ISOXAZOLE AND ISOTHIAZOLE COMPOUNDS THAT ENHANCE COGNITIVE FUNCTION

Abstract: Selective and potent nicotinic agonists of formula (I), or pharmaceutically-acceptable salts thereof, useful in the treatment of cognitive, neurological and mental disorders characterized by decreased cholinergic function.

Description: ISOXAZOLE AND ISOTHIAZOLE COMPOUNDS THAT ENHANCE COGNITIVE FUNCTION This application is a continuation-in-part of copending U.S. Serial No.07/706,920, filed May 29,1991. TECHNICAL FIELD This invention relates to isoxazole and isothiazole compounds and pharmaceutical compositions thereof which are cholinergic agonists selective for neuronal nicotinic receptors, to methods for preparing these compounds, to synthetic intermediates employed in these processes and to a method of treating cognitive, neurological and mental disorders, such as dementias and anxiety, which are characterized by decreased cholinergic function, with such compounds. This invention also relates to a method of treating or preventing withdrawal symptoms caused by the cessation of chronic or long term use of tobacco products, as well as to a method of ameliorating the symptoms of anxiety and frustration associated with withdrawal of other addictive substances such as, for example, cocaine, diazepam or alcohol. BACKGROUND OF THE INVENTION Dementia has been widely recognized as a very serious health problem. Alzheimer's Disease, which has been identified by the National Institutes of Aging as accounting for more than 50% of dementia in the elderly, is the fourth or fifth leading cause of death in Americans over 65 years of age. Four million Americans, 40% of Americans over age 85 (the fastest growing segment of the U.S. population), have Alzheimer's Disease. Twenty-five percent of all patients with Parkinson's Disease also suffer from Alzheimer's Disease-like dementia. And in about 15% of patients with dementia, Alzheimer's Disease and multi-infarct dementia coexist. The third most common cause of dementia, after Alzheimer's Disease and vascular dementia, is cognitive impairment due to organic brain disease related directly to alcoholism, which occurs in about 10% of alcoholics. The precise molecular lesion(s) that contribute to the morphological and functional deficits associated with dementia is unclear despite intensive research efforts over the last decade. However, the most consistent abnormality for Alzheimer's Disease, as well as for vascular dementia and cognitive impairment due to organic brain disease related directly to alcoholism, is the degeneration of the cholinergic system arising from the basal forebrain (BF) to both the cortex and hippocampus (Bigl et at., in Brain Cholinergic Systems, eds. M. Steriade and D. Biesold, Oxford University Press, Oxford, 1990, pp. 364-386). In particular, neurochemical evidence from the brains of patients afflicted with Alzheimer's Disease has revealed reliable decreases in markers of cholinergic neuronal function (Perry etal., Br. Med. J. 1978, 2:1457; Reisine etal.βraiπ Res. 1978, 159:477; Coyle etal., Science 1983, 279:1184; McGeer etal., Neurology 984, 34:741). While there are a number of other neurotransmitter systems affected by Alzheimer's Disease (Davies, Med. Res. Rev. 1983, 3:221), the relative occurrence of such abnormalities is less consistent or the effect is less profound than the decreases in these cholinergic neuronal function markers. More specifically, substantial reductions (30-50%) in nicotinic cholinergic receptors have been consistently reported in the brains of patients with Alzheimer's Disease and Parkinson's Disease (Kellar etal., Brain Res., 1987, 436:62; Whitehouse etal., Neurol. 1988, 33:720), whereas changes in muscarinic cholinergic receptors are less remarkable and more dependent on receptor subtype. However, degeneration of the cholinergic neurotransmitter system is not limited to individuals suffering from dementia. It has also been seen in healthy aged adults and rats. Decreases in cholinergic markers in the basal forebrain, decreases in cortical activities of the biosynthetic and degradative enzymes for acetylcholine, decreases in the ability to release acetylcholine from tissue slices, and decreases in numbers of cortical nicotinic receptors have all been reported in otherwise healthy aged individuals (for a review, see Giacobini, J. Neurosci. Res. 1990, 27:548). Moreover, for those cholinergic neurons that remain, aging may cause a decrease in the temporal fidelity of existing impulse flow from the basal forebrain to the cortex (Aston-Jones etal., Brain Res. 1985, 325:271). Consistent with these findings are pharmacological studies suggesting that cholinergic mechanisms are, at least in part, responsible for the memory disturbances in aged animals and humans not suffering from Alzheimer's Disease (Drachman and Leavitt, Arch. Neurol. 1974, 30:113; Bartus etal., Science 1982, 217:408). Other clinical correlates associated with the neurodegenerative process of Alzheimer's Disease include decreases in regional cerebral blood flow and cerebral glucose utilization, which largely parallel the areas where cholinergic deficits occur (Ingvar and Risberg, Exp. Brain Res., 1962, 3:195; Ingvar etal., Aging: Alzheimer's Disease. Senile Dementia and Related Disorders. Vol. 7 , R. Katzman, R.D. Terry, and K.L. Bick, eds., Raven Press, 1978, p. 203; Dastur, J. Cerebral Blood Flow & Metabol. 1985, 5:1). In fact, it has been suggested that routine measurement of cerebral blood flow may be a useful procedure in evaluating patients suspected of having dementia, and of Alzheimer's Disease in particular. Conflicting reports exist regarding the effect of aging on resting cerebral blood flow and cerebral glucose utilization in "normal, healthy" aged humans (Dastur, J. Cerebral Blood Flow & Metabol. 1985, 5:1 , ) and rats (Smith etal., Brain 1980, 703:351 ; Buchweitz-Milton and Weiss, Neurobiol. Aging 1987, 3:55). Although decreases in cerebral blood flow and cerebral glucose utilization are generally reported in aged populations, if has been suggested that these decreases are secondary to other ongoing cerebral dysfunctions. Nonetheless, deficiencies in metabolic and cerebrovascular responses to pharmacologic and physiologic perturbation are consistently reported. Of particular interest is the recent finding in rats that increases in cerebral blood flow elicited by electrical stimulation of the basal forebrain shows age-related impairments (Linville and Arneric, Soc. Neurosci. Abstract 1989, 75:17.5). Indeed, studies that compare the degree of learning impairment with the degree of reduced cortical cerebral blood flow in aged rats show a good correlation (Berman etal., Neurobiol. Aging 1988, 9:691). Chronic alcoholism, more particularly, the resultant organic brain disease, like Alzheimer's Disease and normal aging, is also characterized by diffuse reductions in cortical cerebral blood flow in those brain regions where cholinergic neurons arise (basal forebrain) and project to (cerebral cortex) (Lofti & Meyer, Cerebrovasc. and Brain Metab. Rev. 1989, 7:2). Moreover, of all the neurotransmitter systems studied, the neurotoxic effects of alcohol on the cholinergic system are thought to be the most important. Recent clinical evidence suggests that the characteristic perfusion abnormality observed in Alzheimer's Disease patients reflects regional nicotinic cholinergic deficits (Prohovnik, Neurobiol. Aging 1990, 77:262). In particular, mecamylamine, a centrally-acting nicotinic receptor antagonist, reduces resting cortical perfusion in the parietotemporal cortex of humans, the area of the cortex most consistently found to be impaired in functional brain imaging of Alzheimer's Disease patients. In agreement with this finding, regulation of cerebral blood flow in the frontoparietal cortex, governed by the basal forebrain, is also dependent upon nicotinic mechanisms in the rat (Arneric, J. Cerebral Blood Flow & Metabol. 1989, 9 (Suppl. 1): S502). Intuitively, regardless of specific etiologic process, therapies directed towards enhancing cognitive processing would be contingent upon maintaining a well-regulated balance between adequate cerebral blood flow, cerebral glucose utilization and cholinergic neurotransmission arising from the basal forebrain. Pilot clinical studies suggest that nicotine may be useful for the acute treatment of deficits in attention and information processing associated with Alzheimer's Disease (Sahakian etal., Brit. J. Psych. 1989, 754:797; Newhouse etal., Psychopharmacol. 1988, 95:171). Anecdotal evidence suggests a negative correlation between Alzheimer's Disease and smoking, and both acutely and chronically-administered nicotine enhances cognitive function in rats (Levin etal., Behav. Neural Biol. 1990, 53:269), an effect that is preserved in aged animals (Cregan etal., Soc. Neurosci. Abstract 1989, 75: 295.2). These clinical findings are supported by animal studies demonstrating a neuroregenerative/neuroprotective action of chronically-administered nicotine on both neuronal and vascular functions following hemitransection or MPTP-induced destruction of the nigro-striatal dopamine system (Janson etal., Prog. Brain Res. 1989, 79:257; Owman etal., Prog. Brain Res. 1989, 79:267). Interestingly, in contrast to the classical down-regulation of receptors typically seen with receptor agonists, chronic nicotine administration up-regulates (50-100%) the number of receptors without affecting affinity (Benwell et al.,J. Neurochem. 1988, 50:1243). This effect occurs both in humans and smaller animals such as rats (Lapchack etal., J. Neurochem. 1989, 52:483). Existing cholinergic agonists, however, are therapeutically sub-optimal. This is due to unfavorable pharmacokinetics (e.g., with arecoiine and nicotine), poor potency and lack of selectivity (e.g., with RS-86), poor CNS penetration (e.g., with carbachol) or poor oral bioavailability (e.g., with nicotine). RS-86, for example, has similar affinity for cholinergic receptors located in the heart and cortical tissues and is a full agonist at cardiac receptors, whereas it is only a partial agonist at cortical receptors (S.B. Freedman, British Journal of Pharmacology 1986, 87: 29P). In addition, known agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lacrimation, defecation and tachycardia (Benowitz etal., in: Nicotine Psvchopharmacologv. S. Wonnacott, M.A.H. Russell, & I.P. Stolerman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; M. Davidson, etal, in Current Research in Alzheimer Therapy. E. Giacobini and R. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336). In addition to treating decline in cognitive ability by improving cholinergic function and cerebral blood flow, it is also desirable to symptomatically treat the mental disorders accompanying the earlier stages of Alzheimer's Disease. Anxiolytics have been used to treat the severe agitation that most Alzheimers patients experience with the initial loss of memory (INPHARMA, March 16, 1991, pg 20). In fact, the use of anxiolytics has become an important aspect of treatment strategies for Alzheimer's Disease (Schmidt etal., Drug Dev. Res., 1988, 74:251). Nicotine is known to have anxiolytic properties (Pomerleau etal., Addictive Behaviors, 1984, 9:265) and, therefore, nicotine or selective nicotine agonists may be useful in the treatment of the anxiety associated with dementias, such as Alzheimer's Disease. Others situations where beneficial therapeutic outcome may be achieved or improved through administration of nicotine or a nicotine agonist, because of the anxiolytic properties of these agents, include attentional deficit disorder and drug withdrawal. Attention-deficit disorder (ADD), with or without hyperactivity, is a behavioral disorder characterized by distractibility and impulsiveness. Children with this disorder are handicapped by their inability to concentrate and control their impulsivity, especially in settings requiring sustained attention, for example, in school. While a cure for this disorder has not been found, stimulants, such as pemoline, have been used successfully in management of the behavioral manifestations of ADD. Nicotine, because of its ability to improve concentration and task performance (F . Etscorn, U.S. Patent 4,597,961, issued July 1 , 1986; D.M. Warburton and K. Wesnes in Smoking Behavior. R.E. Thornton, ed., Churchill-Livingston, Edinburgh, 1978, pp. 19-43) is potentially useful in treating ADD. Tobacco use, especially cigarette smoking, has long been recognized as a major factor leading to disease and death. Approximately 4,000 by¬ products of combustion, many of which are known carcinogens, have been found in cigarette smoke. Of the three most-studied constituents of cigarette smoke, two, tars and carbon monoxide, have been found to cause or exacerbate numerous life-threatening disorders. Tars are most often implicated in the induction of lung, larynx, oral cavity, esophageal and other cancers, and are also thought to be responsible for respiratory diseases, including pulmonary emphysema, chronic bronchitis and smokers respiratory syndrome. Carbon monoxide, on the other hand, combines with hemoglobin in the blood thereby decreasing the ability of the blood to carry oxygen and has been implicated as a causative agent in the development of coronary artery disease and arteriosclerosis. The third highly studied, and the most pharmacologically active substance, in tobacco products is nicotine, which is the reinforcing agent responsible for maintaining tobacco dependency (J.H. Jaffe in Nicotine Pharmacology: Molecular. Cellular and Behavioral Aspects , S.Wonnacott, M.A.H. Russell and I. P. Stolerman, eds., Oxford Science Publications, Oxford, 1990, pp. 1-37). The nicotine withdrawal syndrome associated with smoking cessation is characterized by craving for nicotine, irritability, frustration or anger, anxiety, difficulty concentrating, restlessness, decreased heart rate and increased appetite or weight gain. Nicotine has, not surprisingly, been found to ease the withdrawal experienced by those attempting to break tobacco dependencies. As early as 1942, Johnston reported (L Johnston, Lancet, 1942, 2:742) that injections of nicotine relieved the withdrawal symptoms experienced by cigarette smokers when they stopped smoking. More recently, in double-blind studies, nicotine was far superior to placebo in suppressing or preventing the appearance of many of the signs and symptoms of withdrawal (J.R. Hughes etal., Psychopharmacology, 1984, 83:82-7; N.G. Schneider etal., Addictive Behavior, 1984, 9:149-56; R.J. West etal., Journal of Addiction, 1984, 79:215-9; K.O. Fagerstrom in Nicotine Replacement: a Critical Evaluation , O.F. Pomperleau and C.S. Pomperieau, eds., Alan R. Liss, Inc., New York, 1988, pp. 109-28, ; J.E. Henningfield and D.R. Jasinski, ibid, pp.35- 61). Irritability and impatience were reduced in at least five independent controlled studies, while anxiety and difficulty concentrating were reduced in at least two studies. Other symptoms for which nicotine was significantly more effective than placebo in at least one study include depression, hunger, somatic complaints, and sociability. One approach to alleviating the symptoms of tobacco withdrawal has been to develop more efficient methods of delivering nicotine, itself, for example, in transdermal patches (F . Etscorn, U.S. Patent 4,597,961 , issued July 1 , 1986). The major problem with this approach is the non- selective effects of nicotine and in particular, the stimulant effects of increasing cardiac workload and oxygen demand that nicotine has on the heart . A selective nicotine agonist would be expected to be equally efficacious in relieving withdrawal symptoms with fewer cardiovascular liabilities. Withdrawal from addictive substances in general, regardless of which particular agent is withdrawn, is a traumatic experience characterized by anxiety and frustration. These emotional disturbances contribute to failure in therapy and, consequently, to a return to substance dependence. Although ameliorating these symptoms does not eliminate the craving for the withdrawn drug, improving the individuals ability to cope and to concentrate should vastly improve the chances of successfully completing treatment. Nicotine has been found to be effective in reducing anger, irritability, frustration and feelings of tension, while increasing ability to focus upon the completion of tasks, without causing general response depression, drowsiness or sedation (R.R. Hutchinson etal., U.S. Patent 3,879,794, issued March 11 , 1975). The synthesis of certain 3,5-disubstituted isothiazoles has been reported in the literature. For example, A DeMunno and V. Bertini in Heterocycles, 1989, 29:97-102, describe the preparation of 3,5-dimethyl isothiazole, 3-methyl-5-phenyl isothiazole, 3-methyl-5-hydroxymethyl isothiazole and 3,5-dihydroxymethyl isothiazole. Isothiazoles substituted at either the 3- or the 5-position with a heterocycle are neither disclosed nor suggested in this reference. Further, the isothiazoles disclosed by DeMunno and Bertinini have no known pharmacological activity. Wadsworth and Jenkins in European Patent Application EP 402056, published December 12, 1990, and P.A. Wyman in European Patent Application EP 413545, published February 20, 1991 (both assigned to Beecham Group) discloses certain non-aromatic 1 -azabicyclic ring systems substituted in the 3-position by certain aromatic heterocycles, such as for example, triazole, terazole and oxadiazole. These compounds are agonists at muscarinic receptors in the CNS. SUMMARY OF THE INVENTION This invention relates to novel isoxazole and isothiazole compounds of the formula: or pharmaceutical salts thereof, wherein A, R 1 , and R 2 are specifically defined, which are selective and potent agonists at neuronal nicotinic acetylcholine receptors and, therefore, may be used in the treatment of cognitive, neurological and mental disorders characterized by decreased cholinergic function, such as, for example, dementias, attentional hyperactivity disorder and anxiety associated with cognitive impairment and substance abuse withdrawal. The present invention is also directed to pharmaceutical compositions comprising a therapeutically-effective amount of a compound of the above formula and a pharmaceutically-acceptable carrier or diluent, as well as to a method of treating cognitive, neurological and mental disorders, which are characterized by decreased cholinergic function in humans and lower mammals, by administration of a compound of the above formula. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a graphical representation (bar graph) of the effects of (-)nicotine (0.01 - 1.0 mg/kg) on the performance of CD1 mice in Inhibitory Avoidance Studies expressed as median step-through latency time (seconds). FIGURE 2 is a graphical representation (bar graph) of the effects of the compound of Example 2 (0.001 - 1.0 mg/kg) on the performance of CD1 mice in Inhibitory Avoidance Studies expressed as median step-through latency time (seconds). FIGURE 3 is a graphical representation of the effects of (- )nicotine (0.01 - 1.0 mg/kg) on the performance of CD1 mice in the Elevated-Plus Maze Study expressed as median time (seconds) spent on the open arms of the maze. FIGURE 4 is a graphical representation of the effects of the compound of Example 2 (0.003 - 0.3 mg/kg) on the performance of CD1 mice in the Elevated-Plus Maze Study expressed as median time (seconds) spent on the open arms of the maze. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of the formula: wherein A is O or S; R 1 is located at either position 3 or position 4, or at both positions 3 and 4 and is selected from the group consisting of: (i) hydrogen; (ii) Cι-C 6 -alkyl; (iii) -(CH 2 ) a R 3 ; wherein a is 1 , 2, 3 or 4, and R 3 is C3-C7-cycloalkyl or phenyl; (iv) -(CH 2 ) a OR 4 .wherein a is defined as above, and R 4 is C3-C7-cycloaikyl, phenyl or C-i-Cβ-alkyl; (v) -(CH 2 )bNR 4 , wherein b is O, 1 , 2, 3 or 4 and R 4 is defined as above; and (vi) CF 3 ,- and R 2 is selected from the group consisting of: wherein R 5 is H or Ci -C^alkyl, and R 6 is H, F, CH 2 F, CN, NH 2 , NHCO(C-|-C 6 alkyl), Cι-C 4 -alkyl, -CH 2 CH=CH 2 or CH 2 OR9 wherein R 9 is H, Cι-C 3 -alkyl or -CH 2 CH=CH 2 ; wherein R 5 is defined as above, and R 7 is H, (CH 2 )halogen, 0(CrC 6 -alkyl), O(phenyl), (CH 2 )phenyl, (CH 2 )CN, CN, (CH 2 )SCN, (CH 2 )SH, (CH 2 )SC 1 -C 6 -aikyl, OH, (CH 2 )0, CrC 6 -alkyl or OCO^i-Ce-alkyl); wherein R 5 is defined as above and R8 is H, Cι-C 4 -alkyl, phenyl, CH 2 F or CH 2 CN; 10 15 wherein R5, R7 and R 8 are defined as above; wherein R 5 > R 6 and R 8 are defined as above; 20 and (vi) wherein R 5 , R 6 and R 7 are defined as above. The following are representative of compounds of the present invention: 3-Methyl-5-(2(S)-pyrrolidinyl)-isoxazoie; 3-Methyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 3-Ethyl-5-(2(S)-pyrrolidinyi)-isoxazole; 3-Ethyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 3-Methyl-5-(2(S)-pyrrolidinyl)-isothiazole; 3-Methyl-5-(1-methyl-2(S)-pyrrolidinyl)-isothiazole; 3-Benzyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 3-n-Butyl-5-(1 -methyl-2(S)-pyrrolidinyl)-isoxazole; 5-(1-Ethyl-2(S)-pyrrolidinyl)-3-methyl-isoxazole; 3-Methyl-5-(2(R)-pyrrolidinyl)-isoxazole; 3-Methyl-5-(1-methyl-2(R)-pyrrolidinyl)-isoxazole; 3-Ethyl-5-(2(R)-pyrrolidinyl)-isoxazole; 3-Ethyl-5-(1 -methyl-2(R)-pyrrolidinyl)-isoxazole; 3-Methyl-5-(2(R)-pyrrolidinyl)-isothiazole; 3-Methoxymethyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 3-Methyl-5-(tøns-4-hydroxy-1-methyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(c/s-4-fluoromethyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(c/s-1-methyl-5-(cyanomethyl)-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(c/s-1 ,4-dimethyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(fraπs-1 ,5-methyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(cis-1-methyl-4-benzyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(c/s and trans-1 -methyl-4-cyanomethyl-2-pyrrolidinyl)- isoxazole; 3-Methyl-5-(trans-1-methyl-4-acetyloxy-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(trans-1-methyl-5-fluoromethyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(trans-1-methyl-3-fluoromethyl-2-pyrrolidinyl)-isoxazole; 3-Methyf-5-(trans-1 ,3-dimethyl-2-pyrrolidinyl)-isoxazole; 3-Methyl-5-(1 ,3,4-trimethyl-2-pyrrolidinyl)-isoxazole; 3-Trifluoromethyl-5-(1methyl-2(S)-pyrrolidinyl)-isoxazole; 3,4-Dimethyl-5-(1-methyl-2-pyrrolidinyl)-isoxazole; 5-(2-Pyrrolidinyl)-isoxazole; and 5-(1-Methyl-2-pyrrolidinyl)-isoxazoie; as well as pharmaceutically-acceptable salts thereof. Particularly preferred compounds of the present invention include: 3-Methyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 3-Ethyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 5-(1-Methyl-2(S)-pyrτolidinyl)-3-propyl-isoxazole; and 3-Methyl-5-(2(R)-pyrrolidinyr)-isoxazole; as well as pharmaceutically-acceptable salts thereof. The terms "Cι-C4-alkyl" and "Cι-C6-alkyl" refer to branched or straight-chain, unsubstituted or substituted, alkyl groups comprising one- to-four or one-to-six carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl or isobutyl, or additionally, for Ci-Cβ-alkyl, neopentyl or n-hexyl and the like. The alkyl groups of either of the above two definitions may be substituted with from one-to-three halogens, Ci -C4-alkoxy or Ci -C4-alkylthio. The term "C3-C7-cycloalkyl" refers to a monocyclic saturated hydrocarbon ring containing three-to-seven carbon atoms in the ring. The term "halogen" as used herein refers to bromo (Br), chioro (CI), fluoro (F) or iodo (I). The term "phenyl" refers to an unsubstituted phenyl ring or a phenyl ring substituted with one-to-three substituents independently selected from nitro (N0 2 ), halogen, CrC4-alkyl, C C4-alkoxy and Cι-C4-alkylthio, or with one or two substituents as defined above and one substituent selected from Cι-C4-alkanoyl, di-Cι-C4-alkylamino and methylenedioxy. Compounds of the invention which have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof. The terms "R" and "S_" configuration used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. , 1976, 45: 13-30. The compounds of the present invention may be synthesized as shown in reaction schemes I through VII presented below, in which R 1 -R 9 are as defined above or as depicted in the reaction schemes for formula (I) and Y is a nitrogen protecting group, using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed are suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocyclic ring and other portions of the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to skilled practitioners in the art. The use of nitrogen- protecting groups is well known in the art for protecting amino groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, c.f., T.H. Greene. Protective Groups in Organic Synthesis. John Wiley & Sons, New York (198 , ). Scheme I Scheme Isoxazole compounds of formula (I) wherein R 1 (excluding hydrogen) and R 5 are defined as above may be prepared according to reaction scheme I, in which monosubstituted pyrrolidine is representative of the saturated nitrogen-containing heterocycles as defined above. D or l_ praline with the ring nitrogen protected, for example as the t-butyloxy- carbonyl derivative, is reduced to a hydroxymethyl compound of formula 2 using a suitable reducing agent such as borane or borane-methyl sulfide complex. The hydroxymethyl compound of formula 2 is, in turn, oxidized using a suitable mild oxidizing agent such as pyridine-sulfur trioxide, pyridinium chlorochromate (PCC) or DMSO/oxalyl chloride, to afford the aldehyde of formula 3. The aldehyde is then converted to a dibromovinyl compound of formula 4 by treatment wiih dibromomethyltriphenylphosphonium ylid under standard Wittig reaction conditions. The dibromovinyl compound is, in turn, treated with a suitable base such as n-butyl lithium to afford the acetylenic compound of formula 5. Synthetic methodology for preparing compound of formula 5 are described by J.Y.L. Chung and J. Wasicak in Tetrahedron Letters, 1990, 37:3957. The acetylenic compound of formula 5 is allowed to react with a nitro compound of formula 6 in the presence of an isocyanate such as phenyl isocyanate, chlorophenyl isocyanate, 1-naphthylisocyanate, o-tolyl isocyanate or ethyl isocyanate, preferably phenyl isocyanate, to afford the isoxazole compound of formula 7, the 1 ,3-dipolar cycloaddition product. The compound of formula 7 is then treated with a suitable reagent for removing the nitrogen protecting group. Treatment with a mild acid, such as trifluoroacetic acid or hydrogen chloride in glacial acetic acid, is preferred for removing a t-butyloxycarbonyl (t-BOC) group. The ring nitrogen is then alkylated, for example by treatment with formaldehyde and formic acid or alternately, by treatment with formaldehyde, in the presence of a suitable reducing agent such as sodium cyanoborohydride, to afford a compound of formula I. Alternatively, the ring nitrogen can be treated with an acid chloride or anhydride (such as acetyl chloride or acetic anhydride) in the presence of a base (such as triethylamine) to afford an amide which is then reduced with a suitable reducing agent (such as borane or lithium aluminum hydride) to afford a compound of formula I. Scheme Scheme II Alternately, compounds of formula (I) wherein R 1 (excluding hydrogen) and R 5 are defined as above and may also be prepared according to reaction scheme II, in which monosubstituted pyrrolidine is representative of the saturated nitrogen containing heterocycles. An aldehyde of formula 8 is treated with hydroxylamine to afford an oxime of formula 9. The oxime is, in turn oxidized, for example, by treatment with N-chlorosuccinimide or chlorine gas, and treated with a suitable base, such as triethylamine, to afford the corresponding nitrile oxide of formula 70. The acetylenic compound of formula 5 is allowed to react with the compound of formula 70 to afford the isoxazole compound of formula 7, the 1 ,3-dipolar cycloaddition product. The compound of formula 7 is then treated with a suitable reagent for removing the nitrogen protecting group. The ring nitrogen is then alkylated, for example by treatment with formaldehyde and formic acid or alternately, by treatment with an aldehyde, such as formaldehyde, in the presence of a suitable reducing agent such as sodium cyanoborohydrida, to afford a compound of formula I. Scheme III Scheme III As a further alternative, isothiazole compounds of formula (I) wherein R 1 and R 5 are defined as above are prepared according to reaction scheme III, in which monosubstituted pyrrolidine is representative of the saturated nitrogen-containing heterocycles. A compound of formula 4 is allowed to react with an aldehyde in the presence of a suitable base, such as n-butyllithium, to give the alkynol of formula 73. The compound of formula 18 is, in turn, oxidized with an appropriate oxidizing agent, for example, dimethyl sulfoxide/oxalyl chloride, tetrapropylammonium perruthenate/N-methyl morpholine N-oxide or sulfur trioxide/pyridine, to afford the compound of formula 79. The compound of formula 79 is then treated sequentially with hydroxylamine-O-sulfonic acid, a mild base, such as sodium bicarbonate, and sodium hydrosulfide, in water or in a homogeneous mixture of water and a water-miscible solvent, for example methanol, THF or acetonitrile to afford the compound of formula 20. The compound of formula 20 is then treated with a suitable reagent for removing the nitrogen protecting group. Treatment with acid, such as trifluoroacetic acid or hydrogen chloride in glacial acetic acid, is preferred for removing a t-butyloxycarbonyl (t-BOC) group. The ring nitrogen is then alkylated, for example by treatment with formaldehyde and formic acid or alternately, by treatment with an aldehyde, such as formaldehyde, in the presence of a suitable reducing agent such as sodium cyanoborohydride, to afford a compound of formula I. Scheme IV II R 8 =CH 2 F or CH 2 CN SCHEME IV Isoxazole compounds of the formulas (II), (III), (IV) and (V) wherein R 5 , R 7 , and R 8 are defined as above are prepared according to reaction scheme IV. A compound of formula 27 is allowed to react with an oxime dianion generated with a suitable base such as n-butyl lithium or LDA to give a β-keto oxime which is then cyclodehydrated with an acid such as sulfuric acid or methanesulfoπyl chloride triethylamine to give the isoxazole of formula 22. The compound of formula 22 is allowed to react with borane to afford a compound of formula II (when R 8 =H) or with an organometalic nucieophile which is subsequently reduced with a suitable reagent such as borane or lithium aluminum hydride to afford a compound of the formula II (when R 8 =C-|-C4-alkyl or phenyl). Alternatively, the lactam anion of compound of formula 22 is generated with a suitable base such as LDA and reacted with various electrophiles to afford the compound of formula 23. The compound of formula 23 is then reduced to a compound of formula III by treatment with a suitable reducing agent such as borane or lithium aluminum hydride. Alternatively, the compound of formula 23 is allowed to react with an organometalic nucieophile and the product is reduced with a suitable reagent such as borane or lithium aluminum hydride to afford the compound of formula IV. The lactam of formula 22 is converted to the thioamide of formula 24 by treatment with a suitable reagent such as Lawesson's Reagent or phosphorus pentasulfide. A thiolactam of formula 24 is allowed to react with a suitable Wittig reagent to afford the compound of formula 25. Reduction of the double bond within a compound of formula 25 (when R 8 =CH 2 CN) is achieved with a suitable reducing agent, such as sodium cyanoborohydride or hydrogen and a suitable catalyst, affording the compound of formula II (R 8 =CH 2 CN). Alternatively, unmasking the aldehyde (when R 8 =OCH3) and reduction with a suitable base such as sodium borohydride affords an alcohol which is treated with DAST to afford a compound of formula II (R 8 =CH 2 F). Scheme V SCHEME V Isoxazole compounds of the formulas V, VI, VII and VIII wherein R 6 , R 7 and R 8 are defined as above or are the indicated subsets of the above definitions are prepared according to reaction scheme V. A compound of formula 26 is allowed to react with an amine and maleic anhydride to afford the acid of formula 27. The acid is then esterified with an alcohol such as methanol in the presence of an acid catalyst such as hydrochloric acid. This ester is then reduced to the alcohol of formula 28 with a reducing agent such as sodium borohydride or diisobutylaluminum hydride. Generation of the alkoxyanion with an appropriate base such as sodium hydride followed by treatment with an electrophile affords a compound of formula 30. Reduction of the lactam with a suitable reagent such as borane affords the compound of formula V. Alternatively, conversion of the alcohol into a leaving group by treatment with a reagent such as methansulfonyl chloride in the presence of a base such as triethylamine followed by treatment with an appropriate organometallic nucieophile affords the compound of formula 29. Reduction of the lactam moiety with a suitable reagent such as borane affords the compound of formula VI. Alternatively, generation of the lactam anion of the compound of formula 29 with a suitable base such as LDA followed by subsequent treatment with an electrophile affords the compound of formula 37. Reduction of the lactam with a suitable reagent such as borane affords the compound of formula VII. Alternatively, the compound of formula 29 is allowed to react with an organometalic nucieophile and the product is reduced with a suitable reagent (such as borane or lithium aluminum hydride) to afford the compound of formula VIII. The lactam of formula 29 may be converted to the thiolactam of formula 32 and converted to the compound of the formula VIII via the sequence described in scheme IV. Scheme VI SCHEME VI Isoxazole compounds of formula (I) wherein R 1 is hydrogen may be prepared according to reaction Scheme VI. A compound of the formula 3 is treated with formylmethylene triphenylphosphorane to afford the compound of formula 33. The oxime is then prepared by treatment with hydroxylamine hydrochloride in the presence of a base such as pyridine to give the compound of formula 34. Cyclization to the isoxazole of formula 35 is accomplished by the method described by G. Bϋchi and J.C. Vederas in J. Am. Chem. Soc. 1972, 94: 9128. Specifically, the alpha, β unsaturated oxime is treated with iodine and potassium iodide in a THF-H 2 0 mixture to afford the compound of formula 35. The compound of formula 35 is then treated with a suitable reagent for removing the nitrogen protecting group. Treatment with an acid, such as trifluoroacetic acid or hydrogen chloride in glacial acetic acid, is preferred for removing a t-butyloxycarbonyl (t-Boc) group. The ring nitrogen is then alkylated, for example, by treatment with formaldehyde and formic acid, or, alternatively, by first formation of the amide with a suitable anhydride such as acetic anhydride or acetic formic anhydride then reducing the amide with borane or lithium aluminum hydride. Alternatively, the compound of formula 5 may be treated with fulminic acid generated preferably by the procedure of Huisgen and Christl (Anσew. Chem. Int. Ed. Enαl. 19676:456) to afford the compound of formula 35. Deprotection of the nitrogen and aikylation, preferably according to the procedures described above, affords the compound of formula I. Alternatively, the compound of formula 36 may be treated with the dianion of aldoxime to give a beta-keto oxime which is then cyclized with an OH activating group such as methanesulfonylchloride in the presence of triethylamine to afford the isoxazole of formula 35. Deprotection of the nitrogen and aikylation, preferably according to the procedures described above, affords the compound of formula I. SCHEME Vπ 39 38 H+ SCHEME VII Isoxazoles of formula IX wherein R 1 and R 5 are defined as above are prepared according to reaction scheme VII. A compound of the formula 3 is allowed to react with an oxime carbanion of an O-protected oxime (SiR3 is an acid labile protecting group such as tetrahydropyranyl or trimethylsilyl) to afford the hydroxy compound of the formula 37. Oxidation of the alcohol with an oxident such as pyridinium dichromate affords the ketone of the formula 38. Generation of the ketone anion with a base such as LDA followed by treatment with a suitable electrophile affords a compound of the formula 39. The compound of formula 39 is then cyclodehydrated to an isoxazole of the formula 40 by treatment with an acid, such as sulfuric acid. The compound of formula 40 is then treated with a suitable reagent for removing the nitrogen protecting group. The ring nitrogen is then alkylated, for example by treatment with formaldehyde and formic acid or alternatively acylated by treatment with an acid chloride in the presence of triethylamine, to afford an amide which is then reduced with a suitable reducing agent , such as borane or lithium aluminum hydride, to afford a compound of the formula IX. The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, ascorbate, aspartate, benzoate, beπzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, iaurate, lauryl sulfate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oleate, oxalate, pamoate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate valerate salts and the like. Also, the basic nitrogen-containing groups may be quaternized with such agents as Ci-Cβ-alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyi sulfates like dimethyl, diethyl, dibutyl, and diamyi sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenylethyi bromides, and others. Water- or oil- soluble or dispersibie products are thereby obtained. The pharmaceutically acceptable salts of the present invention may be synthesized from the compounds of formula (I) by conventional chemical methods. Generally, the salts are prepared by treating the free amine with stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid in a suitable solvent or various combinations of solvents. IN VITRO DETERMINATION OF NEURONAL NICOTINIC RECEPTOR BINDING POTENCIES AND SELECTIVITY For the purpose of identifying compounds as cholinergic agonists which are capable of selectively interacting with nicotinic receptors in the brain, ligand-receptor binding assays were carried out as an initial screen. Initial screening indicated that the compounds of the present invention were effective at interacting with neuronal nicotinic receptors and they were, therefore, assayed for their ability (compared to (-)nicotine) to label neuronal nicotinic receptors using [ 3 H]-methylcarbamylcholine ([ 3 H]- MCC) and for their ability (compared to (-)nicotine) to compete with the selective muscarinic antagonist [ 3 HJ-quinuclidinyl benzilate ([ 3 H]-QNB) for binding to muscarinic receptors. The ability of the compounds of the invention to interact with cholinergic receptors and to act as cholinergic agonists can be demonstrated in vitro using the following protocols. Protocols For Determination of Nicotinic Receptor Binding Potencies of AgQnists Binding of [ 3 H]-methylcarbamylcholine ([ 3 H]-MCC) to nicotinic receptors was accomplished using crude synaptic membrane preparations from whole rat brain (Snyder and Enna, Brain Research, 1975, 700:81 ). Washed membranes were stored at -80°C prior to use. Frozen aliquots were slowly thawed and resuspended in 20 volumes of buffer (containing: 120 m/WNaCI, 5 MKCI, 2 mM MgCI 2 , 2 mM CaCI 2 and 50 mM Tris-CI, pH 7.4 @4°C). After centrifuging at 20,000 X g for 15 minutes, the pellets were resuspended in 30 volumes of buffer. Homogenate (containing 125-150 μg protein) was added to triplicate tubes containing concentrations of test compound and [ 3 H]-MCC (3 nM) in a final volume of 500 μL Samples were incubated for 60 minutes at 4°C, then rapidly filtered through Whatman GF/B filters presoaked in 0.5% polyethylimine using 3 x 4 mL of ice-cold buffer. The filters are counted in 4 mL of Ecolume® (ICN). Nonspecific binding was determined in the presence of 10 μM (-)nicotine and values were expressed as a percentage of total binding. IC50 values were determined with the ALLFIT nonlinear least squares curve-fitting program and IC50 values were converted to Ki values using the Cheng and Prusoff correction (Ki=lCso/(1 +[ligand]/Kd of ligand). Alternately, data were expressed as a percentage of the total specific binding. The results are shown in Table 1. Table 1 : Binding to Neuronal Nicotinic Receptors Compound of Example Nicotinic Receptor Ki Number of Number jnM) Determinations (-) Nicotine 1 Arecoline 59 These data suggest that the compounds of the present invention have high affinity for the neuronal nicotinic receptor, although they are slightly less potent than (-)nicotine. The compounds of Example 2 and 4, however, both have 6 to 12-fold more affinity for the neuronal nicotinic receptor than arecoline, a nicotinic agonist that has demonstrated clinical utility. Protocols For Determination of Muscarinic Receptor Binding Potencies of Agonists The potencies of agonist binding at central muscarinic binding sites were determined by analysis of competition with the specific muscarinic receptor radioligand [ 3 H]-quinuclidinyl benzilate ([ 3 H]-QNB). Binding of [ 3 H]-QNB to muscarinic receptors was carried out using crude synaptic membranes prepared from whole rat brains as described above. Competition between various concentrations of agonist molecules and 0.2 nM [ 3 H]-QNB was performed at 25°C in an assay volume of 1 mL. After 75 minutes, the bound radioligand was separated by vacuum filtration on Whatman GF/B glass fiber filters. Non-specific binding was defined as radioactivity remaining in the presence of 10 μ/Watropine. Competition curves were analyzed for Ki values as described above for binding to the nicotinic receptor. The results are shown in Table 2. Table 2: In Vitro Binding Affinities to Nicotinic and Muscarinic Receptors These data suggest that the isoxazole compound of Example 2 is 32,000-fold more selective for the nicotinic receptor than for the muscarinic receptor. Although not as selective as (-)nicotine, the compound of Example 2 is 376-fold more selective than is arecoline for nicotinic receptors. IN VIVO DETERMINATION OF NICOTINIC MODULATORY ACTION AFFECTING BASAL FOREBRAIN NEUROTRANSMISSION Previous studies suggest that activation of neurons arising from the basal forebrain to the cerebral cortex will elicit an increase in cortical cerebral blood flow (CBF) by a mechanism that is mediated by a nicotinic receptor (refer to Background). General Surgery for CBF Measurement Methods for surgical preparation of rats for electrical stimulation of brain and measurement of CBF have been previously described (Nakai et al., Am. J. Physiol. 1982, 243: 226) and are summarized below. Studies are conducted on male Sprague-Dawley rats that are maintained in a thermally-controlled (26-27°C), light-cycled (7.00 hour on - 19.00 hour off) environment, fed standard rat chow and given water ad libitum. Anesthesia is induced with halothane (3.5%; balance 02) delivered through a nose mask and maintained at 2% during the initial surgery. Thin-wall vinyl catheters (o.d. = 0.03 inch) are placed in each femoral artery and vein, and the trachea is cannulated. Animals are subsequently co-anesthetized with urethane (1.5 g/kg, s.c.) and placed in a stereotaxic frame with the head positioned so that the floor of the IVth ventricle was horizontal (incisor bar position: -11 mm.). After connecting the tracheal cannula to a small-animal respirator, the animals are temporarily paralyzed with d-tubocurarine (0.6 mg/kg/h, i.m.), and ventilated (80 cpm) with 100% 02- Arterial pressure (AP) and heart rate (HR) are continuously monitored through one of the arterial catheters connected to a Statham P23Db transducer that is coupled to a chart recorder. The level of anesthesia during surgery or subsequent experimental testing is assessed by the AP response to tail pinch, with increasing levels of arousal giving rise to irregular AP readings. Booster doses of urethane (250 mg/kg, s.c.) are given as needed. Bilateral craniotomies (approximately 4 mm x 11 mm) are performed overlying the frontoparietal cortices taking care to leave the dura intact. Halothane is delivered at a reduced rate of 1 % during cranial surgery and discontinued afterward. A small volume (about 0.2 ml) of arterial blood is sampled after completion of all surgery for measurement of PO2, PCO2 and pH by a blood gas analyzer. Arterial blood gases are maintained so that PO2 was greater than 100 mm Hg, PCθ2=33-38 mmHg, and pH=7.35-7.45. Maintaining these values is accomplished by adjusting the stroke volume of the ventilator. Once appropriate physiological parameters are obtained (approximately 30 min), the experimental protocol is initiated. Electrical Stimulation of the Basal Forebrain tBR The BF is stimulated with cathodal current delivered through a stainless steel concentric bipolar electrode (250 mm diameter) made by Rhodes Medical Instruments (Model SNEX-100). Electrical pulses are generated by a square wave stimulator (Grass, Model S-88) and constant current is passed through a photoelectric stimulus-isolation unit (Grass, Model PSIU6). The stimulus current is measured on an oscilloscope by continuously displaying the voltage drop across a 10-ohm resistor. The procedure for eliciting an increased cortical CBF response requires the stereotaxic placement of the stimulating electrode into the BF. For positioning, the electrode is inclined posteriorly to 18 degrees, and the stereotaxic coordinates used were 5.0 mm posterior to, and 2.6 mm lateral to bregma (stereotaxic zero reference point). Cerebrovascular responsiveness, as measured by LDF, is used to localize the most active site of the BF by stimulating with 10 second trains of 2 msec duration pulses, at a frequency of 50 Hz and intensity of 100, μA. These parameters have been shown previously to elicit maximal increases in cortical CBF (Arneric, Excerpta Medica International Congress Series, Vol. 869:381, 1989). The region of the BFthat selectively affects cortical CBF is restricted, with electrode movements of 0.5 mm dorsal or ventral to this site eliciting potent vasodepressor responses in addition to the increases in CBF. Thus, the vasodepressor responses are also used to help signal the approachment of the most active BF site. When CBF increases of approximately 100% or greater are repeatedly obtained in the absence of significant changes in AP (<10 mm Hg) or HR (<10 beats min.), and when the perfusion rate is stable in the absence of BF stimulation, the experimental testing is started. CBF Measurement with Laser-Doppler Flowmetrv (LDF The principles and technical aspects of LDF are presented in detail in Bonner etal., Appl. Opt.1981, 20:2097 and Stern etal., Am. J. Physiol. 1977, 232:H441. In brief, LDF is used to assess second-to-second changes in microvascular perfusion within a restricted region (1 cubic mm) immediately beneath the laser-doppler probe placed on dura. To monitor cortical CBF, an LDF probe (0.8 mm dia.) is attached to a micromanipuiator and positioned over the exposed frontal CX. The probe is positioned to avoid major surface vessels and to touch the dura without significant surface indentation or occlusion of vessels. Careful exposure and manipulation of the frontal CX in this manner does not impair cerebro vascular reactivity (Arneric et al., Brain Res. 411 :212, 1987). Responses to BF stimulations were assessed within a restricted cortical region (1.3-1.8 mm anterior to, and 3.2-3.9 mm lateral to bregma), defined as frontal CX, in order to select the coordinates giving the largest enhancement of cortical perfusion. The LDF monitor (BPM 403A, TSI Inc.) displays and records blood flow readings in absolute blood flow units (ml/min/100 g). However, for the experiments discussed, these values were treated as comparative numbers and used only to determine relative changes in blood flow. Intravenous (iv) administration of the compound of Example 2 (0.001- 0.1 mg/kg) was examined for its effect on mean arterial pressure (MAP), resting CBF and increases in cortical CBF elicited by electrically stimulating the BF (<2>12.5 Hz; 100 μA; 10 second train). Consistent with the binding experiments, low concentrations were effective in enhancing resting CBF and the BF-elicited CBF response (n = 3). No remarkable effects on MAP were observed. Table 3 Effect of the Compound of Example 2 on CBF and MAP p < 0.05 These data indicate that administration of low concentrations of the compound of Example 2 effectively acts as an agonist at the neuronal nicotinic cholinergic receptor in vivo, since basal forebrain-elicited cerebral blood flow response was enhanced. In contrast to the in vitro data, the compound of Example 2 was between 10- to 100-fold more potent in enhancing the cerebral blood flow response than previously reported for (-)nicotine (D.G. Linville and S.P. Arneric, Soc. for Neurosci. Abstract, 1990, 76:129.11). These data are consistent with the idea that compounds like the compound of Example 2 are biologically more stable than (-)nicotine. Moreover, the compound of Example 2 has the advantage of having no overt effects on blood pressure, unlike those typically observed for direct-acting muscarinic agonists. IN VIVO STUDIES DEMONSTRATING ACTIVITY AS COGNITION ENHANCERS A. Inhibitory Avoidance Studies The inhibitory (or sometimes called passive) avoidance (IA) test is a well accepted animal model of learning/memory used to assess the activity of novel muscarinic agonists to enhance cognitive function (Wanibuchi etal., Eur. J. Pharmacol., 1990, 737:479). Animals are placed in the illuminated (12 X 14 X 11 cm) portion of a two-chambered box, from which they enter through a guillotine door to the larger (24 X 13.5 X 12 cm) dark compartment of the box. Entry to the dark compartment is accompanied by a mild (0.5 mA), brief (2 seconds) footshock. Initial latencies to cross are recorded, with an imposed 60 second ceiling. Following a 72 hour retention interval, animals are returned to the illuminated chamber, and latency to return to the dark compartment is again recorded, with a ceiling of 180 seconds. No footshock is administered on the test day. Animals received systemic injections of (-)nicotine and the compound of Example 2 (0.01-1.0 mg/kg, IP) 15 minutes before training in the inhibitory avoidance task, and retention was evaluated 24 hours later. Twelve animals were used in each group. Figure 1 demonstrates that (-)nicotine induced a dose-dependent facilitation of retention of the avoidance response at 0.1 mg/kg (p<0.05). The compound of Example 2 also significantly facilitated the retention of the avoidance response (Figure 2). In fact, it was equally efficacious at 1/10th the dose of (- )nicotine (0.01 mg/kg, p<0.05). B. Mouse Elevated Plus-Maze Studies The mouse elevated plus-maze is a conflict test that probes anxiolytic activity of test compounds (Lister, Psychopharmacology, 1987, 92:180). It is based on the fact that exposure of mice to an elevated open arm leads to an avoidance response considerably stronger than that evoked by exposure to an enclosed arm. The apparatus required to perform this test is made of plywood and consists of two open arms (17 X 8 cm) and two enclosed arms (17 X 8 X 15 cm) extending from a central platform (8 X 8 cm). It is mounted on a plywood base rising 39 cm above the floor. Mice are released on the central platform and the time spent in the open and enclosed arms is recorded during a 5 minute test period. (-)Nicotine (0.1 and 0.3 mg/kg, p<0.05) induced a significant increase in the time spent by the mice in the open arms of the maze (a measure of anxiolytic effect) as compared to saline-injected mice. Figure 4 demonstrates that the compound of Example 2 has an anxiolytic effect similar to (-)nicotine, but is at least 10-fold more potent. The compound of Example 2 (0.003 - 0.3 mg/kg, IP) was administered to CD1 mice (n = 12 per group) 15 minutes before the test. There was a clear anxiolytic response in mice receiving 0.01-0.3 mg/kg of the compound of Example 2 (p<0.05) as these groups of mice spent significantly more time in the open arms of the maze as compared to control animals. The present invention includes one or more of the compounds of formula (I) formulated into compositions together with one or more non- toxic pharmaceutically-acceptable carriers, adjuvants or vehicles, which are collectively referred to herein as carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal administration, and the like. In order to reduce unwanted peripherally mediated side-effects, it is advantageous, but not essential, to incorporate into the composition a peripherally acting anti-choiinergic such as N-methylscopolamine, N- methylatropine, propantheline, methantheline, or glycopyrrolate. Compositions suitable for parenteral injection may comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. If desired, and for more effective distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes. The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like. Besides such inert diluents, these liquid dosage forms may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of this invention include powders, sprays and inhalants. The active component is admixed under sterile conditions with a pharmaceutically-acceptable carrier and any needed preservative, buffers or propellants as may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The present compounds can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N. Y. (1976), p 33 etseq. Actual dosage levels of active ingredient in the compositions of the invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors. Total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts as determined by the attending physician, typically, for example, of from about 0.001 to 100 mg/kg body weight daily and preferably 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentaily with the specific compound employed; and like factors well known in the medical arts. The following examples, which are provided for illustration and not limitation of the invention, will serve to further illustrate preparation of the novel compounds of the invention. Thin-layer chromatography (TLC) was performed on 0.25 mm E. Merck precoated silica gel plates (60 F-254). Flash chromatography was performed on 200-400 mesh silica gel (E. Merck), while column chromatography was performed on 70-230 mesh silica gel (E. Merck). Example 1 3-Methyl-5-(2fS)-pyrrolidinvπ-isoxazole oxalate salt a. N-t-Butyloxycarbonyl-(S)-prolinal N-t-Butyloxycarbonyl-(S)-proiine was reduced to N- t-butyIoxycarbonyl-(£)-prolinol by treatment with diborane as described by K.E. Rittle, etal. in J. Org. Chem., 1982, 47:3016. N-t-butyloxycarbonyl- (S)-prolinol was then oxidized to N-t-butyloxycarbonyl-(S)-prolinal by treatment with sulfur trioxide-pyridine complex as described by Y. Hamada and T. Shioiri in Chem. Pharm. Bull, 1982, 5:1921. 1 H NMR spectra were recorded on a 300 MHz spectrometer. b. (2S -2-f2.2-DibromoethenylVN-t-butyloxyca ** bonylPyrrolidine At room temperature and under nitrogen, triphenylphosphine (13.0 g, 49.54 mmol), zinc dust (2.16 g, 33.0 mmol) and carbon tetrabromide (11.0 g, 33.0 mmol) was added to dichoioromethane (80 mL). After stirring for 5 minutes, a solution of N-t-butyioxycarbonyl- (S)-prolinal (3.29 g, 16.5 mmol) in dichoioromethane (25 mi) was added. The reaction was slightly exothermic. After stirring for 1 hour, the reaction mixture was diluted with a mixture of ethyl acetate/hexane (1 :1) and filtered through basic alumina (0.25 inch thick)/silica (0.5 inch thick, 40-60 micron) gel cake. The filter cake was then washed with a mixture of dicholoromethane/ethyl acetate/hexane (1 :1 :1). The filtrate was concentrated in vacuo and the residue was taken up in ethyl acetate/hexane (1 :1). The resulting precipitate was filtered off and the filtrate was concentrated. The residual oil was subjected to flash chromatography using ethyl acetate/hexane (1 :6.5 -> 1 :5) as the eluant. The resultant pure solid product was isolated in 91 % yield (5.31 g). TLC Rf = 0.35 (ethyl o acetate/hexane=1 :4). [α]26 __ +20.1° (c 1.10, MeOH). m.p. = 65- 66°C. MS(CI) m/e 354 (M+H)+. 1 H NMR (DMSO-d 6 , 70°C, 300MHz) δ 6.57 (d, J=8.1 Hz, 1H), 4.26 (ddd, J=7.9, 7.9, 4.9 Hz, 1 H), 3.30 (m, 2H), 2.05-2.17 (m, 1 H), 1.72-1.92 (m, 2H), 1.60-1.71 (m, 1 H), 1.40 (s, 9H). Anal, calcd. for Cn Hi7Br2N02: C, 37.21 ; H, 4.83; N, 3.95. Found: C, 37.45; H, 4.85; N, 3.97. c. f2SVEthvnvl-N-t-butvloxvcprbonvlpvrrolidine A solution of Example 1 b (S.65 g, 10.28 mmol) and tetrahydrofuran (THF) (20 mL) was made and cooled to -75°C using a dry ice bath. Under a nitrogen atmosphere, a 1.6 solution of n- butyllithium in hexane (13.2 mL, 21.11 mmol) was then added dropwise to the solution over a 15 minute period. After stirring for 1 hour, saturated aqueous sodium bicarbonate solution was added dropwise to the reaction flask. The dry ice bath was removed and an additional portion of saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate (3X) and the combined organic phases dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified using flash chromatography on silica gel eluting with diethyl ether/hexane (1 :6 to 1 :5) to give 1.29 g (64% yield) of the title compound (1 c) as an oil. TLC Rf= 0.21 (ether:hexane=1 :6). [α? 3 ° = -92.1 °(c 2.20, MeOH). MS (CI) m/e 196 (M+H)+. 1 H NMR (CDCI3, 300 MHz) δ 4.55-4.36 (m, 1 H), 3.53-3.24 (m, 2H), 2.25-1.85 (m, 5H), 1.48 (s, 9H). d. 3-Methyl-5-fN-t-butvloxvcarbonvl-2(S)-Pvrrolidinvn-isoxazole Under a nitrogen atmosphere, the product of Example 1c (1.45 g, 7.43 mmol) and phenyl isocyanate (1.45 mL, 13.37 mmol) were combined with stirring in 3.5 mL of benzene. A solution of triethylamine (10 drops) and nitroethane (535 μL, 7.43 mmol) in 2 mL of benzene was added to the resultant solution. A precipitate began to form about 2 to 3 minutes after addition was complete. The reaction mixture was stirred at ambient temperature for 2 hours, heated at reflux for 1.5 hours, allowed to cool to ambient temperature and stirred overnight. The reaction mixture was then filtered and the filter cake washed with benzene. The filtrate was concentrated in vacuo and the residue was purified using flash chromatography on silica gel eluting with ethyl acetate/hexane (1 :8) to give after concentrating in vacuo, 1.02 g (54.5% yield) of the title compound o (1 d) as a viscous yellow oil. [α]23 = _ι 94.4° (c 0.90, MeOH). MS (DCI/NH3) m/e 253 (M+H)+, 270 (M+NH 4 ) + . 1 H NMR (DMSO-d6; T=100°C) δ 1.32 (s, 9H), 1.80-1.90 (m, 3H), 2.16 (s, 3H), 2.14-2.24 (m, 1H), 3.31-3.42 (m, 2H), 4.87 (dd, 1H), 6.04 (s, 1H). e. 3-Methvl-5-f2fSVpvrrolidinvn-isoxazole The product of Example 1d (880 mg, 3.49 mmol) was dissolved in anhydrous methylene chloride (7.5 mL) and cooled to 0°C. Excess trifluoroacetic acid (TFA) (7.5 mL) was added and the reaction mixture was stirred for 1 hour at 0°C. The reaction mixture was then concentrated in vacuo until all of the excess TFA was evaporated to afford an amber oil. The oil was dissolved in saturated aqueous sodium bicarbonate solution and continuously extracted with methylene chloride for approximately 16 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with a gradient of 5% methanol in chloroform to 10% methanol in chloroform to give 456 mg (86% yield) of the title compound (1e). [α& 3 °= -13.1° (c 0.9, MeOH). MS (DCI/NH3) m/e 153 (M+H)+ 1 H NMR (CDCI3) δ 1.80-2.00 (m, 3H), 1.99 (br s, 1H, NH), 2.14-2.21 (m, 1H), 2.28 (s, 3H), 2.96-3.16 (m, 2H), 4.32 (dd, 1 H), 5.95 (s, 1 H). f. 3-Methvl-5-(2fS)-pvrrolidinvn-isoxazole oxalate salt A solution of the product of Example 1e (20 mg, 0.188 mmol) in diethyl ether was prepared. To this solution a solution of oxalic acid (25 mg, 0.282 mmol) in diethyl ether was added in a dropwise fashion. The resultant white precipitate was filtered and triturated with three portions of diethyl ether. The white solid was recrystallized from methanol/diethyl ether to give, after evaporating the residual solvent in vacuo, 23.7 mg (52% yield) of the title compound, m.p. 133-135°C. MS (DCI/NH 3 ) m/e 253 (M+H)+, 270 (M+NH 4 )+. 1 H NMR (D 2 0) δ 2.11-2.33 (m, 3H), 2.31 (s, 3H), 2.49-2.60 (m, 1H), 2.48 (dd, 2H), 4.92 (t, 1 H), 6.52 (s, 1 H). Anal, calcd. forCιoH-|4N 2 θ5: C, 49.58; H, 5.82; N, 11.56. Found: C, 49.54; H, 5.80; N, 11.51. Example 2 3-Methyl-5- -methyl-2 S pyrrolidinvh-isoxazole oxalate salt a. 3-Methyl-5-M-methyl-2(S pyrrolidinvh-isoxazole A solution of the product of Example 1e (3-methyl-5-(2(S)-pyrrolidinyl)- isoxazole 93.5 mg, 0.61 mmol), in 1.5 mL of 37% aqueous formaldehyde solution and 1.5 mL of 88% aqueous formic acid solution, was heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was then extracted with diethyl ether. The aqueous layer was made basic (pH ~ 10 to 11 ) by sequential addition of saturated aqueous sodium bicarbonate solution and solid potassium carbonate. The basic-aqueous solution was then extracted with three portions of chloroform and combined with the remaining organic phase. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel eluted with ethyl acetate hexane (1 :1 ) to give 71 mg (70% yield) of the title compound (2a) as a clear colorless oil. [α] 23* = -101° (c 0.68, MeOH). MS (FAB) m/e 167 (M+H)+. " Η NMR (CDCI 3 ) δ 1.78-2.03 (m, 3H), 2.17-2.42 (m, 2H), 2.29 (s, 3H), 2.34 (s, 3H), 3.13-3.20 (m, 1 H), 3.43 (dd, 1H), 5.99 (s, 1 H). b. 3-Methvl-5-π-methvl-2(SVpvrrolidinvn-isoxazole oxalate salt A solution of oxalic acid (51 mg, 0.57 mmol) in diethyl ether was added dropwise to a stirring solution of 3-methyl-5-(1 -methyl-2- pyrrolidinyl)-isoxazole (62.8 mg, 0.38 mmol), from Example 2a, in diethyl ether. After 0.5 hour of stirring at ambient temperature, the reaction flask became coated with a glass-like clear colorless solid. The diethyl ether was evaporated and the solid was triturated several times with diethyl ether to give, after evaporation of the solvent in vacuo, 102 mg of the title compound (2b). MS (DCI/NH3) m/e 167 (M+H)+, 184 (M+NH 4 )+. 1 H NMR (D 2 0) δ 2.11-2.33 (m, 3H), 2.31 (s, 3H), 2.49-2.60 (m, 1 H), 2.48 (dd, 2H), 4.92 (t, 1 H), 6.52 (s, 1 H). Anal, calcd. for CιoHi3Nθ5-0.2H 2 00.2C 2 H 2 0 2 : C, 48.65; H, 6.16; N, 9.95. Found: C, 48.80; H, 5.90; N, 9.77. Example 3 3-Ethvl-5-f2fS)-pvrrolidinvn-isoxazole oxalate salt a. 3-Ethv[-5-fN-t-butvloxvcarbonv-2fSVpvrrolidinvn-isoxazole Under a nitrogen atmosphere, (2_≥)-2-Ethynyl-N-t- butoxycarbonylpyrrolidine (885 mg, 4.52 mmol) and phenyl isocyanate (887 μL, 8.16 mmol) were combined, in 2.2 mL of benzene. The solution was stirred throughout the addition of the ingredients. A solution of nitropropane (404 μL, 4.53 mmol) in 1.2 mL of benzene and 7 drops of triethylamine was then added to the above solution. A precipitate began to form about 2 to 3 minutes after addition was complete. The reaction mixture was stirred at ambient temperature for 2 hours, heated at reflux for 1.5 hours, allowed to cool to ambient temperature and stirred overnight. The reaction mixture was then filtered and the filter cake washed with benzene. The filtrate was concentrated in vacuo and the residue was purified using flash chromatography on silica gel eluting with ethyl acetate/hexane (1 :8) to give, after evaporation of the solvent in vacuo, 631.6 mg (52% yield) of the title compound (3a). MS (DCI/NH 3 ) m/e 267 (M+H)+, 284 (M+NH 4 ) + . 1 H NMR (DMSO-d6: T=100°C) δ 1.19 (t, J=7.5 Hz, 1.34 (s,9H), 1.89-1.95 (m, 3H), 2.2-2.3 (m, 1 H), 2.60 (q, J=7.5 Hz, 2H), 3.39-3.45 (m, 2H), 4.91 (dd, J=7.5 Hz, 2.5 Hz, 1 H), 6.10 (s, 1 H). b. 3-Ethyl-5-(2(S -Pyrrolidinvπ-isoxazole The product of Example 3a (610 mg, 2.29 mmol) was dissolved in methylene chloride (7.5 ml) and cooled to 0°C. The solution was then treated with TFA, saturated sodium bicarbonate solution, and methylene chloride in the same manner as described in Example 1e above. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in chloroform to give 245 mg (64% yield) of the title compound (3b) as a light amber-colored oil. MS (DCI/NH3) m/e 167 (M+H)+, 184 (M+NH 4 )+. 1 H NMR (CDCI3) δ 1.25 (t, 3H), 1.80-1.95 (m, 3H), 2.07 (br s, 1 H, NH), 2.11 -2.24 (m, 1 H), 2.66 (q, 2H), 2.97-3.16 (m, 2H), 4.32 (dd, 1 H), 5.99 (s, 1 H). c. 3-Ethvl-5-(2fS)-Pvrrolidinvn-isoxazole oxalate salt A solution of the product of Example 3b (51.2 mg, 0.35 mmol) in diethyl ether was cooled to 0°C. A solution of oxalic acid (2 equivalents) in diethyl ether was added dropwise with vigorous stirring. The reaction mixture was stirred for 1 hour at 0°C and the solvent was evaporated in vacuo. The solid was recrystallized from methanol/diethyl ether to give, after evaporation of the solvent in vacuo, 68.1 mg (86.3% yield) of the title compound (3c) as white needle-like crystals, m.p. 131 -133°C. MS (DCI/NH3) m/e 167 (M+H)+, 184 (M+NH ) + . 1 H NMR (CD3OD) δ 1.27 (t, J=7.5 Hz, 3H), 2.17-2.31 (m, 3H), 2.48-2.53 (m, 1 H), 2.73 (q, J=7.5 Hz, 2H), 3.42-3.47 (m, 2H), 4.91 (buried in H 2 0 peak, 1 H), 6.56 (s, 1 H). Anal, calcd. for Cι ι Hi6N 2 0δ: C, 51.56; H, 6.29; N, 10.93. Found: C, 51.61 ; H, 6.29; N, 10.97. Example 4 3-Ethyl-5-π-methyl-2fS)-pyrrolidinvπ-isoxazole oxalate salt a. 3-Ethyl-5-f 1 -methyl-2( , S)-pyrrolidinvπ-isoxazole The product of Example 3c (150 mg, 0.90 mmol) was treated with excess formaldehyde and excess formic acid as described above in Example 2a. Subsequent steps followed in Example 2a were also followed except the flash chromatography on silica gel was eluted with 2% methanol in chloroform to give 154.5 mg (95% yield) of the title compound (4a) as a clear colorless oil. 1 H NMR (CDCI3) δ 1.26 (t, 3H), 1.81-2.02 (m, 3H), 2.17-2.29 (m, 1H), 2.34 (s, 3H), 2.67 (q, 2H), 3.13-3.21 (m, 2H), 3.43 (dd, 1H), 6.03 (s, 1 H). b. 3-Ethvl-5-π-methvl-2fS -pvrrolidinvn-isoxazole oxalate salt Using the procedure described in Example 2b, the product of Example 4a (135 mg, 0.75 mmol) was converted to the oxalate salt in quantitative yield to give 204.6 mg of the title compound. MS (DCI/NH3) m/e 181 (M+H)+, 198 (M+NH 4 )+. 1 H NMR (CD3OD) δ 1.28 (t, J=7.7 Hz, 3H), 2.21- 2.33 (m, 2H), 2.35-2.50 (m, 1H), 2.52-2.63 (m, 1 H), 2.72 (q, J=7.7 Hz, 2H), 2.90 (s, 3H), 3.35-3.42 (m, 1 H), 3.70-3.80 (m, 1 H), 4.77 (dd, 1 H), 6.68 (s, 1H). Anal, calcd. for C-| -|Hi6N 2 O5.0.5H 2 O: C, 51.61 ; H, 6.86; N, 10.03. Found: C, 51.62; H, 6.48; N, 9.83. Example 5 3-methyl-5-(2(S)-pyrrolidinvπ-isothiazole hvdrochloride a. f2Sϊ-2-f3-hvdroxv-1-butvnvl)-N-t-butvloxvcarbonvl ovrrolidine Under a nitrogen atmosphere, 2.0g (5.63 mmol) of (2£)-2-(2,2- dibromoethenyl)-N-t-butyloxycarbonylpyrrolidine (Example 1b) was added to 10 ml of THF. The solution was cooled to -75°C and n-butyllithium (4.6 mL, 11.54 mmol of a 2.5 M solution in hexane) was added dropwise over a period of 10 minutes. This solution was stirred for 20 minutes before adding acetaldehyde (377 μL, 6.75 mmol). This mixture was allowed to warm slowly to ambient temperature over several hours. The reaction was then quenched by adding aqueous-saturated sodium bicarbonate solution. The aqueous mixture was extracted with two portions of ethyl acetate and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to an orange oil. The oil was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (1 :2) to give 1.27 g (91 % yield) of the title compound (5a) as a colorless oil. MS (DCI/NH3) m/e 240 (M+H)+. " > H NMR (CDCI3300 MHz) δ 1.43 (d, J=6.6 Hz, 3H), 1.48 (s, 9H), 1.4-2.1 (m, 4H), 3.2-3.5 (m, 3H), 4.45 (br s, 1 H), 4.53 (q, J=6.6 Hz, 1H). b. (2SW3-keto-1-butvnvD-N-t-butyloxycarbonyl pyrrolidine At -60°C and under a nitrogen atmosphere, dimethylsulfoxide (1.12 mL, 15.8 mmol) was added to a solution of oxalyl chloride (1.28 mL, 14.7 mmol) in methylene chloride (30 mL). The reaction mixture was stirred for 10 minutes at -60°C, then a solution of the product of Example 5a (1.26 g, 5.26 mmol) in methylene chloride (5 mL) was slowly added (over a two minute period). This mixture was stirred for 15 minutes at -60°C before diisopropylethylamine (5.5 mL, 31.6 mmol) was added. After an additional .10 minutes of stirring at -60°C, the reaction mixture was warmed to 0°C and quenched with aqueous saturated ammonium chloride. The aqueous phase was extracted with methylene chloride and the organic extract was combined with organic phase from the original reaction mixture. The combined organic phases were then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (1 :1 ) to give 824 mg (66% yield) of the title compound (5b) as a colorless oil, [α]22° = -142.3° (c 1.4, CH 2 CI 2 ). MS (DCI/NH3) m/e D 238 (M+H)+. 1 H NMR (DMSO-d6, 300 MHz) δ 1.3-1.5 (m, 9H), 1.8-2.2 (m, 2.5H), 2.30 (s, 2.5H), 3.2-3.4 (m, 4H), 4.60 (br s, 1 H). c. 3-methyl-5-( , N-t-butyloxycarbonyl-2 S)-Pyrrolidinvπ-isothiazole The title compound was prepared using a modification of the procedure described by Lucchesini, etal. in Heterocycles, 1989, 29:97- 102. A solution of (2£)-2-(3-keto-1-butynyl)-N-t-butyloxycarbonyl pyrrolidine (704 mg, 3 mmol), from Example 5b, in 50% aqueous methanol (8 mL) was cooled to 0°C. Hydroxylamineo-sulfonic acid (338 mg, 3 mmol) was added to the solution and the reaction mixture was stirred for 45 minutes. After the 45 minutes of mixing, solid sodium bicarbonate (250 mg, 3 mmol) was added to the reaction mixture, followed by the addition of 2.3 mL of a 1.4 M aqueous solution of sodium hydrosulfide (3.3 mmol). The reaction mixture was then stirred at ambient temperature for 6.5 hours. The reaction mixture was diluted with brine and extracted with two portions of ethyl acetate. The aqueous phase was made basic by the addition of excess sodium bicarbonate. Additional sodium hydrosulfide (800 μL of 1.4 solution) was added and the reaction mixture was stirred overnight. The aqueous phase was again extracted with ethyl acetate and the organic extract was combined with the organic extracts from the previous day. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (1 :1) to yield 135 mg (17% yield) of the title compound (5c) as a yellow oil, [α] 23 ° = -90.9° (c 1.28, CH 2 CI 2 ). MS (DCI/NH 3 ) m/e 269 (M+H)+. 1 H NMR (DMSO-d6, 300 MHz) δ 1.36 (s, 9H), 1.83-1.98 (m, 3H), 2.31 (s, 1 H), 2.37 (s, 3H), 3.40 (dd, J=7.5, 6.1 Hz, 2H), 5.14 (dd, J=9.8, 2.4 Hz, 1H), 6.96 (s, 1H). d, 3-met yl-5-f2(S)-pyuQlidinyl)-ispthiazple hydrochlQride 2 mL of a saturated solution of hydrogen chloride (g) in dioxane was added to the product of Example 5c (115 mg, 0.43 mmol). The reaction mixture was left at ambient temperature for 30 minutes before it was concentrated in vacuo. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 40 mg of a yellow oil. A sample of this oil (9.5 mg) was purified by column chromatography on silica gel eluting with 10% ethanol in ethyl acetate to afford 9 mg of a colorless oil. This material (the free amine) was dissolved in ethanol (1 drop) and diethyl ether (-1.5 mL). A saturated solution of hydrogen chloride in diethyl ether was then added to this solution. A precipitate formed and was collected by centrifugation. The collected precipitate was washed with diethyl ether and dried in vacuo to yield the title compound (5d/5) as a white powder, m.p. 129- 130°C. MS (DCI/NH3) m/e 169 (M+H)+. 1H NMR (D 2 0, 300 MHz) δ 2.15- 2.37 (m, 3H), 2.49 (s, 3H), 2.65 (m, 1 H), 3.47-3.56 (m, 2H), 5.07 (dd, J=8.5, 6.6 Hz, 1 H), 7.31 (s, 1 H). Example 6 3-methyl-5-π-methvl-2(S -pvrrolidinvn-isothiazole hvdrochloride The product of Example 5, 3-methyl-5-(2(S)-pyrrolidinyl)-isothiazole, (30 mg) was treated in the same manner as described in Example 2a, with the exception that, the crude product was purified by column chromatography on silica gel and eluted with 10% ethanol in ethyl acetate to afford 9.8 mg of a colorless oil. This material was then dissolved in diethyl ether (~5 mL). Diethyl ether saturated with hydrogen chloride was then added dropwise with mixing. The precipitate which formed was collected by centrifugation, washed with diethyl ether and dried to yield the title compound as a white powder, m.p. 133-134°C. MS (DCI/NH3) m/e 183 (M+H)+, 270 (M+NH 4 )+. 1 H NMR (D 2 0, 300 MHz) δ 2.21 -2.39 (m, 3H), 2.51 (s, 3H), 2.72 (m, 1 H), 2.84 (br s, 3H), 3.35 (m, 1 H), 3,.78 (m, 1H), 4.79 (m, 1H), 7.39 (s, 1H). Example 7 3-Benzvl-5-M-methvl-2(S -Pvrrolidinvn-isoxazole oxalate salt a. 3-Benzvl-5-fN-t-butvloxvcarbonvl-2fS)-pyrrolidinvπ-isoxazole The nitrile oxide was generated from 2-phenyl-1 -nitroethane which was prepared via the reduction of nitrostyrene as descibed by A.K. Sinhababu in Tet. Let, 1983, 24, 227-30. Nitrostyrene was prepared using the method described by D.E. Worrall in Org. Syn., 1 , 413-14. Under a nitrogen atmosphere, (2S)-Ethynyl-N-t- butyloxycarbonylpyπOlidine (617 mg, 3.16 mmol) and phenyl isocyanate (1.25 mL, 11.38 mmol) were combined in 1.6 mL of benzene. A solution of 2-pheny 1-1 -nitroethane (955 mg, 6.32) in 1.8 mL of benzene and 5 drops of triethylamine was then added to the above solution. A precipitate began to form about 2 to 3 minutes after addition was complete. The reaction mixture was stirred at ambient temperature for 2 hours, heated at reflux for 1.5 hours, allowed to cool to ambient temperature and stirred overnight. The reaction mixture was then filtered and the filter cake washed with benzene. The filtrate was concentrated in vacuo and, the crude product was purified by flash chromatography on silica gel eluted with ethyl acetate/hexane (1 :10) to give 614 mg (59% yield) of the title compound (7a) as a viscous yellow oil. MS (DCI/NH3) m/e 329 (M+H)+, 346 (M+NH 4 )+ 1 H NMR (DMSO-d 6 , 300 MHz, 100°C) δ 1.27 (s, 9H), 1.84-1.97 (m, 3H), 2.19-2.29 (m, 1H), 3.33-3.46 (m, 2H), 3.95 (s, 2H), 4.90 (dd, J=7.8 Hz, 2.7 Hz, 1 H), 6.02 (s, 1 H), 7.20-7.34 (m, 5H). b. 3-Benzvl-5-(2(S)-Pvrrolidinvn-isoxazole The product of Example 7a (600 mg, 1.83 mmol) was treated in the same manner as set forth in Example 1e. However, the purification was accomplished using flash chromatography on silica gel eluted with 1 % methanol in chloroform to give 263 mg (63% yield) of the title compound (7b) as a pale yellow oil. MS (DCI/NH3) m/e 229 (M+H)+, 246 (M+NH 4 )+. 1H NMR (CDCI 3 /D 2 0 exchange, 300MHz) δ 1.88-1.92 (m, 3H), 2.09-2.23 (m, 1 H), 2.93-3.10 (m, 2H), 3.97 (s, 2H), 4.27 (dd, J=7.5 Hz, 5.3 Hz, 1 H), 5.88 (s, 1 H), 7.21-7.37 (m, 5H). £ 3-Benzvl-5-M-methvl-2(S)-Pvrrolidinvn-isoxazole The product from Example 7b (191.0 mg, 0.84 mmol) was treated in the same manner as set forth in Example 2a. However, purification was accomplished using flash chromatography on silica gel eluted with ethyl acetate/hexane (1 :2) to give 152.5 mg (75% yield) of the title compound (7c) as a clear colorless oil. MS (DCI/NH 3 ) m/e 243 (M+H)+, 260 (M+NH4). 1 H NMR (CDCI3, 300MHz) δ 1.79-2.00 (m, 3H), 2.14-2.25 (m, 1 H), 2.29-2.38 (m, 1 H), 2.30 (s, 3H), 3.11-3.18 (m, 1 H), 3.37-3.43 (m, 1 H), 3.99 (s, 2H), 5.92 (s, 1 H), 7.21-7.36 (m, 5H). d. 3-Benzyl-5-(1-methyl-2(S)-pyrrolidinvπ-isoxazole oxalate salt The product from Example 7c (147 mg, 0.61 mmol) was dissolved in diethyl ether. While stirring, a solution of oxalic acid (2 equivalents) in diethyl ether was introduced dropwise into the reaction vessel. The solvent was evaporated leaving a clear viscous oil. The product was triturated several times with diethyl ether and then the solvents evaporated in vacuo to give 147 mg (73% yield) of the title compound (7(07) as a clear oil. MS (DCI/NH3) m/e 243 (M+H)+, 260 (M+NH 4 )+. " " H NMR (CD3OD, 300 MHz) δ 2.19-2.45 (m, 3H), 2.50-2.62 (m, 1 H), 2.88 (s, 3H), 3.40-3.50 (partly buried in MeOH peak, 1 H), 3.67-3.77 (m, 1 H), 4.04 (s, 2H), 4.73 (br dd, J=8.9 Hz, 8.4 Hz, 1 H), 6.58 (s,1 H), 7.21-7.35 (m, 5H). Anal. cald. for Cι H 2 oN 2 0 5 -0.4 C 2 H 2 0 2 : C, 58.04; N, 5.69; H, 7.60. Found: C, 58.41 ; H, 5.75; N, 7.69. Example 8 3-Benzyl-5-M -methyl-2fS)-pyrrolidinyl)-isoxazole hvdrochloride salt A solution of the product from Example 7b (97.0 mg, 0.40 mmol) in diethyl ether was cooled to 0°C. While the above solution was stirring, a solution of diethyl ether saturated with anhydrous HCI gas was added to it dropwise. The solvent was evaporated in vacuo and the residue was triturated with diethyl ether. The solvent was then dried in vacuo to give the title compound (8) as a clear colorless viscous oil in quantitative yield. [α]23 D = -22.30 (c 0.26, MeOH). MS (DCI/NH3) m/e 243 (M+H)+. 1H NMR (CD3OD, 300 MHz) δ 2.21-2.44 (m, 3H), 2.52-2.63 (m, 1 H), 2.91 (br s, 3H), 3.30-3.42 (partly buried in MeOH peak, 1 H), 3.76-3.80 (m, 1H), 4.05 (s, 2H), 4.70-4.82 (m, 1 H), 6.60 (s, 1H), 7.21-7.32 (m, 5H). Anal, calcd. for C 15 H 19 CIN 2 O-0.8 H 2 0: C, 61.45; H, 7.08; N, 9.55. Found: C, 61.42; H, 7.00; N, 9.30. Example 9 5-f 1 -Methyl-2f S -pyrrolidinv0-3-propyl-isoxazole hvdrochloride salt a. 5-(N-t-butyloxycarbonyl-2fSVpyrτolidinvπ-3-propyl-isoxazole Under a nitrogen atmosphere with stirring, (2S)-Ethynyl-N-t- butyloxycarbonylpyrroiidine (1.23 g, 6.30 mmol) and phenyl isocyanate (1.55 mL, 14.2 mmol) were combined in 2.6 mL of benzene. A solution of nitrobutane (1.0 mL, 9.45 mmol) in 3.0 mL of benzene and 7 drops of triethylamine was then added to the solution. A precipitate began to form about 2 to 3 minutes after addition was complete. The reaction mixture was stirred at ambient temperature for 2 hours, heated at reflux for 1.5 hours, allowed to cool to ambient temperature and stirred overnight. The reaction mixture was then filtered and the filter cake washed with benzene. The filtrate was concentrated in vacuo and the residue was purified using flash chromatography on silica gel eluted with ethyl acetate/hexane (1 :12 --> 1 :10 --> 1 :8) to give 1.07 g (61 % yield) of the title compound (9a) as a clear yellow oil. [<X] 23 D = -51.4° (c 0.80, MeOH). MS (DCI/NH3) m/e 281 (M+H) + , 298 (M+NH 4 ) + . 1 H NMR (DMSO-d 6 , 500 MHz, 100°C) δθ.93 (t, J=7.5 Hz, 3H), 1.34 (s, 9H), 1.64 (qt, J=7.5 Hz, 7.3 Hz, 2H), 1.88-1.95 (m, 3H), 2.22-2.27 (m, 1 H), 2.56 (t, J=7.3 Hz, 2H), 3.37-3.46 (m, 2H), 4.92 (dd, J=8.3 Hz, 2.6 Hz, 1 H), 6.08 (s, 1 H). b. 5-(2(S)-pyrrolidinvn-3-propvl-isoxazole The product of Example 9a (987 mg, 3.52 mmol) was treated in the same manner as set forth in Example 1e. However, the residue was purified using flash chromatography on silica gel eluted with 2% -> 5% -- > 10% methanol in chloroform to give 585 mg (92% yield) of the title compound (9b) an amber oil. [α] 23 D = -11.5° (c 1.2, MeOH). MS (DCI/NH3) m/e 181 (M+H)+, 198 (M+NH 4 )+. 1 H NMR (CDCI3, 300 MHz) δ 0.97 (t, J=7.4 Hz, 3H), 1.68 (tq, J=7.5 Hz, 7.4 Hz, 2H), 1.80-1.97 (m, 3H), 2.06 (br s, NH), 2.12-2.25 (m, 1 H), 2.61 (t, J=7.5 Hz, 2H), 2.98-3.16 (m, 2H), 4.32 (dd, J=7.7 Hz, 5.5 Hz, 1 H), 5.97 (s, 1 H). £ 5-π-Methyl-2fS)-pvrrolidinvn-3-propvl-isoxazole The product of Example 9b (370 mg, 2.05 mmol) was treated in the same manner set forth in Example 2a. However the residue was purified using flash chromatography on silica gel eluted with ethyl acetate/hexane (1 :2 -> 1 :1 ) to give 297 mg (74% yield) of the title compound (9c) as a clear yellow oil. [α] 23 D = -84.1° (c 1.2, MeOH). MS (DCI/NH3) m/e 195 (M+H)+, 212 (M+NH 4 ) + . 1 H NMR (CDCI3, 300 MHz) δ 0.98 (t, J=7.4 Hz, 3H), 1.69 (tq, J=7.7 Hz, 7.4 Hz, 2H), 1.80-2.20 (m, 3H), 2.18-2.30 (m, 1 H), 2.32-2.41 (m, 1 H), 2.34 (br s, 3H), 2.62 (t, J=7.7 Hz, 2H), 3.13-3.21 (m, 1 H), 3.43 (dd, J=8.1 Hz, 7.4 Hz, 1 H), 6.01 (s, 1 H). d. 5-π-Methyl-2fS)-pyrrolidinvπ-3-propyl-isoxazole hvdrochloride salt A solution of the product from Example 9c (250 mg, 1.29 mmol) in diethyl ether was cooled to 0°C . Diethyl ether, saturated with anhydrous HCI gas was then added dropwise to the reaction vessel . The solvent was evaporated and the remaining white solid was redisolved in MeOH/diethyl ether. The solvent was evaporated to give 268 mg (90% yield) of the title compound (9d) as hygroscopic short white needles, m.p. = 112-1140c. [α] 23 D = -27.2° (c 0.66, MeOH). MS (DCI/NH3) m/e 195 (M+H)+. 1 H NMR (D 2 0, 300 MHz) δ 0.92 (t, J=7.4 Hz, 3H), 1.70 (tq, J=7.4 Hz, 7.4 Hz, 2H), 2.22-2.48 (m, 3H), 2.57-2.66 (m, 1 H), 2.70 (t, 7.4 Hz, 2H), 2.93 (br s, 3H), 3.37-3.47 (m, 1H), 3.72-3.84 (m,1 H), 4.77-4.87 (partly buried in H 2 0 peak, 1H), 6.70 (s, 1H). Anal, calcd. for CnH 19 CIN 2 0: C, 57.26; H, 8.30; N, 12.14. Found: C, 57.18; H, 8.23; N.11.98. Example 10 3-n-Butyl-5-f1 -methyl-2(SΪ-Pyrrolidinvπ-isoxazole hvdrochloride salt a. 3-n-Butvl-5-rN-t-butvloxvcarbonvl-2rS)-Pvrrolidinvh-isoxazole Under a nitrogen atmosphere a solution containing the product of Example 1c (620 mg, 3.18 mmol) and phenyl isocyanate (1.3 mL, 11.4 mmol) in 1.6 mL of benzene was prepared. A second solution containing nitropentane (782 μL, 6.36 mmol) in 1.7 mL of benzene and 5 drops of triethylamine was then added to the first solution. A precipitate began to form about 2 to 3 minutes after addition was complete. The reaction mixture was stirred at ambient temperature for 2 hours, heated at reflux for 1.5 hours, allowed to cool to ambient temperature and stirred overnight. The reaction mixture was then filtered and the filter cake washed with benzene. The filtrate was concentrated in vacuo and the residue was purified using flash chromatography on silica gel eluted with ethyl acetate/hexane (1 :15 --> 1:12 --> 1 :10 --> 1 :8) to give 567 mg (61 % yield) of the title compound (10a) as a clear yellow oil. [α] 23 o = -90.0° (c 0.60, MeOH). MS (DCI/NH3) m/e 295 (M+H)+, 312 (M+NH 4 )+. 1 H NMR (DMSO-d 6 , 500 MHz, 100°C) δ 0.90 (t, J=7.7 Hz, 3H), 1.12-1.40 (m, 2H), 1.34 (s, 9H), 1.60 (tt, J=7.4 Hz, 2H), 1.87-1.96 (m, 3H), 2.21-2.29 (m, 1 H), 2.58 (t, J=7.4 Hz, 2H), 3.37-3.47 (m, 2H), 4.91 (dd, J=7.8, 2.9 Hz, 1H), 6.08 (S, 1H). 3-π-Butyi-5-f2(S)-pyrrpiidinyiH?p χ azgie The product from Example 10a (540 mg, 1.83 mmol) in methylene chloride was treated in the manner set forth in Example 1 e. However, the purification using flash chromatography was done with silica gel eluted with 2% --> 5% methanol in chloroform to give 301 mg (85% yield) of the title compound (10b) as a clear yellow oil. MS (DCI/NH3) m/e 195 (M+H)+, 212 (M+NH 4 ) + . 1 H NMR (CDCI 3 , 300 MHz) δ 0.93 (t, J=7.4 Hz, 3H), 1.32-1.44 (m, 2H), 1.58-1.68 (m, 2H), 1.80-1.97 (m, 3H), 2.13-2.23 (m, 1H), 2.63 (t, J=7.5 Hz, 2H), 2.97-3.15 ( m, 2H), 4.31 (dd, J=7.4 Hz, 5.5 Hz, 1 H), 5.97 (S. 1H). 5 c. 3-n-Butyl-5-M -methyl-2fS -pyrrolidinvh-isoxazole The product from Example 10b (219 mg, 1.13 mmol) was treated in the same manner as set forth in Example 2a. However, the purification using flash chromatography was done with silica gel eluted with 0.5% --> 10 1 % methanol in chloroform to give 149 mg (63 %yield) of the title compound (10c) as a clear oil. [α] 23 D = -54.4 0 (c 0.59, MeOH). MS (DCI/NH 3 ) m/e 209 (M+H)+. 1 H NMR (CDCI 3 , 300 MHz) δ 0.93 (t, J=7.4 Hz, 3H), 1.38 (brtq, J=7.7 Hz, 7.0 Hz, 2H), 1.59-1.69 (m, 3H), 1.80-2.02 (m, 2H), 2.17-2.29 (m, 1 H), 2.32-2.40 (m, 1H), 2.34 (s, 3H), 2.65 (t, J=7.7 15 Hz, 2H), 3.14-3.20 (m, 1H), 3.42 (brdd, J=7.0 Hz, 7.0 Hz, 1 H), 6.00 (s, 1H). d. 3-n-Butvl-5-M -methvl-2(S)-pvrrolidinvn-isoxazole hvdrochloride salt The product from Example 10c (99 mg, 0.48 mmol) was dissolved in 20 diethyl ether, and cooled to 0°C. An ethereal solution of HCI was then added to the solution dropwise. The solvent was evaporated in vacuo and the remaining white solid was triturated (3X) with diethyl ether. The solvent was then evaporated in vacuo to give 72 mg (61% yield) of the title compound (10) as a hygroscopic white solid, m.p. = 100-102°C.[α] 23 D 25 = -25.20 (c 0.40, MeOH). MS (DCI/NH3) m/e 209 (M+H)+. 1 H NMR (D 2 0, 300 MHz) δ 0.91 (t, J=7.4 Hz, 3H), 1.33 (brtq, J=7.7 Hz, 7.4 Hz, 2H), 1.66 (brtt, J=7.7 Hz, 7.4 Hz, 2H), 2.22-2.48 (m, 3H), 2.56-2.69 (m, 1H), 2.74 (t, J=7.7 Hz, 2H), 2.91 (br s, 3H), 3.33-3.43 (m, 1H), 3.72-3.80 (m, 1H), 4.74-4.82 (partly buried in H 2 0 peak, 1H), 6.69 (s, 1H). Anal. : *■• calcd. for Cι 2 H 21 CIN 2 O-0.4 H 2 0: C, 57.20; H, 8.72; N, 11.12. Found: C, 57.57; H, 8.43; N,10.83. Example 11 3-Methvl-5-π -methvl-2(S)-pvrrolidinvn-isoxazole hvdrochloride salt a. 3-Methvl-5-f1-methvl-2fS)-Pvrrolidinvn-isoxazole hvdrochloride salt The product of example 2a (1.04g, 6.26 mmol) was dissolved in diethyl ether (100 mL) and cooled to 0°C. While the reaction was being stirred, an ethereal solution of HCI was added to the reaction causing a white precipitate to form. The solvent was evaporated in vacuo and the remaining solid was disolved in MeOH/Et 2 0 and recrystalized to give 543 mg (86% yield) of the title compound (11 ) as hygroscopic white needles, m.p. = 155-1570C. [αJ D = -32.4 0 ( C 0.58, MeOH). MS (DCI/NH3) m/e 167 (M+H)+, 184 (M+NH4). 1 H NMR (D 2 0, 300 MHz) δ 2.23-2.48 (m, 3H), 2.34 (s, 3H), 2.55-2.68 (m, 1 H), 2.92 (br s, 3H), 3.33-3.45 (m, 1 H), 3.72- 3.82 (m, 1 H), 4.74-4.84 (partly buried in H 2 0 peak, 1H), 6.65 (s, 1H). Anal, calcd. for C 9 H 15 CIN 2 0: C, 53.33; H, 7.46; N, 13.82. Found: C, 53.52; H.7.49; N, 13.62. Example 12 3-Ethyl-5-π -methvl-2(SΪ-Pvrrolidinvl)-isoxazole hvdrochloride salt a. 3-Ethyl-5-π-methyl-2( " S)-pyrrolidinvπ-isoxazole hvdrochloride salt Using the procedure from Example 11 , the product of Example 4a (75mg, 0.42 mmol) was converted to the hvdrochloride salt. The resultant white precipitate was triturated (4X) with diethyl ether and then the solvent evaporated in vacuo to give 72 mg (80% yield) of a hygroscopic white solid (12). m.p. = 135-136 0 C. [αJ 23 D = -28.6 0 (c 0.42, MeOH). MS (DCI/NH3) m e 181 (M+H)+, 198 (M+NH 4 )+ 1H NMR (DMSO-d 6 , 500 MHz, 30 O C) δ 1.21 (t, J=7.8 Hz, 3H), 2.05-2.28 (m, 4H), 2.67 (q, J=7.8 Hz, 2H), 2.81 (br s, 3H), 3.15-3.25 (m, 1H), 3.63-3.71 (m, 1 H), 4.69-4.76 (m, 1 H), 6.85 (br s, 1 H). Anal, calcd. for C 10 H 17 CIN 2 O: C55.42; H, 7.91 ; N, 12.93. Found: C, 55.15; H, 7.68; N, 12.73. Example 13 5-M -Ethvl-2(S)-pvrrolidinvlV3-methvl-isoxazole hvdrochloride salt a. 5-.1 -Acetyl-2fSVpyrrolidinvπ-3-methyl-isoxazole 3-Methyl-5-(2(S)-pyrrolidinyl)-isoxazole (90 mg, 0.59 mmol) and acetic anhydride (120 mg, 1.2 mmol) were combined in 1 ,4-dioxane (1.5 mL) and refluxed with stirring for one hour. The reaction was allowed to cool to ambient temperature and the solvent was evaporated in vacuo . The crude product was subjected to flash chromatography on silica gel eluted with 2% methanol in chloroform to give 117 mg (quantitative yield) of the title compound (13a) as a clear yellow oil. MS (DCI/NH3) m/e 195 (M+H) + , 212 (M+NH 4 ) + . 1 H NM (CDCI 3 , 300 MHz) δ 1.86-2.45 (m, 10H), 3.47-3.74 (m, 2H), minor conformational isomer 5.00 (d, J=7.0 Hz, 1H), major isomer 5.30 (dd, J=5.9 Hz, 2.6 Hz, 1H), minor conformational isomer 5.91 (s, 1 H), major isomer 5.96 (s, 1 H). b. 5-π -Ethyl-2(S -pyrrolidinvπ-3-methyl-isoxazole The product from Example 13a (108 mg, 0.56 mmol) in 1.0 mL of anhydrous tetrahydrofuran was treated with a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (506 μL, 0.56 mmol). The reaction was allowed to stir at ambient temperature for 2 hours and then worked up under standard conditions found in Fieser and Fieser , Vol. 1 , p.584. The crude product was then purified using flash chromatography on silica gel eluted with ethyl acetate/hexane (1 :1) to give 63 mg (63% yield) of the title compound (13b) as a clear oil. MS (DCI/NH3) m/e 181 (M+H)+. 1 H NMR (CDCI3, 300 MHz) δ 1.07 (t, J=7.2 Hz, 3H), 1.82-2.00 (m, 3H), 2.14- 2.47 (m, 3H), 2.28 (s, 3H), 2.72 (dq, J=12.1 Hz, 7.4 Hz, 1H), 3.19-3.27 (m, 1 H), 3.60 (dd, J=8.3 Hz, 6.4 Hz, 1 H), 5.97 (s, 1 H). c. 5-π-Ethyl-2(S)-PyrrolidinvD-3-methyl-isoxazole hvdrochloride salt The product from Example 13b (59 mg, 0.33 mmol) was processed in the same manner set forth in Example 11. The white solid obtained was dissolved in methylene chloride/hexane and recrystallized to give 41 mg (58% yield) of the title compound (13) as fine white needles, m.p. = 166-168 0 C. [α] 23 D = -33.3 0 ( c o.33, MeOH). MS (DCI/NH3) m/e 181 (M+H)+. 1H NMR (D 2 0, 300 MHz) δ 1.27 (t, J=7.4 Hz, 3H), 2.18-2.41 (m, 4H), 2.31 (s, 3H), 2.50-2.62 (m, 1 H), 3.10-3.23 (m, 1 H), 3.28-3.33 (m, 2H), 3.69-3.82 (m, 1 H), 6.61 (s, 1H). Anal, calcd. for Cι 0 H 17 CIN 2 O: C, 55.42; H, 7.91 ; N, 12.93. Found: C.55.25; H.7.97; N, 12.73. Example 14 3-Methvl-5-(2m)-Pvrrolidinvn-isoxazole oxalate salt a. (2R -Ethvnyl-N-t-butyloxycarbonylPyrrolidine The title compound was prepared in the manner set forth in Examples 1a-c. [α] 3 D = +113.0° (c 0.94, MeOH). i2_ 3-Methvl-5-rN-t-butvloxvcarbonvl-2 )-Pvrrolidinvh-isoxazole The product from Example 14a (1.96 g, 10.04 mmol), phenyl isocyanate (2.45 mL, 22.59 mmol), nitroethane (1.1 mL, 15.06 mmol) and a catalytic amount of triethylamine were treated in the manner set forth in Example 1d to give 1.52 g (60% yield) of the title compound (14b) as a light amber oil. [α] 23 D = +102.4 0 (c 0.70, MeOH). MS and 1 H NMR are simiiiarto those reported in Example 1d. c. 3-Methyl-5-2(R -Pyrrplidinvπ-isoxazole The product from Example 14b (1.41 g, 5.59 mmol) was treated in the same manner set forth in Example 1 e to give 663 mg (78% yield) of the title compound (14c) as a light amber oil. [α] 23 o = +11.6° (c 1.0, MeOH). MS and 1 H NMR are similiar to those described under Example 1e. α\ 1-Methvl-5-f2 )-pvrrolidinvn-isoxazole oxalate salt The product from Example 14c (48.5 mg, 0.32 mmol) was treated in the same manner set forth in Example 1f. The process yielded 63 mg (81% yield) of the title compound (14d) as a white solid, m.p. = 133.5- 134.5°C. [α] 23 D = +11.4° (c 0.55, MeOH). MS and 1 H NMR are simiiiar to those described under Example 1f. Anal, calcd. for CιoHi4N 2 Os: C, 49.58; H, 5.82; N, 11.50. Found: C, 49.57; H, 5.72; N.11.56. Example 15 3-Methvl-5-(2mvpvrrolidinvl)-isoxazole benzoate salt a. 1-Methvl-5-(2m)-Pvrrolidinvn-isoxazole benzoate salt The product of example 14c (855 mg, 5.62 mmol) was dissolved in diethyl ether. At ambient temperature, benzoic acid (755 mg, 6.18 mmol) was then added in one portion. The reaction was allowed to stir for one hour after which the ether was evaporated. The remaining solid was then recrystallized from hot diethyl ether (2X) to give 601 mg (39% yield) of the title compound (15) as pale-tan long needles, m.p, = 90.5-91.5°C. [α] 23 o = +9.5° (c 0.58, MeOH). MS (DCI/NH3) m/e 153 (M+H)+, 170 (M+NH 4 )+. 1 H NMR (CDCI3, 300 MHz) δ 1.95-2.23 (m, 3H), 2.22 (s, 3H), 2.24-2.38 (m, 1 H), 3.00-3.32 (m, 2H), 4.62 (dd, J=7.4 Hz, 5.9 Hz, 1H), 6.12 (s, 1 H), 7.39-7.44 (m, 2H), 7.49-7.55 (m, 1 H), 8.01-8.04 (m, 2H), 8.14 (br s, NH). Anal, calcd. for d5H 18 N 2 0 3 : C, 65.68; H, 6.61 ; N, 10.21. Found: C, 65.61 ; H, 6.50; N, 10.16. Example 1g 3-Methyl-5-d -methyl2(R)-pyrrolidinvh-isoxazole hvdrochloride salt a. 3-Methyl-5-M -methyl-2(R pyrrolidinvπ-isoxazole The product from Example 14c (370 mg, 2.43 mmol) was treated in the same manner set forth in Example 2a. The title compound (16a) 258 mg (64% yield), was isolated as a clear oil. [α] 3 o = +101.0° (c 0.76, MeOH). MS and 1 H NMR are simiiiar to those described under Example 2a. b. 3-Methyl-5-M -methvl-2f Rϊ-pvrrolidinvn-isoxazole hvdrochloride salt The product from Example 16a (228 mg, 1.37 mmol) was converted into a hvdrochloride salt using the method described in Example 10d. The white solid obtained was recrystallized from MeOH/Et 2 0 to give 248 mg (89% yield) of the title compound (16) as white needles, m.p. = 154- 155 0 C. [α] 23 D = +29.1 0 (c 0 .80, MeOH). MS and 1H NMR are simiiiar to those described under Example 15. Anal, calcd. for CgHi5CIN 2 0: C, 53.33; H, 7.46; N, 13.82. Found: C, 53.21 ; H, 7.71 ; N, 13.78. Example 17 3-Ethvl-5-f2fR)-pvrrolidinvh-isoxazole oxalate salt a. 3-Ethyl-5-fN-t-butyloxycarbonyl-2fR)-pyrrolidinO-isoxazole The product of Example 14a (655 mg, 3,35 mmol), phenyl isocyanate (1.3 mL, 12.1 mmol), nitropropane (600 μL, 6.7 mmol) and a catalytic amount of triethylamine were treated in the manner set forth in Example 1d. The process yielded 660 mg (74% yield) of the title compound (17a) as a clear yellow oil. MS and 1 H NMR are simiiiar to those described under Example 3a. b. 3-Eth yl-5-(2f R oyrrolidi nvh-isoxazole The product from Example 17a (650 mg, 2.44 mmol) was treated in the same manner as that described in Example 1e. The process yielded 268 mg (68% yield) of the title compound (17b) as a clear yellow oil. MS and 1 H NMR are simiiiar to those described under Example 3b. £ 3-Ethvl-5-(2fRVpvrrolidinvl)-isoxazole oxalate salt The product of Example 17b (84 mg, 0.51 mmol) was treated with oxalic acid (50 mg, 0.55 mmol) in the same manner set forth in Example 3c. The solid obtained was recrystallized from MeOH/Et 2 0 to give 88 mg (58% yield) of the title compound (17) as white crystals, m.p. = 131- 132 0 C. [α] 23 D = +8.3 0 ( c o.46, MeOH). MS and H NMR are simiiiar to those described under Example 3c. Anal, calcd. for CnHi6N 2 Os: C, 51.56; H, 6.29; N, 10.93. Found: C, 51.62; H, 6.21 ; N, 10.88. Example 18 3-Ethyl-5- 1 -methyl-2f R pyrrolidinvπ-isoxazole hvdrochloride salt a. 3-Ethyl-5-M -methvl-2 ( - p vrolidinvlY-isoxazote The product from Example 17b (152 mg, 0.91 mmol) was treated in the same manner set forth in Example 2a. The process yielded 138 mg (84% yield) of the title compound (18a) as a clear oil. The MS and 1 H NMR are simiiiar to those described under Example 4a. b. 3-Ethvl-5-(1 -methvl-2 pvrrolidinvn-isoxazole hvdrochloride salt The product from Example 18a (130 mg, 0.72 mmol) was converted into the hydrochloride salt by the procedure described in Example 16. The white precipitate obtained was recrystallized from MeOH/Et 2 0 to give 66 mg (42% Yield) of the title compound (18) as fine white needles, m.p. = 134-135°C. [α] 23 D = +33.2 © (c 0.44, MeOH). The MS and 1H NMR are simiiiar to those described under Example 4b. Anal, calcd. for C 10 H 17 CIN 2 O: C, 55.42; H, 7.91 ; N, 12.93. Found: C, 55.06; H.7.92; N.12.64. Example 19 3-methvl-5-(ϊ2R)-pvrrolidinvn-isothiazole hvdrochloride a. (2RH3-hvdroxy-1-butvnvn-N-t-butyloxycarbonyl pyrralidine The title compound (19a) was prepared in the manner described in Example 5a. b. (2RW3-keto-1-butvnvh-N-t-butyloxycarbonyl pyrrolidine The title compound (19b) was prepared in the manner described in Example 5b. [α] 3 D = +143.6 0 (c 1.6, CH 2 CI 2 ). c. 3-methyl-5-fN-t-butvloxvcarbonvl-r2R)-Pvrrolidinvn-isothiazole The title compound (19c) was prepared in the manner described in Example 5c. [α] 3 D = +107.7 0 ( C 1.0, CH 2 CI 2 ). d. 3-methyl-5-((2R -pyrrolidinvπ-isothiazole hvdrochloride The title compound (19) was prepared in the same manner described in Example 5d. [<χ] 23 = -14.8° (c 0.7, MeOH). Erømple 2Q 3-Methoxymethyl-5-f 1 -methyl-2(S\-pyrrolidinvπ-isoxazole fumarate salt a. 3-Hvdroxymethyl-5-fN-t-butyloxycarbonyl-2fS p yrrolidinvπ isoxazole 3-Ethoxycarbonyl-5-(N-t-butyloxycarbonyl-2(S)-pyrroiidinyl) isoxazole (7.10 g), of ~90 % pure material, was prepared using methodology reported by Eung K. Ryu, Heterocycles, 1990, 31 :1693. The compound was then placed in a solution of potassium hydroxide (1.35 g) in (1 :1 ) ethanol:water (70 mL) and allowed to stir overnight at room temperature. The reaction mixture was then acidified with 2N HCI and extracted with chloroform (3X). The organics were combined, dried over Na2Sθ4 and concentrated. The concentrated material was purified using flash chromatography with 10% MeOH in CHCI3 to 10% MeOH in CHCI3 with 0.5 % acetic acid. The product was azeotroped with toluene (2X), benzene (2X) and finally the solvents were evaporated in vacuo to give 3.09 grams of a yellow foamy solid. TLC Rf = 0.16 (10 % MeOH in CHCI3 and three drops of AcOH). The acid (387 mg, 1.37 mmol) and 1.0 M borane THF complex (4.80 mL, 4.80 mmol) were combined at room temperature in THF (4.5 mL) and then heated to reflux for 4 hours. After refluxing, the reaction was allowed to cool to room temperature. When the reaction reached room temperature, saturated NaHCOβ solution was added. The mixture was stirred for one hour and then combined with ethyl acetate. Two phases formed and were separated. The aqueous phase was extracted with CHCI3 (1X) and the organic extranet was combined with the original organic phase. The mixture was then dried over Na2Sθ4, concentrated in vacuo and purified by flash chromatography using 2 % MeOH in CHCI3 as the elutant to give a clear viscous oil (266 mg), 72 % yield. TLC Rf = 0.54 (10 % MeOH in CHCI3 and three drops AcOH). MS(CI) m/e (M+H)+ 269. 1 H NMR (DMSO-d6, 100°C, 500 MHz) δ 6.17 (s, 1H), 4.94 (dd, J=8.4, 2.8 Hz, 1H), 4.47 (s, 2H), 3.46-3.37 (m, 2H), 2.29-2.20 (m, 1H), 1.96-1.87 (m, 3H), 1.35 (s, 9H). b. 3-Methoxvmethvl-5-fN-t-butvloxvcarbonvl-2 S)-Pvrrolidinvn isoxazole The product of example 20a (274 mg, 1.02 mmol), in -1 mL of anhyrous THF, was added to a stirring slurry of 80 % sodium hydride (31 mg, 1.02 mmol), in ~1 mL of anhydrous THF. The reaction was allowed to stir for 15 minutes at ambient temperature, lodomethane (190 mL, 3.06 mmol) was then added via syringe. After an additional 15 minutes of stirring, the reaction was poured over ethyl acetate/saturated NH4CI solution. Two phases formed and the phases were separated. The organic phase was dried over Na2Sθ4, concentrated in vacuo and the residue purified by flash chromatography using ethyl acetate/hexane (1 :3) as the elutant. The purification yielded 234 mg of a clear yellow oil (81 % yield). MS(CI) m/e (M+H)+ 283. 1 H NMR (DMSO-dβ, 100 O C, 500 MHz) δ 6.20 (s, 1 H), 4.94 (dd, J=7.8, 2.6 Hz, 1 H), 4.43 (s, 2H), 3.47-3.36 (m, 2H), 3.32 (s, 3H), 2.30-2.22 (m, 1 H), 1.96-1.87 (m, 3H), 1.34 (s, 9H). c. 3-Methoxvmethvl-5-M-methvl-2(S)-Pvrrolidinvn isoxazole Using an ice bath the product from Example 20b (220 mg, 779 mmol) was cooled neat to 0°C. Approximately 6 mL of 4.0 N HCI in 1 ,4- dioxane was then introduced into the reaction vessel. The ice bath was removed and the reaction was stirred for ~2 hours. The solvent was evaporated in vacuo and the remaining crude product was azeotroped with Et2θ (1X). The crude product was dissolved in ~3 mL of 88 % formic acid and ~3 mL of 37 % aqueous formaldehyde. The reaction was heated at a gentle reflux for ~30 minutes and then allowed to cool to room temperature. The aqueous solution was extracted once with Et2θ and then basified with saturated NaHCθ3 solution followed by solid K2CO3. The basified solution was then extracted with CHCI3 (3X). The chiororform extracts were combined, dried over Na2Sθ4, concentrated in vacuo and the residue purified by flash chromatography to give 142 mg of the title compound (20c) in 93 % overall yield. MS(CI) m/e (M+H)+ 197. H NMR (CDCI3, 300 MHz) δ 6.20 (s, 1 H), 4.51 (s, 2H), 3.47 (dd, J=8.1 , 7.4 Hz, 1H), 3.39 (s, 3H), 3.20-3.13 (m, 1 H), 2.42-2.30 (m, 1 H), 2.34 (s, 3H), 2.28-2.20 (m, 1 H), 2.03-1.80 (m, 3H). d. 3-Methoxymethyl-5-π-methyl-2fs pyrrolidinvπ isoxazole fumarate salt The product from Example 20c (34 mg, 0.17 mmol) and fumaric acid (20 mg, 0.17 mmol) were combined in ~1 mL of MeOH and stirred for 30 minutes. The solvent was evaporated in vacuo and the remaining viscous oil was left on the high vacuum line overnight to give 37 mg of the title compound (20) as a clear viscous oil (60 % yield). MS(CI) m/e (M+H)+ 197. 1 H NMR (MeOD, 300 MHz) δ 6.72 (s, 2H fumarate), 6.54 (s, 1 H), 4.52 (s, 2H), 4.08 (dd, J=8. ' l , 8.1 Hz, 1 H), 3.43-3.37 (m, 1 H), 3.39 (s, 3H), 2.82 (ddd, J=10.7, 10.3, 8.5, 1 H), 2.58 (s, 3H), 2.48-2.37 (m, 1 H), 2.24-2.03 (m, 3H). Anal, calcd. for Ci 4H20N2O6-O.4C4H4O4-O.2H2O: C, 51.71 ; H, 6.12; N.7.73. Found: C, 51.76; H, 6.45; N, 7.60. Example 21 3-Methyl-5-f fra/-?s-4-hvdroxy-1 -methyl-2-pyrrplidinvπ-isoxazole oxalate salt a. fra/7S-4-Hvdroχyproline methyl ester hydrogen chloride salt Acetyl chloride (15.7 ml, 0.22 mol) was slowly added to a solution of fraπs-4-hydroxyproline (26.2 g, 0.20 mol) in methanol (800 ml). The reaction was carried out at room temperature and the resulting solution was allowed to stir for forty eight hours. After evaporation of the solvents in vacuo, the title compound (21a) was obtained as a white solid in quantitative yield. MS (DCI/NH3) m/e 146 (M+H)+, 163 (M+NH4)+, 291 (2M+H)+. 1 H. JMR (DMSO) δ 5.54 (s, H, NH), 4.43 (dd, J = 9.0 Hz, J = 8.1 Hz, 1 H, CHCO), 4.35-4.40 (m, 1 H, OCH), 3.72 (s, 3H, OCH3), 3.28- 3.38 (m, 1 H, NCHH), 3.03 (ddd, J = 11.1 Hz, J = 1.8 Hz, J = 1.8 Hz, NCHH), 2.15 (dddd, J = 13.5 Hz, J = 8.1 Hz, J = 1.8 Hz, J = 1.8 Hz, 1 H, OCCHH), 2.04 (ddd, J = 13.5 Hz, J = 9.0 Hz, J = 4.5 Hz, 1 H, OCCHH). b. frar7S-4-(2.4.6-Trimethylbenzoyloxytoroline methyl ester Trifluoroacetic anhydride (0.93 mL, 6.60 mmol) was added dropwise to a suspension of •* ra 7s-4-hydroxy proline methyl ester hydrochloride salt (21a, 1.00 g, 5.50 mmol) and 2,4,6-trimethyl benzoic acid (1.08 g, 6.60 mmol) in methylene chloride (20 mL). The addition was carried out at room temperature and the resulting clear solution was allowed to stir at room temperature for 30 minutes. The reaction mixture was then basified with 2N NaOH to pH = 12, and extracted with chloroform (30 mL 4X). The chloroform extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The title compound (21 b) was obtained as an oil, which was directly used for the next reaction without further purification. TLC Rf = 0.33 (ethyl acetate:hexane=2:1 ). MS (DCI/NH3) m/e 292 (M+H)+. 1 HNMR (CDCI3) δ 6.85 (s, 2H, 2ArH), 5.49-5.55 (m, 1 H, OCH), 4.01 (dd, J = 9.0 Hz, J = 9.0 Hz, 1 H, COCH), 3.76 (s, 3H, OCH3), 3.43 (dd, J = 13.5 Hz, J = 4.5 Hz, 1H, NCHH), 3.18 (ddd, J = 13.5 Hz, J = 1.5 Hz, J = 1.5 Hz, NCHH), 2.38 (dddd, J = 14.7 Hz, J = 9.0 Hz, J = 1.5 Hz, J =1.5 Hz, 1 H, CMH), 2.29 (s, 6H, 2ArCH3), 2.28 (s, 3H, ArCH3), 2.19-2.29 (m, 1 H, CHJd). c. fraπs-1-Methyl-4-(2.4.6-trimethylbenzoyloxy) proline methyl ester lodomethane (573.0 mL, 9.20 mmol) was slowly added through a condenser at 0° C To a suspension of fraπs-4-(2,4,6-trimethylbenzoyloxy) proline methyl ester (21b, 1.35 g, 4.60 mmol) and triethylamine (1.29 mL, 9.20 mmol) in anhydrous methylenechloride (5 mL). The mixture was then refluxed overnight. Brine (20 mL) was then added to the mixture and the mixture was extracted with chloroform (30 mL 4X). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1 :1 ) to give 543.0 mg (32% yield from 4-hydroxyproline methyl ester hydrogen chloride) of the title compound (21c) as an oil. TLC Rf = 0.65 (ethyl acetate:hexane=2:1). MS (DCI/NH3) m/e 306 (M+H)+. 1 HNMR (CDCI3) δ 6.85 (s, 2H, 2ArH), 5.44-5.52 (m, 1 H, OCH), 3.77 (s, 3H, OCH3), 2.26-2.64 (m, 4H, 2CH2), 2.47 (s, 3H, NCH3), 2.30 (s, 6H, 2A1 H3), 2.28 (s, 3H, A1 H3). d. 3-Methyl-5-f fra/?s-4-f2.4.6-trimethylbenzoyloxy)-1 -methyl-2- pyrrolidinvn-isoxazole Λ -butyl lithium (1.70 mL, 2.5 M, 4.26 mmol) was added dropwise at 0° C to a solution of acetone oxime (155.5 mg, 2.13 mmol) in anhydrous THF (10.0 mL). The resulting solution was stirred at the same temperature for two hours. Trans-1 -Methyl-4-(2,4,6-trimethylbenzoyloxy) proline methyl ester (21c, 500.0 mg, 1.64 mmol) in anhydrous THF (5.0 mL) was slowly added to the solution through syringe. The resulting mixture was further stirred at 0 °C for eight hours and slowly warmed to room temperature overnight. THF was then evaporated in vacuo. A THF-sulfuric acid solution (10.0 mL, prepared in a ratio of sulfuric acid : THF : H2O = 8.2 g : 40 mL : 10 mL) was added and the mixture was refluxed for two hours. The mixture was made basic with 10% NaOH and extracted with ethyl acetate (30 mL 4X). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1 :1 and 2:1) to give 112.5 mg (21% yield) of the title compound (21 d) as an oil. TLC Rf = 0.63 (ethyl acetate :hexane=2:1 ). MS (DCI/NH3) m/e 329 (M+H)+. 1 HNMR (CDCI3) δ 6.86 (s, 2H, 2ArH), 6.03 (s, 1 H, isoxazole H), 5.48-5.54 (m, 1H, OCH), 3.76 (dd, J = 9.6, J = 6.3 Hz, 1 H, ArCHN), 2.38- 2.61 (m, 4H, 2CH2), 2.44 (s, 3H, NCH3), 2.31 (s, 6H, 2ArCH3), 2.30 (s, isoxazole-CH3), 2.29 (s, 3H, A1CH3). e. 3-Methyl-5-f frans- 4-hvdroxy-1 -methyl-2-pyrrolidinvπ-isoxazole A solution of 3-methyl-5-(- ar7s-4-(2,4,6-trimethylbenzoyloxy)-1- methyl-2-pyrrolidinyl)-isoxazole (21 d, 350.0 mg, 1.07 mmol) in 2.0 mL of KOH solution (prepared in a ratio of KOH : EtOH : H2O = 10 g : 30 mL : 2 mL) was refluxed for two hours. Direct chromatography of the residue on silica gel eluting with CHCl3/MeOH (20:1) gave 171.0 mg (88% yield) of the title compound (21 e) as an oil. TLC Rf = 0.65 (CHCl3:MeOH =5:1). MS (DCI/NH3) m/e 183 (M+H)+, 200 (M+NH4) + . 1 HNMR (CDCI3) δ 6.03 (s, 1 H, ArH), 4.55-4.63 (m, 1 H, OCH), 3.93 (dd, J = 8.7 Hz, J = 8.7 Hz, 1 H, ArCHN), 3.53 (dd, J = 9.0 Hz, J = 5.7 Hz, 1 H, NCHH), 2.52 (dd, J = 9.0 Hz, J = 4.2 Hz, 1 H, NCHH), 2.36 (s, 3H, NCH3), 2.33 (ddd, J = 14.1 Hz, J = 8.7 Hz, J = 2.4 Hz, 1H, OCCHH), 2.29 (s, 3H, ArCH3), 2.18 (ddd, J = 14.1 Hz, J = 8.7 Hz, J =3.0 Hz, 1 H, OCCHH). f. 3-Methyl-5-(fraπs- 4-hvdroxy-1 -methyl-2-pyrrolidinvh-isoxazole oxalate salt A solution of oxalic acid (13.6 mg, 0.151 mmol) in diethyl ether was added dropwise to a stirring solution of 3-methyl-5-(tøa/7s-4-hydroxy-1- methyl-2-pyrrolidinyl)-isoxazole (21 e, 25.0 mg, 0.14 mmol) in diethyl ether. After 30 minutes of stirring at ambient temperature, the resulting precipitate was filtered and washed with diethyl ether three times to give, after evaporation of the solvents in vacuo., 26.0 mg of the title compound (21 ). M.P. 125-126 OC. MS (DCI/NH3) m/e 183 (M+H)+, 200 (M+NH4)+. 1 HNMR (D2O) δ 6.67 (s, 1H, ArH), 5.07-5.17 (m, 1H, OCH), 4.82 (dd, J = 10.5 Hz, J = 9.9 Hz, 1H, ArCHN), 3.93-4.03 (m, 1 H, NCHH), 3.34-3.43 (m, 1H, NCHH), 2.98 (s, 3H, NCH3), 2.66 (ddd, J = 14.4 Hz, J = 10.5 Hz, J = 4.8 Hz, 1 H, OCCHH), 2.55 (dddd, J = 14.4 Hz, J = 9.9 Hz, J =1.8 Hz, J = 1.8 Hz, 1 H, OCCHH.), 2.33 (s, 3H, ArCH3). Anal, calcd. for C11 H16N2O6: C, 48.53; H, 5.88; N, 10.29. Found: C, 48.58; H, 5.83; N, 10.04. Example 22 3-Methvl-5-fc/s-4-fluoromethvl-2-Pvrrolidinvn-isoxazole hvdrooen chloride a. Pyroglutamic acid methyl ester Thionyl chloride (16.5 mL, 0.23 mol), DMF (0.20 mL) and pyroglutamic acid (15.0 g, 0.116 mol) were sequentially added to a solution of absolute methanol (50 mL) at -15 °C. The mixture was slowly warmed to room temperature and stirred for eighteen hours. After evaporation of the methanol, the resulting residue was dissolved in ethyl acetate (400 mL) and water (20 mL), followed by the slow addition of sodium bicarbonate (20.0 g). After the mixture was vigorously stirred for 30 minutes, the organic layer was decanted and dried over anhydrous magnesium sulfate. Removal of the solvent gave 15.6 g (94% yield) of the title compound (22a). TLC Rf = 0.42 (CHCl3:MeOH =10:1). MS (DCI NH3) m/e 144 (M+H)+, 161 (M+NH4)+. 1 HNMR (CDCI3) δ 6.01 (s, 1 H, NH), 4.27 (dd, J = 8.1 Hz, J = 4.5 Hz, 1 H, NCH), 3.78 (s, 3H, CH3), 2.20-2.54 (m, 4H, 2CH2). b. 1 -Methyl pyroglutamic acid methyl ester A solution of pyroglutamic acid methyl ester (22a, 10.0 g, 69.9 mmol) in DMF (40 mL) was slowly added at room temperature to a suspension of sodium hydride (2.29 g, 80%, 76.2 mmol) in DMF (100 mL). After the evolution of hydrogen stopped, iodomethane (8.67 mL, 139.8 mmol) was added dropwise, and the solution was stirred for two hours. Ethyl acetate (200 mL) and hexane (500 mL) were then added, and a precipitate was filtered off. The precipitate was washed with ethyl acetate (20 ml 3X) and the washings were combined with the original solution. The solution was concentrated and the remaining residue was distilled to give 8.50 g (78% yield) of the title compound (22b). B.P. 107- 109 oc/2.7 mmHg. TLC Rf = 0.49 (CHCl3:MeOH =10:1). MS (DCI/NH3) m/e 158 (M+H)+, 175 (M+NH4)+ 1 HNMR (CDCI3) δ 4.13 (dd, J = 9.0 Hz, J = 3.9 Hz, 1 H, NCH), 3.78 (s, 3H, OCH3), 2.86 (s, 3H, NCH3), 2.04-2.54 (m, 4H, 2CH2). c. 3-Methyl-5-M -methyl-5-oxo-2-pyrrolidinyl)-isoxazole Λ/-butyl lithium (108.8 mL, 2.5 M, 272.0 mmol) in hexane was slowly added to a cooled (0-5 °C) solution of acetone oxime (9.92 g, 135.9 mmol) in THF (300 mL). After being stirred at 0-5 °C for one hour, a solution of 1 -methyl-pyroglutamic acid methyl ester (22b, 16.32 g, 10.4 mmol) in THF (50 mL) was added. After being stirred for additional eight hours, the resulting reaction mixture was slowly warmed to room temperature overnight. THF was evaporated, and a sulfuric acid solution in THF (160 mL, prepared in the ratio of H2SO4 : H2O : THF = 8.2 g : 10 mL : 40 mL) was added, and the mixture was allowed to reflux for one hour. After the evaporation of THF, the residue was first extracted with chloroform (80 mL 6X), then continuously extracted with chloroform (120 mL) overnight. All the organic phases were combined and dried over magnesium sulfate. The residue obtained after evaporation of the solvents was flash chromatographed on a silica gel column eluting with CHCl3/MeOH (20/1) to give 13.1 g (70% yield) of the title compound (22c) as an oil. TLC Rf = 0.49 (CHCl3:MeOH=10:1 ). MS (DCI/NH3) m/e 181 (M+H)+, 198 (M+NH4)+. 1 HNMR (CDCI3) δ 5.99 (s, 1 H, Ar-H), 4.71 (dd, J = 8.1 Hz, J = 4.5 Hz, 1 H, ArCHN), 2.80 (S, 3H, NCH3), 2.32 (s, 3H, CH3), 2.95-3.25 (m, 1 H, COCH), 2.18-2.64 (m, 3H). d. 3-Methyl-5-(c/s-4-hvdroxymethyl-1-methyl-5-oxo-2-pyrrolidinyl isoxazole and e. 3-methyl-5-(fra 7S-4-hvdroxymethyl-1-methyl-5-oxo-2-pyrrolidinv - isoxazole LDA (14.67 mL, 1.5 M, 22.0 mmol) was slowly added to a cooled (- 78 °C) solution of 3-methyl-5-(1-methy!~5-oxo-2-pyrrolidinyl)-isoxazole (22c, 3.60 g, 20.0 mmol) in THF (100 mL). The resulting solution was stirred at -78 °C for 30 minutes. The mixture was then warmed to -20 °C, and formaldehyde, generated by heating parafomaldehyde on a 140 °C oil bath, was gently bubbled intc the mixture until saturation (over one hour). The reaction mixture was stirred for an additional 30 minutes before methanol (5.0 mL) was added. The solvents were evaporated in vacuo, and the residue was purified on silica gel eluting with CHCl3/MeOH (40:1) to give 2.63 g (63% yield) of the title compounds (22d & 22e) as an inseparable mixture (trans : cis = 2.5 : 1 by NMR spectroscopy analysis). TLC Rf = 0.37 (CHCl3:MeOH =20:1 ). MS (DCI/NH3) m/e 21 1 (M+H)+ , 228 (M+NH4) + . 3-Methyl-5-(c/s-4- hydroxymethyl-1-methyl-5-oxo-2-pyrrolidinyl)-isoxazole (22d): " ΗNMR (CDCI3) δ 5.99 (s, 1H, ArH), 4.68 (dd, J = 9.2 Hz, J = 4.8 Hz, 1 H, ArCHN), 3.96 (dd, J = 12.0 Hz, J = 4.8 Hz, 1 H, OCHH), 3.73 (dd, J = 12.0 Hz, J = 6.6 Hz, 1 H, OCHH), 2.75-2.81 (m, 1 H, COCH), 2.84 (s, 3H, NCH3), 2.34 (ddd, J = 12.9 Hz, J = 9.6 Hz, J = 4.8 Hz, 1 H, CHH), 2.30 (s, 3H, ArCH3), 2.24 (ddd, J = 12.9 Hz, J = 9.2 Hz, J = 3.9 Hz, 1 H, CHH). 3-Methyl-5- (fra 7s-4-hydroxymethyl-1-methyl-5-oxo-2-pyrrolidinyl)-isoxazole (22e): 1 HNMR (CDCI3) δ 6.09 (s, 1 H, ArH), 4.71 (dd, J = 8.8 Hz, J = 5.7 Hz, 1 H, ArCHN), 3.93 (dd, J = 12.0 Hz, J = 4.8 Hz, 1H, OCHH), 3.79 (dd, J = 12.0 Hz, J = 6.6 Hz, 1 H, OCHH), 2.75-2.81 (m, 1 H, COCH), 2.75 (s, 3H, NCH3), 2.58 (ddd, J = 16.5 Hz, J = 8.8 Hz, J = 7.5 Hz, 1 H, CHH), 2.33 (s, 3H, A1CH3), 1.96 (ddd, J = 16.5 Hz, J = 8.2 Hz, J = 5.7 Hz, 1H, CHH). f. 3-Methyl-5-to/s-4-fluoromethyl-1-methyl-5-oxo-2-pyrrolidinyl isoxazole and a 3-methvl-5-ffra 7s-4-fluoromethvl-1-methvl-5-oxo-2-PvrrolidinvlV isoxazole A mixture of the cis and trans isomers of 3-methyl-5-(4- hydroxymethyl-1-methyl-5-oxo-2-pyrrolidinyl)-isoxazole (22d, 22e, 210.0 mg, 1.0 mmol) in methylene chloride (2.0 mL) was added dropwise to a cooled (-78 °C) solution of DAST (198.0 mL, 1.50 mmol) in methylene chloride (2.0 mL). After being stirred at -78 °C for two hours, the resulting solution was slowly warmed to room temperature and stirred for an additional four hours. Methanol (10 mL) was then added, and the solution was made basic with a 50% sodium hydroxide solution. The precipitates were filtered off and washed with ethyl acetate (2 mL 3X). The filtrate and washings were then combined and concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3/MeOH (40:1 and 20:1 ) to give 246.0 mg of the crude title compounds (22f & 22g) as an inseparable mixture (cis:trans = 3:1 by NMR spectroscopy), which was directly used for the next reaction without further purification. TLC Rf = 0.49 (CHCl3:MeOH =20:1 ). MS (DCI/NH3) m/e 213 (M+H)+, 230 (M+NH4)+. 3-Methyl-5-(c/ ' s-4-fluoromethyl-1-methyl-5-oxo-2-pyrrolidinyl)- isoxazole (22f): 1 HNMR (CDCI3) δ 6.00 (s, 1H, ArH), 4.62 (dddd, J = 45.0 Hz, J = 9.0 Hz, J = 9.0 Hz, J = 3.6 Hz, 2H, CH2F), 4.68-4.74 (m, 1 H, ArCHN), 2.65-3.00 (m, 1 H, COCH), 2.84 (s, 3H, NCH3), 2.28-2.40 (m, 2H), 2.30 (s, 3H, ArCH3). 3-Methyl-5-(tøns-4-fluoromethyl-1-methyl-5- oxo-2-pyrrolidinyl)-isoxazole (22g): 1 HNMR (CDCl3) δ 6.08 (s, 1 H, ArH), 4.85 (ddd, J = 45.0 Hz, J = 8.1 Hz, J = 4.2 Hz, 2H, CH2F), 4.68-4.74 (m, 1 H, ArCHN), 2.65-3.00 (m, 2H), 2.78 (s, 3H, NCH3), 2.30 (s, 3H, ArCH3), 2.12-2.25 (m, 1 H). h. 3-Methyl-5-(c/s- 4-fluoromethyl-1 -methyl-2-pyrrolidinvh-isoxazole and i. 3-Methyl-5-^raπs^4-fluoromethyl-1-methyl-2-pyrrolidinvh-isoxazole A borane-THF solution (3.0 mL, 1.0 M, 3.0 mmol) was slowly added, at room temperature, to the solution of 3-methyl-5-(4-fluoromethyl- 1-methyl-5-oxo-2-pyrrolidinyl)-isoxazole (22f and 22g, the entire crude product from the above reaction) in THF (8.0 mL). The resulting mixture was refluxed for two hours. The solvents were then evaporated in vacuo, then ethanol (12.0 mL) was added, followed by the addition of cesium fluoride (348.0 mg, 3.0 mmol). The mixture was then allowed to reflux overnight. Solvents were evaporated again in vacuo, and the residue was purified on silica gel eluting with CHCl3/MeOH (40:1 to 20:1) to give 34.0 mg (17% overall yield from the alcohol) of the trans isomer and 91.0 mg (46% overall yield from the alcohol) of the cis isomer of the title compounds. 3-Methyl-5-(c/s-4-fluoromethyl-1-methyl-2-pyrrolidiπyl)- isoxazole (22h): TLC Rf = 0.48 (CHCl3:MeOH =20:1). MS (DCI/NH3) m/e 199 (M+H)+. 1 HNMR (CDCI3) δ 6.02 (s, 1 H, ArH), 4.50 (ddd, J = 46.0 Hz, J = 5.4 Hz, J = 2.4 Hz, 2H, CH2F), 4.49-3.56 (m, 1 H, ArCHN), 3.26-3.34 (m, 1 H, NCHH), 2.65-2.85 (m, 1 H), 2.00-2.40 (m, 3H), 2.33 (s, 3H, NCH3), 2.28 (s, 3H, ArCH3). 3-Methyl-5-(fraπs-4-fIuoromethyl-1-methyl-2- pyrrolidinyl)-isoxazole (22i): TLC Rf = 0.50. MS (DCI/NH3) m/e 199 (M+H)+. 1 HNMR (CDCI3) δ 6.0 (s, 1 H, Ar-H), 4.30-4.60 (m, 2H, CH2F), 4.35-3.48 (m, 1 H, ArCHN), 3.05-3.18 (m, 1 H), 2.80-2.90 (m, 1 H), 2.25- 2.45 (m, 3H), 2.32 (s, 3H, NCH3), 2.31 (s, 3H, ArCH3). i. 3-Methyl-5-(c/s-4-fluoromethyl-2-pyrrolidinvπ-isoxazole hydrogen chloride salt A solution of hydrogen chloride in diethyl ether was added dropwise to a stirring solution of 3-methyl-5-(c/s-4-fluoromethyl-1-methyl- 2-pyrrolidinyl)-isoxazole (22h, 19.8 mg, 0.10 mmol) in diethyl ether until precipitate no longer formed. The diethyl ether was then decanted and the resulting precipitate was triturated several times with diethyl ether to give, after evaporation of the solvent in vacuo, 24.0 mg of the title compound (22). MS (DCI/NH3) m/e 199 (M+H)+, 216 (M+NH4)+. HNMR (D2O) δ 6.63 (s, 1H, ArH), 4.68-4.76 (m, 1 H, ArCHN), 4.61 (ddd, J = 46.0 Hz, J = 4.8 Hz, J = 2.0 Hz, 2H, CH2F), 3.88 (dd, J = 12.6 Hz, J = 8.7 Hz, 1 H, NCHH), 3.25 (dd, J = 12.6 Hz, J = 8.7 Hz, 1 H, NCHH), 2.85 (S, 3H, NCH3), 2.95-3.25 (m, 1H), 2.43-2.66 (m, 2H), 2.33 (s, 3H, CH3). Anal. calcd. for C10H16N2OFCI-O.3HCI-O.IH2O: C, 48.54; H, 6.72; N, 11.32. Found: C, 48.77; H, 6.52; N, 10.81. Example 23 3-Methvl-5-(c/s-1-methvl-5-(cvanomethvn- 2-pvrrolidinvh-isoxazole oxalate salt a. 3-Methyl-5- 1 -methyl-5-thioxo-2-pyrrolidinvπ-isoxa_.ole Lawesson's reagent (547.0 mg, 1.35 mmol) was added to a solution of 3-methyl-5-(1-methyl-5-oxo-2-pyrrolidinyl)-isoxazole (22c, 450.0 mg, 2.50 mmol ) in toluene (10.0 mL). The reaction mixture was allowed to reflux for 30 minutes before the solvent was evaporated in vacuo. The residue was purified on silica gel eluting with ethyl acetate/hexane (1 :5 and 1 :1) to give 431.0 mg (88% yield) of the title compound (23a). TLC Rf = 0.61 (CHCl3:MeOH =20:1). MS (DCI/NH3) m/e 197 (M+H)+. 1 HNMR (CDCI3) δ 6.04 (s, 1 H, ArH), 5.04 (dd, J = 9.0 Hz, J = 4.5 Hz, 1 H, ArCHN), 3.19 (S, 3H, NCH3), 3.05-3.28 (m, 2H, CSCH2), 2.45-2.58 (m, 1 H, CHM), 2.32 (s, 3H, ArCH3), 2.17-2.30 (m, 1 H, CHH). b. 3-Methyl-5-H -methyl-5-fcvanomethv0-2-pyrrolidinv0-isoxazole Bromoacetonitrile (56.8 mL, 0.60 mmol) is added to a solution of 3- methyl-5-(1 -methyl-5-thioxo-2-pyrrolidinyl)-isoxazole (23a, 98.0 mg, 0.50 mmol ) in acetonitrile (2.0 mL). The reaction mixture is then allowed to stir overnight at room temperature. Triphenylphosphine (196.7 mg, 1.21 mmol) is then added to the reaction mixture. After three minutes, triethylamine (208.7 mL, 1.50 mmol) is added, and the reaction mixture was stirred overnight. The solvent is evaporated in vacuo, and the residue is purified on silica gel to give the title compound (23). Example 24 3-Methvl-5-f c/s-1.4-dimethvl-2-pvrrolidinvn-isoxazole oxalate salt a. 3-Methvl-5-rc/s-1.4-dimethvl-5-oxo-2-Pvrrolidinvn-isoxazole LDA (0.367 mL, mono-THF in hexane, 1.5 M, 0.55 mmol) was added to a cooled (-78 °C) solution of 3-methyl-5-(1-methyl-5-oxo-2- pyrrolidinyl)-isoxazole (22c, 90.0 mg, 0.50 mmol) in THF (2.0 mL). After being warmed to -25 °C and stirred for 2 hours, the solution was cooled again to -78 °C. lodomethane (34.3 mL, 0.55 mmol) was then added dropwise to the solution. After being stirred at -78 °C for another hour, the solution was slowly warmed to room temperature overnight. After evaporation of the solvent, the resulting residue was directly chromatographed on silica gel eluting with CHCl3/MeOH (20:1) to give 69.0 mg (71% yield) of the title compound (24a) as an oil. TLC Rf = 0.49 (CHCl3:MeOH =20:1) MS (DCI/NH3) m/e 195 (M+H)+, 212 (M+NH4)+, 391 (2M+H)+. 1 HNMR (CDCI3) δ 5.94 (s, 1 H, ArH), 4.63 (dd, J = 8.7 Hz, J = 3.9 Hz, 1 H, ArCHN), 2.84 (s, 3H, NCH3) 2.63-2.74 (m, 1 H, COCH), 2.46 (ddd, J = 12.9 Hz, J = 8.7 Hz, J = 3.9 Hz, 1H, CHH), 2.29 (s, 3H, ArCH3), 2.04 (ddd, J = 12.9Hz, J = 10.2 Hz, J = 8.7 Hz, 1 H, CJHH), 1.23 (d, J = 8.4 Hz, CH3). b. 3-Methyl-5-f c/s-1 ^-dimethyl^-pyrrolidinvh-isoxazole A room temperature borane-THF solution (1.08 mL, 1.0 M, 1.08 mmol) was slowly added to a solution of 3-methyl-5-(c/s-1 ,4-dimethyl-5- oxo-2-pyrrolidinyl)-isoxazole (24a, 65.0 mg, 0.36 mmol ) in THF (3.0 mL). The resulting mixture was then refluxed for two hours. The solvents were evaporated in vacuo, and ethanol (4.0 mL) was added, followed by the addition of cesium fluoride (125 mg, 1.08 mmol). After being refluxed overnight, solvents were evaporated in vacuo, and the residue was purified on silica gel eluting with CHCl3/MeOH (20:1 ) to give 35.6 mg (55% yield) of the title compound (24b) as an oil. TLC Rf = 0.49 (CHCl3:MeOH =20:1). MS (DCI/NH3) m/e 181 (M+H)+, 198 (M+NH4) + . 1 HNMR (CDCI3) δ 5.97 (s, 1 H, ArH), 3.50 (dd J = 8.4 Hz, J = 8.1 Hz, 1 H, ArCHN), 3.25 (dd, J = 8.1 Hz, J = 7.9 Hz, 1 H, NCHJd), 2.35-2.48 (m, 1 H, CHCH3), 2.33 (s, 3H, NCH3), 2.28 (s, 3H, ArCH3), 2.08-2.18 (m, 1 H, CHH), 1.99 (dd, J = 8.1 Hz, J = 8.1 Hz, 1 H, NCHH), 1.75-1.85 (m, 1 H, CHH), 1.04 (d, J = 4.5 Hz, CH3). c. 3-Methvl-5-(c/s-1.4-dimethvl-2-Pvrrolidinvh-isoxazole oxalate salt A solution of oxalic acid (17.6 mg, 0.196 mmol ) in diethyl ether was added dropwise to a stirring solution of 3-methyl-5-(1 ,4-dimethyl-2- pyrrolidinyl)-isoxazole (24b, 32.0 mg, 0.178 mmol) in diethyl ether. After 0.5 hours of stirring at ambient temperature, the diethyl ether was decanted off and the resulting precipitate was triturated with diethyl ether three times to give, after evaporation of the solvents in vacuo, 31.0 mg of the title compound (24). MS (DCI/NH3) m/e 181 (M+H)+, 198 (M+NH4)+. 1 HNMR (D2O) δ 6.02 (s, 1 H, Ar-H), 3.48-3.60 (m, 1 H, ArCHN), 3.25-3.32 (m, 1 H, NCHH), 2.40-2.50 (m, 1 H, CHH), 2.34 (s, 3H, NCH3), 2.28 (s, 3H, ArCH3), 2.12-2.22 (m, 1 H, CHCH3), 1.98-2.06 (m, 1 H, NCJdH), 1.78-1.86 (m, 1 H, CHH , 1.06 (d, J = 4.5 Hz, CH3). Anal, calcd. for C12H18N2O5-O.5C2H2O4-O.I H2O: C, 49.24, H; 6.10; N, 8.83. Found: C, 49.06; H, 5.91 ; N, 9.02. Example 25 3-Methyl-5-f fraπs-1.5-methyl-2-Pyrrolidinv0-isoxazole hvdrooen chloride salt a. 3-Methyl-5-( fraπs-1.5-methvl-2-Pvrrolidinvh-isoxazole Methyl lithium (1.57 mL, 1.40 M, 2.2 mmol) was added dropwise to a cooled (-78 °C) solution of 3-methyl-5-(1-methyl-5-oxo-2-pyrrolidinyl)- isoxazole (22c, 360.0 mg, 2.0 mmol) in diethyl ether (8.0 mL). The resulting mixture was slowly warmed to 0 °C, and stirred at the same temperature for twenty minutes. The solution was then warmed to room temperature and stirred for one and a half hours. A lithium aluminum hydride solution (2.20 mL, 1.0 M, 2.20 mmol) was added dropwise to the mixture and the mixture was stirred at room temperature for two hours. The mixture was then cooled to 0 °C, and methanol (2.0 mL) was added to decompose the aluminum salts. After evaporation of the solvents, the residue was purified twice on silica gel eluting with CHCl3/MeOH (40:1 and 20:1) to give 156.7 mg (44% yield) of the title compound (25a). TLC Rf = 0.46 (CHCl3:MeOH =20:1). MS (DCI/NH3) m/e 181 (M+H)+. 1 HNMR (CDCI3) δ 1.14 (d, J = 6.0 Hz, 3H, CH3), 1.54-1.65 (m, 1H), 1.86-1.97 (m, 1H), 2.24 (s, 3H, ArCH3), 2.29 (s, 3H, NCH3), 2.18-2.38 (m, 2H), 2.97- 3.06 (m, 1H, NCH), 4.25-4.32 (m, 1H, NCHAr), 5.94 (s, 1 H, ArH). b. 3-Methyl-5-( fraπs-1.5-methyl-2-pyrrolidinyl)-isoxazole oxalate salt A solution of oxalic acid (19.8 mg, 0.22 mmol) in diethyl ether was added dropwise to a stirring solution of 3-methyl-5-(fraπs-1 ,5-dimethyl-2- pyrrolidinyl)-isoxazole (25a, 36.0 mg, 0.20 mmol) in diethyl ether. After 30 minutes of stirring, the diethyl ether was decanted off and the resulting precipitate was triturated several times with diethyl ether to give, after evaporation of the solvent in vacuo, 56.2 mg of the title compound (25). Example 26 3-Methyl-5-fa/s-1-methyl-4-ethyl-2-Pyrrolidinvπ-isoxazole oxalate Following the procedure of Example 24, a sample of 3-methyl-5-(1 - methyl-5-oxo-2-pyrrolidinyl)-isoxazole from Example 22c, is reacted with ethyl iodide to afford the title compound. Exam le ?7 3-Methyl-5-^c/s-1-methyl-4-benzyl-2-Pyrrolidinvn-isoxazole oxalate Following the procedure of Example 24, a sample of 3-methyl-5-(1- methyl-5-oxo-2-pyrrolidinyl)-isoxazole from Example 22c, is reacted with benzyl chloride to afford the title compound. Example 28 3-Methyl-5-fc/s andfraπs-1-methyl-4-cvanomethyl-2-pyrrolidinvh- isoxazole oxalate The products of examples 22d and 22e are reacted with methanesulfonyl chloride, the resulting mesylates are reacted with sodium cyanide, and the resulting products are converted into oxalate salts to afford the title compounds. Example 29 3-Methvl-5-(fraπs-1-methvl-4-acetvloxv-2-Pvrrolidinvn-isoxazole oxalate The product of example 21 e is reacted with acetic anhydride in the presence of triethylamine to afford 3-methyl-5-(fraπs-1 -methyl-4- acetyloxy-2-pyrrolidinyl)-isoxazole. This free base is then converted into the title compound. Example 30 3-Methyl-5-( aπs-1-methyl-5-fluoromethyl-2-pyrrolidinvπ-isoxazole __x__i2l__ The product of example 23a is reacted under anhydrous-inert conditions with the ylide, methoxymethyltriphenylphosphonium bromide (Aldrich), to convert the compound into the 3-methyl-5-(1-methyl-5- hydroxymethylene-2-pyrrolidinyl)-isoxazole , which is hydrolyzed to the 3- methyl-5-(1-methyl-5-formyl-2-pyrrolidinyl)-isoxazole with mild acid. The aldehyde is then reduced to the 3-methyl-5-(1-methyl-5-hydroxymethyl-2- pyrrolidinyl)-isoxazole by treatment with sodium borohydride in ethanol. The 5'-hydroxymethylisoxazole is reacted with methansulfonyl chloride, the resulting mesylate compound is reacted with tetrabutylammonium fluoride, and the resulting product is converted to the oxalate salt to afford the title compound. Example 31 3-Methyl-5-f fraπs-1 -methyl-3-fluoromethyl-2-pyrrolidinvπ-isoxazole oxalate 3-Methyl-5-formyi-isoxazole (prepared following the procedure of Tetrahedron left., (32), 2961-4, 1979) is reacted with methylamine and succinic anhydride to provide 3-methyl-5-(1 -methyl-3-carboxy-5-oxo-2- pyrrolidinyl)-isoxazole. This acid is converted to the ester and then selectively reduced with sodium borohydride to give the coresponding alcohol, which is reacted with methanesulfonyl chloride. The resulting mesylate is converted to fluromethyl isoxazole by treatment with tetrabutylammonium fluoride. Following the procedure of Example 24b, the 3-methyl-5-(1-methyl-3-fluoromethyl-5-oxo-2-pyrrolidinyl)-isoxazole is reacted with diborane, and the resulting product is converted to the oxalate salt to afford the title compound. Example 32 3-Methyl-5-(fraπs-1.3-dimethyl-2-pyrrolidinvO-isoxazole oxalate A sample of 3-methyl-5-(1-methyl-3-hydroxymethyl-5-oxo-2- pyrrolidinyl)-isoxazole (obtained from Example 31) is reacted with chlorophenoxythiocarbonate, to convert the compound into 3-methyl-5- (1 -methyl-3-phenoxythiocarbonyloxymethyl-2-pyrrolidinyl)-isoxazole. This phenoxythiocarbonyloxymethyl isoxazole is reacted with tris(trimethylsilyl)silane in the presence of azobis(isobutytyronitrile) to provide 3-methyl-5-(1 ,3-dimethyl-5-oxo-2-pyrrolidinyl)-isoxazole. Following the procedure of Example 24b, the 3-methyl-5-(1 ,3-dimethyl-5- oxo-2-pyrrolidinyl)-isoxazole is reacted with diborane, and the resulting product is converted to the oxalate salt to afford the title compound. Example 33 3-Methyl-5-M .3.4-trimethyl-2-Pyrrolidinvπ-isoxazole oxalate The anion of 3-methyl-5-(1 ,3-dimethyl-5-oxo-2- pyrrolidnyl) isoxazole from Example 32 is generated with LDA and then reacted with methyl iodide to afford 3-methyl-5-(1 ,3,4-trimethyl-5-oxo-2-pyrrolidinyl)- isoxazole. Following the procedure fo Example 24b, the 3-methyl-5- (1 ,3,4-trimethyl-5-oxo-2-pyrrolidinyl)-isoxazole is reacted with diborane, and the resulting product is converted to the oxalate salt to afford the title compound. Example 34 3-Methyl-5-M .3.5-trimethyl-2-pyrrolidinvπ-isoxazole oxalate Following the procedure in Example 25a, 3-methyl-5-(1 ,3-dimethyl- 5-oxo-2-pyrrolidinyl)-isoxazole from Example 32 is reacted with methyllithium and the aminal is reduced with lithium aluminum hydride. 3- Methyl-5-(1 ,3,5-trimethyl-2-pyrrolidinyl)-isoxazole is converted to the oxalate salt to afford the title compound. Example 35 3-trifluoromethyl-5-π-methyl-2(Sϊ-pyrrolidinvfl-isoxazole. hvdrochloride a. 3-trifluoromethyl 5-(1 '-t-Butyloxycarbonyl-2VS)-pyrrolidinvπ- isoxazole. To a solution of the product of Example 1c (200 mg, 1.02 mmoL) in toluene (10 mL) was added solid K2CO3 (414 mg, 3.00 mmoL) followed by freshly prepared (trifluoroacetyl) hydroximoyl chloride [W.J. Middleton, J. Pro. Chem.. (1984), 49, 919-922] (295 mg, 2.00 mmoL), and the reaction mixture brought to reflux. After refluxing for -20 hours a second aliquot of K2CO3 (~450 mg) and ftrifluoroacetyl)hydroximoyl chloride (592 mg, 4.01 mmoL) was added and refluxing continued for an additional 7 hours. The reaction mixture was then diluted with Et2θ (50 mL) and washed with 20-mL portions of sat aq. NaHC03, 10% aq. citric acid and brine, dried (MgSθ4) and concentrated to afford the crude product as an oil. Chromatographic purification (silica, EtOAc/Hex 1 :6) to afford the pure isoxazole as a pale yellow oil (130 mg, 41% yield). 1 H-NMR (CDCI3) δ 6.35,6.29 (two br. s, 1 H); 5.11 , 4.99 (two br.s., 1 H); 3.66-3.37 (br. m., 2); 2.43-1.94 (br. m, 4H); 1.47, 1.34 (s, 9H). MS(CI) m/e 307 (M+H)+. 324 (M+ NH4) . Ϊ 3-trifluoromethvl- 5- -methvl-2 ( S ) - p vrroiidinvl.-isoxazola. hvdrochloride To a solution of 3-trifluoromethyl 5-(1 -t-butyloxycarbonyl-2- pyrrolidinyl)-isoxazole (37 mg, 0,121 mmoL) (Example 35a) in CH2CI2 (4 mL) was added trifluoracetic acid (2 mL). After stirring at room temperature for 45 minutes the solvents were evaporated in vacuo to afford the crude amine. To this material was added 37% aqueous formalin (2 mL) and formic acid (0.5 mL) and the mixture refluxed for 2 hours, then stirred at room temperature for 16 hours. The reaction mixture was then diluted with 10% aq. HCI (~6 mL), extracted with Et2θ (3x15 mL), then the aqueous layer basified with sat. aq. K2CO3 and extracted with CH2CI2 (3x15 mL). The combined CH2CI2 layers were dried (MgS04) and concentrated to afford the crude product as an oil. This material was dissolved in Et2θ (5 mL) and 1 M ethereal HCI (1 mL) was added to afford, after concentration, the product as a hydroscopic solid (23 mg, 73%yield). 1 H-NMR (D2O) δ 7.28 (s,1 H); 3.85 (br. s.,1 H); 3.47 (br.s., 1 H); 3.02 (br.s,4 H); 2.74 (m, 1 H); 2.60-2.46 (m, 1 H); 2.43-2.28 (m, 2H). MS(CI) m/e 221 (M+H)+. 238 (M+ NH4) . Example 36 3.4-Dimethyl-5-π -methyl- 2-pyrrolidinv -isoxazole oxalate a. O-t-butyldimethylacetoxime To the solution of acetone oxime (3.65 g, 50.0 mmol) in THF (30 mL) was added sodium hydride (1.80 g, 80% dispersion in mineral oil) carefully, and the resulting mixture was refluxed for five minutes. After the mixture was cooled down to room temperature, f-butyldimethylsilyl chloride (9.34 g, 97%) was introduced carefully. The resulting mixture was brought to reflux for two hours and then cooled down to room temperature overnight. The precipitate was filtered off and washed with THF (3 X 5 mL). The filtrate was concentrated and distilled to give 7.80 g (83% yield) of the title product (36a): b.p. 160-163 °C/760 mmHg; Rf = 0.42 (5:1 hexane/EtOAc). 1 HNMR (CDCI3) δ 1.88 (s, 3H, N=CCH3), 1.87 (s, 3H, N=CCH3), 0.93 (s, 9H, 3 SiCCH3), 0.16 (s, 3H, SiCH3). b. 3.4-Dimethyl-5-f 1 -methyl-2-pyrrolidinvπ-isoxazole oxalate Following the procedure of Example 1 , a sample of benzyloxycarbonyl (S)-proline is reacted with borane and then oxidized with sulfur trioxide pyridine complex to give benzyloxycarbonyl (S)-prolinal . This aldehyde is reacted under anhydrous- inert conditions with anion derived from the product of Example 36a to convert the compound into the corresponding b-hydroxy O-silyloxime, which is then oxidized to the b- ketone O-silyloxime with PDC in the presence of molecular sieves. The diketone is then methylated by treatment with lithium diisopropylamide and methyl iodide. Following the procedure of Example 22c, the a-methyl- b-keto oxime is reacted aqueous sulfuric acid solution in THF to afford the isoxazole. This isoxazole is then treated with hydrogen and 10% palladium on charcoal to give the corresponding amine. Following the procedure of Example 2a, the amine is treated with formaldehyde and formic acid, and the resulting product is converted to the oxalate salt to afford the title compound. Example 37 5-f2-Pyrrolidinvπ-isoxazole oxalate N-Carbobenzyloxyproline methyl ester is reacted under anhydrous- inert conditions with the dilithium anion of aldoxime in a manner similar to that described in Example 23c. The b-keto oxime is treated with methanesulfonyl chloride in the presence of triethylamine to produce the amino protected isoxazole. Hydrogenation in the presence of palladium on carbon catalyst and conversion to the oxalate salt affords the title compound. Example 38 5-C1 -methyl-2-Pyrrolidinvh-isoxazole oxalate N-methylproline methyl ester is reacted under anhydrous-inert conditions with the dilithium anion of aldoxime in a manner similar to that described, in Example 23c. The b-keto oxime is treated with methanesulfonyl chloride in the presence of triethylamine to produce the isoxazole. Conversion to the oxalate salt affords the title compound. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims: What is claimed is: 1. A compound of the formula: wherein A is O or S; R 1 is located at either position 3 or position 4, or at both positions 3 and 4 and is selected from the group consisting of: (i) hydrogen; (ii) d-Ce-alkyl; (iii) -(CH 2 ) a R 3 ; wherein a is 1 , 2, 3 or 4, and R 3 is C3-C7-cycloalkyl or phenyl; (iv) -(CH 2 ) a OR 4 ,wherein a is defined as above, and R 4 is C3-C7-cycloalkyl, phenyl or Ci-Cβ-alkyl; (v) -(CH 2 ) b NR 4 , wherein b is 0, 1 , 2, 3 or 4 and R 4 is defined as above; and (vi) CF 3 ; and R 2 is selected from the group consisting of: wherein R 5 is H or Cι-C4-alkyl, and R6 is H, F, CH 2 F, CN, NH 2 , NHCO(C C 6 alkyl), Cι-C 4 -alkyl, -CH 2 CH=CH 2 or CH 2 OR9. wherein R 9 is H, Cι-C3-alkyl or -CH 2 CH=CH 2 ; wherein 10 R 5 is defined as above, and R7is H, (CH 2 )halogen, 0(C C 6 -alkyl), O(phenyl), (CH 2 )phenyl, (CH 2 )CN, CN, (CH 2 )SCN, (CH 2 )SH, (CH 2 )SCrC 6 -alkyl, OH, (CH 2 )0, Cι-C 6 -alkyl or OCO(CrC 6 -afkyl); 15 wherein R 5 is defined as above and 20 R 8 is H, Cι-C 4 -alkyl, phenyl, CH 2 F or CH 2 CN; wherein R 5 , R 7 and R 8 are defined as above; wherein R 5 - R 6 and R 8 are defined as above; 10 and 15 wherein R 5 , R 6 and R 7 are defined as above; or a pharmaceutically-acceptable salt thereof. 20 2. Acompound according to Claim 1 , wherein R 1 is at position 3 and is H, Ci-Cβ-alkyl or-(CH 2 )OCH 3 , and R 2 is selected from afternate definition (ii), wherein R 7 is H or CrCβ-alkyl. 3. Acompound according to claim 2, wherein R is Ci-Cβ-alkyl, R 5 is H or methyl, and R 7 is H. 4. A compound according to claim 1 which is selected from: 3-Methyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; 5-(1 -Methyl-2(S)-pyrτolidinyl)-3-propyl-isoxazole; 3-MethyI-5-(2(R)-pyrrolidinyl)-isoxazole; 3-Methyl-5-(2(S)-pyrrolidinyl)-isoxazole; 3-Ethyl-5-(1-methyl-2(S)-pyrrolidinyl)-isoxazole; or a pharmaceutically-acceptable salt thereof. 5. A pharmaceutical composition for treating a CNS disorder characterized by decreased neuronal cholinergic function comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a compound of Claim 1. 6. A pharmaceutical composition for treating anxiety comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a compound of Claim 1. 7. A method for treating dementia, hyperkinesia, mania or acute confusion disorders comprising administering to a host in need of such treatment a therapeutically-effective amount of a compound of Claim 1. 8. A method for treating dementia, hyperkinesia, mania or acute confusion disorders comprising administering to a host in need of such treatment a therapeutically-effective amount of a compound of Claim 1 in combination with a therapeutically-effective amount of a peripheral cholinergic antagonist. 9. A method for treating Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically- effective amount of a compound of Claim 1. 10. A method for treating or preventing the withdrawal response or ameliorating the symptoms of anxiety produced by withdrawal from chronic or long term use of tobacco products, such as cigarettes, chewing tobacco and the like, comprising administering to a host in need of such treatment a therapeutically-effective amount of a compound of Claim 1.

Inventors: ARNERIC STEPHEN P, CARRERA GEORGE M JR, GARVEY DAVID S, HE YUN, LIN NAN-HORNG, SHUE YOUE-KONG, ARNERIC, STEPHEN, P., CARRERA, GEORGE, M., JR., GARVEY, DAVID, S., HE, YUN, LIN, NAN-HORNG, SHUE, YOUE-KONG
Applicants: ABBOTT LAB, ABBOTT LABORATORIES
Application year: 1992
Main classification: C07D261
IPC codes: A61K31, A61P25, C07D413, C07D417