METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS

Abstract: This invention relates to a novel series of compounds which are useful in the treatment or prevention of a physiological disorder associated with an excess of stimulation of the human Group I metabotropic glutamate receptors, especially those designated as mGluR5. This invention also provides methods for the treatment of such disorders, as well as pharmaceutical formulations which employ the novel metabotropic glutamate receptor antagonists to which the present invention relates.

Description: METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol. ToxicoL, 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. ToxicoL, 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception. Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic." This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (ΝMDA), α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c- AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). The metabotropic glutamate receptors can be divided into three subgroups according to their amino acid sequence similarity. Group I includes the receptors designated as mGluRl and mGluR5; Group II includes mGluR2 and mGluR3; and Group HI includes mGluR4, mGluRό, mGluR7, and mGluR8. Pinn and Duvoisin, Neuropharmacology, 34(1), 1 (1995). Both the ionotropic and the metabotropic receptor types appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990). The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal. The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Antagonists of these receptors are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents. In addition, antagonists of the metabotropic glutamate receptors are useful for the treatment of acute, chronic, persistent, intractable, and neuropathic pain. The present invention provides antagonists of the Group I human metabotropic glutamate receptors, preferably those designated as mGluR5. The treatment and/or prevention of physiological disorders associated with metabotropic glutamate receptors is hereby furthered. The present invention encompasses novel compounds of the formula : Formula I wherein, n is 0, 1 or 2; X is O, S, NH, or NOH; R 1 and R 2 are each independently H, CN, COOR, CONHR, C j -C^ alkyl, tetrazole, or Rl and R 2 together represent "=O"; R is H or Cj -CO alkyl; R 3 is Cj-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, -CH2OH, -CH2θ-alkyl, -COOH; Ar is an unsubstituted or substituted aromatic or heteroaromatic group; Z represents a group of the formulae wherein, R4 and R^ are each independently H, halogen, Cj-Cg alkoxy , -OAr , Ci -Cg alkyl, -CF3, COOR, CONHR, -CN, -OH, COR, -S-( C;,-C 6 alkyl), -SO2(C;,-C 6 alkyl) A is CH 2 , O, NH, NR, S, SO, SO 2 , CH2-CH2, CH 2 O, CHOH, C(O); wherein R is as defined above; B is CHR, CR2, C!-C 6 alkyl, C(O), -CHOH, -CH 2 -O, -CH=CH, CH 2 -C(O), CH2-S, CH2-S(O), CH2-SO2; -CHCO2R; or -CH-NR2, wherein R is as defined above Het is a heterocycle such as furan, thiophene, or pyridine; or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention encompasses pharmaceutically acceptable solvates and prodrugs of Formula I in addition to pharmaceutical formulations comprising, as an active ingredient, a compound of Formula I in combination with a pharmaceutically acceptable carrier, diluent, or excipient. In yet another embodiment, the present invention encompasses a method for the treatment or prevention of a physiological disorder associated with an excess of stimulation of Group I metabotropic glutamate receptors, and preferably those designated as mGluR5, which method comprises administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present invention further provides a method of antagonizing one or more of the actions of L-glutamate at Group I metabotropic glutamate receptors, which method comprises administering an effective amount of a compound of Formula I. According to yet another aspect, the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof as defined hereinabove, for the manufacture of a medicament for antagonizing one or more of the actions of L-glutamate at Group I metabotropic glutamate receptors. The invention further provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for antagonizing one or more of the actions of L- glutamate at Group I metabotropic glutamate receptors. The terms and abbreviations used in the present document have their normal meaning in the art, unless otherwise designated. All temperatures stated herein are in degrees Celsius (°C). All units of measurement employed herein are in weight units except for liquids which are in volume units. As used herein, the term "C 1 -C6 alkyl" refers to straight or branched, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. "Ar" represents an aromatic carbocyclic group consisting of 6-10 atoms in a single ring (i.e. phenyl) or multiple condensed rings (i.e. napthyl), which can be unsubstituted or substituted with 1 or more, preferably 1-5, substituents independently selected from Ci-Cό alkyl, C^-Cg alkylamino, di(Cι -C6 alkyl)amino, Ci-C alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, nitro, amino, Cι-C6 acylamino, Ci-C6 alkylthio, hydroxy (CJ-C6 )alkyl, Cι-C6 alkyl sulfonyl, halo (C1-C6 alkyl). The term " Ci-Cβ acylamino" represents an acyl group with zero to five carbon, straight, or branched, alkyl chain attached to an amino group. "Halo" or "halogen" represents chloro, fluoro, bromo or iodo. "Halo(Cι-C6)alkyl" represents a straight or branched alkyl chain having from one to six carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(Cι-C6)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3- fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. "Hydroxy(Cι-C6)alkyl" represents a straight or branched alkyl chain having from one to six carbon atoms with hydroxy group attached to it. Typical hydroxy(Cι-C6)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyisopropyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxyisobutyl, hydroxy-t-butyl and the like. "Ci-Cδ alkylthio" represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical Ci-Cό alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. The term "C 2 -C6 alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical C2-C6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-l- propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like. "C1-C6 alkylamino" represents a straight or branched alkylamino chain having from one to six carbon atoms attached to an amino group. Typical Ci-C δ alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like. "Di(Cι-C6 alkyl)amino" represents a straight or branched dialkylamino chain having from one to six carbon atoms attached to an amino group. Typical C 1 -C6 alkyl amino groups include dimethylamino, ethylmethylamino, methylisopropylamino, t- butylisopropylamino, di-t-butylamino, and the like. The term "heterocycle" or "het" refers to a cyclic group of one or more rings containing one or more hetero atoms, and which can be aromatic or non-aromatic. An "aromatic heterocycle" represents a stable 5 to 7 membered ring containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, and which can be fused with a benzene ring or a 5 to 6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen. A "non-aromatic heterocycle" represents a stable 4 to 7 membered ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen. Examples of such aromatic and nonaromatic heterocycles include thienyl, thiophenyl, furyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, imidazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, pyrrolyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like. "Ci-Cβ alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical Ci-Cδ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. "C2-C6 alkanoyl" represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety. Typical C2-C6 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3- methylpentanoyl and the like. "C3-C6 cycloalkyl" represents a saturated hydrocarbon ring structure containing from three to six carbon atoms. Typical C3-C6 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, and the like. The term "amino-protecting group" or "Prot-" as used in the specification refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include "ArCO" wherein "Ar" is defined as above, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyl oxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 1,1-diphenyleth- 1-yloxycarbonyl, 1J -diphenyl prop- 1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p- toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1- methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1- methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)- ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)- ethoxycarbonyl, fluorenylmethoxy-carbonyl ("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)prop-l-enyloxycarbonyl, 5- benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyl oxycarbonyl, isobomyloxycarbonyl, 1-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups. Preferred amino-protecting groups are "ArCO", trityl, t-butoxycarbonyl (t-BOC), phthalimido, allyloxycarbonyl and benzyl oxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam, "Protective Groups in Organic Chemistry", (J.G.W. McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis" (1991), at Chapter 7. The term "carboxy-protecting group" as used in the specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while reacting other functional groups on the compound. Examples of such carboxy-protecting groups include methyl, ethyl, p-nitrobenzyl, p-methylbenzyl, p- methoxy-benzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4'- dimethoxy-benzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4- methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n- butyl)methylsilyl)ethyl, p-toluenesulfonyl ethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, l-(trimethylsilylmethyl)prop-l-en-3-yl and like moieties. Preferred carboxy- protecting groups are allyl, benzyl, ethyl, and t-butyl. Further examples of these groups are found in E. Haslam, supra, at Chapter 5, and T.W. Greene, et al., supra, at Chapter 5. The term "leaving group" as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term "leaving group" as used in this document encompasses, but is not limited to, activating groups. The term "activating group" as used herein refers a leaving group which, when taken with the carbonyl (-C=O) group to which it is attached, is more likely to take part in an acylation reaction than would be the case if the group were not present, as in the free acid. Such activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -O-CO-(C 4 -C7 alkyl). The term "solid support" refers to a solid and insoluble substrate, within a combinatorial chemistry reaction medium, capable of containing chemical functionality. The term "solid supported scavenger" refers to a solid and insoluble substance, within a combinatorial chemistry reaction medium, containing chemical functionality which is reactive with impurities sought to be removed from the reaction medium. The term "scaffold reactant" refers to the reactant within a combinatorial chemistry reaction medium which contains the invariant or core region of the library of compounds synthesized by the combinatorial process. The compounds encompassed by the present invention can have multiple asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention. As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to one of two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers". The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "rel" refers to the relative stereochemistry of a given compound and is used in nomenclature when there is more thatn one asymmetric center in a structure. As used herein, "rel-(R,R)" denotes a racemic mixture of (R,R)- and (S,S)- isomers and "rel-(R,S)" denotes a racemic mixture of (R,S)- and (S,R)- isomers. The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which is found using the following equation: ee = ((E' E 2 )/(E 1 + E 2 )) X 100 wherein E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90: 10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. Examples of resolutions include recrystallization techniques or chiral chromatography. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120. In addition to the (R)-(S) system, the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D" is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left. As noted supra, this invention includes prodrugs and pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. The term "prodrug" as used herein refers to metabolically labile esters of the compounds of Formula I. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. In addition, it is understood in the art that such salts may exist as hydrates. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1- sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. The preferred compounds of the present invention are those represented by Formula I wherein, a) n is O or l; b) X is O or S; c) Rl and R 2 are each independently H, or R* and R 2 together represent "=O"; d) R 3 is Ci-Cg alkyl; e) Ar is meta-substituted aryl (aromatic , heteroaromatic) f) R 4 is H, F, Cl, or OMe; g) A is -CH2-, -O-, or -(CH2)2 and h) B is C1-C3 alkyl, methylene, methylmethylene, -CH2O-, -CH=CH-, - CHOH. More preferred are the compounds represented by Formula I wherein, a) n is 1 b) X is S; c) R 3 is methyl; d) Ar is 3-bromophenyl, 3-chlorophenyl, 6-chloropyridin-2-yl, or 5- chlorofuran-2-yl; e) Z is 1-indanyl, 3-chlorophenethyl, or 3-fluorophenethyl; f) A is -CH2-; and g) B is methylene. Especially preferred compounds of the present invention are those specifically exemplified herein as Example 1, Example 2, Example 25, Example 26, Example 29, and Example 30. (See infra.) Most preferred are the compounds of Example 25 and Example 30. This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formula I. Many of these compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate. This invention also encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of stimulation of Group I metabotropic glutamate receptors, preferably the receptor designated as mGluR5, which method comprises administering to a patient in need thereof, an effective amount of a compound of Formula I. The term "patient" as used herein refers to a mammal such as a mouse, guinea pig, rat, dog, or human. It is understood that the preferred patient is a human. The term "treatment" (or "treating" or "treat") as used herein includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods of the present invention encompass both therapeutic and prophylactic uses. The term "effective amount" as used herein refers to the amount or dose of the compound of Formula I which provides the desired effect in the patient under diagnosis or treatment. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disorder involved; the degree of or involvement or the severity of the disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. The term "neurodegenerative condition or disease" refers to neurological disorders including, for example, cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal hypoxia, cardiac arrest, hypoglyemic neuronal damage, ocular damage and retinopathy, and idiopathic and drug-induced Parkinson's Disease. The compounds of the present invention are also useful for the treatment of pain. "Pain" as used herein refers to acute, chronic, persistent, intractable, and neuropathic pain. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of a compound used in the present methods of treatment. Preferably, the daily dose will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0J mg/kg to about 25 mg/kg. The methods of the present invention are carried out by administering a Group I metabotropic glutamate receptor antagonist at a dose which provides an effective level of compound in the body. The metabotropic glutamate receptor antagonist may be administered in a single dosage form, or may be administered in combination with other therapies. Oral administration is a preferred route of administration. However, oral administration is not the only route or even the only preferred route. The compound may be administered by other routes including the transdermal, percutaneous, intravenous, intramuscular, intranasal or intrarectal route, in particular circumstances. The route of administration may be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the caregiver. The compounds of the present invention may be administered as a pharmaceutical compositions, and so pharmaceutical compositions incorporating the compounds are important embodiments of the present invention. Such compositions may take any physical form which is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred. Such compositions contain an effective amount of a compound of the present invention, which effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a compounds, or may contain a fraction of the daily dose, such as one-half or one-third of the dose. Alternatively, each dosage unit may contain the entire dose of the compounds. The amount of a compound to be contained in each dosage unit depends on the identity of the compound chosen for the therapy, and other factors such as the indication for which the treatment is being given. Preferred compounds for use in the methods of the present invention are those represented by Formula I wherein, a) n is O or l; b) X is O or S; c) Rl and R 2 are each independently H, or Rl and R 2 together represent "=O"; d) R 3 is Cι -C 6 alkyl; e) Ar is meta-substituted aryl (aromatic , heteroaromatic) f) R 4 is H, F, Cl, or OMe; g) A is -CH 2 -, -O-, or -(CH 2 )2-; and h) B is C1-C3 alkyl, methylene, methylmethylene, -CH2O-, -CH=CH-, -CHOH. More preferred for use in the methods of the present invention are those compounds represented by Formula I wherein, a) n is i; b) X is S; c) R 3 is methyl; d) Ar is 3-bromophenyl, 3-chlorophenyl, 6-chloropyridin-2-yl, or 5- chlorofuran-2-yl; e) Z is 1-indanyl, 3-chlorophenethyl, or 3-fluorophenethyl; f) A is -CH2-; and g) B is methylene. Especially preferred compounds for use in the methods of the present invention are those specifically exemplified herein as Example 1, Example 2, Example 25, Example 26, Example 29, and Example 30.(See infra.) Most preferred for use in the present methods are the compounds of Example 25 and Example 30. The compounds of the present invention can be synthesized by a variety of procedures well known to those of ordinary skill in the art. For example, U.S. Patent No. 4,666,901, herein incorporated by reference, describes solution phase synthesis of monocyclic lactams useful as angiotensin converting enzyme(ACE) inhibitors. As with any compound, the particular order of steps required to produce a specific compound given by Formula I is dependent upon the particular compound being synthesized, the starting material, and the relative lability of the substituents as appreciated by one of ordinary skill in the art. General procedures, useful for synthesizing the compounds of the present invention are depicted by the following schemes. Substituents appearing in these descriptions are as defined above, unless otherwise indicated. Note, these are descriptions of general methods and as such, are in no way to be interpreted as limiting the scope of the present invention. All reagents and starting materials are readily available to the ordinarily skilled artisan. Scheme I General method from amine or amine salt Formula U Formula I Compounds of Formula I are prepared under standard conditions from primary amines (Formula U), or an amine salt of (II), such as for example a hydrochloride salt, by amide formation with a carboxylic acid derivative. Many methods are convenient for amide formation, including: (a) reaction with an acid chloride, ArCOCl, in the presence of a base such as triethylamine or pyridine, in an inert solvent such as dichloromethane, chloroform, or tetrahydrofuran, preferably at a temperature between 0 and 40 °C; (b) activation of a carboxylic acid with 2-chloro-l-methylpyridinium iodide (Mukaiyama's reagent) in the presence of a base such as triethylamine or pyridine, in an inert solvent such as dichloromethane, chloroform, or tetrahydrofuran, preferably at a temperature between 0 and 40 °C; (c) activation of a carboxylic acid with EDC (l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and PP-HOBT (piperidino- piperidine derivative of 1 -hydroxy benzotriazole useful as a catlyst for amide formation as described in US Patent Application 09/213734, the entire contents of which is herein incorporated by reference) in a mixture of solvents such as dichloromethane and dimethylformamide, preferably at room temperature between 20 and 30 °C, followed by filtration removal, on an SCX column, of basic reagents from the neutral amide product of Formula I; (d) activation of a carboxylic acid to form a mixed anhydride with, for example, acetic anhydride or trifluoroacetic anhydride, in the presence of a dehydrating agent; and (e) activation of a carboxylic acid with, for example, N, N'- carbonyldiimidazole (CDI) or N, N'-dicyclohexylcarbodiimide (DCC). Compounds of Formula I, in which X is S, are prepared by thionation of compounds of Formula I in which X is O, by reaction with, for example, 4- methoxyphenylthionophosphine sulphide dimer (Lawesson's reagent) or phosphorus pentasulphide, in an inert solvent such as toluene, preferably at a temperature between 20 and 110 °C. Compounds of Formula I, and the intermediates leading to them, can be present in isomeric forms. These isomers can be separated by standard methods such as column chromatography for diastereoisomers, or preparative chiral HPLC for enantiomers. Scheme II Preparation of amine (or amine salt) (V) (VI) (ll) Amines (Formula II) or their salts, as part of the present invention, are prepared from an intermediate aldehyde (Formula IV). The aldehyde (TV) contains a protected amine, in which the protecting groups (Prot-) include t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), ArCO, or phthalimido where Prot -NH is and also contain an ester group, COOR, where R represents Cι-C 6 alkyl, such as, for example, methyl. Boc is the preferred protecting group. Note, where the aldehyde (IV) has the protecting group ArCO , such as, for example, 3-bromobenzoyl, then reductive amination with Z-NH2 and cyclization produces the compounds of Formula I directly. The amines (Formula II), or their salts, are prepared by at least one of the following methods. Note, the particular method chosen is dependant upon the desired structure of the amine (Formula II) sought. Amines (Formula U) in which X is O Reductive amination of the aldehyde (IN) with a primary amine ZΝH 2 is conducted in the presence of reducing agents such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, in alcoholic solvents such as ethanol or in solvents such as tetrahydrofuran or acetic acid. Preferably, this step is performed at a temperature between 0 and 80 °C. Cyclization to the lactam (Formula UJ) can occur spontaneously at room temperature (depending on ring size and Z-group), or can be induced by heating in solvents such as toluene or methanol/triethylamine, preferably at a temperature between 60 and 110 °C, or can be effected by reagents such as trimethylaluminium in inert solvents such as toluene, preferably at a temperature between 20 and 80 °C. The lactam (Formula UJ) is deprotected using standard methods known in the art, with the exact method chosen being dependant on the particular protecting group employed. Where Prot is Boc, the lactam (Formula UJ) is treated with an acid, such as HC1, in the presence of a solvent such as, for example, dioxan or diethylether, preferably at a temperature between 0 and 40 °C, to produce the amine salt. Alternatively, the lactam can be treated with an acid, such as trifluoroacetic acid, preferably at a temperature between 0-40 °C, to produce the amine salt. When Prot is Cbz, the lactam (Formula III) is hydrogenolyzed with hydrogen in the presence of 5% palladium on carbon, in solvents such as methanol, ethanol, toluene, or acetic acid at room temperature, in order to produce the amine. Where Prot is phthalimido, the lactam (Formula UJ) is deprotected by reagents such as hydrazine in solvents, such as ethanol, preferably at a temperature between 20 and 80 °C to produce the amine (U). Amines (TD in which X is S Lactams (Formula UJ) are thionated by reaction with, for example, 4- methoxyphenylthionophosphine sulphide dimer (Lawesson's reagent) or phosphorus pentasulphide, in an inert solvent such as toluene, preferably at a temperature between 20 and 110 °C. Deprotection is then carried out using standard methods as described above, with the exact method chosen being dependant on the particular protecting group employed. Amines (TD in which Rl and R2 together are "=O" Conversion of the aldehyde (Formula IV) to the acid (Formula V) can be carried out using oxidizing agents such as ruthenium tetroxide (formed from sodium periodate and catalytic ruthenium trichloride), in sovents such as a mixture of chloroform, acetonitrile, and water, preferably at a temperature between 0° and 60° C. To form the amide, the acid (Formula V) is reacted with ZNH2 using standard methods such as activation of the acid with 2-chloro-l-methylpyridinium iodide (Mukaiyama's reagent) in the presence of a base such as triethylamine or pyridine, in an inert solvent such as dichloromethane, chloroform or tetrahydrofuran, preferably at a temperature between 0 and 40 °C. Cyclization of the amide to form Formula IN is carried out by treatment with an alkali metal base, such as sodium hydride or lithium bis(trimethylsilyl)amide, in an inert solvent such as dimethylformamide or tetrahydrofuran, preferably at a temperature between 0 and 80 °C. Deprotection is then carried out using standard methods as described above, with the exact method chosen being dependent on the particular protecting group employed. Aldehyde starting reactants, Formula IN in Scheme U above, may be synthesized by typical methods, well known to those of ordinary skill in the art. As such, the following procedure, which describes one such method useful for generating the aldehyde reactant (Formula IV) employed in the synthesis of compounds of Formula I, should not be inteφreted as limiting the present invention in any way. The skilled artisan will recognize that other methods are available for the synthesis of aldehydes, and that the particular method chosen will be dependent on the final product sought. Sche e III Preparation of aldehyde starting reactant (1) (2) I . (4) (5) (6) Preparation of (2) To an amino acid, methanol is added followed by HCl (bubbled) until the solid dissolves. The reaction is heated to reflux and left to stand at room temperature overnight. When the reaction is 90% complete, additional HCl gas is bubbled followed by further reflux. After standing at room temperature for 2 days the methanol is evaporated to yield a white solid which is triturated with diethyl ether. The solid is collected by filtration and dried under vacuum to afford the intermediate (2). Preparation of (3) (2) is added to a flask, followed by a solution of freshly distilled benzaldehyde in a solvent such as dichloromethane. A solution of triethylamine in dichloromethane is then added, followed by additional dichloromethane to facilitate stirring. After stirring overnight at room temperature, the solvents are removed by evaporation and the solid residue is triturated with diethyl ether. The solid (e.g. Et 3 N- HC1) is removed by filtration and the filtrate is evaporated to afford the intermediate (3). Preparation of (4 To a flask equipped with a mechanical stirrer and a nitrogen inlet, sodium hydride is added as a dispersion in an oil, such as mineral oil. The sodium hydride is slurried with hexane to remove the mineral oil then a solution of intermediate (3) in, for example, tetrahydrofuran, is then added dropwise with continuous stirring for approximately 30 minutes. After addition of (3) a solution of allyl bromide or 4-bromo- 1-butene in a solvent, such as tetrahydrofuran, is added dropwise until a precipitate forms. After additional stirring, the reaction is allowed to stand overnight at room temperature. Water is then added to the mixture and the reaction extracted with diethyl ether three times. Intermediate (4) is obtained after drying the combined extracts over sodium sulfate, filtering, and evaporating the filtrate. Preparation of (5) A solution of intermediate (4) in diethyl ether is stirred vigorously with HCl for approximately 3 hours. The layers are separated and the aqueous layer extracted with diethyl ether. The ether layers are discarded and sodium chloride is added to the aqueous solution which is then basified to a pH ~ 9.5 with, for example, sodium hydroxide, then extracted with dichloromethane. The dichloromethane layers are combined, dried (with for example Na 2 SO 4 ), filtered, and evaporated to yield the free base of intermediate (5) as a colorless oil. HCl gas is then bubbled into this solution, followed by evaporation and addition of ethyl acetate. The crystals formed (intermediate 5), can then be collected by filtration. Preparation of (6) The amino group of intermediate (5) is protected, for example with ArCO, then dissolved in a solvent such as dichloromethane. The reaction is cooled under a stream of nitrogen then treated with a stream of ozone until the reaction turns blue. Methyl sulfide is added to the reaction after which the reaction is allowed to stand at room temperature overnight. The reaction is extracted with saturated NaHCO 3 and saturated NaCl, then dried over Na 2 SO 4 , filtered, and evaporated to yield the aldehyde of intermediate (6). Alternatively, the protected intermediate (5) is treated with sodium periodate and osmium tetroxide in a solvent such as dioxan and H2O. In order to preferentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes. The practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" (1991). In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I. Such protocols usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer. In addition to the conventional synthesis methods described above, the compounds of the Formula I wherein X is O can also be generated using the methods of combinatorial chemistry. The techniques of combinatorial chemistry are employed to generate large numbers (i.e. 10^ to 10") of compounds which are therein referred to as "libraries". Theoretically, the total number of compounds that may be produced for a given library is limited only by the number of reagents available to form the substituents on the variable regions of the library's general formula. Further, combinatorial processes lend themselves to automation, both in the generation of compounds and in their screening for biological activity. Combinatorial chemistry can be used both to generate highly "diverse" compound libraries as well as to optimize a particular lead compound from a previous round of syntheses through generation of "directed libraries". As used herein, "diverse library" refers to a library where the substituents on the combinatorial library scaffold of the compounds are highly vaiable in terms of their constituent atoms and/or molecular weight, and the library, therefore, is no a collection of closely related homologues or analogues. "Directed library", as used herein, refers to a collection of compounds created for the puφose of optimizing a lead compound, wherein each compound shares at least one common substituent on the library scaffold, while maintaining variability at another substituent, thus allowing optimization of the variable moeity. Combinatorial chemistry may be performed in a manner wherein libraries of compounds are generated as mixtures, with complete isolation of the individual compounds postponed until after a positive finding of biological activity. However, a preferred form of combinatorial chemistry is "parallel array synthesis" wherein individual compounds are synthesized contemporaneously, but are retained in separate reaction vessels. For example, library compounds may be held in the individual wells of a 96-well microtiter plate (Beckman Coφ., Fullerton CA.). Use of microtiter plates, or an equivalent apparatus, is of particular advantage because of its adaptability to automated robotic machinery. As appreciated by those of ordinary skill in the art, conventional combinatorial chemistry can be performed on a "solid support" or a polymer. As used herein polymer refers to a molecule composed of resin monomers to which the compounds of the present invention are attached. Suitable polymer resins for use in the present invention must be inert to the reaction conditions for compound synthesis. Suitable polymers include Merrifield type resins, Wang type resins, and polyamide type resins. Examples of these include polystyrene(Bachem Inc.), polyamide resins, POLNHTPE™ resin (Aminotech Co., Canada), p-alkoxybenzyl alcohol resin, polystyrene resin grafted with polyethylene giycol, or polydimethylacrylamide resin. (See generally: Solid Phase Peptide Synthesis, J.M. Sheppard et al., 2 nd Ed, 1984, Pierce Chemical Co., Illinois). Preferably, polystyrene is used in the process of the present invention. Here, the library "scaffold reactant" is tethered to the sold support via a chemical linker. Reactants are added to the reaction vessel to modify the scaffold reactant, followed by cleavage of the final product from the solid support. In this solid phase synthesis, variations in the reactants added to the scaffold produce the desired structural diversity of the library's general formula. Separation of the product and the unreacted reactants is accomplished by filtration, decantation, or washing, all techniques well appreciated by those of ordinary skill in the art. Altematively, solution phase combinatorial processes can also be used to generate the compounds of the present invention. Here, an excess of a particular reaction reagent may be added to a soluble solution of a scaffold reactant, driving the solution phase reaction to completion. In this process, unreacted soluble reagents may then be removed from the reaction medium using a "solid supported scavenger". A library of lactam compounds, comprising the Group I metabotropic glutamate receptor antagonists of the present invention, may be generated combinatorially by reacting an aldehyde scaffold reactant with a primary amine reactant. The following scheme (Scheme IV), represents a general process for a conventional solution phase combinatorial synthesis of the compounds given by Formula I, wherein X is O, R* and R^ are H, and further as defined above. Scheme IV Conventional Solution Phase Combinatorial synthesis Aldehyde Scaf fold ( 6a) Formula I The aldehyde scaffold reactants are synthesized essentially as described in Scheme UJ above, where the scaffold reactant is represented by intermediate (6). The scaffold reactants ( (n) equivalents) are each placed in a reaction vessel, followed by an excess (l.l(n) equivalents) of a soluble primary amine, Z-NH2, wherein Z is as defined previously. This reaction is maintained at a suitable temperature and for a suitable time to permit reaction between the various aldehyde scaffold reactants and the various primary amine reactants Next, is added a large excess (~ 4.0(n) equivalents) of a solid supported reducing agent, represented by P-BH4 in Scheme IV, wherein P represents a solid support (i.e polymer) and BH4 is the reducing agent borohydride. Those of ordinary skill in the art will appreciate that other solid supported reducing agents such as cyanoborohydride or triacetoxyborohydride can replace boroydride in Scheme IV and, therefore, the depiction of borohydride as the reducing agent in Scheme IN should not be inteφreted as limiting the invention. The reaction is maintained at a suitable temperature and for a suitable time to allow reaction of intermediates to yield secondary amines. The unreacted primary amine is removed from the reaction by addition of a solid supported aldehyde scavenger, represented by P-CHO in Scheme IN above. The reaction is maintained at a suitable temperature and for a suitable time to permit reaction of said excess primary amine with said scavenger. The separation of the solid supported reducing agent and scavenger from the reaction vessel is done by any of a number of available chemical or physical methods well known to those of ordinary skill in the art. Such physical methods, applicable to all members of a diverse library include: (i) filtration; (ii)centrifugation; (iii) decantation; (iv) washing, and the like. Filtration is particularly useful and is practiced by passing the reaction medium of each library compound through a filter apparatus which retains the excess solid supported reactants while allowing the solution containing the desired compound to pass into a separate vessel. Finally, the solution phase is placed in a glass vial and capped for approximately 12 hours at 60°C. This heating, in turn, promotes cyclization of intermediate U in Scheme IV above, to yield the final lactam product as represented by Formula I. Combinatorial chemistry can also be employed to optimize a particular substituent on a lead compound generated from a previous round of synthesis. As used herein, a "lead compound" refers to a lactam compound, synthesised using the methods of the present invention, which has been shown to possess the desired biological activity of a human Group I metabotropic glutamate receptor antagonist. When employed for lead optimization, combinatorial chemistry results in a "directed library", wherein each compound within the library shares at least one common functional substituent, while maintaining variability at the remaining substituent sites on the library scaffold. The "directed library" is, thus, in its entirety, a collection of closely related homologues or analogues. For example, combinatorial chemistry can be employed to generate a directed library of lactam compounds of Formula I, wherein each compound within the library shares a common lactam amine functionality substituent, while maintaining variability at the amide functional substituent, thus allowing optimization of the amide moiety of the lead compounds of Formula I. The following scheme, Scheme V, depicts a combinatorial process useful for the optimization of the amide substituent of the combinatorial scaffold of Formula I, wherein X is O. In this process, an amine reactant is placed in each of an array of reaction vessels, followed by the addition of various carboxylic acid derivatives. The library of lactam products, made from this combinatorial process, share a common amine functionality substituent, while maintaining variability at the amide moiety. Scheme V Optimization of amide moiety Compounds of Formula I are prepared from primary amines (Formula U), or an amine salt of (U), such as for example a hydrochloride salt, by amide formation with a carboxylic acid derivative. Many methods are convenient for amide formation, including: (a) reaction with an acid chloride, ArCOCl, in the presence of a base such as triethylamine or pyridine, in an inert solvent such as dichloromethane, chloroform, or tetrahydrofuran, preferably at a temperature between 0 and 40 °C; (b) activation of a carboxylic acid with 2-chloro-l-methylpyridinium iodide (Mukaiyama's reagent) in the presence of a base such as triethylamine or pyridine, in an inert solvent such as dichloromethane, chloroform, or tetrahydrofuran, preferably at a temperature between 0 and 40 °C; (c) activation of a carboxylic acid with EDC (l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride) and PP-HOBT (piperidino-piperidine derivative of 1- hydroxy benzotriazole useful as a catlyst for amide formation as described in US Patent Application 09/213734, the entire contents of which is herein incoφorated by reference) in a mixture of solvents such as dichloromethane and dimethylformamide, preferably at room temperature between 20 and 30 °C, followed by filtration removal, on an SCX column, of basic reagents from the neutral amide product of Formula I; (d) activation of a carboxylic acid to form a mixed anhydride with, for example, acetic anhydride or trifluoroacetic anhydride, in the presence of a dehydrating agent; and (e) activation of a carboxylic acid with, for example, N, N'-carbonyldiimidazole (CDI) or N, N'- dicyclohexylcarbodiimide (DCC). Compounds of Formula I, and the intermediates leading to them, can be present in isomeric forms. These isomers can be separated by standard methods such as column chromatography for diastereoisomers, or preparative chiral HPLC for enantiomers. The starting amine salt employed in Scheme V is generated by reductive amination in the usual manner, followed by cyclization, according to the following scheme(Scheme VI). Scheme VI Reductive amination of protected aldehyde followed by cyclization Formula U Reductive amination of a protected aldehyde scaffold reactant (IV) with a primary amine ZNH 2 is conducted in the presence of reducing agents such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, in alcoholic solvents such as methanol or in solvents such as tetrahydrofuran or acetic acid. Preferably, this step is performed at a temperature between 0 and 80 °C. Cyclization to the lactam can occur spontaneously at room temperature (depending on ring size and Z- group), or can be induced by heating in solvents such as toluene or methanol/triethylamine, preferably at a temperature between 60 and 110 °C, or can be effected by reagents such as triethylaluminium in inert solvents such as toluene, preferably at a temperature between 20 and 80 °C. The lactam is deprotected using standard methods known in the art, with the exact method chosen being dependant on the particular protecting group employed. The skilled artisan will recognize that other protecting groups can be employed in Scheme VI, other than Boc and, thus, the depiction of Boc, in Scheme VI should not be construed as limiting the present invention in any way. Where Boc is employed, the lactam is treated with acid in the presence of a solvent such as, for example, dioxan or diethylether, preferably at a temperature between 0 and 40 °C, to produce the amine salt (U). The amine salt is then converted to the free base by well known methods. Preferably, the amine salt used is the hydrochloride salt. Alternatively, the lactam can be treated trifluoroacetic acid, preferably at a temperature between 0-40 C, to produce the amine salt (U). When Prot is Cbz, the lactam is hydrogenolyzed with hydrogen in the presence of 5% palladium on carbon, in solvents such as methanol, ethanol, toluene, or acetic acid at room temperature, in order to produce the amine (U). Where Prot is phthalimido, the lactam is deprotected by reagents such as hydrazine in solvents, such as ehtanol, preferably at a temperature between 20 and 80 °C to produce the amine (U). The biological activity of the compounds of the present invention was evaluated by employing a phosphoinositide hydrolysis assay or a calcium mobilization assay. As mentioned supra, "metabotropic" glutamate receptors are G-protein, or secondary messenger-linked, receptors. As such, these receptors are linked to multiple second messenger systems which enhance phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). A general description of the phosphoinositide hydrolysis assay employed in the present invention is given as follows: (a) Cell cultures: mGluR5 or mGluRl receptor expressing cell lines are cultured in DMEM supplemented with 5% heat inactivated fetal calf serum, sodium pyruvate (lmM), glutamine (lmM), penicillin (lOOU/ml), streptomycin (lOOmg/ml), HEPES (lOmM), geneticin G418 (0.5mg/ml) and hygromycin B (0.2mg/ml). Confluent cultures are passaged weekly. (b) Phosphoinositide Hydrolysis Assay: Transfected cells are seeded into 24 well culture plates at 2.5 x 10 5 cells per well in medium containing no added glutamine and cultured at 37°C in a humidified atmosphere of 5% CO 2 in air. After 24hr, the cells are labeled with [ 3 H]-inositol (4uCi/ml) for a further 20hr. Cells are washed in assay medium containing HEPES (lOmM), inositol (lOmM) and lithium chloride (lOmM). Antagonists are added to the cell cultures 20 min prior to the addition of quisqualate and then the culture is further incubated in the presence of agonist for 60 min. The reaction is terminated by replacing the medium with acetone:methanol (1:1) and then incubating the cultures on ice for 20 min. Separation of the [ 3 H]-inositol phosphates is carried out by Sep -Pak Accell Plus QMA ion exchange chromatography (Waters, Millipore Ltd., UK) according to the method described by Maslanski and Busa (Methods in Inositide Research; ed. Irvine, R.F. pp. 113-126; New York, Raven Press Ltd. 1990). The [ 3 H]-inositol monophosphate (INS PI) fraction is eluted with 0JM triethyl ammonium bicarbonate buffer and radioactivity measured by liquid scintillation counting. Following the measurement of radioactivity for each fraction eluted, IC50 calculations were made for each antagonist examined. Representative compounds of the present invention generated IC50 values equal to or less than 30μM in the phosphoinositide assay herein described, when mGluR5 expressing cell lines were employed. Alternatively, the biological activity of the compounds of the present invention can be determined employing an assay which monitors intracellular calcium ion concentration in response to metabotropic glutamate receptor activation. As stated supra, activation of G-protein coupled receptors triggers a sequence of events which contribute to alterations in intracellular calcium concentration. By monitoring alterations in calcium ion concentration in response to metabotropic glutamate receptor activation, one can identify compounds functional as metabotropic glutamate receptor antagonists. A general description of a calcium flux assay which can be employed to determine the biological activity of the compounds of the present invention is given as follows: (a) Plate Preparation: Plates containing cells expressing mGluR5 or mGluRl are prepared using standard methods well known to those of skill in the art. Reagent plates are prepared containing 160μlΛvell of buffer (1% DMSO or compound in l%DMSO buffer) and additional plates are prepared containing 260μl/well of lOμM Glutamate in assay buffer. (b) Calcium Flux Assay: Media is removed from the plates containing the cells expressing mGluR5 using a hand held aspirator or standard plate washer. 50μl of lOμM Fluo3 Dye is added to each well which in turn will emit fluorescence upon binding to calcium ions. Cells are incubated at room temperature for approximately 90 minutes to allow the Fluo3 Dye to load into the cells. The dye is then aspirated and replaced with 50ul of buffer. The plates are placed in a fluorescent light imaging plate reader (FLIPR) such that the plate containing the buffer or compound is to the right of the cell plate, while the plate containing the glutamate is placed to the left of the cell plate. The FLIPR is programmed to take background fluorescence readings for 10 seconds then add buffer or compound to the cell plates. After 3 minutes, the FLIPR adds lOOμl of lOμM glutamate to mobilize cellular calcium ion stores and fluorescence is measured for about a minute. Fluorescence values for cells containing buffer are compared relative to cells containing mGluR5 antagonist compound. Percent inhibition of mGluR5 elicited calcium ion influx, as indexed by fluorescence, is calculated for each compound. Representative compounds of the present invention at a concentration of 30μM produce percent inhibition values equal to or higher than 70 % in the calcium flux assay described herein, when mGluR5 expressing cells are employed . The compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I and a pharmaceutically-acceptable carrier, diluent, or excipient. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium sterate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the inventions may be formulated so as to provide quick, sustained, or delayed released of the active ingredient after administration to the patient by employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, more usually about 25 to about 300 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. Formulation 1 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) Compound of Formula I 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in mg quantities. Formulation 2 A tablet is prepared using the ingredients below: Quantity (mg tablet) Compound of Formulal 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid _5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg. Formulation 3 An aerosol solution is prepared containing the following components: Weight % Compound of Formula I 0.25 Ethanol 29.75 Propellant 22 70.00 (chlorodifluoromethane) Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. Formulation 4 Tablets each containing 60 mg of active ingredient are made as follows: Compound of Formula I 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formulation 5 Capsules each containing 80 mg medicament are made as follows: Compound of Formula I 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities. Formulation 6 Suppositories each containing 225 mg of active ingredient may be made as follows: Compound of Formula I 225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. Formulation 7 Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows: Compound of Formula I 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution OJO ml Flavor q.v. Color q.v. Purified water to total 5 ml The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. Formulation 8 An intravenous formulation may be prepared as follows: Compound of Formula I 100 mg Mannitol 100 mg Purified water to total 5 ml The following Examples further illustrate the compounds of the present invention and the methods of their synthesis. The examples are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. The abbreviations employed in the following examples are commonly used in the field and would be readily understood by a practitioner in the field. For example; "Ph" refers to a phenyl group; "Me" refers to a methyl group; "Et" refers to an ethyl group; "Bu" refers to a butyl group; "t-Bu" refers to a tert-butyl group; "Mp. °C" refers to the melting point of a compound if it is a solid or, in the alternative, notes the form of the compound at ambient temperature; "MS" defines the mass of the particular compound as determined using mass spectroscopy; "MW" defines the molecular weight of the particular compound; "eq" refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "μL" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "min" refers to minutes; "h" refers to hours; "°C" refers to degrees Celsius; "NMR" refers to nuclear magnetic resonance spectroscopy; 'TR" refers to infrared spectroscopy; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "Rf" refers to retention factor; "R t " refers to retention time; "δ"refers to part per million down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to methyl sulfoxide; "LDA" refers to lithium diisopropylamide; "aq" refers to aqueous; 'TFA" refers to trifluoroacetic acid: "iPrOAc" refers to isopropyl acetate; "iPr" refers to an isopropyl group; "EtOAc" refers to ethyl acetate; and "RT" refers to room temperature. Example 1 rel-(R,R)-3-[(3-Bromobenzoyl)amino]-l-(l-indanyl)-3-methylpyrrolidin-2-one. Mp. °C: Oil MW: 412.9 i ) A solution of triethylamine (37.2ml) in dichloromethane (50ml) was added to a stirred solution of methyl L-alanine hydrochloride (37.3g) and benzaldehyde (27.2ml) in dichloromethane (350ml) cooled in an ice bath under nitrogen atmosphere. After stirring overnight the thick suspension was evaporated and the residue triturated with diethylether (200ml). The solid was filtered, washed with ether and the filtrate washed with water, then brine solution. The ether solution was dried over magnesium sulphate, filtered and evaporated to give a yellow liquid. Distillation gave the imine as a colourless liquid. ii ) The preceding imine (36.5g) in dry tetrahydrofuran (20ml) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in oil, 7.64g) in tetrahydrofuran (200ml) at room temperature under nitrogen atmosphere. After 20 min and approximately one quarter of the addition the reaction became exothermic. After lh the clear red solution was cooled in an ice bath and allyl bromide (19.4ml) was added dropwise. After stirring overnight the yellow suspension was diluted with diethylether (100ml) and cautiously quenched with water (100ml). The mixture was extracted twice with ether and the combined ether solutions washed with water (3x), then brine solution. The ether solution was dried over magnesium sulphate, filtered and evaporated to give an orange oil of the α-allyl imine. ii ) A mixture of the α-allyl imine (91.7g) in diethylether (450ml) and 2M hydrochloric acid (450ml) was stirred rapidly for 4h at room temperature. The aqueous solution was separated, washed with ether and then basified to pH 11 with sodium hydroxide solution. The aqueous solution was saturated with sodium chloride and extracted twice with dichloromethane. The dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to give a yellow oil of methyl α-allylalanine. iv) 3-bromobenzoyl chloride (35.5ml) was added dropwise to a stirred solution of methyl α- allylalanine (30g) and triethylamine (37.3ml) in dichloromethane (330ml) at room temperature under nitrogen. After 4h, the dichloromethane solution was successively washed with 2M hydrochloric acid, saturated aqueous bicarbonate (2x) and brine solution. The dichloromethane solution was dried over magnesium sulphate, filtered and evaporated. The residual oil was purified by chromatography through a pad of silica eluting with ethyl acetate:hexane 80:20 to give methyl N-(3-bromobenzoyl)allylalanine. v) Method 1 A solution of sodium periodate (37.5g) in water (250ml) was added dropwise over 15 min to a stirred solution of methyl N-(3-bromobenzoyl)-α-allylalanine (34.2g) and several crystals of osmium tetroxide (approx. 30mg) in dioxan (390ml) and water (50ml). After 5h at room temperature, water was added and the mixture extracted with diethylether (3x). The ether extracts were washed with water and saturated aqueous sodium bicarbonate, then was dried over magnesium sulphate, filtered and evaporated. The residual oil was purified by chromatography through a pad of silica eluting with 2% methanol in dichloromethane to give methyl N-(3-bromobenzoyl)-α-(2-oxoethyl)alanine as a viscous oil. Method 2 A solution of methyl N-(3-bromobenzoyl)-α-allylalanine (38.9g) in dichloromethane (250ml) was cooled to -78°C and ozone bubbled through until a blue colour persisted (3V6h). The excess ozone was purged by bubbling oxygen through the solution until the colour changed back to yellow. Dimethylsulphide (200ml) was added and the solution allowed to stand at room temperature overnight. The dichloromethane solution was washed with saturated sodium bicarbonate solution (3x), brine, and then was dried over magnesium sulphate, filtered and evaporated. The residual oil was purified by chromatography through a pad of silica eluting with 2% methanol in dichloromethane to give methyl N-(3- bromobenzoyl)-α-(2-oxoethyl)alanine as an oil. i) 1 -amino indane was reacted with methyl N-(3-bromobenzoyl)-α-(2-oxoethyl) alanine as described in Example 2 to give the title product. Example 2 (R,R)-3-[(3-Bromobenzoyl)amino]-l-(l-indanyl)-3-methylpyrrolidin-2-one. Mp. °C: white glass MS: [M+H] 413.415 R-(-)-l-aminoindane (8J2g) was added to a stirred solution of N-(3-bromobenzoyl)-α-(2- oxoethyl)alanine (20g) in methanol (400ml) at room temperature under nitrogen. After lh solid sodium borohydride (4.6g) was added portionwise over 20 min causing effervescence and a temperature rise to 32°C. After VΛ water was added and the mixture extracted with diethylether (2x). The ether extracts were washed with brine (3x), dried over magnesium sulphate, filtered and evaporated to a pale viscous oil. The oil was dissolved in methanol (416ml) and triethylamine (41.6ml) and heated under reflux for 24h. The solution was evaporated and the residue dissolved in ethyl acetate, washed with 2M hydrochloric acid (2x), brine(3x), dried over magnesium sulphate, filtered and evaporated to a white foam. The mixture was purified by flash chromatography eluting with ethyl acetate:hexane 80:20 to give isomer- 1 followed by isomer- 2, the title product as a white solid. Impure column fractions were chromatographed again to give a further crop of the title product. 3-[(3-Chlorobenzoyl)amino]-l-(l-indanyl)-3-methylpyrrolidin-2-one. Mp. °C: 160-161 MS: [M+H] 369, 371 i ) Di-t-butyldicarbonate (57.0g) was added to a stirred solution of methyl α-allylalanine (37.4g) in 10% triethylamine/ methanol (160ml) under nitrogen. The mixture was heated to 45°C for lh, then allowed to stand overnight at room temperature. The solution was evaporated to give methyl N-(t-butoxycarbonyl)-α-allylalanine as a yellow oil. ii ) A solution of methyl N-(t-butoxycarbonyl)-α-allylalanine (29.3g) in dichloromethane (120ml) was cooled to -78°C and ozone bubbled through until a blue colour persisted (4!/2h). The excess ozone was purged by bubbling oxygen through the solution until the colour changed back to yellow. Dimethylsulphide (80ml) was added and the solution allowed to stand at room temperature overnight. The dichloromethane solution was washed with saturated sodium bicarbonate solution (3x), brine (2x), dried over magnesium sulphate, filtered and evaporated to give methyl N-(t-butoxycarbonyl)-α-(2-oxoethyl)alanine as an oil. ii ) A solution of methyl N-(t-butoxycarbonyl)-α-(2-oxoethyl)alanine (5g) and 1-aminoindane (2.85g) in methanol (50ml) was stirred at room temperature under nitrogen atmosphere for 1.25h. The reaction mixture was then cooled to 0°C and sodium borohydride (1.54g) added portionwise, After addition, the reaction mixture was stirred at room temperature for lh, concentrated in vacuo, diluted with water and extracted twice with diethylether. The combined extracts was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to give methyl 2-(t-butoxycarbonyl)amino-4-(indanyl-l-amino)-2- methylbutanoate as a brown oil. iv) A solution of methyl 2-(t-butoxycarbonyl)amino-4-(indanyl-l-amino)-2-methylbutanoate (6.7g) in toluene (100ml) was heated at reflux under a nitrogen atmosphere for 24h. After cooling the solvent was evaporated to give a red oil. The crude oil was purified on flash silica eluting with diethylether: hexane 3:2 to give the diastereomeric mixture of 3-(t- butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-one as an oil. v) A stirred solution of 3-(t-butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-one (5Jg) in dioxan (20ml) was treated with a 4M solution of hydrogen chloride in dioxan (20ml). After 3h at room temperature, the solution was evaporated to a foam. The mixture was dissolved in dichloromethane and washed with a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate, filtered and evaporated to give 3-amino-l-(l-indanyl)-3-methylpyrrolidin-2-one as a red oil. vi ) To a stirred solution of 3-amino-l-(l-indanyl)-3-methylpyrrolidin-2-one (0.5 lg) and dried triethylamine (0.34ml) in dichloromethane (20ml) was added a solution of 3-chlorobenzoyl chloride (0.42g) in dichloromethane (10ml). After stirring overnight at room temperature, the reaction mixture was washed with 2M hydrochloric acid, water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to an oil. The diastereomers were separated on flash silica eluting with diethylether to give the title compound in the slower eluting fraction as a white solid, m.p. 160-161°C. Example 4 3-[(3-Chlorobenzoyl)amino]-l-(3-chlorophenethyl)-3-methylpyrrolidin-2-one. Mp. °C: 137-138 MS: [M+H] 391, 393, 395 i ) The reaction between methyl N-(t-butoxycarbonyl)-α-(2-oxoethyl)alanine (4.04g) and 3- chlorophenethylamine (2.8 lg) in methanol (40ml) was carried out as in example 3(iii). After reduction with sodium borohydride (l.Oδg) and aqueous work-up, the crude product was crystallised from cyclohexane to give 3- (t-butoxycarbonyl)amino-l-(3-chlorophenethyl)-3- methylpyrrolidin-2-one as a white solid. ii ) Following the procedure described in example 3(v), 3-(t-butoxycarbonyl)amino-l-(3- chlorophenethyl)-3-methylpyrrolidin-2-one was converted to 3-amino-l-(3- chlorophenethyl)-3-methylpyrrolidin-2-one to give a brown oil. iii ) Following the procedure described in example 3(vi), 3-amino-l-(3-chlorophenethyl)-3- methylpyrrolidin-2-one was treated with 3-chlorobenzoyl chloride in the presence of triethylamine. After work-up and crystallisation of the crude from methanol, the title compound was obtained as a white solid, m.p. 137-138°C. Example 5 3-[(3-Bromobenzoyl)amino]-l-(3-chlorophenethyl)-3-methylpyrrolidine-2-one. MS: 434.9, 436.9 i.) Reductive amination of a protected aldehyde was performed in the usual fashion. Approximately 0.6 lg of a t-Boc protected aldehyde, as given in Scheme VI above, was weighed out into a 100ml round bottom flask (reaction vessel). Approximately 0.67g (1J (n) equivalents) of 2-(3-chlorophenyl) ethylamine was transferred to the reaction vessel by dilution with MeOH and rinsing with MeOH. Total volume was approximately 6.0ml. The reaction vessel was shaken on a platform shaker for 2 hours to permit mixing of the reactants. The reactions were then evaporated, followed by addition of MeOH to the original volume. After the reaction cooled in an ice/ethanol bath, approximately 185 mg (5mmol) of the reducing agent sodium borohydride was added while mixing with a boiling stick. Reactions were allowed to mix gently on a platform shaker for 2 days at room temperature to allow cyclization of the lactam product, (crude weight ~ 880mg.) Mass spectroscopy revealed cyclized lactam product without amine intermediates. Chromatography of the lactam product was performed over 62g. silica, applied in CHCI3 to a column equilibrated with 60:40 EtOAc:Hexane, and eluted with 100ml of 60:40 EtOAc:Hexane, 100 ml 70:30 EtOAc:Hexane, and 100 ml 80:20 EtOAc:Hexane. The weight of chromatographed product was ~ 439mg. for a percent yield of approximately 50%. ) The t-Boc protecting group was removed form the product of step (i) by dissolving the lactam in 2N HCl in dioxane in a round bottom flask. After one hour the reaction was evaporated and the resulting amine # HCl was obtained. Directed combinatorial synthesis, essentially as described in Scheme V above, was performed on the lactam product obtained from part (i) in order to optimize the amide functional substituent of Formula I. The amine»HCl was dissolved in THF to make a 0.05M solution and 0.7ml (35umoles) of the amine»HCl was aliquoted into each of a 9 X 11 array of 4ml reaction vials. To each vial, next was added 0.6ml (30umol) of a .05M carboxylic acid solution (for this example 3- bromobenzoic acid) dissolved in 25% DMF in CHCI3 , 0.2ml (35 umol) of PP- HOBT, and 0.4ml (40umol) of 0JM EDCΗC1 solution in DCM. The reaction vials were then capped and rocked for 16 hours at room temperature. The reaction was then purified over 500 mg. varian SCX columns conditioned with 2.5ml MeOH and 2.5ml 10% MeOH:CHCl3 . The reaction mixture was loaded as is and washed with 2.5ml 10% MeOH:CHCl3 and eluted by gravity. The products were evaporated with high nitrogen flow at 25° hot plate setting. 0.2ml of CHCI3 and re -evaporated then 0.2ml of CHCI3 was added and the product was evaporated again at 45°C. Yield of product was -100% and NMR showed less than 1 equivalent of DMF after MeOH evaporation. Finally, the product was dissolved in 2.5ml of 1:1 MeOH:CHCl3 and mass spectroscopy and TLC were performed. Title product was then transferred to a 96 well plate for biological activity determination. Examples 6 - 12 The following table (Table I) illustrates additional compounds (Examples 6 -12), produced using the directed combinatorial methods, essentially as described for Example 5 above. The abbreviations used in the table are commmonly used in the field and would be readily appreciated by a practitioner in the field. In the Table I below, the first column gives the example number for the compound. The second column provides the structure of the exemplified compound. The next two columns describe the substitutions of the particular example compound. "ArCOOH" provides the carboxylic acid (or derivative) employed to optimize the amide functionality of the lactam product essentially as described in Scheme V above, wherein "Ar" is as defined previously. "Z-NH2" provides the primary amine employed in the reductive amination of the protected aldehyde scaffold reactant as described in Scheme VI, wherein "Z" is as described previously. The next column, entitled "Stereo" describes the stereochemistry profile of the exemplified compound. "MW", defines the molecular weight of the compound and "MS" defines the mass of the compound as as determined by mass spectroscopy. Table I Example Structure No. ArCOOH Z-NH2 Stereo MW MS 11 12 Example 13 3-[(3-Bromobenzoyl)amino]-l-(5-fluoroindan-l-yl)-3-methylpyrrolidin-2-one. Mp. °C:180-181 MS: [M+H] 431, 432, 433, 434 The reaction between methyl N-(3-bromobenzoyl)-α-(2-oxoethyl)alanine (0.66g) and 1- amino-5-fluoroindane (0.30g) in methanol (10ml) was carried out as described in example 3(iii). Reduction with sodium borohydride (0J5g) and aqueous work-up gave an orange oil. The crude oil was heated at reflux in methanol (10ml) in the presence of triethylamine (1.3ml) for 16h. After cooling the solvent was evaporated and the residue partitioned between diethylether and 2M hydrochloric acid. The aqueous phase was washed with diethylether and the combined organic phases washed with water and brine, dried over magnesium sulphate, filtered and evaporated to a white foam. Separation of the diastereomers on flash silica eluting with ethyl acetate:hexane 70:30 gave the desired diastereomer in the slower eluting fraction. The resulting oil was crystallised from ethyl acetate to give the title compound as a white solid, m.p. 180-181°C. Example 14 3-[(3-Bromobenzoyl)amino]-l-(5-chloroindan-l-yl)-3-methylpyrrolidin-2-one. Mp. °C: 211-214 MS: [M+H] 447, 449, 451 The reaction between methyl N-(3-bromobenzoyl)-α-(2-oxoethyl)alanine (0.66g) and 1- amino-5-chloroindane (0.34g), was followed by reduction with sodium borohydride and carried out as described in example 13. The crude oil was heated at reflux in methanol (10ml) in the presence of triethylamine (1.3ml) for 16h. After similar work-up and chromatography the title compound was obtained as a white solid, m.p. 211-214°C. Example 15 3-[(3-Bromobenzoyl)amino]- 1 -(2,3-dihydro-4H-benzopyran-4-yl)-3-methylpyrrolidin-2-one. Mp. °C: 172-173 MS: [M+H] 429, 431 i.) A stirred suspension of 4-chromanone (25g), potassium carbonate (23.3g) and hydroxylamine hydrochloride (11.6g) in ethanol (200ml) was heated under reflux for l'/∑h. After cooling, water (125ml) was added to crystallise the oxime product. ii.) A solution of the oxime (5.0g) in acetic acid (50ml) and Adams catalyst (0.25g) was hydrogenated at 50 psi for Ih. The catalyst was filtered and the filtrate evaporated to a colourless oil. The oil was suspended in 2M aqueous sodium hydroxide solution (50ml) and extracted with dichloromethane (2x, 50ml). The extracts were dried, filtered and evaporated to a colourless oil. Distillation using a bulb to bulb apparatus gave 2,3- dihydro-4H-benzopyran-4-amine, b.pJ00-120°C @ OJmbar. iii.) A solution of 2,3-dihydro-4H-benzopyran-4-amine (0.3g) and methyl N-(3- bromobenzoyl)-α-(2-oxoethyl)alanine (0.65g) in methanol (13ml) was stirred at room temperature under nitrogen. After lh solid sodium borohydride (0J5g) was added portionwise. The mixture effervesced and became warm. After lh water (20ml) was added and the mixture extracted with diethylether (2x, 20ml). The extracts were washed with brine solution (20ml), dried, filtered and evaporated to a viscous oil (0.78g). A solution of the oil in methanol (13ml) and triethylamine (1.3ml) was heated under reflux for 24h. The mixture was evaporated and the residue dissolved in ethyl acetate (20ml) and washed with 2M hydrochloric acid (2x, 20ml) and brine (20ml). The ethyl acetate solution was dried, filtered and evaporated to a white foam (0.6 lg) containing a mixture of the two diastereomers of the title compound. Chromatography on flash silica eluting with ethyl acetate:hexane 80:20 gave isomer-1 followed by the title compound, isomer-2. m.p. 172- 173°C. Example 16 3-[(3-Bromobenzoyl)amino]-l-(2,3-dihydrobenzofuran-3-yl)-3-methylpyrrolidin-2-one. Mp. °C: 173 MS: [M+H] 415, 417 i ) A stirred mixture of 3-coumaranone(25g), sodium acetate (30.6g) and hydroxylamine hydrochloride (25.7g) in ethanol (125ml) was heated under reflux for lh. After cooling water (150ml) was added to crystallise the oxime product as yellow needles. ii ) Freshly prepared aluminium amalgam (from lOg foil) was added to a stirred mixture of the oxime (4.47 g) in ethanol (60ml) under nitrogen. The exothermic reaction caused the temperature to rise to reflux after lOmin. Additional ethanol (150ml) was added and the reaction was kept at reflux for 4h. The grey voluminous inorganic solid was filtered and the filtrate evaporated. The residue was dissolved in diethylether and washed with 2M aqueous sodium hydroxide solution (50ml). The ether solution was dried, filtered and evaporated and the liquid residue distilled to give 3-amino-2,3-dihydrobenzofuran. b.p. 160-170°C @ 4mbar. ii ) The reaction between 3-amino-2,3-dihydrobenzofuran (0J5g) and methyl N-(t- bromobenzoyl)-α-(2-oxoethyl)alanine (0.65g) was carried out as described in example 15(iii) and the diastereomeric mixture separated on flash silica to give the slower eluting title compound, isomer-2. m. p. 173°C. Example 17 3-[(3-Bromobenzoyl)amino]-l-(6-fluoroindan-l-yl)-3-methylpyrrolidin-2-one. Mp. °C: 196-197 MS: [M+H] 431, 433 The reaction between methyl N-(3-bromobenzoyl)-α-(2-oxoethyl)alanine (0.70g) and 1- amino-6-fluoroindane (0.34g), was followed by reduction with sodium borohydride and was carried out as described in example 13. After work-up and chromatography eluting with ethyl acetate: hex ane 1:1 and then 70:30, the title compound was obtained as a white solid, m.p. 196- 197°C. 3-[(3-Bromobenzoyl)amino] - 1 -(4-fluoroindan- 1 -yl)-3-methylpyrrolidin-2-one. Mp. °C: 193-194 MS: [M+H] 431, 433 The reaction between methyl N-(3-bromobenzoyl)-α-(2-oxoethyl)alanine (0.76g) and 1- amino-4-fluoroindane (0.37g), was followed by reduction with sodium borohydride and was carried out as described in example 13. After work-up and chromatography the title compound was obtained as a white crystals from ethyl acetate:hexane, m.p. 193-194°C. rel-(R,S)-3-[(6-Chloropyridin-2-yl)carboxamido]-l-(l-indanyl)-3-methylpyrrolidin-2-one. Mp. °C: 130-132 MS: [M+H] 370, 372 The reaction between 3-amino-l-(l-indanyl)-3-methylpyrrolidin-2-one (0.33g) and 6- chloro-2-pyridinecarbonyl chloride (0.28g) was carried out as described in example 3(vi). After non acidic aqueous work-up the crude product was partially separated into the respective diastereomers on flash silica eluting with dichloromethane:ethyl acetate 5: 1. The faster eluting diasteroisomer was crystallised from ethyl acetate-hexane to give the title compound as a white solid, m.p. 130-132°C. rel-(R, R)-3-[(6-Chloropyridin-2-yl)carboxamido]- 1 -( 1 -indanyl)-3-methylpyrrolidin-2-one. Mp. °C: 148-151 MS: [M+H] 370, 372 The slower eluting fraction from the chromatography described in example 19 gave the second diasteroisomer as an oil which after trituration with diethylether gave the title compound as a white solid, m.p. 148-151°C 3-[(3-Chlorobenzoyl)amino]-l-(3-chlorophenethyl)-3-methylpyrrolidin-2,5-dione. Mp. °C: 135-136 MS: [M+H] 405, 407, 409 i ) To a stirred solution of methyl N-(t-butoxycarbonyl)-α-(2-oxoethyl)alanine (15.0g) in a mixture of chloroform:acetonitrile:water (1:1:1.5, 56ml) cooled in an ice bath was added sodium periodate (38Jg) and ruthenium (UJ) chloride hydrate (0.66g). The mixture was kept at room temperature for 3! 2 h, then quenched with isopropanol (150ml), filtered through a pad of celite and evaporated. The oil was dissolved in toluene and evaporated to remove traces of isopropanol leaving methyl N-(t-butoxycarbonyl)-α-(carboxymethyl)alanine as a brown oil. ii ) A mixture of methyl N-(t-butoxycarbonyl)-α-(carboxymethyl)alanine (3.0g), 2-chloro-l- methylpyridinium iodide (2.94g) and dried triethylamine (3.2ml) in dichloromethane (30ml) was stirred at room temperature for lh. A solution of 3-chlorophenethylamine (1.79g) in dichloromethane (5ml) was then added. The reaction mixture was stirred at room temperature for l'/ 2 h, then washed with 2M hydrochloric acid, water, a saturated solution of bicarbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to a brown oil. The crude product was purified on flash silica eluting with ethyl acetate:hexane 1:1 to give methyl 2-(t-butoxycarbonyl)amino-3-(3- chlorophenethyl)carbamoyl-2-methylpropanoate as an oil. ii ) To a stirred solution of methyl 2-(t-butoxycarbonyl)amino-3-(3- chlorophenethyl)carbamoyl-2-methylpropanoate (1.7g) in dried tetrahydrofuran (100ml) under nitrogen atmosphere, was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 4.69ml). After 4h at room temperature, the reaction mixture was quenched with water (100ml) and acidified with 2M hydrochloric acid. A yellow solid was filtered and dried in vacuo at 60°C to give 3-(t-butoxycarbonyl)amino-l-(3- chlorophenethyl)-3-methylpyrrolidin-2,5-dione. iv) A stirred solution of 3-(t-butoxycarbonyl)amino-l-(3-chlorophenethyl)-3-methylpyrrolidin- 2,5-dione (0.42g) in dioxan (10ml) was treated with a solution of hydrogen chloride in dioxan (4M, 10ml) and stirred at room temperature for 24h. The reaction solution was evaporated to a solid, dissolved in water and washed with diethylether. The aqueous phase was made basic with aqueous saturated bicarbonate and extracted twice with dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 3-amino-l-(3-chlorophenethyl)-3-methylpyrrolidin-2,5-dione as a white solid. v) Following the procedure described in example 3(vi), 3-amino-l-(3-chlorophenethyl)-3- methylpyrrolidin-2,5-dione (0.37g) was treated with 3-chlorobenzoyl chloride (0.26g) in the presence of triethylamine (0.21ml). After l ^h, the reaction was worked up as described to give a yellow oil, then purified on flash silica eluting with ethyl acetate±exane 1:1, to give the title compound as a white solid, m.p. 135-136°C. 3-[(3-Bromobenzoyl)amino]-l-(3-methoxyphenethyl)-3-methylpyrrolidin-2-one. Mp. °C: viscous glass MS: [M+H] 431, 433 The reaction between 3-methoxyphenethylamine (0J5g) and methyl N-(3- bromobenzoyl)(2-oxoethyl)alanine (0.33g) was carried out as described in example 15(iii) followed by purification on flash silica eluting with ethyl acetate :hexane 75:25 to give the title compound as a colourless viscous glass. 3-[(3-Bromobenzoyl)amino]-l-methyl-3-trifluoromethylphenethylpyrrolidin-2-one. Mp. °C: viscous glass MS: [M+H] 469, 471 The reaction between 3-trifluoromethylphenethyl amine (0J9g) and methyl N-(3- bromobenzoyl)-α-(2-oxoethyl)alanine (0.33g) was carried out as described in example 15(iii) followed by purification on flash silica eluting with ethyl acetate exane 75:25 to give the title compound as a colourless viscous glass. Example 24 3-[(3-Bromobenzoyl)amino]-l-(9-fluorenyl)-3-methyl-pyrrolidin-2-one Mp. °C: 217-218 MS: [M+H] 461, 463 The reaction between 9-aminofluorene hydrochloride (0.22g) and methyl N-(t- butoxycarbonyl)-α-(2-oxoethyl)alanine (0.33g) was carried out as described in example 15(iii) with additional heating in toluene for three days. The crude product was recrystallised from toluene (6ml) to give the title compound as a white solid, m.p. 217-218°C. 3-[(3-Chlorobenzoyl)amino]-l-(3-chlorophenethyl)-3-methylpyrrolidin-2-thione. Mp. °C: 77-78 MS: [M+H] 407, 409, 411 i ) To a stirred solution of 3-(t-butoxycarbonyl)amino-l-(3-chlorophenethyl)-3- methylpyrrolidin-2-one (14.5g) in toluene (100ml) was added 2,4-bis-(4-methoxyphenyl)- l,3-dithia-2,4-diphosphetane-2,4-disulphide (9J2g) and the mixture heated to reflux for 2h. The mixture was cooled and evaporated to a red oil and partially purified on silica eluting with ethyl acetate exane (1:6) to give 3-(t-butoxycarbonyl)amino-l-(3-chlorophenethyl)-3- methylpyrrolidin-2-thione as an orange oil contaminated with reagent by-product. ii ) The deprotection of 3-(t-butoxycarbonyl)amino-l-(3-chlorophenethyl)-3-methylpyrrolidin- 2-thione (5.0g) was carried out as described in example 21(iv) allowing 6h for the completion of the reaction, to give 3-amino-l-(3-chlorophenethyl)-3-methylpyrrolidin-2- thione as a brown oil. iii ) Following the procedure described in example 3(vi), 3-amino-l-(3-chlorophenethyl)-3- methylpyrrolidin-2-thione (0.25g) was treated with 3-chlorobenzoyl chloride (0J6g) in the presence of triethylamine (0.25ml). After lh, the reaction was worked up as described and the resulting oil was purified on silica eluting with ethyl acetate:hexane (1:2, then 2:3) to give the title compound as a white solid, m.p. 77-78°C. (S)-3-[(3-Chlorobenzoyl)amino]-l-(3-chlorophenethyl)-3-methylpyrrolidin-2-thione. Mp. °C: Oil MS: [M+H] 407, 409, 411 The title compound was separated from the racemate in example 25 by preparative chiral HPLC on a 250x4.6mm. id. CHIRALCEL-OD column at a temperature of 40°C eluting at l l.Omin with hexane:isopropanol (9:1) at lml/min to give an oil. Example 27 rel-(R,R)-3-[(3-Bromobenzoyl)amino]-l-(l-indanyl)-3-methylpyrrolidin-2-thione. Mp. °C: 127-128 MS: [M+H] 429, 431 i ) Following the procedure described in example 25(i) 3-(t-butoxycarbonyl)amino-l-(l- indanyl)-3-methylpyrrolidin-2-one (2.0g) was treated with 2,4-bis-(4-methoxyphenyl)-l,3- dithia-2,4-diphosphetane-2,4-disulphide(2.55g) in toluene (10ml). After 4h the solvent was -57- evaporated and the crude oil purified on flash silica eluting with ethyl acetate:hexane (1:1) to give 3-(t-butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-thione as a white solid. i ) The deprotection of 3-(t-butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-thione (0.9g) was carried out as described in example 3(v) to give 3-amino-l-(l-indanyl)-3- methylpyrrolidin-2-thione as solid. ii ) Following the procedure described in example 3(vi) 3-amino-l-(l-indanyl)-3- methylpyrrolidin-2-thione(0.3g) was treated with 3-bromobenzoyl chloride (0.29g) in the presence of triethylamine (0J8ml). The resulting diastereomeric mixture was partially separated on flash silica eluting with diethyletheπhexane (1:1), the slower eluting fractions were combined and evaporated to give the title compound as a white solid, m.p. 127-128°C. Example 28 rel-(R,S)-3-[(3-Bromobenzoyl)amino]-l-(l-indanyl)-3-methylpyrrolidin-2-thione. Mp. °C: 60-61 MS: [M+H] 429, 431 The faster eluting fractions from the chromatography described in example 27(iii) gave the title compound as a white solid, m.p. 60-61°C. (S,R)-3-[(3-Chlorobenzoyl)amino]-l-(l-indanyl)-3-methylpyrrolidin-2-thione. Mp. °C: viscous glass MS: [M+H] 385, 387 i ) A solution of R-(-)-l-aminoindane (8.4g) and methyl N-(t-butoxycarbonyl)-α-(2- oxoethyl)alanine (14.7g) in methanol (150ml) was stirred at room temperature for lh under nitrogen. Solid sodium borohydride (4.54g) was added portionwise over a period of 30min cooling to 20-25°C. After lh the solution was evaporated to a small volume and water was added. The mixture was extracted with ethyl acetate (2x, 100ml) and the extracts washed with brine (2x, 50ml). The organic phase was dried over magnesium sulphate, filtered and evaporated to a yellow viscous oil. A solution of the oil in toluene (100ml) was heated under reflux for 20h, then evaporated to a brown oil. The crude mixture of diastereomers was purified on flash silica eluting with ethyl acetate:hexane 45:55 to give isomer- 1 (S,R)- 3-(t-butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-one followed by isomer-2, (R,R)-3-(t-butoxycarbonyl)amino- 1 -( 1 -indanyl)-3-methylpyrrolidin-2-one. ii ) A solution of (S,R)-3-(t-butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-one (4.4g) in toluene (50ml) was heated to distill approximately 10ml of toluene to ensure an anhydrous solution. After cooling, 2,4-bis-(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane- 2,4-disulphide (2.83g) was added and the mixture heated to reflux for lh. The mixture was evaporated and the residue purified on silica eluting with dichloromethane to give (S,R)-3- (t-butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-thione as a pale yellow solid. iii ) A solution of 4M hydrogen chloride in dioxan (20ml) was added to (S,R)-3-(t- butoxycarbonyl)amino-l-(l-indanyl)-3-methylpyrrolidin-2-thione (2.7g). The solid dissolved and after 2h at room temperature the solution was evaporated to dryness. The residual solid was triturated with diethylether (30ml) and the white solid of (S,R)-3-amino- l-(l-indanyl)-3-methylpyrrolidin-2-mione hydrochloride filtered, m.p. 213 °C. iv) A solution of 3-chlorobenzoyl chloride (0J5g) in dichloromethane (1ml) was added to a stirred solution of (S ,R)-3-amino- 1 -( 1 -indanyl)-3-methylpyrrolidin-2-thione hydrochloride (0.20g) and triethylamine (0J7g) in dry dichloromethane (2ml) at room temperature. After ¥__ water (2ml) was added and the dichloromethane solution was washed successively with 1M hydrochloric acid, water, saturated sodium bicarbonate and brine. The dichloromethane solution was dried, filtered, evaporated and purified on flash silica eluting with ethyl acetate:hexane (33:67), to give the title compound as a colourless viscous glass. Example 30 (S,R)-3-[(6-Chloropyridin-2-yl)carboxamido]-l-(l-indanyl)-3-methylpyrrolidin-2-thione. Mp. °C: 158° MS: [M+H] 385, 387 The reaction between 6-chloropyridine-2-carbonyl chloride (OJ lg) and (S,R)-3-amino-l- (l-indanyl)-3-methylpyrrolidin-2-thione hydrochloride (0.16g) was carried out as described in example 29(iv). The product was purified on flash silica eluting with ethyl acetate:hexane (33:67), to give the title compound as a off white solid of mp. 158°C. Example 31 (S,R)-3-[(5-Chlorofuran-2-yl)carboxamido]-l-(l-indanyl)-3-methylpyrrolidin-2-thione. Mp. °C: glass MS: [M+H] 375, 377 A mixture of 2-chloro-l-methylpyridinium iodide (0J8g), 5-chlorofuroic acid (OJOg), and dry triethylamine (0.2 lg) in dry dichloromethane (2ml) was stirred at room temperature for lh. Solid (S,R)-3-amino-l-(l-indanyl)-3-methylpyrrolidin-2-thione hydrochloride (0.20g) was then added. The reaction mixture was stirred at room temperature for 2h, then washed with a saturated solution of bicarbonate and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated. The residual oil was purified on flash silica eluting with ethyl acetate:hexane 25:75 to give the title product as colourless viscous glass. 3-[(5-Chlorofuran-2-yl)carboxamido]-l-(3-chlorophenethyl)-3-methylpyrrolidin-2-one. Mp. °C: 137-138 MS: [M+H] 381, 383, 385 Following the procedure described in example 31, the title compound was prepared from 3-amino-l-(3-chlorophenethyl)-3-methylpyrrolidin-2-one (0.25g) and 5-chloro-2-furoic acid (0J5g). The crude product was purified on flash silica eluting with ethyl acetate exane (1:1, then 3:2), to give the title compound as a solid, m.p. 137-138°C. 3-[(3-Bromobenzoyl)amino]-l-(3-phenoxyphenethyl)-3-methylpyrrolidin-2-one Mp. °C: 125-127 MS: [M+H] 493, 495 The reaction between methyl N-(3-bromobenzoyl)-α-(2-oxoethyl)alanine (0.32g) and 3- phenoxyphenethyl amine (0.22g) was followed by reduction with sodium borohydride (0.07 g) and was carried out as described in example 3(iii). The crude oil was purified on flash silica eluting with ethyl acetate:hexane 2:1 to give the title compound as a solid, m.p. 125-127°C. 3-[(5-Chlorofuran-2-yl)carboxamido]-l-(3-chlorophenethyl)-3-methylpyrrolidin-2,5-dione. Mp. °C: 133-134 MS: [M+H] 395, 397, 399 Following the procedure described in example 31, the title compound was prepared from 3-amino-l-(3-chlorophenethyl)-3-methylpyrrolidin-2,5-dione (0.2g) and 5-chloro-2-furoic acid (OJlg). The crude product was purified on flash silica eluting with ethyl acetate:hexane (1:1), to give the title compound as a solid, m.p. 133-134°C. Example 35 rel-(R,S)-3-[(3-Bromobenzoyl)amino]- 1 -( 1 -indanyl)-3-methyl-2-piperidone. Mp. °C: Oil MS: [M+H] 427, 429 i ) A mixture of N-[(diphenylmethylene)glycine methyl ester (lOg), anhydrous potassium carbonate (27.2g), tetrabutylammonium bromide (2.5g) and 4-bromobut-l-ene (18.4g) was heated at reflux under an atmosphere of nitrogen in acetonitrile (120ml) for lOh. The reaction mixture was cooled to 0°C, filtered, washed collected solids with diethylether and evaporated the filtrate to give an oil. The oil was taken up in diethylether and the precipitate filtered. The filtrate was evaporated to give methyl 2-[(diphenylmethylene)amino]hex-5- enoate as an oil. ii ) A stirred solution of methyl 2-[(diphenylmethylene)amino]hex-5-enoate (26.4g) in dried tetrahydrofuran (300ml) was cooled to -78°C under nitrogen and a solution of potassium bis(trimethylsilylamide) in toluene (0.5M, 164ml) was added dropwise. After stirring at - 78°C for 45 minutes, a solution of iodomethane (10.2ml) in dried tetrahydrofuran (20ml) was added dropwise and the reaction mixture was allowed to warm slowly to room temperature. The resulting suspension was diluted with diethylether, filtered and evaporated to give methyl 2-[(diphenylmethylene)amino]-2-methylhex-5-enoate as an oil. ii ) A solution of methyl 2-[(diphenylmethylene)amino]-2-methylhex-5-enoate (26.5g) in aqueous citric acid (15%, 120ml) and tetrahydrofuran (130ml) was stirred at room temperature under nitrogen for 21h. The reaction mixture was washed with diethylether (40ml, 5x), the aqueous phase was saturated with sodium chloride and cooled to 0 C. Aqueous sodium hydroxide (50%) was added to the stirred aqueous phase until pH >10, the aqueous phase was then extracted with diethylether (4x) and the combined extracts dried over magnesium sulphate, filtered and evaporated to give methyl 2-amino-2-methylhex-5- enoate as an oil. iv) A solution of methyl 2-amino-2-methylhex-5-enoate (9.83g), phthalic anhydride (9.27g) and triethylamine (0.63g) in toluene (150ml) was heated at reflux under nitrogen with azeotroping of water. After 6h, the reaction was cooled and solvent evaporated to give an oil. The oil was dissolved in diethylether and washed with 2M hydrochloric acid, water (2x), a saturated solution of sodium bicarbonate, water (2x) and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to give methyl 2-(l,3-dihydro-l,3- dioxo-2H-isoindol-2-yl)-2-methylhex-5-enoate as an oil. v) To a stirred solution of methyl 2-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-2-methylhex-5- enoate (1.05g) in a mixture of dioxan (8ml) and water (3ml) containing a crystal of osmium tetroxide, was added portionwise over V__ a solution of sodium periodate (1.32g) in water (9ml). After VΛh the reaction was diluted with water and extracted with diethylether (2x). The combined extracts were washed with aqueous sodium metabisulphite (10%), water, brine, dried over magnesium sulphate, filtered and evaporated to an oil. The crude oil was purified on flash silica eluting with diethyletheπhexane (3:2) then diethylether to give methyl 2-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-4-formyl-2-methylbutanoate as an oil. vi ) A mixture of methyl 2-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-4-formyl-2- methylbutanoate (1.68g), 1-aminoindane (0.85g), sodium acetate (0.95g) and sodium cyanoborohydride (0.73g) in dried tetrahydrofuran (20ml) was stirred over baked molecular sieves (4A, 5.8g) at room temperature. After 4h, the reaction mixture was acidified with 2M hydrochloric acid, then basified with 2M sodium carbonate and extracted (2x) with diethylether. The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated to a red oil. The crude oil was purified on flash chromatography eluting with dichloromethane:methanol (99:1, then 98:2) to give methyl 2- (l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-5-(indan-l-amino)-2-methylpentanoate as an oil. ii ) To a stirred solution of methyl 2-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-5-(indan-l- amino)-2-methylpentanoate (0.62g) in dried toluene (100ml) at room temperature under nitrogen, was added a solution of trimethylaluminium in toluene (2M, 0.77ml). The solution was heated to 75°C for 5h, then cooled to 0°C and 2M hydrochloric acid was added dropwise. The mixture was stirred at room temperature for VΔh then washed with 2M hydrochloric acid, water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to an oil. The crude oil was purified on flash chromatography to give 3-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-l-(l-indanyl)-3-methylpiperidone as an oil. viii ) A solution of 3-(l,3-dihydro-l,3-dioxo-2H-isoindol-2-yl)-l-(l-indanyl)-3-methylpiperidone (O.l lg) and hydrazine monohydrate (0.02g)in ethanol (4ml) was heated at reflux under nitrogen for 6h. The reaction mixture was cooled, filtered and evaporated to an oil. The oil was taken up in chloroform and the fine suspension filtered through a pad of celite. The filtrate was evaporated to give 3-amino-l-(l-indanyl)-3-methyl-2-piperidone as an oil. ix) A mixture of 3-amino-l-(l-indanyl)-3-methyl-2-piperidone (0.05g), 3-bromobenzoyl chloride (0.05g) and dried triethylamine (0.23ml) in dried dichloromethane (3ml) was stirred under nitrogen at room temperature. After 3 hours the mixture was diluted with dichloromethane, washed with water (2X), brine, dired over magnesium sulphate, filtered, and evaporated to an oil. The crude diastereomeric mixture was separated on flash silica eluting with ethyl acetate:hexane (1:1). The faster eluting fractions were combined and evaporated to give the title compound as an oil. Example 36 rel-(R,R)-3-[(3-Bromobenzoyl)amino]-l-(l-indanyl)-3-methyl-2-piperidone. Mp. °C: Oil MS: [M+H] 427, 429 The slower eluting fraction from the chromatography in example 36(ix) gave the title compound as an oil. The following table (Table U) illustrates additional compounds (Examples 37-88), produced using the directed combinatorial methods, essentially as described for Example 5 above. While each of these compounds were made according to a particular directed combinatorial synthesis, the ordinarily skilled artisan will appreciate that all of these compounds could be synthesised as part of a diverse combinatorial library. The abbreviations used in the table are commmonly used in the field and would be readily appreciated by a practitioner in the field. In Table U below , the first column gives the example number for the compound. The second column provides the structure of the exemplified compound. The next two columns describe the substitutions of the particular example compound. "ArCOOH" provides the carboxylic acid (or derivative) employed to optimize the amide functionality of the lactam product essentially as described in Scheme V above, wherein "Ar" is as defined previously. "Z-NH2" provides the primary amine employed in the reductive amination of the protected aldehyde scaffold reactant as described in Scheme VI, wherein "Z" is as described previously. The next column, entitled "Stereo" describes the stereochemistry profile of the exemplified compound. "MW", defines the molecular weight of the compound and "MS" defines the mass of the compound as as determined by mass spectroscopy. Further, any other abbreviations used in Table U are commonly used in the field and, as such, would be readily understood by a practitioner in the field. Table U Example Structure ArCOOH Z-NH2 Stereo MW MS No. Table II Example Structure ArCOOH Z-NH2 Stereo MW MS No. racemic 414.09 417.00 racemic 370.14 371.00 racemic 404.07 406.90 Table II Example Structure ArCOOH Z-NH2 Stereo MW MS No. /y ^ cooH 53 racemic 340.18 341.10 Table II Example Structure ArCOOH Z-NH2 Stereo MW MS No. racemic 418.07 418.90 racemic 374.12 375.00 racemic 408.05 408.90 racemic 364.10 365.00 racemic 381.12 382.00 64 65 racemic 374.12 375.00 67 racemic 424.12 425.00 68 racemic 370.14 371.00 Table II Example Structure ArCOOH Z-NH2 Stereo MW MS No. racemic 360.12 361.00 73 racemic 414.09 415.00 74 racemic 370.14 371.10 75 racemic 404.17 405.10 76 racemic 350.20 351.10 racemic 404.07 404.90 racemic 360.12 361.00 Table II Example Structure ArCOOH Z-NH2 Stereo MW MS No. 79 racemic 365.15 366.00 80 racemic 344.15 345.00 racemic 364.10 365.00 racemic 374.12 375.00 racemic 408.40 409.00 racemic 354.17 355.10 Example 89 3-Chloro-N-{ l-[2-(3-chlorophenyl)ethyl]-3-methyl-2-oxo-3-azetidinyl}benzamide Mp. °C: 98-99 MS: [M+H] 377, 379 Method 1 i) Triethylamine (11 mmol) and chloroacetonitrile (11 mmol) were added to a solution of 3-chlorophenethylamine (10 mmol) in ethanol (30 ml) and the reaction mixture heated under reflux for 4 hours. The mixture was evaporated to a small volume, diluted with ethyl acetate (40 ml) and washed with water (2 x 30 ml) and brine (30 ml). The organic layer was separated, dried over sodium sulphate and evaporated in vacuo. The product was purified by column chromatography (silica, CHCI3: acetone 20:1) to give (2-(3-chlorophenyl)ethylamino)acetonitrile as a liquid. ii) To a stirred solution of diisopropylamine (45 mmol) and tetrahydrofuran (100 ml) cooled in a dry ice acetone bath, n-butyl lithium (43 mmol) was added. After one hour, a solution of (N-tert-butoxy-carbonyl)-L-alanine methyl ester (21.6 mmol) in anhydrous THF (40 ml) was added to the cooled reaction mixture. After one hour, a solution of (2-(3-chlorophenyl)ethylamino)acetonitrile (10.8 mmol) in anhydrous THF (30 ml) was added to the cooled mixture. After a further one hour at -78° C, the mixture was allowed to warm to room temperature and stirred for another 16 hours. The reaction mixture was quenched with aqueous saturated ammonium chloride, diluted with iced water and then extracted with CHCI3. The organic layer was separated, dried over sodium sulphate and evaporated in vacuo. The crude oil was purified by column chromatography twice (silica; hexane:ethyl acetate 1:1) to give tert-butyl l-[2-(3-chlorophenyl)ethyl]-3-methyl-2-oxo-3- azetidinylcarbamate as an oil that solidified on standing. iii) Trifluoroacetic acid (0J ml) was added to a stirred solution of tert-butyl l-[2-(3- chlorophenyl)ethyl]-3-methyl-2-oxo-3-azetidinylcarbamate (50 mg, 0J5 mmol) in CH2CI2 (0.5 ml) and anisole (50 mg). After 30 minutes at room temperature, the solution was evaporated and the residual oil was triturated with diethyl ether (0.2 ml), n-hexane (0.4 ml). The mixture was decanted to leave 3-amino-l-[2-(3- chlorophenyl)ethyl]-3-methyl-2-azetidinone trifluoroacetate as a viscous oil MS: [M+H] 239, 241. iv) A solution of 3-amino-l-[2-(3-chlorophenyl)ethyl]-3-methyl-2-azetidinone trifluoroacetate (35 mg) in dried CH2CI2 (0.5 ml) was added after one hour to a stirred mixture of 3-chlorobenzoic acid (15.7 mg, 0J mmol), 2-chloro-l- methylpyridinium iodide (25.5 mg, 0J mmol) and triethylamine (20 mg, 0.2 mmol) in dry CH2CI2 (0.5 ml) at room temperature. After 2 hours, saturated aqueous sodium bicarbonate (1 ml) was added. The CH2CI2 solution was washed with aqNaHCO3 (3 x 1 ml), brine (1 ml), dried, filtered and evaporated to a viscous oil. The product was purified by chromatography on flash silica (Et2θ then EtOAc) to give the title product as a white solid. Method 2 i) 3-Chlorobenzoy] chloride (9.34 g, 53.4 mmol) was added dropwise to a stirred solution of D,L-alanine methyl ester (5 g, 48.5 mmol) and triethylamine (8J ml, 58.2 mmol) in CH2CI2 (100 ml) cooled in an ice bath. After 30 minutes, allowed to warm to room temperature for 30 minutes. The reaction mixture was washed with water and brine then dried, filtered and evaporated to a yellow oil (11.23 g). The product was purified by chromatography on flash silica (EtOAc:hexane 1 :3) to give methyl 2-[(3-chlorobenzoyl)amino]propanoate as a colourless oil. ii) n-Butyl lithium (2.5 M in hexane, 31.2 ml, 78 mmol) was added to a stirred solution of diisopropylamine (8J4 g, 81 mmol) in dried THF (70 ml) cooled to -78° C. After one hour, a solution of methyl 2-[3-chlorobenzoyl)amino]-propanoate (6.30 g, 26 mmol) in THF (50 ml) was added dropwise. After 1.5 hours at 78° C. a solution of (2-(3-chlorophenyl)ethylamino)acetonitrile (5.05 g, 26 mmol) in THF (50 ml) was added and the mixture stirred for 2 hours before allowing to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The ethyl acetate solution was washed with water, brine, dried, filtered and evaporated to an orange oil. The crude product was purified by flash chromatography (EtOAc:hexane 1:4 then 1:1) to give the title product as a viscous oil (2.65 g). A sample crystallised from EtOAc:hexane 1:2 as a white solid. Example 90 3-Chloro-N{ l-[2-(3-chlorophenyl)ethyl]-3-methyl-2-thioxo-3-azetidinyl}benzamide Mp. °C: glass MS: [M+H] 393; 395 Lawessons reagent (301 mg, 0.745 mmol) was added to a stirred solution of 3-chloro-N-{ l-[2-(3-chlorophenyl)ethyl]-3-methyl-2-oxo-3-azetidinyl }benzamide (500 mg, 1.33 mmol) in toluene and the mixture heated under reflux for 2 hours. The solvent was evaporated and the residue chromatographed on flash silica (CH2CI2 then 10% Et2θ in CH2CI2) and further purified by chromatography (EtOAc:hexane 1:1) to give the title product as a glass. 3-(6-Chloropyridine-2-carboxamido)-l-(3-fluorophenethyl)-3-methylpyrrolidine-2-thione Mp.° C: 89-90 MS: (M+H] 392, 394 i) A solution of 2-(3-fluorophenyl)ethylamine (13.3 g, 95 mmol) and methyl N-(t- butoxycarbonyl)-α- (2-oxoethyl)alanine (23.4 g, 95 mmol) in methanol (200 ml) was stirred at room temperature under nitrogen atmosphere for 1.5 hours. The mixture was then cooled and solid sodium borohydride (7J9 g, 0J9 mol) added portionwise allowing effervescence to subside between additions. After 1.5 hours, the reaction was quenched with water (300 ml) and extracted with diethyl ether (2 x 300 ml). The ether extracts were washed with 2 M aqueous hydrochloric acid, water, brine, dried, filtered and evaporated to a yellow oil of 3-[N-(tert- butoxycarbonyl)amino]-l-(3-fluorophenethyl)-3-methyl-pyrrolidin-2-one that solidified on standing. ii) Lawessons reagent (17.48 g, 43.2 mmol) was added to a stirred solution of 3-[N- tert-butoxycarbonyl)amino]-l-(3-fluorophenethyl)-3-methylpyrrolidin-2-one (26.4 g, 78.6 mmol) in toluene (100 ml). After 2 hours heating under reflux, the mixture was evaporated to a red oil. The crude product was purified by chromatography on flash silica eluting with dichloromethane to give 3-[N-tert-butoxycarbonyl)amino]- l-(3-fluorophenethyl)-3-methylpyrrolidine-2-thione as an oil. iii) A solution of 3-[N-(tert-butoxycarbonyl)amino}-l-(3-fluorophenethyl)-3- methylpyrrolidine-2-thione (16.2 g, 46.2 mmol) in dioxan-HCl (4 M, 100 ml) was stirred at room temperature for 16 hours. The reaction mixture was evaporated and the residue dissolved in dioxan (20 ml). Diethyl ether (30 ml) was added and the product crystallised with cooling in the fridge to give 3-amino-l-(3- fluorophenethyl)-3-methylpyrrolidone-2-thione hydrochloride as a solid. iv) A solution of 6-chloro-2-pyridinecarbonyl chloride (6.04 g, 34 mmol) in dichloromethane was added to a stirred solution of 3-amino-l-(3-fluorophenethyl)- 3-methylpyrrolidine-2-thione hydrochloride (9.00 g, 31.2 mmol) and triethylamine (13 ml, 93.6 mmol) in dichloromethane (50 ml) at room temperature. After 3 hours the organic phase was washed with water, saturated aqueous sodium hydrogen carbonate, 2 M hydrochloric acid, brine, dried, filtered and evaporated to a red oil (12J g). The crude product was purified by column chromatography on flash silica eluting with diethyl ether followed by crystallisation from isopropyl alcohol to give the title product as a white solid. Example 92 (S)-3-(6-Chloropyridine-2-carboxamido)J-(3-fluorophenethyl)-3-methylpyrrolidine-2- thione Mp. ° C: 120-121 MS: (M+H] 392, 394 The title compound was separated from the racemate by preparative chiral HPLC on a 250 x 20 mm id chiracel-OD column using hexane:isopropanol 1:1 and collecting the first eluting enantiomer. The second eluting enantiomer was assigned (R)-configuration by xray structure analysis of crystals grown from ethyl acetate-hexane. Diastereoisomer 1: N-{ l-[2-amino-2-(3-chlorophenyl)ethyl]-3-methyl-2-thioxo-3- pyrrolidinyl}-3-chlorobenzamide hydrochloride salt. MS: [M+H] 422, 424 i) Aminodiphenylmethane (9.36 g) was added to a stirred solution of methyl N-(t- butoxycarbonyl)-α-(2-oxoethyl)alanine (11.92 g) in methanol (100 ml) at room temperature under an atmosphere of nitrogen. After one hour, the reaction mixture was cooled to 0° C. and sodium borohydride (3.71 g) added portionwise. After addition, the reaction mixture was stirred at room temperature for 0.5 hours, concentrated in vacuo, diluted with water and extracted twice with diethyl ether. The combined extracts were washed with water and brine, dried over magnesium sulphate, filtered and evaporated to give methyl 2-(t-butoxycarbonyl)amino-4- (diphenylmethyl)amino-2-methylbutanoate as an oil. ii) A solution of methyl 2-(t-butoxycarbonyl)amino-4-(diphenylmethyl)amino-2- methylbutanoate (18.0 g) in methanol (200 ml) was hydrogenolysed over 10% palladium on carbon (3.0 g) at 70 psi for 2 days. The reaction mixture was filtered through celite and evaporated. The crude was crystallised from a mixture of cyclohexane and hexane to give 3-(t-butoxycarbonyl) amino-3-methylpyrrolidin-2- one as a colourless solid. iii) A suspension of 3-(t-butoxycarbonyl)amino-3-methylpyrrolidin-2-one (1.64 g) and 2,4-bis-(4-methoxyphenyl-l,3-dithia-2,4-diphosphetane-2,4-disulphide (1.61 g) in toluene (40 ml) was heated at reflux for 1 hour. The clear reaction mixture was cooled and evaporated to give a solid. The crude was purified on flash silica eluting with dichloromethane, dichloromethane-diethyl ether (19:1 and then 4:1) to give 3-(t-butoxycarbonyl)amino-3-methylpyrrolidin-2-thione as a colourless solid. iv) A mixture of powdered sodium hydroxide (45 mg), 3-(t-butoxycarbonyl)amino-3- methylpyrrolidin-2-thione (1.73 g) and methyl 2-(3-chlorophenyl)propenoate (1.82 g) in tetrahydrofuran (20 ml) was stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was neutralised with aqueous hydrochloric acid (2 M), concentrated in vacuo and diluted with water. The concentrate was extracted twice with diethyl ether and the combined extracts dried over magnesium sulphate, filtered and evaporated to give methyl 3-{3-[(t- butoxycarbonyl)amino] -3-methyl-2-thioxo- 1 -pyrrolidinyl } -2-(3- chlorophenyl)propanoate as an oil. v) A solution of hydrogen chloride in dioxan (4 M, 10 ml) was added to a stirred solution of methyl 3-{3-[(t-butoxycarbonyl)amino]-3-methyl-2-thioxo-l- pyrrolidinyl}-2-(3-chlorophenyl)propanoate (1.05 g) in dioxan (2 ml) at room temperature. After one hour, the reaction mixture was evaporated to give methyl 3-(3-amino-3-methyl-2-thioxo-l-pyrrolidinyl)-2-(3-chlorophenyl)propanoate hydrochloride salt as a colourless solid, vi) A mixture of methyl 3-(3-amino-3-methyl-2-thioxo-l-pyrrolidinyl)-2-(3- chlorophenyl)propanoate hydrochloride salt (0.89 g), triethylamine (0.75 g) and 3-chlorobenzoyl chloride (0.47 g) in dichloromethane (20 ml) was stirred at room temperature for 45 minutes. The reaction mixture was washed with aqueous hydrochloric acid (2 M), water and brine, dried over magnesium sulphate, filtered and evaporated to give methyl 3-{3-[(3-chlorobenzoyl)amino]-3-methyl-2-thioxo-l- pyrrolidinyl}-2-(3-chlorophenyl)propanoate as an oil. vii) A solution of methyl 3-{3-[(3-chlorobenzoyl)amino]-3-methyl-2-thioxo-l- pyrrolidinyl } -2-(3-chlorophenyl)propanoate (0.48 g) and lithium hydroxide (0.22 g) in a mixture of methanol (30 ml) and water (10 ml) was stirred under an atmosphere of nitrogen at 0° C. for 7 hours. The reaction mixture was diluted with water and washed once with diethyl ether. The aqueous phase was acidified with aqueous hydrochloric acid (2 M) and extracted three times with dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 3- { 3-[(3-chlorobenzoyl)amino]-3-methyl-2-thioxo-l -pyrrolidinyl }-2-(3- chlorophenyl)propanoic acid as a colourless foam. viii) A mixture of 3- { 3-[(3-chlorobenzoyl)amino]-3-methyl-2-thioxo-l -pyrrolidinyl }-2- (3-chlorophenyl)propionic acid (0.35 g), diphenylphosphoric azide (0J6 g) and dried triethylamine (94 mg) in dried t-butanol (10 ml) was heated at reflux for 4 hours. The reaction mixture was cooled, evaporated and the residue purified on flash silica eluting with diethyl ether to give t-butyl 2-{3-[(3-chlorobenzoyl)amino]- 3-methyl-2-thioxo-l-pyrrolidinyl}-l-(3-chlorophenyl)ethylcarbamate as a colourless foam. The mixture of diastereoisomers was separated by preparative HPLC on a 250 x 20 mm id. KR60-5S1L column eluting at ambient temperature with hexane:dichloromethane:ethanol (73.5: 24.5: 2) at a flow rate of 20 ml/min to give diastereoisomer 1 and diastereoisomer 2 as colourless solids. ix) Diastereoisomer 1, t-butyl 2-{3-[(3-chlorobenzoyl)amino]-3-methyl-2-thioxo-l- pyrrolidinyl}-l-(3-chlorophenyl)ethylcarbamate (152 mg) was dissolved in a solution of hydrogen chloride in dioxan (4 M, 0.5 ml) and stirred at room temperature for 2 hours. The reaction mixture was evaporated and the residue triturated with diethyl ether to give the title compound as a solid. Diastereoisomer 2: _ .-{ l-[2-amino-2-(3-chlorophenyl)ethyl]-3-methyl-2-thioxo-3- pyrrolidinyl}-3-chlorobenzamide hydrochloride salt MS: [M+H] 422, 424 The title compound was prepared as a colourless solid from t-butyl 2-{3-[(3- chlorobenzoyl)amino]-3-methyl-2-thioxo-l-pyrrolidinyl}-l-(3- chlorophenyl)ethylcarbamate (170 mg) isolated as diastereoisomer 2 in Example 93 (viii) by the procedure described in Example 93 (ix). Mp. ° C: 118-120 MS: [M+H] 419, 421 i) A suspension of 3-(t-butoxycarbonyl)amino-3-methyl pyrrolidin-2-one (2.47 g) and trimethyloxonium fluoroborate (3.41 g) in dried dichloromethane (80 ml) was stirred at room temperature under an atmosphere of nitrogen for 24 hours. Cold aqueous potassium carbonate (10%, 15 ml) was added and the suspension filtered. The filtrate was separated and the organic phase dried over magnesium sulphate, filtered and evaporated to give t-butyl 5-methoxy-4-methyl-3,4-dihydro-2H-pyrrol- 4-ylcarbamate as a colourless oil. ii) A solution of t-butyl 5-methoxy-4-methyl-3,4-dihydro-2H-pyιτol-4-ylcarbamate (1.9 g) and 3-chloro-2-bromoacetophenone (2J4 g) in dried dimethylformamide (12 ml) was stirred at 60° C. under an atmosphere of nitrogen overnight. The reaction mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed three times with water and brine, dried over magnesium sulphate, filtered and evaporated to a red oil. The crude was purified on flash silica eluting with ethyl acetate-hexane (3:2) to give t-butyl l-[2- (3-chlorophenyl)-2-oxoethyl]-3-methyl-2-oxo-3-pyrrolidinylcarbamate as a yellow solid. iii) t-Butyl l-[2-(3-chlorophenyl)-2-oxoethyl]-3-methyl-2-oxo-3-pyrrolidinyl carbamate (0.70 g) was dissolved in a solution of hydrogen chloride in dioxan (4 M, 5 ml). The solution was stirred at room temperature for 2 hours giving a yellow suspension. The suspension was diluted with diethyl ether and filtered to give 3-amino-l-[2-(3- chlorophenyl)-2-oxoethyl]-3-methylpyrrolidin-2-one hydrochloride salt as a yellow solid. iv) To a stirred solution of 3-amino-l-[2-(3-chlorophenyl)-2-oxoethyl]-3- methylpyrrolidin-2-one hydrochloride (0.52 g) and triethylamine (0.4 g) in dichloromethane (20 ml) at room temperature was added a solution of 3- chlorobenzoylchloride (0.32 g) in dichloromethane (5 ml) dropwise. After stirring for 2 hours, the reaction mixture was washed with aqueous hydrochloric acid (2 M), twice with water and brine, dried over magnesium sulphate, filtered and evaporated to a foam. Trituration with diethyl ether and filtration gave N-{ l-[2-(3- chlorophenyl)-2-oxoethyl]-3-methyl-2-oxo-3-pyrrolidinyl } -3-chlorobenzamide as a colourless solid. v) To a stirred solution of N-{ l-[2-(3-chlorophenyl)-2-oxoethyl]-3-methyl-2-oxo-3- pyrrolidinyl} 3-chlorobenzamide (200 mg) in dried tetrahydrofuran (2 ml) was added a solution of methylamine in tetrahydrofuran (2M, 0.27 ml) followed by sodium triacetoxyborohydride (158 mg) and acetic acid (28 μl). The mixture was stirred at room temperature under an atmosphere of nitrogen for 3 days, then diluted with aqueous hydrochloric acid (2 M) and washed twice with diethyl ether. The aqueous phase was made basic with a saturated solution of sodium bicarbonate and extracted twice with dichloromethane. The combined extracts were washed twice with water, brine and dried over magnesium sulphate, filtered and evaporated to give a colourless oil. Crystallised from diethyl ether-hexane to give the title compound as a colourless solid. Methyl 3-{3-[(3-chlorobenzoyl)amino]-3-methyl-2-thioxo-l-pyrrolidinyl}-2-(3- chlorophenyl)propanoate MS: [M+H] 465, 467 The title compound was prepared by the method described in Example 93 (vi). Examples 97 - 120 The following table (Table HI) illustrates additional compounds (Examples 97 - 120), produced using the directed combinatorial methods, essentially as described for Example 5 above. The abbreviations used in the table are commmonly used in the field and would be readily appreciated by a practitioner in the field. In the Table HI below, the first column gives the example number for the compound. The second column provides the structure of the exemplified compound. The next two columns describe the substitutions of the particular example compound. "ArCOOH" provides the carboxylic acid (or derivative) employed to optimize the amide functionality of the thiolactam product essentially as described in Scheme V above, wherein "Ar" is as defined previously. "Z-NH2" provides the primary amine employed in the reductive amination of the protected aldehyde scaffold reactant as described in Scheme VI, wherein "Z" is as described previously. The next column, entitled "Stereo" describes the stereochemistry profile of the exemplified compound. "MW", defines the molecular weight of the compound and "MS" defines the mass of the compound as as determined by mass spectroscopy. Table HI Example MS Structure ArCOOH Z-NH2 Stereo MW No. [M+H] 102 enantiomer pair ..._.. 387 03 c diastereomeric ΛCrΛ nr . 455 454.95 .„ T N -Q Cl c rΛe » : Λ^ Cl mix 457 CF, ϋ ' racemic 424.46 425 enantiomer pair 4364g 437 43? 106 Table HI Table HI Example MS Structure ArCOOH Z-NH2 Stereo MW No. [M+H] 119 enantiomer P air 392.88 393 enanti ° merpair 376.86 N-{[2-(3-chlorophenoxy)ethyl]-3-methyl-2-thioxo-3-pyrrolidinyl}-3-chlorobenzamide Mp. °C: 114-115 MS: [M+H] 423 425 i) Sodium borohydride (847 mg, 22.4 mmol) was added portionwise to a stirred mixture of zirconium (IV) chloride (5.23 g, 22.4 mmol) in tetrahydrofuran (50 ml) with cooling under nitrogen atmosphere. 3-chlorophenoxy acetonitrile (3.0 g, 17.9 mmol) was added dropwise and the mixture stirred for lh before quenching with water. The mixture was basified with 2M sodium hydoxide and extracted with diethyl ether (2 x 100 ml). The extracts were washed with water, brine, dried filtered and evaporated to a yellow liquid that was purified by bulb to bulb distillation to give 2-(3-chlorophenoxy)ethylamine. ii) 2-(3-chlorophenoxy)ethylamine was reacted with methyl N-(t-butoxycarbonyl)-α- methyl-(2-oxoethyl)alanine as described in example 29 (i) to give 3-[N-(t- butoxycarbonyl)amino]-l-(3-chlorophenoxyethyl)-3-methylpyrrolidin-2-one as an oil. iii) 3-[N-(t-butoxycarbonyl)amino]-l-(3-chlorophenoxyethyl)-3-methylpyrrolidin-2-one was reacted with Lawessons reagent as described in example 29 (ii) to give 3-[N-(t- butoxycarbonyl)amino]-l-(3-chlorophenoxyethyl)-3-methylpyrrolidin-2-thione as an oil. iv) 3-[N-(t-butoxycarbonyl)amino]-l-(3-chlorophenoxyethyl)-3-methylpyrrolidin-2- thione was deprotected with 4M hydrogen chloride in dioxan as described in example 29 (iii) to give 3-amino-l-[2-(3-chlorophenoxy)ethyl]-3-methylpyrrolidin- 2-thione hydrochloride. v) 3-amino-l-[2-(3-chlorophenoxy)ethyl]-3-methylpyrrolidin-2-thione hydrochloride was reacted with 3-chlorobenzoyl chloride as described in example 29 (iv) to give the title product as a white solid. N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2-oxo-3-pyrrolidinyl}-3- chlorobenzamide Mp. °C: 122-125 MS: [M+H] 407, 409 i) To a stirred suspension of N-{ l-[2-(3-chlorophenyl)-2-oxoethyl]-3-methyl-2-oxo-3- pyrrolidinyl } -3-chlorobenzamide (300mg) in ethanol (4ml) at room temperature was added sodium borohydride (56mg) portionwise. The resulting opaque solution was stirred for lh then concentrated in vacuo, diluted with water and extracted twice with dichloromethane. The combined extracts was washed with brine, dried over magnesium sulphate, filtered and evaporated to a colourless foam. The title compound was crystallised from diethyl ether as a colourless solid. Diastereoisomer 1: N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2-thioxo-3- pyrrolidinyl } -3-chlorobenzamide Mp. °C: 66-68 MS: [M+H] 423, 425 i) N-(3-chlorobenzoyl)-α-(2-oxoethyl)alanine was prepared from methyl α- allylalanine and 3-chlorobenzoyl chloride following the procedures described in example 1 iv to v. ii) 2-t-Butyldimethylsilyloxy-2-(3-chlorophenyl)ethylamine (3.0g) was added to a stirred solution of N-(3-chlorobenzoyl)-α-(2-oxoethyl)alanine (3.0g) in methanol (45ml) at room temperature under an atmosphere of nitrogen. After 2h the reaction mixture was cooled in an ice bath and sodium borohydride (4.22g) was added portionwise. After lh at room temperature, the reaction mixture was concentrated in vacuo, diluted with water and extracted twice with dichloromethane. The combined extracts was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to a yellow oil. The oil was heated at reflux in toluene (20ml) under an atmosphere of nitrogen overnight and the solvent removed in vacuo to give N-{ 1- [2-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]-3-methyl-2-oxo-3- pyrrolidinyl } -3-chlorobenzamide as a yellow oil. iii) A suspension of N-{ l-[2-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]-3- methyl-2-oxo-3-pyrrolidinyl } -3-chlorobenzamide (1.44g) and 2,4-bis-(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide (0.57g) in toluene (30ml) was heated at reflux under an atmosphere of nitrogen for 40min. The solvent was removed in vacuo and the residue purified on flash silica eluting with dichloromethane-hexane (4:1) and dichloromethane to give N-{ l-[2-t- butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]-3-methyl-2-thioxo-3-pyrrolidinyl}- 3-chlorobenzamide as a colourless oil. iv) A solution of tetrabutylammonium fluoride in tetrahydrofuran (l.OM, 0.69ml) was added to a stirred solution of N-{ l-[2-t-butyldimethylsilyloxy-2-(3- chlorophenyl)ethyl]-3-methyl-2-thioxo-3-pyrrolidinyl } -3-chlorobenzamide (0.24g) in tetrahydrofuran (8ml). The reaction mixture was stirred at room temperature overnight. After addition of water (1ml), the reaction mixture was evaporated to dryness and the residue purified on flash silica eluting with diethyl ether to give a colourless oil. The resulting mixture of diastereoisomers was separated by preparative HPLC on a 250x20 mm id. KR60-5SIL column eluting at ambient temperature with hexane:tetrahydrofuran:ethanol (70:30:1.5%) at a flow rate of 20ml/min to give diastereomer 1 and diastereomer 2 as colourless solids. Diastereoisomer 2: N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2-thioxo-3- pyrrolidinyl } -3-chlorobenzamide Mp. °C: 126-128 MS: [M+H] 423, 425 i) The title compound was isolated by preparative HPLC from the procedure described in example 123 iv) as a colourless solid. Diastereoisomer 1: 5-Chloro-N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2- thioxo-3-pyrrolidinyl } -2-furamide Mp. °C: 71-73 MS: [M+H] 413, 415 i) 2-t-Butyldimethylsilyloxy-2-(3-chlorophenyl)ethylamine (16.8g) was added to a stirred solution of N-(3-chlorobenzoyl)-α-(2-oxoethyl)alanine (13.7g) in methanol (120ml) at room temperature under an atmosphere of nitrogen. After 3.5h the reaction mixture was cooled in an ice bath and sodium borohydride (0.80g) was added portionwise. After 20min at room temperature, the reaction mixture was concentrated in vacuo, diluted with water and extracted twice with dichloromethane. The combined extracts was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to a yellow oil. The oil was heated at reflux in toluene (120ml) under an atmosphere of nitrogen overnight and the solvent removed in vacuo to give t-butyl l-[2-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]-3- methyl-2-oxo-3-pyrrolidinylcarbamate as a yellow oil. ii) t-Butyl l-[2-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]-3-methyl-2-thioxo-3- pyrrolidinylcarbamate was prepared following the procedure described in examplel23 iii) from t-butyl l-[2-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]- 3-methyl-2-oxo-3-pyrrolidinylcarbamate as a colourless oil. iii) A solution of hydrogen chloride in dioxan (4M, 10ml) was added to a solution of t- butyl l-[2-t-butyldimethylsilyloxy-2-(3-chlorophenyl)ethyl]-3-methyl-2Jhioxo-3- pyrrolidinylcarbamate (1.85g) in dioxan (6ml) and the mixture stirred at room temperature. After 6h, concentrated in vacuo, diluted with water and washed twice with diethyl ether. The aqueous was made basic with sodium hydroxide (2M) and extracted twice with dichloromethane. The combined extracts was dried over magnesium sulphate, filtered and evaporated to give 3-amino-l-[2-hydroxy-2-(3- chlorophenyl)]ethyl-3-methylpyrrolidin-2-thione as a yellow oil. iv) Solid 2-chloro-l-methylpyridine iodide (271mg) was added to a stirred solution of 5-chlorofuroic acid (155mg) and triethylamine (210mg) in dried dichloromethane (5ml) at room temperature under an atmosphere of nitrogen. After lh a solution of 3-amino-l-[2-hydroxy-2-(3-chlorophenyl)]ethyl-3-methylpyrrolidin-2-thione (300mg) in dichloromethane (5ml) was added. After 2h at room temperature, the reaction mixture was washed with aqueous hydrochloric acid (2M), dried over magnesium sulphate, filtered and evaporated to a foam. The crude was purified on flash silica eluting with ethyl acetate-hexane (3:2) to give a colourless foam. The mixture of diastereoisomers was separated by preparative HPLC on a 250 x 20 mm id. KR60-5SIL column eluting at ambient temperature with hexane:tetrahydrofuran:ethanol (80:20:1.5%) at a flow rate of 20ml/min to give diastereoisomer 1 and diastereoisomer 2 as colourless solids. Diastereoisomer 2: 5-Chloro-N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2- thioxo-3-pyrrolidinyl}-2-furamide Mp. °C: 71-73 MS: [M+H] 413, 415 The title compound was isolated by preparative HPLC from the procedure described in example 125 iv) as a colourless solid. Diastereoisomer 1: 6-Chloro-N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2-thioxo-3- pyrrolidinyl } -2-pyridinecarboxamide Mp. °C: 71-74 MS: [M+H] 424, 426 To a stirred solution of 3-amino-l-[2-hydroxy-2-(3-chlorophenyl)]ethyl-3- methylpyrrolidin-2-thione (0.24g) and triethylamine (120mg) in dichloromethane (5ml) was added a solution of 6-chloropyridinecarbonyl chloride (0J7g) in dichloromethane (5ml). After stirring at room temperature for 45min, the reaction mixture was diluted with dichloromethane and washed with aqueous hydrochloric acid (2M), water and brine, dried over magnesium sulphate, filtered and evaporated to colourless foam. The crude was purified on flash silica eluting with ethyl acetate- hexane (3:2) to give a colourless oil. The mixture of diastereoisomers was separated by preparative HPLC on a 250 x 20 mm id. KR60-5SIL column eluting at ambient temperature with hexane:tetrahydrofuran:ethanol (80:20: 1.5%) at a flow rate of 20ml/min to give diastereoisomer 1 and diastereoisomer 2 as colourless solids Example 128 Diastereoisomer 2: 6-Chloro-N-{ l-[2-(3-chlorophenyl)-2-hydroxyethyl]-3-methyl-2- thioxo-3-pyrrolidinyl } -2-pyridinecarboxamide Mp. °C: 72-76 MS: [M+H] 424, 426 The title compound was isolated by preparative HPLC from the procedure described in example 127 i) as a colourless solid. Example 129 N-{ l-[3-(3-chlorophenyl)-2E-propen-l-yl]-3-methyl-2-thioxo-3-pyrrolidinyl}-3- chlorobenzamide Mp. °C: Glass MS: [M+H] 419, 421 i) To a stirred solution of 3-(t-butoxycarbonyl)amino-3-methylpyrrolidin-2-one (2.0g) in dried tetrahydrofuran (60ml) at room temperature under an atmosphere of nitrogen was added sodium hydride as a 60% dispersion in oil (0.4 lg). After 0.5h, a solution of l-bromo-3-(3-chlorophenyl)-2-propene (2.2g) in dried tetrahydrofuran (15ml) was added dropwise. The reaction mixture was stirred at room temperature for 2h, neutralised with aqueous hydrochloric acid (2M) and diluted with a saturated solution of ammonium chloride. The mixture was extracted with diethyl ether and the extract dried over magnesium sulphate, filtered and evaporated to an oil. The crude was purified on flash silica eluting with ethyl acetate-hexane (4:1) to give t- butyl l-[3-(3-chlorophenyl)-2E-propen-l-yl]-3-methyl-2-oxo-3-pyrrodinylcarbamate as a colourless oil. i) A solution of t-butyl l-[3-(3-chlorophenyl)-2E-propen-l-yl]-3-methyl-2-oxo-3- pyrrodinylcarbamate (2J8g) in dioxan(12ml) was stirred at room temperature with a solution of hydrochloric acid in dioxan (4M, 10ml) for 3h. The reaction mixture was diluted with aqueous hydrochloric acid (2M) and washed once with diethyl ether. The aqueous was made basic with aqueous sodium hydroxide and extracted twice with dichloromethane. The combined extracts was dried over magnesium sulphate, filtered and evaporated to give 3-amino-l-[3-(3-chlorophenyl)-2E-propen-l-yl]-3- methylpyrrolidin-2-one as an oil. iii) A solution of 3-chlorobenzyl chloride (0.32g) in dichloromethane (5ml) was added to a stirred solution of 3-amino-l-[3-(3-chlorophenyl)-2E-propen-l-yl]-3- methylpyrrolidin-2-one (0.52g) and triethylamine (0.40g) in dichloromethane (20ml) at room temperature. After 2h the reaction mixture was washed with aqueous hydrochloric acid (2M), twice with water, aqueous saturated sodium bicarbonate, water and brine, dried over magnesium sulphate, filtered and evaporated to a foam. The foam was triturated with diethyl ether to give N-{ l-[3-(3-chlorophenyl)-2E- propen-l-yl]-3-methyl-2-oxo-3-pyrrolidinyl} -3-chlorobenzamide as a colourless solid. iv) A solution of N-{ l-[3-(3-chlorophenyl)-2E-propen-l-yl]-3-methyl-2-oxo-3- pyrrolidinyl } -3-chlorobenzamide ( 200mg) and 2,4-bis-(4-methoxyphenyl)-l,3- dithia-2,4-diphosphetane-2,4-disulphide (106mg) in toluene (5ml) was heated at reflux for 3h. The solvent was removed in vacuo and the residue purifieo n flash silica eluting with dichloromethane and then dichloromethane-ether (95:5) to give the title compound as a glass.

Claims: We Claim: 1. A compound of the formula wherein, n is 0, 1 or 2; X is O, S, NH, or NOH; R 1 and R 2 are each independently H, CN, COOR, CONHR, Ci-Cg alkyl, tetrazole, or Rl and R 2 together represent "=O"; R is H or Cι-C 0 alkyl; R 3 is C1-C6 alkyl, C 2 -C6 alkenyl, C3-C6 cycloalkyl, -CH 2 OH, -CH 2 O-alkyl, -COOH; Ar is an unsubstituted or substituted aromatic or heteroaromatic group; Z represents a group of the formulae wherein, R4 and R^ are each independently H, halogen, C^-Cg alkoxy , -OAr , Cj-Cg a lkyl, -CF 3 , COOR, CONHR, -CN, -OH, COR, -S-( C!-C 6 alkyl), -SO 2 (C 1 -C 6 alkyl) A is CH 2 , O, NR, S, SO, SO 2 , CH 2 -CH 2 , CH 2 O, CHOH, C(O); wherein R is as defined above; B is CHR, CR2, Ci-Cg alkyl, C(O), -CHOH, -CH 2 -O, -CH=CH, CH 2 -C(O), CH2-S, CH 2 -S(O), CH 2 -SO 2 ; -CHCO2R; or -CH-NR 2 , wherein R is as defined above Het is a heterocycle; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in Claim 1, wherein n is 0 or 1; X is O or S; Rl and R 2 are each independently H, or R and R 2 together represent "=O"; R 3 is Ci ^ -Cg alkyl; Ar is meta-substituted aryl (aromatic , heteroaromatic); R^ is H, F, Cl, or OMe; A is -CH2-, -O- , or -(CH2)2 and B is C1-C3 alkyl, methylene, methylmethylene, -CH2O-, -CH=CH, or -CHOH. 3. A compound as claimed in Claim 2, wherein n is 1 ; X is S; R 3 is methyl; Ar is 3- bromophenyl, 3-chlorophenyl, 6-chloropyridin-2-yl, or 5-chlorofuran-2-yl; Z is 1-indanyl, 3-chlorophenethyl, or 3-fluorophenethyl; A is -CH2J and B is methylene. 4. A compound of formula wherein n is 0, 1 or 2; X is O, S, NH, or NOH; R 1 and R 2 are each independently H, CN, COOR, CONHR, Cγ-C alkyl, tetrazole, or Rl and R 2 together represent "=O"; R is H or Ci-Cg alkyl; R 3 is C!-C6 alkyl, C 2 -C6 alkenyl, C3-C6 cycloalkyl, -CH 2 OH, -CH2θ-alkyl, -COOH; Z represents a group of the formulae wherein, R 4 and R 5 are each independently H, halogen, Cj-Cg alkoxy , -OAr , Cj-Cg alkyl, -CF 3 , COOR, CONHR, -CN, -OH, COR, -S-( C!-C 0 alkyl), -SO2(C!-C 6 alkyl) A is CH 2 , O, NR, S, SO, SO 2 , CH 2 -CH 2 , CH 2 O, CHOH, C(O); wherein R is as defined above; B is CHR, CR 2 , Cι -C 6 alkyl, C(O), -CHOH, -CH 2 -O, -CH=CH, CH 2 -C(O), CH 2 -S, CH2-S(O), CH 2 -SO 2 ; -CHCO 2 R; or -CH-NR 2 , wherein R is as defined above Het is a heterocycle. or a pharmaceutically acceptable salt thereof. 5. A composition comprising an effective amount of a compound as claimed in Claim 1 in combination with a pharmaceutically acceptable carrier, diluent, or excipient thereof. 6. A composition comprising an effective amount of a compound as claimed in Claim 2 in combination with a pharmaceutically acceptable carrier, diluent, or excipient thereof. 7. A composition comprising an effective amount of a compound as claimed in Claim 3 in combination with a pharmaceutically acceptable carrier, diluent, or excipient thereof. 8. A method of treating a neurodegenerative condition which comprises administering to a patient in need thereof, and effective amount of a compound as claimed in Claim 1. 9. A method of treating pain which comprises administering to a patient in need thereof, and effective amount of a compound as claimed in Claim 1. 10. A compound as claimed in Claim 1 which is rel-(R,R)-3-[(3-Bromobenzoyl)amino]-l-(l- indanyl)-3-methylpyrrolidin-2-one. 11. A compound as claimed in Claim 1 which is (R,R)-3-[(3-Bromobenzoyl)amino]-l-(l- indanyl)-3-methylpyrrolidin-2-one. 12. A compound as claimed in Claim 1 which is 3-[(3-Chlorobenzoyl)amino]-l-(3- chlorophenethyl)-3-methylpyrrolidin-2-thione. 13. A compound as claimed in Claim 1 which is (S)-3-[(3-Chlorobenzoyl)amino]-l-(3- chlorophenethyl)-3-methylpyrrolidin-2-thione. 14. A compound as claimed in Claim 1 which is (S,R)-3-[(3-Chlorobenzoyl)amino]-l-(l- indanyl)-3-methylpyrrolidin-2-thione. 15. A compound as claimed in Claim 1 which is (S,R)-3-[(6-Chloropyridin-2-yl)carboxamido]-l- (l-indanyl)-3-methylpyrrolidin-2-thione. 16. The use of a compound as claimed in Claim 1, or a pharmaceutically acceptable salt thereof, for antagonizing one or more of the actions of L-glutamate at Group I metabotropic glutamate receptors. 17. The use as claimed in Claim 16 wherein the Group I metabotropic glutamate receptor is mGluR5. 18. The use of a compound as claimed in Claim 1, for the manufacture of a medicament for antagonizing one or more of the actions of L-glutamate at Group I metabotropic glutamate receptors. 19. The use as claimed in Claim 18 wherein the Group I metabotropic glutamate receptor is mGluR5.

Inventors: CLARK BARRY PETER, CWI CYNTHIA LYNN, HARRIS JOHN RICHARD, KINGSTON ANN ELIZABETH, SCOTT WILLIAM LEONARD, CLARK, BARRY, PETER, CWI, CYNTHIA, LYNN, HARRIS, JOHN, RICHARD, KINGSTON, ANN, ELIZABETH, SCOTT, WILLIAM, LEONARD
Applicants: CLARK BARRY PETER, CWI CYNTHIA LYNN, HARRIS JOHN RICHARD, KINGSTON ANN ELIZABETH, LILLY CO ELI, SCOTT WILLIAM LEONARD, CLARK, BARRY, PETER, CWI, CYNTHIA, LYNN, ELI LILLY AND COMPANY, HARRIS, JOHN, RICHARD, KINGSTON, ANN, ELIZABETH, SCOTT, WILLIAM, LEONARD
Application year: 2000
Main classification: C07D207
IPC codes: C07D205, C07D207, C07D211, C07D401, C07D405