WO2009137270A2

WO2009137270A2 - Azetidine derivatives

Info

Publication number: WO2009137270A2
Application number: PCT/US2009/041343
Authority: WO
Inventors: Yu Jiang; Gil Ma; Kai Lu
Original assignee: H. Lundbeck A/S
Priority date: 2008-05-09
Filing date: 2009-04-22
Publication date: 2009-11-12
Also published as: WO2009137270A3

Abstract

The present invention relates to azetidine derivatives which bind to the MCH l receptor. In separate aspects, the subject invention is directed to uses of said compounds in the preparation of a pharmaceutical composition for the treatment of metabolic and CNS related disorders and to methods of treating said disorders comprising administering a therapeutically effective amount of a compound of the invention.

Description

Docket No. 71048-WO-PCT AZETIDWE DERIVATIVES

FIELD OF THE INVENTION

The present invention is directed to azetidine derivatives which bind to the MCHl receptor. In separate aspects, the subject invention relates to uses of said compounds in the preparation of a pharmaceutical composition for the treatment of obesity and CNS related disorders and to methods of treating said disorders comprising administering a therapeutically effective amount of a compound of the invention.

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 the subject 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 predominantly by neurons in the lateral hypothalamus and zona incerta of the brain which project broadly throughout the brain. Mammalian MCH is conserved between rat, mouse, and human, exhibiting 100 % amino acid homology, and the effects of MCH are mediated though its interaction with receptors that belong in the rhodopsin superfamily of G protein- coupled receptors. Presently, two receptor subtypes for MCH have been identified in humans, MCHl-R and MCH2-R.

MCH exerts several physiological effects through interaction with its receptors. For example, an icv injection of MCH in rats stimulates food intake (Levens, et al. Int. J. Obesity 2002, 26, 1289-1295), and chronic administration leads to increased body weight (Kanatani, et al. Am. J. Physiol. Endocrinol. Metah. 2003, 284, E583-E588). The link between MCHl-R and the effects of MCH on feeding is demonstrated by reports on the phenotype of MCH l-R knockout mice. Independent groups generated knock-out mice with the targeted deletion of MCHl-R. The phenotype of these mice was lean, hyperphagic and hypermetabolic, with an increased resistance to diet-induced obesity (Marsh, et al. Proc. Natl. Acad. ScL 2002, 99, 3240-3245) These observations suggest that MCH l -R antagonists could be useful for the treatment of obesity related disorders. As the distribution of MCH l-R binding sites in the CNS such as the amygdala, accυmbens nucleus, dorsal raphe and locus coeruleus is suggestive of a role for MCH in the regulation of mood and stress, several groups have identified selective, high affinity MCHl-R antagonists and evaluated their effects in in-vivo behavioral paradigms predictive of antidepressant and/or anxiolytic activity.

For example, clinically used antidepressants decrease the amount of time mice or rats spend immobile in the forced-swim test (Porsolt, et al. Arch Im Pharmacodyn Ther. 1977, 229, 327-336 and Luki, et al. Psychopharmacology 2001, 155, 315-322). Pretreatment of rats with a single oral dose of SNAP-7941, a selective MCH l-R antagonist, or fluoxetine decreased the duration of immobility compared with vehicle-treated controls, and increased the time these animals spent swimming (Borowsky, et al. Nature Medicine 2002, 8, 825- 830). The profile of SNAP-7941 in the rat forced-swim test is similar to that of clinically used antidepressants, indicating that MCHl-R receptor blockage may be a therapeutic modality for the treatment of mood-disorders such as depression.

The rat social interaction test has been used as a model of anxiety (File and Hyde Br. J. Pharmacol. 1987, 62, 19-24). Acute treatment with 3, 10 and 30 mg/kg SNAP-7941 or 5 mg/kg chlordiazepoxide increased social interaction time compared with vehicle-treated controls (Borowsky, et al. Nature Medicine 2002, 8, 825-830) without an overall increase in locomotor activity. The response to the two lower doses of SNAP-7941 was as robust as the response to 5 mg/kg chlordiazepoxide. The profile of this potent MCHl-R antagonist in the rat social interaction test suggests that MCHl-R antagonists may have potential as anxiolytic agents.

Accordingly, it is expected that the compounds of the subject invention can be used to treat obesity, mood and anxiety related disorders as well as the additional indications which are disclosed herein in the detailed description section. SUMMARY OF THE INVENTION

The objective of die subject invention is to provide compounds which are ligands at the MCHl receptor. Accordingly, the present invention relates to compounds of Formula I.

Formula 1 wherein R¹ is H, -(CH₂)CR^CH₂), propargyl or straight chained or branched C₁-C7 alkyl optionally substituted with one or more halogen, CN, -(CH₂X₁OR², -(CH₂)_nS(O)_pR² or - (CH₂)_nC(O)NHR²;

wherein R² is H or straight chained or branched Ci -Q alkyl optionally substituted with halogen;

wherein R³ is phenyl, thiophenyl, isoxazoyl, pyridyl, pyrimidinyl, indolyl, oxazoyl, thiazoyl, or benzothiophenyl wherein the phenyl, thiophenyl, isoxazoly, pyridyl, pyrimidinyl indolyl, oxazoyl, thiazoyl or benzothiophenyl is optionally substituted with one or more halogen, straight chained or branched Q-C 7 alkyl or alkoxy, or straight chained or branched C1-C7 perfluoroalkyl or perfluoroalkoxyl;

wherein is a single or double bond;

wherein R⁴ represents one or two H, F or straight chained or branched C₁-C₄ alkyl groups provided that is a single bond, and wherein R⁴ is H provided that is a double bond;

wherein R⁵ independently is H, =0, or straight chained or branched C₁-C4 alkyl provided that is a single bond, and wherein R⁵ is H provided that is a double bond;

wherein each A¹, A² and A³ independently is CR⁷ or N provided that if one A is N then the remaining A are CR⁷; wherein each R⁶ and R⁷ independently is H or halogen;

wherein D is CH or N;

wherein each Z¹ and Z² is independently CHi, O, S, NH or a bund, provided that an O, S or NH is separated from another O, S or NH by at least two carbon atoms;

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

wherein n is an integer from O to 4 inclusive; or a pharmaceutically acceptable salt thereof.

In separate aspects of the invention, the compound is selected from one of the exemplified compounds which are disclosed in the Experimental Section.

Furthermore, the subject invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Moreover, the present invention provides a method of treating a subject suffering from mood disorders, anxiety or obesity comprising administering to the subject a therapeutically effective amount of a compound of Formula I. The present invention further provides uses of a compound of Formula I in the manufacture of a pharmaceutical composition for the treatment of mood disorders, anxiety or obesity.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, "treating" and "treatment" refer to an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disorder, stabilized (i.e., not worsening) state of disorder, delay or slowing of disorder progression, amelioration or palliation of the disorder state, and remission (whether partial or total), whether detectable or undetectable.

As used herein, "therapeutically effective amount" is an amount sufficient to effect beneficial or desired clinical or biochemical results. A "therapeutically effective amount" can be administered one or more times. For purposes of this invention, "a therapeutically effective amount" of a compound is an amount that is sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disorder state.

As used in this invention, the term "antagonist" refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis. Conversely, the term "agonist" refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.

As used in the present invention, the teπn "straight chained or branched C1-C7 alkyl" 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 C1-C4 alkyl" refers to a saturated hydrocarbon having from one to four carbon atoms inclusive. 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 substitueπts include, but are not limited to, methoxy, ethoxy, n- butoxy, t-butoxy and n-heptyloxy.

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, pentafluoroethyl, 1-fluoroethyl, 1 ,2-difluoroethyl and 3,4-difluoroheptyl. Similarly, the term "straight chained or branched C_rC₄ 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 "halogen" refers to the following atoms: F, Cl, Br and I.

As used in the subject application, the symbol Δ is used to refer to heat being used during the reaction.

Additionally, the invention further provides certain embodiments of the present invention that are described below. In one embodiment, R¹ is -<CH₂)CR⁶(CH₂) or propargyl.

In a separate embodiment, R¹ is H or straight chained or branched Ci-C₄ alkyl optionally substituted with one or more halogen or CN.

In one embodiment, R³ is phenyl optionally substituted with one or more halogen, straight chained or branched C1-C4 alkyl or alkoxy, or straight chained or branched C]-C₄ perfluoroalkyl or perfluoroalkoxy.

In yet another embodiment, R³ is pyridyl or pyrimidinyl, wherein the pyridyl and pyrimnidinyl are optionally substituted with one or more halogen, straight chained or branched C₁-C₄ alkyl or alkoxy, or straight chained or branched Ci-C₄ perfluoroalkyl or perfluoroalkoxy. In one embodiment, R³ is thiophenyl, isoxazoyl, oxazoyl or thiazoyl, wherein the thiophenyl, isoxazoyl, oxazoyl or thiazoyl are optionally substituted with one or more halogen, straight chained or branched C1-C4 alkyl or alkoxy, or straight chained or branched C1-C4 perfluoroalkyl or perfluoroalkoxy.

In one embodiment, is a single bond.

In yet another embodiment, is a double bond.

In one embodiment, each A¹, A² and A³ is CR^G; and wherein R⁶ is II.

In a separate embodiment, one A¹, A² and A³ is N.

In one embodiment, D is CH.

In one embodiment, D is N.

In one embodiment, R⁴ is H and R⁵ is H.

In one embodiment, R⁴ is H and R⁵ is =0.

In one embodiment, each Z¹ and Z² is a bond; and m is 0.

In one embodiment, Z¹ is a bond; Z² is O; and wherein m is 2.

In a separate embodiment, the compound is selected from the group consisting of 4-(4- chloro-phenyl)- 1 - { 1 -[ 1 -(2-fluoro-ethyi)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl } - 1 h- pyridin-2-one, 4-(4-chloro-phenyl)- 1 -[ 1 -( 1 -methyl-azetidin-3-yl)-2,3-dihydro- 1 h-indol-5- yl]- 1 h-pyridin-2-one, 5-chloro- 1'-{1-[1 -(2-fluoro-aIlyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol- 5-yl } - 1 'h-P^'jbipyridinyl^'-one, 5-chloro- 1 '-[ 1 -(I -isopropyl-azetidin-3-yl)-2,3-dihydro- 1 h- indol-5-yl]- 1 'h-[2,4']bipyridinyl-2'-one, 5-chloro- 1 '-[ I -(I -ethyl-azetidin-3-yl)-2,3-dihydro- lh-indol-S-yO-l'h-^^bipyridinyl^'-one, 5-chloro- T-[ I -(l-methyl-azetidin-3-yl)-2,3- dihydro- 1 h-indol-5-yl]-Th-[2,4']bipyridinyl-2'-one, 5-chloro- T-(I-[I -(2-fluoro-ethyl)- azetidin-3-yl]- 1 h-indol-5-yl } - 1 ^lh-[2,4^l]bipyridinyl-2'-one, 5-chloro- T-(I-[I -(2-fluoro-ethyl)- azetidin-3-yl]-2,3-dihydro-lh-indol-5-yl}-Th-[2_>4']bipyridinyl-2'-one, 4-benzyloxy-l-( l-[l- (2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lh-indoI-5-yl}-l h-pyridin-2-one, 4-benzyloxy-l- [ 1 -( 1 -methyl-azetidin-3-yl)-2,3-dihydro- \ h-indol-5-yl]- ] h-pyridin-2-one, 1 -(I -azetidin-3-yl- 2,3-dihydro- 1 h-indol-5-yl)-4-benzyloxy- 1 h-pyridin-2-one, 1 '- { 1 -[ 1 -(2-fluoro-ethyl)- azetidin^-yπ^.S-dihydro-lh-indol-S-ylJ-S-trifluoromethyl- rh-P^^bipyridinyl^'-one, T- [l-(l-raethyl-azetidin-3-yl)-2,3-dihydro-lh-indol-5-yl]-5-trifluoromethyl- rh-

[2,4']bipyridinyl-2'-one, T-(I-[I -(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl} - ό-trifluoromethyl-rh-P^^bipyridinyl^'-one, 4-(5-ethyl-pyrimidin-2-yl)-l-{ l-[l-(2-fluoro- ethyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl} - 1 h-pyridin-2-one, T-(I-[I -(2-fluoro-ethyl)- azetidin-3-yl]-l h-indol-5-yl }-6-trifluoromethyl-Th-[3,4']bipyπdinyl-2'-one, 6-(4-chloro- phenyl)-3-[ 1 -( I -methyl-azetidin-3-yl)- 1 h-indol-5-yl]-3h-pyrimidin-4-one, 1 - { 1 -[I -(2-fluoro- ethyl)-azetidin-3-yl]-2,3-dihydro-l h-indol-5-yl} -4-(4-fluoro-phenyl)-l h-pyridin-2-one, 5- fluoro- T-(I-[I -(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl} -Th- [2,4']bipyridinyl-2'-one, T-{l-[l-(2-flυoro-ethyl)-azetidin-3-yl]-lh-indol-5-yl}-5- trifluoromethyl-Th-P^bipyridinyl^'-one, T-[I -(I -methyl-azetidin-3-yl)- l h-indol-5-yl]-5- trifluoromethyl- 1 'h-[2,4']bipyridinyl-2'-one, 4-(4-chloro-phenyl)- 1 - ( 1 -[I -(3-fluoro-propyl)- azetidin-3-yl]-2,3-dihydro- 1 H-indol-5-yl } - 1 H-pyridin-2-one; 4-(4-chloro-phenyl)- 1-{ 1-[ 1- ((S)-2-fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indol-5-yl}-l H-pyridin-2-one; 4-(4-chloro-phenyl)-l-(l-[l-((R)-2-fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3-dihydro-l H- indol-5-yl}-l H-pyridin-2-one; and 4-(4-chloro-phenyl)-l -[ l-(l-cyclopropyl-azetidin-3-yl)- 2,3-dihydro-lH-indol-5-yl]-l H-pyridin-2-one.

The present invention is also directed to a pharmaceutical composition comprising a compound of the invention and an acceptable pharmaceutical carrier.

Additionally, the present invention is also directed to a method of creating mood disorders in a subject comprising administering a therapeutically effective amount of a compound of the invention. The present invention is also directed to method of treating anxiety in a subject comprising administering a therapeutically effective amount of a compound of the invention. Moreover, the present invention is also directed to a method of treating obesity in a subject comprising administering a therapeutically effective amount of a compound of the invention. The present invention is also directed to method of treating urinary disorders in a subject comprising administering a therapeutically effective amount of a compound of the invention.

In separate embodiment, the invention is directed to uses of a compound of the invention for the manufacture of a pharmaceutical composition for treating a disorder selected from the group consisting of mood, anxiety and obesity related disorders.

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, 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. Sd., 1977, 66, 2 and Paulekuhn, et al. J. Med. Chem. 2007 (December online publication), the contents of all 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 1- tartaric, mandelic 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., chira! 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 may 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^lh 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, intracistemal, 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 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 foπns 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 foπn 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 expected to bind to MCH 1 receptor and function as receptor antagonists. Accordingly, the present invention provides a method of treating depression in a subject 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 meuiod of treating a subject suffering from obesity 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 urinary disorders ' 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.

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 Aldrich Chemical Company and used as received. The NMR spectra were recorded at Bruker Avance (400 or 300 MHz) or GE QEPlus300 in CDCh, MeOH-d₄ 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).

Source of chemicals

Most of the reagents used in the experimental section were purchased from Λldrich-Sigma. 1 -Boc-3-(hydroxy)azetidine was purchased from CHN Technologies Inc. 3-Fluoropyridine- 4-boronic acid was purchased from Frontier Scientific. 2-Bromo-l-fluoro ethane was purchased from Beta Pharma Inc.

Scheme 1

(a) CuI/ K₂CO₃/ //^•am-N,N'-dimethyl-cyclohexane-l ,2-diamine/ DMF/ Δ, about 18 h.

The compounds of Formula Ia may be synthesized according to the procedures described in Scheme 1. The compounds of Formula II and III are commercially available or may be synthesized by those skilled in the art. For example, the compounds of Formula II may be synthesized according to the procedures described in Scheme 13, 14, and 15. The compounds of Formula III may be synthesized according to the procedures described in

Scheme 5, 6, 7, 8, 9, 10, 1 1 , and 12. Copper-catalyzed coupling reaction of compounds II with compounds III in the presence of copper iodide, potassium carbonate and fran.s-N,N'- dimethyl-cyclohexane- l ,2-diamine in DMF at about 100⁰C affords the compounds of

Formula Ia.

For representative reaction conditions in connection with copper-catalyzed coupling see S. L. Buchwald et al, Org. Letters 2007, 9 (4), 643-646 and references cited therein.

Scheme 2

(a) TFA/ DCM/ it, about 3 h (b) aldehydes (or ketones)/ NaBH(OAc)₃/ AcOH/ DCM or THF/ rt, overnight or alkyl haϋdes/ K₂CO₃/ DMF or CH₃CN/ NaI/ Δ, about 3 h

Alternatively, the compounds of Formula Ia may be prepared according to the procedures described in Scheme 2. The deprotection of the compounds of Formula Ia (R¹⁼Boc) in the presence of TFA affords the compounds of Formula Ia (R'=H). The reductive animation of compounds of Formula Ia (R¹^H) with aldehydes (or ketones) or the alkylation with alkyl halides affords the compounds of Formula Ia (R¹⁼alkyl).

Scheme 3

^Br

(a) CuI/ K₂CO₃/ ?7-α/7.γ-N,N'-dimethyl-cyclohexane-l,2-diamine/ DMF/ Δ, about 18 h. (b) Vϊ/

NaBH(OAc)₃/ AcOH/ DCM or THF/ rt, overnight or VIl/ K₂CO₃/ DMF or CH₃CN/ Δ, about 3 h

Alternatively, the compounds of Formula Ia may be prepared according to the procedures described in Scheme 3. The compounds of Formula IV and III are commercially available or may be synthesized by those skilled in the art. Compounds of Formula III are coupled with compounds IV in the presence of copper iodide, potassium carbonate and trans-N,N'- dimethyl-cyclohexane-l ,2-diamine in DMF at about 100 ⁰C for about 18 h to afford the compound V. The reductive amination of compound V with VI or the alkylation with VII affords the compounds of Formula Ia. Scheme 4

R^>Z'(CH₂)_m

(a) DDQ/ CHCb/ about 30 min

Alternatively, the compounds of Formula Ia may be synthesized according to the procedures described in Scheme 4. The indoles of Formula Ia are prepared by the oxidation of the dihydroindoles of Formula Ia in the presence of 2,3-dicyano-5,6-dichloro- parabenzoquinone (DDQ) in CHCb.

Scheme 5

'^a -*^■ . ^b . " ' R37i (ChU_

J O VIlI IX III

(a) Alcohols or thio alcohols/ TDA-I/ KOH/ K₂CCV toluene/ reflux, about 3 h (b) Ac₂O/ Δ, overnight; KOH/ MeOH.

The compounds of Formula III may be prepared according to the procedures described in

15 Scheme 5. The compounds of Formula IX are synthesized via nucleophilic substitution of

4-chloropyridine N-oxide of Formula VIII with alcohols or thio alcohols in the presence of tris[2-(2-methoxyethoxy)-ethyl]amine (TDA-I), potassium hydroxide, and potassium carbonate in toluene under reflux for 3 h. Pyridinones of Formula III are prepared via reaction of compounds IX in acetic anhydride at about 140 ⁰C overnight, followed by basic 0 work-up. For representative general reactions in connection with synthesis of pyridinones see Parra, M. el a/, Current Org. Chem. 2005, 9, 1757-1779 and references cited therein. Scheme 6

X Xl

W = • Cl. Br

(a) Alcohols or thio alcohols/ PPIh/ DBAD/ THF/ rt, about 2 h (b) AcOH/ Δ, about 12 h

Alternatively, the compounds of Formula III may be synthesized according to the procedures described in Scheme 6. The compounds of Formula X, which are commercially available or synthesized by those skilled in the art, are treated with alcohols or thio alcohols in the presence of triphenylphosphine and dibenzyl azodicarboxylate (DBAD) in THF at room temperature for about 2 h to afford ethers or thio ethers of Formula XI. The compounds of Formula XI are treated with acetic acid at about 120 ⁰C for 12 h to afford pyridinones of Formula III.

Scheme 7

X XII III

W = Cl, Br (a) MsCl/ TEA/ DCM/ rt, about 12 h (b) Alcohols or thio alcohols/ Cs₂CO₃/ MeCN/ rt, about 16 h

Alternatively, the compounds of Formula III may be prepared according to the procedures described in Scheme 7. The mesylates of Formula XII are synthesized from reaction of alcohols of Formula X and mesyl chloride in the presence of base. The compounds of Formula III are prepared via substitution reaction of mesylates of Formula XII with alcohols or thio alcohols in the presence of base such as cesium carbonate. Scheme 8

XIII VIII xiv III

R = aryl, heteroaryl D = CH

Z' and Z² are each a singl > bond m is O

(a) Pd(PPIb)₄/ Na₂CO₃/ 1 ,2-dimethoxy ethane-water/ reflux, about 16 h (b) Ac₂O/ Δ, overnight; KOH/ MeOH.

Alternatively, the compounds of Formula III may be prepared according to the procedures described in Scheme 8. The compounds of Formula XIV are synthesized via Suzuki reaction of 4-chloropyridine N-oxide VIII with aryl boronic acid or aryl boronic ester of Formula XIII, which is commercially available or may be synthesized by those skilled in the art, in the presence Of Pd(PPKO₄ ^a°d Na₂COs in 1 ,2-dimethoxy ethane/water under reflux for about 6 h. Pyridinones of Formula HI are prepared via reaction of compounds XIV in acetic anhydride at about 140 ⁰C overnight, followed by basic work -up.

Scheme 9

XV XIII XVi Ni

₌ p D = CH

W , Cl R = aryl, heteroaryl

Z< and Z² are each a singl > bond m is O

(a) Pd(PPh^)₄/ Na₂CO₃/ 1 ,2-dimethoxy ethane-water/ reflux, about 16 h (b) AcOH/ Δ, overnight

Alternatively, the compounds of Formula III may be prepared according to the procedures described in Scheme 9. The compounds of Formula XV are treated with aryl boronic acid or aryl boronic ester XIII, which are commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPhO₄ and Na₂CO? in 1 ,2-dimethoxy ethane under reflux for about 16 h.to afford the compounds of Formula XVI. The compounds of Formula XVI are treated with acetic acid at about 1 10 ⁰C for overnight to afford pyridinones of Formula III.

Scheme 10

XVII XVIII XVI W = F, Cl X = Cl, Br, I D = CH

Z' and Z¹ are each a singl > bond m is O

(a) Pd(PPh₃V Na₂CO₃/ 1 ,2-dimethoxy ethane-water/ reflux, about 16 h (b) AcOH/ Δ, overnight

Alternatively, the compounds of Formula III may be prepared according to the procedures described in Scheme 10. The compounds of Formula XVHI, which are commercially available or synthesized by those skilled in the art, are treated with pyridinyl boronic acid or pyridinyl boronic ester XVII, which is commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPh₃)₄ and Na₂CO₃ in 1 ,2-dimethoxy ethane under reflux for about 16 h to afford Formula XVI. The compounds of Formula XVI are treated with acetic acid at about 1 10 ⁰C for overnight to afford pyridinones of Formula III.

Scheme 11

III

XIX XIII D = N

Z¹ and Z² are each a singl s bond m Is O

(a) Pd(PPh₃V Na₂CO₃/ 1,2-dimethoxy ethane-water/ reflux, about 16 h

The compounds of Formula III may be prepared according to the procedures described in Scheme 1 1. The compounds of Formula XIX, which are commercially available or may be synthesized by those skilled in the art, are treated with aryl boronic acid or aryl boronic ester XIII, which is commercially available or may be synthesized by those skilled in the art, in the presence of Pd(PPh^ and Na_∑CO.? in 1 ,2-dimethoxy ethane under reflux for about 16 h to afford pyrimidinones of Formula III.

Scheme 12

xx xxi XXIi

(a) /-BuOK/ THF/ about 20 ⁰C, about 4 h

The compounds of pyridinone XXII may be prepared according to the procedures described in Scheme 12. The compounds of Formula XXII are prepared via Wittig reaction of aldehydes XX and phosphonates XXI in the presence of potassium /er/-butoxide in THF at room temperature for about 4 h.

Scheme 13

(a) NaBH(OAc)₃/ AcOH/ DCM/ rt, overnight

The compounds of Formula II may be synthesized according to the procedures described in Scheme 13. The compounds of Formula XXIII and IV are commercially available or may be synthesized by those skilled in the art The reductive amination of compound IV with compound XXIII in the presence of NaBH(OAc)? and AcOH in DCM affords the compounds of Formula II. Scheme 14

Il

(a) DDQ/ CHCl₃/ 30 min

The compounds of Formula II may be synthesized according to the procedures described in Scheme 14. The indoles of Formula II are prepared by the oxidation of the dihydroindoles of Formula II in the presence of 2,3-dicyano-5,6-dichloro-parabenzoquinone (DDQ) in CHCl₃.

Scheme 15

VII IV Il

X = I, OTs₁ OMs _,„• _ /

- = ^

(a) /-BuOK/ l 8-crown-6-ether/ THF

The compounds of Formula II may be synthesized according to the procedures described in Scheme 15. The compounds of Formula VII and IV are commercially available or may be synthesized by those skilled in the art. The compounds of Formula II are prepared via substitution reaction of halides (or mesylates or tosylates) of Formula VII with the indoles of Formula IV in the presence of base such as /-BuOK. Scheme 15

Il Il

= ^ = <^

(a) /-BuOK/ 18-crown-6-ether/ THF

The compounds of Foπnula II, wherein Rl is cyclopropyl may be synthesized according to the procedures described in Scheme 15.

Preparation of intermediates

Representative compounds of were synthesized as follows:

3-(5-Bromo-2,3-dihydro-indol-l-yl)-azetidine-l-carboxylic acid /e/7-butyl ester

To a solution of 5-bromoindoline (30.0 g, 151 mmol) in DCM (150 mL) was added lert- butyl-3-oxoazetidine-l-carboxylate (28.5 g, 167 mmol), acetic acid (1.00 mL, 17.6 mmol) and sodium triacetoxyborohydride (68.5 g, 323 mmol). The reaction mixture was stirred for

3 h and diluted with EtOAc. The organic layer was washed with saturated citric acid, saturated NaHCOi, and brine, and dried over MgSd. Removal of solvent gave crude product which was used without further purification (5Og as crude product, -94% pure by LC/MS). ESMS m/e: 352.9 (M+H)¹.

5-Bromo- 1 -[ 1 -(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 H-indole

To a solution of l-azetidin-3-yl-5-bromo-2,3-dihydro-l H-indole (1.50 g, 3.12 mmol; 2 equivalent of TFA salt) in DMF (10 mL) was added cesium carbonate (3.35 g, 10.3 mmol), 1 -bromo-2-fluoroethane (0.792 g, 6.23 mmol), and sodium iodide (0.467 g, 3.12 mmol). The reaction mixture was stirred at 60 ⁰C for 1 h and quenched with water. The aqueous layer was extracted with with 3:1 chloroform." 2-propanol (3x30 mL). The combined organic phases were concentrated in vacuo. The crude material was purified over silica gel eluting with 0 to 6% MeOH (2M NH₃)/DCM to afford 5-bromo-l-[1 -(2-fluoro-ethyl)-a7.etidin-3-yl]- 2,3-dihydro-l H-indole (0.65 g, 70%) as brown oil. ¹H NMR (400 MHz, CDCb) δ: 7.10-7.17 (m, 2H), 6.18-6.23 (m, IH), 4.39-4.57 (m, 2H), 3.93-4.02 (m, IH), 3.72-3.78 (m, 2H), 3.32- 3.38 (m, 2H), 3.20-3.26 (m, 2H), 2.91-2.97 (m, 2H), 2.73-2.86 (m, 2H); ESMS m/e: 298.9 (M+H)\

3-{5-[4-(4-Chloro-phenyl)-2-oxo-2H-pyridin-l -yl]-2,3-dihydro-indol-l -yl}-azetidine-l- carboxylic acid tert-butyl ester

Into a microwave-reactor vessel was added 3-(5-bromo-2,3-dihydro-indol-l-yl)-azetidine-l- carboxylic acid /e/V-butyl ester (0.30 g, 0.76 mmol), 4-(4-chloro-phenyl)-lH-pyridin-2-one (0.130 g, 0.632 mmol), (l/?,2/?)-N,N'-dimethyl-cyclohexane-l,2-diamine (0.085 g, 0.60 mmol), copper(I) iodide (0.050 g, 0.26 mmol), and potassium carbonate (1.5 g, 1 1 mmol) in DMF (3 mL). The reaction mixture was irradiated at 200°C for 15 minutes. The reaction mixture was diluted with EtOAc (100 mL), washed with water and 10% aqueous LiCI, and dried over MgSO₄. Removal of solvent gave the crude product which was used without further purification (0.4 g as crude product). ESMS m/e: 478.0 (M+H)\

1 -( 1 -Azetidin-3-yl-2,3-dihydro- 1 H-indol-5-yl)-4-(4-chloro-phenyl)- 1 H-pyridin-2-one Into a flask was added 3-{5-[4-(4-chloro-phenyl)-2-oxo-2H-pyridin-l-yl]-2,3-dihydro-indol- l-yl}-azetidine-l-carboxylic acid /<?/7-butyl ester (0.100 g, 0.209 mmol) and TFA (0.68 mL, 8.8 mmol). The reaction mixture was stirred for 2 h at room temperature and concentrated in vacuo to afford l-(l-azetidin-3-yl-2,3-dihydro-l H-indoI-5-yl)-4-(4-chloro-phenyl)-l H- pyridin-2-one as a TFA salt which was used without further purification. ESMS m/e: 378.0 (M+H)\

3-(5-Bromo-indol-l-yl)-azetidine-l-carboxylic acid /er/-butyl ester

To the solution of 3-(5-bromo-2,3-dihydro-indol-l-yl)-azetidine-l-carboxylic acid /<?r/-butyl ester (30.0 g, 67.9 mmol) in DCM (250 mL) at 0 ⁰C was added dichlorodicyanoquinone (23.13 g, 101 .9 mmol) portionwise. The reaction mixture was allowed to warm up to room temperature over 1 h. The reaction mixture was washed with 5% aqueous KOH and brine, and dried over MgSO₄. Removal of solvent gave crude product which was used without further purification (27g as crude product, 90% pure by LC/MS). ESMS m/e: 350.8 (M+H)\

5-Bromo- 1 -[ I -(2-fluoro-ethyl)-azetidin-3-yl]- 1 H-indole

To a solution of 3-(5-bromo-indol-l-yl)-azetidine-l-carboxylic acid ter1-buKy\ ester (2.20 g, 6.26 mmol) in DCM (27.6 mL) was added TFA (5.53 mL, 71.8 mmol) at 0 ⁰C. The reaction mixture was stirred at room temperature for 3 hours and was were concentrated /// vacuo to give crude product as TFA salt, which was used without further purification. To a solution of l-azetidin-3-yl-5-bromo-lH-indole^#TFA (2.10 g) in DMF (10 mL) was added potassium carbonate (3.46 g, 25.0 mmol) and 1 -bromo-2-fluoroethane ( 1.59 g, 12.5 mmol). The reaction mixture was stirred at 60 ⁰C overnight, filtered through celite pad, and concentrated in vacuo. The crude material was purified over silica gel eluting with 0 to 6% MeOH (2M NH₃VDCM to afford 5-bromo-l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-l H-indole (1.22 g, 65.5% over steps) as brown oil. ¹H NMR (400 MHz, CDCIj) δ: 7.72-7.77 (m, 2H), 7.17-7.38 (m, 4H)₁ 6.47-6.55 (m, I H), 5.01-5.1 1 (m, I H), 4.44-4.62 (m, 2H), 3.97-4.04 (m, 2H), 3.46-3.53 (m, 2H), 2.82-2.94 (m, 2H); ESMS m/e: 296.9 (M+H)'.

Compounds of the Invention

The following compounds synthesized according to the schemes described in experimental section:

Example Ia 4-(4-Chloro-phenyl)-l-{ l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-l H- indol-5-yl}-lH-pyridin-2-one

Into the flask was added 3-{5-[4-(4-chloro-phenyl)-2-oxo-2H-pyridin-l-yl]-2,3-dihydro- indol-l-yl}-azetidine-l-carboxylic acid /er/-butyl ester (0.286 g, 0.59 mmol) and TFA (1.0 mL, 13 mmol). The mixture was stirred for 2 h at room temperature and concentrated /// vacuo to remove TFA. To a solution of the residue in DMF (5 mL) was added potassium carbonate (0.50 g, 3.6 mmol), 1 -bromo-2-fluoroethane (0.20 mL, 2.7 mmol), and sodium iodide (0.100 g, 0.667 mmol). The reaction mixture was stirred at 85°C for 2 h and diluted with EtOAc. The organic layer was washed with water and 10% aqueous LiCl, dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative TLC to give 4- (4-chloro-phenyO- 1 - { 1 -[ 1 -(2-fiuoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 H-indol-5-yl } - 1 H- pyridin-2-one (35mg, 14%). ¹H NMR (300 MHz, CDCl₃) δ: 7.34-7.67 (m, 5H), 7.13 (s, 1 H), 7.02 (m, IH), 6.84 (s, IH), 6.33-6.51 (m, 2H), 4.62 (s, I H), 4.46 (s, IH), 4.01-4.29 (m, 2H), 3.85 (s, 2H), 3.41-3.54 (m, 2H), 3.34 (s, I H), 2.70-3.14 (m, 4H); ESMS m/e: 424.0 (M+H)⁴.

Example I b 4-(4-Chloro-phenyl)- 1-[1-(I -methyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol-5- yl]-l H-pyridin-2-one

To a solution of 1 -(I -azetidin-3-yl-2,3-dihydro-l H-indol-5-yl )-4-(4-chloro-phenyl)- I H- pyridin-2-one as the TFA salt (0.2 mmol) and triethylamine (0.30 g, 3.0 mmol) in DCM (5 mL) was added formaldehyde (0.20 mL, 40% in water, 2.6 mmol) and sodium triacetoxyborohydride (0.200 g, 0.944 mmol). The reaction mixture was stirred for 20 min at room temperature and concentrated /// vacuo. The residue was purified by preparative TLC to afford 4-(4-chloro-phenyl)- 1 -[I -( 1 -metliyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol-5-yl]- 1 H- pyridin-2-one (25mg, 31 % for two steps). ¹H NMR (300MHz, CDCl₃) δ: 7.34-7.62 (m, 5H), 7.14 (s, I H), 6.99-7.07 (m, IH), 6.82-6.90 (m, I H), 6.36-6.52 (m, 2H), 4.35-4.48 (m, I H), 4.13-4.32 (m, 2H), 3.65-3.85 (m, 2H), 3.41-3.56 (m, 2H), 2.97-3.1 1 (m, 2H), 2.73 (s, 3H); ESMS m/e: 391.9 (M+H)⁺.

The compounds of examples Ic, Ig, Ih, Ii, 11 and In were prepared analogously to that of Example Ia.

Example Ic 5-Chloro-l'-{ l -[ I -(2-fluoro-allyl)-azetidin-3-yl]-2,3-dihydro-l H-indol-5-yl }- 1¹H-[2,4']bipyridinyl-2¹-one

The compound was prepared from r-(l-azetidin-3-yl-2,3-dihydro-l H-indol-5-yl)-5-chloro- 1 'H-[2,4']bipyridinyl-2^I-one and 3-chloro-2-fluoro-propene. ESMS m/e: 436.9 (M+H)^' .

The compounds of examples Id, Ie, 1 f and Im were prepared analogously to that of Example Ib. Example Id 5-Chloro- 1 '-[1 -( 1 -isopropyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol-5-yl]- 1¹H- [2,4']bipyridinyl-2'-one

The compound was prepared from l'-(l-azetidin-3-yl-2,3-dihydro-l H-indol-5-yl )-5-chloro- IΗ-[2,4']bipyridinyl-2'-one and acetone. ESMS m/e: 421.0 (M+H)¹.

Example Ie 5-Chloro-l'-[l-(l -ethyl-azetidin-3-yl)-2,3-dihydro- l H-indol-5-yl]-rH- [2,4']bipyridinyl-2'-one

The compound was prepared from r-( l -azetidin-3-yl-2,3-dihydro-lH-indol-5-yl)-5-chloro- 1 Η-[2,4']bipyτidinyl-2'-one and acetaldehyde. ESMS m/e: 407.0 (M+H)¹.

Example If 5-Chloro- 1 '-[ 1 -(I -methyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol-5-yl]- 1 'H- [2,4¹]bipyridinyl-2'-one

The compound was prepared from r-(l-azetidin-3-yl-2,3-dihydro-lH-indol-5-yl)-5-chloro- l'H-fZ^'jbipyridinyl^'-one and formaldehyde. ESMS m/e: 393.0 (M+H)⁺.

Example Ig 5-Chloro-l '-{! -[ l-(2-fluoro-ethyl)-azetidin-3-yl]- l H-indol-5-yl }-l 'H- [2,4']bipyridinyl-2'-one

The compound was prepared from r-(l-azetidin-3-yl-lH-indol-5-yl)-5-chloro-l'H- [2,4']bipyridinyl-2'-one and 1 -bromo-2-fluoro-ethane. ESMS m/e:422.9 (M+H) ' .

Example 1 h 5-Chloro- 1 '- { 1 -[ 1 -(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 H-indol-5-yl } -

1 Η-β^bipyridinyW-one

The compound was prepared r-(l-azetidin-3-yl-2,3-dihydro-lH-indol-5-yl)-5-chloro-l'H- [2,4']bipyfidinyl-2'-one and 1 -bromo-2-fluoro-ethane. ESMS m/e: 424.9 (M+H)' .

Example Ii 4-Benzyloxy-l-{l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indol-5- yl}-l H-pyridin-2-one

The compound was prepared from l-(l-azetidin-3-yl-2,3-dihydro-l H-indol-5-yl)-4- benzyloxy-l H-pyridin-2-one and 1 -bromo-2-fluoro-ethane. ESMS m/e: 420.0 (M+H)^" . Example Ij 4-Bertzyloxy-l-[l-(l-methyl-azetidin-3-yI)-2,3-dihydro-l H-indol-5-yI]-l H- pyridin-2-one

The compound was prepared from l-(l-azetidin-3-yl-2,3-dihydro-l H-indol-5-yl)-4- benzyloxy- 1 H-pyridin-2-one and formaldehyde. ESMS m/e: 388.0 (M+H)¹.

Example Ik l-(l-Azetidin-3-yl-2,3-dihydro-lH-indol-5-yl)-4-benzyloxy-lH-pyridin-2- one

The compound was prepared from 3-[5-(4-Benzyloxy-2-oxo-2H-pyridin- 1 -yl)-2,3-dihydro- indol-l-yl]-azetidine-l-carboxylic acid tert-butyl ester. ESMS m/e: 374.2 (M+H)^'.

Example 11 r-{l-[l-(2-Fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indol-5-yl}-5- trifluoromethyl-rH-[2,4']bipyridinyl-2'-one

The compound was prepared from l'-( l-azetidin-3-yl-2,3-dihydro-l H-indol-5-yl)-5- trifluoromethyl- 1 'H-[2,4']bipyridinyl-2'-one and 1 -bromo-2-fluoro-ethane. ESMS m/e: 458.9 (M+H)' .

Example Im 1 '-[ I -(I -Methyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol-5-yl]-5-trifluoromethyl- 1¹H-[2_>4']bipyridinyl-2'-one

The compound was prepared from l'-( l-azetidin-3-yl-2,3-dihydro-l H-indol-5-yl)-5- trifluoromethyl-rH-[2₎4']bipyridinyl-2'-one and formaldehyde. ESMS m/e: 427.0 (M+H)^' Example 1 n 4-(4-Chloro-phenyl)- 1 - { 1 -[ I -(3-fluoro-propyl)-azetidin-3-yl]-2,3-dihydro- 1 H- indol-5-yl}-l H-pyridin-2-one

The compound was prepared from l-(l-Azetidin-3-yI-2_>3-dihydro-l H-indol-5-yl)-4-(4- chloro-phenyl)- 1 H-pyridin-2-one and l-iodo-3-fluoro-propane. ESMS m/e=438 (M+H^f)

Example 2a r-{l-[l-(2-Fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indol-5-yl}-6- tπfluoromethyl-rH-[3,4']bipyridinyl-2'-one

To a solution of 6-trifluoromethyl-rH-[3,4^l]bipyridinyl-2'-one (121 mg, 0.502 mmol), 5- bromo-l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indole (150 mg, 0.501 mmol), CuI (95.5 mg, 0.501 mmol), K₂CO₃ (138 mg, 1.00 mmol) in DMF (3 raL) was added trans- N,N'-dirnethyl-cyclohexane-l ,2-diarnine (71.3 mg, 0.501 mmol) at room temperature. The resulting mixture was heated at 95 ⁰C overnight. The resulting mixture was concentrated in vacuo. The residue was quenched with water and extracted with 3: 1 chloroform: 2-propanol (3x30 mL). The combined organic phases were concentrated in vacuo. The crude material was purified over silica gel eluting with 0 to 10% MeOH (2M NH₃)/DCM to give 1'-{ 1-[1- (2-Fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 H-indol-5-yl} -6-trifluoromethy 1- 1 'H- p^bipyridinyl^'-one (69 mg. 30%). ¹H NMR (400 MHz, CDCl₃) δ: 8.97 (s, I H), 8.05- 8.1 1 (m, I H), 7.79-7.85 (m, I H), 7.44-7.51 (m, IH), 7.10-7.13 (m, I H), 6.99-7.03 (m, I H), 6.89-6.91 (m, I H), 6.38-6.47 (m, 2H), 4.39-4.59 (m, 2H), 4.06-4.15 (m, I H), 3.76-3.83 (m, 2H), 3.42-3.50 (m 2H), 3.23-3.31 (m, 2H), 3. 00-3.07 (m, 2H), 2.75-2.87 (m, 2H). ESMS m/e: 459.0 (M+H)^1".

The compounds of examples 2b-2k were prepared analogously to that of Example 2a. Example 2b 4-(5-Ethyl-pyrimidin-2-yl)-l-{l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-2,3- dihydro-lH-indol-5-yl}-lH-pyridin-2-one

The compound was prepared from 4-(5-ethyl-pyrimidin-2-yl)-l H-pyridin-2-one and 5- bromo-l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indole. ESMS m/e: 419.98 (M+H)\

Example 2c T-(I-[I -(2-Fluoro-ethyl)-azetidin-3-yl]- 1 H-indol-5-yl } -6-trifluoromethyl- 1¹H- [3_>4']bipyridinyl-2^l-one

The compound was prepared from 6-trifluoromethyl- rH-[3,4']bipyridinyl-2'-one and 5- bromo-l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-I H-indole. ESMS m/e: 457.0 (M+H)' .

Example 2d 6-(4-Chloro-phenyI)-3-[ 1 -( 1 -methyl-azetidin-3-yl)- 1 H-indol-5-yl]-3H- pyrimidin-4-one

The compound was prepared from 6-(4-chloro-phenyl)-3H-pyrimidin-4-one and 5-bromo-l- (1 -methyl-azetidin-3-yl)- l H-indole. ESMS m/e: 391.0 (M+H)'.

Example 2e l-{ l-[l-(2-Fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-l H-indol-5-yl} -4-(4- fluoro-phenyl)- 1 H-pyridin-2-one

The compound was prepared from 4-(4-fiuoro-phenyl)-lH-pyridin-2-one and 5-bromo- l-[I- (2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-i H-indoIe. ESMS m/e: 408.0 (M+H)^'.

Example 2f 5-Fluoro- 1 '- { 1 -[ 1 -(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 H-indol-5-yl } rH-[2,4']biρyridinyl-2'-one

The compound was prepared from 5-fluoro-rH-[2,4']bipyridinyl-2'-one and 5-bromo-l-[l- (2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-l H-indole. ESMS m/e: 409.0 (M+H)\

Example 2g l'-{ l-[l-(2-Flυoro-ethyl)-azetidin-3-yl]-lH-indol-5-yl}-5-trifluoromethyl-rH- [2,4']bipyridinyl-2'-one .

The compound was prepared from 5-trifluoromethyl-lΗ-[2₎4']bipyridinyl-2'-one and 5- bromo-l-[l-(2-fluoro-ethyl)-a2etidin-3-yl]-lH-indoie. ESMS m/e: 457.0 (M+H)\

Example 2h r-[l-(l-Methyl-azetidm-3-yl)-lH-indol-5-yl]-5-trifluoromethyl-lΗ- [2,4']bipyridinyl-2'-one

The compound was prepared from 5-trifluoromethyl-lΗ-[2,4']bipyridinyl-2'-one and 5- bromo-l-(l-methyl-azetidin-3-yl)-l H-indole. ESMS m/e: 424.9 (M+H)\

Example 2i 4-(4-Chloro-phenyl)-l-{l-[l-((S)-2-fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3- dihydro-lH-indol-5-yl}-l H-pyridin-2-one

The compound was prepared from 4-(4-Chloro-phenyl)- 1 H-pyridin-2-one and 5-Bromo-l-

[l-((S)-2-fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3-dihydro-lH-indole. ESMS m/e=43S (M+H*)

Example 2j 4-(4-Chloro-phenyl)-l-{l-[]-((R)-2-fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3- dihydro-l H-indol-5-yl}-l H-pyridin-2-one

The compound was prepared from 4-(4-Chloro-phenyl)- lH-pyridin-2-one and 5-Bromo- l - [l -((R)-2-fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3-dihydro-l H-indole. ESMS /w/e=438 (M+H^*)

Example 2k 4-(4-Chloro-phenyl)- 1 -[ 1 -( 1 -cyclopropyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol- 5-yl]- 1 H-pyridin-2-one

The compound was prepared from 4-(4-Chloro-phenyl)- 1 H-pyridin-2-one and 5-Bromo- l- ( l-cyclopropyl-azeridin-3-yl)-2,3-dihydro-l H-indole. ESMS w/e=418 (M+H^s)

PHARMACOLOGICAL EVALUATION OF COMPOUNDS Tn-Vitro Assays

The procedure for determining specific binding of a test compound may be used as described by Audinot, et al. British Journal of Pharmacology, 2001 , 133, 371 -378. Similarly, the specific binding of test compounds can be measured at the rat MCHl receptor (GcnBank Accession No. NM_O31758) using [¹²⁵I]-S36O57 (NEX396; PerkinElmer Life Sciences, Inc.) as the radioligand.

The exemplified compounds of the invention were tested for their binding affinity to the rat MCH I receptor. All of the compounds were found to bind to the rat MCH l receptor with a binding affinity of less than l μM. Moreover, the binding affinities for most of the compounds were determined to be less than about 500 nM.

Table I binding affinity of selected compounds

Example No. Ia Ib In 2k 2k 2i

Ki (nM) 6.5 4.6 4.8 12 14 22 Functional activity

Functional activity of the compounds of the invention can be measured by receptor assays which determine the degree of intracellular second messenger response. For example, Cos-7 cells are transfected with the MCHl receptor using the DEAE-dextran method (Gerald, et al. J. Biol. Chem. 1995, 270, 26758-26761). Other cell transfection methods, employing various host cells, are well-known in the art.

Some of the compounds were determined to behave as antagonists at the MCHl receptor.

In-Vivo Assays

The in-vivo effects of the compounds of the present invention may be evaluated by using the following in-vivo behavioral animal models. The behavioral models described below are not intended to be the only models used to determine the efficacy of a compound of the invention to treat the corresponding disorder. For example, in addition to the Rat Social- interaction test, the marble burying experiment can also be used to screen for compounds for potential as anxiolytics. The skilled artisan would recognize the changes in certain parameters of the experiments to acquire the most exact data.

Diet Induced Obesity (DIO) Model: Male Long-Evans rats are used and housed individually, maintained on about 12 h reverse light/dark cycle with lights off at about 9:00am, and given free access to either a high-fat diet (#D 12451 ; fat percentage, about 45% kcal; Research Diets, New Brunswick, New Jersey) or a control diet (#D 124508, fat percentage, about 10% kcal; Research Diets, New Brunswick, New Jersey) and water. After about 1 1 weeks, rats on the high fat diet began receiving a compound of the invention or vehicle by i.p. injection twice daily, about 1 h before lights off and about 10 h later, for about 4 weeks.

Rat Forced-swim Test:

The procedure which may be used here is similar to that previously described (Luki, et al. Psychophurmacology 2001 , 155, 315-322) with the following modifications. Male Sprague-

Dawley rats may be used. Swim sessions are conducted for about 5 min, by placing rats in a plexiglass cylinder (about 46 cm tall x 20 cm in diameter) filled about 30 cm deep with water at about 23⁰C. A compound of the invention or vehicle (about 0.01% lactic acid, about pH 6) is administered orally as a 1 ml/kg solution. Test sessions are videotaped and recorded for later scoring by a single rater, who is blinded to the treatment condition. Immobility is scored as the time a rat remained floating in the water making only movements necessary to keep its head above the water. Swimming is scored as the time a rat made active swimming motions, more than necessary to maintain its head above water.

Rat Social- interaction Test:

The procedure is performed for about 15 min as previously described (File and Hyde Rr. J. Pharmacol. 1987, 62, 19-24) under low-light conditions using pairs of unfamiliar male Sprague-Dawley rats previously housed singly and exposed to the test arena for about 15 min on the previous day. A compound of the invention, chlordiazepoxide or vehicle is injected i.p. as a - 1.0 ml/kg solution. All test sessions are videotaped and recorded for later scoring. Active social interaction, defined as sniffing, grooming, biting, boxing and crawling over and under, as well as locomotor activity (defined as squares crossed), is scored by a single rater, who is blinded to the treatment of each pair.

Rat Models of Micturition:

Compounds useful in the treatment of urinary disorders are assessed in various animal models of the micturition reflex as described in the art. (See, e.g., Maggi, CA, et al. J. Pharmacol. Exp. Ther., 1987, 240, 998-1005; Morikawa, K, et al. Eur. J. Pharmacol., 1992 213:409-415; Yoshiyama, M, et al. Eur. J. Pharmacol. 287:73-78; and Yoshiyama, Urology, 1999, 54(5), 929-33.)

Claims

What is claimed:

Claim 1. A compound of formula I:

Formula I wherein R¹ is H, -(CH₂)CR¹XCH₂), propargyl or straight chained or branched C1-C7 alkyl ooppttiioonnaallllyy ssuubbssttiittuutted with one or more halogen, CN, -(CH^)_nOR², -(CH₂)_OS(O)_PR² or -

(CH_^)_nC(O)NHR²;

wherein R² is H or straight chained or branched C₁-C₄ alkyl optionally substituted with halogen;

wherein R³ is phenyl, thiophenyl, isoxazoyl, pyridyl, pyrimidinyl, indolyl, oxazoyl, thiazoyl, or benzothiophenyl wherein the phenyl, thiophenyl, isoxazoly, pyridyl, pyrimidinyl indolyl, oxazoyl, thiazoyl or benzothiophenyl is optionally substituted with one or more halogen, straight chained or branched Ci-C? alkyl or alkoxy, or straight chained or branched C1-C7 perfluoroalkyl or perfluoroalkoxyl;

wherein is a single or double bond;

wherein R⁵ independently is H, =0, or straight chained or branched C₁-C₄ alkyl provided that is a single bond, and wherein R⁵ is H provided that is a double bond;

wherein each A¹, A² and A³ independently is CR⁷ or N provided that if one A is N then the remaining A are CR⁷;

wherein each R⁶ and R⁷ independently is H or halogen; wherein D is CH or N;

wherein each Z¹ and Z² is independently CH₂, O, S, NH or a bond, provided that an O, S or NH is separated from another O, S or NH by at least two carbon atoms;

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

Claim 2. The compound of claim 1 , wherein R¹ is -(C Ha)CR^CH₂) or propargyl.

Claim 3. The compound of claim 1, wherein R¹ is H or straight chained or branched C1-C₄ alkyl optionally substituted with one or more halogen or CN.

Claim 4. The compound of claim 1, wherein R is phenyl optionally substituted with one or more halogen, straight chained or branched C₁-C₄ alkyl or alkoxy, or straight chained or branched C₁-C₄ perfluoroalkyl or perfluoroalkoxy.

Claim 5. The compound of claim 1 , wherein R³ is pyridyl or pyrimidinyl, wherein the pyridyl and pyrimidinyl are optionally substituted with one or more halogen, straight chained or branched C₁-C₄ alkyl or alkoxy, or straight chained or branched C₁-C4 perfluoroalkyl or perfluoroalkoxy.

Claim 6. The compound of claim 1 , wherein R³ is thiophenyl, isoxazoyl, oxazoyl or thiazoyl, wherein the thiophenyl, isoxazoyl, oxazoyl or thiazoyl are optionally substituted with one or more halogen, straight chained or branched C₁-C₄ alkyl or alkoxy, or straight chained or branched C₁-C₄ perfluoroalkyl or perfluoroalkoxy.

Claim 7. The compound of claim 1 , wherein is a single bond.

Claim 8. The compound of claim 1 , wherein is a double bond.

Claim 9. The compound of claim 1 , wherein each A¹, A² and A³ is CR⁶; and wherein

R⁶ is H. Claim 10. The compound of claim 1 , wherein one of A¹, A² and A³ is N.

Claim 1 1. The compound of claim 1 , wherein D is CH.

Claim 12. The compound of claim I , wherein D is N.

Claim 13. The compound of claim 7 or 8, wherein R⁴ is one H group and R⁵ is H.

Claim 14. The compound of claim 7, wherein R⁴ is one H group and R⁵ is =0.

Claim 15. The compound of claim 1, wherein each Z¹ and Z² is a bond; and m is 0.

Claim 16. The compound of claim 1 , wherein Z¹ is a bond; Z² is O; and wherein m is 2.

Claim 17. A compound is selected from the group consisting of 4-(4-chloro-phenyl)-l- { l-[l-(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lh-indol-5-yl}- lh-pyridin-2-one, 4-(4- chloro-phenyl)- 1 -[ 1 -( 1 -methyl-azetidin-3-yl)-2,3-dihydro- 1 h-indol-5-yl]- 1 h-pyridin-2-one, 5-chloro- T- { I -[ 1 -(2-fluoro-allyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl } - Th- [2,4']bipyridinyl-2'-one, 5-chloro- 1 *- [ 1 -(I -isopropyl-azetidin-3-yl)-2,3-dihydro-l h-indol-5- yl]- 1 'h-^ΛIbipyridinyl^'-one, 5-chloro- 1 '-[ 1 -( 1 -ethyl-azetidin-3-yl)-2,3-dihydro- 1 h-indol- 5-yl]- 1 'h-[2,4']bipyridinyl-2'-one, 5-chloro- 1 '-[ 1 -( 1 -methyl-azetidin-3-yl)-2,3-dihydro- 1 h- indol-5-yl]- 1 'h-^^bipyridinyl^'-one, 5-chloro- 1 '-{ 1 -[1 -(2-fluoro-ethyl)-azetidin-3-yl]- 1 h- indol-5-yl}- 1 'h-[2,4']biρyridinyl-2'-one, 5-chloro- 1 '- { 1 -[ 1 -(2-fluoro-ethyl)-azetidin-3-yl]- 2,3-dihydro-l h-indol-5-yl}-rh-[2,4']bipyridinyl-2'-one, 4-benzyloxy-l- { l -[ l-(2-fluoro- ethyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl } - 1 h-pyridin-2-one, 4-benzyloxy- 1 -[I -( 1 - methyl-azetidin-3-yl)-2,3-dihydro- 1 h-indol-5-yl]- 1 h-pyridin-2-one, 1 -( 1 -azetidin-3-yl-2,3- dihydro-l h-indol-5-yl)-4-benzyloxy- 1 h-pyridin-2-one, T-( l -[l -(2-fluoro-ethyl)-azetidin-3- yl]-2,3-dihydro- 1 h-indol-5-yl} -5-trifluoromethyl- 1 'h-[2,4']bipyridiny l-2'-one, T-[ I -( I- methyl-azetidin-3-yl)-2,3-dihydro-l h-indol-5-yl]-5-trifluoromethyl-Th-[2,4']bipyridinyl-2'- one, T-( I -[ I -(2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro- 1 h-indol-5-yl } -6-trifluoromethyl- Th-[3,4']bipyridinyl-2'-one, 4-(5-ethyl-pyrimidin-2-yl)-l-( l -[l-(2-fluoro-ethyl)-azetidin-3- yI]-2,3-dihydro- 1 h-indol-5-yl } - 1 h-pyridin-2-one, T-( I -[I -(2-fl uoro-ethyl)-azetidin-3-y I]- 1 h- indol-5-yl}-6-trifluoromethyl-Th-[3,4']bipyridinyl-2'-one, 6-(4-chloro-phenyI)-3-[l -( l- metliyl-azetidin-3-yl)-lh-indol-5-yl]-3h-pyriraidin-4-one, l-{l-[l-(2-fluoro-ethyl)-azetidin- 3-yl]-2,3-dihydro- 1 h-indol-5-yl } -4-(4-fluoro-phenyl)- 1 h-pyridin-2-one, 5-fl uoro- 1 '- { 1 -[ 1 - (2-fluoro-ethyl)-azetidin-3-yl]-2,3-dihydro-lh-indol-5-yl}-rh-[2,4']bipyridinyl-2'-one, 1'- { 1 -[I -(2-fluoro-ethyl)-azetidin-3-yl]- 1 h-indol-5-yl } -5-trifluoromethyl- 1 'h-[2,4']bipyridinyl- 2'-one, r-[l-(l-methyl-azetidin-3-yl)-lh-indol-5-yl]-5-trifluoromethyl-rh-[2,4']bipyridinyl- 2'-one, 4-(4-chloro-phenyl)- 1 - { 1 -[ 1 -(3-fluoro-propyl)-azetidin-3-yl]-2₎3-dihydro- 1 H-indol- 5-yl j - 1 H-pyridin-2-one; 4-(4-chloro-phenyl)- 1 -{ 1 -[ 1 -((S)-2-flυoro- 1 -methyl-ethyl)-azetidin- 3-yl]-2,3-dihydro-l H-indol-5-yl} -1 H-pyridin-2-one; 4-(4-chloro-ρhenyl)-l-{ l-[l-((R)-2- fluoro-l-methyl-ethyl)-azetidin-3-yl]-2,3-dihydro-lIl-indol-5-yI}-lIl-pyridin-2-one; and A- (4-chloro-phenyl)- 1 -[ 1 -( 1 -cyclopropyl-azetidin-3-yl)-2,3-dihydro- 1 H-indol-5-yl]- 1 H- pyridin-2-one.

Claim 18. A pharmaceutical composition comprising a compound of claim 1 and an acceptable pharmaceutical carrier.

> Claim 19. A method of treating mood disorders in a subject comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.

Claim 20. A method of treating anxiety in a subject comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.

Claim 21. A method of treating obesity in a subject comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.

Claim 22. A method of treating urinary disorders in a subject comprising administering a therapeutically effective amount of a compound of claim 1.

Claim 23. The method of claim 19, wherein the mood disorder is depression.

Claim 24. Use of a compound of claim 1 in the manufacture of a pharmaceutical composition for treating a disorder selected from the group consisting of mood, anxiety and obesity related disorders.