MXPA06009953A - Bicyclic substituted indole-derivative steroid hormone nuclear receptor modulators - Google Patents

Abstract

The present invention provides a compound of the formula:Formula (I);or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising an effective amount of a compound of Formula I in combination with a suitable carrier, diluent, or excipient, and methods for treating physiological disorders, particularly congestive heart disease, hypertension, and atherosclerosis, comprising administering to a patient in thereof an effective amount of a compound of Formula I. X-16125

Description

MODULATORS OF THE NUCLEAR RECEIVER OF THE HORMONE STEROID DERIVATIVES OF INDOL BICÍCLICO SUBSTITUTES BACKGROUND OF THE INVENTION Nuclear hormone receptors are an evolutionarily conserved class of intracellular receptor proteins, which have been called "ligand-dependent transcription factors". Evans et al. , SCIENCE, 240: 889 (1988). The superfamily of the nuclear hormone receptor gene encodes structural receptor proteins related to glucocorticoids (eg, cortisol, corticosterone, cortisone), androgens, mineral corticosteroids (eg, aldosterone), progestins, estrogen, and thyroid hormone. Also included within this superfamily of nuclear receptors are receptor proteins for vitamin D, retinoic acid, 9-cis retinoic acid, as well as those receptors for which no cognate ligands ("orphan receptors") have been identified, Ribeiro et al. . , Annual Rev. Med., 46: 443-453 (1995). The steroid hormone receptors represent a subset of the nuclear hormone receptor superfamily. So called in accordance with the cognate ligand which forms complexes with the receptor in its native state, the nuclear steroid hormone receptors include the glucocorticoid receptor (GR), the androgen receptor (AR), the ineralcorticoid receptor (MR), the Estrogen receptor (ER), and the progesterone receptor (PR). Tenbaum et al. , Int. J. Biochem. Cell. Biol., 29 (12): 1325-1341 (1997). Contrary to membrane-bound receptors, the nuclear hormone receptors find their respective ligands after the entry of the ligand into the cell, once ligand binding occurs, the ligand-receptor complex modulates the transcription of target genes inside the nucleus of the cell. For example, most ligand-free nuclear receptors are bound in a complex with heat shock proteins (PCT) in the cytoplasm. After the entry of the circulating hormone into the cell, the binding stimulates a conformational change in the receptor, dissociating the receptor from the pct. The receptors bound to the ligand are translocated to the nucleus, where as monomers, as well as hetero and homodimers they bind to particular hormone response elements (ERH) in the promoter regions of target genes. The ERH-receptor complex then, on the other hand, regulates the transcription of locally located genes, (see Ribeiro et al., Supra.). On the other hand, the thyroid hormone (RT) receptors and other non-steroidal receptors such as the vitamin D receptor (RVD) and retinoic acid receptors (RAR) are bound to their respective ERH in the absence of PCTs and / or cognate ligands. Hormones released from the circulation enter the cell, binding in the nucleus to these receptors which, in turn, hetero-dimerize other nuclear receptors such as 9-cis retinoic acid (RXR). As with nuclear steroid hormone receptors, after binding to the ligand, the receptor complex bound to the ligand again regulates the transcription of nearby genes. The ineralcorticoids and glucocorticoids exert profound influences on a multitude of physiological functions by virtue of their various functions in the growth, development and maintenance of homeostasis. The actions are mediated by the MC and GR, which carry approximately 94% homology in their respective DNA binding regions, and approximately 57% homology in their respective ligand binding domains. Kino et al. , J. of Endocrinology, 169, 437-445 (2001). In visceral tissues, such as the kidney and intestine, MR regulates sodium retention, potassium excretion and water balance, in response to aldosterone. In addition, the expression of MR in the brain, seems to play a role in the control of neuronal excitability, in the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, in the cognitive aspects of behavior performance. Castren et al. , J. of Neuroendocrinology, 3, 461-466 (1993). The GR, which is ubiquitously expressed in almost all tissue and organ systems, is crucial for the integrity of central nervous system function and the maintenance of cardiovascular, metabolic and immune homeostasis. Kino et al. , J. of Endocrinology, 169, 437-445 (2001). Elevations in aldosterone levels, or stimulation in excess of mineralcorticoid receptors, are linked to various physiological disorders or pathological disease states including, Conn syndrome, primary hyperaldosteronism and secondary hyperaldosteronism, increased sodium retention, increased excretion of magnesium and potassium (diuresis), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bertter syndrome and disorders associated with catecholamine excess levels. Hadley, M.E., ENDOCRINOLOGY, 2nd. Ed., Pp. 366-381, (1988); and Brilla et al. , Journal of Molecular and Cellular Cardiology, 25 (5), pp. 563-575 (1993). Additionally, elevated aldosterone levels have been increasingly implicated with congestive heart failure (CHF). In CHF, heart failure activates hormonal mechanisms in other organs, in response to reductions in attention to blood flow and blood pressure seen in CHF. In particular, the kidney activates the renin-angiotensin-aldosterone system (RAAS), causing an increase in the production of aldosterone by the adrenals which, in turn, promote water and sodium retention, potassium loss and additional edema. Although aldosterone was historically thought to have participated in the etiology of CHF only as a result of its salt retention effects, several recent studies have implicated elevated levels of aldosterone with events in extra-adrenal tissues and organs, such as myocardial fibrosis and vascular, direct vascular damage and baroreceptor dysfunction. Pitt et al. , New Eng. J. Med., 341: 709-717 (1999). These findings are particularly significant, since inhibitors of the angiotensin-converting enzyme (ACE), which were once indicated to completely abolish aldosterone production, are now believed to only temporarily suppress aldosterone production, which has been shown to occur in extra-adrenal tissues, which include the heart and vasculature. Eber, New Eng. J. Med., 341: 753-755 (1999); Fardella and Miller, Annu. Rev. Nutr., 16: 443-470 (1996). The involvement of aldosterone acting via MR in ICC was confirmed in the recently completed RALES study (Aldactone Randomized Evaluation Study). Pitt et al. , New. Eng. J. Med., 341: 709-717 (1999). The RALES study demonstrates that the use of Aldactone ™ (spironolactone), a well-known competitive MR antagonist, in combination with standard ICC therapy, reduces the cardiac-related mortality by 30% and the frequency of hospitalization by 35% in patients who suffer of advanced ICC. However, spironolactone therapy has also been associated with side effects of attention, such as gastric bleeding, diarrhea, azotemia, hyperchloremic metabolic acidosis, renal tubular acidosis type 4, nausea, gynecomastia, erectile dysfunction, hyperkalemia, and irregular menstruation. Thus, the mineralcorticoid receptor represents a viable target for ICC therapy either alone or in combination with conventional ICC therapies such as, vasodilators (ACE inhibitors), inotropics (digoxin), diuretics or beta-blockers. Molecules, preferably non-steroids, which bind to the mineralcorticoid receptor and modulate receptor activity without the attendant side effects of current therapies, could be particularly desirable. Recently, aldosterone blockers, selective in the treatment of atherosclerosis, have been implicated. S. Keider, et al., Cardiovascular Pharmacology 41 (6), 955-963 (2003). Finally, the published international PCT application WO 02/17895, discloses that aldosterone antagonists are useful in the treatment of subjects suffering from one or more cognitive dysfunctions including, but not limited to, psychoses, cognitive disorders (such as memory disturbances), mood disorders (such as depression and bipolar disorders), anxiety disorders and personality disorders. Glucocorticoids (eg, cortisol, corticosterone and cortisone), and the glucocorticoid receptor, have also been implicated in the etiology of a variety of physiological disorders or disease states of disease. For example, cortisol hyposecretion is implicated in the pathogenesis of Addison's Disease and may result in muscle weakness, increased skin melanin pigmentation, weight loss, hypotension, and hypoglycemia. On the other hand, excessive or prolonged glucocorticoid secretion has been correlated with Cushing's syndrome and may also result in obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria and polydipsia. Hadley, M.E., ENDOCRINOLOGY, 2nd. Ed., Pp. 366-381 (1988). In addition, US Patent No. 6,166,013, published on December 26, 2000, discloses that GR-selective agents could modulate GR activity and thus be useful in the treatment of inflammation, tissue rejection, self-immunity , malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, proliferation / immune apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little. U.S. Patent No. 6,166,013 also discloses that GR modulators are especially useful in disease states involving systemic inflammation, such as inflammatory bowel disease, systemic lupus erythematosus, polyarthritis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis. , orteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis and cirrhosis; and compounds that modulate GR have been used as immunostimulants, repressors and as wound healers and tissue repair agents. In addition, US Patent No. 6,166,013 also discloses that GR modulators have also found use in a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cystis, atopic dermatitis, pyoderma gangrenosum , pemphigus vulgaris, pemphigus bulosus, systemic lupus erythematosus, dermatomyositis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type I, and capillary angiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme and cutaneous lymphoid-T cells. Thus, it is clear that a ligand which has the affinity for nuclear steroid hormone receptors, and particularly for MR and / or GR, could be used to modulate (that is, suppress, antagonize, agonize , partially antagonizing, partially agonizing) the activity of the receptor and directing the expression of the gene, thereby, influencing a multitude of physiological functions related to alterations in steroid hormone levels and / or steroid hormone receptor activity. In this regard, such ligands could be used to treat a wide range of physiological disorders susceptible to modulation of the nuclear steroid hormone receptor. Published literature references describe indole-derived molecules useful in a wide range of indications from electroluminescent agents to anti-fouling agents. In addition, indole-derived compounds have also been described as having pharmacological utility as, inter alia, serotonin 5HT-6 receptor modulators, anticoagulant, antiangiogenic, antiparasitic agents, integrin inhibitors, phospholipase inhibitors, endothelial receptor antagonists, antiarrhythmics and dopamine antagonists. Surprisingly, however, and in accordance with the present invention, applicants have discovered a series of non-steroidal indole derivatives, particularly bicyclic substituted indole derivatives, with affinity for the nuclear steroid hormone receptors, and particularly, for MR and GR. Such compounds can modulate the activity of the nuclear receptor and, therefore, have utility in treating physiological disorders related to alterations in the level of the steroid hormone and / or alterations in the activity of the nuclear receptor of the steroid hormone. Furthermore, such compounds could indicate a broad sense and need for continuation of safe and effective pharmaceutical interventions without the side effects of attention to steroidal agents. The treatment of disorders related to the steroid hormone is thereby encouraged. The following references describe examples of the state of the art as it relates to the present invention. The International PCT application published WO 96/19458 and U.S. Patent Nos. 5,696,130; 5,994,544; 6,017,924, and 6,121,450, describe quinoline-derived analogs as modulators of the steroid hormone receptor. The International Published PCT application WO 00/06137 and U.S. Patent No. 6,166,013 describe triphenylmethane compounds as glucocorticoid receptor modulators. U.S. Patent No. 6,147,066 discloses ani-mineralcorticoid receptor compounds for use in the treatment of drug abstinence syndrome. U.S. Patent Nos. 6,008,210 and No. 6,093,708, discloses spirolactone compounds, such as spironolactone and epoxymexrenone, with affinity for the mineralcorticoid receptor for use in the treatment of myocardial fibrosis. The International Published PCT Application WO 02/17895, discloses that aldosterone antagonists are useful in the treatment of subjects suffering from one or more cognitive functions. The International Published PCT Application WO 02/09683, discloses aldosterone blockers useful for treating inflammatory disorders. The Published International PCT Application WO 02/051832 describes heterocyclalkylindoles as 5HT-6 ligands. The International Published PCT Application WO 02/016348, discloses indole-derived molecules as anti-angiogenic agents. The International Published PCT Application WO 02/012227 discloses nine- and ten-element bicyclic heteroaryl molecules as inhibitors of angiogenesis. The International Published PCT Application WO 01/058893 discloses indole-3-yl propionates as integrin inhibitors. The published International PCT Application WO 99/43672 describes indole derivatives as inhibitors of the enzyme phospholipase. The published International PCT Application WO 98/42696 and related family elements describe inhibitors of nitric oxide synthase. The International Published PCT Application WO 97/43260 and related family elements describe indole derivatives useful as endothelin receptor antagonists. The published International PCT Application WO 96/03377 and related family elements describe heterocyclic compounds useful as allosteric effectors of muscarinic receptors. US Patent EP683166 discloses l- (3-indolyalkyl) -4- (3-indolyl) piperidines as dopamine agonists or antagonists. Japanese Patent JP 05339565 and JP 3229654 describe indole derivatives for electroluminescent devices. U.S. Patent No. 5,342,547 discloses indole derivatives for controlling underwater incrustations. Whitehead and Whitesitt, Journal of Medicinal Chemistry (1974), 17 (12), 1298-304 describes the effects of lipophilic substituents on the biological properties of Inners. The Co-pending International Patent Application PCT / US04 / 0017 describes indole derivatives as modulators of the mineralcorticoid and glucocorticoid receptor.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to the discovery that certain indole derivative compounds, as defined below, are modulators of the nuclear steroid hormone receptors and, therefore, may have utility as pharmaceutical agents. Accordingly, the present invention provides a compound of the formula: Formula I wherein, X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, -CH2S-, or -CH2NR10-; R1 represents hydrogen, (C1-C4) alkyl, (C3-C) cycloalkyl, (C1-C4) hydroxyalkyl, haloalkyl (C1-C4), (C1-C4) alkyl -heterocycle, (C1-C4) alkyl-NH-alkylamino (C1-C4), or (C1-C4) alkyl-N, N-dialkylamine (C1-C4); R 2 represents hydrogen, halo, (C 1 -C 4) alkyl, heterocycle, or substituted heterocycle; R3 represents hydrogen, halo, (C1-C4) alkyl, heterocycle, or substituted heterocycle; R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, NHS02R7, NHCOR8, or COR9; R5 represents hydrogen or halo; R6 represents hydrogen or (C1-C4) alkyl; R7 represents alkyl (Cj.-C4), aryl, NHalkylamine (C1-C4), or N, N-dialkylamine (C1-C4); R8 represents (C? -C4) alkyl, (C1-C4) alkoxy or (C1-C4) arylalkoxy; and R9 represents alkyl (C? -C4) or alkoxy (Cj-C); R10 represents hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl- (C3-C7) cycloalkyl; or a pharmaceutically acceptable salt thereof. As another aspect, the present invention provides a method for treating a physiological disorder susceptible to modulation of the nuclear steroid hormone receptor comprising, administering to a patient in need thereof, an effective amount of a compound of Formula I as described in this document and previously. Examples of such disorders include Conn syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness , increased pigmentation of melanin in the skin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, rejection of associated tissue with the organ transplant, malignancies such as leukemia and lympholas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of cytosine balance Thl / Th2, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little syndrome, systemic inflammation, inflammatory disease of the intestine, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, dermatitis is exfoliative, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum , pemphigus vulgaris, pemphigus bullosa, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, lymphoma cutaneous T cells, psychosis, cognitive disorders (such as memory disturbances), mood disorders (such as depression and bipolar disorder), anxiety disorders and personality disorders. As a further aspect, the present invention provides a method for treating a physiological disorder susceptible to modulation of the mineralocorticoid or glucocorticoid receptor, which comprises administering to a patient in need thereof, an effective amount of a compound of Formula I as described herein. document and previously. As a particular aspect, the present invention provides a method for treating a physiological disorder susceptible to antagonism of the mineralocorticoid or glucocorticoid receptor., comprising administering to a patient in need thereof, an effective amount of a compound of Formula I. As an even more particular aspect, the present invention provides a method for treating hypertension (isolated systolic and systolic / combined diastolic), heart failure congestive systolic and / or diastolic, atherosclerosis, arthritis or rheumatoid inflammation comprising administering to a patient in need thereof, an effective amount of a compound of Formula I as described herein and above. As a separate aspect, the present invention also provides a method for modulating a nuclear steroid hormone receptor, comprising contacting said receptor with an effective amount of a compound of Formula I. More particularly, the present invention provides a method for modulating the mineralocorticoid or glucocorticoid receptor comprising contacting said receptor with an effective amount of a compound of Formula I. More particularly, the present invention provides a method for antagonizing the mineralocorticoid or glucocorticoid receptor comprising contacting said receptor with a effective amount of a compound of Formula I, as described herein and above. In addition, the present invention provides pharmaceutical compositions of compounds of Formula I, which include any of the pharmaceutically acceptable salts and hydrates thereof, which comprise a compound of Formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of Formula I. The present invention also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a physiological disorder susceptible to modulation of the nuclear steroid hormone receptor. More particularly, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating hypertension, congestive heart failure, atherosclerosis, arthritis or rheumatoid inflammation. Still further, the present invention also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a physiological disorder susceptible to modulation of the nuclear steroid hormone receptor. More particularly, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating hypertension, congestive heart failure, atherosclerosis, arthritis or rheumatoid inflammation.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula I with affinity for nuclear steroid hormone receptors, particularly MR and / or GR, which can be used to modulate (i.e., repress, antagonize, agonize, partially antagonize, partially agonizing) the activity of the nuclear receptor and expression of the target gene, thereby influencing physiological functions related to steroid hormone levels and / or steroid hormone receptor activity. In this regard, the compounds of Formula I are believed to be useful in the treatment or prevention of a multitude of physiological disorders susceptible to modulation of the nuclear steroid hormone receptor. Thus, methods for the treatment or prevention of physiological disorders susceptible to modulation of the nuclear steroid hormone receptor constitute another important embodiment of the present invention. As a particular aspect, the present invention provides compounds useful as modulators of the mineralocorticoid or glucocorticoid receptor. As a more particular aspect, the present invention provides compounds useful as mineralocorticoid or glucocorticoid receptor antagonists. As will be understood by the person skilled in the art, some of the compounds useful for the methods of the present invention may be available for formulation of the prodrug. As used herein, the term "prodrug" refers to a compound of Formula I which has been structurally modified such that the prodrug in vivo is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage. , in the original molecule ("drug") as given by Formula I. Such prodrugs may be, for example, derivatives of the metabolically labile ester of the parent compound, wherein said original molecule carries a carboxylic acid group. Conventional procedures for the selection and preparation of suitable prodrugs are well known to one of ordinary skill in the art. It is understood that many modulators of the nuclear steroid hormone receptor of the present invention can exist as pharmaceutically acceptable salts and, as such, the pharmaceutically acceptable salts are therefore included within the scope of the present invention. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of Formula I, which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or a pharmaceutically acceptable organic or inorganic base. Such salts are known as base addition salts and acid addition. It will further be understood by the skilled reader, that the salt forms of pharmaceutical compounds are commonly used because they are often more easily crystallized, or more easily purified, than what the free bases are. In all cases, the use of pharmaceutical compounds of the present invention as salts is contemplated in the description herein. Therefore, it is understood that wherein the compounds of Formula I are capable of forming salts, the pharmaceutically acceptable salts and isoforms thereof are encompassed in the names provided herein. Acids commonly employed to form acid addition salts are inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, acid p-bromophenylsulfonic, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dehydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, iodide, dihydrodite, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate , succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexin-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylene sulfonate, phenylacetate, phenyl propionate, phenylbutyrate, citrate , lactate, α-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Base addition salts include those derived from inorganic bases, such as alkali metal, alkaline earth or ammonium hydroxides, carbonates, bicarbonates and the like. Such bases useful in the preparation of salts of this invention thus include, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and Similar. As used herein, the term "stereoisomer" refers to a compound made from the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are reflected images not on one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomer" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration in only one chiral center, are referred to herein as "epimers". The terms "racemate", "racemic mixtures" or "racemic modification", refer to a mixture of equal parts of enantiomers. The term "enantiomeric enrichment" as used herein, refers to the increase in the amount of one enantiomer compared to another. A convenient method achieved to express enantiomeric enrichment is the concept of enantiomeric excess, or "ee", which is found using the following equation: ee = E1 - E2 X 100 E1 + E2 where E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, as such it is present in a racemic mixture, and sufficient enantiomeric enrichment is achieved to produce a final ratio of 50:30, ee with respect to the first enantiomer It is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee greater than 90% is preferred, an ee greater than 95% is more preferred, and ee greater than 99% is more especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high-performance liquid chromatography with a chiral column. The selection of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair, is also within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of the compounds of Formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions. ", John Wiley and Sons, Inc., 1981. The compounds of the present invention may have one or more chiral centers and may, therefore, exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention can originate as racemates, mixtures of enantiomers, and as individual enantiomers, as well as diastereomers and mixtures of distereomers. All racemates, enantiomers and distereomers are within the scope of the present invention. Enantiomers of the compounds provided by the present invention can be resolved, for example, by one of ordinary skill in the art using standard techniques such as those described by J. Jacques, et al. , "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. The terms "R" and "S" are used in this document as is commonly used in organic chemistry to denote the specific configuration of a chiral center . The term "R" (right) refers to such a configuration of a chiral center with a clockwise relation of group priorities (highest to the lowest second), when viewed along the link of the chiral carbon towards the lowest priority group. The term "S" (left) refers to that configuration of a chiral center with a counterclockwise relation of group priorities (highest to the lowest second), when viewed along the link of the chiral carbon towards the lowest priority group. The priority of the group is based on its atomic number (to decrease the atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice" (Nomenclature of Organic Compounds: Principles and Practice), (JH Fletcher, et al., Eds., 1974) in the pages 103-120. Specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art using well-known techniques and processes, such as those described by Eliel and Wilen, "Stereochemistry of Organic Compounds" (Stereochemistry of Organic Compounds), John Wiley & Sons, Inc., 1994, Chapter 7; Separation of Stereoisomers, Resolution, Racemization (Separation of stereoisomers, resolution, racemization); and by Collect and Wilen, "Enantiomers, Racemates and Resolutions" (Enantiomers, racemates and resolutions), John Wiley & Sons, Inc., 1981. For example, specific stereoisomers and enantiomers can be prepared by stereospecific synthesis using enantiomeric and geometrically pure starting materials., or enantiomerically or geometrically enriched. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for such purposes. In addition, as will be appreciated by one of ordinary skill in the art, the compounds of the present invention that contain a carbon-carbon double bond can exist as geometric isomers. Two methods are commonly used to designate specific isomers, the "cis-trans" method and the "E" and "Z" methods, these methods designate a particular isomer based on whether the groups attached to each of the ethylene carbons are the same or different. A discussion of geometric isomerism and the appointment of specific isomers is found in March, "Advanced Organic Chemistry", John Wiley & amp; amp;; Sons, 1992, Chapter 4. All geometric isomers, as well as mixtures of individual isomers, are contemplated and provided by the present invention. As appreciated by one of ordinary skill in the art, suitable oxygen or nitrogen protecting groups are used as needed. Suitable oxygen or nitrogen protecting groups, as used herein, refer to those groups proposed to protect or block the oxygen or nitrogen group against undesirable reactions during synthetic procedures. The suitability of the oxygen or nitrogen protecting group used will depend on the conditions that will be employed in subsequent reaction stages where protection is required, and is also within the knowledge of one of ordinary skill in the art. Commonly used protective groups suitable for practicing the present invention are described in "Protective Groups in Organic Synthesis, 3rd Edition" by Theodara Greene, Peter G.M. Wutus, John Wiley & Sons, New York (1999). As used herein, the term "(C? -C4) alkyl" refers to an aliphatic, saturated, monovalent, linear or branched chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl and the like. As used herein, the term "(C? -C6) alkyl" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and the like. It is understood that the term "(C 1 -C 4) alkyl" is included within the definition of "(C 1 -C 6) alkyl". As used herein, the term "(C? -C?) Alkyl" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl , octyl, 4-methyl-3-heptyl and the like. It is understood that the terms "(C 1 -C 4) alkyl" and "(C 1 -C 6) alkyl" are included within the definition of "alkyl (C 1 -C 6)". As used herein, the terms "Me", "Et", "Pr", "I-Pr", "Bu" and "t-Bu" refer to methyl, ethyl, propyl, isopropyl, butyl and ter. -butyl, respectively.

As used herein, the term "(C 1 -C 4) alkoxy" refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to a is limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like. As used herein, the term "(Ci-Cβ) alkoxy" refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, n-hexoxy and the like. It is understood that the term "(C3-C4) alkoxy" is included within the definition of "(Ci-Cß) alkoxy". As used herein, the term "(C 1 -C 4) hydroxyalkyl" refers to a saturated, monovalent, straight or branched aliphatic chain of 1 to 4 carbon atoms carrying a hydroxyl group attached to one of the carbon atoms. As used herein, the term "hydroxyalkyl (Ci-Cß)" refers to an aliphatic, saturated, monovalent, linear or branched chain of 1 to 6 carbon atoms carrying a hydroxyl group attached to one of the carbon atoms. It is understood that the term "(C 1 -C 4) hydroxyalkyl" is included within the definition of "hydroxyalkyl (Ci-Cß)". As used herein, the term "(C 1 -C 4) hydroxyalkoxy" refers to to an oxygen atom carrying a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, furthermore carrying a hydroxyl group attached to one of the carbon atoms As used herein, the term "hydroxyalkoxy" (C? -Ce) "refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms, in addition to carrying a hydroxyl group attached to one of the carbon atoms. It is understood that the term "hydroxyalkoxy (C? -C4)" is included within the definition of "hydroxyalkoxy (C? -C6)". As used in this document, the terms "halo", "halide" or "hal" of "Hal" refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein. As used herein, the term "(C 1 -C 4) haloalkyl" refers to a saturated, monovalent, straight or branched aliphatic chain of 1 to 4 carbon atoms carrying one or more halo groups attached to one or more of the carbon atoms. As used herein, the term "haloalkyl (C? -C6)" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms carrying one or more halo groups attached to one or more of the carbon atoms. It is understood that the term "haloalkyl (C? -C4)" is included within the definition of "haloalkyl (C? -C6)". As used herein, the term "(C 1 -C 4) haloalkoxy" refers to an oxygen atom that carries a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, in addition to carrying one or more halo groups attached to one or more of the carbon atoms. As used herein, the term "haloalkoxy (C-C6)" refers to an oxygen atom carrying a saturated, monovalent, linear or branched aliphatic chain of 1 to 6 carbon atoms, in addition carrying one or more groups Halo bonded to one or more of the carbon atoms It is understood that the term "(C1-C4) haloalkoxy" is included within the definition of "haloalkoxy (C? -C6)." As used herein, the The term "(C2-C6) alkenyl" refers to an unsaturated, monovalent, linear or branched aliphatic chain having from two to six carbon atoms and having a double bond Typical (C2-C6) alkenyl groups include ethenyl (also known as vinyl), 1-methylenetetenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and the like As used herein, the term "(C2-Ce) alkynyl" refers to an unsaturated aliphatic chain, monovalent, linear or branched having two to six carbon atoms and having a triple bond. Typical (C2-C6) alkynyl groups include propynyl, ethynyl and the like. As used herein, the term "acyl" refers to a hydrogen to an alkyl group (Ci-Cß) attached to a carbonyl group. Typical acyl groups include formyl, acetyl, propionyl, butyryl, valeryl and caproyl. As used herein, the term "aryl" refers to a monovalent carbocyclic group that contains one or more unbound phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1 , 2,3,4-tetrahydronaphthyl and the like. The term "substituted aryl" refers to an aryl group optionally substituted with one to three portions, preferably one or two, selected from the group consisting of halo, amino, cyano, alkyl (C? -C4), alkoxy (C? -C4), -S-alkyl (C? -C4). As used herein, the term "arylalkoxy (C? -C6)" (or "alkoxy-aryl (C? -C6)"), refers to an oxygen atom that carries a saturated, monovalent, linear aliphatic chain or branched from 1 to 6 carbon atoms, wherein said aliphatic chain, on the other hand, carries an aryl group. Examples of "arylalkoxy (Cx-Cß)" include benzyloxy, phenylethoxy and the like. As used in this document, the term "(C3-C10) cycloalkyl" refers to a saturated hydrocarbon ring structure composed of one or more fused or unfused rings containing from three to ten carbon atoms. Typical (C3-C? 0) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like. "(C3-C7) cycloalkyl" refers to a saturated hydrocarbon ring structure composed of one or more fused or unfused rings containing three to seven carbon atoms It is understood that the definition of "(C3-C7) cycloalkyl" is included within the definition of "cycloalkyl (C3-C? 0)". "(C3-C7) substituted cycloalkyl", refers to a (C3-C7) cycloalkyl group optionally substituted with one or more portions selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, alkyl (C? -C6) ), alkoxy (C? -Ce), alkyl (C? -C4) -cycloalkyl (C3-C? 0), alkyl-aryl (C? -C4), alkoxycarbonyl (C? -C6), N, N-dialkylamine (C) C6), NH-alkylaminamine (C? -C6), alkyl (C? -C) -N, N-dialkylamine C? -C6, difluoromethyl, difluoromethoxy, trifluoromethyl and trifluoromethoxy. In this document, the term "(C? -C4) alkyl- (C3-C7) cycloalkyl", refers to a saturated, monovalent, linear or branched aliphatic chain, of 1 to 4 carbon atoms, which has a cycloalkyl (C3) -C7) attached to the aliphatic chain. Included within the term "alkyl (C? -C4) -cycloalkyl (C3-C7)", are the following: and similar. As used herein, the term "substituted (C? -C4) alkyl- (C3-C7) cycloalkyl", refers to a saturated, monovalent, linear or branched aliphatic chain, of 1 to 4 carbon atoms, which carries an optionally substituted cycloalkyl (C3-C7) group attached to the aliphatic chain. As used herein, the term "heterocycle" refers to a ring of five or six elements, saturated or unsaturated, which contains one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. It is understood that the remaining atoms are carbon and that the heterocycle may be attached at any point which provides a stable structure. Examples of heterocyclic groups include, thiophenyl, furanyl, tetrahydrofuryl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridinyl, pyrimidyl, pyrazinyl, pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl, tetrahydropyrimidyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrimidinyl, imidazolidimyl, morpholinyl, pyranyl, thiomorpholinyl, and the like. The term "substituted heterocycle", represents a heterocycle optionally substituted with one or two portions, selected from the group consisting of halo, amino, cyano, alkyl (C? -C4), alkoxy (C? -C4), -S- alkyl (C? -C). As used herein, the term "(C? -C4) alkyl -heterocycle" refers to a saturated, monovalent, linear or branched aliphatic chain, of 1 to 4 carbon atoms, which has a linked heterocycle group to the aliphatic chain. Examples of "alkyl heterocycle (C? -C4)" include: Q. ~ 'O and similar. The term "(C 1 -C 4) substituted heterocycle" refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms carrying an optionally substituted heterocycle group attached to the aliphatic chain. As used herein, the term "NH-alkylamine (C? -C4)" refers to a nitrogen atom substituted with saturated, monovalent, linear or branched aliphatic chains of 1 to 4 carbon atoms. Included within the term "NH-alkylamine (C? -C4) are -NH (CH3), -NH (CH2CH3), -NH (CH2CH2CH3), -NH (CH2CH2CH2CH3), and the like. "N, N-dialkylamine (C? -C4)" refers to a nitrogen atom substituted with two saturated, monovalent, linear or branched aliphatic chains of 1 to 4 carbon atoms, included within the term "N, N- dialkyl amine (C1-C4) "are -N (CH3) 2, -N (CH2CH3) 2, -N (CH2CH2CH3) 2, N (CH2CH2CH2CH3) 2, -N, N (CH3) (CH2CH3), -N, N (CH2CH3) (CH2CH3) and the like As used herein, the term "alkyl" (C? -C4) -N, N-dialkylamine (C? -C4) ", refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, which has an N, N-dialkylamine (C? -C4) attached to the aliphatic chain Included within the term "(C? -C4) alkyl-N, N-dialkylamine (C? -C4)", are the following: and similar. As used herein, the term "(C? -C4) alkyl-N-Hyalkylamine (CX-C4)", refers to a saturated, monovalent, linear or branched aliphatic chain of 1 to 4 carbon atoms, which has an NH-alkylamine (C? -C4) attached to the aliphatic chain. Included within the term "alkyl (C? -C4) -NH-alkylamine (C1-C4) are the following: The designation "- ** ß-l" refers to a link that protrudes forward of the plane of the page. The designation "" HMII "refers to a link projecting back from the plane of the page As used herein, the term" nuclear steroid hormone receptor modulator "refers to those ligands of the steroid receptor. Nuclear hormone which bind to any of GR, MR, AR, ER, or PR, of the largest class of nuclear hormone receptors, and either agonize, antagonize, partially agonize or partially antagonize receptor activity. As used herein, the term "mineralocorticoid receptor" or "MR" refers to the mineralocorticoid receptor subtype, the largest class of nuclear hormone receptors, which bind to the aldosterone of the mineralocorticoid hormone, as its cognate ligand The term "mineralocorticoid receptor modulator" or "mineralocorticoid modulator" or "MR modulator" as used herein, refers to those ligands of the hormone receptor. These receptors bind to the mineralocorticoid receptor subtype and modulate (ie, agonize, antagonize, partially agonize, or partially antagonize) receptor activity. As a particular embodiment, the present invention provides antagonists of MR activity. As used herein, the term "glucocorticoid receptor" or "GR" refers to the subtype of the glucocorticoid receptor, the largest class of nuclear hormone receptors, which bind to cortisol, corticosterone or cortisone of the glucocorticoid hormones as their cognate ligand. The term "glucocorticoid receptor modulator" or "glucocorticoid modulator" or "GR modulator," as used herein, refers to those ligands of the nuclear hormone receptor which bind to the glucocorticoid receptor subtype and modulate say, agonize, antagonize, partially agonize or partially antagonize) the activity of the receptor. As used herein, the term "disorder susceptible to modulation of the nuclear steroid hormone receptor" refers to any physiological disorder, of any origin, known or believed to be responsible for the administration of a modulator (i.e. , agonist, antagonist, partially agonist or partially antagonist) of a nuclear steroid hormone receptor. Such disorders include Conn syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and / or combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, atherosclerosis, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, rejection of tissue associated with organ transplantation, malignancies such as leukemia and lympholas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, adrenal insufficiency chronic primary, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid erythematosus lupus, polyartitis nodosa, Wegener's granulomatosis, arthritis giant cell itis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bullosa, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, cutaneous T-cell lymphoma, psychosis, cognitive disorders (such as memory disturbances), mood disorders (such as depression and bipolar disorder), anxiety disorders and personality disorders. As used in this document, the term "Congestive heart failure" (CHF) or "congestive heart disease" refers to a disease state of the cardiovascular system whereby the heart is unable to efficiently pump an adequate volume of blood to meet the requirements of tissues and organ systems of the body. Typically, CFH is characterized by left ventricular failure (systolic dysfunction) and fluid accumulation in the lungs, with the underlying cause being attributed to one or more states of cardiac or cardiovascular disease including coronary artery disease, myocardial infarction, hypertension , diabetes, valvular heart disease, and cardiomyopathy. The term "diastolic congestive heart failure" refers to a state of CHF characterized by impairment in the ability of the heart to properly relax and fill with blood. Reciprocally, the term "systolic congestive heart failure" refers to a state of CFH characterized by impairment in the ability of the heart to properly contract and expel blood. As will be appreciated by one skilled in the art, physiological disorders may present as a "chronic" condition, or an "acute" episode. The term "chronic", as used herein, means a condition of slow progress and long duration. As such, a chronic condition is treated when it is diagnosed and treatment continues throughout the course of the disease. Reciprocally, the term "acute" means an exacerbated event or attack, of short course, followed by a period of remission. Thus, the treatment of physiological disorders includes both acute events and chronic conditions. In an acute event, the compound is administered at the beginning of the symptoms and is interrupted when the symptoms disappear. As described above, a chronic condition is treated throughout the course of the disease. As used in this document, the term "patient" refers to a mammal, such as a mouse, gerbil, guinea pig, rat, dog or human. It is understood, however, that the preferred patient is a human. As used herein, the terms "treated," "treatment," or "to treat," each means alleviating symptoms, eliminating the cause of the resulting symptoms on either a temporary or permanent basis, and preventing, diminishing appearance. , or reverse the progress or severity of the symptoms resulting from the named disorder. As such, the methods of this invention encompass both therapeutic and prophylactic administration. As used herein, the term "effective amount" refers to the amount or dose of the compound, after administration of single or multiple doses to the patient, which provides the desired effect on the patient under diagnosis or treatment. An effective amount can be readily determined by the attending physician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the amount or effective dose of the compound administered, a number of factors are considered by the attending physician, including, but not limited to: the mammalian species; its size, age and general health; the degree of complication or the severity of the disease involved; the patient's individual response; the particular compound administered; the form of administration; the bioavailability characteristics of the preparation administered; the selected dose regimen; the use of concomitant medication; and other relevant circumstances. A typical daily dose will contain from about 0.01 mg / kg to about 100 mg / kg of each compound used in the present treatment method. Preferably, daily doses will be from about 0.05 mg / kg to about 50 mg / kg, more preferably from about 0.1 mg / kg to about 25 mg / kg. Oral administration is a preferred route of administration of the compounds employed in the present invention if administered alone, or as a combination of compounds capable of acting as a modulator of the nuclear steroid hormone receptor. Oral administration, however, is not the only route, not even the only preferred route. Other preferred routes of administration include transdermal, percutaneous, pulmonary, intravenous, intramuscular, intranasal, buccal, sublingual or intrarectal routes. Where the nuclear steroid hormone receptor modulator is administered as a combination of compounds, one of the compounds can be administered by one route, such as orally, and the other can be administered by transdermal, percutaneous, pulmonary, intravenous routes, intramuscular, intranasal, buccal, sublingual, or intrarecal, as the particular circumstances require. The route of administration can be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the care giver. The compounds employed in the present invention can be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating compounds of Formula I are important embodiments of the present invention. Such compositions can take any physical form that is pharmaceutically acceptable, but orally administered pharmaceutical compositions are particularly preferred. Such pharmaceutical compositions contain, as an active ingredient, an effective amount of a compound of Formula I, as described herein and above, which includes the pharmaceutically acceptable salts and hydrates thereof, in which the effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a given compound, or may contain a fraction of the daily dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit depends on the identity of the particular compound chosen for the therapy, and other factors such as the indication for which it is given. The pharmaceutical compositions of the present invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, employing well known procedures. The following discussion provides typical procedures for preparing pharmaceutical compositions incorporating the compounds of the present invention. However, the following is not in any way proposed to limit the scope of the pharmaceutical compositions provided by the present invention. The compositions are preferably formulated in a unit dosage form, each dosage contains from about 1 to about 500 mg of each compound individually or in a unit dosage form, more preferably about 5 to about 300 mg (eg, 25 mg). The term "unit dosage form" refers to a physically discrete unit suitable as unit dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutical carrier, diluent or excipient. suitable. The inert ingredients and the manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science can be used in this document. All usual types of compositions can be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches and suspensions. In general, the compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used. The amount of the compound, however, is better defined as the "effective amount", that is, the amount of each compound which provides the desired dose to the patient in need of such treatment. The activity of the compounds employed in the present invention does not depend on the nature of the composition, therefore, the compositions are chosen and formulated solely for convenience and economy. The capsules are prepared by mixing the compound with a suitable diluent and filling the appropriate amount of the mixture in the capsules. Customary diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain meal and similar edible powders. The tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators, as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellose and waxes can also serve as binders. The tablets are often coated with sugar as a flavor and sealer. The compounds can also be formulated as chewable tablets, using large amounts of pleasant tasting substances such as mannitol in the formulation, as is now well established in practice. Formulations such as tablets that dissolve instantly are also now frequently used to ensure that the patient consumes the dosage form and to avoid difficulties in the expansion of solid objects that bother some patients. A lubricant is often necessary in a tablet formulation, to prevent the tablet and perforations from adhering to the die. The lubricant is chosen from such slippery solids as talcum, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances which expand when wetted to break the tablet and release the compound. They include starches, clays, celluloses, alginas and gums. More particularly, potato and corn starch, methylcellulose, agar, bentonite, wood cellulose, natural powder sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, can be used. sodium lauryl sulfate. Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer, which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate. When it is desired to administer the compound as a suppository, the usual bases can be used. Cocoa butter is a traditional suppository base, which can be modified by the addition of waxes to raise its melting point slightly. Suppository bases miscible in water, particularly polyethylene glycols of various molecular weights, are in wide use as well. Transdermal patches have become popular recently. Typically, they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which are maintained in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other more complicated patch compositions are also in use, particularly those having a perforated membrane with innumerable pores through which the drugs are pumped by osmotic action. It is understood by one of ordinary skill in the art, that the methods as described above, can be readily applied to a method for treating physiological disorders susceptible to modulation of the nuclear steroid hormone receptor, and particularly, congestive heart failure.

Particular Aspects of the Compounds and Methods of the Invention The following list sets forth several groupings of particular substituents for compounds of formula I. It will be understood that compounds of Formula I having such particular substituents, and methods employing such compounds, represent particular aspects of the present invention. It will further be understood that each of these groupings of particular substituents can be combined with other provided groupings to create still further particular aspects of the compounds of the present invention.

Therefore, a particular aspect of the present invention is one wherein the compound of Formula I is one wherein: (a) X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, or -CH2S -; (b) X represents -CH2-, -CH2CH2-, or -CH20-; (c) X represents -CH2-; (d) X represents -CH2CH2-; (e) X represents -CH20-; or (f) X represents -CH2NR10-. (g) R1 represents hydrogen, (C? -C4) alkyl, (C3-C7) cycloalkyl, (C? -C4) hydroxyalkyl, (C? -C4) haloalkyl, (C? -C4) alkyl, -heterocycle, alkyl ( C-C4) -N-Alkylamine (C? -C4), or alkyl (C? -C) -N, N-dialkylamine (C? -C4); (h) R1 represents hydrogen, methyl, ethyl, propyl, isopropyl, (C3-C7) cycloalkyl, hydroxyalkyl (C? -C4), haloalkyl (C? -C4), (C? -C4) alkyl-heterocycle, alkyl ( C? -C4) -NHalkylamine (C? -C4), or alkyl (C? -C4) -N, N-dialkylamine (C? -C4); (i) R1 represents hydrogen, methyl, ethyl, propyl, or isopropyl; (j) R1 represents hydrogen, methyl or ethyl; (k) R1 represents methyl or ethyl; (1) R1 represents hydrogen or (C3-C7) cycloalkyl; (m) R1 represents (C3-C7) cycloalkyl; (n) R1 represents cyclopropyl; (o) R1 represents hydrogen or hydroxyalkyl (C? -C4); (p) R1 represents hydroxyalkyl (C? -C4); (q) R1 represents 3-hydroxypropyl; (r) R1 represents hydrogen or (C? -C4) alkyl-heterocycle; (s) R1 represents alkyl (C? -C4) -heterocycle; (t) R1 represents 3-morpholino-4-ylpropyl (u) R1 represents hydrogen or haloalkyl (C? -C4); (v) R1 represents haloalkyl (C? -C4); (w) R1 represents 3-iodopropyl; (x) R1 represents hydrogen or (C? -C4) alkyl-NHalkylamine (C? -C4); (y) R1 represents alkyl (C? -C4) -NHalkylamine (C? -C); (z) R 1 represents 3-methylamino propyl (aa) R 1 represents hydrogen or (C 1 -C 4) alkyl-N, N-dialkylamine (C 1 -C 4); (bb) R1 represents alkyl (C? -C4) -N, N-dialkylamine (C1-C4); or (ce) R 1 represents 3-dimethylamino propyl. (dd) R 2 represents hydrogen, halo, methyl, ethyl, propyl, isopropyl, heterocycle, or substituted heterocycle; (ee) R2 represents hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, or heterocycle; (ff) R 2 represents hydrogen, fluoro, chloro, or bromo; (gg) R2 represents hydrogen or fluoro; (hh) R2 represents fluoro; (ii) R2 represents hydrogen, methyl, ethyl, propyl, or isopropyl; (jj) R 2 represents hydrogen or heterocycle; (kk) R2 represents pyrazolyl; or (11) R2 represents hydrogen; (mm) R3 represents hydrogen, fluoro, chloro, or bromine; (nn) R3 represents hydrogen, fluoro, or chloro; (oo) R3 represents hydrogen or fluoro; (pp) R3 represents fluoro; or (qq) R3 represents hydrogen; (rr) R4 represents hydrogen, halo, amino, nitro, (C? -C4) alkyl, (C? -C4) alkoxy, NHS02R7, NHCOR8 wherein R8 represents alkyl (C? ~ C4) or (C1-C4) alkoxy , or COR9 wherein R9 represents alkyl (C? -C4) or (C3-C4) alkoxy; (ss) R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, NHS02R7, NHCOR8 wherein R8 represents methyl, ethyl, methoxy, or ethoxy, or COR9 wherein R9 represents methyl , ethyl, methoxy, or ethoxy; (tt) R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C3-C4) alkoxy, NHS02R7, NHCOR8 wherein R8 represents methyl or methoxy, or COR9 wherein R9 represents methyl or methoxy; (uu) R4 represents hydrogen, halo, amino, nitro, (C? -C4) alkyl, (C1-C4) alkoxy, or NHS02R7; (vv) R4 represents hydrogen, fluoro, chloro, bromo, amino, nitro, methyl, ethyl, methoxy, ethoxy or NH S02R7; (ww) R 4 represents hydrogen, fluoro, chloro, bromo, amino, or nitro; (xx) R4 represents fluoro, chloro, bromo, amino, or nitro; (yy) R4 represents fluoro, chloro, or bromo; (zz) R 4 represents amino or nitro; (aaa) R 4 represents hydrogen, methyl, ethyl, methoxy, or ethoxy; (bbb) R 4 represents methyl, ethyl, methoxy, or ethoxy; (ccc) R 4 represents methyl or ethyl; (ddd) R 4 represents methoxy or ethoxy; (eee) R4 represents hydrogen or NHS02R7; (fff) R4 represents hydrogen or NHS02R7 wherein R7 represents (C? -C4) alkyl, aryl, or N, N-dialkylamine (C1-C4); (ggg) R4 represents hydrogen, NHS02CH3, NHS02CH2CH3, NHS02 (C6H5), or NHS02N (CH3) 2; (hhh) R4 represents NHS02CH3, or NHS02CH2CH3; (iii) R represents NHS02CH3; or (jjj) R 4 represents hydrogen. (kkk) R5 represents hydrogen, fluoro, or chloro; (111) R5 represents hydrogen. (mmm) R6 represents hydrogen, methyl, or ethyl; Furthermore, even as another particular embodiment of the present invention, the compounds of Formula I have the following configuration Formula I Furthermore, it will be understood that where X represents -CH20-, -CH2S-, or -CH2NR10, either a heteroatom or the carbon of such groups, they may be directly attached to the fused phenyl ring. The compounds of Formula I can be chemically prepared, for example, by following the synthetic routes set forth in the Reaction Schemes below. However, the following discussion is not proposed to limit the scope of the present invention in any way. For example, the specific synthetic steps for the routes described herein can be combined in different ways, or with different reaction scheme stages, to prepare additional compounds of Formula I. Furthermore, it must be recognized that the sequence in which Synthetic reactions take place, it is not involved and can be done in any way to achieve the desired final product. All substituents, unless otherwise indicated, are as previously defined. Reagents and starting materials are readily available to one of ordinary skill in the art. Reagents and starting materials are readily available to one of ordinary skill in the art. Other necessary reagents and starting materials can be made by methods which are selected from standard techniques of organic and heterocyclic chemistry, techniques which are analogous to the synthesis of known structurally similar compounds, and the methods described in the Preparations and Examples below, which include any of the new procedures. In addition, one of ordinary skill in the art will readily appreciate that many of the necessary reagents and starting materials are readily obtained from commercial suppliers.

The compounds of Formula I can be synthesized by coupling the appropriately substituted or unsubstituted indole with the appropriately substituted or unsubstituted carbinol, in accordance with the procedures as generally described in Reaction Scheme I, below. Any of the subsequent modifications that appear necessary to produce the final product of Formula I, which include but are not limited to deprotection reactions, can be readily performed by one of ordinary skill in the art. The appropriately substituted or unsubstituted carbinols used in the following processes can either be purchased from commercial suppliers or can be prepared from appropriately substituted or unsubstituted ketones, as depicted in Reaction Scheme I, using methods known in the art. . Ketones for use in the following procedures are either purchased from commercial suppliers or synthesized as described in Schemes II through VIII below. The characters for use in the following procedures are also either purchased from commercial suppliers, or synthesized in the manner as described in Reaction Schemes IX and X.

REACTION SCHEME 1 R, gBr or toluene (1) or tetrahydrofuran (2) (3) trifluoroacetic acid dichloromethane Formula I In Reaction Scheme 1, an appropriately substituted or unsubstituted ketone of the general structure (I) is dissolved in a suitable solvent such as diethyl ether or toluene or tetrahydrofuran. An alkylmagnesium or alkyllithium halide reagent is then added under nitrogen at room temperature or lower temperatures and the reaction mixture is allowed to proceed for ten minutes to several days. The reaction is then quenched using a suitable reagent such as aqueous ammonium chloride, and the carbinol of the general structure (2) is isolated using techniques common in the art. Electrophilic aromatic substitution occurs by methods known in the art. For example, the appropriately substituted or unsubstituted indole (3), and the appropriately substituted or unsubstituted carbinol (2), are first dissolved in a suitable solvent such as dichloromethane or acetic acid or methanol, then treated with a suitable Lewis or protic acid such as acid trifluoroacetic, boron trifluoride etherate, hydrogen chloride or aluminum chloride. The reaction proceeds in any way from ten minutes to several days, depending on the stability of the starting materials. The product of Formula I can then be isolated by normal phase chromatographic methods or recrystallization techniques commonly employed in the art. The substituted or unsubstituted indanones of the general structure (6), wherein R 2 and R 3 independently can be, for example, hydrogen, alkyl, aryl, halo, or heterocycle, can be synthesized in accordance with Reaction Scheme II, using techniques common in art.

REACTION SCHEME II In Reaction Scheme II, an appropriately substituted or unsubstituted cinnamic acid of the general structure (4) is reduced using methods known in the art. Hydrogenation can occur in a suitable solvent such as tetrahydrofuran or acetic acid, employing but not limited to, an appropriate catalyst such as palladium on carbon or palladium hydroxide or platinum oxide. The reaction takes place under a hydrogen atmosphere at various pressures and temperatures. The addition of acid such as concentrated sulfuric acid can facilitate the reaction. The substituted or unsubstituted 3-arylpropionic acid of the general structure (5) can then be cycled using common methods in the art such as heating the substituted substituted or unsubstituted cinnamic acid with polyphosphoric acid at various temperatures with or without a suitable solvent (Reaction Scheme II), to form substituted or unsubstituted indanones of the general structure (6). Alternatively, (5) can be activated by conversion to the corresponding acid halide or anhydride using a suitable reagent, such as thionyl chloride or trifluoroacetic anhydride, and then subjecting it to cycles in the presence of a suitable Lewis acid such as aluminum trichloride or Boron trifluoride etherate in a suitable solvent using techniques and methods common in the art. The substituted or unsubstituted tetralones of the general structure (12), wherein R2 and R3 independently, can be for example, hydrogen, alkyl, aryl, halo or heterocycle, can be synthesized according to Reaction Scheme III using common techniques in the art.

REACTION SCHEME III O Br O Ph3P Br CH3CN, OH OH Ph3P heat (6) PPA, heat In Reaction Scheme III, triphenylphosphine can be reacted with 4-bromobutanoic acid in a suitable solvent such as acetonitrile at various temperatures, to obtain the Wittig reagent (2-carboxy-ethyl) -triphenyl-phosphonium bromide (8). As in Reaction Scheme III, (2-carboxy-ethyl) -triphenyl-phosphonium bromide can be used, with an appropriately substituted or unsubstituted aldehyde in the general structure (9), in the presence of a suitable base such as t -sodium butoxide or sodium hydride and a suitable solvent such as dichloromethane or tetrahydrofuran at various temperatures, to obtain the corresponding substituted or unsubstituted beta-gamma-butenoic acid (10), using techniques common in the art. The isolated beta-gamma-butenoic acid (10) can be a mixture of cis / trans isomers, depending on the substitution of the aryl ring, the base, the solvent and other reaction conditions, such as temperature and reagent concentration. The substituted or unsubstituted beta-gamma-butenoic acid can be used in the next step as a cis / trans mixture or after the chromatographic separation. The substituted or unsubstituted beta-gamma-butenoic acid can then be hydrogenated to a 4-aryl butenoic acid of general structure (11) and cycled using the same or similar method and conditions known in the art, which were described in Reaction Scheme II, to obtain the substituted or unsubstituted tetralone of the general structure (12). The substituted or unsubstituted 4-chromanones of the general structure (16), wherein R 2 and R 3 independently can be, for example, hydrogen, alkyl, aryl, halo or heterocyclic, can be synthesized in accordance with Reaction Scheme IV, using common techniques in art.

REACTION SCHEME IV In Reaction Scheme IV, an appropriately substituted or unsubstituted phenol is alkylated with 3-chloro-1-propanol, using a suitable base such as sodium hydride in a suitable solvent such as dimethylformamide. The alcohol resulting from the general structure (14) can be isolated using standard methods known in the art. The alcohol portion of (14) can be oxidized using standard oxidation procedures, common in the art, such as chromium trioxide in aqueous sulfuric acid / acetone. The acid resulting from the general structure (15) can be converted to the corresponding acid halide using methods known in the art such as oxalyl chloride in dichloromethane with a catalytic amount of dimethylformamide. The intramolecular acylation of the aryl ring in (15), can be achieved using a suitable Lewis acid such as aluminum trichloride to obtain the corresponding chromanone of the general structure (16). Compounds of Formula I, wherein R4 represents amino or an amino-derived substituent such as NHS02R7 or NHCOR8 (as represented by structures (18) and (19) below), may be prepared in accordance with Reaction Scheme V , using methods known in the art.

REACTION SCHEME V 1. R6-l or R6-Br or R6-CI NaOM e / D F 2. 5% P / C, H2, EtOH As depicted in Reaction Scheme V, a 7-nitroindole derivative can be fused to a carbinol of the general structure (2), using conditions known in the art that were described in Reaction Scheme I above. The alkylation / acylation / sulfonation of the indole nitrogen atom can take place in the presence of an appropriate alkylation / acylation / sulfonation agent, respectively, such as methyl iodide, acetyl chloride or methanesulfonyl chloride. A suitable base, such as sodium methoxide or sodium hydroxide and solvent, such as dimethylformamide, should also be used. The alkylated / acylated / sulfonated product can be isolated using standard techniques common in the art, such as aqueous lifting and chromatographic purification. The reduction of the nitro group can be achieved using methods known in the art. The nitro compound can be dissolved in an appropriate solvent such as ethyl acetate, methanol, ethanol, tetrahydrofuran or acetic acid, then an appropriate catalyst such as palladium on carbon, or Pearlman catalyst or platinum oxide, and the mixture is added. The resultant is hydrogenated for 10 minutes to 6 hours. The products of the general structure (18), can be isolated using common techniques. The aniline nitrogen atom can then be alkylated / acylated / sulphonated using an appropriate alkylation / acylation / sulfonation agent, and a suitable solvent / base, such as pyridine. Co-solvents such as tetrahydrofuran, dimethyl sulfoxide or dimethylformamide can also be added. Additional procedures for the synthesis of compounds of Formula I, wherein R 4 represents amino or an amino derivative, are provided by Reaction Scheme VI.

REACTION SCHEME VI % Pd (OHyC, H2, BOH In Reaction Scheme VI, a Cbz-protected 7-aminoindole derivative (made according to the procedures as described in Reaction Scheme X, below), can be condensed with a carbinol of the general structure (2), using conditions known in the art which are described in Reaction Scheme 1 above. The removal of the Cbz protecting group in structure (20) can be achieved using methods known in the art. The compound (20) can be dissolved in an appropriate solvent such as ethyl acetate, methanol, ethanol, tetrahydrofuran, or acetic acid, then, an appropriate catalyst such as palladium on carbon, or Pearlman catalyst, or platinum oxide, is added, and the resulting mixture is hydrogenated using conditions known in the art. The products of the general structure (21) can be isolated using common techniques. The aniline nitrogen atom can then be alkylated / acylated / sulphonated using an appropriate alkylation / acylation / sulfonation agent, such as methanesulfonyl chloride or acetyl chloride and a suitable base / solvent such as pyridine. Co-solvents such as tetrahydrofuran, dimethyl sulfoxide or dimethylformamide can also be added. Ketones of the general structure (24) can be prepared according to Reaction Scheme VII using methods known in the art. In Reaction Scheme VII, Rx and R? they can be independently, for example, hydrogen, alkyl or acyl groups or part of a heterocyclic ring such as imidazole, pyrazole, pyrrole, or morpholine, and the like.

REACTION SCHEME VII In Reaction Scheme VII, a structure ketone (24) can be prepared by reacting a compound of structure (23) in an appropriate solvent such as dimethyl sulfoxide in the presence of a base such as potassium carbonate and a nucleophilic amine or nitrogen that contains heterocycle. The reaction takes place at temperatures of 100 degrees Celsius to 300 degrees Celsius, depending on the nucleophilicity of the nitrogen atom. The compounds of Formula I wherein R 1 is, for example, an alkyl-alkylamine derivative (as represented by structure (29) below), can be prepared according to the reaction sequence in Reaction Scheme VIII. In Reaction Scheme VIII, Rx and R? they can be independently, for example, hydrogen, alkyl or acyl group or part of a heterocyclic ring such as imidazole, pyrazole, pyrrole or morpholine and the like.

REACTION SCHEME VII In Reaction Scheme VIII, the cyclopropylcarbinol of structure (2a) is condensed with an N- (lH-indol-7-yl) -methanesulfonamide derivative (prepared according to procedures as described in Reaction Scheme IX , below), under standard conditions that were previously described (Reaction Scheme 1). A mixture of the propyl ester of trifluoroacetate (25) and product (26) results. Compounds (25) and (26) can be separated using standard techniques such as reverse or normal phase chromatography, or taken directly to the next step as a mixture. The hydrolysis of the TFA ester can take place in a suitable solvent such as methanol, using an appropriate base such as aqueous lithium hydroxide. The isolation and separation of (27) from (26), can be achieved using standard techniques common in the art. The propyl alcohol (27) can be converted to the corresponding propyl halide (28), using standard Mitsunobu-type conditions. For example, a suitable halogen such as iodine or bromine can be added to a mixture of triphenylphosphine and imidazole in tetrahydrofuran under nitrogen to prepare the Mitsunobu reagent. For example, a paropylated halogen such as iodine or bromine can be added to a mixture of triphenylphosphine and imidazole in tetrahydrofuran under nitrogen to prepare the Mitsunobu reagent. The alcohol (27) is then added as a solid or in solution in tetrahydrofuran and the reaction mixture is stirred to completion. The propyl iodide derivative can be isolated and purified using standard techniques such as aqueous lifting and normal phase chromatography. The iodide derivative (28) can then be converted to a secondary or tertiary amine by reacting it with an excess of amine such as morpholine or dimethylamine. The reaction can then be run either using the amine as the solvent or using an appropriate co-solvent such as tetrahydrofuran. The amines of the general structure (29) can then be isolated using common methods in the art. Reaction Scheme IX represents the preparation of N- (lH-indol-7-yl) -methanesulfonamide derivatives using methods common in the art.

REACTION SCHEME IX In Reaction Scheme IX, Step A or B, nitro reduction occurs by methods commonly employed in the art. For example, a 7-nitroindole derivative (Step A), is dissolved in a suitable solvent such as ethanol, and is reduced by hydrogenation conditions, such as Pd / C and a source of hydrogen such as hydrogen gas or ammonium formate. The reaction can occur at ambient temperature at reflux conditions and the product can be isolated by standard techniques such as filtration or standard aqueous lifting. Alternatively, (Step B), the 7-nitroindole derivative is treated with a reducing agent, such as tin chloride dihydrate at elevated temperatures. The reaction may proceed for approximately 1-24 hours. The product can be isolated by methods known in the art, such as a standard aqueous lift, and purified by chromatography. In Reaction Scheme IX, Step C, the 7-aminoindole derivative is dissolved in dichloromethane and pyridine and methanesulfonyl chloride is added. The reaction is stirred at room temperature for a minimum of six hours. The structure product (30) can be isolated by methods known in the art, such as standard aqueous lifting, and can be purified via standard chromatography techniques. In Reaction Scheme X, a 7-aminoindole derivative is protected with a Cbz group using conditions common in the art. For example, 7-aminoindole is dissolved in dichloromethane, aqueous sodium hydroxide is added, followed by Cbz chloride. After completion of the reaction, the Cbz-protected product (30) is isolated using techniques known in the art.

X REACTION SCHEME Determination of Biological Activity: To demonstrate that the compounds of the present invention have affinity for nuclear steroid hormone receptors, and thus, have the ability to modulate nuclear steroid hormone receptors, MR binding assays were performed and Soluble GR. All ligands, radioligands, solvents and reagents used in binding assays are readily available from commercial sources, or can be easily synthesized by experts of ordinary skill.

Mineralcorticoid Receptor Linkage Assay (Method 1): The full length human MR gene is cloned from human kidney or human brain cDNA library. Briefly, using synthetic oligonucleotide primers (Eli Lilly and Company, Indianapolis), targeting nucleotides 20-54 and 3700-3666 of the human MR, polymerase chain reaction (PCR) was performed under standard conditions using a human cDNA library . The PCR reaction was performed in a final volume of 50 μl containing approximately 1 μl of a 50X base solution of polymerase; about 1 μl of a 50X base solution of dNTP; approximately 5 μl of an appropriate CPR buffer; about 1 μl of each primer; about 5 μl of a human brain or human kidney cDNA library; and approximately 36 μl of water. The reaction was allowed to denature for about 30 seconds at 95 ° C, strengthened for about 30 seconds at 55 ° C, and extended for about 5 minutes at 72 ° C, the sequence is repeated for a total of about 35 cycles. The desired PCR product (3.68 Kb) was confirmed by gel electrophoresis and subsequently cut from the gel and stored at about -20 ° C until extraction. To extract the cDNA product from the agarose gel, the QIAEX II Gel Extraction protocol (QIAGEN, Inc.) was used, in accordance with the manufacturer's instructions. After extraction, the MR cDNA was cloned into an appropriate cloning vector (Zero Blunt TOPO PCR Cloning Kit (Invitrogen, Inc.), and a pAcHLT-baculovirus (BD / Pharminogen) transfer vector, then expressed in SF9 insect cells, essentially in accordance with the manufacturer's instructions.Sf9 cells are grown on a scale where cell pellets are obtained in gram quantities for subsequent use in the MR binding assay. they are subjected to lysis by repeated freeze-thaw cycles (approximately 4) in a suitable lysis buffer, then centrifuged at approximately 1 x 103G (with the supernatant being stored for future tests). MR binding assays were performed at a total volume final of approximately 250 μl containing approximately 20-25 μg of protein and 0.5nM of [3H] -aldosterone plus varying concentrations of the compound or vehicle The test buffer consists of 30 mM sodium molybdate, 30 mM TRIS-HCl, 5 mM sodium phosphate, 5 mM sodium pyrophosphate, and approximately 10% glycerol, pH = 7.5 . Briefly, TA assays were prepared in 96-well Falcon 3072 plates, each well containing 210 μl of binding buffer, 10 μl of [3 H] -aldosterone, 10 μl of compound / test vehicle, and 20 μl of protein extract of the resuspended receiver. Incubations were carried out at 4 ° C with shaking for approximately 16 hours. 200 μl aliquots of each incubation were filtered on Millipore HA 0.45 micron filter 96-well plates pre-moistened with 30 mM cold TRIS-HC1. The filter plates are suctioned dry with vacuum and immediately washed 3X with 30 mM cold TRIS-HCL. The plates are then perforated and the amount of the receptor-ligand complex was determined by liquid scintillation counting using 4 ml of Ready Protein Plus ™ liquid scintillation cocktail. IC50 values (defined as the concentration of the test compound required to decrease the binding of [3 H] -aldosterone by 50%), are then determined. The Ki values for each respective test compound can then be calculated by applying the Cheng-Prusoff equation as described in Cheng et al. , Relationship Between The Inhibition Constant (Ki) and The Concentration of Inhibitor Which Causes 50% Inhibition (IC50) of an Enzymatic Reaction (Relationship between the inhibition constant (Ki) and the concentration of inhibitor that causes 50% inhibition (IC50 ) of an enzymatic reaction), Biochem. Pharmacol., 22: 3099-31088; (1973).

Glucocorticoid Receptor Binding Assay (Method 1): To demonstrate the GR modulation potency of compounds of the present invention, the following source of the glucocorticoid receptor was employed. Human lung epithelial cells A549 (ATCC) are grown on a scale where cell pellets of gram quantity are obtained. Harvested cell pellets were washed twice in cold phosphate buffered saline, centrifuged, and resuspended in cold binding assay buffer. The binding assay buffer consists of 10% glycerol, 50 mM Tris-HC1 (pH 7.2), 75 mM sodium chloride, 1.5 mM magnesium chloride, 1.5 mM EDTA, and 10 mM sodium molybdate. . The cell suspensions were lysed via sonication, centrifuged and the "extract" supernatant is frozen under pressure and stored at -80 ° C until needed. GR-binding assays were performed in a final volume of 140 ul containing 50-200 ug of cell extract A549 and 1.86 nM of [3H] -dexametasone (Amersham) plus varying concentrations of the test compound or vehicle. Briefly, TA assays were prepared in Fisher 3356 96-well plates, each containing 100 ul of A549 cell extract, 20 ul of [3 H] -dexametasone and 20 ul of the test compound / vehicle. Incubations were carried out at 4 ° C for 16 hours. After incubation, 70 ul of charcoal solution coated with 3X dextran was added to each reaction, mixed and incubated for 8 minutes at RT. The 3X dextran-coated charcoal solution consists of 250 ml of binding assay buffer, 3.75 g of Norit A charcoal (Sigma), and 1.25 g of dextran T-70 (Amersham). Charcoal / unbound radioligand complexes were removed by centrifugation of the plate and 140 ul of supernatant was transferred from each cavity to another 96-well Optiplate (Packard Instruments). 200 ul of Microscint-20 scintillant (Packard Instruments) was added to each well and the amount of bound radioligand receptor was determined using a Packard Instruments TopCount instrument. The IC5o values, defined as the concentration of the test compound, required to decrease the binding of [3 H] -dexametasone by 50%, are then determined. The Ki values for each respective test compound can then be calculated by applying the Cheng-Prusoff equation as described in Cheng et al. , Relationship Between The Inhibition Constant (Ki) and The Concentration of Inhibitor Which Causes 50% Inhibition (IC50) of an Enzymatic Reaction, Biochem. Pharmacol., 22: 3099-31088; (1973).

Alternative Linkage Assay Protocol for MR, GR, AR and PR (Method 2): Cell lysates of 293 cells overexpressing the GR (glucocorticoid receptor), AR (androgen receptor), MR (mineralcorticoid receptor) or PR (progesterone receptor) ) human, are used for competition binding assays to determine Ki values for test compounds. Briefly, competition binding assays are run in a buffer containing 20 mM Hepes, pH 7.6, 0.2 mM EDTA, 75 mM NaCl, 1.5 mM MgC12, 20% glycerol, 20 mM sodium molybdate, 0.2 mM DTT, 20 ug / ml aprotinin and 20 ug / ml leupeptin, using either 0.3 mM of 3H-dexamethasone for GR binding, 0.36 nM of 3H-methyltrienolone for AR binding, 0.25 nM of 3H-aldosterone for linkage MR, or 0.29 nM of 3H-methyltrienolone for PR binding, and either 20 ug of Used 293-GR, 22 ug of Used 293-AR, 20 ug of Used 293-MR or 40 ug of used 293-PR per well. The competition compounds are added at several concentrations in increments of half logarithm. The nonspecific binding is determined in the presence of 500 nM dexamethasone for GR binding, 500 nM aldosterone for MR binding, or 500 nM methyltrienolone for AR and PR binding. The binding reaction (140 μl) is incubated overnight at 4 ° C, then 70 μl of cold charcoal-dextran buffer (containing 50 ml of assay buffer, 0.75 g of carbon) is added to each reaction. vegetable and 0.25 g dextran). The plates are mixed 8 minutes in an orbital shaker at 4 ° C. The plates are then centrifuged at 3,000 rpm at 4 ° C for 10 minutes. An aliquot of 120 μl of the mixture is transferred to another 96-well plate and 175 μl of "Hisafe 3" scintillation fluid from Wallac Optiphase is added to each well. The plates are sealed and shaken vigorously in an orbital shaker. After a 2 hour incubation, the plates are read in a Wallac Microbeta counter. The data is used to calculate an IC50 and% inhibition at 10 μM. The Kd for 3H-dexamethasone for GR bond, 3H-methyltrienolone for AR bond, 3H-aldosterone for MR bond, or 3H-methyltrienolone for PR bond, is determined by saturation bond. The IC50 values for the compounds are converted to Ki using the Cheng-Prusoff equation and the Kd is determined by saturation binding assay. The binding assay protocols for nuclear steroid hormone receptors, similar to those described above, can be easily designated by the ordinarily skilled artisan. U.S. Patent No. 6,166,013 provides examples of such protocols. Representative compounds of the present invention have a Ki in the MR or GR binding assay of <; 50 μM. Table I (see below) provides MR and GR link data for a representative sample of the exemplified compounds of the present invention. To demonstrate the ability of the compounds of the present invention to modulate the activity of a nuclear steroid hormone receptor (i.e., either agonize, antagonize, partially agonize or partially antagonize), bioassays were performed which detected the modulation of the expression of the target gene in cells temporarily transfected with a nuclear receptor protein and a reporter gene-hormone response element construct. The solvents, reagents and ligands employed in the functional assays are readily available from commercial sources, or can be synthesized by one of ordinary skill in the art.

Functional Modulation Assay of the Mineralcorticoid Receptor (Method 1): For the MR transfection assay, COS-7 cells were transfected with full-length human MR and a 2XGRE-luciferase gene construct. After transfection, the ability of the test compounds to modulate the expression of the luciferase reporter gene product is monitored. Briefly, at day one, COS cells are harvested from cell culture plates using standard procedures such as trypsin-EDTA (GIBCO BRL) treatment. The culture medium is then added to the cells and the mixture of the cell medium is placed in plates, in 96 cavity plates coated with poly- (d) -lysine (approximately 3 x 104 cells / well). Cells are grown for approximately 4 hours, then transfected with Fugene-6 reagent with plasmids containing human MR, previously cloned into the expression vector pe.DNA 3.1, and the reporter gene construct 2XGRE (GRE-luciferase), previously cloned in the vector pTAL-luc. Transfection was carried out in DMEM with 5% fetal bovine serum, treated with charcoal. 24 hours later, the cells are exposed to various concentrations of aldosterone in the presence and absence of the test compound and incubated for an additional 24 hours. The reaction was terminated by the addition of lysis buffer, followed by luciferin (luciferase substrate). Luciferase expression, as an indicator of MR-induced transactivation by ligand, is monitored by chemiluminescence measured using a microtiter plate luminometer (MLX). The kinetic inhibition constant (Kb or Kp) can be determined by analysis of dose response curves for aldosterone, in the presence and absence of the test compound, using standard techniques.

Alternative Functional Assay for MR, GR, PR and AR Activity (Method 2): Human embryonic kidney hEK293 cells were co-transfected using Fugene. Briefly, the reporter plasmid containing two copies of GRE (glucocorticoid response element 5'TGTACAGGATGTTCT3) and TK promoter upstream of the luciferase reporter cDNA, was transfected with a plasmid that constitutively expresses either the human glucocorticoid receptor (GR) receptor human mineralcorticoid (MR), or human progesterone receptor (PR), using a viral CMV promoter. The reporter plasmid containing two copies of ARE probasin (element of "androgen response 5'GGTTCTTGGAGTACT3 ') and TK promoter upstream of the luciferase reporter cDNA, was transfected with a plasmid that constitutively expresses the human androgen receptor (AR) using CMV promoter The cells are transfected in T150 cm2 flasks in DMEM medium with Fetal Bovine Serum from 5% charcoal (FBS) After an overnight incubation, the transfected cells are trypsinized, plated on 96-well dishes. cavities in DMEM medium containing FBS released from 5% charcoal, incubated for 4 hours and then exposed to various concentrations of the test compounds in increments of logarithm medium In the antagonist assays, low concentrations of agonist were added for each receptor relative to the medium (0.25 nM dexamethasone for GR, 0.3 nM of methyltrienolone for RA, 0.05 nM of progesterone for PR and 0.05 nM aldosterone). After 24 hours of incubations with the compounds, the cells are lysed and the luciferase activity is determined. The data are adjusted to a logistics of parameter adjustment, to determine the EC50 values. The% of efficacy is determined against the maximum stimulation obtained with 100 nM of methyltrienolone for the AR assay, with 30 nM of progesterone for PR assay, with 30 nM of aldosterone for MR assay and with 100 nM of dexamethasone for GR assay.

Table 1 Glucocorticoid and Mineralocorticoid Receptor Binding Assay Values (values are for racemic mixtures unless otherwise indicated) Continuation of table 1 Continuation of table 1 continuation of table 1 Legend: "+" represents a value of < 10,000 nM "++" represents a value of < 1,000 nM "+++" represents a value of < 500 nM "-" indicates that the value was not determined The following Preparations and Examples further illustrate the invention and represent the typical synthesis of the compounds of Formula I, which include any of the novel compounds, as generally described in the above Reaction Schemes. Reagents and starting materials are readily available from commercial suppliers or can be easily synthesized by one of ordinary skill in the art, following the general procedures as described herein. Where the synthesis of the compound is not explicitly stated, a reference is given to a previous Example or representative Reaction Scheme which describes procedures for the synthesis of the compounds. It should be understood that the Preparations and Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art. As used in this document, the following terms have the indicated meanings: "i.v." refers to intravenously; "p.o" refers to orally; "i.p" refers to intraperitoneally; "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "μL" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles ";" psi "refers to pounds per square inch;" mm Hg "refers to millimeters of mercury;" min "refers to minutes;" h "or" hr "refers to hours "C" refers to degrees Celsius; "CCD" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography "; "Rf" refers to retention factor; "Rt" refers to retention time; "d" refers to low fields of parts per million tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N, N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "ac." refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to methyl tertiary butyl ether; "PPh3" refers to triphenylphosphine; "DEAD" refers to diethyl azodicarboxylate; "TA" refers to room temperature; "Pd-C" refers to palladium on carbon; "SAX" refers to strong anion exchange; "SCX" refers to strong cation exchange; NaBH (Oac) 3 refers to sodium triacetoxyborohydride; "Bn" refers to benzyl; "BnNH2" refers to benzylamine; m-CPBA refers to meta-chloroperoxybenzoic acid; H2 refers to hydrogen; "Ki" refers to the dissociation constant of an enzyme antagonist complex and serves as a ligand binding index; e "ID50" and "ID10o", refers to doses of a therapeutic agent administered which produces, respectively, a reduction of 50% and 100% in a physiological response.

Instrumental Analysis: Unless otherwise stated, the? H NMR spectrum is recorded in either a 300 MHz or 400 MHz Varian Mercury nuclear magnetic resonance spectrometer at room temperature. The data are reported as follows: chemical change (D) in ppm from standard tetramethylsilane, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, and m = multiplet), and integration. Liquid chromatography-mass spectrometry (LC-MS) data were obtained in an Agilent 1100 Series CL / EMD instrument.

PREPARATION 1 l-Ethyl-5-fluoro-indan-1-ol and HOpsF Ethyl magnesium bromide (1.3 ml, 3.90 mmol, 1.30 equivalents, 3.0 M in tetrahydrofuran) was added dropwise to a solution of 5-fluoroindanone (450 mg , 3.00 mmol) in anhydrous ether (5 ml) under nitrogen at room temperature and stirred overnight. The reaction was quenched by dropwise addition of 10% aqueous ammonium chloride, diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (502). mg, 93%). NMR (400 MHz, CDC13) d 0.94 (t, 3H), 1.79 (m, 1H), 1.92 (m, 1H), 2.12 (m, 1H), 2.31 (, 1H), 2.81 (m, 1H), 2.98 (m, 1H), 6.91 (m, 2H), 7.24 (m, 1H).

PREPARATION 2 Bromide (2-carboxy-ethyl) -triphenyl-phosphonium + Br " A solution of triphenylphosphine (91.3 g, 348 mmol, 1.05 equivalents) and 3-bromopropionic acid (50.7 g, 331 mmol) in acetonitrile (250 mL) was allowed to reflux for three hours, allowed to stir at room temperature overnight. Ether (400 ml) was added and cooled in the freezer for two hours. The solids were filtered, rinsed with ether and the solids were dried under high vacuum to obtain the title compound (94.1 g, 68%). NMR (400 MHz, CDC13): d 3.15 (m, 2H), 3.73 (m, 2H), 7.69-7.83 (m, 15H).

PREPARATION 3 4- (3-Fluoro-phenyl) -but-3-enoic acid To a suspension of 3-fluoroaldehyde (13.4 mL, 126 mmol) and (2-carboxy-ethyl) -triphenyl-phosphonium bromide (62.85 g, 151 mmol, 1.20 equivalents) in anhydrous dichloromethane (150 mL) at 0 ° C under nitrogen, portions of t-butoxide (315 mmol, 2.50 equivalents) were added over two hours and stirred at room temperature overnight. It was diluted with water, washed with dichloromethane (2x), the aqueous layer was acidified with 1N hydrochloric acid to pH 1, diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (24.28 g, ~ 99%, containing approximately 1.6 g of triphenylphosphine oxide). NMR (400 MHz, CDC13): d 3.26 (d, 2H), 6.32 (m, 1H), 6.48 (d, 1H), 6.95 (t, 1H), 7.08 (d, 1H), 7.14 (d, 1H) , 7.27 (m, 1H). The product is an EZ 95: 5 mixture.

PREPARATION 4 4- (3-Fluoro-phenyl) -butyric acid A mixture of 4- (3-fluoro-phenyl) -but-3-enoic acid (22 g, 122 mmol), concentrated sulfuric acid (24 mL), and 5% palladium on carbon (3.58 g) in tetrahydrofuran was hydrogenated. (470 ml) at 60 psi at room temperature overnight. After the catalyst filtration, more tetrahydrofuran was removed by rotary evaporation, the residue was diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound ( 22.50 g, 100%). NMR (400 MHz, CDC13): d 1.98 (m, 2H), 2.38 (t, 2H), 2.65 (t, 2H), 6.88 (m, 2H), 6. 96 (d, 1H), 7. 23 (m, 1H) PREPARATION 5 6-Fluoro-3, 4-dihydro-2H-naphthalen-1-one A mixture of 4- (3-fluoro-phenyl) -butyric acid (1.92 g, 10.5 mmol) and phosphoric acid (2 g) was heated at 110 ° C under nitrogen for two hours. After cooling to room temperature, quenched with water, diluted with ether, washed with saturated aqueous sodium bicarbonate (2x), dried over anhydrous sodium sulfate and concentrated to obtain the title compound (1.5 g, 87%). %). NMR (400 MHz, CDC13): d 2.16 (m, 2H), 2.64 (t, 2H), 2.97 (t, 2H), 6.92 (dd, 1H), 6.99 (dt, 1H), 8.04 (dd, 1H) .

PREPARATION 6 5-Pyrazol-l-il-indan-l-one -Fluoro-indan-l-one (1.02 g, 6.79 mmol), pyrazole (0.46 g, 6.79 mmol) and potassium carbonate were combined. (1.03 g, 7.47 mmol, 1.10 equivalents) in dimethyl sulfoxide (5 ml) in a sealed tube and heated at 100 ° C for 48 hours. It was cooled to room temperature, diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a brown solid (0.98 g, 73%). LC-MS m / z 199.1 (M ++ 1).

PREPARATION 7 3- (3,5-Difluoro-phenyl) -propionic acid A mixture of 3,5-difluoroacetic acid (10.0 g, 54.3 mmol), 5% palladium on carbon (1.5 g) and concentrated sulfuric acid (10 ml) in tetrahydrofuran (195 ml) at 60 psi at room temperature was hydrogenated. the night. After filtering the catalyst, it was diluted with ether, washed with water twice, dried over anhydrous sodium sulfate and concentrated to obtain the title compound as clear colorless crystals (9.32 g, 92%). NMR (400 MHz, CDC13): d 2.67 (t, 2H), 2.94 (t, 2H), 6.65 (t, 1H), 6.74 (d, 2H).

PREPARATION 8 l-Cyclopropyl-5-fluoro-indan-l-ol To a solution of 5-fluoroindanone (0.95 g, 6.33 mmol) in anhydrous ether (30 mL) under nitrogen at room temperature, cyclopropyl magnesium bromide (9.1 ml, 7.28 mmol, 1.15 equivalents, 0.80 M tetrahydrofuran) was added by dripping while keeping at gentle reflux. After stirring overnight, the reaction was quenched at room temperature via dropwise addition of 10% aqueous ammonium chloride. The reaction was diluted with ether, washed with water (2x), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.30 g, -100%). NMR (CDC13, 400 MHz): d 0.26 (m, 1H), 0.36-0.51 (m, 3H), 1.21 (m, 1H), 2.13 (m, 1H), 2.28 (m, 1H), 2.80 (m, 1H), 2.95 (m, 1H), 6.88 (m, 2H), 7.29 (m, 1H).

PREPARATION 9 lH-indol-7-ilamine 7-Nitroindole was dissolved in ethanol and ammonium formate (10 equivalents) and a catalytic amount of 10% palladium on carbon were added. The mixture was refluxed for 1 hour before cooling, filtered through celite and evaporated to give the product as a purple solid (99%).

PREPARATION 10 N- (lH-Indol-7-yl) -methanesulfonamide LH-indol-7-ylamine was stirred with pyridine (1 equivalent) and methanesulfonyl chloride (1 equivalent) in dichloromethane for 12 hours. The reaction was washed with 1 N hydrochloric acid and water, dried over magnesium sulfate and evaporated. The residue was recrystallized from isopropanol to obtain the title product as a purple solid (94%). MS (ES +) 210 (M), MS (ES ") 209 (M-1) LC / MS showed 95% impurity.

PREPARATION 11 3- (3-Fluorophenoxy) -propan-1-ol To a pre-dried round bottom flask, equipped with a magnetic stirrer, sodium hydride (60% dispersion in mineral oil, 4.80 g, 0.120 mol) was added under a nitrogen atmosphere. The sodium hydride was washed with hexanes (3 x 100 mL) to remove the mineral oil, then dimethylformamide (165 mL) was added. The resulting suspension was cooled to 0 ° C and a solution of 3-fluorophenol (11.20 g, 0.100 mol) in dimethylformamide (35 ml) was added dropwise resulting in gas evolution and a color change from green to blue-green. After the reaction mixture was stirred at room temperature for approximately 30 minutes, the reaction was cooled to 0 ° C and a solution of 3-chloro-1-propanol (9.46 g, 0.100 mol) in dimethylformamide (35 ml) was added dropwise. ). The resulting reaction mixture was heated at 60 ° C for 2.5 hours. The solution was cooled, the dimethylformamide was removed under reduced pressure and the resulting reaction mixture was diluted with water (250 ml) and extracted with diethyl ether (3 x 150 ml). The organic extracts were washed with water (200 ml), 2M aqueous sodium hydroxide (200 ml), water (200 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate, dried and concentrated to give the title compound slightly impure (13.32 g, 78%) as an amber oil which was used directly in the next reaction without purification: Rf 0. 40 (19: 1 CH2Cl2 / MeOH); XH NMR (300 MHz, CDC13) d 1.68 (t, J = 5.1 Hz, 1H), 2.04 (quintuplet, J = 6.0 Hz, 2H), 3.83-3.89 (, 2H), 4.10 (t, J = 6.0 Hz, 2H), 6.59-6.70 (, 3H), 7.17-7.25 (m, 1H); 19 F NMR (282 MHz, CDC13) d 112.13; APCI MS m / z 153 [C9HuF02 + H - H20] +.

PREPARATION 12 3- (3-fluorophenoxy) -propionic acid Acetone (600 ml) was cooled using a saturated ice / water bath, then chromium trioxide was added (14.45 g, 145 mmol), followed by water (32 ml) and concentrated sulfuric acid (16 ml). The mixture was allowed to stir for several minutes, then a solution of 3- (3-fluorophenoxy) -propan-1-ol (6.15 g, 36.1 mmol) in acetone was slowly added. (300 mi) via an addition funnel for ~ 1 hour. The reaction was stirred at 0 ° C for 5 hours, and then 2-propanol (70 ml) was added. The reaction was filtered over diatomaceous earth, rinsed with acetone (~100 mL), and the filtrate was evaporated under reduced pressure, reconstituted in diethyl ether (500 mL), and washed with brine (2 x 500 mL). The organic layer was then dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound (6.00 g, 90%) as an off-white solid which was used without further purification: Rf 0.34 (95: 5: 0.5 dichloromethane / methanol / ammonium hydroxide); 1H NMR (300 MHz, CDC13) d 2.85 (t, J = 6.2 Hz, 2H), 4.23 (t, J = 6.2 Hz, 2H), 6.59-6.70 (m, 3H), 7.18-7.24 (m, 1H), 7.30-9.60 (br s, 1H); 19 F NMR (282 MHz, CDCl 3) d-112. 01; APCI MS (negative form) m / z 183 [C9H9FO3-H] ".

PREPARATION 13 7-Fluoro-chroman-4-one To a solution of 3- (3-fluorophenoxy) -propionic acid (4.94 g, 26.8 mmol) in dichloromethane (135 ml) were added several drops of anhydrous dimethylformamide., followed by oxalyl chloride (4.68 ml, 53.6 mmol). The reaction was stirred at room temperature until evolution ceased (~ 30 minutes), then it was evaporated under reduced pressure and reconstituted in dichloromethane (135 ml). After the addition of aluminum trichloride (4.28 g, 32.1 mmol), the reaction was stirred for 1 hour, then 2M aqueous hydrochloric acid (100 mL) and dichloromethane (100 mL) were added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude residue was recrystallized twice from 2-propanol to give the slightly impure title compound (1.79 g, 40%), and the mother liquor was subjected to flash chromatography (silica gel, 3: 1 pentane / Et20) provide the pure title compound (1.15 g, 26%): Rf 0.45 (1: 1 ethyl acetate / hexanes); mp 53-56 ° C; E NMR (300 MHz, CDC13) d 2.75 (t, J = 6.4 Hz, 2H), 4.51 (t, J = 6.4 Hz, 2H), 6.61 (dd, J = 2.3, 9.9 Hz, 1H), 6.65-6.72 (m, 1H), 7.87 (dd, J = 6.7, 8.8 Hz, 1H); 19 F NMR (282 MHz, CDC13) d-101.06; APCI EM m / z 167 [C9H7F02 + H] +, PREPARATION 14 lH-Indol-7-ilamine An autoclave of 11.3562 1 (3 gal) was charged with 7-nitroindole (250 g, 1542 moles), ethyl 2B-3 alcohol (5.0 1) and 10% Pd / C (50.0 g). Stirred at 50 psi H2 for 2 hours at < 27 ° C. When the reaction was considered complete, the contents of the reactor were filtered through celite, followed by concentration of the filtrate to dryness to yield 197.0 g (96.7%) of the title compound as a purple solid, ""? -RMN (CD3OD , 300MHz) d 7.16 (d, 1H), 7.00 (dd, 1H), 6.81 (t, 1H), 6.50 (dd, 1H), 6.37 (d, 1H).

PREPARATION 15 (lH-indol-7-yl) -carbamic acid benzyl ester A 12 1 reaction flask was equipped with a cooling bath, air conducting agitation apparatus, addition funnel and thermometer probe. The flask was completely purged with nitrogen, charged with 7-aminoindole (352 g, 2663 moles), CH2C12 (5.30 1, 15 volumes) and 2N NaOH (1.76 1, 3.515 moles). After cooling of the biphasic solution to less than 10 ° C, benzyl chloroformate (500 g, 2,929 moles) was added dropwise at such rate to maintain the temperature at less than 10 ° C for one hour. The reaction was stirred vigorously for 1 hour until complete by CCD. The layers were separated and the aqueous layer was extracted with CH2C12 (1.7 1). The combined organic layers were washed with 2N NaOH (2 x 21) and dried over Na 2 SO 4. After filtering the dried agent, the filtrate was concentrated in vacuo to a volume of ~ 1.5 1 resulting in a thin dark mixture. The solvent gradually changed using heptane (~4 1) to form a slurry as coarse sand and increase the bath temperature to 50-60 ° C. It was concentrated to a volume of ~ 1.5 1, filtered while heating (50-60 ° C), washed with hot heptane (45 ° C) (11) and heptane at room temperature (11), and dried to yield 683.5 g (96.7%) of the title compound as a light purple solid. 1H-RM (DMSO-d6, 300MHz) d 10.79 (br s, 1H), 9.42 (br s, 1H), 7.20-7.56 (m, 8H), 6.92 (t, 1H), 6.41 (dd, 1H), 5.18 (s, 1H).

EXAMPLE 1 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide L-ethyl-5-fluoro-indan-1-ol (502 mg, 2.79 mmol, 1.30 equivalents), N- (1 H -indol-7-yl) -methanesulfonamide (450 mg, 2.14 mmol, 1.00 equivalents) were combined, and trifluoroacetic acid (0.25 ml, 3.21 mmol, 1.50 equivalents) in dichloromethane (5 ml) and stirred at room temperature under nitrogen overnight. The solution was loaded onto silica and purified by levigating with 0 to 100% ethyl acetate / hexanes for 25 minutes to obtain the title compound (672 mg, 84%), LC-MS m / z 373.0 (M ++ l ). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column with methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 230 nm) to provide the individual enantiomers, Examples 1A and IB, in 96.3% ee and 97.4% ee, respectively.

EXAMPLE 2 3- (1-Ethyl-5-fluoro-indan-1-yl) -7-nitro-1H-indole Using l-ethyl-5-fluoro-indan-1-ol and 7-nitroindole, the title compound was prepared as in Example 1. 0.37 g (42%). NMR (400 MHz, CDC13): d 0.85 (t, 3H), 2.18 (m, 2H), 2.35 (m, 1H), 2.53 (m, 1H), 3.00 (m, 2H), 6.83 (t, 1H) , 6.92 (t, 1H), 7.01 (m, 2H), 7.08 (s, 1H), 7.44 (d, 1H), 8.09 (d, 1H), 9.76 (s, 1H, NH).

EXAMPLE 3 3- (1-Ethyl-5-fluoro-indan-1-yl) -l-methyl-7-nitro-1H-indole 3- (1-ethyl-5-fluoro-indan-1-yl) -7-nitro-1H-indole (0.33 g, 1.02 mmol), sodium methoxide (110 mg, 2.04 mmol) and iodomethane (0.10 ml) were combined. , 1.53 mmol) in dimethylformamide (5 ml) and stirred at room temperature under nitrogen overnight. It was diluted with ether, washed with water (2x), dried over sodium sulfate, filtered and concentrated to obtain the title compound as a yellow amorphous solid (0.33 g, 94%). LC-MS m / z 339.1 (M ++ 1).

EXAMPLE 4 3- (1-Ethyl-5-fluoro-indan-1-yl) -l-methyl-1H-indol-7-ylamine A mixture of 3- (1-ethyl-5-fluoro-indan-1-yl) -l-methyl-7-nitro-1H-indole (0.26 g, 0.77 mmol) and 5% palladium on carbon was hydrogenated (26 mg) in ethanol (50 ml) at 60 psi at room temperature overnight. The catalyst was filtered and concentrated under high vacuum to obtain the title compound as oil (0.17 g, 71%). NMR (400 MHz, CDC13): d 0.83 (t, 3H), 2.05 (m, 1H), 2.25 (, 2H), 2.60 (, 1H), 2.96 (, 2H), 3.72 (broad s, 2H, NH2) , 4.02 (s, 3H), 6.43 (m, 2H), 6.76 (d, 2H), 6.83 (t, 1H), 6.97 (d, 1H), 7.02 (m, 1H).

EXAMPLE 5 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -l-methyl-1H-indol-7-yl] methanesulfonamide 3- (1-ethyl-5-fluoro-indol-1-yl) -1-methyl-1H-indole-7-ylamine (0.18 g, 0.58 mmol) was dissolved in pyridine (3 mL). Methanesulfonyl chloride (0.05 ml, 0.70 mmol, 1.20 equivalents) was added and stirred at room temperature under nitrogen overnight. It was diluted with ether, washed with 1N aqueous hydrochloric acid (2x), dried over anhydrous sodium sulfate, filtered and the solution concentrated in vacuo.

The residue was purified on silica by levigating with 0 to 100% ethyl acetate / hexanes for 25 minutes to give the title compound as a white solid. (0.19 g, 86%). LC-MS m / z 387.1 (M ++ l).

EXAMPLE 6 3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indole Using l-ethyl-5-fluoro-indan-1-ol and indole, the title compound was prepared as in Example 1. 89 mg (54%). LC-MS 280.0 (M ++ l).

EXAMPLE 7 3- (1-Ethyl-5-fluoro-indan-1-yl) -7-fluoro-1H-indole Using l-ethyl-5-fluoro-indan-1-ol and 7-fluoroindole, the title compound was prepared as in Example 1. 217 mg (92%). NMR (400 MHz, CDC13): d 0.85 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.31 (m, 1H), 2.58 (m, 1H), 2.97 (m, 2H) , 6.83 (m, 4H), 6.98 (m, 3H), 8.06 (s, 1H, NH).

EXAMPLE 8 7-Bromo-3- (l-ethyl-5-fluoro-indan-l-yl) -lH-indole Using l-ethyl-5-fluoro-indan-1-ol and 7-bromoindole, the title compound was prepared as in Example 1. 51 mg (16%). NMR (400 MHz, CDC13): d 0.82 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.30 (m, 1H), 2.59 (m, 1H), 2.97 (m, 2H), 6.82 (m, 2H), 6.90 (s, 1H), 6.99 (m, 2H), 7.12 (d, 1H), 7.28 (d, 1H), 8.08 (s, 1H, NH).

EXAMPLE 9 7-Chloro-3- (l-ethyl-5-fluoro-indan-1-yl) -IH-indole Using l-ethyl-5-fluoro-indan-1-ol and 7-chloroindole, the title compound was prepared as in Example 1. 90 mg (60%). NMR (400 MHz, CDC13): d 0.85 (t, 3H), 2.15 (m, 1H), 2.22 (m, 1H), 2.34 (m, 1H), 2.59 (m, 1H), 2.98 (m, 2H) , 6.82 (t, 1H), 6.87 (m, 2H), 7.00 (m, 2H), 7.11 (d, 1H), 7.16 (d, 1H), 8.12 (s, 1H, NH).

EXAMPLE 10 7-Ethyl-3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indole Using l-ethyl-5-fluoro-indan-1-ol and 7-ethylindole, the title compound was prepared as in Example 1. 104 mg (58%). LC-MS m / z 308.1 (M ++ 1).

EXAMPLE 11 3- (1-Ethyl-5-fluoro-indan-1-yl) -1H-indole-7-carboxylic acid methyl ester Using l-ethyl-5-fluoro-indan-1-ol and lH-indole-7-carboxylic acid methyl ester, the title compound was prepared as in Example 1. 103 mg (75%). LC-MS m / z 338.1 (M ++ 1).

EXAMPLE 12 3- (1-Ethyl-5-fluoro-indan-1-yl) -7-methoxy-1H-indole Using l-ethyl-5-fluoro-indan-1-ol and 7-methoxyindole, the title compound was prepared as in Example 1. 123 mg (59%). LC-MS m / z 310.2 (M ++ l).

EXAMPLE 13 [3- (L-Ethyl-5-fluoro-indan-1-yl) -1H-indol-7-yl] -carbamic acid benzyl ester Using l-ethyl-5-fluoro-indan-1-ol and (lH-indol-7-yl) -carbamic acid benzyl ester, the title compound was prepared as in Example 1. 7.78 g (100%). LC-MS m / z 249.1 (M ++ 1).

EXAMPLE 14 3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-7-ylamine A mixture of [3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -carbamic acid benzyl ester (7.78 g, 18.2 mmol) and palladium hydroxide on carbon at 20% (1.6 g) in ethanol was hydrogenated at 50 ° C at 60 psi for 18 hours. After filtration of the catalyst, the solution was concentrated in vacuo to give the title compound as a black solid (5.04 g, 94%). LC-MS m / z 295.1 (M ++ 1).

EXAMPLE 15 [3- (L-Ethyl-5-fluoro-indan-1-yl) -1H-indol-7-yl] -carbamic acid methyl ester 3- (1-ethyl-5-fluoro-indan-1-yl) -1H-indol-7-ylamine (0.35 g, 1.19 mmol) was dissolved in pyridine (3 mL). Methyl chloroformate (0.10 ml, 1.31 mmol, 1.1 equivalents) was added and stirred at room temperature under nitrogen overnight. It was diluted with ether, washed with 1N aqueous hydrochloric acid (2x), dried over anhydrous sodium sulfate, filtered and the solution concentrated in vacuo. The residue was purified on silica by levigating with 0 to 75% ethyl acetate / hexanes for 30 minutes to give the title compound as a white solid (0.15 g, 36%). LC-MS m / z 353.1 (M ++ l).

EXAMPLE 16 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -acetamide Using 3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indol-7-ylamine and acetic anhydride, the title compound was prepared as in Example 15. 0.16 g (46%). LC-MS m / z 337.1 (M ++ 1).

EXAMPLE 17 7-Dimethylsulfamoyl-3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indole Using 3- (1-ethyl-5-fluoro-indan-1-yl) -iH-indol-1-ylamine and dimethyl sulfamoyl chloride, the title compound was prepared as in Example 15. 0.16 g (29%) . LC-MS m / z 402.1 (M ++ l).

EXAMPLE 18 N- [3- (1-Ethyl-5-fluoro-indan-1-yl) -lH-indol-1-yl] -benzenesulfonamide Using 3- (1-ethyl-5-fluoro-indan-1-yl) -IH-indol-7-ylamine and benzenesulfonyl chloride, the title compound was prepared as in Example 15. 0.21 g (33%). LC-MS m / z 295.1 (M ++ 1).

EXAMPLE 19 Ethanesulfonic acid [3- (1-ethyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] -amide Using 3- (1-ethyl-5-fluoro-indan-1-yl) -iH-indol-7-ylamine and ethanesulfonyl chloride, the title compound was prepared as in Example 15. 0.18 g (35%). LC-MS m / z 387.1 (M ++ l). Carbinoles used in Examples 20-39 of the appropriate ketone were prepared as in Preparation 1.

EXAMPLE 20 N- [3- (1-Methyl-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 634 mg (74%). LC-MS m / z 341.1 (M ++ 1).

EXAMPLE 21 N- [3- (5-Fluoro-l-methyl-indan-l-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-Indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 737 mg (83%). LC-MS m / z 359.1 (M ++ 1). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column by levigating with 15/85 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 400 ml / min, UV detection at 275 nm) to give the individual enantiomers, Examples 21A and 21B, in greater than 99.9% ee and 97.4% ee, respectively.

EXAMPLE 22 N- [3- (5,7-Difluoro-1-methyl-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-11) -metanesulfonamide, the title compound was prepared as in Example 1. 1.25 g (71%). LC-MS m / z 377.1 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column by levigating with 20/20/60 of 3A alcohol / methanol / heptane with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 300 nm) to provide the individual enantiomers, Examples 22A and 22B, in 99.3% ee and 99.6% ee, respectively.

EXAMPLE 23 N- [3- (1-Ethyl-5,7-difluoro-indan-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 0.41 g (69%). LC-MS m / z 391.0 (M ++ l). The racemic mixture was separated on a Chiralcel OD 8 x 34 cm column by levigating with 30/10/60 isopropanol / methanol / heptane with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 300 nm) to give the enantiomers Individuals, Examples 23A and 23B, in 97.2% ee and 98.5% ee, respectively.

EXAMPLE 24 N- [3- (l-Methyl-5-pyrazol-l-yl-indan-l-yl) -lH-indol-7-yl] • methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 0.43 g (32%). LC-MS m / z 407.1 (M ++ l).

EXAMPLE 25 N- [3- (1, 2, 3, 4-Tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-Indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 197 mg (40%). LC-MS m / z 341.1 (M ++ 1).

EXAMPLE 26 N- [3- (1-Methyl-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 541 mg (78%). LC-MS m / z 355.0 (M ++ l).

EXAMPLE 27 N- [3- (1-Ethyl-1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 140 mg (54%). LC-MS m / z 369.1 (M ++ l).

EXAMPLE 28 N- [3- (6-Fluoro-l-methyl-1,2,3-tetrahydro-naphthalen-1-yl) -1H-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 0.81 g (76%). LC-MS m / z 373.2 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column with 20/80 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 316 nm) to provide the individual enantiomers, Examples 28A and 28B, greater than 99.9% ee and greater than 99.9% ee, respectively.

EXAMPLE 29 N- [3- (1-Ethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl) -1H-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 2.23 g (74%). NMR (400 MHz, CDC13): d 0.89 (t, 3H), 1.62-1.86 (m, 2H), 2.05 (m, 1H), 2.16-2.42 (m, 4H), 2.84 (t, 2H), 3.01 (s, 3H), 6.42 (s, 1H) ), 6.70 (s, 1H), 6.75 (t, 1H), 6.82-6.93 (m, 3H), 7.05 (m, 1H), 7.21 (d, 1H), 8.91 (broad s, 1H, NH). The racemic mixture was separated on a Chiralpak AD 8 x 30 cm column, levigating with alcohol 3A with 0.2% dimethylethylamine (flow: 300 ml / min, UV detection at 270 nm) to provide the individual enantiomers, Examples 29A and 29B, in 99.5% ee and 99.6% ee, respectively.

EXAMPLE 30 N- [3- (6, 8-Difluoro-l-methyl-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-Indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 3.12 g (68%). LC-MS m / z 391.0 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column, by levigating with 5/95 acetonitrile / methanol (flow: 375 ml / min, UV detection at 225 nm) to give the individual enantiomers, Examples 31A and 31B, greater than 99.9% ee and 99.3% ee, respectively.

EXAMPLE 31 N- [3- (1-Ethyl-6,8-difluoro-1,2,4,4-tetrahydro-naphthalen-1-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 380 mg (40%). NMR (400 MHz, CDC13): d 0.82 (t, 3H), 1.58-1.78 (, 2H), 2.08 (m, 1H), 2.17 (m, 1H), 2.40 (m, 1H), 2.55 (m, 1H) ), 2.82 (m, 2H), 3.01 (s, 3H), 6.47 (s, 1H), 6.57 (t, 1H), 6.67 (s, 1H), 6.74 (d, 1H), 6.87 (d, 1H) , 6.94 (t, 1H), 7.31 (d, 1H), 8.94 (broad s, 1H, NH). The racemic mixture was separated on a Chiralcel OJ 8 x 33 xm column, levigated with 5/95 acetonitrile / methanol (flow: 375 ml / min, UN detection at 230 nm) to give the individual enantiomers, Examples 31A and 31B, greater than 99.9% ee and 99.5% ee, respectively.

EXAMPLE 32 N- [3- (4-Methyl-chroman-4-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 226 mg (99%). LC-MS m / z 357.0 (M ++ l).

EXAMPLE 33 N- [3- (6-Fluoro-4-methyl-chroman-4-yl) -lH-indol-7-yl] methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 270 mg (99%). LC-MS m / z 375.0 (M ++ l).

EXAMPLE 34 N- [3- (7-Fluoro-4-methyl-chroman-4-yl) -lH-indol-7-yl] methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 3.6 g (100%). LC-MS m / z 375.0 (M ++ l). The racemic mixture was separated on a Chiralpak AD 8 x 30 cm column, levigating with 100% 3A alcohol (flow: 375 ml / min, UV detection at 230 nm) to give the individual enantiomers, Examples 34A and 34B, in 98.9% ee and 99.1% ee, respectively.

EXAMPLE 35 N- [3- (4-Ethyl-7-fluoro-chroman-4-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 3.85 g (99%). LC-MS m / z 389.1 (M ++ l). The racemic mixture was separated on a Chiralcel OJ column 8 x 33 cm, levigated with 10/90 acetonitrile / methanol (flow: 375 ml / min, UV detection at 230 nm) to give the individual enantiomers, Examples 35A and 35B, 96.5% ee and 98.2% ee, respectively.

EXAMPLE 36 N- [3- (4-Ethyl-5,7-difluoro-chroman-4-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 4.13 g (94%). LC-MS m / z 407.0 (M ++ l). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column, levigating with 20/80 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 280 nm) to give the individual enantiomers, Examples 36A and 36B, greater than 99.9% ee and 99.9% ee, respectively.

EXAMPLE 37 N- [3- (4-Methyl-thiochroman-4-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-11) -metanesulfonamide, the title compound was prepared as in Example 1. 195 mg (74%). LC-MS m / z 390.1 (M ++ H20).

EXAMPLE 38 N- [3- (5-Methyl-6,7,8,8-tetrahydro-5H-benzocyclohepten-5-yl) -lH-indol-7-yl] -methanesulfonamide Using the appropriate carbinol and N- (lH-indol-7-yl) -metanesulfonamide, the title compound was prepared as in Example 1. 213 mg (66%). NMR (400 MHz, CDC13): d 1.47 (m, 1H), 1.75 (m, 1H), 1.78 (s, 3H), 1.87 (m, 3H), 2.60 (m, 1H), 2.67 (, 1H), 2.79 (m, 1H), 6.43 (s, 1H), 6.67 (s, 1H), 6.87 (d, 1H), 6.93 (t, 1H), 7.11 (, 1H), 7.16-7.21 (m, 3H), 7.41 (, 1H), 8.91 (broad s, 1H, NH).

EXAMPLE 39 N- [3- (l-Cyclopropyl-5-fluoro-indan-1-yl) -lH-indol-7-yl] • methanesulfonamide N- (lH-indol-7-yl) -metanesulfonamide (0.95 g, 4.51 mmol), l-cyclopropyl-5-fluoro-indan-1-ol (1.30 g, 6.76 mmol, 1.50 equivalents) and trifluoroacetic acid ( 0.70 ml, 9.02 mmol, 2.00 equivalents) in dichloromethane (20 ml) and stirred at room temperature under nitrogen overnight. The solution was preloaded on silica and purified on 40 g of silica, levigating with 0 to 50 ethyl acetate / hexanes for 30 minutes. The product was isolated as a white crystalline solid (1.42 g). NMR analysis indicated one to one of the mixtures of the title compound and propyl trifluoroacetate ester. The product was dissolved in methanol (20 mL) and 2M aqueous lithium hydroxide (20 mL) and stirred at room temperature overnight. It was diluted with ether, washed with 1N hydrochloric acid (2x), dried over sodium sulfate, filtered and concentrated. It was purified on 40 g of silica by levigating with 0 to 100 ethyl acetate / hexanes for 30 minutes to obtain the title compound as a white solid (0.39 g). The title compound is the less polar component. NMR (400 MHz, CDC13): d 1.47 (m, 1H), -0.15 (m, 1H), 0.11 (m, 1H), 0.49 (m, 2H), 1.45 (m, 1H), 2.21 (m, 1H) ), 2.67 (, 1H), 2.94 (m, 1H), 3.01 (s, 3H), 3.05 (m, 1H), 6.55 (s, 1H), 6.72 (m, 2H), 6.83 (m, 3H), 6.97 (d, 1H), 7.33 (s, 1H), 9.02 (broad s, 1H, NH). The racemic mixture was separated on a Chiralcel OJ 8 x 33 cm column, levigating with 60/40 acetonitrile / methanol with 0.2% dimethylethylamine (flow: 375 ml / min, UV detection at 275 nm) to give the individual enantiomers, Examples 39A and 39B, greater than 99.9% ee and 99.6% ee, respectively.

EXAMPLE 40 N-. { 3- [5-Fluoro-l- (3-hydroxy-propyl) -indan-1-yl] -lH-indol-7-yl} -methanesulfonamide The title compound is the most polar component of the final chromatography described in Example 39. NMR (400 MHz, CDCl 3): d 1.47-1.60 (m, 2H), 2.08-2.29 (, 3H), 2.58 (m, 1H ), 2.97 (m, 2H), 2.99 (s, 3H), 2.61 (m, 2H), 6.77 (t, 1H), 6.85-6.98 (m, 6H), 7.05 (d, 1H), 9.01 (broad) , 1H, NH). The racemic mixture was separated on a Chiralpak AD 8 x 30 cm column, levigating with 40/10/50 isopropanol / methanol / heptane with 0.2% dimethylethylamine (flow: 350 ml / min, UV detection at 232 nm) to give the individual enantiomers, Examples 40A and 40B, in 98.2% ee and 96.8% ee, respectively.

EXAMPLE 41 N-. { 3- [5-Fluoro-l- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} - methanesulfonamide To a solution of triphenylphosphine (422 mg, 1.61 mmol, 1.30 equivalents) and imidazole (219 mg, 3.22 mmol, 2.60 equivalents) in anhydrous tetrahydrofuran (10 mL), iodide (410 mg, 1.61 mmol, 1.30 equivalents) was added. After stirring for 20 minutes at room temperature under nitrogen, N- was added. { 3- [5-Fluoro-l- (3-hydroxy-prspil) -indan-1-yl] -lH-indol-7-yl} -methansulfonamide (500 mg, 1.24 mmol) and stirred for 48 hours. It was diluted with ether, washed with water (2x), washed with 1N aqueous hydrochloric acid (2x), dried over anhydrous sodium sulfate, filtered and the solution was concentrated. The residue was purified on silica by levigating with 50 to 100% ethyl acetate / hexanes for 25 minutes to obtain the title compound as a white solid (254 mg, 40%). LC-MS m / z 385.0 (M + -l).

EXAMPLE 42 N-. { 3- [5-Fluoro-l- (3-methylamino-propyl) -indan-1-yl] -IH-indol-7-yl} -methanesulfonamide N- stirred. { 3- [5-fluoro-1- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} -metanesulfonamide (88 mg, 0.17 mmol) and methylamine (40% in water, 2 ml) in tetrahydrofuran (1 ml) at room temperature under nitrogen for 30 minutes. It was diluted with dichloromethane and 10% aqueous potassium carbonate. The white solids that were compressed were filtered and dried under high vacuum to obtain the title compound (35 mg, 49%). LC-MS m / z 416.1 (M ++ l).

EXAMPLE 43 N-. { 3- [1- (3-Dimethylamino-propyl) -5-fluoro-indan-1-yl] -1H-indol-7-yl} -methanesulfonamide N- stirred. { 3- [5-fluoro-l- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} -metanesulfonamide (65 mg, 0.13 mmol) and dimethylamine (5.0 ml, 2. OM in tetrahydrofiran) at room temperature under nitrogen overnight. The volatiles were removed under high vacuum, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica by levigating with 10% methanol in dichloromethane to obtain the title compound as a white solid (34 mg, 65%). LC-MS m / z 430.2 (M ++ l).

EXAMPLE 44 N-. { 3- [5-Fluoro-l- (3-morpholin-4-yl-propyl) -indan-1-yl] -1H-indol-7-yl} -methanesulfonamide N- was combined. { 3- [5-fluoro-l- (3-iodo-propyl) -indan-1-yl] -lH-indol-7-yl} methansulfonamide (65 mg, 0.13 mmol) and morpholine (2 mL) in anhydrous tetrahydrofuran (2.5 mL) and stirred at room temperature under nitrogen overnight. The volatiles were removed under high vacuum, the residue was dissolved in dichloromethane, solid potassium carbonate was added, stirred for ten minutes, filtered and concentrated in vacuo. The residue was purified on silica by levigating with 5 to 10% methanol in dichloromethane over 15 minutes to obtain the title compound as a white solid (50 mg, 83%). LC-MS m / z 472.2 (M ++ l).

Claims (25)

1. A compound of the formula: Formula I characterized in that X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, -CH2S-, or -CH2NR10-; R1 represents hydrogen, (C? -C4) alkyl, (C3-C7) cycloalkyl, (C? -C4) hydroxyalkyl, (Cj-C4) haloalkyl, (C? -C4) alkyl -heterocycle, (C? -C) alkyl ) -N-Alkylamine (C? -C4), or alkyl (C? -C4) -N, N-dialkylamine (C? -C); R 2 represents hydrogen, halo, (C 1 -C 4) alkyl, heterocycle, or substituted heterocycle; R3 represents hydrogen, halo, alkyl (Cj.-C), heterocycle, or substituted heterocycle; R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (Cj-C4) alkoxy, NHS02R7, NHCOR8, or COR9; R5 represents hydrogen or halo; R6 represents hydrogen or alkyl (C? -C4); R7 represents (C1-C4) alkyl, aryl, NHalkylamine (C1-C4), or N, N-dialkylamine (C1-C4); R8 represents (C1-C4) alkyl, (C1-C4) alkoxy or (C1-C4) arylalkoxy; and R9 represents (C1-C4) alkyl or (C1-C4) alkoxy; R10 represents hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) alkyl- (C3-C7) cycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that X represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH20-, or -CH2S-.

3. The compound according to claim 2, characterized in that X represents -CH2-, -CH2CH2-, or -CH20-.

4. The compound according to claim 3, characterized in that X represents -CH2- or -CH2CH2- •

5. The compound according to claim 3, characterized in that X represents -CH20-.

6. The compound according to any of claims 1-5, characterized in that R1 represents hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, (C1-C4) hydroxyalkyl, (C1-C4) haloalkyl, alkyl -heterocycle (C3.-C4), alkyl (C? -C4) -NHalkylamine (C? ~ C4), or (C1-C4) alkyl-N, N-dialkylamine (Cj.-C4).

7. The compound according to claim 6, characterized in that R1 represents hydrogen, methyl, ethyl, propyl, isopropyl, (C3-C7) cycloalkyl, (C1-C4) hydroxyalkyl, (C1-C4) haloalkyl, (C1-C4) alkyl -heterocycle, (C 1 -C 4) alkyl-N-Hyalkylamine (C 1 -C 4), or (C 1 -C 4) alkyl-N, N-dialkylamine (C 3 -C 4).

The compound according to claim 7, characterized in that R1 represents methyl, ethyl, propyl, isopropyl, (C3-C7) cycloalkyl, (C1-C4) hydroxyalkyl, (C1-C4) haloalkyl, (C1-C4) alkyl -heterocycle, (C3-C4) -NH-alkylamino (C1-C4) alkyl, or (C1-C4) -N, N-dialkylamine (C1-C4) alkyl.

9. The compound according to any of claims 1-8, characterized in that R2 represents hydrogen, halo, methyl, ethyl, propyl, isopropyl, heterocycle or substituted heterocycle.

10. The compound according to claim 9, characterized in that R2 represents hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl and isopropyl.

11. The compound according to any of claims 1-10, characterized in that R3 represents hydrogen, fluoro, chloro or bromo.

12. The compound according to claim 11, characterized in that R3 represents hydrogen or fluoro.

13. The compound according to any of claims 1-12, characterized in that R4 represents hydrogen, halo, amino, nitro, alkyl (C? -C4), alkoxy (C1-C4), NHS02R7, NHCOR8, wherein R8 represents alkyl (Cj-Ca) or (C 1 -C 4) alkoxy or COR 9, wherein R 9 represents (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy.

14. The compound according to claim 13, characterized in that R4 represents hydrogen, halo, amino, nitro, (C? -C4) alkyl, (C1-C4) alkoxy or NHS02R7.

15. The compound according to claim 14, characterized in that R4 represents hydrogen, halo, amino, nitro, (C1-C4) alkyl, (C? -C4) alkoxy or NHS02R7, wherein R7 represents alkyl (C? ~ C4) ), aryl or N, N-dialkylamine (C? -C4).

16. The compound according to any of claims 1-15, characterized in that R5 represents hydrogen, chlorine or fluoro.

17. The compound according to claim 16, characterized in that R5 represents hydrogen.

18. The compound according to any of claims 1-17, characterized in that R6 represents hydrogen, methyl or ethyl.

19. A pharmaceutical composition, characterized in that it comprises the compound according to any of claims 1-18 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

20. A method for treating a disorder selected from the group consisting of Conn Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and systolic / combined diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, rejection of tissue associated with organ transplantation, malignancies such as leukemia and lympholas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and syndrome of Little, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, dermatitis of contact, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis , inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bullosa, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, epidermal necrolysis toxic, erythema multiforme, cutaneous T-cell lymphoma, psychosis, cognitive disorders, memory disorders, mood disorders, depression, bipolar disorder, anxiety disorders and personality disorders, which includes administering a patient in need of it, a compound as claimed in accordance with which of Claims 1-18, or a pharmaceutically acceptable salt.

The method according to claim 20, characterized in that the disorder is selected from the group consisting of diastolic or systolic congestive heart failure, inflammation, rheumatoid arthritis, hypertension, asthma or chronic obstructive pulmonary disease.

22. The method according to claim 21, characterized in that the disorder is diastolic or systolic congestive heart failure, inflammation, hypertension or rheumatoid arthritis.

23. The method according to claim 20, characterized in that the disorder is atherosclerosis.

24. The use of a compound according to any of claims 1-18, or a pharmaceutically acceptable salt thereof, as an agent for the treatment of Conn Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome , disorders associated with excess levels of catecholamine, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin , weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation, autoimmune disorders, tissue rejection associated with organ transplantation, malignancies as leukemia and lymphomas, insuficie Acute adrenal syndrome, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, suppression and regulation of the HPA axis, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic renal disease, apoplexy and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little's syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, disease chronic obstructive pulmonary age, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bullosum, dermatomyositis , eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, cutaneous T-cell lymphoma, psychosis, disorders cognitive disorders, memory disorders, mood disorders, depression, bipolar disorder, anxiety disorders or personality disorders.

25. The use of a compound according to any of claims 1-18, for the manufacture of a medicament for the treatment of Conn Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased excretion of magnesium and potassium (diuresis ), increased water retention, hypertension (isolated systolic and combined systolic / diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, atherosclerosis, Bartter syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF) , peripheral vascular disease, diabetic nephropathy, cirrhosis with edema and ascites, esophageal varices, Addison's disease, muscle weakness, increased pigmentation of skin melanin, weight loss, hypotension, hypoglycemia, Cushing's syndrome, obesity, hypertension, intolerance to glucose, hyperglycemia, diabetes mellitus, osteoporosis, poliur ia, polydipsia, inflammation, autoimmune disorders, rejection of tissue associated with organ transplantation, malignancies such as leukemia and lymphomas, acute adrenal insufficiency, congenital adrenal insufficiency, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation / apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of Thl / Th2 cytosine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, insufficiency secondary adrenal, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia and Little syndrome, systemic inflammation, inflammatory bowel disease, systemic lupus erythematosus, discoid lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arthritis, rheumatoid arthritis, osteoarthritis, fever hay, allergic rhinitis, contact dermatitis, atopic dermatitis, exfoliative dermatitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, hepatitis, cirrhosis, alopecia nflamatoria of the scalp, panniculitis, psoriasis, inflamed cysts, pyoderma gangrenosum, pemphigus vulgaris, pemphigus bulosus, dermatomyositis, eosinophilic fasciitis, recurrent polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, reactive leprosy type 1, capillary hemangiomas, lichen planus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiforme, cutaneous T-cell lymphoma, psychosis, cognitive disorders, memory disorders, mood disorders, depression, bipolar disorder, anxiety disorders or personality disorders.