WO2009081246A2

WO2009081246A2 - Bicyclic diamines as nicotinic receptor agonists

Info

Publication number: WO2009081246A2
Application number: PCT/IB2008/003382
Authority: WO
Inventors: John Adams Lowe, Iii
Original assignee: Pfizer Inc.
Priority date: 2007-12-19
Filing date: 2008-12-04
Publication date: 2009-07-02
Also published as: WO2009081246A3

Abstract

Compounds; pharmaceutically acceptable salts thereof; and stereoisomers of the compound of Formula I and pharmaceutically acceptable salts thereof; are disclosed, wherein the compounds have the structure of Formula (I) as defined in the specification. Corresponding pharmaceutical compositions and methods of treatment are also disclosed.

Description

BICYCLIC DIAMINES AS NICOTINIC RECEPTOR AGONISTS

FIELD OF THE INVENTION

The present invention relates to bicyclic amines and to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, cognitive disorders, attention-deficit hyperactivity disorder, dementia and other disorders in mammals, including humans. These compounds exhibit activity as nicotinic receptor agonists.

BACKGROUND OF THE INVENTION

Nicotine mediates numerous physiological responses through a variety of ligand-gated ion channels, known as nicotinic receptors. Each ion channel is made up of five subunits, comprised of two or three alpha and beta subtypes each. There are eleven alpha subunits and four beta subunits known, making for a considerable complexity of possible pentameric receptor subunit combinations. The alpha 4beta2 nicotinic receptor, comprised of alpha 4 and beta 2 subunits, is thought to mediate the major CNS physiological responses to nicotine. Among these are the reinforcing and addictive activities that are well known for this drug. While the cognition-enhancing activity of nicotine is thought to play a role in its reported efficacy in treating attention- deficit hyperactivity disorder (ADHD), the above-mentioned side effects limit the utility of this approach. As an alternative approach for the treatment of ADHD via the nicotinic receptor mechanism, the alpha 6 receptor subtype has been identified. Nicotinic receptors comprised of alpha 6 subunits are found in specific brain regions, in particular in areas capable of eliciting enhanced release of adrenaline in the pre-frontal cortex. This activity is shared by drugs that treat ADHD, such as methylphenidate, methamphetamine, and atomoxetine. Thus an alpha 6 nicotinic agonist, by mimicking the pharmacology of known ADHD drugs, may be an approach to treating this disease. In addition, by avoiding some of the activities of nicotine, such as alpha4beta2 receptor agonism, and the side effect liabilities of stimulants such as methamphetamine, an alpha 6 agonist drug may represent a safer treatment for ADHD.

International Patent Application No. WO 01/90109 generally discloses heteroaryldiazabicycloallkanes as nicotinic cholinergic receptor ligands. International Patent Application No. WO 07/137030 generally discloses fused bicycloheterocycle substituted azabicyclic alkane derivatives.

The present invention relates to bicyclic diamine compounds of Formula I that exhibit activity as alpha 6 nicotinic receptor agonists.

SUMMARY OF THE INVENTION The present invention relates to compounds of Formula I:

Formula I wherein:

R is H, alkyl, or alkanoyl; X is aryl or heteroaryl, wherein said aryl or heteroaryl may be optionally fused to a five- to seven-membered carbocyclic ring or to a five- to seven- membered heterocyclic ring containing one or two heteroatoms selected from O, N, and S, wherein X may be optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, arylalkoxy, halo, alkylthio, haloalkyl, haloalkoxy, cyano, aryloxy, heteroaryl, -SO₂NR¹R², -NR²R³SO₂, -SO₂R⁴, or -C(=O)NR⁵R⁶; Y is a bond, -O-, -O_m(CH₂)_n-, -(CH₂)_PO-, -C(=O)-, or -SO₂-, wherein said CH₂ moieties may be optionally substituted by one or more groups independently selected from halo, alkyl, and hydroxyl; m is 0 or 1 ; n and p are independently 1, 2, or 3;

R¹, R², and R³ are independently H or alkyl;

R⁴ is alkyl; and R⁵ and R⁶ are independently H or alkyl, or together with the N to which they are attached form a saturated or unsaturated heterocyclic moiety, provided that R⁵ and R⁶ are not both H; or a pharmaceutically acceptable salt thereof; or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from depression, mood disorders, schizophrenia, bipolar disorder, anxiety disorders, Alzheimer's disease, Parkinson's disease, attention deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, cognitive deficits, pain (including neuropathic pain and acute pain), Tourette's syndrome, nicotine dependency, addiction and withdrawal, and post-traumatic stress disorder in a mammal, including a human, the composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

This invention also relates to a pharmaceutical composition for treating

ADHD in a mammal, including a human, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating ADHD.

This invention also is directed, in part, to a method of treating a disorder or condition selected from depression, mood disorders, schizophrenia, bipolar disorder, anxiety disorders, Alzheimer's disease,

Parkinson's disease, attention deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, cognitive deficits, pain (including neuropathic pain and acute pain), Tourette's syndrome, nicotine dependency, addiction and withdrawal, and post-traumatic stress disorder in a mammal, including a human, comprising administering to a mammal in need of such treatment a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating such condition or disorder.

This invention also is directed, in part, to a method of treating attention- deficit hyperactivity disorder (ADHD) in a mammal, including a human, comprising administering to a mammal in need of such treatment a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating ADHD. DETAILED DESCRIPTION OF THE INVENTION

An embodiment of the invention is a compound of Formula I as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof. An embodiment of the invention is a compound of Formula I wherein:

R is H, methyl, ethyl, propyl, methylcarbonyl, ethylcarbonyl, or propylcarbonyl; or a pharmaceutically acceptable salt thereof; or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

X is phenyl, benzofuranyl, benzothiazolyl, thiazolyl, pyridyl, thienyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, tetrazolyl, pyrimidinyl, pyrazolyl, or furyl, wherein X may be optionally substituted with one or more substituents independently selected from methyl, ethyl, propyl, butyl, cyclopropyl, methoxy, ethoxy, propoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, phenylmethoxy, phenylethoxy, chloro, bromo, fluoro, methylthio, ethylthio, propylthio, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluroromethoxy, cyano, phenoxy, benzofuranyl, pyridyl, thienyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, tetrazolyl, pyrimidinyl, pyrazolyl, furyl, -SO₂NR¹R², -NR²R³SO₂, -SO₂R⁴, or -C(=O)NR⁵R⁶; R¹, R², and R³ are independently H, methyl, ethyl, or propyl; R⁴ is methyl, ethyl, or propyl; and R⁵ and R⁶ are independently H, methyl, ethyl, or propyl, or R⁵ and R⁶ together with the N to which they are attached form a piperidinyl, pyrrolidinyl, azetidinyl, or morpholinyl ring, provided that R⁵ and R⁶ are not both H; or a pharmaceutically acceptable salt thereof; or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein: Y is a bond, -O-, -O_m(CH₂)_n-, -(CH₂)_PO-, -C(=O)-, or -SO₂-, wherein said CH₂ moieties may be optionally substituted by one or more groups independently selected from chloro, bromo, fluoro, methyl, ethyl, propyl, and hydroxy I; m is O or 1; and n and p are independently 1 , 2, or 3; or a pharmaceutically acceptable salt thereof; or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein R is H.

An embodiment of the invention is a compound of Formula I wherein R is alkyl. An embodiment of the invention is a compound of Formula I wherein Rs alkanoyl.

An embodiment of the invention is a compound of Formula I wherein Xs aryl, optionally substituted as defined in Formula I.

An embodiment of the invention is a compound of Formula I wherein Xs heteroaryl, optionally substituted as defined in Formula I. An embodiment of the invention is a compound of Formula I wherein X is optionally substituted by one or more halo groups.

An embodiment of the invention is a compound of Formula I wherein Y is a bond. An embodiment of the invention is a compound of Formula I wherein Y is -O-.

An embodiment of the invention is a compound of Formula I wherein Y is -O_m(CH₂)n-, wherein one or more CH₂ moieties may be optionally substituted by one or more groups independently selected from halo, alkyl, and hydroxyl.

An embodiment of the invention is a compound of Formula I wherein Y is -(CH₂)_PO-, wherein one or more CH₂ moieties may be optionally substituted by one or more groups independently selected from halo, alkyl, and hydroxyl.

An embodiment of the invention is a compound of Formula I wherein Y is -C(=O)-.

An embodiment of the invention is a compound of Formula I wherein Y is -SO₂-.

An embodiment of the invention is a compound of Formula I wherein n is 1. An embodiment of the invention is a compound of Formula I wherein p is 1.

An embodiment of the invention is a compound of Formula I wherein

^R h haass t thhpe> s sttperrpenorc.hhpemmiissttrrvy *

An embodiment of the invention is a compound of Formula I wherein

has the stereochemistry

R is H; or a pharmaceutically acceptable salt thereof. An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

X is phenyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, wherein X may be optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, and -C(=O)NR⁵R⁶; and

R⁵ and R⁶ are alkyl, or R⁵ and R⁶ together with the N to which they are attached form a saturated or unsaturated heterocyclic moiety; or a pharmaceutically acceptable salt thereof. An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry ; and

Y is a bond, -CH₂O-, -C(=O)- , -O-, -CH₂-, -CHF-, -CHOH-, -(CH₂)₂-, -OCH₂-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry ; and X is phenyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, wherein X may be optionally substituted with one or more substituents independently selected from ethoxy, isopropoxy, methoxy, methoxyethyl, methoxymethyl, isopropoxycarbonyl, isopropyl, methyl, t-butyl, methylthio, benzyloxy, phenoxy, cyano, cyclopropyl, chloro, fluoro, trifluoromethoxy, trifluoromethyl, thienyl, morpholinylcarbonyl, N₁N- diisopropylaminocarbonyl, and N,N-dimethylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

X is aryl optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, and -C(=O)NR⁵R⁶; and

R⁵ and R⁶ are alkyl, or R⁵ and R⁶ together with the N to which they are attached form a saturated or unsaturated heterocyclic moiety; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

R is H;

X is phenyl optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, and -C(=O)NR⁵R⁶;

R⁵ and R⁶ are alkyl, or R⁵ and R⁶ together with the N to which they are attached form a saturated or unsaturated heterocyclic moiety; and Y is a bond, -CH₂O-, -C(=O)- , -O-, -OCH₂-, -CH₂-, -(CH₂)₂-, -CHF-,

-CHOH-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

X is phenyl optionally substituted with one or more substituents independently selected from ethoxy, isopropoxy, methoxy, methoxyethyl, methoxymethyl, isopropoxycarbonyl, isopropyl, methyl, t-butyl, methylthio, benzyloxy, phenoxy, cyano, cyclopropyl, chloro, fluoro, trifluoromethoxy, trifluoromethyl, morpholinylcarbonyl, N,N-diisopropylaminocarbonyl, and N₁N- dimethylaminocarbonyl; and

Y is a bond, -CH₂O-, -C(=O)- , -O-, -OCH₂-, -CH₂-, -(CH₂)₂-, -CHF-, -CHOH-, or -SO₂-; or a pharmaceutically acceptable salt thereof. An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

X is heteroaryl, optionally fused to a five- to seven-membered carbocyclic ring or to a five- to seven-membered heterocyclic ring containing one or two heteroatoms selected from O, N, and S, wherein X is optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, and -C(=O)NR⁵R⁶; and

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

R is H;

X is benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, optionally substituted by one or more substituents independently selected from alkyl, halo, and heteroaryl; and Y is a bond, -CH₂O-, -O-, -OCH₂-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

R is H;

X is benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, optionally substituted by one or more substituents independently selected from methyl, chloro, fluoro, and thienyl; and

Y is a bond, -CH₂O-, -0-, -OCH₂-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein

has the stereochemistry

An embodiment of the invention is a compound of Formula I wherein

has the stereochemistry

and

R is H; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry ; X is phenyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, wherein X may be optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, and -C(=O)NR⁵R⁶; and

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry ; and Y is a bond, -CH₂O-, -C(=O)- , -O-, -CH₂-, -CHF-, -CHOH-, -(CH₂)₂-, -OCH₂-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry ; and

X is phenyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, wherein X may be optionally substituted with one or more substituents independently selected from ethoxy, isopropoxy, methoxy, methoxyethyl, methoxymethyl, isopropoxycarbonyl, isopropyl, methyl, t-butyl, methylthio, benzyloxy, phenoxy, cyano, cyclopropyl, chloro, fluoro, trifluoromethoxy, trifluoromethyl, thienyl, morpholinylcarbonyl, N₁N- diisopropylaminocarbonyl, and N,N-dimethylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry R is H;

-CHOH-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry R is H;

X is phenyl optionally substituted with one or more substituents independently selected from ethoxy, isopropoxy, methoxy, methoxyethyl, methoxymethyl, isopropoxycarbonyl, isopropyl, methyl, t-butyl, methylthio, benzyloxy, phenoxy, cyano, cyclopropyl, chloro, fluoro, trifluoromethoxy, trifluoromethyl, morpholinylcarbonyl, N,N-diisopropylaminocarbonyl, and N₁N- dimethylaminocarbonyl; and Y is a bond, -CH₂O-, -C(=O)- , -O-, -OCH₂-, -CH₂-, -(CH₂)₂-, -CHF-, -CHOH-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

An embodiment of the invention is a compound of Formula I wherein:

has the stereochemistry

has the stereochemistry V -N N-R

X is benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, optionally substituted by one or more substituents independently selected from alkyl, halo, and heteroaryl; and

An embodiment of the invention is a compound of Formula I wherein:

Y is a bond, -CH₂O-, -O-, -OCH₂-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

Exemplary compounds according to the invention include the examples shown below in Table 1 in free base form.

Table 1

This invention also relates to a method of treating a disorder or condition selected from depression, mood disorders, schizophrenia, bipolar disorder, anxiety disorders, Alzheimer's disease, Parkinson's disease, attention deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, cognitive deficits, pain (including neuropathic pain and acute pain), Tourette's syndrome, nicotine dependency, addiction, and withdrawal, and post-traumatic stress disorder, in a mammal, including a human, comprising administering to a mammal in need of such treatment a glycine transport-inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating ADHD in a mammal, including a human, comprising administering to a mammal in need of such treatment a glycine transport-inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof. Abbreviations and Definitions

Unless otherwise indicated, as used herein, the terms "halogen" and "halo" include fluoro, chloro, bromo, and iodo.

Unless otherwise indicated, as used herein, the term "alkyl" includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and t-butyl.

Unless otherwise indicated, as used herein, the term "cycloalkyl" includes saturated monovalent cyclic hydrocarbon radicals. Examples of alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups also include saturated cyclic alkyl moieties consisting of two or three rings respectively, wherein said rings share at least one carbon atom, i.e., 'cycloalkyl" includes spiro groups and fused ring groups. Examples of bicyclic cycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]-hexyl, bicyclo — 2.2.1]-hept-1-yl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, spiro[4.2]heptyl, indanyl, teralene (1 ,2,3,4- tetrahydronaphlene) and 6, 7, 8, θ-tetrahydro-δH-benzocycloheptene. An example of a tricyclic cycloalkyl group is adamantanyl. Other cycloalkyl, bicycloalkyl, and tricycloalkyl groups are known in the art, and such groups are encompassed by the definition of "cycloalkyl" herein.

Unless otherwise indicated, as used herein, the term "alkoxy", means "alkyl-O-", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy and allyloxy. Unless otherwise indicated, as used herein, the term "alkoxyalkyl" means alkyl-O-alkyl-, wherein alkyl is defined above.

Unless otherwise indicated, as used herein, the term "hydroxyalkyl" means -alkyl-OH, wherein alkyl is defined above.

Unless otherwise indicated, as used herein, the term "aryl" includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl. Unless otherwise indicated, as used herein, the terms "heterocyclic" and "heterocycloalkyl" are used interchangeably and refer to non aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from O, S and N. Heterocyclic groups also include non-aromatic two- or three-ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N); thus, "heterocyclic" includes spiro groups and fused ring groups. In one embodiment, each ring in the heterocyclic group contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom). The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6- tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1 ,4-dioxaspiro[4.5]decyl, 1 ,4-dioxaspiro[4.4]nonyl, 1 ,4-dioxaspiro[4.3]octyl, and 1,4- dioxaspiro[4.2]heptyl.

Unless otherwise indicated, as used herein, "heteroaryl" refers to aromatic groups containing one or more heteroatoms, preferably from one to four heteroatoms, selected from O, S and N. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1,2,3,4- tetrahydroguinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, 1 ,2,4-trizainyl, 1 ,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl. Unless otherwise indicated, as used herein, the term "cycloalkoxy", means "cycloalkyl-O-", wherein "cycloalkyl" is as defined above.

Unless otherwise indicated, as used herein, the term "aryloxy", means "aryl-O-ⁿ, wherein "aryl" is as defined above.

Unless otherwise indicated, as used herein, ^{^} the term "heterocycloalkoxy", means "heterocycloalkyl-O-", wherein "heterocycloalkyl" is as defined above.

Unless otherwise indicated, as used herein, the term "heteroaryloxy", means "heteroaryl-O-", wherein "heteroaryl" is as defined above.

Unless otherwise indicated, the term "one or more" substituents, or "at least one" substituent as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites. (Examples of one or more or at least one substituent include, but are not limited to, 1 to 10 substituents, or 1 to 6 substituents or 1 to 3 substituents). Unless otherwise indicated, all the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g., C₁-C₂₀ alkyl, C₂-C₂0 alkenyl, C₃-C₂0 cycloalkyl, (3-20 membered)heterocycloalkyl, CQ- C₂₀ aryl, (5-20 membered)heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., C₁-C₁₅ alkyl, C₂-Ci₅ alkenyl, C3-C₁₅ cycloalkyl, (3-15 membered)heterocycloalkyl, C₆-C₁₅ aryl, (5-15 membered)heteroaryl, etc.), or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms.

The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C- attached). The terms referring to the groups also encompass all possible tautomers.

The following abbreviations are used herein:

THF: tetrahydrofuran; CH2CI2: dichloromethane;

TFA: trifluoroacetic acid;

NaHCO₃: sodium bicarbonate; HCI: hydrogen chloride;

MgSO₄: magnesium sulfate; Na₂SO₄: sodium sulfate;

DME: dimethoxyethane; n-BuLi: n-butyllithium;

DMF: dimethylformamide; nAChR: nicotinic acetylcholine receptor; and hnAChR: human nicotinic acetylcholine receptor.

Specific embodiments of the present invention are shown in the Examples below.

Compounds of Formula I may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of Formula I₁ as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ("glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO Na⁺, -COO K⁺, or -SO₃ ^"Na⁺) or non-ionic (such as -N^'N⁺(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).

The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of Formula I.

As indicated, so-called 'prodrugs' of the compounds of Formula I are also within the scope of the invention. Thus certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found, for example, in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella). See also Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro- moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include, but are not limited to, (i) where the compound of Formula I contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of Formula I is replaced by (Cr C_β)alkyl; (ii) where the compound of Formula I contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of Formula I is replaced by (Cr C₆)alkanoyloxymethyl; and (iii) where the compound of Formula I contains a primary or secondary amino functionality (-NH₂ or -NHR where R is not H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of Formula I is/are replaced by (Cr Cio)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.. Also included within the scope of the invention are metabolites of compounds of Formula I₁ that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include, but are not limited to, (i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH): (ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);

(iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² -> -NHR¹ or -NHR²); (iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂); (v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH).

Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cis/trans (or

ZJE) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of

Formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or I- lysine, or racemic, for example, dl-tartrate or dl-arginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate or racemic mixture (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art; see, e.g., Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as ²H and

³H; carbon, such as ¹¹C, ¹³C, and ¹⁴C; chlorine, such as ³⁶CI; fluorine, such as 1⁸F; iodine, such as ¹²³I and ¹²⁵I; nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ¹⁵0, ¹⁷O, and ¹⁸O; phosphorus, such as ³²P; and sulphur, such as ³⁵S.

Certain isotopically-labeled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (³H) and carbon-14 (¹⁴C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium (²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O₁ and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

When preparing compounds of Formula I in accordance with the invention, it is open to a person skilled in the art to routinely select the form of compound of Formula Il which provides the best combination of features for this purpose. Such features include, but are not limited to, the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

As used herein, the term "treating" refers to reversing, alleviating or inhibiting the progress of a disease, disorder or condition, or one or more symptoms of such disease, disorder or condition, to which such term applies. As used herein, "treating" may also refer to decreasing the probability or incidence of the occurrence of a disease, disorder or condition in a mammal as compared to an untreated control population, or as compared to the same mammal prior to treatment. For example, as used herein, "treating" may refer to preventing a disease, disorder or condition, and may include delaying or preventing the onset of a disease, disorder or condition, or delaying or preventing the symptoms associated with a disease, disorder or condition. As used herein, "treating" may also refer to reducing the severity of a disease, disorder or condition or symptoms associated with such disease, disorder or condition prior to a mammal's affliction with the disease, disorder or condition. Such prevention or reduction of the severity of a disease, disorder or condition prior to affliction relates to the administration of the composition of the present invention, as described herein, to a subject that is not at the time of administration afflicted with the disease, disorder or condition. As used herein "treating" may also refer to preventing the recurrence of a disease, disorder or condition or of one or more symptoms associated with such disease, disorder or condition. The terms "treatment" and "therapeutically," as used herein, refer to the act of treating, as "treating" is defined above. The compounds of the present invention exhibit glycine transport inhibiting activity and therefore are of value in the treatment of a wide variety of clinical conditions that are characterized by the deficit of glutamateric neurotransmission in mammalian subjects, especially humans. Such conditions include the positive and negative symptoms of schizophrenia and other psychoses, and cognitive deficits. Compounds of the present invention are useful in the treatment of, for example, anxiety disorders including, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder; mood adjustment disorders including, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood; attention adjustment disorders including, for example, in addition to ADHD, attention deficit disorders or other cognitive disorders due to general medical conditions; psychotic disorders including, for example, schizoaffective disorders and schizophrenia; and sleep disorders including, for example, narcolepsy and enuresis. Examples of the disorders or conditions which may be treated by the compound, composition and method of this invention are also as follows: depression, including, for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial Infarction depression, depression in patients with human immunodeficiency virus (HIV)₁ Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I₁ bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia nervosa; chemical dependencies, including, for example, addictions to alcohol, cocaine, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists, Phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's diseases, including, for example, dementia in Parkinson's disease, neuroleptic-induced parkinsonism or tardive dyskinesias; headache, including, for example, headache associated with vascular disorders; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; conduct disorder; cyclothymic disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform NOS; incontinence; inhalation disorders; intoxication disorders; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoric disorder; specific developmental disorders; SSRI "poop out" syndrome, or a patient's failure to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders including Tourette's disease.

The compounds of this invention can be administered via either the oral, parenteral (such as subcutaneous, intraveneous, intramuscular, intrastemal and infusion techniques), rectal, intranasal or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from about 1mg to about 2000 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of from about 0.1 mg to about 20 mg per kg of body weight per day is most desirably employed. Nevertheless, variations may still occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day.

Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandelates mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate, stannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties. Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of three methods:

(i) by reacting the compound of Formula I with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring- opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

Compounds of Formula I may be used in combination with another active agent, for example, an agent used for the treatment of ADHD. Examples of such agents include methamphetamine, methylphenidate, or atomoxetine.

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging about 5.0% to about

70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice. Competitive binding assay

The compounds of the present invention were assayed by evaluating competition binding of experimental compounds of Formula I and ³H- epibatidine to crude membrane fraction from HEKT-hnAChR-α6/α4-β4, a cell line that expresses an Acetylcholine receptor composed of chimeric human α6/α4 receptor subunits and β4 receptor subunits. The purpose of the assay was to establish quantitative affinity values (IC₅₀, Kj ) for compounds at the epibatidine binding site of the hnAChR α6/α4 - β4 receptor. Materials:

1. Crude Membrane Fraction prepared from cell line HEKT-hnAChR- α6/α4-β4. See Cheng and Prussoff, "Relationship between the inhibition constant (Kl) and the concentration of inhibitor that causes 50 percent inhibition (I50) of an enzymatic reaction," Biochem. Pharmacol. 22: 3099-3108 (1973).

2. 3-Bromocytisine, which may be prepared as described by lmming et al., ."Syntheses and evaluation of halogenated cystine derivatives and of bioisosteric thiocystine as potent and selective nAChR ligands," Eur. J. Med. Chem. 36 (2001) 375-388.

3. ³H-epibatidine: Specific activity 55.5 Ci/mmol, 1 mCi/mL (Perkin Elmer, NET-1102). 4. Binding buffer: 50 mM TRIS-HCI pH 7.4.

5. 96-square well polypropylene titer plates, 2ml_ capacity (Beckman Coulter).

6. Whatman GF/B filtermats (PEI coated: 0.5% PEI).

7. Skatron 96-well cell harvester. 8. Wallac Betaplate 1205 scintillation counter.

Dilution of Test Compounds:

DMSO was added to test compound to make a 1 mM stock solution. 10X stock dilutions of the test compound were made from the 1 mM stock solution, by adding 50μL of 1mM stock solution to 450μL buffer solution. Successive solutions of the test compounds were prepared in 250 μl_ amounts at the following final concentrations of test compound: 10μM, 1μM, 10OnM, 1OnM₁ 1nM, 1OpM, and 1 pM. Binding Reactions:

The frozen cell pellet was weighed and polytroned in 25 mL of assay buffer and centrifuged for 10 minutes at 40,000 x G. The supernatant was decanted and the final pellet resuspended at 2mg/ml_ wet weight per 25μl_ of assay buffer (~ 50 μg/well).

200μL of ³H-Epibatidine (0.4nM final concentration) was added to the well along with 25 μl_ of vehicle or 1OuM (final concentration) bromocytisine for non-specific binding.

The incubation was carried out in 96-well deep well plates at room temperature for 2 hours.

The plates were then filtered using a Skatron cell harvester with 0.5% PEI soaked filters. The filters were washed with cold assay buffer, dried overnight and counted on a Wallac Betaplate counter the next day. Six reactions were run for the totals and non-specifics while all test compounds were run in triplicate. Data analysis:

"Average Non-Specific Binding" is the average of counts bound (CPM) in the six 'Non-Specific" binding reactions.

"Specific Binding" for each of the six "Total Binding" reactions is calculated by subtracting the "Average Non-Specific Binding" (CPM) from total counts bound (CPM) for each of the six "Total Binding" reactions.

"Maximum Specific Binding" is the average of "Specific Binding" (CPM) for the six "Total Binding" reactions.

"Compound Specific Binding," for each experimental compound binding reactions, is calculated by subtracting the "Average Non-Specific Binding" from total counts bound (CPM) for each of the binding reactions.

The "% inhibition" for each experimental compound binding reaction is the percentage of "Compound Specific Binding" of the "Maximum Specific Binding":

_0/ (Maximum Specific Binding - _χ ι_«h!κ:«_ftn - Compound Specific Binding) l^nhlbltlon - (Maximum Specific Binding ¹⁰°

IC₅0 (the concentration of compound that displaces 50% of the ³H- epibatidine binding) and Ki were calculated for compounds that showed an inhibition of total radioligand binding that ranged from near 0% to near 100% over the range of concentrations tested. For compounds that did not reach 100% displacement at the highest concentration tested, IC₅₀ and Kj were recorded as >10,000 nM. To generate an IC₅₀, the average of the % inhibition for the three binding reactions for each concentration is plotted against the logarithm of concentration tested to give a single concentration response curve. The normalized data are fit by non-weighted nonlinear regression to a Sigmoid dose-response curve (variable slope). y = Bottom + (Top - Bottom) 1 + 10x - Log IC₅₀

The Cheng-Prussoff equation may be used to convert the IC₅₀ to K₁:

L = radioligand concentration in the binding reaction (nM). See Cheng and Prussoff, supra. Kd of ³H-epibatidine for the chimeric α6Λx4-β4 human Acetylcholine receptor determined from saturation binding is 0.23 nM.

Kj values obtained as described above for compounds of the invention are described below in Table 2.

Table 2

Example No. Alpha 6 K₁, nM

67 , HCI salt 2.52

68 , HCI salt 22.5

69 HCI salt 8.31

70 HCI salt 0.171

71 HCI salt 0.402

72 HCI salt 0.491

73 HCI salt 1.72

74 HCI salt 6.23

75, HCI salt 0.492

76, HCI salt 0.753

77, HCI salt 0.279

78, HCI salt 0.602

79, HCI salt 0.269

80, HCI salt 0.338

81 , HCI salt 4.12

82, HCI salt 6.24

83, TFA salt 9.67

84, TFA salt 27.3

85, TFA salt 13.6

86, TFA salt 27.2

87, TFA salt 26.3

88, TFA salt 49.4

89, TFA salt 92.5

90, TFA salt 656

91 , HCI salt 10.3

92, HCI salt 21.3

93, HCI salt 1.78

94, HCI salt 38.7

Compounds of the invention analyzed by this assay have been found to have significant activity in agonizing nicotinic receptors, having greater than. 20% inhibition at 1 μM.

The compounds of Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and dramatizations that are familiar to those of ordinary skill in the art. Preferred methods include, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry. John Wiley & Sons, 1981; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry. John Wiley & Sons, 1991 , which are hereby incorporated by reference.

Compounds of Formula I or their pharmaceutically acceptable salts, can be prepared according to the following reaction Schemes 1 through 17 as discussed herein below. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

The following schemes and examples are exemplary of the processes for making compounds of Formula I. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following examples. General Synthetic Schemes and Working Examples

The following schemes and examples are exemplary of the processes for making compounds of Formula I. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following examples. The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, in the range of 18-25°C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure with a bath of up to 60⁰C; reactions were monitored by thin layer chromatography (tic) and reaction times are given for illustration only; melting points (m.p.) given are uncorrected (polymorphism may result in different melting points); structure and purity of all isolated compounds were assured by at least one of the following techniques: tic (Merck silica gel 60 F-254 precoated plates),high performance liquid chromatography (HPLC), mass spectrometry, nuclear magnetic resonance (NMR) or infrared spectroscopy (IR). Yields are given for illustrative purposes only. Flash column chromatography was carried out using Baker Silica Gel 40 μm. Low-resolution mass spectral data (El) were obtained on a Waters Micromass mass spectrometer (ZMD or ZQ model).

LC/MSD "Method A": Liquid Chromatography data was collected on a

Hewlett Packard 1100 Liquid Chromatography/ Mass Selective Detector (LC/MSD). Analysis was performed on a Luna C-18 column with dimensions of 3.0x150 mm. The flow rate was 0.425 ml/minute running a gradient of 50%

0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile in 15 minutes. The ionization type for the mass detector of the Mass

Spectrophotometer was atmospheric pressure electrospray in the positive ion mode with a fragmentor voltage of 50 volts.

Melting points were taken with a Buchi micro melting point apparatus and uncorrected. Infrared Ray absorption spectra (IR) were measured by a Shimazu infrared spectrometer (IR-470). ¹H and ¹³C nuclear magnetic resonance spectra (NMR) were measured in CDCI₃ by a Varian NMR spectrometer (Unity, 400MHz for ¹H, 100MHz for ¹³C) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (δ). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad.

Scheme 1

Example Ij (rac)-(5-phenylpyridin-3-yl)-3.6- diazabicvclor3.2.noctane (III. R = -Ph. Scheme 1)

Step A: Preparation of tert-Butyl-(5-bromopyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate

A solution of the tert-butyl 3,6-diazabicyclo[3.2.1]octane-3-carboxylate (prepared as in J. Med. Chem.. 2007, 50, 3627-3644) (2.1 g, 9.9 mmol), 3,5- dibromopyridine (5.86 g., 24.7 mmol), tris(dibenzylideneacetone) dipalladium (181 mg, 0.198 mmol), BINAP (246 mg, 0.396 mmol), and cesium carbonate (4.51 g., 13.8 mmol) in dry DME (40 ml) was refluxed overnight. The reaction mixture cooled, taken up in EtOAc₁ and washed with aqueous sodium bicarbonate and brine, then dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel to afford the title product (1.62 g, 45%) as viscous oil. ¹³C NMR (100MHz, CDCI₃) δ 28.63, 28.74, 32.83, 33.56, 33.68, 34.13, 50.40, 50.74, 50.77, 51.18, 52.06, 52.57, 52.62, 79.65, 79.76, 121.04, 121.49, 121.57, 133.58, 139.27, 139.37, 147.20, 147.26, 153.72, 153.95; LCMS (m/z) 368/370 (M+H). RT (Method A, supra), 1.0 min.

Step B: Preparation of tert-Butyl-(5-phenylpyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate A solution of tert-butyl-(5-bromopyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate) from Step A (250 mg, 0.679 mmol), phenylboronic acid (83 mg, 0.679 mmol), tetrakistriphenylphosphine palladium (39 mg, 0.0339 mmol), and sodium carbonate (288 mg, 2.72 mmol) in 9:1 ethanohwater (10 ml) was refluxed overnight. The reaction mixture was cooled, taken up in EtOAc, and washed with aqueous sodium bicarbonate and brine, then dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel to afford the title product (215 mg, 87%) as viscous oil. ¹³C NMR (100MHz, CDCI₃) δ 28.70, 28.81, 33.03, 33.87, 34.46, 50.47, 50.78, 51.01, 51.38, 52.31, 52.77, 52.88, 79.63, 79.70, 118.00, 127.47, 127.50, 128.08, 129.10, 133.64, 134.47, 134.52, 136.77, 136.84, 137.82, 137.98, 138.78, 138.90, 146.33, 146.40, 153.89, 154.08; LCMS (m/z) 366 (M+H). RT (Method A, supra), 1.0 min.

Step C: Preparation of (5-phenyl-pyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane

A solution of tert-butyl-(5-phenylpyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate (519 mg, 1.42 mmol) in EtOAc was treated with EtOAc saturated with HCI gas at room temperature overnight.

The resulting white precipitate was filtered and dried under nitrogen and high vacuum to afford the title product as the hydrochloride salt (358 mg, 74.5%), mp = 235-240⁰C. ¹³C NMR (100MHz₁ CD₃OD) δ 32.61, 33.35, 48.27, 48.44,

49.41 , 51.65, 54.62, 112.50, 115.31 , 125.40, 126.96, 127.45, 128.68, 129.46, 129.99, 134.55, 141.00, 146.42, 149.03; LCMS (m/z) 266 (M+H). RT (Method

A, supra), 1.0 min.

Examples 2-73, 77-80, and 97-109 (see Table 1 for structures and names) were prepared in similar fashion. Mass spec data for examples 2-73, 77-80, and 97-109 are reported below in Table 3. Table 3

¹³C NMR was obtained (100MHz, CDCI₃) for Example 106: δ 23.91, 29.09, 30.50, 34.13, 34.95, 39.82, 49.25, 53.48, 58.60, 58.68, 68.29, 116.12, 116.35, 118.19, 118.43, 120.07, 125.69, 127.91 , 127.94, 131.46, 131.55, 134.15, 135.06, 138.51 , 138.85, 139.54, 139.61 , 145.74, 160.09, 162.56

Scheme 2

HN \ .N-^

Pd₂(DBA)₃, BINAP Cs₂CO₃, DME

Example 76: 3-(5-phenoxypyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane (III, R = -OPh)

A solution of 3,5-dibromopyridine (474 mg, 2.0 mmol), phenol (188 mg, 2.0 mmol), and cesium carbonate (652 mg, 2.0 mmol) in N-methylpyrrolidine (5 mL) was heated at 100⁰C for 70 hr., then cooled and taken up in EtOAc, washed with 3 portions of water, brine, then dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel to afford the product as an oil (443 mg, 88%). ¹³C NMR (100MHz, CDCI₃) δ 119.70, 120.57, 125.09, 127.70, 127.74, 130.48, 139.41, 145.23, 154.67, 154.69, 155.61. LCMS (m/z) 250/252 (M+H). RT (Method A, supra), 1.0 min. The remainder of the synthesis was carried out as in Example 1 to afford Example 76 in 74% yield as a white solid. ¹³C NMR (100MHz, CDCI₃) δ 32.44, 33.24, 48.47, 49.36, 51.68, 54.53, 116.77, 119.91 , 120.50, 122.66, 126.01, 130.66, 150.07, 154.59, 157.72. LCMS (m/z) 282 (M+H). RT (Method A, supra), 1.0 min. Other compounds prepared in this fashion are Examples 75, 92, 94,

96, 110, and 112-140 (see Table 1 for structures and names). Mass spec data for examples 75, 92, 94, 96, 110, and 112-140 are reported below in Table 4. Table 4

¹³C NMR was obtained (100MHz, CDCI₃) for Example 110: δ 32.62, 33.31, 34.33, 36.31, 51.63, 52.33, 54.59, 124.77, 124.84, 126.31, 128.44, 128.64, 129.79, 129.83, 130.20, 131.83, 132.62, 142.24, 148.63.

Scheme 3

III

Example 86: 3-{5-[(4-methylphenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane (R = -SO₂-p-tolyl, Scheme 3)

This preparation followed the previous examples, as outlined in Scheme 3, except for an oxidation step using 2 equivalents of oxone in methanol at room temperature for 40 hr. ¹H NMR (400MHz, CDCI₃) δ 2.11 (m,

2H); 2.4 (m, 1H); 2.92 (m, 1H), 3.14-3.41 (m, 5H); 3.89 (m, 1H), 4.10 (m, 2H); 4.28 (m, 1H); 7.43 (m, 2H), 7.95 (m, 2H); 8.15 (m, 1H); 8.54 (m, 1H); 8.67 (m, 1H). LCMS (m/z) 344 (M+H); RT (Method A, supra), 2.0 min.

Other compounds prepared in this fashion are Examples 84-91 (see Table 1 for structures and names). Mass spec data for examples 84-91 are reported below in Table 5.

Table 5

Scheme 4

II

Example 110: 3-[5-(2-phenylethyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane, (R = -CH₂CH₂Ph, Scheme 4)

Step A: Preparation of tert-Butyl-(5-carboxaldehydo-pyridin-3-yl)- 3, 6-diazabicyclo[3.2.1]octane-3-carboxylate To a solution of intermediate I (Scheme 4, prepared as in Example 1 ) (342 mg, 0.949 mmol) in 7 mL dry THF cooled to -70⁰C was added a solution of butyl lithium in hexane (0.632 mL, 1.58 mmol, 2.5 M)₁ and the reaction stirred at -70⁰C for 5 minutes, then dimethylformamide (0.143 mL, 1.86 mmol) was added, and the reaction warmed to room temperature and stirred for 4 hr. The reaction was taken up in EtOAc, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed in silica gel to afford the product as an oil, 122 mg (41%). ¹³C NMR (100MHz, CDCI₃) δ 28.06, 28.64, 28.75, 32.86, 32.97, 33.12, 33.58, 33.71, 33.82, 34.13, 34.44, 50.44, 50.79, 50.86, 51.23, 52.07, 52.27, 52.64, 52.84, 79.73, 79.89, 116.42, 116.94, 119.43, 119.53, 119.80, 123.58, 128.71 , 128.83, 130.87, 130.97, 131.50, 131.80, 132.97, 135.55, 139.11, 139.30, 140.63, 141.55, 141.95, 146.30, 146.51, 146.59, 153.80, 153.99, 191.79; LCMS (m/z) 318 (M+H). RT (Method A, supra), 1.0 min. Step B: Preparation of tert-Butyl-(5-phenylethylene-pyridin-3-yl)-

3, 6-diazabicyclo[3.2.1]octane-3-carboxylate

To a solution of benzyl triphenylphosphonium chloride (169 mg, 0.422 mmol) in 4 mL dry THF was added a solution of sodium hexamethyldisilazide (0.461 mL of 1 N, 0.461 mmol), and the resulting solution stirred 45 min. at 40⁰C. To the resulting solution was added a solution of tert-butyl-(5- carboxaldehydo-pyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate (122 mg, 0.382 mmol) in 1 mL dry THF. The reaction was stirred at 50-60⁰C for 24 hr., and the reaction cooled, taken up in EtOAc, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel to afford the product, 141 mg (93%), as an oil, a mixture of olefin isomers. ¹³C NMR (100MHz, CDCI₃) δ 28.70, 28.78, 32.87, 33.02, 33.15, 33.60, 33.73, 33.86, 34.16, 34.40, 34.48, 50.34, 50.46, 50.77, 50.81, 50.88, 50.97, 51.24, 51.40, 52.09, 52.21, 52.32, 52.51 , 52.65, 52.88, 79.66, 79.76, 79.92, 115.97, 116.24, 116.41, 116.94, 119.36, 125.77, 125.93, 126.78, 127.33, 127.61, 128.20, 128.63, 128.75, 128.86, 128.94, 130.40, 130.90, 130.99, 131.52, 131.79, 132.12, 132.14, 132.21 , 132.31 , 132.73, 132.86, 133.08, 133.24, 134.16, 134.28, 134.86, 134.96, 137.01, 138.23, 138.30, 139.12, 139.58, 139.80, 140.69, 141.63, 142.03, 146.39, 154.13; LCMS (m/z) 392 (M+H). RT (Method A, supra), 1.0 min.

Step C: Preparation of (5-(2-phenethyl)-pyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane

To a solution of tert-butyl-(5-phenylethylenepyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate (141 mg, 0.360 mmol) and 1- methylcyclohexane-1,4-diene (2 ml_) in 20 ml_ ethanol was added 105 mg of 20% palladium hydroxide on carbon. The reaction was refluxed 4 hr., cooled, and filtered through Celite with ethanol. The ethanol solution was evaporated to an oil which was chromatographed on silica gel to afford the resulting olefin, 94 mg (66%). ¹³C NMR (100MHz, CDCI₃) δ 28.73, 28.83, 29.91, 33.03, 33.18, 33.86, 33.95, 34.54, 35.39, 35.47, 37.81, 37.87, 39.75, 50.43, 50.76, 50.96, 51.32, 52.34, 52.71, 52.91, 79.61, 79.67, 119.82, 126.29, 128.62, 128.65, 128.70, 128.77, 128.88, 130.93, 131.02, 132.14, 132.17, 132.23, 132.34, 133.23, 133.51, 133.59, 136.89, 139.45, 139.56, 141.40, 146.22, 154.13; LCMS (m/z) 394 (M+H). RT (Method A, supra), 1.0 min. This intermediate was deblocked with HCI in EtOAc as in Example 1 to afford the title compound as the HCI salt, 29 mg (33%). ¹³C NMR (100MHz, CD₃OD) δ 32.62, 33.31, 34.33, 36.31, 51.63, 52.33, 54.59, 124.77, 124.84, 126.31, 128.44, 128.64, 129.79, 129.83, 130.20, 131.83, 132.62, 142.24, 148.63; LCMS (m/z) 294 (M+H). RT (Method A, supra), 1.0 min.

Scheme 5

1. LiOH H₂O, THF, H₂O, MeOH

2. MeO(CH₃)NH, EDAC, HOBt,

DIPEA, CH₃CN

Example 82: [5-(3,6-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl](4- methylphenyl)methanol (Scheme 5)

Step A: Preparation of tert-Bυtyl-(5-carboxmethoxy-pyridin-3-yl)- 3,6-diazabicyclo[3.2.1]octane-3-carboxylate (IV, Scheme 5).

The reaction was carried out as in Example 1 using methyl-5-bromo- nicotinate to afford the product in 46% yield as an oil. ¹³C NMR (100MHz, CDCI₃) δ 28.41 , 28.50, 32.71, 33.44, 33.57, 34.07, 50.28, 50.57, 50.60, 51.05, 52.00, 52.12, 52.15, 52.41, 52.56, 79.24, 79.37, 119.36, 125.62, 138.67, 138.73, 139.41, 139.48, 145.82, 153.54, 153.73, 166.24, 170.75; LCMS (m/z) 348 (M+H). RT (Method A, supra), 1.0 min. Step B: tert-Butyl-(5-(N-methyl, N-methoxy)carboxamido-pyridin- 3-yl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate (V, Scheme 5)

To a solution of tert-butyl-(5-carboxmethoxy-pyridin-3-yl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate (756 mg, 2.18 mmol) in 7 ml_ THF was added a solution of lithium hydroxide hydrate (274 mg, 6.53 mmol) in 3 mL water, and the resulting mixture solubilized with MeOH and stirred 18 hr. at room temperature. The reaction was evaporated to a small volume and the pH adjusted to between 1 and 6 with extraction into EtOAc followed by evaporation to afford the crude product, 559 mg (77%). This product was coupled to give the Weinreb amide using N.O-dimethylhydroxylamine (175 mg, 1.79 mmol), diisopropylethylamine (584 μl_, 3.35 mmol), EDAC (386 mg, 2.01 mmol), a catalytic amount of 1-hydroxybenzotriazole, and 7 mL acetonitrile. The reaction was stirred at room temperature for 4 days, evaporated to a small volume, poured into water, extracted into EtOAc, washed with brine, dried and evaporated. The residue was chromatographed on silica gel to afford 546 mg (86%) of an oil. ¹³C NMR (100MHz, CDCI₃) δ 28.47, 28.58, 32.72, 33.57, 34.10, 50.26, 50.60, 50.63, 51.00, 52.03, 52.41, 52.44, 52.59, 61.27, 61.29, 79.31, 79.43, 118.81 , 129.80, 129.87, 136.69, 136.77, 137.63, 137.75, 145.61, 145.69, 153.61, 153.78, 168.10, 168.22; LCMS (m/z) 377 (M+H). RT (Method A, supra), 1.0 min.

Step C: Preparation of tert-Butyl-(5-(4-toluoyl)-pyridin-3-yl))-3,6- diazabicyclo[3.2.1]octane-3-carboxylate, (Vl, Scheme 5)

To a solution of tert-butyl-(5-(N-methyl, N-methoxy)carboxamido- pyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate (546 mg, 1.45 mmol) in 5 mL dry THF at 0⁰C was added a 1.0 M solution of p-tolyl magnesium bromide in THF (1.45 mmol) and the reaction warmed to room temperature. After the addition of 2 more equivalents of p-tolyl magnesium bromide and stirring at room temperature for 4 days, the reaction was judged complete, and was poured into aqueous ammonium chloride, extracted into EtOAc, washed with brine, dried and evaporated. The residue was chromatographed on silica gel to afford the product as an oil, 440 mg (74%). ¹³C NMR (100MHz, CDCI₃) δ 21.82, 28.62, 28.72, 32.88, 33.66, 33.74, 34.25, 50.43, 50.75, 50.89, 51.22, 52.14, 52.59, 52.66, 52.71, 79.61, 79.73, 119.50, 119.55, 129.31 , 130.38, 133.45, 134.67, 138.26, 138.34, 139.95, 140.05, 143.99, 146.08, 146.14, 153.80, 153.96, 195.40; LCMS (m/z) 408 (M+H). RT (Method A, supra), 1.0 min.

Step D: tert-Butyl-[5-(3, 6-diazabicyclo[3.2.1]oct-3-yl)pyridin-3- yl](4-methylphenyl)methanol-3-carboxylate (VII, Scheme 5)

To a solution of tert-butyl-(5-(4-toluoyl)-pyridin-3-yl))-3,6- diazabicyclo[3.2.1]octane-3-carboxylate (440 mg, 1.99 mmol) in 5 ml_ ethanol was added sodium borohydride (91.6 mg, 1.99 mmol), and the reaction stirred at room temperature for 1.5 hr. The reaction was poured into aqueous ammonium chloride solution, extracted into EtOAc, washed with brine, dried and evaporated. The resulting crude oil was used without purification, 451 mg (55%). ¹³C NMR (100MHz, CDCI₃) δ 21.31, 28.68, 28.73, 29.09, 32.91, 33.76, 34.37, 38.89, 50.38, 50.70, 50.90, 50.98, 51.12, 51.23, 52.23, 52.50, 52.58, 52.66, 52.84, 73.60, 73.67, 73.80, 79.66, 79.73, 112.50, 117.66, 126.63, 126.68, 126.74, 129.31, 129.56, 133.65, 133.83, 137.18, 137.22, 137.27, 137.45, 140.46, 140.53, 141.25, 141.36, 146.30, 146.40, 153.93, 154.01 (mixture of diastereomers); LCMS (m/z) 410 (M+H). RT (Method A, supra), 1.0 min.

Step E: [5-(3, 6-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl](4- methylphenyl) methanol (IX, Scheme 5)

Prepared using HCI in EtOAc on intermediate VII as in Example 1 to afford a white solid, 155 mg (62%). ¹³C NMR (100MHz, CDCI₃) δ 22.67, 26.21, 31.82, 32.50, 33.28, 45.24, 51.56, 54.56, 57.15, 72.27, 92.78, 110.07, 125.44, 126.52, 126.58, 126.68, 128.17, 128.26, 129.31, 138.04, 139.83, 146.22, 146.26, 148.66, 153.71 (mixture of diastereomers); LCMS (m/z) 310 (M+H). RT (Method A, supra), 1.0 min. Example 81 : 3-{5-[fluoro(4-methylphenyl)methyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane (VIII₁ Scheme 5)

A solution of tert-butyl-[5-(3,6-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl](4- methylphenyl)methanol-3-carboxylate (VII, Scheme 5) (451 mg, 1.10 mmol) in bis-(2-methoxyethyl)aminosulfurtrifluoride (203 μL, 1.10 mmol) was heated at 70-80⁰C for 3 days, and the reaction cooled, taken up in CH₂CI₂, washed with aq. NaHCO₃, dried and evaporated. The residue was chromatographed on silica gel to give 21 mg (4%) of the product as an oil. ¹³C NMR (100MHz₁ CDCI₃) δ 21.43, 27.41, 28.71, 28.79, 32.96, 33.81, 34.39, 36.52, 36.76, 37.11, 39.03, 41.90, 45.10, 49.13, 50.46, 50.76, 50.98, 52.22, 52.79, 55.92, 59.09, 62.27, 69.36, 71.00, 74.46, 79.73, 84.84, 92.18, 112.50, 117.02, 126.77, 129.16, 129.52, 130.26, 135.53, 137.09, 174.32, 178.79 (mixture of diastereomers); LCMS (m/z) 310 (M+H). RT (Method A, supra), 1.0 min. This material was treated with HCI in EtOAc as in Example 1 to give the title product, 6 mg (30%) as a solid. ¹³C NMR (100MHz, CDCI₃) δ 22.81, 32.47, 33.26, 47.02, 47.17, 47.32, 47.39, 47.60, 47.81, 48.03, 48.24, 48.45, 49.30, 51.61, 52.87, 54.54, 63.29, 69.47, 74.90, 75.42, 86.04, 95.52, 127.08, 129.57, 142.92, 158.31 , 163.41, 167.79, 178.43 (mixture of diastereomers); LCMS (m/z) 312 (M+H): RT (Method A, supra), 1.0 min.

Scheme 6

Example 74: {5-[3,6-diazabicyclo[3.2.1]oct-3-yl]pyridin-3- yl}(phenyl)methanone (Xl, Scheme 6)

The reactions to prepare intermediates X and Xl were carried out using the methods described in Example 1 and Example 82, intermediate Vl, to afford the product as an orange gum in 55% yield. ¹³C NMR (100MHz, CDCI₃) δ 32.50, 33.27, 51.35, 51.58, 54.55, 56.65, 128.72, 129.01 , 130.21, 130.52, 134.20, 148.69, 160.39, 162.81, 203.49, 207.57; LCMS (m/z) 294 (M+H). RT (Method A, supra), 1.0 min.

Scheme 7

Example 106: 3-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-6-methyl- 3,6-diazabicyclo[3.2.1]octane (Scheme 7)

To a suspension of 3-[5-(2-chloro-5- fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane (151 mg, 0.386 mmol) in 5 ml_ THF was added diisopropylethylamine (138 μl_, 0.772 mmol), 36% aqueous formalin solution

(44 μL, 0.579 mmol), and sodium triacetoxy borohydride (164 mg, 0.772 mmol). The reaction was stirred at room temperature for 2 hr, taken up in

EtOAc, washed with aq. NaHCO₃ and brine, dried and evaporated. The residue was converted to the HCL salt in EtOAc to afford the product as a white solid, mp 150-180⁰C, 156.9 mg (100%). ¹³C NMR (100MHz, CDCI₃) δ

23.91, 29.09, 30.50, 34.13, 34.95, 39.82, 49.25, 53.48, 58.60, 58.68, 68.29,

116.12, 116.35, 118.19, 118.43, 120.07, 125.69, 127.91 , 127.94, 131.46,

131.55, 134.15, 135.06, 138.51 , 138.85, 139.54, 139.61 , 145.74, 160.09, 162.56 (on the free base); LCMS (m/z) 332 (M+H). RT (Method A₁ supra), 1.0 min. Other compounds prepared in this fashion include Examples 103-105, 107, and 108 (see Table 1 for structures and names). Mass spec data for examples 103-105, 107, and 108 are reported below in Table 6.

Table 6

The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles "a," "an," "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations to the invention, the scope of which is defined by the appended claims.

Claims

CLAIMS 1. A compound of Formula I:

Formula I wherein:

R is H, alkyl, or alkanoyl;

X is aryl or heteroaryl, wherein said aryl or heteroaryl may be optionally fused to a five- to seven-membered carbocyclic ring or to a five- to seven- membered heterocyclic ring containing one or two heteroatoms selected from O, N, and S, wherein X may be optionally substituted with one or more substituents independently selected from alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, arylalkoxy, halo, alkylthio, haloalkyl, haloalkoxy, cyano, aryloxy, heteroaryl, -SO₂NR¹R², -NR²R³SO₂, -SO₂R⁴, or -C(=O)NR⁵R⁶; Y is a bond, -O-, -O_m(CH₂)_n-, -(CH₂)_PO-, -C(=O)-, or -SO₂-, wherein said CH₂ moieties may be optionally substituted by one or more groups independently selected from halo, alkyl, and hydroxyl; m is O or 1 ; n and p are independently 1 , 2, or 3; R¹, R², and R³ are independently H or alkyl; R⁴ is alkyl; and

R⁵ and R⁶ are independently H or alkyl, or together with the N to which they are attached form a saturated or unsaturated heterocyclic moiety, provided that R⁵ and R⁶ are not both H; or a pharmaceutically acceptable salt thereof; or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

2. A compound of Formula I according to claim 1 wherein

has the stereochemistry

3. A compound of Formula I according to claim 2 wherein: R is H; or a pharmaceutically acceptable salt thereof.

4. A compound of Formula I according to claim 2 wherein:

5. A compound of Formula I according to claim 2 wherein:

6. A compound of Formula I according to claim 2 wherein:

X is phenyl, benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, wherein X may be optionally substituted with one or more substituents independently selected from ethoxy, isopropoxy, methoxy, methoxyethyl, methoxymethyl, isopropoxycarbonyl, isopropyl, methyl, t-butyl, methylthio, benzyloxy, phenoxy, cyano, cyclopropyl, chloro, fluoro, trifluoromethoxy, trifluoromethyl, thienyl, morpholinylcarbonyl, N, N- diisopropylaminocarbonyl, and N,N-dimethylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

7. A compound of Formula I according to claim 2 wherein:

8. A compound of Formula I according to claim 2 wherein: R is H;

X is phenyl optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, and -C(=O)NR⁵R⁶; R⁵ and R⁶ are alkyl, or R⁵ and R⁶ together with the N to which they are attached form a saturated or unsaturated heterocyclic moiety; and

Y is a bond, -CH₂O-, -C(=O)- , -O-, -OCH₂-, -CH₂-, -(CH₂J₂-, -CHF-, -CHOH-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

9. A compound of Formula I according to claim 2 wherein:

R is H;

Y is a bond, -CH₂O-, -C(=O)- , -O-, -OCH₂-, -CH₂-, -(CH₂)₂-, -CHF-, -CHOH-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

10. A compound of Formula I according to claim 2 wherein: X is heteroaryl, optionally fused to a five- to seven-membered carbocyclic ring or to a five- to seven-membered heterocyclic ring containing one or two heteroatoms selected from O, N, and S, wherein X is optionally substituted with one or more substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylthio, arylalkoxy, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, and -C(=O)NR⁵R⁶; and

11. A compound of Formula I according to claim 2 wherein:

R is H;

Y is a bond, -CH₂O-, -O- , -OCH₂-, or -SO₂-; or a pharmaceutically acceptable salt thereof.

12. A compound of Formula I according to claim 2 wherein: R is H; X is benzofuranyl, benzothiazolyl, dihydrobenzodioxepinyl, dihydrobenzofuranyl, furyl, pyridyl, pyrimidyl, thiazolyl, thienyl, or thiazolyl, optionally substituted by one or more substituents independently selected from methyl, chloro, fluoro, and thienyl; and

13. A compound of Formula I according to claim 1 selected from: 3-(5-phenylpyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane; 3-[5-(4-methoxy-3,5-dimethylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane; isopropyl S-fδ-β.δ-diazabicycloβ^.iloct-S-yllpyridin-S-ylJbenzoate;

3-{5-[4-(benzyloxy)phenyl]pyridin-3-yl}-3,6-diazabicyclo[3.2.1]octane; 3-[5-(4-isopropylphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(5-fluoro-2-methoxyphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(3-chlorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(3,5-dichlorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-{5-[2-(methylthio)phenyl]pyridin-3-yl}-3,6-diazabicyclo[3.2.1]octane; 3-[5-(1-benzofuran-2-yl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; δ-β.e-diazabicycloβ^.iloct-S-ylJ-SΛ'-bipyridine; 3-[5-(3,5-dimethylphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[2-(trifluoromethoxy)phenyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 ]octane;

3-[5-(4-methoxy-3-methylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(4-methyl-2-thienyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-(5-benzylpyridin-3-yl)-3,6-diazabicyclo[3.2.1 ]octane;

S'-chloro-S-IS.Θ-diazabicycloIS^.Iloct-S-yll-S^'-bipyridine; 3-[5-(4-ethoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 2-{5-[3,6-diazabicyclo[3.2.1]oct-3-yl]pyridin-3-yl}-N,N-diisopropyl-6- methoxybenzamide; 3-[5-(3-fluoro-4-methoxyphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

S-lδ-IS.Θ-diazabicycloIS^.Iloct-S-yπpyridin-S-ylJbenzonitrile; 3-[5-(3,4-difIuorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2-methoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(3,4-dihydro-2H-1 ,5-benzodioxepin-7-yl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

S-iS-tS.β-diazabicyclotS^.IJoct-S-yllpyridin-S-ylJ-N.N- dimethylbenzamide;

4-{5-[3,6-diazabicyclo[3.2.1]oct-3-yl]pyridin-3-yl}benzonitrile; 3-[5-(2-ethoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-[5-(4-fluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2,5-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; δ-IS.β-diazabicycloβ^.iloct-S-yll-S.S'-bipyiϊdine; 3-[5-(2-phenoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[4-(morpholin-4-ylcarbonyl)phenyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

3-[5-(2-thienyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(3-chloro-4-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane;

3-[5-(2,3-dihydro-1-benzofuran-5-yl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(3-ethoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(4-fluoro-2-methylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(4-methoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2,4-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane;

3-[5-(4-methylphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(4-chlorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(3,4-dimethoxyphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-{5-[4-(trifluoromethyl)phenyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 Joctane;

3-[5-(2,3-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2-chlorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[2-(benzyloxy)phenyl]pyridin-3-yl}-3_I6-diazabicyclo[3.2.1]octane;

3-[5-(2-fluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2-fluoro-3-methoxyphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(2,6-dimethylphenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(4-fluoro-3-methylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane; 3-[5-(3-fluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(3,5-difluorophenyl)pyridin-3-yl]-3_I6-diazabicyclo[3.2.1]octane; 3-[5-(2-chloro-4-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane; (1 S,5S)-3-(5-phenylpyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane;

(1 S,5S)-3-(5-phenylpyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane; 3-{5-[(4-methylphenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 ]octane;

3-{5-[(3-chlorophenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

3-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane; 3-[5-(3,4-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclot3.2.1]octane;

3-[5-(3,4-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; {5-[3,6-diazabicyclo[3.2.1]oct-3-yl]pyridin-3-yl}(phenyl)methanone; 3-[5-(pyridin-3-yloxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-(5-phenoxypyridin-3-yl)-3,6-diazabicyclo[3.2.1 ]octane; (1 R,5/?)-3-[5-(4-fluoro-2-methylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane;

(1S,5S)-3-[5-(4-fluoro-2-methylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

(1R,5R)-3-[5-(2,4-difluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

(1S,5S)-3-[5-(2,4-difluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane;

3-{5-[fluoro(4-methylphenyl)methyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 ]octane; [5-(3,6-diazabicyclo[3.2.1]oct-3-yl)pyridin-3-yl](4- methylphenyl)methanol; 3-{5-[(4-chlorophenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

3-t5-(phenylsulfonyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[(4-methylphenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

3-{5-[(4-methoxyphenyl)sulfonyl]pyridin-3-yl}-3₁6- d iazabicyclo[3.2.1 ]octane;

3-{5-[(2-methylphenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane; S-fS-p-methoxyphenyOsulfonyltøyridin-S-ylJ-S.e- diazabicyclo[3.2.1 ]octane;

3-[5-(pyridin-4-ylsulfonyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[(4-tert-butylphenyl)sulfonyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 ]octane; 2-({5-[3,6-diazabicyclo[3.2.1]oct-3-yl]pyridin-3-yl}oxy)-1,3- benzothiazole;

3-[5-(2-methyl-1,3-thiazol-4-yl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(pyrazin-2-yloxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[2-(2-thienyl)-1 ,3-thiazol-4-yl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

• 3-[5-(pyrimidin-2-yloxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 6-(5-phenylpyridin-3-yl)-3,6-diazabicyclo[3.2.1 ]octane; 6-[5-(2,4-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 6-[5-(3,4-difluorophenyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

6-[5-(2-chloro-4-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

6-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane; 6-[5-(4-fluoro-2-methylphenyl)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 Joctane; 6-(5-ben2ylpyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane; 6-methyl-3-(5-phenylpyridin-3-yl)-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2,4-difluorophenyl)pyridin-3-yl]-6-methyl-3,6- diazabicyclo[3.2.1]octane; 3-[5-(2,5-difluorophenyl)pyridin-3-yl]-6-methyl-3,6- diazabicyclo[3.2.1]octane;

3-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-6-methyl-3,6- diazabicyclo[3.2.1 ]octane;

4-{5-[6-methyl-3,6-diazabicyclo[3.2.1]oct-3-yl]pyridin-3-yl}benzonitrile; 3-[5-(2-chloro-5-fluorophenyl)pyridin-3-yl]-6-ethyl-3,6- diazabicyclo[3.2.1 ]octane;

3-{5-[(4-fluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

3-[5-(2-phenylethyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[(pyridin-3-yloxy)methyl]pyridin-3-yl}-3,6-diazabicyclo[3.2.1 ]octane;

3-[5-(phenoxymethyl)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-{5-[(2,4-difluorophenoxy)methyl]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane;

3-[5-(3-methoxyphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2-isopropoxyphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-[5-(2-cyclopropyl-4-fluorophenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-{5-[(4-fluoro-2,3-dihydro-1-benzofuran-7-yl)oxy]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 ]octane; 3-[5-(5-fluoro-2-methylphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-[5-(4-chloro-2-methoxyphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1]octane;

3-{5-[4-(2-methoxyethyl)phenoxy]pyridin-3-yl}-3,6- diazabicyclo[3.2.1]octane; 3-[5-(3-fluoro-5-methoxyphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane;

3-[5-(4-fluoro-2-methoxyphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane; 3-[5-(2-methylphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1 ]octane;

3-[5-(2-ethoxy-4-methylphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 Joctane;

3-[5-(4-fluoro-2-methylphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane; 3-[5-(4-ethoxyphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-[5-(4-methoxyphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(3-fluorophenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(2-ethoxyphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(4-methylphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane; 3-[5-(5-fluoro-2-methoxyphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane;

3-(5-phenoxypyridin-3-yl)-3,6-diazabicyclo[3.2.1 ]octane; 3-[5-(2-fluoro-6-methoxyphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 Joctane; 3-[5-(4-chlorophenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-{5-[4-(methoxymethyl)phenoxy]pyridin-3-yl}-3,6- diazabicyclo[3.2.1 ]octane;

3-[5-(4-fluoro-3-methylphenoxy)pyridin-3-yl]-3,6- diazabicyclo[3.2.1 ]octane; 3-[5-(3-ethoxyphenoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane;

3-{5-[(2,4-difluorobenzyl)oxy]pyridin-3-yl}-3,6-diazabicyclo[3.2.1]octane; S-tδ-KSΛ-difluorobenzyOoxyJpyridin-S-ylJ-S.β-diazabicycloIS^.Iloctane; and

3-[5-(2-furylmethoxy)pyridin-3-yl]-3,6-diazabicyclo[3.2.1]octane.

14. A pharmaceutical composition comprising a compound of

Formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipients.

15. A method of treating a disorder or condition selected from depression, mood disorders, schizophrenia, bipolar disorder, anxiety disorders, Alzheimer's disease, Parkinson's disease, attention deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, cognitive deficits, pain, Tourette's syndrome, nicotine dependency, addiction and withdrawal, and post-traumatic stress disorder in a mammal, including a human, comprising administering to a mammal in need of such treatment a compound of Formula I according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer of the compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount that is effective in treating such condition or disorder.