MX2007015998A - Alkyl sulfonamide derivatives. - Google Patents

Abstract

This invention is directed to alkyl sulfonamide derivatives which are ligands at the NPY Y5 receptor. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a pharmaceutical composition made by admixing a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of a compound of the subject invention. This invention also provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of a compound of the subject invention. This invention also provides a method of treating a subject suffering from obesity which comprises administering to the subject an amount of a compound of the subject invention.

Description

DERIVATIVES OF ALKYLSULFONAMIDE FIELD OF THE INVENTION The present invention relates to compounds that are linked to the Y5 receptor of the heuropeptide Y, and as such, are used to treat disorders, such as depression, anxiety and obesity.

BACKGROUND OF THE INVENTION Through the application, several publications are referenced in complete citations. The descriptions of these publications are hereby incorporated by reference in this application to more fully describe the state of the art to which this invention pertains. Neuropeptide Y (NPY) is a neuropeptide of 36 amino acids expressed in the central and peripheral nervous system. This peptide is a member of the pancreatic polypeptide family, which also includes the pancreatic polypeptide (PP) and peptide YY (PYY). However, the biological effects of NPY are mediated through their interaction with receptors that belong to the superfamily of G-protein coupled receptors. Currently, five subtypes of the NPY receptor have been cloned: Yl (D. Larhammar, et al. , J. Biol. Chem., 1992, 267, 10935-10938); Y2 < C. Gerald, et al., J. Biol. Chem., 1995, 270, 26758-26761); Y4 (J. Bard, et al., J. Biol. Chem., 1995, 270, 26762-26765); Y5 (C. Gerald, et al., J. Biol. Chem., 1995, 270, 26758-26761); and y6 (P.Gregor, et al., J. Biol. Chem., 1996, 271, 27776-27781). All of these receptor subtypes are expressed in several species, except for subtype y6, which has been shown to be expressed in mice and rabbits, but not in rats and primates. A Y3 subtype has been proposed in pharmacological data. However, subtype Y3 has not yet been cloned and its existence remains to be fully established. NPY exerts numerous physiological effects. Based on animal studies, it is clear that there is a contribution relationship between NPY and its receptors with disorders such as depression, anxiety and obesity. For example, NPY expression is shown to be sensitive to energy status, while administration of NPY reduces energy consumption, and another significant capacity of NPY is to extremely stimulate feeding (S. Kalra, et al., Endocr. Rev., 1999, 20, 68-100). The NPY Y5 receptor has also been shown to be a receptor subtype responsible for the uptake of food induced by NPY (C. Gerald, et al., Nature, 1996, 382, 168-171). Additionally, the link between NPY or mood disorders, such as depression and anxiety, is established in the literature. For example, rats subjected to medium stress chronic, exhibit anhedonia, a characteristic of clinical depression (P. Willner, et al., Eur. J. Pharmacol., 1997, 340, 121-132); they also contain high levels of NYP mRNA in the hypothalamus, accompanied by a reduction in the hippocampus (V. Sergeyev, et al., Psychopharmacology, 2005, 178, 115-124). The behavioral changes associated with chronic mean stress are reversed by a variety of antidepressants (P. Willner, et al., Eur. J. Pharmacol., 1997, 340, 121-132). In a study of antidepressant therapies, rats treated with citalopram exhibit an increased level of binding to the hippocampal NPY receptor, with no change in NPY-like immunoreactivity (H. Husu, et al., Neuropsychopharmacology, 2001, 2, 183-191); conversely, the electroconvulsive shock produces an increased level of immunoreactivity similar to hippocampal NPY, with no change in the NPY receptor binding. These findings suggest that abnormal levels of NPY play a role in depressive illness, and that agents capable of regulating NPY and / or NPY receptor function, particularly in limbic regions, are employed to treat depression. Y5 is an NPY receptor expressed in limbic regions (M. Wolak, et al., J Comp.Neurol., 2003, 22, 285-311; and K. Nichol, et al., J. Neurosci., 1999, 19, 10295-10304). Therefore, agents capable of regulating the function of the Y5 receptor are therefore predicted to be used to treat depression. Animal models of anxiety also reveal abnormal levels of NPY. In one example, maternally separated rats exhibit an anxious and depressive phenotype throughout adulthood (R. Huot, Psychopharmacology, 2001, 158, 366-73); they also contain high levels of immuno-similar activity to NPY in the hypothalamus, accompanied by a reduction in the hippocampus and cortex (P. Jimenez-Vas'quez, Brain Res. Dev., 2001, 26, 149-152, H. Husum and A. Mathe, Neuropsychopharmacology, 2002 27: 756-64, and H. Husum et al., Neurosci Lett, 2002, 333, 127-130). In a second example, rats subjected to fear conditioning exhibit increased behavior similar to anxiety, they also contain elevated levels of NPY in the hypothalamus, amygdala and acupuncture nucleus, accompanied by a reduction in the frontal cortex. Changes in behavior produced by fear conditioning can be reversed by treatment with anxiolytic drugs. In a fear conditioning study, both anxiety-like behavior and altered expression of NPY were reversed by ... treatment with diazepam (R. Krysiak, et al,? Europeptides, 2000, 34, 148-57). These findings also suggest that? PY plays a role in anxiety, and that agents capable of regulating? PY and / or receptor function, particularly in limbic regions, are employed to treat anxiety. Y5 is an NPY receptor expressed in limbic regions (M. Wolak, et al., J. Comp.Neurol., 2003, 22, 285-311; and K. Nichol, et al., J. Neurosci., 1999 , 19, 10295-10304). Therefore, the agents capable of regulating the function of the Y5 receptor are therefore predicted to be used to treat anxiety. In the laboratory, the compounds of the invention have been evaluated in animal models, predictive for antidepressant activity. It has been discovered that these compounds produce effects similar to those observed by known antidepressants. Numerous groups have postylated several small molecule ligands of NPY Y5 for the treatment of these disorders. In addition to possessing the appropriate pharmacological elements to move forward in the clinic, a compound must have favorable ADME properties, such as metabolic stability. Publications that relate to drug-drug interactions and toxicity should also be addressed. The metabolic stability of a drug can be predicted by its separation ratio in hepatic microsomes. Additionally, cytochrome P450 (CYP) plays a role in metabolism, and the inhibition of CPY can be used to diagnose the potential risks of interactions and / or drug-drug toxicity.

However, current treatments for depression, anxiety and obesity are in the market. However, many patients do not respond to current treatments. Therefore, the need for alternative methods of treatment remains.

BRIEF DESCRIPTION OF THE INVENTION The objective of the present invention is to provide compounds that are ligands to the NPY Y5 receptor. The present invention relates to compounds of Formula I.

Formula I wherein R1 is H or straight or branched chain C6-6 alkyl; wherein R2 is straight or branched chain C? -C6 alkyl; or where R1, R2 and the carbon to which they are. united, they form a C3-C6 cycloalkyl; wherein R3 is H or methyl; wherein R 4 is 2-pyridyl, 3-pyridyl or pyrazinyl, wherein 2-pyridyl, 3-pyridyl or pyrazinyl, can be substituted with methyl; : wherein R5 is H or methyl; where m is an integer from 0 to 2 inclusive; and where n is an integer from 0 to 2 inclusive; or a pharmaceutically acceptable salt thereof. In separate embodiments of the invention, the compound is selected from one of the specific compounds described in the Experimental Section. In addition, the present invention provides a pharmaceutical composition comprising, a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier. The present invention also provides a process for making a pharmaceutical composition comprising, mixing a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier. However, the present invention provides a method for treating a subject suffering from depression comprising, administering to the subject, a therapeutically effective amount of a compound of Formula I. The present invention further provides a method for treating a subject suffering from anxiety comprising, administering to the subject, a therapeutically effective amount of a compound of Formula I. The present invention also, provides a method for treating a subject suffering from obesity comprising, administering to the subject, a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions In the present invention, the term "straight or branched chain Ci-Cß alkyl" refers to a saturated hydrocarbon having from one to six inclusive carbon atoms. Examples of such substituents include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, n- pentyl and n-hexyl. Similarly, the term "straight or branched chain C 1 -C 4 alkyl" refers to a saturated hydrocarbon having one to four inclusive carbon atoms. Examples of such substituents include, but are not limited to, methyl, ethyl and 1-propyl. In addition, the term "C3-C6 cycloalkyl" refers to a saturated cyclohydrocarbon ring having from three to six inclusive carbon atoms. Included within this term are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The specific compounds described in the present invention are identified by their IUPAC names and their respective chemical structure. The names of the compounds were generated using the database of the Chemistry 4-D Draw Nomenclator ™ (Version 7.01c, Cheminnovation Software, Inc.). In accordance with Cheminnovation Software Inc., Nomenclature ™, it automatically assigns systematic names to organic structures in accordance with the IUPAC naming rules. However, as described in Formula I, the stereochemistry of the 1,4-cyclohexyl ring is trans, and the designation has been added. Accordingly, this application describes the alkylsulfonamide derivatives encompassed by Formula I, in accordance with the IUPAC naming rules. For illustrative purposes and without limiting the invention, the compound of Example 2b has the following structure: This compound is constructed of Formula I, wherein R1, R2 and the carbon to which they are attached form cyclopropyl; R3 is H; m is 1; n is 0; R 4 is 2-pyridyl; and R5 is H. Additionally, the invention further provides for certain embodiments of the present invention described below. In an additional embodiment, R5 is H.

In another embodiment, R5 is methyl. In one embodiment, R3 is H; R 4 is 2-pyridyl or pyrazinyl, wherein the 2-pyridyl or pyrazinyl can be substituted with methyl; m is 0 or 1; and n is 0 or 1. In one embodiment, R 1 is H or straight or branched chain C 1 -C 4 alkyl; and R 2 is straight or branched chain C 1 -C 4 alkyl. In one embodiment, R1 is H, methyl or ethyl; R2 is methyl or ethyl; and R 4 is 2-pyridyl, wherein 2-pyridyl can be substituted with methyl. In one embodiment, R1 is methyl and R2 is methyl. In a further embodiment, n is 1. In one embodiment, R1, R2 and the carbon to which they are attached, form C3-C6 cycloalkyl- In one embodiment, R4 is 2-pyridyl. In another embodiment, R1 is H or straight or branched chain C? -C alkyl; R 2 is straight or branched chain C 1 -C 4 alkyl; R3 is H; R 4 is 3-pyridyl or pyrazinyl, wherein 3-pyridyl or pyrazinyl is substituted with methyl; m is 0 or 1; and n is 0 or 1. In one embodiment, R 1 is H or C 1 -C 4 alkyl of straight or branched chain; R 2 is straight or branched chain C 1 -C 4 alkyl; R3 is H; R 4 is 2-pyridyl, wherein the 2-pyridyl can be substituted with methyl; m is 0, or 1; and n is 0 or 1. In one embodiment, R1 is methyl; R2 is methyl; and n is 0. In one embodiment, R1 is methyl; R2 is methyl; and m is 0. In one embodiment, R 4 is 3-pyridyl, wherein 3-pyridyl is substituted with methyl. In one embodiment, R3 is H; m is 0 or 1; and n is 0 or 1; and R 4 is 2-pyridyl or pyrazinyl, wherein the 2-pyridyl or pyrazinyl can be substituted with methyl. In another embodiment, R1 is H or straight or branched chain C? -C alkyl. In one embodiment, R 2 is straight or branched chain C 1 -C 4 alkyl. In yet another embodiment, R1 is H, methyl or ethyl; R2 is methyl or ethyl; and R 4 is 2-pyridyl. In a further embodiment, m is 1. In one embodiment, R1, R2 and the carbon to which they are attached, form cyclopropyl or cyclobutyl; and n is 0.

Pharmaceutically Acceptable Salts The present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable addition salts. The addition salts include salts of inorganic acids, as well as organic acids.

Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include, formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic acids , succinic, methanesulphonic, ethanesulphonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, glusonic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic, theophylline acetic acids, as well as also the 8-haloteofilinas (for example, 8-bromoteofilina and similars). In addition, examples of pharmaceutically acceptable addition salts, of organic or inorganic acid include, the pharmaceutically acceptable salts listed in S. M. Berge, et al., J. Farm. Sci. 1977, 66, 2, contents of which are incorporated herein by reference. In addition, the compounds of this invention can exist in unsolvated forms, as well as in pharmaceutically acceptable solvated forms, such as water, ethanol and the like. In general, solvated forms are considered equivalent to non-standard forms solvated for purposes of this invention. The racemic forms can be resolved in optical antibodies by known methods for example, by separating diastereomeric salts thereof, with an optically active acid, and releasing the optically active amine compound by treatment with a base. The separation of such diastereomeric salts can be achieved, for example, by fractional crystallization. Optically active acids suitable for this purpose can include, but are not limited to, d or l-tartaric, mandelic or camphorsulfonic acids. Another method for resolving racemates in the optical antipodes is based on chromatography in an optically active matrix. The compounds of the present invention can also be resolved by the formation and chromatographic separation of diastereomeric derivatives of the chiral derivatizing reagents, such as acylation reagents or chiral alkylation, followed by cleavage of the chiral auxiliary. Any of the above methods can be applied either to resolve the optical antipodes of the compounds of the invention per se, or to solve the optical antipodes of the synthetic intermediates, which can then be converted by the methods described herein in the optically resolved end products, which are the compounds of the invention.

Additional methods for the resolution of optical isomers, known to those skilled in the art, can be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York 1981. The optically active compounds were also prepared from optically active starting materials. The invention also encompasses prodrugs of the present invention, which upon administration, undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of Formula I, which are readily convertible in vivo to the required compound of Formula I. Conventional procedures for the selection and preparation of suitable drugs are described in > , Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Pharmaceutical Compositions The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition that comprises, a therapeutically effective amount of one of the specific compounds described in the Experimental Section and a pharmaceutically acceptable carrier. The compounds of the invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents, as well as any other known adjuvants and excipients, in accordance with conventional techniques, such as those discussed in, Remington: The Science and Practice of Pharmacy, 19h Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The pharmaceutical compositions can be specifically formulated for administration by any suitable route, such as, oral, rectal, nasal, pulmonary, topical ( which includes buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including, subcutaneous, intramuscular, intrathecal, intravenous and intradermal). It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient. The pharmaceutical compositions for administration oral include, solid dosage forms, such as, capsules, tablets, dragees, pills, dragees, powders and granules. Where appropriate, the compositions can be prepared with coatings such as enteric coatings, or can be formulated to provide controlled release of the active ingredient such as sustained or prolonged release, in accordance with methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include, solutions, sterile aqueous and non-aqueous injectables, dispersions, suspensions or emulsions, as well as sterile powders, to be reconstituted in sterile injectable solutions or dispersions, before use. Other forms of suitable administration include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, skin patches and implants. Typical oral dosages range from about 0.001 to about 100 mg / kg of body weight per day. Typical oral dosages also vary from about 0.01 to about 50 mg / kg of body weight per day. The typical oral dosages also vary from approximately 0.05 to approximately 10 mg / kg of body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend on the frequency and mode of administration, sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated, and other factors evident to those experts in the treatment. technique. The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 to about 200 mg. For parenteral routes such as intravenous, intrathecal, intramuscular administration and the like, typical doses are in the order of half the dose used for oral administration. The present invention also provides a process for making a pharmaceutical composition comprising, mixing a therapeutically effective amount of a compound of Formula I and a pharmaceutically carrier. acceptable. In one embodiment of the present invention, the compound used in the aforementioned process is one of the specific compounds described in the Experimental Section. The compounds of this invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. An example is an acid addition salt of a compound having the utility of a free base. When a compound of Formula I contains a free base such as salts, they are prepared in a conventional manner by treating a solution or suspension of a free base of Formula I with one molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic or inorganic acids are described above. For parenteral administration, solutions of the compounds of Formula I in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil, may be employed. Such aqueous solutions must be adequately buffered if necessary and the liquid diluent first provided isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of Formula I can be easily incorporated in sterile aqueous medium known using standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of Formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the routes of administration described. The formulations can conveniently be presented in unit dosage form by methods known in the art of pharmacy. The formulations of the present invention suitable for oral administration can be presented as discrete units, such as capsules or tablets, each one containing a predetermined amount of the active ingredient, and optionally a suitable excipient. In addition, orally available formulations may be in the form of a powder or granules, or an aqueous or non-aqueous liquid solution or suspension, or a liquid oil-in-water or water-in-oil emulsion. If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in the form of a powder or pellet, or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely, but will be in the range of from about 25 mg to about 1 g per unit dosage. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as a suspension or aqueous or non-aqueous liquid solution.

Treatment of Disorders As mentioned above, the compounds of Formula I are ligands to the NPY Y5 receptor. The present invention provides a method for treating a subject suffering from depression, which comprises administering to the subject, a therapeutically effective amount of a compound of this invention. The present invention provides a method to treat a subject suffering from anxiety, which comprises administering to the subject, a therapeutically effective amount of a compound of this invention. This invention further provides a method for treating a subject suffering from obesity, which comprises, administering to the subject, a therapeutically effective amount of a compound of this invention. In one embodiment of this invention, the subject is a human being. Additionally, the present invention is directed to the use of a compound of Formula I for the preparation of a pharmaceutical composition, for treating a subject suffering from depression. This invention further provides the use of a compound of Formula I for the preparation of a pharmaceutical composition for treating a subject suffering from anxiety. This invention also provides the use of a compound of Formula I for the preparation of a pharmaceutical composition for treating a subject suffering from depression. The invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed herein are merely illustrative of the invention as described more fully in the claims which follow subsequently. In addition, the variables represented in Reaction Schemes 1-7 are consistent with the variables mentioned in the Summary of the Invention. In the Experimental Section, standard acronyms are used. Examples of such acronyms include: DMF (N, N-dimethylformamide); TEA (triethylamine); DPPA (diphenylphosphorylazide); BzNCS (Benzoylisothiocyanate); Et20 (diethyl ether); MTBE (methyl t-butyl ether); EtOAc (ethyl acetate; THF (tetrahydrofuran); ta (room temperature); h (hour); and min (minutes) In addition, in certain cases, the methods for preparing the compounds of the invention are described generally, with reference to representative reagents such as bases or solvents The particular reagent identified is representative but not inclusive and does not limit the invention in any way For example, representative bases include but are not limited to, K2C03, TEA or DIEA (diisopropylethylamine) However, the term "-halo ketone of Formula XII" refers to a ketone with a halogen, being chlorine, bromine or iodine-haloketones are commercially available, for example, 2-bromo-l- (2-pyridine). ethan-1-one and 2-bromo-l- (3-pyridyl) ethan-1-one are sold by Aldrich Alternatively, one skilled in the art will be able to synthesize the -haloketones referred to in this invention in various routes. For example, ketones can be halogenated in the with bromine, chlorine or iodine, to provide - halocetones (V. From Kimpe, The Chemistry -Haloimines; Wiley: New York, 1988). Additionally, haloketones can be synthesized from carboxylic acids by treatment of the acid with TMS-diazomethane, followed by treatment of Cl 2 O Br 2. The term "PG", as defined in the Scheme of Reaction 5, used to designate a "protecting group", a person skilled in the art will be able to select the appropriate protective group by a particular reaction. However, it may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid and hydroxyl groups, in the synthetic methods described below, to synthesize the compounds of Formula I. Methods for protection deprotection of such groups , are well known in the art, and can be found in, T. Green, et al., Protection Groups in Organic Synthesis, 1991, 2nd. Edition, John Wiley & Sons, New York.

Experimental Section General Methods: Anhydrous solvents are purchased from Aldrich Chemical Company, and are used as received. The NMR spectra were measured on a Bruker Avance 400 or 300 MHx (Varian) spectrometer with CDC13, DMSO-d6 or CD3OD, as the solvent, with tetramethylsilane as the internal standard, unless otherwise indicated. The chemical changes (d), they are expressed in ppm, the coupling constants (J) are expressed in Hz, and the division patterns are described as follows: s = singlet; d = doublet; t = triplet; q = quartet; br = broad; m = multiplet; dd = doublet of doublets; dt = doublet of triplets; dt = triplet of doublets; dq = quartet doublet. Unless otherwise noted, mass spectra were obtained using electro dew ionisation (ESMS, Micromass Platform II or Qúattro Micro). For the LC-MS spectrum, the following methods were used: Method-A: Luna C18 column, 5% up to 95% Acetonitrile / H20 with 0.05% formic acid; Method-B: Luna C18 column, 15% up to 85% Acetonitrile / H20 with 0.05% formic acid; Method-C: Luna C8 column, 15% up to 85% methanol in water with 0.05% ammonium formate: D-method: C18 column, Neutral pH, 20% up to 90% Acetonitrile / H20 with 0.2% formate ammonium; or E-method: column C18, acidic pH, 20% up to 90% Acetonitrile / H20 with 0.2% AcOH. The thin-layer chromatography (CCD) was carried out on glass plates pre-coated with silica gel 60 F254 (0.25 mm, EM Separations Tech.). The preparative CCD was carried out on glass sheets pre-coated with silica gel GF (2 mm, Analtech). Silica gel column chromatography was performed on 60 Merck silica gel (230-400 mesh)! List and source of chemicals Cyclohexylsulfonyl chloride, cyclopentylsulfonyl chloride and isopentylsulfonyl chloride were obtained from Array Biopharma. 2-Bromo-l-pierazin-2-yl-ethanone was obtained from Beta Pharma Inc. Secon-butylsulfonyl chloride and 2-pentylsulfonyl chloride were obtained from Oakwood Products Inc. 2-Acetyl-3-methylpyrazine was obtained from Aldrich .

Methods for Preparing the Compounds of Formula I Reaction Scheme 1 C (a) DPPA, TEA, Toluene, BnOH, reflux, (b) 10% Pd-C, H2, MeOH / EtOAc. (c) IM NaOH, Et20, (R1) (R2) (R3) CS02C1. (d) 10% of TFA in CH2C12. (e) BzNCS, THF, ta. (f) K2C03, MeOH / H20, reflux, (g) -halo ketone of Formula XXII, DIEA, EtOH, reflux.

The compounds of Formula I can be synthesized in accordance with the procedures described in Reaction Scheme I. Compounds of Formula II are commercially available or can be synthesized by one skilled in the art. In summary, the carboxylic acids of Formula II are converted to their Cbz-protected amines, to provide the compounds of Formula III. The Cbz protecting group is selectively removed to provide the compounds of Formula IV. The resulting amines are coupled with (R1) (R2) (R3) CS02C1 to provide the intermediates of Formula V. The Boc group is removed and the resulting amines of Formula VI are treated with benzoylisothiocyanate to provide the compounds of Formula VII. The compounds of Formula VII are subjected to basic solvolysis, to provide the thiourea intermediates of Formula VIII. These intermediates are coupled with the appropriate haloketone of Formula XXII to provide the compounds of the invention.

Reaction Scheme 2 a) ÍM NaOH, Et20, BOC20. (b) ÍM NaOH, Et20, (R1) (R2) (R3) CS02C1. (c) DPPA, TEA, Toluene, BnOH, reflux, (d) 10% TFA in CH2C12. (e) ÍM NaOH, Et20, (R1) (R2) (R3) CS02C1. (f) 10% Pd-C, H2, EtOH, heat or HBr / AcOH.

Alternatively, the intermediates of Formula VI can be synthesized in accordance with the procedures outlined in Reaction Scheme 2. The starting materials of Formula IX are commercially available or can be synthesized by one skilled in the art. The amino acids of Formula IX can be coupled with (R1) (R2) (R3) CS02C1, to provide the intermediates of Formula X, which are furthermore, converted to the Cbz-protected amines of Formula XII. Separately, the amino acids of Formula IX can be converted into intermediates protected mono-Cbz of Formula XI. The amines of Formula XI are coupled with (R1) (R2) (R3) CS02C1, to provide the compounds of Formula XII. The Cbz group of Formula XII is removed to provide the intermediates of Formula VI. Finally, the intermediates of Formula VI can be converted to the compounds of the invention, using the methods described in Reaction Scheme 1. Additionally, the intermediates of Formula X can be converted to compounds of Formula V, which are described in Reaction Scheme 1, if the t-butanol is replaced by benzyl alcohol.

Reaction Scheme 3 XIV XV (a) 10% Pd-C, H2, EtOAc / MeOH, ta (b) BzNCS, THF, ta. (c) K2C03, MeOH / H20, reflux, (d) -halo ketone of Formula XXII, DIEA, EtOH, reflux, (e) 10% TFA in CH2C12. (f) (R1) (R2) (R3) CS02C1, DIEA, CH2C12, ta.

Additionally, the compounds of Formula I can be synthesized in accordance with the procedures outlined in Reaction Scheme 3. In summary, the Cbz group of formula III is removed to provide the intermediates of Formula IV. These intermediaries are converted to the thioureas of Formula XIII. The thiazole ring is formed to provide the compounds of Formula XIV. The BOC group is removed to provide the amines of Formula XV. The compounds of the invention are synthesized by coupling the amines with (R1) (R2) (R3) CS02C1.

Reaction Scheme 4 Procedure A HaN? J IV m = l v n = l (a) ÍM NaOH / Et20, BOC20. (b) CH2C12, 1-Methylmorpholine, isobutyl chloroformate, -20 ° C, NH (OMe) aHCl. (c) LAH, Et20, -45 ° C. (d) NaCNBH3, -MeOH, NH4OAc, ta.

Procedure B IV m = 2 v n = 2 (a) CH2C12, MsCl, TEA, 0 ° C. (b) NaCN, DMF, 80 ° C or Et4NCN, Toluene, 80 ° C. (c) LAH, THF. (d) 0.2 'eq. (BOC) 20, Dioxane, ta.

The compounds of Formula IV are used as intermediates in Reaction Schemes 1, 2 and 3. These intermediates, where n = l and m = l (procedure A) or where n = 2 and m = 2 (procedure B), are synthesized in accordance with the procedures described in Reaction Scheme 4. For representative reaction conditions in conjunction with the synthesis of the diamine in Procedure B, see, P. Garcia, et al., J. Org. Chem. ,, 1961, 26, 4167-4168. For representative reaction conditions in conjunction with the synthesis of protected mono Boc diamine in Procedure B, see, for example, J. Hansen, et al., Synthesis, 1982, 5, 404-405 and C. Dardonville, et al. , Bioorg. Med. Chem. Lett., 2004, 14, 491-493.

Reaction Scheme 5 XVI XVII XVIII vs (a) TEA, CH2C12, (R1) (R2) (R3) CS (O) Cl. (b) NaI04, RuCl3 (cat) or mCPBA. (c) deprotection.

The sulfonamides of Formula VI can also be synthesized according to the procedures outlined in Reaction Scheme 5. In summary, the compounds of Formula XVI are reacted with (R1) (R2) (R3) CS (O) Cl to provide the sulfonamides of Formula XVII. These compounds are oxidized with the intermediates of Formula XVIII. The protecting group is removed to form the intermediates of Formula VI. Finally, the intermediates of Formula VI can be converted to the compounds of the invention using the procedures described in Reaction Scheme 1. For representative reaction conditions, see S. Weinreb, J. Org. Chem., 1997, 62, 8604-8608; J. Ell an, Tetrahedron Lett., 2001, 42, 1433-1436; B. Sharpless, Org. Lett., 1999, 1, 783-786; and WO 01/37826.

Reaction Scheme 6 XXIII (a) (COCÍ) 2, cat. DMF, CH2C12, is (b) 2M TMSCH2N2 in Et20, Dioxane, ta. (c) 4M HCl in dioxane, ta or HBr in AcOH, ta. (d) HNMe (OMe) -HCl, EDC, HOBt CH2C12, ta. (e) EtMgBr, THF, -78 ° C, (f) Br2, 33% or 48% HBr in AcOHi ta.

The halo-ketones of Formula XXII can be synthesized in accordance with the procedures described in Reaction Scheme 6. Acids of Formula XIX are commercially available or can be synthesized by one skilled in the art. The acids of Formula XIX can be converted. to the corresponding acid chlorides of Formula XX. Acid chlorides can be treated with trimethylsilyldiazomethane or ethylmagnesium bromide to provide the intermediates of Formulas XXI (wherein R5 is H) or XXIV (wherein R is methyl), respectively. These intermediates can be converted to the -halo ketones of Formula XXII, wherein R5 is H or methyl, respectively. Alternatively, the acids of Formula XIX can be converted to the corresponding Weinreb midas of Formula XXIII, which are also, converted to the halo-ketones of Formula XXII using ethylmagnesium bromide (wherein R5 is methyl). Similarly, if the methylmagnesium bromide is replaced by ethylmagnesium bromide, R5 is H. For purposes of clarity, the R * portion is used to denote that the 2-pyridyl, 3-pyridyl or pyrazinyl group is optionally substituted with methyl. . The variable X is used to denote CH or N. For representative reaction conditions in conjunction with the conversion of carboxylic acids to bromoketones using trimethylsilyldiazomethane, see, A. Gangjee, et al., Bioorg. Med. Chem., 2003, 11, 5155-5170. For representative reaction conditions in conjunction with the conversion of the -haloketones from ketones using Br2 / AcOH or sulfuryl chloride and MeOH, _ see, N. Ikemoto, et al., Tetrahedron, 2003, 59, 1317-1325; or using Pyridine-Br3, HBr / AcOH, see, W.C. Patt and MA Massa, Tetrahedron Lett, 1997, 38, 1297-1300.

Reaction Scheme 7 XXIV XXII (a) EtMgBr, THF, -78 ° C. (b) Br2, 33% or 48% HBr in AcOH.

Alternatively, the halo-ketones of Formula XXII can be synthesized in accordance with the procedures described in Reaction Scheme 7, starting with the starting materials of Formula XXV. The cyano compounds are treated with ethylmagnesium bromide to provide the intermediates of Formula XXIV, wherein R5 is methyl. Similarly, if the methylmagnesium bromide is replaced by ethylmagnesium bromide, R5 is H. The intermediates of Formula XXIV are furthermore, converted to the -haloketones of Formula XXII. For purposes of clarity, the R * portion is used to denote that the 2-pyridyl, 3-pyridyl or pyrazinyl group is optionally substituted with methyl. The variable X is used to denote CH or N. For representative reaction conditions, in conjunction with the transformation of the cyano group, see, N. B. Mehta, J. Clin. Psychiatry, 1983, 44, 56; and S. W. Baldwin and J. E. and Fredericks, Tetrahedron Lett., 1982, 23, 1235-1238.

Preparation of Intermediaries Representative compounds of Formulas II-VIII were synthesized as follows: Intermediary of Formula II Trans-4- acid was added. { [(tert-butoxy) carbonylamino] methyl J-cyclohexanecarboxylic: BoC20 (41.7 g, 190 mmol), to a stirred biphasic solution containing trans-4- (aminomethyl) -cyclohexanecarboxylic acid (25.0 g, 159 mmol), NaHCO 3 (20 g, 238 mmol), water (300 ml) and Et20 (200 ml) at rt. The pH of the solution was adjusted to pH ~ 9.0 by adding additional amounts of saturated aqueous NaHCO 3. After stirring for 24 h at rt, the layers were separated and the aqueous layer was acidified to pH 4.0 with aqueous M HCl. The aqueous layer was extracted with EtOAc. The organic layer was isolated and washed successively with water and brine. The organic layer was concentrated in vacuo and dried under high vacuum to provide the desired product as an incplorous solid (23.3 g, 57%). 1 H NMR (CDC13) 4.60 (br s, 1 H), 2.99 (t, 2 H, J = 6.4 Hz), 2.29-2.23 (m, 3 H), 2.05 (dd, 2 H, J = 13.6 and 3.2 Hz), 1.84 (dd, 2H, J = 13.2 and 2.8 Hz), 1.44 (s, 9H), 1.42. (br, ÍH), 0.97 (dq, 2H, J = 25.6, 12.4 and 3.2 Hz).

Intermediate of Formula III The following was suspended (tert-butoxy) -N- ( { Trans-4- [(phenylmethoxy) carbonylamino] cydohexyl} methyl) carboxamide: trans-4- acid. { [(tert-butoxy) carbonylamino] methyl} Cyclohexanecarboxylic (20.3 g, 0.073 mol) in toluene (420 ml) and cooled to -10 ° C in a dry ice bath. DPPA (15.8 mL, 0.073 mol) was added and cooling was continued. TEA (15.3 ml, 0.11 mol) was added dropwise for 10 min. The color of the solution changed from milky white to transparent. The mixture was removed from the ice bath, heated to 10 ° C and then slowly heated to 70 ° C. After 15 h, nitrogen evolution was observed to be completed and the color of the solution changed to yellow. The mixture was cooled to 47 ° C and benzyl alcohol (22.8 ml, 0.220 mol) was added. The mixture was heated to 110 ° C or and stirred overnight. The mixture was cooled to 50 C and concentrated in vacuo to obtain amber solids. The solids were treated with deionized water (400 ml) and EtOAc (150 ml). The mixture was shaken for 10 min and the layers were isolated. The aqueous layer was extracted several times with EtOAc. The organic layers were combined, dried and concentrated in vacuo. The resulting solid was triturated in MTBE to give a white solid (17.8 g, 67%) as the desired product. 1 H NMR (CDC13) 7.34-7.286 (m, 3H), 7.13 (d, 2H, J = 8.0 Hz), 6.78 (t, 1 Hi J = 6.0 Hz), 4.97 (s, 2H), 3.3-3.14 (br, m, ÍH), 2.73 (t, ÍH, J = 6.3 Hz), 1.78 (d, 2H, J = 10.6 Hz), 1.64 (d, 2H, J = 11.8 Hz), 1.35 (s, 6H) , 1.35-1.00 (m, 3H), 0.87 (q, 2H, J = 12.5 and 2.8 Hz).

Intermediate of Formula IV N- [(trans-4-aminocyclohexyl) methyl] (tert-butoxy) carboxamide: 10% Pd-C (0.20 g) was added to a stirred solution of (tert-butoxy) -N- (. {trans -4- [(Phenylmethoxy) carbonylamino] cydohexyl} methyl) carboxamide (2.0 g, 5.5 mmol) in EtOAc / MeOH (1: 1, 50 mL) at rt. The mixture was degassed and purged with H2 twice, and further, it was stirred at rt, under a static atmosphere of H2 for 2 h. The mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to provide the desired compound as a colorless solid (1.3 g, 91%). lH NMR (CDC13) 4. 59 (br, s, 1 H), 2.97 (t, 2H, J = 6.4 Hz), 2.63-2.58 (m, ÍH), 1.87 (d, 2H, J = 12.4 Hz), 1.75 (d, 2H, J = 12.4 Hz), 1.44 (s, 9H), 1.37 (m, 1 H), 1.12-0.96 (m, 4H). EREM m / e: 173 ((M + H) -55) +.

Intermediate of Formula V Added (tert-butoxy) -N- [(trans-4. {[[(Methylethyl) sulfonyl] amino} cyclohexyl) methyl] carboxamide: isopropyl sulfonyl chloride (6.2 ml, 7.9 g , 56 mmol) by dripping at rt, to a stirred biphasic solution containing N- [(trans-4-aminocyclohexyl) methyl] (tert-butoxy) carboxamide (10 g, 44 mmol), ÍM aqueous NaOH (100 mL) and Et20 (100 mL). After stirring for 2 h, a white precipitate appeared. The precipitate was collected by filtration, washed with Et20 and dried under vacuum to obtain the desired product as a colorless solid (9.5 g, 65%). XH NMR (CDC13) 4.58 (br s, ÍH), 3.89 (d, ÍH, J = 8.0 Hz), 3.23 (septet, 1 H, J = 4.4 Hz), 2.96 (t, 2H, J = 6.4 Hz), 2.61 (m, 1 H), 2.09 (d, 2H, J = l 1.6 Hz), 1.89-1.74 (m, 3H), 1.44 (s, 9H), 1.37 (d, 6H, J = 6.8 Hz), 1.22 (dq, 1 H, J = 13.2 and 3.6 Hz), 1.09-1.00 (br m, 3H). EREM m / e: 279 ((M + H) -55) +.

Intermediate of Formula VI Add [trans-4- (aminomethyl) ciciohexyl] [(methylethyl) sulfonyl] amine: TFA (5 mL) at rt to a stirred solution containing (tert-butoxy) -N- [(trans 4- { [(Methylethyl) sulfonyl] amino.}. Cyclohexyl) methyl] carboxaphthiide (1.3 g, 3.9 mmol) and CH2C12 (45 ml). After 4 h, the solution was concentrated in vacuo and the residue re-dissolved in pHCl3. The CHC13 solution was washed successively with aqueous ÍM NaOH and brine, dried over Na 2 SO 4 and then concentrated in vacuo to give the free base as a colorless solid (0.88 g, 97%). XH NMR (CDC13) 3.19-3.09 (m, 2H), 2.82 (dd, 2Hi J = 13.6 and 7.2 Hz), 2.07 (d, 2H, J = 13.6 Hz), 1.88 (d, 2H, J = 6.0 Hz) , 1.64-1.60 (br m, 2H), 1.51-1.30 (m, 2H), 1.34 (d, 6H, J = 6.8 Hz), 1.23-1.08 (m, 3H). EREM m / e: 235 (M + H) +.

Intermediate of Formula VII N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] amino} cidohexyl) methyl] amino.} Thioxomethyl) benzamide: benzoylisothiocyanate (1.6 g, 10 mmol) ) to a solution of [trans-4- (aminomethyl) ciciohexyl] [(methylethyl) sulfonyl] amine (2.3 g, 10 mmol) in THF (100 ml), under an argon atmosphere and then stirred at rt, during the night. The reaction mixture was concentrated in vacuo and the resulting rubber-like material was triturated with hexanes to obtain the product as a pale yellow solid. (3.8 g, 96%). XH NMR (CDC13) 10.86 (s, 1 H), 9.08 (s, 1 H), 7.86 (d, 1 H, J = 4.0 Hz), 7.64 (dt, 1 H, J = 5.6 and 1.2 Hz), 7.54 -7.49 (m, 3H), 4.18 (d, 1 H, J = 8.4 Hz), 3.59 (t, 2H, J = 6.0 Hz), 3.25 (septet, 1 H, J = 4.0 Hz), 2.14 (dd, 2H, J = 7.2 and 2.4 Hz), 1.91 (d, 2H, J = 6.4 Hz), 1.74 (m, 1 H), 1.29 (d, 6H, J = 12.8 Hz), 1.25-1.12 (m, 2H) . EREM m / e: 398 (M + H) +.

Intermediate of Formula VIII (trans-4. {[[(Aminothioxomethyl) amino] methyl.}. Cyclohexyl) [(methylethyl) sulfonyl] amine: K2C03 (2.00 g, 14.5 mmol) was added to a solution containing N- ( { [(trans-4- { t (methylethyl) sulfonyl] amino.}. cyclohexyl) methyl] amino.} thioxomethyl) benzamide (3.80 g, 9.57 mmol), MeOH (75 mL) and H20 (25 ml). The resulting cloudy mixture was refluxed for 16 h. It is noted that after refluxing, the mixture changed into a clear homogenous solution. The solution was allowed to cool and concentrated in vacuo to provide a solid. This solid was dissolved in acetone and filtered through a pad of celite, followed by washes of the celite with acetone. The filtrate was concentrated in vacuo to provide the desired product as a pale yellow solid (2.20 g, 79%). XH NMR (CDC13) 6.98 (br s, 1 H), 6.39-6.32 (br s, 2H), 3.50 (br, 1 H), 3.32 (m, ÍH), 3.14 (m, 2H), 2.16-2.13 (br m, ÍH), 1.94-1.92 (m, 2H), 1.82-1.79 (m, 2H), 1.52-1.36 (m, 2H), 1.38 (d, 6H, J = 6.8 Hz), 1.26-1.10 ( m, 2H). EREM m / e: 294 (M + H) +.

Representative compounds of Formulas X through XIII and VI were synthesized as follows: Intermediate of Formula X Trans-4- ( { [(Methylethyl) sulfonyl] aminojmethyl) cyclohexanecarboxylic acid: isopropylsulfonyl chloride (10.9 g, 77.0 mmol) was added dropwise to a solution of trans-4- (aminomethyl) -cyclohexanecarboxylic acid (10.0 g, 63.7 mmol) in IM of aqueous NaOH (150 mL, 150 mmol), cooled in an ice bath. The solution was stirred for 24 h and then acidified to pH ~ 4 with 2 M aqueous HCl. The solids were collected by filtration and dried in a vacuum oven at rt, to provide the desired product as a white solid (5.0 g, 33%). LH NMR (CDC13) 4.91 (br s, 1 H), 3.20 (septet, ÍH, J = 6.8 Hz), 2.92 (d, 2H, J = 6.8 Hz), 2.24 (tt, 1 H, J = 12.4 and 3.6 Hz), 2.03 (dd, 2H, J = 10.4 and 3.2 Hz), 1.92 (dd, 2H, J = 10.8 and 3.2 Hz), 1.48-1.41 (m, 3H), 1.34 (d, 6H, J = 6.8 Hz ), 1.01 (dq, 2H, J = 25.2, 13.2 and 3.6 Hz). EREM m / e: 264 (M + H) +.

Intermediate of Formula XI N- [trans-4- (aminomethyl) ciciohexyl] (phenylmethoxy) carboxamide: (tert-butoxy) -N- ( { Trans-4- [(phenylmethoxy) carbonylamino] cyclohexyl) methyl) carboxamide ( 4 g, 11 mmol) with 25% TFA in CH2C12 (50 mL). After stirring 5 h at 40 ° C, the crude product was washed with aqueous NaHCO 3 and then brine. The solution was dried over Na2SO4 and dried under vacuum to provide the desired product as an oil (quantitative yield). 1 H NMR (DMSO-d) 7.18-7.03 (m, 5H), 4.78 (s, 2H), 3.06-2.96 (m, 1 H), 2.35 (d, 2H, J = 6.8 Hz), 1.62-1.48 (m , 4H), 1.20-1.11 (m, 1 H), 0.97-0.69 (m, 4H). EREM m / e: 263 (M + H) +.

Intermediate of Formula XII N- [trans-4- ( { [(Methylethyl) sulfonyl] amino} methyl) cyclohexyl] (phenylmethoxy) carboxamide: isopropylsulfonyl (6.6 g, 46 mmol) dropwise to a solution containing N- [trans -4- (aminomethyl) cyclohexyl] (phenylmethoxy) carboxamide (11 g, 42 mmol), TEA (7.0 g, 70 mmol) in anhydrous CH2C12 (150 ml) at 0 ° C. The reaction was allowed to warm to rt, and was stirred overnight. The solution was washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, using an inorered gradient of EtOAc in Hexanes. The fractions containing the product were combined and concentrated in vacuo. Recrystallization from EtOH gave the desired product (5.0 g, 32%). 1 H NMR (CDC13) 7.38-7.31 (m, 5H), 5.08 (s, 2H), 4.66-4.57 (br m, ÍH), 4.13-4.06 (br m, ÍH), 3.49-3.4 (br m, ÍH) , 3.19-3.11 (m, 1 H), 2.97 (t, 2H, J = 6.7 Hz), 2.08-2.05 (br m, 2H), 1.86-1.83 (br m, 2H), 1.50-1.40 (m, 1 H), 1.36 (d, 6H, J = 0.9 Hz), 1.18-0.99 (m, 4H). EREM m / e: 369 (M + H) +.

Intermediate of Formula XII to Intermediate of Formula VI Shaken [(trans-4-aminociclohexyl) methyl] [(methylethyl) sulfonyl] amine: N- [trans-4- ( { [(Methylethyl) sulfonyl] aminojmethyl) ciciohexyl] (phenylmethoxy) carboxamide (62; g, 0.168 mole) and 10% Pd-C (12 g) in anhydrous EtOH (600 ml), at 55 psi at 60 ° C under an atmosphere of H2. The solution was shaken for 6 h. The white solids dissolved within 2 h. The catalyst it was filtered and the solids were washed with EtOH (3 x 150 ml). The combined EtOH, filtered, was concentrated in vacuo. Toluene (200 ml) was added and evaporated to obtain the desired product as a white solid (quantitative yield). 1 H NMR (CDC13) 3.60 (br s, 2 H), 3.06 (quintet, Í H), 2.69 (d, 2 H, J = 11.2 Hz), 2.58 (m, H H), 1.79 (d, 2 H, J = 11.2 Hz) , 1.68 (d, 2H, J = 11.2Hz), 1.24 (br m, 1 H), 1.14 (d, 6H, J = 11.2 Hz), 1.09 (2H, q, J = 22.5 and 9.0 Hz) and 0.86 ( 2H, q, J = 22.5 and 9.0 Hz).

Intermediate of Formula XIII N- ( { Trans-4- [(aminothioxomethyl) amino] cyclohexylmethyl) (tert-butoxy) carboxamide: benzoylisothiocyanate (0.755 g, 4.63 mmol) was added to a stirred solution of (tert-butoxy) carboxamidemethylcyclohexyl -trans-4-amine (1.2 g, 4.6 mmol) in THF (50 ml) at rt, under an argon atmosphere. After stirring for 24 h, the solution was concentrated in vacuo to give a viscous material. Grinding of the viscous material with Hexanes gave N- ( { Trans-4- [(aminothioxomethyl) amino] cyclohexylmethyl) (tert-butoxy) carboxamidebenzamide as a pale yellow solid pain (1.71 g, 90% yield). ^ H NMR (CDC13) 10.61 (d, 1 H, J = 7.2 Hz), 8.89 (s, 1 H), 7.82 (d, 1 H, J = 7.6 Hz), 7.63 (t, 1 H, J = 7.2 Hz), 7.54-7.49 (m, 3H), 4.61 (br s, 1 H), 4.24-4.19 (m, ÍH), 3.02 (t, 2H, J = 6.0 Hz), 2.27 (dd, 2H, J = 7.6 and 2.0 Hz), 1.86 (d, 2H, J = 11.6 Hz), 1.45 (s, 10H) - 1.32 (dq, 2H, J = 24.8, 12.4 and 3.2 Hz), 1.28 (dq, 2H, J = 25.6, 13.2 and 2. 4 Hz). EREM m / e: 336 ((M + H) -55) +. N- ( { Trans-4- [(aminothioxomethyl) amino] cyclohexylmethyl) (tert-butoxy) carboxamidebenzamide (1.65 g, 4.0 mmol) was dissolved in MeOH (25 ml). Water (5 ml) was added, followed by the addition of K2CO3 (1.66 g, 12.0 mmol). The resulting mixture was refluxed overnight. After refluxing for 16 h, the solvents were removed in vacuo and the resulting solid was dried under high vacuum. The solid was redissolved in acetone and filtered through a pad of celite. Concentration of the filtrate in vacuo afforded the desired product as a pale yellow solid (1.1 g). XH NMR (CDC13) 6.17 (br s, 1 H), 4.85 (br s, 1 H), 2.99 (t, 2H, J = 7.2 Hz), 2.09 (d, 2H, J = 12.0 Hz), 1.83 (d , 2H, J = 12.0 Hz), 1.44 (s, 10H), 1.29-0.78 (m, 4H). EREM m / e: 288 (M + H) +.

Intermediates of Formula XIV Added (tert-buto ^ i) -N- ( { 4- [(trans-4- (2-pyridyl) (1, 3-thiazol-2-yl)) amino] ciciohexyl Jmethyl) carboxamide: DIEA (0.63 mL, 3.6 mmol) to a solution of 2-bromo-l- (2-pyridyl) ethan-1-one (500 mg, 1.8 mmol) in anhydrous EtOH (10 mL), under an argon atmosphere . After stirring for 5 min at rt, N- ( { Trans-4- [daminothioxomethyl) amino] cyclohexylmethyl) (tert-butoxy) carboxamide (520 mg, 1.8 mmol) was added. and the reaction was refluxed overnight. EtOH was removed in vacuo and the residue re-dissolved in CH2C12. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with 2.5% methanolic ammonia in EtOAc to provide the desired product (651 mg, 93%). NMR (CD3OD) 8.40 (d, 1 H, J = 6Hz), 7.86 (d, 1 H, J = 10 Hz), 7.74 (t, 1 H, J = 9.8 Hz), 7.19 (t, 1 H) , J = 8Hz), 7.11 (s, 1 H), 6.56 (br s, 1 H), 3.45 (t, 1 HJ = 9.5 Hz), 2.84 (t, 2H, J = 7.7 Hz), 2.11 (d, 2H, J = 15 Hz), 1.75 (d, 2H, J = 15.5 Hz), 1.35 (s, 9H), 1.20-1.13 (m, 2H), 1.08-0.96 (m, 2H). EREM m / e: 389 (M + H) +. (Tert-Butoxy) -N- [(trans-4. {[[4- (3-methyl-pyrazin-2-yl) (1,3-thiazol-2-yl)] amino} ciciohexyl) methyl was added. ] carboxamide: DIEA (2.0 g, 16 mmol) to a solution containing 2-bromo-l- (3-methylpyrazin-2-yl) ethan-1-one (3.0 g, 14 mmol), H- ( { trans -4- [(aminothioxomethyl) amino] cyclohexyl) methyl (tert-butoxy) carboxamide (3 g, 10 mmol) and EtOH (10 mL). The mixture was refluxed for 3 h, cooled to rt and concentrated in vacuo. The residue was taken up in CH 2 Cl 2, washed with NaHCO 3, brine, dried over Na 2 SO 4 and concentrated in vacuo. Purification by column chromatography on silica gel, with an increased gradient of EtOAc in Hexanes gave the desired product (3.3 g, 82%). XH NMR (CDC13) 8.42-8.38 (m, 2H), 7.05 (s, 1 H), 5.05 (d, 1 H, J = 7.5 Hz), 4.65-4.58 (m, 1 H), 3.40-3.3 (br, m, 1 H), 3.02 (t, 2H, J = 6.4 Hz), 2.84 (s, 3H), 2.26 (d, 2H? J = 12.7 Hz), 1.86 (d, 2H, J = 12.6 Hz), 1.52-1.42 (m, 10H) , 1.30- 1.05 (m, 4H). EREM m / e: 404 (M + H) +.

Intermediates of Formula XV [trans-4- (Aminomethyl) ciciohexyl] (4- (2-pyridyl) (1,3-thiazol-2-yl)) amine: (tert-butoxy) -N- ( { trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] 'cyclohexyl} methyl) carboxamide (651 mg, 1.68 mmol) with 4 M HCl in dioxane (8 ml) under an argon atmosphere. The reaction mixture was stirred at rt, overnight and the product was precipitated from the reaction mixture. The resulting precipitate was collected by filtration as the hydrochloride salt (507 mg). XH NMR (CDC13) 8.70 (d, lHi J = 6.5 Hz), 8.49 (t, ÍH, J = 10 Hz), 8.42 (d, 2H, J = 10 Hz), 7. 87 (s, 1 H), 7.85 (d, 1 H, J = 8.5 Hz), 3.81 (m, ÍH), 2.86 (d, 2H, J = 8.5 Hz), 2.25 (d, 2H, J = 15.5 Hz), 1.95 (d, 2H, J = 15 Hz), 1.72 (m, ÍH), 1.40 (q, 2H, J = 15 Hz), 1.27 (q, 2H, J = 16 Hz). EREM m / e: 289 (M + H) +. [trans-4- (aminomethyl) cyclohexy-1] (4- (3-methylpyrazin-2-yl) (1,3-thiazol-2-yl)) amine: Analogously, N-Boc deprotection was performed as described in the previous procedure. XH NMR (CD3OD) 8.67-8.61 (m, 2H), 7.53 (s, ÍH), 3.68-3.59 (br m, ÍH), 2.89-2.84 (m, 5 '), 2.27 (d, 2H, J = 12.8 Hz) -, 2.02 (d, 2H, J = 12.0 Hz), 1.82-1.72 (m, 2H), 1.63-1.54 (m, 1 H), 1.34-1.24 (m, 4H). EREM m / e: 304 (M + H) +.

Intermediates of Formula IV (where m = n = 1) Representative compounds as described in Reaction Scheme 4 were synthesized as follows: (trans-4. {[[(Tert-butoxy) carbonylamino] methyl} ciciohexyl) -N-methoxy-N-methylcarboxamide: 1-Methylmorpholine (5.0 g, 49.6 mmol) to a stirred solution of trans-4- acid. { [(tert-butoxy) carbonylamino] methyl-J-cyclohexanecarboxylic acid (8.5 g, 33 mmol) in CH2C12 (100 mL). The solution was cooled to -20 ° C and (5.9 g, 43.0 mmol) was added dropwise isobutyl chloroformate for a period of 10 min. The resulting pale yellow solution was allowed to warm to rt and then stirred for an additional hour. The solution was cooled to -20 ° C and 1-Methylmorpholine (5.0 g, 50 mmol) was added followed by the addition of a solution of N, 0-dimethylhydroxylamine (3.9 g, 40 mmol) in CH2C12. After the addition was complete, the solution was heated to rt, and stirred overnight. The reaction was quenched with water and washed successively with aqueous citric acid, water, and brine. The CH2C12 layer was concentrated in vacuo and the resulting material was purified by column chromatography on silica gel, (30% EtOAc in Hexanes) to provide the desired product as a colorless viscous material (7.8 g, 79%). XH NMR (CDCl3) 4.67 (br s, 1 H), 3.69 (s, 3 H), 3.18 (s, 3 H), 2.99 (t, 2 H, J = 6.4 Hz), 2.65 (br m, 1 H, J = 9.6 Hz), 1.83 ( d, 2H, J = 10.0 Hz), 1.53-1.49 (m, 3H), 1.44 (s, 9H), 1.0-0.91 (m, 4H). EREM m / e: 300 (M + H) +. (Tert-Butoxy) -N- t (trans-4-formylcyclohexyl) methyl] carboxamide: a solution of 1 M LAH in THF (24.7 ml, 24.7 mmol) was added over a period of 15 min to a stirred solution of ( trans -4- { [(tert-butoxy) carbonylamino] methyl J-cyclohexyl) -N-methoxy-N-methylcarboxamide (7.4 g, 24.7 mmol) in Et20 (200 mL) under an argon atmosphere at -78 ° C . After the addition was complete, the reaction was stirred for an additional 15 min, then allowed to warm to 0 ° C for 1 h and then re-cooled to -78 ° C. The reaction was quenched with IN of aqueous KHSO4 and filtered over celite containing Na2SO4. The celite was washed with Et20 and the filtrate was concentrated in vacuo to provide the desired product as a viscous gum (6.0 g). 1 H NMR (CDCl 3) 9.62 (s, ÍH), 4.67 (br s, 1 H), 3.00 (t, 2H, J = 6.0 Hz), 2.19 (t, 1 Hi J = 8.8 Hz), 2.03 (d, 2H , J = 13.2 Hz), 1.89 (d, 2H, J = 13.2 Hz), 1.44 (s, 9H), 1.27 (dq, 2H, J = 25.6, 13.2 and 3.6 Hz), 1.05- 0.95 (m, 2H) . EREM m / e: 186 ((M + H) -55) +. N- was added. { [trans-4- (aminomethyl) cydohexyl] methyl} (tert-butoxy) carboxamide: NaCNBH3 (2.4 g, 38 mmol) to a stirred solution containing (tert-butoxy) -N- [(trans-4- formylcyclohexyl) methyl] carboxamide (6.0 g, 25 mmol) * ammonium acetate (29 g, 374 mmol) and MeOH (100 mL) under an atmosphere of argon at rt. The solution was stirred for 18 h at rt, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel, to provide the desired amine (1.5 g, 26%). x ¥ * NMR (CDC13) 4.64 (br s, ÍH), 2.97 (t, 2H, J = 6.4 Hz), 2.53 (d, ÍH, J = 6.4 Hz), 2.41 (d, ÍH, J = 6.4 Hz) , 1.79 (q, 2H, J = 19.6 and 9.2 Hz), 1.44 (s, 9H), 1.50-1.30 (br m, 4H), 1.0-0.81 (m, 4H). EREM m / e: 242 (M + H) +.

Intermediate of Formula XX 2-Methyl-nicotinoyl chloride: Oxalyl chloride (2.78 g, 21.75 mmol) was added to a stirred solution of 2-methyl-nicotinic acid (2.0 g, 14.5 mmol) in CH2C12 (50 mL) at RT. , under an atmosphere of argon. A drop of DMF was added to start the reaction. After stirring for 24 h at rt, the solvents were removed in vacuo to give the acid chloride as a solid (2.85 g,> 99%). EREM m / e: 155 (M + H) +.

Intermediates of Formula XXII 2-Chloro-l- (2-methyl-pyridin-3-yl) -ethanone was added: an ethereal solution of 2M trimethylsilyldiazomethane (15 ml, 11.60 g, 101.7 mmol) by dripping, to a solution of 2-methyl-nicotinoyl chloride (2.85 g, 14.9 mmol) in dioxane (30 ml) at 0 ° C. The reaction temperature was raised to rt to provide 2-diazenyl-1- (2-methyl-pyridin-3-yl) -ethanone, which was used without further purification. 4M HCl in dioxane (10 ml) was added to the crude diazenyl derivative at 0 ° C and the reaction was stirred for 2 h at rt. The solution was concentrated in vacuo to provide the desired compound (2.81 g, 94%) as a brown solid as the HCl salt. EREM m / e: 170 (M + H) +. 2-Bromo-l-pyridin-2-yl-propan-l-one: hydrogen bromide in 33% acetic acid (7.8 ml, 45.1 mmol) was added to a solution of l-pyridin-2-yl-propan- l-one (6.0 g, 45.1 mmol) in acetic acid (50 ml) with vigorous stirring. Bromine (2.32 ml, 45.1 mmol) was added to the solution and the reaction was stirred at rt, for 2 h. The orange colored solution was concentrated in vacuo to give the desired compound (15.7 g, >; 99) as a semi-feolide. EREM m / e: 213 (M + H) +. The following compounds were prepared analogously: 2-Bromo-l- (3-methyl-pyridin-2-yl) -propan-1-one. EREM m / e: 228 (M + H) +. 2-Bromo-l- (4-methyl-pyridin-2-ll) -propan-1-one. EREM m / e: 228 (M + H) +. 2-Bromo-l-pyrazin-2-yl-ethanoria. EREM m / e: 201 (M + H) +. 2-Bromo-l- (6-methyl-pyridin-2-yl) -propan-1-one. EREM m / e: 228 (M + H) +.

Intermediate of Formula XXIII 6-Methyl-pyridine-carboxylic acid N-methoxy-N-methyl-amide: DIEA (1.85 mL, 1.37 g, 10.62 mmol) was added to a stirred solution of 6-methyl-pyridin-2-acid. carboxylic acid (0.97 g, 7.01 mmol) in CH2C12 (30 mL) at rt. The reaction mixture was cooled to 0 ° C and isobutyl chloroformate (1.06 g, 1.20 mL, 7.79 mmol) was added. The reaction was stirred for 30 min at 0 ° C, then a solution of N, 0-dimethyl-hydroxyl-amine hydrochloride (1.03 g, 10.62 mmol) and DIEA (1.85 mL, 1.37 g, 10.62 mmol) was added in the reaction mixture. CH2C12. After stirring for 18 h at rt, the organic layer was diluted with CH2C12 and carefully washed with saturated aqueous NaHCO3. The separated organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50% EtOAc in hexaxanes) to give the product as an oil (1.16 g, 91%). EREM m / e: 181 (M + H) +.

Intermediate of Formula XXIV l-Pyridin-2-yl-propan-l-one was added: 3M Et20 solution of ethylmagnesium bromide (19.2 ml, 57.6 mmol) to a stirred solution of pyridine-2-carbonitrile (5.0 g, 48.0 mmol ) in THF (80 ml) at -78 ° C. The reaction mixture was allowed to warm to rt. The reaction mixture was acidified with aqueous citric acid solution. The THF was removed in vacuo and the product was extracted with EtOAc. The organic layers were combined and washed with aqueous NaHCO and brine. After concentration in vacuo, the product was obtained as a pale yellow liquid. EREM m / e: 271 (2M + H) +.

The following compounds were prepared analogously: 1- (3-Methyl-pyridin-2-yl) -propan-1-one. EREM m / e: 150 (M + H) +. 1- (4-Methyl-pyridin-2-yl) -propan-1-one. EREM m / e: 150 (M + H) +. 1- (6-Methyl-pyridin-2-yl) -propan-1-one. EREM m / e: 150 (M + H) +. The following compounds of the invention were prepared, from the Intermediate of Formula VI, were synthesized in accordance with the procedures described in Reaction Schemes 1 and 2: Example: [(Methylethyl) sulfonyl] (trans-4. {[[(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] methyl.}. Cyclohexyl) amine was added: N- ( { [(Trans -4- {[[(methylethyl) sulfonyl] amino} cidohexyl) methyl] amino} thioxomethyl) amide (0.60 g, 2.0 mmol) to a stirred solution of hydrobromide 2-bromo-l- (2-pyridyl) ethan-1-one (0.57 g, 2.0 mmol) in EtOH (20 mL) at rt, followed by the addition of DIEA (1.05 mL, 6.0 mmol). The reaction mixture was heated to reflux for 4 h, cooled to rt, and concentrated in vacuo. The resulting residue was redissolved in CHC13 and washed successively with aqueous citric acid, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, (60% EtOAc in Hexanes) to provide the desired product as a tan solid (0.56 g, 69%). XH NMR (CDCl 3) 8.58 (d, 1 H, J = 4.8 Hz), 7.89 (dt, 1 H, J = 7.6 and 1.2 Hz), 7.71 (td, 1 H, J = 7.8 and 2.0 Hz), 7.17 ( td. 1 H, J = 4.8 and 1.2Hz), 5.25 (br s, 1 H), 3.85 (d, 1 Hi J = 8.4 Hz), 3.25 (br m, 1 H), 3.18 (t, 2H, J = 6.4 Hz), 2.14 (dt, 2H, J = 12.0 and 1.2 Hz), 2.19 (br, d, 2H, J-12.8 Hz), 1.62 (br m, 3H), 1.38 (d, 6H, J = 6.8 Hz), 1.25 (dq, '2H, J = 12.8 and 1.6 Hz). LC-MS m / e: 395 (M + H) +; tR = 2.14 min (Method-A). The following were prepared analogously compounds Ib [(methylethyl) sulfonyl] ( { Trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl} methyl) amine: Prepared from N- (. {((Trans-4. {[[(Methylethyl) sulfonyl] methylamino} cyclohexyl] amino} thioxomethyl) amide and 2-bromo-l- (2-pyridyl) etan-1-one Yield: 76% LC-MS: m / e 395 (M + H) +; t R = 5.28 min (Method-B).

Example le [(methylethyl) sulfonyl] (trans-4 ~ { [(4- (3-pyridyl) (1,3-thiazol-2-yl)) amino] methyl.}:: Cyclohexyl) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] amino.}. Cyclohexyl) 'methyl] amino.} Thioxomethyl) amide and 2-bromo-l- (3 -pyridyl) ethan-1-one. Performance: 31%. LC-MS: m / e 395 (M + H) +; tR = 2.02 min (Method-A).

EXAMPLE Id [(methylethyl) sulfonyl] ( { Trans -4- [(4- (3-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl) -methyl) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl-J-methylamino} cidohexyl] amino} thioxomethyl) amide and 2-bromo-l- (3-pyridyl) ethan 1-one Yield: 27% LC-MS: m / e 395 (M + H) +; tR = 2.37 min (Method-C).

Example le [(methylethyl) sulfonyl] [( { Trans-4 { [4- (3-methylpyrazin-2-yl) (1,3-thiazol-2-yl))] amino} cyclohexyl) methyl] amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] methylamino}. Cyclohexyl] amino.} Thioxomethyl) amide and 2-bromo-1- (3-methylpyrazine) 2-yl) ethan-1-one Yield: 44% LC-MS: m / e 410 (M + H) +; t R = 2.05 min (Method-A).

Example If [(methylethyl) sulfonyl] ( { Trans -4- [(4- (2-pyridyl) (5-methyl-thiazol-2-yl)) amino] cyclohexyl-Jmet-1) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] methylamino} cydohexyl] amino.} Thioxomethyl) amide and 2-bromo-l-pyridin-2-yl. -propan-1-one Yield: 41% LC-MS m / e: 409 (M + H) +; tR = 0.70 min (Method-E).

Example Ig [(methylethyl) sulfonyl] (trans-4. {[[(4- (2-methyl-pyridin-3-yl) (1,3-thiazol-2-yl)) amino] methyl} ciciohexyl ) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] amino.}. Cyclohexyl)? Methyl] amino.} Thioxomethyl) amide and 2-chloro-1- (2. -methyl-pyridin-3-yl) -ethanone. Yield: 47%. LC-MS m / e: '409 (M + H) +; RT - 0.52 min (Method-E).

Example I [(methylethyl) sulfonyl] (trans -4- {[[4- (2-pyrazinyl) (1,3-thiazol-2-yl)) amino] methyl} cyclohexyl) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] amino} ciciohexyl) methyl] amino.} Thioxomethyl) amide and 2-bromo-l-pyrazin-2 -yl-ethanone. Yield: 37%. LC-MS m / e: 396 (M + H) +; tR = 0.95 min (Method-D).

Example li [(methylethyl) sulfonyl] ( { Trans -4- [(4- (6-methyl-pyridin-2-yl) (5-methyl-thiazol-2-yl)) amino] cydohexyl} methyl. ) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] methylamino} cyclohexyl] amino} thioxomethyl) amide and bromo-1- (6-methyl-pyridine) 2-yl) -propan-1-one Yield: 68% LC-MS m / e: 423 (M + H) +; tR = 0.74 in (Method-E).

EXAMPLE Ij [(methylethyl) sulfonyl] ( { Trans -4- [(4- (4-methyl-pyridin-2-yl) (5-methyl-thiazol-2-yl)) amino] cyclohexyl) -methyl) -amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] methylamino} cydohexyl] amino} thioxomethyl) amide and 2-bromo-l- (4-methyl- pyridin-2-yl) -propan-1-one Yield: 72% LC-MS m / e: 423 (M + H) +; t R = 0.67 (Method-E).

Example Ik [(methylethyl) sulfonyl] ( { Trans -4- [(4- (3-methyl-pyridin-2-yl) (5-methyl-thiazol-2-yl)) amino] cyclohexyl) -methyl) amine: Prepared from N- ( { [(Trans-4. {[[(Methylethyl) sulfonyl] methylamino} cyclohexyl] amino} thioxomethyl) amide and bromo-1- (3-methyl-pyridine) 2-yl) -propan-1-one Yield: 79% LC-MS m / e: 423 (M + H) +; t R = 0.66 min (Method-E).

The following compounds of the invention were synthesized in accordance with the procedures described in Reaction Scheme 3.

Example 2a (ethylsulfonyl) ( { Trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl} methyl) amine: N, N-diisopropyl-N-ethylamine (0.52 ml, 3.0 mmol) was added to a solution of [trans-4- (aminomethyl) ciciohexyl] (4- (2-pyridyl) (1,3-thiazol-2-yl) )) amine (578 mg, 2.00 mmol) in CH2C12 at -78 ° C. Then, ethanesulfonyl chloride (0.19 ml, 2.0 mmol) was added slowly to the solution and stirring was continued for 45 min. The reaction was allowed to warm to rt, then was stirred for an additional 3 h. Aqueous saturated NaHCO3 was added to the reaction mixture and stirred for 15 min. The layers were separated and the aqueous layer was extracted with CH2C12. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography on silica gel, using 8/2/1/1: Hexanes / EtOAc / MeOH / TEA as the eluent, gave the desired product as a béige solid (655 mg, 86%). The additional purification was achieved by grinding with cold CH2C12. 1 H NMR (CDC13). 8.58 (ddd, 1 H, J = 0.8, 1.8 and 4.8 Hz), 7.90 (d, 1 H, J = 6.9 Hz), 7.71 (dt, 1 H, J = 1.9, 7.5 Hz), 7.28 (s, 1 H), 7.19-7.14 (m, 1 H), 5.00 (br d, ÍH, J = 8.0 Hz), 4.17 (br s, 1 H), 3.35 (m, 1 H), 3.05 (q, 2H, J = 14.7 and 7.2 Hz) 3.04 (t, 2H, J = 8.3 Hz), 2.29 (br d, 2H, J = 4.5 Hz), 1.92 (br d, 2H, J = 6.6 Hz), 1.36 (m, ÍH), 1.38 (t, 3H, J = 7.4Hz), 1.17 (m, 4H). LCMS: m / e 381 (M + H) +.

Example 2b (cyclopropylsulfonyl) ( { Trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl} methyl) amine: Q XCrK Prepared from [trans-4- (aminomethyl) cyclohexyl] (4- (2-pyridyl) (1,3-thiazol-2-yl)) amine and cyclopropanesulfonyl chloride. Performance: 80%. LCMS: m / e 393.2 (M + H) +; tR = 5.19 min (Method-B).

Example 2c (butylsulfonyl) ( { Trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexylmethyl) amine: Prepared from [trans-4- (aminomethyl) ciciohexyl] (4- (2-pyridyl) (1,3-thiazol-2-yl)) amine and butanesulfonyl chloride. Yield: 98%. LCMS: m / e 409.2 (M + H) +; tR = 6.20 min (Method-B).

Example 2d (butylsulfonyl) [( { Trans -4- [4- (3-methylpyrazin-2-yl) (1,3-thiazol-2-yl)] amino} cydohexyl) methyl] amine: Prepared from [trans-4- (aminomethyl) ciciohexyl] (4- (3-methylpyrazin-2-yl) (1,3-thiazol-2-yl)) amine and butanesulfonyl chloride. Performance: 19%. LCMS: m / e 424 (M + H) +; tR = 2.28 min (Method-A).

The pharmaceutical formulations of the invention can be prepared by methods conventional in the art. For example, tablets can be prepared by mixing the active ingredient with ordinary adjuvants and / or diluents and the tablets can be prepared, subsequently compressing the mixture in a conventional tableting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, stearate magnesium, gelatin, lactose, gums and the like. Any other diluents or adjuvants usually employed for such purposes as dyes, flavors, preservatives, etc., may be used so long as they are compatible with the active ingredients. 1) Tablets containing 5.0 mg of Compound 2b, calculated as the free base: Compound 5.0 mg Lactose 60 mg Corn starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mg Croscarmellose sodium A type 2.4 mg Magnesium stearate 0.84 mg 2) Tablets containing 0.5 mg of Compound 2b, calculated as the free base: Compound 5.0 mg Lactose 46.9 mg Corn starch '23.5 mg Povidone 1.8 mg Microcrystalline cellulose 14.4 mg Croscarmellose sodium A type 1.8 mg Magnesium stearate 0.63 mg 3) Tablets containing 25 mg of Compound 2b, per milliliter: Compound 25 mg Sorbitol 500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mg Methylparaben 1 mg Propylparaben 0.1 mg Ethanol 0.005 ml Savoring 0.05 mg Saccharin 0.5 mg Water 1 ml Methods in v ±tzo The pharmacological properties of the compounds of the present invention were evaluated in the cloned human NPY Y5 receptor, using the protocols described in U.S. Patent No. 6,124,331, contents of which are hereby incorporated by reference . Using this protocol, binding by compound to a radiolabelled ligand (PYY 125 I-tagged or an alternative radioligand such as NPY 125 I-tagged), to membranes of cloned human NPY Y5 receptors expressed in COS-7 cells was determined in vi tro. .

Link to Radioligand Membrane suspensions were diluted in binding buffer supplemented with 0.1% bovine serum albumin to provide an optimum membrane protein concentration, so that the 125I-PYY bound by the membranes in the assay was less than 10% of 125I-PYY supplied to the sample (100,000 dpm / sample = 0.08 nM for competition binding assays). Competitors of small molecule ligand and 125 I-PYY were also diluted to desired concentrations in supplemented binding buffer. The individual samples were then prepared in 96-well polypropylene microtiter plates., by mixing 125I-PYY, competition peptides or supplemented binding buffer (25 μl), and finally, membrane suspensions (200 μl). The samples were incubated at 30 ° C for 120 minutes. Incubations were terminated by filtration on Whatman GF / C filters (pre-coated with 1% polyethylenimine and air-dried before use), followed by a wash with 5 ml of ice-cold binding buffer. The membranes trapped in the filter were impregnated with solid scylate MeltiLex (Wallac, Turku, Finland), and counted by 125I-PYY in a Beta-Plate Wallac reader. Alternatively, the incubations were carried out on GF / C filter plates (pre-coated with 1% polyethyleneimine and air-dried before use), followed by vacuum filtration and three 300 μl washes of ice-cooled binding buffer. 50 μl of UltimaGold silane (Packard) was added, and counted by 125 I-PYY in Wallac MicroBeta Trilux. The non-specific binding was defined by 300 nM of human PYY. The specific link in time course and competition studies was typically 80%; the majority of the non-specific link was associated with the filter. Link data were analyzed using non-linear regression and statistical techniques available in the GraphPAD Prism package (San Diego, Calif.). The binding affinities for the compounds in the present invention, exemplified above in the NPY Y5 receptor, were determined to be 75 nM or less. For most compounds, Ki values are 10 nM or less, and for a group of compounds, Ki values are 5 nM or less.

Claims (20)

1. CLAIMS 1. Compound that has the structure: characterized in that R1 is H or straight or branched chain Ci-Cß alkyl; wherein R2 is straight or branched chain Ci-Ce alkyl; or wherein R1, R2 and the carbon to which they are attached, form a C3-C6 cycloalkyl, - wherein R3 is H or methyl; wherein R 4 is 2-pyridyl, 3-pyridyl or pyrazinyl, wherein 2-pyridyl, 3-pyridyl or pyrazinyl, can be substituted with methyl; wherein R5 is H or methyl; where m is an integer from 0 to 2 inclusive; and where n is an integer from 0 to ¡2 inclusive; or a pharmaceutically acceptable salt thereof. Compound according to claim 1, characterized in that R5 is H. 3. Compound in accordance with the claim 1, characterized in that R5 is methyl. 4. Compound in accordance with the claim 2, characterized in that R3 is H; wherein R 4 is 2-pyridyl or pyrazinyl, wherein the 2-pyridyl or pyrazinyl can be substituted with methyl; where m is 0 or 1; and where n is 0 or 1. 5. Compound in accordance with the claim 4, characterized in that R1 is H or straight or branched chain C? -C4 alkyl; and wherein R2 is straight or branched chain alkyl. 6. Compound in accordance with the claim 5, characterized in that R1 is H, methyl or ethyl; wherein R2 is methyl or ethyl; and wherein R 4 is 2-pyridyl, wherein the 2-pyridyl can be substituted with methyl. 7. Compound in accordance with the claim 6, characterized in that R1 is methyl and wherein R2 is methyl. 8. Compound in accordance with the claim 7, characterized in that n is 1. 9. Compound according to claim 4, characterized in that R1, R2 and the carbon to which it is attached form a C3-C6 cycloalkyl. 10. Compound according to claim 9, characterized in that R4 is 2-pyridyl. 11. Compound according to claim 3, characterized in that R1 is H or straight or branched chain C? -C4 alkyl; wherein R 2 is straight or branched chain C 1 -C 4 alkyl; wherein R3 is H; wherein R 4 is 3-pyridyl or pyrazinyl, wherein 3-pyridyl or pyrazinyl is substituted with methyl; where m is 0 or 1; and where n is 0 or 1. 12. Compound according to claim 3, characterized in that R1 is H or straight or branched chain Ci-C4 alkyl; wherein R 2 is straight or branched chain C 1 -C 4 alkyl; wherein R3 is H; wherein R 4 is 2-pyridyl, wherein 2-pyridyl can be substituted with methyl; where m is 0 or 1; and wherein n is 0 or 1. 13. Compound according to claim 12, characterized in that R1 is methyl; wherein R2 is methyl; and where n is 0. 14. Compound in accordance with the claim 11, characterized in that R1 is methyl; wherein R2 is methyl; and wherein m is 0. 15. Compound according to claim 14, characterized in that R4 is 3-pyridyl, wherein the 3-pyridyl is substituted with methyl. 16. Compound according to claim 1, characterized in that it is selected from the group consisting of [(methylethyl) sulfonyl] (trans-4 { [(4- ('2-pyridyl) (1,3-thiazole) 2-yl)) amino] methyl} ciciohexyl) amine; ] [(methylethyl) sulfonyl] ( { trans -4- [(4- (2-pyridyl) (1, 3-thiazol-2-yl)) amino] cydohexyl} methyl) amine; [(methylethyl) sulfonyl] (trans -4- {[[4- (3-pyridyl) (1,3-thiazol-2-yl)) amino] methyl} ciciohexyl) amine; [(methylethyl) sulfonyl] ( { trans -4- [(4- (3-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl} methyl) amine; [(methylethyl) sulfonyl] [( { trans-4 { [4- (3-methylpyrazin-2-yl) (1,3-thiazol-2-yl))] amino} cyclohexyl) methyl] amine; [(methylethyl) sulfonyl] ( { trans -4- [(4- (2-pyridyl) (5-methyl-thiazol-2-yl)) amino] cydohexyl-methyl) -amine; [(methylethyl) sulfonyl] (trans -4- {[[4- (2-methyl-pyridin-3-yl) (1,3-thiazol-2-yl)) aminojmethyl} cycloolyl) amine; [(methylethyl) sulfonyl] (trans-4- { [(4- (2-pyrazinyl) (1,3-thiazol-2-yl)) amino] methyl Jcyclohexyl) amine; [(methylethyl) sulfonyl] ( { trans -4- [(4- (6-methyl-pyridin-2-yl) (5-methyl-thiazol-2-yl)) amino] cyclohexyl) -methyl) amine; [(methylethyl) sulfonyl] ( { trans -4- [(4- (4-methyl-pyridin-2-yl) (5-methyl-thiazol-2-yl)) amino] cyclohexyl) -methyl) -amine; [(methylethyl) sulfonyl] ( { trans -4- [(4- (3-methyl-pyridin-2-yl) (5-methyl-thiazol-2-yl)) amino] cyclohexyl) -methyl) amine; (ethylsulphonyl) ( { trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl) -methyl) amine; (cyclopropylsulfonyl) ( { trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexylmethyl) amine; (butylsulfonyl) ( { trans -4- [(4- (2-pyridyl) (1,3-thiazol-2-yl)) amino] cyclohexyl-methyl) -amine; and (butylsulfonyl) [( { trans -4- [4- (3-methylpyrazin-2-yl) (1,3-thiazol-2-yl)] amino} cydohexyl) methyl] amine. 17. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 18. Use of a compound as defined in claim 1, for the preparation of a pharmaceutical composition for treating a subject suffering from depression. 19. Use of a compound as defined according to claim 1, for the preparation of a pharmaceutical composition for treating a subject suffering from anxiety. 20. Use of a compound as defined according to claim 1, for the preparation of a pharmaceutical composition for treating a subject suffering from obesity.