WO2005061462A2

WO2005061462A2 - Diaryl pyrazole derivatives and their use as neurokinin-3 receptor modulators

Info

Publication number: WO2005061462A2
Application number: PCT/US2004/043103
Authority: WO
Inventors: George D. Maynard; Jun Yuan; John M. Peterson
Original assignee: Neurogen Corporation
Priority date: 2003-12-19
Filing date: 2004-12-17
Publication date: 2005-07-07
Also published as: WO2005061462A3

Abstract

The invention relates to compounds of general Formula (I) wherein the variables are as defined herein. Pharmaceutical compositions comprising compounds of general Formula (I), and methods for treating patients suffering from a disorder responsive to neurokinin-3 receptor modulation are also provided. Compounds provided herein are also useful as probes for the localization of NK-3 receptors.

Description

NEUROKL I -3 RECEPTOR MODULATORS: DIARYL PYRAZOLE DERIVATIVES

FIELD OF THE INVENTION This invention relates generally to certain diaryl pyrazole derivatives, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment of certain diseases and disorders that are responsive to NK-3 receptor modulation. Compounds provided herein are further useful as probes for the localization of NK-3 receptors.

BACKGROUND The tachykinins are a family of structurally related peptides originally isolated based upon their smooth muscle contractile and sialogogic activity. These mammalian peptides include substance P (SP), neurokinin (neurokinin A; NKA) and neurokinin β (neurokinin B; NKB). Tachykinins are synthesized in the central nervous system (CNS) and in peripheral tissues, where they exert a variety of biological activities. Three receptors for the tachykinin peptides have been characterized and are referred to as neurokinin- 1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3) receptors. The^'NK-l receptor has a natural agonist potency profile of SP>NKA>NKB. The NK-2 receptor agonist potency profile is NKA>NKB>SP, and the NK-3 receptor agonist potency profile is NKB>NKA>SP. Each of the three receptors mediates a variety of tachykinin-stimulated biological effects, including 1) modulation of smooth muscle contractile activity, 2) transmission of (generally) excitatory neuronal signals in the CNS and periphery (e.g., pain signals), 3) modulation of immune and inflammatory responses, 4) induction of hypotensive effects via dilation of the peripheral vasculature, and 5) stimulation of endocrine and exocrine gland secretions. These receptors transduce intracellular signals via the activation of pertussis toxin-insensitive (G_αq/n) G proteins, resulting in the generation of the intracellular second messengers mositol 1,4,5-trisphosyphate and diacylglycerol. NK-1 receptors are expressed in a wide variety of peripheral tissues and in the CNS. NK-2 receptors are expressed primarily in the periphery, while NK-3 receptors are primarily (but not exclusively) expressed in the CNS, including the human brain. NK-3 receptor antagonists show considerable potential for treating a variety of CNS and peripheral disorders. In the CNS, activation of NK-3 receptors has been shown to modulate dopamine and serotonin release, indicating therapeutic utility in the treatment of disorders such as anxiety, depression, schizophrenia, and obesity. Further, studies in primate brain detect the presence of NK-3 mRNA in a variety of regions relevant to these disorders. With regard to obesity, it has also been shown that NK-3 receptors are located on melanin concentrating hormone-containing neurons in the rat lateral hypothalamus and zona incerta. hi the periphery, administration of NKB into the airways is known to induce mucus secretion and bronchoconstriction, indicating therapeutic utility for NK-3 receptor antagonists in the treatment of patients suffering from airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Localization of NK-3 receptors in the gastrointestinal (Gϊ) tract and the bladder indicates therapeutic utility for NK-3 receptor antagonists in the treatment of GI and bladder disorders including inflammatory bowel disease and urinary incontinence. Both peptide and nonpeptide antagonists have been developed for each of the tachykinin receptors. Peptide antagonists for the tachykinin receptors have been characterized by low potency, partial agonism, poor metabolic stability and toxicity, but non-peptide antagonists have been found to display more drug-like properties. Unfortunately, non-peptide NK-3 receptor antagonists have suffered from other disadvantages including species selectivity, which limits the evaluation of these compounds in appropriate disease models. There is thus a need for new non-peptide NK-3 receptor antagonists for use as therapeutic agents, and as tools to investigate the anatomical and ultrastructural distribution of NK-3 receptors, as well as the physiologic and pathophysiologic consequences of NK-3 receptor activation. The present invention fulfills this need, and provides further related advantages. SUMMARY OF THE INVENTION The present invention provides diaryl pyrazole derivatives that are characterized by the formula: Formula I

or are a pharmaceutically acceptable salt of such a compound. Within Formula I,

X is N(R₃a) or C(R_3a)(R₃b);

Ari is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl (or a 6- to 10-membered heteroaryl), each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₃ is (6- to 10-membered aryl)Co-C₄alkyl, (5- to 10-membered heteroaryl)Co-C alkyl or phenoxyC₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro and oxo; (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R_3a or R_3b to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ri is: (i) hydrogen or halogen; or (ii) Ci-C₆alkyl, Ci-C₆alkoxy, or mono- or di-(Ci-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R₂ is: (i) hydrogen, Ci-C₆alkyl, or Cι-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from R ; or (ii) taken together with R_3a or R₃ to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R_3a and R₃b are: (i) independently (a) hydrogen; (b) d-Csalkyl, -Csalkenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; O II

L is independently selected at each occurrence from a bond, O, C(=O) (i.e., ^~c~~ ), OC(=O) 0 O O O (i.e., -0-C- ), C(=O)O(t.e., -C-0-), O-C(=O)O (i.e., -0-C-O-), S(O)_m (i.e., -S-, -S- or

-),

N(R_x)S(O)_m (e.^ -N-S-), S(O)_mN(R_x) (e.g-., -S-N- ) and N[S(O)_mR_x]S(O)_m

(e.g., ^~N— s— ); 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; M is independently selected at each occurrence from: (i) hydrogen; and (ii) Ci-C₈alkyl, C₂- alkenyl, C₂-C₈all:ynyl, phenylC₀-C₆alkyl and (3- to 10-membered heterocycle)Co- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b; and R_b is independently chosen at each occurrence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Ci-Cealkyl, Cι-C₆alkenyl, Ci-C₆alkynyl, haloCι-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-C₈alkyl, Ci-C₆alkoxy, haloCi- alkoxy, Cι-C₆alkanoyl, C - C₆alkoxycarbonyL C -C₆alkanoyloxy, Ci-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(Ci -C₆alkyl)aminoCo-C₆alkyl. In one class of compounds of Formula I: (i) if Ri is hydrogen or halogen, then at least one of R and R _a is not hydrogen and Ar is not 2-bromo-4-fluoro-phenyl; (ii) if Ri is hydrogen or methyl and R₂ is hydrogen, then R_3a is not hydrogen, methyl or ethyl; and (iii) if X is C(R_3a)(R_3b) and R_l5 R_3a and R_3b are each hydrogen, then R₃ is not benzyl. In another class of compounds, Ri is: (i) halogen; or (ii) C₂-C₆alkyl, Ci-C₆alkoxy, or mono- or di-(Cι- C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M. Within certain aspects, methods are provided herein for using one or more compounds provided herein to treat a patient suffering from a condition that is responsive to NK-3 receptor modulation. Such conditions include certain central nervous system and peripheral diseases or disorders including, but not limited to anxiety, depression, psychosis, obesity, chronic pulmonary obstructive disorder, gastrointestinal conditions such as irritable bowel syndrome or colitis, pain, and cognitive disorders (e.g., cognition impairment, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), traumatic brain injury, Down's Syndrome, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, stroke, ADDS associated dementia, and dementia associated with depression, anxiety and psychosis (including schizophrenia and hallucinatory disorders). Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from such conditions with a therapeutically effective amount of a compound provided herein is contemplated by the present invention. Within further aspects, the present invention provides pharmaceutical compositions comprising one or more compounds provided herein. Packaged pharmaceutical compositions including instructions for use of the composition to treat a condition that is responsive to CB1 or NK-3 receptor modulation are also provided. In a separate aspect, the present invention provides methods for potentiating the action of other CNS active compounds. Such methods comprise administering to a patient a therapeutically effective amount of a compound provided herein in combination with another CNS active compound. In further aspects, methods are provided herein for using one or more compounds provided herein to treat a patient suffering from a condition that is responsive to CB1 modulation. Such conditions include appetite disorders, obesity, addictive disorders, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders and movement disorders. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from such conditions with a therapeutically effective amount of a compound provided herein is contemplated by the present invention. In a related aspect, methods are provided for suppressing appetite in a patient, comprising administering to the patient an appetite reducing amount of at least one compound provided herein. Within other aspects, methods are provided for identifying an agent that binds to NK- 3 receptor, comprising: (a) contacting NK-3 receptor with a radiolabeled compound or salt as described above, under conditions that permit binding of the compound or salt to NK-3 receptor, thereby generating bound, labeled compound; (b) detecting a signal that corresponds to the amount of bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and (e) detecting a decrease in signal detected in step (d), as compared to the signal detected in step (b). The present invention provides, within still further aspects, methods for determining the presence or absence of NK-3 receptor in a sample, comprising the steps of: (a) contacting a sample with a compound or salt as described above, under conditions that permit binding of the compound to NK-3 receptor; and (b) detecting a level of the compound bound to NK- 3 receptor. The sample may be, for example, a tissue section. The present invention further provides methods for using the compounds described herein as positive controls in assays for NK-3 receptor activity.

DETAILED DESCRIPTION OF THE INVENTION As noted above, the present invention provides diaryl pyrazole derivatives of Formula I, including the pharmaceutically acceptable salts of such compounds, hi certain aspects, such compounds are NK-3 receptor modulators and may be used in vivo or in vitro to modulate NK-3 receptor activity in a variety of contexts.

TERMINOLOGY Compounds 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, h 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., Ari, Ri). 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. A "pharmaceutically acceptable salt" is an acid or base salt form of a compound, which salt form is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without 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-(CH )_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, EtOAc, EtOH, isopropanol or acetonitrile, is preferred. It will be apparent that each compound of Formula I may, but need not, be formulated as a hydrate, solvate or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention. Also provided herein are prodrugs of the compounds of Formula I. 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, or other formula provided herein. 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 hydroxy, 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 in vivo to yield the parent compounds. 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 substituent 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. When a substituent is oxo (i.e., =O), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted with an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example, a pyridyl group substituted with oxo is a pyridone. The phrase "optionally substituted" indicates that a group may either be unsubstituted or substituted at one or more of any of the available positions, typically 1, 2, 3, 4, or 5 positions, by one or more suitable substituents such as those disclosed herein. Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," in which X is the maximum number of substituents. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(=O)NH is attached through the carbon atom. 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 (Ci-C₈alkyl), from 1 to 6 carbon atoms (Cι-C₆alkyl), and from 1 to 4 carbon atoms (Ci-C₄alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, ^ec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cycloheptyl and norbornyl. "C₀-C₄alkyl" refers to a bond or an alkyl group having 1, 2, 3, or 4 carbon atoms; "Co-C₆alkyl" refers to a bond or a Ci-C₆alkyl group; "Co-C₈alkyl" refers to a bond or a Cι-C₈alkyl group, hi 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, "cyanoCι-C₄alkyl" refers to a Ci-C 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 C -C₄alkenyl 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-C₄alkynyl 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. The term "alkylene" refers to a divalent alkyl group. By "alkoxy," as used herein, is meant an alkyl group as described above attached via an oxygen bridge. Alkoxy groups include Ci-C₈alkoxy, Ci-C₆alkoxy, and Ci-C alkoxy 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-hexoxy, 3- hexoxy, and 3-methylpentoxy. Similarly, "alkylthio" refers to an alkyl group as described above attached via a sulfur 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=O)-H, which (along with C₂-C₈alkanoyl) is encompassed by the term "Ci-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-C alkanone" 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, "alkylether" refers to a linear or branched ether substituent linked via a carbon-carbon bond. Alkylether groups include C₂-C₈alkylether, C₂-C₆alkylether, and C - C₄alkylether groups, which have 2 to 8, 6, or 4 carbon atoms, respectively. By way of example, a C₂ alkylether group has the shiicture -CH₂-O-CH₃. A representative branced alkylether substituent is -C(CH₃)₂CH₂-O-CH₃. The term "alkoxycarbonyl" refers to an alkoxy group linked via a carbonyl (i.e., a group having the general structure -C(=O)-O-alkyι). 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 " C i -C₈ alkoxycarbonyl. " "Alkanoyloxy," as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure -O-C(=O)-alkyl). Alkanoyloxy groups include C₂-C₈, C₂-C₆ and C -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-(Ci-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-(d- C₆alkyl)amino groups and mono- and di-(Ci-C₄alkyl)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-(d- C₈alkyl)aminoCi-C₈alkyl, mono- and di-(Ci-C₆alkyl)aminoCi-C₆alkyl and mono- and di-(Cι- C₄allcyl)aminoCι-C₄alkyl, in which each alkyl may be the same or different. "Mono- or di- (Ci-C₆alkyl)aminoCo-C₆alkyl" refers to a mono- or di-(Ci-C₆alkyl)amino group linked via a direct bond or a Ci-C₆alkyl group. The following are representative alkylaminoalkyl groups:

The term "aminocarbonyl" refers to an amide group (i.e., -(C=O)NH₂). 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., "haloCi-C₈alkyl" groups have from 1 to 8 carbon atoms; "haloCi- C₆alkyl" 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-, tetra- or penta-chloroethyl; and 1,2,2,2- teu-afluoro-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. "Halod-C₈alkoxy" groups have 1 to 8 carbon atoms. 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., C -C₈); C₅-C₇ 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 only 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-Cioaryl)C₀-C₄alkyl (i.e., groups in which a carbocyclic group comprising at least one aromatic ring is linked via a direct bond or a d- 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 d-C₄alkyl. Phenyl groups linked via a direct bond or alkyl group may be designated phenylC₀-C₄alkyl (e.g., benzyl, 1-phenyl-ethyl, 1-phenyl-propyl, and 2-phenyl-ethyl). If such a group is substituted, it will be apparent that substitution may occur on the aryl and/or alkyl portion. A phenylC₀- 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). PhenoxyC₀-C alkyl refers to a group of the structure:

wherein A is absent or Cι-C₄alkylene. 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 SO₂. 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, morpholinyl, 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, pyrroiyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, tliiazolyl, 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 "heterocycleC₀-C₈alkyl" is a heterocyclic group linked via a direct bond or d- C₈alkyl group. A (5- to 10-membered heterocycle)Co-C₄alkyl is a heterocyclic group having from 5 to 10 ring members linked via a direct bond or an alkyl group having from 1 to 4 carbon atoms. If the heterocycle is heteroaryl, the group is designated (5- to 10-membered heteroaryl)C₀-C₄alkyl. A (5- to 7-membered heterocycle)C₀-C alkyl is a 5- to 7-membered heterocyclic ring linked via a bond or a d-C₄alkyl group. If such a group is substituted, it will be apparent that substitution may occur on the heterocycle and/or alkyl portion. Certain heterocyclic groups are 3- to 8-membered, 5- to 10-membered, 6- to 10- membered, 4- to 7-membered or 5- to 8-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, pyrrolidinyl, azepanyl, morpholino, thiomorpholino and l,l-dioxo-thiomo holin-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. The term "NK-3 receptor" is used herein to refer to human neurokinin-3 receptor (see Huang et al. (1992) Biochem. Biophys. Res. Commun. 184:966-12; Regoli et al. (1994) Pharmacol. Rev. 46:551-99), as well as homologues thereof found in other species. A "NK-3 receptor modulator," also referred to herein as a "modulator," is a compound that modulates NK-3 receptor activation and/or NK-3-mediated signal transduction. NK-3 receptor modulators specifically provided herein are compounds of Formula I and pharmaceutically acceptable salts of such compounds. A NK-3 receptor modulator may be a NK-3 receptor agonist or antagonist. A modulator binds with "high affinity" if the K; at NK-

3 receptor is less than 1 micromolar, preferably less than 500 nanomolar, 100 nanomolar, or 10 nanomolar. A representative assay for determining Kj at NK-3 receptor is provided in Example 4, herein. A modulator is considered an "antagonist" if it detectably inhibits NK-3 ligand (e.g., neurokinin) binding to NK-3 receptor and/or NK-3 receptor-mediated signal transduction (using, for example, the representative assays provided in Example 5); in general, such an antagonist inhibits NK-3 receptor activation with a IC₅₀ value of less than 1 micromolar, preferably less than 500 nanomolar, and more preferably less than 100 nanomolar or 10 nanomolar within the assay provided in Example 5. NK-3 receptor antagonists include neutral antagonists and inverse agonists. An "inverse agonist" of NK-3 receptor is a compound that reduces the activity of NK- 3 receptor below its basal activity level in the absence of added NK-3. Inverse agonists of NK-3 receptor may also inhibit the activity of neurokinin at NK-3 receptor, and/or may also inhibit binding of neurokinin to NK-3 receptor. The ability of a compound to inhibit the binding of neurokinin to NK-3 receptor may be measured by a binding assay, such as the binding assay given in Example 4. The basal activity of NK-3 receptor, as well as the reduction in NK-3 receptor activity due to the presence of NK-3 inverse agonist, may be determined from a calcium mobilization assay, such as the assay of Example 5. A "neutral antagonist" of NK-3 receptor is a compound that inhibits the activity of NK-3 at NK-3 receptor, but does not significantly change the basal activity of the receptor (i.e., within a calcium mobilization assay as described in Example 5 perfonned in the absence of NK-3, receptor 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 NK-3 receptor may inhibit the binding of NK-3 to the receptor. As used herein a "NK-3 receptor agonist" is a compound that elevates the activity of the receptor above the basal activity level of the receptor (i.e., enhances NK-3 receptor activation and/or NK-3 mediated signal transduction). NK-3 receptor agonist activity may be identified using the representative assay provided in Example 5. hi general, such an agonist has an EC₅₀ value of less than 1 micromolar, preferably less than 500 nanomolar, and more preferably less than 100 nanomolar within the assay provided in Example 5. A "therapeutically effective amount" (or dose) is an amount that, upon administration to a patient, results in a discernible patient benefit. Such an amount or dose generally results in a concentration of compound in a body fluid (e.g., blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to inhibit the binding of NK-3 receptor ligand to NK-3 in vitro, as determined using the assay described in Example 4. It will be apparent that the therapeutically effective amount for a compound will depend upon the indication for which the compound is administered, as well as any co-administration of other therapeutic agent(s). The patient benefit may be detected using any appropriate criteria, including alleviation of one or more symptoms. It will be apparent that the patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a prescribed regimen, depending upon the indication for which the compound is administered. A "patient" is any individual treated with a compound of Formula I 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 NK-3 receptor modulation (e.g., anxiety, depression, psychosis, obesity, chronic pulmonary obstructive disorder, gastrointestinal conditions such as irritable bowel syndrome or colitis, pain and cognitive disorders as described herein), or may be free of such symptom(s) (i.e., treatment may be prophylactic).

DIARYL PYRAZOLE DERIVATIVES As noted above, the present invention provides compounds of Fonnula I, with the variables as described above, as well as pharmaceutically acceptable salts of such compounds. Formula I

Certain preferred compounds are NK-3 receptor antagonists and have no detectable agonist activity in the assay described in Example 5. Preferred compounds further bind with high affinity to NK-3 receptor. Certain compounds of Formula I further satisfy Formula la:

Formula la

Within Formulas I and la, R_3a and R_3b are generally as described above. In certain embodiments, at least one of R₂ and R_3a is not hydrogen; in certain compounds R _a is not hydrogen; and in further such compounds R_3a is not hydrogen or methyl, hi certain compounds, R_3a is d-C₈alkyL d-C₈alkenyl, C₃-C₈cycloalkylCo-C₄alkyl, or phenylCo- C₂alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy and cyano; in certain embodiments thereof, R _a is d-C alkyl. R _b, in certain compounds, is hydrogen. Within other compounds, R_3b is hydrogen, methyl or ethyl, and R_3a is phenyl, benzyl or C₂-C₆alkyl that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, and 5- and 6-membered heterocycles. Within still further compounds, R_3b is hydrogen and R_3a is taken together with a substituent of Ar₃ to form an optionally substituted, fused 6- or 7-membered carbocycle or heterocycle. For example, the group:

, wherein W is CH₂, NH, O or S, m certain representative compounds. Alternatively, R_3a and R_3b may be taken together to form a spiro 5- to 7-membered carbocycle. Ri, in certain compounds of Formulas I and la, is hydrogen, halogen, Ci-C₄alkyl, haloCι-C₄alkyl, Ci-C₄alkoxy, or d-C₄alkoxy substituted with hydroxy, halogen or a 5- to 7- membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, oxo, and Cι-C₄alkyl. Representative Ri groups include halogen, Ci-C alkyl, d-C₄alkoxy, d-C alkoxy substituted with hydroxy, or alkoxy substituted with a 5- or 6-membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1 or 2 substituents independently chosen from Ci-C₄alkyl. R₂, in certain compounds of Formulas I and la, is hydrogen, Cι-C alkyl, or d- Qalkenyl. hi other such compounds, R₂ is hydrogen. In further such compounds, R₂ is taken together with R _a or a substituent of Ar₃ to form a 5- to 7-membered heterocycloalkyl. Certain compounds of Formula I and la further satisfy Formula II, or are a pharmaceutically acceptable salt thereof:

Formula π

wherein:

R and R₅ each represent 0, 1, or 2 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₆alkyl, d-C₆alkenyl, haloCι-C₆alkyl, hydroxyd-Cβalkyl, cyanoCi- C₆alkyl, and d-C₆alkoxy; and R₆ represents 0, 1, or 2 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₈alkyl, d-dalkenyl, halod-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-C₆alkyl, Ci-C₆alkoxy, and phenyl. Certain compounds of Formula I further satisfy Formula IH, or are a pharmaceutically acceptable salt thereof: ^R3a R_3b ^Ars _N,R₂ ° Fonnula m

Within Formula HI:

Ari and Ar₂ are independently chosen from 6- to 10-membered aryl and 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

(i) halogen; or (ii) C₂-C₆alkyl, Ci-C₆alkoxy or mono- or di-(Cι-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; and Ar_3j R₂, R_3a, R_3b, L, M and R_b are as described for Formula I. In certain compounds, R_3b is d-C₈alkyl, Cι-C₈alkenyl, C3-C₈cycloalkylC₀-C alkyl, or phenylC₀-C₂alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy and cyano; in certain embodiments thereof, R_3b is Cι-C alkyl. R_3a, in certain compounds, is hydrogen. Within other compounds, R₃ is hydrogen, methyl or ethyl, and R_3a is phenyl, benzyl or C₂-C₆alkyl that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano and 5- and 6-membered heterocycles. Within still further compounds, R_3a is hydrogen and R_3b is taken together with a substituent of Ar₃ to form an optionally substituted, fused 6- or 7-membered carbocycle or heterocycle. For example, the group:

, wherein W is CH , NH, O, or S, in certain representative compounds. Alternatively, R_3a and R_3b may be taken together to form a spiro 5- to 7-membered carbocycle. Ri, in certain compounds of Fonnula m, is halogen, C₂-C₆alkyl, halod-C₄alkyl, d- C₄alkoxy, d-C alkoxy substituted with hydroxy, Cι-C₄alkoxy substituted with halogen, or d-C alkoxy substituted with a 5- to 7-membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, oxo, and Ci-C₄all yl. Representative Ri groups include halogen, ethyl, propyl, isopropyl, butyl, d- C₄alkoxy, and d-C₄alkoxy substituted with hydroxy or a 5- or 6-membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1, or 2 substituents independently chosen from d-C₄alkyl. R₂, in certain compounds of Formula DI, is hydrogen, Ci-C₄alkyl or d-C alkenyl. In other such compounds, R₂ is taken together with R_3a or a substituent of Ar₃ to form a 5- to 7- membered heterocycloalkyl. Certain compounds of Formula I further satisfy Formula IV, or are a pharmaceutically acceptable salt thereof:

Formula IV

Within Formula IV:

R₂ is: (i) Ci-C₆alkyl or Cι-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from R ; (ii) taken together with R₃ to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to - 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; and

Aτ_3; R₂, R_3a, R_3b, L, M and R_b are as described for Formula I. Ri, in certain compounds of Fonnula TV, is hydrogen, halogen, Cι-C₄alkyl, halod-

C₄alkyl, d-C₄alkoxy or d-C₄alkoxy substituted with hydroxy, halogen or a 5- to 7- membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, oxo, and d-C₄alkyl. Representative Ri groups include hydrogen, halogen, Cι-C alkyl, d-C₄alkoxy, d-C alkoxy substituted with hydroxy, or C₁-ⁱC alkoxy substituted with a 5- or 6-membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1, or 2 substituents independently chosen from d-C₄alkyl. R₂, in certain compounds of Formula TV, is d-C₄alkyl or Cι-C₄alkenyl. In other such compounds, R₂ is taken together with R_3a or a substituent of Ar₃ to form a 5- to 7-membered heterocycloalkyl. In certain compounds of Formula TV, R_3a and R_3b are independently chosen from hydrogen, phenyl, benzyl, and Cι-C₆alkyl that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, and 5- and 6-membered heterocycles. For example, in representative compounds of Formula lb, R_3b is hydrogen, methyl or ethyl and R _a is taken together with a substituent of Ar₃ to form a fused 5- to 7-membered carbocycle or heterocycle. hi other such compounds, R_3a and R_3b are taken together to form a spiro 5- to 7-membered carbocycle. h each Formula provided herein, Ari, Ar , and Ar₃ are generally as described above. In certain compounds, Ari and Ar₂ are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Ci-C₆alkyl, d-C₆alkenyl, halod-C₆alkyl, hydroxyd- C₆alkyl, cyanod-C₆alkyl and d-C₆alkoxy. For example, Ari and Ar₂ are, within certain such compounds, independently phenyl or pyridyl, substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, d-C₄alkyl, halod-C₄alkyl, hydroxyCι-C₄alkyl, cyanod-C₄alkyl, and d-C₄alkoxy. In further such compounds, Ari and Ar₂ are independently chosen from phenyl that is substituted with from 0 to 2 substituents independently chosen from halogen, cyano, d-C₄alkyl, haloCι-C₄alkyl and d-C₄alkoxy. Ar , in certain compounds of the above Formulas, is phenylCo-C alkyl, pyridylCo- C₄alkyl or phenoxyC₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₈alkyl, Cι-C₆alkenyl, haloCi-C₆alkyl, hydroxyd-Cealkyl, cyanoCi-C₆alkyl, d-C₆alkoxy and phenyl. Representative Ar₃ groups include, for example, phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl and phenoxymethyl, each of which is substituted with 0, 1, 2 or 3 substituents independently chosen from halogen, d-C₈alkyl, halod-C₄alkyl, d-C₄alkoxy and phenyl. Representative compounds of Formula I, 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 salt. NK-3 receptor modulators provided herein detectably alter (modulate) NK-3 receptor activity, as determined using an in vitro NK-3 receptor ligand binding assay (Example 4) and/or a functional assay such as a calcium mobilization assay (Example 5; also referred to herein as a "signal transduction assay"). Briefly, to assess binding to NK-3 receptor, a competition assay may be performed in which a NK-3 receptor preparation is incubated with labeled (e.g., ¹²⁵I or ³H) compound that binds to NK-3 receptor (e.g., a NK-3 receptor agonist such as neurokinin B or a variant thereof) and unlabeled test compound. Within the assays provided herein, the NK-3 receptor used is preferably mammalian, more preferably human or rat NK-3 receptor. The receptor may be recombinantly expressed or naturally expressed. The NK-3 receptor preparation may be, for example, a membrane preparation from HEK293 or CHO cells that recombinantly express human NK-3 receptor. Incubation with a compound that detectably modulates ligand binding to NK-3 receptor results in a decrease or increase in the amount of label bound to the NK-3 receptor preparation, relative to the amount of label bound in the absence of the compound. This decrease or increase may be used to determine the K; at NK-3 receptor as described herein. In general, compounds that decrease the amount of label bound to the NK-3 receptor preparation within such an assay are preferred. As noted above, compounds that are NK-3 receptor antagonists are preferred within certain embodiments. IC₅₀ values for such compounds may be determined using a standard in vitro NK-3 receptor-mediated calcium mobilization assay, as provided in Example 5. Briefly, cells expressing NK-3 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 Ca^"1"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 NK-3 receptor agonist (e.g., neurokinin B or an analog thereof), 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 NK-3 receptor 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 Ido for NK-3 receptor antagonists provided herein is preferably less than 1 micromolar, less than 500 nM, less than 100 nM or less than 10 nM. In other embodiments, compounds that are NK-3 receptor agonists are prefened. When cells are contacted with 1 micromolar of a compound that is a NK-3 receptor agonist, the fluorescence response is generally increased by an amount that is at least 30% of the increase observed when cells are contacted with neurokinin B. The EC₅₀ or NK-3 receptor agonists provided herein is preferably less than 1 micromolar, less than 100 nM or less than 10 nM. Preferred compounds provided herein are non-sedating, hi other words, a dose of compound that is twice the minimum dose sufficient to provide a therapeutic effect, causes only transient (i.e., lasting for no more than Vz the time that the therapeutic effect 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 therapeutic effect does not produce statistically significant sedation. More preferably, compounds provided herein do not produce sedation at intravenous doses of 10 mg/kg or 25 mg/kg, or at oral doses of 30 mg kg, 50 mg kg or 140 mg/kg. In certain embodiments, preferred compounds provided herein have favorable pharmacological properties, including oral bioavailability (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose, preferably less than 2 grams, more preferably less than or equal to one gram or 200 mg, can provide a detectable in vivo effect), low toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), minimal side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), low serum protein binding, and a suitable in vitro and in vivo half-life (a prefened compound exhibits 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). 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, such as 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, such as those described by Oravcova, et al. (1996) Journal of Chromatography B 677:1-27. Compound half-life is inversely proportional to the required frequency of dosage. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described within Example 6, herein. As noted above, preferred compounds provided herein are nontoxic. hi 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 prefened nontoxic compound generally satisfies one or more of the following criteria when administered at a minimum therapeutically effective amount or when contacted NK-3 receptor in vitro: (1) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement or (4) does not cause substantial release of liver enzymes. As used herein, a compound that does not substantially inhibit cellular ATP production is a compound that, when tested as described in Example 7, does not decrease cellular ATP levels by more than 50%. Preferably, cells treated as described in Example 7 exhibit ATP levels that are at least 80% of the ATP levels detected in untreated cells. Highly prefened compounds are those that do not substantially inhibit cellular ATP production when the concentration of compound is at least 10-fold, 100-fold or 1000-fold greater than the EC₅₀ or IC5Q for the compound. A compound 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 a dose that yields a serum concentration equal to the EC₅₀ or IC₅₀ for the compound. 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 compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5-10 days with a dose that yields a serum concentration equal to the EC5₀ or IC₅₀ for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls, h 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. Prefened 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 compound does not promote substantial release of liver enzymes if administration of a dose that yields a serum concentration equal to the EC₅₀ or IC₅₀ for the compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 3 -fold (preferably no more than 2-fold) over matched mock-treated controls. In more highly prefened embodiments, such doses do not elevate such serum levels by more than 75% or 50%) over matched controls. Alternately, a compound 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) concentrations that are equal to the EC₅₀ or IC₅₀ for 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, hi more highly prefened embodiments, there is no detectable release of any of such liver enzymes into culture medium above baseline levels when such compound concentrations are two-fold, five-fold, and preferably ten-fold the EC₅₀ or IC₅₀ for the compound. In other embodiments, certain preferred compounds 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 EC₅₀ or IC₅₀ for the compound. Certain prefened compounds are not clastogenic or mutagenic (e.g., as determined using standard assays such as the Chinese hamster ovary cell vitro micronucleus assay, the mouse lymphoma assay, the human lymphocyte chromosomal abenation assay, the rodent bone marrow micronucleus assay, the Ames test or the like) at a concentration equal to the EC₅₀ or IC₅₀ for the compound. In other embodiments, certain prefened compounds do not induce sister cliromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations. For detection purposes, as discussed in more detail below, compounds provided herein may be isotopically-labeled or radiolabeled. For example, compounds recited in Formulas I-m 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, ^πC, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶C1. In addition, substitution with heavy isotopes such as deuterium (i.e., ²H) can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements and, hence, may be prefened in some circumstances.

PREPARATION OF COMPOUNDS Compounds provided herein 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 the following Schemes may be used, together with synthetic methods lαiown 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 Formulas I herein. Where a structure contains more than one variable "R," each R is selected independently of any other R group(s). Those skilled in the art will recognize that in certain instances it will be necessary to utilize compounds bearing protecting groups and that these groups can be removed in a subsequent reaction to yield compounds of Formula I as described in "Protective Groups in Organic Synthesis", 2nd Ed., Greene, T. W. and related publications. Abbreviations used in the following Schemes and elsewhere herein include: BOP benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate

CDCI₃ deuterated chloroform

DCE 1,2-dichloroethane

DMA N,N-dimethylacetamide

DMF N,N-dimethylformamide

Et₃N triethylamine

EtOAc ethyl acetate

HOAc acetic acid

HPLC high pressure liquid chromatography

1H NMR proton nuclear magnetic resonance

Hz hertz

LC-MS liquid chromatography/mass spectrometry

MeOH methanol

MS mass spectrometry

M+l mass + 1

NaOMe sodium methoxide

PPI1₃ triphenylphosphine

PTLC preparative thin layer chromatography

SPE solid phase extraction

TBS Tris-buffered saline

THF tetrahydrofuran

TLC thin layer chromatography Scheme 1

hi step 1 of Scheme 1, diaryl hydrazone 1 is condensed with β-ketoester 2 with heating in the presence of zinc chloride. This reaction is generally carried out without solvent in the presence of air. Hydrolysis of the resulting diaryl pyrazole ester 3 in step 2 yields carboxylic acid 4. Carboxylic acid 4 can be converted to amide derivatives by standard coupling strategies. For example, as shown in steps 3 and 4, carboxylic acid 4 is converted to acid chloride 4 and reacted with amine to produce diaryl pyrazole 6 according to Formula I.

R'l = alkyl iodides

Scheme 2 illustrates a method for preparing compounds of Formula I wherein Ri is alkoxy. h step 1, ketomalonate 7 is reacted with aryl hydrazine 8 in the presence of acetic acid to produce diaryl pyrazole 9. Step 2 involves regioselective alkyation of diaryl pyrazole 9 to obtain alkyoxypyrazole 10. Depending on the choice of alkylating agent and reaction conditions variable amounts of N-alkyation vs O-alkylation is obtained in step 2. Prefonning the oxyanion using a cesium carbonate in DMF followed by alkyation with a reactive alkylating agent such as methyl iodide favors formation of the desired O-alkyated product. Alternatively, treatment of 9 with sodium hydride in THF followed by dimethylsulfate provides O-alkylated product 10. Steps 3 and 4 involve ester hydrolysis and coupling with amine as described in Scheme 1 to provide pyrazole 12 according to Formula I. In certain embodiments, a compound provided herein 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., ¹⁴C), hydrogen (e.g., ³H), sulfur (e.g., ³⁵S), or iodine (e.g., ¹²⁵I). 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 compounds provided herein, 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, hi 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 prefened. 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. Fonnulation for topical administration may be prefened for certain conditions. 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, polyvinylpynolidone, 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, such as 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 fonnulation. 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. 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 compound of Formula I, 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, hi 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. Compounds 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 compound 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 compound release. The amount of compound 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. h addition to, or together with, the above modes of administration, a compound of Formula I 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. Compounds provided herein are generally present within a pharmaceutical composition in a therapeutically effective amount, as described above. Compositions providing dosage levels ranging from about 0.1 mg to about 140 mg per kilogram of body weight per day are prefened (about 0.5 mg to about 7 g per human patient 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 form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the optimal dose 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 and diet of the patient; the time and route of administration; the rate of excretion; any simultaneous treatment, such as a drug combination; and the type and severity of the particular disease undergoing treatment. 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 NK-3 receptor modulation (e.g., treatment or psychosis, schizoprenia, depression, or chronic pulmonary obstructive disorder). Packaged pharmaceutical compositions may include a container holding a therapeutically effective amount of at least one compound described herein and instructions (e.g., labeling) indicating that the contained composition is to be used for treating a condition responsive to NK-3 receptor modulation in the patient. METHODS OF USE Compounds provided herein may be used to alter activity and/or activation of NK-3 receptors in a variety of contexts, both in vitro and in vivo. Within certain aspects, NK-3 receptor antagonists may be used to inhibit the binding of NK-3 receptor agonist (such as neurokinin) to NK-3 receptor in vitro or in vivo. In general, such methods comprise the step of contacting a NK-3 receptor with one or more compounds provided herein in the presence of NK-3 receptor ligand in aqueous solution and under conditions otherwise suitable for binding of the ligand to NK-3 receptor. The NK-3 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 NK-3 receptor is expressed by a neuronal cell present in a patient, and the aqueous solution is a body fluid. Preferably, one or more NK-3 modulators are administered to an animal in an amount as described above. Also provided herein are methods for modulating, preferably inhibiting, the signal- transducing activity of a NK-3 receptor. Such modulation may be achieved by contacting a NK-3 receptor (either in vitro or in vivo) with a one or more compounds provided herein under conditions suitable for binding of the compound(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 refened to as calcium mobilization or flux). Modulation of signal transducing activity may alternatively be assessed by detecting an alteration of a symptom of a patient being treated with one or more compounds provided herein. The present invention further provides methods for treating conditions responsive to NK-3 receptor 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 NK-3 receptor modulation" if it is characterized by inappropriate activity of a NK-3 receptor, regardless of the amount of NK-3 receptor ligand present locally, and/or if modulation of NK-3 receptor activity results in alleviation of the condition or a symptom thereof. Such conditions include, for example, anxiety, depression, psychosis, obesity, chronic pulmonary obstructive disorder, gastrointestinal conditions such as irritable bowel syndrome or colitis, pain and cognitive disorders (e.g., cognition impairment, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), traumatic brain injury, Down's Syndrome, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, stroke, AIDS associated dementia, and dementia associated with depression, anxiety and psychosis (including schizophrenia and hallucinatory disorders). Such conditions may be diagnosed and monitored using criteria that have been established in the art. Patients include humans, domesticated companion animals and livestock, with dosages as described above. Also provided herein are methods for using diaryl pyrazoles of Formula I to treat a condition responsive to cannabinoid receptor (especially CB1) modulation in a patient. The patient may be afflicted with such a condition, or may be considered at risk for developing such a condition. A condition is "responsive to CB1 modulation" if the condition or symptom(s) thereof are alleviated, attenuated, delayed or otherwise improved by modulation of CB1 activity. Such conditions include, for example, appetite disorders, obesity, addictive disorders, asthma, liver cinhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders and movement disorders. Methods are further provided herein for appetite suppression, h general, methods for treating such conditions comprise administering to the patient a therapeutically effective amount of at least one compound according to Formula I. It will be apparent that compounds provided herein may be administered alone or in combination with one or more additional agents that are suitable for treating the disorder of interest. Within combination therapy, the compound(s) of Formula I and additional agent(s) may be present in the same pharmaceutical composition, or may be administered separately in either order. Representative additional agents are as described above. Suitable dosages for compounds provided herein within such combination therapy are generally as described above. Dosages and methods of administration of the additional agent(s) can be found, for example, in the manufacturer's instructions or in the Physician's Desk Reference. In certain embodiments, combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect (i.e., a decrease in the minimum therapeutically effective amount). Thus, preferably, the dosage of additional 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 agent without combination with a compound of Formula I. More preferably this dose is less than %, even more preferably less than Vz, 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 agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound of Formula I needed to achieve the desired effect may similarly be affected by the dose and potency of the additional agent. hi certain preferred embodiments, the combination administration is accomplished by packaging one or more compounds provided herein and one or more additional agents in the same package, either in separate containers within the package or in the same container as a mixture. Prefened mixtures are formulated for oral administration (e.g., as pills, capsules, tablets or the like), i certain embodiments, the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of anxiety, depression, schizophrenia, psychosis, chronic pulmonary obstructive disorder, irritable bowel syndrome, colitis, pain, an appetite disorder, obesity or an addictive disorder. Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal administration, or intravenous, intramuscular, subcutaneous, intrathecal, epidural, intracerebroventrilcular or like injection. Oral administration is prefened in certain embodiments (e.g., formulated as pills, capsules, tablets or the like). 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 prefened, with once a day dosing particularly prefened. 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 prefened. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented. 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 NK- 3 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 NK-3 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 NK-3 receptors in living subjects. For example, a compound provided herein 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 NK-3 receptor in the sample. Detection assays, including receptor autoradiography (receptor mapping) of NK-3 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) ohn Wiley & Sons, New York. Compounds provided herein may also be used within a variety of well known cell separation methods. For example, such compounds 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, NK-3 receptors (e.g., isolating receptor-expressing cells) in vitro. Within one prefened embodiment, a compound 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.

EXAMPLES

LC/MS data provided herein is obtained by the following method: Analytical HPLC/MS instrumentation: Analyses are performed using a Waters 600 series pump (Waters Corporation, Milford, MA), a Waters 996 Diode Array Detector and a Gilson 215 auto-sampler (Gilson ie, Middleton, WI), Micromass® LCT time-of- flight electrospray ionization mass analyzer. Data are acquired using MassLynx^™ 4.0 software, with OpenLynx Global Server™, OpenLynx™, and AutoLynx^™ processing. Analytical HPLC conditions: 4.6x50mm, Chromolith™ SpeedROD RP-18e column (Merck KGaA, Darmstadt, Germany); UV 10 spectra sec, 220-340mn summed; flow rate 6.0 mL/min; injection volume lμl; Gradient conditions - mobile phase A is 95% water, 5% methanol with 0.05% TFA; mobile phase B is 95% methanol, 5% water with 0.025%> TFA, and the gradient is 0-0.5 minutes 10-100% B, hold at 100%B to 1.2 minutes, return to 10 %B at 1.21 minutes inject-to-inject cycle time is 2.15 minutes. Analytical MS conditions: capillary voltage 3.5kV; cone voltage 30V; desolvation and source temperature are 350°C and 120°C, respectively; mass range 181-750 with a scan time of 0.22 seconds and an inter scan delay of 0.05 minutes. EXAMPLE 1. PREPARATION OF REPRESENTATIVE DIARYL PYRAZOLE DERIVATIVES

A. (S)-5 -Methyl- 1 -diphenyl-lH-pyrazole-4-carboxylic acid (1-phenyl-propyD-amide a. 5-Methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid ethyl ester

A mixture of N-benzylidene-N'-phenyl-hydrazine (20.4 mmol), ethyl acetoacetate (112 mmol) and catalytic anyhydrous zinc (II) chloride pellets is heated at 125°C with stirring under air for 3 hours. Volatiles are removed with heat and vacuum. The resulting residue is dissolved in EtOAc (120 mL), washed with 0.1 N HCl (50 mL x 2), cold 0.2 N NaOH (50 mL x 3), bring (40 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure. The resulting yellow viscous oil is mixed with 15 mL of absolute ethanol and cooled to form crystals. After standing overnight at room temperature, the crystals are collected by suction filtration and dried at 0.2 Ton/ 50°C to obtain 5-methyl-l,3-diphenyl-lH- pyrazole-4-carboxylic acid ethyl ester as a cream-colored solid. TLC (10% EtOAc/Hexanes) Rf= 0.28. LCMS M+H = 307.2.

b. 5-Methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid

5-Methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid ethyl ester (3.26 mmol) is suspended in 4:1 methanol/water (30 mL) under nitrogen with magnetic strrring and treated with sodium hydroxide (16.3 mmol). The mixture is heated at reflux for 3 hours to form a solution. The reaction mixture is cooled, evaporated at reduced pressure and partitioned between water (60 mL) and ether (20 mL). The aqueous layer is separated, washed with ether (20 mL), cooled to 5°C and adjusted to pH 3-4 using concentrated hydrochloric acid. The resulting suspension is extracted with dichloromethane (40 mL x 2) and the combined extracts are dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid as a white solid. TLC (5% MeOH/CH₂Cl₂/0.5% NH4OH) R_f = 0.46. MS M+H = 279.2.

c. 5-Methyl-l,3-diphenyl-lH-pyrazole-4-carbonyl chloride

To a solution of 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (2.87 mmol) in anhydrous dichloromethane (50 mL) under nitrogen with magnetic stirring at 0-5°C is added 2 drops of DMF followed by oxalyl chloride (3.45 mmol). The reaction mixture is allowed to warm to room temperature and stined for 30 minutes. The resulting solution is evaporated at reduced pressure and dried at 0.2 Ton for 1 hour to obtain 5-methyl-l,3-diphenyl-lH- pyrazole-4-carbonyl chloride as a yellow oil solid. TLC (20% EtOAc/Hexanes) Rf = 0.14.

d. (S)-5 -Methyl- 1, 3 -diphenyl-lH-pyrazole-4-carboxylic acid (l-phenyl-propyl)-amide

To a solution of 5-methyl-l,3-diphenyl-lH-pyrazole-4-carbonyl chloride (1.35 mmol) in anhydrous dichloromethane (30 mL) at 0-5°C under nitrogen with magnetic stirring is added Et₃N (4.04 mmol) followed by (S)-l-phenylpropylamine (1.62 mmol). After 30 minutes, the reaction mixture is evaporated at reduced pressure and partitioned between EtOAc (60 mL)/water (20 mL). The organic phase is separated, washed with saturated ammonium chloride solution (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a beige solid. This material is dissolved in diisopropyl ether and allowed to precipitate. The resulting white solid is collected by suction filtration and dried at 0.2 Ton/100°C to obtain the title compound. TLC (20% EtOAc/Hexanes) R_f = 0.16. . 5-Methyl- 3-diphenyl-lH-pyrazole-4-carboxylic acid (3 -hydroxy- l-phenyl-propyD-amide

A mixture of 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (1.0 g, 3.59 mmol), 3-amino-3-phenyl-propan-l-ol (0.6 g, 3.95 mmol), BOP (1.90 g, 4.31 mmol), Et₃N (0.73 g, 7.19 mmol) in DMF (5 mL) is stined at room temperature overnight. EtOAc and water are added to the mixture. The organic layer is separated and washed with brine and concentrated to yield the title compound as foam. 1H NMR (CDC1₃) 7.60-7.20 (m, 13H), 6.95 (d, 2H), 5.97 (m, IH), 5.25(m, IH), 3.62 (m, 2H), 2.60(s, 3H), 1.98 (m, IH), 1.60 (m, IH). LC-MS (QC): R_t=1.16 min, 412.2 (M+l)

C. 5-Methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (3-morphorin-4-yl-l-phenyl- propyp-amide

a. 5 -Methyl- 1, 3-diphenyl-lH-pyrazole-4-carboxylic acid (3-bromo-l-phenyl-propyl)-amide

A mixture of 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (3-hydroxy-l- phenyl-ρropyl)-amide (1.0 g, 2.43 mmol), CBr₄ (1.0 g, 3.02 mmol) and PPh₃ (0.83 g, 3.16 mmol) in CH₂C1₂ ( 30 mL) is stirred at room temperature overnight. After concentrated in vacuo, the residue is purified by flash chromatography to give the title compound as an oil. b. 5 -Methyl- l,3-diphenyl-lH-pyrazole-4-carboxylic acid (3-morpholin-4-yl-l-phenyl- propyl)-amide

A mixture of 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (3-bromo-l- phenyl-propyl)-amide (16.7 mg) and morpholine (lOmg) in DMF (0.5 mL) is heated at 80°C overnight. After cooling and evaporation, the residue is purified on PTLC (1 : 1 Hexane and EtOAc) to give the title compound. LC-MS (QC): R_t =1.08 min, 481.33 (M+l).

D. 2-(5-Methyl-1.3-diphenyl-lH-pyrazol-4-yl -4-phenyl-5.6-dihvdro-4H-r 31oxazine

A mixture of 5-methyl-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (3 -bromo- 1- phenyl-ρropyl)-amide (30 mg) and NaOMe (13.7 mg) in DMF (0.5 mL) is heated at 80°C overnight. After cooling and evaporation, the residue is purified on PTLC (4:1 Hexane and EtOAc) to give the title compound. 1H NMR (CDC1₃): 7.80-7.60 (m, 3H), 7.58-7.22 (m, 12H), 4.80 (m, IH), 4.25-4.17 (m, 2H), 2.55 (s, 3H), 2.30 (m, IH), 1.97 (m, 1). LC-MS (QC): R_t =1.08 min, 394.23 (M+l). E. 5-Methoxy-L3-diphenyl-N- (lS -l-phenylpropyl1-lH-pyrazole-4-carboxamide a. Diethylbenzoyl malonate

To a mixture of diethylmalonate (50 g, 312 mmol) and magnesium chloride (29.7 g, 312 mmol) in 350 mL acetonitrile at 0°C is added Et₃N (86.6 mL, 1.18 mol). The mixture is stined for 15 minutes at 0°C. Benzoyl chloride (43.8g, 312mmol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stined overnight. The reaction mixture is cooled to 0°C and quenched with 50 mL 6N HCl. To the resulting mixture is added 1 L ether and the mixture is transfened to a separatory funnel. The aqueous layer is removed and the organics are washed with 2 X 300 mL water followed by washings with brine until the ether layer is clear. The organic layer is dried over magnesium sulphate, filtered, then concentrated to give benzoyl malonate which is used without further purification.

b. 1 -3-Diphenyl-4-carboethoxy-5-hydroxypyrrazole

Diethylbenzoyl malonate (20 g, 75 mmol) is dissolved in 100 L HO Ac at room temperature. A solution of phenyl hydrazine (33 g, 302 mmol) in 110 mL of 70% HOAc is added dropwise. The reaction mixture is stined for 2 days during which time a precipitate formed. This is collected by filtration, washed with water and air dried to afford the title compound. MS 309 (M+l). c. 1 -3-Diphenyl-4-carboethoxy-5-methoxypyrrazole

l-3-Diphenyl-4-carboethoxy-5-hydroxypyrazole (1.8 g, 5.8 mmol) is dissolved in 25 mL THF and cooled to 0°C. Sodium hydride (250 mg of a 60% oil dispersion, 6.4mmol) is added and the mixture is stined for 15 minutes. Dimethylsulphate (800 mg, 6.4 mmol) is added. The ice bath is removed and the mixture is stirred at room temperature overnight. The reaction is quenched by addition of saturated ammonium chloride solution then transfened to a separatory funnel. The aqueous layer is removed and the organic layer is washed with brine. The organic layer is dried over magnesium sulphate, and then filtered and concentrated to give the title compound. Alternatively, a mixture of l-3-diphenyl-4-carboethoxy-5-hydroxypyrazole (8.00 g, 25.9 mmol) and cesium carbonate (12.7g, 38.9 mmol) is stined in anhydrous DMF (52 mL) at 50°C under nitrogen for 1 hour. The resulting dark brown suspension is allowed to cool to ambient temperature. Methyl iodide (1.61 mL, 3.68 g, 25.9 mmol) is added and the reaction is stined for 48 hours. The reaction mixture is partitioned between EtOAc (125 mL) and water (60 mL), the organic layer is separated, washed with water (40 mL x 3), washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a dark yellow oil. Analysis by proton NMR indicates a ~3 : 1 isomeric mixture. Purification by flash chromatography on silica gel eluting with 10% EtOAc/Hexanes provides l-3-diphenyl-4-carboethoxy-5-methoxypyrrazole as a yellow oil. 1H NMR (CDC1₃): 7.75-7.66 (m, 4H), 7.50-7.34 (m, 6H), 4.25 (q, 2H), 4.06 (s, 3H), 1.22 (t, 3H); MS 295.3 (M+l). d. l-3-Diphenyl—5-methoxypyrrazole-4-carboxylic acid

A mixture of l-3-diphenyl-4-carboethoxy-5-methoxypynazole (4.15 g, 12.9 mmol) and sodium hydroxide (2.58 g, 64.5 mmol) in MeOH/water (50 mL of 4:1) is heated at reflux under nitrogen with stirring for 2.5 hours and monitored by TLC for disappearance of starting material. The reaction mixture is evaporated at reduced pressure and diluted with water (125 mL). The aqueous solution is washed with diethyl ether (50 mL x 2), cooled to 0-5°C and acidified to pH 3-4 using concentrated hydrochloric acid. The resulting suspension is extracted with EtOAc (100 mL) and the organic extract is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain 1-3- diphenyl-5-methoxypyrrazole-4-carboxylic acid as a cream-colored solid. 1H NMR (CDC1₃): 7.75-7.70 (m, 4H), 7.51-7.37 (m, 6H), 4.06 (s, 3H); MS 323.3 (M+l).

e. l-3-Diphenyl-5-methoxypyrrazole-4-carboxylic acid chloride

To a solution of l-3-diphenyl-5-methoxypynazole-4-carboxylic acid (3.64 g, 12.4 mmol) in anhydrous dichloromethane (50 mL) at 0-5°C with stirring is added 2 drops of DMF followed by dropwise addition of oxalyl chloride (7.42 mL of 2 molar solution in dichloromethane, 14.8 mmol). The reaction mixture is allowed to warm to ambient temperature and stir for 2 hours. Evaporation at reduced pressure followed by addition of dichoromethane and repeated evaporation provides l-3-diphenyl-5-methoxypynazole-4- carboxylic acid chloride as a viscous yellow oil. 1H NMR (CDCI₃): 7.75-7.61 (m, 4H), 7.56- 7.35 (m, 6H), 4.00 (s, 3H). / 5-Methoxy-l,3-diphenyl-N-[(lS)-l-phenylpropyl]-lH-pyrazole-4-carboxamide

To a solution of l-3-diphenyl-5-methoxypyrrazole-4-carboxylic acid chloride (300 mg, 1.02 mmol) in anhydrous dichloromethane (2 mL) with stirring is added (1S)-1- phenylpropylamine (276 mg, 2.04 mmol) followed by triethylamine (310 mg, 3.06 mmol). After 2 hours, the reaction mixture is diluted with EtOAc (50 mL), washed with saturated ammonium chloride (15 mL x 3), saturated sodium bicarbonate (15 mL), and brine (15 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a pale yellow oil. Purification by chromatography on silica gel (10% EtOAc/Hexanes) provides the 5-methoxy-l,3-diphenyl-N-[(lS)-l-phenylpropyl]-lH-pyrazole-4-carboxamide as a colorless waxy solid. 1H NMR (CDC1₃): 7.73-7.63 (m, 4H), 7.54-7.11 (m, 11H), 6.10 (d, IH), 5.00 (q, IH), 3.95 (s, 3H), 1.82-1.60 (m, 2H), 0.81 (t, 3H); MS 412.3 (M+l).

E. 5-(2-Hvdroxyethoxy)-l,3-diphenyl-N-(l-phenylpropyl -lH-pyrazole-4-carboxamide

a. 5-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-l,3-diphenyl-lH-pyrazole-4-carboxylic acid ethyl ester

A mixture of l-3-diphenyl-4-carboethoxy-5-hydroxypyrrazole (1.00 g, 3.24 mmol) and cesium carbonate (1.59 g, 4.86 mmol) in anhydrous DMF (6.4 mL) is heated at 50°C with stirring for 1 hour. To the resulting dark brown reaction mixture is added tert-butyl-(2-iodo- ethoxy)-dimethylsilane (2.78 g, 9.72 mmol). After an additional 3 hours, the reaction mixture is allowed to cool. After 88 hours, the reaction mixture is partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer is separated, washed with water (30 mL x 3), washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a tan-colored liquid. Purification by chromatography on silica gel (5% EtOAc/Hexanes) provides the title compound as a colorless oil. MS 467.3 (M+l).

b. 5-(2-Hydroxy-ethoxy)-l, 3-diphenyl-lH-pyrazole-4-carboxylic acid

A mixture of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-l,3-diphenyl-lH-pyrazole- 4-carboxylic acid ethyl ester (1.00 g, 2.14 mmol) and sodium hydroxide (429 mg, 10.7 mmol) in 4:1 MeOH/water (42 mL) is heated at reflux for 30 minutes to form a homogenous solution, and then allowed to stir at ambient temperature for 18 hours. Evaporation at reduced pressure provides a cream colored solid. The residue is dissolved in water (75 mL), washed with diethyl ether (25 mL x 2), cooled to 0-5°C and acidified to pH ~3 using 1 N HCl. The resulting mixture is extracted with EtOAc (100 mL). The EtOAc extract is washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain the title compound as a white solid. 1H NMR (CDC1₃): 7.75-7.62 (m, 4H), 7.58-7.41 (m, 6H), 4.17 (dd, 2H), 3.78 (dd, 2H).

c. 5 -(2-B.ydroxy ethoxy)-! , 3-diphenyl-N-(l -phenylpropyl)-lH-pyrazole-4-carboxamide

5-(2-Hydroxy-ethoxy)-l,3-diphenyl-lH-pyrazole-4-carboxylic acid (600 mg, 1.85 mmol), (lS)-l-phenylpropylamine (500 mg, 3.70 mmol) and N-methylmorpholine (374 mg, 3.70 mmol) are dissolved in 5 mL of 1:1 DMA/DCE under nitrogen with stirring. The reaction mixture is cooled to 0-5°C and BOP (818 mg, 1.85 mmol) is added. The reaction mixture is stined overnight at room temperature, evaporated at reduced pressure, diluted with EtOAc (60 mL), washed with water (20 mL x 2), saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a white solid. Purification on silica gel (20-60% EtOAc/Hexanes) provides the title compound as a pale yellow solid foam. 1H NMR (CDC1₃): 7.72-7.06 (m, 13H), 7.01-6.97 (dd, 2H), 5.89 (d, IH), 4.96 (q, IH), 4.08 (dd, 2H), 3.77 (dd, 2H), 1.78-1.57 (m, 2H), 0.74 (t, 3H); MS 442.3 (M+l). 5-(2-Hydroxyethoxy)- 1 ,3 -diphenyl-N-(l -phenylpropyl)- 1 H-pyrazole-4-carboxamide serves as a versatile intermediate for formation of a variety of additional compounds of Formula I via transformations of the hydroxyethyl substitutuent. For example, the hydroxyethyl substituent is converted to the mesylate following standard procedures and reacted with a variety of primary and secondary amines to provide additional compounds of Formula I.

Example 2. HIGH SPEED SYNTHESIS PROTOCOL FOR PREPARAΉON OF REPRESENTATIVE DIARYL PYRAZOLE DERIVATIVES To a solution of an appropriately substituted pyrrazole carboxylic acid (0.1 mL of a 0.2 M solution in 95/5 toluene/4-methylmorpholine) is added an amine (0.1 mL of a 0.2M solution in toluene. To this mixture is added benzotriazol-1-yl- tris(dimethylamino)phosphonium hexafluorophosphate (0.12 mL of a 0.2M solution in dichloroethane). The mixture is stined for 3 hours at room temperature at which time 0.5 mL saturated aqueous ammonium chloride and 0.5 mL isopropyl ether are added. The organic phase is applied to a lg silica gel SPE column and eluted with 3mL EtOAc to afford the desired amide. Example 3. PREPARATION OF ADDITIONAL REPRESENTATIVE DIARYL PYRAZOLE DERIYATΓVES Compounds shown in the following Table are prepared using methods illustrated above. LC-MS data are given as HPLC retention times (in minutes) and [MH]⁺. All compounds in the following Table have an IC₅₀ of less than 4 micromolar in a standard assay of neurokinin-3 receptor binding as provided in Example 4 and/or a NK-3 receptor-mediated signal transduction assay (calcium mobilization assay), as provided in Example 5.

Ret. LCMS Compound Name Time M+H hiral

5-chloro- 1 ,3 -diphenyl-N- [(lS)-l-phenylpropylj-lH- 1.22 416.2 pyrazole-4-carboxamide

5-methyl- 1 ,3-diphenyl-N- [( 1 S)- 1 -phenylpropyl]- 1H- 1.21 396.2 pyrazole-4-carboxamide

53 Ret. LCMS Compound Name Time M+H

5-methyl-N-(3-methyl- 1 - phenylbutyl)- 1 ,3-diphenyl- 1.26 424.3 lH-pyrazole-4-carboxamide

N-(3 -bromo- 1- phenylpropyl)-5-methyl-l,3- diphenyl- 1 H-pyrazole-4- carboxamide

54 Ret. LCMS Compound Name Time M+H

N-{3-[4-(l,3-benzodioxol-5- ylmethyl)piperazin- 1 -yl]- 1 - phenylpropyl } -5 -methyl- 1,3- 1.12 614.4 diphenyl- 1 H-pyrazole-4- carboxamide

55 Ret. LCMS Compound Name Time M+H

5-methyl- 1 ,3 -diphenyl-N-( 1 - phenylbutyl)-lH-ρyrazole-4- 1.24 410.3 carboxamide

N-(2,3-dihydro- 1 H-inden- 1 - yl)-5-mefhyl-l,3-diρhenyl- 1.27 394.2 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

1 - [(5-methyl- 1 ,3-diphenyl- lH-pyrazol-4-yl)carbonyl]-2- 1.32 422.2 phenylpiperidine

N-(3 ,4-dihydro-2H-chromen- 4-yl)-5-methyl- 1 ,3-diphenyl- 1.25 410.2 1 H-pyrazole-4-carboxamide

Chiral

5-hydroxy- 1 ,3-diphenyl-N- [(lS)-l-phenylpropyl]-lH- 1.3 398.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H Chiral l,3-diphenyl-N-[(lS)-l- phenylpropyl]-5-propyl-lH- 1.24 424.3 pyrazole-4-carboxamide

hiral

5-methoxy- 1 ,3-diphenyl-N- [(lS)-l-phenylpropyl]-lH- 1.22 412.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(l,3-benzodioxol-5- ylmethyl)-N- (cyclopentylmethyl)-5- 1.3 494.3 methyl- 1 ,3-diphenyl- 1H- pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-methyl-N-(4- methylbenzyl)-l,3-diphenyl- 1.25 382.3 lH-pyrazole-4-carboxamide

5-ethyl-N-(4-methylbenzyl)- l,3-diphenyl-lH-pyrazole-4- 1.27 396.3 carboxamide

N-(4-methylbenzyl)- 1 ,3 - diphenyl-5 -propyl- 1H- 1.28 410.3 pyrazole-4-carboxamide

05 0 60 Ret. LCMS Compound Name Time M+H

5-methoxy-N-(4- methylbenzyl)-l,3-diphenyl- 1.27 398.2 1 H-pyrazole-4-carboxamide

5-methyl-N-(3- methylbenzyl)-l,3-diρhenyl- 1.26 382.3 1 H-pyrazole-4-carboxamide

5-ethyl-N-(3 -methylbenzyl)- l,3-diphenyl-lH-ρyrazole-4- 1.27 396.3 carboxamide

N-(3-methylbenzyl)-l,3- diphenyl-5-propyl- 1 H- 1.29 410.3 pyrazole-4-carboxamide

61 Ret. LCMS Compound Name Time M+H

N-(4-fluorobenzyl)-5 -methyl l,3-diphenyl-lH-pyrazole-4- 1.23 386.2 carboxamide

5-ethyl-N-(4-fluorobenzyl)- l,3-diρhenyl-lH-ρyrazole-4- 1.25 400.2 carboxamide

N-(4-fluorobenzyl)- 1 ,3- diphenyl-5-propyl-lH- 1.26 414.3 pyrazole-4-carboxamide

N-(4-fluorobenzyl)-5 - methoxy- 1 ,3-diphenyl- 1 H- 1.24 402.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(3 -fluorobenzyl)- 5 -methyl l,3-diphenyl-lH-pyrazole-4- 1.23 386.2 carboxamide

5-ethyl-N-(3-fluorobenzyl)- l,3-diphenyl-lH-pyrazole-4- 1.24 400.2 carboxamide

N-(3 -fluorobenzyl)- 1,3- diphenyl-5-propyl- 1H- 1.26 414.3 pyrazole-4-carboxamide

N-(3-fluorobenzyl)-5- methoxy- 1 ,3 -diphenyl- 1H- 1.24 402.2 pyrazole-4-carboxamide

63 Ret. LCMS Compound Name Time M+H

N-(3-methoxybenzyl)-5- methyl- 1 ,3 -diphenyl- 1H- 1.22 398.3 pyrazole-4-carboxamide

N-(3-methoxybenzyl)-l,3- diphenyl-5-propyl- 1H- 1.26 426.3 pyrazole-4-carboxamide

N-(4-chlorobenzyl)-5- methyl- 1 ,3-diphenyl- 1 H- 1.27 402.2 pyrazole-4-carboxamide

64 Ret. LCMS Compound Name Time M+H

N-(4-chlorobenzyl)-5-ethyl- l,3-diphenyl-lH-pyrazole-4- 1.27 416.2 carboxamide

N-(4-chlorobenzyl)- 1,3- diphenyl-5-propyl- 1H- 1.29 430.2 pyrazole-4-carboxamide

N-(4-chlorobenzyl)-5- methoxy- 1 ,3-diphenyl- 1 H- 1.28 251.2 pyrazole-4-carboxamide

N-(3-chlorobenzyl)-5- methyl- 1 ,3-diphenyl- 1H- 1.26 402.2 pyrazole-4-carboxamide

65 Ret. LCMS Compound Name Time M+H

N-(3-chlorobenzyι)-5-ethyl- 1, 3 -diphenyl- lH-pyrazole-4- 1.27 416.2 carboxamide

N-(3-chlorobenzyl)- 1 ,3- diphenyl-5-propyl- 1H- 1.29 430.2 pyrazole-4-carboxamide

N-(3-chlorobenzyl)-5- methoxy- 1 ,3-diphenyl- 1 H- 1.27 418.2 pyrazole-4-carboxamide

5-methoxy- 1 ,3-diphenyl-N- [4-(trifluoromethyl)benzyl]- 1.27 452.2 1 H-pyrazole-4-carboxamide

66 Ret. LCMS Compound Name Time M+H

5-methyl- 1 ,3-diphenyl-N-[3- (trifluoromethyl)benzyl]-lH- 1.26 436.2 ρyrazole-4-carboxamide

5-ethyl-l,3-diphenyl-N-[3- (trifluoromethyl)benzyl]-lH- 1.28 450.2 pyrazole-4-carboxamide

l,3-diphenyl-5-propyl-N-[3- (trifluoromethyl)benzyl]-lH- 1.29 464.3 pyrazole-4-carboxamide

5 -methoxy- 1 ,3 -diphenyl-N- [3-(trifluoromethyl)benzyl]- 1.28 452.2 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(4-bromobenzyl)-5- methyl- 1 ,3-diphenyl- 1 H- 1.27 446.1 pyrazole-4-carboxamide

N-(4-bromobenzyl)- 1,3- diphenyl-5-propyl- 1H- 1.3 474.2 pyrazole-4-carboxamide

N-(4-bromobenzyl)-5- methoxy- 1 ,3-diphenyl- 1 H- pyrazole-4-carboxamide

N-benzyl-5-methyl- 1 ,3- diphenyl- 1 H-pyrazole-4- 1.25 368.1 carboxamide

68 Ret. LCMS Compound Name Time M+H

N-benzyl-5-ethyl- 1 ,3- diphenyl- lH-pyrazole-4- 1.25 382.1 carboxamide

N-benzyl- 1 ,3-diphenyl-5- propyl- 1 H-pyrazole-4- 1.27 396.2 carboxamide

N-benzyl-5 -methoxy- 1 ,3- diphenyl- 1 H-pyrazole-4- 1.25 384.1 carboxamide

5-methyl-l,3-diphenyl-N-(l- phenylethyl)-lH-pyrazole-4- 1.26 382.1 carboxamide

69 Ret. LCMS Compound Name Time M+H

5-ethyl- 1 ,3-diphenyl-N-(l - phenylethyl)- lH-pyrazole-4- 1.27 396.2 carboxamide

l,3-diphenyl-N-(l- phenylethyl)-5-propyl- 1H- 1.29 410.2 pyrazole-4-carboxamide

5-methoxy- 1 ,3-diphenyl-N- (l-phenylethyl)-lH-pyrazole- 1.27 398.1 4-carboxamide

5 -methyl- 1 ,3 -diphenyl-N-( 1 - phenylethyl)- lH-ρyrazole-4- 1.26 382.2 carboxamide

70 Ret. LCMS Compound Name Time M+H

5-ethyl-l,3-diphenyl-N-(l- phenylethyl)-lH-pyrazole-4- 1.27 396.2 carboxamide

l,3-diphenyl-N-(l- phenylethyl)-5-propyl- 1H- 1.28 410.2 pyrazole-4-carboxamide

5-methoxy-l,3-diphenyl-N- (1 -phenylethyl)- lH-pyrazole' 1.27 398.1 4-carboxamide

5-methyl- 1 ,3-diphenyl-N-(l - phenylethyl)- lH-pyrazole-4- 1.26 382.2 carboxamide

71 Ret. LCMS Compound Name Time M+H

l,3-diphenyl-N-(l- ρhenylethyl)-5-propyl-lH- 1.28 410.2 pyrazole-4-carboxamide

5 -methoxy- 1 ,3 -diphenyl-N- (l-phenylethyl)-lH-pyrazole- 1.27 398.1 4-carboxamide

5-methyl- 1 ,3-diphenyl-N-(l - phenylpropyl)- IH-pyrazole- 1.28 396.2 4-carboxamide

72 Ret. LCMS Compound Name Time M+H

5-ethyl- 1 ,3-diphenyl-N-(l - phenylpropyl)- 1 H-pyrazole- 1.28 410.2 4-carboxamide

l,3-diphenyl-N-(l- phenylpropyl)-5-propyl-lH- 1.31 424.2 pyrazole-4-carboxamide

5 -methoxy- 1 ,3 -diphenyl-N- ( 1 -phenylpropyl)- 1 H- 1.28 412.2 pyrazole-4-carboxamide

5 -methyl- 1 ,3 -diphenyl-N-( 1 - phenylpropyl)- IH-pyrazole- 1.28 396.2 4-carboxamide

73 Ret. LCMS Compound Name Time M+H

5-ethyl- 1 ,3-diphenyl-N-(l - phenylpropyl)- IH-pyrazole- 1.29 410.2 4-carboxamide

l,3-diphenyl-N-(l- phenylpropyl)-5-propyl-lH- 1.31 424.2 pyrazole-4-carboxamide

5-methoxy- 1 ,3-diphenyl-N- (l-phenylpropyl)-lH- 1.28 412.2 pyrazole-4-carboxamide

5-methyl-l,3-diphenyl-N-(l- phenylpropyl)- IH-pyrazole- 1.28 396.2 4-carboxamide

Ret. LCMS Compound Name Time M+H

5-methyl-N-(2-methyl- 1 - phenylpropyl)- 1 ,3 -diphenyl- 1.3 410.2 lH-pyrazole-4-carboxamide

5-ethyl-N-(2-methyl- 1 - phenylpropyl)-l,3-diphenyl- 1.3 424.2 lH-pyrazole-4-carboxamide

75 Ret. LCMS Compound Name Time M+H

5-methoxy-N-(2 -methyl- 1 - phenylpropyl)- 1,3-diphenyl- 1.3 426.2 1 H-pyrazole-4-carboxamide

5-methyl- 1 ,3 -diphenyl-N-( 1 - phenylbutyl)-lH-pyrazole-4- 1.31 410.2 carboxamide

5-ethyl- 1 ,3 -diρhenyl-N-( 1 - phenylbutyl)-lH-pyrazole-4- 1.32 424.2 carboxamide

l,3-diρhenyl-N-(l- phenylbutyl)-5-propyl- 1H- 1.33 438.2 pyrazole-4-carboxamide

76 Ret. LCMS Compound Name Time M+H

5-methoxy- 1 ,3-diphenyl-N- ( 1-phenylbutyl)- IH-pyrazole 1.29 426.2 4-carboxamide

5-methyl- 1 ,3-diphenyl-N-( 1 - phenylpentyl)- lH-pyrazole- 4-carboxamide

5-ethyl-l,3-diphenyl-N-(l- phenylpentyl)- IH-pyrazole- 1.34 438.3 4-carboxamide

l,3-diphenyl-N-(l- phenylpentyl)-5-propyl-lH- 1.35 452.3 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-methoxy-l,3-diphenyl-N- ( 1 -phenylpentyl)- 1 H- 1.33 440.2 pyrazole-4-carboxamide

5-ethyl-N-(3-methyl- 1 - phenylbutyl)- 1,3 -diphenyl- 1.33 438.2 1 H-pyrazole-4-carboxamide

N-(3-methyl- 1 -phenylbutyl)- l,3-diphenyl-5-propyl-lH- 1.34 452.2 pyrazole-4-carboxamide

5 -methoxy-N-(3 -methyl- 1 - phenylbutyl)- 1 ,3-diphenyl- 1.33 440.2 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

79 Ret. LCMS Compound Name Time M+H

5-methyl- 1 ,3-diphenyl-N-(l - phenylhexyl)-lH-pyrazole-4- 1.34 438.3 carboxamide

5-ethyl- 1 ,3-diρhenyl-N-(l- phenylhexyl)- lH-pyrazole-4- 1.34 452.3 carboxamide

l,3-diphenyl-N-(l- phenylhexy I)- 5 -propyl- 1 H- 1.37 466.3 pyrazole-4-carboxamide

5-methoxy-l ,3-diphenyl-N- ( 1 -phenylhexyl)- 1 H- 1.35 454.3 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-methyl-N-(4-methyl- 1 - phenylpentyl)- 1,3 -diphenyl- 1.33 438.3 lH-pyrazole-4-carboxamide

5-ethyl-N-(4-methyl-l- phenylpentyl)- 1,3-diphenyl- 1.35 452.3 1 H-pyrazole-4-carboxamide

5-methoxy-N-(4-methyl- 1 - phenylpentyl)- 1,3 -diphenyl- 1.34 454.3 lH-pyrazole-4-carboxamide

81 Ret. LCMS Compound Name Time M+H

82 Ret. LCMS Compound Name Time M+H

N-(diphenylmethyl)-5- methyl- 1 ,3-diphenyl- 1 H- 1.3 444.3 pyrazole-4-carboxamide

N-(diphenylmethyl)-5-ethyl- 1 ,3-diphenyl- 1 H-ρyrazole-4- 1.3 458.3 carboxamide

N-(diphenylmethyl)-5- methoxy- 1 ,3-diphenyl- 1 H- 1.3 460.3 pyrazole-4-carboxamide

83 Ret. LCMS Compound Name Time M+H

N-(l,2-diphenylethyl)-5- methyl- 1 ,3-diphenyl- 1H- 1.3 458.3 pyrazole-4-carboxamide

84 Ret. LCMS Compound Name Time M+H

N-(l,2-diρhenylethyl)-5- ethyl-l,3-diphenyl-lH- 1.3 472.3 pyrazole-4-carboxamide

N-( 1 ,2-diphenylethyl)- 1,3- diphenyl-5-propyl- 1H- 1.32 486.3 pyrazole-4-carboxamide

N-(l,2-diphenylethyl)-5- methoxy- 1 ,3-diphenyl- 1 H- 1.31 474.3 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(2-cyclohexyl- 1- phenylethyl)-5-methoxy- 1 ,3- diphenyl- 1 H-pyrazole-4- 1.37 480.3 carboxamide

5 -methyl-N- ( 1 -methyl- 1 - phenylethyl)- 1,3-diphenyl- 1.27 396.3 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-ethyl-N-(l -methyl- 1- phenylethyl)- 1,3-diphenyl- 1.28 410.3 lH-pyrazole-4-carboxamide

N-( 1 -methyl- 1 -phenylethyl)- 1 ,3 -diphenyl-5-propyl- 1 H- 1.3 424.3 pyrazole-4-carboxamide

5-methoxy-N-( 1 -methyl- 1 - phenylethyl)- 1,3-diphenyl- 1.27 412.3 lH-pyrazole-4-carboxamide

N-( 1 -ethyl- 1 -phenylpropyl)- 5-methyl-l,3-diphenyl-lH- 1.33 424.3 pyrazole-4-carboxamide

5-ethyl-N-(l-ethyl-l- phenylpropyl)- 1,3 -diphenyl- 1.33 438.3 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(l -ethyl- 1 -phenylpropyl)- 1 ,3-diphenyl-5-propyl- 1H- 1.34 452.3 pyrazole-4-carboxamide

N-( 1 -ethyl- 1 -phenylpropyl)- 5-methoxy-l,3-diphenyl-lH- 1.32 440.3 pyrazole-4-carboxamide

5 -methyl- 1 ,3-diphenyl-N-( 1 - phenylcyclohexyl)-lH- 1.32 436.3 pyrazole-4-carboxamide

5-ethyl-l,3-diphenyl-N-(l- phenylcyclohexyl)- 1 H- 1.34 450.3 pyrazole-4-carboxamide

88 Ret. LCMS Compound Name Time M+H

l,3-diphenyl-N-(l- phenylcyclohexyl)-5-propyl- 1.35 464.3 lH-pyrazole-4-carboxamide

5 -methoxy- 1 ,3 -diphenyl-N- (l-phenylcyclohexyl)-lH- 1.32 452.3 pyrazole-4-carboxamide

5-methyl-N-(2- methylbenzyl)- 1,3-diphenyl- 1.27 382.2 1 H-pyrazole-4-carboxamide

5-ethyl-N-(2-methyιbenzyι)- l,3-diphenyl-lH-pyrazole-4- 1.28 396.2 carboxamide

Ret. LCMS Compound Name Time M+H

N-(2-methylbenzyl)- 1,3- diphenyl-5-propyl-lH- 1.3 410.3 pyrazole-4-carboxamide

5-methoxy-N-(2- methylbenzyl)- 1,3-diphenyl- 1.28 398.2 1 H-pyrazole-4-carboxamide

N-(2-fluorobenzyl)-5-methyL l,3-diphenyl-lH-pyrazole-4- 1.25 386.2 carboxamide

5-ethyl-N-(2-fluorobenzyl)- l,3-diphenyl-lH-ρyrazole-4- 1.26 400.2 carboxamide

Ret. LCMS Compound Name Time M+H

N-(2-fluorobenzyl)-l,3- diphenyl-5 -propyl- 1 H- 1.27 414.2 pyrazole-4-carboxamide

N-(2-fluorobenzyl)-5 - methoxy- 1 ,3 -diphenyl- 1 H- 1.25 402.2 pyrazole-4-carboxamide

N-(2-methoxybenzyl)-5- methyl- 1 ,3-diphenyl- 1 H- 1.26 398.2 pyrazole-4-carboxamide

91 Ret. LCMS Compound Name Time M+H

N-(2-methoxybenzyl)- 1,3- diphenyl-5-propyl-lH- 1.29 426.2 pyrazole-4-carboxamide

N-(2-chlorobenzyl)-5- methyl- 1 ,3-diphenyl- 1 H- 1.27 402.2 pyrazole-4-carboxamide

N-(2-chlorobenzyl)-5-ethyl- l,3-diρhenyl-lH-ρyrazole-4- 1.29 416.2 carboxamide

Ret. LCMS Compound Name Time M+H

N-(2-chlorobenzyl)- 1,3- diphenyl-5-propyl- 1H- 1.3 430.2 pyrazole-4-carboxamide

N-(2-chlorobenzyl)-5 - methoxy- 1 ,3-diphenyl- 1 H- 1.27 418.2 pyrazole-4-carboxamide

5 -methyl- 1 ,3 -diphenyl-N- [2- (trifluoromethyl)benzyl]-lH- 1.29 436.2 pyrazole-4-carboxamide

5-ethyl-l,3-diphenyl-N-[2- (trifluoromethyl)benzyl]-lH- 1.29 450.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

1 ,3-diphenyl-5-propyl-N-[2- (trifluoromethyl)benzyl]-lH- 1.31 464.2 pyrazole-4-carboxamide

5-methoxy- 1 ,3 -diphenyl-N- [2-(trifluoromethyl)benzyI]- 1.29 452.2 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

N-(l,l-diphenylethyl)-5- methyl- 1 ,3 -diphenyl- 1H- 1.34 458.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(l,l-diphenylethyl)-5- ethyl- 1 ,3-diphenyl- 1 H- 1.34 472.2 pyrazole-4-carboxamide

N-( 1 , 1 -diphenylethyl)- 1,3- diphenyl-5 -propyl- 1 H- 1.37 486.3 pyrazole-4-carboxamide

N-( 1 , 1 -diphenylethyl)-5- methoxy- 1 ,3-diphenyl- 1 H- 1.34 474.2 pyrazole-4-carboxamide

5 -methyl-N-( 1 -methyl- 1 - phenylbutyl)- 1,3-diphenyl- 1.34 424.3 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-ethyl-N-(l-methyl-l- phenylbutyl)-l,3-diphenyl- 1.35 438.3 lH-pyrazole-4-carboxamide

N-(l -methyl- 1 -phenylbutyl)- l,3-diphenyl-5-propyl-lH- 1.36 452.3 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-methyl- 1 ,3-diphenyl-N-(l - ρhenylcycloρentyl)-lH- 1.31 422.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-ethyl-l,3-diphenyl-N-(l- phenylcyclopentyl)- 1 H- 1.32 436.3 pyrazole-4-carboxamide

l,3-diphenyl-N-(l- phenylcyclopentyl)-5-propyl- 1.33 450.3 lH-pyrazole-4-carboxamide

5-niethoxy- 1 ,3-diphenyl-N- ( 1 -phenylcyclopentyl)- 1H- 1.28 251.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

N-benzyl-5-ethyl-N-methyl- l,3-diphenyl-lH-pyrazole-4- 1.29 396.2 carboxamide

Ret. LCMS Compound Name Time M+H

N-benzyl-N-methyl- 1,3- diphenyI-5-propyl- 1H- 1.31 410.2 pyrazole-4-carboxamide

N-benzyl-5-methoxy-N- methyl- 1 ,3-diphenyl- 1H- 1.29 398.2 pyrazole-4-carboxamide

N,5-dimethyl- 1 ,3-diphenyl- N-(l-phenylethyl)-lH- 1.3 396.2 pyrazole-4-carboxamide

5-ethyl-N-methyl-l,3- diphenyl-N-(l-phenylethyl)- 1.32 410.2 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3 -diphenyl-N-(l - phenylethyl)-5-propyl-lH- 1.34 424.3 pyrazole-4-carboxamide

5-methoxy-N-methyl-l,3- diphenyl-N-(l -phenylethyl)- 1.32 412.2 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl-l,3-diρhenyl-N-(l- phenylethyl)-5-propyl- IH- 1.34 424.2 pyrazole-4-carboxamide

5-methoxy-N-methyl-l,3- diphenyl-N-(l -phenylethyl)- 1.32 412.2 lH-pyrazole-4-carboxamide

N,5 -dimethyl- 1 ,3-diphenyl- N-(l-phenylethyl)-lH- 1.3 396.2 pyrazole-4-carboxamide

5-ethyl-N-methyl-l,3- diρhenyl-N-(l-ρhenylethyl)- 1.32 410.2 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3 -diρhenyl-N-(l - phenylethyl)-5-propyl-lH- 1.33 424.2 pyrazole-4-carboxamide

5 -methoxy-N-methyl- 1,3- diphenyl-N-(l -phenylethyl)- 1.33 412.2 1 H-pyrazole-4-carboxamide

N,5-dimethyl-l ,3-diphenyl- N- ( 1 -phenylpropyl)- 1 H- 1.31 410.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3 -diphenyl-N-(l - phenylpropyl)-5-propyl-lH- 1.35 438.3 pyrazole-4-carboxamide

N,5-dimethyl-N-(2-methyl- 1 - phenylpropyl)- 1,3 -diphenyl- 1.33 424.2 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N,5-dimethyl- 1 ,3-diphenyl- N-(l-phenylbutyl)-lH- 1.33 424.3 pyrazole-4-carboxamide

5-ethyl-N-methyl-l,3- diphenyl-N-( 1-phenylbutyl)- 1.36 438.3 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3-diphenyl-N-(l- phenylbutyl)-5-propyl- IH- 1.38 452.3 pyrazole-4-carboxamide

5 -methoxy-N-methyl- 1,3- diphenyl-N-( 1-phenylbutyl)- 1.37 440.3 lH-pyrazole-4-carboxamide

N,5-dimethyl-l ,3-diphenyl- N-(l-phenylpentyl)-lH- 1.37 438.3 pyrazole-4-carboxamide

5-ethyl-N-methyl-l,3- diphenyl-N-(l -phenylpentyl)' 1.39 452.3 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3 -diρhenyl-N-( 1 - phenylpentyl)-5-propyl-lH- 1.41 466.3 pyrazole-4-carboxamide

5-methoxy-N-methyl- 1,3- diphenyl-N-(l -phenylpentyl) 1.39 454.3 lH-pyrazole-4-carboxamide

N,5-dimethyl-N-(3-methyl- 1 - phenylbutyl)- 1,3-diphenyl- 1.36 438.3 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3-diphenyl-N-( 1 - ρhenylhexyl)-5-propyl-lH- 1.44 480.3 pyrazole-4-carboxamide

5-methoxy-N-methyl-l,3- diphenyl-N-(l-ρhenylhexyl)- 1.42 468.3 lH-pyrazole-4-carboxamide

N,5-dimethyl- 1 ,3-diphenyl- N-(l -phenylheptyl)- 1H- 1.44 466.3 pyrazole-4-carboxamide

5-ethyl-N-methyl-l,3- diphenyl-N-(l -phenylheptyl) 1.45 480.3 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3-diphenyl-N-(l - phenylheptyl)-5-proρyl-lH- 1.47 494.3 pyrazole-4-carboxamide

5 -methoxy-N-methyl- 1,3- diphenyl-N-(l -phenylheptyl) 1.45 482.3 lH-pyrazole-4-carboxamide

N-benzyl-N-ethyl-5-methyl- l,3-diphenyl-lH-pyrazole-4- 1.28 396.1 carboxamide

N-benzyl-N,5-diethyl-l,3- diphenyl- lH-pyrazole-4- 1.3 410.1 carboxamide

Ret. LCMS Compound Name Time M+H

N-benzyl-N-ethyl-1,3- diphenyl-5-propyl-lH- 1.32 424.1 pyrazole-4-carboxamide

N-benzyl-N-ethyl-5- methoxy- 1 ,3-diphenyl- 1 H- 1.3 412.1 pyrazole-4-carboxamide

N-benzyl-N-isopropyl-5- methoxy- 1 ,3-diphenyl- 1 H- 1.32 426.1 pyrazole-4-carboxamide

N-benzyl-5-methyl-l,3- diphenyl-N-propyl- 1 H- 1.31 410.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-benzyl-5-methoxy-l,3- dipheny 1-N-propy 1- 1 H- 1.33 426.1 pyrazole-4-carboxamide

N-allyl-N-benzyl-5-methyl- l,3-diphenyl-lH-pyrazole-4- 1.3 408.1 carboxamide

N-allyl-N-benzyl-5-ethyl- l,3-diphenyl-lH-pyrazole-4- 1.32 422.1 carboxamide

N-allyl-N-benzyl-1,3- diphenyl-5-propyl- 1H- 1.34 436.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-allyl-N-benzyl-5-methoxy- 1 ,3 -diphenyl- 1 H-pyrazole-4- 1.33 424.1 carboxamide

N-benzyl-N-cyclopropyl- 5 - methyl- 1 ,3-diphenyl- 1H- 1.29 408.1 pyrazole-4-carboxamide

N-benzyl-N-cyclopropyl-5- ethyl-l,3-diphenyl-lH- 1.3 422.0 pyrazole-4-carboxamide

N-benzyl-N-cyclopropyl- 1 ,3- diphenyl-5-propyl-lH- 1.33 436.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-benzyl-N-cyclopropyl-5- methoxy- 1 ,3 -diphenyl- 1H- 1.31 424.1 pyrazole-4-carboxamide

N-benzyl-N-butyl-5 -methyl- 1,3 -diphenyl- lH-pyrazole-4- 1.33 424.1 carboxamide

N-benzyl-N-butyl-5- methoxy- 1 ,3-diphenyl- 1 H- 1.35 440.1 pyrazole-4-carboxamide

N-benzyl-5-methyl-N-pentyl- 1,3 -diphenyl- lH-pyrazole-4- 1.36 438.0 carboxamide

Ret. LCMS Compound Name Time M+H

N-benzyl-N-pentyl- 1,3- diphenyl-5-propyl-lH- 1.39 466.2 pyrazole-4-carboxamide

N-benzyl-5 -methoxy-N- pentyl- 1 ,3 -diphenyl- 1 H- 1.38 454.1 pyrazole-4-carboxamide

N-benzyl-5-methyl-N-(3- methylbutyl)- 1,3 -diphenyl- 1.35 438.2 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

Ret. LCMS

H- 1.34 450.3

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

1.38 476.4

Ret. LCMS Compound Name Time M+H

Ret. LCMS

2-[(l,3-diphenyl-5-propyl- lH-pyrazol-4-yl)carbonyl]- 1 - (3-methylbutyl)-l,2,3,4- tetrahydroisoquinoline

N,5-dimethyl-N-(4- methylbenzyl)- 1,3 -diphenyl- 1.29 396.1 lH-pyrazole-4-carboxamide

5-ethyl-N-methyl-N-(4- methylbenzyl)- 1,3 -diphenyl- 1.31 410.1 1 H-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N,5-dimethyl-N-(3- methylbenzyl)- 1,3-diphenyl- 1.29 396.1 lH-pyrazole-4-carboxamide

5-ethyl-N-methyl-N-(3- methylbenzyl)- 1,3 -diphenyl- 1.31 410.1 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5 -methoxy-N-methyl-N-(3 - methylbenzyl)- 1 ,3 -diphenyl- 1.31 412.1 lH-pyrazole-4-carboxamide

N-(4-fluorobenzyl)-N,5- dimethyl- 1 ,3-diphenyl- 1 H- 1.26 400.1 pyrazole-4-carboxamide

5-ethyl-N-(4-fluorobenzyl)- N-methyl-l,3-diphenyl-lH- 1.28 414.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(3 -fluorobenzyl)-N, 5 - dimethyl- 1 ,3-diphenyl- 1 H- 1.26 400.0 pyrazole-4-carboxamide

5-ethyl-N-(3-fluorobenzyl)- N-methyl- 1 ,3 -diphenyl- 1H- 1.27 414.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(4-methoxybenzyl)-N,5- dimethyl- 1 ,3-diphenyl- 1H- 1.26 412.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

Ret. LCMS Compound Name Time M+H

N-(3-chlorobenzyl)-N,5- dimethyl- 1 ,3-diphenyl- 1H- 1.28 416.1 pyrazole-4-carboxamide

N-(3-chlorobenzyl)-5-ethyl- N-methyl-l,3-diphenyl-lH- 1.31 430.1 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5-ethyl-N-methyl-l,3- diphenyl-N-[4- 1.3 464.1 (trifluoromethyl)benzyl]- 1H- pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-methyl- 1 ,3 -diphenyl-5 - propyl-N-[3- (trifluoromethyl)benzyl]- 1H- pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(4-bromobenzyl)-N,5- dimethyl- 1 ,3-diphenyl- 1H- 1.3 460.0 pyrazole-4-carboxamide

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l-[(5-ethyl- 1 ,3-diphenyl- 1H- pyrazol-4-yl)carbonyl]-2- 1.34 436.2 phenylpiperidine

l-[(l,3-diphenyl-5-propyl- lH-pyrazol-4-yl)carbonyl]-2- 1.37 450.2 phenylpiperidine

1 - [(5 -methoxy- 1 ,3 -diphenyl- lH-pyrazol-4-yl)carbonyl]-2- 1.35 438.2 phenylpiperidine

1 - [(5 -methyl- 1 ,3 -diphenyl- lH-ρyrazol-4-yl)carbonyl]-2- 1.34 436.2 phenylazepane

l-[(5-ethyl-l,3-diphenyl-lH- pyrazol-4-yl)carbonyl]-2- 1.35 450.2 phenylazepane

Ret. LCMS Compound Name Time M+H

1 -[(1 ,3-diphenyl-5-propyl- lH-pyrazol-4-yl)carbonyl]-2- 1.36 464.2 phenylazepane

1 -[(5-methoxy- 1 ,3-diphenyl- lH-pyrazol-4-yl)carbonyl]-2- 1.35 452.2 phenylazepane

N,5-dimethyl-N-(2- methylbenzyl)- 1,3 -diphenyl- 1.31 396.2 lH-pyrazole-4-carboxamide

5-ethyl-N-methyl-N-(2- methylbenzyl)- 1,3-diphenyl- 1.32 410.2 lH-pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

5 -methoxy-N-methyl-N-(2- methylbenzyl)- 1,3 -diphenyl- 1.32 412.2 1 H-pyrazole-4-carboxamide

N-(2-fluorobenzyl)-N,5 - dimethyl- 1 ,3-diphenyl- 1 H- 1.28 400.1 pyrazole-4-carboxamide

5-ethyl-N-(2-fluorobenzyl)- N-methyl- 1 ,3 -diphenyl- 1H- 1.29 414.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(2-chlorobenzyl)-N,5- dimethyl- 1 ,3-diphenyl- 1H- 1.31 416.1 pyrazole-4-carboxamide

N-(2-chlorobenzyl)-5-ethyl- N-methyl-l,3-diphenyl-lH- 1.32 430.2 pyrazole-4-carboxamide

Ret. LCMS Compound Name Time M+H

N-(2-methoxybenzyl)-N,5- dimethyl- 1 ,3 -diphenyl- 1 H- 1.29 412.2 pyrazole-4-carboxamide

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Ret. LCMS Compound Name Time M+H

Example 4. Assay For NK-3 Receptor Binding Activity The following assay is a standard assay for NK-3 receptor binding activity. Assays are performed as described in Krause et al (Proc. Natl. Acad. Sci. USA 94:310-15, 1997). The NK-3 receptor complementary DNA is cloned from human hypothalamic RNA using standard procedures. The receptor cDNA is inserted into the expression vector pM² to transfect the mammalian Chinese hamster ovary cell line, and a stably expressing clonal cell line is isolated, characterized and used for the cunent experiments. Cells are grown in minimal essential medium alpha containing 10% fetal bovine serum and 250 μg/ml G418. Cells are liberated from cell culture plates with No-zyme (PBS base, JRH Biosciences), and harvested by low speed centrifugation. The cell pellet is homogenized in TBS (0.05 m TrisHCl, 120 mM NaCl, pH 7.4) with a Polytron homogenizer at setting 5 for 20 seconds, and total cellular membranes are isolated by centrifugation at 47,500 x g for 10 minutes. The membrane pellet is resuspended by homogenization with the Polytron as above, and the membranes are isolated by centrifugation at 47,500 x g for 10 minutes. This final membrane pellet is resuspended in TBS at a protein concentration of 350 μg/ml. Receptor binding assays contain a total volume of 200 μl containing 50 μg membrane protein, 0.05-0.15 nM I-methylPhe -neurokinin B, drug or blocker in TBS containing 1.0 mg/ml bovine serum albumen, 0.2 mg/ml bacitracin, 20 μg/ml leupeptin and 20 μg/ml chymostatin. Incubations are carried out for 2 hours at 4°C, and the membrane proteins are harvested by passing the incubation mixture by rapid filtration over presoaked GF/B filters to separate bound from free ligand. The filters are presoaked in TBS containing 2% BSA and 0.1% Tween 20. After filtration of the incubation mixture, filters are rinsed 4 times with ice- cold TBS containing 0.01% sodium dodecyl sulfate and radioactivity is quantitated in a β- plate scintillation counter. One μM methylPhe -neurokinin B is added to some tubes to determine nonspecific binding. Data are collected in duplicate determinations, averaged, and the percent inhibition of total specific binding is calculated. The total specific binding is the total binding minus the nonspecific binding, h many cases, the concentration of unlabeled drug is varied and total displacement curves of binding is carried out. Data are converted to a form for the calculation of IC₅₀ and Hill coefficient (nH). Example 5. Assay For NK-3 Functional Activity This Example illustrates a calcium mobilization assays for evaluating NK-3 receptor modulator activity. The human NK-3 receptor-bearing Chinese hamster ovary cells are grown in minimal essential media supplemented with 250 ug/ml G418, 10% fetal bovine serum and 25 mM Hepes, pH=7.4. Forty eight hours prior to the day of assay, the cells are plated in fresh media that does not contain the G418. On the day of assay, cells grown to 70-90% confluency in 96- well plates are washed with Krebs-Ringer buffer (25 mM HEPES, 5 mM KC1, 0.96 mM NaH₂PO , 1 mM MgSO₄, 2 mM CaCl₂, 5 mM glucose, 1 mM probenecid, pH 7.4) and are then incubated for 1-2 hours in the above buffer supplemented with Fluo3-AM (2.5 to 10 μg/ml; Teflabs) at 37 degrees C in an environment containing 5% CO₂. The wells are then washed twice with Krebs Ringers HEPES buffer. Agonist-induced (methylPhe7 -neurokinin B) calcium mobilization is monitored using a FLIPR (Molecular Devices) instrument. The agonist is added to the cells and fluorescence responses are continuously recorded for up to 5 minutes. For the examination of antagonist drug candidates, compounds are preincubated with the cells for up to 30 min. prior to administration of the methylPhe7-neurokinin B agonist usually at a concentration that brings about a 50% maximal activity. Responses are recorded for times up to 5 min. Kaleidagraph software (Synergy Software, Reading, PA) is utilized to fit the data to the equation y = a*(l/(l+(b/x)c)) to determine the EC₅0 value or IC₅₀ value for the response. In this equation, y is the maximum fluorescence signal, x is the concentration of the agonist or antagonist, a is the E_max, b conesponds to the EC₅₀ or IC₅₀ value, and, finally, c is the Hill coefficient.

Example 6. 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, N ). 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 NaH₂PO₄, 81 mL 0.1 M Na₂HPO₄, adjusted to pH 7.4 with H PO₄). 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 lαiown metabolic properties (e.g., DIAZEPAM or CLOZAPLNE). 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 L 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 rpm (Sorval T 6000D centrifuge, H1000B 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 t ₂ value of the test compound is extrapolated. Prefened compounds provided herein exhibit in vitro t ₂ values of greater than 10 minutes and less than 4 hours, preferably between 30 minutes and 1 hour, in human liver microsomes.

Example 7. MDCK Toxicity 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 rpm 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 prefened 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 prefened test compomids exhibit ATP levels that are at least 50%o, preferably at least 80%), of the ATP levels detected in untreated cells.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula:

Ar r^N'^Ar2 or a pharmaceutically acceptable salt thereof, wherein:

X is N(R_3a) or C(R_3a)(R₃b);

Ari is a 6- to 10-membered aryl or 6- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M;

Ar₃ is (6- to 10-membered aryl)Co-C₄alkyl, (5- to 10-membered heteroaryl)Co-C₄alkyl or phenoxyCo-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro and oxo; (ii) groups of the fonnula L-M, and (iii) groups that are taken together with R₂, R_3a, or R₃ to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

(i) hydrogen or halogen; or (ii) Ci-C_δalkyl, CrC_δalkoxy or mono- or di-(C₁-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

R₂ is: (i) hydrogen, Ci-C₆alkyl, or Ci-Cβalkenyl, each of which al yl or alkenyl is substituted with from 0 to 4 substituents independently chosen from R ; or (ii) taken together with R_3a or R_3b to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R_3a and R₃ are: (i) independently (a) hydrogen; (b) Ci-Cgalkyl, Ci-C₈allcenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)Co-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M;

L is independently selected at each occunence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, O-C(=O)O, N(R_X), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_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 -Csalkyl;

M is independently selected at each occunence from: (i) hydrogen; and (ii) Ci-Csalkyl, C₂- C₈alkenyl, C₂-C₈alkynyl, phenylC₀-C₆alkyl, and (3- to 10-membered heterocycle)C₀- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen

R_b is independently chosen at each occunence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Ci-C₆alkyl, Cι-C₆alkenyl, Ci-C₆alkynyl, haloCi-Cealkyl, hydroxyCi-C₆alkyl, cyanoCi-C₈alkyl, Ci-C₆alkoxy, haloC^Csalkoxy, Ci-Cealkanoyl, C₂- Cealkoxycarbonyl, C₂-C₆alkanoyloxy, Ci-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(Ci-C₆alkyl)aminoC₀-C₆alkyl; such that: (i) if Ri is hydrogen or halogen, then at least one of R₂ and R_3a is not hydrogen and Ar₃ is not 2-bromo-4-fluoro-phenyl; (ii) if Ri is hydrogen or methyl and R₂ is hydrogen, then R_3a is not hydrogen, methyl or ethyl; and (iii) if X is C(R_3a)(R_3b) and R_l5 R_3a, and R₃ are each hydrogen, then R is not benzyl.

2. A compound or salt according to claim 1, wherein the compound has the formula:

3. A compound or salt according to claim 2, wherein R_3a is Cι-C₈alkyl, Q- C₈alkenyl, C₃-C₈cycloalkylCo-C₄alkyl, or phenylCo-C₂alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, and cyano.

4 A compound or salt according to claim 3, wherein R is hydrogen.

5. A compound or salt according to claim 3, wherein R_3a is Ci-C₄alkyl.

6. A compound or salt according to claim 2, wherein R_3b is hydrogen, methyl or ethyl, and R_3a is phenyl, benzyl, or C₂-C₆alkyl that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano and 5- and 6-membered heterocycles.

7. A compound or salt according to claim 3, wherein R₃ is hydrogen and R_3a is taken together with a substituent of Ar₃ to form an optionally substituted, fused 6- or 7- membered carbocycle or heterocycle.

8. A compound or salt according to claim 7, wherein the group represented by

<- , wherein W is CH₂, NH, O or S.

9. A compound or salt according to claim 2, wherein R_3a and R_3b are taken together to form a spiro 5- to 7-membered carbocycle.

10. A compound or salt according to any one of claims 1 to 9, wherein Ri is hydrogen, halogen, Cι-C₄alkyl, haloCι-C alkyl, Ci-C₄alkoxy, or Cι-C₄alkoxy substituted with hydroxy, halogen or a 5- to 7-membered heterocycloalkyl ring that is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxy, oxo, and Ci-C₄alkyl.

11. , A compound or salt according to claim 10, wherein Ri is halogen, C₁-C₄alkyl, Cι-C₄alkoxy, or Ci-C₄alkoxy substituted with hydroxy, or Ci~C₄alkoxy substituted with a 5- or 6-membered heterocycloalkyl ring that is substituted with 0, 1 or 2 substituents independently chosen from Ci-C alkyl.

12. A compound or salt according to any one of claims 1 to 11, wherein R₂ is hydrogen, Ci-C₄alkyl or Ci-C alkenyl.

13. A compound or salt according to claim 12, wherein R is hydrogen.

14. A compound or salt according to any one of claims 1 to 11, wherein R is taken together with R_3a or a substituent of Ar₃ to form a 5- to 7-membered heterocycloalkyl.

15. A compound or salt according to any one of claims 1 to 14, wherein Ari and Ar₂ are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Ci-C₆alkyl, Ci-C₆alkenyl, haloCi-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-C₆alkyl, and Cι-C₆alkoxy.

16. A compound or salt according to claim 15, wherein Ari and Ar₂ are independently phenyl or pyridyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Ci-C₄alkyl, haloCi-C₄alkyl, hydroxyCi-C alkyl, cyanoCi-C₄alkyl, and Ci-C₄alkoxy.

17. A compound or salt according to claim 16, wherein Ari and Ar are independently chosen from phenyl that is substituted with from 0 to 2 substituents independently chosen from halogen, cyano, Ci-C₄alkyl, haloCi-C alkyl, and Ci-C alkoxy.

18. A compound or salt according to any one of claims 1 to 17, wherein Ar₃ is phenylC₀-C₄alkyl, pyridylCo-C₄alkyl, or phenoxyCo-C alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, C_\- C₈alkyl, Ci-C₆alkenyl, haloCi-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-C₆alkyl, Ci-C₆alkoxy, and phenyl.

19. A compound or salt according to claim 18, wherein Ar₃ is phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, or phenoxymethyl, each of which is substituted with 0, 1, 2 or 3 substituents independently chosen from halogen, Cι-C₈alkyl, haloCι-C₄alkyl, C_\- C alkoxy, and phenyl.

20. A compound or salt according to any one of claims 2 to 14, wherein the compound has the formula:

wherein: i and R₅ each represent 0, 1, or 2 substituents independently chosen from hydroxy, halogen, cyano, amino, Ci-C₆alkyl, Ci-C₆alkenyl, haloCi-C₆alkyl, hydroxyCi-C₆alkyl, cyanod- C₆alkyl, and Cι-C₆alkoxy; and R₆ represents 0, 1 or 2 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₈alkyl, Ci-C₆alkenyl, haloCi-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCι-C₆alkyl, Cι-C₆alkoxy, and phenyl.

21. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ari and Ar₂ are independently chosen from 6- to 10-membered aryl and 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar is chosen from (6- to 10-membered aryl)C₀-C₄alkyl, (5- to 10-membered heteroaryl)C₀- C₄alkyl, and phenoxyCo-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro, oxo, (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R_3a, or R₃ to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ri is: (i) halogen; or (ii) C₂-C₆alkyl, Ci-C₆alkoxy, or mono- or di-(Cι-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R₂ is: (i) hydrogen, d- alkyl, or Ci-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from R ; or (ii) taken together with R_3a or R₃b to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R_3a and R₃ are: (i) independently (a) hydrogen; (b) Cι-C₈alkyl, Ci-C₈alkenyl, C₃-C₈cycloalkyl, or phenyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (c) taken together with a substituent of Ar₃ to form a fused, partially saturated. 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; L is independently selected at each occurrence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, O-C(=O)O, N(R_X), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_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 C Csalkyl; M is independently selected at each occurrence from: (i) hydrogen; and (ii) Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkynyl, phenylC₀-C₆all yl, and (3- to 10-membered heterocycle)Co- Cβalkyl, each of which is substituted with from 0 to 4 substituents independently chosen

R_b is independently chosen at each occurrence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Ci-C₆alkyl, Ci-C₆alkenyl, Cι-C₆alkynyl, haloCi-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-C₈alkyl, Ci-C₆alkoxy, haloCi-C₈alkoxy, Ci-C₆alkanoyl, C₂- C₆alkoxycarbonyl, C -C₆alkanoyloxy, Cι-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(Cι -C₆alkyl)aminoC₀-C₆alkyl.

22. A compound or salt according to claim 21, wherein R_3a is Ci-C₈alkyl, Ci- C₈alkenyl, C₃-C₈cycloalkylCo-C₄alkyl, or phenylCo-C alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy and cyano.

23. A compound or salt according to claim 22, wherein R_3b is hydrogen.

24. A compound or salt according to claim 22, wherein R_3a is Ci-C₄alkyl.

25. A compound or salt according to claim 21, wherein R _a and R₃ are hydrogen.

26. A compound or salt according to claim 21, wherein R is hydrogen, methyl or ethyl, and R_3a is phenyl, benzyl, or C₂-C₆alkyl that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano and 5- and 6-membered heterocycles.

27. A compound or salt according to claim 21, wherein R_3b is hydrogen and R_3a is taken together with a substituent of Ar₃ to form an optionally substituted, fused 6- or 7- membered carbocycle or heterocycle.

28. A compound or salt according to claim 27, wherein the group represented by

, wherein W is CH₂, NH, O or S.

29. A compound or salt according to claim 21, wherein R_3a and R_3b are taken together to form a spiro 5- to 7-membered carbocycle.

30. A compound or salt according to claim 21, wherein Ri is halogen, C -C₆alkyl, haloCi-C₄alkyl, Ci-C₄alkoxy or Ci-C alkoxy substituted with hydroxy, halogen or a 5- to 7- membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1 or 2 substituents independently chosen from halogen, hydroxy, oxo, and Ci-C₄alkyl.

31. A compound or salt according to claim 30, wherein Ri is halogen, ethyl, propyl, isopropyl, butyl, Ci-C alkoxy, Ci-C₄alkoxy substituted with hydroxy, or Ci-C₄alkoxy substituted with a 5- or 6-membered heterocycloalkyl ring, wherein the ring is substituted with 0, 1 or 2 substituents independently chosen from Cι-C₄alkyl.

32. A compound or salt according to any one of claims 21 to 31, wherein R₂ is hydrogen, Ci-C₄alkyl, or Ci-C alkenyl.

33. A compound or salt according to any one of claims 21 to 32, wherein Ari and Ar₂ are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Ci-C₆alkyl, Cι-C₆alkenyl, haloCι-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-C₆alkyl, and Cι-C₆alkoxy.

34. A compound or salt according to claim 33, wherein Ari and Ar₂ are independently phenyl or pyridyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₄alkyl, haloCi- alkyl, hydroxyCi-C alkyl, cyanoCι-C₄alkyl, and Cι-C alkoxy.

35. A compound or salt according to claim 34, wherein Ari and Ar₂ are independently chosen from phenyl that is substituted with from 0 to 2 substituents independently chosen from halogen, cyano, C₁-C alkyl, haloCi-C₄alkyl, and Ci-C alkoxy.

36. A compound or salt according to any one of claims 21 to 35, wherein Ar₃ is phenylC₀-C₄alkyl or pyridylCo-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, cyano, amino, Ci-C₈alkyl, Ci- C₆alkenyl, haloCι-C₆alkyl, hydroxyCi-C₆alkyl, cyanod-C_δalkyl, Cι-C₆alkoxy, and phenyl.

37. A compound or salt according to claim 36, wherein Ar₃ is phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, or phenoxymethyl, each of which is substituted with 0, 1, 2, or 3 substituents independently chosen from halogen, Ci-C₈alkyl, haloCi-C alkyl, Ci- C₄alkoxy, and phenyl.

38. A compound or salt according to any one of claims 21 to 32, wherein the compound has the formula:

wherein:

R₄ and R₅ each represent 0, 1, or 2 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₆alkyl, Cι-C₆alkenyl, haloCi-Cealkyl, hydroxyCi-C₆alkyl, cyanoCi- C₆alkyl, and Cι-C₆alkoxy; and R₆ represents 0, 1 or 2 substituents independently chosen from hydroxy, halogen, cyano, amino, Cι-C₈alkyl, Ci-C₆alkenyl, haloCi-C₆alkyl, hydroxyCι-C₆alkyl, cyanoCι-C₆alkyl, Cι-C₆alkoxy and phenyl.

39. A compound according to claim 1 or claim 21, wherein in a standard assay of NK-3 receptor binding the compound exhibits an IC₅₀ of 1 micromolar or less.

40. A compound according to claim 39, wherein in a standard assay of NK-3 receptor binding the compound exhibits an ICso of 100 nanomolar or less.

41. A compound according to claim 40, wherein in a standard assay of NK-3 receptor binding the compound exhibits an IC₅₀ of 10 nanomolar or less.

42. A pharmaceutical composition comprising a compound or salt according to claim 1 or claim 21, in combination with at least one physiologically acceptable carrier or excipient.

43. A packaged pharmaceutical composition comprising a pharmaceutical composition according to claim 42 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to NK-3 receptor antagonism.

44. A packaged pharmaceutical composition according to claim 43, wherein the patient is suffering from anxiety, depression, psychosis, obesity, chronic pulmonary obstructive disorder, irritable bowel syndrome, colitis, pain, or a cognitive disorder.

45. A method for the treatment of a disease or disorder that is responsive to NK-3 receptor modulation, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula: AT3-X._N, ₂

ArΛτ^{N 'Ar2} or a pharmaceutically acceptable salt thereof, wherein:

X is N(R_3a) or C(R_3a)(R_3b);

Ari is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₃ is (6- to 10-membered aryl)Co-C alkyl, (5- to 10-membered heteroaryl)Co-C₄alkyl or phenoxyC₀-C alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro and oxo; (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R _a, or R_3b to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ri is: (i) hydrogen or halogen; or (ii) Cι-C₆alkyl, Cι-C₆alkoxy, or mono- or di-(Cι-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R₂ is: (i) hydrogen, Cι-C₆alkyl or Cι-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from R ; or (ii) taken together with R_3a or R_3b to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; R_3a and R₃ are: (i) independently (a) hydrogen; (b) Ci-C₈alkyl, Ci-C₈alkenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, ρhenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)C₀-C alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; L is independently selected at each occurrence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, O-C(=O)O, N(R_x), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_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 Ci-C₈alkyl; M is independently selected at each occurrence from: (i) hydrogen; and (ii) Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkynyl, phenylCo-C₆alkyl, and (3- to 10-membered heterocycle)C₀- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_b; and R_b is independently chosen at each occurrence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Ci-C₆alkyl, Cι-C₆alkenyl, Ci-C₆alkynyl, haloCι-C₆alkyl, hydroxyCi-C₆alkyl, cyanoCi-Csalkyl, Ci-C₆alkoxy, haloCi-C₈alkoxy, Cι-C₆alkanoyl, C₂- C₆alkoxycarbonyl, C₂-C₆alkanoyloxy, Ci-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(Cι-C₆alkyl)aminoC₀-C₆alkyl.

46. A method according to claim 45, wherein the compound is a compound according to claim 1 or claim 21.

47. A method according to claim 45 or claim 46, wherein the disease or disorder is anxiety, depression, psychosis, obesity, chronic pulmonary obstructive disorder, irritable bowel syndrome, colitis, pain, or a cognitive disorder.

48. A method for suppressing appetite in a patient, comprising administering to the patient an appetite reducing amount of at least one compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is N(R_3a) or C(R_3a)(R_3b);

Ari is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₃ is (6- to 10-membered aryl)Co-C₄alkyl, (5- to 10-membered heteroaryl)Co-C₄alkyl, or phenoxyC₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro and oxo; (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R_3a, or R_3b to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ri is: (i) hydrogen or halogen; or (ii) Cι-C₆alkyl, Cι-C₆alkoxy or mono- or di-(Cι-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; R is: (i) hydrogen, Cι-C₆alkyl, or Ci-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from R_b; or (ii) taken together with R_3a or R _b to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R_3a and R _b are: (i) independently (a) hydrogen; (b) Ci-C₈alkyl, Ci-C₈alkenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; L is independently selected at each occunence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, O-C(=O)O, N(R_X), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_ra, S(O)_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 occunence from hydrogen and Ci-C₈alkyl; M is independently selected at each occunence from: (i) hydrogen; and (ii) Ci-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkynyl, phenylCo-C₆alkyl, and (3- to 10-membered heterocycle)C₀- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen

R_b is independently chosen at each occurrence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Ci-C₆alkyl, CrC₆alkenyl, Cι-C₆alkynyl, haloCι-C₆alkyl, hydroxyCi-Cβalkyl, cyanoCi-C₈alkyl, Cι-C₆alkoxy, haloCι-C₈alkoxy, Cι-C₆alkanoyl, C ~ C₆alkoxycarbonyl, C -C₆alkanoyloxy, Cι-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(Ci-C₆alkyl)aminoCo-C₆alkyl.

49. A method according to claim 48, wherein the compound is a compound according to claim 1 or claim 21.

50. A method for treating a condition in a patient, wherein the condition is an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder or a movement disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the fonnula:

or a pharmaceutically acceptable salt thereof, wherein:

X is N(R_3a) or C(R_3a)(R3b);

Ari is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; Ar₃ is (6- to 10-membered aryl)Co-C alkyl, (5- to 10-membered heteroaryl)Co-C alkyl, or phenoxyC₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro and oxo; (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R_3a or R_3b to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

(i) hydrogen or halogen; or (ii) Cι-C₆alkyl, Cι-C₆alkoxy or mono- or di-(Ci-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R₂ is: (i) hydrogen, Cι-C₆alkyl, or Cι-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from Rb; or (ii) taken together with R_3a or R_3b to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R_3a and R _b are: (i) independently (a) hydrogen; (b) Cι-C₈alkyl, Cι-C₈alkenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)Co-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; L is independently selected at each occurrence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, O-C(=O)O, N(R_X), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_mN(R_x), and N[S(O)_raR_x]S(O)_m; wherein m is independently selected at each occunence from 0, 1, and 2; and R_x is independently selected at each occunence from hydrogen and Cι-C₈alkyl; M is independently selected at each occunence from: (i) hydrogen; and (ii) Cι-C₈alkyl, C - C₈alkenyl, C₂-C₈alkynyl, phenylCo-C₆alkyl, and (3- to 10-membered heterocycle)C₀- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen

R_b is independently chosen at each occurrence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Cι-C₆alkyl, Cι-C₆alkenyl, Cι-C₆alkynyl, haloCι-C₆alkyl, hydroxyCι-C₆alkyl, cyanoCι-C₈alkyl, Ci-C₆alkoxy, haloCi-C₈alkoxy, C_!-C₆alkanoyl, C₂- C₆alkoxycarbonyl, C₂-C₆alkanoyloxy, Cι-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(C i -C₆alkyl)aminoCo-C₆alkyl.

51. A method according to claim 50, wherein the compound is a compound according to claim 1 or claim 21.

52. A method according to claim 50 or claim 51, wherein the condition is obesity, bulimia, alcohol dependency, or nicotine dependency.

53. A method for inhibiting the binding of a neurokinin to a NK-3 receptor, comprising contacting a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

X is N(R_3a) or C(R_3a)(R₃b);

Aii is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; Ar₃ is (6- to 10-membered aryl)C₀-C₄alkyl, (5- to 10-membered heteroaryl)Co-C₄alkyl or phenoxyC₀-C alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro, and oxo; (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R_3a, or R_3b to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

(i) hydrogen or halogen; or (ii) Cι-C₆alkyl, Cι-C₆alkoxy, or mono- or di-(Ci-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R₂ is: (i) hydrogen, Cι-C alkyl, or Cι-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from Rb; or (ii) taken together with R_3a or R₃ to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the fonnula L-M; R_3a and R _b are: (i) independently (a) hydrogen; (b) Cι-C₈alkyl, Cι-C₈alkenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; L is independently selected at each occurrence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, 0-C(=O)O, N(R_X), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_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;

M is independently selected at each occurrence from: (i) hydrogen; and (ii) Cι-C₈alkyl, C₂- C₈alkenyl, C₂-C₈alkynyl, phenylC₀-C₆alkyl, and (3- to 10-membered heterocycle)C₀- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen

R_b is independently chosen at each occunence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Cι-C₆alkyl, Cι-C₆alkenyl, Cι-C₆alkynyl, haloCi-C_δalkyl, hydroxyCι-C₆alkyl, cyanoCι-C₈alkyl, Cι-C₆alkoxy, haloCι-C₈alkoxy, Cι-C₆alkanoyl, C₂- C₆alkoxycarbonyl, C₂-C₆alkanoyloxy, Cι-C₆alkylthio, C -C₆alkylether, and mono- and di-(Cι-C₆alkyl)aminoC₀-C₆alkyl; with cells expressing such a receptor in the presence of a neurokinin, wherein the compound is present at a concentration sufficient to inhibit neurokinin binding to cells expressing a cloned human NK-3 receptor in vitro.

54. A method according to claim 53, wherein the compound is a compound according to claim 1 or claim 21.

55. A method for altering the signal-transducing activity NK-3 receptors, comprising contacting cells expressing such receptors with a compound of the formula:

ArΛr^N'^A,2 or a pharmaceutically acceptable salt thereof, wherein:

X is N(R_3a) or C(R_3a)(R₃b);

Ari is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

Ar₂ is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

Ar₃ is (6- to 10-membered aryl)Co-C₄alkyl, (5- to 10-membered heteroaryl)C₀-C₄alkyl, or phenoxyC₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) halogen, cyano, nitro, and oxo; (ii) groups of the formula L-M, and (iii) groups that are taken together with R₂, R_3a, or R_3b to form a fused, partially saturated, 5- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

Ri is: (i) hydrogen or halogen; or (ii) Cι-C₆alkyl, Cι-C₆alkoxy, or mono- or di-(Cι-C₆alkyl)amino, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; R₂ is: (i) hydrogen, Cι-C₆alkyl, or Cι-C₆alkenyl, each of which alkyl or alkenyl is substituted with from 0 to 4 substituents independently chosen from Rb; or (ii) taken together with R _a or R_3b to form a 5- to 8-membered heterocycloalkyl substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (iii) taken together with a substituent of Ar₃ to form a fused, partially saturated, 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

(i) independently (a) hydrogen; (b) d-C₈alkyl, Cι-C₈alkenyl, (C₃-C₈cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, or (4- to 8-membered heterocycle)Co-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; (c) taken together with R₂ to form an optionally substituted 5- to 8-membered heterocycloalkyl; or (d) taken together with a substituent of Ar₃ to form a fused, partially saturated 5- to 8- membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M; or (ii) taken together to form a spiro 3- to 8-membered carbocycle or heterocycle, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, nitro, oxo, and groups of the formula L-M;

L is independently selected at each occunence from a bond, O, S(O)_m, C(=O), OC(=O), C(=O)O, 0-C(O)0, N(R_X), C(=O)N(R_x), N(R_x)C(=O), N(R_x)S(O)_m, S(O)_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; M is independently selected at each occurrence from: (i) hydrogen; and (ii) Cι-C₈alkyl, C - C₈alkenyl, C₂-C₈alkynyl, phenylC₀-C₆allcyl, and (3- to 10-membered heterocycle)C₀- C₆alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rb; and R_b is independently chosen at each occunence from: (i) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, and -COOH; and (ii) Cι-C₆alkyl, Cι-C₆alkenyl, Cι-C₆alkynyl, haloCι-C₆alkyl, hydroxyCι-C₆alkyl, cyanoCι-C₈alkyl, Cι-C₆alkoxy, haloCi-Qalkoxy, Cι-C₆alkanoyl, C₂- C₆alkoxycarbonyl, C₂-C₆alkanoyloxy, Cι-C₆alkylthio, C₂-C₆alkylether, and mono- and di-(Cι-C₆alkyl)aminoCo-C₆alkyl; at a concentration sufficient to inhibit neurokinin binding to cells expressing a cloned human neurokinin-3 receptor in vitro.

56. A method according to claim 53, wherein the compound is a compound according to claim 1 or claim 21.

57. A compound or salt according to claim 1 or claim 21, wherein the compound or salt is radiolabeled.

58. A method for localizing NK-3 receptors in a tissue sample comprising: contacting with the sample a detectably-labeled compound of claim 1 or claim 21 under conditions that permit binding of the compound to NK-3 receptors, washing the sample to remove unbound compound, and detecting the bound compound.

59. A method for identifying an agent that binds to NK-3 receptor, comprising: (a) contacting NK-3 receptor with a radiolabeled compound or salt according to claim 57, under conditions that permit binding of the compound or salt to NK-3 receptor, thereby generating bound, labeled compound; (b) detecting a signal that conesponds to the amount of bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and (e) detecting a decrease in signal detected in step (d), as compared to the signal detected in step (b), and therefrom identifying an agent that binds to NK-3 receptor.

60. A method for determining the presence or absence of NK-3 receptor in a sample, comprising the steps of: (a) contacting a sample with a compound or salt according to claim 1 or claim 21, under conditions that permit binding of the compound to NK-3 receptor; and (b) detecting a level of the compound bound to NK-3 receptor, and therefrom determining the presence or absence of NK-3 receptor in the sample.

1. A method according to claim 60, wherein the compound is radiolabeled, 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.