WO2007114916A2

WO2007114916A2 - Arylbenzylpiperidine compounds

Info

Publication number: WO2007114916A2
Application number: PCT/US2007/008291
Authority: WO
Inventors: Mohammad Marzabadi; Chien-An Chen; Jiang Yu; Michael Reitman; Andersen Kim
Original assignee: H. Lundbeck A/S
Priority date: 2006-04-04
Filing date: 2007-04-02
Publication date: 2007-10-11
Also published as: WO2007114916A3

Abstract

This invention is directed to arylbenzylpiperidine compounds which are ligands at the MCHl receptor. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of treating a subject suffering from depression comprising administering to the subject a therapeutically effective amount of a compound of the subject invention. This 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 the subject invention. This invention also provides a method of treating a subject suffering from obesity comprising administering to the subject a therapeutically effective amount of a compound of the subject invention. Furthermore, the present invention is directed to the use of a compound of the subject invention for the manufacture of a medicament for treating a subject suffering from depression, anxiety or obesity.

Description

Docket No. 71014-WO-PCT ARYLBENZYLPIPERIDINE COMPOUNDS

Field of the Invention The present invention relates to compounds that are ligands at the MCHl receptor, and as such are useful to treat depression, anxiety or 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.

Melanin-concentrating hormone (MCH) is a cyclic 19-amino acid peptide produced by neurons in the lateral hypothalamus and zona incerta of the brain. Mammalian MCH is conserved between rat, mouse, and human, exhibiting 100 % amino acid homology, and the effects of MCH are mediated through receptors that belong in the rhodopsin superfamily of G protein-coupled receptors. Presently, two receptor subtypes for MCH have been identified in humans, MCHl and MCH2.

The link between MCHl and the effects of MCH on feeding was suggested by reports on the phenotype of the MCHl knockout mice. Independent groups generated knock-out mice with the targeted deletion of the MCHl receptor. The phenotype of these mice was lean, hyperphagic and hypermetabolic, with increased resistance to diet-induced obesity (D. J. Marsh, et al., Proc. Natl. Acad. Sci. 2002, 99, 3240-3245). These observations evidence that MCHl antagonists are useful to treat obesity.

To further assess the physiological role of the MCHl receptor, SNAP-7941, a selective MCHl small molecule antagonist, was evaluated in several animal models (B. Borowsky, et al., Nature Medicine, 2002, 8, 825-830). Pharmacological blockade of the MCHl receptor with SNAP-7941 produced a profile similar to clinically used anti-depressants and anxiolytics in behavioral models of depression and/ or anxiety: the rat forced-swim, rat social interaction and guinea pig maternal-separation vocalization tests. These observations evidence that MCHl antagonists are useful to treat depression and anxiety. Current treatments for depression, anxiety and obesity are on the market. However, numerous patients do not 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 MCHl receptor. The present invention relates to compounds of Formula I.

Formula I wherein each X¹, X², X³, X⁴ and X⁵ is independently CR³ or N, provided that if one X is N then the remaining X are each CR³;

wherein each U¹, U², U³ and U⁴ is independently CR⁴ or N, provided that if one U is N then the remaining U are each CR⁴;

wherein each Y¹, Y², Y³ and Y⁴ is independently CR⁵ or N, provided that if two Y are each N then the remaining Y are each CR⁵;

wherein Z is S(O)_n or O;

wherein R¹ is straight chained or branched C₁-C₇ alkyl;

wherein R² is straight chained or branched C₁-C7 alkyl, C₃-C7 cycloalkyl or straight chained or branched Ci -C₇ alkoxy;

wherein each R³ is independently H, straight chained or branched Ci-C₇ alkyl, straight chained or branched Ci -C₇ fluoroalkyl, straight chained or branched C₁-C₇ alkoxy, F, Cl, Br or I;

wherein each R⁴ is independently H, straight chained or branched Ci-C₇ alkyl, straight chained or branched Ci-C₇ fluoroalkyl, straight chained or branched Ci-C₇ alkoxy, F, Cl, Br or I;

wherein each R⁵ is independently H, CH₃, F, Cl or Br; and

wherein n is an integer from 0 to 2 inclusive;

or a pharmaceutically acceptable salt thereof. In separate embodiments of the invention, the compound is selected from one of the specific compounds 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 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 of Formula I for the manufacture of a medicament for treating a subject suffering from depression, anxiety or obesity.

Detailed Description of the Invention

Definitions

In the present invention, the term "straight chained or branched Ci-C₇ alky I" refers to a saturated hydrocarbon having from one to seven 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- 1-propyl and n-heptyl. Similarly, the term "straight chained or branched Ci -C₄ alkyl" refers to a saturated hydrocarbon having from one to four carbon atoms inclusive.

The term "straight chained or branched Ci-C₇ fluoroalkyl" 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, pentafluoroethyl, 1-fluoroethyl and 1 ,2-difluoroethyl and 2,3-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.

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. Similarly, the term "straight chained or branched Ci -C₄ alkoxy" refers to a saturated alkoxy group having from one to four carbon atoms inclusive with the open valency on the oxygen.

The term "C₃-C₇ cycloalkyl" refers to the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.

The aromatic ring containing Y¹, Y², Y³ and Y⁴ refers to the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, in which the aromatic ring may be optionally substituted with one ore more CH3, F, Cl or Br.

For illustrative purposes, and without limiting the invention, the compound of example 2a has the following structure:

This compound is constructed from Formula I wherein R¹ is methyl; wherein R² is methoxy; wherein each X¹, X², X³, X⁴ and X^s is independently CR³; wherein each R³ is independently H or F; wherein each U¹, U², U³ and U⁴ is CR⁴; wherein R⁴ is H; wherein each Y¹, Y², Y³ and Y⁴ is CR⁵; wherein each R⁵ is independently H or F; wherein Z is S(O)_n; and wherein n is 2.

Additionally, the invention further provides certain embodiments of the present invention that are described below.

In one embodiment, each Y¹, Y², Y³ and Y⁴ is independently CR⁵ or N, provided that if one Y is N then the remaining Y are each CR⁵.

In another embodiment, each U¹, U², U³ and U⁴ is independently CR⁴; and each R⁴ is independently H, straight chained or branched Ci-C₄ alkyl, F, CI, Br or I.

In one embodiment, each X¹, X², X³, X⁴ and X⁵ is independently CR³; and each R³ is independently H, straight chained or branched Ci-C₄ alkyl, straight chained or branched Ci- C₄alkoxy, F, Cl, Br or I.

In one embodiment, Z is O.

In yet another embodiment, R¹ is straight chained or branched Ci-C₄ alkyl; and each R⁴ is H.

In one embodiment, each Y¹, Y², Y³ and Y⁴ is independently CR⁵; R¹ is CH₃; and R² is straight chained or branched Cj-C₄ alkyl.

In one embodiment, Z is S(O)_n.

In one embodiment, R¹ is straight chained or branched Ci-C₄ alkyl; and each R⁴ is H.

In a further embodiment, each R³ is independently H, straight chained or branched Ci-C₄ alkyl, straight chained or branched Ci-C₄ alkoxy, F or Cl.

In one embodiment, R² is straight chained or branched Cj-C₄ alkoxy.

In one embodiment, each Y¹, Y², Y³ and Y⁴ is independently CR⁵; and R¹ is CH₃. In one embodiment, R² is straight chained or branched C1-C₄ alkyl.

In one embodiment, R¹ is CH₃.

In one embodiment, each Y¹, Y², Y³ and Y⁴ is independently CR^S; and n is 0.

Furthermore, the present invention is directed to the use of a compound as defined above for the manufacture of a medicament for treating a subject suffering from depression.

In one embodiment, the present invention is directed to the use of a compound as defined above for the manufacture of a medicament for treating a subject suffering from anxiety.

In a separate embodiment, the present invention is directed to the use of a compound as defined above for the manufacture of a medicament for treating a subject suffering from 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. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

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 1- 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, e.g., 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 compound 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 were also be prepared from optically active starting materials.

The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of Formula I which are readily convertible in vivo into the required compound of Formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

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 mg 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 £ 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 ligands at the MCHl 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. This invention further 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 also 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. 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 1-7 are consistent with the variables recited in the Summary of the Invention. For clarity purposes, the variables X¹, X², X³, X⁴ and X⁵ are designated as variable X in the experimental schemes. The variables U¹, U², U³ and U⁴ are designated as variable Y in the experimental schemes. Moreover, the variables Y¹, Y², Y³ and Y⁴ are designated as variable Y in the experimental schemes.

In the Experimental Section, standard acronyms are used. Examples of such acronyms include AIBN (2,2'-Azobisisobutyronitrile); ACN (Acetonitrile); DMF (N,N- Dimethylformamide); DMSO (Dimethylsulfoxide); NBS (N-Bromosuccinimide); MTBE (methyl t-butyl ether); TMP (2,2,6,6-tetramethylpiperidine); HATU (0-(7-Azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); mCPBA (3-chloroperoxybenzoic acid); CbzCl (Benzyl chloroformate); and BOC (/erf-butoxycarbonyl). 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 or does not limit the invention in any way. For example, representative bases include but are not limited to K₂CO₃, Et₃N or DIPEA (Diisopropylethylamine).

Experimental Section

General Methods: All reactions were performed under a nitrogen atmosphere and the reagents, neat or in appropriate solvents, were transferred to the reaction vessel via syringe and cannula techniques. Anhydrous solvents were purchased from the Aldrich Chemical Company and used as received. The NMR spectra were recorded on a Bruker Avance (400 MHz) or GE QEPlus300 in CDCl₃, MeOHnI₄ or DMSO-d₆ as solvent with tetramethylsilane as the internal standard unless otherwise noted. 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; quintet; sextet; septet; br = broad; m = multiplet; dd = doublet of doublets; dt = doublet of triplets; td = triplet of doublets; dm = doublet of multiplets; ddd = doublet of doublet of doublets. Unless otherwise noted, mass spectra were obtained using electrospray ionization (ESMS, Micromass Platform II or Quattro Micro) and (M+H)⁺ is reported. 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). Flash column chromatography was performed on Merck silica gel 60 (230-400 mesh). Microwave experiments were carried out using a Biotage Emyrs Optimizer or Smithcreator.

List and source of chemicals

Most of the reagents used in the experimental section such as 2-chlorothiophenol, potassium carbonate, 3-chloroperoxybenzoic acid, 4-fluoroacetophenone, methanesulfonyl chloride, methyl chloroformate, 2,2,6,6-tetramethylpiperidine, sodium borohydride and nitronium tetrafluoroborate were purchased from the Aldrich Chemical Company, Lancaster, Maybridge or Oakwood.

Scheme 1

Il III IV

^>sAs^Λ ru-^u u*^U

JVa IVb IVc wherein Z is S(O)_n and n is 0 wherein Z Is S(O)_n and n is 1 wherein Z is S(O)_n and n is 2

IV

(a) K₂CO₃/ DMF or DMSO/ 90 ⁰C, 10 h or microwave/ 250 ⁰C, 5 min. (b) mCPBA (leq)/ CH₂Cl₂/ 5 ⁰C, 10 min. (c) mCPBA (1.5 eq)/ CH₂Cl₂/ 5 ⁰C, 15 min. (d) (R₂= C_rC₇ alkyl)/ Ti(OiPr)₄/ THF/ rt, 12 h, then NaBH₄/ EtOH/ rt, 1 h.

The compounds of Formula I may be synthesized according to the procedures described in Scheme 1. The compounds of Formula π and III are commercially available or may be synthesized by one skilled in the art. In summary, the ketones of Formula IV are prepared via aromatic nucleophilic reaction of activated 4-halo-ketones of Formula II and phenyl or pyrindyl thiols of Formula III in the presence of base under reflux or microwave conditions. If Z is S(O)_n, the corresponding sulfoxides IVb and sulfones IVc may be prepared via sequential oxidations of IVa by mCPBA. The compounds of Formula IV may be coupled with the amine of Formula V to afford the compounds of the invention.

Alternatively, the ketones of Formula IV may be prepared via Ullmann type reactions. For reaction conditions in connection with Ullmann type reactions, see T. Kondo, et al., Chem. Rev., 2000, 100, 3205-3220 and the references cited therein. Scheme 2

IV Vl VII

(a) NaBH₄/ EtOH/ it, 12 h. (b) MsCl/ TEA/ CH₂Cl₂/ 0 ⁰C, 30 min. (c) TEA/ THF/ it, or TMP/ ACN /microwave 110⁰C / 40 min.

Alternatively, the compounds of Formula I may be synthesized according to the procedures described in Scheme 2. The intermediates of Formula IV may be reduced to the alcohols of Formula VI, which may be treated with mesylchloride in the presence of triethylamine in CH₂Cl₂ to afford the mesylates of Formula VII. The mesylates may be coupled with the amines of Formula V to afford the compounds of the invention.

(a) NBS/ AIBN/ CCl₄/ refluxing, 12 h. (b) Amine of Formula V; K₂CO₃/ DMF/ 90 ⁰C, 5h or K₂CO₃/ EtOH/ 90⁰C/ 10 h.

Alternatively, the compounds of Formula I may be synthesized according to the procedures described in Scheme 3. The compounds of Formula VQI, which are commercially available or synthesized by those skilled in the art, may be treated with NBS to afford the bromides of Formula IX. The bromides may be coupled with the amines of Formula V to afford the compounds of the invention. Scheme 4

XiIi xi xiv

(a) K₂CO₃/ PdCl₂dρpf/ DMF/ 60-80 ⁰C 12 h. (b) 10% Pd/C/ H₂ (50-60 psi)/ EtOH/ it, 24-72 h. (c) Acid chloride or chloroformate/ Pyridine/ CH₂Cl₂. (d) 4M HCl in 1,4-dioxane/ rt, 1 h or TFA/ CH₂Cl₂/ rt, 10 min.

The amines of Formula V may be prepared according to the procedures described in Scheme 4. In summary, the compounds of Formula X may be coupled with fer/-butyl 4-(3- aminoaryl)piperidinecarboxylate of Formula XI to afford the N-Cbz protected intermediates of Formula XII. The Cbz group is removed to provide the compounds of Formula XV, which may be coupled with acid chlorides or chloroformates to yield the intermediates of Formula XVI. The Boc group is removed to afford the amines of Formula V. Alternatively, the nitro compounds of Formula XIII may be used. These compounds are also coupled with /er/-butyl 4-(3-aminoaryl)piperidinecarboxylate of Formula XI to afford the compounds of Formula XIV. The nitro group and the double bond are simultaneously reduced to provide the compounds of Formula XV which may be converted to the amines of Formula V.

For representative reaction conditions in connection with Suzuki couplings and hydrogenation reactions, see A. Suzuki et al., Chem. Rev. 1995, 95, 2457-2483; A. Suzuki, J.

Organomet. Chem. 1999, 576, 147-168 and the references cited therein; and P. Ν. Rylander,

Hydrogenation Methods (Best Synthetic Methods Series), Academic Press, 1990. tert-Butyl

4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,2,5,6-tetrahydropyridine carboxylate of

Formula XI may be prepared according to the procedures described in P. R. Eastwood, Tetrahedron Lett., 2000, 41, 3705-3708 and references cited therein. Scheme 5

XVII X XVIII

(a) CbzCl/ K₂CO₃/ THF. (b) Curtius reaction.

The N-Cbz bromo or iodo intermediates of Formula X may be prepared according to the procedures described in Scheme 5. The amino group of the commercially available starting materials of Formula XVII may be protected by treatment with benzyl chloroformate in the presence of base to afford the intermediates of Formula X. Alternatively, Λf-Cbz protected intermediates X may be prepared from the corresponding acids of Formula XVIII using diphenylphosphoryl azide via a Curtius type rearrangement, followed by trapping the isocyanates with benzyl alcohol to afford the compounds of Formula X.

For reaction conditions in connection with the Curtius reaction, see Yamada et al., Tetrahedron 1974, 30, 2151-2157.

Scheme 6 γ,^'γ^i — ^■ _^ rV^N°² -. - _Y-v^N°² ^YY^{Y γ}γ^γ Ϋ^Y

Br (or I) Br (or I) XIX XIII ^

(a) nitration, (b) bromination.

The intermediates of Formula XIII may be prepared according to the procedures described in Scheme 6. The 3-bromo or 3-iodo nitro intermediates of Formula XIII are available from commercial sources or may be prepared from the corresponding bromo or iodo precursors XIX by nitration methods or from the corresponding nitro compounds of Formula XX by bromination methods.

General information regarding aromatic nitration is described in the following references: J. G. Hoggett, et al., Nitration and Aromatic Reactivity, Cambridge University Press, London, 1971; K. Schofield, Aromatic Nitration, Cambridge University Press, London, 1980; and G. A. Olah, et al., Nitration: Methods and Mechanism, (Ed.: H. Feuer), VCH Publishers, New York, 1989. Scheme 7

(a) IV, (R'=H)/ Ti(OPr)₄/ HOAc/ CH₂Cl₂ or 1,2-dichloroethane (b) IX/ K₂CO₃/ DMF/ 90 ⁰C, 5h or IX/ K₂CO₃/ EtOH/ it, 10 h. (c) VII/ TEA/ THF/ it. (d) Acid chloride or chloroformate/ Pyridine/ CH₂CI₂/ rt.

Alternatively the compounds of the invention may be prepared according to the procedures as outlined in Scheme 7. The compounds of Formula XV may be coupled with the benzophenones of Formula IV in the presence of Ti(OPr)₄ to provide the advanced intermediates of Formula XXI. Likewise, compounds of Formula XV may be coupled with the mesylates of Formula VII or benzyl bromides of Formula IX in the presence of base to provide the advanced intermediates of Formula XXI. The advanced intermediates of Formula XXI may be treated with acid chlorides or chloroformates under standard coupling conditions to afford the compounds of Formula I.

Preparation of intermediates

Representative intermediates of the compounds of the Formula I were synthesized as follows:

Intermediate of Formula IVa wherein Z is S(O)_n and n is O l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-ethanone: 4-Chlorothiophenol (289 mg, 2.0 mmol) was added to a stirred solution of 4'-fluoroacetophenone (276 mg, 2.0 mmol) and K₂CO₃ (276 mg, 2.0mmol) in DMF (3 mL). The mixture was stirred in a sealed glass tube at 90⁰C for 18 h. After cooling, the reaction was filtered and the solvent removed in vacuo to produce a yellow oil which was purified by silica gel flash chromatography (2-15 % EtOAc in Hexane) to furnish of the title compound as a yellow colored solid (450 mg, 86 % yield). ¹H NMR (CDCl₃, 400 MHz), δ 7.85(m, 2H), 7.39 (m, 4H), 7.22 (m, 2H), 2.53 (s, 3H).

Intermediate of Formula IVb wherein Z is S(O)_n and n is 1 l-[4-(4-Chloro-benzenesulfinyl)-phenyl]-ethanone: mCPBA (448 mg, 2.0 mmol) was added to a solution of l-[4-(4-Chloro-phenylsulfanyl)- phenylj-ethanone (524 mg, 2.0 mmol) in CH₂Cb which was cooled at 0⁰C in an ice bath and stirred for 1 h. The mixture was diluted with additional CH₂Cb and washed with saturated aqueous NaHCOa and H₂O. The phases were separated. The organic layers were combined, dried over Na₂SO₄ and the solvent removed in vacuo to produce a yellowish solid, which was purified by silica gel flash column chromatography (20-50 % EtOAc in Hexane) to furnish the title compound as a white solid (139 mg). ¹H NMR (CDCl₃, 400 MHz), δ 8.03 (d, J=8.3Hz, 2H), 7.73 (d, J=8.3Hz, 2H), 7.60 (d, J=8.5Hz, 2H), 7.45 (d, J=8.5Hz, 2H), 2.53 (s, 3H).

Intermediate of Formula IVc wherein Z is S(O)_n and n is 2 l-[4-(4-Chloro-benzenesulfonyl)-phenyl]-ethanone: mCPBA (448 mg, 2.0 mmol) was added to a solution of l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-ethanone (524 mg, 2.0 mmol) in CH₂CI₂ which was cooled at 0⁰C in an ice bath and stirred for 1 h. The mixture was diluted with additional CH₂CI₂ and washed with saturated aqueous NaHCθ₃ and H₂O. The phases were separated. The organic layers were combined, dried over Na₂SO₄ and the solvent removed in vacuo to produce a yellowish solid, which was purified by silica gel flash column chromatography (20-50 % EtOAc in Hexane) to furnish of the title compound as a white solid (371 mg, 86 % yield). ¹H NMR (CDCl₃, 400 MHz), δ 8.04 (d, J=8.4Hz, 4H), 7.89 (d, J=8.6Hz, 2H), 7.50 (d, J=8.6Hz, 2H), 2.62 (s, 3H).

Intermediate of Formula VI l-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-ethanol: NaBH₄ (57 mg, 1.50 mmol) in EtOH

(3 mL) was added to a solution of l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethanone (400 mg, 1.35 mmol) in THF (10 mL) and stirred at rt for 12 h. The reaction was quenched with the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine and dried over Na₂SO₄. The solvents were removed in vacuo to produce a yellow oil, which was used without further purification (395 mg, 98 % yield). ¹H NMR (CDCl₃, 400 MHz), δ 7.84 (d, J=8.4Hz, 2H), 7.70-7.77 (m, 2H), 7.51 (d, J=8.4Hz, 2H), 7.30 (m, IH), 4.93 (q, J=6.5Hz, 1 H), 2.91 (s, 3H), 1.69 (d, J=6.6Hz, 3H).

Intermediate of Formula VII

Methanesulfonic acid l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl ester

Methanesulfonyl chloride (182 mg, 1.60 mmol) was added dropwise to a solution of l-[4- (3,4-difluoro-benzenesulfonyl)-phenyl]-ethanol (395 mg, 1.32 mmol) and TEA (268 mg, 1.60 mmol) in CH2CI2 and cooled to 0⁰C in an ice bath. The reaction was stirred for 30 min. The mixture was diluted with additional CH2CI₂ and washed with 2% HCl, water, saturated aqueous NaHCCb and brine. The organic layers were combined, dried over Na2SC>4 and concentrated in vacuo to produce a yellowish oil which was purified by silica gel column chromatography (0-60 % EtOAc in Hexane) to furnish the title compound as a clear oil (423 mg, 85% yield). ¹H NMR (CDCl₃, 400 MHz), δ 7.95 (d, J=8.4Hz, 2H), 7.73-7.80 (m, 2H), 7.55 (d, J=8.4Hz, 2H), 7.31 (m, IH), 5.75 (q, J=6.6Hz, IH), 1.44 (d, J=6.5Hz, 3H).

Intermediates of Formula XIII l-Bromo-2,4-difluoro-5-nitrobenzene: HNO3 (68.0 mL) was added to a 0 ⁰C solution of 1- bromo-2,4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H₂SO₄ (76.8 mL) over 45 min at such a rate that the internal temperature remained < 7⁰C. The resulting mixture was stirred for 1 h at 0 ⁰C and poured into ice water (400 mL). This reaction was vigorously stirred for 2-3 min and extracted with CH₂CI₂ (400 mL). The organic layers were combined and washed with brine (1 X 500 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the product as a yellow oil (23.5 g, 95 % yield). ¹H NMR (CDCl₃) δ 8.39 (t, J=7.2Hz, IH), 7.14 (ddd, J=0.3, 7.8, 9.9Hz, IH).

The following compound was prepared analogously: l-Bromo-3-nitro-2,4,6-trifluorobenzene: ¹H NMR (CDCl₃) δ 7.01 (ddd, J=2.4, 7.8, 9.3Hz, IH); ¹⁹F NMR (CDCI₃) δ -1 16.20 to -116.10, -107.73 to -107.71, -93.80 to - 93.70.

2-Bromo-5-fluoro-4-nitro toluene: 2-bromo-5-fluoro toluene (15.0 g, 10.0 mL, 79.0 mmol) was added to a solution of nitronium tetrafluoroborate (11.6 g, 87.0 mmol) in CH₂Cl₂ (60.0 mL) over 5 min. After refluxing for 4.5 h, the mixture was cooled to rt and poured into ice water (150 mL). The mixture was extracted with CH₂Cl₂ (3 X 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give the crude product (18.3 g). The crude product was treated with Hexane and cooled to —70 ⁰C. The Hexane was decanted away from the resulting solid to give the desired product as a semi-solid (9.77 g, 53 % yield). The mother liquors were combined and evaporated. Additional product was purified by silica gel flash column chromatography (2 % EtOAc in Hexane) to give the desired product (1.0 g). ¹H NMR (CDCl₃) δ 8.26 (d, J=6.9Hz, IH), 7.20 (d, J=I 1.7Hz, IH), 2.48 (s, 3H). The following compound of Formula XIII was prepared via a series of functional group transformations that are known to one skilled in the art:

3-Bromo-2-methyl-5-nitropyridine: Step 1: Bromine (21.1 mL, 0.393 mol) was added dropwise over —20 min to a mixture of 2-hydroxy-5-nitropyridine (50.0 g, 0.358 mol) in water (7 L), which was warmed to 40 ⁰C. After stirring at 40 ⁰C for 2.5 h, the mixture was cooled to 10 ⁰C and the crude product was isolated by filtration. The solid was washed with water and dried in vacuo to give 3-bromo-2-hydroxy-5-nitropyridine as a solid (70.0 g, 90 % yield), mp 212-214 ⁰C (with decomposition); ¹H NMR (CD₃OD) δ 8.66 (d, J=2.9Hz, IH), 8.64 (d, J=2.9Hz, IH).

Step 2: To a cooled (0-5 ⁰C) mixture of 3-bromo-2-hydroxy-5-nitropyridine (47.0 g, 0.214 mol) and quinoline (13.7 g, 0.107 mol) was added POCI₃ (26.0 mL, 0.278 mol) dropwise over ~10 min (the mixture was difficult to stir initially but became less viscous as the reaction progressed and the mixture warmed). After stirring at 120 ⁰C for 3.5 h, the mixture was cooled to 100 ⁰C and water (90 mL) was added. The resulting mixture was stirred vigorously while cooling to 0-5 ⁰C. The product was collected by filtration, washed with water and dried in vacuo at 45 ⁰C to give 3-bromo-2-chloro-5-nitropyridine (42.0 g, 82 % yield). ¹H NMR (CD₃OD) δ 9.19 (d, J=2.4Hz, IH), 8.93 (d, J=2.4Hz, IH).

Step 3: NaH (as a 60 % dispersion in oil, 2.32 g, 58.0 mmol) was added over 5 min to a cooled (15 ⁰C) solution of diethyl malonate (8.8 mL; 58.0 mmol) in diethyl ether (110 mL). 3-Bromo-2-chloro-5-nitropyridine (12.5 g, 52.6 mmol) was added in four portions over -15 min (an exotherm to 26 ⁰C was observed), followed by removal of diethyl ether in vacuo to give a red oil. After stirring the resulting red oil at 114 ⁰C for 1 h 15 min, H₂SO₄ (6M, 67.0 mL) was added. The resulting mixture was heated at reflux for 8 h then cooled to 0 ⁰C and the pH value was adjusted to 7 with 25 % KOH aqueous solution (135 mL). The resulting mixture was stirred in an ice bath for 25 min and the crude product was collected and washed with water (50 mL) by filtration. The crude product was stirred in CH₂Cl₂ (350 mL) for 30 min and the impurity was removed by filtration. The organic layer was dried over Na₂SO₄, filtered and concentrated to give the impure product as red oil. The red oil was dissolved in CH₂Cb (100 mL) and Hexane (200 mL). The resulting mixture was filtered and the organic portion was concentrated to give 3-bromo-2-methyl-5-nitropyridine as an orange crystalline solid (9.30 g, 81 % yield). ¹H NMR (CDCl₃) δ 9.25 (d, J=2.3Hz, I H), 8.61 (d, J=2.3Hz, IH), 2.80 (s, 3H). Intermediate of Formula X

Benzyl 5-bromo-3-pyridinyl carbamate: To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at rt for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at rt for 1 h and refluxed overnight. After cooling to it, the reaction mixture was washed with H₂O, saturated aqueous NaHCC>₃ and brine. The organic layers were combined, dried over MgSO₄ and concentrated in vacuo. Purification by silica gel flash chromatography (15-50 % EtOAc in Hexane) provided benzyl 5-bromo-3-pyridinylcarbamate (22.2 g, 72.5 mmol, 73 % yield): ¹H NMR (CDCI₃) δ 8.39- 8.32 (m, 2H), 8.29 (s, IH), 7.45-7.32 (m, 5H), 6.94 (s, IH), 5.22 (s, 2H); ESMS m/e: 307.0 (M + H)⁺.

/e/7-butyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- 1 ,2,5,6-tetrahydropyridine carboxylate of Formula XI was prepared according to the procedures described by P. R. Eastwood, Tetrahedron Lett., 2000, 41, 19, 3705-3708 and references cited therein.

Intermediates of Formula XV

/er/-Butyl 4-(3-aminophenyl)piperidine carboxylate, /er/-butyl 4-(3-amino-4-fluorophenyI) piperidine carboxylate and tert-butyl 4-(3-amino-4,6-difluorophenyl)piperidine carboxylate were prepared according to the procedures described by M. R. Marzabadi et al., PCT International Publication No. WO 2004/005257 (pp. 48-82).

The following intermediates were prepared analogously:

terr-Butyl 4-(3-amino-6-methylphenyl)piperidinecarboxylate

¹H NMR (CDCl₃) δ 6.93 (d, J=8.1Hz, IH), 6.53 (d, J=IAHz, IH), 6.47 (dd, J=2.4, 8.1 Hz, IH), 4.30-4.18 (m, 2H), 3.53 (br s, 2H), 2.86-2.51 (m, 3H), 2.23 (s, 3H), 1.77-1.68 (m, 2H), 1.50-1.63 (m, 2H), 1.49 (s, 9H).

ter/-Butyl 4-(3-amino-6-fluorophenyl)piperidinecarboxylate

¹H NMR (CDCl₃) δ 6.85 -6.76 (m, IH), 6.51-6.44 (m, 2H), 4.30-4.15 (m, 2H), 3.51 (br s, 2H), 2.98-2.73 (m, 3H), 1.82 -1.73 (m, 2H), 1.66 -1.50 (m, 2H), 1.48 (s, 9H).

terf-Butyl 4-(3-amino-4-fluoro-6-methylphenyl)piperidinecarboxylate ¹H NMR (CDCl₃) δ 6.77 (d, J=12.0Hz, IH), 6.60 (d, J=9.0Hz, IH), 4.32-4.16 (m, 2H), 3.86- 3.52 (br, 2H), 2.86-2.67 (m, 3H), 2.22 (s, 3H), 1.69 (m, 2H), 1.60-1.43 (m, 1 IH).

/erf-Butyl 4-(3-amino-2,4,6-trifluorophenyl)piperidinecarboxyIate ¹H NMR (CDCl₃) δ 6.67-6.54 (m, IH), 4.32-4.15 (m, 2H), 3.60-3.48 (m, 2H), 3.10-2.97 (m, IH), 2.84-2.68 (m, 2H), 2.06-1.88 (m, 2H), 1.70-1.60 (m, 2H), 1.46 (s, 9H).

/erf-Butyl 4-(5-amino-3-pyridyl) piperidinecarboxylate

¹H NMR (CDCl₃) δ 8.01-7.95 (m, IH), 7.89 (s, IH), 6.83 (s, IH), 4.39-4.09 (br, 2H), 3.90- 3.50 (br, 2H), 2.88-2.68 (m, 2H), 2.67-2.52 (m, IH), 1.88-1.71 (m, 2H), 1.68-1.49 (m, 2H), 1.48 (s, 9H); ESMS m/e: 278.3 (M + H)⁺.

tert-Butyl 4-(5-amino-2-methyI-3-pyridyl)piperidinecarboxylate

¹H NMR (CDCI₃) δ 7.87 (d, J=2.7Hz, I H), 6.80 (d, J=2.7Hz, IH), 4.33-4.17 (m, 2H), 3.57- 3.50 (br, 2H), 2.88-2.70 (m, 3H), 2.46 (s, 3H), 1.79-1.70 (m, 2H), 1.61-1.43 (m, H H).

Compounds of the Invention

The following compounds of the invention were synthesized according to the procedures described in Scheme 1 :

Example Ia N-[3-(l-{ l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide:

Titanium (IV) isopropoxide (39 mg, 0.14mmol) was added to a stirred solution of N-(4- methyl-3-(piperidin-4-yl)phenyl)isobutyrarnide (30 mg, 0.12 mmol) and l-[4-(4-Chloro- phenylsulfanyl)-phenyl]-ethanone (19mg, 0.12 mmol) in dry THF (1 mL). The mixture was stirred in a sealed glass tube under argon at rt for 24 h. A solution of NaBH₄ (l lmg, 0.29mmol) in ethanol (1.5m L) was added and stirred for an additional 18 h. Water was added to quench the reaction and the precipitate was removed by filtration and the solvent removed in vacuo. The crude product was purified by preparative TLC (5% 2M ammonia in methanol, 95% dichloromethane) to furnish 37.4mg (58% yield) of the title compound as a white solid. ESMS m/e: 507.4 (M+H)⁺; ¹H NMR (CDCl₃, 400MHz), δ 7.89 (m, 4H), 7.50 (m, 5H), 7.22 (dd, J=8.4,1.6Hz, IH), 7.12 (br, IH), 7.05 (d, J=8.4Hz, IH,), 3.51 (q, I H, J=6.6Hz), 3.12 (apparent d, J=10.9Hz, IH), 2.80 (apparent d, J=10.9Hz, IH), 2.49 (m, IH), 2.47 (septet, IH), 2.25 (s, 3H), 2.18-1.98 (m, 2H), 1.84-1.62 (m, 4H), 1.35 (d, J=6.7Hz, 3H), 1.25 (d, J=6.9Hz, 6H).

The following compounds were prepared analogously:

Example Ib N-[3-(l -{ l-[4-(4-Chloro-benzenesulfinyl)-phenyI]-ethyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide.

Prepared from l-[4-(4-Chloro-phenyIsulfinyl)-phenyl]-ethanone and N-(4-Methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 34.7 %. ESMS m/e: 523.5 (M+H)⁺.

Example lc N-[3-(l-{l-[4-(4-Chloro-benzenesulfonyl)-phenyl]-ethyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide.

Prepared from l-[4-(4-Chloro-phenylsulfonyl)-phenyl]-ethanone and N-(4-Methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 50.1 %. ESMS m/e: 539.4 (M+H)⁺.

Example Id [3-(l-{ l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyI- phenylj-carbamic acid methyl ester.

Prepared from l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-ethanone and (4-methyl-3-piperidin- 4-yl-phenyl)-carbamic acid methyl ester. Yield: 15.6 %. ESMS m/e: 495.4 (M+H)⁺.

Example Ie [3-(l-{l-[4-(4-chloro-benzenesulfinyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl- phenylj-carbamic acid methyl ester.

Prepared from l-[4-(4-chloro-phenylsulfinyl)-phenyl]-ethanone and (4-methyI-3-piperidin-4- yl-phenyl)-carbamic acid methyl ester. Yield: 35.1 %. ESMS m/e: 51 1.4 (M+H)⁺.

Example If [3-(l-{l-[4-(4-Chloro-benzenesuIfonyl)-phenyI]-ethyl}-piperidin-4-yl)-4- methyl-phenyl]-carbamic acid methyl ester.

Prepared from l-[4-(4-chloro-phenyIsulfonyl)-phenyl]-ethanone and (4-methyl-3-piperidin-4- yl-phenyl)-carbamic acid methyl ester. Yield: 15.6 %. ESMS m/e: 527.4 (M+H)⁺.

Example Ig N-(4-Methyl-3-{ l-[l-(4-phenoxy-phenyl)-ethyl]-piperidin-4-yI}-phenyl)- isobutyramide.

Prepared from l-(4-phenoxy-phenyl)-ethanone and N-(4-methyl-3-piperidin-4-yl-pheπyl)- isobutyramide. Yield: 72.0 %. ESMS m/e: 457 (M+H)⁺.

Example Ih N-[3-(l-{l-[4-(2,4-Dichloro-phenoxy)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl- phenylj-isobutyramide.

Prepared from l-[4-(2,4-dichloro-phenoxy)-phenyl]-ethanone and N-(4-methyl-3-piperidin-4- yl-phenyl)-isobutyramide. Yield: 50.1 %. ESMS m/e: 525.2 (M+H)⁺.

Example Ii N-(4-Methyl-3-{ l-[l-(4-phenylsulfanyl-phenyl)-ethyl]-piperidin-4-yl}-phenyl)- isobutyramide.

Prepared from l-(4-phenylsulfanyl-phenyl)-ethanone and N-(4methyl-3-piperidin-4-yl- phenyO-isobutyramide. Yield: 71.9 %. ESMS m/e: 473.4 (M+H)⁺. Example Ij N-[3-(l-{ l-[4-(2-Chloro-6-methyl-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4- y l)-4-m ethyl-phenyl]-i sobutyram ide.

Prepared from l-[4-(2-chloro-6-methyl-phenylsulfanyl)-phenyI]-ethanone and N-(4-methyI- 3-piperidin-4-yl-phenyl)-isobutyramide. Yield: 38.0 %. ESMS m/e: 521.5 (M+H)⁺.

Example lk N-[3-(l-{l-[4-(3,4-Dimethoxy-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)- 4-methyl-phenyl]-isobutyram ide.

Prepared from l-[4-(3,4-dimethoxy-phenyIsulfanyl)-phenyl]-ethanone and N-(4-methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 25.6 %. ESMS m/e: 533.5 (M+H)⁺.

Example ll N-[3-(l-{l-[4-(3,4-Dichloro-phenylsulfanyI)-phenyl]-ethyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide.

Prepared from l-[4-(3,4-dichloro-phenylsulfanyl)-phenyl]-ethanone and N-(4-methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 16.6 %. ESMS m/e: 541.4 (M+H)⁺.

Example Im N-[3-(l-{l-[4-(2,4-Dichloro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4- methyl-phenylj-isobutyramide.

Prepared from l-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-ethanone and N-(4-methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 22.8 %. ESMS m/e: 541.4 (M+H)⁺. Example In N-[3-(l-{l-[4-{3,4-Difluoπ>benzenesuIfonyl)-phenyl]-ethyl}-piperidin-4-yl)-4- methyl-phenylj-isobutyramide.

Prepared from l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethanone and N-(4-methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 1 1.3 %. ESMS m/e: 541.1 (M+H)⁺.

Example Io [3-(l-{ l-[4-(3,4-Difluoro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4- fluoro-phenyl]-carbamic acid methyl ester.

Prepared from l-[4-(3,4-difluoro-benzenesulfanyl)-phenyl]-ethanone and (4-fluoro-3- piperidin-4-yl-phenyl)-carbamic acid methyl ester. Yield: 12.7 %. ESMS m/e: 501.1 (M+H)⁺.

Example Ip [3-(l-{ l-[4-(3,4-Difluoro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yI)-4- methyl-phenylj-carbamic acid methyl ester.

Prepared from l-[4-(3,4-difluoro-benzenesulfanyl)-phenyl]-ethanone and N-(4-methyl-3- piperidin-4-yl-phenyl)-isobutyramide. Yield: 16.6 %. ESMS m/e: 497.1 (M+H)⁺.

Example Iq N-[3-(l-{l-[4-(4-Chloro-phenylsulfanyl)-phenyl]-propyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide.

Prepared from l-[4-(4-chloro-phenylsulfanyl)-phenyl]-propan-l-one and N-(4-methyl-3- piperidin-4-yI-phenyl)-isobutyramide. Yield: 16.4 %. ESMS m/e: 521.4 (M+H)⁺. The following compounds of the invention were synthesized according to the procedures described in Scheme 2:

Example 2a [3-(l-{l-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-ethyl}-piperidin-4-yl)-4- fluoro-phenyl]-carbamic acid methyl ester:

A mixture of (4-Fluoro-3-piperidin-4-yI-phenyl)-carbamic acid methyl ester (67 mg, 0.27 mmol) and methanesulfonic acid l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl ester (100 mg, 0.27 mmol) and 2,2,6,6 tetramethylpiperidine (45 mg, 0.27 mmol) in dry ACN (3 mL) were heated to 110 ⁰C for 40 min in the microwave reactor. The solvent was removed in vacuo and the crude product was purified by preparative TLC (5 % 2M ammonia in methanol in CH₂Cl₂) to furnish of the title compound as a white solid (73.2 mg, 52 % yield). ¹H NMR (CDCl₃.400MHz), δ 7.86 (d, J=8.4Hz, 2H), 7.74-7.82 (m, 2H), 7.53 (d, J=8.4Hz, 2H), 7.32 (m, 2H), 7.10 (m, IH), 6.92 (t, IH), 6.60 (br, IH), 3.77 (s, 3H), 3.49 (m, IH), 3.10 (d, J=I LlHz, IH), 2.77 (d, J=I LOHz, 2H), 1.99-2.12 (m, 2H), 1.69-1.81 (m, 4H), 2.25 (s, 3H), 2.18-1.98 (m, 2H), 1.33 (d, J=6.7Hz, 3H). ESMS m/e: 533 (M+H)⁺.

The following compounds were prepared analogously:

Example 2b N-(l-{ l-[4-(3,4-Difluoro-benzenesulfonyI)-phenyl]-ethyI}-2-methyl- l,2,3,4,5,6-hexahydro-[3,4]bipyridinyl-5-yl)-isobutyrarnide.

Prepared from methanesulfonic acid l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl ester and N-(2-nethyl-l',2',3',4',5^f,6'-hexahydro-[3,4']bipyridinyl-5-yl)-isobutyramide. Yield: 39.4 %. ESMS m/e: 542.2 (M+H)⁺.

Example 2c (l-{l-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-ethyl}-2-methyl-l,2,3,4,5,6- hexahydro-[3,4]bipyridinyl-5-yl)-carbamic acid ethyl ester.

Prepared from methanesulfonic acid l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl ester and (2-methyl-r,2',3',4^t,5',6'-hexahydro-[3,4^t]bipyridinyl-5-yl)-carbamic acid ethyl ester.

Yield: 42.4 %. ESMS m/e: 544.3 (M+H)⁺.

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 tabletting machine 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 2a calculated as the free base:

Compound 2a 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

2) Tablets containing 0.5 mg of Compound 2a calculated as the free base:

Compound 2a 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 2a per milliliter:

Compound 2a 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 Vitro Methods

The pharmacological properties of the compounds of the present invention were evaluated at the cloned rat MCHl receptor using the protocols disclosed in U.S. Patent No. 6,727,264, the contents of which are hereby incorporated by reference.

Using this protocol, the inhibition by the compound of the binding of a radiolabeled ligand

(tritiated SNAP-7941) to membranes harvested from CHO cells expressing cloned rat MCHl receptors was determined in vitro. The radiochemical synthesis of tritiated SNAP-7941 was performed by Amersham Pharmacia Biotech, Cardiff, Wales.

Briefly, the affinity of the compounds was measured by their ability to displace tritiated

SNAP-7941 from rat MCHl expressing membranes. The compound and radioligand were incubated with the membranes at 25 ⁰C for 90 min. Incubation was terminated by rapid vacuum filtration over GF/C glass fiber filters, presoaked in 5 % PEI using 50 πM Tris pH 7.4 as wash buffer. In all experiments, nonspecific binding was defined using 10 pM of tritiated SNAP-7941.

The binding affinities for the compounds in the present invention, described herein, at the MCHl receptor were determined to be 100 nM or less. For many of the compounds, the Ki values were determined to be 30 nM or less. For some compounds, the Ki values were determined to be 10 nM or less.

Claims

What is claimed:

Claim 1. A compound having the structure:

wherein each X¹, X², X³, X⁴ and X^s is independently CR³ or N, provided that if one X is N then the remaining X are each CR³;

wherein each U¹. U², U³ and U⁴ is independently CR⁴ or N, provided that if one U is N then the remaining U are each CR⁴;

wherein Z is S(O)_n or O;

wherein R¹ is straight chained or branched C₁-C7 alkyl;

wherein R² is straight chained or branched C1-C7 alkyl, C3-C7 cycloalkyl or straight chained or branched Ci -C₇ alkoxy;

wherein each R³ is independently H, straight chained or branched C₁-C₇ alkyl, straight chained or branched C₁-C7 fluoroalkyl, straight chained or branched C₁-C₇ alkoxy, F, Cl, Br or l;

wherein each R⁴ is independently H, straight chained or branched Ci-C₇ alkyl, straight chained or branched Cj-C₇ fluoroalkyl, straight chained or branched C₁-C₇ alkoxy, F, Cl, Br or l;

wherein each R⁵ is independently H, CH3, F, Cl or Br; and

wherein n is an integer from 0 to 2 inclusive;

or a pharmaceutically acceptable salt thereof.

Claim 2. The compound of claim 1, wherein each Y¹, Y², Y³ and Y⁴ is independently CR* or N, provided that if one Y is N then the remaining Y are each CR⁵.

Claim 3. The compound of claim 2, wherein each U¹, U², U³ and U⁴ is independently CR⁴; and wherein each R⁴ is independently H, straight chained or branched C₁-C₄ alkyl, F, Cl, Br or I.

Claim 4. The compound of claim 3, wherein each X^!, X², X³, X⁴ and X⁵ is independently CR³; and wherein each R³ is independently H, straight chained or branched Cr C₄ alkyl, straight chained or branched Ci-G»alkoxy, F, Cl, Br or I.

Claim 5. The compound of claim 4, wherein Z is O.

Claim 6. The compound of claim 5, wherein R¹ is straight chained or branched C₁-C₄ alkyl; and wherein each R⁴ is H.

Claim 7. The compound of claim 6, wherein each Y¹, Y², Y³ and Y⁴ is independently

CR⁵; wherein R¹ is CH₃; and wherein R² is straight chained or branched C₁-C₄ alkyl.

Claim 8. The compound of claim 3, wherein Z is S(O)_n.

Claim 9. The compound of claim 8, wherein R¹ is straight chained or branched C1-C4 alkyl; and wherein each R⁴ is H.

Claim 10. The compound of claim 9, wherein each R³ is independently H, straight chained or branched C₁-C₄ alkyl, straight chained or branched C₁-C₄ alkoxy, F or Cl.

Claim 11. The compound of claim 10, wherein R² is straight chained or branched Ci-C₄ alkoxy.

Claim 12. The compound of claim 11, wherein each Y¹, Y², Y³ and Y⁴ is independently CR⁵; and wherein R¹ is CH₃.

Claim 13. The compound of claim 10, wherein R² is straight chained or branched Ci-C₄ alkyl.

Claim 14. The compound of claim 13, wherein R¹ is CH3.

Claim 15. The compound of claim 14, wherein each Y¹, Y², Y³ and Y⁴ is independently CR⁵; and wherein n is 0.

Claim 16. The compound of claim 1, wherein the compound is selected from the group consisting of N-[3-(l-{l-[4-(4-chloro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl- phenylj-isobutyramide; N-[3-(l-{l-[4-(4-chloro-benzenesulfinyl)-phenyl]-ethyl}-piperidin-4-yl)- 4-methyl-phenyI]-isobutyramide; N-[3-(l-{l-[4-(4-chloro-benzenesulfonyl)-phenyl]-ethyl}- piperidin-4-yl)-4-methyl-phenyl]-isobutyramide; [3-(l-{l-[4-(4-chloro-phenylsulfanyl)-phenyl]- ethyl}-piperidin-4-yl)-4-methyl-phenyl]-carbamic acid methyl ester; [3-(l-{l-[4-(4-chloro- ben2snesulfinyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl-phenyl]-carbamic acid methyl ester; [3- (^{l-^^-chloro-benzenesulfonylVphenylJ-ethylJ-piperidin^-yO^-methyl-phenyll-carbamic acid methyl ester; N-(4-methyl-3-{l-[l-(4-phenoxy-phenyl)-ethyl]-piρeridin-4-yl}-phenyl)- isobutyramide; N-[3-(l-{ l-[4-(2,4-dichIoro-phenoxy)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl- phenyl]-isobutyramide; N-(4-methyl-3-{l -[l-(4-phenylsulfanyl-phenyl)-ethyl]-piperidin-4- yl}-phenyl)-isobutyramide; N-[3-(l-{ l-[4-(2-chloro-6-methyl-phenylsulfanyl)-phenyl]- ethyl}-piperidin-4-yl)-4-methyl-phenyl]-isobutyramide; N-[3-(l-{l-[4-(3,4-dimethoxy- phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl-phenyl]-isobutyramide; N-[3-(l-{l- [4-(3,4-dichloro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl-phenyl]- isobutyramide; N-[3-(l-{l-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide; N-[3-(l-{l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl}- piperidin-4-yl)-4-methyl-phenyl]-isobutyramide; [3-(l -{ l-[4-(3,4-difluoro-phenylsulfanyl)- phenyl]-ethyl}-piperidin-4-yl)-4-fluoro-phenyl]-carbamic acid methyl ester; [3-(l-{l-[4-(3,4- difluoro-phenylsulfanyl)-phenyl]-ethyl}-piperidin-4-yl)-4-methyl-phenyl]-carbamic acid methyl ester; N-[3-(l-{ 1 -[4-(4-chloro-phenylsulfanyl)-phenyl]-propyl}-piperidin-4-yl)-4- methyl-phenyl]-isobutyramide; [3-(l-{ l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl}- piperidin-4-yl)-4-fluoro-phenyl]-carbamic acid methyl ester; N-(l-{l-[4-(3,4-difluoro- benzenesulfonyl)-phenyl]-ethyl}-2-methyl-l,2,3_>4,5,6-hexahydro-[3,4]bipyridinyl-5-yl)- isobutyramide; and (l-{ l-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-ethyl}-2-methyl- l,2,3,4,5,6-hexahydro-[3,4]bipyridinyl-5-yl)-carbamic acid ethyl ester.

Ctaim 17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

Claim 18. Use of a compound as defined in claim 1 for the manufacture of a medicament useful for treating a subject suffering from depression.

Claim 19. Use of a compound as defined in claim 1 for the manufacture of a medicament useful for treating a subject suffering from anxiety.

Claim 20. Use of a compound as defined in claim 1 for the manufacture of a medicament useful for treating a subject suffering from obesity.