THE PATENTS ACT, 1970 COMPLETE SPECIFICATION
Section 10
''Heterocyclic Substituted Aminoazacycles Useful as Central Xervous System Agents. "
Abbott Laboratories, a corporation organized and existing under the laws of USA, of Dept. 377 Bldg Ap6A-l, 100 Abbott Park Road, Abbott Park, Illinois 60064-600S USA.
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

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HETEROCYCLIC SUBSTITUTED AMINOAZACYCLES USEFUL AS CENTRAL
NERVOUS SYSTEM AGENTS

TECHNICAL FIELD
The present invention is directed to a series of heterocyclic substituted aminoazacycles, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions including those compounds.
BACKGROUND OF INVENTION
Compounds that selectively control chemical synaptic transmission offer therapeutic utility in treating disorders that are associated with dysfunctions in synaptic transmission. This utility may arise from controlling either pre-synaptic or post-synaptic chemical transmission. The control of synaptic chemical transmission is, in turn, a direct result of a modulation of the excitability of the synaptic membrane. Presynaptic control of membrane excitability results from the direct effect an active compound has upon the organelles and enzymes present in the nerve terminal for synthesizing, storing, and releasing the neurotransmitter, as well as the process for active re-uptake. Postsynaptic control of membrane excitability results from the influence an active compound has upon the cytoplasmic organelles that respond to neurotransmitter action.
An explanation of the processes involved in chemical synaptic transmission will help to illustrate more fully the potential applications of the invention. (For a fuller explanation of chemical synaptic transmission refer to Hoffman et ah. "Neurotransmission: The autonomic and somatic motor nervous systems." In: Goodman and Oilman's, The Pharmacological
Basis of Therapeutics, 9th ed., J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, and A. Goodman Oilman, 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 elicits an all-or-

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none action potential in a nerve axon. The action potential propagates to the nerve terminal where ion fluxes activate a mobilization process leading to neurotransmitter secretion and "transmission" to the postsynaptic cell. Those cells which receive communication from the central and peripheral nervous systems in the form of neurotransmitters are referred to as
"excitable cells." Excitable cells are cells such as nerves, smooth muscle cells, cardiac cells and glands. The effect of a neurotransmitter upon an excitable cell may be to cause either an excitatory or an inhibitory postsynaptic potential (EPSP or IPSP, respectively) depending upon the nature of the postsynaptic receptor for the particular neurotransmitter and the extent to which other neurotransmitters are present. Whether a particular neurotransmitter causes
excitation or inhibition depends principally on the ionic channels that are opened in the postsynaptic membrane (i.e., in the excitable cell).
EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na+ and K+), whereas IPSPs are the result of stabilization or hyperpolarization of the membrane excitability due to a increase in
permeability to primarily smaller ions (including K+ and CI"). For example, the
"neurotransmitter acetylcholine excites at skeletal muscle junctions by opening permeability channels for Na+ and K+. At other synapses, such as cardiac cells, acetylcholine can be inhibitory , primarily resulting from an increase in K+ conductance.
The biological effects of the compounds of the present invention result from
modulation of a particular subtype of acetylcholine receptor. It is, therefore, important to understand the differences between two receptor subtypes. The two distinct subfamilies of acetylcholine receptors are defined as nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. (See Goodman and Gilman's, The Pharmacological Basis of Therapeutics, op. cit.).
The responses of these receptor subtypes are mediated by two entirely different classes
of second messenger systems. When the nicotinic acetylcholine receptor is activated, the response is an increased flux of specific extracellular ions (e.g. Na+, K+ and Ca++) through the neuronal membrane. In contrast, muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and
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inositol phosphates. Thus, the biological consequences of nicotinic acetylcholine receptor
activation are distinct from those of muscarinic receptor activation. In an analogous manner,
inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are
distinct and different from those arising from muscarinic receptor inhibition
As indicated above, the two principal sites to which drug compounds that affect
chemical synaptic transmission may be directed are the presynaptic membrane and the postsynaptic membrane. Actions of drugs directed to the presynaptic site may be mediated through presynaptic receptors that respond to the neurotransmitter which the same secreting structure has released (i.e., through an autoreceptor), or through a presynaptic receptor that
responds to another neurotransmitter (i.e.. through a heteroreceptor). Actions of drugs
directed to the postsynaptic membrane mimic the action of the endogenous neurotransmitter or inhibit the interaction of the endogenous neurotransmitter with a postsynaptic receptor.
Classic examples of drugs that modulate postsynaptic membrane excitability are the neuromuscular blocking agents which interact with nicotinic acetylcholine-gated channel
receptors on skeletal muscle, for example, competitive (stabilizing) agents, such as curare, or depolarizing agents, such as succinylcholine.
In the central nervous system (CNS), postsynaptic cells can have many neurotransmitters impinging upon them. This makes it difficult to know the precise net balance of chemical synaptic transmission required to control a given cell. Nonetheless, by
designing compounds that selectively affect only one pre- or postsynaptic receptor, it is possible to modulate the net balance of all the other inputs. Obviously, the more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders.
Knowing how specific neurotransmitters act in the CNS allows one to predict the
disorders that may be treatable with certain CNS active drugs. For example, dopamine is
widely recognized as an important neurotransmitter in the central nervous systems in humans and animals. Many aspects of the pharmacology of dopamine have been reviewed by Roth and Elsworth, "Biochemical Pharmacology of Midbrain Dopamine Neurons", In: Psychopharmacology: The Fourth Generation of Progress. F.E. Bloom and D.J. Kupfer. Eds.,
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Raven Press, NY, 1995, pp 227-243). Patients with Parkinson's disease have a primary loss of dopamine containing neurons of the nigrostriatal pathway, which results in profound loss of motor control. Therapeutic strategies to replace the dopamine deficiency with dopamine mimetics, as well as administering pharmacologic agents that modify dopamine release and other neurotransmitters have been found to have therapeutic benefit ("Parkinson's Disease", In: Psychopharmacology: The Fourth Generation of Progress, op. cit.. pp 1479-1484).
New and selective neurotransmitter controlling agents are still being sought, in the hope that one or more will be useful in important, but as yet poorly controlled, disease states or behavior models. For example, dementia, such as is seen with Alzheimer's disease or
Parkinsonism, remains largely untreatable. Symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does the behavioral disorder Attention Deficit Hyperactivity Disorder (ADHD). Specific agents for treatment of these and related disorders are few in number or nonexistent.
A more complete discussion of the possible utility as CNS active agents of compounds
with activity as cholinergic ligands selective for neuronal nicotinic receptors, (i.e., for
controlling chemical synaptic transmission) may be found in U.S. Patent 5,472,958. to Gunn et al., issued Dec. 5, 1995, the disclosure of is incorporated herein by reference.
Existing acetylcholine agonists are therapeutically suboptimal in treating the conditions discussed above. For example, such compounds have unfavorable
pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability (e.g., nicotine). In addition, other agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lachrymation, defecation and tachycardia (Benowitz et al.. in: Nicotine Psychopharmacology, S. Wonnacott,
M.A.H. Russell, & LP. Stolerman, eds., Oxford University Press. Oxford, 1990, pp. 112-157; and M. Davidson, et al., in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336).
Williams et al. reports the use of cholinergic channel modulators to treat Parkinson's and Alzheimer's Diseases (M. Williams et al.. "Beyond the Tobacco Debate: Dissecting Out
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the Therapeutic Potential of Nicotine", Exp. Opin. Invest. Drugs 5. pp. 1035-1045 (1996). Salin-Pascual et al. reports short-term improvement of nonsmoking patients suffering 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 pp. 387-389 (1996).
Various 2-pyridines substituted with a 4-aminopiperidine have been disclose by (US 5,604,245) as serotoninergic agonists. Certain pyridazines substituted with an azacycle have been disclosed by (EP 156433B1) as anti-viral agents. Azacyclic pyridazines of the present invention are distinct in that the azacycle is substituted with an alkylamino or dialkylamino
substituent. Pyrrolidine and azetidine azacycles substituted at the 3-position have been disclosed (cf. U.S. Patents 4,592,866 to A.D. Cale; 4,705.853 to A.D. Cale; 4.956,359 to Taylor et al.; and 5,037,841 to Schoehe et al. and European patent application EP296560A2, to Sugimoto et al.).
Certain nicotine related compounds having utility in enhancing cognitive function
have been reported by Lin in U.S. Patent 5,278,176, issued Jan. 11, 1994. Also, 2-
(nitrophenoxymethyl)heterocyclic compounds with similar function have been reported by Gunn et al., U.S. Patent 5,472,958, issued Dec. 5, 1995.
Certain (pyrid-3-yloxymethyl)heterocyclic compounds useful in controlling chemical synaptic transmission have been described by Lin et al. in U.S. Patent 5,629,325, issued May
13,1997.
WO 94/08922 describes pyridyl ether compounds which enhance cognitive function. U.S. patent applications 08/474,873 and 08/485,537 describe certain substituted pyridyl ether compounds as well as other compounds which also act at the nicotinic acetylcholine receptor to stimulate or inhibit neurotransmitter release. WO 96/31475 describes certain 3-substituted
pyridine derivatives which are described as being useful for a variety of disorders as
modulators of acetylcholine receptors. While some of these references have alluded to pain control as a potential use of the compounds or analogs recited therein, the Applicants have discovered that compounds of formula I shown below have a surprising and unexpected analgesic effect.
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In addition, cholinergic channel modulators may be useful in treating pain. The search for more potent and more effective pain controllers or analgesics continues to be a significant research goal in the medical community. A substantial number of medical disorders and conditions produce pain as part of the disorder or condition. Relief of this pain is a major aspect of ameliorating or treating the overall disease or condition. Pain and the possible allievation thereof is also attributable to the individual patient's mental condition and physical condition. One pain reliever, or a class, may not be effective for a particular patient, or group of patients, which leads to a need for finding additional compounds or pharmaceuticals which are effective analgesics. Opioid and non-opioid drugs are the two major classes of analgesics (Dray, A. and Urban, L., Ann. Rev. Pharmacol. Toxicol., 36: 253-280, 1996). Opioids, such as morphine, act at opioid receptors in the brain to block transmission of the pain signals in the brain and spinal cord (Cherney, N.I., Drug, 51:713-737, 1996). Opioids such as morphine have abuse and addiction liability. Non-opioids such as non-steroid anti-inflammatory agents (NSAIDs) typically, but not exclusively, block the production of prostaglandins to prevent sensitization of nerve endings that facilitate the pain signal to the brain (Dray, et al, Trends in Pharmacol. Sci., 15: 190-197, 1994~ Catty, T.J. and Marfat, A., "COX-2 Inhibitors. Potential for reducing NSA1D side-effects in treating inflammatory diseases", In: Emerging Drugs: Prospect for Improved Medicines. (W. C. Bowman, J.D. Fitzgerald, and J.B. Taylor, eds.), Ashley Publications Ltd., London, Chap. 19., pp. 391411). Most of the commonly prescribed over-the-counter (OTC) NSAIDs are also commonly associated with at least one side effect or another, such as stomach ulceration or pain. For example, NSAIDs such as aspirin are also known to cause irritation and ulceration of the stomach and duodenum.
Certain compounds, with primary therapeutic indications other than analgesia, have been shown to be effective in some types of pain control. These are classified as analgesic adjuvants, and include tricyclic antidepressants (TCAs) and some anticonvulsants such as gabapentin (Williams et al, J. Med. Chem. (1999), 42, 1481-1500). The exact mechanism of action of these drugs is not fully understood, but they are used increasingly for treatment, especially for pain resulting from nerve injury due to trauma, radiation, or disease.
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The compounds of the present invention are novel and may have utility in treating disorders and medical conditions listed herein. The compounds of the present invention may also have utility when administered in combination with an opioid such as morphine, or a non-steroid anti-inflammatory agent such as aspirin, or a tricyclic antidepressant, or an anticonvulsant such as gabapentin or pregabalin for treating disorders and medical conditions listed herein.
SUMMARY OF THE INVENTION
The present invention discloses heterocyclic substituted aminoazacyclic compounds, a method for selectively controlling neurotransmitter release in mammals using these
compounds, and pharmaceutical compositions including those compounds. More particularly, the present invention is directed to compounds of formula I
Z-R3
I,
or pharmaceutically acceptable salts and prodrugs thereof wherein,
Z is selected from the group consisting of —
NR^R,
NR,R2 NR,R, KIO 0
A J A r-i o r^^NR1R2
N B N N N
NR,R2
i i
'~r~ . and "~r~ ;
R1 and R1 are independently selected from the group consisting of hydrogen and alkyl;
A and B arc independently absent or independently selected from the group consisting of alkenyl, alkoxy. alkoxycarbonyl, alkyl, alkynyl, carboxy. haloalkyl, halogen, hydroxy, and hydroxyalkyl;
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R3 is selected from the group consisting of

R4 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
-NR10R11 wherein Rio and R] 1 are independently selected from the group consisting of hydrogen and lower alkyl;
R6 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)NR8R9, -CH2C(NR7)NR8R9, -C(NOR7)R8, -C(NCN)R7, -C(NNR7R8)R9, -S(O)2OR7, and -S(O)2R7; and
R7, R8, and R9 are independently selected from the group consisting of hydrogen and alkyl;
provided that when R3 is pyridazine then R1 is alkyl.
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DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention are disclosed compounds of formula II
NR,R2
R3 II,
or pharmaceutically acceptable salts thereof wherein A, B, Ri, R2, and R3 are as defined in formula I.
In another embodiment are disclosed compounds of formula II wherein A is as defined in formula I; B is absent; R\ and R2 are independently selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; R3 is
R4 5; R4 is hydrogen; R5 is selected from hydrogen, halogen, and lower alkyl; and
R$ is selected from hydrogen, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
A representative compound of formula II includes, but is not limited to: l-(6-chloro-3-pyridinyl)-3-azetidinylamine.
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In another embodiment of the present invention are disclosed compounds of formula III
NR1R2
V
i R3
HI,
or pharmaceutically acceptable salts thereof wherein A. B, Rh R2, and R3 are as defined in formula I.
In another embodiment are disclosed compounds of formula III wherein A is as defined in formula I; B is absent; R| and R2 are independently selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; R3 is
R4 N R5. j^ js hydrogen; R5 is selected from hydrogen, halogen, and lower alkyl; and R^ is selected from hydrogen, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
Representative compounds of formula III include, but are not limited to:
N-[(3S)-l-(6-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3 S)-1 -(6-chloro-3 -pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-chloro-3-pyridinyl)pyrrolidinyl]-N,N-dimethylamine;
(3R)-l-(6-chloro-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-1 -(6-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
N-[(3R)-l-(6-chloro-3-pyridinyl)pyrrolidinyl]-N,N-dimethylamine;
1 -(6-chloro-3-pyridinyl)-3-pyrrolidinylamine;
(3S)-1 -(3-pyridinyl)pyrrolidinylamine;
N-methyl-N-[(3S)-l-(3-pyridinyl)pyrrolidinyl]amine;
l-(3-pyridinyl)-3-pyrrolidinylamine;
(3R)-1 -[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinylamine;
N-methyl-N-{(3R)-l-[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinyl}amine;
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(3S)-1 -[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinylamine;
N-methyl-N-{(3S)-l-[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinyl}amine;
(3R)-l-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5,6-dichloro-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(5,6-dichloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(5,6-dichloro-3-pyridinyl)pyrrolidinylamine;
10 N-|(3R)-l-(5,6-dichloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-chloro-5-methoxy-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-chloro-5-methoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5-nitro-3-pyridinyl)pyrrolidinylamine;
N-methyl-N-[(3S)-l-(5-nitro-3-pyridinyl)pyrrolidinyl]amine;
(3R)-l-(5-nitro-3-pyridinyl)pyrrolidinylamine;
N-methyl-N-[(3R)-l-(5-nitro-3-pyridinyl)pyrrolidinyl]amine; and
(2S, 3R)-2-(chloromethyl)-1-(3-pyridinyl)pyrrolidinylamine.
The following additional compounds, representative of formula III, may be prepared
by one skilled in the art using known synthetic chemistry methodology or by using synthetic
chemistry methodology described in the Schemes and Examples contained herein.
(3R)-l-(3-pyridinyl)pyrrolidinylamine;
N-methyl-N-[(3R)-l-(3-pyridinyl)pyrrolidinyl]amine;
(3R)-l-(6-chloro-5-methoxy-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-chloro-5-methoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5-methoxy-3-pyridinyl)pyrrolidinylamine;
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N-[(3S)-l-(5-methoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-1 -(5-methoxy-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(5-methoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-bromo-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-1 -(6-bromo-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(6-bromo-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-bromo-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5-fluoro-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(5-fluoro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(5-fluoro-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(5-fluoro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-chloro-5-fluoro-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-chloro-5-fluoro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(6-chloro-5-fluoro-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-1 -(6-chloro-5-fluoro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-bromo-5-fluoro-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-bromo-5-fluoro 3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(6-bromo-5-fluoro-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-bromo-5-fluoro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5-bromo-6-chloro-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(5-bromo-6-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(5-bromo-6-chloro-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(5-bromo-6-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(6-bromo-5-chloro-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-bromo-5-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(6-bromo-5-chloro-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-bromo-5-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine; (3S)-l-(6-bromo-5-ethoxy-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(6-bromo-5-ethoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;
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(3R)-l-(6-bromo-5-ethoxy-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(6-bromo-5-ethoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5-cyano-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(5-cyano-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(5-cyano-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(5-cyano-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-(5-ethynyl-3-pyridinyl)pyrrolidinylamine;
N-[(3S)-l-(5-ethynyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3R)-l-(5-ethynyl-3-pyridinyl)pyrrolidinylamine;
N-[(3R)-l-(5-ethynyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;
(3S)-l-furo[3,2-b]pyridin-6-ylpyrrolidinylamine;
N-[(3S)-l-furo[3,2-b]pyridin-6-ylpyrrolidinyl]-N-methylamine;
(3R)-l-furo[3,2-b]pyridin-6-ylpyrrolidinylamine;
N-[(3R)-l-furo[3,2-b]pyridin-6-ylpyrrolidinyl]-N-methylamine; l-(6-chloro-3-pyridinyl)-3-methyl-3-pyrrolidinylamine;
N-[l-(6-chloro-3-pyridinyl)-3-methyl-3-pyrrolidinyl]-N-methylamine;
l-(3-pyridinyl)-3-methyl-3-pyrrolidinylamine; and
N-[ 1 -(3-pyridinyl)-3-methyl-3-pyrrolidinyl]-N-methylamine.
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In another embodiment of the present invention arc disclosed compounds of formula
IV
NR,R2

IV.
or pharmaceutically acceptable salts thereof wherein A. B. R|, R:. and R3 are as defined in formula I.
In another embodiment are disclosed compounds of formula IV wherein A is as defined in formula I: B is absent: Ri and R? are independently selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred: R3 is

R4 N R5. j^ is hydrogen; R5 is selected from hydrogen, halogen, and lower alkyl; and
R(, is selected from hydrogen, cyano, haloalkoxy. haloalkyl. halogen, hydroxy, lower alkoxy,
lower alkyl. lower alkynyl. and nitro. _
Representative compounds of formula IV include, but are not limited to:
l-(6-chloro-3-pyridinyl)-3-piperidinylamine;
(3R,4R)-l-(6-chloro-3-pyridinyl)-4-methylpiperidinylamine;
(3R,4S)-l-(6-chloro-3-pyridinyl)-4-methylpiperidinylamine;
(3S)-l-(3-pyridinylipiperidinylamine:
N-methyl-N-[(3S)-l-(3-pyridinyl)piperidinyl]amine;
(3R)-l-(3-pyridinyl)piperidinylamine;
N-methyl-N-[(3R)-l-(3-pyridinyl)piperidinyl]amine;
(3S)-l-(6-chloro-3-pyridinyl)piperidinylamine;
N-[GS)-l-(6-chloro-3-pyridinyl)piperidinyl|-N-methylamine;
(3R)-l-(6-chloro-3-pyridinyl)piperidinyl amine:
N-[(3R)-l-(6-chloro-3-pyridinyl)piperidinyl]-N-methylamine; and
N-[(3S)-1 -(6-chloro-5-methyI-3-pyridinyl)piperidinyl]-N-methylamine.
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The following additional compounds, representative of formula IV. may be prepared by one skilled in the art using known synthetic chemistry methodology or by using synthetic chemistry methodology described in the Schemes and Examples contained herein.
(3S)-l-(5,6-dichloro-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(5,6-dichloro-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(5,6-dichloro-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(5.6-dichloro-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(6-chloro-5-methoxy-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(6-chloro-5-methoxy-3-pyridinyl)piperidinyl]-N-methylamine:
(3R)-l-(6-chloro-5-methoxy-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(6-chloro-5-methoxy-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)^l-(6-chloro-5-methyl-3-pyridinyl)piperidinylamine;
(3R)-l-(6-chloro-5-methyl-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(6-chloro-5-methyl-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(5-methoxy-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(5-methoxy-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(5-methoxy-3-pyridinyl)piperidinylamine;
N-[(3R)-1-(5-methoxy-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(6-bromo-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(6-bromo-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(6-bromo-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(6-bromo-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(5-fluoro-3-pyridinyl)piperidinylamine;
N-[(3S)-1-(5-fluoro-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(5-fluoro-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(5-fluoro-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(6-chloro-5-fluoro-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(6-chloro-5-fluoro-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(6-chloro-5-fluoro-3-pyridinyl)piperidinylamine;
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N-[(3R)-l-(6-chloro-5-fluoro-3-pyridinyl)piperidinyl]-N-methylamine; (3S)-l-(6-bromo-5-fluoro-3-pyridinyl)piperidinylamine; N-[(3S)-l-(6-bromo-5-fluoro-3-pyridinyl)piperidinyl]-N-methylamine; (3R)-l-(6-bromo-5-fluoro-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(6-bromo-5-fluoro-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(5-bromo-6-chloro-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(5-bromo-6-chloro-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(5-bromo-6-chloro-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(5-bromo-6-chloro 3-pyridinyl)piperidinyl]-N-methylamine:
(3S)-l-(6-bromo-5-chloro-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(6-bromo-5-chloro-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(6-bromo-5-chloro-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(6-bromo-5-chloro-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(6-bromo-5-ethoxy-3-pyridinyl)piperidinylamine;
N-[(3S)-1 -(6-bromo-5-ethoxy-3-pyridinyl)piperidinyl ]-N-methylamine;
(3R)-1-(6-bromo-5-ethoxy-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(6-bromo-5-ethoxy-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(5-cyano-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(5-cyano-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(5-cyano-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(5-cyano-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-(5-ethynyl-3-pyridinyl)piperidinylamine;
N-[(3S)-l-(5-ethynyl-3-pyridinyl)piperidinyl]-N-methylamine;
(3R)-l-(5-ethynyl-3-pyridinyl)piperidinylamine;
N-[(3R)-l-(5-ethynyl-3-pyridinyl)piperidinyl]-N-methylamine;
(3S)-l-furo[3,2-b]pyridin-6-ylpiperidinylamine;
N-[(3S)-l-furo[3.2-b]pyridin-6-ylpiperidinyl]-N-methylamine;
(3R)-l-furo[3,2-b]pyridin-6-ylpiperidinylamine: and
N-[(3R)-l-furo[3.2-b]pyridin-6-ylpiperidinyl]-N-methylamine.
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In another embodiment of the present invention are disclosed compounds of formula V
NR,R2
A- ~B
N
i
R3 V, or pharmaceutical ly acceptable salts thereof wherein A. B, R|, Ri, and R3 are as defined in formula I.
In another embodiment are disclosed compounds of formula V wherein A is as defined in formula I; B is absent; R| and R2 are independently selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; R3 is
vxx" .
R4 N R5. j^ is hydrogen; Rs is selected from hydrogen, halogen, and lower alkyl; and R(, is selected from hydrogen, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
A representative compound of formula V includes, but is not limited to:
l-(6-chloro-3-pyridinyl)-4-piperidinylamine.
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In another embodiment of the present invention are disclosed compounds of formula VI
•NR^
N
i
R3 VI,
or pharmaceutical^' acceptable salts thereof wherein A. B. R|, R?. and R3 are as defined in formula I.
In another embodiment are disclosed compounds of formula VI wherein A is as defined in formula I; B is absent; R| and R: are independently selected from hydrogen and lower alky! wherein hydrogen and methyl are preferred; Rj is
iY6 •
R<* N Rs; R4 is hydrogen; Rs is selected from hydrogen, halogen, and lower alkyl; and R6 is selected from hydrogen, cyano, haloalkoxy, haloalkyl. halogen, hydroxy, lower alkoxy, lower alkyl. lower alkynyl. and nitro.
The following additional compounds, representative of formula VI, may be prepared by one skilled in the art using known synthetic chemistry methodology or by using synthetic chemistry methodology described in the Schemes and Examples contained herein.
(3S)-l-(3-pyridinyl)azepanylamine;
N-methyl-N-[(3S)-l-(3-pyridinyl)azepanyl]amine;
(3R)-l-(3-pyridinyl)azepanylamine;
N-methy 1-N-[(3R)-1 -(3-pyridinyl)azepanyl]amine;
(3S)-l-(6-chloro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(6-chloro-3-pyridinyl)azepanylamine;
N-[(3R)-l-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(5,6-dichloro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;
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(3R)-l-(5,6-dichloro-3-pyridinyl)azepanylamine;
N-[(3R)-l-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine:
(3S)-l-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-1 -(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;
N-[(3R>l-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(6-chloro-5-methyl-3-pyridinyl)azepanylamine:
N-[(3S)-l-(6-chloro-5-methyl-3-pyridinyl)azepan\i]-N-methylamine:
(3R)-l-(6-chloro-5-methyl-3-pyridin\i)azepanylamine;
N-[(3R)-l-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine:
(3S)-1 -(5-methoxy-3-pyridinyl)azepanylamine;
N-[(3S)-l-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(5-methoxy-3-pyridinyl)azepanylamine;
N-[(3R)-l-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(6-bromo-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-1 -(6-bromo-3-pyridinyl)azepanylamine;
N-[(3 R)-1 -(6-bromo-3-pyridinyl )azepanyl]-N-methylamine;
(3S)-1 -(5-fluoro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(5-fluoro-3-pyridinyl)azepanylamine;
N-[(3R)-l-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine:
(3R)-l-(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;
N-[(3R)-l-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine:
(3R)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;
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N-[(3R)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;
N-[(3R)-1 -(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;
N-[(3R)-l-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;
N-[(3S)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;
N-[(3R)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(5-cyano-3-pyridinyl)azepanylamine;
N-[(3S)-l-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(5-cyano-3-pyridinyl)azepanylamine;
N-[(3R)-l-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-(5-ethynyl-3-pyridinyl)azepanylamine;
N-[(3S)-l-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;
(3R)-l-(5-ethynyl-3-pyridinyl)azepanylamine;
N-[(3R)-l-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;
(3S)-l-furo[3,2-b]pyridin-6-ylazepanylamine;
N-[(3S)-l-furo[3.2-b]pyridin-6-ylazepanyl]-N-methylamine;
(3R)-l-furo[3,2-b]pyridin-6-ylazepanylamine; and
N-[(3R)-l-furo[3.2-b]pyridin-6-ylazepanyl]-N-methylamine.
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In another embodiment of the present invention are disclosed compounds of formula VII
NR-,R2 / N
i
R3 VII. or pharmaceutically acceptable salts thereof wherein A. B. R|. RT. and R3 are as defined in formula 1.
In another embodiment are disclosed compounds of formula VII wherein A is as defined in formula 1; 13 is absent: R| and Ri arc independently selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; R3 is
R4 N R5; R4 is hydrogen; R> is selected from hydrogen, halogen, and lower alkyl; and R6 is selected from hydrogen, cyano, haloalkoxy, haloalkyl halogen, hydroxy, lower alkoxy, lower alkyl, lower alkynyl. and nitro.
The following additional compounds, representative of formula VII, may be prepared by one skilled in the art using known synthetic chemistry methodology or by using synthetic chemistry methodology described in the Schemes and Examples contained herein.
(4S)-l-(3-pyridinyl)azepanylamine;
N-methyl-N-[(4S)-1 -(3-pyridinyl)azepanyl)amine;
(4R)-1 -(3-pyridinyl)azepanylamine;
N-methyl-N-[(4R)-1 -(3-pyridinyl)azepanyl]amine;
(4S)-l-(6-chloro-3-pyridinyl)azepanylamine;
N-f(4S)-l-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-l-(6-chloro-3-pyridinyl)azepanylamine;
N-|(4R)-l-(6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-1 -(5,6-dichloro-3-pyridinyl)azepanylamine;
N-[(4S)-l-(5.6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;

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(4R)-l-(5,6-dichloro-3-pyridinyl)azepanylamine:
N-[(4R)-l-(5,6-dichloro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine:
N-[(4S)-l-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-l-(6-chloro-5-methoxy-3-pyridinyl)azepanylamine;
N-[(4R)-l-(6-chloro-5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(6-chloro-5-methyl-3-pyridinyl)azepanylamine;
N-f(4S)-l-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine:
(4R)-l-(6-chloro-5-methyl-3-pyridinyl)azepanylamine;
N-[(4R)-l-(6-chloro-5-methyl-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(5-methoxy-3-pyridinyl)azepanylamine;
N-[(4S)-l-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-1 -(5-methoxy-3-pyridinyl)azepanylamine;
N-[(4R)-l-(5-methoxy-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(6-bromo-3-pyridinyl)azepanylamine;
N-[(4S)-l-(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-l-(6-bromo-3-pyridinyl)azepanylamine;
N-[(4R)-1 -(6-bromo-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(5-fluoro-3-pyridinyl)azepanylamine;
N-[(4S)-l-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-1 -(5-fluoro-3-pyridinyl)azepanylamine;
N-[(4R)-l-(5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-1 -(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;
N-[(4S)-l-(6-chloro-5-fluoro-3-pyridinyl]azepanyl]-N-methylamine;
(4R)-1 -(6-chloro-5-fluoro-3-pyridinyl)azepanylamine;
N-[(4R)-1-(6-chloro-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;
N-[(4S)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanylamine;
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N-[(4R)-l-(6-bromo-5-fluoro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(5-bromo-6-chloro-3-pyridinyl)azepanylamine;
N-[(4S)-l-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-1 -(5-bromo-6-chloro-3-pyridinyl)azepanylamine;
N-[(4R)-l-(5-bromo-6-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(6-bromo-5-chloro-3-pyridinyl)azepanylamine;
N-[(4S)-l-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-1 -(6-bromo-5-chloro-3-pyridinyl)azepanylamine;
N-[(4R)-l-(6-bromo-5-chloro-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;
N-[(4S)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanylamine;
N-[(4R)-l-(6-bromo-5-ethoxy-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(5-cyano-3-pyridinyl)azepanylamine;
N-[(4S)-l-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-1 -(5-cyano-3-pyridinyl)azepanylamine;
N-[(4R)-l-(5-cyano-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-(5-ethynyl-3-pyridinyl)azepanylamine;
N-[(4S)-l-(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;
(4R)-1 -(5-ethynyl-3-pyridinyl)azepanylamine;
N-[(4R)-1 -(5-ethynyl-3-pyridinyl)azepanyl]-N-methylamine;
(4S)-l-furo[3,2-b]pyridin-6-ylazepanylamine;
N-[(4S)-l-furo[3,2-b]pyridin-6-ylazepanyl]-N-methylamine;
(4R)-1 -furo[3,2-b]pyridin-6-ylazepanylamine; and
N-[(4R)-l-furo[3,2-b]pyridin-6-ylazepanyl]-N-methylamine.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
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Another embodiment of the present invention relates to 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.
Another embodiment of the present invention relates to a method of treating a disorder, such as Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration. inflammation, neuroprotection, anxiety, depression, mania, schizophrenia, anorexia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease, migraines, premenstraul syndrome, erectile dysfunction, substance abuse, smoking cessation. inflammatory bowel syndrome, and pain, in a host mammal in need of such treatment
comprising administering a therapeutically effective amount of a compound of formula 1.
Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with an opioid and a pharmaceutical ly acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain
in a mammal in need of such treatment comprising administering a therapeutically effective
amount of a compound of formula I in combination with a non-steroid anti-inflammatory
agent and a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain
in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with a tricyclic antidepressant and a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain 25 in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with an anticonvulsant such as gabapentin or pregabalin and a pharmaceutically acceptable carrier.
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In another embodiment of the present invention are disclosed compounds of formula VIII
VIII, or pharmaceutically acceptable salts or prodrugs thereof wherein, R3 is selected from the group consisting of
NR1R2
VS ATr_VB A-r TB A-f ^B
N "B N N N"
NR1R2
NR!R2
■ , and
R1 is alkyl preferably methyl; R2 is selected from hydrogen and alkyl preferably "~
selected from hydrogen and methyl; and R5, R6, A and B are as defined in formula I.
Another embodiment of the present invention relates to pharmaceutical compositions
comprising a therapeutically effective amount of a compound of formula VIII 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 comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula VIII.
Another embodiment of the present invention relates to a method of treating a disorder, such as Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, anxiety, depression, mania, schizophrenia, anorexia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease,
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migraines, premenstraul syndrome, erectile dysfunction, substance abuse, smoking cessation, inflammatory bowel syndrome, and pain, in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VIII.
Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VIII in combination with an opioid and a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VIII in combination with a non-steroid anti-inflammatory agent and a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VIII in combination with a tricyclic antidepressant and a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VIII in combination with an anticonvulsant such as gabapentin or pregabalin and a pharmaceutically acceptable carrier.
Definition of Terms
As used throughout this specification and 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 10 carbons, wherein 2 to 6 carbon atoms are preferred, and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl. 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl. 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl. and 3-decenyl.
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The term "alkoxy," as used herein, refers to an alkyl group, as defined herein,
appended to the parent molecular moiety through an oxy moiety, 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,
appended 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. appended 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, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples 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, appended to the parent molecular moiety 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.
The term "alkyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, wherein 1 to 6 carbon atoms are preferred. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl. isopentyl, neopentyl, n-hexyl, 3-25 methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl. n-heptyl, n-octyl, n-nonyl, and n-decyl. The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended 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-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
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The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group, as
defined herein, appended to the parent molecular moiety through an oxy moiety, 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,
appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.
The term "alkynyl," as used herein, refers to a straight or branched chain hydrocarbon 10 group containing from 2 to 10 carbon atoms, wherein 2 to 6 carbon atoms are preferred, and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, l-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "amino," as used herein, refers to a -NR20R21 group wherein R20 and R21 are independently selected from hydrogen, alkyl, and alkylcarbonyl as defined herein. Representative examples of amino include, but are not limited, amino, methylamino, dimethylamino, ethylamino, and methylcarbonylamino.
The term "aminoalkyl," as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminoalkyl include, but are not limited, aminomethyl, (methylamino)methyl, 2-aminoethyl, and (dimethylamino)methyl.
The term "aminocarbonyl," as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of aminocarbonyl include, but are not limited, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, and ethylaminocarbonyl.
The term "aminocarbonylalkyl," as used herein, refers to an aminocarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aminocarbonylalkyl include, but are not limited to. 2-
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WO 00/71534 PCT/US00/13339
amino-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 4-amino-4-oxobutyl, and 4-(dimethylamino)-4-oxobutyl.
The term "aminosulfonyl," as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of aminosulfonyl include, but are not limited, aminosulfonyl, dimethylaminosulfonyl, methylaminosulfonyl, and ethylaminosulfonyl.
The term "aryl," as used herein, refers to a monocyclic-ring system, or a fused bicyclic-ring system wherein one or more of the fused rings are aromatic. Representative examples of aryl include, but are not limited to. azulenyl, indanyl. indenyl. naphthyl, phenyl, and tetrahydronaphthyl.
The aryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro.
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, appended 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, appended to the parent molecular moiety 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 -C(0)H group. The term "formylalkyl," as used herein, refers to a formyl group, as defined herein,
appended to the parent molecular moiety through an alkyl group, as defined herein.
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