NZ548231A

NZ548231A - Fused bicycloheterocycle substituted quinuclidine derivatives

Info

Publication number: NZ548231A
Application number: NZ548231A
Authority: NZ
Inventors: Jianguo Jl; Tao Ll; Kathleen H Mortell; Michael R Schrimpf; Diana L Nersesian; Liping Pan
Original assignee: Abbott Lab
Priority date: 2003-12-22
Filing date: 2004-12-10
Publication date: 2010-06-25
Also published as: ZA200605897B; IL176493A0

Abstract

Disclosed are fused bicycloheterocycle substituted quinuclidine derivatives of formula (I) wherein n is 0, 1, or 2; A is N or N+-O-; X is O, S, -NH-, and -N-alkyl-; Ar1 is a 6-membered aromatic ring; and Ar2 is a fused bicycloheterocycle. These compounds are useful in treating conditions or disorders prevented by or ameliorated by alpha7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 548231 RECEIVED at IPONZ on 18 March 2010 548231 FUSED BICYCLOfiETEROCYCLE SUBSTITUTED QUINUCLIDINE DERIVATIVES Technical Field The invention relates to fused bicycloheterocycle substituted quinuclidine derivatives, and compositions comprising such compounds. Methods of treating conditions and disorders using such compounds and compositions are described herein. Description of Related Technology Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central (CNS) and peripheral (PNS) nervous systems. Such receptors play an important role in regulating CNS function, particularly by modulating release of a wide range of neurotransmitters, including, but not necessarily limited to acetylcholine, norepinephrine, 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 and memory, neurodegeneration, pain and inflammation, psychosis and sensory gating, mood and emotion, among others. 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 proteins. At least 12 subunit proteins, a2-al0 and (52-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 nicotine in brain tissue has composition (a4)2(P2)3 (the a4p2 subtype), while another major population of receptors is comprised of the homomeric (a7)5 (the a7 subtype). -1- RECEIVED at IPONZ on 18 March 2010 548231 Certain compounds, like the plant alkaloid nicotine, interact with all subtypes of the nAChRs, accounting for the profound physiological effects of this compound. 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 beneficial therapeutic effects with an improved margin for safety. The al 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, al nAChRs have been linked to conditions and disorders related to attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, dementia associated with Lewy bodies, dementia associated with Down's syndrome, AIDS dementia, Pick's Disease, as well as cognitive deficits associated with schizophrenia, among other systemic activities. The activity at the al nAChRs can be modified or regulated by the administration of al nAChR ligands. The ligands can exhibit antagonist, agonist, partial agonist, or inverse agonist properties. Thus, al ligands have potential in treatment of various cognitive disorders. Although various classes of compounds demonstrating al nAChR-modulating activity exist, it would be beneficial to provide additional compounds demonstrating activity at the al nAChRs that can be incorporated into pharmaceutical compositions useful for therapeutic methods. Specifically, it would be beneficial to provide compounds that interact selectively with a7-containing neuronal nAChRs compared to other subtypes. It is an object of this invention to go at least some way towards satisfying these desiderata; and/or to at least provide the public with a useful choice. In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless -2- RECEIVED at IPONZ on 18 March 2010 548231 specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. In a first aspect, the present invention provides a compound of the formula (I): X Ar1—Ar2 or a pharmaceutical^ acceptable salt, ester, or amide thereof, wherein: n is 0, 1, or 2; A is N or N+-0"; X is selected from the group consisting of O, S, and -N(R1)-; Ar1 is a 6-membered aromatic ring containing 0, 1,2, 3, or 4 nitrogen atoms, wherein Ar1 is substituted with 0, 1, 2, 3, or 4 alkyl groups; Ar2 is a group of the formula: Z5, Z6, Z7, and Z8 are independently selected from the group consisting of C and -C(R3b); provided that zero or one of Z5, Z6, Z7, and Z8 is C; Y1 is selected from the group consisting of O, S, -N(R2), -C(R3), and -C(R3)(R3a); Y2a and Y3a are independently selected from the group consisting of N, C and -C(R3a); provided that when Y1 is -C(R3), Y2a and Y3a are selected from the group SUMMARY OF THE INVENTION JK (I) z -3- RECEIVED at IPONZ on 18 March 2010 548231 consisting of N and -C(R3a), and when one of Y2a and Y3a is C, then Y1 is O, S, -N(R2), or -C(R3)(R3a); wherein when one of Z5, Z6, Z7, and Z8 is C, then Y1 is selected from the group consisting of O, S, -N(R2), and -C(R3)(R3a); Y2a and Y3a are each independently selected from the group consisting of N and -C(R3a); and the group of formula (b) is attached to Ar1 through the C of Z5, Z6, Z7, or Z8 ; and also wherein when Y1 is -C(R3) or one of Y2a and Y3a is C, then Z5, Z6, Z7, and Z8 are each -C(R3b) and the group of formula (b) is attached to Ar1 through the C atom of-C(R3) of Y1 in the group of formula (b) or through the C atom of Y2a or Y3a; R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen and alkyl; R3 and R3a at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4 and -NR5R6; R3b at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4, -NR5R6, -alkyl-OR4, -alkyl-NR5R6, and -SCN; R4 is selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, and arylcarbonyl; R5 and R6 at each occurrence are each independently selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, and arylcarbonyl, provided that at least one of R5 and R6 is hydrogen or alkyl; and R8 is selected from the group consisting of hydrogen and alkyl. In a further aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier. In a yet further aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for selectively modulating the effects of a7 nicotinic acetylcholine receptors. RECEIVED at IPONZ on 18 March 2010 548231 In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for treating a disorder associated with al nicotinic acetylcholine receptors. In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for 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 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation. In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for treating or preventing a condition or disorder selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia. In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for selectively modulating, in combination with an atypical antipsychotic, the effects of al nicotinic acetylcholine receptors. In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for treating, in combination with an atypical antipsychotic, a disorder associated with al nicotinic acetylcholine receptors. In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for treating or preventing, in combination with an atypical antipsychotic, 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 -5- RECEIVED at IPONZ on 18 March 2010 548231 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation. In another aspect, the present invention provides use of a compound of the invention in the manufacture of a medicament for treating or preventing, in combination with an atypical antipsychotic, a condition or disorder selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia. In another aspect, the present invention provides a compound of the invention for selectively modulating the effects of a.7 nicotinic acetylcholine receptors. In another aspect, the present invention provides a compound of the invention for treating a disorder associated with a7 nicotinic acetylcholine receptors. In another aspect, the present invention provides a compound of the invention for 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 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation. In another aspect, the present invention provides a compound of the invention for treating or preventing a condition or disorder selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia. -6- RECEIVED at IPONZ on 18 March 2010 548231 Described herein are fused bicycloheterocycle substituted quinudidine compounds as well as compositions comprising such compounds, and method of using the same. Such compounds have the formula: (I) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: n is 0, 1, or 2; A is N or N+-0"; X is selected from the group consisting of O, S, and -N(R1)-; Ar1 is a 6-membered aromatic ring containing 0, 1, 2, 3, or 4 nitrogen atoms, wherein Ar1 is substituted with 0, 1,2, 3, or 4 alkyl groups; Ar2 is a group of the formula: 7?^ ZV \ \ // (a) , (b) , or <c> ; Z\ Z2, Z3, and Z4 are independently selected from the group consisting of C and -C(R3b); provided that zero or one of Z1, Z2, Z3, and Z4 is C; Z5, Z6, Z7, and Z8 are independently selected from the group consisting of C and -C(R3b); provided that zero or one of Z5, Z6, Z7, and Z8 is C; Z9, Z10, Z11, Z12, Z13, Z14, Z15, and Z16 are independently selected from the group consisting of C and -C(R3c); provided that one of Z9, Z10, Z11, Z12, Z13, Z14, Z15, and Z16 is C and the group of formula (c) is attached to Ar1 through the C atom; Y1 at each occurrence is independently selected from the group consisting of O, S, -N(R2), -C(R3), and -C(R3)(R3a); -7- RECEIVED at IPONZ on 18 March 2010 548231 Y2 is selected from the group consisting of-N(R2), C(=0), -C(R3), and -C(R3)(R3a); Y3 is selected from the group consisting of -N(R2), -C(R3), and -C(R3)(R3a); provided that zero or one of Y1, Y2, and Y3 is -C(R3) in a group of formula (a); wherein when one of Y1, Y2, and Y3 is -C(R3) in a group of formula (a), then Z1, Z2, Z3, and Z4 are each -C(R3b) and the group of formula (a) is attached to Ar1 through the C atom of-C(R3) of Y1, Y2, or Y3; and also when one of Z\ Z2, Z3, and Z4 is C, then Y1, Y2 and Y3 are other than -C(R3) and the group of formula (a) is attached to Ar1 through the C atom of Z1, Z2, Z3, or Z4; Y2a and Y3a are independently selected from the group consisting of N, C and -C(R3a); provided that when Y1 is -C(R3) in a group of formula (b), Y2a and Y3a are selected from the group consisting of N and -C(R3a), and when one of Y2a and Y3a is C, then Y1 in a group of formula (b) is O, S, -N(R2), or-C(R3)(R3a); wherein when one of Z5, Z6, Z7, and Z8 is C, then Y1 in a group of formula (b) is selected from the group consisting of O, S, -N(R2), and -C(R3)(R3a); Y2a and Y3a are each independently selected from the group consisting of N and -C(R3a); and the group of formula (b) is attached to Ar1 through the C of Z5, Z6, Z7, or Z8; and also wherein when Y1 in a group of formula (b) is -C(R3) or one of Y2a and Y3a is C, then Z5, Z6, Z7, and Z8 are each -C(R3b) and the group of formula (b) is attached to Ar1 through the C atom of-C(R3) of Y1 in the group of formula (b) or through the C atom of Y2a or Y3a; R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen and alkyl; R3 and R3a at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4, -NR5R6, -alkyl-OR4, and -alkyl-NR5R6; R3band R3c at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4, -NR5R6, -alkyl-OR4, -alkyl-NR5Rs, and -SCN; -8- RECEIVED at IPONZ on 18 March 2010 548231 R4 is selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, and arylcarbonyl; R5 and R6 at each occurrence are each independently selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, and arylcarbonyl, provided that at least one of R5 and R6 is hydrogen or alkyl; and R8 is selected from the group consisting of hydrogen and alkyl. Another aspect of the invention relates to pharmaceutical compositions comprising compounds of the invention. Such compositions can be administered in accordance with a method described herein, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to nAChR activity, and more particularly al nAChR activity. Described herein is a method of selectively modulating to nAChR activity, for example al nAChR activity. The method is useful for treating and/or preventing conditions and disorders related to al nAChR activity modulation in mammals. More particularly, the method is useful for conditions and disorders related to 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, 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, more particularly circulation around a vascular occlusion, among other systemic activities. The compounds, compositions comprising the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein. The term "comprising" as used in this specification means "consisting at least in part of". When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also -9- RECEIVED at IPONZ on 18 March 2010 548231 be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner. In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims. DETAILED DESCRIPTION OF THE INVENTION Definition of Terms Certain terms as used in the specification are intended to refer to the following definitions, as detailed below. The term "acyl", as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyi group, as defined herein. Representative examples of acyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term "acyloxy", as used herein, means an acyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of acyloxy include, but are not limited to, acetyloxy, propionyloxy, and isobutyryloxy. 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-1-heptenyl, and 3-decenyl. The term "alkoxy", as used herein, means an alkyl group as defined herein, 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. -10- 548231 RECEIVED at IPONZ on 18 March 2010 The term "alkoxyalkoxy", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy. The term "alkoxyalkyl", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl. The term "alkoxycarbonyl", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(O)-, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term "alkoxyimino", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of alkoxyimino include, but are not limited to, ethoxy(imino)methyl and methoxy(imino)methyl. The term "alkoxysulfonyl", as used herein, means an alkoxy 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 propoxysulfonyl. The term "alkyl", as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 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, and n-hexyl. 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-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. The term "alkylcarbonyloxy", as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen -11- RECEIVED at IPONZ on 18 March 2010 548231 atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy, 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 "alkylthio", as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio. 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, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term "amido", as used herein, means an amino, alkylamino, or dialkylamino group appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of amido include, but are not limited to, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and ethylmethylaminocarbonyl. The term "aryl", as used herein, means a monocyclic or bicyclic aromatic ring system. Representative examples of aryl include, but are not limited to, phenyl and naphthyl. The aryl groups of this invention are substituted with 0,1,2, 3, 4, or 5 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amino, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy, -NRaRb, (NRarb)alkyl, (NRARB)alkoxy, (NRARB)carbonyl, and (NRARB)suifonyl. The term "arylcarbonyl", as used herein, means an aryl group, as defined herein, or a benzyl group appended to the parent molecular moiety through a -12- RECEIVED at IPONZ on 18 March 2010 548231 carbonyl group, represented by -C(O)-, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, phenylcarbonyl and benzylcarbonyl. The term "aryloxycarbonyl", as used herein, means an aryl-O- group, wherein the aryl of aryl-O- is as defined herein, or a benzyoxyl group appended to the parent molecular moiety through a carbonyl group, represented by -C(O)-, as defined herein. Representative examples of aryloxycarbonyl include, but are not limited to, phenoxycarbonyl and benzyloxycarbonyl. The term "arylsulfonyl", as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, (methylaminophenyl)sulfonyl, (dimethylaminophenyl)sulfonyl, and (naphthyl)sulfonyl. The term "carbonyl", as used herein, means a -C(O)- group. The term "carboxy", as used herein, means a -CO2H group. The term "cyano", as used herein, means a -CN group. The term "formyl", as used herein, means a -C(0)H group. The term "halo" or "halogen", as used herein, means -CI, -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 defined herein. Representative examples of haloalkoxy include, but are not limited to, 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-fluoropentyl. The term "heteroaryl" means an aromatic five- or six-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The heteroaryl groups are connected to the parent molecular moiety through a carbon or nitrogen atom. Representative examples of heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, -13- RECEIVED at IPONZ on 18 March 2010 548231 pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl. The heteroaryl groups of the invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)alkoxy, (NRARB)carbonyl, and (NRARB)sulfonyl. The term "bicyclic heteroaryl" refers to fused aromatic nine- and ten-membered bicyclic rings containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a tautomer thereof. The bicyclic heteroaryl groups are connected to the parent molecular moiety through a carbon or nitrogen atom. Representative examples of bicyclic heteroaryl rings include, but are not limited to, indolyl, benzothiazolyl, benzofuranyl, isoquinolinyl, and quinolinyi. Bicyclic heteroaryl groups of the invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)alkoxy, (NRARs)carbonyl, and (NRARs)sulfonyl. The term "hydroxy", as used herein, means an -OH group. The term "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-ethyl-4-hydroxyheptyl. The term "mercapto", as used herein, means a -SH group. The term "nitro", as used herein, means a -NO2 group. The term "-NRaRb", as used herein, means two groups, RA and Rb, which are appended to the parent molecular moiety through a nitrogen atom. Ra and Rb are each independently hydrogen, alkyl, alkylcarbonyl, or formyl. Representative -14- RECEIVED at IPONZ on 18 March 2010 548231 examples of -NRaRb include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino. The term "(NRARB)alkyr, as used herein, means a -NRaRb group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARB)alkyl include, but are not limited to, (amino)methyl, (dimethylamino)methyl, and (ethylamino)methyl. The term "(nrarb)alkoxy", as used herein, means a -NRaRb group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of (NRarb)alkoxy include, but are not limited to, (amino)methoxy, (dimethylamino)methoxy, and (diethylamino)ethoxy. The term "(NRARB)carbonyr, as used herein, means a -NRaRb group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRarb)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl. The term ,l(NRARB)sulfonyl", as used herein, means a -NRARB group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (NRarb)sulfonyl include, but are not limited to, aminosulfonyl, (methylamino)sulfonyl, (dimethylamino)sulfonyl, and (ethylmethylamino)sulfonyl. The term "sulfonyl", as used herein, means a -S(0)2- group. The term "thioalkoxy", as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and propylthio. 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 a3b4* indicates a receptor that contains the a3 and P4 proteins in combination with other subunits, the term al as used herein is intended to include receptors wherein the exact subunit composition is both certain and uncertain. For example, as used herein al -15- RECEIVED at IPONZ on 18 March 2010 548231 includes homomeric (a7)5 receptors and al* receptors, which denote a nAChR containing at least one al subunit. Compounds of the Invention Compounds of the invention are within the scope of the formula (I) as described above. More particularly, compounds of formula (I) can include, but are not limited to, compounds wherein Ar1 is a group of the formula: In a group of formula (b), X1, X2, X3, and X4 are each independently selected from the group consisting of N and -CR10, wherein R10 at each occurrence is independently selected from the group consisting of hydrogen and alkyl. Preferably, at least one of X1, X2, X3, and X4 is -CR10, such that group of formula (b) contains 0, 1, 2, or 3 nitrogen atoms. Specific examples of groups for Ar1 are, for example, -16- RECEIVED at IPONZ on 18 March 2010 548231 .10 .R 10 N N and R " and the like. Specific examples of groups for Ar2 in a compound of formula (I) are, for example, / 6 -N Z' \/2a i' // z\ - \/3a -Q \ i // z7, j3a 7^ z° /N k' '/ z\ ^ /3a /3a \ / ■N ■ (i) '°\ // ■N y 2a (ii) (iii) R N \ / N ,2a (iv) \ / ■2a N (v) (vi) // (vii) N (viii) R -N N H -N (x) *Z1' f -Y1 , (ix) \ // N and \ // N N (xi) -17- RECEIVED at IPONZ on 18 March 2010 548231 wherein: Z1, Z2, Z3, and Z4 are independently selected from the group consisting of C and -C(R3b); provided that one of Z1, Z2, Z3, and Z4 is C and formula (ix) is attached to Ar1 through the C atom of Z1, Z2, Z3, and Z4; Y1 is selected from the group consisting of O, S, and -C(R3)(R3a); Z5, Z6, Z7, and Z8 are independently selected from the group consisting of C and -C(R3b); provided that zero or one of Z5, Z6, Z7, and Z8 is C; Y2a and Y3a are independently selected from the group consisting of C and -C(R3a); wherein when one of Z5, Z6, Z7, and Z8 is C, then Y2a and Y3a in the group of formulae (i)-(vii) are each -C(R3a); and each of the group of formulae (i)-(vii) is attached to Ar1 through the C of Z5, Z6, Z7, or Z8; and also wherein when one of Y2a and Y3a is C in the group of formulae (i)-(vii), then Z5, Z6, Z7, and Z8 are each -C(R3b) and each of the group of formulae (i)-(vii) is attached to Ar1 through the C atom of Y2a or Y3a; and R2, R3, R3a and R3b are as defined for a compound of formula (I). Also, other specific examples of groups for Ar2 in a compound of formula (I) are, for example, wherein Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, and R8 are as defined for compounds of formula (I). Specific compounds contemplated herein include, but are not limited to, compounds of formula (I), as defined, wherein: 3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole; 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole; 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole; 5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1H-indole; 6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole; R8 -18- RECEIVED at IPONZ on 18 March 2010 548231 2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1 H-indole; 5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1 H-indole; 4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1 H-indole; 5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1 H-indole; 5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1 H-indole; 5-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1 H-indole; 4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1 H-indole; 5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1 H-indole; 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-3-methyl-1H-indazole; 6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-amine; 6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1,3-benzothiazol-2-amine; 6-{4-[(3R)-1-azabicycio[2.2.2]oct-3-yloxy]phenyl}-4-thiocyanato-1,3-benzothiazol-2-amine; 6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-bromo-1,3-benzothiazol-2-amine; N-[4-(3-methyl-1H-indazol-5-yl)phenyl]quinuclidin-3-amine; (R)-3-[6-(3-methyl-1H-indazol-5-yl)-pyridazin-3-yloxy]-1-aza- bicyclo[2.2.2]octane; (R)-3-[6-(1 -methyl-1 H-indol-5-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; (R)-{5-[6-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-1H-indol-3-ylmethyl}-dimethyl-amine; (R)-3-[6-(1 H-indol-5-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane 1 -oxide; 6-{6-[(3R)-1 -aza-bicyclo[2.2.2]oct-3-yloxy]-pyrid azi n-3-yl}-benzoth iazol-2-ylamine; (3R)-3-[6-(3-bromo-1 H-indol-5-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; 5-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro-indol-2-one; 5-{6-[(3R)-1 -oxy-1 -aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazi n-3-yl}-1,3-d i hyd ro-indol-2-one; -19- RECEIVED at IPONZ on 18 March 2010 548231 5-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro-benzoim idazol-2-one; (R)-3-[6-(1 H-benzoimidazol-5-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; (S)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-3-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; (3R)-3-[5-(1H-indol-4-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[2.2.2]octane 1-oxide; (3R)-3-(5-benzooxazol-5-yl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane; (3R)-3-[5-(2-methyl-benzooxazol-5-yl)-pyrimidin-2-yloxy]-1-aza- bicyclo[2.2.2]octane; (3R)-3-[5-(2-ethyl-benzooxazol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; (3R)-3-[5-(2-phenyl-benzooxazol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-5-[2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyrimidin-5-yl]-3H-benzooxazol-2-one; (R)-3-[6-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-9H-carbazole; 3-[6-(1H-indol-3-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-3-[6-(1 H-indol-3-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; and (S)-3-[6-(1H-indol-3-yl)-pyridazin-3-yloxy]-1-aza-bicyc]o[2.2.2]octane; or pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. Compound names are assigned by using AutoNom naming software, which is provided by MDL Information Systems GmbH (formerly known as Beilstein Informationssysteme) of Frankfurt, Germany, and is part of the CHEMDRAW® ULTRA v. 6.0.2 software suite. 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 IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The invention -20- RECEIVED at IPONZ on 18 March 2010 548231 contemplates various stereoisomers and mixtures thereof and these 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 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 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 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods. Compounds of the invention demonstrate beneficial binding at a7 neuronal nicotinic receptors. Moreover, such compounds generally demonstrate more beneficial binding at a.7 neuronal nicotinic receptors when compared with a less desirable effect of binding to the human ether-a-go-go related gene (hERG) ion channel. As such, compounds of the invention demonstrate an improved cardiovascular profile, i.e. are less likely to induce cardiovascular complications associated with hERG, than other ampiphilic molecules demonstrating at a7 neuronal nicotinic receptor binding. Methods for Preparing Compounds of the Invention As used in the descriptions of the schemes and the examples, certain abbreviations are intended to have the following meanings: Ac for acetyl; Bu for butyl; dba for dibenzylidene acetone; DEAD for diethyl azodicarboxylate; DMSO for dimethylsulfoxide; EtOAc for ethyl acetate; EtOH for ethanol; EtaN for triethylamine; Et20 for diethyl ether; HPLC for high pressure liquid chromatography; 'Pr for isopropyl; Me for methyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc for -21- RECEIVED at IPONZ on 18 March 2010 548231 acetoxy; o-tol. for o-toluene; Ph for phenyl; t-Bu for tert-butyl; TFA for trifluoroacetic acid; and THF fortetrahydrofuran. The reactions exemplified in the schemes are performed in a solvent 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. 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), acetyl, and trifluoracetyl. 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 trifluoracetyl protecting groups may be removed by a hydroxide ion. The methods described below can entail use of various enantiomers. Where the stereochemistry is shown in the Schemes, it is intended for illustrative purposes only. -22- RECEIVED at IPONZ on 18 March 2010 548231 Scheme 1 tSr0H, ik+x. N (1) ,-OH Me3SnSnlVle3 or RO._ B-Bv, RO' OR O) R=alkyl, aryl Pd(0)/L. X- Ar2 (6) csr' Ar'-fM M=Sn, B (5) Pd(0)/L. X'—Ar2 (6) Pd(0)/L. X'=Br,CI, I X'=Br,CI, I Me3SnSnMe3 ** OR B-B^ RO' 0R (9) R= alkyl, aryl M=Sn, B, - (8) Quinuclidine ethers of general formula (8), wherein Ar1 and Ar2 are as defined in formula (I), can be prepared as described in Scheme 1. 3-Quinuclidinol of formula (1) is treated with a halophenyl iodide of formula (2), wherein X' is bromide, chloride, or iodide, with Cul and CS2CO3 in 1,10-phenanthroline as described in Org. Lett., 2002, 4, 973, to obtain a halophenoxy quinuclidine of formula (4). Alternatively, a compound of formula can be obtained by treating 3-quinuclidinol with a halo phenyl alcohol of formula (3), wherein X" is bromide, chloride, or iodide, and diethyl azodicarboxylate in the presence of a phosphine, such as triphenylphosphine. Compounds of formula (4) can be treated with hexamethylditin ordiboron of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, wherein R is hydrogen, alkyl, butyloxycarbonyl, or benzyloxycarbonyl, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (5), which is reacted with a desired halide of a fused bicycloheterocycle represented by Ar2 of formula (6), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (8). Alternatively, halides of a desired Ar2 group can be treated with -23- RECEIVED at IPONZ on 18 March 2010 548231 hexamethylditin ordiboron of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide a corresponding tin or boronic acid reagent that is reacted with a compound of formula (4) in the presence of a palladium catalyst to provide a compound of formula (8). Scheme 2 Me3SnSnMe3 or ROv x0R B-B. R=alkyl, aryl , n v RO' OR 0—x'x3 (9) fcl ]\ ? N (10) %4^Y2 Y1, Y2=Br, CI, I X1,X3,X4=N, CH (11) rcrv-, N^X4 Y2 Pd(0)/L (12) Pd(0)/L. X4 "M M=Sn, B (13) M=Sn, B, X1—Ar2 X'=Br,CI, (6) rCr°YxY (14) Quinuclidine ethers of formula (14), wherein Ar1 is a nitrogen-containing heteroaryl, for example pyridazine, and Ar2 is as defined for formula (I), can be prepared as shown in Scheme 2. Potassium quinuclidinoxide (10) can be reacted with a dihaloaromatic ring, for example, dichloropyridazine, of formula (11) to obtain a quinuclidine ether of formula (12). The quinuclidine ether can be reacted with a suitable tin or boron reagent, as described in Scheme 1, to provide a fused bicycloheterocycle substituted quinuclidine ether of formula (14). Alternatively, the quinuclidine ether of formula (12) can be treated with hexamethylditin or diboron of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, to activate the aromatic group to provide (13), wherein M is tin or boronic acid ester, and further -24- RECEIVED at IPONZ on 18 March 2010 548231 treated with a halide of a desired group Ar2 in the presence of a palladium catalyst to provide compounds of formula (14). Quinuclidine ethers of formula (8), wherein Ar1 and Ar2 are as defined for formula (I) also can be obtained by the methods described in Scheme 3. The activated tin or boronic acid reagent of formula (7) can be coupled with the diiodoaromatic ring of formula (17) in the presence of a palladium catalyst to provide a compound of formula (18). Compounds of formula (18) can be reacted with 3-quinuclidinol and Cul with CS2CO3 in 1,10-phenanthroline as described in Org. Lett. 2002, 4, 973, to provide a desired compound of formula (8). Alternatively, the compound of formula (7) is treated with a compound of formula (19), wherein Ra is benzyl, in the presence of a palladium catalyst to provide a compound of formula (20). Compounds of formula (20), wherein Ra is benzyl, are hydrogenated to provide compounds of formula (21) under standard hydrogenation conditions, for example Pd/C, and further treated with 3-quinuclidinol in the presence -25- RECEIVED at IPONZ on 18 March 2010 548231 of a phosphine, for example triphenylphosphine, and diethyl azodicarboxylate to provide compounds of formula (8). Scheme 4 N (27) NH2Y' + -X' Y-Br, I (28) X'=Br,CI,l Pd/Ligand CS2C03, tol. N (25) NaBH(OAc)3 OH2Nx^ H0Ac,Na2S04 + |Ar1-T-X' _ X-Br,CI,l (26) Pd(0)/L. Me3SnSnMe3 or Ar i X' RO. ^0R B-B. RO' OR (9) R= alkyl, aryl ST Pd(0)/L. M—Ar2 (7) M=Sn, B, lAr1-rM (30) w=Sn, B Pd(0)/L X' Ar2 (6) X'=Br,CI, I Ar1-;—Ar2 (31) Compounds of formula (31), wherein X is -NH- and Ar1 and Ar2 are as described for compounds of formula (I), can be prepared as shown in Scheme 4. 3-Quinuclidinone (25) and a haloarylamine of formula (26), wherein X' is bromide, chloride, or iodide, can be treated with sodium triacetoxy borohydride and acetic acid in Na2S04 to provide a compound of formula (29). Alternatively, a compound of formula (29) can be obtained by treating 3-aminoquinuclidine (27) with haloaromatic group as described in formula (28) with CS2CO3 in the presence of palladium catalyst, preferably in toluene. A compound of formula (29) can be treated with a tin -26- RECEIVED at IPONZ on 18 March 2010 548231 or diboron of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, under conditions previously described to provide the corresponding tin or boronic acid reagent of formula (30), which can be reacted with the halide of a desired group represented by Ar2 in a compound of formula (I) to provide a compound of formula (31). Alternatively, the compound of formula (29) is treated with a tin or boronic acid ester of the desired Ar2 group in the presence of a palladium catalyst to provide a compound of formula (31). Scheme 5 Me3SnSnMe3 (39) Compounds of formula (39), wherein X is S and Ar1 and Ar2 are as defined in a compound of formula (I), can be prepared as shown in Scheme 5. 3-Chloroquinuclidine (35) can be reacted with a haloarylthiol of formula (36), wherein X' is bromide, chloride, or iodide, to provide a compound of formula (37). The compound of formula (37) can be treated with a tin or boron reagent of a desired group for Ar2 as described for a compound of formula (I) to provide a compound of formula (39). Alternatively, the compound of formula (37) can be reacted with a -27- RECEIVED at IPONZ on 18 March 2010 548231 hexamethylditin ordiboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide a compound of formula (38), which is reacted with the halide of a desired Ar2 group in the presence of a palladium catalyst to provide a compound of formula (39). Scheme 6 Me3SnSnMe3 or ROs„ nPR B~Bs RO' OR (9) Pd(0)/L. x R=alkyl, aryl (4) X-Br,CI, I Pd(0)/L. M'-Ai^-NHRh (40) M'=Sn, B, Zn, Mg, Rb=H, alkyl, Boc, Cbz %N ^ M (5) M=Sn, B Pd(0)/L. X'-Ar2-NHRb (41) X'=Br, CI, I •N- W (42) NHR Compounds of formula (42), wherein X is O, R3 is NHRb, and Ar1, Ar2 are defined as in compounds of formula (I), can be prepared as shown in Scheme 6. Compounds of formula (4) obtained as shown in Scheme 1 can be treated with a metal of the desired amino-substituted Ar2 group, as described for compounds of formula (I) to provide compounds of formula (42), wherein Rb is hydrogen, alkyl, butyloxycarbonyl, or benzyloxycarbonyl. Compounds of formula (4) can be treated with a hexamethylditin ordiboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (5), which is -28- RECEIVED at IPONZ on 18 March 2010 548231 reacted with a desired halide of an amine-substituted fused bicycloheterocycle represented by Ar2 of formula (41), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (42). rCr°YxV (12) X1, X2', X3 =N, CH Y=Br, CI, I Scheme 7 Me3SnSnMe3 or RCXD d--0R B-Bv RO' 0R U (9) Pd(0)/L. R=alkyl, aryl Pd(0)/L. M'-Ai^-NHR15 (45) M-Sn, B, Zn, Mg, Rb=H, Boc,Cbz, alkyl, aryl N °yxy N "" X4 M (13) M=Sn, B Pd(0)/L. X'-Ar2-NHRb (46) X'=Br, CI, I [CfYr N N" X4 Ar2- NHRb (47) Compounds of formula (47), wherein X is O, Ar1 is a nitrogen containing aromatic group, for example pyridazine, R3 is NHRb, as previously defined, and Ar2 is defined as in compounds of formula (I), can be prepared as shown in Scheme 7. Compounds of formula (12), which can be obtained as shown in Scheme 2, are treated with a metal of the desired amino-substituted Ar2 group, as described for compounds of formula (I), of formula (45) to provide compounds of formula (47). Compounds of formula (12) also can be treated with a hexamethylditin or diboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (13), which is reacted with a desired halide of an amine-substituted -29- RECEIVED at IPONZ on 18 March 2010 548231 fused bicycloheterocycle represented by Ar2 of formula (46), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (47). Scheme 8 X"=Br,C!,l,N02,NR'R" (51) Out, CS2CO3 1,10-phenanthroline Tol. reflux n voh ho. Ph3P, dead + ija^j—ar2—x" jhf, rt, 2 days (50) X"=Br,CI,l,N02,NR'R" x"=n02 .,) Pd/C, H2 2) R'CI or R'Br (53) Ar-]—Ar2—X" (52) X"=CI, Br, I Pd/Ligand, R'NHR" (54) NHR' (56) (57) R', R"=H, alkyl, aryl, RCO, Boc, Cbz Quinuclidine ethers of formula (56) and (57), wherein Ar1 is as defined for formula (I) and Ar2 is substituted with a group NR5R6 can be obtained by the -30- RECEIVED at IPONZ on 18 March 2010 548231 methods described in Scheme 8. Compounds of formula (50) can be treated with 3-quinuclidinoi in the presence of a phosphine, for example triphenylphosphine, and diethyl azodicarboxylate to provide compounds of formula (52). Alternatively, compounds of formula (51), wherein X" is bromide, chloride, or iodide, can be reacted with Cul, Cs2C03 in 1,10-phenanthroline as described in Org. Lett. 2002, 4, 973, to provide a desired compound of formula (52). Compounds of formula (52), wherein X" is NO2, can be reduced with hydrogen in the presence of a palladium catalyst and reacted with a chloride or bromide of a desired R group of formula (53), wherein R' is hydrogen, alkyl, aryl, alkycarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl, to provide compounds of formula (56). Compounds of formula (52), wherein X" is bromide, chloride, or iodide, can be treated with a compound R'NHR" of formula (54), wherein R' and R" are as previously described for R' in compounds of formula (53), to provide a corresponding compound of formula (57). i)NaBH(OAck HOAc, Scheme 9 Dk H N 2) Chiral (60) X"=Br,CI,l,N02,NHR'R' (61) X'=N02 1) Pd/C, H2 2) R'CI or R'Br (53) R', R"=H, alkyl, aryl, RCO, Boc, Cbz (64) H N (63) -31- RECEIVED at IPONZ on 18 March 2010 548231 Compounds of formulas (63) and (64) can be prepared as shown in Scheme 9. 3-Quinuclidinone and a halobiarylamine of formula (60), wherein X' is bromide, chloride, or iodide, can be treated with sodium triacetate borohydride and Na2S04in acetic acid to provide a compound of formula (61) as described in Tetrahedron Lett. 1996, 37, 6045. Compounds of formula (61), wherein X' is bromide, chloride, or iodide, can be treated with a compound R'NHR" of formula (54), wherein R' and R" are as previously described for R' in compounds of formula (53), to provide a corresponding compound of formula (64). Compounds of formula (61), wherein X is NO2, can be reduced with hydrogen in the presence of a palladium catalyst and reacted with a chloride or bromide of a desired R' group of formula (53), wherein R' is hydrogen, alkyl, aryl, alkycarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl, to provide compounds of formula (63). Scheme 10 Me3SnSnMe3 H N Pd(0)/L. R=alkyl, aryl (29) X'=Br, CI, I Pd(0)/ M'-Ar2-Nf Pd(0)/L. X-Ai^-NHR13 (46) (45) \ M'=Sn, B, Zn, Mg, \ Rb=H, Boc,Cbz, alkyl, aryl X=Br, CI, I H N (69) -32- RECEIVED at IPONZ on 18 March 2010 548231 Compounds of formula (69), wherein X is -NH-, R3 is NHRb, and Ar1, Ai^are defined as in compounds of formula (I), can be prepared as shown in Scheme 10. Compounds of formula (29) obtained as shown in Scheme 7 can be treated with a metal of the desired amino-substituted Ar2 group, as described for compounds of formula (I), of formula (45) to provide compounds of formula (69). Compounds of formula (29) also can be treated with a hexamethylditin or diboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (30), which is reacted with a desired halide of an amine-substituted fused bicycloheterocycle represented by Ar2 of formula (46), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (69). Scheme 11 SH JL 1) NaH, DMF „"T1 + Ar 4—X N 2) Chiral separation HCI (70) t$rc: (71) X^Br.CI.I.NO^NHR'R" X=N02 1) Pd/C, H2 2) R'CI or R'Br (53) X=Br,CI,l Pd/Ligand R'NHR" (54) -A^-NR'R" (73) Quinuclidine biarylsulfides of formulas (72) and (73), wherein Ar1 is as defined for formula (I) and Ar2 is substituted with a group NR'R" can be obtained by the -33- RECEIVED at IPONZ on 18 March 2010 548231 methods described in Scheme 11. 3-Chloroquinuclidine can be reacted with a halobiarylthiol of formula (70), wherein X" is bromide, chloride, iodide, N02, or NHR'R", as described in Tetrahedron Lett. 1996, 37, 6045, to provide a compound of formula (71). Compounds of formula (71), wherein X" is NO2, can be reduced with hydrogen in the presence of a palladium catalyst and reacted with a chloride or bromide of a desired R" group of formula (53), wherein R' is hydrogen, alkyl, aryl, alkycarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl, to provide compounds of formula (72). Compounds of formula (71), wherein X" is bromide, chloride, or iodide, can be treated with a compound R'NHR" of formula (54), wherein R' and R" are as previously described for R' in compounds of formula (53), to provide a corresponding compound of formula (73). Scheme 12 Me3SnSnMe3 or M (37) Pd(0)/L. R=alkyl, aryl M=Sn, B X'=Br,CI,l (38) Rb=H, Bo (7 M'=Sn Pd(0 M'-AP Pd(0)/L. X'-Ai^-NHR" (76) X'=Br, CI, I (77) -34- RECEIVED at IPONZ on 18 March 2010 548231 Compounds of formula (77), wherein X is S, R3 is NHRb, and Ar1, Ar^are defined as in compounds of formula (I) can be prepared as shown in Scheme 12. Compounds of formula (37) obtained as shown in Scheme 5 can be treated with a metal of the desired amino-substituted Ar2 group, as described for compounds of formula (I), of formula (75) to provide compounds of formula (77). Compounds of formula (37) also can be treated with a hexamethylditin or diboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (38), which is reacted with a desired halide of an amine-substituted fused bicycloheterocycle represented by Ar2 of formula (76), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (77). -35- RECEIVED at IPONZ on 18 March 2010 548231 VNH2 y—NHRC (82) R -alkyl, aryl, RCO, Cbz, Boc bromination Br (86) Aminobenzothiazole-substituted quinuclidines of formula (82) can be obtained as shown in Scheme 13. Amino-substituted quinuclidine ethers, thioethers, and amines of formula (80) are obtained by methods described in Schemes 6-12. Compounds of formula (80) are reacted with bromine and KSCN in acetic acid to provide aminobenzothiazole-substituted quinuclidines of formula (81). Compounds of formula (81) can be further treated with the halide of a desired Rc group, wherein Rc as defined for R5 or R6 in compounds of formula (I) to provide the desired aminobenzothiazole-substituted quinuclidine derivative (82). -36- RECEIVED at IPONZ on 18 March 2010 548231 Compounds of formula (82) can be further treated to obtain compounds of formulas (84), (86), and (88). Bromination of compounds with formula (82) provides compounds of formula (83). Compounds of formula (83) are reacted with a nucleophilic agent, for example KSCN, to give compounds of formula (84). Compounds of formula (83) can be treated with a metal of a suitable aryl group, as described for compounds of formula (I), of formula (85), in the presence of palladium catalyst to provide the corresponding compounds of formula (86). Compounds of formula (83) also can be treated with an alcohol of formula (87) or an amine of formula (87a), wherein R4, R5, and R6 are as defined for compounds of formula (I), in the presence of palladium catalyst to provide the corresponding compounds of formula (88). N Scheme 14 HNO, Y'=0, NH, S (89) NRP H2S04 (90) 1) H2, Pd/C MeOH 2) (EtO)3CR DMF N y; Ar' (91) R3 = alkyl, aryl N y~R3 N Rp Benzoimidazole-substituted quinuclidines of formula (92), wherein Y' is O, NH, or S and Ar1 is as defined for compounds of formula (I), can be obtained as shown in Scheme 14. Compounds of formula (89), which are obtained by treating -37- RECEIVED at IPONZ on 18 March 2010 548231 compounds of formula (80) in Scheme 13 under standard nitrogen-protection conditions, are reacted with nitric acid in sulfuric acid to provide compounds of formula (90). Compounds of formula (90) are hydrogenated by palladium catalysis and treated with excess triethylorthoformate to obtain compounds of formula (91). Compounds of formula (91) are deprotected under standard nitrogen-deprotection conditions to obtain compounds of formula (92). OBn X'=Br,CI,l (95) rcVBC RO' (9) 0R Scheme 15 .OR RO. Pd(0)/L. R=alkyl, aryl ROX B-^VN°2 OBn (96) (97) X-Br, CI, I Pd(0)/L. Y-O, NH, S 1) H2, Pd/C MeOH 2) (EtO)3CR DMF (99) Benzooxazole-substituted quinuclidines of formula (99), wherein Y' is O, NH, or S and Ar1 and R3 are as defined for compounds of formula (I), can be obtained as shown in Scheme 14. Compounds of formula (95) can be treated with a diboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic -38- RECEIVED at IPONZ on 18 March 2010 548231 acid of formula (96). Compounds of formula (96) are reacted with a desired halide of a quinuclidine-substituted heteroaromatic group Ar1 as represented by compounds of formula (97), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (98). Compounds of formula (98) are hydrogenated by palladium catalysis and treated with excess triethylorthoformate to obtain compounds of formula (99). Compounds of formula (I) wherein A is N can be converted to compounds of formula (I) wherein A is N+-0" by treatment with an oxidizing agent. Examples of the oxidizing agent include, but not limited to, aqueous 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 room temperature to about 80°C, for a period of about 1 hour to about 4 days. The compounds of the invention, and intermediates thereof, may be isolated and 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 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. 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 at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, 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. -39- RECEIVED at IPONZ on 18 March 2010 548231 Compositions of the Invention The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically 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 administration. The term "pharmaceutically acceptable carrier," as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; 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; 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 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), 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. -40- RECEIVED at IPONZ on 18 March 2010 548231 Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, 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 mixtures 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, 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 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 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 form. 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 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 -41- RECEIVED at IPONZ on 18 March 2010 548231 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 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 compatible 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 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 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 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, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and -42- RECEIVED at IPONZ on 18 March 2010 548231 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 such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol 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. 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, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known 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 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 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 agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, -43- RECEIVED at IPONZ on 18 March 2010 548231 germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. 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, 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. 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 invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Compounds of the invention also can be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in 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. -44- RECEIVED at IPONZ on 18 March 2010 548231 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., (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 carrier and any needed preservatives, buffers or propellants. Ophthalmic formulations, eye ointments, 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, esters, or amides derived from inorganic or organic acids. The term "pharmaceutically acceptable salts, esters and amides," as used herein, include salts, zwitterions, esters and amides of compounds of formula (I) 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 the like, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "pharmaceutically acceptable salt" refers to those salts 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 the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically 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. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- -45- RECEIVED at IPONZ on 18 March 2010 548231 phenyipropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized 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 others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically 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, 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 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 nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, 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. The term "pharmaceutically acceptable ester," as used herein, refers to esters of compounds of the invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esters of the invention include Ci-to-Ce alkyl esters and C5-to-C7 cycloalkyl esters, although Crto-C4 alkyl esters are preferred. Esters of the compounds of formula (I) can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto -46- RECEIVED at IPONZ on 18 March 2010 548231 hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, alkyl triflate, for example with methyl iodide, benzyl iodide, cyclopentyl iodide. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. The term "pharmaceutically acceptable amide," as used herein, refers to nontoxic amides of the invention derived from ammonia, primary Crto-C6 alkyl amines and secondary Ci-to-C6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Ci-to-C3 alkyl primary amides and Crto-C2 dialkyl secondary amides are preferred. Amides of the compounds of formula (I) can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions as with molecular sieves added. The composition can contain a compound of the invention in the form of a pharmaceutically acceptable prodrug. The term "pharmaceutically acceptable prodrug" or "prodrug," as used herein, represents those prodrugs of the compounds of the invention which are, within the -47- RECEIVED at IPONZ on 18 March 2010 548231 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 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 in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). The invention contemplates pharmaceutically active compounds either chemically synthesized or formed by in vivo biotransformation to compounds of formula (I). Methods Compounds and compositions of the invention are useful for modulating the effects of nAChRs, and more particularly al nAChRs. In particular, the compounds and compositions of the invention can be used for treating and preventing disorders modulated by al nAChRs. Typically, such disorders can be ameliorated by selectively modulating the al nAChRs in a mammal, preferably by administering a compound or composition of the invention, either alone or in combination with another active agent, for example, as part of a therapeutic regimen. The compounds of the invention, including but not limited to those specified in the examples, possess an affinity for nAChRs, and more particularly al nAChRs. As al nAChRs ligands, the compounds of the invention can be useful for the treatment and prevention of a number of al nAChR-mediated diseases or conditions. For example, al 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). As such, al 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 impairment, senile dementia, AIDS dementia, Pick's Disease, dementia -48- RECEIVED at IPONZ on 18 March 2010 548231 associated with Lewy bodies, and dementia associated with Down's syndrome, as well as cognitive deficits associated with schizophrenia. In addition, a7-containing nAChRs have been shown to be involved in the neuroprotective effects of nicotine both in vitro (Jonnala, R. B. and Buccafusco, J. 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 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 a7 nAChRs by (3-amyloid peptides 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 al 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 al activity can counter the deficits of Alzheimer's and other neurodegenerative diseases. Schizophrenia is a complex disease that is characterized by abnormalities in perception, cognition, and emotions. Significant evidence implicates the involvement of al nAChRs in this disease, including a measured deficit of these receptors in post-mortem 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 normalized by nicotinic ligands that operate at the al nAChR (Adler L. E. et al., Schizophrenia Bull. 24:189-202, 1998; Stevens, K. E. et al., Psychopharmacology 136: 320-327, 1998). Thus, al 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 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 al -49- RECEIVED at IPONZ on 18 March 2010 548231 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 angiogenesis with an improved side effect profile. A population of al 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 al nAChR 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 neuropathic pain. Moreover, al nAChRs are expressed on the surface of primary macrophages that are involved in the inflammation response, and that activation of the al receptor inhibits release of TNF and other cytokines that trigger the inflammation response (Wang, H. et al Nature 421: 384-388, 2003). Therefore, selective al ligands demonstrate potential for treating conditions involving inflammation and pain. The mammalian sperm acrosome reaction is an exocytosis process important in fertilization of the ovum by sperm. Activation of an al nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J.-H. and Meizel, S. Biol. Reproduct. 68: 1348-1353 2003). Consequently, selective al 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. 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 activity at al receptors. (Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 2002). Thus, activators of al receptors can provide useful treatment for enhancing cognitive function in schizophrenic patients who are being treated with atypical antipsychotics. Accordingly, the combination of an al nAChR ligand and an atypical antipsychotic -50- RECEIVED at IPONZ on 18 March 2010 548231 would offer improved therapeutic utility. Specific examples of suitable atypical 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, 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 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, 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 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 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 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 -51- RECEIVED at IPONZ on 18 March 2010 548231 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 human or lower animal range from about 0.10 mg/kg body weight to about 1 g/kg body weight. More preferable doses can be in the range of from about 0.10 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 daily dose. The compounds and processes of the invention will be better understood by reference to the following examples and reference examples, which are intended as an illustration of and not a limitation upon the scope of the invention. EXAMPLES Example 1 3-f4-(1-Azabicvclof2.2.2'|oct-3-vloxv)phenvn-1 H-indole Example 1A 3-(4-lodophenoxv)auinuclidine Under N2, the mixture of 3-hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol), 1,4-diiodobenzene {Aldrich, 7.9 g, 24 mmol), Cul (Strem Chemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol) in toluene (anhydrous, Aldrich, 50 mL) was stirred at 110 °C for 40 h. After the reaction went to completion, the reaction mixture was diluted with chloroform (100 mL) and washed with water (2x10 mL). The organic solution was concentrated and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) 5 1.40-1.56 (m, 1H), 1.64-1.80 (m, 2H), 1.90-2.08 (m, 1H), 2.10-2.21 (m, 1H), 2.60-3.00 (m, 5H), 3.34-3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCI/NH3) m/z 330 (M+H)+. -52- RECEIVED at IPONZ on 18 March 2010 548231 Example 1B 3-r4-( 1 -Azabicvclof2.2.21oct-3-vloxvtohenvll-1 H-ind ole The mixture of the product of Example 1A (330 mg, 1 mmol), N-(2-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (ref. Tetrahedron Lett. 1992, 33, 3915.; 280 mg, 1.3 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol) and K2CO3 (180 mg, 1.3 mmol) in DMSO (3 mL) was stirred at 40 °C under N2 for 2 hours. The reaction was monitored with TLC. After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (50 mL). It was then washed with brine (3x5 mL). The organic solution was concentrated and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (113 mg, yield, 36%). 1H NMR (300 MHz, CD3OD) 5 1.43-1.57 (m, 1H), 1.62-1.89 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.23 (m, 1H), 2.73-3.03 (m, 5H), 3.28-3.40 (m, 1H), 4.51-4.58 (m, 1H), 6.97 (dt, J=8.8, 2.1 Hz, 2H), 7.03-7.17 (m, 2H), 7.36 (s, 1H), 7.37-7.42 (m, 1H), 7.57 (dt, J=8.8, 2.0 Hz, 2H), 7.81 (dt, J= 7.8, 1.2 Hz, 1H) ppm. MS (DCI/NH3) m/z 319 (M+H)+. Example 1C 3-[4-(1-Azabicvclof2.2.21oct-3-vloxv)phenvll-1 H-indole hemifumarate The product of Example 1B (113 mg, 0.36 mmol) was treated with fumaric acid (46 mg, 0.4 mmol) in EtOAc/EtOH (v. 1:1,4 mL) at ambient temperature for 10 h. The title compound was obtained as solid (131 mg, yield, 89%). 1H NMR (300 MHz, CD3OD) 5 1.73-2.13 (m, 3H), 2.23-2.37 (m, 1H), 2.43-2.51 (m, 1H), 3.12-3.43 (m, 5H), 3.64-3.76 (m, 1H), 4.77-4.88 (m, 1H), 6.67 (s, 1.4H), 6.99-7.18 (m, 4H), 7.38 (s, 1H), 7.39-7.43 (m, 1H), 7.61 (dt, J=8.8, 2.0 Hz, 2H), 7.80 (d, J= 7.8 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N200.85 C4H404: C, 70.27; H, 6.14; N, 6.72. Found: C, 70.20; H, 6.35; N, 6.88. RECEIVED at IPONZ on 18 March 2010 548231 Example 2 4-f4-M-Azabicvclor2.2.21oct-3-vloxv)phenvn-1 H-indole Example 2A 3-f4-n~rimethvlstannv0phenoxv1auinuclidine The mixture of the product from Example 1A (330 mg, 1mmol), hexamethylditin (Aldrich, 654 mg, 2 mmol) and Pd(PPh3)4 (Aldrich, 116 mg, 0.1 mmol) in toluene (10 mL) was stirred at 110 °C under N2for2 hours. The reaction was monitored with TLC. After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (50 mL). It was then washed with brine (2 x 5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by flash chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.35) as solid (300 mg, yield, 82%). 1H NMR (300 MHz, CD3OD) 5 0.25 (s, 9H), 1.79-2.16 (m, 3H), 2.23-2.36 (m, 1H), 2.45-2.52 (m, 1H), 3.17-3.43 (m, 5H), 3.73-3.83 (m, 1H), 4.84-4.92 (m, 1H), 6.96 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H) ppm. MS (DCI/NHs): m/z 364 (M+H)+, 366 (M+H)+, 368 (M+H)+. Example 2B 4-[4-( 1 -Azabicvclo[2.2.2loct-3-vloxv)phenvll-1 H-indole The product of 2A (300 mg, 0.8 mmol), 4-bromoindole (Aldrich, 196 mg, 1 mmol), Pd2(dba)3 (Aldrich, 27 mg, 0.03 mmol) and (o-tol.)3P (Aldrich, 27 mg, 0.09 mmol) in DMF (Aldrich, anhydrous, 5 mL) were heated to 80 °C under N2 and stirred overnight. It was then cooled down to room temperature and diluted with EtOAc (50 mL). The mixture was washed with brine (2x5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by flash chromatography (Si02, CH2CI2: MeOH : NH3 H20, 90:10:1, Rf. 0.30) as a solid (48 mg, yield, 19%). 1H NMR (300 MHz, CD3OD) 5 1.46-1.58 (m, 1H), 1.64-1.91 (m, 2H), 2.01-2.17 (m, 1H), 2.19-2.26 (m, 1H), 2.75-3.03 (m, 5H), 3.32-3.42 (m, 1H), 4.55-4.63 (m, 1H), 6.58 (dd, J=3.4, 1.0 Hz, 1H), 6.98-7.04 (m, 3H), 7.14 (t, J=7.8 Hz, 1H), 7.25 (d, J=3.1 Hz, 1H), 7.33 (dt, J=8.1, 1.0 Hz, 1H), 7.59 (dt, J=9.2, 2.7 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+ -54- RECEIVED at IPONZ on 18 March 2010 548231 Example 2C 4-f4-(1 -Azabicvclor2.2.21oct-3-vloxvtohenvn-1 H-indole fumarate The product of Example 2B (48 mg, 0.15 mmol) was treated with fumaric acid (23 mg, 0.2 mmol) in EtOAc/EtOH (v. 1:1, 3 mL) at ambient temperature for 15 h. The title compound was obtained as solid (60.2 mg, yield, 90%). 1H NMR (300 MHz, CD3OD) 5 1.82-2.19 (m, 3H), 2.29-2.42 (m, 1H), 2.51-2.58 (m, 1H), 3.16-3.46 (m, 5H), 3.75-3.85 (m, 1H), 4.89-4.96 (m, 1H), 6.56 (dd, J=3.4, 1.0 Hz, 1H), 6.69 (s, 2.2H), 7.02 (dd, J=7.1, 1.0 Hz, 1H), 7.08 (dt, J=8.8, 2.5 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.26 (d, J=3.4 Hz, 1H), 7.35 (dt, J=8.1, 1.0 Hz, 1H), 7.64 (dt, J=8.8, 2.6 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N2O II2 C4H404: C, 68.25; H, 5.95; N, 6.25. Found: C, 68.43; H, 5.58; N, 6.20. Example 3 5-f4-( 1 -Azabicvclor2.2.21oct-3-vloxv')phenvn-1 H-indole Example 3A 5-r4-( 1 -Azabicvclor2.2.21oct-3-vloxv)phenvll-1 H-indole Under N2, the product of Example 1A (329 mg, 1 mmol), 5-indolylboronic acid (Frontier, 193 mg, 1.2 mmol), Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol), (tBu3P)2Pd (26 mg, 0.05mmol), K2CO3 (276 mg, 2 mmol) and KF (80 mg, 1.4 mmol) in THF(8 mL) was stirred at 60 °C overnight. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2 x 5 mL). The organic solution was concentrated under reduced pressure and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 |jm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg, yield, 25%). 1H NMR (300 MHz, CD3OD) 5 1.44-1.58 (m, 1H), 1.62-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m, 5H), 3.27-3.40 (m, 1H), 4.51-4.59 (m, 1H), 6.46 (dd, J=3.4, 1.1 Hz, 1H), 6.95 (dt, J=8.8, 2.6 Hz, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.40 (dt, J=8.5, 1.0 Hz, 1H), 7.54 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 0.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+Hf. -55- RECEIVED at IPONZ on 18 March 2010 548231 Example 3B 5-f4-(1-Azabicvclof2.2.2loct-3-vloxv)phenvn-1 H-indole fumarate The product of Example 3A (80 mg, 0.25 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1,4 mL) at ambient temperature for 10 h. The title compound was obtained as solid (57 mg, yield, 52%). 1H NMR (300 MHz, CD3OD) 5 1.78-2.16 (m, 3H), 2.25-2.39 (m, 1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89 (m, 1H), 6.46 (dd, J=3.0, 1.0, 1H), 6.68 (s, 2H), 7.02 (dt, J=8.8, 2.5 Hz, 2H), 7.23 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (dt, J=8.4, 0.8 Hz, 1H), 7.58 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 1.0 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N2OC4H4O4: C, 69.11; H, 6.03; N, 6.45. Found: C, 69.23; H, 5.81; N, 6.59. Example 4 5-f4-r(3R)-1-Azabicvclo[2.2.21oct-3-vloxv1phenviy-1 H-indole Example 4A (3R)-3-Quinuclidinol (3R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution(20%, 50 mL) at ambient temperature for 10 min. It was then extracted with CHCI3/'PrOH (v. 10 : 1, 3 x 200 mL). The extracts were combine, washed with brine (50 mL) and dried over MgS04. The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15. 5 g, yield, 99%). 1H NMR (300 MHz, CD3OD) 5 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCI/NH3): m/z 128 (M+H)+. -56- RECEIVED at IPONZ on 18 March 2010 548231 Example 4B f3R)-3-(4-Bromophenoxv)ciuinuclidine The product of Example 4A (1.27 g, 10 mmol) was coupled with 1-iodo-4-bromobenzene (Aldrich, 2.83 g, 10 mol) according to the procedure of Example 1A. The title product was purified by chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.30) as solid (400 mg, yield, 14%). 1H NMR (300 MHz, CD3OD) 6 1.41-1.54 (m, 1H), 1.59-1.73 (m, 1H), 1.73-1.86 (m, 1H), 1.92-2.06 (m, 1H), 2.09-2.17 (m, 1H), 2.71-2.97 (m, 5H), 3.24-3.34 (m, 1H), 4.45-4.52 (m, 1H), 6.83 (dt, J=9.2, 2.6 Hz, 2H), 7.37 (dt, J=9.2, 2.7 Hz, 2H) ppm. MS (DCI/NH3): m/z 282 (M+H)+, 284 (M+H)+. Example 4C 5-f4-F(3R)-1-Azabicvclof2.2.21oct-3-vloxvlphenvl}-1 H-indole The product of 4C (282 mg, 1 mmol) coupled with 5-indolylboronic acid (Frontier, 190 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H20, 90:10:1, Rf. 0.35) as solid (50 mg, yield, 16%). 1H NMR (300 MHz, CD3OD) 6 1.44-1.58 (m, 1H), 1.62-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m, 5H), 3.27-3.40 (m, 1H), 4.51-4.59 (m, 1H), 6.46 (dd, J=3.4, 1.1 Hz, 1H), 6.95 (dt, J=8.8, 2.6 Hz, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.40 (dt, J=8.5, 1.0 Hz, 1H), 7.54 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 0.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Example 4D 5-f4-f(3R)-1-Azabicvclof2.2.21oct-3-vloxvlphenvl>-1 H-indole fumarate The product of Example 4C (50 mg, 0.25 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1,4 mL) at ambient temperature for 10 h. The title compound was obtained as solid (56.9 mg, yield, 52%). 1H NMR (300 MHz, CD3OD) 6 1.78-2.16 (m, 3H), 2.25-2.39 (m, 1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89 (m, 1H), 6.46 (dd, J=3.0, 1.0, 1H), 6.68 (s, 2.2H), 7.02 (dt, J=8.8, 2.5 Hz, 2H), 7.23 (d, J=3.1 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.43 (dt, J=8.4, 0.8 Hz, 1H), 7.58 (dt, J=9.2, 2.6 Hz, 2H), 7.71 (dd, J=1.7, 1.0 Hz, 1H) -57- RECEIVED at IPONZ on 18 March 2010 548231 ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N2OI .14 C4H4O4: C, 68.11; H, 5.94; N, 6.21. Found: C, 68.12; H, 6.04; N, 6.18. Example 5 6-f4-( 1 -Azabicvclof2.2.21oct-3-vloxv)phenvn-1 H-indole Example 5A 6-f4-( 1 -Azabicvclor2.2.21oct-3-vloxv)phenvn-1 H-indole The product of Example 2A (300 mg, 0.8 mmol) was coupled with 6-bromoindole (Aldrich, 196 mg, 1 mmol) according to the procedure in 2B. The title compound was purified by chromatography (S1O2, CH2CI2: MeOH : NH3 H20, 90:10:1, Rf. 0.20) as a solid (30 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) 6 1.45-1.58 (m, 1H), 1.64-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.04 (m, 5H), 3.30-3.42 (m, 1H), 4.53-4.61 (m, 1H), 6.43 (dd, J=3.1, 0.7 Hz, 1H), 6.97 (dt, J=8.8, 2.6 Hz, 2H), 7.21-7.27 (m, 2H), 7.52-7.60 (m, 4H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Example 5B 6-r4-f1-Azabicvclof2.2.21oct-3-vloxv)phenvll-1 H-indole fumarate The product of Example 5A (30 mg, 0.1 mmol) was treated with fumaric acid (12 mg, 0.1 mmol) in EtOAc/EtOH (v. 1:1, 2 mL) at ambient temperature for 15 h. The title compound was obtained as solid (38.4 mg, yield, 79%). 1H NMR (300 MHz, CD3OD) 5 1.80-2.19 (m, 3H), 2.27-2.40 (m, 1H), 2.48-2.56 (m, 1H), 3.17-3.63 (m, 5H), 3.72-3.83 (m, 1H), 4.80-4.88 (m, 1H), 6.43 (dd, J=3.1, 0.7 Hz, 1H), 6.68 (s, 2H), 7.04 (dt, J=8.8, 2.5 Hz, 2H), 7.21-7.27 (m, 2H), 7.53-7.65 (m, 4H) ppm. MS(DCI/NH3): m/z 319 (M+H)+. Anal. Calcd. for C19H2oN40-1.3 C4H404: C, 67.05; H, 5.84; N, 5.97. Found: C, 67.15; H, 5.99; N, 5.95. -58- RECEIVED at IPONZ on 18 March 2010 548231 Example 6 2-r4-f 1-Azabicvclof2.2.21oct-3-vloxvbhenvl1-1 H-indole Example 6A S-M-Ethvnvlphenoxvkiuinuclidine Under N2, the mixture of the product from Example 1A (800 mg, 2.4 mmol), trimethylsilylacetylene (Aldrich, 392 mg, 4 mmol), Pd(PPh3)4 (Aldrich, 29 mg, 0.025 mmol) and Cul (Strem Chemicals, 10 mg, 0.05 mmol) in DMF (10 mL) was stirred at ambient temperature overnight. DMF then was removed under reduced pressure. The residue was treated with tetrabutyl ammonium fluoride (Aldrich, in THF, 1M, 5 mL) at room temperature for 3 h. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (50 mL) and washed with brine (2 x 10 mL). The organic solution was concentrated and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) 5 1.42-1.54 (m, 1H), 1.61-1.87 (m, 2H), 1.93-2.07 (m, 1H), 2.10-2.18 (m, 1H), 2.71-3.00 (m, 5H), 3.19-3.37 (m, 2H), 4.49-4.56 (m, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H) ppm. MS (DCI/NH3): m/z 228 (M+H)+. Example 6B 2.2.2-Trifluoro-N-(2-iodophenvnacetamide 2-lodo-phenylamine (Aldrich, 1.09 g, 5 mmol) was treated with trifluoroacetic anhydride (Aldrich, 1.26 g, 6 mmol) and 2,6-di-tert-butyl-4-methyl-pyridine (Aldrich, 1.23 g, 6 mmol) in CH2CI2 (10 mL)at room temperature overnight. It was then quenched with water (5 mL) and extracted with EtOAc (3x10 mL). The extracts were combined and washed with brine (5 mL). The organic solution was concentrated and the title compound was purified by flash chromatography (Si02, Hexanes/EtOAc, 80:20, Rf. 0.50) as a solid (1.1 g, yield, 70%). 1H NMR (300 MHz, CD3OD) 5 7.07-7.12 (m, 1H), 7.39-7.47 (m, 2H), 7.95 (dd, J=7.8, 1.3 Hz, 1H) ppm. MS (DCI): m/z 316 (M+H)+. -59- RECEIVED at IPONZ on 18 March 2010 548231 Example 6C 2-r4-(1-Azabicvclof2.2.21oct-3-vloxv)phenvll-1 H-indole Under N2, the mixture of product from Example 6A (114 mg, 0.5 mmol), the product from Example 6B (157 mg, 0.5 mmol), Cul (Strem Chemicals, 14 mg, 0.075 mmol), PPh3 (Aldrich, 39 mg, 0.15 mmol) and K3P04 (212 mg, 1 mmol) in dioxane (5 mL) was stirred at 80 °C for 20 h. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2x5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3-H20, 90:10:1, Rf. 0.30) as solid (70 mg, yield, 44%). 1H NMR (300 MHz, CD3OD) 5 1.45-1.59 (m, 1H), 1.65-1.91 (m, 2H), 2.00-2.14 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.01 (m, 5H), 3.31-3.42 (m, 1H), 4.54-4.62 (m, 1H), 6.66 (d, J=0.7 Hz, 1H), 6.93-7.00 (m, 3H), 7.01-7.08 (m, 1H), 7.35 (dq, J=8.2, 1.0 Hz, 1H), 7.48 (dq, J=7.8, 0.7 Hz, 1H), 7.71 (dt, J=8.8, 2.6 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Example 6D 2-f4-(1-Azabicvclof2.2.21oct-3-vloxvtohenvll-1 H-indole fumarate The product of Example 6C (70 mg, 0.22 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1,3 mL) at ambient temperature for 10 h. The title compound was obtained as solid (87 mg, yield, 89%). 1H NMR (300 MHz, CD3OD) 5 1.81-2.18(m, 3H), 2.25-2.39 (m, 1H), 2.48-2.56 (m, 1H), 3.19-3.48 (m, 5H), 3.73-3.85 (m, 1H), 4.86-4.93 (m, 1H), 6.65-6.80 (m, 2H), 6.94-7.10 (m, 4H), 7.36 (dd, J=8.1, 0.7 Hz, 1H), 7.49 (dt, J=7.8, 1.0 Hz, 1H), 7.75 (dt, J=9.2, 2.4 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+. Anal. Calculated for C21H22N2O I.I C4H4O4: C, 68.39; H, 5.96; N, 6.28. Found: C, 68.10; H, 6.22; N, 6.25. -60- RECEIVED at IPONZ on 18 March 2010 548231 Example 7 5-r6-(1-Azabicvclof2.2.21oct-3-vloxv)pyridazin-3-vH-1 H-indole Example 7A 3-f(6-Chloropvridazin-3-vl)oxv1quinuclidine 3-Quinuclidinol (Aldrich, 508 mg, 4 mmol) was treated with lBuOK (Aldrich, 448 mg, 4 mmol) in THF(20 mL) at ambient temperature for 1 hour. 3,6-Dichloropyradazine (Aldrich, 740 mg, 5 mmol) was then added. The mixture was stirred at ambient temperature for additional 1 h. The reaction was monitored with TLC. After the reaction was complete, it was concentrated under reduced pressure. The residue was dissolved in CHCh/'PrOH (v. 10 : 1, 50 mL) and washed with brine (2x5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.45) as a solid (780 mg, yield, 82%). 1H NMR (300 MHz, CD3OD) 5 1.48-1.61 (m, 1H), 1.65-1.90 (m, 2H), 1.94-2.08 (m, 1H), 2.23-2.31 (m, 1H), 2.73-3.01 (m, 5H), 3.37-3.48 (m, 1H), 5.18-5.27 (m, 1H), 7.23 (d, J=9.2 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH3): 240 (M+H)+, 242 (M+H)+. Example 7B 5-f6-(1-Azabicvclor2.2.2loct-3-vloxv)pvridazin-3-vn-1 H-indole The product of Example 7A (200 mg, 0.8 mmol) was coupled with 5-indolylboronic acid (161 mg, 1 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 |jm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (35 mg, yield, 14%). 1H NMR (300 MHz, CD3OD) 5 1.50-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.00-2.16 (m, 1H), 2.29-2.37 (m, 1H), 2.78-3.05 (m, 5H), 3.44-3.55 (m, 1H), 5.26-5.35 (m, 1H), 6.56(dd, J=3.3, 1.1 Hz, 1H)), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.4 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.73 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. RECEIVED at IPONZ on 18 March 2010 548231 Example 7C 5-r6-(1-Azabicvclor2.2,2loct-3-vloxv)pvridazin-3-vn-1 H-indole hemifumarate The product of Example 7B (35mg, 0.11 mmol) was treated with fumaric acid (23 mg, 0.2 mmol) in EtOAc/EtOH (v. 1:1, 3 mL) at ambient temperature for 10 h. The title compound was obtained as solid (42 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) 5 1.76-1.91 (m, 1H), 1.92-2.13 (m, 2H), 2.22-2.36 (m, 1H), 2.51-2.59 (m, 1H), 3.12-3.40 (m, 5H), 3.77-3.88 (m, 1H), 5.42-5.51 (m, 1H), 6.56 (dd, J=2.0, 1.0Hz, 1H), 6.67 (s, 1H), 7.27-7.33 (m, 2H), 7.52 (dt, J=8.5, 1.0 Hz, 1H), 7.74 (dd, J=8.8, 1.7 Hz, 1H), 8.10-8.16 (m, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)*. Anal. Calculated for C19H20N4O O.55C4H4O4: C, 66.27; H, 5.82; N, 14.58. Found: C, 66.12; H, 5.53; N, 14.63. Example 8 4-r6-(1-Azabicvclo[2.2.21oct-3-vloxv)pyridazin-3-vl1-1 H-indole Example 8A 4-r6-(1-Azabicvclof2.2.21oct-3-vloxv)pvridazin-3-vn-1 H-indole Under N2, the mixture of Example 7A (168 mg, 0.7 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-indole (ref. W002055517,170 mg, 0.7 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol), 1,3-bis(2,6-iso-propylphenyl)imidazolium chloride (Strem Chemicals, 26 mg, 0.06 mmol) and aqueous Na2C03 (2 M, 1 mL) in toluene (10 mL) was stirred at 110 °C overnight, After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (30 mL). The mixture was then washed with brine (2x5 mL) and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H20, 90:10:1, Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) 5 1.51-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.01-2.16 (m, 1H), 2.31-2.39 (m, 1H), 2.78-3.09 (m, 5H), 3.45-3.56 (m, 1H), 5.30-5.38 (m, 1H), 6.78 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.5 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.40 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (dt, J= 8.1, 1.0 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. -62- RECEIVED at IPONZ on 18 March 2010 548231 Example 8B 4-f6-(1 -Azabicvclof2.2.21oct-3-vloxv)pvridazin-3-yn-1 H-indole fumarate The product of Example 8A (45 mg, 0.14 mmol) was treated with fumaric acid (23 mg, 0.2 mmol) in EtOAc/EtOH (v. 1:1,3 mL) at ambient temperature for 10 h. The title compound was obtained as solid (56 mg, yield, 85%). 1H NMR (300 MHz, CD3OD) 5 1.90-2.23 (m, 3H), 2.33-2.48 (m, 1H), 2.62-2.70 (m, 1H), 3.21-3.54 (m, 5H), 3.92-4.03 (m, 1H), 5.54-5.62 (m, 1H), 6.69 (s, 2.5H), 6.78 (dd, J=3.4, 1.0 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.35-7.44 (m, 3H), 7.55 (dt, J=8.1, 1.1 Hz, 1H), 8.13 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Anal. Calculated for C19H20N4O I.3C4H4O4: C, 61.67; H, 5.39; N, 11.89. Found: C, 61.49; H, 5.52; N, 12.17. Example 9 5-f6-r(3R)-1-Azabicvclor2.2.21oct-3-vloxvlpvridazin-3-vlM H-indole Example 9A (3R)-3-r(6-Chloropyridazin-3-vl)oxv1quinuclidine The product of Example 4A (635 mg, 5 mmol) was coupled with 3,6-dichloropyridazine (Aldrich, 925 mg, 6.25 mmol) according to the procedure of Example 7A. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3-H20, 90:10:1, Rf. 0.45) as solid (750 mg, yield, 63%). 1H NMR (300 MHz, CD3OD) 6 1.54-1.68 (m, 1H), 1.71-1.95 (m, 2H), 2.00-2.14 (m, 1H), 2.28-2.36 (m, 1H), 2.83-3.08 (m, 5H), 3.44-3.56 (m, 1H), 5.23-5.30 (m, 1H), 7.24 (d, J= 9.2 Hz, 1H), 7.66 (d, J= 9.2 Hz, 1H) ppm. MS (DCI/NH3): 240 (M+H)+, 242 (M+H)+. Example 9B 5-(6-f(3R)-1-Azabicvclor2.2.2loct-3-vloxvlpyridazin-3-vl>-1 H-indole The product of Example 9A (480 mg, 2 mmol) was coupled with 5-indolylboronic acid (Frontier, 403 mg, 2.5 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, -63- RECEIVED at IPONZ on 18 March 2010 548231 Symmetry® C-8 7 )jm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (240 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) 5 1.49-1.64 (m, 1H), 1.68-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.05 (m, 5H), 3.43-3.55 (m, 1H), 5.26-5.34 (m, 1H), 6.56 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.50 (d, J= 8.5 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Example 9C 5-(6-f<,3RM-Azabicvclor2.2.2k>ct-3-vloxvlpvridazin-3-vl}-1 H-indole fumarate The product of Example 9B (240 mg, 0.75 mmol) was treated with fumaric acid (93 mg, 0.8 mmol) in EtOAc/EtOH (v. 1:1, 10 mL) at ambient temperature for 15 h. The title compound was obtained as solid (247 mg, yield, 72%). 1H NMR (300 MHz, CD3OD) 5 1.88-2.22 (m, 3H), 2.31-2.47 (m, 1H), 2.59-2.68 (m, 1H), 3.23-3.50 (m, 5H), 3.89-4.00 (m, 1H), 5.49-5.57 (m, 1H), 6.56(dd, J=3.0, 1.0 Hz, 1H), 6.69 (s, 2H), 7.29-7.35 (m, 2H), 7.52 (dt, J= 8.5, 1.0 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.12-8.17 (m, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Anal. Calcd. for C19H20N4O-I.IC4H4O4 O.4H2O: C, 61.73; H, 5.58; N, 12.31. Found: C, 61.67; H, 5.52; N, 12.33. Example 10 5-(6-r(3R)-1-Azabicvclor2.2.2loct-3-vloxvlpyridazin-3-vl>-3-methvl-1 H-indole Example 10A 3-Methvl-5-(4.4.5.5-tetramethvl-1.3.2-dioxaborolan-2-vn-1 H-indole Under N2, a mixture of 5-bromo-3-methyl-1 H-indole (Aldrich, 1.05 g, 5 mmol), bis(pinacolato)diboron (Aldrich, 1.40 g, 5.5 mmol), PdCI2(dppf)CH2Cl2 (Aldrich, 122 mg, 0.15 mmol) and KOAc (Aldrich, 1.47 g, 15 mmol) in DMSO (20 mL) was stirred at 90 °C for 1 h. The reaction was monitored with TLC. After the reaction was complete, it was then diluted with EtOAc (100 mL) and washed with brine (3x10 mL). The organic solution was then concentrated and the title compound was -64- RECEIVED at IPONZ on 18 March 2010 548231 purified by flash chromatography (Si02, Hexane : EtOAc, 80:20, Rf. 0.70) as solid (510 mg, yield, 40%). 1H NMR (300 MHz, CDCI3) 5 1.38 (s, 12H), 2.35 (s, 3H), 6.98 (s, 1H), 7.34 (dd, J=8.1, 0.7, Hz, 1H), 7.65 (dd, J=8.1, 1.0 Hz, 1H), 8.12 (s, 1H) ppm. MS (DCI/NH3): m/z 258 (M+H)+. Example 10B 5-f6-r(3R)-1-Azabicvclor2.2.21oct-3-vloxv1pvridazin-3-viy-3-methvl-1 H-indole The product of Example 10A (240 mg, 1 mmol) coupled with the product of Example 9A (250 mg, 1mmol) according to the procedure in Example 8A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 ml_/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) 5 1.50-1.64 (m, 1H), 1.69-1.92 (m, 2H), 2.01-2.14 (m, 1H), 2.29-2.35 (m, 1H), 2.37 (s, 3H), 2.81-3.04 (m, 5H), 3.43-3.55 (m, 1H), 5.27-5.34 (m, 1H), 7.06 (d, J=1.4 Hz, , 1H), 7.24 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.5, 0.7 Hz, 1H), 7.71 (dd, J=8,8, 2.0, Hz, 1H), 8.07-8.12 (m, 2H) ppm. MS (DCI/NH3): m/z 335 (M+H)+. Example 10C 5-(6-f(3R)-1-Azabicvclof2.2.21oct-3-vloxvlpvridazin-3-vl)-3-methvl-1 H-indole fumarate The product of Example 10B (40 mg, 0.12 mmol) was treated with fumaric acid (23 mg, 0.2 mmol) in EtOAc/EtOH (v. 1:1,5 mL) at ambient temperature for 10 h. The title compound was obtained as solid (40 mg, yield, 62%). 1H NMR (300 MHz, CD3OD) 5 1.90-2.24 (m, 3H), 2.33-2.48 (m, 4H), 2.61-2.68 (m, 1H), 3.22-3.53 (m, 5H), 3.93-4.03 (m, 1H), 5.51-5.58 (m, 1H), 6.70 (s, 3.6 H), 7.08 (d, J=1.0 Hz, 1H), 7.32 (d, J=9.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.72 (dd, J=8.8, 1.7 Hz, 1H), 8.10 (d, J=1.7 Hz, 1H), 8.17 (d, J=9.5 Hz, 1H) ppm. MS (DCI/NH3): m/z 335 (M+H)+. Anal. Calculated for C2oH22N40-1.8 C4H4O4: C, 60.13; H, 5.42; N, 10.31. Found: C, 60.02; H, 5.53; N, 10.27. -65- RECEIVED at IPONZ on 18 March 2010 548231 Example 11 5-f2-f(3R)-1-Azabicvclor2.2.2loct-3-vloxvlpyrimidin-5-vll-1 H-indole Example 11A (3RV3-r(5-Bromopvrimidin-2-vlk>xvlauiniiclidine The product of Example 4A (508 mg, 4 mmol) was coupled with 5-bromo-2-iodo-pyrimidine (Aldrich, 1.42 g, 5 mmol) according to the procedure of Example 7A. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H2O, 90:10:1, Rf. 0.40) as solid (760 mg, yield, 67%). 1H NMR (300 MHz, CD3OD) 5 1.54-1.68 (m, 1H), 1.68-1.95 (m, 2H), 2.03-2.16 (m, 1H), 2.24-2.33 (m, 1H), 2.82-3.11 (m, 5H), 3.41-3.52 (m, 1H), 5.09-5.17 (m, 1H), 8.65 (s, 2H). MS (DCI/NH3): 284 (M+H)+ 286 (M+H)+. Example 11B 5-(2-[(3R)-1-Azabicvclof2.2.2loct-3-vloxvlpyrimidin-5-vl>-1 H-indole The product of Example 11A (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (Aldrich, 193 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) 5 1.50-1.63 (m, 1H), 1.67-1.93 (m, 2H), 2.04-2.17 (m, 1H), 2.24-2.31 (m, 1H), 2.75-3.05 (m, 5H), 3.38-3.48 (m, 1H), 5.14-5.21 (m, 1H), 6.53 (dd, J=3.1, 0.7 Hz, 1H), 7.30 (d, J= 3.1 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Example 11C 5-f2-f(3R)-1-Azabicvclof2.2.2loct-3-vloxy]pvrimidin-5-vl}-1 H-indole hemifumarate The product of 11B (40 mg, 0.12 mmol) was treated with fumaric acid (12 mg, 0.1 mmol) in EtOAc/EtOH (v. 1:1, 3 mL) at ambient temperature for 10 h. The title compound was obtained as solid (42 mg, yield, 88%). 1H NMR (300 MHz, CD3OD) -66- RECEIVED at IPONZ on 18 March 2010 548231 5 1.72-2.10 (m, 3H), 2.20-2.34 (m, 1H), 2.43-2.51 (m, 1H), 3.04-3.43 (m, 5H), 3.65-3.76 (m, 1H), 5.28-5.36 (m, 1H), 6.52 (dd, J=3.1,1.1 Hz, 1H), 6.67 (s, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd, J=8.5, 1.7 hz, 1H), 7.51 (dt, J=8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.84 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Anal. Calcd. for C19H2oN40 0.6 C4H4O4: C, 65.90; H, 5.79; N, 14.36. Found: C, 65.65; H, 5.24; N, 14.41. Example 12 4-f2-f(3R)-1-Azabicvclof2.2.2loct-3-vloxv1Pvrimidin-5-vn--1 H-indole Example 12A 4-l2-f(3R)-1-Azabicvclo[2.2.21oct-3-vloxvlpyrimidin-5-vl>-1 H-indole The product of Examplel 1A (170 mg, 0.6 mmol) was coupled with 4-(4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-1 H-indole ((ref. W002055517, 146 mg, 0.6 mmol) according to the procedure in Example 8A. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H2O, 90:10:1, Rf. 0.10) as a solid (76 mg, yield, 40%). 1H NMR (300 MHz, CD3OD) 5 1.50-1.64 (m, 1H), 1.67-1.93 (m, 2H), 2.05-2.19 (m, 1H), 2.25-2.33 (m, 1H), 2.73-3.12 (m, 5H), 3.39-3.50 (m, 1H), 5.17-5.25 (m, 1H), 6.55 (dd, J= 3.4, 1.0 Hz, 1H), 7.11 (dd, J=7.1, 1.0, Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 7.44-7.49 (m, 1H), 8.85 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Example 12B 4-(2-K3R)-1 -Azabicvclor2.2.21oct-3-vloxvlpyrimidin-5-vl)-1 H-indole fumarate The product of Example 12A (76 mg, 0.24 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc/EtOH (v. 1:1,4 mL) at ambient temperature for 10 hours. The title compound was obtained as solid (94.6 mg, yield, 90%). 1H NMR (300 MHz, CD3OD) 5 1.88-2.21 (m, 3H), 2.33-2.48 (m, 1H), 2.59-2.66 (m, 1H), 3.22-3.50 (m, 5H), 3.84-3.95 (m, 1H), 5.41-5.49 (m, 1H), 6.55 (dd, J=3.4, 1.0 Hz, 1H), 6.68 (s, 2H), 7.11 (dd, J=7.5, 1.0 Hz, 1H), 7.24 (t, J= 8.1 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.48 (dt, J=8.1, 0.7 Hz, 1H), 8.89 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. -67- RECEIVED at IPONZ on 18 March 2010 548231 Anal. Calculated for Ci9H2oN40-C4H404: C, 63.29; H, 5.54; N, 12.84. Found: C, 62.95; H, 5.85; N, 12.61. Example 13 5-f2-[(3S)-1-Azabicvclor2.2.2loct-3-vloxvlpyrimidin-5-vlV1 H-indole Example 13A C3RV1 -Azabicvclor2.2.21oct-3-vl benzoate (LVtartrate (+/-)-3-Quinuclidinol benzoate (Sigma, 17.9 g, 77.5 mmol) was treated with L-tartaric acid (Aldrich, 99% ee, 11.63 g, 77.5 mmol) in EtOH (80%, 222 mL) at ambient temperature for 1 week. The white solid was filtered off and dried under reduced pressure. 6.5 g of 3-(R)-quinuclidinol benzoate * (L)-tartrate was obtained with ~80% ee (assayed by HPLC. HPLC conditions: chiralpak AD column 25cmX4mm ID. solvent, EtOH : hexanes = 15 : 85. flow rate, 1 mL/min. uv, 220 nm. Retention time: (S)-3-quinuclidinol benzoate, 7.87 min; (R)-3-quinuclidinol benzoate 13.3 min.) Recrystallization of the above solid in EtOH (80%, 35 mL) gave the title product (4.5 g , yield, 15%, >98% ee). MS (DCI/NH3) m/z 232 (M+H)+. Example 13B (3R)-Quinuclidin-3-ol The product of the Example 13A (4.5 g, 11.8 mmol) was treated with Hydrolysis was NaOH (15%, 40 mL) MeOH (40 mL)at 50°C for 10h. The methanol was removed under reduced pressure and the residue was extracted with chloroform (4 x 80 mL). The extracts were combined and dried over MgS04 (anhydrous). The drying agents were filtered off and the filtrate was concentrated to give the title product as white solid (1.35 g, yield, .90%). MS (DCI/NH3) m/z 128 (M+H)+. Example 13C (3SV1-Azabicvclof2.2.2loct-3-vl benzoate (D)-tartrate The mother liquid of Example 13A was combined and concentrated under reduced pressure. The residue was then treated with NaOH (1 N, 50 mL) at room -68- RECEIVED at IPONZ on 18 March 2010 548231 temperature for 30 min. It was extracted with chloroform (3 x mL) The extracts were combined and dried (MgS04). The drying agents were filtered off. The filtrates was concentrated to give 3-quinuclidinol benzoate (15.25 g, 66 mmol) It was then treated with (D)-tartaric acid (Aldrich, 97%ee, 9.9 g, 66 mmol,) in EtOH (80%, 190 ml) at room temperature for 3 days according to the procedure of Example 1A. The title product was obtained (7.0 g, yield, 28%, 92.3% ee). Example 13D (3S)-Quinuclidin-3-ol The product of Example 13C (7.0 g, 18.4 mmol) was treated with NaOH (aqueous) according to the procedure of Example 1B. The title product was obtained as white solid (2.0 g, yield, 86% ) MS (DCI/NH3) m/z 128 (M+H)+. Example 13E (3S)-3-f(5-Bromopvrimidin-2-vl)oxv1auinuclidine The product of Example 13D (508 mg, 4 mmol) was coupled with 2-iodo-5-bromo-pyrimidine (1.42 g, 5 mmol) according to the procedure of Example 7A.The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3-H20, 90:10:1, Rf. 0.20) as solid (780 mg, yields, 69%)as a solid. 1H NMR (300 MHz, CD3OD) 5 1.47-1.61 (m, 1H), 1.63-1.90 (m, 2H), 1.96-2.12 (m, 1H), 2.19-2.27 (m, 1H), 2.73-3.03 (m, 5H), 3.33-3.45 (m, 1H), 5.05-5.14 (m, 1H), 8.64 (s, 2H) ppm. MS (DCI/NH3): 284 (M+Hf 286 (M+H)+. Example 13F 5-f2-f(3S)-1-Azabicvclof2.2.21oct-3-vloxvlpvrimidin-5-vl}-1H-indote The product of Example13E (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (193 mg, 1.2 mmol) according to the procedure of Example 3A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 jjm, 40 x 100 mm. Eluting Solvent, MeCN / H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (120 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) 5 1.50-1.63 (m, 1H), 1.66-1.92 (m, 2H), 2.03- -69- RECEIVED at IPONZ on 18 March 2010 548231 2.18 (m, 1H), 2.24-2.32 (m, 1H), 2.75-3.07 (m, 5H), 3.38-3.49 (m, 1H), 5.13-5.21 (m, 1H), 6.53 (dd, J=3.0, 0.7 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=9.2, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.81 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Example 13G 542-f(3S)-1-Azabicvclof2.2.21oct-3-vloxv1pyrimidin-5-vl>-1 H-indole hemifumarate The product of Example 13F (120mg, 0.38 mmol) was treated with fumaric acid (44 mg, 0.38 mmol) in EtOAc/EtOH (v. 1:1,10 ml_). The title compound was obtained as solid (123 mg, yield, 84%). 1H NMR (300 MHz, CD3OD) 5 1.75-2.13 (m, 3H), 2.22-2.37 (m, 1H), 2.46-2.54 (m, 1H), 3.03-3.45 (m, 5H), 3.68-3.79 (m, 1H), 5.30-5.38 (m, 1H), 6.52 (dd, J=3.1, 1.1 Hz, 1H), 6.67 (s, 1.2H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J= 8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+. Anal. Calculated for C19H20N4O O.6 C4H4O4: C, 65.90; H, 5.79; N, 14.36. Found: C, 65.62; H, 5.76; N, 14.40. Example 14 5-[4-(1-Azabicvclof2.2.21oct-3-vloxv)phenvll-3-methvl-1 H-indazole trifluoroacetate The product of Example 1A (200 mg, 0.61 mmol) was coupled with t-butyl-(3-methyl-5-trimethylstannanyl-indazole)-1-carboxylate (ref. US 2003199511, 294 mg, 1 mmol) according to the procedure of Example 2B. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 |jm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (70 mg, yield, 26%). 1H NMR (300 MHz, CD3OD) 5 1.85-2.13 (m, 3H), 2.22-2.37 (m, 1H), 2.46-2.50 (m, 1H), 2.58 (s, 3H), 3.23-3.45 (m, 5H), 3.78-3.86 (m, 1H), 4.90-5.00 (m, 1H), 7.07 (dt, J=8.8, 2.0 Hz, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.61-7.68 (m, 3H), 7.85 (s, 1H) ppm. MS (DCI/NH3): m/z 334 (M+H)+. Anal. Calculated for C21H23N3O I.O CF3C02H 0.5 H20: C, 60.52; H, 5.52; N, 9.21. Found: C, 60.79; H, 5.39; N, 9.17. -70- RECEIVED at IPONZ on 18 March 2010 548231 Example 15 6-r4-d-Azabicvclof2.2.21oct-3-vloxv)phenvll-1,3-benzothiazol-2-amine Example 15A 3-[(4'-Nitro-1.1'-biphenvl-4-vnoxv1auinuclidine 3-Quinuclidinol (Aldrich, 0.51 g, 4 mmol) was coupled with 4'-nitro-1,1'-biphenyl-4-ol (TCI, 0.43 g, 2 mmol) with DIAD (di-isopropyl azadicarboxylate, Aldrich, 0.81 g, 4 mmol) and Ph3P (Aldrich, 1.04 g, 4 mmol) in THF (anhydrous, Aldrich, 40 mL) at ambient temperature for two days. The reaction mixture was concentrated. The title product was purified by chromatography (Si02, CH2CI2: MeOH : NH3-H20, 90:10:1, Rf. 0.20) as solid (400 mg, yield, 62%). 1H NMR ( 300 MHz , CD3OD) 8 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H), 2.17-2.24 (m, 1H), 2.66-3.00 (m, 5H), 3.30-3.41 (m, 1H), 4.56-4.64 (m, 1H), 7.05 (dt, J=8.8, 2.6 Hz, 2H), 7.68 (dt, J=9.2, 2.6 Hz, 2H), 7.82 (dt, ,J=8.8, 2.7 Hz, 2H), 8.28 (dt, J=8.8, 2.8 Hz, 2H) ppm. MS (DCI/NH3) m/z 325 (M+H)+. Example 15B 4'-(1-Azabicvclo[2.2.21oct-3-vloxvV1.1'-biphenvl-4-amine The product of Example 15A (300 mg, 0.92 mmol) was treated with Pd/C (Aldrich, wt.10%, 30 mg) in methanol (20 mL) under H2 at ambient temperature for 30 min. After the reaction was complete, the catalyst was removed through a short column of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound (200 mg, yield, 74%). 1H NMR (300 MHz, CD3OD) 6 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m, 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J= 8.8, 2.5 Hz, 2H), 6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.32 (dt, J= 8.5, 2.5 Hz, 2H), 7.43 (dt,J= 9.2, 2.8 Hz, 2H) ppm. MS (DCI/NH3) m/z 295 (M+H)+. -71- RECEIVED at IPONZ on 18 March 2010 548231 Example 15C 6-f4-( 1 -Azabicvclor2.2.21oct-3-vloxv) phenvll-1.3-benzothiazol-2-amine The product of Example 15B (200 mg, 0.68 mmol) and KSCN (Aldrich, 140 mg, 1.52 mmol) were dissolved in HOAc (5 mL). Bromine [Aldrich, 99%, 40 pL, 0.76 mmol, in HOAc (1 mL) was added slowly to the above solution over 5 min. The mixture was stirred at ambient temperature for additional 1 h. and then quenched with aqueous NaOH (10%, 20 mL) at 5-10 °C. It was then extracted with CHCh/'PrOH (v. 10 : 1, 2 x 50 mL). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.10) as solid (140 mg, yield, 59%). 1H NMR (300 MHz, CD3OD) 5 1.27-1.37 (m, 1H), 1.51-1.72 (m, 2H), 1.79-1.88 (m, 1H), 2.02-2.07 (m, 1H), 2.51-2.84 (m, 5H), 3.21-3.39 (m, 1H), 4.45-4.52 (m, 1H), 6.97(d, J=8.8 Hz, 2H), 7.35 (d, J=8.5 Hz, 7.45 (dd, J=8.5, 2.1 Hz, 1H), 7.55 (d, J=8.5, 2H), 7.90 (d, J=2.0 Hz, 1H) ppm. MS (DCI/NH3) m/z 352 (M+H)+. Example 15D 6-f4-(1-Azabicvclof2.2.21oct-3-vloxv)phenvn-1.3-benzothiazol-2-amine bistrifluoroacetate The product of Example 15C (140 mg, 0.4 mmol) was treated with trifluoroacetic acid (Aldrich, 99%, 114 mg, 80 pL, 1 mmol) in 'PrOH (5 mL) at ambient temperature for 15 h. The title compound was obtained as solid (90 mg, yield, 39%). 1H NMR (300 MHz, DMSO-D6) 5 1.75-2.16 (m, 3H), 2.30-2.52 (m, 2H), 3.03-3.45 (m, 5H), 3.75-3.82 (m, 1H), 4.78-4.85 (m, 1H), 7.05 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.5, 2.1 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.76 [s(broad.), 2H], 7.96 (d, J=1.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 352 (M+H)+. Anal. Calculated for C20H21N3OS-2.08 CF3C02H C, 49.30; H, 3.95; N, 7.14. Found: C, 49.70; H, 3.42; N, 7.03. RECEIVED at IPONZ on 18 March 2010 548231 Example 16 6-(4-f(3R)-1-Azabicvclof2.2.2loct-3-vloxvlphenvl>-1.3-benzothiazol-2-amine Example 16A (3RV3-f (4'-Nitro-1.1 '-biphenvl-4-vl)oxv1qui n uclid ine The product of Example 4A (1.28 g, 10 mmol) was coupled with 4-iodo-4-nitro-biphenyl (TCI, 1.62 g, 5 mmol) according to the procedure of Example 1A. The title product was purified by chromatography (Si02, CH2CI2: MeOH : NH3-H20, 90:10:1, Rf. 0.20) as solid (930 mg, yield, 57%). 1H NMR ( 300 MHz , CD3OD) 6 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H), 2.17-2.24 (m, 1H), 2.66-3.00 (m, 5H), 3.30-3.41 (m, 1H), 4.56-4.64 (m, 1H), 7.05 (dt, >8.8, 2.6 Hz, 2H), 7.68 (dt, >9.2, 2.6 Hz, 2H), 7.82 (dt, >8.8, 2.7 Hz, 2H), 8.28 (dt, >8.8, 2.8 Hz, 2H) ppm. MS (DCI/NH3) m/z 325 (M+H)+. Example 16B 4'-f(3RV1-Azabicvclor2.2.2loct-3-vloxv1-1.r-biphenvl-4-amine The product of Example 16A (580 mg, 1.79 mmol) was treated with Pd/C (Aldrich, wt.10%, 100 mg) in ethanol (50 mL) under H2 at ambient temperature for 30 min. After the reaction was complete, the catalyst was removed through a short column of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound (520 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) § 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m, 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J- 8.8, 2.5 Hz, 2H), 6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.32 (dt, J= 8.5, 2.5 Hz, 2H), 7.43 (dt,J= 9.2, 2.8 Hz, 2H) ppm. MS (DCI/NH3) m/z 295 (M+H)+. Example 16C 6-f4-f(3R)-1-Azabicvclof2.2.2loct-3-vloxvlphenvl)-1.3-benzothiazol-2-amine tri(trifluoroacetate) The product of Example 16B (250 mg, 0.85 mmol) and KSCN (Aldrich, 165 mg, 1.70 mmol) were dissolved in HOAc (5 mL). Bromine [Aldrich, 99%, 47 pL, 0.90 -73- RECEIVED at IPONZ on 18 March 2010 548231 mmol, in HOAc (1 mL)] was slowly added to the above solution over 5 min. The mixture was stirred at ambient temperature for additional 2 hours, and quenched with aqueous NaOH (10%, 20 mL) at 5-10 °C. It was then extracted with CHCI3/'PrOH (v. 10 : 1, 2 x 50 mL). The extracts were combined and concentrated under reduced pressure. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (150 mg, yield, 19%). 1H NMR (300 MHz, DMSO-D6) 6 1.84 - 2.20 (m, 3 h), 2.22 -2.44 (m, 1 H), 2.47 - 2.69 (m, 1 H), 3.32 - 3.51 (m, 5 H), 3.74 - 3.93 (m, 1 H), 4.89 -5.02 (m, 1 H), 7.01 - 7.15 (m, 2 h), 7.53 (d, > 8.5 Hz, 1 h), 7.59 - 7.66 (m, 2 H), 7.69 (dd, >8.5,1.7 Hz, 1 H), 7.98 (d, >2.0 Hz, 1 H) ppm. MS (DCI/NH3): m/z 352 (M+H)+. Anal. Calculated for C20H21N3OS 3.OO CF3C02H C, 45.03; H, 3.49; N, 6.06. Found: C, 44.70; H, 3.42; N, 6.00. Example 17 6-(4-r(3RM-Azabicvclor2.2.2loct-3-vloxvlphenvl}-4-thiocvanato-1.3-benzothiazol-2- amine trifluoroacetate The product of Example 16B (250 mg, 0.85 mmol) and KSCN (Aldrich, 165 mg, 1.70 mmol) were dissolved in HOAc (5 mL). Bromine [Aldrich, 99%, 47 |jL. 0.90 mmol, in HOAc (1 mL)] was added slowly to the above solution over 5 min. according to procedure of Example 16C. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 |jm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (55 mg, yield, 12%). 1H NMR (300 MHz, MeOH-D4) 5 1.79 - 2.24 (m, 3 H), 2.22 - 2.44 (m, 1 H), 2.46 - 2.65 (m, , 1 H), 3.30 - 3.52 (m, 5 H), 3.74 - 3.90 (m, 1 H), 4.93 (dd, >9.2, 5.1 Hz, 1 H), 6.96 - 7.23 (m, 2 H) 7.48 -7.70 (m, 3 H) 7.88 (d, >1.7 Hz, 1 H) ppm. MS (DCI/NH3): m/z 409 (M+H)+ RECEIVED at IPONZ on 18 March 2010 548231 Example 18 6-(4-F(3R)-1-Azabicvclor2.2.2k>ct-3-vloxv1phenvlM-bromo-1.3-benzothiazol-2-amine bis(trifluoroacetate) The product of Example 16B (250 mg, 0.85 mmol) and KSCN (Aldrich, 165 mg, 1.70 mmol) were dissolved in HOAc (5 mL). Bromine [Aldrich, 99%, 47 pL, 0.90 mmol, in HOAc (1 mL) was added slowly to the above solution over 5 min. according to procedure of Example 16C. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40 x 100 mm. Eluting Solvent, MeCN / H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (50 mg, yield, 9%). 1H NMR (300 MHz, MeOH-D4) 5 1.78 - 2.21 (m, 3 H), 2.23 - 2.44 (m, 1 H), 2.47 - 2.63 (m, 1 H), 3.23 - 3.53 (m, 5 H), 3.66 - 3.97 (m, 1 H), 4.88 - 5.03 (m, 1 H), 6.96 - 7.22 (m, 2 H), 7.52 - 7.65 (m, 2 H), 7.68 (d, J= 1.7 Hz, 1 H), 7.82 (d, J= 1.7 Hz, 1 H) ppm. MS (DCI/NH3): m/z 430 (M+H)\ 432 (M+Hf. Anal. Calculated for C20H20BrN3OS-2.00 CF3C02H C, 43.78; H, 3.37; N, 6.38. Found: C, 44.70; H, 3.42; N, 6.32. Example 19 N-r4-(3-Methvl-1H-indazol-5-vnphenvllauinuclidin-3-amine Example 19A N-f4-lodophenvlkiuinuclidin-3-amine 3-Quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) was treated with 4-iodo-aniline (Aldrich, 2.19 g, 10 mmol), Na2S04 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)3 (Aldrich, 3.16 g, 15 mmol) in HOAc (25 mL) at ambient temperature for 15 h. After the reaction was complete, the reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHC03 and stirred for 20 min. It was then extracted with EtOAc (3 x 100 mL). The extracts were combined and washed with brine (2 x 20 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H20, 90:10:2, Rf. 0.10) as oil (3.24 g, yield, 98%). 1H NMR (300 MHz, CD3OD,) S 1.70-1.81 (m, 1H), 1.93-2.04 (m, 2H), 2.08-2.24 (m, 2H), 2.89 -75- RECEIVED at IPONZ on 18 March 2010 548231 (ddd, >12.9, 5.1, 2.7 Hz, 1H), 3.12-3.28 (m, 4H), 3.64 (ddd, >12.9, 9.5, 2.4 Hz, 1H), 3.79-3.85 (m, 1H), 6.46 (dt, >9.0, 2.7 Hz, 2H), 7.39 (dt, >9.1, 2.7 Hz, 2H) ppm. MS (DCI/NHs) m/z 329 (M+Hf. Example 19B N-f4-(3-Methvl-1H-indazol-5-vDphenvnquinuclidin-3-amine trifluoroacetate The product of Example 19A (200 mg, 0.61 mmol) was coupled with t-Butyl-(3-Methyl-5-trimethylstannanyl-indazole)-1-carboxylate (ref. US 2003199511, 294 mg, 1 mmol) according to the procedure of Example 2B. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 pm, 40 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (28 mg, yield, 10%). 1H NMR (300 MHz, CD3OD) 5 1.85-1.96 (m, 1H), 2.08-2.15 (m, 2H), 2.24-240 (m, 2H), 2.59 (s, 3H), 3.02-3.15 (m, 1H), 3.20-3.45 (m, 4H), 3.78-3.88 (m, 1H), 3.98-4.06 (m, 1H), 6.77 (dt, >8.8, 2.0 Hz, 2H), 7.46-7.52 (m, 3H), 7.59 (dd, >8.9, 1.6 Hz, 1H), 7.78 (s, 1H) ppm. MS (DCI/NH3): m/z 333 (M+H)+. Anal. Calculated for C21H24N4-1 -25 CF3C02H; C, 59.43; H, 5.36; N, 11.80. Found: C, 59.20; H, 4.96; N, 11.62. Example 20 (R)- 3-r6-(3-Methvl-1H-indazol-5-vh-Pvridazin-3-vloxv1-1-aza-bicvclof2.2.21octane fumarate Example 20A 3-Methvl-5-trimethvlstannanvl-indazole-1-carboxylic acid tert-butvl ester 5-Bromo-3-methyl-indazole-1-carboxylic acid tert-butyl ester (3.0 g, 9.6 mmol) was coupled with hexamethylditin (Aldrich, 4.73 g, 14.4 mmol) catalyzed by Pd(PPh3)4 (Aldrich, 1.1 g, 0.96 mmol) in anhydrous toluene (Aldrich, 50 mL) at 115 °C (oil bath) under N2 for 2 h. After the reaction went to completion, the black reaction mixture was cooled down to ambient temperature and directly loaded to a flash silica gel column (5-30% EtOAc in hexane) for purification to provide the title compound (3.06 g, 80%). *H NMR (MeOH-d4, 300 MHz) 0.23 - 0.45 (m, 9 H) 1.71 (s, -76- RECEIVED at IPONZ on 18 March 2010 548231 9 H) 2.59 (s, 3 H) 7.67 (d, >8.1 Hz, 1 H) 7.87 (s, 1 H) 8.06 (d, J=8.5 Hz, 1 H) ppm. MS (DCI/NH3) m/z 397(M+H)+. Example 20B fR)-3-r6-(3-Methvl-1H-indazol-5-vl)-Pvridazin-3-vloxv1-1-aza-bicvclor2.2.21octane The product of Example 9A (120 mg, 0.5 mmol) was coupled with the product of Example 20A (278 mg, 0.7 mmol) under the catalysis of by Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol) and (fBu3P)2 Pd (Strem Chemicals, 26 mg, 0.05 mmol) with CsF (Strem Chemicals, 152 mg, 1 mmol) in dioxane (10 ml) at 80°C under N2 for 16 hours. After the reaction went to completion, it was diluted with EtOAc (50 mL) and washed with brine (2x10 mL). The organic solution was concentrated under vacuum and the residue was treated with TFA (1 mL) in CH2CI2 (5 mL) at ambient temperature for 2 hours. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 |jm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (68 mg, 41%). 1H NMR (MeOH-D4, 300 MHz) 1.50- 1.66 (m, 1 H) 1.70-1.94 (m, 2 H) 2.01 -2.15(m, 1 H) 2.29 - 2.37 (m, 1 H) 2.62 (s, 3 H) 2.81 - 3.04 (m, 5 H) 3.44 - 3.56 (m, 1 H) 5.28 - 5.36 (m, 1 H) 7.28 (d, > 9.2 Hz, 1 H) 7.59 (d, >8.8 Hz, 1 H) 8.05 (dd, >8.8, 1.4 Hz, 1 H) 8.16 (d, > 9.2 Hz, 1 H) 8.31 (s, 1 H) ppm. MS (DCI/NH3) m/z 336 (M+H)+. Example 20C ("R)-3-f6-(3-Methvl-1 H-indazol-5-vl)-Pvridazin-3-vloxvl-1-aza-bicvclo[2.2.2loctane fumarate The product of Example 20B (68 mg, 0.11 mmol) was treated with fumaric acid (Aldrich, 14 mg, 0.12 mmol) in EtOAc/MeOH (v. 10:1, 5 mL) to provide the title compound as solid (59.1 mg, 65%). 1H NMR (MeOH-D4, 300 MHz) 1.82-2.18 (m, 3 H) 2.27 - 2.42 (m, 1 H) 2.55 - 2.66 (m, 4 H) 3.21 - 3.43 (m, 5 H) 3.82 - 3.95 (m, 1 H) 5.47 - 5.57 (m, 1 H) 6.68 (s, 2 H) 7.34 (d, J=9.2 Hz, 1 H) 7.60 (d, >8.8 Hz, 1 H) 8.06 (dd, >8.8, 1.7 Hz, 1 H) 8.21 (d, > 9.2 Hz, 1 H) 8.32 (s, 1 H) ppm. MS -77- RECEIVED at IPONZ on 18 March 2010 548231 (DCI/NH3) m/z 336(M+H)+. Anal. Calculated for C19H21N5O IO C4H4O4O.35 H2O: C, 60.35; H, 5.66; N, 15.30. Found: C, 60.06; H, 5.40; N, 15.56. Example 21 (RV3-f6-( 1 -Methvl-1 H-indol-5-vn-pvridazin-3-vloxvl-1 -aza-bicvclof2.2.21octane trifluoroacetate The product of Example 4A (120 mg, 0.5 mmol) was coupled with N-methyi-indole-5-boronic acid (Aldrich, 250 mg, 1.5 mmol) catalyzed by Pd2(dba)3 (24 mg, 0.025 mmol) and (tBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) in dioxane (8 mL) at 80°C under N2 for 16 hours according to the procedure of Example 20B. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 pm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (109.9 mg, 49%). 1H NMR (MeOH-D4, 300 MHz) 1.91 - 2.25 (m, 3 H), 2.34 - 2.48 (m, 1 H), 2.61 - 2.70 (m, 1 H), 3.33 - 3.56 (m, 5 H), 3.86 (s, 3 H), 3.94 -4.04 (m, 1 H), 5.50 - 5.59 (m, 1 H), 6.56 (d, J=3.1 Hz, 1 H), 7.25 (d, J=3.1 Hz, 1 H), 7.29 - 7.36 (m, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.81 (dd, J=8.6, 1.9 Hz, 1 H), 8.10 -8.19 (m, 2 H) ppm. MS (DCI/NH3) m/z 335 (M+H)+. Anal. Calculated for C20H22N4O-1.075 C2F302H: C, 58.22; H, 5.09; N, 12.26. Found: C, 58.21; H, 5.00; N, 12.30. Example 22 (RH5-r6-(1-Aza-bicvclof2.2.2loct-3-vloxv)-pyridazin-3-vll-1H-indol-3-vlmethvl)- dimethvl-amine bis(fumarate) Example 22A (R)-l5-f6-( 1 -Aza-bicvclof2.2.2loct-3-vloxv)-pyridazin-3-vn-1 H-indol-3-vlmethvl)- dimethvl-amine The product of Example 9B (150 mg, 0.47 mmol) was treated with HCHO (Aldrich, 37%, 76 mg, 0.94 mmol) and dimethylamine (Aldrich, 42 mg, 0.94 mmol) in dioxane/HOAc (v. 1:1, 5 mL) at ambient temperature for 16 hours. It was then -78- RECEIVED at IPONZ on 18 March 2010 548231 concentrated and the title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 |jm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (80 mg, 45%). 1H NMR (MeOH-D4, 300 MHz) 1.59 -1.75 (m, 1 H), 1.77 -1.99 (m, 2 H), 2.07 - 2.23 (m, 1 H), 2.36 - 2.44 (m, 1 H), 2.60 - 2.69 (m, 6 H), 2.91 - 3.13 (m, 5 H), 3.52 - 3.65 (m, 1 H), 4.22 (s, 2 H), 5.32 - 5.40 (m, 1 H), 7.30 (d, >9.5 Hz, 1 H), 7.49 (s, 1 H), 7.56 (d, > 8.5 Hz, 1 H), 7.81 (dd, >8.5, 1.7 Hz, 1 H), 8.15 (d, >9.5 Hz, 1 H), 8.29 (s, 1 H) ppm. MS (DCI/NH3) m/z 378(M+H)+. Example 22B (R)-f5-f6-(1-Aza-bicvclof2.2.21oct-3-vloxv)-pyridazin-3-vn-1H-indol-3-vlmethvlV- dimethvl-amine bis(fumarate) The product of Example 22A (80 mg, 0.21 mmol) was treated with fumaric acid (Aldrich, 49 mg, 0.42 mmol) in EtOAc / MeOH (v. 10:1) to give the title compound as white solid (74.8 mg, 53%). 1H NMR (MeOH-D4, 300 MHz) 1.79 - 2.17 (m, 3 H), 2.25 - 2.41 (m, 1 H), 2.54 - 2.61 (m, 1 H), 2.84 (s, 6 H), 3.19 - 3.42 (m, 5 H), 3.78 - 3.90 (m, 1 H), 4.50 (s, 2 H), 5.45 - 5.54 (m, 1 H), 6.66 (s, 5 H), 7.34 (d, > 9.2 Hz, 1 H), 7.54 - 7.63 (m, 2 H), 7.84 (dd, >8.5, 1.7 Hz, 1 H), 8.17 (d, >9.2 Hz, 1 H), 8.35 (s, 1 H) ppm. MS (DCI/NH3) m/z 378(M+H)+. Anal. Calculated for C22H27N5O 2.5 C4H4O4 O.5 H20: C, 56.80; H, 5.66; N, 10.35. Found: C, 56.62; H, 5.78; N, 10.09. Example 23 (R)-3-r6-(1H-lndol-5-vD-pyridazin-3-vloxv1-1-aza-bicvcloF2.2.21octane 1-oxide trifluoroacetate The product of Example 9B was treated with H202 (Aldrich, aq. 30% 1 mL, 8.8 mmol) in acetonitrile (3 mL) for 5 h. The mixture was quenched by Na2S03 solution carefully until no more peroxide was noticed, and it was then concentrated under vacuum. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 pm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid -79- RECEIVED at IPONZ on 18 March 2010 548231 (15.6 mg, 13%). 1H NMR (MeOH-d4, 300 MHz) 2.14 - 2.38 (m, 3 H) 2.55 - 2.71 (m, 2 H) 3.68 - 3.92 (m, 5 H) 4.37 - 4.47 (m, > 8.5 Hz, 1 H) 5.62 - 5.70 (m, J=4.4 Hz, 1 H) 6.57 (d, >2.0 Hz, 1 H) 7.30 - 7.38 (m. 2 H) 7.52 (d, >8.5 Hz, 1 H) 7.74 (dd, >8.6, 1.9 Hz, 1 H) 8.13 - 8.20 (m, 2 H) ppm. MS (ESI) m/z 337(M+H)+. Anal. Calculated for C19H20N4O2 I.I5 CF3CO2H: C, 54.72; H, 4.56; N, 11.98. Found: C, 54.72; H, 4.07; N, 12.08. Example 24 6-(6-f('3R')-1-Aza-bicvcloF2.2.21oct-3-vloxv1-Pvridazin-3-vl)-benzothiazol-2-vlamine tri(hvdroaen chloride) Example 24A 6-(4-Bromo-phenvD-4.5-dihvdro-2H-pyridazin-3-one 4-(4-Bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) was treated with NH2NH2 H20 (Aldrich, 55%, 9.1 mL, 156 mmol) in EtOH (Aldrich, 100 mL) at refluxing for 2h. It was cooled down to ambient temperature and the white solid was filtered off to give the title compound (24.2 g, 98%) 1H NMR (CDCI3, 300 MHz) 5 2.50 - 2.76 (m, 2 H), 2.85 - 3.09 (m, 2 H), 7.43 - 7.71 (m, 4 H), 8.55 (s, 1 H) ppm. MS (DCI/NH3) m/z 253 (M+H)+, 255 (M+Hf, 270 (M+NH4f, 272 (M+NH4)+. Example 24B 6-(4-Bromo-phenvD-4.5-dihvdro-2H-pvridazin-3-one The product of Example 24A (24.0 g, 95 mmol) was oxidized with bromine (Aldrich, 18.81g, 6.1 mL, 104.5 mmol) in HOAc (Aldrich, 200 mL) at 100°C for 1h. The brown mixture was then cooled down to ambient temperature. The white solid was filtered off and the filtrate was washed with water (2 x 20 mL). The solid was collected and dried under vacuum to give the title compound (25.0 g, 100%). 1H NMR (CDCI3, 300 MHz) 8 7.07 (d, >10.2 Hz, 1 H), 7.55 - 7.69 (m, 4 H), 7.72 (d, >9.8 Hz, 1 H) ppm. MS (DCI/NH3) m/z 251 (M+H)+, 253 (M+H)+, 268 (M+NH4)+, 270 (M+NH4)+. -80- RECEIVED at IPONZ on 18 March 2010 548231 Example 24C 3-(4-Bromo-phenvl)-6-chloro-pvridazine The product of Example 24B (25.0g, 100 mmol) was stirred in POCI3 (Aldrich, 200 mL) at 100°C for 18 h. Most of POCI3was then distilled off (around 150 mL was collected). The residue was then poured into 300 mL of ice/water and stirred vigorously for 1 h. The solid was filtered off. The filtrate was washed with water (2 x 50 mL) and dried under vacuum to give the title compound (26.2 g, 98%). 1H NMR (MeOH-D4, 300 MHz) S 7.72 (d, J=8.8 Hz, 2 H), 7.86 (d, J=8.8 Hz, 1 H), 8.02 (d, J= 8.8 Hz, 2 H), 8.19 (d, J= 9.2 Hz, 1 H) ppm. MS (DCI/NH3) m/z 269 (M+H)+, 271 (M+H)+, 273 (M+H)+. Example 24D (3RY-3-f6-(4-Bromo-phenvD-pvridazin-3-vloxvl-1-aza-bicvclo[2.2.21octane The product of Example 24C (2.43 g, 9 mmol) was coupled with the product of Example 4A (1.27g, 10 mmol) using f-BuOK (Aldrich, 1.12g, 10 mmol) as base in THF (anhydrous, Aldrich, 50 mL) according to the procedure of Example 7A. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:2, Rf. 0.30) as slightly yellow solid (3.30g, 100%). 1H NMR (MeOH-D4, 300 MHz) 1.47 - 1.66 (m, 1 H), 1.66- 1.93 (m, 2 H), 1.96-2.18 (m, 1 H), 2.23 - 2.42 (m, 1 H), 2.71 - 3.06 (m, 5 H), 3.38 - 3.58 (m, 1 H), 5.17 - 5.47 (m, 1 H), 7.28 (d, J= 9.2 Hz, 1 H), 7.59 - 7.78 (m, 2 H), 7.82 - 7.99 (m, 2 H), 8.06 (d, J=9.2 Hz, 1 H) ppm. MS (DCI/NH3) m/z 360 (M+H)+, 362 (M+Hf. Example 24E f4-f6-IY3R)-1-Aza-bicvdof2.2.21oct-3-vloxy1-pyridazin-3-vll-phenvl)-benzhvdrvlidene- amine The product of Example 24D (360 mg, 1 mmol) was coupled with benzhydrylideneamine (Aldrich, 270 mg, 1.5 mmol) under the catalysis of Pd2(dba)3 (Aldrich, 18.3 mg, 0.02 mmol) and Xantphos (Strem Chemicals, 36 mg, 0.06 mmol) with t-BuONa (Aldrich, 150 mg, 1.5 mmol) in toluene (anhydrous, Aldrich, 10 mL) at 100°C for 2h. The mixture was then cooled down to ambient temperature and diluted -81- RECEIVED at IPONZ on 18 March 2010 548231 with EtOAc (50 mL), washed with water (2x5 mL). The organic solution was concentrated and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H20, 90:10:1, Rf. 0.4) as a solid (360 mg, yield, 78%). 1H NMR (300 MHz, CD3OD) 5 1.45-1.63 (m, 1 H), 1.64 - 1.94 (m, 2 H), 1.94 - 2.13 (m, 1 H), 2.23 - 2.41 (m, 1 H), 2.71 - 3.06 (m, 5 H), 3.39 - 3.55 (m, 1 H), 5.10 - 5.37 (m, 1 H), 6.82 -6.93 (m, 2 H), 7.12 - 7.23 (m, 3 H), 7.25 - 7.35 (m, 3 H), 7.39 - 7.57 (m, 3 H), 7.67 -7.74 (m, 2 H), 7.74 - 7.83 (m, 2 H), 7.96 (d, > 9.2 Hz, 1 H) ppm. MS (DCI/NH3): 461 (M+H)+. Example 24F 4~f6-f(3R)-1-Aza-bicvclof2.2.21oct-3-vloxv1-pvridazin-3-vlV-phenvlamine The product of Example 24E (360 mg, 0.78 mmol) was treated with HCI (aq. 10%, 5 mL) in THF (5 mL) at ambient temperature for 4 h. It was then concentrated and the title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H2O, 90:10:1, Rf. 0.1) as solid (210 mg, yield, 90%). 1H NMR (300 MHz, CD3OD) 5 1.44-1.66 (m, 1 H), 1.65 -1.94 (m, 2 H), 1.95-2.16 (m, 1 H), 2.20-2.40 (m, 1 H), 2.68 - 3.06 (m, 5 H), 3.37 - 3.57 (m, 1 H), 5.15 - 5.37 (m, 1 H), 6.65 - 6.89 (m, 2 H), 7.18 (d, >9.5 Hz, 1 H), 7.55 - 7.81 (m, 2 H), 7.93 (d, >9.2 Hz, 1 H) ppm. MS (DCI/NH3): 297 (M+H)+. Example 24G 6-f6-f(3R)-1-Aza-bicvclor2.2.21oct-3-vloxvl-pvridazin-3-vl>-benzothiazol-2-vlamine The product of Example 24F (150 mg, 0.5 mmol) was treated with KSCN (Aldrich, 97 mg, 1 mmol) and bromine (Aldrich, 96 mg, 0.6 mmol) in HOAc (5 mL) at ambient temperature for 0.5 h. It was then quenched with Na2S03(aq. 10%, 1 mL) and concentrated. The title compound was purified by chromatography (Si02, CH2CI2 : MeOH : NH3 H20, 90:10:2, Rf. 0.1) as solid (170 mg, yield, 80%). 1H NMR (300 MHz, CD3OD) 5 1.60-1.70 (m, 1 H), 1.72 -1.98 (m, 2 H), 2.02 - 2.19 (m, 1 H), 2.23 -2.42 (m, 1 H), 2.82 - 3.13 (m, 5 H), 3.42 - 3.68 (m, 1 H), 5.15 - 5.54 (m, 1 H), 7.26 (d, > 9.2 Hz, 1 H), 7.49 (d, >8.5 Hz, 1 H), 7.87 (dd, >8.6, 1.9 Hz, 1 H), 8.07 (d, >9.5 Hz, 1 H), 8.23 (d, >1.4 Hz, 1 H) ppm. MS (DCI/NH3): 354 (M+H)+. -82- RECEIVED at IPONZ on 18 March 2010 548231 Example 24H 6-(6-f(3R)-1-Aza-bicvclor2.2.2loct-3-vloxv1-pvridazin-3-vll-benzothiazol-2-vlamine tri(hvdroaen chloride) The product of Example 24G (170 mg, 0.48 mmol) was treated with HCI (Aldrich, 4 M in dioxane, 0.5 mL, 2 mmol) in EtOAc (anhydrous, Aldrich, 5 mL) at ambient temperature for 0.5 h to give the title compound as a yellow solid (170 mg, yield, 77%). 1H NMR 8 1.88 - 2.29 (m, 3 H) 2.30-2.42 (m, 1 H) 2.57 - 2.75 (m, 1 H), 3.33 - 3.60 (m, 5 H), 3.99 (dd, >14.2, 8.1 Hz, 1 H), 5.41 - 5.71 (m, 1 H), 7.50 (d, >9.2 Hz, 1 H), 7.68 (d, >8.8 Hz, 1 H), 8.16 (dd, >8.5, 1.7 Hz, 1 H), 8.26 (d, >9.2 Hz, 1 H), 8.48 (d, >1.4 Hz, 1 H) ppm; MS (DCI/NH3): 354 (M+H)+. Anal. Calculated for C18H19N5OS -3.00 HCM.OO H20: C, 44.96; H, 5.03; N, 14.56. Found: C, 44.70; H, 5.17; N, 14.24. Example 25 (3R)-3-r6-(3-Bromo-1H-indol-5-vl)-pvridazin-3-vloxv1-1-aza-bicvclof2.2.2loctane tri(hvdroqen chloride) Example 25A (3R)-3-f6-(3-Bromo-1H-indol-5-vl)-pvridazin-3-vloxv1-1-aza-bicvcloF2.2.21octane The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10 mL) and treated with HOAc (Sigma, 60 mg, 1 mmol) for 10 min. N-bromosuccinimide (Aldrich, 110 mg, 0.6 mmol) in MeCN (Aldrich, 5 mL) was slowly added over 5 min. The mixture was stirred for 1 hour at ambient temperature and concentrated under vacuum. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3 H20, 90:10:1, Rf. 0.15) as a solid (70 mg, yield, 35%). 1H NMR (300 MHz, CD3OD) 5 1.55-1.62 (m, 1 H), 1.70 - 1.96 (m, 2 H), 2.05-2.20 (m, 1 H), 2.29 - 2.43 (m, 1 H), 2.74 - 3.13 (m, 5 H), 3.42 - 3.66 (m, 1 H, 5.24 - 5.46 (m, 1 H), 7.27 (d, >9.2 Hz, 1 H), 7.38 (s, 1 H), 7.53 (d, >8.5 Hz, 1 H), 7.82 (dd, >8.5, 1.7 Hz, 1 H), 8.05 (s, 1 H), 8.11 (d, >9.5 Hz, 1 H) ppm. MS (DCI/NH3): 399 (M+H)+, 401 (M+H)+. -83- RECEIVED at IPONZ on 18 March 2010 548231 Example 25B (3R)-3-f6-(3-Bromo-1H-indol-5-vl)-pvridazin-3-vloxv1-1-aza-bicvclof2.2.2loctane tri(hvdroaen chloride) The product of Example 25A (50 mg, 0.125 mmol) was treated with HCI (Aldrich, 4 M in dioxane, 0.25 mL, 1 mmol) in EtOAc (anhydrous, 5 mL) at ambient temperature for 1h to provide the title compound as yellow solid (60 mg, yield, 95%). 1H NMR (300 MHz, CD3OD) 5 1.89 - 2.28 (m, 3 H), 2.29 - 2.56 (m, 1 H), 2.63 - 2.80 (m, 1 H), 3.35 - 3.71 (m, 5 H), 3.81 - 4.10 (m, 1 H), 5.37 - 5.74 (m, 1 H), 7.56 (s, 1 H), 7.72 (d, J=8.5 Hz, 1 H) 7.80 (dd, >8.5, 1.8 Hz, 1 H), 8.01 (d, J= 9.5 Hz, 1 H) 8.21 (d, J=1.4 Hz, 1 H), 8.76 (d, >9.5 Hz, 1 H) ppm; MS (DCI/NH3): 399 (M+H)\ 401 (M+H)+. Anal. Calculated for C19H19BrN40 -3.00 HCI-1.50 H20: C, 42.60; H, 4.70; N, 10.46. Found: C, 42.59; H, 4.79; N, 10.09. Example 26 5-{6-r(3R)- 1-Aza-bicvclof2.2.21oct-3-vloxv1-pvridazin-3-vl}-1.3-dihvdro-indol-2-one bisfhvdroqen chloride) Example 26A 5-(4.4,5.5-Tetramethvl-H.3.21dioxaborolan-2-vl)-1.3-dihvdro-indol-2-one 5-Bromo-1,3-dihydro-indol-2-one (Aldrich, 1.06 g, 5 mmol) was coupled with bis(pinacolato)diboron (Aldrich, 1.52 g, 6 mmol) catalyzed by PdC^dppfVC^Cfe (Aldrich, 82 mg, 0.1 mmol) using KOAc (Aldrich, 0.98 g, 10 mmol) as base in dioxane (anhydrous, Aldrich, 50 mL) at 80CC for 10h. After being cooled down to ambient temperature, the mixture was diluted with EtOAc (50 mL) and washed with brine (2 x 10 mL). The organic solution was then concentrated under vacuum. The title compound was purified by chromatography (Si02, hexane : EtOAc, 70:30, Rf. 0.5) as a solid (0.96 g, yield, 74%).1H NMR (300 MHz, CDCI3) 5 1.24 (s, 3 H), 1.28 (s, 3 H), 1.34 (s, 6 H), 3.69 (s, 2 H), 6.86 (d, J= 7.8 Hz, 1 H), 7.57 - 7.78 (m, 2 H) ppm. MS (DCI/NH3): 260 (M+H)+. RECEIVED at IPONZ on 18 March 2010 548231 Example 26B 5-f6-f(3R)- 1-Aza-bicvclof2.2.2loct-3-vloxvl-Pvridazin-3-vl>-1.3-dihvdro-indol-2-one The product of Example 4A (240 mg, 1 mmol) was coupled with the product of Example 26A (520 mg, 2 mmol) catalyzed by PdCl2(PPh3)2 (Aldrich, 35 mg, 0.05 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 52.5 mg, 0.15 mmol) in dioxane/EtOH/Na2C03 (aq, 1 M) (v. 1/1/1, 4.5 mL) at 130°C at 330 watts for 15 min in an Emry™ Creator microwave. The inorganic solid was filtered off with a syringe filter and the mixture was then directed purified by chromatography (Si02, EtOAc: MeOH (v. 2% NH3.H20), 50:50, Rf. 0.2) to give the title compound (240 mg, 71%). 1H NMR (300 MHz, MeOH-D4) 5 1.53- 1.72 (m, 1 H), 1.73- 1.96 (m, 2 H), 2.05 - 2.22 (m, 1 H), 2.24 - 2.49 (m, 1 H), 2.83 - 3.15 (m, 5 H), 3.34 (S, 2 H), 3.47 -3.65 (m, 1 H), 5.16 - 5.49 (m, 1 H), 7.02 (d, J=7.7 Hz, 1 H), 7.25 (d, J=9.2 Hz, 1 H), 7.73 - 7.90 (m, 2 H), 8.01 (d, J= 9.2 Hz, 1 H) ppm. MS (DCI/NH3): 337 (M+H)+. Example 26C 5-(6-r(3RV 1-Aza-bicvclor2.2.21oct-3-vloxv1-pvridazin-3-vlM.3-dihvdro-indol-2-one bisfhvdroaen chloride) The product of Example 26B (80 mg, 0.24 mmol) was treated with HCI (Aldrich, 4 M in dioxane, 0.25 mL, 1 mmol) in EtOAc (anhydrous, 5 mL) at ambient temperature for 1 h to provide the title compound as yellow solid (100 mg, yield, 100%). 1H NMR (300 MHz, MeOH-D4) 5 1.89 - 2.28 (m, 3 H), 2.29 - 2.49 (m, 1 H), 2.60-2.72 (m, 1 H), 3.34 - 3.63 (m, 5 H), 3.67 (s, 2 H), 3.81 - 4.10 (m, 1 H), 5.45 -5.71 (m, 1 H), 7.12 (d, >6.1 Hz , 1 H), 7.77 (d, >9.2 Hz, 1 H), 7.82 - 7.97 (m, 1 H), 8.46 (d, >9.5 Hz, 1 H) ppm; MS (DCI/NH3): 337 (M+H)+. Anal. Calculated for Ci9H2oN402 -2.00 HCI-2.00 H20: C, 51.24; H, 5.88; N, 12.58. Found: C, 51.34; H, 5.75; N, 12.62. RECEIVED at IPONZ on 18 March 2010 548231 Example 27 5-(6-f(3RV1-Oxv-1-Aza-bicvclof2.2.21oct-3-vloxvl-Pvridazin-3-vlV1.3-dihvdro-indol-2- one bis(hvdroaen chloride) Example 27 A 5-(6-f(3R)-1 -Oxv-1 -Aza-bicvclof2.2.2loct-3-vloxv1-pvridazin-3-vl)-1.3-dihvdro-indol-2- one The product of Example 26B (100 mg, 0.30 mmol) was treated with H202 (Aldrich, 30%, 0.5 mL, 1.3 mmol) in MeCN/H20 (v. 4/1, 10 mL) at60°Cfor70 hours according to the procedure of Example 23. The title compound was purified by chromatography (Si02, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.1) as solid (80 mg, 76%). 1H NMR (300 MHz, MeOH-D4) 5 2.01 - 2.29 (m, 3 H), 2.37 - 2.61 (m, 2 H), 3.33 - 3.54 (m, 5 H), 3.68 (s, 2 H), 3.87 - 4.18 (m, 1 H), 5.46 - 5.77 (m, 1 H), 7.03 (d, > 8.1 Hz, 1 H), 7.31 (d, >9.5 Hz, 1 H), 7.75 - 7.93 (m, 2 H), 8.06 (d, >9.5 Hz, 1 H) ppm. MS (DCI/NH3): 353 (M+H)+. Example 27B 5-{6-f(3R)-1-Oxv-1-Aza-bicvclof2.2.21oct-3-vloxvl-pyridazin-3-vi)-1,3-dihvdro-indol-2- one bisfhvdroaen chloride) The product of Example 27A (80 mg, 0.23 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.25 mL, 1 mmol) in /"-PrOH (5 mL) at ambient temperature for 1h to provide the title compound as yellow solid (90 mg, yield, 93%). 1H NMR 5 2.10 - 2.50 (m, 3 H), 2.54 - 2.81 (m, 2 H), 3.35 (s, 2 H), 3.71 - 3.94 (m, 4 H), 4.02 (d, >13.2 Hz, 1 H), 4.30-4.58 (m, 1 H), 5.51 - 5.86 (m, 1 H), 7.18 (d, >8.9 Hz, 1 H), 7.84 - 8.00 (m, 2 H), 7.99 (d, >9.2 Hz, 1 H), 8.63 (d, >9.2 Hz, 1 H) ppm; MS (DCI/NH3): 353 (M+H)+. Anal. Calculated for C^Hso^Oa -2.00 HCI-1.65 H20: C, 50.15; H, 5.60; N, 12.31. Found: C, 49.77; H, 5.29; N, 12.03. RECEIVED at IPONZ on 18 March 2010 548231 Example 28 5-f6-f (3R)-1 -Aza-bicvclor2.2.21oct-3-vloxvl-p vridazin-3-vl)-1.3-d ihvdro-benzoim idazol- 2-one trifluoroacetate Example 28A (4-Bromo-2-nitro-phenvl)-carbamic acid tert-butvl ester 4-Bromo-2-nitro-phenylamine (Aldrich, 10.8 g, 50 mmol) was treated with di(tert-butyl) dicarbonate (Aldrich, 11.99 g, 55 mmol) in THF (Aldrich, 100 mL) at reflux for 6 hours. It was then concentrated and the title compound was purified by recrystallization in EtOH as white solid (12.8 g, yield, 81%). 1H NMR (300 MHz, MeOH-D4) 5 1.40 (S, 9 H), 7.21 (d, >8.5 Hz, 1 H), 7.76 (dd, >8.4, 2.3 Hz, 1 H), 8.21 (d, >2.1 Hz, 1 H) ppm. MS (DCI/NH3): 334 (M+Hf, 336 (M+H)+. Example 28B f2-Nitro-4-(4.4.5.5-tetramethvl-[1.3.21dioxaborolan-2-vl)-phenvll-carbamic acid tert- butvl ester The product of Example 28A (10.05 g, 30 mmol) was coupled with bis(pinacolato)diboron (Aldrich, 9.14 g, 36 mmol) under the catalysis of PdCI2(dppf)2-CH2Cl2 (Aldrich, 490 mg, 0.6 mmol) with KOAc (Aldrich, 6.0 g, 60 mmol) in dioxane (anhydrous, Aldrich, 150 mL) at 80°C for 10 hours according to the procedure of Example 26A. The title compound was purified by chromatography (Si02, hexane : EtOAc, 70:30, Rf. 0.5) as solid (9.0 g, yield, 83%). 1H NMR (300 MHz, CDCI3) 5 1.37 (s, 9 H), 1.38 (s, 12 H), 7.99 (d, >1.4 Hz, 1 H), 8.02 (d, >1.4 Hz, 1 H), 8.45 (d, >1.4 Hz, 1 H) ppm. MS (DCI/NH3): 382 (M+NH4)+. Example 28C (4-(6-ff3R)-1-Aza-bicvclof2.2.21oct-3-vloxv1-pyridazin-3-vl>-2-nitro-phenvl)-carbamic acid tert-butvl ester The product of Example 9A (240 mg, 1 mmol) was coupled with the product of Example 28B (0.72, 2 mmol) under the catalysis of Pd2(dba)3 (24 mg, 0.025 mmol) and (fBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) -87- RECEIVED at IPONZ on 18 March 2010 548231 in dioxane (8 mL) and DMF (Aldrich, 1 mL) at 80°C under N2 for 16 hours according to the procedure of Example 20B. The title compound was purified by chromatography (Si02, EtOAc: MeOH (v. 2% NH3.H20), 50:50, Rf. 0.3) as yellow solid (350 mg, 79%). 1H NMR (300 MHz, MeOH-D4) 5 1.40 (s, 9 H), 1.51 -1.70 (m, 1 H), 1.70-1.98 (m, 2 H), 2.00-2.23 (m, 1 H), 2.37-2.51 (m, 1 H), 2.71 -3.18 (m, 5 H), 3.47 - 3.69 (m, 1 H), 5.33 - 5.49 (m, 1 H), 7.30 (d, > 9.2 Hz, 1 H), 7.54 (d, > 8.5 Hz, 1 H), 7.62 (s, 1 H), 8.14 (d, >9.5 Hz, 1 H), 8.37 (dd, >8.1, 2.0 Hz, 1 H), 8.80 (d, > 2.0 Hz, 1 H) ppm. MS (DCI/NH3): 442 (M+H)+. Example 28D 4-16-f (3RV1 -Aza-bicvclol2.2.21oct-3-vloxv1-pyrid azi n-3-vl)-2-n itro-phenvlam ine The product of Example 28C (350 mg, 0.79 mmol) was treated with HCI (Aldrich, 4 M in dioxane, 2 mL, 8 mmol) in EtOH (5 mL) at ambient temperature for 1 h. The mixture was concentrated and the title compound was purified by chromatography (Si02, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.1) as white solid (250 mg, 93%). 1H NMR (300 MHz, MeOH-D4) 5 1.54 - 1.66 (m, 1 H), 1.72 -2.02 (m, 2 H), 2.07 - 2.24 (m, 1 H), 2.35 - 2.57 (m, 1 H), 2.79 - 3.18 (m, 5 H), 3.48 -3.69 (m, 1 H), 5.27 - 5.47 (m, 1 H), 7.10 (d, J=8.8 Hz, 1 H), 7.22 (d, >9.5 Hz, 1 H), 7.66 (s, 1 H), 7.98 (d, >9.2 Hz, 1 H), 8.08 (dd, >9.0, 2.2 Hz, 1 H), 8.68 (d, >2.4 Hz, 1 H) ppm. MS (DCI/NH3): 342 (M+H)+. Example 28E 4--f6-f(,3R)-1-Aza-bicvcloF2.2.21oct-3-vloxv'l-pvridazin-3-vlVbenzene-1,2-diamine The product of Example 28D (200 mg, 0.59 mmol) was hydrogenated under the catalysis of Pd/C (Aldrich, 10wt.%, 50 mg) in EtOH (10 mL) under hydrogen at ambient temperature for 10 h. After the reaction went to completion, the catalyst was removed through a short column of diatomaceous earth (~ 2 g) and the filtrate was washed with EtOH (2x5 mL). The ethanol solution was concentrated to give the title compound (180 mg, yield, 98%). 1H NMR (500 MHz, CD3-OD) 5 1.58 - 1.73 (m, 1 H), 1.76 - 2.00 (m, 2 H), 2.06 - 2.27 (m, 1 H), 2.29 - 2.47 (m, 1 H), 2.81 - 3.20 (m, 5 H), RECEIVED at IPONZ on 18 March 2010 548231 3.52 - 3.68 (m, 1 H), 5.11 - 5.57 (m, 1 H), 6.78 (d, >8.2 Hz, 1 H), 7.12-7.26 (m, 2 H), 7.32 (d, >2.1 Hz, 1 H), 7.92 (d, >9.2 Hz, 1 H) ppm. MS (DCI/NH3): 312 (M+H)+. Example 28F 5-f6-r(3RV1-Aza-bicvclof2.2.21oct-3-vloxv1-pvridazin-3-vll-1.3-dihvdro-benzoimidazol- 2-one trifluroacetate The product of Example 28E (62 mg, 0.2 mmol) was treated with 1,1'-carbonyldiimidazole (Aldrich, 50 mg, 0.31 mmol) in THF/DMF (v. 1:1,5 mL) at ambient temperature for 10h. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 pm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (20.0 mg, 22%). 1H NMR (500 MHz, CD3-OD) 8 1.94 - 2.33 (m, 3 H), 2.30 - 2.48 (m, 1 H), 2.65 - 2.79 (m, 1 H), 3.38 - 3.70 (m, 6 H), 3.94 - 4.06 (m, 1 H), 5.41 - 5.73 (m, 1 H), 7.31 (d, >7.6 Hz, 1 H), 7.62 - 7.78 (m, 2 H), 8.00 (d, >7.0 Hz, 1 H), 8.65 (d, >7.3 Hz, 1 H) ppm; MS (DCI/NH3): 338 (M+H)+. Anal. Calculated for C18H19N5O2 -1.15 CF3C02H -2.30 H20: C, 47.81; H, 4.89; N, 13.73. Found: C, 47.69; H, 5.27; N, 14.09. Example 29 (R)-3-[6-(1H-Benzoimidazol-5-vP-pvridazin-3-vloxv1-1-aza-bicvclor2.2.21octane Example 29A (R)-N-(4-r6-(1-Aza-bicvclo[2-2-2loct-3-vloxv)-pyridazin-3-vn-phenvl)-acetamide The product of Example 9A (182 mg, 0.76 mmol), N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (Aldrich, 500 mg, 1.9 mmol), dichlorobis(triphenylphosphine)palladium (II) (Aldrich, 53 mg, 0.076 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 6.5 mg, 0.019 mmol) were combined with 1 mL each of ethanol, p-dioxane, and 1 M aq. sodium carbonate. The mixture was heated in a sealed tube to 150 °C at 330 watts for 10 min in an Emry™ Creator microwave. The mixture was cooled to room temperature, filtered through Celite®, and concentrated onto silica. The product was purified by column -89- RECEIVED at IPONZ on 18 March 2010 548231 chromatography (Si02, 5% methanol containing 1% NH4OH -CH2CI2) to provide the title compound (203 mg, 79%).1H NMR (300 MHz, CD3OD) 8 1.96 (m, 1 H), 2.09 (m, 1 H), 2.16 (m, 1 H), 2.16 (s, 3 H), 2.38 (m, 1 H), 2.64 (td, >6.5, 3.6 Hz, 1 H), 3.33 -3.53 (m, 6 H), 3.97 (dd, >13.9, 8.1 Hz, 1 H), 5.54 (m, 1 H), 7.32 (d, >9.4 Hz, 1 H), 7.69 - 7.78 (m, 2 H), 7.91 - 7.98 (m, 2 H), 8.11 (d, >9.3 Hz, 1 H) ppm; MS (DCI/NH3): m/z 339 (M+Hf. Example 29B 4-(6-r(3R)-1-Aza-bicvclof2.2.2loct-3-vloxv1-pvridazin-3-vl>-2-nitro-phenvlamine trifluoroacetate To an ice-cold solution of Example 29A (160 mg, 0.47 mmol) in conc. sulfuric acid (5 mL) was added 90% nitric acid (0.020 mL, 0.47 mmol). After 2 h at 4°C, the mixture was poured over ice and neutralized with ice-cold NaOH (1 N aq.). The mixture was concentrated and the residue was dissolved in MeOH and filtered to give a crude red solid. The product was purified by preparative RP HPLC (Symmetry® C-8, 7 nm, 40 x 100 mm; 10-90% MeCN / H2O with 0.2% v. TFA) to give the title compound (54 mg, 0.11 mmol, 23%). 1H NMR (400 MHz, CD3OD) 8 1.97 (m, 1 H), 2.03 - 2.23 (m, 2 H), 2.39 (m, 1 H), 2.65 (td, >6.5, 3.6 Hz, 1 H), 3.35 -3.47 (m, 4 H), 3.49 (m, 1 H), 3.85 (m, 1 H), 3.97 (dd, >14.0, 8.4 Hz, 1 H), 5.54 (m, 1 H), 7.12 (d, >8.9 Hz, 1 H), 7.33 (d, >9.2 Hz, 1 H), 8.04 (dd, >8.9, 2.1 Hz, 1 H), 8.11 (d, >9.2 Hz, 1 H), 8.71 (d, >2.1 Hz, 1 H) ppm. MS (ESI): m/z 342 (M+H)+. Example 29C (R)-3-f6-(1H-Benzoimidazol-5-vl)-Pvridazin-3-vloxv1-1-aza-bicvclof2.2.21octane The product of Example 29B (29 mg, 0.064 mmol) was dissolved in 2.0 mL of methanol and 6 mg of Pd(OH)2/C (Aldrich, 10 wt%) was added. The mixture was stirred under 50 psi of H2 for 30 min. The solution was filtered through a nylon membrane and concentrated. The residue was dissolved in DMF (0.25 mL) and treated with excess triethylorthoformate (0.1 mL). The solution was heated at 80 °C for 2 h, then cooled down to ambient temperature and stirred for 4 h. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 pm, 30 -90- RECEIVED at IPONZ on 18 March 2010 548231 x 100 mm. Eluting Solvent, MeCN / H2O (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (13 mg, 0.04 mmol, 63%). 1H NMR (300 MHz, CD3OD) 5 1.57 (m, 1 H), 1.73 -1.94 (m, 2 H), 2.08 (m, 1 H), 2.34 (td, >6.4, 3.6 Hz, 1 H), 2.80 - 3.03 (m, 6 H), 3.50 (ddd, >14.5, 8.1, 1.5 Hz, 1 H), 5.32 (m, 1 H), 7.28 (d, >9.2 Hz, 1 H), 7.74 (d, >8.5 Hz, 1 H), 7,91 (d, >8.5 Hz, 1 H), 8.11 (d, > 9.2 Hz, 1 H), 8.22 (s, 1 H), 8.25 (s, 1 H) ppm; MS (DCI/NH3): m/z 322 (M+H)+. Example 30 (S)-3-f6-( 1 H-lndol-5-vD-pvridazin-3-vloxvl-1-aza-bicvclo[2.2.21octane Fumarate Example 30A (S)-3-(6-Chloro-pvridazin-3-vloxv)-1-aza-bicvclof2.2.2loctane The product of Example 13D (254 mg, 2 mmol) was coupled with 3,6-dichloropyridazine (Aldrich, 596 mg, 4 mmol) according to the procedure of Example 7A. The title compound was purified by flash chromatography (Si02, CH2CI2: MeOH : NH3 H2O, 90:10:2, Rf. 0.30) as solid (346 mg, 72%). 1H NMR (300 MHz, MeOH-D4) 6 1.47-1.63 (m, >12.9 Hz, 1 H), 1.65- 1.92 (m, 2 H), 1.94 - 2.10 (m, >5.9, 3.6 Hz, 1 H), 2.22 - 2.32 (m, >2.7 Hz, 1 H), 2.72 - 3.02 (m, 5 H), 3.36 - 3.49 (m, 1 H), 5.17 -5.28 (m, 1 H), 7.23 (d, >9.2 Hz, 1 H), 7.65 (d, >9.5 Hz, 1 H) ppm. MS (DCI/NH3) m/z 240 (M+H)+, 242 (M+H)+. Example 30B (S)-3-f6-(1H-lndol-5-vP-pvridazin-3-vloxv1-1-aza-bicvclof2.2.21octane The product of Example 30A (270 mg, 1.1 mmol) was coupled with 5-indolylboronic acid (215 mg, 1.4 mmol) according to the procedure of Example 20B. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 jjm, 30 x 100 mm. Eluting Solvent, MeCN I H20 (NH4HCO3, 0.1 M, PH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (200 mg, 57%). 1H NMR (300 MHz, MeOH-D4) 8 1.49 - 1.63 (m, 1 H), 1.67 -1.92 (m, 2 H), 1.99 - 2.14 (m, 1 H), 2.28 - 2.36 (m, 1 H), 2.76 - 3.04 (m, 5 H), 3.48 (ddd, >14.7, -91- RECEIVED at IPONZ on 18 March 2010 548231 8.2, 1.9 Hz, 1 H), 5.24 - 5.34 (m, 1 H), 6.56 (d, >4.1 Hz, 1 H), 7.24 (d, >9.5 Hz, 1 H), 7.30 (d, >3.4 Hz, 1 H), 7.50 (d, > 8.5 Hz, 1 H), 7.73 (dd, > 8.6, 1.9 Hz, 1 H) ,8.07 (d, J=9.5 Hz, 1 H), 8.13 (s, 1 H) ppm. MS (DCI/NH3) m/z 321 (M+H)+. Example 30C (S)-3-F6-(1H-lndol-5-vn-Pvridazin-3-vloxv1-1-aza-bicvclof2.2.21octane fumarate The product of Example 30B (200 mg, 0.625 mmol) was treated with fumaric acid (Aldrich, 73 mg, 0.63 mmol) in EtOAc/MeOH (v.10:1, 10 mL) at ambient temperature for 10 hours to give title compound (240.2 mg, 85%). 1H NMR (300 MHz, MeOH-D4) 5 1.87 - 2.22 (m, 3 H), 2.31 - 2.45 (m, 1 H), 2.60 - 2.67 (m, 1 H), 3.30 -3.50 (m, 5 H), 3.89 - 4.00 (m, 1 H), 5.49 - 5.57 (m, 1 H), 6.57 (d, >3.1 Hz, 1 H), 6.68 (s, 2 H), 7.28 - 7.35 (m, 2 H), 7.52 (d, J=8.5 Hz, 1 H), 7.74 (dd, >8.6, 1.9 Hz, 1 H), 8.11 - 8.19 (m, >9.5 Hz, 2 H) ppm. MS (DCI/NH3) m/z 321 (M+H)+. Anal. Calculated for C19H2oN40-1.0 C404H40.50 H20: C, 62.01; H, 5.66; N, 12.58. Found: C, 61.79; H, 5.46; N, 12.43. Example 31 (R)-3-f5-(1H-lndol-5-vl)-pvridin-2-vloxv1-1-aza-bicvclo[2.2.21octane trifluoroacetate Example 31A (R)-3-(5-Bromo-Pvridin-2-vloxv)-1-aza-bicvclof2.2.21octane The product of Example 4A (1.27 g, 10 mmol) was coupled with 5-bromo-2-chloro-pyridine (Aldrich, 1.54 g, 8 mmol) according to the procedure of Example 7A. The title compound was purified by column chromatography (Si02, CH2CI2: MeOH : NH3 H2O, 90:10:1, Rf. 0.2) as a solid (2.0 g, yield, 88%). 1H NMR (MeOH-d4, 300 MHz) 1.49- 1.64 (m, 1 H), 1.66-1.91 (m, 2 H), 1.97-2.11 (m, 1 H), 2.17-2.26 (m, 1 H), 2.77 - 3.05 (m, 5 H), 3.36 - 3.47 (m, 1 H), 5.02 - 5.10 (m, 1 H), 6.77 (d, >8.8 Hz, 1 H), 7.78 (dd, >8.8, 2.7 Hz, 1 H), 8.16 (t, >2.5 Hz, 1 H) ppm. MS (DCI/NH3) m/z 283 (M+H)+, 285(M+H)+. RECEIVED at IPONZ on 18 March 2010 548231 Example 31B fR)-3-f5-( 1 H-lndol-5-vD-pvridin-2-vloxvl-1 -aza-bicvclof2.2.21octane trifluoroacetate The product of Example 31A (140 mg, 0.5 mmol) was coupled with 5-indolylboronic acid (Ryscor Science, 161 mg, 1.0 mmol) according to the procedure of Example 29A. The title compound was preparative HPLC (Xterra™, column, Xterra RP-18, 5 pm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (with 0.2% v. TFA), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (72.9 mg, 32%). 1H NMR (MeOH-d4l 300 MHz) 1.86 - 2.22 (m, 3 H), 2.31 - 2.46 (m, 1 H), 2.52 - 2.63 (m, 1 H), 3.29 - 3.50 (m, 5 H), 3.85 - 3.97 (m, 1 H), 5.34 - 5.42 (m, 1 H), 6.49 (d, >2.4 Hz, 1 H), 6.93 (d, >8.5 Hz, 1 H), 7.24 - 7.35 (m, 2 H), 7.46 (d, >8.5 Hz, 1 H), 7.74 (d, >1.7 Hz, 1 H), 8.00 (dd, >8.6, 2.5 Hz, 1 H), 8.38 (d, >2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 320(M+H)+. Anal. Calculated for C20H21N3O-1.14 CF3CO2H: C, 59.55; H, 4.97; N, 9.35. Found: C, 59.59; H, 4.99; N, 9.03. Example 32 (3R)-3-r5-(1H-lndol-4-vl)-pvrimidin-2-vloxvl-1-aza-bicvclof2.2.21octane 1-oxide The product of Example 12A (10 mg, 0.03 mol) was oxidized with H202 (Aldrich, aq., 30%) according to the procedure of Example 23. The title compound was purified by chromatography [Si02, CH2CI2: MeOH (v. 5% NH3.H20), 90 : 10]. 1H NMR (300 MHz, CD3OD) 8 2.01 - 2.32 (m, 3 H), 2.42 - 2.64 (m, 2 H), 3.41 - 3.70 (m, 5H), 3.91 - 4.24 (m, 1 H), 5.39 - 5.59 (m, 1 H), 6.55 (d, >4.0 Hz, 1 H), 7.12 (d, >8.0 Hz, 1 H), 7.23 (t, >8.0 Hz, 1 H), 7.36 (d, >3.0 Hz, 1 H), 7.47 (d, >8.0 Hz, 1 H), 8.96 (s, 2 H) ppm. -93- 548231 RECEIVED at IPONZ on 18 March 2010 Example 33 (3R)-3-(5-Benzooxazol-5-vl-pvrimidin-2-vloxv)-1-aza-bicvclof2.2.21octane bisftwdroaen chloride) Example 33A 1-Benzvloxv-4-bromo-2-nitro-benzene 4-Bromo-2-nitro-phenol (Aldrich, 2.18 g, 10 mmol) was treated with K2CO3 (Aldrich, 2.76 g, 20 mmol) in DMF (Aldrich, 100 mL) at ambient temperature for 20 min. Benzyl chloride (Aldrich, 1.52 g, 12 mmol) was added. The mixture was stirred at 100°C for 6 h. It was then poured into ice/water (200 mL) and stirred at ambient temperature for 10 hours. The white solid was filtered and dried to give the title compound (3.0 g, yield, 100%). 1H NMR (300 MHz, CDCI3) 5 5.23 (s, 2 H), 7.01 (d, > 9.2 Hz, 1 H), 7.31 - 7.49 (m, 5 H), 7.58 (dd, >9.0, 2.5 Hz, 1 H), 7.98 (d, >2.7 Hz, 1 H) ppm. MS (DCI/NH3): 325 (M+H)+, 327 (M+H)+. Example 33B r2-Nitro-4-(4.4.5,5-tetramethvl-f1,3,21dioxaborolan-2-vh-phenvn-carbamic acid tert- butvl ester The product of Example 33A (3.0 g, 10 mmol) was coupled with bis(pinacolato)diboron (Aldrich, 3.04 g, 12 mmol) according to the procedure of Example 28B. The title compound was purified by chromatography (Si02, hexane : EtOAc, 70:30, Rf. 0.5) as a solid (3.05 g, yield, 86%). 1H NMR (300 MHz, MEOH-D4) 5 1.34 (s, 12 H), 5.30 (s, 2 H), 7.27 - 7.43 (m, 4 H), 7.42 - 7.51 (m, 2 H), 7.89 (dd, >8.3, 1.5 Hz, 1 H), 8.09 (d, >1.7 Hz, 1 H) ppm. MS (DCI/NH3): 373 (M+NH4f. Example 33C (3RV3-[5-(4-Benzvloxv-3-nitro-phenvD-pvrimidin-2-vloxv1-1-aza-bicvcloI2.2.21octane The product of Example 11A (1.42 g, 5 mmol) was coupled with the product of Example 33B (2.50 g, 7.0 mmol) according to the procedure of Example 20B. The title compound was purified by chromatography (Si02, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.3) as solid (1.75 g, 81%). 1H NMR (300 MHz, MeOH-D4) 5 -94- RECEIVED at IPONZ on 18 March 2010 548231 1.46-1.61 (m, 1 H), 1.63-1.92 (m, 2 H), 1.97-2.15 (m, 1 H), 2.17-2.33 (m, 1 H), 2.69 - 3.04 (m, 5 H), 3.35 - 3.49 (m, 1 H), 5.11 - 5.22 (m, 1 H), 5.34 (s, 2 H), 7.25 -7.55 (m, 5 H), 7.85 (dd, J=8.8, 2.4 Hz, 1 H), 8.13 (d, J=2.0 Hz, 1 H), 8.63 (s, 1 H), 8.82 (s, 2 H) ppm. MS (DCI/NH3): 433 (M+H)+. Example 33D 2-Amino-4-(2-r(3R)-1-aza-bicvclor2.2.2loct-3-vloxv1-pvrimidin-5-vl)-phenol The product of Example 33C (380 mg, 0.88) was hydrogenated under the catalysis of Pd/C (Aldrich, 10 wt. %, 100 mg) according to the procedure of Example 28E. The title compound was obtained as yellow solid (220 mg, yield, 92%). 1H NMR (300 MHz, CD3OD) 8 1.47 - 1.93 (m, 3 H), 1.95 - 2.35 (m, 2 H) 2.70 - 3.05 (m, 5 H), 3.33 - 3.48 (m, 1 H), 5.04 - 5.30 (m, J=8.8 Hz, 1 H), 6.72 - 6.88 (m, 2 H), 6.98 (d, J=1.7 Hz, 1 H), 8.70 (s, 2 H)ppm. MS (DCI/NH3): 313 (M+H)+. Example 33E (3R)-3-(5-Benzooxazol-5-vl-pvrimidin-2-vloxv)-1-aza-bicvclof2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthoformate (Aldrich, 0.5 mL) in DMF (1 mL) at 100°C for 10h. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 (jm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (50.0 mg, 78%). 1H NMR (300 MHz, CD3-OD) 8 1.46 - 1.64 (m, 1 H), 1.64 - 1.93 (m, 2 H), 2.00 - 2.19 (m, 1 H), 2.19-2.39 (m, 1 H), 2.67 - 3.13 (m, 5 H), 3.36-3.51 (m, 1 H), 5.09 - 5.38 (m, 1 H), 7.72 (dd, J=8.5, 2.0 Hz, 1 H), 7.81 (d, J= 8.9 Hz, 1 H), 8.03 (d, J=1.7 Hz, 1 H), 8.53 (s, 1 H), 8.87 (s, 2 H) ppm; MS (DCI/NH3): 323 (M+H)* Example 33F (3R)-3-(5-Benzooxazol-5-vl-pyrimidin-2-vloxv)-1-aza-bicvclor2.2.21octane bisfhvdrogen chloride) The product of Example 33E (50 mg, 0.15 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.50 mL, 2.0 mmol) in EtOAc (5 mL) at ambient temperature -95- RECEIVED at IPONZ on 18 March 2010 548231 for 1 hour to afford the title compound as yellow solid (55.0 mg, 93%). 1H NMR (300 MHz, CD3-OD) 8 1.83 - 2.28 (m, 3 H), 2.30 - 2.50 (m, 1 H), 2.58 - 2.75 (m, 1 H), 3.34 - 3.51 (m, 5 H), 3.84 - 3.97 (m, 1 H), 5.33 - 5.52 (m, 1 H), 7.15 (d, >8.5 Hz, 1 H), 7.51 - 7.67 (m, 1 H), 7.80 (s, 1 H), 8.09 (s, 1 H), 8.81 (s, 2 H) ppm; MS (DCI/NH3): 323 (M+H)+. Anal. Calculated for C18H18N402 -2.38 HCI -2.60 H20: C, 47.41; H, 5.65; N, 12.29. Found: C, 47.33; H, 5.25; N, 11.92. Example 34 (3R)-3-r5-(2-Methvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvclof2.2.21octane hvdroaen chloride Example 34A (3R)-3-[5-(2-Methvl-benzooxazol-5-vl)-Pvrimidin-2-vloxvl-1-aza-bicvclof2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthoacetate (Aldrich, 0.5 mL) in DMF (1 mL) at 100°C for 10h. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 (jm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (20.0 mg, 30%). 1H NMR (500 MHz, CD3OD) 8 1.51 -1.64 (m, 1 H), 1.66 - 1.77 (m, 1 H), 1.78-1.91 (m, 1 H), 2.02 - 2.16 (m, 1 H), 2.19-2.36 (m, 1 H), 2.67 (s, 3 H), 2.74 - 3.07 (m, 5 H), 3.37 - 3.48 (m, 1 H), 5.07 - 5.39 (m, 1 H), 7.62 (dd, >8.5, 1.3 Hz, 1 H), 7.68 (d, >8.3 Hz, 1 H),7.87 (d, >1.2 Hz, 1 H), 8.79 - 8.93 (s, 2 H) ppm; MS (DCI/NH3): 327 (M+H)+. Example 34B (3Ry3-r5-(2-Methvl-benzooxazol-5-vD-pvrimidin-2-vloxvl-1-aza-bicvclof2.2.21octane hydrogen chloride The product of Example 34A (20 mg, 0.06 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (3 mL) at ambient temperature for 1 hour to afford the title compound as yellow solid (20.0 mg, 92%). 1H NMR (500 MHz, CD3OD) 6 1.92 - 2.25 (m, 3 H), 2.33 - 2.47 (m, 1 H), 2.59 - 2.65 (m, 1 H), 2.65 -96- RECEIVED at IPONZ on 18 March 2010 548231 - 2.71 (s, 3 H), 3.33 - 3.54 (m, 5 H), 3.87 - 4.00 (m, 1 H), 5.34 - 5.54 (m, 1 H), 7.63 (d, > 8.5 Hz, 1 H), 7.70 (d, > 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.90 (s, 2 H) ppm; MS (DCI/NH3): 327 (M+Hf. Anal. Calculated for Ci9H2oN402 -1.20 HCI -1.50 H20: C, 56.39; H, 5.60; N, 13.45. Found: C, 56.05; H, 5.99; N, 13.76. Example 35 (3R)-3-f5-(2-Ethvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvclor2.2.21octane bis(hvdroaen chloride) Example 35A (3R)-3-f5-(2-Ethvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvclor2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthopropionate (Aldrich, 0.5 mL) in DMF (1 mL) at 100°C for 10h. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 pm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (20.0 mg, 30%). 1H NMR (500 MHz, CD3OD) 5 1.45 (t, > 7.6 Hz, 3 H), 1.49 -1.64 (m, 1 H), 1.66-1.78 (m, 1 H), 1.79- 1.94 (m, 1 H), 2.04-2.16 (m, 1 H), 2.21 -2.36 (m, 1 H), 2.72 - 3.11 (m, 7 H), 3.37 - 3.53 (m, 1 H), 5.07 - 5.31 (m, 1 H), 7.62 (dd, > 8.5, 1.7 Hz, 1 H) 7.69 (d, > 8.6 Hz, 1 H), 7.89 (d, >1.2 Hz, 1 H), 8.82 - 8.90 (m, 2 H) ppm; MS (DCI/NH3): 351 (M+H)+. Example 35B (3R)-3-f5-(2-Methvl-benzooxazol-5-vl)-pvrimidin-2-vloxvl-1-aza-bicvclof2.2.2loctane bis(hvdroqen chloride) The product of Example 35A (20 mg, 0.06 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (3 mL) at ambient temperature for 1 hour to afford the title compound as yellow solid (15.0 mg, 92%). 1H NMR (500 MHz, CD3-OD) 6 1.46 (t, >7.6 Hz, 3 H), 1.89 - 2.25 (m, 3 H), 2.28 - 2.52 (m, 1 H), 2.54 - 2.72 (m, 1 H), 3.02 (q, >7.6 Hz, 2 H), 3.22 - 3.56 (m, 5 H), 3.92 (dd, >13.6, -97- RECEIVED at IPONZ on 18 March 2010 548231 8.7 Hz, 1 H), 4.99 - 5.63 (m, 1 H), 7.63 (d, >8.5 Hz, 1 H), 7.71 (d, >8.5 Hz, 1 H), 7.90 (s, 1 H), 8.90 (s, 2 H) ppm; MS (DCI/NH3): 351 (M+H)+. Anal. Calculated for C2oH22N402 2.00 HCI: C, 56.74; H, 5.71; N, 13.23. Found: C, 56.82; H, 5.69; N, 13.13. Example 36 (3R)-3-f5-(2-Phenvl-benzooxazol-5-vl)-pyrimidin-2-vloxv1-1-aza-bicvclof2.2.21octane bisfhvdroaen chloride) Example 36A (3R)-3-[5-(2-Phenvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvclor2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthobenzoate (Aldrich, 0.5 ml) in DMF (1 ml) at 100°C for 10h. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 |jm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (40.0 mg, 50%). 1H NMR (500 MHz, CD3OD) 5 1.52 -1.64 (m, 1 H), 1.68 - 1.80 (m, 1 H), 1.80-1.92 (m, 1 H), 2.06 - 2.18 (m, 1 H), 2.25-2.31 (m, 1 H), 2.75 - 3.10 (m, 5 H), 3.39 - 3.49 (m, 1 H), 5.14 - 5.27 (m, 1 H), 7.55 - 7.66 (m, 3 H), 7.69 (dd, >8.5, 1.8 Hz, 1 H), 7.81 (d, >8.2 Hz, 1 H), 8.00 (d, >1.5 Hz, 1 H), 8.27 (dd, >8.1, 1.7 Hz, 2 H), 8.89 (s, 2H) ppm; MS (DCI/NH3): 399 (M+H)+. Example 36B (3R)-3-r5-(2-Phenvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvcloF2.2.21octane bisfhvdroqen chloride) The product of Example 36A (40 mg, 0.10 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (3 mL) at ambient temperature for 1 hour to afford the title compound as yellow solid (20.0 mg, 92%). 1H NMR (500 MHz, CD3OD) S 1.93 - 2.23 (m, 3 H), 2.33 - 2.48 (m, 1 H), 2.60 - 2.71 (m, 1 H), 3.34 -3.57 (m, 5 H), 3.90 - 3.99 (m, 1 H), 5.35 - 5.61 (m, 1 H), 7.54 - 7.68 (m, 3 H), 7.72 (dd, >8.4, 1.7 Hz, 1 H), 7.84 (d, >8.5 Hz, 1 H), 8.03 (d, >1.2 Hz, 1 H), 8.21 - 8.37 -98- RECEIVED at IPONZ on 18 March 2010 548231 (m, 2 H), 8.98 (s, 2 H) ppm; MS (DCI/NH3): 399 (M+H)+. Anal. Calculated for C24H22N4O2 1.40 HCI-1.50 H20: C, 60.49; H, 5.58. Found; C, 60.12; H, 5.72. Example 37 (R)-5-f2-(1-Aza-bicvclof2.2.21oct-3-vloxv)-pyrimidin-5-vll-3H-benzooxazol-2-one bis(hvdrochloride) Example 37A (R)-5-F2-(1-Aza-bicvclor2.2.21oct-3-vloxv)-pyrimidin-5-vll-3H-benzooxazol-2-one The product of Example 33D (62 mg, 0.2 mmol) was treated with 1,1'-carbonyldiimidazole (Aldrich, 50 mg, 0.31 mmol) in THF/DMF (v. 1:1, 5 mL) at ambient temperature for 10h. It was then concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 jjm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HC03, 0.1 M, pH=10), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (60.0 mg, 34%). 1H NMR (500 MHz, CD3-OD) 5 1.46 -1.96 (m, 3 H), 2.02- 2.18 (m, 1 H), 2.19-2.38 (m, 1 H), 2.70-3.11 (m, 5 H), 3.37 - 3.51 (m, 1 H), 5.08 - 5.29 (m, 1 H), 7.14 - 7.60 (m, 3 H), 8.79 (s, 2 H) ppm; MS (DCI/NH3): 338 (M+H)+. Example 37B (R)-5-[2-(1~Aza-bicvclof2.2.2loct-3-vloxv)-pvrimidin-5-vl1-3H-benzooxazol-2-one bis(hvdrochloride) The product of Example 37A (60 mg, 0.18 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (3 mL) at ambient temperature for 1 hour to afford the title compound as yellow solid (60.0 mg, 83%). 1H NMR (500 MHz, CD3OD) 8 1.89 - 2.28 (m, 3 H), 2.30 - 2.54 (m, 1 H), 2.61 - 2.76 (m, 1 H), 3.36 -3.52 (m, 5 H), 3.82 - 3.99 (m, 1 H), 5.40-5.52 (m, 1 H) 7.20 - 7.47 (m, 2 H), 7.68 (s, 1 H), 8.80 (s, 2 H) ppm; MS (DCI/NH3): 338 (M+H)+. Anal. Calculated for C^H^Os 2.00 HCI -1.50 H20: C, 49.33; H, 5.29; N, 12.78. Found: C, 49.40; H, 5.07; N, 12.60. RECEIVED at IPONZ on 18 March 2010 548231 Example 38 (R)-3-r6-(1-Aza-bicvclof2.2.21oct-3-vloxv)-pvridazin-3-vn-9H-carbazole Example 38A 3-(4.4.5.5-Tetramethvl-f1.3.21dioxaborolan-2-vl)-9H-carbazole 3-Bromo-9H-carbazole (Aldrich, 0.97 g, 3.96 mmol) was coupled with bis(pinacolato)diboron (Aldrich, 1.13 g, 4.46 mmol) under the catalysis of dichloro [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (Aldrich, 103 mg, 0.125 mmol) with KOAc (Aldrich, 1.21 g, 12.3 mmol) in DMF (anhydrous, Aldrich, 25 mL) at 80°C overnight according to the procedure of Example 26A, The title compound was purified by chromatography (Si02, gradient 5 to 50% EtOAc-hexanes) to give 0.80 g (2.73 mmol, 69% yield). 1H NMR (300 MHz, CDCI3) 8 1.40 (s, 12 H), 7.26 (s, 1 H), 7.40 - 7.47 (m, 3 H), 7.88 (d, J= 7.0 Hz, 1 H), 8.11 (d, J=7.0 Hz, 2 H), 8.58 (s, 1 H) ppm. MS (DCI/NH3) m/z 294 (M+H)+. Example 38B (R)-3-[6-(1-Aza-bicvclof2.2.2loct-3-vloxv)-pvridazin-3-yl1-9H-carbazole The product of Example 9A (0.173g, 0.72 mmol) was coupled with the product of Example 38A (0.267 g, 0.91 mmol) under the catalysis of dichlorobis(triphenyl-phosphine)palladium(ll) (Aldrich, 5.3 mg, 0.007 mmol) and 2-(dicyclohexylphosphino)biphenyl (Strem Chemicals, 7.3 mg, 0.021 mmol) at 150 °C for 10 min. according to the procedure of Example 29A. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid. 1H NMR (300 MHz, CD3OD) 8 1.45-1.62 (m, 1 H), 1.68- 1.92 (m, 2 H), 2.00-2.15 (m, 1 H), 2.27-2.40 (m, Hz, 1 H), 2.75 - 3.05 (m, 5 H), 3.43 - 3.59 (m, Hz, 1 H), 5.22 - 5.42 (m, Hz, 1 H), 7.16 -7.24 (m, 1 H), 7.28 (d, J=9 Hz, 1 H), 7.36 - 7.44 (m, 1 H), 7.45 - 7.52 (m, 1 H), 7.57 (d, J= 8 Hz, 1 H), 8.02 (dd, J= 9, 2 Hz, 1 H), 8.17 (t, J=9 Hz, 2 H), 8.67 (s, 1 H) ppm; MS (DCI/NH3) m/z 371 (M+H)+ RECEIVED at IPONZ on 18 March 2010 548231 Example 39 3-r6-(1H-lndol-3-vl)-pvridazin-3-vloxvl-1 -aza-bicvclo[2.2.21octane hemifumarate Example 39A 3-f6-(1H-lndol-3-vl)-pyridazin-3-vloxvl-1-aza-bicvclo[2.2.21octane 3-Quinuclidinol (Aldrich, 254 mg, 2 mmol) was coupled with 3-(6-chloro-pyridazin-3-yl)-1 H-indole (Bionet, 458 mg, 2 mmol) at 60°C for 16 hours according to the procedure of Example 7A. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 pm, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, pH=10), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (400 mg, 63%). 1H NMR (MeOH-D4, 300 MHz) 1.50 -1.64 (m, 1 H), 1.71 -1.93 (m, 2 H), 2.00 - 2.15 (m, 1 H), 2.29 - 2.36 (m, 1 H), 2.78-3.04 (m, 5 H), 3.43 - 3.55 (m, 1 H), 5.24 - 5.32 (m, 1 H), 7.12 - 7.25 (m, 3 H), 7.42 - 7.48 (m, 1 H), 7.87 (s, 1 H), 8.01 (d, J=9.2 Hz, 1 H), 8.26 - 8.33 (m, 1 H) ppm. MS (DCI/NH3) m/z 321(M+H)+. Example 39B 3-F6-(1H-lndol-3-vl)-pvridazin-3-vloxv1-1-aza-bicvclor2.2.2k>ctane hemifumarate The product of Example 39A (200 mg, 0.63 mmol) was treated with fumaric acid (Aldrich, 73 mg, 0.63 mmol) in EtOAc/MeOH(v.10:1, 10 mL) at ambient temperature overnight to give the title compound (247.3 mg, 100%). 1H NMR (MeOH-D4, 300 MHz) 1.76 -1.91 (m, 1 H), 1.92 - 2.14 (m, 2 H), 2.22 - 2.37 (m, 1 H), 2.51 - 2.58 (m, 1 H), 3.16 - 3.39 (m, 5 H), 3.82 (ddd, J=14.0, 8.2, 1.9 Hz, 1 H), 5.40 -5.49 (m, 1 H), 6.67 (s, 1 H), 7.12 - 7.26 (m, 3 H), 7.42 - 7.49 (m, 1 H), 7.89 (s, 1 H), 8.05 (d, J= 9.5 Hz, 1 H), 8.26 - 8.32 (m, 1 H) ppm. MS (DCI/NH3) m/z 321(M+H)+. Anal. Calculated forCigH20N400.5 C404H40.35 H20: C, 65.56; H, 5.95; N, 14.56. Found: C, 65.49; H, 6.21; N, 14.34. RECEIVED at IPONZ on 18 March 2010 548231 Example 40 (R)-3-f6-(1H-lndol-3-vl)-pvridazin-3-vloxvl-1-aza-bicvclof2.2.21octane fumarate The product of Example 4A (127 mg, 1 mmol) was coupled with 3-(6-chloro-pyridazin-3-yl)-1 H-indole (Bionet, 229 mg, 1 mmol) according to the procedure of Example 39. The title compound was obtained as solid (208.3 mg, yield, 35%). 1H NMR (MeOH-d4, 300 MHz) 1.90 - 2.24 (m, 3 H), 2.33 - 2.48 (m, 1 H), 2.61 - 2.69 (m, 1 H), 3.32 - 3.55 (m, 5 H), 3.98 (dd, >13.7, 8.3 Hz, 1 H), 5.49 - 5.57 (m, 1 H), 6.71 (s, 4 H), 7.13 - 7.28 (m, 3 H), 7.46 (d, >7.1 Hz, 1 H), 7.90 (s, 1 H), 8.07 (d, >9.2 Hz, 1 H), 8.30 (d, >7.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 321(M+H)+. Anal. Calculated for C19H2oN40-2.1 C404H40.35 EtOAc: C, 58.14; H, 5.29; N, 9.42. Found: C, 57.91; H, 5.35; N, 9.42. Example 41 (SV3-r6-(1H-lndol-3-vl)-pvridazin-3-vloxv1-1-aza-bicvclof2.2.2loctane fumarate The product of Example 13D (127 mg, 1 mmol) was coupled with 3-(6-chloro-pyridazin-3-yl)-1 H-indole (Bionet, 229 mg, 1 mmol) according to the procedure of Example 39. The title compound was obtained as solid (239 mg, yield, 39%).1H NMR (MeOH-d4, 300 MHz) 1.90 - 2.24 (m, 3 H), 2.33 - 2.48 (m, 1 H), 2.61 - 2.69 (m, 1 H), 3.33 - 3.55 (m, 5 H), 3.93 - 4.04 (m, 1 H), 5.49 - 5.57 (m, 1 H), 6.72 (s, 4 H), 7.13 -7.28 (m, 3 H), 7.46 (d, >8.1 Hz, 1 H), 7.90 (s, 1 H), 8.07 (d, >9.2 Hz, 1 H), 8.30 (d, >7.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 321(M+H)+. Anal. Calculated for C19H20N4O 2.I C404H4 0.5 EtOAc: C, 58.06; H, 5.37; N, 9.21. Found: C, 57.81; H, 5.54; N, 9.53. Example 42 DETERMINATION OF BIOLOGICAL ACTIVITY To determine the effectiveness of representative compounds of this invention as a7 nAChRs, the compounds of the invention were evaluated according to the [3H]-methyllycaconitine (MLA) binding assay and considering the [3H]-cytisine binding assay, which were performed as described below. -102- RECEIVED at IPONZ on 18 March 2010 548231 f3H1-Cvtisine binding Binding conditions were modified from the procedures described in Pabreza LA, Dhawan, S, Kellar KJ, [3H]-Cytisine Binding to Nicotinic Cholinergic Receptors in Brain, Mol. Pharm. 39: 9-12, 1991. 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-Tris buffer (120 mM NaCI/5 mM KCI/2 mM CaCI2/2 mM MgCI2/50 mM Tris-CI, pH 7.4, 4 °C). Samples containing 100-200 pg of protein and 0.75 nM [3H]-cytisine (30 Ci/mmol; Perkin Elmer/NEN Life Science Products, Boston, MA) were incubated in a final volume of 500 pL for 75 minutes at 4 °C. Seven log-dilution concentrations of each compound were tested in duplicate. Non-specific binding was determined in the presence of 10 pM (-)-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 mM NaCI/5 mM KCI/2 mM CaCh/2 mM MgCI2). Packard MicroScint-20® scintillation cocktail (40 pL) was added to each well and radioactivity determined using a Packard TopCount® instrument. The IC50 values were determined by nonlinear regression in Microsoft Excel® software. Kj values were calculated from the IC50S using the Cheng-Prusoff equation, where K = IC5o/1+[Ligand]/KD]. f3Hl-Methvllvcaconitine (MLA) binding Binding conditions were similar to those for [3H]-cytisine binding. 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-Tris buffer (120 mM NaCI, 5 mM KCI, 2 mM CaCI2, 2 mM MgCI2, and 50 mM Tris-CI, pH 7.4, 22 °C). Samples containing 100-200 pg of protein, 5 nM [3H]-MLA (25 Cj/mmol; 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 pL 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 pM MLA. Bound radioactivity was isolated by vacuum filtration onto glass fiber filter plates -103- RECEIVED at IPONZ on 18 March 2010 548231 prewetted with 2% BSA using a 96-well filtration apparatus (Packard Instruments, Meriden, CT) and then rapidly rinsing with 2 mL of ice-cold BSS. Packard MicroScint-20® scintillation cocktail (40 |JL) was added to each well and radioactivity was determined using a Packard TopCount® instrument. The IC50 values were determined by nonlinear regression in Microsoft Excel® software. Kj values were calculated from the IC50S using the Cheng-Prusoff equation, where Ki = IC50/I +[Ligand]/KD]. Compounds of the invention had Kj values of from about 1 nanomolar to about 10 micromolar when tested by the MLA assay, many having a Kj of less than 1 micromolar. [3H]-Cytisine binding values of compounds of the invention ranged from about 50 nanomolar to at least 100 micromolar. The determination of preferred compounds typically considered the Kj value as measured by MLA assay in view of the K value as measured by [3H]-cytisine binding, such that in the formula D = K3H-cytisine /KiMLA, D is about 50. Preferred compounds typically exhibited greater potency at al receptors compared to a4p2 receptors. Compounds of the invention are al nAChRs ligands that modulate function of al nAChRs by altering the activity of the receptor. 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 be partial agonists that partially block or partially activate the al nAChR receptor or agonists that activate the receptor. Some compounds of the invention also have been evaluated for potential binding to the hERG ion channel. Blockade of the hERG ion channel has been associated with interference of heart muscle repolarization, which presents a cardiovascular risk. Binding affinities to the hERG channel were measured by displacement of the radioligand [3H]-dofetilide and expressed in K value, i.e. K hERG-Compounds of the invention demonstrating a higher ratio of al receptor binding to the ratio of hERG binding, i.e. (K| mla)/(K! hERG), were considered to demonstrate a better cardiovascular risk profile. Compounds of the invention that were tested all demonstrated a beneficial cardiovascular risk profile for al receptor ligands. -104- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> RECEIVED at IPONZ on 18 March 2010 548231 It is understood that the foregoing detailed description and accompanying 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, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. -105- RECEIVED at IPONZ on 18 March 2010 548231 WHAT WE CLAIM IS:

1. A compound of the formula (I): X—Ar1—Ar2 X (I) or a pharmaceutically acceptable salt, ester, or amide thereof, wherein: n is 0, 1, or 2; A is N or N+-0~; X is selected from the group consisting of O, S, and -N(R1)-; Ar1 is a 6-membered aromatic ring containing 0,1, 2, 3, or 4 nitrogen atoms, wherein Ar1 is substituted with 0, 1, 2, 3, or 4 alkyl groups; Ar2 is a group of the formula: Z5, Z6, Z7, and Z8 are independently selected from the group consisting of C and -C(R3b); provided that zero or one of Z5, Z6, Z7, and Z8 is C; Y1 is selected from the group consisting of O, S, -N(R2), -C(R3), and -C(R3)(R3a); Y2a and Y3a are independently selected from the group consisting of N, C and -C(R3a); provided that when Y1 is -C(R3), Y2a and Y3a are selected from the group consisting of N and -C(R3a), and when one of Y2a and Y3a is C, then Y1 is O, S, -N(R2), or -C(R3)(R3a); wherein when one of Z5, Z6, Z7, and Z8 is C, then Y1 is selected from the group consisting of O, S, -N(R2), and -C(R3)(R3a); Y2a and Y3a are each z (b> -106- RECEIVED at IPONZ on 18 March 2010 548231 independently selected from the group consisting of N and -C(R3a); and the group of formula (b) is attached to Ar1 through the C of Z5, Z6, Z7, or Z8; and also wherein when Y1 is -C(R3) or one of Y2a and Y3a is C, then Z5, Z6, Z7, and Z8 are each -C(R3b) and the group of formula (b) is attached to Ar1 through the C atom of-C(R3) of Y1 in the group of formula (b) or through the C atom of Y2a or Y3a; R1 and R2 at each occurrence are each independently selected from the group consisting of hydrogen and alkyl; R3 and R3a at each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4 and -NR5R6; R3bat each occurrence are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4, -NR5RS, -alkyl-OR4, -alkyl-NR5R6, and-SCN; R4 is selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, and arylcarbonyl; R5 and R6 at each occurrence are each independently selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, and arylcarbonyl, provided that at least one of R5 and R6 is hydrogen or alkyl; and R8 is selected from the group consisting of hydrogen and alkyl.

2. The compound of claim 1, wherein Ar1 is a group of the formula: wherein: X1, X2, X3, and X4 are each independently selected from the group consisting of N and -CR10; and x ■X (b) -107- RECEIVED at IPONZ on 18 March 2010 548231 R10 at each occurrence is independently selected from the group consisting of hydrogen and alkyl.

3. The compound of claim 1, wherein Ar1 is selected from the group consisting of: wherein R10 at each occurrence is independently selected from the group consisting of hydrogen and alkyl.

4. The compound of claim 1, wherein Ar2 is selected from the group consisting of: (v) (vi) <vii> -108- RECEIVED at IPONZ on 18 March 2010 548231 (x) and (x>) wherein: Z5, Z6, Z7, and Z8 are independently selected from the group consisting of C and -C(R3b); provided that zero or one of Z5, Z6, Z7, and Z8 is C; Y2a and Y3a are independently selected from the group consisting of C and -C(R3a); wherein when one of Z5, Z6, Z7, and Z8 is C, then Y2a and Y3a in the group of formulae (i)-(vii) are each -C(R3a); and each of the group of formulae (i)-(vii) is attached to Ar1 through the C of Z5, Z6, Z7, or Z8; and also wherein when one of Y2a and Y3a is C in the group of formulae (i)-(vii), then Z5, Z6, Z7, and Z8 are each -C(R3b) and each of the group of formulae (i)-(vii) is attached to Ar1 through the C atom of Y2a or Y3a; and R2, R3, and R3a are as defined in claim 1.

5. The compound of claim 1, or a pharmaceutically acceptable salt, ester, or amide thereof, selected from the group consisting of: 3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1 H-indole; 4-[4-(1 -azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1 H-indole; 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1 H-indole; 5-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1 H-indole; 6-[4-( 1-azabicyclo[2.2.2]oct-3-yloxy)phenyl3-1 H-indole; 2-[4-(1-azabicycio[2.2.2]oct-3-yloxy)phenyl]-1 H-indole; -109- RECEIVED at IPONZ on 18 March 2010 548231 5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1 H-indole; 4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1 H-indole; 5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole; 5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-3-methyl-1 H-indole; 5-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1 H-indole; 4-{2-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1 H-indole; 5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1 H-indole; 5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-3-methyl-1H-indazole; 6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-2-amine; 6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-1,3-benzothiazol-2-amine; 6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-thiocyanato-1,3-benzothiazol-2-amine; 6-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-bromo-1,3-benzothiazol-2-amine; N-[4-(3-methyl-1H-indazol-5-yl)phenyl]quinuclidin-3-amine; (R)-3-[6-(3-methyl-1 H-indazol-5-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; (R)-3-[6-(1-methyl-1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-{5-[6-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-1H-indol-3-ylmethyl}-dimethyl-amine; (R)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane 1-oxide; 6-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-benzothiazol-2- ylamine; (3R)-3-[6-(3-bromo-1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-3-[6-(1 H-benzoimidazol-5-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; (S)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-3-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; -110- RECEIVED at IPONZ on 18 March 2010 548231 (3R)-3-[5-(1 H-indol-4-yl)-pyrimidin-2-yloxy]-1 -aza-bicyclo[2.2.2]octane 1 -oxide; (3R)-3-(5-benzooxazol-5-yl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane; (3R)-3-[5-(2-methyl-benzooxazol-5-yl)-pyrimidin-2-yloxy]-1-aza- bicyclo[2.2.2]octane; (3R)-3-[5-(2-ethyl-benzooxazol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; (3R)-3-[5-(2-phenyl-benzooxazol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-5-[2-(1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyrimidin-5-yl]-3H-benzooxazol-2-one; 3-[6-(1H-indol-3-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane; (R)-3-[6-(1 H-indol-3-yl)-pyridazin-3-yloxy]-1 -aza-bicyclo[2.2.2]octane; and (S)-3-[6-(1H-indol-3-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane.

6. The compound of claim 1, wherein the compound is 5-{6-[(3R)-1 -azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1 H-indole.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 6 in combination with a pharmaceutically acceptable carrier.

8. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for selectively modulating the effects of al nicotinic acetylcholine receptors.

9. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for treating a disorder associated with al nicotinic acetylcholine receptors. -111- RECEIVED at IPONZ on 18 March 2010 548231

10. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for 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 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation.

11. The use according to claim 10, wherein the lack of circulation is a lack of circulation around a vascular occlusion.

12. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for treating or preventing a condition or disorder selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia.

13. The use according to any one of claims 8 to 10 and 12, further comprising use of an atypical antipsychotic.

14. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for selectively modulating, in combination with an atypical antipsychotic, the effects of al nicotinic acetylcholine receptors.

15. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for treating, in combination with an atypical antipsychotic, a disorder associated with al nicotinic acetylcholine receptors.

16. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for treating or preventing, in combination with an atypical antipsychotic, -112- RECEIVED at IPONZ on 18 March 2010 548231 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 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation.

17. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for treating or preventing, in combination with an atypical antipsychotic, a condition or disorder selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia.

18. A compound of any one of claims 1 to 6 for selectively modulating the effects of al nicotinic acetylcholine receptors.

19. A compound of any one of claims 1 to 6 for treating a disorder associated with al nicotinic acetylcholine receptors.

20. A compound of any one of claims 1 to 6 for 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 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, inflammatory pain, neuropathic pain, infertility, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation. -113- 548231 RECEIVED at IPONZ on 14 May 2010

21. The compound according to claim 20, wherein the lack of circulation is a lack of circulation around a vascular occlusion.

22. A compound of any one of claims 1 to 6 for treating or preventing a condition or disorder selected from the group consisting of a cognitive disorder, neurodegeneration, and schizophrenia.

23. The compound according to any one of claims 18 to 20 and 22, wherein said compound is in combination with an atypical antipsychotic.

24. A compound, as defined in any one of claims 1, 18 to 20 and 22, substantially as herein described with reference to any example thereof.

25. A pharmaceutical composition, as claimed in claim 7, substantially as herein described with reference to any example thereof.

26. Use, as defined in any one of claims 8 to 10 and 12 or as claimed in any one of claims 14 to 17, substantially as herein described with reference to any example thereof. intellectual property OFFICE OF N.Z I 4 MAY 2010 received J </div>