NOVEL USES OF HALOGENATED ALKYL SULFONAMIDES

FIELD OF THE INVENTION The present invention relates to methods of treating disorders relating to mood, anxiety, stress, sleep, cognitive impairment/dysfunction, substance dependency/abuse, metabolism, eating and chronic pain comprising administering a therapeutically effective amount of a compound of Formula I, and to uses of a compound of Formula 1 in the manufacture of a medicament for treating said disorders.

BACKGROUND OF THE INVENTION

The compounds of Formula I, which are the subject of the present invention, have the following structure:

Formula 1

The compounds of Formula 1 are disclosed in PCT/US2007/05563, which is hereby incorporated by reference into this application in its entirety. These compounds belong to a series of halogenated sulfonamide derivatives which are ligands at the neuropeptide Y Y5 receptor subtype, and as such are known to be useful to treat obesity, depression and anxiety. Herein, we describe the unexpected result that the compounds of Formula 1 may be used to treat disorders relating to mood, anxiety, stress, sleep, cognitive impairment/dysfunction, substance dependency/abuse, metabolism, eating and chronic pain.

Neuropeptide Y (NPY) is a 36 amino acid neuropeptide expressed in the peripheral and central nervous system and is implicated in an array of biological functions and disorders. Presently, receptors for the NPY receptor are divided into the following subtypes: Y 1. Y2. Y4, Y5 and y6. All these receptor subtypes are expressed in several species except for the y6 subtype, which are expressed in mouse and rabbit but not in rat and primate. A Y3 subtype is proposed based on pharmacological data. However, the Y3 subtype has yet to be cloned and its existence remains to be fully established.

For some decades now, researchers have been aware of the importance of the hypothalamus-pituitary-adrenal gland (HPA) axis in the physiological response to stress (Gold, P. W. and Chrousos, G.P. MoI. Psychiatry 2002, 7, 254-275; and Antonijevic, I.A. Psychorteuroendocrinology 2006, 31, 1-15), and likewise the importance of the correlations between emotional and biological factors in mood, stress and anxiety related disorders. The normal function of the HPA axis is to enable an organism to adapt to various stressors whether they are physical, psychosocial or environmental. In normal subjects, the perception of stress activates the central nervous system (CNS) resulting in the release of corticotrophin-releasing hormone (CRH) and vasopressin (AVP) from the hypothalamus, followed by adrenal corticotrophic hormone (ACTH) from the anterior pituitary, followed by Cortisol from the adrenal cortex. The elevated Cortisol concentration in the plasma inhibits the HPA axis via negative feedback.

NPY is considered to exert a critical role for the homeostatic regulation of the HPA axis system. For example, an acute injection of NPY in the paraventricular nucleus (PVN) produces increases in circulating ACTH and Cortisol in both conscious and anesthetized rats (Walhlestedt, C. et al. Brain Res. 1987, 417, 33-38; Inoue, T. et al. Life ScL 1989, 44, 1043-1051 ; and Hanson, E. and Dallman, M. J. Neuroendocrinal. 1995, 7, 273-279). Chronic infusion of NPY into the cerebral ventricule in normal rats also causes hypercorticosteronemia (Zarjevski, N., et al. Endocrinology 1993, 133. 1753-1758).

The NPY Y5 receptor subtype is of interest for its widespread distribution throughout the limbic system and along the hypothalamus-pituitary-adrenal gland (HPA) axis. Y5- like immunoreactivity has been documented throughout the hypothalamus, particularly along the NPY projection path from arcuate to paraventricular (PVN) and supraoptic nuclei (Campbell, R. et al. Neuroendocrinology 2001, 74, 106-1 19). Y5 receptors in these nuclei arc positioned to modulate the release of stress-related neurotransmitters such as CRF, vasopressin, oxytocin and/or urocortin, with subsequent effects on the HPλ axis and other circuits important for mood and anxiety disorders. In male Fischer 344 rats, it was shown that exogenous administration of a NPY Y5 specific agonist in undisturbed conscious rats produces increases in plasma ACTH and Cortisol and prior

treatment with a NPY Y5-selective receptor antagonist blocked these alterations (Kakui, N. and Kitamura, K. Endocrinology, 2007, 148, 2854-2862).

Additionally, our in-house experiments demonstrate the efficacy of selective NPY Y5 receptor antagonists in two in-vivo animal models where the dysfunction of the HPA axis resembles that reported for various patient populations. In these disease state models, our evidence indicates that the NPY Y5 receptor is endogenously activated and therefore contributes to the output of the HPA axis. In one aspect, the HPA axis dysfunction in the models resembles those patients with HPA overdrive and impaired negative feedback, which includes patients with moderate to severe and/or melancholic depression and metabolic disturbances. In another aspect, the HPA axis dysfunction in the models resembles patients with a sensitized HPA response resulting in exaggerated Cortisol and ACTH secretion to a stressful stimulus, which includes patients with MDD and disorders resulting from stressful life events.

Moreover, the link between NPY and mood disorders is established in the literature. In one study of antidepressant therapy, rats treated with citalopram displayed an increased level of hippocampal NPY receptor binding with no change in NPY-like immunoreactivity (H. Husum, et al., Neuropsychopharmacology. 2001. 2, 183-191 ); conversely, electroconvulsive shock produced an increased level of hippocampal NPY-like immunoreactivity with no change in NPY receptor binding. These findings suggest that abnormal levels of NPY play a role in mood-related illnesses, and that modulators of NPY receptor function, particularly in limbic regions, are useful for treating mood disorders.

Accordingly, the compounds of Formula I are predicted to be useful for treating mood disorders such as major depressive disorder; minor depressive disorder; dysthymia; cyclothymia; bipolar depression; and depression NUD. Furthermore, the compounds of Formula I are expected to treat patients who have stress-related disorders such as acute stress disorder; adjustment disorder; post traumatic stress disorder; exhaustion depression; and stress following surgery or fever conditions.

Animal models of anxiety also reveal abnormal levels of NPY. In one example, maternally separated rats display an anxious and depressive phenotype throughout adulthood (R. Huot,

Psychopharmacology, 2001 , 158, 366-73); they also contain elevated levels of NPY-like immunoreactivity in hypothalamus accompanied by a reduction in hippocampus and cortex

(P. Jimene7-Vasque7, Brain Res. Dev., 2001, 26, 149-152; H. Husum and A. Mathe, Neuropsychophatmacology, 2002 27:756-64; and H. Husum et al., Neurosci. Lett.. 2002. 333, 127-130). In a second example, rats subjected to fear conditioning display increased anxiety-like behavior; they also contain elevated levels of NPY in hypothalamus, amygdala and nucleus accumbens accompanied by a reduction in frontal cortex. The behavioral changes produced by fear conditioning can be reversed by treatment with anxiolytic drugs. In one study of fear conditioning, both the anxiety-like behavior and altered expression of NPY were reversed by treatment with diazepam (R. Krysiak, et al., Neuropeptides, 2000, 34, 148-57). These findings further suggest that NPY plays a role in anxiety, and that agents capable of regulating NPY and/or receptor function particularly in limbic regions are useful for treating anxiety. Accordingly, the compounds of Formula I are expected to be useful for treating anxiety disorders such as panic disorder: agoraphobia; social phobia (aka social anxiety disorder); obsessive compulsive disorder; and generalized anxiety disorder.

Several groups disclose the nexus between the NPY Y5 receptor and sleep disorders related to circadian rhythm disruptions. This nexus is based on the discover}' that NPY Y5 receptors mediate an important physiologic response in the suprachiasmatic nucleus (SCN) of the hypothalamus in response to the application of NPY. For example, WO 99/0591 1 and WO 05/30208 disclose this link and further propose the use of selected NPY Y5 receptor ligands for treating sleep disorders. Accordingly, it is expected that the compounds of Formula I can be also used for treating sleep disorders which includes primary insomnia.

The pharmaceutical industry also is targeting NPY Y5 receptor as a potential therapy for the treatment of cognitive impairment/dysfunction disorders. For example, the NPY Y5 receptor antagonist, MK-0557, is currently in clinical trials for the treatment of cognitive impairment in patients with schizophrenia. In support of this indication, WO 03/51356 proposes that NPY Y5 receptor antagonism can be used to treat dementias. Accordingly, it is expected that the compounds of Formula I can used for treating cognitive impairment/dysfunction disorders such as cognitive impairment associated with schizophrenia; schizophrenia; dementias; autism; ADHD; and Alzheimer's disease.

WO 02/28393 discloses methods of reducing self-administration of alcohol in a patient suffering from alcoholism comprising administering a NPY Y5 receptor antagonist. Accordingly, it is expected that the compounds of Formula I can used for treating substance dependency/abuse disorders such as alcoholism as well as nicotine and cocaine addictions.

Furthermore, it is expected that the compounds of Formula I can be used for treating metabolic disorders such as dyslipidemia: hyperlipidemia; insulin hyposcnsitivity; hyperglycemia; metabolic syndrome; and diabetes mellitus.

NPY expression is shown to be sensitive to energy status while NPY administration reduces energy expenditure, and another significant ability of NPY is to acutely 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 NPY-induced food intake (C. Gerald, et al., Nature. 1996, 382, 168-171). Accordingly, it is predicted that the compounds of Formula 1 can be used for treating eating disorders such as bulimia; bulimia nervosa; binge eating disorder; and night eating disorder.

Analgesic-like effects of NPY have been shown in rats and mice both after intrethecal administration and ICV administration, and after infusion directly into specific brain regions. These studies have used either "spinal" pain models or "supraspinal models. The involvement of the Y5 receptor subtype has been linked to chronic pain disorders

(Woldbye, et al. Brain Research, 2007, 49-55). Accordingly, it is expected that the compounds of Formula I can used for treating chronic pain disorders such as neuropathic pain; neuralgic pain; migraine; fibromyalgia; IBS; chronic fatigue syndrome: chronic tension type headache; chronic low back pain; myofascial pain and chronic osteoarthritis.

As described above, the present invention is directed to novel uses of the compounds of Formula 1 to treat certain disorders and novel uses of the compounds of Formula I to treat particular subtypes of mood and anxiety anxietys.

SUMMARY QP THE INVENTION

The subject invention relates to methods of treating a disorder selected from the group consisting of mood disorder, anxiety disorder, stress disorder, sleep disorder, cognitive impairment/dysfunction disorder, substance dependency/abuse disorder, metabolic disorder, eating disorder and chronic pain disorder comprising administering a therapeutically effective amount of a compound of Formula I:

Formula I wherein R ¹ is H or Ci-Ce straight chained or branched alkyl; wherein R ² is Ci-Cs straight chained or branched alkyl; or wherein R ¹ , R ² and the carbon to which they are attached may form C ₃ -C ₆ cycloalkyl; wherein R ³ is H or methyl: wherein R ⁴ is 2-pyridyl or 3-pyridyl, wherein the 2-pyridyl or 3-pyridyl is substituted with one or more F, Cl, Br, 1 or CF _3, and optionally substituted with CHy, wherein R ⁵ is H or methyl; wherein m is an integer from 0 to 2 inclusive; and wherein n is an integer from 0 to 2 inclusive; or a pharmaceutically acceptable salt thereof.

Additionally, the present invention relates to uses of a compound of Formula I in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of a mood disorder, anxiety disorder, stress disorder, sleep disorder, cognitive impairment/dysfunction disorder, substance dependency/abuse disorder, metabolic disorder, eating disorder and a chronic pain disorder.

In one aspect of the invention, the disorder is separately a mood disorder, anxiety disorder, stress disorder, sleep disorder, cognitive impairment/dysfunction disorder, substance dependency/abuse disorder, metabolic disorder, eating disorder or chronic pain disorder.

DETAILED DESCRIPTION QF THE INVENTION

The present invention is based on the discovery that the compounds of Formula I can be used to treat certain disorders and to treat particular subtypes of depression and anxiety.

The invention is explained in greater detail below but this description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. Hence, the following specification is intended to illustrate some embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.

Definitions

As used herein, the term "'mood disorders ^" includes major depressive disorder; minor depressive disorder; dysthymia; cyclothymia; bipolar depression; and depression NUD; and depressive obesity. Moreover, "major depressive disorder" is further divided into melancholic or atypical depression.

As used herein, the term "anxiety disorders" includes panic disorder; agoraphobia; social phobia (aka social anxiety disorder): obsessive compulsive disorder; and generalized anxiety disorder.

As used herein, the term "stress-related disorders" includes acute stress disorder; adjustment disorder; post traumatic stress disorder; exhaustion depression; and stress following (e.g. surgery and fever conditions).

As used herein, the term "sleep disorders" includes primary insomnia.

As used herein, the term "cognitive impairment/dysfunction" includes cognitive impairment associated with schizophrenia; schizophrenia; dementias; autism: ADHD; and Alzheimer's disease. Moreover, "dementias" is further divided into age preceding dementia or AIDS dementia.

As used herein, the term ''substance dependency/abuse'" includes alcohol; nicotine; and cocaine addictions.

As used herein, the term "metabolic disorders" includes dyslipidemia; hyperlipidemia; insulin hypersensitivity; overweight/obesity: hyperglycemia; metabolic syndrome; and diabetes mellitus.

As used herein, the term "chronic pain disorders" include neuropathic pain; neuralgic pain; migraine; fibromyalgia; IBS; chronic fatigue syndrome; chronic tension type headache; chronic low back pain; myofascial pain and chronic osteoarthritis.

A "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as

"therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. Ft will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

The term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being.

As stated above, the present invention relates to methods of treating disorders comprising administering a compound of Formula I. Additionally, the present invention relates to a uses of a compound of Formula I in the manufacture of a medicament for the treatment of disorders. One aspect of the invention is directed to uses or methods of

one of the exemplified compounds of the invention. Additionally, the invention further provides for certain embodiments which are described below.

In one embodiment, the disorder is a mood disorder selected from the group consisting of major depressive disorder; minor depressive disorder; dysthymia; cyclothymia; bipolar depression; and depression NUD. In an embodiment, the mood disorder is major depressive disorder. In an embodiment, the mood disorder is minor depressive disorder. In an embodiment, the mood disorder is dysthymia. In an embodiment, the mood disorder is cyclothymia. In an embodiment, the mood disorder is bipolar depression. In an embodiment, the mood disorder is depression NUD.

In another embodiment, the disorder is an anxiety disorder selected from the group consisting of panic disorder; agoraphobia; social phobia; obsessive compulsive disorder; and generalized anxiety disorder. In one embodiment, the anxiety disorder is panic disorder; In one embodiment, the anxiety disorder is agoraphobia. In one embodiment, the anxiety disorder is social phobia. In one embodiment, the anxiety disorder is obsessive compulsive disorder. In one embodiment, the anxiety disorder is generalized anxiety disorder.

In a separate embodiment, the disorder is a stress-related disorder selected from the group consisting of acute stress disorder; adjustment disorder; post traumatic stress disorder; exhaustion depression; and stress following (e.g. surgery and fever conditions). In one embodiment, the disorder is acute stress disorder. In one embodiment, the disorder is adjustment disorder. In one embodiment, the disorder is post traumatic stress disorder. In one embodiment, the disorder is exhaustion depression. In one embodiment, the disorder is stress following (e.g. surgery and fever conditions).

In one embodiment, the disorder is a sleep disorder is primary insomnia.

In one embodiment, the disorder is a cognitive impairment/dysfunction disorder selected from the group consisting of cognitive impairment associated with schizophrenia; schizophrenia; dementias; autism; ADHD; and Alzheimer's disease.

One embodiment is directed to cognitive impairment associated with schizophrenia. One embodiment is directed to schizophrenia. One embodiment is directed, to

dementias. One embodiment is directed to autism. A separate embodiment is directed to ADHD. Another embodiment is Alzheimer's disease.

In one embodiment, the disorder is a metabolic disorder selected from the group consisting of dyslipidemia; hyperlipidemia; insulin hyposensitivity; hyperglycemia; metabolic syndrome; and diabetes mellilus. One embodiment is directed to dyslipidemia. One embodiment is directed to hyperlipidemia. One embodiment is directed to insulin hyposensitivity. One embodiment is directed to hyperglycemia. One embodiment is directed to metabolic syndrome. One embodiment is directed to diabetes mellitus.

In one embodiment, the disorder is a chronic pain disorder selected from the group consisting of neuropathic pain; neuralgic pain; migraine; fibromyalgia; IBS; chronic fatigue syndrome; chronic tension type headache; chronic low back pain; myofascial pain and chronic osteoarthritis. One embodiment is directed to neuropathic pain. One embodiment is directed to neuralgic pain. One embodiment is directed to migraine. One embodiment is directed to fibromyalgia. One embodiment is directed to IBS. One embodiment is directed to chronic fatigue syndrome. One embodiment is directed to chronic tension type headache. One embodiment is directed to chronic low back pain. One embodiment is directed to myofascial pain. One embodiment is directed to chronic osteoarthritis.

In a separate embodiment, the compound is selected from the group consisting of [(methylethyl)sulfonyl](trans-4-{[(4-(6-fluoro-pyridin-2-yl) (l,3-thiazol-2- yl))amino]methyl}cyclohexyl)amine; [(methylethyl)sulfonyl]({trans-4-[(4-(6-fluoro- pyridin-2-yl)(l ,3-thiazol-2-yl))amino]cyclohexyl}methyl)amine; [(methylethyl)sulfonyl]({trans-4-[(4-{2-methyl,6-fluoro-pyri din-3-yl)(l,3-thia2ol-2- yl))amino]cyclohexyl}methyl)amine; (methylethyl)sulfonyl](trans-4-{[(4-(2-fluoro- pyridin-3-yl)(l,3-thiazol-2-yl))aminoJmethyl}cyclohexyl)amin e ;[(mcthylcthyl)sulfonyl]({trans-4-[(4-(2-fluoro-pyridin-3-yI )(l,3-thiazol-2- yl))amino]cyclohexyl}methyl)amine; [(methylethyl)sulfonyl]({trans-4-[(4-(6-fluoro- pyridin-3-yl)(5-methyl-!,3-thiazol-2-yl))amino]cyclohexyl}me thyl)amine; (methylethyl)sulfonyI]({trans-4-[(4-(2-fluoro-pyridin-3-yl)( 5-methyl-l ,3-thiazol-2- yl))amino] cyclohexyl}methyl)amine; [(methylethyl)sulfonyl]({trans-4-[(4-(6- trifluoromethyl-pyridin-3-yl)(5-methyl- 1 ,3-thiazol-2-

IO

yl))amino]cyclohexyl}methyl)amine; and [(methylethyl)sulfonyl](trans-4-{[(4-(6- bromopyridin-2-yl)(l,3-thiazol-2-yl))amino]methyl}cydohexyl) amine or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions

The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Compound I and a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier.

The compound of Compound 1 may 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 may 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 disclosed in Remington: The Science and Practice of Pharmacy, 19 ^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pλ, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. 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.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

U

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.

Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg 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 upon the frequency and mode of administration, the 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 skilled in the art.

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 and similar administration, typical doses arc in the order of half the dose employed for oral administration.

The present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound I of Formula 1 and a pharmaceutically acceptable carrier. In an embodiment of the present invention the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.

For parenteral administration, solutions of a compound of Formula I in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous

solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. A compound of Formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodcxtrin, talc, gelatin, agar, pectin, acacia, magnesium stcarate, 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 a compound of Formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tabletted. placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. 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 an aqueous or non-aqueous liquid suspension or solution.

EXPERIMFNTAL SRCTlQN

General Methods: Anhydrous solvents were purchased from the Aldrich Chemical Company and used as received. The NMR spectra were measured on a Bruker Avance 400 spectrometer and or 300 MHz (Varian) with CDCl ₃ , DMSO-d ₆ or CD ₃ OD as the solvent. Chemical shifts (δ) are expressed in ppm, coupling constants (J) are expressed in Hz, and splitting 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: td=triplet of doublets; dq=doublet of quartet. Unless otherwise noted, mass spectra were obtained using electrospray ionization (ESMS, Micromass Platform Il or Quattro Micro) or Waters ZQ mass spectrometry with Agilent 1 100 HPLC system with an autosampler using DAD/UV and Waters ELSD detection system and lnertsil ODS-3 column. For LC-MS determination, two methods were used: Method — I: 8 column, Neutral pH, 20 % to 90 % Acetonitrile/ H ₂ O with 0.2 % Ammonium formate; or Method - II: Cl 8 Column, Acidic pH, 20 % to 90 % Acetonitrile/ H ₂ O with 0.2 % AcOH. Thin-layer chromatography (TLC) was carried out on glass plates prc-coatcd with silica gel 60 F ₂ 5 ₄ (0.25 mm, EM Separations Tech.). Preparative TLC was carried out on glass sheets pre-coated with silica gel GF (2 mm, Analtech). Silica gel column chromatography was performed on Merck silica gel 60 (230-400 mesh).

List and source of chemicals

Most of the reagents used in the experimental section such as 2-fluoro nicotinic acid, 6- trifluoromethyl nicotinic acid. 4-trifluoromethyl nicotinic acid, oxalyl chloride, trimethylsilyldiazomethane, isopropyl sulfonyl chloride, benzoylisothiocyanate, bromine, 48 % Hydrobromic acid in AcOH, Diisopropylethyl amine and ethyl magnesium bromide were purchased from the Aldrich Chemical Company. 6-Fluoro- 2-methyl nicotinic acid was purchased from Asychem. 2-Fluoronicotinonitrile was purchased from Alfa Aesar. 6-Fluoropicolinic acid and 6-fluoronicotinic acid were purchased from Oakwook Products Inc. and Martrix Scientific.

Preparation of the compounds of the invention

Scheme 1

(a) DPPA. TEA, Toluene, BnOH, reflux, (b) IO % Pd-C, H ₂ , MeOH/ EtOAc. (c) I M NaOH, Et ₂ O, (R')(R ² )(R ³ )CSO ₂ CI. (d) 10 % TFA in CH ₂ CI ₂ . (e) BzNCS. THF, rt. (f) K ₂ CO ₃ , MeOH/ H ₂ O, reflux, (g) α-haloketone of Formula XIX, DIEA, EtOH, reflux.

The compounds of Formula I may be synthesized according to the procedures described in Scheme 1. The compounds of Formula II are commercially available or may be synthesized by one skilled in the art. In summary, the carboxylic acids of Formula II are converted to their Cbz-protected amines to afford the compounds of Formula HI. The Cbz protecting group is selectively removed to afford the compounds of Formula IV. The resultant amines are coupled with (R')(R ² )(R ³ )CSO ₂ CI to afford the intermediates of Formula V. The Boc group is removed and the resultant amines of Formula VI are treated with benzoylisothiocyanate to afford the compounds of Formula VII. The compounds of Formula VII are subjected to basic sÏ…lvolysis to afford the thiourea intermediates of Formula VIIl. These intermediates are coupled with the appropriate α-haloketone of Formula XIX to afford the compounds of the invention.

Scheme 2

x x»

R ^! . _{J H} < >* ^λNHCbz

XII Vl

(a) I M NaOH, Et ₂ O ₅ BOC ₂ O. (b) I M NaOH, Et ₂ O, (R ^I )(R ² )(R ³ )CSO ₂ CI. (c) DPPA, TEA, Toluene, BnOH, reflux, (d) IO % TFA in CH ₂ CI ₂ . (e) I M NaOH, Et ₂ O. (R')(R ² )(R ³ )CSO ₂ CI. (f) 10 % Pd-C, H ₂ , EtOH, heat or HBr/ AcOH.

Alternatively, the intermediates of Formula VI may be synthesized according to the procedures outlined in Scheme 2. The starting materials of Formula IX are commercially available or may be synthesized by one skilled in the art. The amino acids of Formula IX may be coupled with (R')(R ² )(R ³ )CSO ₂ CI to afford the intermediates of Formula X which are further converted to the Cbz-protected amines of Formula XII. Separately, the amino acids of Formula IX may be converted into the mono-Cbz protected intermediates of Formula XI. The amines of Formula XI are coupled with (R')(R ² )(R ³ )CSθ2CI to afford the compounds of Formula XJJ. The Cbz group of Formula XII is removed Io alTord the intermediates of Formula Vl. Finally, the intermediates of Formula VI may be converted to the compounds of the invention by using the procedures described in Scheme 1.

Additionally, the intermediates of Formula X can be converted to the compounds of Formula V, which are described in Scheme 1 , if t-butanol is substituted for benzyl alcohol.

Scheme 3

XIV _χv ,

(a) 10 % Pd-C, H ₂ , EtOAc/ MeOH, rt. (b) BzNCS, THF, rt. (c) K ₂ CO ₃ , MeOH/ H ₂ O, reflux, (d) α-haloketone of Formula XlX, DlEA, EtOH, reflux, (e) IO % TFA in CH ₂ Cl ₂ Or 4 M HCl in Dioxane. (0 (R')(R ² )(R ³ )CSθ2CI, DlEA, CH ₂ CI ₂ , rt.

Additionally, the compounds of Formula I may be synthesized according to the procedures outlined in Scheme 3. In summary, the Cbz group of Formula III is removed to afford the intermediates of Formula IV. These intermediates are converted to the thioureas of Formula XlH. The thiazole ring is formed to afford the compounds of Formula XlV. The Boc group is removed to afford the amines of Formula XV. The compounds of the invention are synthesized by coupling of the amines with (R')(R ² )(R ³ )CSO ₂ CI.

(a) (COCl) ₂ , cat. DMF, CH ₂ Cl ₂ , rt. (b) 2M TMSCH ₂ N ₂ in Et ₂ O, Dioxanc, rt. (c) 4M HCl in dioxane, rt or HBr in AcOH, rt. (d) HNMe(OMe).HCI, EDC, HOBt CH ₂ CI ₂ , rt. (e) EthylMgBr, THF, -78°C, (f) Br ₂ , 48 % HBr in λcOH, rt.

The α-haloketones of Formula XIX may be synthesized according to the procedures described in Scheme 4. The picolinic acids or nicotinic acids of Formula XVI are commercially available or may be synthesized by one skilled in the art. The picolinic acids or nicotinic acids of Formula XVI may be converted to the corresponding acid chlorides of Formula XVIl. The acid chlorides may be treated with diazomethane or ethylmagnesiumbromide to afford the intermediates of Formulas XVIII and XXI, respectively. These intermediates may be converted to the α-haloketones of Formula XlX, wherein R ⁵ is H or methyl, respectively. Alternatively, the picolinic acids or nicotinic acids of Formula XVI may be converted to the corresponding Weinreb amide of Formula XX which is further converted to the α-haloketones of Formula XlX using ethylmagnesium bromide, wherein R ⁵ is methyl. Similarly, if methylmagnesium bromide is substituted for ethylmagnesium bromide, R ⁵ is H,

For clarity purposes, the moiety R* is used to denote one or more F, Cl, Br, I or CF ₃ , and the 2-pyridyl or 3-pyridyl group shown above may optionally be further substituted with methyl.

For representative reaction conditions in connection with the conversion of the carboxylic acids to bromoketones using diazomethane, see A. Gangjee, et al., Bioorg.

Med. Chem., 2003, 1 1, 5155-5170. For representative reaction conditions in connection with the conversion of the haloketones from ketones using Br ₂ / AcOH or

sulfurylchloride and MeOH, see N. Ikemoto, et al., Tetrahedron, 2003, 59, 1317-1325; or using Pyridine-Brj, HBr/ AcOH, see W.C. Patt and M.A. Massa, Tetrahedron Lett., 1997, 38, 1297-1300.

Scheme 5

(a) EtMgBr, THF, -78 ⁰ C. (b) Br ₂ , 33 % or 48 % HBr in AcOH. Alternatively, the α-haloketones of Formula XIX may be synthesized according to the procedures described in Scheme 5 from the starting materials of Formula XXTI. The cyano compounds are treated with ethylmagnesium bromide to afford the intermediates of Formula XXl, wherein R ⁵ is methyl. Similarly, if methylmagnesium bromide is substituted for ethylmagnesium bromide, R ⁵ is H. The intermediates of Formula XXI are further converted to the α-haloketones of Formula XIX.

For clarity purposes, the moiety R* is used to denote one or more F, Cl, Br, I or CF3, and the 2-pyridyl or 3-pyridyl group shown above may optionally be further substituted with methyl.

For representative reaction conditions in connection 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.

Scheme 6

(a) Tebbe Reagent, DCM, rt. (b) NBS, THF/H ₂ O. (c) Me ₃ S ⁺ OI ^' , KOtBu, THF. (d) HCI or LiCl, CH ₃ SO ₃ H.

Alternatively, the α-haloketones of Formula XIX wherein R ⁵ is H may be synthesized according to the procedures described in Scheme 6. The compounds of Formula XXIlI are commercially available or may be synthesized by one skilled in the art. The carboxylate compounds of Formula XXIII are treated with Tebbe reagent to afford the intermediates of Formula XXIV which are converted to the α-haloketones of Formula XIX. Alternatively, the carboxylates of Formula XXIII may be treated with dimethyl sulfonium ylide in the presence of base, such as KOtBu, to afford the intermediates of Formula XXV which are converted to the u-haloketones of Formula XIX.

For clarity purposes, the moiety R* is used to denote one or more F, Cl, Br, I or CF3, and the 2-pyridyl or 3-pyridyl group shown above may optionally be further substituted with methyl. For representative reaction conditions in connection with the transformation of the esters to the enol ethers using Tebbe reagent, see S. H. Pine, et al., J. Am. Chem. Soc., 1980, 102, 3270. For representative reaction conditions in connection with the transformation of the enol ethers to the α-haloketones, see S.E. Kazzouli, et al., Tetrahedron Lett., 2002, 43. 3193-3196; and F. Bracher, and A. Puzik, Heterocyclic Chem., 2004, 41, 173-176. For representative reaction conditions in connection with the transformation of the esters to the α-haloketones via the dimethylsulfoxonium ylide, see J. E. Baldwin, et al., Synlett, 1993, 51-53; and D. Wang, et al., J. Org. Chem., 2004, 69, 1626-1633.

Scheme 7

Procedure A

IV m=1 and n=1 (a) I M NaOH/ Et ₂ O, BOC ₂ O. (b) CH ₂ CI ₂ , I-Methylmorpholine, Isobutyl chloroformate, -20 ⁰ C, NH(OMe)Me.HCl. (c) LAH, Et ₂ O, -45 ⁰ C. (d) NaCNBH ₃ , MeOH, NH ₄ OAc, rt.

Procedure B

IV m=2 and n=2

(a) CH ₂ CI ₂ , MsCI, TEA, O ⁰ C. (b) NaCN, DMF, 80 ⁰ C or Et ₄ NCN, Toluene, 80 ⁰ C. (c) LAH, THF. (d) 0.2 cq. (BOC) ₂ O, Dioxanc, rt.

The compounds of Formula IV are used as intermediates in Schemes 1 , 2 and 3. These intermediates, wherein n=l and m=l (procedure A) or wherein n=2 and m=2, (procedure B) are synthesized according to the procedures described in Scheme 7.

For representative reaction conditions in connection with the synthesis of the diamine in Procedure ft see P. Garcia, et al., J. Org. Chem., 1961 , 26, 4167-4168. For representative reaction conditions in connection with the synthesis of the mono- protected Boc diamine in Procedure B see J. Hansen, et al., Synthesis, 1982, 5, 404- 405 and C. Dardonville, et al., Bioorg. Med. Chem. Lett., 2004, 14, 491-493.

Scheme 8

XXVI XXVII XXVIII Vl (a) TEA, CH ₂ CI ₂ , (R')(R ² )(R ³ )CS(O)C1. (b) NaIO ₄ , RuCI ₃ (cat) or mCPBA. (c) deprotection.

- The sulfonamides may also be synthesized according to the procedures outlined in Scheme 8. In summary, the compounds of Formula XXVI are reacted with (R')(R ² )(R ³ )CS(O)CI. to afford the sulfinamides of Formula XXVII. These compounds are oxidized to the intermediates of Formula XXVlH. The protecting group is removed to form the intermediates of Formula VI. Finally, the intermediates of Formula VI may be converted to the compounds of the invention by using the procedures described in Scheme 1.

For representative reaction conditions, see S. Weinreb, J. Org. Chem.. 1997, 62, 8604- 8608; J. Ellman, Tetrahedron Lett., 2001 , 42, 1433-1436; B. Sharpless, Org. Lett., 1999, 1, 783-786; and WO 01/37826.

Preparation of intermediates

Representative intermediates were synthesized as follows:

Intermediate of Formula II

/røm-4-{[(tert-butoxy)carbonylamino]methyl Jcyclohexanecarboxylic acid: BoC ₂ O (41.7 g, 190 mmol) was added to a stirred biphasic solution containing tran.s-4- (aminomethyl)cyclohexanecarboxylic acid (25.0 g, 159 mmol), NaHCO ₃ (20.0 g, 238 mmol), water (300 mL) and Et ₂ O (200 mL) at rt. The pH of the solution was adjusted to pH ~ 9.0 by adding additional quantities 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 I M aqueous HCI. 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 yield the desired product as a colorless solid (23.3 g, 57 %). ¹ H NMR (CDCI ₃ ) δ 4.60 (br s, I H) ₁ 2.99 (t, 2H, J=6.4 Hz), 2.29-2.23 (m, 3H). 2.05 (dd, 2H, J=I 3.6 and 3.2 Hz), 1.84 (dd, 2H. J= 13.2 and 2.8 Hz), 1.44 (s, 9H), 1.42 (br m, I H), 0.97 (dq. 2H. J=25.6, 12.4 and 3.2 Hz).

Intermediate of Formula HI (tert-butoxy)-N-({/rcrm--4-[(phenylmcthoxy)carbonylamino]cyc lohcxyl} methyl)carboxamide: /røns^-IKtert-butoxyJcarbonylaminoJmethyUcycIohexane carboxylic acid (20.3 g. 0.073 mol) was suspended in toluene (420 mL) and chilled to - I O ⁰ C in a dry ice bath. DPPA (15.8 mL, 0.073 mol) was added and chilling was continued. TEA (15.3 mL, 0.1 1 mol) was added drop wise over 10 min. The mixture was removed from the ice bath, warmed to 10 ⁰ C and then slowly heated to 70 ⁰ C. After 15 h, nitrogen evolution was observed to be finished and the solution color turned to yellow. The mixture was cooled to 47 ⁰ C and benzyl alcohol (22.8 mL, 0.220 mol) was added. The mixture was heated to I IO °C and stirred overnight. The mixture was cooled to 50 ⁰ C and concentrated in vacuo to obtain amber solids. The solids were treated with dcionizcd 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 resultant solid was triturated in MTBE to afford a white solid (17.8 g, 67 %) as the desired product. ¹ H NMR (CDCI ₃ ) δ 7.34-7.286 (m, 3H). 7.13 (d, 2H, J=8.0 Hz). 6.78 (t. I H, J=6.0 Hz), 4.97 (s, 2H), 3.3-3.14 (br, m, I H), 2.73 (t, I H, J=6.3 Hz), 1.78 (d.

2H, J= 10,6 Hz), 1.64 (d, 2H, J=I I . $ 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-[(rmm-4-aminocyclohexyl)methyl](tert-butoxy)carboxamide: 10 % Pd-C (0.20 g) was added to a stirred solution of (tert-buloxy)-N-({/rαm-4-[(phenylmethoxy) carbonylamino]cyclohexyl}methyl)carboxamide (2.0 g, 5.5 mmol) in EtOAc/ MeOH (1 : 1, 50 inL) at it. The mixture was degassed and purged with hydrogen twice, and further stirred at rt under atmospheric pressure of hydrogen for 2 h. The mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to afford the desired compound as a solid (1.3 g, 91 %). ¹ H NMR (CDCI ₃ ) δ 4.59 (br s, I H), 2.97 (t, 2H, J=6.4 Hz), 2.63-2.58 (m, 1 H), 1.87 (d, 2H, J=12.4 Hz), 1.75 (d, 2H ₌ J=12.4 Hz), 1.44 (s, 9H), 1.37 (m, IH), 1.12-0.96 (m, 4H). ESMS m/e: 173 ((M+H)-55)\

Intermediate of Formula V

(tert-butoxy)-N-[(/rom-4-{[(methylethyl)sulfonyl]amino}cyclo hexyl)methyl] carboxamide: Isopropyl sulfonyl chloride (6.2 mL, 7.9 g, 56 mmol) was added drop wise at rt to a stirred biphasic solution containing N-[(/røm-4- aminocyclohexyl)methyl](tcrt-butoxy)carboxamide (10 g, 44 mmol) _. . I M aqueous NaOH (100 mL) and Et ₂ O (100 mL). After stirring for 2 h, a white precipitate appeared. The precipitate was collected by filtration, washed with Et ₂ θ and dried in vacuo to obtain the desired product as a solid (9.5 g, 65 %), ¹ H NMR (CDCI ₃ ) δ 4,58 (br s, I H), 3.89 (d, I H, J=8.0 Hz), 3.23 (septet, I H, J=4.4 Hz), 2.96 (t, 2H, J=6.4 Hz), 2.61 (m, IH), 2.09 (d, 2H, J=I 1.6 Hz), 1.89-1.74 (n% 3H), 1.44 (s, 9H), 1.37 (d, 6H, J=6.8 Hz), 1.22 (dq, I H, J=13.2 and 3.6 Hz), 1.09-1.00 (br m, 3H). ESMS m/e: 279 ((M+H)-55) ⁺ .

Intermediate of Formula VI [/rø/iÏŠ-4-(aminomcthyl)cyclohcxyl][(mcthylcthyl)sulfonyl]a minc: TFA (5 mL) was added at rt to a stirred solution containing (tert-butoxy)-N-[(//wκ-4-{[(rnethylethyl) sulfonyl]amino}cyclohexyl)methyl]carboxamide (1.3 g. 3.9 mmol) and CIhCI? (45 mL). After 4 h, the solution was concentrated in vacuo and the residue was re- dissolved in CHCb. The CHCb solution was washed successively with I M aqueous NaOH and brine, dried over Na ₂ SO4 and then concentrated in vacuo to provide the free

base as a solid (0.88 g, 97 %). ¹ H NMR (CDCI ₃ ) δ 3.19-3.09 K 2H), 2.82 (dd, 2H, 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). LSMS m/e: 235 (M+H) ^* .

Intermediate of Formula VII

N-({[(/ron.y-4-{[(methylethyl)sulfonyl]amino}cyclohexyl)meth yl]amino}thioxomethyl) benzamide: Benzoylisothiocyanatc (1.6 g, 10 mmol) was added to a solution of [irans- 4-(aminomethyl)cyclohexyl][(methylethyl)sulfonyl]amine (2.3 g, IO mmol) in THF (100 mL) under an argon atmosphere and then stirred at rt overnight. The reaction mixture was concentrated in vacuo and the resultant gum-like material was triturated with Hexanes to obtain the product as a pale yellow solid. (3.8 g, 96 %). ¹ H NMR (CDCl ₃ ) δ 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, I H, J=8.4 Hz), 3.59 (t, 2H, J=6.0 Hz). 3.25 (septet. lH, J=4.0 Hz) ₅ 2.14 (dd, 2H, J=7.2 and 2.4 Hz), 1.91 (d, 2H, J=6.4 Hz), 1.74 (m, I H), 1.29 (d, 6H, J= 12.8 Hz), 1.25-1.12 (m, 2H). ESMS m/e: 398 (M+H) ⁺ .

Intermediate of Formula VIII (trans-A- {[(aminothioxomethyOaminolmethylJcyclohcxyOKmethylethyOsulfo nylJamine:

KaCO ₃ (2.00 g, 14.5 mmol) was added to a solution containing N-({[(/rø/v.v-4- {[(methylethyljsulfonyljaminojcyclohexy^methyljaminojthioxom ethyljbenzamide (3.80 g, 9.57 mmol), MeOI I (75 mL) and H ₂ O (25 mL). The resulting turbid mixture was refluxed for 16 h. Note that upon refluxing the mixture turned into a clear homogenous solution. The solution was allowed to cool and concentrated in vacuo to yield a solid. This solid was dissolved in acetone and filtered through a pad of celitc, followed by additional washings of the celite with acetone. The filtrate was concentrated in vacuo to afford the desired product as a pale yellow solid (2.20 g, 79 %). ¹ H NMR (CDCl ₃ ) δ 6.98 (br s, I H), 6.39-6.32 (br s. 2H), 3.50 (br s, I H), 3.32 (m, I H), 3.14 (m, 2H), 2.16-2.13 (br m, I H), 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). ESMS m/e: 294 (M+H)\

Intermediate of Formula X

/r<JW-4-({[(methylethyl)sulfonyl]amino}methy!)cyclohexane carboxylic acid: lsopropyl sulfonyl chloride ( 10.9 g, 77.0 mmol) was added drop wise to a solution of /røm-4-(aminomethyl)cyclohexanecarboxylic acid (10.0 g, 63.7 mmol) in I M 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 HCI. The solids were collected by filtration and dried under vacuum at rt to afford the desired product as a white solid (5.0 g, 33 %). ¹ H NMR (CDCI ₃ ) δ 4.91 (br s, I H), 3.20 (septet, I H, J=6.8 Hz). 2.92 (d, 2H, J=6.8 Hz), 2.24 (tt, I 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 ₃ 2H, J=25.2, 13.2 and 3.6 Hz). ESMS m/e: 264 (M+H) ⁺ .

Intermediate of Formula XI

N-[/ro«5-4-(aminomethyl)cyclohexyl](phenylmethoxy)carboxami de: (tert-butoxy)-N-({ /røM.y^-^phenylmethoxyXarbonylaminolcyclohexylJmethyOcarbox amide (4 g, I l mmol) was treated with 25 % TFA in CH ₂ CI ₂ (50 mL). After stirring 5 h, the solvents were removed in vacuo. The crude product was redissolved in CH ₂ CI ₂ and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was isolated, dried over Na ₂ SCu and concentrated in vacuo to afford the desired product as an oil (quantitative yield). ¹ H NMR (DMSO-d) δ 7.18-7.03 (m, 5H), 4.78 (s, 2H), 3.06-2.96 (m, 1 H), 2.35 (d, 211, J = 6.8 Hz), 1.62-1.48 (m, 4H), 1.20-1.1 1 (m, I I I), 0.97-0.69 (m, 411). ESMS m/e: 263 (M+H) ⁺ .

Intermediate of Formula XH N-['rø«-s-4-({[(methylethyl)sulfonyl]amino}methyl)cyclohex yl](phenylmethoxy) carboxamide: lsopropyl sulfonyl chloride (6.6 g, 46 mmol) was added drop wise to a solution containing N-[/røm-4-(aminomethyl)cyclohexylJ(phenylmethoxy) carboxamide (1 1 g, 42 mmol), TEA (7.0 g. 70 mmol) in anhydrous CH ₂ Cb ( 150 mL) at 0 ⁰ C. The reaction was allowed to warm to rt and stirred overnight. The solution was washed with saturated aqueous NaHCO ₃ , dried over Na ₂ Sθ4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography using an increasing 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 (CDCI ₃ ) δ 7.38-7.31 (m, 5H), 5.08 (s, 2H), 4.66-4.57 (br m, I H), 4.13-4.06 (br m, I H), 3.49-3.4 (br m, IH), 3.19-3.1 1 (m, I H). 2.97 (t. 2H,

,1=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). ESMS m/e: 369 (M+H) ⁺ .

Intermediate of Formula XlI to Intermediate of Formula VI [(/røw-4-aminocyclohexyl)methyl] [(methylethyl)sulfonyl]amine: η-[frans-4-

({[(methylethyOsulfonyÏ€aminoJmethyOcyclohexylKphenylmethoxy ^arboxamide (62 g, 0.168 mole) and 10% Pd-C (12 g) in anhydrous EtOH (600 mL) was shaken under hydrogen at 55 psi at 60 ⁰ C for 6 h. The reaction mixture was filtered through eclite and celite was washed with EtOH. The combined EtOH filtrate 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 (CDCI ₃ ) δ 3.60 (br s, 2H), 3.06 (quintet, I H), 2.69 (d, 2H, J=I 1.2 Hz), 2.58 (m, I H), 1.79 (d, 2H, J=I 1.2Hz), 1.68 (d, 2H, J=I 1.2Hz), 1.24 (br m, 1 H), 1.14 (d, 6H, J=I 1.2 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-({//-«m-4-[(aminothioxomethyl)amino]cyclohexyl}methyl) (tert- butoxy)carboxamide:

Benzoylisothiocyanate (0.755 g, 4.63 mmol) was added to a stirred solution of (tert- butoxy)carboxamidemethylcyclohexyl-/ra«.?-4-amine (1.2 g, 4.6 mmol) in THF (50 mL) at rt under argon atmosphere. After stirring for 24 h, the solution was concentrated in vacuo to afford a viscous material. Trituration of the viscous material with Hexanes afforded N-( {frøw-4-[(aminothioxomethyl)amino]cyclohexyl}methyl) (tcrt- butoxy)carboxamidebenzamide as a pale yellow color solid (1.71 g, 90 % yield). ¹ H NMR (CDCl ₃ ) δ 10.61 (d, I H, J=7.2 Hz), 8.89 (s, I H), 7.82 (d, I H, J=7.6 Hz), 7.63 (t, I H, J=7.2 Hz), 7.54-7.49 (m, 3H). 4.61 (br s, I H), 4.24-4.19 (m, I H), 3.02 (L 2H, J=6.0 Hz), 2.27 (dd, 2H, J=7.6 and 2.0 Hz), 1.86 (d, 2H, J=I 1.6 Hz), 1.45 (s, I OH), 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). ESMS m/e: 336 ((M+H) - 55) ⁺ .

N-({//Om-4-[(aminothioxomethyl)amino]cyclohexyl}methyl)(t ert- butoxy)carboxamidebenzamide (1.65 g, 4.0 mmol) was dissolved in MeOH (25 mL).

Water (5 mL) was added followed by the addition Of K ₂ CO ₃ (1.66 g, 12.0 mmol). The resultant mixture was allowed to reflux overnight. After refluxing for 16 h, the solvents were removed in vacuo and the resultant solid was dried under high vacuum. The solid

was re-dissolved in acetone and filtered through a pad of celite. Concentration of the filtrate in vacuo afforded the desired product as a pale yellow color solid (1.1 g). ¹ H NMR (CDCI ₃ ) δ 6.17 (br s, I H), 4.85 (br s, I H), 2.99 (t, 2H, J=7.2 Hz). 2.09 (d, 2H, J=12.0 Hz), 1.83 (d, 2H, J=I2.O Hz), 1.44 (s, 10H), 1.29-0.78 (m, 4H). ESMS m/e: 288 (M+H) ⁺ .

Intermediate of Formula XIV

(lcrtA>utoxy)-N-({A-[(jramA-(6-fluoro-pyridin-2-yI)(\3-Mâ ˆž.o\-2- y l))amino]cyclohexyl} methyl) carboxamide: DIEA (1.17 mL, 6.45 mmol) was added to a solution of 2-bromo-l-(6-fluoro-pyridin-2- yl)ethan-l-one HCI salt (450 mg, 2.18 mmol) in anhydrous EtOH (5 mL) under an argon atmosphere. After stirring for 5 min at it, N-({fra/w-4-[(arninothioxornethy|) aminoJcyclohexyljmethylXtert-butoxyJcarboxamide (627 mg, 2.18 mmol) was added and the reaction was refluxed overnight. EtOH was removed in vacuo and the residue was re-dissolved in CH ₂ CI ₂ . The organic layer was washed with water, brine, dried over Na _∑ SOα and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 60 % EtOAc in Hexanes to yield the desired product (425 mg, 48 %) as a yellow colored solid. ¹ H NMR (CDCI ₃ ) δ 7.81-7.78 (m, 2H), 7.31 (S, IH), 6.81-6.78 (m, I H), 5.04 (d, I H, J=8 Hz), 4.60 (br s, I H), 3.36-3.30 (m, H-I), 3.02 (t, 211, J=6.4 Hz), 2.25 (d, 211, J=I 2.0 Hz), 1.86 (d, 211, J=I 2.4 Hz), 1.49- 1.30 (br m, I H), 1.45 (s, 9H), 1.28-1.22 (m, 2H), 1.1 1 (q, 2H, J=25.0 and 12.0 Hz). ESMS m/e: 407 (M+H) ⁺ .

Intermediate of Formula XV [trans-4-(am'momethy\)cyc\obexy\](4-(6-flιιoro-pγridin-2- y[)( 1 ,3-thiazol-2-yl))amine: (tert-butoxy)-N-({/røm-4-[(4-(2-pyridyl)(l,3-thiazol-2-yl)) amino]cyclohexyl}methyI) carboxamide (300 mg, 0.74 mmol) was treated with 4 M HCI in dioxane ( 15 mL) in CH ₂ CI ₂ (10 mL) under argon atmosphere. The reaction mixture was stirred at rt overnight and the product precipitated from the reaction mixture. The resulting precipitate was collected by filtration as the hydrochloride salt (280 mg, 92 %). ¹ H NMR (CD ₃ OD) δ 8.14-8.07 (m. I H), 7.89 (d, IH. J=8.0 Hz), 7.18 (d, I H, J=8.0 Hz), 3.66 (br m, IH), 2.88 (d. 2H, J=7.2 Hz), 2.25 (d, 2H, J=12.0 Hz), 2.01 (d, 2H, J=12.0 Hz), 1.77-1.73 (br m, IH), 1.59 (q. 2H, J=24.0 and 12.0 Hz), 1.29 (q, 2H, J=24.0 and 12.0 Hz). ESMS m/e: 307 (M+H) ⁺ .

" Intermediate of Formula IV (wherein m=n= 1 )

Representative compounds as described in Scheme 7 were synthesized as follows: (/raw^-IKtert-butoxyjcarbonylaminoJmethylJcyclohexyO-N-metho xy-N- methylcarboxamide: 1-Methylmorpholine (5.0 g, 49.6 mmol) was added to a stirred solution of /rom-4-{[(tert-butoxy)carbonylamino]methyl}cyclohexanecarbox ylic acid (8.5 g, 33 mmol) in CH ₂ CI ₂ (100 mL). The solution was cooled to -20 ⁰ C and isobutyl chloroformate (5.9 g, 43.0 mmol) was added drop wise over a period of 10 min. The resulting pale yellow color solution was allowed to warm to rt and then stirred for an additional hour. The solution was cooled to -20 ⁰ C and 1-Methylmorpholine (5.0 g, 50 mmol) was added followed by the addition of a solution of N, O- dimethylhydroxylamine (3.9 g, 40 mmol) in CH ₂ Cb. After the addition was complete, the solution was warned to rt and was stirred overnight. The reaction was quenched with water and washed successively with aqueous citric acid, water, and brine. The CH2CI ₂ layer was concentrated in vacuo and the resulting material was purified by silica gel column chromatography (30 % EtOAc in Hexanes) to afford the desired product as a colorless viscous material (7.8 g, 79 %). ¹ H NMR (CDCI ₃ ) δ 4.67 (br s, I H), 3.69 (s, 3H), 3.18 (s, 31-1), 2.99 (t, 2H, J=6.4 Hz). 2.65 (br m, I H, J=9.6 Hz). 1.83 (d, 2H, J=IO-O Hz), 1.53-1.49 (m, 3H) ₃ 1.44 (s, 9H), 1.0-0.91 (m, 4H). ESMS m/e: 300 (M-H I) ⁺ .

(tert-butoxy)-N-[(//Oλ.y-4-foimylcyclohexyl)methyl]carboxam ide: A solution of I M LAH in THF (24.7 mL, 24,7 mmol) was added over a period of 15 min to a stirred solution of (/ram^-IKtert-butoxyOcarbonylaminoJmethylJcyclohexyO-N-metho xy-N- methylcarboxamide (7.4 g. 24.7 mmol) in Et ₂ θ (200 mL) under argon atmosphere at - 78 ⁰ C. After the addition was complete, the reaction was stirred for an additional 15 min then allowed to warm to 0 ⁰ C for 1 h and then re-cooled to -78 ⁰ C. The reaction was quenched with IN aqueous KHSO4 and filtered over celite containing NajSCM. The celite was washed with Et ₂ θ and the filtrate was concentrated in vacuo to afford the desired product as a viscous gum (6.0 g, >99%). ¹ H NMR (CDCl ₃ ) δ 9.62 (s. I H), 4.67 (br s, I H), 3.00 (t, 2H, J=6.0 Hz), 2.19 (t, I H, J=8.8 Hz), 2.03 (d. 2H, J=I 3.2 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). ESMS m/e: 186 ((M+H)-55) ⁺ .

N-{[//-<3n.y-4-(aminomethyl)cyclohexyl]methyi}(tert-butox y)carboxamide: NaCNBH ₃ (2.4 g, 38 mmol) was added to a stirred solution containing the (tert-butoxy)-N-[(/rø«.v- 4-formylcyclohexyl)methyl]carboxamide (6.0 g. 25 mmol), ammonium acetate (29 g, 374 mmol) and MeOH (100 mL) under argon atmosphere at rt. The solution was stirred for 18 h at rt and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography to yield the desired amine (1.5 g, 26 %). ¹ H NMR (CDCl ₃ ) δ 4.64 (br s _s IH), 2.97 (t, 2H, J=6.4 Hz), 2.53 (d, I H, J=6.4 Hz), 2.41 (d. I H, J=6.4 Hz), 1.79 (q, 2H, J=I 9.6 and 9.2 Hz), 1.44 (s, 9H), 1.50-1.30 (br m, 4H), 1.0- 0.81 (m, 4H). ESMS m/e: 242 (M+H) ⁺ .

Intermediate of Formula XVIl

6-Fluoro-pyridine-2-carbonyl chloride: Oxalyl chloride (1.35 g, 10.6 mmol) was added to a stirred solution of 6-fluoropicolinic acid (1.0 g. 7.09 mmol) in CH ₂ Cb (25 mL) at rt under argon atmosphere. A drop of DMF was added to initiate reaction. After stirring for 24 h at rt, the solvents were removed in vacuo to yield the acid chloride as a colorless solid (1.35 g, 97 %).

Intermediate of Formula XIX (wherein R is H) 2-Chloro-I-(6-fluoro-pyridin-2-yl)-ethanone: 6-Fluoro-pyridine-2-carbonyl chloride (1.35 g, 6.90 mmol) was dissolved in dioxanc (25 mL) and cooled to 0 °C. A 2M ethereal solution of trimethylsilyldiazomethane (6.90 mL, 1.57 g, 13.82 mmol) was added drop wise and the reaction was stirred at rt for 24 h to generate the intermediate of Formula XVIIl, 4M HCI in dioxane (10 mL) was added to the solution and stirred for 2 h at rt. The solution was concentrated in vacuo to afford the title compound as a dark brown colored solid (1.45 g, >99 %). ¹ H NMR (CDCI ₃ ) δ 8.05-7.99 (m, 3H), 7.24-7.20 (m, 1 H), 5.02 (s, 2H). ESMS m/e: 174 (M+H) ⁺ .

The following compounds were prepared analogously:

2-Chloro-l-(2-tluoro-pyridin-3-yl)-ethanone: ¹ H NMR (CDCl ₃ ) δ 9.26 (s, 1 H), 8.96 (d, 1 H, J=8.4 Hz), 8.06 (d, 1 H, J=8.4 Hz), 4.87 (s, 2H). ESMS m/c: 174 (M+H) ⁺ .

2-Chloro-l-(6-fluoro-2-methyl-pyridin-3-yl)-ethanone: ¹ H NMR (CDCI ₃ ) δ 8.39 (t, IH, J=8.04 Hz). 7.01 (d, I H, J=5.8 Hz), 4.87 (s. 2H), 2.61 (s, 3H). ESMS m/e: 188 (M+H)\

Intermediate of Formula XX

6-Fluoro-N-methoxy-N-methyl-nicotinamide: DIEA (5.0 ml.., 3.63 g, 28.4 mmol) was added to a stirred solution of 2-fluoro-5-pyridine carboxylic acid (2.0 g, 14.2 mmol) and N,O-dimethyl-hydroxyIamine hydrochloride (1.66 g, 17.0 mmol) in CH ₂ Cb (30 mL) at rt. Diethyl cyanophosphonate (4.25 mL, 28.4mmol) was added to the solution with slight warming. After stirring for 18 h at rt, the solution was diluted with CH ₂ CI ₂ and carefully washed with saturated aqueous NaHCC>3. The organic layer was separated, dried over anhydrous Na?Sθ4 and concentrated in vacuo. The product was purified by silica gel flash chromatography (50 % EtOAc in Hexanes) to furnish the title product as an oil (2.58 g, 99 %). ¹ H NMR (CDCI ₃ ) δ 8.62 (s, I H), 8.19 (t, I H, J=5.3 Hz), 6.95 (d, I H, J=4.0 Hz), 3.59 (s, 3H), 3.40 (s, 3H). ESMS m/e: 185 (M+H ⁺ ).

The following compound was prepared analogously:

2-Fluoro-N-methoxy-N-methyl-nicotinamide: ¹ H NMR (CDCI ₃ ) δ 8.29 (d, I H, J=3.8 Hz), 7.91 (t, I H, J=5.3 Hz), 7.22 (m, I H), 3.58 (s. 3H), 3.35 (s, 3H). ESMS m/e: 185 (M+H) ⁺ .

Intermediate of Formula XXI l-(6-Fluoro-pyridin-3-yl)-propan-l-one: A 3M solution of ethylmagnesium bromide in

Et ₂ O (3.26 mL, 9.8 mmol) was added to a stirred solution of 6-fluoro-N-methoxy-N- methyl-nicotinamide (2.0 g, 6.53 mmol) in THF (20 mL) at -78 "C. After stirring for 2 h at -78 ⁰ C, the reaction was quenched by the addition of aqueous citric acid (10 % w/v, 1 mL). The reaction mixture was warmed to rt and stirred for an additional 18 h. The organic layer was separated, dried over anhydrous Na ₂ SC^ and concentrated in vacuo. The product was purified by silica gel flash chromatography (35 % EtOAc in Hexanes) to furnish the title compound as an oil (0.47 g, 50 %). ¹ H NMR (CDCI ₃ ) δ 8.82 (S ₅ IH), 8.39 (t, I H, J=5.4 Hz), 7.00 (d, I H. J = 4.1 Hz), 3.01 (q, 2H. J=7.4 Hz), 1.21 (t, 3H, J=7.2 Hz). ESMS m/e: 154 (M+H) ⁺ .

The following compounds were prepared analogously: l -(2-Fluoro-pyridinc-3-yl)-propan- l-onc: ¹ H NMR (CDCl ₃ ) δ 8.29-8.39 (m, 2H), 7.32 (m, I H), 3.05 (q, 2H, J=7.4 Hz), 1.21 (t, 3H, J=7.2 Hz). ESMS m/e: 154 (M+H) ⁺ .

l -(6-Trifluoromethyl-pyridin-3-yl)-propan-l-one: ¹ H NMR (CDCl ₃ ) δ 8.89 (d, I H, J=1.2 Hz), 8.79 (s, I H), 7.62 (d, I H, J=5.1 Hz), 2.92 (q, 2H, J=14.4 and 7.2 Hz), 1.25 (t, 3H, J=7.2 Hz). ESMS m/e: 204 (M+H) ⁺ .

Intermediate of Formula XIX (wherein R ⁵ is CH3)

2-Bromo-l-(6-fluoro-pyridin-3-yl)-propan- l-one HBr salt: l-(6-Fluoro-pyridin-3-yl)- propan-l-one (0.47 g, 3.10 mmol) was dissolved in AcOH (4 mL). 33 % HBr in AcOH was added (0.54 mL, 3.10 mmol) to the solution with vigorous stirring. Bromine (0.16 mL, 3.10 mmol) was added to the solution and stirred at rt for 1.5 h. The orange solution was concentrated in vacuo to give the title compound as an orange semi solid. (1.13 g, >99 %). ESMS m/e: 233 (M+H) ⁺ .

The following compounds were prepared analogously:

2-Bromo-l-(2-fluoro-pyridin-3-yl)-propan-l-one. ESMS m/e: 233 (M+H) ⁺ . 2-Bromo-l-(6-trifluoromethyl-pyridin-3-yl)-propan-l-one. ESMS m/e: 281 (M+H) ⁺ .

Compounds of the Invention

The following compounds of the invention were prepared from intermediate Formula VlII and synthesized according to the procedures described in Scheme 1 :

Example Ia [(Methylethyl)sulfonyl](trans-4-{[(4-(6-fluoro-pyridin-2-yl) (l ,3-thiazol-2- yl))amino]methyl}cyclohexyl)amine.

amide (0.10 g, 0.34 mmol) was added to a stirred solution of 2-chloro- l-(6-fluoro- pyridin-2-yl)-ethanone (0.075 g, 0.34 mmol) in EtOH (10 mL) at rt. DlEA (0.18 mL. 0.132 g, 1.02 mmol) was added to the solution. The reaction mixture was heated at reflux for 4 h, cooled to rt and concentrated in vacuo. The resulting residue was re- dissolved in CHCb and washed successively with aqueous citric acid, water and brine. The organic layer was isolated, dried over anhydrous Na ₂ SO4, and concentrated in vacuo. The product was purified by preparative TLC (70 % EtOAc in Hexanes) to furnish the title compound as a colorless foam (O. I 12 g, 76 %). ¹ H NMR (CDCI ₃ ) S 7.81-7.76 (m, 2H), 7.30 (s, I H), 6.79 (dd, I H, J=5.7 and 2.7 Hz), 5.59 (t, I H ₅ J=5. l Hz), 4.29 (d, I H, J=8.4 Hz), 3.27-3.20 (m, I H), 3.15 (septet, I H, J=6.6 Hz), 3.12 (t,

2H, J=7.5 Hz), 2.09 (d, 2H, J=I 1.7 Hz), 1 .88 (d, 2H, J=12.6 Hz), 1 .60-1.54 (br m, 1 H), 1.37 (d, 6H, J=6.9 Hz). 1 .25- 1.06 (m _: 4H). LC-MS m/e: 413 (M+H) ⁺ ; t _R = 1.29. (Method - II).

The following compounds were prepared analogously:

Example Ib [(Methylethyl)sulfonyl]({trans-4-[(4-(6-fluoro-pyridin-2-yl) ( l ,3-thiazol-2- yl))amino]cyclohexyl}methyl)amine.

Prepared from N-({[(trans-4-{[(methylethyl)sulfonyl]methylamino}cyclohexyl ]amino} thioxomethyl) amide and 2-chloro-I-(6-fluoro-pyridin-2-yl)-ethanone. Yield: (87 %). LC-MS m/e: 413 (M+H) ⁺ ; t _R = 1.26. (Method - II).

Example Ic [(Methylethyl)sulfonyl]({trans-4-[(4-(2-methyl,6-fluoro-pyri din-3-yl)( l ,3- thiazol-2-yl))amino]cyclohcxyl}mcthyl)aminc.

Prepared from N-({[(trans-4-{[(methylethyl)sulfonyl]methylamino}cyclohexyl ]amino} thioxomethyl) amide and 2-chloro-l-(6-fluoro-2-mcthyl-pyridin-3-yl)-ethanone. Yield: 97 %. LC-MS m/e: 427 (MH-H) ⁺ : t _R = 1.15. (Method - II).

Example Id [(Methy1ethyl)sulfonyl](trans-4-{[(4-(2-fluoro-pyridin-3-yl) ( l,3-thiazol-2- yl))amino]methyl}cyclohexyl)amine.

Prepared from N-d^trans^-f^methylethy^sulfonylJaminoJcyclohexy^mcthyl] amino} thioxomethyl) amide and 2-chIoro-l -(2-fluoro-pyridin-3-yl)-cthanonc. Yield: 56 %. LC-MS m/e: 413 (M+H) ⁺ ; t _R = 1.23. (Method - I).

Example U [(Methylethyl)sulfonyl]({trans-4-[(4-(2-fluoro-pyridin-3-yl) ( 1 ,3-thia7.ol-2- yl))amino]cyclohexyl}methyl)amine.

Prepared from N-({[(trans-4-{[(methylethyl)sulfonyl]methylamino}cyclohexyl ]amino } thioxomethyl) amide and 2-chloro-l-(2-fluoro-pyridin-3-yl)-ethanone. Yield: 98 %. LC-MS m/e: 413 (M+H) ⁺ ; t _R = 1.24. (Method - II).

Example If [(Methylethyl)sulfoπyl]({trans-4-[(4-(6-fluoro-pyridin-3-yl )(5-methyl-l ,3- thiazol-2-yl))amino]cyclohexyl}methyl)amine.

Prepared from N-({[(trans-4-{[(methylethyl)sulfonyl]methylamino}cyclohexyl ]amino} thioxomethyl) amide and 2-bromo-l-(6-fluoro-pyridin-3-yl)-propan-l-one HBr salt. Yield: 77 %. LC-MS m/e: 427 (M+H) ⁺ ; t _R = 1.26 (Method - I).

Example Ig [(Methylethyl)sulfonyl]({trans-4-[(4-(2-fluoro-pyridin-3-yl) (5-methyl-l ,3- thiazol-2-yl))amino]cyclohexy I } melhy l)am i ne.

Prepared from N-({[(trans-4-{[(methylethyl)sulfonyl]methylamino}cyclohexyl ]amino} thioxomethyl) amide and 2-bromo-l-(2-fluoro-pyridin-3-yl)-propan-l-one HBr salt. Yield: 55 %. LC-MS m/e: 427 (M+H) ⁺ ; t _R = 1.17 (Method - I).

Example Ih [(Methylethyl)sulfonyl]({4-[(trans-4-(6-trifluoromethyl-pyri din-3-yl)(5- methyl-l,3-thiazol-2-yl))amino]cyclohexyl}methyl)aminιe.

Prepared from N-({f(trans-4-{f(methylethyl)sulfonyllmethylamino}cyclohexyl lamino} thioxomethyl) amide and 2-bromo-l -(6-trifluoromethyI-pyridin-3-yl)-propan-l -one. Yield: 38 %. LC-MS m/e: 477 (M+H) ⁺ ; t _R = 1.47 (Method - 1).

Example ti [(Methylethyl)sulfonyl](trans-4-{[(4-(6-bromopyridin-2-yl)(l ,3-thiazol-2- yl))aminoj methyl} cyclohexyl)amine.

Prepared from N-({[(trans-4-{[(methylethyl)sulfonyl]amino}cyclohexyl)methy l] aminojthioxomethyl) amide and 2-bromo-l -(6-bromo-pyridin-2-yl)-ethanone HBr salt. Yield: 47 %. LC-MS m/e: 475 ((M+H) ⁺ +2); t _R = 1.44 (Method - II).

Example Ij [(tert-butyl)sulfonyl]( {4-[(trans-4-(6-trifluoromethyl-pyridin-3-y I)(S- methyl- 1 ,3-thiazol-2-y l))am ino]cyclohexyl } methy l)amine

Prepared from ^^-({[(trans^-JKtert-butyOsulfonyÏ€methylaminoJcyclohexylJam ino} thioxomethyl) amide and 2-bromo-l-(6-trifluorornethyl-pyridin-3-yl)-propan-l -one HBr salt. Yield: 6.0 %. LC-MS m/e: 491 (M+H) ⁺ ; t _R = 1.56 (Method - II).

The following compound of the invention was prepared from intermediate Formula XV and synthesized according to the procedures described in Scheme 3:

Example 2a [(cyclopropyl)sulfonyl]({4-[(trans-4-(6-trifluoromethyl-pyri din-3-yl)(5- methyl- 1 ,3-thiazol-2-y l))am ino]cyclohexyl} methyl)amine

Cyclopropanesulfonyl chloride (0.05 g, 0.48mM) was added to a solution of the lrifluoroacetate salt of [trans-4-(aιninomethyl)cyclohexyl](4-(6-trifluoromethyl-pyr idin- 3-yl)(l,3-thiazol-2-yl))amine (0.10 g) and DlEA (0.2 mL) in CH ₂ Cl ₂ (2 mL) at rt. The reaction was stirred at rt for 10 min. The solvent was removed in vacuo and the product was purified by preparative TLC (50 % Hexanes in EtOAc), to afford the title compound (0.015 g, 19%). ¹ H NMR (CDCI ₃ ) δ 9.06 (s, I H), 8.15 (d, I H. J= 14 Hz),

7.79 (d, I H, J=4.8 Hz), 5.7S (br, m, I H), 4.70 (t, I H, J=4.8 Hz), 3.31 (br., m, I H), 3.10 (t, 2H, J=4.8 Hz), 2.54 (s, 3H), 2.29 (d ₃ 2H, J=14.3 Hz), 1.96 (d, 2H, J=I4.O Hz), 1.60 (br., m, IH) ₅ 1.38 -0.94 (m, 8H). LC-MS m/e: 475 (M+H) ⁺ ; t _R = 1.43 (Method - II).

Formulations

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.

For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/ or diluents and subsequently compressing the mixture in a conventional tablεtting machine may prepare tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.

1) Tablets containing 5.0 mg of Compound Ib calculated as the free base:

Compound 5.0 mg

Lactose 60 mg

Maize starch 30 mg

Hydroxypropylcellulose 2.4 mg

Microcrystalline cellulose 19.2 mg

Croscarmellose ^' Sodium Type A 2.4 mg

Magnesium stearate 0.84 mg

lets containing 0.5 mg of Compound l b calcula

Compound 0.5 mg

Lactose 46.9 mg

Maize starch 23.5 mg

Povidone 1.8 mg

Microcrystalline cellulose 14.4 mg

Croscarmellose Sodium Type A 1.8 mg

Magnesium stearate 0.63 mg

3) Syrup containing 25 mg of Compound I b per milliliter:

Compound 25 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerol 50 mg

Methyl-paraben 1 mg

Propyl -paraben 0.1 mg

Ethanol 0.005 mL

Flavor 0.05 mg

Saccharin 0.5 mg

Water I mL

In- Vitro Methods The pharmacological properties of the compounds of the present invention were evaluated at the cloned human NPY Y5 receptor using the protocols disclosed in U.S. Patent No. 6,124,331, the contents of which are hereby incorporated by reference.

Using this protocol, the binding by the compound to a radiolabeled ligand ( I-labeled PYY or an alterative radioligand such as ' ^2:> l-labeled NPY) to membranes of cloned human NPY Y5 receptors expressed in COS-7 cells was determined in vitro.

Radioligand Binding

Membrane suspensions were diluted in binding buffer supplemented with 0.1 % bovine serum albumin to yield an optimal membrane protein concentration so that ¹²⁵ I-PYY bound by membranes in the assay was less than 10 % of ¹²⁵ I-PYY delivered to the sample ( 100,000 dpm/ sample = 0.08 nM for competition binding assays). '' ⁵ I-PY Y and small molecule ligand competitors were also diluted to desired concentrations in supplemented binding buffer. Individual samples were then prepared in 96-well polypropylene microtiter plates by mixing ¹²⁵ I-PYY, competing peptides or supplemented binding buffer (25 μL), and finally, membrane suspensions (200 μL). Samples were incubated in at 30 ⁰ C for 120 min. Incubations were terminated by filtration over Whatman GF/C filters (pre-coated with 1% polyethyleneimine and air- dried before use), followed by washing with 5 mL of ice-cold binding buffer. Filter- trapped membranes were impregnated with MeltiLex solid scintillant (Wallac, Turku, Finland) and counted for ¹²⁵ I-PYY in a Wallac Beta-Plate Reader. Alternatively.

incubations were carried out in C»F/C filter plates (pre-coated with 1 % polyethyleneimine and air-dried before use), followed by vacuum filtration and three washes of 300 μL of ice-cold binding buffer. 50 μL of UltimaGold (Packard) scintillant were added and counted for ¹²⁵ I-PYY in a Wallac MicroBeta Trilux. Non-specific binding was defined by 300 nM human PYY. Specific binding in time course and competition studies was typically 80 %; most non-specific binding was associated with the Filter. Binding data were analyzed using nonlinear 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, at the NPY Y5 receptor were determined to be 50 nM or less. The binding affinities for some of the compounds were determined to be 10 nM or less. The compounds of Formula I were determined to be antagonists at the NPY Y5 receptor.