AU2012203831B2 - Azaadamantane derivatives and their uses as nicotinic acetylcholine receptors ligands - Google Patents

Abstract

AZAADAMANTANE DERIVATIVES AND THEIR USES AS NICOTINIC ACETYLCHOLINE RECEPTORS LIGANDS The invention relates to compounds that are azaadamantane derivatives of formula (I), particularly ether- or amine-substituted azaadamantane derivatives and salts and prodrugs thereof, compositions comprising such compounds, methods of using such compounds and compositions, processes for preparing such compounds, and intermediates obtained during such processes.

Description

S&FRef: 902110D1 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address Abbott Laboratories, of 100 Abbott Park Road, Abbott of Applicant: Park, Illinois, 60064, United States of America Actual Inventor(s): Chih-Hung Lee Diana L. Nersesian Geoff G.Z. Zhang Jianguo Ji Kevin B. Sippy Lei Shi Willaim H. Bunnelle Michael R. Schrimpf Paul J. Brackemeyer Rodger F. Henry Shuang Chen Tao Li Marc Scanio Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Azaadamantane derivatives and their uses as nicotinic acetylcholine receptors ligands The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(6421987_1) AZAADAMANTANE DERIVATIVES AND THEIR USES AS NICOTINIC ACETYLCHOLINE RECEPTORS LIGANDS BACKGROUND OF THE INVENTION Cross-Reference of Related Applications 5 This application claims the benefit of U.S. Provisional Patent Application Serial No. 60/856,992, filed November 6, 2006, and U.S. Provisional Patent Application Serial No. 60/908,143, filed March 26, 2007, each application of which is herein incorporated by reference in its entirety. 10 Technical Field The invention relates to azaadamantane derivatives, and more particularly ether- or amine-substituted azaadamantane derivatives, compositions comprising such compounds, methods of preventing or treating conditions and disorders using such _ compounds and compositions, processes for preparing such compounds, and 15 intermediates obtained during such processes. Description of Related Technology Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central (CNS) and peripheral (PNS) nervous systems. Such receptors play an 20 important role in regulating CNS function, particularly by modulating release of a wide range of neurotransmitters, including, but not necessarily limited to, acetylcholine, norepinepluine, dopamine, serotonin, and GABA. Consequently, nicotinic receptors mediate a very wide range of physiological effects, and have been targeted for therapeutic treatment of disorders relating to cognitive function, learning 25 and memory, neurodegeneration, pain, inflammation, psychosis, sensory gating, mood, and emotion, among other conditions. Many subtypes of the nAChR exist in the CNS and periphery. Each subtype has a different effect on regulating the overall physiological function. Typically, nAChRs are ion channels that are constructed from a pentameric assembly of subunit -1proteins. At least 12 subunit proteins, c2-alO and p2-p4, have been identified in neuronal tissue.. These subunits provide for a great variety of homomeric and heteromeric combinations that account for the diverse receptor subtypes. For example, the predominant receptor that is responsible for high affinity binding of 5 nicotine in brain tissue has composition (a4)z(P2)3 (the a4p2 subtype), while another major population of receptors is comprised of homomeric (L7)5 (the a7 subtype) receptors. Certain compounds, like the plant alkaloid nicotine, interact with all subtypes of the nAChRs, accounting for the profound physiological effects of this compound. 10 While nicotine has been demonstrated to have many beneficial properties, not all of the effects mediated by nicotine are desirable. For example, nicotine exerts gastrointestinal and cardiovascular side effects that interfere at therapeutic doses, and its addictive nature and acute toxicity are well-known. Ligands that are selective for interaction with only certain subtypes of the nAChR offer potential for achieving 15 beneficial therapeutic effects with an improved margin for safety. The a7 and cx4p2 nAChRs have been shown to play a significant role in enhancing cognitive function, including aspects of learning, memory and attention (Levin, E.D., J. Neurobiol. 53: 633-640, 2002). For example, a7 nAChRs have been linked to conditions and disorders related to attention deficit disorder, attention deficit 20 hyperactivity disorder (ADHD), schizophrenia, Alzheimer's disease (AD), mild cognitive impairment, senile dementia, dementia associated with Lewy bodies, dementia associated with Down's syndrome, AIDS dementia, and Pick's disease, as well as inflammation. The ca4p2 receptor subtype is implicated in attention, cognition, epilepsy, and pain control (Paterson and Norberg, Progress in 25 Neurobiology 61 7.5-111, 2000) as well as smoking cessation or nicotine withdrawal syndrome. The activity at both a7 and a4p2 nAChRs can be modified or regulated by the administration of subtype selective nAChR ligands. The ligands can exhibit antagonist, agonist, or partial agonist properties. Compounds that function as 30 allosteric modulators are also known. Although compounds that nonselectively demonstrate activity at a range of nicotinic receptor subtypes including the a.4p2 and (7 nAChRs are known, it would be beneficial to provide compounds that interact selectively with a7-containing -2neuronal nAChRs, a4P2 nAChRs, or both c.7 and a4 2 nAChRs compared to other subtypes. BRIEF DESCRIPTION OF THE DRAWINGS 5 FIGURE 1 is a powder X-ray diffraction pattern of an anhydrous L-bitartrate of (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- I -azatiicyclo[3.3 1.1 3 7 ]decane. FIGURE 2 is a powder X-ray diffraction pattern of a L-bitartrate hydrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)- 1 -azatricyclo[3.3.1 .1 3 7 }decane. 10 FIGURE 2A is a thermogram of a L-bitartrate hydrate of (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-1 -azatricyclo[3.3.1.1 3 7 ]decane obtained by thermal gravimetric analysis (TGA). FIGURE 3 is a powder X-ray diffraction pattern of an anhydrous dihydrogen phosphate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-I 15 azatricyclo[3.3.1 .1 3 ,]decane. FIGURE 4 is a powder X-ray diffraction pattern of a dihydrogen phosphate hydrate of (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- 1 -azatricyclo[3.3 .1.13 ' 7 ]decane. FIGURE 4A is a thermogram of a dihydrogen phosphate hydrate of (4s)-4-(5 phenyl-l,3,4-thiadiazol-2-yloxy)- 1 -azatricyclo[3..3.1 .1 7 ]decane obtained by thermal 20 gravimetric analysis. FIGURE 5 is a powder X-ray diffraction pattern of an anhydrous bisuccinate of (4s)-4-(5-phenyl- 1,.3,4-thiadiazol-2-yloxy)- I -azatricyclo[3.3. 1.1 3 7 ]decane. FIGURE 6 is a powder X-ray diffraction pattern of a bisuccinate hydrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 -azatricyclo[3.3.1.1 3

,

7 ]decane. 25 FIGURE 6A is a thernogram of a bisuccinate hydrate of (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-I-azatricyclo[3.3 1 1 3 ]decane obtained by thermal gravirmetric analysis.. FIGURE 7 is a powder X-ray diffraction pattern of a hydrochloride quarterhydrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 30 azatricyclo[3.3.1,1 3 ,]decane. FIGURE. 8 is a powder X-ray diffraction pattern of a hydrochloride sesquihydrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)- 1 azatricyclo[3.3.1.1 V']decane. -3- FIGUR.E 8A is a thermogram of a hydrochloride sesquihydrate of (4s)-4-(5 phenyl-1,3,4-thiadiazol-2-yloxy)-I-azatricyclo[3.3.1 1 3 7 ]decane obtained by thermal gravimetric analysis. FIGURE 9 is a powder X-ray diffraction pattern of a dihydrogen citrate of 5 (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)- 1-azatricyclo[3.3.1.1 3 ']decane. FIGURE 10 is a powder X-ray diffraction pattern of a monohydrogen citrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3. 3.1 1Jdecane. FIGURE 11 is a powder X-ray diffraction pattern of the (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1 1 3 7 ]decane free base. 10 FIGURES 5, 7, 9, and 11 were determined from the single cell crystal data of their respective compounds, SUMMARY OF THE INVENTION The invention is directed to azaadamantane derivatives, compositions 15 comprising such compounds, processes for preparing such compounds, and intermediates obtained during such processes. More particularly, the invention relates to ether- or amine-substituted azaadamantane compounds and related methods and processes thereof. One aspect of the invention relates to a compound of formula (1) 20 A (I); or a phannaceutically acceptable salt or prodrug thereof, wherein Li is-O- or -NR,-; 25 A is -Arl, -Ar 2

-L

2 -Ar 3 or -Ar 4

-L

3 -Ar 5 ; Ari is aryl or heteroaryl; Ar 2 is aryl or monocyclic heteroaryl; Ar 3 is aryl or heteroaryl; Ar 4 is a bicyclic heteroaryl; 30 Ar 5 is aryl or heteroaryl; L2 is a bond, -0-, -NRe-, -C(O)NR,-, or -CH-;

L

3 is a bond, -0-, -NR,- or -CH 2 -; and -4- Ra is hydrogen or alkyl. Another aspect of the invention relates to phannaceutical compositions comprising compounds of the invention. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen 5 for treatment or prevention of conditions and disorders related to nAChR activity, and more particularly a7 nAChR activity, a4p2 nAChR activity, or both 7 nAChR activity and a4p2 nAChR activity. Yet another aspect of the invention relates to a method of modulating both a7 and a43P2 nAChR activity. The method is useful for treating, preventing or both 10 treating and preventing conditions and disorders related to both a7 and ct4p2 nAChR activity, particularly in mammals A further aspect of the invention relates to a method of selectively modulating nAChR activity, for example 7 nAChR activity. The method is useful for treating, preventing or both treating and preventing conditions and disorders related to a7 15 nAChR activity in mammals. A method of selectively modulating a4P2 nAChR activity also is contemplated. Such methods are useful for conditions and disorders related to attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), schizophrenia, mild cognitive impairment, age-associated memory impairment 20 (AAMI), senile dementia, AIDS dementia, Pick's disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, schizophrenia, smoking cessation, nicotinic withdrawal syndrome, amyotrophic lateral sclerosis, Huntington's disease, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, neuropathic pain, infertility, lack 25 of circulation, need for new blood vessel growth associated with wound healing, more particularly circulation around a vascular occlusion, need for new blood vessel growth associated with vascularization of skin grafts, ischemia, inflammation, sepsis, wound healing, and other complications associated with diabetes, among other systemic and neuroimmunomodulatory activities. 30 The invention also relates to particular salts of certain compounds of the invention as well as compositions comprising and processes for preparing such compounds and salts. The compounds, including salts thereof, compositions comprising the -5compounds, methods for using the compounds, and processes for preparing the compounds, as well as intermediates obtained in such processes, are further described herein 5 DETAILED DESCRIPTION OF THE INVENTION Definition of Terms As used throughout this specification and the appended claims, the following terms have the following meanings: 10 The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2 propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3 15 decenyl. The term "alkenylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one double bond. Representative examples of alkenylene include, but are not limited to, -CH=CH-, -CH=CH 2

CH

2 -, and -CH=C(CH3)CH 2 20 The term "ailcenyloxy" as used herein, means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2 butenyloxy and 3-butenyloxy. The term "alkoxy" as used herein, means an alkyl group, as defined herein, 25 appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2 propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkoxy" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as 30 defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy. The term "alkoxyalkoxyalkyl" as used herein, means an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not -6limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2 methoxyethoxy)methyl, and 2-(2-methoxyethoxy)ethyl. The tern "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined 5 herein. Representative examples of alkoxyalkyl include, but are not limited to, tert butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. The term "alkoxycarbonyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, 10 methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, .3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert 15 butoxycarbonylethyl. The term "alkoxysulfonyl" as used herein, means an allcoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysul fonyl. 20 The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from I to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2 dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. 25 The term "alkylcarbonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- I -oxopropyl, 1 -oxobutyl, and I -oxopentyl. The term "alkylcarbonylalkyl" as used herein, means an alkylcarbonyl group, 30 as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl. The term "alkylcarbonyloxy" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. -7- Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The tenn "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples 5 of alkylene include, but are not limited to, -CH 2 -, -CI-(CH 3 )-, -C(CH 3 )2-, -CH 2

CH

2 -,

-CH

2

CH

2

CH

2 -, -CH 2 CH2CH 2 CH2-, and -CH 2

CH(CH

3 )CH2 The term "alkylsulfinyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, 10 methylsulfinyl and ethylsulfinyl. The term "alkylsulfinylalkyl" as used herein, means an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl and ethylsulfinylmethyl. 15 The term "alkylsulfonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The term "alkylsulfonylalkyl" as used herein, means an alkylsulfonyl group, as 20 defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl. The term "alkylthio" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative 25 examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert butylthio, and hexylthio. The term "alkylthioalkyl" as used herein, means an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited to, 30 methylthiomethyl and 2-(ethylthio)ethyl. The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, I -propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. -8- The term "alkynylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one triple bond. Representative examples of alkynylene include, but are not limited to, -C=C-, -CH 2 C=C-, -CH(CH 3

)CH

2 C=C-, -C=CCH 2 -, and -C=CCH(CH 3

)CH

2 -. 5 The term "alkyinyloxy" as used herein, means an alkynyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkynyloxy include, but are not limited to, 2-piopynyloxy and 2-butynyloxy. The tenn "aryl," as used herein, means phenyl, a bicyclic aryl or a tricyclic 10 aryl. The bicyclic aryl is naphithyl, a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl. Representative examples of the bicyclic aryl include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl The tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or a bicyclic aryl 15 fused to a phenyl. Representative examples of tricyclic aryl ring include, but are not limited to, aztilenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl. The aryl groups of this invention can be substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, 20 alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioallcyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, hydioxy, hydroxyalkyl, mercapto, nitro, -NZIZ 2 , and (NZ 3

Z

4 )carbonyl. The term "arylalkoxy" as used herein, means an aryl group, as defined herein, 25 appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2 phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy. The term "arylalkoxycarbonyl" as used herein, means an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as .30 defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphth-2-ylmethoxycarbonyl. The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. -9- Representative examples of arylalkyl include, but are not limited to, benzyl, 2 phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl. The term "arylalkylthio" as used herein, means an arylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. 5 Representative examples of arylalkylthio include, but are not limited to, 2 phenylethylthio, 3-naphth-2-ylpropylthio, and 5-phenylpentylthio. The term "arylcarbonyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, 10 benzoyl and naphthoyl. The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3 bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy. 15 The term "aryloxyalkyl" as used herein, means an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxyalkyl include, but are not limited to, 2 phenoxyethyl, 3-naphth-2-yloxypropyl and 3-bromophenoxymethyl. The term "arylthio" as used herein, means an aryl group, as defined herein, 20 appended to the parent molecular moiety through a sulfur atom. Representative examples of arylthio include, but are not limited to, phenylthio and 2-naphthylthio. The term "arylthioalkyl" as used herein, means an arylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylthioalkyl include, but are not limited to, 25 phenylthiomethyl, 2-naphth-2-ylthioethyl, and 5-phenylthiomethyl. The term "azido" as used herein, means a -N 3 group. The term "carbonyl" as used herein, means a -C(O)- group. The term "carboxy" as used herein, means a -CO 2 H group. The term "carboxyalkyl" as used herein, means a carboxy group, as defined 30 herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl. The term "cyano" as used herein, means a -CN group. The term "cyanoalkyl" as used herein, means a cyano group, as defined herein, -10appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoallcyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl. The term "cycloalkenyl" as used herein, means a cyclic hydrocarbon 5 containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of cycloalkenyl include, but are not limited to, 2-cyclohexen-I-yl, 3-cyclohexen-I-yl, 2,4 cyclohexadien-1-yl and 3-cyclopenten-1-yl. The term "cycloalkyl" as used herein, means a monocyclic, bicyclic, or 10 tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two adjacent or non-adjacent carbon atoms of the monocyclic ring 15 are linked by an alkylene bridge of between one and three additional carbon atoms Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3. 1.1] heptane, bicyclo[2.2. I ]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1 ]nonane, and bicyclo[4 .2.1 Jnonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon 20 atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3. 1.0 3

,

7 ]nonane and tricyclo[3 3.1 .7 Jdecane (adamantane). The cycloalkyl groups of the invention are optionally substituted with 1, 2, 3, 25 4 or 5 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, fornyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo,

-NZIZ

2 , and (NZ 3

Z

4 )carbonyl. 30 The term "cycloalkylalkyl" as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and -11- 4-cycloheptylbutyl. The term "cycloalkylcarbonyl" as used herein, means cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not 5 limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and cyclohexylcarbonyl. The temi "cycloalkyloxy" as used herein, means cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, as defined herein. Representative examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and 10 cyclooctyloxy. The term "cycloalkylthio" as used herein, means cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom, as defined herein. Representative examples of cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, and 15 cyclooctylthio. The term "ethylenedioxy" as used herein, means a -O(CH 2

)

2 0- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two 20 adjacent carbon atoms forming a six membered ring. The term "formyl" as used herein, means a -C(O)H group. The term "formylalkyl" as used herein, means a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of fornylalkyl include, but are not limited to, 25 formylmethyl and 2-formylethyl. The term "halo" or "halogen" as used herein, means -Cl, -Br, -I or -F. The term "haloalkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defincherein. Representative examples of haloalkoxy include, but are not limited to, 30 chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3 -12fluoropentyl. The term "heteroaryl," as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring that contains at least one heteroatom selected from the group consisting of nitrogen, 5 oxygen and sulfur. The 5 membered ring contains two double bonds and the 6 membered ring contains three double bonds. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the heteroaryl, provided that proper valance is maintained. Representative examples of monocyclic heteroaryl include, 10 but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, 15 or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the bicyclic heteroaryl, provided that proper valance is maintained. Representative examples of bicyclic heteroaryl include, but are not limited to, azaindolyl, benzimidazolyl, benzofuranyl, benzoxadiazolyl, 20 benzoisoxazole, benzoisothiazole, benzooxazole, 1,3-benzothiazolyl, benzothienyl( or benzothiophenyl), cinnolinyl, furopyridine, indolyl, indazolyl, indolinonyl, isobenzofuran, isoindolyl, isoquinolinyl, naphthyridinyl, oxadiazolyl, oxazolopyridine, quinolinyl, quinoxalinyl, thiadiazolyl and thienopyridinyl, The heteroaryl groups of the invention are optionally substituted with 1, 2, 3 25 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, fornyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZIZ 2 and (NZ 3

Z

4 )carboniyl. 30 Heteroaryl groups of the invention that are substituted with a hydroxy group may be present as tautomers. The heteroaryl groups of the invention encompasses all tautomers including non-aromatic tautomers. In addition, the nitrogen heteroatoms can be optionally quaternized or oxidized to the N-oxide. The term "heteroarylalkoxy" as used herein, means a heteroaryl group, as -13defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heteroarylalkoxy include, but are not limited to, fur-3-ylmethoxy, I H-imidazol-2-ynethoxy, IH-imidazol-4-ylmethoxy, 1-(pyridin-4-y)ethoxy, pyridin-3-ylmethoxy, 6-chloropyridin-3-ylnethoxy, pyridin 5 4-ylmethoxy, (6-(trifluorometlhyl)pyridin-3-yl)nethoxy, (6-(cyano)pyridin-3 yl)methoxy, (2-(cyano)pyridin-4-yl)methoxy, (5-(cyano)pyridini-2-yl)methoxy, (2-(chloro)pyridin-4-yl)methoxy, pyrimidin-5-ynethoxy, 2-(pyrimidin-2-yl)propoxy, thien-2-ylmethoxy, and thien-3-ylmethoxy. The term "lheteroarylalkyl" as used herein, means a heteroaryl, as defined 10 herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, IH-imidazol-2-ylmethyl, IH-imidazol-4-ylmethyl, 1-(pyridin-4 yl)ethyl, pyridin-3-ylmethyl, 6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl, (6-(tri fluoromethyl)pyridin-3-yl)mlethyl, (6-(cyano)pyrid in-3-yl)methyl, 15 (2-(cyano)pyridin-4-yl)methyl, (5-(cyano)pyridin-2-yl)methyl, (2-(chloro)pyridin-4 yl)methyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl. The term "heteroarylalkylcarbonyl" as used herein, means a heteroarylalkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as 20 defined herein. The term "heteroarylakylthio" as used herein, means a heteroarylalkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of heteroarylalkylthio include, but are not limited to, fur-3 ylmethylthio, IH-imidazol-2-ylimiethylthio, 1H-imidazol-4-ylmethylthio, pyridin-3 25 ylmethylthio, 6-chloropyridin- 3 -ylnethylthio, pyridin-4-ylmethylthio, (6-(tri fluoromethyl)pyrid in-3-yl)methylthio, (6-(cyano)pyridin- 3 -yl)methylthio, (2-(cyano)pyridinl-4-yl)methylthio, (5-(cyano)pyridin-2-yl)methylthio, (2-(chloro)pyridin-4-yl)methylthio, pyrimidin-5-ylmethylthio, 2-(pyrimidin- 2 yl)propylthio, thien-2-ylmethylthio, and thien-3-ylmethylthio. 30 The term "heteroarylcarbonyl" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein Representative examples of heteroarylcarbonyl include, but are not limited to, fur-3-ylcarbonyl, I H-imidazol-2-ycarbonyl, 1 H-imidazol-4-ylcaibonyl, pyridin-3-ylcarbonyl, 6-chloropyridin-3-ylcarbonyl, pyridin-4-ycarbonyl, -14- (6-(tri fluoromethyl)pyridi n-3-yl)carbonyl, (6-(cyano)pyidin-3-yl)carbonyl, (2-(cyano)pyridin--4-yl)carboiyl, (5-(cyano)pyridin-2-yl)carbonyl, (2-(chloro)pyridin 4-yl)carbonyl, pyrimidin-5-ylCarbonyl, pyrimidin-2-yicarbonyl, thien-2-ylcarbonyl, and thien-3-ylcarbonyl. 5 The term "heteroaryloxy" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of heteroaryloxy include, but are not limited to, fur-3-yloxy, 1 H-imidazol-2-yloxy, I H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3 yloxy, pyridin-4-yloxy, (6-(tri fluoromethyl)pyridin- 3 -yl) oxy, (6-(cyano)pyridin-3-yl) 10 oxy, (2-(cyano)pyridin-4-yl)oxy, (5-(cyano)pyridin- 2 -yl)oxy, (2-(chloro)pyridin- 4 yl)oxy, pyrimidin-5-yloxy, pyrimidin-2-yloxy, thien-2-yloxy, and thien-3-yloxy The term "heteroaryloxyalkyl" as used herein, means a heteroaryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroaryloxyalkyl include, but are not 15 limited to, pyridin-3-yloxymethyl and 2-quinolin-3-yloxyethyl. The term "heteroarylthio" as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of heteroarylthio include, but are not limited to, pyridin-3 ylthio and quinolin-3-ylthio 20 The term "heteroarylthioalkyl" as used herein, means a heteroarylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylthioalkyl include, but are not limited to, pyridin-3-ylthiomethyl, and 2-quinolin-3-ylthioethyl The term "heterocycle" or "heterocyclic" as used herein, means a monocycli 25 heterocycle, a bicyclic heterocycle or a tricyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of 0, N, and S. The 3 or 4 membered ring contains I heteroatom selected from the group consisting of 0, N and S. The 5 membered ring contains zero or one double bond and one, two or three 30 heteroatoms selected from the group consisting of 0, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of 0, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of -15monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, 5 piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofur anyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1 -dioxidothiomorpholilnyl (thiomorpholine sulfone), thiopyranyl, and tnthianyl. The bicyclic heterocycle is a 5 or 6 membered monocyclic heterocycle fused to a phenyl group, or a 5 or 6 membered monocyclic 10 heterocycle fused to a cycloalkyl, or a 5 or 6 membered mionocyclic heterocycle fused to a cycloalkenyl, or a 5 or 6 membered monocyclic heterocycle fused to a monocyclic heterocycle. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heterocycle. Representative examples of bicyclic heterocycle include, but are 15 not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, benzodioxolyl, 2,3-dihydro-l -benzofuranyl, 2,3-dihydro-1 -benzothienyl, chromenyl and 1,2,3,4-tetrahydroquinolinlyl The tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic 20 heterocycle. The tricyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle. Representative examples of tricyclic heterocycle include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-IH-carbazolyl, 5a,6,7,8,9,9a hexahydrodibenzo[b,d] furanyl, and 5a,6,7,8,9,9a-hexahydTodibelzo(b,d]thienyl. 25 The heterocycles of this invention are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, 30 halogen, hydroxy, hydroxyalkyl, mercapto, oxo, -NZIZ 2 and (NZ 3

Z

4 )carboiyl. The term "heterocyclealkoxy" as used herein, means a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyridin-3-ylethoxy, 3-quinolin-3-ylpropoxy, and 5-pyridin-4 -16ylpentyloxy The term "heterocyclealkyl" as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein Representative examples of heterocyclealkyl include, but are not limited to, 5 piperidin-4-ylmethyl, piperazin-1-ylmethyl, 3-methyl-I -pyrrolidin-I -ylbutyl, (I R)-3 methyl-i-pyrrolidin-1-ylbutyl, (IS)-3-methyl-1-pyrrolidin-1-ylbutyl. The term "heterocyclealkylcarbonyl" as used herein, means a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclealkylcarbonyl include, but 10 are not limited to, piperidin-4-ylmethylcarbonyl, piperazin-1-ylmethylcarbonyl, 3 methyl-i-pyrrolidin-1-ylbutylcarbonyl, (1R)-3-methyl-1-pyrrolidin-l ylbutylcarbonyl, (1 S)-3-methyl- 1 -pyrrolidin-I -ylbutylcarbonyl The term "heterocyclealkylthio" as used herein, means a heterocyclealkyl group, as defined herein, appended to the parent molecular moiety through a sulfur 15 atom. Representative examples ofheterocyclealkylthio include, but are not limited to, 2-pyridin-3-ylethythio, 3-quinolin-3-ylpropythio, and 5-pyridin-4-ylpentylthio. The term "heterocyclecarbonyl" as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.. 20 The term "lieterocyclecarbonylalkyl" as used herein, means a heterocyclecarbonyl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.. The term "heterocycleoxy" as used herein, means a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxygen atom. 25 Representative examples of heterocycleoxy include, but are not limited to, pyridin- 3 yloxy and quinolin-3-yloxy. The term "heterocycleoxyalkyl" as used herein, means a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycleoxyalkyl include, 30 but are not limited to, pyridin-3-yloxymethyl and 2-quinolin-3-yloxyethyl The term "heterocyclethio" as used herein, means a heterocycle group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of heterocyclethio include, but are not limited to, pyridin-3 ylthio and quinolin-3-ylthio -17- The term "heterocyclethioalkyl" as used herein, means a heterocyclethio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclethioalkyl include, but are not limited to, pyridin-3-ylthiomethyl, and 2-quinolin-3-ylthioethyl. 5 The teri "hydroxy" as used herein, means an -OH group The tern "hydroxyalkyl" as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2 10 ethyl-4-hydroxyheptyl The term "hydroxy-protecting group" or "O-protecting group" means a substituent which protects hydroxy groups against undesirable reactions during synthetic procedures. Examples of hydroxy-protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 15 2-methoxyethoxymethyl, 2-(trimethylsilyl)-ethoxynethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2 trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, 20 methoxymethylene; cyclic carbonates; and cyclic boronates. Commonly used hydroxy-protecting groups are disclosed in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). The term "lower alkenyl" as used herein, is a subset of alkenyl, as defined herein, and means an alkenyl group containing from 2 to 4 carbon atoms. Examples 25 of lower alkenyl are ethenyl, propenyl, and buteny. The tenn " lower alkoxy" as used herein, is a subset of alkoxy, as defined herein, and means a lower alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, as defined herein. Representative examples of lower alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 30 2-propoxy, butoxy, and tert-butoxy. The term "lower alkyl" as used herein, is a subset of alkyl as defined herein and means a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n butyl, iso-butyl, sec-butyl, and tert-butyl. -18- The term "lower alkylthio" as used herein, is a subset of alkylthio, means a lower alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of lower alkylthio include, but are not limited to, methylthio, ethylthio, and tert-butylthio 5 The term "lower allynyl" as used herein, is a subset of alkynyl, as defined herein, and means an alkynyl group containing from 2 to 4 carbon atoms.. Examples of lower alkynyl are ethynyl, propynyl, and butynyl. The term "lower haloalkoxy" as used herein, is a subset of haloalkoxy, as defined herein, and means a straight or branched chain haloalkoxy group containing 10 from I to 4 carbon atoms. Representative examples of lower haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, dichloromethoxy, fluoromethoxy, and pentafluoroethoxy. The term "lower haloalkyl" as used herein, is a subset of haloalkyl, as defined herein, and means a straight or branched chain haloalkyl group containing from 1 to 4 15 carbon atoms.. Representative examples of lower haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, dichloromethyl, fluoromethyl, and pentafluoroethyl. The term "mercapto" as used herein, means a -SH group. The term "mercaptoalkyl" as used herein, means a mercapto group, as defined 20 herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, 2 mercaptoethyl and 3-mercaptopropyl. The term "methylenedioxy" as used herein, means a -OCH 2 0- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety 25 through two adjacent carbon atoms. The term "nitrogen protecting group" as used herein, means those groups intended to protect an amino group against undesirable reactions during synthetic procedures Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert 30 butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl) The term "nitto" as used herein, means a -NO 2 group. The term "NZIZ 2 " as used herein, means two groups, ZI and Z 2 , which are appended to the parent molecular moiety through a nitrogen atom. ZI and Z, are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, -19alkoxycarbonyl, aryl, arylalkyl, formyl and (NZ 5 Z()carbonyl. In certain instances within the invention, Z, and Z2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring. Representative examples of NZ 1

Z

2 include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, 5 phenylamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl. The tern "NZ 3

Z

4 " as used herein, means two groups, Z3 and Z4, which are appended to the parent molecular moiety through a nitrogen atom. Z 3 and Z4 are each independently selected from the group consisting of hydrogen, alkyl, aryl and arylalkyl. Representative examples of NZ 3 Z4 include, but are not limited to, amino, 10 methylamino, phenylamino and benzylamino. The term "NZ 5

Z

6 " as used herein, means two groups, Z5 and Zr, which are appended to the parent molecular moiety through a nitrogen atom.

Z

5 and Z 6 are each independently selected from the group consisting of hydrogen, alkyl, aryl and arylalkyl. Representative examples of NZsZ 6 include, but are not limited to, amino, 15 methylamino, phenylamino and benzylamino. The term "(NZ 3

Z

4 )carbonyl" as used herein, means a NZ 3

Z

4 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NZ 3 Z4)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dirnethylamino)carbonyl, and 20 (ethylmethylami no)carbonyl. The term "oxo" as used herein, means a =0 moiety. The tenn "sulfinyl" as used herein, means a -S(O)- group. The term "sulfonyl" as used herein, means a -SO 2 - group The term "tautomer" as used herein means a proton shift from one atom of a 25 compound to another atom of the same compound wherein two or more structurally distinct compounds are in equilibrium with each other. Although typically it may be recognized that an asterisk is used to indicate that the exact subunit composition of a receptor is uncertain, for example a3p4* indicates a receptor that contains the 3 and P4 proteins in combination with other subunits, the 30 term c7 as used herein is intended to include receptors wherein the exact subunit composition is both certain and uncertain. For example, as used herein 7 includes homomeric (ct7)5 receptors and a7* receptors, which denote a nAChR containing at least one a7 subunit -20- Compounds of the Invention Compounds of the invention can have the formula (1) as described in the Summary of the Invention. 5 Within the scope of the invention, the compounds of the invention have the formula Ar, LPAr2-,;Ar3 L Ar4L Ar 5 (1) Il) , or (IV) L* wherein L, Arl, Arm, L 2 , L 3 , Ar 3 , Ar 4 and Ar 5 are defined in formula (I) In one embodiment, the compounds of the invention can have the formula (11) 10 wherein L, and Ar are as previously defined for formula (I). In compounds of formula (11), Ari can more particularly be selected from a group having the structure E E1 F1 j<Ei Dj-G ; Gc-D1 D1 E'K1 X x 12 X 1 1

X

12 X12 X\

X

14 11 X9 X 1 4 X N 15 1 H , 1/X X15 X1 /3 wherein D 1 , Ei, Fl, J 1 , K 1 , and X$-X, 1 are each independently -CRi or N; X 12

-X

1 5 , MI and M 2 are each independently CR 1 , N, or C; G, is -0-, NRI,, or -S-; Y 1 is -CRi or N; 1 5 Y 2 is -CR or N; Y 3 is NH, -0-, or -S-; R, is hydrogen, alkyl, alkoxy, alkoxycarbonyl, cyano, halo, nitTo, -NRbRc, haloalcyl, or -C(O)NRbRc; Ria is hydrogen or alkyl; Rb and Rc are each independently hydrogen, alkyl, alkoxycarbonyl or alkylcarbonyl. In a group represented by Ari, preferably no more than two of D 1 , E 1 , F 1 , Ji 1 , and K, are N. In a group represented by Ar,, preferably no more than two in the groups X 12

-X

1 5 or -21- X-X 1 are N. In a group represented by Ari, one of X 12

-X

15 is C In a group represented by Arl, MI or M 2 is C. Preferably, Arl is imidazolyl, isoxazolyl, furyl, oxazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, 1,3 thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, benzoxazolyl, or 1,3-benzothiazolyl. 5 Preferred Ar groups are pyridazinyl, pyridinyl, 1,3-thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, benzoxazol-2-yl or 1,3-benzothiazol-2-yi. In a particular embodiment, L, is -0- and Ar is as described herein for formula (1) or any of the particular or preferred embodiments. In another particular emodiment, L, is -NRa and Ar is as described herein for formula (1) or any of the particular or preferred 10 embodiments. In another embodiment, compounds of the invention can have the formula (III), wherein LI, Ar 2 , L2, and Ar 3 are as previously described for compounds of formula (1). In compounds of formula (III), Ar 2 can more particularly be selected from a group having the structure 15

E*

2 E2 r2or F2

D

2

-G

2 ; G2-D2 D2 EK2 (W (ii) (iii) wherein D 2 , E 2 , F 2 , J2, and K 2 are each independently -CT2 or N; G 2 is -0-, -NR2a, or -S-; in each group of (i), (ii), and (iii) above, one substituent represented by T 2 , or R 2 a wherein R 2 . is T 2 , is -L 2 -Ar 3 and the other substituents represented by T 2 are 20 hydrogen, alkyl, alkoxy, alkoxycarbonyl, cyano, halo, nitio, or -NRbRe; R 2 , is hydrogen, alkyl, or T 2 ; and Rb and R, are each independently hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl. Ar 3 can more particularly be selected from a group of the structure -22-

E

3

E

3 F

F

3 \ G 3

-D

3 .3 K . D 3

-E

3 D-

E

3 1XI X 11 - i x xxeXe x X10 0

X

1 X18 N : x9 xr X19 H

~X

16 Y X M 1 x x Y2 . M2 x/ ;or x N1Y 3 xl3 wherein D 3 , E 3 , F 3 , J3, K3, and Xg, X), X 1 0 , andX 1 are each independently

-CR

3 or N; X1, X, 17

XI

8 , X 19 , M 1 , and M 2 are each independently

-CR

3 , N, or C; G 3 is -0-, -NRa., or -S-; Y I andY 2 are -CR 3 or N; Y 3 is NH, -0-, or -S-; R 3 is hydrogen, alkyl, alkoxy, 5 alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, nitro, ReRrN-, or aryl; R 3 . is hydrogen, alkyl, alkycarbonyl, trityl, or aryl, wherein aryl is preferably phenyl; Re and Rr are each independently hydrogen, alkyl, alkoxycarbonyl or alkylcarbonyl, or Re and Rr are each taken together with the nitrogen atom to which they are attached forn a heterocyclic ring.. The preferred aryl 10 group for R 3 is phenyl optionally substituted with halo, alkyl or cyano. The preferred heterocyclic ring wherein Re and Rf are each taken together to form a ing is pyrrolidinyl, piperidinyl or piperazinyl. In a group represented by Ar 3 , preferably no more than two of D 3 , E 3 , F 3 , J 3 , and K 3 are N. In a group represented by Ar 3 , preferably no more than two in the groups Xi 6

-X

10 or Xg-Xn are N. In a group 15 represented by Ar 3 , one of Xi 6 , X 1 , X 18 , or XI is C. in a group represented by Ar 3 , M, or M 2 is C. One particular embodiment relates to compounds of formula (111) wherein L, is -0- or -NRia and L 2 is -0- . Compounds of formula (III) wherein L. is -0- or -NRI, and L 2 is a bond also are contemplated Preferably, LI is -0-; and L 2 is a bond in compounds of formula (Ill) wherein Ar 2 and Ar 3 are as previously described -23for compounds of fornmla (1) or particular or preferred embodiments as previously described. In one particular embodiment, the invention relates to compounds of formula (III) wherein Li is -0- or -NR,; Ar 2 is phenyl or a heteroaryl ring; L 2 is a bond, -0-, -NR.-, -CH 2 -, or -C(O)NR-; and Ar 3 is an aryl or heteroaryl ring, 5 preferentially phenyl, pyrazinyl or pyridyl. In another embodiment, compounds of the invention can have the formula (IV), wherein LI, Ar 4 , L 3 , and Ai 5 are as defined for compounds of formula (1). Preferably, in compounds of formula (IV), Ar 4

-L

3 -Ar5 group is a group selected from Ar 5 y X x 5 /Ar\ L 3

Y

4 X Ys -i--L3 Y Xe or oy 6 X7 6 *X7 10 wherein

Y

4 is -NR.,-, -0- or -S-; Y 5 and Y 6 are -N-, -CR 4 - or C, provided that one of

Y

5 or Y 6 is C; R 4 is hydrogen, alkyl, alkoxy, alkoxylalkyl, alkoxycarbonyl, alkylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, nitro, oxo, or ReRrN-; R4a is hydrogen or alkyl; Re and Ri are each independently hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl, or R, and Rj are each taken together with the 15 nitrogen atom to which they are attached form a heterocyclic ring, wherein the heterocyclic ring is preferably pyrrolidinyl, piperidinyl or piperazinyl;

X

4 is -N-, -CRx 4 -, or C, X 5 is -N-, -CRX5-, or C, X 6 is -N-, -CRx 6 -, or C, and X 7 is -N-, -CRX7-, or C, provided that only one of X 4 , Xs, X6 or X 7 may be -N-, only one is C, and the remaining must be other than -N-, and RX4, Rxs, Rx6 and RX7 are each 20 independently hydrogen or alkyl. Preferably Ar 4 is 1,3-benzothiazol- 2 -yl. Suitable and preferred groups for Ar 5 in compounds of formula (IV) are as defined for Ar, for compounds of formula (II) or Ar 3 for compounds of formula (111). In addition, the invention also contemplates compounds of formula (VI) or compounds of formula (VII) 25

BH

3 0 A or LA A (VI (V) or a pharmaceutically acceptable salt or prodrug thereof, wherein L, is-0- or -NR,; -24- A is -Ari, -Ar 2 -L-Ar3 or -Ar 4

-L

3 -Ars; Ari is aryl or heteroaryl; Ar 2 is aryl or heteroaryl; Ar 3 is aryl or heteroaryl; Ar 4 is a bicyclic heteroaryl; Ar 5 is aryl or heteroaryl;

L

2 is a bond, -0-, -NRg,, -CH 2 -, or -C(O)NR-;

L

3 is a bond, -0-, -NR.- or

-CH

2 -; and R, is hydrogen or alkyl. 5 Furthermore, compound of formula (VI) or of formula (VII), are useful as prodrugs of compounds of formula (1). Specific embodiments contemplated as part of the invention include, but are not limited to compounds of formula (I), or salts or prodrugs thereof, for example: (4s)-4-(6-chloropyridazin-3-yloxy)-l -azatricyclo[ 3 .3 1.1 3 )decane; 10 (4r)-4-(6-chloropyridazin-3-yloxy)- -azatricyclo( 3 .3.1.1 3

,

7 )decane;

(

4 s)-4-(6-phlenylpyridazin-3-yloxy)-1-azatiicyclo[3 .3.1 .1 3 7 )decane;

(

4 r)-4-(6-phenylpyfidazin-3-yloxy)-l-azatricyclo[3.3.1.1, I)decane; (4s)- 4

-[

6 -( H-indol-5-yl)pyridazin-3-yloxy)-1-azatricyclo[ 3

.

3 .1 -1 V)Idecane; (4r )-4-[6-(1H-indol-5-yl)pyridazin-3-yloxy)--azatricyclo[ 3 .3.1 .1 3 Idecane; 15 (4s)-4-[ 6 -(1 -benzothien-5-yl)pyridazin-3-yloxy)-l azatricyclo[ 3

.

3 . 1.1 3

,

7 decane; (4r)-4-[6-(I-benzothien-5-y1)pyridazin-3-yloxy)-1 azatricyclo( 3 .3.1.13 ' 7 )decane;

(

4 r)-4-(5-brom-iopyridin-2-yloxy)-I -azatricyclo[3.3.1.

1 3

.

7 )decane; 20 (4s)-4-(5-phenylpy idin-2-yloxy)-1-azatricyclo[3.3.1 1 37 )decane;

(

4 r)-4-(5-phenylpyridin-2-yloxy)- -azatricyclo[ 3 3.1.1 3 - )decane (4s)-4-[5-(l H-indol-5-yl)pyridin-2-yloxy)-1-azatricyclo( 3 .3,1.1 3 7 ]decane; (4r)-.4-[5-( H--indol-5-yl)pyridin-2-yloxy)- -azatricyclo[ 3 .3.1.1 V )decane; (4r)-4-[5-(benzothien-5-yl)pyridin-2-yloxy)-1-azatricyclo[ 3 .3.1 1 )decane; 25 (4s)-4-(6-chloropyridin-3-yloxy)- I-azatricyclo( 3 .3. 1 .1 V ]decane;

(

4 s)-4-(6-nitropyridin-3-yloxy)- -azatricyclo[ 3 3.1 .1 V Idecane;

(

4 s)-4-(6-aminopyridii-3-yloxy)-1-azatricyclo[ 3 .3.1.1 3 )decane; (4r)-4-(6-nitropyfidin-3-yloxy)-1-azatricyclo{ 3 3.1.1 3

,

7 decane;

(

4 r)-4-(6-aminopyridin-3-yloxy)-1-azatricyclo[ 3 .3.1.1 3

.

7 ]decane; 30

(

4 s)-4-(5-bronothiazol-2-yloxy)-l-azatricyclo[3.3.1.1 V ]decane; (4s)-4-(thiazol-2-yloxy)-l-azatricyclo[ 3 .3.1.1 3

.

7 ldecane; (4s)-4-(5-phenylthiazol-2-yloxy)-l -azatricyclo[ 3 .3 1.13)]decane; (4s)-4-[5-(4-methoxyphenyl)-thiazol-2-yloxy)-1-azatricyclo[ 3 .3.1 1' 7 dccane; (4s)-4-{5-(3-chlorophenyl)-thiazol-2-yloxy]- -azatricyclo( 3 .3.1.1 3 ')decane; -25- (4s)-4-[5-(3-chloro-4-methoxyphenyl)-thiazol-2-yloxy]- I azatricyclo[3 3.1 .1 3 7 ]decane; (4s)-4-[5-(4-fluorophenyl)-thizoI-2-yloxy)-1-azatricyclo[3.3.1.1 3

'

7 ]decane;

(

4 s)-4-[5-(3,5-difluorophenyl)-thiazol-2-yloxy]-1 5 azatricyclo[3.

3 .1 1 3

,

7 ]decane; (4s)-4-[5-(1H-indol-5-yl)-thiazol-2-yloxy)-I-azatricyclo[3 3-1 .1 V ]decane; (4s)-4-[5-(IH-indol-5-y)-thiazol-2-yloxy]-1-azatricyclo[ 3 .3.1.1 3

'

7 ]decane-1 oxide; 5-[2-(l -azatricyclo[3 .3 1.13 ]decan-(4s)-yloxy)thiazol-5-yl]-indolin-2-one; 5-{2-(1 -azatuicyclo[ 3 .3 1.1 3

,

7 ]decan- 1 -oxide-(4s)-yloxy)thiazol-5-yl]-indolin 10 2-one; (4s)-4-[5-(2-trifluoromethyl-I H-indol-5-y)-thiazol-2-yloxy]-1 azatricyclo[3.3. 1.1 M]decane; (4s)-4-{5-(1 H-indol-4-yl)-thiazol-2-yloxy]- -azatricyclo[ 3 .3.1 .1 37 ]decane; (4s)-4-[5-(l H-indol-6-yl)-thiazol-2-yloxy]- -azatricyclo[3.3.1.1 M)decane; 15 (4s)-4-[5-(1 H-iindol-3-yl)-thiazol-2-yloxy]- -azatricyclo[3.3.1 .13 7 ]decane; (4s)-4-[5-(pyridin-4-yl)-thiazol-2-yloxy- I -azatricyclo[3.3.1.1 3 3 ]decane; (4s)-4-[5-(fuan-2-yl)-thiazol-2-yloxy]-1 -azatricyclo[ 3 .3.1.1 3.

7 ]decane; (4s)- 4 -[5-(furan-3-yI)-thiazol- 2 -yloxy)-1 -azatricyclo[ 3

.

3 .1.1 V ]decane; (4s)-4-[5-(ti-en-3-y1)-tiazol-2-yloxy]- -azatricyclo[ 3 .3.1.1 V ]decane; 20 (4s)-4-[5-(pyrazol-4-y1)-thiazol-2-yloxy]- -azatricyclo[ 3 .3.1 .1 3

,

7 ]decane; (4s)-4-(5-bromo-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3 1..1 )decane; (4s)-4-(1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[3.3.1.1 3 ]decane; (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3

.

3 .1.1 3

.

7 ]decane; (4s)-4-(5-phenyl-1,.3,4-thiadiazol-2-yloxy)-1-azatricyclo( 3 .3.1.1 3

,

7 ]decane-l 25 oxide; (4r)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1.1 3 ,7]decane; (4s)-4-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yloxy]- I azatricyclo[3.3.1.1 3 7 ]decane; (4r)-4-{5-(4-fluorophenyl)-I,3,4-thiadiazol-2-yloxy]-1 30 azatricyclo[3.

3 .l. ]decane; (4s)-4-[5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yloxy]-1 azatricyclo[ 3 .3.1 .1 3

,

7 ]decane; (4r)-4-[5-(3-fluorophlenyl)-I,.3,4-thiadiazol-2-yloxy]-1 azatricyclo[3.

3 .1 .1 V ]decane; -26- (4.s)-4-[5-(1 H-inldol-5-yl)-1,3,4-thliadiazol-2-yloxy]-1I azatricyclo[ 3 3.1 .A"']decane; (4s)-4-[ 5 -(1 H-indol-6-yl)-1,3,4-thiadiazol-2-yloxy]- 1 azatricyclo[ 3 .3.1 1 3 ]decane; 5 (4s)-4-[5-(1H-indol-4-yl)- 1,3,4-tiiadiazol-2-yloxy]-1 azatricyclo[ 3

.

3 .1 .1 3 7 ]decane; (4s)-4-{5-(benzothiei-5-yl)-1,3,4-thiadiazol-2-yloxy]-l azatricyclo[ 3

.

3 . 1.1 3 7 ]decane; (4s)-4-[5-(pyrazol-4-yl)-1,3,4-thiadiazol-2-yloxy- 1 10 azatricyclo[3.3.1.1 3 7 ]decane; (4s)-4-(5-phenoxy-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3 3.1 .1 ]decane; (4s)-4-(5-tert-butyl-1,3,4-thiadiazol-2-yloxy)-l -azatricyclo[ 3 .3.1.1 3 3 ]decane; (4r)-4-(5-tert-butyl-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3 .3.1.1 3 7 )decane; (4s)-4-(5-phenyl-1,3,4-oxadiazol-2-yloxy)-I -azatricyclo[3.3.1.13 7 ]decane; 15 (4r)-4-(5-phenyl-1,3,4-oxadiazol-2-yloxy)-l-azatricyclo[ 3 .3.1.1 3 7 ]decane; (4s)-4-(benzothiazol-2-yloxy)-1 -azatricyclo[ 3 .3.1. 1 3 7 ]decane; (4r)-4-(benzothiazol-2-yloxy)-1-azatricyclo[ 3

.

3 1 1 ']decane; (4s)-4-(6-chlorobenlzothiazol-2-yloxy)-l -azatricyclo[ 3

.

3 . 1.1 3 ]decane;

(

4 r)-4-(6-cllorobenzothiazol-2-yloxy)- I -azatricyclo[ 3 .3.1 .1 3

.

7 ]decane; 20 (4s)-4-(benzoxazol-2-yloxy)-1 -azatricyclo[ 3

.

3 .1 .1 3

,

7 ]decane; (4s)-N-(6-chiloropyridin-3-yi)-1-azatricyclo[ 3 .3.1.1 3 7 ]decan-4-amine; (4r)-N-(6-chloropyridin-3-yl)- I -azatricyclo[ 3 .3.1. 1 3 7 1decan-4-amine; (4s)-N-(6-phenylpyridin-3-yl)-1 -azatricyclo[3.3.1.1 3 7 ]decan-4-anine; (4s)-N-[6-(indol-5-y)-pyridin

-

3-yl]- -azatricyclo{ 3 .3.1.1 3 V]decan-4-anine; 25 (4s)-N-(5-bromopyridin-3-yl)- I -azatnicyclo[ 3 .31 .1 3 7 ]decan-4-amine; (4s)-N-{5-(indol-5-y)-pyridin-3-yl}-l-azatricyclo[ 3 3.1.1 V ]decan-4-amine; (4s)-N-[5-(indol-6-y)-pyridin-3-yi]- -azatricyclo[3.3.1.13,7]decan-4-amfline; (4s)-N-[5-(indol-4-yl)-pyridii-3-yl- -azatnicyclo[ 3

.

3 .1.1 3

,

7 ]decan-4-amine; (4s)-N-[5-(3-methylphenyl)-pyridin-3-yl]- -azatiicyclo[ 3 .3.1 .13 7 decan-4 30 amine; (4s)-N-[5-(3-chlorophenyl)-pyridin-3-yli--azatricyclo[ 3 .3 1.1 3 ']decan-4 amine; (4s)-4 N-5-(3-chlorophenylphen-3-yl)-pyridin-3-yl]-1 azatricyclo( 3 .3.1 13} Idecan-4-amine; -27- (4s)-4-(pyridin-3-yloxy)-1 -azatricyclo[ 3 .3.1 1 3 -]decane; (4s)- 4 -[(I-oxidopydidin-3-yl)oxy]-1-azatricyclo[ 3 3 11 3 7 ]decane; (4r)-4-(pyridin-3-yloxy)-1 -azatricyclo[3.3.1 .13,7]decane; (4s)-4-[(2-chloropyfidin-3-yl)oxy)- -azatricyclo[ 3 .3 1.1 3 *]decane; 5 (4s)-4-[(2-broiopyridin-3-yl)oxy)- -azatricyclo[ 3 .3 1.1 3 ,]decane; (4s)-4-[(4-chloropyridin-3-yl)oxy)-I -azatricyclo{ 3 3.1 .13- 7 ]decane; (4s)-4-[(4-methylpyridin-3-yl)oxy]-I -azatricyclo[ 3

.

3 .1 1 3 7 ]decane; (4s)- 4 -{[4-(trifluoronethyl)pyidin-3-yl]oxy} -1 -azatricyclo[ 3 .3.1 13 7 ]decane; (4s)-4-[(5-fluoropyridin-3-yl)oxy-1 -azatiicyclo[3.3.1 . I ]decane; 10 (4s)-4-{(5-chloropyridin-3-yl)oxy]- -azatricyclo{ 3 .3..1 .1 3 7 ]decane; (4s)-4-[(5-bromopyridin-3-yl)oxy-1 -azatricyclo( 3 .3.1.1 3

.

7 decane; (4s)-4-[(5-iodopyridin-3-yi)oxy)-1-azatricyclo( 3 31.1 1 ]decane; 5-[(4s)- I -azatricyclo[ 3

.

3 .1. 1 3 ]dec-4-yloxy]niicotinamide; (4s)- 4 -{[5-(l H-pyrazol-4-yl)pyidin-3-yl]oxy) -1 -azatricyclo[3.3. 1.1 3

.

7 decane; 15 (4y)-4- {[5-(l -methyl-I H-pyrazol-4-yl)pyridin-3-yl]oxy -1 azatricyclo[ 3

.

3 I 1 3

,

7 ]decane; (4s)- 4 - {[5-(l H-pyrazol- 1 -yl)pyridin-3-yl]Oxy} -1 -azatricyclo[ 3 .3.1.1' 3 ])decane; (4s)-4- [5-(4-chlorophenyl)pyridi-3-ylloxy) -I -azatricyclo[ 3 .3.1.1 '-]decane; (4s)-4-(3,4'-bipyridin-5-yloxy)-l-azatricyclo[ 3 .3 1.1 3

.

7 decane; 20

(

4 s)-4-[(5-pyfimidin-5-ylpyridin-3-yl)oxyl- -azatricyclo[ 3 .3. 1.1 3

,

7 ]decane;

(

4 r)-4-[(6-chloropyridin-3-yl)oxy]-l-azatricyclo[ 3 .3.1.1 3 3 ]decane; (4s)-4-[(6-bromopyfidin-3-yl)oxy]- -azatricyclo[ 3 .3. 1.1 3

,

7 ]decane; 5-[(4s)- 1 -azatricyclo[ 3 3. 1.1 ]dec-4-yloxy]pyridine-2-carbonitrile; (4s)-4-{(5-thien-2-ylpyridin-2-yl)oxy]- -azatricyclo[ 3

.

3 1.1 3 7 ]decane; 25 (4s)- 4 -{[6-(1 H-indol-5-yl)pyridin-3-yl]oxy} -1 -azatricyclo( 3 .3 1. 13 , 7 ]decane; (4r)-4- {[6-(l H-indol-5-yl)pyridin-3-ylloxy) -1 -azatricyclo[3.3.1,1 3 ']decane; (4s)- 4 -{[6-(IH-indol-6-yl)pyridin-3-yl]oxy} -1 -azatricyclo[ 3 .. 3.1 .1 3

,

7 ]decane; (4r)-4-{[6-(1 H-indol-6-yl)pyrdiln-3-yl]oxy} -1 -azatricyclo[ 3 .3.1.1 M]decane; 5-{5-[(4s)- I -azatricyclo[3.3.1 .13 3]dec-4-yloxypyridin-2-yl} -1,.3-dihydro-2H 30 indol-2-one; (4r)-4- {[6-(1 -benzofuran-5-yl)pyridin-3-yl]oxy} -1 azatricyclo( 3

.

3 .1 1 3

-

7 ]decane; (4s)-4-[(5,6-dibromopyridin-3-yI)oxy]-1-azatricyclo[3.

3 .1 .1 I ]decane; (4s)-4-(pyridin-2-yloxy)-1-azatricyclo[ 3 .3.1 1]3.7 decane; -28- (4s)-4-{(5-fluoropyr idin-2-yl)oxy]1 -azatricyclo[ 3 .3.1. I ]decane; (4s)-4-[(5-bronopyridin-2-yl)oxy)-l-azatricyclo[ 3 3 1 .1 V']decane; (4s)-4-[(4-bromopyridin-2-yl)oxy]-1-azatricyclo[ 3 .3.1 .1 3

,

7 ]decane; (4s)-4-(3,3'-bipyridin-6-yloxy)-l-azatricyclo[ 3 .3.1.1 ' ]decane; 5 (4s)-4-(3,4'-bipyridin-6-yloxy)-1-azatricyclo[3.3.1.1 37 ]decane; (4r)-4-( 3 ,4'-bipyidin-6-yloxy)- I -azatricyclo[ 3 .3. 1 .1 ) 3 7 decane; (4s)-4-[(5-pyrinidin-5-ylpyridin-2-yl)oxy- I -azatricyclo[3.3. 1.1] 37 decane; (4s)-4- ([5-(1 H-pyrazol-4-yl)pyridin-2-yl]oxyl-1 -azatricyclo{ 3 .3.1 .1 3 7]decane; 6-[(4s)-1 -azatricyclo[ 3 .3.1.1 37]dec-4-yloxy]-N-pyridin-4-ylpyridine-2 10 carboxarnide;

(

4 s)-4-[(2-chloropyfidin-4-yl)oxy-1 -azatricyclo[ 3

.

3 .1 .13 3 7 )decane; (4s)-4-[(6-methylpyridazinl-3-yl)oxy-1 -azatricyclo[ 3 3 1 .13 3 )decane; (4s)-4-(pyrimidin-2-yloxy)- I -azatricyclo[3.31 t0 7 ]decane; (4s)-4-[(5-bromopyrimidifn-2-yl)oxy-I -azatricyclo[ 3

.

3 .1 .1 3

,

7 ]decane; 15 (4s)-4-(pyrirnidin-5-yloxy)- 1 -azatricyclo[3.3.1 .13 7 ]decane; (4s)-4-(pyriim-idini-4-yloxy)- -azatricyclo[ 3 .3.1 .1 3 7 ]decane;

(

4 s)-4-[(6-chloropyrimidin-4-yl)oxy]-1-azatricyclo[ 3 .3 1 1 3 .]decane; (4s)- 4 -{[6-(I-trityl-1H-pyrazol-4-yl)pyrimidin-4-ylloxy)-1 azatricyclo[ 3

.

3 .1.1 3 ]decane; 20 (4s)- 4 -{ [6-(I H-pyrazol-4-yl)pyrimidin-4-ylloxy) -1 azatricyclo[ 3

.

3 .1 .1 3 7 ]decane; (4s)-4-[(6-pyridin-4-ylpyrimidin-4-yl)oxy]- -azatricyclo[3.3.1 .1 3 7 )decane; (4s)-4-(pyrazin-2-yloxy)- I -azatricyclo( 3 .3.1. 1 3 .]decane; 4-[(6-methylpyrazin-2-yl)oxy]- .- azatricyclo[ 3 .3.1.1 1]decane; 25 (4r)-4-[(6-phenylpyrazin-2-yl)oxy]-I -azatricyclo[ 3 3.1 .13 ' 7 ]decane; (4r)-4-(1,3-thiazol-2-yloxy)- 1-azatricyclo[ 3 .3. 1.1 3

,

7 decane; (4r)-4-[(5-bromo-1,3-thiazol-2-yl)oxy]- -azatricyclo[3-.3.1 .I 3

.

7 )decane; (4s)-4-({ 5-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl } oxy)- 1 azatricyclo[ 3

.

3 .1 1 3 0']decane; 30 (4s)-4-t[5-(4-chlorophenyl)-1,3-thiazol-2-ylloxy} -1 azatiicyclo[ 3 .3 1.1 3 7 ]decane; 4-{2-[(4s)- I-azatricyclo[ 3

.

3 1.1 3 ,7]dec-4-yloxy]-1,3-thiazol-5-yl} aniline; (4s)-4-{(5-pyridin-3-yl- 1,3-thiazol-2-yl)oxyl- -azatricyclo[ 3 .3.1.1 3 7 ]decane; (4 1 )-4-{(5-pyridin-3-yl-1,.3-thiazol-2-yl)oxy)-l-azatricyclo[3.3 1.1 3

,

7 )decane; -29- (4s)-4-[(5-pyrimidin-5-yl- 1,3-thiazol-2-yl)oxy-1 azatricyclo(3.

3 . .1 3

,

7 ]decane; (4s)-4- {[5-(2-nethoxypyrimidin-5-yl)-1,3-thiazol-2-yl]oxy} -1 azatricyclo[3 3.1 .13 "]decane; 5 (4s)- 4 - {[5-(2-pyrrolidin- I -ylpyrimidin-5-yl)- 1,3-thiazol-2-yl]oxy)

-I

azatricyclo( 3

.

3 .1 .1 3

,

7 ]decane; (4s)-4- {[5-(6-piperazin- 1 -ylpyridin-3-yl)- 1,3-thiazol-2-yl]oxy} -I azatricyclo[3.

3 1-_ 3

,

7 ]decane; (4s)-4- ([5-(1 H-pyrazol- 1-yl)-1,3-thiazol-2-yl]oxy -1 10 azatricyclo[ 3

.

3 .1 3 7 ]decane; (4s)-4-{[5-(l -trityl- 1 H-pyrazol-4-yi)- 1,3-thiazol-2-yl]oxy) -1 azatricyclo[3.3.1.1 3

,

1 ]decane; (4s)-4-{[5-(1 -piopyl- IH-pyrazol-4-yl)- 1,3-thiazol-2-yl]oxy} -1 azatricyclo[ 3 .3.1 .1 3 7 ]decane; 15 (4s)-4- {[5-(l -isobutyl- 1 H-pyrazol-4-yl)-1,3-thiazol-2-yl]oxyI -1 azatricyclo[3.3.1.1 3

,

7 ]decane; (4s)- 4 -{[5-(1 -acetyl- I H-pyrazol- 4 -yl)-1,3-thiazol-2-yl]oxy} -I azatiicyclo[ 3

.

3 1. 3

,

1 ]decane; (4s)-4- {[5-(5-methyl- 1 -phenyl- I H-pyrazol-4-y)-1,3-thiazol-2-yloxy}

-I

20 azatricyclo[3.

3

.

1 .1 3 '7]decane; (4s)-4-[(5-isoxazol- 4 -yi-1,3-thiazol-2-yl)oxy]-I -azatricyclo[3.3.1.1 37 ]decane; (4s)-4-[(4-bromo- 1,3-thiazol-2-yl)oxy]-1 -azatiicyclo[ 3 .3. 11 37 ]decane; (4r-)-4-[(4-bromo- 1,3-thiazol-2-yl)oxy)-I -azatricyclo[ 3 .3.1.1 M ]decane; (4s)-4-[(4-chloro- 1,3-thiazol-2-yl)oxy- 1 -azatficyclo[ 3 3. 1.1 3 7 ]decane; 25 (4s)-4- {[4-(l H-pyrazol-4-yl)- 1,3-thiazol-2-y]oxy) -1 azaticyclo[ 3

.

3 . 1.1 3

,

7 ]decane; (4s)-4-[(4-phenyl-1,3-thiazol-2-yl)oxy]-l-azatricyclo[3.3 11 3

,

7 ]decane; (4s)-4-[(4-pyridin-4-yl-1,3-thiazol-2-yl)oxy]- 1 -azatricyclo[ 3 .3.1 .1 V ]decane; (4s)-4-[(4-pyridin-3-yl- 1,3-thiazol-2-yl)oxy]-1 -azatricyclo[ 3 .3.1.13 7 ]decane; 30 2-[(4s)-l -azatricyclo[3.3.1 .1 3 7 ]dec-4-yloxy]-N-pyridin-4-yl- 1,3-thiazole- 4 carboxamide; 2-[4s)-1 -azatricyclo[ 3 .3. 1.1 ]dec-4-yloxy-N-(4-chlorophenyl)-1,3-oxazole 4-carboxamide; 2-[(4s)- 1 -azatficyclo[ 3

.

3 . 1.1 3 7 ]dec-4-yloxy)-N-phenyl-1,3-oxazole- 4 -30carboxamide; (4s)-4-{15-(3-bronophelnyl)-1,3,4-thiadiazol-2-yl]oxy} -1 azatricyclo[ 3

.

3 .1 .1 3 ]decane; (4s)-4-15-[1 -azatricyclo[ 3 .3 .1 13] dec-4-yloxy)-1,3,4-thiadiazol-2-yl) phenol; 5 (4s)-N-pyridin-3-yl- I -azatricyclo[ 3 .3.1.1 M]decan-4-amine; (4s)-N-(5-bromo-6-chloropyridin-3-yl)-l-azatricyclo[ 3 3.1.13 3 7 ]decan-4 amine; (4s)-N-[6-(IH-indol-6-yl)pyridinl-3-yl]-l-azatricyclo[ 3 .3.1..1 3

'

7 ]decan-4-amine; (4s)-N-[6-(1 H-indol-3-yl)pyridin-3-yl]-l-azatricyclo[ 3 .3.1.1 3 7 Idecan-4-amine; 10 (4s)-4-[5-(1H-indol-5-yl)pyridin-3-yloxy]-1-azatricyclo[3.3.1,13 7 ]decane; (4s)-4-[5-(IH-indol-6-yl)pyidin-3-yloxy]-1-azatricyclot 3

.

3 .1.. 1M ]decane; (4r)-4-[ 5 -(1H-indol-5-yl)pyridin-3-yloxy]-l-azatricyclo[ 3

.

3 .1.1 3 decane; (4r)-4-[5-(lH-indol-6-yl)pyridin-3-yloxy]-l-azatricyclo[ 3 .3.1.1 3 ']decane; azatricyclo[ 3

.

3 .1 .1 3

*

7 ]decane; and 15 (4r)-4-[5-(1-benzofLiran-5-yl)pyridin-3-yloxy]-l-azatricyclo[ 3 .3.1.13 -]decane. Compounds of the invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral element. The terms "R" and "S" used herein are configurations as defined in UPAC 1974 Recommendations for Section E, 20 Fundamental Stereochemistry, Pure Appl Chem., 1976, 45: 13-30. The invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the invention may be prepared synthetically from 25 commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and 30 optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2.JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic colunms or (3) fractional recrystallization methods. -31- More particularly, the compounds of the invention can exist in the forms represented by formula (1a) and (Tb) QL ,A Z L-A (1a) (Ib) The aza-adamantane portion of isomer (Ia) and isomer (Ib) is not chiral, 5 however the C-4 carbon at which Li is attached is considered pseudoasymmetric. Compounds represented by formula (Ia) and (Ib) are diastereomers. The configurational assignment of structures of formula (]a) are assigned 4r in accordance with that described in Synthesis, 1992, 1080, Becker, D P.; Flynn, DL. and as defined in Stereochemistry of Organic Compounds, E L. Eliel, S H Wilen; John Wiley 10 and Sons, Inc. 1994. In addition the configurational assignment of structures of formula (Ib) are assigned 4s using the same methods. The isomers (Ta) and (Ib) may be synthesized separately using the individual steroisomers according to the Schemes or the Experimentals described herein. Alternatively, isomers (1a) and (Ib) may be synthesized together after which the 15 individual isomers may be separated by chromatographic methods from the mixture of both isomers when mixtures of stereoisomers are used in the synthesis. The mixtures of isomers may also be separated through fractional crystallization of salts of amines contained in the compounds of formula (I) made with enantiomerically pure carboxylic acids. 20 It is contemplated that a mixture of both isomers may be used to modulate the effects of nAChRs. Furthermore, it is contemplated that the individual isomers of formula (Ia) and (Tb) may be used alone to modulate the effects of nAChRs. Therefore, it is contemplated that either a mixture of the compounds of formula (la) and (Ib) or the individual isomers alone represented by the compounds of formula (Ia) 25 or (Tb) would be effective in modulating the effects of nAChRs, and more particularly a7 nAChRs, a402 nAChRs, or a combination of 07 nAChRs and a4p2 nAChRs and is thus within the scope of the invention. More specifically, preferred compounds contemplated as part of the invention include -32- Ar t H (la) H (hib) L 1 -Ar1 N H LVAr2LAra (ilila) (1lib) Ar , orArP H H 3 LAr4 Ar5 (Iva) (lvb) wherein Li, L 2 , L 3 , Ari, A.

2 , Ar 3 , Ar 4 , and Ar 5 are defined herein. In addition the use of compounds of formula (V) BH3 OH 5 which may be used to generate compounds of formula (I) are contemplated to be within the scope of the invention Also within the scope of the invention are contemplated compounds of formula (VI) and compounds of formula (VII),

BH

3 or 4 LT A Lr A 1.0~ 10 (VI) (VII) or a pharmaceutically acceptable salt or prodrug thereof, wherein L, is-O- or -NR-; A is -Arl, -Ar 2

-L

2 -Ar3 or -Ar 4

-L

3 -Ars; Arl is aryl or heteroaryl; Ar 2 is aryl or monocyclic heteroaryl; Ar 3 is aryl or heteroaryl; Ar 4 is a bicyclic heteroalyl; Ar 5 is aryl or heteroaryl;

L

2 is a bond, -0-, -NR,-, -CH2-, or -C(0)NR,..;

L

3 is a bond, -0-, 15 NR,- or -CH 2 -; and R, is hydrogen or alkyl. In addition, compounds of formula (VI) are useful as a prodnig of a compound of formula (1). Furthermore, compounds of fonnula (VII) also are useful as a prodrug -33of a compound of formula (1) Specific embodiments contemplated as part of the invention include, but are not limited to compounds of formula (VI), for example: (4,.)-4-(5-bromopyridin-2-yloxy)- I-azatricyclo[ 3 .31..13 3

'

7 decane N-botane 5 complex;, ('Is) -4-(6-cfiloropyfldiI-3 -yloxy)- 1-azatricyclo[ 3 .3 .1 I~ ]decane N-borane complex; (4s)-4-(6-nitropyfldif-3-yloxy)-I -azatricyclo[ 3 . 3.1 .13.7 Idecane N-borane complex; 10 ('4,j)4-(6-flitropy11dif-3-yloxyV I-azatricyclo[ 3 .3 1 .1 3 '7 decane N.-borane complex; (4s)-4-(5-bromnothiazol-2-yloxy)-I -azatricyclo[ 3 .3.1 .1 3

,

7 decane N-borane complex; (4.s)-4-(5-phcflyl- 1,3 ,4-thliadia7ol-2-yIoxy)-lI-azatr-icyclo[ 3 . 3. 1 .1 3 decane N 15 borane complex; ('4r)-4-(5-phelyl-1I,3,4-tliiadiazol-2-yloxy)lazatricyclo[ 3 .3.1.1 3 7 decane N borane complex; (4s)-4-[5-(4-flitoropheflyl)- 1,3 ,4-thiiadiazol-2-yloxy)-l azatricyclo[ 3 .. 3.1 .1 3

,

7 ]decane N-borane complex; 20 ('4r)-4-[5-(4-fluoroplie1yl)- 1,3 ,4-thiadiazol-2-yloxy1 -1 azatricyclo[3.

3 ,l.1 3,7 )decane N-borane complex; (4s)-4-[5-(3-fluorophefl)- 1,3 ,4-thiadiazol-2-yloxy]- 1 azatricyclo[ 3

.-

3 . 1.1 ' 7 ]decane N-borane complex; (4,;}-4-[5-(3-fltuorophenyl)-l ,3,4-thiadiazol-2-yloxy]-l 25 azatricyclo[ 3 .3.1 .13 3 ]decane N-borane complex; (4,s)-4-[ 5 -( 1H-indol-5-yl)- 1,3,4-thiadiazo-2-yloxyl azatricyclo[ 3 .3.1 1M 3 Idecane N-borane complex;, (4s)-4-(S -teril-butyl-1I,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3 .3.1 .1 3 3 7 Idecane N-boiane complex; 30 (4r)-4-(5-tet-JutlY- 1 ,3,4-thiadiazol-2-yloxy)-l1-azatricyclo[ 3 .3.1. 1 3

*

7 decafle N-borane complex; (4v)-4-(benzothiazol-2-yloxy)- 1 -azatricyclo[ 3 .11 33 ]decane N-borane complex; (4,.)..4.(beflzothiiazol.2-yloxy)-I -azatricyclo[ 3 .3. 1.1 3. ]decane N-borane -34complex; (4s)-4-(6-chlorobenzothiazol-2-yloxy)- -azatricyclo[ 3 .3.1 .1 3 ]decane

N

borane complex;

(

4 r)-4-(6-chlorobenzothiazol-2-yloxy)-1-azatricyclo(3.

3 .1.1 3 decane

N

5 borane complex; (4s)-4-(benzoxazol-2-yloxy)- I-azatricyclo[ 3 .3 1.1 M ]decane N-borane complex; (4s)-4-(pyridin-3-yloxy)- I -azaticyclo[ 3 .3.1.1 3 "]decane N-borane complex; (4s)- 4 -[(I-oxidopyridin-3-yl)oxy-l -azatricyclo[ 3

.

3 .1.1 3 7 ]decane N-borane 10 complex; (4r)-4-(pyridin-3-yloxy)-1 -azatricyclo[ 3 .3.1.1 3,7]decane N-borane complex;

(

4 s)-4-[( 2 -chloropyidin-3-yl)oxy)-1-azatricyclo[ 3 31.1

'

7 ]decane N-borane complex;

(

4 s)-4-[(2-bromopyridin-3-yl)oxy-I -azatricyclo{ 3 .3.1.1 V ]decane N-borane 15 complex; (4s)-4-[(4-chloropyridin-3-yl)oxy]-1 -azatricyclo[ 3 . 3 1.1 3 0]decane N-borane complex; (4s)-4-[(4-methylpyrilin-3-yl)oxy)-I -azatricyclo[ 3 .3.1.1 3

.

7 decane N-borane complex; 20 (4s)- 4 -{[4-(trifluoromethyl)pyridin-3-ylloxy -1 -azatricyclo[ 3 .3.1.1 V ]decane N-borane complex;

(

4 s)-4-[(5-fluoropyidin-3-yl)oxyl -1 -azatricyclo[3 3 1 1.) decane N-borane complex; (4.s).4-{(5-chloropyridin-3-yl)oxy]-1-azatricyclo[ 3 .3.1 .1 3 7 ]decane N-borane 25 complex; (4s)-4-[(5-bromlopyridin-3-yl)oxy]- -azatricyclo[ 3 .3 1.1 3

,

7 ]decane N-borane complex;

(

4 s)-4-[(5-iodopyridin-3-yl)oxy)-1-azatricyclo( 3 .3.1.1 3 7 ]decane N-borane complex; 30 5-[(4s)-1 -azatricyclo[ 3 3. 1.1 37)dec-4-yloxy]lnicotinamide N-borane complex; (4s)-4- ([5-(l H-pyrazol-4-yl)pyridin-3--yloxy) -1 -azatricyclo 3 .3.1.13 ,]decane N-borane complex; (4s)- 4 -{[5-(I-methyl-l H-pyrazol-4-yl)pyridin-3-yl]oxy) -1 azatricyclo[ 3 .3.1.1 3 7 ]decane N-borane complex; -35- (4s)-4- [5-(4-cliloropiely1)pyfidifl3-ylloxy) -l -azatricyclo[ 3 3 .11 3

.

7 decane N-borane complex; (4s)-4-( 3 ,4Thbipyridiil-5-yloxy)-I -azatricyclo[ 3

.

3 .1 1 3

*

7 ]decafle N-borane complex; 5 (4.s)-4-[(5-pyriiiiln5-ylpyridil- 3 -yl)oxy]-l -azatricyclo[ 3 -3.1 .1 3

*

7 decane N borane complex; (4.s)-4-((6-chloropyt-idin- 3 -yl)oxy]- I -azatri-cycio( 3 .3. 1 .1 3

,

7 ]decane N-borane complex; (4i )-4-[(6-cloropyfldiii-3-yl)oxy1-l -azatricyclo[ 3 .3.1 1 ,']decane N-borane 10 complex; (4s)-4-(5-FluoTo-pyfidin-2-yloxy)-I -aza-tn'cyclO[ 3 .3. I11 I'-'decane N-borane complex; (4 1 )..4.(5Fluoro..pyfldifl-2-yloxy)-l -aza-tricyclo[ 3 .3 1 .1 3

,

7 Idecane N-borane complex; 15 (4s)-4-[(6-bromopyidin3-yloxy]Il -azatricyclo[ 3 .3.1.1 3

'

7 Idecane N-borane complex N-borane complex; 5-[(4s)- l -azatricyclo[ 3 .3. 1.1 V.7Idec-4-yloxy]pyridine-2carbolitrile N-borane complex N-borane complex; (4s)-4-[(5,6-dibronopyridin-3-yl)oxy]- I -azatricyclo[ 3 .3 I .1 3

,

7 decane N 20 borane complex N-borane complex; (4s)-4-(pyridil-2-yloxy)-l1-azatricyclo[ 3 . 3. 1.1 3

,

7 decane N-borane complex

N

borane complex; (4s)-4-[(5-bromrilPfdin-2-yI)oxyl-azatricyclo.

3 3. 1.13 ' 7 ]decane N-borane complex N-borane complex; 25 (4s)-4-[(4-bror-nopyfdifl2-yI)oxyD l-azatnicycloi 3 .3.1. IM 3 'decane N-borane complex N-borane complex;

(

45 )-4-(3,3'-bipyn'di-6-yloxy)-I -azatTicycloli 3

.

3 . l .17 3 'decarie N-borane complex N-borane complex; (4s)- 4

-(

3 ,4'-bipyridil-6-yloxy)- I -azatricyclo[ 3 .3.1. 1 3

,

7 decane N-botane 30 complex N-borane complex; (41-)-4-( 3 ,4'-bipyridiin-6-yloxy)-l -azatricyclo[ 3 .3 .1 .1 3

,

7 ]decane N-borane complex N-borane complex; (4)4[5p~mdn5ylyiii2y~x] -azatricyclol 3

-

3 . 1.1 V ldecaile

N

borane complex N-borane complex; -36- (4s)-4-[(2-chlloropyiidin-4-yl)oxy)-l -azatricyclo[ 3 .3.1.1 )decane N-borane complex N-borane complex; (4s)-4-[(6-m ethypyridazin-3-yl)oxy)-l-azatricyclo[ 3 3. 1,1 V)decane N-borane complex N-borane complex; 5 (4s)-4-(pyrimidin-2-yloxy)- -azatricyclo[ 3 3. 1 .1 V]decane N-borane complex N-borane complex; (4s)-4-{(5-bromopyimidii-2-yl)oxyf-1-azatricyclo[ 3 . 3.1 .1 3

,

7 decane N-borane complex N-borane complex; (4s)-4-(pyrimidin-5-yloxy)- -azatricyclo[ 3 .3 1.1 3

'

7 ]decane N-bo ane complex 10 N-borane complex; (4s)-4-(pyrazin-2-yloxy)-l-azatricyclo{ 3 .3.1 .1 3 3 )decane N-borane complex

N

borane complex; 4-[(6-methylpyrazin-2-yl)oxy-1 -azatricyclo[ 3 .3.1.1 37 )decane N-borane complex N-borane complex; 15

(

4 r-)-4-[(6-plenylpyraziin-2-yl)oxy)-l-azatticyclo[ .3.1.1 3 ']decaneN-borane complex N-borane complex; (4r)-4-(1,3-thiazol-2-yloxy)- I-azatricyclo[ 3 .3.1 .1 3

'

7 ]decane N-borane complex; (4s)-4-({5-[4-(trifluoromethoxy)plhenyl)-1,3-thiazol-2-yl}oxy)- 1 20 azatricyclo[ 3

.

3 .1 .1 3

]

7 decane N-borane complex; (4s)-4-[(5-pyrimidin-5-yl-1,3-thiazol-2-yl)oxy)-1 .azatricyclo[ 3 .3.1 1 - ]decane N-borane complex; (4s)-4-{[5-(1 -trityl-I H -pyrazol-4-yl)-1,3-thiazol-2-yiloxy} -1 azatricyclo( 3

.

3 1.1 3

,

7 decane N-borane complex; 25 (4s)-4-[(4-bTomo-1,3-thiazol-2-yl)oxy)-l-azatricyclo[ 3 .3.1 .1 3

,

7 ]decane

N

borane complex; and (4s)-4-[(4-chloro-1,3-thiazol-2-yl)oxy]- -azatricyclo[ 3 .3.1.1 3 7 )decane

N

borane complex. Specific embodiments contemplated as part of the invention include, but are 30 not limited to compounds of formula (VII), for example: (4s)-4-[5-(lH-indol-5-yl)-thiazol-2-yloxyl-i-azatricyclo[ 3 .3.1.1 V]Idecane-I oxide; (4s)-5- 4

-{

2 -(l -azatricyclo( 3 .3.1 .13 7 ]decan-i-ox ide-yloxy)thiazol-5-yl] indolin-2-one; or -37- (4s)-4-(5-phlnyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3 3 .1 1 3

.

7 decane-1 oxide. Salt Properties 5 Paiticular salts of compounds of the invention also have been identified and are described herein. More particularly, such salts are (4s)-4-(5-phCilyl-1,3,4 thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.13Idecane L-bitartrate anhydrate, L-bitartrate hydrate, dihydrogen phosphate anhydrate, dihydrogen phosphate hydrate, bisuccinate anhydrate, bisuccinate hydrate, hydrochloride quarterhydrate, hydrochloride 10 sesquihydrate, dihydrogen citrate, and monohydrogen citrate. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo{ 3

.

3 . 1.1 V ]decane

L

bitartrate anhydrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 1). One with skill in the art of analytical chemistry would be able to readily identify (4s)- 4 -(5-phenyl-1,3,4-thiadiazol- 2 15 yloxy)-1-azaticyclo[3.3.1 1]decane L-bitartrate anhydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-l,3,4 thiadiazol-2-yloxy)-l-azatricyclo{3.3.1 .1 3

,

7 decane L-bitartrate anhydrate are 4.96+0.20, 9.99±0.20, 11.77±0.20, 14.62t0.20, 14.99+0.20, 18.14+0.20, 18.44t0.20, 20 19.48+0..20, 20.05±0.20, 21.02±0.20, 21.38±0.20, 22.76±0.20, 24.74±0.20, 26.65±0.20, and 32.19±0.20. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1 13 3 7 decane

L

bitartrate hydrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 2). One with skill in the art of analytical 25 chemistry would be able to readily identify (4s)-4-(5-phenyl--1,3,4-thiadiazol-2 yloxy)-I-azatricyclo[ 3

.

3 .1 .1 3 V]decane L-bitartrate hydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-1,3,4 thiadiazol-2-yloxy)- l -azatricyclo[3 .31.1 )decane L-bitartrate hydrate are 30 4.63t0.20, 9,26+0.20, 13.43±0.20, 13.91±0.20, 15.98±0.20, 17.86+0.20, 21.36±0.20, and 22.33±0.20 The TGA (Figure 2A) shows the dehydration of (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-1 -azatricyclo[ 3 3 1 .1 3

,

7 decane L-bitartrate hydrate. (4s)-4-(5-Phenfyl-1,3,4-thiadiazol-2-yloxy)-1 -azatricyclo[ 3 .3.1.1 3 ,]decane dihydrogen phosphate anhydrate crystalline solid can be identified by characteristic -38peaks in its powder X-ray diffraction pattern (Figure 3). One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl-l,3,4 thiadiazol-2-yloxy)-1-azatricyclo[3.3 1.1 3 7 ]decane dihydrogen phosphate anhydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern 5 Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yoxy)- I -azatricyclo[ 3 .3.1 .1']decane dihydrogen phosphate anhydrate are 5.14±0.20, 10.31±0.20, 11.20±0.20, 13.17±0.20, 13.47±0,20, 15.61±0.20, 16.69±0.20, 17.27±0.20, 17-50±0.20, 18 56±0.20, 18.90±0.20, 19.41±0.20, 20.93±0.20, 21.80±0.20, 22.53±0 20, 23.96±0 20, 10 26.01+0.20, and 26.44+0 20. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3. 1.13 7 ]decane dihydrogen phosphate hydrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 4). One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl-l, 3

,

4 15 thiadiazol-2-yloxy)-1 -azatricyclo[ 3 .3.1 .13 3 ]decane dihydrogen phosphate hydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3. 1.13 , 7 ]decane dihydrogen phosphate hydrate are 5 28+0.20, 9.82±0.20, 10.61±0.20, 13.79±0.20, 20 14.24±0.20, 15.13±0.20, 16.65±0.20, 16.95±0 20, 18.35±0.20, 19.52±0.20, 19.84±0.20, 21.55±0.20, 23.85±0.20, 24.26±0.20, and 25.80±0.20. The TGA (Figure 4A) shows the dehydration of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)- 1 azatricyclo[ 3

.

3 .1 .1 3 7 ]decane dihydrogen phosphate hydrate. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3

.

3 .1.13 7]decane 25 bisuccinate anhydrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 5). One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl-1,3,4-thiadiazol-2 yloxy)-1 -azatricyclo[ 3

.

3 .1.1 3

,

7 ]decane bisuccinate anhydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions 30 of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-l,3,4 thiadiazol-2-yloxy)-1-azatricyclo[3.3. 1.1V ]decane bisuccinate anhydiate are 12.53±0.20, 13.50±0.20, 14.76±0.20, 16.98±0.20, 18.07±0.20, 18.34±0.20, 18.35±0.20, 18.88±0.20, 19.62±0.20, 19.67±0 20, 20.00±0.20, 20.71±0.20, 23.64±0.20, 23.96±0.20, 25.61±0.20, and 36 29+0 20. Crystallographic unit cell -39parameters of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.

3 .1. 1 37 ]decane bisuccinate anhydrate also were obtained and were determined as: a is 12.958(17) A, b is 7.561(10) A, c is 39.66(5) A, and P is 94.54(2)0 to afford a cell volume of 3873.51 A , wherein a, b, and c are each a 5 representative length of the crystal lattice and P is a unit cell angle. The salt crystallizes in the monoclinic P21/c space group (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[3,3.1.1 V ]decane bisuccinate hydrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 6). One with skill in the art of analytical 10 chemistry would be able to readily identify

(

4 s)-4-(5-phenyl-1,3,4-thiadiazol- 2 yloxy)-I-azatricyclo[3.3.1.13]decane bisuccinate hydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-l,3,4 thiadiazol-2-yloxy)-l-azatricyclo[ 3 .3.1. 1 V]decane bisuccinate hydrate are 8.92±0.20, 15 10.94±0.20, 11.71±0.20, 13.41±0.20, 14.90±0.20, 17.61±0.20, 17.92±0.20, 18.19t0.20, 19.60t0.20, 22.58±0.20, 26 19±0.20, and 27.07±0.20. The TGA (Figure 6A) shows the dehydration of (4s)- 4 -(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo[ 3

.

3 . .1 1decane bisuccinate hydrate. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3

.

3 .1.1 3 7 ldecane 20 hydrochloride quarterhydrate (1 salt: 0.25 water) crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 7). One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3 3.1.1 3

,

7 ]decane hydrochloride quarterhydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. 25 Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3 .3.1.1 3 7 )decane hydrochloride quarterhydrate are 5.19±0.20, 12 96±0.20, 13 00±0.20, 14.88±0.20, 14.98±0.20, 15.61±0.20, 17.79*0.20, 18.26±0.20, 18.93±0_20, 20.02±0.20, 20.67±0.20, 20.86±0.20, 21.72±0.20, 22 38±0.20, 22.55±0.20, 24.09±0,20, and 30 26.10±0 20. Crystallographic unit cell parameters of (4.s)-4-(5-phenyl-l, 3

,

4 thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3 .1.1 31 decane hydrochloride quarterhydrate also were obtained and were determined as: a is 19.440(7) A, b is 9.969(4) A, c is 35 .322(13) A, and P is 105.325(17)* to afford a cell volume of 6601-91

A

3 , wherein a, -40b, and c are each a representative length of the crystal lattice and P is a unit cell angle. The salt crystallizes in the monoclinic P21/c space group. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3 .3 1 ,1 3

,

7 ]decane hydrochloride sesquihydrate (I salt:1.5 water) crystalline solid can be identified by 5 characteristic peaks in its powder X-ray diffraction pattern (Figure 8). One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3 .3.1.1' 7 ]decane hydrochloride sesquihydIate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction 10 pattern of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1.1' 3 a]decane hydrochloride sesquihydrate are 4.94±0.20, 9-93±0.20, 14.09±0.20, 14.90±0.20, 17.85±0.20, 19.92±0.20, 21.72±0.20, 22.43±0.20, 22.63±0.20, and 23.95±0.20. The TGA (Figure 8A) shows the dehydration of ('4s)-4-(5-phenyl-1,3,4-thiadiazol-2 yloxy)- I -azatricyclo[ 3 .3.1.1 ")decane hydrochloride sesquihydrate. 15 (4s)-4-(5-Phenyl- 1,3,4-thiadiazol-2-yloxy)-l -azatricyclo[ 3

.

3 .1.1 3

,

7 )decane dihydrogen citrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 9), One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl-1,3,4-thiadiazol- 2 yloxy)-I-azatricyclo[ 3

.

3 .1.1 3

'

7 ]decane dihydrogen citrate solid by as few as one 20 chat acteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-l,3,4 thiadiazol-2-yloxy)-l -azatricyclo[ 3 3.1.13 7 ]decane dihydrogen citrate are 7,98±0.20, 11 .98±0.20, 12.45±0.20, 15.76±0.20, 16.0010.20, 17.75±0.20, 18 .79±0.20, 18.82±0.20, 20 59±0.20, 22.25±0.20, 22.61±0.20, 24.16±0.20, 24.79±0.20, 25 25 06±0.20, 26.21±0.20, and 29.43±0.20. Crystallographic unit cell parameters of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 -azatricyclo[ 3

.

3 . .13,7]decane dihydrogen citrate also were obtained and were determined as: a is 22.651(8) A, b is 9.992(3) A, c is 10.338(4) A, and P is 101.961(5)0 to afford a cell volume of 2288.99 A , wherein a, b, and c are each a representative length of the crystal lattice and P is a unit cell 30 angle. The salt crystallizes in the ionoclinic P21/c space group (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3

.

3 .1 .13 "]decane monohydrogen citrate crystalline solid can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 10). One with skill in the art of analytical -41chemistry would be able to readily identify (4s)-4-(5-phenyl-1,3,4-thiadiazol-2 yloxy)-1-azatricyclo[ 3

.

3 1.13 7 ]decane monohydrogen citrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Two-theta angle positions of characteristic peaks in a powder X-ray diffraction pattern of (4s)-4-(5-phenyl-1,3,4 5 thiadiazol-2-yloxy)--1-azatricyclo[ 3 3. 1 1 3

,

7 decane monohydrogen citrate are 9.37±0.20, 9.62±0.20, 10.30±0-20, 11 24±0.20, 12.18±0.20, 13.73±0.20, 15.55±0.20, 16.17±0.20, 16.37±0.20, 16 76±0 20, 18.35±0.20, 18.67±0 20, 18.8910 20, 19-98±0.20, 20.48±0.20, 20.94±0.20, 21.54±0.20, and 22.02±0.20. (4.s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3 .3 1.1 3 7 ]decane free 10 base can be identified by characteristic peaks in its powder X-ray diffraction pattern (Figure 11). One with skill in the art of analytical chemistry would be able to readily identify (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)--1-azatricyclo[ 3

.

3 .1. IM ]decane flee base by as few as one characteristic peak in its powder X-ray diffraction pattern Two-theta angle positions of characteristic peaks in a powder X-ray diffraction 15 pattern of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)--azatricyclo[3.3.1 .I ldecane free base are 7.18±0.20, 10.19t0.20, 13.90±0 20, 14.37±0.20, 14.40±0.20, 14,66±0.20, 15.09±0.20, 15,21±0.20, 18.13±0.20, 18.43±0.20, 19.41+0 20, 19.88±0.20 (two peaks), 20.09±0.20, 20 46±0.20, 21 66±0,20, 23 08±0 20, 26,84±0.20, 28.71±0.20, and 30.90±0.20. Crystallographic unit cell parameters of 20 (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.1 3 3 )decane free base also were obtained and were detennined as: a is 6.4427(17) A, b is 9.895(3) A, c is 13.102(4) A, and a is 70.145(4)0, p is 81.691(4)*, and y is 73.391(4)0 to afford a cell volume of 751.787 A 3 , wherein a, b, and c are each a representative length of the crystal lattice and a, P, and y are each a unit cell angle. The salt crystallizes in the 25 triclinic P-I space group. As used herein the term "substantially pure", when used in reference to a salt of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1 .1 3 3 ]decane, refers to a salt that is greater than about 90% pure. The crystalline form of (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3

.

3 1. .1 3 7 ]decane does not contain more than 30 about 10% of any other compound and, in particular, does not contain more than about 10% of any other fonn of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)- 1 azatricyclo[3.

3 .l .1 ]decane, such as amorphous, solvated forns, non-solvated forms, desolvated forms, and the enantiomer. -42- More preferably, a "substantially pure" salt refers to a salt that is greater than about 95% pure, wherein the crystalline fonn of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2 yloxy)-1-azatricyclo[ 3

.

3 1.1 3

'

7 )decane does not contain more than about 5% of any other compound and, in particular, does not contain more than about 5% of any other 5 form of ('4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3

.

3 .1 .13 3 ]decane, such as amorphous, solvated forms, non-solvated forms, desolvated forns, and the enantiomer. Even more preferably, a "substantially pure" salt refers to a salt that is greater than about 97% pure, wherein the crystalline form of (4s)-4-(5-phenyl- 1,3,4 10 thiadiazol-2-yloxy)-1-azatricyclo[ 3

.

3 .I 1 3 3]decane does not contain more than about 3% of any other compound and, in particular, does not contain more than about 3% of any other form of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3 .31.1 3 7 ]decane, such as amorphous, solvated forms, non-solvated forms, desolvated forms, and the enantiomer, 15 Compositions comprising (4s)-4-(5-phenyl-1,3,4-tbiadiazol-2-yloxy)-I azatricyclo[ 3

.

3 .1.13 ]decane salts also are contemplated. A suitable pharmaceutical composition comprises a substantially pure (4s)-4-(5-phenyl-1,3,4-thiadiazol-2 yloxy)-1-azatricyclo[3.31.l 3 "]decane salt fonnulated together with one or more non toxic pharmaceutically acceptable carriers as previously described for the 20 compositions. Such compositions comprising (4s)-4-(5-phenyl-1,3,4-thiadiazol-2 y1oxy)-l-azatricyclo[3.3.1.1'Idecane salts are administered and can be used in the methods of the invention as previously described for the compounds of the invention, except substituting a desired salt in place of a compound, which would readily understood by one with skill in the art. 25 Powder X-ray diffraction (PXRD) analysis of samples was conducted in the following manner. Samples for X-ray diffraction analysis were prepared by spreading the sample in a thin layer on the sample holder and gently flattening the sample with a microscope slide. For example, the sample may have been ground to a fine powder with mortar and pestle, or with glass microscope slides for limited quantity samples. 30 Samples were run in one of three configurations: circular bulk holder, a quartz zero background plate, or hot stage mount (similar mounting to a zero background plate). Diffraction patterns were collected using an Inel G3000 difrractometer equipped with an incident beam germanium monochronator to provide Cu-Kai -43radiation. The X-ray generator was operated at a voltage of 40 kV and a current of 30 mA. The Inel G3000 is equipped with a position sensitive detector that monitors all diffraction data simultaneously The detector was calibrated by collecting the attenuated direct beam for seven seconds in I degree intervals across a 90 degree two 5 theta range. The calibration was checked against a silicon line position reference standard (NIST 640c). Samples were placed on an aluminum sample holder and leveled with a glass slide. Alternatively, X-ray powder diffraction can be perfonned using a Rigaku Mini flex diffractorneter (30 kV and 15 mA; X-ray source: Cu; Range: 2.00-40.00* 10 Two Theta; Scan rate: 1-5 degree/minute) or a Scintag Xl or X2 diffractometer (2 kW normal focus X-ray tube with either a liquid nitrogen or Peltier cooled gennanium solid state detector; 45 kV and 40 mA; X-ray source: Cu; Range: 2.00-40.00* Two Theta; Scan Rate: 1-5 degree/minute). Characteristic powder X-ray diffraction pattern peak positions are reported in 15 terms of angular positions (two theta) with an allowable variability of ±0.20*. The variability of ±0.10* is intended to be used when comparing two powder X-ray diffraction patterns. In practice, if a diffraction pattern peak from one pattern is assigned a range of angular positions (two theta) which is the measured peak position ±0.20* and a diffraction pattern peak from another pattern is assigned a range of 20 angular positions (two theta) which is measured peak position ±0.20* and if those ranges of peak position overlap, then the two peaks are considered to have the same angular position (two theta). For example, if a diffraction pattern peak from one pattern is determined to have a peak position of 5.20* for comparison purposes the allowable variability allows the peak to be assigned a position in the range of 5.00* 25 5.40*. If a comparison peak from the other diffraction pattern is determined to have a peak position of 5.35* and the allowable variability allows the peak to be assigned a position in the range of 5.150 - 5 550, then the two peaks being compared are considered to have the same angular position (two theta) because there is overlap between the two ranges of peak positions. 30 Single crystal X-ray diffraction analysis of samples was conducted in the following manner, Samples for X-ray diffraction analysis were prepared by affixing selected single crystals to glass pins with epoxy adhesive. X-ray diffraction data was collected using a Bruker SMART system with an APEX area detector (50 kv and 40 mA; X-ray source: Mo). Data were collected at -100*C. -44- Thermal gravimetric analysis of samples was conducted in the following manner. A Mettler Toledo Model TGA/SDTA 851e thermal gravimetric analysis instrument was used to determine the weight change against sample temperature. Experiments and analysis conducted with Mettler STARe software. The experimental 5 parameters were: sample weight 2-20 mg, placed in an open aluminum pan; heating rate 10 'C per minute,

N

2 purge flow rate 50 mL per minute. Samples were heated from 25 *C to 200 'C at a rate of 10 *C per minute Methods of the Invention 10 Compounds and compositions of the invention are useful for modulating the effects of nAChRs, and more particularly 7 nAChRs. In particular, the compounds and compositions of the invention can be used for treating or preventing disorders modulated by or7 nAChRs- Typically, such disorders can be ameliorated by selectively modulating the 7 nAChRs in a mammal, preferably by administering a 15 compound or composition of the invention, either alone or in combination with another active agent, for example, as part of a therapeutic regimen. In addition, the invention relates to a method for treating or preventing conditions, disorders or deficits modulated by an c7 nicotinic acetylcholine receptor, an a4p2 nicotinic acetylcholine receptor or both c7 and (x40 2 nicotinic acetylcholine 20 receptor wherein the condition, disorder, or deficit is selected from the group consisting of a memory disorder, cognitive disorder, neurodegeneration, or neurodevelopmental disorder, or a combination thereof comprising administration of a therapeutically suitable amount of a compound of formula (1), 25 LTA (I); or a pharmaceutically acceptable salt or prodrug thereof, wherein L, is-O- or -NR,-; A is -Arl, -Ar-L 2 -Ar3 or -Ar 4

-L

3 -Ars; Ar is aryl or heteroaryl; Arz is aryl or monocyclic heteroaryl; Ar 3 is aryl or heteroaryl; Ara is a bicyclic heteroaryl; Ars is 30 aryl or heteroaryl; L, is a bond, -0-, -NR.-, -CH 2 -, -C(O)NR3 -; L 3 is a bond, -0-, NR- or -CH 2 -; and Ra is hydrogen or alkyl -45- The invention also contemplates the method for treating or preventing a condition or disorder modulated by an 7 nicotinic acetylcholine receptor comprising the step of administering a compound of the formula (I), wherein the condition or disorder is selected from a memory disorder, cognitive disorder, neurodegeneration, 5 and neurodevelopmental disorder The invention also contemplates a method for treating or preventing a condition or disorder modulated by an 7 nicotinic acetylcholine receptor comprising the step of administering a compound of the formula (I), wherein the condition or disorder is selected from attention deficit disorder, attention deficit hyperactivity 10 disorder (ADHD), Alzheimer's disease (AD), mild cognitive impainnent, schizophrenia, senile dementia, AIDS dementia, Pick's disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, amyotrophic lateral sclerosis, Huntington's disease, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain and inflammatory pain. 15 The invention also contemplates a method for treating or preventing a condition or disorder modulated by an 7 nicotinic acetylcholine receptor comprising the step of administering a compound of the formula (I), wherein the condition or disorder is schizophrenia. The invention also contemplates a method for treating or preventing a 20 condition or disorder modulated by an 7 nicotinic acetylcholine receptor comprising the step of administering a compound of the formula (1) in combination with an atypical antipsychotic. The invention also contemplates a method for treating or preventing a condition or disorder modulated by an 7 nicotinic acetylcholine receptor comprising 25 the step of administering a compound of the formula (1), wherein the condition or disorder is infertility, lack of circulation, need for new blood vessel growth associated with wound healing, more particularly circulation around a vascular occlusion, need for new blood vessel growth associated with vascularization of skin grafts, ischemia, inflammation, particularly those associated with rheumatoid arthritis, wound healing, 30 and other complications associated with diabetes The invention also contemplates a method for treating or preventing a condition or disorder modulated both by a7 and c4p2 nicotinic acetylcholine receptors comprising the step of administering a compound of the formula (1), -46wherein the condition or disorder is selected from a group of disorders where both r7 and oc4p2 nicotinic receptors are implicated These include attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, schizophrenia, senile dementia, AIDS dementia, Pick's disease, 5 dementia associated with Lewy bodies, dementia associated with Down's syndrome, amyotrophic lateral sclerosis, Huntington's disease, inflammation, arthritis of various types, smoking cessation, nicotinic withdrawal syndrome, traumatic brain injury, acute pain, post-surgical pain, osteoarthritic pain, neuropathic and inflammatory chronic pain states. 10 Compounds for the method of the invention, including but not limited to those specified in the examples or otherwise specifically named, can modulate, and often possess an affinity for, nAChRs, and more particularly c7 nAChRs. As C7 nAChRs ligands, the compounds of the invention can be useful for the treatment or prevention of a number of 7 nAChR-mediated diseases or conditions. Certain compounds of 15 the invention includes, in addition to affinity for cr7 nAChRs, affinity for cr4D2 nAChRs. For example, 7 nAChRs have been shown to play a significant role in enhancing cognitive function, including aspects of learning, memory and attention (Levin, E.D., 1. Neurobiol. 53: 633-640, 2002). As such, c7 ligands are suitable for 20 the treatment of conditions and disorders related to memory and/or cognition including, for example, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, Pick's disease, dementia associated with Lewy bodies, and dementia associated with Down's syndrome, as well as cognitive deficits associated 25 with schizophrenia. In addition, c7-containing nAChRs have been shown to be involved in the cytoprotective effects of nicotine both in vitro (Jonnala, R. B. and Buccafusco, . J., J. Neurosci. Res. 66: 565-572, 2001) and in vivo (Shimohama, S. et al., Brain Res. 779: 359-363, 1998). More particularly, neurodegeneration underlies several progressive 30 CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, as well as diminished CNS function resulting from traumatic brain injury. For example, the impaired function of c7 nAChRs by P-amyloid peptides linked to -47- Alzheimer's disease has been implicated as a key factor in development of the cognitive deficits associated with the disease (Liu, Q.-S., Kawai, H., Berg, D. K., PNAS 98: 4734-4739, 2001). a7 selective ligands can influence neuroprotective pathways leading to decreased phosphorylation of the tau protein, whose 5 hyperphosphorylation is required for neurofibrillary tangle formation in various tau related pathologies such as Alzheimer's disease and various other dementias (Bitner et al., Soc. Neuroscience, 2006 abst 325.6). The activation of 7 nAChRs has been shown to block this neurotoxicity (Kihara, T. et al., J. Biol. Chem. 276: 13541-13546, 2001). As such, selective ligands that enhance a7 activity can counter the deficits of 10 Alzheimer's and other neurodegenerative diseases. Alpha-7 nAChRs also have been implicated in aspects of neurodevelopment, for example neurogenesis of the brain. (Falk, L. et al., Developmental Brain Research 142:151-160, 2003; Tsuneki, H., et al., J Physiol. (London) 547:169-179, 2003; Adams, C.E., et al., Developmental Brain Research 139:175-187, 2002). As such, 7 15 nAChRs can be useful in preventing or treating conditions or disorders associated with impaired neurodevelopment, for example schizophrenia. (Sawa A., Mol. Med 9:3-9, 2003), Several compounds with high affinity for a4p 2 neuronal nicotinic receptors (NNRs) have been shown to improve attentive and cognitive performance in 20 preclinical models that are relevant to attention-deficit/hyperactivity disorder (ADHD), a disease characterized by core symptoms of hyperactivity, inattentiveness, and impulsivity. For example, ABT-418, a full agonist at a41 32 NNRs is efficacious in a variety of preclinical cognition models. ABT-418 administered transdemalH, was shown in a controlled clinical trial in 32 adults to be effective in treating ADHD 25 in general, and attentional/cognitive deficits in particular (Wilens, T.E ; Biederman, J.; Spencer, T.J.; Bostic, J.; Prince, J.; Monuteaux, M.C.; Soriano, J.; Fince, C.; Abrams, A.; Rater, M.; Polisner, D. The American Journal of Psychiatry (1999) 156(12), 1931-1937.). Likewise, ABT-418 showed a signal of efficacy in a pilot Alzheimer's disease trial. ABT-089, a a40 2 selective partial agonist, has been shown 30 in rodent and primate animal models to improve attention, learning, and memory deficits. ABT-089 and another u4p2 agonist, ispronicline has shown efficacy in a pilot clinical trials. In addition to cognition, compounds that interact with a4p2 nAChRs such as ABT-594 and others are also efficacious in preclinical and clinical -48models of pain. As such, ligands that modulate both a 7 and a4p2 activity can have broader spectrum of therapeutic efficacy in disease states such as those involving cognitive and attentive deficits, pain, neurodegenerative diseases and others, Schizophrenia is a complex disease that is characterized by abnormalities in 5 perception, cognition, and emotions- Significant evidence implicates the involvement of 7 nAChRs in this disease, including a measured deficit of these receptors in post mortem patients (Sawa A., Mol. Med 9:3-9, 2003; Leonard, S. Eur. J. Pharmacol. 393: 237-242, 2000). Deficits in sensory processing (gating) are one of the hallmarks of schizophrenia. These deficits can be normalized by nicotinic ligands that operate at 10 the 7 nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189-202, 1998; Stevens, K_ E. et al., Psychophannacology 136: 320-327, 1998)- More recent studies have shown that at4p 2 nicotinic receptor stimulation also contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating (Radek et al., Psychopharmacology (Berl). 2006 187:47-55. Thus, a and a7/a4p2 ligands demonstrate potential in the treatment 15 schizophrenia. Angiogenesis, a process involved in the growth of new blood vessels, is important in beneficial systemic functions, such as wound healing, vascularization of skin grafts, and enhancement of circulation, for example, increased circulation around a vascular occlusion. Non-selective nAChR agonists like nicotine have been shown 20 to stimulate angiogenesis (Heeschen, C. et al, Nature Medicine 7: 833-839, 2001). unproved angiogenesis has been shown to involve activation of the 7 nAChR (Heeschen, C. et al., .. Clin. Invest. 110: 527-536, 2002) For example, improved conditions related to inflammation, ischemia, cardiac ischemia, and wound healing, for example in diabetic persons, have been associated with a7 nAChR activity 25 (Jacobi, J., et al., Am. J. Pathol. 161:97-104, 2002). Therefore, nAChR igands that are selective for the 7 subtype offer improved potential for stimulating angiogeniesis with an improved side effect profile. A population of 7 or oL 4 p 2 nAChRs in the spinal cord modulate neurotransmission transmission that have been associated with the pain-relieving 30 effects of nicotinic compounds (Cordero-Erausquin, M and Changeux, J.-P. PNAS 98:2803-2807, 2001). The (x 7 nAChR or and a7/4p 2 ligands demonstrate therapeutic potential for the treatment of pain states, including acute pain, post surgical pain, as well as chronic pain states including inflammatory pain and -49neuropathic pain. Moreover, 07 nAChRs are expressed on the surface of primary macrophages that are involved in the inflammation response, and that activation of the a7 receptor inhibits release of TNF and other cytokines that trigger the inflammation response (Wang, H. et al Nature 421: 384-388, 2003). Therefore, selective a7 ligands 5 demonstrate potential for treating conditions involving inflammation including those associated with various forms of arthritis. The mammalian sperm acrosome reaction is an exocytosis process important in fertilization of the ovum by sperm. Activation of an 7 nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J.H. and Meizel, S. 10 Biol. Reproduct. 68: 1348-1.353 2003). Consequently, selective 7 agents demonstrate utility for treating fertility disorders. Compounds of the invention are particularly useful for treating and preventing a condition or disorder affecting memory, cognition, neurodegeneration, neurodevelopment, and schizophrenia. 15 Cognitive impairment associated with schizophrenia often limits the ability of patients to function normally, a symptom not adequately treated by commonly available treatments, for example, treatment with an atypical antipsychotic. (Rowley, M. et al., J. Med. Chem. 44: 477-501, 2001). Such cognitive deficit has been linked to dysfunction of the nicotinic cholinergic system, in particular with decreased 20 activity at x7 receptors. (Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 2002). Thus, activators of a7 receptors can provide useful treatment for enhancing cognitive function in schizophrenic patients who are being treated with atypical antipsychotics. Accordingly, the combination of an 7 nAChR ligand and an atypical antipsychotic would offer improved therapeutic utility. Specific examples of suitable atypical 25 antipsychotics include, but are not limited to, clozapine, risperidone, olanzapine, quietapine, ziprasidone, zotepine, iloperidone, and the like. Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, 30 compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated However, it is within the skill of the art to start doses of the -50compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the invention can be employed in pure form or, where 5 such forms exist, in pharmaceutically acceptable salt, ester, amide, or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat 10 disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder 15 being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like 20 factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a 25 human or lower animal range from about 0.10 tgfkg body weight to about 10 mg/kg body weight. More preferable doses can be in the range of from about 0.10 pg/kg body weight to about 1 mg/kg body weight. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily 30 dose. Methods for Preparing Compounds of the Invention As used in the descriptions of the schemes and the examples, certain -51abbreviations are intended to have the following meanings: Bu for butyl; DMAP for 4-dimethylaminopyridine; DMF for dimethyl formamide; DME for 1,2 diimethoxyethane; EDAC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiiimide hydrochloride, Et for ethyl; EtOAc for ethyl acetate; eq. for equivalents; HOBt for 5 hydroxybenzotriazole; HPLC for high pressure liquid chromatography; mCPBA for m-chloroperbenzoic acid; Me for methyl; MeOH for methanol; OAc for acetoxy; OTf for trifluoromethanesulfonate; Pd/C for palladium on carbon; Ph for phenyl; THF for tetrahydrofuran; and TLC for thin layer chromatography. The reactions exemplified in the schemes are performed in a solvent 10 appropriate to the reagents and materials employed and suitable for the transformations being effected. The described transformations may require modifying the order of the synthetic steps or selecting one particular process scheme over another in order to obtain a desired compound of the invention, depending on the functionality present on the molecule. 15 Nitrogen protecting groups can be used for protecting amine groups present in the described compounds Such methods, and some suitable nitrogen protecting groups, are described in Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999). For example, suitable nitrogen protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), 20 acetyl, and trifluoroacetyl. More particularly, the Boc protecting group may be removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid. The Cbz and Bn protecting groups may be removed by catalytic hydrogenation. The acetyl and trifluoroacetyl protecting groups may be removed by a hydroxide ion. 25 Scheme 1 0CN

NH

2 S TOSMIC UH (HCH0), KOtBu, DME L l 2

S

4 , EtOH O 000 0 00 1.2 3 4 As outlined in Scheme 1, compound of formula I (commercially available from Aldrich Chemical Co., {4746-97-8]) when treated with tosylmethyl isocyanide -52- (TOSMIC, commercially available from Aldrich Chemical Co., [36635-61-7)) in the presence of a base such as potassium tert-butoxide in a solvent such as ethylene glycol dimethyl ether will provide the compound of formula 2. Compound of formula 2 when treated with lithium aluminum hydride in THIF will provide the compound of 5 formula 3. Compound of formula 3 when treated with paraformaldehyde along with sulfuric acid in ethanol will provide the compound of formula 4 (1-azaadamantan- 4 one). A further description of the synthesis may be found in Synthesis, 1992, 1080, Becker, D. P ; Flynn, D.L. 10 Scheme 2 i. BH 3 -THF, THF OH 0 Ar .0 Ar Oii. NaBH4, MeOH ArC02Hf'i VI -- - 0+0 4

BH

3 DMAP BH 3

BH

3 5

CH

2

CI

2 6 NaOH NaOH Ar p-CICH 4

THF-H

2 0 THF-H 2 0 OH OH

BH

3

BH

3 8 p As outlined in Scheme 2, compounds of formula 4 (1-azaadamantan-4-one) 15 when treated with borane-THF complex in THF will provide the boiane complexed amine, which when further treated with a reducing agent such as sodium borohydride in methanol will provide compounds of formula 5 which consists of a mixture of (r) and (s) isomers. The compound of formula 5 may be further treated according to the methods outlined in the Schemes 3-11 to obtain an (rs) mixture of the compound of 20 fonnula (I), or the mixture may be separated into the individual (r) or (s) isomers and then treated according to the methods outlined in the Schemes 3-1 1 to generate a single (r) or (s) isomer of the compounds of formula (1). To effect the separation of the (r) isomer from the (s) isomer, the treatment of the compound of formula 5 with reagents such as a substituted benzoic acid (for example para-chlorobenzoic acid) and -53- N-(3-dimethylaminopropyl)-N'ethylcarbodiimiide hydrochloride (EDAC) in the presence of 4-dimethyl aminopyridine in a solvent, such as dichloromethane, will provide compounds of fonnula 6 and 7. The mixture of compounds of formula 6 and 2 may be separated through the use of chromatographic procedures known to one 5 skilled in the art. The individual isomers, the compound of formula 6 or the compound of formula 7, when further treated with sodium hydroxide in a mixture of THF and water will provide the compound of formula 8 or the compound of formula 9_ respectively. 10 Scheme 3 OH Os. 0,A + X-A NaHD F o or /- (BH 3 )n - KOtBu, THF (BH 3 )n 10 n=1 12 13 n=0,1- = wherein X-A is defined as X F, X E x Yo xii or o1),K

D

1

G

1 ; G-ED 1 ; E and X is halo As outlined in Scheme 3, compounds of formula 10, which may be either the mixture of compounds of formula 8 and 9 or the individual isomers represented by the compound of formula 8 or the compound of formula 9, or the corresponding free 15 amine lacking the borane group, when treated with sodium hydride in DMF, potassium tert butoxide, or potassium bis(trimethylsilylamnide), in THF or DMSO followed by treatment with compounds of formula 11, wherein X is chloro, bromo, fluoro or iodo and A is as defined for compounds of fornula (I), and more particularly for Arl of compounds of formula (II) or similarly Ar, of compounds of formula (III), 20 will provide compounds of formula 12. Compounds of formula 12 when treated with either aqueous hydrochloric acid in acetone or with palladium on carbon in methanol will provide compounds of formula 13 which are representative of compounds of the invention.. -54- Scheme 4 CuBr 2 BrAr

H

2 N-Arj t-BuONO BA 14 MeCN 15 Cu, HCI Scheme 3 NaNO 2 HOAc-H 2 0 CI.Ar, Scheme 3 16

BH

3 17 Wherein

H

2 N-Arj is defined as H2N F1

H

2 N <E1~i

H

2 N E

DG

1 ; GD1 or E, As shown in Scheme 4, compounds of formula 15 and 16 each represent 5 compounds of formula A-X, wherein A is Art and is defined in formula (1) and X is chloro or bromo. Compounds of formula 15 and of fonnula 16 may be obtained from compounds of fonnula

H

2 N-Ari as outlined. Compounds of formula

H

2 N-Arj (formula 14) wherein DI, El, F 1 , Ji, and Ki are each independently -CRia or N, G is -0-, -NRia, or -S-, R, is hydrogen, alkyl, alkoxy, alkoxycarbonyl, cyano, halo, nitro 10 or -NRbRe, Ria is hydrogen or ailcyl, Rb and Re are each independently hydrogen, alkyl, alkoxycarbonyl or alkylcarbonyl, and n is 0, 1, 2 or 3 for groups shown in Scheme 4, when treated with cuprous bromide and tert butyl nitrite in acetonitrile will provide compounds of formula 15. Alternatively, compounds of formula 14, wherein Art is as defined above in Scheme 4 when treated with copper powder, aqueous 15 hydrochloric acid, sodium nitrite in a solution of aqueous acetic acid will provide compounds of formula 16. Furthermore, when either compounds of formula 15 or compounds of formula 16 are subjected to the conditions outlined in Scheme 3 compounds of formula 17 which are representative of compounds of the invention which contain an A group that is defined as Art or Ar 2 in formula (1), will be 20 provided -55- Scheme 5 G O H Br G Br Cs 2

CO

3 , Br G OAr3 + NaH,DMF NN + HO-Ar 3 THF N-N N or 18 19 20KOtBu, THF

(BH

3 ) 10 S G O HCI (aq) OAr 3 N-N acetone N N-N N or

(BH

3 ) 21 Pd/C, MeOH 22 As outlined in Scheme 5, compounds of formula 18, wherein G is -0-, NRia, 5 or -S-, and R 1 , is hydrogen or alkyl, when treated with compounds of fonnula 19, wherein Ar 3 as defined for compounds offormula (I), in the presence of cesium carbonate and a solvent such as but not limited to THF will provide compounds of formula 20, which are representative of compounds of formula A-X, (compounds of formula 11), described in Scheme 3, wherein A is -Ar 2

-,L

2 -Ar 3 as defined in formula 10 (f). When compounds of formula 20 and compounds of formula 10 are treated according to the conditions outlined in Scheme 3, compounds of formula 21 are obtained. When compounds of formula 21 are treated with aqueous hydrochloric acid in acetone or with palladium on carbon in methanol, compounds of formula 22 are obtained which are representative of compounds of the invention which contain an A 15 group that is defined as -Ar 2 - L 2 -Ar 3 in formula (I). Scheme 6 OH H2N M~ F M -- 1 O H2 M t-BuONO, HBF '- f K base or 'E N 23 NaNO 2 , HBF 4 24

(BH

3 )n 10 0 M0 O, MHCI (aq) O D'E-K acetone. N D' E-K or

(BH

3 )n 25 Pd/C, MeOH 26 n=1 -56- As outlined in Scheme 6, compounds of formula 23, wherein D, E, J, K, and M are each independently

-CR

2 .- , -CX 2 -, or -N-, X 2 is halo, haloalkyl, cyano, or nitro, when treated with either tert-butyl nitrite and tetrafluoroboric acid, or sodium nitrite and tetrafluorobotic acid, will provide compounds of formula 24. Compounds 5 of formula 24 when treated with compounds of formula 10 in the presence of a base such as but not limited to, either sodium hydride in DMF, potassium tert butoxide in THF or potassium bis(hexamethyldi-silylamine) in THF will provide compounds of formula 25. Compounds of formula 25 when treated with either aqueous hydrochloric acid in acetone or with palladium on carbon in methanol will provide compounds of 10 formula 26 which are representative of compounds of the invention. Scheme 7 0 Ar 3 -B(OH)h o Ar 3 Ar-X B(OR.)2 S Pd(O), K 2

CO

3 Pd(O), K 2

CO

3 IN dioxan-ROH 7-- dioxane-ROH Nj 2790 C 28 0 C 30 27 28 As outlined in Scheme 7, compounds of formula 27, wherein Ar7 is defined in 15 formula (I) and X 3 is halo or -O-trifluoromethanesulfonyl, which can be obtained according to the methods outlined in Schemes 3, 4, or 6, when heated in the presence of Ar 3 -B(OH)2, a palladium catalyst, as known to one skilled in the art, and potassium carbonate in a solvent such as, but not limited to, a mixture of dioxane and water or an alcoholic solvent such as ethanol under heated conditions, will provide compounds of 20 formula 28 which is representative of compounds of the invention, wherein A is -Ar 2 L 2 -Ar 3 , and L 2 is a bond. Alternatively, compounds of formula 30, which contain a boronic acid or a boronic acid ester, wherein R, is hydrogen or alkyl, which may be obtained according to the methods described herein, when treated with Ar-X, wherein Ar 3 is defined in formula (1) and X is chloro, bromo or -O-trifluoromethane 25 sulfonyl in the presence of a palladium catalyst as known to one skilled in the art and potassium carbonate in a mixture of solvents such as, but not limited to, a mixture of dioxane and an alcoholic solvent, for example ethanol, under heated conditions will also provide compounds of formula 28. .30 Scheme 8 -57- OH X16 Ars NaH, DMF

L

3 + X NN N ,X/ Ar ,N N X / X 1 gXI 8

(BH

3 )n

(BH

3 )n 33 32 10 HCI (aq) L3 acetone La Ars OR NN ~ 1 r Pd/C, MeOH

X

19 X1e n=1 34 As outlined in Scheme 8, compounds of formula 10 when treated with compounds of formula 32, wherein X is chloro, bromo, or iodo, J is -0- or -S-, and

X

1

,-X

19 , L 3 , and Ar 5 are as defined for compounds of formula (IV) in the presence of 5 sodium hydride in DMF will provide compounds of formula 3 Compounds of formula 33 when treated with aqueous hydrochloric acid in acetone or with palladium on carbon in methanol will provide compounds of formula 34 which are representative of compounds of the invention wherein A is -Ar 4

-L

3 -Ars. 10 Scheme 9 R, R, 0 NN A§~ JNH O+ HN-A AX-A 4 35 36 37 la As outlined in Scheme 9, compounds of formula 4 when treated with compounds of formula 35 and a reducing agent such as but not limited to sodium triacetoxyborohydride will provide compounds of formula 3. Typical conditions for 15 this transformation include stirring the compound of formula 4 and compound of formula 35 in a solvent such as THF in the presence of glacial acetic acid and/or magnesium sulfate followed by the addition of the reducing agent. Alternatively, compounds of formula 37, which can be obtained from the reductive amination of compounds of formula 4 with amine of formula

R,-NH

2 , may be further treated with 20 compounds of formula A-Xz(compound llIa) wherein A is as defined in formula (1) and X, is halo or -OTf in the presence of a palladium catalyst such as but not limited to palladium tetrakis(triphenylphosphine) and a base such as but not limited to sodium carbonate will also provide compounds of formula 36 which are representative of compounds of the invention, wherein L 1 is -NR, in compounds of formula (1). -58- Scheme 10 E F-Ar 2 -Br F-Ar 2 -N Cu(Il)O, Cs 2 CO3 OH 38 DMF,A 40 OH

H

3 I KOtBu, DMSO 2) HCI

'

2 DE2 O0ArBr H M Ar2 I ' Ar 2 ferric acetylacetonate N N Cu(II)O, Cs 2 C0 3 42 4_3 DMF, A As outlined in Scheme 10, compounds of formula 3, wherein Ar 2 , E 2 , and D 2 5 are as defined for compounds of formula (111), when treated with compounds of formula 39, copper(II) oxide, and a base like cesium carbonate heated in solvent such as DMF supplies compounds of formula 40. Treatment of compounds of formula 41 with a base such as potassium t-butoxide in a solvent like dimethyl sulfoxide or tetrahydrofuran, then reacting with compounds of formula 40, and subsequent 10 treatment with a hydrochloric acid in acetone provides compounds of formula 42. Alternatively, compounds of formula 42 can be prepared from compounds of formula 43 by treatment with compounds of formula 39 in the presence of ferric acetylacetonate, copper(Il) oxide, a base like cesium carbonate and heated in a solvent like DMF. 15 Scheme 11 Ar 3

-NH

2 -OH 46 X-Ar 2

-CO

2 Et X-Ar 2

-CO

2 H 44 45 0 Scheme 3 0 A N -Ar 2

CO

2 NH-Ar 3 Ar 2 H 47 1N/ 48 As outlined in Scheme 11, esters of fonula 44, wherein Ar 2 is defined for -59compounds of formula (Il) and X is halogen, when treated with a base such as sodium hydroxide, potassium hydioxide or lithium hydroxide in a solvent such as a mixture of water and ethanol at a temperature in the range of 25 to 40 C for 30 minutes to 2 hours provides compounds of formula 45. Compounds of formula 45 5 can be coupled with compounds of formula 46 under aide bond forming conditions familiar to one skilled in the art to give compounds of formula 47. For example, compounds of formula 45 can be combined with compounds of formula 46, hydroxybenzotriazole, dirnethylami nopyridine, and 1-(3-dimethylaminopropyl)- 3 ethylcarbodiimide hydrochloride in a solvent, such as pyridine, to supply compounds 10 of formula 47. Alternatively, compounds of formula 45 can be converted to the corresponding acid chloride by reacting in neat thionyl chloride. The acid chlorides can then be reacted with compounds of formula 46 in the presence of a base, such as triethylamine, in dichloromethane at or near room temperature to provide compounds of formula 47. Compounds of formula 47 can be converted to compounds of formula 15 48 using the conditions described in Scheme 3. In addition, compounds of formula (1) may be converted to compounds of formula (VII) wherein the azaadamantane exists as an N-oxide by treatment with an oxidizing agent. Examples of the oxidizing agent include, but not limited to, aqueous 20 hydrogen peroxide and m-chloroperbenzoic acid. The reaction is generally performed in a solvent such as, but not limited to, acetonitrile, water, dichloromethane, acetone or mixture thereof, preferably a mixture of acetonitrile and water, at a temperature from about 0 "C to about 80 "C, for a period of about 1 hour to about 4 days. The compounds and intermediates of the invention may be isolated and 25 purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer 30 chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England. -60- The compounds of the invention have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid to provide the desired salt. The salt may be collected by any suitable means. Examples of acids suitable for the reaction include, 5 but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, or hydroxybutyric acid, camphorsulfonic, malic, phenylacetic, aspartic, glutamic, and the like. Preferred salts can include, but are not 10 limited to, p-toluenesulfonate, L-bitartrate, dihydrogen phosphate, bisuccinate, hydrochloride, dihydrogen citrate, and monohydrogen citrate. Citrate salts are more preferred. The compounds of the invention and processes for making compounds for the method of the invention will be better understood by reference to the following 15 Examples, which are intended as an illustration of and not a limitation upon the scope of the invention. EXAMPLES 20 Method A: Etherification A solution of I -azaadamantan- 4 -ol N-borane complex (1 eq.) and a heteroaryl halide (1.1 eq.) in anhydrous DMF (0.5-1 M) was chilled to between -20 and 0 *C and treated with sodium hydride (1.5 equiv; 95%, Aldrich). After 15 minutes, the cooling bath was removed and the mixture was allowed to warm to room temperature. 25 When I -azaadamantan- 4 -ol N-borane complex was consumed as determined by TLC analysis (generally 1-2 hours), the mixture was diluted with water and stirred for I hour. The resulting solid product was collected by filtration, washed with water, and dried under reduced pressure to afford the desired product. 30 Method B: Etherification A solution of I -azaadamantan- 4 -ol (or I -azaadamantan- 4 -ol N-borane complex, I eq.) and a heteroaryl halide (I I eq.) in anhydrous tetrahydrofuran (-0.5 M) was chilled to 0 'C under a nitrogen atmosphere and treated with potassium tert butoxide in THF (1.0 M; 1 eq ; Aldrich), added dropwise. The ice bath was removed, -61and the mixture was allowed to warn to room temperature overnight. After diluting with water, the mixture was extracted with chloroform (3x), and the combined extracts were purified by flash chromatography (silica gel eluting with a gradient of 5 10% MeOH-CHC3 containing 1% NH 4 0H) to afford the desired product. 5 Method C: Acidic Deboronation A suspension of the 1-azaadamantane N-borane complex (I eq.) in acetone (-0.5 M) was chilled to 0 *C and treated with 3 N HCI (4 eq.). After 15 minutes, the ice bath was removed and the mixture was stirred until the borane complex was 10 consumed as monitored by TLC (the borane complexes can be visualized with basic KMnO4 stain). The pH of the solution was then adjusted with 5 N NaOH to ~ pH 10, extracted with chloroform (3x), and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was purified by either flash chromatography [Analogix pre-packed silica gel cartridges, 5-50% 15 gradient of ammonium hydroxide-methanol-chloroforn (2:20:78) in chloroform] or by preparative HPLC [Waters@ XTerra RPI 8 column, Sy[, 30x100 mm, flow rate 40 mL/minute, 5-95% gradient over 22 minutes of acetonitrile in buffer (0. 1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the desired product as its free base. (Stotter, P. L.; Friedman, M. D ; Dorsey, G. 0.; 20 Shiely, R. W ; Williams, R. F.; Minter, D. E. Heterocycles 1987, 25, 251). Method D: Pd/C-Catalyzed Deboronation A solution of the 1-azaadamantane N-borane complex in methanol was treated with 10% palladium on carbon (-10% by weight; Aldrich) until the starting material 25 was consumed as indicated by TLC or HPLC (generally overnight) In some instances, the solution was warmed briefly to 50 *C to accelerate the reaction. The catalyst was removed by filtration and the product was purified by either flash chromatography [Analogix pre-packed silica gel cartridges, 5-50% gradient of ammonium hydroxide-methanol-chloroform (2:20:78) in chloroform] or by 30 preparative HPLC [Waters@ XTerra RPI8 column, 5sL, 30x 100 mm, flow rate 40 mL/minute, 5-95% gradient over 22 minutes of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the desired product. -62- Method E. Suzuki Coupling A flask with a septum cap was charged with the azaadaniantane containing heteroaryl halide (I eq.), a heteroaryl-boronic acid or heteroaryl-boronate ester (2 5 eq.), potassium carbonate (4 eq.), and tetrakis(triphlenylphosphile)-palladium(O) (0.04 eq.; Strem). The flask was stoppered, evacuated, flushed with nitrogen, and charged with the solvent mixture 1,4-dioxane-water (3:1; - 0.1 M of the halide), added through the septum. The mixture was then warmed to 90 *C for 3-8 hours. Upon completion of the reaction, the mixture was diluted with EtOAc, washed with water, 10 the extracts dried over magnesium sulfate and filtered. The resulting material was purified by preparative HPLC (Waters@ XTerra RP18 column, 5 yA, 30x100 mm, flow rate 40 mL/rninute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nm]. Fractions containing the desired product were pooled, 15 concentrated under vacuum, diluted with methanol or ethyl acetate, and filtered to afford the desired product. Method F. Anhydrous Suzuki Coupling A flask with a septum cap was charged with the heteroaryl halide (1 eq.), a 20 heteroaryl-boronic acid or heteroaryl-boronate ester (2 eq.), potassium carbonate (3 eq.), [1,1 '-bis(diphenylphosphi no)fenrocene]dichloropalladium(I1) complex with

CH

2 C1 2 (0.2 eq.; Aldrich) and anhydrous 1,4-dioxane-ethanol (1:1; - 0.1 M of the halide). The mixture was flushed with nitrogen and warmed to 90 aC for 2 hours. After cooling, the mixture was concentrated and purified by preparative HPLC 25 [Waters@ XTerra RPI 8 column, 5 y, 30x 100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nml. Fractions containing the desired product were pooled, concentrated under vacuum, diluted with methanol or ethyl acetate, and filtered to afford the desired product as a free base. 30 Method G. Microwave Suzuki Coupling In a microwave reaction tube were combined the heteroaryl halide (-0.1 mmol), the heteroaryl-boronic acid or heteroaryl-boronate ester (3 eq.), -63bis(triphenylphosphine)-palladiumi(II) chloride (0.1 eq.; Aldrich), and biphenyl-2 yldicyclohexylphosphane (0.03 eq ; Strem), followed by the solvents 1,4-dioxane (1.0 mL), ethanol (1.0 mL), and aqueous sodium carbonate (1.0 M; 1.0 mL). The tube was sealed, and the reaction was heated to 150 *C at 300 W for 10 minutes in a microwave 5 reactor. After cooling to room temperature, the mixture was diluted with 5% Na 2 CO3 and extracted with CHC1 3 (3x). The combined organic extracts were washed with brine, dried (Na 2 SO4), filtered and concentrated under reduced pressure, and the resulting material was purified by preparative HPLC [Waters@ XTerra RP 18 column, 5 s, 30x 100 mm, flow rate 40 mUminute, 5-95% gradient of acetonitrile in buffer 10 (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the product as its free base. Alternatively, the product was purified by preparative HPLC under acidic conditions [Waters@ XTerra RP18 column, 5p, 30x 100 mm, flow rate 40 mLminute, 5-50% gradient of acetonitrile in 0.1% aq. TFA] to afford the trifluoroacetate salt 15 Method H. Salt Fornation A rapidly stifling solution of the free base in ethyl acetate-ethanol, ethanol, or dioxane was treated with either p-toluenesulfonic acid monohydrate (1 eq..; Aldrich; added as a solution in ethyl acetate) or fumaric acid (1 eq., Aldrich; added as a 20 solution in methanol) or HCl-dioxane (1-2 eq.; 4 M; Aldrich) at room temperature. After stirring for 2-16 hours, the precipitate was collected by filtration, rinsed with ethyl acetate, and dried to afford the title compound. Method : Etherification 25 A solution of 1-azaadamantan- 4 -ol (or 1-azaadamantan- 4 -ol N-borane complex, I eq.) and potassium lert-butoxide (1 I eq.) in anhydrous dimethyl sulfoxide (-0.5 M) was stirred at room temperature for 1 hour. A heteroaryl halide (2.2 eq.) was added and the reaction mixture was stirred at room temperature ovemight The reaction mixture was purified by preparative HPLC on a Waters Nova-Pak@ HR C1 8 30 6 pm 60A Prep-Pak@ cartridge column (40 x 100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 nL/minute to provide the desired compound. -64- Method J: Acidic Deboronation and Hydrochloride salt isolation A suspension of the l-azaadamantane N-borane complex (1 eq ) in acetone (-0.5 M) was chilled to 0 *C and treated with 3 N HCI (5-10 eq.). After 15 minutes, the ice bath was removed and the mixture was stirred until the borane complex was 5 consumed as monitored by TLC (the borane complexes can be visualized with basic KMnO4 stain). The reaction mixture was concentrated under reduced pressure The resulting material was dissolved in MeOH (-0 1 M) and stirred for 30 minutes at room temperature. The reaction mixture was concentrated again. The residue was dissolved in a minimal amount of MeOH, then triturate by the slow addition of diethyl 10 ether/MeOH 9:1 to afford the desired product as powder. The product was isolated by filtration, washed with additional diethyl ether and dried in a vacuum oven overnight. Method K. Suzuki Coupling A flask with a septum cap was charged with the azaadamantane-containing 15 heteroaryl halide (1 eq.), a heteroaryl-boronic acid or heteroaryl-boronate ester (1.2 2.0 eq.), cesium carbonate (2 5 eq.), and dichlorobis(triphenylplhosphine) palladium(II) (0.05 eq.). The flask was stoppered, evacuated, flushed with nitrogen, and charged with DMF (- 0 1 M of the halide), added through the septum. The mixture was then warmed to 65 *C for 18 hours. Upon completion of the reaction, the 20 mixture was diluted with ethyl acetate, washed with water, and the extracts were dried over sodium sulfate and filtered. The resulting material was purified by preparative HPLC on a Waters Nova-Pak@ HR C18 6 pm 60A Prep-Pak@ cartridge column (40x 100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/minute to provide the 25 desired compound. Method L: Removal of Acid Labile Protecting Groups A mixture of the compound with an acid labile protecting group (e.g. trityl) (1 eq.) in acetone (-0.5 M) was chilled to 0 "C and treated with 3 N HCI (4 eq.). After 30 15 minutes, the ice bath was removed and the mixture was stirred until the protecting group has cleaved as monitored by TLC. The pH of the solution was then adjusted with 5 N NaOH to - pH 10, extracted with chloroform (3x), and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting -65material was purified by either flash chromatography [Analogix pre-packed silica gel cartridges, 5-50% gradient of ammonium hydroxide-methanol-chloroform (2:20:78) in chloroform] or by preparative HPLC [Waters@ XTerra RPI8 column, 5p, 30x 100 mm, flow rate 40 mL/min, 5-95% gradient over 22 minutes of acetonitrile in buffer 5 (0.1 M aqueous amnionium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the desired product as its free base. Example I 10 (4s)-4-(6-Chloropyridazin-3-yloxy)l -azatricyclo{ 3

.

3 . 1.1 'ldecane p-toluenesulfoate Example IA 4-(6-Chloropyridazin-3-ylox) -1-azatricyclo[ 3 .3.1.1 3 7 ldecane 15 Prepared from I-azaadamantan- 4 -ol (3:2 diastereomer mixture; 150 mg, 0.979 mmol; see WO 9215579) and 3,6-dichloropyridazine (182 mg, 1.22 mrnol; Aldrich) according to Method B to afford the title compound as a mixture of stereoisomers: MS (DCI/NH 3 ) m/z= 266 (M+H)*. 20 Example IB

(

4 s)-4-(6-Chloropyidazin3-loxyl-l -azatricyclo[ 3 .3.1.1 "ldecane A portion of the mixture from Example I A (100 mg, 0.38 mmol) was purified further by flash chromatography (25 g silica gel, 2-12% gradient of NH40H-MeOH (1:10) in CHCl 3 ) to provide the title compound as a single stereoisomer: TLC 25 Rr=03 3 [silica gel, NH 4 0H-MeOH-CHCl3 (1:12:87)]. Example IC (4r)-4-(6-Chloopyridazin-3-yloxy)-l-azatricyclo( 3 .3.1.1 ldecane A portion of the mixture from Example IA (100mg, 0.38 mmol) was purified 30 further by flash chromatography (25 g silica gel, 2-12% gradient of NH 4 0H-MeOH (1:10) in CHC1 3 ) to provide the title compound as a single stereoisomer: TLC Rf=0.28 [silica gel, NH 4 0H-MeOH-CHCl3 (1:12:87)] Example 1D -66- (4s)-4-(6-Chloropyridazin- 3 -yloxy)-_ -azatricyclo[ 3 .3.1 .1 3 l]decane p-toluenesulfonate Prepared from the product of Example 1B (28 mg, 0.075 mmol) and p toluenesulfonic acid monohydrate (0 016 g, 0.083 mmol; Aldrich) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.65 (s, I H), 1.82 (d, J=12,5 5 Hz, 2 H), 2 17 (s, 2 H), 2.26 (d, J=12 5 Hz, 2 H), 3 17 (d, J=12.5 Hz, 4 H), 3.31 (d, J=13.9 Hz, 2 H), 5.55 (t, J=3.2 Hz, I H), 6.98 (d, J=9.2 Hz, 1 H), 7.37 (d, J=9 2 Hz, I H). MS (DCI/NH 3 ) m/z= 226 (M+H)*; Anal. Calcd for

C,

3 Hi 6 ClN 3 0C7HgO3S-0.3H2O: C, 54 18; H, 5.59; N, 9.84; Found: C, 54.16; H, 5.55; N, 9 22. 10 Example 2 (4r)-4-(6-ChIloropridazin-3-yloxy--l-azatricyclo[ 3 .3.1.1vldecane p toluenesulfonate Prepared from the product of Example IC (12 mg, 0.045 mmol) and p 15 toluenesulfonic acid monohydrate (9.5 mg, 0.049 mmol; Aldrich) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.74 (s, 1 H), 2.00 - 2.23 (m, 6 H), 3.02 (d,.J=11.9 Hz, 2 H), 3.18 (s, 2 H), 3.51 (d, J=13.2 Hz, 2 H), 5.57 (s, I H), 7.00 (d, .1=9.2 Hz, I H), 7.38 (d, J=9.2 Hz, 1 H). MS (DCI/NH3) m/z= 226 (M+H) ; Anal. Calcd. for C1 3 Hi 6

CIN

3 0-C 7 HsO3S: C, 54.85; H, 5.52; N, 9.59; Found: C, 20 54.46; H, 5.42; N, 937. Example 3 (4s)- 4 -( 6-Phenylnyidazin-3-vlox)-l-azatricvclof3.3.1.1 3 7 decane tifluoroacetate Prepared from the product of Example 1B (31 mg, 0-11 mmol) and 25 phenylboronic acid (41 mg, 0.34 mmol; Aldrich) according to Method G, with purification by preparative HPLC [Waters@ XTerra RP18 column, 5p, 30x100 mm, flow rate 40 mL/minute, 5-50% gradient of acetonitrile in 0.1% aq. TFA) to afford the title compound: 'H NMR (300 Mz, methanol-D 4 ) S ppm 1.97 (d, J=12.5 Hz, 2 H), 2.22 (s, 1 H), 2.41 (d, J=13.2 Hz, 2 H), 2.68 (s, 2 H), 3.60 (s, 2 H), 3.72 (s, 3 H), 5.68 30 (s, 1 H), 7.37 (d, J=9.2 H z, 1 H), 7.47 - 7.59 (m, 3 H), 7 94 - 8.01 (m, 2 H), 8.12 (d, J=9.2 Hz, I H). MS (DC1/NH3) m/z= 308 (M+1-1)*; Anal. Called. for

C

19 H7 1

N

3

O-C

2 HF300.5H2 0: C, 58.60; H, 5.39; N, 9.76; Found: C, 58.32; H, 4.98; N, 9.62. -67- Example 4 (4r)-4-(6-Phenylyvridazin-3-yloxy)-1 -azatricyclo[3.3. 1.1 3

.

7 decane hydrochloride The free base of the title compound was prepared from the product of 5 Example 1C (50 mg, 0.19 mmol) and phenylboronic acid (46 mg, 0.37 nmol; Aldrich) according to Method G, followed by conversion to the HCI salt according to Method H: 'H NMR (300 MHz, iethanol-D4) 8 ppm 2.10 - 2.22 (m, 2 H), 2.22 2.33 (i, 3 H), 2.66 (s, 2 H), 3.51 (d, J=12.5 Hz, 2 H), 3.59 (s, 2 H), 3.87 (d, J=12.5 Hz, 2 H), 5.60 (t, J=3.4 Hz, I H), 7.39 (d, J=9.5 Hz, I H), 7.47 - 7.60 (m, 3 H), 7.92 10 8.03 (m, 2 H), 8 13 (d, J=9.5 Hz, 1 H). MS (DCI/NIH 3 ) m/z= 308 (M+H)*; Anal. Calcd. for CjqH 2 jN 3 0-HCl-0.3H2O: C, 65.34; H, 6 52; N, 12.03; Found: C, 65.33; H, 6.47; N, 12.01. Example 5 15 (4s)-4-f6-(IH-indol-5-yl)pyridazin-3-yloxyl-l-azatricyclo(3.3.1.1 3 7 ldecane dihydrochloride The free base of the title compound was prepared from the product of Example lB (46 mg, 0.17 mnol) and 5-indolylboronic acid (84 mg, 0.52 mmnol; Maybridge) according to Method G, followed by conversion to the dihydrochloride 20 salt according to Method H: 1H NMR (300 MHz, methanol-D4) S ppm 2.01 (d, J=13.4 Hz, 2 H), 2.25 (s, I H), 2.41 (d, J=13.4 Hz, 2 H), 2.71 (s, 2 H), 3,62 (s, 2 H), 3.75 (s, 4 H), 5.63 (s, 1 H), 6.68 (d, J=3.1 Hz, I H), 7.44 (d, J=3.1 Hz, I H), 7 62 7-69 (m, 1 H), 7.71 - 7.80 (n, I H), 7.90 (d, J=9,5 Hz, I H), 8.27 (s, 1 H), 8.62 (d, J=9.5 Hz, 1 H). MS (DCl/NH 3 ) m/z= 374 (M+H)*; Anal. Calcd. for 25 C 21

H

22

N

4 0-2HCl-1.4H20: C, 56.74; H, 6,08; N, 12.60; Found: C, 56.74; H, 6.05; N, 12.44. Example 6 (4)-4-[6-(l1H-indol-5-yl)pyridazin-3-yloxyl- I -azatricyclof 3.3.1.1 3 7 ldecane 30 dihydrochloride The free base of the title compound was prepared from the product of Example IC (31 ng, 0. 11 mmol) and coupled with 5-indolylboronic acid (55 mg, 0.34 nmol; Maybridge) according to Method G. This material was converted to the -68dihydrochloride salt according to Method H: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 2.15 (d, J=12.5 Hz, 2 H), 2.25 - 2.39 (m, 3 H), 2.69 (s, 2 H), 3.55 (d, J= 11 .9 H z, 2 H), 3.61 (s, 2 H), 3.89 (d, J=12.9 Hz, 2 H), 5.52 (t, J=3.2 Hz, I H), 6.70 (d, J=3.1 Hz, I H), 7.46 (d, J=3.1 Hz, 1 H), 7.65 - 7.78 (m, 2 H), 7 99 (d, J=9.5 Hz, I H), 8 30 5 (d, J=2-0 Hz, I H), 8 72 (d, J=9.5 Hz, I H). MS (DCI/NH3) m/z= 347 (M+H)*; Anal. Called. for C 21

H

2 2

N

4 0-2HCI-Hi: C, 57.67; H, 5.99; N, 12.81; Found: C, 57.49; H, 5.94; N, 12.56. Example 7 10 (4s)-4-[6-(1 -Benzothien-5-yl)P ridin-3-yoxyl -azatricyclo[ 3 L.3.1. 1decane bis(trifluoroacetate) Prepared from the product mixture of Example IA (125 mg, 0.470 mmol) and 2-benzo[blthiophen-5-yl-4,4,5,5-tetamethyl-[1,3,2]dioxaborolanie (171 mg, 0.658 mmol; Maybridge) according to Method G. The desired stereoisomer was separated 15 by preparative HPLC [Waters@ XTerra RP18 column, 5s, 30x100 mm, flow rate 40 mL/minute, 5-50% gradient of acetonitrile in 0.1% aq. TFA) to afford the title compound: 'H NMR (300 MHz, nethanol-D 4 ) 8 ppm 1.98 (d, J=1 2.5 Hz, 2 H), 2.23 (s, 1 H), 2.42 (d, J=13.6 Hz, 2 H), 2.69 (s, 2 H), 3.60 (s, 2 H), 3 73 (s, 4 H), 5.70 (s, 1 H), 7-39 (d, J=9.5 Hz, 1 H), 7.50 (d, .=5.4 Hz, 1 H), 7.68 (d, J=5.4 Hz, 1 H), 7.95 20 8.02 (n, I H), 8.03 - 8 11 (m, I H), 8.21 (d, J=9.5 H z, I H), 8.45 (s, I H). MS (DCI/NH 3 ) m/z= 364 (M+H)*; Anal. Called. for C 2 1

H

2 jN 3 0S-1.4C2HF302: C, 54.65; H, 4.32; N, 8.03 Found: C, 54.61; H, 4.09; N, 8,04 Example 8 25 (4r)-4-[ 6 -(I-Benzothien-5-yl)pridazin3loxyl- -azatricycj o3..1 3 7 decane bis(trifluoroacetate) Separation of the stereoisomers in Example 7 by preparative HPLC provided the title compound: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 2.12 - 2.34 (m, 5 H), 2.67 (s, 2 H), 3.51 (d, J=12.2 Hz, 2 H), 3.59 (s, 2 H), 3.88 (d, J=12.5 Hz, 2 H), 5.61 (t, 30 J=3.4 Hz, 1 H), 7.38 (d, J=9.2 Hz, I H), 7.50 (d, J=5.1 Hz, I H), 7.67 (d, J=5.4 Hz, I H), 7.96 - 8. 01 (m, I H), 8.04 - 8.09 (m, I H), 8 21 (d, J=9.5 Hz, I H), 8.44 (d, J=1 4 Hz, I H). MS (DCI/NH 3 ) m/z= 364 (M+H); Anal Calcd. for

C

2 1

H

2 jN 3 0S-1 1C 2

HF

3 0 2 0.25H 2 0: C, 56.47; H, 4.62; N, 8.52; Found: C, 56.56; H, -69- 4.33; N, 8.54. Example 9 (4r)-4-(5-Bromopyridin-2-yloxy)- -azatricycloF 3

.

3 . 1ldecane p-toluenesulfolate 5 Example 9A I -Azaadamantan- 4 -ol N-borane complex. A solution of 1-azaadamantan- 4 -one (29 g, 190 mmol; see Becker, D. P; Flynn, D. L.. Synthesis 1992, 1080) in anhydrous tetrahydrofuran (200 mL) was 10 chilled in an ice-water bath and treated with borane-THF complex (1.0 M in THF; 200 mL, 200 mmol; Aldrich), added dropwise. After stiring for 30 minutes, the mixture was diluted with methanol (1000 mL) and calefily treated with sodium borohydride (8.8 g, 230 mmol; Aldrich), keeping the internal temperature about 5-7 *C. The mixture was stirred for 2 hours, and then the ice bath was removed and 15 stirring was continued for 4 hours. The volatile components were removed on the rotary evaporator and the residue was dissolved in chloroform (-500 mL) and washed with saturated aqueous sodium carbonate. The aqueous layer was extracted with chloroform and the organic phases were dried over magnesium sulfate and filtered The resulting material was purified by flash chromatography (Analogix 400 g 65x220 20 mm silica gel column, 5-95% gradient of ethyl acetate in hexanes over 50 minutes) to afford an inseparable 3.7:1.0 mixture of isomers [according to integration of 'H NMR signals (chlorofonn-D) at 63.96 (t, major) and 63.82 (t, minor)] (33 g, 200 mmol; 100% yield). The product spot can be visualized on the TLC plate (silica gel) using KMnO4 stain. 25 Example 9B (4)-4-(4-Chlorobenzovloxv)-l-azatricvclo(3.

3 .1.1 3 ldecane N-borane complex Example 9C (4r)-4-(4-Chlorobenzoyloxy)-1 -azatricyclof 3.3.1.1 3 1decane N-borane complex 30 A solution of the product of Example 9A (28 g, 170 mmol; 3.2:1.0 mixture of diastereomers), 4-chlorobenzoic acid (28.0 g, 179 mmol; Aldrich), and 4 dimethylaminopyridine (4.2 g, 34 mmol; Aldrich) in dichloromethane (700 iL) was chilled to 0 *C and treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC; 42 0 g, 219 mmol; Aldrich).. After 1 hour, the mixture was -70warmed to room temperature and stirred overnight. The solution was washed quickly with I M HCl (200 mL) followed by saturated sodium bicarbonate, dried over magnesium sulfate and filtered. The resulting material was purified in ~ 5 g batches by flash chromatography (Analogix 400 g 65x220 mm silica gel column, 5-55% 5 gradient of ethyl acetate in hexanes over 45 minutes). Example 9B (4s) stereoisoner: TLC RI=0.49 (silica gel, 3:1 hexanes-EtOAc). 'H NMR (300 MHz, chloroform-D) 8 ppm 1.76 (d, .=12.5 Hz, 2 H), 2.06 (s, 1 H), 2.16 2.33 (in, 4 H), 3.12 - 3.32 (m, 6 H), 5.26 (t, J=3.2 Hz, 1 H), 7 45 (dt, J=8.7, 2.4, 2.1 Hz, 2 H), 8.00 (dt, J=8.7, 2.4, 2.1 Hz, 2 H). MS (DCINH 3 ) m/z= 321/323 (M+H)*. 10 Anal. Called. for Ci 6

H

2 ,BCINO2: C, 62.88; H, 6.93; N, 4.58. Found: C, 63,00; H, 6.80; N, 4.50. Example 9C (4r) stereoisomer: TLC Rf=0.34 (silica gel, .3:1 hexanes-EtOAC). 'H NMR (300 MHz, chloroform-D) 6 ppm 1.84 - 2.11 (m, 5 H), 2.24 (s, 2 H), 3.03 (d, J=12.5 Hz, 2 H), 3.14 (s, 2 H), 3.46 (d, J=13.2 Hz, 2 H), 5.16 (t, J=3.2 Hz, I H), 7.39 15 - 7.51 (i, 2 H), 7.89 - 8.05 (m, 2 H). MS (DCI/NH 3 ) m/z= 321/323 (M+H)*. Anal. Called. for C1 6

H

2 iBCINO2: C, 62.88; H, 6.93; N, 4.58; Found: C, 62.83; H, 6.95; N, 4.53. Example 9D 20 (4r)-4-( 1-Azatricyclo 3 .3.1.1 ldecan-4-ol) N-borane complex A suspension of the product of Example 9C (10.0 g, 32.7 mmol) in tetrahydrofuran (20 mL) was treated with 5 M sodium hydroxide (20 mL) and the mixture was warmed to 50 "C for 4 hours. The mixture was diluted with chloroform and washed with water, and the aqueous phase was reextracted with additional 25 chloroform. The product was purified by flash chromatography (Analogix 80 g 40x1 70 mm silica gel column, 10-95% gradient of ethyl acetate in hexanes) to afford the product: 'H NMR (300 MHz, methanol-D4) 8 ppm 0.82 - 2.02 (br m, 3 H), 1.76 (d, J=11 9 Hz, 2 H), 1.83 - 1.99 (m, 6 H), 2 81 (d, J=12 2 Hz, 2 H), 3.00 (s, 2 H), 3.37 (d, J=12.9 Hz, 2 H), 3.82 (s, I H). MS (DCI/NH3) m/z= 183 (M+H)*. 30 Example 9E 4 r)4(5-Boopidin2loxy)-l-azatcclo 3

.

3 . .

3 7 Idecane N-borane complex Prepared from the product of Example 9D (500 mg, 2.99 nmol) and 2-chlioro -71- 5-bromopyridine (115 g, 5.99 mmol; Aldrich) according to Method B to provide material, which was carried on without additional purification: MS (DCI/NH3) m/z= 309/311 (M-BH 3 +H)*. 5 Example 9F {4r)-4-(5-Bromopyridin-2-loxy)- -azatricyclo3 .3.1.1 3 1 ldecane Prepared from the product of Example 9E (732 mg, 2.11 mmol) according to Method C to afford the title compound: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.73 (s, I H), 1.95 - 2.07 (in, 4 H), 2.11 - 2.22 (in, 2 H), 2.96 (d, J=12.9 Hz, 2 H), 3 13 10 (s, 2 H), 3.45 (d, J=12.9 Hz, 2 H), 5.28 (t, J=3.2 Hz, 1 H), 6.80 (d, J=8.8 Hz, I H), 7.78 (dd, J=8.8, 2.7 Hz, I H), 8.17 (d, J=2.7 Hz, I H). MS (DCI/NH 3 ) m/z= 309/311 (M+H)*. Example 9G 15 (4r)-44-(5-Bromopyridin-2-yoxy- -azatricyclo{3.3.1.lfLdecane p-toluenesulfonate Prepared from the product of Example 9F (70 mg, 0.23 mnol) according to Method H: ' H NMR (300 MHz, methanol-D4) 8 ppm 2.02 - 2.14 (in, 2 H), 2.16 2.26 (in, 3 H), 2 36 (s, 3 H), 2.49 (s, 2 H), 3.44 (d, J=11 9 H z, 2 H), 3.55 (s, 2 H), 3.79 (d, J=12-2 Hz, 2 H), 5.31 (t, J=3.6 Hz, 1 1-I), 6.85 (dd, .=8.8, 0.7 Hz, I H), 7.19 - 7.26 20 (m, 2 H), 7.70 (ddd, J=8.3, 1.9, 1.7 Hz, 2 H), 7.84 (dd, J=8.6, 2.5 Hz, 1 H), 8.21 (dd, J=2,7, 0.7 Hz, I H). MS (DCI/NH 3 ) m/z= 309/311 (M+H)*. Anal. Calcd. for C14H1 7 BrN 2 O C 7 H803S: C 52.39, H 5-23, N 5.82; Found: C 52.29, H 5.17, N 5.73 Example 10 25 (4s)-4-(5-Phenylpyridin-2-yloxy)-1 -azatricyclo[3.3.1.1 V 1decane p-toluenesulfoniate Example 1OA (4s)-4-(I-Azatricyclo[3.3.1.13 3 ldecan-4-ol) N-borane complex A suspension of the product of Example 9B (25.0 g, 81.8 mmol) in 30 tetrahydrofuran (50 mL) was treated with 5 M sodium hydroxide (50 mL). After I hour, the mixture was warmed to 50 "C for 3 hours Most of the solvent was removed on the rotary evaporator, and the residue was purified by flash chromatography (Analogix 220 g 65x 120 mm silica gel column, 5-95% gradient of ethyl acetate in -72hexanes) to afford the product: 'H NMR (300 MHz, methanol-D 4 ) S ppm 0.87 - 2 09 (br n, 3 H; BH 3 ), 1 59 (d, J=12.5 Hz, 2 H), 1 78- 1.98 (n, 2 H), 222 (d,J=12.5 Hz, 2 H), 2.97 - 3.18 (m, 6 H), 3.96 (t, J=3.4 Hz, I H). MS (DCI/NH 3 ) m/z= 183 (M+H)*. 5 Example IOB (4s) -4-( 1-Azatricyclo{ 3 .3.1.1 ldecan-4-ol) A solution of the product of Example IOA (1.00 g, 6. 00 mmol) in acetone (30 mL) was chilled to 0 'C and treated with 3 N HCI (10 mL). After 10 minutes, the ice bath was removed and the mixture was stined for 4 hours. The solution was 10 concentrated to dryness on the rotary evaporator and azeotroped with methanol (3x) The resulting white solid was suspended in EtOAc (25 mL), cooled to 0 *C, and anhydrous ammonia was bubbled into the mixture for about I minute. After stirring for an additional 15 minutes, the mixture was filtered, rinsed with EtOAc, and concentrated to afford the product: 'H NMR (300 MHz, chloroform-D) S ppm 1,51 15 1.84 (in, 5 H), 2.26 (d, J=1 1.9 Hz, 2 H), 2.36 (s, I H), 2.99 (d, J=12.9 Hz, 2 H), 3.09 (s, 2 H), 3.25 (d, J=13.6 Hz, 2 H), 4.00 (s, 1 H). MS (ESI) m/z= 154 (M+H)* Example 10C (4s)-4-(5-Bromopyridin-2-lox )-1--azatricyclo[3.3.1.1 '1Ldecane 20 Prepared from the hydrochloride salt of the product of Example 1OB (220 mg, 1.16 mniol) and 2,5-dibromopyridine (550 mg, 2.30 mmol; Aldrich) using excess potassium tert-butoxide in THF (2.4 mL, 2.4 mmol; 1.0 M; Aldrich) according to Method B: MS (DCI/NH3) m/z= 309/311 (M+H)*. 25 Example I OD (4s)- 4 -(5-Phenylpyridin-2-yloxy) -- azatricyclo[ 3 .3.1.1 Jdecane p-toluenesulfonate The free base of the title compound was prepared from the product of Example 10C (45 mg, 0.14 mmol) and phenylboronic acid (25 mg, 0.20 mmol) according to Method F, and converted to the p-toluenesulfonate salt using the 30 procedure of Method H: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 1 94 (d, J=13.2 Hz, 2 H), 2.20 (s, I H), 2.36 (s, 5 H), 2.41 (s, I H), 2-57 (s, 2 H), 3.58 (s, 2 H), 3.70 (s, 4 H), 5.47 (t, J=3.4 Hz, I H), 7.09 (d, J=8.5 Hz, 1 H), 7 22 (d, J=7.8 Hz, 2 H), 7.30 7.41 (m, I H), 7.42 - 7.51 (m, 2 H), 7.56 - 7-63 (m, 2 H), 7.67 - 7.75 (in, 2 H), 8.07 -73- (dd, J=86, 2.5 Hz, I H), 8.40 (d, J=2.4 Hz, i-H) MS (DCI/NH 3 ) m/z= 307 (M+H)+; Anal. Calcd. for C 20

H

22

N

2 0-1 3C 7

H

8 0 3 S 0.5H 2 0: C, 64.81; H, 6.24; N, 5.19 Found: C, 64.77; H, 6 30; N, 5,15. 5 Example I1 (4r)- 4-(5-Phenylpyridin-2-yloxy)--l-azatricyclof3.3.1.1 ldecane ptoluenesulfonate Example l IA 10 (4)-4-(5-Phenylpvridin-2-ylox)- -azatricyclo 3 .3.1.1 3 'ldecane Prepared from the product of Example 9F (496 mg, 1.60 mmol) and phenylboronic acid (480 mg, 3.1 mmol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.75 (s, I H), 2.00 - 2.25 (m, 6 H), 2.98 (d, J=1 2,9 Hz, 2 H), 3.15 (s, 2 H), 3.51 (d, J=12 9 Hz, 2 H), 5.33 (s, I H), 6.90 - 6.96 (m, I H), 15 7.30 - 7.38 (m, I H), 7.40 - 7.48 (m, 2 H), 7.54 - 7.61 (m, 2 H), 7.94 (dd, J=8.6, 2.5 Hz, I H), 8.35 (d, J=2.4 Hz, 1 H). MS (EST) ilz= 307 (M+H)*. Example 1 1B

(

4 r)--4-(5-Pheniylpyidin-2-yloxy)-- -azatricyclo[3.3.1.1 3 ]decane -touenesulfonate 20 Prepared from the product of Example 11 A (277 ing, 0.904 mmol) according to Method H: 'H NMR (.300 MHz, methanol-D 4 ) S ppm 2.07 - 2.19 (n, 2 H), 2.20 2.31 (m, 3 H), 2 36 (s, 5 H), 2.56 (s, 2 H), 3.49 (d, J=12.5 Hz, 2 H), 3.57 (s, 2 H), 3 85 (d, J=12.2 Hz, 2 H), 5.38 (t, J=3.4 Hz, I H), 7.16 (d, J=8.5 Hz, I H), 7.23 (d, J=8.1 Hz, 3 H), 7.34 - 7.42 (m, 1 H), 7 43 - 7.52 (m, 2 H), 7.58 - 7.64 (m, 2 H), 7.66 - 7.74 25 (m-, 3 H), 8.14 (dd,.J=8,8, 2 7 Hz, 1 H), 8.45 (d, J=2.4 Hz, 1 H). MS (DCI/NH3) i/z= 307 (M+H)*; Anal. Calcd. for C 20

H

22

N

2 OC7H8O3S: C, 67.76; H, 6.32; N, 5,85; Found: C, 67.70; H, 6 39; N, 5-74 Example 12 30 {4s)-4-[5-(1H-Indol-5--l)pyrdin-2-yloxyl- -azatricyclo[3.3.1.l 3 ldecane Prepared from the product of Example 1OC (45 mg, 0.14 mmol) and 5 indolylboronic acid (33 mg, 0.204 mmol; Maybridge) according to Method G: MS (DCI/NH 3 ) nl/z= 346 (M+H)+. -74- Example 13 (4r)-4-f5-( H--Indol-5-yl)pyrdin-2-ylo xy -- azatricyclo{3.3.1.1 3 ldecane Prepared from the product of Example 9F (45 mg, 0.14 mmol) and 5 5 indolylboronic acid (33 mg, 0.204 mmol; Maybridge) according to Method E: 'H NMR (300 MHz, CHCl 3 ) 5 ppm 1.76 - 1.86 (m, 2 H), 2..26 (s, 2 H), 2.39 (d, J= 1.5 Hz, 2 H), 3.26 - 3-44 (m, 5 H), 5.37 (t, J=3 2 Hz, I H), 6.61 (t, J=2.5 Hz, I H), 6.85 (d, J=8.5 Hz, I H), 7.25 - 7 30 (in, 1 H), 7.31 - 7.41 (m, I H), 7.48 (d, J=8.5 Hz, 1 H), 7.77 (s, I H), 7.86 (dd, J=8 5, 2.7 Hz, 1 H) MS (DCI/NH 3 ) m/z= 346 (M+H)*; Anal. 10 Calcd. for C 2 2

H

22

N

3 01 .6H 2 0: C, 70.79; H, 6-80; N, 11.26; Found: C, 70.78; H, 6.44; N, 10.91. Example 14 15 (4r-4 in-2-yloxyk1-azatricyclof 3.3.1.13 3 decane r toluenesulfonate Example 14A (4r)-4-[5-(Benzothien-5-yl)pyridin-2-yloxyl-1-azatricyclo 3.3.1.1 "ldecane 20 Prepared fiom the product of Example 9F (45 mg, 0.14 mmol) and 2 benzo[b)thiophen-5-yl-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (53 mg, 0.204 mmol; Maybridge), according to Method E: MS (DCI/NH 3 ) m/z= 363 (M+H)+. Example 14B 25 (4r)-4-[5-( -Benzothien-5-yllPYridin-2-yloxYl- -azatricyclo[ 3.3.1.1]decane p toluenesulfonate Prepared from the product of Example 14A (50 mg, 0.14 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.94 (d, I= 2.9 Hz, 2 H), 2.20 (s, 1 H), 2.34 - 2.46 (i, 5 H), 2 58 (s, 2 H), 3.58 (s, 2 H), 3.69 (s, 4 H), 5.48 (t, J=3.1 30 Hz, I H), 7.00 (dd, J=8,5, 0.7 Hz, I H), 7 22 (d, J=8.1 Hz, 2 H), 7.44 (dd, J=5.6, 0,8 Hz, 1 H), 7.57 (dd, J=8.5, 1.4 Hz, 1 H), 7.62 (d, J=5.4 Hz, I H), 7.70 (d, J=8.1 Hz, 2 H), 7.98 (d, J=8.5 Hz, I H), 8.03 - 8.10 (m, 2 H), 8.44 (dd,J=2.5, 0.8 Hz, I H). MS

(DCI/NH

3 ) n/z= 363 (M+H)*. Anal. Calcd. for C 22

H

22 N2OS-C7HsO3S: C, 65.14; H, 5.66; N, 5.24; Found: C, 64.78; H, 5.26; N, 5.18 -75- Example 15 {_4s)-4-(6-Cloropyridin-3-yloxy)-I-azatricyclo(3.3.1.1 1decane p-toluenesulfonate 5 Example 15A (4s)-4-(6-Chloropyridin-3-yloxy-I -azatricyclo 3 .3.1 .1 3 7 ldecane N-borane complex A mixture of the product of Example 10A (1.00 g, 5.99 mmol), 2-chloro-5 iodopyridine (1.44 g, 6.01 mmol; Aldrich), copper(l) iodide (110 mg, 0.60 rnmol; Aldrich), o-phenanthroline (220 mg, 1.2 mmol; Aldrich), and cesium carbonate (3.9 g, 10 12 mmol; Aldrich) in toluene (6 mL) was heated to 110 "C with vigorous stirring for 3 days. The black mixture was cooled to room temperature, diluted with dichloromethane, and filtered through diatomaceous earth. The crude material was purified by flash chromatography (Analogix 34 g silica gel column, 5-60% gradient of ethyl acetate in hexanes) to afford the title compound: 'H NMR (300 MHz, 15 methanol-D4) 8 ppm 1.65 - 1.75 (m, 2 H), 1.96 (s, 1 H), 2,16 - 2.27 (ma, 4 H), 3.14 (s, 2 H), 3.16 - 3.27 (m, 4 H), 4.76 (t, J=3.1 Hz, I H), 7.36 (dd, J=8.8, 0.7 Hz, I H), 7.52 (dd, J=8.8, 3.1 Hz, I H), 8.12 (dd, J=3.1, 0.7 Hz, I H). MS (DCI/NH3) m/z= 279/281 (M+H)*. 20 Example 15B {4s)4-(6-Chloropydin-3-loxy-I-azatricyclo[ 3 .3.1.1 3 1decane Prepared from the product of Example 15A (210 mg, 0.60 mmol) according to Method C: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.67 (s, I H), 1.83 (d, J=12.9 Hz, 2 H), 2.04 (s, 2 H), 2.31 (d, J=12.2 Hz, 2 H), 3.08 - 3.18 (m, 4 H), 3.22 - 3-27 (in, 25 2 H), 4.75 (t, J=3.2 Hz, I H), 7 35 (dd, J=8.8, 0.7 Hz, I H), 7 50 (dd, J=8.8, 3.1 Hz, I H), 8.10 (d, J=3.1 Hz, 1 H). MS (DCI/NH 3 ) m/z= 265/267 (M+H)*. Example 15C (4s)-4-(6-Chloropyridinl-3-yloxy)- -azatricyclo{3 .3.1.1 decane p-toluenesulfonate 30 Prepared from the product of Example 15B (40 mg, 0.15 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.90 (d, .1=13.2 Hz, 2 H), 2.18 (s, 1 H), 2,30 - 2.41 (m, 5 H), 2.46 (s, 2 H), 3.56 (s, 2 H), 3.57 - 3.74 (m, 4 H), 4.88 (t, J=3.4 Hz, 1 H), 7.20 - 7.25 (in, 2 H), 7,39 (d, J=8.8 Hz, 1 1-1), 7.55 (dd, J=8.8, 3.1 Hz, -76- 1 H), 7.70 (dt, J=8.1, 1.9 Hz, 2 1-1), 8.17 (dd, J=3.1, 0 7 Hz, I H). MS (DCI/NH 3 ) m/z= 265/267 (M+H)*. Anal. Calcd. for C1 4

H,

7 ClN 2 0-C7Hs03S-0 05H 2 0: C, 57.61; H, 5.78; N, 6.40; Found: C, 57.23; H, 5.71; N, 6.34. 5 Example 16 (4s) -4-(6-Nitror Vidin-3-yloxy)-I-azatriccloI33..1.1 3 ldecane hydrochloride Example 16A (4s)-4-(6-Nitropyrdin-3-yloxy)-l -azatricyclof 33.1.1 3 decane N-borane complex 10 Prepared from the product of Example 10A (419 g, 2.51 mmol) and 5-fluoro 2-nitropyridine (420 mg, 2 9 mmol; see US Patent Appl 20040209886) according to Method A: 'H NMR (300 MHz, chloroform-D) 6 ppm 1.68 - 1.78 (n, 2 H), 2.07 (s, 1 H), 2.20 - 2.35 (m, 4 H), 3.19 - 3 34 (m, 6 H), 4.74 (t, J=3.4 Hz, I H), 7.42 (dd, J=9.0, 2,9 Hz, I H), 8.26 - 8.31 (mn, 2 H). MS (DCI/NH 3 ) m/z= 290 (M+H)*. 15 Example 16B 4s)-4(6-Nitropr -- azatricyclo[ 3 .3.1.1 ldecane hydrochloride Prepared from the product of Example 16A (599 mg, 2 07 mmol) according to Method C. The product precipitated from the reaction mixture, so it was collected by 20 filtration and dried to afford the title compound: 'H NMR (300 MHz, methanol-D 4 ) 6 ppm 1.95 (d, J=12-.5 Hz, 2 H), 2.21 (s, 1 H), 2.38 (d, J= 13.6 Hz, 2 H), 2.53 (s, 2 H), 3.59 (s, 2 H), 3.61 - 3.79 (m, 4 H), 5.11 (t, J=3.4 Hz, I H), 7.80 (dd, J=9.2, 2.7 Hz, 1 H), 8.31 - 8.38 (m, 2 H). MS (+ESI) m/z= 276 (M+H)+ 25 Example 17 (4s)-4-(6-Aminopyridin-3-yloxy)-1-azatricyclo[3.3.1 .1 3 ldecane dihydrochlride Example 17A (4s)-4-(6-Aminopyridin-3-yloxy)-1-azatricyclofL33..1L 3 'ecane 30 A solution of the product of Example 16B (380 mg, 1.2 mmol) in THF-MeOH (10 mL, 1:1) was treated with Raney nickel (401 mg, 6.83 mmol) under an atmosphere of hydrogen (60 psi), and the mixture was warmed to 50 'C for I hour. After removing the catalyst by filtration, the product was purified by preparative -77- HPL.C [Waters@ XTerra RP18 column, 5 y., 30x 100 mm, flow rate 40 mL/minutes, 5 95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 nm). Fractions containing the desired compound were pooled, concentrated under vacuum, 5 diluted with methanol, and filtered to afford the title compound: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.66 (s, 1 H), 1.80 (d, J=12.5 Hz, 2 H), 1.99 (s, 2 H), 2.28 - 2.39 (in, 2 H), 3.01 - 3.12 (in, 4 H), 3.24 (ddd, J=14 1, 2.4, 2.2 Hz, 2 H), 4.45 (t, J=3 2 Hz, I H), 6.57 (dd, J=9.2, 0 7 Hz, I H), 7.27 (dd, J=9.0, 2.9 Hz, I H), 7.67 (dd, J=3.1, 0.7 Hz, I H), MS (+ESI) m/z= 246 (M+H)*. 10 Example 17B (4s)-4-(6--Aminopyridin-3-.loxyl]-azatric clo3.

3 .1.1 3 7 ]decane dihydrochloride Prepared from the product of Example 17A (81 mg, 0.33 mmol) and HC dioxane (160 pL, 0.66 mmol; Aldrich, 4.0 M) according to Method H: 'H NMR (300 15 MHz, methanol-D4) 8 ppm 1.92 (d, J=1 2.2 Hz, 2 H), 2.19 (s, 1 1-1), 2 34 (d, J=13 2 Hz, 2 H), 2.46 (s, 2 H), 3.56 (s, 2 H), 3.58 - 3.74 (in, 4 H), 4.77 (t, J=3.2 Hz, I H), 7.04 (dd, J=9.5, 0.7 Hz, I H), 7.73 (dd, J=3.1, 0.7 Hz, I H), 7.89 (dd, J=9,5, 2.7 Hz, I H). MS (+ESI) m/z= 246 (M+H)*. Anal. Called. for CWH1 9

N

3 0 2HC-0 5H20: C, 51.38; H, 6.78; N, 12.84; Found: C, 51,06; H, 6.47; N, 12 68 20 Example 18 (4r)-4-(6-Nitropyridin-3-yloxy)-I-azatIicVclo[ 3.31. ldecane p-toluenesulfonate Example 18A 25 (4r)-4-(6-Nitropyridin-3-vloxy)--azatricycLoL 3 .3.1.1 decade N-borane complex Prepared from the product of Example 9D (500 g, 2.99 mmol) and 5-fluoro-2 nitropyridine (500 ng, 3.5 mmol; see US Patent Appl. 20040209886) according to Method A: 'H NMR (300 MHz, chloToformn-D) 8 ppm 1.84 - 1.95 (rn, 2 H), 2.01 2 13 (m, 3 H), 2.30 (s, 2 H), 3.00 (d, J=12.5 Hz, 2 H), 3 15 (s, 2 H), 3.48 (d, J=13.6 30 Hz, 2 H), 4 60 (t, J=3 2 Hz, I H), 7.43 (dd, J=8,8, 3 1 Hz, I H), 8.24 - 8.30 (in, 2 H). MS (DCI/NH 3 ) m/z= 290 (M+H)'. Example 18B -78- (4r)-4-(6-Nitropyridin-3-yloxy)- I -azatricyclof 3 .3.1 .1 3

.

7 ldecane Prepared from the product of Example 18A (599 mg, 2-07 mmol) according to Method C: 'H NMR (300 MHz, methanol-D4): 8 ppm 1-76 (s, I H), 2.00 - 2.13 (m, 4 H), 2.16 - 2.28 (n, 2 H), 2.99 (d, J=12.9 Hz, 2 1-1), 3,15 (s, 2 H), 3.48 (d, J=12.9 Hz, 2 5 H), 4.96 (t, J=3.2 Hz, 1 H), 7.70 (dd, J=9.0, 2.9 Hz, I H), 8.25 - 8.36 (m, 2 H). MS (+ESI) m/z= 276 (M+H)*. Example 18C (4r ?-4-(6-Nitropyridin-3-y1oxy) 1 -azatricyclo 3.3.1.1 ldecane p-toluenesulfonate 10 Prepared from the product of Example 18B (25 ig, 0.091 mmol) and p toluenesulfonic acid monohydrate (17 mg, 0.091 mmol; Aldfich) according to Method H: '1-1 NMR (300 MHz, methanol-D4) S ppm 2.07 - 2.30 (m, 5 H), 2.36 (s, 3 H), 2.51 (s, 2 H), 3.47 (d, J=1 1.9 Hz, 2 H), 3.56 (s, 2 H), 3.83 (d, J=12.5 Hz, 2 H), 5.01 (t, J=3.4 Hz, I H), 7.23 (d, J=8.1 Hz, 2 H), 7.70 (d, J=8.1 Hz, 2 H), 7.79 (dd, J=9.0, 2.9 15 Hz, I H), 8.31 - 8.37 (m, 2 H). MS (+ESI) m/z= 276 (M+H)*. Anal. Calcd. for C1 4 HI7N 3

O

3

.C

7

HBO

3 S-0.9H20: C, 54.39; H, 5 83; N, 9.06; Found: C, 54.32; H, 5.87; N, 8.97. Example 19 20 (4r).4-(6-Aminopyridin-3-yloxy)-I -azatricyclo[3.3.1.1 V decane dihydrochloride Example 19A (4r)-4-(6-Aminopyidin-3-yloxy)-1--azatricyclo[3.

3 1

.

3 7 ]dcane A solution of the product of Example 18B (322 mg, 117 mmol) in THF 25 MeOH (10 nL, 1:1) was treated with Raney nickel (400 mg, 6 82 mmol) under an atmosphere of hydrogen (60 psi), and the mixture was warmed to 50 *C for I hours. After removing the catalyst by filtration, the product was purified by preparative HPLC [Waters@ XTerra RPI 8 column, 5 pi, 30x 100 mm, flow rate 40 mL/minute 5 95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, 30 adjusted to pH 10 with ammonium hydroxide), with UV detection at 254 mn]. Fractions containing the desired compound were pooled, concentrated under vacuum, diluted with methanol, and filtered to afford the title compound: 'H NMR (300 MHz, methanol-D4) S ppm 1.71 (s, I H), 1.89 - 2.01 (in, 4 H), 2.10 - 2.20 (in, 2 H), 2,93 -79- (dd,J=12.5, 1.0 Hz, 2 H), 3.11 (s, 2 H), 3.49 (d,J=12.9 Hz, 2 H), 4.45 (t,J=3.4 Hz, I H), 6 57 (dd, J=8.8, 0.7 Hz, I H), 7.26 (dd, J=9.0, 2.9 Hz, I H), 7.65 (dd, J=3.1, 0.7 Hz, I H). MS (+ESI) m/z- 246 (M+H)*. 5 Example 19B (e4r)-4-(6-Aninopyridin- 3 -vloxy)-1-azatricyclo[ 3 .3.1.1 ]decane dihydrochloride Prepared from the product of Example 19A (50 mg, 0.20 mnmol) and HCl dioxane (100 pL, 0.41 mmol; Aldrich, 4.0 M) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 2.00 - 2.12 (m, 2 H), 2-16 - 2.29 (m, 3 H), 2.46 (s, 2 1), 10 3.45 (d, J=12.2 Hz, 2 H), 3.55 (s, 2 H), 3.81 (d, J=1 2.2 Hz, 2 H), 4.64 (t, J=3.4 Hz, 1 H), 7.03 (dd, J=9.5, 0.7 Hz, I H), 7.72 (d, J=2.7 Hz, I H), 7.89 (dd, J 9.7, 2.9 Hz, 1 H). MS (+ESI) m/z= 246 (M+H)*. Anal. Calcd. for C1 4 H ,eN 3 0-2HCl-1.1H20: C, 49 74; H, 6.92; N, 12.43; Found: C, 49.57; H, 6.75; N, 12.37. 15 Example 20 (4s)- 4 -(5-Broinothiazol-2-yloxv)- I -azatricclo[ 3.3.1.1.-ldecane toluenesulfonate Example 20A (4s)-4-(5-Bromothiazol-2-yloxy)-1 -azatricyclo[ 3

.

3 .1.1 decadee N-borane complex 20 Prepared from the product of Example I0A (1.67 g, 10.0 mmol) and 2,5 dibromothiazole (2.90 g, 11.9 mmol; Aldrich) according to Method A: 'H NMR (300 MIz, chloroform-D) 8 ppm 1.69 (d, J=12.2 Hz, 2 H), 2.01 (s, I H), 2 19 (d, J=12.9 Hz, 2 H), 2.39 (s, 2 H), 3 13 - 3.25 (m, 6 H), 5.19 (t, J=34 Hz, 1 H), 7.03 (s, 1 H). MS (DCI/NHI3) m/z= 329/331 (M+H) 4 . 25 Example 20B (4s)-4-(5-Bromothiazol-2-ylox y)-I-azatricyclo 3.3.1 . 1decane Prepared from the product of Example 20A (3.1 g, 9.4 nmmol) according to Method C: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 1,68 (s, 1 H), 1.87 (d, .J=11.5 30 Hz, 2 H), 2.10 - 2.31 (m, 4 H), 3.04 - 3.17 (m, 6 11), 5.22 (t, J=3.4 Hz, I H), 7.11 (s, 1 H) Example 20C -80- (4s)-4-(5-Bromothiazol-2-yloxY)- I -azatticyclof 3.3.1.1 7 decane p-toluenesulfonate Prepared from the product of Example 20B (80 mg, 0.25 mmol) according to Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.94 (d, J=13.2 Hz, 2 H), 2.18 (s, 2 H), 2.28 (d, J=13 2 Hz, 2 H), 2.37 (s, 3 H), 2.61 (s, 2 H), 3.56 (s, 2 H), 3.57 5 3.74 (m, 4 H), 5.37 (t, J=3.2 Hz, I H), 7.15 (s, 1 H), 7-23 (d,.1=8.I Hz, 2 H), 770 (d, J=8 I Hz, 2 H). Anal. Calcd. for C1 2 HisBrN 2 OS - C 7

H

8 0 3 S -0.5 H 2 0: C, 45 97; H, 4.87; N, 5.64; Found: C, 45 64; H, 4.63; N, 5 57. Example 21 10 (4s)-4-(Thiazol-2-yloxy)-I-azatricyclo[3.3.1.1 3 '1decane p-toluenesulfonate Example 21A (4s)-4-(Thiazo-2-yloxy)- -azatricyclo[ 3

.

3 .1.1 33 ldecane A solution of the product of Example 20B (93 mg, 0.30 mmol) in ethanol (3 15 ml.) was treated with 10% Pd/C (10 mg; Aldrich) under a hydrogen balloon with vigorous stirring for 7 hours. The mixture was filtered to remove the catalyst, rinsing with methanol. The compound was purified by preparative HPLC [Waters@ XTerra RP18 5 yk column, 30x 100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with 20 ammonium hydroxide) over 22 minutes, with UV detection at 254 nm]. Fractions containing the desired product were pooled and concentrated under vacuum to afford the title compound: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.68 (s, I H), 1.87 (d, J= 11.9 Hz, 2 H), 2.18 (s, 2 H), 2.27 (d, J=12.9 Hz, 2 H), 3 04 - 3.17 (m, 6 H), 5.16 (t, J=3 4 Hz, I H), 6.88 (d, J=3.7 Hz, I H), 7.12 (d, J=3-7 Hz, I H). MS (DCI/NH3) 25 m/z= 237 (M+H)'. Example 21B (4s)-4-(Thiazol-2-yloxy- -azatricyclo( 3

.

3 . 1.11decane p-toluenesulfonate Prepared from the product of Example 21A (30 mg, 0.13 mmol) according to 30 Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.94 (d,J=13..2 Hz, 2H), 2.18 (s, I H), 2.31 (d,J=13.6 Hz, 2 H), 2.37 (s, 3 H), 261 (s, 2 H), 3.56 (s, 2 H), 3.58 3.74 (m, 4 H), 5.33 (t, J=3.4 Hz, I H), 6 94 (d,,J=3 7 Hz, 2 H), 7.15 (d, J=4.1 Hz, I H), 7.23 (d, J=7 8 Hz, 2 H), 7 71 (d, J=8.5 Hz, 2 H). MS (DCINIi3) m/z= 237 -81- (M+H)*'; Anal- Calcd. for C1 2 H 6N2OS-C7HS03S: C, 55.86; H, 5.92; N, 6.86; Found: C, 55.48; H, 5.95; N, 6.84 Example 22 5 (4s)-4-(5-Phenylthiazol-2-yloxy)-l-azatricyclo[ 3 .3. 1.1l 3 7 decane p-toluenesulfonate Example 22A (4s)-4-(5-Phenylthiaol-2-yloxy)- -azatricyclo[3.3.1.1 3 decane Prepared from the product of Example 20B (100 mg, 0.317 mmol) and 10 phenylboronic acid (80 ing, 0.66 minmol; Aldrich) according to Method E: 'H NMR (300 MI-lz, methanol-D4) 8 ppm 1 70 (s, I H), 1.89 (d, J= 1.9 Hz, 2 H), 2.18 - 2.35 (in, 4 H), 3.09 - 3.19 (in, 4 H), 5.22 (t, J=3.4 Hz, 1 H), 725 - 7.32 (in, 1 H), 7.34 7.42 (m, 3 H), 7 47 - 7 53 (in, 2 H). MS (DCI/NH 3 ) m/z= 313 (M+H)+ 15 Example 22B (4s)-4-(5-Phenylthiazoo-2-yloxy)-1-azacyco[_3.3.1 .1 3 ,1ldecane p-toluenesulfonate Prepared from the product of Example 22A (85 mg, 0.27 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) & ppm 1.96 (d, J=13.2 Hz, 2 H), 2.20 (s, 1 H), 2.28 - 2.39 (in, 5 H), 2.66 (s, 2 H), 3.58 (s, 2 H), 3.60 - 3 76 (in, 4 H), 5.38 (t, 20 J=3.2 Hz, 1 H), 7.23 (d, J=7 8 Hz, 2 H), 7.27 - 7.34 (in, 1 H), 7.35 - 7.42 (i, 2 H), 7.44 (s, I H), 7.48 - 7.54 (in, 2 H). MS (DCI/NH3) m/z= 313 (M+H)*. Anal. Calcd, for C,8H 2 oN2OS-C 7 HBO3S: C, 61.96; H, 5.82; N, 5.78; Found: C, 61.71; H, 5.74; N, 5.71. 25 Example 23 (4s)-4-[5-(4-Methoxyphenyl)-thiazol-2-vloxyl-1-azatricyclof3.3.1.1 1decane p toluenesulfonate Example 23A 30 (4s)-4- zol-2-yloxyl-1-azatricyclo[ 3

.

3 .1.1 3 7 ldecane Prepared from the product of Example 20B (100 nig, 0.317 mmol) and 4 methoxyphenylboronic acid (100 mg, 0.66 inmol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.69 (s, 1 H), 1.89 (d, J=11.9 Hz, 2 H), -82- 2 21 (s, 2 H), 2.29 (d, J=12.9 Hz, 2 H), 3.08 - 3.17 (m, 4 H), 3.26 - 3.29 (m, 2 H), 3 81 (s, 3 H), 5 18 (t, J=3.4 Hz, I H), 6.91 - 6.97 (m, 2 H), 7.26 (s, I H), 7.42 (ddd, J=9 3, 2.7, 2 5 Hz, 2 H) MS (DCI/NH 3 ) n/z= 343 (M+H)*, 5 Example 23B (4s)-4-[5-(4-Methoxyphenyl)-thiazol-2-ylOxyl-1 -azatricycloF3.3.1.1 3

,

7 decane p toluenesulfonate Prepared from the product of Example 23A (87 mg, 0.25 mmol) according to Method H-: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.95 (d, J=12.9 Hz, 2 H), 2.19 10 (s, I H), 2.32 (d, J=13.6 Hz, 2 H), 2.36 (s, 3 H), 2.64 (s, 2 H), 3.57 (s, 2 H), 3.59 3.76 (m, 4 H), 3.81 (s, 3 H), 5.34 (t, J=3.4 Hz, I H), 6.90 - 6.99 (m, 2 H), 7.23 (d, J=8.5 Hz, 2 H), 7.29 (s, I H), 7.39 - 7.47 (m, 2 H), 7.71 (d, J=8.1 Hz, 2 H). MS (ESI) m/z= 343 (M+H)*. Anal. Calcd. for CjHn 2

N

2 0 2 S C7HeO3S: C, 60.68; H, 5.88; N, 5.44; Found: C, 60.57; H, 5-87; N, 5.37. 15 Example 24 (4s)-4-[5-( 3-Chloropheniyl)-thiazol-2-yloxyl-l-azatricyclo[ 3 .3.1.I decade p toluenesulfonate 20 Example 24A (4s)-4-[5-( 3 -Chliorophenyl)-thiazol-2-yloxyl-1-azatricyclo[3.3.1.1 3 'tdecane Prepared from the product of Example 20B (100 mg, 0.317 mmol) and 3 chlorophenylboronic acid (100 mg, 0.66 mmol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) S ppm 1.69 (s, I H), 1.89 (d, J=12.5 Hz, 2 H), 2.18 25 2.35 (m, 4 H), 3.08 - 3.18 (m, 4 H), 3.26 - 3.29 (m, 2 H), 5.24 (t, J=3.2 Hz, I H), 7.29 (dt, J=8.1, 1.6 Hz, I H), 7.36 (t, J=7.8 Hz, I H), 7.43 (ddd,.J=7.6, 1.5, 14 Hz, 1 H), 7.48 (s, I H), 7.54 (t, J=1.7 Hz, I H) MS (ESI) m/z= 347/349 (M+H)* Example 24B 30 (4s)-4-[5-(3-Chlorophenyll-thiazol-2-yloxyl-1-azatricyclo[ 3 .3.1 .ldecane p toluenesul fonate Prepared from the product of Example 24A (96 ing, 0.28 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.96 (d, .J=13.2 Hz, 2 H), 2.20 -83- (s, I H), 2..27 - 2.39 (In, 5 H), 2.66 (s, 2 H), 3 58 (s, 2 H), 3.61 - 3 76 (i, 4 H), 5.40 (t, J=3.2 Hz, I H), 7.23 (d, J=8.5 Hz, 2 H), 7.31 (dt, J=7.8, 1 7 Hz, I H), 7.37 (t, J=7.5 Hz, 1 H), 7.44 (dt, J=7.5, 1.7 Hz, 1 H), 7.51 (s, I H), 7.55 (t, J=1.9 Hz, I H), 7.67 7.75 (m, 2 H). MS (ESI) m/z= 347/349 (M+H)*. Anal. Calcd.. for 5 C 8

H,

9

CIN

2 OS C 7 HsO 3 S-0.2H20: C, 57 45; H, 5 28; N, 5.36; Found: C, 57.13; H, 5.31; N, 5.10. Example 25 (4s)-4-[5-(3-Chloro-4-miethoxyphenyl)-thiazol-2-yloxyl-1 10 azatricyclo[3.3.1.1 V ]decane p-toluenesulfonate Example 25A {4s)-4-[5-(3-Chloro-4-methioxyphienyl)-thiiazol-2-yloxyl-1 azatricyclo[ 3

.

3 .1. 1 Ldecane 15 Prepared from the product of Example 20B (100 mg, 0.317 mmol) and 3 chloro-4-methoxyphlenyl-boronic acid (120 ig, 0.63 imol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D 4 ) S ppm 1.70 (s, I H), 1.89 (d,.J=l 1.9 Hz, 2 H), 2.17 - 2.35 (n, 4 H), 3.09 - 3.18 (n, 4 H), 3.26 - 3.30 (mn, 2 H), 3.90 (s, 3 11), 5.21 (t, J=3.4 Hz, I H), 7.09 (d, J=8.8 Hz, I H), 7.32 (s, 1 H), 7.40 (dd, J=8.5, 2.4 20 Hz, 1 H), 7.53 (d, J=2.4 Hz, I H). MS (ESI) m/z= 377/379 (M+H)*. Example 25B as--4-15-(-Chloro-4-met azatricyclo{ 3 .3.1 .13 7 1decane p-toluenesulfonate 25 Prepared from the product of Example 25A (105 ig, 0.278 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) S ppm 1.96 (d, J=13.2 Hz, 2 H), 2.20 (s, I H), 2.32 (d, J=1 2.9 Hz, 2 H), 2.36 (s, 3 H), 2.65 (s, 2 H), 3.58 (s, 2 H), 3.60 - 3.76 (m1, 4 H), 3.91 (s, 3 H), 5.37 (t, J=3.2 Hz, I H), 7.10 (d, J=8.8 Hz, 1 H), 7.23 (d, J=8.1 Hz, 2 H), 7.35 (s, I H), 7.41 (dd, J=8.5, 2.4 Hz, I H), 7.54 (d, J=2.4 Hz, 1 H), 30 7.71 (d, J=8.1 Hz, 2 H). MS (ESI) n/z= 377/379 (M+H)+. Aial. Caled. for Cj9H 2 1ClN 2 OS-C7HsO3S-0.2H 2 0: C, 56.50; H, 5.36; N, 5 07; Found: C, 56.15; H, 5.40; N, 5-02 -84- Example 26 (4s)-4-[ -(4-Fluorophen-tliiazol-2-yloxy--azatricyclo..3..1 l 3 decale

_

toluenesulfonate The free base was prepared from the product of Example 20B (75 mg, 0.24 5 mmol) and 4-fluorophenyl-boronic acid (73 mg, 0.46 mmol; Aldrich) according to Method E, and then converted to the salt by the procedure of Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.91 - 2.01 (m, 2 H), 2.19 (s, 1 H), 2.32 (d, J=13.5 Hz, 2 H), 2,36 (s, 3 H), 2.64 (s, 2 H), 3.52 - 3.77 (m, 6H) 5.38 (s, 1 H), 7 14 (d, J=24.1 Hz, 2 H), 7.37 - 7.40 (m, 1 H), 7.48 - 7.58 (m, 2 H), 7.70 (d, J=8.1 Hz, 2 H). 10 MS (DCI/NH3) m/z= 331. Anal. Calcd. for C 18

H,

9

)FN

2

OS-C

7 HO3S: C, 59.74; H, 5.41; N, 5.57; Found: C, 53.36; H, 5.13; N, 5.50. Example 27 (4s -4-[5-(3,5-Difluorophenyl -thiazol-2- 3.3.1.1 decane p 15 toluenesulfonate The free base was prepared from the product of Example 20B (75 ig, 0.24 mmol) and coupled with 3,5-difluorophenyl-boroniic acid (75 mg, 0.46 mmol; Aldrich) according to Method E, and then converted to the salt by the procedure of Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1,96 (d, J=15.2 Hz, 2 H), 2.18 20 (s, 1 H), 2.32 (d, J=14.9 Hz, 2 H), 2.36 (s, 3 H), 2.63 (s, 2 H), 3.49 - 3.76 (m, 6 H), 5.41 (s, I H), 6.79 - 6.97 (m, 1 H), 7.15 - 7.19 (m, 2 H), 7-21 - 7.24 (in, 2 H), 7.58 (s, I H), 7.71 (m, 2 H). MS (DCI/NH 3 ) m/z= 349- Anal. Calcd. for CIsHIsF2N 2 OS-C7HSSO3: C, 57.68; H, 5.03; N, 5.38; Found: C, 55 49; H, 5 17; N, 5.14 25 Example 28 (4s)-4-[5-(1H-Indol-5lthiazo2loxyl- -azatricyclo 3 .3.1.1 3 7 decane toluenesulfonate 30 Example 28A (4s)-4-[5-(1H-Indol-5-I)-thiazol-2-yloxyl-1-azatric yclol 3 .1 3 7 lecae Prepared from the product of Example 20B (110 mg, 0 349 nimol) and 5 indolylboronic acid (140 ng, 0.72 minol; Frontier) according to Method E: MS -85-

(DCI/NH

3 ) m/z= 352 Example 28B (4s)-4-[5-(1H-Indol-5-yl)-thiazol-2-yloxyl-1-azatricyclo[3.

3 .1.1 3

,

7 ldecane p toluenesul fonate 5 Prepared from the product of Example 28A (72 mg, 0.20 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.96 (d, J=13.6 Hz, 2 H), 2.20 (s, i H), 2.29 - 2.38 (n, 5 H), 2-65 (s, 2 H), 3.59 - 3.75 (in, 6 H), 5.34 (t, J=3-2 H z, I H), 6.46 (d,.J=3.4 Hz, I H), 7.19 - 7.32 (m, 5 H), 7.40 (d, J=8.5 Hz, I H), 7.65 - 7.74 (in, 3 H). MS (DCI/NH 3 ) m/z= 352 (M+H)*; Anal Calcd for 10 C 20

H

2

IN

3 0S-C 7 H3O 3 S-0,25H20: C, 61.40; H, 5.63; N, 7.96 Found: C, 61.36; H, 5.64; N, 7.86. Example 29 {4s)-4-[5-(H-Indol-5-yl)-thiazol-2-3.11 3 7 decane--oxide 15 A solution of the product of Example 28A (105 ing, 0.30 mmol) in methanol (4 mL) was treated with 3-chloroperbenzoic acid (mCPBA; 70-75%; 71.0 mg, 0.30 minol; Aldrich) and stirred at ambient temperature for 4 hours.. The resulting material was purified by preparative HPLC [Waters@ XTerra RP18 column, 5 s, 30x100 mm, flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous 20 ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the title compound: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.70 - 2.02 (in, 2 H), 2.10 - 2.29 (in, I H), 2.29 - 2.47 (in, 1 H), 2.58 - 2.78 (in, 2 H), .3.57-3.67 (i, 5 H), 5.32 (t, J=3.3 Hz, I H), 6.46 (d, J=3.0 Hz, I H), 7.26 (d, J=3.3 Hz, I H), 7.27 - 7 31 (in, 2 H), 7.36 - 7-42 (in, 1 H), 7-66 (d, .J=1.3 Hz, I H). MS (DCI/NH 3 ) rn/z= 368 (M+H)*. 25 Example 30 (4s)-5-4-[2-(1 -Azatricyclo[3.3. 1.13,1decan-4-yloxy)thiazol-5-yll-indolin- 2 -one Prepared from the product of Example 20B (200 mg, 0 63 mmol) and 5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-indolin- 2 -one (260 mg, 1.0 mmol; see 30 US Patent Appl. 20050245531) according to Method E: 'H NMR (300 MHz, nethanol-D4) 5 ppm 1.52 - 1.79 (m, I H), 1.80 - 2.00 (in, 2 H), 2.07 - 2.43 (in, 4 H), 3-00 - 3.20 (in, 5 H), 3.35 (s, 2 H), 5 20 (t, J=3.2 Hz, I H), 6.90 (d, J=81 Hz, 1 H), 7.30 (s, I H), 7.35 (dd, J=8.1, 2.0 Hz, I H), 7.43 (d,.J=1.7 Hz, 1 H). MS (DCL/NH 3 ) -86m/z= 368 (M+H)+. Example 31 (4s)-5-4-[2-(1-Azatricyclo[ 3.3..1 adccan. 1.oxide-4-v1oV1iaZOl5Vll-ifldolin 2 5 one A solution of the product of Example 30 (100 mg, 0.27 mmol) in methanol (4 mL) was treated with 3-chloroperbenzoic acid (mCPBA; 70-75%; 71.0 mg, 0.30 mmol; Aldrich) and stirred at ambient temperature for 4 hours. The resulting material was purified by preparative HPLC (Waters@ XTerra RP18 column, 5 t, 30x 100 mm, 10 flow rate 40 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide] to afford the title compound: 'H NMR (300 MHz, methanol-D4) 8 ppm 1 71 - 1.94 (n, 2 H), 2.07 - 2.26 (i, 2 H), 2.29 - 2.45 (in, I H), 2.58 - 2 80 (in, 2 H), 3.44 - 3.75 (i, 8 H), 5.34 (t, J=3.2 Hz, 1 H), 6.90 (d, J=8-1 Hz, I H), 7.32 (s, 1 H), 7.35 (dd, J=8.1, 1.7 Hz, 1 15 H), 7.43 (d, J=1 .3 Hz, I H). MS (DCIfNH 3 ) m/z= 384 (M+H)+. Example 32 (45)-4-f5-(2-Trifluoromethyl-IH-indol-5-yl)-thiazol- 2 -yloxyl- 1 azatricyclof3.3.1.1 37 ldecane p-toluenesulfonate 20 The free base of the title compound was prepared from the product of Example 20B (100 mg, 0.30 imol) and 5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2 yl)-2-(trifluoromethyl)-1H-indole (197 mg, 0.64 mmol; US Patent AppI 2005043347) according to Method E, and then converted to the salt according to the procedure of Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.96 (d, .=12.2 Hz, 2 H), 2.13 25 (s, I H), 2.32 (s, 2 H), 2.36 (s, 3 H), 2.60 (s, 2 H), 3 48 - 3.71 (in, 6 H), 5.35 (s, 1 H), 6.91 (s, I H), 7.22 (d, J=7.8 Hz, 2 H), 7.34 - 7.39 (in, I H), 7.48 (s, 2 H), 7.71 (d, J=8.1 Hz, 2 H), 7.78 (s, 1 H). MS (DCI/NH 3 ) m/z- 420 (M+H)+. Anal. Calcd. for

C

2

,H

2 0

F

3

N

3

OS-C

7 H803S: C, 56.84; H, 4.77; N, 7. 10; Found: C, 55.39; H, 4.57; N, 7.02 30 Example 33 (4s)-4-f5-(lH-Indol-4-yl)-thiazol-2-yloxyl-l-azatricyclof 3

.

3 .1.1 3 'ldecane p toluenesulfonate -87- The free base of the title compound was prepared from the product of Example 20B (110 mg, 0.349 mmol) and indole-4-boronic acid (120 mg, 0.72 minol; Frontier) according to Method E, and then converted to the salt according to the procedure of Method H: 1H NMR (300 MHz, methanol-D4) S ppm 1.97 (d, J=12.2 5 Hz, 2 H), 2.21 (s, I H), 228 - 2.44 (m, 5 H), 2.68 (s, 2 H), 3.58 (s, 2 H), 3.62 - 3.77 (m, 4 H), 5.39 (s, I H), 6.71 (dd, J=3.4, 1.0 Hz, 1 H), 7.09 - 7.19 (m, 2 H), 7.23 (d, J=7.8 Hz, 2 H), 7.34 (d, J=3.1 Hz, I H), 7,37 - 7.43 (m, 1 H), 7.47 (s, 1 H), 7 71 (d, .1=8.1 Hz, 2 H). MS (DCI/NH 3 ) m/z= 352 (M+H)*; Anal Caled. for

C

20

H

2 1

N

3 0S-C 7

H

8 0 3 S-0.2H20: C, 61 50; H, 5 62; N, 7.97 Found: C, 61.48; H, 5.59; 10 N, 7.91. Example 34 (4s)-4-f 5-( 1H-Indol-6-yl)-thiazol-2-yloxyl-1-azatricyclof 3 .3.1.1 ldecane p toluenesul fonate 15 The free base of the title compound was prepared from the product of Example 20B (110 ing, 0.349 mmol) and indole-6-boronic acid (120 mg, 0.72 nmol; Frontier) according to Method E, and then converted to the salt according to the procedure of Method H: 'H NMR (300 MHz, methanol-D4) S ppm 1.96 (d, J=14.2 Hz, 2 H), 2.21 (s, I H), 2.28 - 2.46 (m, 5 H), 2.66 (s, 2 H), 3.58 (s, 2 H), 3.61 - 3.77 20 (in, 4 11), 5 35 (t, J=3.2 Hz, I H), 6-45 (dd, J=3.1, 1.0 Hz, 1 H), 7.12 - 7 25 (m, 3 H), 7.27 (d, J=3.1 Hz, I H), 7.35 (s, 1 H), 7.45 - 7.51 (m, I H), 7.55 (d, J=8.1 Hz, 1 H), 771 (d, J=8 1 Hz, 2 H). MS (DC1/NH 3 ) m/z= .352 (M+H)*. Anal. Calcd. for

C

2 0H 2

IN

3

OS-C

7 HsO3SO .2H 2 0: C, 61.50; H, 5.62; N, 7.97; Found: C, 61 48; H, 5.59; N, 7 91 25 Example 35

(

4 s)-4-[5--(lH-Indo-3-yl)-thiazoL-2-yloxyl-I-azatricyclo[3.

3 .1.1 ldecane p toluenesulfonate 30 Example 35A (4s)-4-[5-( 1 -Benzenesulfonyl-1 H-indol-3-yl)1-thiazol-2-yloxy-I azatricyclo[3.3. 1. lEldecane Prepared from the product of Example 20B (110 mg, 0.349 mnol) and I -88phenyisulfonyl-l H-indol-3-ylboronic acid (220 mg, 0.72 mmol; Aldrich) according to Method E: MS (DCI/NH 3 ) n/z= 492 (M+H)+ Example 35B 5 (4s)-4-[5-(1H-Indol-3-yl)-thiazol-2-yloxyl- I -azatricyclof 3 .3.1.1ldecane p toluenesulfonate A solution of the product of Example 35A (150 mg, 0.31 mmol) and potassium carbonate (100 mg, 0.76 mmol) in methanol (3 mL) was heated to reflux for 90 minutes. After cooling, the solvent was removed, the residue was dissolved in 10 water, and the mixture was extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried (Na 2 SO4), filtered and concentrated to afford the free base of the title compound. This material was converted to the salt according to Method H: '1H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.96 (d, J=12.9 Hz, 2 H), 2.21 (s, I H), 2 30 - 2.40 (i, 5 H), 2 66 (s, 2 H), 3.58 (s, 2 H), 3.62 - 3.79 (m, 4 H), 5.35 (t, 15 J=3.6 Hz, I H), 7.08 - 7.25 (in, 4 H), 7.29 (s, I H), 7.39 - 7.44 (in, I H), 7.45 (s, I H), 7.67 - 7 77 (in, 3 H), MS (DCI/NH 3 ) m/z=352 (M+H)*; Anal. Calcd. for

C

20

H

2 1

N

3 0S'C 7

H

8 03S: C, 61.93; H, 5.58; N, 8.02; Found: C, 61.56; H, 5.20; N, 7.77. 20 Example 36 (4s)-4-[5-(Pyridin-4-yl )-thiazol-2-yloxyl--azatricyclo[ 3 .3.1 .1 3

,

7 ldecane bis(p toluenesulfonate) Example 36A 25 riazol-2-yloxyl- -azatricyclo[ 3 .3.1.1 3 3 ldecane Prepared from the product of Example 20B (100 mg, 0.317 mmol) and 4 pyridylboronic acid (100 mg, 0.814 mmol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) & ppm 1.70 (s, I H), 1.90 (d, J=1 1.9 Hz, 2 H), 2 19 - 2.34 (n, 4 H), .309 - 3.19 (in, 4 H), 5.31 (t, J=3.2 Hz, 1 H), 7 53 - 7.58 (in, 2 H), 7 78 (s, 1 30 H), 8.46 - 8.52 (m, 2 H). MS (DCI/NH3) in/z=31 4 (M+H)+. Example 36B (4s)-4-[5-(Pyridin-4-yl)-thiazol-2-yloxY-l -azatricyclof3.3.1 .1 3 7 ldecane bis(p -89toluenesulfonate) Prepared from the product of Example 36A (77 mg, 0.24 mmol) and p toluenesulfonic acid monohydrate (93 mg, 0.49 mmol; Aldrich) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.98 (d, J=12.5 Hz, 2 H), 2.22 (s, I H), 5 2.26 - 2.39 (n, 8 H), 2.69 (s, 2 H), 3.59 (s, 2 H), 3.63 - 3.78 (m, 4 H), 5 57 (t, J=3-2 Hz, I H), 7.22 (d, J=8.5 Hz, 4 H), 7.67 - 7.74 (m, 4 H), 8.12 - 8.17 (m, 2 H), 8.25 (s, I H), 8 67 - 8.73 (in, 2 H). MS (ESI) m/z=31 4 (M+H)*. Anal. Called. for C1 7 H19N 3 OS-2C 7 HsO3S-0.2HO: C, 56.29; H, 5.39; N, 6.35; Found: C, 56.03; H, 5.29; N, 6.12. 10 Example 37 (4s)-4-[5-(Furan-2-yl)-thiazol-2-yloxyl-I -azatricyclo 3 .3.1 .11.7 ldecane bis(p toluenesulfonate) The free base of the title compound was prepared from the product of 15 Example 20B (101 mg, 0.32 mmol) and 2-furylboronic acid (53 mg, 0.48 mnol; Aldrich) according to Method E, and then converted to the salt according to the procedure of Method H: 'H NMR (300 MHz, methanol-D4) S ppm 1.96 (d, J=12 5 Hz, 2 1), 2.19 (s, I H), 2.33 (d, J=13 .6 Hz, 2 H), 2.36 (s, 3 H), 2.64 (s, 2 H), 3 52 3.77 (in, 6 H), 5.36 (s, I H), 6 52 (d, J=21.0 Hz, 2 H), 7.22 (d, J=8.1 Hz, 2 H), 7.33 (s, 20 1 H), 7.51 (d, J=1.4 Hz, I H), 7.70 (d, J=8.1 Hz, 2 H). MS (DCI/NH 3 ) mIz= 304 (M+H)*- Anal. Calcd. for C, 6

HI

7

N

2 02S-C 7 H803S: C, 58.21; H, 5.52; N, 5.90; Found: C, 55.59; H, 5.18; N, 5.55 Example 38 25 (4s)-4-[5-(Furan-3-yl)-thiazol- 2 -yloxy-l--azatricyclo[3.3.1.1 3

,

1 ldecane bis(p toluenesulfonate) The free base of the title compound was prepared from the product of Example 20B (101 mg, 0.32 mmol) and 3-furylboronic acid (106 mg, 0.99 mmol; Aldrich) according to Method E, and then converted to the salt according to the 30 procedure of Method H: 'H NMR (300 MHz, methanol-D4) 6 ppm 1.96 (d, J=12.5 -lz, 2 H), 2.19 (s, I H), 2.33 (d, J=13.6 Hz, 2 H), 2 36 (s, 3 H), 2.64 (s, 2 H), 3-52 3.77 (m, 6 H), 5.36 (s, I H), 7.16 (s, I H), 7.23 (d, J=8.1 Hz, 3 H), 7.67 - 7.74 (i, 4 H). MS (DCI/NH 3 ) m/z= 304 (M+H)*. Anal. Calcd. for C 6 H iN 2 O2S C 7 HBO3S: C, -90- 58.21; H, 5.52; N, 5.90; Found: C, 55,77; H, 4.99; N, 5.57. Example 39 (4s)-4-[5-(Thien-3-yi)-thiazol-2-yloxyl- -azatticyclof 3 .3.1.1 ldecane bis(p 5 toluenesulfonate) The free base of the title compound was prepared from the product of Example 20B (110 ig, 0.35 nmol) and 3-thiopheneboronic acid (77 mg, 0.60 nmol; Aldrich) according to Method E, and then converted to the salt according to the procedure of Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.96 (d,J=12 5 10 Hz, 2 H), 2.19 (s, I H), 2.32 (d, J=13.9 Hz, 2 H), 2.36 (s, 3 H), 2.64 (s, 2 H), 3.51 3.78 (m, 6 H), 5.36 (s, 1 H), 7.22 (d, J=8.4 Hz, 2 H), 7,30 (dd, J=5 1, 1.4 Hz, I H), 7.34 (s, I H), 7.42 - 7.52 (m, 2 H), 7.70 (d, J=8.1 Hz, 2 H). MS (DCI/NH 3 ) m/z= 320 (M+H)*. Anal.. Calcd. for C, 6

H

7

N

2

OS

2

-CHBSO

3 : C, 53.74; H, 5.13; N, 8.55; Found: C, 53.51; H, 5.37; N, 10.89. 15 Example 40 (4s)-4-[5-(Pyrazol-4-yl)-thiazol-2-yloxvl-1-azatricyclof3.3.1.1 3

,

7 decane bis(p toluenesulfonate) Prepared from the product of Example 20B (111 mg, 0.315 mmol) and 4 20 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-IH-pyrazole (272 ng, 0.624 mmol; JP 2005232071) according to Method E, followed by deprotection using the procedure or Method L, and salt formation according to Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.96 (d, J=12.5 Hz, 2 H), 2.19 (s, I H), 2.32 (d, J=13.9 Hz, 2 H), 2.36 (s, .3 H), 2.64 (s, 2 H), 3.51 - 3.78 (m, 6 H), 5.36 (s, I H), 7.13 - 7 31 25 (m, 3 H), 7.71 (d, J=8.4 Hz, 2 H), 7 80 (s, 2 H). MS (DCI/NH 3 ) m/z= 304 (M+H)+. Example 41 (4s)-4-(5-Bromo- 1,3,4-thiadiazol-2-yloxy)- I -azatricyclof3.3.1 .1 3

,

7 ldecane p toluenesulfonate 30 Example 41A (4s)-4-(5-Bromo-1,3,4-thiadiazol-2-yloxy)-1-azatricycloi3.3.1.1 Vl]decane N-borane complex -91- Prepared from the product of Example I0A (1 .3 g, 8.0 mmol) and 2,5 dibromo-1,3,4-thiadiazole (2.1 g, 8.8 mrnmol; prepared as described in Yasuda, T.; Imase, T; Sasaki, S.; Yamamoto, T. Macromolecules 2005, 38, 1500) according to Method A: 'H NMR (300 MHz, chloroforn-D) 8 ppm 1.72 (d, J= 1 .9 Hz, 2 H), 2.03 5 (s, I H), 2.17 (d, J=12.9 Hz, 2 H), 2.48 (s, 2 H), 3.15 - 3.26 (m, 6 H), 5.34 (t, J=3-6 Hz, 1 H). Example 41B (4s)-4-(5-Bromo-1,3,4-thiadiazol-2-yloxy)-1-azatricyclof 3

.

3 .1.1 ]decane 10 Prepared from the product of Example 41 A (1.35 g, 4.09 mmol) according to Method C: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.68 (s, I H), 1.84 - 1.95 (m, 2 H), 2.24 (s, 4 H), 3.07 - 3 17 (m, 4 H), 3,25 - 3.29 (m, 2 H), 5.34 (t, J=3 .1 Hz, I H). MS (ESI) m/z= 316/318 (M+H)F. 15 Example 41C (4s)-4-(5-Bromo-1,3,4-thiadiazol-2-yloxv)-1-azatricyclof 3.3.1.1 3

,

7 ldecane p toluenesulfonate Prepared from the product of Example 41 B (80 mg, 0.25 mmol) according to Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.96 (d, J=14.2 Hz, 2 H), 2.19 20 (s, 1 H), 2.30 (d, J=13.9 Hz, 2 H), 236 (s, 3 H), 2.68 (s, 2 H), 3.57 (s, 2 H), 3.59 3.76 (m, 4 H), 5,47 (t, J=3.4 Hz, I H), 7.23 (d, J=7.8 Hz, 2 H), 7.66 - 7 74 (m, 2 H). MS (ES]) m/z= 316/318 (M+H)*. Anal. Calcd. for CIIH1 4 BrN 3 OS-C7HsO3S: C, 44.26; H, 4.54; N, 8.60; Found: C, 44 35; H, 4.58; N, 8.61. 25 Example 42 (4s)- 4 -(1,3,4-Thiadiazol-2-ylox -- 1-azatricyclo[ 3 .3.1.1 ldecane p-tolenesulfonate Example 42A [_4s)-4-(1,3,4-Thiadiazol-2-Yloxy)-l -azatricyclo[3.3.1.1 3 7 ldecane 30 A solution of the product of Example 41B (100 mag, 0.32 mmol) in ethanol (3 mL) was treated with 10% Pd/C (10 mg; Aldrich) under a hydrogen balloon with vigorous stirring for 3 days. Since the reaction did not go to completion, it was filtered to remove the catalyst, rinsed with ethanol, and resubjected to the reaction conditions with fresh Pd/C. After 6 hours, the mixture was filtered and the compound -92was purified by preparative HPLC [Waters@ XTera RP18 5 p column, 30x 100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitTile in buffer (0 1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nm]. Fractions containing the desired product 5 were pooled and concentrated under vacuum to afford the title compound: 'H NMR (300 MHz, methanol-D4) & ppm 1.69 (s, I H), 1.90 (d, J=13.6 Hz, 2 H), 2.20 - 2.33 (m, 4 H), 3.07 - 3.20 (m, 4 H), 5 30 (t, J=2 9 Hz, I H), 8.88 (s, 1 H). MS (DCI/NH 3 ) n/z= 238 (M+H)*. 10 Example 42B (4s)-4-(1,3,4-Thiadiazol-2-yloxV)- -azatricyclo[ 3

.

3 .l. I V 1decane p-toluenesulfonate Prepared from the product of Example 42A (38 mg, 0.16 mmol) according to Method H: ' H NMR (300 MHz, inethanol-D4) 8 ppm 1.96 (d, J=12.5 Hz, 2 H), 2 20 (s, I H), 2.31 (d, .J=13-2 H z, 2 H), 2.37 (s, 3 H), 2 70 (s, 2 H), 3.58 (s, 2 H), 3.61 15 3.77 (in, 4 H), 5.46 (t, .1=3.2 H z, 1 H), 7.23 (d, J=8 5 Hz, 2 H), 7.71 (d, J=8.1 Hz, 2 H), 8.94 (s, I H). MS (DCI/NH 3 ) m/z= 238 (M+H)+. Anal. Calcd. for C,,H1 5

N

3 0S C7HBO3S-0 3H 2 0: C, 52.10; H, 5.73; N, 10.13; Found: C, 51.94; H, 5.69; N, 9.76. 20 Example 43 (4s)-4-(5-Phenyll- 1,3 4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1.17 3 ldecane Example 43A I -Azaadamantan- 4 -ol N-borane complex. 25 A solution of azaadamantan- 4 -one (29 g, 190 mmol, see Becker, D. P.; Flynn, D. L. Synthesis, 1992, 1080) in anhydrous tetrahydrofuran (200 mL) was chilled in an ice-water bath and treated with borane-THF complex (1 0 M in THF; 200 mL, 200 mmol; Aldrich), added dropwise. After stirring for 30 minutes, the reaction mixture was diluted with methanol (1000 mL) and carefully treated with sodium borohydride 30 (8.8 g, 230 mmol; Aldrich), keeping the internal temperature about 5-7 *C. The reaction was stirred for 2 hours, and then the ice bath was removed and stirring was continued for 4 hours. The volatile components were removed on the rotary evaporator and the residue was dissolved in chloroform (-500 mL) and washed with -93saturated aqueous sodium carbonate. The aqueous layer was extracted with chloroform and the organic phases were dried over magnesium sulfate The resulting material was purified by flash chromatography (Analogix 400 g 65x220 mm silica gel column, 5-95% gradient of ethyl acetate in hexanes over 50 minutes) to afford an 5 inseparable 3.7 : 1.0 mixture of isomers [according to integration of 'H NMR signals

(CDC

3 ) at 63.96 (t, major) and 83.82 (t, minor)] The product spot can be visualized on the TLC plate (silica gel) using KMnO 4 stain Example 43B 10 4-Chlorobenzoic acid (4s)-4.-azatricyclo(3_.1.13 7 }dec-4-yl ester N-borane complex and Example 43C 4-Chlorobernzoic acid (4)- 1-azatricyclo[33.1.1 lvdec-4-yl ester N-borane complex. A solution of 1-azaadamantan- 4 -ol N-borane complex (28 g, 170 mmol; 3.2 : 15 1.0 mixture of diastereomers), 4-chlorobenzoic acid (28.0 g, 179 mmol; Aldrich), and 4-dinethylaminopyridine (4.2 g, 34 mmol; Aldrich) in dichloromethale (700 mL) was chilled to 0 'C and treated with N-(3-dimethylaminopropyl)-N' ethylcarbodiimide hydrochloride (42.0 g, 219 mmol; Aldrich). After I hour, the reaction mixture was warmed to room temperature and stirred overnight. The 20 solution was washed quickly with 1 M HC1 (200 mL) followed by saturated sodium bicarbonate, and dried over magnesium sulfate. The resulting material was purified in - 5 g batches by flash chromatography (Analogix 400 g 65x220 mm silica gel column, 5-55% gradient of ethyl acetate in hexanes over 45 minutes).. Example 43B: Major (4s) isomer: TLC Ri=0.49 (silica gel, 3:1 hexanes-EtOAc). 'IH 25 NMR (300 MHz, CDC 3 ) 6 ppm 1.76 (d, J=12.5 Hz, 2 H), 2.06 (s, I H), 2-16 - 2.33 (m, 4 H), 3.12 - 3.32 (m, 6 H), 5..26 (t, J=3.2 Hz, I H), 7.45 (dt, J=8.7, 2 4, 2.1 Hz, 2 H), 8.00 (dt, J=8.7, 2.4, 2.1 Hz, 2 H). MS (DC1/NH3) m/e 321/323 (M+H)*- Anal Calculated for C 16

H

2 BCINO2: C 62.88, H 6 93, N 4.58; Found C 63.00, H 6.80, N 4.50. 30 Example 43C: Minor (4r) isomer: TLC Rf=0.3 4 (silica gel, 3:1 hexanes-EtOAc). 'H NMR (300 MHz, CDC 3 ) 8 ppm 1.84 - 2 11 (m1, 5 H), 2.24 (s, 2 H), 3,03 (d, J=12.5 Hz, 2 H), 3.14 (s, 2 H), 3.46 (d, J=1 3.2 Hz, 2 H), 5 16 (t, J=3.2 Hz, I H), 7 39 - 7 51 (in, 2 H), 7.89 - 8.05 (m, 2 Hf1). MS (DCI/NH 3 ) m/e 321/323 (M+H)*. Anal. Calculated -94for C, 6 HuIBCINO2: C 62.88, H 6.93, N 4.58; Found C 62.83, H 6.95, N 4.53 Example 43D (4s)- 1 -Azatricyclof3.3.1.1 3 7 ldecan-4-ol N-borane complex. 5 A suspension of 4-chlorobenzoic acid (4s)-l -azatricyclo[ 3

.

3 .1.1 3

,

7 )dec-4-yI ester N-borane complex (Example 43B, 25.0 g, 81.8 mmol) in tetrahydrofuran (50 mL) was treated with 5 M sodium hydroxide (50 mL). After 1 hour, the reaction mixture was warmed to 50 *C for 3 hours. Most of the solvent was removed on the rotary evaporator, and the residue was purified by flash chromatography (Analogix 10 220 g 65x120 mm silica gel column, 5-95% gradient of ethyl acetate in hexanes) to afford the title product: 'H NMR (.300 MHz, methanol-d4) 8 ppm 0.87 - 2,09 (br m, 3 H; BH 3 ), 1.59 (d, J=12.5 Hz, 2 H), 1.78 - 1.98 (m, 2 H), 2.22 (d, J=l 2.5 Hz, 2 H), 2.97 - 3.18 (m, 6 H), 3.96 (t, J=3.4 Hz, I H). MS (DCI/NH 3 ) m/e 18.3 (M+H)*. 15 Example 43E 2-Chloro-5-phenyl-[1,3,41thiadiazole A stirred suspension of 2-amino-5-phenyl-[1,3,4)thiadiazole (6 45 g, 36,4 mmol; Aldrich) and copper (230 mg, 3.6 mmol; Aldrich) in hydrochloric acid (36 mL, 12 M) and glacial acetic acid (180 mL) was chilled to 0 "C and treated with a solution 20 of sodium nitrite (2.64 g, 38.2 mmol; Aldrich) in water (12 mL), added dropwise over 40 minutes. After stirring at room temperature for 4 hours, the mixture was poured into ice water. The aqueous solution was extracted with chloroform (.3x), and the combined extracts were washed sequentially with 5% sodium bicarbonate and brine, and dried over sodium sulfate. The crude product was filtered through a short silica 25 gel plug with chloroform to afford the title product: 'H NMR (300 MHz, CDC 3 ) 5 ppm 7,46 - 7.55 (m, 3 H), 7.85 - 7.93 (in, 2 H). MS (DCI/NH 3 ) mle 197/199 (M+H)*. Example 43F (4s)-4-(5-Phenyl-[1,3,41thiadiazol-2-yloxy)-1-azatricyclo[3.3.1 .1 3 7 ldecane N-borane 30 complex A solution of (4s)-1-azatricyclo[ 3 .3.1 1 3 7 ]decan-4-ol N-borane complex (Example 43D, 2.31 g, 13.8 mmol) and 2-chloro-5-phenyl-[1,3,4]thiadiazole (Example 43E, 2.78 g, 14.1 mimol) in anhydrous DMF (20 mL) was chilled to 0 "C -95and treated with sodium hydride (500 ing, 20.8 nimol; Aldrich, 95%). Vigorous bubbling was observed, and the solution turned orange. After 15 minutes, the cooling bath was removed and the reaction was stirred for 4 hours. The reaction mixture was diluted with water and stirred overnight. The resulting precipitate was collected by 5 filtration, washed with water, and dried under vacuum to afford the title product: 'H NMR (300 MHz, CDCl 3 ) S ppm 1.73 (d, J=12.5 Hz, 2 H), 2.04 (s, I H), 2.22 (d, J=13.2 Hz, 2 H), 2.54 (s, 2 H), 3.17 - 3.28 (in, 6 H), 5.38 (t, J=3.6 Hz, I H), 7.42 7 51 (m, 3 H), 7.77 - 7.87 (m, 2 H). MS (+ESI) m/e 328 (M+H)*. 10 Example 43G (4s)-4-(5-Phenyl-[1,3,4lthiadiazol-2-Vloxy)-l-azatricyclo 3 .3.1.1 ldecane

(A

913958.0) A suspension of (4s)-4-(5-phenyl-[1,3,4)thiadiazol-2-yloxy)-l azatricyclo[ 3

.

3 .1.1 3 7 )decane N-borane complex (Example 43F, 580 rg, 1.77 mimol) 15 in acetone (18 mL) was chilled to 0 "C and treated with 3 N HC1 (6 mL). The suspension slowly cleared, and then a precipitate began to fonm. After 20 minutes, the ice bath was removed and the mixture was stirred for 2 hours. The solution was then basified with 5 N NaOH to pH 10, extracted with chloroform (3x), and dried over anhydrous magnesium sulfate. The resulting material was purified by flash 20 chromatography [Analogix 34 g 25 mm silica gel column, 5-50% gradient of ammonium hydroxide-methanol-chloroform (2:20:78) in chloroformn]. It was purified further by preparative HPLC [Waters XTerra RP18 5p column, 30x100 mm, flow rate 40 mL/min, 5-95% gradient of acetonitrile in buffer (0.1 M ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 25 254 nm]. Fractions containing the desired product (center of peak only) were pooled and concentrated to afford the title product: 'H N'MR (300 MHz, methanol-d 4 ) 5 ppm 1.71 (s, 1 H), 1.92 (d, J=12.5 Hz, 2 H), 2.29 (s, 4 H), 3.10 - 3.21 (m, 4 H), 3.30- 3.38 (m, 2 H), 5.35 (t, J=3.1 Hz, 1 H), 7.46 - 7 54 (m, 3 H), 7.80 - 7.89 (m, 2 H). MS (+ESI) m/e 314 (M+H)+. Anal. Calculated for C1 7

H

19 N0 3 S: C 65 15, 1 6.11, N 30 13.41; Found C 64.94, H 6.10, N 13.41 Example 44 -96- (4s)-4-(5-Phenyl-1 3 ,4-thiadiazol-2-lox)-1 -azatricyclof 3 .3.1.1 3 'ldecane-1 -oxide A solution of the product of Example 43B (50 mg, 0 16 mmol) in methanol (3 mL) was chilled to 0 'C and treated with 3-chloroperbenzoic acid (70-75%; 39 mg, 0.16 mmol; Aldrich). Afler 30 minutes the ice bath was removed and stiring was 5 continued ovemight The mixture was concentrated, and the residue was purified by flash chromatography (Analogix 15 g silica gel column, 5-50% gradient of ammonium hydroxide-methanol-chloroform (2:20:78) in chloroform) to afford the title compound: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 1.85 (d, J= 13.2 Hz, 2 H), 2.20 (d, J=12.9 Hz, 2 H), 2.37 (s, 1 H), 2 77 (s, 2 H), 3.50 - 3.59 (m, 4 H), 3.63 - 3.72 10 (m, 2 H), 5.49 (t, J=3.6 Hz, 1 H), 7.48 - 7.55 (m, 3 H), 7.82 - 7.88 (m, 2 H). MS (+ESI) m/z= 330 (M+H) 4 . Example 45 (4r)-4-(5-Phenyl- ,3,4-thiadiazol-2-loxy)-1-azatricyclo[3.3.1.1 Vldecane fumnarate 15 Example 45A (4r)- 4 -(5-Phenyl- 1,3,4-thiadiazol-2-loxy)- 1-azatricclol3.3. 1.1 3 'ldecane N-borane complex Prepared from the product of Example 9D (500 mg, 2.99 imol) and 2-chloro 20 5-phenyl-1,3,4-thiadiazole (600 mg, 3,05 mmol; WO 2003094831) according to Method A: 'H NMR (300 MHz, chloroform-D) 8 ppm 1.87 - 2.08 (m, 5 H), 2.51 (s, 2 H), 3.00 (dd, J=13.4, 1 2 Hz, 2 H), 3.14 (s, 2 H), 3.46 (d, J=13 6 Hz, 2 H), 5.31 (t, J=34 Hz, I H), 7.43 - 7.49 (m, 3 H), 7.80 - 7-85 (m, 2 H). MS (+ESI) m/z= 328

(M+H)

4 . 25 Example 45B (4-)-4-(5-Phenyl-1,3,4-thiadiazol-2-loxy icyclo3.3.1.1ldecane Prepared from the product of Example 45A (960 mg, 2.90 mmol) according to Method C: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.76 (s, I H), 2 06 (d, J=11 .9 30 Hz, 2 H), 2.17 - 2 29 (m, 4 H), 3 04 (d, J=12.9 Hz, 2 H), 3.16 (s, 2 H), 3-45 (d, J=13.6 Hz, 2 H), 5.37 (s, I H), 7.47 - 7.53 (i, 3 H), 7.81 - 7.88 (m, 2 H). MS (DCI/NH3) m/z= 314 (M+H)+ -97- Example 45C (42)-4-(5-Phenyl-1,3.4-thiadiazol-2-yloxy1-azatricycloF 3 .3.1.1 decadee fumarate Prepared from the product of Example 45B (860 mg, 2.74 mmol) and fumaric acid (318 mg, 2.74 mmol; Aldrich) according to Method H: 'H NMR (300 MHz, 5 methanol-D 4 ) S ppm 2.06 - 232 (m, 5 H), 2.70 (s, 2 H), 3.49 (d, J=12.5 Hz, 2 H), 3.56 (s, 2 H), 3.80 (d, J=12.2 Hz, 2 H), 5.42 (t, J=3.4 H z, 1 H), 6.69 (s, 2 H), 7.49 7.55 (in, 3 H), 7.82 - 7.88 (m, 2 H). MS (+ESI) m/z= 314 (M+H)*. Anal. Called for C1 7

HI

9

NO

3 S-C4H404: C, 58 73; H, 5.40; N, 9.78; Found: C, 58.79; H, 5.52; N, 9.70. 10 Example 46 (4s)- -[5-(4-Fluorophenyl)-1,3,4-thiadiazol-2-yloxyl- -azatrcyclo[3.

3 .1.l 3 decan e p-toluenesulfonate Example 46A 1 5 ~~ .3 .4tlhiadiazol-2-yloxl-l -azatricyclo[ 3 .3.1 .1 ldea 15 s)-4-[5-(4-Fluorophenyl-j yclo[3.3.1.1decane N-borane complex Prepared from the product of Example I 0A (254 mg, 1.5 minmol) and 2-bromo 5-(4-fluorophenlyl)-1,3,4-thiadiazole (402 mg, 1.5 minol; WO 2003044020) according to Method A: 'H NMR (300 MHz, chloroforn-D) S ppm 1.26 (s, I H), 1.74 (d, 20 J=12.2 H-z, 2 H), 2.05 (s, I H), 2.22 (d, J= 13.2 Hz, 1 H), 2.54 (s, 2 H), 3.17 - 3.33 (in, 6 1-1), 5.33 - 5.47 (m, 1 H), 7 08 - 7 24 (m, 2 H), 7.76 - 7.96 (m, 2 H). MS (DCL/NH3) m/z= 346 (M+H)*. Example 46B 25 (4s)-4-[5-(4-Fluorophenyl)-1,3,4-thiadiazol-2-yloxyl-azatricyclo[ 3 .3.1.1 decadee p-toluenesulfonate The product of Example 46A (204 mg, 0.59 mmol) was deprotected according to Method C and converted to the p-toluenesulfonate salt by the procedure of Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.99 (d, J=13.6 Hz, 2 H), 2.21 (s, I H), 30 2.32 (s, 2 H), 2.36 (s, 3 H), 2.73 (s, 2 H), 3.52 - 3.81 (m, 6 H), 5 52 (s, I H), 7.19 7.32 (m, 4 H), 7 71 (d, J=8.1 Hz, 2 H), 7.85 - 7.95 (m, 2 H). MS (DCI/NH 3 ) m/z= 332 (M+H). Anal. Calcd. for C1 7

HSFN

3 OS C 7 HgO 3 S: C, 57 24; H, 5.20; N, 8.34; Found: C, 56.08; H, 5.16; N, 8. 31 -98- Example 47 (4r)-4-{5-(4-Fluoropheinyl-1,3,4-thiadiazol-2-vloxl-1-azatricyclo[ 3 .3.1.1 ldecane p-toluenesulfonate 5 Example 47A (4)-4544-Fluorophenyl)-1,3,4-thiadiazol-2-yloxyl-l-azatricyclo[ 3.3.1.1 3 7 ldecane N-borane complex Prepared from the product of Example 9D (203 mg, 1.22 mmol) and 2-bromo 10 5-(4-fluorophenyl)-1,3,4-thiadiazole (316 mg, 1.22 rnmol; see WO 2003044020) according to Method A: 'H NMR (300 MHz, chloroform-D) S ppm 1.70 (s, I H), 1.96 - 2.08 (n, 2 H), 2.12 - 2.23 (in, 4 H), 3.01 (d, .J=12.9 Hz, 2 H), 3.16 (s, 2 H), 3.49 (d, J=13.2 Hz, 2 H), 5.46 (s, 1 H), 7.08 - 7.19 (m, 2 H), 7.75 - 7.87 (in, 2 H). MS (DCI/NH3) m/z= 346 (M+Hi) 4 . 15 Example 47B (4r)-4-5-(4-Fluorophenyl)-1,3,4-thiadiazol-2-yloxy1- azatricyclo[ 3 .3.1.1 ldecane p-toluenesulfonate The product of Example 47A (204 mg, 0.59 mmol) was deprotected according 20 to Method C and converted to the p-toluenesulfonate salt by the procedure of Method H: 'H NMR (300 MHz, methanol-D 4 ) S ppm 2.05 - 2.32 (m, 5 H), 2.36 (s, 3 H), 2.71 (s, 2 H), 3.42 - 3.63 (m, 4 H), 3.81 (d, J=12.5 H z, 2 H), 5.41 (s, I H), 7.18 - 7.32 (m, 4 H), 7,70 (d, .J=8.1 Hz, 2 H), 7.90 (dd, J=8.9, 5.2 Hz, 2 H). MS (DCI/NH3) m/z= 332 (M+H)*. Anal. Calcd. for C 7 Hi 8

FN

3

OS-C

7 HSO3S: C, 57.21; H, 5.20; N, 8 34; 25 Found: C, 55.19; H, 5.40; N, 8.02. Example 48 (4s)-4-[5-(3-Fluorophenyl)-1,3,4-thiadiazol-2-yloxyl-1-azatricyclo( 3

.

3 .1.1 Vldecane p-toluenesul fonate 30 Example 48A 2-Bromo-5-(3-flu1orophenyl-1 ,3,4-thiadiazole A vigorously stirred suspension of copper (II) bromide (1.37 g, 0.615 mmol; -99- Acros) and amyl nitrite (1.20 g, 10.2 mrnol) in acetonitrile (20 mL) was treated with 5-( 3 -fluorophenyl)-1,3,4-thiadiazol-2-ylamine (1 00 g, 0 512 mmol; Aldrich), added in portions. The mixture was stirred overnight, quenched with saturated ammonum chloride, and extracted with ether (2x). The combined organic phases were dried 5 (MgSO4), filtered, concentrated, and the residue was purified by flash chromatography (Analogix 12 g silica gel column, 5-85% gradient of ethyl acetate in hexanes) to afford the title compound: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 7,29 - 7.38 (in, I H), 7.57 (td, J=8.1, 5.8 Hz, I H), 7.71 - 7.79 (in, 2 H). MS (+ESI) m/z= 259/261 (M+H). 10 Example 48B (4s)-4-[5-(3-Fluorophenyl)-1.,3,4-thiadiazol-2-yloxyl-1-azatricclo[ 3 .3.1.1 ldecane N-borane complex Prepared from the product of Example IOA (257 mg, 1 .5 mmol) and the 15 product of Example 48A (398 ig, 1.5 mmol) according to Method A: 'H NMR (300 MHz, chloroform-D) S ppm 1.26 (s, I H), 1 74 (d, J=12.2 Hz, 2 H), 2.05 (s, I H), 2.22 (d, J=13.2 Hz, 1 H), 2.54 (s, 2 H), 3.17 - 3.33 (m, 6 H), 5 33 - 5.47 (m, I H), 7.10 7.25 (m, I H), 7.37 - 7.53 (m, 1 H), 7.54 - 7.70 (m, 2 1-1) MS (DCI/NH3) m/z= 346 (M+H)*. 20 Example 48C {4s)-4-F5-(3-F3uorophenyll- 13,4-thiadiazol-2-yloxyl-azatricyclo[ 3 .3.1.1 ldecane p-toluenesulfonate The product of Example 48B (245 mg, 0.71 mol) was deprotected according 25 to Method C and converted to the p-toluenesulfonate salt by the procedure of Method H: 'H NMR (300 MHz, rnethanol-D 4 ) 5 ppm 1.99 (d, J=13.6 Hz, 2 H), 2.21 (s, 1 H), 2.32 (s, 2 H), 2.36 (s, 3 H), 2.73 (s, 2 H), 3.52 - 3.81 (m, 6 H), 5.52 (s, I H), 7.23 (d, J=8.5 Hz, 2 H), 7.25 - 7.32 (m, I H), 7.49 - 7.58 (m, 1 H), 7,62 - 7.73 (m, 4 H). MS (DCI/NH 3 ) m/z= 332 (M+H)*. Anal. Calcd. for C 17

HBFN

3

OS-C

7 H803S: C, 57.24; H, 30 5.20; N, 8.34; Found: C, 56.97; H, 4.90; N, 8.22. Example 49 (4r-4-[5-f(3-Fluorophenl"lY-1,3,4-thiadiazol-2-yloxyl-l-azatricyclo{3.3.1.1 V ldecane -100p-toluenesul fonate Example 49A {4r-445-(3-Fluorophenl)- 1 ,3.4-thiadiazol-2-vloxyl-1-azatricvclo[ 3 .3.1.1 decane 5 N-borane complex Prepared from the product of Example 9D (203 mg, 1.38 mmol) and the product of Example 48A (398 mg, 1.5 mmol) according to Method A: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.70 (s, I H), 1.96 - 2.08 (m, 2 H), 2.12 - 2.23 (m, 4 H), 3.01 (d, J=12.9 Hz, 2 H), 3.16 (s, 2 H), 3.49 (d, J=13.2 Hz, 2 H), 5.46 (s, I H), 7 08 10 7.19 (m, 2 H), 7.75 - 7.87 (m, 2 H). MS (DCI/NH3) m/z= 346 (M+H) 4 . Example 49B (4r)-4-[5-(3-Fluoropheiyl)-l,3,4-thiadiazol-2-yloxyl-1-azatricyclo(3.3.1.1'l decane p-toluenesulfon ate 15 The product of Example 49A (245 mg, 0.71 mmol) was deprotected according to Method C and converted to the p-toluenesulfonate salt by the procedure of Method H: 1 H NMR (300 MHz, methanol-D4) 8 ppm 2.05 - 2.32 (m, 5 H), 2.36 (s, 3 H), 2.71 (s, 2 H), 3.42 - 3.63 (m, 4 H), 3-81 (d, J=12.5 Hz, 2 H), 5.41 (s, I H), 7.18 - 7 32 (n, 4 H), 7.70 (d, J=8.1 Hz, 2 H), 7 90 (dd, J=8.9, 5.3 Hz, 2 H). MS (DCINH 3 ) m/z= 332 20 (M+H)*. Anal. Calcd. for C 17

HSFN

3 OSC7H803S: C, 57 21; H, 5.20; N, 8.34; Found: C, 55,19; H, 5.40; N, 8.02 Example 50 (4s)-4-[5-(1H-Indol-5-yl)-1_ 3 4-thiadiazo-2-yloxyl-1-azatricyclo 3 .3.1.10 ldecane 25 p-toluenesulfonate Example 50A (4s)-4-[5-(1H-Indol-5-yl)-1,3,4-thiadiazol-2-Vlox -_ -azatric cloF3.

3 . 1.1- 37 ldecane N borane complex 30 Prepared from the product of Example IOA (131 mg, 0.785 mnol) and 2 bromo-5-( I H-indol-5-yl)-1,3,4-thiadiazole (200 mg, 0.714 mmol; see WO 2003044020) according to Method B, with purification by flash chromatography -101- (Analogix 80 g 40x 120 mm silica gel column, 5-95% gradient of ethyl acetate in hexanes) to afford the title compound: 'H NMR (300 MHz, chloroforn-D) 8 ppm 1.73 (d, J=12.5 Hz, 2 H), 2.05 (s, I H), 2.24 (d,.J=12 9 Hz, 2 H), 2 55 (s, 2 H), 3.18 3.27 (i, 6 H), 5.36 (t, J=3 6 Hz, I H), 6-64 (ddd, J=3 4, 2 0, 1.0 Hz, I H), 7.29 (dd, 5 J=3 2, 2.5 Hz, I H), 7.46 (ddd,.I=8.6, 0.8, 0.7 Hz, I H), 7.75 (dd, J=8.5, 1.7 Hz, 1 H), 8.04 - 8.07 (m, I H), 8.35 (s, I H) MS (+ESI) rn/z= 353 (M+H)*. Example 50B (4s).4-[5-(IH-Indol-5-vl)-1,3,4-thiadiazo1-2-vloxVVI -azatricyclo{3.3.1.1 3

'

7 decane 10 p-toluenesulfonate The free base of the title compound was prepared from the product of Example 50A (140 mg, 0 38 mrmol) according to Method D, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 'H NMR (300 MHz, methanol-D4) S ppm 1.99 (d, J=12.5 Hz, 2 H), 2.22 (s, 1 H), 2 29 - 2,40 (m, 5 H), 15 2.73 (s, 2 H), 3.59 (s, 2 H), 3.63 - 3.79 (m, 4 H), 5.47 (t, .1=3.2 Hz, I H), 6.56 (dd, J=3 2, 0.8 Hz, 1 H), 7.19 - 7.27 (i, 2 H), 7.34 (d, J=3.4 Hz, I H), 7.49 (ddd, J=8.6, 0.8, 0 7 Hz, 1 H), 7.63 (dd, J=8.5, 1.7 Hz, 1 H), 7.71 (ddd, J=8.3, 2.0, 1.9 Hz, 2 H), 8.04 (dd, J=1.7, 0.7 Hz, I H).. MS (+ESI) n/z= 353 (M+H)*. Anal. Calcd. for Cl,H2ON 4 OS-C7H8O3S-0 2H 2 0: C, 59.12; H, 5.42; N, 10.61; Found: C, 58.77; H, 20 5.11; N, 10.35. Example 51 (4s)-4-[5-(1H-Indol-6-yl)-1,3,4thiadiaz ricclo[ 3

.

3 .1. 13 3 ldecane p-toluenesulfonate 25 Example 51A (4s)-4-[5-(1H-Indol-6-yl)-1,3,4-thiadiazol-2-yloxy l--azatricyclo[ 3 .3.1.13 3 ldecane Prepared from the product of Example 41B (100 mg, 0.316 mnol) and indole 6-boronic acid (102 mg, 0.632 mmol; Frontier) according to Method F: 'H NMR 30 (300 MHz, methanol-D 4 ) S ppm 1.71 (s, I H), 1.92 (d, J=12.2 Hz, 2 H), 2.26 - 2,37 (i, 5 H), 3.12 - 3.22 (m, 5 H), 5.33 (t, J=3.1 Hz, I H), 6.52 (d,J=3 1 Hz, I H), 7.39 (d, J=3.1 Hz, I H), 7.47 (dd, J=83, 1.5 Hz, I H), 7-64 (d, J=8.1 Hz, I H), 7.87 - 7.

92 (m, I I). MS (+ESI) i/z= 353 (M+H)*. -102- Example 51B (4s)-4-{ 5 -(IH-lndol-6-yI)-1,3,4-thiadiazol-2-yox yl-1--azatricyclof 3 .3.1.1 "ldecane p-toluenesul fonate 5 Prepared from the product of Example 51A (18 mg, 0.052 mmol) according to Method H: 'H NMR (300 MH z, methanol-D 4 ) 8 ppm 1.99 (d, J=12.5 Hz, 2 H), 2.22 (s, I H), 2.30 - 2.41 (m, 5 H), 2.73 (s, 2 H), 3.59 (s, 2 H), 3.64 - 3.78 (m, 4 H), 5 49 (t, J=3.4 Hz, 1 H), 6.53 (dd, J=3.2, 0.8 Hz, 1 H), 7.23 (d, J=7.8 Hz, 2 H), 7.40 (d, J=3 1 Hz, I H), 7.48 (dd, J=8.1, 1.7 Hz, 1 H), 7.65 (d, J=8-5 Hz, I H), 7.71 (ddd, J=8.3, 2.0, 10 1.9 Hz, 2 H), 7.89 - 7.92 (m, 1 H). MS (+ESI) m/z= 353 (M+H)*. Anal. Calcd. for CjqH 2 0N 4 OS'C7HsO3S-L 5H 2 0: C, 56.61; H, 5.66; N, 10.16; Found: C, 56.65; H, 5.49; N, 9.89. Example 52 15 (4s)- 4 - 5-( 1H-Indol-4-yl)-1,3, 4-thiadiazol-2--loxyl.azatricyclo[ 3 .3.1.1 Vldecane p-toluenesulfonate The flee base of the title compound was prepared from the product of Example 41B (190 mg, 0 60 mmol) and indole-4-boronic acid (192 mg, 1.19 minol; Frontier) according to Method F, and converted to the p-toluenesulfonate salt using 20 the procedure of Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.96 (d, J=12.5 Hz, 2 H), 2.19 (s, I H), 2.33 (d, J=13.5 Hz, 2 H), 2.36 (s, 3 H), 2.64 (s, 2 H), 3.52 - 3.77 (m, 6 H), 5.36 (s, I H), 7.04 (d, J=3.0 Hz, I H), 7.17 - 7.27 (n, 3 H), 7.43 (d, J=3 4 Hz, I H), 7.49 (d, J=6.7 Hz, 1 H), 7.58 (d, J=8.1 Hz, 1 H), 7 70 (d, J=8.1 Hz, 2 H). MS (DCIINH3) m/z= 354 (M+H)*. Anal. Calcd. for C, 9 H2ONAOS-C7HS0S: 25 C, 59.92; H, 5.38; N, 10.68; Found: C, 56.90; H, 5.11; N, 10.13. Example 53 (4s)-4-[5-(Benzothien-5-y')l .3.4-thiadiazol-2- 3.7 1decane p-toluenesulfonate 30 The free base of the title compound was prepared from the product of Example 41B (193 mg, 0.60 mrnol) and 2-(benzo[b]thiophen-5-yl)-4,4,5,5 tetramethyl-1,3,2-dioxaborolane (317 ng, 0.74 mmol; Maybridge) according to Method F, and converted to the p-toluenesulfonate salt using the procedure of Method -103- H: 'H NMR (300 MHz, nethanol-D4) 8 ppm 1.96 (d,.J=12..5 Hz, 2 H), 2.19 (s, 1 H), 2.33 (d, J=1-3.6 Hz, 2 H), 2.36 (s, 3 H), 2 64 (s, 2 H), 3,52 - 3.77 (i, 6 H), 5.36 (s, 1 1H), 7 22 (d, J=8 8 Hz, 2 H), 7.49 (d, J=5.4 Hz, I H), 7.67 - 7.75 (m, 3 H), 7 85 (dd, J=8.4, 1.7 Hz, I H), 8.05 (d, J=8.8 Hz, I H), 8.32 (d, J=1.7 Hz, I H). MS (DCI/NH 3 ) 5 m/z= 370 (M--H)*- Anal Calcd. for CjHjiN 3 0S 2

.C

7 H803S: C, 57.65; H, 5.02; N, 7.76; Found: C, 56.45; H, 4.59; N, 7.45. Example 54 (4s)-445-(Pyrazol- 4 -yl)- 1.3 ,4-thiadiazol-2-yloxyl-1 -azatricyclof 3 .3.1 .1 3 ldecane 10 bis(p-tol uenesulfonatel Example 54A (4s)- 4 -[5-( -Trityl-IH-piazol-4-yl)- 1,3,4-thiadiazol-2-yloxyl-1 azatricyclo[3.

3 .1.1l 3 decane 15 Prepared from the product of Example 41B (120 mg, 0.38 mmol) and 4 (4,4,5,5-tetranethyl-1,3,2-dioxaborolan- 2 -yl)-i-trityl- IHJ-pyrazole (335 mg, 0.77 nmol; .JP 2005232071) according to Method F: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.70 (s, I H), 1-96 - 2.08 (m, 2 H), 2.12 - 2.23 (m, 4 H), 3.01 (d, J=12.9 Hz, 2 H), 3-16 (s, 2 H), 3.49 (d, J=13.2 Hz, 2 H), 5 46 (s, I H), 7.16 (dd, J=6.8, 3 0 Hz, 6 20 H), 7.29 - 7.38 (m, 9 H), 7.87 (s, I H), 7.95 (s, I H). MS (DCI/NH 3 ) m/z= 546 (M+H)*. Example 54B (4s)-4-[5-(Pyrazol- 4 -yi)-1.3.4-thiiazol-2-yloxyv l -azatricyclo(3.3.1.1'ldecane 25 bis( -toluenesulfonatel The free base of the title compound was prepared from the product of Example 54A (100 mg, 0.18 mmol) according to Method L, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 'HNMR (300 MHz, methanol-D4) S ppm 1.99 (d, J=13.6 Hz, 2 H), 2.21 (s, I H), 2.32 (s, 2 H), 2.36 (s, 3 30 H), 2.73 (s, 2 H), 3.52 - 3.81 (i, 6 H), 5.52 (s, I H), 7.23 (d, J=8.1 Hz, 2 H), 7.71 (d, J=8- 1 Hz, 2 H), 8.09 (br.s, 2 H). MS (DCI/NH 3 ) m/z= 304 (M+H)*. Anal. Calcd. for C1 4 H7N 5

OS-C

7

H

8

O

3 S: C, 53.03; H, 5.30; N, 14.73; Found: C, 52.48; H, 5.03; N, 14-46. -104- Example 55 (4s)-4-(5-Phenoxy-1,3,4-thiadiazol-2-yloxy)-i-azatricyclof 3 .3.1.1 3

.

7 ldecane p-toluenesul fonate 5 Example 55A 2-Bromo-5 -phenoxy- 1,3 ,4-thiadiazole A solution of 2,5-dibromo-1,3,4-thiadiazole (1.00 g, 4.10 mmol; prepared as described in Yasuda, T.; Inase, T.; Sasaki, S.; Yamamoto, T. Macromolecules 2005, 10 38, 1500) and phenol (188 mg, 2.00 mmol; Aldrich) in anhydrous tetrahydrofuran (4 mL.) was treated with cesium carbonate (2.0 g, 6.0 mmol) and heated to reflux for 5 hours. The mixture was cooled to room temperature, diluted with chloroform, filtered through Celite, and the residue was purified by flash chromatography (Analogix 40x120 mm 80 g silica gel column, chloroform) to afford the title compound: 'H 15 NMR (300 MHz, chloroform-D) 8 ppm 7.28 - 7.35 (m, 3 H), 7.41 - 7.49 (in, 2 H). MS (+ESI) mi/z= 257/259 (M+H), Example 55B (4s)-4-(5-Phenoxy-1,3,4-thiadiazol-2-yloxy)-1-azatricycloi3.3.1.1 ldecane 20 The coupling of the product of Example I0A (100 mg, 0.599 mmol) and the product of Example 55A (180 mg, 0.700 minol) was performed according to Method A, and the resulting product was converted to the title compound using the procedures of Method C followed by using the procedure of Method H: 'H NMR (300 MHz, methanol-D4) S ppm 1.95 (d, J=13.2 Hz, 2 H), 2.18 (s, 1 H), 2.29 (d, J=13.9 Hz, 2 H), 25 2.36 (s, 3 H), 2.66 (s, 2 H), 3.56 (s, 2 H), 3,58 - 3.74 (m, 4 H), 5,41 (t, J=3.4 Hz, I H), 7.19 - 7 26 (in, 2 H), 7.28 - 7,36 (m, 3 H), 7.43 - 7.51 (m, 2 H), 7.68 - 7.73 (m, 2 H). MS (+ESI) m/z= 330 (M+H)*. Anal. Calcd. for C1 7 Hj9N 3 02S-C 7 H03S 0.5H 2 0: C, 56.45; H, 5.53; N, 8.23; Found: C, 56.11; H, 5.38; N, 8.02. 30 Example 56 (4s)-4-(5-tet-BButyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .31 1decane p toluenesulfonate -105- Example 56A {4s)-4-(5-tet-Butyl-1,3,4-thiadiazol-2-vloxY-1 -azatricyclof 3 .3.1 .1 Ildecane

N

borane complex 5 Prepared from the product from Example 10A (515 mig, 3 1 mmrnol) and 2 bromo-5-tert-btyl-1,3,4-thiadiazole (682 mg, 3.1 rmol; see TP 58140084) according to Method A: 'H NMR (300 MHz, methanol-D 4 ) 6 ppm 1.26 (s, 1 H), 1.42 (s, 9H), 1.74 (d, J=12.2 Hz, 2 H), 2.05 (s, I H), 2.22 (d, J=1 3.2 Hz, I H), 2.54 (s, 2 H), 3.17 3.33 (m, 6 H), 5.33 - 5.47 (in, 1I H). MS (DCI/NH 3 ) m/z= 308 (M+H), 10 Example 56B (4s)-4-(5-ert-Butyl-1,3,4-thiadiazol-2-yloxy)-I-azatricyclo 3.3.1.1jldecane p toluenesulfonate The free base of the title compound was prepared from the product of 15 Example 56A (929 mg, 3.02 mmol) according to Method C, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 1.42 (s, 9H) 1.99 (d, J=13.6 Hz, 2 H), 2.21 (s, 1 H), 2.32 (s, 2 H), 2.36 (s, 3 H), 2.73 (s, 2 1), 3.52 - 3.81 (m, 6 H), 5.52 (s, I H), 7.23 (d, J=7.8 Hz, 2 H), 7.70 (d, J=8.1 Hz, 2 H). MS (DCI/NIH3) m/z= 294 (M+H)+. Anal. Calcd. for 20 C 5

H

23

N

3 0S C7H03S: C, 56.75; H, 6,71; N, 9.02; Found: C, 56.62; H, 6.81; N, 8 98 Example 57 (4r)-4-(5-tert-Butyl-1,3,4-thiadiazol-2-ylox) -- azatricyclo[ 3 .3.1.1 3

,

7 1decane p 25 toluenesulfonate Example 57A (4r)-4-(5-tert-Butyl-1.,3,4-thiadiazol-2-vloxy)-1-azatricyclo[3.3.1.1l 3

,

7 decane N borane complex 30 Prepared from the product from Example 9D (200 mg, 1.2 mmol) and 2 bromo-5-ter-t-btyl-1,3,4-thiadiazole (270 ing, 1.2 mmol; see JP 58140084) according to Method A: 'H NMR (300 MH-z, chlorofonn-D) 8 ppm 1.42 (s, 9H), 1.70 (s, I H), -106- 1.96- 2.08 (m, 2 H), 2.12 - 2.23 (i, 4 H), 3.01 (d, J=l2.9 Hz, 2 H), 3.16 (s, 2 H), 3,49 (d, J=13.2 Hz, 2 H), 5.46 (s, I H). MS (DCI/NH) n/z= 308 (M+H)'. Example 57B 5 (4r)- 4 -(5-tert-Butyl-I, 3,4-thiadiazol-2-ylOxY)-1-azatricyclo[ 3 .3.1.1" ldecane p toluenesulfonate The free base of the title compound was prepared from the product of Example 57A (106 ng, 0. 34 minol) according to Method C, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 'H NMR (300 MHz, 10 methanol-D 4 ) 8 ppm 1.42 (s, 9H), 2 05 - 2.32 (in, 5 H), 2.36 (s, 3 H), 2.71 (s, 2 H), 3.42 - 3.63 (in, 4 H), 3.81 (d, J=12.5 Hz, 2 H), 5.41 (s, 1 H), 7.23 (d, J=7.8 Hz, 2 H), 7.70 (d, J=8.1 Hz, 2 H). MS (DCI/NH3) in/z 294 (M+H)*. Anal. Calcd. for

C

15

H

3

N

3 OS CHsO3S: C, 56.75; H, 6.71; N, 9 02; Found: C, 54,04; H, 6.43; N, 8,41. 15 Example 58 (4s-4-(5-Phenl--1,34oxadiazol-2-yloxy)-1 -azatricyclo[3.3.1 .1 3 ldecane p toluenesulfonate 20 Example 58A {4s)-4-(5-PhenIl-1 3,4-oxadiazol-2-yloxy)-1 -azatricyclof 3 .3.1.1 3ldecane N-borane complex Prepared from the product of Example 1OA (100 mg, 0.599 imol) and 2 bromo-5-phenyl-1,3,4-oxadiazole (148 ing, 0.658 mmol; Vachl, P.; Toth, L. M 25 Tetiahedron Lett. 2004,45, 7157) according to Method A, followed by conversion to the free amine using the procedure of Method C: 'H NMR (300 MHz, methanol-D 4 ) 6 ppm 1.71 (s, I H), 1.94 (d, J=13-6 Hz, 2 H), 2.25 - 2.37 (m, 4 H), 3.09 - 3.21 (in, 4 H), 5.25 (t, J=3.2 Hz, 1 H), 7.49 - 7.59 (m, 3 -1), 7.90 - 7.99 (in, 2 H). MS (+ESI) m/z= 298 (M+H) 4 . 30 Example 58B (4s)-4-(5-Phenyl-1,3,4-oxadiazol-2-yloxy)-l-azatricyclo 3 .3.1 .1ldecane p toluenesulfonate -107- Prepared from the product of Example 58A (77 mg, 1.77 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 2.00 (d, J=13.6 Hz, 2 H), 2 23 (s, I H), 2.30 - 2 41 (n, 5 H), 2.73 (s, 2 H), 3.60 (s, 2 H), 3.63 - 3.80 (m, 4 H), 5.36 (t, .=3.4 Hz, 1 H), 7 23 (d, J=7.8 Hz, 2 H), 7.51 - 7.63 (m, 3 H), 7.67 - 7.74 (m, 2 H), 5 7 92 - 7.99 (m, 2 H). MS (+ESI) m/z= 298 (M+H)+. Example 59 (4r)-4-(5-Phenyl-1,3,4oxadiazol-2-ylox y-1-azatricyclo[3.

3 .1.1 3 ldecane p toluenesulfonate 10 Example 59A (4,r)-4-(5-Phenyl-13,4-oxadiazol-2-yloxy)-1-azatricyclog3.3.1.10 )decane N-borane complex Prepared from the product of Example 9D (100 mg, 0.599 nmol) and 2 15 bromo-5-phelnyl-1,3,4-oxadiazole (148 mg, 0.658 mmol; Vachl, P.; Toth, L. M. Tetrahedron Lett. 2004, 45, 7157) according to Method A, followed by conversion to the free amine using the procedure of Method C: 'H NMR (300 MHz, methanol-D 4 ) S ppm 1.76 (s, I H), 2.05 (d, J=11.9 Hz, 2 H), 2.19 - 2.30 (m, 4 H), 3.05 (d,J =12.9 Hz, 2 H), 3.17 (s, 2 H), 3.46 (d, J=13.2 Hz, 2 H), 5 27 (s, I H), 7.49 - 7.59 (m, 3 H), 20 7.91 - 7.97 (n, 2 H). MS (+ESI) m/z= 298 (M+H)*. Example 59B (4,)-4-(5-Phenyl-1,3,4-oxadiazol-2-y.oxy)-3 -azatricyco[.1lIdecanep toluenesulfonate 25 Prepared from the product of Example 59A (45 mg, 0.15 mmol) according to Method H: 'H NMR (300 MHz, methanol-D 4 ) S ppm 2.05 - 2.17 (i, 2 H), 2.21 2.34 (m, 3 H), 2.36 (s, 3 H), 2.73 (s, 2 H), 3 53 (d, J=12.5 Hz, 2 H), 3.59 (s, 2 H), 3.82 (d, J=12.5 Hz, 2 H), 5.27 (t, J=3.6 Hz, I H), 7.23 (d, J=7.8 Hz, 2 H), 7.50 - 7.63 (n, 3 H), 7.70 (d, J=8 5 Hz, 2 H), 7.90 - 7.98 (i, 2 H). MS (+ESI) m/z= 298 (M+H)+. 30 Anal. Calcd. for C 17 HjqN 3 0 2 : C, 61.39; H, 5.80; N, 8 95; Found: C, 61 .11; H, 5.83; N, 8 91 Example 60 -108- (4s)-4-(Benzothiazol-2-yloxy)-l-azatTicyclo[3.3.1 .1 7 ldecane p-toluenesulfoniatc Example 60A (4s)-4- (Benzothiazol-2-loxcclo3.3.1.1 3 31decane N-borane complex 5 Prepared from the product of Example IOA (100 mg, 0.599 mmol) and 2 chlorobenzothiazole (102 mg, 0.599 mmol; Aldrich) according to Method A: 'H NMR (300 MHz, chloroform-D) 6 ppm 1.71 (d, J=12.9 Hz, 2 H), 2.00 - 2.07 (in, I H), 2.25 (d, J=13.2 Hz, 2 H), 2-50 (s, 2 H), 3-18 - 3.35 (m, 6 H), 5.43 (t, J=3.4 Hz, I H), 7.21 - 7.28 (m, I H), 7.34 - 7.41 (m, I H), 7.63 - 7.68 (m, 2 H). MS (+ESI) m/z= 10 301 (M+H)*. Example 60B ('4s)-4-(Benzothiazol-2-yloxy)-l-azatricyclof 3 .3. 1 l decane Prepared from the product of Example 60A (180 mg, 0.60 mmol) according to 15 Method C: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.70 (s, I H), 1.86 - 1.95 (m, 2 H), 2.23 - 2.35 (m, 4 H), 3.13 - 3.22 (i, 4 H), 543 (t, J=3.1 Hz, 1 H), 7.25 (ddd, J=8.3, 7 0, 1.0 Hz, I H), 7.37 (td, .J=7.7, 1.2 Hz, 1 H), 7.59 - 7.64 (m, 1 H), 7.70 7.75 (m, I H). MS (+ESI) n/z= 287 (M+H) 4 20 Example 60C (4s)--4(Benzothiazol-2-loxy)- 1-azatricyclof3.3.1.13 3 ldecane p-toluenesulfonate Prepared from the product of Example 60B (131 mg, 0.457 mmol) according to Method H: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 1.97 (d, J=1 2.5 Hz, 2 H), 2.21 (s, I H), 2.28 - 2.39 (m, 5 H), 2.71 (s, 2 H), 3.59 (s, 2 H), 3.64 - 3.78 (m, 4 H), 25 5.57 (t,1=3.6 Hz, 1 H), 7.22 (d, J=8.1 Hz, 2 H), 7.28 (td, J=7.6, 1.4 H-z, 1 H), 7.40 (td, J=7.6, 14 Hz, 1 H), 7.61 - 7.65 (m, I H), 7.71 (dt,J=8.4, 1.9 Hz, 2 H), 7.74 - 7.78 (m, 1 H). MS (+ESI) m/z= 287 (M+H)+. Anal. Calcd. for C 1 ,Hj 8

N

2 OS-C7HsO 3 S-0.2H2 0 : C, 59.77; H, 5.76; N, 6.06; Found: C, 59.63; 11, 5.81; N, 5.76. 30 Example 61 (4)- 4-(Benzothiazol-2-yloxy)- I -azatricyclof3.3. 1.1 3

,

7 )decane p-toluenesulfonate -109- Example 61A r)- 4-(Benzothiazol- 2 -yloxv)l -azaticycloD.3.1 37 ]decane N-borane complex Prepared from the product of Example 9D (100 ig, 0.599 mmol) and 2 chlorobenzothiazole (102 mg, 0.599 mnol; Aldrich) according to Method A: 'H 5 NMR (300 MHz, chloroform-D) S ppm 1.90 - 2 09 (m, 5 H), 2 46 (s, 2 H), 2 99 (d, J=12.9 Hz, 2 H), 3.14 (s, 2 H), 3.48 (d, J=13.2 Hz, 2 H), 5.33 (t, J=3.2 Hz, I H), 7.24 (ddd, J=8.3, 7.0, 1.0 Hz, I H), 7.33 - 7.41 (m, I H), 7.62 - 7 69 (m, 2 H) MS (+ESI) m/z= 287 (M+H)*. 10 Example 61B {4r)-4(Benzotiazol-2-yloxy)-l-azatijcyclof 3 .3.1 .1 7 1decane Prepared fiom the product of Example 61A (180 mg, 0.60 mmol) according to Method C: 1 H NMR (300 MHz, methanol-D4) S ppm 1.72 - 1.80 (m, I H), 2.02 2.14 (m, 2 H), 2.15 - 2.29 (in, 4 H), 3.03 (dd, J=13.1, 1.2 Hz, 2 H), 3.16 (s, 2 H), 3.46 15 (d, J=13.2 Hz, 2 H), 5.41 - 5.48 (m, 1 H), 7.25 (td, J=7.7, 1.2 Hz, I H), 7.37 (td, J=7.8, 1.4 Hz, I H), 7.62 (dt, J=8.1, 0.7 Hz, I H), 7.72 (dd, J=7.6, 1.2 Hz, I H) MS (+ESI) n/z= 287 (M+H)*. Example 61C 20 (4r)-4-(Benzothiazol-2-yloxy)-i-azatricyclo( 3 .3.1.1 'ldecane p-toluenesulfonate Prepared from the product of Example 61B (123 mg, 0.429 minol) according to Method H: 'H NMR (300 MHz, methanol-D4) 5 ppm 2.07 - 2.19 (in, 2 B), 2.20 2.31 (in, 3 H), 2.36 (s, 3 H), 2.69 (s, 2 H), 3.50 (d, J=12.5 Hz, 2 1-1), 3.57 (s, 2 H), 3.80 (d, J=12.5 Hz, 2 H), 5.49 (t, J=3.4 Hz, I H), 7.22 (d, J=8.1 Hz, 2 H), 7.28 (td, J=7.6, 25 1.0 Hz, I H), 7.40 (td, J=7.8, 1.4 Hz, I H), 7.63 - 7 79 (m, 4 H) MS (+ESI) m/z= 287 (M+H)*. Anal. Calcd. for Ci 6 HsN 2 OS-C7H8O3S: C, 60.24; H, 5 71; N, 6.11; Found: C, 60.36; H, 5.73; N, 6 18. Example 62 30

(

4 s)-4-(6-Chlorobenzothiazol-2-lioxy)- -azatricyclo[ 3 .3.1.1 ldecane p-toluenesulfonate Example 62A -- 110- (4s)-4-(6-Chlorobenzothiazol- 2 -yloxy)-1 -azatricycloi 3 .3.1.13 3 ldecane N-borane complex Prepared from the product of Example IOA (102 mg, 0.610 mmol) and 2,6 dichlorobenzothiazole (122 mg, 0.599 mmol; Aldrich) according to Method A: 'H 5 NMR (300 MHz, chloroform-D) S ppm 1.72 (d, J=12.2 Hz, 2 H), 2.04 (s, 1 H), 2.24 (d, J=12.9 Hz, 2 H), 2.48 (s, 2 H), 3.17 - 3 34 (m, 6 H), 5.41 (t, J=3.6 Hz, 1 H), 7.33 (dd, J=9.0, 2.2 Hz, I H), 7.56 (d, J=8.5 H z, 1 H), 7 63 (d, J=2 .0 Hz, 1 H). MS (+ESI) m/z= 335/337 (M+H)* 10 Example 62B (4s)-4-(6-Chlorobenzothiazol-2-yloxy)- -azatricyclo[3.3.1.1 1 Vldecane Prepared from the product of Example 62A (184 mg, 0.55 mol) according to Method C: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.65 (s, I H), 1 79 - 1.89 (m, 2 H), 2.19 - 2.35 (m, 4 H), 3.12 - 3.22 (m, 4 H), 3.27 - 3.36 (m, 2 H), 5.43 (t, J=3.2 Hz, 15 1 H), 7.31 (dd, J=8.6, 2.2 Hz, I H), 7.55 (d, J=8.5 Hz, 1 H), 7.61 (d, J=2.0 Hz, I H). Example 62C (4s)-4-(6-Chlorobenzothiazol 2 -yoxy)-l -azatricclo[ 3 .3.1. 3 ' 7 decane p toluenesulfonate 20 Prepared from the product of Example 62B (138 mg, 0.430 mnol) according to Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.97 (d, J=12.9 Hz, 2 H), 2 21 (s, I H), 2.27 - 2.39 (m, 5 H), 2.71 (s, 2 H), 3.58 (s, 2 H), 3.63 - 3.78 (m, 4 H), 5.58 (t, J=3.4 Hz, I H), 7.22 (d, .J=8 5 Hz, 2 H), 7 39 (dd, J=8.6, 2 2 Hz, 1 H), 7.59 (d, J=8.8 Hz, I H), 7.70 (d, J=8-1 Hz, 2 H), 7.82 (d, J=2.0 H z, I H). MS (+ESI) m/z= 25 321/323 (M+H)*. Anal. Calcd. for C1,Hu7CIN2OS-C7HBOS: C, 56.03; H, 5 11; N, 5.68; Found: C, 56.12; H, 5.14; N, 5.65. Example 63 (4)-4-(6-ChlorIobenzothiazol-2-yoxy) -azatricyclo 3 .3.1.1 3 ldecane 30 p-toluenesulfonate Example 63A (4r)-4-(6-Chlorobcnzothiazol-2-yloxyl-1-azatricyclo 3 .3.1.I1ldecane N-boane -1 11complex Prepared from the product of Example 9D (102 mg, 0.610 mmol) and 2,6 dichlorobenzothiazole (122 mg, 0.599 mnmol; Aldrich) according to Method A: 'H NMR (300 MHz, chloroform-D) 5 ppm 1 .88 - 2.10 (m, 5 H), 2,45 (s, 2 H), 2.99 (dd, 5 J=13 2, 1.4 Hz, 2 H), 3.14 (s, 2 H), 3 46 (d, J=13.2 Hz, 2 H), 5.31 (t, J=3.4 Hz, 1 H), 7.33 (dd, J=8.5, 2.0 Hz, 1 H), 7.55 (d, J=8.5 Hz, 1 H), 7.64 (d, J=2.0 Hz, I H). MS (+ESI) n/z= 321/323 (M+H-BH 3 )+. Example 63B 10 (4r)-4-(6-Chlorobenzothiazol-2VIoxyl-azatricyclof.3 .1 decade Prepared from the product of Example 63A (190 mg, 0.57 mmol) according to Method C: 'H NMR (300 MHz, chlorofom-D) 8 ppm 1.67 - 1.78 (m, 2 H), 1.98 2.23 (i, 5 H), 3.00 (dd, .J=1 3.2, 1.0 Hz, 2 H), 3.16 (s, 2 H), 3.51 (d, J=13.2 Hz, 2 H), 5.46 (s, 1 H), 7.28 - 7.34 (in, I H), 7.56 (d, J=8.8 Hz, I H), 7.62 (d, J-2.7 H z, I H). 15 MS (+ESI) m/z= 321/323 (M+H)*. Example 63C

(

4 r)-4-(6-Chlorobenzothiazol-2-ylox)-I -azatricyclof3.

3 . 1.1 3

,

7 ldecane p-toluenesulfonate 20 Prepared from the product of Example 63B (152 mg, 0.474 miol) according to Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 2.07 - 2.19 (n, 2 H), 2.20 2.31 (m, 3 H), 2.36 (s, 3 H), 2.68 (s, 2 H), 3.50 (d, J=1 1.9 Hz, 2 H), 3.57 (s, 2 H), 3-79 (d, J=12.5 Hz, 2 H), 5,50 (t, J=3.4 Hz, I H), 722 (d, J=7.8 Hz, 2 H), 7.39 (dd, J=8.6, 2.2 Hz, 1 H), 7.61 (d,J=8 Hz, 1 H), 7.70 (ddd, J=8.3, 2.

0 , 1.9 Hz, 2 H), 7.81 (d, 25 J=2 4 Hz, I H). MS (+ESI) m/z= 321/323 (M+H)*. Anal.. Calcd. for C1 6 H1 7 ClN 2

OS-C

7 H8O 3 S-0.4H20: C, 55.22; H, 5.20; N, 5.60; Found: C, 55.00; Fl, 5.19; N, 5.64. Example 64 30 (4s)-4-(Benzoxazol-2-yloxyL-1-azatricyclo[3.3.1.1 3 1 ldecane p-toluenesulfonate Example 64A (4s)-4-(Benzoxazol-2-yloxy)-l -azatricyclo[3.3.1.1 3 ldecane N-borane copex -112- Prepared from the product of Example 1OA (103 mg, 0.616 mmol) and 2 chlorobenzoxazole (100 mg, 0.86 rnmol; Aldrich) according to Method A: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.74 (d, J=12 2 Hz, 2 H), 2 06 (s, I H), 2 27 (d, J=12.9 Hz, 2 H), 2.50 (s, 2 H), 3-19 - 3.34 (m, 6 H), 5.29 (t, J=3.4 Hz, 1 1-1), 7.17 5 7.30 (n, 2 H), 7.35 - 7.40 (m, 1 H), 7.48 (dd,.J=7.5, 1.7 Hz, 1 H). Example 64B (4s)4-(Benzoxazol--2-yoxy)- 1-azatricyclo[ 3 .3.1.1 )decane Prepared from the product of Example 64A (141 mg, 0.496 mmol) according 10 to Method D: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.71 (s, 1 H), 1.87 - 1.98 (m, 2 H), 2.23 - 2.36 (m, 4 H), 3.11 - 3.22 (m, 4 H), 3.32 - 3.39 (m, 2 H), 5.32 (t, J=2 9 Hz, I H), 7.17 - 7.31 (m, 2 H), 7.39 - 7.46 (m, 2 H). MS (+ESI) m/z= 271 (M+H)*. Example 64C 15 (4s)-4-(Benzothiazol-2-yloxy)-I -azatricyclo[3.3.1 .1 3

)'

7 decane p-toluenesulfonate Prepared from the product of Example 64B (124 mg, 0.459 mmol) and p toluenesulfonic acid monohydrate (87 mg, 0.46 mmol; Aldrich) according to Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 2.00 (d, J=13.2 Hz, 2 H), 2.23 (s, I H), 2.29 - 2 41 (i, 5 H), 2.72 (s, 2 H), 3,60 (s, 2 H), 3.63 - 3.80 (in, 4 H), 5.43 (t, J=3.4 20 Hz, 1 H), 7.18 - 7.34 (m, 4 H), 7 45 (dd, J=7.5, 1.4 Hz, 2 H), 7.71 (ddd, J=8.3, 2 0, 1.9 Hz, 2 H). MS (+ESI) m/z= 271 (M+H)* Anal. Calcd. for

C

6 HisN 2 O2C7H80 3 S-H20: C, 59.98; H, 6.13; N, 6.08; Found: C, 59.77; H, 6.18; N, 6.33. 25 Example 65 (4s)-4-N-(6-Chloropyridin-3-yl)-1 -azatricyclof3.3.1.1 3

,

7 decan-4-amine hydrochloride Example 65A 30 (4s)-4-N-(6-Chloropyridin-3-yl)-1-azatricyclo[ 3 .3.1.11' 7 ]decan-4-amine Example 65B (4r)-4-N-(6-Chloropyridin-3-yi)-1 -azatricyclof3.3.1.1 3

,

7 1decan-4-arnine A solution of 1-azatricyclo[3.3.1.1V]decan-4-one (1.51 g, 10 mmnol; see -113- Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) in HOAc (50 mL) was treated with 3-amino-6-chloropyridine (1.90 g, 15 mmol; Aldrich), anhydrous Na2SO4 (18 5 g, 0.1 3 mol; Aldrich), and NaBH(OAc)3 (4.22 g, 20 mmol; Aldrich) and was stirred at ambient temperature for 10 houis After the reaction was complete, the solid was 5 filtered off, and the filtrate was concentrated. The residue was carefully basified with saturated aqueous Na 2

CO

3 (pH 10), extracted with CHC1 3 (3x 100 mL), and the combined extracts were purified by flash chromatography [silica gel, ammonium hydroxide-methanol-chloroforn (2:10:90)] to afford the title compounds: Example 65A (4s) stereoisomer: 'H NMR (300 MHz, methanol-D4) S ppm 1.74 10 1.94 (m, 4 H), 1.97 - 2.10 (m, 2 H), 2.18 - 2.43 (in, 2 H), 3.23 - 3.28 (m, 2 H), 3.33 3.45 (m, 4 H), 3.78 (s, 1 H), 6.84 - 7 36 (m, 2 H), 7.69 - 7.94 (m, I H). MS (DC/NH3) mI/z= 264/266 (M+H)*. Example 65B (4r) stereoisomer: ' H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.71 1.93 (in, 4 H), 2.02 - 2.26 (n, 4 H), 2 90 - 3 03 (m, 2 H), 3.08 - 3.16 (m, 2 H), 3.35 15 3.46 (m, 2 H) 3.67 (s, I H), 7.03 - 7.10 (m, I H), 7.11 - 7.17 (in, I H), 7.74 (d, J=3.05 Hz, 1 H). MS (DCI/NH 3 ) m/z=26 4 (M+H). 266 (M+14)*. Example 65C (4s)-4-N-(6-Chloropyridin-3-yI)-1-azatricyclo[ 3 .3.1.1 ldecan-4d 20 Prepared from the product of Example 65A (100 mg, 0.38 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) S ppm 1.81 - 2.10 (m, 2 H), 2.11 2.23 (m, I H), 2.23 - 2.48 (m, 4 H), 3.50 - 3.60 (m, 2 H), 3.64 - 3 81 (in, 4 H), 3.98 (s, 1 H), 7.36 - 7.56 (m, 2 H), 7.98 (d, J=2.7 Hz, I H). MS (DCI/NH 3 ) m/z= 264/266 (M+H)*. Anal. Calcd. for Cj 4 HsClNy.1.15HCl-1.65H20: C, 50.13; H, 6.75; N, 12.53; 25 Found: C, 50.01; H, 6.35; N, 12.15 Example 66 (4r)-4-N-(6-Chloropyridin-3-yi)-l-azatricyclo[3.3.1.1'l decan-4-amine trihydrochloride 30 Prepared from the product of Example 65B (100 mg, 0.38 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) S ppm 2.08 - 2.52 (m, 7 H), 3.40 3.61 (m, 4 H), 3 75 - 3.90 (m, 3 H), 7.54 - 7.68 (m, 2 H), 8 03 (d, J=3 0 Hz, 1 H). MS (DCI/NH 3 ) m/z= 264/266 (M+H)*. Anal Calcd. for C, 4 Hi 8 ClNr3.15HCl-l.2H 2 0: C, -114- 42.01; H, 5.93;N, 10.50; Found: C,42.29;H, 5 56;N, 10.10. Example 67 (4s)-4-N-(6-Phenylpyridin-3-yl)-1-azatricyclo[33.1 .13 7 1decan-4-amine 5 dihydrochloride Example 67A (4s)-4-N-(6-Phenylpyridi n-3-yl)-1-azatricyclof3.

3 . 1.1 3 7 decan-4-amine Prepared from the product of Example 65A (200 mg, 0.76 nimol) and 10 phenylboronic acid (121 mg, 1.0 immol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) 6 ppm 1.58 - 1.77 (m, 1 H), 1.78 - 1.92 (m, 2 H), 1.90 - 2.02 (in, 2 H), 2.16 - 2.42 (m, 3 H), 3.06 - 3.41 (m, 7 H), 3.75 (s, 1 H), 7.17 (dd, J=8.6, 2.8 Hz, 1 H), 7.26 - 7.34 (m, 1 H), 7.59 - 7.70 (in, 3 H), 7.73 - 7.83 (m, 2 H), 8.09 (d, J=2.7 Hz, 1 H). MS (DCI/NH 3 ) m/z= 306 (M+H)*. 15 Example 67B (4s)-4-N-(6-Phenylpyridin-3-l)- -azatricyclo[ 3 .3.1. 3

.

7 1ecan-4-amine dihydrochloride Prepared from the product of Example 67A (150 mg, 0.49 mmol) according to 20 Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.93 - 2.08 (m, 2 H), 2.15 2.26 (m, 1 H), 2.26 - 2.51 (n, 4 H), 3.55 - 3.63 (m, 2 H), 3.66 - 3.82 (m, 4 H), 4.12 4.19 (m, I H), 7.52 - 7.70 (m, 3 H), 7.76 - 7.85 (in, 2 H), 7.99 (dd, J=9.2, 2.7 Hz, I H), 8.08 (d, J=9.2 Hz, I H), 8.20 (d, J=2.7 Hz, I H). MS (DCI/NH 3 ) n/z= 306 (M+H)*. Anal. Calcd. for C 2 0 H2N 3 2HCl-0.9H20: C, 60 25; H, 7.08; N, 9 58; 25 Found: C, 60.24; H, 6.92; N, 9.47. Example 68 (4s)-4-N-6-(Indol-5-yl)-yridin- 3 -yll-azatricyclof 3 .3.1.1 3 decan-4-amine dihydrochloride 30 Example 68A (4s)-4-N-[6-(Indol-5-yl)-pyidin-3-vll- -azatiicyclo[3.3. 1.1 3 3 ldecan-4-amine -115- Prepat ed from the product of Example 65A (200 mg, 0.76 mmol) and 5 indolylboronic acid (160 mg, 1.0 mrnol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.62 - 1.76 (m, I H), 1.80 - 1.90 (m, 2 H), 1.93 - 2.02 (m, 2 H), 2.21 - 2.39 (m, 2 H), 3.13 - 3.17 (n, 2 H), 3.18 - 3.30 (m, 4 H), 3.77 - 3.86 5 (m, 1 H), 6.49 (d, J=4.0 Hz, 1 H), 7.18 (dd, J=8.6, 2.8 Hz, 1 H), 7.24 (d, J=34 Hz, 1 H), 7.41 (d, J=84 Hz, I H), 7.52 - 762 (m, 2 H), 7.95 (s, I H), 8.06 (d, J=2.4 Hz, I H) MS (DCI/NH 3 ) m/z= 345 (M+H) 4 Example 68B 10 (4s)-4-N-[6-(Indol-5-vl)-pvrldin-3-vll-1-azatricyclof 3 .3.1.13 ' 7 decan-4-amie dihydrochloride Prepared from the product of Example 68A (110 mg, 0.32 mmol) according to Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.88 - 2.07 (i, 2 H), 2.13 2.28 (m, 1 H), 2.28 - 2.51 (m, 4 H), 3.55 - 3.63 (m, 2 H), 3.68 - 3.83 (m, 4 H), 4.09 15 4.14 (m, I H), 6.62 (d, J=3.0 Hz, I H), 7.40 (d, J=3.0 Hz, I H), 7.54 (dd,J=8.8,2.1 Hz I H), 7.60 - 7.65 (m, I H), 7.97 (dd, J=9.2, 2.7 HzI H), 8.03 - 8.16 (m, 2 H). MS

(DCI/NH

3 ) m/z= 345 (M+H)*. Anal. Calcd. for C 2 0

H

23 Ny2HCl-2-5H 2 0: C, 57.14; H, 6.76; N, 12.12; Found: C, 57.22; H, 6 63; N, 11.77 20 Example 69 (4s)-4-N-(5-Broiopyridin-3-vl)-1-azatricyclo[3.3.1 .1 3

,

7 ldecan-4-arine dihydrochloride Example 69A 25 (4s)-4-N-(5-Bromopyridin-3-yl)-1-azatricvclo[3.3.1.1

'

1 decan-4-am-ine Prepared from 1-azatricyclo[3.

3 1 3 - ]decan-4-one (1.51 g, 10 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) and 3-amino-5-bromopyridine (2.06 g, 12 mmol; Aldrich) according to the procedure described in Example 65A: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.81 - 1.99 (m, 2 H), 2.02 - 2.15 (m, I H), 2.17 30 - 2.40 (m, 4 H), 3.44 - 3.51 (m, 2 H), 3.53 - 3.66 (in, 4 H), 3.91 (s, 1 H), 7.26 - 7.41 (m, I H), 7.84 (d, J=1.7 Hz, I H), 8-01 (d, J=2 7 Hz, 1 H). MS (DCIfNH 3 ) m/z= 308/310 (M+H)*. -116- Example 69B (s)-4-N-(5-Bromopyidin-3-vl)-1--azatricyclo[f3.3.1.1 3

'

7 ldecan-4-amine dihydrochloride Prepared from the product of Example 69A (50 mg, 0.16 mmol) according to 5 Method H: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.89 - 2.04 (m, 2 H), 2.15 2.49 (in, 5 H), 3 53 - 3.61 (m, 2 H), 3.64 - 3.81 (m, 4 H), 4.08 [s (br-), I H), 8.03 (dd, 1=2.37, 1 70 Hz, 1 H), 8.20 (d, J=1 36 Hz, I H), 8.28 (d, J=2.37 Hz, 1 H). MS (DCI/NH3) m/z= 308/310 (M+H)*. Anal. Calcd. for C1 4

H

1 iBrN 3 -2HCl I.1H 2 0: C, 41.94; H, 5,58; N, 10.48; Found: C, 42.13; H, 5.26; N, 10.13. 10 Example 70 (4s)-4-N-[5-(Indol-5-1)-pyridin-3-vl-1-azatricvlol3 .3.1 A-4-Amine Prepared rom the product of Example 69A (150 mg, 0.50 inmol) and 5 indolylboronic acid (160 mg, 1.0 mmol; Aldrich) according to Method E: 'H NMR 15 (300 MHz, methanol-D4) 6 ppm 1.59 - 1.77 (m, I H), 1.79 - 1.93 (in, 2 H), 1.93 - 2.07 (in, 2 H), 2.28 - 2.32 (m, 2 H), 3.10 - 3.32 (in, 6 H), 3.88 (s, I H), 6.51 (dd, J=3,0, 0 7 Hz, I H), 7.27 (d, J=3.4 Hz, 1 H), 7.30 - 7.34 (in, I H), 7.36 (d, J=1.7 Hz, I H), 7-47 (d, J=8.3 Hz, 1 H), 7.78 (d, J=1 0 Hz, I H), 7.93 (d, J=2.4 Hz, 1 H), 8.03 (d, J=1.7 Hz, 1 H). MS (DCI/NH 3 ) m/z= 345 (M+H)*. 20 Example 71 (4s)-4-N-f5-(Indol-6-yl)-pyridin--3-yl l-azatricyclo.[ 3 .3.1.13,71decan-4-ainine bis(trifluoroacetate) Prepared from the product of Example 69A (100 ng, 0 325 mmol) and 6 25 indolylboronic acid (130 mg, 0.807 mmol; Frontier) according to Method F, with HPLC purification using the acidic conditions to afford the trifluoroacetate salt: 'H NMR (300 MHz, methanol-D4) & ppm 1.95-2.04 (in, 2 H), 2.18 - 2.45 (m, 5 H), 3.59 (in, 2 H), 3.72 (in, 4 H), 4.15 (s, I H), 6.53 (dd, J=3 2, 0.8 Hz, I H), 7 33 - 7.41 (m, 2 H), 7.68 - 7.77 (in, 2 H), 8.03 - 8.07 (m, 1 H), 8 10 (d, J=2.4 Hz, I H), 8.32 (d, J=1.0 30 -Iz, 1 1-1). MS (DCI/NH 3 ) m/z= 345 (M+H)*. Anal. Calcd. for Cn1H 2 4

N

4 2.3C 2 HF30 2

-H

2 0: C, 51.22; H, 4.41; N, 8.98; Found: C, 51.17; H, 4 75; N, 8.98. -117- Example 72 (4s)-4-N-[5-(Indol-4-yl)-pyridinl-3-yll-1-azatricycLO[3.3.1.1 3

,

7 ldecan-4-amine fumarate The free base of the title compound was prepared from the product of 5 Example 69A (100 mg, 0.325 mmol) and 4-indolylboronic acid (130 mg, 0.807 mmol; Frontier) according to Method F, followed by conversion to the fumarate salt using the procedure of Method H: '1H NMR (300 MHz, methanol-D4) 5 ppm 1.90-1.95 (i, 2 H), 2,15-2.19 (m, 1 H), 2 32-2.45 (in, 4 H), 3.50-3.58 (m, 2 H), 3.62-3.73 (m, 4 H), 4.04 (s, I H), 6.56 (dd, J=3.2, 0 8 Hz, I H), 6.69 (s, 2 H), 7.09 (dd, J=7- 1, 1 0 Hz, I 10 H), 7.16 - 7.24 (m, 1 H), 7 32 (d, J=3.4 Hz, I H), 7.41 - 7.45 (m, 2 H), 8.04 (d, J=2.7 Hz, I H), 8.12 (d,.J=l.7 Hz, I H). MS (DCI/NH3) m/z= 345 (M+H)*. Anal. Calcd. for Cn 2

H

2 4

N

4 -1.5C 4 H40 4 0.7H 2 0: C, 63.31; H, 5.96; N, 10.55; Found: C, 63.05; H, 5.95; N, 10,74. 15 Example 73 f4s)-4-N-[5-(3-Methylphenyl)-i Ydin- 3 -yll-1-azatricyclo(3.3.1.13

'

7 ldecan-4-amine fumarate The free base of the title compound was prepared from product of Example 69A (100 mg, 0.325 mmol) and n-tolylboronic acid (110 mg, 0. 808 mmol; Aldrich) 20 according to Method F, followed by conversion to the fumarate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) 5 ppm 1.83 - 1.98 (m, 2 H), 2.08 - 2.26 (m, 1 H), 2 27 - 2.40 (m, 4 H), 2.41 (s, 3 H), .3.50 - 3.59 (m, 2 H), 3 60 - 3-80 (m, 4 H), 3.97 - 4.08 (m, 1 H), 6.70 (s, 2 H), 7 17 - 7.59 (m, 5 H), 7.93 - 8 18 (m, 2 H). MS (DC1INH 3 ) m/z= 320 (M+H)*- Anal. Calcd. for 25 C 2 1

H

2 5 N3-2C 4 H404 1.6H 2 0: C, 60.01; H, 6.29; N, 7.24; Found: C, 59.88; H, 6.55; N, 7.54. Example 74 (4s)-4-N-[5-(3--Chlorophenyl)-pyridin-3-yll-1-azatricyclof3.3.1 .1 3 7 1decan-4-amine 30 bis(trifluoroacetate) Prepared from the product of Example 69A (100 mg, 0.325 minol) and m chlorophenylboronic acid (101 mg, 0.650 mmol; Aldrich) according to the procedure of Method F: 'H NMR (300 MHz, methanol-D4) 6 ppm 1 86 - 2.06 (m, 2 H), 2 15 -118- 2.26 (in, 1 H), 2.26 - 2 54 (in, 4 H), 3.53 - 3 65 (in, 2 H), 3.64 - 3 83 (in, 4 H), 4.14 (s, I H), 7.48 - 7.58 (in, 2 H), 7.60 - 7-70 (in, I H), 7.74 - 7.80 (in, I H), 7 89 (s, 1 H), 8.10-8.24 (in, 2H). MS (DCI/NH 3 ) nz= 340/342 (M+H)*. Anal. Calcd. for

C

20

H

22

N

3 C1 2.5C 2

F

3 0 2 H-1.2H20: C, 46.44; H, 4.19; N, 6.50; Found: C, 46.23; H, 5 4.17; N, 6 67. Example 75 ((ylohen -3-yl}-pyrdin-3-yll-1-azatricyclo 3.3.1.1 3 ldecan 4-amine bis(tiifluoroacetatc) 10 Prepared from the product of Example 69A (100 mg, 0.325 minmol) and m chlorophenylboronic acid (101 mg, 0.650 mmol; Aldrich) according to the procedure of Method F: 'H NMR (300 MHz, methanol-D4) S ppm 1.88 - 2.11 (in, 2 H), 2.15 2.28 (in, 1 H), 2.27 - 2.49 (in, 4 H), 3.54 - 3.64 (m, 2 H), 3.65 - 3.87 (m, 4 H), 4.07 4.28 (in, I H), 7.36 - 7.44 (in, I H), 7.48 (t, J=7.8 Hz, 1 11), 7.61 - 7.70 (m, 2 H), 7.71 15 - 7.76 (in, 2 H), 7.78 (dt, J=7.7, 1.6 Hz, I H), 7.94 (t, J=1.7 Hz, I H), 8.00 (s, 1 H), 8.19 (s, I H), 8.37 (s, 1 H). MS (DCI/NH 3 ) m/z= 41 6

/

4 1 8 (M+H)*. Anal. Calcd, for

C

2 6H 2 6N 3 Cl-2.2C2HF302: C, 54.76; H, 4,26; N, 6.30; Found: C, 54.75; H, 4.15; N, 6,12 20 Example 76 (4s)-4-(Pyridin-3-yloxy)-I-azatricyclo[ 3 .3.1.

3 ldecanelydrochloide Example 76A 25 (4s)-4-(Pyridin-3-loxy)-1-azatricyclo[ 3

.

3 .1.1l 1decane N-borane complex Prepared from the product of Example 10A (84.2 mg, 0.51 mmol) and 3 fluoropyridine (66 pL, 0.77 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) S ppm 1.65-1.69 (in, 2 H), 2.03 (br s, I H), 2.26-2.31 (in, 4 1), 3.19 3.27 (m, 6 H), 4.58 (t, J=3.2 Hz, 1 H), 7.23-7.24 (m, 2 H), 8.25-8.27 (in, 1 1-1), 8 34 30 8.36 (in, I H). MS (DCI/NH 3 ) m/z= 245 (M+H)*. Example 76B (4s)-4-(Pyridin-3-yloxy)-l -azatricyclo[3.3.1.1 V 1decane hydrochloride -119- Prepared from the product of Example 76A (69 8 mg, 0.27 mmol) according to Method .: 'H NMR (300 MHz, methanol-D 4 ) S ppm 1.94-1.99 (m, 2 H), 2.22 (br s, 1 H), 2.35-2.38 (n, 2 H), 2.55 (br s, 2 H), 3.60 (s, 2 H), 3.64-3.77 (m, 4 H), 5.15 (t, J=3.2 Hz, I H), 8.02 (dd, J=9-0, 5.6 Hz, I H), 8.34-8.38 (m, 1 H), 8 50 (d, J=5.4 Hz, 5 1 H), 8-77 (d, J=2.7 Hz, I H). MS (DCI/NH3) m/z= 231 (M+H)*. Anal. Called. for

C

14 HIsN 2 02.05 HCL: C, 55.12; H, 6.62; N, 9.18; Cl, 23.82. Found: C, 54.91; H, 6 79; N, 9.04; Cl, 23 59. Example 77 10 (4s)-4-[(1-Oxidopridi-3-ylloxyVl1--azatricyclof 3 .3.1.1 3 'ldecane hydrochloride Example 77A {'4s--4-{(I-Oxidopyridin-3-yl)oxyl-l-azatiicyclo{ 3 .3.1.1 3 7 decane N-borane complex Prepared from the product of Example IA (85.2 mg, 0.51 mmol) and 3 15 fluoropyridine N-oxide (87.2 mg, 0.77 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) 8 ppm 1.67-1.71 (m, 2 H), 2.03 (br s, 1 H), 2.19-2.26 (m, 4 H), 3.15-3.27 (m, 6 H), 4.54 (t, J=3.4 Hz, I H), 6.88 (dd, J=8.7, 2.4 Hz, I H), 7.19 (dd, J=8.7, 6.4 Hz, I H), 7.91-7 93 (m, I H), 8.00 (t, J=2.0 Hz, 1 H). MS (DCI/NH 3 ) m/z= 261 (M+H)*. 20 Example 77B (4s)-4-[(1- Oxidopyridin-3-yl)oxyl-1-azatricyclof 3 .3.1.1 3

'

7 ldecane hydrochloride Prepared from the product of Example 77A (100.4 mg, 0.39 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 5 ppm 1.93-1.97 (m, 2 H), 2.21 (br 25 s, I H), 2.33-2.38 (m, 2 H), 2.53 (br s, 2 H), 3.58 (s, 2 H), 3.64-3.76 (n, 4 H), 5.08 (t, J=34 Hz, I H), 7.78 (dd, J=8.8, 6.1 Hz, 1 H), 7.88 (ddd, J=8.8, 2.4, 1.0 Hz, I H), 8.37 (ddd, J=6.1, 1 9, 1.0 Hz, I H), 8.66 (app t, J=2.0 Hz, I H). MS (DCI/NH 3 ) n/z= 247 (M+H)".+ Anal. Calcd. for C1 4 HiRN202 2 HCI-0.6

H

2 0: C, 50.95; H, 6 47; N, 8.49; Cl, 21 48. Found: C, 51.18; H, 6.39; N, 8.48; Cl, 21.27. 30 Example 78 (4r)-4-(Pyridin-3-yloxy)-i-azatricyclo[ 3

.

3 .1.1 V Idecane hydochloride -120- Example 78A (4r)-4-(Pyidin-3-yloxy)-L -azatricyclo3 3 . 1 .1 V1decane N-borane complex Prepared from the product of Example 9D (85.0 mg, 0.51 mmol) and 3 5 fluoropyridine (66 pL, 0.77 mmol) according to Method 1: 'H NMR (300 MHz, chloroforn-D) 8 ppm 1.83-1.87 (in, 2 H), 1.99-2.14 (in, 3 H), 2.26 (br s, 2 H), 2.29 2.96 (m, 2 H), 3.12 (s, 2 H), 3.49-3.53 (in, 2 H), 4.44 (t, J=3.2 Hz, I H), 7.23-7.24 (in, 2 H), 8.26 (t, J=3.0 Hz, 1 H), 8.33-8.34 (m, 1 H). MS (DCI/NH 3 ) m/z= 245 (M+H)*. 10 Example 78B (4 1 j-4-(Pyridin-3-yloxy)-1-azatricyclo 3.3.1 . ldecane hydrochloride Prepared from the product of Example 78A (81.0 mg, 0.33 mmol) according to Method J: '1H NMR (300 MHz, methanol-D4) S ppm 2.12-2.16 (in, 2 H), 2.25-2.29 (in, 2 H), 2.54 (br s, 2 H), 3.47-3.51 (in, 2 H), 3.58 (s, 2 H), 3.83-3.87 (in, 2 H), 5.07 15 (t, J=3.4 Hz, I H), 8.05 (dd, J=8.72, 5.55 Hz, I H), 8.37-8.41 (in, I H), 8.50-8 52 (in, I H), 8.79 (d, J=2.78 Hz, 1 H). MS (DCI/NH 3 ) m/z= 231 (M+H)*. Anal. Calcd. for C1 4 Hi 8

N

2 0-2.l HCL: C, 54-80; H, 6.60; N, 9.13; Cl, 24.26. Found: C, 54-72; H, 6.87; N, 9.06; Cl, 24.37. 20 Example 79 (s)-4-(2-Chloropyridin-3-yloxyl-l-azatricyclo[3.3.1.13,7 ldecane hydrochloride Example 79A 25 (4s)-4--(2-Chloropyridin-3-yl)oxyl- 1 -azatricyclo[ 3

.

3 . 1.1 3 Eldecane N-borane complex Prepared from the product of Example IOA (85.1 mg, 0.51 mmol) and 2 chloro-3-fluoropyridine (141.6 mg, 1.08 mmol) according to Method I: 'H NMR (300 MHz, chloroform-D) 8 ppm 1.66-1.70 (in, 2 H), 2.06 (br s, 1 H), 2.26 (br s, 2 H), 2.35-2.40 (m, 2 H), 3.16-3.28 (m, 6 H), 4.62 (t, J=3.4 Hz, 1 H), 7.20-7-21 (in, 2 H), 30 8.04-8.06 (in, I H). MS (DCI/NH 3 ) m/z= 294 (M+NH 3 -H) Example 79B (4s)-4-(2-Chloropyridin-3-vl)oxyl-1-azatricyclof3.3.1.1 3

,

7 decade hydrochloride -121- Prepared from the product of Example 79A (110.6 mg, 0-40 minol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.92-1 96 (mi, 2 H), 2.22 (br s, 1 H), 2.41-2.48 (m, 4 H), 3.58 (s, 2 H), 3.62-3.74 (n, 4 H), 5 02 (t, J=3.2 Hz, I H), 7 38 (dd, .=8.3, 4.8 Hz, 1 H), 769 (dd, J=8.1, 1.4 Hz, I H), 8.01 (dd, J=4.8, 1.6 Hz, 5 1 H) MS (DCI/NH 3 ) m/z= 265 (M+H)*. Anal. Calcd. for C1 4 H 7CINO-1 65 HCI 0.4

H

2 0: C, 50.63; H, 5 90; N, 8.43; Cl, 28 29. Found: C, 50.80; H, 5 66; N, 8.43; Cl, 28.29. 10 Example 80 4s)-4-(2-Bromopridin3-yloxy] -azatricyclo(3.3.1.1 3 7 ldecane hydrochloride Example 80A (s-azatricyclo[3.3.1.1 ldecane N-boiane complex 15 Prepared from the product of Example IA (88.0 mg, 0.53 mmol) and 2 bromo-3-fluoropyridine (146.3 mg, 0.83 mmol) according to Method 1: 'H NMR (300 MHz, chloroformr-D) 5 ppm 1.67-1.71 (i, 2 H), 2,06 (br s, I H), 2 27 (br s, 2 H), 2.38-2-42 (m, 2 H), 3.17-3.29 (m, 6 H), 4.64 (t, J=3-4 Hz, 1 H), 7-13-7 16 (in, I H), 7.20-7.24 (m, I H), 8.04 (dd, J=4.4, 1.6 Hz, I H). MS (DCI/NH3) m/z 323 (M+H) . 20 Example 80B

(

4 s)- 4

-{(

2 Bromopridin3-)oxyv1-azaticycloi 3 .3.1.1 3 decane hydrochode Prepared from the product of Example 80A (92.7 ng, 0 29 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 6 ppm 1.92-1 96 (m, 2 H), 2.22 (br 25 s, I H), 2-44-2.49 (m, 4 H), 3.58 (s, 2 H), 3.63-3.75 (n, 4 H), 5.05 (t, J=3 .2 Hz, I H), 7.43 (dd, J=8.5, 4.8 Hz, 1 H), 7-67 (dd, J=8.3, 1.5 Hz, I H), 8.02 (dd, .J=4.8, 1.4 Hz, I H). MS (DCI/NH3) m/z 309 (M+H)*. Anal. Calcd. for C1 4 HIlBrN2O-2 HCI: C, 44.00; H, 5.01; N, 7.33. Found: C, 44.00; H, 5.16; N, 7.23. 30 ExaMple 81 (4s)-4-I(4-Choropydin3ylloxyl--azatricyclo[ 3 .3.1.1 ldecane hydrochiode -122- Example 81 A (4s)-4((4-Chloropridin-3-yl)oxy- I -azatricyclo[3.3.1 .1 ' 7 ldecane N-borane complex Prepared fiom the product of Example I0A (81 0 ng, 0 .49 mmol) and 4 chloro-3-fluoropyridine (131.7 mg, 1.00 mmol) according to Method 1: 'H NMR 5 (300 MHz, chloroform-D) 8 ppm 1.67-1.71 (m, 2 H), 2.05 (br s, 1 H), 2 31-2 38 (m, 4 H), 3.16-3.28 (i, 6 H), 4.69 (t, J=3.4 Hz, I H), 7.36 (d, J=5.1 Hz, 1 H), 7.19 (d, J=5 1 Hz, I H), 8.29 (s, I H). MS (DCI/NH3) m/z= 294 (M+NH 3 -H)*. Example 81B 10 (4s)-4-[(4-Chloropyidin-3-vl)oxvl-1 -azatricycloi 3 .3. 1.1 37 ldecane hydrochloride Prepared from the product of Example 81A (88.6 mg, 0.32 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.96-2.00 (m, 2 H), 2.24 (br s, 1 H), 2.40-2.44 (m, 2 H), 2 57 (br s, 2 H), 3-60 (s, 2 H), 3.66-3.77 (m, 4 H), 5.21 (t, J=3.4 Hz, I H), 7.98 (d, J=5.9 Hz, I H), 8.40 (d, J=5.6 Hz, 1 H), 8.80 (s, I H). MS 15 (DCI/NH 3 ) n/z= 2 6 5 (M+H)*. Anal. Calcd. for C1 4 H7ClN 2 O175 HCIl 1.65 H 2 0: C, 46.93; H, 6.20; N, 7.82; Cl, 27.21. Found: C, 47.03; H, 5.90; N, 7.82; Cl, 26.92. Example 82 20 (4s)-4-[(4-MethylPYridi3)oxy clo 3 .3.1.1 ' 7 ldecane hydrochloride Example 82A (4s)-4-(4-MethylpIidin-3-lloxyl-1-azatricyclof 3 .3.1.1 Mldecane N-borane complex Prepared from the product of Example IOA (82.7 mg, 0.50 mmol) and 3 25 fluoro-4-methylpyridine (117 7 mg, 1.06 mmol) according to Method I: 'HI NMR (300 MHz, chloroform-D) S ppm 1 67-1.71 (m, 2 H), 2.03 (br s, I H), 2.24-2.31 (m, 7 H), 3.19-3.28 (m, 6 H), 4.65 (t, J=3.2 Hz, 1 H), 7.11 (d, J=4-8 Hz, I H), 8.13-8.1 4 (in, 2 H). MS (DCI/NH 3 ) m/z= 259 (M+H)*. 30 Example 82B (4s)-4-[(4-Methy1pyridin-3-ylo]x-l -azatricyclo 3

.

3 .1 ldecane hydrochlorde Prepared from the product of Example 82A (46.0 mg, 0.18 minol) according to Method .J: ' H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.97-2 02 (n, 2 H), 2.24 (br -123s, 1 H), 2.34-2.38 (m, 2 H), 2.58-2.60 (m, 5 H), 3.60 (s, 2 H), 3.69-3.79 (n, 4 H), 5 18 (t, J=3.4 Hz, I H), 7.93 (d, J=5 6 Hz, 1 H), 8.40 (d, J=5.6 Hz, I H), 8 73 (s, I H). MS (DCI/NH 3 ) m/z= 245 (M+H) 4 Anal. Calcd. for C 15

H

2 0

N

2 0-2 HCI 1.15 H20: C, 53.31; H, 7.25; N, 829; Cl, 20.98. Found: C, 53 34; H, 7 27; N, 8.31; Cl, 20.81. 5 Example 83 (4s)-4-{f4-(Trifluoromethyllpyridin-3-ylIOxy-I-azatricycloF 3

.

3 .1.1 ldecane hydrochloride 10 Example 83A (4s)- 4 -{f4-(Trifluorometh ylbpyndi-3-y]Loxy -1-azatic clo 3

.

3 .l.l decaneN borane complex Prepared fTom the product of Example IOA (86.0 mg, 0.52 mmol) and 3 15 fluoro-4-(trifluoromethyl)pyridine (139.1 mg, 0.84 mnol) according to Method I: 'H NMR (300 MHz, chlorofori-D) 8 ppm 1.67-1.71 (m, 2 H), 2.04 (br s, I H), 2.26-2.35 (n, 4 H), 3.20-3.31 (i, 6 H), 4.82 (t, J=3.2 Hz, I H), 7.50 (d, J=4.8 Hz, 1 H), 8 39 8 43 (m, 2 H). MS (DCI/NH 3 ) m/z= 313 (M+H)+ 20 Example 83B (4s)- 4 -(4-(Trifluoroiethyl)pyfidin-3-ylloxyl-1-azatricyclo[ 3 .3._1.13 ]decan hydrochloride Prepared from the product of Example 83A (76.3 mg, 0.24 mrnmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 8 ppm 1 93-1 97 (m, 2 H), 2.21 (br 25 s, I H), 2.33-2.38 (m, 2 H), 2.57 (br s, 2 H), 3.59 (s, 2 H), 3.65-3.71 (m, 4 H), 5.22 (t, 1=3.2 Hz, I H), 7.69 (d, J=4.8 Hz, 1 H), 8.42 (d, J=4.8 Hz, 1 H), 8.70 (s, I H). MS (DCI/NH 3 ) m/z= 299 (M+H)Y Anal. Calcd, for C, 5 H 7

F

3

N

2 0-1.15 HCI 0.55 H 2 0: C, 51.45; H, 5.54; N, 8.00; Cl, 11.64. Found: C, 51.60; H, 5.72; N, 8.03; Cl, 11 59. 30 Example 84 (4s)-4--((5-Fluoropyidin-3-yl)oxy-l-azatticyclof 3 .3.1.1 , Idecane hydrochloride -124- Example 84A (4s)-4-[(5- uorop -1-azatriccloi3.

3 .1.1" 7 ldecane N-borane complex Prepared from the product of Example IOA (84.2 mg, 0.50 mmol) and 3,5 difluoropyridine (100.2 mg, 0.87 mmol) according to Method 1: 'H NMR (300 MHz, 5 chloroform-D) 8 ppm 1.66-1.71 (m, 2 H), 2.03 (br s, I H), 2.24-2.27 (i, 4 H), 3 19 3.28 (m, 6 H), 4.58 (t, J=3.2 Hz, 1 H), 6.98 (dt, J=10.2, 2.4 Hz, I H), 8.15 (d, J=2.4 Hz, 1 H), 8 18-8.19 (m, I H). MS (DCI/NH 3 ) i/z= 263 (M+H). Example 84B 10 (4s)-4-I(5-FluoroPyridin-3-yl)oxyl- I -azatricyclo 3 .3.1.1 3 "Ldecane hydrochloride Prepared from the product of Example 84A (105.8 mg, 0.40 imol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.93-1 97 (m, 2 H), 2,21 (br s, 1 H), 2.34-2.39 (m, 2 H), 2.54 (br s, 2 H), 3.59 (s, 2 H), 3.65-3.76 (m, 4 H), 5.10 (t, J=3.2 Hz, 1 H), 8.09 (dt, J= 102, 2.4 Hz, 1 H), 8.48 (dd, J=2.3, 1.4 Hz, 1 H), 8.58 (d, 15 J=2.3 Hz, I H). MS (DCI/NH3) m/z= 249 (M+H)*. Anal. Called. for C1 4 H1 7 FN20 1.85 HCL: C, 53.25; H, 6.02; N, 887; Cl, 20.77. Found: C, 53.03; H, 5.97; N, 8.87; Cl, 20.48, Example 85 20 {4s)-4- (5-Chloropyridin-3-ylloxyl-1-azatricyclo[3.

3 .1.1 ldecane hydrochloride Example 85A {_4s)-4-[(5-Chloropyridin-3-yl)oxyl-1-azatricyclo[ 3

.

3 .1.1 3 Idecane N-borane complex Prepared from the product of Example 10A (85.9 mg, 0.51 minol) and 3,5 25 dichloropyridine (108.0 nig, 0.73 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) S ppm 1.66-1.70 (m, 2 H), 2.03 (br s, I H), 2.23-2.27 (m, 4 H), 3.19 3.28 (n, 6 H), 4.58 (t, J=3.2 Hz, I H), 7.23-7.25 (m, I H), 8.23-8.24 (i, 2 H). MS (DCI/NH3) m/z= 279 (M+H)*. 30 Example 85B (4s)-4-f(5-Chloropydrdin-3-yl)oxyl-1-azatricyclo[ 3

.

3 .1 .13 ' 7 ldecane hydrochloride Prepared from the product of Example 85A (57.7 mg, 0.21 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) S ppm 1 92-1.96 (n, 2 H), 2.21 (br -125s, I H), 2.34-2.39 (m, 2 H), 2.51 (br s, 2 H), 3.58 (s, 2 H), 3.63-3.75 (i, 4 H), 5.06 (t, J=3,4 Hz, I H), 8.09-8.10 (m, I H), 8.45 (d, J=1.98 Hz, 1 H), 8.54 (d, J=2.38 Hz, 1 H). MS (DCI/NH 3 ) rn/z= 265 (M+14)+. Anal. Caled- for C1 4

H,

7 C1N 2 0-2 HCI: C, 49,80; H, 5.67; N, 8.30; Cl, 31.50. Found: C, 49.64; H, 5.82; N, 8.15; Cl, 31.30 5 Example 86 (4s)-4-f(5-Bromopyridin-3-yl)oxyl-1-azatricyclo 3 .3.1.1 ldecane hydrochloride 10 Example 86A (4s)-4-[(5-Bromopyridin-3-yl)oxyl-1-azatricyclof 3

.

3 .1.1 ldecane N-borane complex Prepared from the product of Example IOA (85.3 mg, 0.51 mmol) and 3 bromo-5-fluoropyridine (141.8 mg, 0.81 mniol) according to Method 1: 'H NMR (300 MHz, chloroform-D) 8 ppm 1-66-1.70 (m, 2 H), 2.03 (br s, 1 H), 2.23-2.26 (i, 4 15 H), 3.19-3.28 (m, 6 H), 4.57 (t, 1=3.2 Hz, 1 H), 7.39-7.40 (n, I H), 8.26 (d, J=2.7 Hz,1 H), 8.23 (d, J=2.0 Hz, I H) MS (DCL/NH 3 ) m/z= 323 (M+H)*. Example 86B (4s)-4-[(5-Bromopyridin-3-yl)oxy]-I-azatticyclo 3.3.1 .1ldecane hydrochloride 20 Prepared from the product of Example 86A (105.1 mg, 0.33 mmol) according to Method J: 11H NMR (300 MH z, methanol-D4) S ppm 1.92-1-96 (m, 2 H), 2.21 (br s, 1 H), 2.34-2.38 (m, 2 H), 2.51 (br s, 2 H), 3.58 (s, 2 H), 3.64-3.75 (mn, 4 H), 5.07 (t, J=3.6 Hz, I H), 8.26-8.27 (m, 1 H), 8.55-8.62 (m, 2 H). MS (DCL/NH 3 ) m/z= 309 (M+H)*. Anal. Calcd. for C1 4 HI7BrN 2 0-1.85 HCl: C, 44.54; H, 5.06; N, 7.42. 25 Found: C, 44.51; H, 4.99; N, 7.36. Example 87 (4s)-4-f(5-lodopyridin-3-l)oxyl-1 -azatricyclo[3.3.1.1"ldecane hydrochloride 30 Example 87A (4s)-4-[(5-lodopyridin-3-yl)oxyl-1 -azatficyclo(3.3.1.1 V ldecane N-borane complex Prepared from the product of Example 10A (86.3 ing, 0.52 mmol) and 3 -126fluoro-5-iodopyridine (186.1 mg, 0 84 rnmol) according to Method I: 'H NMR (300 MHz, chloroform-D) 8 ppm 1 66-1 70 (n, 2 H), 2.03 (br s, I H), 2.23-2.26 (m, 4 H), 3 19-3.28 (i, 6 H), 4 56 (t, J=3.2 Hz, I H), 7.57-7.57 (m, I H), 8.28 (d, J=2 7 Hz,IH), 8 .46 (d, J=1.7 Hz, 1 H). MS (DCI/NH3) i/z= 371 (M+H)*, 5 Example 87B (4s)-4-[(5-Iodopyridin-3-yl)oxyl- -azatricyclo[ 3 .3.1.1 3 -1decane hydrochloride Prepared from the product of Example 87A (67.3 mg, 0. 18 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.91-1.95 (m, 2 H), 2.20 (br 10 s, 1 H), 2.34-2.38 (m, 2 H), 2,50 (br s, 2 H), 3 56 (s, 2 1-1), 3 64-3.75 (m, 4 H), 5 07 (t, J=3 2 Hz, I H), 8.43-8.45 (m, I H), 8.62 (d,J2 4 Hz, 1 H), 8 66 (d, J=1.6 Hz, I H). MS (DCI/NH3) m/z= 357 (M+H)*. Anal. Calcd. for C 1

H

17

IN

2 0-2.25 HCl: C, 38.30; H, 4.62; N, 6.34. Found: C, 38.37; H, 4.43; N, 6.39. 15 Example 88 5-[(4s)-1-Azatricyclo[ 3

.

3 .1.1 .dec-4-yloxynicotinanide hydrochloride Example 88A 5-[(4s)-1-Azatricyclol 3

.

3 .1.1 ldec-4-yloxylnicotinaniide N-borane complex 20 Prepared from the product of Example IA (86.0 mg, 0.52 mmol) and 5 fluoronicotinarnide (102.0 mg, 0.73 mmol) according to Method I: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.66-1.70 (m, 2 H), 2.04 (br s, I H), 2.23-2.26 (m, 4 H), 3.19-3.23 (i, 6 H), 4.58 (t, J=3.2 Hz, I H), 7.54-7.56 (i, I H), 8.49 (d, J=2.7 Hz,I H), 8.59 (d, J=1.7 Hz, I H). MS (DCI/NH3) m/z= 288 (M+H)*. 25 Example 88B 5-[(4s)-1-Azatricyclo[ 3

.

3 .1.1, i1dec-4-yloxylnicotinanide hydochloide Prepared from the product of Example 88A (16.9 mg, 0.059 mmniol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.94-1.99 (m, 2 H), 2.23 (br 30 s, I H), 2.37-2.41 (m, 2 H), 2 57 (br s, 2 H), 3.60 (s, 2 H), 3 67-3.77 (m, 4 H), 5.19 (t, J=3.39 Hz, I H), 8.53 (dd, J=2.7,1.4 Hz, I H), 8.83 (d, J=2.7 Hz, 1 H), 8.85 (d, J=1,7 Hz, I H). MS (DCI/NH 3 ) m/z= 274 (M+H)*. Anal. Calcd- for Ci 5 H1 9 N302-2.65 HCI: C, 48.70; H, 5.90; N, 11.36. Found: C, 48.45; H, 6.17; N, 11 44. -127- Example 89 (4s)-4- [5-( 1H-Pyrazol-4-yl)pyridin-3-ylloxyl-I-azatricyclof 3 .3.1..13 3 1decane hydrochloride 5 Example 89A ('4s)-4- 5-(1-Trityl-IH-pyrazol-4-yl)pyridin-3-ylloxyl-1 azatricyclo[3.3.1 .13* 7 ldecane N-borane complex Prepared from the product of Example 86A (83.6 mg, 0.26 mmol) and 4 10 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2 -yl)-1-trityl-1H-pyrazole (155.3 mg, 0.36 mmol) according to Method K: 'H NMR (300 MHz, chloroform-D) S ppm 1.76-1.81 (m, 2 H), 1.90 (br s, I H), 2.23-2.26 (m, 4 H), 3.22-3.26 (m, 4 H), 3.34-3.39 (m, 2 H), 4.65 (t, J=3.2 Hz, I H), 7.17-7.22 (m, 6 H), 7.32-7.37 (m, 9 H), 7 66 (s, 1 H), 7.94 (s, I H), 8.16 (d, J=2.7 Hz, I H), 8.32 (d, J=2.0 Hz, I H).. MS (DCI/NH3) n/z= 539 (M 15 BH 3 +H)*. Example 89B (4s)-4-{f5-(IH-Pyrazol-4-yl)pyridin-3-ylloxy}-1-azatricyclo[3.3.1.19 1decane hydrochloride 20 Prepared from the product ofExample 89A (47.0 mg, 0.085 mmol) according to Method J: 1 H NMR (300 MHz, inethanol-D 4 ) S ppm 1.95-1.99 (m, 2 H), 2.23 (br s, I H), 2.39-2.43 (m, 2 H), 2.57 (br s, 2 H), 3.60 (s, 2 H), 3.68-3.78 (n, 4 H), 5.24 (t, J=3.2 Hz, 1 H), 8.34 (s, 2 H), 8.47-8.48 (m, I H), 8.55 (d, J=2 4 Hz, I H), 8 77 (d, J=1.4 Hz, 1 H). MS (DCI/NH 3 ) m/z= 297 (M+H)*. Anal. Calcd. for C 7

H

2 oN 4 0-2 25 HCI2 H 2 0: C, 50.38; H, 6.47; N, 13 82. Found: C, 50.51; H, 6.57; N, 13.76. Example 90 (4s)-4-{[5-(1 -Methyl-IH-pyrazol-4-yl)pyrdin-3-vlloxyl-1 30 azatricyclo[ 3 .3.1.1 3

,

7 decane hydrochloride Example 90A (4s)-4-{i5-(1-Methyl-IH-pyrazol-4-vl)pyridin-3-vlloxyl-1 -128azatricyclo(3.3.1.1 3 ldecane N-borane complex Prepared from the product of Example 86A (102.7 mg, 0.32 mmol) and 1 nethyl-4-(4,4,5,5-tetranethyl-1,3,2-dioxabor olan-2-yl)-l H-pyrazole (94.7 mg, 0.46 mnmol) according to Method K: 'H NMR (300 MHz, chloroforn-D) 5 ppm 1.66-1 70 5 (in, 2 H), 2.04 (br s, I H), 2.28-2 32 (n, 4 H), 3.19-3.28 (m, 6 H), 3.97 (s, 3 H), 4.63 (t, J=3.2 Hz, 1 H), 7.26-7.28 (i, 1 H), 7.66 (s, I H), 7.76 (s, 1 H), 8 18 (d, J=2.8 Hz,lH), 8.39 (d, J=2.0 Hz, 1 H). MS (DCI/NH 3 ) m/z= 325 (M+H) . Example 90B 10 (4s)-4-{[5-( -Methyl-lH-pyrazol-4-yllpyridin- 3 -ylloxy} azatricyclof 3

.

3 .1.1 3 7 ldecane hydrochloride Prepared from the product of Example 90A (92.2 mg, 0 28 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.95-1.99 (m, 2 H), 2 23 (br s, I H), 2.38-2.42 (m, 2 H), 2.57 (br s, 2 H), 3.60 (s, 2 H), 3.70-3.79 (m, 4 H), 3.98 (s, 15 3 H), 5.26 (t, J=3.2 Hz, I H), 8.13 (s, 1 H), 8.39 (s, I H), 8.46-8.47 (in, I H), 8.57 (d, J=2.4 Hz, I H), 8.73 (d, J=1 .6 Hz, 1 H). MS (DCI/NH3) m/z= 311 (M+H)*. Anal. Calcd. for CisH 2 2N40-2 HCI 1.55 H 2 0: C, 52.57; H, 6.67; N, 13.62; Cl, 17 24. Found: C, 52.79; H, 6.62; N, 13 44; Cl, 17.03. 20 Example 91 ('4s)-4-{[5-(IH-Pyrazol-1-yl)pyridin-3-ylloxy)-1-azatricyclo[ .3..11 'ldecane Example 91A 3-Fluoro-5-(1H-pyrazol-1-ylpyridine 25 3-Bromo-5-fluoropyridine (300 mg, 1 705 mmol), 1 H-pyrazole (180 mg, 2.64 nmol), ferric acetylacetonate (181 mg, 0.511 mmol), copper(Il) oxide (13.6 mg, 0.170 mmol) and cesium carbonate (1 11 g, 3.41 mmol) were suspended in DMF (2.0 mL). The reaction mixture was stined at 90 "C for 60 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (3x30 mL) 30 and water (100 mL). The organic layers were combined, washed with brine (50 mL) and dried (sodium sulfate) It was then concentrated and the residue was purified by silica gel flash chromatography to afford the titled compound: 'H NMR (400 MHz, methanol-D4) 8 ppm 6.55 - 6.65 (m, I H), 7.80 (d, .11 2 Hz, I H), 8.10 (dt, J=9.9, -129- 2.3 H z, I H), 8.38 (d, J=2.5 H z, I H), 8.42 (d, J=1.5 H z, I H), 8.93 (s, I H). MS (ESI) m/z = 163 (M+H)*. Anal. Calcd. for CSHGFN3-0.15CH30H: C, 61.99; H, 4.48; N, 32.42; Found: C, 62.30; H, 4 12; N, 32.21. 5 Example 91B (4s)-4-{[5-( H-Pyrazol-1-yl)pyridin-3-lloXy)-1 -azatricyclo[ 3

.

3 .lv d1ecane bishydrochloride The product of Example 1OA (23.7 nig, 0 142 mmol) and potassium tert 10 butoxide (18.2 mg, 0.162 mmol) were dissolved in dimethyl sulfoxide (0.3 mL) and stirred at 25 "C for 1 hour.. A solution of the product of Example 91A (22 mg, 0.135 mmol) in DMSO (0.3 mL) was added dropwise. The reaction mixture was stirred at 25 "C for 18 hours. The mixture was dissolved in DMF (2 mL), filtered and purified by preparative HPLC [Waters@ XTerra RP 18 5 pm column, 30x 100 mm, flow rate 40 15 mL/minutes, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nm]. Fractions containing the desired product were pooled, concentrated under vacuum and then processed as described in Method C. The resulting mixture in 3 N HCI was concentrated to dryness and stirred in 10:1 diethyl 20 ether/MeOH- The precipitate was filtered and dried under vacuum to afford the titled compound: 'H NMR (400 MHz, methanol-D 4 ) 8 ppm 1.98 (m, 2 H), 2.24 (br s, 1 H), 2.41 (m, 2 H), 2.60 (br s, 2 H), 3.61 (br s, 2 H), 3.70 - 3.80 (m, 4 H), 5.33 (t, J=3.2 Hz, 1 H), 6.65 - 6.71 (m, I H), 7.88 (d, J= 1.5 Hz, 1 H), 8 56 -8 77 (m, 3 H), 9.04 (s, I H). MS (ESI) m/z= 297 (M+H)*. Anal- Caled. for C 1 7H 2

ON

4 0.2HCl-1.6

H

2 0: C, 25 51.29; H, 6.38; N, 14.07; Cl, 17.81; Found: C, 51.21; H, 6.18; N, 13.87; Cl, 17.96. Example 92 (4s)-4-5-(4-Chlorophenyl)pyrdin3-yllox .-1 -azatricyclof 3

.

3 I .1ldecane 30 hydrochloride Example 92A (4s)-4-{f5-(4-Chlorophenyl)pyridin- 3 -ylloxy-1-azatricyclo[ 3

.

3 .1.1 3 .ldecane

N

-130borane complex Prepared from the product of Example 86A (82.6 ng, 0.26 mrnmol) and 4 chlorophenylboronic acid (66.3 mg, 0.42 mmol) according to Method K: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.67-1.71 (m, 2 H), 2.03 (br s, I H), 2 28-2 32 (m, 4 5 H), 3 19-3.28 (m, 6 H), 4.66 (t, J=3.2 Hz, I H), 7.35-7 37 (n, I H), 7.44-7.51 (m, 4 H), 8.32 (d, J=2.8 Hz, I H), 8.46 (d, .1=2.0 Hz, I H). MS (DCI/NH 3 ) m/z= 355 (M+H)*. Example 92B 10 {4s!-4- [5-(4-ChlorophenlylDiidin-3 -yllox-1-azatncyclo_ 3 ... L decan hydrochloride Prepared from the product of Example 92A (52.4 mg, 0.15 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.95-1.99 (m, 2 H), 2.24 (br s, I H), 2.40-2.44 (m, 2 H), 2.59 (br s, 2 H), 3.60 (s, 2 H), 3.68-3.78 (m, 4 H), 5.26 (t, 15 J=3.2 Hz, 1 H), 7.58-7.62 (n, 2 H), 7.81-7.85 (m, 2 H), 8.51 (dd, J=2.7, 1.4 Hz, I H), 8.74 (d, J=2.7 Hz, I H), 8.79 (d, J=1 .4 Hz, I H). MS (DC1/NH 3 ) n/z= 341 (M+H) . Anal. Calcd. for C 20

H

21 CN20-2 HCH-1.5

H

2 0: C, 54.50; H, 5.95; N, 6.36; Cl, 24.13. Found: C, 54.80; H, 5.86; N, 6.31; Cl, 23.79 20 Example 93 (4s)-4-(3,4'-Bipyrdin-5-yloxy)-1-azatricyclo[ 3 .3.1.1 ldecane hydrochloride Example 93A 5-Fluoro-3,4'-bipyridine 25 Prepared from 3-bromo-5-fluoropyridine (439.0 mg, 2.50 minol) and pyridin 4-ylboronic acid (509.9 mg, 3.73 nmol) according to Method K, except the product was purified by silica gel chromatography (ethyl acetate, R, = 0.21) instead of preparative HPLC: 'H NMR (300 MHz, chloroform-D) 8 ppm 7.50-7.51 (m, 2 H), 7.65 (dt, J=9.1, 2.4 Hz, I H), 8.56 (d, J=2.8 Hz, I H), 8.73-8.76 (n, 3 H). MS 30 (DCI/NH 3 ) m/z= 175 (M+H)*. Example 93B (4s)-4-(3,4'-Bipyridin-5-yloxy)-I -azatricyclor3.

3 .1.1 3

,

7 decane N-borane complex -131- Prepared from the product of Example IOA (84.0 mg, 0.50 miol) and the product of Example 93A (111.3 mg, 0.64 mmol) according to Method I: 'H NMR (300 MHz, chloroforn-D) 8 ppm 1.68-1.72 (m, 2 H), 2.05 (br s, I H), 2,30-2 32 (m, 4 H), 3.20-3 30 (m, 6 H), 4.68 (t, J=3.1 Hz, I H), 7.43-7.44 (m, I H), 7.48-7.50 (m, 2 5 H), 8.40 (d, J=2.7 Hz, I H), 8.53 (d, J=1.7 Hz, 1 H), 8.72-8 74 (m, 2 H). MS (DCI/NI 3 ) m/z= 322 (M+H). Example 93C (4s)-4-(3,4'-Bipyridin-5-yoxy)- -azatricyclo[ 3 .3.1.1 33 ldecane hydrochloride 10 Prepared from the product of Example 93B (141.8 mg, 0.44 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.95-1.99 (m, 2 H), 2.24 (br s, I H), 2.41-2.45(m, 2 H), 2.59 (br s, 2 H), 3.60 (s, 2 H), 3.70-3.78 (m, 4 H), 5.31 (t, J=3.39 Hz, 1 H), 8.52-8.54 (n, I H), 8.57-8.60 (m, 2 H), 8.82 (d, J=2.71 Hz, I H), 8.95 (d, J=1.36 Hz, I H), 9.00-9.02 (m, 2 H). MS (DCI/NH3) m/z= 308 (M+H) . 15 Anal. Calcd. for COH 2 N30-3 HCl-2 H 2 0: C, 50.40; H, 6.23; N, 9.28 Found: C, 50.70; H, 6.23; N, 9.23. Example 94 (4s)-4-f(5-Pyrimidin-5-ylpyidin3-l)oxyl -azatricyclo[ 3 .3.1.1 _ ]decane 20 hydrochloride Example 94A s4- 5-Pimidin-5-ypyridin-3-yl -azatricyclo 3.3 .1.1ldecane N-boane complex 25 Prepared from the product of Example 86A (101.0 mg, 0.31 mmol) and pyrimidin-5-ylboronic acid (53.1 mg, 0.43 mmol) according to Method K: 'H NMR (300 MHz, chloroforni-D) 5 ppm 1.68-1 73 (m, 2 H), 2.06 (br s, 1 H), 2.30-2.32 (m, 4 H), 3.20-3.30 (m, 6 H), 4.70 (t, J=3.1 Hz, 1 H), 7.40-7.41 (m, 1 H), 8.44 (d, J=27 Hz, 1 H), 8 49 (d, J=2 0 Hz, 1 H), 8.98 (s, 2 H), 9.29 (s, 1 H) MS (DCI/NH3) m/Z= 30 323 (M+H). Example 94B (4s)-4-(5-PYriidin-5-ylp-azatriccloF 3 .3.1 .1 "'ldecane -132hydrochloride Prepared from the product of Example 94A (24.0 mg, 0.074 mmol) according to Method J: 'H NMR (300 MHz, rnethanol-D4) 5 ppm 1,95-1.99 (m, 2 H), 2.24 (br s, 1 H), 2 41-2.45(m, 2 H), 2.59 (br s, 2 H), 3.60 (s, 2 H), 3.70-3 78 (i, 4 H), 5.31 (t, 5 J=3-4 Hz, I H), 8.66-8.68 (in, 1 H), 8 88 (d, J=2 4 Hz, 1 H), 8.94 (d, J=1.6 Hz, I H), 9-26 (s, 2 H), 9.32 (s, I H). MS (DCI/NH 3 ) m/z= 309 (M+H)*. Example 95 (4r)-4-(6-Chloro-pyidin-3-yloxy)-1-aza-tricyclo 3 .3.1.1 ]decane hydiochloride 10 Examples 95A1, 95A2, 95A3, and 95A4 (4s)-4--(6-Chloro-PYidin-3-yloxy)-'-aza-tricyclo[3.1.1 V ]decane N-borane complex (95A l), (4r)-4-(6-Chloro-Pyrdin-3-yloxy)-1-aza-tricycl[3.l ]'ldecane N-borane complex 15 (95A2), (4s)-4-(5-Fluoro-pyridin-2-yloxy)-1-aza-tiicclo 3.3.1.1 3 -]decane N-borane complex (95A3), and (4ri)-4-(5-Fluoro-pyridin-2-yloxy)--a-tricyclo 3.3.1 .1ldecane N-borane complex (95A4) 20 A solution of the product of Example 9A (2.4:1 diastereomer mixture; 3.34 g, 20 mmol) in dry THF (40 mL) was treated with potassium bis(trimethylsilyl)amide (4.0 g, 20 mmol), and the mixture was stirred at room temperature for 1 hour. 2 Chloro-5-fluoropyridine (2-6 g, 20 nmol) was added, and the mixture was heated at 60 *C for 2 hours. The mixture was purified by flash chromatography [200 g silica 25 gel, eluting with hexanes-ethyl acetate (100% to 60% gradient over 72 minutes at 40 mL/minute flow rate)]. Four products were collected: (4s)-4-(6-chloro-pyridin- 3 yloxy)- 1 -aza-tricyclo[ 3 3.1 .1 3

,

7 ]decane N-borane complex (95A1); (4r )-4-(6-chloro pyiidin-3-yloxy)-l-aza-tricyclo[ 3 .31.1 V]decane N-borane complex (95A2); (4s)- 4 (5-fluoro-pyridin-2-yloxy)- I -aza-tricyclo[ 3 .3.1. 1 3 7 ]decane N-borane complex 30 (95A3); and (4r-)-4-(5-fluoro-pyridin-2-yloxy)-I -aza-tiicyclo[ 3

.

3 . 1.1 V ]decane N borane complex (95A4) Example 95B -133- (4r)-4-(6-Chloro-pyridin-3-yloxy)-i-aza-tricyclo 3.3.1.13 3 ldecane Prepared from the product of Example 95A2 (750 mg, 2.69 mmol) according to Method C to provide the titled compound: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.75 (s, I H), 1.97 - 2-08 (ni, 4 H), 2.14 - 2.25 (m, 2 H), 2 95 (s, I H), 2.99 (s, I 5 H), 3.14 (s, 2 H), 3.45 (s, I H), 3.49 (s, 1 H), 4 74 (s, I H), 7.33 - 7.38 (in, I H), 7.45 7.52 (m, I H), 8.09 (d, J=3.1 Hz, I H). MS (DCI/NH 3 ) m/e= 265/267 (M+H). Example 95C 10 (4r)-4-(6-Chloro-pyridin-3-yloxvy)--aza-tricyclo[ 3

.

3 .1.1 ldecane Hydrochloride Prepared from the product of Example 95B (120 mg, 0.453 mmol) according to Method H to provide the titled compound: 'H NMR (300 MHz, methanol-D4) 8 ppm 2.04 - 2.29 (m, 5 H), 2.47 (s, 2 H), 3.43 (s, I H), 3.46 (s, I H), 3.55 (s, 2 H), 3.80 (s, I H), 3.84 (s, 1 H), 4.81 (t, J=3.4 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1 H), 7.57 (dd, 15 J=8..8, 3.4 Hz, I H), 8.18 (d, J=3.1 Hz, 1 H). MS (DCI/NH 3 ) m/e= 265, 267 (M+H)*. Anal. calcd. for C1 4

H,

7

N

2 CO-1.51-ICI: C, 52.64; H, 5,84; N, 8.77; Found C, 52.44; H, 5.86; N, 8,68. 20 Example 96 (4s)-4-[(6-Bromopyridi n-3-yl)oxyl-l -azatricyclo[3.3.1.1 3 l7Idecane hydrochloride Example 96A (4s)-4-f(6-Broio pidii-3-l)oxl-l-azatiicvclor3.3.l.1 3 ldecane N-borane complex 25 Prepared from the product of Example 10A (81 .6 mg, 0.49 mmol) and 2 bromo-5-fluoropyridine (160.8 mg, 0.91 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) 8 ppm 1.65-1.69 (m, 2 H), 2.03 (br s, I H), 2.20-2.26 (m, 4 H), 3.15-3.27 (m, 6 H), 4.54 (t, J= 3 .1 Hz, I H), 7.13 (dd, J=8.8, 3.1 Hz, I H), 7.40 (d, J=8 8 Hz, I H), 8.09 (d, J=3.4 Hz, 1 H). MS (DCI/NH 3 ) m/z= 323 (M+H) 4 . 30 Example 96B (4s)-4-[(6-Bromopyridin-3-yl)oxyl-I-azatricyclo[ 3 .3.1.1 3

,

7 ldecane hydrochloride Prepared from the product of Example 96A (111.3 mg, 0 35 mmol) according -134to Method J: 'H NMR (300 MIz, methanol-D4) 5 ppm 1.89-1.93 (m, 2 H), 2.19 (br s, 1 H), 2.34-2.38 (i, 2 H), 2.47 (br s, 2 H), 3.56-3 72 (n, 6 H), 4.90 (t, J=3.4 Hz, I H), 7.47 (dd, J=8-7, 3.2 Hz, 1 H), 7.54 (d, J=9.1 Hz, 1 H), 8.18 (d, J=3.2 Hz, I H). MS (DCI/NH 3 ) m/z= 309 (M+H)*. Anal. Calcd. for C 4

H,

7 BrN 2 0-1 2 HCI: C, 47.62; 5 H, 5.17; N, 7.94. Found: C, 47.62; H, 5.17; N, 7 90. Example 97 5-f(4s)-1 -Azatricyclo[3.3.1.1 V ldec-4-yloxylpyridine-2-carbonitrile hydrochloride 10 Example 97A 5-[(4s)-1-Azatricvclof 3 .3.1.1 ldec-4-loxylpyridine-2-carbonitrile N-borane complex Prepared from the product of Example 10A (88.1 mg, 0.53 mmol) and 5 15 fluoropicolinonitrile (61.5 mg, 0.50 mmol) according to Method 1: 'H NMR (300 MH1z, chloroform-D) 5 ppm 1.69-1.73 (m, 2 H), 2.06 (br s, 1 H), 2.22-2.27 (m, 41H), 3.21-3.30 (i, 6 H), 4.68 (t, J=3.1 Hz, I H), 7.24-7.28 (m, I H), 7.66 (d, J=8.7 Hz, I H), 8 41 (d, J=3.6 Hz, 1 H). MS (DCI/NH 3 ) m/z= 287 (M+N1V) 4 . 20 Example 97B 5-[(4s)-1-Azatricyclo 3 .3.1 .137ldec-4-yloxylpyridine-2-carbonitrile hydrochoride Prepared from the product of Example 97A (54 8 ing, 0.20 mmol) according to Method .J: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.91-1.95 (m, 2 H), 2.20 (br s, 1 H), 2.34-2.39 (m, 2 H), 2.50 (br s, 2 H), 3.57 (s, 2 H), 3.61-3.74 (m, 4 H), 5.04 (t, 25 J=3.4 Hz, 1 H), 7.64 (dd, J=8.8, 3.1 Hz, 1 H), 7.85 (d, J=8.8 Hz, I H), 8.49 (d, J=3.1 Hz, 1 H). MS (DCI/NH3) m/z= 256 (M+H)*. Anal. Calcd. for C 15 H1 7

N

3 0-HClIH20: C, 61.75; H, 6.22; N,14.40; Cl, 12.15. Found: C, 61.64; H, 6-41; N, 14.36; Cl, 12.24. 30 Example 98 (4s)-4-{(5-Thien-2-ylpYridin-2-ylloxl-1-azatricyclo 3.3.1.1v ldecane The free base of the title compound was prepared from the product of Example IOC (50 mg, 0 16 mmol) and 2-thiophene boronic acid (29 mg, 0.23 mmol; -135- Aldrich) according to Method G, and converted to the p-toluenesulfonate salt using the procedure of Method H: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.92 (d, J=13.6 Hz, 2 H), 2.19 (s, I 11), 2.32 - 2.46 (m, 6 H), 2.55 (s, 2 H), 3.57 (s, 2 H), 3.68 (s, 4 H), 5.46 (s, I H), 6.93 (d, J=8.5 Hz, 1 H), 7.10 (dd, J=5.1, 3.4 Hz, I H), 7,22 (d, 5 J=8.5 Hz, 2 H), 7.37 (dd,1=5.3, 4.4 Hz, 2 H), 7.70 (d, J=8 I Hz, 2 H), 7.97 (dd, J=8.6, 2-5 Hz, I H), 8.38 (d,.1=2 7 Hz, 1 H). MS (DCI/NH3) n/z= 31 3

(M+H)

4 . 10 Example 99 (4s)- 4

-

6 -( H-Indol- 5-vl)-idin-3-yloxyl-1-azatricyclo[ 3

.

3 .1.1"']decane dihydrochloride Prepared from the pi oduct of Example 15B (165 mg, 0.623 mmol) and I H indol-5-ylboronic acid using the microwave Suzuki coupling Method G and the salt 15 formation Method H to provide the titled compound: 'H NMR (300 MHz, methanol D4) S ppm 1.96 (s, I H), 2.00 (s, I H), 2 24 (s, I H), 2.40 (s, 1 H), 2 44 (s, 1 H), 2.59 (s, 2 H), 3.61 (s, 2 H), 3.74 (s, 4 H), 5.19 (t, J=3 2 Hz, I H), 6.66 (dd, J=3.2, 0.8 Hz, I H), 7.43 (d, J=3.4 Hiz, 1 H), 7.59 - 7.64 (m, 1 H), 7.64 - 7.68 (n, 1 H), 8.16 (dd, J=1 .9, 0.8 Hz, I H), 8.31 - 8.35 (m, I H), 8.36 - 8 41 (in, 1 H), 8.61 (d, J=2.0 Hz, 1 20 H). MS (DCI/NH3) m/e= 346 (M+H)*- Anal- calcd. for C 22

H

2 3

N

3 O2HCl-H20: C, 60-55; H, 624; N, 9.63; Found C, 60.71; H, 6.38; N, 9,39. Example 100 25 (4)-4-[6-( H-Indol-5-y1)-pvfidin-3-yloxyjl--azatr icyclo[3.1 .ldegane trifluoroacetate Prepared from the product of Example 95B (135 mg, 0.510 mmol) and I H indol-5-ylboronic acid using the microwave Suzuki coupling Method G and the salt formation Method H to provide the titled compound: ' H NMR (300 MHz, methanol 30 D4) 8 ppm 2.06 - 2 30 (n, 5 H), 2.52 (s, 2 H), .3.44 (s, 1 H), 3.49 (s, I H), 3.57 (s, 2 H), 3 86 (s, 1 H), 3.90 (s, I H), 4.84 - 4.86 (n, 1 H), 6.52 (d, J=3.1 Hz, I H), 7-26 7.30 (in, I H), 7.46 (d, J=8.5 Hz, I H), 7.59 - 7.67 (m, 2 H), 7-83 (d, J=8.8 Hz, 1 1-1), 8 06 (s, 1 H), 8.37 (d, J=2.7 Hz, I H). MS (DCI/NIj3) m/e= 346 (M+H)*. Anal. -136calcd. for C 22

H

23

N

3 0l.17C2HF 3 02: C, 61.05; H, 5.09; N, 8.78; Found C, 60.98; H, 4.98; N, 8.75. 5 Example 101 {4s)-4-{ 6 -( 1H-Indol-6vl)-pvril-V vl ricyclo3 .3.1.1 ldecane trihydrochloride Prepared from the product of Example 15B (115 mg, 0.434 mmol) and I H indol-6-ylboronic acid using the microwave Suzuki coupling Method G and the salt 10 fonnation Method H to provide the titled compound: 'H NMR (300 MHz, methanol D4) S ppm 1. 93 - 2.05 (m, 2 H), 2.24 (s, I H), 2.40 (s, I H), 2.44 (s, 1 H), 2.59 (s, 2 H), 3.61 (s, 2 H), 3.67 - 3.81 (m, 4 H), 5.19 (t, J=3.2 Hz, I H), 6.61 (d, J=3.1 Hz, I H), 7.48 - 7.55 (m, 2 H), 7.82 (d, J=8.5 Hz, 1 H), 7.97 (s, I H), 8.31 - 8.36 (in, i H), 8.36 - 8.42 (m, I H), 8.62 (d, J=2.4 Hz, I H). MS (DCI/NH3) m/e= 346 (M+H) . 15 Anal. calcd. for C 22

H

23

N

3 0-3HCl-0.3H20: C, 57.42; H, 5.83; N, 9.13; Found C, 57.46; H, 5.98; N, 9.01. Example 102 20 (4r)-4-[ 6 -(1H-Indol-6-yl)--pyidin-3-yloxyl-I-azatricyclo[ 31.1dl..decane dihydrochloride Prepared from the product of Example 95B (125 mg, 0.472 mmol) and IH indol-6-ylboronic acid using microwave Suzuki Coupling Method G and the salt formation Method H to provide the titled compound: 'H NMR (300 MHz, methanol 25 D4) S ppm 2.11 - 2.34 (m, 5 H), 2.58 (s, 2 H), 3.49 (s, 1 H), 3.54 (s, 1 H), 3.60 (s, 2 H), 3.87 (s, I H), 3.92 (s, I H), 5.09 (t, J=34 Hz, 1 H), 6.61 (dd, J=3.2, 0.8 Hz, I H), 7.49 - 7.54 (m, 2 H), 7.83 (d, J=8.5 Hz, I H), 7.98 (s, I H), 8.32 - 8.38 (m, I H), 8.38 - 8.43 (m, I H), 8.61 (d, .1=2 7 Hz, I H). MS (DCI/NH 3 ) m/e= 346 (M+H)+. Anal. calcd. for C 2 2

H

23

N

3 0-2HCI-2.2H20: C, 57 69; H, 6.47; N, 9 17; Found C, 57.35; H, 30 626; N, 8.95. Example 103 -137- 5-{5-[(4s)-1 -azatricyclo( 3 .3.1 .1 3 7 ldec-4-yloxylpyridin-2-yl}-_1,3-dihydio-2H-indol-2 one dihydrochloride Prepared from the product of Example 15B (185 mg, 0.699 mrnol) and 5 (4,4,5,5-tetranethyl-1,3,2-dioxaborolan-2-yl)inldolin-2-one using the microwave 5 Suzuki coupling Method G and the salt formation Method H to provide the titled compound: 'H NMR (300 MHz, methanol-D4) S ppm 1.93 - 2.00 (m, 2 H), 2.23 (s, I H), 2.39 (s, 1 H), 2.43 (s, 1 H), 2.56 (s, 2 H), 3.58 - 3.78 (m, 8 H), 5 09 - 5 16 (m, I H), 710 (d, J=8.5 Hz, I H), 7.73 - 7.82 (m, 2 H), 8.10 - 8.23 (m, 2 H), 8.57 (d, J=2.7 Hz, 1 H). MS (DCI/NH 3 ) m/e= 362 (M+H)*. Anal calcd for 10 C 22

H

2 3N 3 02HCI-H20: C, 58.64.; H, 6 02; N, 9.29; Found C, 58.64; H, 5.99; N, 9 11 Example 104 (4,)-46-(Benzofuran-5--idin-3-yloxyl-azticlof 3 . .decne 15 trifluoroacetate Prepared from the product of Example 95B (165 mg, 0.623 mnol) and 2 (benzofuran-5-yl)-4,4,5,5-tetTamethyl-1,3,2-dioxaborolane using the microwave Suzuki coupling Method G and the salt formation Method H to provide the titled compound: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 2.07 - 2.30 (m, 5 H), 2.52 (s, 2 20 H), 3.45 (s, I H), 3.49 (s, I H), 3.57 (s, 2 H), 3.86 (s, 1 H), 3.90 (s, 1 11), 4.87 (t, J=3-2 Hz, 1 H), 6.91 (d, J=3.1 Hz, 1 H), 7.58 (d, J=8.8 Hz, I H), 7.63 (dd, J=8.8, 3.1 Hz, 1 H), 7.79 - 7.88 (m, 3 H), 8.13 (d, J=1.4 Hz, 1 H), 8.42 (d, J2.4 Hz, I H). MS

(DCI/NH

3 ) m/e= 347 (M+H)*. Anal. calcd. for C 22 H2N 2 O.1.15C2HF302: C, 61-12; H, 4.89; N, 5.87; Found C, 60.98; H, 4.74; N, 5.87 25 Example 105 (4s)-4-[(5,6-DibomopyridinV-3-yl)oxyl-1-azatricyclof3.3.1.1 3 7 1decane hydrochloride 30 Example 105A (4s)-4-[(5,6-Dibrom opyrdin-3-yl)oxyl-1-azatricyclo[3.3.1 .1.

3

-

7 decane N-borane complex Prepared fron the product of Example IOA (108.6 mg, 0.65 minol) and 2,3 -138dibrono-5-fluoropyridine (24 5 mg, 0.96 mnol) according to Method 1: 'H NMR (300 MHz, chlorofori-D) 6 ppm 1 67-1.70 (m, 2 H), 2.03 (br s, I H), 2.22-2.24 (m, 4 H), 3.19-3.28 (m, 6 H), 4.55 (t, J=3. 1 Hz, I H), 7.49 (d, J=2.7 Hz, 1 H), 8.06 (d, J=2.7 Hz, I H). MS (DCI/NH 3 ) m/z= 401 (M+H)' 5 Example 105B (4s)-4-[(5,6-Dibromopyridin-3-yloxYl-' -azatricyclo[ 3

.

3 . 1'ldecane hydrochloride Prepared from the product of Example 105A (142.3 mg, 0.35 minol) according to Method J: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.89-1.93 (m, 2 H), 2.18 (br 10 s, I H), 2.33-2.37 (m, 2 H), 2.46 (br s, 2 H), 3.56-3.71 (m, 6 H), 4.92 (t, J=3.2 Hz, I H), 7.91 (d, J=2.8 Hz, I H), 8.19 (d, J=2.8 Hz, I H). MS (DCI/NH3) m/z= 387 (M+H)*. Anal Calcd for CwHi 6 Br 2 N20-l.5 HCI: C, 37.98; H, 3.98; N, 6.33. Found: C, 37.98; H, 4.07; N, 6.30. 15 Example 106

(

4 s)-4-(Pyridin-2-ylo x)-azatricyclot 3 .3.1.1 3 ldecane hydrochloride Example 106A 20 (4s)-4-(Pyridin-2-yloxy)-1-azatricyclo[ 3 .3.1.1 3 7 ldecane N-borane complex Prepared from the product of Example I0A (101.3 mg, 0.61 mmol) and 2 chloropyridine (120 mg, 1.06 mmol) according to Method 1: 'H NMR (300 MHz, chloroforml-D) 8 ppm 1.63-1.67 (m, 2 H), 2.01 (br s, I H), 2.23-2.29 (in, 4 H), 3.17 3.30 (m, 6 H), 5.29 (t, J=3.1 Hz, I H), 6.77 (d, J=8 3 Hz, I H), 6.85-6.89 (m, I H), 25 7.56-7 62 (in, 1 H), 8.11 (dd, J=5.2, 2.0 Hz, I H). MS (DCI/NH3) m/z= 260

(M+NH

3 -H)*. Example 106B (4s)-4-(Pyridin-2-yloxy)-l-azatricyclo( 3 .3.1.1 ldecane hydrochloride 30 Prepared fiom the product of Example 106A (53.7 mg, 0 22 mmol) according to Method J: 'H NMR (.300 MHz, methanol-D 4 ) 8 ppm 1.96-2.00 (m, 2 H), 2.23 (br s, I H), 2.34-2 39 (in, 2 H), 2.58 (br s, 2 H), 3.59 (s, 2 H), 3.67-3 71 (m, 4 H), 5.44 (t, J=3.4 Hz, I H), 7.30-7 34 (m, 1 H), 7.42 (d, J=8.7 Hz, I H), 8.16-8.22 (m, 1 H), 8.30 -139- 8.32 (m, 1 H). MS (DCI/NH 3 ) m/z= 231 (M+H)*. Anal. Called. for CWHisN 2 0 2 HCI: C, 55.45; H, 6.65; N, 9 24; Cl, 23.38. Found: C, 55.43; H, 6.67; N, 9.10; Cl, 23.49 5 Example 107 {_s--5Fur-prdn2yo -- aza-tricyclo[ 3

.

3 .1 3 'ldecane dihydrochloride Prepared from the product of Example 95A3 (4s)-4-(5-fluoro-pyridin- 2 10 yloxy)-1-aza-tricyclo[ 3

.

3 .1.1 3 7 ]decane N-borane complex (200 mg, 0.763 mmol) using the acid deboronation Method C and the salt formation Method H to provide the titled compound: 'H NMR (300 MHz, methanol-D 4 ) S ppm 1.89 (s, 1 H), 1.94 (s, I H), 2.18 (s, I H), 2.33 (s, 1 H), 2.37 (s, 1 H), 2.52 (s, 2 11), 3-56 (s, 2 H), 3.61 - 3.72 (m, 4 H), 5.38 (t, J=3.2 Hz, I H), 6.94 (dd, J=9.3, 3.9 Hz, 1 H), 7.58 (ddd, J=9.2, 7.8, 15 3.1 Hz, I H), 8.01 (d, J=3.1 Hz, 1 H). MS (DCI/NH 3 ) mle= 249 (M+H) 4 . Anal calcd. for C, 4

H

7

N

2 FO-2.9HCI

H

2 0: C, 45.20; 1, 5.93; N, 7 53; Found C, 45 29; H, 6.11; N, 7.48. 20 Example 108 (4s)-4-f(5-Bromopyridin-2-yl)oxyl-1-azatricyclo[ 3

.

3 .1.1' 7 decane hydrochloride Example 108A [4s)-4-[(5-Bromopyridin -2-ylloxyl-azatricyclo[ 3 .3.1.1 jdecane N-borane complex 25 Prepared from the product of Example I0A (419.0 mg, 2.51 mmol) and 5 bromo-2-chloropyridine (592.4 mg, 3.08 mmol) according to Method 1, except the product was purified by silica gel chromatography (2.5% ethyl acetate in dichloromethane, R, = 0.39) instead of preparative HPLC: 'H NMR (300 MHz, chloroforn-D) 8 ppm 1.63-1.67 (m, 2 H), 1.99 (br s, I H), 2.23-2.29 (n, 4 H), 3.17 30 3.28 (in, 6 H), 5.22 (t, J=3.1 Hz, 1 H), 6.69 (d, J=8.8 Hz, I H), 7.67 (dd, J=8.8, 2.0 Hz, 1 H), 8.15 (d, J=2.0 Hz, I H). MS (DCI/NIH 3 ) rn/z= 338 (M+NH 3 -H)*. Example 108B -140- (4s)-4-[(5-Bromopyridin-2-yl)oxyl-l-azatricyclo[3.

3 .1.1ldecane hydrochloride Prepared from the product of Example 108A (151.9 mg, 0.47 mmol) according to Method .: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.90-1 94 (m, 2 H), 2.18 (br s, I H), 2.33-2.37 (m, 2 H), 2.52 (br s, 2 H), 3 54-3.71 (m, 6 H), 5.41 (t, J=3 2 Hz, 1 5 H), 6.85 (d, J=8.8 Hz, 1 H), 7.84 (dd, J=88, 2.7 Hz, 1 H), 8 19 (d, J=2.7 Hz, I H) MS (DCI/NI 3 ) m/z= 309 (M+H)*. Anal. Calcd. for CHiBrN 2 0-1 15 HCI: C, 47.89; H, 5 21; N, 7 98. Found: C, 47.91; H, 5.14; N, 7.

84 . 10 Example 109 (4s)-4-[(4-Bromopyridin-2-yl)oxyl-1-azatricyclo[ 3 .3.1.1 ldecane hydrochloride Example 109A (4s)-4-(4-Bromopydi-2-yloxyl-1-azatricyclo[3.

3 .1.1 3

,

7 ldecane N-borane complex 15 Prepared from the product of Example 10A (86.7 mg, 0.51 mmol) and 4 bromo-2-fluoropyridine (166.3 mg, 0.95 mmol) according to Method 1: 'H NMR (300 MHz, chlioroform-D) 8 ppm 1.63-1.67 (in, 2 H), 2.00 (br s, I H), 2.20-2.28 (in, 4 H), 3.17-3.28 (in, 6 H), 5.27 (t, J=3.4 Hz, I H), 7.00 (d, J=1.6 Hz, I H), 7.04 (dd, J=4.8, 1.6 H z, 1 H), 7.94 (d, J=48 Hz, I H). MS (DCI/NH 3 ) m/z= 338 (M+NH 3 -H). 20 Example 109B (d -yl)ox- I -azatricyclo[3.3. 1.1 3

,

7 ldecane hydrochloride Prepared from the product of Example 109A (41.8 mg, 0.13 mmol) according~ to Method J: 1 H NMR (300 MHz, rnethanol-D4) S ppm 1.90-1.94 (m, 2 H), 2.19 (br 25 s, 1 H), 2.33-2.38 (m, 2 H), 2.53 (br s, 2 H), 3.57 (br s, 2 H), 3.62-3.72 (m, 4 H), 5 44 (t, J=3.4 Hz, 1 H), 7 17-7.21 (in, 2 H), 8.01 (d, J=5 .4 Hz, I H). MS (DCI/NH 3 ) Im/z= 309 (M+H)*. Anal. Calcd. for C1 4

H

7 BrN20-1.15 HC: C, 47.89; H, 5.21; N, 7.98. Found: C, 47.99; H, 5,06; N, 7.82. 30 Example 110 (4s)-4-(3,3'-Bipyridin-6-yloxy)-l-azatricyclo[3.3. .1 - 7 ldecane hydochloride -141- Example I 1OA (4s)-4-(3.3'-Bipcyidin-6-loxy)-1-azatricyclo[3.3.1.1' 7 1decane N-borane complex Prepared from the product of Example 108A (118.8 mg, 0.37 mmol) and pyridin-3-ylboronic acid (69.3 mg, 0.56 mmol) according to Method K: 'H NMR 5 (300 MHz, chloroform-D) 8 ppm 1.66-1 70 (m, 2 H), 2.02 (br s, I H), 2.26-2.34 (m, 4 H), 3.19-3 32 (m, 6 H), 5.35 (t, J=3.2 Hz, 1 H), 6.88-6.91 (m, I H), 7.38 (dd, J.=7.9, 4.8 Hz, 1 H), 7.80-7.83 (n, 2 H), 8.34 (d, J=2.0 Hz, I H), 8.61 (dd, J=4.8, 1.6 Hz, 1 H), 8.79 (d, J=2.0 Hz, I H). MS (DCI/NH3) n/z= 322 (M+H)*. 10 Example I IOB {_4s)-4-(3,3'-Bipyridin.-6-ylox y--azatricvclo{ 3 .3.1.1 3 7 lldecane hydrochloride Prepared from the product of Example I IOA (58.5 mg, 0.18 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.94-1.98 (m, 2 H), 2.22 (br s, I H), 2.37-2.41 (m, 2 H), 2,59 (br s, 2 H), 3.59 (br s, 2 H), 3.66-3.75 (in, 4 H), 5.56 15 (t, J=3.4 Hz, 1 H), 7.12 (d, J=8.7 Hz, I H), 8.14-8.22 (, 2 H), 8 61 (d, J=2.8 Hz, I H), 8.83 (d, J=6.0 Hz, I H), 8.88-8.92 (m, 1 H), 9.19 (d, J=24 Hz, I H). MS (DCI/NH3) m/z=- 308 (M+H)*. Anal. Calcd.. for C1 9

H

2 IN30-2 HCI-H 2 0: C, 57.29; H, 6.33; N, 10.55; Cl, 17.80. Found: C, 57.21; H, 6.42; N, 10.46; Cl, 17.63. 20 Example 111 {4s)-4-(3,4'-Bipyridin-6-yoxy)-1 -azatricyclo( 3

.

3 .1.1 3 ldecane hydrochloride Example 11 A 25 6-Fluoro-3,4'-bipyridine Prepared from 5-bromo-2-fluoropyridine (881 ing, 5.00 mmol) and pyridin-4 ylboronic acid (979 mg, 7.96 mmol) according to Method K, except the product was purified by silica gel chromatography (10% ethanol in ethyl acetate, Rf = 0.32) instead of preparative HPLC: 'H NMR (300 MHz, chloroforn-D) 8 ppm 7.08 (dd, J=8.5, .3.0 .30 Hz, I H), 7.48-7.50 (in, 2 H), 8.01-8.07 (m, 1 H), 8.51 (d, J=2.7 Hz, I H), 8.72-8.74 (in, 2 H). MS (DCI/NH3) m/z= 175 (M+H)*. Example 111B -142- (4s)-4-(3,4'-Bipyidin-6-loxy) I-azatricyclo[3.3.1 .1 -1decane N-borane complex Prepared from the product of Example I0A (101.1 mg, 0.62 mmol) and the product of Example I 1IA (107 3 mg, 0.62 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) 5 ppm 1.66-1.70 (in, 2 H), 2.02 (br s, I H), 2.25-2.34 (i, 4 5 H), 3.19-3.32 (in, 6 H), 5.35 (t, J=3.2 Hz, I H), 6.90 (d, J=8.5 Hz, I H), 7 47-7-49 (in, 2 H), 7.88 (dd, J=8.6, 2.5 Hz, I H), 8.43 (d, J=2 4 Hz, I H), 8.67-8.68 (in, 2 H). MS (DCI/NH3) m/z= 322 (M+H)+. Example 111C 10 (4s)-4-(3,4'-Bipyridin-6-yloxy)-1-azatricyclo[ 3 .3.1.l1l ldecane hydrochloride Prepared from the product of Example 11 lB (134.6 mg, 0.42 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 5 ppm 1 95-1.99 (in, 2 H); 2.22 (br s, 1 H); 2 37-2.41 (in, 2 H), 2.60 (br s, 2 H); 3.36 (br s, 2 H); 3.71 (br s, 4 H); 5.61 (t, J=3.2 Hz, I H); 7.15 (d, J=8.8 Hz, I H); 8.36-8.42 (in, 3 H); 8.83-8.87 (m, 3 H). MS 15 (DCI/N-3) m/z= 308 (M+H)*. Anal. Calcd. for C1,H 21 N30-1.8 HCI-I 45 H 2 0: C, 57.17; H, 6.49; N, 10.53; Cl, 15 99. Found: C, 57.43; H, 6.

8 5 ; N, 10.17; Cl, 16.12. Example 112 20 (4r)-4-(3,4'-Bipyridin-6-yloxy)-l-azatricyclo[ 3 .3.1 .1 3 ldecane hydrochloride Example I 12A (4r-)-4-(3,4'-Bipyridin-6-yloxy)- I -azatricyclof 3 .3.1.1 3 1ldecane N-borane complex Prepared from the product of Example 9D (100.1 mg, 0.60 mmol) and the 25 product of Example 11 IA (109.6 mg, 0.63 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) S ppm 1.97-2.03 (in, 5 H), 2.31 (br s, 2 H), 2.94-2.99 (in, 2 H), 3.13 (s, 2 H), 3.49-3.53 (m, 2 H), 5.24 (t, J=2,8 Hz, I H), 6.92 (d, J=8.5 Hz, I H), 7.46-7.48 (m, 2 H), 7.88 (dd, J=8.8, 2.7 Hz, 1 H), 8.42 (d, J=2.4 Hz, 1 H), 8.67-8.68 (in, 2 H). MS (DCI/NH3) m/z= 322 (M+H), 30 Example 112B (4r-4-.(3,4'-Bipyridin-6-yloxy)-1-azatricyclo[ 3 .3.1. 1 3

'

7 ldecane hydrochloride Prepared from the product of Example 1 12A (123.8 mg, 0.39 mmol) according -143to Method J: 'H NMR (300 MHz, methanol-D4) a ppm 2.11-2.17 (in, 2 H), 2.24-2.28 (in, 3 H), 2.57 (br s, 2 H), 3.46-3.52 (in, 2 H), 3.58 (br s, 2 H), 3 83-3.87 (in, 2 H), 5.52 (t, J=2.8 Hz, 1 11); 7.15 (d, J=8 8 Hz, 1 H); 8.35-8.42 (in, 3 H); 8.85-8.86 (n, 3 H). MS (DCI/NH 3 ) n/z 308 (M+H). Anal. Calcd. for C 9 H2IN30-2.4 HC-2.25 5 H 2 0: C, 52.41; H, 6.46; N, 9.65; Cl, 19.54. Found: C, 52.28; H, 6 33; N, 9.54; Cl, 19,69 Example 113 {idin-2-y Ioxyl-1-azatricyclof 3.3.1 3 1ldecane 10 hydrochloride Example 113A 4s)-4-(5-Pymidi-5-ylpyridin-2ricyclo 3.3.1.1' 7 decane N-borane coliplex 15 Prepared from the product of Example 108A (102.3 mg, 0.32 mmol) and pyridin-3-ylboronic acid (61.1 mg, 0.49 mmol) according to Method K: 'H NMR (300 MHz, chloroform-D) S ppm 1.67-1.71 (m, 2 H), 2.03 (br s, 1 H), 2.25-2.34 (m, 4 H), 3.19-3.32 (in, 6 H), 5.36 (t, J=3.1 Hz, I H), 6.94 (d, J=8.7 Hz, I H), 7.82 (dd, J=8,7, 2.8 Hz, 1 H), 8.35 (d, J=2.8 Hz, I H), 8.91 (s, 2 H), 9.22 (s, I H). MS 20 (DCIINH3) mlz= 323 (M+H). Example 113B rimidin-5-ylpyridin-2-ylricclo[ 3.3.1 .1ldecane hydrochloride 25 Prepared from the product of Example 113A (58.5 mg, 0.18 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 6 ppm 1 94-1.98 (m, 2 1), 2.22 (br s, I H), 2.37-2 41 (in, 2 H), 2.59 (br s, 2 H), 3.59 (br s, 2 H), 3.66-3.75 (in, 4 H), 5.56 (t, J=3.4 Hz, 1 H), 7.07 (d, J=8.7 Hz, I H), 8.12-8.17 (in, 2 H), 8 56 (d, J=2.8 Hz, I H), 9.06 (s, 2 H), 9.15 (s, I H). MS (DC/NH3) n/z= 309 (M+H)*. 30 Example 114 (4s)-4-{5-( I H-Pyrazol-4.yl)pyrdin-2-vlloxy) -1 -azatricyclof 3..1 .1 ldecane -144hydrochloride Example 1 14A {4s)- 4 -{[5-(-Trityl-1H-pyrazol4--yl)pyridin-2-ylloxy -1 5 azatricyclo[3.3.1.13 Ildecane complex Prepared fiom the product of Example 108A (48.5 mg, 0.15 minol) and 4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2 -yi)-1-trityl-1H-pyrazole (109.9 mg, 0.25 inmol) according to Method K: 'H NMR (300 MHz, chlorofon-D) S ppm 1.76-1.81 (im, 2 H), 1.99 (br s, I H), 2.25-2,30 (in, 4 H), 3.16-3.25 (m, 6 H), 5.27 (t, J=3.2 Hz, 1 10 H), 6.77 (d, J=9.2 Hz,1H), 7.17-7.21 (m, 6 H), 7.32-7.37 (m, 9 H), 7 56 (s, I H), 7.67 (dd, J=8.7, 2.5 Hz,IH), 7.88 (s, I H), 8.19 (d, J=2.0 Hz, I H) MS (DCI/NH 3 ) m/z= 568 (M+NH 3 -H)*. Example 114B 15 (4s)-4- [5-(1H-Pyrazol-4-yl)pyridin-2-ylloxy)-1-azatricyclo{ 3

.

3 -. i.ildecane hydrochloride Prepared from the product of Example 114A (44.4 mg, 0.080 mmol) according to Method .: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.93-1 97 (in, 2 H), 2.21 (br s, I H), 2.36-2.41 (in, 2 H), 2.57 (br s, 2 H), 3.58 (br s, 2 H), 3.66-3.75 (m, 4 H), 5.45 20 (t, J=3.2 Hz, 1 H), 7-12 (d, J=9.1 Hz, I H), 8.13 (dd, J=8.6, 2.5 Hz, 1 H), 8.25 (s, 2 H), 8.47 (d, J=1.7 Hz, I H). MS (DCI/NH 3 ) m/z= 297 (M+H)*. Anal. Calcd. for C1 7

H

2 0

N

4 0-2 HCl-L.15 H20: C, 52.11; H, 6.30; N, 14.30. Found: C, 52.14; H, 6.33; N, 14.24. 25 Example 115 6-[(4s)- 1 -Azatricyclo[3.3.1.l 3ldec-4-yloxyl-N-pridinylpyridine2carplaminde Example 115A 30 6-Chloro-N-(pyrdin-4-yl)picoinaide 6-Chloropicolinic acid (0.50 g, 3.17 mmol) was dissolved in thionyl chloride (5.0 mL) and stirred at 25 *C for 1 hour. The thionyl chloride was evaporated, and 4 aminopyridine (0.28 g, 2.98 mmol), triethylamine (0 415 mL, 2.98 mmol) and -145dichloromethane (50 mL) were added. The solution was stirred at 25 0 C for 18 hours The reaction mixture was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (100 nL). The organic layer was dried (sodium sulfate) and concentrated, and the residue was purified by silica gel flash column 5 chromatography to afford the titled compound: 'H NMR (500 MHz, methanol-D 4 ) 6 ppm 7.71 (dd, J=7.9, 0.9 Hz, 1 H), 7.91 - 7.95 (m, 2 H), 8.05 (t, J=7.8 Hz, I H), 8.20 (dd, J=7.6, 0.6 Hz, I H), 8,43 - 8.52 (m, 2 H). MS (ESI) m/z = 335 (M+H)+ Example 115B 10 6-V4s)-1-Azatiicyclo3.3..l-N-idin-4-lyridine-2-carboxamide fumarate Prepared from the product of Example I1SA (134 mg, 0.574 nmol) and the product of Example 1OB (80 mg, 0.522 mmol ) according to Method B to provide the free base. It was then reacted with fumaric acid according to Method H to provide the 15 titled compound: 'H NMR (500 MHz, methanol-D 4 ) 8 ppm 1.91 - 2.01 (m, 2 H), 2.20 (br s, 1 H), 2.37 - 2.46 (m, 2 H), 2.58 (br s, 2 H), 3.58 (s, 2 H), 3.67 - 3.81 (m, 4 H), 5.80 (t, J=3.2 Hz, I H), 6.69 (s, 2 H, C 4

H

4 04), 7 18 (dd, J=8.2, 0.6 Hz, 1 H), 7.86 - 7.90 (m, 3 H), 7.97 (dd, .J=8.2, 7.3 Hz, I H), 8.48 (d, J=6.1 Hz, 2 H). MS (ESI) m/z = 351 (M+H)*. Anal.. Calcd. for C 20

H

2 2

N

4 0 2 -1.05C4H404: C, 61.54; H, 5-59; N, 20 11.86; Found: C, 61 40; H, 5.76; N, 11.78. Example 116 (4s)-4-[(2-Chloiopyridin-4-yloxyl-1-azatricyclo 3 .3.1 .13,7 ldecane hydrochloride 25 Example 116A (4s)-4-[(2-Chloiopyridin-4-ylloxy -1 -azatricyclo[ 3 .3.1. IVldecane N-borane complex Prepared from the product of Example 10A (82.8 mg, 0.50 mmol) and 4 bromo-2-chloropyridine (85 pL, 0.77 minol) according to Method 1: 'H NMR (300 30 MHz, chlorofomi-D) S ppm 1.67-1.71 (i, 2 H), 2.03 (br s, I H), 2.19-2.27 (m, 4 H), 3 19-3.25 (n, 6 H), 4.64 (t, J=3.4 Hz, I H), 6.76 (dd, J=5 8, 2.4 Hz,I H), 6.85 (d, J=2 4 Hz, IH), 8.22 (d, J=5.8 Hz, I H). MS (DCINH3) m/z= 279 (M+H)+. -146- Example 116B (4s-4- 2-Chloroy nl-azatricyclo[ 3 .3.1-.1ldecane hydrochloride Prepared from the product of Example I 16A (86 6 mg, 0.31 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.93-1.97 (m, 2 H), 2.21 (br 5 s, I H), 2.31-2.35 (in, 2 H), 2.52 (br s, 2 H), 3.59 (bi s, 2 H), 3.66-3.76 (in, 4 H), 5.17 (t, J=3.4 Hz, I H), 7.32 (dd, J=6.4, 2.4 Hz, I H), 750 (d, J=2.4 Hz, I H), 8 38 (d, J=6.4 Hz, I H). MS (DCI/NH 3) m/z= 265 (M+H)*- Anal. Calcd. for C1 4 H 7ClN20-2 HCI-0.3 H2O: C, 49.01; H, 5.76; N, 8.17. Found: C, 49.18; H, 5.85; N, 7.92. 10 Example 117 (4s)-4-[(6-Mez-azatricyclof.

3 .1.1il decane hydrochloride Example 117A 15 {4s)-4-I(6-Methylpyridazi- 3 -ylox y--1 -azatricyclo[3.3.1.1 ldecane N-borane complex Prepared from the product of Example I0A (83.7 mg, 0 50 mmol) and 3 chloro-6-methylpyidazine (100.6 mg, 0.78 mmol) according to Method 1: 'H NMR (300 MHz, chlorofori-D) 8 ppm 1.65-1.69 (m, 2 H), 2.00 (br s, I H), 2.20-2.24 (m, 2 20 H), 2.42 (br s, 2 H), 3.18-3.30 (m, 6 H), 5.50 (t, J=3.6 Hz, I H), 6.92 (d, J=8.8 Hz,1H), 7.25 (d, J=8,8 Hz, I H). MS (DCVNH3) m/z= 260 (M+H) . Example 11 7B s)-4 6-MeypYdazi azatricclo3.3.1.1 3

,

7 Idecane hydrochloride 25 Prepared from the product of Example 117A (28.2 mg, 0.11 mmol) according to Method .1: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.97-2.01 (m, 2 H), 2.23 (br s, 1 H), 2.35-2.39 (m, 2 H), 2.64 (br s, 2 H), 2.81 (s, 3 H), 3.60 (br s, 2 H), 3.68-3,78 (m, 4 H), 5.58 (t, J=3.4 Hz, 1 H), 7.98 (d, J=9.1 Hz, 1 H), 8.22 (d, J=9.1 Hz, I H). MS (DCIINH3) m/z= 246 (M+H)*. Anal. Called. for C 14

H,

9

N

3 0-2.25 HCI: C, 51.37; 30 H, 6.54; N, 12.84. Found: C, 51.37; H, 6 70; N, 12.90. Example 18 -147- (4s)-4-(Pyrimidin-2-yloxy)--azatneyclo3 .3.1.1 lldecane hydrochloride Example 118A (4s)-4-(Pyrimnidin-2-yloxy- 1--azatricyclof 3 .3.1.13 -'ldecane N-borane complex 5 Prepared from the product of Example 10A (86.3 mg, 0.52 mmol) and 2 chlioropyrinidine (99.2 mg, 0.87 mmol) according to Method I: 'H NMR (300 MHz, chlorofonn-D) 8 ppm 1.65-1.70 (m, 2 H), 2.02 (br s, I H), 2.30-2.40 (m, 4 H), 3 19 3-29 (m, 6 H), 5.27 (t, J=3.4 Hz, 1 H), 6.96 (t, J=4.8 Hz,IH), 8 52 (d, J=4.8 Hz, 2 H). MS (DCI/NH 3 ) m/z= 246 (M+H)*. 10 Example 118B (4s)-4-(Pyrimidin-2-loxy)-1-azatricyclo[3.3.1.1 M Idecane hydrochloride Prepared from the product of Example I I8A (61.6 mg, 0.25 mnol) according to Method J: 'H NMR (300 MHz, methanol-D4) S ppm 1.92-1 97 (m, 2 H); 2.21 (br 15 s, 1 H); 2.38-2.41 (m, 2 H), 2.57 (br s, 2 H); 3.58 (br s, 2 H); 3-64-3.74 (mi, 4 H); 5.48 (t, .=3.2 Hz, I H); 7. 15 (t, J=4.9 Hz, I H); 8.60 (d, J=4.8 Hz, 2 H). MS (DCI/NTH3) m/z= 232 (M+H)*. Anal. Calcd. for C 3

H,,N

3 0-HCl-0 I H 2 0: C, 57.93; 1, 6.81; N, 15.59; Cl, 13.15. Found: C, 57.74; H, 6.60; N, 15.55; Cl, 13.38 20 Example 19 (4s)-4-[(5-Bromopyimidin-2-l )oxyl-1 -azatricyclo[3.3.1.1 1.

7 ldecane hydrochloride Example 119A 25 (4s)-4-[(5-bromopynimidin-2-yl)oxyl-1-azatricyclo[3.

3 .1.1 3 3 ldecane N-borane complex Prepared from the product of Example I0A (81.5 mg, 0.49 mmol) and 5 bromo-2-chloropyriimfidine (135.6 mg, 0.70 mmol) according to Method 1: 'H NMR (300 MHz, chloroforn-D) S ppm 1.66-1.70 (m, 2 H), 2.02 (br s, I H), 2.29-2.33 (i, 4 30 H), 3.19-3.29 (m, 6 H), 5.21 (t, J=3.2 Hz, 1 H), 8.53 (s, 2 H). MS (DCI/NH 3 ) m/z= 339 (M+NH-H)*. Example 119B -148- (4s)-4-((5-Brornopyrimidin-2-ylloxyl- 1 -azatricyclof 3 .3.1 ldccane hvdrochloijde Prepared from the product of Example 119A (20.4 mg, 0.063 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.92-1.96 (n, 2 H), 2,20 (br s, I H), 2.36-2 40 (m, 2 H), 2.56 (br s, 2 H), 3.58-3.73 (m, 6 H), 5.42 (t, J=3.4 Hz, I 5 H), 8.68 (s, 2 H). MS (DCI/NH 3 ) rn/z= 310 (M+H)+. Anal. Calcd. for C13H, 6 BrN 3 0-HCl: C, 45.04; H, 4.94; N, 12.12. Found: C, 45.22; H, 5.24; N, 11.90. Example 120 10 (4s)-4-(Pyrimidin-5-ylox)- 1 -azatricyclo[ 3

.

3 .3. decane hydrochloride Example 120A (4s)-4-(Pvrimidin-5-yloxy)--azatiicyclo[3.3.1.1 3

,

7 1decane N-borane complex Prepared from the product of Example 10A (88.4 mg, 0.53 mmol) and 5 15 fluoropyrimidine (92.0 mg, 0.94 mmol) according to Method I: 'H NMR (300 MHz, chlorofonn-D) 8 ppm 1.68-1.73 (m, 2 H), 2.05 (br s, 1 H), 2.24-2 29 (in, 4 H), 3.18 3.29 (m, 6 H), 4.65 (t, J=3.2 Hz, I H), 8.46 (s, 2 H), 8.89 (s, I H). MS (DCI/NH 3 ) m/z= 261 (M+NH 3 -H)*. 20 Example 120B (4s)-4-(Pyrimidin-5-yloxy)-1-azatricyclo(3.3.1.1 3

,

7 decane hydrochloride Prepared from the product of Example 120A (91.5 mg, 0.37 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.92-1.96 (m, 2 H), 2.21 (br s, I H), 2.36-2.41 (m, 2 H), 2.53 (br s, 2 H), 3.58 (s, 2 H), .3.63-3.75 (in, 4 H), 5 08 (t, 25 J=3 2 Hz, I H), 8 79 (s, 2 H), 8.93 (s, 1 H). MS (DCI/NH 3 ) m/z= 232 (M+H)*. Anal. Calcd. for C1 3 H1 7

N

3 0-2 HCl: C, 51.33; H, 6.30; N, 13.81. Found: C, 51,59; H, 6.70; N, 13.80. Example 121 30 (4s)-4-(Pyrimidin-4-yloxy)-I-azatricyclor3.3. 1.1 3

,

7 decane Prepared from the product of Example 1OB (89 mg, 0.581 mmol) and 4 chloropyrinidine hydrochloride (98 ng, 0.651 nmol) according to Method B to provide the free base. It was then reacted with fumaiic acid according to Method H to -149provide the titled compound as a fumarate: 'H NMR (500 MHz, methanol-D 4 ) 8 ppm 1.90 - 1.99 (m, 2 H), 2.19 (br s, 1 H), 2 30 - 2.38 (m, 2 H), 2.55 (br s, 2 H), 3.56 (br s, 2 H), 3 61 - 3.72 (m, 4 1), 5.59 (t, J=3.2 Hz, 1 H), 6 69 (s, 2 H, C 4 H4,0 4 ), 7.01 (dd, J=6.0, 11 Hz, I H), 8.51 (d, J=5.8 Hz, 1 H), 8.74 (s, 1 H). MS (ESI) m/z = 232 5 (M+H)-. Example 122 (4s)-4--[(6-Chloropyrinidin-4-l)oxyl-1-azatricyclof 3 .3.1.1 37 1decane 10 The product of Example 1OB (73 mg, 0.43 7 mmol) and potassium tert butoxide (51 mg, 0.454 mol) were dissolved in dimethyl sulfoxide (2.5 mL) and stirred at 25 "C for 1 hour.. 4,6-Dichloropyrimidine (111 Img, 0.743 mmol) was added. The reaction mixture was stirred at 25 *C for 18 hours. The mixture was dissolved in DMF (2 mL), filtered and purified by preparative HPLC [Waters@ XTerra RP 18 5 sm 15 column, 30x 100 mm, flow rate 40 mL/min, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 min, with UV detection at 254 nm]. Fractions containing the desired product were pooled, concentrated under vacuum and then processed as described in Method C to provide the free base It was then reacted with furnaric acid 20 according to Method H to provide the titled compound: 'H NMR (400 MHz, methanol-D4) 5 ppm 1.89 - 2.01 (m, 2 H), 2.18 (br s, I H), 2.27 - 2.39 (m, 2 H), 2.53 (br s, 2 H), 3.55 (br s, 2 H), 3,59 - 3.72 (m, 4 H), 5.58 (t, J=3.1 Hz, 1 H), 6.68 (s, 2 H,

C

4

H

4 0 4 ), 7.10 (d, J=0.9 Hz, I H), 8.58 (s, I H). MS (ESI) m/z = 266 (M+H) 25 Example 123 (4s)- 4 -{[6-(I-Trityl- H-pyrazo1-4-yl)yrimidin-4-Yloxyl-1 azatricyclor3.3.1.1 3

,

7 decane 30 Example 123A 4-Chloro-6-(I -trityl- I H-pyrazol-4-yl)lpYimidine In a microwave reaction tube were combined 4,6-dichloropyrimidine (480 mg, 3.22 mmol), 4-(4,4,5,5-tetramethyl-1,.3,2-dioxaborolan-2-yi)-1-trityl-I H-pyrazole -150- (1.28 g, 2.93 mnol; JP 2005232071), bis(triphenylphosphine)-palladium(11) chloride (82 mg, 0. 117 mmol), sodium carbonate (776 mg, 7.32 mmol), followed by the solvents 2-propanol (9,0 mL) and water (3 0 mL). The tube was sealed, and the reaction was heated to 108 *C for 30 minutes in the microwave reactor- Afler cooling 5 to room temperature, the mixture was partitioned between ethyl acetate (2 x 100 mL) and water (200 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure, and the resulting material was purified by silica gel flash column chromatography to afford the titled compound: 1H NMR (300 MHz, methanol-D 4 ) S ppm 7.11 - 7.22 (m, 6 H), 7.28 - 7.41 (m, 9 H), 10 7 81 - 7.83 (m, 1 H), 8.23 - 8.26 (m, 1 H), 8.30 (s, 1 H), 8.75 - 8.78 (m, 1 H). MS (DCI/NH 3 ) m/z= 423 (M+H)*. Example 123B 15 (4s)-4- {6-(1-Trityl-_H- yrazol-4-lpriidin-4-ylloxyazatricvclo[ 3

.

3 .1.1 Vldecane Prepared from the product of Example 1OB (80 mg, 0.522 mmol) and the product of Example 123A (243 mg, 0.574 nmol) according to Method B: 1 H NMR (500 MHz, chloroforn-D) 8 ppm 1.63 (br s, I H), 1.76 - 1 .85 (m, 2 H), 2.05 (br s, 2 20 H), 2.23 - 2.32 (m, 2 H), 3.11 - 3.21 (i, 4 H), 3.24 - 3.34 (m, 2 H), 5.41 (t, J=3.1 Hz, I H), 6.81 (d, J=0.9 Hz, I H), 7.14 - 7.21 (m, 6 H), 7.29 - 7.36 (m, 9 H), 8.05 (s, 1 H), 8.15 (s, 1 H), 8.62 (d, J=0.9 Hz, 1 H). MS (ESI) m/z= 540 (M+H) Example 124 25 {4s)-4- [6-(IH-Pyrazol-4-yl)P~rimidin- 4 -lloxY}-1 -azatricyclo[3.3.1.1 ldecane A suspension of the product of Example 123 (76 mg, 0.141 mmol) in THF (10 mL) was treated with 3 N HCI (5 mL) and stirred at room temperature for 18 hours. The mixture was partitioned between aqueous sodium carbonate (1 0 M, 100 mL) and chloroform-isopropanol (4:1, 200 mL). The organic extract was washed with brine, 30 dried (sodium sulfate) and concentrated under reduced pressure, and the resulting material was purified by preparative HPLC on a Waters Nova-Pak HR C18 6pm 60A Prep-Pak cartridge column (40 x 100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 -151mL/minute to provide the titled compound: 'H NMR (500 MHz, methanol-D 4 ) & ppm 1.70 (br s, I H), 1.88 (m, 2 H), 2.12 (br s, 2 H), 2.29 - 2.36 (m, 2 H), 3.12 - 3.20 (m, 4 H), 3 27 - 3.35 (m, 2 H), 5.47 (t, J=3.1 Hz, 1 H), 7 17 (d, J=0.9 Hz, 1 H), 8 26 (s, 2 H), 8.62 (d, J=0 9 Hz, I H). MS (APC[) m/z = 298 (M+H)*. Anal. Calcd. for 5 C1 6

HI

9

N

5 O'0.5H20: C, 62.73; H, 6.58; N, 22.86; Found: C, 62.66; H, 6.53; N, 22.76. Example 125

(

4 s) -4-(6-Pyidin-4-vlpyrimidin-4-vl)oxyl- -azatricyclo 3.3.1.1 7 ldecane 10 Example 125A 4-Chloro-6-(pyridin-4-yl)pyrimidine A sealed tube was charged with 4,6-dichloropyrimidine (252 mg, 1.690 mmol), trinethyl(phenyl)stannanie (345 mg, 1.432 mmol), toluene (10 mL) and tetrakis(tiphenylphosphifne)-palladium(O) (66.2 mg, 0.057 mmol). The reaction 15 mixture was degassed with nitrogen and then heated at 120 *C for 4 hours. After cooling to room temperature, activated carbon was added and the reaction mixture was filtered through a frit and concentrated under reduced pressure. The resulting material was purified by silica gel flash chromatography to provide the titled compound: 'H NMR (500 MHz, methanol-D 4 ) 8 ppm 8.16 - 8.21 (m, 2 H), 8.27 (d, 20 J=0.9 Hz, 1 H), 8.71 - 8.79 (m, 2 H), 9 11 (d, J=0.9 Hz, I H). MS (ES]) in/z = 192 (M+H) Example 125B 25 (s-4-[(6-Pyridin- -ylyrimidin-4-yloxy-1-azatricyclo 3

.

3 .l.1'decane The borane complex of the titled compound was prepared from the product of Example I0A (48 mg, 0.287 mmol) and the product of Example 125A (55 mg, 0.287 mmol) according the Method B. It was then processed as described in Method C to provide the titled compound: 'H NMR (400 MHz, methanol-D 4 ) S ppm 1.74 (br s, 1 30 H), 1.85 - 1.96 (m, 2 H), 2.18 (br s, 2 H), 2 29 - 2.44 (m, 2 H), 3.15 - 3.24 (m, 4 H), 3.32 - 337 (m, 2 -), 5.55 (t, J=2.7 Hz, I H), 7.54 (d, J=1 .2 Hz, 1 H), 8.09 -8 13 (m, 2 H), 8 68 - 8 72 (m, 2 H), 8.83 (d, J=0.9 Hz, I H). MS (ESI) m/z = 309 (M+H)*. -152- Example 126 (4s)-4-(Pyrazin-2-vloxy)-l-azatricyclo[ 3 .3.1.1 3 7 ldecane hydrochloride 5 Example 126A {4s)-4-(Pyazi-2-yloxy)-1-azatricyclof3.3.1.1 3

,

7 decane N-borane complex Prepared from the product of Example I A (82.5 mg, 0.49 mmol) and 2 chloropyrazine (80 pL, 0.91 nmol) according to Method I: MS (DCI/NH 3 ) ni/z= 261 (M+NH 3

-H)

4 . 10 Example 126B (4s)-4-(Pyrazin-2-yloxy)- I -azatricyclo{ 3 .3.1.1 3 'ldecane hydrochloride Prepared from the product of Example 126A (18.2 mg, 0.074 mmol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.92-1.96 (m, 2 H), 2.21 (br 15 s, 1 H), 2.36-2.40 (m, 2 H), 2.56 (br s, 2 H), 3.58 (br s, 2 H), 3.64-3.74 (m, 4 H), 5.49 (t, J=3.2 Hz, I H), 8.15-8.18 (n, 2 H); 8.32 (d, J=1.4 Hz, 1 H). MS (DCI/NH 3 ) m/z= 232 (M+H) 4 . Anal. Calcd. for C1 3

H

7

N

3 0-1 32 HCI: C, 55.88; H, 6.61; N, 15.04. Found: C, 56.22; H, 6.43; N, 14-68. 20 Example 127 4-[(6-Methylpyrazin-2-yl)oxyl- -azatricyclof3.3.1.1 3

*

7 decane hydrochloride Example 127A 25 4-[(6-Methylpyrazin-2-ylloxyl-l-azatricyclo[ 3 .3.1.1 decadee N-borane complex Prepared from the product of Example 9A (101.4 mg, 0.61 mmol) and 2 chloro-6-methylpyrazine (100.7 mg, 0.78 mmol) according to Method 1: MS (DCI/NH3) m/z= 275 (M+NH13-H)+. 30 Example 127B 4-{(6-Methylpyrazin-2-l)oxyl-1-azatricyclo[ 3

.

3 . 1.1 3 7 ldecane hydrochloride Prepared from the product of Example 127A (18.2 mg, 0.074 mmol) according to Method J: 3.1:1.0 mixture of isomers [according to integration of 'H NMR (300 -153- MHz, methanol-D4) 8 ppm 5.53 (t, J=3.22, major) and 5 42 (t, J=3.39, minor)]. MS

(DCI/NH

3 ) m/z= 246 (M+H)*. Anal Calcd. for C 14 Hi 8

N

2 0 1.5HC-0.65

H

2 0: C, 53 94; H, 7.05; N, 13 48; Cl, 17.06. Found: C, 54.17; H, 7.26; N, 13.52; Cl, 16 80. 5 Example 128 (4-)-4-[(6-Phenylpyrazin-2-yl)oxyl-l-azatricyclold3.3.1 .13 ' 7 decane Example 128A 10 2-Chloro-6-phenylpyrazine Prepared from 2,6-dichloropyrazine (1.01 g, 6.78 mnol) and phenylboronic acid (946.7 mg, 7.76 mmol) according to Method K, except the product was purified by silica gel chromatography (DCM, Rf= 0.37) instead of preparative HPLC: 'H NMR (300 MHz, chlorofonn-D) 5 ppm 7.46-7.53 (m, 3 H), 794-7.98 (in, 2 H), 8 22 15 (s, 1 H), 8.63 (s, I H). MS (DCI/NH 3 ) nz= 191 (M+H)*. Example 128B (4r-)-4-r(6-Phenylpyrazin-2-ylloxyl-1-azatricyclof3.3.1.1 3 7 1decane N-borane complex Prepared from the product of Example 9D (163.6 mg, 0.98 mmol) and the 20 product of Example 128A (99.0 mg, 0.52 mmol) according to Method I: 'H NMR (300 MHz, chloroform-D) S ppm 1.89-2.06 (m, 5 H), 2.37 (br s, I H), 2,97-3.01 (in, 2 H), 3.15 (s, 2 H), 3.51-3.55 (m, 2 H), 5.33 (t, J=3.2 Hz, 1 H), 7.50-7.56 (m, 3 H), 8.00-8.05 (m, 2 H), 8.53 (s, 1 H), 8.94 (s, I H). MS (DCI/NH 3 ) m/z= 322 (M+H). 25 Example 128C (4r)-4-f(6-Phenylpyrazin-2-yl)oxyl- I -azatricyclo[3.3.1.13 7ldecane hydrochloride Prepared from the product of Example 128B (45.1mg, 0.14 mmol) according to Method J: 'H NMR (300 MHz, methanol-D4) S ppm 2.20-2.31 (m, 5 H), 2 62 (br s, 2 H), 3.34-3.54 (m, 2 H), 2.59 (br s, 2 H), 3-86-3.91 (m, 4 H), 5.56 (t, J=3.4 Hz, 1 30 H), 7.47-4.55 (n, 3 H); 8.04-8.08 (in, 2 H), 8.25 (s, 1 H), 8.73 (s, I H). MS

(DCI/NH

3 ) m/z= 308 (M+H)*. Anal. Calcd. for C 19

H

21

N

3 0 1 25HCI H 2 0: C, 61.51; H, 6.59; N, 11.33; Cl, 11 .95. Found: C, 6136; H, 6.49; N, 11.30; Cl, 11.93 -154- Example 129 (40-4-(1,3-Thiazol-2-yloxy)-1-azatricyclo[3.

3 .1.1 3 decane hydrocholide Example 129A 5 (4r)-4-(1,3-Thiazol-2-yloxy)-I_-azatricyclof 3 .3.1 .1 3 "ldecane N-borane compex Prepared from the product of Example 9D (168 7 mg, 1.01 mmol) and 2 chlorothiazole (162.5 mg, 1.36 mmol) according to Method 1: 'H NMR (300 MHz, chloroform-D) 8 ppm 1.87-2.01 (m, 5 H), 2.39 (bi s, I H), 2.94-2.98 (m, 2 H), 3.12 (s, 2 H), 3.43-3.48 (m, 2 H), 5.12 (t, .J=3.4 Hz, I H), 6.70 (d, J=3.6 Hz, 1 H), 7,11 (d, 10 J=4.0 Hz, I H). MS (DCI/NH 3 ) m/z= 251 (M+H) Example 129B (4r)-4-(1,3-Thiazol-2-yloxy)- -azatricyclo 3.3.1.17 decane hydrochloride Prepared from the product of Example 129A (125.7 mg, 0.50 mmol) according 15 to Method J: 'H NIVIR (300 MHz, methanol-D4) S ppm 2.07-2.11 (n, 2 H), 2 22-2.28 (m, 3 H), 2.62 (br s, 1 H), 3 46-3.57 (m, 4 H), 3.75-3.79 (m, 4 H), 5.25 (t, J=3.4 Hz, 1 H), 6.99 (d, J=3.73 Hz, I H), 7.20 (d, J=3.73 Hz, I H)- MS (DCI/NH3) m/z= 237 (M+H)+. Anal. Called. for C1 2

HI

6 N20S 1.91 HCL: C, 47.11; H, 5.90; N, 9.16. Found: C, 47.47; H, 5.51; N, 9.10. 20 Example 130 4mloxyl-aza-tricyclo[3.3.1.1 3

'

7 decane tosylate 25 Examples 130A1 and 130A2 (4r)-4-(5-Bromo-thiazol-2vloxy)l-aza-tr icclo 3.3.1.1 vdecne (130A1) and (4s)-4-(5-Bromo-thiazol-2yloxy)i-aza-tricyclo( 3 .3.1.1 3 7 ldecane (1 30A2) A solution of the product of Example 9A (2.4:1 diastereomer mixture; 334 mg, 2.0 mmol) and 2,5-dibromothiazole following the etherification method B to provide 30 a mixture of N-borane complex diastereomers. The diastereomers were separated by silica gel chromatography eluting with hexane/ethyl acetate to fumish the 4r-isomer as the minor product and the 4s-isomer as the major product. Then each isomer was subjected to acidic deboronation Method C to give the titled compounds 130A] and -155- 130A2. Minor product 130A1: 1H NMR (300 MHz, methanol-D4) 8 ppm 1.70 - 1 75 (m, I H), 1.95 - 2.13 (m, 4 H), 2.17 (d,.J=2.7 Hz, 1 H), 2 21 (d, J=2.4 Hz, I H), 2.97 (d, J=1.4 Hz, I H), 3.01 (d, J=1.4 Hz, I H), 3.13 (s, 2 H), 3.37 (s, 1 H), 3.41 (s, I H), 5.23 (t, J=3.4 Hz, I H), 7.11 (s, I H). MS (DCI/NH 3 ) m/e= 315, 317 (M+H) Major 5 product 130A2: Major product 130A2: 'H NMR (300 MHz, methanol-D4) S ppm 1.67 (s, I H), 1.85 (s, 1 H), 1.89 (s, I H), 2,13 - 2.30 (m, 4 H), 3.05 - 3.16 (m, 4 H), 3.26 (s, 1 H), 5-22 (t, J=3.4 Hz, I H), 7.11 (s, 1 H).. MS (DCI/NH 3 ) m/e= 315, 317 (M+H)+. 10 Example 130B (4r)-4-(5-Bromo-thiazol-2yloxl--aza-tricyclo( 3 .3.1.1 ldecane tosylate Prepared from the product of Example 130A1 (32 mg, 0.101 mumol) following the salt formation method H to give the titled compound: 'H NMR (300 MHz, methanol-D4) 8 ppm 2.00 - 2.28 (m, 5 H), 2.37 (s, .3 H), 2.59 (s, 2 H), 3.46 (d, J=12,2 15 Hz, 2 H), 3.55 (s, 2 H), 3.73 (s, I H), 3.77 (s, I H), 5.28 (t, J=3.6 Hz, I H), 7-16 (s, I H), 7.23 (d, J=7.8 Hz, 2 H), 7.70 (d, J=81 Hz, 2 H). MS (DCI/NH 3 ) m/e= 315, 317 (M+H)*. Anal. calcd. for C 1 2 HIsN 2 BrOS-C 7 H8O3S: C, 46 82; H, 4.76; N, 5.75; Found C, 46.72; H, 4.42; N, 5.68. 20 Example 131 (4s)-4-({ 5-{4-(Trifluoromethoxy)phenyll--1,3-thiazol-2-ylloxy)-1 azatricyclo[3.3. 1.1 3

,

7 decane hydrochloride 25 Example 131A (4s)-4-({5-[4-(Trifluoromethoxy)phenyll-1,3-thiazol-2-vlloxy)-1 azatricyclo(3 .3.1.1ldecane N-borane complex Prepared from the product of Example 20A (65.0 mg, 0.20 minol) and 4 (trifluoromethoxy)phenylboronic acid (74.8 mg, 0.36 mmol) according to Method K: 30 'H NMR (300 MHz, chloroform-D) 5 ppm 1.69-1.73 (m, 2 H), 2.03 (br s, I H), 2.22 2-26 (m, 2 H), 2.43 (s, 2 H), 3.19-3.24 (n, 6 H), 5.42 (t, J=3.4 Hz, 1 H), 6.81-6.84 (In, 2 H), 7.27 (s, I H), 7.43-7.47 (m, 2 H) MS (DCI/NH 3 ) i/z= 411 (M+H)* -156- Example 131B (4s)-4-({5-f4-(Trifluoromethoxylp)PeYlH ,3-thi~azol-2-ylloxY-l azatricyclof 3

.

3 .1. 3 3 1 1decane hydrochloride Prepared from the product of Example 131A (45 7 mg, 0.11 mmol) according 5 to Method J: 'H NMR (300 MHz, methanol-D4) 8 ppm 1.95-1.99 (n, 2 H), 2.21 (br s, I H), 2.31-2.35 (m, 2 H), 2.66 (br s, 2 H), 3.58 (bi s, 2 H), 3.63-3 73 (n, 4 H), 5 41 (t, J=3.4 Hz, I H), 7.30-7.32 (m, 2 H), 7.48 (s, 1 H), 7 59-7.64 (in, 2 H). MS (DCI/NH 3 ) m/z= 397 (M+H)*. Anal. Calcd. for C, 9

H

9

F

3

N

2 0 2 S-Il 5 HCl 0.35 HCl: C, 51.32; H, 4.73; N, 6.30; Cl, 9.17. Found: C, 51.42; H, 4.77; N, 6 29; Cl, 9.05. 10 Example 132 {_4s-[5-(4-Chlorophenl-1,3-thiazol-2-ylloxyl--1--azatricyclo[ 3.3.1.11decane The product of Example 20A (50 mg, 0 152 minol) and 4-chlorophenylboronic acid (30.9 mg, 0. 198 mmol) were processed as described in Example 123A to provide 15 the N-borane complex of the titled compound. It was then processed as described in Method C. The resulting mixture in 3 N HC1 was concentrated to dryness and stirred in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as a hydrochloride salt: 'H NMR (500 MEz, methanol D4) 8 ppm 1.91 - 2.03 (m, 2 H), 2.21 (br s, I H), 2.27 - 2.38 (in, 2 H), 2.66 (br s, 2 H), 20 3.58 (br s, 2 H), 3.62 - 3.76 (m, 4 H), 5.40 (t, .=3.2 Hz, 1 H), 7.37 - 7.42 (m, 2 H), 7.47 (s, I H), 7 48 - 7.53 (m, 2 H). MS (ESI) m/z = 347 (M+H)*. Example 133 4-Q-[(4s)-1-Azatricyclor3.3.1.1l 3

,

7 dec-4-yloxyl-1,3-thiazol-5-yl aniline 25 In a sealed tube were combined the product of Example 20A (50 mg, 0.152 mmol), 4-(tert-butoxycarbonylamino)phenylboronic acid (46.8 mg, 0.198 mmol), bis(triphenylphosphine)-palladiun(II) chloride (4.3 mg, 6.08 pmol), and aqueous sodium carbonate (1 0 M, 0.38 mL), followed by 2-propanol (1 2 mL). The tube was heated to 93 *C for 90 minutes. After cooling to room temperature, the mixture was 30 partitioned between ethyl acetate (2 x 50 mL) and water (50 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure. The resulting material was purified by preparative HPLC on a Waters Nova-Pak HR C18 6ptm 60A Prep-Pak cartridge column (40mm x 100mm) -157using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammoniumn acetate over 12 minutes at a flow rate of 70 mL/minute to provide a white solid. The solid was then processed as described in Method C to provide the free base It was then reacted with HCI-dioxane according to Method H to provide the titled compound: '1H 5 NMR (500 MHz, methanol-D 4 ) 6 ppm 1.91 - 2.04 (m, 2 H), 2.21 (br s, I H), 2.28 2.39 (m, 2 H), 2.66 (br s, 2 H), 3.59 (bi s, 2 H), 3.62 - 3.75 (n, 4 H), 5 40 (t, J=3.3 Hz, I H), 7.17 - 7.30 (m, 2 H), 7.45 (s, I H), 7.52 - 7.63 (in, 2 H). MS (ESI) m./z 328 (M+H)*. 10 Example 134 (4s)-4-(5-(P idin-3yl)-thiaz-aza-tricclo 3 .3.1.1 3

,

7 ldecane tosylate Prepared from the major product of Example 130A2 (31 mg, 0.098 mmol) and pyridin-3-ylboronic acid using the microwave Suzuki coupling Method G and then the salt fonnation Method H to provide the titled compound: 'H NMR (300 MHz, 15 methanol-D 4 ) 8 ppm 1.95 (s, 1 H), 1.99 (s, 1 H), 2.20 (s, I H), 2.31 (s, I H), 2.36 (s, 3 H), 2.66 (s, 2 H), 3.55 - 3 75 (in, 6 H), 5.43 (t, J=3.4 Hz, 1 H), 7.23 (d, J=7.8 Hz, 2 H), 7.47 (dd, J=8 5, 5.4 Hz, I H), 7.60 (s, I H), 7.70 (d, J=7.8 Hz, 2 H), 7 96 - 8.02 (m, I H), 8.45 - 8.49 (m, 1 H), 8.72 (d, J=2.0 Hz, I H). MS (DCI/NH3 ) m/e= 314 (M+H)-. 20 Example 135

(

4 r)-4-(5-(Pyridin-3vl)-thiazol-2yloxy)l-aza-tricyclo[3.3.1.1 3

,

7 ldecane tosylate Prepared from the minor product of Example 130A 1 (40 mg, 0.127 mmol) and pyridin-3-ylboronic acid using the microwave Suzuki coupling Method G and then 25 the salt formation Method H to provide the titled compound: 'H NMR (300 MHz, methanol-D 4 ) 6 ppm 2.04 - 2.30 (m, 5 H), 2.36 (s, 3 H), 2.65 (s, 2 H), 3.43 - 3.84 (m, 6 H), 5.35 (t, J=3.6 Hz, 1 H), 7.23 (d, J=8..5 Hz, 2 H), 7.47 (dd, J=8.1, 4.7 Hz, 1 H), 7.61 (s, I H), 7.70 (d, J=8.5 Hz, 2 H), 7.99 (dt, J=8.1, 1.9 Hz, 1 H), 8.47 (dd, J=5 1, 1 .4 Hz, 1 H), 8.71 (d, J=2.4 Hz, 1 H). MS (DCI/NH 3 ) m/e= 314 (M+H) 4 Anal. 30 calcd for C1 7 H9N 3 OS- 1.05C 7 HS03S: C, 59.18; H, 5.59; N, 8.50; Found C, 59.02; H, 5.43; N, 8.55 Example 136 -158- (4s)-4-[(5-Pyrimidin-5-yl-I,3-thiazol-2-Yl)0XY -lI-azatricyclo(3.3.1.v decane hydrochloride Example 136A 5 {-4s)-4-(5-Pyrimidin-5-yl-1,3-thiazol-2-yl {3ox.3-azaticvclo .31.1'ldecane

N

borane complex Prepared from the product of Example 20A (95 2 mg, 0.29 mmol) and pyrimidin-5-ylboronic acid (59.2 mg, 0.48 mmol) according to Method K: 'H NMR (300 MHz, chloroform-D) S ppm 1.70-1.74 (m, 2 H), 2 05 (br s, 1 H), 2.21-2.25 (m, 2 10 H), 2.45 (s, 2 H), 3.20-3.25 (m, 6 H), 5.29 (t, J=3 4 Hz, 1 H), 7.41 (s, 1 H), 8.81 (s, 2 H), 9.13 (s, I H). MS (DCI/NH 3 ) m/z= 329 (M+H)*. Example 136B ('4s)-4-(5-Pyrimidin-5-yl-1 3-thiazol-2-ylloxyl- -azatricyclo[ 3 .3.1 ldecane 15 hydrochloride Prepared from the product of Example 136A (17.3 mg, 0.053 imol) according to Method J: 'H NMR (300 MHz, methanol-D 4 ) 8 ppm 1.95-2.00 (m, 2 H), 2.21 (br s, I H), 2.31-2.36 (in, 2 H), 2.68 (br s, 2 H), 3.59 (s, 2 H), 3.63-3.75 (m, 4 H), 5.47 (t, J=3.6 Hz, 1 H), 7.72 (s, 1 H), 8.98 (s, 2 H), 9.07 (s, I H). MS (DCI/NI 3 ) m/z= 315 20 (M+H)*. Anal. Calcd. for CicHaN 4 OS-2 HC: C, 49.62; H, 5.20; N, 14.46. Found: C, 49.86; H, 5.23; N, 14.26. Example 137 (4s)- 4 -{[5-(2-Methoxypy imidin-5-l)-13-thiazol-2-ylloxy}-1 25 azatricyclof 3

.

3 .1.1 3

.

7 decane To a solution of the product of Example 20A (80 mg, 0.243 mmol) in DMF (2.5 mL) was added 2-methoxypyrimidin-5-ylboronic acid (70.4 mg, 0.457 mrnmol), bis(triphenylphosphine)-palladium(II) chloride (8.5 mg, 0.012 mmol) and cesium carbonate (206 mg, 0.632 miol). The reaction mixture was stirred at 65 "C for 18 30 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and partitioned between ethyl acetate (2 x 30 mL) and water (30 mL). The organic layers were combined and washed with brine (200 mL), dried (sodium sulfate) and concentrated in vacuo The residue was purified by silica gel flash -159chromatography to afford the N-borane complex, which was then processed as described in Method C. The resulting mixture in 3 N HCI was concentrated to dryness and stirred in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as hydrochloride salt: 'H NMR 5 (500 MHz, methanol-D4) 8 ppm 1.94 - 2.02 (m, 2 H), 2.22 (br s, I H), 2.28 - 2.38 (m, 2 H), 2.62 - 2.71 (in, 2 H), 3 59 (br s, 2 H), 3 62 - 3.79 (i, 4 H), 4.04 (s, 3 H), 5.43 (t, J=3.2 Hz, I H), 7.51 (s, I H), 8.71 - 8.75 (m, 2 H).. MS (ESI) m/z = 345 (M+H)+ Anal Calcd. for C1 7

H

2 0

N

4 0 2 S-1.3 HCI: C, 52 11; H, 5.48; N, 14.30; Found: C, 52.08; H, 5 52; N, 14.33 10 Example 138 (4s)-4- 5-(2-Pyrrolidin-1-ylpyrimidin-5-y )-1,3-thiazol-2-lloxy}-1 azatricyclof3.3.1.1 3 7 decane To a solution of the product of Example 20A (62 mg, 0.188 nmol) in DMF 15 (2.0 mL) was added 2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramilethylI-1,3,2-dioxaborolan-2 yl)pyrimidine (78 mg, 0.283 mmol), bis(triphenylphosphine)-palladium(II) chloride (6.6 mg, 9.42 pmol) and cesium carbonate (153 mg, 0.471 mmol), and the reaction mixture was stirred at 65 *C for 4 hours, After cooling to room temperature, the reaction mixture was diluted with methanol (4.0 mL.), filtered, and purified by 20 preparative HPLC [Waters@ XTerra RP18 5 pim column, 30x 100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nm]. Fractions containing the desired N-borane complex were pooled, concentrated under vacuum and processed as described in Method C. The 25 resulting free base was converted to the tosylate salt by the procedure of Method H: 'H NMR (400 MHz, methanol-D4) S ppm 1.93 - 2.01 (m, 2 H), 2.11 - 2.17 (m, 4 H), 2.18 - 2.23 (m, I H), 2-27 - 2.34 (m, 2 H), 2.36 (s, 12 H), 2.65 (br s, 2 H), 3.56 - 3.60 (m, 2 H), 3.62 - 3.75 (m, 8 H), 5.43 (t, J=3,5 Hz, I H), 7.19 - 7.26 (in, 8 H), 7.55 (s, I H), 7.67 - 7.73 (m, 8 H), 8.72 (s, 2 H). MS (APCI) m/z = 384 (M+H) . .30 ExamOle 139 (4s)- 4 -{{5-(6-Piperazin-1-ylpyridin-3-yl)-1,3-thiazol-2-ylloxyL

-

-160azatricyclo[ 3

.

3 .1. 1 3 7 ldecane To a solution of the product of Example 20A (75 mg, 0.228 mmol) in DMF (2.0 rL) was added 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin- 2 yl)piperazine (99 mg, 0.342 mmol), bis(triphenylphosphine)-palladiunm(11) chloride 5 (8.0 mg, 0.011 mmol) and cesium carbonate (186 mg, 0.570 mmol) and the reaction mixture was stifred at 65 *C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with methanol (2.0 mL), Filtered, and purified by preparative HPLC [Waters@ XTerra RP18 5 sum column, 30x100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium 10 bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nm] Fractions containing the free base were pooled, concentrated under vacuum and then processed as described in Method H to provide the tosylate salt: 'H NMR (400 MHz, methanol-D 4 ) 8 ppm 1.92 - 2.00 (m, 2 H), 2.14 - 2.23 (in, I H), 2.27 - 2.34 (m, 2 H), 2.36 (s, 9 H), 2.65 (br s, 2 H), 3.39 - 3.45 (m, 4 H), 3.58 (s, 2 15 H), 3.61 - 3.76 (m, 4 H), 3.91 - 3.97 (in, 4 H), 5.41 (t, J=3.2 Hz, I H), 7.18 - 7.24 (m, 6 H), 7.26 (d, J=9.2 Hz, I H), 7.46 (s, I H), 7.66 - 7.73 (m, 6 H), 8.04 (dd, J=9.2, 2.5 Hz, I H), 8.18 (d, J=2.1 Hz, 1 H). MS (ESI) m/z = 398 (M+H)*. Anal Calcd for

C

2 1

H

2 7

N

5 0S-2.75TsOH: C, 55.50; H, 5.67; N, 8.04; Found: C, 55.31; H, 5.88; N, 7,93. 20 Example 140 (4s)- 4 -[5-(1 H-Pyrazol-1 -yi)- 1,3-thiazol-2-ylloxy -1-azatricyclo[ 3 .3.1.1 ldecane The product of Example 20B (100 mg, 0.304 mmol), IH-pyrazole (32.1 mg, 0.471 mmol), fenic acetylacetonate (32 2 mg, 0.091 mmol), copper(II) oxide (2 4 mg, 25 0.030 mmol) and cesium carbonate (198 mg, 0.608 mmol) were suspended in DMF (0.5 nL) and stirred at 90 *C for 60 hours. After cooling to room temperature, the reaction mixture was diluted with methanol (3 0 mL), filtered and purified by preparative HPLC [Waters@ XTerra RP18 5 pm column, 30x 100 mm, flow rate 40 rnLminute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium 30 bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nm]. Fractions containing the free base were pooled, concentrated tinder vacuum and then treated with methanol (0.3 nL) and HCI-diethyl ether (0.5 M, 3 mL). After stirring for 10 minutes at room temperature, the precipitate was filtered -161and dried under vacuum to afford the titled compound as the hydrochloride salt: 'H NMR (500 MHz, methanol-D4) 8 ppm 1.90 - 2,01 (n, 2 H), 2.21 (br s, I H), 2.27 2.38 (in, 2 H), 2 66 (br s, 2 H), 3.58 (br s, 2 H), 3.61 - 3.75 (m, 4 H), 5.42 (t, .1=33 Hz, I H), 6 50 (t,.J=2.1 Hz, 1 H), 7 32 (s, I H), 7.68 (d, J=1.5 Hz, I H), 8.05 (d,.1=2 4 5 Hz, I H) MS (ESI) m/z = 303 (M+H)*. Anal. Calcd. for CI 5 H1N 4 0S 1.2H Cl: C, 52.05; H, 5.59; N, 16.19; Found: C, 52,14; H, 5 79; N, 15-83. Example 141 10 (4s)-4-1I[5-(1-Trityl-IH-pyrazol-4-yl)-1,3-thiazol-2-ylloxy}-1 azatricyclo[ 3

.

3 .1.1ldecane Example 141A (4s)-4-{([5-(I-Trityl-lIH-pyrazol-4-yl)-1,3-thiazol-2-ylloxy}-l 15 azatricyclo[3.3.1.1 3

-

7 ldecane N-borane complex To a solution of the product of Example 20B (1.06 g, 3.23 mmol) in DMF (32 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-IH-pyrazole (1.83 g, 4.20 mmol; JP 2005232071), bis(triphenylphosphine)-palladium(II) chloride (113 mg, 0.161 imol) and cesium carbonate (2.57 g, 7.87 mmol), and the reaction 20 mixture was stirred at 65 *C for 6 hours. After cooling to room temperature, the reaction mixture was partitioned between water (250 mL) and ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure, and the resulting material was purified by silica gel flash column chromatography to afford the titled compound: 'H NMR (400 25 MHz, chloroform-D) 8 ppm 1.62 - 1.72 (m, 2 H), 1.96 - 2.03 (m, I H), 2.16 - 2 24 (m, 2 H), 2.39 (br s, 2 H), 3.11 - 3.24 (in, 6 H), 5.17 (t, J=2.9 Hz, I H), 7.00 (s, 1 H), 7.11 - 7.22 (m, 6 H), 7.29 - 7.36 (m, 9 H), 7.43 (d, J=0.6 Hz, 1 H), 7.73 (d, J=0.6 Hz, I H). MS (APCI) m/z = 545 (M-BH 3 +H)*. 30 Example 141B (4s)-4-{f5-(I-Trityl-1H-pyrazol-4-Vl)-1,3-thiazol-2-ylloxyl -1 azatricyclo[3.3.1.1 3

,

7 ldecane A suspension of the product of Example 141A (60 mg, 0.107 mol) in -162acetone (3.0 mL), was treated with HCI (3 N, 1 0 mL) and the reaction mixture was stirred at room temperature for 10 minutes. Sodium hydroxide (2.5 M, 2.0 mL) was added and the reaction mixture was partitioned between water (50 nL) and chloroform (3 x 30 mL). The combined organic extracts were dried (sodium sulfate) 5 and concentrated under reduced pressure, and the resulting material was purified by silica gel flash column chromatography to afford the titled compound: 'H NMR (400 MHz, chloroform-D) 8 ppm 1 .79 - 1.88 (in, 2 H), 2.21 (br s, 1 H), 2.32 - 2 39 (m, 2 H), 2.65 (br s, 2 H), 3.43 - .3.59 (mn, 6 H), 5.25 (t, J=3.1 Hz, 1 H), 7.00 (s, I H), 7.12 7.20 (i, 6 H), 7.29 - 7.36 (m, 9 H), 7,45 (s, I H), 7.73 (s, I H-). MS (APCI) n/z 10 545 (M+H-)* Example 142 (4s)-4- { f5-( -Propyl- I H-pyrazol- 4 -yl)-1,3-thiazol-2-ylloxy)-I 15 azatricyclof 3.3.1 .lELdecane A solution of the product of Example 20A (120 mg, 0.365 mmol) in 2 propanol (2.5 mL) was combined with I-propyl-4-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan- 2 -yl)-1H-pyrazole (103 mg, 0.438 mmol), bi s(triphenylphosphinle) palladium(II) chloride (12.8 mg, 0.018 rnmol) and aqueous sodium carbonate (1. 0 M, 20 0.91 mL). The reaction mixture was degassed with nitrogen and then heated with stirring at 100 *C for I hour. After cooling to room temperature, the reaction mixture was passed through a glass microfiber frit, concentrated, dissolved in DMF (2 mL), and purified by preparative HPLC [Waters@ XTerra RP1 8 5 pm column, 30x 100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous 25 ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 un]. Fractions containing both the desired free base and the N-borane complex were pooled and concentrated under vacuum. It was then processed as described in Method C. The resulting mixture in 3 N HCl was concentrated to dryness and stirred in 10:1 diethyl ether/MeOH. The precipitate was 30 filtered and dried under vacuum to afford the titled compound as a trihydrochloride salt: 'H NMR (400 MH z, methanol-D 4 ) 8 ppm 0.93 (t, J=7.5 Hz, 3 H), 1.91 (hex, 7 4 Hz, 2 H), 1.96 - 2.02 (m, 2 H), 2.22 (br s, I H), 2.27 - 2.37 (m, 2 H), 2.66 (br s, 2 H), 3.59 (br s, 2 H), 3.63 - 3.75 (m, 4 H), 4.19 (t,.J=7.1 Hz, 2 H), 5.38 (t, J=3.2 Hz, I H), -163- 7 31 (s, I H), 7.89 (s, 1 1), 8.08 (s, 1 H). MS (ESI) m/z= 345 (M+H)*. Anal. Calcd. for C 1 iH, 4

N

4 0S-2.75HCl 0.7H 2 0: C, 47.27; H, 6.20; N, 12.25; Cl, 21 32; Found: C, 46.98; H, 6.21; N, 12.60; Cl, 21.18 5 Example 143 (4s)-4-{[5-(I-Isobutyl-1H-pyrazol-4-vl)-1.3-thiazol-2-ylloxy)-l azatricyclof[3.3.1.1 V ldecane To a solution of the product of Example 20A (95 mg, 0.289 rnmol) in DMF 10 (2.5 mL) were added I -isobutyl-4-(4,4,5,5-tetranethyl- 1,3,2-dioxaborolan-2-yl)-1

H

pyrazole (87 mg, 0.346 mmol), bis(triphenylphosphine)-palladium(II) chloride (10.1 mg, 0.014 mmol) and cesium carbonate (235 mg, 0.722 mmol). The reaction mixture was purged with nitrogen and then heated with stirring at 65 *C for 18 hours. After cooling to room temperature, methanol (2.0 mL) was added and the reaction mixture 15 was passed through a glass microfiber frit and purified by preparative HPLC [Waters@ XTerra RP18 5 ym column, 30x100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nm]. Fractions containing the N-borane complex were pooled and concentrated under 20 vacuum. It was then processed as described in Method C. The resulting mixture in 3 N HCI was concentrated to dryness and stirred in 10:1 diethyl etheri/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as the hydrochloride salt: 'H NMR (400 MHz, methanol-D4) 8 ppm 0 91 (d, J=6.8 Hz, 6 H), 1.90 - 2.01 (m, 2 H), 2.10 - 2.24 (m, 2 H), 2.28 - 2.36 (m, 2 H), 2 64 (br s, 2 H), 25 .3.58 (br s, 2 H), 3.61 - 3.75 (m, 4 H), 3.95 (d, J=7-4 Hz, 2 H), 5.34 (t, J=3.4 Hz, I H), 7.19 (s, I H), 7.65 (d, J=0.9 Hz, 1 H), 7.85 (d, J=0.9 Hz, I H). MS (ESI) m/z = 359 (M+H)*. Anal. Calcd. for C 1

>H

26

N

4 0S 1HCl-0.25H20: C, 57 13; H, 6.94; N, 14.03; Cl, 8.88; Found: C, 57.08; H, 7.07; N, 14.13; Cl, 8.92. 30 Example 144 (4s)-4- [5-(1-Acetyl-IH-pyrazol-4-yl)-1 3-thiazol-2-vlloxyl- azatricyclo[3.3.1 .1 3

,

7 decane -164- Example 144A (4s)-4-{5-(Pyrazol-4-yl)-thiaz o--2yloxy]-- -azatricyclo[ 3.3.1 .1 dcane 5 bishydrochloride The product of Example 141A (128 mg, 0.229 mmol) was processed according to Method L. The resulting mixture in 3 N HCI was concentrated to dryness and stirred in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as a bishydrochloride salt: 1H 10 NMR (400 MH z, methanol-D 4 ) 5 ppm 1-93 - 2.01 (m, 2 H), 2.22 (s, 1 H), 2.27 - 2.37 (m, 2 H), 2.66 (s, 2 H), 3 59 (s, 2 H), 3.62 - 3.75 (i, 4 H), 5.40 (t, J=3 1 Hz, I H), 7.37 (s, 1 H), 8.22 (s, 2 H). MS (APCI) m/z = 303 (M+H)+ Anal. Calcd. for Ci 5

H

1

N

4 0S-2HCl: C, 48.00; H, 5.37; N, 14.93; Cl, 18.89; Found: C, 47.86; H, 5.64; N, 14.57; Cl, 18.58. 15 Example 144B (4s)-4- {[5-(1-Acetyl-1H-pyrazol- 4 -y)-1 ,3-thiazol-2-ylloxyv-1 azatricyclof 3

.

3 . 1.1 3

,

7 decane 20 A suspension of the product of Example 144A (80 mg, 0.213 mmol) in acetic acid (1 0 mL) was treated with acetic anhydride (1.00 g, 9.80 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and methanol (1.0 mL) was added. After stiring at room temperature for 10 minutes, the precipitate was filtered and dried under vacuum to 25 afford the titled compound as a hydrochloride salt: '1H NMR (500 MHz, methanol D4) S ppm 1.93 - 2.01 (m, 2 H), 2.21 (br s, 1 H), 2.27 - 2.35 (m, 2 H), 2.65 (br s, 2 H), 2.67 (s, 3 H), 3.58 (br s, 2 H), 3.62 - 3.75 (m, 4 H), 5.39 (t, .J=3.2 Hz, I H), 7 40 (s, I H), 8.01 (s, I H), 8.47 (s, I H). MS (APCI) m/z= 345 (M+H). Anal Calcd. for C1 7

H

2 oN 4 02S1 .5HCI: C, 51.16; H, 5.43; N, 14 04; Found: C, 51.42; H, 5.19; N, 30 13.81. Example 145 -165- (4s)- 4 -{r5-(5-Methyl-1-plhenyl-IH-pyrazol-4-yl)-1 ,3-thiazol-2-yllVoxy-1 azatricyclor3.3.1.1l7decane To a solution of the product of Example 20A (139 mg, 0.422 nmol) in 2 propanol (2.7 mL) were added 5-methyl-I-phenyl-4-(4,4,5,5-tetramlCthyl-1,3,2 5 dioxaborolan-2-yi)-IH-pyrazole (100 mg, 0.352 mmol), bis(triphenylphosphile) palladium(li) chloride (12.4 mg, 0.018 mmol) and aqueous sodium carbonate (I OM, 0.88 mL). The reaction mixture was degassed with nitrogen and stiired at 100 'C for 1 hour. Afler cooling to room temperature, the reaction mixture was passed through a glass microfiber frit, concentrated, dissolved in MeOH (2.0 mL), and purified by 10 preparative HPLC [Waters@ XTerra RP18 5 pm column, 30x100 mm, flow rate 40 nL/minute, 5-95% gradient of acetonitrile in buffer (0 1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 22 minutes, with UV detection at 254 nrn]. Fractions containing both the desired free base and the N borane complex were pooled, concentrated under vacuum, and processed as described 15 in Method C. The resulting mixture in 3 N HCI was concentrated to dryness and stined in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as the hydrochloride salt: 'H NMR (400 MI-1z, methanol-D4) 5 ppm 1.93 - 2.02 (in, 2 H), 2.21 (br s, 1 H), 2.27 - 2 36 (m, 2 H), 2.37 2.43 (in, 3 H), 2.66 (br s, 2 H), 3.58 (br s, 2 H), 3,60 - 3.77 (in, 4 H), 5.38 (br s, I H), 20 7.15 - 7.21 (m, I H), 7.45 - 7.53 (in, 3 H), 7.53 - 7.60 (in, 2 H), 7 71 - 7.78 (in, 1 H) MS (ESI) m/z = 393 (M+H)+. Example 146 25 (4 5 )-4-f(5-soxazol-4-yl- ll--azatricyclo[3.3.1.1 3 3ldecane To a solution of the product of Example 20A (100 ing, 0.304 mmol) in 2 propanol (2.0 mL) were added 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)isoxazole (71.1 mg, 0 365 mmol), bis(triphenylphosphine)-palladitim(II) chloride (10.7 mg, 0.015 minol) and aqueous sodium carbonate (1.OM, 0.76 mL). The reaction 30 mixture was degassed with nitrogen and heated with stirring at 100 'C for 2 hours. After cooling to room temperature, the reaction mixture was passed through a glass microfiber frit, concentrated, dissolved in MeOH (2.0 mL), and purified by preparative HPLC [Waters® XTerra RP18 5 pIm column, 30x 100 mm, flow rate 40 -166mL/rninute, 5-95% giadient of acetonitrile in buffer (0.1 M aqueous ammonum bicarbonate, adjusted to pH 10 with amnionium hydroxide) over 22 minutes, with UV detection at 254 nm). Fractions containing both the desired free base and the N boTane complex were pooled, concentrated under vacuum, and processed as described 5 in Method C. The resulting material was taken into 3 N HCI, was concentrated to dryness and stined in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as the trihydrochloride salt: 'H NMR (400 MHz, methanol-D 4 ) S ppm 1.90 - 2.02 (m, 2 H), 2.20 (br s, I H), 2.25 2.39 (m, 2 H), 2.64 (br s, 2 H), 3.58 (br s, 2 H), 3.60 - 3.75 (m, 4 H), 5.36 (t, J=3.3 10 Hz, I H), 7 19 (s, I H), 7.43 (s, I H). MS (ESI) m/z = 304 (M+H)*. Anal. Calcd. for Ci 5 H N 3 0 2 S-2.95H Cl-0.45NH4Cl: C, 41.42; H, 5.04; N, 11.11; Found: C, 41.35; H, 4.99; N, 11.05. 15Example 147 (4)-4-(4-Brom-l.3thiazol-2-loxl-aza clO 3 .3.1 .1 7 ecane Example 147A 20 (4s)-4-f(4-Bromo- 1,3-thiazol-2-ylloxy 1-azatricyclol 3

.

3 .1.1 3

'

7 1decane N-borane complex Prepared from the product of Example 10A (600 mg, 3.59 mmol) and 2,4 dibromothiazole (1047 mg, 4.31 mmol) according to Method B: 'H NMR (500 MHz, methanol-D 4 ) S ppm 1.70 - 1.78 (m, 2 H), 1.96 (br s, I H), 2.11 - 2.19 (m, 2 H), 2.36 25 (br s, 2 H), 3.14 (br s, 2 H), 3 15 - 3.24 (in, 4 H), 5.21 (t, J=3.4 Hz, 11H), 6.88 (s, 1 H). MS (APCI) m/z = 329 (M+H)*. Example 147B 30 (4s)-4-.(4-Bromo-1,3-thiazo-2-yloxl1-azatr icyclo[3.3.1. 1 ldecane Prepared from the product of Example 147A (455 mg, 1.38 mmol) according to Method C: 'H NMR (500 MHz, methanol-D 4 ) S ppm 1.68 (br s, I H), 1.83 - 1.93 (m, 2 H), 2.19 (br s, 2 H), 2.21 - 2.30 (m, 2 H), 3.10 -3 16 (m, 4 H), 3.25 - 3.29 (m, -167- 2 H), 5.22 (t, J=3.2 Hz, 1 H), 6.86 (s, I H). MS (ESI) m/z = 315/317 (M+H)*. Anal. Calcd. for C 12 HisBrN2OS-0.3H2O: C, 44.95; H, 4.90; N, 8.74; Found: C, 44.78; H, 4 62; N, 8.60 5 Example 148 (4s)-4-{(4-Bromo-I 3-thiazol-2-ox -ayt clo 3

.

3 . .1 3 7 ldecae The N-borane complex of the titled compound was prepared from the product of Example 9D (117 mg, 0.700 mmol) and 2,4-dibromothiazole (191 mg, 0.784 10 mmol) according to Method B. It was then processed as described in Method C to provide the free base, which was then converted to the furnarate by the procedure of Method H: 'H NMR (500 M.Hz, methanol-D 4 ) S ppm 2.05 - 2.12 (m, 2 H), 2.18 2.28 (m, 3 H), 2.60 (br s, 2 H), 3.46 (m, 2 H), 3.54 (br s, 2 H), 3.70 - 3.80 (m, 2 H), 5.28 (t, J=3.4 Hz, I H), 6.69 (s, 2 H; C 4

H

4 04), 6.93 (s, 1 H). MS (ESI) m/z = 315/317 15 (M+H)*. Anal. Calcd. for C 12 HisBrN2OS 1.15C 4

H

4 04: C, 44.43; H, 4.40; N, 6.24; Found: C, 44.62; H, 4.36; N, 6.12, Example 149 20 (4s)-4-{(4-Chloro-1,3-thiazol-2-yl oxY-1-azatricyclo[ 3

.

3 . 1.1 Idecane Example 149A (4s)-4-f(4-Chloro- 3thiazol-2-ltriclof 3 .3.1.1 3

,

7 ldecane N-borane 25 complex Prepared from the product of Example I A (66 mg, 0.395 mmol) and 2,4 dichlorothiazole (66.9 mg, 0 4.35 mmol) according to Method B: 1 H NMR (500 MHz, methanol-D4) 5 ppm 1 64 - 1.86 (m, 2 H), 1.96 (br s, I H), 2.06 - 2 22 (m, 2 H), 2.36 (br s, 2 H), 3.10 - 3.25 (m, 6 H), 5.20 (t, J=3.4 Hz, I H), 6.74 (s, I H). MS (DCI/NH 3 ) 30 m/z =300 (M+NH 2 )'. Example 149B -168- {4s)-4-f(4-Chloio-1,3-thiazol-2-yl)oxyl-1-azatricvclo[3.3.11 3 7 ldecane The free base was prepared from the product of Example 149A (80 mg, 0.281 mmol) according to Method C The resulting materia was taken up in 3 N HCl, was concentrated to dryness and stirred in 10:1 diethyl ether/MeOH The precipitate was 5 filtered and dried under vacuum to afford the titled compound as a hydrochloride salt: 1H NMR (500 MHz, methanol-D4) 5 ppm 1.91 - 2.02 (m, 2 H), 2.20 (br s, I H), 2.24 2 33 (m, 2 H), 2.63 (br s, 2 H), 3.57 (br s, 2 H), 3.61 - 3.81 (m, 4 H), 5-37 (t, J=3.2 Hz, 1 H), 6.80 (s, I H). MS (ESI) m/z = 271 (M+H)*. Anal. Called. for C1 2

H

5 ClN 2 OS-1.OHCI: C, 46.91; H, 5.25; N, 9 12; Cl, 23.08; Found: C, 46.64; H, 10 5.01; N, 8.92; Cl, 23 06. Example 150 (4s)- 4 - {4-(1H-Pyrazol- 4 -y-_1 ,3-thiazol-2-yloxy}.-l-azatricyclo[ 3.3.1.1 vdecane 15 In a sealed tube were combined the product of Example 147A (50 mg, 0.152 mmol), 4-(4,4,5,5-tetrainethyl-1,3,2-dioxaborolan- 2 -yl)-l-trityl-1 H -pyrazole (86 mg, 0.198 mmol; JP 2005232071), bis(triphenylphosphifne)-palladiumll(U) chloride (5.3 mg, 7.60 jimol), cesium carbonate (121 mg, 0.371 mmol), and DMF (1.5 mL). The tube was heated at 65 *C for 6 hours. After cooling to room temperature, the mixture 20 was partitioned between ethyl acetate (3 x 10 mL) and water (100 nL). The combined organic extracts were washed with brine (100 mL), dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to provide the trityl protected N-borane complex as a white solid. The solid was then processed as described in Method L to provide the free base. It 25 was then reacted with p-toluenesulfonic acid monohydrate according to Method H to provide the titled compound as a bistosylate: 'H NMR (400 MHz, nethanol-D 4 ) S ppm 1.91 - 2.01 (m, 2 H), 2.20 (br s, I H), 2.27 - 2.34 (m, 2 H), 2.36 (s, 6 H; TsOH), 2.68 (br s, 2 H), 358 (br s, 2 H), 3.63 - 3.77 (m, 4 H), 5.46 (t, J=3.4 H z, 1 H), 7.13 (s, 1 H), 7.22 (d, J=8.0 Hz, 4 H; TsOH), 7.70 (d, J=8.3 Hz, 4 H; TsOH), 8.35 (s, 2 H). 30 MS (ESI) m/z =303 (M+H)*. Anal. Calcd for C, 5 HjsN 4 0S-2.2TsOH-0.7H20: C, 52.63; H, 5.37; N, 8.07; Found: C, 52.46; H, 5.19; N, 8.21. -169- Example 151 {4s)-4-[(4-Phenyl-1,3-thiazol-2-yl)oxl- 1-azatricyclo[3.3.1.1 ldecane To a solution of the product of Example 147A (71 mg, 0.216 mmol) in 2 propanol (3.0 mL.) and water (1.0 mL) were added phenylboronic acid (34.2 mg, 5 0.280 nimol), bis(triphenylphosplhine)-palladium(II) chloride (6.1 mug, 8.6 plimol) and aqueous sodium carbonate (2.5M, 0.54 mL.). The reaction mixture was degassed with nitrogen and then heated with stirring at 90 "C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (5.0 rnL), passed through a glass microfiber frit, concentrated and purified by silica gel flash 10 chromatography to provide the N-borane complex. It was then processed as described in Method C. The resulting material was taken into 3 N HCl, was concentrated to dryness and stined in 10:1 diethyl ether/MeOH. The precipitate was filtered and dried under vacuum to afford the titled compound as hydrochloride salt: 'H NMR (500 MHz, methanol-D4) 5 ppm 1.93 - 2.03 (in, 2 H), 2.22 (br s, 1 H), 2.31 - 2.41 (m, 15 2 H), 2.73 (br s, 2 H), 3.59 (br s, 2 H), 3.67 - 3.77 (i, 4 H), 5-51 (t, J=3.2 Hz, 1 H), 7.20 (s, I H), 7.27 - 7.32 (m, I H), 7.33 - 7.47 (m, 2 H), 7.77 - 7.90 (m, 2 H). MS (ESI) rn/z = 313 (M+H)g. 20 Example 152 (4s)-4-[(4-Pvridin-4-yl-1,3-thiazol-2-yl)oxyl- ane The product of Example 147A (65 mg, 0.198 mmol) was dissolved in 2 propanol (1.5 nL). Pyridine-4-boronic acid (31.6 mg, 0.257 mmol), bis(triphenylphosphine)-palladitum(II) chloride (5.6 mg, 7.90 pmol) and aqueous 25 sodium carbonate (1.0 M, 0.49 mL) were added, and the reaction mixture was degassed with nitrogen and heated with stirring at 90 "C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (5.0 mL), passed through a glass microfiber frit, concentrated and purified by silica gel flash chromatography to provide the N-borane complex. It was then processed as described 30 in Method C. The resulting material was taken into .3 N 1CI, was concentrated to dryness and stirred in 10:1 diethyl ether/MeOH- The precipitate was filtered and dried under vacuum to afford the titled compound as the hydrochloride salt: 'H NMR (500 MHz, methanol-D4) S ppm 1.92 - 2.08 (mn, 2 H), 2.23 (br s, I H), 2-28 - 2.40 (m, -170- 2 H), 2.75 (br s, 2 H), 3-61 (br s, 2 H), 3.75 (br s, 4 H), 5.62 (t, J=3.3 Hz, I H), 8.23 (s, I H), 8.50 (d, J=6.4 Hz, 2 H), 8.80 (d, J=6 4 Hz, 2 H). MS (APCI) m/z = 314 (M+H)*. Anal. Called. for C 7

H

9

N

3 OS-2.15HCl2.35H20: C, 47.03; H, 6 00; N, 9 68; Cl, 17.56; Found: C, 47.20; H, 6.25; N, 9.62; Cl, 17+56. 5 Example 153 (4s)-44(4-PYridin-3-yl-I .3-thiazol-2-ylloxyl-1-azatricyclo 3 .3Llvdgecane In a microwave reaction tube were combined the product of Example 147A 10 (70 mg, 0.213 mmol), pyridin-3-ylboronic acid (26.1 mg, 0.213 mmol), bis(triphenylphosphine)-palladium(II) chloride (5.2 mg, 7.45 .mol) and sodium carbonate (56.4 mg, 0.532 mmol) followed by the solvents 2-propanol (2.5 mL) and water (0.83 mL). The tube was sealed, and the reaction was heated to 105 *C for 10 minutes in the microwave reactor. After cooling to room temperature, the reaction 15 mixture was diluted with 2-propanol (5.0 mL), passed through a glass microfiber frit, concentrated and purified by silica gel flash chromatography to provide the N-borane complex. It was then processed as described in Method C to provide the titled compound: 'H NMR (500 MHz, methanol-D 4 ) 8 ppm 1.71 (br s, 1 H), 1.86 - 1.93 (m, 2 H1), 2.24 - 2.34 (m, 4 H), 3.14 - 3.22 (m, 4 H), 3.31 - 3 35 (im, 2 H), 5.37 (t, 20 J=2.9 Hz, 1 H), 7.38 (s, I H), 7.46 (ddd, J=8-l, 4.9, 0.8 Hz, I H), 8.25 (ddd, J=8.2, 2.1, 1.5 Hz, I H), 8.45 (dd, J=4 9, 1.5 Hz, I H), 9.00 (dd, J=2 3, 0 8 Hz, 1 H). MS (APCI) m/z = 314 (M+H)". 25 Example 154 2-(4s)-1-Azatricyclo[ 3 .3.1 .1ldec4vloxN rin-4-yl- 1,3-thiazole- 4 carboxamide 30 Example 154A 2-Bromo-N-(pyridin-4-yl)thiazole-4-carboxarnide Ethyl 2-bromothiazole-4-carboxylate (97 mg, 0.409 mmol) was dissolved in a solvent mixture of ethanol (15 mL) and water (7.5 niL) and treated with aqueous -171sodium hydroxide (2.50 M, 2.54 mL). The mixture was stirred at 35 'C for 30 minutes, and then partitioned between ethyl acetate (100 mL) and HCl (1 0 M, 100 mL) The organic phase was dried (sodium sulfate) and concentrated to afford the carboxylic acid as a white solid. To a solution of this material in pyridine (5 mL) 5 were added 4-aminopyridine (46.1 mg, 0.490 nmol), HOBt (78 mg, 0.511 mnmol), DMAP (10.0 mg, 0.082 nmol) and EDAC (117 mg, 0.613 mrnmol). The reaction mixture was stirred at room temperature for 18 hours then filtered through a frit. The filtrate was concentrated in vacuo and purified by preparative HPLC [Waters Nova Pak HR C18 6pm 60A Prep-Pak cartridge column (40 x 100 mm), 10%-100% 10 gradient of acetonityile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mUrnminute] to provide the titled compound: 'H NMR (400 MHz, methanol-D4) 8 ppm 7.83 - 7.90 (m, 2 H), 8 40 (s, 1 H), 8 43 - 8.46 (n, 2 H). MS (ESI) m/z= 284/286 (M+H)*. 15 Example 154B 2-[(4s)-1-Azatricyclo[3.3.1. ldec4-loxyl-N-pyridin- 4 l-1,3-thiazole- 4 carboxamide The N-borane complex of the titled compound was prepared from the product 20 of Example 10A (32.3 mg, 0.194 mol) and the product of Example 154A (50 mg, 0.176 mmol) according to Method B.. It was then processed as described in Method C to provide the free base which was converted to the fumarate by the procedure of Method H: 1 H NMR (500 MHz, methanol-D 4 ) 8 ppm 1.92 - 2.04 (m, 2 H), 2.21 (br s, 1 H), 2.29 - 2.38 (m, 2 H), 2.70 (br s, 2 H), 3.59 (br s, 2 H), 3.64 - 3 82 (m, 4 H), 5.62 25 (t, J=3.1 Hz, 1 H), 6 71 (s, 2 H; C 4

H

4 0 4 ), 7.85 - 7.87 (m, 2 H), 7.88 (s, I H), 8.46 (d, J=4.6 Hz, 2 H). MS (ESI) m/z = 357 (M+H)*. Anal. Calcd. for CisH 20

N

4 0 2 S-1 55C 4

H

4 04 1.65H 2 0: C, 51.35; H, 5.25; N, 9.90; Found: C, 51.52; H, 5.47; N, 9.75. 30 Example 155 2-[(4s)- 1 -azatricyclor3.3.1.1 3 dec-4-ylxyl-N-(4-chlorophenyl)-1,3-oxazole- 4 carboxamide -172- Example 155A 2-chloro-N-(4-chlorophenyoxazole-4-carboxamnide Prepared from ethyl 2-chlorooxazole-4-carboxylate (83 5 mg, 0.475 mmol) 5 and 4-chloroaniline (60.5 mg, 0.475 mmol) as described in Example 154A: 'H NMR (500 MHz, DMSO-D6) 8 ppm 7.37 - 7.45 (i, 2 H), 7-81 - 7.89 (m, 2 H), 8.91 (s, I H), 10.45 (s, I H). MS (DCI/NH 3 ) m/z = 274 (M+NH 4 )*. Example 155B 10 2-[(4s)-1-azatricyclo[ 3 .3.1. ldec-4-yloxyl-N-(4-chloro henyl)-1,3-oxazole- 4 carboxamide The N-borane complex of the title compound was prepared from the product of Example IOA (38.9 mg, 0.233 mmol) and the product of Example 155A (57 mg, 0.222 mmol) using methods described in Example 122. It was then converted first to 15 the free base as described in Method C, and then to the fumarate salt according to Method H: 'H NMR (400 MHz, methanol-D 4 ) S ppm 1.93 - 2.05 (m, 2 H), 2.20 (br s, I H), 2.26 - 2.36 (m, 2 H), 2.70 (br s, 2 H), 3.57 (br s, 2 H), 3.59 - 3.77 (m, 4 H), 5.36 (br s, 1 H), 6.66 - 6.75 (m, 2 H), 7.31 - 7.40 (s, 2 H; C 4 H404), 7.64 - 7.72 (m, 2 H), 8.05 - 8.15 (s, I H). MS (APCI) m/z = 374 (M+H) 4 20 Example 156 2-[(4s)- I -azatricyclof3.3.1 .1ldec-4-yloxyl-N-phenyl--1,3-oxazole-4-carboxamide 25 Example 156A 2-chloro-N-pheyloxazole4carboxamide Prepared from ethyl 2-chlorooxazole-4-carboxylate (45.4 mg, 0.258 mmol) and aniline (24 mg, 0.258 mmol) as described in Example 154A: 'H NMR (500 MHz, methanol-D4) 8 ppm 7.13 - 7.18 (m, I H), 7.32 - 7.38 (m, 2 H), 7.65 - 7.71 (m, 30 2 H), 8.53 (s, I H). MS (APCI) m/z = 223 (M+H). Example 156B -173- 2-[(4s)-1 -azatricyclof3.3.1.1" ldec--4-yloxyl-N-phenyl-1 .3-oxazole-4-carboxamide The N-borane complex of the title compound was prepared from the product of Example 10A (33 mg, 0 198 mmol) and the product of Example 156A (42 mg, 0.189 mmol) using methods described in Example 122. It was then processed as 5 described in Method C to provide the title compound: 1 H NMR (500 MHz, methanol D4) S ppm 1.70 (br s, I H), 1.86 - 1.95 (m, 2 H), 2 23 - 2.32 (m, 4 H), 3.13 - 3.19 (i, 4 H), 3.32 - 3.36 (m, 2 H), 5 30 (t, J=2.9 Hz, I H), 7 12 - 7.17 (m, I H), 7.32 - 7 3 8 (in, 2 H), 7.65 - 7.69 (m, 2 H), 8.04 (s, 1 H). MS (ESI) m/z = 340 (M+H)*. Anal. Calcd. for C 9

H

21

N

3 030.05H20: C, 67.06; H, 6.25; N, 12.35; Found: C, 66.77; H, 10 6.04; N, 12.73. Example 157 (4s)-4-{[5-(3-bromophenyl)-1,3,4-thiadiazol-2-yI oxy)-1 azatricyclo[ 3

.

3 .1.1 3 -Idecane 15 Prepared from the product of Example 1OB and 2-(3-bromophenyl)-5-chloro 1,3,4-thiadiazole (Zubets, 1. V.; Boikov, Yu. A.; Viktorovskii, I. V.; V'yunov, K. A. Khimiya Geterotsiklicheskilch Soedinenii, 1986, 10, 1416-1419) according to Method B: 'H -NMR (DMSO-d6) 8 8.02 (m, 1H), 7 86 (d, J=9Hz, 1H), 7.73 (d, .1= 9H z, IH), 7.49 (t, .J=9Hz, IH), 5.28 (m, 1H), 3.2-3.15 (in, 3H), 3.02-3.0 (m1, 5H), 2.16-2.13 (m, 20 5H), 1.84-1.79 (2H), 1.56 (m, 1).. MS (ESI) m/z = 394, 392 (M+H)* (4%); 136 (100%) Example 158 (4s)-4-{5-[1-azatricyclo[3.3.1.1 3 1dec-4-ylox yl-1,3,4-thiadiazol-2-y }phenol 25 Example 158A 2-(4-(benzyloxy)phenyl)-5-bromo- 1,3,4-thiladiazole The titled compound is prepared from 4-(benzyloxy)benzoyl chloride using the methodology described in Vachal, P.; Toth, L M. Tetrahedron Lett. 2004, 45, 30 7157-7161. Example 158B (4s)-4-( 5-[4-(benzyloxy)phenl1l-1 3,4-thiadiazol-2-yI oxy)-1 -174azatricyclof 3.3.1.1 3 7 lldecane N-borane complex Example 158A is coupled to Example I0A using the methodology described in Method A 5 Example 158C (4s)-4-({5-[4-(benzyloxy)phenyll-1,3,4-thiadiazol-2-yloxy)-I azatricyclo[3.3. 1.1 3 7 decane Example 158B is converted to the titled compound according to Method C. 10 Example 158D (4s)-4-45-[ I-azatricyclof3.3.1. 1 3 "ldec-4-yloxyl-1 ,34-thiadiazol-2-yl phenol Example 158C is hydrogenated (-15 psi) in the presence of palladium on carbon (-10% by weight) in ethanol. Removal of the solvent by filtration and concentration in vacuo supplies the titled compound. 15 Example 159 (4s)-N-Pyridin-3-yl-1--azatricvclo[ 3

.

3 .1 .13 'ldecan-4-amine bis(4 methylbenzenesulfonate) hemiihydrate Pyridine-3-amine (143 mg, 1.52 mmol) was added to a solution of 1 20 azaticyclo[3 3 1.1 3 7 ]decan-4-one (151 mg, 1.00 mmol) in acetic acid (5 mL). Anhydrous sodium sulfate (1.82 g, 12.8 mmol) was added, and the mixture was stirred at room temperature. After 10 minutes, sodium triacetoxyborohydride (412 mg, 1.94 mmol) was added and the mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered through diatomaceous earth with a 25 chloroform (5 mL) rinse. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography on silica (eluted with chloroform methanol-concentrated ammonium hydroxide, 90:10:1) to provide a colorless gum. This was combined with 4-methylbenzenesulfonic acid monohydrate (29 mg) in a boiling mixture of ethyl acetate (5 mL) and EtOH (0.5 mL) and cooled to room 30 temperature. After 30 hours, the product was collected by filtration, washed with ethyl acetate (2 mL) and dried under vacuum to provide the titled compound: 'H NMR (300 MHz, methanol-D4) S 1.91 - 2.00 (m, 3 H), 2.14 - 2.33 (m, 5 H), 2.36 (s, 6 H), 3.57 (s, 2 H), 3.69 (s, 4 H), 4.03 (s, I H), 7.23 (d, J-7.9 Hz, 4 H), 7.70 (d, .1=8.3 -175- Hz, 4 H), 7.72 - 7.77 (m, 1 H), 7.81 - 7.87 (i, I H), 8.01 (d, J=5.6 Hz, I H), 8.18 ppm (d, J=2.8 Hz, 1 H): MS (DCI/NH 3 ) rn/z 230 (M+H)*; Anal. Calcd for C1 4 H N3 -2C7HsO3SO 51H20: C, 57.71; H,6.23;N, 721. Found: C, 57.78; H, 603; N, 7.19. 5 Example 160 4 s)-N-(5-Bromo-6-chloroDYidin-3-yIl -azatricyclo 3 .3.1.1 " 7 decan-4-ainife 4 nethylbenzeniesul fonate 10 Magnesium sulfate (1.80 g, 15 mmol) and 5-bromo-6-chloropyridin-3-ainie (310 mg, 1 49 mrnol) were added to a solution of I-azatricyclo[ 3

.

3 .1 .1 3 3 ]decan-4-one (151 mg, 1.00 mmol) in acetic acid (5 mL). The resulting suspension was stirred for 10 minutes, then sodium triacetoxyborohydride (412 mg, 1.94 mmol) was added. The mixture was stirred at room temperature for 14 hours, then concentrated under 15 vacuum to dryness. The white solid residue was slurried in ethyl acetate (3 mL), applied to the top of a silica column and eluted with chloroform-methanol concentrated ammonium hydroxide (90:10:1) to provide a pink solid. This material was heated with ethyl acetate (3 nL) and a solution of 4-methylbenzenesulfonlic acid monohydrate (40 mg, I eq.) in warm ethyl acetate (1 mL) was added. Additional 20 ethyl acetate (3 mL) and EtOH (3 mL) were added with heating to bring the mixture to homogeneity. After cooling to room temperature and finally to -10 *C, the mixture was filtered and the collected solid was washed with ethyl acetate (3 mL) and dried under vacuum to provide the titled compound: 'H NMR (300 MHz, methanol-D4) 6 1.91 (br d, J=13.1 Hz, 2 H), 2.11 - 2.21 (in, 1 H), 2.22 - 2.32 (m, 4 H), 2.

3 6 (s, 3 H), 25 3.54 (s, 2 H), 3.59 - 3.72 (n, 4 H), 3.91 (s, 1 H), 7.23 (d, J=7.9 Hz, 2 H), 7.47 (d, J=2.8 Hz, I H), 7.70 (d, J=8.3 HIz, 2 H), 7.85 ppm (d, J=2.8 Hz, 1 H); MS DCI/NH 3 m/z 342/344/346 (M+H)*; Anal. Called for C1 4

H,

7

N

3 ClBr - C 7 HS0 3 S: C, 48 99; H, 4.89; N, 8.16. Found: C, 48.95; H, 4.66; N, 8.02. 30 Example 161 (4s)-N-{6-(IH-indol-6-yl)pyridin-3-yll- 1-azatricyclo 3.3.1.1 ldecan-4-amiine The free base of the titled compound was prepared from the product of -176- Example 65A (150 mg, 0.57 mmol) and indole-6-boionic acid (190 mg, 1.2 mmol; Aldrich) according to Method E: 'H NMR (300 MHz, methanol-D4) 5 ppm 1.70 (s, I H), 1.82 - 1.92 (m, 2 H), 1.97 (s, 2 H), 2 28 (d, J=1 1.2 Hz, 2 H), 3.13 - 3.29 (im, 4 H), 3.31 - 3.44 (m, 4 H), 3.84 (s, 1 H), 7.18 (dd, J=8.6, 2.9 Hz, 1 H), 7.51 (d, J=8.5 Hz, 1 5 H), 7.54 - 7.68 (m, I H), 7.97 (d, J=6.8 Hz, 2 H), 8.03 (d, J=9.2 Hz, 2 H), 8.13 (d, J=3.1 Hz, I H) MS (DCI/NH 3 ) m/z= 345 (M+H)*. Example 162 10 (4s)-N-6-(1 H-indol-3-yl)pyridin- 3 -yll-1-azatricyclo[ 3 .3.1.1 ldecan-4-amine Example 162A (4s)-N-[6-(1-Benzenesulfonyl-IH-indol-3-yl)pyridifn- 3 -ll--l azatricyclof3.

3 . 1.1 3 'ldecan-4-amine 15 Prepared from the product of Example 65A (150 mg, 0.569 mmol) and I phenysulfonyl-1H-inidol-3-ylboroinic acid (350 mg, 1.2 rnol; Aldrich) according to Method E: MS (DCI/NH 3 ) mI/z= 485 (M+H)*. Example 162B 20 (4s)-N-[6-( 1IH-indol-3-yllpyridin-3-yl-I-azatricyclo( 3 .3.1.1 Jdecan-4-amife A solution of the product of Example 162A (50 mg, 0.103 mmol) and potassium carbonate (34 ig, 0.25 minol) in methanol (3 mL) was heated to reflux for 90 minutes. After cooling, the solvent was removed, the residue was dissolved in water, and the mixture was extracted with ethyl acetate (3x). The combined extracts 25 were washed with brine, dried (Na 2

SO

4 ), filtered and concentrated to afford the free base of the title compound: 'H NMR (300 MHz, methanol-D4) S ppm 1.68 (s, I H), 1.86 (d, J=14.9 Hz, 2 H), 1.96 (s, 2 H), 2.29 (d, J=12.2 Hz, 2 H), 3.09 - 3.29 (m, 8 H), 3.81 (s, 1 H), 7 01 - 7.24 (m, 3 H), 7.40 (d, J=7.1 H z, 1 H), 7.50 - 7.61 (m, 2 H), 7.98 (d, J=7,5 Hz, I H), 8.07 (d, J=2.4 Hz, I H). MS (DCIINH 3 ) n/z= 345 (M+H)*. 30 Compositions of the Invention The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (1) in combination with a -177pharmaceutically acceptable carrier The compositions comprise compounds of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal 5 administration. The term pharmaceuticallyy acceptable carrier," as used herein, means a non toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharnaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; 10 starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; 15 buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and 20 antioxidants can also be present in the composition, according to the judgment of one skilled in the art of formulations. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), 25 bucally or as an oral or nasal spray The term "parenterally," as used herein, refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaquCous solutions, dispersions, 30 suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous cariers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate, or suitable -178mixtures thereof Suitable fluidity of the composition may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants These compositions can also contain adjuvants such as preservative agents, 5 wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It also can be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by 10 the use of agents delaying absorption, for example, aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous 15 material with poor water solubility. The rate of absorption of the drug can depend upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline forn. Alternatively, a parenterally administered drug form can be administered by dissolving or suspending the drug in an oil vehicle. Suspensions, in addition to the active compounds, can contain suspending 20 agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar, tragacanth, and mixtures thereof. If desired, and for more effective distribution, the compounds of the invention can be incorporated into slow-release or targeted-delivery systems such as polymer 25 matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use. Injectable depot forms are made by forming microencapsulated matrices of the 30 drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations also are prepared by entrapping the drug in liposomes or microemulsions which are -179compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other 5 sterile injectable medium just prior to use. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also can be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally 10 acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution- In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In 15 addition, fatty acids such as oleic acid are used in the preparation of injectables. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, one or more compounds of the invention is mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, 20 lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators 25 such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceiol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. 30 Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragecs, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well -180known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of materials useful for delaying release of the active agent can include 5 polymeric substances and waxes. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore 10 melt in the rectum or vaginal cavity and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing 15 agents and emulsi fiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 20 Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, 25 inhalants or patches. A desired compound of the invention is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. 30 The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the compounds of this -181invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chloro fluorohydrocarbons. Compounds of the invention also can be administered in the form of 5 liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances, Liposomes are formed by mono- or multi lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome forn may contain, in 10 addition to the compounds of the invention, stabilizers, preservatives, and the like. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., 15 (1976), p 33 et seq. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable canier and any needed preservatives, buffers or propellants. Ophthalmic formulations, eye ointments, 20 powders and solutions are also contemplated as being within the scope of this invention. Aqueous liquid compositions of the invention also are particularly useful. The compounds of the invention can be used in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact 25 with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/nsk ratio. Phanrnaceutically acceptable salts are well-known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. 30 Representative acid addition salts can be prepared using various suitable acids for example, including, but are not limited to, acetic, adipic, alginic, citric, aspartic, benzoic, benzenesulfonic, butyric, camphoric, camphorsulfonic, carbonic, diglucoic, glycerophosphoric, heptanoic, hexanoic, fumaric, hydrochloric, hydrobromic, hydroiodic, 2-hydroxyethansulfonic (isethionic), lactic, maleic, methanesulfonic, -182nicotinic, 2-naphthalenesulfonic, oxalic, pamoic, pectinic, persulfuric, 3 phenylpropionic, picric, pivalic, propionic, succinic, sulfuric, tartaric, thiocyanic, phosphoric, glutamatic, p-toluenesulfonic, and undecanoic acids. Particular examples of acids which can be employed to form pharmaceutically 5 acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid, tartaric acid, and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing 10 moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and 15 nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylanine, diethylamine, ethylamine and the such as. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. 20 Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and 25 others. Water or oil-soluble or dispersible products are thereby obtained. The term "pharmaceutically acceptable prodrug" or "prodnig," as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and 30 the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the invention can be rapidly transformed in vivo to a parent compound of formula (I), for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers -183in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). The invention also contemplates phannaceutically acceptable compounds that when administered to a patient in need may be converted through in vivo biotransformation into compounds of formula (1). 5 Detennination of Biological Activity To determine the effectiveness of representative compounds of this invention as ligands for az7 nAChRs, the compounds of the invention were evaluated according to the [ 3 HI-methyllycaconitine (MLA) binding assay, or the [ 3 HI-DPPB binding 10 assay. To determine the effectiveness of representative compounds of this invention as ligands for a4p2 nAChRs, the compounds of the invention were evaluated according to the [ 3 H}-cytisine binding assay, which were performed as described below. 15 FH)-Cytisine binding Binding to the a4p 2 nAChR subtype was determined according to conditions which were modified from the procedures described in Pabreza LA, Dhawan, S, Kellar K1, [3H]-Cytisine Binding to Nicotinic Cholinergic Receptors in Brain, Mol. Pharm 39: 9-12, 1991. Membrane enriched fractions from rat brain minus 20 cerebellum (ABS Inc., Wilmington, DE) were slowly thawed at 4 *C, washed and resuspended in 30 volumes of BSS-Tris buffer (120 mM NaCI/5 mM KCI/2 mM CaCl2/2 mM MgCI2/5 0 mM Tris-Cl, pH 7.4, 4 *C). Samples containing 100-200 jig of protein and 0.75 nM [ 3 H]-cytisine (30 Ci/mmol; Perkin Elmer/NEN Life Science Products, Boston, MA) were incubated in a final volume of 500 jiL for 75 minutes at 25 4 *C. Seven log-dilution concentrations of each compound were tested in duplicate. Non-specific binding was determined in the presence of 10 piM (-)-nicotine. Bound radioactivity was isolated by vacuum filtration onto prewetted glass fiber filter plates (Millipore, Bedford, MA) using a 96-well filtration apparatus (Packard Instruments, Meriden, CT) and were then rapidly rinsed with 2 mL of ice-cold BSS buffer (120 30 mM NaCl/5 mM KCI/2 mM CaCI 2 /2 mM MgCl2). Packard MicroScint-20 scintillation cocktail (40 [LL) was added to each well and radioactivity determined using a Packard TopCount* instrument. The IC 50 values were determined by nonlinear regression in Microsoft Excel* software. Ki values were calculated from -184the IC 50 s using the Cheng-Prusoff equation, where K = IC 5 0 /(l+[Ligand)/KD).

[

3 H)-Methyllycaconitine (MLA) binding Binding to the 7 nAChR subtype was determined according to conditions 5 which were similar to those used for the [ 3 H)-cytisine binding assay. Membrane enriched fractions from rat brain minus cerebellum (ABS Inc., Wilmington, DE) were slowly thawed at 4 "C, washed and resuspended in 30 volumes of BSS-Tiis buffer (120 mM NaCI, 5 mM KCJ, 2 mM CaCI2, 2 mM MgCl 2 , and 50 mM Tris-Cl, pH 7 4, 22 *C). Samples containing 100-200 pg of protein, 5 nM [ 3 H]-MLA (25 Ci/mimol; 10 Perkin Elmer/NEN Life Science Products, Boston, MA) and 0.1% bovine serum albumin (BSA, Millipore, Bedford, MA) were incubated in a final volume of 500 jiL for 60 minutes at 22 'C. Seven log-dilution concentrations of each compound were tested in duplicate. Non-specific binding was determined in the presence of 10 jiM MLA. Bound radioactivity was isolated by vacuum filtration onto glass fiber filter 15 plates prewetted with 2% BSA using a 96-well filtration apparatus (Packard Instruments, Meriden, CT) and were then rapidly rinsed with 2 mL of ice-cold BSS. Packard MicroScint-20* scintillation cocktail (40 pLL) was added to each well and radioactivity was determined using a Packard TopCount* instrument. The IC 5 o values were determined by nonlinear regression in Microsoft Excel® software. Ki values 20 were calculated from the IC 50 s using the Cheng-Prusoff equation, where Ki = IC5a/(l +[Ligand]/Ko).

{

3 H)-DPPB binding

[

3 H)-DPPB, ['H)-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2 25 azonia-bicyclo[2.2.1)]heptane iodide, binding to the a7 nAChR subtype was determined using membrane enriched fractions from rat brain minus cerebellum or human cortex (ABS Inc, Wilmington, DE). Pellets were thawed at 4*C, washed and resuspended with a Polytron at a setting of 7 in 30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCI, 2 mM CaCIz, 2 mM MgC 2 , and 50 mM Tris-Cl, pH 7.4, 4*C). 30 Seven log-dilution concentrations of test compounds containing 100-200 jig of protein, and 0.5 nM [ 3 H]-DPPB (62.8 Ci/mmol; R46V, Abbott Labs) were incubated in a final volume of 500 tl for 75 minutes at 4*C in duplicate. Non-specific binding was determined in the presence of 10 piM methyllycaconitine. Bound radioactivity -185was collected on Millipore MultiScreen@ harvest plates FB presoaked with 0.3% PEI using a Packard cell harvester, washed with 2.5 ml ice-cold buffer, and radioactivity was determined using a Packard TopCount Microplate beta counter. ICso values were determined by nonlinear regression in Microsoft@ Excel or Assay Explorer. Ki 5 values were calculated from the IC 5 os using the Cheng-Prusoff equation, where Ki

IC

5 o/(I+[Ligand]/KD)- >H]-DPPB was obtained according to the preparation procedures described below. [ Methy-3H12,2-Dimethyl-a5-(6--henyl-ridazin-3-Y--5-aza-2-azorna 10 bicyclo2.2.lheptane; iodide Preparation [Methyl-3H2,2-dimethyl-5-(6-phenyl-pydazin-3-yl)-5-aza-2-azonia bicyclo[2.2.1]heptane; iodide used in the [ 3 H]-DPPB binding assay above was prepared according to the following procedures. 15 Step 1: Preparation of t-But -5-6-Peyl-pdazin-3-yl-2,5-diaza bicyclo[2.2. 1]heptane-2-carbolate Triethylamine (20 mL) was added to a suspension of t-butyl (S,S)-2,5 diazabicyclo[ 2

.

2 .1]heptane-2-carboxylate (3.43 g, 17.3 mmol, Aldrich Chemical Company) and 3-chloro-6-phelnylpyridazine (3.30 g, 17.3 mmol, Aldrich Chemical 20 Company) in toluene (50 mL) and the mixture was heated under nitrogen at 100 "C for 7 days. The dark mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration, washed with toluene (15 mL) and dried under vacuum to provide the title compound as an off-white solid (3.00 g). The filtrate was concentrated and the residue was purified by column chromatography on silica gel, 25 eluting with ethyl acetate, to provide additional product (0.41 g, total yield 3.41 g, 56%): MS (DCI/NH3) m/z 353 (M+H)*-. Step 2: Preparation of (SS)-2-Methyl 5-(6phenyl-pyridazin-3-yl)-2,5-diaza bicyclo[2.2. lheptane 30 The product obtained from Step 1 (3.41 g, 9.7 rnmol) was dissolved in formic acid (20 mL) and treated with formalin (37/6 by weight, 1.0 g, 12.3 mmol). The mixture was heated at 100 'C for I hour, and the brown solution was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography on silica gel, eluting with CH 2 Cl 2 - CH30H7l - NH40H (95:5:1) to -186provide the title compound as an off-white solid (2.50 g, 96%): MS (DCI/NH3) m/z 267 (M+H)*. Step 3: Preparation of [3-(SS) 2 ,2Di le yidazin-3-yl)-5-aza-2 5 azonia-bicyclo[ 2

.

2 .Ilheptane iodide ([ 3 H1-DPPB)

[

3 HIMethyl iodide in toluene (250 mCi in 0.1 mL, 85 Ci/mmol, American Radiolabeled Chemicals, Inc.) was combined with a solution of the product obtained from Step 2 in dichloromethane (0.788 mg, 2.96 pmole in 0.45 mL). The vial was capped and the mixture was allowed to react overnight at room temperature 10 Methanol was added and the solvents were evaporated to give 42 mCi. The product was taken up in methanol for HPLC purification. Step 4: Purification by High Performance Liquid Chromatography (HPLC About 7 mCi of [ 3 H]-DPPB was evaporated to dryness and the residue was 15 dissolved in total about 4.5 ml acetonitrile:water:TFA (15:85:0.1) Approximately 0.9 mL per injection were made onto a Phenomenex Luna C18(2) column (5 micron, 250 mm x 4.6 mm ID) using an Agilent HPLC system.

[

3 H]-DPPB was eluted by a gradient mobile phase from 10% B to 20% B in 20 min where Mobile Phase A= 0.1% trifluoroacetic acid in water and Mobile Phase B= 0. 1% trifluoroacetic acid in 20 acetonitrile at a flow rate of approximately I mL/min. Peak detection and chromatograms were obtained with an Agilent variable wavelength UV detector set at 275 nm. The fractions containing

[

3 H)-DPPB were collected at approximately 14 minutes using an Agilent fraction collector. The fractions were combined and the solvents were evaporated in vacuo. The residue was dissolved in 200 proof ethanol (2 25 mL) to give 0.7 mCi. Step 5: Determination of Purity and Spifctivity

[

3 H)-DPPB was assayed using an Agilent I100 series HPLC system consisting of a quaternary pump, an autosampler, and a photodiode array UV detector. A 30 Packard Radiomatic A 500 radioactivity detector was connected to the HPLC system. For radiodetection, a 500 p.L flow cell and a 3:1 ratio ofUltima-Flo M scintillation cocktail to HPLC mobile phase were used. The analyses were performed using a Phenomenex Luna C 18(2) column (5 microns, 250 mm x 4.6 mm ID). The mobile -187phase consisted of a gradient starting with 10% B and ramping to 20% B in 20 minutes followed by ramping to 90% B in I minute and hold at 90% B for 9 minutes, where Mobile Phase A = 0.1% trifluoroacetic acid in water and Mobile Phase B= 0. 1% trifluoroacetic acid in acetonitrile. The flow rate was set at approximately I 5 mL/min and the UV detection was set at 275 nm. Preferred compounds of the invention had Ki values of from about 0.1 nanomolar to about 10 micromolar when tested by the [ 3 H)-MLA assay, many having a K; of less than I micromolar. Other preferred compounds demonstrated [3H-H Cytisine binding values of compounds of the invention ranged from about 0.1 10 nanomolar to at least 10 micromolar. Some preferred compounds exhibited greater potency at a7 receptors compared to cA4P2 receptors. The determination of such preferred compounds typically considered the K; value as measured by MLA assay in view of the Ki value as measured by [ 3 H]-cytisine binding, such that in the formula D = Ki 3 1-cyiisinc / Ki MLA, D is greater than about 50. Alternatively, the Ki value as 15 measured by [ 3 H]-DPPB assay can be used in place of the Ki MLA such that in the formula D'= Ki 3 H-cytisine / Ki [311-DPpm, D' is greater than about 50. Compounds of the invention are a7 nAChRs ligands and/or a4p2 ligands that modulate function of 7 nAChRs and/or o4 2 ligands by altering the activity of the receptor or signaling. The compounds can be inverse agonists that inhibit the basal 20 activity of the receptor or antagonists that completely block the action of receptor activating agonists The compounds also can be partial agonists that partially block or partially activate the 7 nAChR receptor or agonists that activate the receptor. Binding to the a7 nicotinic receptor also triggers key signaling processes involving various kinases and phosphatases and protein-protein interactions that are important to 25 effects on memory, cytoprotection, gene transcription and disease modification. Methods of the Invention Compounds and compositions of the invention are useful for modulating the effects of nAChRs, and more particularly 07 nAChRs. In particular, the compounds 30 and compositions of the invention can be used for treating and preventing disorders modulated by a7 nAChRs. Typically, such disorders can be ameliorated by selectively modulating the a7 nAChRs in a mammal, preferably by administering a compound or composition of the invention, either alone or in combination with -188another active agent, for example, as part of a therapeutic regimen. Also, some compounds of the invention possess affinity at the a4p2 nAChRs in addition to a7 nAChRs, and selective compounds with dual affinities at both receptor subtypes also are expected to have beneficial effects. 5 The compounds of the invention, including but not limited to those specified in the examples, possess an affinity for nAChRs, and more particularly a7 nAChRs. As 07 nAChRs ligands, the compounds ofthe invention can be useful for the treatment and prevention of a number of a7 nAChR-mediated diseases or conditions For example, 07 nAChRs have been shown to play a significant role in 10 enhancing cognitive function, including aspects of learning, memory and attention (Levin, E.D., J. Neurobiol. 53: 633-640, 2002). As such, 07 ligands are suitable for the treatment of cognitive disorders including, for example, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impainrent, senile dementia, AIDS dementia, Pick's disease, dementia 15 associated with Lewy bodies, and dementia associated with Down's syndrome, as well as cognitive deficits associated with schizophrenia. In addition, c7-containing nAChRs have been shown to be involved in the neuroprotective effects of nicotine both in vitro (Jonnala, R. B. and Buccafusco, . 1., J. Neurosci. Res. 66: 565-572, 2001) and in vivo (Shimoharna, S. et al., Brain Res, 20 779: 359-363, 1998). More particularly, neurodegeneration underlies several progressive CNS disorders, including, but not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, as well as diminished CNS function resulting from traumatic brain injury. For example, the impaired function of 7 nAChRs by p-amyloid peptides 25 linked to Alzheimer's disease has been implicated as a key factor in development of the cognitive deficits associated with the disease (Liu, Q.-S., Kawai, H., Berg, D. K., PNAS 98: 4734-4739, 2001). The activation of c7 nAChRs has been shown to block this neuiotoxicity (Kihar a, T. et al., J. Biol. Chen. 276: 13541-13546, 2001). As such, selective ligands that enhance 7 activity can counter the deficits of Alzheimer's 30 and other neurodegenerative diseases, Schizophrenia is a complex disease that is characterized by abnonnalities in perception, cognition, and emotions Significant evidence implicates the involvement of c7 nAChRs in this disease, including a measured deficit of these receptors in post -189mortem patients (Leonard, S Eur, J. Pharmacol. 393: 237-242, 2000). Deficits in sensory processing (gating) are one of the hallmarks of schizophrenia. These deficits can be nonalized by nicotinic ligands that operate at the a7 nAChR (Adler L. E. et al , Schizophrenia Bull. 24: 189-202, 1998; Stevens, K E et al., Psychopharmacology 5 136: 320-327, 1998). Thus, a7 ligands demonstrate potential in the treatment schizophrenia. Angiogenesis, a process involved in the growth of new blood vessels, is important in beneficial systemic functions, such as wound healing, vascularization of skin grafts, and enhancement of circulation, for example, increased circulation around 10 a vascular occlusion. Non-selective nAChR agonists like nicotine have been shown to stimulate angiogenesis (Heeschen, C_ et al , Nature Medicine 7: 833-839, 2001). Improved angiogenesis has been shown to involve activation of the 7 nAChR (Heeschen, C. et al., J. Clin. Invest. 110: 527-536, 2002). Therefore, nAChR ligands that are selective for the a7 subtype offer improved potential for stimulating 15 angiogenesis with an improved side effect profile. A population of 7 nAChRs in the spinal cord modulate serotonergic transmission that have been associated with the pain-relieving effects of nicotinic compounds (Cordero-Erausquin, M. and Changeux, J -P. PNAS 98:2803-2807, 2001). The a7 nAChR ligands demonstrate therapeutic potential for the treatment of pain 20 states, including acute pain, post-surgical pain, as well as chronic pain states including inflammatory pain and neuropathic pain. Moreover, a7 nAChRs are expressed on the surface of primary macrophages that are involved in the inflammation response, and that activation of the 7 receptor inhibits release of TNF and other cytokines that trigger the inflammation response (Wang, H. et al Nature 421: 384-388, 2003). 25 Therefore, selective 7 ligands demonstrate potential for treating conditions involving TNF-mediated diseases, for example, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, sepsis syndrome, depression, and 30 rheumatoid spondylitis. The mammalian sperm acrosome reaction is an exocytosis process important in fertilization of the ovum by sperm. Activation of an c7 nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J.-H. and Meizel, S. -190- Biol. Reproduct. 68: 1348-1353 2003). Consequently, selective cx7 agents demonstrate utility for treating fertility disorders Compounds of the invention are particularly useful for treating and preventing a condition or disorder affecting cognition, neurodegeneration, and schizophrenia 5 Cognitive impainnent associated with schizophrenia often limits the ability of patients to function normally, a symptom not adequately treated by commonly available treatments, for example, treatment with an atypical antipsychotic. (Rowley, M. et al., J. Med Chem. 44: 477-501, 2001). Such cognitive deficit has been linked to dysfunction of the nicotinic cholinergic system, in particular with decreased 10 activity at a7 receptors. (Friedman, J. I. ct al., Biol Psychiatry, 51: 349-357, 2002). Thus, activators of a7 receptors can provide useful treatment for enhancing cognitive function in schizophrenic patients who are being treated with atypical antipsychotics. Accordingly, the combination of an a7 n.AChR ligand and an atypical antipsychotic would offer improved therapeutic utility. Specific examples of suitable atypical 15 antipsychotics include, but are not limited to, clozapine, risperidone, olanzapine, quietapine, ziprasidone, zotepine, iloperidone, and the like Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, 20 compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated.. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and 25 to gradually increase the dosage until the desired effect is achieved. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, arnide or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition 30 containing the compound of interest in combination with one or more pharmaceutically acceptable carriers The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It -191will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder 5 being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like 10 factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a 15 human or lower animal range from about 0.010 mg/kg body weight to about I g/kg body weight. More preferable doses can be in the range of from about 0.010 mg/kg body weight to about 100 mg/kg body weight. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the 20 daily dose. Compounds of the invention are a7 nAChRs ligands that modulate function of 7 nAChRs by altering the activity of the receptor or signaling. The compounds can be inverse agonists that inhibit the basal activity of the receptor or antagonists that completely block the action of receptor-activating agonists. The compounds also can 25 be partial agonists that partially block or partially activate the a7 nAChR receptor or agonists that activate the receptor. Binding to a7 receptor also trigger key signaling processes involving various kinases and phosphatases and protein-protein interactions that are important to effects on memory, cytoprotection, gene transcription and disease modification. Therefore, the administration of a therapeutically effective .30 amount of a compound of formula (1) to a mammal provides a method of selectively modulating the effects of a4@ 2 , 7, or both a4 2 and a7 nicotinic acetylcholine receptors. Furthermore, the administration of a therapeutically effective amount of a -192compound of fonnula (1) to a mammal provides a method of treating or preventing a condition or disorder selected from the group consisting of attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, Pick's disease, dementia 5 associated with Lewy bodies, dementia associated with Down's syndrome, arryotrophic lateral sclerosis, Huntington's disease, smoking cessation, nicotinic withdrawal syndrome, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, 10 need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, more particularly circulation around a vascular occlusion, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic 15 shock, toxic shock syndrome, sepsis syndrome, depression, and rheumatoid spondylitis. More preferred, the administration of a therapeutically effective amount of a compound of formula (I) to a mammal provides a method of treating cognitive disorders, neurodegeneration, and schizophrenia. Furthermore, compounds of formula (1) may also be administered in combination with an atypical antipsychotic. 20 Preparation of Salts Example A (4s)- 4 -(5-Phenyl-1,3,4-thiadiazol-2-yloxy-h-azatricyclo3 .3.1.l 7 decane 25 L-bitartrate anhydrate (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1. V]decane free base (21.5 mg, 0.07 mmol) was dissolved in 1.0 mL of 200 proof ethanol Meanwhile, 11.75 mg of L-tartaric acid (0.08 mmol) was dissolved in 250 LL 200 30 proof ethanol. The L-tartaric acid solution was added dropwise to the (4s)-4-(5 phenyl-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3 .3.1.1 V }decane free base solution while stirring. The vial was removed from the stir plate after the addition. The L bitartrate anhydrate crystallized upon standing. -193- Example B (4s)-4-(5-Phenyl- 1,3,4-thiadiazol-2-vloxy)- 1-azatricyclof3.3.1.1 3 '-ldecane L-bitartrate hydrate 5 The anhydrate of (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- 1 azatricyclo[ 3

.

3 .1 .1 3 ]decane L-bitartrate solid (60 ng) was suspended in water (500 pL) at ambient temperatures. The hydrate of ( 4 s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)-1-azatricyclo[ 3 .3l .13,7 ]decane L-bitartrate crystallized over time. 10 Example C (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-ylox -1-azatricvclo 3.3.1.1 3 decane dihydrogenl phoshate anhydrate 15 (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)- 1 -azatricyclo[ 3 .3.1 1' 3 ]Idecane free base (20 mg, 0.064 mmol) was dissolved in 1.0 mL of methanol. Meanwhile, 5 p.L of 85% phosphoric acid (0.073 mmol) was diluted with 245 ptL methanol. The phosphoric acid solution was then added dropwise to the (4s)-4-(5-phenyl-1,3,4 thiadiazol-2-yloxy)-l -azatricyclo[ 3

.

3 . 1.1 3

,

7 ]decane free base solution while stirring 20 The vial was removed from the stir plate after the addition. The dihydrogen phosphate anhydrate crystallized upon standing. Example D (4sl-4-(5-Phenyl-1,3,4-thiadiazol-2-vloxy)- -azatricvclof 3 .3A. .1 3 dece 25 dihydrogen phosphate hdLate The anhydrous (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo{3.3..1 3 7 ]decane dihydrogen phosphate solid was exposed to high humidity. The hydrate of (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 30 azatricyclo[ 3

.

3 -l.1 3 ']decane dihydrogen phosphate crystallized over time. Example E (4s)-4-(5-Phenyl-1,3 4-thiadiazol-2Vlox -aZatticvclo[ 3 .3.1.1" ldecane -194bisuccinate anhydrate (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1.1 37 ]decane free base (20 mg, 0.064 mmol) was dissolved in 1.0 mL of 2-propanol (or 5 tetrahydrofuran). Meanwhile, succinic acid (8.25 mg, 0.07 mmol) was dissolved in 500 prL of 2-propanol (or tetrahydrofuran). Both solutions were heated to 50*C. The succinic acid solution was then added dropwise to the (4s)-4-(5-phenyl-l,3,4 thiadiazol-2-yloxy)-1-azatricyclo[ 3 3 -1 .1 3

,

7 ]decane free base solution while stirring at 50*C. The vial was removed from the hot/stir plate afterwards. The bisuccinate 10 anhydrate crystallized upon standing and natural cooling to ambient temperatures. Example F (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy -1-azatricyclo[3.

3 .1 .1 ldecane bisuccinate hydrate 15 The anhydrate of (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- 1 azaticyclo[ 3

.

3 -1 1 3 7 ]decane bisuccinate solid (25 mg) was suspended in 100 pIL of water at ambient temperatures. The hydrate of (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2 yloxy)-1-azatricyclo[3.3.1.1 3

,

7 ]decane bisuccinate crystallized over time. 20 Example G (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-ioxy)-1-azatricyclo[3.3.1.17 1 decane hydrochloride quarterhydrate (1 salt: 0.25 water) 25 (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 33 .3 13. ' 7 ]decane free base (40 mg, 0 13 mmol) was dissolved in 2.0 mL of 200 proof ethanol, Concentrated HCI solution (5N, 30 pL, 0.15 mmol) was diluted with 220 pL of 200 proof ethanol. The diluted HCI solution was added to the (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy) I-azatricyclo[3.3. 1.1 3

,

7 ]decane free base solution while stirring. The vial was 30 removed from the stir plate, and the solvent was allowed to evaporate. The hydrochloride quarterhydrate crystallized over time To prepare a (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-I azatricyclo[.

3 3 .1 .1 3

,

7 decane hydrochloride quarterhydrate single crystal, the -195supernatant obtained from the above experiment was used for this experiment. Solvent was allowed to evaporate slowly. Single crystals of the hydrochloride quarterhydrate formed over time. 5 Example H {y )-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-I-azatricyclo[3.3.1.1 3 7 ldecane hydrochloride sesquihydrate (1 salt: 1.5 water) (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3. 31 .1 3 7 ]decane 10 hydrochloride quarterhydrate solid, 50 ng, was suspended of in 200 PL of water. (4s).-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.1 3 7 decane hydrochloride sesquihydrate crystallized over time.. Example I 15 {4s)-4-(5-Phel-34-thiadiazol-2-loxV)-l-azaticclor3.3.1.1 3

'

7 decane dihydrogen citrate (4s)-4-(5-Phen yl-1,3,4-thiadiazol-2-yloxy)- I -azatricyclo[3.3 1 .1 3

'

7 ]decane free base (63 mg, 0.2 mmol) was dissolved in 1.0 mL of methanol. Citric acid (41 mg, 20 0.21 inmol) was dissolved in 0.5 mL of methanol. The citric acid solution was added to the (4s)- 4 -(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3.1.1 3 7 ]decane freebase solution while stirring.. The vial was removed from the stir plate after the addition, and the solvent allowed to evaporate slowly. (4s)-4-(5-Phenyl-1,3, 4 thiadiazol-2-yloxy)- I -azatricyclo(3.3.1 .11.

7 ]decane dihydrogen citrate crystallized 25 over time To prepare a (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-

I

azatricyclo[3.3.1 .. 1 3 7 )decane dihydrogen citrate single crystal, (4s)-4-(5-phenyl-1,3,4 thiadiazol-2-yloxy)- 1 -azatricyclo[3.3. 1.1 3 ,]decane dihydrogen citrate (20 mg) was dissolved in 0.8 mL water/2-propanol (1:6, V/V) at 50 'C. The solution was seeded 30 with (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 .3. 1.1 3

,

7 ]decane dihydrogen citrate solid and allowed to cool to ambient temperatures in a sealed vial. Single crystals formed over time. -196- Example 3 (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo 3.3.1 .1 3 'ldecane monohydrogen citrate 5 (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo[ 3 .3.1.1 ,7]ldecane free base (62 mg, 0 2 mmol) was dissolved in 1.5 mL of methanol. Citric acid (19 mg, 0.1 mmol) was dissolved in 0. 5 mL of methanol.. The citric acid solution was added to the (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3

.

3 .1 .1 3

,

7 ]decane free base solution while stirring. (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-l 10 azatricyclo[3.3.1.1 3

,

7 ]decane monohydrogen citrate crystallized over time while stirring. Example K (4s)-4-(5-Phlenyl-1,3,4-thiadiazol-2-yloxy)l-azatricvclor3.3.11 3 ldecane 15 free base To prepare a (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-I azatricyclo[ 3 .3.1.1 3

,

7 ]decane free base single crystal, (4s)-4-(5-phenyl-1,3,4 thiadiazol-2-yloxy)-1 -azaticyclo[ 3 .3.1.13 3 )decane free base (13 mg) was dissolved in 20 1.0 mL of 2-propanol. The solvent was allowed evaporate slowly. Single crystals of (4s)-4-(5-phenyl-I ,3,4-thiadiazol-2-yloxy)-1 -azatricyclo{ 3

.

3 .1 .1 3

,

7 ]decane free base formed over time. A process for preparing a citric acid salt of (4s)-4-(5-phenyl-1,3,4-thiadiazol 25 2-yloxy)-l-azatricyclo[ 3 .3.1.1 ' 7 ]decane by recrystallizing (4s)-4-(5-pheny-1,3,4 thiadiazol-2-yloxy)-I--azatricyclo(3.3.1-l.]decane in citric acid and methanol also is contemplated. It is understood that the foregoing detailed description and accompanying 30 examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, -197syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. -198-

Claims (25)

1. 2. The compound according to claim 1, wherein A is Arl. 20 3 The compound according to claim 2, wherein Ar is selected from -199- Ei El G1G 1 D E'K1 ; - X 12 X X 12 X0 11 1 11 X 14 X X14, N Is X8X 1 5 H X8 X 1 Y2 o or3'or A 1 4 x 1 0 1 wherein D , Ei, Fi, JI, KI, Xg, X9, Xio, and X 1 1 are each independently -CRI or N; X1 2 , X 13 , X1 4 , X 15 , MI, and M 2 are each independently -CRI, N or C; 5 G, is 0, -NRi 3 , or S; Yj is -CR, or N; Y 2 is -CRI or N; Y 3 is NH, 0, or S Ri is hydrogen, alkyl, alkoxy, alkoxycarbonyl, cyano, halo, nitro, -NRbR, 10 haloalkyl , or -C(O)NRbRe ; Ria is hydrogen or alkyl; Rb and Re are each independently hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl; one of X 2 -Xi 5 is C; and 15 M, or M 2 is C.
2. 4. The compound according to claim 3, wherein L, is -0- 20 5- The compound according to claim 3, wherein Li is -NR,-, -200-
3. 6. The compound according to claim 1, wherein A is -Ar 2 - Lr-Ar 3
4. 7. The compound according to claim 6, wherein 5 Ar, is a group selected from ~s E 2 _ E -J2, F 2 J E2 E2/ I . or F D2-G2 ' G2-D2 'D 2 ' K 2 D 2 , E 2 , F 2 , 32, and K 2 are each independently -CT 2 or N; G 2 is 0, -NR 2 2, or S; in each group of (i), (ii), and (iii), one substituent represented by T 2 , or R 2 , 10 wherein R 2 , is T 2 , is -L 2 -Ar3 and the other substituents represented by T 2 are hydrogen, alkyl, alkoxy, alkoxycarbonyl, cyano, halo, nitro, or -NRbRc; R 2 is hydrogen, alkyl, or T 2 ; and RI and Rc are each independently hydrogen, alkyl, alkoxycarbonyl or alkylcarbonyl. 15
5. 8. The compound according to claim 6, wherein Ar 3 is a group selected from -201- E3 3E3 F3 F3 J3// J3 3 D 3 G 3 -D 3 D 3 K Da E3 D3--G3 .E 3 X, X11 X15 ~X16 xll ' X X10 X17 X 1 X N 0' 1 X 1 1 N; ) X 1 9 X x 1 ; \r7 7 2 ;or N\M 2 X1 8 or x 10 / X1g X11 wherein D 3 , E 3 , F 3 , J 3 , K 3 , X 8 , X 9 , X 1 0 , and XI are each independently -CR 3 or N; X 16 , X 17 , XIs, Xi , M 1 , and M 2 are each independently -CR 3 , N, or C; 5 G3 is 0, -NR1 3 , Or S; Yj is -CR 3 or N; Y 2 is -CR 3 or N; Y 3 is NH, 0, or S; R 3 is hydrogen, alkyl, alkoxy, alkoxylalkyl, alkoxycarbonyl, alkylcarbonyl, 10 cyano, halo, haloalkoxy, haloalkyl, hydroxy, nitro, ReRrN-, or aryl, wherein aryl is preferably phenyl optionally substituted with halo, alkyl or cyano; R 3 ., is hydrogen, alkyl, alkylcarbonyl, tritylaryl, wherein aryl is preferably phenyl; Rc and Ri are each independently hydrogen, alkyl, alkoxycarbonyl, or 15 alkylcarbonyl, or Re and Rf are each taken together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein the heterocyclic ring is preferably pyrrolidinyl, piperidinyl or piperazinyl; one of X 16 , X 17 , X18, and Xjo, is C; and M, or M 2 is C; -202-
6. 9. The compound according to claim 6, wherein L, is -NR,-; and L- 2 is a bond. 5
7. 10. The compound according to claim 6, wherein L, is -0-; and L 2 is a bond. 10 11. The compound according to claim 1, wherein A is -Ar 4 -L 3 -Ars.
8. 12. The compound according to claim 1, wherein -Ar 4 -L 3 -Ars is Y4 X 5 Ar 5 L3 YAr4 5 X Y 5 . -L 3 5 ~ - 6 ~ X6 or . X 7 15 or Y X Y 4 is -NR4,, 0 or S; Ys is N, C or -CR4; Y 6 is N, C or -CR4; provided that one of Ys and Y( is C; 20 R4 is hydrogen, alkyl, alkoxy, alkoxylalkyl, alkoxycarbonyl, alkylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, nitro, oxo, or ReRrN-; R4, is hydrogen or alkyl; Re and Rj are each independently hydrogen, alkyl, alkoxycarbonyl or alkylcarbonyl, or Re and Rr are each taken together with the nitrogen atom to which 25 they are attached forn a heterocyclic ring, wherein the heterocyclic ring is preferably pyrrolidinyl, piperidinyl or piperazinyl; X4 is N, C, or -CRx4; X 5 is N, C, or -CRx 5 ; X 6 is N, C, or -CRx6; 30 X 7 is N, C, or -CRx7; provided that only one of X 4 , Xs, X 6 , or X 7 may be N, only one is C, and the -203- remaining must be other than N; and RX 4 , Rx5 Rx 6 , and RX 7 are each independently hydrogen or alkcyl.
9. 13. A compound of claim 1, wherein the compound is 5 (4s)-4-(6-clhloropyridazil-3-yloxy)-l -azatficyclo[3 .3.1 .1 3 , 7 ]decane; (4r-)-4-(6-chloropyridazin-3-yloxy)- I -azatricyclo[ 3 .3.1. 1 3 , 7 decane; (4s)-4-(6-plhenylpyridazil-3-yloxy)- I -azatricyclo[ 3 .3. 1 .13 37 1decane; (4r-)-4-(6-phelyiidail-3-yloxy)- l-azatricyclo[ 3 .3. 1.1 3 , 7 ldecane; (4s)-4-[ 6 -( I H-1iidol-5-y1)pyridazifl-3-yloxy]-I -azati-icyclo[ 3 .3. 1 .1 3 , 7 ]decane; 10 (4ir)-4-[6-( 1 H-indo1-5-yI)pyridazifl-3-yloxyF- I -azatricyclo[ 3 . 3 .1.1 3 , 7 ]decane; (4.s)-4-[ 6 -( I -benzothiien-5 -yl)pyridazil-3-Yloxy]- 1 azatricyclo[3-.1 .13,7 ]decane; (4ir)-4-[6-(l I benzothiien-5-yI)pyridazin-3-yloxy]- I azatricyclo[ 3 . 3 .I .1 3 7 ]decane; 15 ('4,.-4.(5..bromTopyidin..2-yloxy)- I -azatricyclo[3 .3. 1 .13*7 decane; (4s)- 4 -( 5 -plenylpyridin-2-yIoxy)- I -azatricyclo[ 3 .3. 1.13,7"]decane; (4j)-4-(5-plhenylpytidini-2-yloxy)-l -azatricyclo[ 3 . 3 .1 .1 3 7 ]decane; (4s)-4-[5-( 1 H-indo1.5-yl)pyridifl-2-yloxy][ I -azatticyclo[ 3 .3. 1.1 V' 7 ]decane; (41)-4-[5-(] JJindol-5-y1)pyri dinl-2-yoxy]- I -azatricyclo[ 3 .3. . -1 3 , 7 ]decane; 20 ( 4 ,)-4-[5-(beflzotiief-5yl)pyn'di-2-yloxyl -azatricyclo[ 3 .. .1.1 3 . 7 ]decane; (4s)-4-(6-chloropyfidin-3>yIoxy)- -azatiicyclo[ 3 . 3 .1 .1 3 . 7 Idecane; (4s)-4-(6-nit-opyridi-3-yloxy)- I -azatricyclol 3 .3. 1. IM ]decane; (4s)-4-(6-amiflopyridifl-3-yloxy) 1 -azatncyclo[ 3 .3.1 .1 3 , 7 ]decane; (4,.)..4.(6.nitropynidin.3-yloxy)- I -azatricyclo[ 3 .3.1 .13 37 decane; 25 (4r)-4-(6-amiflopyridin-3-yloxy) I -azatricyclo[ 3 3.1 1 3 , 7 decane; (4s)-4-(5-bronothiazo1-2-yloxy)- I -azatricyclo[ 3 . 3 -1. 1 3 , 7 decane; (4.s)-4-(thiazoI-2-yloxy)- I-azatricyclo[ 3 3 .1 .1 3 . 7 ]decane; (4s)-4-(5-phenylthiazo1-2-yloxy)- I -azatricyclo[ 3 3 1. 1 3 , 7 ]decane; (4)4[-4mtixpinl-lizl2yoy- -azatricyclo[ 3 . 3 .l1 .1 3 , 7 ]decane; 30 (4)4[-3clrpinl-lizl2yoy- -azatricyclol 3 .3 .1 .1 3 ' 7 ]decane; (4s)-4- [ 5-(3 -ch lot o-4-m ethox yphenyl)-thi azol-2 y1oxy -I azatricyclo[3.3.l .1-1,7 ]decane; (s-5-4floopniyh)tiac)--ixl -azatricyclo[ 3 .3.1 .13 37 ]decanle; (4)4[-35dfurpiiy)tizl2yoy- -204- azatricyclo[ 3 . 3 . 1-1 3 , 7 ]decane; (4s)-4-[5-(l H-indol-5-yl)-thiazol-2-yloxy-1 -azatricyclo[ 3 .3.1 ,1 3 , 7 }decane; (4s)-4-[5-(1H-indol-5-yl)-thiazol-2-yloxy]- -azatricyclo[ 3 3.1.1 3 , 7 decane- 1 oxide; 5-[2-(1-azatricyclo[ 3 .3 1 1 37]decan-(4s)-yloxy)thiazol-5-yl]-indolin-2-one; 5 5-[2-(I-azatricyclo[ 3 .3 1.1 3 Idecan-1-oxide-(4s)-yloxy)thiazol-5-yl)-indolin 2-one; (4s)- 4 -[5-(2-tri fluoronethyl-I H-indol-5-y)-thiazol-2-yloxy]-l azatricyclo[ 3 , 3 . 1. 1]decane; (4s)-4-[5-(1H-indol-4-yl)-thiazol-2-yloxy]- -azatricyclo[ 3 .3. 1.1 3 , 7 ]decane; 10 (4s)-4-[5-(1 H-indol-6-yl)-thiazol-2-yloxy]-I -azatricyclo[3.3.1 .13 7 ]decane; (4s)-4-[5-(1H-indol-3-yl)-thiazol-2-yloxy-1 -azatricyclo[3.3-1 .1']decane; (4s)-4-[5-(pyridin-4-y1)-thiazol-2-yloxy]- -azatricyclo[3.3.1 .1 3 a]decane; (4s)-4-{5-(furan-2-yl)-thiazol-2-yloxy-1 -azatricyclo[3.3.1.13 ']decane; (4s)-4-[5-(furan-3-y)-thiazol-2-yloxy]-1 -azatricyclo[3.3.1.1 V]decane; 15 (4s)-4-[5-(thien-3-yl)-thiazol-2-yloxy]-- I-azatricyclo[ 3 .3.1..17]decane; (4s)-4-{5-(pyrazol-4-yl)-thiazol-2-yloxy-1 -azatricyclo[33 .1 .1 3 7]decane; (4s)-4-(5-broio-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3 . 3 .1.1 3 .]decane; (4s)-4-(1,3,4-thiadiazol-2-yloxy)- I -azatricyclo[ 3 . 3 .1 .13 3 7 ]decane; (4s)- 4 -(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- 1 -azatricyclo[ 3 .3.1 1 3 7 ]decane; 20 (4s)-4-(5-phenyl- 1,3,4-thiadiazol -2-yloxy)- 1 -azatricyclo[ 3 . 3 1.1 3 7]decane-1 oxide; (4r)-4-(5-phenyl- 1,3,4-thiadiazol-2-yoxy)- I-azatricyclo[ 3 . 3 .1.1 3 7 ]decane; ( 4 s)-4-[5-(4-fluorophenyl)- 1,3,4-thiadiazol-2-yloxy- 1 azatncyclo[ 3 .3.1.13 7 ]decane; 25 (4r)-4-[5-(4-fluorophenyl)- 1,3,4-thiadiazol-2-yloxyl azatricyclo[ 3 . 3 .11 3 ' 7 ]decane; (4s)- 4 -[5-(3-fluorophenyl)- 1,3,4-thiadiazol-2-yloxy- 1 azatricyclo{ 3 . 3 .l .1 3 , 7 )decane; (4r)-4-[5-(3-fluoropheny)- 1,3,4-thiadiazol-2-yloxy]-I 30 azatricyclo[3.3.1.1 ]decane; (4s)-4-[5-(l H-indol-5-yl)- 1,3,4-thiadiazol-2-yloxy]-l azatricyclo[ 3 .3.1. 1 V ]decane; (4s)-4-[5-(1 H-indol-6-yl)- 1,3,4-thiadiazol-2-yloxy]-1 azatricyclo[3.3 .1 11 3 7 ]decane; -205- (45)-4-[5-(1 H-indol-4-yl)- 1,3,4-thiadiazol-2-yloxy1- 1 azatricyclo[3. 3 1.1 3 ' 7 ]decane; (4s)-4-[5-(benzothien-5-yl)- 1,3,4-thiadiazol-2-yloxy- 1 azatricyclo[3.3 1 1 3 7 ]decane; 5 (4s)-4-[5-(pyrazol- 4 -yl)-1,3,4-thiadiazol-2-yloxy]-1 azatricyclo[3. 3 .1. l' 3 ]decane, (4s)-4-(5-phenoxy- 1,3,4-thiadiazol-2-yloxy)-1 -azatricyclo[ 3 .3.1. 1 3 ' 7 decane; (4s)-4-(5-tert-butyl-1,3,4-thiadiazol-2-yloxy)-l -azatricyclo( 3 .3. 1.1 ']decane; (4r)-4-(5-tert-butyl-1,3,4-thiadiazol-2-yloxy)-I -azatricyclo[ 3 .3 1.1 3 * 7 decane; 10 (4s)-4-(5-phenyl-1,3,4-oxadiazol-2-yloxy)-1-azatricyclo[ 3 . 3 1.1 3 , 7 decane; (4r)-4-(5-phenyl- 1,3,4-oxadiazol-2-yloxy)- I -azatricyclo[ 3 . 3 .1. 13 }decane; (4s)-4-(benzothiazol-2-yloxy)- -azatricyclo[ 3 .31.1 3 7 ]decane; (4r)-4-(benzothiazol- 2 -yloxy)-I -azatricyclo[ 3 .. 3 1.1 ]decane; (4s)-4-(6-chlorobenzothiazol-2-yloxy)- -azatricyclo[ 3 3 1.1 V]decane; 15 (4r)-4-(6-cilorobenzothiazol-2-yloxy)- -azatricyclo[ 3 . 3 .1.13 3 )decane; (4s)-4-(benzoxazol-2-yloxy)- -azatricyclo[3. 3 .1 .13 7 )decane; (4s)-N-(6-chloropyridin-3-yl)- -azatricyclo[ 3 ,3.1. 1 3 7 )decan-4-amine; (4r)-N-(6-chloropyfidin-3-yl)-1-azatricyclo{3 3 1.13,"]dccan-4-amine; (4s)-N-(6-phenylpyridin-3-yl) 1 -azatricyclo [ 3 .3.1.1 3 ,)decan-4-amine; 20 (4s)-N-[6-(indol-5-y)-pyridin-3-yi]-1-azatricyclo[ 3 .. 3.1.1 V ]decan-4-amine; (4s)-N-(5-bronopyridin-3-yl)-1-azatricyclo{ 3 . 3 .1.1 3 7 )decan-4-amine; (4s)-N-[5-(indol-5-yl)-pyridin-3-yl)-1-azatricyclo[3.3.1.1 3] decan-4-amine; (4s)-N-[5-(indol-6-yi)-pyridin-3-yI]- -azatricyclo[ 3 .3.1.13,7]decan-4-amine; (4s)-N-[5-(indol-4-y1)-pyridin-3-yl-I -azatricyclo[ 3 3.1.1 3 7 ]decan-4-amine; 25 (4s)-N-[5--(3-methylphenyl)-pyridin-3-yl)-1-azatricyclo[ 3 3.1 .1 3 7 ]decan-4 amine; (4s)-N-[5-(3-chlorophenyl)-pyridin-3-yl)-l-azatricyclo[ 3 .3 1 .1 V')decan-4 amine; (4s)-4 N-[5-(3-chlorophenylphen-3-yl)-pyridin-3-yl]-1 30 azatricyclo[3.3.1. 1 3 , 7 decan-4-amine; (4s)-4-(pyridin-3-yloxy)-1-azatricyclo[ 3 ,3.1 .1 3 , 7 decane; (4s)-4-[(1 -oxidopyidin-3-yl)oxy}-1 -azatricyclo[ 3 - 3 .1 1 3 , 7 decane; (4r)-4-(pyridln-3-yloxy)-1 -azatricyclo[ 3 .3 1.13,7]decane; (4s)-4-[(2-chloropyridin-3-yl)oxy-1 -azatricyclo[ 3 .3.1 .13 7 ]decane; -206- (4s)-4-[(2-bronopyridin-3-yl)oxy]-. -azatricyclo[ 3 .3 1 1 3)decane; (4s)-4-[(4-chloropyridin-3-yl)oxy)-I -azatricyclo[ 3 -3.1 .1 3 ']decane; (4s)-4-[(4-nethylpyridin-3-yl)oxy-1 -azatricyclo[ 3 .3 1. 1 33 ]decane; (4s)- 4 -i [4-(tri fluoronethyl)pyridin-3-yloxy} -1 -azatricyclo[3.3.1 1 3 , 7 ]decane; 5 ( 4 s)-4-[(5-fluoropyridin-3-yl)oxy}-l-azatricyclo[ 3 3.1.1' 7 ]decane; (4s)-4-[(5-chloropyridin-3-yl)oxy)-l -azatricyclo[ 3 .3,1 .1, 3 ]decane; (4s)-4-[(5-bromopyridin-3-yl)oxy]-1-azatricyclo[ 3 .3.1 .1 V)decane; ( 4 s)-4-[(5-iodopyridin-3-yl)oxy-I -azatricyclo[ 3 .3.1 .1 V ]decane; 5-((4s)-1-azatricyclo[ 3 3. 1.1 37]dec-4-yloxy]nicotinamide; 10 (4s)- 4 - { [5-(1 H-pyrazol-4-yl)pyridin-3-ylloxy} -Iazatricyclo[ 3 . 3 1.13 7 ]decane; (4s)-4- {[5-(1-methyl-I H-pyrazol-4-yl)pyridin-3-yl]oxy) -1 azatricyclo3..3.1.1 3 7 ]decane; (4s)- 4 -{[5-(1H-pyrazol-1-yl)pyridin-3-yl]oxy}-1-azatricyclo[ 3 .3.1 1 } Idecane; (4s)-4-{[5 -(4-chlorophenyl)pyridin-3-y loxy) -1 -azatricyclo[3.3.1.1 ) 3 7 decane; is ( 4 s)-4-(3,4'-bipyridin-5-yloxy)-l-azatricyclo[ 3 . 3 .1 .1 3 7 )decane; ( 4 s)-4-[(5.-pytimidin-5-yipyridin-3-yl)oxy)-l-azatricyclo[ 3 .3.1.1 decadee; ( 4 r)-4-[(6-chloropyridin-3-yl)oxy-l--azatricyclo[ 3 .3 .1 1 3 ' 7 ]decane; ( 4 s)-4-[(6-bromopyridin-3-yl)oxy]-l-azatricyclo[ 3 .3.1.1 V ]decane; 5-[(4s)-I-azatricyclo[ 3 . 3 .1.1 3dec-4-yloxylpyridine.2-carbonitrile; 20 (4s)-4- [(5-thien-2..ypyridin-2-yl)oxy]-I-azatricyclo( 3 .3.1.1 3 7 ]decane; (4s)- 4 -{[6-(1 H-indol-5-yl)pyridin-3-yI]oxy}-1 -azatricyclo{ 3 .3.1.1 V )decane; (4r)-4-{[6-(I H-indol-5-yI)pyridin-3-ylI]oxy) -1 -azatricyclo[ 3 . 3 .1 .1 7 decadee; (4s)- 4 -{[6-(1 H-indo--6-y)pyridin-3-yloxy} -1 -azatricyclo[3. 3 .1.1 3 ]decane; (4r)- 4 - {[6-(l H-indoI-6-yl)pyridin-3-yI]oxy} -1 -azatricyclo[ 3 .3.1 .13 ' 7 ]decane; 25 5-{5-[(4s)- 1 -azatricyclo[ 3 . 3 .1. 1 V]dec-4-yloxy)pyridin-2-yl} -1,3-dihydro-2H indol-2-one; (4r)-4-{[6-(1 -benzofuran-5-yl)pyridin-3-yloxy) -1 azatricyclo[ 3 .3.1,1 3 - 7 decane; (4s)-4-[(5,6-dibromiopyrdin-3-yl)oxy)- -azatricyclo[ 3 .3. 1.1 ' 7 ]decane; 30 (4s)-4-(pyridin-2-yIoxy)- -azatricyclo[ 3 . 3 .1.1 3 , 7 decane; (4s)-4-[(5-fluoropyidin-2-yl)oxy)- -- azatricyclo[ 3 .3.1.. 1 3 7 )decane; ( 4 s)-4-[(5-bromilopyridini-2-y)oxyl- -azatricyclo[3. 3.1.1 V']decane; (4s)-4-[(4-bromopyridin-2-y1)oxyl-I -azati icyclo[3.3.1.1 3 7 ]decane; (4s)-4-(3,3'-bipyridin-6-yloxy)- -azatricyclo[3. 3 . 1 .1 7 ]decane; -207- (4s)-4-(3,4'-bipyridin-6-ylOXY)-1-azatiicyclo[ 3 .3 1 .1 7 ]decane; (4r)-4-(3,4'-bipyridin-6-yloxy)-1-azatricyclo[3.3.1,1 37 ]decane; (4s)-4-{(5-p yrimidin-5-ylpyridin-2-yl)oxy]-l-azatricyclo{ 3 .3.1.1 3 , 7 )decane; (4s)-4-{{5-(I H-pyrazol-4-yl)pyridin-2-ylloxy)-1-azatricyclo( 3 .3 1 .1 3 , 7 ]decane; 5 6-[(4s)-1-azatricyclo[ 3 .3.1.1 M ]dec-4-yloxy]-N-pyridin-4-ylpyndine-2 carboxamide; (4s)-4-[(2-chiloropyridin-4-yl)oxy]-l-azatricyclo 3 3. 1.1 3 7 ]decane; (4.s)-4--(6-methylpyTidazin-3-yl)oxy]-1-azatricyclo{ 3 .3.1.1' 7 ]decane; (4s)-4-(pyrirnidin-2-yloxy)- I -azatricyclo[ 3 3.1.1 3 , 7 ]decane; 10 (4s)-4-{(5-bromopyrimidinl-2-yl)oxy]- I -azatricyclo[3.3.1 .1 3 7 ]decane; (4s)-4-(pyrimidin-5-yloxy)- I -azatricyclo{ 3 . 3 .1 .13] Idecane; (4s)-4-(pyrimidin-4-yloxy)-1 -azatricyclo[ 3 . 3 .1 .1 3 ,]decane; (4s)-4-[(6-chloropyrimidin-4-yl)oxy]- -azatricyclo( 3 .3. 1 .1 3 , 7 ]decane; (4s)-4-{[6-(1 -trityl-1 H-pyrazol-4-yl)pyimidin-4-yloxy) -1 15 azatricyclo[ 3 .3.1. 1 3 7 decane; (4s)-4- {[6-(1 H-pyrazol-4-yl)pyrimidin-4-ylloxy} -1 azatricyclo3 3.1.1 3 7 ]decane; (4s)-4-[(6-pyridin-4-ylpyriiidin-4-yl)oxy]-l-azatricyclo[3 3 .1.13 7 ]decane; (4s)-4-(pyrazin-2-yloxy)- I-azatricyclo[ 3 .3.1.1 3 7 ]decane; 20 4-[(6-methylpyrazin-2-yl)oxy]-l-azatricyclo(3.3.1 1 3 , 7 ]decane; (4))-4-{(6-phenylpyrazin-2-yl)oxy]-1-azatricyclo[ 3 . 3 .1.1 3 ' 7 ]decane; (4r)-4-(1,3-thiazol-2-yloxy)-l-azatricyclo[ 3 .3,1. 13 7 ]decane; (4r)-4-{(5-bromo-1,3-thiazol-2-yl)oxy)-- -azatricyclo[ 3 .3.1.1 V]decane; (4s)-4-({5-[4-(trifluoromethoxy)phenyll-1,3-thiazol-2-yl}oxy)-1 25 azatricyclo{3.3.1.1 3 7 ]decane; (4.s)-.4-{{5-(4-chlorophenyl)-1,3-thiazol-2--ylloxy}-1 azatricyclo[ 3 . 3 .1. 1 3 7]decane; 4- {2-[(4s)- I -azatricyclo[ 3 .3. 1.13,7]dec-4-yloxy]- 1,3-thiazol-5-yl} aniline; (4s)-4-[(5-pyridin-3-yi-1,3-thiazol-2-yl)oxy]-l -azatricyclo{ 3 .3.1.13 ' 7 ]decane; 30 (4,)-4-[(5-pyidin--3-yl-1,3-thiazol-2-yl)oxy)-l-azatricyclo[3.3 1 3 7 ]decane; (4s)-4-[(5-pyrimidin-5-yI-1,3-thiazol-2-yl)oxy]-1 azatricyclo[ 3 . 3 .1.1 3 7 ]decane; (4s)-4-{[5-(2-nethoxypyrimidin-5-yl)- 1,3-thiazol-2-yl]oxy) -1 azatricyclo[ 3 . 3 .1 .1 3 * 7 ]decane; -208- (4s)-4- [5-(2-pyrrolidin- 1 -ylpyrimidin-5-yi)-1,3-thiazol-2-ylloxy} -1 azatiicyclo{3.3.1.13 "]decane; (4s)- 4 -{[5-(6-piperazin- I -ylpyridin-3-yl)-1,3-thiazol-2-yl]oxy)-1 azatricyclo[3 3.1 .13 7 ]decane; 5 (4s)- 4 -{[5-(IH-pyrazol-1-yl)-1,3-thiazol-2-yloxy}-1 azatricyclo[3.3.l .1 3 7 ]decane; (4s)- 4 -{[5-(I-trityl-1H-pyiazol-4-yl)-1,3-thiazol-2-yl]oxy}-1 azatricyclo[3.3.1. I 7]decane; (4s)-4-{ [5-(1 -propyl-1 H-pyrazol-4-yi)- 1,3-thiazol-2-yi]oxy) -1 10 azatiicyclo[ 3 . 3 .1 1 3 7 ]decane; (4s)-4-{[5-(I-isobutyl-IH-pyrazol-4-yI)-1,3-thiazol-2-yl]oxy}-1 azatricyclo[3. 3 .1. IM ]decane; (4s)- 4 - {[5-(1 -acetyl-I H-pyrazol-4-yl)-1,3-thiazol-2-yl]oxyI -1 azatricyclo[ 3 3.1.1 ]decane; 15 (4s)- 4 -{[5-(5-methyl-1-phenyl-IH-pyrazol-4-yI)-I,3-thiazol-2-yl]oxy}-1 azatricyclo[3.3.1.1 3 7 ]decane; (4s)-4-[(5-isoxazol- 4 -yI-1,3-thiazol-2-yl)oxy]-1-azatricyclo[ 3 .3 1.1 3 , 7 ]decane; (4s)-4-[(4-bromo-1,3-thiazol-2-yl)oxy]-1-azatricyclo[ 3 3 1.1 3 7 ]decane; (4r)-4-[(4-biromo-1,3-thiazol-2-yl)oxy]-l -azatricyclo[3.3.1 13 3 7 ]decane; 20 (4s)-4-[(4-chloro-1,3-thiazol-2-yl)oxyl-l -azatricyclo[3.3.1.1 3 7 decane; (4s)-4-{[4-(1H-pyrazol-4-yl)-1,3-thiazol-2-ylloxy}-1 azatricyclo[ 3 . 3 . 1 .13 ]decane; (4s)-4-[(4-phenyl-1,3-thiazol-2-yl)oxy]-l -azatricyclo[3. 3 .1.1 ]decane; (4s)-4-[(4-pyridin-4-yI-1,3-thiazol-2-yl)oxy--azatricyclo[3 .3.1 .1 3 7 ]decane; 25 (4s)-4-[(4-pyridin-3-yI-l,3-thiazol-2-yl)oxyl-l -azatricyclo[33. 1.1 ]decane; 2-[(4s)-1-azatricyclo[3.3.1.1 ]dec-4-yloxy]-N-pyridinl-4-yl-1,3-thiazole-4 carboxamide; 2-[(4s)-I-azatricyclo[3.3 .1.1 3 , 7 ]dec-4-yloxy]-N-(4-chlorophenyl)-1,3-oxazole 4-carboxamide; 30 2-[(4s)- I -azatricyclo[3.3. 1.1 3 , 7 ]dec-4-yloxy]-N-phenyl- 1,3-oxazole- 4 carboxamide; (4s)-4-{[5-(3-bromophenyl)- 1,3,4-thiadiazol-2-yl]oxy} -1 azatricyclo[3. 3 .1 1 3 , 7 ]decane; (4s)-4- {5-[1 -azatricyclo[3.3.1 .1 3 7 ]dec-4-yloxy]- 1,3,4-thiadiazol-2-yl } phenol; -209- (4s)-N-pyridin-3-yl- 1 -azatricyclo[ 3 - 3 .. 1 3 7 ]decan-4-amine; (4s)-N-(5-brono-6-chloropyridin- 3 -yl)- -azatricyclo[ 3 .3.1.1 3 7 ]decan-4 amine; (4s)-N-[6-(I H-indol-6-yl)pyidin-3-yl-I -azatricyclo[ 3 .3.11, ]decan-4-amine; 5 (4s)-N-[6-(1 H-indol-3-yl)pyridin-3-yl]-I1-azatricyclo[ 3 .3 .1 1 ]decan-4-amiine; (4s)-4-{5-(1 H-indol-5-yl)pyridin-3-yloxy)- 1 -azatricyclo[3.3. 1.1 3 , 7 ]decane; (4s)- 4 -[5-(1 -Iindol-6-yl)pyridin-3-yloxy]- I -azatricyclo[ 3 .3.1.1 3 7 ]decane; (4r)-4-[5-(1 H-indol-5-yl)pyridin-3-yloxy]-1 -azatricyclo[ 3 . 3 .1.1 3 7 ]decane; (4r)-4-[5-(1 H-indol-6-yl)pyridin-3-yloxy-1 -azatricyclo[3.3.1 1 3 , 7 ]decane; or 10 (4r)-4-[5-(1-benzofuran-5-yl)pyfidin-3-yloxy-I -azatricyclo[3.3.1 1 V']decane.
10. 14. A method for treating or preventing conditions, disorders, or deficits modulated by a7 nicotinic acetylcholine receptors, a4P 2 nicotinic acetylcholine receptors, or both ax7 and 4p2 nicotinic acetylcholine receptors wherein the 15 condition, disorder, or deficit is selected from the group consisting of a memory disorder, cognitive disorder, neurodegeneration, and neurodevelopmental disorder comprising administration of a therapeutically suitable amount of a compound of formula (1). 20 15. The method according to claim 14, wherein the condition or disorder is selected from the group consisting of attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, schizophrenia, age-associated memory impairment (AAMI), senile dementia, AIDS dementia, Pick's disease, dementia associated with Lewy bodies, 25 dementia associated with Down's syndrome, amyotrophic lateral sclerosis, Huntington's disease, smoking cessation, nicotinic withdrawal syndrome, schizoaffective disorder, bipolar and manic disorders, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, and neuropathic pain. 30 16 The method according to claim 14, wherein the condition or disorder is cognitive deficits associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's disease, mild cognitive impairment, age-associated -210- memory impairment, and cognitive deficits of schizophrenia.
11. 17. The method according to claim 14, further comprising administering a compound of fonnula (1) in combination with an atypical antipsychotic. 5
12. 18. The method according to claim 14, wherein the condition or disorder is selected from the group consisting of infertility, lack of circulation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, ischemia, inflammation, arthritis 10 and related disorders, wound healing, and complications associated with diabetes.
13. 19. A method of using the compound of formula (V) BH3 N 'OH (V), 15 to prepare compounds of formula (1) of claim 1.
14. 20. A compound of formula (VI) BH3 LTA (VI) or a pharmaceutically acceptable salt or prodrug thereof, wherein 20 L, is-O- or -NR-; A is -Arl, -Ar 2 -L 2 -Ar3 or -Ar 4 -L 3 -Ar 5 ; Ar is aryl or heteroaryl; Ar 2 is aryl or monocyclic heteroaryl; Ar 3 is aryl or heteroaryl; 25 Ar 4 is bicyclic heteroaryl; Ar 5 is aryl or heteroaryl; L 2 is a bond, -0-, -NR,-, -CH 2 -, or -C(O)NRr; L 3 is a bond, -0-, -NR,- or -CH-; and -211- R, is hydrogen or alkyl.
15. 21. The compound of claim 20, wherein the compound is a prodrug of a compound of formula (I) of claim 1. 5
16. 22. The compound of claim 20, wherein the compound is (4r)-4-(5-bTomopyridinl-2-yloxy)-l-azatricyclo[ 3 . 3 . .1 ']decane N-borane complex; (4s)-4-(6-chloropyridin-3-yloxy)-l-azatricyclo[ 3 . 3 .1 1 V ]decane N-borane 10 complex; (4s)-4-(6-nitropyridin-3-yloxy)- -azatricyclo[ 3 .3.1.1 3 7 ]decane N-borane complex; (4r)-4-(6-nitropyridin-3-yloxy)-1-azatricyclo{ 3 . 3 . 1.1 V']decane N-borane complex; 15 (4s)-4-(5-bromothiazol-2-yloxy)-l-azatricyclo[ 3 .3.1.1 3 7 ]decane N-borane complex; (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-l -azatricyclo[ 3 3 .1 .1 3 , 7 ]decane N borane complex; (4r)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[ 3 . 3 . 1 3 , 7 decane N 20 borane complex; (4s)-4-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yloxy]-I azatricyclo[ 3 .3.1..1 3 , 7 ]decane N-borane complex; (4r)-4-[5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yloxy]- 1 azatricyclo(3.3.1.1 3 , 7 ]decane N-borane complex; 25 (4s)-4-[5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3..3.1 1 3 ,]decane N-borane complex; (4r)-4-[5-(3-fluorophenyl)-1,3,4-thiadiazol-2-yloxy]-I azatricyclo[ 3 .3.1.1 3 ,7]decane N-borane complex; (4s)-4-[5-(IH-indol-5-yl)-1,3,4-tliiadiazol-2-yloxy]I 30 azatricyclo[ 3 .3 .1.1 3 7 ]decane N-borane complex; (4s)-4-(5-tet-butyl-1,3,4-thiadiazol-2-yloxy)- -azatricyclo[. 3 .3.1.1 ,]ldecane N-borane complex; (4r)-4-(5-tet-bityl-1,3,4-thiadiazol-2-yloxy)-1-azatuicyclo[ 3 .3.1.1 3 , 7 ]decane N-borane complex; -212- (4s)-4-(benzothiazol-2-yloxy)-I -azatricyclo[ 3 .3 1 .1 2 ' 7 decane N-borane complex; (4r,)-4-(benzothiazol-2-yoxy)- I -azatricyclo[3.3. 1, 1'-]decane N-borane complex; 5 (4s)-4-(6-chlorobenzothiazol-2-yloxy)- I -azatricyclo[3.3.1 .1 3 3Idecane N borane complex; (4r)-4-(6-chlorobenlzothiazol-2-yloxy)-1-azatricyclo[3 3.1.1 3 , 7 decane N borane complex; or (4s)-4-(benzoxazol-2-yloxy)-1 -azatricyclo[3.3.1_ 137 ]decane N-borane 10 complex.
17. 23. A compound of formula (VII) 0 or a pharmaceutically acceptable salt or prodrug thereof, wherein 15 L, is-O- or -NR,-; A is -Arl, -Ar-L 2 -Ar 3 or -Ar 4 -L 3 -Ars; Arl is aryl or heteroaryl; Arz is aryl or monocyclic heteroaryl; Ar 3 is aryl or heteroaryl; 20 Ar 4 is bicyclic heteroaryl; Ar 5 is aryl or heteroaryl; L 2 is a bond, -0-, -NRa-, -CH 2 -, or -C(O)NR,; L 3 is a bond, -0-, -NR- or -CH 2 -; and R; is hydrogen or alkyl. 25 24 The compound of claim 23, wherein the compound is a prodrug of a compound of formula (I) of claim 1.
18. 25. The compound of claim 23, wherein the compound is 30 (4s)-4-[5-(1H-indol-5-yl)-thiazol-2-yloxy]- I -azatricyclo[3 .3 1.1 3 ' 7 ]decane-1 -213- oxide; (4s)-5-4-[2-(1 -azatricyclo[3.3.1 1 3 , 7 ]decan- I -oxide-yloxy)thiazol-5-yl) indolin-2-one; or (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yoxy)-1-azatricyclo[ 3 31 .1 V ]decane-1 5 oxide.
19. 26. A compound that is (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.3.1. 1 3 7 ]decane L-bitartrate anhydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)- 1 -azatricyclo[ 3 3 .1.1 3 7 ]decane L-bitartrate hydrate, (4s)-4-(5-phenyl-1,3,4 10 thi adiazol-2-yloxy)-I-azatricyclo{ 3 .3.1 .1 3 , 7 ]decane dihydrogen phosphate anhydrate, (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- -azatricyclo[3.3. 1.1 3 , 7 ]decane dihydrogen phosphate hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[ 3 .3 .1.13,7]decane bisuccinate anhydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)-1-azatricyclo[ 3 .3.1.1 V']decane bisuccinate hydrate, (4s)-4-(5-phenyl- 1,3,4 15 thiadiazol-2-yloxy)-1-azatricyclo{ 3 . 3 .1.13,7 ]decane hydrochloride quarterhydrate, (4s)-4-(5-plhenyl-1,3,4-thiadiazol-2-yloxy)-l-azatricyclo{ 3 .3.1.1 3 7 ]decane hydrochloride sesquihydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[ 3 .3.1. 13,7]decane dihydrogen citrate, or (4s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)-l.-azatricyclo[ 3 .3.1.1 3 . 7 ]decane monohydrogen citrate. 20
20. 27. A crystalline salt (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)- 1 azatricyclo[3.. 3 .1 .1 3 ' 7 ]decane identified by powder X-ray diffraction wherein the salt is: crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 25 azatricyclo[3. 3 .1. 1 3 ]decane L-bitartrate anhydrate demonstrating at least one characteristic peak in the powder X-ray diffraction patten at values of two theta of 4.96+0.20, 9.9910.20, 11.77±0.20, 14.62±0.20, 14.99±0.20, 18.14±0,20, 18.44±0.20, 19.48±0 20, 20.05±0.20, 21.02±0.20, 21.38±0 20, 22.76±0.20, 24.74±0 20, 26,65±0.20, and 32.19±0.20; 30 crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.3.1 .1 3 , 7 ]decane L-bitartrate hydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 4.63±0.20, 9.26±0.20, 13 43±0.20, 13.91t0.20, 15.98±0.20, 17.86±0.20, 21.36±0.20, and 22.33t0.20; -214- crystalline (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[ 3 .. 3 1 .1 ]decane dihydrogen phosphate anhydrate demonstrating at least one characteristic peak in the powder X-ray diffraction patten at values of two theta of 5.14±0.20, 10.31±0.20, 1 1.20±0.20, 13.17+0.20, 13.47±0 20, 15.61±0 20, 5 16.69t0.20, 17.27±0.20, 17.50±0.20, 18.56±0.20, 18.90±0.20, 19.410.20, 20.93±0,20, 21.80±0.20, 22.53±0.20, 23.96±0.20, 26.01±0.20, and 26.44±0.20; crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo[33.1.1 3 7 )decane dihydrogen phosphate hydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 10 5.28±0.20, 9.82±0.20, 10.61±0-20, 13.79±0,20, 14.24±0.20, 15.13+0.20, 16.65±0.20, 16.95±0.20, 18.35±0.20, 19.52±0.20, 19.84±0.20, 21.55±0.20, 23.85±0.20, 24.26±0.20, and 25 80±0.20; crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo[ 3 . 3 .1 .1 decane bisuccinate anhydrate demonstrating at least one 15 characteristic peak in the powder X-ray diffraction pattern at values of two theta of 12.53±0.20, 13.50±0-20, 14.76±0.20, 16.98±0.20, 18.07±0.20, 18.34±0.20, 18-35±0.20, 18.88±0.20, 19.62±0.20, 19.67±0.20, 20.00±0.20, 20.71±0.20, 23.64±0.20, 23 96+0.20, 25.61±0.20, and 36.29±0.20; crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 20 azatricyclo[ 3 . 3 .l .1 3 7 ]decane bisuccinate hydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 8.92±0.20, 10.94±0.20, 11.71±0.20, 1.3.41±0,20, 14.90±0.20, 17.61±0.20, 17.92±0.20, 18.19±0.20, 19.60±0.20, 22 58±0.20, 26.19±0.20, and 27.07±0.20; crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 25 azatricyclo[3 3.1 .13 7 ]decane hydrochloride quarterhydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 5- 19±0.20, 12.96±0 20, 13.00±0 20, 14.88±0.20, 14.98±0.20, 15.61±0.20, 17.79±0.20, 18.26±0.20, 18 93±0.20, 20.02±0.20, 20.67±0.20, 20.86±0.20, 21.72±0.20, 22.38±0.20, 22.55±0.20, 24.09±0.20, and 26 10±0.20; 30 crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3. 3 .11 ]decane hydrochloride sesquihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 4.94±0.20, 9.93±0.20, 14.09±0.20, 14900.20, 17.85±0.20, 19.92±0.20, 21.72±0.20, 22.43±0.20, 22.63±0.20, and 23.95±0 20; -215- crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.3.1 .1 3 ]decane dihydrogen citrate demonstrating at least one characteristic peak in the powder X-ray di fraction pattern at values of two theta of 7.98±0.20, 11.98±0.20, 12.45±0.20, 15 76±0.20, 16 00±0 20, 17.75±0 20, 18.79±0 20, 5 18.82±0.20, 20.59±0.20, 22.25±0 20, 22.61±0.20, 24.16±0.20, 24 79±0 20, 25.06±0.20, 26.21±0.20, and 29.43±0.20; or crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3 3 1 ).1 3 7 decane monohydrogen citrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 10 9.37±0.20, 9 62±0,20, 10.30±0.20, 11.24±0.20, 12.18±0.20, 13.73±0.20, 15.55±0.20, 16.17±0-20, 16.37±0.20, 16.76±0 20, 18.35±0.20, 18.67±0.20, 18.89±0.20, 19.98±0.20, 20.48±0.20, 20.94±0.20, 21.54±0.20, and 22.02±0.20.
21. 28. Crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1 15 azatiicyclo[3.3.1.1 3 , 7 ]decane free base demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.18±0.20, 10.19±0.20, 13.90±0.20, 14.37*0.20, 14.40±0.20, 14.66±0.20, 15.09±0 20, 15,21±0.20, 18 13±0.20, 18.43±0-20, 19.41±0.20, 19.88±0.20 (two peaks), 20 09±0.20, 20 46±0 20, 21.66±0.20, 23.08±0-20, 26.84±0.20, 28.71±0 20, and 20 30.90±0.20. 29, Substantially pure crystalline (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-1 azatricyclo[3.3.1.1 V ]decane L-bitartrate anhydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)- 1 -azatricyclo[3.3.1.1 3 7 )decane L-bitartrate hydrate, (4s)-4-(5-phenyl- 1,3,4 25 thiadiazol-2-yloxy)- 1 -azatricyclo[3.3.1.1 V']decane dihydrogen phosphate anhydrate, (4s)-4-(5-phenyl- 1,3,4-thiadi azol-2-yloxy)- 1 -azatricyclo[3. 3 . 1.1 3 ,]ldecane dihydrogen phosphate hydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-I azatricyclo[3.3.1 13, I)decane bisuccinate anhydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)-1-azatricyclo[3.3. 1. 13 ']decane bisuccinate hydrate, (4s)-4-(5-phenyl- 1,3,4 30 thiadiazol-2-yloxy)-1-azatricyclo[3.3 1. 1 3 3]decane hydrochloride quarterhydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.
22. 31.1 7 ]decane hydrochloride sesquihydrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo[3.3 1 .1 3 , 7 )decane dihydrogen citrate, (4s)-4-(5-phenyl-1,3,4-thiadiazol-2 yloxy)-1-azatricyclo[3.3.1.1 3 * 7 ]decane monohydrogen citrate, or (4s)-4-(5-phenyl -216- 1,3,4-thiadiazol-2-yloxy)- I -azatricyclo[3 3 .1 .1 3 3]decane 30. Crystalline (4s)-4-(5-plienyl-1,3,4-thiadiazol-2-yloxy)-I azatricyclo[ 3 .3.1 1 V ]decane bisuccinate anhydrate having unit cell parameters 5 wherein a is 12.958(17) A, b is 7.561(10) A, c is 39.66(5) A, and P is 94.54(2)*. 31. Crystalline (4s)-4-(5-phenyl- 1,3,4-thiadiazol-2-yloxy)-I azatricyclo[3. 3 .1.1 3 V]decane hydrochloride quarterhydrate having the unit cell parameters wherein a is 19.440(7) A, b is 9.969(4) A, c is 35.322(13) A, and D is 10 105 325(17)0.
23. 32. Crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo[3.3..1A ]decane dihydrogen citrate having the unit cell parameters wherein a is 22.651(8) A, b is 9.992(3) A, c is 10.338(4) A, and P is 101 .961(5)0. 15
24. 33. Crystalline (4s)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-l azatricyclo[3.3.l.1 3 , 7 ]decane free base having the unit cell parameters wherein a is 6.4427(17) A, b is 9.895(3) A, c is 13.102(4) A, and ax is 70.145(4)*, P is 81.691(4)0, and y is 73 391(4)". 20
25. 34. A process for preparing a citric acid salt of (4s)-4-(5-phenyl-1,3,4-thiadiazol 2-yloxy)- I -azatricyclo[3.3.1.1 3 , 7 ]decane comprising recrystallizing (4s)-4-(5-phenyl 1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3,1 .1 3 7 ]decane in citric acid and methanol. Dated 26 June, 2012 Abbott Laboratories Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON -217-