis of exemplary and preferred compounds of the invention. While each of the specific and exemplary synthetic routes shown in these schemes can describe the specific compounds of the invention only within the scope of one or two of the general Formulas 1 to 17, the synthetic procedures and methods used herein are adaptable to the knowledge. practical of the practicing organic chemist and can be used with such an adaptation for the synthesis of the compounds of the invention that are not specifically described here as examples.

Analysis to confirm the activity The ability of a compound to selectively inhibit CYP26A or CYP26B can be determined using any of a variety of assays. Such assays can be performed, for example, in a cell or tissue expressing endogenous or recombinant CYP26A or CYP26B, and generally involve the determination of the enzymatic activity of CYP26A or CYP26B or a downstream effect of the CYP26A or CYP26B enzyme activity before and after the application of a test compound. A downstream effect of the enzymatic activity of CYP26A or CYP26B may be, without limitation, a change in the level of a retinoid in a cell. Methods for measuring the activity of CYP26A or CYP26B are well known to those skilled in the art, and are described, for example, in U.S. Patent No. 6,495,552; WO 01/44443; White et al., Proc. Nati Acad. Sci. USA 97: 6403-6408 (2000); White et al., J. Biol. Chem. 272: 18538-18541 (1997), and in Examples I and II. One type of analysis useful for evaluating the activity of CYP26A or CYP26B involves determining the catabolism of retinoic acid to more polar derivatives including 4-hydroxyiretinic acid and 4-oxoretinoic acid (White et al., Supra 1997). A variety of cell types, including natural and genetically engineered cells, can be used in an in vitro assay to detect the activity of CYP26A or CYP26B or a downstream effect of the enzymatic activity of CYP26A or CYP26B. Natural cells expressing endogenous CYP26A or CYP26B include, for example, cells obtained from an organ that expresses CYP26A or CYP26B, as described above. Cell lines expressing CYP26A include, but are not limited to, HEK293, LC-T, SK-LC6, MCF, NB4, and U937 (White et al., Supra 1997). Cell lines expressing CYP26B include, but are not limited to, HPKla-ras, HeLa and MCF-7 (White et al., Supra 2000). Other natural cells and cell lines that express CYP26A or CYP26B can be identified by those skilled in the art using the methods described herein and other methods well known in the art. Cells for use in the assay of a compound for its ability to selectively inhibit CYP26A or CYP26B can be obtained from a mammal, such as a mouse, rat, pig, goat, primate or human, or a non-mammal. Cells that express CYP26A or CYP26B can be prepared using a variety of methods. Recombinant expression may be advantageous by providing a level of CYP26A or CYP26B expression superior to that found endogenously, and also allows expression in cells or extracts in which expression is not normally found. A recombinant nucleic acid expression construct generally contains a constitutive or inducible promoter of RNA transcription appropriate for the host cell or the transcription-translation system, operably linked to a nucleotide sequence encoding a polypeptide corresponding to CYP26A or CYP26B or an active fragment of it. The expression construct can be a DNA or an RNA, and optionally it can be contained in a vector, such as a plasmid or viral vector. The nucleotide and amino acid sequences of human CYP26A are available to one skilled in the art, for example, with GenBank Accession Number NM_000783 and NM_057157; the nucleotide and amino acid sequences of human CYP26B are available to one skilled in the art, for example, with Genbank Accession Number NM_019885. Other nucleotide and polypeptide sequences of CYP26A and CYP26B are available from GenBank, as are the otoplog sequences of CYP26A and CYP26B from rat, mouse and other species. Any of these nucleotide sequences of CYP26A or CYP26B can be used to recombinantly express CYP26A or CYP26B in an assay to confirm the activity of a selective CYP26A inhibitor or of selective CYP26B. One skilled in the art can recombinantly express desired levels of CYP26A or CYP26B using routine laboratory methods, described, for example, in the molecular biology technical manuals, such as Sambrook et al., Supra (1992) and Ausubel et al., supra (1998). Exemplary host cells that can be used to express recombinant CYP26A and / or CYP26B include isolated mammalian primary cells; established mammalian cell lines, such as COS, CHO, HeLa, NIH3T3, HEK 293-T and PC12; amphibian cells, such as Xenopus embryos and oocytes; and other vertebrate cells. Exemplary host cells also include insect cells such as Drosophila cells, yeast cells such as S. cerevisiae, S. pombe, or Pichia pastoris and prokaryotic cells such as E. coli.

An exemplary cell-based analysis to confirm the ability of a compound to selectively inhibit CYP26A or CYP26B is described in U.S. Patent No. 6,495,552. In summary, CYP26A or CYP26B can be stably transfected in HeLa cells. The cells that grow exponentially are harvested by incubation in trypsin. The cells are then washed and plated in a 48-well plate at 5 x 105 cells in 0.2 ml of MEM medium containing 10% FBS and 0.05 μCi RA- [H3] in the presence or absence of increasing concentrations of the test compounds. The compounds are diluted in 100% DMSO and then added to wells in triplicate to a final concentration of 10, 1 or 0.1 μM. As a positive control for the inhibition of RA metabolism, the cells are also incubated with ketoconazole at 100, 10 and 1 μM. The cells are incubated for 3 hours at 37 ° C. The retinoids are then extracted using the procedure of Bligh et al., Canadian Journal of Biochemistry 37: 911-917 (1959), modified using methylene chloride instead of chloroform. This publication by Bligh et al., Is specifically incorporated herein by reference. The water-soluble radioactivity is quantified using a scintillation counter, and the IC50 values are determined. An exemplary animal model analysis to confirm the ability of a compound to selectively inhibit CYP26A or CYP26B is also described in U.S. Patent No. 6,531,599. Topical application of a selective CYP26A inhibitor or a selective CYP26B inhibitor may result in an increase in endogenous levels of retinoic acid resulting in an irritation induced by retinoic acid in the skin of mice lacking hair. Thus, a hairless mouse model is an exemplary animal model that can be used to confirm that a selective CYP26A inhibitor or a selective CYP26B inhibitor has in vivo activity.

Confirmation of the efficacy of a selective CYP26A inhibitor or inhibitor of CYP26B The efficacy of a selective CYP26A inhibitor or CYP26B inhibitor, such as a compound represented by any of Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29, or a salt, ester, amide, stereoisomer or racemic mixture thereof, in the treatment of a retinoid sensitive disorder in an individual can be confirmed using any of a variety of well-known methods. For example, well-known animal models may be useful to confirm the efficacy of a selective CYP26A inhibitor or of a selective CYP26B inhibitor in the treatment of a retinoid responsive disorder such as a skin disorder, an inflammatory disorder, a autoimmune disorder, a neurological disorder, a proliferative disorder, an eye disorder or a pulmonary disorder. Animal models predictive of such disorders can be used to confirm the efficacy of treatment by measuring the experimental endpoints or appropriate clinical or physiological indicators, which will depend on the particular animal model selected. Those skilled in the art will know which animal models can be used to determine the efficacy or effective amount of a selective CYP26A inhibitor or a selective CYP26B inhibitor useful in the methods of the invention. An exemplary animal model to confirm the efficacy of a selective CYP26A inhibitor or a selective CYP26B inhibitor in the treatment of acne is described in Example 1. A variety of well-known animal models for acne can be used to confirm the efficacy of a selective CYP26A inhibitor or a selective CYP26B inhibitor. A variety of exemplary animal models of inflammatory or autoimmune disorders responsive to retinoids are well known to those skilled in the art. Some of these models are described, for example, in Progress in Inflamation Research, (.J. Parnham, Ed.) Birkh user Verlag, Basel, Switzerland (1998). Those skilled in the art will be able to select an appropriate animal model depending, in part, on the particular disorder to be treated using the method of the invention. An exemplary animal model to confirm the efficacy of a selective CYP26A inhibitor or a selective CYP26B inhibitor in the treatment of retinoid sensitive proliferative disorders generally involves the inoculation or implantation in a laboratory animal of heterologous tumor cells followed by the simultaneous or subsequent administration of a therapeutic treatment. The effectiveness of the treatment can be determined, for example, by measuring the degree of cell or tumor growth or tumor metastasis. The measurement of clinical or physiological indicators can be evaluated alternatively or additionally as an indicator of the effectiveness of the treatment. Exemplary animal tumor models are described, for example, in Brugge et al., Origins of Human Cancer. Cold Spring Harbor Laboratory Press, Plain View, New York, (1991). Among the animal models to confirm the efficacy of a selective CYP26A inhibitor or a selective CYP26B inhibitor in the treatment of a retinoid responsive neurological disorder include, for example, animal models of trauma due to stroke or neural injury that are known in the art. The technique. An experimental model of stroke involves occluding the right middle cerebral artery and both common rat carotid arteries for a short period, followed by reperfusion (Moore et al., J. Neurochem. 80: 111-118 (2002)). An experimental model of CNS injury is the fluid percussion injury (FPI) model, in which a moderate impact (1.5-2.0 atm.) Is applied to the cerebral parietal cortex (Akasu et al., Neurosci. Lett 329: 305-308 (2002)). Experimental models of spinal cord injury are also used in the art (Scheifer et al., Neurosci, Lett 323: 117-120 (2002)). Suitable models of neural injury due to oxidative stress, hypoxia, radiation and toxins are also known in the art and are useful for confirming the efficacy of selective CYP26A inhibitor or a selective CYP26B inhibitor. A variety of animal models of eye disorders are also known to those skilled in the art. An exemplary animal model of retinal degeneration is described, for example, Lewis et al., Eye 16: 375-387 (2002). In a similar manner, a variety of animal models of lung disorders are known to those skilled in the art. An exemplary animal model of emphysema is described, for example, in Chen et al., J. Invest Surg 11: 129-137 (1998).

Tracing other selective CYP26A and CYP26B inhibitors The selective CYP26A inhibitor or the selective CYP26B inhibitor used in the method of the invention may also be a small molecule of natural or unnatural origin, or a macromolecule of natural or non-natural origin such as a peptide, a peptidomimetic, an acid nucleic acid, a carbohydrate or a lipid. A selective CYP26A inhibitor or a selective CYP26A inhibitor may additionally be an antibody, or an antigen-binding fragment thereof such as a monoclonal antibody, a humanized antibody, a chimeric antibody, a minibodi, a bifunctional antibody, an antibody of single chain (scFv), a fragment of the variable region (Fv or Fd), Fab or F (ab) 2. A selective CYP26A or CYP26B inhibitor can also be a partially or fully synthetic derivative, an analog or mimetic of a macromolecule of natural origin, or a small organic or inorganic molecule. A variety of methods can be used to confirm that a selective CYP26 inhibitor has a 10-fold selectivity for CYP26B relative to CYP26A. Analyzes to determine the activity of CYP26A and CYP26B are described herein and are well known to those skilled in the art. Therefore, by screening for known or newly synthesized compounds for their ability to selectively inhibit CYP26B activity, a selective inhibitor of CYP26B can be identified and used to treat a retinoid responsive disorder according to a method of the invention.

Therapeutic administration The methods of the invention involve administering a selective CYP26A inhibitor or a selective CYP26B inhibitor to an individual to treat a retinoid sensitive disorder. As used herein the term "treatment" represents the reduction, delay or prevention of the onset of one or more clinical symptoms, physiological indicators or biochemical markers of a retinoid sensitive disorder, or reduction of the need for concurrent therapy. . Clinical symptoms include perceptible, external or visible signs of the disease. Physiological indicators include the detection of the presence or absence of physical and chemical factors associated with a body process or function. Biochemical markers include those signs of disease that are observable at the molecular level, such as the presence of a marker of the disease, such as a tumor marker. A person skilled in the art will be able to recognize specific clinical symptoms, physiological indicators and biochemical markers associated with a particular retinoid responsive disorder. The term "treatment" encompasses any significant reduction in the symptoms of a retinoid sensitive disorder such as a reduction of at least 30%, 40%, 60%, 70%, 80%, 90% or 100%. The skilled clinician will be able to determine the clinical symptoms, physiological indicators or other appropriate biochemical markers associated with a particular retinoid responsive disorder, such as a skin disorder, a neurological disorder, an autoimmune disorder, an inflammatory disorder, a disorder ocular or a pulmonary disorder. The skilled clinician will know how to determine whether an individual is a candidate for treatment with a selective CYP26A inhibitor or a selective CYP26B inhibitor, based in part on the type and severity of the disorder, the degree of sensitivity of the disorder to retinoid therapy, the affected tissue, and the medical history and the individual's condition. The appropriate effective amount to be administered for a particular application of the methods can be determined by those skilled in the art, using the guidelines provided herein. For example, an effective amount can be extrapolated from in vitro and in vivo assays as described hereinbefore. One skilled in the art will recognize that the clinical symptoms, physiological indicators and biochemical markers of a disorder in an individual can be controlled throughout the course of therapy and that the effective amount of a selective CYP26A inhibitor or an inhibitor of Selective CYP26B that is administered can be adjusted accordingly. The invention may also be practiced by administering an effective amount of a selective CYP26A inhibitor or a selective CYP26B inhibitor with one or more other agents including, but not limited to, one or more retinoids. In such "combined" therapy, it is understood that a selective CYP26A inhibitor or a selective CYP26B inhibitor can be released independently or simultaneously, in the same or different pharmaceutical compositions, and by the same or different routes of administration as the other or other agents more. A selective CYP26A inhibitor or a selective CYP26B inhibitor can beneficially decrease the destruction of therapeutically administered retinoids and thereby allow a reduced amount of retinoids or a reduced frequency of retinoid administration to be administered.; and may increase the efficacy of a retinoid or prevent the development of retinoid resistance in individuals treated with a retinoid. Exemplary retinoids that may be useful in the combination therapy include, without limitation, tretinoin (all-trans-retinoic acid, vitamin A acid), alitretinoin (9-cis-retinoic acid), bexarotene (Tagretin), isotretinoin ( 13-cis-retinoic acid), and tazarotene.

Modifications and pharmaceutical formulations Selective CYP26A inhibitors have a selectivity for CYP26A of at least 10-fold relative to CYP26B are described herein in Formulas 1 to 4, 6 to 14, 16, 17 and 18 to 29. The exemplary selective CYP26B inhibitors which have the less a 10-fold selectivity for CYP26B relative to CYP26A are described herein in Formulas 5, 15 and 30 to 32. Also included in the present invention are methods employing pharmaceutically acceptable salts, esters and amides derived from formulas 18 to 32 acceptable Suitable pharmaceutically acceptable salts of the selective CYP26A inhibitors and of the selective CYP26B inhibitors useful in the invention include, without limitation, acid addition salts, which can be formed, for example, by mixing a solution of the inhibitor with a solution of an appropriate acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid and phosphoric acid. When an inhibitor carries an acid radical, suitable pharmaceutically acceptable salts thereof may include alkaline salts such as sodium or potassium salts; alkaline earth salts such as calcium or magnesium salts; salts formed with suitable organic ligands, for example, quaternary ammonium salts. Representative pharmaceutically acceptable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulonate, citrate, dihydrochloride, edetate, edisilate. , stellate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methylisulfate, mucate , napsylate, nitrate, ammonium salt of N-methylglucamine, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethyodide and valerate It is understood that the functional groups of the selective CYP26A inhibitors and the selective CYP26B inhibitors useful in the invention can be modified to enhance the pharmacological utility of the compounds. Such modifications are within the knowledge of the skilled chemist and include, without limitation, esters, amides, ethers, N-oxides, and pro-drugs of the indicated inhibitor. Examples of modifications that can enhance the activity of an inhibitor include, for example, esterification such as the formation of Cx to C6 alkyl esters, preferably Cx to C4 alkyl esters, where the alkyl group is a straight or branched chain . Other acceptable esters include, for example, C5 to C7 cycloalkyl esters and arylalkyl esters such as benzylic esters. Such esters can be prepared from selective CYP26A or CYP26B inhibitors described herein using conventional methods well known in the art of organic chemistry. Other pharmaceutically acceptable modifications include the formation of amides. Modifications of useful amides include, for example, those derived from ammonia; Cx to C6 primary dialkylamines, where the alkyl groups are straight or branched chain; and arylamines having various substitutions. In the case of the secondary amines, the amine may also be in the form of a 5- or 6-membered ring. Methods for preparing these and other amides are well known in the art. It is understood that, when an inhibitor useful in the invention is a compound having at least one chiral center, the compound can exist in the form of chemically distinct enantiomers. further, when a compound has two or more chiral moieties, the compound exists in the form of diastereoisomers. All these isomers and mixtures thereof are encompassed within the scope of the indicated inhibitor. Similarly, when an inhibitor has a structural arrangement that allows the structure to exist in the form of tautomers, these tautomers are encompassed within the scope of the indicated inhibitor. In addition, in crystalline form, an inhibitor can exist in the form of polymorphs; in the presence of a solvent, an inhibitor can form a solvate, for example, with water or a common organic solvent. Such polymorphs, hydrates and other solvates are also encompassed within the scope of the indicated inhibitors as defined herein. A selective CYP26A inhibitor or a selective CYP26B inhibitor useful in the invention is generally administered in a pharmaceutical composition. Such pharmaceutical compositions include the active inhibitor and additionally may include, if desired, an excipient such as a pharmaceutically acceptable carrier or diluent, which is any carrier or diluent that does not substantially have a long-term or permanent deleterious effect when is administered to an individual. Such an excipient is usually mixed with an active compound, or allowed to dilute or englobe the active compound. A carrier can be a solid, semi-solid, or liquid agent that acts as an excipient or vehicle for the active compound. Examples of the pharmaceutically acceptable carriers and diluents include, without limitation, water, such as distilled or deionized water; Saline solution; and other aqueous media. It is understood that the active ingredients may be soluble or may be released as a suspension in the desired carrier or diluent. A pharmaceutical composition may additionally, if desired, include one or more agents such as emulsifying agents, wetting agents, sweetening or flavoring agents, tonicity adjusters, preservatives, buffers or anti-oxidants. Useful tonicity adjusters useful in a pharmaceutical composition may include salts such as sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjusters. Preservatives useful in the pharmaceutical compositions of the invention include, without limitation, benzalkonium chloride, chlorobutanol, trimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Various buffers and means for adjusting the pH can be used to prepare a pharmaceutical composition, including, but not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. In a similar manner, antioxidants useful in the pharmaceutical compositions of the invention are well known in the art and include, for example, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. It is understood that these and other substances known in the pharmacology art can be included in a pharmaceutical composition useful in the invention. A selective CYP26A inhibitor or an inhibitor of Selective CYP26B useful in a method of the invention is administered to an individual in an effective amount.

Such an effective amount is generally the minimum dose necessary to achieve the desired therapeutic effect, which may be, for example, the amount broadly necessary to reduce a symptom of a retinoid responsive disorder to a more comfortable, tolerable, acceptable level, or improved. For example, the term "effective amount" when used with respect to the treatment of a retinoid sensitive disorder may be a sufficient dose to reduce a symptom, for example, at least 30%, 40%, 50%, 60 %, 70%, 80%, 90% or 100%. Such a dose is generally in the range of 0.1-1000 mg / day and may be, for example, in the range of 0.1-500 mg / day, 0.5-500 mg / day, 0.5-100. mg / day, 0.5-50 mg / day, 0.5-20 mg / day, 0.5-10 mg / day or 0.5-5 mg / day, determining the actual amount that will be administered physical that takes into consideration the relevant circumstances including the severity of the disorder, the age and weight of the individual, the general physical condition of the individual, and the route of administration. When repeated administration is used, the frequency of administration depends, in part, on the half-life of the inhibitor. Suppositories and sustained-release formulations may be useful in the invention and include, for example, skin patches, depot formulations on or under the skin and formulations for intramuscular injection. It is understood that slow release formulations may also be useful in the methods of the invention. The individual receiving a selective CYP26A inhibitor or a selective CYP26B inhibitor can be any mammal or other vertebrate susceptible to experiencing a retinoid sensitive disorder, eg, a human, primate, horse, cow, pig, dog, cat, hamster, or bird.

Administration of a selective CYP26A inhibitor or a selective CYP26B inhibitor Various routes of administration may be useful for treating a retinoid sensitive disorder according to the method of the invention depending, for example, on the organ or tissue to be treated, the selective inhibitor or other compound to be included in the composition. , and of the history, the risk factors and the symptoms of the subject. Suitable administration routes for the methods of the invention include both systemic and local administration. As non-limiting examples, a pharmaceutical composition useful for treating a retinoid sensitive disorder can be administered orally or by a subcutaneous pump or other implanted device; using transdermal patches; by intravenous, subcutaneous or intramuscular injection; by means of topical drops, creams, gels or ointments; through suppositories; in the form of a prolonged release formulation implanted or injected; by mini-pump or intrathecal injection; or by epidural injection. It is understood that the frequency and duration of the dosage will depend, in part, on the desired relief and the half-life of the selective CYP26A inhibitor or the selective CYP26B inhibitor. In particular embodiments, the method of the invention is practiced by peripheral administration of a selective CYP26A inhibitor or the selective CYP26B inhibitor. As used herein, the term "peripheral administration" represents methods of administration in which an agent is introduced into a subject outside the central nervous system. Peripheral administration encompasses any route of administration other than direct administration to the marrow or the brain. As such, it is clear that intrathecal and epidural administration as well as injection or cranial implant are not within the scope of the term "peripheral administration" or "peripherally administered". Peripheral administration can be local or systemic. The Local administration causes significantly more pharmaceutical composition to be released at the site of local administration than at regions remote from the site of administration. Systemic administration results in the release of a pharmaceutical composition essentially to the entire peripheral nervous system of the subject and may also make the release to the central nervous system dependent on the properties of the composition. Peripheral administration routes useful in the methods of the invention encompass, without limitation, oral administration, topical administration, intraocular administration, intravenous or other injection, and implanted minipumps or other prolonged release devices or formulations. A pharmaceutical composition useful in the invention may be administered peripherally, for example, orally in any acceptable form such as a tablet, liquid, capsule, powder, or , Similary; by intravenous, intraperitoneal, intramuscular, subcutaneous or parenteral injection; by transdermal diffusion or electrophoresis; topically in any acceptable form such as drops, creams, gels or ointments; by inhalation; and by means of minipumps or other devices or prolonged release formulations implanted. Topical ophthalmic administration may be useful in the methods of the invention for treating an ocular disorder responsive to retinoids. Such administration can be achieved using, without limitation, eye drops, eye ointments, ocular gels and ocular creams. Such ophthalmic preparations are easy to apply and release the active ingredient effectively and avoid possible systemic side effects. Topical administration includes administration to the skin or mucosa, including the surfaces of the lung. Compositions for topical administration, including those for inhalations, can be prepared in the form of dry powder which can be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredients in finely divided form can be used in admixture with a larger pharmaceutically acceptable inert carrier comprising particles having a size, for example, up to 100 μm in diameter. Suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 μm.

Synthetic Methods SPECIFIC EXAMPLES The reaction schemes provided below together with the applicable experimental descriptions describe the synthetic routes currently preferred for preparing the preferred compounds of the invention.

Synthetic Procedures for Preparing Coupling Reagents Reagent 1 Reagent 2 General Procedure A: Methyl 2- (4-iodophenyl) propionate (Reagent 1) A stirred, cooled (-78 ° C) solution of methyl 4-iodophenyl acetate (described in US 6,252,090, incorporated herein by reference, 2.77 g, 10 mmol) in anhydrous tetrahydrofuran (20 ml) was treated with a solution 1.5 M lithium diisopropylamide in tetrahydrofuran and cyclohexane (8 ml, 12 mmol). The reaction mixture was allowed to warm to 0 ° C over 40 minutes, cooled again to -78 ° C and treated with methyl iodide (0.75 ml, 12 mmol). The reaction mixture was allowed to warm to room temperature over Ih. It was then quenched with a saturated aqueous solution of ammonium chloride, diluted with water and extracted with diethyl ether. The combined organic phase was washed with brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow oil (2.7 g, 92.7 g. %). H1 NMR (300 MHz, CDC13): d 7.66 (d, 2H, J = 8.5 Hz), 7.06 (d, 2H, J = 8.5 Hz), 3.70-3.66 (m, 1H), 3.67 (s, 3H), 1.49 (d, 3H, J = 7.0Hz).

Methyl-2- (4-iodophenyl) -2-methyl propionate (Reagent 2) Following General Procedure A and using methyl 2- (4-iodophenyl) propionate (1.45 g, 5 mmol), lithium diisopropylamide ( 1.5 M in tetrahydrofuran and cyclohexane, 4 mL, 6 mmol), tetrahydrofuran (15 mL) and methyl iodide (0.5 mL, 8 mmol), the title compound was obtained as an oil (1.5 g, 98%). NMR H1 (300 MHz, CDCl3): d 7.66 (d, 2H, J = 8.7Hz), 7.11 (d, 2H, J = 8.7Hz), 3.66 (s, 3H), 1 , 58 (s, 6H). 4-Iodo-benzyl alcohol A stirred, cooled solution (-78 ° C) of ethyl 4-iodobenzoate (available from Lancaster, 12.9 g, 45 mmol) in anhydrous dichloromethane (100 ml) under argon was treated with a 1 M solution of diisobutylaluminum hydride. in dichloromethane (100 ml, 100 mmol). The reaction mixture was allowed to warm to 0 ° C for 1.5 h, quenched with a saturated aqueous solution of ammonium chloride and the resulting emulsion was filtered on a pad of celite. The phases in the filtrate were separated and the aqueous phase was extracted with dichloromethane (xl). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title product as a white solid (9 g, 85%). NMR H1 (300 MHz, CDCl3): d 7.65 (d, 2H, J = 7.6 Hz), 7.05 (d, 2H, J "= 7.6Hz), 4.57 (s, 2H), 2.40 (broad s, 1H). 4-Iodo-benzaldehyde A solution of 4-iodobenzyl alcohol (9 g, 38.29 mmol) in dichloromethane (90 ml) and acetonitrile (10 ml) was treated sequentially with 4 A molecular sieve powder (9 g), tetra-n-propylammonium perruthenate. (0.13 g) and N-methylmorpholine N-oxide (9 g, 76.6 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with hexane and subjected to column chromatography on silica gel (230-400 mesh) using 6-10% ethyl acetate in hexane as eluent to provide the title compound (2.5 g pure and 4 g -95% pure, 73%). H1 NMR (300 MHz, CDC13): d 9.96 (s, 1H), 7.92 (d, 2H, J = 8.5Hz), 7.59 (d, 2H, J = 8.5Hz). 4-Ethyl iodo-cinnamate (Reagent 3) A stirred, cooled (-78 ° C) solution of triethyl phosphonoacetate (11.1 ml, 56 mmol) in anhydrous tetrahydrofuran (100 ml) was treated with a 1.6 M solution of n-butyl lithium in hexanes (27 ml. , 43.75 mmoles). After 10 min, the reaction mixture was introduced via a cannula into a refrigerated (-78 ° C) solution of 4-iodo-benzaldehyde (6.5 g, 28 mmol) in tetrahydrofuran (20 ml). The reaction mixture was allowed to warm to 0 ° C over 1h. It was quenched with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 6-8% ethyl acetate in hexane as eluent to provide the title compound (2.7 g pure, 3.2 g -95% pure, 69%).

NMR H1 (300 MHz, CDCl3): d 7.70 (d, 2H, J = 8.5 Hz), 7.57 (d, 1H, J = 15.8Hz), 7.21 (d, 2H, J = 8.5Hz), 6.43 (d, 1H, "7 = 15.8Hz), 4.25 (c, 2H, J = 7.1Hz), 1.33 (t, 3H, J = 7.1Hz) . 4-iodine-cinnamic acid A solution of ethyl 4-iodo cinnamate (3.2 g, 10.5 mmol) in methanol (25 ml), tetrahydrofuran (25 ml) and water (15 ml) was treated with lithium hydroxide monohydrate (4, 2 g, 100 mmol) and the resulting reaction mixture was stirred at room temperature for 2 days. The volatiles were evaporated in vacuo and the residue was neutralized with a saturated aqueous solution of ammonium chloride. The precipitated solid was filtered, washed with water and hexane and dried to give the title product as a white solid (2.9 g, 91%). This was used as is for the next stage. 4-Methyl iodo-cinnamate (Reagent 4) A stirred, cooled solution (ice bath) of iodo-cinnamic acid in methanol was treated with a solution of diazomethane in diethyl ether. The reaction mixture was allowed to warm to room temperature, the volatiles were evaporated in vacuo to provide the title compound.

Ethyl 3- (4-iodo-phenyl) -but-2-enoic acid ester (Reagent 5) A stirred, cooled (-78 ° C) solution of triethyl 2-phosphonoacetate (4.55 g, 20 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with a 1.6 M solution of n-butyl lithium in hexanes ( 12.8 ml, 20.5 mmol). After 30 min, a solution of 4-iodoacetophenone (2.5 g, 10 mmol) in tetrahydrofuran (5 ml) was introduced via a cannula into the reaction mixture. After 4 h, quenched with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent, followed by preparative normal phase HPLC to give the title compound (0.53 g, 15%). NMR H1 (300 MHz, CDCl3): d 7.67 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 5.91 (s, 1H), 4 , 01 (c, J = 7, lHz, 2H), 2.14 (s, 6H), 1.12 (t, J "= 7, lHz, 3H). 3-Iodo-benzaldehyde A solution of 3-iodobenzyl alcohol (Aldrich, 4.72 g, 20 mmol) in dichloromethane (50 ml) and acetonitrile (5 ml) was treated sequentially with molecular sieve powder 4 A (5 g), tetra-n-propylammonium perruthenate (0.1 g) and N-Methylmorpholine N-oxide (2.34 g, 40 mmol). After stirring at room temperature for 3 h, the reaction mixture was diluted with hexane and subjected to column chromatography on silica gel (230-400 mesh) using 6-10% ethyl acetate in hexane as eluent to provide the title compound (3.7 g, 80%). This was used as is for the next stage.

Reagent 6 3-Ethyl iodo cinnamate (Reagent 6) A stirred, cooled (-78 ° C) solution of triethyl phosphonoacetate (11.44 g, 51 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a 1.6 M solution of n-butyl lithium in hexanes (30 mL). ml, 48 mmol). After 10 min, the reaction mixture was introduced via a cannula into a refrigerated (-78 ° C) solution of 4-iodo-benzaldehyde (3.7 g, 16 mmol) in tetrahydrofuran (20 ml). The reaction mixture was allowed to warm to 0 ° C over 1h. It was quenched with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 8-10% ethyl acetate in hexane as eluent to provide the title compound (4.6 g, 95%). H1 NMR (300 MHz, CDC13): d 7.83 (s, 1H), 7.65 (dd, 1H, J = 7.9, 2Hz), 7.53 (d, 1H, J = 15.8Hz) , 7.43 (dd, 1H, J = 7.6, 2Hz), 7.07 (dd, 1H, J = 7.6, 7.9Hz), 6.38 (d, 1H, «7 = 15, 8Hz), 4.24 (c, 2H, «7 = 6.9Hz), 1.34 (t, 3H, J = 6.9Hz).

Ethyl ester of (E) -3- (4-iodo-phenyl) -2-methyl-acrylic acid (Reagent 7) A stirred, cooled (-78 ° C) solution of triethyl 2-phosphonopropionate (10 g, 41.9 mmol) in anhydrous tetrahydrofuran (100 ml) was treated with a 1.6 M solution of n-butyl lithium in hexanes ( 25 ml, 40 mmol). After 10 min, the reaction mixture was introduced via a cannula into a refrigerated (-78 ° C) solution of 4-iodo-benzaldehyde (4.66 g, 20 mmol) in tetrahydrofuran (25 ml). After 30 minutes, it was quenched with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 9-10% ethyl acetate in hexane as eluent to provide the title compound (6.3 g, 99%). NMR H1 (300 MHz, CDCl3): d 7.71 (d, 2H, J = 8.4Hz), 7.58 (s, 1H), 7.12 (d, 2H, J = 8.4Hz), 4 , 27 (c, 2H, J = 7.2Hz), 2.08 (d, 3H, J = 1.5Hz), 1.35 (t, 3H, J = 7.2Hz). 2-Chloro-3- (4-iodo-phenyl) -acrylic acid ethyl ester (Reagent 8) A stirred, cooled (-78 ° C) solution of chloro- (dipropyl-phosphinoyl) -acetic acid ethyl ester (6.1 g, 23.5 mmol) in anhydrous tetrahydrofuran (70 ml) was treated with a solution 1, 6 M n-butyl lithium in hexanes (14 ml, 22 mmol). After 10 min, the reaction mixture was introduced via a cannula into a refrigerated (-78 ° C) solution of 4-iodo-benzaldehyde (2.61 g, 11.2 mmol) in tetrahydrofuran (25 mL). After 30 minutes, it was quenched with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 4-5% ethyl acetate in hexane as eluent to provide the title compound as a 1: 1 mixture of E and Z isomers (3.6 g, 95%) 4-Iodo-butylphenyl acetate (Reagent 10) A solution of 4-iodophenylacetic acid (Lancaster, 1.31 g, 5 mmol) in anhydrous toluene (10 ml) was heated to 80 ° C and treated with a solution of di-t-butylacetal of N, N-dimethylformamide. After 2 h the reaction mixture was cooled to room temperature and subjected to flash chromatography on silica gel (23-400 mesh) using 10% ethyl acetate in hexane as eluent to provide the title compound (0.degree. , 7 g, 44%). NMR H1 (300 MHz, CDC13): d 7.62 (d, 2H, J = 8.2Hz), 7.01 (d, 2H, J = 8.2Hz), 3.45 (s, 2H), 1 , 43 (s, 9H).

Reagent 11 Acid (2-fluoro-iodo-phenyl) -acetic acid acetoxymethyl ester (Reagent 11) A solution of 2-fluoro-4-iodophenylacetic acid (described in US 6,252,090, incorporated herein by reference, 0.82 g, 2.93 mmol) in anhydrous acetonitrile (10 ml) was treated with N, N-diisopropylethylamine (1.27 ml, 7.32 mmol) followed by bromide of acetoxymethyl / bromomethyl acetate (0.896 g, 5.86 mmol) and the resulting reaction mixture was stirred overnight at room temperature. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane. as eluent to provide the title compound as an oil (0.75 g, 72%). H1 NMR (300 MHz, CDC13): 7.42 (m, 2H), 6.97 (dd, J = 8.0 and 8.0 Hz, 1H), 5.73 (s, 2H), 3.65 (s, 2H), 2.08 (s, 3H). 2-Trimethylsilane-ethyl ester of (2-fluoro-4-iodo-phenyl) -acetic acid (Reagent 12) A solution of 2-fluoro-4-iodophenylacetic acid (0.3 g, 1.07 mmol) and 2- (trimethylsilyl) ethanol (0.28 mL, 1.95 mmol) in anhydrous dichloromethane (5 mL) was treated with 4- (dimethylamino) pyridine (0.275 g, 2.3 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.37 g, 1.95 mmol) and the resulting reaction mixture was stirred to the Room temperature during the night. The reaction mixture was then subjected to flash column chromatography using 5% ethyl acetate in hexane as eluent to give the title compound as a white solid (0.37 g, 91%). NMR H1 (300 MHz, CDCl3): 7.44 (m, 2H), 7.02 (dd, J = 8.0, 8.0 Hz, 1H), 4.20 (t, J = 8.5Hz, 2H ), 3.59 (s, 2H), 0.98 (t, J = 8.5 Hz, 2H), 0.02 (s, 9H).

Synthesis of the Preferred Embodiments Compound 2 Reagent 2 6.252.090 Reaction Scheme 1 General Procedure B: 2- Methyl ester. { 4 - [(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2,1'-cyclopropane] -6-yl) ethynyl] -phenyl} -propionic (Intermediate 1) A solution of 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] (described in U.S. Patent No. 6,252,090) 0.068 g, 0.27 mmol), and methyl-2- (4-iodo phenyl) propionate (Reagent 1, 0.086 g, 0.3 mmol) in triethylamine (3 ml), was treated with copper iodide (I) (0.028 g, 0.15 mmol) and purged with argon for 5 minutes. Dichlorobis (triphenylphosphine) palladium (II) (0.057 g, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered on a pad of celite. The filtrate was evaporated in vacuo to a brown oil which was subjected to column chromatography on silica gel (230-400 mesh) to give the title compound as an oil (0.072 g, 56%). NMR H1 (300 MHz, CDCl3): d 7.46 (d, 2H, J = 8.4Hz), 7.29 (d, 1H, J = 2.1Hz), 7.25 (d, 2H, J = 8.4Hz), 6.80 (d, 1H, J = 2.1Hz), 3.68 (c, 1H, J = 7.2Hz), 3.66 (s, 3H), 2.02-1, 90 (m, 1H), 1.90 (s, 2H), 1.49 (d, 3H, J "= 7.2Hz), 1.39 (s, 6H), 1.03-0.99 (m , 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H). 2- (4- [(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl) ethynyl] -phenyl} - Propionic (Compound 1) A solution of 2- methyl acid ester. { 4 - [(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2,1'-cyclopropane] -6-yl) ethynyl] -phenyl} -propionic (Intermediate 1, 0.072 g, 0.174 mmol) in methanol (5 ml) was treated with a 1 M solution of sodium hydroxide (1 ml, 1 mmol) and the resulting reaction mixture was heated at 55 ° C for 4 h . The reaction mixture was cooled to room temperature and the volatiles were evaporated in vacuo to a residue which was diluted with 10% hydrochloric acid until neutral and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title product as a white solid after flash column chromatography on silica gel (230-400 mesh) (0.04 g). g, 57%). H 1 NMR (300 MHz, CDCl 3): d 7.46 (d, 2 H, J = 8.1 Hz), 7.30-7.25 (m, 3 H), 6.80 (d, 1 H, J = 1, 8Hz), 3.74 (c, 1H, J = 7.2Hz), 1.99-1.96 (m, 1H), 1.91 (s, 2H), 1.51 (d, 3H, J = 7.2 Hz), 1.39 (s, 6H), 1.04-0.99 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.59 (m, 4H).

Methyl ester of acid 2-. { 4- [(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1 '-cyclopropane] -6-yl) ethynyl] -phenyl} -2-methyl-propionic (Intermediate 2) Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] (0.096 g, 0.38 mmol), Methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.127 g, 0.41 mmol), triethylamine (3 mL), copper (I) iodide (0.040 g, 0.21 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.080 g, 0.11 mmol) followed by flash column chromatography on silica gel (230-400 mesh), the title compound was obtained as an oil (0.046 g, 47 %). NMR H1 (300 MHz, CDCl3): d 7.39 (d, 2H, J = 8.4Hz), 7.23-7.20 (, 3H), 6.72 (d, 1H, J = 2.1Hz ), 3.58 (s, 3H), 1.92-1.84 (m, 1H), 1.84 (s, 2H), 1.51 (s, 6H), 1.33 (s, 6H) , 0.97-0.92 (m, 2H), 0.83-0.76 (m, 2H), 0.59-0.52 (m, 4H). 2- (4- [(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl) ethynyl] -phenyl} - 2-methyl-propionic (Compound 2) A solution of 2- methyl acid ester. { 4 - [(8-Cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2,1'-cyclopropane] -6-yl) ethynyl] -phenyl} -2-methyl-propionic (Intermediate 2, 0.046 g, 0.107 mmol) in methanol (5 mL) was treated with a 1 M solution of sodium hydroxide (1.2 mL, 1.2 mmol) and the resulting reaction mixture it was heated at 55 ° C for 4 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated in vacuo to a residue which was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a white solid after flash column chromatography on silica gel ( 230-400 mesh) (0.067 g, 89%). H1 NMR (300 MHz, CDCl3): d 7.47 (d, 2H, J = 8.1 Hz), 7.36 (d, 2H, J = 8.1 Hz), 7.30 (d, 1H, J = 2.1Hz), 6.80 (d, 1H, J "= 2.1Hz), 1.99-1.91 (m, 1H), 1.91 (s, 2H), 1.60 (s, 6H), 1.40 (s, 6H), 1.04-0.99 (m, 2H), 0.90-0.84 (m, 2H), 0.69-0.59 (m, 4H). 2. NaOH Reagent 7 Compound 3 2. HPLC Reagent 3. NaOH Compound 4 Reaction Scheme 2 Ethyl ester of (E) -3- acid. { 4- [8-cyclopropyl-3,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl] ethynyl-phenyl} -2-methyl-acrylic (Intermediate 3) Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, '-cyclopropane] (0.077 g, 0.3 mmol), ester Ethyl (E) -3- (4-iodo-phenyl) -2-methyl-acrylic acid (Reagent 7, 0.106 g, 0.23 mmol), triethylamine (3 ml), copper (I) iodide (0.029 g) , 0.15 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.064 g, 0.09 mmol) followed by flash column chromatography on silica gel (230-400 mesh), gave the title compound (0, 06 g, 45%). NMR H1 (300 MHz, CDC13): d 7.65 (d, 1H, J = 1.5Hz), 7.52 (d, 2H, J = 8.7Hz), 7.37 (d, 2H, J " = 8.7Hz), 7.32 (d, 1H, J = 1.8Hz), 6.82 (d, 1H, J "= 1.8Hz), 4.27 (c, 2H, J" = 7, 2Hz), 2.14 (d, 3H, J = 1.5Hz), 1.99 (m, 1H), 1.91 (s, 2H), 1.40 (s, 12H), 1.35 (t , 3H, J = 7.2 Hz), 1.04-1.00 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.59 (m, 4H).

Acid (E) -3-. { 4- [8-Cyclopropyl-3,4-dimethylspiro [2H-l-benzopyran-2, 1'-cyclopropane] -6-yl] ethynyl-phenyl} -2-methyl-acrylic (Compound 3) A solution of ethyl ester of (E) -3- acid. { 4- [8-cyclopropyl-3,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl] ethynyl-phenyl} -2-methyl-acrylic (Intermediate 3, 0.06 g, 0.13 mmol) in ethanol (2 ml) was treated with a 1 M solution of sodium hydroxide (0.5 ml, 0.5 mmol) and the The resulting reaction mixture was heated at 55 ° C for 4 h. The reaction mixture was cooled to room temperature and the volatiles were evaporated in vacuo to a residue which was neutralized with 5% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid after flash column chromatography on silica gel (230-400 mesh) (0.044 g, 82%). H1 NMR (300 MHz, CDC13): d 7.81 (d, 1H, J = 1.5Hz), 7.54 (d, 2H, J = 8.4Hz), 7.41 (d, 2H, J = 8.4Hz), 7.33 (d, 1H, J = 2.1Hz), 6.83 (d, 1H, J "= 2.1Hz), 2.17 (d, 3H, J = 1.5Hz) , 2.00 (m, 1H), 1.92 (s, 2H), 1.41 (s, 12H), 1.05-1.00 (m, 2H), 0.91-0.84 (m , 2H), 0.69-0.60 (m, 4H).

Ethyl ester of (Z) -2-chloro-3- (4- [8-cyclopropyl-3,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl] ethynyl}. -Acrylic (Intermediate 4) Following General Procedure B and using 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2,1'-cyclopropane] (0.11 g, 0.436 mmol), ethyl ester of (E, Z) -2-chloro-3- (4-iodo-phenyl) -acrylic acid (Reagent 8, 0.162 g, 0.48 mmol), triethylamine (3 ml), copper iodide (I) (0.041 g, 0.21 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.092 g, 0.13 mmol) followed by flash column chromatography on silica gel (230-400 mesh), and preparative normal phase HPLC. using 5% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.09 g, 45%). H1 NMR (300 MHz, CDC13): d 7.88 (s, 1H), 7.83 (d, 2H, J = 8.1Hz), 7.55 (d, 2H, J = 8.1Hz), 7 , 33 (d, 1H, J = 2.1Hz), 6.82 (d, 1H, J = 2.1Hz), 4.36 (c, 2H, J = 6.9Hz), 1.99 (m, 1H), 1.92 (s, 2H), 1.41 (s, 12H), 1.39 (t, 3H, "7 = 6.9Hz), 1.05-1.00 (m, 2H), 0.91-0.84 (m, 2H), 0.70-0.60 (m, 4H).

Acid (Z) -2-chloro-3-. { 4- [8-cyclopropyl-3,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl] ethynyl} -Acrylic (Compound 4) A solution of ethyl ester of (Z) -2-chloro-3- acid. { 4- [8-cyclopropyl-3,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] -6-yl] ethynyl} Acrylic (Intermediate 4, 0.09 g, 0.19 mmol) in ethanol (1 ml) and tetrahydrofuran (3 ml) was treated with a 1 M solution of sodium hydroxide (0.7 ml, 0.7 mmol) and the resulting reaction mixture was heated at 55 ° C overnight. The reaction mixture was cooled to room temperature and the volatiles were evaporated in vacuo to a residue which was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid after flash column chromatography on silica gel ( 230-400 mesh) (0.08 g, 95%). H1 NMR (300 MHz, CDC13): d 7.74 (s, 1H), 7.55 (d, 2H, J = 8.1Hz), 7.31 (d, 2H, J = 8.1Hz), 7 , 20 (d, 1H, «7 = 1.8Hz), 6.70 (d, 1H, J = 1.8Hz), 1.86 (, 1H), 1.79 (s, 2H), 1.27 (s, 12H), 0.94-0.81 (m, 2H), 0.77-0.71 (m, 2H), 0.59-0.47 (m, 4H).

United States Patent Intermediate 5 No. 6,252,090 Intermediate 6 Compound 5 Reaction Scheme 3 6-Amino-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] (Intermediate 5) A solution of 6-bromo-8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro [2JT-1-benzopyran-2, 1'-cyclopropane] (described in US 6,252,090, 0.322 g, 1.049 mmol), benzophenone imine (Fluka 0.093 ml, 1.15 mmol), sodium t-butoxide (0.142 g, 1.47 mmol), tris (dibenzylidene ketone) dipalladium (0) (0.023 g, 0.025 mmol) and (S) - (-) -2, 2'-bis (diphenylphosphino) -l, 1-binaphthyl (Aldrich, 0.047 g, 0.075 mmol) in 7 ml of anhydrous toluene was purged with argon and heated at 95 ° C for 36 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a thick brown oil (0.73 g). The oil was dissolved in tetrahydrofuran (3.5 ml) and treated with 2 M hydrochloric acid (1.7 ml). After stirring at room temperature for 20 minutes, 0.5 ml of 2M hydrochloric acid and 40 ml of water were added and the reaction mixture was extracted with hexane: ethyl acetate (2: 1, 3x60 ml). The aqueous phase was neutralized with potassium hydroxide and extracted with dichloromethane (3 × 50 ml). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide an oil which in column chromatography on silica gel (230-400 mesh) gave the title product as a white solid. Brown color (0.15 g, 58%). H1 NMR (300 MHz, CDC13): d 6.46 (d, 1H, J = 2.7Hz), 6.01 (d, 1H, J = 2.7Hz), 3.28 (s broad, 2H), 2.02-1.93 (m, 1H), 1.87 (s, 2H), 1.34 (s, 6H), 0.97-0.93 (m, 2H), 0.85-0, 78 (m, 2H), 0.61-0.59 (m, 4H).

Methyl ester of 4- acid. { 3 - [8-Cyclopropyl-3, 3-dihydro-4,4-dimethylspiro (2H-1-benzopyran-2, 2'-cyclopropane) -6-yl] -ureido} -benzoic (Intermediate 6) A solution of 4-isocyanatobenzoic acid methyl ester (Aldrich, 0.17 g, 0.97 mmol) in anhydrous toluene (5 ml) was treated with a solution of 6-amino-8-cyclopropyl-3, 4- dihydro-4,4-dimethylspiro [2H-1-benzopyran-2, 1'-cyclopropane] (Intermediate 5, 0.07 g, 0.28 mmol) in toluene (15 ml). The resulting reaction mixture was stirred at room temperature overnight and at 50-60 ° C for 5h. The volatiles were evaporated in vacuo and the residue was subjected to column chromatography on silica gel (230-400 mesh) to give the title compound as a white solid (0.073 g, 62%). NMR H1 (300 MHz, CDCl3): d 7.93 (d, 2H, J = 9.0Hz), 7.39 (d, 2H, "7 = 9.0Hz), 7.06 (d, 1H, J = 2.4Hz), 6.62 (broad s, 1H), 6.53 (d, 1H, J = 2.4Hz), 3.88 (s, 3H), 2.05-1.97 (m, 1H), 1.89 (s, 2H), 1.35 (s, 6H), 1.01-0.97 (m, 2H), 0.90-0.83 (m, 2H), 0.67. -0.54 (m, 4H).

Acid 4-. { 3- [8-cyclopropyl-3,3-dihydro-4,4-dimethylspiro (2H-l-benzopyran-2, 2'-cyclopropane) -6-yl] -ureido} -benzoic (Compound 5) A solution of methyl ester of 4- acid. { 3- [8-cyclopropyl-3, 3-dihydro-4,4-dimethylspiro (2H-1-benzopyran-2,2'-cyclopropane) -6-yl] -ureido} -benzoic acid (Intermediate 6, 0.072 g, 0.17 mmol) in methanol (3.4 ml) and tetrahydrofuran (7 ml) was treated with a 0.5 M solution of sodium hydroxide (3.4 ml, 1.7 mmoles) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo to a residue which was diluted with water, neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a white solid (0.066 g, 95%). NMR H1 (300 MHz, CD3COCD3): d 8.27 (broad s, 1H), 7.82 (d, 2H, J "= 9.0Hz), 7.52 (d, 2H, J" = 9.0Hz ), 7.20 (d, 1H, J = 2.4Hz), 6.66 (d, 1H, J "= 2.4Hz), 1.93-1.90 (m, 1H), 1.80 ( s, 2H), 1.24 (s, 6H), 0.80-0.73 (m, 2H), 0.72-0.67 (m, H), 0.57-0.41 (m, 4H).

(US Patent 6,252,090) R2 = H, R5 = R5 '= H (US Patent 6,252,090) R2 = F, R5 = R5' = H Reagent 1 R2 = H, R5 = H, R5 '= Me Compound 6 R2 = H, R5 = R5 l '= =? H Compound 7 R2 = F, R5 = R5l = H Compound 8 R2 = H, R5 = H, R5 '= Compound 9 R2 = H, R5 = R5' = Me Reaction Scheme 4 General Procedure C: 6-Bromo-8- [(cyclopropyl-amino) methyl] -2,2,4, 4-tetramethyl-chroman (Intermediate 7) A stirred, cooled solution (ice bath) of 6 -bromo-2,2,4,4-tetramethylchroman-8-carbaldehyde (U.S. Patent No. 6,252,090, 2.4 g, 8.4 mmol) in dichloromethane (10 ml) and acetonitrile (9 ml) was treated with cyclopropylamine (1.45 ml, 21 mmol). After 5 minutes, acetic acid (1 ml) was added followed by sodium cyanoborohydride (1.33 g, 21 mmol). The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed by vacuum distillation, the residue was diluted with water and extracted with ethyl acetate (x2). The combined organic extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) gave the title compound (1.4 g, 50%) as a clear oil. NMR H1 (300 MHz, CDC13): d 7.27 (d, 1H, J = 2.1Hz), 7.16 (d, 1H, J = 2.1Hz), 3.73 (s, 2H), 2 , 19 (broad s, 1H), 2.09-2.04 (m, 1H), 1.82 (s, 2H), 1.35 (s, 6H), 1.32 (s, 6H), 0 43-0.36 (m, 4H). 6-Bromo-8- [(cyclopropyl-formyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman (Intermediate 8) A solution of 6-bromo-8 - [(cyclopropyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman (Intermediate 7, 1.4 g, 4.14 mmol) in ethyl formate was subjected to at reflux for 6 h. The solvent was distilled off in vacuo to give the title compound as a clear oil (1.56 g, 100%).

NMR H1 (300 MHz, CDCl3): d 8.37, 8.27 (2s, 1H), 7.35, 7.29 (2d, 1H, J = 2.1Hz), 7.13, 7.11 (2d, 1H, J = 2.1Hz), 4.48 (s, 2H), 2.60-2.50 (m, 1H), 1.81 (s, 2H), 1.34 (s, 6H), 1.32 (s, 6H), 0.74- 0.70 (m, 4H). 6-Bromo-8- [(cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman (Intermediate 9) A solution of 6-bromo-8 - [(cyclopropyl-formyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman (Intermediate 8, 1.46 g, 4.0 mmol) in anhydrous tetrahydrofuran ( 30 ml) was treated with a 2 M solution of borane complex: methyl sulfide in tetrahydrofuran (5 ml, 10 mmol) and the resulting reaction mixture was refluxed for 2 h. It was then cooled in an ice bath, a saturated aqueous solution of sodium carbonate was carefully quenched and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a white solid (1.55 g, 100%). H1 NMR (300 MHz, CDC13): d 7.26 (d, 1H, J = 2.1Hz), 7.20 (d, 1H, J = 2.1Hz), 3.64 (s, 2H), 2 , 27 (s, 3H), 1.83 (s, 2H), 1.83-1.78 (m, 1H), 1.34 (s, 6H), 1.33 (s, 6H), 0, 48-0.47 (m, 4H).

General Procedure D: 8- [(Cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman (Intermediate 10) A solution of 6-bromo-8 - [(cyclopropyl-formyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman (Intermediate 9, 1.5 g, 4.2 mmol) in triethylamine ml) and anhydrous tetrahydrofuran (10 ml) was treated with copper (I) iodide (0.32 g, 1.68 mmol) and purged with argon for 5 minutes. Then trimethylsilylacetylene (2.5 ml, 17.6 mmol) was added followed by dichlorobis (triphenylphosphine) palladium (II) (0.737 g, 1.05 mmol). The resulting reaction mixture was heated at 70 ° C for 17 h. It was then cooled to room temperature, diluted with diethyl ether and filtered on a pad of celite. The filtrate was evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) to give the title compound as a brown oil. NMR H1 (300 MHz, CDC13): d 7.08 (d, 1H, J = 2.1Hz), 6.97 (d, 1H, J = 2.1Hz), 3.40 (s, 2H), 2 , 03 (s, 3H), 1.57 (s, 2H), 1.57-1.53 (m, 1H), 1.09 (2s, 12H), 0.25-0.22 (m, 4H) ), 0.012 (S, 9H).

General Procedure F: 8- [(Cyclopropyl-methyl-amino) -methyl] -6-ethynyl-2, 2,4, 4-tetramethyl-chroman (Intermediate 11) A solution of 8 - [(cyclopropyl-methyl-amino) -methyl] -2,2,4, 4-tetramethyl-6-trimethylsilanylethynyl-chroman (Intermediate 10, 0.729 g, 1.97 mmol) in methanol (30 ml) it was treated with potassium carbonate (1.4 g, 10.2 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as a brown oil (0.571 g, 98%).

H1 NMR (300 MHz, CDC13): d 7.35 (d, 1H, J = 2.1Hz), 7.25 (d, 1H, J = 2.1Hz), 3.66 (s, 2H), 2 , 98 (s, 1H), 2.28 (s, 3H), 1.83 (s, 2H), 1.83-1.77 (m, 1H), 1.35 (s, 6H), 1, 34 (s, 6H), 0.50-0.47 (m, 4H). (4 { 8 - [(Cyclopropyl-methyl-amino) -methyl] -2,2,4, 4-tetramethyl-chroman-6-ylethynyl} phenyl) -acetic acid ester (Intermediate 12) Following General Procedure B and using 8- [(cyclopropyl-methyl-amino) -methyl] -6-ethynyl-2, 2,, -tetramethyl-chroman (Intermediate 11, 0.09 g, 0.3 mmol), ester methyl 4-iodophenylacetic acid (U.S. Patent No. 6,252,090, 0.092 g, 0.33 mmol), triethylamine (3 ml), copper (I) iodide (0.029 g, 0.15 mmol) and dichlorobis (triphenylphosphine) aladium (II) (0.064 g, 0.09 mmol) followed by flash column chromatography on silica gel (230-400 mesh), the title compound was obtained as a yellow oil (0.085 g) , 65%). H1 NMR (300 MHz, CDCl3): d 7.46 (d, 2H, J = 8.4Hz), 7.37 (d, 1H, J = 2.1Hz), 7.27-7.22 (m, 3H), 3.70 (s, 3H), 3.67 (s, 2H), 3.63 (s, 2H), 2.29 (s, 3H), 1.83 (s, 2H), 1, 83-1.81 (m, 1H), 1.35 (2s, 12H), 0.50-0.47 (m, 4H). (4 { 8 - [(Cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} phenyl) -acetic acid (Compound 6) A solution of (4- {8 - [(cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} phenyl) -acetic acid methyl ester ( Intermediate 12, 0.057 g, 0.13 mmol) in methanol (1 ml) and tetrahydrofuran (3 ml) was treated with a 1 M solution of sodium hydroxide (0.4 ml, 0.4 mmol) and the reaction mixture The resulting mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo to a residue which was washed with hexane, neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow oil (0.046 g, 84%). H NMR (300 MHz, CDC13): d 7.42-7.26 (m, 6H), 3.94 (s, 2H), 3.57 (s, 2H), 2.48 (s, 3H), 2.04 (m, 1H), 1.82 (s, 2H), 1.35 (s, 6H), 1.33 (s, 6H), 0.55-0.50 (m, 4H).

Methyl ester of 4- ({8- [(cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} -2-fluorophenyl) -acetic acid ester ( Intermediate 13) Following General Procedure B and using 8- [(cyclopropyl-methyl-amino) -methyl] -6-ethynyl-2, 2,4,4-tetramethyl-chroman (Intermediate 11, 0.084 g, 0.28 mmol), ester methyl 2-fluoro-4-iodophenylacetic acid (US Pat. No. 6,252,090, 0.091 g, 0.3 mmol), triethylamine (3 ml), copper (I) iodide (0.027 g, 0.14 g) mmoles) and dichlorobis (triphenylphosphine) palladium (II) (0.060 g, 0.085 mmol) followed by flash column chromatography on silica gel (230-400 mesh), the title compound was obtained as a yellow oil ( 0.083 g, 64%). NMR H1 (300 MHz, CDCl3): d 7.37 (d, 1H, J = 2.1 Hz), 7.27-7.24 (m, 4H), 3.72 (s, 3H), 3.67 (s, 4H), 2.29 (s, 3H), 1.83 (s, 2H), 1.83-1.81 (m, 1H), 1.35 (s, 12H), 0.50- 0.47 (m, 4H).

Acid (4-. {8- [(cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} -2-fluoro-phenyl) -acetic acid (Compound 7) A solution of (4- {8 - [(cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} -2-fluoro- methyl ester. phenyl) -acetic (Intermediate 13, 0.060 g, 0.13 mmol) in methanol (1 ml) and tetrahydrofuran (3 ml) was treated with a 1 M solution of sodium hydroxide (0.4 ml, 0.4 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo to a residue which was washed with hexane, neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow oil (0.056 g, 95%). H1 NMR (300 MHz, CDC13): d 7.43 (d, 1H, J "= 2.1Hz), 7.37-7.13 (m, 4H), 3.99 (s, 2H), 3, 61 (s, 2H), 2.52 (s, 3H), 2.10-2.04 (m, 1H), 1.83 (s, 2H), 1.83-1.81 (m, 1H) , 1.36 (s, 6H), 1.35 (s, 6H), 0.90-0.82 (m, 2H), 0.59-0.57 (m, 2H). 2- (4- { 8 - [(Cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} -phenyl) -propionic acid methyl ester ( Intermediate 14) Following General Procedure B and using 8- [(cyclopropyl-methyl-amino) -methyl] -6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mmol) Methyl 2- (4-iodophenyl) propionate (Reagent 1, 0.086 g, 0.29 mmol), triethylamine (3 ml), copper iodide (I) (0.026 g, 0.14 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.057 g, 0.08 mmol) followed by flash column chromatography on silica gel (230-400 mesh), the title compound was obtained as a brown oil (0.067 g, 54% ). H1 NMR (300 MHz, CDC13): d 7.46 (d, 2H, J = 8.4Hz), 7.37 (d, 1H, J = 2.1Hz), 7.27-7.22 (m, 3H), 3.72 (c, 1H, J = 7.2Hz), 3.67 (s, 5H), 2.29 (s, 3H), 1.83 (s, 2H), 1.83-1 , 79 (m, 1H), 1.50 (d, 3H, J "= 7.2Hz), 1.35 (s, 12H), 0.50-0.47 (m, 4H). 2- (4- (8 - [(Cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} -phenyl) -propionic acid (Compound 8) A solution of 2- (4- { 8 - [(Cyclopropyl-methyl-amino) -methyl] -2,2,4, 4-tetramethyl-chroman-6-ylethynyl} -phenyl ester) -propionic (Intermediate 14, 0.057 g, 0.12 mmol) in methanol (1 ml) and tetrahydrofuran (3 ml) was treated with a 1 M solution of sodium hydroxide (0.3 ml, 0.3 mmol) and the The resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo to a residue which was washed with hexane, neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid (0.024 g, 45%). H1 NMR (300 MHz, CDC13): d 7.38-7.23 (2m, 6H), 3.85-3.82 (m, 1H), 3.82 (s, 2H), 2.39 (s, 3H), 1.94-1.85 (m, 1H), 1.80 (s, 2H), 1.41 (d, 3H, "7 = 7.2Hz), 1.33 (s, 12H), 0.70-0.60 (m, 2H), 0.50-0.48 (, 2H).

Methyl ester of 2- (4- { 8 - [(cyclopropyl-methyl-amino) -methyl] -2, 2,4,4-tetramethyl-chroman-6-ylethynyl} - phenyl) -2 -methyl-propionic (Intermediate 15) Following General Procedure B and using 8- [(cyclopropyl-methyl-amino) -methyl] -6-ethynyl-2, 2,4,4-tetramethyl-chroman (Intermediate 11, 0.08 g, 0.27 mmol) Methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.082 g, 0.27 mmol), triethylamine (2 ml), copper (I) iodide (0.020 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent, was obtained the title compound in the form of a brown oil (0.040 g, 31%). NMR H1 (300 MHz, CDCl3): d 7.50-7.28 (m, 6H), 3.68 (s, 3H), 3.66 (s, 2H), 2.30 (s, 3H), 1.85 (s, 2H), 1.85-1.81 (m, 1H), 1.60 (s, 3H), 1.59 (s, 3H), 1.37 (s, 6H), 1 , 36 (s, 6H), 0.50-0.47 (m, 4H). 2- (4- { 8 - [(Cyclopropyl-methyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-ylethynyl} -phenyl) -2-methyl-propionic acid (Compound 9) A solution of 2- (4- { 8 - [(cyclopropyl-methyl-amino) -methyl] -2, 2,4,4-tetramethyl-chroman-6-ylethynyl} -phenyl ester) -2-Methyl-propionic (Intermediate 15, 0.040 g, 0.084 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) was treated with a 2 M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Preparative reverse phase HPLC on a Partisil 10 ODS-3 column using 10% water in acetonitrile as the mobile phase yielded the title compound (0.008 g, 27%). H1 NMR (300 MHz, CDC13): d 7.46-7.32 (m, 6H), 6.90-6.50 (broad s, 1H), 3.84 (s, 2H), 2.41 ( s, 3H), 1.97-1.92 (m, 1H), 1.83 (s, 2H), 1.55 (s, 6H), 1.36 (2s, 12H), 0.73-0 , 68 (, 2H), 0.52-0.46 (m, 2H).

Intermediate 15A Intermediate 17 Compound 13 Compound 11 R5 = H, R5 = Compound 12 R5 = R5, = Me Intermediate 19 United States No. Compound 10 6,252,090 2. NaOH Reaction Scheme 5-Acetyl-6-bromo-2,2,4,4-tetramethylchroman (Intermediate 5A) A stirred, cooled solution (-78 ° C) of 6- Bromo-2,2,4,4,4-tetramethylchroman (1 g, 3.72 mmol) in anhydrous dichloromethane (10 ml) was treated with aluminum chloride (0.8 g, 6.8 mmol) followed by acetyl chloride ( 0.4 ml, 6.08 mmol). After 10 minutes, the reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with water, and dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane. as eluent to provide the title compound as a solid (0.78 g, 67%).

H1 NMR (300 MHz, CDC13): d 7.64 (d, 1H, J = 2.6Hz), 7.49 (d, 1H, J = 2.6Hz), 2.60 (s, 3H), 1 , 87 (s, 2H), 1.41 (s, 6H), 1.36 (s, 6H). - 8-Acetoxy-6-bromo-2, 2,4, 4-tetramethylchroman (Intermediate 16) A solution of 8-acetyl-6-bromo-2,2,4,4-tetramethylchroman (Intermediate 15A, 1.3 g, 4.18 mmol) in anhydrous dichloromethane (30 ml) was treated with a 77% aqueous solution. of 3-chloroperoxybenzoic acid (5.75 g, 33.44 mmol) and the resulting reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then cooled in an ice bath and carefully quenched with a saturated solution of sodium thiosulfate. The phases were separated and the organic phase was washed with an aqueous solution of saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to provide a residue which in column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent afforded the title compound as an oil (1.3 g, 92%). NMR H1 (300 MHz, CDC13): d 7.27 (s, 1H), 7.00 (s, 1H), 2.29 (s, 3H), 1.83 (s, 2H), 1.34 ( s, 6H), 1.32 (s, 6H). 6-Bromo-8-hydroxy-2, 2,4, 4-tetramethylchroman (Intermediate 17) A solution of 8-acetoxy-6-bromo-2,2,4,4-tetramethylchroman (Intermediate 16, 1.3 g, 3.98 mmol) in methanol was treated with sodium carbonate (0.8 g, 7%). 95 mmoles) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide a residue which in column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent provided the title product in the form of an oil (0.95 g, 84%). NMR H1 (300 MHz, CDCl3): d 6.91 (d, 1H), 6.88 (d, 1H), 5.67 (s, 1H), 1.84 (s, 2H), 1.37 ( s, 6H), 1.32 (s, 6H). 6-Bromo-8-trimethylsilanylethynyl-2,4,4,4-tetramethylchroman (Intermediate 18) Following General Procedure D and using 6-bromo-8-hydroxy-2,2,4,4-tetramethylchroman (Intermediate 17, 1.0 g, 3.51 mmol), triethylamine (5 ml), copper iodide (I) (0.066 g, 0.351 mmol), trimethylsilylacetylene (2.5 ml, 17.6 mmol) and dichlorobis (triphenylphosphine) palladium ( II) (0.246 g, 0.351 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 0.5% ethyl acetate in hexane as eluent, the title compound was obtained (1.08 g. , -100%) in the form of a brown oil. NMR H1 (300 MHz, CDC13): d 6.97 (d, 1H), 6.86 (d, 1H), 5.61 (s, 1H), 1.84 (s, 2H), 1.37 ( s, 6H), 1.33 (s, 6H), 0.24 (s, 9H). 6-Ethynyl-8-hydroxy-2, 2,4, 4-tetramethyl-chroman (Intermediate 19) A solution of 6-bromo-8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman (Intermediate 18, 0.47 g, 1.56 mmol) in methanol (5 ml) was treated with potassium carbonate (0.2 g, 1.45 mmol) and the resulting reaction mixture was heated at 80 ° C for 3 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as a brown oil (0.35 g, 99%). NMR H1 (300 MHz, CDC13): d 6.97 (d, 1H), 6.86 (d, 1H), 5.70 (broad s, 1H), 2.92 (s, 1H), 1.84 (s, 2H), 1.37 (s, 6H), 1.33 (s, 6H). [4- (8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 20) Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.035 g, 0.15 mmol), 4-iodophenylacetic acid methyl ester (0.060 g, 0.23 mmol), triethylamine (3 ml), copper iodide (I) (0.020 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by chromatography in an instantaneous column on silica gel (230-400 mesh), and preparative normal phase HPLC using 10% ethyl acetate in hexane as mobile phase, the title compound was obtained (0.015 g, 25%). NMR H1 (300 MHz, CDCl3): d 7.46 (d, 2H, J = 8.1 Hz), 7.24 (d, 2H, J = 8.1 Hz), 7.03 (d, 1H, J = 2.1Hz), 6.91 (d, 1H, J = 2.1Hz), 5.72 (s, 1H), 3.69 (s, 3H), 3.63 (s, 2H), 1.86 (s, 2H), 1.38 (s, 6H), 1.35 (s, 6H).

Methyl ester of acid [2-fluoro-4- (8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid (Intermediate 21) Following General Procedure B and using 6-ethynyl-8-hydroxy-, 2, 4, 4-tetramethyl-chroman (Intermediate 19, 0.05 g, 0.22 mmol), 2-fluoro-4-iodophenylacetic acid methyl ester (0.096 g, 0.33 mmol), triethylamine (3 ml), copper (I) iodide (0.020 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh), and preparative normal phase HPLC using acetate from ethyl to % in hexane as mobile phase, the title compound was obtained (0.037 g, 43%). NMR H1 (300 MHz, CDCl3): d 7.27-7.18 (m, 3H), 7.03 (d, 1H, J = 1.8Hz), 6.90 (d, 1H, J = 1.8Hz), 5.68 (s, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 1.87 (s, 2H), 1.39 (s, 6H), 1.36 (s, 6H).

Acid [2-fluoro-4- (8-hydroxy-2,4,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid (Compound 10) A solution of [2-fluoro-4- (8-hydroxy-2, 2,4, 4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid methyl ether (Intermediate 21, 0.037 g, 0.0493 mmoles) in methanol (2 ml) and tetrahydrofuran (1 ml) was treated with a 2 M solution of potassium hydroxide (2 ml, 4 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product. (0.024 g, 69%). H NMR (300 MHz, CDCl 3): d 7.26-7.24 (m, 3H), 7.03 (d, 1H, J = 1.8Hz), 6.90 (d, 1H, J = 1, 8Hz), 3.71 (s, 2H), 1.87 (s, 2H), 1.39 (s, 6H), 1.36 (s, 6H). 2- [4- (8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -propionic acid methyl ester (Intermediate 22) 87 Following the general procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.04 g, 0.17 mmol), 2- (4-iodophenyl) propionate methyl (Reagent 1, 0.075 g, 0.26 mmol), triethylamine (3 ml), copper iodide (I) (0.020 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh), and preparative normal phase HPLC using 5% ethyl acetate in hexane as mobile phase, the title compound was obtained as a brown oil (0.018 g, 26%). NMR H1 (300 MHz, CDC13): d 7.46 (d, 2H, J = 8.5Hz), 7.26 (d, 2H, J "= 8.5Hz), 7.03 (d, 1H, J = 1.8Hz), 6.91 (d, 1H, J = 1.8Hz), 5.66 (s, 1H), 3.67 (c, 1H, J = 7.5Hz), 1.87 (s) , 2H), 1.50 (d, 3H, "7 = 7.5Hz), 1.39 (s, 6H), 1.36 (s, 6H). 2- [4- (8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -propionic acid (Compound 11) A solution of 2- [4- (8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -propionic acid methyl ester (Intermediate 22, 0.018 g, '0.046 mmol) in methanol (1 ml) and tetrahydrofuran (0.5 ml) was treated with a 2 M solution of potassium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at 80 ° C for 2 h. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid (0.017 g, 100%). NMR H1 (300 MHz, CDC13): d 7.50-7.30 (m, 4H), 7.02 (s, 1H), 6.91 (s, 1H), 3.80-3.70 (m , 1H), 1.86 (s, 2H), 1.52 (d, 3H, J = 7.2Hz), 1.39 (s, 6H), 1.36 (s, 6H).

Methyl ester of 2- [4- (8-hydroxy-2, 2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -2-methyl-propionic acid ester (Intermediate 23) Following General Procedure B and using 6-ethynyl-8-hydroxy-2, 2,4,4-tetramethyl-chroman (Intermediate 19, 0.057 g, 0.25 mmol), methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.112 g, 0.37 mmol) , triethylamine (3 ml), copper (I) iodide (0.020 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on gel of silica (230-400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as mobile phase, the title compound was obtained as a brown oil (0.035 g, 35%). H1 NMR (300 MHz, CDCl3): d 7.46 (d, 2H, J = 8.5 Hz), 7.29 (d, 2H, J = 8.5 Hz), 7.03 (d, 1H, J = 1.8Hz), 6.91 (d, 1H, J = 1.8Hz), 5.67 (s, 1H), 3.66 (s, 3H), 1.86 (s, 2H), 1.58 (s, 6H), 1.39 (s, 6H), 1.36 (s, 6H). 2- [4- (8-Hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -2-methyl-propionic acid (Compound 12) A solution of 2- [4- (8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -2-methyl-propionic acid methyl ester (Intermediate 23, 0.035 g, 0.087 mmoles) in methanol (2 ml) and tetrahydrofuran (1 ml) was treated with a 1 M solution of potassium hydroxide (2 ml, 4 mmol) and the resulting reaction mixture was stirred at 80 ° C for 2 h. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid (0.034 g, 100%). NMR H1 (300 MHz, CDCl3): d 7.47 (d, 2H, J = 8.7Hz), 7.35 (d, 2H, J = 8.7Hz), 7.03 (d, 1H, J = 1.8Hz), 6.91 (d, 1H, J = 1.8Hz), 1.86 (s, 2H), 1.60 (s, 6H), 1.39 (s, 6H), 1.36 (s, 6H).

Methyl ester of [4- (8-isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid (Intermediate 24) A solution of [4- (8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 20, 0.02 g, 0.076 mmol) in acetone (2 ml) was treated with potassium carbonate (0.026 g, 0.19 mmol) and 2-iodopropane (5 ml, large excess) and the resulting reaction mixture was refluxed for 3Oh. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as an oil (0.02 g, 91%). H1 NMR (300 MHz, CDC13): d 7.47 (d, 2H, J = 8.4Hz), 7.24 (d, 2H, J = 8.4Hz), 7.14 (d, 1H, J = 2.1Hz), 6.93 (d, 1H, J "= 2.1Hz), 4.40 (heptet, 1H, J" = 6.3Hz), 3.70 (s, 3H), 3.63 ( s, 2H), 1.83 (s, 2H), 1.38 (s, 6H), 1.35 (s, 6H), 1.33 (d, 3H, J = 6.3Hz).

Acid [4- (8-isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid (Compound 13) A solution of [4- (8-isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 24, 0.02 g, 0.05 mmol) in methanol (1 ml) was treated with a 2 M solution of sodium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 5% methanol in ethyl acetate as eluent followed by preparative reverse phase HPLC using 10% water in acetonitrile as mobile phase yielded the title product (0.015 g, 78%). NMR H1 (300 MHz, CDCl3): d 7.47 (d, 2H, J = 8.4Hz), 7.24 (d, 2H, J = 8.4Hz), 7.14 (d, 1H, J = 2.1Hz), 6.92 (d, 1H, J = 2.1Hz), 4.40 (heptet, 1H, «7 = 7.5Hz), 3.65 (s, 2H), 1.83 (s) , 2H), 1.37 (s, 6H), 1.35 (s, 6H), 1.33 (d, 3H, J = 7.5Hz).

A1C13, CH3COCI, CH2C12 United States Intermediate No. 25 6,252,090 Intermediate 26 Intermediate 27 Compound 14 Reagent 2 2. KOH Reaction Scheme 6 6-Bromo-2, 2-diethyl-4, 4-dimethylchroman (Intermediate 25) A solution of 6-bromo-4,4-dimethyl-chroman-2-one (U.S. Patent No. 6,252,090, 4 g, 15.7 mmol) in anhydrous tetrahydrofuran (20 ml) was treated with a solution 3 M ethylmagesium bromide (10.5 ml, 31.5 mmol) and stirred at room temperature for 2 h. The reaction mixture was poured into cold dilute hydrochloric acid and extracted with ethyl acetate (x2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a residue which was dissolved in 50 ml of benzene, was treated with p-toluenesulfonic acid (1 g, 3.92 mmol) and the resulting reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, filtered over silica gel and washed with 10% ethyl acetate in hexane. The filtrate and washings were evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent to give the title compound a of a light yellow oil (3.9 g, 84%). H 1 NMR (300 MHz, CDCl 3): d 7.36 (d, 1 H, J = 2.4 Hz), 7.35 (dd, 1 H, J = 2.4, 8.4 Hz), 6.70 (d, 1H, J = 8.4Hz), 1.79 (s, 2H), 1.73-1.55 (m, 4H), 1.34 (s, 6H), 0.90 (t, 6H, J = 7.5Hz). 8-Acetyl-6-bromo-2,2-diethyl-4,4-dimethylchroman (Intermediate 26) A stirred, cooled suspension (ice bath) of aluminum chloride (1.1 g, 8.38 mmol) in anhydrous dichloromethane (20 ml) was treated with acetyl chloride (0.6 ml, 8.38 mmol). After 5 minutes, a solution of 6-bromo-2,2-diethyl-4,4-dimethylchroman (Intermediate 25, 1.66 g, 5.59 mmol) in dichloromethane. The reaction mixture was stirred for 1 h. The reaction mixture was then poured into water and extracted with diethyl ether (x2) The combined organic phase was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh). ) using 10% ethyl acetate in hexane as eluent to give the title compound as an oil (1.6 g, 84%). NMR H1 (300 MHz, CDCl3): d 7.64 (d, 1H, J = 2.1Hz), 7.48 (d, 1H, J = 2.1Hz), 2.62 (s, 3H), 1 , 84 (s, 2H), 1.75-1.59 (m, 4H), 1.36 (s, 6H), 0.93 (t, 6H, J = 7.5Hz). 6-Bromo-2, 2-diethyl-8-isopropyl-4, 4-dimethylchroman (Intermediate 27) A stirred, cooled solution (ice bath) of 8-acetyl-6-bromo-2,2-diethyl-4,4-dimethylchroman (Intermediate 26, 1.57 g, 4.62 mmol) in anhydrous tetrahydrofuran (10 ml. ) was treated with a 3 M solution of methylmagnesium bromide in diethyl ether (3.1 ml, 9.24 mmol). The reaction mixture was allowed to warm to room temperature over 2h. The reaction mixture was poured into cold, diluted aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which in flash column chromatography silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent provided an oil (1.41 g, 86%). A stirred, cooled solution (ice bath) of the oil (1.4 g, 3.93 mmol) in dichloromethane (10 ml) was treated with triethylsilane (5 ml, 31.46 mmol) followed after 30 minutes of acid trifluoroacetic acid (2.4 ml, 31.46 mmol) and the resulting reaction mixture was allowed to warm to room temperature and stirred for 3 h. The volatiles were removed by vacuum distillation and the residue was diluted with water and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) to provide the title compound as an oil. clear (0.89 g, 66%) and some starting material recovered (0.23 g, 16.4%). H1 NMR (300 MHz, CDC13): d 7.21 (d, 1H, J = 2.1 Hz), 7.11 (d, 1H, J = 2.1 Hz), 3.40-3.30 (m, 1H), 1.78 (s, 2H), 1.68-1.58 (m, 4H), 1.33 (s, 6H), 1.90 (d, 6H, J = 6.6Hz), 0 , 92 (t, 6H, J = 7.5 Hz). 2, 2-Diethyl-8-isopropyl-6-trimethylsilanylethynyl-4,4-dimethylchroman (Intermediate 28) Following General Procedure D and using 6-bromo-2, 2-diethyl-8-isopropyl-4,4-dimethylchroman (Intermediate 27, 0.89 g, 2.62 mmol), triethylamine (5 ml), tetrahydrofuran (10 ml), copper iodide (I) (0.050 g, 0.26 mmol), trimethylsilylacetylene (2.5 ml, 17.6 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.184 g, 0.26 mmol) followed of flash column chromatography on silica gel (230-400 mesh) using hexane at 2% ethyl acetate in hexane as eluent, the title compound was obtained (0.73 g, 79%) as a color oil brown. H NMR (300 MHz, CDCl3): d 7.31 (d, 1H), 7.12 (d, 1H), 3.20-3.10 (m, 1H), 1.70 (s, 2H), 1.70-1.45 (m, 4H), 1.34 (s, 6H), 0.95 (d, 6H), 0.68 (t, 6H), 0.00 (s, 9H). 2,2-Diethyl-6-ethynyl-8-isopropyl-4,4-dimethylchroman (Intermediate 29) A solution of 2,2-diethyl-8-isopropyl-6-trimethylsilanylethynyl-4,4-dimethylchroman (Intermediate 28.0 , 73 g, 2.04 mmol) in methanol (40 ml) was treated with potassium carbonate (0.degree., 15 g, 1.08 mmol) and the resulting reaction mixture was heated at 80 ° C for 3 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as a brown oil (0.56 g, 96%). NMR H1 (300 MHz, CDCl3): d 7.27 (d, 1H), 7.16 (d, 1H), 3.31-3.06 (m, 1H), 2.96 (s, 1H), 1.81 (s, 2H), 1.81-1.56 (m, 4H), 1.31 (s, 6H), 1.17 (d, 6H), 0.91 (t, 6H). 2- [4- (2, 2-Diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl) -phenyl] -2-methyl-propionic acid methyl ester (Intermediate 30) Following General Procedure B and using 2,2-diethyl-6-ethynyl-8-isopropyl-4,4-dimethylchroman (Intermediate 29, 0.069 g, 0.24 mmol), methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.146 g, 0.48 mmol), triethylamine (3 ml), copper iodide (I ) (0.025 g, 0.13 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.075 g, 0.107 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent, the title compound was obtained as a yellow oil (0.070 g, 62%). H1 NMR (300 MHz, CDCl3): d 7.47 (d, 2H, J "= 8.2 Hz), 7.31 (d, 2H, J = 8.2Hz), 7.30 (d, 1H, J = 2.1Hz), 7.20 (d, 1H, J = 2.1Hz), 3.65 (s, 3H), 3.40-3.20 (m, 1H), 1.78 (s, 2H), 1.68-1.57 (m, 4H), 1 , 58 (s, 6H), 1.34 (s, 6H), 1.21 (d, 6H, J = 7.0Hz), 0.91 (t, 6H, J = 7.3Hz). 2- [4- (2,2-Diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl) -phenyl] -2-methyl-propionic acid (Compound 14) A solution of 2- [4- (2,2-diethyl-8-isopropyl-4,4-dimethyl-chroman-6-ylethynyl) -phenyl] -2-methyl-propionic acid methyl ester (Intermediate 30, 0.070 g , 0.15 mmol) in methanol (3 ml) and tetrahydrofuran (0.5 ml) was treated with a 5 M solution of potassium hydroxide (2 ml, 10 mmol) and the resulting reaction mixture was stirred at room temperature for 2 days . The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide a residue which in preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase provided the title product in the form of a yellow solid (0.035 g, 51%). NMR H1 (300 MHz, CDC13): d 7.48 (d, 2H, J "= 8.1 Hz), 7.36 (d, 2H, J = 8.2 Hz), 7.31 (d, 1H, J = 2.1Hz), 7.20 (d, 1H, J "= 2.1Hz), 3.40-3.20 (m, 1H), 1.79 (s, 2H), 1.69-1, 60 (m, 4H), 1.61 (s, 6H), 1.35 (s, 6H), 1.21 (d, 6H, J = 7.2Hz), 0.92 (t, 6H, "7 = 7.5Hz).

(US 6,252,090) Intermediate 15A Intermediate 31 I Reaction Scheme 7 6-Bromo-8-isopropyl-2, 2,4, 4-tetramethyl-chroman (Intermediate 31) A stirred, cooled solution (ice bath) of 8-acetyl-6-bromo-2,2,4,4-tetramethylchroman (Intermediate 15A, 3.1 g, 10 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with a 3 M solution of methylmagnesium bromide in diethyl ether (11 ml, 44 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into cold, diluted aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that in flash column chromatography silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent provided a oil (2.85 g, 87%). The oil (1.67 g, 5.12 mmol) was cooled (ice bath) and treated with triethylsilane (10 ml, 62 mmol) followed after 30 minutes of trifluoroacetic acid (5 ml, 65 mmol) and the The resulting reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) to provide the title compound as an oil clear (1 g, 63%). NMR H1 (300 MHz, CDC13): d 7.20 (d, 1H, J = 2.3Hz), 7.09 (d, 1H, J = 2.3Hz), 3.25 (heptet, 1H, J = 7.1 Hz), 1.79 (s, 2H), 1.33 (s, 6H), 1.31 (s, 6H), 1.15 (d, 6H, J = 7.1Hz). 6-Ethynyl-8-isopropyl-2, 2,4, 4-tetramethyl-chroman (Intermediate 32) Following General Procedure D and using 6-bromo-8-isopropyl-2,2,4,4-tetramethylchroman (Intermediate 31, 1 g, 3.2 mmol), triethylamine (10 ml), copper iodide (I) (0.04 g, 0.21 mmol), trimethylsilylacetylene (5 mL, 35 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.12 g, 0.17 mmol) followed by flash column chromatography on silica gel (230-400 mesh), intermediate trimethylsilylacetylene was obtained, which was dissolved in methanol and treated with potassium carbonate and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title compound as a brown oil (0.6 g, 73%). %). H NMR (300 MHz, CDCl 3): d 7.34 (d, 1 H, J = 2.1 Hz), 7.21 (d, 1 H, J = 2.1 Hz), 3.50 (heptet, 1 H, J = 6.8Hz), 3.00 (s, 1H), 1.85 (s, 2H), 1.38 (s, 6H), 1.37 (s, 6H), 1.22 (d, 6H, J = 6.8Hz).

Ethyl 3- [3- (8-isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acrylic acid ester (Intermediate 33) Following General Procedure B and using 6-ethynyl-8-isopropyl-2,2,4,4-tetramethylchroman (Intermediate 32, 0.05 g, 0.2 mmol), ethyl 3-iodocinnamate (Reagent 6, 0.118 g , 0.39 mmoles), triethylamine (2 ml), copper (I) iodide (0.025 g, 0.13 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.075 g, 0.107 mmol) followed by flash column chromatography on silica gel (230-400 mesh), the title compound was obtained (0.058 g, 69%). NMR H1 (300 MHz, CDCl3): d 7.62-7.22 (m, 6H), 7.14 (d, 1H, J = 1.8Hz), 6.39 (d, 1H, J = 16, 1Hz), 4.19 (c, 2H, J = 7.0Hz), 3.21 (heptet, 1H, "7 = 6.7Hz), 1.76 (s, 2H), 1.29 (s, 12H). ), 1.27 (t, 3H, J = 7.0Hz) .l, 13 (d, 6H, J = 6.7Hz). 3- [3- (8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acrylic acid (Compound 15) A solution of 3- [3- (8-isopropyl-2, 2,4, 4-tetramethyl-chroman-6-ylethynyl) -phenyl] -acrylic acid ethyl ester (Intermediate 33, 0.058 g, 0.13 mmol) in ethanol (2 ml) and tetrahydrofuran (2 ml) was treated with a 5 N solution of potassium hydroxide (2 ml, 10 mmol) and the reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound (0.036 g, 66%). NMR H1 (300 MHz, CDCl3): d 7.69 (d, 1H, J = 15.8Hz), 7.65 (s, 1H), 7.47 (d, 1H, J = 7.6Hz), 7.39 (d, 1H, «7 = 7.9Hz), 7.32-7.17 (m, 2H), 7.14 (d, 1H, "7 = 1.8Hz), 6.41 (d, 1H, J = 15.8Hz), 3.21 (heptet, 1H, J = 6.7Hz), 1.76 ( s, 2H), 1.29 (s, 12H), 1.13 (d, 6H, J = 6.7Hz).

Intermediate 31 Intermediate 34 Intermediate 35 Compound 16 Reaction Scheme 8 8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 34) A stirred, cooled solution (-78 ° C) of 6-bromo-8- isopropyl-2,2,4,4,4-tetramethyl-chroman (Intermediate 31, 0.39 g, 1.26 mmol) in anhydrous diethyl ether (10 ml) was treated with a 1.7 M solution of t-butyl lithium in pentane (1.48 ml, 2.516 mmol) and the reaction mixture was stirred for 20 minutes. Carbon dioxide (generated from dry ice) was bubbled into the reaction mixture. The reaction mixture was then quenched with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography to provide the title compound (0.3, 86%). H1 NMR (300 MHz, CDC13): d 7.87 (d, 1H, J = 2Hz), 7.72 (d, 1H, J = 2Hz), 3.21 (heptet, 1H, J = 7.0Hz) , 1.78 (s, 2H), 1.39 (s, 12H), 1.14 (d, 6H, J = 7.0Hz). 8-isopropyl-2,4,4,4-tetramethyl-chroman-6-carboxylic acid ester (Intermediate 35) 4- (2-benzyloxycarbonyl-vinyl) -phenyl ester A solution of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 34, 0.05 g, 0.18 mmol) and 3- (4-hydroxy-phenyl) benzyl ester ) -acrylic (described in Journal of Natural Products, 1990, 53 (4), pp. 821-824, Bankova V., 0.046 g, 0.18 mmol) in anhydrous dichloromethane (5 ml) was treated with 4- (dimethylamino) pyridine ( 0.052 g, 0.27 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.044 g, 0.36 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then subjected to flash column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as a white solid (0.076 g, 83%). H1 NMR (300 MHz, CDC13): d 7.93 (d, 1H, J = 2Hz), 7.78 (d, 1H, "7 = 2Hz), 7.66 (d, 1H," 7 = 16, 1Hz), 7.49 (d, 2H, J = 8.5Hz), 7.35-7.25 (m, 5H), 7.15 (d, 2H, J = 8.5Hz), 6.39 ( d, 1H, "7 = 16.1Hz), 5.18 (s, 2H), 3.24 (heptet, 1H, J = 7.1Hz), 1.80 (S, 2H), 1.31 (s) , 12H), 1.16 (d, 6H, "7 = 7.1Hz). 8-Isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid 4- (2-carboxy-vinyl) -phenyl ester (Compound 16) A suspension of t-butyldimethylsilane (0.3 ml, 1.85 mmole), palladium (II) acetate (0.013 g, 0.06 mmole) and triethylamine (0.03 ml, 0.2 mmole) in anhydrous dichloromethane (2 ml) in argon was treated with a solution of 4- (2-benzyloxycarbonyl-vinyl) -phenyl ester of 8-isopropyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 35, 0.063 g, 0.123 mmol) in dichloromethane (2 ml) and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with diethyl ether. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to flash column chromatography to yield an intermediate which was treated with acetic acid (1 ml) in water (0.3 ml) and tetrahydrofuran (0.3 ml) at room temperature for lh. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was subjected to preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to give the title compound (0.007 g). NMR R1 (300 MHz, CDCl3): d 7.89 (d, 1H, J = 2Hz), 7.74 (d, 1H, J = 2Hz), 7.67 (d, 1H, «7 = 15.8Hz ), 7.49 (d, 2H, J = 8.8Hz), 7.15 (d, 2H, J = 8.8Hz), 6.32 (d, 1H, J = 15.8Hz), 3.20 (heptet, 1H, J = 6.8Hz), 1.77 (s, 2H), 1.29 (s, 6H), 1.28 (s, 6H), 1.12 (d, 6H, J = 6 , 8Hz).

United States No. 6,252,090 l. > - NH2 5NaCNBH3) CH2C12, CH3CN, CH3COOH 2. z'-Prl, K2C03, CH3COCH3 Intermediate 36 Intermediate 37 Intermediate 38 Intermediate 39 Reaction Scheme 9 Ethyl-2, 2,4,4-tetramethylchroman-6-carboxylate (Intermediate 36) A solution of 6-bromo-2,2,2,4-tetramethylchroman (U.S. Patent No. 6,252,090, 2.2 g, 8.08 mmol), palladium acetate (0.145 g, 0.65 mmol) and 1,3-bis (diphenylphosphino) propane (0.267 g, 0.65 mmol) in a mixture of N, N-dimethylformamide (25 ml), ethanol (20 ml) and triethylamine (7 ml) was heated at 90 ° C. in an atmosphere of carbon monoxide at night. The volatiles were removed by vacuum distillation and the residue was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate. 5-10% ethyl in hexane as eluent to give the title compound (1.9 g, 90%). 1 H-NMR (300 MHz, CDCl 3): d 8.00 (d, 1H, J = 2.3Hz), 7.76 (dd, 1H, "7 = 2.1.8.5Hz), 6.79 (d , 1H, J "= 8.5Hz), 4.33 (c, 2H, J = 7.1Hz), 1.85 (s, 2H), 1.36 (s, 6H), 1.37 (s, 6H), 1.39-1.33 (m, 3H).

Ethyl ester of 8-formyl-2,2,4,4,4-tetramethylchroman-6-carboxylic acid (Intermediate 37) A stirred, cooled solution (ice bath) of 2, 2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 ml. ) was treated with titanium tetrachloride (0.4 ml, 3.26 mmol) followed by dichloromethyl ether (0.17 ml, 1.92 mmol). The reaction was allowed to warm to room temperature over 2 days, carefully quenched with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography to provide the title compound (0.11 g, 20%) . H NMR (300 MHz, CDCl 3): d 10.46 (s, 1H), 8.33 (d, 1H, "7 = 2Hz), 8.20 (d, 1H, J = 2Hz), 4.36 ( c, 2H, "7 = 6.7Hz), 1.93 (s, 2H), 1.45 (s, 6H), 1.42 (s, 6H), 1.39 (t, 3H, J = 6 , 7Hz). 8- [(Cyclopropyl-isopropyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 38) Following General Procedure C and using ethyl ester of 8-formyl-2, 2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 37, 0.11 g, 0.23 mmol) in dichloromethane (4 ml) and acetonitrile (2 ml), cyclopropylamine (0.08 ml, 1.1 mmol), acetic acid (0.8 ml) and sodium cyanoborohydride (0.072 g, 1.1 mmol) followed by working-up and flash column chromatography provided an intermediate. The intermediate (0.122 g, 0.22 mmol) was dissolved in acetone (10 ml) and treated with potassium carbonate (0.153 g, 1.1 mmol) and isopropyl iodide (0.04 ml). The resulting reaction mixture was at 60 ° C for 4 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Flash column chromatography on silica gel (230-400 mesh) using 15-20% ethyl acetate in hexane as eluent afforded the title compound (0.09 g, 71%) as a clear oil. H1 NMR (300 MHz, CDC13): d 7.87 (d, 1H, J = 2.1 Hz), 7.85 (d, 1H, J = 2.1Hz), 4.35 (c, 2H, J "= 7.0Hz), 3.72 (s, 2H), 2.97 (heptet, 1H, J = 6.7Hz), 1.97 (m, 1H), 1.83 (s, 2H), 1.37 (t, 3H, J = 7.0Hz), 1.37 (s) , 6H), 1.35 (s, 6H), 1.08 (d, 6H, J = 6.7 Hz), 0.38-0.30 (m, 4H). 8- [(Cyclopropyl-isopropyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 39) A solution of 8- [(cyclopropyl-isopropyl-amino ) -methyl] -2, 2, 4, 4-tetramethylchroman-6-carboxylic acid (Intermediate 38, 0.09 g, 0.26 mmol) in ethanol (3 ml) and tetrahydrofuran (1 ml) was treated with a solution 1 M sodium hydroxide (3 ml, 3 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (0.079 g, 96%). This was used as is for the next stage. 8- [(Cyclopropyl-isopropyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-carboxylic acid ester (Intermediate 40) 4-benzyloxycarbonylmethyl-phenyl ester A solution of 8 - [(cyclopropyl-isopropyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 39, 0.079 g, 0.25 mmol) and benzyl acetate 4-hydroxy-phenyl (APIN, 0.06 g, 0.25 mmol) in anhydrous dichloromethane (5 ml) was treated with 4- (dimethylamino) pyridine (0.06 g, 0.5 mmol) and hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.072 g, 0.37 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then subjected to flash column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as an oil (0.093 g, 69%). H NMR (300 MHz, CDCl 3): d 7.98 (s, 2H), 7.32-7.21 (m, 7H), 7.13 (d, 2H, "7 = 8.5Hz), 5, 11 (s, 2H), 3.73 (s, 2H), 3.66 (s, '2H), 2.93 (heptet, 1H, J = 6.5Hz), 1.93 (m, 1H), 1.84 (s, 2H), 1.07 (s, 12H), 1.07 (d, 6H, J "= 6.5Hz).

Ester 4-carboxymethyl-phenyl 8- [(cyclopropyl-isopropyl-amino) -methyl] -2,2,4,4-tetramethyl-chroman-6-carboxylic acid ester (Compound 17) A solution of 4-benzyloxycarbonylmethyl-phenyl ester of 8 - [(cyclopropyl-isopropyl-amino) -methyl] -2, 2,, 4-tetramethyl-chroman-6-carboxylic acid (Intermediate 40, 0.093 g, 0.17 mmol ) in ethyl acetate (3 ml) was treated with a suspension of 10% palladium on carbon (20 mg) in ethyl acetate and the resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 h. The reaction mixture was filtered on a pad of celite and the filtrate was evaporated to a residue which was purified by flash column chromatography on silica gel to provide the title compound.

Pate 6,303,785 Intermediate 41 Intermediate 41 Intermediate 42 Intermediate 41 Intermediate 46 Intermediate 50 Intermediate 41 Cl2, Cul, NEt3 COOMe Int 2. LÍOH int Int Reaction Scheme 10 6-Bromo-2, 2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 41) A stirred, cooled solution (ice bath) of 6-bromo-2,2,4,4-tetramethylchroman -6-carbaldehyde (US Patent No. 6,303,785 incorporated herein by reference, 3.31 g, 11.15 mmol) in 2-methyl-2-propanol (30 ml) was treated with glacial acetic acid (30 ml). ml) followed by 2-methyl-2-butene (12 ml, 111.5 mmol). A solution of sodium chlorite (2.15 g, 18.95 mmol) in water (15 ml) was added dropwise to the reaction mixture. The reaction mixture was then allowed to warm gradually to room temperature and was stirred for 4 h, to which end it was basified with a 2 N solution of sodium hydroxide and then acidified with 2 N hydrochloric acid and extracted with ethyl acetate. . The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid (3.23 g, 93%). H NMR (300 MHz, CDCl3): d 8.14 (d, 1H, J = 2.7Hz), 7.60 (d, 1H, J = 2.7Hz), 1.95 (s, 2H), 1 50 (s, 6H), 1.39 (s, 6H). 6-Bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid isopropyl ester (Intermediate 42) A solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 41, 0.3 g, 0.96 mmol) in anhydrous dichloromethane (15 ml) was treated with thionyl chloride (0.degree. , 7 mL, 9.6 mmol) and the reaction mixture was refluxed for 18 h. After cooling to room temperature, the volatiles were removed by vacuum distillation and the residue was dissolved in isopropanol (15 ml). 4- (Dimethylamino) pyridine (0.35 g, 9.6 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. It was diluted with ethyl acetate and washed with 2N hydrochloric acid (x2), 2N sodium hydroxide (x2), and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the product of the product. title in the form of a brown oil (0.32 g, 93%). NMR H1 (300 MHz, CDCl3): d 7.60 (d, 1H, J = 2.4Hz), 7.45 (d, 1H, J "= 2.4Hz), 5.23 (heptet, 1H, J = 6.0Hz), 1.84 (s, 2H), 1.37 (s, 6H), 1.36 (s, 6H), 1.33 (d, 6H, J = 6.0Hz).

Isopropyl Ester of 2, 2, 4, 4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid (Intermediate 43) Following General Procedure D and using isopropyl ester of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 42, 0.32 g, 0.89 mmol), triethylamine (2 ml), iodide copper (I) (0.060 g, 0.33 mmol), trimethylsilylacetylene (0.5 ml, 3.56 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.16 g, 0.22 mmol) followed by chromatography in a flash column on silica gel (230-400 mesh) using 20% ethyl acetate in hexane as eluent, the title compound (0.23 g, 69%) was obtained as a yellow oil. H1 NMR (300 MHz, CDC13): d 7.58 (d, 1H, J = 2.4Hz), 7.44 (d, 1H, J = 2.4Hz), 5.18 (heptet, 1H, J = 6.3 Hz), 1.80 (s, 2H), 1.32 (s, 6H), 1.31 (s, 6H), 1.29 (d, 6H, J = 6.3Hz), 0.00 (s, 9H). 6-Ethynyl-2,4,4,4-tetramethylchromane-8-carboxylic acid isopropyl ester (Intermediate 44) A solution of 2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid isopropyl ester (Intermediate 43, 0.23 g, 0.62 mmol) in methanol (5 ml) was treated with potassium carbonate (0.85 g, 6.2 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a brown oil which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate 20% in hexane as eluent to give the title compound (0.0246 g, 13%). NMR H1 (300 MHz, CDCl3): d 7.66 (d, 1H, J = 2.1 Hz), 7.53 (d, 1H, J "= 2.1Hz), 5.25 (heptet, 1H, J = 6.3 Hz), 3.02 (s, 1H), 1.88 (s, 2H), 1.40 (s, 6H), 1.37 (d, .6H, J = 6.3Hz), 1 , 36 (s, 6H). 6- (4-Methoxycarbonylmethyl-phenylethynyl) -2, 2,4, 4-tetramethyl-chroman-8-carboxylic acid isopropyl ester (Intermediate 45) Following General Procedure B and using isopropyl ester of 6-ethynyl-2, 2, 4-tetramethylchroman-8-carboxylic acid (Intermediate 44 0.025 g, 0.08 mmol), methyl 4-iodophenylacetic acid ester (0.027 g, 0.1 mmol), triethylamine (2 ml), copper (I) iodide (0.008 g, 0.04 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.017 g, 0.024 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 40% ethyl acetate in hexane as eluent, the title compound was obtained as a yellow oil (0.019 g, 53%). H1 NMR (300 MHz, CDC13): d 7.68 (d, 1H, J = 2.1Hz), 7.55 (d, 1H, J = 2.1Hz), 7.49-7.24 (m, 4H), 5.25 (m, 1H), 3.70 (s, 3H), 3.64 (s, 2H), 1.88 (s, 2H), 1.39 (s, 6H), 1, 37 (s, 6H), 1.39-1.35 (d, 6H). 6- (4-Carboxymethyl-phenylethynyl) -2,2, -tetramethyl-chroman-8-carboxylic acid isopropyl ester (Compound 18) A solution of 6- (4-methoxycarbonylmethyl-phenylethynyl) -2,2,4,4-tetramethyl-chroman-8-carboxylic acid isopropyl ester (Intermediate 45, 0.019 g, 0.043 mmol) in ethanol (0.3 ml) , tetrahydrofuran (0.3 ml) and water (0.3 ml) was treated with 1 N lithium hydroxide (0.086 ml, 0.086 mmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. The volatiles were evaporated in vacuo to a residue which was washed with hexane-ethyl acetate (3: 1), neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a brown oil (0.015 g, 80%). NMR H1 (300 MHz, CDC13): d 7.69 (d, 1H, J "= 2.4Hz), 7.55 (d, 1H, J" = 2.4Hz), 7.50-7.26 ( m, 4H), 5.25 (heptet, 1H), 3.67 (s, 2H), 1.88 (s, 2H), 1.39 (s, 6H), 1.37 (s, 6H), 1.39-1.35 (d, 6H).

Ester 2, 2-dimethylpropyl of 6-bromo-2,2,4,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 46) A cooled stirred solution (ice bath) of acid 6-bromo-2, 2,4, 4-tetramethylchroman-8-carboxylic acid (Intermediate 41, 0.5 g, 1.6 mmol), neopentyl alcohol (0.35 ml, 3.2 mmol) and 4- (dimethylamino) ) pyridine (0.03 g, 0.24 mmol) in anhydrous dichloromethane (5 ml) was treated with 1,3-dicyclohexylcarbodiimide (0.36 g, 1.76 mmol) and the reaction mixture was allowed to warm to room temperature ambient. After 2 h, the reaction mixture was filtered, the filtrate was diluted with ethyl acetate and washed with 2 N hydrochloric acid, 2 N sodium hydroxide, and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title product as a yellow solid (0.537 g, 88%). NMR H1 (300 MHz, CDC13): d 7.60 (d, 1H, J = 2.4Hz), 7.41 (d, 1H, J = 2.4Hz), 3.91 (s, 2H), 1 , 78 (s, 2H), 1.30 (s, 6H), 1.27 (s, 6H), 0.95 (s, 9H). 2, 2, 4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid ester 2 (2-dimethylpropyl) (Intermediate 47) Following General Procedure D and using 2, 2-dimethylpropyl ester of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 46, 0.54 g, 1.4 mmol), triethylamine (3 ml), copper iodide (I) (0.10 g, 0.52 mmol), trimethylsilylacetylene (0.8 ml, 5.6 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.25 g, 0, 35 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent, the title compound (0.396 g, 71%) was obtained as an oil. yellow color . NMR H1 (300 MHz, CDC13): d 7.64 (d, 1H, J = 1.8Hz), 7.46 (d, 1H, "7 = 1.8Hz), 3.94 (s, 2H), 1.81 (s, 2H), 1.33 (s, 6H), 1.30 (s, 6H), 0.98 (s, 9H), 0.002 (s, 9H).

Ester 2, 2-dimethylpropyl 6-ethynyl-2,4,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 48) A solution of 2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid ester (Intermediate 47, 0.396 g, 1 mmol) in methanol (5 ml) was treated with potassium carbonate. (1.4 g, 10 mmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as a brown oil (0.227 g, 70%). NMR H1 (300 MHz, CDCl3): d 7.72 (d, 1H, J = 1.5Hz), 7.55 (d, 1H, "7 = 1.5Hz), 4.00 (s, 2H), 3.02 (s, 1H), 1.88 (s, 2H), 1.40 (s, 6H), 1.36 (s, 6H), 1.04 (s, 9H). 2- (4-Methoxycarbonylmethyl-phenylethynyl) -2,2,4,4-tetramethyl-chroman-8-carboxylic acid ester 2 (2-dimethylpropyl) (Intermediate 49) Following General Procedure B and using 2, 2-dimethylpropyl ester of 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 48, 0.227 g, 0.70 mmol), methyl 4-methyl ester -iodophenylacetic acid (0.23 g, 0.83 mmol), triethylamine (3 ml), copper (I) iodide (0.07 g, 0.39 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.15 g) g, 0.21 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 20% ethyl acetate in hexane as eluent, the title compound was obtained as a yellow oil ( 0.198 g, 60%). NMR H1 (300 MHz, CDC13): d 7.76 (d, 1H, J = 2.4Hz), 7.58 (d, 1H, J = 2.4Hz), 7.49 (d, 2H, J = 8.1Hz), 7.26 (d, 2H, J = 8.1Hz), 4.01 (s, 2H), 3.70 (s, 3H), 3.64 (s, 2H), 1.88 (s, 2H), 1.40 (s, 6H), 1.38 (s, 6H), 1.05 (s, 9H).

Ester 2, 2-dimethylpropyl of 6- (4-carboxymethyl-phenylethynyl) -2,2,4,4-tetramethyl-chroman-8-carboxylic acid (Compound 19) A solution of 2- (4-methoxycarbonylmethyl-phenylethynyl) -2, 2,4,4-tetramethyl-chroman-8-carboxylic acid ester, 2,4-dimethylpropyl ester (Intermediate 49, 0.198 g, 0.42 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL) was treated with 1 N lithium hydroxide (1.5 mL, 1.5 mmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. . The reaction mixture was neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the product of the txtule as a greenish-yellow solid (0.16 g, 84%). . NMR H1 (300 MHz, CDCl3): d 7.76 (d, 1H, J = 2.1Hz), 7.59 (d, 1H, J = 2.1Hz), 7.50 (d, 2H, J = 8.1Hz), 7.28 (d, 2H, J = 2.1Hz), 4.02 (s, 2H), 3.67 (s, 2H), 1.89 (s, 2H), 1.41 (s, 6H), 1.39 (s, 6H), 1.06 (s, 9H). 6-Bromo-2,2,4,4,4-tetramethylchroman-8-carboxylic acid t-butyl ester (Intermediate 50) A solution of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 41, 0.3 g, 0.96 mmol) and triethylamine (0.1 g, 0.96 mmol) in anhydrous tetrahydrofuran (3 ml) was treated with 2,4,6-trichlorobenzoyl chloride (0.23 g, 0.23 g), , 96 mmol) and the reaction mixture was allowed to stir for 20 minutes. The precipitated solid was separated by filtration and the filtrate was evaporated in vacuo to give a residue which was dissolved in benzene (3 ml) in argon and treated with 4- (dimethylamino) pyridine (0.47 g, 3.84 mmol ) and 2-methyl-2-propanol (0.14 g, 1.92 mmol). After 18 h, the reaction mixture was diluted with ethyl acetate and washed with 2 N hydrochloric acid, 2 N sodium hydroxide and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide a residue that was subjected to column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent to give the title product as a white solid (0.14 g, %). NMR H1 (300 MHz, CDCl3): d 7.54 (d, 1H, J = 2.4Hz), 7.43 (d, 1H, J = 2.4Hz), 1.84 (s, 2H), 1 , 58 (s, 9H), 1.37 (s, 6H), 1.33 (s, 6H). 2, 2, 4, 4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid t-butyl ester (Intermediate 51) Following General Procedure D and using t-butyl ester of 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 50, 0.195 g, 0.53 mmol), triethylamine (2 ml), iodide copper (I) (0.040 g, 0.2 mmol), trimethylsilylacetylene (0.3 ml, 2.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.09 g, 0.13 mmol) followed by chromatography on a flash column on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent, the title compound (0.064 g, 32%) was obtained as a brown oil. H1 NMR (300 MHz, CDC13): d 7.57 (d, 1H, J = 2.1Hz), 7.46 (d, 1H, J = 2.1Hz), 1.84 (s, 2H), 1 , 57 (s, 9H), 1.37 (s, 6H), 1.34 (s, 6H), 0.045 (s, 9H). 6-Ethynyl-2,4,4-tetramethylchromane-8-carboxylic acid t-butyl ester (Intermediate 52) A solution of 2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid t-butyl ester (Intermediate 51, 0.064 g, 0.17 mmol) in methanol (5 ml) was treated with potassium carbonate (0.23 g, 1.7 mmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title compound as a brown oil (0.051 g, 97%). NMR H1 (300 MHz, CDCl3): d 7.52 (d, 1H, J = 2.1Hz), 7.42 (d, 1H, "7 = 1.5Hz), 2.93 (s, 1H), 1.79 (s, 2H), 1.51 (s, 9H), 1.31 (s, 6H), 1.27 (s, 6H). 6- (4-Methoxycarbonylmethyl-phenylethynyl) -2,2,4, 4-tetramethyl-chroman-8-carboxylic acid t-butyl ester (Intermediate 53) Following General Procedure B and using t-butyl ester of 6-ethynyl-2,2,4,4-tetramethylchroman-8-carboxylic acid (Intermediate 52, 0.051 g, 0.16 mmol), methyl 4-methyl ester -iodophenylacetic acid (0.053 g, 0.19 mmol), triethylamine (3 ml), copper (I) iodide (0.02 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.03 g, 0.043 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 20% ethyl acetate in hexane as eluent, the title compound was obtained as a yellow oil (0.014 g, %). NMR H1 (300 MHz, CDC13): d 7.63 (d, 1H, J = 2.1 Hz), 7.53 (d, 1H, J = 2.1 Hz), 7.48 (d, 2H, J = 8.2Hz), 7.26 (d, 2H, J = 8.2Hz), 3.72 (s, 3H), 3.65 (s, 2H), 1.88 (s, 2H), 1.60 (s, 9H), 1.40 (s, 6H), 1.38 (s, 6H). 6- (4-Carboxymethyl-phenylethynyl) -2,2,4,4-tetramethyl-chroman-8-carboxylic acid t-butyl ester (Compound 20) A solution of 6- (4-methoxycarbonylmethyl-phenylethynyl) -2,2,4, 4-tetramethyl-chroman-8-carboxylic acid t-butyl ester (Intermediate 53, 0.014 g, 0.03 mmol) in ethanol (0 , 3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with 1 N lithium hydroxide (0.12 mL, 0.12 mmol) and the resulting reaction mixture was stirred at the temperature environment for 3 h. The reaction mixture was neutralized with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow oil (0.012 g, 88%). NMR H1 (300 MHz, CDCl3): d 7.63 (d, 1H, J = 2.1 Hz), 7.52 (d, 1H, J "= 2.1 Hz), 7.47 (d, 2H, J "= 8.2Hz), 7.26 (d, 2H, J" = 2.1Hz), 3.67 (s, 2H), 1.87 (s, 2H), 1.59 (s, 9H), 1.39 (s, 6H), 1.36 (s, 6H).

Reaction Scheme 11 - (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl ester of trifluoromethanesulfonic acid (Intermediate 54) A solution of 4,4-dimethyl-6-trifluoromethylsulfonyl-1, 2,3,4-tetrahydronaphthalen-1-one (U.S. Patent No. 6,252,090, 0.85 g, 2.64 mmoles) in dichloromethane (6 ml) and acetonitrile (3 ml) was treated with cyclopropylamine (3 ml.43.4 mmol). After 5 minutes, acetic acid (3 ml) was added followed by sodium cyanoborohydride (0.66 g, 10.55 mmol). The reaction was stirred overnight at room temperature. It was then diluted with water and a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The combined organic extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. The oil was dissolved in acetone (20 ml) and treated with potassium carbonate (1.08 g, 7.8 mmol) and methyl iodide (1.6 mL, 26 mmol). The resulting reaction mixture was stirred at room temperature overnight. The solids were separated by filtration, the filtrate was evaporated in vacuo and the residue was subjected to column chromatography on silica gel (230-400 mesh) to give the title compound (0.85 g, 87%) in form of a colorless oil. NMR H1 (300 MHz, CDC13): d 7.61 (d, 1H, J ~ = 9.0Hz), 7.11 (d, 1H, J = 2.4Hz), 6.97 (dd, 1H, J = 2.4, 9.0Hz), 3.92 (t, 1H, J = 8.4Hz), 2.14-2.10 (m, 1H), 2.12 (s, 3H), 1.96. -1.89 (m, 2H), 1.79-1.57 (m, 2H), 1.29 (s, 3H), 1.25 (s, 3H), 0.52-0.36 (m , 4H).

General Procedure E: 5- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (Intermediate 55) A solution of 5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-yl ester of trifluoromethanesulfonic acid (Intermediate 54, 0.37 g, , 98 mmoles), palladium acetate (0.05 g, 0.22 mmol) and 1,3-bis (diphenylphosphino) propane (0.096 g, 0.23 mmol) in a mixture of dimethylformamide (4 ml), methanol ( 4 ml) and triethylamine (2 ml) was heated at 70 ° C in an atmosphere of carbon monoxide overnight. The volatiles were distilled in vacuo and the residue was diluted with water and extracted with diethyl ether (x3). The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent, to provide the title compound (0.236 g, 85%). NMR H1 (300 MHz, CDCl3): d 7.96 (d, 1H, J = 1.8Hz), 7.73 (dd, 1H, J = 1.8.8.1Hz), 7.59 (d, 1H, J = 8.1Hz), 3.96 (t, 1H, J = 7.5Hz), 3.89 (s, 3H), 2.17-2.10 (m, 1H), 2.12 ( s, 3H), 1.98-1.83 (m, 2H), 1.82-1.60 (m, 2H), 1.34 (s, 3H), 1.28 (s, 3H), 0 , 54-0.39 (m, 4H).

- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (Intermediate 56) A solution of 5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (Intermediate 55, 0.236 g, 0.83 mmol) in methanol (4 ml) and tetrahydrofuran (4 ml) was treated with a 2 M solution of sodium hydroxide (4 ml, 8 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as a solid (0.22 g, 100%). H1 NMR (300 MHz, CDC13): d 7.98 (d, 1H, J = 1.8Hz), 7.72 (dd, 1H, J = 1.8.8.2Hz), 7.51 (d, 1H, J = 8.2Hz), 3.93 (t, 1H, J = 7.8Hz), 2.15-2.04 (m, 1H), 2.10 (s, 3H), 1.94- 1.85 (m, 2H), 1.79-1.62 (m, 2H), 1.27 (s, 3H), 1.22 (s, 3H), 0.52-0.40 (m, 4H). 5- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid azide (Intermediate 57) A stirred, cooled solution (ice bath) of 5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (Intermediate 56, 0.22 g, 0.83 mmoles) in anhydrous tetrahydrofuran (4 ml) was treated with triethylamine (0.16 ml, 1.1 mmol) followed by ethyl chloroformate (0.10 ml, 1.08 mmol). After 5 h, sodium azide (0.081 g, 1.24 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title product which was used as such for the next reaction (0.24 g, 98%). 1- [5- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -3- (4-iodo-phenyl) -urea (Intermediate 58 ) A solution of 5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid azide (Intermediate 57, 0.12 g, 0.4 mmol) in Anhydrous toluene (14 ml) was refluxed in argon for 2 h. 4-iodoaniline (0.114 g, 0.52 mmol) was added and the solution was cooled to room temperature and stirred overnight. The volatiles were evaporated in vacuo and the residue was subjected to column chromatography on silica gel (230-400 mesh) using 20-25% ethyl acetate in hexane as eluent to give the title compound (0.13 g). , 67%). H1 NMR (300 MHz, CDC13): d 7.58 (d, 2H, J = 8.7Hz), 7.51 (d, 1H, J = 8.1Hz), 7.23 (d, 1H, J = 1.8Hz), 7.14 (d, 2H, J = 8.7Hz), 6.99 (dd, 1H, "7 = 1.8.8.1Hz), 6.99 (s wide, 1H), 6.57 (broad s, 1H), 3.92 (t, 1H, "= 7.2Hz), 2.13-2.05 (m, 1H), 2.13 (s, 3H), 1.93 -1.88 (m, 2H), 1.78-1.62 (m, 2H), 1.29 (s, 3H), 1.26 (s, 3H), 0.52-0.39 (m , 4H).

Methyl ester of 4- acid. { 3- [5- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -ureido} -benzoic (Intermediate 59) Following General Procedure E and using 1- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -3- (4-iodo- phenyl) -urea (Intermediate 58, 0.13 g, 0.267 mmole), palladium acetate (0.02 g, 0.09 mmole), 1,3-bis (diphenylphosphino) propane (0.042 g, 0.101 mmole), N , N-dimethylformamide (3 ml), methanol (3 ml) and triethylamine (1 ml) followed by flash column chromatography on silica gel (230-400 mesh) using 30-40% ethyl acetate in hexane as eluent obtained the title compound (0.045 g, 40%). H1 NMR (300 MHz, CDC13): d 7.91 (d, 2H, J = 8.4Hz), 7.51 (d, 1H, J = 8.1Hz), 7.42 (s, 1H), 7 , 37 (d, 2H, J = 8.4Hz), 7.26 (d, 1H, «7 = 1.8Hz), 7.09 (s, 1H), 6.97 (dd, 1H, J" = 2.1.8.1Hz), 3.89 (s, 3H), 3.90-3.84 (m, 1H), 2.11-2.06 (m, 1H), 2.09 (s, 3H), 1.89-1.80 (m, 2H), 1.80-1.64 (m, 2H), 1.24 (s, 3H), 1.21 (s, 3H), 0.50 -0.36 (m, 4H).

Acid 4-. { 3- [5- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -ureido} -benzoic (Compound 21) A solution of methyl ester of 4- acid. { 3- [5- (Cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -ureido} -benzoic (Intermediate 59, 0.045 g, 0.106 mmol) in methanol (2 ml) and tetrahydrofuran (3 ml) was treated with a 2 M solution of sodium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a solid which was recrystallized from hot acetonitrile to give the title product as a white solid (0.012 g, 28%).

NMR R1 (300 MHz, CD30D): d 7.95 (d, 2H, J = 9.0 Hz), 7.53 (d, 2H, "7 = 9.0Hz), 7.46 (d, 1H, J = 2.1Hz), 7.40 (d, 1H, J = 8.7Hz), 7.09 (s, 1H), 7.19 (dd, 1H, J = 2.1.8.7Hz), 4.06 (t, 1H, J = 6.0Hz), 2.30-2.25 (m, 1H), 2.28 (s, 3H), 2.05- 1.98 (m, 2H), 1, 82-1.68 (m, 2H), 1.32 (s, 3H), 1.30 (s, 3H), 0.60-0.48 (m, 4H).

Intermediate 60 Intermediate 60 Intermediate 62 Intermediate 64 A1C13, CH2C12 Intermediate 65 -Irn * t.ermed Ji-o r6-7¡ Intermediate Intermediate 69 Compound 22 Reaction Scheme 12 4- (4-Bromo-2-methoxy-phenyl) -4-oxo-butyric acid ethyl ester (Intermediate 60) A stirred, cooled (-30 ° C) solution of 3-bromoanisole (Aldrich, 18.7 g, 100 mmol) and ethylsuccinyl chloride (21 mL, 150 mmol) in anhydrous dichloromethane (200 ml) was treated with aluminum chloride (26.6 g, 200 mmol) and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with dichloromethane (x2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a brown oil. A solid separated upon standing. The liquid supernatant was decanted and the solid was washed with dichloromethane: hexane 1: 3 and dried to provide the title compound. The combined mother liquors and washings were evaporated to a brown oil which was subjected to column chromatography on silica gel (230-400 mesh) using 15% ethyl acetate in hexane as eluent to provide the title compound ( overall 12 g, 38%), and its isomer ethyl ester of 4- (2-chromosome-4-methoxyphenyl) -4-oxo-butyric acid (11.4 g, 36%) and a 1: 1 mixture of both ( 2 g, 6.3%). NMR H1 (300 MHz, CDCl3): d 7.56 (d, 1H, J = 8.7Hz), 7.07-7.03 (m, 2H), 4.07 (c, 2H, J = 7, 2Hz), 3.84 (s, 3H), 3.20 (t, 2H, J = 6.3Hz), 2.61 (t, 2H, J = 6.3Hz), 1.19 (t, 3H, J = 7.2 Hz).

Ethyl 4- (4-bromo-2-methoxy-phenyl) -butyric acid ester (Intermediate 61) A solution of 4- (4-bromo-2-methoxy-phenyl) -4-oxo-butyric acid ethyl ester ( Intermediate 60, 14.73 g, 46.8 mmol) in trifluoroacetic acid (72 ml, 935 mmol) was treated with triethylsilane (30 ml, 187 mmol) and the resulting reaction mixture was heated at 55 ° C for 4 h. The reaction mixture was then cooled to room temperature, neutralized with solid sodium bicarbonate, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a residue which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate to 8% in hexane as eluent to provide the title compound (7.4 g, 53%) as a colorless oil. H1NMR (300 MHz, CDCl3): d 7.02-6.94 (m, 3H), 4.11 (c, 2H, J = 7.2Hz), 3.79 (s, 3H), 2.60 (t, 2H, "7 = 7.2Hz), 2.29 (t, 2H, J = 7.2Hz), 1.88 (quinter, 2H, J = 7.2Hz), 1.25 (t, 3H) , J = 7.2 Hz). - (4-Bromo-2-methoxy-phenyl) -2-methyl-pentan-2-ol (Intermediate 62) A stirred, cooled solution (-10 ° C) of 4- (4-bromo-2-methoxy-phenyl) -butyric acid ethyl ester (Intermediate 61, 7.4 g, 24.6 mmol) in anhydrous tetrahydrofuran (50 ml) was treated with a 3 M solution of methylmagnesium bromide (20.5 ml, 61.5 mmol) and the resulting reaction mixture was left tempering at room temperature for 3 hours. It was quenched with an aqueous solution of saturated ammonium chloride, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title product (7.3 g, 100%). H1 NMR (300 MHz, CDCl3): d 6.92-6.87 (m, 3H), 3.71 (s, 3H), 2.48 (t, 2H, J = 7.2Hz), 1.55 -1.38 (m, 4H), 1.11 (s, 6H). 7-Bromo-5-methoxy-1,1-dimethyl-1,2,4,4-tetrahydro-naphthalene (Intermediate 63) - (4-bromo-2-methoxy-phenyl) -2-methyl-pentan-2-ol (Intermediate 62, 7.3 g, 24.6 mmol) was treated with 85% sulfuric acid (25 ml) at room temperature. After 30 minutes, the reaction mixture was diluted with cold water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product (5.6 g, 83%). NMR H1 (300 MHz, CDCl3): d 7.01 (d, 1H, "7 = 1.8Hz), 6.68 (d, 1H, J = 'l, 8Hz), 3.71 (s, 3H) , 2.49 (t, 2H, "7 = 6.3Hz), 1.71-1.65 (m, 2H), 1.55-1.51 (m, 2H), 1.18 (s, 6H) ). 6-Bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 64) A solution of 7-bromo-5-methoxy-1,1-dimethyl-1,2,3-tetrahydro-naphthalene (Intermediate 63, 5.6 g, 20.81 mmol) in glacial acetic acid (20 ml) was cooled to 0 ° C and treated with a solution of chromium trioxide (6.16 g, 61.6 mmol) in acetic acid and water (25 ml). The reaction mixture was then allowed to cool to room temperature and stirred for 48 h. It was diluted with water and extracted with diethyl ether (x2). The combined organic phase was washed with water (x3), saturated aqueous sodium bicarbonate (xl) and brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide an oil. Flash column chromatography on silica gel (230-400 mesh) using 10-20-100% ethyl acetate in hexane as eluent afforded the title compound (2 g, 33%) in the form of a yellow oil and recovered starting material (2.2 g, 39%). NMR H1 (300 MHz, CDCl3): d 7.12 (d, 1H, J = 1.8Hz), 6.97 (d, 1H, J = 1.8Hz), 3.87 (s, 3H), 2 , 66 (t, 2H, J = 6.6Hz), 1.92 (t, 2H, J - = 6.6Hz), 1.33 (s, 6H). 6-Bromo-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-l-one (Intermediate 65) A stirred, cooled solution (ice bath) of 6-bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 64, 0.24 g, 0.83 mmol) in anhydrous dichloromethane (4 ml) was treated with aluminum chloride (0.4 g, 3 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. It was poured into water and extracted with dichloromethane and ethyl acetate. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a brown oil which was subjected to column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent to provide the title product as a light yellow solid (0.13 g, 56%). H1 NMR (300 MHz, CDC13): d 12.85 (s, 1H), 7.00 (d, 1H, J = 1.5Hz), 6.98 (d, 1H, J = 1.5Hz), 2 , 74 (t, 2H, "7 = 6.9Hz), 1.96 (t, 2H," 7 = 6.9Hz), 1.36 (s, 6H). 8-Hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalene-l-one (Intermediate 66) Following General Procedure D and using 6-bromo-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 65, 1.56 g, 5.8 mmol), triethylamine (20 ml), copper iodide (I) (0.088 g, 0.46 mmol), trimethylsilylacetylene (3 ml, 21.22 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.325 g, 0.46 mmol) followed of flash column chromatography on silica gel (230-400 mesh) using hexane to 2-5% ethyl acetate in hexane as eluent, the title compound (1.67 g, 100%) was obtained in the form of a Solid orange. H NMR (300 MHz, CDC13): d 12.72 (s, 1H), 6.93 (d, 1H, J = 1.5Hz), 6.88 (d, 1H, J = 1.5Hz), 2 , 74 (t, 2H, J = 6.6Hz), 1.96 (t, 2H, J = 6.6Hz), 1.36 (s, 6H), 0.27 (s, 9H). 6-Ethynyl-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalene-lime (Intermediate 67) A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 2.2 g, 7.4 mmol) in methanol (20 ml) it was treated with potassium carbonate (2.04 g, 14.8 mmol) and the resulting reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as an oil (1.58 g, -100%).

NMR H1 (300 MHz, CDCl3): d 12.76 (s, 1H), 6.97 (d, 1H, J = 1.5Hz), 6.88 (d, 1H, J = 1.5Hz), 3 , 28 (s, 1H), 2.73 (t, 2H, "7 = 6.6Hz), 1.94 (t, 2H, J = 6.6Hz), 1.34 (s, 6H).

Methyl ester of acid. { 4- [8, 8-dimethyl-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 68) Following General Procedure B and using 6-ethynyl-8-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 67, 1.58 g, 7.4 mmol), 4-iodophenylacetic acid methyl ester (2.2 g, 7.94 mmol), triethylamine (12 ml), copper iodide (I) (0.38 g, 1.99 mmol) and dichlorobis (triphenylphosphine) palladium (II) (1.2 g, 1.71 mmol) followed by flash column chromatography on gel of silica (230-400 mesh) using 16% ethyl acetate in hexane as eluent, the title compound was obtained as a yellow oil (2.1 g, 78%). NMR H1 (300 MHz, CDCl3): d 12.79 (s, 1H), 7.52 (d, 2H, "7 = 8.7Hz), 7.29 (d, 2H, J = 8.7Hz), 7.01 (d, 1H, J = 1.5Hz), 6.94 (d, 1H, J = 1.5Hz), 3.71 (m, 3H), 3.65 (s, 2H), 2.76 (t, 2H, J = 6.6Hz), 1.97 (t, 2H, J = 6.6Hz), 1.38 (s, 6H).

Methyl ester of acid. { 4- [8, 8-Dimethyl-5-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 69) A stirred, cooled (0 ° C) solution of (4- [8,8-dimethyl-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl}. -acetic (Intermediate 68, 2.1 g, 5.8 mmol) in anhydrous dichloromethane (20 ml) was treated with 4- (dimethylamino) pyridine (1.21 g, 9.9 mmol) followed by N-phenyltrifluoromethanesulfonimide (2). , 2 g, 6.16 mmol) After stirring at room temperature overnight, the reaction mixture was subjected to column chromatography on silica gel (230-400 mesh) using 20% ethyl acetate in hexane. as eluent to provide the title compound (2.6 g, 91%). H NMR (300 MHz, CDC13): d 7.57 (d, 1H, J = 1.2 Hz), 7.49 (d, 2H) , J = 8.4Hz), 7.27 (d, 2H, J = 8.4Hz), 7.19 (d, 1H, J = 1.2Hz), 3.66 (m, 3H), 3.62 (s, 2H), 2.72 (t, 2H, "7 = 6.9Hz), 1.99 (t, 2H, J = 6.9Hz), 1.38 (s, 6H).

Methyl ester of [4- (8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -acetic acid (Intermediate 70) A solution of acid methyl ester. { 4- [8,8-dimethyl-5-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 69, 0.233 g, 0.47 mmol) in anhydrous 1-methyl-2-pyrrolidinone (3 ml) was purged with argon, and treated with lithium chloride (0.061 g, 1.45 mmol), tri-2-furylphosphine (0.0071 g, 0.031 mmol) and tris (dibenzylidene) dipalladium (0) (0.007 g, 0.015 mmol). After 5 minutes, tributyl (vinyl) tin (0.175 g, 0.55 mmol) was added and the resulting reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate 10-15% in hexane as eluent to give the title compound (0.15 g, 86%) as a white solid. NMR H1 (300 MHz, CDCl3): d 7.53 (d, 2H, J = 7.8Hz), 7.51 (d, 1H, J "= 1.8Hz), 7.50 (d, 1H, J = 1.8Hz), 7.43 (dd, 1H, J = 10.5, 17.1Hz), 7.29 (d, 2H, J = 7.8Hz), 5.57 (dd, 1H, J = 1.5, 17.1 Hz), 5.33 (dd, 1H, J = 1.5, 10.5Hz), 3.71 (s, 3H), 3.66 (s, 2H), 2.74 ( t, 2H, J = 6.9Hz), 2.00 (t, 2H, J = 6.9Hz), 1.40 (s, 6H). [4- (8,8-Dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -acetic acid (Compound 22) A solution of [4- (8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 70, 0.082 g, 0.22 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 2M solution of lithium hydroxide (1.5 ml, 3 mmol) and the resulting reaction mixture was stirred to the room temperature during l, 5h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid (0.065 g, 82%). NMR H1 (300 MHz, CDCl3): d 7.53 (d, 2H, J = 8.1 Hz), 7.50 (s, 2H), 7.43 (dd, 1H, J = 10.8, 17, 4Hz), 7.31 (d, 2H, J = 8.1Hz), 5.57 (dd, 1H, J = 1.5, 17.4Hz), 5.33 (dd, 1H, J "= 1, 5, 10.8 Hz), 3.68 (s, 2 H), 2.74 (t, 2 H, J = 6.3 Hz), 1.99 (t, 2 H, J = 6.3 Hz), 1.39 ( s, 6H).

Methyl ester of acid. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acetic (Intermediate 71) A solution of [4- (8,8-dimethyl-5-oxo-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 70, 0.205 g, 0.55 mmol) in dichloromethane (4 ml) and acetonitrile (2 ml) was treated with cyclopropylamine (1 ml, 14.45 mmol). After 5 minutes, acetic acid (1 ml) was added followed by sodium cyanoborohydride (0.138 g, 2.2 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with water and a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. The oil was dissolved in acetone (10 ml) and treated with potassium carbonate (0.227 g, 1.65 mmol) followed by methyl iodide (0.54 ml, 8.7 mmol) and the resulting reaction mixture was stirred overnight at room temperature. Diethyl ether was added to the reaction mixture and the precipitated solids were removed by filtration, the filtrate was evaporated in vacuo to a residue. Flash column chromatography on silica gel (230-400 mesh) using 4-5% ethyl acetate in hexane as eluent afforded the title compound (0.14 g, 60%). H NMR (300 MHz, CDCl 3): d 7.50 (d, 2H, J = 8.4Hz), 7.47 (s, 1H), 7.45 (s, 1H), 7.26 (d, 2H) , J = 8.4Hz), 7.13 (dd, 1H, J = 10.8, 17.7Hz), 5.47 (dd, 1H, J = 1.5, 17.7Hz), 5.11 ( dd, 1H, J = 1.5, 10.8Hz), 4.04 (t, 1H, J = 5.4Hz), 3.69 (s, 3H), 3.63 (s, 2H), 2, 18 (s, 3H), 2.18-2.14 (m, 1H), 2.02 (, 1H), 1.90-1.75 (m, 2H), 1.58-1.51 (m , 1H), 1.35 (s, 3H), 1.24 (s, 3H), 0.39-0.31 (m, 3H), 0.21-0.17 (m, 1H).

Acid { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acetic (Compound 23) A solution of acid methyl ester. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acetic (Intermediate 71, 0.14 g, 0.327 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 2M solution of lithium hydroxide (1.5 ml, 3 mmol) and the mixture of The resulting reaction was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title product as a white solid (0.135 g, 96%). NMR H1 (300 MHz, CDC13): d 9.99 (broad s, 1H), 7.47 (d, 2H, J = 8.1Hz), 7.44 (s, 1H), 7.43 (s, 1H), 7.22 (d, 2H, J = 8.1Hz), 7.11 (dd, 1H, J = 10.8, 17.1Hz), 5.47 (dd, 1H, J = 0.9 , 17.1 Hz), 5.11 (dd, 1H, J = 0.9, 10.8Hz), 4.06 (t, 1H, J = 6.0Hz), 3.55 (s, 2H), 2 , 18 (s, 3H), 2.18-2.15 (, 1H), 2.04 (m, 1H), 1.91-1.77 (m, 2H), 1.56-1.50 ( m, 1H), 1.34 (s, 3H), 1.22 (s, 3H), 0.42-0.29 (m, 3H), 0.28-0.21 (m, 1H).

Intermediate 66 Intermediate 73 SEM = CH2OCH2CH2SiMe3 Intermediate 76 Compound 24 Reaction Scheme 13 4, 4-Dimethyl-8- (2-trimethylsilanyl-ethoxymethoxy) -6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 72) A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 1.67 g, 5.8 mmol) in anhydrous benzene was treated with triethylamine (1.41 g, 11.6 mmol) and a catalytic amount of 4- (dimethylamino) pyridine followed by 2- (trimethylsilyl) ethoxymethyl chloride (1.93 g, 11.6 mmol) and the reaction mixture The resultant was refluxed for 3 days. This was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate 2-6% in hexane as eluent to provide the title product as a yellow oil (1.58 g, 66%). H NMR (300 MHz, CDCl 3): d 7.16 (d, 1H, J = 1.2 Hz), 7.12 (d, 1 H, J = 1.2 Hz), 5.28 (s, 2 H), 3 , 81 (m, 2H), 2.68 (t, 2H, J = 6.9Hz), 1.94 (t, 2H, J = 6.9Hz), 1.34 (s, 6H), 0.96 (m, 2H), 0.27 (s, 9H), 0.00 (s, 9H). 6-Ethinyl-4,4-dimethyl-8- (2-trimethylsilanyl-ethoxymethoxy) -3,4-dihydro-2H-naphthalene-1-one (Intermediate 73) A solution of 4,4-dimethyl-8- (2-trimethylsilanyl-ethoxymethoxy) -6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 72, 1.58 g, 3.79 mmol) in methanol (20 ml) was treated with potassium carbonate (0.43 g, 3.11 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (1.28 g, 98%). NMR H1 (300 MHz, CDC13): d 7.19 (d, 1H, "7 = 1.2Hz), 7.15 (d, 1H, J = 1.2Hz), 5.26 (s, 2H), 3.79 (m, 2H), 3.19 (s, 1H), 2.67 (t, 2H, J = 6.6Hz), 1.94 (t, 2H, J = 6.6Hz), 1, 33 (s, 6H), 0.95 (m, 2H), -0.016 (s, 9H).

Methyl ester of (4- [8,8-dimethyl-5-oxo-4- (2-trimethylsilanyl-ethoxymethoxy) -5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} - acetic (Intermediate 74) Following General Procedure B and using 6-ethynyl-4, -dimethyl-8- (2-trimethylsilanyl-ethoxymethoxy) -3,4-dihydro-2H-naphthalen-1-one (Intermediate 73, 1.28 g, 3, 7 mmoles), 4-iodophenylacetic acid methyl ester (1.02 g, 3.7 mmol), triethylamine (30 ml), copper (I) iodide (0.095 g, 0.5 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.35 g, 0.5 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as eluent, the title compound was obtained in the form of a yellow oil (1.61 g, 88%). NMR H1 (300 MHz, CDC13): d 7.51 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, J = 8.1 Hz), 7.24 (d, 1H, J = 1.5Hz), 7.19 (d, 1H, J = 1.5Hz), 5.31 (s, 2H), 3.82 (m, 2H), 3.70 (s, 3H), 3.65 (s, 2H), 2.69 (t, 2H, J = 6.6Hz), 1.96 (t, 2H, J "= 6.6Hz), 1.37 (s, 6H), 0.97 ( m, 2H), 0.00 (s, 9H).

Methyl ester of (4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -5,6,7,8-tetrahydro-naphthalene-2-ethynyl] -phenyl.}. -acetic (Intermediate 75) A solution of acid methyl ester. { 4- [8, 8-dimethyl-5-oxo-4- (2-trimethylsilanyl-ethoxymethoxy) -5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 74, 0.905 g, 1.84 mmol) in dichloromethane (8 ml) and acetonitrile (4 ml) was treated with cyclopropylamine (4 ml, 57.8 mmol). After 5 minutes, acetic acid (4 ml) was added followed by sodium cyanoborohydride (0.46 g, 7.32 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with water and a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (x2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. The oil dissolved in acetone (15 ml) and treated with potassium carbonate (0.745 g, 5.4 mmol) followed by methyl iodide (1.2 ml, 19 mmol) and the resulting reaction mixture was stirred overnight at room temperature. The precipitated solids were separated by filtration, the filtrate was evaporated in vacuo to a residue. Flash column chromatography on silica gel (230-400 mesh) using 2-20% ethyl acetate in hexane as eluent afforded the title compound (0.6 g, 63%). NMR H1 (300 MHz, CDCl3): d 7.49 (d, 2H, J = 8.4Hz), 7.23 (d, 2H, J = 8.4Hz), 7.18 (d, 1H, J = 1.5Hz), 7.06 (d, 1H, J = 1.5Hz), 5.21 (s, 2H), 4.03 (m, 1H), 3.76 (m, 2H), 3.68 (s, 3H), 3.62 (s, 2H), 2.30 (s, 3H), 2.04-1.40 (m, 5H), 1.33 (s, 3H), 1.18 ( s, 3H), 0.97 (m, 2H), 0.26-0.01 (m, 4H), 0.00 (s, 9H).

Methyl ester of 4- [5- (cyclopropyl-methyl-amino) -4-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acetic (Intermediate 76) A solution of acid methyl ester. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -5,6,7,8-tetrahydro-naphthalene-2-ylethynyl] -phenyl ester} -acetic (Intermediate 75, 0.37 g, 0.73 mmol) in tetrahydrofuran (12 ml) was treated with 2% sulfuric acid in methanol (14 ml) and the resulting reaction mixture was stirred at room temperature during the night. It was neutralized with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which after flash column chromatography on silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as The eluent afforded the title product as a white solid (0.295 g, 87%). H1 NMR (300 MHz, CDC13): d 12.26 (s, 1H), 7.45 (d, 2H, J = 8.4Hz), 7.22 (d, 2H, J = 8.4Hz), 6 , 96 (d, 1H, J = 1.5Hz), 6.69 (d, 1H, J = 1.5Hz), 4.31 (m, 1H), 3.67 (s, 3H), 3.61 (s, 2H), 2.23 (s, 3H), 2.23-2.17 (m, 1H), 2.05-1.97 (m, 2H), 1.71-1.65 (m , 2H), 1.28 (s, 3H), 1.24 (s, 3H), 0.80-0.45 (m, 4H).

Methyl ester of 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl) -acetic acid ester (Intermediate 77) A stirred, cooled (0 ° C) solution of 4- [5- (cyclopropyl-methyl-amino) -4-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene- methyl ester 2-iletinyl] -phenyl} -acetic (Intermediate 76, 0.15 g, 0.275 mmol) in anhydrous dichloromethane was treated with 4- (dimethylamino) pyridine (0.067 g, 0.55 mmol) followed by N-phenyltrifluoromethanesulfonimide (0.147 g, 0.413 mmol). After stirring at room temperature overnight, the reaction mixture was subjected to column chromatography on silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent to give the title compound (0.14 g, 93%). H NMR (300 MHz, CDCl 3): d 7.51 (d, 2H, J = 8.4Hz), 7.30-7.26 (m, 3H), 7.17 (d, 1H, J = 1, 5Hz), 4.04 (m, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 2.37 (s, 3H), 2.25-2.17 (m, 1H) ), 2.09-1.74 (m, 3H), 1.59-1.52 (m, 1H), 1.40 (s, 3H), 1.23 (s, 3H), 0.28- 0.10 (m, 3H), 0.09-0.005 (m, 1H).

Ethyl ester of 8- (cyclopropyl-methyl-amino) -3- (4-methoxycarbonylmethyl-phenylethynyl) -5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (Intermediate 78) Following the General Procedure? and using 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acetic (Intermediate 77, 0.14 g, 0.26 mmol), palladium acetate (0.013 g, 0.06 mmol), 1,3-bis (diphenylphosphino) propane (0.025 g, 0.061 mmol), N, N dimethylformamide (4 ml), ethanol (1.5 ml) and triethylamine (1.5 ml) followed by flash column chromatography on silica gel (230-400 mesh) using 7-10% ethyl acetate in hexane as eluent, the title compound was obtained (0.09 g, 75%). H NMR (300 MHz, CDCl 3): d 7.49 (d, 1 H, J = 1.8 Hz), 7.47 (d, 2 H, J = 8.1 Hz), 7.30 (d, 1 H, J = 1.8Hz), 7.25 (d, 2H, J = 8.1Hz), 4.33 (m, 1H), 4.28-4.13 (m, 2H), 3.70 (s, 3H) , 3.63 (s, 2H), 2.06-1.93 (2m, 6H), 1.72-1.66 (m, 2H), 1.36 (t, 3H, «7 = 7.2Hz ), 1.31 (s, 3H), 1.29 (s, 3H), 0.60-0.40 (m, 1H), 0.40-0.25 (m, 2H), 0.15- 0.00 (m, 1H).

Ethyl 3- (4-carboxymethyl-phenylethynyl) -8- (cyclopropyl-methyl-amino) -5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid ester (Compound 24) A solution of 8- (cyclopropyl-methyl-amino) -3- (4-methoxycarbonylmethyl-phenylethynyl) -5,5-dimethyl-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 78, 0.09 g, 0.19 mmol) in ethanol (2 ml), tetrahydrofuran (3 ml) and water (1.5 ml) was treated with lithium hydroxide (0.11 g, 2.62 mmol) and The resulting reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the product of the tittle in the form of a white solid (0.085 g, 94%). NMR H1 (300 MHz, CDCl3): d 7.49 (d, 1H, J = 1.8Hz), 7.46 (d, 2H, "7 = 8.1Hz), 7.30 (d, 1H, J = 1.8Hz), 7.22 (d, 2H, J = 8.1Hz), 4.32 (, 1H), 4.30-4.10 (m, 2H), 3.58 (s, 2H) , 2.06-1.93 (2m, 6H), 1.72-1.65 (m, 2H), 1.35 (t, 3H, J = 7.0Hz), 1.34 (s, 3H) , 1.29 (s, 3H), 0.60-0.40 (m, 1H), 0.40-0.25 (m, 2H), 0.15-0.00 (m, 1H).

I, Int Intermediate 79 I and Diagram of Reaction 14 2 - . 2-Bromo-5 - (cyclopropyl-methyl-amino) -8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphne (Intermediate 79) A solution of 6-bromo-8-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 64, 1.08 g, 3.81 mmol) in dichloromethane (8 ml) and acetonitrile (4 ml) was treated with cyclopropylamine (5 ml, 72.3 mmol). After 5 minutes, acetic acid (5 ml) was added followed by sodium cyanoborohydride (0.96 g, 15.26 mmol). The reaction mixture was stirred for 2 days at room temperature. It was then diluted with water and a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. The oil was dissolved in acetone (20 ml) and treated with potassium carbonate (1.58 g, 11.43 mmol) followed by methyl iodide (2.1 ml, 33 mmol) and the resulting reaction mixture was stirred overnight at room temperature. Diethyl ether was added and the precipitated solids were removed by filtration, the filtrate was evaporated in vacuo to a residue. Flash column chromatography on silica gel (230-400 mesh) using 2.5-10% ethyl acetate in hexane as eluent afforded the title compound (1.08 g, 84%). NMR H1 (300 MHz, CDC13): d 7.08 (d, 1H, J = 1.8Hz), 6.78 (d, 1H, J = 1.8Hz), 3.97 (m, 1H), 3 , 79 (s, 3H), 2.30 (s, 3H), 2.04-1.82 (m, 3H), 1.65-1.27 (m, 2H), 1.30 (s, 3H), 1.16 (s, 3H), 0.30-0.22 (m, 2H), 0.07-0.00 (m, 2H).

- (Cyclopropyl-methyl-amino) -8,8-dimethyl-4-methoxy-2-trimethylsilanylethynyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 80) Following General Procedure D and using 2-bromo-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 79, 1.08 g , 3.2 mmol), triethylamine (5 ml), copper iodide (I) (0.061 g, 0.32 mmol), tri-ethylsilylacetylene (3 ml, 21.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) ( 0.225 g, 0.32 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using hexane-10% ethyl acetate in hexane as eluent, the title compound was obtained (0.87 g, 80%).

H1 NMR (300 MHz, CDC13): d 7.09 (d, 1H, J = 1.5Hz), 6.73 (d, 1H, J = 1.5Hz), 3.99 (m, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.02-1.80 (m, 3H), 1.65-1.26 (2m, 2H), 1.31 (s, 3H), 1.16 (s, 3H), 0.26 (s, 9H), 0.26-0.00 (m, 2H), 0.00- -0.01 (, 2H).

- (Cyclopropyl-methyl-amino) -2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81) A solution of 5- (cyclopropyl-methyl-amino) -8,8-dimethyl-4-methoxy-2-trimethylsilanylethynyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 80, 0.87 g, 2.45 mmoles) in methanol (20 ml) was treated with potassium carbonate (0.4 g, 2.89 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (0.635 g, 92%). H1 NMR (300 MHz, CDC13): d 7.16 (d, 1H, J = 1.4Hz), 6.79 (d, 1H, J = 1.4Hz), 4.04 (, 1H), 3, 82 (s, 3H), 2.32 (s, 3H), 2.03-1.95 (m, 2H), 1.90-1.80 (m, 1H), 1.70-1.55 (s, m, 1H), 1.45-1.35 (m, 1H), 1.34 (s, 3H), 1.19 (s, 3H), 0.40-0.20 (m, 2H), 0 , 07-0.00 (m, 2H).

Methyl ester of (4- [5- (Cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} - acetic (Intermediate 82) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethynyl-8, 8-dimethyl-4-methoxy-5, 6, 7, 8-tetrahydro-naphthalene (Intermediate 81, 0.065 g, , 23 mmoles), methyl 4-iodophenylacetate (0.063 g, 0.23 mmol), triethylamine (8 ml), copper (I) iodide (0.018 g, 0.093 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.065) g, 0.093 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as eluent, the title compound was obtained as a yellow solid ( 0.09 g, 90%). H1 NMR (300 MHz, CDC13): 7.50 (d, J = 8.2 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.17 (d, J "= 1, 2Hz, 1H), 6.81 (d, J = 1, 2Hz, 1H), 4.04 (s broad, 1H), 3.82 (s, 3H), 3.70 (s, 3H), 3, 64 (s, 2H), 2.32 (s, 3H), 2.05-1.94 (m, 2H), 1.90-1.80 (m 1H), 1.70-1.58 (m , 1H), 1.45-1.35 (m, 1H), 1.38 (s, 3H), 1.20 (s, 3H), 0.38-0.20 (m, 2H), 0, 18-0.02 (m, 2H).

Acid { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Compound 25) A solution of acid methyl ester. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acetic (Intermediate 82, 0.090 g, 0.208 mmol) in methanol (3 ml) and tetrahydrofuran (2 ml) was treated with a 1.9 M lithium hydroxide solution (1.5 ml, 2.8 mmol) and the The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using methanol at room temperature. -10% in ethyl acetate as eluent to give the title product as a white amorphous solid (0.062 g, 60%). H1 NMR (300 MHz, CDC13): 7.46 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.18 (d, J = 1, 2 Hz) , 1H), 6.81 (d, "7 = 1, 2Hz, 1H), 4.27 (s, 2H), 3.81 (s, 3H), 3.58 (s, 2H), 2, 42 (s, 3H), 2.28-2.18 (m, 1H), 2.15-1.88 (m 2H), 1.75-1.65 (m, 1H), 1.45-1 , 38 (m, 1H), 1.32 (s, 3H), 1.17 (s, 3H), 0.75-0.65 (m, 1H), 0.55-0.42 (m, 2H) ), 0.25-0.15 (m, 1H).

Methyl ester of acid. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl] -2-fluoro-phenyl} -acetic (Intermediate 83) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, , 3 mmoles), methyl 2-fluoro-4-iodophenylacetate (0.088 g, 0.3 mmol), triethylamine (8 ml), copper iodide (I) (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate 5-20% in hexane as eluent, the title compound was obtained as a yellow solid (0.12 g, 89%). NMR H1 (300 MHz, CDCl3): 7.36-7.17 (m, 4H), 6.81 (d, J = 1, 2Hz, 1H), 4.12 (broad s, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 3.69 (s, 2H), 2.33 (s, 3H), 2.08-1.98 (m 2H), 1.98-1 , 88 (m, 1H), 1.75-1.60 (m, 1H), 1.45-1.35 (m, 1H), 1.35 (s, 3H), 1.19 (s, 3H) ), 0.35-0.25 (m, 2H), 0.15-0.05 (m, 1H).

Acid { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl] -2-fluoro-phenyl} -acetic (Compound 26) A solution of acid methyl ester. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl] -2-fluoro-phenyl} -acetic (Intermediate 83, 0.12 g, 0.27 mmol) in methanol (4 ml) and tetrahydrofuran (4 ml) was treated with a 2 M solution of lithium hydroxide (2 ml, 4 mmol) and the mixture of The resulting reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using methanol at room temperature. -8% in ethyl acetate as eluent to give the title product as a white amorphous solid (0.041 g, 35%). H1 NMR (300 MHz, CDC13): 7.35-7.15 (m, 4H), 6.81 (d, "7 = 1.2Hz, 1H), 4.31 (broad s, 1H), 3, 82 (s, 3H), 3.64 (s, 2H), 2.46 (s, 3H), 2.32-2.22 (m, 1H), 2.18-1.88 (m 2H), 1.78-1.65 (m, 1H), 1.50-1.40 (m, 1H), 1.32 (s, 3H), 1.17 (s, 3H), 0.80-0, 70 (m, 1H), 0.58-0.40 (m, 2H), 0.28-0.18 (m, 1H).

Methyl ester of acid 2-. { 4- [5- (Cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl) -propionic acid (Intermediate 84) Following the General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.30 mmoles), methyl 2- (4-iodophenyl) propionate (Reagent 1, 0.087 g, 0.3 mmol), triethylamine (8 ml), copper iodide (I) (0.019 g, 0.1 mmol) and dichlorobis ( triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as eluent, the compound of the title in the form of a yellow solid (0.115 g, 86%). H1 NMR (300 MHz, CDC13): d 7.50 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, "J = 8.1 Hz), 7.16 (d, 1H," 7 = 1.2Hz), 6.81 (d, 1H, J = 1.2Hz), 4.04 (m, 1H), 3.83 (s, 3H), 3.74 (c, 1H, J = 6.9Hz), 3.67 (s, 3H), 2.31 (s, 3H), 2.03-1.98 (m, 2H), 1.89-1.83 (, 1H), 1, 68-1.59 (m, 1H), 1.51 (d, 3H, J = 6.9Hz), 1.42-1.27 (m, 1H), 1.35 (s, 3H), 1, 20 (s, 3H), 0.31-0.23 (m, 2H), 0.07-0.008 (m, 2H).

Acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -propionic (Compound 27) A solution of 2- methyl acid ester. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -propionic (Intermediate 84, 0.115 g, 0.26 mmol) in methanol (3 ml) and tetrahydrofuran (2 ml) was treated with a 3 M solution of potassium hydroxide (1 ml)., 3 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using methanol at room temperature. % in ethyl acetate as eluent to give the title product as a yellow solid (0.062 g, 56%). H1 NMR (300 MHz, CDC13): d 7.50 (d, 2H, "7 = 8.1Hz), 7.32 (d, 2H, "7 = 8.1Hz), 7.17 (s, 1H), 6.80 (s, 1H), 4.23 (m, 1H), 3.80 (s, 3H), 3.68 (c, 1H, "7 = 7.2Hz), 2.38 (s, 3H), 2.22-2.18 (m, 1H), 2.07 -1.87 (m, 2H), 1.70-1.57 (m, 1H), 1.47 (d, 3H, "7 = 7.2Hz), 1.38-1.27 (m, 1H), 1.31 (s, 3H), 1.16 (s, 3H), 0.65-0, 62 (m, 1H), 0.41-0.35 (m, 2H), 0.17-0.00 (m, 1H).

Methyl ester of acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -2-methyl-propionic (Intermediate 85) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.090 g, , 32 mmol), methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.097 g, 0.3 mmol), triethylamine (8 ml), copper (I) iodide (0.019 g, , 1 mmole) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as eluent, the title compound was obtained as a solid (0.09 g, 78%). H1 NMR (300 MHz, CDC13): d 7.50 (d, 2H, "7 = 8.1Hz), 7.31 (d, 2H," 7 = 8.1Hz), 7.16 (d, 1H, J = 1.2Hz), 6.80 (d, 1H, «7 = 1.2Hz), 4.03 (m, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 2.31 (s, 3H), 2.01-1.97 (m, 2H), 1.89-1.83 (, 1H), 1.68-1.59 (m, 1H), 1.59 (s, 6H), 1.42-1.27 (m, 1H), 1.34 (s, 3H), 1.20 (s, 3H), 0.31-0.22 (m, 2H), 0.07-0.00 (m, 2H).

Acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -2-methyl-propionic (Compound 28) A solution of 2- methyl acid ester. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} -2-methyl-propionic (Intermediate 85, 0.09 g, 0.196 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 3 M solution of potassium hydroxide (1.5 mL, 4.5 mmoles) and the resulting reaction mixture was stirred at room temperature for 3 days. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using methanol at room temperature. % in ethyl acetate as eluent to give the title product as a yellow solid (0.057 g, 65%). H1 NMR (300 MHz, CDC13): d 7.46 (d, 2H, "7 = 8.4Hz), 7.37 (d, 2H," 7 = 8.4Hz), 7.18 (d, 1H, «7 = 1.2Hz), 6.81 (d, 1H,« 7 = 1.2Hz), 4.22 (m, 1H), 3.83 (s, 3H), 2.38 (s, 3H) , 2.19-1.90 (m, 3H), 1.71-1.56 (m, 1H), 1.56 (s, 6H), 1.45-1.33 (m, 1H), 1 , 33 (s, 3H), 1.17 (s, 3H), 0.70-0.50 (m, 1H), 0.38-0.25 (m, 2H), 0.16-0.00 (m, 1H).

Intermediate 81 Reagent 4 R, = H R¡ > = Me ",. p _ -u -, P ^, P ^ Compound 5 - hl Reagent 7 R5 = Me R8 = Et _ ^ v _ Mp, 0 d Compound K-5- e 2. KOH Reaction Scheme 15 Methyl ester of (E) -3- acid. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acrylic (Intermediate 86) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.095 g, 0.336 mmoles), methyl 4-iodocinnamate (Reagent 4, 0.097 g, 0.336 mmol), triethylamine (8 ml), copper (I) iodide (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) ( 0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as eluent, the title compound was obtained in the form of a solid white (0.12 g, 80%). H NMR (300 MHz, CDCl 3): d 7.68 (d, 1H, J = 15.9Hz), 7.53 (cAb, 4H, J = 8.4Hz), 7.19 (s, 1H), 6 , 83 (s, 1H), 7.46 (d, 1H, "7 = 15.9Hz), 4.04 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H) , 2.32 (s, 3H), 2.04-1.97 (m, 2H), 1.90-1.83 (m, 1H), 1.68-1.60 (m, 1H), 1 , 43-1.27 (m, 1H), 1.36 (s, 3H), 1.21 (s, 3H), 0.32-0.23 (m, 2H), 0.08-0.00 (m, 2H).

Acid (E) -3-. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} Acrylic acid (Compound 29) A solution of methyl ester of (E) -3- acid. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} Acrylic (Intermediate 86, 0.12 g, 0.27 mmol) in methanol (4 ml) and tetrahydrofuran (3 ml) was treated with a 3 M solution of potassium hydroxide (1 ml, 3 mmol) and the mixture of The resulting reaction was stirred at room temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using methanol at room temperature. % in ethyl acetate as eluent to give the title product as a white solid (0.041 g, 35%). NMR H1 (300 MHz, CDC13): d 7.58 (d, 1H, "7 = 16.2Hz), 7.44 (cAb, 4H), 7.13 (s, 1H), 6.77 (s, 1H), 7.45 (d, 1H, J = 16.2Hz), 4.05 (m, 1H), 3.79 (s, 3H), 2.42 (s, 3H), 2.19-1 , 97 (m, 2H), 1.67-1.45 (m, 1H), 1.45-1.37 (m, 1H), 1.37-1.20 (m, 1H), 1.30 (s, 3H), 1.12 (s, 3H), 0.80-0.60 (m, 1H), 0.50-0.30 (m, 2H), 0.20-0.00 (m , 1 HOUR) .

Ethyl ester of (E) -3- acid. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -cyclohexa-2,4-dienyl} -2-methyl-acrylic (Intermediate 87) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81 0.08 g, 0.28 mmol), ethyl ester of (E) -3- (4-iodo-phenyl) -2-methyl-acrylic acid (Reagent 7, 0.09 g, 0.28 mmol), triethylamine (8 ml), copper (I) iodide (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) ) using 5-10% ethyl acetate in hexane as eluent, the title compound was obtained as a white solid (0.12 g, 90%). NMR H1 (300 MHz, CDC13): d 7.67 (d, 1H, "7 = 1.2Hz), 7.57 (d, 2H," 7 = 8.4Hz), 7.40 (d, 2H, «7 = 8.4Hz), 7.19 (d, 1H,« 7 = 1.5Hz), 6.83 (d, 1H, «7 = 1.5Hz), 4.28 (c, 2H,« 7 = 7.2Hz), 4.04 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H), 2.15 (d, 3H, "7 = 1.2Hz), 2 , 03-1.83 (m, 3H), 1.68-1.50 (m, 1H), 1.45-1.20 (m, 1H), 1.36 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz), 1.20 (s, 3H), 0.32-0.23 (m, 2H), 0.08-0.00 (m, 2H).

Acid (E) -3-. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -cyclohexa-2,4-dienyl} -2-methyl-acrylic (Compound 30) A solution of methyl ester of (E) -3- acid. { 4- [5- (cyclopropyl-methyl-amino) -4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl] -cyclohexa-2,4-dienyl} -2-methyl-acrylic acid (Intermediate 87, 0.12 g, 0.25 mmol) in methanol (3 ml) and tetrahydrofuran (2 ml) was treated with a 3 M potassium hydroxide (1 ml, 3 mmol) solution and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was recrystallized from hot acetonitrile to give the title product as a white solid ( 0.055 g, 49%). H1 NMR (300 MHz, CDC13): d 7.78 (d, 1H, "7 = 1.2Hz), 7.57 (d, 2H," 7 = 8.1Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.29 (d, 1H, «7 = 1.5Hz), 6.93 (d, 1H,« 7 = 1.5Hz), 4.93 and 4.70 (2m, 1H ), 3.97 (s, 3H), 2.54 (s, 3H), 2.40-1.60 (m, 4H), 2.16 (d, 3H, "7 = 1.2Hz), 1 , 46-1.23 (m, 1H), 1.46 (s, 3H), 1.23 (s, 3H), 0.90-0.20 (m, 4H). 2. HPLC Intermediate Intermediate 90 Intermediate 91 Reagent 4 Compound 31 2. NaOHTLiOH / KOH 2. NaOH / LiOH / KOH Reagent 5 Compound 32 2. NaOH / LiOH / KOH Reaction Scheme 16 Cyclopropyl- (3-iodo-benzyl) -amine (Intermediate 88) A solution of 3-iodobenzyl bromide (Aldrich, 3.2 g, 10.77 mmol) in ethanol (20 ml) was treated with cyclopropylamine (7 ml, 101.5 mmol) and the resulting reaction mixture was stirred at 3 days long at room temperature. The volatiles were evaporated in vacuo, the residue was diluted with ethyl acetate and washed with an aqueous solution of saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo until an oil that was subjected to column chromatography on silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as eluent afforded the title product (2.4 g, 81%). H1 NMR (300 MHz, CDC13): d 7.67 (s, 1H), 7.58 (d, 1H, "7 = 9.0Hz), 7.27 (d, 1H," 7 = 6.0Hz) , 7.05 (dd, 1H, "7 = 6.0, 9.0Hz), 3.78 (s, 2H), 2.13 (m, 1H), 1.76 (s broad, 1H), 0 50-0.35 (m, 4H).

Cyclopropyl- (3-iodo-benzyl) -methyl-amine (Intermediate 89) A solution of cyclopropyl- (3-iodo-benzyl) -amine (Intermediate 88, 4.1 g, 15 mmol) in acetone (20 ml) was treated with potassium carbonate (2.07 g, 15 mmol) and sodium iodide. methyl (1.4 ml, 22.5 mmol) and the resulting reaction mixture was stirred at room temperature for Ih. Diethyl ether was added, the solids were removed by filtration and the filtrate was evaporated to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent to provide the title compound (3.3 g, 77%). NMR H1 (300 MHz, CDCl3): d 7.62 (d, 1H, J = 1.5Hz), 7.55 (dd, 1H, "7 = 1.5, 7.8Hz), 7.21 (dd) , 1H, J "= 1.5, 7.8Hz), 7.01 (t, 1H," 7 = 7.8Hz), 3.61 (s, 2H), 2.22 (s, 3H), 1 69 (m, 1H), 0.50-0.38 (m, 4H) Cyclopropylmethyl- (3-trimethylsilanylethynyl-benzyl) -amine (Intermediate 90) Following General Procedure D and using cyclopropyl- (3-iodo-benzyl) -methyl-amine (Intermediate 89, 0.97 g, 3.4 mmol), triethylamine (10 ml), copper iodide (I) (0.051 g) , 0.27 mmol), trimethylsilylacetylene (2 ml, 14 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.19 g, 0.27 mmol) followed by flash column chromatography on silica gel (230-400 mesh). ) using hexane-5% ethyl acetate in hexane as eluent, the title compound was obtained (0.695 g, 80%). H NMR (300 MHz, CDCl 3): d 7.37-7.31 (m, 2H), 7.25-7.20 (m, 2H), 3.61 (s, 2H), 2.22 (s) , 3H), 1.69 (m, 1H), 0.50-0.32 (m, 4H), 0.25 (s, 9H).

Cyclopropyl- (3-ethynyl-benzyl) -methyl-amine (Intermediate 91) A solution of cyclopropylmethyl- (3-trimethylsilanylethynyl-benzyl) -amine (Intermediate 90, 0.355 g, 1.38 mmol) in methanol (10 ml) was treated with potassium carbonate (0.13 g, 0.95 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (0.22 g, 86%). NMR H1 (300 MHz, CDC13): d 7.41-7.35 (m, 2H), 7.26-7.23 (m, 2H), 3.63 (s, 2H), 3.05 (s) , 1H), 2.23 (s, 3H), 1.70 (m, 1H), 0.48-0.40 (m, 4H).

Methyl ester of (E) -3- (4-. {3, 3- [(cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -acrylic acid (Intermediate 92) Following General Procedure B and using cyclopropyl- (3-ethynyl-benzyl) -methyl-amine (Intermediate 91, 0.060 g, 0.32 mmol), methyl 4-iodo-cinnamate (Reagent 4, 0.093 g, 0.32 mmoles), triethylamine (8 ml), copper (I) iodide (0.015 g, 0.08 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.056 g, 0.08 mmol) followed by flash column chromatography on gel of silica (230-400 mesh) using 5-15% ethyl acetate in hexane as eluent, the title compound was obtained (0.11 g, 100%). NMR H1 (300 MHz, CDC13): d 7.66 (d, 2H, < 7 = 16.2Hz), 7.54-7.39 (m, 2H), 7.31-7.25 (m, 2H), 6.43 (d, 2H, "7 = 16.2Hz), 3.80 (s, 3H), 3.65 (s, 2H), 2.25 (s, 3H), 1.72 ( m, 1H), 0.49-0.42 (m, 4H).

Acid (E) -3- (4- { 3- [(cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -acrylic (Compound 31) A solution of (E) -3- (4- {3 - [(cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -acrylic acid methyl ester (Intermediate 92, 0.11 g , 0.32 mmol) in methanol (3 ml) and tetrahydrofuran (2 ml) was treated with a 3M solution of potassium hydroxide (1 ml, 3 mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. days. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using 10% methanol. % in ethyl acetate as eluent to give the title product as a yellow solid (0.038 g, 36%). H1 NMR (300 MHz, CD30D): d 7.61-7.38 (m, 9H), 6.53 (d, 1H, J = 15.9Hz), 3.93 (s, 2H), 2.48. (s, 3H), 2.09 (m, 1H), 0.64-0.61 (m, 4H).

Ethyl 3- (4-. {3- [3- (cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -but-2-enoic acid ester (Intermediate 93) Following General Procedure B and using cyclopropyl- (3-ethynyl-benzyl) -methyl-amine (Intermediate 91, 0.12 g, 0.64 mmol), 3- (4-iodo-phenyl) -butyl ethyl ester -2Z-enoic (Reagent 5, 0.2 g, 0.64 mmol), triethylamine (8 ml), copper (I) iodide (0.012 g, 0.063 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.045 g) , 0.064 mmol) followed by flash column chromatography on silica gel (230-400 mesh), gave the title compound (0.17 g, 70%). NMR H1 (300 MHz, CDC13): d 7.52-7.40 (m, 4H), 7.31-7.18 (m, 4H), 5.91 (s, 1H), 4.01 (c , "7 = 7, 1Hz, 2H), 3.66 (s, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 1.74-1.70 (m, 1H) , 1.10 (t, "7 = 7, 1Hz, 3H), 0.50-0.43 (m, 4H). 3- (4- (3- [(Cyclopropyl-methyl-amino) -methyl] -phenylethynyl] -phenyl) -but-2-enoic acid (Compound 32) A solution of 3- (4- (3- [(cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -but-2-enoic acid ethyl ester (Intermediate 93, 0.17 g, , 46 mmole) in ethanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 3.4 M solution of potassium hydroxide (1 ml, 3.4 mmole) and the resulting reaction mixture was stirred at room temperature for 36 h The reaction mixture was extracted with diethyl ether, and the aqueous phase was neutralized with 10% aqueous hydrochloric acid and evaporated to a solid The solid was subjected to flash column chromatography using ethyl acetate as eluent to give the title product as a white solid (0.05 g, 32%). H NMR (300 MHz, CDC13): d 7.49-7.43 (m, 4H), 7.32-7.20 (m, 4H), 5.93 (s, 1H), 3.70 (s, 2H), 2.29 (s, 3H), 2.17 ( s, 3H), 1.76-1.73 (m, 1H), 0.50-0.48 (m, 4H).

Ethyl 3- (4-. {3- [3- (cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -2-methyl-acrylic acid ester (Intermediate 94) Following General Procedure B and using cyclopropyl- (3-ethynyl-benzyl) -methyl-amine (Intermediate 91, 0.1 g, 0.54 mmol), ethyl ester of (E) -3- (4-iodo- phenyl) -2-methyl-acrylic (Reagent 7, 0.17 g, 0.54 mmol), triethylamine (10 ml), copper iodide (I) (0.019 g, 0.1 mmol) and dichlorobis- (triphenylphosphine) palladium (II) (0.071 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 2-10% ethyl acetate in hexane as eluent, the title compound was obtained (0.15 g). , 75%). H 1 NMR (300 MHz, CDCl 3): d 7.66-7.25 (m, 9H), 4.27 (c, J = 7.3 Hz, 2H), 3.65 (s, 2H), 2.25 (s, 3H), 2.13 (d, "7 = 1.2 Hz, 3H), 1.75-1.65 (m, 1H), 1.35 (t," 7 = 7, 3Hz, 3H ), 0.50-0.40 (m, 4H). 3- (4- { 3- [(Cyclopropyl-methyl-amino) -methyl] -phenylethynyl} -phenyl) -2-methyl-acrylic acid (Compound 33) A solution of 3- (4-. {3- [3- (cyclopropylmethyl-amino) -methyl] -phenylethynyl] -phenyl) -2-methyl-acrylic acid ethyl ester (Intermediate 94, 0.15 g, 0.4 mmol) in ethanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 3M solution of potassium hydroxide (1 ml, 3 mmol) and the resulting reaction mixture was stirred at room temperature. the room temperature during the night. The reaction mixture was concentrated, neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to a solid. The solid was subjected to flash column chromatography using 5% methanol in ethyl acetate as eluent to give the title product as an amorphous solid (0.115 g, 83%). NMR H1 (300 MHz, CDC13): 7.71-7.25 (, 9H), 3.81 (s, 2H), 2.44 (s, 3H), 2.13 (d, "7 = 1, 2 Hz, 3H), 1.92-1.80 (m, 1H), 0.76-0.66 (m, 2H), 0.58-0.48 (m, 2H). 1. NaH, THF; Mei, ref lux 2. BH3: Me2S, THF.refiujo Intermediate 95 -G I Reagent 3 2. KOH Reaction Scheme 17 3 - . 3-Bromo-N-cyclopropyl-4-methyl-benzamide (Intermediate 95) A stirred, cooled solution (ice bath) of 3-bromo-4-methyl-benzoic acid (Aldrich, 5 g, 23.25 mmol) in benzene (50 ml), dichloromethane (10 ml) and N, N-dimethylformamide (0.5 ml) was treated with oxalyl chloride (4 ml, 46.5 mmol). The reaction mixture was allowed to warm to room temperature over 3 h. The volatiles were then removed by vacuum distillation, the residue was diluted with anhydrous dichloromethane (50 ml) under argon, cooled (ice bath) and treated with 4- (dimethylamino) pyridine (5.67 g, 46, 5 mmoles) followed by cyclopropylamine (1.93 ml, 27.9 mmoles). After 3 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title product which was used as such for the next step (6.0 g, -100%). 3-Bromo-N-cyclopropyl-4, N-dimethyl-benzamide (Intermediate 96) A stirred, cooled solution (ice bath) of 3-bromo-N-cyclopropyl-4-methyl-benzamide (Intermediate 95.6 g, 23.25 mmol) in anhydrous tetrahydrofuran (100 mL) in argon was treated with small portions. of sodium hydride (1.6 g, 40 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to warm to room temperature and after Ih, methyl iodide (3.11 ml, 50 mmol) was added and the reaction mixture was refluxed for 5 h. It was cooled to room temperature, poured into cold water and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a dirty brown solid which was used as such for the next step (6.3 g, - 100%). (3-Bromo-4-methyl-benzyl) -cyclopropyl-methyl-amine (Intermediate 97) A solution of 3-bromo-N-cyclopropyl-4, N-dimethyl-benzamide (Intermediate 96, 5.3 g, 19.77 mmol) in anhydrous tetrahydrofuran (50 ml) was treated with borane-methyl sulfide complex ( 10 ml, 100 mmol) and the resulting reaction mixture was refluxed for 2 h. It was cooled to room temperature and carefully treated with a saturated solution of sodium carbonate, saturated until the effervescence ceased, and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent afforded the title product as an oil (3.2 g, 63%). NMR H1 (300 MHz, CDC13): d 7.47 (s, 1H), 7.17 (d, 1H, "7 = 7.8Hz), 7.12 (d, 1H," 7 = 7.8Hz) , 3.63 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H), 1.73 (m, 1H), 0.92-0.43 (m, 4H).

Cyclopropyl-methyl- (4-methyl-3-trimethylsilanylethynyl-benzyl) -amine (Intermediate 98) Following General Procedure D and using cyclopropyl- (3-bromo-4-methyl-benzyl) -methyl-amine (Intermediate 97, 2.24 g, 8.81 mmol), triethylamine (10 ml), tetrahydrofuran (5 ml) , copper iodide (I) (0.4 g, 2.1 mmol), trimethylsilylacetylene (5 ml, 35.4 mmol) and dichlorobis (triphenylphosphine) palladium (II) (1.45 g, 2.06 mmol) followed of flash column chromatography on silica gel (230-400 mesh) using 6-10% ethyl acetate in hexane as eluent, the title compound was obtained (2.25 g, 94%). NMR H1 (300 MHz, CDC13): d 7.08 (s, 1H), 6.84 (2s, 2H), 3.31 (s, 2H), 2.15 (s, 3H), 1.95 ( s, 3H), 1.41 (m, 1H), 0.25-0.00 (m, 4H), 0.00 (s, 9H).

Cyclopropyl- (3-ethynyl-4-methyl-benzyl) -methyl-amine (Intermediate 99) A solution of cyclopropylmethyl- (4-methyl-3-trimethylsilanylethynyl-benzyl) -amine (Intermediate 98, 0.95 g, 3.5 mmol) in methanol (10 ml) was treated with potassium carbonate (2)., 3 g, 16.6 mmol) and the resulting reaction mixture was stirred at room temperature for lh. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (0.67 g, 96%). H NMR (300 MHz, CDC13): d 7.12 (s, 1H), 6.87 (2s, 2H), 3.33 (S, 2H), 2.98 (s, 1H), 2.16 ( s, 3H), 1.96 (s, 3H), 1.42 (m, 1H), 0.24-0.00 (m, 4H).

Ethyl ester of (E) -3- (4- {5- [(Cyclopropyl-methyl-amino) -methyl] -2-methyl-phenylethynyl} -phenyl) -acrylic acid (Intermediate 100) Following General Procedure B and using cyclopropyl- (3-ethynyl-4-methyl-benzyl) -methyl-amine (Intermediate 99, 0.095 g, 0.48 mmol), ethyl 4-iodo-cinnamate (Reagent 3, 0.144 g , 0.47 mmol), triethylamine (13 ml), copper iodide (I) (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.071 g, 0.1 mmol) followed by Flash column on silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as eluent gave the title compound (0.14 g, 82%). H1 NMR (300 MHz, CDCl3): d 7.66 (d, 1H, "7 = 15.9Hz), 7.53 (cAb, 4H," 7 = 6.3Hz), 7.41 (s, 1H) , 7.15 (2s, 2H), 6.44 (d, 1H, "7 = 15.9Hz), 4.26 (c, 2H," 7 = 7.2Hz), 3.62 (s, 2H) 2.48 (s, 3H), 2.24 (s, 3H), 1.68 (m, 1H), 1.33 (t, 3H, "7 = 7.2Hz), 0.49-0, 41 (m, 4H).

Acid (E) -3- (4- { 5- [(Cyclopropyl-methyl-amino) -methyl] -2-methyl-phenylethynyl} -phenyl) -acrylic (Compound 34) A solution of (E) -3- (4-. {5- [(cyclopropyl-methyl-amino) -methyl] -2-methyl-phenylethynyl} -phenyl) -acrylic acid ethyl ester (Intermediate 100, 0.14 g, 0.37 mmol) in ethanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 3M solution of potassium hydroxide (1 ml, 3 mmol) and the resulting reaction mixture was stirred to the Room temperature during the night. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using methanol at room temperature. % in ethyl acetate as eluent to give the title product as an amorphous solid (0.071 g, 55%). NMR H1 (300 MHz, CDCl3): d 7.62 (d, 1H, "7 = 15.9Hz), 7.61 (s, 1H), 7.38 (s, 4H), 7.19 (s, 2H), 6.56 (d, 1H, "7 = 15.9Hz), 3.87 (s, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 1.94 ( m, 1H), 0.89-0.83 (m, 2H), 0.60-0.57 (m, 2H).

Intermediate 101 Intermediate 102 K2C03, MeOH Intermediate 103 2. NaOH Reaction Scheme 18 Trifluoromethanesulfonic acid 3-tert-butyl-phenyl ester (Intermediate 101) A stirred, cooled solution (ice bath) of 3-t-butylphenol (Aldrich, 2 g, 13.3 mmol) in anhydrous dichloromethane (15 ml) was treated with 2- [N, N'-bis (trifluoromethylsulfonyl) amino] ] -5-chloropyridine (7.8 g, 20 mmol) followed by 4- (dimethylamino) pyridine (3.2 g, 26.6 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 h. It was diluted with ethyl acetate, washed with 2 N hydrochloric acid, 2 N sodium hydroxide, and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent afforded the title product as a clear oil (3.06 g, 82%). NMR H1 (300 MHz, CDCl3): d 7.42-7.32 (m, 2H), 7.24 (d, 1H, "7 = 1.8Hz), 7.10-7.06 (m, 1H ), 1.33 (s, 9H). (3-t-Butyl-phenylethynyl) -trimethyl-silane (Intermediate 102) Following General Procedure D and using trifluoromethanesulfonic acid 3-tert-butyl-phenyl ester, (Intermediate 101, 2.54 g, 9.0 mmol), triethylamine (2 ml), copper (I) iodide (0.63) g, 3.33 mmol), trimethylsilylacetylene (5 ml, 36 mmol) and dichlorobis (triphenylphosphine) palladium (II) (1.6 g, 2.25 mmol) followed by flash column chromatography on silica gel (230 mesh). 400) using 10% ethyl acetate in hexane as eluent, the title compound was obtained as a brown oil which was used as such for the next step. 1-t-Butyl-3-ethynyl-benzene (Intermediate 103) A solution of 3-t-butyltrimethylsilanylethynylbenzene (Intermediate 102, 0.47 g, 2.04 mmol) in methanol (20 ml) was treated with potassium carbonate (2)., 8 g, 20.2 mmol) and the resulting reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent afforded the title compound as a light yellow oil (0.125 g, 39%).

NMR H1 (300 MHz, CDCl3): d 7.40 (d, 1H, J = 1.5Hz), 7.39-7.10 (m, 3H), 2.91 (s, 1H), 1.18 (s, 9H).

(E) -3- [4- (3-Butyl-phenylethynyl) -phenyl] -acrylic acid (Compound 35) A solution of (E) -3- [4- (3-t-butyl-phenylethynyl) -phenyl] -acrylic acid ethyl ester (Intermediate 103, 0.015 g, 0.047 mmol) in ethanol (2 ml) and tetrahydrofuran (2) ml) was treated with a 2M solution of lithium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 10% aqueous hydrochloric acid and evaporated in vacuo to a solid which was washed with water and hexane and dried to give the title product as a white solid (0.012 g, 85%). %). NMR H1 (300 MHz, CDC13): d 7.78 (d, 1H, J = 16.2Hz), 7.59-7.26 (m, 8H), 6.47 (d, 1H, "7 = 16.2Hz), 1.34 (s, 9H). 2. NaBH4, Intermediate MeOH 104 * "" 4 'Intermediate 106 2. MeOH, K2C03 Intermediate 107 Intermediate 108 Intermediate 110 2. Compound KOH 36 Reaction Scheme 19 4-t-Butyl-2-hydroxy-benzaldehyde (Intermediate 104) A stirred, cooled solution (ice bath) of 3-t-butylphenol (1.5 g, 10 mmol) in anhydrous dichloromethane was treated with titanium tetrachloride (1.86 ml, 17 mmol) followed by dichloromethyl ether (0, 9 ml, 20 mmol). The reaction was allowed to warm to room temperature over 1 h, quenched carefully with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography using 2-2.5% ethyl acetate in hexane as eluent to provide the title compound (1.37 g, 77%). RM1 H1 (300 MHz, CDC13): d 11.02 (s, 1H), 9.81 (s, 1H), 7.45 (d, J = 8.2Hz, 1H), 7.03 (dd, "7 = 8.2, 1.7Hz, 1H), 6.99 (d," 7 = 1.7 Hz, 1H), 1.31 ( s, 9H).

Trifluoromethanesulfonic acid 5-t-butyl-2-formyl-phenyl ester (Intermediate 105) A stirred, cooled solution (ice bath) of 4-t-butyl-2-hydroxy-benzaldehyde (Intermediate 104, 0.75 g, 4.21 mmol) in anhydrous dichloromethane (10 ml) was treated with triethylamine (1.76 ml, 12.64 mmol) followed by 2 - [N, N-bis (trifluoromethylsulfonyl) amino] pyridine (1.81 g, 4.62 mmol). The reaction mixture was allowed to warm to room temperature overnight. The volatiles were evaporated and the residue was subjected to flash column chromatography using 2-2. 5% ethyl acetate in hexane as eluent to provide the title compound (0.16 g) and a 1: 1 mixture of product and starting material (0.47 g). The title compound was used as such for the next step. -t-Butyl-2-hydroxymethyl-phenol (Intermediate 106) A stirred, cooled solution (ice bath) of a 1: 1 mixture of 5-t-butyl-2-formyl-phenyl ester of trifluoromethanesulfonic acid and 4-t-butyl-2-hydroxy-benzaldehyde (Intermediate 105, 0, 47 g) in methanol (8 ml) was treated with sodium borohydride (0.1 g, 2.64 mmol). After Ih, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash chromatography on silica gel (230-400 mesh) to provide the title product. (0.3 g). 1 H-NMR (300 MHz, CDC13): d 6.94-6.84 (m, 3H), 4.72 (s, 2H), 1.26 (s, 9H). -t-Butyl-2-methyl-phenol (Intermediate 107) A solution of 5-t-butyl-2-hydroxymethyl-phenol (Intermediate 106, 0.215 g, 1.19 mmol) in ethyl acetate was treated with 5% palladium on carbon (0.04 g) and the resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. , 5h. The reaction mixture was then filtered on a pad of celite and the filtrate was evaporated in vacuo to give the title compound as a white solid (0.19 g, 97%). NMR H1 (300 MHz, CDC13): d 7.03 (d, J = 7.9 Hz, 1H), 6.86 (dd, "7 = 7.9, l, 7Hz, 1H), 6.78 (d) , "7 = 1.7 Hz, 1H), 5.20 (s, 1H), 2.20 (s, 3H), 1.25 (s, 9H). -t-Butyl-2-methyl-phenyl ester of trifluoromethanesulfonic acid (Intermediate 108) A solution of 5-t-butyl-2-methyl-phenol (Intermediate 107, 0.19 g, 1.15 mmol) and 4- (dimethylamino) pyridine (0.28 g, 2.3 mmol) in anhydrous dichloromethane ( 8 ml) was treated with N-phenyltrifluoromethanesulfonimide (0.54 g, 1.5 mmol), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel (230-400 mesh) to give the title compound as a colorless oil (0.28 g, 82%). 1 H-NMR (300 MHz, CDC13): d 7.30-7.20 (m, 3H), 2.33 (s, 3H), 1.30 (s, 9H). (5-t-Butyl-2-methyl-phenylethynyl) -trimethyl-silane (Intermediate 109) Following General Procedure D and using 5-t-butyl-2-methyl-phenyl ester of trifluoro-methanesulfonic acid (Intermediate 108, 0.28 g, 0.94 mmol), triethylamine (3 ml), trimethylsilylacetylene (1 ml, 7 mmoles), N, N-dimethylformamide (6 ml) and dichlorobis (triphenylphosphine) palladium (II) (0.053 g, 0.076 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using hexane as eluent, the title compound was obtained (0.16 g, 69%). H1 NMR (300 MHz, CDC13): d 7.44 (d, "7 = 1.7Hz, 1H), 7.22 (dd," 7 = 8.2, 1, 7Hz, 1H), 7.10 ( d, "7 = 8, 2Hz, 1H), 2.39 (s, 3H), 1.28 (s, 9H), 0.26 (s, 9H). 4-t-Butyl-2-ethynyl-l-methyl-benzene (Intermediate 110) Following the general procedure F and using (5-t-butyl-2-methyl-phenylethynyl) -trimethyl-silane (Intermediate 109, 0.16 g, 0.66 mmol), methanol (5 ml) and potassium carbonate ( , 05 g, 0.36 mmol), the title compound was obtained (0.08 g, 67%). H1 NMR (300 MHz, CDC13): d 7.49 (d, "7 = 1.7Hz, 1H), 7.30 (dd," 7 = 8.2, 1.7Hz, 1H), 7.15 ( d, "7 = 8, 2Hz, 1H), 3.16 (s, 1H), 2.42 (s, 3H), 1.32 (s, 9H).

Ethyl 3- [4- (5-t-butyl-2-methyl-phenylethynyl) -phenyl] -acrylic acid ester (Intermediate 111) Following General Procedure B and using 4-t-butyl-2-ethynyl-1-methyl-benzene (Intermediate 110, 0.08 g, 0.47 mmol), ethyl 4-iodocinnamate (0.12 g, 0, 4 mmoles), triethylamine (8 ml), copper iodide (I) (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by column chromatography Flash on silica gel (230-400 mesh) using 2-4% ethyl acetate in hexane as eluent, the title compound was obtained (0.09 g, 55%). 1 H-NMR (300 MHz, CDCl 3): d 7.67 (d, "7 = 16, 1Hz, 1H), 7.56-7.48 (m, 5H), 7.28 (dd," 7 = 8, 2, 1.7Hz, 1H), 7.16 (d, «7 = 8, 2Hz, 1H), 6.44 (d,« 7 = 16, 1Hz, 1H), 4.27 (c, «7 = 7, 1Hz, 2H), 2.48 (s, 3H), 1.33 (t, "7 = 7, 1Hz, 3H), 1.32 (s, 9H). 3- [4- (5-t-Butyl-2-methyl-phenylethynyl) -phenyl] -acrylic acid (Compound 36) A solution of 3- [4- (5-t-butyl-2-methyl-phenylethynyl) -phenyl] -acrylic acid ethyl ester (Intermediate 111, 0.09 g, 0.26 mmol) in ethanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 3M solution of potassium hydroxide (1 ml, 3 mmol) and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo slightly, the residue was neutralized with dilute hydrochloric acid, and the solid that formed was filtered and washed with water and acetonitrile and dried to provide the title product (0.064 g, 77%) .

H1 NMR (300 MHz, CDC13): d 7.78 (d, "7 = 16, 1Hz, 1H), 7.58-7.53 (m, 5H), 7.29 (dd," 7 = 7, 9, 1.7Hz, 1H), 7.17 (d, «7 = 7, 9Hz, 1H), 6.47 (d,« 7 = 16, 1Hz, 1H), 2.48 (s, 3H), 1.32 (s, 9H).

Intermediate 112 Intermediate 113 , 2. NaOH Compound 37 Reaction Scheme 20 N- (3-Bromo-phenyl) -N-methyl-formamide (Intermediate 112) A solution of 3-bromo-N-methylaniline (prepared as described by Lopez et al in Tet. Lett., 1999, 40, 11, pp. 2071-2074 incorporated herein by reference; 7.4 g, 39.5 mmol) in formic acid (20 ml) was refluxed for 3 h. The reaction mixture was then cooled to room temperature, diluted with water and extracted with diethyl ether. The organic phase was washed with an aqueous solution of saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a dark brown oil. . (3-Bromo-phenyl) -cyclopropyl-methyl-amine (Intermediate 113) A stirred, cooled solution (0 ° C) of N- (3-bromophenyl) -N-methyl-formamide (Intermediate 112, 2.6 g, 9.7 mmol) and titanium tetra-iso-propoxide (3.9 ml, 10.67 mmol) in tetrahydrofuran (40 ml) was treated with a 3 M solution of ethylmagesium bromide in ether (8.08 ml, 24.25 mmol) in argon and the resulting reaction mixture was allowed to warm to the ambient temperature gradually and refluxed at 55 ° C overnight. It was then cooled in an ice bath, quenched with a saturated aqueous solution of ammonium chloride, filtered over celite and the aqueous phase extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide an oil. Flash column chromatography on silica gel (230-400 mesh) using 1.5% ethyl acetate in hexane as eluent afforded the title compound (0.321 g, 15%).

Cyclopropyl-methyl- (3-trimethylsilanylethynyl-phenyl) -amine (Intermediate 114) Following General Procedure D and using (3-bromo-phenyl) -cyclopropyl-methyl-amine (Intermediate 113, 0.056 g, 0.25 mmol), triethylamine (3 ml), copper iodide (I) (0.025 g, 0.13 mmol), trimethylsilylacetylene (2.5 ml, 17.6 mmol) and dichlorobiphenyl (triphenylphosphine) -palladium (II) (0.065 g, 0.09 mmol) followed by flash column chromatography on silica gel. silica (230-400 mesh) using 1.5% ethyl acetate in hexane as eluent, the title compound was obtained (0.051 g, 84%).

Cyclopropyl- (3-ethynyl-phenyl) -methyl-amine (Intermediate 115) A solution of cyclopropyl-methyl- (3-trimethylsilanylethynyl-phenyl) -amine (Intermediate 114, 0.05 g, 0.2 mmol) in methanol (5 ml) was treated with potassium carbonate (0.063 g, 0.46 mmol) ) and the resulting reaction mixture was heated at 80 ° C for 3 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (0.035 g, 100%).

Ethyl ester of (E) -3- (4- [3- (cyclopropyl-methyl-amino) -phenylethynyl} -acrylic acid (Intermediate 116) Following General Procedure B and using cyclopropyl- (3-ethynyl-phenyl) -methyl-amine (Intermediate 115, 0.035 g, 0.2 mmol), ethyl 4-iodo-cinnamate (0.082 g, 0.27 mmol), triethylamine (3 ml), copper iodide (I) (0.025 g, 0.13 mmol) and dichlorobis (triphenylphosphine) -palladium (II) (0.033 g, 0.047 mmol) followed by flash column chromatography on silica gel (230-400 mesh), and preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, gave the title compound (0.020 g, 29%).

(E) -3- (4- [3- (Cyclopropyl-methyl-amino) -phenylethynyl] -phenyl} -acrylic acid (Compound 37) A solution of ethyl ester of (E) -3- acid. { 4- [3- (cyclopropyl-methyl-amino) -phenylethynyl} -acrylic (Intermediate 116, 0.020 g, 0.057 mmol) in ethanol (1 ml) was treated with a 1 M solution of sodium hydroxide (1 ml, 1 mmol) and the resulting reaction mixture was heated at 80 ° C for minutes. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide a residue which in preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase gave the title product as a solid yellow (0.006 g, 33%).

Intermediate 118 Intermediate 120 Intermediate 122 R2 = H R5 = H R2 = F, R5 = H Reagent 1 R2 = H, R5 = Me Compound 38 R2 = H R5 = H Compound 39 R¡ = F, R5 = H Compound 40 R2 = H, R5 = Me Reaction Scheme 21 4-Bromo-2-methyl-benzoic acid isopropyl ester (Intermediate 117) A solution of 4-bromo-2-methyl-benzoic acid (Aldrich, 5.4 g, 25 mmol) in benzene (75 ml) and isopropanol (75 ml) was treated with concentrated sulfuric acid (1.5 ml) and heated to reflux for 4 days using a Dean water trap. -Stark. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a clear oil which was used as is. for the next stage (6.12 g, 95%).

Isopropyl ester of 4-bromo-2-bromomethyl-benzoic acid (Intermediate 118) A solution of 4-bromo-2-methyl-benzoic acid isopropyl ester (Intermediate 117, 6.12 g, 23.8 mmol) in carbon tetrachloride (120 ml) was treated with N-bromosuccinimide (4.6 g, 26.18 mmoles) and 2,2'-azobisisobutyronitrile (0.6 g) and the resulting reaction mixture was refluxed overnight. It was cooled to room temperature, the solids were separated by filtration and washed with hexane: diethyl ether 1: 1, and the filtrate and the washings were evaporated in vacuo to provide an oil (5.1 g, 64%) whIt was used as is for the next stage.

Isopropyl ester of 4-bromo-2-cyclopropylaminomethyl-benzoic acid (Intermediate 119) A stirred, cooled solution (ice bath) of 4-bromo-2-bromomethyl-benzoic acid isopropyl ester (Intermediate 118, 5.1 g, 15.17 mmol) in acetonitrile (25 ml) was treated with cyclopropylamine (2 ml). ml, 28.9 mmol). The reaction mixture was allowed to warm to room temperature. After 2 h, the volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 4-20% ethyl acetate in hexane as eluent afforded the title product (1.33 g, 28%). NMR H1 (300 MHz, CDCl3): d 7.73 (d, 1H, "7 = 8.4Hz), 7.56 (d, 1H," 7 = 2.1Hz), 7.41 (dd, 1H, "7 = 2.1, 8.4Hz), 5.21 (heptet, 1H, J = 6.3Hz), 4.00 (s, 2H), 2.39 (s broad, 1H), 2.06 ( , 1H), 1.35 (d, 6H, "7 = 6.3Hz), 0.42-0.34 (m, 4H).

Isopropyl ester of 4-bromo-2- [(cyclopropyl-methyl-amino) -methyl] -benzoic acid (Intermediate 120) A solution of 4-bromo-2-cyclopropylaminomethyl-benzoic acid isopropyl ester (Intermediate 119, 1.33 g, 4.26 mmol) in acetone (8 ml) was treated with potassium carbonate (2.36 g, 17%). 05 mmoles) and methyl iodide (0.53 ml, 8.52 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered over a short pad of silica gel (230-400 mesh) and evaporated in vacuo to give the title product (1.23 g, 70%). NMR H1 (300 MHz, CDCl3): d 7.64 (d, 1H, "7 = 2.1Hz), 7.58 (d, 1H, J = 8.4Hz), 7.39 (dd, 1H," 7 = 2.1, 8.4Hz), 5.20 (heptet, 1H, «7 = 6.0Hz), 3.97 (s, 2H), 2.22 (s, 3H), 1.77 (m , 1H), 1.35 (d, 6H, < 7 = 6.0Hz), 0.46-0.38 (m, 4H). 2- [(Cyclopropyl-methyl-amino-methyl) -methyl] -4-trimethylsilanylethynyl-benzoic acid isopropyl ester (Intermediate 121) Following General Procedure D and using isopropyl ester of 4-bromo-2- [(cyclopropyl-methyl-amino) -methyl] -benzoic acid (Intermediate 120, 1.23 g, 3.68 mmol), triethylamine (10 ml) , tetrahydrofuran (5 ml), copper (I) iodide (0.21 g, 1.1 mmol), trimethylsilylacetylene (2.1 ml, 14.7 mmol) and dorobis (triphenylphosphine) palladium (II) (0.77 g) g, 1.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 7% ethyl acetate in hexane as eluent, the title compound was obtained as an oil (1.2 g, -100%). NMR H1 (300 MHz, CDCl3): d 7.62 (d, 1H, "7 = 8.1Hz), 7.53 (s, 1H), 7.35 (d, 1H," 7 = 8.4Hz) , 5.20 (heptet, 1H, "7 = 6.3Hz), 3.95 (s, 2H), 2.22 (s, 3H), 1.74 (m, 1H), 1.36 (d, 6H, "7 = 6.3Hz), 0.37-0.28 (m, 4H), 0.27 (s, 9H). 2- [(Cyclopropyl-methyl-amino) -methyl] -4-ethynyl-benzoic acid isopropyl ester (Intermediate 122) A solution of 2- [(cyclopropyl-methyl-amino) -methyl] -4-trimethylsilanylethynyl-benzoic acid isopropyl ester (Intermediate 121, 0.34 g, 1 mmol) in methanol (2 ml) was treated with potassium carbonate (0.207 g, 1.5 mmol) and the resulting reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound as an oil. (0.21 g, 78%). H1 NMR (300 MHz, CDC13): d 7.67 (d, 1H, "7 = 7.8Hz), 7.64 (d, 1H, "7 = 1.8Hz), 7.38 (dd, 1H, J = 1.8, 7.8Hz), 5.21 (heptet, 1H," 7 = 6.0Hz), 3.96 (s) , 2H), 3.16 (s, 1H), 2.22 (s, 3H), 1.74 (m, 1H), 1.36 (d, 6H, «7 = 6.0Hz), 0.44-0.33 (m, 4H). 2- [(Cyclopropyl-methyl-amino) -methyl] -4- (4-methoxycarbonylmethyl-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 123) Following General Procedure B and using 2- [(cyclopropyl-methyl-amino) -methyl] -4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.09 g, 0.33 mmol), methyl 4-methyl ester -iodophenylacetic acid (0.09 g, 0.33 mmol), triethylamine (2 ml), copper (I) iodide (0.04 g, 0.21 mmol) and dichlorobis (triphenylphosphine) -palladium (II) (0, 1 g, 0.14 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as eluent, the title compound was obtained as an oil. (0.1 g, 72%). H1 NMR (300 MHz, CDCl3): d 7.70 (d, 1H, "7 = 7.8Hz), 7.62 (d, 1H," 7 = 1.8Hz), 7.52 (d, 2H, «7 = 8.1 Hz), 7.43 (dd, 1H,« 7 = 1.8, 7.8Hz), 7.28 (d, 2H, «7 = 8.1Hz), 5.25 (heptet, 1H, "7 = 6.0Hz), 4.00 (s, 2H), 3.71 (s, 3H), 3.65 (s, 2H), 2.26 (s, 3H), 1.78 ( m, 1H), 1.38 (d, 6H, "7 = 6.0Hz), 0.44-0.40 (m, 4H). 4- (4-Carboxymethyl-phenylethynyl) -2- [(cyclopropyl-methyl-amino) -methyl] -benzoic acid isopropyl ester (Compound 38) A solution of 2- [(cyclopropyl-methyl-amino) -methyl] -4- (4-methoxycarbonylmethyl-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 123, 0.1 g, 0.23 mmol) in a mixture of methanol (2 ml), tetrahydrofuran (2 ml) and water (1 ml) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase gave the title product as a white solid (0.068 g, 72%). H1 NMR (300 MHz, CDC13): d 9.05 (s broad, 1H), 7.73 (d, 1H, "7 = 8.4Hz), 7.66 (s, 1H), 7.44-7.37 (m, 3H), 7.23-7.21 (m , 2H), 5.20 (heptet, 1H, «7 = 6.0Hz), 4.21 (s, 2H), 3.52 (s, 2H), 2.36 (s, 3H), 1.94 (m, 1H), 1.36 (d, 6H, "7 = 6.0Hz), 0.55-0.43 (m, 4H). 2- [(Cyclopropyl-methyl-amino) -methyl] -4- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 124) Following General Procedure B and using 2- [(cyclopropyl-methyl-amino) -methyl] -4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.05 g, 0.18 mmol), 2-methyl-2-methyl ester -fluoro-4-iodophenylacetic acid (0.07 g, 0.24 mmol), triethylamine (2 ml), copper (I) iodide (0.04 g, 0.21 mmol) and dichlorobis (triphenylphosphine) aladin (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 16% ethyl acetate in hexane as eluent, the title compound was obtained as an oil (0.04 g, 50%). NMR H1 (300 MHz, CDC13): d 7.63 (d, 1H, "7 = 7.8Hz), 7.55 (d, 1H," 7 = 1.2Hz), 7.35 (dd, 1H, "7 = 1.2, 7.8Hz), 7.26-7.17 (m, 3H), 5.16 (heptet, 1H," 7 = 6.3Hz), 3.93 (s, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 2.20 (s, 3H), 1.71 (m, 1H), 1.31 (d, 6H, «7 = 6.3Hz ), 0.40-0.33 (m, 4H). 4- (4-Carboxymethyl-3-fluoro-phenylethynyl) -2- [(cyclopropyl-methyl-amino) -methyl] -benzoic acid isopropyl ester (Compound 39) A solution of 2- [(cyclopropyl-methyl-amino) -methyl] -4- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 124, 0.04 g, 0.09 mmol) in a mixture of methanol (2 ml), tetrahydrofuran (2 ml) and water (1 ml) was treated with lithium hydroxide monohydrate (0 ml)., 042 g, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase gave the title product as a white solid (0.026 g, 54%). H1 NMR (300 MHz, CDC13): d 7.71 (d, 1H, "7 = 8.1Hz), 7.64 (s, 1H), 7.41 (d, 1H," 7 = 8.1Hz) , 7.17-7.09 (m, 3H), 5.20 (heptet, 1H, "7 = 6.3Hz), 4.16 (s, 2H), 3.54 (s, 2H), 2, 34 (s, 3H), 1.91 (m, 1H), 1.36 (d, 6H, "7 = 6.3Hz), 0.50-0.41 (m, 4H). 2- [(Cyclopropyl-methyl-amino) -methyl] -4- (4-methoxycarbonylmethyl-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 125) Following General Procedure B and using 2- [(cyclopropyl-methyl-amino) -methyl] -4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.07 g, 0.26 mmol), 2- (4- methyl iodophenyl) -propionate (Reagent 1, 0.081 g, 0.29 mmol), triethylamine (2 ml), copper (I) iodide (0.03 g, 0.158 mmol) and dichlorobis (triphenylphosphine) palladium (II) ( 0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as eluent, the title compound was obtained in the form of a oil (0.09 g, 81%).

NMR H1 (300 MHz, CDCl3): d 7.57 (d, 1H, "7 = 8.1 Hz), 7.49 (d, 1H," 7 = 1.8Hz), 7.39 (d, 2H, «7 = 8.4Hz), 7.30 (dd, 1H,« 7 = 1.8, 8.1Hz), 7.18 (d, 2H, «7 = 8.4Hz), 5.10 (heptet, 1H, "7 = 6.0Hz), 3.88 (s, 2H), 3.63 (c, 1H," 7 = 7.2Hz), 3.56 (s, 3H), 2.13 (s, 3H), 1.65 (m, 1H), 1.40 (d, 3H, "7 = 7.2Hz), 1.25 (d, 6H," 7 = 6.0Hz), 0.35-0, 27 (m, 4H). 4- [4- (1-carboxy-ethyl) -phenylethynyl] -2- [(cyclopropyl-methyl-amino) -methyl] -benzoic acid isopropyl ester (Compound 40) A solution of 2- [(cyclopropyl-methyl-amino) -methyl] -4- (4-methoxycarbonylmethyl-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 125, 0.09 g, 0.21 mmol) in a mixture of methanol (2 ml), tetrahydrofuran (2 ml) and water (1 ml) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a white solid foam (0.053 g, 61%). H1 NMR (300 MHz, CDC13): d 7.68 (d, 1H, "7 = 8.1Hz), 7.58 (d, 1H," 7 = 1.8Hz), 7.44-7.25 ( m, 5H), 5.13 (heptet, 1H, "7 = 6.0Hz), 4.18 (s, 2H), 3.79 (m, 1H), 2.32 (s, 3H), 1, 89 (m, 1H), 1.39 (d, 3H, "7 = 6.6Hz), 1.28 (d, 6H," 7 = 6.3Hz), 0.52-0.21 (m, 4H) ).

I Intermediate 12 í Intermediate 129 Compound 41 Reaction Scheme 22 4,4-Dimethyl-8- (2-propoxy) -6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalene-1-one (Intermediate 126) A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 0.32 g, 1.12 mmol) in acetone (20 ml) it was treated with potassium carbonate (0.773 g, 5.6 mmol) and 2-iodopropane (2 g, 11.76 mmol) and the resulting reaction mixture was refluxed for 3 days. Cooled to room temperature, the solids were removed by filtration and the filtrate was evaporated in vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 2-6% ethyl acetate. in hexane as eluent to provide the title product as (0.055 g, 15%). NMR H1 (300 MHz, CDCl3): d 7.04 (d, 1H, "7 = 1.2Hz), 6.89 (d, 1H," 7 = 1.2Hz), 4.57 (heptet, 1H, «7 = 6.3Hz), 2.66 (t, 2H,« 7 = 7.2Hz), 1.92 (t, 2H, «7 = 7.2Hz), 1.38 (d, 6H,« 7 = 6.3 Hz), 1.33 (s, 6H), 0.27 (s, 9H). 4, 4-Dimethyl-6-ethynyl-8- (2-propoxy) -3,4-dihydro-2H-naphthalen-1-one (Intermediate 127) A solution 4,4-dimethyl-8- (2-propoxy) -6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 126, 0.055 g, 0.167 mmol) in methanol (5 ml) was treated with potassium carbonate (0.03 g, 0.22 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (0.042 g, 98%). H NMR (300 MHz, CDCl3): d 7.08 (d, 1H, "7 = 1.2Hz), 6.93 (d, 1H," 7 = 1.2Hz), 4.56 (heptet, 1H, «7 = 6.0Hz), 3.19 (s, 1H), 2.67 (t, 2H,« 7 = 6.9Hz), 1.93 (t, 2H, «7 = 6.9Hz), 1 , 39 (d, 6H, "7 = 6.0Hz), 1.34 (s, 6H).

Methyl ester of acid. { 4- [8, 8-dimethyl-5-oxo-4- (2-propoxy) -5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 128) Following General Procedure B and using 4,4-dimethyl-6-ethynyl-8- (2-propoxy) -3,4-dihydro-2H-naphthalene-lime (Intermediate 127, 0.075 g, 0 , 29 mmol), 4-iodophenylacetic acid methyl ester (0.081 g, 0.29 mmol), triethylamine (8 ml), tetrahydrofuran (3 ml), copper (I) iodide (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as eluent, obtained the title compound as a yellow oil (0.07 g, 64%). NMR H1 (300 MHz, CDC13): d 7.52 (d, 2H, "7 = 8.4Hz), 7.29 (d, 2H," 7 = 8.4Hz), 7.12 (d, 1H, «7 = 1.5Hz), 6.97 (d, 1H,« 7 = 1.5Hz), 4.60 (heptet, 1H, «7 = 5.8Hz), 3.71 (s, 3H), 3 , 66 (s, 2H), 2.68 (t, 2H, "7 = 6.6Hz), 1.95 (t, 2H," 7 = 6.6Hz), 1.41 (d, 6H, "7 = 5.8Hz), 1.36 (s, 6H).

Methyl ester of acid. { 4- [5- (cyclopropyl-methyl-amino) -4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 129) A solution of acid methyl ester. { 4- [8, 8-dimethyl-5-oxo-4- (2-propoxy) -5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Intermediate 128, 0.07 g, 0.187 mmol) in dichloromethane (3 ml) and acetonitrile (1.5 ml) was treated with cyclopropylamine (1 ml, 14.45 mmol). After 5 minutes, acetic acid (1 ml) was added followed by sodium cyanoborohydride (0.12 g, 1.91 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with water and a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (x2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. The oil was dissolved in acetone (15 ml) and treated with potassium carbonate (0.2 g, 1.45 mmol) followed by methyl iodide (1 ml, 15.8 mmol) and the resulting reaction mixture was stirred overnight at room temperature. The precipitated solids were separated by filtration, the filtrate was evaporated in vacuo to a residue. Flash column chromatography on silica gel (230-400 mesh) using 2.5-6% ethyl acetate in hexane as eluent afforded the title compound (0.045 g, 53%). H1 NMR (300 MHz, CDC13): d 7.50 (d, 2H, "7 = 8.4Hz), 7.26 (d, 2H," 7 = 8.4Hz), 7.12 (d, 1H, «7 = 1.5Hz), 6.77 (d, 1H,« 7 = 1.5Hz), 4.58 (heptet, 1H, «7 = 6.3Hz), 4.04 (m, 1H), 3 , 70 (s, 3H), 3.64 (s, 2H), 2.32 (s, 3H), 2.10-1.95 (m, 2H), 1.84-1.78 (m, 1H) ), 1.66-1.60 (m, 1H), 1.40-1.26 (m, 1H), 1.39 and 1.35 (2d, 6H, "7 = 6.3Hz), 1, 34 (s, 3H), 1.19 (s, 3H), 0.29-0.22 (m, 2H), 0.083-0.00 (m, 2H).

Acid { 4- [5- (cyclopropyl-methyl-amino) -4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acetic (Compound 41) A solution of (4- [5- (cyclopropyl-methyl-amino) -4-isopropoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl ester} -acetic (Intermediate 129, 0.045 g, 0.098 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) was treated with 2M lithium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred to the ambient temperature for 2 h The volatile substances were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate.The organic phase was washed with water and brine, and dried over sulfate of anhydrous magnesium, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using 5% methanol in ethyl acetate as eluent to provide the title product in the form of a white solid (0, 027 g, 61%). NMR H1 (300 MHz, CDCl3): d 7.46 (d, 2H, "7 = 8.1Hz), 7.29 (d, 2H," 7 = 8.1Hz), 7.14 (d, 1H, «7 = 1.2Hz), 6.80 (d, 1H,« 7 = 1.2Hz), 4.62 (, heptet, 1H, J = 6.0Hz), 4.31 (, 1H), 3.58 (s, 2H), 2.46 (s, 3H), 2.46-2.39 (m, 1H), 2.14-1.87 (m, 2H), 1.72-1.67 (m , 1H), 1.42-1.23 (m, 1H), 1.40 and 1.34 (2d, 6H, "7 = 6.0Hz), 1.31 (s, 3H), 1.16 ( s, 3H), 0.80-0.70 (m, 1H), 0.53-0.38 (m, 2H), 0.23-0.18 (m, 1H).

Br Nc to EtOH, conc. H2S04) »- 2. K2C03, EtOH Intermediate 130 Intermediate 132 Compound 42 R2 = H R2 = H Compound 43 R2 = F R2 = F 2. LiOH, EtOH, THF, H20 Intermediate 136 Reaction Scheme 23 Ethyl 2- (3-bromo-phenyl) -2-methyl-propionic acid ester (Intermediate 130) A solution of 2- (3-bromo-phenyl) -2-methyl-propionitrile (prepared as described by Barlaam et al., "7. Med. Chem., 1999, 42, 23, 4890-4908 incorporated herein by reference; 4 g, 6.24 mmol) was dissolved in ethanol (40 ml), treated with concentrated sulfuric acid (1 ml) and the resulting reaction mixture was refluxed for 36 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate 5% in hexane as eluent to give the title product as an orange oil (0.77 g, 46%). NMR H1 (300 MHz, CDC13): d 7.48 (s, 1H), 7.36 (dd, 1H, J = 2.8, 7.7Hz), 7.26 (dd, 1H,, 7 = 2 , 8, 8.3Hz), 7.20 (dd, 1H, "7 = 7.8, 8.3Hz), 4.12 (c, 2H," 7 = 7.0Hz), 1.55 (s, 6H), 1.18 (t, 3H, "7 = 7.0Hz).

Ethyl ester of 2-methyl-2- (3-trimethylsilanylethynyl-phenyl) -propionic acid (Intermediate 131) Following General Procedure D and using 2- (3-bromo-phenyl) -2-methyl-propionic acid ethyl ester (Intermediate 130, 0.77 g, 2.84 mmol), triethylamine (5 ml), copper iodide (I) (0.044 g, 0.23 mmol), trimethylsilylacetylene (2 ml, 14.1 mmol) and dichlorobis ( triphenylphosphine) palladium (II) (0.159 g, 0.23 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using hexane to 5% ethyl acetate in hexane as eluent, the title (0.74 g, 90%) in the form of a orange-colored oil. H1 NMR (300 MHz, CDC13): d 7.45 (s, 1H), 7.33-7.24 (m, 3H), 4.12 (c, 2H, "7 = 7.0Hz), 1, 56 (s, 6H), 1.17 (t, 3H, "7 7.0Hz), 0.25 (s, 9H).

Ethyl 2- (3-ethynyl-phenyl) -2-methyl-propionic acid ester (Intermediate 132) A solution of 2-methyl-2- (3-trimethylsilanylethynyl-phenyl) -propionic acid ethyl ester (Intermediate 131, 0.74 g, 2.56 mmol) in ethanol (10 ml) was treated with potassium carbonate (0.degree. , 2 g, 1.45 mmol). The resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate 1-5% in hexane as eluent to provide the title product (0.4 g, 72%). NMR H1 (300 MHz, CDC13): d 7.56 (s, 1H), 7.45-7.33 (m, 3H), 4.18 (c, 2H, "7 = 7.0Hz), 3, 14 (s, 1H), 1.63 (s, 6H), 1.24 (t, 3H, "7 = 7.0Hz).

Ethyl 2- [3- (4-methoxycarbonylmethyl-phenylethynyl) -phenyl] -2-methyl-propionic acid ester (Intermediate 133) Following General Procedure B and using 2- (3-ethynyl-phenyl) -2-methyl-propionic acid ethyl ester (Intermediate 132, 0.101 g, 0.47 mmol), methyl 4-iodophenylacetic acid ester (0.129 g, 0.47 mmol), triethylamine (8 ml), copper iodide (I) (0.01 g, 0.05 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.035 g, 0.05 mmol) followed by chromatography in an instantaneous column on silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as eluent, the title compound was obtained as an oil (0.14 g, 82%). NMR R1 (300 MHz, CDCl3): d 7.52-7.25 (m, 8H), 4.13 (c, 2H, "7 = 7.0Hz), 3.70 (s, 3H), 3, 64 (s, 2H), 1.58 (s, 6H), 1.18 (t, 3H, "7 = 7.0Hz). 2- [3- (4-Methoxycarbonylmethyl-phenylethynyl) -phenyl] -2-methyl-propionic acid (Compound 42) A solution of 2- [3- (4-methoxycarbonylmethyl-phenylethynyl) -phenyl] -2-methyl-propionic acid ethyl ester (Intermediate 133, 0.12 g, 0.33 mmol) in ethanol (2 ml) and tetrahydrofuran (2 ml) was treated with 2M lithium hydroxide. (1 mL, 2 mmol) and the resulting reaction mixture was stirred at room temperature for Ih. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as an oil (0.11 g, 95%). NMR H1 (300 MHz, CDCl3): d 7.48 (s, 1H), 7.35-7.04 (m, 7H), 4.11 (c, 2H, "7 = 7.0Hz), 3, 32 (s, 2H), 1.50 (s, 6H), 1.11 (t, 3H, "7 = 7.0Hz).

Ethyl 2- [3- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -phenyl] -2-methyl-propionic acid ester (Intermediate 134) Following General Procedure B and using 2- (3-ethynyl) ethyl ester phenyl) -2-methyl-propionic (Intermediate 132, 0.10 g, 0.46 mmol), 2-fluoro-4-iodophenylacetic acid methyl ester (0.136 g, 0.46 mmoles), triethylamine (8 ml), copper iodide (l) (0.01 g, 0.05 mmol) and dichlorobis (triphenylphosphine) -palladium (II) (0.035 g, 0.05 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as eluent, the title compound was obtained as an oil (0.15 g, 85%). NMR H1 (300 MHz, CDCl3): d 7.52 (s, 1H) 7.39-7.21 (m, 6H), 4.13 (c, 2H, "7 = 7.0Hz), 3.71 (s, 3H), 3.68 (s, 2H), 1.58 (s, 6H), 1.18 (t, 3H, "7 = 7.0Hz). 2- [3- (3-Fluoro-4-methoxycarbonylmethyl-phenylethynyl) -phenyl] -2-methyl-propionic acid (Compound 43) A solution of 2- [3- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -phenyl] -2-methyl-propionic acid ethyl ester (Intermediate 134, 0.13 g, 0.34 mmol) in ethanol (2 ml) and tetrahydrofuran (2 ml) was treated with 2 M lithium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at room temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product (0.125 g, -100%). NMR H1 (300 MHz, CDCl3): d 7.48 (s, 1H) 7.34-7.06 (m, 6H), 4.10 (c, 2H, "7 = 7.0Hz), 3.41 (s, 2H), 1.52 (s, 6H), 1.13 (t, 3H, "7 = 7.0Hz).

Isopropyl ester of 3-bromo-benzoic acid (Intermediate 135) A solution of 3-bromobenzoic acid (Aldrich, 2.4 g, 11.9 mmol) in isopropanol (20 ml) was treated with 1 ml of concentrated sulfuric acid and the resulting reaction mixture was refluxed overnight. The reaction mixture was then cooled to room temperature and diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent to provide the compound of the title in the form of an oil (2.54 g, 88%). H1 NMR (300 MHz, CDC13): d 8.14 (s, 1H), 7.95 (d, "7 = 7, 6Hz, 1H), 7.64 (d," 7 = 7, 6Hz, 1H) , 7.29 (t, "7 = 7, 6Hz, 1H), 5.24 (hept," 7 = 6, 1Hz, 1H), 1.35 (d, "7 = 6, 1Hz, 6H). 3-Trimethylsilanylethynyl-benzoic acid isopropyl ester (Intermediate 136) Following General Procedure D and using isopropyl ester of 3-bromo-benzoic acid (Intermediate 135, 1.25 g, 5.14 mmole), triethylamine (12 ml), copper iodide (I) (0.078 g, 0.41 mmoles), trimethylsilylacetylene (4 ml, 28.16 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.288 g, 0.41 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate. 3% ethyl in hexane as eluent, the title compound (1.25 g, 94%) was obtained as an orange oil. H1 NMR (300 MHz, CDC13): d 8.09 (s, 1H), 7.96 (d, "7 = 7, 6Hz, 1H), 7.59 (d," 7 = 7, 6Hz, 1H) , 7.35 (t, «7 = 7, 6Hz, 1H), 5.24 (hept,« 7 = 6, 1Hz, 1H), 1.35 (d, «7 = 6, 1Hz, 6H), 0 , 25 (s, 9H).

Isopropyl ester of 3-ethynyl-benzoic acid (Intermediate 137) A solution of 3-trimethylsilanylethynyl benzoic acid isopropyl ester (Intermediate 136, 0.6 g, 2.3 mmol) in anhydrous tetrahydrofuran (3 ml) was treated with a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran. (4.6 mL, 4.6 mmoles) and the resulting reaction mixture was stirred in an ice bath for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil which was purified by flash column chromatography using 5% -30% ethyl acetate in hexane as eluent to provide the title compound as a solid (0.33 g, 76%). H1 NMR (300 MHz, CDC13): d 8.15 (s, 1H), 8.01 (d, "7 = 7, 6Hz, 1H), 7.64 (d," 7 = 7, 6Hz, 1H) , 7.39 (t, «7 = 7, 6Hz, 1H), 5.25 (hept,« 7 = 6, 1Hz, 1H), 3.13 (s, 1H), 1.37 (d, «7 = 6, 1Hz, 6H). 3- (4-Ethoxycarbonylmethyl-3-fluoro-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 138) Following General Procedure B and using 3-ethynyl-benzoic acid isopropyl ester (Intermediate 137, 0.099 g, 0.53 mmol), 2-fluoro-4-iodophenylacetic acid ethyl ester (0.164 g, 0.53 mmol), triethylamine (3 ml), copper (I) iodide (0.01 g, 0.05 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.035 g, 0.5 mmol) followed by flash column chromatography on silica gel. silica (230-400 mesh) using 7-10% ethyl acetate in hexane as eluent, the title compound was obtained as a light orange oil (0.08 g, 92%). H1 NMR (300 MHz, CDC13): d 8.17 (s, 1H), 8.01 (d, "7 = 7, 6Hz, 1H), 7.67 (d," 7 = 7, 6Hz, 1H) , 7.42 (t, «7 = 7, 6Hz, 1H), 7.29-7.22 (m, 3H), 5.21 (hept,« 7 = 6, 1Hz, 1H), 4.18 ( c, .7 = 7, 1Hz, 2H), 3.68 (s, 2H), 1.38 (d, «7 = 6, 1Hz, 6H), 1.26 (t,« 7 = 7, 1Hz, 3H). 3- (4-Carboxymethyl-3-fluoro-phenylethynyl) -benzoic acid isopropyl ester (Compound 44) A solution of 3- (4-ethoxycarbonylmethyl-3-fluoro-phenylethynyl) -benzoic acid isopropyl ester (Intermediate 138, 0.1 g, 0.27 mmol) in isopropanol (2 ml) and tetrahydrofuran (2 ml) was treated with a 2 M solution of lithium hydroxide (1 ml, 2 mmol). After 40 min. at room temperature, the reaction mixture was concentrated in vacuo a little, neutralized with 10% hydrochloric acid and the solid formed was filtered, washed with water and dried to give the title compound (0.09 g, 97%). H NMR (300 MHz, CDC13): d 8.18 (s, 1H), 8.02 (d, J = 7.6Hz, H), 7.68 (d, "7 = 7, 6Hz, 1H), 7.44 (t, "7 = 7, 6Hz, 1H), 7.31-, 24 (m, 3H), 5.27 (hept," 7 = 6, 1Hz, 1H), 3.74 (s, 2H), 1.39 (d, "7 = 6, 1Hz, 6H).

TiCl4, C12CH (0CH3), CH2C12 Intermediate 139 Intermediate 140 Intermediate 141 Intermediate 144 Compound 45 Reaction Scheme 24 4-Bromo-2-t-butyl-5-methyl-phenol (Intermediate 139) A solution of 4-bromo-3-methylphenol (Aldrich, 5.1 g, 27.3 mmol) in anhydrous dichloromethane (50 ml) was treated with 2-methyl-2-propanol (15 ml) and concentrated sulfuric acid (3 ml). ml) and stirred at room temperature for 3 months. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 3-5% ethyl acetate in hexane as eluent afforded the title compound as a dark yellow oil (3.42 g, 51%). This was used as is for the next stage. H NMR (300 MHz, CDC13): d 7.40 (s, 1H), 6.56 (s, 1H), 5.23 (s, 1H), 2.30 (s, 3H), 1.41 ( s, 9H). 3 - . 3-Bromo-5- t-butyl-6-hydroxy-2-methyl-benzaldehyde (Intermediate 140) A stirred, cooled solution (ice bath) of 4-bromo-2-t-butyl-5-methyl-phenol (Intermediate 139, 0.85 g, 3.5 mmol) in anhydrous dichloromethane (7 ml) was treated with titanium tetrachloride (0, 64 ml, 5.8 mmol) followed by D, rj-dichloromethyl ether (0.3 g, 3.5 mmol). The reaction mixture was allowed to warm to room temperature for 4 h. The reaction mixture was diluted with diethyl ether, washed with brine (xl) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230 mesh) -400) using 1% ethyl acetate in hexane to provide the title compound as a yellow solid (0.58 g, 61%). NMR H1 (300 MHz, CDCl3): d 12.89 (s, 1H), 10.32 (s, 1H), 7.60 (s, 1H), 2.63 (s, 3H), 1.38 ( s, 9H). 3-Bromo-5-t-butyl-6-isopropoxy-2-methyl-benzaldehyde (Intermediate 141) A stirred, cooled solution (ice bath) of 3-bromo-5-t-butyl-6-hydroxy-2-methyl-benzaldehyde (Intermediate 140, 0.58 g, 2.14 mmol) in anhydrous N, N-dimethylformamide (10 ml) was treated with sodium hydride (0.34 g of 60% suspension in mineral oil, 8.56 mmol). After 30 minutes, 2-iodopropane (1.3 ml, 12.84 mmol) was added and the reaction mixture was heated at 75 ° C overnight. The reaction mixture was then cooled and poured into ice water and extracted with diethyl ether. The organic extract was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography using 2-4% ethyl acetate in hexane as eluent afforded the title product (0.43 g, 64%). NMR H1 (300 MHz, CDC13): d 10.23 (s, 1H), 7.68 (s, 1H), 4.34 (heptet, 1H, "7 = 6.2Hz), 2.57 (s, 3H), 1.40 (s, 9H), 1.28 (d, 6H, "7 = 6.2Hz). 3- t-Butyl-2-isopropoxy-6-methyl-5-trimethylsilanylethynyl-benzaldehyde (Intermediate 142) Following General Procedure D and using 3-bromo-5-t-butyl-6-isopropoxy-2-methyl-benzaldehyde (Intermediate 141, 0.43 g, 1.37 mmol), triethylamine, copper iodide (I) ( 0.021 g, 0.11 mmol), trimethylsilylacetylene (1 ml), and dichlorobis- (triphenylphosphine) palladium (II) (0.077 g, 0.11 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 2% ethyl acetate in hexane as eluent, the title compound was obtained (0.45 g, -100%). NMR H1 (300 MHz, CDCl3): d 10.10 (s, 1H), 7.41 (s, 1H), 4.19 (heptet, 1H, "7 = 6.1Hz), 2.44 (s, 3H), 1.21 (s, 9H), 1.09 (d, 6H," 7 = 6.1Hz), 0.08 (s, 9H). 3- Butyl-5-ethynyl-2-isopropoxy-6-methyl-benzaldehyde (Intermediate 143) A solution of 3-butyl-2-isopropoxy-6-methyl-5-trimethylsilanylethynyl-benzaldehyde (Intermediate 142, 0.45 g, 1.37 mmol) in methanol (5 ml) and tetrahydrofuran was treated with potassium carbonate ( 0.2 g, 1.45 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo and the residue was extracted with diethyl ether and washed with water and brine. The organic phase was dried, filtered and evaporated in vacuo to give the title compound (0.35 g, 90%). H1 NMR (300 MHz, CDC13): d 10.28 (s, 1H), 7.63 (s, 1H), 4.38 (s, 4.38 (s, 1H, "7 = 6.2Hz), 4.38 (s, 1H), 2.63 (s, 3H), 1.39 (s, 9H), 1.29 (d, 6H, J = 6.2Hz). [4- (5-t-Butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 144) Following General Procedure B and using 3-t-butyl- 5-ethynyl-2-isopropoxy-6-methyl-benzaldehyde (Intermediate 143, 0.35 g, 1.35 mmol), 4-iodophenylacetic acid methyl ester (0.374 g, 1.35 mmol), triethylamine (8 ml) , copper iodide (I) (0.02 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.072 g, 0.1 mmol) followed by flash column chromatography on silica gel (230 mesh) 400) using 3-5% ethyl acetate in hexane as eluent, the title compound was obtained as a white solid (0.37 g, 75%). H1 NMR (300 MHz, CDC13): d 10.29 (s, 1H), 7.65 (s, 1H), 7.48 (d, 2H, "7 = 8.2Hz), 7.53 (d, 2H, "7 = 8.2Hz), 4.38 (heptet, 1H," 7 = 6.1Hz), 3.68 (s, 3H), 3.62 (s, 2H), 2.68 (s, 3H), 1.41 (s, 9H), 1.27 (d, 6H, "7 = 6.1Hz). [4- (5- t-Butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 145) Anhydrous tetrahydrofuran (3 ml) was added to a 2 M solution of trimethylsilyldiazomethane in hexanes (0.37 ml, 0.74 mmol) and the resulting reaction mixture was cooled to -78 ° C. A solution of 1.6 M zi-butyl lithium in hexanes (0.5 ml, 0.8 mmol) was added followed, after 30 minutes, by a solution of methyl ester of acid [4- (5-t- butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic (Intermediate 144, 0, 2 g, 0.49 mmol) in anhydrous tetrahydrofuran and the resulting reaction mixture was stirred at -78 ° C for Ih and at 0 ° C for 40 minutes. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using ethyl acetate at 2, 5-4% in hexane as eluent followed by preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase to give the title product as a colorless oil (0.023 g, 11.6%). H1-NMR (300 MHz, CDC13): d 7.49 (d, 2H, "7 = 8.0Hz), 7.44 (s, 1H), 7.26 (d, 2H," 7 = 8.0Hz) 5,76 (heptet, 1H, "7 = 6.1Hz), 3.70 (s, 3H), 3.64 (s, 2H), 3.58 (s, 1H), 2.58 (s, 3H), 1.39 (s, 9H), 1.31 (d, 6H, "7 = 6.1Hz). [4- (5- t-Butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] acetic acid (Compound 45) A solution of [4- (5-butyl-3-ethynyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 145, 0.023 g, 0.057 mmol) in methanol (1, 5 ml) and tetrahydrofuran (1.5 ml) was treated with 1M lithium hydroxide (0.5 ml, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product (0.020 g, 91%). H1 NMR (300 MHz, CDC13): d 7.47 (d, 2H, "7 = 8.0Hz), 7.43 (s, 1H), 7.24 (d, 2H," 7 = 8.0Hz) , 5.75 (heptet, 1H, "7 = 6.1Hz), 3.62 (s, 2H), 3.57 (s, 1H), 2.57 (s, 3H), 1.38 (s, 9H), 1.30 (d, 6H, "7 = 6.1Hz). [4- (5- t-Butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 146) A solution of methylidene triphenylphosphorane [5 ml of a 0.1 M solution, 0.5 mmol, generated from methyltriphenylphosphonium bromide (2.5 g, 7 mmol) and a 1.6 M solution of n-butyl lithium in hexanes (2.9 ml, 4.7 mmol) in 50 ml of tetrahydrofuran] was added to a solution of [4- (5-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl) methyl ester) phenyl] -acetic (Intermediate 144, 0.052 g, 0.13 mmol) in tetrahydrofuran (1 ml). After lh the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil which after flash column chromatography on silica gel (230-400 mesh) using ethyl acetate 5% hexane as eluent afforded the title compound (0.02 g, 39%). NMR H1 (300 MHz, CDCl3): d 7.48 (d, 2H, "7 = 7.9Hz), 7.39 (s, 1H), 7.25 (d, 2H," 7 = 7.9Hz) ", 6.73 (dd, 1H," 7 = 11.4, 17.9Hz), 5.49 (dd, 1H, "7 = 2.0, 11.4Hz), 5.37 (dd, 1H, "7 = 2.1, 17.9Hz), 4.93 (heptet, 1H," 7 = 6.4Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.44 ( s, 3H), 1.40 (s, 9H), 1.17 (d, 6H, "7 = 6.4Hz). [4- (5- t-Butyl-4-isopropoxy-2-methyl-3-vinyl-phenylethynyl) -phenyl] -acetic acid (Compound 46) A solution of [4- (5-t-butyl) methyl ester -4-isopropoxy-2-methyl-3-vinyl-phenylethynyl) -phenyl] -acetic acid (Intermediate 146, 0.02 g, 0.049 mmol) in methanol (1.5 ml) and tetrahydrofuran (1.5 ml) was treated with 1M lithium hydroxide (0.5 ml, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 45 minutes. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the product of the txtule (0.020 g, -100%). H1 NMR (300 MHz, CDC13): d 7.48 (d, 2H, "7 = 8.2Hz), 7.39 (s, 1H), 7.24 (d, 2H, 7 = 8.2Hz), 6.72 (dd, 1H, "7 = 11.4, 17.9Hz), 5.49 (dd, 1H," 7 = 2.0, 11.4Hz), 5.37 (dd, 1H, "7 = 2.1, 17.9Hz), 4.92 (heptet, 1H, «7 = 6.2Hz), 3.64 (s, 2H), 2.43 (s, 3H), 1.40 (s, 9H), 1.17 (d, 6H, "7 = 6.2Hz).

Intermediate 142 Intermediate 147 Intermediate 148 Reaction Scheme [4 - (5-t-Butyl-3-hydroxymethyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 147) A stirred, cooled solution (ice bath) of [4- (5-t-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 142, 0.172 g , 0.42 mmol) in methanol (4 ml) was treated with sodium borohydride (0.degree., 02 g, 0.51 mmol) and the mixture. The resulting reaction mixture was stirred for 1.5 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was washed with water (xl) and brine (xl), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh). ) using 15-20% ethyl acetate in hexane as eluent to give the title product as a white solid (0.15 g, 88%). NMR H1 (300 MHz, CDC13): d 7.48 (d, 2H, «7 = 8.5Hz), 7.47 (s, 1H), 7.25 (d, 2H, <7 = 8.5 Hz), 4.74 (s broad, 2H), 4.74-4.60 (m, 1H), 3.69 (s, 3H), 3.63 (s, 2H), 2 , 60 (s, 3H), 1.40 (s, 9H), 1.27 (d, 6H, "7 = 6.2Hz). [4- (3-Bromomethyl-5-t-butyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 148) A stirred, cooled solution (ice bath) of [4- (5-butyl-3-hydroxymethyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 147, 0.15 g, 0.37 mmol) and triphenylphosphine (0.125 g, 0.48 mmol) in anhydrous dichloromethane (5 ml) was treated with N-bromosuccinimide (0.085 g, 0.48 mmol) in argon and the resulting reaction mixture was left tempering at room temperature and stirred overnight. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with diethyl ether. The organic phase was washed with water (xl) and brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which in flash column chromatography silica gel (230-400 mesh) using 4-5% ethyl acetate in hexane as eluent afforded the title compound (0.12 g, 69%) as a colorless oil. This was used as is for the next stage.

Methyl ester of acid. { 4- [5- t -butyl-4-isopropoxy-2-methyl-3- (3-trimethylsilanyl-prop-2-ynyl) -phenylethynyl] -phenyl} -acetic (Intermediate 149) A solution of [4- (3-bromomethyl-5-t-butyl-4-isopropoxy-2-methyl-phenylethynyl) -phenyl] -acetic acid methyl ester (Intermediate 148, 0.12 g, 0.25 mmol) in triethylamine (1 ml) and N, N-dimethylformamide (4 ml) was purged with argon and treated with trimethylsilylacetylene (0.5 ml, 3.5 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.025 g, 0.036 g). mmoles). The resulting reaction mixture was heated at 85 ° C overnight at the end of which it was cooled to room temperature and subjected to column chromatography on silica gel (230-400 mesh) using 4% ethyl acetate in hexane as eluent followed by preparative normal phase HPLC using 3% ethyl acetate in hexane as mobile phase to provide the title compound as an oil (0.038 g, 31%). H1-NMR (300 MHz, CDC13): d 7.50 (d, 2H, "7 = 7.9Hz), 7.48 (s, 1H), 7.26 (d, 2H," 7 = 7.9Hz) , 4.89 (heptet, 1H, «7 = 6.5Hz), 3.70 (s, 3H), 3.64 (s, 2H), 3.50 (s, 2H), 2.57 (s, 3H), 1.40 (s, 9H), 1.27 (d, 6H, "7 = 6.5Hz), 0.12 (s, 9H). [4- (5- t-Butyl-4-isopropoxy-2-methyl-3-prop-2-ynyl-phenylethynyl) -phenyl] -acetic acid (Compound 47) A solution of acid methyl ester. { 4- [5- t -butyl-4-isopropoxy-2-methyl-3- (3-trimethylsilanyl-prop-2-ynyl) -phenylethynyl] -phenyl} -acetic (Intermediate 149, 0.038 g, 0.078 mmol) in methanol (1.5 ml) and tetrahydrofuran (1.5 ml) was treated with 2M lithium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. The volatiles were evaporated in vacuo to a residue which was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product (0.032 g, 98%). H1 NMR (300 MHz, CDC13): d 7.50 (d, 2H, "7 = 8.1Hz), 7.43 (s, 1H), 7.27 (d, 2H," 7 = 8.1Hz) , 4.82 (heptet, 1H, «7 = 6.4Hz), 3.67 (s, 2H), 3.48 (d, 2H, J = 2.5Hz), 2.58 (s, 3H), 1.39 (s, 9H), 1.28 (d, 6H, "7 = 6.4Hz).

Intermediate 150 Intermediate 152 intermediate 154 Intermediate 155 Intermediate 156 Compound 49 R5 = H, R5l = Me Compound 50 R5 = R '= Me Intermediate 164 THF, H20 Compound 48 Reaction Scheme 26 Ethyl 4- (2-bromo-4-methoxy-phenyl) -4-oxo-butyric acid (Intermediate 150) A stirred, cooled (-30 ° C) solution of 3-bromoanisole (18.7 g, 100 mmol) and ethylsuccinyl chloride (21 mL, 150 mmol) in anhydrous dichloromethane (200 mL) was treated with aluminum chloride (26 mL). , 6 g, 200 mmol) and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with dichloromethane (x2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a brown oil. A solid separated upon standing. The liquid supernatant was decanted and the solid was washed with dichloromethane: hexane 1: 3 and dried to give the ethyl ester isomer of 4- (4-bromo-2-methoxy-phenyl) -4-oxo-butyric acid. The combined mother liquors and washings were evaporated to a brown oil which was subjected to column chromatography on silica gel (230-400 mesh) using 15% ethyl acetate in hexane as eluent to provide the ethyl ester isomer of 4- (4-bromo-2-methoxy-phenyl) -4-oxo-butyric acid (overall 12 g, 38%), and the title compound (11.4 g, 36%) and a 1: 1 mixture of both (2 g, 6.3%). H NMR (300 MHz, CDCl3): d 7.59 (d, 1H, "7 = 8.8Hz), 7.14 (d, 1H," 7 = 2.6Hz), 6.87 (dd, 1H, «7 = 2.6, 8.8Hz), 4.14 (c, 2H,« 7 = 7.0Hz), 3.83 (s, 3H), 3.23 (t, 2H, «7 = 6, 4Hz), 2.74 (t, 2H, "7 = 6.4Hz), 1.25 (t, 3H," 7 = 7.0Hz).

Ethyl 4- (2-bromo-4-methoxy-phenyl) -butyric acid ester (Intermediate 151) A solution of 4- (2-bromo-4-methoxy-phenyl) -4-oxo-butyric acid ethyl ester (Intermediate 150, 6.45 g, 20.5 mmol) in trifluoroacetic acid (32 ml, 409 mmol) treated with triethylsilane (14.4 ml, 90 mmol) and the resulting reaction mixture was heated at 55 ° C for 3 h. The reaction mixture was then cooled to room temperature, neutralized with solid sodium bicarbonate, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (5.4 g, 88%) as a colorless oil. NMR H1 (300 MHz, CDCl3): d 7.11 (d, 1H, "7 = 8.2Hz), 7.08 (d, 1H," 7 = 2.6Hz), 6.79 (dd, 1H, «7 = 2.6, 8.2Hz), 4.13 (c, 2H,« 7 = 7.3Hz), 3.76 (s, 3H), 2.71 (t, 2H, 7 = 7.6Hz ), 2.34 (t, 2H, "7 = 7.6Hz), 1.92 (quint, 2H," 7 = 7.6Hz), 1.26 (t, 3H, J = 7.3Hz). - (2-Bromo-4-methoxy-phenyl) -2-methyl-pentan-2-ol (Intermediate 152) A stirred, cooled solution (-10 ° C) of 4- (2-bromo-4-methoxy-phenyl) -butyric acid ethyl ester (Intermediate 151, 5.4 g, 18 mmol) in anhydrous tetrahydrofuran (100 ml) it was treated with a 3 M solution of methylmagnesium bromide (16 ml, 48 mmol) and the resulting reaction mixture was allowed to warm to room temperature over 3 h. It was quenched with an aqueous solution of saturated ammonium chloride, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a viscous oil (5.16 g, -100%).

H1NMR (300 MHz, CDCl3): d 7.11 (d, 1H, "7 = 8.5Hz), 7.08 (d, 1H, "7 = 2.6Hz), 6.78 (dd, 1H," 7 = 2.6, 8.5Hz), 3.77 (s, 3H), 2.67 (t, 2H, J = 7.3 Hz), 1.69-1.43 (m, 4H), 1.21 (s, 6H).

-Bromo-2-methoxy-l, 1-dimethyl-l, 2,3, 4-tetrahydro-naphthalene (Intermediate 153) - (2-Chromium-4-methoxy-phenyl) -2-methyl-pentan-2-ol (Intermediate 152, 5.16 g, 17.9 mmol) was treated with 85% sulfuric acid (50 mL) at room temperature. After 30 minutes, the reaction mixture was diluted with cold water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product (4.63 g, 96%) a light yellow oil form. H1 NMR (300 MHz, CDC13): d6, 96 (d, 1H, "7 = 2.6Hz), 6.86 (d, 1H," 7 = 2.6Hz), 3.76 (s, 3H) , 2.68 (t, 2H, "7 = 6.7Hz), 1.83-1.75 (m, 2H), 1.62-1.58 (m, 2H), 1.26 (s, 6H) ). 8-Bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-l-one (Intermediate 154) A solution of 5-bromo-2-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 153, 4.6 g, 17.1 mmol) in glacial acetic acid (20 ml) it was cooled to 0 ° C and treated with a solution of chromium trioxide (5.5 g, 55 mmol) in acetic acid and water (20 ml each). The reaction mixture was then allowed to cool to room temperature and stirred for 24 h. It was diluted with water and extracted with diethyl ether (x2). The combined organic phase was washed with water (x3), saturated aqueous sodium bicarbonate (xl) and brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title compound (3.9 g, 81%) as a yellow oil. H1 NMR (300 MHz, CDCl3): d 7.09 (d, 1H, "7 = 2.6Hz), 6.87 (d, 1H," 7 = 2.6Hz), 3.85 (s, 3H) , 2.71 (t, 2H, "7 = 7.0Hz), 1.96 (t, 2H," 7 = 7.0Hz), 1.35 (s, 6H). 6-Methoxy-4,4-dimethyl-8-vinyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 155) A solution of 8-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 154, 2.83 g, 10 mmol) and tributyl (vinyl) tin (3 ml, 10 mmol) in anhydrous N, N-dimethylformamide (30 ml) was purged with argon and treated with tetrakis (triphenylphosphine) palladium (0) (0.3 g, 0.26 mmol). The resulting reaction mixture was heated at 91 ° C for two days at the end of which it was cooled to room temperature, diluted with water and extracted with diethyl ether (x2). The combined organic phase was washed with water (xl), and brine (xl), dried over anhydrous magnesium sulfate, filtered and evaporated to a pale yellow oil. Flash chromatography using 15% ethyl acetate in hexane as eluent afforded the title product (1.7 g, 73%) a light yellow oil form. NMR H1 (300 MHz, CDCl3): d 7.50 (dd, 1H, "7 = 10.8, 17.3Hz), 6.85 (s, 2H), 5.50 (dd, 1H," 7 = 1.4, 17.3 Hz), 5.28 (dd, 1H, "7 = 1.4, 10.8Hz), 3.88 (s, 3H), 2.68 (t, 2H," 7 = 6). , 7Hz), 1.95 (t, 2H, "7 = 6.7Hz), 1.35 (s, 6H). 8-Cyclopropyl-6-methoxy-4, 4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 156) A stirred, cooled solution (-40 ° C) of 6-methoxy-4,4-dimethyl-8-vinyl-3,4-dihydro-2H-naphthalene-1-one (Intermediate 155, 51.7 g, 7.4 mmol) in diethyl ether (10 ml) was treated with a solution of diazomethane in ether (40 mmol in 50 ml of ether) followed by palladium (II) acetate. (0.08 g) and the resulting reaction mixture was warmed to -25 ° C when effervescence was observed. The reaction mixture was then filtered through a plug of silica and the filtrate was evaporated to give a dark brown residue which was subjected to column chromatography on silica gel (23-400 mesh) using ethyl acetate 20% in hexane as eluent to provide the title product as a light yellow solid (1.5 g, 83%). H NMR (300 MHz, CDCl3): d 6.71 (d, 1H, "7 = 2.6Hz), 6.44 (d, 1H," 7 = 2.6Hz), 3.82 (s, 3H) 2.98 (m, 1H), 2.69 (t, 2H, J = 6.7Hz), 1.94 (t, 2H, "7 = 6.7Hz), 1.34 (s, 6H), 1.02-0.88 (m, 2H), 0.65-0.59 (m, 2H). 8-Cyclopropyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (Intermediate 157) A solution of 8-cyclopropyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 156, 1.5 g, 6.14 mmol) and sodium cyanide (2 g, 40.8 mmol) in anhydrous dimethylsulfoxide (25 ml) was heated at 230 ° C overnight in argon. The reaction mixture was then cooled to room temperature, poured into ice and acidified (Caution! Hydrogen cyanide evolution!) With dilute hydrochloric acid and extracted with ethyl acetate (x2). The combined organic extract was washed with brine (xl), dried over anhydrous sodium sulfate, filtered and evaporated to give a dark brown oil. Flash column chromatography on silica gel (230-400 mesh) using 2-5% ethyl acetate in hexane as eluent afforded the title compound as a solid (1.1 g, 78%). NMR H1 (300 MHz, CD3COCD3): d 8.14 (s, 1H), 6.75 (d, 1H, "7 = 2.4Hz), 6.40 (d, 1H," 7 = 2.4Hz) , 3.02 (m, 1H), 2.62 (t, 2H, "7 = 6.8Hz), 1.94 (t, 2H," 7 = 6.8Hz), 1.33 (s, 6H) , 0.93-0.89 (m, 2H), 0.59-0.55 (m, 2H).

Ester 4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-trifluoro-methanesulfonic acid (Intermediate 158) A solution of 8-cyclopropyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 157, 1.1 g, 4.78 mmol) and 4-dimethylaminopyridine (1 , 22 g, 10 mmol) in anhydrous dichloromethane (20 ml) was treated 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloro-pyridine (2.07 g, 5.26 mmol) in argon to the room temperature. After 3.5 h, the reaction mixture was subjected to flash chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent to give the title compound as a solid (1.76 g, 100%). H1 NMR (300 MHz, CDC13): d 7.10 (d, 1H, "7 = 2.3Hz), 6.78 (d, 1H," 7 = 2.3Hz), 2.90 (m, 1H) , 2.78 (t, 2H, "7 = 7.0Hz), 2.01 (t, 2H," 7 = 7.0Hz), 1.38 (s, 6H), 1.10-1.04 ( m, 2H), 0.67-0.62 (m, 2H). 8-Cyclopropyl-4,4-dimethyl-6- (trimethylsilanyl) ethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 159) Following General Procedure B and using 4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-trifluoro-methanesulfonic acid ester (Intermediate 158, 1.09 g, 3 mmol), triethylamine (5 ml), tetrahydrofuran (5 ml), copper (I) iodide (0.12 g, 0.6 mmol), dichlorobis (triphenylphosphine) palladium (II ) (0.42 g, 0.6 mmol) and (trimethylsilyl) acetylene (2.2 ml, 15 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 7% ethyl acetate in hexane as eluent, the title compound was obtained as an orange oil (1.05 g, quantitative). H1 NMR (300 MHz, CDC13): d 7.29 (d, 1H, "7 = 1.2Hz), 6.98 (d, 1H," 7 = 1.2Hz), 2.81 (m, 1H) , 2.72 (t, 2H, «7 = 6.7Hz), 1.95 (t, 2H, J = 6.7Hz), 1.34 (s, 6H), 1.01-0.95 (m , 2H), 0.66-0.61 (m, 2H), 0.26 (s, 9H). 8-Cyclopropyl-4,4-dimethyl-6-ethynyl-tetralone (Intermediate 160) Following General Procedure F and using 8-cyclopropyl-4,4-dimethyl-6- (trimethylsilanyl) ethynyl-1-tetralone (Intermediate 159, 1.05 g, 3.38 mmol), methanol (20 ml) and carbonate potassium (1 g, 14.5 mmol) followed by flash column chromatography using 7% ethyl acetate in hexane as eluent, the title compound (0.57 g, 80%) was obtained as a solid of color light yellow.

NMR H1 (300 MHz, CDCl3): d 7.34 (d, 1H, "7 = 2.5Hz), 7.02 (d, 1H," 7 = 2.5Hz), 3.19 (s, 1H) , 2.83 (m, 1H), 2.74 (t, 2H, "7 = 6.7Hz), 1.97 (t, 2H," 7 = 6.7Hz), 1.35 (s, 6H) , 1.03-0.86 (m, 2H), 0.66-0.61 (m, 2H).

Ethyl 3- [4- (4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -acrylic acid ester (Intermediate 161) Following General Procedure B and using 8-cyclopropyl-4,4-dimethyl-6-ethynyl-1-tetralone (Intermediate 160, 0.1 g, 0.42 mmol), ethyl ester of (E) -3- ( 4-iodo-phenyl) -acrylic (0.13 g, 0.42 mmol), triethylamine (1 ml), copper (I) iodide (0.02 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium ( II) (0.070 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh), the title compound was obtained (0.12 g, 69%). NMR H1 (300 MHz, CDCl3): d 7.65 (d, 1H, J = 15.8Hz), 7.52 (cAB, 4H, "7 = 8.1Hz), 7.37 (d, 2H," 7 = 1.5Hz), 7.05 (d, 1H, J = 1.5Hz), 6.45 (d, 1H, «7 = 15.8Hz), 4.26 (c, 2H,« 7 = 7 , 2Hz), 2.88-2.79 (m, 1H), 2.77-2.71 (m, 2H), 2.00-1.92 (m, 2H), 1.36-1.21 (m, 9H), 1.04-0.97 (m, 2H), 0.69-0.59 (m, 2H).

Ethyl ester of 3- acid. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -acrylic (Intermediate 162) Following General Procedure C and using ethyl ester of 3- [4- (4-cyclopropyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -acrylic (Intermediate 161, 0.12 g, 0.29 mmol) in dichloromethane (4 ml) and acetonitrile (2 ml), cyclopropylamine (1 ml, 14.5 mmol), acetic acid (1 ml) and sodium cyanoborohydride. (0.16 g, 2.4 mmol) followed by work-up gave an intermediate in the form of an oil, which was used as such for the next step. The residue (crude 0.18 g) was dissolved in acetone (6 ml) and treated with potassium carbonate (0.28 g, 2 mmol) and methyl iodide (1 ml, 16 mmol). The resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Flash column chromatography on silica gel (230-400 mesh) followed by preparative normal phase HPLC using 5% ethyl acetate in hexane as mobile phase gave the title compound (0.08 g) as an oil Of course, it was used as is for the next stage. 3- (4- [4-Cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -acrylic acid (Compound 48) A solution of ethyl ester of 3- acid. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} Acrylic (Intermediate 164, 0.08 g, 0.17 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 2 M solution of sodium hydroxide (2 ml, 4 mmol) and the mixture of The resulting reaction was refluxed overnight. The reaction mixture was cooled to room temperature, the volatiles were evaporated in vacuo, the residue was diluted with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate (x2). The combined organic extract was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase gave the title product as a solid (0.04 g, 50%). H1 NMR (300 MHz, CDC13): d 7.76 (d, 1H, "7 = 15.8Hz), 7.54 (cAb, 4H," 7 = 8.8Hz), 7.38 (d, 1H, J = 1.5Hz), 6.96 (d, 1H, «7 = 1.5Hz), 6.47 (d, 1H,« 7 = 15.8Hz), 4.31 (t, 1H, «7 = 4.7 Hz) 2.27 (s, 3H), 2.40-1.43 (m, 6H), 1.38 (s, 3H), 1.23 (s, 3H), 0.98-0, 78 (m, 4H), 0.39-0.13 (m, 4H). 8-Cyclopropyl-5- (cyclopropyl-methyl-amino) -4,4-dimethyl- (2-trimethylsilanyl) ethynyl-1,2,3,4-tetrahydronaphthalene (Intermediate 163) Following General Procedure C and using 8-cyclopropyl-4,4-dimethyl-6- (trimethylsilanyl) ethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 159, 0.77 g, 2.5 mmol ) in dichloromethane (6 ml) and acetonitrile (3 ml), cyclopropylamine (3 ml, 45 mmol), acetic acid (1 ml) and sodium cyanoborohydride (0.63 g, 9.5 mmol) followed by working-up was given a intermediate in the form of an oil, which was used as is for the next stage. The residue (2.5 mmol) was dissolved in acetone (20 ml) and treated with potassium carbonate (1.03 g, 7.5 mmol) and methyl iodide (1.55 ml, 25 mmol). The resulting reaction mixture was stirred at room temperature for 2 days. The solids were separated by filtration, the filtrate and the washings were evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 2-4% ethyl acetate in hexane as the mobile phase afforded the title compound (0.58 g, 75%). 1 H-NMR (300 MHz, CDCl 3): d 7.31 (d, "7 = 1, 6Hz, 1H), 6.89 (d," 7 = 1, 6Hz, 1H), 4.27 (broad s, 1H ), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.24 (s, 3H), 2.10-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.60-1.50 (m, 1H), 1.35 (s, 3H), 1.20 (s, 3H), 0.90-0, 75 (m, 4H), 0.40-0.25 (m, 3H), 0.26 (s, 9H), 0.20-0.10 (m, 1H). 8-Cyclopropyl-5- (cyclopropyl-methyl-amino) -2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 164) A solution of 8-cyclopropyl-5- (cyclopropyl-methyl-amino) -4,4-dimethyl- (2-trimethylsilanyl) ethynyl-1, 2,3,4-tetrahydronaphthalene (Intermediate 163, 0.3 g, 0, 82 mmol) in methanol (10 ml) was treated with potassium carbonate (0.2 g, 1.44 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The solids were separated by filtration, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (0.22 g, 92%). 1 H-NMR (300 MHz, CDCl 3): d 7.44 (d, "7 = 1, 6Hz, 1H), 7.01 (d," 7 = 1, 6Hz, 1H), 4.38 (broad s, 1H) ), 3.11 (s, 1H), 2.48-2.38 (m, 1H), 2.38-2.28 (m, 1H), 2.34 (s, 3H), 2.18- 2.08 (m, 1H), 2.05-1.85 (m, 2H), 1.70-1.60 (m, 1H), 1.44 (s, 3H), 1.30 (s, 3H), 1.00- 0.85 (m, 4H), 0.50-0.35 (m, 3H), 0.30-0.18 (m, 1H).

Methyl ester of acid 2-. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -propionic (Intermediate 165) Following General Procedure B and using 8-cyclopropyl-5- (cyclopropyl-methyl-amino) -2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 164, 0.11 g, 0 , 37 mmole), methyl 2- (4-iodophenyl) propionate (Reagent 1, 0.108 g, 0.37 mmol), triethylamine (10 ml), copper (I) iodide (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0 , 1 mmol) followed by work-up and flash column chromatography on silica gel (230-400 mesh) using l -4% ethyl acetate in hexane as eluent, the title compound was obtained as an amorphous solid pale yellow color (0.148 g, 87%). H1 NMR (300 MHz, CDC13): d 7.51 (d, "7 = 8, 5Hz, 2H), 7.39 (d," 7 = 1, 6Hz, 1H), 7.29 (d, "7 = 8, 5Hz, 2H), 6.97 (d, «7 = 1, 6Hz, 1H), 4.32 (broad s, 1H), 3.75 (c, .7 = 7, 0Hz, 1H), 3.70 (s, 3H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.28 (s, 3H), 2.18-2, 08 (m, 1H), 2.02-1.82 (m, 2H), 1.62-1.52 (m, 1H), 1.52 (d, "7 = 7, 0Hz, 3H), 1 , 39 (s, 3H), 1.25 (s, 3H), 0.98-0.80 (m, 4H), 0.45-0.25 (m, 3H), 0.20-0.15 (m, 1H). 2- (4- [4-Cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -propionic acid (Compound 49) A solution of 2- methyl acid ester. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5, 6,7, 8 -tetrahydro-naphthalen-2-ethynyl] -phenyl} -propionic (Intermediate 165, 0.075 g, 0.16 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) was treated with 2 M lithium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture was stirred at the room temperature for 5h. The reaction mixture was neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title product as a yellow solid (0.07 g, 96%). H1 NMR (300 MHz, CDC13): d 7.50 (d, «7 = 8, 5Hz, 2H), 7.39 (d,« 7 = 1, 6Hz, 1H), 7.31 (d, «7 = 8, 5Hz, 2H), 6.97 (d, «7 = 1, 6Hz, 1H), 4.34 (broad s, 1H), 3.74 (c,« 7 = 7, 0Hz, 1H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.29 (s, 3H), 2.18-2.08 (m, 1H), 2, 02-1.82 (m, 2H), 1.62-1.52 (m, 1H), 1.52 (d, "7 = 7, 0Hz, 3H), 1.39 (s, 3H), 1 , 24 (s, 3H), 0.98-0.80 (m, 4H), 0.40-0.30 (m, 3H), 0.20-0.15 (m, 1H).

Methyl ester of acid 2-. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl ester} -2-methyl-propionic (Intermediate 166) Following General Procedure B and using 8-cyclopropyl-5- (cyclopropyl-methyl-amino) -2-ethynyl-4,4-dimethyl-1, 2,3,4-tetrahydronaphthalene (Intermediate 164, 0.11 g, 0 , 37 mmol), methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.118 g, 0.39 mmol), triethylamine (10 mL), copper (I) iodide (0.019 g, , 1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by work-up and flash column chromatography on silica gel (230-400 mesh) using ethyl acetate at 1% - 4% in hexane as eluent, the title compound was obtained as a pale yellow amorphous solid (0.125 g, 70%). H1 NMR (300 MHz, CDCl3): d 7.51 (d, "7 = 8, 5Hz, 2H), 7.39 (d," 7 = 1, 6Hz, 1H), 7.33 (d, "7 = 8, 5Hz, 2H), 6.97 (d, «7 = 1, 6Hz, 1H), 4.32 (broad s, 1H), 3.68 (s, 3H), 2.40-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.28 (s, 3H), 2.15-2.05 (m, 1H), 2.00-1.80 (m , 2H), 1.61 (s, 6H), 1.62-1.52 (m, 1H), 1.39 (s, 3H), 1.25 (s, 3H), 0.95-0, 80 (m, 4H), 0.45-0.30 (m, 3H), 0.20-0.10 (m, 1H).

Acid 2-. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -2-methyl-propionic (Compound 50) A solution of 2- methyl acid ester. { 4- [4-cyclopropyl-5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -2-methyl-propionic (Intermediate 166, 0.125 g, 0.266 mmol) in methanol (2.5 ml) and tetrahydrofuran (2.5 ml) was treated with 3M potassium hydroxide (1 ml, 3 mmol) and the mixture of The resulting reaction was stirred at room temperature overnight. The reaction mixture was neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give the title product as a pale yellow amorphous solid (0.12 g, 98% ). H1 NMR (300 MHz, CDCl3): d 7.51 (d, "7 = 8.5Hz, 2H), 7.40-7.38 (m, 3H), 6.97 (d," 7 = 1, 6Hz, 1H), 4.33 (s broad, 1H), 2.40-2.30 (, 1H), 2.30-2.20 (m, 1H), 2.28 (s, 3H), 2 , 10-2.00 (m, 1H), 2.00-1.80 (m, 2H), 1.62 (s, 6H), 1.60-1.50 (m, 1H), 1.39 (s, 3H), 1.24 (s, 3H), 0.95-0.80 (m, 4H), 0.45-0.30 (m, 3H), 0.20-0.10 (m , 1 HOUR) .

United States Patent No.

Reaction Scheme 27 Cyclopropyl- (4, -dimethyl-6-trimethylsilanylethynyl-1, 2,3,4-tetrahydro-naphthalen-1-yl) -methyl-amine (Intermediate 167) Following General Procedure C and using 4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (described in U.S. Patent No. 6,252,090, 1.23 g, 4.6 mmol) in dichloromethane (7 ml) and acetonitrile (3 ml), cyclopropylamine (2.5 ml, 36 mmol), acetic acid (2.5 ml) and sodium cyanoborohydride (0.58 g, 8.6 mmoles) followed by work-up and flash column chromatography on silica gel (230-400 mesh) using 8% ethyl acetate in hexane as eluent an intermediate was provided as a golden yellow solid (1.07 g, 76%). The intermediate (0.67 g, 2.62 mmol) was dissolved in acetone (10 ml) and treated with potassium carbonate (2.2 g, 16 mmol) and methyl iodide (0.75 ml, 12 mmol). . The resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil which was used as such for the next step.

Cyclopropyl- (6-ethynyl-4, 4-dimethyl-l, 2,3,4-tetrahydro-naphthalen-1-yl) -methyl-amine (Intermediate 168) A solution of cyclopropyl- (4,4-dimethyl-6-trimethylsilanylethynyl-1, 2,3,4-tetrahydro-naphthalen-1-yl) -methyl-amine (Intermediate 167, 0.67 g, 2.62 mmol) in methanol (10 ml) was treated with potassium carbonate (1 g, 7.23 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a light yellow oil (0.5 g, 75%). NMR H1 (300 MHz, CDC13): d 7.47 (d, 1H, "7 = 8.2Hz), 7.41 (d, 1H," 7 = 1.4Hz), 6.79 (dd, 1H, «7 = 8.2, 1.4Hz), 3.92 (t, 1H,« 7 = 8.2Hz), 3.01 (s, 3H), 2.11 (s, 3H), 2.15- 2.07 (m, 1H), 1.95-1.57 (m, 4H), 1.29 (s, 3H), 1.24 (s, 3H), 0.53-0.37 (m, 4H).

Methyl ester of acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -propionic (Intermediate 169) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethenyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 168, 0.116 g, 0.46 mmol) Methyl 2- (4-iodophenyl) propionate (Reagent 1, 0.17 g, 0.59 mmol), triethylamine (0.75 ml), copper iodide (I) (0.07 g, 0.37 mmol) ) and tetrakis (triphenylphosphine) palladium (0) (0.022 g, 0.019 mmol) followed by flash column chromatography on silica gel (230-400 mesh) and preparative normal phase HPLC using 5% ethyl acetate in hexane as eluent , the title compound was obtained (0.08 g, 42%). NMR H1 (300 MHz, CDC13): d 7.51-7.43 (, 3H), 7.29-7.22 (m, 4H), 3.94 (t, 1H, "7 = 7.9Hz) , 3.76-3.62 (m, 1H), 3.65 (s, 3H), 2.12 (s, 3H), 2.15-2.08 (m, 1H), 2.00-1 , 54 (2m, 4H), 1.52-1.46 (2d, 3H, "7 = 7.4Hz), 1.31 (s, 3H), 1.27 (s, 3H), 0.53- 0.38 (m, 4H).

Acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} -propionic (Compound 51) A solution of 2- methyl acid ester. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -propionic (Intermediate 169, 0.022 g, 0.05 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) was treated with a 2 M solution of sodium hydroxide (1 ml, 2 mmol) and the resulting reaction mixture it was stirred at room temperature overnight. The reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to preparative reverse phase HPLC using 10% water in acetonitrile as mobile phase to provide the product of the title (0.008 g, 40%).

H NMR (300 MHz, CDCl 3): d 7.50-7.44 (m, 3H), 7.31-7.27 (m, 3H), 7.20 (dd, 1H, "7 = 8.2. , 1.5Hz), 4.00 (t, 1H, J = 8.2Hz), 3.74 (c, 1H, «7 = 7.1Hz), 1H), 2.15 (s, 3H), 2 , 15-2.10 (m, 1H), 1.98-1.81 (m, 2H), 1.80-1.63 (m, 2H), 1.51 (d, 3H, "7 = 7"). , 1Hz), 1.31 (s, 3H), 1.27 (s, 3H), 0.52-0.49 (m, 4H).

Methyl ester of 2- (4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -2- methyl-propionic (Intermediate 170) Following General Procedure B and using 5- (cyclopropyl-methyl-amino) -2-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 168, 0.16 g, 0.63 mmoles), methyl 2- (4-iodophenyl) -2-methyl-propionate (Reagent 2, 0.18 g, 0.58 mmol), triethylamine (3 ml), copper iodide (I) (0.048 g, 0.25 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.032 g, 0.027) mmoles) followed by flash column chromatography on silica gel (230-400 mesh) and preparative normal phase HPLC using 6% ethyl acetate in hexane as mobile phase, the title compound was obtained (0.14 g, 56 %). NMR H1 (300 MHz, CDCl3): d 7.54-7.47 (m, 4H), 7.34-7.26 (m, 3H), 3.97 (t, 1H, "7 = 7.9Hz ), 3.68 (s, 3H), 2.16 (s, 3H), 2.16-2.00 (m, 1H), 2.00-1.61 (2m, 4H), 1.61 (s). s, 6H), 1.35 (s, 3H), 1.30 (s, 3H), 0.56-0.44 (m, 4H).

Acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -2-methyl-propionic (Compound 52) A solution of 2- methyl acid ester. { 4- [5- (cyclopropyl-methyl-amino) -8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl ester} -2-methyl-propionic (Intermediate 170, 0.08 g, 0.19 mmol) in methanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 2 M solution of sodium hydroxide (2 ml, 4 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo and the residue was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title product. (0.07 g, -100%). H1 NMR (300 MHz, CDC13): d 9.47 (broad s, 1H), 7.53-7.49 (m, 4H), 7.39 (d, 2H, "7 = 8.5Hz), 7 , 26 (dd, 1H, "7 = 7.9, 1.5Hz), 3.97 (t, 1H, «7 = 7.9Hz), 2.16 (s, 3H), 2.16-2.00 (m, 1H), 2.00-1.61 (2m, 4H), 1.61 (s, 6H), 1.35 (s, 3H), 1.30 (s, 3H), 0.56-0.44 (m, 4H).

PhNTf2, DMAP, CH2C12 Application from the United States Published Intermediate No. 171 2003/0166932.

Intermed o 172 3. Mei, K2C03, acetone intermediate 173 Reaction Scheme 28 6-Hydroxy-4, 4, 7-trimethyl-3, 4-dihydro-2H-naphthalen-l-one (Intermediate 171) A solution of 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (described in US 2003/0166932, published September 4, 2003, incorporated herein by reference; , 5 g, 25.6 mmol) and sodium cyanide (6.25 g, 127 mmol) in anhydrous dimethyl sulfoxide (100 ml) was heated at 230 ° C for 48 h in argon. The reaction mixture was then cooled to room temperature, poured into ice and acidified (Caution! Evolution of hydrogen cyanide!) With dilute hydrochloric acid and extracted with ethyl acetate (x2). The combined organic extract was washed with brine (xl), dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound, which was used as is for the next step (5.2 g, -100% ). NMR H1 (300 MHz, CDC13): d 7.86 (s, 1H), 6.87 (s, 1H), 2.70 (t, 2H, "7 = 7.0Hz), 2.24 (s, 3H), 1.97 (t, 2H, "7 = 7.0Hz), 1.32 (s, 6H).

Ester 3.8, 8-trimethyl-5-oxo-5, 6,7, 8-tetrahydro-naphthalene-2-yl of trifluoromethanesulfonic acid (Intermediate 172) A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-l-one (Intermediate 171, 5.2 g, 25.6 mmol) and 4-dimethylaminopyridine (6.1 g, 50 mmol) in anhydrous dichloromethane (50 ml) was treated with N-phenyltrifluoromethanesulfonimide (9.54 g, 26.7 mmol) in argon and stirred at room temperature for lh. The reaction mixture was subjected to flash chromatography on silica gel (230-400 mesh) using 6-7% ethyl acetate in hexane as eluent to give the title compound (6.4 g, 75%). NMR H1 (300 MHz, CDC13): d 7.96 (s, 1H), 7.28 (s, 1H), 2.74 (t, 2H, "7 = 7.0Hz), 2.37 (s, 3H), 2.04 (t, 2H, "7 = 7.0Hz), 1.39 (s, 6H). 4,4, 7-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 173) Following General Procedure D and using ester 3,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl of trifluoromethanesulfonic acid (Intermediate 172, .04 g, 15 mmol), triethylamine (20 ml), copper iodide (I) (0.6 g, 3 mmol), trimethylsilylacetylene (5.3 ml, 37.5 mmol) and dichlorobis (triphenylphosphine) -palladium (II) (2.2 g, 3 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 6% ethyl acetate in hexane as eluent, the title compound was obtained (4 g, 93%) in the form of a light yellow solid. NMR H1 (300 MHz, CDC13): d 7.54 (s, 1H), 7.19 (s, 1H), 2.42 (t, 2H, "7 = 7.0Hz), 2.14 (s, 3H), 1.70 (t, 2H, "7 = 7.0Hz), 1.08 (s, 6H), 0.00 (s, 9H).

Cyclopropyl- (6-ethynyl-4, 4, 7-trimethyl-1,2,4,4-tetrahydro-naphthalen-1-yl) -methyl-amine (Intermediate 174) Following General Procedure C and using 4,4, 7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 173, 4 g, 14 mmol) in dichloromethane (30 ml) and acetonitrile (10 ml), cyclopropylamine (3.11 ml, 45 mmol), acetic acid (3.2 ml) and sodium cyanoborohydride (2 g, 30 mmol) followed by work-up and flash column chromatography on silica gel (230 mesh) -400) using 10% ethyl acetate in hexane as eluent an intermediate was provided in the form of a light yellow solid, which was used as such for the next step (4.1 g, 90%). The intermediate (4.1 g, 13 mmol) was dissolved in acetone (40 ml) and treated with potassium carbonate (10 g, 72 mmol) and methyl iodide (2.5 ml, 40 mmol). The resulting reaction mixture was stirred at room temperature overnight. The volatile substances were evaporated in vacuumThe residue was dissolved in methanol (100 ml) and treated with potassium carbonate (10 g, 72 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (x2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to an oil which was filtered over a short plug of silica gel (230-400 mesh) to give the title compound (3.2 g, 92%). %) in the form of a clear oil. H NMR (300 MHz, CDCl3): d 7.42 (s, 1H), 7.38 (s, 1H), 3.49 (t, 1H, "7 = 7.0Hz), 3.23 (s, 1H), 2.40 (s, 3H), 2.15 (s, 3H), 2.15-2.10 (m, 1H), 1.97-1.62 (2m, 4H), 1.30 (s, 3H), 1.26 (s, 3H), 0.56-0.28 (m, 4H). 2- (4- [5- (Cyclopropyl-methyl-amino) -3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester. 2-methyl-propionic (Intermediate 175) Following General Procedure B and using cyclopropyl- (6-ethynyl-4,4,7-trimethyl-1, 2,3,4-tetrahydro-naphthalen-1-yl) -methyl-amine (Intermediate 174, 0.1 g 0.29 mmole), methyl 2- (4-iodophenyl) -2-methylpropionate (Reagent 2, 0.09 g, 0.29 mmol), triethylamine (8 ml), copper (I) iodide ( 0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 1-2% acetate of ethyl in hexane as eluent, the title compound was obtained (0.035 g, 26%). H1 NMR (300 MHz, CDC13): d 7.49 (d, J = 8.5 Hz, 2 H), 7.41 (s, 1 H), 7.38 (d, J = 8.5 Hz, 2 H), 7 , 32 (s, 1H), 3.92 (m, 1H), 3.67 (s, 3H), 2.43 (s, 3H), 2.18-2.10 (m, 1H), 2, 14 (s, 3H), 1.98-1.85 (m, 2H), 1.80-1.64 (m, 2H), 1.60 (s, 6H), 1.31 (s, 3H) , 1.26 (s, 3H), 0.58-0.42 (m, 4H).

Acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} -2-methyl-propionic (Compound 53) A solution of 2- methyl acid ester. { 4- [5- (cyclopropyl-methyl-amino) -3,8,8-trimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl ester} -2-methyl-propionic (Intermediate 175, 0.035 g, 0.08 mmol) in methanol (2 ml) and tetrahydrofuran (2 ml) was treated with a 2 M solution of sodium hydroxide (2 ml, 4 mmol) and the The resulting reaction mixture was refluxed for 2 days. The volatiles were evaporated in vacuo and the residue was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in acetonitrile as mobile phase to provide the product of the title (0.022 g, 64%). NMR H1 (300 MHz, CDCl3): d 7.48 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.37-7.34 (m, 3H), 3.95 (m, 1H), 2.40 (s, 3H), 2.18-2.10 (m, 1H), 2.14 (s, 3H), 1.98-1.85 (m, 2H), 1.80-1.64 (m, 2H), 1.57 (s, 6H), 1.29 (s, 3H), 1.25 (s, 3H), 0.56-0.42 (m, 4H).

Inte 2. [> -NH2, NaCNBH3, CH2C12, CH3CN, CH3COOH 3. Mei, K2C03, CH3COCH3 4. KOH Compound 54 Reaction Scheme 29 8-Ethyl -4,4-dimethyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (Intermediate 176) A solution of 8-vinyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthaleri-1-one (Intermediate 155, 1.12 g, 4.86 mmol) in ethyl acetate ml) was treated with 10% palladium on carbon (100mg) and the resulting reaction mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered on a pad of celite and the filtrate was evaporated to give the title product (1.1 g, 98%). NMR H1 (300 MHz, CDCl3): d 6.77 (d, 1H, "7 = 2.6Hz), 6.54 (d, 1H, < 7 = 2.6Hz), 3.87 (s, 3H) ), 3.05 (c, 2H, "7 = 7.3Hz), 2.67 (t, 2H," 7 = 6.7Hz), 1.95 (t, 2H, "7 = 6.7Hz), 1.36 (s, 6H), 1.23 (t, 3H, "7 = 7.3Hz). 8-Ethyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 177) A solution of 8-ethyl-4,4-dimethyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (Intermediate 176, 1.1 g, 4.73 mmol) and sodium cyanide (1 , 6 g, 33 mmol) in anhydrous dimethyl sulfoxide (20 ml) was heated at 210 ° C overnight in argon. The reaction mixture was then cooled to room temperature, poured into ice and acidified (Caution! Evolution of hydrogen cyanide!) Using 10% hydrochloric acid and extracted with ethyl acetate. The combined organic extract was washed with brine (xl), dried over anhydrous sodium sulfate, filtered and evaporated to give a dark orange solid. Flash column chromatography on silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as eluent afforded the title compound as a yellow solid (0.82 g, 82%) . H1 NMR (300 MHz, CD3C0CD3): d 8.99 (s, 1H), 6.81 (d, 1H, "7 = 2.6Hz), 6.64 (d, 1H," 7 = 2.6Hz) , 2.99 (c, 2H, J = 7.3Hz), 2.60 (t, 2H, J = 6.7Hz), 1.93 (t, 2H, «7 = 6.7Hz), 1.34 (s, 6H), 1.17 (t, 3H, "7 = 7.3Hz). 4-Ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-trifluoro-methanesulfonic acid ester (Intermediate 178) A solution of 8-ethyl-6-hydroxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 177, 0.27 g, 1.24 mmol) and 4-dimethylaminopyridine (0.242) g, 1.98 mmol) in anhydrous dichloromethane (10 ml) was treated with 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloro-pyridine (0.58 g, 1.48 mmol) in argon a the room temperature for 5h. The reaction mixture was subjected to flash chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent to give the title compound (0.43 g, 98%). NMR H1 (300 MHz, CDCl3): d 7.15 (d, 1H, "7 = 2.6Hz), 7.04 (d, 1H," 7 = 2.6Hz), 3.05 (c, 2H, «7 = 7.3Hz), 2.74 (t, 2H,« 7 = 6.7Hz), 2.00 (t, 2H, «7 = 6.7Hz), 1.38 (s, 6H), 1 , 24 (t, 3H, «7 = 7.3Hz). 8-Ethyl-4,4-dimethyl-6- (trimethylsilanyl) ethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 179) Following General Procedure D and using ester 4-ethyl-8, 8- dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-trifluoro-methanesulfonic acid (Intermediate 178, 0.9 g, 2.57 mmol), triethylamine (6 ml), N, N-dimethylformamide anhydrous (5 ml), dichlorobis (triphenylphosphine) palladium (II) (0.144 g, 0.2 mmol) and (trimethylsilyl) acetylene (2 ml, 13.64 mmol), the reaction was carried out overnight in a tube sealed at 90 ° C. Work-up followed by flash column chromatography on silica gel (230-400 mesh) using 2-3% ethyl acetate in hexane as eluent afforded the title compound as an orange oil (0.82 g). , quantitative). H1 NMR (300 MHz, CDC13): d 7.34 (d, 1H, "7 = 1.5Hz), 7.21 (d, 1H," 7 = 1.5Hz), 2.97 (c, 2H, «7 = 7.6Hz), 2.69 (t, 2H,« 7 = 6.7Hz), 1.95 (t, 2H, .7 = 6.7Hz), 1.35 (s, 6H), 1 , 20 (t, 3H, "7 = 7.6Hz), 0.27 (s, 9H). 8-Ethyl-6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalene-1-one (Intermediate 180) Following General Procedure F and using 8-ethyl-4,4-dimethyl-6- (trimethylsilanyl) ethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 179, 0.66 g, 2.2 mmol ), methanol (10 ml) and potassium carbonate (0.4 g, 2.9 mmol) gave the title compound as an orange oil (0.59 g, 100%). H1 NMR (300 MHz, CDC13): d 7.51 (d, 1H, "7 = 1.5Hz), 7.37 (d, 1H," 7 = 1.5Hz), 3.32 (s, 1H) , 3.10 (c, 2H, "7 = 7.3Hz), 2.84 (t, 2H," 7 = 6.7Hz), 2.08 (t, 2H, "7 = 6.7Hz), 1 , 48 (s, 6H), 1.33 (t, 3H, "7 = 7.3Hz).

Methyl ester of 2- [4- (4-ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] -2-methyl-propionic acid ester ( Intermediate 181) Following General Procedure B and using 8-ethyl-6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 180, 0.09 g, 0.39 mmol), methyl 2- (4-iodo phenyl) -2-methyl-propionate (Reagent 2, 0.152 g, 0.5 mmol), triethylamine (8 ml), copper iodide (I) (0.024 g, 0.12 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.087 g, 0.12 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 2-10% ethyl acetate in hexane as eluent, the title compound was obtained as an oil (0.095 g, 59%). H1 NMR (300 MHz, CDC13): d 7.53 (d, "7 = 8, 8Hz, 2H), 7.43 (d," 7 = 1, 8Hz, 1H), 7.35 (d, "7 = 8, 8Hz, 2H), 7.30 (d, «7 = 1, 8Hz, 1H), 3.68 (s, 3H), 3.03 (c,« 7 = 7, 3Hz, 2H), 2 , 73 (t, «7 = 6, 9Hz, 2H), 1.99 (t,« 7 = 6, 9Hz, 2H), 1.61 (s, 6H), 1.40 (s, 6H), 1 , 25 (t, «7 = 7, 3Hz, 3H).

Methyl ester of acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl] -phenyl} -2-methyl-propionic (Intermediate 182) Following General Procedure C and using 2- [4- (4-ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -phenyl] methyl ester] -2-methyl-propionic (Intermediate 181, 0.095 g, 0.23 mmol) in dichloromethane (3 ml) and acetonitrile (1.5 ml), cyclopropylamine (1 ml, 14.5 mmol), acetic acid (1 ml) and sodium cyanoborohydride (0.12 g, 1.91 mmol) followed by work-up gave an intermediate in the form of an oil, which was used as such for the next step. The intermediate (crude 0.23 mmol, 0.13 g) was dissolved in acetone (6 ml) and treated with potassium carbonate (0.23 g, 1.66 mmol) and methyl iodide (1.5 ml, 25 mmol). The resulting reaction mixture was stirred at room temperature overnight. The solids were separated by filtration, the filtrate and the washings were evaporated in vacuo to an oil. Flash column chromatography on silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent afforded the title compound (0.07, 65%). H1 NMR (300 MHz, CDC13): d 7.55 (d, «7 = 8, 8Hz, 2H), 7.43 (d,« 7 = 1, 7Hz, 1H), 7.37 (d, «7 = 8, 8Hz, 2H), 7.22 (d, «7 = 1, 7Hz, 1H), 4.13 (m, 1H), 3.72 (s, 3H), 2.78-2.68 ( m, 2H), 2.32-2.24 (m, 1H), 2.25 (s, 3H), 2.18-2.08 (m, 1H), 1.99-1.79 (m, 2H), 1.65 (s, 6H), 1.63-1.53 (m, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.23 (t, « 7 = 7, 3Hz, 3H), 0.50-0.40 (m, 3H), 0.30-0.20 (m, 1H).

Acid 2-. { 4- [5- (cyclopropyl-methyl-amino) -4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} -2-methyl-propionic (Compound 54) A solution of 2- methyl acid ester. { 4- [5- (cyclopropyl-methyl-amino) -4-ethyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ethynyl] -phenyl} -2-methyl-propionic (Intermediate 182, 0.035 g, 0.076 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with 3M potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was heated at 80 ° C for 2 days. The reaction mixture was neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to provide a residue which was purified by preparative reverse phase HPLC to provide the title product (0.023 g, %). NMR H1 (300 MHz, CDCl3): d 7.49 (d, "7 = 8, 4Hz, 2H), 7.36-7.26 (m, 3H), 7.16 (d, "7 = 1, 7Hz, 1H), 4.06 (m, 1H), 2.71-2.63 (m, 2H), 2.25-2.17 (m, 1H), 2.18 (s, 3H), 2.05-2.00 (m, 1H), 1.95-1.78 (m, 2H) , 1.60-1.50 (m, 1H), 1.58 (s, 6H), 1.35 (s, 3H), 1.22 (s, 3H), 1.16 (t, "7 = 7, 3Hz, 3H), 0.4-0.3 (m, 3H), 0.2-0.1 (m, 1H).

Intermediate 184 Intermediate 173 3. LiOH, EtOH, H20 4. HCOOH,], 4-dioxane Reaction Scheme 30 Ester 4,4, 7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-yl of trifluoromethanesulfonic acid (Intermediate 183) A stirred, cooled solution (-78 ° C) of 4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 173, 0.95 g, 3.33 mmol ) in anhydrous tetrahydrofuran (10 ml) under argon was treated with a 1 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (5 ml, 5 mmol). After lh, N-phenyltrifluoromethanesulfonimide (1.08 g, 3.33 mmol) was added and the reaction mixture was stirred at room temperature for lh. The reaction was quenched with a saturated aqueous solution of ammonium chloride, diluted with water and extracted with diethyl ether (x2). The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash chromatography on silica gel using 2-4% ethyl acetate in hexane as eluent to provide the title compound. title (0.73 g, 52%). H NMR (300 MHz, CDC13): d 7.08 (s, 1H), 6.92 (s, 1H), 5.67 (t, 2H, "7 = 5.0Hz), 2.15 (s, 3H), 2.08 (d, 2H, "7 = 5.0Hz), 1.00 (s, 6H), 0.00 (s, 9H).

Ethyl ester of 4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 184) Following General Procedure E and using 4,4, 7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-yl ester of trifluoromethanesulfonic acid (Intermediate 183, 0.73 g, 1.75 mmol) , palladium acetate (0.1 g, 0.45 mmol), 1,3-bis (diphenylphosphino) propane (0.1 g, 0.24 mmol), N, N-dimethylformamide (3.5 ml), ethanol (3.5 ml) and triethylamine (3.5 ml) followed by flash column chromatography on silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent was obtained the title compound (0.435 g, 73 %). NMR H1 (300 MHz, CDC13): d 7.42 (s, 1H), 7.10 (s, 1H), 6.76 (t, 2H, "7 = 5.0Hz), 4.04 (c, 2H, "7 = 7.0Hz), 2.15 (s, 3H), 2.02 (d, 2H," 7 = 5.0Hz), 1.09 (t, 3H, "7 = 7.0Hz) , 0.97 (s, 6H), 0.00 (s, 9H).

Ethyl ester of 6-ethynyl-4, 4, 7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 185) Following General Procedure F and using 4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 184, 0.43 g, 1.3 mmol), ethanol (4 ml) and potassium carbonate (0.84 g, 6.06 mmol), the title compound was obtained (0.33 g, 95% ). NMR H1 (300 MHz, CDC13): d 7.70 (s, 1H), 7.40 (s, 1H), 7.05 (t, 2H, "7 = 5.0Hz), 4.30 (c, 2H, "7 = 7.0Hz), 2.43 (s, 3H), 2.30 (d, 2H, "7 = 5.0Hz), 1.36 (t, 3H," 7 = 7.0Hz), 1.23 (s, 6H).

Ethyl 6- (4-methoxycarbonylmethyl-phenylethynyl) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Intermediate 186) Following General Procedure B and using ethyl ester of 6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 185, 0.126 g, 0.47 mmol), methyl ester of 4-iodophenylacetic acid (0.13 g, 0.47 mmol), triethylamine (2 ml), copper (I) iodide (0.029 g, 0.15 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10-12% ethyl acetate in hexane as eluent, the title compound was obtained in the form of a viscous oil (0.144 g, 74%). H NMR (300 MHz, CDCl 3): d 7.72 (s, 1 H), 7.47 (d, 2 H, "7 = 8.1 Hz), 7.35 (s, 1 H), 7.27 (d, 2H, "7 = 8.1Hz), 7.05 (t, 2H," 7 = 5.0Hz), 4.34 (c, 2H, "7 = 7.0Hz), 3.70 (s, 3H) , 3.64 (s, 2H), 2.48 (s, 3H), 2.32 (d, 2H, "7 = 5.0Hz), 1.38 (t, 3H," 7 = 7.0Hz) , 1.27 (s, 6H).

Ethyl 6- (4-carboxymethyl-phenylethynyl) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Compound 55) A solution of 6- (4-carboxymethyl-phenylethynyl) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 186, 0.144 g, 0.35 mmol) in ethanol (2 ml) was treated with a 1 M solution of lithium hydroxide (1 ml, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in acetonitrile as mobile phase to give the title product (0.071 g, fifty%). NMR H1 (300 MHz, CDCl3): d 7.68 (s, 1H), 7.47 (broad d, 2H, "7 = 8.1Hz), 7.41 (s, 1H), 7.21 (d width, 2H), 7.04 (t, 2H, «7 = 5.0Hz), 4.31 (c, 2H,« 7 = 7.0Hz), 3.65 (s wide, 2H), 2.46 (s, 3H), 2.30 (d, 2H, "7 = 5.0Hz), 1.37 (t, 3H," 7 = 7.0Hz), 1.24 (s, 6H).

Ethyl 6- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Intermediate 187) Following General Procedure B and using ethyl ester of 6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 185, 0.2 g, 0.75 mmol), ester methyl 2-fluoro-4-iodophenylacetic acid (0.22 g, 0.75 mmol), triethylamine (2 ml), copper iodide (I) (0.03 g, 0.16 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.1 g, 0.14 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 10-12% ethyl acetate in hexane as eluent, the title in the form of a viscous oil (0.23 g, 73%). H NMR (300 MHz, CDCl3): d 7.73 (s, 1H), 7.42 (s, 1H), 7.30-7.20 (m, 3H), 7.06 (t, 2H, « 7 = 5.0Hz), 4.32 (c, 2H, «7 = 7.0Hz), 3.71 (s, 3H), 3.68 (s, 2H), 2.47 (s, 3H), 2.32 (d, 2H, "7 = 5.0Hz), 1.37 (t, 3H," 7 = 7.0Hz), 1.26 (s, 6H).

Ethyl 6- (4-carboxymethyl-3-fluoro-phenylethynyl) -4,4,7-trimethyl-3,4-dihydro-naphthalene-l-carboxylic acid ester (Compound 56) A solution of 6- (4-carboxymethyl-3-fluoro-phenylethynyl) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 187, 0.24 g, 0 , 54 mmoles) in ethanol (2 ml) was treated with a 2 M solution of lithium hydroxide (1 ml, 2 mmoles) and the resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to provide the title product (0.05. g, 22%). H NMR (300 MHz, CDC13): d 7.69 (s, 1H), 7.41 (s, 1H), 7.27-7.19 (m, 3H), 7.05 (t, 2H, « 7 = 4.7Hz), 4.32 (c, 2H, «7 = 7.0Hz), 3.64 (broad s, 2H), 2.45 (s, 3H), 2.31 (d, 2H, "7 = 4.7Hz), 1.37 (t, 3H," 7 = 7.0Hz), 1.25 (s, 6H). 6- (t-Butyl-dimethyl-silanyloxy) -4,4, 7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 188) A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 171, 2.04 g, 10 mmol) in N, N-dimethylformamide anhydrous (10 ml) in argon was treated with imidazole (1 g, 14.7 mmol) followed by t-butyldimethylsilyl chloride (1.5 g, 10 mmol). After stirring the reaction mixture at room temperature overnight, it was poured into water and extracted with diethyl ether (x2) The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue which was purified by flash column chromatography on silica gel (230-400 mesh) using 8-14% ethyl acetate in hexane as eluent to provide the title compound (2.5 g, 79%). NMR H1 (300 MHz, CDCl3): d 7.74 (s, 1H), 6.65 (s, 1H), 2.56 (t, 2H, "7 = 6.8Hz), 2.09 (s, 3H), 1.88 (t, 2H, "7 = 6.8Hz), 1.24 (s, 6H), 0.93 (s, 9H), 0.17 (s, 6H).

Ester 6- (t-butyl-dimethyl-silanyloxy) -4,4, 7-trimethyl-3,4-dihydro-naphthalene-1-yl of trifluoromethanesulfonic acid (Intermediate 189) A stirred, cooled solution (-78 ° C) of 6- (t-butyl-dimethyl-silanyloxy) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-yl ester of trifluoromethanesulfonic acid (Intermediate 188, 2.53 g, 8 mmol) in anhydrous tetrahydrofuran (25 ml) in argon was treated with a 1 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (12 ml, 12 mmol). After lh, N-phenyltrifluoromethanesulfonimide (4.28 g, 12 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride, diluted with water and extracted with diethyl ether (x2). The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash chromatography on silica gel using 4% ethyl acetate in hexane as eluent to provide the title compound ( 1.4 g, 39%). NMR H1 (300 MHz, CDCl3): d 6.90 (s, 1H), 6.49 (s, 1H), 5.53 (t, 2H, "7 = 5.0Hz), 2.09 (d, 2H, "7 = 5.0Hz), 1.95 (s, 3H), 1. 01 (s, 6H), 0.78 (s, 9H), 0.00 (s, 6H).

Ethyl ester of 6- (t-butyl-dimethyl-silanyloxy) -4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 190) Following General Procedure E and using ester 6- ( t-butyl-dimethyl-silanyloxy) -4,4, 7-trimethyl-3,4-dihydro-naphthalene-1-yl of trifluoromethanesulfonic acid (Intermediate 189, 3.4 g, 7.55 mmol), palladium (0.36 g, 1.62 mmol), 1,3-bis (diphenylphosphino) propane (0.36 g, 0.86 mmol), N, N-dimethylformamide (7 mL), ethanol (7 mL) and triethylamine (7 ml) followed by flash column chromatography on silica gel (230-400 mesh) using 7% ethyl acetate in hexane as eluent gave the title compound (1.35 g, 48%). H NMR (300 MHz, CDCl 3): d 7.40 (s, 1H), 6.65 (t, 2H, "7 = 5.0Hz), 6.65 (s, 1H), 4.08 (c, 2H, "7 = 7.0Hz), 2.04 (d, 2H," 7 = 5.0Hz), 1.96 (s, 3H), 1.13 (t, 3H, "7 = 7.0Hz) , 0.99 (s, 6H), 0.79 (s, 9H), 0.00 (s, 6H). Ethyl 6- (t-butyl-dimethyl-silanyloxy) -4,4,7-trimethyl-l, 2,3,4-tetrahydro-naphthalene-1-carboxylic acid ester (Intermediate 191) A solution of 6- (t-butyl-dimethyl-silanyloxy) -4,4,7-trimethyl-3,4-dihydro-naphthalene-l-carboxylic acid ethyl ester (Intermediate 190, 0.95 g, 2.54 mmoles) in ethanol was treated with a suspension of palladium on carbon at 5% (0.3 g) in ethyl acetate (0.5 ml) and the resulting reaction mixture was stirred under a hydrogen atmosphere overnight. The solids were filtered on a pad of celite and the filtrate was evaporated in vacuo to give the title compound as a viscous oil (0.95 g, -100%). NMR H1 (300 MHz, CDC13): d 6.66 (s, 1H), 6.51 (s, 1H), 3.95 (c, 2H, "7 = 7.0Hz), 3.46 (m, 1H), 1.92 (s, 3H), 1.93-1.75 (m, 2H), 1.64-1.55 (m, 1H), 1.38-1.30 (m, 1H), 1.06 (s, 3H), 1.01 (t, 3H, "7 = 7.0Hz), 1.01 (s, 3H), 0.80 (s, 9H), 0.00 (s, 6H).

Ethyl ester of 4,4,7-trimethyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (Intermediate 192) The ethyl ester of 6- (t-butyl-dimethyl-silanyloxy) -4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (Intermediate 191, 0.95 g, 2) , 54 mmol) was treated with a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (4 mL, 2 mmol) in argon and the resulting reaction mixture was stirred at room temperature for 45 min. Water was added and the reaction mixture was extracted with 10% ethyl acetate in diethyl ether. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil which was used for the next step. The oil was dissolved in anhydrous dichloromethane under argon and treated with 4- (dimethylamino) pyridine (0.62 g, 5.1 mmol) and N-phenyltrifluoromethanesulfonimide (0.91 g, 2.54 mmol). After ih at room temperature, the reaction mixture was subjected to flash column chromatography using 8% ethyl acetate in hexane as eluent to give the title compound as an oil (0.86 g, 86% ). NMR H1 (300 MHz, CDC13): d 7.19 (s, 1H), 7.07 (s, 1H), 4.17 (c, 2H, J = 7.0Hz), 3.73 (t, 1H) , "7 = 5.9Hz), 2.30 (s, 3H), 2.18-1.97 (m, 2H), 1.87-1.78 (m, 1H), 1.70-1, 56 (m, 1H), 1.31-1.25 (2s, 3H and It, 3H, overlapping).

Ethyl ester of 4,4,7-trimethyl-6-trimethylsilanylethynyl-1, 2,3,4-tetrahydro-naphthalene-l-carboxylic acid (Intermediate 193) Following General Procedure D in a sealed tube and using 4,4, 7-trimethyl-6-trifluoromethanesulfonyloxy-1, 2,3,4-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 192, 0.86 g , 2.2 mmol), triethylamine (2 ml), copper iodide (I) (0.083 g, 0.44 mmol), trimethylsilylacetylene (2 ml, 14 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.306 g, 0.44 mmole) followed by flash column chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent, and preparative normal phase HPLC using 5% ethyl acetate in hexane as the phase mobile in order to separate the starting material recovered from the product, the title compound (0.26 g) was obtained. H NMR (300 MHz, CDCl 3): d 7.21 (s, 1H), 6.72 (s, 1H), 3.95 (c, 2H, "7 = 7.0Hz), 3.49 (t, 1H, "7 = 5.8Hz), 2.13 (s, 3H), 1.95-1.62 (m, 2H), 1.60-1.48 (m, 1H), 1.42-1 , 31 (m, 1H), 1.10-1.00 (2s, 3H and lt, 3H, overlapping), 0.04 (s, 9H).

Ethyl 6- (4-t-butoxycarbonylmethyl-phenylethynyl) -4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid ester (Intermediate 194) The ethyl ester of 4,4,7-trimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (Intermediate 193, 0.26 g, 0.76 mmol) was treated with a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (3 ml, 3 mmol) in argon and the resulting reaction mixture was stirred at room temperature for 1 h. Water was added and the reaction mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil which was used as such for the next step. Following General Procedure B and using the oil (0.76 mmol), 4-iodo-butylphenyl acetate (Reagent 10, 0.23 g, 0.72 mmol), triethylamine (2 ml), copper iodide (I ) (0.06 g, 0.32 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.14 g, 0.2 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using acetate of 12% ethyl in hexane as eluent, the title compound was obtained as a pale yellow, viscous oil (0.23 g, 66%). H1 NMR (300 MHz, CDC13): d 7.50 (s, 1H), 7.48 (d, 2H, "7 = 8.5Hz), 7.24 (d, 2H," 7 = 8.5Hz) , 6.98 (s, 1H), 4.17 (c, 2H, "7 = 7.0Hz), 3.74 (t, 1H," 7 = 5.8Hz), 3.52 (s, 2H) , 2.42 (s, 3H), 2.27-1.99 (m, 2H), 1.87-1.78 (m, 1H), 1.63-1.44 (m, 1H), 1 , 43 (s, 9H), 1.32 (s, 3H), 1.26 (s, 3H), 1.23 (t, 3H, hidden).

Ethyl 6- (4-carboxymethyl-phenylethynyl) -4,4,7-trimethyl-1,3,4,4-tetrahydro-naphthalene-1-carboxylic acid ester (Compound 57) A solution of 6- (4-t-butoxycarbonylmethyl-phenylethynyl) -4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 194, 0.23 g , 0.5 mmol) in 1,4-dioxane (1 ml) was treated with formic acid (3 ml) and the resulting reaction mixture was stirred at room temperature for 6 h. Water was added and the reaction mixture was extracted with ethyl acetate (x2). The combined organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase gave the title compound (0.15 g, 74%). NMR H1 (300 MHz, CDC13): d 7.48 (s, 1H), 7.46 (broad d, 2H), 7.23 (broad d, 2H), 6.96 (s, 1H), 4, 17 (c, 2H, "7 = 7.0Hz), 3.73 (t, 1H," 7 = 5.8Hz), 3.54 (broad s, 2H), 2.40 (s, 3H), 2 , 29-1.95 (m, 2H), 1.85-1.77 (m, 1H), 1.62-1.44 (m, 1H), 1.31 (s, 3H), 1.26 (s, 3H), 1.25 (t, 3H, hidden) Intermediate 195 Intermediate 199 Intermediate 197 R2 = H Compound 58 R2 = H R2 = F Compound 59 R2 = F 3. LiOH, H20, EtOH, Reaction Scheme 31-Hydroxy-2,4,4-trimethyl-3,4-dihydro-2H-naph talen-1-one (Intermediate 195) A solution 6-methoxy-2,4,4-trimethyl-3,4-dihydro-2H-naphthalen-1-one (described in the Journal of Pharmaceutical Sciences, 1970, 59 (6), pp. 869-870, Floyd et al, incorporated herein by reference: 1.2 g, 5.5 mmol) and sodium cyanide (2 g, 41 mmol) in anhydrous dimethyl sulfoxide (15 ml) was heated at 230 ° C for 24 h in argon. The reaction mixture was then cooled to room temperature, poured into ice and acidified (Caution! Evolution of hydrogen cyanide!) With dilute hydrochloric acid and extracted with ethyl acetate (x2). The combined organic extract was washed with brine (xl), dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound, which was used as such for the next step (1 g, 89%). 6.8, 8-Trimethyl-5-oxo-5, 6,7,8-tetrahydro-naphthalene-2-yl ester of trifluoromethanesulfonic acid (Intermediate 196) A solution of 6-hydroxy-2,4,4-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 195, 1 g, 5 mmol) and 4- (dimethylamino) pyridine (1.22 g) , 10 mmol) in anhydrous dichloromethane (10 ml) was treated with N-phenyltrifluoromethanesulfonimide (1.78 g, 10 mmol), and the resulting reaction mixture was stirred at room temperature for 2 h. Flash column chromatography of the reaction mixture on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent afforded the title compound as a white solid (1.45 g, 86%). H1 NMR (300 MHz, CDC13): d 8.06 (d, 1H, "7 = 8.5Hz), 7.25 (d, 1H," 7 = 2.0Hz), 6.79 (dd, 1H, "7 = 8.5, 2.0Hz), 2.79 (m, 1H), 1.94 (m, 2H), 1.41 (s, 3H), 1.37 (s, 3H), 1, 22 (d, 3H, "7 = 6.7Hz). 2,4, 4-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 197) Following General Procedure D and using 6,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-yl ester of trifluoromethanesulfonic acid (Intermediate 196, 1.45 g, 4.3 mmol), triethylamine (5 ml), copper iodide (I) (0.21 g, 0.26 mmol), trimethylsilylacetylene (3 ml, 21 mmol) and dichlorobis (triphenylphosphine) palladium ( II) (0.75 g, 1.07 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent, the title compound was obtained (1.28 g. , -100%). NMR H1 (300 MHz, CDC13): d 7.64 (d, 1H, "7 = 7.9 Hz), 7.22 (d, 1H," 7 = 2.0Hz), 7.08 (dd, 1H) , "7 = 7.9, 2.0Hz), 2.50 (m, 1H), 1.94 (d, 2H," 7 = 8.8Hz)), 1.13 (s, 3H), 1, 08 (s, 3H), 0.96 (d, 3H, "7 = 6.8Hz), 0.00 (s, 9H). 2,4,5-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-yl ester of trifluoro-methanesulfonic acid (Intermediate 198) A stirred, cooled solution (ice bath) of 2,4,4-Trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 197, 1.28 g, 4.5 mmol) in anhydrous dichloromethane (10 ml) was treated with 2%. , 6-di-t-butyl-4-methylpyridine (2.04 g, 9.91 mmol) and trifluoromethanesulfonic anhydride (1.52 mL, 9 mmol) and the resulting reaction mixture was stirred at room temperature for 5 days at the end of which it was subjected to flash chromatography on silica gel (230-400 mesh) using 5% ethyl acetate in hexane as eluent to give the title compound as an oil (1.59 g, 85% ). H1 NMR (300 MHz, CDC13): d 7.09 (d, 1H, J = 7.9Hz), 7.07 (d, 1H, "7 = 1.5Hz), 6.98 (dd, 1H, J = 7.9, 1.5Hz), 2.04 (s, 2H), 1.72 (s, 3H), 1.03 (s, 6H), 0.00 (s, 9H).

Ethyl ester of 2,4,4-trimethyl-β-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 199) Following General Procedure E and using 2,4,4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-yl ester of trifluoromethanesulfonic acid (Intermediate 198, 1.59 g, 3.8 mmol), palladium acetate (0.1 g, 0.45 mmol), 1,3-bis (diphenylphosphino) propane (0.1 g, 0.24 mmol) , N, N-dimethylformamide (2.4 ml), ethanol (2.4 ml) and triethylamine (2.4 ml) followed by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate 5%. % in hexane as eluent was obtained the title compound (0.31 g, 24%) as a yellow oil. H1 NMR (300 MHz, CDC13): d 7.12 (d, 1H, "7 = 1.5Hz), 7.01 (dd, 1H," 7 = 8.2, 1.8Hz), 6.77 ( d, 1H, "7 = 8.2Hz), 4.10 (c, 2H," 7 = 7.0Hz), 1.93 (s, 2H), 1.73 (s, 3H), 1.08 ( t, 3H, "7 = 7.0Hz), 0.99 (s, 6H), 0.00 (s, 9H).

Ethyl ester of 6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 200) Following the general procedure F and using 2, 4, 4-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-l-carboxylic acid ethyl ester (Intermediate 199, 0.31 g, 0.92 mmol), ethanol (2 ml) and potassium carbonate (0.3 g, 2.2 mmol), the title compound was obtained (0.26 g, > 100%). H1-NMR (300 MHz, CDC13): d 7.32 (d, 1H, "7 = 1.5Hz), 7.20 (dd, 1H," 7 = 8.2, 1.5Hz), 6.96 ( d, 1H, "7 = 8.2Hz), 4.27 (c, 2H, "7 = 7.0Hz), 3.00 (s, 1H), 2.10 (s, 2H), 1.90 (s, 3H), 1.27 (t, 3H, "7 = 7.0Hz), 1.16 (s, 6H).

Ethyl 6- (4-methoxycarbonylmethyl-phenylethynyl) -2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Intermediate 201) Following General Procedure B and using ethyl ester of 6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (Intermediate 200, 0.106 g, 0.38 mmol), methyl ester of 4-iodophenylacetic acid (0.106 g, 0.38 mmol), triethylamine (2 ml), copper iodide (I) (0.02 g, 0.105 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 12-15% ethyl acetate in hexane as eluent, the title compound was obtained a light yellow oil form (0.075 g, 47%). H NMR (300 MHz, CDCl3): d 7.49 (d, 2H, "7 = 7.9Hz), 7.45 (d, 1H," 7 = 1.5Hz), 7.32 (dd, 1H, «7 = 7.9, 1.5Hz), 7.26 (d, 2H,« 7 = 7.9Hz), 7.07 (d, 1H, «7 = 7.9Hz), 4.37 (c, 2H, "7 = 7.0Hz), 3.70 (s, 3H), 3.63 (s, 2H), 2.22 (s, 2H), 2.00 (s, 3H), 1.38 ( t, 3H, "7 = 7.0Hz), 1.27 (s, 6H).

Ethyl 6- (4-carboxymethyl-phenylethynyl) -2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Compound 58) A solution of 6- (4-carboxymethyl-phenylethynyl) -2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (0.075 g, 0.18 mmol) in ethanol (2 ml) ) was treated with a 1 M solution of lithium hydroxide (1 ml, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 0.5 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to provide the title product (0.055 g, 76%). H NMR (300 MHz, CDCl3): d 7.48 (d, 2H, "7 = 7.9Hz), 7.44 (d, 1H," 7 = 1.5Hz), 7.31 (dd, 1H, «7 = 7.9, 1.7Hz), 7.23 (broad d, 2H,« 7 = 7.7Hz), 7.06 (d, 1H, «7 = 7.9Hz), 4.36 (c , 2H, "7 = 7.0Hz), 3.60 (broad s, 2H), 2.20 (s, 2H), 1.99 (s, 3H), 1.37 (t, 3H," 7 = 7.0Hz), 1.26 (s, 6H).

Ethyl 6- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Intermediate 202) Following General Procedure B and using ethyl ester of 6-ethynyl-2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid (0.16 g, 0.59 mmol), methyl ester of acid 2-fluoro-4-iodophenylacetic acid (Intermediate 200, 0.16 g, 0.56 mmol), triethylamine (2 ml), copper iodide (I) (0.07 g, 0.37 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.11 g, 0.16 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 15% ethyl acetate-in hexane as eluent, the title in the form of a viscous oil (0.15 g, 58%). H1 NMR (300 MHz, CDCl3): d 7.44 (d, 1H, "7 = 1.5Hz), 7.32 (dd, 1H," 7 = 7.9, 1.5Hz), 7.30- 7.19 (m, 3H), 7.08 (d, 1H, "7 = 7.9Hz), 4.37 (c, 2H," 7 = 7.0Hz), 3.71 (s, 3H), 3.68 (s, 2H), 2.21 (s, 2H), 2.00 (s, 3H), 1.37 (t, 3H, "7 = 7.0Hz), 1.27 (s, 6H).

Ethyl 6- (4-carboxymethyl-3-fluoro-phenylethynyl) -2,4,4-trimethyl-3,4-dihydro-naphthalene-l-carboxylic acid ester (Compound 59) A solution of 6- (4-carboxymethyl-3-fluoro-phenylethynyl) -2,4,4-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 202, 0.15 g, 0 , 35 mmol) in ethanol (2 ml) was treated with a 1 M solution of lithium hydroxide (1 ml, 1 mmol) and the resulting reaction mixture was stirred at room temperature for 0.5 h. The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product (0.1 g, 67%). NMR H1 (300 MHz, CDCl3): d 7.44 (d, 1H, "7 = 1.5Hz), 7.32 (dd, 1H," 7 = 8.2, 1.5Hz), 7.22- 7.18 (m, 3H), 7.07 (d, 1H, "7 = 7.9Hz), 4.36 (c, 2H, 7 = 7.0Hz), 3.66 (s wide, 2H), 2.20 (s, 2H), 1.99 (s, 3H), 1.37 (t, 3H, "7 = 7.0Hz), 1.26 (s, 6H).

Ethyl ester of [4- (8,8-dimethyl-5-trifluoromethanesulfonyloxy-7,8-dihydro-naphthalen-2-ylethynyl) -2-fluoro-phenyl] -acid acid (Intermediate 203) A solution of [4- (8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -2-fluoro-phenyl] -acetic acid methyl ester (Patent of the United States No. 6,252,090; 0.28 g, 0.77 mmol) in anhydrous dichloromethane (5 ml) was treated with 2,6-di-t-butyl-4-methylpyridine (0.189 g, 0.92 mmol) and trifluoromethanesulfonic anhydride (0.136 ml, 0.81 mmol) and the resulting reaction mixture was stirred at room temperature for 4 h at the end of which it was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash chromatography on silica gel (230-400 mesh) using ethyl acetate at room temperature. % in hexane as eluent to give the title compound as a pale orange oil (0.32 g, 84%). NMR H1 (300 MHz, CDC13): d 7.46-7.22 (m, 6H), 6.00 (t, «7 = 4, 8Hz, 1H), 3.72 (s, 3H), 3, 70 (s, 2H), 2.41 (d, "7 = 4, 8Hz, 2H), 1.33 (s, 6H).

Ethyl 6- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -4,4-dimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Intermediate 204) Following General Procedure E and using acid methyl ester [4- (8,8-dimethyl-5-trifluoromethanesulfonyloxy-7,8-dihydro-naphthalen-2-ylethynyl) -2-fluoro-phenyl] -acetic (Intermediate 203, 0.32 g, 0.65 mmol), palladium acetate (0.015 g, 0.064 mmol), 1,3-bis (diphenylphosphino) propane (0.027 g, 0.064 mmol), N, N-dimethylformamide (5 ml), ethanol (2 ml) and triethylamine (2 ml) followed of flash column chromatography on silica gel (230-400 mesh) using 5-15% ethyl acetate in hexane as eluent gave the title compound (0.15 g, 55%) as a color oil yellow. 1 H-NMR (300 MHz, CDCl 3): d 7.84 (d, 7 = 8, 2Hz, 1H), 7.47 (d, "7 = 1.7Hz, 1H), 7.37 (dd," 7 = 8.2, 1.7Hz, 1H), 7.30-7.15 (m, 3H), 7.08 (t, «7 = 4, 8Hz, 1H), 4.31 (c,« 7 = 7 , 0Hz, 2H), 3.71 (s, 3H), 3.68 (s, 2H), 2.34 (d, «7 = 4, 8Hz, 2H), 1.37 (t,« 7 = 7 , 0Hz, 3H), 1.28 (s, 6H).

Ethyl 6- (4-carboxymethyl-3-fluoro-phenylethynyl) -4,4-dimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ester (Compound 60) A solution of 6- (3-fluoro-4-methoxycarbonylmethyl-phenylethynyl) -4,4-dimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 204, 0.15 g, 0.36 mmoles) in ethanol (3 ml) and tetrahydrofuran (3 ml) was treated with a 2M solution of lithium hydroxide (1.5 ml, 3 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 hrs. . The volatiles were evaporated in vacuo, the residue was neutralized with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 5% water in acetonitrile as the mobile phase to give the title product (0.04 g). g, 27%). H1 NMR (300 MHz, CDC13): d 7.81 (d, «7 = 8, 2Hz, 1H), 7.46 (d,« 7 = 1, 7Hz, 1H), 7.37 (dd, «7 = 8.2 yl, 7Hz, 1H), 7, 27-7.09 (m, 3H), 7.07 (t, «7 = 4, 8Hz, 1H), 4.31 (c,« 7 = 7, 0Hz, 2H), 3.66 (s, 2H) ), 2.33 (d, J = 4.8 Hz, 2H), 1.37 (t, "7 = 7, 0Hz, 3H), 1.27 (s, 6H). 3. TBAF, Intermediate THF 205 Reagent 11 Reaction Scheme 32 Isopropyl Ester 3,5-dibromobenzoic acid (Intermediate 205) A solution of 3,5-dibromobenzoic acid (Aldrich, 2.4 g, 8.6 mmol) in benzene (150 ml) and isopropanol (50 ml) was treated with concentrated sulfuric acid (2 ml) and heated to reflux for the night using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a clear oil which was used as is. for the next stage (2.7 g, -100%). 3, 5-Diethynyl-benzoic acid isopropyl ester (Intermediate 206) Following General Procedure D and using 3,5-dibromo-benzoic acid isopropyl ester (Intermediate 205, 2.7 g, 8.6 mmol), triethylamine (30 ml), copper (I) iodide (0.45 g) , 2.4 mmol), trimethylsilylacetylene (6.8 ml, 48 mmol) and dichlorobis (triphenylphosphine) palladium (II) (1.75 g, 2.4 mmol) followed by flash column chromatography on silica gel (230 mesh) -400) using 3% ethyl acetate in hexane as eluent, the isopropyl 3,5-bis-trimethylsilanylethynyl-benzoic acid intermediate is obtained. The intermediate (2.8 g, 7.85 mmol) was treated with a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (25 mL, 25 mmol) and the resulting reaction mixture was stirred in an ice bath. during Ih. Water was added and the reaction mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil which was redissolved in diethyl ether (10 ml) and treated with hexane (150 ml). The precipitated solid was filtered and dried to provide the title compound (1.3 g, 78%). NMR H1 (300 MHz, CDC13): d 8.08 (d, 1H, "7 = 1.4Hz), 7.73 (d, 1H," 7 = 1.4Hz), 5.23 (heptet, 1H, "7 = 6.3 Hz), 3.13 (s, 2 H), 1.35 (d, 6 H," 7 = 6.1 Hz). 3-Ethynyl-5- [3-fluoro-4- (3-trimethylsilanyl-propoxycarbonylmethyl) -phenylethynyl] -benzoic acid isopropyl ester (Intermediate 207) Following General Procedure B and using 3, 5-diethynyl-benzoic acid isopropyl ester (Intermediate 206, 0.36 g, 1.72 mmol), 2-trimethylsilane-ethyl ester of (2-fluoro-4-iodo) acid phenyl) -acetic (0.132 g, 0.86 mmol), triethylamine (8 ml), copper iodide (I) (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent, the title compound was obtained as a colorless oil (0, 15 g, 37%). H1NMR (300 MHz, CDC13): d 8.10 (m, 1H), 8.07 (m, 1H), 7.75 (m, 1H), 7.19-7.25 (m, 3H), 5.24 (hept, "7 = 6.2Hz, 1H), 4.19 (t," 7 = 8, 5Hz, 2H), 3.64 (s, 2H), 3.14 (s, 1H), 1.35 (d, "7 = 6, 2Hz, 6H), 0.97 (t," 7 = 8, 5Hz, 2H), 0.00 (s, 9H). 3- (4-Carboxymethyl-3-fluoro-phenylethynyl) -5-ethynyl-benzoic acid isopropyl ester (Compound 61) A solution of 3-ethynyl-5- [3-fluoro-4- (3-trimethylsilanyl-propoxycarbonylmethyl) -phenylethynyl] -benzoic acid isopropyl ester (Intermediate 207, 0.15 g, 0.32 mmol) in anhydrous dimethylsulfoxide ( 4 ml) was treated with tetra-n-ethylammonium fluoride (0.19 ml, 1.3 mmol) and the resulting reaction mixture was stirred at room temperature for 5 min. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil which was purified by recrystallization from ethyl acetate / hexane to give the title compound as a solid of color white (0.045 g, 38%). H NMR (300 MHz, CDCl 3): d .8.13 (m, 1H), 8.10 (, 1H), 7.78 (m, 1H), 7.23-7.30 (m, 3H), 5.29 (hept, "7 = 6, 4Hz, 1H), 3.74 (s, 2H), 3.15 (s, 1H), 1.38 (d," 7 = 6, 4Hz, 6H). 3- (4-Acetoxymethoxycarbonylmethyl-3-fluoro-phenylethynyl) -5-ethynyl-benzoic acid isopropyl ester (Compound 62) Following General Procedure B and using 3,5-diethynyl-benzoic acid isopropyl ester (Intermediate 206, 0.27 g, 1.27 mmol), acetoxymethyl acid ester (2-fluoro-4-iodo-phenyl) -acetic acid (0.224 g, 0.64 mmol), triethylamine (8 ml), copper (I) iodide (0.019 g, 0.1 mmol) and dichlorobis (triphenylphosphine) palladium (II) (0.07 g, 0.1 mmol) followed by flash column chromatography on silica gel (230-400 mesh) using 2.5-20% ethyl acetate in hexane as eluent, compound was obtained of the title in the form of an orange solid (0.09 g, 32%). H1 NMR (300 MHz, CDC13): d 8.13 (m, 1H), 8.10 (m, 1H), 7.79 (m, 1H), 7.23-7.32 (m, 3H), 5.78 (s, 2H), 5.27 (hept, J = 6.4Hz, 1H), 3.75 (s, 2H), 3.15 (s, 1H), 2.12 (s, 3H),, 38 (d, «7 = 6, 4Hz, 6H) Intermediate 36 Intermediate 208 Intermediate 210 Intermediate 211 Intermediate 212 Compound 63 Reaction Scheme 33 8-Iodo-2, 2, 4,4-tetramethylchroman-6-carboxylate ethyl (Intermediate 208) A solution of ethyl 2, 2, 4, 4-tetramethylchroman-6-carboxylate (Intermediate 36, 0.733 g, 2.8 mmol) in anhydrous dichloromethane (10 ml) was treated with silver trifluoromethanesulfonate (I) (0.719 g, 2.8 mmol) and iodine (0.71 g, 2.8 mmol) and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was treated with a saturated, aqueous solution of sodium thiosulfate and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue which was subjected to column chromatography on silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as eluent to provide the title compound (0.88 g, 81%) a light yellow oil form. H1 NMR (300 MHz, CDC13): d 8.26 (d, 1H, "7 = 2.0Hz), 7.96 (d, 1H," 7 = 2.0Hz), 4.34 (c, 2H, "7 = 7.1 Hz), 1.87 (s, 2H), 1.40 (s, 6H), 1.37 (s, 6H), 1.41-1.35 (m, 3H). 8-Trimethylsilanylethynyl-2, 2,4, 4-tetramethylchroman-6-carboxylic acid ethyl ester (Intermediate 209) A solution of ethyl 8-iodo-2, 2,4,4-tetramethylchroman-6-carboxylate (Intermediate 208, 0.88 g, 2.26 mmol) in triethylamine (10 ml) was treated with copper iodide (I ) (0.043 g, 0.266 mmol) and purged with argon for 5 minutes. Then trimethylsilylacetylene (3 ml, 21.22 mmole) followed by dichlorobis (triphenylphosphine) palladium (II) (0.159 g, 0.226 mmol). The resulting reaction mixture was heated at 70 ° C overnight in a sealed tube. It was then cooled to room temperature, diluted with diethyl ether and filtered on a pad of celite. The filtrate was evaporated off vacuo to an oil which was subjected to column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as eluent to give the title compound (0.803 g, 99%) . H NMR (300 MHz, CDCl 3): d 7.93 (s, 1H), 7.92 (s, 1H), 4.32 (c, 2H, "7 = 7.0Hz), 1.86 (s, 2H), 1.38 (s, 6H), 1.34 (s, 6H), 1.38-1.34 (m, 3H), 0.24 (s, 9H). 8-Ethinyl-2, 2,4, 4-tetramethylchroman-6-carboxylic acid (Intermediate 210) A solution of ethyl 8-trimethylsilanylethynyl-2,2,4,4-tetramethylchroman-6-carboxylate (Intermediate 209, 0.525 g, 1.47 mmol) in ethanol (5 ml) was treated with a 2N aqueous solution of sodium hydroxide. sodium (5 ml, 10 mmol) and the resulting solution was adjusted to pH -5 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give the title product as a brown solid. (0.316 g, 84%). H NMR (300 MHz, CDCl 3): d 8.02 (s, 2H), 3.23 (s, 1H), 1.89 (s, 2H), 1.42 (s, 6H), 1.38 ( s, 6H). 8-Ethynyl-2,4,4,4-tetramethyl-chroman-6-carboxylic acid azide (Intermediate 211) A stirred, cooled solution (ice bath) of 8-ethynyl-2,2,4,4-tetramethyl-chroman-6-carboxylic acid (Intermediate 210, 0.52 g, 2 mmol) in anhydrous tetrahydrofuran (10 ml) in argon, treated with triethylamine (0.86 ml, 6 mmol) followed by ethyl chloroformate (0.25 ml, 2.6 mmol) and the resulting reaction mixture was allowed to warm to room temperature and was stirred for 2 h.

Sodium azide (0.19 g, 3 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with water and extracted with diethyl ether.

The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to a residue which was purified by flash column chromatography on silica gel (230-400 mesh) to give the title compound as a solid color yellow (0.32 g, 56%). H NMR (300 MHz, CDCl 3): d 7.96 (cAB, 2H, "7 = 2.1Hz), 3.24 (s, 1H), 1.89 (s, 2H), 1.42 (s, 6H), 1.37 (s, 6H).

Ethyl 4- [3- (8-ethynyl-2,2,4,4-tetramethyl-chroman-6-yl) -ureido] -2-fluoro-benzoic acid ester (Intermediate 212) A solution of 8-ethynyl-2,2,2,4-tetramethyl-chroman-6-carboxylic acid azide (Intermediate 211, 0.104 g, 0.37 mmol) in anhydrous toluene was refluxed under argon overnight. Ethyl 4-amino-2-fluoro-benzoate (described by Teng et al., In the Journal of Medicinal Chemistry, 1996, 39, pp. 3035-3038, 0.114 g, 0.622 mmol) was added and the reaction mixture was added. refluxed for 5.5 h. The reaction mixture was cooled to room temperature and subjected to column chromatography on silica gel (230-400 mesh) using 20-33% ethyl acetate in hexane as eluent to give the title compound contaminated with some of the same. ethyl-2-fluoro-benzoate. This was used as is for the next stage. 4- [3- (8-Ethynyl-2,2,4,4-tetramethyl-chroman-6-yl) -ureido] -2-fluoro-benzoic acid (Compound 63) A solution of 4- [3- (8-ethynyl-2, 2,4,4-tetramethyl-chroman-6-yl) -ureido] -2-fluoro-benzoic acid ethyl ester (Intermediate 212, 0.12 g) in methanol (2 ml), tetrahydrofuran (2 ml) and water (1 ml) was treated with lithium hydroxide (0.177 g, 4.2 mmol) and the resulting reaction mixture was stirred at room temperature overnight. The volatiles were evaporated in vacuo, the residue was diluted with water and neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound as a solid (0.07 g, 46% for two steps). H1 NMR (300 MHz, CD3OD): d 7.86 (dd, 1H, "7 = 8.8, 8.5Hz), 7.53 (dd, 1H," 7 = 13.7, 2.0Hz), 7.42 (d, 1H, «7 = 2.3Hz), 7.28 (d, 1H,« 7 = 2.3Hz), 7.14 (dd, 1H, «7 = 2.0, 8.8Hz ), 3.50 (s, 1H), 1.86 (s, 2H), 1.35 (s, 12H).

Alternatively, the composition can be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and of course the total composition is preferably such that the active inhibitor does not dissolve there to a substantial degree.

It is understood that modifications that do not substantially affect the activity of the different embodiments of this invention are also included in the definition of the invention provided herein. Accordingly, it is desired that the following examples illustrate but not limit the present invention.

EXAMPLE I Inhibition of the Differentiation of Sebaceous Glands in Hamster by Blocking the Signaling of Retinoic Acid Receptors This example shows that inhibitors of CYP26B block the differentiation of sebaceous glands in hamsters. The differentiation of the sebaceous gland from the side organ of hamsters is a model system for the development of acne. To determine the efficacy of selective CYP26B inhibitors for treating acne, similar inhibitors were tested in this model system. To confirm that this model system can predict the efficacy of a compound in the reduction of acne, 13-cis-retinoic acid (acutan) was used as a positive control. As shown in Figure 1, 13-cis-retinoic acid was effective in reducing the differentiation of the sebaceous gland in the side organ of hamsters. For the model hamster system, Syrian golden male hamsters were fed with LabDiet # 5002 rodent diet and housed individually in a 14/10 hour light / dark cycle. For the treatment, the animals were randomized according to body weight and were also weighed in each treatment, so that the drug doses could be adjusted accordingly. The animals were treated daily by oral gavage, 6 days / week for 4 weeks. At the end of the treatments, the animals were sacrificed by inhalation of carbon dioxide. The organs of the side were then excised and extended on a small piece of record that was placed in a small histology cassette for fixation in 10% buffered formaldehyde. The specimen was divided into 5 portions equally spaced to make paraffin blocks and a H & E section of 5 micrometers was prepared for each block. The two sections that contained more sebaceous glands were used to determine the average area of the acini of the side organ. A video camera anchored to a standard microscope with the objective of 4X was used to capture the images of the sebaceous glands. The computer programs Videoshop and NIH Image 1.63 were used to quantify the areas of the acini. All the recognizable sebaceous glands of the two sections were analyzed and the means were derived for the comparison between different treatments. In all studies, blood samples were also collected to determine serum triglyceride levels using a Ginder Trinder Trinder Kit from Sigma Chemicals (St. Louis, MO).

To determine whether retinoic acid receptor (RAR) signaling is required for the 13-cis-retinoic acid-induced reduction of sebaceous gland differentiation from the hamster side organ, a RAR pan-agonist was assayed. As shown in Figure 2, compound X pan-agonist of RAR blocked the effect of the treatment of 13-cis-retinoic acid on the differentiation of the sebaceous glands.

The ability of the different RAR antagonists to reduce the differentiation of sebaceous glands from the hamster side was determined. As shown in Figure 3, 13-cis-retinoic acid (30 mg / kg) and TTNPB (0.02 mg / kg and 0.08 mg / kg) were effective in reducing the differentiation of sebaceous glands, while Compound Y (100 mg / kg) and all trans retinoic acid (3 mg / kg) had substantially the same activity as the control vehicle.

Table 1 shows a summary of the experimental results showing the effect of different retinoid compounds on the differentiation of the sebaceous glands in the organ of the hamster side. These results indicate that the activation of retinoic acid receptor signaling is sufficient to reduce the differentiation of the sebaceous glands. However, toxicity of RAR agonists such as TTNPB was observed at effective doses. Inactive pro-drugs such as 13-cis-retinoic acid and 4-oxo-13-cis-RA, which had lower toxicity levels, appeared to be more effective.

Since CYP26 functions in cells by reducing the signaling of retinoic acid receptors, the effect of CYP26 inhibition to increase signaling of retinoic acid receptors was examined, thereby reducing the differentiation of hamster sebaceous glands . The expression of CYP26A and CYP26B in sebaceous glands of the hamster side organ was determined using Taqman RT-PCR. The hamsters were treated as described above and sacrificed at different times in time (1 day to 3 weeks). The organs of the side were excised and placed in a dissecting microscope. The sebaceous glands were removed and placed in liquid nitrogen immediately. The RNAs were isolated from the glands using Trizol reagents (Invitrogen, San Diego, CA) as described by the manufacturer. The RNAs were treated with DNase to remove the contaminating genomic DNAs and further purified with the DNA-free kit (Ambion; Austin, TX). Quantitative RT-PCR was performed on an ABI 7700 machine using the Platinum qRT-PCR kit from Invitrogen with primers and probes specific for CYP26.

As shown in Table 2, both CYP26A and CYP26B are expressed in sebaceous glands of the hamster side, and the expression of both is induced by 13-cis-retinoic acid. It seems that the expression of CYP26B is higher in cells in a late state of differentiation.

To determine whether selective CYP26B inhibitors reduce the differentiation of sebaceous glands from the hamster side, two CYP26B inhibitors were tested. As shown in Figure 4, Compound A (50 mg / kg) and Compound Y (12.5 mg / kg) reduced the differentiation of sebaceous glands from the hamster side at least as effectively as 13-cis acid -retinoic (30 mg / kg). Compound A is a selective inhibitor of CYP26A that has a selectivity of at least 10-fold for CYP26A relative to CYP26B. Compound Y is a selective inhibitor of CYP26B that has a selectivity of at least 10-fold for CYP26B relative to CYP26A. The chemical structures of these compounds are shown in Table 3, below. Therefore, it is expected that selective inhibitors of CYP26A or CYP26B effectively reduce or prevent acne.

Table 3 In summary, this example demonstrates that selective inhibitors of CYP26 are effective in reducing the differentiation of sebaceous glands from the side into hamsters, a model system for the development of acne.

EXAMPLE II Cell-based method for the identification of CYP26 inhibitors In this example, a cell-based analysis is described to identify compounds that selectively inhibit CYP26A or CYP26B activity.

HeLa cells stably transfected with CYP26A and CYP26B were kept in plates for 100 mm tissue culture in MEM medium containing 10% FBS and 100 μg / ml hygromycin. The cells that grew exponentially were harvested by incubation in trypsin. The cells were then washed with IX PBS and plated in 48-well plates at 5 x 10 5 cells in 0.2 ml of MEM medium containing 10% FBS and RA- [H3] of 0.5 μCi in the presence or absence of concentrations increasing of the test compounds. The compounds were diluted in 100% DMSO and then added to wells in triplicate at final concentrations of 10, 1 or 0.1 μM. As a positive control for the inhibition of RA metabolism, the cells were also incubated with ketoconazole at 100, 10 and 1 μM. The cells were incubated for 3 hours at 37 ° C. The retinoids were then extracted using a modified Bligh and Dyer procedure (Bligh and Dyer, supra (1959)), in which methylene chloride, as opposed to chloroform, was used, and the aqueous soluble radioactivity was quantified using a scintillation counter H.H . The values of the ID50 represent the inhibitor concentration required to inhibit the metabolism of RA by 50 percent and were derived manually from the transformed logarithmic data.

A variety of compounds identified by inhibiting CYP26A or CYP26B selectively are shown in Table 4. It was determined that the compounds listed did not have a substantial RAR inhibitory activity. To determine the selectivity of a CYP26A inhibitor, the ID50 of the inhibitor was divided with respect to CYP26A by the ID50 of the inhibitor with respect to CYP26B. To determine the selectivity of a CYP26B inhibitor, the DI50 of the inhibitor was divided with respect to CYP26B by the DI50 of the inhibitor with respect to CYP26A.

Table 4 Note: DA = Weakly Active; NA = Not Active While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the related claims.

Claims

1. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to such an individual an effective amount of a selective CYP26B inhibitor, wherein said selective CYP26B inhibitor has a selectivity of at least 10 times for CYP26B in relation to CYP26A.

2. The method of claim 1, wherein said retinoid sensitive disorder is a skin disorder.

3. The method of claim 2, wherein said skin disorder is acne.

4. The method of claim 1, wherein said retinoid sensitive disorder is a disorder selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

5. The method of claim 1, wherein said inhibitor is administered peripherally.

6. The method of claim 5, wherein said inhibitor is administered orally.

7. The method of claim 1, wherein said individual is a human.

8. The method of claim 1, wherein said selective CYP26B inhibitor has a selectivity of at least 20-fold for CYP26B relative to CYP26A.

9. The method of claim 8, wherein said selective CYP26B inhibitor has a selectivity of at least 100-fold for CYP26B relative to CYP26A.

.10. The method of claim 9, wherein said selective CYP26B inhibitor has a selectivity of at least 500 times for CYP26B relative to CYP26A.

11. The method of claim 10, wherein said selective CYP26B inhibitor has a selectivity of at least 1000 times for CYP26B relative to CYP26A.

12. The method of claim 1, wherein said selective CYP26B inhibitor has the formula: Formula 30 wherein, R = t-Butyl, CH2N (Me) (cyc-Pr), or N (Me) (cyc-Pr); Y X = H or Me.

13. The method of claim 1, wherein said selective CYP26B inhibitor has the formula: Formula 31 wherein, R = t-Butyl, CH2N (Me) (cyc-Pr), or N (Me) (cyc-Pr); Y X = H or Me.

14. The method of claim 1, wherein said selective CYP26B inhibitor has the formula: Formula 32 where, n = 0 or 1; Y R? = R2 = Me; X = O, S, where R = lower alkyl; and Y = cycloalkyl, alkenyl, alkynyl, lower alkoxy, halo, or haloalkyl; or R? = Me; R2 = -CH2CH2-; X = O or S; and Y = cycloalkyl, alkenyl, alkynyl, lower alkoxy, halo, or haloalkyl; or Ra = Me; R2 = H; X = -CHCH2N (Me) (cyc-Pr); and Y = H, lower alkyl, cycloalkyl, alkenyl, lower alkoxy, halo or haloalkyl; or Rx = Me; R = H; X = CMe2; and Y = H, lower alkyl, cycloalkyl, alkenyl, alkynyl, lower alkoxy, halo or haloalkyl.

15. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 18 where, R3 = H or lower alkyl; and R? = R2 = H, Me or Et; X = 0 or S; and Y = CH2N (Me) (cyc-Pr), H, halo, OH, lower alkoxy, lower alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; or R? = Me; R2 = H; X = H (C) CH2N (Me) (cyc-pr); and Y = H, halo, lower alkoxy, lower alkyl, cycloalkyl or haloalkyl; or R1 = Me, R2 = H; X = C = 0; and Y = H, lower alkyl, haloalkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl.

16. The method of claim 15, wherein said retinoid responsive disorder is a skin disorder.

17. The method of claim 15, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

18. The method of claim 15, wherein said administration is oral administration.

19. The method of claim 16, wherein said skin disorder is acne.

20. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 19 where, R3 = H or lower alkyl; R1 = R2 = H, Me or Et; X = 0 or S; and Y = CH2N (Me) (cyc-Pr), H, halo, OH, lower alkoxy, lower alkyl, haloalkyl, cycloalkyl, alkenyl, or alkynyl; or R3 = H or lower alkyl; and R? = Me; R2 = H; X = H (C) CH2N (Me) (cyc-Pr); and Y = H, halo, lower alkoxy, lower alkyl, cycloalkyl or haloalkyl; or R3 = H or lower alkyl; and R? = Me; R2 = H; X = C = 0; and Y = H, lower alkyl, haloalkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

21. The method of claim 20, wherein said retinoid responsive disorder is a skin disorder.

22. The method of claim 20, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

23. The method of claim 20, wherein said administration is oral administration.

24. The method of claim 21, wherein said skin disorder is acne.

25. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 20 where, R? = R2 = Me; X = O or S; and Y = CH2N (Me) (cyc-Pr), OR, COOR, where R = lower alkyl, cycloalkyl; or R? = Me; R2 = H; X = H (C) CH2N (Me) (cyc-Pr); and Y = OR, COOR where R = lower alkyl, or cycloalkyl; or R? = Me; R2 = H; X = C = 0; and Y = alkenyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

26. The method of claim 25, wherein said retinoid sensitive disorder is a skin disorder.

27. The method of claim 25, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

28. The method of claim 25, wherein said administration is oral administration.

29. The method of claim 26, wherein said skin disorder is acne.

30. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 21 where, R? = R2 = Me; X = O or S; and Y = lower alkyl, haloalkyl, cycloalkyl, CH2N (Me) (cyc-Pr), OR, or COOR, where R = lower alkyl, or cycloalkyl; or R1 = Me; R2 = H; X = H (C) CH2N (Me) (cyc-Pr); and Y = lower alkyl, haloalkyl, cycloalkyl, OR, COOR, where R = lower alkyl or cycloalkyl; or R? = Me; R2 = H; X = C = 0; and Y = alkenyl, lower alkyl, or cycloalkyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

31. The method of claim 30, wherein said retinoid sensitive disorder is a skin disorder.

32. The method of claim 30, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

33. The method of claim 30, wherein said administration is oral administration.

34. The method of claim 31, wherein said skin disorder is acne.

35. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 22 wherein, R3 = lower alkyl; and Rx = R2 = H or Me; or Rx = Me; and R2 = H, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

36. The method of claim 35, wherein said retinoid sensitive disorder is a skin disorder.

37. The method of claim 35, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

38. The method of claim 35, wherein said administration is oral administration.

39. The method of claim 36, wherein said skin disorder is acne.

40. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 23 wherein, R3 = lower alkyl; Y R1 = H and R2 = H; and Y = alkenyl, or alkynyl; or Rx = Me and R2 = H or Me; and Y = lower alkyl, alkenyl, or alkynyl; or R? = H or Me and R2 = Me; and Y = lower alkyl, alkenyl, or alkynyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

41. The method of claim 40, wherein said retinoid sensitive disorder is a skin disorder.

42. The method of claim 40, wherein said retinoid responsive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

43. The method of claim 40, wherein said administration is oral administration.

44. The method of claim 41, wherein said skin disorder is acne.

45. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 24 where, R3 = H or lower alkyl; Y Rx = H, Me or Et; X = O or S; and Y = CH2N (Me) (cyc-Pr), H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl, or alkynyl; or Rx = Me; X = H (C) CH2N (Me) (cyc-Pr); and Y = H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl or alkynyl; or R? = Me; X = C = 0; and Y = H, lower alkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

46. The method of claim 45, wherein said retinoid responsive disorder is a skin disorder.

47. The method of claim 45, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

48. The method of claim 45, wherein said administration is oral administration.

49. The method of claim 46, wherein said skin disorder is acne.

50. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 25 where, R3 = H or lower alkyl; and Rx = H, Me or Et; X = O or S; and Y = CH2N (Me) (cyc-Pr), H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl or alkynyl; or Rx = Me; X = H (C) CH2N (Me) (cyc-Pr); and Y = H, lower alkoxy, lower alkyl, cycloalkyl, alkenyl or alkynyl; or R = Me; X = C = 0; and Y = H, lower alkyl, lower alkoxy, cycloalkyl, alkenyl or alkynyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

51. The method of claim 50, wherein said retinoid sensitive disorder is a skin disorder.

52. The method of claim 50, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

53. The method of claim 50, wherein said administration is oral administration.

54. The method of claim 51, wherein said skin disorder is acne.

55. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 26 where, R? = H, Me or Et; X = 0 or S; and Y = CH2N (Me) (cyc-Pr), OR, or COOR, where R lower alkyl or cycloalkyl; or R? = Me, X = H (C) CH2N (Me) (cyc-Pr); and Y = alkenyl, OR, COOR, where R = lower alkyl or cycloalkyl; or R? = Me; X = C = 0; and Y = alkenyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

56. The method of claim 55, wherein said retinoid sensitive disorder is a skin disorder.

57. The method of claim 55, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

58. The method of claim 55, wherein said administration is oral administration.

59. The method of claim 56, wherein said skin disorder is acne.

60. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 27 where, Z = H, Me or Cl; Y Rx = H, Me or Et; X = O or S; and Y = lower alkyl, cycloalkyl, CH2N (Me) (cyc-Pr), OR, or COOR, where R = lower alkyl or cycloalkyl; or Rs = Me, X = H (C) CH2N (Me) (cyc-Pr); and Y = lower alkyl, cycloalkyl, OR, or COOR, where R = lower alkyl, or cycloalkyl; or R? = Me; X = C = 0; and Y = alkenyl, lower alkyl, or cycloalkyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

61. The method of claim 60, wherein said retinoid sensitive disorder is a skin disorder.

62. The method of claim 60, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

63. The method of claim 60, wherein said administration is oral administration.

64. The method of claim 61, wherein said skin disorder is acne.

65. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to such an individual an effective amount of a selective CYP26A inhibitor having the formula: Formula 28 where, R = lower alkyl; Y R? = H; and R2 = Me; OR RX = R2 = Me or H, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

66 The method of claim 65, wherein said retinoid sensitive disorder is a skin disorder.

67. The method of claim 65, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

68. The method of claim 65, wherein said administration is oral administration.

69. The method of claim 66, wherein said skin disorder is acne.

70. A method for the treatment of an individual having a retinoid responsive disorder, comprising administering to an individual such an effective amount of a selective CYP26A inhibitor having the formula: Formula 29 where, X = COOR, C (CH3) 2COOR, CH2N (CH3) (cyc-Pr), where R = lower alkyl; Y = H, lower alkyl, haloalkyl, alkenyl or alkynyl; Y RX = H and R2 = Me; or R1 = R2 = Me or H, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof.

71. The method of claim 70, wherein said retinoid responsive disorder is a skin disorder.

72. The method of claim 70, wherein said retinoid sensitive disorder is a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a neurological disorder, an eye disorder, and a pulmonary disorder.

73. The method of claim 70, wherein said administration is oral administration.

74. The method of claim 71, wherein said skin disorder is acne.