MXPA01007660A

MXPA01007660A - Diazabicyclic derivatives as nicotinic acetylcholine receptor ligands

Info

Publication number: MXPA01007660A
Application number: MXPA/A/2001/007660A
Authority: MX
Inventors: Michael J Dart; Michael D Meyer; William H Bunnelle; Daniela Barlocco Cristina; Jerome F Daanen; Keith B Ryther; Michael R Schrimpf; Kevin B Sippy; Richard B Toupence
Original assignee: Abbott Laboratories
Priority date: 1999-01-29
Filing date: 2001-07-27
Publication date: 2002-05-09

Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein:V is selected from the group consisting of a covalent bond and CH2;W is selected from the group consisting of a covalent bond, CH2 and CH2CH2;X is selected from the group consisting of a covalent bond and CH2;Y is selected from the group consisting of a covalent bond, CH2, and CH2CH2;Z is selected from the group consisting of CH2, CH2CH2, and CH2CH2CH2;L1 is selected from the group consisting of a covalent bond and (CH2)n;n is 1-5;R1 is selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l);R2 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, aminoalkyl, aminocarbonylalkyl, benzyloxycarbonyl, cyanoalkyl, dihydro-3-pyridinylcarbonyl, hydroxy, hydroxyalkyl, phenoxycarbonyl, and -NH2;are useful for controlling synaptic transmission in mammal.

Description

«- - - -« DIAZABICICLIC DERIVATIVES AS NICÓTICIC HANDS OF THE ACETI COLINA RECEPTOR FIELD OF THE INVENTION The present invention is directed to a series of N-substituted diazabicyclic compounds, methods for selectively controlling the release of the neurotransmitter in mammals using these compounds, and pharmaceutical compositions which contain these compounds. # BACKGROUND OF THE INVENTION The compounds that selectively control the transmission synaptic chemistry offer therapeutic utility for the treatment of disorders that are associated with malfunctions in synaptic transmission. This utility may originate from the control of chemical transmission either pre-synaptic or post-synaptic. The control of synaptic chemical transmission, in turn, is a direct result of a modulation of the excitation capacity of the synaptic membrane. The pre-synaptic control of the membrane excitation capacity results from the direct effect that an active compound has on the organelles and enzymes present in the nerve terminals to synthesize, store and release the neurotransmitter, as well as the process to activate re-consumption. The post-synaptic control of the membrane excitation capacity results from the influence that an active compound has on the cytoplasmic organelles that respond to the action of the neurotransmitter. An explanation of the processes involved in chemical synaptic transmission will help to more fully illustrate 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." In: Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 9th ed., JG Hardman, LE Limbírd, PB Molinoff, RW Ruddon, and A. Goodman Gilman, eds., Pergamon Press, New York, (1996), pp. 105-139). Typically, chemical synaptic transmission begins with a stimulus that depolarizes the transmembrane potential of the synaptic junction above the threshold that produces a total or no action potential in a nerve axon. The action potential is propagated to the nerve terminal, where the ion fluxes activate a mobilization process leading to the secretion of the neurotransmitter and to the "transmission" to the post-synaptic cell. Those cells that 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, smooth muscle cells, cardiac cells and glands. The effect of a neurotransmitter on an excitable cell may be to cause either an excitatory potential or post-synaptic inhibitor (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 are open in the post-synaptic membrane (ie, in the excitable cell). EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability for cations (notably Na + and K +), while IPSPs are the result of stabilization or hyperpolarization of membrane excitation capacity due to an increase in the permeability to mainly smaller ions (including K + and C1 +). For example, the neurotransmitter acetylcholine is excited in skeletal muscle joints by opening permeability channels for N + and K +. In other synapses, such as cardiac cells, acetylcholine can be inhibitory, mainly resulting 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. Thus, it is important to understand the differences between the 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 different kinds of second messenger systems. When the nicotinic acetylcholine receptor is activated, the response is a high flow of specific extracellular ions (eg, Na + .K + and Ca ++) through the neuronal membrane. In contrast, activation of the muscarinic acetylcholine receptor leads to changes in intracellular systems containing complex molecules such as G proteins and inositoi phosphates. Of this, the biological consequences of nicotinic acetylcholine receptor activation are different from those of muscarinic receptor activation. In an analogous form, the inhibition of nicotinic acetylcholine receptors results in other biological effects, which are distinct and different from those that originate from inhibition of the muscarinic receptor. As indicated above, the two main sites to which drug compounds that affect chemical synaptic transmission can be targeted are the presynaptic membrane and the post-synaptic membrane. The actions of drugs directed to the presynaptic site can be mediated through presynaptic receptors that respond to the neurotransmitter, where it has secreted the structure (that is, through a self-receptor), or through a presynaptic receptor that responds to another neurotransmitter (that is, a heteroreceptor). The actions of drugs directed to the post-synaptic membrane mimic 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 the excitatory capacity of the postsynaptic membrane are neuromuscular blocking agents, which interact with nicotinic acetylcholine compound channel receptors in skeletal muscle, for example, competitive (stabilizing) agents, as curare, or depolarization agents, such as succinylcholine. In the central nervous system, post-synaptic cells can have many neurotransmitters colliding with them. This makes it difficult to know the precise net equilibrium of the chemical synaptic transmission required to control a given cell. However, when designing compounds that selectively affect only one pre- or post-synaptic receptor, it is possible to modulate the net balance of all other inputs. Obviously, the more one understands about chemical synaptic transmission in central nervous system disorders, the easier it can be to design drugs to treat such disorders. Knowing how specific neurotransmitters act in the central nervous system can predict the disorders that can be treated with certain drugs active in the central nervous system. For example, ta dopamine is widely recognized as an important neurotransmitter in the central nervous systems and animals. Many aspects of dopamine pharmacology have been reviewed by Roth and Elsworth, "Biochemicaf Pharmacology of Midbrian Dopamine Neurons," I n: Psvchopharmacology: The Fourth Generatio n of Progress. F. E. Bloom and D. J. Kupfer, Eds. , Raven Press, NY, 1995, p. 227-243). Patients with Parkinson's disease have a primary loss of neurons containing dopamine from the nigrostriatal path, which results in a profound loss of motor control. It has been found that therapeutic strategies to replace dopamine deficiency with dopamine mimetics, as well as administering pharmacological agents to modify the release of dopamine and other neurotransmitters have a therapeutic benefit ("Parkinson's Disease", in: Psvchopharmacology: The Fourth Generation of Progress op.cit., page 1479-1484). New and selective neurotransmitter control agents are still being sought, with the hope that one or more will be useful in important disease states or behavioral models, but still poorly controlled. For example, dementia, as seen with Alzheimer's or Parkinson's disease, remains enormously untreatable. The symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as well as behavioral disorder, attention deficit disorder (ADD). The specific agents for the treatment of these disorders and other related ones are few in number or do not exist. A more complete discussion of the possible utility as active agents in the central nervous system of compounds coff activity as selective cholinergic ligands for neuronal nicotinic receptors (i.e., to control chemical synaptic transmission) can be found in US Patent 5,472,958 to Gunn et al. others, issued December 5, 1995, which is incorporated herein by reference. Existing acetylcholine agonists are therapeutically suboptimal for the treatment of the conditions discussed above. For example, such compounds have unfavorable pharmacokinetics (eg, arecoline and nicotine), poor potency and lack of selectivity (eg, nicotine), poor penetration into the central nervous system (eg, carbachol) or poor bioavailability ( for example, nicotine). In addition, other agents have many undesired central agonist actions, including hypothermia, hipolocomoción and tremor and peripheral lateral effects, miosis, lacrimation, defecation and tachycardia (Benowitz et al., In: Nicotine Psychopharmacology, S. Wonnacott, MAH Russell, & IP Stoierman, eds., Oxford University Press, Oxford, 1990, pp. 112-157, and M. Davidson and others, in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed .; Taylor &Francis: New York, 1998; pp. 333-336 Williams and others report the use of cholinergic channel modulators for the treatment of Parkinson's and Alzheimer's diseases M. Williams et al., "Beyond the Tobacco Debate: Dissecting Out the Therapeutic Potential of Nicotine ", Exp. Opin. invest. Drugs 5, p. 1035-1045 (1996). Salin-Pascual and others ^ report a short-term improvement in nonsmokers who suffer from depression by treatment with nicotine patches. R. J. Salin-Pascual et al., "Antidepressant Effect of Transdermal Nicotine Patches in Non-Smoking Patients with Major Depression", J. Clin. Psychiatry, v. 57 p. 387-389 (1996). Some diazabicyclo [2.2.1] heptane derivatives have been described for several purposes. For example, the diazabicyclo [2.2.1] heptenes N-alkylaryl substituted, N-heteroaromatics have been described in the European patent application No. 0 400 661 for the prevention of disorders resulting from anoxia of the brain and / or spinal cord; the N-alkylaryl diazabicyclo [2.2.1] heptane derivatives, N-heteroaromatics have been described in the European patent application 0 324 543 as antiarrhythmic agents; the derivatives of -alkylaryl diazabicyclo [2.2.1] heptane, N-heteroaromatics have been described in the European patent application No. 0 345 808 B1 for the treatment of depression; the aromatic diazabicyclo [2.2.1] heptane N-alkylamido derivatives, N-alkyl aromatics have been described in US Patent No. 5,382,485 for effective anti-ischemic protection for the central nervous system and cardiac tissue, the diazabicyclo derivatives [ 2.2.1] heptane di-N-acyheteroaromatics have been described in PCT publication No. WO 97/27961 for stimulating hematopoiesis and for the treatment of infectious viral, fungal and bacterial diseases. In addition, diazabicyclo [2.2.1] heptane N H or N-methyl-N-heteroaromatics derivatives for the treatment of central cholinergic malfunction have been described in the U.S. patent. A. No. 5,478, 939. The heteroaromatic compounds can be pyrazines, thiazoles, thiadiazoles, thiophene or halogen-substituted nitrobenzene, as described in the patent of E. U. A. No. 5,478, 939. Also, the substituted diazabicyclo [3.2.1] octane derivatives have been described for various uses. For example, derivatives of N H or N-alkyl, N-2-pyrimidyl diazabicyclo [3.2. 1] octane for sedatives have been described in the French publication 2 531 709; diazabicium derivatives [3.2. 1] octane N-acyl-acyheteroaromatics have been described in PCT publication No. WO 95/23152 for central analgesic activity, 3- [6-C1-pyridazin-3-yl] -diazabicyclo [3.2.1] octane, having anti-nociceptive effect, has been described in Drugs Development Research, 40: 251-258 (1997); and diazabicyclo [3.2.1] octane N H, N-halosubstituted, heteroaromatic derivatives, as analgesics, have been described in J. Med. Chem, 1998, 41, 674-681. However, there is a need for much more effective N-substituted diazabic compounds. Therefore, it is an object of this invention to provide novel N-substituted diazabicyclic compounds. Yet another object of this invention is to provide such compounds that selectively control neurotransmitter release.

COMPENDIUM OF THE INVENTION The present invention describes N-substitide diazabicylic compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions including these compounds. More particularly, the present invention is directed to compounds of the formula I: I, and their pharmaceutically acceptable salts, wherein: V is selected from the group consisting of a covalent bond and CH2; W is selected from the group consisting of a covalent bond, X is selected from the group consisting of a covalent bond and CH2; Y is selected from the group consisting of a covalent bond, CH2, and CH2CH2; Z is selected from the group consisting of CH2, CH2CH2, and L1 is selected from the group consisting of a covalent bond and (CH2) n; n is 1 -5; Rn is selected from the group consisting of: R 2 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, aminoalkyl, aminocarbonylalkyl, benzyloxycarbonyl, cyanoalkyl, dihydropyridin-3-ylcarbonyl, hydroxy, hydroxyalkyl, phenoxycarbonyl, and -NH 2; R 4 is selected from the group consisting of hydrogen, alkyl and halogen; R5 is selected from the group consisting of hydrogen, alkoxy, alkyl, halogen, nitro, and -NH2; Rβ is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl, -N R7SO2R8, -C (NR7) NR7R8, -CH2C (NR7) NR7R8, -C (NOR7) R8, -C (NCN) R7, -C (NN R7R8) R8, -S (O) 2OR7, and -S (O) 2R7; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; provided that the following compounds are excluded: 3- (6-chloro-3-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-chloro-2-pyrazinyl) -3,8-diazabicyclo [3.2.13octane; 8- (6-chloro-3-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane; and 8- (6-chloro-2-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane; and with the proviso that when V and X each is a covalent bond; W, Y, and Z are each CH2; and Li is a covalent bond, so Ri is different from: DETAILED DESCRIPTION OF THE INVENTION In the embodiment of the present invention, compounds of Formula II are described: H, and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and Li, R f and R2 are as defined in the formula Compounds representative of this embodiment include but are not limited to: (1S, 4S) -2- (6-chloro-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-methyl-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-methyl-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (4-chloro-1-phthalazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (4-Chloro-1-phthalazinyl) -5-methylene-2, 5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-methoxycarbonyl-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (3-pyridazinyl) -2I5-diazabicyclo [2.2.13heptane; (1S, 4S) -2- (5-pyrimidinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (3-quinolinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 3-methyl-5-isothiazolyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 6-amino-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 5- (benzyloxy) -3-pyridinyl] -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-hydroxy-3-pyridyl] -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-nitro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.13heptane; (1S, 4S) -2- 5-bromo-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 5-aminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-aminocarbonyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 6-chloro-5-hydroxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; The following additional compounds, representative of formula II, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. (1S.4S) -2- (thieno [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (Forum [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-3-pyridinyl) -5-cyanomethyl-2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2,6-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptan or; (1 S, 4 S) -2 6-chloro-5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2 6-chloro-5-methyl-3-pyridinyl) -2,5-d aza bicyclo [2.2.1] heptan or; (1S, 4S) -2,5,6-dichloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2 6-chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2 6-chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2,5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2,6-fluoro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2-ethyl-nyl-6-f-1-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2 5-cyano-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2,5-bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2 5-cyano-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2-hydroxymethyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2-hydroxymethyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2-5-hydroxymethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2,5-aminomethyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2 (5-aminon-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-Am'momethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-carboxy-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-carboxy-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-carboxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminocarbonyl-6-fluoro-3-pyridinyl) -2,5-d? Azabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminocarbonyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Fluoro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (2-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-methyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminosulfonyl-6-fluoro-3-pyridinyl) -2,5-diazab [cyclo] [2.2.1] heptane; (1S, 4S) -2- (5-aminosulfonyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminosulfonyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5,6-dichloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Fluoro-S-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-Cyano-6-fluoro-3-pyridinyl) -2, S-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (S-Bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; and (1S, 4S) -2- (6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane. In another embodiment of the present invention, compounds of the formula III are described: m, and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and Li, Ri and R2 are as defined in the formula Compounds representative of this embodiment include, but are not limited to: (1 R, 4R) -2- (6-chloro-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; 2- (3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (thieno [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (3-pyri inii) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-3-pyridinyl) -5-cyanomethyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-hydroxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-hydroxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methyl-3-pipdinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5,6-dichloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-aminocarbonyl-3-pyridyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methoxy-3-pyrridinyl) -2,5-diazabicyclo [2.2.1] heptane; and (1 R, 4R) -2- (3-pyridiniummethyl) -2,5-diazabicyclo [2.2.1] heptane. The following additional compounds, representative of formula III, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the Schemes and Examples contained herein. (1 R, 4R) -2- (furo [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methyl-3-pyridazinyl) -2,5-d-azabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methyl-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (4-chloro-1-phthalazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (4-Chloro-1-phthalazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-chloro-5-methoxycarbonyl-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-pyrimidinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (3-quinolinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (3-Methyl-5-isothiazolyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-Bromo-3-pyridinium) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Nitro-3-pyridinyl) -2,5-diazabicyclo [2 2.1] heptane; (1 R, 4R) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-bromo-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-amino-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2-I5- (benzyloxy) -3-pyridinyl] -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2J5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-Cyano-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-Bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4 R) -2- (5-Cyano-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-Hydroxymethyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1RJ4R) -2- (5-hydroxymethyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4 R) -2- (5-h idroxymethyl-3-pyridinyl) -2,5-d-azabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminomethyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminomethyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-carboxy-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-carboxy-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-carboxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminocarbonyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminocarbonyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-chloro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-fluoro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (2-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-methyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-aminosulfonyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-aminosulfonyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-aminosulfonyl-3-iridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Cyoro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 Rl4R) -2- (5) 6-dichloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (6-Chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (6-Chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (5-methoxy-3-pyrridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (6-Fluoro-5-methyl-3-pyridinyl) -2I5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (5-cyano-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (5-Bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1 R, 4R) -2- (3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; and (1 R, 4R) -2- (6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane.

In another embodiment of the present invention, compounds of the formula IV are described: IV, and their pharmaceutically acceptable salts, wherein Z is selected from CH2CH2 and CH2CH2CH2; and L ^ R and R2 are as defined in formula I. Compounds representative of this embodiment include, but are not limited to: 3- (3-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-Nitro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-amino-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-chloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; and 3- (3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane. The following additional representative compounds of formula IV can be prepared by one skilled in the art using known synthetic chemical methodology or using synthetic chemical methodology described in the schemes and examples contained herein. 3- (6-chloro-5-methyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (5,6-dichloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-chloro-5-ethynyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-chloro-5-cyano-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (5-methoxy-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-fluoro-5-methyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (5-cyano-6-fluoro-3-pyridinium) -3,8-diazabicyclo [3.2.1] octane; 3- (5-Bromo-6-chloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (5-aminomethyl-6-chloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (5-aminomethyl-6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; and 3- (5-aminomethyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane. In another embodiment of the present invention, compounds of the formula V are described: V, and their pharmaceutically acceptable salts, wherein Z is selected from CH2CH2 and CH2CH2CH2; and L1 (Ri and R2 are as defined in formula I. In another embodiment of the present invention, compounds of formula VI: VI, and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and Li, Ri and R2 are as defined in the formula A representative compound of this embodiment includes, but is not limited to: 2- (6-chloro-3-pyridinium) -2,6-diazabicyclo [3.2.1] octane. The following additional compounds, representative of formula VI, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. 2- (3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (6-Chloro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (5,6-dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (6-chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (6-Chloro-5-cyano-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (6-fluoro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (6-fIuoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1 Joctane; (1S, 5R) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (5-Cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1 Joctane; (1S, 5R) -2- (5-Bromo-6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.] Octane; (1 R, 5S) -2- (6-chloro-5-methyl-3-pyridinii) -2,6-diazabicyclo [3.2.1] octane; (R, 5S) -2- (5,6-dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (6-Chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (6-chloro-5-cyano-3-pyridinii) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (6-fluoro-5-methyl-3-pyridinyl) -2I6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (5-Cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -2- (5-Bromo-6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane.

In another embodiment of the present invention, compounds of the formula VII are described: vp, and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and Li, Ri and R2 are as defined in formula I. The following compounds, representative of the formula VII, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained here. (1R, 5R) -6 (6-chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (5,6-dichloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6 (6-chloro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6 (6-chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6 (5-methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6 (6-fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (5-ethynyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (5-Cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (5-Bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -6 - (6-Chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-Chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 S, 5 S) -6 - (5,6-dichloro-3-pip'dinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-Chloro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-Chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S.5 S) -6 - (5-methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5-ethynyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5-Cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5-Bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (S-pyridinium-S.-diazabicyclo S ^ .Joctane; and (1S, 5S) -6- (6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2 .1] octane In another embodiment of the present invention, compounds of the formula VII I are described: vm, and their pharmaceutically acceptable salts, wherein Z is selected from CH2CH2 and CH2CH2CH2; and L, Ri and R2 are as defined in formula I. A compound representative of this embodiment includes, but is not limited to: 9- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2. 1) nonane. The following additional compounds, representative of formula VIII, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. (1 R, 6S) -9- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5,6-dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-fIuoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-ethynyl-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-Cyano-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-chloro-3-pyridinium) -3,9-diazabicycloi 4.2.1] nonane; (1 R, 6S) -9- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (5,6-Dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-5-cyano-3-? Iridinyl) -3,9-diazabicyclo [4.2.13nnan; (1 Sl6R) -9- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1 lnonano; (1S, 6R) -9- (6-Fluoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.13nnan; (1 Sl6R) -9- (5-ethynyl-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 S, 6 R) -9- (5-Cyano-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 S, 6 R) -9- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; and (1S, 6R) -9- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane. In another embodiment of the present invention, compounds of the formula IX are described: and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and L,, R ^ and R2 are as defined in the formula A representative compound of this embodiment includes, but is not limited to: 6- (6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1) octane. The following additional compounds, representative of formula IX, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. (1 R, 5S) -6- (6-Chloro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R5S) -6- (5) 6-dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1 loctane; (1 R, 5S) -6- (6-Chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-Chloro-5-cyano-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-fluoro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-ethynyl-6-fiuoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-Cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-Bromo-6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5,6-Dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-5-cyano-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-fluoro-5-metii-3-yl-ridinyl) -2) 6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-ethynyl-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-Cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-Bromo-6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; and (1S, 5R) -6- (3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane. In another embodiment of the present invention, compounds of the formula X are described: x. and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and Li, Ri and R2 are as defined in the formula The following compounds, representative of the formula X, can be prepared by a person skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. (1 R, 5R) -3- (6-Chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; , 6-dichloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -coro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -etinyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; , 6-dichloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -chloro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -etinyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; -cl or ro-3-pyridin i l) -3,6-d azabicyclo [3.2.1] octane; and -pyridinyl) -3,6-diazabicyclo [3.2.1] octane. In another embodiment of the present invention, compounds of the formula XI: XI are described, and their pharmaceutically acceptable salts, wherein Z is selected from CH2CH2 and CH2CH2CH2; and Lt, Ri and R2 are as defined in formula I. Compounds representative of this embodiment include, but are not limited to: 3- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1 ) nonane; 9-methyl-3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; and 3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane. The following additional compounds, representative of formula XI, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. (1 R, 6S) -3- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5,6-dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Fluoro-5-methyl-3-pyridinium) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-Cyano-6-f! Uoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1 jno na no; (1R, 6S) -3- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1R, 6S) -3- (6-Chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1R, 6S) -3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5,6-dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1Jonathan; (1S, 6R) -3- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Fluoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-ethynyl-6-fIuoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-Cyano-6-fluoro-3-pyridinyl) -3I9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; and (1S, 6R) -3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane. In another embodiment of the present invention, compounds of the formula XII are described: xp, and their pharmaceutically acceptable salts, wherein Z is selected from CH2 and CH2CH2; and L1; R - and R2 are as defined in the formula Compounds representative of this embodiment include, but are not limited to: 3- (3-pyridinyl) -3,7-diazabicyclo [3.3. 1) nonane and 3- (6-chloro-3-pyridinyl) -3,7-diazabicyclo [3.3. 1] nonane. The following additional compounds, representative of formula XI I, can be prepared by one skilled in the art using known synthetic chemistry methodology or using synthetic chemistry methodology described in the schemes and examples contained herein. 3- (6-chloro-5-metii-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (5,6-dichloro-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (6-chloro-5-ethynyl-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (6-chloro-5-cyano-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (5-methoxy-3-pyridinyl) -3,7-diazabicicio [3.3.1] nonane; 3- (6-fluoro-5-methyl-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (6-fluoro-3-pyridinyl) -3,7-diazabicyclo [3.3. 1] nonane; 3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (5-Cyano-6-fluoro-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; and 3- (5-bromo-6-chloro-3-pyridinyl) -3,7-diazabicyclo [3.3. 1] nonane. Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier. Another embodiment of the present invention relates to a method for selectively controlling neurotransmitter release in a mammal, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I. Another embodiment of present invention relates to a method for treating a disease, such as Alzheimer's disease, Parkinson's disease, memory malfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, atral amyotrophic sclerosis, anxiety, depression, mania, anorexia schizophrenia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease, migraines, premenstrual syndrome, erectile dysfunction, substance abuse, smoking term, syndrome Inflammatory bowel and pain in an animal host with the need for said treatment, comprising administering a therapeutically effective amount of a compound of formula I.

Definition of Terms As used throughout this specification and in the appended claims, the following terms have the following meanings. The term "alkenyl", as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of 2 carbon atoms. hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl and 4-pentenyl. The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, attached to the molecular portion of origin through an oxy portion, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkoxy", as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy. The term "alkoxyalkyl", as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.

The term, "alkoxycarbonyl", as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl The term "alkoxycarbonylalkyl", as used herein, refers to an alkoxycarbonyl group, as defined herein, attached to the molecular moiety originating through an alkyl group, as defined herein Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl and 2-tert-butoxycarbonylethyl. used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms Representative examples of alkyl include, but are not limited to, methyl, eti it, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. The term "alkylcarbonyl", as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1 -oxobutyl and 1 -oxopentyl. The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group, as referred to herein, attached to the parent molecular moiety through an oxy portion, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The term "alkylthio", as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl and hexylsuiphanyl. The term "alkynyl" as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term "amino", as used herein, refers to -NR10Rn, wherein Rio and Rn are independently selected from hydrogen, alkyl, alkylcarbonyl, and formyl, as defined herein. Representative examples of amino include, but are not limited to, amino, methylamino, ethylmethylamino, methylisopropylamino, dimethylamino, diisopropylamino, diethylamino, formylamino and acetylethylamino. The term "aminoalkyl", as used herein, refers to an amino group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminoalkyl include, but are not limited to, aminomethio, 2-aminoethyl, 3-aminopropyl, 4-amino-1-methyIhexyl, and 2- (dimethylamino) ethyl. The term "aminocarbonyl" as used herein, refers to an amino group, as defined herein, attached to the molecular portion of origin through a carbonyl group, as defined herein. Representative examples of aminocarbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl and ethylmethylaminocarbonium. The term "aminocarbonylalkyl", as used herein, refers to an aminocarbonyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminocarbonylalkyl include, but are not limited to, 2- (aminocarbonyl) ethyl, 3- (dimethylaminocarbonyl) propyl, and ethyl methylammonium methyl. The term "aminosulfonyl", as used herein, refers to an amino group, as defined herein, attached to the molecular portion of origin through a sulfonyl group, as defined herein. Representative examples of aminosulfonyl include, but are not limited to, aminosulfonyl, dimethylaminosulfonyl and ethylmethylaminosulfonyl. The term "carbonyl", as used herein, refers to a -C (O) - group. The term "carboxy", as used herein, refers to a -CO2H group. The term "carboxyalkyl", as used herein, refers to a carboxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl and 3-carboxypropyl. The term "cyano", as used herein, refers to a -CN group. The term "cyanoalkyl", as used herein, refers to a cyano group, as defined herein, attached to the molecular moiety of origin through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl. The term "formyl," as used herein, refers to a group -C (O) H. The term "formylalkyl," as used herein, refers to a formyl group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of formylalkyl include, but are not limited to, formimethyl and 2-formylethyl. The term "halo," or "halogen," as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkoxy", as used herein, refers to at least one halogen, as defined herein, attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy. The term "haloalkyl", as used herein, refers to at least one halogen, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl. The term "hydroxy," as used herein, refers to an OH group. The term "hydroxyalkyl," as used herein, refers to a hydroxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl. The term "mercapto", as used herein, refers to a -SH group. The term "mercaptoalkyl", as used herein, refers to a mercapto group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl. The term "N-protecting group" or "nitrogen-protecting group" as used herein, refers to those groups intended to protect an amino group against undesirable reasons during synthetic procedures. N-protecting groups include carbamates, amides, alkyl derivatives, aminoacetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives, and heterogeneous N-atom derivatives. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, triphenylmethyl (trityl), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz). The commonly used N-protecting groups are described in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd. edition, John Wiley &; Sons, New York (1991). The term "nitro", as used herein, refers to a group -NO2. The term "oxy", as used herein, refers to a -O- portion. The term "sulfonyl", as used herein, refers to a group -SO2. The term "uncle," as used herein, refers to a -S- portion. The compounds of the present invention can exist as stereoisomers, wherein asymmetric or chiral centers are present. The stereoisomers are designated as "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem., (1976), 45: 13-30). In particular, the stereochemistry at the two bridged carbon atoms, shown in Figure I, can independently be either (R) or (S), unless otherwise specifically noted. The present invention contemplates various stereoisomers and their mixtures and are specifically included within the scope of this invention. Stereoisomers include enantiomers, distereomers and mixtures of enantiomers or diastereomers. The individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or through the preparation of racemic mixtures followed by resolution well known to those skilled in the art. These resolution methods are illustrated by (1) the binding of a mixture of enantiomers to a chiral auxiliary, the separation of the resulting mixture from diastereomers through recrystallization or chromatography and release of the optically pure product from the auxiliary, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means those salts which, within the scope of medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation or allergic response, and the like, and are in agreement. with a reasonable benefit / risk 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, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately, by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphor, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride. , hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized with such agents as alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates such as dimethyl, diethyl, dibutyl and diamiisulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides, and others. In this way, soluble or dispersible products are obtained in water or oil. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, sodium 4 methylbenzenesulfonic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of this invention by reacting a carboxylic acid containing portion with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia. or a primary, secondary or tertiary organic amine. The pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like and non-toxic quaternary ammonia and amine cations including ammonium. , tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylene diamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

Abbreviations The abbreviations that have been used in the descriptions of the schemes and examples are set forth below: Ac for acetyl; AcOH for acetic acid; BI NAP for 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl; Boc for tert-butoxycarbonyl; (Boc) 2O for di-tert-butyl dicarbonate; dba for dibenzylideneacetone; DMF for N, N-dimethylformamide; dppf for 1, 1 '- (diphenylphosphino) ferrocenium; EtOAc for ethyl acetate; Et2O for diethyl ether, EtOH for ethanol; eq for equivalents; formalin for a solution of formaldehyde (37% by weight) in water; HPLC for high pressure liquid chromatography; LAH for lithium-aluminum hydride; MeOH for ethanol; Tf for SO2CF3; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMS for trimethylsilyl; and TsOH for paratoluenesulfonic acid monohydrate.

Preparation of coughs Compounds of the Present Invention The compounds and processes of the present invention will be better understood in relation to the following synthetic schemes and methods which illustrate a means by which the compounds of the present invention can be prepared.

Scheme 1 The compounds of the present invention can be prepared according to the general aspect presented in Scheme 1. The bicyclic diamines conveniently protected, as shown in Scheme 1, wherein P is a nitrogen-protecting group such as alkyl, benzyl, or Boc, can be coupled with halogenated heterocycle, wherein R4, R5 and R6 are as defined in formula i, in the presence of an amine base. Alternatively, less reactive heterocycles can be coupled using the methods described by (Wagaw, S. and Buchwald, SL, J. Org. Chem. 1996, 61, 7240-7241; Bryant, HY and Buchwald, SL, Journal of Organometallic Chemistry ( 1999) 576, 125-146). Deprotection under standard conditions offers the desired compounds. The diazabicycloheptanes can be prepared as generally taught and described in Examples 1, 2, 15 and 16. The diazabicyclooctanes can be prepared as generally taught and described in Examples 10, 35, 42, 49, 59 and 60. diazabicyclononanes can be prepared as generally taught and described in Examples 36, 56 and 57. A person skilled in the art could understand that the preparation of larger diazabicyclo compounds, for example, decanes, etc. , can be prepared synthetically through the schemes and examples contained herein, as well as by the general synthetic methodology.

Scheme 2 The transformations presented in Scheme 2 provide compounds which in turn can be elaborated to provide other 5-substituted pyridines. For example, complete or partial hydrolysis of the nitrile leads to the carboxylic acid and amide, respectively. The reduction of the nitrile affords the amine, although cyclization with TMSN3 in the presence of Bu2O as described by (Wittenberg and Donner, J. Org Chem. 1993 58, 41 39) provides the tetrazolyl derivative. The aldehyde can be converted to oximes and hydrazones or subjected to reductive amination conditions to provide a variety of substituted aminomethyl compounds. Grignard reactions in the aldehyde provide a route for a variety of substituted hydroxymethyl analogues.

Esq uema 3 X = C!, Br, l The aldehydes, as shown in Scheme 3, can be processed to terminal alkynes using the procedure described in (Tetrahedron Lett. (1972), 3769-3772). Further elaborations are possible from the tin and boronic acid derivatives of Scheme 2, which can be coupled with a variety of aryl and vinyl halides and sulfonate esters using transition metal catalysis (for example, Stille and Suzuki). The 5-bromo derivatives can be coupled in a variety of Pd-catalyzed couplings with alkenes and alkynes (Heck couplings), aryl and vinyl esters and boronic acids (Stille and Suzuki couplings), as well as alkoxycarbonylations.

Scheme 4 Chain extensions (CN shift, malonic ester synthesis) can be performed as described in Example 4 to provide the scale of substitution patterns encompassed by the claims.

Scheme 5 In cases where the 6-position of the heterocycle is substituted with halogen, an alternative method for the functionalization of position 5 involves the ortho-directed metalation according to (Gribble et al., Tetrahedron Lett (1980) 21, 4237). The metallated species can be trapped with electrophiles, as illustrated in Scheme 5, to provide intermediates that can also be processed as described in Schemes 3 and 4.

Scheme 6 Compounds with 1 -5 methylenes between the aromatic heterocycle and the diazabicyclic ring system can be prepared according to the procedure described in Example 6. Aminoalkyl heterocycles, prepared using standard or commercially purchased synthetic chemistry methodology, can be condensed with monocyclic precursors to provide N-substituted diazabicyclic systems. For example, (3S, 5R) - [(4-methylphenyl) sulfonyl] -3 - [(4-methylphenyl) sulfonyloxy] -5 - [(4-methylphenyl) sulfonyloxymethyl] pyrrolidine, prepared as described in (J. Med. Chem., (1990) 33, 1344), can be condensed with an aminoalkyl heterocycle to provide the N-substituted diazabicyclic [2.2.1] system, which after removal of the protecting group, for example, with HBr / HOAc, provides the desired compounds. Other separation lengths are possible through a direct variation of the starting aminoalkyl heterocycle.

Scheme 7 Scheme 7 describes an alternative method for preparing compounds with 1-5 methylenes between the aromatic heterocycle and the diazabicyclic ring system. Mono-protected diazabicyclic systems can be acylated with chlorides or heterocyclic acid anhydrides followed by reduction of the resulting amides using standard methods available to those skilled in the art, and provides the desired chain extended compounds. The following examples are presented to describe the preferred embodiments and utilities of the invention and are not intended to limit the invention unless otherwise stated in the appended claims.

Example 1 4-methybenzenesulfonate of (1 S.4S) -2- (ß-chloro-3-pyridinyl) -2,5-d iaza b icicl or T2.2.11 he tano Example 1 A (1S.4S) -5- (6-chloro-3-pyridinin-2,5-diazabicyclo2.2.11 heptan-2-tert-butyl carboxylate In a flask purged with dry nitrogen, it was treated (1S, 4S ) -2,5-diazabicyclo [2.2.1] heptan-2-carboxylic acid tert-butyl ester (330 mg, 1.6 mmoles), prepared as described in J. Med. Chem., (1988) 31, 1598- 161 1), in 6 ml of anhydrous toluene, with 2-chloro-5-iodopyridine (383 mg, 1.6 mmol), available as described in (Tetrahedrom Lett, (1993), 34, 7493-7496), Pd2 (dba ) 3 (156 mg, 0.16 mmole), B1NAP (212 mg, 0.34 mmole), and sodium tert-butoxide (230 mg, 2.4 mmole). The mixture was heated at 70 ° C for 24 hours. The reaction mixture was poured into 10 ml of diethyl ether and washed successively with 1 N of HCl, saturated NaHCO3, and brine. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified on SiO2, eluting with ethyl acetate: hexanes (1: 1) to give the title compound (300 mg, 58% yield) as a light brown solid. 1 H NMR (CDCl 3, 300 MHz) d 1.41 (s, 4.5H), 1.46 (s, 4.5H), 1.93- 2.05 (m, 2H), 3.14 (d, J = 14.7 Hz, 0.5H), 3.35 (d, J = 14.7 Hz, 0.5H), 3.42 (m, 2H), 3.57 (d, 8.45 Hz, 1 H), 4.37 (s, 1 H), 4.53 (s, 0.5H), 4.65 (s) , 0.5H), 6.82 (dd, J = 2.94, 8.83 Hz, .1 H), 7.13 (d, J = 8.46 Hz, 1 H), 7.71 (s, 1 H); MS (DCI / N H3) m / z 310 (M + H) +.

Example 1 B 4-methylbenzenesulfonate of (1S, 4S) -2- (β-chloro-3-pyridin-2, 5-diazabicyclo2.2.11heptane The product of Example 1 A, (1S, 4S) -5 - (6-Chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptan-2-carboxylic acid tert-butyl ester (386 mg, 1.25 mmol) was charged to a dry purged flask with nitrogen and The mixture was cooled to 0 ° C and treated with 4N HCl / dioxane (1.3 ml), the mixture was allowed to warm to room temperature for 0.5 hours, the solvent was removed under reduced pressure and the The residue was purified on SiO2, eluting with 10% MeOH / CH2Cl2 / 1% NH4OH to give the title compound (202 mg, yield 775) as the free base.The free base was combined with one equivalent of p-toluenesulfonic acid and recrystallized from ethanol / ethyl acetate to provide the title compound.1H NMR (free base, CDCl3, 300 MHz) d 1.91 -2.13 (AB quad band, J = 17.6, 40.7 Hz, 2H), 3.03 ( d, J = 1 1.3 Hz, 1 H), 3.19 (s, 2 H), 3 .63 (dd, J = 2.0, 11.3 Hz, 1 H), 3.89 (s, 1 H), 4.30 (s, 1 H), 6.80 (dd, J = 3.4, 8.9 Hz, 1 H), 7.20 (d) , J = 8.8 Hz, 1 H), 7.72 (d, J = 3.3 Hz, 1 H); MS (DC1 / NH3) m / z 210 (M + H) +, 227 (M + NH4) +; Anal. cale, for C10H12N3CI-1.25 TsOH C.52.92; H.5.21; N, 9.69. C.52.92 was found; H, 5.35; N, 9.64.

Example 2 Bis (4-methyl benzene sulfon ate of (1 S.4S) -2- (6-chloro-3-pyridazinyl- 2.5-d aza bicyclo ["2.2.11 heptane Example 2A p S, 4S) -5- (6-chloro-3-pyridazinyl) -2,5-diazabicyclo2.2. pheptan-2-tert-butyl carboxylate It was treated (1 S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (342 mg, 1.7 mmoles) prepared as described in (J. Med. Chem., (1988) 31, 1598-161 1), in 8.5 ml of anhydrous toluene, with 3,6-dichloropyridazine (256 mg, 1.7 mmol, Aldrich Chemical Company) and triethylamine (0.24 ml, 170 mg, 1.7 mmol). The reaction mixture was heated at reflux for 16 hours, concentrated under reduced pressure and the residue was purified on SiO2 (5% MeOH / CH2Cl2 / 1% N H4OH) to provide the title compound, 432 mg, 81% yield ) as a white solid. 1 H NMR (CDCl 3, 300 MHz) d 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.91 - 2.05 (m, 2H), 3.36-3.46 (m, 3H), 3.54-3.60 (m, 1 H), 4.57 (s, 0.5H), 4.70 (s, 0.5H), 4.92 (s, 0.5H), 5.07 (s, 0.5H), 6.59 (d, J = 9.20 Hz, 1 H ), 7.34 (d, J = 9.56 Hz, 1 H); MS (DCI / NH3) m / z 31 1 (M + H) +, 328 (M + NH4) + - Example 2B Bis (4-methylbenzene sulphonate) of (1S, 4S) -2- (6-chloro-3-yldazinyl) -2,5-d-azabicyclo2.2.11 heptane The product of Example 2A (432 mg, 1.4 mmoles) in 14 ml of EtOH at 0 ° C was treated with 4M HCl / dioxane (1.4 ml). The reaction was allowed to warm to room temperature, concentrated under reduced pressure and the residue was purified on SiO2 (10% MeOH / CH2Cl2 / 1% NH4OH) to give the free base (231 mg, 79% yield). The free base was treated with 3 equivalents of p-toiuenesulfonic acid and the resulting salt was recrystallized from ethanol / ethyl acetate. 1 H NMR (free base, CDCl 3, 300 MHz) d 2.23 (d, J = 11.77 Hz, 1 H), 2.38 (d, J = 11.77 Hz, 1 H), 3.54 (AB quartet, J = 11.77, 24.27 Hz, 2 H) , 3.90 (m, 2H), 4.72 (s, 1H), 5.21 (s, 1H), 7.72 (d, J = 9.56 Hz, 1H), 7.87 (d, J = 9.92 Hz, 1H); MS (DCI / NH3) m / z 211 (M + H) +, 228 (M + NH4) +; Anal. cale, for C9H11N4CI »2.65 TsOH'1.05 H2O, C, 48.24; H, 5.04; N, 8.17. C, 48.29 was found; H, 5.38; N, 8.18.

Example 3 Trichlorohydrate (1 S.4S) -2- (6-amino-3-pyridinin-2,5-diazabicyclo [2.2.11 heptan or Example 3A (1S.4S) -5- (6-Nitro-3-pyridin-2,5-diazabicyclic2.2.n-heptane-2-tert-butyl carboxylate) They were coupled, according to the procedure of Example 2A, to provide the title compound, 5-bromo-2-nitropyridine, prepared as described in (J. Am. Chem. Soc, (1945) 67.668), and (1S, 4S) -2,5-diazabicyclo [2.2.1] tert-butyl heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611).

Example 3B (lS.4S) -2- (6-amino-3-pyridinep-2.5-di-azabicyclo2.2.11 heptane) trichlorohydrate The product of Example 3A in methanol (1: 1) was treated with 10% Pd / C. % under a hydrogen atmosphere for 14 hours The mixture was filtered, concentrated and the residue was treated with HCl / ether to give the title compound (65% yield) 1 H NMR (DMSO-d6.300 MHz) d 2.00 (m, 2H), 3.00 (br s, 2H), 3.4-3.5 (m, 2H), 4.40 (s, 1H), 4.60 (s, 1H), 7.00 (d, J = 6.3 Hz, 1H), 7.30 (s, 1H), 7.50 (br s, 2H, interchangeable), 7.70 (d, J = 6.3 Hz, 1H), 9.40 (br s, 1H, interchangeable), 9.80 (br s, 2H, interchangeable), 13.0 ( br s, 1H, interchangeable).

Example 4 Bis (4-methyl-benzenesulfonate of (1S.4S) -2- (6-chloro-5-methyl-3-pyridazinyl) -2,5-diazabicyclo2.2.1 heptane Example 4A (1S.4S) -5- (6-Chloro-5-methyl-3-pipdazinyl) -2.5- diazabicyclochloride.2.2n-heptane-2-carboxylic acid tert-butyl 3,6-dichloro-4-methylpyridazine (Aldrich Chemical Company) and (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate of tert-butyl, prepared as described in (J. Med. Chem., (1988) 31, 1598- 1611), were processed as described in Example 2A to provide the title compound (56% yield). 1H NMR (CDCl3.300 MHz) d 1.41 (s, 4.5H), 1.43 (s, 4.5H), 1.90-2.09 (m, 2H), 2.31 (s, 3H), 3.35-3.45 (m, 3H), 3.53-3.60 (m, 1H), 4.56 (s, 0.5H), 4.69 (s, 0.5H), 4.90 (s, 0.5H), 5.08 (s, 0.5H), 6.48 (s, 1H); MS (DCI / NH3) m / z 325 (M + H) +.

Example 4B Bis (4-methylbenzenesulfonate) from f1S.4S) -2- (β-chloro-5-methyl-3-pyridazinyl) -2,5-diazabicyclochloride.2.2 n-heptane The product of Example 4A was processed as described in Example 2B to provide the title compound (81% yield). 1 H NMR (CDCl 3, 300 MHz) d 1.84 (d, J = 10.29 Hz, 1 H), 1.96 (d, J = 9.93 Hz, 1 H), 2.32 (s, 3 H), 2.92-3.02 (m, 2 H), 3.36 (s, 1H), 3.58 (dd, J = 2.21, 9.56 Hz, 1H), 3.83 (s, 1H), 4.76-4.88 (m, 1H), 6.94 (s, 1H); MS (DCI / NH3) m / z 225 (M + H) +, 242 (M + NH4); Anal. cale, for C? 0H? 3N4CI »2.0 TsOH C, 50.63; H, 5.13; N-9.70. We found C, 50.32; H, 5.15; N, 9.82.

Example 5 4-methylbenzenesulfonate of MS.4S) -2- (ß-chloro-3-pyridazinyl) -5-methyl-2,5-diazabicyclochloride.2.2pheptane The product of Example 2B (1.0 equivalents) in 0.1 M formalin was treated with NaCNBH3 (1.2 equivalents) at 0 ° C. The reaction was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was quenched with saturated aqueous K2CO3, extracted with CH2Cl2, dried (MgSO4), and concentrated under reduced pressure. The residue was purified on SiO2 (10% MeOH / CH2CI2 (1% NH OH) to give the free base as a colorless oil (87% yield) The free base was treated with 1.5 equivalents of p-toluenesulfonic acid and the The resulting salt was recrystallized from ethanol / ethyl acetate to provide the title compound.1 H NMR (free base, CD3OD, 300 MHz) d 2.33 (d, J = 10.30 Hz, 1 H), 2.48 (s, 3H ), 2.50 (d, J = 1 1.77 Hz, 1 H), 2.98-3.01 (m, 1 H), 3.71 -3.87 (m, 3H), 4.49 (s, 1 H), 5.06 (s, 1 H) , 7.54 (d, J = 10.26 Hz, 1 H), 7.78 (d, J = 8.09 Hz, 1 H); MS (DCI / NH3) m / z 225 (M + H) +, 242 (M + NH4) Anal cale, for C? O H13N4Ch0.95 TsOH »0.60 H2O: C, 50.1 1; H, 5.51; N, 14.04 C was found, 50.21; H, 5.76; N, 13.98.

Example 6 Bis (4-methy1benzenesulfonate) of (1S.4S) -2- (6-chloro-5-methyl-3-pyridazinyl) -2,5-diazabicyclo2.2.11heptane The product of Example 4B was processed as was described in Example 5 to provide the title compound (39% yield). 1H NMR (CD3OD, 300 MHz) d 1.89 (d, J = 9.93 Hz, 1 H), 2.05 (d, J = 9.93 Hz, 1 H), 2.29 (s, 3 H), 2.45 (s, 3 H), 2.76 (d, J = 9.56 Hz, 1 H), 2.97 (dd, J = 1.83, 5.14 Hz, 1 H), 3.39 (dd, J = 2.21, 9.56 Hz, 1 H), 3.58-3.68 (m, 2H) 4.80 (br s, 1 H), 6.48 (s, 1 H); MS (DCI / N H3) m / z 239 (M + H) +, 256 (M + NH4) +; Anal. cale, for CnH15N4CI'2.2 TsOH-1.80 H2O: C, 48.65; H, 5.62; N, 8.48. C, 48.61; H, 5.50; N, 8.53.

Example 7 Bis (4-methyl-1-benzenesulfonate) of (1S, 4S) -2- (4-chloro-1-phthazinip-2.5-diazabicyclo2.2.nheptane Example 7A (1S, 4S) -5- (4-Chloro-1-phthalazin-2.5-d-azabicyclic2.2.pheptan-2-tert-butylcarboxylate 1,4-Dichlorophthalazine (Aldrich Chemical Company) and (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-1-carboxylate ter-butyium, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (62% yield): 1 H NMR (CDCl 3, 300 MHz) d 1.44 (s, 4.5H), 1.47 (s, 4.5H), 1.95-2.08 ( m, 2H), 3.46-3.58 (m, 1H), 3.64 (d, J = 8.47 Hz, 0.5H), 3.75 (d, J = 8.81Hz, 0.5H), 3.91 (d, J = 10.51Hz, 1H ), 4.19 (dd, J = 2.03, 6.78 Hz, 1H), 4.59 (brs, 0.5H), 4.69 (brs, 0.5H), 5.15 (s, 1H), 7.26-7.81 (m, 2H), 8.04-8.12 (m, 1H), 8.21 (dd, J = 1.70, 7.80 Hz, 1H); MS (DCI / NH3) m / z 361 (M + H) +.

Example 7 Bis (4-methylbenzenesulfonate) of (1S.4S) -2- (4-chloro-1-phthalazine D-2,5-diazabicyclo2.2.11heptane The product of Example 7A was processed according to the procedure described in the example 2B to provide the title compound (83% yield). (1S 1 H NMR (free base, CDC, 300 MHz) d 1.91 (d, J = 9.93 Hz, 1H), 2.05 (d, J = 9.93 Hz, -1H ), 3.22 (dd, J = 1.84, 8.45 Hz, 1H), 3.55-3.70 (m, 2H), 3.95 (s, 1H), 4.21 (dd, J = 2.21, 9.19 Hz, 1H), 5.07 (s, 1H), 7.767.94 (m, 2H), 8.06 (d, J = 8.09 Hz, 1H), 8.15 (d, J = 9.56 Hz, 1H); MS (DCI / NH3) m / z 261 (M + H ) +; Anal cale, for C? 3H? 3N4CI «2,105 TsOH« 0.25 H2O: C, 53.08; H, 4.87; N, 8.94 C was found, 53.14; H, 5.24; N, 8.87.

Example 8 Bis (4-metH-ben-sulphonate) of (1S, 4S) -2- (4-chloro-1-phthalazinyl) -5-methyl 1-2,5-diazabicyclo? .2.11 so tan The product of the Example 7B was processed according to the procedure described in Example 5 to provide the title compound (53% yield). 1H NMR free base (CD3OD, 300 MHz) d 2.34 (s, 3H), 2.54 (d, J = 8.47 Hz, 1H), 2.68 (d, J = 10.51Hz, 1H), 3.48 (d, J = 11.19 Hz , 1H), 4.28-4.45 (m, 2H), 4.59-4.66 (m, 2H), 5.34 (s, 1H), 8.08-8.15 (m, 1H), 8.23 (t, J = 7.80 Hz, 1H), 8.38-8.46 (m, 2H); MS (DCI / NH3) m / z 275 (M + H) +; Anal. cale, for C? H1sN4CI-2.0 TsOH: C, 54.52; H, 5.50; N, 9.05 C, 54.18; H, 4.98; N, 9.08.

Example 9 Bis (4-methylbenzenesulfonate) of (1 S.4S) -2- (6-chloro-5-methoxycarbonyl-3-pyridazinyl) -2,5-diazabicyclochloride2.2.11 heptane Example 9A (1S, 4S) -5-rß-chloro-5-r-methoxy-rbonyl) -3-pyridazinyl-1-2.5-diazabicyclochloride2.2.11heptan-2-carboxylic acid tert-butyl 3,6-dichloropyridazine-4-carboxylate and (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate of tert-butyl, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), processed as described in Example 2A to provide the title compound (41% yield). 1 H NMR (CDCl 3l300 MHz) d 1.42 (s, 4.5H), 1.47 (s, 4.5H), 1.90-2.11 (m, 2H), 2.86 (d, J = 9.93 Hz, 1H), 3.40-3.62 (m, 2H), 3.72 (d, J = 9.90 Hz, 1H), 3.93 (s, 3H), 3.51 (s, 0.5H), 4.63 (s, 0.5H), 5.05-5.15 (m, 1H), 7.49 (s) , 1 HOUR); MS (DCI / NH3) m / z 368 (M + H) +.

Example 9B Bis (4-methylbenzenesulfonate) of (1S.4S) -2- (β-chloro-5-methoxycarbonyl-3-pyridazinyl) -2,5-diazabicyclo2.2.nheptane The product of Example 9A was processed according to the procedure described in Example 2B to provide the title compound (73% yield). 1 H NMR (CDCl 3, 300 MHz) d 1. 88 (d, J = 10.29 Hz, 1H), 2.01 (d, J = 9.92 Hz, 1H), 2.81 (d, J = 9.92 Hz, 1H), 3.13-3.27 (m, 2H), 3.76 (dd, J = 2.21, 9.93 Hz, 1H), 3.87 (s, 1H), 3.93 (s, 3 H), 5.00 (s, 1H), 7.48 (s, 1H); MS (DCI / NH3) m / z 269 (M + H) +; Anal. cale, for CnH13N4? 2CI * 2.5 TsOH «1.1H, O: C, 47.61; H, 4.93; N, 7.79. C, 47.61; H, 5.07; N, 7.75.

Example 10 3- (6-Nitro-3-pyridinyl) -3,8-diazabicyclo r3.2.11octane dihydrochloride Example 10A 3- (6-nitro-3-pyridinyl) -3,8-diazabicyclo3.2. 3-tert-butyl 3,8-Diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butylated carboxylate (0.4 g, 1.9 mmol), prepared as described in (J. Med. Chem. (1998 ) 41, 674), 5-bromo-2-nitropyridine (0.43 g, 2.27 mmole), prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and triethylamine (0.23 g; 2.27 mmoles) in 10 ml of toluene were heated at reflux for 14 hours. After evaporation of the solvent, an additional 0.23 g of triethylamine was added and the mixture was further heated to 140 ° C for 2 hours. The residue was purified on SiO2 (CH2Cl2; EtOAc 9: 1) to give the title compound.

Example 10 3- (6-Nitro-3-pyridinin-3,8-diazabicyclo r3.2.11octane Dichlorohydrate The product of Example 10A was treated with 1M HCl / ether to provide the title compound (55% yield). 1H NMR ( DMSO-d6.300 MHz) d 1.9-2.0 (m, 4H), 3.4-3.5 (m, 2H), 4.00 (d, J = 11Hz, 2H), 4.20 (br s, 2H), 7.5-7.6 (m , 1H), 8.2-8.3 (m, 2H), 9.6-9.7 (br s, 3H, interchangeable).

Example 1 3- (β-amino-3-pyridinip-3,8-d aza bicyclo3.2.11 octane trichlorohydrate Example 11A 3- (6-amino-3-pyridinip-3,8-diazabicyclo3.2.poctane-8-carboxylic acid tert-butyl ester The product of Example 10A (200 mg) was treated with 10% Pd / C (20 mg). mg) in a 1: 1 mixture of methanol-ethanol (5 ml) under an atmosphere of hydrogen (1 atm) After filtration to remove the catalyst, the filtrate was concentrated and the residue was titrated with diethyl ether to provide the title compound as a violet solid.

Example 11B 3- (β-amino-3-pyridinyl) -3,8-diazabicyclo3.2.11octane trichlorohydrate The product of Example 11A was treated with 1M HCl / ether to provide the title compound (72% yield). 1H NMR (DMSO-d6, 300 MHz) d 2.00 (s, 4H), 3.2 (d, J = 11Hz, 2H), 3.4 (s, J = 11Hz, 2H), 4.20 (br s, 2H), 5.80 ( s, 2H, interchangeable), 7.00, (d, J = 8.5 Hz, 1H), 7.40 (br s, 1H), 7.80 (br s, 2H, interchangeable), 7.9-8.0 (m, 1H), 9.10 (br s, 2H, interchangeable).

Example 12 3- (β-Chloro-3-pyridinip-3,6-diazabicyclo3.2.11octane dihydrochloride The product of Example 11A (0.03 g, 0.103 mmole) in 12M HCl (0.12 ml) was treated with sodium nitride (10 mg, 0.129 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture was neutralized by the addition of NaHCO 3 and then extracted with CH 2 Cl 2. The extracts were dried (Na2SO), concentrated under reduced pressure and the residue was purified on SiO2 (10% MeOH / CH2CI2 / 1% NH4OH) to provide the free base, the free base was treated with 1M HCl / ether to provide the title compound (43% yield). 1H NMR free base (CDCI3, 300 MHz) d 1.8 (m, 4H), 2.1 (br s, 1H), interchangeable), 3.0 (dK = 11 Hz, 2H), 3.4-3.7 (br s, 2H), 7.0 -7.2 (m, 2H0, 7.9 (m, 1H).

Example 13 3- (3-pyridinyl) -3,8-diazabicyclochloride.2.2.11octane Dichlorohydrate The product of Example 12 was processed as described in Example 11 A. The crude product was purified on SiO2 (10% MeOH / CH2Cl2 / 1% NH4OH) and then treated with 1M HCl / ether to provide the title compound (40% yield). 1 H NMR (DMSO-de, 300 MHz) d 2.20 (br s, 4 H), 3.5 (d, J = 11 Hz, 2 H), 400 (d, J = 11 Hz, 2 H), 4.4 (br s, 1 H) , 7.9-8.0 (m, 1H), 8.2-8.3 (m, 2H), 8.5 (d, J = 3.6 Hz, 1H); MS (DCI / NH3) m / z 190 (M + H) +.

Example 14 3- (3-Pyridazinyl) -3,8-diazabicyclochloride.2.2noctane Hydrochloride 3- (6-Chloro-3-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane, prepared as described in (J. Med. Chem., (1998) 41, 674) according to the procedure described in Example 11 A. The crude product was purified on SiO 2 (10% MeOH / CH 2 Cl 2/1% NH 4 OH) and treated with 1M HCl / ether to provide the title compound (40% yield). 1H NMR (free base, CDCI3, 300 MHz) d 1.9-2.0 (m, 5H), 3.1 (d, J = 11Hz, 2H), 3.70 (br s, 2H), 4.0 (d, J = 11Hz, 2H) , 6.8 (d, J = 8.8 Hz, 1H), 7.2 (dd, J = 8.8, 3.8 Hz, 1H), 8.6 (d, J = 3.6 Hz, 1H); MS (DCI / NH3) m / z 191 (M + H) \ Example 15 4-methylbenzenesulfonate of (1R.4R) -2- (6-chloro-3-pyridinyl) -2.5- diaza biciclof 2.2.11 heptane Example 15A (1R.4R) -5-benzyl-2,5-diazabicyclo2.2.pheptan-2-carboxylate of tert-butyl Dihydrobromhydrate of (1R, 4R) -2- (benzyl) -2,5-diazabicyclo [ 2.2.1] heptane (12.4 g, 35.5 mmol), prepared as described in (J. Med. Chem., (1990) 33, 1344) and K2CO3 (16.2 g, 17 mmol) in 100 ml of DMF with dicarbonate of di-tert-butyl (8.1 g, 37 mmol) at room temperature. After stirring for 16 hours, the mixture was filtered and the filtrate was diluted with 500 ml of water. The mixture was extracted with Et2O (3x300 ml). The extracts were combined and washed with 50% brine (10 x 20 ml), dried over MgSO and the solvent was removed under reduced pressure to provide the title compound (9.7 g, 94%). 1 H NMR (DMSO-de, 300 MHz) d 1.62 (m, 1 H), 1.79 (d, J = 9.2 Hz, 1 H), 2.51 (m, 1 H), 2.75 (m, 1 H) 3. 07 (t, J = 10.2 Hz, 1 H), 3 .3 2-3.41 (m, 2H), 3 .67 (s, 1 H), 4.16 (d, 9.8 Hz, 1 H), 7.19-7.33 ( m, 5H); MS (DCI / NH3) m / z 199 (M + H) +, 216 (M + NH4) + - Example 15B (1 R.4R) -2.5-diazabicyclo2.2.11heptan-2-carboxylate of tert-butyl The production of Example 15A (2g, 6.9mmol) in 50ml of EtOH was treated with 10% Pd / C ( 150 mg) under an atmosphere of H2 (1 atm) for 16 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to yield 1.28 g (93.4%) of the title compound. 1 H NMR (DMSO-d 6, MHz) d 1.39 (s, 9 H), 1.54 (d, J = 5.6 Hz, 1 H), 1.58 (t, J = 9.5 Hz, H), 2.70-2.81 (M, 2H), 3.50 (dd, J = 1.02, 10.50.1 H), 3.17 (m, 1 H), 3.50 (s, 1 H), 4.17 (d, J = 10.17 Hz, H); MS (DCI / N H3) m / z 199 (M + H)? 216 (M + NH4) +.

Example 15C (1R.4R) -5- ß-chloro-3-pyridinyl) -2.5-d-iazabicyclo2.2.11 heptane-2-tert-butyl carboxylate The product of Example 15B (0.5 g, 2.5 mmol), 2 -coro-5-iodopyridine (0.88 g, 3.35 mmol, available as described in Tetrahedron Lett., 1993, 34, 7493-7496), Pd2 (dba) 3 (0.13 g, 0.16 mmol), BINAP (0.22 g, 0.34 mmoles), and sodium tert -butoxide (0.325 g, 3.57 mmol) in 10 ml of anhydrous toluene, were heated at 70 ° C for 16 hours. The mixture was filtered, concentrated under reduced pressure and the residue was purified by chromatography (silica gel, hexane: EtOAc, 9: 1 to 1: 1) to provide the title compound (0.522 g, 67%). 1 H NMR (DMSO-d 6, 300 MHz) d 1.33-1.38 (m 9 H), 2.50 (br s, 2 H), 3.02 (m, 1 H), 3.16 (d, J = 14.17 Hz, 1 H), 3.27 (m, 1H), 3.53 (m, 1H), 4.43 (m, 1H), 4.58 (br, s 1H), 7.11 (dd, J = 3.05, 8.81 Hz, 1H), 7.24 (d, J = 27.46 Hz, 1H) 7.77 (d.J = 3.05Hz, 1H); MS (DCI / NH3) m / z 310 (M + H) +.

Example 15D 4-Methylbenzenesulfonate of (1R.4R) -2- (β-chloro-3-pyridinyl) -2,5-diazabicyclo2.2.nheptane The product of Example 15C (478 mg, 1.5 mmol) in CH 2 Cl 2 (3 ml ) was treated with 3 ml of trifluoroacetic acid. After stirring for 1 hour at room temperature, the solvent was removed and the residue was dissolved in 20 ml of saturated Na 2 CO 3. The mixture was extracted with EtOAc (4 x 20 ml), dried over MgSO 4, concentrated under reduced pressure and the residue was purified (SiO 2, 10% MeOH / CHCl 2/1% NH 4 OH) to provide the free phase. The free base was treated with TsOH in hot EtOAc to provide the title compound (451 mg, 71%). [a] D23 -8.21 (c 0.21, MeOH); 1 H NMR (DMSO-de, 300 MHz) d 1.93 (d, J = 11.52 Hz, 1H), 2.14 (d J = 11.19 Hz 1H), 2.29 (s, 3H), 3.13-3.31 (m, 3H), 3.61 (dd, J = 2.37, 10.85, 1H), 4.48 (s, 1H), 4.68 (s, 1H), 7.13 (d, J = 8.48 Hz, 2H), 7.17 (dd, J = 3.05, 8.62 Hz, 1H ), 7.31 (d, J = 8.82, 1H), 7.49 (d J = 7.66 Hz, 2H), 7.85 (d J = 3.39 Hz, 1H); MS (DCI / NH3) m / z 210 (M + H) +; Anal. cale, for C? 0H12N3CI «C2HdO3S: C, 53.47; H, 5.28; N, 11.00 Found: C, 53.43; H, 5.36; N, 10.97.

Example 16 Bis (4-methylbenzenesulfonate) of MR.4R) -2-fß-chloro-3-pyridazinih- 2.5-diazabichloride2.2.11heptane Example 16A (1R.4R) -5- (6-Chloro-3-pyridazinyl-2,5-diazabicycloi2.2.pheptane-2-tert-butyl carboxylate The product of Example 15B and 3,6-dichloropyridazine (purchased from Aldrich Chemical Co.) were processed as described in Example 2A to provide the title compound: H NMR (DMSO-de, 300 MHz) d 1.48 (m 9H), 2.93 (br, s 2H), 3.18 (d, J = 12.17Hz, 1H), 3.3-3.51 (m, 2H), 3.55 (m, 1H), 4.49 (m, 1H), 4.86 (br, s 1H), 7.12 (m, 1H), 7.51 (d, J = 9.49 Hz, 1H); MS (DCI / NH3) m / z 31 1 (M + H) \ Example 16B B is (4-m ethylene benzene sulphonate) of (1 R, 4R) -2- (β-chloro-3-pyridazol-2, 5-diazabicycite2.2.11 heptane The product of Example 16A (353 mg, 1.1 mmol) in para-toluenesulfonic acid (660 mg 3.5 mmol) in 10 ml of EtOAc were heated at 70 ° C for 1 hour and then cooled to room temperature The solid obtained was washed with EtOAc ( 2 x 10 ml), ether (2 x 10 ml), and dried under reduced pressure to provide the title compound (597 mg, 94.7%). [A] D23 +59.3 (c 1.0, MeOH): 1 H NMR (DMSO-d6.300 MHz) d 1.96 (d, J = 10.51 Hz, 1 H), 2.17 (d, J = 10.17 Hz 1 H), 2.29 (s, 6H), 3.24-3.28 (m, 2H) ), 3.56-3.67 (m, 2H), 4:53 (s, 1 H), 4.95 (s, 1 H), 7.1 -1 (d, J = 7.79, 4H), 7.21 (d, J = 9.41 Hz , 1 H), 7.49 (d, J = 8.1 1 Hz, 4H), 7.62 (d, J = 9.49 Hz, 1 H); MS (DCI / NH3) m / z 21 1 (M + H) +; Cale, for C, 49.77; H, 4.90; N. 10.09, was found: C, 49.77; H, 4.99; N, 9.96.

Example 17 4-methylbenzenesuifonate of (1 S, 4S) -2- (3-pyridine-p-2,5-diaza bicyclo r2.2.11hept anus Example 17A (1S.4S) -5- (3-pyridinyl) -2,5-diazabicyclo2.2.11heptane-2-carboxylate of tert-butyl (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane- 2-Terbutyl carboxylate, prepared as described in J. Med. Chem., (1988) 31, 1598-1611, and 3-bromopyridine (Aldrich Chemical Company) were processed as described in Example 1A to provide the title (99% yield). 1 H NMR (CDCl 3 <300 MHz) d 1.42 (s, 4.5H), 1.48 (s, 4.5H), 1.91-2.03 (m, 2H), 3.14 (d, J = 14.7 Hz, 0.5H), 3.23 ( d, J = 14.7 Hz, 0.5H), 3.37-3.48 (m, 2H), 3.60 (d, 8.45 Hz, 1H), 4.41 (s, 1H), 4.53 (s, 0.5H), 4.67 (s, 0.5 H), 6.85 (dd, J = 2.94, 8.83 Hz, 1H), 7.09-7.21 (m, 1H), 7.95-8.06 (m, 2H); MS (DCI / NH3) m / z 276 (M + H) +.

Example 17B 4-Methylbenzenesulfonate of (1S.4Sl-2- (3-pyridinyl-2,5-diazabicyclo2.2.11 heptane The product of Example 17A was processed as described in Example 1B to provide the title compound (yield 65%). 1 H NMR (CDCl 3, free base, 300 MHz) d 1821.98 (m, 2 H), 3.01 (d, J = 12.0 Hz, 1 H), 3.08 (s, 2 H), 3.67 (dd, J = 2.0, 11.5 Hz , 1H), 3.76 (s, 1H), 4.32 (s, 1H), 6.78-6.85 (m, 1H), 7.05-7.13 (m, 1H), 7.82-8.01 (m, 2H); MS (DCI / NH3) m / z 176 (M + H) +, 193 (M + NH4) +; Anal. Cale, for C10H13N3'1.0 TsOH «0.4H20: C, 57.58; H.6.20; N, 11.85. C, 57.85 was found; H, 6.33; N, 11.47.

Example 18 (1S, 4S) -2- (5-Chloro-2-pyridin-2,5-diazabicyclof2.2.11 heptane) dihydrochloride Example 18A (1S.4S) -5- (5-Chloro-2-pyridinyl) -2,5-diazabicyclo-2,2-n-heptane-2-tert-butyl carboxylate They were processed as described in Example 2A to provide the compound Title (99% yield), (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 2,5-dichloropyridine commercially available.

EXAMPLE 18B f1S.4S) -2- (5-chloro-2-pyridinyl) -2,5-diazabicyclochloride.2.2 heptane dichloride. The product of Example 18A was treated with HCl in ether to provide the dihydrochloride salt. 1 H NMR (DMSO-d 6, 300 MHz) d 2. 00 (m, 2H), 3.2-3.3 (m, 4H), 4.64.8 (m, 2H) 6.80 (d, J = 7.4Hz, 1H), 7.8 (dd, J = 7.5, 3.1Hz, 1H), 8.2 (d, J = 3.1Hz, 1H), 9.2 (br.s.1H), 9.8 (br.s., 1H); MS (DCI / NH3) m / z 210, 212 (M + H) +.

Example 19 3- (5-Chloro-2-pyridinyl) -3,8-diazabicyclo3.2.noctane dihydrochloride Example 19A 3- (5-Chloro-2-pyridinyl) -3,8-diazabicyclo3.2.11octane-8-carboxylic acid tert -butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert -butyl ester, prepared as described in (J. Med. Chem., (1998) 41, 674), and 2,5-dichloropyridine were processed as described in Example 10A to provide the title compound.

Example 19B 3- (5-chloro-2-pi? Ridinyl) -3,8-diazabicyclo3.2.noctane dihydrochloride The product of Example 19A was processed as described in Example 10B to provide the title compound. 1 H NMR (DMSO-de 300 MHz) d 1.9-2.0 (m, 4H), 3.2 (d, J = 11Hz, 2H), 4.0-4.2 (m, 4H), 7.0 (d, J = 7.1Hz, 1H), 7.8 (dd, J = 7.5, 3.1Hz, 1H), 8.2 (d, J = 3.1Hz, 1H), 9.4 (br.s.2H); MS (DCI / NH3) m / z 224, 226 (M + H) +.

Example 20 Tribromhydrate of (1 R.4R) -2- (3-pyridinylmetip-2.5- d i azabite lof2.2.11 heptane Example 20A (1R.4R) -2-rf4-methylphenylsulphonin-5-p3-pyridinylmethyl) -2.5- diazabicyclochloride2.2.11 heptane. 4 (methyl, 2-benzene sulphonate ((2R)) was heated under reflux for 16 hours. 4S) -1 - [(4-methylphenyl) sulfonyl] -4-. {[[(4-methylphenyl) sulfonyl] oxy} pyrrolidinyl) methyl (1.5 g, 2.6 mmol) prepared as described in (J. Med. Chem. (1990) 33, 1344) and 3- (aminomethyl) pyridine (1.0 g, 9.3 mmol) in 20 ml of toluene. The mixture was cooled, filtered and the filter cake was washed with 20 ml of toluene. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (silica gel; hexanes: EtOAc, 9: 1 to 1: 1) to provide the title compound (410 mg, 46%). 1 H NMR (DMSO-d 6, 300 MHz) d 0.86 (d, J = 8.5 Hz, 1 H), 1.62 (d, J = 9.7 Hz, 1 H), 2.42 (s, 3 H), 2.44 (m, 1 H), 2.66 (dd, J = 2.4, 9.5 Hz, 1 H), 2.99 (dd, J = 2.0, 9.5 Hz, 1 H), 3.39-3.48 (m, 2H), 3.62-3.41 (d, J = 9.5 Hz, 1 H), 4.23 (br s, 1 H), 4.35 (t, J = 5.1 Hz, 1 H), 7.31 (m, 1 H), 7.43-7.46 (m, 2H), 7.62 (m , 1 H), 7.71-7.74 (m, 2H), 8.31-8.43 (m, 2H).

Example 20B (1R.4R) -2- (3-pyridinylmethyl) -2.5- di aza bic i clof2.2.11 heptane Tribromhydrate The product of Example 20A (320 mg, 0.9 mmol) in 3.4 ml acetic acid and HBr / acid 33% acetic acid (7 ml) was heated at 70 ° C for 18 hours. After cooling to room temperature, the precipitate was filtered, washed with ether and dried. The resulting solids were recrystallized from EtOH / EtOAc to provide the title compound (332 mg, 80%). 1 H NMR (, DMSO-d 6, 300 MHz) d 2.22 (m; 1 H), 2.47 (m, 1 H), 3.29-3.48 (m, 2 H), 3.35 (m, 1 H), 3.69 (m, 1 H), 4.19 -4.53 (m, 2H), 5.59 (m, 2H), 8.05 (m, 1H), 8.62 (m, 1H), 8.78-8.88 (m, 2H); MS (DCI / NH3) m / z 190 (M + H) +; Anal. Cale, for C ?? H? 5N3-3.0 HBr «0.1H2O: C, 30.46; H, 4.23; N, 9.69. It was found: C, 30.83; H, 4.25; N, 9.30.

Example 21 4-Methylbenzene sulphonate of (1S.4S) -2-r5- (benzyloxy) -3-pyridinyl1 2.5-diazabicyclochloride2.2.11 heptane Example 21A (1S.4S) -5-r5- (benzyloxy) -3-pyridin-2,5-diazabicyclo-2,2-n-heptane-2-carboxylate tert -butyl (1S, 4S) -2.5- diazabicyclo [2.2.1] heptane-2-carboxylate of tert-butyl, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611) and 3- (benzyloxy) -5-bromopyridine, prepared in accordance with (US 5,733,912), were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI / N H2 m / z 382 (M + H) +.

Example 21 B 4-methyl benzenesulfonate of (1 S.4S) -2-r5- (benzyloxy) -3-pyridinyl-2-, 5-d-aza bicyclo T2.2.11 heptane The product of Example 21A was processed as described in Example 2B to provide the title compound. 1 H NMR (CDCI3, 300MHz) d 1.78-2.00 (m.4H), 2.97 (d, J = 12.0 Hz, 1 H), 3.05 (s, 2H), 3.62 (dd, J = 3.0, 10.0 Hz, 1 H), 3.81 (s, 1 H), 4.28 (s, 1 H), 6.42 (dd, J = 2.0.8.0 Hz, 1 H), 7.31 -7.51 (m, 5H), 7.65 (d, J = 3.0 Hz, 1 H), 7.78 (d, J = 3.0 Hz, 1 H); MS (DCI / NH3) m / z 282 (M + H) +; Anal. cale, for C24H27N3O4S »030 TsOH.0.55 H2O: C, 60.86; H, 5.97; N, 8.16. Found C, 60.83; H, 6.00; N, 8.12.

Example 22 4-Methylbenzene sulphonate of (1S.4S) -2-r5-hydroxy-3-pyridinyl-1-2.5-diazabicic or2.2. nheptane Example 22A (1S.4S) -5-f5-hydroxy-3-pyridinin-2.5-diazabicyclo2.2. n-heptane-2-tert-butyl carboxylate The product of Example 21A (0.50 g, 1.31 mmol) in EtOH (15 ml) was treated with 10% Pd / C (0.02 g) under an atmosphere of hydrogen (1 atm) at 40 ° C for 16 hours. The reaction mixture was allowed to cool to room temperature and the catalyst was removed by filtration. The filtrate was diluted with 125 ml of diethyl ether, washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (5% MeOH / CH2CI2) to give the title compound (0.345 g, 90% yield) as a yellow oil. MS (DCI / NH3) m / z 292 (M + H) +.

Example 22B 4-methyl benzenesulfonate of (1S.4S) -2-r5-hydroxy-3-pyridinyl-1-2.5-diazabicyclochloride.2.2H heptane The product of Example 22A was processed as described in Example 2B to provide the compound of the title. 1H NMR (MeOD, 300 MHz) d 2.07 (d, J = 12.0 Hz, 1H), 2.280, J = 13.0 Hz, 1H), 3.32-3.42 (m, 3H), 3.71 (dd, J = 4.0, 10.0 Hz) , 1H), 4.51 (s, 1H), 4.68 (s, 1H), 6.62 (t, J-2.0 Hz, 1H), 7.51-7.56 (m, 2H); MS (DCI / NH3) m / z 192 (M + H) +; Anal. cale, for C? 7H21N3O4S # 0.55 TsOH «2.35 H2O: C, 50.04; H, 6.06; N, 8.40. Found C, 50.09, H, 6.35; N, 8.38.

Example 23 4-Methylbenzene sulfonate (1 S.4S) -2- (6-methyl-3-pyridinyl) -2.5- diaza bic ic or T2.2. 1 heptane Example 23A (1S.4S) -5- (ß-methyl-3-pyridinyl) -2.5-diazabicyclo2.2. n-butptan-2-tert-butyl carboxylic acid (1S, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate terbutyl, prepared as described in (J. Med. Chem., (1988) 31, 1598-161 1), and 5-bromo-2-methyl-pyridine (purchased from Emka Chemie) were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI / NH3) m / z 290 (M + H) +.

Example 23B 4-Methylbenzenesulfonate of (1S.4S) -2- (6-metii-3-pyridinyl) -2,5-d azabicyclic or 2.2.1 heptane The product of Example 23A was processed as described in Example 2B to provide the title compound. 1 H NMR (CDCl 3, 300 MHz) d 1.84 (d J = 9.0 Hz, 1 H), 1.93 (d, J = 9.0 Hz, 1 H), 2.42 (s, 3 H), 2.92 (d, J = 7.0 Hz, 1 H), 3.03-3.10 (m, 2H), 3.65 (dd, J = 2.0, 6.0 Hz, 1 H), 3.78 (s, 1 H), 4.28 (s, 1 H), 6.78 (dd, J = 4.0, 7.0 Hz, 1 H), 6.97 (d, J = 4.0 Hz, 1 H), 7.85 (d, J = 2.0 Hz, 1 H); MS (DCI / NH3) m / z 190 (M + H) +; Anal. cale, for C18H23N3O3S «0.5 TsOH« 0.5 H2O: C, 56.56; H, 6.18; N, 9.20. C, 56.57; H, 6.03; N, 9.28.

Example 24 4-methylbenzenesulfonate of (1 R.4R) -2- (3-pyridinyl) -2,5-diazabicyclo2.2.11 heptan or Example 24A (1 R, 4R) -5- (3-pyridinyl) -2,5-diazabicycloi 2.2. n-heptane-2-tert-butyl carboxylate The product of Example 15B and 3-bromopyridine (available from Aldrich Chemical Co.) were coupled according to the procedure described in Example 15C to provide the title compound. MS (DCI / NH3) m / z 276 (M + H) +.

Example 24B 4-methylbenzenesulfonate of (1 R.4R) -2-f3-pyridinyl) -2,5-diaza bicyclo? 2.2.11 heptane The product of Example 24A was processed as described in Example 22B to provide the title compound. 1 H NMR (CDCl 3, 300 MHz) d 1.90 (dd, J = 12.0, 30.0 Hz, 2H), 2.98 (d, J = 9.0 Hz, 1 H), 3.08 (s, 2H), 3.63 (dd, J = 3.0, 10.0 Hz, 1 H), 3.82 (s, 1 H), 4.32 (s, 1 H), 6.78-6.84 (m, 1 H), 7.08-7.15 (m, 1 H), 7.95 (dd) , 2.0.8.0 Hz, 1 H), 8.00 (d, J = 3.0 Hz, 1 H); MS (DCI / NH3) m / z 176 (M + H) +; Anal. cale, for C? 7H21N3O3S »0.45 H2O: C, 57.43; H, 6.21 -; N, 11.82. C, 57.64 was found; H, 6.1 1; N, 1 1.43.

Example 25 4-methylbenzenesulfonate of 1 R.4R) -2- (3-pyridazinyl) -2.5- diazabicyclo2.2.11heptane Example 25A 1 R.4R) -5- (3-pi ridazin il) -2.5-diaza bicyclo T2.2.11heptane-2-tert-butyl carboxylate The product of Example 16A was processed according to the procedure described in Example 29a to provide the title compound. MS (DCI / NH3) m / z 277 (M + H) +.

Example 25B 4-methylbenzenesulfonate of (1 R.4R) -2- (3-pyridazinyl) -2,5-diazabicyclo2.2.11heptane The product of Example 25A was processed as described in Example 2B to provide the title compound. 1 H NMR (MeOH, 300 MHz) d 2.11 (d, J = 12.0 Hz, 1 H). 2.26-2.39 (m, 3H), 3.65-3.82 (m, 2H), 4.60 (s, 1 H). 5.09 (s, 1 H), 7.30 (dd, J = 1.0, 9.0 Hz, 1 H), 7.57-7.65 (m, 1 H), 8.56 (dd, J = 1.06.0 Hz, 1 H); MS (DCI / NH3) m / z 176 (M + H) +; Anal. cale, for C? 6H2oN4? 3S «0.25 TsOH« 0.85 H2O: C, 52.41; H, 5.87; N, 13.77. Found C, 52.45; H, 5.88; N, 13.69.

Example 27 4-Methylbenzenesulfonate of (1 R.4R) -2- (6-chloro-3-pyridin-p-5-cia nometi I -2.5-d aza b ici cl \ 2.2.11 heptane The product of Example 15D (140 mg, 0.37 mmol) in 5 ml of DMF was treated with triethylamine (0.26 ml, 1.8 mmol) and bromoacetonitrile (0.03 ml, 0.43 mmol) under a nitrogen atmosphere.After stirring for 72 hours at room temperature, the The reaction mixture was emptied into 30 ml of saturated, aqueous Na 2 CO 3 and extracted with ether (5 x 50 ml) The organic phase was dried (MgSO 4) and concentrated under reduced pressure The residue was purified on SiO 2 (CHCl 2 / MeOH NH 4 OH 95: 4.5: 0.5) and combined with 4-methylbenzenesulfonic acid (21 mg, 0.11 mmol) to provide the title compound (47 mg, yield 30%). 1 H NMR (D 2 O, 300 MHz) d 2.14 (m, 2H), 2.39 (s, 3H), 3.34-3.48 (m, 2H), 3.36 (d, J = 9.03 Hz 1H), 3.62 (m, 1H), 3.93-3.95 (m. 2H), 4.10 (br s, 1H), 4.52 (br s, 1H), 7.17 (dd, J = 2.84,7.72 Hz, 1 H) 7.28-7.38 (m, 3H), 7.69 (d, J = 8.11Hz, 2H) 7.77 (d, J = 2.94 Hz, 1H); MS (DCI / NH3) m / z 249 (M + H) +, 266 (M + NH 4) +; Anal cale, for C12H13N4C1- C7H8O3S-0.1H2O: C, 53. 99; H, 5.05; N, 13.25. C, 53.99 was found; H, 5.19; N, 13.19.

Example 28 MS, 4S) -2- (6-ntr-3-pyridinyl) 2,5-diazabicycloi2.2.11heptane The product of Example 3A was treated with trifiuoroacetic acid: methylene chloride (1: 2) at room temperature for 2 hours. The volatiles were removed under reduced pressure and the residue was purified on SiO2 (5% MeOH / CH2 / 1% NH4OH) to provide the title compound as a yellow gum. MS (DCI / NH2) m / z 221 (M + H) +, 238 (M + NH4) +.

Example 29 (1S, 4S) -2- (3-pyridazinyl) 2,5-diazabicyclo2.2.pheptane 4-methybenzenesulfonate Example 29A (1S, 4S) -5- (3-pyridazinin-2,5-diazabicyclo2.2.1heptane-2-tert-butyl carboxylate The product of Example 2A (0.885 g, 2.85 mmol) in 14 ml of MeOH and 0.55 ml of triethylamine was treated with Pd / C at 105 (0.002 g) and stirred under a hydrogen atmosphere (4,218 kg / cm2) at 50 ° C for 80 minutes.The catalyst was removed by filtration and the filtrate was concentrated The residue was purified on SiO2 (5% MeOH / CH2Cl2) to provide the title compound (0.72 g, 92%) as a white solid MS (DCI / NH3) m / z 276 (M + H) +.

Example 29B (1S.4S) -2- (3-pyridazinyl) -2,5-diazabicyclochloride.2.2nheptane 4-methylbenzenesulfonate The product of Example 29A was processed as described in Example 2B to give the title compound. 1 H NMR (MeOH, 300 MHz) d 2.13 (d, J = 13.0 Hz, 1H), 2.28-2.40 (m, 3H), 3.68-3.87 (m, 2H), 4.62 (s, 1H), 5.11 (s, 1H), 7.36 (dd, J = 1.0.9.0 Hz, 1H), 7.60-7.68 (m, 1H), 8.60 (dd, J = 1.0.5.0 Hz, 1H); MS (DCI / NH3) m / z 176 (M + H) +; Anal. cale, for C16H20N4O3S «0.25 TsOH.0.85 H2O: C, 52.34; H, 5.85; N, 13.49. We found C, 52.29; H, 6.03; N, 13.52.

Example 30 Bis (4-methylbenzenesulfonate) of (1S.4S) -2- (6-fluoro-3-pyridinyl) -2.5-d azab ici clof2.2.11 heptan or Example 30A riS.4S) -5- (ß-fluoro-3-pyridinyl) -2,5-diazabicyclo2.2.nheptane-2-tert-butyl carboxylate (1S, 4S) -2,5-diazabicyclo [ 2.2.1] tert-butyl heptane-2-carboxylate (0.300 g, 1.01 mmol), prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), in 30 ml anhydrous toluene was treated with 2-fluoro-5-iodopyridine (0.34 g, 1.52 mmole), available as described in (US 5,733,912), Pd 2 (dba) 3 (0.028 g, 0.03 mmole), (S) - (-) - 2- ( diphenylphosphino) -2'-methoxy-1,1'-b-naphthyl (0.028 g, 0.06 mmol), available from Strem Chemical, and sodium tert-butoxide (0.248 g, 2.58 mmol). The reaction mixture was heated at 80 ° C for 5 hours. The reaction mixture was poured into 100 ml of diethyl ether, washed with 100 ml of brine, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (3% MeOH / CH2Cl2) to provide the s and? < *. 86 compound of the title (0.095 g, 21% yield) as a yellow oil. MS (DCI / NH3) m / z 276 (m + H) +.

Example 30B Bis (4-methyl-1-benzenesulfonate) of (1S.4S) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyl or T2.2.11 heptane The product of Example 30A was processed as described. described in Example 2B to provide the title compound. 1 H NMR (MeOD, 300 MHz) d 2.06 (d, J = 12.0 Hz, 1H), 2.29 (d, J = 12.0 Hz. 1H), 3.25-3.30 (m, 1H), 3.35 (s, 2H), 3.73 (dd, J = 3.0, 12.0 Hz, 1H), 4.50 (s, 1H), 4.68 (3, 1H), 6.96 ( dd, J = 3.0, 9.0 Hz, 1H), 7.28-7.38 (m, 1H), 7.52-7.54 (m, 1H); MS (DCI / NH3) m / z 194 (M + H) +; Anal. cale, for C24H28N3OeS2F.0.75 TsOH-1.15 H2O: C, 51.10; H, 5.32; N, 6.11. C, 51.11 was found; H, 5.54; N, 6.10. 15 Example 31 4-methylbenzenesulfonate of (1Sl4S) -2- (5-bromo-3-pyridinyl) -2,5-diazabicic or 2 .2.11 heptane Example 31A (1S.4S) -5- (5-Bromo-3-pyridinium) -2,5-diazabicyclochloride.2.2-n-heptane-tert-butyl carboxylate (1S, 4S) -2,5-diazabicyclo [ 2.2.1] tert-butyl heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 25 1598-1611), and 3,5-dibromopyridine (purchased from Avocado Research 87 Chemicals, Ltd.) were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI / NH2) m / z 354 (m + H) \ Example 31B 1S, 4S) -2- (5-bromo-3-pyridinyl) -2,5-diazabicyclo2.2.11heptane 4-methylbenzenesulfonate The product of Example 31A was processed as described in Example 2B to provide the title compound . 1H NMR (CDCI3, 300 MHz) d 1.92-2.10 (m, 2H), 3.21 (s, 2H), 3.60-3.71 (m, 2H), 4.05 (s, 1H), 4.38 (s, 1H), 6.97 (t, J = 1.0 Hz, 1H), 7.90 (d, J = 2.0Hz, 1H), 8.03 (d, J = 1.0 Hz, 1H); MS (DCI / NH3) m / z 254 (M + H) +; Anal. cale, for C? 7H20N3O3SBr.0.30 TsOH: C, 47.99; H, 4.72; N, 8.79. C, 48.02; H, 4.95; N, 8.87. 15 Example 32 4-methybenzenesu fonate of (1S, 4S) -2- (5-cyano-3-pyridinip-2.5-diazabicyclo2.2.11he tan Example 32A (1S.4S) -5- (5-cyano-3-pyridinyl) -2,5-d-azabicyclof? -2.11 heptane-2-tert-butyl carboxylate The product of Example 31A (2.89 g, 8.2 mmoles) in 60 ml of Anhydrous / degassed DMF was treated with Zn (CN) 2 (0.481 g, 4.1 mmole), and tetrakis (triphenylphosphine) -palladium (0) (0.95 g, 0.8 mmole).

The mixture was heated at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and was emptied into 150 ml of diethyl ether. The organic products were washed with brine / water (1/1) (200 ml), dried (MgSO), and concentrated under reduced pressure. The residue was purified on SiO2 (5% MeOH / CH2Cl2) to provide the title compound (1.90 g, 77% yield) as a white solid. MS (DCI / NH2) m / z 301 (M + H) +.

Example 32B 4-Methylbenzenesulfonate of (1S.4S) -2- (5-cyano-3-pyridinip-2.5-d-aza b-cycle T2.2.11 heptane The product of Example 32A was processed as described in Example 2B to provide the title compound.1 H NMR (MeOD, 300 MHz) dd 2.0 (d, J = 13.0 Hz, 1 H), 2.21 (d, J = 13.0 Hz, 1 H), 3.38 (s, 2H) , 3.42 (d, J = 1.0 Hz, 1 H), 3.75 (dd, J = 3.0, 12.0 Hz, 1 H), 4.56 (s, 1 H), 4.82 (s, 1 H), 7.48 (t, J) = 1.0 Hz, 1 H), 8.19-8.31 (m, 2H), MS (DCI / NH3) m / z 201 (M + H) +, Anal cale, for C18H2oN4O3S: C, 58.05; H, 5.41; N , 15.04 C was found, 57.84, H, 5.47, N, 14.81.

Example 33 4-methylbenzenesulfonate of (1R, 4R) -2- (β-fluoro-3-pyridinyl) -2,5-diazabicyclo f2.2.11hept anus Example 33A (1R, 4R) -5- (ß-fluoro-3-pyridinip-2,5-diazabicyclo2.2.nheptane-2-tert-butylated carboxylate) The product of Example 15B and 2-fluoro-5- iodopyridine were processed as described in Example 30A to provide the title compound, MS (DCI / NH3) m / z 294 (M + H) +.

Example 33B (1R, 4R) -2- (ß-fluoro-3-pyridinin-2,5-diazabicyclochloride2.2.11 heptane) 4-methy1benzenesulfonate The product of Example 33A was processed as described in Example 2B to provide the compound of Title: 1H NMR (CDCl3.300 MHz) d 1.75 (d, J = 12.0 Hz, 1H), 1.96 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 9.0 Hz, 1H), 3.07 (s) , 2H), 3.66 (dd, J = 3.0, 9.0 Hz, 1H), 3.81 (s, 1H), 4.26 (s, 1H), 6.78 (dd, J = 1.0, 6.0 Hz, 1H), 6.92-7.0 ( m, 1H), 7.45 (t, J = 1.0 Hz, 1H); MS (DCI / NH3) m / z 194 (M + H) +, 211 (M + NH4); Anal cale, for C? 7H20N3O3SF: C, 55.20; H, 5.59; N, 11.36, C, 55.21; H, 5.61; N, 11.13.

Example 34 (1 S, 4 S) -2- (5-aminomethyl-3-pyridinyl) -2,5-diazabicyclo trichlorohydrate r2.2.11hept anus Example 34A (1S.4S) -5- (5-aminomet I -3-p iri d8nil) -2.5-diaza bicyclo r2.2.11heptan-2-carboxylate of tert-butyl The product of Example 32A (0.267 g, 0.80 mmole) in 30% NH3 / methanol was treated with Raney nickel (0.10 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (4218 kg / cm2) for 4 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; 10% MeOH / CH2Cl2 / 1% NH OH) to provide the title compound (0.199 g, 73% yield).

Example 34B (1S, 4S) -2- (5-aminomeyl-3-pyridinyl) -2,5-diazabicyclochloride.2.2pheptane trichlorohydrate The product of Example 34A (0.199 g, 0.65 mmole) in EtOH (5%). ml) was treated with 4N HCl / dioxane (5 ml). After stirring at room temperature for 1 hour, the volatiles were removed under reduced pressure to provide the title compound (0.042 g, 20% yield) as a white solid. 1 HOUR NMR (CDCI3.300 MHz) d 2.18 (d, J = 12.0 Hz, 1 H), 2.34 (d, J = 12.0 Hz, 1 H), 3.45-3.58 (m, 3H), 3.83 (d, J = 15.0 Hz, 1 H), 4.32 (s, 2H), 4.68 (s, 1H), 4.89 (s, 1H), 7.68 (s, 1H), 8.11 (s, 1H), 8.15 (s, 1H); MS (DCI / NH3) m / z 205 (M + H) +; Anal. cale, for CnH16N4 «3.6 HC 0.45 EtOH: C, 40.12; H, 6.31; N, 15.73. We found C, 40.22; H, 6.20; N, 15.72.

Example 35 2- (6-Chloro-3-pyridinyl) -2.β-diazabicyclo3.2.11octane trichlorohydrate Example 35A 3-oxo-2, benzyl 5-oxo-2-azabicyclo [2.2.1] heptan-2-carboxylic acid benzyl-2-diazabicyclo3.2.noctane-6-carboxylate (2.46 g, 10.0 mmol) prepared in accordance with the procedures described by (Carroll, FI; et al., J. Med. Chem. (1992) 35, 2184), in 50 ml of 95% aqueous ethanol at room temperature, treated with sodium acetate (2.47 g, 30.1 mmoles) and hydroxylamine hydrochloride (3.48 g, 50.1 mmoles). After 45 minutes, the mixture was concentrated under pressure and the residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated to provide 2.50 g (96%) of a mixture of the desired oximes as a white solid. A portion of this material (1.57 g, 6.03 mmol) was stirred in a 5: 1 solution of CH2Cl2 / trimethylsilyl-diphosphate for 12 hours at room temperature. The solution was diluted with H2O and extracted 2 times with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; 95: 5 CH2Cl2 / MeOH) to provide 1.08 grams (68%) of the title compound as a white solid. MS (DCI / N H3) m / z 261 (M + H)? 278 (M + N H4) +.

Example 35B 2, β-diazabicyclo3.2. benzyl noctane-6-carboxylate The product of Example 35A (800 mg, 3.07 mmol) in 12 ml of THF at 0 ° C was treated dropwise with a 2.0 M solution of a borane-methyl sulfide complex in TH F (3.4 ml, 6.8 mmol). The solution was stirred for 14 hours at room temperature, then cooled again to 0 ° C and quenched through careful addition of MeOH and concentrated under reduced pressure. The residue was dissolved in 12 ml of toluene and treated with 1.7 ml of N-propylamine. The mixture was stirred for 3 hours at 50 ° C, allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (4X). The organic extracts were combined, dried (K2CO3) and concentrated. The residue was purified by chromatography (silica gel; 90: 10: 1 CH2Cl2 / MeOH / NH4OH) to provide 453 mg (60%) of the title compound as a colorless oil. MS (DCI / NH3) m / z 247 (M + H) +.

Example 35C 2- (β-Chloro-3-pyridinyl) -2.β-diazabicyclof3.2.1 | oct-ano -6-benzylcarboxylate The product of Example 35B and 2-chloro-5-iodopyridine were processed as described in Example 1 A to provide the title compound (yield 30%) as a light yellow oil. (MS (DCI / N H3) m / z 358, 360 (M + H) +.

Example 35D 2- (6-Chloro-3-pyridinyl) -2-, β-diazabicyclo-r2.2.11octane trichlorohydrate The product of Example 35C (62 mg, 0.17 mmole) in 3 ml of acetonitrile at 0 ° C was treated with iodotrimethysilane (37 ml, 0.26 mmol). The solution was stirred at 0 ° C for 3 hours, quenched with MeOH and concentrated under reduced pressure. The residue was diluted with 1 N aqueous HCl and extracted with EtOAc (2X). The aqueous phase was basified with 10% aqueous NaOH and extracted with 3: 1 CH2Cl2 / iPrOH (4X). The combined extracts were dried (K2CO3) and concentrated to provide a light yellow oil. The oil was diluted with EtOH and treated with a solution of HCl in diethyl ether. The resulting precipitate was collected, titrated with diethyl ether and dried under high vacuum to provide the title compound as a light yellow solid. 1 H NMR (DMSO-d 6, 300 MHz) d 1.80-2.02 (m, 4H), 3.00 (m, 1 H), 3.34-3.40 (m, 2H), 3.60 (m, 1 H), 4.15 (m, 1 H), 4.68 (m, 1 H), 7.33 (d, J = 8.8 Hz, 1 H), 7.43 (d, J = 3.3, 8.8 Hz, 1 H), 8.08 (d, J = 3.0 Hz, 1 H); MS (CI / N H3) m / z 224, 226 (M + H) +; Anal. Cale, for Cn H 14CI N3-3 HCM .2 H2O: C, 37.25; H, 5.51; N, 1 1 .85. Found: C, 36.99; H, 5.21; N, 12.13.

Example 36 2- (6-Chloro-3-pyridinyl-3,9-diaza bicyclo r4.2.11nonane Hydrochloride The product of Example 37A (1.15 g, 4.6 mmol) in 10 ml of chloroform was treated with 1 .1 equivalents of a-chloroethyl chloroformate at 0 ° C. The solution was allowed to warm to room temperature for 0.5 hours and then heated to reflux for 1 hour.The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in 20 ml of methanol and heated to reflux for 1 hour.The solvent was removed under reduced pressure to provide a solid which was recrystallized from ethanol to give the title compound (1.03 g, 83% yield) .1 H NMR (CD 3 OD, 300 MHz) d 1.72-1.84 (m, 1 H), 1.87-2.0 (m, 1 H), 2.0-2.36 (m, 4 H), 3.5-3.65 (m, 2 H), 3.65- 3.78 (m, 1 H), 3.8-3.9 (br d, J = 15 Hz, 1 H), 4.22 (br s, 2 H), 7.25 (d, J = 12 Hz, 1 H), 7.38 (dd, J = 4.5, 12 Hz, 1 H), 7.97 (d, J = 4.5 Hz, 1 H); MS (DCI / NH3) m / z 238 (M + H) +, 255 (M + NH4) +; Anal.Cal, for C12H16CIN3.HCI: C, 52.57; H, 6.25; N, 15.32. Found: C, 52.82; H, 6.33; N, 15.32.

Example 37: 4-methyl-3-f3-pyridinyl-3,9-diaza bicyclo f4.2 4-methylbenzenesulfonate. Unonano Example 37A 9-methyl-3- (β-chloro-3-pyridinyl) -3,9-diazabicyclo4.2.pnonano 9-methyl-3,9-diazabicyclo [4.2.1] nonane (prepared as described in US Pat. 2,999,091) and 2-chloro-5-iodopyridine were coupled according to the procedure of Example 15C to provide the title compound (yield 78%). 1 H NMR (free base, CDCl 3, 300 MHz) d 1.23-1.48 (m, 2H), 1.65-1.76 (m, 1H), 1.91-2.27 (m, 3H), 2.44 (s, 3H), 3.18-3.35 (m, 3H), 3.48-3.54 (m, 2H), 3.65 (br d , J = 13.5 Hz, 1H), 6.98 (dd, J = 3, 8.25 Hz, 1H), 7.06 (d, J = 8.25 Hz, 1H), 7.87 (d, J = 3 Hz, 1H); MS (DCI / NH3) m / z 252 (M + H)? 269 (M + NH4) +; Anal. Cale, for C13H18CIN3'C7H8O3S: C, 56.66; H, 6.18; N, 9.91. Found: C, 56.76; H, 6.15; N, 9.77.

Example 37B 9-Methyl-3- (3-pyridinyl) -3,9-diazabicyclochloro-2-nanene-4-methylbenzenesulfonate The product of Example 37A (641 mg) was treated with Pd / C at % (61.8 mg) in 11 ml of methanol and 0.64 ml of triethylamine under a nitrogen atmosphere (4.218 kg / cm2) at 50 ° C for 1 hour. The mixture was filtered and concentrated under reduced pressure to provide a solid. The resulting solid was taken up in EtOAc and washed with saturated NaHCO3 and brine. The organic phase was dried with (MgSO4) and concentrated under reduced pressure to provide the free base (91% yield). The free base was treated with 4-methylbenzenesulfonate (1.0 equivalent) and the solid obtained was recrystallized from ethanol / ethyl acetate. 1 H NMR (CD 3 OD, 300 MHz) d 1.83-1.93 (m, 1 H), 1.93-2.11 (m, 2 H), 2.15-2.29 (m, 1 H), 2.37 (s, 3 H), 2.44-2.56 (m, 2 H) ), 2.95 (s, 3H), 3.61-3.82 (m, 4H), 4.02-4..15 (m, 2H), 7.23 (d, J = 7.5 Hz, 2H), 7.29 (dd, J = 4.5, 7.5 Hz, 1H), 7.69 (d, J = 7.5 Hz, 2H), 7.94 (dd, J = 1.5, 4.5 Hz, 1H), 8.2 (d, J = 3 Hz, 1H); MS (DCI / NH3) m / z 218 (M + H) +, 235 (M + NH4) +; Anal. cale, for C, 61.67; H, 6.99; N, 10.79. Found: C, 61.50; H, 7.03; N, 10.76.

Example 38 Bis (4-methylbenzene fonate) of (1S.4S) -2- (5-aminocarbonit-3-pyridinyl) -2,5-diazabicicof2.2.nheptane Example 38A1S.4S-5- (5-aminocarbonyl-3-pyridinium) -2,5-diazabicyclo2.2.11heptan-2-carboxylic acid tert-butyl ester The product of Example 32A (0.43 g, 1.43 mmole) in 20 ml of ethanol it was treated with 30% H2O2 (1.40 ml) and 6N NaOH and heated at 50 ° C for 2 hours. The mixture was emptied into 15% NaOH (50 mL) and extracted with CH2Cl2 (150 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified on SiO2 (5% MeOH / CH2Cl2), to give the title compound (0.20 g, 44%) as a white solid. MS (DCI / N H3) m / z 319 (M + H) +.

Example 38B Bis (4-methylbenzenesulfonate) of (1S, 4S) -2- (5-aminocarbonyl-3-pyridinyl) -2,5-diazabicyclo2.2.11 heptane The product of Example 38A was processed as described in Example 2B to provide the title compound. 1 H NMR (MeOD, 300 MHz) d 2.12 (d, J = 15.0 Hz, 1 H), 2.32 (d, J = 15.0 Hz, 1 H), 3.42 (s, 2H), 3.79 (dd, J = 2.0 , 10.0 Hz, 1 H), 4.60 (s, 1 H), 4.88 (s, 1 H), 7.70 (t, J = 1.0 Hz, 1 H), 8.21 (d, J = 3.0 Hz, 1 H), 8.42 (d, J = 1.0 Hz, 1 H); MS (DCI / NH3) m / z 219 (M + H) +; Anal. cale, for C24H3oN4? 6S2: C, 52.27; H, 5.73; N, 11.55. C, 51.92; H; 5.66; N, 10.48.

Example 39 4-Methylene Benzenesulfonate of H R.4R) -2- (5-hydroxy-3-pyridinyl) -2,5-diazabicyclo2.2.11heptane Example 39A (1 R.4R) -5- (5-benzyloxy-3-pyridine-2,5-diazabicyc2.2 pheptan-2-tert-butyl carboxylate The product of Example 15B and 5 - (benzyloxy) -3-bromo-pyridine, prepared as described in (US 5,733,912) were coupled according to the procedure described in Example 15C to give the title compound: MS (DCI / NH3) m / z 382 ( M + H) \ Example 39B M R.4R) -2- (5-benzyloxy-3-pyridyl) -2,5-diazabicyclo2.2. n-heptane The product of Example 39A (0.52 g, 1.36 mmol) in EtOH (10 mL) was treated with 4N HCl / dioxane (10 mL) and stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was purified on SiO2 (10% MeOH / CH2Cl2 / 1% N H4OH) to provide the title compound (0.347 g, 90% yield) as a white solid. MS (DCI / N H3) m / z 282 (M + H) +.

Example 39C M R.4R) -2- (5-hydroxy-3-pyridinyl-2,5-diazabicyclochlorite.2.2 lheptane The product of Example 39B (0.347 g, 1.23 mmole) in EtOH (10 ml) was treated with 10% Pd / C (10 mg) and stirred at room temperature under a hydrogen atmosphere (1 atm) for 16 hours. The catalyst was filtered, washed with 10 mL of EtOH and the combined filtrate was concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (10% MeOH / CH2Cl2 / 1% NH4OH) to give the free base of the title compound (0.168 g, 71% yield) as a light yellow solid. The free base was dissolved in EtOH and treated with a solution of para-toluenesulfonic acid (0.167 g., 1 eq) in a minimum volume of EtOH. The solution was concentrated under reduced pressure to provide the title compound (330 mg, 71% yield) as a whitish foam. H NMR (MeOD, 300 MHz) d 2.05 (d, J = 13.0 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 3.32-3.36 (m, 3H), 3.70 (dd, J = 3.0, 10.0 Hz, 1H), 4.51 (s, 1H), 4.67 (s, 1H), 6.55 (t, J = 2.0 Hz, 1H), 7.51 * (d, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H); MS (DCI / NH3) m / z 192 (M + H) +; Anal, cale, for C? 7H2? N3O4S-0.8 H20: C, 54.04; H, 6.03; N, 11.12. C, 54.15 was found; H, 6.11; N, 10.83.

Example 40 4-methybenzenesulfonate (1R, 4R) -2- (ß-chloro-5-hydroxy-3-pyridinyl) _- 2,5-diazabicyclo r2.2.11heptane Example 40A 5-bromo-3-pyridinol 3- (Benzyloxy) -5-bromopyridine (15.0 g, 56.8 mmol), prepared as described in (US 5,733,912) and 30% HBr / HOAC (200 ml) were stirred. at room temperature for 16 hours. The reaction mixture was diluted with 500 ml of diethyl ether and the resulting solid (12.9 g) was isolated by filtration. The solid, in 300 ml of methanol, was treated with 50 ml of NH 4 OH. After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure to provide the title compound (9.8 g, 89%) as a white solid. MS (DCI / NH3) m / z 174, 176 (M + H) \ Example 40B 5-Bromo-2-chloro-3-pyridinol The product of Example 40A (9.8 g, 56.3 mmol) and NaOH (2.40 g) 100 mmoles) in 100 ml of water was treated with NaOCI (35% 10% solution). The reaction mixture was stirred at room temperature for 16 hours and then quenched with 5 ml of acetic acid, extracted with 500 ml of ethyl acetate, dried (MgSO4) and concentrated under reduced pressure. The residue was purified on SiO2 (3% MeOH / CH2CI2) to give the title compound (11.1 g, 96% yield) as a yellow solid. MS (DCI / NH3) m / z 208, 210 (M + H) +.

Example 40C 5-Bromo-2-chloro-3- (methoxymethoxy) pyridine The product of Example 40B (1.2 g, 53.1 mmol) in 50 ml of diethyl ether was added to a suspension of NaH (1.69 g, 70 mmol). ) in 300 ml of DMF and 60 ml of diethyl ether. The mixture was stirred at room temperature for 30 minutes and then treated with a solution of chloromethyl-methyl ether (5.65 g, 70 mmol, Aldrich Chemical Co.) in 30 ml of diethyl ether. After stirring at room temperature for 2 hours, the mixture was quenched through the careful addition of 200 ml of water. The aqueous mixture was extracted with 300 ml of diethyl ether, and the organic phase was dried (MgSO2) and concentrated under reduced pressure. The residue was purified on SiO2 (ethyl acetate / hexane (1/4)) to provide the title compound (8.29 g, 61% yield) as a colorless oil. MS (DCI / NH3) m / z 252, 254 (M + H) +.

Example 40D (1 R.4R) -5- (ß-chloro-5-methoxymethoxy-3-pyridinyl) -2,5-diazabicyclo r2.2.11heptan-2-carboxylate of tert-butyl The product of Example 15B ( 1.0 g, 5.0 mmol) in 50 ml of anhydrous toluene was treated with the product of Example 40 (1.27 g, 5.0 mmol), Pd2 (dba) 3 (0.093 g, 0.1 mmol), BINAP (0.126 g, 0.2 mmol) and Sodium tert-butoxide (0.83 g, 8.6 mmol). The reaction mixture was heated at 80 ° C for 4 hours. The mixture was allowed to cool to room temperature, diluted with 100 ml of ether, washed with 100 ml of brine, dried (MgSO 4), and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (5% MeOH / CH2Cl2) to provide the title compound (1.0 g, 52% yield) as a yellow oil. MS (DCI / NH3) m / z 370 (M + H) +.

Example 40E 4-Methylbenzenesulfonate 1 R.4R) -2- (6-chloro-5-hydroxy-3-pyridinin-2,5-diazabicyclo f2.2.11heptane The product of Example 40D (0.60 g, 1.62 mmole) in 8 ml of acetonitrile was treated with 7.5 g of Amberlist resin and stirred at room temperature for 48 hours.The resin was moved through filtration and the filtrate was concentrated under reduced pressure.The residue was purified on SiO2 (10% MeOH / CH2Cl2 / 1 % N H4OH) to provide the free base of the title compound (0.121 g) as a white solid.The free base in EtOH was treated with 4-methylbenzenesulfonic acid (0.102 g, 1 eq.) For 10 minutes. under reduced pressure to provide the title compound (222 mg, 33% yield) as a white solid: 1 H NMR (MeOD, 300 MHz) d 2.06 (d, J = 12.0 Hz, 1 H), 2.37 (d, J = 12.0 Hz, 1 H), 3.28-3.3 5 (m, 3 H), 3.70 (dd, J = 3.0, 12.0 Hz, 1 H), 4.51 (s, 1 H), 4.65 (s, 1 H), 6.65 (d, J = 3.0 Hz, 1 H), 7.35 (d, J = 3.0 Hz, 1 H); MS (DCI / NH3) m / z 226 (M + H) +, 243 (M + N H 4) +; Anal. Cale, for C17H20N3O4SCI »0.2 TsOH.0.60 H2O: C, 49.87; H, 5.19; N, 9.48. C, 49.86; H, 5.36; N, 9.52.

Example 41 Bis (4-methyl-benzenesulfonate) of 3- (3-pyridinium) -3,9-diazabicyclo r4.2.11-nonane The product of Example 36 (1.6 mmol) was hydrogen in accordance with the procedure of Example 37B to provide the base free (86% yield). This was combined with 2.0 equivalents of 4-methylbenzenesulfonate and the solid obtained was recrystallized from ethanol / ethyl acetate to provide the title compound. H NMR (CD3OD, 300 MHz) d 1.73-1.83 (m.H1), 1.92-2.35 (m, 5H), 2.47 (s, 3H), 3.71 -3.82 (m, 3H), 3.94 (br d , J = 15 Hz, 1 H), 4.27 (br d, J = 15 Hz, 2 H), 7.23 (d, J = 7.5 Hz, 4 H), 7.69 (d, J = 7.5 Hz, 4 H), 7.80 (m , 1 H), 8.0-8.09 (m, 2H), 8.48 (d, J = 3 Hz, 1 H); MS (DCI / NH3) m / z 204 (M + H) \ 221 (M + NH4) +; Anal. Cale, for C 12 H 17 N 3"C 14 H 16 O 6 S 2: C, 57.02; H, 6.07; N, 7.67. Found: C, 56.88; H, 6.17; N, 7.57.

EXAMPLE 42 2- (3-Pyridinyl) -2,5-diazabicyclo-dichlorohydrate r2.2.11octane Example 42A 5- (3-pyridinyl) -2,5-diazabicyclo r2.2.11octan-2-carboxylate of terbutyl 2-5-diazabicyclo [2.2.2] octane (390 mg, 3.5 mmol), prepared by the Sturm method and Henry (J. Med. Chem. (1974), 17, 481), was treated with 3-bromopyridine (545 mg, 3.5 mmol), BINAP (92 mg, 0.14 mmol), Pd2 (dba) 3 (40 mg, 0.07). mmoles) and sodium tert -butoxide (431 mg, 4.5 mmol) in 10 ml of toluene under a nitrogen atmosphere. After heating the mixture at 75 ° C-5 ° C for 2 hours, the mixture was allowed to cool to room temperature and treated with di-tert-butyl dicarbonate (1.5 g, 6.9 mmol) and then allowed to stir for 16 hours. hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, hexanes: ethyl acetate 9: 1 to 1: 1) to provide the title compound (193 mg, yield 19%). MS (DCI / NH3) m / z 290 (M + H) +, 307 (M + N H4) +.

Example 42B 2- (3-pyridinyl-2,5-diazabicyclo r2.2.11octane dihydrochloride The product of Example 42A (137 mg, 0.6 mmol) was treated with a 1: 1 mixture of CH2Cl2 and TFA (3 ml After 2 hours, the solvent was removed under reduced pressure and the residue was purified by chromatography (SiO2, CHCl3, MeOH: N H4OH 95: 5: 0 to 95: 4.5: 0.5) to provide the free base. free was treated with an excess of 1 M HCl in diethyl ether to provide the title compound (65 mg, yield 37%) .1 H NMR (CD3OD, 300 MHz) d 2.04-2.17 (m, 2H), 2 -2.25 (m, 2H), 3.5-3.69 (m, 3H), 3.90 (d, J = 1 1.63 Hz 1 H), 4.00 (br s, 1 H), 4.45 (br s, 1 H), 7.87 ( dd, J = 5.01, 8.82 Hz, 1 H), 7.94 (dd, J = 1.01, 9.16 Hz, 1 H), 8.00 (d, J = 5.08 Hz, 1 H), 8.28 (d, J = 1.70 Hz, 1 H); MS (DCI / NH3) m / z 190 (M + H) +, 207 (M + NH4) +, Anal.Cal, for CnH? 5N3"2.1 HCI-0.4 C4H8O2: C, 50.27; H, 6.80; N, 13.96 was found: C, 50.05; H, 7.12; N, 14.34.

Example 43 Bis (4-methylbenzenesulfonate) of (1 S.4S) -2- (5-methoxy-3-pyridinyl) -2,5-d aza bicyclo r2.2.11heptane Example 43A 3-Bromo-5-methoxypyridine A suspension of NaH (0.47 g, 19.6 mmol) in 20 ml of DMF was carefully treated with methanol (0.59 g, 18.4 mmol). After 30 minutes, the mixture was treated with a solution of 3,5-dibromopyridine (4.0 g, 16.9 mmol) in 5.0 ml of DMF. After stirring overnight, the reaction mixture was quenched with saturated aqueous NH 4 Cl and extracted. with 200 ml of diethyl ether. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (CH2Cl2) to provide the title compound (2.24 g, 70% yield) as a yellow solid.

Example 43B MS.4Sl-5- (5-methoxy-3-pyrridinyl) -2,5-diazabi cycle r2.2.11heptan-2-tert-butylated carboxylate (1S, 4S) -2,5-diazabicyclo [2.2 .1] tert-butyl heptane-2-carboxylate, prepared as descd in (J. Med. Chem., (1988) 31, 1598-1611), and the product of Example 43A were coupled according to the procedure descd in Example 1A to provide the title compound. MS (DC1 / NH3) m / z 306 (M + H) +.

Example 43C Bis (4-methylbenzenesulfonate) of (1S.4S) -2- (5-methoxy-3-pyridinyl) -2,5-diazabicyclo r2.2.11heptane The product of Example 43B was processed as descd in Example 2B to provide the title compound. 1H NMR (CDCI3, 300 MHz) d 1.82-2.01 (m, 2H), 3.02 (d, J = 10 Hz, 1H), 3.08 (s, 2H), 3. 63 (dd, J = 3.0.9.0 Hz, 1H), 3.82 (s, 3H), 3.87 (s, 1H), 4.32 (s, 1H), 6.33 (t, J = 2.0 Hz, 1H), 7.64 (d , J = 3.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1 H); MS (DCI / NH3) m / z 206 (M + H) +; Anal. cale for C25H3i N3O7S2.0.78 H2O: C, 52.89; H, 5.86; N, 7.40. C, 52.63 was found; H, 5.91; N, 7.12.

Example 44 Bis (4-methyl I-benzenesulfonate) of (1 R.4R) -2- (5-cyano-3-pyridinyl) -2.5- diazabicyclo r2.2.11heptane Example 44A (1 R.4R) -5- (5-bromo-3-pyridinyl) -2.5-diaia bicyclo r2.2.11heptan-2-tert-butylated carboxylate The product of Example 15B and 3,5-dibromopyridine processed as described in Example 1A to provide the title compound.

Example 44B (1 R.4R) -5- (5-Cyano-3-pyridinyl -2.5-diazabicyclo f2.2.11heptan-2-tert-butyl carboxylate The product of Example 44A was processed as described in Example 32A for provide the title compound: MS (DCI / NH3) m / z 301 (M + H) +.

Example 44C 4-methylbenzenesulfonate of (1 R.4R) -2- (5-cyano-3-pyridinyl) -2,5-diazabicyclo f2.2.11heptane The product of Example 44B was processed as described in Example 2B to provide the compound of the title. 1H NMR (MeOD, 300 MHz) S 2.10 (dt, J = 1.0, 11.0 Hz, 1H), 2.31 (dt, J = 1.0, 11.0 Hz, 1H), 3.38 (d, J = 2.0 Hz, 2H), 3.42 (d, J = 1.0 Hz, 1H), 3.75 (dd, J = 3.0, 9.0 Hz, 1H), 4.56 (s, 1H), 4.82 (s, 1H), 7.50 (dd, J = 1.0, 4.0 Hz; 1H), 8.23 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 3.0 Hz, 1H); MS (DCI / NH3) m / z 201 (M + H) +, 218 (M + NH4) +; Anal. cale, for C18H2oN4O3S «0.50 H2O: C, 56.68; H, 5.55; N, 14.69. Found C, 56.92; H, 5.48; N, 14.29.

Example 45 4-methylbenzenesulfonate of (1S.4S) -2- (6-chloro-5-hydroxy-3-pyridine I) -2.5-d aza bicyclo r2.2.11heptane Example 45A (1S.4S) -5- (ß-Chloro-5-methoxymethoxy-3-pyridinyl) -2,5-diaza bicyclo r2.2.11heptan-2-carboxylic acid tert -butyl ester (1S, 4S) - 2,5-Diazabicyclo [2.2.1] heptane-2-carboxylate of tert-butyl, prepared as described in (J. Med. Chem. (1988) 31, 1598-1611), and the product of Example 40C were processed as described in Example 40D to provide the title compound. MS (DCI / NH3) m / z 370 (M + H) +.

Example 45B 4-Methylbenzenesulfonate of (1 S.4S) -2-f-chloro-5-hydroxy-3-pyridinyl) -2,5-diaia bicyclo T2.2.11 heptan or The product of Example 45A (1. 00 g, 2.7 mmol) in EtOH (2.0 ml) was treated with 4N HCl / dioxane (5 ml) and then heated at 60 ° C for 4 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified on SiO2 (10% MeOH / CH2Cl2 / 1% NH OH) to provide the free base of the title compound (0.424 g) as a light yellow solid. The free base was treated with 4-methylbenzenesulfonic acid (0.356 g, 1 eq) in a minimum amount of EtOH for 10 minutes, then concentrated under reduced pressure to yield the title compound (0.78 g, 72% yield) as a solid. White. < H NMR (MeOD, 300 MHz) d 2.08 (d, J = 12.0 Hz, 1 H), 2.28 (d, J = 12.0 Hz, 1 H), 3.32-3.38 (m, 3H), 3.70 (dd, J = 3.0, 12.0 Hz, 1 H), 4.52 (t, J = 1.0 Hz, 1 H), 4.65 (s, 1 H), 6.64 (d, J = 3.0 Hz, 1 H), 7.32 (d, J = 3.0 Hz, 1 H); MS (DCI / NH3) m / z 226 (M + H) +, 243 (M + NH4) +; Anal. cale, for C17H2oN3Cl? 4S «3.0 H2O: C, 45.18; H, 5.80; N, 9.30. Found C, 45.12; H, 5.68; N, 9.29.

EXAMPLE 46 4-MethyIbenzenesulfonate of (1R, 4R) -2- (β-methoxy-3-pyridinyl) -2,5-diazabicyclo r2.2.11heptane Example 46A (1 R.4R) -5- (ß-methoxy-3-pyrid i nyl) -2.5-d aia bicyclo f2.2.11 heptan-2-tert-butyl carboxylate The product of Example 15B and 2-methoxy- 5-Bromopyridine (purchased from Frontier Scientific) were processed as described in Example 15C to provide the title compound. MS (DCI / NH3) m / z 306 (M + H).

Example 46B 4-methylbenzenesulfonate of (1 R.4R) -2- (β-methoxy-3-pyridinin-2,5-diazabicyclo r2.2.11heptane The product of Example 46A was processed as described in Example 2B to provide the compound of title. * H NMR (MeOD, 300 MHz) d 2.05 (d, J = 1 1 .0 Hz, 1 H), 2.28 (d, J = 1 1.0 Hz, 1 H), 3.25 (dd, J = 3.0, 12.0 Hz, 1 H), 3.35 (s, 2H), 3.72 (dd, J = 3.0, 12.0 Hz, 1 H), 3.78 (s, 3H), 4.48 (t, J = 1.0 Hz, 1 H), 4.61 (s, 1 H), 6.84 (d, J = 1 1.0 Hz, 1 H), 7.28 (dd, J = 3.0, 9.0 Hz, 1 H), 7.53 (d, J = 3.0 Hz, 1 H); (DCI / NH3) m / z 206 (M + H) +; Anal cale, for C? 8H23N3O4S «0.45.0 H2O: C, 56.07; H, 6.25; N, 10.90 C was found, 56.14; H, 6.12; N, 10.52.

Example 47 4-methyl benzenesulfonate of f R, 4R) -2- (6-chloro-5-methyl-3-pyrridinyl) -2,5-diazabicyclo r2.2.11heptane Example 47A (1 R.4R) -5- (ß-chloro-5-methyl-3-pyridinyl) -2.5-diaza bicyclo r2.2.11heptan-2-carboxylate of tert-butyl The product of Example 15B and 2-chloro -5-iodo-3-methy! Pyridine, prepared as described in (US 5,733,912) were processed as described in Example 15C to provide the title compound. MS (DCI / NH3) m / z 324 (M + H) +.

Example 47B 4-Methylbenzenesulfonate of (1 R.4R) -2- (β-chloro-5-methyl-3-pyridinyl) -2,5-diazabicyclo r2.2.11heptane The product of Example 47A was processed as described in Example 2B to provide the title compound. H NMR (CDCl 3, 300 MHz) d 1.89 (d, J = 10.0 Hz, 1 H), 1.98 (d, J = 10.0 Hz, 1 H), 2.31 (s, 3 H), 3.00 (dd, J = 1.0, 10.0 Hz, 1 H), 3.09 (s, 2H), 3.63 (dd, J = 3.0, 9.0 Hz, 1 H), 3.88 (s, 1 H), 4.29 (s, 1 H), 6.72 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 3.0 Hz, 1 H); MS (DCI / NH3) m / z 224 (M + H) +; Anal. cale, for C? sH22N3O3SCL0.2 H2O: C, 54.12; H, 5.65; N, 10.52. Found C, 54.21; H, 5.80; N, 10.18.

Example 48 4-methyl benzene sulphonate of (R.4R) -2- (5,6-dichloro-3-pyridinyl) -2,5-diazabicyclo f2.2.11heptane Example 48A (1 R.4R) -5- (5β-dichloro-3-pyridinyl) -2.5-diazabicyclo r2.2.11heptan-2-carboxylate The product of Example 15B and 2,3-dichloro-5- iodopyridine, prepared as described in (US 5,733,912) were processed as described in Example 15 to provide the title compound. MS (DCI / NH3) m / z 344 (M + H) +.

Example 48B 4-methyl Ibencenesulfonate of (1 R.4R) -2- (5,6-dichloro-3-pyridinyl) -2,5-diazabicyclo r2.2.11heptane The product of Example 48A was processed as described in Example 2B to provide the title compound. 1 H NMR (MeOD, 300 MHz) d 2.07 (m, 1 H), 2.30 (m, 1 H), 3.28-3.34 (m, 1 H), 3.47 (s, 2H), J.72 (dd, J = 2.0, 10.0 Hz, 1 H), 4.53 (t, J = 1.0 Hz, 1 H), 4.75 (s, 1 H), 7.36 (d, J = 3.0 Hz, 1 H), 7.77 (d, J = 3.0 Hz, 1 H); MS (DCI / NH3) m / z 244 (M + H) +; Anal. cale, for EtOH: C, 49.06; H, 4.65; N, 10.04. We found C, 49.22; H, 5.04; N, 1.05.

Example 49 Bis (4-methyl-benzenesulfonate) ß- (ß-chloro-3-pyridinyl) -2.β-diazabicyclo r3.2.11octane Example 49A 2, 6-diazabicyclo f3.2. poctan-2-carboxy tert-butyl ester The product of Example 35B (140 mg, 0.568 mmol) in CH 2 Cl 2 at room temperature was treated with triethylamine followed by di-tert-butyium dicarbonate. The solution was stirred for 2 hours, diluted with saturated aqueous K2CO3, and extracted with CH2Cl2 (2X). The organic extracts were combined, dried (Na2SO4), and concentrated under reduced pressure to provide 190 mg of a colorless oil. A suspension of the oil and Pd / C at 10% (20 mg) in ml of MEOH was stirred under a hydrogen atmosphere (balloon) for 6 hours. The catalyst was removed by filtration through a plug of Celite by washing (CH2Cl2). The filtrate was filtered to provide the title compound (106 mg, 91%) as a colorless oil. MS (DCI / N H3) m / z 213 (M + H) \ 230 (M + N H4) +.

Example 49B 6- (6-chloro-3-pyrid i nyl) -2.6-d iaza bicyclo r3.2. H -octane-2-carboxylate of tert-butyl The product of Example 49A and 2-chloro-5-iodopyridine were processed as described in Example 1A to give the title example (yield 30%) as a light yellow oil. MS (CDI / NH3) m / z 324, 326 (M + H) +.

Example 49C Bis (4-methyl-1-benzenesulfonate) 6- (β-chloro-3-pyridinyl) -2,6-diazabicyclo-r3.2.11-octane The product of Example 49B (40 mg, 0.12 mmol) in EtOAc (3 ml) was treated with p-toluenesulfonic acid «monohydrate (59 mg, 0.31 mmol). The solution was refluxed for 2 hours and allowed to cool to room temperature resulting in the formation of a precipitate. The precipitate was titrated with diethyl ether (2X) and placed under high vacuum to provide 70 mg (85%) of the title compound as a white solid. 1 H NMR (D 2 O) d 1.92 (m, 1 H), 2.14-2.28 (m, 3H), 2.99 (s, 6H), 2.99 (dt, J = 5.5, 12.9 Hz, 1 H), 3.31 (dd, J = 6.6, 13.4 Hz, 1 H), 3.56 (d, J = 12.1 Hz, 1 H), 3.77 (dd, J = 4.4, 12.1 Hz, 1 H), 4.3 8 (m, 2H), 7.25 (dd, J = 3.2, 9.0 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 4H), 7.40 (d, J = 9.2 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 4H), 7.78 ( d, J = 2.9 Hz, 1 H); MS (CI / NH3) m / z 224, 226 (M + H) +; Anal. Cale, for C11H14CIN3-2.5C7H8O3S-0.5 H2O: C, 51.61; H, 5.32; N, 6.34. It was found: C, 51.31; H, 5.43; N, 6.21.

Example 50 Bis (4-methylbenzenesulfonate) of (1 R.4R) -2- (5-aminocarbonyl-3-pyridinyl) -2,5-diazabicyclo f2.2.11 heptane Example 50A (1 R.4R) -5- (5-aminocarbonyl-3-pyridin i I) -2.5-diaza bicyclo r2.2.11heptan-2-carboxylate of tert-butyl The product of Example 44A was processed from according to the procedure described in Example 38A to provide the title compound. MS (DC1 / NH3) m / z 319 (M + H) +.

Example 50B Bis (4-methylbenzenesulfonate) of (1 R.4R) -2- (5-aminocarbonyl-3-pyridinyl) -2,5-diazabicyclo f2.2.11 heptane The product of Example 50A was processed as described in Example 2B to provide the title compound. 1 H NMR (MeOD, 300 MHz) d 2.26 (d, J = 12.0 Hz, 1 H), 2.25 (d, J = 12.0 Hz, 1 H), 3.41 -3.52 (m, 3H), 3.82 (dd, J = 2.0, 10.0 Hz, 1 H), 4.65 (t, J = 1.0 Hz, 1 H), 5.96 (s, 1 H), 8.14 (dd, J = 1.0, 3.0 Hz, 1 H), 8.32 (d, J = 2.0 Hz, 1 H), 8.47 (d, J = 1.0 Hz, 1 H); MS (DCI / NH3) m / z 219 (M + H) +; Anal, cale, for C24H30N4O7S2 »0.40 TsOH« 1 .0 H2O: C, 50.49; H, 5.57; N, 8.79. C, 50.53 was found; H, 5.75; N, 8.76.

Example 51 4-methylobenzenesulfonate (1R, 4R) -2- (6-chloro-5-methoxy-3-pyridine i!) - 2, 5-diazabicyclo2.2.11heptane Example 51 To 5-Bromo-chloro-3-methoxy pyridine The product of Example 40B (1.2 g, 5.8 mmol) in 5 ml of diethyl ether was added to a suspension of NaH (81 mg, 7.5 mmol) in 30 ml of dry DM F and 6 ml of diethyl ether. After stirring at room temperature for 30 minutes, the mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in 3 ml of diethyl ether and stirring was continued for a further 30 minutes. The reaction mixture was quenched with 20 ml of water, extracted with 100 ml of diethyl ether, dried (MgSO4), and concentrated under reduced pressure. The residue was purified over SiO2 (ethyl acetate / hexane, 1/4) to provide the title compound (0.32 g, 25%) as a colorless oil. MS (DCI / N H3) m / z 222/224/226 (M + H) \ Example 51 B (1 R.4R) -5- (ß-chloro-5-methoxy-3-pyridinii) -2.5- diazabicyclo2.2.11heptan-2-carboxylate of tert-butyl The product of Example 15B and the product of Example 51 A were processed as described in Example 15 to provide the title compound (yield 74%). MS (DCI / N H3) m / z 340 (M + H) +.

Example 51C 4-methyl-1-benzenesulfonate (1R.4R) -2- (6-chloro-5-methoxy-3-pyridinyl) -2,5-diazabicyclochloride2.2.1 heptane The product of Example 51B was processed as described in Example 2B to provide the title compound (yield 50%). 1H NMR (MeOD, 300 MHz) d 1.82 (d, J = 12.0 Hz, 1H), 1.96 (d, J = 12.0 Hz, 1H), 2.97 (s, 3H), 3.58 (dd, J = 3.0, 12.0 Hz, 1H), 3.78-3.82 (m, 2H), 3.89 (s, 1H), 4.46 (s, 1H), 4.79 (s, 1H), 6.68 (d) , J = 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H); MS (DCI / NH3) m / z 240 (M + H) +; Anal. cale, for C? 8H22N3O4SCI «0.25 TsOH« 0.60 H2O: C, 50.93; H, 5.45; N, 9.02. C, 50.94 was found; H, 5.57; N, 8.95.

Example 52 4-Methylbenzenesulfonate of (1S.4S) -2- (5-pyrimidinyl) -2,5-diazabicyclo2.2.nheptane Example 52A (1S.4S) -5- (5-pyrimidinin-2,5-diazabicyclo2.2.pheptan-2-tert-butyl carboxylate (1S, 4S) -2,5-diazabicynic [2.2.1] heptane-2- Terbutyl carboxylate (330 mg, 1.6 mmol) prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 5-bromopyrimidine (purchased from Acros Scientific) were processed as described in Example 15C to provide the title compound (99% yield) MS (DCI / NH3) m / z 277 (M + H) +.

Example 52B 4-met i I benzenesulfonate (1S, 4S) -2- (5-pyrimidinyl) -2,5-diazabicyclo2.2.11 heptane The product of Example 52B was processed as described in Example 2B to provide the title compound (33% yield) 1 H NMR (MeOD, 300 MHz) d 1.87-2.01 (m, 2H), 3.01 -3.16 (m, 3H), 3.67 (dd, J = 2.0, 8.0 Hz, 1 H), 3.79 (s, 1 H), 4.37 (s, 1 H), 8.06 (s, 2H), 8.57 (s, 1 H); MS (DCI / NH3) m / z 177 (M + H) +; Anal cale, for C? 6H20N4O3S.0.10 TsOH.0.25 H2O: C, 54.19; H, 5.80; N, 15.14. C, 54.24; H, 5.89; N, 15.17.

Example 53 Acetate of (1 S.4S) -2- (3-qui nol ini l) -2.5-diazabicyclo2.2.11 heptane Example 53A (1S.4S) -5- (3-quinolinyl) -2,5-d-iazabicyclochloro.2.11 heptan-2-tert-butyl carboxylate (1S, 4S) -2,5-diazabicyclo [2.2.1 ] tert-butyl heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 3-bromoquinoline (purchased from Aldrich Chemical Co.) were coupled in accordance with procedure described in Example 1 A to provide the title compound.

Example 53B Acetate (1S.4S) -2- (3-quinolinyl) -2.5-diazabicyclo2.2.nheptane The product of Example 53A was processed as described in Example 34B to provide the crude hydrochloride. The crude hydrochloride was purified by preparative HPLC (Water Nova-Pak HR C186 μm 60A 25 x 100 mm, 0-95% CH3CN / 10 mM NH4OAc for 10 minutes at 40 ml / minutes) to provide the title compound after the Removal of solvents under reduced pressure. 1 H NMR (MeOD, 300 MHz) d 1.90 (s, 3 H), 2.06 (br d, J = 11 Hz, 1 H), 2.24 (br d, J = 11 Hz, 1 H), 3.30, (br s, 2 H), 3.41 (d, J = 10 Hz, 1H), 3.84 (d, J = 10 Hz, 1H), 4.33 (br, 1H), 4.80 (br, 1H), 7.34 (m, 1H), 7.46 (m, 2H), 7.73 (br d, J = 7 Hz, 1H), 7.87 (br d, J = 7 Hz, 1H), 8.51 (br d, J = 3 Hz, 1H).

Example 54 Acetate of MS.4S) -2- (3-methyl-5-isothiazolyl) -2.5- diazabicyclo2.2.11 heptane Example 54A f1S.4S) -5- (3-Methyl-5-isothiazolin-n-2,5-diazabicyclo2.2.nheptan-2-tert-butyl carboxylate (1S, 4S) -2,5-diazabicyclo [2.2.1 ] tert-butyium heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611) and 5-bromo-3-methylisothiazole prepared as described in (US 3,840,665) were coupled according to the procedure described in Example 1A to provide the title compound.

Example 54B (1S.4S) -2- (3-Methyl-5-isothiazolyl) -2,5-diazabicyclic2.2.11heptane Acetate The product of Example 54A was processed as described in Example 53B to provide the compound of Title. 1 H NMR (MeOD, 300 MHz) d 1.84 (s, 3 H), 1.86 (m, 1 H), 2.04 (br d, J = 11 Hz, 1 H), 2.18 (s 3 H), 3.06 (m, 2 H), 3.16. (br d, J = 10 Hz, 1H), 3.30 (m, 1H), 4.05 (br s, 1H), 4.17 (br s, 1H), 5.99 (s, 1H).

Example 55 Acetate (1R.4R) -2- (thienor3.2-bl-ridin-2-n-2.5-diazabicyclo2.2.nheptane Example 55A (1R.4R) -5- (thienor3.2-blpyridin-2-in-2.5-diazabicyclo2.2.nheptan-2-carboxylate The product of Example 15B and 2-bromotinne [3,2-b] pyridine, prepared as described in (J. Het Chem. (1984), 785-789), were processed as described in Example 1A to provide the title compound.

Example 55B Acetate of (1 R.4R) -2- (thienor3.2-blPiridin-2-yl) -2.5- diaza bi cid of2.2.11 heptan or The product of Example 55A was processed as in Example 53B to provide the composed of the title. 1 H NMR (MeOD, 300 MHz) d 1.92 (s, 3 H), 2.04 (br d, J = 1 1 Hz, 1 H), 2.26 (br d, J = 1 1 Hz, 1 H), 3.28 (m , 1 H), 3.41 (m, 2H), 3.74 (dd, J = 10, 2 Hz, 1 H), 4.33 (br s, 1 H), 4.53 (br s, 1 H), 6.18 (s, 1 H), 7.01 (dd, J = 8, 4 Hz, 1 H), 8.01 (br d, J = 8 Hz, 1 H), 8.29 (br d, J = 4 Hz, 1 H).

Example 56 9- (β-Chloro-3-pyridinyl) -3,9-diazabicyclochloride fumarate4.2. Uñona no Example 56A 9-methyl-3,9-diazabicyclo4.2.pnonan-3-carboxylic acid tert-butyl 9-methyl-3,9-diazabicyclo [4.2.1] nonane (4.60 g, 33 mmol), prepared as was deciphered in ( US 2,999,091), in 50 ml of CHCl3 at 0 ° C, treated with triethylamine (6.7 g, 66 mmol) and di-t-butyl dicarbonate (14.4 g, 66 mmol). The mixture was allowed to warm to room temperature and was stirred for 12 hours. The reaction mixture was washed in succession with NaHCO3 and brine. The organic phase was dried (MgSO4) and concentrated under reduced pressure to provide the title compound (99% yield). MS (DCI / NH3) m / z 241 (M + H) +.

Example 56B 3,9-diazabicyclof4.2.11nonan-3-carboxylate of t-butyl The product of Example 56A was processed (on a scale of 33 mmole) according to the procedure of Example 36 to provide the title compound ( 51% yield). MS (DCI / N H2) m / z 227 (M + H) +, 241 (MNH4) +.

Example 56C 9- (6-Chloro-3-pyridinyl) -3,9-diazabicycloflu.2.2nnonan-3-carboxylate of t-butyl The product of Example 56B (17 mmol) and 2-chloro-5-iodopyridine (21 mmoles) were coupled according to the procedure of Example 15C to provide the title compound (21% yield). MS (DCI / NH3) m / z 338 (M + H) +.

Example 56D 9- (6-Chloro-3-pyridinyl) -3.9-diazabicyclo4.2-nano-Nato fumarate The product of Example 56C was treated with trifluoroacetic acid according to the procedure of Example 15D. After purification by chromatography (SiO2; 10% MeOH: 89% CH2CI2: 1% NH4OH), the free base was combined with 1.1 equivalents of fumaric acid in hot EtOAc. After cooling, the title compound was separated as a solid with a yield of 97%. 1 H NMR (CD3OD, 300 MHz) d 1.84-2.08 (m, 3H), 2.22-2.56 (m, 3H), 2.92-3.02 (m, 1 H), 3.16-3.29 (m, 2H). 3.58 (d, J = 4.5, 13.5 Hz, 1H), 4.47-4.55 (m, 1H), 4.57-4.66 (m, 1H), 6.67 (s, 2H), 7.25 (s, 2H), 7.86 (s, 1 HOUR); MS (DCI / NH3) m / z 238 (M + H)? 255 (M + NH4) +; Anal. Cale, for C? 2Hi6CIN3 »C4H4O4: C, 54.32; H, 5.70; N, 11.88. Found: C, 54.33; H, 5.77; N, 11.77.

Example 57 Bis (4-methylbenzenesulfonate) 3- (3-pyridinyl) -3,7-diaza bicyclic3.3.nnone not Example 57A 3- (3-pyridinyl) -3,7-diazabicyclo3.3.pnonano-3,7-diazabicyclo [3.3.1] nonane, prepared as described in (Garrison, GL et al., J. Org. Chem. , 27, (1993) 7670), and 3-bromopyridine, were processed as described in Example 1A. The proportions of reactants were changed from Example 1A to the following: Pd2 (dba) 3 (0.02 eq), BINAP (0.05 eq), and NaOt-Bu (1.7 eq). The title compound was obtained in a 25% yield after purification by flash chromatography (silica gel; CHCl3; MeOH: NH4OH; 90: 5: 1). MS (DCI / NH3) m / z 204 (M + H) +.

Example 57B Bis (4-methylbenzenesulfonate) 3-f3-pyridinyl) -3,7-diazabicyclo3.3.11nonane The product of Example 57A was treated with 2.0 equivalents of p-toluenesulfonic acid and the solid obtained was recrystallized from ethanol. ether to provide the title compound (yield 53%) .1H NMR (CD3OD, 300MHz) d 2.04 (m, 2H), 2.37 (s, 6H), 2.39 (m, 2H), 3.23 (m, 2H), 3.31 (m, 2H), 3.59 (bd, J = 13.24 Hz, 2H), 4.04 (bd, 12.14 Hz, 2H), 7.23 (d, J = 8.09 Hz, 4H), 7.67 (d, J = 8.09 Hz, 4H ), 7.88 (dd, J = 5.52, 8.83 Hz, 1H), 8.20-8.24 (m, 2H), 8.50 (d, J = 2.57 Hz, 1H); MS (DCI / NH3) m / z 204 (M + H) +; Anal. cale, for C? 2H17N3 «-2.2 TsOH« H2O C, 56.01; H, 6.04; N, 7.15. C, 56.25 was found; H, 6.10; N, 6.79.

Example 58 4- (6-Chloro-3-pyridinyl) -3,7-diazabicyclo3.3.11nonano-methylbenzenesulfonate Example 58A 3- (6-c! Oro-3-pyridinyl) -3,7-diazabicyclo3.3.11nonane 3,7-Diazabicyclo [3.3.1] nonane, prepared as described in (Garrison, GL et al., J. Org. Chem. 58, 27, (1993) 7670), and 2-cyoro-5-iodopyridine were processed as described in Example 57A. The crude was purified by flash chromatography (silica gel; CHCl3: MeOH: NH4OH; 90: 5: 1) to provide the title compound (10% yield). MS (DC1 / NH3) m / z 238 (M + H) +.

Example 58B 3- (6-Chloro-3-pyridinyl) -3,7-diaza bicyclo 3-3-n-n-3-methylbenzenesulfonate no The product of Example 58A was treated with 1.0 equivalents of p-toluensuiphonic acid and the solid obtained was recrystallized from of ethanol / ether to provide the title compound (53% yield) .1H NMR (CD3OD, 300 MHz) d 2.00 (m, 2H), 2.31 (bs, 2H), 2.37 (s, 3H), 3.10 (m, 2H), 3.35 (m, 2H), 3.57 (bd, J = 13.22 Hz, 2H), 3.85 (bd, 11.19 Hz, 2H), 7.23 (d, J = 8.14 Hz, 2H), 7.34 (d, J = 8.13 Hz, 1H), 7.57 (dd, J = 3.05, 8.81Hz, 1H), 7.70 (d, J = 8.13 Hz, 2H), 8.15 (d, J = 3.39 Hz, 1H); MS (DCI / NH3) m / z 238 (M + H) +; Anal. cale, for C? 2H 6CIN3 «1.1 TsOH.0.5 H2O C, 54.25; H, 5.96; N, 9.63. C, 54.05 was found; H, 5.60; N, 9.61.

Example 59 6- (3-pyridinyl) -3,6-diazabicyclochloro.2.2noctane Example 59A 2-r (2-nitrophenin-sulfonyl-1-2-azab-cyclor-2. 2 -phept-5-ene-2-Azabicyclo [2.2.1] hept-5-ene (52.5 g, 54 mmol), prepared as described in ( J. Am Chem. Soc., (1985) 107, 1768), 2-nitrobenzenesulfonyl chloride (119.6, 54 mmol), and triethylamine (75 ml, 0.54 mmol) were combined in 500 ml of methylene chloride under an atmosphere of The mixture was quenched with 500 ml of water and the phases were separated.The organic phase was washed with 2M HCl (5 x 100 ml), dried (MgSO4) and concentrated under pressure. The residue was purified by chromatography on silica gel (chloroform then hexane: EtOAc 95: 5 to 8: 2) to give the title compound (23 g, yield 23%) MS (DCI / N H3) m / e 281 (M + H) +, 298 (M + NH 4) +.

Example 59B 3-benzyl-6-r (2-nitrophenyl) sulfonip-3,6-diazabicyclo3.2.11octane Ozone (O 3 / O 2) was bubbled through a solution of the product of Example 59A (5.6 g, 2%). mmoles) in 100 ml of methanol at -78 ° C. After 1 hour, an oxygen stream was bubbled through the reaction mixture to remove excess ozone. The mixture was treated with 2 ml of dimethyl sulfide and the reaction mixture was allowed to warm to room temperature. After 30 minutes, benzylamine chloride (25 g, 170 mmol) and 30 g of 3A molecular sieves were added. After 2 hours, NaBH3CN (6.3 g, 10 mmol) was added and the reaction mixture was stirred for a further 16 hours. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 ml of water, acidified with 6N HCl (200 ml), and allowed to stir for 16 hours. Solid NaOH was added to bring the mixture to a pH of about 13. The mixture was extracted with EtOAc (5 x 200 ml). The extracts were combined, dried (K2CO3), and concentrated. The residue was purified by chromatography on silica gel (CHCl3: MeOH 1: 00 to 95: 5) to give the title compound (2.0 g, 28% yield). MS (DCI / N H3) m / e 288 (M + H) +.

Example 59C 3-Benzy-3-β-diazabicyclof3.2.11octane The product of Example 59B (1.98 g, 5 mmol) in 5 ml of DM F was treated with mercaptoacetic acid (0.7 ml, 10 mmol) and lithium hydroxide. (0.48 g, 20 mmol). After stirring under a nitrogen atmosphere for 2 hours, the reaction mixture was emptied into 20 ml of saturated Na 2 CO 3 and extracted with EtOAc (5 x 20 ml). The organic extracts were combined, dried (K2CO3), and concentrated under reduced pressure. The residue was purified on silica gel (CHCl3: MeOH: NH4OH 95: 5: 0 to 9: 1: 0.1) to provide the title compound (450 mg, 45% yield). MS (DCI / NH 3 m / e 203 (M + H) +.

Example 59D 3-Benzyl-6- (3-pyridinyl) -3,6-diazabicyclo3.2. poctane The product of Example 59C (290 mg, 1.4 mmol) and 3-bromopyridine (340 mg, 2.15 mmol) were coupled using the procedure of Example 1 A to provide the title compound (306 mg, 90% yield). MS (DCI / NH 3 m / e 280 (M + H) +.

Example 59E 6- (3-Prididinyl) -3, β-diazabicyclo3.2.11octane The product of Example 59D (290 mg, 1.1 mmol), in 2.9 ml of ethanol, was treated with Pd (OH) 2 / C ( 17 mg) to 20% (17 mg) under a hydrogen atmosphere (4,218 kg / cm2) for 36 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by chromatography (SiO2, CHCl3: MeOH: N H4OH, 9: 1: 0 to 9: 1: 0.1) to provide the title compound (42 mg, 21% yield). H NMR (CD3OD, 300 MHz) d 2.17 (br s, 1 H), 2.91 (br s, 1 H), 3.40-3.70 (m, 8H) 4.51 (m, 1 H), 7.84-7.85 (m, 2H ), 8.09 (m, 1 H), 8.19 (br s, 1 H); MS (DCI / NH3) m / e 190 (M + H) +.

Example 60 Bis (4-methylbenzenesulfonate) of 3- (3-pyridinium) -3,6-diazabicyclo3.2. poctano Example 60A 3-benzyl-3,6-diazabicyclo-t-butyl chloro.2.2octane-6-carboxylate The product of Example 59C can be treated with 1.1 equivalents of di-t-butyl dicarbonate in methylene chloride for 4 hours . The solvent was removed under reduced pressure and the residue was purified by chromatography to provide the title compound.

Example 60B 3,6-diazabicyclo3.2. t-butyl noctane-6-carboxylate The product of Example 60A can be processed according to the procedure of Example 59E to provide the title compound.

Example 60C Bis (4-methylbenzenesulfonate) 3- (3-pyridinyl) -3,6-diaza bicyclo T3.2.11oct The product of Example 60B can be processed according to the procedure of Example 2B to provide the title compound.

In Vitro Data Determination of Union Potencies of the Nicotinic Acetylcholine Receptor The compounds of the invention were subjected to in vitro assays against the nicotinic acetylcholine receptor as described below and found to be effective binders for the receptor. The in vitro protocols for determining the binding potencies of the nicotinic acetylcholine channel receptor ligands were determined as follows. The binding of [3H] -cysteine ([3H] -CYT to neuronal nicotinic acetylcholine receptors was achieved using whole rat 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 volumes of pH buffer (containing: 120 mM NaCl, 5 mM KC1, 2 mM MgCl2, 2 mM CaCI2 and 50 mM Tris-Cl, pH 7.4 @ 4 ° C ). After centrifugation at 20,000 x g for 15 minutes, the pellets were resuspended in 30 volumes of pH buffer. The test compounds were dissolved in water to make 10 mM supply solutions. Each solution was then diluted (1: 100) with pH regulator (as was done previously) and was further taken through 7 serial serial dilutions to produce test solutions from 10 to 10 M. The homogenate was added (containing 125-150 μg of protein) to triplicate tubes containing the concentration of test compound concentrations described above 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 pre-soaked in 0.5% polyethyleneimine using 3 x 4 ml of ice-cooled pH regulator. The filters were counted in 4 ml of Ecolume® (ICN). The non-specific binding was determined in the presence of 10 μM (-) nicotine and the values were expressed as a percentage of the total binding. The IC50 values were determined with the RS-1 non-linear least squares curve fitting program (BBN) and the IC50 values were converted to Ki values using the Cheng and Prusoff correction (K¡ = IC5o / (1 + [ligand] / Kd of ligand.) The results are detailed in Table 1. Each Example number corresponds to the synthetic Examples described above Examples 1 -17 and 20-59 are compounds of the present invention. 19 are comparative Examples 18 is the 6-chloro-2-pyridinyl derivative [2.2.1], corresponding to Example 1, the 6-cioro-3-pyridinyl derivative; and Example 19 is the 6-chloro-2-pyridinyl derivative [3.2.1], corresponding to Example 12, the 6-chloro-3-pyridinyl derivative [3.2.1]. Since a lower K + value is more desirable, the binding data suggests that the 3-pyridinyl derivative compounds of the present invention have a higher affinity for the neuronal nicotinic acetylcholine receptor than the 2-pyridinyl derivative compounds.

Table 1 Union Data In Vivo Data Determination of the Effectiveness of Nicotinic Acetylcholine Receptor Ligands as Analgesic Agents in the Mouse Hot Plate Paradigm An in vivo protocol was used to determine the effectiveness of nicotinic acetylcholine receptor ligands as analgesic agents in the plaque paradigm hot on mouse. Separate groups of mice (n = 8 / group) were used for each dose group. All drugs were administered through the intraperitoneal route of administration. The test drugs were dissolved in water to make a 6.2 mM supply solution. The animals were dosed with this solution (10 ml / kg of body weight) for a dose of 62 micromoles / kg. The lowest doses were similarly administered, following a serial dilution of the supply solution in increments of average registration. The animals were dosed 30 minutes before the test on the hot plate. The hot plate used was an automatic analgesia monitor (model # AHP16AN, Omnitech Electronics, Inc. Of Columbus, Ohio). The temperature of the hot plate was maintained at 55 ° C and a cut-off time of 180 seconds was used. Latency was recorded up to the tenth jump as the dependent measure. An increase in latency of the tenth jump in relation to control was considered an effect. Table 2 shows the minimally effective dose (MED), between the doses tested, where an important effect, as defined above, was observed for the compounds of the present. The data show that the selected compounds of the invention have a significant antinociceptive effect at doses ranging from 0.62 to 62 μmol / kg.

Table 2 Data and Hot Plate in Mouse Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is shown under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative, pH regulator or propellant that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated within the scope of this invention.

The actual dose levels of the active ingredients in the pharmaceutical compositions of this invention can be varied in order to obtain an amount of the active compound, which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. administration. The level of dose selected will depend on the activity of the particular compound, the route of administration, the severity of the condition to be treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start with doses of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. When used in the above treatments or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where this form exists, in a pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention represents an amount of the compound for treating diseases, at a reasonable benefit / risk ratio applicable to any medical treatment. However, it should 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 medical judgment. The therapeutically effective and specific dose level for any particular patient will depend on a variety of factors including the disease to be treated and the severity of the disease; activity of the specific compound employed; specific composition employed; age, body weight, general health, sex and the patient's diet; the time of administration, the route of administration, and the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or with the specific compound used; and similar factors well known in the medical art. For example, it is within the skill of the art to start with doses of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a human or lower animal can vary from 0.001 to about 1000 mg / kg / day. For purposes of oral administration, highly preferred doses may be in the range of about 0.001 to 5 mg / kg / day. If desired, the effective daily dose can be divided into multiple doses for administration purposes; consequently, individual dose compositions may contain such amounts or submultiples thereof to form the daily dose.

The present invention also provides pharmaceutical compositions comprising compounds of the present invention formulated together with one or more pharmaceutically acceptable, non-toxic vehicles. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical compositions of this invention can be administered to humans or other mammals, whether oral, rectal, parenteral, intracisternal, intravaginai, intraperitoneai, topical (through powders, ointments or drops, buccally or as an oral or nasal spray. The term "parenterally", as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion.The pharmaceutical compositions of this invention for parenteral injection comprise solutions, sterile pharmaceutically acceptable aqueous or non-aqueous dispersions or suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just before use Examples of aqueous and non-aqueous vehicles, diluents, solvents or carriers include water, ethanol, polyols (such as glycerol, propylene glycol) ico, polyethylene glycol, etc. , and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and their suitable mixtures. The proper fluidity can be maintained, for example, through the use of coating materials such as lecithin through the maintenance of the required particle size in the case of dispersions and through the use of surfactants. These compositions may also contain auxiliaries such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be produced by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to reduce the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved through the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its dilution rate which, in turn, may depend on the crystal size and crystal form. Alternatively, the delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle. Injectable container forms are made by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio 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 (anhydride). Injectable container formulations can also be prepared by trapping the drug in liposomes or microemulsions, which are compatible with body tissues. The injectable formulations can be used, for example, by filtration through a bacteria retention filter or by incorporating sterilization agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound can be mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate and / or, a) fillers or spreading agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; 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 delay agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbers such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise pH regulating agents. Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as polyethylene glycols with a high molecular weight, and the like. The solid dosage forms of tablets, dragees, capsules and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Optionally these may contain opacifying agents and may also be of a composition so that they release the active ingredient (s) only, or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of absorption compositions that can be used include polymeric substances and waxes.

The active compounds may also be in a 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, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, isopropyl alcohol, ethyl carbonate, lime acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to the inert diluents, the oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and perfume-providing agents. The suspensions, in addition to the active compounds, may contain suspending agents, for example, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

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 room temperature but liquid at body temperature, and therefore, will melt in the rectum or vaginal cavity and release the active compound. The compounds of the present invention can also be administered in the liposome form. As is well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed through mono- or muti-amine hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are phospholipids and natural and synthetic phosphatidylcotins (iecytins) used separately or together. Methods for forming liposomes are well known in the art. See, for example, Prescott, Ed., Methods in Ceil Biology, Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq. The compounds of the present invention that are formed through the in vivo conversion of a different compound that was administered to a mammal are intended to be included within the scope of the present invention. The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemihydrates. In general, solvated forms with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to unsolvated forms for the purposes of the invention. The compounds of the present invention may have activity against disorders that are mediated through the central nervous system. The following references describe various diseases affected by nicotinic acetylcholine receptors; 1) Williams, M.; Americ, S. P .: Bevond the Tobacco Debate: dissecting out the therapeutic potential of nicotine. Exp. Opin. Invest. Drugs (1996) 5 (8): 1035-1045; 2) Americ,. S. P.; Sullivan, J. P.; Williams, W.: Neuronal nicotinic acetylcholine receptors. Novel targets for central nervous system therapeutics. In: Psychopharmacology: The Fourth Generation of Progress. Bloom FE, Kupfer DJ (Eds.), Raven Press, New York (1995): 95-109; 3) Americ, S. P.; Holladay, M. W.; Sullivan, J. P.: Cholinergic channel modulators as a novel therapeutic strategy for Alzheimer's disease. Exp. Opin. Invest. Drugs (1996) 5 (1): 79-100; 4) Lindstrom, J.: Nicotinic Acetylcholine Receptors in Health and Disease. Molecular Neurobiology (1997) 15: 193-222; and 5) Lloyd, G K; Menzaghi, F; Bontempi B; Suto, C; Siegel, R; Akong, M; Stauderman, K; Velicelebi, G; Johnson, E; Harpold, M M; Rao, T S; They take out, A I; Chavez-Noriega, L E; Washburn, M S; Vernier, J M; Oxford, N D P; McDonald, L A: The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonist as therapeutic agents. Life Sciences (1,998) 62 (1 7/1 8): 1601-1606. These diseases include, but are not limited to the following: pain (references 1 and 2), Alzheimer's disease (references 1-5), disease of Parkinson's (references 1, 4 and 5), memory malfunction, Tourette's syndrome (references 1, 2 and 4), sleep disorders (reference 1), attention deficit hyperactivity disorder (references 1 and 3), neurodegeneration, inflammation, neuroprotection (references 2 and 3), amyotrophic atral sclerosis, anxiety (references 1, 2 and 3), depression (reference 2), mania, schizophrenia (references 1, 2 and 4), anorexia and other eating disorders , dementia induced by SI DA, epilepsy (references 1, 2 and 4), urinary incontinence (reference 1), Crohn's disease, PMS migraines, erectile dysfunction, substance abuse, cessation of smoking (references 1 and 2) and syndrome inflammation of the intestine (references 1 and 4), among others. The present invention is illustrated by way of the description and previous examples. The following description is intended as a non-limiting illustration, since many variations will be apparent to those skilled in the art. It is intended that all these variations fall within the scope and spirit of the appended claims. Changes can be made in the composition, operation and arrangement of the method of the present invention described herein without departing from the concept and scope of the invention as defined in the following claims.

Claims

CLAIMING IS 1 . - A com ponent of formula I: i, and their pharmaceutically acceptable salts, wherein: V is selected from the group consisting of a covalent bond and CH2; W is selected from the group consisting of a covalent bond, X is selected from the group consisting of a covalent bond and CH2; Y is selected from the group consisting of a covalent bond, CH2, and CH2CH2; Z is selected from the group consisting of CH2, CH2CH2, and Li is selected from the group consisting of a covalent bond and (CH2) "; n is 1 -5; R1 is selected from the group consisting of: R 2 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, aminoalkyl, aminocarbonylalkyl, benzyloxycarbonyl, cyanoalkyl, dihydropyridin-3-ylcarbonyl, hydroxy, hydroxyalkyl, phenoxycarbonyl, and -NH 2; R 4 is selected from the group consisting of hydrogen, alkyl and halogen; R5 is selected from the group consisting of hydrogen, alkoxy, alkyl, halogen, nitro, and -NH2; Re is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl, -NR7SO2R8, -C (NR7) NR7R8, -CH2C (NR7) NR7R8, -C (NOR7) R8, -C (NCN) R7. -C (NN R7R8) R8, -S (O) 2OR7, and -S (O) 2R7; and R7 and R8 are independently selected from the group consisting of hydrogen and alkyl; provided that the following compounds are excluded: 3- (6-chloro-3-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-C! Gold-2-pyrazinyl) -3,8-diazabicyclo [3.2. 1 Joctano; 8- (6-chloro-3-pyridazinyl) -3,8-diazabicyclo [3.2. 1 Joctano; and 8- (6-chloro-2-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane; and with the proviso that when V and X each is a covalent bond; W, Y, and Z are each CH2; and Li is a covalent bond, so Rt is different from: 2. - A compound according to claim 1 of formula I: p or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of CH2 and CH2CH2. 3. A method according to claim 2, wherein it is selected from the group consisting of: (1 S, 4 S) -2- (6-chloro-3-pyridazinyl) -2,5-d-azabicyclo [2.2 .1] heptane; (1S, 4S) -2- (6-Chloro-5-methyl-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-methyl-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (4-chloro-1-phthalazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (4-Chloro-1-phthalazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-chloro-5-methoxycarbon i-3-pyridazine i) -2, 5-d iaza bicyclo [2.2.1] heptane; (1S, 4S) -2- (3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-pyrimidinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (3-quinolinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (3-methyl-5-isothiazoliI) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (thieno [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane; Y (1S, 4S) -2- (furo [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane. 4. A compound according to claim 2, wherein: Z is CH2; Li is a covalent bond; and Ri is 5. A compound according to claim 4, which is selected from the group consisting of: 1S, 4S) -2- (6-chloro-3-pyridinyl) -2,5-diazabicicio [2.2.1] heptane; 1S, 4S) -2- (6-amino-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- [5- (benzyloxy) -3-pyridinyl] -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- [5-hydroxy-3-pyridinyl] -2,5-diazabicic or [2.2.1] heptane; 1S, 4S) -2- (6-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (6-nitro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (6-fluoro-3-pyridinium) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (5-bromo-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (5-cyano-3-pyridinyl) -2,5-diazabicynic [2.2.1] heptane; 1S, 4S) -2- (5-aminomethyl-3-pyridinium) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (5-aminocarbonyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (6-chloro-5-hydroxy-3-pyridinyl) -2,5-diazabicynic [2.2.1] heptane; 1S, 4S) -2- (6-chloro-3-pyridinyl) -5-cyanomethyl-2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (6-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; 1S, 4S) -2- (6-chloro-5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-chloro-5-methyl-3-pyridinyl) -2,5-diaza bicyclo [2.2.1] heptane; (1S, 4S) -2- 5,6-dicyoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 6-Chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 6-fluoro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-ethynyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-cyano-6-fiuoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-bromo-6-chloro-3-pyridinyl) -2,5-diazabicyc [2.2.1] heptane; (1S, 4S) -2- 5-cyano-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-hydroxymethyl-6-chloro-3-pyrridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 S, 4 S) -2- 5-hydroxymethyl-6-fluoro-3-pyridinyl) -2J 5 -diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-hydroxymethyl-3-pyridinyl) -2,5-diazabicyclo [.2.2.1 Jheptane, • (1S, 4S) -2- 5-aminomethyl-6-chloro- 3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-aminomethyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-aminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- 5-carboxy-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-carboxy-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-carboxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminocarbonyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminocarbonyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (6-Chloro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1 Jheptane; (1S, 4S) -2- (6-Fluoro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-Hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (2-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-methyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminosulfonyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1S, 4S) -2- (5-aminosulfonyl-6-chloro-3-pipdinyl) -2l5-diazabicyclo [2.2.1] heptane; and (1S, 4S) -2- (5-aminosulfonyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane. 6. A compound according to claim 2, wherein: Z is CH2CH2; Li is a covalent bond; and Ri is 7 '.- A compound according to claim 6, which is selected from the group consisting of: (1 S, 4 S) -2- (6-chloro-5-methyl-3-pyridinii) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5,6-dichloro-3-pyridinium) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-f! Uoro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-fIuoro-3-pyrridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-Cyano-6-fIuoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-Bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (3-pyridinium) -2,5-diazabicyclo [2.2.2] octane; and (1S, 4S) -2- (6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane. 8. A compound according to claim 1, of formula I II: neither, or a pharmaceutically acceptable salt thereof wherein: Z is selected from the group consisting of CH2 and CH2CH2- 9. A compound according to claim 8, selected from the group consisting of: (1 R, 4R) -2- (6-chloro-3-pyridazinyl) - 2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (thieno [3,2-b] pyridin-2-yl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (Forum [3,2-b] pyridin-2: yl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methyl-3-pyridazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methyl-3-pyridazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (4-Chloro-1-phthalazinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (4-Chloro-1-phthalazinyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4 R) -2- (6-Chloro-5-methoxycarbonyl-3-pyrid azi nyl) -2,5-d-aza bicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-? Irimidinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (3-quinoiinyl) -2,5-diazabicyclo [2.2.1] heptane; and (1 R, 4R) -2- (3-methyl-5-isothiazoliI) -2,5-diazabicyclo [2.2.1] heptane. 10. A compound according to claim 8, wherein: Z is CH2; it is a covalent bond; and R, is 1. A compound according to claim 10, which is selected from the group consisting of: (1 R, 4R) -2- (6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1 ] heptane; (1 R, 4 R) -2- (3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-3-pyridinyl) -5-cyanomethyl-2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4 R) -2- (5-hydroxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-hydroxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5,6-diorioro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-aminocarbonyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Chloro-5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-Bromo-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-Nitro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- (5-Bromo-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4 R) -2- (6-amino-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5- (benzyloxy) -3-pyridinyl] -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 6-chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 6-chloro-5-cyano-3-pyridinyl) -2,5-diazabicynic [2.2.1] heptane; (1 R, 4R) -2- 5-ethynyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-cyano-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-cyano-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-hydroxymethyl-6-cioro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-hydroxymethyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-hydroxymethyl-3-pyridinyl) -2,5-diazabicynic [2.2.1] heptane; (1 R, 4R) -2- 5-aminomethyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-aminomethyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-aminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-carboxy-6-cioro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-carboxy-6-fiuoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4R) -2- 5-carboxy-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1 R, 4 R) -2- (5-to my noca rbonyl-6-f luo ro-3-pyridin i l) -2, 5-diaza bicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminocarbonyl-6-cynor-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (6-Chloro-5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4 R) -2- (6-fluoro-5-hydroxyiminomethyl-3-pyrid i nyl) -2, 5-d iaza bicyclo [2.2.1] heptane; (1R, 4R) -2- (5-hydroxyiminomethyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (2-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-methyl-6-fluoro-3-pyridinium) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminosulfonii-6-phtoro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; (1R, 4R) -2- (5-aminosulfonyl-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane; and (1R, 4R) -2- (5-aminosulfonyl-3-pyridinyl) -2,5-diazabicyclo [2.2.1] heptane. 12. A compound according to claim 8, wherein: Z is CH2CH2; L-i is a covalent bond; Y XX 13. - A compound according to claim 12, which is selected from the group consisting of: (1 S, 4 S) -2- (6-Cioro-5-methyl-3-iridinyl) -2,5-diazabicyclo [2.2 .2] octane; (1S, 4S) -2- (5,6-dichloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Chloro-5-ethynyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Chloro-5-cyano-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-methoxy-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-Fluoro-5-methyl-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-Cyano-6-fluoro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (5-Bromo-6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; (1S, 4S) -2- (3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane; and (1S, 4S) -2- (6-chloro-3-pyridinyl) -2,5-diazabicyclo [2.2.2] octane. 14. A compound according to claim 8, wherein: Z is CH2; Lt is (CH2); Y 15. - A compound according to claim 14, which is (! R, 4R) -2- (3-pyridinylmethyl) -2,5-diazabicyclo [2.2.1] heptane. 16. A compound according to claim 1, of formula IV: IV, or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of CH2CH2 and CH2CH2CH2. 17. A compound according to claim 16, wherein Z is CH2CH2. 18. A compound according to claim 17, which is 3- (3-pyridazinyl) -3,8-diazabicyclo [3.2.1] octane. 19. A compound according to claim 16, wherein: Z is CH2CH2; L is a covalent bond; and R? is 20. - A compound according to claim 19, which is selected from the group consisting of: 3- (6-nitro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- (6-amino-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-6-chloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- 3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-6-Chloro-5-methyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- 5,6-dichloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-6-chloro-5-ethynyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-6-cyano-5-cyano-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- 5-methoxy-3-pyridinyl) -3,8-di aza bicyclo [3.2.1] octane; 3-6-fluoro-5-methyl-3-pyridyl) -3,8-diazabicyclo [3.2.1] octane; 3-6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-5-ethynyl-6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-5-cyano-6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3- 5-bromo-6-chloro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; 3-5-aminomethyl-6-cyoro-3-pyridinyl) -3,8-diazabicynic [3.2.1] octane; 3-5-aminomethyl-6-fluoro-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane; and 3- (5-aminomethyl-3-pyridinyl) -3,8-diazabicyclo [3.2.1] octane. 21. A compound according to claim 1, of formula V: v, or a pharmaceutically acceptable salt thereof wherein: Z is selected from the group consisting of CH2CH2 and CH2CH CH2. 22. A compound according to claim 21, wherein: Li is a covalent bond: and Ri is 23. - A compound according to claim 1 of formula VI SAW, or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of CH2 and CH2CH2. 24. A compound according to claim 23, wherein: Z is CH2; Li is a covalent bond; and Ri is 25. - A compound according to claim 24, which is selected from the group consisting of: 2- (6-cioro-3-pi ridin i l) -2,6-diaza bicyclo [3.2.1] octane; 2- (3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (6-chloro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (5,6-dichloro-3-pyridinium) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (6-chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (6-chloro-5-cyano-3-pyridinii) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -2- (6-Furo-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (6-fiuoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (5-ethynyl-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (S-cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1S, 5R) -2- (5-bromo-6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1R, 5S) -2- (6-chloro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1R, 5S) -2- (5,6-dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1R, 5S) -2- (6-cyclo-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1R, 5S) -2- (6-chloro-5-cyano-3-pyridinyl) -2,6-diazabicicio [3.2.1] octane; 1R, 5S) -2- (5-methoxy-3-pyridinium) -2,6-diazabicyclo [3.2.1] octane; (1R, SS) -2- (6-fluoro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1R, 5S) -2- (6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.13octane; 1R, 5S) -2- (5-etinii-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; 1R, 5S) -2- (5-cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; Y 1R, 5S) -2- (5-bromo-6-cioro-3-pyridinii) -2,6-diazabicyclo [3.2.1] octane. 26. A compound according to claim 1, of the formula Vi l: VII, or a pharmaceutically acceptable salt, wherein: Z is selected from the group consisting of CH2 and CH2CH2. 27. A compound according to claim 16, wherein: Li is a covalent bond and is 28. A compound according to claim 27, which is selected from the group consisting of: (1R, 5R) -6- (6-chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2. 1] octane; (1 R, 5R) -6- (5,6-dichloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1 Joctane; (1 R, 5R) -6- (6-Chloro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -6- (6-Chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -6- (5-methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5 R) -6- (6-fluoro-5-methyl-3-pyridinit) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -6- (6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -6- (5-ethynyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -6- (5-Cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (5-Bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -6- (6-chloro-3-pyridinium) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-Chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5,6-Dichloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-Cioro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-Chloro-5-cyano-3-pyridinyl) -3,6-diaza bicyclo [3.2.1] octane; (1S, 5S) -6- (5-methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5-Ethyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5-Cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (5-Bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -6- (3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; and (1S, 5S) -6- (6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane. 29. A compound according to claim 1, of the formula HIV: vpi, or a pharmaceutically acceptable salt, wherein: Z is selected from the group consisting of CH2CH2 and CH2CH2CH2. 30. A compound according to claim 29, wherein: Z is CH2CH2; i is a covalent bond; Y 31. - A compound according to claim 30, which is selected from the group consisting of: 9- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-C! Gold-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5,6-dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-fluoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-ethynyl-6-fluoro-3-pyridinium) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-Cyano-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -9- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (5,6-dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (5-methoxy-3-? Iridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 S, 6 R) -9- (6-fluoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 S, 6 R) -9- (6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 S, 6 R) -9- (5-ethynyl-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 S, 6 R) -9- (5-Cyano-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -9- (6-Chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; and (1S, 6R) -9- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane. 32. A compound according to claim 1 of formula IX: D or a pharmaceutically acceptable salt, wherein: Z is selected from the group consisting of CH2 and CH2CH2. 33. A compound according to claim 32, wherein: Z is CH2; Li is a covalent bond; and R, is 34. - A compound according to claim 33, selected from the group consisting of: 6- (6-chloro-3-pipdinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-Chloro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5,6-dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-Chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-Chloro-5-cyano-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-fluoro-5-methyl-3-? Iridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-ethynyl-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-cyano-6-fluoro-3-pyridin) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (5-bromo-6-cioro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1 R, 5S) -6- (6-chloro-3-pyridinyl) -2,6-diazabicon [3.2.1] octane; (1 R, 5S) -6- (3-pyridinyl) -2,6-diazabicyclo [3.2.1) octane; (1S, 5R) -6- (6-Chloro-5-methi-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5,6-Dichloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-5-ethynyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-5-cyano-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-methoxy-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Fluoro-5-methyl-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-ethynyl-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-Cyano-6-fluoro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (5-Bromo-6-chloro-3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane; (1S, 5R) -6- (6-Chloro-3-pyridinyl) -2,6-diazabicyclolol.2.2.1] octane; and (1S, 5R) -6- (3-pyridinyl) -2,6-diazabicyclo [3.2.1] octane. 35.- A compound according to claim 1, of formula X: X, or a pharmaceutically acceptable salt, wherein: Z is selected from the group consisting of CH2 and CH2CH2. 36.- A compound according to claim 35, wherein: Li is a covalent bond and 37. - A compound according to claim 36, selected from the group consisting of: (1 R, 5R) -3- (6-chloro-5-methyl-3-pipdini!) - 3,6-diazabicyclo [3.2.1 ]octane; (1 R, 5R) -3- (5,6-dicyoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -3- (6-Chloro-5-ethynyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -3- (6-Chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -3- (5-methoxy-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1 R, 5R) -3- (6-Fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -3- (6-Fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -3- (5-Cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -3- (5-Bromo-6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -3- (6-Chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1R, 5R) -3- (3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (6-Chloro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (5,6-Dichloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (6-chloro-5-ethynyl-3-pyrid i n i I) -3,6-d aza bicyclo [3.2.1] octane; (1S, 5S) -3- (6-Chloro-5-cyano-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (5-methoxy-3-pyridinium) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (6-Fluoro-5-methyl-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (5-Cyano-6-fluoro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; (1S, 5S) -3- (5-Bromo-6-chloro-3-pyrridinyl) -3,6-diazabicyc [3.2.1] octane; (1S, 5S) -3- (6-chloro-3-pyridinyl) -3,6-diazabicyclo [3.2.1] octane; and (1S, 5S) -3- (3-pyridinium) -3,6-diazabicyclo [3.2.1] octane. 38.- A compound according to claim 1, of formula XI XI, or a pharmaceutically acceptable salt, wherein: Z is selected from the group consisting of CH2CH2 and CH2C H2C H2. 39.- A compound according to claim 38, wherein: Z is CH2CH2; i is a covalent bond; Y 40. - A compound according to claim 39, selected from the group consisting of: 3- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; 9-methyl-3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; 3- (3-pyridinium) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5,6-dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-Fluoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-Cyano-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1 R, 6S) -3- (5-Bromo-6-chloro-3-pyridinyl) -3,9-iazabicyclo [4.2.1] nonane; (1R, 6S) -3- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1 nno nano; (1R, 6S) -3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Chloro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5,6-Dichloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Chloro-5-ethynyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-Chloro-5-cyano-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-methoxy-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-fluoro-5-methyl-3-pyridinyl) -3,9-diazabicyclo [4.2.1 nno nano; (1S, 6R) -3- (6-Fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-Cyano-6-fIuoro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (5-Bromo-6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; (1S, 6R) -3- (6-chloro-3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane; and (1S, 6R) -3- (3-pyridinyl) -3,9-diazabicyclo [4.2.1] nonane. 41. A compound according to claim 1, of formula XII: xn, or a pharmaceutically acceptable salt, wherein: Z is selected from the group consisting of CH2 and CH2CH2. 42.- A compound according to claim 41, wherein: »" IV 172 Z is CH2; Li is a covalent bond; and R? is 43. - A compound according to claim 42, which is selected from the group consisting of: 3- (3-pyridinium) -3,7-diazabicyclo [3.3. 1] nonane; 3- (6-chloro-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (6-chloro-5-methyl-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (5,6-dichloro-3-pyridinyl) -3,7-diazabicyclo [3.3. 1] nonane; 3- (6-Chloro-5-ethynyl-3-pyridinyl) -3,7-diazabicyclo [3.3. 1] nonane; 3- (6-chloro-5-cyano-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (5-methoxy-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 15 3- (6-fluoro-5-methyl-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (6-fluoro-3-pyridinyl) -3,7-diazabicyclo [3.3.1] nonane; 3- (5-ethynyl-6-fluoro-3-pyridinyl) -3,7-diazabicynic [3.3.1] nonane; 3- (5-cyano-6-fluoro-3-pyridinium) -3,7-diazabicyclo [3.3.1] nonane; and 3- (5-bromo-6-chloro-3-pyridinyl) -3,7-diazabicyclo [3 .3.1] nonane. 44. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I in combination with a pharmaceutically acceptable carrier. 45. A method for selectively controlling neurotransmitter release in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I. 46.- A method for treating a disease in a mammalian host with the need for said treatment comprising administering a therapeutically effective amount of a compound of the formula I. 47.- The method according to claim 46, wherein the disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, memory malfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, amyotrophic atrat sclerosis anxiety, depression, mania, schizophrenia, anorexia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease, migraines, premenstrual syndrome, erectile dysfunction, substance abuse, smoking cessation, inflammatory syndrome intestine. 48. The method according to claim 46, wherein the disorder is pain.