Title of Invention	PIPERIDINE AND PIPERAZINE DERIVATIVES AS P2X3 ANTAGONISTS
Abstract	Compounds of formula I wherein R1 ,R2bR3, Y, X, A, R6 R7and R8are as described herein, are modulators of P2X3 useful for the treatment of pain and genitourinary, gastrointestinal, and respiratory disorders.

Full Text

This invention pertains to compounds useful for treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X3 antagonists usable for treatment of genitourinary, gastrointestinal, respiratory, and pain-related diseases, conditions and disorders. The urinary bladder is responsible for two important physiological functions: urine storage and urine emptying. This process involves two main steps: (1) the bladder fills progressively until the tension in its walls rises above a threshold level; and (2) a nervous * reflex, called the micturition reflex, occurs that empties the bladder or, if this fails, at least causes a conscious desire to urinate. Although the micturition reflex is an autonomic spinal cord reflex, it can also be inhibited or mediated by centers in the cerebral cortex or brain. Purines, acting via extracellular purinoreceptors, have been implicated as having a varied of physiological and pathological roles. (See, Burnstock, Drags Dev. Res. (1993) 28:195-206). ATP, and to a lesser extent, adenosine, can stimulate sensory nerve endings resulting in intense pain and a pronounced increase in sensory nerve discharge. ATP receptors have been classified into two major families, the P2Y- and P2X-purinoreceptors, on the basis oi molecular structure, transudations mechanisms, and pharmacological characterization. The P2Y-purinoreceptors are G-protein coupled receptors, while the P2X-purinoreceptors arc a family of ATP-gated cation channels. Purinergic receptors, in particular, P2X receptors. are known to form homomultimers or heteromultimers. To date, cDNAs for several P2X receptor subtypes have been cloned, including: six chromomeric receptors, P2Xi; P2X2: P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors P2X2/3, P2X4/6, P2Xi/. (Sec, e.g., Chen et al., Nature (1995) 377:428-31; Lewis et al.. Nature (1995) 377:432-35: and Burnstock, Neuropharmacol (1997) 36:1127-39). The structure and chromosomal mapping of mouse genomic P2X3 receptor subunit has also been described (Sullivan ei al, Gene (1997) 195:101-11). In vitro, co-expression of P2X2 and P2X3 receptor subunits is necessary to produce ATP-gated currents with the properties seen in some sensory neurons (Lewis et al., supra). P2X receptor subunits are found on afferents in rodent and human bladder urolhcliurn. Data exists suggesting that ATP may be released from epithelial/endothelial cells of the urinary bladder or other hollow organs as a result of distention (Burnstock, J. Anatomy (1999) 194:335-42; and Ferguson et al., J. Physiol. (1997) 505:503-11). ATP released this manner may serve a role in conveying information to sensory neurons located in subepithelial components, e.g., suburothelial lamina propria (Namasivayam et al., BJU Intl. (1999) 84:854-60). The P2X receptors have been studied in a number of neurons, including sensory, sympathetic, parasympathetic, mesenteric, and central neunMis {'/hooey'.\ et al., Br. J. Pharmacol. (1998) 125:771-81). These studies indicate that purinergic receptors play a role in afferent neurotransmission from the bladder, and that modulators of P2X receptors are potentially useful in the treatment of bladder disorders and other genitourinary diseases or conditions. Recent evidence also suggests a role of endogenous ATP and purinergic receptors in nociceptive responses in mice (Tsuda et al., Br. J. Pharmacol. (1999) 128:1497-504). ATP-induced activation of P2X receptors on dorsal root ganglion nerve terminals in the spinal cord has been shown to stimulate release of glutamate, a key neurotransmitter involved in nociceptive signaling (Gu and MacDermott, Nature (1997) 389:749-53). P2X3 receptors have been identified on nociceptive neurons in the tooth pulp (Cook et al., Nature (1997) 387:505-08). ATP released from damaged cells may thus lead to pain by activating P2X:, and/or P2X2/3 containing receptors on nociceptive sensory nerve endings. This is consistent with the induction of pain by intradermally applied ATP in the human blister-base model (Bleehen, Br J Pharmacol (1978) 62:573-77). P2X antagonists have been shown to be analgesic in animal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol (1994) 350:618-25). This evidence suggests that P2X2 and P2X3 are involved in nociception, and that modulators of P2X receptors are potentially useful as analgesics. Other researchers have shown that P2X3 receptors are expressed in human colon, and are expressed at higher levels in inflamed colon than in normal colon (Yiangou et al, Neuro-gastroenterol Mot (2001) 13:365-69). Other researchers have implicated the P2X3 receptor in detection of distension or intraluminal pressure in the intestine, and initiation of reflex contractions (Bian et HIM, J Physiol (2003) 551.1:309-22), and have linked this to colitis (Wynn et al., Am J Physiol Gastrointestinal Liver Physiol (2004) 287:G647-57). Ingo Bonus et al. {Am J Respir Cell Mol Biol (2000) 23:52-61) found that P2X3 receptors are expressed in pulmonary neuroepithelial bodies (Nabs), implicating the receptor in pain transmission in the lung. More recently, others have implicated P2X2 and P2X3 receptors in p02 detection in pulmonary NEBs (Rong et sd.,J Neurosci (2003) 23(36):11315-21). There is accordingly a need for methods of treating diseases, conditions and disorders * mediated by P2X3 receptors, as well as a need for compounds that act as modulators ol P2X receptors, including antagonists of P2X3 receptors. The present invention satisfies these needs as well as others. The invention provides compounds of formula I is N or CH; A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl; R’, R'‘ and R*’ are each independently H, kilo, lower alkyl, cycloalkyl, alkylthio, alkylihio- lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyL tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl; where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfur- onamido, trifluoromethyl, lower alkoxy or lower alkylthio; or R’ and R’ together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl. lower alkoxy, 0x0, halo, thiophenyl-lower alkyl, phenyl, benzyl; where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, tri-fluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl; and pharmaceutically acceptable salts thereof; wherein when R’ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl. The compounds of formula I are useful modulators of P2X3 receptor activity. The invention provides methods for treating a disease mediated by a P2X3 receptor antagonist, said method comprising administering to a subject in need thereof an effective amount of a compound of formula I. Another aspect of the invention is a method for modulating the activity of a P2X3 receptor. comprising contacting a P2X3 receptor with a compound of formula I. Another aspect of the invention is a method for treating genitourinary disorders responsive to P2X3 modulators, comprising administering to a subject in need thereof a compound of formula I. Another aspect of the invention is a formulation for treating genitourinary disorders responsive to P2X3 modulators, comprising administering to a subject in need thereof a compound of formula I in combination with a pharmaceutically acceptable excipient. Another aspect of the invention is a method for treating gastrointestinal disorders responsive to P2X3 modulators, comprising administering to a subject in need thereof a compound of formula I. Another aspect of the invention is a formulation for treating gastrointestinal discus. ■ responsive to P2X3 modulators, comprising administering to a subject in need thereof ;; compound of formula I in combination with a pharmaceutically acceptable excipient. Another aspect of the invention is a method for treating respiratory disorders responsive io P2X3 modulators, comprising administering to a subject in need thereof a compound of formula L Another aspect of the invention is a formulation for treating respiratory disorders responsive to P2X3 modulators, comprising administering to a subject in need thereof a compound of formula I in combination with a pharmaceutically acceptable excipient. Another aspect of the invention is a method for treating pain responsive to P2X3 modulators, comprising administering to a subject in need thereof a compound of formula I. Another aspect of the invention is a formulation for treating pain symptoms responsive 10 P2X3 modulators, comprising administering to a subject in need thereof a compound of formula I in combination with a pharmaceutically acceptable excipient. All publications cited in this disclosure are incorporated herein by reference in their entirety. Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and '"the" include plural referents unless the context clearly dictates otherwise. "Agonist" refers to a compound that enhances the activity of another compound or receptor site. "Alkyl" means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alky!" refers to an alkyl group of one to six carbon atoms, i.e. C]-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropvL isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms. e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene. pentalene, and the like. "Alkoxy" mean's a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. "Alkoxyalkyl" means a moiety of the formula R'‘-O-R'‘-, where R’ is alkyl and R’ is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, l-methyl-2-methoxyethyl, l-(2-methoxyethyl)-3-meth-oxypropyl, and l-(2-methoxyethyl)-3-methoxypropyl. "Alkylcarbonyl" means a moiety of the formula -R'-R", where R' is oxo and R" is alkyl as defined herein. "Alkylsulfonyl" means a moiety of the formula -R'-R", where R' is -SO2- and R" is alkyl as defined herein. "Alkylsulfonylalkyl means a moiety of the formula -R'-R"-R"' where R' is alkyl, R" is -SO2- and R'" is alkyl as defined herein. 'Antagonist" refers to a compound that diminishes or prevents the action of another compound or receptor site. •'Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi-or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfonyl, diphenylsulfonyl, diphenyliso-propylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpho-linyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. 'Arylalkyl" and "Aralky!"\ which may be used interchangeably, mean a radical -R’'R"' where R’ is an alkylene group and R*’ is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl. "Cyanoalkyl" " means a moiety of the formula -R'-R", where R' is alkylene as defined herein and R" is cyano or nitrile. 'Cycloalkyi' means a monovalent saturated carbocvclic moiety consisting of mono- or bicyclic rings. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof. "Cycloalkylalkyl" means a moiety of the fondle -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein. "Heteroalkyl" means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of -OR', -NR*'R’ and -S(0)nor'* (where m is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R’ is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R*’ and R*’ are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when m is 0, R’ is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when m is 1 or 2, R’ is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-l-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-l-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonyl propyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like . "Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrol-yl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzo-thiopyranyl, benzimidazolyl, benzoxazinyl, benzooxadiazolyl, benzothiazolyJ, benzothia-diazolyl, benzopyranyl indolyl, isoindole], triazolyl, triazinyl, quinoxalinyl,,.puriTwl, quin-azolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepam, acridity and the like, including partially hydrogenated derivatives thereof. The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo. "Haloalkyl" means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyl include -CH2CI, -CH2CF3, -CH2CCI3, perfluoroalky] (e.g., -CF3), and the like. "Haloalkoxy" means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy. "Heterocycloamino" means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group. "Heterocyclyl'" means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imid-azolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidine, quinolinyl, isoquinolinyl, benzimidazolyi, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thia-morpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetra-hydrisoquinoh"nyL and the like. "Hydroxyalkyl" means an alkyl moiety as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxy-methyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxy-propyl, 2-hydroxy-l-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxy!nethyl)-3-hydroxypropyl "Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclo-hexyl, and the like. •'Urea" or "redo" means a group of the formula -NR'-C(0)-NR"R’" wherein R', R" and R'" each independently is hydrogen or alkyl. "Carbamate" means a group of the formula -0-C(0)-NR'R" wherein R' and R" each independently is hydrogen or alkyl. "Carboxy" means a group of the formula -0-C(0)-OH. "Sulfonamide" means a group of the formula -S02-NR'R" wherein R', R" and R'" each independently is hydrogen or alkyl. "Optionally substituted", when used in association with "aryl", "phenyl", "heteroaryl" "cyclohexyl" or "heterocyclyl", means an aryl, phenyl, heteroaryl, cyclohexyl or hetero-cyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R")ni-COOR (where m is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or -(CR'R")n-CONR’R'‘ (where m is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R’ and R’ are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). "Leaving group" means the group with the meaning conventionally associated vita it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include. Hut are not limited to, halogen, alkane- or arylcnesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzene-sulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like. "Modulator" means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein, "Optional" or "optionally*' means that the subsequently described eqn or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. "Disease" and "Disease state" means any disease, condition, symptom, disorder or indication. "Inert organic solvent" or "inert solvent" means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including e.g., benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, fert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use, "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: - acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid. ethanesulfonic acid, fumaric acid, glucoheptonic acid, glycolic acid, glutamic acid, glycolic acid, hydr-oxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maieic acid, malic acid, malonic acid, mandclic acid, methanesulfonic acid, muconic acid. 2 naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or - salts formed when an acidic proton present in the parent compound either is replaced in a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or cord notes with an organic or inorganic base. Acceptable organic bases include diethanolaminc ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. The preferred pharmaceutically acceptable salts are the salts formed from acetic acid. hydrochloric acid, sulfuric acid, methanesulfonic acid, maieic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt. "Protective group" or "protecting group" means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon protective groups to block reactive nitrogen and/or oxygen atoms present in the reclaim. For example, the terms "amino-protecting group" and "nitrogen protecting group" are u-e interchangeably herein and refer to those organic groups intended to protect the niiroiivn atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited lo, trifluoroaceiyl, acetamide. ; benzyloxycarbonyl (carbobenzyioxy, CBZ), p-methoxybenzyloxycarbonyL p-nitrobenzyloxycarbonyl, error-butoxycarbonyl (BOC), and the like. The artisan in the an will know how to chose a group for the ease of removal and for the ability to washstand di following reactions. 'Solvates" means solvent additions forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a-solvale. solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the ‘ formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as HoO, such combination being able to form one or more hydrate. "Subject" means mammals and non-mammals. Mammals means any member of the mammalian class including, but not limited to, humans; non-human primates such as chin panzers and other apes and monkey species; farm animals such as cattle, horses, sheep. goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does nc denote a particular age or sex. "Genitourinary disorders" and "Disorders of the urinary tract" or "uropathy" used interchangeably with "symptoms of the urinary tract" mean the pathologic changes in the genitourinary tract. Examples of urinary tract disorders include, but are not limited to. incur-, benign prostatic hypertrophy (BPH), prostitutes, detrusor hyperreflexia, outlet urinary frequency, nocturnal, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, arthritis, prostatodynia, cystitis, idiophatic bladder -sensitivity, and the like. "Disease states associated with the urinary tract" or "urinary tract disease states" or "un pathy" used interchangeably with "symptoms of the urinary tract" mean the pathologic changes in the urinary tract, or dysfunction of urinary bladder smooth muscle or its innervations causing disordered urinary storage or voiding. Symptoms of the urinary tract include, but are not limited to, overactive bladder (also known as detrusor outlet obstruction, outlet insufficiency, and pelvic hypersensitivity. "Overactive bladder" or "detrusor hyperactivity" includes, but is not limited to. the changes symptomatically manifested’ as urgency, frequency, altered bladder continence, micturition threshold, unstable bladder contractions, sphincter plasticity, detrusor hyperreflexia (Neutrogena bladder), detrusor instability, and the like. '■'Outlet obstruction" includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors, low flow rates, difficulty in initiating urination, urgency, suprapubic pain, and the like. "Outlet insufficiency" includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, mixed incontinence, stress incontinence, and the like. "Pelvic Hypersensitivity" includes, but is not limited to, pelvic pain, interstitial (cell) cystitis, prostatodynia, prostitutes, vulvadynia, arthritis, orchidalgia, overactive bladder, and the like. 'Gastrointestinal disorder" refers to, without limitation, inflammatory disorders of the bowel, colon, and/or rectum, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and the like. "Respiratory disorder" refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like. "Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The terms "those defined above" and "those defined herein" when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any. "Treating" or 'treatment" of a disease state includes: (i) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state. (ii) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or (iii) relieving the disease state , Le., causing temporary or permanent regression of the disease state or its clinical symptoms. The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. In general, the nomenclature used in this Application is based on AUTONOM v.4.0, a Beilstein Institute computerized system for the generation of lUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS ' version 2.2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. For example, oxazol-5-yl can be illustrated by In a presently preferred class of the invention, R" is methyl, R and R are H, and Y is a bond. A particularly preferred subclass of the invention is that wherein A is oxazolyl, thiazolyl, or furanyl, particularly where R , R , and R are each independently selected from the group consisting of methyl, propyl, r-butyl, phenyl, fluorophenyl, chlorophenyl, methylthioethyl, methylsulfanylethyl, morpholine-methyl, 4-methyl-piperazin-l-ylmethyl, trifluoromethyl, benzyl, halo-benzyl, and methoxypheny. Presently preferred embodiments of this group are those wherein R’ is pyrimidinyl, amino-pyrimidinyl, acetyl, thio-acetyl, or thiazolyl. Another presently-preferred subclass of the invention is that wherein A is pyrazolyl, tri-azolyl, or pyrrolyl, particularly where R , R , and R are each independently selected from the group consisting of methyl, propyl, ‘butyl, phenyl, fluorophenyl, chlorophenyl, mcthylphenyl, biphcnyl, isopropyl, pyridyl, methoxyphenyl, methylthiophenyl, tritluoro--methylphenylj or morpholino-propyl. Presently preferred embodiments of this group are those wherein R’ is pyrimidinyl or acetyl. Another presently-preferred subclass of the invention is that wherein A is IH-thieno-[2,3-c]pyrazolyl, indolyl, indazolyl, pyrazolyl[l,5-a]pyrimidinyl, 6,7-dihydro-5H-pyrazolo[l,5-a]pyrazin-4-onyl, 2H-phthalazin-l-onyl, or imidazo[l,5-a]pyridinyl, particularly where R’, R’, and R’ are each independently selected from the group consisting of methyl, ethyl, cyclopropyl, 5-butyl, n-butyl, cyclopentyl, phenyl, fluorophenyl, alkylphenyl, benzyl, halobenzyl, trifluoromethyl, methoxybenzyl, thiophenylmethyl, tnfluoromethylphenyl, or pyridyl. Presently preferred embodiments of this group are those wherein R’ is pyrimidinyl or acetyl. Another presently preferred subclass of the invention is that wherein A is benzofuranyl, di-hydrobenzofuranyl, pyridyl, pyrimidinyl, or phenyl, particularly where R’, R', and R’ are each independently selected from the group consisting of methyl, methoxy, phenyl, methoxyphenyl, halo, alkylphenyl, thiophenyl, methylthiophenyl, halophenyl, tetrazolyl, and propyl. Presently preferred embodiments of this group are those wherein R’ is pyrimidinyl or acetyl. Another presently preferred subclass of the invention is that wherein R’ is -C(=S)CH3, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furylcarbonyl, acetyl or carbamoyl wherein when R’ is pyrimidin-2-yl, X is N, Y is a bond and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl. Another presently preferred subclass of the invention is that wherein R""" is methyl and R"‘ is H; or R'"" and R" are methyl. Another presently preferred subclass of the invention is that wherein R is H. Another presently preferred subclass of the invention is that wherein Y is a bond wherein when R’ is pyrimidin-2-yl, X is N and A is oxazol-5-yl the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl. Another presently prefemed subclass of the invention is that wherein Y is -(CR'‘R’)!!- or -CR'‘=CR’-; wherein R"‘ and R’ are each independently H or methyl and n is 1 or 2. Still another presently preferred subclass of the invention is that wherein Y is -CH2-, -CH2CH2- or -CH=CH-. Another presently preferred subclass of the invention is that wherein A is phenyl, oxazolyl, thiazolyl, furanyl, pyrimidinyl, pyridinyl, pyrazolyl, imidazolyl, pyrrolyl, IH-[l,2,3]triazolyl or 4,5-dihydro-lH-[l,2,4]triazolyl, wherein when A is oxazol-5-yl, R’ is pyrimidin-2-yl, X is N and Y is a bond the carbon atom at position 4 in said oxazol-S-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl. Still another presently preferred subclass of the invention is that wherein A is wherein R , R and R are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-pipera2inyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl; where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfon-amido, trifluoromethyl, lower alkoxy or lower alkylthio, wherein when A is oxazol-5-yl, R’ is pyriniidin-2-yl, X is N and Y is a bond the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl. Still another presently preferred subclass of the invention is that wherein A(R )(R )R is pyrazolo[l,5a]pyrimidinyl, lH-thieno[2,3-c]pyrazolyl, IH-indazolyl, 2H-indazolyl, IH-indolyl, benzofuranyl, 2H-phthala2inyl, imidazo[l,5-a]pyridyl or 4,5,6,7-tetrahydropyr-azolo[l,5-a]pyrazinyl each of which substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl; where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamido, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl. Still another presently preferred subclass of the invention is that wherein -A(R')(R )R is * wherein R’, R’ and R’ are each independently hydrogen; halogen; alkyl; alkyl substituted by 1 to 3 halogen; phenyl; phenyl substituted by halogen, alkyl or haloalkyl; cycloalkyl; alkoxy; benzyl; benzyl substituted by halogen; pyridinyl; or thiophenyl substituted by alkyl. Compounds of the invention can be prepared by a variety of different synthetic schemes. For example, Scheme I illustrates a general synthesis of compounds of the invention. In Scheme I, R\ X\ and Ar are as defined above. "G" represents a protecting group, e.g. t-butyl. The carbon atom that R’ is attached to can be racemic or chiral. In step La, a substituted piperazine is condensed an equimolar amount of a protected alpha-amino-aldehyde, e.g. using excess HB(0Ac)3 in an aprotic solvent such as dichloroethane at room temperature (RT) until the reaction is complete. The protecting group is then removed by means appropriate to the group selected; e.g., t-butyl can be removed by hydrolysis with trifluoroacetic acid (TFA). In step Lb, the deprotected intermediate is condensed with a carboxylic acid (Ar-COOH) or equivalent under basic catalysis to form the product. The product can then be purified, e.g., by extraction, crystallization, preparative HPLC, and the like, SCHEME I: For example. Scheme II illustrates a general synthesis of compounds of the invention. In Scheme I, R , X , and Ar are as defined above. "G " and G represents a protecting groups, e.g. ‘butyl and where G’ cannot equal G'. LG is a leaving group. The carbon atom that R’ is attached to can be racemic or chiral. In step Il.a, an orthogonally protected piper-azine is condensed with an equimolar amount of a protected alpha-aminoaldehyde, e.g. using excess HB(0Ac)3 in an aprotic solvent such as dichloroethane at room temperature until the reaction is complete. The first protecting group, G2, is then removed by means appropriate to the group selected; e.g., t-butyl can be removed by hydrolysis with orfluoro-acetic acid (TFA). In step Il.b, the mono-deprotected intermediate is condensed with a carboxylic acid (Ar-COOH) or equivalent under basic catalysis to form the product. The product can then be purified, e.g., by extraction, crystallization, preparative HPLC, and the like. The remaining protecting group, a carbobenzyloxy group, is removed by hydrogen and palladium on carbon. In step II.c, the deprotected intermediate is reacted with an acid chloride, sulfonyl chloride, carbamoyl chloride, isocyanate, chloroformate or other deriva-tizing agent to form the product. The product can then be purified, e.g., by extraction, crystallization, preparative HPLC, and the like. Representative compounds of the invention are set forth in the Examples below. Specific screening methods are known in the art and along with integrated robotic systems and collections of chemical compounds/natural products are extensively incorporated in high throughput screening so that large numbers of test compounds can be tested for antagonist or agonist activity within a short amount of time. These methods include homogeneous assay formats such as fluorescence resonance energy transfer, fluorescence polarization, time-resolved fluorescence resonance energy transfer, scintillation proximity assays, reporter gene assays, fluorescence quenched enzyme substrate, chromogenic enzyme substrate and electrochemiluminescence, as well as more traditional heterogeneous assay formats such as enzyme-linked immunosorbant assays (ELISA) or radio immunoassays. Homogeneous assays are preferred. Also comprehended herein are cell-based assays, e.g. those utilizing reporter genes, as well as functional assays that analyze the effect of an antagonist or agonist on biological function(s) or of compounds of the invention on P2X3 receptors, and biological systems containing P2X3 receptors. Compositions comprising an effective amount of a compound of the present invention, in combination with other components such as a physiologically acceptable diluent, carrier, or excipient, are provided herein. The compounds can be formulated according to known methods used to prepare pharmaceutically useful compositions. They can be combined in admixture, either as the sole active material or with other known active materials suitable for a given indication, with pharmaceutically acceptable diluents (e.g., saline, Tris-HCl, acetate, and phosphate buffered solutions), preservatives (e.g., thimerosal, benzyl alcohol, parabens), emulsifiers, solubilizers, adjuvants and/or carriers. Suitable formulations for pharmaceutical compositions include those described in "Remington's Pharmaceutical Sciences", 16th ed. 1980, Mack Publishing Company, Easton, PA. In addition, such compositions can be complexed with polyethylene glycol (PEG), metal ions, or incorporated into polyincTJc compounds such as polyacctic acid, polyglycolic acid, hydrogels, dextrin, and the like, or incorporated into liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance, and are thus chosen according to the intended application. The compositions of the invention can be administered in any suitable manner, e.g., topically, parenterally, or by inhalation. The term "parenteral" includes injection, e.g., by subcutaneous, intravenous, or intramuscular routes, also including localized administration, e.g., at a site of disease or injury. Those of ordinary skill in the art recognize that other types of localized administration (e.g., intraarticular, intracapsular, intracarpal, intracelial, intracerebroventricular, intrasynovial, intraspinal, intraligamentus, intrameningeal, intraocular, epidural, transepithelially, and/or administration by one or more of these routes at a site near or adjacent to a site of disease or injury) are suitable for use in administering the compositions of the present invention. Sustained release from implants is also contemplated. One skilled in the pertinent art will recognize that suitable dosages will vary, depending upon such factors as the nature of the disorder to be treated, the patient's body weight, age, and general condition, and the route of administration. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices. Compounds of the invention are useful for treating a wide range of genitourinary diseases, conditions and disorders, including urinary tract disease states associated with bladder outlet obstruction and urinary incontinence conditions such as reduced bladder capacity, frequency of micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity, and other symptoms related to overactive bladder. Compounds of the invention are also useful for treating gastrointestinal disorders, including inflammatory bowel syndrome (IBS), inflammatory bowel disease (IBD), reduced diarrhea in D-dominant IBS, and the like. Further, compounds of the invention are useful for treating respiratory disorders, including chronic obstructive pulmonary disorder (COPD), asthma, bronchospasm, and the like. The compounds of the invention are useful as analgesics in the treatment of diseases and conditions associated with pain from a wide variety of causes, including, but not limited to, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias. poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome. EXAMPLES ... The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Example 1: Preparation of 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid {2-[4-(6'aminopyridin-2-yl)-piperazin-l-yI]-l-methyl-ethyl} amide (A) To a solution of 6-chloro-2-pyridinylamine (406 mg, 3.16 mmol) and piperazine (381 mg, 4.42 mmol) in m-xylene (10 ml), were added sodium tert-butoxide (425 mg, 4.42 mmol) and bis-(tri-o-tolylphosphine)palladium (II) dichloride (124 mg, 0.158 mmol). The mixture was heated at reflux under N2 for 24 h. The reaction was cooled down and tetra-hydrofuran (THF, 10 ml) added, and the mixture was filtered on a celite pad. The filtrate was evaporated and purified via flash chromatography (CH2Cl2/MeOH/NH40H) affording 30 mg of 2-amino-6-(pipera2in-l-yl)pyridine (Intermediate "la") as a tan solid (5% yield). H-NMR (CD3OD): 2.95 (m, 4H), 3.47 (m, 4H), 5.93 (m, IH), 6.01 (m, IH), 7.24 (m, IH). M'=179. (B) To a solution of intermediate la (30 mg, 0.169 mmol) in dichloroethane (DCE, 10 mL) was added (l-methyl-2-oxo-ethyl)-carbamic acid f-butyl ester (29 mg, 0.169 mmol) and sodium triacetoxyborohydride (NaBH(0Ac)3, 71 mg, 0.339 mmol). The reaction mixture was stirred at RT for 60 h. The solvent was evaporated, and the residue was partitioned between CH2CI2 and a saturated solution of NaHCOs, the organic layer was separated and washed twice with a saturated solution of NaHCOs to provide {2-[4-(6-aminopyridin-2-yl)-piperazin-l-yl]-l-methyl-ethyl}-carbamic acid t-butyl ester (intermediate lb). The crude mixture was used without further purification for the deprotection reaction. M’=336. (C) The crude mixture from part (B) above was dissolved in CH2CI2 (1.5 ml) and TFA (0.5 ml) was added at 0°C. The mixture was stirred at 0°C for 5 min., then at RT for 4 h to provide the deprotected product, 6-[4-(2-aminopropyl)-piperazine-l-yl]-pyridin-2-ylamine (intermediate Ic), The solvent was evaporated and the crude mixture used without further purification. M"‘=236. (D) 3-oxo-hexanoic acid ethyl ester (29.7 g, 188 mmol) was dissolved in Et20 (400 ml). The solution was cooled to 0*’0, and sulfuryl chloride (22.6 ml, 282 mmol) was added dropwise. The solution gradually warmed to RT over 4 h. The solution was neutralized to pH 7 with a solution of aqueous saturated NaHC03. The organic layer was separated, washed with brine, and dried over sodium sulfate. Evaporation under reduced pressure yielded 2-chloro-3-oxo-hexanoic acid ethyl ester (intermediate Id, 36 g, 100%). ‘H-NMR (CDCI3, ppm): 0.95 d (3H); 1.35 d (3H); 1.58 m (2H); 2.7 t (2H); 4.28(d (2H); 4.78 s (IH). (E) Intermediate Id (36 g, 188 mmol) was combined with 4-fluorobenzamide (26.2 g, 188 mmol), and the reaction mixture heated to 150°C for 4 h. The residue was purified by flash chromatography on silica gel with gradient elution (0% to 2% EtOAc in hexanes) to provide 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid ethyl ester (intermediate le, 3.18 g, 6.1%). ‘H-NMR (CDCI3, ppm) 1.0 t (3H); 1.421 (3H); 1.77 m (2H); 2.88 t (2H); 4.4 q (2H); 7.17 t (2H); 8.14 t (2H). (F) Intermediate le (3.18 g, 11.5 mmol) was dissolved in THF (80 ml) and water (8 ml), and 15% aqueous NaOH (15 ml) was added. The reaction mixture was heated to 70'C for 3 h, then cooled to RT. The organic solvents were removed by evaporation under reduced pressure, and the residue taken up in water (100 ml). HCl (6 N) was added to adjust the pH of the solution to 1. The resulting solid was filtered and dried under reduced pressure to yield 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid (intermediate If, 3 g, 100%). ‘H-NMR (CDCb, ppm): 1.05 t (3H); 1.70 sextet (2H); 2.93 t (2H); 7.17 t (2H); 8.17 t (2H). (G) To a suspension of dicyclohexylcarbodiimide polymer supported (250 mg, 0.338 mmol) in CH2CI2 (3 ml) were added 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid (46 mg, 0.186 mmol), intermediate 'Mf, and hydroxybenzotriazole (HOBT, 34 mg, 0.253 mmol). The mixture was stirred at RT for 2 h, then the crude intermediate Ic in CH2CI2 solution (2 ml) and diisopropylethylamine (0.147 ml, 0.845 mmol) was added. The mixture was stirred for 20 h at RT. The resin was filtered off and washed with dichloro- methane. The filtrate was washed with a saturated solution of NaHCOs, dried on sodium sulfate and evaporated. The product, 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxyIic acid {2-[4-(6-aminopyridin-2-yl)-piperazin-l-yl]-l-methyl-ethyl} amide (compound 1) was purified via preparative HPLC. M'*"=467. (H) Similarly, following the procedure set forth in Example 1 (B-G) substituting 1-pyridin-2-yl-piperazine for (intermediate 'Ma'"), 2-(4-fluorophcnyl)-4-propyl-oxazolc-5-carboxylic acid [l-methyl-2-(4-pyridin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 24) was prepared. Example 2: Preparation of 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid {2-[4-(4-aminopyrimidin-2-yl)-piperazin-l-yI]-l-methyl-ethyl} amide (A) To a solution of 2,4-dichloropyrimidine (7.5 g, 50 mmol) in ethanol (EtOH, 25 ml) was added ammonium hydroxide (25 ml, 30%). The reaction mixture was stirred at RT for 18 h. The white precipitate that formed was filtered and washed with ethanol, and dried under vacuum to provide a mixture of 2-chloro-pyrimidin-4-ylamine (Ila) and 4-chloro-pyrimidin-2-ylamine (4.13 g, 64 % yield). (See Caravatti et al., Bioorg Med Chem Lett (1999) 9:1973-78.) M’=130. (B) To a solution of the mixture of pyrimidines (4.13 g, 32 mmol) in absolute EtOH (80 ml) were added piperazine 1-carboxylic acid benzyl ester (7.05 g, 32 mmol) and NaHCOs (8.07 g, 94 mmol). The reaction was heated at reflux for 20 h. The mixture was then cooled down, and the white precipitate of unreacted starting material was filtered off. The filtrate was evaporated and the residue was partitioned between EtOAc and water, the organic layer was separated and the aqueous phase was extracted twice with EtOAc. The organic layers were combined, dried over sodium sulfate and evaporated. The crude mixture was purified via flash chromatography (CH2Cl2/MeOH) affording 2.4 g (23% yield) of 4-(4-aminopyrimidin-2-yl)-piperazine-l-carboxylic acid benzyl ester (intermediate lib) and 3.4 g (34% yield) of the other regioisomer. H-NMR (CDCI3): 3.55 (m, 4H), 3.76 (m, 4H), 4.56 (bs, 2H), 5.17 (s, 2H), 5.78 (d, J=5.61 Hz), 7.32-7.38 (m, 5H), 7.93(d,J=5.61Hz). (C) To a solution of lib (2.4 g, 7.67 mmol) in MeOH (80 ml) at RT was added palladium 10% on carbon (600 mg). The reaction mixture was stirred under Ho (approx. 2 atm) for 60 h. The catalyst was filtered on a celite pad, and the filter cake was washed with methanol. The filtrate was evaporated providing 2-piperazin-l-yl-pyrimidin-4-ylamine (intermediate lie) (1.37 g, quantitative yield) as a white solid. H-NMR (CD3OD): 2.82 (m, 4H), 3.65 (m, 5H), 5.82 (d, 1 H, J=5.85), 7.72 (d, 1 H, J-5-85). (D) To a solution of lie (985 mg, 5.5 mmol) in DCE (60 mL) were added (l-methyl-2- oxo-ethyl)-carbamic acid r l>utyl ester (951 mg, 5.5 mmol) and NaBH(OAc).’ (2.33 g, 11 mmol). The reaction mixture was stirred at RT for 60 h. The solvent was evaporated and the residue was partitioned between CH2CI2 and a saturated solution of NaHCOs, the organic layer was separated and washed twice with a saturated solution of NaHC03. The crude mixture was purified via flash chromatography CH2Cl2/MeOH providing {2-[4-(4- aminopyrimidin-2-yl)-piperazin-l-yl]-l-methyl-ethyl}-carbamic acid t-butyl ester (inter mediate lid, 880 mg, 48% yield) as colorless oil. H-NMR (CDCI3): 1.27 (d, 3H, J=11.8 Hz), 1.45 (s, 9H), 2.13-2.57 (m, 7H), 3.71 (m, 5H), 4.83 (bm, 3H), 5.74 (d, IH, J=5.64), 7.90(d, 2H,J=5.64). (E) Intermediate lid was deprotected following the procedure set forth in Example 1(C) above to provide 2-[4-(2-aminopropyl)-piperazin-l-yl]-pyrimidin-4-ylamine (intermediate He) in quantitative yield as a foamy white solid. M"‘=237. (F) Intermediate He was condensed with 2-(4-fluorophenyl)-4-propyloxazole-5-carboxylic acid as described in Example 1(G) above to provide compound 2 as a white solid in 62% yield. H-NMR (CDCI3): 1.01 (t, 3H, J= 7.41 Hz), 1.34 (d, 3H, J= 6.39 Hz), 1.77 (m, 2H), 2.37-2.68 (m, 6H), 2.95 (m, 2H), 3.75 (m, 4H), 4.20 (m, IH), 4.71 (bs, 2H), 5.75 (d, IH, J= 5.64 Hz), 6.80 (bd, IH, J=6.06 Hz), 7.12 (m, 2H), 7.90 (d, IH, J= 5.61 Hz), 8.05 (m, 2H). MP= 77.1-88.0°C. M’= 468. Example 3: Preparation of 2-(4-fluorophenyI)-4-propyl-oxazole-5-carboxylic acid [l-methyl-2-(4-thiazol-2-ylpiperazin-l-yl)-ethyI] amide (A) Piperazine (3.44 g, 40 mmol) was added to a solution of 2-bromothiazole (1.8 ml, 20 mmol) in acetonitrile (90 ml). The mixture was heated at reflux for 20 h. The reaction was cooled down at RT and the precipitate (disubsdtuted piperazine) was filtered off. The filtrate was evaporated, the residue was partitioned between water and ethyl acetate, the organic phase was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were extracted with HCl (1 M). The organic phase was discarded, and the aqueous layer was neutralized by addidon of NaHC03 (solid) to pH 8, and then extracted with EtOAc. The organic extracted was dried over sodium sulfate and evapora- ted, providing l-thiazol-2'ylpiperazine (intermediate Ilia, 860 mg, 25% yield) as colorless oil. H-NMR (CDCI3): 2.98 (m, 4H), 3.48 (m, 4H), 6.56 (d, IH, J= 3.63 Hz), 7.20 (d, IH, J- 3.63 Hz). (B) Proceeding as set forth in Example 2(B'C) but substiluting intermediate ITIa for intermediate Ila, [l-methyl-2-(4-thiazol-2-yl-piperazin-l-yl)-ethyI]-carbamic acid t-butyl ester (intermediate Illb) was obtained as a foamy solid in 92 % yield. (C) Intermediate Illb was deprotected following the procedure set forth in Example 1(C) to provide l-methyl-2-(4-thiazol-2-yl-piperazin-l-yl)-ethylamine (intermediate IIIc) in quantitative yield as a colorless oil. M"‘=227. (D) Following the procedure set forth in Example 1(G) above, but substituting intermediate IIIc, 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [l-methyl-2-(4-thiazol-2-yl-piperazin-l-yl)-ethyl]-amide (compound 3) was obtained as a white solid in 75% yield. M’=458. Example 4: Preparation of 2-(4-fluorophenyI)-4-propyI-oxazole-5-carboxyHc acid [l-methyl-2-(4-thioacetylpiperaziii-l-yl)-ethyI] amide (A) To a solution of ,l-[4-(2-amino-propyl)-piperazin-l-yl]-ethanone (149 mg, 0.4 mmol) and triethylamine (TEA, 118 fj.1, 0.8 mmol) was added Lawesson's reagent (162 mg, 0.4 mmol) at RT. The reaction mixture was heated at reflux for 3 h to provide l-[4-(2-amino- propyl)-piperazin-l-yl]-ethanethione (intermediate IVa). The solvent was evaporated and the residue was partitioned between ethyl ether and HCl (1 N), the organic layer was dis carded and the aqueous layer was basified by addition of a saturated solution of K2CO3. The aqueous solution was extracted with ethyl acetate four times. The organic layers were combined, dried over sodium sulfate and evaporated. The crude mixture was used for the next coupling reaction. M'‘=202. (B) Following the procedure set forth in Example 1(G) above, but substituting inter mediate IVa for Ic, the compound 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amide (compound 4) was obtained, and purified via preparative HPLC to yield 15 mg of compound 4 as the TFA salt as a yellow viscous oil. M'‘=433. Example 6: Preparation of 2-(4-Fluorophenyl)-4-propyl-oxazole-5-carboxylic acid {(R)-2-[4-(furan-2-ylcarbonyI)-piperazin-l-yl]-l-methyl-ethyl}-amide (A) (R)-(2-hydroxy-l-methyl-ethyl)-carbaniic acid tert-butyl ester (2.0 g, 11.4 mmol) in 10 mLof CH2CI2 was added dropwise to a stirred solution of oxalyl chloride (LI mL, 12.6 mmol) and DMSO (1.62 mL, 22.8 mmole) in 20 mL of CH2CI2 at -60°C. The reaction mixture was stirred for 5 minutes before TEA (5.6 nil, 57.1 mmole) was added slowly. The resultant reaction mixture was warmed to RT over 1 hour. The organics were washed with water, and the aqueous fractions back extracted with CH2CI2. The organics were combined and dried over sodium sulfate. The solvent was evaporated under reduced pressure to provide 2.0 g (99%) of (l-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (Intermediate Via) (‘H-NMR (CDCb, ppm) 1.34 d (3H); 1.45 s (9H); 3.10 q (IH); 9.45 (IH)). (B) 1.9 g (8.7 mmol) of piperazine-1-carboxylic acid benzyl ester was dissolved in 20 ml of 1,2-dichloroethane. 3.4 ml (34.6 mmol) of triethyl amine was added to the solution followed by 1.5 g (8.7 mmol) of Intermediate Via and 3.7 g (17.3 mmol) sodium triacet-oxyborohydride. The reaction mixture stirred for 18 hours. The solution was diluted with CH2CI2 (100 ml). The organics were washed 3 times with saturated aqueous sodium bicarbonate, then dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with gradient elution (20% to 30% ethyl acetate in hexanes) to provide 2.55 g (78%) of (R)-4-(2-tert-butoxycarbonylamino-propyl)-piperazine-l-carboxylic acid benzyl ester (Intermediate VIb) (M’ = 378). (C) 1.51 g (4.0 mmol) of Intermediate VIb was dissolved in 50 ml of 25% trifluoroacetic acid in CH2CI2. The reaction mixture stirred for 4 hours. The solvent was evaporated under reduced pressure to provide 1.6 g (99%) of (R)-4-(2-aminopropy])-piperazine-l-carboxylic acid benzyl ester trifluoroacetic acid salt (Intermediate VI c) (M"‘ = 278). (D) 1.6 g (4.0 mmol) of Intermediate VIc was combined with 997 mg (4.0 mmol) of 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid, 805 mg (4.2 mmol) of l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, 540 mg (4.0 mmol) 1-hydroxy-benzotriazole hydrate and 336 mg (16.0 mmol) sodium bicarbonate in 50 ml of dimethyl-formamide. The reaction mixture was stirred lor 18 hours, and then filtered. The soivcnl was evaporated under reduced pressure, and the residue dissolved in CH2CI2 (100 ml). The organics were washed with 2% hydrochloric acid followed by saturated sodium bicarbonate and brine, then dried over anhydrous sodium sulfate. The solvent was evapora- ted under reduced pressure, and the residue was purified by flash chromatography on silica gel (5% methanol in dichloromethane) to provide 843 mg (41%) of (R)-4-(2{[2-(4-fluorophenyl)-4-propyl-oxazole-5-carbonyl]-amino}-propyl)-piperazine-l-carboxylic acid bcn/iyl ester (Intermediate VI d) (JM' = 509). (E) 843 mg (1.7 mmol) of Intermediate VId was dissolved in 50 ml of ethanol. 3.4 mg (0.17 mmol) of palladium on carbon (Degussa) was added. The reaction mixture stirred under atmouspheric hydrogen for 18 hours. The solution was filtered through Celite then evaporated under reduced pressure to provide 595 mg (94%) of (R)-2-(4-fluoro-phenyl)-4-propyl-oxazole-5-carboxylic acid (l-methyI-2-piperazin-l-yl-ethyl)-amide (Intermediate Vl-e) (M"" = 375) 134 mg (0.28 mmol) of Intermediate Vl-e was dissolved in 10 ml of dichloromethane. 1.0 ml of diisopropylethyl amine was added to the reaction mixture followed by 72 mg (0.56 mmol) of 2-furoyl chloride. The reaction mixture stirred for 18 hours. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel with gradient elution (2% to 5% methanol in dichloromethane) to provide 65.2 mg (50%) of 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid (R)-{2-[4-(furan-2-carbonyl)-piperazin-l-yl]-l-methyl-ethyI}-amide (Compound 6) (M"‘ = 469). Example 7: Preparation of 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxyHc acid [(R)-l-methyl-2-(4-pyrimidin-4-yl-piperazin-l-yl)-ethyl]-amide Following the procedure set forth in Example 6 A-D substituting 4-piperazin-l-yl-pyrimi-dine for piperazine-1-carboxylic acid benzyl ester, 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [(R)-l-methyl-2-(4-pyrimidin-4-yl-piperazin-l-yl)-ethyl]-amide (compound 7) was prepared. M+ = 453. Example 8: Preparation of 2-(4-Fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [(R)-l-methyl-2-(4-pyridin-2-yl-piperazin-l-yl)-ethy!]-amide Following the procedure set forth in Example 6 A-D substituting l-pyridin-2-yl-piperazine for piperazine-1-carboxylic acid benzyl ester, 2-(4-nuoropheny!)-4-propyl-oxazole-5-carboxylic acid [(R)-l-methyl-2-(4-pyridin-2-yl-piperazin-l-yl)-ethyl]'amide (compound 8) was prepared as the TEA salt. M"‘ = 452. Example 9: Preparation of 2-(4-Fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [(R)-l-methyI-2-(4-pyraz!n-2-yl-piperazin-l-yl)-ethyl]-amide Following the procedure set forth in Example 6 A-D substituting 3,4,5,6-tetrahydro-2H-[l,2']bipyraziiiyl for piperazine-1-carboxylic acid benzyl ester, 2-(4-fluorDphenyl)-4-propyl-oxazole-5-carboxylic acid [(R)-l-methyl-2-(4-pyrazin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 9) was prepared as the TFA salt. M"‘ = 453. Example 10: Preparation of 4-((R)-2-{[2-(4-FIuorophenyl)-4-propyl-oxazole-5-carbonyI]-amino}-propyI)-piperazine-l-carboxylic acid amide Intermediate Vie (93.4 mg, 0.269 mmol) was dissolved in 0.15 ml of 17% acetic acid in water. Water (0.15 ml) w’as added to the solution followed by 43.6 mg (0.538 mmol) potassium cyanate. The reaction mixture stirred for 18 hours. The solvent was evaporated. Purification by reverse phase high pressure liquid chromatography gave, 4-((R)-2-{[2-(4-fluoropheny])-4-propyl-oxazole-5-carbonyl]-amino}-propyl)-piperazine-l-carboxylic acid amide (compound 10) was prepared as the TFA salt. M"‘ = 418. Example 11: Preparation of 2-(4-Fluorophenyl)-4-propyI-oxazole-5-carboxyIic acid [(R)-l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide Following the procedure set forth in Example 6 but substituting acetyl chloride for 2-furoyl chloride, the compound 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [(R)-2-(4-acety]-piperazin-l-yl)-l-methyl-ethyl]-amide (compound 11) was prepared as a TFA salt. M’ = 417. Example 12: Preparation of 2-(2-Fiuorophenyl)-4-(2-methylsulfanylethyl)-oxazole-5-carboxylic acid [l"methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (A) To a clear solution of D,L-methionine (10 g, 67.02 mmol) and NaOH (4.0 g, 100.53 mmol) in acetone (100 ml)/ HoO (100 ml) was added 2-fluorobenzoyl chloride dropwise with stirring between each addition. Basicity was maintained by adding 2N NaOH when necessary. After addition was completed, the reaction mixture was acidified to pH 2 with 6N HCl and extracted into EtOAc. The organic layer was dried with Na2S04, filtered, and concentrated to give provide 2-(2-fluorobenzoylamino)-4-methylsulfanyl-butyric acid (intermediate Xlla, 13.6g) as an oil. ,". (B) To a solution of intermediate Xlla (13 g, 47.97 mmol) in anhydrous THF (150 ml) was added oxalyl chloride (28g, 216.1 mmol), and siirred al RT lor 72 h. Solvent and excess oxalyl chloride were removed under reduced pressure. The reaction residue was cooled in an ice bath. TEA (7.3 g, 71.96 mmol) was added carefully, followed by anhydrous MeOH (200 ml). Stirring was continued for another 3 h at RT before solvent was removed under reduced pressure. The residue was flash chromatographed (silica , 20% EtOAc in hexane) yield 2-(2-fluorophenyl)-4-(2-methylsulfanyl-ethyl)-oxazole-5-carboxylic acid (intermediate Xllb, 11.59 g) as a cream solid. (C) Following the procedure for Xlllc-d below substituting 1-acetylpiperazine for 2-piper-azin-l-yl-pyrimidine, l-methyl-2-(acetylpiperazin-l-yl)ethyl amine 2HC1 (intermediate XIIc, 1.52 g) was prepared. M"" = 185. (D) To a solution of intermediate Xllb (0.2 g, 0.71 mmole) in anhydrous THF (10 mL) was added HBTU (0.27 g, 0.71 mmol), intermediate XIIc (0.27 g, 0.71 mmole) and DIEA (0.55 mL, 4.26 mmol). The reaction mixture was stirred at RT 18h before concentration. Purification by flash chromatography 3% methanol in CH2CI2 afforded compound 2-(2-fluorophenyl)-4-(2-methylsulfanylethyl)-oxazole-5-carboxylic acid [l-methyl-2-(4-acetylpiperazin-l-yl)-ethyl]-amide (compound 12). M"‘=449. Example 13: Preparation of 2-(2,4-DifluorophenyI)-4-(2-methylsulfanylethyl)- oxazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-ainide (A) 2-t-butoxycarbonylamino-propionic acid (25g, 132 mmole) was dissolved in dimethylformamide (300 ml). N,0-dimethylhydroxylamine HCI (12.9 g, 132 mmol) was added, followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCI (26.6 g, 139.0 mmol), HOBT (17.8 g, 132 mmol), and NaHCOr, (44.4g, 528 mmol). The reaction mixture was siirred under nitrogen for 48 h. The solution was then filtered, and the solvent evaporated under reduced pressure. The residue was dissolved in CH2CI2 and washed with 2% aqueous HCI, saturated aqueous NaHC03, and water. The organic layers were dried over sodium sulfate and evaporated under reduced pressure to provide [l-(methoxy- methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (intermediate Xllla, 12.84 g, 42%), M’ = 233. ■ • (B) Intermediate Xllla (12.84 g, 55.3 mmol) was dissolved in dry THF (400 ml). The sohjtion was cooled to 0°C\ and LiAlIU (fS9.] ml, 69.1 mmol; 1.0 M in THF>was added dropwise. The reaction mixture stirred at 0°C for 30 min. KHSO4 (13.18g,) in water (200 ml) was then added dropwise, and the solution diluted with diethyl ether (500 ml). The aqueous layer was extracted 3x with diethyl ether. The organic layers were combined and washed 3x with HCl (3 N), 3x with saturated sodium bicarbonate, and twice with brine. The organic layers were dried over sodium sulfate and evaporated under reduced pressure to provide (l-methyl-2-oxo-ethyl)-carbamic acid t-butyl ester (intermediate Xlllb, 61.36 g, 69%). M"" = 174. (C) 2-piperazin-l-yl-pyrimidine (4.4g, 26.6 mmol) was dissolved in DCE (125 ml), and TEA (10.5 ml, 106 mmol) added. Intermediate Xlllb (4.6g , 26.6 mmol) was dissolved in DCE (125 ml) and added to the reaction mixture, followed by NaBH(0Ac)3 (11.3 g, 53 mmol). The reaction mixture was stirred 18 h, and the solution then diluted with CH2CI2 and the organics were washed with saturated aqueous NaHC03 (250 ml). The aqueous layer was back extracted with CH2CI2. The combined CH2CI2 extracts were dried over Na2S04. The solvent was evaporated under reduced pressure, and the residue purified by flash chromatography on silica gel (5% MeOH in CH2CI2) to provide [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-carbamic acid t-butyl ester (intermediate XIIIc, 8.5 g) M" = 322. (D) Intermediate XIIIc (8.5 g, 26 mmole) was dissolved in CH2CI2 (50 mL). HCl (119 ml, 119 mmol, 1.0 M in Et20) was added. The reaction mixture was agitated for 18 hours. The solvent was evaporated under reduced pressure to yield l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethyl amine 2HC1 (intermediate Xllld, 9.34g (100%). M"" = 222. (E) Following the procedure set forth in Example 12 but substituting 2,4-difluorobenzoyl chloride for 2-fluorobenzoyl chloride, and using intermediate Xllld, the compound 2-(2,4- difluorophenyl)-4-(2~methylsulfanylethyl)-oxazole-5-carboxyIic acid [l-methyl-2-(4- pyrimidin-2-yl-piperazin-3-yl)-elhyl]-amide (compound 13) was prepared. Example 14: Preparation of 2-(2-FIuorophenyI)-4-(2-methylsuIfonylethyI)-oxazole-5-carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide To a solution of compound 12 (0.16 g, 0.357 mmol) in MeOH/H20(6 ml/2 ml) was added oxone, and the mixture stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH. The remaining aqueous solution was ex-Iraclcd into CII2CI2, was washed with NaOH and water; dried with K2CO3, filtered and concentrated. PTLC (silica, 5%MeOH/CH2Cl2) gave 2-(2-fluorophenyl)-4-(2-methylsulf-onylethyl)-oxazole-5-carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 14, 0.1 g) as white solid. M"‘H = 481. Example 15: Preparation of 2-(2,4-DifluorophenyI)-4-(2-methylsulfonylethji)- oxazole-5-earboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-ainide Proceeding as in Example 14 above, but substituting compound 13 for compound 12, 2-(2,4-difluorophenyl)-4-(2-methylsulfonylethyl)-oxazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 15) was prepared. Example 16: Preparation of 2-(4-fluorophenyl)-4-propyl-oxazoIe-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperidin-l-yl)-ethyl]-amide (A) The compound l-(l-benzylpiperidin-4-yl)propan-2-one (intermediate XVIa) was prepared according to Bosch et al., Tetrahedron (1982) 38:2883. To a solution of intermediate XVIa (1.3 g, 5.63 mmol) in MeOH (20 ml) was added NH4OAC (5.1 g, 67.56 mmol), and the mixture stirred at RT for 15 min., followed by addition of NaCNBHs (0.25 g, 3.94 mmol). Stirring was continued for 16 h, and solvent was removed under reduced pressure. The residue was dissolved in 6N HCl (20 ml), and washed twice with ether. The acidic aqueous solution was basified with 6N NaOH to pH 10 and extracted into CH2CI2. The organic extract was dried with Na2S04, filtered and concentrated to provide l-(l-benzyl-piperidin-4-yl)-2-aminopropane (intermediate XVIb, 1.27 g) as an oil. (B) A solution of XVIb (1.29 g, 5.75 mmol) and (B0C)20 (1.25 g, 5.75 mmol) in anhvdrous THF (20 ml) was stirred at RT for 16 h. Solvent was removed under reduced pressure. The residue was partitioned between CH2CI2 and water. The organic layer was dried with Na2S04, filtered and concentrated. The residue was flash chromatographed (silica, 8% MeOH in CH2CI2 with NH4OH) to give l-(l-benzylpiperidin-4-yl)-2-(butoxy-carbonylamino)propane (intermediate XVIc, 1.64 g) as a white solid. (C) A mixture of XVIc (1.6g, 4.82 mmol) and 10% Pd/C (0.4 g) in EtOH (50 ml) was hydrogenated at 45 psi for 16 h. The reaction mixture was filtered through celite and the filtrate concentrated to give l-(piperidin-4-yl)-2-(butoxycarbonylamino)propane (intermediate XVIdj 1.049 g) as an oil. (D) To a solution of XVId (0.4 g, 1.65 mmol) in anhydrous EtOH (8 ml) was added TEA (0.24 g, 239 mmol), followed by 2-chloropyrimidine (0.24 g, 2.05 mmol). The reaction mixture heated at reflux for 4 h, and solvent was removed under reduced pressure. The residue was dissolved in CH2CI2, washed with H2O, dried with Na2S04, filtered, and concentrated. The residue was chromatographed (silica, 10% MeOH in CH2CI2 with NH4OH) to yield l-(l-pyrimidin-2-ylpiperidin-4-yl)-2-(butoxycarbonylamino)propane (intermediate XVIe, 0.26 g) as yellow crystals. (E) A solution of XVIe (0.25 g, 0.78 mmol), TFA (0.5 ml) in CH2CI2 (5 ml) was stirred at RT for 16 h. Solvent and excess TFA were removed under reduced pressure. The residue was redissolved in CH2CI2, and washed with ether. The aqueous layer was basified with NaOH to pH 10 and extracted into CH2CI2. The organic solution was dried with K2CO3, filtered and concentrated to provide l-(l-pyrimidin-2-ylpiperidin-4-yl)-2-amino-propane (intermediate XVIf, 0.163 g) as an oil. (F) Intermediates XVIf and Xllld were condensed following the procedure of Example 12(D) to provide 2-(4-fluorophenyI)-4-propyl-oxa2ole-5-carboxylic acid [l-methyl-2-(4- pyrimidin-2-yl-piperidin-l-yl)-ethyl]-amide (compound 16). M"‘H = 452. Example 17: Preparation of 2-(2-fluorophenyl)-4-phenyl-oxazole-5-carboxylic acid [l-methyl-2-(4-pyrid-2-yl-piperazin-l-yl)-ethyl]-amide (A) Proceeding as set forth in Example l(A-C), but substituting 2-pyridinylamine for 6-chloro-2-pyridinylamine, the compound l-methyl-2-[(4-pyridin-2-yl)piperazin-l-yI]-ethylamine (intermediate XVIIa) was prepared. (B) 2-Fluorobenzoic acid (6 g, 42.8 mmole) was dissolved in 300 mL of anhydrous THF and the resulting reaction solution was cooled to 0°C. To this solution was added sodium hydride (] .88 g of a 60% oil dispersion, 47.1 mmole). The reaction mixture was allowed to warm to RT over 1 h. The THF was removed by evaporation before addition of 2-chloro-3-oxo-3-phenyl-propionic acid ethyl ester (9.7 g, 42.8 mmole) in 250 mL of ethanol. Reaction solution was warmed at reflux for 24 h. The ethanol was removed by evaporation and the resulting product was dissolved in water and extracted with toluene. Thetoluene was washed with 2 N aqueous Na2C03, and saturated NaCl. The resulting toluene layer was concentrated and purified by chromatography (5-8% ethyl acetate in hcxancs gradicnl) providing 2-tluoro-benzoic acid l-cthoxycarbonyl-2-oxo-2-phenyl-elhyl ester (Intermediate XVIIb, 5.3 g, 38% yield) (C) Intermediate XVII b (5.7 g, 17.4 mmole) was dissolved in 80 mL of acetic acid and 10.7 g of ammonium acetate (14 mmole) was added. The reaction mixture was warmed at reflux for 1 h. Solvent was removed by evaporation. Purification by chromatography (silica, 10% ethyl acetate in hexanes eluant) provided 2-(2-fluorophenyl)-4-phenyl-oxazole-5-carboxyhc acid ethyl ester (Intermediate XVIIc, 2.73 g, 27% yield) M’H = 312 (D) Intermediate XVIIc (1.44 g, 4.6 mmole) was dissolved in 30 mL THE and 2 mL of water. To the reaction solution was added 14 mL of 2N NaOH (aqueous) and the resulting reaction mixture was warmed at reflux for 4 h. The solvent was removed by evaporation to afford a white solid. The solid was washed with aqueous HCl (pH = 1) and collected by filtration and dried under vacuum to give 2-(2-fluorophenyl)-4-phenyl-oxazole-5-carboxylic acid (Intermediate XVIId, 1.29 g, 98 % yield) (E) Intermediates XVIIa and XVIId were condensed following the procedure of Example 12(D) to provide the compound 2-(2-fluorophenyl)-4-phenyl-oxazole-5~carboxylic acid [1- methyl-2-(4-pyrid-2-yl-piperazin-l-yl)-ethyl]-amide (compound 17). Example 18: Preparation of 2-(2-fluorophenyl)-4-(2-methyIsulfanylethy!)-oxazole-5-carboxylic acid [l-methyl-2-(4-pyriinidin-2-yl-piperazin-l-yI)-ethyl]-amide Proceeding as set forth in Example 13, but substituting 2-fluorobenzoyl chloride for 2,4-difluorobenzoyl chloride, the compound 2-(2-fluorophenyl)-4-(2-methyIsulfanylethyl)-oxazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 18) was prepared. Example 19: Preparation of 2-(2-fluorophenyl)-4-(2-methyIsu!fonylethyl)-oxazole-5-carboxylic acid [l-methyl-2-(4-pyrimldin-2-yI-piperazin-l-yl)-ethyl]-amide Proceeding as set forth in Example 14, but substituting compound 18 for compound 12, the compound 2-(2-fluorophenyl)-4-(2-methylsulfonylethyl)-oxazole-5-carboxylic acid [1-methyl-2-(4~pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 19) was prepared. Example 20: Preparation of 2,5-diphenyloxazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-p!perazin-l-yI)-ethyl]-amide (A) To a suspension of ethyl 2-amino-acetate (1.0 g, 7.16 mmol) in anhydrous CH2CI2 (5 ml) was added TEA(1.82 g, 17.96 mmol). The reaction mixture was cooled in an ice bath, and a solution of benzoyl chloride (l.Og, 7.17 mmol) in CH2CI2 (2 ml) was added drop-wise. After addition was completed, stirring was continued at RT for two more hours. The reaction mixture was washed with water, dried with MgS04r filtered, and concentrated. Column chromatography (silica, 30% EtOAc in hexanes) gave benzoylaminoacetic acid ethyl ester (intermediate XXa, 1.24 g) as a white solid. (B) To a solution of intermediate XXa (0.62 g, 2.99 mmol) in anhydrous THF (10 ml) was added Lawesson's reagent (0.85 g, 2.09 mmol). The reaction mixture was heated at reflux for 1 h, and solvent was removed under reduced pressure. Column chromatography (sihca, 25% EtOAc in hexanes) gave thiobenzoylaminoacetic acid ethyl ester (intermediate XXb, 0.48 g) as yellow solid. (C) To a solution of intermediate XXb (0.24 g, 1.09 mmol) in CH2CI2 (3 ml) at -78°C was added BF3 etherate (0.18 g, 1.2 mmol). The reaction mixture was stirred at 0°C for 2 h before it was quenched with water (1 ml). The organic layer was washed with sat. NaHCOs solution, H2O, dried with Na2S04, filtered, and concentrated to yield (methylsulfanyl-phenyl-methyleneimino) acetic acid ethyl ester (intermediate XXc, 0.24 g) as yellow oil. (D) To a solution of intermediate XXc (0.23 g, 0.97 mmol) in CH2CI2 (1.5 ml) was added benzoyl chloride (0.82 g, 5.81 mmol)and TEA (0.59 g, 5.81 mmol) in that order. The reaction mixture was stirred at RT for 16 h. Saturated NaHC03 solution (2 ml) was added and stirring was continued for another hour. The organic layer was separated, washed with H2O, dried over MgS04, filtered and concentrated. Column chromatography (silica, 10% EtOAc in hexanes) yielded 2,5-diphenyloxazole-4-carboxylic acid ethyl ester (intermediate XXd, 0.254 g) as pale yellow solid. (E) To a solution of intermediate XXd (0.254 g, 0.87 mmol) in THE (6 mL) was added a solution of NaOH (0.34 g, 8.66 mmol) in H2O (3 ml). The reaction mixture was Heated at 70°C for 3 h. Most af the THE was removed under reduced pressure and the residue was acidified lo pH 2 using 3N HCl. The solid precipiiated out was collected and dried to pro vide 2,5-diphenyloxazole-4-carboxyIic acid (intermediate XXe, 0.151 g) as white solid. (F) Following the procedure set forth in Example 21(F), but substituting intermediate XXe for XXIe, the compound 2,5-diphenyloxa2o]e-4-carboxylic acid [l-methyl-2-(4- pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 20) was prepared. M"‘H = 469. (G) Similarly, following the procedure set forth in Example 20 (F) but substituting 2-(2- fluorophenyl)-4-propyl-oxazole-5-carboxylic acid for XXe, the compound 2-(2-fluoro- phenyl)-4-propyl-oxazole-5-carboxylicacid [l-methyl-2-(4-pyrimidin-2-yl-piperizin-l- yl)ethyl]-amine (compound 23) was prepared. Example 21: Preparation of 2-(2-fluorophenyl)-4-(4-morphoIinyIinethyl)-oxazoIe-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyI]-amide (A) To a homogeneous solution of L-alanine(5g, 56.1 mmol) in acetone (90 ml) and IN NaOH (90 ml) was added 2-fluorobenzoyl chloride (8.9g, 56.1 mmol) dropwise. Basicity of the reaction was maintained by adding IN NaOH periodically. After the addition of 2-fluorobenzoyl chloride was completed, the reaction mixture was acidified to pH 2 using IN HCl. The oil that precipitated out was extracted into EtOAc, which was dried over MgS04, filtered, and concentrated to yield 2-(2-fluorobenzcylamino)propionic acid (intermediate XXIa, 3.92 g). Upon standing, more crystals of intermediate XXIa (2.3 g) precipitated from the acidic aqueous solution and were collected. (B) A solution of intermediate XXIa (2.3 g, 10.9 mmol), and oxalyl dichloride (13.8 g, 108.9 mmol) in anhydrous THE (50 ml) was stirred at RT for 16 h and concentrated. The residue was taken up in toluene and concentrated again. This processes was repeated to ensure complete removal of excess oxalyl dichloride. To the cold residue (in an ice bath) was added TEA (1.66 g, 16.3 mmol) and anhydrous jMeOH (70 ml). The reaction mixture was stirred at RT overnight and concentrated. Flash chromatography (silica, 10% EtOAc in hex) yielded 2-(2-fluorophenyl)-4-methyloxazole-5-carboxylic acid methyl ester (intermediate XXIb, 1.34g) as a white solid. (C) A solution of intermediate XXIb (489 mg, 2.08 rtimol) and azobisisobutyronitrile (AIBN, 68 mg, 0.42 mmol) in CCI4 (25 ml) was heated at reflux, and N~bromosuccinimide (NBS, 370 mg, 2.08 mmol) was added portionwise. The reaction mixture heated at reflux overnight and was washed with HJO. The organic solution was dried over MgSO.-i, filtered, and concentrated to yield a mixture of 2-(2-fluorophenyl)-4-bromomethyl-oxa2ole-5-carboxylic acid methyl ester (intermediate XXIc, 705 mg) and intermediate XXIb in a 7:3 ratio, (D) To solution of morpholine (40 mg, 0.45 mmol) in CH2CI2 (chilled in an ice bath) was added a solution of intermediate XXIc (140 mg, 0.45 mmol) and TEA (51 mg, 0.49 mmol). The reaction mixture was stirred at RT overnight and flash chromatographed (14% MeOH in CH2CI2) yielded 2-(2-fluorophenyl)-4-morpholinomethyl-oxazole-5-carboxyIic acid methyl ester (intermediate XXId, 60 mg) as pale yellow glass. (E) To a solution of NaOH (75 mg, 1.87 mmol) in H2O (0.7 ml) was added a solution of intermediate XXId (60 mg, 0.19 mmol) in THF (1.5 ml). The reaction mixture was heated at 70°C for 3 h and concentrated. The solution was adjusted to pH 1 with 3N HCl and con centrated to provide crude 2-(2-fluorophenyl)-4-morpholinomethyl-oxazole-5-carboxylic acid (intermediate XXIe) as an HCl salt. (F) A solution of crude intermediate XXIe and intermediate Xllld (50 mg, 0.17 mmol), di-isopropyl-ethylamine (DIEA, 267 mg, 2.04 mmol) and 2-(l-H-benzotriazol-l-yl-)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 64 mg, 0.17 mmol) in anhydrous THF (2.5 ml) was stirred at RT for 16 h. The reaction mixture was pardtioned between EtOAc and H2O. The organic layer was dried over MgS04, filtered and concentrated. PTLC (6% MeOH in CH2CI2) provided 2-(2-fluorophenyl)-4-(4- morpholinylmethyl)-oxazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l- yl)-ethyl]-amide (compound 21, 25 mg) as a white soHd. M"‘H = 510. (G) Similarly, proceeding as set forth above but substituting 1-methylpiperazine for mor pholine, the compound 2-(2-fluorophenyl)-4-(l-methyl-piperazin-4-ylmethyl)-oxazole-5- carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 22) was prepared. jExample 22: Preparation of 2-phenyl-4-(4"Chlorophenyl)-thiazoIe-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (A) To a suspension of dicyclohexylcarbodiimide polymer (128 mg, 0.1 mmol) supported' in CH2CI2 (1.5 ml) were added [4-(4-chlorophenyl)-2-phenyl-thiazol-5-yl]-acetic acid, (0.06 mmol) and hydroxybenzotriazole (HOBT, O.OBSmmol). The mixture was agitated at RT lor .1 h. l-methyl-2-(4-pyrimidin-2-yl-pipcrazin-l-y])ethyl amine (0.05 mmole) in DMF solution (0.1 ml) was added. The mixture was agitated for 18 h at RT. The resin was filtered off and washed 3 times with dichloromethane. The product, 2-[4-(4-Chloro-phenyl)-2-phenyl-thiazol-5-yl]-N-[l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-acetamide (compound 25) was purified via preparative HPLC. M"‘=533. (B) Similarly, proceeding as set forth in part (A) above but substituting 3-(4,5-diphenyl-oxazol-2-yl)propionic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 4,5-diphenyloxazol-2-yl propionic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethyl]-amine or 3-(4,5-diphenyl-oxazol-2-yl)-N-[l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-propionamide (according to AUTONOM)(compound 26) was prepared. M+H = 497 (C) Similarly, proceeding as set forth in part (A) above but substituting 2-methyl-4-phen-yloxazol-5-yl acetic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 2-methyl-4-phenyl-oxazole-5-acetic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethyl]-amine or 2-(5-methyl-2-phenyl-oxazol-4-yl)-N-[l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-acetamide (according to AUTONOM)(compound 27) was prepared. M+ H = 421 (D) Similarly, proceeding as set forth in part (A) above but substituting 2,4-diphenyl-thiazole-5-acetic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 2,4-diphenyl-thiazole-5-acetic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethyl]-amine or 2-(2,4-diphenyl-thiazol-5-yl)-N-[l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-acetamide (according to AUTONOM)(compound 28) was prepared. M+ H = 499 (E) Similarly, proceeding as set forth in part (A) above but substituting 2-(4-chloro- phenyl)-4-phenyl-oxazol-5-yl acetic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5- carboxylic acid, the compound 2-(4-chlorophenyl)-4-phenyl-oxazolc-5-aceuc acid [i- methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)ethyl]-amine or 2-[2-(4-chloro-phenyl)-4- phenyl-thiazol-5-yl]-N-[l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-acetamide (according to AUTONOM) (compound 29) was prepared. M+ H = 533 (F) Proceeding as set forth in part (A) above but substituting 2-phenyl-4-trifluoromethyl- thiazole-5-carboxylic acid for 2-phenyl-4-(4-chlorophenyI)-thiazole-5-carboxylic acid, the compound 2-phenyl-4-trifluoromethyl-thiazole-5-carboxylic acid [l-methyl-2-(4-pyrin7i- din-2-y]-piperazin-l-y])~cthvlj-aniide (compound 30) was prepared. M+ H - 477 (G) Proceeding as set forth in part (A) above, but substituting 4-methyl-2-pyridin-2-yl- thiazole-5-carboxylic acid for 2-phenyl-4*(4-chlorophenyl)-thiazo]e-5-carboxylic acid and substituting intermediate Xllld and DIEA (0,03 mL) for l-methyl-2-(4-pyrimidin-2-yl- piperazin-l-yl)ethyl amine, the compound 2-(pyrid-2-yl)-4-methyl-thiazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 31) was pre pared. M+ H = 424 (H) Proceeding as set forth in part (G) above, but substituting 4-methyl-2-p-tolyl-thiazole-5-carboxyIic acid for4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid, the compound 2-(4-methylphenyl)-4-methyl-thiazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 32) was prepared. M+ H = 437 (I) Proceeding as set forth in part (G) above, but substituting 2-(thiophen-2-yl)-4-methyl-thiazole-5-carboxylic acid for 4-methyl-2-pyridin-2-yl-thia2ole-5-carboxylic acid, the compound 2-(thiophen-2-yl)-4-methyl-thiazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]~amide (compound 33) was prepared, M+ H = 429 (J) Proceeding as set forth in part (A) above but substituting 5-methyl-l,3-diphenyI-lH-pyrazole-4-carboxylic acid for 2-phenyl-4-(4-ch]orophenyl)-thiazole-5-carboxylic acid, the compound 5-methyl-l,3-diphenyl-lH-pyra2ole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 35) was prepared. M+ H = 482 Example 23: Preparation of 2,4-diphenyl-thiazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yI)-ethyl]-amide (A) To a solution sulfuryl chloride (0.78 g, 5.78 mmol) in anhydrous CH2CI2 (3 ml), was slowly added a solution of 3-oxo-3-phenylpropionic acid (1.09 g, 5.67 mmol) in anhydrous CH2Cb (10 ml) at -S'‘C, the mixture was stirred at RT for 2 h, partitioned between CH2CI2, and water, and the organic phase was washed with brine, and dried over anhydrous sodmm sulfate. After decanting from the drying agent, the organic solution was concentrated under reduced pressure to yield 2-chloro-3-oxo-3-phenylpropionic acid ethyl ester (intermediate XXIIIa, 1.255 g) as a yellow oil (97%). (B) A solution of intermediate XXIIa (1.24 g, 5.47 mmol) and thiobenzamide (0.90 g, 6.56 mmol) in dry EtOH (10 ml) was heated at reflux for 2.5 h, evaporating most of the EtOH. The residue was partitioned between EtOAc and water, the organic phase was washed with brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in hexanes) to yield 2,4-diphenyl-thiazole-5-carboxylic acid ethyl ester (intermediate XXIIb, 1.16 g) as a white solid (68%). M+H = 310. (C) Following the procedure set forth in Example 20(E - F), but substituting intermediate XXIIIb for XXIe, the compound 2,4-diphenyl-thiazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 34) was prepared. Example 24: Preparation of 5-propyl-l-phenyMH-pyrazole-4-carboxylic acid [1-methyI-2-(4-pyriinidin-2-yl-piperazin-l-yl)-ethyI]-amide (A) Similarly, proceeding as set forth in Example 22A above, but substituting l-phenyl-5- propyl-lH-pyrazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazoIe-5-carb- oxylic acid, the compound 5-propyl-l-phenyl-lH-pyrazole-4-carboxylic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yI)-ethyl]-amide (compound 36) was prepared. M+ H = 434 (B) Similarly, proceeding as set forth in Example 22A above but substituting l-(3,5-di- chlorophenyl)-5-propyl-lH-pyrazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)- thiazole-5-carboxylic acid, the compound 5-propyl-l-(3,5-dichlorophenyl)-lH-pyrazole-4- carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 37) was prepared. M+ H = 502 (C) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-fluoro-phenyI)-5-propyl-lH-pyrazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 5-propyl-l-(4-fluorophenyl)-lH-pyrazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 38) was prepared. M+ H = 424 (D) Similarly, proceeding as set forth in Example 22A above but substituting 5-t-buty!-2~ (4-fluorobenzyI)-2H-pyrazole-3"Carboxylic acid for 2-phenyl-4-(4-ch]orophenyl)-thiazolc-5-carboxylic acid, the compound 5-t-butyl-2-(4-fluorobenzyl)-2H-pyrazole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 39) was prepared. M+ H = 480 (E) Similarly, proceeding as set forth in Example 22A above but substituting l-phenyl-5- (4-chlorophenyl)-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole- 5-carboxylic acid, the compound l-phenyl-5-(4~chlorophenyl)-lH-pyrazole-3"Carboxylic acid [l-methy]-2~(4-pyrimidin-2-yl-piperazin-1 -yl)-ethyl]--amide (compound 40) was prepared. M+ H = 502 (F) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-fluoro- phenyl)-5-(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid for 2-phenyl-4~(4-chlorophen- yl)-thiazole-5-carboxylic acid, the compound l-(4-fluorophenyl)-5-(4-chlorophenyl)-lH- pyrazole~3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 41) was prepared. M+H = 520 (G) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-fluoro- phenyl)-5-phenyl-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thi- azole-S-carboxylic acid, the compound l-(4-fluorophenyl)-5-phenyl-lH-pyrazole-3-carb- oxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 42) was prepared. M+ H = 486 (H) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-methyl-phenyI)-5-phenyl-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thi-azole-5-carboxylic acid, the compound l-(4-methylphenyl)-5-phenyl-lH-pyrazole-3-carb-oxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 43) was prepared. M+ H = 482 (I) Similarly, proceeding as set forth in Example 22A above but substituting l-phenyl-5-(2-chlorophenyl)-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyI)-thiazole-5-carboxyIic acid, the compound l-phenyl-5-(2-chlorophenyl)-lH-pyrazole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 44) was prepared. M+ H = 502 (J) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-sulf-amoylphenyl)-5-(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound l-(4-sulfamoylphenyl)-5-(4-chlorophenyl)-lH"pyrazolc-3-carboxylic acid [l-melhyl-2-(4-pyrim)dln-2-yi-pipcrazin-l-yl)-elhyl]-amide (compound 45) was prepared. M+ H = 581 (K) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-chloro-phenyl)-5-phenyl-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thi- azole-5-carboxylic acid, the compound l-(4-chlorophenyl)-5-phenyl-lH-pyra2ole-3-carb-' oxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 46) was prepared. M+ H == 502 (L) Similarly, proceeding as set forth in Example 22A above h\:\ subslituting 1,5-di- phenyl-lH-pyrazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5- carboxylic acid, the compound l,5-diphenyl-lH-pyrazole-4-carboxylic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 47) was prepared. M+ H - 468 (M’ .Similarly, proceeding as set forth in Example 22A above but substituting l,5-bis(4- chlorophenyl)-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5- carboxylic acid, the compound l,5-bis(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid [1- methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 48) was prepared. M+H = 536 (N) Similarly, proceeding as set forth in Example 22A above but substituting l-(2-chloro- phenyl)-5-phenyl-lH-pyrazole-3-carboxyIic acid for 2-phenyl-4-(4-chlorophenyl)-thia- zole-5-carboxylic acid, the compound l-(2-chlorophenyl)-5-phenyl-lH-pyrazole-3-carb- oxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 49) was prepared. M+ H = 502 (O) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-chloro- phenyl)-5-propyl-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole- 5-carboxyIic acid, the compound l-(4-chlorophenyl)-5-propyl-lH-pyrazole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 50) was prepared. M+ H = 468 (P) Similarly, proceeding as set forth in Example 22A above but substituting 1,3-di- phenyl-lH-pyrazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5- carboxylic acid, the compound l,3-diphenyl-lH-pyrazole-4-carboxylic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 51) was prepared. M+ H = 468 (Q) Similarly, proceeding as set forth in Example 22A above but substituting 2,5-di- phenyl-2H-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5- carboxylic acid, the compound 2,5-diphenyl~2H-pyrazole-3-carboxylic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 52) was prepared. M+ H = # 468 (R) Similarly, proceeding as set forth in Example 22A above but substituting 1,5-di- phenyi-lH-pyrazole-3-carboxyJic acid for 2-phenyl-4-(4-chlorophenyl)-ihiazo]e-5- carboxylic acid, the compound l,5-diphenyl-lH-pyrazole-3-carboxylic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 53) was prepared. M+ H = 468 (S) Similarly, proceeding as set forth in Example 22A above but substituting l-(4-methyl- phenyl)-5-(2-chlorophenyl)-lH-pyrazole-3-carboxyIic acid for 2-phenyl-4-(4-ch]oro- phenyl)-thiazole-5-carboxylic acid, the compound l-(4-methylphenyl)-5-(2-chlorophenyl)- lH-pyrazole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]- amide (compound 54) was prepared. M+ H = 516 (T) Similarly, proceeding as set forth in Example 22G above but substituting l-phenyl-3- (biphen-4-yl)-lH-pyra2ole-4-carboxylic acid for 4-methy]-2-pyridin-2-yl-thiazole-5- carboxylic acid, the compound l-phenyl-3-(biphen-4-yI)-lH-pyrazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 55) was prepared. M+ H = 544 (U) Similarly, proceeding as set forth in Example 22G above but substituting 2-phenyl-5- isopropyl-2H-pyrazo]e-3-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5- carboxylic acid, the compound 2-pheny]-5-isopropyl-2H-pyrazole-3-carboxylic acid [1- methyl-2-(4-pyrimidin-2-yl-pipera2in-l-yl)-ethyl]-amide (compound 56) was prepared. M+ H = 434 (V) Similarly, proceeding as set forth in Example 22G above but substituting l-(2-tri- fluoromethyl-phenyl)-3-(pyridin-4-yl)-lH-pyrazole-4-carboxylic acid for 4-methyl-2- pyridin-2-yl-thiazole-5-carboxylic acid, the compound l-(2-trifluoromethy]-phenyl)-3- (pyridin-4-yl)-lH-pyrazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l- yl)-ethyl]-amide (compound 57) was prepared. M+ H = 537 (W) Similarly, proceeding as set forth in Example 22G above but substituting l-(4-meth- oxypheny])-5-pheny!-lH-pyrazole-3-carboxylic acid for 4-methyl-2-pyridin~2~yl-thiazole- 5-carboxyiic acid, the compound l-(4-methoxyphenyl)-5-phenyl-lH~pyrazole-3-carb- oxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 58) was prepared. M+H = 498 (X) Similarly, proceeding as set forth in Example 22G above but substituting l-phenyI-3-(4-chlorophenyl)-lH-pyrazole-4-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid, the compound l-phenyl-3-(4-chloropheny})-lH-pyrazole-4-carboxylic acid [l-methy]-2-(4-pyrimidin-2-yl"piperazin-l-y])-cthylJ-amide (compound 59) was prepared. M+ H = 502 (Y) Similarly, proceeding as set forth in Example 22G above but substituting l-phenyl-3-(4-fluorophenyl)-lH'pyrazole-4-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acidthe compound l-phenyl-3-(4-fluorophenyl)-lH-pyrazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 60) was prepared. M+ H = 486 (Z) Similarly, proceeding as set forth in Example 22G above but substituting l,5-bis(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid, and l-methyl-2-(4-acetyl-piperazin-l-yl)ethyl amine for intermediate Vd, the compound l,5-bis(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 61) was prepared. M+ H = 500 (AA) Similarly, proceeding as set forth in Example 220 above but substituting l-(2-chlorophenyl)-5-(4-methylphenyl)-lH-pyrazole-3-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid, and l-methyl-2-(4-acetyI-piperazin-l-yl)ethyl amine for intermediate Vd, the compound l-(2-chlorophenyl)-5-(4-methylphenyl)-lH-pyrazole-3-carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 62) was prepared. MH- H = 480 (BB) Similarly, proceeding as set forth in Example 22A above but substituting 1,3-di-phenyl-lH-pyrazol-4-yl acrylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound l,3-diphenyMH-pyrazol-4-yl acrylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 64) was prepared. M+ H = 524 (CC) Similarly, proceeding as set forth in Example 22A above, but substituting 2-methyl-l,5-diphenyl-lH-pyrrole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 2-methyl-l,5-diphenyl-lH-pyrrole-3-carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 65) was prepared. M+H = 481 (DD) Similarly, proceeding as set forth in part (A) above, but substituting 2-methyl-l-(4-methylsulfanylphenyl)-5-phenyl-lH-pyrrole-3-carboxylic acid for 2-phenyl-4-(4-chloro- phenyl)-thiazole-5-carboxylic acid, the compound 2-methyl-l-(4-methylsulfanylphenyl)-5-phenyMH-pyrrole-3-carboxylic acid [l-methyl-2-(4-pyrimidiTi-2-yl-piperazin-l-yl)-ethylj-amide (compound 66) was prepared. M+ H = 527 (EE) Similarly, proceeding as set forth in Example 22A above but substituting 5-t-buty]-2-(2-methylbenzyl)-2H-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thi-azole-5-carboxylic acid, the compound 5-t-butyl-2-(2-methylbenzyl)-2H-pyrazole-3-carb-oxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 67) was prepared. M+ H = 476 (FF) Similarly, proceeding as set forth in Example 22A above but substituting l-(3-chlorophenyl)-5-(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyI)-thiazole-5-carboxylic acid, the compound l-(3-chlorophenyl)-5-(4-chloro-phenyl)-lH-pyrazole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-pipera2in-l-yl)-ethyl]-amide (compound 68) was prepared. M+ H = 536 Example 25: Preparation of 2-(4-fluorophenyl)-5-phenyl-3H-imidazole-4-carboxync acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide Proceeding as set forth in Example 23 above but substituting 2-(4-fluorophenyl)-5-phenyl-3H-imidazole-4-carboxylic acid for 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid, the compound 2-(4-fluorophenyl)-5-phenyl-3H-imidazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 63) was prepared. Example 26: Preparation of 3,5-diphenyI-furan-2-carboxyHc acid [l-methyl-2-(4-pyrimidin-2-yI-piperazin-l-yI)-ethyl]-amide (A) To a mixture of benzaldehyde (2.6 ml, 25.58 mmol) and acetophenone (6 ml, 51.44 mmol) in anhydrous benzene (3 ml), was added boron trifluoride diethyl etherate (8 ml, 63.13 mmol) at RT. The mixture was heated at reflux for 2 h, cooled to RT, acetone was added (5 ml), and the resulting dark red solution was poured into ether (250 ml), A dark yellow precipitate forme.d, which was isolated and redissolved in acetone (30 ml), ether was added until the yellow solid was formed, isolated and dried to provide 2,4,6-triphenyl-pyranylium (3.87g, 48%, mw = 309). To a suspension of 2,4,6-triphenyl-pyranylium (3.86 g, 12.5 mmol) in acetone (50 ml), was added a solution of Na2C03 (1.7 g, 16 mmol) in H2O (4.6 ml), and the mixture was stirred at RT for 2 h. To the reaction mixture, iodine (4.1 g, 16.1 mmol) was added, and the resulting mixture was stirred at RT overnight, then poured into a solution of sodium thiosulfate pentahydrate (40.0 g, 160 mmol) in water (250 ml), extracted with CHoCh. The organic phase was washed with brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced . pressure. The residue was purified by silica gel chromatography (1% EtOAc in hexane) to provide (3,5-diphenylfuran-2"yl)-phenyl-methanone (intermediate XXVIa, 1.6 g, 19%) as a yellow solid. (B) To a suspension of potassium t-butoxide (5.6 g, 50 mmol) in dioxane (25 ml) and water (0.27 ml), was added intermediate XXVIa. The mixture was stirred at RT for 30 min, poured into ice water (250 ml), and stirred for 1.5 h. The precipitate was isolated and redissolved in EtOAc, which was washed with water and brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% EtOAc in hexane) to yield 2,4-diphenylfuran (intermediate XXVIb, 0.99 g, 91%) as a pale yellow solid. (C) To a solution of chlorosulfonyl isocyanate (0.45 ml, 5.16 mmol) in acetonitrile (15 ml) and CH2CI2 (15 ml) was added dropwise a solution of intermediate XXVIb (0.748 g, 3.4 mmol) in CH2CI2 (10 ml) at -78°C. The mixture was stirred at -78'C for one h, and was then treated with a solution of N,N-dimethyl formamide (DMF, 1 ml, 14.1 mmol) in CH2CI2 (1 ml). The resulting solution was stirred from -78°C to -35°C over 3.5 hours, at RT for 2 h, then poured into ice, partitioned between EtOAc and 5% aqueous NaHCOs. The organic phase was washed with brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced pressure. The residue was purified by silica gel chromatography (2%, 6% EtOAc in hexane) to yield 3,5-diphenylfuran-2-carbonitrile (intermediate XXVIc, 0.512 g, 61%) as a yellow solid. (D) A mixture of the intermediate XXVIc (0.14 g, 0.57 mmol) in MeOH (10 ml) and KOH (4,0 g, 71.3 mmol) in water (10 ml) was heated at reflux for 8 h, and cooled to RT. After most of the MeOH was removed, the pH of the aqueous solution was adjusted to acidic, and the sohd was isolated and redissolved in EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, decanted , and the organic solution concentrated under reduced pressure to provide 3,5-diphenylfuran-2-carboxylic acid (intermediate XXVId, 0.147 g, 98%) as a pale yellow solid. MW-1 = 263. (E) Proceeding as set forth in Example 21(F), but substituting intermediate XXVId for intermediate XXIe, the compound 3,5-diphenyl-furan-2-carboxylic acid [l-methyl~2-(4- pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 81) was prepared. M"*’H - 468. (F) A suspension of 2,5-dipheny]ruran-3-carbunitnle (0.87 g, 3.56 mmol) in ethylene glycol and 3M NaOH (10 ml) was heated at reflux for 3 days. Water was added to the reaction mixture and extracted into CH2CI2 . The organic layer was dried with MgS04, filtered and concentrated to provide 2,5-diphenylfuran-3-carboxylic acid (intermediate XXVIf, 900 mg) as white solid. (G) Proceeding as set forth in part (E) above, but substituting intermediate XXVIf for intermediate XXVId, the compound 2,5-diphenyl-furan-3-carboxylic acid [l-methyl-2-(4- pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 80) was prepared. M"‘H = 468. (H) Similarly, proceeding as set forth in part (E) above, but substituting l-methyl-2-(4- acetyl-piperazin-l-yl)ethyl amine for intermediate Xllld, the compound 3,5-diphenyl- furan-2-carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 78) was prepared. M+ H = 432 Example 27: Preparation of l-(2,4-difluorophenyl)-5-phenyl-lH-[l,2j3]triazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (A) Proceeding as set forth in Example 22(A), but substituting l-(2,4-difluorophenyl)-5-phenyl-lH-[l,2,3]triazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound l-(2,4-difluorophenyl)-5-phenyl-lH-[l,2,3]triazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 70) was prepared. M+ H = 505 (B) Proceeding as set forth in Example 22(A), but substituting l-(3-trifluoromethyl-phenyl)-5-phenyl-lH-[l,2,3]triazole-4-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound l-(3-trifluoromethylphenyl)-5-phenyl-lH-['l,2.3]triazole-4-carboxylic acid f ] -methyl-2-(4-pyri-midin-2-yl-piperazin-l -yl)-ethyl]-amide (compound 71) was prepared. M+ H - 537 (C) Proceeding as set forth in Example 22(A), but substituting l,5-diphenyl-lH-[l,2,4]-triazole-3-carboxylic acid for 2-phenyl-4-(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound l,5-diphenyl-lH-[l,2,4]triazole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-elhyl]-amide (compound 72) was prepared. M+ H = 469 (D) Proceeding as set forth in Example 22(A), but substituting l,5-diphenyl'-lH-[l,2,3]~ triazole-4-carboxylic acid for 2-phcnyl-4-(4-chlorophenyl)4hiazole-5-carboxyIic acid, the compound l,5-diphenyl-lH-[l,2,3]triazole-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2- yl-piperazin-l"yl)-ethyl]-amide (compound 82) was prepared. M+ H - 469 (E) Proceeding as set forth in Example 22(A), but substituting 5-methyl-2-phenyI-furan-3- carboxylic acid for 2-phenyl-4~(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 5-methyl-2-phenyl-furan-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)- ethylj-amide (compound 69) was prepared. M+ H = 406 (F) Proceeding as set forth in Example 22(G), but substituting 2-methyl-5-phenyl-furan-3- carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid, the compound 2- methyl-5-phenyl-furan-3-carboxylicacid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)- ethyl]-amide (compound 73) was prepared. M-f H = 406 (G) Proceeding as set forth in Example 22(G), but substituting 5-(4-fluorophenyl)-furan- 2-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazole-5-carboxylic acid, the compound 5- (4-fluorophenyl)-furan-2-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yI-piperazin-l-yl)- ethyl]-amide (compound 74) was prepared. M+ H = 410 (H) Proceeding as set forth in Example 22(G), but substituting 2-(N,N-diethylamino-methyl)-5-phenyl-furan-3-carboxylic acid for 4-methyl-2-pyridin-2-yl-thiazoie-5-carb-oxylic acid, the compound 2-(N,N-diethylaminomethyl)-5-phenyl-furan-3-carboxylic acid [l-methyI-2-(4-pyrin:iidin-2-yl-piperazin-l-yl)-ethyI]-amide (compound 75) was prepared. M+ H = 477 (I) Similarly, proceeding as set forth in part (H) above, but substituting 2-methyl-l-(3-morpholin-4-ylpropyl)-5-phenyl-lH-pyrrole-3-carboxylic acid for 2-(N,N-diethylamino-methyI)-5-phenyl-furan-3-carboxylic acid, the compound 2-methyl-l-(3-morpholin-4-yl-propyl)-5-phenyl-lH-pyrrole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-y]-piperazin-l-yl)-ethyl]-amide (compound 76) was prepared. M+ H = 532 (J) Similarly, proceeding as set forth in part (H) above, but subsliluting 2-methy]-l-(4-methylsulfanylphenyl)-5-phenyl-lH-pyrrole-3-carboxylic acid for 2-(N,N-diethylamino-methyl)-5-phenyl-furan-3-carboxylic acid, the compound 2-methyl-l-(4-methylsulfanyl- phenyl)-5-phenyl-lH-pyrrole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 77) was prepared. M+ H - 491 (K) Proceeding as set forth in Example 22(A), but substituting 2-methyl-5-(4-ch]oro-phcnyl)~furan-3-carboxylic acid for 2-phenyl-4~(4-chlorophenyl)-thiazole-5-carboxylic acid, the compound 2-methyl-5-(4-chlorophenyl)-furan-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 79) was prepared. M-f H = 440 Example 28: Preparation of 3-(2-fluorophenyl)-l-methyI-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amide (A) To a solution of ethyl-2-fluorobenzoylacetate (4.3 ml, 24 mmol) in EtOH (48 ml) was added methylhydrazine (1.32 ml, 25 mmol) under N2 at RT. The reaction was heated at reflux for 18 h. The mixture was then evaporated, and the off white solid residue taken up in hot EtOAc. The mixture was cooled down, and the white solid not dissolved was collected via filtration and washed with hexane, then dried under reduced pressure to yield 5-(2-fluorophenyl)-2-methyl-2H-pyrazol-3-ol (intermediate XXVIIIa, 3.54 g, 77% yield). M"" = 193. (B) To DMF (2.32 ml, 30 mmol) at 0°C under N2, phosphorus oxychloride (6.52 ml, 70 mmol) was added dropwise over 10 min. The reaction was stirred for 20 min at 0°C (phosphorus oxychloride tends to freeze, so the ice bath was removed to let the reaction stir: it was never allowed over 10°C). Intermediate XXVIIIa was added in one portion and the mixture stirred at reflux temperature for 30 min. The reaction was cooled down at RT, poured on ice, and quenched with NaOH (15% aqueous). The mixture was acidified to reach pH 6-7, and extracted 3x with CH2CI2. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The crude mixture was purified via flash chromatography, affording 5-chloro-3-(2-fluorophenyl)-l-methyl-lH~pyrazole-3-carbaldehyde (intermediate XXVIIIb, 1.6 g, 67 % yield) as a white solid. M"'= 239. (C) To a solution of finely ground KOH (753 mg, 13 mmol) in a mixture of MeOH (4.5 ml) and water (1.1 ml), thioglycolic acid (0.349 ml, 5 mmol) was added, followed by intermediate XXVIIIb (800 mg, 3.4 mmol) at RT. The reaction mixture was heated at reflux for 3 h. The solvent was evaporated, and the off white solid residue taken up in hot water and filtered. The filtrate was cooled down at RT, and acidified with HCl (6N) to pH 3. The white solid precipitated, and was filtered and washed with water and hexane. It was dried at 40°C under reduced pressure to yield 3-(2-fIuorophenyl)-l-methyl-lH-thieno[2-3-c]-pyrazole-5-carboxylic acid (intermediate XXVIIIc, 926 mg, 92% yield). (D) Following the procedure set forth in Example 4 but substituting intermediate XXVIIIc for intermediate If, the compound 3-(2-fluorophenyl)-l-methyl-lH-thieno[2,3-c]pyrazole- 5-carboxylicacid [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amide (compound 85, 22% yield) was obtained as a yellow foam. M"‘ = 460. (E) Proceeding as set forth in part D above, but substituting l-methyl-3-phenyl-lH-thi- eno[2,3-c]pyrazole-5-carboxylic acid for intermediate XXVIIIc, the compound 3-phenyl- l-methyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [l-methyl-2-(4-thioacetyl-piperazin- l-yl)-ethyl]-amide (compound 83, 23% yield) was obtained as a white foam. M"‘ = 442. (F) Proceeding as set forth in part (E) above, but substituting l-methyl-2-(4-pyrimidin-2- yl-piperazin-l-yl)ethyl amine 2HC1 (intermediate Xllld) for [l-methyl-2-(4-thioacetyl- piperazin-l-yl)-ethyl]-amine and using DMF as the solvent, the compound 3-phenyl-l- methyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piper- azin-l-yl)-ethyl]-amide (compound 89, yield). M+ H = 462 (G) Proceeding as set forth in part (E) above, but substituting [l-methyl-2-(4-acetyl- piperazin-l-yl)-ethyl]-amine for [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amine, the compound 3-phenyl-l-methyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [1-methyl- 2-(4-acetyl-piperazin-l-yI)-ethyl]-amide (compound 91) M"‘ = 426. (H) Proceeding as set forth in part (E) above, but substituting [l,l-dimethyl-2-(4-pyrimi-din-2-yl-piperazin-l-yl)-ethyl]-amine for [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amine, the compound 3-phenyl-l-methyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [1,1-dimethyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 90) was obtained. M+ H = 476 (I) Proceeding as set forth in part (E) above, but substituting intermediate IIIc for [1-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amine, the compound 3-(2-fluorophenyl)-l-methyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [l-methyl-2-(4-thiazol-2-yl-piperazin-l-yl)-elhyl]-amide (compound 84) was obtained as a white foam in 86'‘;? yield. M" = 467. (J) Proceeding as set forth in part (C) above, but substituting ethylhydrazine for methyl-hydrazine, the acid 3-phenyl-l-ethyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid (Intermediate XXVIIIj) was obtained. Proceeding as set forth in part (F), but substituting Inter- mediate XXVIIIj for l"methy]-3-phenyl-lH-thieno[23-c]pyrazole-5-carboxylic acid , the compound 3-phenyl-l-ethyl-lH-thieno[2,3-c]pyrazole-5-carboxyIic acid [l-methy]-2-(4- pyrimidin-2-yI-piperazin-l-yl)-ethyl]-amide (compound 86) was obtained as a white powder (yield 48%, mp 64-68.5’C, M’ = 476). (K) Proceeding as set forth in part (D) above, but substituting [l-methyl-2-(4-acetyl- piperazin-l-y])"ethyl]-aminefor [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amine, the compound 3-(2-fluorophenyl)-l-methyI-lH~thieno[2,3-c]pyra2ole-5--carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 87) was obtained (82% yield, M’ := 444). (L) Proceeding as set forth in part (J) above, but substituting ethyl-2-methyIbenzoyl- acetate for ethyl-2-fluorobenzoylacetate, the compound 3-(2-methylphenyl)-l-ethyl-lH- thieno[2,3-c]pyrazole-5-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-pipera2in'l-yl)- ethyl]-amide (compound 88) was obtained as a white powder (yield 30%, mp 89-93°C, M"‘ = 476). (M) Proceeding as set forth in part (F) above, but substituting l-phenyl-3-methyl-lH- thieno[23-c]pyrazole-5-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]pyrazole- 5-carboxyIic acid, the compound 3-methyl-l-phenyl-lH-thieno[2,3-c]pyra2ole-5- carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 92) was obtained. M+ H = 462 (N) Proceeding as set forth in part (D) above, but substituting intermediate Vd for [1- methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amine, the compound 3-(2-fluorophenyl)-l- methyl-lH-thieno[2,3-c]pyrazole-5-carboxylicacid [l-methyl-2-(4-pyrimidin-2-yl- piperazin-l-yl)-ethyl]-amide (compound 96) was obtained. Example 29: Preparation of (R)-l-methyl-3-phenyl-lH-thieno[2,3-c]pyrazole-5-carb-oxylicacid [l-methyl-2-(4-thioacetyl-piperazin-l-yl)-ethyl]-amide (A) (R)-(l-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.85 g, 10.7 mmole) and acetyl piperazine (1.53g, 12 mmole) were combined in dichloroethane (125 mL). NaBH(OAc)3 (4,53 g. 21 mmole) was added. The resultant reaction solution was stirred at RT for 20 h. An equal volume of saturated NaHCOs was added. The aqueous phase was extracted 3 times with CH2CI2. The combined organic extracts were washed with saturated NaCl, dried over Na2S04 and concentrated under vacuum. Purification by silica chroma- tography (5% methanol in CH2C12 provided (R)-[2-(4-acetylpipera2in-l-yl)-l-methyl~ ethyl]-carbamic acid tert-butyl ester (intermediate XXIXa, 2.6 g) (B) Intermediate XXIXa (2.6 g) was dissolved in 80 mL of CHiCk TFA(10mL)was added. The reaction solution was slirred at RT for 2 h to afford (R)-l-[4-(2'-amino-propyl)-piperazin-l-yl]-ethanone (Intermediate XXIXb, 100% yield) (C) To a solution of l-methy]-3-phenyI-lH-thieno[2,3-c]pyrazole-5-carboxylic acid (Tg, 4 mmole) in anhydrous THF (60 mL) was added HBTU (1.5 g, 4 mmol), intermediate XXIXd (4 mmol) in THF (8 mL) and DIEA (4 mL). The reaction mixture was stirred at RT 18h before concentration. Purification by flash chromatography 5% methanol in CHnCh afforded (R)-l-methyl-3-phenyl-lH-thieno[23-c]pyrazole-5-carboxylic acid [2-(4-acetyl-piperazin-l-yl)-l-methyl-ethyl]-amide (Compound 93,1.13g). Compound 93 was converted to the oxylate salt (1.37 g). M+ = 426, ‘H nmr 5D(MeOH, 1.0) = -95.2, mp 133.9 -139.9°C (D) Proceeding as set forth in part (A -C) above, but substituting (S)-(l-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (R)-(l-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester, the compound (S)-l-methyl-3-phenyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid [2-(4-acetyl-piperazin-l-yl)-l-methyl-ethyl]-amide (compound 94, 0.7 g) was obtained. Compound 94 was converted to the oxylate salt (0.6 g). M+ = 426, IH nmr: 5D(MeOH, 1.0) = +94.5, mp 133.5 -140.1°C. (E) Proceeding as set forth in part C above, but substituting l-methyl-3-(2-fluorophenyl)- lH-thieno[2,3-c]pyrazole-5-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]' pyrazole-5-carboxylic acid, the compound (R)-l-methyI-3-(2-fluorophenyI)-lH-thieno- [2,3-c]pyrazole-5-carboxylic acid [2-(4-acetyl-piperazin-l-yl)-l-methyl-ethyl]-amide (Compound 95) was prepared. M+ H = 444 Example 30: Preparation of l-methyI-3-phenyI-lH-indazole-5-carboxylic acid [1-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (A) To a solution of phenylmagnesium chloride (5.5 ml, 11 mmol, 2M in THF), 5-bromo-2-fluorobenzaldyde (2.03 g, 10 mmol) was added at -78'C under N2. The reaction was allowed to warm up to RT and stirred at RT for 18 h. The milky suspension was poured into a saturated solution of NH4CI and extracted 3x with EtOAc. The organic layers were combined, dried over sodium sulfate, and evaporated. The crude mixture was purified via flash chromatography affording (5-bromo-2-fluorophenyl)-phenyl-methanol (intermediate XXXa, 2.235 g, 80 % yield) as a colorless oil. M'= 281. (B) To a suspension of pyridinium chlorochromate (166 mg, 0.769 mmol) in CH2CI2 (36 ml), a solution of intermediate XXXa (180 mg, 0. 64.1 mmol) ui CH2CI2 (4 ml) was added at RT under No. The reaction was stirred for 4 h at RT, then Et20 (25 ml) was added and the mixture filtered on a plug of fluorisyl. The filtrate was evaporated and the crude residue was purified via flash chromatography to provide (5-bromo-2-fluorophenyl)-phenyl-methanone (intermediate XXXb, 150 mg, 83 % yield) of as a colorless oil. M’= 279. (C) A solution of intermediate XXXb (150 mg, 0.538 mmol) in methyl hydrazine (1.5 ml) was heated at reflux for 3 h. The reaction was cooled down and poured into ice water. The precipitate was not suitable to filtration, so the mixture was extracted 3x with EtOAc. The organic layers were combined, dried and evaporated. The crude product was purified via flash chromatography, affording 5-bromo-l-methyl-3-phenyl-lH-indazole (intermediate XXXc, 125 mg, 81% yield) as a white solid. M'= 287. (D) To a solution of intermediate XXXc (123 mg, 0.429 mmol) in THF (3 ml) at -78°C under No was added butyl-lithium (Bu-Li, 321 |il, 1.6 M in hexane). The orange colored solution was stirred at -78°C under nitrogen for 10 min, then dry CO2 was bubbled trough the solution for 20 min until it discolored. The reaction was allowed to rise to RT, the solvent evaporated, and water added to the residue. HCl (IM) was added to the mixture until pH 2-3 was reached. A white precipitate formed. The solid was filtered and dried, affording l-methyl-3-phenyl-lH-indazole-5-carboxylic acid (intermediate XXXd, 72 mg, 67 % yield). M’= 253. (E) Following the procedure set forth in Example 24(Z) but substituting intermediate XXXc for l,5-bis(4-chlorophenyl)-lH-pyrazole-3-carboxylic acid, the compound 1- methyl-3-phenyl-lH-indazole-5-carboxylicacid [l-methyl-2-(4-acetyl-piperazin-l-yl)- ethyl]-amide (compound 97, 65% yield, mp = 98.8-100.5°C, M"‘ = 420) was produced as a white foam. (F) To a solution of XXXb (976 mg, 3.5 mmol) in EtOH (4 ml) was added hydrazine hydrate (204 fal, 4.2 mmol). The reaction was heated at reflux for 2 h, and stirred at RT for 18 h. The solvent was evaporated, and the residue partitioned between water and EtOAc, the organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated. The crude material was purified via flash chromatography, affording 5-bromo-3-phenyl-lH-indazole (intermediate XXXf, 320 mg, 33% yield) as a white solid. M' == 273. (G) To a solution of intermediate XXXf (136 mg, 0.5 mmol) in EtOAc (3 ml), trimcthyl oxonium tetrafluoroborate (96 mg, 0.65 mmol) was added at RT under N2. The reaction mixture was stirred at RT for 3 h, and the milky suspension partitioned between a saturated solution of NaHC03 and EtOAc. The organic layer was separated and the aqueous fraction was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated. The crude residue was purified via flash chromatography, affording 5-bromo-3-phenyl-2-methyl-lH-indazole (intermediate XXXg, 120 mg, 84 % yield) as a white solid. M’= 287. (H) To a solution of intermediate XXXg (120 mg, 0.418 mmol) in THF (4 ml), Bu-Li (314 )j,l, 1.6 M in hexane) was added at -78°C under No. The reaction mixture was stirred at -78°C for 5 min, and then dry CO2 was bubbled through the reaction mixture for 15 min, until discoloration occurred. The reaction was warmed up to RT and the solvent evaporated. The crude lithium carboxylate (intermediate XXXh) was used in part (I) below. M"‘= 253. (I) Following the procedure set forth in part (E) above, but substituting intermediate XXXh for intermediate XXXc, the compound 2-methyl-3-phenyl'lH-indazole-5-carb-oxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 98) was prepared. The product was purified by preparative HPLC, resulting in a trifluoroacetate salt in 7% yield. M+ = 420 Example 31: Preparation of 3-phenyI-lH-indoIe-2-carboxylic acid [l-inethyl-2-(4-pyrimidin-2-yI-piperazin-l-yI)-ethyI]-ainide (A) Proceeding as set forth in Example 28(F) above, but substituting 3-phenyl-lH-indole-2-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]pyra2ole-5-carboxylic acid, the compound 3-phenyl-lH-indole-2-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piper-azin-l-yl)-ethyl]~amide (compound 99) was obtained- M+ H = 441 (B) Proceeding as set forth in Example 28(F) above, but substituting 5,7-diphenyl-pyrazolo[l,5-a]pyrimidine-2-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]-pyrazole-5-carboxylic acid, the compound 5,7-diphenyl-pyrazolo[l,5-a]pyrimidine-2- carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 100) was obtained. M+H = 519 (C) Proceeding as set forth in Example 28(F) above, but substituting 1-benzyI-lH-indole-3-cyrboxylic acid for l-mcihyl-3-phenyi-]H-lhicno|2,3-c]pyrazoleO-carboxylic acid, the compound l-benzyl-lH-indole-3-carboxylic acid [l-methyl-2-(4-pyriniidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 101) was obtained. M+ H = 455 (D) Proceeding as set forth in Example 28(F) above, but substituting 5-methoxy-2-meth-yl-benzofuran-3-carboxylic acid for l-methyl-3-phenyMH-thieno[2,3-c]pyrazole-5-carb-oxylic acid, the compound 5-methoxy-2-methyl-benzofuran-3-carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 102) was obtained. M+ H = 410 (E) Proceeding as set forth in Example 28(F) above, but substituting 5-phenyl-7-trifluoro- methyl-pyrazolo[l,5-a]pyrimidine-3-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3- c]pyrazole-5-carboxylic acid, the compound 5-phenyl-7-trifluoromethyl-pyrazolo[l,5- a]pyrimidine-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]- amide (compound 103) was obtained. M+ H = 511 (F) Proceeding as set forth in Example 28(F) above, but substituting 5-(4-methoxybenzyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid for l-methyl-3-phenyl- lH-thieno[2,3-c]pyrazole-5-carboxylic acid, the compound 5-(4-methoxybenzyl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid [l-methyl-2-(4-pyrimidin-2- yl-piperazin-l-yl)-ethyl]-amide (compound 105) was obtained. M+ H = 505 (G) Proceeding as set forth in Example 28(F) above, but substituting 5-(thiophen-2-yl- methyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid for 1-methyl- 3-phenyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid, the compound 5-(thiophen-2-yl- methyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 106) was obtained. M+ H = 481 (H) Proceeding as set forth in Example 28(F) above, but substituting 4-oxo-3-(3-trifluoro-methylphenyl)-3,4-dihydro-phthalazine-l-carboxylic acid for l-methyl-3-phenyl-lH-thi-eno[2,3-c]pyrazole-5-carboxylic acid, the compound 4-oxo-3-(3-trifluoromethylphenyl)-3,4-dihydro-phthalazine-l-carboxylicacid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 107) was obtained. M+ H = 538 (I) Proceeding as set forth in Example 28(F) above, but substituting 3-methyl-23:benzo- furan-2-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]pyrazole-5-carboxy]ic acid, the compound 3-methyl-23- benzofuran-2-carboxylic acid [l-methyl-2-(4-pyrimi- din-2-yI-piperazin-l-yl)-ethyl]~amidc (compound 108) was obtained. M+ H = 380 (J) Proceeding as set forth in Example 28(F) above, but substituting 2,3- benzofuran-2- carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid, the compound 2,3- benzofuran-2-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l- yl)-ethyl]-amide (compound 109) was obtained. M+ H = 366 (K) Proceeding as set forth in Example 28(F) above, but substituting 4,6-diphenylpyrimi- dine-2-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]pyrazole-5-carboxylic acid, the compound 4,6-diphenylpyrimidine-2-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl- piperazin-l-yl)-ethyl]-amide (compound 104) was obtained. M+ H = 480 (L) Proceeding as set forth in Example 28(F) above, but substituting 5,7-dimethyl-pyr- azolo[l,5-a]pyrimidine-3-carboxylic acid for l-methyl-3-phenyl-lH-thieno[2,3-c]- pyrazole-5-carboxylic acid, the compound 5,7-dimethyl-pyrazolo[l,5-a]pyrimidine-3- carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 110) was obtained. M+ H = 395 (M) Proceeding as set forth in Example 28(F) above, but substituting 5-(2-chlorobenzyl)- 4-oxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid for l-methyl-3-phenyl- lH-thieno[2,3-c]pyra2ole-5-carboxylic acid, the compound 5-(2-chloroben2yl)-4-oxo- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carboxylic acid [l-methyl-2-(4-pyrimidin-2- yl-piperazin-l-yl)-ethyl]-amide (compound 119) was obtained. M+ H = 509 Example 32: Preparation of 2-(2-fluorophenyl)-pyridine-4"Carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyI]-amide (A) To a solution of 48% HBr (50 ml) was added 2-aminopicoline (10.0 g, 92.5 mmol) in portions with vigorous stirring between 20°C to 30°C. After addition, the mixture was cooled to -20°C, and cold Br’ (13 ml, 254 mmol) was added dropwise, maintaining the temperature at -20°C. The resulting paste was kept at -20°C with hand stirring for 70 min, followed by the dropwise addition of a solution of sodium nitrite (17 g, 246 mmol) in water (30 ml) at -20°C. The mixture was warmed to 15°C over 2 hours, then cooled back to -20°C, treated with cold NaOH (67 g in 120 ml water), maintaining the temperature below -10°C during addition, the mixture was allowed to warm to RT overnight. The reaction mixture was then partitioned between EtOAc and water, the organic phase washed with brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced pressure. The residue was purified by silica gel . ' chromatography (20%, 40% EtOAc in hexane) to provide 2-bromo-4-methylpyridine (intermediate XXXIIa, 12.65 g, 79%) as a yellow oil. MW+1 = 111, (B) To a solution of intermediate XXXIIa (1 g) and 2-fluorophenyl boronic acid (1.5 g) in diglyme/EtOH (21 ml of 20:1) was added a solution of NasCOs (sat'd, 3 ml), followed by tetrakis(triphenylphosphine) palladium (0) (0.2 g). The mixture was heated at 88°C for 4 h, cooled to RT, and purified to provide 2-(2-fluorophenyl)-4-methylpyridine (intermediate XXXIIb, 0.97g). (C) To a suspension of intermediate XXXIIb (0.44g, 2.35 mmol) in water (25 ml) was added KMn04 (0.82 g, 5.18 mmol) in two portions, the mixture heated at reflux for 20 h, cooled to RT. The resulting solid was filtered through celite, washed with water and EtOAc, and the two phases separated. The pH of aqueous solution was adjusted to 3, and the white precipitate that formed was isolated and dried to yield 2-(2-fluorophenyl)-pyridine-4-carboxylic acid (intermediate XXXIIc, 0.17 g, 33%). MW+1: 218, MW-1: 216. (D) Proceeding as set forth in Example 21(F), but substituting intermediate XXXIIc for intermediate XXIe, the compound 2-(2-fluorophenyl)-pyridine-4-carboxylic acid [1-methyl-2-(4-pyrimidin-2~yl-piperazin-l-yl)-ethyl]-amide (compound 118) was obtained. (E) Proceeding as set forth in Example 28(F), but substituting 2,6-diphenyl-pyridine-4- carboxylic acid for l-methyl-3-phenyI-lH-thieno[2,3-c]pyrazole-5-carboxyIic acid, the compound 2,6-diphenyl-pyridine-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piper- azin-l-yl)-ethyl]-amide (compound 111) was obtained. M+ H = 479 (F) Similarly, proceeding as set forth in part (E) above, but substituting [l-methyI-2-(4- acetyl-piperazin-l-yl)-ethyl]-amine for intermediate Xllld, the compound 2,6-diphenyl- pyridine-4-carboxylic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 117) was obtained. M+ H = 443 (G) SimiJarly, proceeding as set forth in part (E) above, but substituting 2-chloro-6-(4- methoxyphenyl)-pyridine-4-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 2-chloro-6-(4-methoxyphenyl)-pyridine-4-carboxylic acid [l-methyl-2-(4- pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 112) was obtained. M+ H = 467 (H) Similarly, proceeding as set forth in part (E) above’ but substituting 2-chloro-6-(2-methoxyphenyl)-pyridine-4-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 2-chloro-6-(2-methoxyphenyl)-pyridine-4-carboxylic acid [l-methyl-2-(4-pyrimid!n-2-yl-pipcrazin-l-Yl)-ethy]]-amide (compound 113) was obtained. M+ H - 467 (I) Similarly, proceeding as set forth in part (E) above, but substituting 2-chloro-6-(2-methylphenyl)-pyridine-4-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 2~chloro-6-(2-methylphenyl)-pyridine-4-carboxylic acid [l-methyl-2-(4-pyri-midin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 114) was obtained. M+ H - 451 (J) Similarly, proceeding as set forth in part (E) above, but substituting 2-chloro-6-(thio-phen-2-yl)-pyridine-4-carboxylic acid for intermediate 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 2-chloro-6-(thiophen-2-yl)-pyridine-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 115) was obtained. M+ H = 443 (K) Similarly, proceeding as set forth in part (E) above, but substituting 2-chloro-6-(4-methyl-thiophen-2-yl)-pyridine-4-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 2-chloro-6-(4-methyl-thiophen-2-yl)-pyridine-4-carboxylic acid [1-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 116) was obtained. M+ H = 457 (L) Similarly, proceeding as set forth in part (E) above, but substituting 5-(thiophen-2-yl)-nicotinic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 5-(thiophen-2-yl)-nicotinic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 121) was obtained. M+ H = 409 (M) Similarly, proceeding as set forth in part (E) above, but substituting 1,3-diphenyl-pyrimidine-4-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxyIic acid, the compound l,3-diphenyl-pyrimidine-4-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 120) was obtained. M+ H = 480 (N) Similarly, proceeding as set forth in part (E) above but substituting 3-cyclopropyl-imidazo[l,5-a]pyridine-l-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 3-cyclopropyl-imidazo[l,5-a]pyridine-l-carboxylic acid [l-methyl-2-(4-pynmidin-2-yl-piperazin-l-yij-eihylJ-amide (compound 122) was obtained. M+ H - 406 (O) Similarly, proceeding as set forth in part (E) above, but substituting 3-ethyl-imidazo-[l,5-a]pyridine-l-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 3-ethyl-imidazo[l,5-a]pyridine-l-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin~l-yl)-ethyl]-amide (compound 123) was obtained. M+ H = 394 (P) Similarly, proceeding as set forth in part (E) above, but substituting 3-(2-methylprop-y))-imidazo[l,5-aJpyridine-l-carboxyliC acid for 2,6-diphenyl--pyridine-4-carboxylic acid, the compound 3-(2-methylpropyl)-imidazo[l,5-a]pyridine-l-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 124) was obtained. M+ H = 422 (Q) Similarly, proceeding as set forth in part (E) above, but substituting 3-cyclopentyl-imidazo[l,5-a]pyridine-l-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 3-cyclopentyl-imidazo[l,5-a]pyridine-l-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 125) w’as obtained. M+ H = 434 (R) Similarly, proceeding as set forth in part (E) above, but substituting 3-(pyridin-2-yl)-imida2o[l,5-a]pyridine-l-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 3-(pyridin-2-yl)-imidazo[l,5-a]pyridine-l-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 126) was obtained. M+ H = 443 (S) Similarly, proceeding as set forth in part (E) above, but substituting 3-phenyl-imidazo-[l,5-a]pyridine-l-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 3-phenyl-imidazo[l,5-a]pyridine-l-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 127) was obtained. M+ H = 442 (T) Similarly, proceeding as set forth in part (E) above, but substituting l-butyl-5-fluoro-lH-indole-3-carboxylic acid for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 1-butyl-5-fluoro-lH-indole-3-carboxylic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 128) was obtained. M+ H = 439 Example 33: Preparation of 3,5-di(4-fluorophenyI)benzoic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yI)-ethyl]-amide (A) To a solution of methyl 3,5-dibromobenzoate (3.00 g, 10.2 mmol) and 4-fluorophenyl boronic acid (1.43 g, 10.2 mmol) in 2-methoxyethyl ether (60 ml) and ethanol (3 ml) was added Na2C03 (saturated, 9 ml), followed by tetrakis(triphenylphosphine) palladium (0) (0.2 g). The mixture was heated at 88°C for 1.5 h, then cooled to RT, partitioned between hexane and water, and "the organic phase washed with brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced pressure. The resi- due was purified by silica gel chromatography (1% EtOAc in hexane) to yield methyl 3-bromo-5-(4-fluorophenyl)benzoate (intermediate XXXIVa, 0.725 g, 23%) as a white solid, and methyl 3,5-di(4-fluorophenyl)benzoate (intermediate XXXIVb, 0.128 g, 4%) as a while solid. (B) A solution of intermediate XXXIVb (0.31 g, 0.956 mmol) in THF (5 ml) and NaOH (0.3 g in 5 ml of water) was heated at 70°C for 3 h. After most of THF had evaporated, the aqueous solution was adjusted to pH (C) Proceeding as set forth in Example 21(F), but substituting intermediate XXXIVc for intermediate XXIe, the compound 3,5-di(4-fluorophenyl)benzoic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 133) was obtained. (D) Similarly, proceeding as set forth in (32F), but substituting intermediate XXXIVa for 2,6-diphenyl-pyridine-4-carboxylic acid, the compound 3-bromo-5-(4-fluorophenyl)-benzoic acid [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 132) was obtained. M+ H = 462, 464 (E) To a solution of intermediate XXXIVa (0.2 g, 0.65 mmol) in anhydrousDMF (10 ml) was added allytributyltin (0.25 ml, 0.81 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.2 g). The mixture was heated at 80°C for 24 h. The mixture was then filtered through celite and washed with 50 % EtOAc in hexane, the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, decanted, and the organic solution concentrated under reduced pressure. The residue was purified by silica gel chromatography (2% EtOAc in hexane) to yield 5-allyl-4'-fluoro-biphenyl-3-carboxylic acid methyl ester (intermediate XXXIVe, 0.138 g, 78%) as a white solid. (F) A mixture of intermediate XXXIVe (0.138 g, 0.51 mmol) and 10 % Pd/C (0.1 g) in EtOH (10 ml) was stirred at RT under H’ ( balloon) for 4 h. The reaction mixture was then filtered through celite, washed with more EtOH, and the combined solvent was concen trated under reduced pressure. The residue was purified by silica gel chromatography (2% EtOAc in hexane) to yield 5-propyl-4'-fluoro-biphenyl-3-carboxylic acid methyl ester (intermediate XXXIVf, 0.124 g, 89%) as a clear oil. (G) A solution of intermediate XXXIVf (0.12 g, 0.44 mmol) in THF (5 ml) and NaOH (0.12 g in 3 ml of water) was heated at TO’'C for 24 h. After most of the THF had evaporated, the aqueous solution was adjusted to pH (H) Proceeding as set forth in part (D) above, but substituting intermediate XXXIVg for intermediate XXXIVa, the compound 5-propyl-4'-fluoro-biphenyl-3-carboxylic acid [1-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 131) was obtained. MW+1 = 426. (I) Proceeding as set forth in part (C) above, but substituting [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amine for [l-methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amine, the compound 3,5-di(4-fluorophenyl)benzoic acid [l-methyl-2-(4-acetyl-piperazin-l-yl)-ethyl]-amide (compound 130) was obtained. M+ H = 478 (J) To a solution of 3-bromo-5-nitro benzoic acid (1 g, 4.06 mmol) and 2-fluorophenyl boronic acid (569 mg, 4.06 mmol) in dimethoxyethane (20 ml) and EtOH (1 ml) was added Na2C03 (7 ml saturated solution) and palladium tetrakis(triphenylphosphine) (94 mg, 0.08 mmol). The mixture was heated at reflux for 4 h and then stirred at RT for 16 h. The grey precipitate that formed was filtered off and washed with CH2CI2. The filtrate was evaporated, affording 3-nitro-5-(2-fluorophenyl)benzoic acid (intermediate XXXIVj, 880 mg, 83 % yield) as a white solid. M'‘= 262. (K) To a solution of intermediate XXXIVj (104 mg, 0.4 mmol) in EtOH (5 ml) was added hydrazine (26 mg, 0.8 mmol) and a catalytic amount of palladium (10 %) on carbon. The reaction mixture was stirred for 18 h at RT and 18 h at reflux. The catalyst was filtered off on a celite pad and washed with warm EtOH. The filtrate was evaporated, affording the product 3-amino-5-(2-fluorophenyl)benzoic acid (intermediate XXXIVk) in quantitative yield as a white solid. M'‘= 232. (L) A mixture of intermediate XXXIVk (92.4 mg, 0.4 mmol), triethylonhoformate (116 1’1, 0.7 mmol) and AcOH (370 |al) was stirred at RT for 18 h. The mixture was evaporated, and to the residue acetic acid (0.5 ml) and NaNs (104 mg, 1.6 mmol) were added. The reaction mixture was heated at 70°C for 5 h and stirred at RT for 18 h. Water was added to the reaction, and the product precipitated out as white solid that was washed with water to yield 2'-fluoro-5-tetrazoM-yl-biphenyl-3-carboxylic acid (intermediate XXXIVI, 52 mg, 48% yield). M’- 285. (M) Proceeding as set forth in part (I) above, but substitiiiing intermediate XXXiVl for intermediate XXXIVc, the compound 2'-fluoro-5-tetrazol-l-yl-biphenylo-carboxylic acid [l-methyl-2-(4-acety]-piperazin-l-yl)-elhy)]-amide (compound 129) was obtained as a yellow foam (11% yield M’= 451). (N) Proceeding as set forth in Example 21(F), but substituting intermediate XXXIVg for intermediate XXIe, the compound 5-propyl-4'-fluoro-biphenyl-3-carboxylic acid [1- methyl-2-(4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 134) was obtained. (O) Proceeding as set forth in Example 21(F), but substituting intermediate XXXIVa for intermediate XXIe, the compound 3-bromo-5-(4-fluorophenyI)benzoic acid [l-methyl-2- (4-pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 135) was obtained. (P) Proceeding as set forth in Example 21(F), but substituting 3,5-dibromoben2oic acid for intermediate XXIe, the compound 3,5-dibromobenzoic acid [l-methyl-2-(4-pyrimidin- 2-yl-piperazin-l-yl)-ethyl]-amide (compound 136) was obtained. (Q) Proceeding as set forth in Example 21(F), but substituting 3-(4-fluorophenyl)-benzoic acid for intermediate XXIe, the compound 3-(4-fluorophenyl)-benzoic acid [l-methyl-2- (4-pyrimidin-2-yl-pipera2in-l-yl)-ethyl]-amide (compound 137) was obtained. (R) Proceeding as set forth in (H) above, but substituting 3-(4-fluorophenyl)-benzoic acid for intermediate XXXIVg, the compound 3-(4-fluorophenyl)-ben2oic acid [l-methyl-2-(4- pyrimidin-2-yl-piperazin-l-yl)-ethyl]-amide (compound 138) was obtained. M+ H = 384 Example 34: Formulations Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. "Active ingredient" or "Active compound" as used in the Tables means one or more of the Compounds of Formula I. Nasal Spray Formulations Several aqueous suspensions containing from about 0.025-0.5% active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a 'nasal spray metered pump typically delivering about 50-100 ‘iL of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours. Example 35: P2X3 FLIPR (Fluorometric Imaging Plate Reader) Assay CHO-Kl cells were transfected with cloned rat P2X3 receptor subunits and passaged in flasks. 18-24 hours before the FLIPR experiment, cells were released from their flasks, centrifuged, and resuspended in nutrient medium at 2.5 x 10’ cells/ml. The cells were aliquoted into black-walled 96-well plates at a density of 50,000 cells/well and incubated overnight in 5% CO2 at SV'C. On the day of the experiment, cells were washed in FLIPR buffer (calcium- and magnesium-free Hank's balanced salt solution, 10 mM HEPES, 2 mM CaCl2, 2.5 mM probenecid; FB). Each well received 100 \x] FB and 100 \il of the fluorescent dye Fluo-3 AM (2 ‘M final cone). After a 1 hour dye loading incubation at 37°C, the cells were washed 4 times with FB, and a final 75 fal/well FB was left in each well. Test compounds (dissolved in DMSO at 10 mM and serially diluted with FB) or vehicle were added to each well (25 fil of a 4X solution) and allowed to equilibrate for 20 minutes at RT. The plates were then placed in the FLIPR and a baseline fluorescence measurement (excitation at 488 nm and emission at 510-570 nm) was obtained for 10 seconds before a 100 |al/well agonist or vehicle addition. The agonist was a 2X solution of a,P-meATP producing a final concentration of 1 \xM (P2X3) or 5 |_LM (P2X2/3). Fluorescence was measured for an additional 2 minutes at 1 second intervals after agonist addition. A final addition of ionomycin (5 faM, final concentration) was made to each well of the FLIPR test plate to establish cell viability and maximum fluorescence of dye-bound cytosolic calcium. Peak fluorescence in response to the addition of a,P-meATP (in the absence and presence of test compounds) was measured and inhibition curves generated using nonlinear regression. PPADS, a standard P2X antagonist, was used as a positive control. Using the above procedure, compounds of the invention exhibited activity for the P2X3 receptor. Example 36: In vivo Assay for Asthma and Lung Function BALb/cJ mice are immunized with a standard immunization protocol. Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 |J.g) in alum on days 0 and 14. Mice are then challenged with aerosolized OVA (5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound of the invention (100 mg/kg p.o.) all starting on day 20, Lung function is evaluated on day 23 using the Buxco system to measure PenH in response to an aerosol methacholine challenge. Mice are then euthanized and plasma samples collected at the end of the study. Example 37: Volume Induced Bladder Contraction Assay Female Sprague-Dawley rats (200-300g) were anesthetized with urethane (1.5 g/kg, sc). The animals were tracheotomized, and a carotid artery and femoral vein were cannulated for blood pressure measurement and drug administration, respectively. A laparotomy was performed and the ureters were ligated and transected proximal to the ligation. The external urethral meatus was ligated with silk suture and the urinary bladder was cannulated via the dome for saline infusion and bladder pressure measurement. Following a 15-30 minute stabilization period the bladder was infused with RT saline at 100 i’l/min until continuous volume-induced bladder contractions (VIBCs) were observed. The infusion rate was then lowered to 3-5 |J.l/min for 30 minutes before the bladder was drained and allowed to rest for 30 minutes. All subsequent infusions were performed as indicated except the lower infusion rate was maintained for only 15 minutes instead of 30 minutes. Bladder filling and draining cycles were repeated until the threshold volumes (TV; the volume needed to trigger the first micturition bladder contraction) varied by less than 10% for two consecutive baselines and contraction frequency was within 2 contractions for a 10 minute period following the slower infusion rale. Once reproducihie TVs and VIBCs were established the bladder was drained and the animal was dosed with drug or vehicle (0.5 ml/kg, i.v.) 3 minutes prior to the start of the next scheduled infusion. Example 38: Formalin Pain Assay Male Sprague Dawley rats (180-220 g) are placed in individual Plexiglas cylinders and allowed to acclimate to the testing environment for 30 min. Vehicle, drug or positive control (morphine 2 mg/kg) is administered subcutaneously at 5 ml/kg. 15 min post dosing, formalin (5% in 50’ul) is injected into plantar surface of the right hind paw using a 26-gauge needle. Rats are immediately put back to the observation chamber. Mirrors placed around the chamber allow unhindered observation of the formalin-injected paw. The duration of nociphensive behavior of each animal is recorded by a blinded observer using an automated behavioral timer. Hindpaw licking and shaking / lifting are recorded separately in 5 min bin, for a total of 60 min. The sum of time spent licking or shaking in seconds from time 0 to 5 min is considered the early phase, whereas the late phase is taken as the sum of seconds spent licking or shaking from 15 to 40 min. A plasma sample is collected. Example 39: Colon Pain Assay Adult male Sprague-Dawley rats (350-425 g; Harlan, Indianapolis, IN) are housed 1-2 per cage in an animal care facility. Rats are deeply anesthetized with pentobarbital sodium (45 mg/kg) administered intraperitoneally. Electrodes are placed and secured into the external oblique musculature for electromyographic (EMG) recording. Electrode leads are tunneled subcutaneously and exteriorized at the nape of the neck for future access. After surgery, rats are housed separately and allowed to recuperate for 4-5 days prior to testing. The descending colon and rectum are distended by pressure-controlled inflation of a 7-8 cm-long flexible latex balloon tied around a flexible tube. The balloon is lubricated, inserted into the colon via the anus, and anchored by taping the balloon catheter to the base of the tail. Colorectal distension (CRD) is achieved by opening a solenoid gate to a constant pressure air reservoir. Intracolonic pressure is controlled and continuously monitored by a pressure control device. Response is quantified as the visceromotor response (VMR), a contraction of the abdominal and hindlimb musculature. EMG activity produced by contraction of the external oblique musculature is quantified using Spike2 software (Cambridge Electronic Design). Each distension trial lasts 60 sec, and EMG activity is quantified for 20 sec before distension (baseline), during 20 sec distension, and 20 sec after distention. The increase in total number of recorded counts during distension above baseline is defined as the response. Stable baseline responses to CRD (10, 20, 40 and 80 mmHg, 20 seconds, 4 minutes apart) are obtained in conscious, unsedated rats before any treatment. Compounds are evaluated for effects on responses to colon distension initially in a model of acute visceral nociception and a model of colon hypersensitivity produced by intra-colonic treatment with zymosan (1 mL, 25 mg/mL) instilled into the colon with a gavage needle inserted to a depth of about 6 cm. Experimental groups will consist of 8 rats each. Acute visceral nociception: For testing effects of drug on acute visceral nociception, 1 of 3 doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) are administered after baseline responses are established; responses to distension are followed over the next 60-90 minutes. Visceral hypersensitivity: For testing effects of drug or vehicle after intracolonic treatment with zymosan, intracolonic treatment is given after baseline responses are established. Prior to drug testing at 4 hours, responses to distension are assessed to establish the presence of hypersensitivity. In zymosan-treated rats, administration of 1 of 3 doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) are given 4 hours after zymosan treatment and responses to distension followed over the next 60-90 minutes. Example 40: Cold Allodynia in Rats with a Chronic Constriction Injury of the Sciatic Nerve The effects of compounds of this invention on cold allodynia are determined using the chronic constriction injury (CCI) model of neuropathic pain in rats, where cold allodynia is measured in a cold-water bath with a metal-plate floor and water at a depth of 1.5-2.0 cm and a temperature of 3-4°C (Gogas et al.. Analgesia, 1997, 3,1-8). Specifically, rats are anesthetized; the trifurcation of the sciatic nerve is located and 4 ligatures (4-0, or 5-0 chromic gut) are placed circumferentially around the sciatic ner\'e proximal to the trifurcation. The rats are then allowed to recover from the surgery. On days 4-7 after surgery, the rats are initially assessed for cold-induced allodynia by individually placing the animals in the cold-water bath and recording the total lifts of the injured paw during a 1-min period of time: The injured paw is lifted out of the water. Paw lifts associated with locomotion or body repositioning are not recorded. Rats that displayed 5 lifts per min or more on day 4-7 following surgery are considered to exhibit cold allodynia and are used in subsequent studies. In the acute studies, vehicle, reference compound or compounds of this invention are administered subcutaneously (s.c.) 30 min before testing. The effects of repeated administration of the compounds of this invention on cold allo-dynia are determined 14, 20 or 38 h following the last oral dose of the following regimen: oral (p.o.) administration of vehicle, reference or a compound of this invention at -12 h intervals (BID) for 7 days. Example 41: Cancer Bone Pain in C3H/HeJ Mice The effects of compounds of this invention on bone pain are determined between Day 7 to Day 18 following intramedullary injection of 2472 sarcoma cells into the distal femur of C3H/HeJ mice. Specifically, NCTC 2472 tumor cells (American Type Culture Collection, ATCC), previously shown to form lytA lesions in bone after intramedullary injection, are grown and maintained according to ATCC recommendations. Approximately 10’ cells are injected directly into the medullary cavity of the distal femur in anesthetized C3H/HeJ mice. Beginning on about Day 7, the mice are assessed for spontaneous nocifensive behaviors (flinching & guarding), palpation-evoked nocifensive behaviors (flinching & guarding), forced ambulatory guarding and limb use. The effects of compounds of this invention are determined following a single acute (s.c.) administration on Day 7 - Day 15. In addition, the effects of repeated (BID) administration of compounds of this invention from Day 7 -Day 15 are determined within 1 hour of the first dose on Days 7, 9, 11,13 and 15. While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. WHAT IS CLAIMED: 1. A compound of formula I wherein R’ is -C(=S)CH3, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, furylcarbonyl, acetyl, or carbamoyl; R-’ and R"' are independently H, methyl, or ethyl; R' is H or methyl; Y is a bond, -(CR'‘R’)n- or -CR'*=Cur’s wherein R’ and R’ are each independently H or methyl and n is 1 or 2; X is N or CH; A is phenyl, 5-membered heterocyclyl, or 6-membered heterocyclyl; R°, R' and R° are each independently H, halo, lower alkyl, cycloalkyl, alkylthio, alkylthio-lower alkyl, alkylsulfonyl-lower alkyl, di(lower alkyl)amino-lower alkyl, morpholinyl-lower alkyl, 4-methyl-piperazinyl-methyl, trifluoromethyl, pyridyl, tetrazolyl, thiophenyl, phenyl, biphenyl, or benzyl; where thiophenyl, phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamide, trifluoromethyl, lower alkoxy or lower alkylthio; or R and R together form a 5-membered or 6-membered carbocyclic or heterocyclic ring substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl; where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamide, trifluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkylamino-lower alkyl; and pharmaceutically acceptable salts thereof; wherein when R’ is pyrimidin-2-y}, X is N, Y is a bond and A is oxazol-5-yI the carbon atom at position 4 in said oxazol-5-yl is not substituted by propyl when the carbon atom at position 2 in said oxazol-5-yl is substituted by substituted phenyl and the carbon atom at position 4 in said oxazol-5-yl is not substituted by phenyl when the carbon atom at position 2 is substituted by unsubstituted or substituted phenyl. 2. The compound according to claim 1 wherein Y is a bond. 3. The compound according to claim 1 wherein A is phenyl, oxazolyl, thiazolyl, furanyl, pyrimidinyl, pyridinyl, pyrazolyl, imidazolyl, pyrrolyl, lH-[l,2,3]triazolyl or 4,5-dihydro-lH-[l,2,4]triazolyl. 4. The compound according to claim 1 wherein A(R )(R )R is pyrazolo[l,5a]pyrimidinyl, lH-thieno[23"C]pyrazolyl, IH-imidazolyl, 2H-indazolyl, IH-indolyl, benzofuranyl, 2H-phthalazinyl, imidazo[l,5-a]pyridyl or 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazinyl each of which substituted with 0-3 substituents selected from the group consisting of lower alkyl, lower alkoxy, oxo, halo, thiophenyl-lower alkyl, phenyl, benzyl; where phenyl and benzyl are substituted with 0-3 lower alkyl, halo, sulfonamide, tri-fluoromethyl, lower alkoxy, lower alkylthio, amino-lower alkyl, lower alkylamino-lower alkyl, or di(lower alkyl)amino-lower alkyl. 5. A method for modulating the activity of a P2X3 receptor, comprising contacting a P2X3 receptor with a compound of formula I according to claim 1. 6. A method for treating a genitourinary disorder, a respiratory disorder or pain responsive to a P2X3 modulator, comprising administering to a subject in need thereof a compound of formula I according to claim 1. 7. A composition comprising (a) a pharmaceutically acceptable excipient; and (b) a compound of Claim 1. 8. The use of a compound of formula I according to claim 1 for the preparation of a medicament for the treatment of a disorder responsive to a P2X3 modulator. 9. The invention as hereinbefore described.

Documents:

764-CHENP-2008 AMENDED CLAIMS 31-05-2012.pdf

764-CHENP-2008 CORRESPONDENCE OTHERS 21-10-2011.pdf

764-CHENP-2008 FORM-3 31-05-2012.pdf

764-CHENP-2008 OTHER PATENT DOCUMENT 31-05-2012.pdf

764-CHENP-2008 EXAMINATION REPORT REPLY RECEIVED 31-05-2012.pdf

764-CHENP-2008 POWER OF ATTORNEY 31-05-2012.pdf

764-chenp-2008-abstract.pdf

764-chenp-2008-assignement.pdf

764-chenp-2008-claims.pdf

764-chenp-2008-correspondnece-others.pdf

764-chenp-2008-description(complete).pdf

764-chenp-2008-form 1.pdf

764-chenp-2008-form 18.pdf

764-chenp-2008-form 26.pdf

764-chenp-2008-form 3.pdf

764-chenp-2008-form 5.pdf