Title of Invention	4- (PHENYL OR PYRIDYL)- IMIDAZOLE DERIVATIVE NEUROPEPTIDE Y Y5 RECEPTOR ANTAGONISTS
Abstract	ABSTRACT "4-(PHENYL OR PYRIDYL)-IMIDAZOLE DERIVATIVE NEUROPEPTIDE Y Y5 RECEPTOR ANTAGONISTS" lN/PCT/2002/00909/CHE The present invention relates to a compound of formula I or a pharmaceutically acceptable salts, solvate or N -oxide thereof, wherein the substituents are as described m the description.

Full Text

The present invention relates to selective 4-(phenyl or pyridyl)-imidazole derivative neuropeptide Y Y5 receptor antagonists useful in the treatment of eating disorders, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. Neuropeptide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that activation of neuropeptide Y Y5 receptors results in hyperphagia and decreased thermogenesis. Therefore compounds that antagonize neuropeptide Y at the Y5 receptor subtype represent an approach to the treatment of eating disorders such as obesity and hyperphagia, and diabetes. Substituted imidazoles are used in various pharmaceutical and non-pharmaceutical applications. WO 99/01128 discloses substituted diarylimidazoles as NPY Y5 receptor antagonists. WO 99/48873 discloses non-peptidergic antagonists of NPY receptors, which are Alkyl represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. If the number of carbon atoms is not specified, e.g., if the term lower alkyl is used, chain lengths of 1 to 6 carbons are intended. AryMlncluding the aryl portion of arytalkyl and heteroarytalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more (e.g., 1 Halogano represents fluoro, chtoro, bromo or todo. As defined above, heterocycloaikvl represents 4 to 6 membered rings comprising 3 to 5 carbon ring members and 1 to 3 ring members selected from the group consisting of -NR12-, -O- and -S-. Where a heterocydoalkyl ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent suffur atoms, or three consecutive heteroatoms. Examples of heterocycloalkyl rings are piperazinyl, tetrahydrofuranyl, pyrrotidinyl, piperidinyt, morpholinyl and thiomorpholinyl. Heteroaryl means a 5 or 6-membered aromatic ring comprising 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S- and -N=, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of heteroaryl groups are pyridyl, isoxazotyt, oxadiazolyl, furanyt, pyrrolyi, thienyl, imidazolyl, pyrazolyl, tetrazotyl, thiazolyt, thiadiazolyl, pyrazinyl, pyrimidinyt, pyridaanyl and triazolyt. The heteroaryl rings are attached to the rest of the molecule through a ring carbon atom. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. The substituted heteroaryl groups specifically identified in the definition of R, e.g. R^pyridyl and R3-thiazolyt, can be substituted at any available ring carbon atom. W-oxides can form on a tertiary nitrogen present in an R substftuent (e.g., R Is 3-pyridyl W-oxide) or when X is = N-, in the Y substituted ring. Compounds of formula I can exist in unsptvated and sofvated forms, including hydrated forms. In general, the sotvated forms, with pharmaceuticany acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention. A. compound of formula I may form pharmaceuticalty acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesuffonic and other mineral and carboxylic acids well known to those skilled in the art The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from thBir respective sari forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Compounds of formula I may be produced by processes known to those skilled in the art as shown in the following reaction schemes and in the preparations and examples below. The following reaction schemes are provided by way of illustrating how compounds of the invention may be prepared. It will be appreciatated that the parts of the schemes that refer to compounds outside of the scope of the invention are provided by way of showing analogous procedures by which compounds of the invention may be made. Scheme 1: Compounds of formula 1a or 1b wherein X is - Compounds of formula id can be converted to compounds of formula I wherein R is N-substrtuted-4-piperidyI by reducing the compound of formula 1d, for example by hydrogenation. Starting materials of formula II are prepared according to the acetal and the product is reacted with ammonium acetate to form an imidazole substituted at the 2-position by N-protected 4-piperidinyl. A (2-tnmethylsilyl)ethoxyoKymethy! group is placed on the imidazole nitrogen and the resultant product is brominated to give a mixture of regioisomeric 4- and 5-bromoimidazotes of formula XII. The pyridyl amidine shown in Scheme 1 is prepared by treating 3-cyanopyridlne with an ammonia equivalent such as LHMDS or methytchloroaluminum amide. Substituted amidines used in the method of Scheme 1 are known or can be prepared by known procedures. The compounds of formula I exhibit selective neuropeptide Y Y5 antagonizing activity, which has been correlated with pharmaceutical activity for treating eating disorders, such as obesity and hyperphagia, and diabetes. The compounds of formula I display pharmacological activity in test procedures designated to indicate neuropeptide Y Y5 receptor antagonist activity. The compounds are non-toxic at pharmaceutically therapeutic doses. Following are descriptions of the test procedures. cAMP Assay CHO cells expressing NPY Y5 receptors were maintained in Ham's F-12 media (Gfocc-BRL) supplemented with 10% FCS (ICN), 1% penicillin-streptomycin, 1 % non-essential amino acids and 200 //g/ml Geneticin (GibcoBRL #11811-031) under a humidified 5% C02 atmosphere. Two days prior to assay, cells were released from T-175 tissue culture flasks using cell dissociation solution (1X; non-enzymatic [Sigma #C-5914]) and seeded into 96-well, flat-bottom tissue culture plates at a density of 15,000 to 20,000 cells per well. After approximately 48 hours, the cell monolayers were rinsed with Hank's balanced salt solution (HBSS) then preincubated with approximately 150 /;l/well of assay buffer (HBSS supplemented with 4 mM MgCI2,10 mM HEPES, 0.2% BSA [HH]) containing 1 mM 3-isobutyl-1-methylxanthine ([IBMX] Sigma #I-5B79) with or without the antagonist compound of interest at 37°C. After 20 minutes the 1 mM IBMX-HH assay buffer (± antagonist compound) was removed and replaced with assay buffer containing 1.5 pM forskolin (Sigma #F-6686} and various concentrations of NPY in the presence or absence of one concentration of the antagonist compound of interest. At the end of 10 minutes, the media were removed and the cell monolayers treated with 75 (A ethanol. The tissue culture plates were agitated on a platform shaker for 15 minutes, after which the plates were transferred to a warm water bath in order to evaporate the ethanol. Upon bringing ail wells to dryness, the cell residues were resolubilized with 250 ^IFlashPiate assay buffer. The amount of cAMP m each we!) was quantified using the [125l]-cAMP FiashPlate kit (NEN #SMP-001) and according to the protocol provided by the manufacturer. Data were expressed as either pmo! cAMP/ml or as percent of control. All data points were determined in triplicate and ECso's (nM) were calculated using a nonlinear (sigmoidal) regression equation (GraphPad Prism™). The KB of the antagonist compound was estimated using the following formula: KB = [B] / (1 . flAV [A]}) where [A] is the ECM of the agonist (NPY) in the absence of antagonist, [A1] is the ECso of the agonist (NPY) in the presence of antagonist, and [B] is the concentration of the antagonist NPY Receptor Binding Assay Human NPY Y5 receptors were expressed in CHO cells. Binding assays were performed in 5D mM HEPES, pH 7.2, 2.5 mM CaCl2,1 mM MgCi2 and 0.1% BSA containing 5-10 j/g of membrane protein and 0.1 125 nM l-peptide YY in a total volume of 200 (A. Non-specific binding was determined in the presence of 1 uM NPY. The reaction mixtures were incubated for 90 minutes at room temperature, then filtered through MilUpore MAFC glass fiber fitter plates which had been pre-soaked in 0.5% polyethyleneimine. The filters were washed with phosphate-buffered saline, and radioactivity was measured in a Packard TopCount scintillation counter. For the compounds of this invention, a range of neuropeptide Y5 receptor binding activity from about 0.5 nM to about 1000 nM was observed. Compounds of this invention preferably have a binding activity in the range of about 0.5 nM to 500 nM, more preferably about 0.5 to 100 nM, and most preferably about 0.5 to 10 nM. Neuropeptide Y Y5 receptor binding activity results for illustrative compounds are shown below. Examples marked with as astersk (*) represent compounds of the invention. The reamining examples are not within the scope of the invention and are provided by way of illustrating analogous compounds to those of the present invention. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceuticatiy acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutical^ acceptable carriers and methods ot manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifisrs for oral solutions, suspensions and emulsions. Liquid form preparations may also Include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermal^. The transdermal compositions can take the form Of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutical^ acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day. In two to four divided doses. The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art In the preparations and examples, the following abbreviations are used: room temperature (R.T.), phenyl (Ph), acetyl (Ac), ether (B2O), ethyi acetate (EtOAc), dlmethyWormarnide (DMF), tetrabutyt ammonium fluoride (TBAF), tetrahydrofuran fTHF), ethanol (EtOH), (rthium aluminum hydride (LAH), 4-(dimethylamino)pyridine (DMAP), preparative thin layer chromatography (PTLC), 1,1'-bis{diphenylphosphino)ferrocene (dppf), lithium hexamethyldisilazide (LHMDS) and 1-(3-dimethyl(aminopropyl)-3- mixture was allowed to cool to R.T., then poured into aqueous sard NaHC03 solution (120 ml) and extracted with EtOAc (2x100 ml). The organic layer was washed with water (60 ml) and sat'd NaCl (60 ml), then dried (MgSC>4), filtered and concentrated. Purification of the residue by column chromatography (CH2CI2, then gradient of increasing CH3OH concentration to 5:95 CHsOH/CHaCk) gave a white solid (3.B3 g, 87%). 1H NMR (400 MHz, CDCb): 68.09 (bs, 1H). 8.01 (m. 1H), 7.90 (bs, 1H), 7.57 (m, 2H). 7.49 {bs, 1H). MS m/e 213 (M+H)+. To a stirred, ice-cold solution of the product of Step 1 (0.70 9,3.3 mmol) in THF (13 ml) under N2 was added 95% NaH (0.10 g, 4.3 mmol). After 20 min., {2-trimethylsilyl)ethoxymethyt chloride (0.70 ml, 4.0 mmol) was added dropwise over 5 min. The reaction was warmed to R.T- After 2 h, EtaO was added, and the whole washed with water, dried {Mg;S04), filtered and concentrated under vacuum. Purification by flash chromatography (20:80, then 40:60 EtOAc/hexanes) yielded the product (0.69 g, 61%). 1HNMR(400MHz,CDCI3); 68.11 (bs, 1H), 8.03(m, 1H), 7.74 (d, 1H, J*1.3 Hz), 7.56 (m, 2H), 7.47 (d, 1H, J=1.3 Hz), 5.36 (s, 2H), 3.60 (t, 2H, JsB.2 Hz), 1.00 (t, 2H, J=6.2 Hz), 0.07 (S, 9H). HRMS: Calcd forCi6H2iN2 OF3Si (M+H)+: 343.1454. Found: 343.1452. Step 3: A 1.6N solution of n-BuLi in hexanes (1.4 ml, 2.3 mmol) was added dropwise to a stirred -78°C solution of the product of Step 2 (0.52 9, t .5 mmol) in THF (15 ml) under N2. Immediately after the addition was complete, a solution of iodine (0.58 g, 2.3 mmol) in THF {4.5 ml) was added dropwise over 10 min. After warming to R.T. over 1 h, the reaction was diluted with CH2G2 and water, The organic layer was washed with sat'd aqueous Na2S23 and water, then dried (MgSCU), filtered and concentrated under vacuum to give the title compound (0.71 g) which was used without further purification. 1HNMR (400 MHz, CDCI3): 8 8.07(bs, 1H), 7.99 (m, 1H), 7.56 (m, 3H), 5.34 (s, 2H), 3.65 (t, 2H, J=8.2 HZ), 1.02 (t, 2H, J=8.2 Hz), 0.07 (s, 9H). MSm/e469(M+H)* l Isonipecotfc acid (5.116 g, 39.63 mmol) and potassium carbonate (12.94 g, 93.63 mmol) were dissolved in water (52 ml). The solution was cooled in an ice-water bath and benzyl chloroformate (7.3 ml, 51 mmol) was added dropwise. The mixture was brought to R.T. and stirred for 16 h. The reaction was extracted with EtOAc (3x30 ml). The aqueous layer was acidified to pH 1 -2 with cone. HC1 (15 ml) and then extracted with CHjCb (3x60 ml). The combined organic layer was dried (Na2SO«) and concentrated to give the product (10.306 g, 99%). 'H-NMR (400 MHz, CDCI3) 6 7.32 (5H, m), 5.11 (2H, s), 4.09 (2H, m), 2.93 (2H, m), 2.50 (1H, m). 1.90 (2H, m), 1.67 (2H, m). A solution of the product of Step 2 (5.09 g, 14.5 mmol) and ammonium acetate (32.0 g, 415 mmol) in glacial acetic acid (25 ml) was reftuxed for 5 h. The volatiles were evaporated in vacuo and the residue was partitioned between CHsCl2{2x100 ml) and aqueous NH A mixture of the product of Step 3 (1.844 g, 6.471 mmol) and 60% sodium hydride dispersion in mineral oil (0.355 g, 8.875 mmol) in dry DMF {20 ml) was stirred for 1 h. (2-Trimethylsilyl)ethoxymethyl chloride (1.396 g, 7.643 mmol) was added and the mixture was stirred for 3 days. DMF was evaporated in vacuo and the residue was partitioned between EtOAc (100 ml) and water (3x100 ml). The organic layer was dried (MgSO*), conoentrated, and purified by a flash column (1:99 MeOH/CH^fe, then 2:98 MeOH/CH2Cl2) yielded the product (2.420 g, 90%). To an ice-cold solution of the product of Step 4 (1.601 g, 3.B58 mmol) in DMF (15 ml) was added N-bromosuccinimide (0.383 g, 2.15 mmol). After 0.5 h another portion of N-bromosuccinimide (0.313 g, 1.76 mmol) was added. The solution was wanned to R.T. and stirred for 3 h. DMF was evaporated in vacuo and the residue was partitioned between EtOAc (200 ml) and 0.5N NaOH (80 ml). The organic layer was washed with water (100 ml) and dried over MgSO,. Evaporation followed by flash chromatography (O^Cl,, then gradient of increasing MeOH concentration to 1:99 MeOH/CHjClj) gave the product as a mixture of 4- and 5-bromo regioisomers. Major, more polar isomer (1.042 g, 54%), MS(ES)m/e 496 (M+H)*. Minor regioteomer (0.339 g, 18%), MS(ES)mfe496 (M+H)*. The following examples marked with an astersk (*), i.e. 17, 17A, 18, 18A, 19, 20, 20A, 20B, 20C, 21, 21A, 21B, 21C, 22, 22A, 22B; illustrate compounds of the invention. The remaining examples are not within the scope of the invention and are provided by way of illustrating analogous compounds to those of the present invention, and analogous methods by which compounds of the invention may be formed. To a stirred solution of 3-nitrobenzamidine (5,4 g, 33 mmol) in DMF (80 ml) was added Na^Oa (2.8 g, 26 mmol) followed by Preparation 1 (3.4 g, 13 mmol), and the mixture was heated at BO. °C for 5 h. The reaction mixture was diluted with EtOAc and washed several times with H2O. The organic layer was dried (MgS04), filtered, and concentrated. Rash chromatography of the residue (1:99 CH3OH/ CH^fe) afforded the product (3.73 g, 86%). 1H NMR (400 MHz, CDCb) 8 B.74 (1H, bs), 8.41 (1H, d, J=7.7 Hz), 8.28 (1H, d. J=8.2 Hz), 8.14 (s, TH), 8.07 (m, 1H), 7.70 (1H, t, J=7.9 HZ), 7.59 (m, 3H). HRMS (FAB): Catcd. forCeHmNgOzFa (M+H)4: 334.0803. Found: 334.0B15. Using appropriate starting materials and essentially the same Using the procedure of Preparation 2, Step 2, reaction of the product of Example 1B (0.98 g, 2.B mmol) with NaH and (2-trimethylsityl)-ethoxymethyl chloride afforded the product (1.1 g, 85%). was added piperidine (10 yl, 0.13 mmol). The reaction was stirred at B.T. for 17 h, then more EDCI (17 mg, 0.090 mmol) and DMAP (7.0 mg, 0-055 mmol) were added. The reaction was stirred for an additional 48 h, washed with 1 N NaOH, extracted with CH2O2. dried (MgSCXj), filtered and concentrated under vacuum. Purification via PTLC (5:95 CH3OH/ CH2CI2) yielded the product as a solid (41 mg, 70%). 1H NMR (400 MHz, CDCI3): 6 8.16 (m, 1H), 8.07 (m, 1H), 7.95 (dd, 1H, J=1.6, 7.5 Hz). 7.90 (m, 1H), 7.62-7.51 (m, 5H), 5.35 (s, 2H), 3.78 (br s, 2H), 3.68 (t, 2H, J=B.2 Hz), 3.43 (br s, 2H), 1.59-1.74 (m, 6H), 1.01 (t, 2H, J=B.2 Hz), 0.06 (s, 9H). HRMS (FAB): Calc'd for C2eH34N302F3Si (M+H)+ 530.2451. Found: 530.2440. gtep 4: A solution of the product of Step 3 (41 mg, 0.080 mmol) in CH3OH (3.0 ml) and 6 N HCI (3.0 ml) was refluxed for 3 h. After cooling to R.T., the reaction was diluted with CH2C12, washed with 1 N NaOH, dried over K2CO3, filtered and concentrated under vacuum to give the crude product (25 mg, 79%), which was purified by PTLC (1:99 CH3OH/ CH2Cl2). 1H NMR (400 MHz, CDCb): 6 8.14 (bs, 1H), 8.01 (m, 2H), 7.85 (m, 1H), 7.54 (m, 2H). 7.49 (s, 1H), 7.36 (t, 1H, J^7.7 Hz), 7.22 (m, 1H), 3.82 (m, 2H), 3.41 (m, 2H), 1.76 (bs, 4H), 1.59 (m, 2H). MS (CI) nVe 400 was added LAH (3.0 mg, 0.08 mmol). The reaction was stirred for 15 h at R.T., then more LAH (6.0 mg, 0.16 mmol) was added. The reaction was stirred for an additional 5 h, then 1 N NaOH was added. The mixture was extracted with CH2CI2, dried over K2CO3, filtered and concentrated under vacuum. Purification by PTLC (5:95 CH3OH/ CH2CI2) yielded the title compound (10 mg, 53%). 1H NMR (400 MHz, CDCI3): 5 7.96-B.17 (m, 2H), 7.81-7.96 (m, 2H), 7.51 (m, 2H), 7.30-7.47 (m, 3H), 3.54 (s, 2H), 2.46 (bs, 4H), 1.63 (quintet, 4H, J=5.2 Hz), 1.49 (m, 2H). HRMS (FAB): Calc'd for C22H2oN3F3 (M+H)*: 386.1844. Found: 386.1636. A mixture of Preparation 2 (661 mg, 1.41 mmol), 3-formyl-benzeneboronic acid (433 mg, 2.BS mmol), Pd(dppf)C!2 (120 mg, 0.147 mmof), and K3PO4 (660 mg, 3.08 mmol) in 1,2-dimethoxyethane (11 ml) was purged with N2, and heated at 95 "C overnight in a sealed vessel. The reaction mixture was allowed to cool, diluted with CHgCfc {60 ml), and filtered. The filtrate was washed with water (30 ml), dried (MgSO^, filtered, and evaporated. Purification of the residue by flash chromatography (CH2CI2, then 1:99 CH3OH/CH2CI2) afforded the product (492 mg, 78%). 1H NMR {400 MHz, CDCI3); 6 10.09 (s, 1H), B.39 (s, 1H), 8.2-7.9 (m, 4H), 7.67 (m, 1H), 7.52 (m, 3H), 5.33 (s, 2H), 3.66 (m, 2H), 0.98 (m, 2H),-0.02 (s,9H). A mixture of the product of Step 1 (30 mg, 0.067 mmol), pyrrolidine (15 uJ, 0.18 mmol), and sodium triacetoxyborohydride (22 mg, 0.10 mmol) in 1,2-dichloroethane (2 ml) was strirred overnight. The mixture was partitioned between CH2CI2 (35 ml) and 1N NaOH (10 ml). The organic layer was dried (MgSCU), filtered and evaporated. Purification of the residue by PTLC (5:95 CH30H/CH2CI2) gave the product (31 mg, 93%). 1H NMR {400 MHz, CDCI3): 6 8.09 (s, 1H), 8.02 (m, 1H), 7.73 (m, 1H), 7.67 (m, 1H), 7.53-7.37 (m, 5H), 5.31 (s, 2H), 3.67 (s, 2H), 3.56 (m, 2H), 2.54 (bm, 4H), 1.78 {bm, 4H), 0.92 (m, 2H), -0.04 (s, 9H). 11.1 mmol) in THF (95 ml) was added NaH (0.32 g, 13 mmol). After 10 min., (2-trimethylsilyl)ethoxymethyl chloride (2.2 ml, 12 mmol) was added, and the reaction mixture was stirred at RT for 6 h. The reaction mixture was diluted with EtgO, washed with H20 and sat'd NaCl. dried (MgS04). filtered and evaporated. Rash chromatography (4:1 hexanes/EtOAc) afforded the product (4.0B g, 79%). 'H NMR (400 MHz, CDCI3) 6 9.86 (1H, t, J=2.0 Hz), B.35 (1H, m), 8.33 (1H, m), B.14 (1H, m), 8.08 (1H, m), . 7.72 (1H, t, J=8.0 HZ), 7.56 (3H, m), 5.38 (2H, S), 3.76 (2H, t, J-8.6 Hz), (M+H)+: 540.1963 Found: 540.1937. Step 4: A mixture of the product of Step 3 (114 mg, 0.21 mmot), 5 N HCI (5 ml), and CH3OH (5 ml) was refluxed for 3 h. The reaction mixture was allowed to cool, sat'd NaHC03 was cautiously added, and the whole was extracted with CH2CI2. The organic layer was dried (MgS04), filtered, and evaporated. The residue was subjected to PTLC to afford the product (84 mg, 95%). 'H NMR (400 MHz, CDCI3) 8 6.07 (s, 1H), 7.96 (1H, d, J-7.3 Hz), 7.80 (1H, d, J=7.7 Hz), 7.76 (1H, m), 7.65-7.46 (3H, m), 7.38 (1H, t. J*7.9 Hz), 7.28 (1H, m), 3.15 (2H, m), 1.89 (2H, m), 1.03 (3H, t, J=7.4 Hz). HRMS (FAB): Gated, for Ci9H1BN302SF3 (M+H)+: 410.1150 Found: 410.1160. Using appropriate starting materials and essentially the same water (2 x 40 ml). The organic layer was dried (MgSO*), filtered, and concentrated. Purification of the residue by column chromatography (hexanes, then gradient of increasing concentration to 1:5 EtOAc/ hexanes) afforded the product (723 mg, 97%). 'H NMR {400 MHz, CDCI3) 6 8.08 Step 5: A solution of the product of Step 4 (51 mg, 0.095 mmol) in CH3OH (7 ml) and 5N HCt (5 ml) was heated to 90 "C for 4 h. After the mixture was cooled, it was partitioned between CH2Cl2 (50 ml) and aqueous NH,OH {20 ml). The organic layer was dried (MgSOJ, filtered and concentrated. Purification of the residue by PTLC (1:66 CR,OH/ CHpy gave the product (38 mg, 98%). 'H NMR (400 MHz, CDCy 6 8.02 (s, 1H), 7.91 (m, 2H), 7.72 (m, 1H), 7.32-7.47 (m, 5H), 3.33 (s, 3H). 3.05 (q, 2H. J=7A Hz), 1.35 (t, 3H, ^7.4 Hz). MS (ES) m/e 410 (M+H)*. By using appropriate starting materials and essentially the same A mixture of the product of Step 1 (22.6 ml, 20.6 mmol) and 5-bromopyridine-3-carbonltrile (1.915 g, 10.46 mmol) in a sealed tube was heated to 95 "C overnight. The mixture was cooled and poured Into a « slurry of silica gel (40 g) in CHCI3 (100 ml). This slurry was stirred for 1 h and the silica was filtered off. The filter cake was washed with CH3OH (200 ml). Evaporation erf the nitrate gave the product (2.65 g, 65%). 1H NMR (CD3OD, 400 MHz): 5 9.00 (d, 1H, J=2.4 Hz), 8.91 (d, 1H, J=Z Hz), 8,45 ft 1H, J=ZA Hz). MS (CI) m/e 200 (M+H)+, A mixture of the product of Step 2 (1.303 g, 6.6 mmol), Preparation 1 (1.199 g, 4.51 mmol), and Na2C03 (1-15 g, 10.9 rnmof) in acetone (20 ml) and DMF (20 ml) was refluxed for 5 h. The solvents were removed under vacuum and the residue was partitioned between water (50 ml) and CH2CI2 (100 ml). The organic layer was washed with water (50 ml), dried (MgSO*), filtered, and evaporated to dryness. The crude product was purified by column chromatography (gradient 0.5:99.5 CH3OH/CH2Ct2 to 1.5:98.5 CH3OH/CH2Cf2) to give a light-yellow solid (0.705 g, 42%). 1H NMR (CD3OD, 400 MHz): 6 9.10 (d, 1H, J=1.6 Hz), 8.66 (d, 1H, J*2 Hz), 8.57 (t, 1H, J=Z Hz), 8.14 (S, 1H), 8.06 (d, 1H, J=6.8 Hz), 7.75 (s, 1H), 7.57 (m,2H). MS(CI)nVe368(M+H)+. Using the procedure of Example 5, Step 1, reaction of the product of Step 3 (311 mg, 0.845 mmol) with NaH (60% disp., 43 rrtg, 1.1 mmol) and (2-trimethy(silyl)ethoxymethyl chloride (0.21 ml, 1.07 mmol) afforded the product (292 mg, 69%). 1H NMR (CDCI3.400 MHz): S 9.05 (d, 1H, J=2 Hz), B.74 (d, 1H, J=2 Hz), 8.42 (t, 1H, J=2 Hz). 8.08 (s, 1H), 8.01 (m, 1H), 7.51 (m, 3H), 5.31 (s, 2H), 3.68 (t, 2H, J=B Hz), 0.99 (t, 2H, J=8 Hz), 0.02 (s, 9H). A solution of the product of Step 5 (127.4 mg, 0.213 mmol), sodium acetate (43 mg, 0.52 mmol), and H2NOHHCI (29 mg, 0.42 mmol) in CH3OH (3 ml) was stirred for 40 min. The solution was partitioned between 0.1 M aqueous NaOH (30 ml) and CH2O2 (50 ml). The organic layer was dried (MgSt^), filtered and evaporated to dryness. PTLC (2:98 CH3OH/CH2CI2) gave a solid (82 mg, 89%). 1H NMR (CDCI3, 400 MHz): 6 8.43 (d, 1H, Jb2 Hz), 8.16 (d, 1H, J=2.8 Hz), B.09 (s, 1H), B.00 (m, 1H), 7.49 (m, 4H), 5.32 (S, 2H), 3.87 (bs, 2H), 3.62 (t, 2H, J=B Hz), 0.95 (t, 2H, J=B Hz), 0.00 (S, 9H). Step 2: THF (1.8 ml) was added to LAH (2.5 mg, 0.066 mmol) under N2 at 0 °C. The product of Example 1B (20 mg, 0.058 mmol) was dissolved in THF (1.4 ml) and added dropwise over 5 min. to the LAH/THF slurry. After 0.5 h, more LAH (3.8 mg, 0.10 mmol) was added and the reaction was stirred at 0 °C for 1.25 h. 10% NaOH (0.1 ml) and EtOAc (2.0 ml) ■ was added to the reaction, followed by MgS04. The mixture was stirred, filtered and concentrated under vacuum to give the product (16 mg, B8%) as a white solid. 1H NMR (CD3OD, 400 MHz): 6 B.15 (bs, 1H), 8.05 (m, 1H), 7.96 (s, 1H), 7.86 (m, 1H), 7.72-7.39 (m, 5H), 4.70 (s, 2H). HRMS (FAB):CalcdtorCi7Hi3N20F3 (M+H)+: 319.1058. Found: 319.1059. SteDl: A solution of the product of Example 5, Step 2 (68 mg, 0.16 mmol), acetic anhydride (26 ui, 0.28 mmot) and pyridine (0.13 ml, 1.55 mmol) in CH2CI2 (4 ml) was stirred for 3 days. The reaction mixture was diluted with CH2CI2 (40 ml) and washed with aq. NH4CI (2 x 20 ml). The organic layer was dried (MgSCU), filtered and evaporated. Purification of the residue by PTLC (3:97 CH3OH/CH2CI2) gave the product (62 mg,84%). 1H NMR (400 MHz, CDCI3): S 8.09 (s, 1H), 8.00 (m, 2H), 7.85 (s, 1H), 7.77 (m, 1H), 7.49 (m, 3H),7.40 (m, 1H), 5.33 (s, 2H>, 3.61 (t, 2H, J=8 HZ), 2.65 (bs, 1H), 2.11 (s, 3H), 0.94 (t, 2H, J=B Hz), 0.01 (s, 9H). Step 2: The product of Step 1 (62 mg, 0.13 mmot) and 1 .OM TBAF in THF (3.6 ml, 3.0 mmol) was stirred at R.T. until no starting material remained. The reaction mixture was diluted with CH2CI2 and washed with water several times, dried (K2C03), filtered and evaporated. PTLC (2:98 CH3OH/CH2CI2) gave the product (37 mg, 7B%). ""H NMR (400 MHz, CDCI3): 6 B.01 (S, 1H). 7.98 (S, 1H), 7.89 (s, 1H), 7.85 (d, 1H, J=7.2 Hz), 7.55 (d, 1H, ^8.0 Hz), 7.42 (m, 2H), 7.32 (s, 1H), 7.29 (d, 1H, ^=8.4 Hz), 7.19 (t, 1H, J=7.6 Hz), 2.10 (s, 3H). MS (FAB) m/e 364 (M+H)+. Using appropriate starting materials and essentially the same A mixture of the product of Example 4, Step 1 (759 mg, 1.70 mmol), (erf-butyl 1-piperazine carboxylate (356 mg, 1.91 mmol), and sodium triacetoxyborohydride (565 mg, 2.67 mmol) in dichloroethane (9 ml) was stirred at R.T. overnight, The mixture was diluted with CH2Cl2 (100 ml) and washed with 1N aqueous NaOH (20 ml). The organic layer was dried (MgSO*), filtered, and evaporated. Purification of the residue by flash chromatography (gradient; CH^to 1.5:96.5 CH3OH/ CH2Cl2) afforded the product (902 mg, 86%). nH NMR (400 MHz, CDCI3) 5 8.09 (1H, s), B.OO (1H, m), 7.76 (1H, bs), 7.S9 (1H, m), 7.23-7.48 (5H, m), 5.29 (2H, s), 3.58 (4H, m), 3.42 (4H, bm), 2.40 (4H, bm), 1.43 (9H, s), 0.92 (2H, t, J=B Hz), -0.02 (9H, s). MS m/e 617 (M+H)*. A solution of the product of Step 1 (701 mg, 1.14 mmol) in CH3OH (5 ml) and 5N aqueous HCI (10 ml) was refluxed tar 8 h. The reaction i mixture was allowed to cool, then partitioned between CHgCt2 (60 ml) and aqueous NH4OH {20 ml). The aqueous layer was extracted with G-feCfe (40 ml) and the combined organic layers were driBd (MgSOt), filtered and evaporated. Purification of the residue by flash chromatography (gradient; 5:95 to 8:92 2.0 M NH3 in CH9OH/ CH2CI2) afforded the product (451 mg, 100%). 'H NMR (400 MHz, CD3OD) 5 8.14 (1H, s), 8.04 (1H, d, J=7.6 HZ), 7.94 (1H, 8), 7.86 (1H, d, J=7.6 Hz), 7.66 (1H, S), 7.57 1 with 1 N NaOH, extracted with CH2CI2, dried over K2CO3, filtered and concentrated under vacuum. Purification via PTLC (40:60 EtOAc/ hexanes) yielded the product (0.15 g, 84%). MS (CI) ro/e632 (M+H)+. Step 2: To solution of the product of Step 1 (0.15 g, 0.24 mmol) in CH3OH (4.5 ml) under N2 was added HCI (6 N in CH3OH, 4 ml). The reaction was heated to 80 °C in a sealed tube. After stirring for 15 min., the reaction was treated with 1 N NaOH, extracted with CH2CI2, dried over K2CC-3, filtered and concentrated under vacuum to yield the free imidazole (0.092 g, 77%) which was used in the next reaction without further purification. The imidazole (0.092 g, 0.18 mmol) in AcOH (3 ml) and AcjO (90 f/L, 0.90 mmol) was heated to 140 °C. After 2.25 h. the AcOH was evaporated off and water was added, followed by a few drops of EtOAc. The mixture was stirred for a few minutes, then basified with K2CO3, extracted with EtOAc, dried over K2CO3 and concentrated under vacuum. The residue was subjected to PTLC (4:96 2 M NH3 in CH3OH/ CH2CI2) to yield the product (0.059 g, 68%). ^ NMR (400 MHz, CDCI3): S 8.76 (d, for 4 h. The volattles were evaporated and the residue was subjected to a flash column (neutral alumina, hexanes, then gradient of increasing EtOAc concentration to 4:96 EtOAc/hexanes) to give the product (1.440 g, 33%). 1H-NMR (400 MHz, CDCW 8 5-74 (1H, b), 4.02 (2H, m), 3.61 (2H, m),2.42(2H, m), 1.45 (9H, B). A mixture of 20-1-4 {179 mg, 0.319 mmol), 50% aq. KOH (6 ml), and EtOH (6 ml) was heated at 100°C for 3 h. The mixture was concentrated and the residue was partitioned between CH2CI2 (50 ml) and water (20 ml). The aqueous layer was washed with CH2Cb (20 ml). The combined organic layer was dried (NasSC^) and concentrated to give the product (164 mg), which was used without further purification. MS (ES) m/e426(M+H) The following examples were prepared from the corresponding products of Example 20, Step 2 using essentially the same procedures described in Step 1 and Step 2: A solution of 20-2-1 (40 mg, 0.11 mmol), acetic anhydride (12 mg, 0.12 mmol), and triethylamine (24 mg, 0.24 mmol) in CH2CI2 (4 ml) was stirred at R.T, for 16 h. The mixture was diluted with CH2CI2 (40 ml) and washed with 1N NaOH (10 ml). The organic layer was dried (MgSO*), concentrated, and purified by PTLC (2:98 MeOH/CHzCfe) to give the product (30 mg, 69%). MS (ES) m/e 418 (M+H) Step 2: A solution of the product of Step 1 (30 mg, 0.072 mmol) in MeOH (1 ml) and 5N HCI (3 ml) was refiuxed for 4 h. The mixture was partitioned between CH2CI2 (30 ml) and aqueous NHaOH (15 ml). The organic layer was concentrated and the residue was reacted with acetic anhydride {8 mg, 0.08 mmol) in CH2CI2 (5 m!) at R.T. for 16 h. The mixture was diluted with CH2CI2 (30 ml) and washed with 1N NaOH (10 ml). The organic layer was dried (MgS04), concentrated, and purified by PTLC (5:95 MeOH/CH2Cl2) to give the product (14 mg, 66%). 'H-NMR (400 MHz, CDCI3) 6 7.42 (2H, m), 7.29 (1H, m), 7.23 (1H, s), 6.88 (1H, m), 4.66 (1H, m), 3.91 (1H. m), 3.21 (1H, m), 3.09 (1H, m), 2.73 (1H. m), 2.14 (1H,m), 2.11 (3H, s), 2.01 (1H, m), 1.74 (2H,m). MS(ES)m/e2B8 (M+H)+. The following examples were prepared from the corresponding products of Example 20, Step 2 using essentially the same procedures described in Step 1 and Step 2: APPENDIX NPY Ys receptor binding activity For compounds of the invention. We claim: 1 .A compound having the structural formula or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein X is =CH -; Y is 1 to 3 substituents independently selected from the group consisting of H, halogen, trihaloalkyl, C1-C6 alkyl, C1-C6 alkenyl, C3-C7-cycloalkyl, C1-C6 alkyl substituted by C3-C7-cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, -S (C1-C6) alkyl, or -CN; Ris R4 is hydrogen or C1-C6 alkyl; R5 is C1-C6 alkyl, aryl, or heteroaryl; provided R4 and R5 are not both C1-C6 alkyl, and provided that when R4 is hydrogen, R5 is not C1-C6 alkyl; or R4 and R5 together are C3-C6 alkylene and together with the nitrogen to which they are attached form a 4-7 membered ring; or R4 and R5, together with the nitrogen to which they are attached, form a 5, 6 or 7- membered ring, wherein I or 2 ring members are independently selected from the group consisting of-0-, -S- and - NR12-; R7is C1-C6 alkyl, C3-C7 cycloalkyl, benzyl, aryl, or heteroaryl; R8is -C(0)-( C1-C6 alkyl), -C(0)-( C3-C7 cycloalkyl), -C(0)-aryl, -C(O)-heteroaryl, -S02-R7, aryl, heteroaryl, or -CONR4R5; R9 is 1 to 3 substituents independently selected from the group consisting of hydrogen, C1-C6, alkyl, C1-C6 alkoxy, halogeno and -CF3; and R12 is hydrogen, C1-C6 alkyl, -C{0)-( C1-C6 alkyl), -S02-R7, R9-phenyl, -CONR4R5, -C(O)-0-( C1-C6 ) alkyl, -CHO, C3-C7 cycloalkyl,(C3-C7) cycloalkyl (C1-C6) alkyl, benzyl, benzoyl, -C(0)( C3-C7) cycloalkyl, -C(OX C1-C6 ) alkylphenyl, pyridylmethyl, -C(0)pyridyl, -C(0)N(di-(C1-C6)-alkyI) or 4-tetrahydropyranyl; wherein aryl-(including the aryl portion of arylalkyl)- represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring, with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, or -NO2; heteroaryl means a 5 or 6-membered aromatic ring comprising 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S- and -N=, provided that the rings do not include adjacent oxygen and/or sulfur atoms, the heteroaryl rings are attached to the rest of the molecule through a ring carbon atom and all positional isomers are contemplated; alkyl represents a straight or branched, saturated hydrocarbon chain of 1 to 6 carbon atoms. The definition of alkyl applies to alkyl as well as the alkyl portion of alkoxy, trihaloalkyl, alkylamino and dialkylamino. 2. The compound as claimed in claim I selected from the group consisting of compounds of the formula wherein Y is 1-3 substituents selected from the group consisting of H, halogen, frihaloalkyl, or C1-C6 alkyl. i.The compound as claimed in claim I selected from the group consisting of 4. A pharmaceutical composition comprising a compound as claimed in claim 1 in combination with a pharmaceutically acceptable carrier as herein desC1-ibed. 5. A pharmaceutical composition comprising a compound as claimed in claim 3 in combination with a pharmaceutically acceptable carrier as herein desC1-ibed.

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