MXPA06007141A - Aryl sulfonamide compounds and uses related thereto - Google Patents

Abstract

The present invention provides Aryl Sulfonamide Compounds having the formula:(I);and prodrugs or pharmaceutically acceptable salts or prodrugs thereof. The Aryl Sulfonamide Compounds are useful for treating diabetes, obesity, and other diseases and disorders.

Description

ARILSULPONAMIDE COMPOUNDS AND USES RELATED THERETOUS FIELD OF THE INVENTION This invention is generally directed to novel compounds, compositions, and the use of any of these in methods to modulate hydroxysteroid dehydrogenases, such as 11 beta-HSDl, and to treat or prevent diseases. associated with the modulation of hydroxysteroid dehydrogenases, such as diabetes and obesity. These methods comprise the administration, to patients in need thereof, of a therapeutically effective amount of an arylsulfonamide compound. The novel arylsulfone compounds a or their pharmaceutically acceptable salts, solvates, stereoisomers or pro-drug thereof are hereby presented. Background of the Invention Hydroxysteroid dehydrogenases (HSDs) regulate the occupation and activation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. For a current review, see Nobel et al., Eur. J. Biochem.2001, 268: 113-4125. There are numerous kinds of HSDs. The 11-beta dehydrogenases hydroxysteroids (llbeta-HSDs) catalyze the interconversion of active glucocorticoids (such as cortisol and corticosterone), and their inert forms (such as cortisone and 11-dehydrocorticosterone). Type 1 of the isoform 11-beta hydroxysteroid dehydrogenase (llbeta-HSDl) is expressed in the liver, adipose tissue, brain, lung and other glucocorticoid tissues, and is a potential target for targeted therapy for various disorders that can be improved by reduction of glucocorticoid action, such as diabetes, obesity and cognitive dysfunction related to advanced age. Seckl, et al., Endocrinology, 2001 142: 1371-1376. It is well known that glucocorticoids play a central role in the development of diabetes and that glucocorticoids allow the effect of glucagon in the liver. Long et al., J.Exp.Med.1963, 63: 465-490; and Houssay, Endocrinology 1942, 30: 884-892. Furthermore, it has been well justified that 11 beta-HSDl plays an important role in the regulation of the local glucocorticoid effect and in the production of glucose in the liver. Jamieson et al., J. Endocrinol. 2000, 165: 685-692. In Walker, et al., J. Clin. Endocrinol.Metab. 1995, 80: 3155-3159, it was reported that administration of the non-specific inhibitor llbeta-HSDl of carbenoxolone resulted in improved hepatic insulin sensitivity in humans. In addition, the hypothetical mechanism of action of HSDs in the treatment of diabetes has been supported by several experiments conducted in mice and rats. These studies show that mRNA levels and activities of the two key enzymes in the production of hepatic glucose, carboxykinase phosphoenolpyruvate (PEPCK), and 6-glucose phosphatase (G6Pase) decreased by the administration of HSD inhibitors. In addition, it was shown that the levels of . Blood glucose and hepatic glucose production decrease in llbeta-HSDl knockout mice. The additional information gathered using this murine knockout model also confirms that the inhibition of 11 beta-HSDl would not cause hypoglycemia, since the basic levels of PEPCK and G6Pase are regulated independently of glucocorticoids. Kotelevtsev et al., Proc. ati .Acad, Sci. USA 1997.94: 14924-14929. It is also believed that HSDs play a role in obesity. Obesity is an important factor in the . Syndrome X known as Type II Diabetes (non-insulin dependent), and omental fat seems to be of central importance in the development of both diseases, as abdominal obesity has been linked to glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and others factors of Syndrome X (for example high blood pressure, reduced HDL levels and increased VLDL levels, Montague et al., Diabetes 2000, 49: 883- 888, 2000. It has also been reported that the inhibition of llbeta-HSDs in pre-adipocytes (stoma cells) resulted 'at a reduced rate of differentiation in adipocytes.

It is predicted that this would cause the reduced expansion (possibly reduction) of the omental fat deposit, which can lead to reduced central obesity. Bujalska et al., 1997, 349: 1210-1213. It is expected that the inhibition of llbeta-HSDl in mature adipocytes will reduce the secretion of plasminogen activator type 1 inhibitor (PAI-1), which is an independent cardiovascular risk factor, as reported in Halleux et al., J. Clin. Endocrinol .Metab. 1999, 84: 4097-4105. In addition, it has been shown that there is a correlation between glucocorticoid activity and certain cardiovascular risk factors. This suggests that a reduction in the effects of glucocorticoids would be beneficial in the treatment or prevention of certain cardiovascular diseases. Walter et al., Hypertension 1998, 31: 891-895; and Fraser et al., Hypertension 1999, 33: 1364-1368. HSDs have also been implicated in the appetite control process and are also thought to play an additional role in weight-related disorders. It is known that adrenalectomy decreases the fasting effect to increase both the food intake and the Y expression of the hypothalamic neuropeptide. This suggests that glucocorticoids play a role in the promotion of food intake and that the inhibition of llbeta-HSDl in the brain can increase satiety, which results in reduced feed intake. Woods et al., Science 1998, 280: 1378-1383. Another possible therapeutic effect associated with the modulation of HSDs is that it is related to several pancreatic foods. It is reported that the inhibition of 11 beta-HSDl in murine beta-pancreatic cells leads to increased insulin secretion. Davani et al., J. Biol. Chem. 2000, 275: 34841-34844. This follows from the previous finding that previously found that glucocorticoids are responsible for the reduced release of pancreatic insulin in vivo Billaudel et al., Horm. Metab. Res. 1979, 11: 555-560. In this way, it is suggested that the inhibition of llbeta-HSDl may yield other beneficial effects in the treatment of diabetes to the predicted effects in the liver and in the reduction of fat. The llbeta-HSDl also regulates glucocorticoid activity in the brain and thus contributes to neurotoxicity. Rajan et al., Neuroscience 1996, 16: 65-70; and Seckl et al., Neuroendocrinol. 2000, 18: 49-99. It is known that stress and / or glucocorticoids have an influence on cognitive function (de Quervain et al., Nature 1998, 394: 787-790), and unpublished results indicate a significant improvement in memory in rats treated with non-inhibitory inhibitors. specific for 11 beta-HSD. These reports, in addition to the known effects of glucocorticoids in the brain, suggest that the inhibition of HSDs in the brain may have a positive therapeutic effect against anxiety and related conditions. Tronche et al., Nature Genetics 1999, 23: 99-103. The llbeta-HSDl reactivates 11-DHC to corticosterone in hippocampal cells and can potentiate kinase neurotoxicity, causing damage to learning related to advanced age. Therefore, it is believed that selective inhibitors of 11 beta-HSDl protect against decreased hippocampal function with age. Yau et al., Proc Nati.Acad. Sci. USA 2001,98: 4716-4721. Thus, it has been assumed that the inhibition of llbeta-HSDl in the human brain would protect against the impairment of glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, depression and increased appetite. It is believed that HSDs play a role in immune modulation based on the general perception that glucocorticoids suppress the immune system. A dynamic interaction between the immune system and the HPA (hypotalamopituitary-adrenal) axis is known (Rook, Baillier's Clin, Endocrinol.Metab., 2000, 13: 576-581), and glucocorticoids help balance between cell-mediated responses and humoral responses. The increased glucocorticoid activity, which can be induced by stress, is associated with a humoral response and, likewise, the inhibition of the llbeta-HSD1 can cause the change of response towards a base-cell reaction. In certain disease states, such as tuberculosis, leprosy and psoriasis, the immune reaction is typically based on a humoral response when the base-cell response might be more appropriate. The inhibition of the llbeta-HSDl is studied to be used in the direct base-cell response in these cases. Masonn, Immunology Today 1991, 12: 57-60. It goes on, then, that an alternative utility of inhibiting 11 beta-HSDl should sustain a temporary immune response in association with immunization to ensure that a base-cell response is obtained. Recent reports suggest that the levels of target glucocorticoid receptors and HSDs are connected to the risks of developing glaucoma. Stokes et al., Invest. Ophthalmol.2000, 41: 1629-1638. In addition, a connection between the inhibition of HSDl and a reduction in intraocular pressure was recently reported. Walker and others. , poster P3-698 at the Endocrine society meeting on June 12-15, 1999, in San Diego. It was shown that administration of the non-specific inhibitor of llbeta-HSDl, carbenoxolone, resulted in the reduction of intraocular pressure by 20% in normal patients. In the eye, the llbeta-HSDl is exclusively expressed in the corneal epithelial base cells, the non-pigmented epithelium of the cornea (aqueous production site), ciliary muscle, and the sphincter and iris dilator muscles. On the contrary, type 2 hydrobesteroid llbeta-dehydrogenase ("llbeta-HSD2") is completely expressed in the non-pigmented ciliary epithelium and the corneal endothelium. No HSDS has been found in the trabecular network, which is the drainage site. In addition, it is suggested that llbeta-HSDl has a role in aqueous production. Glucocorticoids also play a fundamental role in skeletal development and function but are detrimental to such development and function when they occur in excess. The loss of bone induced by glucocorticoids is partially derived from the suppression of osteoblastic proliferation and collagen synthesis, as reported by Kim et al., J. Endocrinol. 1999, 162: 371-379. It has been reported that the deleterious effects of glucocorticoids on the formation of bone nodules can be reduced by the administration of carbenoxolone, which is a non-specific inhibitor of llbeta-HSDl. Bellows et al., Bone 1998, 23: 119-125. Additional reports suggest that llbeta-HSDl may be responsible for providing increased levels of active glucocorticoids in osteoclasts, and thus in the reabsorption of bone augmentation. Cooper et al., Bone 2000,27: 375-381. This information suggests that the inhibition of llbeta-HSD1 can have favorable effects against osteoporosis via one or more mechanisms, which can act in parallel. It is known that bile acids inhibit llbeta-HSD2 and that such inhibition results in a change in cortisol / cortisol balance in favor of cortisol. Quattropani et al., J. Clin. Invest. Nov.2001, 108: 1299-305. A reduction in hepatic activity of the llbeta-HSD2 is therefore predicted to reverse the cortisol / cortisone balance in favor of cortisone, which could provide a therapeutic benefit in diseases such as hypertension. The various isozymes of 17beta-dehydrogenase hydroxysteroid (17beta-HSDs) bind to androgen receptors or estrogen receptors and catalyze the interconversion of several sex hormones including estradiol / estrone and testosterone / androstenedione. So far, six isoenzymes have been identified in humans and are expressed in several human tissues including endometrial tissue, breast tissue, colon tissue and testicles. Type 2 17beta-hydroxysteroid dehydrogenase (17beta-HSD2) is expressed in human endometrium and its activity has been reported to be linked to cervical cancer. Kitawaki et al., J. clin.Endocrin.Metab. , 2000, 85: 1371-3292-3296. Type 3 hydrobesteroid 17beta-dehydrogenase (17beta-HSD3) is expressed in the testes and its modulation may be useful for the treatment of androgen-related disorders. The androgens and estrogens are active in their 17beta-hydroxy configurations, while their keto derivatives do not bind to androgen and estrogen receptors and are thus inactive. The conversion between the active and inactive forms (estradiol / estrone and testosterone / androstenedione) of sex hormones is catalyzed by members of the 17beta-HSD family. 17beta-HSDl catalyzes the formation of estradiol in breast tissue, which is important for the growth of malignant breast tumors. Labrie et al., Mol. Cell. Endochronol.l991.78: CH3-CH8. A similar role has been suggested for 17beta-HSD4 in colon cancer. English and others-, J.Clin.Endocrinol.Metab.1999, 84: 2080-2085. 17beta-HSD3 is expressed almost exclusively in the testes and converts androstenedione to testosterone. The deficiency of this enzyme during fetal development leads to male pseudohemaphroditis. Geissler et al., Nat.Genet.1994, 7: 34-39. Both 17beta-HSD3 and several isozymes of 3alpha-HSD are involved in complex metabolic pathways, which lead to the androgen to mix between active and inactive forms. Penning and others. , Biochem. J.2000, 351: 67-77. Thus, the modulation of certain HSDs may have potentially favorable cts in the treatment of disorders related to androgen and estrogen. 20alpha-dehydrogenases hydroxysteroids (20alpha-HSDs) catalyze the interconversion of progestins (such between progesterone and 20alpha-hydroxyprogesterone). Other substrates for 20alpha-HSDs include 17alpha-hydroxypregnenolone or 17alpha-hydroxyprogesterone, leading to 20alpha-OH steroids. Several isoforms 20alpha-HSD have been identified and 20alfa-HSDs are expressed in various tissues, including the placenta, ovaries, testes and adrenals. Peltoketo, et al., J. Mol. Endocrinol. 1999, 23: 1-11. Hydroxysteroid 3alpha-dehydrogenase (3alpha-HSDs) catalyze the interconversion of androgen dihydrotestosterone (DHT) and 5alpha-androstane-3alpha, 17 beta-diol and the interconversion of androgens DHEA and androstenedione and also play an important role in androgen metabolism . Ge et al., Biology of Reproduction 1999,60: 855-860.

The aryl sulfonamide compounds and methods for their synthesis are described in Klioze et al., J. Med.Chem 1980, 23: 677-679, and the international publication WO01 / 02371. The disclosure of these publications, however, does not cover the compounds of the present invention, nor the use of the compounds disclosed as modulators of HSD. International publications No. WO01 / 90090, WO01 / 90091, WO01 / 90092, and WO03 / 044009 disclose sulfonamides and their uses as llbeta-HSDl modulators, but the disclosure of these publications does not cover the aryl sulfonamide compounds of the present invention or its uses as modulators of HSD. Despite previous research in the field of HSD inhibition, there remains a need for new compounds that are potent inhibitors for several families of HSDs and effective for the treatment of HSD-mediated conditions such as diabetes, obesity, glaucoma, osteoporosis. , cognitive disorders, immunological disorders, depression, hypertension and others. The citation of any reference in this application is not an admission that the reference is prior art to this request.

SUMMARY OF THE INVENTION In summary, the present invention relates to novel compounds, compositions thereof and methods for modulating the activity of hydroxysteroid dehydrogenases (HSDs), such as 11-beta dehydrogenase hydroxysteroid, 17 beta-dehydrogenase hydroxysteroid, 20alpha-dehydrogenase hydroxysteroid, and hydroxysteroid 3alpha-dehydrogenase, including all isoforms thereof, including but not limited to llbeta-dehydrogenase hydroxysteroid type 1 (hereinafter "llbeta-HSDl"), llbeta-dehydrogenase hydroxysteroid type 2 (hereinafter "llbeta-HSD2"), and 17 beta-dehydrogenase hydroxysteroid type 3 (hereinafter" 17beta-HSD3"). In a preferred embodiment, the compounds of the invention inhibit the activity of HSD. The present invention also relates to methods for treating or preventing diseases or disorders associated with the action of hydroxysteroid dehydrogenase, which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound or a pharmaceutically acceptable salt, a solvate , stereoisomer or a prodrug thereof. The invention comprises both selective and non-selective inhibitors of hydroxysteroid dehydrogenases.

It should be understood that each of the selective and non-selective inhibitors of hydroxysteroid dehydrogenases has benefits in the treatment or prevention of diseases associated with, for example, abnormal glucose levels or hypothalamic function. Two types of selectivity are contemplated, which with respect to selectivity for HSDs as a class over other types of receptors or target genes related to glucose metabolism, or those that are selective for several HSDs or specific isoforms thereof compared to other HSDs or specific isoforms thereof. In one embodiment, the aryl sulfonamide compounds can act as selective or non-selective inhibitors of llbeta-HSD. The compounds can inhibit the interconversion of inactive 11-ketosteroids with their active hydroxy equivalents. Therefore, the present invention provides methods by which the conversion of the inactive form to the active form can be controlled, and useful therapeutic effects can be obtained as a result of such control. More specifically, but not exclusively, the invention relates to the interconversion between cortisone and cortisol in humans.

In another embodiment, the aryl sulfonamide compounds can act as in vivo inhibitors of llbeta-HSD. In another embodiment, the arylsulfonamide compounds of the present invention can be orally active. The aryl sulfonamide compounds are also useful for modulating numerous metabolic functions including, but not limited to, one or more of (i) regulation of carbohydrate metabolism, (ii) regulation of protein metabolism, (iii) regulation of lipid metabolism, (iv) regulation of normal growth and development, (v) influence on cognitive function, (vi) resistance to stress and ineralocorticoid activity. The aryl sulfonamide compounds may also be useful for inhibiting hepatic gluconeogenesis, and may also be effective in relieving the effects of endogenous glucocorticoids in diabetes itus, obesity (including enteric obesity), neuronal loss and / or cognitive impairment in the elderly. Therefore, in a further aspect, the invention provides the use of an HSD inhibitor in methods directed to produce one or more therapeutic effects in a patient to whom the aryl sulfonamide compound has been administered, said selected therapeutic effects of inhibition. of hepatic gluconeogenesis, an increase in insulin sensitivity in adipose tissue and muscle, and the prevention of, or reduction in, neuronal loss / cognitive impairment due to neurotoxicity potentiated by glucocorticoid or neuronal dysfunction or damage.

The invention further provides methods for treating a condition selected from the group consisting of: hepatic insulin resistance, adipose tissue insulin resistance, muscle insulin resistance, neuronal loss or dysfunction due to neurotoxicity enhanced by glucocorticoids, and any combination of the aforementioned conditions, the methods comprise administering to a patient in need thereof a therapeutically acceptable amount of an aryl sulfonamide compound. The aryl sulfonamide compounds of the invention include compounds having formula (I): R is selected from -H, -halo, NO, -Ci-Cs alkyl, C2-Cs alkenyl, C-Cs alkynyl, alkoxy, -haloalkyl, C2-C8 hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, - (Ci-Cd alkyl) cycloalkyl, (L-C6 alkyl) heterocycle, (C?-C6 alkyl) heteroaryl, (Ci-Cß alkyl) aryl, -C (0) R ', -C ( 0) OR ', -C (0) N (R') 2, C (OR ') R', -OR ', -SR', -OC (0) R ', -C (0) N (R' ) 2, -S (0) R ', -S02R', -S02N (R ') 2, -N (R') 2, and -NR'C (0) R '; R5 is selected from -H, -halo, -CN, -N02, -C6-C8alkyl, -C2-C8alkenyl, -C2-C8alkynyl, -alkoxy, -haloalkoxy, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl, -aryl, - (C?-C6 alkyl) cycloalkyl, (C?-C6 alkyl) heterocycle, - (C?-C6 alkyl) heteroaryl, (d-C6 alkyl) aryl, -C (0) R ', -C (0) 0R ', -C (0) N (R') 2, -C (0R ') R', SR ', -0C (0) R', -C (0) N (R ') 2, -S (0) R ', -S02R', -S02N (R ') 2, -N (R'), and -NR'C (0) R ', or R5 and R6, together with the carbon to which they are attached, join to form an optionally substituted cycloalkane ring; R6 is selected from -H, -halo, -CN, -N02, -C6-C8alkyl, -C2-C8alkenyl, C2-C8alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocyclealkyl, heteroaryl , -aryl, - (C? -C6 alkyl) cycloalkyl, (C1-Cg alkyl) heterocycle, -C? -C6 alkyl) heteroaryl, C1-C6 alkyl) aryl, -C (0) R ', -C (0) ) 0R ', -C (0) N (R') 2, C (OR ') R', OR ', SR', - 0C (0) R ', -C (0) N (R') 2, S (0) R ', -S02R', - S02N (R ' ) 2, -N (R ') 2, and -NR'C (0) R', or is combined with R5 as described above; R7 is selected from -H, -halo, CN, -N02, amino and C1-C8 alkyl; and in some embodiments it is in a position ortho to the sulfonamide portion of formula I. Q is selected from a group consisting of -H, -halo, -CN, -N02, -alkyl C? -C8, -alkenyl C2-C8, -alkynyl of C2-C8, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, - (Ci-C6 alkyl) cycloalkyl, - (C?-C6 alkyl) heterocycle, - (Ci-C6 alkyl) heteroaryl, - (C?-C6 alkyl) aryl, -C (0) R ', -C (0) OR', -C (0) N (R ') 2, -C (OR') R ', -OR', -SR ', -OC (0) R ', -C (0) N (R') 2, -S (0) R ', -S02R', -S02N (R ') 2, -N (R'), and -NR'C (0) R '; Ll is a direct bond, C? -C- alkylene, or C1-C7 -heteroalkylene-; L2 is a direct bond, C1-C7 alkylene or C1-C7 heteroalkylene; and each presence of R 'is independently -H, Ci-C8 alkyl, -C2-C8 alkenyl, -C2-C8alkynyl, -alkoxy, alkoxyalkyl, -haloalkyl, -hydroxyalkyl, cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, - (C C-C6 alkyl) cycloalkyl, - (C?-C6 alkyl) eterocycle, - (C?-C6 alkyl) heteroaryl, - (C?-C6 alkyl) aryl, or two R 'groups, when attached to the The same nitrogen atom can be combined with the nitrogen atom to which they are linked to form a heterocycle or heteroaryl group. Where when R1, R2 and R3 are each -F or -CH3, R4 is different from -H; and said compound is other than: wherein Ra is selected from 4-methoxyphenyl, 4-chlorophenyl and 4-bromophenyl and Rb is 4-fluorophenyl or 4-bromophenyl. In one aspect, the invention provides pharmaceutical compositions comprising an aryl sulfonamide compound and a pharmaceutically acceptable carrier, carrier, excipient or diluent. In another aspect, the invention provides methods for the treatment of insulin dependent diabetes mellitus which comprise administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides methods for treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides methods of treating obesity which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides methods for modulating the production of cortisol which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides methods for modulating hepatic glucose production which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides methods for modulating hypothalamic function which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides methods for treating a condition mediated by hydroxysteroid dehydrogenase or a disorder comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides a method for modulating the function of a hydroxysteroid dehydrogenase in a cell comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In a further aspect, the invention provides methods for modulating a hydroxysteroid dehydrogenase, which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In one aspect, the invention provides methods for treating a condition mediated by llbeta-HSD2 or a disorder comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides a method for modulating the function of llbeta-HSD2 in a cell comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In a further aspect, the invention provides methods for modulating llbeta-HSD2, which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In one aspect, the invention provides methods for treating a condition mediated by 17beta-HSD3 or a disorder comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In another aspect, the invention provides a method for modulating the function of 17beta-HSD3 in a cell comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). In a further aspect, the invention provides methods for modulating the function of 17beta-HSD3 in a cell comprising administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). These and other aspects of this invention will be apparent with reference to the following detailed description. For that purpose certain patents and other documents are cited herein to more specifically establish various aspects of this invention. Each of these documents was included herein by reference in its entirety. DETAILED DESCRIPTION OF THE INVENTION Definitions and abbreviations As used herein, the terms used above have the following meanings: The term "C?-C6 alkyl" as used herein, refers to straight or branched chain saturated hydrocarbon having from 1 to 6 carbon atoms. Representative Ci-Cβ alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, secbutyl, tertbutyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. A C? -C6 alkyl group may be unsubstituted or optionally substituted with one or more substituents as described below. The term "C?-C8 alkyl" as used herein, refers to a straight or branched chain hydrocarbon having from 1 to 8 carbon atoms. Representative C? -C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptium, octyl, isooctyl, and neooctyl. A Ci-Cβ alkyl group may be unsubstituted or optionally substituted with one or more substituents as described hereinafter. The term "C2-C8 alkenyl" as used herein, refers to a straight or branched chain hydrocarbon containing from 2-8 carbon atoms and at least one double bond. Examples of the C-C8 alkenyl group include, but are not limited to ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, isoheptene, 1-octene, 2-octene, 3-octene, 4-octene and isooctene. The term "C2-C8 alkynyl" as used herein, refers to a straight or branched chain unsaturated hydrocarbon containing from 2-8 carbon atoms and at least one triple bond. Examples of C-C8 alkynyl groups include, but are not limited to, acetylene, propylene, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1- pentyne, 2-pentyne, isopentine, 1 -hexine, 2 -hexine, 3 -hexine, isohexine, 1-heptin, 2-heptin, 3 -heptin, isoheptin, 1-octino, 2-octino, 3-octino, 4-octino, and isooctino. The term "C al-C7 alkylene" as used herein, refers to an alkyl group in which one of the hydrogen atoms of the alkyl group of L-C7 has been replaced with a bond. Examples of C? -C7 alkylene include -CH2-, CH2CH2-, -CH2CH2CH2-, CH2CH2CH2CH2-, CH 2 CH 2 CH 2 CH 2 CH 2 -, CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2. The term "Ci-Cd alkoxy" as used herein, refers to a group having the formula -0- (C? -C6 alkyl). Examples of Ci-C? Alkoxy group include -0-ethyl, -0 -ethyl, -0-propyl, -0-isopropyl, -0-butyl, -0- 25. sec-butyl, -0-tert-butyl, -0-pentyl, -0-isopentyl, -0-neopentyl, - O-hexyl, -O-isohexyl, and -O-neohexyl. The term "aminoalkyl", as used herein, refers to a Ci-Cd alkyl group where one or more of the hydrogen atoms of the Ci-Cß alkyl group is replaced with an amine of the formula -N (Ra) 2 , wherein each occurrence of Ra is independently a hydrogen or a C? -C6 alkyl. Examples of aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, CH2CH2CH2NH2, CH2CH2CH2CH2NH2, -CH2CH2CH2CH2CH2NH2, CH2CH2CH2CH2CH2CH2NH2, t-butylamine and isopropylamine. The term "aryl" as used herein, refers to a cyclic monocyclic, bicyclic or tricyclic hydrocarbon system of 6-14 members. Examples of an aryl group include phenyl and naphthyl. An aryl group may be unsubstituted or optionally substituted with one or more substituents described below. The term "cycloalkyl" and "cycloalkane" is used interchangeably and refers to a cyclic saturated or unsaturated monocyclic, bicyclic or tricyclic 3 to 15-membered unsaturated hydrocarbon system. Included in this class are cycloalkyl groups which are fused to a benzene ring and cycloalkyl groups which are spirocyclic, as well as spirocyclic and fused to benzene ring. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl, 1, -cyclo eptadienyl, -1,3, 5-cycloheptatrienyl, cyclooctyl, cyclooctenyl, 1, 3-cyclooctadienyl, 1,4-cyclooctadienyl, 1/3, 5- cyclooctatrienyl, Taleno decahidrona, octahydronaphthalene, hexahydronaphthalene, octahydroindene, hexahydroindene, tetrahydroinden, decahydrobenzocycloheptene, octahydrobenzocycloheptene, hexahydrobenzocycloheptene, tetrahidrobenzociclohepteno, dodecahydroheptalene , decahydroheptalene, octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene. A cycloalguyl or cycloalkane group may be unsubstituted or optionally substituted with one or more substituents as described below. The term "halo" as used herein refers to -F, -Cl, -Br or -I. The term "haloalkyl" as used herein, refers to a C? -C6 alkyl group where one or more hydrogen atoms of the C? -C6 alkyl group is replaced with a halogen atom, which may be the same or different. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroetyl, 4-chlorobutyl, 3-bromopropyl, pichloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl. The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise stated, a straight or branched chain, or a cyclic hydrocarbon radical or a combination thereof, consists of a number of atoms carbon and one to three heteroatoms selected from the group consisting of 0, N, Si and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom (S) 0, N and S can be replaced by any internal position of the heteroalkyl group. The heteroatom Si can be replaced at any position of the heteroalkyl group including the position at which the alkyl group was bound to the rest of the molecule. Examples include -CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2-S (0) -CH3, -CH2-CH2-S (0) 2-CH3, -CH = CH-0-CH3, Si (CH3) 3, -CH2-CH = N-0CH3, I-CH = CH-N (CH3) -CH3. Up to two heteroatoms can be consecutive such as, for example, -CH2-NH-0-CH3 and -CH2-0-Si (CH3) 3. The term "heteroalkylene C? -C7" as used herein, refers to a C? -C7 alkylene in which one to three of the -CH2- groups of the C1-C7 alkylene have been replaced by an sulfur, an oxygen atom, or -NH-. A C1-C7 heteroalkylene group may have a heteroatom in either or both of its terms. The term "heteroaryl" as used herein refers to a 5- to 14-membered aromatic heterocycle ring and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and contains at least 1 carbon atom, which includes monocyclic, bicyclic and tricyclic ring. Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, tizolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl. , cinolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl. A heteroaryl group may be unsubstituted or optionally substituted with one or more substituents as described below. As used herein, the term "heteroatom" is intended to include oxygen (0), nitrogen (N), and sulfur (S). As used herein, the term "heterocycle" refers to ring systems of 5 to 14 members that may be saturated, unsaturated, or aromatic, and which contain 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized, including monocyclic, bicyclic, and tricyclic ring systems. The bicyclic and tricyclic ring systems can include a heterocycle or heteroaryl fused to a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Representative examples of heterocycles include, but are not limited to, aziridinyl, oxiranyl, tyranyl, triazolyl, tetrazolyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl, benzthiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl, quinolinyl, and quinazolinyl. A heterocycle group may be unsubstituted or optionally substituted with one or more substituents as described herein below. The term "hydroxyalkyl", as used herein, refers to a C 1 -C 7 alkyl group where one or more hydrogen atoms of the C 1 -C 7 alkoyl group is replaced with an -OH group. Examples of. hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH20H, -CH2CH2CH2CH2OH, -CH2CH2CH2CH2CH20H, -CH2CH2CH2CH2CH2CH2OH, t-butanol and isopropanol. Substituents for the alkyl and heteroalkyl radicals as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl can be a variety of groups selected from: -OR ', -NR'R ", - SR ', -halo, -SiR'R "R'", -0C (0) R ', -C (0) R', -C02R ', -CONR'R' ', -OC (O) NR'R '', NR''C (0) R ', -NR' "C (0) NR'R '', -NR '" S02NR'R' ', NR''C02R', -NHC (NH2) = NH, -NR 'C (NH2) = NH, -NHC (NH2) = NR', -S (0) R ', S02R', - S02NR'R '', -NR''S0R ', -CN and -N02 and a number which varies from zero to three, with those groups having zero, one or two substituents are particularly preferred. R ', R' 'and R' '' each independently refers to hydrogen, unsubstituted (C? -C8) alkyl or (C? -C8) alkyl substituted with hydroxy, cyano or amino, heteroalkyl (C? -C8) ) unsubstituted, unsubstituted aryl, unsubstituted alkoxy and aryl substituted with one to three substituents selected from -halo, unsubstituted alkyl, unsubstituted alkoxy, unsubstituted thioalkoxy and unsubstituted arylalkyl (C3.-C4). When R 'and R "are linked to the same nitrogen atom, they can be combined with a nitrogen atom to form a 5, 6 or 7 membered ring. For example, -NR'R "means that it includes 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkenyl heteroalkyl group will have from zero to three substituents, with those groups having two or less substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the foregoing discussion of the substituents, one skilled in the art will understand that the term "alkyl" means that it includes groups such as trihaloalkyl (for example-CF3 and -CH2CF3). Preferred substituents for the alkyl and heteroalkyl radicals are selected from: -OR ', NR'R ", -SR', -halo, -SiR'R '?' ', -0C (0) R', -C (0) R ', -C02R', -C (0) NR'R ", -OC (O) NR'R", -NR "C (0) R ', -NR "C02R', -NR" 'S02NR'R ", -S (0) R', -S02R ', -S02NR'R", -NR "S02R', -CN and -N02, where R ', R "and R" are as defined above, further preferred substituents are selected from: - OR', -NR'R ", -halo, -0C (0) R ', -C02R', -C (0) NR'R ", OC (0) NR'R", -NR "C (0) R ', -NR" C02R', NR '' 'S02NR'R ", -S02R', -S02NR'R ", -NR" S02R ', -CN and -N02 Similarly, the substituents for the aryl and heteroaryl groups are varied and selected from: -halo, -OR', -0C (0) R ', -NR' R ", -SR ', -R', -CN, -N02, -C0R ', -C (0) NR'R", -C (0) R', -0C (0) NR'R ", - NR "C (0) R ', -NR" C02R', -NR '"' C (0) NR'R", -NR '"S02NR'R", NHC (NH2) = NH, -NR'C ( NH) = NH, -NH-C (NH2) = NR ', -S (0) R', -S02R ', -S02NR'R ", - NR" S02R', N3, -CH (Ph) 2, perfluoroalkoxy , perfluoroalkyl (C? -C4), cyano (C1-C4) alkyl, hydroxyalkyl (C? -C), and aminoalkyl (C? -C4), in a number ranging from zero to the total number of open valencies in the aromatic ring system; and wherein R ', R "and R"' are independently selected from hydrogen, unsubstituted (C? -C8) alkyl, hydroxyalkyl, aminoalkyl, unsubstituted (Ci-C8) heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, aryl (C1-C4) alkyl and unsubstituted aryloxyalkyl (Ci-C4). Typically, an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or less substituents being preferred in the present application. In one embodiment of the invention, an aryl or heteroaryl group will be unsubstituted or monosubstituted. In another embodiment, an aryl or heteroaryl group will be unsubstituted. Preferred substituents for the aryl and heteroaryl groups are selected from: -halo, -OR ', -0C (0) R', NR'R ", -SR ', -R', -CN, -N02, -C02R ', -CONR'R ", C (0) R ', - 0C (0) NR'R", -NR "C (0) R', -S (0) R ', -S02R', -S02NR'R" , -NR "S02R ', -N3, -CH (Ph), perfluoroalkoxy and perfluoroalkyl (C? -C4), where R' and R" are as defined above. Additional preferred substituents are selected from: -halo, -OR ', -0C (0) R', -NR'R ", -R ', -CN, -N02, -C02R', -CONR'R '', - NR "C (0) R ', -S02R', -S02NR'R", -NR "S02R ', perfluoroalkoxy and perfluoroalkyl (C1-C4). Two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with substituents of the formula -TC (OJ (CH2) qU-, where T and U are independently -NH-, -0-, -CH2- or a simple bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituent of the formula -A- (CH2) rB-, where A and B are independently -CH2-, -0- ,. -NH-, - S-, -S (0) 2-, -S (0) 2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed can optionally replace with a double link. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituent of the formula - (CH2) s-, -X- (CH2) t-, where syt are independently integers from 0 to 3 , and X is -O-, -NR'-, -S-, -S (0) -, -S (0) 2- or -S (0) 2NR'-. The substituent R 'on NR'- and -S (0) 2NR'- is selected from hydrogen or unsubstituted (C1-C6) alkyl. It is to be understood that the -C02H substituent, as used herein, may be optionally replaced with bioisosteric substitutes such as: and the similar ones. See, for example, the Practice of Medicinal Chemistry; Wermuth, CG. , Ed .; Academic Press: New York, 1996, -p.203. The aryl sulfonamide compound can also exist in various isomeric forms, including configurational, geometric and conformational isomers, as well as exist in various tautomeric forms, particularly those that differ at the point of hydrogen atom bonding. As used herein, the term "isomer" is intended to encompass all isomeric forms of an aryl sulfonamide compound, including tautomeric forms of the compound.

Certain aryl sulfonamide compounds can have centers of symmetry and therefore exist in different enantiomeric and diastereomeric forms. An aryl sulfonamide compound may be in the form of an optical isomer or diastereomer. Accordingly, the invention includes aryl sulfonamide compounds and their uses as described herein in the form of their optical isomers, diastereomers and mixtures thereof, including a racemic mixture. The optical isomers of the aryl sulfonamide compounds can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, mobile simulator bed technology or chemical separation of stereoisomers by the use of optically active resolving agents. As used herein and unless otherwise indicated, the term "stereomerically pure compound" means a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having a chiral center will be substantially free of the opposite enantiomer of the compound. A substantially pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises more than about 80% by weight of a stereosomer of the compound and less than about 20% by weight of another stereoisomer of the compound, more preferably more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of another stereoisomer, still more preferably more than about 95% by weight of a stereoisomer of the compound, and less than about 5% by weight of another stereoisomer of the compound, and more preferably more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of another stereoisomer of the compound. It should be noted that if there is a discrepancy between a structure represented and a name given to that structure, the structure represented is dominant. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated by, for example, highlighted or dotted lines, the structure or portion of the structure will be construed as encompassing all stereoisomers thereof.

An aryl sulfonamide compound may be in the form of a pharmaceutically acceptable salt. Depending on the structure of the compound, the phrase "pharmaceutically acceptable salt", as used herein, refers to an acidic or basic, organic or inorganic pharmaceutically acceptable salt of an aryl sulfonamide compound. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water soluble and insoluble salts, such as acetate, (4,4-diaminostilbene-2,2-disulfonate) amsonate, benzene sulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisilate, estolate, esilate, fiunarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelato, mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, salt N-methylglucamine ammonium, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, (l, l-methane-bis-2-hydroxy-3) -naftoate, einbonate) pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalisulate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide, and salts of valerate, In addition, a pharmaceutically acceptable salt can have more than one atom charged in its structure. In this case the pharmaceutically acceptable salt can have multiple counterparts. Hence, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions. As used herein, the term "isolated and purified form" means that when it is isolated (from other components of a chemical organic synthetic reaction mixture), the isolate contains at least 30%, at least 35%, at least 40%. %, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% , at least 95%, at least 98% of an aryl sulfonamide compound by weight of the isolate. In one embodiment, the isolate contains at least 95% of an arylsulfonamide compound by weight of the isolate. As used herein, the term "prodrug" means a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vivo or in vi tro) to provide an active compound, particularly an aryl compound sulfonamide. Examples of prodrugs include, but are not limited to, derivatives and metabolites of an arylsulfonamide compound including biohydrolyzable groups such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and analogous biohydrolyzable phosphates (monophosphate, diphosphate or triphosphate). Preferably, prodrugs of compounds with carboxy functional groups are esters of lower alkeyl of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present in the molecule. Prodrugs can be commonly prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6hed- (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh). As used herein, the terms "treat", "treating" and "treatment" refer to the elimination or amelioration of a disease or symptom associated with a disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease as a result of the administration of one or more prophylactic or therapeutic agents to a patient with such a disease.

As used herein, the term "prevent", "preventing" and "prevention" refers to the prevention of the onset, recurrence or spread of the disease in a patient as a result of the administration of a prophylactic or therapeutic agent. The term "effective amount" as used herein refers to an amount of an aryl sulfonamide compound or other active ingredient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease or to delay or minimize the symptoms associated with a disease. In addition, a therapeutically effective amount with respect to an aryl sulfonamide compound means the amount of therapeutic agent alone, or in combination with other therapies, which provide a therapeutic benefit in the treatment or prevention of a disease. Used in connection with an arylsulfonamide compound, the term can encompass an amount that improves all therapies, reduces or avoids symptoms or causes of the disease, or increases the therapeutic or synergistic efficacy with another therapeutic agent. As used herein, "Syndrome X" refers to a collection of abnormalities including hyperinsulinemia, obesity, elevated levels of triglycerides, uric acid, small fibrinogen, dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1) and reduced levels of HDL cholesterol. Syndrome X also means that it includes metabolic syndrome. The terms "modulate" "modulation" and the like refer to the ability of a compound to increase or decrease the function or activity of a hydroxysteroid dehydrogenase, for example llbeta-HSDl. "Modulation" as used herein in its various forms, is intended to include inhibition, antagonism, partial antagonism, activation, pain and / or partial pain of the activity associated with a hydroxysteroid dehydrogenase. Hydroxysteroid dehydrogenase inhibitors are compounds that bind to, partial or total block stimulation, decrease, prevention, activation, retardation, inactivation, desensitization, or regulation of signal translation. Hydroxysteroid dehydrogenase activators are compounds that, bind to, stimulate, increase, open, activate, increase activation, sensitize or regulate signal translation. The ability of a compound to modulate a hydroxysteroid dehydrogenase can be demonstrated in an enzyme assay or cell-based assay. For example inhibition of llbeta-HSDl can decrease cortisol levels in a patient and / or increase cortisone levels in a patient by blocking the conversion of cortisone to cortisol. Alternatively, the inhibition of llbeta-HSD2 can increase the levels of contisol in a patient and / or decrease the levels of cortisone in a patient by blocking the conversion of cortisol to cortisone. A "patient" includes an animal (e.g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig), in a mammalian mode such as a non-primate and a primate (for example monkey and human), and in another embodiment a human. In a preferred embodiment, a patient is a human. In specific modalities, the patient is a baby, child, adolescent, or human adult. The term "HSD" as used herein, refers to hydroxysteroid dehydrogenase enzymes in general, including but not limited to, llbeta dehydrogenases hydroxysteroids (llbeta-HSDs), 17beta-dehydrogenases hydroxysteroids (17beta-HSDs), 20alfa dehydrogenases hydroxysteroids ( 20alfa-HSDs), 3alpha-dehydrogenases hydroxysteroids (3alpha-HSDs), and all the isoforms thereof. The term "llbeta-HSDl" as used herein, refers to the hydroxysteroid type 1 lbeta-dehydrogenase enzyme variant, or isoform thereof. Variants of llbete-HSDl includes proteins substantially homologous to the native llbeta-HSDl, proteins that have one more amino acid deletions that occur naturally or not naturally, insertions or substitutions (llbeta-HSDl derivatives, homologs and fragments). The amino acid sequence of a variant of llbeta-HSDL is preferably at least about 80% identical to native llbeta-HSDL, more preferably at least about 90% identical and more preferably at least about 95% identical. The term "llbeta-HSD2" as used herein refers to the hydroxysteroid type IIbeta-dehydrogenase enzyme, a variant or isoform thereof. Llbeta-HSD2 the variants include proteins substantially homologous to native llbeta -HSD2, proteins having one or more amino acid deletions that occur naturally or not naturally, insertions or substitutions (llbeta-HSD2 derivatives homologues and fragments). The amino acid sequence of llbeta-HSD2 variant preferably is at least about 80% identical to native llbeta-HSD2 more preferably at least about 90% identical and more preferably at least about 95% identical. (See Bart and others; J. Med, Chem., 2002 45: 3813-3815). The term "llbeta-HSD3" as used herein refers to the type 3 enzyme 17beta-dehydrogenase hydroxysteroid, variant, or isoform thereof. The 17beta-HSD3 variants include proteins substantially homologous to the native 17beta-HSD3, proteins having one or more amino acid deletions that occur naturally or unnaturally, insertions or substitutions (derivatives of 17beta-HSD3, homologs and fragments). The amino acid sequence of the 17beta-HSD3 variant is preferably at least about 80% identical to the native, more preferably at least about 90% identical, and more preferably at least about 95% identical. As used herein, the term "condition or disorder responsive to HSD" and related terms and phrases refers to a condition or disorder that responds favorably to the modulation of a hydroxysteroid dehydrogenase (HSD) enzyme. Responses favorable to the modulation of HSD include relief or abrogation of the disease and / or its concomitant symptoms, inhibition of the disease, that is, arrest or reduction of the development of the disease, or its clinical symptoms, and regression of the disease or its clinical symptoms A condition or disorder responsive to HSD may be completely or partially sensitive to HSD modulation. A condition or disorder responsive to HSD may be associated, for example, less than or greater than normal, with HSD activity inadequate and at least partially sensitive or affected by HSD modulation (eg, an HSD inhibitor leads to some improvement in the patient's well-being in at least some patients). Inadequate HSD functional activity should increase as a result of HSD expression in cells which do not express normally for HSD, reduced HSD expressions or increased expressions of HSD. A condition or disorder responsive to HSD may include condition or disorder mediated by any HSD or isoform thereof. As used herein, the term "llbeta-HSD1 sensitive condition or disorder" and related terms and phrases refer to a condition or disorder that responds favorably to the modulation of the activity of llbeta-HSD. Responses favorable to the modulation of llbeta-HSDl include alleviation or abrogation of the disease and / or its concomitant symptoms, inhibition of the disease, that is, arrest or reduction of the development of the disease, or its clinical symptoms, and regression of the disease or of its clinical symptoms. A condition or disorder responsive to llbeta-HSDl may be fully or partially sensitive to the modulation of llbeta-HSDl. A condition or disorder responsive to llbeta-HSDl may be associated eg, less than or greater than normal, with the activity of llbeta-HSD and at least partially sensitive to / or affected by the modulation of llbeta-HSDl (e.g., a llbeta-HSDl inhibitor leads to some improvement in the patient's well-being in at least some patients). The functional activity of inadequate llbeta-HSDl should increase as a result of the expression of llbeta-HSDl in cells which do not normally express llbeta-HSDl, reduced llbeta-HSDl expression or increased llbeta-HSDl expression. A condition or disorder responsive to Ibeta-HSD1 may include a condition or disorder mediated by Ibeta-HSD1. As used herein, the term "llbeta-HSD2-responsive condition or disorder" and related terms and phrases refer to a condition or disorder that responds favorably to the modulation of the activity of llbeta-HSD2. Responses favorable to the modulation of llbeta-HSD2 include alleviation or abrogation of the disease and / or its concomitant symptoms, inhibition of the disease, this is arrest or reduction of the development of the disease, or of its clinical symptoms and regression of the disease or of his clinical symptoms. A condition or disorder responsive to llbeta-HSD2 may be fully or partially sensitive to the modulation of llbeta-HSD2. A condition or disorder sensitive to llbeta-HSD2 may be associated, for example, less than or greater than normal, with the activity of llbeta-HSD2 and at least partially sensitive or affected by the llbeta-HSD2 modulation (for example, an inhibitor of llbeta-HSD2 leads to some improvement in patient's well-being in at least some patients). As used herein, the term "Condition or disorder responsive to 17beta-HSD3" and terms and phrases related to a condition or disorder that responds favorably to the modulation of 17beta-HSD3 activity. Responses favorable to modulation 17beta-HSD3 includes alleviation or abrogation of the disease and / or its concomitant symptoms, inhibition of the disease, this is arrest or reduction of the development of the disease, or its clinical symptoms and regression of the disease or its clinical symptoms A condition or disease responsive to llbeta-HSD3 may be fully or partially sensitive to the modulation of 17beta-HSD3. A condition or disorder of 17beta-HSD3 may be associated, for example, less than or greater than normal, with the activity of 17beta-HSD3 and at least sensitive to / or affected by the modulation of 17beta-HSD3 (e.g. 17beta-HSD3 inhibitor leads to some improvement in patient well-being in at least some patients). Inadequate functional activity of 17beta-HSD3 should increase as a result of the expression of 17beta-HSD3 in cells which do not normally express at 17beta-HSD3, the reduced expression of 17beta-HSD3 or the increased expression of 17beta-HSD3. A condition or disorder responsive to 17beta-HSD3 may include a condition or disorder mediated by 17beta-HSD3. As used herein, the term "condition or disorders mediated by HSD" and related terms and phrases refers to a condition or disorder characterized by less than or greater than normal activity of a hydroxysteroid dehydrogenase.

(HSD). A condition or disorder mediated by HSD may be fully or partially characterized by inappropriate HSD activity. However, a condition or disorder mediated by HSD is one in which the modulation of an HSD results in some effect on the fundamental condition or disorder (A llbeta-HSDl inhibitor results in some patient improvements in good condition in at least some patients ). As used herein, the term "condition or disorder mediated by llbeta-HSD2" and related terms and phrases refers to a condition or disorder characterized, for example, less than or greater than normal, by the activity of the Ibeta- HSD2. A condition or disorder mediated by llbeta-HSD2 may be characterized in whole or in part by the inappropriate activity of llbeta-HSD2. However, a condition or disorder mediated by llbeta-HSD2 is one in which the modulation of llbeta-HSD2 has some effect on the underlying condition or disease (for example, an inhibitor of llbeta-HSD2 causes some improvement in the patient's well-being in at least some patients). As used herein, the term "condition or disorder mediated by 17beta-HSD3" and related terms and phrases refers to a condition or disorder characterized, for example, less than or greater than normal, by the activity of 17beta- HSD3. A condition or disorder mediated by 17beta-HSD3 may be characterized in whole or in part by the inappropriate activity of 17beta-HSD3. However, a condition or disorder mediated by 17beta-HSD3 is one in which modulation of 17beta-HSD3 leads to some effect on the underlying condition or disease (for example, a 17beta-HSD3 inhibitor leads to some improvement in the patient's well-being. in at least some patients). The following abbreviations that are used herein have the indicated definitions: ATP is adenosine triphosphate; t-BuOH is tert-butyl alcohol; CHO is Chinese hamster ovary; Dess-Martin Periodinane is 1,1,1, -triacetoxy-1,1, -dihiro-l, 2-benziodoxol-3 (lH) -one, -DIBAL-H is aluminum disubethyl hydride; DMEM is Medium Eagle modified by Dulbecc; DMF is N, N-dimethyl formamide; Et 3 N is triethyl amine; Et4NCN is tetraethyl ammonium cyanide; TeOAc is ethyl acetate; EtOH is ethanol; LAH is lithium aluminum hydride; LDA is lithium disopropylamide; LiAl (OfcBu) 3H is tri-tert-butoxy alumino lithium hydride; MeOH is methanol; MS is mass spectrometry; MsCl is methanesulfonyl chloride; NaBH is boron sodium hydride; NMR is nuclear magnetic resonance; PBS is phosphate buffered saline solution; SPA is scintillation proximity test; TBS is tert-butyldimethylsilyl; TBSCl is tert-butyldimethylsilyl chloride; THF is tetrahydrofuran; TMS is trimethylsilyl. THE ARIL SULFONAMIDE COMPOUNDS FORMULA COMPOUNDS (I) As stated above, the present invention encompasses aryl sulfonamide compounds having the formula (I) OR) or pharmaceutically acceptable salts, prodrugs or stereoisomers thereof. R1, R2 and R3 are independently selected from -H.-halo, -OH, -CN, -N02, -C1-C8alkyl, -C2-C8alkenyl, -C2-C8alkynyl, -alkoxy, -haloalkyl, hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl and aryl, and at least one of R1, R2 and R3 is different from -H; R4 is -H, -halo, -CN, -N02, -alkyl C? -C8, -alkenyl C2-C8, -alkynyl C2-C8, -alkoxy, -haloalkyl, -hydroxyalkyl C2-C8, -cycloalkyl, -heterocycloalkyl , -heteroaryl, -aryl, -cycloalkyl (C? -C6 alkyl), heterocycle- (Ci-Ce alkyl), -heteroaryl- (C? -C6 alkyl), -aryl- (Cx-Ce alkyl), -C ( 0) R ', -C (0) OR', -C (0) N (R ') 2, -C (OR') R ', OR', -SR ', -OC (0) R', - C (OL) N (R ') 2, -S (0) R', -S02R ', -S02N (R') 2, -N (R ') 2, O -NR'C (O) R'; R5 is -h, -halo, -CN, -N02, -alkyl C? -C8, C2-C8 alkenyl, -alkynyl C-C8, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl, - aryl, -cycloalkyl- (Ci-Ce alkyl), heterocycle- (Ci-Ce alkyl), -heteroaryl- (C? -C6 alkyl), aryl- (C? -C6 alkyl), -C (0) R ', -C (0) OR', -C (0) N (R ') 2, - C (OR ') R', -OR ', -SR', -0C (0) R ', -C (O) N (R') 2, -S (0) R ', - S02R', - S02N (R ') 2, -N (R') 2, or -NR'C (0) R ', or R5 and R6, together with the carbon atom to which they are attached, join to form a cycloalkane ring optionally replaced. R6 is -H, -halo, -CN, -N02, -C6-C8alkyl, C2-C8alkenyl, -C2-C8alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl, aryl, -cycloalkyl- (C? -C6 alkyl), heterocycle- (C? -C6 alkyl), -heteroaryl- (C? -C6 alkyl), -aryl- (C? -C6 alkyl), -C (0) R ', -C (0) 0R', -C (0) N (R ') 2, -C (OR') R ', -OR', -SR ', -OC (0) R', -C (0) N (R ') 2, S (0) R', -S02R ', -S02N (R') 2, -N (R ') 2, or -NR'C (O) R'; R7 is selected from a group consisting of -H, -halo, -CN, amino and -C6 -alkyl; and in some embodiments it is in an ortho position to the sulfonamide moiety of formula I; Q is selected from a group of -H, -halo, -CN, C-C8-alkenyl, -C2-C8-alkenyl, -C2-C8alkynyl, -alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, heterocycloalkyl, -heteroaryl , -aryl, -cycloalkyl- (C? -C6 alkyl), -heterocycle- (C? -C6 alkyl), -heteroaryl- (C? -C6 alkyl), -aryl- (Ci-Ce alkyl), -C ( 0) R ', -C (0) OR', -C (0) N (R ') 2, -C (0R') R ', -OR', -SR ', -OC (0) R', -C (O) N (R ') 2, -S (0) R', -S02R ', -S02N (R') 2, -N (R ') 2, or -NR'C (O) R'; Ll is a direct bond, -C1-C7alkylene- or -heteroalkylene C- -C7-, -L2 is a direct bond, -C1-C7alkylene- or -C1-C7heteroalkylene-; Each presence of R 1 is independently -H, -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl. , -cycloalkyl- (C 1 -C 6 alkyl), -heterocycle- (C 1 -C 6 alkyl), -heteroaryl (C 1 -C 6 alkyl), or -aryl- (C 6 -C 6 alkyl), or 2 R groups, when they are linked to the same nitrogen atom, they can be combined with the nitrogen atom to which they are linked to form a heterocycle or heteroaryl group; and where when R1, R2 and R3 are each -F or CH3, R4 is different from -H; and said compound is another different to Where Ra is selected from 4-methoxyphenyl, 4-chlorophenyl and 4-bromophenyl and R is 4-fluorophenyl or 4-bromophenyl. A first subclass of aryl sulfonamide compounds of formula (I) is where L 1 is -C 7 alkylene-C 7-, L 2 is a direct bond, and R 5 and R 6, together with the carbon atom to which they are attached, join to form a cycloalkane ring. A second subclass of aryl sulfonamide compounds of formula (I) is where Ll is -C1-C7alkylene-, L2 is -C1-C7alkylene-, and R5 and R6, together with the carbon atom to which they are attached, are attached to form a cycloalkane ring. A third subclass of aryl sulfonamide compounds of formula (I) is where Ll is-C 7 -C 7 alkylene, L 2 is a direct bond, and R 5 and R 6, together with the carbon atom to which they are attached, join to form a Cycloalkane cycle, and Q is -aryl or -heteroaryl. A fourth subclass of aryl sulfonamide compounds of formula (I) is where Ll is -C1-C7alkylene-, L2 is -C1-C7alkylene-, and R5 and R6, together with the carbon atom to which they are attached, are attached to form a cycloalkane ring, and Q is -aryl or -heteroaryl. A fifth subclass of aryl sulfonamide compounds of formula (I) is where Ll is -C1-C7 alkylene-, L2 is a direct bond, and R5 and R6, together with the carbon atom to which they are linked, join to form a cycloalkane ring, and Q is -COOH or -C (0) NH2. A sixth subclass of aryl sulfonamide compounds of formula (I) is where Ll is -C1-C7alkylene-, L2 is alkylene L-C7-, and R5 and R6, together with the carbon atom to which they are attached, are attached to form a cycloalkane ring, and Q is -COOH or -C (0) NH2. A seventh subclass of aryl sulfonamide compounds of formula (I) is where R4 is -H, -alkyl or C3-C6 hydroxyalkyl. An eighth subclass of aryl sulfonamide compounds of formula (I) is where R 1 is -OH or C 1 -C 8 alkyl. A ninth subclass of aryl sulfonamide compounds of formula (I) is where El is -OH and R 2 and R 3 are independently C 1 -C 8 alkyl, or haloalkyl. A tenth subclass of aryl sulfonamide compounds of formula (I) is where R 1, R 2 and R 3 are each C 1 -C 8 alkyl. An eleventh subclass of aryl sulfonamide compounds of formula (I) is where Ll and L2 are each a direct bond, R5 and R6 together form a cycloalkane ring, and Q is -H. For each of the above subclasses where R5 and R6 together form a cycloalkane ring, the ring is optionally substituted with one to three numbers selected from the substituents described above for "alkyl". Additionally, the cycloalkane ring may be substituted with (C? -C8) alkyl, = 0 (and acetonite forms thereof), optionally substituted aryl (phenyl), heteroaryl (imidazole, triazole or optionally substituted pyridyl) and an optionally substituted heterocycloalkyl (morpholyl, pyrrolidinyl and piperidinyl). More preferably, the cycloalkane ring formed by the bonding of R5 and R6 is substituted with one to three members selected from unsubstituted (C? -C8) alkyl, -OR ', = 0 (and acetonite forms thereof), -NR' R ", -halo, -0C (0) R ', -C (0) R', -C02R ', -CONR'R", -0C (0) NR'R ", -NR" C (0) R ', -NR "C02R', -CN, -N02, aryl, heteroaryl and heterocyclyl, R ', R" and R "' each independently refer to hydrogen, (C? -C8) unsubstituted alkyl, alkyl (C? -C8) substituted with hydroxy, cyano or amino, unsubstituted heteroalkyl (Ca-Cs), unsubstituted aryl and aryl substituted with one to three substituents selected from -halo, unsubstituted alkyl, unsubstituted alkoxy, unsubstituted thioalkoxy and arylalkyl (C1-C4). The aryl, heteroaryl and heterocyclyl groups directly linked to the cycloalkane ring are optionally substituted In one preferred embodiment, Ll is -CH2- and L2 is a direct link In another preferred embodiment, Ll is a direct bond and L2 is -CH2-. In another modality preferred, Ll and L2 are each -CH2.

In yet another preferred embodiment, Ll and L2 are each a direct link. In a preferred embodiment, Q is -aryl or -heteroaryl, optionally substituted with more than four groups independently selected from -Calkyl-C8, -halo, -C02R ', C (0) N (R') 2 and -CN. In another preferred embodiment, Q is pyridyl. In another preferred embodiment, Q is imidazolyl. In another preferred embodiment, Q is -COOH. In another preferred embodiment, Q is -C (0) NH2. In yet another preferred embodiment, Q is-H. In a preferred embodiment, R5 and R6, together with the atom to which they are attached, join to form a cyclopropane ring. In another preferred embodiment, R5 and R6, together with the carbon atom to which they are attached, join to form a ring of a chlorobutane. In yet another preferred embodiment, R5 and R6, together with the carbon atom to which they are attached, join to form a cyclopentane ring. In a preferred embodiment, R4 is -H. In yet another preferred embodiment, R 4 is -CH 3. In another preferred embodiment, R 4 is -CH 2 CH 2 OH. In another preferred embodiment, R1 is -OH, R2 is -CH3, and R3 is CF3.

In yet another preferred embodiment, R1 is OH, R2 is CF3, and R3 is CF3. In one embodiment, the aryl sulfonamide compounds of formula (I) have the formula: where R1, R2, R3, R4, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In one embodiment, the aryl sulfonamide compounds of formula (I) have the formula: Where R1, R2, R3, R4, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In another embodiment, the aryl sulfonamide compounds of formula (I) have the formula: Where R1, R2, R3, R4, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In another embodiment, the aryl sulfonamide compounds of formula (I) have the formula: Where R1, R2, R3, R4, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In yet another embodiment, the aryl sulfonamide compounds of formula (I) have the formula: Where R1, R2, R3, R4, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In yet another embodiment, the aryl sulfonamide compounds of formula (I) have the formula: Where R1, R2, R3, R43, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In a further embodiment, the aryl sulfonamide compounds of formula (I) have the formula: Where R1, R2, R3, R4, R5, R6, Ll, L2 and Q are as defined above for the compounds of formula (I). In a further embodiment, the aryl sulfonamide compounds of formula (I) have the formula: -ol¬ Where R1, R2, R3, R4, R5, R6, Ll, L2- and Q are as defined above for the compounds of formula (I) In certain preferred embodiments the aryl sulfonamide compounds of formula (I), the aryl sulfonamide moiety have the formula: In more preferred embodiments of the aryl sulfonamide compounds of formula (I), the aryl sulfonamide moiety has the formula: In a preferred embodiment, the aryl sulfonamide compounds of formula (I) have a piperazine ring substituted with the following stereochemistry: In still preferred embodiments, the aryl sulfonamide compounds of formula (I) comprise an aryl sulfonyl piperazine component having the formula and stereochemistry below: Illustrative arylsulfonamide compounds of formula (I) include the compounds listed below: 23 24a H.6 n and pharmaceutically acceptable salts, solvates, stereoisomers and prodrugs thereof. The aryl sulfonamide compounds can have asymmetric centers and also exist in different enantiomeric and diastereomeric forms. The invention relates to the use of all optical isomers and stereoisomers of the aryl sulfonamide compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment which may employ or contain them. It should be noted that racemates, racemic mixtures and stereoisomers, particularly diastereomeric mixtures or diastereomerically pure compounds and enantiomers or enantiomerically pure compounds of the above are all included. The present invention also provides compositions comprising a therapeutically effective amount of an aryl sulfonamide compound of formula (I) and of a pharmaceutically acceptable carrier, carrier, diluent or excipient. The invention further provides aryl sulfonamide compounds of formula (I) which are in isolated and purified form. The invention provides methods for treating diabetes which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention also provides methods for treating obesity which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention also provides methods for treating a condition or disorder mediated by HSD which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder mediated by 11 beta-HSDl which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder mediated by 11 beta-HSD2 which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder mediated by 17beta-HSD3 which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder responsive to HSD which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder responsive to 11-beta-HSDl which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder responsive to 11 beta-HSD2 which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). The invention further provides methods for treating a condition or disorder responsive to 17 beta-HSD3 which comprises administering to a patient in need thereof a therapeutically effective amount of an aryl sulfonamide compound of formula (I). PREPARATION OF ARIL SULFONAMIDE COMPOUNDS The aryl sulfonamide compounds can be prepared using synthesis methods well known to a person skilled in the art of organic synthesis or by the use of synthetic processes summarized in scheme 1-2 below. Scheme 1 In scheme 1, substituted sulfonamide compounds of formula A can be alkylated using electrophilic compounds of formula B (where LG is an aldehyde or a good leaving group such as halide, mesylate or triflate) to provide compounds of formula (I) using well-known methods by those skilled in the relevant art. The substituent (s) on the aryl sulfonamide ring can further be modified using known processes to provide the desired compound of formula (I). The stereochemistry in the substituent can be directed by the control of the substrate, control via an auxiliary, or control via a chiral catalysis. Scheme 2 In scheme 2, substituted phenylsulfonyl chloride compounds of formula C can be alkylated using piperazine compounds of formula D to provide compounds of formula (I) using methods well known to those skilled in the related art. The substituent (s) in the arylsulfonamide ring can be further modified using known processes to provide the desired compounds of formula (I). The stereochemistry in the substituent can be driven by the control of the substrate, the control via an auxiliary, or the control via a chiral catalysis. Demonstration methods for the preparation of compounds of formulas A, B, C and D are given below.

One of ordinary skill in the related art will recognize that methods additional to the methods presented herein may be useful for preparing aryl sulfonamide compounds of formula (I) and that the aryl sulfonamide compounds of formula (I) may be prepared using conventional methods of synthesis. organic chemistry, raw materials and reagents. The aryl sulfonamide compounds of formula (I) may have one or more asymmetric centers and also exist in different enentiomeric and diastereomeric forms. An aryl sulfone compound may be in the form of an optical isomer, an enantiomer, a racemate or a diastereomer. Accordingly, the invention encompasses aryl sulfonamide compounds and their uses as described herein in the form of their optical isomers, racemates, diastereomers, enantiomers, and mixtures thereof, including a racemic mixture. Some technician in the art will understand that the synthetic routes described above can be modified to use different raw materials and alternate reagents to obtain the desired transformations. In general, the compounds of the invention can be synthesized via link forming reactions that disconnect any deformed bonds present in the compound. Particularly easy synthesis of compounds of the invention occurs when the synthesis is carried out via the joining of fragments at the separation points a, b, c and d, as shown below for an aryl sulfonamide compound of formula (I). 0) Those skilled in the art will recognize that the fragments can be assembled in any order to synthesize the compounds of the invention. COMPOSITIONS AND METHODS OF ADMINISTRATION The invention encompasses pharmaceutical compositions and simple unit dosage forms comprising an aryl sulfonamide compound, or a pharmaceutically acceptable steroisomer, prodrug, salt, solvate, hydrate, clartrate thereof. The individual dosage forms of the invention may be suitable for oral, mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus, intraarterial, or intravenous), transdermal, or oral administration. Topical Simple dosage unit forms of the invention are suitable for oral, mucosal (ie, nasal, sublingual, vaginal, buccal, or rectal), parenteral (ie, subcutaneous, intravenous, bolus, intramuscular, or intra arterial) administration , or transdermal to a patient. Examples of dosage forms include, but are not limited to: tablets; pills, capsules, such as soft elastic gelatin capsules; seals; pills; dispersions; suppositories; ointments; poultices (cataplasms); pasta; powder; bandages; creams; plasters; solutions; patches; aerosols (that is, nasal sprays or inhalers); gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (ie, aqueous and non-aqueous liquid suspensions), solutions, and elixirs; liquid forms of doses suitable for parenteral administration to a patient; and sterile solids (ie, crystalline or amorphous solids) which can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. The composition, appearance, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form used in the treatment of diabetes or a related disease may contain greater amounts of one or more of the active ingredients than the one comprising a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain small amounts of one or more of the active ingredients than the one comprising an oral dosage form used to treat the same disease or disorder. These and other forms in which specific dosage forms included in this invention will vary from one to the other, will apparently be for those in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing, Easton PA (1990). Typical pharmaceutical compositions and dosage forms comprise one or more carriers, excipients or diluents. Suitable excipients are well known to those in the pharmacy art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the manner in which the dosage form will be administered to a patient. . For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient also depends on the specific active ingredients in the dosage form. This invention also includes anhydrous pharmaceutical compositions (i.e., < 1% water) and dosage forms comprise active ingredients, since water may facilitate the degradation of some compounds. For example, the addition of water (5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage to determine characteristics such as duration or stability of the formulations out of time. See, Jens T. Carstensen, Drug Stability: Principies & Practice, 2 Ed., Marcel DeKker, NY, NY, 1995, pp.379-380. In fact, water and heat accelerate the decomposition of some compounds. In this way, the effect of water on a formulation can be of great importance from the hydration and / or humidity commonly encountered during the preparation, handling, packaging, storage, transportation, and use of the formulation.The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or slightly moist ingredients and conditions of low hydration or low humidity. It is assumed that pharmaceutical compositions and dosage forms comprising lactose and at least one ingredient comprising a primary or secondary amine are preferably anhydrous even though they are in contact with hydration and / or moisture during preparation, packaging, and / or storage. An anhydrous pharmaceutical composition should be prepared and stored so that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using known materials to prevent exposure to water such that they can be included in suitable formulating equipment. Examples of suitable packages include, but are not limited to, hermetically sealed sheets, plastics, unit dose packages (ie, vials), blister packs, and tape packages. The invention further encompasses pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the range by which an active ingredient will decompose. Such compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, buffer solutions, or salts. Aryl sulfonamide compound may be administered to a mammal (human, mouse, rat, rabbit, dog, cat, bovine, pig, monkey etc.) as modulator llbeta-HSD, a prophylactic or therapeutic drug of diabetes, a prophylactic drug or therapeutic diabetic complication (retinopathy, nephropathy, cardiac infarction and cerebral infarction based on arteriosclerosis etc.), a prophylactic or therapeutic drug of hyperlipemia, a prophylactic or therapeutic drug of obesity, neurodegenerative disease and the like, or a prophylactic or therapeutic drug of diseases mediated by llbeta -HSDl. The aryl sulfonamide compound can be administered to a mammal simultaneously with an additional therapeutic agent for the treatment of a disease, such as diabetes or obesity, for the purpose of prophylaxis or treatment of a disease. As well as the aryl sulfonamide compounds of the present invention can be administered in combination with another therapeutic agent for the treatment or prevention of numerous diseases, including, but not limited to, diabetes and obesity. Depending on the disease to be treated and the patient's condition, the compounds of the invention may be administered by routes of oral, parenteral (ie, intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant) , inhalation, nasal, vaginal, rectal, sublingual, or topical (i.e., transdermal, local) and may be formulated alone or together, in formulations suitable unit dosage form, containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and suitable for each route vehicles of administration. The invention also contemplates the administration of the compounds of the invention in a depot formulation, wherein the active ingredient is released for a defined period of time. In the case of a combined administration, the Aryl sulfonamide compound may be administered concurrently with another therapeutic agent gue is useful for the treatment or prevention of diabetes, obesity or other disease or may be administered to a previous or subsequent time to another therapeutic agent. In the case of combined administration, a pharmaceutical composition containing the aryl sulfonamide compound and an additional therapeutic agent can be administered. Alternatively, a pharmaceutical composition containing the aryl sulfonamide compound and a pharmaceutical composition containing an additional therapeutic agent can be administered separately. The routes of administration of respective pharmaceutical compositions may be the same or different. In the case of a combined administration, the aryl sulfonamide compound can be administered in doses of 5Omg to 800 mg per administration, which is given one to several times a day. In addition, the compound can be administered at a smaller dose. The combined pharmaceutical agent can be administered at a dose generally employed for prophylaxis or treatment of diabetes or obesity or at a dose lower than that. As the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which they are administered to patients. However, characteristic dosage forms of the invention comprise an aryl sulfonamide compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorphous or pro-drug substances thereof. In the treatment or prevention of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immunological disorders, depression or other conditions or disorders associated with the modulation of a hydroxysteroid dehydrogenase, a convenient dosage level will generally be from about 0.001 to about 100 mg per Kg of the weight of the patient per day, which can be administered in single or multiple doses. Preferably, the dosage level will be from about 0.01 to about 25 mg / Kg per day; more preferably from about 0.05 to about 10 mg / kg per day. A convenient dosage level may be from about 0.01 to about 25 mg / kg per day, about 0.05 to about 10 mg / kg per day, or about 0.1 to about 5 mg / kg per day. Within this range the dosage may be from about 0.005 to about 0.05, about 0.05 to about 0.5, or about 0.5 to about 5.0 mg / Kg per day. For oral administration, the dosage levels fall within the range of about 0.1 μg to about 2000 mg per day, given as a single dose once a day in the morning but preferably as a divided dose during the day taken with food. More preferably, the daily dose is administered twice a day in equally divided doses. Preferably, a daily dosage range should be from about 5 mg to about 500 mg per day, more preferably, between about 10 mg and about 200 mg per day. In the management of the patient, therapy should be initiated at lower doses, perhaps from about 1 mg to about 25 mg, and if necessary increased from about 200 mg to about 2000 mg per day either in single dosage or divided dosages , depending on the patient's overall response. For multiple drug therapy, the weight ratio of the compound of the invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Therefore, for example, when a compound of the invention is combined with an NSAID, the weight ratio of the compound of the invention to the NSAID will generally vary from about 1000: 1 to about 1: 1000, preferably about 200: 1 to approximately 1: 200. Combinations of a compound of the invention and other active ingredients will generally be within the aforementioned proportion, but in each case, an effective dose of each active ingredient should be used. It will be understood, however, that the specific dosage level and frequency of dosing for any patient may vary and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, age , body weight, general health, sex, diet, form and time of administration, range of excretion, combination of medications, the severity of the particular condition, and the guest who undergoes the therapy. ORAL DOSAGE FORMS The pharmaceutical compositions of the invention which are suitable for oral administration may be presented as discrete dosage forms, including, but not limited to, tablets (ie, chewable tablets), lozenges, capsules, and liquids (ie. , flavor syrups). Such dosage forms contain predetermined amounts of active ingredients, and can be prepared by pharmacy methods well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing,? Aston PA (1990). Typical dosage forms of the invention are prepared by combining the active ingredient (s) in an intimate mixture with at least one excipient in accordance with conventional pharmaceutical compounding techniques. The excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in liquid dosage or aerosol forms include, but are not limited to, water, glycol, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of suitable excipients for use in oral dosage forms (ie, powders, tablets, capsules, and lozenges) include, but are not limited to,, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. Due to their easy administration, tablets and capsules represent the most advantageous unit forms of oral dosage, in which case solid excipients are employed. If desired, the tablets can be coated by standard aqueous and non-aqueous techniques. Such dosage forms can be prepared by any of the pharmacy methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powders, granules, optionally mixed with an excipient. The molded tablets can be prepared by molding in a convenient machine a mixture of the wet compound powder with an inert liquid diluent. Examples of excipients that may be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrators, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, and other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates , powdered tragacanth, guar gum, cellulose and its derivatives (ie, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), hydroxypropylmethyl cellulose, (ie Nos. 2208, 2906.2910), microcrystalline cellulose, and mixtures thereof. Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talcum, calcium carbonate (ie, granules or powders), microcrystalline cellulose, powdered cellulose, dextrates , kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the invention are typically present in from about 50 to about 99% by weight of the pharmaceutical composition or dosage form. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viseos division, Avicel Sales , Marcus Hook, PA), and mixtures thereof. In specific binder it is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Excipients or suitable anhydrous or low moisture additives include AVICEL.PH-103 ™ and Starch 1500 LM: Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. The. Tablets containing too many disintegrants may disintegrate in storage, while those containing too few may not disintegrate at a desired time or under desired conditions. Therefore, a sufficient amount of disintegrant, which is neither quite nor very undesirable to change the release of the active ingredients should be used to form the oral dosage forms of the invention. The amount of disintegrant used varies depending on the type of formulation, and is easily discernible by those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15% by weight of the disintegrant, specifically from about 1 to about 5% by weight of the disintegrant. Disintegrants that can be used in the compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato starch or tapioca, pregelatinized starch, other starches, clays, other algines, other celluloses, gums and mixtures thereof. Lubricants that may be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, acid stearic acid, sodium lauryl sulfate, talcum, hydrogenated vegetable oil (ie, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil) zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures of same. Additional lubricants include, for example, a siloid silica gel (AEROSIL 200, manufactured by WR Grace Co. of Baltimore, MD), a coagulated silica gel aerosol (labeled by Degusta Co. of Plano, TX), CAB-O -SIL (a pyrogenic silicon dioxide product marketed by Cabot Co. of Boston, MA), and mixtures thereof. If used all, the lubricants are typically used in an amount of less than about 1% by weight of the compositions or dosage forms in which they are incorporated. For oral administration, the compositions are preferably provided in the form of tablets containing from about 1 to about 1000 milligrams of the active ingredient. In another embodiment, the compositions are provided in the form of tablets containing approximately 1.0, approximately 5.0, approximately 10.0, approximately 15.0, approximately? > 20.0,, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, or about 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably one to two times per day. DOSAGE FORMS OF DELAYED RELEASE The active ingredients of the invention may be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in United States Patent No. 3, 845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595; 5,591,767; 5,120,548; 5,076,543; 5,639,476; 5,354,556, and 5,733,566, each of which are incorporated herein by reference. Such dosage forms can be used to provide a slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres. , or a combination thereof to provide the desired release profile in varied proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention therefore encompasses simple convenient unit dosage forms for administration such as, but not limited to, tablets, capsules, gel capsules, and lozenges that are adapted for controlled release. Controlled-release pharmaceuticals can improve therapy over the achievements of their uncontrolled counterparts. Ideally, the use of a controlled release preparation optimally designated in medical treatment is characterized by a minimum drug substance being used to cure or control the human condition in a minimum amount of time. Advantages of the controlled release formulations include increased drug activity, reduced dosing frequency, and increased patient compliance. In addition, controlled release formulations can be used to influence the onset time of action or other characteristics, such as drug levels in the blood, and can therefore affect the presence of side effects (ie, adverse) .

Most controlled release formulations are designed to initiate the release of a quantity of drug (active ingredient) that produces the desired therapeutic effect in a timely manner, and gradually and continuously release other amounts of medication to maintain this level of therapeutic or prophylactic effect for an increased period of time. To maintain this constant level of drug in the body, the drug must be released from a dosage form at a rate that allows the amount of drug metabolized and eliminated from the body to be replaced. The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological or compound conditions. PARENTERAL DOSAGE FORMS Parenteral dosage forms can be administered to patients by several routes including, but not limited to, subcutaneous, intravenous, (includes bolus injection), intramuscular, and intra-arterial. Because their administration typically avoids the natural defenses of patients against contaminants, sterile parenteral dosage forms are preferred or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready to be injected, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle to be injected, suspensions ready for injections, and emulsions. For example, sterile lyophilized compositions suitable for reconstitution in dosage forms free of particles suitable for administration to humans. Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: water for USP injection, aqueous vehicles, such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactate injection, Ringer; immiscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients described herein may also be incorporated within the parenteral dosage forms of the invention. Parenteral dosage forms are preferred for methods of preventing, treating or managing the disease in a patient with cancer. TRANSDERMAL AND TOPICAL DOSAGE FORMS Transdermal and topical dosage forms of the invention include, but are not limited to, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include "reservoir type" or "type matrix" patch, which can be applied to the skin and used for a specific period of time to allow the penetration of a desired amount of active ingredients. that is, carriers and diluents) and other materials that can be used to provide transdermal and topical dosage forms included by this invention are well known to those skilled in the pharmaceutical art, and depend on the particular tissue to which a pharmaceutical or pharmaceutical composition will be applied. a given dosage form.

With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butan-1,3-diol, isopropyl, myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, dyes, creams, emulsions , gels or ointments, which are not toxic and pharmaceutically acceptable. If desired, moisturizers or humectants can be added to pharmaceutical compositions and dosage forms. Examples of such additional ingredients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Pubblishing, Easton PA (1990). Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention. For example, penetration enhancers may be used to assist in the release of active ingredients into the tissue. Suitable penetration enhancers include, but are not limited to: acetone, various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulphoxides such as di-ethylsulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon degrees (povidone, polyvidone); urea; and several soluble and insoluble sugars esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate). The pH of a pharmaceutical composition or dosage form, or of the tissue to which a pharmaceutical composition or dosage form is applied, can also be adjusted to improve the release of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic amplitude, or tonicity can be adjusted to improve the release. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to improve the release. In this care, stearates can serve as a lipid vehicle for the formulation, as an emulsifying or surfactant agent, as a release-intensifying or penetrating-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. FORMS OF MUCOSAL DOSING AND PULMONARY RELEASE Mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, vaporizer and aerosols, or other forms known to one skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990), - and Introduction to Pharmaceutical Dosage Forms, 4th ed. , Read & Febiger, Philadelphia (1985). Suitable dosage forms can be formulated for the treatment of mucosal tissues within the oral cavity as in uages or as oral gels. In one embodiment, the aerosol comprises a carrier. In another embodiment, the aerosol is a free carrier. A compound of the invention can be administered directly to the lungs by inhalation (see e.g., TONG et al., PCT Application, W097 / 39745; Clark et al., PCT Application, W099 / 47196, which are incorporated herein by reference). An aryl sulfonamide compound can be conveniently released for administration by inhalation to the lungs by a number of different devices. For example, Metered Dose Inhaler ("MDI") using bottles containing a convenient low boiling propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas can be used to deliver an aryl sulfonamide compound directly to the lung. . MDI devices are suitable from a number of providers such as 3M Corporation, Aventis, Boehringer Inglehei, Forest Laboratories, Galxo-Wellcome, Shering Plow and Vectura.

Alternatively, a dry powder inhaler (DPI) device can be used to deliver an aryl sulfonamide compound to the lung (See, for example, Raleigh et al., Proc.Amer.Assoc.Cancer Research Annual Meeting, 1999,40,397, which is incorporated herein) by reference). DPI devices typically use a mechanism such as a gas explosion to create a cloud of dust inside the container, which can be inhaled by the patient. DPI devices are well known in the art and can be purchased from a number of vendors including, for example, Fisons, Galxo-Wellcome, Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. A popular variation is the multiple dosing system ("MDDPI"), which allows one of more than one therapeutic dose. MDDPI devices are available from companies such as AstraZeneca, GlaxoWellcome, IVAX, Shering Plow, SkyePhar and Vectura. For example, gelatin capsules and jars for use in an inhaler or insufflator can be formulated containing a powder mixture of a compound and a suitable powder base such as lactose or starch for these systems. Another type of device that can be used for the delivery of an aryl sulfonamide compound to the lung is a liquid vaporizer device supplied, for example by Aradigm Corporation. Liquid nebulizer systems: - '"". - ':'., -96- use extremely small hole injectors to spray formulations of liquid medications that can be inhaled directly into the lung. In a preferred embodiment, a nebulizer device is used to deliver an aryl sulfonamide compound to the lung. Nebulizers create aerosols of liquid drug formulations by using, for example, ultrasonic energy to form fine particles which can be rapidly inhaled (see, for example, Verschoyle et al., British J. Cancer, 1999, 80, -Suppl 2, 96 , which is incorporated herein by reference). Examples of nebulizers include devices supplied by Sheffield / Systemic Pulmonary Delivery Ltd. (see, Armer et al., U.S. Pat No. 5, 954, 047, van der Linden et al., US Pat. No. 5, 50, 619; van der Linden et al., US Pat. No. 5,970,974, which are incorporated herein by reference, Ayentis and Batelle Pulmonary Therapeutics A compound of the invention inhaled, released by nebulizing devices, is currently under investigation as a treatment for aerodigestive cancer (Engelke et al., Poster 342 and American Association of Cancer Research, San Francisco, Calif., Apr.1-5,2000) and lung cancer (Dahl et al. > -.:. Poster 524 and American Association of Cancer Research, San Francisco, Calif., April 1-5, 2000) In a particular preferred embodiment, an electrohydrodynamic aerosol device ("EHD") is used to deliver an aryl sulfonamide compound to the lung. EHD spray use electric power to spray solution liquid drug suspensions or suspensions (see, for example, Noakes et al., U.S. Pat. No. 4,765,539; Coffee, PCT Application, W094 / 12285; Coffee, PCT Application, W094 / 14543; Coffee, PCT Application, W095 / 26234, Coffee, PCT Application WO 95/26235, Coffee, PCT, Application, WO 95/32807 which are incorporated herein by reference). The electrochemical properties of the compound of the formulation of the invention can be important parameters to optimize when this drug is released to the lung with an EHD aerosol device and such optimization is routinely performed by one skilled in the art. EHD aerosol devices can release drugs more efficiently to the lung than existing lung release technologies. Other methods of intra-pulmonary release of an aryl sulfonamide compound will be known to the skilled artisan and are within the scope of the invention. Liquid dosage formulations suitable for use with nebulizers and liquid spray devices and the EHD aerosol devices will typically include an aryl sulfonamide compound with a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid such as alcohol, water, polyethylene glycol or perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of an aryl sulfonamide compound. Preferably, this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating solutions or suspensions of liquid drugs suitable for use in aerosol devices are known to those skilled in the art (see for example, Biesalski, U.S.Pat.No.5, 112, 598; Biesalkski, 5,556,611, which are incorporated here by reference). A compound of the invention can also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, an aryl sulfonamide compound can be formulated as a depot preparation. Such a formulation of prolonged activity can be administered by implantation (for example subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, an emulsion in an acceptable oil) or ion exchange resin, or as soluble, moderate derivatives, for example, a soluble, moderate salt. OTHER RELEASE SYSTEMS Alternatively, other pharmaceutical release systems can be used. Liposomes and emulsions are well known, examples of release vehicles can be used to release an aryl sulfonamide compound. Certain organic solvents such as dimethisulfoxide can also be used, although usually at the expense of greater toxicity. A compound of the invention can be released in a controlled release system. In one embodiment, a pump can be used (Sefton, CRC Crit Ref Biomed Eng., 1987, 14, 201, Buchwaid et al., Surgery, 1980, 88, 507, Saudek et al., N.Eng.J Med, 1989, 321 , 574). In another embodiment, polymeric materials may be used (see Medical Applications of Controlled Relay, Langer and Wise (eds), CRC Pres., Boca Raton, Fia. (1997), contolled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball. (eds), wiley, New Cork (1984), Ranger and Peppas, J Macromol, Sci.Rev, Macromol, Chem., 1983, 23.61, see also Levy et al., Science 19985, 228, 190; , Ann Neurol., 1989, 25, 351, Howard et al, 1989, J. Neurosurg, 71, 105). In yet another embodiment, a controlled release system can be placed in proximity to the objective of the compound of the invention, e.g. the lung, thus regulating only a fraction of the systematic dosage (see for example, Goodson, in Medical Applications of controlled Reléase, supra, vol.2, ppll5 (1984).) Another system of controlled release can be used (see for example Langer , Science, 1990, 299, 1527) Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide mucosal dosage forms contained in this invention are well known to those skilled in the pharmaceutical art, and depend on the particular site or method in which a given pharmaceutical composition or a dosage form will be administered With that fact in mind, characteristic excipients include, but are not limited to, water, ethanol, ethylene glycol, propylene glycol, butane-l-3-diol , isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, which are non-toxic and pharmaceutically acceptable. Additional ingredients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990). The pH of a pharmaceutical composition or dosage form, or the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve the release of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve the release. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously modify the hydrophilicity or lipophilicity of one or more active ingredients to thereby improve the release. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as an agent that increases release or increases penetration. Difnt salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the composition obtained. THERAPEUTIC USES OF ARIL SULFONAMIDE COMPOUNDS In one aspect, the invention provides methods for treating or preventing a condition or disorder associated with the modulation of hydroxysteroid dehydrogenases by administering to a patient having such a condition or disorder a therapeutically effective amount of a compound or composition. of the invention. In a group of modalities, conditions and disorders, including chronic diseases of humans and other species, can be treated with modulators, stimulators, or hydroxysteroid dehydrogenase inhibitors, such as 11 beta-HSDl. TREATMENT OR PREVENTION OF DIABETES Diabetes and diabetic conditions can be treated or prevented by the administration of a pharmaceutically effective amount of an aryl sulfonamide compound. Types of diabetes can be treated or prevented by administering a therapeutically effective amount of an aryl sulfonamide compound including diabetes mellitus type I (juvenile diabetes, insulin-dependent diabetes mellitus or IDDM), diabetes mellitus type II (non-insulin-dependent diabetes mellitus or NIDDM) ), insulinopathies, diabetes associated with pancreatic disorders, diabetes associated with other disorders (such as Cushing's syndrome, acromegaly, fecitinoma, glucagonoma, aldosteronis, and somatostatinoma), insulin resistance syndromes type A and B, lipatrophic diabetes, and diabetes induced by beta-cell toxins. In a preferred embodiment, the type of diabetes being treated is type II diabetes. TREATMENT OR PREVENTION OF OBESITY Obesity can be treated or prevented by administration of a therapeutically effective amount of an aryl sulfonamide compound. Obesity can have genetic, environmental determinants (for example, the expenditure of less energy consumed) and regulators. Obesity includes exogenous, hyperinsuline, hyperplastic, hypothyroid, hypothalamic, symptomatic, infantile, overweight, alimentary, hypogonodal, simple and central obesity, hipofiseal adiposity, and hyperphagia. Metabolic disorders, such as hyperlidemia and diabetes, and cardiovascular disorders, such as hypertension and coronary artery diseases, are generally associated with obesity. Complications due to obesity can also be treated or prevented by administration of a therapeutically effective amount of an aryl sulfonamide compound. Such complications include, but are not limited to, sleep apnea, Pickwickian syndrome, orthopedic disturbances of joints that support weight and not, and skin disorders causing an increase in sweat or skin secretions. TREATMENT OR PREVENTION OF OTHER CONDITIONS Other conditions that can be treated or prevented by administration of a therapeutically effective amount of an aryl sulfonamide compound include, but are not limited to, any condition that is sensitive to the modulation, preferably inhibition, of hydroxysteroid dehydrogenases or isoforms. specific to them, and. These conditions and disorders include, but are not limited to, metabolic disorders and factors related to cardiovascular risk such as syndrome X, polycystic ovary disease, eating disorders (e.g., anorexia, and bulimia), craniopharyngioma, Prader-Willi syndrome, Frohlich, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulemia and Cushing's syndrome; diseases associated with this, such as hypertension, atherosclerosis, vascular restenosis, retinopathy and neuropathy; neurological disorders such as, neurodegenerative disease, neuropathy and muscle loss; Cognitive disorders, such as learning disorders related to age; disorders related to androgen and / or estrogen such as prostate cancer, colon cancer, breast cancer, benign prostatic hyperplasia, ovarian cancer, cancer of the uterus, and pseudohemaphrodis or male, endometriosis, dementia, depression, psoriasis, glaucoma, osteoporosis , viral infections, inflammatory disorders, and immune disorders.

ADDITIONAL THERAPEUTIC AGENTS In one embodiment, the present methods of treating or preventing further comprise administering a therapeutically effective amount of another therapeutic agent useful for treating or preventing the diseases or disorders disclosed herein. In this embodiment, the time in which the therapeutic effect of another therapeutic agent acts overlaps with the time in which the therapeutic effect of the aryl sulfonamide compound acts. The compounds of the invention can be combined or used in combination with other agents in the treatment, prevention, suppression or amelioration of the conditions or disorders for which the compounds of the invention are useful, include diabetes, obesity, glaucoma, osteoporosis, disorders cognitive, immunological disorders, depression and those pathologies indicated above. Such other agents, or drugs, can be administered, by a dwarven route, generally used amount thereof, simultaneously, or sequentially with an aryl sulfonamide compound. When an aryl sulfonamide compound is used contemporaneously with one or more drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the invention include those which also contain one or more of the other active ingredients or therapeutic agents, in addition to an aryl sulfonamide compound. In one embodiment, for the treatment or prevention of diabetes, an aryl sulfonamide compound can be administered with another therapeutic agent, including, but not limited to, anti-diabetic agents such as insulin, inhaled insulin (Exubera®), insulin mimics, stimulator of insulin secretion, sulfonylureas (for example, glyburide, meglinatide, glimepiride, gliclazide, glipizide, gliquidone, chloropropresponthionamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepide, glibutiazole, glybuzole, glihexamide, glimidine, glipinamide, fenbutamide, tolcylamide and tolazamide), biguanides (for example, metformin (Glucophage®)), alpha-glucosidase inhibitors (ie, acarbose, voglibose and miglitol), thiazolidinone compounds (Actos®) and englitazone), glucose regulators (eg, repaglinide and nateglinide) and glucagon receptor antagonists. In another embodiment, for the treatment or prevention of obesity, an aryl sulfonamide compound can be administered with another therapeutic agent, including, but not limited to, beta3 adrenergic receptor agonists, leptin or derivatives thereof, neuropeptide Y antagonists (e.g. NPY5), and Mazindol. Examples of other therapeutic agents that can be combined with an aryl sulfonamide compound, whether administered separately or in the same pharmaceutical composition, include, but are not limited to: (i) cholesterol lowering agents such as HMG reductase inhibitors. CoA (for example, lovastatin, simvastatin (Zocor®), pravastatin, fluvastatin, atorvastin (Lipitor® and other statins), bile acid sequestrants (for example cholestyramine and colestipol), vitamin B3 (also known as nicotinic acid, or niacin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), fibric acid derivatives (ie, gemfibrozil, clofribate, fenofibrate and benzafibrate), probucol, nitroglycerin, and cholesterol absorption inhibitors (eg, beta-sitosterol and cholesterol inhibitors acylCoA acyltransferase (ACAT) such as melinamide), HMG-synthetase inhibitors CoA, squalene epoxidase inhibitors and squalene synthetase inhibitors; (ii) antithrombotic agents such as thrombolytic agents (e.g., streptokinase, alteplase, anistreplase and reteplase), heparin, hirudin and warfarin derivatives, beta-blockers (e.g., atenolol), beta-adrenergic agonists (e.g., isoproterenol) , angiotensin II antagonists, ACE inhibitors and vasodilators (for example sodium nitroprusside, nicardipine, hydrochloride, nitroglycerin and enalopridat), PPAR agonists, for example PPAR agonists -gamma and PPAR-delta; (iv) DP antagonists; (v) lubricants or emollients such as petrolatum and lanolin, keratolytic agents, vitamin D3 derivatives (eg, calcipotriene and calcipotriol (Dovonex®), PUVA, antralin (Drithrocreme®, etretinate (Tegison® and isotretinoin, - (vi)) of glaucoma such as clonergic agonists (e.g., pilocarpine and carbacol), clolinesterase inhibitors (e.g., physostigmine, neostigmine, demacariu, ecothiophate iodide and isofluorophoste), carbonic anhydrase inhibitors (e.g. acetazolamide, diclofenamide, methozolamide, etoczolamide and dorzolamide ), nonselective adrenergic agonists (eg epinephrine, and dipivefrin) alpha2-selective adrenergic agonists (eg apraclonidine and bridgitine), beta-blockers (eg timolol, betazolol, levubunolol, carteolol, and metipranolol), prostaglandin analogues (eg example latanoprost) and osmotic diuretics (eg glycerin, mannitol, isosorbide), - corticosteroids, such as beclo metasone, methylprednisolone, betamethasone, prednisone, prenisolone, dexamethasone, fluticasone and hydrocortisone, and analogous corticosteroids such as budesonide; (vii) immunosuppressants such as cyclosporine (cyclosporin A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), - rapamycin (sirolimus, Rapamune®) and other immunosuppressants of the type FK-506, Prograf®, and mycophenolate, e.g. mycophenolate mofetil (CelCept ®); (viii) non-spheroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (e.g. alminoprofen, benozaprofen, bucloxicoi carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprosin, pirprofen , pranoprofen, suprofeno, tiaprofenico acid, and thioxaprofenj, acetic acid derivatives (for example . indomethacin, acemetacin, alcofenac, clidanac, diclofenac, fenclofenac, fencloric acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidometacin and zomepirac), derivatives of fenamic acid (for example) flufenamic acid, meclofenamic acid, niflumic acid, tolfenamic acid), biphenyl carboxylic acid derivatives (for example diflunisal and flufenisal), oxicams (for example isoxieam, piroxicam, sudoxicam, and tenoxicam,), salicylates (for example acetylsalicylic acid and sulfasalazine) and the pyrazolones (for example, apazone, bezpiperilon, feprazone, mofebutazone, oxifenbutazone, and phenylbutazone); (ix) cyclooxygenase inhibitors -2 (COX-2) such as celecoxib (Celebrex ®) and rofecoxib (Vioxx ®); (xi) phosphodiesterase type IV (PDE-IV) inhibitors, - (xii) opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, deoxid, nalbuphine, and pentazoxine; (xiii) a hepatoprotective agent; and (xiv) other compounds such as 5-aminosalicylic acid and medicaments thereof. The average weight of the compound of the invention for the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example when an aryl sulfonamide compound is combined with an NSAID, the average weight of the compound of the invention for the NSAID will generally vary from about 1000: 1 to about 1: 1000, preferably about 200: 1 to about 1: 200. Combinations of an aryl sulfonamide compound and other active ingredients will generally also be within the aforementioned range, but in each case an effective dose of each active ingredient should be used. EQUIPMENT The invention encompasses kits that can simplify the administration to a patient of the aryl sulfonamide compounds or compositions of the invention.

A typical equipment of the invention comprises a unit dosage of an aryl sulfonamide compound. In one embodiment, the unit dosage form is in a container, which may be sterile, containing a therapeutically effective amount of an aryl sulfonamide compound and a pharmaceutically acceptable carrier. In another embodiment, the unit dosage form is in a container containing a therapeutically effective amount of an aryl sulfonamide compound as a lyophilate or pharmaceutically acceptable salt. In this case, the equipment may further comprise another container containing a solution useful for the reconstitution of the lyophilate or dissolution of the salt. The equipment may also include a label or printed instructions for the use of the aryl sulfonamide compounds. In a further embodiment, the kit comprises a unit dosage form of a composition of the invention. The kits of the invention may further comprise one or more devices that are useful for the administration of unit dosage forms of aryl sulfonamide compounds or a composition of the invention. Examples of such devices include, but are not limited to, a syringe, a drip bag, a patch or an enema that optionally contain unit dosage forms. The present invention is not limited in scope by specific embodiments described in the examples, which are intended to illustrate some aspects of the invention and any modality that is functionally equivalent is within the scope of this invention. Indeed, several modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to fall within the scope of the attached claims. For this purpose, it should be noted that one or more hydrogen atoms or methyl groups can be omitted from the drawn structures compatible with the accepted type notation of such organic compounds, and that one skilled in the art of organic chemistry would readily appreciate their presence. EXAMPLES The aryl sulfonamide compounds represented by the formulas of the present invention and the methods of preparation thereof are explained in detail in the following examples, which are not presented as limiting. Example 1. Preparation of 1,1,1-trifluoro-2-4- 2- (R) -methyl-4- (l-pyridin-4-yl-cyclopropylmethyl) piperazine-l-sulfonyl phenyl-2-propanol (1) Stage a. Ethyl ester of l-pyridin-4-yl-cyclopropanecarboxylic acid. A 500 ml flask was charged with 2.5 g of ethyl 4-pyridiacetate (15.15 mmol, 1.0 equiv), 45 ml of THF and 45 ml of DMF, followed by the addition of 1.8 g of sodium hydride (75.0 mmol, 5.0 equiv. ). The resulting suspension was stirred at room temperature for 15 min, and then 2 ml of 1,2-dibromoethane (46.38 mmol, 3 equiv) was introduced via an addition funnel. After stirring for another 2 hours, the solution was diluted with saturated NaHCO 3, extracted (2 x 10% MeOH / CH 2 Cl 2, washed (1 x brine), dried (Na 2 SO) and concentrated under reduced pressure to obtain the product. Purification of the residue by flash chromatography (SiOs, 5% MeOH / CH2CL2) gives the product as a yellow liquid (2.2 g, 12.15 mmol) Step b (l-pyridin-4-yl-cyclopropyl) ethanol. of 100 ml containing 165 mg of l-pyridin-4-yl-cyclopropanecarboxylic acid ethyl ester (1.0 mmol, 1.0 equiv) and 10 ml of THF, 3.0 ml of 1.0 M DIBAL-H in toluene was carefully added. The reaction was stirred for 1 hour and diluted with 5 ml of 1 N HCl. The solution was then extracted (2 x MeOH / CH2Cl), washed (Ix brine), dried (NaSO4) and concentrated under reduced pressure. purification by flash chromatography (Si02, 10MeOH / CH2CL2) gives the product as a white solid (80 mg, 0.54 mmol) Step c. 1-chloromethylcyclopropyl) pyridine. To a 250ml flask containing 333 mg of l-pyridin-4-cyclopropylmethanol 2.23mmol, 1.0 equiv) and 10 ml CH2C12 under nitrogen atmosphere was added 0.18ml of thionyl chloride (2.46mmol, 1.1 equiv). After stirring for 2 h, the solution was concentrated under reduced pressure to provide the product as a white solid which is sufficiently pure to continue with the next step. Stage d. (R) -3-methyl-l- (l-pyridin-4-yl-cyclopropylmethyl) piperazine. A 250 ml flask was charged with 250 mg of (R) - (-) - 2-methylpiperazine (10Ommol, 2.5 equiv), 334 mg of 4- (1-chloromethylcyclopropyl) pyridine (2.0mmol, 1.0 equiv) and 15 ml of acetonitrile. The flask was equipped with a reflux condenser, and then placed in a preheated bath at 100 ° C. After stirring for 24 h, the solution was diluted with saturated NaHCO 3, extracted (2x 10% MeOH / CH 2 Cl 2), washed (lx brine), dried (Na2SO4) and concentrated under reduced pressure to give the product as a yellow liquid. Stage e. (R) -l- 4- 2-methyl-4- (l-pyridin-4-yl-cyclopropylmethyl) piperazine-l-sulfonyl-phenyl ethanone. A part of the product obtained above was combined in a flask (462 mg, 2.0 mmol, 1.0 equiv) in 10 ml of CH2C12 with 436 mg of 4-acetylbenzenesulfonyl chloride (1.0 mmol, 1.0 equiv) and 0.34 ml of triethylamine (2.0 mmol, 1.2 equiv). The solution was stirred for 2 h, followed by a dilution with 50 ml of CH2C12. The resulting solution was washed (lx brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 5% MeOH / CH2CL2) gives the product as a yellow liquid. , Stage f. alcohol 1, 1, l-trifluoro-2-4- (R) -methyl-4- (l-pyridin-4-yl-cyclo-pyrmethylpiperazine-l-sulfonyl-2-propanol (1). To a 100-ml flask It contains 413 mg of (R) -1- 4- 2-methyl-4- (l-pyridin-4-yl-cyclopropylmethyl) -piperazine-1-sulfonyl-phenyl ethanone (l.Ommol, l.Oequiv) and 5 ml of 0.5 M TMS-CF3, 1 ml of 1.0 M -lß-tetrabutylammonium fluoride in THF was added at 0 ° C. After stirring for 2 h the solution was diluted with saturated NaHCO 3, extracted (2x 10% MeOH / CH 2 Cl 2), washed (Brine Ix), dried (Na2SO) and concentrated under reduced pressure Purification by flash chromatography (Si02, 5% MeOH / CHCl2) gives the product as a yellow liquid (0.3g, 0.2mmol). XHNMR (DMSO, 400MHz) 8.38 (d, J5.58HZ, 2H), 7.84 (s, 4H), 7.26 (d, J = 5.58Hz, 2H), 6.86 (s, lH), 3.94 (m, lH) , 3.51 (d, J = 12.80Hz, ÍH), 2.97 (m.lH), 2.81 (m, lH), 2.70 (d, J = ll .21Hz, lH), 2.61 (d, J = 12.90HZ, ÍH) ), 2.41 (d, J = 12.90Hz, lH), 1.94 (m, lH), 1.83 (, 1H), 1.73 (s, 3H), 0.99 (m, 4H), 0.83 (d, J = 7.12Hz, 3 H). Example 2. Preparation of alcohol 1,1,1-trifluoro-2-4- (R) -methyl-4- (l-pyridin-3-yl-cyclopropylmethyl) piperazin-1-sulfonyl phenyl-2-propanol (2) . 2 Using the methods described above in example 1, and substituting ethyl 4-pyridylacetate with ethyl 4-pyridylacetate in step a, compound 2 is prepared. NMR (CDC 13,400 MHz) delta 8.30 (d, J = .03Hz, 1H), 8.27 (s, lH), 7.60 (s, 4H), 7.20 (dd, J = 7.84, 4.03 Hz, 1H) 6.86 (s, 1H), 4.00 (, 1H), 3.59 (, 1H) 3.13 (t, J) = 12.26 Hz, 1H) 2.65 (d, J = 12.46 Hz, 2H), 2.53 (d, J = 12.46 Hz, 2H), 2.13 (, lH), 2.02 (m, lH), 1.81 (s, 3H), 1.01 (d, J = 6.65 Hz, 3H), 0.88 (m, 4H). Example 3.Preparation of 1,1, 1-trifluoro-2-. { 4- [4- (l- pyridin-4-yl-cyclopropylmethyl) piperazin-1-sulfonyl] phenyl} 2-propanol (3) Using the same methods as in Example 1 and substituting piperazine for (R) -2-methyl piperazine in the step of, compound 3 was prepared. 1 H NMR (DMSO, 400 MHz) delta 8.34 (d, J = 4.85 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 4.85 Hz 2H), 2.82 (m, 4H), 2.52 (, 6H) , 1.73 (s, 3H), 0.94 (, 2H) 0.84 (, 2H). Example 4. Preparation of 1,1,1, 3,3,3-hexafluoro-2. { 4- [2- (R) -methyl-4- (1-pyridin-4-yl] cyclopropylmethyl) piperazine-1-sulfonyl} 2- propanol (4) Stage a. 4- (1,1,1,3,3,3, hexafluoropropan-2-ol-2-yl) benzenesulfonyl chloride. For a mixture of 4- (hexafluoro-2-hydroxylisopropyl) aniline (15.0 grams 58mmol), HCl (37% in water, 30 ml.) And CH3 COOH (9 ml.) At -15 ° C, a solution was added dropwise NaN02 (4.4g, 64 mmol) in H20 (5ml.) The internal reaction temperature was maintained at < -5 ° C while stirring for approximately 45 min. Sulfur dioxide was introduced into a canister flask in CH3COOH (30 ml) with a pipette for 15 min until saturation of the solution. CuCl (1.43g, 14.5 mmol) was added to the solution at room temperature. While stirring was continued, S02 was introduced for 20 min to form a S02-CuCl complex. At 0 ° C, the mixture of the diazotization reaction in fractions was added to the solution of the S02-CuCl complex. When the addition was complete, stirring was continued for 10 min while the temperature was kept below 10 ° C. The reaction mixture was poured into a 1: 1 mixture of H20-ice (500 ml), and stirring was continued until the ice melted. The mixture was then extracted with Et20 (3 x 100 ml), the combined organic extracts were washed with H20 (2x 100 ml), saturated aqueous NaHCO3, (care, vigorous gas evolution), and brine, dried and concentrated under pressure reduced. Flash chromatography of the residue, (SiO2, 100% CH2Cl), gave the intermediate compound 4- (1,1,1,3,3,3-hexafluoropropan-2-yl-2-yl) benzenesulfonyl chloride (11.42g). 1H NMR (CDC13) delta 8.17 (d, J = 8.8Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 3.90 (s, 1H), MS 341.2 (M-H). Stage b. Using the same methods as in Example 1, and substituting 4- (1,1, 1,3, 3,3-hexafluoropropan-2-ol-2-yl) benzenesulfonyl chloride for 4-acetylbenzenesulfonyl chloride in step e of Example 1, 1, 1,1, 3, 3, 3-hexafluoro-2- was prepared. { 4- [2- (R) -methyl-4- (1-pyridin-4-yl-cyclopropylmethyl) piperazin-1-sulfonyl] phenyl} -propan-2-ol (4). x H NMR (CDCl3, 500 MHz) delta 8.33 (d, J = 4.00 Hz, 2H), 7.97 (d, J = 6.4 Hz, 2H), 7.83 (d, J = 6.4 Hz, 2H), 7.24 (d, J = 4.00 Hz, 2H), 4.05 (m, lH), 3.68 (m, 1H), 3.10-2.10 (m, 7H), 1.05 (m, 2H), 0.87 (m, 2H), 0.76 (d, J = 5.2Hz, 3H). Example 5. Preparation of 1,1,1,3,3,3-hexafluoro-2-. { 4- [2- (R ) -methyl-4- (l-pyridin-3-IL-methylcyclopropylmethyl) piperazin-1-sulfonyl] phenyl} propan-2-ol (5) Stage a. monoethyl ether of 2-pyridin-3-yl-methylmalonic acid. A stirred solution of 2.72 ml of diisopropylamine (19.55 mmol, 2.3 eguiv) in THF under N atmosphere was cooled to -10 ° C and treated with 7.5 ml of -BuLi in hexane. After 10 min, the mixture was cooled to -78 ° C and 3-pyridin-3-yl-propionic acid ethyl ester (1.4 g, 8.5 mmol, 1.0 equiv) was added. After stirring for an additional 20 min at -78 ° C, the reaction mixture was treated with CO 2 gas for 10 min, and then quenched with 30 ml of 3N HCl. The resulting mixture was warmed to room temperature and neutralized with saturated aqueous NaHCO3. The solution was extracted with 20% MeOH / CHCl2, dried (Na2SO) and concentrated under reduced pressure to provide the product as a white solid. Stage b. 2-pyridin-3-yl-methylacrylic acid ethyl ester. The monoethyl ester of 2-pyridin-3-yl-methylmalonic acid (8.5mmol, 1.0 equiv) was combined in a flask with 73 mg of piperazine (0.85 mmol, 0.1 equiv), 255mg of paraformaldehyde (8.5mmol, l.Oequiv) and 15 ml of pyridine. The mixture was refluxed for 2 h, cooled to room temperature and then diluted with saturated NAHC03. The solution was extracted (2x 10% MeOH / CH2Cl), diluted (Ix brine), dried (Na2SO), concentrated under reduced pressure to provide 0.92 g of the product as a white solid (4.82 mmol). Stage c. Ethyl ester of l-pyridin-3-ylmethylcyclopropanecarboxylic acid. To a 250 ml flask containing 720 mg of the 2- [1-iridin-3-ylmethylacrylic acid monsetyl ester (4.07 mmol, 1.0 equiv) and 25 ml of CH2C12 under an Nitrogen atmosphere was added a solution of diazomethane (16.60 mmol, 4.08 equiv) in ether. After stirring for 24 h it was quenched with acetic acid and then saturated aqueous NaHCO 3, and then extracted with 10% MeOH / CH 2 Cl 2. The extracts were dried (Na2SO) and concentrated under reduced pressure to provide the product. Purification by flash chromatography (Si02, 5% MeOH / CH2 Cl2) gave 380 mg of the ethyl ester of l-pyridin-3-yl-methylcyclopropanecarboxylic acid as a white solid (1.85mmol). Stage d. l, l, l, 3,3,3-hexafluoro-2- 4- (r) -methyl-4- (l-pyridin-3-yl-methylcyclopropylmethyl) piperazine-l-sulfonyl phenyl-2-propanol (5) . Following the steps be, d and e as provided for Example 1, and substituting l-pyridin-3-yl-methylcyclopropanecarboxylic acid ethyl ester for 1-pyridin-4-yl-cyclopropanecarboxylic acid ethyl ester in step b and chloride of 4- (1,1,1,3,3,3-hexafluoropropan-2-yl-2-yl) benzenesulfonyl by 4-acetylbenzenesulfonyl chloride in step e, compound 5 was prepared. 1HNMR (CDC13, 400HZ) 8.37 ( m, 2H), 7.96 (d, J = 8.0Hz, 2H), 7.89 (d, J = 8.0Hz, 2H), 7.72 (d, J = 7.8Hz, 1H), 7.28 (m, lH), 4.16 ( m, ÍH), 3.72 (, 1H), 3.26 (m, ÍH), 2.73 (m, 3H), 2.47 (m, lH), 2.20- 1.50 (d, J = 6.5Hz, 3H), 1.20 (d, J = 6.5Hz, 3H), 0.59 (m, 2H), 0.37 (, 2H). Example 6. Preparation of 2- (4- 4- [1- (6-chloro-pyridin-3-yl) cyclopropylmethyl] -2- (R) -methyl-piperazine-1-sulfonyl phenyl) -1,1,1 -trifluoro-2-propanol (6) Stage a. 1- (6-chloro-pyridin-3-yl) cyclopropanecarbamide. 1.52 g of Dess-Martin periodinane (3.6mmol, 1.2 equiv) were added to a solution of 549mg 1- (6-chloro-pyridin-3-yl) cyclopropyl methanol (3. Ommol, 1.0 equiv) in 30 ml of THF. After stirring for 3 h, the solution was diluted with saturated NaHCO 3, extracted (2x 10% MeOH / CH 2 Cl 2), washed (1 x brine), dried (Na 2 SO) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 5% MeOH / CH2Cl2) gave the product as a yellow solid (0.5 g, 2.75 mmol). Stage b. (R) -1- 1- (6-Chloro-pyridin-3-yl) cyclopropylmethyl-3-methylpiperazine. To a 250 ml flask containing 1.38 g of (R) - (-) - 2-methylpiperazine (13.81 mmol, 5.0 equiv) and 500 mg l- (6-chloro-pyridin-3-yl) cyclopropanecarbaldehyde (2.76 mmol, 1.0 equiv) in 40 ml of 1,2-dichloroethane was added 1.17 g of NaBH (OAc) 3 (5.52 mmol, 2 equiv). After stirring for 24 h, the solution was diluted with saturated NaHCO 3, extracted (2 x 10% MeOH / CH 2 Cl 2), washed (1 x brine), dried (Na 2 SO) and concentrated under reduced pressure to provide a clear liquid. color that can be used directly in the next step. Stage c. Alcohol 2- (4- 4- l- (6-chloro-pyridin-3-yl) cyclopropylmethyl-2- (R) -methyl-piperazin-1-sulfonyl-phenyl-1,1,1-trifluoro-2-propanol (6) Using steps e and f of Example 1, and substituting (R) -1- 1- (6-chloro-pyridin-3-yl) cyclopropylmethyl) piperazine is step e, compound 6 was prepared. XE NMR (CDC13, 500 MHz ) 8.23 (d, J = 2.50Hz, 1H), 7.81 (d, J = 8.50HZ, 2H), 7.75 (d, J = 8.50Hz, 2H), 7.52 (dd, J = 9.0, 2.5 Hz, ÍH) , 7.22 (d, J = .0Hz, ÍH), 4.10 (m, 1H), 3.65 (m, ÍH), 3.10 (, 1H), 2.94 (d, J = 5.0Hz, 1H), 2.78 (m, ÍH) ), 2.60 (m, 2H), 2.45 (m, 1H), 2.15 (m, 1H), 2.10 (m, ÍH), 1.83 (s, 3H), 0.99 (d, J = 6.50Hz, 3H), 0.91 (m, 2 H), 0.77 (, 2H). Example 7.Preparation of 1,1,1, 1-trifluoro-2-. { 4- (1-hydroxymethyl-1-yl-cyclopropylmethyl] -2- (R) -methylpiperazin-1-sulfonyl] phenyl}. 2-propanol (7).

TBSCI Step to 1- (tert-butyldimethylsilanyloxymethyl) cyclopropyl methanol. Tert-butyldimethylsilyl chloride (4.5 g, 30.0 mmol, 1.0 equiv) was added to a suspension of 3 g of 1,1-bis (hydroxymethyl) cyclopropane (30.0 mmol, 1.0 equiv) and 4.08 g of imidazole (60 mmol, 2 equiv) in THF at 0 ° C. The mixture was stirred at 0aC for 30 min, and water was added. The resulting solution was extracted with CH2Cl, washed (Ix brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 5% MeOH / CH2Cl2) gave the product as a colorless liquid (2.2 g, 10.65 mmol). Stage b. Cyclopropylmethyl ester of 1- (tert-butyldimethylsilanyloxymethyl) methanesulfonic acid. Methanesulfonyl chloride (0.92 ml, 2. Ommol, 1.2 equiv) was added to a solution of 2.16 g l- (tert-butyldimethylsilanyloxymethyl) cyclopropyl methanol (10.0 mmol., 1.0 equiv) and 2.5 ml of triethylamine (20 mmol, 2 equiv) in 20 ml of CH2C12 at 0 = C. The mixture was stirred at 02C for 30 min, and water was added. The resulting solution was extracted with CHC12, washed (1 x brine), dried (Na2SO) and concentrated under reduced pressure to provide the product as a colorless liquid which can be used in the next step. , Stage c. 1- (tert-Butyldimethylsilanyloxymethyl) cyclopropylmethyl -3- (R) -methylpiperazine. The cyclopropylmethyl ester of 1- (tert-butyldimethylsilanyloxymethyl) methane sulfonic acid (1.5g, S.molm, 1.0 equiv) was combined in a sealed tube with 1.28 g of (R) -2-methylpiperazine (12.76mmol, 2.5 equiv). The mixture was heated at 130 aC for 24 h, cooled to room temperature and diluted with saturated NaHCO 3. The solution was extracted (2 x 10% MeOH / CH2Cl2), washed (1 x brine), dried (Na2SO4) and concentrated under reduced pressure to provide a liquid that can be used in the next step. Stage d. 1, 1, 1-trifluoro-2- 4- (1-hydroxymethyl-1-yl-cyclopropylmethyl-2- (R) -methylpiperazine-1-sulfonyl-phenyl-2-propanol (7) Using steps e and f of Example 1, and substituting (R) -l- 1- (tert-butyldimethylsilanyloxymethyl) cycloprphenyl ethyl-3-methylpiperazine by (R) -3-methyl-1- (1-pyridin-4-yl-cyclopropylmethyl) piperazine in step e, prepared compound 7. ^? NMR (CDC13, 500 MHz) delta 7. 84 (d, J = 8.50 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 4.85 (brs, 1H), 4.16 (m, ÍH), 3.64 (m, 2H), 3.43 (d, J = 8.50Hz, 1H), 3.25 (m, ÍH), 3.12 (d, J = 10.5Hz, ÍH), 2.85 (, 2H), 2.40 (m, 2H), 2.20 (m, 1H), 2.10 (m, 1H), 1.82 (s, 3H), 1.16 (d, J = 7.00Hz, 3H), 0.56 (m, 2H), 0.3 (m, 2H). Example 8.Preparation of 1, 1, 1-trif luoro-2-. { 4- [4- (1-imidazol-1-yl-cyclopropylmethyl) -2- (R) -methylpiperazin-1-sulfonyl] phenyl} 2-propanol (8) s Using steps b and c in Example 7, and substituting 1,1, 1-trifluoro-2-. { 4- [4- (1-hydroxymethylcyclopropylmethyl) -2- (R) -methylpiperazin-1-sulfonyl] phenyl} 2-propanol by [1-tert-butyldi-ethylsilanyloxymethyl) cyclopropyl] ethanol in the step be imidazole by (R) -2-methylpiperazine in step c, compound 8.x? I NMR (CDC13, 400 MHz) delta 7.83 ( , 4H), 7.44 (brs, ÍH), 7.00 (brs, 1H), 6.94 (brs, 1H), 4.14 (m, ÍH), 3.82 (m, 2H), 3.77 (d, J = 11.60Hz, 1H) , 2.28 (m, 1H), 2.76 (d, J = 10.50Hz, ÍH), 2.64 (d, J = 10.50 Hz, ÍH), 2.20-1.80 (m, 4H), 1.83 (s, 3H), 1.25 ( d, J = 6.40Hz, 3H), 0.64 (m, 2H), 0.45 (m, 2H). Example 9. Preparation of 1,1,1-trifluoro-2-. { 4- [2- (R) -methyl-4- (l-pyridin-4-yl-cyclopentylmethyl) piperazine-l-sulfonyl] phenyl} -2propanol (9) 9 Using steps a and b in Example 1, and substituting 1,4-dibromobutane for 1,2-dibromoethane in step a, and then steps b and c in Example 7, and substituting (l-pyridin-4-yl-cyclopentyl) ethanol by [1-tert-butyldimethylsilanyloxymethyl) cyclopropyl] methanol in step b, followed by steps e and f in Example 1, and substituting (R) -3-methyl-1- (l-pyridin-4-yl-cyclopentyl ethyl) ) piperazine by (R) -3-methyl-1- (1-pyridin-4-yl-cyclopropylmethyl) piprazine in step e, compound 9 was prepared. R NMR (DMS0, 400 MHz) delta 8.46 (d, J = 5.60 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 5.60 Hz, 2H), 3.92 (m, ÍH), 3.80-3.30 (m, 2H), 3.05 (, ÍH), 2.40 (s, 2H), 2.30-1.60 (, HH), 1.79 (s, 3H), 1.03 (d, J = 6.50 Hz, 3H). Example 10. Preparation of 2- (1 -. {3-methyl-4- [4- (2, 2, 2-trifluoro-1-hydroxy-1-methylethyl) benzenesulfonyl] -2- (1-). 3- (R ) -methylpiperazin-1-yl-methyl} cyclopropyl) acetamide (10) Step a (1-hydroxymethylcyclopropyl) acetonitrile. In a flask was combined 5, 7-dioxa-spiro 2.5 octan-6-one (1.48 g, 10. Ommol, 1.0 equiv) with 3.12 g of tetraethylammonium cyanide (20.0 mmol, 2.0 equiv) in 30 ml of DMF. The mixture was heated at 70 aC for 24 h, cooled to room temperature and diluted with saturated NaHCO 3. The solution was extracted (2 x 10% MeOH / CH2Cl2), washed (Ix brine), dried (Na2SO4) and concentrated under reduced pressure to give 360 mg of the product as a colorless residue which can be used in the next step. Following steps c, d, e and f of Example 1, and substituting (1-hydroxymethylcyclopropyl) acetonitrile for (l-pyridin-4-yl-cyclopropyl) methanol in step c, (1- 3- (R) -methyl was prepared -4- 4-2, 2, 2-trifluoro-l-hydroxy-1-methylethyl) benzenesulfonyl piperin-1-yl-methylcyclopropyl) acetonitrile. 2- (l- -3-Methyl-4- (2,2,2-trifluoro-l-hydroxy-l-methylethyl) -benzenesulfonyl-2- (l- 3- (R) -methylpiperazin-1-yl-ethyl) cyclopropyl) acetamide (10) 300 mg of potassium hydroxide (5.36 mmol, 30 equiv) was added to a solution of 80 mg of (1- 3- (R) -methyl-4- 4- (2, 2, 2 -trifluoro-1-hydroxy-1-methylethyl) -benzenesulfonyl-piperin-1-yl-methyl-cyclopropyl) acetonitrile (O.ldmmol, equiv) in 5 ml of ter-BuOH The mixture was heated to 100 SC for 2 hours. hy was quenched with water, the resulting solution was extracted with 15% MeOH / CH2Cl2), washed (1 x brine), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 5% MeOH / CH2C12) gave 30 mg of compound 10 as a white solid. 1H NMR- (DMSO, 400MHZ) 7.84 (s, 4H), 7.05 (s, lH), 6.90 (s, ÍH), 6.63 (s, 1H), 3.98 (m, 1H), 3.56 (m, 1H), 3.20 (m, lH), 2.80 (d, J = 11.20Hz, 1H), 2.63 (d, J = 11.20 HZ, lH), 2.10-1.80 (m, 6H),. 1.78 (s, 3H), 1.10 (d, J = 6.70Hz, 3H), '0.42 (, H), 0.20 (m, 2H) Example 11. Preparation of 1,1, 1-trifluoro-2-. { 4- [- (1-pyridin-4-yl-cyclobutylmethyl) piperazin-1-sulfonyl] phenyl} - 2propanol (11). eleven Stage a. ethyl ester of l-pyridin-4-yl-cyclobutanecarboxylic acid. A 250 ml flask was charged with 3.30 g of pyridin-4-yl-acetic acid ethyl ester (20. Ommol, 1.0 equiv), 30 ml of THF and 30 ml of DMF, then 2.4 g of NaH (100.0 g) was added. mmol, 5 eguiv) followed slowly by 6.04 g of 1,3-dibromo-propane (30 Ommol, 1.5 equiv). The resulting suspension was stirred for 2 h, then it was diluted (water) and extracted (3 x 10% MeOH / CH 2 Cl 2). The organics were washed (2 x water), dried (MgSO), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, CH2C12, 2% MeOH / CH2Cl2) gave the product as an oil to arillo (2.0 g, 9.74 mmol) Step b (l-pyridin-4-yl-cyclobutyl) -methanol. The 250 ml bottle was loaded with the product obtained above (2.0 g, 9.7 mmol, 1.0 equiv) and 10 ml of THF. 30 ml of DIBAL-H (1. Oml n hexanes, 30 mmol, 3.0 equiv) was added to the vial. The resulting solution was stirred for 2 h and then diluted with saturated NaHCO 3 and extracted (4 x 10% MeOH / CH 2 Cl 2). The organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 3% MeOH / CH2Cl2) gave the product as a yellow oil (0.78 g, 4.8 mmol). Stage c. L-pyridin-4-yl-cyclobutylmethyl ester of methanesulfonic acid. A portion of the product obtained above (750 mg, 4.6 mmol, 1.0 equiv) in 50 ml of CH 2 Cl 2 was combined in a flask with 700 mg of triethylamine (6.9 ramol, 1.5 equiv), and 580 mg of methanesulfonic acid chloride (5.1 mmol). , 1.1 equiv.). The solution was stirred for half an hour then diluted with saturated NaHCO 3, and extracted (3 x 10% MeOH / CH 2 Cl 2). The organics were dried (MgSO), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 4% MeOH / CH2Cl2) gave the product as a yellow oil (0.92 g, 3.8 mmol). Stage d. 1- (1-pyridin-4-yl-cyclobutylmethylpiperazine) A portion of the product obtained above (200 mg, 0.83 mmol, 0.1 equiv.) Was combined in a pressure tube with 500 mg of piperazine. in a bath preheated to 100 ° C. After stirring for 4 h, the mixture was diluted with 50 ml CH2C12 and saturated NaHCO3, extracted with (3 x 10% MeOH / CH2Cl2) The organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 4% MeOH / CH2Cl2, 8% MeOH / CH2Cl2 with 1% NH40H) gave the compound as a yellow oil ~ (16Omg, 0.69 mmol) Step D. 1-4-4 - (l- pyridin-4-yl-skybutylmethyl) -piperazin-1-sulfonyl-phenyl ethanone The product obtained above (160 mg, 0.69 mmol, 1.0 equiv) in 5 ml of CH 2 Cl 2 was combined in a flask with 152 mg of 4-acetylbenzenesulfonyl chloride (0.69 mmol, 1.0 equiv) and 142 mg of triethylamine (1.40 mmol, 2.0 equiv.) The solution was stirred by h, followed by a dilution with 20 m. l of CH2C12 and saturated NaHCO3. The aqueous solution was extracted (2 x-1% MeOH / CH 2 / Cl 2). The organics were dried (MgSO) and concentrated under reduced pressure. Purification by flash chromatography (Si0, 5% Me0H / CH2CL2) gives the product as a white solid. Stage e. 1,1, 1-trifluoro-2- 4- (l-pyridin-4-yl-cyclobutylmethyl) -piperazin-1-sulfonyl phenyl-2-propanol (11). The product obtained above (210 mg, 0.51 mmol, 1.0 equiv) with 4 ml TMS-CF3 (0.5 M in THF) was charged in a 100 ml flask. The solution was stirred for 1 h, 4 ml of tetrabutylammonium fluoride (1.0 in THF) was added. After stirring for 1 h, the solution was diluted with saturated NaHCO 3, extracted (2x 10% MeOH / CH 2 Cl 2). The organics were dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 2.5% MeOH / CH2Cl2) gave compound 11 as a white solid (140 mg, 0.29 mmol). x? í NMR (DMSO, 400 MHz) delta 8.383 (d, J = 6.00Hz, 2H), 7.85 (d, J = 8.40HZ, 2H), 7.72 (d, J = 8.50Hz, 2H), 7.13 (d , J = 6.1 Hz, 2H), 2.72 (s, 4H), 2.66 (s, 2H), 2.23 (t, J = 4.7Hz, 4H), 2.14 (m, 4H), 1.92 (m, 1H), 1.74 (m, 4H). Example 12.Preparation of 1,1,1-trifluoro-2- (R) -2-methyl-4- (l-pyridin-3-yl-cyclobutylmethyl) piperazine-l-sulfonyl-phenyl-2-propanol (12) 12 Using the methods described in Example 10, and substituting the ethyl ester of 1-pyridin-3-yl-cyclobutanecarboxylic acid for 1-pyridin-4-yl-cyclobutanecarboxylic acid ethyl ester in step a and substituting (R) -2 -methylpiperazine by piperazine in step d, compound 12. "R (CDC13, 400MHz) delta 8.36 (d, 2H), 7.754 (m, 4 H), 7.54 (m, 1H), 7.32 (m, lH), 3.92 (m, lH), 3.45 (m, ÍH), 3.02 (t, J = 12.31, 1H), 2.71 (s, 2H), 2.31-2.17 (m, 7H), 2.05 (m, 2H) , 1.87 (m, ÍH), 1.82 (s, 3H), l.OKd, J = 6.66Hz, 3H).

Example 13.Preparation of l- acid. { 3- (R) -methyl-4- [4- (2, 2, 2-trifluoro-1-hydroxy-l-methyl-ethyl) -benzenesulfonyl] -piperazin-1-ylmethyl} -cyclobutanecarboxylic acid (13a) and l- amide. { 3- (R) -methyl-4- [4- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl] -piperazin-1-ylmethyl} -cyclobutanecarboxylic (13 b) Stage a. ethyl ester of hydroxymethylcyclobutanecarboxylic acid. A 500 ml flask was charged under N2 atmosphere with 5.0 g of cyclobutan-1, 1-dicarboxylic acid diethyl ester (25. Ommol, 1.0 equiv.), 30 ml of THF and 55 ml of lithium tri-tert-butoxyaluminohydride. (l.OM in THF, 55 mmol, 2.2 equiv.). The solution was heated to reflux for 5 h before cooling to room temperature. Then the suspension was diluted with saturated NH 4 Cl. After stirring for Ih, the suspension was filtered through a Buckner funnel. The solid was washed (Et20). Combined fractions were extracted (3 x Et20), dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (Si02, CH2C12, 2% MeOH / CH2Cl2) afforded the product as a colorless oil (1.8 g, 11.4 mmol). Stage b. ethyl ester of 1- to il-cyclobutanecarboxylic acid. A portion of the product obtained above (700 mg, 4.4mmol, 1.0 equiv.) In 15 ml of THF was combined in a flask with 2.8 Dess-Martin periodinane (6.6mmol, 1.5 equiv.) The resulting suspension was stirred for 2 h followed by dilution with NaHCO3. The aqueous solution was extracted with (3 x CHC12). Purification by flash chromatography (Si02, CH2C12) gave the product as a colorless oil (480 mg, 3.08 mmol). Stage c. 3- (R) -methyl-piperazin-1-ylmethyl-cyclobutanecarboxylic acid ethyl ester. The product obtained above (470 mg, 3. Ommol, 1.0 equiv.) In 25 ml of 1,2-dichloroethane was combined in a flask with 750 mg of (R) - (-) -2-methylpiperazine (7.5mmol, 2.5 equiv.) and several drops of acetic acid. 2.54 g of sodium triacetoxyborohydride (12.0 mmol, 4.0 equiv.) Were added and the suspension was stirred overnight. The mixture was diluted with saturated NaHCO 3, extracted (3 x 10% MeOH / CH 2 Cl 2), dried (MgSO 4) and concentrated under reduced pressure. Stage d. 1-4- (4-acetyl-benzenesulfonyl) -3- (R) -methyl-piperazin-1-ylmethyl-cyclobutanecarboxylic acid ethyl ester. The residue obtained in 6 ml of CH2C12 was combined in a flask with 272 mg of 4-acetylbenzenesulfonyl chloride (1.25 mmol) and 250 mg of triethylamine (2.5 mmol). The solution was stirred for 1 h, followed by dilution with 20 ml of CH 2 Cl 2 and saturated NaHCO 3. The aqueous solution was extracted (2 x 10% MeOH / CH 2 Cl 2). The organics were dried (MgSO 4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 5% MeOH / CH2Cl2) gave the product as a colorless oil (230 mg, 0.54 mmol). Stage e. 3- (R) -methyl-4- (2,2,2-trifluoro-1-methyl-ethyl) -benzenesulfonyl-piperazin-1-ylmethyl-cyclobutanecarboxylic acid ethyl ester. A 100 ml flask containing the product obtained above (230 mg, 0.54 mmol, 1.0 equiv.) Was charged with 4 ml of TMS-CF3 (0.5 M in THF). The solution was stirred for 1 h followed by addition of 4 ml of tetrabutylammonium fluoride (l.OM in THF). After stirring for 1 h, the solution was diluted with saturated NaHCO3, extracted (2 x 10% MeOH / CHCl2). Organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 2% Me0H / CH2Cl2) gave the product as a colorless oil (205 mg, 0.42 mmol). Stage f. 3- (R) -methyl-4- (2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl-β-piperazin-1-ylmethyl-cyclobutanecarboxylic acid. A 100 l flask containing the product obtained above was charged (205mg, 0.42mmol) with 7ml of THF, 3ml of H20, 3ml of MeOH and 50 mg of LiOH. The resulting mixture was placed inside a bath preheated to 37 aC. After stirring overnight, the mixture was diluted with 20 ml of H20 and 5 ml of saturated NaHCO3, extracted (CH2C12). The aqueous solution was acidified with 3 N HCl to a pH of about 3 and then extracted (3 x 10% MeOH / CH 2 Cl 2). Organics were dried (MgSO4), concentrated under reduced pressure to provide compound 13 as a yellow solid. (170mg, 0.36 mmol). ^? MR CDCls, 400HZ) delta 12. 2 (width, 1H), 7.84 (s, 4H), 6.86 (s, 1H), 3.91 (m, lH), 3.5Q (m, lH), 3.02 (t, J = 12.15Hz, ÍH), 2.65- 2.46 (m, 5H), 2.25 (, 2H), 2.05 (, ÍH), 1.87 (m, 3H), 1.78-1.72 (, 4H), 0.98 (d, J = 6.5Hz, 3H). Stage g. 3- (R) -methyl-4- (2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl-piperazin-1-ylmethyl-cyclobutanecarboxylic acid amide (13). A 50 ml flask containing the product obtained above was charged (40 mg, 0.086 mmol) with 1 ml of CH2C12 and 5 ml of S02C1.

After stirring for 1 h, all of the solvent was removed under reduced pressure. The residue was then dissolved in 4 ml of CH2C12 and an excess amount of NH3 (in DCM) was added to the solution. The resulting solution was stirred for 0.5 h followed by dilution with saturated NaHCO 3. The aqueous solution was extracted (2 x 10% MeOH / CH2Cl2). Organics were dried (MgSO4) and concentrated under reduced pressure to provide 24 mg of compound 13 as a white solid (0.052 mmol). H NMR (CDCl 3, 400MHz)) delta 7.79 (dd,, J = 8.4 Hz, 32.3 Hz, 4H), 4.12 (m, ÍH), 3.63 (, 1H), 3.20 (t, J = 12.15 Hz, 1H), 2.75 (s, 2H), 2.62 (, 3H), 2.43 (m, 2H), 2.33 (m, ÍH), 2.20-2.09 (m, 2H), 1.89 (m, 2H), 1.82 (, 3H), 1.12 (d, J = 5.7Hz, 3H). Example 14. Preparation of amide of l- acid. { 3- (R) -methyl- 4- [4- (2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl) -i-benzenesulfonyl] -piperazin-1-yl-methyl} - Cyclobutanecarboxylic (14) 14 Using the methods described above in the example 12, and substituting 4- (2,2,2-trifluoro-l-hydroxy-l-trifluoromethyl-ethyl) -benzenesulfonyl chloride for 4-acetylbenzenesulfonyl chloride in step d, Compound 14. XH NMR (CDC13, 400 MHz) delta 7.87 (m, 4H), 4.11 (m, 1H), 3.64 (m, 1H), 3.19 (t, J = ll.lHz, 1H), 2.73 (d, lH), 2.60 (m, 3H ), 2.40 (m, 2H), 2.30 (m, ÍH), 2.20-2.05 (m, 2H), 1.88 (m, 3H), 1.10 (d, J = 6.7Hz, 3H).

Example 15. Preparation of 1- 3- (R) -methyl-4 acid amide 4- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl-piperazinyl-1-ylmethyl-cyclopropanecarboxylic acid (15) Stage a. 1-hydroxymethyl-cyclopropanecarbonitrile. A 250 ml flask was charged with 1-cyano-cyclopropanecarboxylic acid ethyl ester (2.0 g, 14.4 mmol, 1.0 equiv.), Ethylene glycol dimethyl ether (100 ml), MeOH (10 ml), and NaBH 4 (4.4 g, 115.0 mmol, 8.0 equiv.). After stirring for 12 h, the solution was diluted slowly with saturated NaHCO 3, extracted (3 x 10% MeOH / CH 2 Cl 2), dried (MgSO), and concentrated under reduced pressure. Purification by flash chromatography (Si02, CH2C12, 5% MeOH / CH2Cl2) gave the product as a colorless oil (1.25g, 12.9mmol). Stage b. 1-cyano-cyclopropylmethyl ester of methanesulfonic acid. The product obtained above (1.25mg, 12.9mmol, 1.0 equiv.) In 30 ml of CH2C12 was combined in a flask with 2.6 g of triethylamine (25.8mmol, 2.0 equiv.) And 1.92 g of methanesulfonic acid chloride (16.8mmol, 1.3equiv.) At 0aC. The solution was stirred for 1 h followed by dilution with saturated NaHCO 3 and extracted (3 x 10% MeOH / CH 2 Cl 2). Organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 1% MeOH / CH2Cl2) gave the product as a yellow oil (1.9g, 10.8 mmol). Stage c. 1- (3- (R) -methyl-piperazin-1-ylmethyl) -cyclopropanecarbonitrile. The product obtained above (1.9 g, 10.8 mmol, 1.0 equiv.) With 2.7 g of (R) - (-) -2-methylpiperazine (27.1 mmol) was combined in a pressure tube., 2.5 equiv.). The resulting solution was then placed into a bath preheated to 100 ° C. After stirring for 12 h, the mixture was cooled to room temperature, diluted with 50 ml of CH 2 Cl 2 and saturated NaHCO 3, extracted (3 x 10% MeOH / CH 2 Cl The organics were dried (MgSO 4) and concentrated under reduced pressure, Step 1-4- (4-acetyl-benzenesulfonyl) -3- (R) -methyl-poiperazin-1-ylmethyl-cyclopropanecarboxylic acid. in a flask the residue obtained above in 20 ml of CH2Cl2 with 1.88 g of 4-acetylbenzenesulfonyl chloride (8.64 mmol) and 1.75 g of triethylamine (17.3 mmol). -The mixture was stirred for 1 h followed by dilution with 20 ml. CH2C12 and saturated NaHCO3 The aqueous solution was extracted (2 x 10% MeOH / CHCl) The organics were dried (MgSO4) and concentrated under reduced pressure Purification by flash chromatography (Si02, 1% MeOH / CH2Cl2) provided the product in the form of a colorless oil (1.98g, 5.48mmol) Step e.l-. {3- (R) -methyl-4- [4- (2, 2, 2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl] -piperazin-1-ylmethyl} -cyclopropan carbonitrile. A 100 ml flask containing the product obtained above (1.98g, 5.48mrt, 1.0 equiv) was charged with 22ml of TMS-CF3 (0.5M in THF, llmmol, 2.0 equiv). The reaction was stirred for 2 h followed by dilution by adding 22 ml of tetrabutylammonium fluoride (l.OM.in THF, 22mmol, 4.0 equiv). After stirring for 0.5 h, it was diluted with NaHCO 3, extracted (3 x MeOH / CH 2 Cl 2). Organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 2% MeOH / CH2CL2) provided 2. Og of the product as a white solid (4.6mmol). Stage f. 3- (R) -methyl-4- (2,2,2-trifluoro-l-hydroxy-l-methyl-ethyl) -benzenesulfoni-piperazin-1-yl-methyl-cyclopropanecarboxylic acid amide (15) . A 100 ml flask containing a portion of the product obtained above (1.2 g, 2.78 mmol) was charged with 60 ml of t-BuOH and 4.0 g of KOH. The mixture was then placed in a bath preheated to 100 ° C. After stirring for 4 h, the mixture was diluted with saturated NaHCO 3, extracted (3 x 10% MeOH / CH 2 Cl 2) The organics were dried (MgSO), concentrated under reduced pressure Purification by flash chromatography (Si02, ethyl acetate) to give 1. Og of the product as a white solid (2.2mmol) XH NMR (DMSO, 400 MHz) delta 8.11 (s, ÍH), 7.84 (m, 4H), 7.02 (s, 1H), 6.86 (s, lH), 4.02 (m, lH), 3.58 (, 1H), 3.16 (t, J = 12.6Hz, 1H), 2.89 (d, J) = 11.4, lH), 2.76 (d, J = 11.4Hz, ÍH), 2.32 (dd, J = 13.0Hz, 74.1Hz, 2H), 1.92 (dd, J = 3.5Hz, 11.4Hz, 1H), 1.79 ( , lH), 1.72 (s, 3H), 1.03 (d, J = 6.7Hz, 3H), 0.95 (d, J = 4.3Hz, 2H), 0.43 (d, J = 4.lHz, 2H).

Preparation of - ((R) -3-methyl-4- (4- ((R) -1,1, ltrifluroro-2-hydroxypropan-2-yl) phenylsulfonyl) piperazin-1-yl) ethylcyclopropanecarboxa ida (15 a ) and 1- (((R) -3-methyl-4- (4- ((S) -1,1,1-trifluoro-2-hydroxypropan-2-yl) phenylsulfonyl) piperazin-1-yl) methyl) Cyclopropanecarboxamide (15 b) fifteen Stage g. (S) -2- (4- ((R) -4- ((1-cyanocyclopropyl) methyl) 2-methylpiperazin 1-ylsulfonyl) phenyl) -1,1,1-trifluoropropan-2-yl (S) - l-hydroxybutane-2-carbamate. To a 2 1 flask containing the product obtained above (160g, 37.1mmol, 1.0 equiv) in 465ml of CH3CN 67.9g of DMAP (55.6mol, 1.5 equiv) at 0aC was added 4-nitrophenyl chloroformate (89.7g) , 44.5 mol, 1.2 equiv) in portions. The mixture was stirred for 15 min at 0aC and 5.5h at room temperature. (S) - (+) -2-amine-1-butanol (56.2 g, 63.1 mmol, 1.7 equiv) was added dropwise via an addition funnel. After the addition, the solution was stirred for 12 h. The majority of CHCN was removed under reduced pressure and the residue was diluted with EtOAc. The solid was filtered and washed with EtOAc. The filtrate was washed with saturated NH 4 Cl, dried and concentrated under reduced pressure. The two diastereomers were purified and separated by flash chromatography (SiO2, 50% EtOAc / hexanes). The first portion of the two nearby spots was collected and concentrated under reduced pressure to give 70 g of the distereoisomer as a colorless oil (12.8 mol). Step hl- (((R) -3-methyl-4- (4- ((S) -1,1,1-trifluoro-2-hydroxypropan-2-yl) phenylsulfoni) piperazin-1-yl) methyl) cyclopropanecarboxamide (15b). ). It was added to a 500 ml flask containing the product obtained above (70. Og, 12.8mmol), l.Oeguiv) 300 ml of t-BuOH and 50.0 g KOH.

The resulting mixture was placed in a bath preheated to 90 ° C. After stirring for 12 h, the mixture was diluted with H20, extracted with (5 x 10% MeOH / CH2Cl2). Organics were dried (MgSO4), concentrated under reduced pressure. Purification by flash chromatography (Si0, 90% EtOAc / hexanes) gave 50.Og of the product as a white solid (11.1 mmol, 88% ee). The white solid was dissolved in 800 ml of boiling CH3CN. The solution was cooled overnight in an open flask. The crystals formed overnight were filtered. The filtrate was concentrated under reduced pressure to give 46 g of the final product as a white solid (10.2mmol, 94% ee). ^ HMR (DMSO, 500MHz) delta 8.02 (s, 1H), 7.84 (m, 4 H), 7.00 (s, ÍH), 6.86 (s, lH), 4.03 (m, lH), 3.59 (, 1H), 3.15 (ddd, J = 12.0.6.0, 3.0 Hz, 1H), 2.85 (d, J = 11.5Hz, 1H), 2.73 (d, J = 11.5Hz, ÍH), 2.45 (d, J = 13.0Hz, 1H ), 2.21 (d, J = 13.0Hz, ÍH), 2.06 (dd, J = 3.5Hz, 11. OHz, lH), 1.95 (ddd, J = 11.5, 5.8, 3.0Hz / 1H), 1.73 (s, 3H), 1.20 (m, 2H), 1.09 (d, J = 6.5Hz, 3H), 0.86 (m, 2H). Stage i. The diastereoisomers were resolved by HLPC. The flow rate was 22 ml / min in a column of 5 microns 10 Chiralpak AD 20 mm i.d x 250 mm (Daciel Chemical Industries Ltd), using alcoholisopropyl / hexanes (30/70) as eluent. The first peak was collected to produce 1- (((R 9-3-methyl-4- (4- ((S) -1,1, l-trifluoro-2-hydroxypropan-2-yl) phenylsulfoni) piperazin-1- il) ethyl) cyclopropanecarboxamide (15b). ^ HN IKDMSO, 500MHz) 8.02 (s, lH), 7.84 (m, 4H), 7.00 (s, 1H), 6.86 (s, 1 H), 4.03 (m, lH), 3.59 (m, lH), 3.15 (ddd, J = 12.0, 6.0, 3.0Hz, 1H), 2.85 (d, J = 11.5Hz, lH), 2.73 (d, J = ll .5Hz, 1H), 2.45 (d, J = 13.0Hz, ÍH), 2.2 1 (d, J = 13. OHz, ÍH), 2.06 (dd, J = 3.5Hz, 11.0Hz, ÍH), 1.95 (dddJ = ll .5, . 8, 3. OHz, ÍH), 1.73 (s, 3H), 1.20 (m, 2H), 1.09 (d, J = 6.5Hz, 3H), 0.86 (m, 2H). The second peak of the column gave 1- (((R) -3-methyl-4- (4- ((R)), 1,1,1-trifluoro-2-Hydroxypropan-2-) phenylsulfonyl (piperazin-1) -yl) methylcyclopropanecarboxamide (15a). aHNMR (DMSO, 500MHz) 8.02 (s, lH), 7.84 (m, 4H), 7.00) s, lH), 6.86 (s, l H), 4.03 (m, lH), 3.59 (m, lH), 3.15 (ddd, J = 12.0, 6.0, 3.0Hz, 1H), 2.85 (d, J = 11.5Hz, lH), 2.73 (d, J = ll .5Hz, 1H), 2.45 ( d, J = 13.0Hz, 1H), 2.2 (d, J = 13. OHz, 1H), 2.06 (dd, J = 3.5, 11. OHz, 1H, 1.95 (ddd, J = ll.5.5. , 3.0Hz, lH), 1.73 (s, 3H), 1.20 (m, 2H), 1.09 (d, J = 6.5Hz, 3H), 0.86 (m, 2H), MS (M + H +) 450.1.

Example 16. Preparation of 1,1-trifluoro-2- (2-hydroxyethyl) -4 (l-pyridin-4-yl-cyclopropylmethyl) -piperazin-1-sulfonyl-phenyl-2-propanol (16) Using the methods described above in steps a and b of Example 10, and replacing the ethyl ester of (l-pyridin-4-yl-cyclopropyl) acetic acid with the ester of (l-pyridin-4-yl-cyclobutyl) acetic acid, was prepared (1-pyridin-4-yl-cyclopropyl) methanol. Step a.4- (1-chloromethyl-cyclopropyl-pyridine) was added to a 50ml flask containing 20Omg of (1-pyridin-4-yl-cyclopropyl) -methanol (1.34mmol, l.Oequiv.) In lOml of CH2C12 174mg thionyl chloride (1. 8mmol, 1.1 equiv.) After stirring for 1 h, the solution was concentrated under reduced pressure to give the product in the form of a brown solid. benzyl-4- (l-pyridin-4-cyclopropylmethyl) -piperazin-2-yl] ethanol A 250 ml flask was charged with the product obtained above (1.34mmol, l.Oquim.), 2- (l-benzyl) -piperazin-2-yl) ethanol (1.18g, 5.36mmol, 4.0equiv.), and lOml of acetonitrile The flask was fitted with a reflux condenser, and then placed in a preheated bath at 100 ° C. After stirring for 24 h, the solution was diluted with CH2C12 and saturated NaHC03, extracted (2 x 10% MeOH / CH2Cl2), dried (Na2SO), and concentrated under reduced pressure Purification by flash chromatography (Si02, 3). % MeOH / CH2Cl2) prop Orione 310 mg of the product in the form of a yellow oil. Stage c. 2- [4- (l-pyridin-4-yl-cyclopropylmethyl) -piperazin-2-yl] ethanol. A 100 ml flask was charged with 500 mg 5% Pd / C and 30 ml EtOH under N2 atmosphere. Then, the product obtained above (0.88 mmol) followed by 10 ml of cyclohexane was added. The flask was heated with a reflux condenser, and then placed in a preheated bath at 80 ° C. After stirring for 2 h, the mixture is filtered hot through a plug of zelite. The zelite plug (3 x EtOH) was washed, the combined EtOH fractions were concentrated under reduced pressure to provide the product as a colorless oil. Stage d. 1- . { 4- [2- (2-hydroxyethyl) -4- (l-pyridin-4-yl-cyclopropyl methyl) -piperazin-1-sulfonyl] -phenyl} -etanone. The product obtained above (0.88 mmol, 1.0 equiv) in 5 ml of CH2C1 was combined in a flask with 193 mg of 4-acetylbenzenesulfonyl chloride (0.88 mmol, 1.0 equiv) and 178 mg of triethylamine (1.760 mmol, 2.0 equiv). The solution was stirred for 1 h, followed by dilution with 20 ml of CHC12 and saturated NaHCO3. The aqueous solution was extracted (2 x 10% MeOH / CH2 / Cl2). The organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (Si02, 2% MeOH / CH2CL2) affordedOmg of the product as a yellow oil (0.22mmol). Stage e. 1, 1, 1-trifluoro-2-. { 4-. { 2- (2-hydroxyethyl) -4- (l-pyridin-4-yl-cyclopropylmethyl) -piperazin-1-sulfonyl] phenyl} -2propanol (16). It was loaded in a 100 ml flask containing the product obtained above (26 mg, 0.059 mmol, 1.0 equiv) with Iml TMS-CF3 (0.5 M in THF). The solution was stirred for 0.5 h, followed by the addition of 0.5 ml of tetrabutylammonium fluoride (1.0 in THF). After stirring for 0.5 h, the solution was diluted with saturated NaHCO 3, extracted (2x 10% MeOH / CH 2 Cl 2). The organics were dried (MgSO4), and concentrated under reduced pressure. Purification by flash chromatography (Si02, 4% MeOH / CH2Cl2) gave 11 mg of compound 16 as a colorless oil (0.021 mmol). ^ H MRÍCDCIB, 400HZ) delta 8.39 (d, J = 5.8Hz, 2H), 7.80 (dd, J = 8.7Hz, J = 21.9Hz, 4H), 7.13 (d, J = 6.lHz, 2H), 4.06 (m, 1H), 3.72 (m, lH), 3.62 (, 1H), 3.49 (, 1H), 3.12 (t, J = 12.6Hz, 1H), 2.64 (dd, J = 6.7Hz, 11.6Hz, 2H ), 2.43 (dd, J = 13.0Hz, 49.1Hz, 2H), 1.83-1.69 (m, 7H), 0.95 (m, 2H), 0.75 (m, 2H).

Example 17.Preparation of 1, 1, 1-trifluoro-2-. { 4- [4- (1-imidazol-1-yl-cyclopropylmethyl) -2- (R) -methyl-piperazin-1-sulfonyl} -2propanol (17) or Stage a. A mixture of 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride (l.Og), 6.60mmol) in H20 (4ml), phosphoric acid (85% in water, 0.2ml), glyoxal (40% in water, 0.76ml, 6.60mmol) and formaldehyde (37% in water, O.SOml, 6.60mmol) it was heated and stirred for 90 ° C in an oil bath. NH4C1 (354mg, 6.60mmol) in H20 (3ml) was added dropwise to the mixture. Stirring continued for 1 h. The viscous solution was cooled to room temperature and stirred for 1 h. The mixture was cooled to 0 ° C and KOH (3N) was added dropwise to neutralize the solution to pH 7. The mixture was concentrated and dried in vacuo. The dried mixture obtained was reduced with LAH. Stage b. The product obtained from the reaction above was added dropwise in THF (20 ml) LAH (1.0 M in THF, 13.2 mmol). The ice-water bath was removed and stirring was continued at room temperature for 4 h. The solution was cooled to 0 ° C and H20 (0.4ml), NaOH (15% in water, 0.4ml) and H20 (1.2ml) were sequentially added. The cold bath was removed, stirring was continued for 15 min. Then, the mixture was filtered through a pad of Celite, using THF as a rinse. Evaporation of the combined filtrates in vacuo, and flash chromatography of the residue, using 1.5: 8.5: 0.05MeOH-CH2Cl2-NH4, gave 0.23 g of the product. Stage c. It was added dropwise to an alcohol solution (0.23g, 1.66mmol) in CH2C12, S0C12 (0.24ml, 3.32mmol). Stirring was continued at room temperature for 14 h. Evaporation of the solvent and the remainder of S0C12 in vacuo and titration in EtOAc provided the chloride (195 mg, HCl salt). XHNMR (CDC13) delta 9.40 (s, lH), 7.95 (s, 1H), 7.73 (s, lH), 4.12 (s, 2H), 1.53 (t, J = 6.0Hz, 2H), 1.32 (t, J) = 6.0Hz, 2H); msl57.1 (M + H +).

Stage d. It was heated and stirred in a 100 ° C bath for 5 h, a mixture of (R) - (-) -2-methylpiperazine (348mg, 3.48mmol) and chloride (195mg, 0.99mmol). The mixture was cooled to room temperature and dissolved in CH2C12 (3ml). Instant chromatography of the solution, using 1.5: 8.5: 0.05 Me0H-CH2Cl2-NH0H, provided the coupled product (123 mg) 1HNMR (CDC13) delta 7.55 (s, lH), 6.96 (s, 1H), 6.93 (s, 1H ), 2.88-2.71 (m, 3 H), 2.69-2.62 (, 2 H), 2.52 (d, J = 13.5 Hz, 1 H), 2.47 (d, J = 13.5 Hz, 1 H), 2.20 (br , 1 H), 2.02 (td, J = ll .0 Hz, J = 3.0 Hz, 1H), 1.79 (t, J = 11.0 Hz, 1 H), 1.13-1.06 (, 2 H), 0.95, J = 6.5 Hz, 3 H), 0.91-0.88 (m, 2H); ms 221.2 (M + H +). Step e.A mixture of the coupled product from step d (105.4 mg, 0.48 mmol), Acetyl-benzenesulfonyl chloride (105 mg, 0.53 mmol), NEt3 (0.1 ml, 0.58 mmol), in CH2C1 was stirred at room temperature for 14 h. h. Evaporation of the solvent in Vacuo, and flash chromatography of the residue, using 1: 9: 0.05MeOH-CH2Cl2-NH4OH provided the sulfonamide (0.17g). 1HNMR (CDC13) delta 8.07 (d, J = 8.0Hz, 2H), 7.89 (d, J = 8.0Hz, 2H), 0.52 (s, lH), 0.96 (s, ÍH), 0.9 (s, 1H), 13-4.05 (m, 1 H), 3.68-3.60 (m, 1 H), 3.14 (td, J = 12.4 Hz, J = 3.1 Hz, 1 H), 2.75-2.68 (m, 1 H) 2.68 (s) , 3 H), 2.57-2.52 (m, 2H), 2.46 (d, J = 13.6 Hz, 1 H), 2.28 (dd, J = 11.2 Hz, J = 3.6 Hz, ÍH), 2.13 (td, J = 11.5 Hz, J = 3.3 Hz, lH), 1.18-1.13 (, 2H), 1.03 (d, J = 6.8 Hz, 3H), 0.92-0.88 (m, 2H); MS 403.5 (M + H +). Stage f. It was added to a mixture of Sulfonamide (0.17g, 0.42mmol) and CF3SiMe3 (0.5M in THF, 2.6ml, 1.3mmol) TBAF (l.OM, 1.3 ml, 1.3 mmol) at room temperature. The mixture was stirred for 20 h, diluted with Et2O (20 ml). The solution was washed with saturated aqueous NaHCO3, and brine, dried and concentrated. Instant chromatography of the residue, using 0. 5: 9.5 MeOH-CH2Cl yielded compound 17 (125 mg) HNMR (CDC13) delta 7.82 (d, J = 8.5 Hz, 2H), delta 7.79 (d, J = 8.5 Hz, 2H), 7.06 (s, 1 H), 6.92-6.88 (m, 2 H), 6.43 (br, 1 H), 4.10-3.97 (m, 1 H), 3.72-3.60 (m, 1 H), 3.25-3.18 (m, 1 H), 2.76 (dd, J = 14.5 Hz, J = .5 Hz, 1 H), '2.68 (dd, J = 14.5 Hz, J = 3.0 Hz, 1 H), 2.55-2.46 (m, 1 H), 2.42-2.32 (m, 1 H), 2.22-2.18 (m, 0.5 H), 2.08-2.02 (m, 1 H), l.; 95-l;., 86_ (, 0.5 H), 1.83 (s, 3 H), 1.17 (dd, J = 7.0 Hz, J = 4.0 Hz,; 3H), 1.15-1.00 (, 2H), 0.89-0.81 (m, 2H); MS473.2 (M + H +). Example 18.Preparation of 3- (R) -methyl-4- (2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl-piperazin-1-ylmethyl-cyclopropanecarboxylic acid (18) ) 1S The title compound was prepared in a manner similar to that described for compound 13 a, starting with diethyl ester of cyclopropanedicarboxylic acid in place of diethyl ester of cyclobutane dicarboxylic acid. 1HNMR (DMSO, 400 MHz) delta 13.11 (s, lH), 7.84 (m, 4H), 6.86 (s, lH), 4.01 (m, lH), 3.58 (m, lH), 3.14 (ddd, J = 12.0, 6.0, 3. 0Hz, lH), 2.85 (d, J = 12.0 Hz, ÍH), 2.71 (d, J = 12.0 Hz, 1H), 2. 51 (m, 2H), 2.11 (dd, J = 3.6, 11.5 Hz, lH), 1.97 (ddd, J = 11.5, 5.8, 3.6 Hz, 1H), 1.74 (s, 3H), 1.04 (, 5H), 0.73 (m, 2H). Example 19. Synthesis of 1,1,1-trifluoro-2-. { 4- [2-®-methyl-4- (cis-3-hydroxy-l-yl-cyclopentyl) piperazine-l-sulfonyl] phenyl} -2propanol (19) Using the same methods as in the preceding examples, 1, 1, 1-trifluoro-2 was prepared. { 4- [2- (R) -methyl-4- (cis-3-hydroxy-1-yl-cyclopentyl) piperazine-1-sulfonyl} phenyl } -2-propanol (19). ^? NMR (DMSO, 400 MHz) delta 7.81 (s, 4 H), 6.85 (s, 1 H), 4.50 (d, 1 H), 3.95 (m, 2 H), 3.50 (d, 1 H), 3.09 (m, HH), 2.69 (m, HH), 2.53 (m, 1 H), 2.31 (m, 1 H), 1.88 (m, 2 H), 1.72 (, 1 H) ), 1.70 (s, 3 H), 1.55 (m, 3) H), 1.42 (, 2 H), 1.19 (, 1 H), 1.05 (d, 3 H) Example 20. Synthesis of 1, 1, 1, -trifuoro-2-. { 4- [2- (R) -methyl-4- (cis-3-imidazol-1-yl-cyclopentyl) piperazin-1-sulfonyl] phenyl} -2-propanol (20) twenty Using the same methods as in the preceding examples, the following compound was prepared: 1,1-trifluoro-2-. { 4- [2- (R) -methyl-4- (cis-3-imidazol-1-yl-cyclopentyl) piperazine-1-sulfonyl] phenyl} -2-propanol: "? NMR (CDC13, 400 MHz) delta 7.82 (s, 4 H), 7.66 (d, J = 2.9 Hz, 1 H), 7.22 (d, J = 5.0 Hz, 1 H), 6.86 (s, 2 H), 4.49 (m, 1 H), 3. 98 (, 1 H), 3.51 (d, J = 10.8 Hz, 1 H), 3.13 (m, 1 H), 2. 79 (t, J = 10.5 Hz, 1 H), 2.62 (t, J = 11.7 Hz, 1 H), 2.21 (m, 1 H), 2.04 (m, 1 H), 1.92 (ddd, J = 3.4, 11.2, 11.3 Hz, 1 H), 1. 83-1.55 (m, 5 H), 1.72 (s, 3 H), 1.08 (d, J = 6.6 Hz, 3 H).

Example 21.2- (4- (4- (2, 2-difluoro-2- (pyridn-3-yl) ethyl) -2- (R ) -methylpiperazin-1-ylsulfonyl) phenyl) -1,1,1-trifluoro-2 21 Using the same methods as in the preceding examples, 2- (4- (2, 2-difluoro-2- (pyridin-3-yl) ethyl) -2- (R) -methylpiperazin-1-sulfonyl) phenyl was prepared ) -1,1,1-trifluoro-2-propanol. ^? NMR (CDC13, 400MHZ) delta8.7-8.60 (m, 2H), 7.80-7.77 (m, 5H), 7.38 (m, ÍH), 4.35 (d, J = 4.80Hz, 1H), 4.18 (, 1H), 3.61 (d, J = 4.80Hz, 1H), 3.11 (m, ÍH), 3.05 (, 2H), 2.68 (m, 1H), 2.45 (s, 2H), 2.32 (m, 1H), 1. 82 (s, 3H), 1.00 (d, J = 6.70Hz, 3H); MS 494.2 (M + H +). Example 22 .2- (4- (4- (2, 2-difluoro-2- (pyridin-4-yl) ethyl) -2- (R) -methylpipßrazin-1-ylsulfonyl) phenyl) -1, 1, 1- trif luoro 2 propanol (22) 22 Using the same methods as in the preceding examples, 2- (4-. {4- (2, 2-difluoro-2- (pyridin-4-yl) ethyl) -2- (R) -methylpiperazin-1 was prepared. -sulfonyl) phenyl (-1,1,1-trifluoro-2-propanol (22). 1HNMR (CDC13, 400 MHz) delta 8.6 (d, J = 5.27Hz, 2H), 7.80 (d, J = 8.67Hz, 2H) , 7.75 (d, J = 8.67Hz, 2H), 7.39 (d, J = 5.27Hz, 2H), 4.04 (m, ÍH), 3.56 (d, J = 12.8 Hz, 1H), 3.35 (d, J = 8.20Hz, lH), 3.08 (m, lH), 2.97-2.90 (m, 2H), 2.67 (d, J = 11.2Hz, 1H), 2.54-2.47 (m, 2H), 2.36 (m, lH), 1.83 (s, 3H), 0.97 (d, J = 5.82Hz, 3H); MS494.2 (M + H +). Example 23.1,1, 1-trifluoro-2- (4- (4- ((1- (2-hydroxypropan-2-yl) cyclopropyl) methyl) -2- (R) -methylpiperazin-1-ylsulfonyl) phenyl) -2- propanol (23) Using the same methods as in the preceding examples, 1, 1, 1-trifluoro-2- (4- (4- ((1- (2-hydroxypropan-2-yl) cyclopropyl) methyl) -2- ( R) -methylpiperazin-1-ylsulfonyl) phenyl) -2-propanol (23). XHNMR (DMSO, 500 MHz) delta 7.82 (m, 4 H), 6.86 (s, 1 H), 4.71 (m, 1 H), 4.01 (m, 1 H), 3.62 (d, J = 13.4 Hz, 1 H), 3.10 (m, 1 H), 2.93 (d, J = 11.5 Hz, 1 H), 2.68 (d, J = 9.55 Hz, 1 H), 2. 35 (d, J = 15.3 Hz, 1 H), 2.08 (d, J = 15.30 Hz, 1 H), 1.90 (m, 1 H), 1.72 (s, 3 H), 1.70 (, 1 H), 1.11 (s, 3 H), 1.06 (s, 3 H), 1.03 (d, J = 6.50 Hz, 3 H), 0.68 (, 2 H), 0.05 (m, 2H); MS465.1 (M + H +). Example 24.4- (l - (((R) -3-methyl-4- (4- ((S) -1,1- trifluoro-2-hydroxypropan-2-yl) phenylsulfonyl) piperazin-1-yl ) methyl) cyclopropyl) benzenamide (24b) and 4- (l - (((R) -3-methyl-4- (4- ((R) -1,1,1- trif) luoro-2-hydroxypropan-2 il) f-enylsulfonyl) piperazine-1-1) methyl) cyclopropyl) benzenamide (24 a) 24b 24a Using the same methods as in the preceding examples, the following compound was prepared by following the separation of the diastereomer mixture via HLPC (column Daicel chiralpak AD 2cm x 25 cm) with an isocratic obil phase 18% isopropanol / hexanes and a flow range of 17 ml / minute of 4- (l - (((R) -3-methyl-4- (4 - ((S) - 1,1, 1-trifluoro-2-hydroxypropan-2-yl) phenylsulfonyl) piperazin-1-yl) methylcyclopropyl) benzenamide (24 b) and 4- (1 - (((R) -3- methyl-4- (4- ((R) -l, 1-l-trifluoro-2-hydroxypropan-2-yl) phenylsulfonyl) piperazin-1-yl) ethyl) cyclopropyl) benzenamide (24 a). 1 H NMR (DMSO, 500MHz, both R and S isomers of trifluoromethylcarbinol have the same NMR spectrum at this resolution) delta 7.88 (s, lH), 7.80 (s, 4H), 7.73 (d, J = 8.50Hz, 2H), 7.33 (d, J = 8.50Hz, 2H), 7.20 (s, 1H), 6.84 (s, lH), 3.95 (m, 1H), 3.50 (d, J = 14.3Hz, 1H), 3.00 (m, ÍH), 2.80-2.73 (m, 2H), 2.58 (d, J = 17.8Hz, ÍH), 2.35 (d, J = 17.8Hz, lH), 1.96-1.82 (m, 2H), 1.72 (s, 3H), 0.83 (m, 2H) 0.82 (d, J = 6.50Hz, 3H), 0.71 (, 2H); MS526.2 (M + H +). Example 25. Preparation of l-. { 3- (R) -methyl-4- [4- (S) - (2, 2,2-trifluoro-l-hydroxy-l-methyl-ethyl-benzenesulfonyl}. Piperazin-1-ylmethyl.} - Cyclopropanecarbonitrile (25) Using the same methods as in the preceding examples, l- (3- (R) -methyl-4- (4- (S) - (2,2,2-trifluoro-1-hydroxy-l-methyl-ethyl) -benzenesulfonyl) -piperazin- was prepared. 1-ylmethyl (-cyclopropanecarbonitrile (25) .1HNR (DMSO, 500MHz) 7.84 (m, 4H), 6.86 (s, lH), 4.01 (m, lH), 3.58 (m, l H), 3.16 (ddd, J = 13.0.6.5.3Hz, lH), 2.85 (d, J = ll.OHz, ÍH), 2.73 (d, J = 11.0Hz, lH), 2.45 (d, J = 13.OHz, 1H), 2.21 (d, J = 13. OHz, 1H), 2.05 (dd, J = 3.5Hz, 11.5Hz, 1H), 1.95 (ddd, J = ll.5.5.8.3.5Hz, ÍH), 1.73 (s, 3H) ), 1.20 (m, 2H), 1.09 (d, J = 7. OHz, 3H, 0.86 (, 2H), -MS (M + H +) 432.1.

Example 26.Preparation of 2- (S) - (4- (4-cyclopropylmethyl-2- (R) -methyl-piperazin-1-sulfonyl) -phenyl) -1,1, l-trifluoro-2-propanol (26 26 Using the same methods as in the preceding examples, 2- (S) - [4- (4-cyclopropylmethyl-2- (R) -methyl-piperazin-1-sulfonyl) -phenyl] -1,1, 1- was prepared trifluoro-2-propanol (26) The product was resolved by chiral HPLC. The flow rate was 20 ml / min in a column 5 micron Chiralcel OD-H 20mml Dx250mm (Daciel chemical Industries LTD), using isopropyl alcohol / hexanes (8/92) as the eluent. The second peak was collected. XE NMR (CDC13, 400 MHz) delta 7.82 (d, J = Hz, 2H), 7.72 (d, J = 8.5Hz, 2H), 4.04 (, ÍH), 3.56 (m, 1H), 3.27 (t, J) = 11.5Hz, 1H), 2.83 (d, J = 11.0Hz, ÍH), 2.69 (d, J = 11.0Hz, lH), 2.16 (m, 3H), 2.04 (m, 1H), 1.80 (S, 3H) ), 1.19 (d, J = 6.7Hz, 3H), 0.76 (m, 1H), 0.46 (m, 2H), 0.04 (m, 2H); MS (M + H +) 407.0 Example 27 .2- (S) - [4- (4-Cyclobutylmethyl-2- (R) -methyl-piperazin-1-sulfonyl) -phenyl] -1,1,1-trifluoro-2-propanol (27) Using the same methods as in the preceding examples, 2- (S) - [4- (4-cyclobutylmethyl-2- (R) -methyl-piperazin-1-sulfonyl] -1,1, trifluoro-2-propanol ( 27) XHNMR (CDC13, 400 MHz) delta 7.83 (d, J = 8.3Hz, 2H), 7.73 (d, J = 8.2Hz, 2H), 4.04 (m, lH), 3.56 (m, lH), 3.22 ( t, J = ll.5Hz, 1H), 2.64 (d, J = 11.5Hz, lH), 2.47 (m, 2H), 2.29 (m, 2H), 2.11 (m, lH), 2.00 (m, 3H) 1.98-1.80 (m, 5H), 1.63 (m, 2H), 1.15 (d, J = 6.7Hz, 3H); MS (M + H +) 421.1 Example 28.Preparation of amide of 4- (1- ( 3- (R) -methyl-4- (4- ((S) -2,2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl (-piperazin-1-ylmethyl) -cyclopropyl (- pyridine-2-carboxylic acid (28b) and 4- (l- (3- (R) -methyl-4- (4- ((R) -2,2,2-trifluorol-hydroxy-l-methyl-) amide ethyl) -benzenesulfonyl) -piperazin-1-ylmethyl) -cyclopropyl) -pyridine-2-carboxylic acid (28a) 28b 28a The amide of 4- (1- (3- (R) -methyl-4- (4- ((S) -2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl was prepared (-piperazin-1-ylmethyl) -cyclopropyl (-pyridine-2-carboxylic acid (28b) and 4- (l- (3- (R) -methyl-4- (4- ((R) -2) amide, 2,2-tri-fluoro-1-hydroxy-1-methyl-ethyl) -benzenesulfonyl) -piperazin-1-ylmethyl) -cyclopropyl) -pyridine-2-carboxylic acid (28a) using the same methods as in the preceding examples, following Preparation of the mixture of diastereomers via HPLC The flow range was 20ml / min in a 5 micron column Chiralcel AD-H 20mm ID x 250mm (Daciel chemical Industries LTD), using isopropyl alcohol / hexanes (8:92) as an eluent, the first peak was collected as 28b.HNMR (CDC13, 00MHz) delta 8.40 (br, 1H), delta 8.04 (s, ÍH), 7.83 (br, lH), 7.79 (d, J = 8.0Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.33 (dd, J = 5.6 Hz, J = 2.4 Hz, 1H), 5.49 (br, ÍH), 4.06 (br, lH), 3.60-3.53 ( m, ÍH), 3.49 (d, J = 4.0 Hz, ÍH), 3.20-3.05 (m, lH), 2.85-2.50 (m, 4H) , 2.15-2.08. (M, 1H), 2.08-1.95 (, 1H), 1.81 (s, 3H), 1.10- 0.97 (m, 2H), 0.97-0.88 (m, 3H), 0.90-0.80 (m, 2H); - MS527.1 (M + H +). The second peak was collected as 28a. 1HNR (CDC13, 400MHz) delta 8.40 (d, J = 4 Hz,, 1H), delta 8.05 (s, 1H), .7.83 (br, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.33 (dd, J = 4.8 Hz, J = 2.0 Hz, 1H), 5.50 (br, ÍH), 4.03 (br, 1H), 3.60-3.53 (m, 1H) , 3.49 (br, lH), -3.08 (dd, J = 10.8 Hz, J = 10.8 Hz, ÍH) 2.87 (br, 1H), 2.81 (d, J = 8.0 Hz,; .HH), 2.70-2.56 (m, 2H), 2.54 (d, J = 10.8 Hz, lH), 2.20-2.10 (m, 1H), 2.05-1.95 (m, ÍH), 1.80 (s, 3H), 1.10-0.97 (m, 2H) ), 0.95 (d, J = 5.6 Hz, 3H), 0.90-0.80 (m, 2H); MS527.1 (M + H +). Example 29. Processes useful for the biological evaluation of the aryl sulfonamide compounds In addition to the extensive literature describing the role of HSDs in various diseases and disorders, useful assays are provided for testing the aryl sulfonamide compounds of the present invention. Assays Inhibitory action of the in vitro activity of llbeta-HSDl hydroxysteroid dehydrogenase The inhibitory activity of llbeta-HSDl was examined by quantitative determination by a SPA system (scintillation proximity assay) of the suppressive action in the conversion of cortisone to cortisol using human llbeta-HSDl (hereinafter recombinant llbeta-HSDl) expressed using a baculovirus system as an enzyme source. A 96-well plate reagent (96 well opti-plates TM-96 (Packard)) was added to the reaction for the next final concentration and a volume of 100 microliters reacted at room temperature for 90 min. The reaction solution used was 0.1 microg / ml recombinant llbeta-HSDl, 500 icroM NADPH, 16? M3H of cortisone (Amersham Biosciences, 1.78 Tbq / mol) were dissolved in 0.1% BSA (Sigma) - containing PBS and the test drug was 2 microliters of a compound solution (dissolved in DMSO) ). After 90 min, the reaction was stopped by adding to the reaction solution PBS (40 microliters, containing 0.1% BSA (Sigma) contains 0.08 microg of mouse monoclonal anti-cortisol antibody (East COSAT Biologics), 365 microg SPA PVT antibody binding beads (Amersham Biosciences) and 175 microM carbenoxolone (Sigma) After the completion of the reaction, the plate was incubated overnight at room temperature and the radioactivity was measured by a counter (Packard). used the value (0% inhibition) of the box containing 2 microliters of DMSO in place of the drug test, and for the positive control, the value (100% inhibition) of the box containing carbenoxolone was used in place of the drug test at the end of the 50 microM concentration.Inhibition (%) of the drug test was calculated by ((control value-drug value test) / (control value-value of positive control)) x 100 (%) The IC50 value was analyzed using a A computer-aided soft curve test. Ibeta-HSDl biochemical assay by SPA Recombinant human, mouse and rat llbeta-HSDl were expressed in baculovirus expression systems, isolated by purification and used as a source of enzymes for the conversion of cortisone to cortisol. 3H-cortisone (Amersham Bioscience, 1.78 Tbq / mol .49 Ci / mmol) was used as the substrate, and a monoclonal anti-cortisol antibody and the scintillation proximity assay system (SPA) were used to detect the reaction product. catalyzed from llbeta-HSDl, 3H-cortisol. Reactions were carried out at room temperature for 90 min in 96-well Opti-plate TM-96 (Packard) in a volume of 100 microliters with 2 microliters of control or control compounds in DMSO, 0.1 micrograms / mL protein llbeta-HSDl, 500 microM of NADPH and 16hM of radioactive cortisone, in a buffer solution of PBS supplemented with 0.1% BSA (Sigma). The reaction was stopped with the addition of 40 microliters of buffer containing 0.08 micrograms of monoclonal antibody. anti-cortisol (East CoasT Biologics), 365 micrograms of SPA PVT antibody binding drops (Amersham Biosciences) and 175 microM carbenoxolone (Sigma). Plates were incubated at room temperature overnight before being read in a counter (Packard). The 50 5 point of inhibition of the enzymatic activity of llbeta-HSDl was determined by the computer-assisted curve test. Assay based on llbeta-HSDl cell by SPA This cell-based assay measures the conversion of 3H-cortisone to 3H-cortisol in a stable cell line HEK-293 overexpressing human 11 beta-HSD. The HEK-293 cells were cultured in DMEM / F12 supplemented with 10% bovine fetal serum, and placed on 96-well plates coated with poly-D-lysine. (Costar 3903), 100, OOO cells per box in 50 μl of test medium (free phenol of DMEM / F12 (Invitrogen) + 0.2% BSA +1% s antibiotic-antifungal solutions). The solution was incubated at 37 ° C for 24 h, and the reaction was started by the addition of 25 microL of test medium containing compounds of desired concentration and 25 microliters of test medium containing 40 nM of 3H-cortisone for each Deposit. The reaction mixture was incubated for 37 ° C for 90 min. And it was terminated by adding 25 microliters of test medium containing 0.2 micrograms of an anti-cortisol monoclonal antibody (East COSAT Biologics), 500 micrograms of SPA PVT antibody binding drops (Amersham Biosciences) and 500 microM of carbenoxolone (Sigma ). The plates were incubated at room temperature for at least 2 h before being read in a counter (packard). The point of 50% inhibition of the enzymatic activity of llbeta-HSDl (IC50) was determined by the computer assisted curve test.

Claims (70)

1. NOVELTY OF THE INVENTION Having described the present invention is considered novelty and therefore the content of the following is claimed as priority: CLAIMS 1. A compound having the formula: v ¥ or salts, solvates, stereoisomers, or pharmaceutically acceptable drugs thereof wherein: R1, R2 and R3 are independently selected from -H, -halo, -OH, -CN, -N02, -C? -C8 alkyl, -C2 -C8 alkenyl-C2-C8 alkynyl, alkoxy, haloalkyl, -hydroxyalkyl, cycloalkyl, -heterocyclolyl, -heteroaryl and -aryl and at least one of R1, R2 and R3 is other than -H; R4 is -H halo, -CN, -N02, -C-C8 alkyl, -C2-C8 alkenyl -C2-C8 alkynyl, -alkoxy, -haloalkyl, -C2-C8 hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl, -aryl, -cycloalkyl- (C? -C6 alkyl), -heterocycle- (C1-C6 alkyl), -heteroaryl- (C? -C6 alkyl), aryl- (Ci-Ce alkyl), -C (0) R ', -C (0) OR', -C (0) N (R) 2, -C (0 R ') R', -OR ', - SR', -0C (0) R ', - C ( 0) N (R ') 2, -S (0) R', -SO 2 R ', -S02N (R') 2, -N (R ') 2, 0 -NR', C (0) R '; R5 is -H, Halo, -CN, -N02, -C? -C8 alkyl, -C2-C8 alkenyl -C2-Cs alkenyl, -alkoxy, -haloalkyl, hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl, -aryl , -cycloalkyl- (C? -C6 alkyl), -heterocycle- (Ci-Ce alkyl), -heteroaryl- (C? -C6 alkyl), -aryl- (Ci-Ce alkyl), -C (0) R ' , -C (0) 0R ', -C (0) N (R') 2, -C (OR ') R', -OR ', - SR', -OC (0) R ', -C (0 ) N (R ') 2, -S (0) R', -S02 R ', -S02N (R') 2, -N (R ') 2, O -NR', C (0) R ', or R5 and R6 together with the carbon atom to which they are attached are joined to form an optionally substituted alkane ring. R6 is -H, halo, -CN, -N02, -C? -C8 alkyl, -C2-C8 alkenyl, -alkoxy, -haloalkyl, -C2-C8 hydroxyalkyl, -cycloalkyl, cycloalkyl, -heterocycloalkyl, heteroaryl, - aryl, -cycloalkyl- (L-C6 alkyl), -heterocycle- (Ci-Ce alkyl), -heteroaryl- (L-C6 alkyl), aryl- (Ci-Ce alkyl), -C (0) R ', - C (0) 0R ', -C (0) N (R) 2, - C (0) R', -OR ', - SR', -0C (0) R ', -C (0) N (R ') 2, -S (0) R', -S02 R ', -S02N (R') 2, -N (R ') 2, O -NR'C (0) R'; R7 is selected from the group consisting of -H, -halo, -CN, -NO2, amino and -C? -C8 alkyl. Q is selected from the group consisting of -H, -halo, -CN, -N02, -C? -C8 alkyl, -C2-Cs alkenyl, alkoxy, -haloalkyl, -hydroxyalkyl, -cycloalkyl, heterocycloalkyl, -heteroaryl, aryl, -cycloalkyl- (-Ci-Cd), -heteroaryl- (C? -C6 alkyl, heteroaryl- (C? -C6 alkenyl), -C (0) R ', -C (0) 0R', -C (0) N (R) 2, -C (OR ') R', -OR ', -SR', -OC (0) R ', -C (0) N (R') 2, -S (0 ) R ', - S (0) 2R', -SO2N (R ') 2, -N (R') 2, O -NR'C (0) R '; L1 is a direct bond, -C? ~ C7 alkylene or -C? -C7 heteroalkylene L2 is a direct bond, -C? -C7 alkylene or -C? ~ C7 heteroalkylene, wherein in each presence of R 'it is independent -H, -C? -C8 alkyl, - C2-C8 alkenyl, -C2-C8 alkenyl, alkoxy, -alkoxyalkyl, -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heteroalkyl, -heteroaryl, -aryl, cycloalkyl- (Ci-Ce alkyl), -heterocycle- (C? C6 alkyl), -heteroaryl- (Ci-Cd alkyl), or -aryl- (C? -C? Alkyl), or two R 'groups, when attached to the same nitrogen atom, can be combined with the nitrite atom. the oxygen to which they are linked to form a heterocycle or heteroaryl group; and Where when R1, R2 and R3 are each -F or -CH3, R4 is other than -H. and said compound is another that Where R is selected from 4-methoxyphenyl, 4-bromophenyl and Rb is 4-fluorophenyl or 4-bromophenyl.
2. 2. The compound of claim 1 wherein Q is heteroaryl- or aryl.
3. 3. The compound of claim 2 wherein Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, hexazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, triazolyl, pyrimidyl, benzothiophenyl, benzothiazolyl, pyrinyl, benzimidazolyl, indolyl, indazolyl, carbazolyl, carbolinyl, quinolyl, isoquinolyl, quinoxylinyl and quinazolinyl.
4. 4. The compound of claim 2 wherein R1 is methyl or -OH.
5. 5. The compound of claim 2 wherein R1, R2 and R3 are each methyl.
6. 6. The compound of claim 4 wherein R1 is -OH and R2 and R3 are independently methyl or trifluoromethyl.
7. 7. The compound of claim 2 wherein L1 is -C? -C7 alkylene and L2 is a direct bond.
8. 8. The compound of claim 7 wherein L1 is -CH2- L2 is a direct link.
9. 9. The compound of claim 2 wherein L1 is -C? -C7 alkylene and L2 is -C? -C7 alkylene.
10. 10. The compound of claim 9 wherein L1 and L2 are each -CH2-.
11. 11. The compound of claim 2 wherein R5 and R6 and the carbon atom to which they are attached combine to form a cycloalkane.
12. 12. The compound of claim 11 wherein R5 and R5 and the carbon atom to which they are attached combine to form a cyclopropane ring.
13. 13. The compound of claim 11 wherein R5 and R5 and the carbon atom to which they are attached combine to form a cyclobutane ring.
14. 14. The compound of claim 11 wherein R5 and R6 and the carbon atom to which they are attached combine to form a cyclopentane ring.
15. 15. The compound of claim 1 wherein Q is -H, -C? -C8 alkenyl, -cycloalkyl, -heterocycle, heteroaryl, -aryl, -OR ', -C (0) OR' O -CON (R ' )2.
16. 16. The compound of claim 15 wherein Q is -C (0) OR 'O -CON (R') 2.
17. 17. The compound of claim 16 wherein Q is -COOH or -CONH2.
18. 18. The compound of claim 16 wherein R1 is methyl or -OH.
19. 19. The compound of claim 18 wherein R1, R2, and R3 are each methyl.
20. The compound of claim 18 wherein R1 is -OH and R2 and R3 is independently methyl or trifluoromethyl.
21. 21. The compound of claim 16 wherein L1 is -C1-C7 alkylene and L2 is a direct bond.
22. 22. The compound of claim 21 wherein La is -CH2- and L2 is a direct bond.
23. 23. The compound of claim 16 wherein L1 is -Ci C7 alkylene and L2 is -Ca-C7 alkylene.
24. 24. The compound of claim 23 wherein L1 and L2 is each -CH2 ~.
25. 25. The compound of claim 16 wherein R1 and R2 and the atom to which they are linked combine to form a (C3-C6) cycloalkane ring.
26. 26. The compound of claim 25 wherein R5 and R6 and the carbon atom to which they are attached combine to form a cycloalkane ring.
27. 27. The compound of claim 25 wherein R5 and R6 and the carbon atom to which they are attached combine to form a cyclobutane ring.
28. 28. The compound of claim 25 wherein R5 and R6 and the carbon atom to which they are attached combine to form a cyclopentane ring.
29. 29. The compound of claim 3 has the structure: or a pharmaceutically acceptable salt, solvate, stereoisomer, or drug thereof.
30. 30. The compound of claim 17 has the structure: or a pharmaceutically acceptable salt, solvate, stereoisomer, or drug thereof.
31. 31. The compound of claim 17 has the structure:
32. 32. A pharmaceutical composition comprising the compound of any of claims 1, 29, 30 or 31 and a pharmaceutically acceptable carrier or vehicle.
33. 33. A pharmaceutical combination comprising the compound of any one of claims 1, 29, 30 or 31 and an additional therapeutic agent.
34. 34. The pharmaceutical combination of claim 33 wherein the additional therapeutic agent is used to treat a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovary disorder, an eating disorder, craniopharyngioma, Prader syndrome. Willi, Frohlich syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing syndrome, hypertension, arteriosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, worn muscles, cognitive disease, dementia, depression, psoriasis, glaucoma, osteoporosis, viral infection, inflammatory disorders and immune disorder.
35. 35. A pharmaceutical composition comprising the pharmaceutical combination of claim 33 and a pharmaceutically acceptable carrier or vehicle. 36. A pharmaceutical composition comprising the pharmaceutical combination of claim 34 and a pharmaceutically acceptable carrier or vehicle.
36. 36. A pharmaceutical composition comprising the pharmaceutical combination of claim 34 and a pharmaceutically acceptable carrier or vehicle.
37. 37. A method for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovary disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, worn muscles, cognitive disorders, dementia, depression , psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and immune disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I): or salts, solvates, stereoisomers, or pharmaceutically acceptable drugs thereof, wherein: R1, R2 and R3 are independently selected from -H, -halo, -OH, CN, -N02, -C? -C8 alkyl -C2-C8 alkenyl-alkoxy, haloalkyl, hydroxyalkyl, -cycloalkyl, heterocyclyl-alkyl, -heteroaryl and -aryl and at least one of R1, R2 and R3 is other than -H; R4 is -H, halo, -CN, -N02, R2 and R3 -C? -C8 alkyl, -C2-C8 alkenyl -C2-C8 alkenyl -C2-C8 alkynyl, -alkoxy, -haloalkyl, -C2-C8 hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl- (Ci-Cβ alkyl), -heterocycle- (C? -C6 alkyl), -heteroaryl- (C? -C6 alkyl), aryl- (C? -C6 alkyl), C (0) R ', -C (0) OR', -C (0) N (R) 2, -C (0) R ', -OR', - SR ', -0C (0) R', - C (0) N (R ') 2, -S (O) R', -so 2 R ', -S02N (R') 2, -N (R ') 2, O -NR', C (0) R ', R5, is -H, -halo, -CN, -N02, -C? -C8 alkyl, -C2-C8 alkenyl -C2-C8 alkenyl, -alkoxy, -haloalkyl, hydroxyalkyl, -cycloalkyl, -heterocycloalkyl, heteroaryl, -aryl, -cycloalkyl-C? -C6 alkyl), -heterocycle- (C1-C6 alkyl), -heteroaryl- (C? -C6 alkyl), -aryl- (C? -C6 alkyl), -C ( 0) R ', -C (0) N (R') 2, -C (OR ') R', -OR ', - SR ', -OC (0) R', - C (0) N (R ') 2, -S (0) R', -S02 R ', -S02N (R') 2, -N (R ' ) 2, O -NR ', C (0) R', and R5 and R6 together with the carbon atom to which they are attached are bonded to form an optionally substituted cycloalkane ring. R6 is -H, halo, -CN, -N02, -C? -C8 alkyl, -C-C8 alkynyl, alkoxy, -haloalkyl, -hydroxyalkyl, cycloalkyl, -heterocycloalkyl, -heteroaryl, -aryl, -cycloalkyl-Ci -C-alkyl), -heterocycle- (Ci-Cβ alkyl), -C (0) R ', -C (0) 0R', -C (0) N (R ') 2, C (OR'), OR ', -SR', -0C (0) R ', - C (0) N (R') 2, -S (0) R ', -S02R', - S02N (R ') 2, -N (R ') 2, OR -NR'C (0) R'; R7 is selected from the group consisting of -H, -halo, -CN, -N02, amino and -C? -C8 alkyl. Q is selected from the group consisting of -H, -halo, -CN, -NO2, -Ci-Cs alkyl, -C2-C8 alkenyl, alkoxyl, -haloalkyl, -hydroxyalkyl, -cycloalkyl, heterocycloalkyl, -heteroaryl, -aryl , -cycloalkyl- (- C? -C6), -heteroaryl- (C? -C6 alkyl, -aryl- (C1-C6 alkenyl), -C (0) R ', -C (0) 0R', -C (0) N (R) 2, -C (OR ') R', -OR ', - SR', --C (0) N (R ') 2, -S (0) R', -SO2R ' , -S02N (R ') 2, -N (R') 2, O -NR ', C (0) R'; L1 is a direct bond, -C1-C7 alkylene or -C1-C7 heteroalkylene. direct bond, -C1-C7 alkylene or -C1-C7 heteroalkylene Where each presence of R 'is independent -H, -C? -C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, alkoxy, -alkoxyalkyl , -haloalkyl, -hydroxyalkyl, -cycloalkyl, -heteroalkyl, -heteroaryl, -aryl, cycloalkyl- (C? -C6 alkyl), -heterocycle- (Ci-Ce alkyl), -heteroaryl (Ci-C? alkyl), or aryl- (C? -C6 alkyl), or two R 'groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached. linked to form a heterocycle or heteroaryl group; and where when R1 and R3 are each -F or -CH3, R4 is other than -H.
38. 38. A method for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovary disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, worn muscles, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immunological disorder, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
39. 39. The method of claim 38, where the condition or disorder is diabetes u obesity.
40. 40. The method of claim 38, wherein the condition or disorder responsive to the modulation of a hydroxysteroid dehydrogenase, comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
41. 41. The method of claim 40 wherein the hydroxysteroid dehydrogenase is llbeta-HSDl.
42. 42. The method of claim 40, wherein the hydroxysteroid dehydrogenase is llbeta-HSD2.
43. 43. The method of claim 40, wherein the hydroxysteroid dehydrogenase is 17beta-HSD3.
44. 44. The method of claim 41, wherein the condition or disorder is selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, worn muscles, disorders cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immunological disorder.
45. 45. The method of claim 43, wherein the condition or disorder is a disorder related to an androgen or estrogen.
46. 46. A method for treating a condition or disorder mediated by hydroxysteroid dehydrogenase, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
47. 47. The method of claim 46, in hydroxysteroid dehydrogenase it is llbeta-HSDl.
48. 48. The method of claim 38, wherein the hydroxysteroid dehydrogenase is llbeta-HSD2.
49. 49. The method of claim 38, wherein the hydroxysteroid dehydrogenase is llbeta-HSD3.
50. 50. The method of claim 46, wherein the condition or disorder is selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, worn muscles, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immunological disorder.
51. 51. The method of claim 46, wherein the condition or disorder is a disorder related to an estrogen or androgen.
52. 52. The method of claim 38, 40 and 46, wherein the compound is administered orally, parenterally or topically.
53. 53. The method of claim 38, 40 and 46, wherein the compound is administered in combination with a second therapeutic agent.
54. 54. The method of claim 38, 40 and 46, wherein the patient is a human.
55. 55. The method of claim 53, wherein the second therapeutic agent is useful for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovary disease, an eating disorder, craniopharyngioma, Prader syndrome. -Willi, Frohlich syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative diseases , neuropathy, worn muscles, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immunological disorder.
56. 56. A method for modulating the function of a hydroxysteroid dehydrogenase in a cell, comprising contacting a cell with a compound of claim 1.
57. 57. A method for modulating a hydroxysteroid dehydrogenase, comprising contacting a hydroxysteroid dehydrogenase protein, with a compound of claim 1.
58. 58. The method of claim 56 or 57, wherein the compound inhibits a hydroxysteroid dehydrogenase.
59. 59. The method for modulating the function of llbeta-HSDl in a cell, comprising contacting a cell with a compound of claim 1.
60. 60. The method for modulating the function of llbeta-HSDl, comprising contacting a llbeta-HSDl protein with a compound of claim 1.
61. 61. The method of claim 59 or 60, wherein the compound inhibits the llbeta-HSDl.
62. 62. A method for modulating the function of llbeta-HSD2 in a cell, comprising contacting a cell with a compound of claim 1.
63. 63. A method for modulating the llbeta-HSD2, comprising contacting a protein of llbeta-HSD2 with a compound of claim 1.
64. 64. The method of claim 62 or 63, wherein the compound inhibits the llbeta-HSD2.
65. 65. A method for modulating the function of llbeta-HSD3 in a cell, comprising contacting a cell with a compound of claim 1.
66. 66. The method for modulating 17beta-HSD3, which comprises contacting a 17beta protein. HSD3 with a compound of claim 1.
67. 67. The method of claim 65 or 66, wherein the compound inhibits 17B-HSD3.
68. 68. The compound of claim 1, which is pure in enantiomeric form.
69. 69. The compound of claim 1, which is pure in diastereomeric form.
70. 70. The compound of claim 1, which is isolated and in pure form.