WO2004055003A1

WO2004055003A1 - 2-substituted quinazolin-4-ylamine analogues as capsaicin receptor modulators

Info

Publication number: WO2004055003A1
Application number: PCT/US2003/039606
Authority: WO
Inventors: Rajagopal Bakthavatchalam; Charles A. Blum; Harry Brielmann; Timothy M. Caldwell; Stephane De Lombaert; Kevin J. Hodgetts; Xiaozhang Zheng
Original assignee: Neurogen Corp
Current assignee: Neurogen Corp
Priority date: 2002-12-13
Filing date: 2003-12-12
Publication date: 2004-07-01
Anticipated expiration: 2005-06-13
Also published as: US7432275B2; EP1569926A1; CA2509233A1; AU2003296984A1; WO2004055004A8; JP2006515846A; WO2004055004A1; KR20050084292A; AU2003300898A1; TW200418480A; PE20040935A1; CN1726205A; US20060089354A1; BR0317168A; JP2006515847A; US20040156869A1; AR042461A1; MXPA05006123A; CA2509239A1; EP1569925A1

Abstract

Certain 2-substituted quinazolin-4-ylamine analogues are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Description

-SUBSTiTUTED QUINAZOLIN-4-YLAMINE ANALOGUES AS CAPSAICIN RECEPTOR MODULATOR

FIELD OF THE INVENTION This invention relates generally to 2-substituted quinazolin-4-ylarnine analogues that are modulators of capsaicin receptors, and to the use of such compounds for treating conditions related to capsaicin receptor activation. The invention further relates to the use such compounds as probes for the detection and localization of capsaicin receptors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application 60/433,139, filed December 13, 2002.

BACKGROUND OF THE INVENTION Pain perception, or nociception, is mediated by the peripheral terminals of a group of specialized sensory neurons, termed "nociceptors." A wide variety of physical and chemical stimuli induce activation of such neurons in mammals, leading to recognition of a potentially harmful stimulus. Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain. Neuropathic pain involves pain signal transmission in the absence of stimulus, and typically results from damage to the nervous system. In most instances, such pain is thought to occur because of sensitization in the peripheral and central nervous systems following initial damage to the peripheral system (e.g., via direct injury or systemic disease). Neuropathic pain is typically burning, shooting and unrelenting in its intensity and can sometimes be more debilitating that the initial injury or disease process that induced it.

Existing treatments for neuropathic pain are largely ineffective. Opiates, such as morphine, are potent analgesics, but their usefulness is limited because of adverse side effects, such as physical addictiveness and withdrawal properties, as well as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems. In addition, neuropathic pain is frequently non-responsive or only partially responsive to conventional opioid analgesic regimens. Treatments employing the N-methyl-D-aspartate antagonist ketamine or the alpha(2)-adrenergic agonist clonidine can reduce acute or chronic

Claims

pain, and permit a reduction in opioid consumption, but these agents are often poorly tolerated due to side effects.Topical treatment with capsaicin has been used to treat chronic and acute pain, including neuropathic pain. Capsaicin is a pungent substance derived from the plants of the Solanaceae family (which includes hot chili peppers) and appears to act selectively on the small diameter afferent nerve fibers (A-delta and C fibers) that are believed to mediate pain. The response to capsaicin is characterized by persistent activation of nociceptors in peripheral tissues, followed by eventual desensitization of peripheral nociceptors to one or more stimuli. From studies in animals, capsaicin appears to trigger C fiber membrane depolarization by opening cation selective channels for calcium and sodium.Similar responses are also evoked by structural analogues of capsaicin that share a common vanilloid moiety. One such analogue is resiniferatoxin (RTX), a natural product of Euphorbia plants. The term vamlloid receptor (VR) was coined to describe the neuronal membrane recognition site for capsaicin and such related irritant compounds. The capsaicin response is competitively inhibited (and thereby antagonized) by another capsaicin analog, capsazepine, and is also inhibited by the non-selective cation channel blocker ruthenium red. These antagonists bind to VR with no more than moderate affinity (typically with K, values of no lower than 140 μM).Rat and human vanilloid receptors have been cloned from dorsal root ganglion cells. The first type of vanilloid receptor to be identified is known as vanilloid receptor type 1 (VR1), and the terms "NR1" and "capsaicin receptor" are used interchangeably herein to refer to rat and/or human receptors of this type, as well as mammalian homologs. The role of VR1 in pain sensation has been confirmed using mice lacking this receptor, which exhibit no vanilloid-evoked pain behavior, and impaired responses to heat and inflammation. VR1 is a nonselective cation channel with a threshold for opening that is lowered in response to elevated temperatures, low pH, and capsaicin receptor agonists. For example, the channel usually opens at temperatures higher than about 45°C. Opening of the capsaicin receptor channel is generally followed by the release of inflammatory peptides from neurons expressing the receptor and other nearby neurons, increasing the pain response. After initial activation by capsaicin, the capsaicin receptor undergoes a rapid desensitization via phosphorylation by cAMP-dependent protein kinase.Because of their ability to desensitize nociceptors in peripheral tissues, VR1 agonist vanilloid compounds have been used as topical anesthetics. However, agonist application may itself cause burning pain, which limits this therapeutic use. Recently, it has been reported that VRl antagonists, including nonvanilloid compounds, are also useful for the treatment of pain (see, PCT application Number WO 02/08221, which published January 31, 2002).Thus, compounds that interact with VRl, but do not elicit the initial painful sensation of VRl agonist vanilloid compounds, are desirable for the treatment of chronic and acute pain, including neuropathic pain. Antagonists of this receptor are particularly desirable for the treatment of pain, as well as conditions such as tear gas exposure, itch and urinary incontinence. The present invention fulfills this need, and provides further related advantages.SUMMARY OF THE INVENTIONThe present invention provides VRl modulators that alter, and preferably inhibit, capsaicin receptor activation. Within certain aspects, VRl modulators provided herein are 2- substituted quinazolin-4-ylamine analogues of Formula I:Formula I or pharmaceutically acceptable forms thereof. Within Formula I:X, V, W, Y and Z are each independently N or CRi, with the proviso that at least one of V and X is N; Ri is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, optionally substituted alkyl or more preferably Cι-C6alkyl, optionally substituted haloalkyl or more preferably haloCi-Cδalkyl, optionally substituted alkoxy or more preferably Cι-C6alkoxy, optionally substituted haloalkoxy or more preferably haloCi- C6alkoxy, optionally substituted alkoxycarbonyl or more preferably Cι-C alkoxycarbonyl and opsbu mono- and dialkylamino or more preferably mono- and di-(Cι-C6allcyl)ammo;Ris -O-R7 or -N'-R ; R7 is: (i) hydrogen;(ii) optionally substituted alkyl or more preferably Cι-C8alkyl, optionally substituted alkenyl or more preferably C2-C8alkenyl, optionally substituted alkynyl or more preferably C2-C8alkynyl, optionally substituted alkanoyl or more preferably C2- C8alkanoyl, optionally substituted alkanone or more preferably C3-C8alkanone, optionally substituted alkyl ether or more preferably C2-C8alkyl ether, optionally substituted aryl or arakyl or more preferably C6-CιoarylCo-C8alkyl or optionally substituted heterocycle or heterocycle-alkyl or more preferably (5- to 10-membered heterocycle)Co-C8alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R ; or (iii) taken together with an R5 or Pg to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from Rt,; R3 and R4 are: (i) each independently selected from:(a) hydrogen;(b) optionally substituted alkyl or more preferably Cι-C8alkyl, optionally substituted alkenyl or more preferably C2-C8alkenyl, optionally substituted alkynyl or more preferably C2-C8alkynyl, optionally substituted alkanone or more preferably C3- alkanone, optionally substituted alkanoyl or more preferably C2-C8alkanoyl, optionally substituted alkyl ether or more preferably C2-C8alkyl ether, optionally substituted aryl or aralkyl or more preferably C6-CιnarylCo-C8alkyl, optionally substituted heterocycle or heterocycle-alkyl or more preferably (5- to 10- membered heterocycle)Co-C8alkyl and optionally substituted alkylsulfonate or more preferably -(SO2)Cι-C8alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rt,; and(c) groups that are taken together with an R5 or Rδ to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from Rt,; or (ii) taken together to form, with the N to which they are bound, a 4- to 10-membered heterocyclic group that is substituted with from 0 to 4 substituents independently chosen from Rt,; and R5 and R$ are, independently at each occurrence:(i) each independently hydrogen, Cι-C8alkyl substituted with from 0 to 2 substituents independently chosen from R , or taken together with R3, or R7 to form a 4- to 10- membered heterocyclic group that is substituted with from 0 to 4 substituents independently chosen from Rt,; (ii) taken together to form a keto group (C=O); or (iii) taken together to form a 3- to 7-membered carbocyclic or heterocyclic ring that is substituted with from 0 to 4 substituents independently chosen from Rb; n iε 1, 2 or 3;Ari and Ar2 are independently selected from carbocycles or heterocycles or more preferably are independently selected from 6- to 10-membered carbocycles (preferably aryl) and 5- to 10-membered heterocycles, each of which is substituted with from 0 to 3 substituents independently selected from groups of the formula LRa;L is independently selected at each occurrence from a bond, O, S(O)m, C(=0), OC(=O),C(=0)0, O-C(=O)O, N(RX), C(=O)N(Rx), N(Rx)C(=O), N(Rx)S(O)m, S(0)mN(Rx) and N[S(0)mRx]S(0)m; wherein m is independently selected at each occurrence from 0, 1 and2; and Rx is independently selected at each occurrence from hydrogen and Cι-C8alkyl;Ra is independently selected at each occurrence from: (i) hydrogen, halogen, cyano and nitro; and (ii) alkyl or more preferably Cι-C8alkyl, alkenyl or more preferably C2-C8alkenyl, alkynyl or more preferably C2-C8alkynyl, alkyl ether or more preferably C2-C8alkyl ether, heterocycle or heterocycle-alkyl or more preferably (4- to 10-membered heterocycle)Co-C8alkyl and mono- and di-alkylamino or more preferably mono- and di-(Cι-C8alkyl)amino, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, oxo, ^COOH, Cι-C4alkyl, Q- alkoxy, haloCι-C4alkyl, haloCι-C4alkoxy, hydroxyCι-C4alkyl, and mono- and di-(Cι- C6alkyl)amino; andRb is independently chosen at each occurrence from:(i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo and -COOH; and (ii) alkyl or more preferably Cι-C8alkyl, haloalkyl or more preferably Cι-C8haloalkyl, alkoxy or more preferably Cι-C8alkoxy, haloalkoxy or more preferably Ci- C8haloalkoxy, alkanoyl or more preferably Cι-C8alkanoyl, alkoxycarbonyl or more preferably C2-C8alkoxycarbonyl, alkanoyloxy or more preferably C2-C8alkanoyloxy, alkylthio or more preferably Cι-C8alkylthio, alkyl ether or more preferably C2-C8alkyl ether, phenyl or phenyl-alkyl or more preferably phenylCo-C8alkyl, phenyl or phenyl- alkoxy or more preferably phenylCn-C8alkoxy, mono- or di-alkyl amino or mono- and di-alkylamino alkyl or more preferably mono- and di-(Cι-C6alkyl)aminoCo-C6alkyl, alkylsulfonate or more preferably -(SO2)Cι-C8alkyl and heterocycle or heterocycle- alkyl or more preferably (4- to 7-membered heterocycle)(Co-C8alkyl); each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, Cι-C4alkyl, Cι-C4alkoxy, hydroxyCι-C4alkyl, haloCι-C alkyl, and mono- and di-(Cι-C4alkyl)amino.Within further aspects, compounds provided herein are 2-hydroxyalkyl-quinazolin-4- yl mine analogues of Formula II:Formula II or pharmaceutically acceptable forms thereof, wherein X, W, Y, Z, R5, Rβ, R7, n, Arj and Ar2 are as described for Formula I.Within still further aspects, compounds provided herein are 2-aminoalkyl-quinazolin- 4-ylamine analogues of Formula III:Formula III or pharmaceutically acceptable forms thereof, wherein X, W, Y, Z, R3, R4, R5, Re, n, Ari and Ar2 are as described for Formula I.Within certain aspects, VRl modulators as described herein exhibit a K; of no greater than 1 micromolar, 100 nanomolar, 50 nanomolar, 10 nanomolar or 1 nanomolar in a capsaicin receptor binding assay and/or have an EC50 or IC50 value of no greater than 1 micromolar, 100 nanomolar, 50 nanomolar, 10 nanomolar or 1 nanomolar in an assay for determination of capsaicin receptor antagonist activity.In certain embodiments, VRl modulators as described herein are VRl antagonists and exhibit no detectable agonist activity in an in vitro assay of capsaicin receptor activation.Within certain aspects, VRl modulators and pharmaceutically acceptable forms thereof as described herein are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one VRl modulator as described herein (i.e., a compound as provided herein or a pharmaceutically acceptable form thereof) in combination with a physiologically acceptable carrier or excipient. Within further aspects, methods are provided for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell (e.g., neuronal) expressing a capsaicin receptor with a capsaicin receptor modulatory amount of at least one VRl modulator as described herein. Such contact may occur in vivo or in vitro. Methods are further provided for inhibiting binding of vanilloid ligand to a capsaicin receptor. Within certain such aspects, the inhibition takes place in vitro. Such methods comprise contacting a capsaicin receptor with at least one VRl modulator as described herein, under conditions and in an amount sufficient to detectably inhibit vanilloid ligand binding to the capsaicin receptor. Within other such aspects, the capsaicin receptor is in a patient. Such methods comprise contacting cells expressing a capsaicin receptor in a patient with at least one VRl modulator as described herein in an amount sufficient to detectably inhibit vanilloid ligand binding to cells expressing a cloned capsaicin receptor in vitro, and thereby inhibiting binding of vanilloid ligand to the capsaicin receptor in the patient.The present invention further provides methods for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a capsaicin receptor modulatory amount of at least one VRl modulator as described herein.Within other aspects, methods are provided for treating pain in a patient, comprising administering to a patient suffering from pain a capsaicin receptor modulatory amount of at least one VRl modulator as described herein. Methods are further provided for treating itch, urinary incontinence, cough and or hiccup in a patient, comprising administering to a patient suffering from one or more of the foregoing conditions a capsaicin receptor modulatory amount of at least one VRl modulator as described herein.The present invention further provides methods for promoting weight loss in an obese patient, comprising administering to an obese patient a capsaicin receptor modulatory amount of at least one VRl modulator as described herein.Within further aspects, the present invention provides methods for determining the presence or absence of capsaicin receptor in a sample, comprising: (a) contacting a sample with a VRl modulator as described herein under conditions that permit binding of the VRl modulator to capsaicin receptor; and (b) detecting a level of the VRl modulator bound to capsaicin receptor.The present invention also provides packaged pharmaceutical preparations, comprising: (a) a pharmaceutical composition as described herein in a container; and (b) instructions for using the composition to treat one or more conditions responsive to capsaicin receptor modulation, such as pain, itch, urinary incontinence, cough, hiccup, and/or obesity.In yet another aspect, the invention provides methods of preparing the compounds disclosed herein, including the intermediates. These and other aspects of the present invention will become apparent upon reference to the following detailed description.DETAILED DESCRIPTIONAs noted above, the present invention provides 2-substituted quinazolin-4-ylamine analogues which are capsaicin receptor modulators. Such modulators may be used in vitro or in vivo, to modulate capsaicin receptor activity in a variety of contexts.TERMINOLOGYCompounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Certain compounds are described herein using a general formula that includes variables (e.g., R2, A , Y, Z). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence.The term "2-substituted quinazolin-4-ylamine analogue" is used herein to refer to all compounds that satisfy one or more of Formulas I, II and III, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable forms of such compounds. The terms "2-hydroxyalkyl-quinazolin-4-ylamine analogue" and "2-aminoalkyl- quinazolin-4-ylamine analogue," as used herein, encompass all compounds of Formula II or Formula III, respectively, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable forms of such compounds. 2-Substituted quinazolin-4- ylamine analogues include compounds in which the bicyclic core (which comprises V, X, W, Y and Z) is modified in the number and/or placement of ring nitrogen atoms, as well as analogues in which varied substituents, as described in more detail below, are attached to such a core structure. In other words, compounds that are substituted quinoline-4-ylamines, quinoline-2-ylamines, quinazoline-4-ylamines (as well as analogues of the foregoing in which one or more of W, Y and Z are nitrogen, such as pyrido[2,3-J]pyrimidine-4-ylamines, pyrido[3,2-JJpyrimidin-4-ylamines, [l,8]naphthyridin-4-ylamines and [l,6]naphthyridin-5- ylamines) are within the scope of 2-substituted quinazolin-4-yIamine analogues."Pharmaceutically acceptable forms" of the compounds recited herein are pharmaceutically acceptable salts, hydrates, solvates, crystal forms, polymorphs, chelates, non-covalent complexes, esters, clathrates and prodrugs of such compounds. As used herein, a pharmaceutically acceptable salt is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound of Formula I, II or III. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved to the parent compounds.As used herein, the term "alkyl" refers to a straight chain, branched chain or cyclic saturated aliphatic hydrocarbon. An alkyl group may be bonded to an atom within a molecule of interest via any chemically suitable portion. Alkyl groups include groups having from 1 to 8 carbon atoms (Cι-C8alkyl), from 1 to 6 carbon atoms (Ci-Cβalkyl) and from 1 to 4 carbon atoms (Cι-C4alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl and norbornyl. "Co-C4alkyl" refers to a bond or an alkyl group having 1, 2, 3 or 4 carbon atoms; "Co-Cδalkyl" refers to a bond or a Ci-Cβalkyl group; "Co-C8alkyl" refers to a bond or a Cι-C8alkyl group. In certain embodiments, preferred alkyl groups are straight or branched chain. In some instances herein, a substituent of an alkyl group is specifically indicated. For example, "cyanoCrC alkyl" refers to a Ci- alkyl group that has a CN substituent. One representative branched cyanoalkyl group is -C(CH3)2CN. Similarly, "alkenyl" refers to straight or branched chain alkene groups or cycloalkene groups, in which at least one unsaturated carbon-carbon double bond is present. Alkenyl groups include C2-C8alkenyl, C2-C6alkenyl and C2-C alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, allyl or isopropenyl. "Alkynyl" refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C2- C8alkynyl, C2-C6alkynyl and C2-C alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively. In certain embodiments, preferred alkenyl and alkynyl groups are straight or branched chain.By "alkoxy," as used herein, is meant an alkyl, alkenyl or alkynyl group as described above attached via an oxygen bridge. Alkoxy groups include Cι-C8alkoxy, Cι-C6alkoxy and Cι-C4alkoxy groups, which have from 1 to 8, 1 to 6 or 1 to 4 carbon atoms, respectively. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec- butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2- l exoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, "alkylthio" refers to an alkyl, alkenyl or alkynyl group as described above attached via a sulfur bridge. Preferred alkoxy and alkylthio groups are those in which an alkyl group is attached via the heteroatom bridge.The term "alkanoyl" refers to an acyl group in a linear, branched or cyclic arrangement (e.g., -(C=O)-alkyl). Alkanoyl groups include C2-C8alkanoyl, C2-C6alkanoyl and C2-C alkanoyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively. "Cialkanoyl" refers to -(C=0)-H, which (along with C2-C8alkanoyl) is encompassed by the term "Cι-C8alkanoyl."An "alkanone" is a ketone group in which carbon atoms are in a linear, branched or cyclic alkyl arrangement. "C3-C8alkanone," "C3-C6alkanone" and "C3-C4alkanone" refer to an alkanone having from 3 to 8, 6 or 4 carbon atoms, respectively. By way of example, a C3 alkanone group has the structure -CH2-(C=O)-CH3.Similarly, "alkyl ether" refers to a linear or branched ether substituent linked via a carbon-carbon bond. Alkyl ether groups include C2-C8alkyl ether, C2-C6alkyl ether and C2- C alkyl ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively. By way of example, a C2 alkyl ether group has the structure -CH2-O-CH3. A representative branced alkyl ether substituent is -C(CH3)2CH2-0-CH3.The term "alkoxycarbonyl" refers to an alkoxy group linked via a carbonyl (i.e., a group having the general structure -C(=0)-0-alkyl). Alkoxycarbonyl groups include C2-C8, C2-C6 and C2-C4alkoxycarbonyl groups, which have from 2 to 8, 6 or 4 carbon atoms, respectively. "Cialkoxycarbonyl" refers to -C(=O)-OH, which is encompassed by the term"Cι-C8alkoxycarbonyl.""Alkanoyloxy," as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure -0-C(=O)-alkyl). Alkanoyloxy groups include C2-C8, C2-C6 and C2-C4alkanoyloxy groups, which have from 2 to 8, 6 or 4 carbon atoms, respectively."Alkylamino" refers to a secondary or tertiary amine having the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl may be the same or different. Such groups include, for example, mono- and di-(C]-C8alkyl)amino groups, in which each alkyl may be the same or different and may contain from 1 to 8 carbon atoms, as well as mono- and di-(Cι-C6alkyl)amino groups and mono- and di-(Cι-C alkyl)amino groups."Alkylaminoalkyl" refers to an alkylamino group linked via an alkyl group (i.e., a group having the general structure -alkyl-NH-alkyl or -alkyl-N(alkyl)(alkyl)) in which each alkyl is selected independently. Such groups include, for example, mono- and di-(Cι- C8alkyl)aminoCι-C8alkyl, mono- and di-(Cι-C6all-yl)aminoCι-C6alkyl and mono- and di-(Cι- C alkyl)aminoCι-C4alkyl, in which each alkyl may be the same or different. "Mono- or di- (Cι-C6alkyl)aminoCo-C6alkyl" refers to a mono- or di-(Cι-C6alkyl)amino group linked via a direct bond or a Ci-Cόalkyl group. The following are representative alkylaminoalkyl groups:AN^- yA~^"^^^- ^ jThe term "aminocarbonyl" refers to an amide group (i.e., -(C=O)NH2). "Mono- or di- (Cι-C8alkyl)aminocarbonyl" is an aminocarbonyl group in which one or both of the hydrogen atoms is replaced with Cι-C8alkyl. If both hydrogen atoms are so replaced, the Cι-C8alkyl groups may be the same or different.The term "halogen" refers to fluorine, chlorine, bromine and iodine. A "haloalkyl" is a branched, straight-chain or cyclic alkyl group, substituted with 1 or more halogen atoms (e.g., "haloCι-C8alkyl" groups have from 1 to 8 carbon atoms; "haloCp Cealkyl" groups have from 1 to 6 carbon atoms). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, terra- or penta-chloroethyl; and 1,2,2,2- tetrafluoro-1-trifluoromethyl-ethyl. Typical haloalkyl groups are trifluoromethyl and difluoromethyl. The term "haloalkoxy" refers to a haloalkyl group as defined above attached via an oxygen bridge. "HaloCι-C8alkoxy" groups have 1 to 8 carbon atoms. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A "heteroatom," as used herein, is oxygen, sulfur or nitrogen.A "carbocycle" or "carbocyclic group" comprises at least one ring formed entirely by carbon-carbon bonds (referred to herein as a carbocyclic ring), and does not contain a heterocyclic ring. Unless otherwise specified, each carbocyclic ring within a carbocycle may be saturated, partially saturated or aromatic. A carbocycle generally has from 1 to 3 fused, pendant or spiro rings; carbocycles within certain embodiments have one ring or two fused rings. Typically, each ring contains from 3 to 8 ring members (i.e., C3-C8); C5-G7 rings are recited in certain embodiments. Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain representative carbocycles are cycloalkyl (i.e., groups that comprise saturated and/or partially saturated rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, and partially saturated variants of any of the foregoing, such as cyclohexenyl). Other carbocycles are aryl (i.e., contain at least one aromatic carbocyclic ring). Such carbocycles include, for example, phenyl, naphthyl, fluorenyl, indanyl and 1,2,3,4-tetrahydro-naphthyl. Certain carbocycles recited herein are C6-CιoarylCo-C8alkyl groups (i.e., groups in which a carbocyclic group comprising at least one aromatic ring is linked via a direct bond or a Cι-C8alkyl group). Such groups include, for example, phenyl and indanyl, as well as groups in which either of the foregoing is linked via d-C8alkyl, preferably via Cι-C4alkyl. Phenyl groups linked via a direct bond or alkyl group may be designated phenylCo-C8alkyl (e.g., benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl). A phenylCo-C8alkoxy group is a phenyl ring linked via an oxygen bridge or an alkoxy group having from 1 to 8 carbon atoms (e.g., phenoxy or benzoxy).A "heterocycle" or "heterocyclic group" has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a heteroatom, with the remaining ring atoms being carbon). Typically, a heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring has 1 or 2 heteroatoms per ring. Each heterocyclic ring generally contains from 3 to 8 ring members (rings having from 4 or 5 to 7 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or S02. Heterocycles may be optionally substituted with a variety of substituents, as indicated. Unless otherwise specified, a heterocycle may be a heterocycloalkyl group (i.e., each ring is saturated or partially saturated) or a heteroaryl group (i.e., at least one ring within the group is aromatic). A heterocyclic group may generally be linked via any ring or substituent atom, provided that a stable compound results. N-linked heterocyclic groups are linked via a component nitrogen atom.Heterocyclic groups include, for example, azepanyl, azocinyl, benzimidazolyl, benzimidazolinyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzothiazolyl, benztetrazolyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, dihydroisoquinolinyl, dihydrotetrahydrofuranyl, l,4-dioxa-8-aza-spiro[4.5]decyl, dithiazinyl, furanyl, furazanyl, imidazolinyl, imidazolidinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl, isoquinolinyl, moipholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoimidazolyl, pyridooxazolyl, pyridothiazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolidonyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, thiazolyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thiophenyl, thiomorpholinyl and variants thereof in which the sulfur atom is oxidized, triazinyl, and any of the foregoing that are substituted with from 1 to 4 substituents as described above.A "heterocycleCo-C8alkyl" is a heterocyclic group linked via a direct bond or C\- C8alkyl group. A (5- to 10-membered heterocycle)Cn-C8alkyl is a heterocyclic group having from 5 to 10 ring members linked via a direct bond or an alkyl group having from 1 to 8 carbon atoms. If the heterocycle is heteroaryl, the group is designated (5- to 10-membered heteroaryl)Co-C8alkyl. A (5- to 7-membered heterocycle)Co-C8alkyl is a 5- to 7-membered heterocyclic ring linked via a bond or a Cι-C8alkyl group; a (4- to 7-membered heterocycle)Co-C8alkyl is a 4- to 7-membered heterocyclic ring linked via a bond or a Cj- C8alkyl group.Certain heterocyclic groups are 4- to 10-membered, 5- to 10-membered, 3- to 7- membered; 4- to 7-membered or 5- to 7-membered groups that contain 1 heterocyclic ring or 2 fused or spiro rings, optionally substituted. 4- to 10-membered heterocycloalkyl groups include, for example, piperidinyl, piperazinyl, pyπolidinyl, azepanyl, l,4-dioxa-8-aza- spiro[4.5]dec-8-yl, morpholino, thiomorpholino and l,l-dioxo-thiomorpholin-4-yl. Such groups may be substituted as indicated. Representative aromatic heterocycles are azocinyl, pyridyl, pyrimidyl, imidazolyl, tetrazolyl and 3,4-dihydro-lH-isoquinolin-2-yl.A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.Groups that are "optionally substituted" are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions, by one or more suitable groups (which may be the same or different). Such optional substituents include, for example, hydroxy, halogen, cyano, nitro, Cι-C8alkyl, C2-C8alkenyl, C2- C8alkynyl, Cι-C8alkoxy, C2-C8alkyl ether, C3-C8alkanone, Cι-C8alkylthio, amino, mono- or di-(Cι-C8alkyl)amino, haloCι-C8alkyl, haloCi- alkoxy, Cι-C8alkanoyl, C2-C8alkanoyloxy, Ci-Cgalkoxycarbonyl, -COOH, -CONH2, mono- or di-(Cι-C8alkyl)aminocarbonyl, -SO2NH2, and or mono or di(Cι- C8alkyl)sulfonamido, as well as carbocyclic and heterocyclic groups. Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents).The terms "VRl" and "capsaicin receptor" are used interchangeably herein to refer to a type 1 vanilloid receptor. Unless otherwise specified, these terms encompass both rat and human VRl receptors (e.g., GenBank Accession Numbers AF327067, AJ277028 and NM_018727; sequences of certain human VRl cDNAs are provided in SEQ ID NOs:l-3, and the encoded amino acid sequences shown in SEQ ID NOs:4 and 5, of U.S. Patent No. 6,482,611), as well as homologs thereof found in other species.A "VRl modulator," also referred to herein as a "modulator," is a compound that modulates VRl activation and/or VRl -mediated signal transduction. VRl modulators specifically provided herein are compounds of Formula I and pharmaceutically acceptable forms of compounds of Formula I. A VRl modulator may be a VRl agonist or antagonist. A modulator binds with "high affinity" if the Kj at VRl is less than 1 micromolar, preferably less than 100 nanomolar, 10 nanomolar or 1 nanomolar. A representative assay for deteπnining Kj at VRl is provided in Example 5, herein.A modulator is considered an "antagonist" if it detectably inhibits vanilloid ligand binding to VRl and/or VRl -mediated signal transduction (using, for example, the representative assay provided in Example 6); in general, such an antagonist inhibits VRl activation with a IC50 value of less than 1 micromolar, preferably less than 100 nanomolar, and more preferably less than 10 nanomolar or 1 nanomolar within the assay provided in Example 6. VRl antagonists include neutral antagonists and inverse agonists. In certain embodiments, capsaicin receptor antagonists provided herein are not vanilloids.An "inverse agonist" of VRl is a compound that reduces the activity of VRl below its basal activity level in the absence of added vanilloid ligand. Inverse agonists of VRl may also inhibit the activity of vanilloid ligand at VRl, and/or may also inhibit binding of vanilloid ligand to VRl. The ability of a compound to inhibit the binding of vanilloid ligand to VRl may be measured by a binding assay, such as the binding assay given in Example 5. The basal activity of VRl, as well as the reduction in VRl activity due to the presence of VRl antagonist, may be determined from a calcium mobilization assay, such as the assay of Example 6. A "neutral antagonist" of VRl is a compound that inhibits the activity of vanilloid ligand at VRl, but does not significantly change the basal activity of the receptor (i.e., within a calcium mobilization assay as described in Example 6 performed in the absence of vanilloid ligand, VRl activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity). Neutral antagonists of VRl may inhibit the binding of vanilloid ligand to VRl.As used herein a "capsaicin receptor agonist" or "VRl agonist" is a compound that elevates the activity of the receptor above the basal activity level of the receptor (i.e., enhances VRl activation and/or VRl -mediated signal transduction). Capsaicin receptor agonist activity may be identified using the representative assay provided in Example 6. In general, such an agonist has an EC50 value of less than 1 micromolar, preferably less than 100 nanomolar, and more preferably less than 10 nanomolar within the assay provided in Example 6. In certain embodiments, capsaicin receptor agonists provided herein are not vanilloids. A "vanilloid" is capsaicin or any capsaicin analogue that comprises a phenyl ring with two oxygen atoms bound to adjacent ring carbon atoms (one of which carbon atom is located para to the point of attachment of a third moiety that is bound to the phenyl ring). A vanilloid is a "vanilloid ligand" if it binds to VRl with a Kj (determined as described herein) that is no greater than 10 μM. Vanilloid ligand agonists include capsaicin, olvanil, N- arachidonoyl-dopamine and resiniferatoxin (RTX). Vanilloid ligand antagonists include capsazepine and iodo-resiniferatoxin.A "capsaicin receptor modulatory amount" is an amount that, upon administration to a patient, achieves a concentration of VRl modulator at a capsaicm receptor within the patient that is sufficient to alter the binding of vanilloid ligand to VRl in vitro (using the assay provided in Example 5) and/or VRl -mediated signal transduction (using an assay provided in Example 6). The capsaicin receptor may be present, or example, in a body fluid such as blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine.A "therapeutically effective amount" is an amount that, upon administration, is sufficient to provide detectable patient relief from a condition being treated. Such relief may be detected using any appropriate criteria, including alleviation of one or more symptoms such as pain.A "patient" is any individual treated with a VRl modulator as provided herein. Patients include humans, as well as other animals such as companion animals (e.g., dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to capsaicm receptor modulation (e.g., pain, exposure to vanilloid ligand, itch, urinary incontinence, respiratory disorders, cough and/or hiccup), or may be free of such symptom(s) (i.e., treatment may be prophylactic).VRl MODULATORS As noted above, the present invention provides VRl modulators that may be used in a variety of contexts, including in the treatment of pain (e.g., neuropathic or peripheral nerve- mediated pain); exposure to capsaicin; exposure to acid, heat, light, tear gas air pollutants, pepper spray or related agents; respiratory conditions such as asthma or chronic obstructive pulmonary disease; itch; urinary incontinence; cough or hiccup; and/or obesity. VRl modulators may also be used within in vitro assays (e.g., assays for receptor activity), as probes for detection and localization of VRl and as standards in ligand binding and VR1- mediated signal transduction assays.VRl modulators provided herein are 2-substituted quinazolin-4-ylamine analogues that detectably modulate the binding of capsaicin to VRl at nanomolar (i.e., submicromolar) concentrations, preferably at subnanomolar concentrations, more preferably at concentrations below 100 picomolar, 20 picomolar, 10 picomolar or 5 picomolar. Such modulators are preferably not vanilloids. Certain preferred modulators are VRl antagonists and have no detectable agonist activity in the assay described in Example 6. Preferred VRl modulators further bind with high affinity to VRl, and do not substantially inhibit activity of human EGF receptor tyrosine kinase.As noted above, X, V, W, Y and Z are each independently N or CRj, with at least one of X and V being N, and Rj is as described above. In certain embodiments, no more than 2 of W, Y and Z are N, and each Rj is hydrogen. Representative 2-substituted quinazolin-4- ylamine analogues include, but are not limited to, compounds in which W is CH and X, V, Y and Z are as indicated for any one of the embodiments listed in Table I. Table I Representative Ouinazoline-4-ylamine Analogue Core StructuresIn certain embodiments of Formula I and Fonnula II, R7 is (i) hydrogen or (ii) Cp C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkanoyl, C3-C8alkanone, C2-C8alkyl ether, C6- CioarylCo-Cgalkyl, or (5- to 10-membered heterocycle)Co-C8alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rb. Within other embodiments, R is (i) hydrogen or (ii) Ci-Cδalkyl, C2-C6alkenyl, C2-C6alkanoyl, C2-C6alkyl ether, mono- or di-(Cι-C6alkyl)aminoCι-C6alkyl, phenylCo-C alkyl, 5- or 6-membered heteroarylCo-C4alkyl, or 5- to 7-membered heterocycloalkylCo-C alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, Cι-C alkyl, haloCι-C4alkyl, Cι-C alkoxy and halo - alkoxy. Representative R7 groups include Cι-C4alkyl, C2-C alkyl ether, mono- and di-(Cι-C6alkyl)aminoCι-C6aIkyl, 6- membered heterocycles and benzyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen and Cι-C alkyl. Alternatively, R7 may be taken together with an R5 or Rό group (along with the O to which R7 is bound and any carbon atoms between the O and R5 or R^) to form an optionally substituted heterocycle, such as a 4- to 10-membered mono- or bi-cyclic group. The resulting heterocycle may, for example, be substituted with from 0 to 4 (e.g., 0, 1 or 2) substituents independently chosen from hydroxy, halogen, Cι-C alkyl, haloCι-C4alkyl, Cι-C4aIkoxy, haloCι-C alkoxy, Cι-C alkanoyl, Cι-C alkoxycarbonyl, aminocarbonyl, heterocycleCo- C8alkyl and heterocycleCι-C8alkoxycarbonyl.Within certain embodiments, R3 and 1^ of Formulas I and III are each independently selected from (i) hydrogen; and (ii) Cι-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8alkanone, Ci-Csalkanoyl, C2-C8alkyl ether, C6-Cι0arylCo-C8alkyl, (5- to 10-membered heterocycle)Co- C8alkyl and -(S0 )Ci-C8alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rb. Within other embodiments, R3 and R are each independently selected from (i) hydrogen and (ii) Cι-C8alkyl, C2-C8alkenyl, phenylCo-C alkyl, indanylC0- C alkyl, 5- to 6-membered heteroarylCo-C alkyl and (5- to 7-membered heterocycloalkyl)Co- C alkyl, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, amino, Cι-C6alkyl, haloCi-Cόalkyl, Cι-C6alkoxy and haloC C6alkoxy. Representative R3 and ^ groups include hydrogen,Cι-C6alkyl, C2-C6alkenyl, (5- to 7-membered heterocycle)C0-C alkyl, C -C6alkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1- phenyl-propyl and 2-phenyl-ethyl, each of which is substituted with from 0 to 3 substituents independently selected from hydroxy, halogen and Cι-C4alkyl. For example, at least one of R3 and R-i may be pyridylC0-C4alkyl, pyrimidylCo-C alkyl, imidazolylCo-C alkyl or tetrazolylCo-C4alkyl, each of which is substituted with 0, 1 or 2 substituents. Preferably, at least one of R3 and R-( is not hydrogen. In certain embodiments, compounds of Formula I and III are not [2-pyrrolidin-l-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl)-amine.Within other embodiments, R3 and/or 1?^ of Formulas I and III may form an optionally substituted heterocycle. For example, R3 and may be taken together to form, with the N to which they are bound, an optionally substituted heterocycle; or one of R3 and R4 may be taken together with an R5 or R6 moiety (along with the N to which R3 and R are bound and any carbon atoms located between the N and the linked R5 or Re) to from an optionally substituted heterocycle. In either case, the resulting heterocycle may be, for example, a 4-, 5- or 6- to 10-membered, mono- or bi-cyclic group substituted with from 0 to 4 substituents (e.g., from 1 to 4 substituents or 0, 1 or 2 substituents). In certain embodiments, each substituent is independently selected from hydroxy, halogen, Cι-C4alkyl, haloCι-C alkyl, Ci- C alkoxy, haloCι-C alkoxy, Cj-C alkanoyl, Cι-C alkoxycarbonyl, aminocarbonyl and (4- to 10-membered)heterocycleCo-C8alkyl. In certain embodiments, each substituent, if any, is a lower alkyl group such as methyl or ethyl.A heterocyclic group that comprises R3 and/or R-t may be an optionally substituted heteroaryl or heterocycloalkyl group. Such heterocyclic groups include, for example, azepane, azocine, benzimidazoline, benzimidazole, benzotriazole, cinnoline, decahydroquinoline, dihydroisoquinoline, l,4-dioxa-8-aza-spiro[4.5]decane, imidazole, imidazolidine, imidazoline, indazole, indoline, indole, isoquinoline, quinoxaline, morpholine, naphthyridine, octahydroquinoline, phthalazine, piperazine, piperidine, pteridine, purine, pyridazine, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiomorpholine or thiomorpholine 1,1-dioxide. One suitable heteroaryl group is 3,4-dihydro-lH-isoquinolin-2-yl.Within certain compounds of Formulas I-III, R5 and Re are independently (at each occurrence) hydrogen or optionally substituted Ci-Cealkyl or Cr alkyl; in addition, or alternatively, any R5 or R6 may be taken together with any other R5 or Re to form an optionally substituted 5- to 7-membered cycloalkyl or heterocycloalkyl, or (as discussed above) taken together with R7, R3 or R-i to form an optionally substituted heterocycle. Preferably, no more than one R5 or R6 moiety is taken together with another group to form a carbocycle or heterocycle. In certain compounds, one R5 or Re is hydrogen or methyl and the other(s) are hydrogen. In further compounds, each R5 and Re is hydrogen. The variable n is generally 1, 2 or 3; in certain compounds n is 1. In other compounds of Formulas I-III, n is chosen from 2 and 3.Within certain embodiments of Formulas I-III, Ari and Ar2 are independently selected from optionally substituted phenyl and optionally substituted 5- to 7-membered heterocycles. For example, Ari and Ar2 may be independently selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted with 0, 1 or 2 substituents. Substituents of Ari and Ar2 are generally groups of the formula LRa, in which L is a bond, O, S(O)m (i.e.,O o 0 ° ° °S, -S- or -S-), C(=O) (i.e., -£-), OC(=O) (i.e., -0-C-), C(=O)O (i.e., -C-0-), O-C(=O)O (-.β.. -0-C-θ-), N(RX) (/.e., -N-), C(=0)N(Rx) (ι.e.. -C-N- ). N(Rx)C(=O)(i.e., -N-C- ), N(Rx)S(0)m (e.g., -N-S- ), S(0)mN(Rx) (e.g., -S-N- ), or N[S(0)mRx]S(0)mO .9-N-c--(e.g., O- arjfj Ra js as described above. If L is a bond, Ra is linked directly to a ring atom of Ari or Ar2; otherwise, L is located between a ring atom and Ra. It will be apparent that L is generally a bond if Ra is halogen, cyano or nitro. In the structural drawings of L moieties shown above, the bond on the left side is attached to the ring atom and the bond on the right is attached to Ra.In certain embodiments, Ari is phenyl or pyridyl, each of which is substituted with from 0 to 3 substituents as described above; preferably such substituents, if any, are independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- CeaIkyl)amino, -Cealkyl, haloCi-Cβalkyl, Ci-Cβalkoxy and haloCi-Cδalkoxy. For example, Ari may contain one substituent selected from halogen, cyano, Cι-C4alkyl, Cι-C aIkoxy, ha!oCι-C alkyl and haloCι-C4alkoxy. If one or more Ari substituents is present, at least one such substituent is preferably located in the ortho position (e.g., Ari may be phenyl substituted at the 2-position, or pyridin-2-yl substituted at the 3-position). Ari groups include, but are not limited to, pyridin-2-yl, 3-methyl-pyridin-2-yl, 3-trifluoromethyl-pyridin- 2-yl, 3-halo-pyridin-2-yl, phenyl, 2-methyl-phenyl, 3-trifluoromethyl-phenyl and 3-halo- phenyl.Ar2 groups include, but are not limited to, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and thiadiazolyl, each of which is optionally substituted as described above. Preferred Ar2 groups are phenyl, pyridyl, isoxazolyl, thiadiazolyl and pyrazolyl, each of which is optionally substituted as described above. Within certain embodiments, Ar2 is phenyl or pyridyl, each of which is substituted with 0, 1 or 2 substituents as described above.Optional substituents on the foregoing Ar2 groups are preferably independently chosen from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι-C6alkyl)amino, - C6alkyl, haloCi-Cόalkyl, Cj-Cealkoxy, haloCι-C6alkoxy, C2-Cealkyl ether, Ci-Cβalkanoyl, - (SO2)R , -N(Rx)S(0)mRd, and -N[S(Om)Rχ]S(0)mRd; wherein m is 1 or 2, Rx is hydrogen or Cj-Cόalkyl, and R is Ci-Cβalkyl, haloCi-Cβalkyl, amino, mono- or di-(Cι-C6alkyl)amino or a 5- to 10-membered, N-linked heterocyclic group, each of which Rd is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, mono- and di-(C]-C6alkyl)amino, Cι-C alkyl, haloCι-C alkyl, Cι-C alkoxy and haloCι-C alkoxy. Certain substituents of Ar2 (e.g., when Ar2 is phenyl or pyridyl) are independently chosen from halogen, hydroxy, cyano, amino, nitro, Cι~C alkyl, haloCι-C alkyl, C2-C alkyl ether, Cι-C alkanoyl and groups of the formula -(S02)Rd or -S02N(Rx)-Rd, wherein Rd is - Cβalkyl or haloCi-Cβalkyl. For example, each substituent is, in certain embodiments, independently chosen from halogen, Cι-C alkyl, haloCι-C alkyl, cyano and groups of the formula -(SO2)Rd, wherein Rd is C C4alkyl or haloCι-C alkyI. Certain Ar2 groups have 1 or 2 substituents independently chosen from halogen, cyano, C]-C alkyl and haloCι-C alkyl.In certain embodiments, one Ar2 substituent is located in the para position of a 6- membered Ar2. Optional Ar2 substituents are as described above and include, for example, groups in which Ra is independently selected at each occurrence from: (i) hydrogen, halogen, cyano and nitro; and (ii) Cι-C8alkyl, C2-C8alkenyl, C2-C8alkynyl and 4- to 10-membered heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, Cι-C6alkyl and haloCι-C6alkyl. Preferred Ra moieties include halogen, hydroxy, cyano, amino, mono- and di-(C]-C6alkyl)amino, Ci-Cealkyl, haloCi-Cealkyl, Cι-C6alkoxy, haloCι-C6alkoxy, C2-C6alkyl ether, Cι-C6alkanoyl, -(SO2)Ra, - NRxS(0)m, and -N(S(O)m)2; wherein m is 1 or 2, Rx is hydrogen or Cι-C6alkyl, and Ra is - Cόalkyl, haloCι-C6alkyl, or a 5- to 10-membered, N-linked heterocyclic group, each of which Ra is substituted with from 0 to 4 substituents as described for Formula I. Preferred Ar2 substituents include Cι-C alkyl, haloCι-C alkyl and groups of the formula -(SO2)Ra, wherein Ra is Cι-C alkyl or haloCι-C alkyl.Certain preferred Ar groups are phenyl, pyridin-2-yl and pyridin-3-yl, each of which is substituted at the /κ.r -position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t- butyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl. The term "pαrα-position" is used herein to refer to the position on a 6-membered Ar2 group that is para to the point of attachment to the core of the molecule. In other words, if Ar2 is phenyl, the 4-position is the /?αrα-position; if Ar2 is pyridin-2-yl, the 5- position is the αrα-position; and if Ar2 is pyridin-3-yl, the 6-position is the / rø-position. Additional substitutions, not at the para position, may also be present on certain preferred Ar2 groups - preferably no more than 2 additional substitutions, and more preferably 0 or 1 additional substitution.Certain compounds provided herein satisfy one or more of subformulas Ia-Ic, Ila-IId and Illa-IIId, in which A, B and C are independently N or CH, and other variables are as described above for Formulas I-III or preferred embodiments thereof. X, in certain embodiments, is N or CH. (LRa)ι-3 indicates 1, 2 or 3 ring substituents independently chosen from LRa as described above; (LRa)o-2 indicates 0, 1 or 2 ring substituents (in addition to the substituent shown at the para position) independently chosen from LRa as described above.In certain compounds of the above subformulas, Y and Z are independently CH or N. In further compounds of Formulas la, lib and Illb, Ari is pyridyl, unsubstituted or substituted with halogen, cyano, Cι-C alkyl or haloCι-C alkyl; Ar2 is phenyl or pyridyl, unsubstituted or substituted with Cι-C alkyl, cyanoCι-C alkyl, haloC]-C alkyl, C2-C6alkyl ether or a group of the formula -(SO2)Rd, wherein Rd is Cι-C alkyl or haloCι-C4alkyl; and R5 and Re are independently selected from hydrogen and Cι-C alkyl. In certain compounds of Formulas Ila-IIe, R7 is (a) hydrogen; or (b) Ci-Cealkyl, C2-Cealkenyl or phenyl Co-C4alkyl, each of which is substituted with 0, 1 or 2 substituents independently selected from hydroxy, halogen, Cι-C alkyl and haloCι-C alkyl. In certain compounds of Formulas Illa-IIIe, R3 and R4 are (a) independently selected from: (i) hydrogen; and (ii) Ci-Cealkyl, C2-Cealkenyl, (5- to 7- membered heterocycle)Co-C alkyl, C2-Cealkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1- phenyl-propyl and 2-phenyl-ethyl, each of which is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C alkyl and haloCι-C alkyl; or (b) taken together to form a 5- to 7-membered heterocycloalkyl that is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, C]-C alkyl and haloCi- C alkyl. In Formulas Ilc-IIe and Illc-IIIe, Re is preferably hydrogen or methyl.In certain embodiments of the invention, preferred compounds of Formula III and subformulas thereof (e.g., Illa-IIIe) include those compounds in which at least one of R5 and Re is not hydrogen when n is 1.Representative compounds of Formulas I-III, and subformulas thereof, include, but are not limited to, those specifically described in Examples 1-3. It will be apparent that the specific compounds recited therein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds of the present invention may be present as a pharmaceutically acceptable form, such as a hydrate or acid addition salt.2-Substituted quinazolin-4-ylamine analogues provided herein detectably alter (modulate) VRl activity, as determined using an in vitro VRl ligand binding assay and/or a functional assay such as a calcium mobilization assay, dorsal root ganglion assay or in vivo pain relief assay. References herein to a "VRl ligand binding assay" are intended to refer to a standard in vitro receptor binding assay such as that provided in Example 5, and a "calcium mobilization assay" (also referred to herein as a "signal transduction assay") may be performed as described in Example 6. Briefly, to assess binding to VRl, a competition assay may be performed in which a VRl preparation is incubated with labeled (e.g., 125I or 3H) compound that binds to VRl (e.g., a capsaicin receptor agonist such as RTX) and unlabeled test compound. Within the assays provided herein, the VRl used is preferably mammalian VRl, more preferably human or rat VRl. The receptor may be recombinantly expressed or naturally expressed. The VRl preparation may be, for example, a membrane preparation from HEK293 or CHO cells that recombinantly express human VRl. Incubation with a compound that detectably modulates vanilloid ligand binding to VRl results in a decrease or increase in the amount of label bound to the VRl preparation, relative to the amount of label bound in the absence of the compound. This decrease or increase may be used to determine the Ki at VRl as described herein. In general, compounds that decrease the amount of label bound to the VRl preparation within such an assay are preferred.As noted above, compounds that are VRl antagonists are preferred within certain embodiments. IC50 values for such compounds may be determined using a standard in vitro VRl-mediated calcium mobilization assay, as provided in Example 6. Briefly, cells expressing capsaicin receptor are contacted with a compound of interest and with an indicator of intracellular calcium concentration (e.g., a membrane permeable calcium sensitivity dye such as Fluo-3 or Fura-2 (both of which are available, for example, from Molecular Probes, Eugene, OR), each of which produce a fluorescent signal when bound to Ca4"1"). Such contact is preferably carried out by one or more incubations of the cells in buffer or culture medium comprising either or both of the compound and the indicator in solution. Contact is maintained for an amount of time sufficient to allow the dye to enter the cells (e.g., 1-2 hours). Cells are washed or filtered to remove excess dye and are then contacted with a vanilloid receptor agonist (e.g., capsaicin, RTX or olvanil), typically at a concentration equal to the EC50 concentration, and a fluorescence response is measured. When agonist-contacted cells are contacted with a compound that is a VRl antagonist the fluorescence response is generally reduced by at least 20%, preferably at least 50% and more preferably at least 80%, as compared to cells that are contacted with the agonist in the absence of test compound. The IC50 for VRl antagonists provided herein is preferably less than 1 micromolar, less than 100 nM, less than 10 nM or less than 1 nM.In other embodiments, compounds that are capsaicin receptor agonists are preferred. Capsaicin receptor agonist activity may generally be determined as described in Example 6. When cells are contacted with 1 micromolar of a compound that is a VRl agonist, the fluorescence response is generally increased by an amount that is at least 30% of the increase observed when cells are contacted with 100 nM capsaicin. The EC50 for VRl agonists provided herein is preferably less than 1 micromolar, less than 100 nM or less than 10 nM.VRl modulating activity may also, or alternatively, be assessed using a cultured dorsal root ganglion assay as provided in Example 9 and/or an in vivo pain relief assay as provided in Example 10. Compounds provided herein preferably have a statistically significant specific effect on VRl activity within one or more functional assays provided herein.Within certain embodiments, VRl modulators provided herein do not substantially modulate ligand binding to other cell surface receptors, such as EGF receptor tyrosine kinase or the nicotinic acetylcholine receptor. In other words, such modulators do not substantially inhibit activity of a cell surface receptor such as the human epidermal growth factor (EGF) receptor tyrosine kinase or the nicotinic acetylcholine receptor (e.g., the ICS0 or IC o at such a receptor is preferably greater than 1 micromolar, and most preferably greater than 10 micromolar). Preferably, a modulator does not detectably inhibit EGF receptor activity or nicotinic acetylcholine receptor activity at a concentration of 0.5 micromolar, 1 micromolar or more preferably 10 micromolar. Assays for determining cell surface receptor activity are commercially available, and include the tyrosine kinase assay kits available from Panvera (Madison, WI).Preferred VRl modulators provided herein are non-sedating. In other words, a dose of VRl modulator that is twice the minimum dose sufficient to provide analgesia in an animal model for determining pain relief (such as a model provided in Example 10, herein) causes only transient (i.e., lasting for no more than lA the time that pain relief lasts) or preferably no statistically significant sedation in an animal model assay of sedation (using the method described by Fitzgerald et al. (1988) Toxicology 49(2-3):433-9). Preferably, a dose that is five times the minimum dose sufficient to provide analgesia does not produce statistically significant sedation. More preferably, a VRl modulator provided herein does not produce sedation at intravenous doses of less than 25 mg/kg (preferably less than 10 mg/kg) or at oral doses of less than 140 mg/kg (preferably less than 50 mg/kg, more preferably less than 30 mg/kg). If desired, VRl modulators provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailable to an extent allowing for therapeutically effective concentrations of the compound to be achieved at oral doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg, still more preferably less than 1 mg/kg and most preferably less than 0.1 mg/kg), toxicity (a preferred VRl modulator is nontoxic when a capsaicin receptor modulatory amount is administered to a subject), side effects (a preferred VRl modulator produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), serum protein binding and in vitro and in vivo half- life (a preferred VRl modulator exhibits an in vitro half-life that is equal to an in vivo half- life allowing for Q.I.D. dosing, preferably T.I.D. dosing, more preferably B.I.D. dosing, and most preferably once-a-day dosing). In addition, differential penetration of the blood brain barrier may be desirable for VRl modulators used to treat pain by modulating CNS VRl activity such that total daily oral doses as described above provide such modulation to a therapeutically effective extent, while low brain levels of VRl modulators used to treat peripheral nerve mediated pain may be preferred (i.e., such doses do not provide brain (e.g., CSF) levels of the compound sufficient to significantly modulate VRl activity). Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays. Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described within Example 7, herein.As noted above, preferred VRl modulators provided herein are nontoxic. In general, the term "nontoxic" as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans). In addition, a highly preferred nontoxic compound generally satisfies one or more of the following criteria: (1) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement, and (4) does not cause substantial release of liver enzymes.As used herein, a VRl modulator that "does not substantially inhibit cellular ATP production" is a compound that satisfies the criteria set forth in Example 8, herein. In other words, cells treated as described in Example 8 with 100 μM of such a compound exhibit ATP levels that are at least 50% of the ATP levels detected in untreated cells. In more highly preferred embodiments, such cells exhibit ATP levels that are at least 80% of the ATP levels detected in untreated cells.A VRl modulator that "does not significantly prolong heart QT intervals" is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, minipigs or dogs upon administration of twice the minimum dose yielding a therapeutically effective in vivo concentration. In certain preferred embodiments, a dose of 0.01, 0.05. 0.1, 0.5, 1, 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals. By "statistically significant" is meant results varying from control at the p<0.1 level or more preferably at the p<0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test.A VRl modulator "does not cause substantial liver enlargement" if daily treatment of laboratory rodents (e.g., mice or rats) for 5-10 days with twice the minimum dose that yields a therapeutically effective in vivo concentration results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls. If non-rodent mammals (e.g., dogs) are used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls. Preferred doses within such assays include 0.01, 0.05. 0.1, 0.5, 1, 5, 10, 40 or 50 mg/kg administered parenterally or orally.Similarly, a VRl modulator "does not promote substantial release of liver enzymes" if administration of twice the minimum dose yielding a therapeutically effective in vivo concentration does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls. In more highly preferred embodiments, such doses do not elevate such serum levels by more than 75% or 50% over matched controls. Alternatively, a VRl modulator "does not promote substantial release of liver enzymes" if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro) equivalent to twofold the minimum in vivo therapeutic concentration of the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells. In more highly preferred embodiments, there is no detectable release of any of such liver enzymes into culture medium above baseline levels when such compound concentrations are five-fold, and preferably ten-fold the minimum in vivo therapeutic concentration of the compound.In other embodiments, certain preferred VRl modulators do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the minimum therapeutically effective in vivo concentration.Certain preferred VRl modulators are not clastogenic (e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) at a concentration equal to the minimum therapeutically effective in vivo concentration. In other embodiments, certain preferred VRl modulators do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.For detection purposes, as discussed in more detail below, VRl modulators provided herein may be isotopically-labeled or radiolabeled. For example, compounds recited in Formulas I-III may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, nC, 13C, 14C, 15N, 180, 17O, 31P, 32P, 35S, I8F and 36C1. In addition, substitution with heavy isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.PREPARATION OF VRl MODULATORS 2-Substituted quinazolin-4-ylamine analogues may generally be prepared using standard synthetic methods. Starting materials are commercially available from suppliers such as Sigma-Aldrich Corp. (St. Louis, MO), or may be synthesized from commercially available precursors using established protocols. By way of example, a synthetic route similar to that shown in any of Schemes 1-13 may be used, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Variables in the following schemes refer to any group consistent with at least one of Formulas I-III herein. Where a structure contains more than one variable "R," each R is selected independently of any other R group(s).In the Schemes that follow, the term "activate" refers to a synthetic transformation in which a carbonyl of an amide moiety is converted to a suitable leaving group (L). Such a transformation can be used to prepare compounds of general structure II (Scheme 1), 2G (Scheme 2), 3G and 3L (Scheme 3), 4C (Scheme 4), 5F (Scheme 5), 7H (Scheme 7), 10H (Scheme 10), 121 (Scheme 12) and 131 (Scheme 13). Reagents suitable for carrying out this transfoπnation are well known to those skilled in the art of organic synthesis and include, but are not limited to, SOCl2, POCl3 and triflic anhydride.The term "catalyst" refers to a suitable transition metal catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate. In addition, the catalytic systems may include ligands such as, but not limited to, 2- (Dicyclohexylphosphino)biphenyl and tri-tert-burylphosphine, and may also include a base such as K3PO , Na2CO3 or sodium or potassium tert-butoxide. Transition metal-catalyzed reactions can be carried out at ambient or elevated temperatures using various inert solvents including, but not limited to, toluene, dioxane, DMF, N-methylpyrrolidinone, ethyleneglycol, dimethyl ether, diglyme and acetonitrile. When used in conjunction with suitable metallo- aryl reagents, transition metal-catalyzed (hetero)aryl-aryl coupling reactions can be used to prepare the compounds encompassed in general structures IC (Scheme 1), 2 A (Scheme 2), 3D (Scheme 3), 5C (Scheme 5), 6C (Scheme 6), 11D (Scheme 11), 12C (Scheme 12) and 13C (Scheme 13). Commonly employed reagent/catalyst pairs include aryl boronic aciαVpalladium(O) (Suzuki reaction; Miyaura and Suzuki (1995) Chemical Reviews 95:2451) and aryl trialkylstannane/palladium(0) (Stille reaction; T. N. Mitchell, (1992) Synthesis 9:803-815), arylzinc/palladium(0) and aryl Grignard/nickel(II).The term "demethylation" refers to the cleavage of the Me-O bond in a methyl ether functionality as exemplified by the conversion of 3-D to 3-E (Scheme 3). This transformation can be carried out in a variety of ways familiar to those skilled in the art of organic synthesis including, but not limited to, treatment with HBr, treatment with Lewis acid/nucleophile combinations, Trimethylsilyl iodide, etc."Diazotize," in Scheme 11 refers to the process whereby a primary aromatic amine is converted to a diazonium salt. This transformation is carried out by treating the aromatic amine with nitrous acid which can be generated in a number of ways well known to those skilled in the art of organic synthesis. The diazonium group thus generated can then be replaced by a cyano group upon treatment with CuCN (Sandmeyer reaction) as shown in Scheme 11.In Scheme 12, the term "deprotection" refers to the process of cleaving the C-O bond of a benzylic ether to give a "deprotected" alcohol using various methods familiar to those who are skilled in the art of organic synthesis. This is exemplified in Scheme 12 in which compounds of general structure 121 can be converted to deprotected alcohols of general structure 12J. Methods to effect this transfonnation include, but are not limited to, hydrogenolysis using hydrogen gas and an appropriate catalyst system such as palladium on carbon or Raney nickel. For an overview of protection and deprotection methods as used by those skilled in the art of organic synthesis, see: Greene, T. and Wuts, P. Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons, 1999.The term "hydrolyze" refers to the conversion of a nitrile functionality to an amide functionality by reaction with water. The reaction with water can be catalyzed by a variety of acids or bases well known to those skilled in the art of organic synthesis. This process is exemplified by the conversion of 8-B to 8-C (Scheme 8) and 10-E to 10-F (Scheme 10).The term "oxidize" refers to a synthetic transformation wherein a methyl group is converted to a carboxylic acid functionality. Such a transformation can be used to prepare compounds such as IE, 6D, 12E and 13E (Schemes 1, 6, 12 and 13 respectively). Various reagents familiar to those skilled in the art of organic synthesis may be used to carry out this transformation including, but not limited to, KMn0 in basic media (e.g., NaOH solution or aqueous pyridine) and K Cr2O7 in acidic media (e.g., H2SO ).The term "reduce" in the following Schemes refers to the process of reducing a nitro functionality to an amino functionality. This transformation can be carried out in a number of ways well known to those skilled in the art of organic synthesis including, but not limited to, catalytic hydrogenation, reduction with SnCl2 and reduction with titanium trichloride. For an overview of reduction methods see: Hudlicky, M. Reductions in Organic Chemistry, ACS Monograph 188, 1996.Scheme 1 Scheme 2Br CONH,CuCN H30+ ReduceBr' ^ - NO, Br^^ 02 Br' ^N022-B 2-C 2-DR-Ar-NH2 ' REST OF THIS PAGE LEFT INTENTIONALLY LEFT BLANK Scheme 3Activate ReduceScheme 4 Scheme 5Oxidize 6-DScheme 7Scheme 8Base Activate RAr-NH,(See Scheme 1) (see Scheme 1) Scheme 9 Scheme 10HydrolyzeActivate R-Ar-NH,Scheme 1111-E 11-D Scheme 12OxidizeScheme 13OxidizeIn certain embodiments, a VRl modulator may contain one or more asymmetric carbon atoms, so that the compound can exist in different stereoisomeric forms. Such forms can be, for example, racemates or optically active forms. As noted above, all stereoisomers are encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms). Standard methods for preparing single enantiomers include asymmetric synthesis and resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography using, for example a chiral HPLC column.Compounds may be radiolabeled by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. Each radioisotope is preferably carbon(e.g., 114,C), hydrogen (e.g., Η), sulfur (e.g., or iodine (e.g., 1 '2-"STI). Tritium labeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous- catalyzed exchange with tritium gas using the compound as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate. Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.PHARMACEUTICAL COMPOSITIONS The present invention also provides pharmaceutical compositions comprising one or more VRl modulators, together with at least one physiologically acceptable carrier or excipient. Pharmaceutical compositions may comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. In addition, other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.Pharmaceutical compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions of the present invention may be formulated as a lyophilizate. Formulation for topical administration may be preferred for certain conditions (e.g., in the treatment of skin conditions such as burns or itch). Formulation for direct administration into the bladder (intravesicular administration) may be preferred for treatment of urinary incontinence.Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate). Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present. Pharmaceutical compositions may also be formulated as oil-in-water emulsions. The oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monoleate) and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate). An emulsion may also comprise one or more sweetening and/or flavoring agents.Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale~The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.A topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions. The physical appearance and viscosity of such pharmaceutically acceptable forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate. Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. A gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquatemiums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG- dimonium chloride, and ammonium laureth sulfate may be used within topical formulations. Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included a topical fonnulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.An example of a suitable topical vehicle for formulation of a gel is: hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%); propylene glycol (5.1%); and Polysorbate 80 (1.9%). An example of a suitable topical vehicle for fonnulation as a foam is: cetyl alcohol (1.1%); stearyl alcohol (0.5%; Quaternium 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing. Controlled release vehicles can also be used.A pharmaceutical composition may be prepared as a sterile injectible aqueous or oleaginous suspension. The modulator, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Such a composition may be formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents such as those mentioned above. Among the acceptable vehicles and solvents that may be employed are water, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.Modulators may also be formulated as suppositories (e.g., for rectal administration). Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.Pharmaceutical compositions may be formulated as sustained release formulations (i.e., a formulation such as a capsule that effects a slow release of modulator following administration). Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.In addition to or together with the above modes of administration, a modulator may be conveniently added to food or drinking water (e.g., for administration to non-human animals including companion animals (such as dogs and cats) and livestock). Animal feed and drinking water compositions may be formulated so that the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to feed or drinking water.Modulators are generally administered in a capsaicin receptor modulatory amount, and preferably a therapeutically effective amount. Preferred systemic .doses are no higher than 50 mg per kilogram of body weight per day (e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses (e.g., ranging from 0.01 to 40 mg per kilogram of body weight per day).The amount of active ingredient that may be combined with the carrier materials to produce a single dosage unit will vary depending, for example, upon the patient being treated and the particular mode of administration. Dosage units will generally contain between from about 10 μg to about 500 mg of an active ingredient. Optimal dosages may be established using routine testing, and procedures that are well known in the art.Pharmaceutical compositions may be packaged for treating conditions responsive to VRl modulation (e.g., treatment of exposure to vanilloid ligand, pain, itch, obesity or urinary incontinence). Packaged pharmaceutical compositions may include a container holding a therapeutically effective amount of at least one VRl modulator as described herein and instructions (e.g., labeling) indicating that the contained composition is to be used for treating a condition responsive to VRl modulation in the patient. METHODS OF USEVRl modulators provided herein may be used to alter activity and/or activation of capsaicin receptors in a variety of contexts, both in vitro and in vivo. Within certain aspects, VRl antagonists may be used to inhibit the binding of vanilloid ligand agonist (such as capsaicin and/or RTX) to capsaicin receptor in vitro or in vivo. In general, such methods comprise the step of contacting a capsaicin receptor with a capsaicin receptor modulatory amount of one or more 2-substituted quinazolin-4-ylamine analogues, or pharmaceutically acceptable forms thereof, in the presence of vanilloid ligand in aqueous solution and under conditions otherwise suitable for binding of the ligand to capsaicin receptor. The capsaicin receptor may be present in solution or suspension (e.g., in an isolated membrane or cell preparation), or in a cultured or isolated cell. Within certain embodiments, the capsaicin receptor is expressed by a neuronal cell present in a patient, and the aqueous solution is a body fluid. Preferably, one or more VRl modulators are administered to an animal in an amount such that the analogue is present in at least one body fluid of the animal at a therapeutically effective concentration that is 1 micromolar or less; preferably 500 nanomolar or less; more preferably 100 nanomolar or less, 50 nanomolar or less, 20 nanomolar or less, or 10 nanomolar or less. For example, such compounds may be administered at a dose that is less than 20 mg/kg body weight, preferably less than 5 mg/kg and, in some instances, less than 1 mg/kg. Also provided herein are methods for modulating, preferably inhibiting, the signal- transducing activity of a capsaicin receptor. Such modulation may be achieved by contacting a capsaicin receptor (either in vitro or in vivo) with a capsaicin receptor modulatory amount of one or more VRl modulators provided herein under conditions suitable for binding of the modulator(s) to the receptor. The receptor may be present in solution or suspension, in a cultured or isolated cell preparation or within a patient. Modulation of signal tranducing activity may be assessed by detecting an effect on calcium ion conductance (also referred to as calcium mobilization or flux). Modulation of signal transducing activity may alternatively be assessed by detecting an alteration of a symptom (e.g., pain, burning sensation, broncho- constriction, inflammation, cough, hiccup, itch, and urinary incontinence) of a patient being treated with one or more VRl modulators provided herein.VRl modulator(s) provided herein are preferably administered to a patient (e.g., a human) orally or topically, and are present within at least one body fluid of the animal while modulating VRl signal-transducing activity. Preferred VRl modulators for use in such methods modulate VRl signal-transducing activity in vitro at a concentration of 1 nanomolar or less, preferably 100 picomolar or less, more preferably 20 picomolar or less, and in vivo at a concentration of 1 micromolar or less, 500 nanomolar or less, or 100 nanomolar or less in a body fluid such as blood.The present invention further provides methods for treating conditions responsive to VRl modulation. Within the context of the present invention, the term "treatment" encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms). A condition is "responsive to VRl modulation" if it is characterized by inappropriate activity of a capsaicin receptor, regardless of the amount of vanilloid ligand present locally, and/or if modulation of capsaicin receptor activity results in alleviation of the condition or a symptom thereof. Such conditions include, for example, symptoms resulting from exposure to VRl -activating stimuli, pain, respiratory disorders such as asthma and chronic obstructive pulmonary disease, itch, urinary incontinence, cough, hiccup, and obesity, as described in more detail below. Such conditions may be diagnosed and monitored using criteria that have been established in the art. Patients may include humans, domesticated companion animals and livestock, with dosages as described above.Treatment regimens may vary depending on the compound used and the particular condition to be treated. However, for treatment of most disorders, a frequency of administration of 4 times daily or less is preferred. In general, a dosage regimen of 2 times daily is more preferred, with once a day dosing particularly preferred. For the treatment of acute pain, a single dose that rapidly reaches effective concentrations is desirable. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.Patients experiencing symptoms resulting from exposure to capsaicin receptor- activating stimuli include individuals with burns caused by heat, light, tear gas or acid and those whose mucous membranes are exposed (e.g., via ingestion, inhalation or eye contact) to capsaicin (e.g., from hot peppers or in pepper spray) or a related irritant such as acid, tear gas or air pollutants. The resulting symptoms (which may be treated using VRl modulators, especially antagonists, provided herein) may include, for example, pain, broncho-constriction and inflammation.Pain that may be treated using the VRl modulators provided herein may be chronic or acute and includes, but is not limited to, peripheral nerve-mediated pain (especially neuropathic pain). Compounds provided herein may be used in the treatment of, for example, postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, toothache (dental pain), denture pain, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome and/or bilateral peripheral neuropathy. Additional neuropathic pain conditions include causalgia (reflex sympathetic dystrophy - RSD, secondary to injury of a peripheral nerve), neuritis (including, for example, sciatic neuritis, peripheral neuritis, polyneuritis, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis and Gombault's neuritis), neuronitis, neuralgias (e.g., those mentioned above, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia and vidian neuralgia), surgery-related pain, musculoskeletal pain, AIDS-related neuropathy, MS-related neuropathy, and spinal cord injury-related pain. Headache, including headaches involving peripheral nerve activity, such as sinus, cluster (i.e., migranous neuralgia) and some tension headaches and migraine, may also be treated as described herein. For example, migraine headaches may be prevented by administration of a compound provided herein as soon as a pre-migrainous aura is experienced by the patient. Further pain conditions that can be treated as described herein include "burning mouth syndrome," labor pains, Charcot's pains, intestinal gas pains, menstrual pain, acute and chronic back pain (e.g., lower back pain), hemorrhoidal pain, dyspeptic pains, angina, nerve root pain, homotopic pain and heterotopic pain - including cancer associated pain (e.g., in patients with bone cancer), pain (and inflammation) associated with venom exposure (e.g., due to snake bite, spider bite, or insect sting) and trauma associated pain (e.g., post-surgical pain, pain from cuts, bruises and broken bones, and burn pain). Additional pain conditions that may be treated as described herein include pain associated with inflammatory bowel disease, irritable bowel syndrome and/or inflammatory bowel disease. Within certain aspects, VRl modulators provided herein may be used for the treatment of mechanical pain. As used herein, the term "mechanical pain" refers to pain other than headache pain that is not neuropathic or a result of exposure to heat, cold or external chemical stimuli. Mechanical pain includes physical trauma (other than thermal or chemical burns or other irritating and/or painful exposures to noxious chemicals) such as post-surgical pain and pain from cuts, bruises and broken bones; toothache, denture pain; nerve root pain; osteoartiritis; rheumatoid arthritis; fibromyalgia; meralgia paresthetica; back pain; cancer-associated pain; angina; carpel tunnel syndrome; and pain resulting from bone fracture, labor, hemorrhoids, intestinal gas, dyspepsia, and menstruation. Itching conditions that may be treated include psoriatic pruritis, itch due to hemodialysis, aguagenic pruritus, and itching associated with vulvar vestibulitis, contact dermatitis, insect bites and skin allergies. Urinary incontinence, as used herein, includes overactive bladder conditions, detrusor hyperflexia of spinal origin and bladder hypersensitivity, all of which may be treated as described herein. In certain such treatment methods, VRl modulator is administered via a catheter or similar device, resulting in direct injection of VRl modulator into the bladder. Compounds provided herein may also be used as anti-tussive agents (to prevent, relieve or suppress coughing) and for the treatment of hiccup, and to promote weight loss in an obese patient.Within other aspects, VRl modulators provided herein may be used within combination therapy for the treatment of conditions involving inflammatory components. Such conditions include, for example, autoimmune disorders and pathologic autoimmune responses known to have an inflammatory component including, but not limited to, arthritis (especially rheumatoid arthritis), psoriasis, Crohn's disease, lupus erythematosus, irritable bowel syndrome, tissue graft rejection, and hyperacute rejection of transplanted organs. Other such conditions include trauma (e.g., injury to the head or spinal cord), cardio- and cerebo-vascular disease and certain infectious diseases.Within such combination therapy, a VRl modulator is administered to a patient along with an anti-inflammatory agent. The VRl modulator and anti-inflammatory agent may be present in the same pharmaceutical composition, or may be administered separately in either order. Anti-inflammatory agents include, for example, non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and cyclooxygenase-2 (COX-2) specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) receptor antagonists, anti-TNF alpha antibodies, anti-C5 antibodies, and interleukin-1 (IL-1) receptor antagonists. Examples of NSAIDs include, but are not limited to ibuprofen (e.g., ADVIL™, MOTRIN™), flurbiprofen (ANSAID™), naproxen or naproxen sodium (e.g., NAPROSYN, ANAPROX, ALEVE™), diclofenac (e.g., CATAFLAM™, VOLTAREN™), combinations of diclofenac sodium and misoprostol (e.g., ARTHROTEC™), sulindac (CLINORIL™), oxaprozin (DAYPRO™), diflunisal (DOLOBID™), piroxicam (FELDENE™), indomethacin (INDOCiN™), etodolac (LODINE™), fenoprofen calcium (NALFON™), ketoprofen (e.g., ORUDIS™, ORUVAIL™), sodium nabumetone (RELAFEN™), sulfasalazine (AZULFIDINE™), tolmetin sodium (TOLECTIN™), and hydroxychloroquine (PLAQUENIL™). A particular class of NSAIDs consists of compounds that inhibit cyclooxygenase (COX) enzymes, such as celecoxib (CELEBREX™) and rofecoxib (VIOXX™). NSAIDs further include salicylates such as acetylsalicylic acid or aspirin, sodium salicylate, choline and magnesium salicylates (TRILISATE™), and salsalate (DISALCID™), as well as corticosteroids such as cortisone (CORTONE™ acetate), dexamethasone (e.g., DECADRON™), methylprednisolone (MEDROL™) prednisolone (PRELONE™), prednisolone sodium phosphate (PEDIAPRED™), and prednisone (e.g., PREDNICEN-M™, DELTASONE™, STERAPRED™).Suitable dosages for VRl modulator within such combination therapy are generally as described above. Dosages and methods of administration of anti-inflammatory agents can be found, for example, in the manufacturer's instructions in the Physician's Desk Reference. In certain embodiments, the combination administration of a VRl modulator with an anti- inflammatory agent results in a reduction of the dosage of the anti-inflammatory agent required to produce a therapeutic effect. Thus, preferably, the dosage of anti-inflammatory agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the anti-inflammatory agent without combination administration of a VRl antagonist. More preferably this dosage is less than %, even more preferably less than lA, and highly preferably, less than of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the anti-inflammatory agent(s) when administered without combination administration of a VRl antagonist. It will be apparent that the dosage amount of VRl antagonist component of the combination needed to achieve the desired effect may similarly be affected by the dosage amount and potency of the anti- inflammatory agent component of the combination.In certain preferred embodiments, the combination administration of a VRl modulator with an anti-inflammatory agent is accomplished by packaging one or more VRl modulators and one or more anti-inflammatory agents in the same package, either in separate containers within the package or in the same contained as a mixture of one or more VRl antagonists and one or more anti-inflammatory agents. Preferred mixtures are formulated for oral administration (e.g., as pills, capsules, tablets or the like). In certain embodiments, the package comprises a label bearing indicia indicating that the one or more VRl modulators and one or more anti-inflammatory agents are to be taken together for the treatment of an inflammatory pain condition. A highly preferred combination is one in which the anti- inflammatory agent(s) include at least one COX-2 specific cyclooxgenase enzyme inhibitor such as valdecoxib (BEXTRA®), lumiracoxib (PREXIGE™), etoricoxib (ARCOXIA®), celecoxib (CELEBREX®) and/or rofecoxib (VIOXX®). Within further aspects, VRl modulators provided herein may be used in combination with one or more additional pain relief medications. Certain such medications are also anti- inflammatory agents, and are listed above. Other such medications are narcotic analgesic agents, which typically act at one or more opioid receptor subtypes (e.g., μ, K and/or δ), preferably as agonists or partial agonists. Such agents include opiates, opiate derivatives and opioids, as well as pharmaceutically acceptable salts and hydrates thereof. Specific examples of narcotic analgesics include, within preferred embodiments, alfentanyl, alphaprodine, anileridine, bezitramide, buprenorphine, codeine, diacetyldihydromorphine, diacetylmorphine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphane, levorphanol, meperidine, metazocine, methadone, methorphan, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, paregoric, pentazocine, pethidine, phenazocine, piminodine, propoxyphene, racemethorphan, racemorphan, thebaine and pharmaceutically acceptable salts and hydrates of the foregoing agents. Other examples of narcotic analgesic agents include acetorphine, acetyldihydrocodeine, acetylmethadol, allylprodine, alphracetylmethadol, alphameprodine, alphamethadol, benzethidine, benzylmorphine, betacetylmethadol, betameprodine, betamethadol, betaprodine, butorphanol, clonitazene, codeine methylbromide, codeine-N- oxide, cyprenorphine, desomorphine, dextromoramide, diampromide, diethylthiambutene, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiamubutene, dioxaphetyl butyrate, dipipanone, drotebanol, ethanol, ethylmethylthiambutene, etonitazene, etorphine, etoxeridine, furethidine, hydromorphinol, hydroxypethidine, ketobemidone, levomoramide, levophenacylmorphan, methyldesorphine, methyldihydromorphine, morpheridine, morphine methylpromide, morphine methylsulfonate, morphine-N-oxide, myrophin, naloxone, nalbuyphine, naltyhexone, nicocodeine, nicomorphine, noracymethadol, norlevorphanol, normethadone, normorphine, norpipanone, pentazocaine, phenadoxone, phenampromide, phenomorphan, phenoperidine, piritramide, pholcodine, proheptazoine, properidine, propiran, racemoramide, thebacon, trimeperidine and the pharmaceutically acceptable salts and hydrates thereof.Further specific representative analgesic agents include, for example: TALWIN® Nx and DEMEROL® (both available from Sanofi Winthrop Pharmaceuticals; New York, NY); LEVO-DROMORAN®; BUPRENEX® (Reckitt & Coleman Pharmaceuticals, Inc.; Richmond, VA); MSIR® (Purdue Pharma L.P.; Norwalk, CT); DILAUDID® (Knoll Pharmaceutical Co.; Mount Olive, NJ); SUBLIMAZE®; SUFENTA® (Janssen Pharmaceutica Inc.; Titusville, NJ); PERCOCET®, NUBAIN® and NUMORPHAN® (all available from Endo Pharmaceuticals Inc.; Chadds Ford, PA) HYDROSTAT® IR, MS/S and MS/L (all available from Richwood Pharmaceutical Co. Inc; Florence, KY), ORAMORPH® SR and ROXICODONE® (both available from Roxanne Laboratories; Columbus OH) and STADOL® (Bristol-Myers Squibb; New York, NY) .Suitable dosages for VRl modulator within such combination therapy are generally as described above. Dosages and methods of administration of other pain relief medications can be found, for example, in the manufacturer's instructions in the Physician's Desk Reference. In certain embodiments, the combination administration of a VRl modulator with one or more additional pain medications results in a reduction of the dosage of each therapeutic agent required to produce a therapeutic effect (e.g., the dosage or one or both agent may less than 3/4, less than Vz, less than Vi or less than 10% of the maximum dose listed above or advised by the manufacturer). In certain preferred embodiments, the combination administration of a VRl modulator with one or more additional pain relief medications is accomplished by packaging one or more VRl modulators and one or more additional pain relief medications in the same package, as described above.Modulators that are VRl agonists may further be used, for example, in crowd control (as a substitute for tear gas) or personal protection (e.g., in a spray formulation) or as pharmaceutical agents for the treatment of pain, itch or urinary incontinence via capsaicin receptor desensitization. In general, compounds for use in crowd control or personal protection are formulated and used according to conventional tear gas or pepper spray technology.Within separate aspects, the present invention provides a variety of non- pharmaceutical in vitro and in vivo uses for the compounds provided herein. For example, such compounds may be labeled and used as probes for the detection and localization of capsaicin receptor (in samples such as cell preparations or tissue sections, preparations or fractions thereof). Compounds may also be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to capsaicin receptor, or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT). Such methods can be used to characterize capsaicin receptors in living subjects. For example, a VRl modulator may be labeled using any of a variety of well known techniques (e.g., radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e.g., determined by first assaying a time course of binding). Following incubation, unbound compound is removed (e.g., by washing), and bound compound detected using any method suitable for the label employed (e.g., autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to detect luminescent groups and fluorescent groups). As a control, a matched sample containing labeled compound and a greater (e.g., 10-fold greater) amount of unlabeled compound may be processed in the same manner. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of capsaicin receptor in the sample. Detection assays, including receptor autoradiography (receptor mapping) of capsaicin receptor in cultured cells or tissue samples may be performed as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York.Modulators provided herein may also be used within a variety of well known cell separation methods. For example, modulators may be linked to the interior surface of a tissue culture plate or other support, for use as affinity ligands for immobilizing and thereby isolating, capsaicin receptors (e.g., isolating receptor-expressing cells) in vitro. Within one preferred embodiment, a modulator linked to a fluorescent marker, such as fluorescein, is contacted with the cells, which are then analyzed (or isolated) by fluorescence activated cell sorting (FACS).The following Examples are offered by way of illustration and not by way of limitation. Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification. Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein. EXAMPLESIn the following Examples, mass spectroscopy data is Electrospray MS, obtained in positive ion mode with a 15V or 30V cone voltage, using a Micromass Time-of-Flight LCT, equipped with a Waters 600 pump, Waters 996 photodiode array detector, Gilson 215 autosampler, and a Gilson 841 microinjector. MassLynx (Advanced ChemistryDevelopment, Inc; Toronto, Canada) version 4.0 software was used for data collection and analysis. Sample volume of 1 microliter was injected onto a 50x4.6mm ChromolithSpeedROD C18 column, and eluted using a 2-phase linear gradient at 6ml/min flow rate.Sample was detected using total absorbance count over the 220-340nm UV range. The elution conditions were: Mobile Phase A- 95/5/0.05 Water/Methanol/TFA; Mobile Phase B-5/95/0.025 Water/Methanol/TFA.Gradient: Time(min) %B0 100.5 100

1.2 100

1.21 10

The total run time was 2 minutes inject to inject.

The following abbreviations appear herein:

BOP benzotriazol- 1 -yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate

DCM dichloromethane

DME ethylene glycol dimethyl ether

DMF dimethylformamide

DPPF 1 , 1 '-bis(diphenylphosphino)ferrocene EDC1 l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

EtOAc ethyl acetate

Pd₂(dba)₃ tris[dibenzylidineacetone]di-palladium

Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0)

THF tetrahydrofuran TLC thin layer chromatography EXAMPLE 1 Preparation of Representative Compounds This Example illustrates the preparation of representative substituted 2-hydroxyalkyl- quinazolin-4-ylamine analogues.

A. [2-ISOPROPOXYMETHYL-7-(3 -TRIFLUOROMETHYL-PYRIDIN-2- YL)-QUINAZOLIN-4-YL]-(4- TRIFLUOROMETHYL-PHENYL)-AMINE (COMPOUND 1)

1. 2-p-tolyl-3-trifluoromethyl-pyridine

To a de-gassed mixture of 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mmol), p- tolylboronic acid (70.6 mmol), and 2M Na₂C0₃ (175.0 mmol), in DME (200 mL) under nitrogen add Pd(PPh₃) (2.8 mmol). Stir the mixture at 80°C overnight, concentrate, and extract with EtOAc. Dry over Na S0 , concentrate under vacuum, and pass through a silica gel pad to give 2-_jp-tolyl-3 -trifluoromethyl-pyridine.

2. 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine

To a solution of 2-7~tolyl-3-trifluoromethyl-pyridine (8.4 mmol) in H SO (6 mL) cautiously add fuming HNO₃ (2 ml). Stir the mixture for 60 minutes at room temperature.

Pour the mixture onto ice-water (30 mL), extract with EtOAc, neutralize with 1 N NaOH, dry over Na₂S0₄, and concentrate under vacuum to obtain 2-(4-methyl-3-nitro-phenyl)-3- (trifluoromethyl)-pyridine.

3. 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzoic acid

To a solution of 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine (7.1 mmol) in a mixture of pyridine (10 mL) and water (5 ml), add KMnO₄ (25.3 mmol) portionwise. Stir the mixture for 4 hours at 110°C, and then add another 25.3 mmol of KMn0 with 10 ml of water. Stir the mixture at 110°C overnight. Cool to room temperature, and filter through celite pad. Concentrate the filtrate under vacuum, dilute with water, and wash the aqueous solution with EtOAc. Neutralize the aqueous solution with 2 N HCl and collect the precipitate to give 2-nitro-4(3-trifluoromethyl-pyridin-2-yl)-benzoic acid.

4. 2-nitro-4- (3-trifluoromethyl-pyridin-2-yl)-benzamide

Reflux a mixture of 2-amino-4(3-trifluoromethyl-pyridin-2-yl)-benzoic acid (25 g) with SOCl₂ (50 ml) for 4 hours and concentrate. Dissolve the residue in DCM, cool with ice- water bath, pass NH₃ gas through the solution for 30 minutes, and stir for 15 minutes at room temperature. Concentrate and wash with water to give 2-nitro-4-(3-trifluoromethyl-pyridin- 2-yl)-benzamide. 5. 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide

Hydrogenate 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (l.Og, 0.0032 mol) with 50 psi of H and 100 mg of 10% Pd/C in ethanol. After 16 hours, filter the mixture through celite and concentrate under reduced pressure to give 2-amino-4-(3-trifluoromethyl- pyridin-2-yl)-benzamide as a solid.

6. 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one

Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (100 mg, 0.356 mmol) in 2-chloro-l,l,l-trimethoxyethane (bp 138°C) at 130°C for 4 hours. Concentrate the mixture under reduced pressure to give 2-chloromethyl-7-(3-trifluoromethyl- pyridin-2-yl)-3H-quinazolin-4-one as an oil which crystallizes on standing.

7. 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline

Reflux a mixture of 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H- quinazolin-4-one (obtained from the reaction above) and POCl₃ for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaΗC0₃ solution. Wash the EtOAc portion with additional NaHC0₃ and then dry (Na₂SO ) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4- chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline.

8. [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoro methyl-phenylj-amine

Heat a mixture of 4-chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)- quinazoline (42 mg, 0.117 mmol) and 4-trifluoromethyl-aniline (19 mg, 0.117 mmol) in isopropyl alcohol (1 mL) at 75°C for 4 hours. Cool the mixture and wash the precipitate with isopropyl alcohol followed by ether to give [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2- yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as the mono-HCl salt.

9. [2-Isopropoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl) -amine

To a suspension of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4- yl]-(4-trifluoromethyl-phenyl)-amine hydrochloride (1.9 g, 0.0037 mol) in dry isopropanol (100 mL), add 20 equivalents of NaO-i-Pr (prepared from Na and isopropanol). Stir the pale yellow mixture at 60°C for 5 hours, cool and evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate and water and wash the organic layer with water (IX). Dry the organic layer (Na₂S0 ) and concentrate to give [2-isopropoxymethyl-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-4-yI]-(4-trifluoromethyl-phenyl)-amine as a foam. B. 2-[4-(4-TMFLUOROMETIT-X-PHENYLAMINO)-7-(3-TRIFLUOROMETHYL-PYRIDIN-2-YL)-

QUINAZOLIN-2-YL]-ETHANOL (COMPOUND 2)

1. 3-Benzyloxy-propionic acid

Add sodium hydride (2.22 g, 60% dispersion in mineral oil, 55.4 mmol) in small portions to a cold (0°C) solution of benzyl alcohol (4.0 g, 37 mmol) in toluene (100 mL). Add ethyl 3-bromopropionate (8.0 g, 44 mmol) dropwise to the mixture, allow the resulting solution to warm to room temperature and stir for 1 hour. Quench the reaction with the addition of water until all bubbling ceases. Dilute the mixture with ethyl acetate (100 mL) and extract with water (100 mL) and brine (100 mL). Dry the organic extract over Na₂S0 and remove the solvent under reduced pressure to yield the crude ester as a clear oil. Dissolve the oil in methanol (20 mL) and 6 N NaOH (20 mL), stir for 1 hour, concentrate the mixture (~ 20 mL) and dilute with water (20 mL). Extract the aqueous mixture once with CH₂C1₂ (40 mL). Acidify the aqueous phase with cone. HCl, extract with EtOAc (3 x 50 mL), and dry the combined EtOAc extracts over Na₂S0₄. Remove the solvent under reduced pressure to yield the title compound as a clear oil that solidifies upon standing.

2. 2-(2-Benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-3H-quinazolin-4-one

Cool a solution of 3-benzyloxy-propionic acid (1.66 g, 9.19 mmol) in hexanes (40 mL) to 0°C and add oxalyl chloride (3.50 g, 27.6 mmol) dropwise. After the addition is completed, add DMF (2 drops) and stir the resulting mixture for 1 hour. Remove the solvent under reduced pressure and dissolve the crude acid chloride in dry THF (20 mL). In a separate flask, dissolve 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (2.35 g, 8.37 mmol) in dry THF (40 mL) and pyridine (0.727 g, 9.19 mmol) and cool to 0°C. Add the solution containing the crude acid chloride dropwise to the second solution. Allow the mixture to warm to room temperature and stir for 1 hour. Add a solution of 10% NaOH(_aq) (20 mL) to the mixture and stir the solution for 1 hour. Concentrate the mixture (-20 mL), dilute with water (20 mL), and acidify with cone. HCl. Extract the resulting solution with EtOAC (3 x 50 mL). Wash the combined organic extracts with brine and dry over Na₂SO₄. Remove the solvent under reduced pressure to yield the title compound as a white solid.

3. 2-(2-Benzyloxy-ethyl)4-chloro-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazoline

Dissolve 2-(2-benzyloxy-ethyl)-7-(3 -trifluoromethyl-pyridiny-2-yl)-3H-quinazolin-4- one (3.24 g, 7.62 mmol) in CΗC1₃ (40 mL) and 2,6-lutidine (2.45 g, 22.9 mmol). Add phosphorous oxycloride (1.77 mL, 19.0 mmol) dropwise and heat the resulting solution to reflux for 18 hours. Cool the solution and remove the solvent under reduced pressure. Partition the crude residue between EtOAc (200 mL) and saturated NaHC0₃(_aq) (200 mL). Remove the organic phase and extract the aqueous phase with EtOAc (200 mL). Combine the two organic extracts, wash with brine (200 mL), and dry over Na₂S0 . Remove the solvent to yield the title compound as a light brown solid.

4. [2- (2-Benzyloxy-ethyl) - 7- (3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-ylJ- (4- trifluoromethyl-phenyl) -amine

Dissolve 2-(2-benzyloxy-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridiny-2-yl)- quinazoline (2.47 g, 5.57 mmol) in a solution of acetonitrile (50 mL) and 4-trifluoromethyl- aniline (0.986 g, 6.12 mmol). Heat the mixture to 80°C for 2 hours. A white precipitate forms. Cool the solution in an ice bath and add diethyl ether (25 mL). Filter off the white precipitate and dry in a vacuum oven to yield the title compound as the mono-hydrochloride salt.

5. 2-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2- yϊj-eihanol

Dissolve [2-(2-benzyloxy-ethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-yl]- (4-trifluoromethyl-phenyl)-amine hydrochloride (2.96 g, 4.89 mmol) in MeOH (150 mL) and add 10% Pd/C (200 mg). Hydrogenate the mixture at 50 p.s.i. at 60°C for 8 hours. Quickly filter the mixture through Celite and wash the Celite filter cake with hot MeOH (200 mL). Remove the solvent under reduced pressure to yield the mono-hydrochloride salt of title compound as a white solid.

C. [2-(2-METHOXY-ETHYL)-7-(3-TRIFLUOROMETHYL-PYRIDIN-2-YL)-QUINAZOLIN-4-YL]-(4- TRIFLUOROMETHYL-PHENYL)-AMINE (COMPOUND 3)

1. 2-(2-methoxy-ethyl)-7-(3-trifluorornethyl-pyridin-2-yl)-quinazolin-4-ol

To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (3.56 mmol) and pyridine (3.91 mmol) in THF (20 ml), add 4-methoxy-butyryl chloride (3.91 mmol). Stir the mixture 20 minutes at room temperature, add 20 ml of 20% NaOH, stir for 60 minutes at

50°C. Concentrate, add water, filter, acidify to pH=6, collect the precipitate to obtain 2-(3- benzyloxy-propyl)7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.

2. 2-(2-methoxy-ethyl)-4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline

Using procedures analogous to those described above, 2-(2-methoxy-ethyl)-4-chloro- 7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline is prepared from 2-(2-methoxy-ethyl)-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.

3. [2-(2-methoxy-ethyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyϊ) -amine

Using procedures analogous to those described above, [2-(2-methoxy-ethyl)-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine is prepared from 2-(2-methoxy-ethyl)-4-chloro-7-(3-trifluoro-methyl-pyridin-2-yl)-quinazoline.

D. 3-[4-(4-TRIFLUOROMETHYL-PHENYLAMINθ)-7-(3-TRIFLUORO-METHYL-PYRIDIN-2-YL)- QUINAZOLIN-2-YLj-PROPAN-l-OL (COMPOUND 4)

1. 2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol

To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (3.56 mmol) and pyridine (3.91 mmol) in THF (20 ml) add 4-benzyloxy-butyryl chloride (3.91 mmol). Stir the mixture 20 minutes at room temperature, add 20 ml of 20% NaOH, stir for 60 minutes at 50°C. Concentrate, add water, filter, acidify to pH=6, collect the precipitate to obtain 2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.

2. 2-(3-benzyloxy-propyl)-4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline

Using procedures analogous to those already described 2-(3-benzyloxy-propyl)-4- chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline can be prepared from 2-(3-benzyloxy- propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.

3. [2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl)-amine

Using procedures analogous to those already described, [2-(3-benzyloxy-propyl)-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine is prepared fiOm 2-(3-benzyloxy-propyl)-4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline.

4. 3-[4-(4-trifluoromethyl-phenylamino)~7-(3-trifluoro~methyl-pyridin-2-yl)-quinazolin- 2-ylJ-propan- -ol

Hydrogenate the mixture of 2-(3-benzyloxy-propyl)-4-chloro-7-(3-trifluoromethyl- pyridin-2-yl)-quinazoline (0.5 mmol) and 10% Pd-C in EtOH (100 ml) at 50 psi for 30 hours. Filter, concentrate, and chromatograph to give 3-[4-(4-trifluoromethyl-phenylamino)-7-(3- trifluoro-methyl-pyridin-2-yl)-quinazolin-2-yl]-propan- 1 -ol.

E. [2-METHOXYMETHYL-7-(3 -METHYLPYRIDΓN-2- YL)-QUINAZOLIN-4-YL)-(4~ TRIFLUOROMETHYLPHENYL)-AMINE (COMPOUND 5)

J 7-bromo-2-methoxymethylquinazolin-4-yl)-(4-trifluoromethylphenyl)-amine

Heat a mixture of 7-bromo-2-chloromethylquinazolin-4-yl)-(4- trifluoromethylphenyl)-amine (from Example C, 200 mg, 0.48 mmol), 4.4M sodium methoxide in methanol (2.4 mL), and methanol (1 mL) to 60°C for 4 hours. Cool to room temperature and evaporate the mixture. Dilute with EtOAc (10 mL) and wash 2X with water (10 mL each). Dry the organic layer (Na₂SO ) and evaporate. Purify by preparative TLC (3:1 hexanes.ΕtOAc) to obtain 2-methoxymethyl-7-pyridin-4-yl-quinazolin-4-yl)-(4- trifluoromethylphenyl)-amine as a yellow solid.

2. [2-Methoxymethyl-7-(3-inethy1pyridin-2-yl)-quinazolin-4-yl)-(4-trifluoromethyl phenyl)-amine

Heat a mixture of 2-methoxymethyl-7-pyridin-4-yl-quinazolin-4-yl)-(4- trifluoromethylphenyl)-amine (100 mg, 0.243 mmol), 3-methyl-2~pyridylzinc bromide (1 mL of a 0.5M THF solution), tetrakis(triphenylphosphinepalladium(0) (50 mg, 0.043 mmol) in 1,2-dimethoxymethane (5 mL) for 3 hours at 80°C under nitrogen. Cool to room temperature and dilute with EtOAc (10 mL). Wash with water (2 x 10 mL) and dry the organic layer (Na₂SO₄) and evaporate. Purify by preparative TLC to obtain [2-methoxymethyl-7-(3- methylpyridin-2-yl)-quinazolin-4-yl)-(4-trifluoromethylphenyl)-amine as an off-white solid.

F. 7-(3-TmFLUOROIvffiTI -X-PYRIDIN-2-YL)-2-METHOXYMETHYL-PYRIDθ[3,2-D]PYRIMIDIN-4- YL]-(4-TRIFLU0R0METHYL-PHENYL)-AMINE (COMPOUND 6)

1. 6'-Methoxy-3-trifluoromethyl-[2,3]' bipyridinyl

Heat a mixture of 2-chloro-3-trifluoromethylpyridine (37 g, 0.2 mol), 2- methoxypyridine-5-boronic acid (32 g, 0.21 mol), tetrakis(triphenylphosphine)palladium(0) (9 g, 7 mmol) and 2M potassium carbonate (150 mL) in toluene (500 mL) under a nitrogen atmosphere at 90°C for 8 hours. Cool the reaction mixture and separate the layers. Extract the aqueous layer with ethyl acetate (2 x 250 mL) and wash the combined organics with 4M sodium hydroxide (250 mL), water (250 mL), and brine (250 mL). Dry (MgSO₄) and concentrate under reduced pressure. Purify the resulting oil by flash chromatography on silica gel (50%o ether/ 50% hexane) to give the title compound as a colorless oil.

2. 3-Trifluoromethyl-l 'H-[2, 3 ']bipyridinyl-6'-one

Heat 6'-methoxy-3-trifluoromethyl-[2,3']bipyridinyl (41 g, 0.16 mol) in 30% HBr/AcOH (100 mL) to reflux for 1 hour. Cool the mixture, filter and wash the precipitate with ether (100 mL). Transfer the precipitate into 10M sodium hydroxide (500 mL) and stir for 1 hour. Treat the solution with hydrochloric acid until the solution is pH 7. Collect the white solid by filtration and air dry to give the title compound as a white solid.

3. 5 '-Nitro-3-trifluoromethyl-l 'H-[2, 3] ' bipyridinyl-6'-one

To a solution of 3-trifluoromethyl-lΗ-[2,3']bipyridinyl-6'-one (25 g, 0.1 mol) in concentrated sulfuric acid (100 mL) at 0°C, add dropwise a solution of fuming nitric acid (35 mL) and concentrated sulfuric acid (10 mL). Heat the reaction mixture to 70 °C for 1 hour, cool and pour onto ice (500 mL). Filter the mixture and treat the filtrate with 10 M sodium hydroxide until the solution is at pH 4-5. Collect the precipitate by filtration and air dry to give the title compound as a white solid.

4. 6 '-Chloro-5 '-nitro-3-trifluoromethyl-[2, 3J ' bipyridinyl

Heat a solution of 5'-nitro-3-trifluoromethyl-l'H-[2,3']bipyridinyl-6'-one (25 g, 0.088 mol), thionyl chloride (300 mL) and DMF (3 mL) to reflux for 4 hours. Remove the volatiles by rotary evaporation and partition the residue between ethyl acetate (350 mL) and saturated sodium bicarbonate solution (250 mL). Extract the aqueous layer with further ethyl acetate (250 mL) and wash the combined organics with brine (250 mL). Dry (MgSO ) and concentrate under reduced pressure to give the title compound as a yellow oil.

5. 6'-Chloro-3-trifluoro?nethyl-[2, 3J ' bipyridinyl-5 '-ylamine

To a solution of 6'-chloro-5'-nitro-3-trifluoromethyl-[2,3']bipyridinyl (25 g, 0.082 mol) and calcium chloride (l lg, 0.1 mol) in ethanol (300 mL) and water (50 mL), add iron powder (45 g, 0.82 mol). Heat the solution to reflux for 1.5 hours, cool and filter through

Celite. Concentrate the mixture under reduced pressure, re-dissolve in ethyl acetate (300 mL) and wash with brine (200 mL). Concentrate the solution under reduced pressure and purify by flash chromatography on silica gel (50% ether/ 50% hexane) to give the title compound as a pale yellow solid.

6. 3-Amino-5-[3- (triβuoromethyl) (2-pyridyl)]pyridine-2-carboxamide

Heat a solution of 6'-chloro-3-trifluoromethyl-[2,3']bipyridinyl-5'-ylamine (25 g, 0.091 mol), zinc cyanide (6.75 g, 0.058 mol), pd₂(dba)₃ (2.63 g, 2.86 mmol), and DPPF (3.16g, 5.72 mmol) in DMF (250 mL) and water (2.5 mL), under a nitrogen atmosphere, at 120°C for 1 hour. Add water (30 mL) and heat the solution at 120°C for a further 4 hours to complete the hydrolysis. Cool the reaction to 0°C and add a solution of saturated ammonium chloride (200 ml), water (200 mL) and concentrated ammonium hydroxide (50 mL). After stirring at 0°C for 1 hour, filter the yellow precipitate, and wash with water (200 mL) and a 1:1 mixture of ether-hexane (200 mL). Air dry the solid, and then dry in a vacuum oven to give the title compound. 7. 2-(Chloromethyl)-7-[3-(trifluoromethyl) (2-pyridyl)]-3-hydropyridino[3,2-d]pyrimidin-

4-one

Heat a solution of 3-amino-5-[3-(trifluoromethyl)(2-pyridyl)]pyridine-2-carboxamide (23 g, 81.5 mmol) and 2-chlorol,l,l-trimethoxyethane (250 mL) at 130°C for 1 hour. Remove the volatiles by evaporation and triturate the solid (50% ether/ 50% hexane) to give the title compound as a light brown solid.

8. 4-Chloro-2-chloromethyl-7-(3-chloro-pyridin-2-yl) -pyrido[3,2-d]pyrimidine

Heat a solution of 2-(chloromethyl)-7-[3-(trifluoromethyl)(2-pyridyl)]-3- hydropyridino[3,2-d]pyrimidin-4-one (2.49 g, 7.31 mmol), phosphorous oxychloride (10 mL), 2,6-lutidine (2.13 mL, 18.3 mmol) and toluene to reflux for 8 hours. Remove the solvent and partition the crude residue between EtOAc (150 mL) and H 0 (150 mL). Remove the organic phase and extract the aqueous phase with EtOAc (150 mL). Combine the organic extractions, wash with saturated NaHCO₃(aq) (150 mL) and brine (150 mL), and dry over Na₂S0 . Remove the solvent to yield the title compound as a light brown solid.

9. [2-(2-Chloromethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl) -amine

Dissolve 4-chloro-2-chloro-methyl-7-(3 -chloro-pyridin-2-y l)-pyrido [3 ,2-d]pyrimidine

(2.30 g, 6.40 mmol) in a solution of acetonitrile (20 mL) and 4-trifluoromethyl aniline (1.13 g, 7.04 mmol). Heat the mixture at 80°C for 18 hours. Cool the mixture to 0°C and dilute with diethyl ether (20 mL). The mono-hydrochloride salt of the title compound forms a light brown precipitate, which is removed by filtration and dried in a vacuum oven.

10. 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4- trifluoromethyl-phenyl) -amine

Treat [2-(2-chloromethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl)-amine with NaOMe as described in Example 1A, step 9, above. This affords 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4- trifluoromethyl-phenyl)-amine as a solid.

G. 7-(3-METHYL-PYRIDIN-2-YL)-2-METH0XYMETHYL-PYRID0[3,2-D]PYRIMIDIN-4-YL]-(4- TRIFLU0R0METHYL-PHENYL)-AMINE (COMPOUND 7)

1. 5-Bromo-3-nitropyridine-2-carbonitrile

Heat a solution of 2-amino-5-bromo-3-nitropyridine (2.18 g, 10 mmol), cuprous cyanide (1.33 g, 15 mmol) and tert-butylnitrite (2.0 mL, 15 mmol) in acetonitrile (50 mL) at 60°C for 2 hours. Cool the solution and partitioned between ethyl acetate (100 mL) and saturated aqueous NaHCO₃ (100 mL). Extract the aqueous layer with ethyl acetate (2 x 50 mL), wash with water (100 mL) and brine (100 mL), dry (MgSO ) and evaporate. Purify the solid by flash chromatography on silica gel (25% ether / 75% hexane) to give the title compound as a pale yellow solid.

2. 5-(3-Methyl(2-pyridyl))-3-nitropyridine-2-carbonitrile

Heat a solution of 5-bromo-3-nitropyridine-2-carbonitrile (228 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg), 3-methyl-2-pyridylzinc bromide (0.5 M in THF, 3 mL, 1.5 mmol) in THF (5 mL) at 60°C for 2 hours. Cool the solution and partition between ethyl acetate (10 mL) and saturated aqueous NaHC0₃ (10 mL). Extract the aqueous layer with ethyl acetate (2 x 15 mL), wash with water (10 mL) and brine (10 mL), dry (MgS0 ) and evaporate to give the title compound as a pale yellow solid.

3. 3-Amino-5-(3-methyl(2-pyridyl))pyridine-2-carboxamide

Heat a solution of 5-(3-methyl(2-pyridyl))-3-nitropyridine-2-carbonitrile (1 g, 4.1 mmol), iron (2.3 g, 40 mmol) and calcium chloride (560 mg, 5 mmol) in ethanol (15 mL) and water (4 mL) to reflux for 1 hour. Cool the mixture, filter through Celite and wash with ethyl acetate. Evaporate the filtrate and re-dissolve the residue in ethyl acetate. Wash with water and brine, dry (MgSO ) and evaporate to give the title compound as a pale yellow solid.

4. 7-(3-methyl-pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4- trifluoromethyl-phenyl) -amine

The title compound is prepared from 3-amino-5-(3-methyl(2-pyridyl))pyridine-2- carboxamide using procedures analogous to those described in the foregoing examples. H. 7-(3-TIUFLUOROMETHYL-PYRIDIN-2-YL)-2-METHOXYMETHYL-PYRIDθ[3,2-D]PYRIMIDIN-4- YL]-(4-TMFLUOROMETHYL-PHENYL)-AMINE (COMPOUND 6)

1. 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[3,2-d]pyrimidin-4-one

Treat a solution of 3-amino-5-[3-(chloro-pyridin-2-yl)]pyridine-2-carboxamide (340 mg, 1.21 mmol) in THF (5 mL) and pyridine (0.11 mL) with methoxy-acetyl chloride (0.1 lmL, 144 mg, 1.33 mmol). Stir the mixture for 3 hours at room temperature. Then, add 5 N NaOH (10 mL) and stir the solution for an additional 18 hours. Concentrate the solution (~ 5 mL) and acidify with cone. HCl. Extract the aqueous mixture with EtOAc (3 x 25 mL), and dry the combined organic extracts over Na₂S0 . Remove the solvent under reduced pressure to yield the title compound as a white solid.

2. 4-Chloro-7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidine

Dissolve 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[3,2- d]pyrimidin-4-one (276 mg, 0.822 mmol) in CΗC1₃ (25 mL) and 2,6-lutidine (294 mg, 2.74 mmol). Add phosphorous oxycloride (0.255 mL, 2.74 mmol) dropwise and heat the resulting solution to reflux for 24 hours. Cool the solution and remove the solvent under reduced pressure. Partition the crude residue between EtOAc (50 mL) and saturated NaHC0_3(aq) (50 mL). Remove the organic phase and extract the aqueous phase with additional EtOAc (50 mL). Combine the two organic extracts, wash with brine (100 mL), and dry over Na₂SO . Remove the solvent to yield the title compound as a light brown solid.

3. 7-(3-trifluoromethyl-pyridin-2-yl)-2-methoxymethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4- trifluoromethyl-phenyl) -amine

Dissolve 4-chloro-7-(3-trifluoromethyl-ρyridin-2-yl)-2-methoxymethyl-pyrido[3,2- d]pyrimidine (30 mg, 0.0934 mmol) into a solution of acetonitrile (3 mL) and 4- trifluoromethyl-aniline (18.0 mg, 0.112 mmol). Heat the mixture to 80°C for 16 hours. Cool the reaction mixture in an ice bath and add diethyl ether (3 mL). Filter off the off-white precipitate and dry in a vacuum oven to yield the title compound as the mono-hydrochloride salt.

I. [7-(3-CHL0R0-PYRIDIN-2-YL)-2-METH0XYMETHYL-PYRID0[2,3-D]PYRIMIDIN-4-YL]-(4- TRIFLUOROMETHYL-PHENYL)-AMINE (COMPOUND 8) 1. 2-Acetyl-3-chloropyridine

Dissolve 3-chloro-2-cyanopyridine (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33:565-571) in anhydrous THF (200 mL) under N₂ atmosphere and cool in an ice bath. Add drop wise 3.0 M MeMgl in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3 x 100 mL) and dry over anhydrous MgS0₄. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate / hexane as eluent. Removal of solvent under reduced pressure gives pure 2-acetyl-3-chloropyridine as oil.

2. l-(3-Chloro-pyridin-2-yl)-3-dimethylaminopropenone

Heat 2-acetyl-3-chloropyridine (0.77 g, 5.0 mmol) with N,N-dimethylformamide dimetylacetal (3.0 g) at 105°C for 20 hours. Concentrate under reduced pressure to give l-(3- chloro-pyridin-2-yl)-3-dimethylaminopropenone as oil.

3. 2-Amino-4-(3-chloro-pyridin-2-yl)-benzonitrile

Heat a solution of l-(3-Chloro-pyridin-2-yl)-3-dimethylaminopropenone (1.05 g, 5 mmol), 3-amino-3-methoxy-acrylonitrile hydrochloride (1.35 g, 10 mmol) and ammonium acetate (2.2 g, 15.0 mmol) in ethanol (25 mL) at reflux for 20 hours. Cool the mixture and concentrate under reduced pressure to give dark oil. Dissolve the residue in EtOAc / water (100 mL). Extract the aqueous solution with EtOAc, wash the EtOAc with brine, dry (MgSO ) and concentrate under reduced pressure to give 2-amino-4-(3-chloro-pyridin-2-yl)- benzonitrile as a brown solid.

4. 6-Amino-3 '-chloro-[2,2']bipyridinyl-5-carboxylic acid amide

Cool concentrated sulfuric acid (10 mL) in an ice bath under nitrogen atmosphere. Add in portions 2-amino-4-(3-chloro-pyridin-2-yl)-benzonitrile (1.0 g, 4.3 mmol) over a period of 15 minutes. Stir at room temperature overnight. Pour the reaction mixture over ice, adjust the pH to 10 using 10 N aq. NaOH, filter the solid, wash the solid with water and dry under vacuum to give 6-amino-3'-chloro-[2,2']biρyridinyl-5-carboxylic acid amide as a yellow solid.

5. 7-(3-ChJoro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one

Dissolve 6-amino-3'-chloro-[2,2']bipyridinyl-5-carboxylic acid amide (0.5 g, 2.02 mmol) in anhydrous THF (10 mL) under N₂ atmosphere. Add dropwise pyridine (0.36 g, 4.04 mmol) and methoxyacetyl chloride (0.48 g, 4.04 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and reflux for 4 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and dry under vacuum to give 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3- d]pyrimidin-4-one as a white solid.

6. 4-Chloro-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidine

Reflux a mixture of 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3- d]pyrimidin-4-one (0.25 g), 2,6-lutidine (0.44 g), and POCl₃ (0.51 g) in CHC1₃ (5 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO₃ solution. Wash the EtOAc portion with additional NaHCO₃ and then dry (Na₂S0 ) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3- d]pyrimidine.

7. [7-(3-Chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4- trifluoromethyl-phenyl) -amine

Heat a mixture of 4-chloro-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3- djpyrimidine (0.1 mmol) and 4-trifluoromethyl-aniline (16.1 mg, 0.1 mmol) in AcCN (1 mL) at 80°C for 24 hours. Cool the mixture and wash the precipitate with ether to give [7-(3- chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl- phenyl)-amine as the mono-HCl salt.

EXAMPLE 2 Additional Representative Substituted 2-Hydroxyalkyl-Quinazolin-4-ylamine Analogues Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein. Compounds listed in Table II were prepared using the above methods, with readily apparent modifications. In the column labeled Kj in Table II, * indicates that the Kj for the compound determined as described in Example 5, herein, is 1 micromolar or less. Mass Spectrometry data was obtained as described above and is given as M+l.

Table II Representative Substituted 2-Hvdroxyalkyl-Quinazoline-4-ylamine Analogues

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91

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20040

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EXAMPLE 3 Preparation of Representative Compounds This Example illustrates the preparation of representative substituted 2-aminoalkyl- quinazolin-4-ylamine analogues.

A. [2-PYRROLIDIN- 1 -YLMETHYL-7-(3 -TRIFLU0R0METHYL-PYRIDIN-2-YL)-QUINAZ0LIN-4-YL]- (4-TRIFLUORO METHYL-PHENYL)-AMINE (COMPOUND 315)

1. [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoro methyl-phenyl) -amine

This compound is prepared as described in Example 1A.

2. [2-Pyrrolidin-l-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifliioromethyl-phenyl) -amine

Heat a solution of [2-chloromethyI-7-(3-trifluoromethyI-pyridin-2-yl)-quinazolin-4- yl]-(4-trifluoromethyl-phenyl)-amine HCl (30 mg, 0.058 mmol) in pyrrolidine (ImL) at 100°C for 1 hour. Remove the excess pyrrolidine under reduced pressure and partition the residue between EtOAc and 10% NaOH solution. Dry the EtOAc layer (Na₂SO ) and concentrate under reduced pressure to give [2-pyrrolidin-l-ylmethyl-7-(3-frifluoromethyl- pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a foam. Mass Spec 517.2.

B . [2-(2,6-DlMETHYL-MORPHOLIN-4- YLMETHYL)-7-(2-TRIFLUOROMETHYL-PHENYL)- PYRID0[4,3-D]PYRIMIDIN-4-YL]-(4-TRIFLU0R0METHYL-PHENYL)-AMINE (CIS) (COMPOUND 316)

1. 4-Hydroxy-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester

Dissolve LiHMDS (34 g, 0.20 mol) in dry THF (150 mL) and cool to -70°C under N₂ atm. Add 4-dimethylamino-3-ethoxy-but-3-en-2-one (15 g, 0.081 mol; see J. Heterocyclic Chem. (1987) 24:1669) and 2-(trifluoromethyl)benzoyl chloride (20.0 g, 0.097 mol) in THF (50 L) into the solution for 10 minutes. Remove the cooling bath and stir for 10 minutes. Add ammonium acetate (10 g) and acetic acid (200 mL) to the reaction mixture and distil THF under reduced pressure. Heat the mixture at 60-65°C for 18 hours, cool and add water (250 mL) and CH₂C1₂ (250 mL). Separate the CH₂C1₂ layer, and extract the aqueous layer twice with CH₂C1₂ (2 x 250 mL each). Combine the CH₂C1₂ extracts, dry (MgSO₄), and evaporate. Purify by silica gel chromatography to provide 4-hydroxy-6-(2-trifluoromethyl- phenyl)-nicotinic acid ethyl ester as a yellow solid.

2. 4-Chloro-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester

Heat a mixture of 4-Hydroxy-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester

(9.0 g, 0.029 mol) in POCl₃ (22 g) at 110°C for 2 hours. Evaporate the POCl₃, and add ice (100 g) followed by careful addition of saturated NaHCO₃. Extract with EtOAc, dry (MgSO ), and evaporate to provide 4-chloro-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester as a brown oil.

3. 4-Amino-6-(2-trifluoromethyl-phenyl)-nicotinamide

Heat a mixture of 4-Chloro-6-(2-trifluoromethyl-phenyl)-nicotinic acid ethyl ester

(5.2 g) and 28% aq. NH OH (100 mL) in a 350 ml resealable pressure vessel for 60 hours.

Cool, extract with EtOAc (3 x 100 mL each), dry (MgSO ), and evaporate to provide the crude product. Purify by silica gel chromatography to provide 4-amino-6-(2-trifluoromethyl- phenyl)-nicotinamide as a solid.

4. 2-(2,6-Dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3- dJpyrimidin-4-ol

Heat a solution of 4-amino-6-(2-trifluoromethyl-phenyl)-nicotinamide (1 g, 3.5 mmol), 2,6-dimethyl-morpholin-4-yl)-acetic acid ethyl ester (2.85 g, 14 mmol), NaOEt (5.0 eq.) in EtOH (10 mL) for 20 hours. After cooling, concentrate the reaction mixture under reduced pressure, dilute the mixture with water (25 mL) and extract with EtOAc (3 x 25 mL each), then wash twice with water (25 mL each) and dry with MgS0 . Evaporate, and purify by flash chromatography to obtain 2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2- trifluoromethyl-phenyl)-pyrido[4,3-d]- pyrimidin-4-ol.

5. 4-Chloro-2-(2, 6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)- pyrido[4, 3-dJpyrimidine

Reflux a mixture of 2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl- phenyl)-pyrido[4,3-d]- pyrimidin-4-ol (0.6 g), 2,6-lutidine (0.62 g), and POCl₃ (1.1 g) in

CHC1₃ (15 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure.

Partition the residue between EtOAc and saturated NaHCO₃ solution. Wash the EtOAc portion with additional NaHCO₃ and then dry (Na₂SO₄) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-(2,6-dimethyl-morpholin-4- ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3-d]pyrimidine.

6. [2-(2,6-Dimetlτyl-morpholin-4-ylmethyl)-7-(2-triβuoromethyl-phenyl)-pyrido[4,3- d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine (cis)

Heat a mixture of 4-chloro-2-(2,6-dimethyl-moφholin-4-ylmethyl)-7-(2~ trifluoromethyl-phenyl)-pyrido[4,3-d]pyrimidine (43.7 mg, 0.1 mmol) and 4-trifluoromethyl- aniline (16.1 mg, O.lmmol) in AcCN (1 mL) at 80°C for 24 hours. Cool the mixture and wash the precipitate with ether to give 4-chloro-2-(2,6-dimethyl-moφholin-4-ylmethyl)-7-(2- trifluoromethyl-phenyl)-pyrido[4,3-d]pyrimidine as the mono-HCl salt. Mass Spec 561.2.

C. [2-M0RPH0LIN-4-YLMETHYL-7(3-TRIFLU0R0METHYL-PYRIDIN-2-YL)-PYRID0[3,2- A]PYRIMIDIN-4-YL]-(4-TRIFLUOROMETHYL-PHENYL)-AMINE (COMPOUND 317)

1. 2-(Chloromethyl)-7-[3-(trifluoromethyl)(2-pyridyl)]-3-hydropyridino[3,2- dJpyrimidin-4-one

This compound is prepared as described above (Example IF).

2. 2-(Morpholin-4-ylmethyl)- 7-[3-(trifluoromethyl) (2-pyridyl)]-3-hydropyridino[3,2- dJpyrimidin-4-one

Heat a solution of 2-(chIoromethyl)-7-[3-(trifluoromethyl)(2-pyridyl)]-3- hydropyridino[3,2-d]pyrimidin-4-one (20 g, 0.058 mol), moφholine (15.66 g, 0.18 mol) in acetonitrile (500 mL) at 80°C for 12 hours. Evaporate the solution and partition the residue between ethyl acetate (500 mL) and saturated sodium bicarbonate solution (500 mL). Extract the aqueous layer with further ethyl acetate (250 mL) and wash the combined organics with brine (500 mL). Dry (MgSO₄) and concentrate under reduced pressure to give the title compound as a brown solid.

3. 4-({4-Chloro-7-[3-(trifluoromethyl)(2-pyridyl)]pyridino[3,2-d]pyrimidin-2-yl}methyl)- methylmorpholine

Heat a solution of 2-(moφholin-4-ylmethyl)-7-[3-(trifluoromethyl)(2-pyridyl)]-3- hydropyridino[3,2-d]pyrimidin-4-one (11.73 g, 0.03 mol), POCl₃ (13.8 g, 0.09 mol) and 2,6- lutidine (9.63 g, 0.09 mol) in chloroform (500 mL) at 60°C for 12 hours. Evaporate the solution and partition the residue between ethyl acetate (500 mL) and saturated sodium bicarbonate solution (500 mL). Extract the aqueous layer with further ethyl acetate (250 mL) and wash the combined organics with brine (500 mL). Dry (MgSO ) and concentrate under reduced pressure to give the title compound as a brown solid.

4. [2-Morpholin-4-ylmethyl- -yl)-pyrido[3,2-a]pyrimidin-4- yl]-(4-trifluoromethyl-phe

Heat a solution of 4-({4-chloro-7-[3-(trifluoromethyl)(2-pyridyl)]pyridino[3,2- d]pyrimidin-2-yl}methyl)-methylmorpholine (12.2 g, 0.03 mol), 4-(trifluoromethyl)aniline (4.8 g, 0.03 mol) in acetonitrile (500 L) at 80°C for 12 hours. Evaporate the solution and partition the residue between ethyl acetate (500 mL) and saturated sodium bicarbonate solution (500 mL). Extract the aqueous layer with further ethyl acetate (2 x 250 mL) and wash the combined organics with brine (500 mL). Dry (MgSO ) and concentrate under reduced pressure. Purify the residue by flash chromatography on silica gel (90% ether/ 10% hexane then 100% ether) to give the title compound. Mass Spec. 534.2. D. [2-(2-PYrøOLIDIN-l-YL-ETITi .)-7-(3-TmFLUOROMETHYL-PYPJDINY-2-YL)-QUINAZOLIN-4- YL]-(4-TRIFLU0R0METHYL-PHENYL)-AMINE (COMPOUND 318)

1. 2-[4-(4-Tήβuoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin- 2-yl]-ethanol

This compound is prepared as described above (Example IB).

2. [2-(2-Chloro-ethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl) -amine

Dissolve 2-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)- quinazolin-2-yl]-ethanol hydrochloride (1.54 g, 2.99 mmol) in thionyl chloride (20 mL) and heat to 60°C for 1 hour. Remove the excess thionyl chloride under reduced pressure and triturate the residue with diethyl ether to yield the mono-hydrochloride salt of the title compound as a light brown solid. 3. [2-(2-Pyrrolidin-l-yl-ethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl) -amine

Dissolve [2-(2-chloro-ethyl)-7-(3-trifluoromethyl-pyridiny-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl)-amine hydrochloride (20 mg, 0.0375 mmol) in CH₃CN / 10% diisopropylethylamine (0.187 mL) and add a 0.2 N solution of pyrrolidine in acetonitrile

(0.281 mL). Heat the mixture at 70°C for 18 hours. Remove the solvent under reduced pressure and partition the crude reaction mixture between EtOAc (1 mL) and 1 N (NaOH).

Remove the organic extract and extract the aqueous phase again with EtOAc (1 mL). Chromatograph the combined organic extracts through a small pad of silica gel, eluting with acetone to yield the title compound as a light brown solid.

E. [2-(3-MORPHOLIN-4-YL-PROPYL)7-(3-TRIFLUOROMETHYL-PYRIDIN-2-YL)-QUINAZOLIN-

4-YL]-(4-TRIFLUOROMETHYL-PHENYL)-AMΓNE HYDROCHLORIDE (COMPOUND 320)

1. 3-[4-hydroxy- 7- (3-trifluoromethyl-pyridin-2-yl) -quinazolin-2-ylJ-propionic acid ethyl ester

To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (0.5 mmol) and pyridine (0.55 mmol) in THF (5 ml), add 3-chlorocarbonyl-propionic acid ethyl ester chloride (0.55 mmol). Stir the mixture for 20 minutes at room temperature, add 20 ml of 21% NaOEt in EtOH, and stir for 30 minutes at 50°C. Concentrate, add water, filter, acidify to pH 6, and collect the precipitate to give 3-[4-hydroxy-7-(3-trifluoromethyl-pyridin-2-yl)- quinazolin-2-yl]-propionic acid ethyl ester.

2. 3-[4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester

Using procedures analogous to those already described, 3-[4-chloro-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester is prepared from 3- [4-hydroxy-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester. 3. 3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2- ylj-propionic acid ethyl ester

Using procedures analogous to those already described, 3-[4-(4-trifluoromethyl- phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester is prepared from 3-[4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester.

4. 3~[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2- ylj-propionic acid

To a mixture of 3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoro-methyl-pyridin- 2-yl)-quinazolin-2-yl]-propionic acid ethyl ester (0.5 mmol) in THF (20 ml) and H₂O (20 ml), add LiOH (1.5 mmol). Stir the mixture for 2 hours at 60°C. Concentrate, add water, extract with ether, acidify the aqueous layer to pH 4-5, extract with EtOAc, and concentrate to give 3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoro-methyl-pyridin-2-yl)-quinazolin-2-yl]- propionic acid. 5. l~morpholin-4-yl-3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-

2-yl)-quinazolin-2-yl]-propan-l-one (compound 319)

To a solution of 3-[4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoro-methyI-pyridin- 2-yl)-quinazolin-2-yl]-propionic acid (0.5 mmol) and triethylamine (0.5 mmol) in DMF (10 ml), add BOP (0.5 mmol). Stir the mixture for 18 hours at room temperature, dilute with water, extract with EtOAc, and wash with brine. Concentrate to give l-moφholin-4-yl-3-[4- (4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propan- 1-one. Mass Spec. 575.2.

6. [2-(3-morpholin-4-yl-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl) -amine hydrochloride (compound 320)

To a solution of l-morpholin-4-yl-3-[4-(4-trifluoromethyl-phenylamino)-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propan-l-one (0.14 mmol) in THF (20 ml), add LAH (0.67 mmol). Stir the mixture for 6 hours at room temperature, quench with 10%) NaOH, extract with EtOAc, dry over Na₂S0 , and add HCl-EtOAc. Collect the precipitate to give £2-(3-moφholin-4-yl-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4- trifluoromethyl-phenyl)-amine hydrochloride. Mass Spec. 561.2.

F. 4-TRIFLUOROMETHYLPHENYL-[2-(2,6-DIMETHYLMORPHONLI-4-YLMETHYL)-7-(2- TRIFLUOROMETHYL PHENYL)-QUINAZOLIN-4-YL] -AMINE (COMPOUND 321)

1. 7-Bromo-2-chloromethyl-3H-quinazolin-4-one

Reflux a solution of 2-amino-4-bromobenzamide (27 g, 0.13 mol; see Joshi and Chaudhari (1987) Indian J. Chem., Sect. B, 26B (6) :602-4) in 2-chloro-l,l,l-trimethoxyethane

(50 mL) for 30 minutes, during which time a large precipitate appears. Evaporate the mixture fully and triturate with ether to collect 7-bromo-2-chloromethyl-3H-quinazolin-4-one as a white solid.

2. 7-Bromo-4-chloro-2-chloromethylquinazoline

Heat a mixture of 7-bromo-2-chloromethyl-5H-quinazolin-4-one (5 g, 18.2 mmol),

2,6-lutidine (5 g), and phosphorus oxychloride (5 mL) in 1,2-dimethoxyethane (500 mL) at

80°C for 16 hours. Cool the mixture to room temperature and fully evaporate the mixture, then dilute with ether and wash with water. Dry the solvent (Na₂S0 ) and evaporate the ether to obtain 7-bromo-4-chloro-2-chloromethylquinazoline as a yellow solid.

3. 7-Bromo-2-chloromethylquinazolin-4-yl)-(4-trifluoromethylphenyl)-amine

Heat a mixture of 7-bromo-4-chloro-2-chloromethylquinazoline (1168 mg, 4.0 mmol) and 4-(trifluoromethyl)aniline (644 mg, 4.0 mmol) in chloroform (50 mL) at 60°C for 16 hours. Cool and collect the precipitated product 7-bromo-2-chloromethylquinazolin-4-yl)-(4- trifluoromethylphenyl)-amine as the HCL salt.

4. [7-Bromo-2-(cis-2,6-dimethylmorpholin-4-ylmethyl)-quinazolin-4-yl]-4- (trifluoromethylphenyl) -amine

Heat a mixture of 7-bromo-2-chloromethylquinazolin-4-yl)-(4- trifluoromethylphenyl)-amine (416 mg, 1.0 mmol), cώ-2,6-dimethylmoφholine (150 mg, 1.3 mmol), and triethylamine (202 mg, 2.0 mmol) in N,N-dimethylacetamide (7 mL) for 1 hour.

Cool to room temperature, dilute with EtOAc (50 mL), and wash four times with water (25 mL each). Dry (Na₂SO₄) and evaporate. Triturate with ether to give [7-bromo-2-(c/>s^,-2,6- dimethylmoφholin-4-ylmethyl)-quinazolin-4-yl]-4-(trifluoromethylphenyl)-amine as a yellow solid.

5. [2-(cis-2,6-dimethylmorpholin-4-yloxymethyl)-7-(2-trifluoromethylphenyl)- quinazolin-4-yl]-(4-trifluoromethylphenyl) -amine

Under nitrogen, heat a mixture of [7-bromo-2-(cis-2,6-dimethylmorpholin-4- ylmethyl)-quinazolin-4-yl]-4-(trifluoromethylphenyl)-amine (75 mg, 0.15 mmol), 2- (trifluoromethyl phenyl)boronic acid (45 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol), 2M Na₂C0₃ in water (ImL), and 1,2-dimethoxyethane (5 mL) at 60°C for 16 hours. Cool the mixture to room temperature, dilute with EtOAc, and wash twice with water (10 mL each). Dry the organic layer (Na₂SO₄) and evaporate. Purify by preparative TLC (9:1 CH₂CL₂:MeOH) to obtain [2- (cM-2,6-dimethylmorpholin-4-yloxymethyl)-7-(2-trifluoromethylphenyl)-quinazolin-4-yl]-(4- trifluoromethylphenyl)-amine as a yellow solid. Mass Spec. 560.2.

G. [7-(3-METHYL-PYRIDIN-2-YL)-2-PYRROLIDΓN-1-YLMETHYL-PYRIDO[3,2-D]PYRIMIDIN-4- YL]-(4-TRIFLUOROMETHYL-PHENYL)-AMINE (COMPOUND 322) 1. 3-Amino-5-(3-methyl(2-pyridyl))pyridine-2-carboxamide

This compound is prepared as described above (Example 1G).

2. [7-(3-Methyl-pyridin-2-yl)-2-pyrrolidin-l-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-(4- trifluoromethyl-phenyl) -amine

This compound is prepared from 3-amino-5-(3-methyl(2-pyridyl))pyridine-2- carboxamide in a manner analogous to that used to prepare [2-pyrrolidin-l-ylmethyl-7-(3- trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 3A).

H. ADDITIONAL REPRESENTATIVE SUBSTITUTED 2-AMINOALKYL-QUINAZOLIN-4-YLAMINE ANALOGUES

Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce other compounds encompassed by the present invention. Compounds listed in Table III were prepared using the above methods, with readily apparent modifications. In the column labeled Kj in Table III, * indicates that the Kj for the compound is 1 micromolar or less. Mass Spectrometry data was obtained as described above and is given as M+l .

Table III Representative Substituted 2-Aminoalkyl-quinazolin-4-ylamine Analogues

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EXAMPLE 4 VRl -Transfected Cells and Membrane Preparations This Example illustrates the preparation of VRl -transfected cells and VRl -containing membrane preparations for use in capsaicin binding assays (Example 5). A cDNA encoding full length human capsaicin receptor (SEQ ID NO:l, 2 or 3 of U.S. Patent No. 6,482,611) was subcloned in the plasmid pBK-CMV (Stratagene, La Jolla, CA) for recombinant expression in mammalian cells.

Human embryonic kidney (HEK293) cells were transfected with the pBK-CMV expression construct encoding the full length human capsaicin receptor using standard methods. The transfected cells were selected for two weeks in media containing G418 (400 μg/ml) to obtain a pool of stably transfected cells. Independent clones were isolated from this pool by limiting dilution to obtain clonal stable cell lines for use in subsequent experiments. For radioligand binding experiments, cells were seeded in T175 cell culture flasks in media without antibiotics and grown to approximately 90% confluency. The flasks were then washed with PBS and harvested in PBS containing 5 mM EDTA. The cells were pelleted by gentle centrifugation and stored at -80°C until assayed.

Previously frozen cells were disrupted with the aid of a tissue homogenizer in ice-cold HEPES homogenization buffer (5mM KCl 5, 5.8mM NaCl, 0.75mM CaCl₂, 2mM MgCl₂, 320 mM sucrose, and 10 mM HEPES pH 7.4). Tissue homogenates were first centrifuged for 10 minutes at 1000 x g (4°C) to remove the nuclear fraction and debris, and then the supernatant from the first centrifugation is further centrifuged for 30 minutes at 35,000 x g (4°C) to obtain a partially purified membrane fraction. Membranes were resuspended in the HEPES homogenization buffer prior to the assay. An aliquot of this membrane homogenate was used to determine protein concentration via the Bradford method (BIO-RAD Protein Assay Kit, #500-0001, BIO-RAD, Hercules, CA).

EXAMPLE 5 Capsaicin Receptor Binding Assay This Example illustrates a representative assay of capsaicin receptor binding that may be used to determine the binding affinity of compounds for the capsaicin (VRl) receptor.

Binding studies with [³H] Resiniferatoxin (RTX) are carried out essentially as described by Szallasi and Blumberg (1992) J. Pharmacol. Exp. Ter. 2«52:883-888. In this protocol, non-specific RTX binding is reduced by adding bovine alphai acid glycoprotein (100 μg per tube) after the binding reaction has been terminated.

[³H] RTX (37 Ci/mmol) is synthesized by and obtained from the Chemical Synthesis and Analysis Laboratory, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD. [³H] RTX may also be obtained from commercial vendors (e.g., Amersham Pharmacia Biotech, Inc.; Piscataway, NJ).

The membrane homogenate of Example 4 is centrifuged as before and resuspended to a protein concentration of 333μg/ml in homogenization buffer. Binding assay mixtures are set up on ice and contain [³H]RTX (specific activity 2200 mCi/ml), 2 μl non-radioactive test compound, 0.25 mg/ml bovine serum albumin (Cohn fraction V), and 5 x 10⁴ - l x l 0⁵ VR1- transfected cells. The final volume is adjusted to 500 μl (for competition binding assays) or 1,000 μl (for saturation binding assays) with the ice-cold HEPES homogenization buffer solution (pH 7.4) described above. Non-specific binding is defined as that occurring in the presence of 1 μM non-radioactive RTX (Alexis Coφ.; San Diego, CA). For saturation binding, [³H]RTX is added in the concentration range of 7-1,000 pM, using 1 to 2 dilutions. Typically 11 concentration points are collected per saturation binding curve.

Competition binding assays are performed in the presence of 60 pM [³H]RTX and various concentrations of test compound. The binding reactions are initiated by transferring the assay mixtures into a 37°C water bath and are terminated following a 60 minute incubation period by cooling the tubes on ice. Membrane-bound RTX is separated from free, as well as any alphai-acid glycoprotein-bound RTX, by filtration onto WALLAC glass fiber filters (PERKIN-ELMER, Gaithersburg, MD) which were pre-soaked with 1.0% PEI (polyethyleneimine) for 2 hours prior to use. Filters are allowed to dry overnight then counted in a WALLAC 1205 BETA PLATE counter after addition of WALLAC BETA SCLNT scintillation fluid.

Equilibrium binding parameters are determined by fitting the allosteric Hill equation to the measured values with the aid of the computer program FIT P (Biosoft, Ferguson, MO) as described by Szallasi, et al. (1993) J. Pharmacol. Exp. Ther. 266:678-683. Compounds provided herein generally exhibit Kj values for capsaicin receptor of less than 1 μM, 100 nM, 50 nM, 25 nM, 10 nM, or InM in this assay.

EXAMPLE 6 Calcium Mobilization Assay

This Example illustrates representative calcium mobilization assays for use in evaluating test compounds for agonist and antagonist activity.

Cells transfected with expression plasmids (as described in Example 4) and thereby expressing human capsaicin receptor are seeded and grown to 70-90% confluency in FALCON black-walled, clear-bottomed 96-well plates (#3904, BECTON-DICKLNSON, Franklin Lakes, NJ). The culture medium is emptied from the 96 well plates and FLUO-3 AM calcium sensitive dye (Molecular Probes, Eugene, OR) is added to each well (dye solution: 1 mg FLUO-3 AM, 440 μL DMSO and 440 μl 20% pluronic acid in DMSO, diluted 1:250 in Krebs-Ringer HEPES (KRH) buffer (25 mM HEPES, 5 mM KCl, 0.96 mM NaH₂PO₄, 1 mM MgSO , 2 mM CaCl₂, 5 mM glucose, 1 mM probenecid, pH 7.4), 50 μl diluted solution per well). Plates are covered with aluminum foil and incubated at 37°C for 1-2 hours in an environment containing 5% C0₂. After the incubation, the dye is emptied from the plates, and the cells are washed once with KRH buffer, and resuspended in KRH buffer.

DETERMINATION CAPSAICIN EC₅₀

To measure the ability of a test compound to agonize or antagonize a calcium mobilization response in cells expressing capsaicin receptors to capsaicin or other vanilloid agonist, the EC₅₀ of the agonist capsaicin is first determined. An additional 20 μl of KRH buffer and 1 μl DMSO is added to each well of cells, prepared as described above. 100 μl capsaicin in KRH buffer is automatically transferred by the FLIPR instrument to each well.

Capsaicin-induced calcium mobilization is monitored using either FLUOROSKAN ASCENT

(Labsystems; Franklin, MA) or FLIPR (fluorometric imaging plate reader system; Molecular

Devices, Sunnyvale, CA) instruments. Data obtained between 30 and 60 seconds after agonist application are used to generate an 8-point concentration response curve, with final capsaicin concentrations of 1 nM to 3 μM. KALEIDAGRAPH software (Synergy Software,

Reading, PA) is used to fit the data to the equation: y=a*(l/(l+(b/x)^c)) to determine the 50% excitatory concentration (EC₅₀) for the response. In this equation, y is the maximum fluorescence signal, x is the concentration of the agonist or antagonist (in this case, capsaicin), a is the E_maχ, b corresponds to the EC₅₀ value and c is the Hill coefficient.

DETERMINATION OF AGONIST ACTIVITY

Test compounds are dissolved in DMSO, diluted in KRH buffer, and immediately added to cells prepared as described above. 100 nM capsaicin (an approximate EC₉o concentration) is also added to cells in the same 96-well plate as a positive control. The final concentration of test compounds in the assay wells is between 0.1 nM and 5 μM.

The ability of a test compound to act as an agonist of the capsaicin receptor is determined by measuring the fluorescence response of cells expressing capsaicin receptors elicited by the compound as function of compound concentration. This data is fit as described above to obtain the EC50, which is generally less than 1 micromolar, preferably less than 100 nM, and more preferably less than 10 nM. The extent of efficacy of each test compound is also determined by calculating the response elicited by a concentration of test compound (typically 1 μM) relative to the response elicited by 100 nM capsaicin. This value, called Percent of Signal (POS), is calculated by the following equation:

POS=100*test compound response /100 nM capsaicin response This analysis provides quantitative assessment of both the potency and efficacy of test compounds as human capsaicin receptor agonists. Agonists of the human capsaicin receptor generally elicit detectable responses at concentrations less than 100 μM, or preferably at concentrations less than 1 μM, or most preferably at concentrations less than 10 nM. Extent of efficacy at human capsaicin receptor is preferably greater than 30 POS, more preferably greater than 80 POS at a concentration of 1 μM. Certain agonists are essentially free of antagonist activity as demonstrated by the absence of detectable antagonist activity in the assay described below at compound concentrations below 4 nM, more preferably at concentrations below 10 μM and most preferably at concentrations less than or equal to 100 μM.

DETERMINATION OF ANTAGONIST ACTIVITY

Test compounds are dissolved in DMSO, diluted in 20 μl KRH buffer so that the final concentration of test compounds in the assay well is between 1 μM and 5 μM, and added to cells prepared as described above. The 96 well plates containing prepared cells and test compounds are incubated in the dark, at room temperature for 0.5 to 6 hours. It is important that the incubation not continue beyond 6 hours. Just prior to determining the fluorescence response, 100 μl capsaicin in KRH buffer at twice the EC₅0 concentration determined as described above is automatically added by the FLIPR instrument to each well of the 96 well plate for a final sample volume of 200 μl and a final capsaicin concentration equal to the EC₅₀. The final concentration of test compounds in the assay wells is between 1 μM and 5 μM. Antagonists of the capsaicin receptor decrease this response by at least about 20%, preferably by at least about 50%, and most preferably by at least 80%, as compared to matched control (i.e., cells treated with capsaicin at twice the EC₅₀ concentration in the absence of test compound), at a concentration of 10 micromolar or less, preferably 1 micromolar or less. The concentration of antagonist required to provide a 50% decrease, relative to the response observed in the presence of capsaicin and without antagonist, is the IC₅₀ for the antagonist, and is preferably below 1 micromolar, 100 nanomolar, 10 nanomolar or 1 nanomolar.

Certain preferred VRl modulators are antagonists that are essentially free of agonist activity as demonstrated by the absence of detectable agonist activity in the assay described above at compound concentrations below 4 nM, more preferably at concentrations below 10 μM and most preferably at concentrations less than or equal to 100 μM.

EXAMPLE 7 Microsomal in vitro half-life This Example illustrates the evaluation of compound half-life values (tι_/2 values) using a representative liver microsomal half-life assay.

Pooled human liver microsomes are obtained from XenoTech LLC (Kansas City, KS). Such liver microsomes may also be obtained from In Vitro Technologies (Baltimore, MD) or Tissue Transformation Technologies (Edison, NJ). Six test reactions are prepared, each containing 25 μl microsomes, 5 μl of a 100 μM solution of test compound, and 399 μl 0.1 M phosphate buffer (19 mL 0.1 M NaH₂P0₄, 81 mL 0.1 M Na₂HPO₄, adjusted to pH 7.4 with H₃P0₄). A seventh reaction is prepared as a positive control containing 25 μl microsomes, 399 μl 0.1 M phosphate buffer, and 5 μl of a 100 μM solution of a compound with known metabolic properties (e.g., DIAZEPAM or CLOZAPINE). Reactions are preincubated at 39°C for 10 minutes.

CoFactor Mixture is prepared by diluting 16.2 mg NADP and 45.4 mg Glucose-6- phosphate in 4 mL 100 mM MgCl₂. Glucose-6-phosphate dehydrogenase solution is prepared by diluting 214.3 μl glucose-6-phosphate dehydrogenase suspension (Roche Molecular Biochemicals; Indianapolis, IN) into 1285.7 μl distilled water. 71 μl Starting Reaction Mixture (3 mL CoFactor Mixture; 1.2 mL Glucose-6-phosphate dehydrogenase solution) is added to 5 of the 6 test reactions and to the positive control. 71 μl 100 mM MgCl₂ is added to the sixth test reaction, which is used as a negative control. At each time point (0, 1, 3, 5, and 10 minutes), 75 μl of each reaction mix is pipetted into a well of a 96-well deep-well plate containing 75 μl ice-cold acetonitrile. Samples are vortexed and centrifuged 10 minutes at 3500 φm (Sorval T 6000D centrifuge, HIOOOB rotor). 75 μl of supernatant from each reaction is transferred to a well of a 96-well plate containing 150 μl of a 0.5 μM solution of a compound with a known LCMS profile (internal standard) per well. LCMS analysis of each sample is carried out and the amount of unmetabolized test compound is measured as AUC, compound concentration vs. time is plotted, and the tι_/ value of the test compound is extrapolated.

Preferred compounds provided herein exhibit in vitro tι_/2 values of greater than 10 minutes and less than 4 hours, preferably between 30 minutes and 1 hour, in human liver microsomes.

EXAMPLE 8 MDCK Toxicitv Assay

This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) cell cytotoxicity assay. 1 μL of test compound is added to each well of a clear bottom 96-well plate

(PACKARD, Meriden, CT) to give final concentration of compound in the assay of 10 micromolar, 100 micromolar or 200 micromolar. Solvent without test compound is added to control wells.

MDCK cells, ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet. Confluent MDCK cells are trypsinized, harvested, and diluted to a concentration of 0.1 x 10⁶ cells/ml with warm (37°C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30-2003). 100 μL of diluted cells is added to each well, except for five standard curve control wells that contain 100 μL of warm medium without cells. The plate is then incubated at 37°C under 95% O₂, 5% CO₂ for 2 hours with constant shaking. After incubation, 50 μL of mammalian cell lysis solution (from the PACKARD (Meriden, CT) ATP-LITE-M Luminescent ATP detection kit) is added per well, the wells are covered with PACKARD TOPSEAL stickers, and plates are shaken at approximately 700 rpm on a suitable shaker for 2 minutes. Compounds causing toxicity will decrease ATP production, relative to untreated cells.

The ATP-LITE-M Luminescent ATP detection kit is generally used according to the manufacturer's instructions to measure ATP production in treated and untreated MDCK cells. PACKARD ATP LITE-M reagents are allowed to equilibrate to room temperature. Once equilibrated, the lyophilized substrate solution is reconstituted in 5.5 mL of substrate buffer solution (from kit). Lyophilized ATP standard solution is reconstituted in deionized water to give a 10 mM stock. For the five control wells, 10 μL of serially diluted PACKARD standard is added to each of the standard curve control wells to yield a final concentration in each subsequent well of 200 nM, 100 nM, 50 nM, 25 nM and 12.5 nM. PACKARD substrate solution (50 μL) is added to all wells, which are then covered, and the plates are shaken at approximately 700 φm on a suitable shaker for 2 minutes. A white PACKARD sticker is attached to the bottom of each plate and samples are dark adapted by wrapping plates in foil and placing in the dark for 10 minutes. Luminescence is then measured at 22°C using a luminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS), and ATP levels calculated from the standard curve. ATP levels in cells treated with test compound(s) are compared to the levels determined for untreated cells. Cells treated with 10 μM of a preferred test compound exhibit ATP levels that are at least 80%, preferably at least 90%, of the untreated cells. When a 100 μM concentration of the test compound is used, cells treated with preferred test compounds exhibit ATP levels that are at least 50%, preferably at least 80%, of the ATP levels detected in untreated cells.

EXAMPLE 9 Dorsal Root Ganglion Cell Assay

This Example illustrates a representative dorsal root ganglian cell assay for evaluating VRl antagonist or agonist activity of a compound.

DRG are dissected from neonatal rats, dissociated and cultured using standard methods (Aguayo and White (1992) Brain Research 570:61-61). After 48 hour incubation, cells are washed once and incubated for 30-60 minutes with the calcium sensitive dye Fluo 4 AM (2.5-10 ug/ml; TefLabs, Austin, TX). Cells are then washed once. Addition of capsaicin to the cells results in a VRl -dependent increase in intracellular calcium levels which is monitored by a change in Fluo-4 fluorescence with a fluorometer. Data are collected for 60- 180 seconds to determine the maximum fluorescent signal. For antagonist assays, various concentrations of compound are added to the cells.

Fluorescent signal is then plotted as a function of compound concentration to identify the concentration required to achieve a 50% inhibition of the capsaicin-activated response, or IC50- Antagonists of the capsaicin receptor preferably have an IC5₀ below 1 micromolar, 100 nanomolar, 10 nanomolar or 1 nanomolar. For agonist assays, various concentrations of compound are added to the cells without the addition of capsaicin. Compounds that are capsaicin receptor agonists result in a VR1- dependent increase in intracellular calcium levels which is monitored by a change in Fluo-4 fluorescence with a fluorometer. The EC₅₀, or concentration required to achieve 50% of the maximum signal for a capsaicin-activated response, is preferably below 1 micromolar, below 100 nanomolar or below 10 nanomolar.

EXAMPLE 10 Animal Models for Determining Pain Relief

This Example illustrates representative methods for assessing the degree of pain relief provided by a compound.

A. Pain Relief Testing

The following methods may be used to assess pain relief. MECHANICAL ALLODYNIA

Mechanical allodynia (an abnormal response to an innocuous stimulus) is assessed essentially as described by Chaplan et al. (1994) J. Neurosci. Methods 53:55-63 and Tal and Eliav (1998) Pain 64(3):511-518. A series of von Frey filaments of varying rigidity (typically 8-14 filaments in a series) are applied to the plantar surface of the hind paw with just enough force to bend the filament. The filaments are held in this position for no more than three seconds or until a positive allodynic response is displayed by the rat. A positive allodynic response consists of lifting the affected paw followed immediately by licking or shaking of the paw. The order and frequency with which the individual filaments are applied are determined by using Dixon up-down method. Testing is initiated with the middle hair of the series with subsequent filaments being applied in consecutive fashion, ascending or descending, depending on whether a negative or positive response, respectively, is obtained with the initial filament.

Compounds are effective in reversing or preventing mechanical allodynia-like symptoms if rats treated with such compounds require stimulation with a Von Frey filament of higher rigidity strength to provoke a positive allodynic response as compared to control untreated or vehicle treated rats. Alternatively, or in addition, testing of an animal in chronic pain may be done before and after compound administration. In such an assay, an effective compound results in an increase in the rigidity of the filament needed to induce a response after treatment, as compared to the filament that induces a response before treatment or in an animal that is also in chronic pain but is left untreated or is treated with vehicle. Test compounds are administered before or after onset of pain. When a test compound is administered after pain onset, testing is performed 10 minutes to three hours after administration. MECHANICAL HYPERALGESIA

Mechanical hyperalgesia (an exaggerated response to painful stimulus) is tested essentially as described by Koch et al. (1996) Analgesia 2(3):157-164. Rats are placed in individual compartments of a cage with a warmed, perforated metal floor. Hind paw withdrawal duration (i.e., the amount of time for which the animal holds its paw up before placing it back on the floor) is measured after a mild pinprick to the plantar surface of either hind paw.

Compounds produce a reduction in mechanical hyperalgesia if there is a statistically significant decrease in the duration of hindpaw withdrawal. Test compound may be administered before or after onset of pain. For compounds administered after pain onset, testing is performed 10 minutes to three hours after administration.

THERMAL HYPERALGESIA

Thermal hyperalgesia (an exaggerated response to noxious thermal stimulus) is measured essentially as described by Hargreaves et al. (1988) Pain. 32(l):77-88. Briefly, a constant radiant heat source is applied the animals' plantar surface of either hind paw. The time to withdrawal (i.e., the amount of time that heat is applied before the animal moves its paw), otherwise described as thermal threshold or latency, determines the animal's hind paw sensitivity to heat.

Compounds produce a reduction in thermal hyperalgesia if there is a statistically significant increase in the time to hindpaw withdrawal (i.e., the theπnal threshold to response or latency is increased). Test compound may be administered before or after onset of pain.

For compounds administered after pain onset, testing is performed 10 minutes to three hours after administration.

B. Pain Models Pain may be induced using any of the following methods, to allow testing of analgesic efficacy of a compound. In general, compounds provided herein result in a statistically significant reduction in pain as determined by at least one of the previously described testing methods, using male SD rats and at least one of the following models.

ACUTE INFLAMMATORY PAIN MODEL Acute inflammatory pain is induced using the carrageenan model essentially as described by Field et al. (1997) Br. J. Pharmacol. 121(8):1513-1522. 100-200 μl of 1-2% carrageenan solution is injected into the rats' hind paw. Three to four hours following injection, the animals' sensitivity to thermal and mechanical stimuli is tested using the methods described above. A test compound (0.O1 to 50 mg/kg) is administered to the animal, prior to testing, or prior to injection of carrageenan. The compound can be administered orally or through any parenteral route, or topically on the paw. Compounds that relieve pain in this model result in a statistically significant reduction in mechanical allodynia and/or thermal hyperalgesia.

CHRONIC INFLAMMATORY PAIN MODEL

Chronic inflammatory pain is induced using one of the following protocols:

1. Essentially as described by Bertorelli et al. (1999) Br. J. Pharmacol. 128(6):1252- 1258, and Stein et al. (1998) Pharmacol. Biochem. Behav. 31(2):455-51, 200 μl

Complete Freund's Adjuvant (0.1 mg heat killed and dried M. Tuberculosis) is injected to the rats' hind paw: 100 μl into the dorsal surface and 100 μl into the plantar surface.

2. Essentially as described by Abbadie et al. (1994) J Neurosci. 14(10):5865-5871 rats are injected with 150 μl of CFA (1.5 mg) in the tibio-tarsal joint.

Prior to injection with CFA in either protocol, an individual baseline sensitivity to mechanical and thermal stimulation of the animals' hind paws is obtained for each experimental animal.

Following injection of CFA, rats are tested for thermal hyperalgesia, mechanical allodynia and mechanical hyperalgesia as described above. To verify the development of symptoms, rats are tested on days 5, 6, and 7 following CFA injection. On day 7, animals are treated with a test compound, moφhine or vehicle. An oral dose of moφhine of 1-5 mg/kg is suitable as positive control. Typically, a dose of 0.01-50 mg/kg of test compound is used. Compounds can be administered as a single bolus prior to testing or once or twice or three times daily, for several days prior to testing. Drugs are administered orally or through any parenteral route, or applied topically to the animal.

Results are expressed as Percent Maximum Potential Efficacy (MPE). 0% MPE is defined as analgesic effect of vehicle, 100%) MPE is defined as an animal's return to pre-CFA baseline sensitivity. Compounds that relieve pain in this model result in a MPE of at least 30%.

CHRONIC NEUROPATHIC PAIN MODEL

Chronic neuropathic pain is induced using the chronic constriction injury (CCI) to the rat's sciatic nerve essentially as described by Bennett and Xie (1988) Pain 33:87-107. Rats are anesthetized (e.g. with an intraperitoneal dose of 50-65 mg/kg pentobarbital with additional doses administered as needed). The lateral aspect of each hind limb is shaved and disinfected. Using aseptic technique, an incision is made on the lateral aspect of the hind limb at the mid thigh level. The biceps femoris is bluntly dissected and the sciatic nerve is exposed. On one hind limb of each animal, four loosely tied ligatures are made around the sciatic nerve approximately 1-2 mm apart. On the other side the sciatic nerve is not ligated and is not manipulated. The muscle is closed with continuous pattern and the skin is closed with wound clips or sutures. Rats are assessed for mechanical allodynia, mechanical hyperalgesia and thermal hyperalgesia as described above. Compounds that relieve pain in this model result in a statistically significant reduction in mechanical allodynia, mechanical hyperalgesia and/or thermal hyperalgesia when administered (0.01-50 mg/kg, orally, parenterally or topically) immediately prior to testing as a single bolus, or for several days: once or twice or three times daily prior to testing.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for puφoses of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

What is claimed is:

A compound of the formula:

or a pharmaceutically acceptable form thereof, wherein:

X, V, W, Y and Z are each independently N or CRi, with the proviso that at least one of V and X is N; Ri is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, Ci-C_δalkyl, haloCι-C₆alkyl, Ci-Cβalkoxy, haloCι-C₆alkoxy, Cι-C₄alkoxy carbonyl and mono- and di-(Cι-C₆alkyl)amino;

R is -O-R₇ or -N _R ⁴ ; R₇ is:

(i) hydrogen;

(ii) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₂-C₈alkanoyl, C₃-C₈alkanone, C₂-C₈alkyl ether, C₆-Ci₀arylC₀-C₈alkyl or (5- to 10-membered heterocycle)Co-C₈alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b; or (iii) taken together with an R₅ or Re to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from R_b; R₃ and R are:

(i) each independently selected from:

(a) hydrogen;

(b) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈alkanone, C -C₈alkanoyl, C₂- C₈alkyl ether, C₆-CιoarylCo-C₈alkyl, (5- to 10-membered heterocycle)Co-C₈alkyl and. -(S0₂)Ci-C₈alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b; and

(c) groups that are taken together with an R₅ or R_ό to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from R_b; or

(ii) taken together to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from R_b; R₅ and Re are, independently at each occurrence:

(i) each independently hydrogen, Cι-C₈alkyl substituted with from 0 to 2 substituents independently chosen from R , or taken together with R₃, R-i or R₇ to form a 4- to 10- membered heterocyclic group that is substituted with from 0 to 4 substituents independently chosen from R_b; (ii) taken together to form a keto group; or

(iii) taken together to form a 3- to 7-membered carbocyclic or heterocyclic ring that is substituted with from 0 to 4 substituents independently chosen from R_b; n is 1, 2 or 3;

Ari and Ar₂ are independently selected from 6- to 10-membered aryl groups and 5- to 10- membered heterocycles, each of which is substituted with from 0 to 3 substituents independently selected from groups of the formula LR_a; L is independently selected at each occurrence from a bond, O, S(O)_m, C(=0), OC(=O), C(=0)O, O-C(=0)0, N(R_X), C(=0)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_mN(R_x) and N[S(0)_mR_x]S(O)_m; wherein m is independently selected at each occurrence from 0, 1 and 2; and R_x is independently selected at each occurrence from hydrogen and Cι-C₈alkyl; R_a is independently selected at each occurrence from: (i) hydrogen, halogen, cyano and nitro; and (ii) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₂-C₈alkyl ether, (4- to 10-membered heterocycle)Co-C₈alkyl and mono- and di-(Cι-C₈alkyl)amino, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, oxo, -COOH, Cι~C alkyl, Cι-C₄alkoxy, haloCι-C alkyl, haloCι-C alkoxy, hydroxyCι-C alkyl, and mono- and di-(Cι-C₆alkyl)amino; and R_b is independently chosen at each occurrence from:

(i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo and -COOH; and (ii) Cι-C₈alkyl, Cι-C₈haloalkyl, C C₈alkoxy, Cι-C₈haloalkoxy, Cι-C₈alkanoyl, C₂- C₈alkoxycarbonyl, C₂-C₈alkanoyloxy, Cι-C₈alkylthio, C₂-C₈alkyl ether, phenylC₀- C₈alkyl, phenylC₀-C₈alkoxy, mono- and di-(Cι-C₆alkyl)aminoCo-C6alkyl, ~(SO )Cι- C₈alkyl and (4- to 7-membered heterocycle)(C₀-C₈alkyl); each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C]-C₄alkyl, Cι-C alkoxy, hydroxyCι-C alkyl, haloC]-C alkyl, and mono- and di-(Cι-C alkyl)amino.

2. A compound or form thereof according to claim 1, wherein V and X are N.

3. A compound or form thereof according to claim 1, wherein V is N and X is CH.

4. A compound or form thereof according to claim 1, wherein X is N and V is CH.

5. A compound or form thereof according to any one of claims 1-4, wherein Y is N and W and Z are each CH.

6. A compound or form thereof according to any one of claims 1-4, wherein Z is N and W and Y are each CH.

7. A compound or form thereof according to any one of claims 1-4, wherein W, Y and Z are each CH.

8. A compound or form thereof according to claim 1, wherein Ari and Ar are independently selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted with 0, 1 or 2 substituents independently selected from groups of the formula LR_a.

9. A compound or form thereof according to claim 8, wherein:

Ari is phenyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C6alkyl)amino, Cι-C₆alkyl, haloCi-C_δalkyl, Cι-C₆alkoxy and haloCi-Cβalkoxy; and

Ar₂ is phenyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι~ C₆alkyl)amino, Cι-C₆alkyl, haloCι-C₆alkyl, cyano -Cealkyl, Ci-Cβalkoxy, haloC C₆alkoxy, C₂-C₆alkyl ether, Cι-C₆alkanoyl, -(SO₂)Rd, - N(R_x)S(0)_mRd, and - N[S(Om)R_x]S(O)_mR ; wherein m is 1 or 2, R_x is hydrogen or Ci-Cδalkyl, and R is - C₆alkyl, haloCι-C₆alkyl, amino, mono- or di-(Cι-C₆alkyl)amino or a 5- to 10-membered, N-linked heterocyclic group, each of which R_d is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C₆alkyl)amino, Cι-C alkyl, halo - alkyl, Cι-C alkoxy and haloCι-C alkoxy.

10. A compound or form thereof according to claim 9, wherein:

Ari is pyridyl, unsubstituted or substituted with halogen, cyano, Cι-C alkyl or haloCi-

C alkyl; and Ar₂ is phenyl or pyridyl, substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C₄alkyl, cyanoCι-C₄alkyl, haloCι-C₄alkyl, C₂-C₆alkyl ether and groups of the formula -(SO₂)Rd, wherein R is Cι-C₄alkyl or haloCι-C₄alkyl.

11. A compound or form thereof according to claim 9, wherein:

Ari is phenyl, unsubstituted or substituted with halogen, cyano, Cι-C₄alkyl or haloCι-C alkyl; and Ar₂ is phenyl or pyridyl, substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C₄alkyl, cyanoCι-C₄alkyl, haloCι-C₄alkyl, C₂-C₆alkyl ether and groups of the formula -(S0₂)R_d, wherein R_d is Cι-C₄alkyl or haloCι-C alkyl.

12. A compound or form thereof according to claim 9, wherein:

Ari is pyridin-2-yl, 3-methyl-pyridin-2-yl, 3-trifluoromethyl-pyridin-2-yl or 3-halo-pyridin-2- yl; and

Ar₂ is phenyl, pyridin-2-yl or pyridin-3-yl, each of which is substituted at the _/?-.ra-position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl .

13. A compound or form thereof according to claim 9, wherein: Ari is phenyl, 2-methyl-phenyl, 2-trifluoromethyl-phenyl or 2-halo-phenyl; and

Ar₂ is phenyl, pyridin-2-yl or pyridin-3-yl, each of which is substituted at the _/-.αr -position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl.

14. A compound of the formula:

or a pharmaceutically acceptable form thereof, wherein:

V, X, W, Y and Z are each independently N or CRi, with the proviso that at least one of V and X is N; Ri is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, Cι-C₆alkyl, haloCi-C_όalkyl, Cι-C₆alkoxy, haloCι-C₆alkoxy, Cι-C alkoxycarbonyl and mono- and di-(Cι-C₆alkyl)amino; R₇ is:

(i) hydrogen;

(ii) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₂-C₈alkanoyl, C₃-C₈alkanone, C₂-C₈alkyl ether, C₆-CιoarylC₀-C₈alkyl or (5- to 10-membered heterocycle)Co-C₈alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b; or (iii) taken together with an R₅ or R₆ to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from R_b; R₅ and ₅ are, independently at each occurrence:

(i) each independently hydrogen, Cι-C₈alkyl substituted with from 0 to 2 substituents independently chosen from R_b, or taken together with R₇ to form a 4- to 10-membered heterocyclic group that is substituted with from 0 to 4 substituents independently chosen from R_b; (ii) taken together to form a keto group; or

Ari and Ar₂ are independently selected from 6- to 10-membered aryl groups and 5- to 10- membered heterocycles, each of which is substituted with from 0 to 3 substituents independently selected from groups of the formula LR_a; L is independently selected at each occurrence from a bond, O, S(0)_m, C(=0), OC(=O), C(=0)O, 0-C(=O)O, N(R_X), C(=0)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(0)_mN(R_x) and N[S(0)_mR_x]S(O)_m; wherein m is independently selected at each occurrence from 0, 1 and 2; and R_x is independently selected at each occurrence from hydrogen and Cι~C₈alkyl; R_a is independently selected at each occurrence from: (i) hydrogen, halogen, cyano and nitro; and (ii) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₂-C₈alkyl ether, (4- to 10-membered heterocycle)Co-C₈alkyl and mono- and di-(Cι-C₈alkyl)amino, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, oxo, -COOH, Cι-C alkyl, Cι-C alkoxy, haloCι-C alkyl, haloCι-C alkoxy, hydroxyCι~C alkyl, and mono- and di-(Cι-C6alkyl)amino; and R_b is independently chosen at each occurrence from:

(i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo and -COOH; and (ii) Cι-C₈alkyl, Cι-C₈haloalkyl, Cι-C₈alkoxy, Cι-C₈haloalkoxy, C[-C₈alkanoyl, C₂- C₈alkoxycarbonyl, C₂-C₈alkanoyloxy, Cι-C₈alkylthio, C₂-C₈alkyl ether, phenylC₀- C alkyl, phenylC₀-C₈alkoxy, mono- and di-(Cι-C₆alkyl)aminoCo-C₆alkyl, -(S0₂)Cι- C₈alkyl and (4- to 7-membered heterocycle)(C₀-C₈alkyl); each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, Cι-C₄alkyl, Cι-C alkoxy, hydroxyCι-C₄alkyl, haloCι-C₄alkyl, and mono- and di-(Cι -C₄alkyl)amino.

15. A compound or form thereof according to claim 14, wherein V and X are N.

16. A compound or form thereof according to claim 14, wherein V is N and X is CH.

17. A compound or form thereof according to claim 14, wherein X is N and V is CH.

18. A compound or form thereof according to any one of claims 14-17, wherein Y is N and W and Z are each CH.

19. A compound or form thereof according to any one of claims 14-17, wherein Z is N and W and Y are each CH.

20. A compound or form thereof according to any one of claims 14-17, wherein W, Y and Z are each CH.

21. A compound or form thereof according to claim 14, wherein Ari and Ar₂ are independently selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted with 0, 1 or 2 substituents independently selected from groups of the formula LR_a.

22. A compound or form thereof according to claim 21, wherein:

Ari is phenyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C₆alkyl)amino, Ci-Cόalkyl, haloCi-Cβalkyl, Cι-C₆alkoxy and haloCi-Cόalkoxy; and

Ar₂ is phenyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C₆alkyl)amino, Cι-C₆alkyl, haloCι-C₆alkyl, cyanoCι-C₆alkyl, Cι-C₆alkoxy, haloCi- C₆alkoxy, C₂-C₆alkyl ether, C_rC₆alkanoyl, -(SO₂)Rd, N(R_x)S(O)_mR_d, and - N[S(O_m)R_x]S(O)_mRd; wherein m is 1 or 2, R_x is hydrogen or Cι-C₆alkyl, and R_d is - C₆alkyl, haloCι-C₆alkyl, amino, mono- or di-(Cι-C₆alkyl)amino or a 5- to 10-membered, N-linked heterocyclic group, each of which R is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C₆alkyl)amino, Cι-C alkyl, haloC]-C alkyl, Cι-C alkoxy and haloCι-C alkoxy.

23. A compound or form thereof according to claim 22, wherein:

C₄alkyl; and Ar₂ is phenyl or pyridyl, substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C₄alkyl, cyanoCι-C₆alkyl, haloCι-C₄alkyl, C₂-C₆alkyl ether and groups of the formula -(S0₂)R_d, wherein R_d is Cι-C₄alkyl or haloCι-C₄alkyl.

24. A compound or form thereof according to claim 22, wherein:

Ari is phenyl, unsubstituted or substituted with halogen, cyano, Cι-C alkyl or haloCι-C alkyl; and Ar₂ is phenyl or pyridyl, substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C alkyl, cyanoCi-Cβalkyl, haloCι-C alkyl, C₂-C₆alkyl ether and groups of the formula -(SO₂)R_d, wherein R is Cι-C alkyl or haloCι-C₄alkyl.

25. A compound or form thereof according to claim 22, wherein:

Ar₂ is phenyl, pyridin-2-yl or pyridin-3-yl, each of which is substituted at the y^αrα-position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl.

26. A compound or form thereof according to claim 22, wherein: Ari is phenyl, 3-methyl-phenyl, 3-trifluoromethyl-phenyl or 3-halo-phenyl; and

Ar₂ is phenyl, pyridin-2-yl or pyridin-3-yl, each of which is substituted at the αrø-position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl .

27. A compound or form thereof according to claim 14, having the formula:

wherein A, B, C, X, Y and Z are each independently CH or N, and wherein each "(LR_a)ι-₃" represents from 1 to 3 substituents independently chosen from groups of the formula LR_a.

28. A compound or form thereof according to claim 27, wherein X is CH.

29. A compound or form thereof according to claim 27, wherein X is N.

30. A compound or form thereof according to claim 14 or claim 27, wherein R₇ is: (i) hydrogen; or

(ii) Cι-C₈alkyl, C -C₈alkenyl, C₂-C₈alkynyl, C₂-C₈alkanoyl, C₃-C₈alkanone, C₂-C₈alkyl ether, C₆-CιoarylCo-C₈alkyl or (5- to 10-membered heterocycle)Co-C₈alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b.

31. A compound or form thereof according to claim 30, wherein R₇ is: (i) hydrogen; or

(ii) Cι-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₂-C₆alkyl ether, mono- or di-(Cι- C₆alkyl)aminoCι-C₆alkyl, phenylCo-C alkyl, (5- to 6-membered heteroaryl)Co- C alkyl or (5- to 7-membered heterocycloalkyl)Co-C alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, Cι-C alkyl, haloCι-C₄alkyl, Cι-C₄alkoxy and haloCι-C₄alkoxy.

32. A compound or form thereof according to claim 30, wherein R₇ is Cι-C alkyl, C₂-C alkyl ether, mono- or di-(Cι-C₄alkyl)aminoCι-C₆alkyl, a 6-membered heterocycle or benzyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen and Cι-C₄alkyl.

33. A compound or form thereof according to claim 14 or claim 27, wherein each R₅ and R, is independently selected from hydrogen and Cι-C alkyl.

34. A compound or form thereof according to claim 33, wherein each R₅ and R₆ is hydrogen.

35. A compound or form thereof according to claim 14 or claim 27, wherein one R₅ and one Re attached to the same carbon atom are taken together to form a keto group.

36. A compound or form thereof according to claim 14 or claim 27, wherein n is 1.

37. A compound or form thereof according to claim 14, having the formula:

wherein:

X, Y and Z are independently CH or N;

Ari is phenyl or pyridyl, unsubstituted or substituted with halogen, cyano, Cι-C₄alkyl or haloCι-C₄alkyl; Ar₂ is phenyl or pyridyl, unsubstituted or substituted with Cι-C₄alkyl, cyanoCι-C alkyl, haloCι-C alkyl, C₂-C₆alkyl ether or a group of the formula -(S0₂)Rd, wherein R is

Cι-C alkyl or haloCι-C alkyl; R_s and Re are independently selected from hydrogen and Cι-C₄alkyl; and R₇ is (a) hydrogen; or (b) Cι-C₆alkyl, C₂-C₆alkenyl or phenylCo-C₄alkyl, each of which is substituted with 0, 1 or 2 substituents independently selected from hydroxy, halogen, Cι-C₄alkyl and haloC C alkyl.

38. A compound or form thereof according to claim 27, having the formula:

wherein:

A, B, C, Y and Z are each independently CH or N;

R₇ is (a) hydrogen; or (b) Cι-C₆alkyl, C₂-C₆alkenyl or phenylCo-C alkyl, each of which is substituted with 0, 1 or 2 substituents independently chosen from hydroxy, halogen,

Cι-C alkyl and haloC]-C alkyl; and each Rό is independently hydrogen or methyl.

39. A compound or form thereof according to claim 27, having the formula:

wherein:

A, B, C, Y and Z are each independently CH or N;

R₇ is (a) hydrogen; or (b) Cι-C6alkyl, C₂-C₆alkenyl or phenylCo-C alkyl, each of which is substituted with 0, 1 or 2 substituents independently chosen from hydroxy, halogen,

Cι-C alkyl and haloCι-C alkyl; and each Re is independently hydrogen or methyl.

40. A compound or form thereof according to claim 14, wherein the compound is selected from compounds listed in Table II.

41. A compound of the formula:

or a pharmaceutically acceptable form thereof, wherein:

V, X, W, Y and Z are each independently N or CRi, with the proviso that at least one of V and X is N; Ri is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, Cι-C₆alkyl, haloCi-Cδalkyl, Cι-C₆alkoxy, halo -Cealkoxy, Cι-C₄alkoxycarbonyl and mono- and di-(Cι-C₆alkyl)amino;

(i) each independently selected from:

(a) hydrogen;

(b) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈alkanone, C₂-C₈alkanoyl, C₂- C₈alkyl ether, (C₆-Cιoaryl)C₀-C₈alkyl, (5- to 10-membered heterocycle)C₀-C₈alkyl and -(SO₂)Cι-C₈alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R ; and

(c) groups that are taken together with an R₅ or R_ό to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from Rb; or

(ii) taken together to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently chosen from Rb; R₅ and R_ό are, independently at each occurrence:

(i) each independently hydrogen, Cι-C₈alkyl substituted with from 0 to 2 substituents independently chosen from R_b, or taken together with R₃ or R₄ to form a 4- to 10- membered heterocyclic group that is substituted with from 0 to 4 substituents independently chosen from R_b; (ii) taken together to form a keto group; or

Ari and Ar₂ are independently selected from 6- to 10-membered aryl groups and 5- to 10- membered heterocycles, each of which is substituted with from 0 to 3 substituents independently selected from groups of the formula LR^; L is independently selected at each occurrence from a bond, O, S(O)_m, C(=0), OC(=O), C(=O)O, O-C(=O)O, N(R_x), C(=0)N(R_x), N(R_x)C(=O), N(R_x)S(0)_m, S(0)_mN(R_x) and N[S(O)mR_x]S(O)m; wherein m is independently selected at each occurrence from 0, 1 and 2; and R_x is independently selected at each occurrence from hydrogen and Cι-C₈alkyl; R_a is independently selected at each occurrence from: (i) hydrogen, halogen, cyano and nitro; and (ii) Cι-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₂-C₈alkyl ether, (4- to 10-membered heterocycle)Co-C₈alkyl and mono- and di-(Cι-C₈alkyl)amino, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, oxo, -COOH, Cι-C alkyl, Cι-C₄alkoxy, haloCι-C alkyl, haloCι-C alkoxy, hydroxyCι-C alkyl, and mono- and di-(Cι-C₆alkyl)amino; and R_b is independently chosen at each occurrence from:

(i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo and -COOH; and (ii) Cι-C₈alkyl, Cι-C₈haloalkyl, Cι-C₈alkoxy, Cι-C₈haloalkoxy, Cι-C₈alkanoyl, C - C₈alkoxycarbonyl, C₂-C₈alkanoyloxy, Cι-C₈alkylthio, C₂-C₈alkyl ether, phenylCo- C₈alkyl, phenylCo-C₈alkoxy, mono- and di-(Cι-C₆alkyl)aminoCo-C₆alkyl, -(S0₂)Cι- C₈alkyl and (4- to 7-membered heterocycle)(Co-C₈alkyl); each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, Cι-C₄alkyl, Cι-C₄alkoxy, hydroxyCι-C alkyl, haloCι-C alkyl, and mono- and di-(Cι-C alkyl)amino.

42. A compound or form thereof according to claim 41, wherein V and X are N.

43. A compound or form thereof according to claim 41, wherein V is N and X is CH.

44. A compound or form thereof according to claim 41, wherein X is N and V is CH

45. A compound or form thereof according to any one of claims 41-44, wherein Y is N and W and Z are each CH.

46. A compound or form thereof according to any one of claims 41-44, wherein Z is N and W and Y are each CH.

47. A compound or form thereof according to any one of claims 41-44, wherein W, Y and Z are each CH.

48. A compound or form thereof according to claim 41, wherein Ari and Ar₂ are independently selected from phenyl and 6-membered aromatic heterocycles, each of which is substituted with 0, 1 or 2 substituents.

49. A compound or form thereof according to claim 48, wherein:

Ari is phenyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C6alkyl)amino, Ci-Cβalkyl, haloCi-Cβalkyl, Cι-C₆alkoxy and haloCι-C₆alkoxy; and

Ar₂ is phenyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C6alkyl)amino, Cι-C₆alkyl, haloCι-C₆alkyl, cyanoCι-C₆alkyl, Cι-C₆alkoxy, haloCi- C₆alkoxy, C₂-C₆alkyl ether, C_rC₆alkanoyl, -(S0₂)Rd, - N(R_x)S(0)_mR_d, and - N[S(O_m)R_x]S(O)_mRd; wherein m is 1 or 2, R_x is hydrogen or C]-C₆alkyl, and R_d is Ci- C₆alkyl, haloCι-C₆alkyl, amino, mono- or di-(Cι-C₆alkyl)amino or a 5- to 10-membered, N-linked heterocyclic group, each of which R is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, mono- and di-(Cι- C₆alkyl)amino, Cι-C alkyl, haloCι-C alkyl, - alkoxy and haloCι-C alkoxy.

50. A compound or form thereof according to claim 49, wherein:

C₄alkyl; and Ar₂ is phenyl or pyridyl, substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C alkyl, cyanoCι-C alkyl haloCι-C alkyl, C₂-C₆alkyl ether and groups of the formula -(SO₂)R_d, wherein R_d is Cι-C₄alkyl or haloCr alkyl.

51. A compound or form thereof according to claim 49, wherein:

Ari is phenyl, unsubstituted or substituted with halogen, cyano, Cι-C alkyl or haloCι-C alkyl; and Ar₂ is phenyl or pyridyl, substituted with from 0 to 2 substituents independently chosen from halogen, Cι-C₄alkyl, cyanoCι-C₄alkyl haloCι-C alkyl, C₂-C₆alkyl ether and groups of the formula -(SO₂)R_d, wherein R_d is Cι-C alkyl or haloC]-C₄alkyl.

52. A compound or form thereof according to claim 49, wherein:

Ari is ρyridin-2-yl, 3-methyl-pyridin-2-yl, 3-trifluoromethyl-pyridin-2-yl or 3-halo-pyridin-2- yl; and

Ar₂ is phenyl, pyridin-2-yl or pyridin-3-yl, each of which is substituted at the j->-7rø-position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl.

53. A compound or form thereof according to claim 49, wherein: Ari is phenyl, 2-methyl-phenyl, 2-trifluoromethyl-phenyl or 2-halo-phenyl; and

Ar₂ is phenyl, pyridin-2-yl or pyridin-3-yl, each of which is substituted at the ?αrα-position with halogen, cyano, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trifluoro-l -methyl-ethyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-sulfonyl, trifluoromethanesulfonyl or 2,2,2- trifluoroethanesulfonyl.

54. A compound or form thereof according to claim 30, having the formula:

wherein A, B, C, Y and Z are each independently CH or N, and wherein each "(LR_a)ι-₃" represents from 1 to 3 substituents independently chosen from groups of the formula LR_a.

55. A compound or form thereof according to claim 41 or 54, wherein R₃ and R-_t are independently selected from (i) hydrogen and (ii) Cι-C₈alkyl, C -C₈alkenyl, C₂- C₈alkynyl, C₃-C₈alkanone, Cι-C₈alkanoyl, C -C₈alkyl ether, (C₆-Cι₀aryl)Co-C₈alkyl, (5- to 10-membered heterocycle)Co~C₈alkyl and ~(S0₂)Ci-C₈alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b.

56. A compound or form thereof according to claim 55, wherein R₃ and R-i are independently selected from (i) hydrogen and (ii) Cι-C₈alkyl, C₂-C₈alkenyl, phenylCo- C₄alkyl, indanylC₀-C₄alkyl, (5- to 6-membered heteroaryl)Co-C₄alkyl and (5- to 7-membered heterocycloalkyl)Co-C alkyl, each of which is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, amino, Cι-C₆alkyl, halo -C_δalkyl, - C₆alkoxy and haloCι-C₆alkoxy.

57. A compound or form thereof according to claim 56, wherein R₃ and i are independently selected from hydrogen, Ci-C_όalkyl, C₂-C₆alkenyl, (5- to 7-membered heterocycle)Co-C₄alkyl, C₂-C₆alkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl, each of which substituted with from 0 to 3 substituents independently selected from hydroxy, halogen and Cι-C alkyl, with the proviso that at least one of R₃ and i is not hydrogen.

58. A compound or form thereof according to claim 41 or claim 54, wherein one of R₃ or i is taken together with an R₅ or R₆ to form a 4- to 10-membered heterocyclic group that is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, Cι-C alkyl, haloCι-C alkyl, Cι-C alkoxy, haloCι-C alkoxy, Cι-C₄alkanoyl, - C alkoxycarbonyl, aminocarbonyl and (4- to 10-membered heterocycle)C₀-C₈alkyl.

59. A compound or form thereof according to claim 41 or claim 54, wherein R₃ and _t are taken together to form a 4- to 10-membered heterocycle that is substituted with from 0 to 4 substituents independently selected from hydroxy, halogen, aminocarbonyl, Ci- C alkyl, hydroxyC]-C alkyl, haloC C₄alkyl, Cι-C₄alkoxy, haloCι-C alkoxy, Cι-C alkanoyl, C₂-C₄alkoxycarbonyl, aminocarbonyl and (4- to 7-membered heterocycle)C₀-C₈alkyl.

60. A compound or form thereof according to claim 59, wherein the 4- to 10- membered heterocycle is moφholinyl, piperidinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl.

61. A compound or form thereof according to claim 41 or claim 54, wherein each R₅ and s is independently selected from hydrogen and Cι-C₄alkyl.

62. A compound or form thereof according to claim 61, wherein each R₅ and s is hydrogen.

63. A compound or form thereof according to claim 41 or claim 54, wherein one R₅ and one RQ attached to the same carbon atom are taken together to form a keto group.

64. A compound or form thereof according to claim 41 or claim 54, wherein n is 1.

65. A compound or form thereof according to claim 30, having the formula:

wherein:

Ari is phenyl or pyridyl, unsubstituted or substituted with halogen, cyano, Cι-C alkyl or haloCι-C alkyl; Ar₂ is phenyl or pyridyl, unsubstituted or substituted with Cι-C₄alkyl, cyanoCι-C₄alkyl, haloCι-C alkyl, C₂-C₆alkyl ether or a group of the formula -(S0₂)Rd, wherein Rd is Cι-C alkyl or haloCι-C alkyl;

(a) independently selected from: (i) hydrogen; and

(ii) Cι-C₆alkyl, C₂-C₆alkenyl, (5- to 7-membered heterocycle)C₀-C alkyl, C₂- C₆alkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl- ethyl, each of which is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C alkyl and haloCι-C alkyl; or

(b) taken together to form a 5- to 7-membered heterocycloalkyl that is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C₄alkyl and haloCι-C alkyl; and

Rs and Re are independently selected from hydrogen and Cι-C alkyl.

66. A compound or form thereof according to claim 54, having the formula:

wherein:

A, B, C, Y and Z are each independently CH or N;

(a) independently selected from: (i) hydrogen; and (ii) Ci-C_όalkyl, C -C₆alkenyl, (5- to 7-membered heterocycle)Co-C alkyl, C₂- C₆alkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl- ethyl, each of which is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C alkyl and haloCι-C alkyl; or (b) taken together to form a 5- to 7-membered heterocycloalkyl that is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C₄alkyl and haloCι-C alkyl; and each Re is independently hydrogen or methyl.

67. A compound or form thereof according to claim 54, having the formula:

wherein:

A, B, C, Y and Z are each independently CH or N;

(a) independently selected from: (i) hydrogen; and

(ii) Ci-Cealkyl, C₂-C₆alkenyl, (5- to 7-membered heterocycle)C₀-C₄alkyl, C₂- C₆alkyl ether, indanyl, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl- ethyl, each of which is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C alkyl and haloCι-C₄alkyl; or

(b) taken together to form a 5- to 7-membered heterocycloalkyl that is substituted with from 0 to 3 substituents independently selected from hydroxy, cyano, halogen, Cι-C₄alkyl and haloCι-C alkyl; and each Re is independently hydrogen or methyl.

68. A compound or form thereof according to claim 30, wherein the compound is selected from compounds listed in Table III.

69. A compound or form thereof according to any one of claims 1, 14 or 41, wherein the compound has an IC50 value of 100 nanomolar or less in a capsaicin receptor calcium mobilization assay.

70. A compound or form thereof according to any one of claims 1, 14 or 41, wherein the compound has an IC50 value of 10 nanomolar or less in a capsaicin receptor calcium mobilization assay.

71. A pharmaceutical composition, comprising at least one compound or form thereof according to any one of claims 1, 14 or 41, in combination with a physiologically acceptable carrier or excipient.

72. A pharmaceutical composition according to claim 71 wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.

73. A method for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell expressing a capsaicin receptor with at least one compound or form thereof according to any one of claims 1, 14 or 41, and thereby reducing calcium conductance of the capsaicin receptor.

74. A method according to claim 73, wherein the cell is a neuronal cell that is contacted in vivo in an animal.

75. A method according to claim 74, wherein during contact the compound is present within a body fluid of the animal.

76. A method according to claim 74, wherein the compound is present in the blood of the animal at a concentration of 1 micromolar or less.

77. A method according to claim 76, wherein the compound is present in the blood of the animal at a concentration of 500 micromolar or less.

78. A method according to claim 77, wherein the compound is present in the blood of the animal at a concentration of 100 micromolar or less.

79. A method according to claim 74, wherein the animal is a human.

80. A method according to claim 74, wherein the compound is administered orally.

81. A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in vitro, the method comprising contacting capsaicin receptor with at least one compound or form thereof according to any one of claims 1, 14 or 41, under conditions and in an amount sufficient to detectably inhibit vanilloid ligand binding to capsaicin receptor.

82. A method for inhibiting binding of vanilloid ligand to capsaicin receptor in a patient, comprising contacting cells expressing capsaicin receptor with at least one compound or form thereof according to any one of claims 1, 14 or 41, in an amount sufficient to detectably inhibit vanilloid ligand binding to cells expressing a cloned capsaicin receptor in vitro, and thereby inhibiting binding of vanilloid ligand to the capsaicin receptor in the patient.

83. A method according to claim 82, wherein the patient is a human.

84. A method according to claim 82, wherein the compound is present in the blood of the patient at a concentration of 1 micromolar or less.

85. A method for treating a condition responsive to capsaicin receptor modulation in a patient, comprising administering to the patient a capsaicin receptor modulatory amount of at least one compound or form thereof according to any one of claims 1, 14 or 41, and thereby alleviating the condition in the patient.

86. A method according to claim 85, wherein the patient is suffering from (i) exposure to capsaicin, (ii) burn or irritation due to exposure to heat, (iii) burns or irritation due to exposure to light, (iv) burn, bronchoconstriction or irritation due to exposure to tear gas, air pollutants or pepper spray, or (v) burn or irritation due to exposure to acid.

87. A method according to claim 85, wherein the condition is asthma or chronic obstructive pulmonary disease.

88. A method for treating pain in a patient, comprising administering to a patient suffering from pain a capsaicin receptor modulatory amount of at least one compound or form thereof according to any one of claims 1, 14 or 41, and thereby alleviating pain in the patient.

89. A method according to claim 88, wherein the compound is present in the blood of the patient at a concentration of 1 micromolar or less.

90. A method according to claim 89, wherein the compound is present in the blood of the patient at a concentration of 500 nanomolar or less.

91. A method according to claim 89, wherein the compound is present in the blood of the patient at a concentration of 100 nanomolar or less.

92. A method according to claim 88, wherein the patient is suffering from neuropathic pain.

93. A method according to claim 88, wherein the pain is associated with a condition selected from: postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, toothache, postheφetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal cord injury-related pain, surgery-related pain, musculoskeletal pain, back pain, headache, migraine, angina, labor, hemorrhoids, dyspepsia, Charcot's pains, intestinal gas, menstruation, cancer, venom exposure, irritable bowel syndrome, inflammatory bowel disease and trauma.

94. A method according to claim 88, wherein the patient is a human.

95. A method for treating itch in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or form thereof according to any one of claims 1, 14 or 41, and thereby alleviating itch in the patient.

96. A method for treating cough or hiccup in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or form thereof according to any one of claims 1, 14 or 41, and thereby alleviating cough or hiccup in the patient.

97. A method for treating urinary incontinence in a patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or form thereof according to any one of claims 1, 14 or 41, and thereby alleviating urinary incontinence in the patient.

98. A method promoting weight loss in an obese patient, comprising administering to a patient a capsaicin receptor modulatory amount of a compound or form thereof according to any one of claims 1, 14 or 41, and thereby promoting weight loss in the patient.

99. A compound or form thereof according to any one of claims 1, 14 or 41, wherein the compound or form thereof is radiolabeled.

100. A method for determining the presence or absence of capsaicin receptor in a sample, comprising the steps of:

(a) contacting a sample with a compound or form thereof according to any one of claims 1, 14 or 41, under conditions that permit binding of the compound to capsaicin receptor; and

(b) detecting a level of the compound bound to capsaicin receptor, and therefrom determining the presence or absence of capsaicin receptor in the sample.

101. A method according to claim 100, wherein the compound is a radiolabeled compound according to claim 99, and wherein the step of detection comprises the steps of:

(i) separating unbound compound from bound compound; and

(ii) detecting the presence or absence of bound compound in the sample.

102. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 71 in a container; and

(b) instructions for using the composition to treat pain.

103. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 71 in a container; and

(b) instructions for using the composition to treat cough or hiccup.

104. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 71 in a container; and

(b) instructions for using the composition to treat obesity.

105. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 71 in a container; and

(b) instructions for using the composition to treat urinary incontinence.

106. Use of a compound according to claim 1 as a medicament for the treatment of a patient suffering from a condition responsive to capsaicin receptor modulation.

107. Use of a compound according to claim 1 as a medicament for the treatment of a patient suffering from a condition responsive to capsaicin receptor modulation selected from (i) exposure to capsaicin, (ii) bum or irritation due to exposure to heat, (iii) bums or irritation due to exposure to light, (iv) burn, bronchoconstriction or irritation due to exposure to tear gas, air pollutants or pepper spray, or (v) bum or irritation due to exposure to acid.

108. Use of a compound according to claim 1 as a medicament for the treatment of a patient suffering from to pain.

108. Use of a compound according to claim 1 as a medicament for the treatment of a patient suffering from neuropathic pain associated with a condition selected from: postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, toothache, postheφetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Guillain-Barre syndrome, meralgia paresthetica, buming-mouth syndrome, bilateral peripheral neuropathy, causalgia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal cord injury-related pain, surgery-related pain, musculoskeletal pain, back pain, headache, migraine, angina, labor, hemorrhoids, dyspepsia, Charcot's pains, intestinal gas, menstruation, cancer, venom exposure, irritable bowel syndrome, inflammatory bowel disease and trauma.