WO2008134228A1 - Benzoxazole compounds - Google Patents

Abstract

The present invention is directed to benzoxazole compounds which are ltgands at the NPY Y5 receptor. The invention further 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 method of treating a subject suffering from depression, anxiety or obesity which comprises administering to the subject an amount of a compound of the subject invention. Furthermore, this invention also provides uses of a compound of the invention for the manufacture of a medicament for treating a subject suffering from depression, anxiety or obesity.

Description

Docket No. 71022-WO-PCT BENZOXAZOLE COMPOUNDS

Field of the Invention The present invention relates to compounds that are ligands at the neuropeptide Y YS receptor, and as such are useful to treat disorders such as depression, anxiety and obesity.

Background of the Invention

Throughout this application, various publications are referenced to in full citations. The disclosures of these publications are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

Neuropeptide Y (NPY) is a 36 amino acid neuropeptide expressed in the peripheral and central nervous system. This peptide is a member of the pancreatic polypeptide family, which also includes pancreatic polypeptide (PP) and peptide YY (PYY). Moreover, the biological effects of NPY are mediated through its interaction with receptors that belong in the superfamily of G protein-coupled receptors.

Presently, five NPY receptor subtypes 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 these receptor subtypes are expressed in several species except for the y6 subtype, which has been shown to be expressed in mouse and rabbit but not in rat and primate. A Y3 subtype has been proposed based on pharmacological data. However, the Y3 subtype has yet to be cloned and its existence remains to be fully established.

NPY exerts numerous physiological effects. On the basis of animal studies, it is evident that a contributory relationship exists between NPY and its receptors with disorders such as depression, anxiety and obesity. For instance, NPY expression is shown to be sensitive to energy status while NPY administration reduces energy expenditure. 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).

Additionally, the link between NPY and mood disorders such as depression and anxiety is established in the literature. For example, rats subjected to chronic mild stress exhibit anhedonia, a feature of clinical depression (P. Willner, et al., Eur. J. Pharmacol., 1997, 340, 121-132); they also contain elevated levels of NPY mRNA in hypothalamus accompanied by a reduction in hippocampus (V. Sergeyev, et ah, Psychopharmacology, 2005, 178, 1 15-124). The behavioral changes associated with chronic mild stress are reversed by a variety of antidepressants (P. Willner, et al., Eur. J. Pharmacol., 1997, 340, 121-132). In one study of antidepressant therapies, 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 depressive illness, and that agents capable of regulating NPY and/or NPY receptor function particularly in limbic regions are useful for treating depression. Y5 is a NPY receptor expressed in limbic regions (M. Wolak, et al., J Comp. Neurol., 2003, 22, 285-31 1; and K. Nichol, et al., J. Neurosci., 1999, 19, 10295-10304). Accordingly, agents capable of regulating Y5 receptor function are therefore predicted to be useful for treating depression.

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. Jimenez-Vasquez, 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 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. Y5 is a 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). Accordingly, agents capable of regulating Y5 receptor function are therefore predicted to be useful for treating anxiety.

In our laboratories, the compounds of the invention are to be evaluated in animal models predictive for antidepressant and anti-anxiolytic activity. It is expected that these compounds will produce effects similar to that observed by known antidepressants and anti-anxiolytics.

Current treatments for depression, anxiety and obesity are on the market. However, a number of patients may not fully respond to current treatments. Hence, there remains the need for alternative methods of treatment.

Summary of the Invention

The objective of the present invention is to provide compounds that are ligands at the NPY Y5 receptor. Accordingly, the present invention relates to compounds of Formula I.

wherein each R¹ independently is F, Cl, Br, I, -CN, -COR³, -CO₂R³, straight chained or branched C₁-C₇ alkyl or C₁-C₇ perfluoroalkyl, straight chained or branched C₁-C₇ alkoxy or C₁-C₇ perfluoroalkoxy, or phenyl optionally substituted with one or more R⁴;

wherein R² is C₃-C₆ cycloalkyl, straight chained or branched C₁-C₇ alkyl or phenyl optionally substituted with one or more R⁵;

wherein each R³ independently is H or straight chained or branched C1-C7 alkyl;

wherein each R⁴ independently is F, Cl, Br, I or straight chained or branched C1-C7 alkyl;

wherein each R⁵ independently is F, Cl, Br, I, straight chained or branched C₁-C 7 alkyl or straight chained or branched C1-C7 alkoxy;

wherein A is

wherein n is an integer from O to 4 inclusive;

wherein p is an integer from O to 2 inclusive; and

wherein q is an integer from O 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 disclosed in the Experimental Section.

Furthermore, 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 admixing a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.

Moreover, the present invention provides a method of 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 of treating a subject suffering from anxiety comprising administering to the subject a therapeutically effective amount of a compound of Formula I. The present invention further provides a method of treating a subject suffering from obesity comprising administering to the subject a therapeutically effective amount of a compound of Formula I.

Furthermore, the present invention is directed to the use of a compound as defined in Formula I for the manufacture of a medicament useful for treating depression. Additionally, the present invention is directed to the use of a compound as defined in Formula I for the manufacture of a medicament useful for treating anxiety. The present invention further provides for the use of a compound as defined in Formula I for the manufacture of a medicament useful for treating obesity.

Detailed Description of the Invention

Definitions

In the present invention, the term "straight chained or branched C₁-C₇ alkyl" refers to a saturated hydrocarbon having from one to six carbon atoms inclusive. 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-l -propyl, n-pentyl and n-hexyl. Similarly, the term "straight chained or branched C₁-C₄ alkyl" refers to a saturated hydrocarbon having from one to four carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl and n-butyl.

Similarity, the term "straight chained or branched C₁-C₇ alkoxy" refers to a saturated alkoxy group having from one to seven carbon atoms inclusive with the open valency on the oxygen. Examples of such substituents include, but are not limited to, methoxy, ethoxy, n-butoxy, t-butoxy and n-heptyloxy.

Furthermore, the term "C3-C6 cycloalkyl" refers to a saturated cyclohydrocarbon ring having from three to six carbon atoms inclusive. Included within this term are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "straight chained or branched C₁-C₇ perfluoroalkyl" refers to a saturated hydrocarbon having from one to seven carbon atoms inclusive substituted with one or more fluorine atoms. Examples of such substituents include, but are not limited to, trifluoromethyl, pentafiuoroethyl, 1-fluoroethyl, 1,2-difluoroethyl and 3, 4 difluoroheptyl. Similarly, the term "straight chained or branched C₁-C₄ fluoroalkyl" refers to a saturated hydrocarbon having from one to four carbon atoms inclusive substituted with one or more fluorine atoms per carbon atom.

Similarity, the term "straight chained or branched C₁-C₇ perfluoroalkoxy" refers to a saturated perfluoroalkoxy group having from one to seven carbon atoms inclusive with the open valency on the oxygen.

Additionally, the invention further provides certain embodiments of the present invention that are described below. In one embodiment, each R¹ independently is phenyl optionally substituted with one or more R⁴; and wherein each R⁴ independently is F, Cl, Br or I.

In another embodiment, each R¹ independently is F, Cl, Br, I, -CN, straight chained or branched C₁-C₄ alkyl, or straight chained or branched C₁-C₄ alkoxy.

In one embodiment, R¹ independently is -COR³, -CO₂R³, straight chained or branched C₁-C₄ perfluoroalkyl, or straight chained or branched C₁-C₄ perfluoroalkoxy; and each R³ independently is straight chained or branched C₁-C₄ alkyl.

In one embodiment, A is in the trans configuration.

In a separate embodiment, A is A'.

In one embodiment, A is A".

In another embodiment, A is A'".

In yet another embodiment, n is an integer from O to 2 inclusive.

In one embodiment, p and q are each 0 or 1.

In one embodiment, R² is phenyl optionally substituted with one R⁵; and R⁵ is F, Cl, Br or I.

In one embodiment, R² is straight chained or branched C₁-C₄ alkyl.

In another embodiment, R² is C3-C6 cycloalkyl.

In separate embodiments, the invention is directed to one of the specific compounds disclosed herein.

Furthermore, the present invention is directed to the use of a compound as defined above for the manufacture of a medicament useful for treating depression. Additionally, the present invention is directed to the use of a compound as defined above for the manufacture of a medicament useful for treating anxiety. The present invention further provides for the use of a compound as defined above for the manufacture of a medicament useful for treating obesity. Pharmaceutically Acceptable Salts

The present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid 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, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines (for example, 8- bromotheophylline and the like). Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in S. M. Berge, et al., J. Pharm. ScL, 1977, 66, 2, the contents of which are hereby incorporated by reference.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.

Racemic forms may be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization. The optically active acids suitable for this purpose may include, but are not limited to d- or /- tartaric, madelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. The compounds of the present invention may also be resolved by the formation and chromatographic separation of diastereomeric derivatives from chiral derivatizing reagents, such as, chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Any of the above methods may be applied either to resolve the optical antipodes of the compounds of the invention per se or to resolve the optical antipodes of synthetic intermediates, which can then be converted by methods described herein into the optically resolved final products which are the compounds of the invention.

Additional methods for the resolution of optical isomers, known to those skilled in the art, may 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. Optically active compounds can also be prepared from optically active starting materials.

Pharmaceutical compositions

The present invention further 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 comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier.

The compounds of the invention 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, PA, 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.

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 are 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 of Formula I 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.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One 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 salts are prepared in a conventional manner by treating a solution or suspension of a free base of Formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and 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 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. The compounds 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, 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 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.

Treatment of Disorders

As mentioned above, the compounds of Formula I are Iigands at the NPY Y5 receptor.

The present invention provides a method of 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 of treating 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 of treating a subject suffering from obesity which comprises administering to the subject a therapeutically effective amount of a compound of this invention. In an embodiment of this invention, the subject is a human being.

Furthermore, the present invention is directed to the use of a compound of this invention for the manufacture of a medicament useful for treating depression. Additionally, the present invention is directed to the use of a compound of this invention for the manufacture of a medicament useful for treating anxiety. The present invention further provides for the use of a compound of a compound of this invention for the manufacture of a medicament useful for treating obesity.

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 therein are merely illustrative of the invention as described more fully in the claims which follow thereafter. Furthermore, the variables depicted in Schemes 1-5 are consistent with the variables recited in the Summary of the Invention.

Experimental Section

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 CDCl₃, DMSO-d₆ or CD₃OD 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; sept=septet; 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 II 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 Inertsil ODS-3 column. For LC-MS determination, two methods were used: Method - I: C18 column, Neutral pH, 20 % to 90 % Acetonitrile/ H₂O with 0.2 % Ammonium formate; or Method - II: C8 column, Neutral pH, 10 % to 90 % Acetonitrile/ H₂O with 0.2 % Ammonium formate. Prep-HPLC purifications were done using C8 or Cl 8 column, Neutral pH, 35 % to 95 % Acetonitrile/ H₂O with 0.2 % Ammonium formate. Thin- layer chromatography (TLC) was carried out on glass plates pre-coated with silica gel 60 F₂₅₄ (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).

In the Experimental Section, standard acronyms are used. Examples of such acronyms include DMF (N,N-Dimethylformamide); TEA (Triethylamine); DIEA (Diisopropylethylamine); DPPA (Diphenylphosphoryl azide); AcOH (Acetic Acid); BzNCS (Benzoylisothiocyanate); BnOH (Benzyl alcohol); MeOH (Methanol); Et₂O (Diethyl Ether); MTBE (Methyl t-butyl ether); EtOAc (Ethyl Acetate); EDC (l-(3- DImethylaminopropyl)3-ethylcarbodiimide; Pd(OAc)₂ (Paladium (II) Acetate); S-Phos (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl); THF (Tetrahydrofuran); rt (room temperature); h (hour); and min (minutes). Furthermore, in certain instances, the methods of preparing the compounds of the invention are described generally by referring to representative reagents such as bases or solvents. The particular reagent identified is representative but is not inclusive and does not limit the invention in any way. For example, representative bases include but are not limited to K₂CO3, TEA or DIEA.

The term 'PG' as defined in Scheme 4 is used to designate a 'protecting group'. One skilled in the art would be able to select the appropriate protecting group for a particular reaction. Moreover, it may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid and hydroxy 1 groups in the synthetic methods described below to synthesize the compounds of Formula I. Methods for protection and deprotection of such groups are well known in the art, and may be found in T. Green, et al., Protection Groups in Organic Synthesis,

1991, 2^nd Edition, John Wiley & Sons, New York.

List and source of chemicals

Most of the reagents used in the experimental section such as isopropyl sulfonyl chloride, benzoylisothiocyanate, diisopropylethylamine, thiophosgene, EDC, 2-amino-

5-chlorophenol, 2-amino-4-chlorophenol, 2-amino-4-methylphenol, 4-methoxy-2- nitrophenol and tert-butylsulfinyl chloride were purchased from the Sigma/Aldrich

Chemical Company. 2-Amino-4,5-dichlorophenol, 2-amino-4,6-difluorophenol and 2- amino-3-flourophenol was purchased from Apollo Scientific Ltd. 2-Amino-5- flourophenol was purchased from Matrix Scientific. 2-Amino-4-

(triflouromethyl)phenol was purchased from Enamine/Ryan Scientific. 2-Amino-5-

(triflouromethyl)phenol was purchased from Atlantic Research Chemicals. 2-Amino-4-

(triflouromethoxy)phenol and 6-Acetyl-3H-benzooxazol-2-one were purchased from

Indofine Chemical Company. 2,6-Dichloro-benzoxazole was purchased from 3B Medical Systems Inc. 2-Hydroxy-4-methoxy aniline hydrochloride was purchased from TCI.

Preparation of the compounds of the invention

Scheme 1

(a) DPPA, TEA, Toluene, BnOH, reflux, (b) 10 % Pd-C, H₂, MeOH/ EtOAc. (c) thiophosgene, NaHCO₃, H₂O/CHC1₃, rt. (d) 2-aminophenol, EDC, DMF, 80°C. (e) 10

% TFA in CH₂Cl₂ or 4 M HCl in Dioxane. (f) R²,SO₂Cl, R²SOCl or R²COCI, DIEA, CH₂Cl₂, rt.

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 car boxy Hc acids of

Formula II are converted to their Cbz-protected amines to afford the compounds of

Formula III. The Cbz protecting group is selectively removed to afford the compounds of Formula IV. These intermediates are converted to the isothiocyanates of Formula V. The isothiocyanates are condensed with substituted 2-aminophenols followed by carbodiimide-mediated cyclodesulfurization to afford the compounds of Formula VI.

The compounds of Formula IV can also be reacted with the 2-chlorobenzoxazoles in the presence of a base to obtain the compounds of Formula VI. The Boc group is removed to afford the amines of Formula VIL These amines are reacted with sulfonyl chlorides (R²SO₂CI), sulfinyl chlorides (R²SOCl) or acid chlorides (R²COCl) to afford the compounds of the invention.

Aside from carbodiimide, other cyclodesulfurization methods may be used. Metallic reagents such as HgO, NiO₂ and AgNO₃ have been reported to facilitate such a transformation (EP 0199400; D. Simov, Chem. Heterocycl. Compd. (Engl. Trans.) 1976, 12, 151; and H. Ogura, Chem. Pharm. Bull. 1981, 29, 1518). Oxidative desulfurization using KO₂ or LiOH/H₂O₂ has been reported as well (H. Chang, Chem. Lett. 1986, 1291 ; and Tian, Z. Tet. Lett. 2005, 46, 8341).

Scheme 2

(a) IM NaOH, Et₂O, R²SO₂Cl. (b) 10 % TFA in CH₂Cl₂ or 4 M HCl in Dioxane. (c) thiophosgene, NaHCO₃, H₂O/CHC1₃, it. (d) 2- aminophenol, EDC, DMF, 80°C.

Alternatively, compounds of Formula I may also be synthesized according to the procedures outlined in Scheme 2. The compounds of Formula IV are directly coupled with R²SO₂Cl to afford the intermediates of Formula VIII. The Boc group is removed and the resultant amines of Formula IX are treated with thiophosgene to afford the compounds of Formula X. The compounds of Formula X are condensed with 2- aminophenols followed by cyclodesulfurization to afford the compounds of the invention. Compounds of Formula IX can also be reacted 2-chlorobenzoxazoles in the presence of a base to obtain the compounds of the invention.

Scheme 3

(a) IM NaOH, Et₂O, BOC₂O. (b) IM NaOH, Et₂O, R²SO₂Cl. (c) DPPA, TEA, Toluene, BnOH, reflux, (d) 10 % TFA in CH₂Cl₂. (e) 1 M NaOH, Et₂O, R²SO₂Cl. (f) 10 % Pd-C, H₂, EtOH, heat or HBr/ AcOH.

Alternatively, the intermediates of Formula IX may be synthesized according to the procedures outlined in Scheme 3. The starting materials of Formula XI are commercially available or may be synthesized by one skilled in the art. The amino acids of Formula XI may be coupled with R²SO₂Cl to afford the intermediates of Formula XII which are further converted to the Cbz-protected amines of Formula XIV. Separately, the amino acids of Formula XI may be converted into the mono-Cbz protected intermediates of Formula XIII. The amines of Formula XIII are coupled with R²SO₂Cl to afford the compounds of Formula XIV. The Cbz group of Formula XIV is removed to afford the intermediates of Formula IX. Finally, the intermediates of Formula IX may be converted to the compounds of the invention by using the procedures described in Scheme 2.

Additionally, the intermediates of Formula XII can be converted to the compounds of Formula VIII, which are described in Scheme 2, if /-butanol is substituted for benzyl alcohol. Scheme 4

(a) TEA, CH₂Cl₂, R²S(O)Cl. (b) NaIO₄, RuCl₃ (cat) or mCPBA. (c) deprotection.

The sulfonamides of Formula IX may also be synthesized according to the procedures outlined in Scheme 4. In summary, the compounds of Formula XV are reacted with (R¹XR²XR³JCS(O)CI to afford the sulfinamides of Formula XVI. These compounds are oxidized to the intermediates of Formula XVII. The protecting group is removed to form the intermediates of Formula IX. Finally, the intermediates of Formula IX may be converted to the compounds of the invention by using the procedures described in Scheme 2. 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.

(a) HNO3, glacial acetic acid, it. (b) Fe powder, glacial acetic acid or 10 % Pd-C, H₂, EtOAc/MeOH.

If the desired substituted 2-aminophenol used in Schemes 1 and 2 is not commercially available, it may be synthesized by nitration of the corresponding phenol followed by reduction. Likewise, commercially available 2-nitrophenol may be reduced to obtain the desired 2-aminophenol (Scheme S). Alternatively, 2-aminophenols may be synthesized by ring opening with sodium hydroxide of 3H-benzooxazol-2-ones. For representative reaction conditions in connection with the synthesis of the desired substituted 2-aminophenols, see R. Lok, J. Org. Chem., 1996, 61, 3289-3297; J. Jeong, Tetrahedron Lett., 2005, 46, 3987-3990; US2005886044 and J.P. Henichart, Synthesis, 1990, 679. Preparation of intermediates

Representative intermediates were synthesized as follows: Intermediate of Formula II trans-4-{[(tert-butoxy)carbonylamino]methyl}cyclohexanecarboxylic acid: BoC₂O (41.7 g, 190 mmol) was added to a stirred biphasic solution containing trans-4- aminomethyl-cyclohexanecarboxylic acid (25.0 g, 159 mmol), NaHCO₃ (20.0 g, 238 mmol), water (300 mL) and Et₂O (200 mL) at it. The pH of the solution was adjusted to pH ~ 9.0 by adding additional quantities of saturated aqueous NaHCθ3. After stirring for 24 h at rt, the layers were separated and the aqueous layer was acidified to pH 4.0 with IM aqueous 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 yield the desired product as a colorless solid (23.3 g, 57 %). ¹H NMR (CDCl₃) δ 4.60 (br s, IH), 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=I 3.2 and 2.8 Hz), 1.44 (s, 9H), 1.42 (br m, 1 H), 0.97 (dq, 2H, J=25.6, 12.4 and 3.2 Hz).

Intermediate of Formula III

[ trans-4-(tert-Butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester: trans-4-{[(tert-butoxy)carbonylamino]methyl}cyclohexanecarboxylic acid (20.3 g, 0.073 mol) was suspended in toluene (420 mL) and chilled to -10 ⁰C 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°C and then slowly heated to 70°C . After 15 h, nitrogen evolution was observed to be finished and the solution color turned to yellow. The mixture was cooled to 47 ⁰C and benzyl alcohol (22.8 mL, 0.220 mol) was added. The mixture was heated to 1 10 ⁰C and stirred overnight. The mixture was cooled to 50 ⁰C 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 resultant solid was triturated in MTBE to afford a white solid (17.8 g, 67 %) as the desired product. ¹H NMR (CDCl₃) δ 7.34-7.286 (m, 3H), 7.13 (d, 2H, J=8.0 Hz), 6.78 (t, IH, 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 1.8 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

( trans-4-Amino-cyclohexylmethyl)-carbamic acid tert-butyl ester: 10 % Pd-C (0.20 g) was added to a stirred solution of [ trans-4-(tert-butoxycarbonylamino-methyl)- cyclohexyl]-carbamic acid benzyl ester (2.0 g, 5.5 mmol) in EtOAc/ MeOH (1 : 1, 50 mL) 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 %). ¹H NMR (CDCl₃) δ 4.59 (br s, 1 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=I 2.4 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 ( trans-4-Isothiocyanato-cyclohexylmethyl)-carbamic acid tert-butyl ester: A mixture of ( trans-4-amino-cyclohexylmethyl)-carbamic acid tert-butyl ester (10.0 g, 43.8 mmol), NaHCO₃ (18.4 g, 219 mmol), CHCl₃ (675 mL) and water (450 mL) was stirred for 10 min at rt and then treated with thiophosgene (3.67mL, 48.2 mmol). After vigorous stirring for 20 min, the phases were separated and the CHCl₃ layer was washed with saturated NaHCO₃ solution (150 mL) and brine (150 mL), dried (Na₂SO₄) and concentrated in vacuo. The crude material was recrystallized from hexane/isopropanol to afford the desired product as a white solid (10.25 g, 92 %). ¹H NMR (CDCl₃) δ 4.47 (br s, IH), 3.41 (m, IH), 2.89 (d, 2H, J=4.6 Hz), 2.09-2.04 (m, 2H), 1.75-1.72 (m, 2H), 1.49-1.38 (m, 3H), 1.35 (s, 9H), 0.95-0.84 (m, 2H).

Intermediate of Formula VI

[ trans-4-(6-Chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]-carbamic acid tert- butyl ester: A solution of ( trans-4-isothiocyanato-cyclohexylmethyl)-carbamic acid tert-butyl ester (270 mg, 1.00 mmol) and 2-amino-5-chlorophenol (150 mg, 1.05 mmol) in DMF (2 mL) was stirred at 80°C for 1 h. The solution was cooled to rt followed by the addition of EDC (200 μL, 1.10 mmol). The resulting solution was stirred at 80°C overnight. The solution was diluted with CH₂Cl₂ (100 mL) and washed with 10% LiCl aqueous solution, dried (Na₂SO₄) and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (50%- 100 % EtOAc in Hexanes) to yield the desired product (250 mg, 66%). ¹H NMR (MeOD) δ 7.31 (d, 1 H, J=I .5 Hz), 7.2 - 7.10 (m, 2H), 3.56 (m, IH), 2.94 (d, 2H, J=6.6 Hz), 2.19-2.10 (m, 2H), 1.94-1.81 (m, 2H), 1.46 (s, 9H), 1.43-1.27 (m, 3H), 1.20-1.03 (m, 2H). ESMS m/e: 380 (M+H)⁺.

Intermediate of Formula VII trans-(4-Aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine: To a solution of [4-(6-chloro-benzooxazol-2-ylamino)- trans-cyclohexylmethyl]-carbamic acid tert- butyl ester (240 mg, 0.63 mmol) dissolved in THF (20 niL) and MeOH (10 itiL) under argon atmosphere was added dropwise a solution of 4M HCl in dioxane (2 mL). The reaction was stirred at it overnight. The solvent was removed and the residue was suspended in a mixture of chloroform/isopropanol (3:1, 100 mL) and saturated aqueous NaHCO₃ solution (20 mL). After stirring at rt for 15 min, the layers were separated and the organic layer was dried (Na₂SO₄), concentrated in vacuo and left under high vacuum for 3 h to yield the product as a free base (110 mg, 62 %). ¹H NMR (MeOD) δ 7.28 (d, IH, J=1.6 Hz), 7.18-7.11 (m, 2H), 3.55 (m, IH), 2.51 (d, 2H, J=6.4 Hz), 2.16- 2.14 (m, 2H), 1.92-1.88 (m, 2H), 1.41-1.30 (m, 3H), 1.14-1.05 (m, 2H). ESMS m/e: 280 (M+H)⁺.

Intermediate of Formula VIII [4-(Propane-2-sulfonylamino)- trans-cyclohexylmethyl]-carbamic acid tert-butyl ester: Isopropyl sulfonyl chloride (6.2 mL, 7.9 g, 56 mmol) was added drop wise at rt to a stirred biphasic solution containing ( trans-4-Amino-cyclohexylmethyl)-carbamic acid tert-buty\ ester (10 g, 44 mmol), IM aqueous NaOH (100 mL) and Et₂O (100 mL). After stirring for 2 h, a white precipitate appeared. The precipitate was collected by filtration, washed with Et₂O and dried in vacuo to obtain the desired product as a solid (9.5 g, 65 %). ¹H NMR (CDCl₃) δ 4.58 (br s, 1 H), 3.89 (d, 1 H, J=8.0 Hz), 3.23 (septet, IH, 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 (m, 3H), 1.44 (s, 9H), 1.37 (d, 6H, J=6.8 Hz), 1.22 (dq, IH, J= 13.2 and 3.6 Hz), 1.09- 1.00 (br m, 3H). ESMS m/e: 279 ((M+H)-55)⁺.

Intermediate of Formula IX

Propane-2-sulfonic acid ( trans-4-aminomethyl-cyclohexyl)-amide: TFA (5 mL) was added at rt to a stirred solution containing [4-(propane-2-sulfonylamino)- trans- cyclohexylmethyl]-carbamic acid tert-butyl ester (1.3 g, 3.9 mmol) and CH₂Cl₂ (45 mL). After stirring for 4 h, the solution was concentrated in vacuo and the residue was re-dissolved in CHCI₃. The CHCI₃ solution was washed successively with IM aqueous NaOH and brine, dried over Na₂SCU and then concentrated in vacuo to provide the free base as a solid (0.88 g, 97 %). ¹H NMR (CDCl₃) δ 3.19-3.09 (m, 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). ESMS m/e: 235 (M+H)⁺.

Intermediate of Formula X

Propane-2-sulfonic acid ( trans-4-isothiocyanatomethyl-cyclohexyl)-amide: A mixture of propane-2-sulfonic acid ( trans-4-aminomethyl-cyclohexyl)-amide (HCI salt) (25.0 g, 110 mmol), NaHCO₃ (45.0 g, 530 mmol), CHCl₃ (480 mL) and water (320 mL) was stirred for 10 min at rt and then treated with thiophosgene (7.75 mL, 102 mmol). After vigorous stirring for 1 h, the phases were separated and the CHCl₃ layer was washed with saturated NaHCO₃ solution (200 mL) and brine (200 mL), dried (MgSO₄) and concentrated in vacuo. The crude material was recrystallized from hexane/isopropanol to afford the desired product as a white solid ( 15.1 g, 59 %). ' H NMR (CDCl₃) δ 4.17 (br d, IH, J=8.2 Hz), 3.39 (d, 2H, J=6.4 Hz), 3.29-3.19 (m, IH), 3.14 (septet, 1 H, J=6.8 Hz), 2.17-2.13 (m, 2H), 1.89-1.86 (m, 2H), 1.71-1.61 (br m, IH), 1.38 (d, 6H, J=6.9 Hz), 1.36-1.25 (m, 2H), 1.23-1.12 (m, 2H).

Intermediate of Formula XII

4-[(Propane-2-sulfonylamino)-methyl]- trans-cyclohexanecarboxylic acid: Isopropyl sulfonyl chloride (10.9 g, 77.0 mmol) was added drop wise to a solution of trans-4- aminomethyl-cyclohexanecarboxylic acid (10.0 g, 63.7 mmol) in IM 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 under vacuum at rt to afford the desired product as a white solid (5.0 g, 33 %). ¹H NMR (CDCl₃) δ 4.91 (br s, IH), 3.20 (septet, IH, J=6.8 Hz), 2.92 (d, 2H, J=6.8 Hz), 2.24 (tt, IH, 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). ESMS m/e: 264 (M+H)⁺.

Intermediate of Formula XIII

( trans-4-Aminornethyl-cyclohexyl)-carbamic acid benzyl ester: [trans-4-(tert-

Butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (4 g, 11 mmol) was treated with 25 % TFA in CH₂Cl₂ (50 mL). After stirring 5 h, the solvents were removed in vacuo. The crude product was redissolved in CH₂CI₂ and washed with saturated aqueous NaHCO₃ and brine. The organic layer was isolated, dried over Na₂SO₄ and concentrated in vacuo to afford the desired product as an oil (quantitative yield). ¹H NMR (DMSO-d) δ 7.18-7.03 (m, 5H), 4.78 (s, 2H), 3.06-2.96 (m, IH), 2.35 (d, 2H, J = 6.8 Hz), 1.62-1.48 (m, 4H), 1.20-1.1 1 (m, IH), 0.97-0.69 (m, 4H). ESMS m/e: 263 (M+H)⁺.

Intermediate of Formula XIV { trans-4-[(Propane-2-sulfonylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester: Isopropyl sulfonyl chloride (6.6 g, 46 mmol) was added drop wise to a solution containing ( trans-4-Aminomethyl-cyclohexyl)-carbarnic acid benzyl ester (1 1 g, 42 mmol), TEA (7.0 g, 70 mmol) in anhydrous CH₂Cl₂ (150 mL) at 0°C . The reaction was allowed to warm to rt and stirred overnight. The solution was washed with saturated aqueous NaHCO₃, dried over Na₂SO₄ 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 %). ¹H NMR (CDCl₃) 7.38-7.31 (m, 5H), 5.08 (s, 2H), 4.66-4.57 (br m, IH), 4.13- 4.06 (br m, IH), 3.49-3.4 (br m, IH), 3.19-3.1 1 (m, IH), 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, I H), 1.36 (d, 6H, J=0.9 Hz), 1.18- 0.99 (m, 4H). ESMS m/e: 369 (M+H)⁺.

Intermediate of Formula XIV to Intermediate of Formula IX Propane-2-sulfonic acid ( trans-4-amino-cyclohexylmethyl)-amide: {trans-4-

[(Propane-2-sulfonylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (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°C for 6 h. The reaction mixture was filtered through celite 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). ¹H NMR (CDCl₃) δ 3.60 (br s, 2H), 3.06 (m, IH), 2.69 (d, 2H, J=I 1 ,2 Hz), 2.58 (m, IH), 1.79 (d, 2H, J=I 1.2Hz), 1 ,68 (d, 2H, J=I 1.2Hz), 1.24 (br m, IH), 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 X

Propane-2-sulfonic acid ( trans-4-isothiocyanato-cyclohexylmethyl)-amide: A mixture of propane-2-sulfonic acid ( trans-4-amino-cyclohexylmethyl)-amide (25.0 g, 1 10 mmol), NaHCO₃ (45.0 g, 530 mmol), CHCl₃ (480 mL) and water (320 mL) was stirred for 10 min at rt and then treated with thiophosgene (8.90 mL, 120 mmol). After vigorous stirring for 1 h, the phases were separated and the CHCl₃ layer was washed with saturated NaHCO₃ solution (200 mL) and brine (200 mL), dried (MgSO₄) and concentrated in vacuo. The crude material was recrystallized from hexane / isopropanol to afford the desired material as a white solid (16.2 g, 55 %). ¹H NMR (CDCl₃) δ 4.37 (br t, IH, J=6.0 Hz), 3.52 (m, IH), 3.14 (septet, 1 H, J=6.8 Hz), 2.99 (t, 2H, J=6.5 Hz), 2.20-2.16 (m, 2H), 1.93-1.89 (m, 2H), 1.61-1.46 (m, 3H), 1.37 (d, 6H, J=6.8 Hz), 1.08-0.98 (m, 2H).

Intermediate of Formula XX

2-Amino-4,5-dichlorophenol: A solution of 90% nitric acid (1.8 g, 25 mmol) in glacial acetic acid (6 mL) was added dropwise to a stirring solution of 3,4-dichlorophenol (3.0 g, 18 mmol) in glacial acetic acid (20 mL) while maintaining the temperature below 55⁰C. The resulting solution was stirred at rt for 1 hr and then poured into ice-water (100 mL). The aqueous mixture was filtered and the solid was washed with water. The crude material was purified by preparative TLC (20% EtOAc: 80 % hexane) yield 4,5- dichloro-2-nitrophenol (1.4 g, 35%).

A solution of 4,5-dichloro-2-nitrophenol (2.0 g, 9.6 mmol) in glacial acetic acid (25 mL) and water (2.5 mL) was stirred and heated to reflux. Iron powder was added for a period of 10 min. and immediately filtered through Celite. The filtrate was poured into ice-water (250 mL), extracted with EtOAc. The combined EtOAc extracts was dried

(Na₂SO₄), filtered and concentrated in vacuo. The crude material was purified by preparative TLC (50% EtOAc: 50 % hexanes) to yield the desired compound (1.4 g, 85%). ¹H NMR (MeOD) δ 6.79 (s, 1 H), 6.76 (s, 1 H).

Intermediate of Formula XX l-(4-Amino-3-hydroxy-phenyl)-ethanone: A mixture of 6-acetyl-3H-benzooxazol-2- one (1.5 g, 8.5 mmol) and 10% aqueous NaOH solution (25 mL) was refluxed for 4 h. The solution was cooled to room temperature and acidified with 6N HCl. The solution was basified by dropwise addition of saturated aqueous Na₂CO₃ solution and extracted with EtOAc (5 x 50 mL). The combined EtOAc extracts was dried (Na₂SO₄), filtered and concentrated in vacuo. The resulting solid was dried in vacuum overnight to yield the desired product (1.0 g, 77%). ¹H NMR (DMS0-d₆) δ 9.34 (br s, IH), 7.29 (d, IH, J=8.3 Hz), 7.23 (s, 1 H), 6.58 (d, 1 H, J=8.3 Hz, 5.44 (br s, 2H).

A synthesis for the intermediates of Formula FV (wherein m=n=l and m=n=2) can be in WO 07/02126, the contents of which are hereby incorporated by reference in its entirety.

Compounds of the Invention

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

Example Ia Ethanesulfonic acid [ trans-4-(6-chloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

Ethanesulfonyl chloride (102 μL, 1.07 mmol) was added to a solution of the (trans-A- aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine (0.150 mg, 0.54 mmol) and DIEA (0.28 mL, 1.61 mmol) in CH₂Cl₂ (5 mL) at rt. The reaction was stirred at rt overnight. The reaction mixture was diluted with CH₂CI₂ (80 mL) and washed with saturated NaHCO₃ and brine, dried (MgSO₄) and concentrated in vacuo. The crude material was purified by preparative TLC (10 % 2M NH₃ in methanol: 90% CH₂Cl₂) to furnish the title compound as a white solid (132 mg, 66 %). ¹H NMR (MeOD) δ 7.32 (d, I H, J=1.8 Hz), 7.21-7.14 (m, 2H), 3.57 (m, I H), 3.06 (q, 2H, J=7.2 Hz), 2.93 (d, 2H, J=6.7 Hz), 2.1-2.16 (m, 2H), 1.97-1.94 (m, 2H), 1.52 (br m, IH), 1.42-1.31 (m, 5H), 1.21-1.1 1 (m, 2H). LC-MS m/e: 372 (M+H)⁺; t_R = 1.14 (Method - 1).

The following compounds were prepared analogously:

Example Ib N-[ trans-4-(6-Chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]- acetamide

Prepared from trans-(4-aminomethyl-cycIohexyl)-(6-chloro-benzooxazol-2-yl)-amine and acetyl chloride. Yield: 82 %. LC-MS m/e: 322 (M+H)⁺; t_R = 0.95 (Method - I).

Example Ic N-[trans-4 -(6-Chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]-3- methoxy-benzenesulfonam ide.

P repared from trans-(4-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine and 3-methoxybenzenesulfonyl chloride. Yield: 44 %. LC-MS m/e: 450 (M+H)⁺; t_R = 1.45. (Method-I).

Example Id N-[ trans-4-(6-Chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]-3- fluoro-benzenesulfonamide.

Prepared from trans^-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol^-yl^amine and 3- fluorobenzenesulfonyl chloride. Yield: 32 %. LC-MS m/e: 438 (M+H)⁺; t_R = 1.47. (Method- I).

Example Ie N-trans-4 -(6-Chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]- methanesulfonamide.

Prepared from trans-(4-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine and methanesulfonyl chloride. Yield: 38 %. LC-MS m/e: 358 (M+H)⁺; t_R = 1.06 (Method -

I)- Example If Cyclopropanesulfonic acid [trans-4-(6-chloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

Prepared from tτans-(4-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine and cyclopropanesulfonyl chloride. Yield: 79 %. LC-MS m/e: 384 (M+H)⁺; t_R = 1.18 (Method - I).

Example Ig Cyclopropanecarboxylic acid [ trans-4-(6-chloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

^H

Prepared from tτans-(4-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine and cyclopropanesulfonyl chloride. Yield: 66 %. LC-MS m/e: 348 (M+H)⁺; t_R = 1.11 (Method - I).

Example Ih N-[trans-4 -(6-Chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]- isobutyramide

H

Prepared from trans-(4-aminomethyl-cycIohexyl)-(6-chloro-benzooxazol-2-yl)-amine and isobutyryl chloride. Yield: 90 %. LC-MS m/e: 350 (M+H)⁺; t_R = 1.15 (Method - I).

Example 1i N-[trans-4 -(6-Chloro-benzooxazol-2-yIamino)-cyclohexylmethyl]-4- fluoro-benzenesulfonamide.

Prepared from /ttιrø^4<uiimome%l<yclohexylK6<hlc^ and 4- flourobenzenesulfonyl chloride. Yield: 18 %. LC-MS m/e: 438 (M+H)⁺; t_R = 1.45. (Method - I).

Example Ij N-Itrans^-fό-Chloro-benzooxazol^-ylaminoJ-cyclohexylinethyl]^- fluoro-benzenesulfonamide.

Prepared from trans-(4-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine and 2- flourobenzenesulfonyl chloride. Yield: 17 %. LC-MS m/e: 438 (M+H)⁺; t_R= 1.44. (Method- I).

Example Ik N-[trans-4-(6-Chloro-benzcκ)xazol-2-ylamino)-cyclohexylmethyl]-4- methoxy-benzenesulfonam ide.

Prepared from transK4-aminomethyl-cyclohexyl)-(6-chloro-benzooxazol-2-yl)-amine and 4- methoxybenzenesulfonyl chloride. Yield: 26 %. LC-MS m/e: 450 (M+H)⁺; IR = 1.42. (Method- I).

Example 11 2-Methyl-propane-2-suIfinic acid [/ra/ιs-4-(5-methoxy-benzooxazol-2- ylamino)-cyclohexylmethyl]-amide

Prepared from trans-(4-aminomethyl-cyclohexyl)-(5 -methoxy-benzooxazol-2-y l)-amine and tert-butylsulfinyl chloride. Yield: 59 %. LC-MS m/e: 380 (M+H)⁺; t_R = 1.16. (Method-II).

Example Im 2-Methyl-propane-2-sulfinic acid [trans-4-(5,7-difluoro-benzooxazol-2- ylamino)-cyclohexylmethyl]-amide ⁰

c

Prepared from trans-(4-aminomethyl-cyclohexyl)-(5,7-difluorc>-benzooxazol-2-yl)-amine and tert-bulylsulfinyl chloride. Yield: 69 %. LC-MS m/e: 386 (M+H)⁺; t_R = 1.32. (Method-II).

Example In 2-Methyl-propane-2-sulfinic acid [/ra/w-4-(4-fluoro-benzooxazol-2- ylamino)-cyclohexylmethyl]-amide

Prepared from trans-(4-aminomethyl-cyclohexyl)-(4-fluoro-benzooxazol-2-yl)-amine and tert-butylsulfinyl chloride. Yield: 80 %. LC-MS m/e: 368 (M+H)⁺; t_R = 1.24. (Method-II).

Example Io 2-Methyl-propane-2-sulfinic acid [trans-4-(6-methoxy-benzooxazol-2- ylamino)-cyclohexylmethyl]-amide

,"V^ s

Prepared from trans-(4-aminomethyl-cyclohexyl)-(6-methoxy-benzooxazol-2-yl)-amine and tert-butylsulfinyl chloride. Yield: 75 %. LC-MS m/e: 380 (M+H)⁺; t_R = 1.16. (Method-II).

The following compounds were prepared from intermediate Formula X and synthesized according to the procedures described in Scheme 2:

Example 2a Propane-2-sulfonic acid [/rø«s-4-(5-chloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

H

A solution of propane-2-sulfonic acid (trans-4-isothiocyanato-cyclohexylmethyl)- amide (138 mg, 0.50 mmol) and 2-amino-4-chlorophenol (73 mg, 0.50 mmol) in DMF

(2 mL) was stirred at 80°C for 1 h. The solution was cooled to rt followed by the addition of EDC (88 uL, 0.50 mmol). The resulting solution was stirred at 80°C overnight. The solution was diluted with CH₂Cl₂ (100 mL) and washed with 10% LiCl aqueous solution, dried (Na₂SO^ and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (20% - 100 % EtOAc in Hexanes) to yield the desired product (120 mg, 61 %). ¹H NMR (MeOD) δ 7.21-7.18 (m, 2H), 6.98 (d, IH, J=8.3 Hz), 3.56 (m, IH), 3.19 (m, IH), 2.94 (d, 2H, J=6.7 Hz), 2.22-2.13 (m, 2H), 1.97-190 (m, 2H), 1.49 (br m, IH), 1.42-1.25 (m, 8H), 1.22-1.06 (m, 2H). LC-MS m/e: 386 (M+H)⁺; t_R = 1.22 (Method - 1).

The following compounds were prepared analogously: Example 2b Propane-2-sulfonic acid [/røwΛ-4-(6-chloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

s,o

SXrVt

Prepared from propane-2-sulfonic acid (trans-4-isothiocyanato-cyclohexylmethyl)-amide and 2-amino-5-chlorophenol. Yield: 56 %. LC-MS m/e: 386 (M+H)⁺; t_R = 1.26 (Method - I).

Example 2c Propane-2-sulfonic acid [/rans-4-(5-methyl-benzooxazol-2-ylamino)- cyclohexylmethylj-amide.

C=UD-Vr Prepared from propane-2-sulfonic acid (trans^-isothiocyanato-cyclohexylmethyO-amide and 2-amino-4-methylphenol. Yield: 72 %. LC-MS m/e: 366 (M+H)⁺; t_R = 1.14 (Method - 1).

Example 2d Propane-2-sulfonic acid [*ran.s-4-(5,6-dichloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

f Prepared from propane-2-sulfonic acid (trans-Φisothiocyanato-cyclohexylmethyO-amide and 2-amino-4,5-dichlorophenol. Yield: 80 %. LC-MS m/e: 420 (M+H)⁺; t_R = 1.38 (Method - I).

Example 2e Propane-2-sulfonic acid [trans-4-(5,6-difluoro-benzooxazol-2-ylamino)- cyclohexylmethylj-amide.

Prepared from propane-2-sulfonic acid (trans^-isothiocyanato-cyclohexylmethyO-amide and 2-amino-4,5-difIourophenol. Yield: (31 %). LC-MS m/e: 388 (M+H)⁺; t_R = 1.19 (Method - I).

Example 2f Propane-2-sulfonic acid [trans-4-(5-methoxy-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

MeO ¹H^ \_^

CU>V 1.f0

Prepared from propane-2-sulfonic acid (trans-4-isothiocyanato-cyclohexylmethyl)-amide and 2πamino-4-methoxyphenol. Yield: 64 %. LC-MS m/e: 382 (M+H)⁺; t_R = 1.03 (Method - I).

Example 2g Propane-2-sulfonic acid [/ran5-4-(6-fluoro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

F

H

Prepared from propane-2-sulfonic acid (trans-4-isothiocyanato-cyclohexylmethyl)-amide and 2namino-5-flourophenol. Yield: 37 %. LC-MS nVe: 370 (M+H)⁺; t_R = 1.10 (Method -

I).

Example 2h Propane-2-sulfonic acid [/rαm-4-(6-acetyl-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

H

Prepared from propane-2-sulfonic acid (trar-s^isothiocyanato-cyclohexylmethyl^arnide and l-(4- ammc-θ-hyclroxy-ρhenyl)-ethanone. Yield: 43 %. LC-MS m/e: 394 (M+H)⁺; t_R= 0.92 (Method -I).

Example 2i Propane-2-sulfonic acid {/røras-4-[(6-chloro-benzooxazol-2-ylamino)- methyl]-cyclohexyl}-amide.

o

Prepared from propane-2-sulfonic acid (trans^-isothiocyanatomethyl-cyclohexyO-amide and 2-amino-5-chlorophenol. Yield: 49 %. LC-MS m/e: 386 (M+H)⁺; t_R = 1.17 (Method - I).

Example 2j Propane-2-sulfonic acid {frα«s-4-[(5-trifiuoromethyl-benzooxazoI-2- ylamino)-methyl]-cyclohexyl}-amide.

F ^N H^>B ^

Prepared from propane-2-sulfonic acid (trans-Φisothiocyanatomethyl-cyclohexyO-amide and 2-amino-4-(triflouromethyl)phenol. Yield: 60 % LC-MS m/e: 420 (M+H)⁺; t_R = 128 (Method - I).

Example 2k Propane-2-sulfonic acid {/røws-4-[(5-frifluoromethoxy-benzooxazol-2- ylamino)-methyl]-cyclohexyl}-amide.

Xfr ^'hrO

Prepared from propane-2-sulfonic acid (traiis^isoώiocyanatomethyl-cyclohexylj-arnide and 2- amino4<triflouromethoxy)phenol. Yield: 54%. LC-MS m/e: 436 (MfH)⁺; t_R= 132 (Method - 1). Example 21 Propane-2-sulfonic acid {/ra/w-4-[(5-methyl-benzooxazol-2-ylamino)- methyl]-cyclohexyl} -amide.

oJ

Prepared from propane-2-sulfonic acid (trans^-isothiocyanatomethyl-cyclohexyO-amide and 2-amino-4-methylphenol.Yield: 49 %. LC-MS m/e: 366 (M+H)⁺; t_R = 1.23 (Method-I).

Example 2m Propane-2-sulfonic acid {trans-4-[(5,6-dichloro-benzooxazol-2-ylamino)- methyl]-cyclohexyl} -amide.

CU

H ^v— ' H

Prepared from propane-2-sulfonic acid (trans-Φisothiocyanatomethyl-cyclohexyO-amide and 2πamino4,5-dichlorophenol. Yield: 75 %. LC-MS m/e: 420 (M+H)⁺; tκ= 1.35. (Method- I).

Example 2n Propane-2-sulfonic acid { trans-4-[(6-trifluoromethyl-benzooxazol-2- ylamino)-methyl]-cyclohexyl} -amide.

<-C\ -^έV

Prepared from propane-2-sulfonic acid (trans-Φisothiocyanatomethyl-cyclohexyO-amide and 2- amino-5-(triflouromethyl)phenol. Yield: 60 %. LC-MS m/e: 420 (M+H)⁺; fe = 1.27. (Method

-0-

Example 3a Propane-2-sulfonic acid {fraras-4-[6-(3-fluoro-phenyl)-benzooxazol-2- ylamino]-cyclohexylmethyl}-amide.

Cr^r

A mixture of propane-2-sulfonic acid [4-(6-chloro-benzooxazol-2-ylamino)-trans- cyclohexylmethyl]-amide (100 mg, 0.26 mmol), 3-flourophenylboronic acid (43 mg,

0.31 mmol), Pd(OAc)₂ (3.0 mg, 0.01 mmol), S-Phos (10.5 mg, 0.02 mmol), K₃PO₄ (165 mg, 0.78 tnmol) in acetonitrile/water (1.0 mL/0.2 mL) was subjected to microwave irradiation with stirring at 165 ⁰C for 1 h. The reaction mixture was filtered through a short column of silica gel to obtain the crude material which was purified by prep-HPLC to yield the final product (47 mg, 41 %). ¹H NMR (CDCl₃) δ 7.43 (s, IH), 7.39-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.26-7.20 (m, IH), 6.98 (m, 1 H), 5.53 (br s, 1 H), 4.12 (U H₁ J = 6.9 Hz), 3.72 (br s, 1 H), 3.15 (sept, 1 H, J = 6.9 Hz), 3.00 (t, 2 H, J = 6.6 Hz), 2.26 (m, 2H), 1.92 (m, 2H), 1.52 (m, 1 H), 1.35 (d, 6 H, J = 6.9 Hz), 1.31- 1.00 (m, 4H). LC-MS m/e: 446 (M+H)⁺; t_R = 1.48 (Method - II).

The following compound of the invention was prepared from intermediate Formula IX and synthesized according to the procedures described in Scheme 1:

Example 4a 2-Methyl-propane-2-sulfonic acid [/ra/w-4-(6-chloro-benzooxazol-2- ylamino)-cyclohexylmethyl]-amide.

H

A mixture of 2,6-dichloro-benzoxazole (150 mg, 0.80 mmol), 2-methyl-propane-2- sulfonic acid (trans-4-amino-cyclohexylmethyl)-amide (200 mg, 0.81 mmol) and diisopropyl ethyl amine (0.2 mL) in DMF (3.0 mL)was subjected to microwave irradiation with stirring at 240°C for 10 min. The reaction mixture was then cooled to room temperature and was directly purified by prep-HPLC to afford the pure product (149 mg, 37%). ¹H NMR (CD₃OD) δ 7.26-7.20 (m, IH), 7.19-7.04 (m, 2H), 3.65-3.45 (m, IH), 3.01 (d, 2H, J=6.9 Hz), 2.26-2.08 (m, 2H), 2.01-1.83 (m, 2H),1.62-0.98 (m, 5H), 1.37 (s, 9H); ESI-MS m/e: 400 (M + H)⁺ t_R = 1.35 (Method - 1).

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 tab letting 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 Ib 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

ip containing 25 mg of Compound Ib per millil

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 1 mL

In-VUro 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 (^l25I-labeled PYY or an alterative radioligand such as ^l25I-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 ¹²⁵I-PYY bound by membranes in the assay was less than 10 % of ¹²⁵I-PYY delivered to the sample (100,000 dpm/ sample = 0.08 nM for competition binding assays). ¹²⁵I-PYY 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 ¹²⁵I-PYY, competing peptides or supplemented binding buffer (25 uL), and finally, membrane suspensions (200 μL). Samples were incubated in at 30 ⁰C 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 ¹²⁵I-PYY in a Wallac Beta-Plate Reader. Alternatively, incubations were carried out in GF/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 ¹²⁵I-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 10 μM or less. The binding affinities for most of the compounds were determined to be 500 nM or less. The binding affinities for a several compounds were determined to be SO nM or less.

Claims

What is claimed:

Claim 1. A compound having the structure:

wherein each R¹ independently is F, Cl, Br, I, -CN, -COR³, -CO₂R³, straight chained or branched C1-C7 alkyl or C1-C7 perfluoroalkyl, straight chained or branched C1-C7 alkoxy or C1-C7 perfluoroalkoxy, or phenyl optionally substituted with one or more R⁴;

wherein R² is C₃-Q cycloalkyl;

wherein each R³ independently is H or straight chained or branched C₁-C7 alkyl;

wherein each R⁴ independently is F, Cl, Br, I or straight chained or branched C₁-C₇ alkyl;

wherein each R⁵ independently is F, Cl, Br, I, straight chained or branched C₁-C 7 alkyl or straight chained or branched C₁-C7 alkoxy;

wherein A is

A' A" A" wherein n is an integer from O to 4 inclusive;

wherein p is an integer from O to 2 inclusive; and

wherein q is an integer from O to 2 inclusive;

or a pharmaceutically acceptable salt thereof.

Claim 2. The compound of claim 1, wherein each R¹ independently is phenyl optionally substituted with one or more R⁴; and wherein each R⁴ independently is F, Cl, Br or I.

Claim 3. The compound of claim 1, wherein each R¹ independently is F, Cl, Br, I, -CN, straight chained or branched C₁-C₄ alkyl, or straight chained or branched C₁-C₄ alkoxy.

Claim 4. The compound of claim 1, wherein R¹ independently is -COR³, -CO₂R³, straight chained or branched C₁-C₄ perfluoroalkyl, or straight chained or branched C₁- C₄ perfluoroalkoxy; and wherein each R³ independently is straight chained or branched C₁-C₄ alkyl.

Claim 5. The compound of anyone of claims 1-4, wherein A is in the trans configuration.

Claim 6. The compound of anyone of claims 1 -5, wherein A is A'.

Claim 7. The compound of anyone of claims 1 -5, wherein A is A".

Claim 8. The compound of anyone of claims 1 -5, wherein A is A'".

Claim 9. The compound of anyone of claims 1-8, wherein n is an integer from 0 to 2 inclusive.

Claim 10. The compound of anyone of claims 1 -9, wherein p and q are each 0 or 1.

Claim 11. A compound selected from the group consisting of cyclopropanesulfonic acid [/rαn-;-4-(6-chloro-benzooxazol-2-ylamino)-cyclohexylmethyl]-amide and cyclopropanecarboxylic acid [/rαn_f-4-(6-chloro-benzooxazol-2-ylamino)- cyclohexylmethyl]-amide.

Claim 12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

Claim 13 A method of treating a subject suffering from depression comprising administering the compound of claim 1 and a pharmaceutically acceptable carrier.

Claim 14, A method of treating a subject suffering from anxiety comprising administering the compound of claim 1 and a pharmaceutically acceptable carrier. Claim IS. A method of treating a subject suffering from obesity comprising administering the compound of claim 1 and a pharmaceutically acceptable carrier.