MXPA99007626A - 7a-HETEROCYCLE-SUBSTITUTED HEXAHYDRO-1H-PYRROLIZINE COMPOUNDS USEFUL IN CONTROLLING CHEMICAL SYNAPTIC TRANSMISSION - Google Patents

Abstract

7a-Substituted hexahydro-1H-pyrrolizine compounds having formula (I), wherein A is a defined heterocycle moiety, pharmaceutical compositions of these compounds, and use of said compositions to selectively control synaptic transmission in mammals.

Description

Hexahydro-1 H-pyrrolizine 7a-heterocycle-substituted compounds useful for controlling chemical synaptic transmission TECHNICAL FIELD This invention relates to exahydro-1 H-pyrrolizine 7a-heterocycle-substituted compounds, which control chemical synaptic transmission; to therapeutically effective pharmaceutical compositions of these compounds; and to the use of said compositions to control synaptic transmission in mammals.

BACKGROUND OF THE INVENTION Compounds that selectively control chemical synaptic transmission offer therapeutic utility for treating disorders that are associated with dysfunctions in synaptic transmission. This utility may arise from controlling either pre-synaptic or post-synaptic chemical transmission. The control of the synaptic chemical transmission is, in turn, a direct result of a modulation of the excitability of the synaptic membrane. The presynaptic control of membrane excitability results from the direct effect that an active compound has on the organelles and enzymes present in the nerve terminal to synthesize, store and release the neurotransmitter, as well as the process for re-uptake. The post-synaptic control of membrane excitability results from the influence that an active compound has on the cytoplasmic organelles that respond to the neurotransmitter action.

An explanation of the processes involved in chemical synaptic transmission will help to illustrate more fully the potential applications of the invention. (For a more complete explanation of the chemical synaptic transmission refer to Hoffman et al., "Neurotransmission: The autonomic and somatic motor nervous systems" (Neurotransmission: autonomic and somatic motor nervous systems) In: Goodman and Gilman's, The Pharmacoloqical Basis of Therapeutics, 9th ed., JG Hardman, LE Limbird, PB Molinoff, RW Ruddon, and A. Goodman Gilman, eds., Pergamon Press, New York, 1996, pp. 1 05-139). Normally, chemical synaptic transmission begins with a stimulus that depolarizes the transmembrane potential of the synaptic junction above the threshold that produces an all-or-nothing action potential in a nerve axon. The action potential propagates to the terminal nerve, where the ion fluxes activate a mobilization process that leads to the secretion of neurotransmitters and the "transmission" to the post-synaptic cell. Those cells, which receive communication from the central and peripheral nervous systems in the form of neurotransmitters, are referred to as "excitable cells". Excitable cells are cells such as nerves, soft muscle cells, cardiac cells and glands. The effect of a neurotransmitter on an excitable cell may be to cause either an excitatory or inhibitory post-synaptic potential (EPSP or I PSP, respectively) depending on the nature of the post-synaptic receptor for the particular neurotransmitter and the degree to which, other neurotransmitters are present. Whether a particular neurotransmitter causes excitation or inhibition depends mainly on the ion channels that open up in the post-synaptic membrane (ie, in the excitable cell). EPSPs usually result from a local depolarization of the membrane due to the increased permeability generalized to cations (notably Na + and K +), while I PSPs are the result of stabilization or hyperpolarization of membrane excitability due to an increase in permeability for mostly smaller ions (including K + and CI ") For example, acetylcholine neurotransmitter excites skeletal muscle joints by opening permeability channels for Na + and K + At other synapses, such as cardiac cells, acetylcholine can be inhibitory , resulting mainly from an increase in K + conductance.The biological effects of the compounds of the present invention result from the modulation of a particular subtype of acetylcholine receptor., it is important to understand the differences between two receptor subtypes. The two distinct subfamilies of acetylcholine receptors are defined as nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. (See Goodman and Gilman's, The Pharmacological Basis of Therapeutics, op. Cit.). The responses of these receptor subtypes are mediated by two completely different classes of second messenger systems. When the nicotinic aceticoline receptor is activated, the response is an increased flow of specific extracellular ions (eg, Na +, K + and Ca "" ") through the neuronal membrane.In contrast, muscarinic acetylcholine receptor activation leads In this way, the biological consequences of nicotinic acetylcholine receptor activation are different from those of the muscarinic receptor activation, in an analogous manner to intracellular systems, which contain complex molecules, such as G proteins and inositol phosphates. , the inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are different and different from those that arise from inhibition of muscarinic receptor.As indicated above, the two main sites to which the drug compounds that affect the chemical synaptic transmission can be directed, they are the nerve terminal pre-sin optics and the postsynaptic membrane. The actions of drugs directed to the pre-synaptic site can be mediated through presynaptic receptors that respond to the neurotransmitter, which has released the same secretory structure (that is, through a self-receptor), or through a pre-receptor. synaptic that responds to another neurotransmitter (that is, through a hetero-receptor). The actions of drugs directed to the post-synaptic membrane imitate the action of the endogenous neurotransmitter or inhibit the interaction of the endogenous neurotransmitter with a post-synaptic receptor. Classical examples of drugs that modulate post-synaptic membrane excitability are neuromuscular blocking agents, which interact with nicotinic acetylcholine gate channel receptors in skeletal muscle, for example, competitive agents (stabilizers), such as, curare, or depolarizing agents, such as, succinylcholine.

In the central nervous system, post-synaptic cells may have many neurotransmitters that make an effect on them. This makes it difficult to know the precise net balance of the chemical synaptic transmission required to control a given cell. However, when designing compounds that selectively affect only one pre- or post-synaptic receiver, it is possible to modulate the net balance of all other inputs. Obviously, the more one understands about chemical synaptic transmission in CNS disorders, the easier it will be to design drugs to treat such disorders. Knowing how specific neurotransmitters act in the CNS allows one to speculate on disorders that may be treatable with certain CNS-active drugs. For example, dopamine is widely recognized as an important neurotransmitter in the central nervous system in humans and animals. Many aspects of the pharmacology of dopamine have been reviewed by Roth and Elsworth, "Biochemical Pharmacology of Midbrain Dopamine Neurons" (Biochemical Pharmacology of Neurons of the Brain Center of Dopamine), In: Psvchopharmacology: The Fourth Generation of Proqress, FE Bloom and DJ Kupfer, Eds, Raven Press, NY, 1995, pp 227-243). Patients with Parkinson's disease have a primary loss of neurons containing dopamine from the nigrostriatal route, which results in profound loss of motor control. It has been found that therapeutic strategies to replace dopamine deficiency with dopamine mimics, as well as administering pharmacological agents that modify the release of dopamine and other neurotransmitters have a therapeutic benefit ("Parkinson's Disease", in: Psychopharmacoloav: The Fourth Generation of Progress, op. cit. , pp 1479-1484). Other studies have shown that certain compounds, which potently affect neurotransmission in nicotinic acetylcholine receptors, are effective for pain relief (Badio et al., Drug Devel. Res., 1995, 36: 46-59). Neuroprotective actions have also been found for several nicotinic acetylcholine receptor ligands, as reviewed in Brioni et al. , Med. Chem. Res., 1 996, 487-51 0. Still selective and new neurotransmitter controlling agents are being seen, in the hope that one or more will be useful in important but still poorly controlled disease states or models of behavior. For example, dementia, as seen with Alzheimer's or Parkinson's disease, remains highly untreatable. The symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does Attention Deficit Disorder (ADD) behavior disorder. Specific agents for treatment of these and related disorders are few or nonexistent. A more complete discussion of the possible utility as agents CNS-active compounds with activity as selective cholinergic ligands for neuronal nicotinic receptors, (i.e., to control chemical synaptic transmission) can be found in U.S. Patent 5,472,958 to Gunn et al. , issued December 5, 1995, which is incorporated herein by reference. Existing acetylcholine agonists are therapeutically sub-optimal to treat the conditions discussed above. For example, such compounds have unfavorable pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability (e.g., nicotine) . In addition, other agents have many undesired central agonist actions, including hypothermia, hipolocomodation and tremor, and peripheral side effects, including miosis, lacrimation, defecation, and tachycardia (Benowitz et al., In: Nicotine Psychopharmacology, S. Wonnacott, MAH Russell, & I. P. Stolerman, eds. , Oxford University Press, Oxford, 1990, p. 12-157; and M. Davidson, et al. , in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336). Orlek et al (PCT application WO 91/1 3885, published September 19, 1991) describe bridged azabicyclic compounds that support triazine substituents having utility for enhancing acetylcholine function via action on muscarinic receptors in the central nervous system . Hedley et al (European Patent Application 287,356, published October 19, 1988) describe bridged azabicyclic compounds that support 5-membered heteroaromatic ring substituents, having utility for enhancing acetylcholine function via the action on muscarinic receptors in the nervous system central.

Baker et al. (European patent application 412,798, published February 1, 1 991) disclose pyrazine, pyridazine and pyrimidine compounds substituted with various azabicyclic ring portions having utility for stimulating the central muscarinic acetylcholine receptors. Carmosin et al. (U.S. Patent 4,800,207, issued January 24, 1989) disclose hexahydropyrrolizines substituted with various hetero ring containing portions having utility in pharmaceutical compositions for treating pain. Carmosin et al. (U.S. Patent 4,582,836, issued April 5, 1986) describe octahydroindolizidines substituted with various hetero ring containing portions, which have utility in pharmaceutical compositions for treating pain. Miyana et al. (European patent application 39, 903, published November 1, 1981) describe pyrrolizidines substituted in position 8 with acyclic substituents having spasmolytic activity in the soft muscle of guinea pig ileum.

BRIEF DESCRIPTION OF THE INVENTION It has been found, in accordance with the present invention, that certain hexahydro-1H-pyrrolizine 7a-heterocycle-substituted compounds are selective and potent cholinergic compounds useful for selectively controlling synaptic transmission. In its main aspect, the present invention provides a compound of formula (I) below, or a pharmaceutically acceptable salt thereof, wherein a 7a-hexahydro-1 H-pyrrolizine is directly linked to a 5-isoxazole group, -pyrazol, 3-pyridine, 5-pyrimidine, 2-pyrazine, 3-pyridazine, or substituted 3-quinoline. Another aspect of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), in combination with a pharmaceutically acceptable carrier or diluent. In still another aspect, the present invention provides a method for selectively controlling synaptic transmission in a mammal. A further aspect of the invention is a process for preparing compounds of formula (I). The novel compounds of the present invention are represented by the formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein the group designated A is selected from the group consisting of: wherein R1 is C ^ Cs-alkyl, as defined below, -CH2-aryl, -CH2-substituted aryl, or -CH2-CH2-substituted aryl, wherein aryl and substituted-aryl are as defined below; wherein R.1 is as defined above, and R2 is H or d -Cs-alkyl; wherein R3 is substituted at the 2, 4 or 6 position and is selected from the group consisting of H, C? -C3-alkyl, Br, Cl or F; and R 4 is substituted in one of the remaining positions not occupied by R 3 and is independently selected from the group consisting of H, dCa-alkyl, Br, Cl, F or dCs-alkyl-O-; or when substituted at position 5, R4 may be further selected from the group consisting of (1) O-R6, wherein R6 is selected from the group consisting of; (a) hydrogen, (b) alkyl of one to six carbon atoms, (c) alkenium of one to six carbon atoms, (d) alkynyl of one to six carbon atoms, (e) haloalkyl of one to six atoms carbon, (f) hydroxyalkyl of two to six carbon atoms, (h) amino, (i) alkylamino of one to six carbon atoms, (j) dialkylamino, in which the two alkyl groups are independently from one to six carbon atoms, (k) phenyl, (I) naphthyl, (m) biphenyl, (n) furyl, (o) thienyl, (p) pyridinyl, (q) pyrazinyl, (r) pyridazinyl, (s) pyrimidinyl, t) pyrrolyl, (u) pyrazolyl, (v) imidazolyl, (w) indolyl, (x) thiazolyl, (and) oxazolyl, (z) isozasolyl, (aa) thiadiazolyl, (bb) oxadiazolyl, (ce) quinolinyl, ( dd) isoquinolinyl, (ee) aryl-C? -C6-alkyl, (ff) heteroaryl-C? -C6-alkyl t (gg) any of groups (i) to (ff) of R6 above substituted in the aromatic ring with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl, in which the alkoxy and alkyl portions are independently from one to six carbon atoms, alkoxyalkoxy, in which the alkoxy portions are independently of one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl and alkoxycarbonyl of two to six carbon atoms; (2) -S-R6, wherein R6 is as defined above; (3) -N (R6) (R7), wherein R6 is as defined above and R7 is selected from H or alkyl of 1 to 6 carbon atoms; (4) LR8, wherein L is absent or selected from the group consisting of (a) - (CH2) P-, where p is 1 to 6; (b) - (CH = CH) q-, where q is one or two; (c) -C (O) -; (d) -OC (O) -; (e) -N (R7) -C (O) -, wherein R7 is as defined above; (f) -CH2-CH2-C (O) -; (g) -CH2-O-C (O) -; -CH2-N H-C (O) -; or (h) -C = C-; and wherein -R8 is selected from the group consisting of: (a) hydrogen; (b) alkyl of one to six carbon atoms, (c) alkenyl of one to six carbon atoms, (d) alkynyl of one to six carbon atoms, (e) haloalkyl of one to six carbon atoms, (f) ) hydroxyalkyl of two to six carbon atoms, (g) alkoxy of one to six carbon atoms (h) amino, (i) alkylamino of one to six carbon atoms, (j) dialkylamino, in which the two alkyl groups are independently from one to six carbon atoms, (k) phenyl, (I) naphthyl, (m) biphenyl, (n) furyl, (o) thienyl, (p) pyridinyl, (q) pyrazinyl, (r) pyridazinyl, (s) pyrimidinyl, (t) pyrrolyl, (u) pyrazolyl, (v) imidazolyl, (w) indolyl, (x) thiazolyl, (y) oxazolyl, (z) isozasolyl, (aa) thiadiazolyl, (bb) oxadiazolyl, (ce) quinolinyl, (dd) isoquinolinyl, and (ee) any of the groups (i) to (dd) of R 6 above substituted with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbons, alkoxy from one to six carbon atoms, alkoxyalkyl, in which the alkoxy and alkyl portions are independently from one to six carbon atoms, alkoxyalkoxy, in which the alkoxy portions are independently from one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms; with the requirement that in groups of the type -O-R6, -S-R6, -N (R6) (R7) and L-R8, none of R6, -N (R6) (R7) or L-R8 can contain a nitrogen atom, which is conjugated with a double or triple ligature; (d) where R3 is as defined above; (e), where R3 is as defined above; (f) where R3 is as defined above; and (g) wherein R5 is H, d-Cs-alkyl, Cl or F.

DETAILED DESCRIPTION OF THE INVENTION Certain compounds of this invention may possess one or more asymmetric centers and may exist in optically active forms. Additional asymmetric centers may be present in a substituent group, such as an alkyl group. The 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 should be understood that the present invention anticipates and includes within its scope all those isomers and mixtures thereof. The terms "R" and "S" used herein are configurations as defined in 1 UPAC 1 974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem., 1976, 45: 13-30. In particular, the stereochemistry at position 7a and the point of attachment of A, as shown in Formula (I), can be independently either (R) or (S), unless specifically noted otherwise. The chiral forms of certain compounds of this invention are contemplated and are specifically included within the scope of this invention.

"Alkoxy" refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.

Examples of alkoxy of one to six carbon atoms include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, tert-butoxy, neo-pentoxy and n-hexoxy. The term "alkoxyalkoxy" refers to an alkoxy group, as defined above, substituted by the replacement of a hydrogen atom of the alkyl portion thereof with an alkoxy group. Examples of alkoxyalkoxy include, but are not limited to methoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, and the like. The term "alkoxyalkyl" refers to an alkyl group, as defined above, substituted with one or more alkoxy groups. Examples of alkoxyalkyl include methoxymethyl, methoxyethyl, hydroxypropyl, methoxypropyl and the like. The term "alkoxycarbonyl" refers to an alkoxy group, as defined above, connected to the parent molecular moiety through a carbonyl linking group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, and similar. "Alkyl" refers to a univalent alkyl radical derived from the removal of a simple hydrogen atom from a straight or branched chain saturated hydrocarbon, and specifically "CT-Ca-alkyl" refers to an alkyl group comprising one to three carbon atoms, including, methyl, ethyl, n-propyl and isopropyl, "Ci-Ce-alkyl" or "alkyl of one to six carbon atoms" refers to an alkyl group comprising one to six carbon atoms. "C ^ Cs-alkyl" includes methyl, ethyl, n-propyl and isopropyl; "d-Cβ-alkyl" or "alkyl of one to six carbon atoms" includes all the previous examples, as well as butyl, butyl, t-butyl, pentyl, neopentyl, hexyl and the like. "Alkenyl" refers to a univalent alkyl radical derived from the removal of a single hydrogen atom from a straight or branched chain hydrocarbon containing one or more double bonds. Examples of alkenyl groups include ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, hexadienyl and the like. "Alkylamino" refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an NH-linking group. Examples of Ci-Cs-alkylamino comprising an alkyl of one to three carbon atoms attached to the NH group, include methylamino, ethylamino, n-propylamino and isopropylamino. "Alkynyl" refers to a univalent alkyl radical derived from the removal of a simple hydrogen atom from a straight or branched chain hydrocarbon containing one or more triple bonds. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and the like. The term "aryl", as used herein, refers to unsubstituted carbocyclic aromatic groups including, but not limited to, phenyl, 1- or 2-naphthyl, biphenyl, and the like. The term "aryl-Ci-Cβ-alkyl" refers to a d-Ces-alkyl group as defined above, substituted by replacing one of the hydrogen atoms in the alkyl group with an aryl group, as defined herein .

Dialkylamino refers to two alkyl groups, as previously defined, attached to the parent molecular moiety through an N-atom linking group. Examples of dialkylamino groups of one to three carbon atoms include dimethylamino, diethylamino, di-n -propylamino, and di-isopropylamino. "Haloalkyl" refers to an alkyl group, as defined above, of one to six carbon atoms substituted by one or more halogen atoms and includes, for example, trifluoromethyl, chloroethyl, bromobutyl, and the like. The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which, a ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, including, but not limited to, furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, and the like. The term "heteroaryl-Ci-Ce-alkyl" refers to a d-Cß-alkyl group as defined above, substituted by replacing one of the hydrogen atoms in the alkyl group with a heteroaryl group, as defined above. The term "hydroxyalkyl" refers to an alkyl group, as defined above, substituted with one or more hydroxy groups. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypentyl and the like. "Substituted alkenyl" refers to an alkenyl group, as defined above, substituted with one or more groups selected from halogen, hydroxy, alkoxy, amino, alkylamino or dialkylamine, CN and the like. Examples of substituted alkenyl groups include methoxyethenyl, chloropropenyl, dimethylaminobutenyl and the like. "Alkenyl substituted" refers to an alkynyl group, as defined above, substituted with one or more groups selected from halogen, hydroxy, alkoxy, amino, alkylamino, or dialkylamino, CN and the like.

Examples of substituted alkynyl groups include methoxyetinyl, chloropropinyl, dimethylaminobutinyl and the like. The term "substituted aryl", as used herein, refers to an aryl group as defined above, substituted with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl, in which, the alkoxy and alkyl portions are independently from one to six carbon atoms, alkoxyalkoxy, in which the alkoxy portions are independently one to six carbon atoms, halogen, cinna, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms. A preferred substitution is by replacement of 1 to 2 hydrogen atoms with F, Cl, Br, d-Cs-alkyl, as defined above, or C ^ Cs-alkoxy. Examples of substituted aryl radicals include, but are not limited to, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-bromophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-methyl-1-naphthyl and 8-chloro -2-naphthyl. The term "substituted heteroaryl" as used herein, refers to a heteroaryl group as defined above, substituted with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl, in which the alkoxy and alkyl portions are independently from one to six carbon atoms, alkoxyalkoxy in which the alkoxy portions are independently from one to six atoms carbon, halogen, cinna, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms. There may be one or more asymmetric centers in the compounds of the present invention. Unless otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of current medical judgment, suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J \ Pharmaceutical Sciences, 66: 1-9 (1977), incorporated herein by reference. The salts can be prepared in situ during the isolation and final purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art, such as, ion exchange. Other pharmaceutically acceptable salts include salts of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate , heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and aryl sulfonate. The term "promedication" refers to compounds that rapidly transform in vivo to produce the parent compounds of Formula (I), as for example, by hydrolysis in the blood. T. Higuchi and V. Stella provide an extensive discussion of the concept of promediation in Prodrugs as Novel Delivery Systems, (Promedications as novel delivery systems) Vol. 14 of A. C.S. Symposium Series, American Chemical Society (1 975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, (Bio-reversible carriers in drug design: theory and application), edited by EB Roche, Pergamon Press (1 987). The term "prodrug ester group" refers to any of the various ester-forming groups that are hydrolyzed under physiological conditions. Examples of ester groups of averaly include pyroloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. As used herein, the term "pharmaceutically acceptable ester" refers to esters, which are hydrolyzed in vivo and include those that are easily broken in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl portion suitably has no more than 6 carbon atoms. Examples of particular esters include formats, acetates, propionates, butyrates, acrylates and ethylsuccinates. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means an encapsulating material, diluent, liquid or semi-solid filler, inert solid, non-toxic or formulation aid of any kind. Some examples of materials, which can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose.; starches, such as, corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients, such as cocoa butter and suppository waxes; oils, such as, peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols, such as a propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar, buffering agents, such as, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol, and phosphate buffers, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents; sweetening, flavoring and flavoring agents, preservatives and antioxidants, according to the formulator's judgment. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemutions, 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, for example, water or other solvents, solubilizing agents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include auxiliaries, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents. Injectable, sterile, injectable preparations, for example aqueous or oily suspensions, can be formulated according to the known art using suitable wetting or dispersing agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to enhance the effect of a medicament, it is often desirable to decrease the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its rate of dissolution which, in turn, may depend on the crystal size and the crystalline form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the medicament in an oily vehicle. Injectable depot forms are made by forming microencapsulated matrices of the medically biodegradable polymers, such as, polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the medically in liposomes or microemulsions, which are compatible with body tissues. Compositions for rectal or vaginal administration 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 to room temperature but liquid at body temperature, and therefore, they melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable excipient or carrier, inert, such as sodium citrate or dicalcium phosphate and / or to) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic, c) humectants, such as, glycerol, d) disintegrating agents, such as, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as bentonite clay and kaolin, and i) lubricants, such as, talc, calcium stearate, mag stearate solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be employed as fillings in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, "dragees", capsules, pills and granules can be prepared with coatings and shells, such as, enteric coatings and other coatings well known in the art of pharmaceutical formulations. Optionally, they may contain opacifying agents and may also be of a composition that they may release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embossed compositions, which may be used, include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers, in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings., release control coatings and other coatings well known in the art of pharmaceutical formulations. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient (s) alone, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embossed compositions, which may be used, include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as may be required. Ophthalmic formulation, eardrops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as vegetable and animal fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid. , talc and zinc oxide, or mixtures thereof. The powders and sprays may contain, in addition to the compounds of this invention, excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The atomizers may additionally contain customary propellants, such as chlorofluorohydrocarbons. Transdermal patches have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in an appropriate medium. Absorption intensifiers can also be used to increase the flow of compound through the skin. The speed can be controlled either by providing a speed controlling membrane or by dispersing the compound in a gel or polymer matrix. According to the methods of treatment of the present invention, disorders in synaptic transmission are treated or prevented in a patient, such as a human or minor mammal, by administering to the patient a therapeutically effective amount of a compound of the invention, in such quantities and for such a time as necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat disorders in synaptic transmission, at a reasonable risk / benefit ratio applicable to any medical treatment. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the current medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the administration time, route of administration and rate of excretion of the specific compound employed; the duration of the treatment; medications used in combination or coincident with the specific compound used; and similar factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other mammal in single or divided doses may be in amounts, for example, from 0.001 to 50 mg / kg of body weight or more usually, from 0.01 to 25 mg. / kg of body weight. The single dose compositions may contain such amounts or submultiples thereof to make the daily dose. In general, treatment regimens according to the present invention comprise administering to a patient in need of such treatment from about 1 mg to about 1000 mg of the compound or compounds of this invention per day in single or multiple doses. In a preferred embodiment of the present invention, there are provided compounds of Formula (I) above, wherein A is selected from options (a) and (c). In a more preferred embodiment of the present invention, there are provided compounds of Formula (I) above, wherein A is selected from option (c). Representative of the compounds of the invention are: 7a- (3-methyl-5-isoxazolyl) -hexahydro-1 H-pyrrolizine; 7a- (1 H-3-methyl-5-pyrazo I il) -hexahydro-1 H-pyrrolizine; 7a- (3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (3-quinolinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-chloro-3-pyridinyl) -hexah id ro-1 H-pyrrolizine; 7a- (2-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (2-chloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5,6-dichloro-3-pyridinyl) -hexah id ro-1 H-pyrrolizine; 7a- (5-pyrimidinyl) -hexahydro-1 H -pyrrolizine; 7a- (2,6-difluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine; 7a- (2,6-dichloro-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-f luoro-3-pyridinyl) -hexah id ro-1 H-pyrrolizine; 7a- (3-eti l-5-isoxazo I i l) -hexah id ro-1 H-pyrrolizine; 7a- (3-propyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine; 7a- (3-benzyl-5-isoxazo I i) -hexah id ro-1 H-pyrrolizine; 7a- (5-hydroxy-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-benzyloxy-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-bromo-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-fluoro-5-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (6-chloro-5-methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (5-methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (5-bromo-6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-chloro-6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (4-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-phenyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine; and or a pharmaceutically acceptable salt or prodrug thereof. Also included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions, in the manner described below. Compositions suitable for parenteral injection may comprise aqueous, non-aqueous, sterile, pharmaceutically acceptable solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous 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 maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain auxiliaries, such as preservatives, humectants, emulsifiers and dispersants. 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. The prolonged absorption of the injectable pharmaceutical form can be caused by the use of absorption retarding agents, for example, aluminum monostearate and gelatin. If desired, and for a more effective distribution, the compounds can be incorporated in focused delivery or slow release systems, such as polymer matrices, Mposomes and microspheres. They can be sterilized, for example, by filtration through a bacteria retainer 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 mixed with at least one customary inert (or carrier) excipient, such as, sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, such as, for example, starches, lactose , sucrose, glucose, mannitol and silicic acid; (b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato starch or tapioca, algic acid, certain complex silicates and sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, such as, for example, kaolin and bentonite; e (i) lubricants, such 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 fillings in soft and hard filled gelatin capsules, using excipients such 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 can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and may also be a composition such that it releases the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embossed compositions, which may be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the aforementioned 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, such 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, peanut oil, corn germ oil, olive oil, castor oil and oil. sesame, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids or mixtures of these substances, and the like. In addition to such inert diluents, these liquid dosage forms may also include auxiliaries, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

The suspensions, in addition to the active compounds, may contain suspending agents, such 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 similar. Compositions for rectal or vaginal administration 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 solids at ordinary temperatures but liquid at body temperature, and therefore, they melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical or transdermal administration of a compound of this invention also include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a preferred and particularly effective dosage form of the present invention. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative, buffer or propellant as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require mixing with special formulation agents or with special packaging materials to ensure delivery of the appropriate dosage.

In addition, compounds that are absorbed very rapidly through the skin may require a formulation with agents or retarding absorption barriers. Ophthalmic formulations, powders, solutions and eye ointments are also contemplated 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. The liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any metabolizable, physiologically acceptable and non-toxic liquid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming 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 et seq. In order to reduce unwanted peripherally mediated side effects, it is desirable, but not essential, to incorporate an anti-cholinergic that acts peripherally, such as, N-methylcopolamine, N-methylatropine, propanthelin, metanyl or glycopyrrolate into the composition. .

Synthetic Methods The compounds of the present invention can be synthesized as shown in Reaction Schemes I and I I presented below using the reactions and techniques described in this section. The reactions are carried out in a suitable solvent for the reagents and the materials used are suitable for the transformation that is taking place. Those skilled in the art of organic synthesis understand that the functionality present in the heterocyclic ring and other portions of the molecule must be consistent with the proposed chemical transformation. This will need, in due course, the practitioner's judgment in order to decide the order of the synthetic steps, required protective groups and conditions of deprotection. The substituents in the starting materials may be incompatible with some of the reaction conditions required in some of the described methods, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to practitioners skilled 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 process and many such protective groups are known, cf. , for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & amp; amp;; Sons, New York (1 991).

Esguema 1 1 2 According to Scheme 1, compounds of Formula (I) are prepared, wherein A is selected from options (c) - (g), as described above. A compound AX, wherein A is selected from options (c) - (g), as described above, and wherein X is I or Br, is treated with an alkyl lithium, for example, n-butyllithium or t-butyllithium , at a temperature of about -100 ° C to -28 ° C, to give a compound A-Li, for example, wherein RO, R and R are as previously defined for compounds of Formula (I). The compound A-Li is reacted with the compound (1), a starting material prepared according to the procedure of Miyano et al. (Synthesis, 701 (1978)), starting the reaction at a temperature from about -100 ° C to -70 ° C and heating at a temperature from -30 ° C to ambient, in a suitable solvent, such as ether or THF , for example, for a period of from 0.2 to 24 hours to give the desired compounds (2), which are specific examples of Formula (I) above. Alternatively, when R3, R4 or R5 is F, Cl or Br, particularly when substituted at a ring position adjacent to a ring nitrogen atom, any may be displaced by another nucleophile, eg, a different halogen, ammonia or an amine, a C ^ Cs-alkoxide, or a C ^ Cs-thiolate to give additional compounds of Formula (I) above. A primary amino group can be further modified by acylation with suitably activated carboxylic, carbonic or carbamic acid, or by conversion to hydrosi using a diazotization / hydrolysis sequence, or to halo, by a diazotization / halide displacement, for example, under Sandmeyer well known, or nitro by oxidation, for example, with hydrogen peroxide in sulfuric acid.

Scheme 2 by transition metal Alternatively, as illustrated in Scheme 2, R3 or R4 may be a group G, where G is a sulfonate, for example O-SO2CF3, or halo, particularly bromine or iodine, which is replaceable by a variety of groups functional with the help of transition metal catalysis using methods well known to those skilled in the art. In this way, the reaction of compound (3) with Zn (CN) 2 with the aid of palladium and heat catalysis and a suitable solvent, such as DMF or N-methylpyrrolidinone, provides compounds I (R3 = CN). Moreover, using well established methods, the cyano group can be further transformed, for example, reduction (to -CH2NH2), or by hydrolysis (to CO2H), or by reaction with any of a variety of organometallic agents followed by hydrolysis (for give ketones), or by cycloaddition of 1, 3-dipolabafilos (to give heterocycles). The -CH2NH2 group can be further modified by alkylation with an alkyl halide, or alternatively by reaction with an aldehyde or ketone under reducing conditions, or by acylation with a suitably activated carboxylic, carbonic or carbamic acid. Alternatively, replacement of G with aryl, substituted aryl, heteroaryl or substituted heteroaryl can be achieved by the reaction of (3) with the appropriate aryl or heteroarylboronic acid under palladium catalysis in a suitable solvent, such as benzene, toluene, DMF. , THF or similar, at temperatures from approximately 40 ° C to 120 ° C. Replacement of G with substituted akenyl, alkenyl, dienyl or substituted dienyl can be achieved by reaction of (3) with the appropriate alkene or diene under Heck conditions, ie, under palladium catalysis in a suitable solvent, such as benzene, toluene, DMF, THF or the like, at temperatures from about 40 ° C to 120 ° C. Replacement of G with alkynyl or substituted alkynyl can be achieved by reaction of (3) with the appropriate alkyne or alkyne substituted under palladium catalysis in the presence of a Cu (I) salt and a base such as a tertiary amine, by example, triethylamine, in a suitable solvent, such as benzene, toluene, DMF, THF or the like, at temperatures from about 40 ° C to 120 ° C. The alkenes or alkynes obtained as described above, can be reduced to alienes by appropriate hydrogenation techniques, such as, treatment with hydrogen on a noble metal catalyst.

Esguema 3 T T R1-CH2-NO2 + Ph-NCO R ^ C = N-O 4 5 1 7 6 8 According to Scheme 3, compounds of Formula (I) are prepared, wherein A is selected from option (a) as described above. Compound (7) was first prepared from compound (1) by treatment with ethynylmagnesium bromide under the conditions described for Scheme 1 above. In the presence of the acetylene compound (7), the nitrile-oxide compound (6) is generated from a nitro compound (4), wherein R1 is as previously described, by reaction with phenylisocyanate (5) in benzene or toluene, for example, from 60 ° C to the reflux temperature of the solvent for 6 to 24 hours, and the compounds (6) and (7) react to give the desired isoxazolyl compound (8), which also it is a specific specimen of Formula (I). According to Scheme 4 below, compounds of Formula (I) are prepared, wherein A is selected from options (a) and (b) above, wherein R 1 is methyl. A protected proline carboxylic ester (9) is reacted with LDA at -78 ° C to 0 ° C, and then with allyl bromide at a temperature from -78 ° C to room to give the pyrrolidine compound substituted with allyl ( 10). Compound (10) is selectively hydrated at the terminal carbon atom by sequential treatment with BH3 and H2O2. The intermediate alcohol is then mesylated by treatment with methanesulfonyl chloride in the presence of base to give the compound (11). The compound (1) is deprotected by standard methods, such as, removal of carbobenzoxy with hydrogen in the presence of palladium catalyst, for example, which also induces cyclization to provide the bicyclic compound (12). The compound (12) is then treated with the dilithium anion of acetone oxime (of course, other oximes can be produced from the corresponding ketone to vary R1 in accordance), and the intermediate compound is cyclized by treatment with dehydrating conditions, such as , H2SO4, to give the compound (13), also a representative example of Formula (I). Alternatively, compound 12 is treated with the dilithium anion of acetone oxime, then treated with an appropriately substituted hydrazine to give compound (14), wherein R2 is as described by compounds of Formula (I), previously , which is also a representative example of Formula (I). Esguema 4 e 1 2 1 3 A. Protocol for determination of ligand-nicotinic acetylcholine receptor binding strengths In order to identify compounds as cholinergic agents, which are capable of interacting with nicotinic acetylcholine receptors in the brain, a ligand-receptor binding assay was performed as the initial screen. The compounds of the present invention were effective in interacting with neuronal nicotinic acetylcholine receptors as tested for their ability to displace radioligand from neuronal nicotinic acetylcholine channel receptors labeled with [3H] -cystine ([3H] -CYT). Displacement of [3H] -CYT of nicotinic acetylcholine receptors was determined using crude rat whole brain synaptic membrane preparations (Pabreza et al., Molecular Pharmacol., 1990, 39: 9). The washed membranes were stored at -80 ° C before use. The frozen aliquots were thawed slowly and resuspended in 20 buffer volumes (containing: 120 mM NaCI, 5 mM KCI, 2 mM MgCl2, 2 mM CaCl2 and 50 mM Tris-CI, pH 7.4 @ 4 ° C). After centrifugation at 20,000 x g for 15 minutes, the pellets were resuspended in 30 volumes of buffer. The homogenate (containing 125-150 μg of protein) was added to triplicate tubes containing concentrations of the test compound and [3 H] -CYT (1.25 nM) in a final volume of 500 μl. The samples were incubated for 60 minutes at 4 ° C, then quickly filtered through Whatman GF / B filters in 0.5% polyethylimine using 2 x 4 ml of ice-cold buffer. The filters were counted in 4 ml of Ecolume® (ICN). Non-specific ligation was determined in the presence of 10 μM (-) - nicotine and the values were expressed as a percentage of total ligation. The IC50 values were determined with the non-linear least squares curve adjustment program RS-1 (BBN) and the IC50 values were converted to Ki values using the Cheng and Prusoff correction (Ki = IC50 / 1 + [ligand] / Kd of ligand). Alternatively, the data were expressed as a percentage of the total specific binding. The results (shown in Table 1) suggest that the compounds of the present invention have high affinity for the neuronal nicotinic acetylcholine receptor.

B. Protocols for the determination of functional effects of nicotinic acetylcholine receptor ligands on synaptic transmission The ability of the compounds of the invention to interact with neuronal nicotinic acetylcholine receptors and thereby activate or inhibit synaptic transmission can be demonstrated in vitro using The following protocol. The cells of the human neuroblastoma clonal cell line I MR-32 (ATCC, Rockville, MD) were maintained in a logarithmic growth phase according to established procedures (Lukas, 1993). The experimental cells were seeded at a density of 500,000 cells / ml in a 24-well tissue culture plate. The platinum cells were allowed to proliferate for at least 48 hours before loading with 2 μCi / ml of 86Rb + (35 Ci / mmol) overnight at 37 ° C. The 86Rb + effluvium assays were performed according to previously published protocols (Lukas, RJ m J. Pharmacol, Exp. Ther., 265: 294-302, 1993) except that Dulbecco's modified serum-free Eagle's medium was used for the load steps of 86Rb +, rinse and effluvium induced by agonist. The responses (reported as percent relative to the response produced by 100 μM of (S) -nicotine) are shown for the indicated concentrations of the selected compounds of the invention. The inhibition data (given by other selected compounds) reflect the inhibition of the effluvium produced by 1 00 μM of (S) -nicotine at the indicated concentration. The results (also shown in Table 1) suggest that the selected compounds of the present invention either activate or inhibit aspects of initial ion fluxes of synaptic transmission mediated by neuronal nicotinic acetylcholine receptors. This finding is in agreement with the results of others, who have linked the release of dopamine, which is dependent on the flow of ions in synaptic transmission, to bind to nicotinic receptors (cf., for example, Lippiello and Caldwell, US Pat. 5,242, 935, issued September 7, 1993; Caldwell and Lippiello, U.S. Patent 5,248,690, issued September 28, 1993; and Wonnacott et al., Prog. Brain Res., 79: 1 57-163 (1 989)).

Table 1 Ligation to neuronal nicotinic acetylcholine receptors and activation or inhibition of neuronal nicotine acetylcholine receptors in IMR-32 cells Ex. No. Ligature (nM) IMR-32 IMR-32% response% inhibition (conc.) (Conc.) 1 0.97 110 (10 μM) 2 70 3 0.38 71 (10 μM) 4 4.3 40 (10 μM) 5 0.10 82 (1 μM) 6 5.7 7 436 8 0.055 71 (1 μM) 9 3.7 39 (100 μM) 10 2.9 13 (10 μM) 12 (10 μM) 11 1417 12 0.27 93 (10 μM) 13 1.4 108 (100 μM) 14 1.7 74 (100 μM) 15 4.0 16 1.4 53 (100 μM) 16b 0.27 17 0.61 41 (10 μM) 18 0.11 66 (10 μM) 19 0.05 91 (1 μM) 20 0.56 98 (1 μM) 21 0.33 56 (1 μM) 22 0.22 42 (10 μM) 23 0.23 68 (10 μM) 24 72 0 (100 μM) 14 (10 μM) In addition, the compounds of the invention are useful as binders for the a7-nicotinic acetylcholine receptor, which is a useful indicator for treating certain forms of psychosis, for treating certain forms of cognitive deficits, or as neuroprotective agents. Compounds (1-14, 16b, 20, 21 and 25) exhibited a binding affinity relative to the known bungarotoxin binder alpha7 of between 0.9-16.200 nM. Accordingly, the compounds bind to several nicotinic receptor subtypes. The present invention is therefore directed to a compound of formula I or a pharmaceutical composition thereof, which binds both the alpha4beta2 receptor and the alpha7 receptor in mammals including humans, and a method for binding either or both subtypes of receptors comprising administering a pharmaceutically effective amount of said compound or salt thereof in an in vitro or in vivo screen or to a patient in need of treatment thereof.

EXAMPLES The following examples will serve to further illustrate the preparation of the novel compounds of the invention and their biological activity. They are not to be read as limiting the scope of the invention, as defined by the appended claims. Thin layer chromatography (TLC) was performed on 0.25 mm E. Merck pre-coated silica gel plates (60 F-254). Flash chromatography on 200-400 mesh silica gel (E. Merck) was performed, and column chromatography on 70-230 mesh silica gel (E. Merck) was performed. The following abbreviations are used: THF for tetrahydrofuran, DMF for N, N-dimethylformamide, D2O for deuterium oxide, CDCI3 for deuteriochloroform, DMSO-d6 for deuterodimethylsulfoxide, BOC for tert-butyloxycarbonyl, CBZ for benzyloxycarbonyl, Bn for benzyl, MS for methanesulfonyl, PAW for pyridine / acetic acid / water (20: 6: 1 1), DCC for dicyclohexylcarbodiimide, DI BALH for diisobutylaluminum hydride, DI EA for diisopropylethylamine, DME for 1,2-dimethoxyethane, DMSO for dimethylsulfoxide; DPPA for diphenylphosphorayl azide, EDCI for (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, HOBT for 1-hydroxybenzotriazole, LAH for lithium aluminum hydride, NH4OAc for ammonium acetate, dppp for 1 , 3-bis (diphenylphosphino) propane, NMM for N-methylmorpholine, TEA for triethylamine, THF for tetrahydrofuran.

EXAMPLE 1 7a- (3-Met-il-5-is-oxazole-1-hydroxychloride) -hexah id ro-1 H-pyrrolizine 1 a. 1-benzyloxycarbonyl-2- (methoxycarbonyl) -2- (2-propenyl) pyrrolidine Under a nitrogen atmosphere, diisopropylamine (16.4 ml, 11.1 mmol) was dissolved in THF (17 ml) and cooled to -78 ° C. C. Then a solution of 2.5 M of n-butyllithium in hexane (43 ml, 1 07.5 mmol) was added in the form of drops, followed by stirring for 15 minutes and then 1-benzyloxycarbonylproline methyl ester (25.7 g, 97.7 mmol) was added. in THF (575 ml) to the reaction vessel in the form of drops over a period of 40 minutes. The reaction mixture was allowed to stir for 15 minutes at -78 ° C, pure allyl bromide (25.4 ml, 293 mmol) was added at a stable rate, followed by stirring for 15 minutes at -78 ° C and for 2 additional hours between -35 ° C and -25 ° C. Then, a phosphate buffer solution (-100 ml), pH = 7, was poured into the reaction vessel and the reaction mixture was allowed to warm to room temperature. The mixture was diluted with EtOAc, washed in succession with 2N HCl and brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography (silica gel; EtOAc / hexane 1:20 to 1:15 to 1:10) to give a yellow oil (17.8 g, 63%). Rf 0.31 (EtOAc / hexane, 1: 4). MS (CI / NH3) m / e: 304 (M + H) +. 1 H NMR (DMSO-d 6, 300 MHz) d 1.77-1.86 (m, 2H), 1.94-2.13 (m, 2H), 2.50-2.59 (m, 1H partially buried under DMSO), 2.84 minor former and 2.92 major former ( dd, J = 14.0 Hz, 7.0 Hz, 1H), 3.28-3.62 (m, 5H), 4.96-5.11 (m, 4H), 5.64-5.75 (m, 1H), 7.27-7.41 (m, 5H). 1 B. 1-Benzyloxycarbonyl-2- (3-hydroxypropyl) -2- (methoxycarbonyl) pyrrolidine 1-benzyl oxy-carbon il-2- (methoxycarbonyl) -2- (2-pro peny I) pyrrolidine was dissolved (from step 1a, 21.0 g, 69.4 mmol) in THF (70 ml) and borane complex 1.0 M THF (45 ml, 45 mmol) was added dropwise to the reaction vessel over a period of 40 minutes. The reaction mixture was allowed to stir for one hour, then ~ 10 ml of water was added carefully followed by the successive addition of 3 N NaOH (16.2 ml, 48.5 mmol) and 30% hydrogen peroxide (5.5 ml, 48.5 mmol). The mixture was allowed to stir for one hour, then was emptied into a separatory funnel containing 250 ml of water and 15 ml of 10% Na2S2O3. The aqueous solution was extracted with CH2Cl2 (3X) and the organic fractions were combined, washed in succession with saturated NaHCO3 and then with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel; EtOAc / hexane, 1: 4 to 1: 2 to 1: 1 to EtOAc) to give a clear viscous oil (12.3 g, 55% yield). Rf 0.18 (EtOAc / hexane, 1: 1). MS (CI / NH3) m / e: 322 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.20-2.41 (m, 8H), 3.45-3.82 (m, 7H), 5.06-5.18 (m, 2H), 7.29-7.37 (m, 5H). 1 C. 1-Benzyloxycarbonyl-2- (methoxycarbonyl) -2- (3-methylsulfonyloxy-propyDpyrrolidine) 1-Benzyloxycarbonyl-2- (3-hydroxypropyl) -2- (methoxycarbonyl) pyrrolidine (from step 1b, 10.7 g, 33.2 mmol) was combined and triethylamine (4.9 ml, 34.9 mmol) in THF (133 ml) and cooled to 0 ° C under a nitrogen atmosphere, methanesulfonyl chloride (2.70 ml, 34.9 mmol) was added dropwise to the reaction mixture and stirred for 30 minutes at 0 ° C. Water was added and the contents of the reaction vessel were emptied into a separatory funnel.The mixture was washed in succession with 10% citric acid solution and then with saturated NaHCO3 solution, dried (Na2SO4), concentrated and the residue was chromatographed (silica gel; EtOAc / hexane, 1: 1 to 1: 2) to give a clear oil (11.0 g, 83%). Rf 0.25 (EtOAc / hexane , 1: 1) MS (CI / NH3) m / e: 400 (M + H) + .1H NMR (CDCI3, 300 MHz) d 1.59-2.35 (m, 8H), 2.93 minor former and 2.99 major former ( s, 3H), 3.46-3.80 (m , 5H), 4.07-4.27 (m, 2H), 5.05-5.17 (m, 2H), 7.29-7.36 (m, 5H). 1d. 7 a- (methoxy carbon i) -hexah id ro-1 H-pyrrolizine 1-Benzyloxycarbonyl-2- (methoxycarbonyl) -2- (3-methylsulfonyloxy-propyl) pyrrolidine was dissolved (from step 1c, 11.0 g, 27.6 mmol ) in MeOH and exposed to hydrogen gas at a pressure of 4 atmospheres in the presence of 10% palladium on carbon (11.0 g) for 48 hours. The reaction was filtered and the filtrate was evaporated. The crude was subjected to chromatography (silica gel; CHCl3 / MeOH, 98: 2 to 95: 5 to 90:10) to give a yellow oil (4.23 g, 90%). Rf 0.53 (CHCl3 / MeOH, 90:10). MS (CI / NH3) m / e: 170 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.24-1.85 (m, 6H), 2.30 ("qt", J = 6.0 Hz, 2H), 2.72 (ddd, J = 9.9 Hz, 6.6 Hz, 6.6 Hz, 2H), 3.23 (ddd, J = 9.9 Hz, 5.9 Hz, 5.9 Hz, 2H), 3.72 (s, 3H). 1e 7a- (3-methyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine 8- (methoxycarbonyl) -hexahydro-1H-pyrrolizine (from step 1d, 1.56 g, 9.22 mmol), acetone oxime (1.45 g, 19.8 mmol) and n-butyllithium (2.5 M in hexane, 16 ml, 39.6 mmol) in a manner similar to that reported by J. Saunders et al., J. Med. Chem. 1990, 33: 1128. The crude material was subjected to chromatography (silica gel; CHCl3 / MeOH, 99: 1) to give a yellow oil (199 mg, 11%). MS (CI / NH3) m / e: 193 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.76-1.92 (m, 6 H), 2.14-2.29 (m, 2 H), 2.24 (s, 3 H), 2.61-2.69 (m, 2 H), 3.13-3.32 (m, 2 H) ), 5.95 (s, 1H). 1 f. 7a- (3-Methyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine hydrochloride. 7a- (3-Methyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine was submerged (from step 1 e, 1.89 mg, 0.98 mmol) in Et 2 O (7 mL) and cooled to 0 ° C. An Et20 solution saturated with HCl (g) was added to the reaction vessel in the form of drops with stirring. The solvent was carefully removed and the remaining white solid was triturated with Et 2 O (2X) followed by recrystallization out of MeOH / Et 2 O (126.5 mg, 56%). mp 169-171 ° C. MS (CI / NH3) m / e: 1 93 (M + H) +. H NMR (D2O, 300 MHz) d 2.20-2.41 (m, 9H), 2.60-2.68 (m, 2H), 3.31 -3.39 (m, 2H), 3.71 -3.79 (m, 2H), 6.59 (s, 1 H). Anal. Caled for C1 1 H17CIN2O: C, 57.76; H, 7.49; N, 12.25. Found: C, 57.84; H, 7.34; N, 12.13.

Example 2 Di 7a- (1 H-S-methyl-S-pyrazolo-OH-hexahydro-1 H-pyrrolizine hydrochloride 2a. 7a- (1 - (1, 3-butanedione-3-oxim a)) -hexah id ro-1 H-pyrrolizine Butyllithium (1.6 M / hexane, 6.2 ml, 9.88 mmol) was added to an acetone solution of oxime (365 mg, 4.9 mmol) in THF (7.5 ml) previously cooled to 0 ° C. After ten minutes of stirring, 8- (methoxycarbonyl) -hexahydro-1 H -pyrrolizine (from Example 1 d, 645 mg, 3.8 mmol) in THF (7.6 ml) was added and the reaction mixture was allowed to warm to room temperature. room temperature and stirred an additional 8 hours. Saturated N H 4 Cl solution was added, and the phases were separated. Solid K2CO3 was added to the aqueous phase followed by extraction with CHCl3 (3X). The organics were combined, dried (MgSO), concentrated and the crude product was chromatographed (silica gel; CHCl3 / MeOH, 90:10) to give an amber solid (257 mg, 32%). MS (CI / NH3) m / e: 211 (M + H) +. 2b. 7a- (1 H -3-methyl-5-pyrazolyl) -hexahydro-1 H-pyrrolizine Ethanol (2.0 ml) saturated with HCl (g) was added to a solution of the 7a- [1- (1,3-butanedione- 3-oxime)] hexahydro-1H-pyrrolizine (from step 2a, 245 mg, 1.16 mmol) and hydrazine (182 μl, 5.80 mmol) in EtOH (2.5 ml). The reaction mixture was heated to reflux for 3 hours and then allowed to cool to room temperature. Saturated NH CI was added and the phases were separated. Solid K2CO3 was added and the aqueous mixture was extracted with CHCl3. The organic fraction was dried (MgSO4), concentrated and chromatographed (CHCl3 / MeOH / NH4OH, 90: 10: 0 to 90: 9.5: 0.5) to give a solid (97 mg, 44%). mp 56-58 ° C. MS (CI / NH3) m / e: 192 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.72-1.97 (m, 6 H), 2.02-2.12 (m, 2 H), 2.26 (s, 3 H), 2.61-2.71 (m, 2 H), 3.18-3.26 (m, 2 H) ), 5.82 (s, 1H). 2 C. 7a- (1H-3-Methyl-5-pyrazolyl) -hexahydro-1H-pyrrolizine dihydrochloride salt 7a- (1H, 3-methyl-5-pyrazolyl) -hexahydro-1H-pyrrolizine (from step 2b, 90.0 was dissolved mg, 0.47 mmol) in THF: MeOH (10: 1, 11 mL) and Et2O saturated with HCl (g) was added dropwise. The solvent was removed and the remaining solid was triturated with Et2O (2X) and then recrystallized from MeOH / Et2O to give a white crystalline solid (90.0 mg, 72%). mp 130-132 ° C. MS (CI / NH3) m / e: 192 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.08-2.33 (m, 9H), 2.50-2.59 (m, 2H), 3.22-3.31 (m, 2H), 3.65-3.74 (m, 2H), 6.27 (s, 1H ). Anal. Caled for CnH ^ CUNa: C, 50.01; H, 7.25; N, 15.90. Found: C, 49.71; H, 7.49; N, 15.77.

Example 3 7a- (3-pyridinium-hexahydro-1H-pyrrolizine hydrochloride 3a. 7a- (3-pi ridi ni l) -hexahydro-1 H-pyrrolizine A solution of n-butyllithium 2.5M in hexanes (2.9 ml) was added, 7.2 mmol) in the form of drops to a solution of 3-bromopyridine (0.690 ml, 7.2 mmol) in Et2O (10 ml) at -78 ° C. After stirring for 10 minutes, 1,2,3,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.4 mmol), prepared according to S. Miyano et al., Was introduced into the reaction vessel, Synthesis 1978, 701-702 and S. Miyano et al., Journal of Heterocyclic Chemistry, 1982, 19: 1465-1468, followed by shaking at -78 ° C for 4 hours. The reaction mixture was allowed to warm to room temperature, and 2 N HCl was added. The phases were separated and the aqueous phase was basified with 15% NaOH solution and extracted with CHCl3 (3X). The organic fractions were combined, dried (MgSO4), concentrated and subjected to chromatography (silica gel; CHCl3 / MeOH, 97.5: 2.5) to give an amber oil (260 mg, 58%). Rf = 0.2 (CHCl3 / MeOH, 90:10). MS (CI / NH3) m / e: 189 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.58-1.76 (m, 2 H), 1.79-1.90 (m, 2 H), 1.92-2.08 (m, 4 H), 2.66-2.74 (m, 2 H), 3.13-3.20 (m , 2H), 7.19 (dd, J = 7.7, 4.8 Hz, 1H), 7.82 (ddd, J = 7.7, 2.6, 1.4 Hz, 1H), 8.41 (dd, J = 4.8, 1.4 Hz, 1H), 8.71 ( d, J = 2.6 Hz, 1H). 3b. 7a- (3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (3-pyridinyl) -hexahydro-1H-pyrrolizine (from step 3a, 125 mg, 0.66 mmol) was dissolved in CH2Cl2 (15). ml) and Et2O saturated with HCl (g) was added dropwise. The solvent was removed, and the remaining solid was triturated with CH2Cl2 (2X) to give a yellow hygroscopic solid (140 mg, 81%). MS (CI / NHs) m / e: 189 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.13-2.29 (m, 2 H), 2.32-2.43 (m, 2 H), 2.48-2.69 (m, 4 H), 3.40 (3.49 (m, 2 H), 3.83-3.92 (m , 2H), 7.92 (dd, J = 8.5, 5.5 Hz, 1H), 8.43 (ddd, J = 8.5, 2.6, 1.4 Hz, 1H), 8.75 (dd, J = 5.5, 1.4 Hz, 1H), 8.88 ( d, J = 2.6 Hz, 1H) Anal Caled for C12H18CI2N2 «0.5H2O: C, 53.34; H, 7.09; N, 10.37 Found: C, 53.28; H, 6.96; N, 10.22.

Example 4 7a- (3-quinolinyl) -hexahydro-1H-pyrrolizine dihydrochloride 4a. 7a- (3-quinolinyl) -hexahydro-1 H -pyrrolizine A solution of 2.5 M nBuLi (1.2 ml, 2.8 mmol) in hexanes was added to 3-bromoquinoline (386 μl, 2.8 mmol) in THF (10 ml) at - 100 ° C followed immediately by 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (200 mg, 0.9 mmol). The reaction mixture was allowed to stir for 2 hours at -100 ° C and then 2N HCl was added at 0 ° C. After warming to room temperature, the mixture was poured into EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (3X). The fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; EtOAc) to give a pale solid (104 mg, 46%). mp 80-83 ° C. MS (CI / NH3) m / e: 239 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.61-1.75 (m, 2 H), 1.83-1.94 (m, 2 H), 2.03-2.17 (m, 4 H), 2.71-2.80 (m, 2 H), 3.20-3.27 (m , 2H), 7.52 (ddd, J = 7.0, 7.0, 1.1 Hz, 1H), 7.65 (ddd, J = 7.0, 7.0, 1.5 Hz, 1H), 7.82 (d, H = 8.1 Hz, 1H), 8.05 ( d, J = 8.5 Hz, 1H), 8.32 (d, J = 2.2, Hz, 1H), 8.97 (d, J = 2.2 Hz, 1H). 4b. 7a- (3-quinolinyl) -hexahydro-1H-pyrrolizine dihydrochloride salt 7a- (3-quinolinyl) -hexahydro-1 H -pyrrolizine (from step 4a, 95 mg, 0.4 mmol) was dissolved in CH 2 Cl 2 (5 ml) , and Et2O saturated with HCl (g) was added to the reaction solution. The solvent was removed and the remaining solid was recrystallized from MeOH / Et2O to give white, short hygroscopic needles (65 mg, 52%). MS (CI / NH3) m / e: 239 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.21-2.49 (m, 4 H), 2.55-2.64 (m, 2 H), 2.72-2.81 (m, 2 H), 3.42-3.51 (m, 2 H), 3.90-3.98 (m , 2H), 7.87 (ddd, J = 7.0, 7.0, 1.1 Hz, 1H), 8.05 (ddd, J = 7.0, 7.0, 1.1 Hz, 1H), 8.17 (m, 2H), 8.85 (d, J = 2.6 Hz, 1H), 9.13 (d, J = 2.6 Hz, 1H). Anal. Cale for C 16 H 20 Cl 2 N 2"1.4 H 2 O: C, 57.11; H, 6.83; N, 8.33. Found: C, 57.17; H, 6.90; N, 8.17.

Example 5 Hydrochloride of 7a- (6-chloro-3-p i ridin i l) -hexah id ro-1 H-pyrrolizine 5a. 7a- (6-Chloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine A 2.5 M solution of nBuLi (1.8 mL, 4.4 mmol) in hexanes was added dropwise to 2-chloro-5-iodopyridine (1.0 g) , 4.2 mmol, prepared according to SC Clayton and AC Regan, Tetrahedron Letters 1993, 34: 7493-7496), was made into Et2O (17 ml) at -78 ° C. After stirring for 15 minutes, 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.0 g, 5.0 mmol) was added, and the reaction mixture was allowed to warm to room temperature. A solution of 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (3X). The organic phases were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 99: 1) to give a yellow oil (219 mg, 23%). Rf = 0.2 (CHCl3 / MeOH, 98: 2). MS (CI / NH3) m / e: 223 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.58-1.71 (m, 2 H), 1.79-2.08 (m, 6 H), 2.63-2.71 (m, 2 H), 3.11-3.18 (m, 2 H), 7.22 (d, J = 8.5 Hz, 1H), 7.80 (dd, J = 8.5, 2.6 Hz, 1), 8.48 (d, J = 2.6 Hz, 1H). 5b. 7a- (6-Chloro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (6-Chloro-3-pyridinyl) -hexahydro-1H-pyrrolizine (from step 5a) was dissolved, 210 mg, 0.94 mmol) in Et 2 O (8 mL), and Et 2 O saturated with HCl (g) was added at room temperature. The solvent was then removed, and the remaining solid was recrystallized from MeOH / Et2O to give short white needles (189 mg, 78%). mp 141-143 ° C. MS (CI / NH3) m / e: 223 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.12-2.50 (m, 6H), 2.58-2.65 (m, 2H), 3.33-3.42 (m, 2H), 3.69-3.88 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.99 (dd, J = 8.5, 2.7 Hz, 1H), 8.53 (d, J = 2.7 Hz, 1H). Anal. Caled for C12H16CI2N2: C, 55.61; H, 6.22; N, 10.81. Found: C, 55.10; H, 6.36; N, 10.57.

EXAMPLE 6 Salt of 7a- (2-fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride 6a. 7a- (2-f luoro-3-pyridinyl) -hexah id ro-1 H-pyrrolizine A solution of nBuLi 2.5 M (680 μl, 1.7 mmol) in hexanes was added to diisopropylamine (220 μl, 1.7 mmol) in THF ( 4.5 ml) at room temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78 ° C, pure 2-fluoropyridine was added and stirring was continued for 4 hours at -78 ° C. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.4 mmol) was added and the reaction mixture was allowed to stir for 2 hours at -78 ° C, then was warmed to room temperature. A solution of 2N HCl was added, then the mixture was emptied over EtOAc. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 98: 2) to give a clear oil (66 mg, 20%). Rf = 0.38 (CHCl3 / MeOH, 95: 5). MS (CI / NH3) m / e: 207 (M + H) +. H NMR (CDCl 3, 300 MHz) d 1.52-1.64 (m, 2H), 1.78-1.89 (m, 2H), 1.97-2.12 (m, 4H), 2.65-2.72 (m, 2H), 3.08-3.14 (m , 2H), 7.08-1.89 (m, 2H), 1.97-2.12 (m, 4H), 2.65-2.72 (m, 2H), 3.08-3.14 (m, 2H), 7.08-7.12 (m, 1H), 8.00 -8.03 (m, 1H), 8.18-8.24 (m, 1H). 6b. Salt of 7a- (2-fluoro-3-pyridinyl-hexahydro-1H-pyrrolizine hydrochloride 7a- (2-Fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine was dissolved (from step 6a, 59 mg, 0.3 mmol) in Et 2 O (8 ml), and Et 2 O saturated with HCl was added. (g) The solvent was removed and the precipitate was recrystallized from MeOH / Et2O to give a white solid (54 mg, 77%). mp 185-186 ° C. MS (CI / NH3) m / e: 207 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.06-2.21 (m, 2H), 2. 27-2.41 (m, 4H), 2.65-2.77 (m, 2H), 3.32-3.40 (m, 2H), 3.85-3.95 (m, 2H), 7. 47 (ddd, J = 7.7, 4.8, 1.8 Hz, 1H), 8.14 (ddd, J = 10.7, 7.7, 1.8 Hz, 1H), 8. 27 (ddd, J = 4.8, 1.8, 1.1 Hz, 1H). Anal. Caled for C 12 H 16 ClFN 2: C, 59.38; H, 6.64; N, 11.54. Found: C, 59.14; H, 6.53; N, 11.34.

Example 7 7a- (2-chloro-3-pyridinyl) -hexahydro-1 H-pyrrolizine hydrochloride 7a. 7a- (2-Chloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine A solution of nBuLi 2.5 M (680 μL, 1.7 mmol) in hexanes was added to diisopropylamine (0.220 mL, 1.7 mol) in THF (4.5 mL) at room temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78 ° C, pure 2-chloropyridine was added, and stirring was continued for 4 hours at -78 ° C. 1,2,3,5,6,7-Hexahydro-pyrrolizinium perchlorate (500 mg, 2.4 mmol) was added and the reaction mixture was allowed to stir for 2 hours at -78 ° C, and then heated to room temperature. A solution of 2N HCl was added, and the mixture was poured into EtOAc. The phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 100: 0 to 99.5: 0.5) to give a clear oil (18 mg, 5% ). Rf = 0.30 (CHCl3 / MeOH, 99: 1). MS (CI / m / e: 223 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.50-1.61 (m, 2H), 1.78-1.89 (m, 2H), 2.10-2.29 (m, 4H), 2.69-2.75 (m, 2H), 3.04-3.11 (m , 2H), 7.17 (dd, J = 7.7, 4.8 Hz, 1H), 8.21 (dd, J = 4.8, 1.8 Hz, 1H), 8.36 (dd, J = 7.7, 1.8 Hz, 1H). 7b. 7a- (2-chloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride salt 7a- (2-Chloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine (21 mg, 0. 1 mmol) in Et2O (6 ml), and Et2O saturated with HCl (g) was added. The solvent was removed and the precipitate was triturated (3X) with Et2O to give a yellow solid (26 mg, quant.) Mp 186-188 ° C. MS (CI / NH3) m / e: 223 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.03-2.18 (m, 2 H), 2229-2.41 (m, 2 H), 2.54-2.64 (m, 2 H), 2.75-2.84 (m, 2 H), 3.41-2.51 (m , 2H), 2.93-4.02 (m, 2H), 7.57 (dd, J = 8.1, 4.7 Hz, 1H), 8.01 (dd, J = 8.1, 1.7 Hz, 1H), 8.42 (dd, J = 4.7, 1.7 Hz, 1H). Anal. Caled for C 12 H 16 Cl 2 N 2: C, 55.61; H, 6.22; N, 10.81. Found: C, 55.21; H, 6.25; N, 10.45.

Example 8 7a- (5,6-Dichloro-3-pyridinyl) -hexahydro-1 H-pyrrolizine hydrochloride 8a. 2,3-dichloro-5-iodopyridine 5-amino-2,3-dichloropyridine (15.0 g, 92.0 mmol, prepared according to V. Koch and S. Schnatterer, Synthesis, 1990, 499-501) was dissolved in DME ( 30 ml) and subjected to diazotization conditions according to the procedure of MP Doyle and WJ Bryker (Journal of Organic Chemistry, 1 979, 44, 1572). The dissolved pyridine analog was added to a solution of BF3 complex etherate (17 ml, 138 mmol) at -15 ° C. Then t-butyl nitrite in DME (92 ml) was added at a rate so that the temperature never rose from -5 ° C. After complete addition, the reaction mixture was allowed to warm to 5 ° C and was stirred an additional 45 minutes. Pentane was added and the resulting paste was filtered. The filter cake was washed with cold Et 2 O, and the solid was dried with air to give a light orange solid (22.3 g). A salt sample of crude diazonium tetrafluoroborate (5.1 g, 19.5 mmol) and Kl (3.5 g, 21.4 mmol) in CH3CN (1 30 mL) was combined and allowed to stir at room temperature for 1 8 hours. A 1 0% solution of Na 2 S 2 O 3 was carefully added, the biphasic mixture was poured over Et 2 O, and the phases were separated. The organic phase was dried (MgSO) and concentrated, and the residue was subjected to chromatography (silica gel; hexanes / CH2Cl2, 10: 1) to give a white solid (4.0 g, 75%). mp 55-57 ° C. Rf = 0.43 (hexanes / CH2Cl2, 2: 1). 1 H NMR (CDCl 3, 300 MHz) d 8.09 (d, J = 1.8 Hz, 1 H), 8.5 (d, J = 1.8 Hz, 1 H). 8b. 7a- (5,6-dichloro-3-pyridinyl) -hexahydro-1H-pyrrolizine A solution of 1.7 M tBuLi (4.7 ml, 8.0 mmol) enpentane was added to 2,3-dichloro-5-iodopyridine ( step 8a, 1.0 g, 3.65 mmol) in Et2O (15 ml) pre-cooled -100 ° C. After stirring for 2 minutes, 1, 2, 3,5,6,7-hexahydropyrrolizinium perchlorate (1.5 g, 7.3 mmol) was added and the reaction mixture was allowed to stir for 20 minutes at -100 ° C. C, and then gradually warm to -20 ° C. HCl 2N was added, and the ice bath was removed. After warming to room temperature, the reaction mixture was poured into EtOAc and the phases were separated. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2X). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue chromatographed (silica gel; CHCl3 / MeOH, 99.5: 0.5) to give a light yellow oil (510 mg, 54%). MS (CI / NH3) m / e: 257 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.59-1.71 (m, 2 H), 1.80-2.08 (m, 6 H), 2.64-2.72 (m, 2 H), 3.11-3.20 (m, 2 H), 7.99 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H). 8c. 7a- (5,6-Dichloro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt. Paste 7a- (5,6-dichloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine (from step 8b) , 128 mg, 0.50 mmol) in Et 2 O (8 ml), and Et 2 O saturated with HCl (g) was added. The solvent was removed, and the solid was recrystallized from MeOH / Et2O to give a white solid (111 mg, 75%). Mp 215-217 ° C. MS (CI / NH3) m / e: 257 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.12-2.50 (m, 6H), 2.54-2.65 (m, 2H), 3.35-3.43 (m, 2H), 3.79-3.88 (m, 2H), 8.21 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H). Anal. Caled for C 12 H 15 Cl 3 N 2: C, 49.09; H, 5.15; N, 9.54. Found: C, 49.01; H, 5.15; N, 9.44.

EXAMPLE 9 7a- (5-Pyrimidin-N-hexahydro-1 H -pyrrolizine 9a. 7a- (5-pi rim idyl) -hexah id ro-1 H-pyrrolizine hydrochloride A 1.7 M tBuLi solution was added ( 1.6 ml, 2.6 mmol) in pentane to 5-bromopyrimidine (190 mg, 1.2 mmol) in Et 2 O: THF (1: 1, 12 ml) at -100 ° C. After stirring for 10 minutes, perchlorate of 1 was added, 2,3,5,6,7-hexahydropyrrolizinium (500 mg, 2.4 mmol) was added to the reaction paste, and stirring was continued for 30 minutes, then the reaction mixture was allowed to warm to 0 ° C and stir for 1 hour, a 2N HCl solution was added, and the reaction mixture was poured into Et20 and the phases were separated.The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2X). of CH2Cl2 were combined, dried (MgSO4), concentrated and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 98: 2) to give a clear oil (40 mg, 18%). NH 3) m / e: 190 (M + H) +. H NMR (CDCl 3, 30 0 MHz) d 1.60-1.73 (m, 2H), 1.82-2.11 (m, 6H), 2.66-2.75 (m, 2H), 3.15-3.21 (m, 2H), 8.85 (s, 2H), 9.05 (s) , 1 HOUR). 9b. 5- (7a-Hexahydro-1H-pyrrolizinyl) pyrimidine hydrochloride salt Paste 7a- (5-pyrimidinyl) -hexahydro-1 H -pyrrolizine (from step 9a, 33 mg, 0.2 mmol) in Et2O (7 ml) and saturated HCl was added with HCl (g). The solvent was removed to give a hygroscopic white solid (23 mg, 60%). MS (CI / NH3) m / e: 190 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.13-2.70 (m, 8 H), 3.38-3.46 (m, 2 H), 3.81-3.90 (m, 2 H), 8.99 (s, 2 H), 9.17 (s, 1 H). Anal. Caled for CnH ^ CINs-O.d HCl: C, 54.16; H, 6.82; N, 17.22. Found: C, 54.42; H, 7.26; N, 16.95.

Example 10 7a- (2,6-difluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride 10a. 7a- (2,6-difluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine A solution of nBuLi 2.5 M (675 μl, 1.7 mmol) in hexanes was added to diisopropylamine (220 μl, 1.6 mmol) in THF (4.5 ml) at room temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78 ° C, 2,6-difluoropyridine (145 μl, 1.6 mmol) was introduced and stirring was continued for 1 hour at -78 ° C. Then perchlorate 1, 2,3,5,6,7-hexahydropyrrolizinium (500 mg, 2.4 mmol) was added, and the cold bath was removed. After warming to room temperature, a 2N HCl solution was added and the phases were separated after the reaction mixture was poured into EtOAc. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2X). The CH2Cl2 extracts were combined, dried (MgSO), concentrated and chromatographed (silica gel; CHCl3 / MeOH, 98: 2) to give a clear oil (180 mg, 50%). MS (CI / IMH3) m / e: 225 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.5-1.63 (m, 2 H), 1.78-1.89 (m, 2 H), 1.92-2.10 (m, 4 H), 2.63-2.70 (m, 2 H), 3.08-3.12 (m , 2H), 6.72 (dd, J = 8.1, 3.0 Hz, 1H), 8.33 (dd, J = 18.0, 8.1 Hz, 1H). 10b. 7a- (2,6-difluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt A solution of Et2O saturated with HCl (g) was added to 7a- (2,6-difluoro-3-pyridinyl) - hexahydro-1 H-pyrrolizine (from step 10a, 1 74 mg, 0.8 mmol) in Et 2 O (10 mL). The paste was filtered and the filter cake was washed with Et2O to give a white solid (1.38 mg, 68%). Mp 205-206 ° C. MS (CI / NH3) m / e: 225 (M + H) +. 1 H NMR (D 2 O, 300 MHz) d 2.08-2.21 (m, 2H), 2.26-2.40 (m, 4H), 2.64-2.73 (m, 2H), 3.31 -3.40 (m, 2H), 3.82-3.90 ( m, 2H), 7.14 (dd, J = 8.5, 2.7 Hz, 1 H), 8.22-8.30 (m, 1 H). Anal. Caled for C12H15CIF2N2: C, 54.92; H, 5.70; N, 10.52. Found: C, 55.28; H, 5.80; N, 10.74.

Example 1 1 Hydrochloride salt of 7α- (2,6-dichloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine 1 1 a. 7a- (2,6-dichloro-3-pyridinyl) -hexah id ro-1 H-pyrrolizine A solution of nBuLi 2.5 M (675 μl, 1.7 mmol) in THF (4.5 ml) was added at room temperature. After stirring for 10 minutes, the reaction mixture was cooled to -78 ° C, 2,6-dichloropyridine (237 μl, 1-60 mmol) was added pure, and the stirring was continued for 1 hour at -78 ° C. . Perchlorate of 1, 2,3, 5,6,7-hexahydropyrrolizinium (550 mg, 2.40 mmol) was added and the reaction mixture was allowed to stir for 2 hours at -78 ° C, then was warmed to room temperature. A solution of 2N HCl was added and the mixture was emptied over EtOAc. The phases were separated and the aqueous phase was basified with 1% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 98: 2) to give a clear oil (70.6 mg, 17%). MS (CI / NH3) m / e: 257/259 (M + H) +. 1 H NMR (CDCl 3, 300 MHz) d 1.47-1.61 (m, 2 H), 7.19 (d, J = 8.5 Hz, 1 H), 8.37 (d, J = 8.35 Hz, 1 H). 11b. 7a- (2,6-Dichloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride salt 7a- (2,6-Dichloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine (from step 11a) was dissolved , 62 mg, 0.24 mmol) in Et20, and Et2O saturated with HCl (g) was added. The solvent was removed, and the precipitate was triturated with Et2O to give a white solid (35.6 mg). mp 212-214 ° C.1H NMR (D2O, 300 MHz) d 2.02-2.18 (m, 2H), 2.28-2.41 (m, 2H), 2.52-2.64 (m, 2H), 2.72-2.83 (m, 2H ), 3.41-3.50 (m, 2H), 3.92-4.02 (m, 2H), 7.60 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H); MS (CI / NH3) m / e: 257/259 (M + H) +. Anal. Caled for C12H16CIFN2: C, 49.26; H, 4.82; N, 9.57. Found: C, 49.14; H, 5.03; N, 9.47.

EXAMPLE 12 Salt of 7a- (6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride 12a. 2-fluoro-5-nitropyridine 2-chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), KF were combined (84.1 g, 1448 mol), Ph4PBr (95.3 g, 0.227 mol) and acetonitrile (1.5 I) and heated to reflux until no starting material remained. The volume was reduced to 750 ml, and the mixture was diluted with 21 ether, filtered and concentrated. The residue was triturated with hot hexane (5 x 1 L). The hexane extracts were combined and concentrated to give 48 g, (54%). 1 H NM R (D 2 O, 300 MHz) d 7.15 (dd, J = 3, 6 Hz, 1 H), 8.64 (m, 1 H), 9.15 (d, J = 1.6 Hz, 1 H). 12b. 5-amino-2-fluoropyridine. 2-Fluoro-5-nitropyridine (52.35 g, 368 mmol, step 12a) with 5% Pd / C (1000 mg) in EtOH (100 ml) and the mixture was stirred under an atmosphere of H2 for 4 days. The mixture was filtered and concentrated, and the residue was subjected to chromatography (silica gel; EtOAc / hexane, 1: 9 to 1: 1) to give 30.9 g (75%) of the title compound: 1 H NMR (DMSO -d6, 300 MHz) d 6.74 (dd, J = 3, 6 Hz, 1 H), 7.1 1 (m, 1 H), 7.26 (t, J = 1 Hz, 1 H); MS (CI / NH 3) m / z: 1 1 3 (M + H) +, 1 30 (M + NH 4) +. 12c. 2-fluoro-5-vodopyridine 5-Amino-2-fluoropyridine (990 mg, 8.83 mmol, from step 12b) in DME (5 ml) was added dropwise to a solution of diethyl etherate boron trifluoride (1. 6 ml, 13.2 mmol) at -1 0 ° C. After stirring for 15 minutes, t-butyl nitrite in DME (1.5 ml) was carefully added to the reaction mixture, while keeping the temperature below -5 ° C. After complete addition, the temperature was allowed to gradually rise to 5 ° C over 1 hour. The solution was re-cooled to -10 ° C, the residue was triturated with pentane (2X) and Et2O, then all solvents were removed in vacuo. The crude diazonium tetrafluoroborate salt was dissolved in acetonitrile (50 ml), Kl (1.6 g, 9.7 mmol) was added and the mixture was stirred for 24 hours. A solution of 10% sodium thiosulfate was carefully added, the mixture was emptied over Et20 and the phases were separated. The organic phase was dried (MgSO 4) and concentrated, and the residue was subjected to chromatography (silica gel; EtOAc / hexane, 1:20) to give a white solid (1.2 g, 59%): 1 H NMR (CDCl 3, 300 MHz) d 6.79 (dd, J = 8.4, 2.6 Hz, 1H), 8.04 (ddd, J = 8.4, 7.4 2.6 Hz, 1H), 8.43 (dd, 2.6, 0.7 Hz, 1H). 12d. 7a- (6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine 2-Fluoro-5-iodopyridine (200 μl, 0.90 mmol) was dissolved in Et 2 O and cooled to -78 ° C. A solution of t-BuLi 2.5 M (1.2 ml, 1.98 mmol) in pentane was added, and the reaction was stirred for 2 minutes. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (375 mg, 1.80 mmol) was added, and the reaction mixture was allowed to stir for 10 minutes at -78 ° C, then allowed to warm at -20 ° C. The ice bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH; 98: 2) to give a clear oil (75 mg, 40%). 1 H NMR (CDCl 3, 300 MHz) d 1.58-1.73 (m, 2H), 1.79-2.05 (m, 6H), 2.64-2.73 (m, 2H), 3.12-3.19 (m, 2H), 6.82 (dd, J = 8.4, 2.7 Hz, 1H), 7.90 (m, 1H), 8.30 (dd, J = 1.4, 0.7 Hz, 1H); MS (CI / NH3) m / z: 207 (M + H) +. 12e. 7a- (5-Fluoro-3-pyridinyl-hexahydro-1H-pyrrolizine hydrochloride salt) 7a- (5-Fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine (62 mg, 0.24 mmol, from step 12d) was dissolved. ) in Et2O, and Et2O saturated with HCl (g) was added.The solvent was removed and the precipitate was triturated to give a white solid (57.1 mg, 69%), mp 168-169 ° C.1H NMR (D2O, 300 MHz) d 2.13-2.50 (m, 6H), 2.58-2.67 (m, 2H), 3.34-3.42 (m, 2H), 3.78-3.87 (m, 2H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 8.13 (ddd, J = 8.8, 7.2, 2.7 Hz, 1H), 8.36 (dd, J = 2.7, 1.4 Hz, 1H); MS (CI / NH3) m / z: 207 (M + H) + Anal Caled for C12H16CIFN2: C, 59.38; H, 6.64; N, 11.54 Found: C, 59.51; H, 6.52; N, 11.30.

EXAMPLE 13 7α- (3-Ethyl-5-isoxazolyl) -hexahydro-1H-pyrrolizine hydrochloride salt 13a. 7a-ethynyl-hexahydro-1 H-pyrrolizine 1, 2,3,5,6,7-hexahydropyrrolizinyl perchlorate (1.0 g, 4.8 mmol) was added to a solution of ethynylmagnesium bromide 0.5M (29 ml, 14.3 mmol) in THF at room temperature. The reaction mixture was allowed to stir for 45 minutes, and 15% NaOH was added. The paste was diluted with brine: water (1: 1) and extracted with CH2Cl2 (3X). The organic phases were combined, dried (MgSO4), concentrated and subjected to chromatography (silica gel; CHCl3 / MeOH, 90:10), to give an amber oil (463 mg, 71%): 1H NMR (CDCl3, 300 MHz ) d 1.75-2.06 (m, 6H), 2.14-2.23 (m, 2H), 2.33 (s, 1H), 2.53-2.62 (m, 2H), 3.22-3.28 (m, 2H); MS (CI / NH3) m / z: 136 (M + H) +. 13b. 7a- (3-et i l-5-isoxazole i Q-hexah id ro-1 H-pyrrolizine Nitropropane (0.475 ml, 5.29 mmol) and phenylisocyanate (1.0 ml, 9.5 mmol) were dissolved in benzene (10 ml) and They were added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (358 mg, 2.65 mmol, from step 13a) .The solution was stirred at room temperature for 1 hour and refluxed for 5 hours.The mixture was cooled, filtered, concentrated and diluted with EtOAc The solution was extracted with 6N HCl The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride The organic extracts were combined, dried (MgSO 4) and concentrated. chromatography (silica gel; CHCl 3 / MeOH, 98: 2) to give an amber oil (274 mg, 50%). 1 H NMR (CDCl 3, 300 MHz) d 1.25 (t, J = 7.5 Hz, 3 H), 1.75- 1.92 (m, 6H), 2.15-2.25 (m, 2H), 2.60-2.69 (m, 4H), 3.13-3.20 (m, 2H), 5.98 (s, 1H); MS (CI / NH3) m / z : 207 (M + H) +. 13c. 7a- (3-ethyl-5-oxazole P-hexahydro-1H-pyrrolizine hydrochloride salt) 7a- (3-ethyl-5-isoxazolyl) -hexahydro-1H-pyrrolizine (265 mg, 1. 30 mmol, from step 13b) in Et 2 O, and Et 2 O saturated with HCl (g) was added. The solvent was removed and the precipitate was recrystallized from methanol / ethanol to give the title compound as a white solid: mp 139-140 ° C; 1 H NMR (D 2 O, 300 MHz) d 1.23 (t, J = 7.5 Hz, 3 H), 2.17-2.40 (m, 6 H), 2.58-2.75 (m, 4 H), 3.29-3.38 (m, 2 H), 3.69- 3.77 (m, 2H), 6.64 (s, 1H), MS (CI / NH3) m / z: 207 (M + H) +; Anal. Caled for C? 2H18N2O »HCl: C, 59.38; H, 7.89; N, 11.54. Found: C, 59.44; H, 7.94; N, 11.48.

EXAMPLE 14 7a- (3-Propyl-5-oxazole-OH-hexahydro-1H-pyrrolizine-14a-7a- (3-propyl-5-isoxazolyl) -hexahydro-1H-pyrrolizine hydrochloride salt) Nitrobutane (0.705 ml, 6.66 mmol) and phenylisocyanate (1.50 ml, 13.3 mmol) in benzene (13.5 ml) were added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (450 mg, 3.33 mmol, from step 13a). At room temperature for 1 hour and reflux for 5 hours, the mixture was cooled, filtered, concentrated and diluted with EtOAc, the solution was extracted with 6N HCl, the aqueous phase was made basic with 15% NaOH and extracted with sodium chloride. The organic extracts were combined, dried (MgSO4) and concentrated, the residue was subjected to chromatography (silica gel, CHCl3 / MeOH, 98: 2) to give an amber oil (392 mg, 53%). CDCI3, 300 MHz) d 0.97 (t, J = 7.5 Hz, 3H), 1.61-1.92 (m, 8H), 2.15-2.26 (m, 2H), 2.55-2.69 (m, 4H), 3.13-3.20 (m , 2H), 5.96 (s, 1H), MS (CI / NH3) m / z: 221 (M + H) +. 14b. 7a- (3-Propyl-5-isoxazolyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (3-propyl-5-isoxazolyl) -hexahydro-1H-pyrrolizine (265 mg, 1.30 mmol, from step 14a) was dissolved ) in Et2O, and Et2O saturated with HCl (g) was added. The solvent was removed and the precipitate was triturated with Et 2 O and dried to give the title compound as a free flowing white powder, mp 97-98 ° C. MS (NH3 / CI) m / z: 207 (M + H) +; 1 H NMR (D 2 O, 300 MHz) d 0.92 (t, J = 7.5 Hz, 3 H), 1.63-1.75 (m, 2 H), 2.20-2.40 (m, 6 H), 2.59-2.71 (m, 4 H), 3.30- 3.38 (m, 2H), 3.70-3.78 (m, 2H), 6.65 (s, 1H); MS (CI / NH3) m / z: 221 (M + H) +. Anal. Caled for C1 3H20N2O »HCl: C, 59.38; H, 7.89; N, 1 1 .54. Found: C, 59.44; H, 7.94; N, 1 1 .48.

Example 1 5 Hydrochloride salt of 7a- (3-benzyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine 15a. 2-phenylnitroetene Benzaldehyde (1.0 g, 94.2 mmol) and nitromethane (5.1 mL, 94.2 mmol) were dissolved in MeOH, the solution was cooled to -1 8 ° C, and NaOH (3.9 g, 98.9 mmol) in solution was added. aqueous (80 ml) while maintaining the temperature below -1 0 ° C. The mixture was stirred at 0 ° C for 2 hours, then stored at 5 ° C overnight. The solution was then emptied into stirred acid (200 ml of conc HCl / 300 ml of H2O). The precipitate was collected, washed and recrystallized from EtOH to give the title compound as light orange needles (5.15 g, 37%). 15b. 2-phenylnitroethane 2-phenylnitroethene (5.12 g, 34.3 mmol, from step 1 5a) was dissolved in CHCl3 / i-PrOH (41 0:85 ml) and SiO2 (51.4 g) was added. NaBH 4 (5.2 g, 1 37 mmol) was added in portions, and the mixture was stirred for 90 minutes at room temperature. HCl (0.5 N, 100 ml) was added and the mixture was stirred for 30 minutes. The layers were separated and the aqueous phase was extracted with methylene chloride. The organic layers were combined, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (levigando with ether 1: 30) to give the title compound as an oil (3.89 g, 75%). 15c. 7a- (3-benzyl-5-isoxazol-yl) -hexah id ro-1 H-pyrrolizine 2-phenylnitroethane (895 mg, 5.92 mmol, from step 15b) and phenylisocyanate (1.3 ml, 11.8 mmol) were dissolved in benzene (12 ml) and added to a flask containing 7a-ethynyl-hexahydro-1 H-pyrrolizine (400 mg, 2.96 mmol, from step 13a). The solution was stirred under reflux for 5 hours, cooled and stirred for 48 hours at room temperature. The mixture was filtered and extracted with 6 N HCl. The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 99: 1) to give an amber oil (415 mg, 52%). H NMR (CDCl 3, 300 MHz) d 1.71-1.92 (m, 6H), 2.11-2.23 (m, 2H), 2.58-2.66 (m, 2H), 3.08-3.15 (m, 2H), 3.95 (s, 2H) ), 5.87 (s, 1H), 7.20-7.34 (m, 5H); MS (CI / NH3) m / z: 269 (M + H) +. 15d. 7a- (3-Benzyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine hydrochloride salt 7a- (3-benzyl-5-isoxazolyl) -hexahydro-1H-pyrrolizine (407 mg, 1.52 mmol, from step 15c) in Et2O, and Et2O saturated with HCl (g) was added. The solvent was removed and the precipitate was recrystallized from MeOH and dried to give the title compound as white needles: mp 126-127 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.17-2.36 (m, 6 H), 2.53-2.62 (m, 2 H), 3.28-3.36 (m, 2 H), 3.67-3.75 (m, 2 H), 4.08 (s, 2 H) ), 6.57 (s, 1H), 7.34-7.45 (m, 5H); MS (CI / NH3) m / z: 269 (M + H) +; Anal. Caled for C17H20N2O «HCI: C, 66.99; H, 6.94; N, 9.19. Found: C, 66.99; H, 6.87; N, 9.09.

Example 16 Salt of 7a- (3-hydroxy-5-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride 16a. 3-benzyloxy-5-bromopyridine Sodium hydride (60% in mineral oil, 40.9 g, 1.0 mole) was cooled in DMF (800 ml) at 0 ° C, and benzyl alcohol was added slowly (105 ml, 1. 0 mol). After stirring for 1 hour at room temperature, 3, 5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture was allowed to stir for 16 hours. The saturated N HCl solution (500 ml) was added followed by water (400 ml), and the mixture was extracted with Et 2 O (5 x 300 ml). The combined Et2O extracts were washed with 50% brine (6x300 ml), dried (MgSO4), concentrated and the residue was crystallized from Et2O to give a white solid (161 g, 72%): 1 H NMR (CDCl 3, 300 MHz) d 5.1 0 (s, 2H), 7.50-7.35 (m, 6H), 8.37-8.27 (m, 2H); MS (CI / NH3) m / z: 264/266 (M + H) +. 16b. 7a- (3-benzyloxy-5-pyridi ni l) -hexahydro-1 H -pyrrolizine 3-Benzyloxy-5-bromopyridine (1.1 g, 4.47 mmol) was dissolved in Et 2 O and cooled to -78 ° C. A solution of t-BuLi 2.5 M (5.8 μl, 9.83 mmol) in pentane was added., and the reaction was stirred for 10 minutes. 1, 2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.4 g, 6.70 mmol) was added and the reaction mixture was allowed to stir for 3 hours at -78 ° C, then allowed to settle. warm to -20 ° C and stir for 2 hours. The cold bath was removed, 2N HCl was added, and the mixture was extracted with Et2O. The phases were separated and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 98: 2) to give a clear oil (286 mg, 22%): mp 45-49 ° C. 1 H NMR (CDCl 3, 300 MHz) d 1.58-1.69 (m, 2 H), 1.78-1.83 (m, 2 H), 1.89-2.03 (m, 4 H), 2.63-2.72 (m, 2 H), 3.05-3.18 (m , 2H), 5.12 (s, 2H), 7.31-7.54 (m, 6H), 8.17 (d, J = 3.0 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H); MS (CI / NH3) m / z: 295 (M + H) +. 16c. 7a- (3-h-idroxy-5-pyridinyl) -hexah id ro-1 H-pyrrolizine 7a- (3-benzyloxy-5-pyridinyl) -hexahydro-1H-pyrrolizine (260 mg, 0.88 mmol, from step 16b) was dissolved. ) in methanol (9 ml), 10% Pt / C (35 mg) was added and the mixture was stirred under 1 atm of H2 for 16 hours. The catalyst was removed, the filtrate was concentrated and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH) 0.5% NH4OH, 90: 10: 0 to 90: 10: 0.5) to give the title compound as a solid. white (114 mg, 63%). 1 H NMR (D 2 O, 300 MHz) d 2.07-2.40 (m, 6H), 2.49-2.58 (m, 2H), 3.26-3.34 (m, 2H), 3.71-3.80 (m, 2H), 7.00 (dd, J = 2.4, 2.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H); MS (CI / NH3) m / z: 205 (M + H) +. 16d. 7a- (3-Hydroxy-5-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (3-hydroxy-5-pyridinyl) -hexahydro-1 H -pyrrolizine (150 mg, 0.56 mmol, step 16c) in methylene chloride, and Et2O saturated with HCl (g) was added. The solvent was removed, and the solid was dried to give the title compound as a white powder (114 mg, 91%): mp 175-180 ° C (dec); 1 H NMR (D 2 O, 300 MHz) d 2.11-2.63 (m, 8 H), 3.35-3.44 (m, 2 H), 3.80-3.89 (m, 2 H), 7.66 (dd, J = 2.4, 2.0 Hz, 1 H), 8.23 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H); MS (CI / NH3) m / z: 205 (M + H) +. Anal. Caled for C12H16N2O «HCI: C, 53.40; H, 6.65; N, 10.38. Found: C, 53.55; H, 6.62; N, 10.24.

Example 17 Salt of 7a- (5-bromo-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride 17a. 7a- (5-bromo-3-pyrid i ni l) -hexahydro-1 H -pyrrolizine 3,5-Dibromopyridine (500 mg, 2.11 mmol, Aldrich) was dissolved in Et 2 O and cooled to -95 ° C. A solution of 2.5 M t-BuLi (1.7 M in pentane, 2.7 ml, 4.64 mmol) in pentane was added dropwise. 1, 2,3,5,6,7-hexahydropyrrolizinium perchlorate (663 mg, 3.2 mmol) was added and the reaction mixture was allowed to stir and warm to -10 ° C and stir for 2 hours. The cold bath was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 98: 2) to give a clear oil (160 mg, 28%): 1H NMR ( CDCI3, 300 MHz) d 1.57-1.71 (m, 2H), 1.79-2.04 (m, 6H), 2.62-2.73 (m, 2H), 3.11-3.20 (m, 2H), 8.04 (dd, J = 2.0, 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H); MS (Ci / NH3) m / z: 267/269 (M + H) +. 17b. 7a- (5-bromo-3-pyridyl-hexahydro-1H-pyrrolizine hydrochloride salt) 7a- (5-bromo-3-pyridinyl) -hexahydro-1H-pyrrolizine (107 mg, 0. 52 mmol, from step 16c) in methylene chloride, and Et2O saturated with HCl (g) was added. The solvent was removed and the solid was crystallized from MeOH / Et2O and dried to give the title compound as an off-white powder (118 mg). mp 192-194 ° C. 1 H NMR (D 2 O, 300 MHz) d 2.13-2.51 (m, 6H), 2.57-2.66 (m, 2H), 3.36-3.44 (m, 2H), 3.81-3.89 (m, 2H), 8.22 (s, 1H ), 8.65 (s, 1H), 8.72 (s, 1H); MS (CI / NH3) m / z: 267/269 (M + H) +. Anal. Caled for C12H15BrN2 «HCI: c, 47.47; H, 5.31; N, 99.23. Found: C, 47.40; H, 5.22; N, 8.98.

EXAMPLE 18 Salt of 7a- (6-fluoro-5-methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride 18. 2-fluoro-3-methyl-5-nitropyridine 2-Chloro-3-methyl-5-nitropyridine (15 g, 86.9 mmol; Maybridge Chemical Co.), KF (12 g, 258 mmol) and tetraphenylphosphonium bromide (20 g, 47.7 mmol; Aldrich) in 200 ml of acetonitrile and heated at reflux for 4 days. The mixture was diluted with Et2O (500 mL) and filtered, and the filtrate was concentrated. The residue was triturated with hot hexane (4 x 200 ml), and the hexane solutions were combined and concentrated to give the title compound as a solid (8.4 g, 60%); 1 H NMR (DMSO-d 6, 300 MHz) d 2.42 (s, 3 H), 8.43 (m, 1 H), 8.95 (dd, J = 1.6 Hz, 1 H); MS (CI / NH3) m / z: 57 (M + H) +. 1 8b. 5-amino-2-fluoro-3-methyl pyridine. 2-Fluoro-3-methyl-5-nitropyridine (8.2 g, mmol) was combined with 5% Pd / C (100 mg) in EtOH (100 ml) under one atmosphere. of H2 for 16 hours. The mixture was filtered and concentrated, and the crude product was subjected to chromatography (silica gel; CHCl3 / MeOH 99: 1 to 96.4) to give a solid (5.2 g, 78%): 1 H NMR (DMSO-d6, 300 M Hz) d 2.1 0 (s, 3H), 5.1 1 (brs, 2H), 6.95 (dd, J = 8.14 Hz, 1 H), 7.26 (t, J = 2.72 Hz, 1 H); MS (CI / NH3) m / z: 127 (M + H) +, 144 (M + NH4) +. 18c. 2-Fluoro-5-iodo-3-methylpyridine 5-Amino-2-fluoro-3-methylpyridine (397 mg, 3.1 mmol) in DME (1.7 mL) was added dropwise to a solution of diethyl etherate of Boron trifluoride (5.8 μl, 4.6 mmol) in DME (6 ml) at -1 7 ° C. After stirring for 1 5 min, neat t-butyl nitrite (442 μl, 3.7 mmol) was carefully added to the reaction mixture, while maintaining the temperature below -5 ° C. After complete addition, the temperature was allowed to gradually rise to 5 ° C over 1 h. After re-cooling to -1 7 ° C, pentane was added and then decanted. The light orange solid was triturated with pentane (2X) and Et2O (2X) and then the solvent was removed via positive N2 pressure to give a light orange solid. The curd diazonium tetrafluoroborate salt was dissolved in acetonitrile (6 ml) and Kl (570 mg, 3.4 mmol) was added at -10 ° C. The reaction was allowed to warm gradually to room temperature and was stirred overnight. A solution of 10% sodium thiosulfate was carefully added to the reaction mixture, which was then poured onto Et2O and the phases were separated. The organic phase was dried (MgSO4), concentrated and the residue was subjected to chromatography (silica gel; EtOAc / hexane, 1:50) to give a white solid (500 mg, 68%): 1H NMR (DMSO-de , 300 MHz) d 2.21 (s, 3H), 8.21 (m, 1H), 8.27 (m, 1H). 18d. 7a- (6-fluoro-5-methyl-3-pyridinyl ') -hexahydro-1 H -pyrrolizine 2-Fluoro-5-iodo-3-methylpyridine (200 mg, 0.84 mmol) was dissolved in Et 2 O and cooled at -95 ° C. A solution of 2.5 M t-BuLi (1.7 M in pentane, 1.1 ml, 1.80 mmol) in pentane was added dropwise. 1, 2,3,5,6,7-hexahydropyrrolizinium perchlorate (265 mg, 1.26 mmol) was added, and the reaction mixture was allowed to warm to -10 ° C with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 99: 1) to give the title compound as an oil (123 mg, 67%). . 1 H NMR (CDCl 3, 300 MHz) d 1.55-1.71 (m, 2 H), 1.78-2.04 (m, 6 H), 2.26 (s, 3 H), 2.64-2.72 (m, 2 H), 3.11-3.18 (m, 2 H) ), 7.70 (m, 1H), 8.09 (m, 1H); MS (CI / NH3) m / z: 221 (M + H) +. 18e. 7a- (6-Fluoro-5-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride salt 7a- (6-fluoro-5-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine was dissolved > (15 mg, 0.52 mmol, from step 18d) in Et 2 O, and Et 2 O saturated with HCl (g) was added. The solvent was removed, and the solid crystallized from MeOH / Et 2 O and dried to give the title compound (white needles, 92 mg, 60%): mp 170-171 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.12-2.47 (m, 9H), 2. 56-2.66 (m, 2H), 3.32-3.41 (m, 2H), 3.77-3.86 (m, 2H), 7.94 (m, 1 H), 8.14 (m, 1 H); MS (CI / NH3) m / z: 221 (M + H) +; MS (CI / NH3): m / z 221 (M + H +). Anal. Caled for C13H17FN2 »HCI: C, 60.82; H, 7.07; N, 1 0.91. Found: C, 60.83; H, 6.80; N, 1 0.63.

Example 1 9 Hydrochloride salt of 7a- (6-chloro-5-methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine 1 9a. 5-am i non-2-chloro-3-methyl pyridine 2-Chloro-3-methyl-5-nitropyridine (15 g, 86.9 mmol, from Maybridge Chemical Co.) was dissolved in a solution of H 2 O / AcOH (5%). : 1, 60 ml). Iron powder was added to the reaction mixture while maintaining the temperature below 40 ° C, and the mixture was stirred for 5 hours. The mixture was filtered through celite and the aqueous filtrate was extracted with EtOAc (4X). The filter cake was washed with EtOAc, and the EtOAc solutions were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 / MeOH, 98: 2) to give an orange solid (2.3 g, 89%): 1 H NMR (CD3OD, 300 MHz) d 2.25 (s, 3 H), 7.01 (d, J = 2.0 Hz, 1 H), 7.58 (d, J = 2.0 Hz, 1 H); MS (CI / NH3) m / z: 243/245 (M + H) +. 1 9b. 2-chloro-5-iodo-3-methyl pyridine 5-amino-2-chloro-3-methylpyridine (2.3 g) was added in the form of drops., 16.3 mmol) in DME (9.0 mL) was added to a solution of boron trifluoride diethyl etherate (3.0 mL, 24.4 mmol) in DME (30.5 mL) at -1 7 ° C. After stirring for 1 5 min, t-butyl nitrite (442 μL, 3.7 mmol) in DME (30.5 mL) was carefully added to the reaction mixture while maintaining the temperature below -5 ° C. After complete addition, the temperature was allowed to gradually warm to 5 ° C over 1 h. The mixture was re-cooled to -1 7 ° C, pentane was added and then decanted. The solid was triturated with pentane (3X) and Et2O (3X) and then the solvent was removed via positive N2 pressure. The crude diazonium tetrafluoroborate salt was dissolved in acetonitrile (15 ml) and Kl (3.0 g, 7.9 mmol) was added at -1 0 ° C. The reaction was allowed to warm gradually to room temperature and stir overnight. A solution of 10% sodium thiosulfate) was carefully added to the reaction mixture, which was then poured over Et2O and the phases were separated. The organic phase was dried (MgSO 4), concentrated and the residue was subjected to chromatography (silica gel; EtOAc / hexane, 1:50) to give a white solid (3.42 g, 83%): 1 H NMR (CD3OD, 300 MHz) d 2.34 (s, 3 H), 8.09 (d, J = 2.2 Hz, 1 H) , 8.42 (d, J = 2.2 Hz, 1 H). 19c. 7a- (6-Cl or ro-5-methyl-3-pyridinyl) -hexah id ro-1 H-pyrrolizine 2-Chloro-5-iodo-3-methylpyridine (1.0 g, 3.94 mmol) was dissolved in Et 2 O and it was cooled to -95 ° C. A solution of 2.5 M t-BuLi (1.7 M in pentane, 5.1 ml, 7.67 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (1.2 g, 5.92 mmol) was added and the reaction mixture was allowed to warm to -10 ° C with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 99: 1) to give the title compound (694 mg, 74%): -33 ° C; 1 H NMR (CDCl 3, 300 MHz) d 1.56-1.70 (m, 2 H), 1.78-2.05 (m, 6 H), 2.36 (s, 3 H), 2.64-2.72 (m, 2 H), 3.11-3.18 (m, 2 H) ), 7.67 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H); MS (CI / NH3) m / z: 237/239 (M + H) +. 19d. 7a- (6-Chloro-5-methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (6-chloro-5-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine was dissolved ( 245 mg, 1.03 mmol) in Et 2 O, and Et 2 O saturated with HCl (g) was added. The solvent was removed and the solid was recrystallized from MeOH / Et2O and dried to give the title compound as white plates: mp 179-18 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.14-2.48 (m, 9H), 2.56-2.65 (m, 2H), 3.34-3.42 (m, 2H), 3.79-3.87 (m, 2H), 7.89 (d, J = 3.0 Hz, 1H), 8.33 (d, J = 3.0 Hz, 1H); MS (CI / NH3) m / z: 237/239 (M + H) +; MS (CI / NH3): m / z 237 (M + H +). Anal.

Caled for C1 3H17CIN2 »HCl: C, 55.67; H, 6.54; N, 9.99. Found: C, 55.90; H, 6.57; N, 9.76.

EXAMPLE 20 7α- (6-Methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine hydrochloride salt a. 5-amino-2-methylpyridine. 2-Methyl-5-nitropyridine (1.4 g, 10 mmol) and 1.0% Pd / C (200 mg) in MeOH (40 ml) were combined and allowed to stir under a H2 atmosphere for 1 8 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 95: 5) to give the title compound (845 mg, 77%): H NMR (CD3OD, 300 MHz) d 2.35 (s, 3H), 6.97 -7.06 (m, 2H), 7.85 (d, J = 2.5 Hz, 1 H). 20b. 5-iodo-2-methylpyridine 5-Amino-2-methylpyridine (825 mg, 7.6 mmol) in DME (4.0 ml) was added dropwise to a solution of boron trifluoride diethyl etherate (1.4 ml, 1 ml). 1.4 mmol) in DME (14.5 ml) at -17 ° C. After stirring for 1 5 min, t-butyl nitrite (1.1 ml, 9.2 mmol) in DME (14.5 ml) was carefully added to the reaction mixture while maintaining the temperature below -5 ° C. . After complete addition, the temperature was allowed to gradually rise to 5 ° C over 1 h. After re-refluxing at -1 7 ° C, pentane was added and then decanted. The solid was triturated with pentane (2X) and Et2O (2X) and then the solvent was removed via positive N2 pressure. The crude diazonium tetrafluoroborate salt was dissolved in acetonitrile (15 ml) and Kl (1.4 g, 8.4 mmol) was added at -10 ° C. The reaction was allowed to warm gradually to room temperature and stir overnight. A solution of 10% sodium thiosulfate was carefully added to the reaction mixture, which was then poured onto Et2O and the phases were separated. The organic phase was dried (MgSO4), concentrated and the residue was subjected to chromatography (silica gel; EtOAc / hexane, 1: 1 5) to give a pale white solid (31 5 mg, 83%): 1 H NMR (CDCl 3, 300 MHz) d 250 (s, 3 H), 6.97 (d, J = 8.1 Hz, 1 H), 7.86 (d, J = 8.1, 2.0 Hz, 1 H), 8.70 (d, J = 2.0 Hz , 1 HOUR); MS (CI / N H3) m / z: 220 (M + H) +. 20c. 7a- (6-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine 5-iodo-2-methylpyridine (345 mg, 1.39 mmol) was dissolved in Et 2 O and cooled to -95 ° C. A solution of 2.5 M t-BuLi (1.7 M in pentane, 1.8 ml, 3.06 mmol) in pentane was added dropwise. 1, 2,3,5,6,7-hexahydropyrrolizinium perchlorate (435 mg, 2.1 mmol) was added and the reaction mixture was allowed to warm to -1 0 ° C with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 1% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl 3 / MeOH, 95: 5) to give the title compound as an oil (126 mg, 45%): 1 H NMR (CDCl 3, 300 MHz) d 1.57-1.71 (m, 2H), 1. 77-2.05 (m, 6H), 2.52 (s, 3H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H), 7.71 (dd, J = 8.1, 2.6 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H); MS (CI / NH3) m / z: 203 (M + H) +. 20d. 7a- (6-Methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine dihydrochloride salt 7a- (6-Methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine (115 mg, 0.57 mmol) was dissolved in Et2O, and Et2O saturated with HCl (g) was added. The solvent was removed, and the solid was crystallized from MeOH / Et2O and dried to give the title compound as a free flowing white powder: mp 205-208 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.14-2.49 (m, 6H), 2.57-2.66 (m, 5H), 3.34-3.42 (m, 2H), 3.78-3.87 (m, 2H), 7.56 (d, J = 8.1 Hz, 1H), 8.05 (dd, J = 8.1, 2.7 Hz, 1H), 8.61 (d, J = 2.7 Hz, 1H); MS (CI / NH3) m / z: 203 (M + H) +; MS (CI / NH3): m / z 203 (M + H +). Anal. Caled for C13H18N2-2 HCμ? .8 H2O: C, 53.91; H, 7.52; N, 9.67. Found: C, 53.80; H, 7.46; N, 9.68.

Example 21 Salt of 7a- (5-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine hydrochloride 21a.7a- (5-methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine 7a- (6-chloro-5-methyl-3-pipdinyl) -hexahydro-1H-pyrrolizine (274 mg, 1.16 mmol, of Example 19c) and LAH (1.0 M in THF, 1.2 ml, 1.16 mmol) in THF (4.5 ml) and the mixture was stirred at room temperature for 4 hours. An additional amount of LAH (1.0 M in THF, 1.2 mL, 1.16 mmol) was added and the mixture was stirred overnight. An additional amount of LAH (2 equivalents) was added, and the reaction was stirred at room temperature for 24 hours and at 80 ° C for 5 hours. The reaction was quenched with 10% K2CO3 solution), and the resulting paste was filtered. The filtrate was diluted with EtOAc and 15% NaOH, and the phases were separated. The aqueous phase was extracted with methylene chloride, and all the organic solutions were combined, dried and concentrated. The residue was subjected to chromatography (silica gel; CHCl 3 / MeOH, 98: 2) to give the title compound as an oil (116 mg, 49%): 1 H NMR (CDCl 3, 300 MHz) d 1.57-1.71 (m , 2H), 1.77-2.06 (m, 6H), 2.32 (s, 3H), 2.66-2.74 (m, 2H), 3.12-3.19 (m, 2H), 7.63 (s, 1H), 8.24 (s, 1H) ), 8.50 (s, 1H); MS (CI / NH3) m / z: 203 (M + H) +. 21b. Salt of 7a- (5-methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride 7a- (5-Methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine was dissolved (109 mg, 0. 54 mmol) in Et 2 O, and Et 2 O saturated with HCl (g) was added. The solvent was removed and the solid was triturated with Et 2 O and dried to give the title compound as a white powder (112 mg, 87%); mp 153-154 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.12-2.49 (m, 9H), 2.57-2.66 (m, 2H), 3.34-3.43 (m, 2H), 3.79-3.87 (m, 2H), 7.90 (s, 1H ), 8.46 (s, 1H), 8.52 (s, 1H); MS (CI / NH3) m / z: 203 (M + H) +; MS (CI / NH3): m / z 203 (M + H +), 220 (M + NH4 +). Anal. Caled for C13H18N2 »1.4 HCl: C, 61.63; H, 7.72; N, 11.06. Found: C, 61.82; H, 7.89; N, 11.00 EXAMPLE 22 Salt of 7a- (5-bromo-6-fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine 22a.7a- (5-bromo-6-fluoro-3-pyridinyl) -hexahydro-1 H- hydrochloride pyrrolizine n-BuLi (2.5 M in hexanes, 0.252 ml, 0.63 mmol) was added to di-isopropylamine (0.082 ml, 0.63 mmol) in THF and stirred at room temperature for 10 minutes, then cooled to -78 ° C. 7a- (6-Fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine (123 mg, 0.60 mmol, from Example 12d) and 1,2-dibromo-1,1,1,2-tetrafluoroethane (0.215 ml, 1.80 mmol). The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with HCi 2 N, and the mixture was washed with Et 2 O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 99: 1) to give the title compound as an oil (64 mg, 37%). 1 H NMR (CDCl 3, 300 MHz) d 1.59-1.71 (m, 2H), 1.79-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 8.14 (dd, J = 8.8, 2.2 Hz, 1H), 8.19 (dd, J = 2.2, 1.2 Hz, 1H); MS (CI / NH3) m / z: 285/287 (M + H) +. 22b. 7a- (5-Bromo-6-fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (5-bromo-6-fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine was dissolved in Et2O , and Et2O saturated with HCl (g) was added. The solvent was removed, and the solid was triturated with Et 2 O and dried to give the title compound as a white powder (59 mg, 87%): mp 213-215 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.15-2.49 (m, 6H), 2.56-2.65 (m, 2H), 3.34-3.42 (m, 2H), 3.78-3.87 (m, 2H), 8.31 (dd, J = 2.4, 1.0 Hz, 1H), 8.38 (dd, J = 7.8, 2.4 Hz, 1H); MS (CI / NH3) m / z: 285/287 (M + H) +; MS (CI / NH3): m / z 285/287 (M + H +). Anal. Caled for C12H14BrFN2 «HCI: C, 44.81; H, 4.70; N, 8.71. Found: C, 45.04; H, 4.25; N, 8.48.

EXAMPLE 23 Salt of 7a- (5-chloro-6-fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride 7a- (5-Chloro-6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine n-BuLi (2.5 M in hexanes, 0.232 mL, 0.58 mmol) was added to di-isopropylamine (0.077 mL, 0.58 mmol) in THF and stirred at room temperature for 15 minutes, then cooled to -78 ° C. 7a- (6-Fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine (115 mg, 0.56 mmol, from Example 12d) and hexachloroethane (400 mg, 1.7 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was subjected to chromatography (silica gel; CHCl 3 / MeOH, 99: 1) to give the title compound as an oil (45 mg, 34%): 1 H NMR (CDCl 3, 300 MHz) d 1.60-1.72 (m , 2H), 1.80-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.14-3.27 (m, 2H), 8.00 (dd, J = 8.8, 2.0 Hz, 1H), 8.15 (dd, J = 2.0, 1.0 Hz, 1H); MS (CI / NH3) m / z: 241 (M + H) \ 7a- (5-Chloro-6-fluoro-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt 7a- (5-chloro) -6-fluoro-3-pyridinyl) -hexahydro-1 H-pyrrolizine in Et 2 O, and Et 2 O saturated with HCl (g) was added. The solvent was removed and the solid was triturated with Et 2 O and dried to give the title compound as a white powder (35 mg, 74%): mp 181-183 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.15-2.50 (m, 6H), 2.56-2.65 (m, 2H), 3.34-3.42 (m, 2H), 3.79-3.87 (m, 2H), 8.24-8.29 (m 2H); MS (CI / NH3) m / z: 241 (M + H) +; MS (CI / NH3): m / z 241/243 (M + H) +. Anal. Caled for C12H14CIFN2 »HCl: C, 52.00; H, 5.45; N, 10.11. Found: C, 51.81; H, 5.62; N, 9.84.

Example 24 Salt of 7a- (4-methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine hydrochloride 24a. 3-amino-4-methylpyridine 2-Chloro-4-methyl-3-nitropyridine (10.2 g, 59.1 mmol, Aldrich) and 10% Pd / C (1.5 g) in MeOH (250 mL) were combined under 4 atmospheres of H2 for 20 hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to chromatography (silica gel; CHCl 3 / MeOH, 95: 5) to give a white solid (6.1 g, 96%): 1 H NMR (CDCl 3, 300 MHz) d 2.17 (s, 3 H), 6.96 ( d, J = 4.8 Hz, 1H), 7.94 (d, J = 4.8 Hz, 1H), 8.02 (s, 1H); MS (CI / NH3) m / z: 109 (M + H) +. 24b. 3-Iodo-4-methylpyridine. 3-Amino-4-methylpyridine (2.0 g, 8.5 mmol) in DME (9.0 ml) was added dropwise to a solution of boron trifluoride diethyl etherate (3.4 ml, 27.7 mmol). ) in DME (35 ml) at -1 7 ° C. After stirring for 1 5 min, t-butyl nitrite (2.6 ml, 22.2 mmol) in DME (37.0 ml) was carefully added to the reaction mixture while maintaining the temperature below -5 ° C. After complete addition, the temperature was allowed to gradually rise to 5 ° C over 1 h. After re-cooling to -1 7 ° C, pentane was added and decanted. The solid was triturated with pentane (2X) and Et2O (2X), then the solvent was removed via positive N2 pressure to give a white solid. The crude diazonium tetrafluoroborate salt was dissolved in acetonitrile (70 ml) and Kl (3.4 g, 20.3 mmol) was added at -10 ° C. The reaction was allowed to warm gradually to room temperature and stirred overnight. A solution of 10% sodium thiosulfate) was carefully added to the reaction mixture, which was then poured onto Et2O and the phases were separated. The organic phase was dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; EtOAc / hexane, 1: 1 5) to give an amber oil (2.2 mg, 54%): 1 H NMR (CDCl 3 , 300 MHz) d 2.42 (s, 3H), 7.19 (d, J = 4.8 Hz, 1 H), 8.38 (d, J = 4.8 Hz, 1 H), 8.86 (s, 1 H). 24c. 7a- (4-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine 3-iodo-4-methylpyridine (330 mg, 3.10 mmol) was dissolved in Et 2 O and cooled to -95 ° C. A solution of t-BuLi (1.7 M in pentane, 4.0 mL, 6.80 mmol) in pentane was added in the form of drops. 1, 2,3,5,6,7-hexahydropyrrolizinium perchlorate (960 mg, 4.60 mmol) was added and the reaction mixture was allowed to warm to -10 ° C with stirring for 2 hours. The cold bath was removed, 2N HCl was added and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2X). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl 3 / MeOH, 99: 1) to give the title compound as an oil (41 mg, 6%): 1 H NMR (CDCl 3, 300 MHz) d 1.54-1.69 (m, 2H), 1.77-1.89 (m, 2H ), 1.93-2.11 (m, 4H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 3.08-3.15 (m, 2H), 7.02 (d, J = 4.8 Hz, 1H), 8.32 ( d, J = 4.8 Hz, 1H), 9.06 (s, 1H); MS (CI / NH3) m / z: 203 (M + H) +. 24d. 7a- (4-Methyl-3-pyridinyl) -hexahydro-1H-pyrrolizine dihydrochloride salt 7a- (4-Methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine (37 mg, 0.18 mmol) was dissolved in Et2O , and Et2O saturated with HCl (g) was added. The solvent was removed and the solid was triturated with Et20 and dried to give the title compound as a white solid (26.2 mg, 61%): mp 244-247 ° C; 1 H NMR (D 2 O, 300 MHz) d 2.01-2.16 (m, 2 H), 2.27-2.52 (m, 4 H), 2.65 (s, 3 H), 2.65-2.78 (m, 2 H), 3.45-3.54 (m, 2 H) ), 3.87-3.96 (m, 2H), 7.75 (d, J = 5.6 Hz, 1H), 8.49 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H); MS (CI / NH3) m / z: 203 (M + H) +. Anal. Caled for C 13 H 18 N 2 »2 HCl: C, 56.73; H, 7.32; N, 10.18. Found: C, 56.94; H, 7.24; N, 9.99.

Example 25 7a- (5-phenyl-3-pyridyl-hexahydro-1H-pyrrolizine-25a, 3-bromo-5-phenylpyridine hydrochloride salt) 3,5-Dibromopyridine portions (1.0 g, 4.22 mmol) were combined phenylboronic acid (570 mg, 4.6 mmol) and palladium tetra (triphenylphosphine) (60 mg) in toluene (20 ml) with aqueous sodium carbonate solution (2M, 3.0 ml) and heated to reflux for 6 hours. it was cooled to room temperature, and the solvent was removed The residue was purified by chromatography (silica gel, levigating with ether: hexane 1: 1 0 to give the title compound: MS (CI / NH3) m / z: 234 / 236 (M + H) +, 251/153 (M + NH 4) +; 1 H NMR (CDCl 3, 300 MHz) d 7.21 -8.02 (dd, J = 2.0, 2.0 Hz), 8.65 (d, J = 2.0 Hz), 8.75 (d, J = 2.0 Hz). 25b. 7a- (5-phenyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine 3-Bromo-3-phenylpyridine (200 mg, 0.85 mmol) was dissolved in Et 2 O and cooled to -30 ° C. A solution of t-BuLi 2.5 M (1.1 mL, 1.90 mmol) in pentane was added, and the reaction was stirred for 10 minutes. Add 1, 2,3, 5,6,7-hexahydropyrrolizinium perchlorate (230 mg, 1.30 mmol) and allow the reaction mixture to stir for 30 minutes at -30 ° C, then allow Warm to room temperature and stir for 1 hour. Then 2N HCl was added, the phases were separated and the aqueous phase was basified with 1% NaOH and extracted with CH2Cl2 (2X). The organic phases were combined, dried (MgSO) and concentrated, and the residue was subjected to chromatography (silica gel; CHCl3 / MeOH, 95: 5) to give a clear oil (32.5 mg). 25c. 7a- (5-phenyl-3-pyridinyl) -hexahydro-1H-pyrrolizine hydrochloride salt The compound 7a- (5-phenyl-3-pyridinyl) -hexahydro-1H-pyrrolizine from step 25b was dissolved in ether (5H-pyrrolizine hydrochloride). ml) and Et 2 O saturated with HCl (g). The solvent was removed, and the solid was dried to give the title compound as yellow needles (13.5 mg): mp 217-220 ° C (dea); 1 H NMR (D 2 O, 300 MHz) d 2.17-2.47 (m, 4 H), 2.57-2.73 (m, 4 H), 3.41-3.50 (m, 2 H), 3.87-3.97 (m, 2 H), 7.60-7.68 (m , 3H), 7.75-7.81 (m, 2H), 8.60 (dd, J = 2.0, 2.0 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 2.0 Hz, 1H); MS (CI / NH3) m / z: 265 (M + H) +. Anal. Caled for C18H20N2.2.0 HCU0.1 H2O: C, 63.76; H, 6.60; H, 8.26. Found: C, 63.62; H, 6.48; N, 8.02.

Claims (8)

REIVI NDICATIONS

1 . A compound that has the formula or a pharmaceutically acceptable salt or prodrug thereof, wherein the group designated A is selected from the group consisting of: (a) wherein R1 is C? -C3-alkyl, as defined below, -CH2-aryl, -CH2-substituted aryl, or -CH2-CH2-substituted aryl, wherein aryl and substituted-aryl are as define later; (b) wherein R1 is as defined above, and R2 is H or dCa-alkyl; (c) wherein R3 is substituted at the 2, 4 or 6 position and is selected from the group consisting of H, d-Cs-alkyl, Br, Cl or F; and R4 is substituted in one of the remaining positions not occupied by R3 and is independently selected from the group consisting of H, C? -C3-alkyl, Br, Cl, F or d-C3-alkyl-0-; or when substituted at position 5, R4 may be further selected from the group consisting of (1) O-R6, wherein R6 is selected from the group consisting of; (a) hydrogen, (b) alkyl of one to six carbon atoms, (c) alkenyl of one to six carbon atoms, (d) alkynyl of one to six carbon atoms, (e) haloalkyl of one to six atoms carbon, (f) hydroxyalkyl of two to six carbon atoms, (h) amino, (i) alkylamino of one to six carbon atoms, (j) dialkylamino, in which the two alkyl groups are independently from one to six carbon atoms, (k) phenyl, (I) naphthyl, (m) biphenyl, (n) furiio, (o) thienyl, (p) pyridinyl, (q) pyrazinyl, (r) pyridazinyl, (s) pyrimidinyl, t) pyrrolyl, (u) pyrazolyl, (v) imidazolyl, (w) indolyl, (x) thiazolyl, (and) oxazoyl, (z) isozasolyl, (aa) thiadiazolyl, (bb) oxadiazolyl, (ce) quinolinyl, ( dd) isoquinolinyl, (ee) aryl-Ci-Ce-alkyl, (ff) heteroaryl-d-Cß-alkyl t (gg) any of groups (i) to (ff) of R 6 above substituted with one or two selected substituents independently of the group consisting of at alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl, in which the alkoxy and alkyl portions are independently from one to six carbon atoms, alkoxyalkoxy, wherein the alkoxy moieties are independently from one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl and alkoxycarbonyl of two to six carbon atoms; (2) -S-R6, wherein R6 is as defined above; (3) -N (R6) (R7), wherein R6 is as defined above and R7 is selected from H or alkyl of 1 to 6 carbon atoms; (4) LR8, wherein L is absent or selected from the group consisting of (a) - (CH2) p-, where p is 1 to 6; (b) - (CH = CH) q-, where q is one or two; (c) -C (O) -; (d) -OC (O) -; (e) -N (R7) -C (O) -, wherein R7 is as defined above; (f) -CH2-CH2-C (O) -; (g) -CH2-O-C (O) -; -CH2-NH-C (O) -; or (h) -C = C-; and wherein -R8 is selected from the group consisting of: (a) hydrogen; (b) alkyl of one to six carbon atoms, (c) alkenyl of one to six carbon atoms, (d) alkynyl of one to six carbon atoms, (e) haloalkyl of one to six carbon atoms, (f) hydroxyalkyl of two to six carbon atoms, (g) alkoxy of one to six carbon atoms (h) amino, (i) alkylamino of one to six carbon atoms, (j) dialkylamino, in which the two alkyl groups are independently from one to six carbon atoms, (k) phenyl, (I) naphthyl, (m) biphenyl, (n) furyl, (o) thienyl, (p) pyridinyl, (q) pyrazinyl, (r) pyridazinyl, (s) pyrimidinyl, (t) pyrrolyl, (u) pyrazolyl, (v) imidazolyl, (w) indolyl, (x) thiazolyl, (y) oxazolyl, (z) isozasolyl, (aa) thiadiazolyl, (bb) oxadiazolyl, (ce) quinolinyl, (dd) -syquinolinyl, and (ee) any of groups (i) to (dd) of R 6 above substituted with one or two substituents independently selected from the group consisting of alkyl of one to six atoms of carbon, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl, in which the alkoxy and alkyl portions are independently from one to six carbon atoms, alkoxyalkoxy, in which the portions of alkoxy are independently from one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms; with the requirement that in groups of the type -O-R6, -S-R6, -N (R6) (R7) and L-R8, none of R6, -N (R6) (R7) or L-R8 can contain a nitrogen atom, which is conjugated with a double or triple ligature; (), where R3 is as defined above; (e) where R3 is as defined above; (f) where R3 is as defined above; Y (9) where R5 is H, C? -C3-alkyl, Cl or F.

2. A compound according to claim 1, wherein A is selected from options (a) and (c).

3. A compound according to claim 2, wherein A is selected from option (c).

4. A compound according to claim 1, which is 7a- (3-methyl-5-isoxazolyl) -hexahydro-1 H-pyrrolizine; 7a- (1 H-3-methyl-5-pyrazo I il) -hexahydro-1 H-pyrrolizine; 7a- (3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (3-quinolinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-chloro-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (2-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (2-chloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5,6-dichloro-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (5-pyrimidinyl) -hexahydro-1 H -pyrrolizine; 7a- (2,6-difluoro-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (2,6-dichloro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (3-ethyl-5-isoxazole i) -hexah id ro-1 H-pyrrolizine; 7a- (3-propyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine; 7a- (3-benzyl-5-isoxazolyl) -hexahydro-1 H -pyrrolizine; 7a- (5-hydroxy-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-benzyloxy-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-bromo-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-fluoro-5-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (6-chloro-5-methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (6-methyl-3-pyridinyl) -hexahydro-1 H-pyrrolizine; 7a- (5-methyl-3-pyridinium) -hexahydro-1 H -pyrrolizine; 7a- (5-bromo-6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-chloro-6-fluoro-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (4-methyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine; 7a- (5-phenyl-3-pyridinyl) -hexahydro-1 H -pyrrolizine.

5. A compound according to claim 1, wherein the compound has binding affinity in both a nicotinic alpha-4-beta-2 receptor subtype and a nicotinic alpha-7 receptor subtype.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

7. A method for selectively controlling synaptic transmission in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need of treatment thereof. A method for ligating a nicotinic alpha-7 receptor subtype, which comprises administering a compound of formula (I) to an in vitro or in vivo screen or to a patient in need or treatment thereof. SUMMARY 7a-substituted hexahydro-1H-pyrrolizine compounds having formula (I), wherein A is a defined heterocyclic moiety, pharmaceutical compositions of these compounds, and the use of said compositions to selectively control synaptic transmission in mammals. (