Title of Invention	FUSED BICYCLOHETEROCYCLE SUBSTITUTED QUINUCLIDINE COMPOUND
Abstract	Compounds 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. The compounds are useful in treating conditions or disorders prevented by or ameliorated by a7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.

Title of Invention

FUSED BICYCLOHETEROCYCLE SUBSTITUTED QUINUCLIDINE COMPOUND

Abstract

Compounds 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. The compounds are useful in treating conditions or disorders prevented by or ameliorated by a7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.

Full Text	FORM 2 The Patents Act, 1970 (39 of 1970) & The Patent Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) "FUSED BICYCLOHETEROCYCLE SIBSTITUTED QUINUCLIDINE DERIVATIVES" Abbott Laboratories, a company incorporated in USA having its Registered Office at Dept. 377 Bldg. AP6A-1, 100 Abbott Park Road, Abbott Park, Illinois 60064-6008, USA. The following specification particularly describes the invention and the manner in which it is to be performed Specification/Claims filed as PCT/US2004/41471 on December 10, 2004 Priority Claim to USSN 10/744,208 filed December 22, 2003 FUSED BICYCLOHETEROCYCLE SUBSTITUTED QUINUCLIDINE DERIVATIVES Technical Field The invention relates to fused bicycloheterocycle substituted quinuclidine 5 derivatives, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions. Description of Related Technology Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout 10 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 15 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. 20 Typically, nAChRs are ion channels that are constructed from a pentameric assembly of subunit proteins. At least 12 subunit proteins, α2-α10 and β2-β4, 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 25 binding of nicotine in brain tissue has composition (α4)2(β2)3 (the α4β2 subtype), while another major population of receptors is comprised of the homomeric (α7)5 (the α7 subtype). -1- or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: n is 0,1,or2; A is N or N+-O-, 5 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: 10 Z , Z , Z , and Z 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 15 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); Y2 is selected from the group consisting of -N(R2), C(=O), -C(R3), and 20 -C(R3)(R3a); Y3 is selected from the group consisting of -N(R2), -C(R3), and -3- 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 5 comprising compounds of the invention. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to nAChR activity, and more particularly a7 nAChR activity. Yet another aspect of the invention relates to a method of selectively 10 modulating to nAChR activity, for example α7 nAChR activity. The method is useful for treating and/or preventing conditions and disorders related to α7 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 15 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 20 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 25 further described herein. DETAILED DESCRIPTION OF THE INVENTION Definition of Terms 30 Certain terms as used in the specification are intended to refer to the following definitions, as detailed below. -5- 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. 5 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 10 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 15 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 atom. Representative examples of alkylcarbonyloxy include, but are not limited to, 20 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. 25 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 30 hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one -7- 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(O)H group. The term "halo" or "halogen", as used herein, means -CI, -Br, -I or -F. 5 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 10 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-fluoroethyi; trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl. The term "heteroaryl" means an aromatic five- or six-membered ring 15 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, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl. 20 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, 25 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 30 groups are connected to the parent molecular moiety through a carbon or nitrogen atom. Representative examples of bicyclic heteroaryl rings include, but are not -9- limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl. The term "(NRARB)sulfonyl", as used herein, means a -NRARB group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, 5 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(O)2- group. The term "thioalkoxy", as used herein, means an alkyl group, as defined 10 herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of thioalkoxy include, but are no 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 α3b4* indicates 15 a receptor that contains the α3 and β4 proteins in combination with other subunits, the term a7 as used herein is intended to include receptors wherein the exact subunit composition is both certain and uncertain. For example, as used herein a7 includes homomeric (α7)5 receptors and α7* receptors, which denote a nAChR containing at least one α7 subunit. 20 Compounds of the Invention Compounds of the invention can have 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: 25 -11- 5 wherein: Z1, Z2r 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); 10 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; -13- 5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-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; 5 6-{4-[(3R)-1 -azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-thiocyanato-1,3- benzothiazol-2-amine; 6-{4-[(3R)-1-azabicycio[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; 1 o (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}- 15 dimethyl-amine; (R)-3-[6-(1 H-intiol-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-1 H-indol-5-yl)-pyridazin-3-yloxy]-1 -aza- 20 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]-pyridazin-3-yl}-1,3-dihydro- indol-2-one; 25 5-{6-[(3R)-1 -aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro- benzoimidazol-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; 30 (R)-3-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane; -15- 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 5 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 oc7 neuronal 10 nicotinic receptors. Moreover, such compounds generally demonstrate more beneficial binding at α7 neuronal nicotinic receptors when compared with a less desireable 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 like to to induce cardiovascular complications 15 associated with hERG, than other ampiphilic molecules demonstrating at α7 neuronal nicotinic receptor binding. Methods for Preparing Compounds of the Invention As used in the descriptions of the schemes and the examples, certain 20 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; Et3N for triethylamine; Et2O for diethyl ether; HPLC for high pressure liquid chromatography; 'Pr for isopropyl; Me for methyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc for 25 acetoxy; o-tol. for o-toluene; Ph for phenyl; t-Bu for tert-butyl; TFA for trifiuoroacetic acid; and THF for tetrahydrofuran. 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 30 modifying the order of the synthetic steps or selecting one particular process scheme -17- Quinuclidine ethers of general formula (8), wherein Ar1 and Ar2 are as defined 5 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 10 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 or diboron 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 15 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 -19- treated with a halide of a desired group Ar2 in the presence of a palladium catalyst to provide compounds of formula (14). 5 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 10 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 15 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 of a phosphine, for example triphenylphosphine, and diethyl azodicarboxylate to provide compounds of formula (8). -21- 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). 5 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- 10 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 15 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 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). -23- 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 5 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 10 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 fused bicycloheterocycle represented by Ar2 of formula (46), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (47). 15 -25- compounds of formula (51), wherein X" is bromide, chloride, or iodide, can be reacted with Cul, Cs2CO3 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 5 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 10 of formula (53), to provide a corresponding compound of formula (57). Compounds of formulas (63) and (64) can be prepared as shown in Scheme 15 9. 3-Quinuclidinone and a halobiarylamine of formula (60), wherein X' is bromide, chloride, or iodide, can be treated with sodium triacetate borohydride and Na2SO4in -27- 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 5 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). 10 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 methods described in Scheme 11. 3-Chloroquinuclidine can be reacted with a 15 halobiarylthiol of formula (70), wherein X" is bromide, chloride, iodide, NO2, 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 -29- (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, 5 chloride, or iodide, to provide compounds of formula (77). 10 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. -31- 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 5 shown in Scheme 14. Compounds of formula (89), which are obtained by treating 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). 10 Compounds of formula (91) are deprotected under standard nitrogen-deprotection conditions to obtain compounds of formula (92). Scheme 15 -33- 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. 5 The compounds and intermediates of the invention 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 10 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. 15 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, 20 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. 25 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 30 acceptable carriers. The pharmaceutical compositions can be formulated for oral -35- 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, 5 wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It also can be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought 10 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 15 material with poor water solubility. The rate of absorption of the drug can depend upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline 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 20 agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof. If desired, and for more effective distribution, the compounds of the invention can be incorporated into slow-release or targeted-delivery systems such as polymer 25 matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use. Injectable depot forms are made by forming microencapsulated matrices of 30 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, -37- 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 5 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 10 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- 15 irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at arnbient 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. 20 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, 25 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. 30 Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, -39- The compounds of the invention can be used in the form of pharmaceutical^ 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 5 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, 10 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 15 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- 20 hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such 25 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. 30 Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, -41- The term "pharmaceutically acceptable amide," as used herein, refers to nontoxic amides of the invention derived from ammonia, primary C1-to-C6 alkyl amines and secondary C-i-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 5 atom. Amides derived from ammonia, C1-to-C3 alkyl primary amides and C1-to-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 10 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, 15 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 20 prodrug. The term "pharmaceutically acceptable prodrug" or "prodrug," as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and 25 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., 30 Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). -43- injury. For example, the impaired function of α7 nAChRs by β-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 α7 nAChRs has been shown to block 5 this neurotoxicity (Kihara, T. et al., J. Biol. Chem. 276: 13541-13546, 2001). As such, selective ligands that enhance a7 activity can counter the deficits of 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 10 of α7 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 α7 nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189-202, 1998; Stevens, K. E. et al., 15 Psychopharmacology 136: 320-327,1998). Thus, a7 ligands demonstrate potential in the treatment schizophrenia. Angiogenesis, a process involved in the growth of new blood vessels, is important in beneficial systemic functions, such as wound healing, vascularization of skin grafts, and enhancement of circulation, for example, increased circulation 20 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 α7 nAChR (Heeschen, C. et al, J. Clin. Invest. 110: 527-536, 2002). Therefore, nAChR ligands that are selective for the α7 subtype offer improved potential for stimulating 25 angiogenesis with an improved side effect profile. A population of α7 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 α7 nAChR ligands demonstrate therapeutic potential for the treatment of 30 pain states, including acute pain, post-surgical pain, as well as chronic pain states -45- including inflammatory pain and neuropathic pain. Moreover, α7 nAChRs are expressed on the surface of primary macrophages that are involved in the inflammation response, and that activation of the α7 receptor inhibits release of TNF and other cytokines that trigger the inflammation response (Wang, H. et al Nature 5 421: 384-388, 2003). Therefore, selective α7 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 α7 nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J.-H. and Meizel, S. 10 Biol. Reproduct. 68: 1348-1353 2003). Consequently, selective α7 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 15 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 a7 receptors. (Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 2002). Thus, 20 activators of oc7 receptors can provide useful treatment for enhancing cognitive function in schizophrenic patients who are being treated with atypical antipsychotics. Accordingly, the combination of an α7 nAChR ligand and an atypical antipsychotic would offer improved therapeutic utility. Specific examples of suitable atypical antipsychotics include, but are not limited to, clozapine, risperidone, olanzapine, 25 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 30 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 -46- 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. 5 EXAMPLES Example 1 3-[4-(1 –Azabicvclo[2.2.2]oct-3-yloxy)phenyl1-1 H-indole 10 Example 1A 3-(4-lodophenoxv)quinuclidine 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 15 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 : NH3H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) δ 1.40-1.56 (m, 1H), 1.64-1.80 (m, 2H), 20 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)+. Example 1B 25 3-[4-(1 –Azabicvclo[2.2.2]oct-3-vloxv)phenyl]-1 H-indole 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 K2C03 (180 mg, 1.3 mmol) in DMSO (3 mL) was stirred at 40 °C under N2 for 2 hours. The reaction was monitored 30 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 -48- compound was purified by flash chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.35) as solid (300 mg, yield, 82%). 1H NMR (300 MHz, CD3OD) δ 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) 5 ppm. MS (DCI/NH3): m/z 364 (M+H)\ 366 (M+H)+, 368 (M+H)+. Example 2B 4-[4-(1-Azabicvclo[2.2.2loct-3-vloxv)phenyl]-1H-indole The product of 2A (300 mg, 0.8 mmol), 4-bromoindole (Aldrich, 196 mg, 1 10 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 15 chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.30) as a solid (48 mg, yield, 19%). 1KNMR (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) 20 ppm. MS (DCI/NH3): m/z 319 (M+H)+. Example 2C 4-[4-(1 -Azabicvclo[2.2.2loct-3-yloxy)phenvn-1 H-indole fumarate The product of Example 2B (48 mg, 0.15 mmol) was treated with fumaric acid 25 (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 MHzr CD3OD) δ 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, 30 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) -50- 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 C21H22N2O.C4H4O4: C, 69.11; H, 6.03; N, 6.45. Found: C, 69.23; H, 5.81; N, 6.59. 5 Example 4 5-(4-[(3R)-1 -Azabicvclor2.2.2]oct-3-vloxv]phenyl}-1 H-indole Example 4A (3RV3-Quinuclidinol 10 (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 CHCl3/PrOH (v. 10 : 1, 3 x 200 mL). The extracts were combine, washed with brine (50 mL) and dried over MgSO4. The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the 15 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/z128(M+H)+. 20 Example 4B (3R)-3-(4-Bromophenoxv)quinuclidine 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 : NH3-H20, 25 90:10:1, Rf. 0.30) as solid (400 mg, yield, 14%). 1H NMR (300 MHz, CP3OD) 5 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)+. 30 Example 4C 5-(4-[(3R)-1-Azabicvclo[2.2.2]oct-3-yloxvlphenyl)-1 H-indole -52- 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/z319(M+H)+. 5 Example 5B 6-[4-(1-Azabicvclo[2.2.2loct-3-vloxv)phenyl]-1H-indole fumarate T 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. 10 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, 15 5.84; N, 5.97. Found: C, 67.15; H, 5.99; N, 5.95. Example 6 2-[4-(1 –Azabicvclo[2.2.2]oct-3-vloxv)phenvl-1 H-indole 20 Example 6A 3-(4-Ethynylphenoxv)quinuclidine 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 25 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 30 by chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) 6 1.42-1.54 (m, 1H), 1.61-1.87 -54- Example 6D 2-[4-( 1 –Azabicyclo[2.2.2]oct-3-vloxv)phenyl]-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. 5 The title compound was obtained as solid (87 mg, yield, 89%). 1H NMR (300 MHz, CD3OD) δ 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 C21H22N2CM.I C4H404: 10 C, 68.39; H, 5.96; N, 6.28'. Found: C, 68.10; H, 6.22; N, 6.25. Example 7 5-[6-(1-Azabicyclo[2.2.2]oct-3-yloxy)pvridazin-3-yl]-1 H-indole 15 Example 7A 3-[(6-Chloropyridazin-3-yl)oxy]quinuclidine 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 20 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 CHCI3/'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 : NH3H20, 25 90:10:1, Rf. 0.45) as a solid (780 mg, yield, 82%). 1H NMR (300 MHz, CD3OD) 6 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)+. 30 Example 7B 5-[6-(1-Azabicyclo[2.2.2]oct-3-yloxy)pvridazin-3-yl]-1 H-indole -56- 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 5 compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) δ 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 10 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/z321 (M+H)+. Example 8B 4-[6-(1 -Azabicyclor2.2.2]oct-3-vloxv)pyridazin-3-yl]1-1 H-indole fumarate 15 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) δ 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, 20 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 C19H2oN4O-1.3C4H404: C, 61.67; H, 5.39; N, 11.89. Found: C, 61.49; H, 5.52; N, 12.17. 25 Example 9 5-(6-[(3R)-1-Azabicyclor[2.2.2]oct-3-vloxylpyridazin-3-vl)-1 H-indole Example 9A (3R)-3-r(6-Chloropvridazin-3-yl)oxv1quinuclidine 30 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 -58- Example 10 5-(6-[(3R)-1-Azabicvclo[2.2.2]oct-3-vloxylpyridazin-3-yl)-3-methyl-1H-indole Example 10A 5 3-Methyl-5-(4.4.5,5-tetramethvl-1.3.2-dioxaborolan-2-vn-1H-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)CH2CI2 (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 10 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 purified by flash chromatography (SiO2, 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. 15 MS (DCI/NH3): m/z 258 (M+H)+. Example 10B 5-(6-[(3R)-1-Azabicvclor[2.2.2]oct-3-vloxv1pyridazin-3-vl)-3-methvl-1 H-indole The product of Example 10A (240 mg, 1 mmol) coupled with the product of 20 Example 9A (250 mg, 1 mmol) according to the procedure in Example 8A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 um, 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), 25 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)+. 30 Example 10C 5-(6-[(3R)-1 –Azabicvclo[2.2.2]oct-3-vloxvlpyridazin-3-yl)-3-methvl-1 H-indole fumarate -60- 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)+. 5 Example 11C 5-(2-[(3R)-1 –Azabicvclo[2.2.2]oct-3-vloxvlpyrimidin-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 10 compound was obtained as solid (42 mg, yield, 88%). 1H NMR (300 MHz, CD3OD) δ 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. 15 for C19H20N4OO.6 C4H4O4: C, 65.90; H, 5.79; N, 14.36. Found: C, 65.65; H, 5.24; N, 14.41. Example 12 4-(2-[(3R)-1-Azabicvclo[2.2.2]oct-3-vloxvlpyrimidin-5-yl)-1 H-indole 20 Example 12A 4-(2-[(3R)-1-Azabicvclo[2.2.2]oct-3-vloxy]pyrimidin-5-yl)-1 H-indole The product of Examplel 11A (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. WO02055517, 146 mg, 0.6 25 mmol) according to the procedure in Example 8A. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H20, 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 30 (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)+. -62- 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 5 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 (3S)-1-Azabicvclo[2.2.2]oct-3-yl benzoate (D)-tartrate 10 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 temperature for 30 min. It was extracted with chloroform (3 x mL) The extracts were combined and dried (MgSO4). The drying agents were filtered off. The filtrates was concentrated to give 3-quinuclidinol benzoate (15.25 g, 66 mmol) It was then treated 15 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 1 A. The title product was obtained (7.0 g, yield, 28%, 92.3% ee). Example 13D 20 (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)+. 25 Example 13E (3S)-3-[(5-Bromopyrimidin-2-yl)oxy]quinuclidine 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 : NH3H20, 30 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, -64- 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 um, 40 x 100 mm. Eluting 5 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)+. 10 Anal. Calculated for C2iH23N3O-1.0 CF3CO2H0.5 H20: C, 60.52; H, 5.52; N, 9.21. Found: C, 60.79; H, 5.39; N, 9.17. Example 15 6-[4-(1-Azabicvclo[2.2.2]oct-3-yloxy)phenyl-1,3-benzothiazol-2-amine 15 Example 15A 3-[(4'-Nitro-1,1'-biphenyl-4-yl)oxy]quinuclidine 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, 20 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 (Si02l CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.20) as solid (400 mg, yield, 62%). 1H NMR ( 300 MHz , CD3OD) 5 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H), 2.17-2.24 25 (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 30 4'-(1 –Azabicyclo[2.2.2]oct-3-vloxy)-1.1 '-biphenyl-4-amine -66- 1H NMR (300 MHz, DMSO-D6) δ 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.)f 2H], 7.96 (d, J=1.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 352 (M+H)+. Anal. Calculated for 5 C20H21N3OS2.O8 CF3CO2H C, 49.30; H, 3.95; N, 7.14. Found: C, 49.70; H, 3.42; N, 7.03. Example 16 6-[4-[(3R)-1-Azabicvclo[2.2.2]oct-3-yloxvlphenyl)-1.3-benzothiazol-2-amine 10 Example 16A (3R)-3-[(4'-Nitro-1.1'-biphenyl-4-vl)oxy]quinuclidine 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 (SiO2, CH2CI2: MeOH : NH3.H2O, 15 90:10:1, Rf. 0.20) as solid (930 mg, yield, 57%). 1H NMR ( 300 MHz , CD3OD) 8 1.45-1.57 (m, 1H)4, 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)+. 20 Example 16B 4'-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxyl-1.1'-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 25 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) 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 30 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)+. -68- 5 H). 3.74 - 3.90 (m, 1 H), 4.93 (dd, J=9.2, 5.1 Hz, 1 H), 6.96 - 7.23 (m, 2 H) 7.48 -7.70 (m, 3 H) 7.88 (d, J=1.7 Hz, 1 H) ppm. MS (DCI/NH3): m/z 409 (M+H)+. Example 18 5 6-(4-[(3R)-1-Azabicvclo[2.2.2]oct-3-yloxvlphenvl)-4-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 µL, 0.90 mmol, in HOAc (1 mL) was added slowly to the above solution over 5 min. 10 according to procedure of Example 16C. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 urn, 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 (50 mg, yield, 9%). 1H NMR (300 MHz, MeOH-D4) 6 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 15 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+H)+. Anal. Calculated for C2oH20BrN3OS-2.00 CF3C02H C, 43.78; H, 3.37; N, 6.38. Found: C, 44.70; H, 3.42; N, 6.32. 20 Example 19 N-[4-(3-Methvl-1H-indazol-5-yl)phenvl]quinuclidin-3-amine Example 19A N-(4-lodophenvl)quinuclidin-3-amine 25 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 NaHCO3 and stirred for 20 30 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 -70- 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%). 1H NMR (MeOH-d4, 300 MHz) 0.23 - 0.45 (m, 9 H) 1.71 (s, 9 H) 2.59 (s, 3 H) 7.67 (d, J=8.1 Hz, 1 H) 7.87 (s, 1 H) 8.06 (d, J=8.5 Hz, 1 H) ppm. 5 MS (DCI/NH3) m/z 397(M+H)+. Example 20B (R)-3-f6-(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 10 of Example 20A (278 mg,-0.7 mmol) under the catalysis of by Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol) and ('Bu3P)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 15 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 urn, 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 20 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, J=9.2 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.05 (dd, J=8.8, 1.4 Hz, 1 H) 8.16 (d, J=9.2 Hz, 1 H) 8.31 (s, 1 H) ppm. MS (DCI/NH3) m/z 336 (M+H)+. 25 Example 20C (RV3-r6-(3-Methvl-1H-indazol-5-vn-pvridazin-3-vloxv1-1-aza-bicvclo[2.2.21octane 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 30 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 -72- 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 concentrated and the title product was purified by preparative HPLC (Xterra™, 5 column, Xterra RP-18 5 urn, 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, J=9.5 Hz, 1 10 H), 7.49 (s, 1 H), 7.56 (d, J=8.5 Hz, 1 H), 7.81 (dd, J=8.5, 1.7 Hz, 1 H), 8.15 (d, J=9.5 Hz, 1 H), 8.29 (s, 1 H) ppm. MS (DCI/NH3) m/z 378(M+H)+. Example 22B (R)-{5-[6-(1-Aza-bicvclo[2.2.2]oct-3-vloxv)-pvridazin-3-yl-]1H-indol-3-ylmethyl)- 15 dimethyl-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 20 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, J=9.2 Hz, 1 H), 7.54 - 7.63 (m, 2 H), 7.84 (dd, J=8.5, 1.7 Hz, 1 H), 8.17 (d, J=9.2 Hz, 1 H), 8.35 (s, 1 H) ppm. MS (DCI/NH3) m/z 378(M+H)+. Anal. Calculated for C22H27N5O2.5 C4H4O4O.5 H20: C, 56.80; H, 5.66; N, 10.35. Found: C, 56.62; H, 5.78; N, 10.09. 25 Example 23 (R)-3-[6-(1H-lndol-5-yl)-pyridazin-3-vloxvl-1-aza-bicvclo[2.2.2]octane 1- oxidetrifluoroacetate The product of Example 9B was treated with H2O2 (Aldrich, aq. 30% 1 mL, 30 8.8 mmol) in acetonitrile (3 mL) for 5 h. The mixture was quenched by Na2SO3 solution carefully until no more peroxide was noticed, and it was then concentrated -74- J=9.8 Hz, 1 H) ppm. MS (DCI/NH3) m/z 251 (M+H)+, 253 (M+H)\ 268 (M+NH4)+, 270 (M+NH4)+. Example 24C 5 3-(4-Bromo-phenyl)-6-chloro-pvridazine The product of Example 24B (25.Og, 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 10 50 mL) and dried under vacuum to give the title compound (26.2 g, 98%). 1H NMR (MeOH-D4, 300 MHz) 8 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)+. 15 Example 24D (3R)-3-[6-(4-Bromo-phenyl-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane The product of Example 24C (2.43 g, 9 mmol) was coupled with the product of Example 4A (1.27g, 10 mmol) using t-BuOK (Aldrich, 1.12g, 10 mmol) as base in THF (anhydrous, Aldrich, 50 mL) according to the procedure of Example 7A. The title 20 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 25 (DCI/NH3) m/z 360 (M+H)\ 362 (M+H)+. Example 24E (4-[6-[(3R)-1-Aza-bicvclo[2.2.2]oct-3-vloxvl-pyridazin-3-yl]-phenyll-benzhydrylidene- amine 30 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 -76- 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, J=9.2 Hz, 1 H), 7.49 (d, J=8.5 Hz, 1 H), 7.87 (dd, J=8.6, 1.9 Hz, 1 H), 8.07 (d, J=9.5 Hz, 1 H), 8.23 (d, J=1.4 Hz, 1 H) ppm. MS (DCI/NH3): 354 (M+H)+. 5 Example 24H 6-(6-[(3R)1-Aza-bicvclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl)-benzothiazol-2-ylamine tri(hydroqen 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 10 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, J=14.2, 8.1 Hz, 1 H), 5.41 - 5.71 (m, 1 H), 7.50 (d, J=9.2 Hz, 1 H), 7.68 (d, J=8.8 Hz, 1 H), 8.16 (dd, J=8.5, 1.7 Hz, 1 H), 8.26 (d, J=9.2 Hz, 1 H), 8.48 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3): 354 (M+H)+. Anal. Calculated 15 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-f6-(3-Bromo-1H-indol-5-vn-pyridazin-3-vloxvl-1-aza-bicvclor2.2.2loctane 20 trifhydroqen chloride) Example 25A (3R)-3-[6-(3-Bromo-1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10 25 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 : NH3H2C\ 90:10:1, Rf. 0.15) as a solid (70 30 mg, yield, 35%). 1H NMR (300 MHz, CD3OD) δ 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, -78- (s, 3 H), 1.34 (s, 6 H), 3.69 (s, 2 H), 6.86 (d, J=7.Q Hz, 1 H), 7.57 - 7.78 (m, 2 H) ppm. MS (DCI/NH3): 260 (M+H)+. Example 26B 5 5-(6-[(3R)-1 -Aza-bicvclo[2.2.2]oct-3-vloxv]-pyridazin-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 PdCI2(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 10 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 - 15 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, 2JH), 8.01 (d, J=9.2 Hz, 1 H) ppm. MS (DCI/NH3): 337 (M+Hf. Example 26C 5-(6-[(3R)-1-Aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-vl)-1.3-dihvdro-indol-2-one 20 bis(hydroqen 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), 25 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, J=6.1 Hz , 1 H), 7.77 (d, J=9.2 Hz, 1 H), 7.82 - 7.97 (m, 1 H), 8.46 (d, J=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. 30 Example 27 -80- Example 28A (4-Bromo-2-nitro-phenvl)-carbamic acid tert-butyl 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 5 refluxing 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) δ1.40 (S, 9 H), 7.21 (d, J=8.5 Hz, 1 H), 7.76 (dd, J=8.4, 2.3 Hz, 1 H), 8.21 (d, J=2.1 Hz, 1 H) ppm. MS (DCI/NH3): 334 (M+H)+, 336 (M+H)+. 10 Example 28B [2-Nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert- butyl ester The product of Example 28A (10.05 g, 30 mmol) was coupled with with bis(pinacolato)diboron (Aldrich, 9.14 g, 36 mmol) under the catalysis of 15 PdCI2(dppf)2CH2CI2 (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) 6 1.37 (s, 9 H), 1.38 (s, 12 H), 7.99 (d, J=1.4 Hz, 1 H), 8.02 (d, J=1.4 20 Hz, 1 H), 8.45 (d, J=1.4 Hz, 1 H) ppm. MS (DCI/NH3): 382 (M+NH4)+. Example 28C (4-(6-[(3R)-1-Aza-bicyclo[2.2.2]oct-3-yloxyl-pyridazin-3-yl]-2-nitro-phenyl)-carbamic acid tert-butyl ester 25 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 (lBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) 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 30 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, -82- Example 28F 5-(6-[(3R)-1-Aza-bicvclo[2.2.2loct-3-vloxv1-pyridazin-3-yl}-1.3-dihydro-benzoimidazol- 2-one trifluroacetate The product of Example 28E (62 mg, 0.2 mmol) was treated with 1,1'- 5 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 urn, 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) δ 10 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, J=7.6 Hz, 1 H), 7.62 - 7.78 (m, 2 H), 8.00 (d, J=7.0 Hz, 1 H), 8.65 (d, J=7.3 Hz, 1 H) ppm; MS (DCI/NH3): 338 (M+H)+. Anal. Calculated for C18Hi9N502 1.15 CF3CO2H -2.30 H20: C, 47.81; H, 4.89; N, 13.73. Found: C, 47.69; H, 5.27; N, 14.09. 15 Example 29 (R)-3-[6-(1H-Benzoimidazol-5-yl)-pyridazin-3-vloxvl-1-aza-bicvclo[2.2.2]octane Example 29A 20 (R)-N-[4-[6-(1-Aza-bicvclo[2.2.2]oct-3-yloxy)-pvridazin-3-yl]—phenyl}-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 25 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 chromatography (Si02, 5% methanol containing 1% NH4OH -CH2CI2) to provide the 30 title compound (203 mg, 79%).1H NMR (300 MHz, CD3OD) 5 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, J=6.5, 3.6 Hz, 1 H), 3.33 - -84- H), 2.34 (td, J=6.4, 3.6 Hz, 1 H), 2.80 - 3.03 (m, 6 H), 3.50 (ddd, .7=14.5, 8.1, 1.5 Hz, 1 H), 5.32 (m, 1 H), 7.28 (d, J=9.2 Hz, 1 H), 7.74 (d, J=8.5 Hz, 1 H), 7.91 (d, J=8.5 Hz, 1 H), 8.11 (d, J=9.2 Hz, 1 H), 8.22 (s, 1 H), 8.25 (s, 1 H) ppm; MS (DCI/NH3): m/z 322 (M+H)+. 5 Example 30 (S)-3-r6-(1H-lndol-5-yl)-pyridazin-3-vloxv1-1-aza-bicvclor2.2.21octane Fumarate Example 30A 10 (S)-3-(6-Chloro-pyridazin-3-vloxv)-1-aza-bicvclo[2.2.21octane 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 : NH3H2O, 90:10:2, Rf. 0.30) as solid (346 mg, 72%). 1H NMR (300 MHz, MeOH-D4) 15 5 1.47 -1.63 (m, J=12.9 Hz, 1 H), 1.65 -1.92 (m, 2 H), 1.94 - 2.10 (m,J=5.9, 3.6 Hz, 1 H), 2.22 - 2.32 (rp, J=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, J=9.2 Hz, 1 H), 7.65 (d, J=9.5 Hz, 1 H) ppm. MS (DCI/NH3) m/z 240 (M+H)+, 242 (M+H)+. 20 Example 30B (S)-3-r6-(1H-lndol-5-yl-pyridazin-3-yloxy]-1-aza-bicvclo[2.2.2loctane 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- 25 18 5 urn, 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 (200 mg, 57%). 1H NMR (300 MHz, MeOH-D4) 5 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, J=14.7, 8.2, 1.9 Hz, 1 H), 5.24 - 5.34 (m, 1 H), 6.56 (d, J=4.1 Hz, 1 H), 7.24 (d, J=9.5 Hz, 1 30 H), 7.30 (d, J=3.4 Hz, 1 H), 7.50 (d, J=8.5 Hz, 1 H), 7.73 (dd, J=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)+. -86- of Example 29A. The title compound was preparative HPLC (Xterra™, column, Xterra RP-18, 5 urn, 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-d4, 300 MHz) 1.86 - 2.22 (m, 3 H), 2.31 - 2.46 (m, 1 H), 5 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, J=2.4 Hz, 1 H), 6.93 (d, J=8.5 Hz, 1 H), 7.24 - 7.35 (m, 2 H), 7.46 (d, J=8.5 Hz, 1 H), 7.74 (d, J=1.7 Hz, 1 H), 8.00 (dd, J=8.6, 2.5 Hz, 1 H), 8.38 (d, J=2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 320(M+H)+. Anal. Calculated for C20H21N3CM.I4 CF3CO2H: C, 59.55; H, 4.97; N, 9.35. Found: C, 59.59; H, 4.99; N, 9.03. 10 Example 32 (3R)-3-[5-(1H-lndol-4-yl-pyrimidin-2-vloxy]-1-aza-bicvclor[2.2.2]loctane 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 15 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, J=4.0 Hz, 1 H), 7.12 (d, J=8.0 Hz, 1 H), 7.23 (t, J=8.0 Hz, 1 H), 7.36 (d, J=3.0 Hz, 1 H), 7.47 (d, J=8.0 Hz, 1 H), 8.96 (s, 2 H) ppm. 20 Example 33 (3R)-3-(5-Benzooxazol-5-yl-pvrimidin-2-vloxv)-1-aza-bicvclo[2.2.2]octane bis(hydroqen chloride) 25 Example 33A 1-Benzyloxv-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 30 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-88- 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 5 (3R)-3-(5-Benzooxazol-5-vl-pvrimidin-2-vloxv)-1-aza-bicyclo[2.2.2]octane 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 urn, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M, 10 pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mUmin., uv, 250 nm) as solid (50.0 mg, 78%). 1H NMR (300 MHz, CD3-OD) 5 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)+. 15 Example 33F (3R)-3-(5-Benzooxazol-5-vl-pyrimidin-2-vloxv)-1-aza-bicvclo[2.2.2]octane bis(hydrogen chloride) The product of Example 33E (50 mg, 0.15 mmol) was treated with HCI 20 (Aldrich, 4M in dioxane, 0.50 mL, 2.0 mmol) in EtOAc (5 mL) at ambient temperature for 1 hour to afford the title compound as yellow solid (55.0 mg, 93%). 1H NMR (300 MHz, CD3-OD) δ 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, J=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): 25 323 (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-[5-(2-Methvl-benzooxazol-5-yl)-pyrimidin-2-vloxv1-1-aza-bicvclo[2.2.2]octane 30 hydrogen chloride -90- Example 35A (3R)-3-[5-(2-Ethvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvclo[2.2.2]octane 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 5 concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 urn, 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 (20.0 mg, 30%). 1H NMR (500 MHz, CD3OD) 5 1.45 (t, J=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 10 (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, J= 8.5, 1.7 Hz, 1 H) 7.69 (d, J= 8.6 Hz, 1 H), 7.89 (d, J=1.2 Hz, 1 H), 8.82 - 8.90 (m, 2 H) ppm; MS (DCI/NH3): 351 (M+H)+. Example 35B 15 (3R)-3-[5-(2-Methvl-benzooxazol-5-vl)-pyrimidin-2-vloxvl-1-aza-bicvclo[2.2.2]octane bis(hydroqen 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 20 MHz, CD3-OD) δ 1.46 (t, J=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, J=7.6 Hz, 2 H), 3.22 - 3.56 (m, 5 H), 3.92 (dd, J=13.6, 8.7 Hz, 1 H), 4.99 - 5.63 (m, 1 H), 7.63 (d, J=8.5 Hz, 1 H), 7.71 (d, J=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, 25 13.13. Example 36 (3R)-3-[5-(2-Phenyl-benzooxazol-5-yl)-pvrimidin-2-vloxy]-1-aza-bicyclo[2.2.2]octane bishydroqen chloride) 30 -92- 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 urn, 30 x 100 mm. Eluting 5 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 (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)+. 10 Example 37B (R)-5-[2-(1-Aza-bicvclo[2.2.2]oct-3-vloxv)-pvrimidin-5-yl-3H-benzooxazol-2-one bis(hydrochloride) The product of Example 37A (60 mg, 0.18 mmol) was treated with HCI 15 (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) δ 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 C18H18N403 20 -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. Example 38 (R)-3-[6-M-Aza-bicyclo[2.2.2]oct-3-yloxy)-pvridazin-3-yl]-9H-carbazole 25 Example 38A 3-(4.4.5.5-Tetramethyl-[1,3,2]dioxaborolan-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 30 [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, -94- (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 (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 5 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/z321(M+H)+. Example 39B 3-f6-(1H-lndol-3-vl)-pvridazin-3-vloxv1-1-aza-bicyclo[2.2.21octane hemifumarate 10 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-D4l 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 - 15 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 for C19H2oN400.5 C4O4H40.35 H20: C, 65.56; H, 5.95; N, 14.56. Found: C, 65.49; H, 6.21; N, 14.34. 20 Example 40 (R)-3-r6-(1H-lndol-3-vn-pvridazin-3-yloxv1-1-aza-bicvclor2.2.2loctanefumarate The product of Example 4A (127 mg, 1 mmol) was coupled with 3-(6-chloro-pyridazin-3-yl)-1/-/-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 25 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, J=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, J=7.1 Hz, 1 H), 7.90 (s, 1 H), 8.07 (d, J=9.2 Hz, 1 H), 8.30 (d, J=7.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 321(M+H)+. Anal. Calculated for C19H20N4O-2.1 C4O4H40.35 EtOAc: C, 58.14; H, 5.29; N, 9.42. 30 Found: C, 57.91; H, 5.35; N, 9.42. -96- (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 CaCI2/2 mM MgCI2). Packard MicroScint-20® scintillation cocktail (40 µL) was added to each well and radioactivity determined using a 5 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 Kj = IC5o/1+[Ligand]/KD]. [3H1-Methvllvcaconitine (MLA) binding 10 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 ug of protein, 5 nM [3H]-MLA (25 Cj/mmol; Perkin 15 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 uL 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 uM MLA. Bound radioactivity was isolated by vacuum filtration onto glass fiber filter plates 20 prewetted with 2% BSA using a 96-well filtration apparatus (Packard Instruments, Meriden, CT) and were then rapidly rinsed with 2 mL of ice-cold BSS. Packard MicroScint-20® scintillation cocktail (40 uL) 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 25 calculated from the IC50S using the Cheng-Prusoff equation, where Kj = • IC50/1+[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 30 about 50 nanomolar to at least 100 micromolar. The determination of preferred compounds typically considered the Ki value as measured by MLA assay in view of -98- 1. A compound of the formula (I): or a pharmaceutical^ acceptable salt, ester, amide, or prodrug thereof, wherein: n is 0, 1, or 2; A is N or N+-CT; 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: Z1, 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; -100- R3b and R3c 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. 2. The compound of claim 1, wherein Ar1 is a group of the formula: wherein: X1, X2, X3, and X are each independently selected from the group consisting of N and -CR10; and 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: -102- 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, R3b, R8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, and Z16 are as defined in claim 1. 5. The compound of claim 1, or a pharmaceutically acceptable salt, ester, amide, or prodrug 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; -104- 5-{6-[(3R)-1-oxy-1-Aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro- indol-2-one; 5-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro- benzoimidazol-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-(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; (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-bicyclo[2.2.2]octane. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier. 7. A method of selectively modulating the effects of a.7 nicotinic acetylcholine receptors in a mammal comprising administering an effective amount of a compound of claim 1. -106- ABSTRACT Compounds of formula (I) wherein n is 0,1, or 2; A is N or N+-0"; X is O, S, -NH-, and -N-alkyl-; Ar1 is a 6-membered aromatic ring; and Ar2 is a fused bicycloheterocycle. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions. -108-

Full Text

FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"FUSED BICYCLOHETEROCYCLE SIBSTITUTED QUINUCLIDINE DERIVATIVES"
Abbott Laboratories, a company incorporated in USA having its Registered Office at Dept. 377 Bldg. AP6A-1, 100 Abbott Park Road, Abbott Park, Illinois 60064-6008, USA.
The following specification particularly describes the invention and the manner in which it is to be performed

Specification/Claims filed as PCT/US2004/41471 on
December 10, 2004
Priority Claim to USSN 10/744,208 filed December 22, 2003

FUSED BICYCLOHETEROCYCLE SUBSTITUTED QUINUCLIDINE DERIVATIVES
Technical Field
The invention relates to fused bicycloheterocycle substituted quinuclidine
5 derivatives, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.
Description of Related Technology
Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout
10 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
15 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.
20 Typically, nAChRs are ion channels that are constructed from a pentameric
assembly of subunit proteins. At least 12 subunit proteins, α2-α10 and β2-β4, 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
25 binding of nicotine in brain tissue has composition (α4)2(β2)3 (the α4β2 subtype),
while another major population of receptors is comprised of the homomeric (α7)5 (the α7 subtype).
-1-

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
n is 0,1,or2;
A is N or N+-O-,
5 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:

10 Z , Z , Z , and Z 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
15 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);
Y2 is selected from the group consisting of -N(R2), C(=O), -C(R3), and
20 -C(R3)(R3a);
Y3 is selected from the group consisting of -N(R2), -C(R3), and
-3-

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
5 comprising compounds of the invention. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to nAChR activity, and more particularly a7 nAChR activity.
Yet another aspect of the invention relates to a method of selectively
10 modulating to nAChR activity, for example α7 nAChR activity. The method is useful for treating and/or preventing conditions and disorders related to α7 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
15 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
20 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
25 further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
30 Certain terms as used in the specification are intended to refer to the following
definitions, as detailed below.
-5-

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.
5 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
10 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
15 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 atom. Representative examples of alkylcarbonyloxy include, but are not limited to,
20 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.
25 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
30 hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one
-7-

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(O)H group.
The term "halo" or "halogen", as used herein, means -CI, -Br, -I or -F.
5 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
10 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-fluoroethyi; trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "heteroaryl" means an aromatic five- or six-membered ring
15 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, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl.
20 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,
25 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
30 groups are connected to the parent molecular moiety through a carbon or nitrogen atom. Representative examples of bicyclic heteroaryl rings include, but are not
-9-

limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
The term "(NRARB)sulfonyl", as used herein, means a -NRARB group, as defined herein, appended to the parent molecular moiety through a sulfonyl group,
5 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(O)2- group.
The term "thioalkoxy", as used herein, means an alkyl group, as defined 10 herein, appended to the parent molecular moiety through a sulfur atom.
Representative examples of thioalkoxy include, but are no 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 α3b4* indicates
15 a receptor that contains the α3 and β4 proteins in combination with other subunits, the term a7 as used herein is intended to include receptors wherein the exact subunit composition is both certain and uncertain. For example, as used herein a7 includes homomeric (α7)5 receptors and α7* receptors, which denote a nAChR containing at least one α7 subunit.
20
Compounds of the Invention
Compounds of the invention can have 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:
25
-11-

5 wherein:
Z1, Z2r 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);
10 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;
-13-

5-{2-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyrimidin-5-yl}-1H-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;
5 6-{4-[(3R)-1 -azabicyclo[2.2.2]oct-3-yloxy]phenyl}-4-thiocyanato-1,3-
benzothiazol-2-amine;
6-{4-[(3R)-1-azabicycio[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;
1 o (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}-
15 dimethyl-amine;
(R)-3-[6-(1 H-intiol-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-1 H-indol-5-yl)-pyridazin-3-yloxy]-1 -aza-
20 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]-pyridazin-3-yl}-1,3-dihydro-
indol-2-one;
25 5-{6-[(3R)-1 -aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro-
benzoimidazol-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;
30 (R)-3-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane;
-15-

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
5 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 oc7 neuronal
10 nicotinic receptors. Moreover, such compounds generally demonstrate more beneficial binding at α7 neuronal nicotinic receptors when compared with a less desireable 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 like to to induce cardiovascular complications
15 associated with hERG, than other ampiphilic molecules demonstrating at α7 neuronal nicotinic receptor binding.
Methods for Preparing Compounds of the Invention
As used in the descriptions of the schemes and the examples, certain
20 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; Et3N for triethylamine; Et2O for diethyl ether; HPLC for high pressure liquid chromatography; 'Pr for isopropyl; Me for methyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc for
25 acetoxy; o-tol. for o-toluene; Ph for phenyl; t-Bu for tert-butyl; TFA for trifiuoroacetic acid; and THF for tetrahydrofuran.
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
30 modifying the order of the synthetic steps or selecting one particular process scheme
-17-

Quinuclidine ethers of general formula (8), wherein Ar1 and Ar2 are as defined
5 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
10 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 or diboron 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
15 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
-19-

treated with a halide of a desired group Ar2 in the presence of a palladium catalyst to provide compounds of formula (14).

5
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
10 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
15 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 of a phosphine, for example triphenylphosphine, and diethyl azodicarboxylate to provide compounds of formula (8).
-21-

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).
5

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-
10 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
15 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 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).
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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
5 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
10 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 fused bicycloheterocycle represented by Ar2 of formula (46), wherein X' is bromide, chloride, or iodide, to provide compounds of formula (47).
15
-25-

compounds of formula (51), wherein X" is bromide, chloride, or iodide, can be reacted with Cul, Cs2CO3 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
5 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
10 of formula (53), to provide a corresponding compound of formula (57).

Compounds of formulas (63) and (64) can be prepared as shown in Scheme
15 9. 3-Quinuclidinone and a halobiarylamine of formula (60), wherein X' is bromide, chloride, or iodide, can be treated with sodium triacetate borohydride and Na2SO4in
-27-

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
5 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).

10

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 methods described in Scheme 11. 3-Chloroquinuclidine can be reacted with a
15 halobiarylthiol of formula (70), wherein X" is bromide, chloride, iodide, NO2, 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
-29-

(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,
5 chloride, or iodide, to provide compounds of formula (77).

10 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.
-31-

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
5 shown in Scheme 14. Compounds of formula (89), which are obtained by treating 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).
10 Compounds of formula (91) are deprotected under standard nitrogen-deprotection conditions to obtain compounds of formula (92).

Scheme 15

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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.
5 The compounds and intermediates of the invention 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
10 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.
15 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,
20 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.
25 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
30 acceptable carriers. The pharmaceutical compositions can be formulated for oral
-35-

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,
5 wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It also can be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought
10 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
15 material with poor water solubility. The rate of absorption of the drug can depend upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline 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
20 agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
If desired, and for more effective distribution, the compounds of the invention can be incorporated into slow-release or targeted-delivery systems such as polymer
25 matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
Injectable depot forms are made by forming microencapsulated matrices of
30 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,
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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
5 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
10 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-
15 irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at arnbient 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.
20 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,
25 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.
30 Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders, solutions,
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The compounds of the invention can be used in the form of pharmaceutical^ 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
5 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,
10 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
15 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-
20 hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
Also, the basic nitrogen-containing groups can be quatemized with such
25 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.
30 Examples of acids which can be employed to form pharmaceutically
acceptable acid addition salts include such inorganic acids as hydrochloric acid,
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The term "pharmaceutically acceptable amide," as used herein, refers to nontoxic amides of the invention derived from ammonia, primary C1-to-C6 alkyl amines and secondary C-i-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
5 atom. Amides derived from ammonia, C1-to-C3 alkyl primary amides and C1-to-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
10 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,
15 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
20 prodrug.
The term "pharmaceutically acceptable prodrug" or "prodrug," as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and
25 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.,
30 Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
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injury. For example, the impaired function of α7 nAChRs by β-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 α7 nAChRs has been shown to block
5 this neurotoxicity (Kihara, T. et al., J. Biol. Chem. 276: 13541-13546, 2001). As such, selective ligands that enhance a7 activity can counter the deficits of 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
10 of α7 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 α7 nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189-202, 1998; Stevens, K. E. et al.,
15 Psychopharmacology 136: 320-327,1998). Thus, a7 ligands demonstrate potential in the treatment schizophrenia.
Angiogenesis, a process involved in the growth of new blood vessels, is important in beneficial systemic functions, such as wound healing, vascularization of skin grafts, and enhancement of circulation, for example, increased circulation
20 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 α7 nAChR (Heeschen, C. et al, J. Clin. Invest. 110: 527-536, 2002). Therefore, nAChR ligands that are selective for the α7 subtype offer improved potential for stimulating
25 angiogenesis with an improved side effect profile.
A population of α7 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 α7 nAChR ligands demonstrate therapeutic potential for the treatment of
30 pain states, including acute pain, post-surgical pain, as well as chronic pain states
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including inflammatory pain and neuropathic pain. Moreover, α7 nAChRs are expressed on the surface of primary macrophages that are involved in the inflammation response, and that activation of the α7 receptor inhibits release of TNF and other cytokines that trigger the inflammation response (Wang, H. et al Nature
5 421: 384-388, 2003). Therefore, selective α7 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 α7 nAChR on the sperm cell has been shown to be essential for the acrosome reaction (Son, J.-H. and Meizel, S.
10 Biol. Reproduct. 68: 1348-1353 2003). Consequently, selective α7 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
15 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 a7 receptors. (Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 2002). Thus,
20 activators of oc7 receptors can provide useful treatment for enhancing cognitive
function in schizophrenic patients who are being treated with atypical antipsychotics. Accordingly, the combination of an α7 nAChR ligand and an atypical antipsychotic would offer improved therapeutic utility. Specific examples of suitable atypical antipsychotics include, but are not limited to, clozapine, risperidone, olanzapine,
25 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
30 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
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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.
5 EXAMPLES
Example 1
3-[4-(1 –Azabicvclo[2.2.2]oct-3-yloxy)phenyl1-1 H-indole
10 Example 1A
3-(4-lodophenoxv)quinuclidine
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
15 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 : NH3H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (300 MHz, CD3OD) δ 1.40-1.56 (m, 1H), 1.64-1.80 (m, 2H),
20 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)+.
Example 1B
25 3-[4-(1 –Azabicvclo[2.2.2]oct-3-vloxv)phenyl]-1 H-indole
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 K2C03 (180 mg, 1.3 mmol) in DMSO (3 mL) was stirred at 40 °C under N2 for 2 hours. The reaction was monitored
30 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
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compound was purified by flash chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.35) as solid (300 mg, yield, 82%). 1H NMR (300 MHz, CD3OD) δ 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)
5 ppm. MS (DCI/NH3): m/z 364 (M+H)\ 366 (M+H)+, 368 (M+H)+.
Example 2B
4-[4-(1-Azabicvclo[2.2.2loct-3-vloxv)phenyl]-1H-indole
The product of 2A (300 mg, 0.8 mmol), 4-bromoindole (Aldrich, 196 mg, 1
10 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
15 chromatography (Si02, CH2CI2: MeOH : NH3H2O, 90:10:1, Rf. 0.30) as a solid (48 mg, yield, 19%). 1KNMR (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)
20 ppm. MS (DCI/NH3): m/z 319 (M+H)+.
Example 2C
4-[4-(1 -Azabicvclo[2.2.2loct-3-yloxy)phenvn-1 H-indole fumarate
The product of Example 2B (48 mg, 0.15 mmol) was treated with fumaric acid
25 (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 MHzr CD3OD) δ 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,
30 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)
-50-

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 C21H22N2O.C4H4O4: C, 69.11; H, 6.03; N, 6.45. Found: C, 69.23; H, 5.81; N, 6.59.
5 Example 4
5-(4-[(3R)-1 -Azabicvclor2.2.2]oct-3-vloxv]phenyl}-1 H-indole
Example 4A
(3RV3-Quinuclidinol
10 (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 CHCl3/PrOH (v. 10 : 1, 3 x 200 mL). The extracts were combine, washed with brine (50 mL) and dried over MgSO4. The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the
15 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/z128(M+H)+.
20 Example 4B
(3R)-3-(4-Bromophenoxv)quinuclidine
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 : NH3-H20, 25 90:10:1, Rf. 0.30) as solid (400 mg, yield, 14%). 1H NMR (300 MHz, CP3OD) 5 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)+.
30 Example 4C
5-(4-[(3R)-1-Azabicvclo[2.2.2]oct-3-yloxvlphenyl)-1 H-indole
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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/z319(M+H)+.
5
Example 5B
6-[4-(1-Azabicvclo[2.2.2loct-3-vloxv)phenyl]-1H-indole fumarate T
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.
10 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,
15 5.84; N, 5.97. Found: C, 67.15; H, 5.99; N, 5.95.
Example 6
2-[4-(1 –Azabicvclo[2.2.2]oct-3-vloxv)phenvl-1 H-indole
20 Example 6A
3-(4-Ethynylphenoxv)quinuclidine
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
25 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
30 by chromatography (Si02, CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) 6 1.42-1.54 (m, 1H), 1.61-1.87
-54-

Example 6D
2-[4-( 1 –Azabicyclo[2.2.2]oct-3-vloxv)phenyl]-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.
5 The title compound was obtained as solid (87 mg, yield, 89%). 1H NMR (300 MHz, CD3OD) δ 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 C21H22N2CM.I C4H404:
10 C, 68.39; H, 5.96; N, 6.28'. Found: C, 68.10; H, 6.22; N, 6.25.
Example 7
5-[6-(1-Azabicyclo[2.2.2]oct-3-yloxy)pvridazin-3-yl]-1 H-indole
15 Example 7A
3-[(6-Chloropyridazin-3-yl)oxy]quinuclidine
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
20 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 CHCI3/'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 : NH3H20,
25 90:10:1, Rf. 0.45) as a solid (780 mg, yield, 82%). 1H NMR (300 MHz, CD3OD) 6 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)+.
30 Example 7B
5-[6-(1-Azabicyclo[2.2.2]oct-3-yloxy)pvridazin-3-yl]-1 H-indole
-56-

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
5 compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H2O,
90:10:1, Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) δ 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
10 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/z321 (M+H)+.
Example 8B
4-[6-(1 -Azabicyclor2.2.2]oct-3-vloxv)pyridazin-3-yl]1-1 H-indole fumarate
15 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) δ 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,
20 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 C19H2oN4O-1.3C4H404: C, 61.67; H, 5.39; N, 11.89. Found: C, 61.49; H, 5.52; N, 12.17.
25 Example 9
5-(6-[(3R)-1-Azabicyclor[2.2.2]oct-3-vloxylpyridazin-3-vl)-1 H-indole
Example 9A
(3R)-3-r(6-Chloropvridazin-3-yl)oxv1quinuclidine
30 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
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Example 10
5-(6-[(3R)-1-Azabicvclo[2.2.2]oct-3-vloxylpyridazin-3-yl)-3-methyl-1H-indole
Example 10A
5 3-Methyl-5-(4.4.5,5-tetramethvl-1.3.2-dioxaborolan-2-vn-1H-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)CH2CI2 (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
10 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 purified by flash chromatography (SiO2, 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.
15 MS (DCI/NH3): m/z 258 (M+H)+.

Example 10B
5-(6-[(3R)-1-Azabicvclor[2.2.2]oct-3-vloxv1pyridazin-3-vl)-3-methvl-1 H-indole
The product of Example 10A (240 mg, 1 mmol) coupled with the product of
20 Example 9A (250 mg, 1 mmol) according to the procedure in Example 8A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 um, 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),
25 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)+.
30 Example 10C
5-(6-[(3R)-1 –Azabicvclo[2.2.2]oct-3-vloxvlpyridazin-3-yl)-3-methvl-1 H-indole fumarate
-60-

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)+.
5
Example 11C
5-(2-[(3R)-1 –Azabicvclo[2.2.2]oct-3-vloxvlpyrimidin-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
10 compound was obtained as solid (42 mg, yield, 88%). 1H NMR (300 MHz, CD3OD) δ 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.
15 for C19H20N4OO.6 C4H4O4: C, 65.90; H, 5.79; N, 14.36. Found: C, 65.65; H, 5.24; N, 14.41.
Example 12
4-(2-[(3R)-1-Azabicvclo[2.2.2]oct-3-vloxvlpyrimidin-5-yl)-1 H-indole
20
Example 12A
4-(2-[(3R)-1-Azabicvclo[2.2.2]oct-3-vloxy]pyrimidin-5-yl)-1 H-indole
The product of Examplel 11A (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. WO02055517, 146 mg, 0.6
25 mmol) according to the procedure in Example 8A. The title compound was purified by chromatography (Si02, CH2CI2: MeOH : NH3H20, 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
30 (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)+.
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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
5 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
(3S)-1-Azabicvclo[2.2.2]oct-3-yl benzoate (D)-tartrate
10 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 temperature for 30 min. It was extracted with chloroform (3 x mL) The extracts were combined and dried (MgSO4). The drying agents were filtered off. The filtrates was concentrated to give 3-quinuclidinol benzoate (15.25 g, 66 mmol) It was then treated
15 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 1 A. The title product was obtained (7.0 g, yield, 28%, 92.3% ee).
Example 13D
20 (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)+.
25 Example 13E
(3S)-3-[(5-Bromopyrimidin-2-yl)oxy]quinuclidine
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 : NH3H20,
30 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,
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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 um, 40 x 100 mm. Eluting
5 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)+.
10 Anal. Calculated for C2iH23N3O-1.0 CF3CO2H0.5 H20: C, 60.52; H, 5.52; N, 9.21. Found: C, 60.79; H, 5.39; N, 9.17.
Example 15
6-[4-(1-Azabicvclo[2.2.2]oct-3-yloxy)phenyl-1,3-benzothiazol-2-amine
15
Example 15A
3-[(4'-Nitro-1,1'-biphenyl-4-yl)oxy]quinuclidine
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,
20 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 (Si02l CH2CI2: MeOH : NH3H20, 90:10:1, Rf. 0.20) as solid (400 mg, yield, 62%). 1H NMR ( 300 MHz , CD3OD) 5 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H), 2.17-2.24
25 (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
30 4'-(1 –Azabicyclo[2.2.2]oct-3-vloxy)-1.1 '-biphenyl-4-amine
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1H NMR (300 MHz, DMSO-D6) δ 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.)f 2H], 7.96 (d, J=1.7 Hz, 1H) ppm. MS (DCI/NH3): m/z 352 (M+H)+. Anal. Calculated for
5 C20H21N3OS2.O8 CF3CO2H C, 49.30; H, 3.95; N, 7.14. Found: C, 49.70; H, 3.42; N, 7.03.
Example 16
6-[4-[(3R)-1-Azabicvclo[2.2.2]oct-3-yloxvlphenyl)-1.3-benzothiazol-2-amine
10 Example 16A
(3R)-3-[(4'-Nitro-1.1'-biphenyl-4-vl)oxy]quinuclidine
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 (SiO2, CH2CI2: MeOH : NH3.H2O,
15 90:10:1, Rf. 0.20) as solid (930 mg, yield, 57%). 1H NMR ( 300 MHz , CD3OD) 8 1.45-1.57 (m, 1H)4, 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)+.
20
Example 16B
4'-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxyl-1.1'-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
25 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) 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
30 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)+.
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5 H). 3.74 - 3.90 (m, 1 H), 4.93 (dd, J=9.2, 5.1 Hz, 1 H), 6.96 - 7.23 (m, 2 H) 7.48 -7.70 (m, 3 H) 7.88 (d, J=1.7 Hz, 1 H) ppm. MS (DCI/NH3): m/z 409 (M+H)+.
Example 18
5 6-(4-[(3R)-1-Azabicvclo[2.2.2]oct-3-yloxvlphenvl)-4-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 µL, 0.90 mmol, in HOAc (1 mL) was added slowly to the above solution over 5 min.
10 according to procedure of Example 16C. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 urn, 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 (50 mg, yield, 9%). 1H NMR (300 MHz, MeOH-D4) 6 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
15 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+H)+. Anal. Calculated for C2oH20BrN3OS-2.00 CF3C02H C, 43.78; H, 3.37; N, 6.38. Found: C, 44.70; H, 3.42; N, 6.32.
20 Example 19
N-[4-(3-Methvl-1H-indazol-5-yl)phenvl]quinuclidin-3-amine
Example 19A
N-(4-lodophenvl)quinuclidin-3-amine
25 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 NaHCO3 and stirred for 20
30 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
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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%). 1H NMR (MeOH-d4, 300 MHz) 0.23 - 0.45 (m, 9 H) 1.71 (s, 9 H) 2.59 (s, 3 H) 7.67 (d, J=8.1 Hz, 1 H) 7.87 (s, 1 H) 8.06 (d, J=8.5 Hz, 1 H) ppm.
5 MS (DCI/NH3) m/z 397(M+H)+.
Example 20B
(R)-3-f6-(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
10 of Example 20A (278 mg,-0.7 mmol) under the catalysis of by Pd2(dba)3 (Aldrich, 24 mg, 0.025 mmol) and ('Bu3P)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
15 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 urn, 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
20 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, J=9.2 Hz, 1 H) 7.59 (d, J=8.8 Hz, 1 H) 8.05 (dd, J=8.8, 1.4 Hz, 1 H) 8.16 (d, J=9.2 Hz, 1 H) 8.31 (s, 1 H) ppm. MS (DCI/NH3) m/z 336 (M+H)+.
25 Example 20C
(RV3-r6-(3-Methvl-1H-indazol-5-vn-pvridazin-3-vloxv1-1-aza-bicvclo[2.2.21octane
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
30 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
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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 concentrated and the title product was purified by preparative HPLC (Xterra™,
5 column, Xterra RP-18 5 urn, 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, J=9.5 Hz, 1
10 H), 7.49 (s, 1 H), 7.56 (d, J=8.5 Hz, 1 H), 7.81 (dd, J=8.5, 1.7 Hz, 1 H), 8.15 (d, J=9.5 Hz, 1 H), 8.29 (s, 1 H) ppm. MS (DCI/NH3) m/z 378(M+H)+.
Example 22B
(R)-{5-[6-(1-Aza-bicvclo[2.2.2]oct-3-vloxv)-pvridazin-3-yl-]1H-indol-3-ylmethyl)-
15 dimethyl-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
20 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, J=9.2 Hz, 1 H), 7.54 - 7.63 (m, 2 H), 7.84 (dd, J=8.5, 1.7 Hz, 1 H), 8.17 (d, J=9.2 Hz, 1 H), 8.35 (s, 1 H) ppm. MS (DCI/NH3) m/z 378(M+H)+. Anal. Calculated for C22H27N5O2.5 C4H4O4O.5 H20: C, 56.80; H, 5.66; N, 10.35. Found: C, 56.62; H, 5.78; N, 10.09.
25
Example 23
(R)-3-[6-(1H-lndol-5-yl)-pyridazin-3-vloxvl-1-aza-bicvclo[2.2.2]octane 1- oxidetrifluoroacetate
The product of Example 9B was treated with H2O2 (Aldrich, aq. 30% 1 mL,
30 8.8 mmol) in acetonitrile (3 mL) for 5 h. The mixture was quenched by Na2SO3
solution carefully until no more peroxide was noticed, and it was then concentrated
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J=9.8 Hz, 1 H) ppm. MS (DCI/NH3) m/z 251 (M+H)+, 253 (M+H)\ 268 (M+NH4)+, 270 (M+NH4)+.
Example 24C
5 3-(4-Bromo-phenyl)-6-chloro-pvridazine
The product of Example 24B (25.Og, 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
10 50 mL) and dried under vacuum to give the title compound (26.2 g, 98%). 1H NMR (MeOH-D4, 300 MHz) 8 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)+.
15 Example 24D
(3R)-3-[6-(4-Bromo-phenyl-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane
The product of Example 24C (2.43 g, 9 mmol) was coupled with the product of Example 4A (1.27g, 10 mmol) using t-BuOK (Aldrich, 1.12g, 10 mmol) as base in THF (anhydrous, Aldrich, 50 mL) according to the procedure of Example 7A. The title
20 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
25 (DCI/NH3) m/z 360 (M+H)\ 362 (M+H)+.
Example 24E
(4-[6-[(3R)-1-Aza-bicvclo[2.2.2]oct-3-vloxvl-pyridazin-3-yl]-phenyll-benzhydrylidene-
amine
30 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
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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, J=9.2 Hz, 1 H), 7.49 (d, J=8.5 Hz, 1 H), 7.87 (dd, J=8.6, 1.9 Hz, 1 H), 8.07 (d, J=9.5 Hz, 1 H), 8.23 (d, J=1.4 Hz, 1 H) ppm. MS (DCI/NH3): 354 (M+H)+.
5 Example 24H
6-(6-[(3R)1-Aza-bicvclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl)-benzothiazol-2-ylamine
tri(hydroqen 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
10 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, J=14.2, 8.1 Hz, 1 H), 5.41 - 5.71 (m, 1 H), 7.50 (d, J=9.2 Hz, 1 H), 7.68 (d, J=8.8 Hz, 1 H), 8.16 (dd, J=8.5, 1.7 Hz, 1 H), 8.26 (d, J=9.2 Hz, 1 H), 8.48 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3): 354 (M+H)+. Anal. Calculated
15 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-f6-(3-Bromo-1H-indol-5-vn-pyridazin-3-vloxvl-1-aza-bicvclor2.2.2loctane
20 trifhydroqen chloride)
Example 25A
(3R)-3-[6-(3-Bromo-1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane
The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10
25 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 : NH3H2C\ 90:10:1, Rf. 0.15) as a solid (70
30 mg, yield, 35%). 1H NMR (300 MHz, CD3OD) δ 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,
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(s, 3 H), 1.34 (s, 6 H), 3.69 (s, 2 H), 6.86 (d, J=7.Q Hz, 1 H), 7.57 - 7.78 (m, 2 H) ppm. MS (DCI/NH3): 260 (M+H)+.
Example 26B
5 5-(6-[(3R)-1 -Aza-bicvclo[2.2.2]oct-3-vloxv]-pyridazin-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 PdCI2(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
10 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 -
15 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, 2JH), 8.01 (d, J=9.2 Hz, 1 H) ppm. MS (DCI/NH3): 337 (M+Hf.
Example 26C
5-(6-[(3R)-1-Aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-vl)-1.3-dihvdro-indol-2-one
20 bis(hydroqen 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),
25 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, J=6.1 Hz , 1 H), 7.77 (d, J=9.2 Hz, 1 H), 7.82 - 7.97 (m, 1 H), 8.46 (d, J=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.
30
Example 27
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Example 28A
(4-Bromo-2-nitro-phenvl)-carbamic acid tert-butyl 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
5 refluxing 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) δ1.40 (S, 9 H), 7.21 (d, J=8.5 Hz, 1 H), 7.76 (dd, J=8.4, 2.3 Hz, 1 H), 8.21 (d, J=2.1 Hz, 1 H) ppm. MS (DCI/NH3): 334 (M+H)+, 336 (M+H)+.
10 Example 28B
[2-Nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-
butyl ester
The product of Example 28A (10.05 g, 30 mmol) was coupled with with bis(pinacolato)diboron (Aldrich, 9.14 g, 36 mmol) under the catalysis of
15 PdCI2(dppf)2CH2CI2 (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) 6 1.37 (s, 9 H), 1.38 (s, 12 H), 7.99 (d, J=1.4 Hz, 1 H), 8.02 (d, J=1.4
20 Hz, 1 H), 8.45 (d, J=1.4 Hz, 1 H) ppm. MS (DCI/NH3): 382 (M+NH4)+.
Example 28C
(4-(6-[(3R)-1-Aza-bicyclo[2.2.2]oct-3-yloxyl-pyridazin-3-yl]-2-nitro-phenyl)-carbamic
acid tert-butyl ester
25 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 (lBu3P)2Pd (26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) 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
30 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,
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Example 28F
5-(6-[(3R)-1-Aza-bicvclo[2.2.2loct-3-vloxv1-pyridazin-3-yl}-1.3-dihydro-benzoimidazol-
2-one trifluroacetate
The product of Example 28E (62 mg, 0.2 mmol) was treated with 1,1'-
5 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 urn, 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) δ
10 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, J=7.6 Hz, 1 H), 7.62 - 7.78 (m, 2 H), 8.00 (d, J=7.0 Hz, 1 H), 8.65 (d, J=7.3 Hz, 1 H) ppm; MS (DCI/NH3): 338 (M+H)+. Anal. Calculated for C18Hi9N502 1.15 CF3CO2H -2.30 H20: C, 47.81; H, 4.89; N, 13.73. Found: C, 47.69; H, 5.27; N, 14.09.
15
Example 29
(R)-3-[6-(1H-Benzoimidazol-5-yl)-pyridazin-3-vloxvl-1-aza-bicvclo[2.2.2]octane
Example 29A
20 (R)-N-[4-[6-(1-Aza-bicvclo[2.2.2]oct-3-yloxy)-pvridazin-3-yl]—phenyl}-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
25 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 chromatography (Si02, 5% methanol containing 1% NH4OH -CH2CI2) to provide the
30 title compound (203 mg, 79%).1H NMR (300 MHz, CD3OD) 5 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, J=6.5, 3.6 Hz, 1 H), 3.33 -
-84-

H), 2.34 (td, J=6.4, 3.6 Hz, 1 H), 2.80 - 3.03 (m, 6 H), 3.50 (ddd, .7=14.5, 8.1, 1.5 Hz, 1 H), 5.32 (m, 1 H), 7.28 (d, J=9.2 Hz, 1 H), 7.74 (d, J=8.5 Hz, 1 H), 7.91 (d, J=8.5 Hz, 1 H), 8.11 (d, J=9.2 Hz, 1 H), 8.22 (s, 1 H), 8.25 (s, 1 H) ppm; MS (DCI/NH3): m/z 322 (M+H)+.
5
Example 30
(S)-3-r6-(1H-lndol-5-yl)-pyridazin-3-vloxv1-1-aza-bicvclor2.2.21octane Fumarate
Example 30A
10 (S)-3-(6-Chloro-pyridazin-3-vloxv)-1-aza-bicvclo[2.2.21octane
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 : NH3H2O, 90:10:2, Rf. 0.30) as solid (346 mg, 72%). 1H NMR (300 MHz, MeOH-D4)
15 5 1.47 -1.63 (m, J=12.9 Hz, 1 H), 1.65 -1.92 (m, 2 H), 1.94 - 2.10 (m,J=5.9, 3.6 Hz, 1 H), 2.22 - 2.32 (rp, J=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, J=9.2 Hz, 1 H), 7.65 (d, J=9.5 Hz, 1 H) ppm. MS (DCI/NH3) m/z 240 (M+H)+, 242 (M+H)+.
20 Example 30B
(S)-3-r6-(1H-lndol-5-yl-pyridazin-3-yloxy]-1-aza-bicvclo[2.2.2loctane
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-
25 18 5 urn, 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 (200 mg, 57%). 1H NMR (300 MHz, MeOH-D4) 5 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, J=14.7, 8.2, 1.9 Hz, 1 H), 5.24 - 5.34 (m, 1 H), 6.56 (d, J=4.1 Hz, 1 H), 7.24 (d, J=9.5 Hz, 1
30 H), 7.30 (d, J=3.4 Hz, 1 H), 7.50 (d, J=8.5 Hz, 1 H), 7.73 (dd, J=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)+.
-86-

of Example 29A. The title compound was preparative HPLC (Xterra™, column, Xterra RP-18, 5 urn, 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-d4, 300 MHz) 1.86 - 2.22 (m, 3 H), 2.31 - 2.46 (m, 1 H),
5 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, J=2.4 Hz, 1 H), 6.93 (d, J=8.5 Hz, 1 H), 7.24 - 7.35 (m, 2 H), 7.46 (d, J=8.5 Hz, 1 H), 7.74 (d, J=1.7 Hz, 1 H), 8.00 (dd, J=8.6, 2.5 Hz, 1 H), 8.38 (d, J=2.7 Hz, 1 H) ppm. MS (DCI/NH3) m/z 320(M+H)+. Anal. Calculated for C20H21N3CM.I4 CF3CO2H: C, 59.55; H, 4.97; N, 9.35. Found: C, 59.59; H, 4.99; N, 9.03.
10
Example 32
(3R)-3-[5-(1H-lndol-4-yl-pyrimidin-2-vloxy]-1-aza-bicvclor[2.2.2]loctane 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
15 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, J=4.0 Hz, 1 H), 7.12 (d, J=8.0 Hz, 1 H), 7.23 (t, J=8.0 Hz, 1 H), 7.36 (d, J=3.0 Hz, 1 H), 7.47 (d, J=8.0 Hz, 1 H), 8.96 (s, 2 H) ppm.
20
Example 33
(3R)-3-(5-Benzooxazol-5-yl-pvrimidin-2-vloxv)-1-aza-bicvclo[2.2.2]octane
bis(hydroqen chloride)
25 Example 33A
1-Benzyloxv-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
30 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-88-

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
5 (3R)-3-(5-Benzooxazol-5-vl-pvrimidin-2-vloxv)-1-aza-bicyclo[2.2.2]octane
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 urn, 30 x 100 mm. Eluting Solvent, MeCN / H20 (NH4HCO3, 0.1 M,
10 pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mUmin., uv, 250 nm) as solid (50.0 mg, 78%). 1H NMR (300 MHz, CD3-OD) 5 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)+.
15
Example 33F
(3R)-3-(5-Benzooxazol-5-vl-pyrimidin-2-vloxv)-1-aza-bicvclo[2.2.2]octane
bis(hydrogen chloride)
The product of Example 33E (50 mg, 0.15 mmol) was treated with HCI
20 (Aldrich, 4M in dioxane, 0.50 mL, 2.0 mmol) in EtOAc (5 mL) at ambient temperature for 1 hour to afford the title compound as yellow solid (55.0 mg, 93%). 1H NMR (300 MHz, CD3-OD) δ 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, J=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):
25 323 (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-[5-(2-Methvl-benzooxazol-5-yl)-pyrimidin-2-vloxv1-1-aza-bicvclo[2.2.2]octane
30 hydrogen chloride
-90-

Example 35A
(3R)-3-[5-(2-Ethvl-benzooxazol-5-vl)-pvrimidin-2-vloxv1-1-aza-bicvclo[2.2.2]octane
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
5 concentrated. The title product was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 urn, 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 (20.0 mg, 30%). 1H NMR (500 MHz, CD3OD) 5 1.45 (t, J=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
10 (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, J= 8.5, 1.7 Hz, 1 H) 7.69 (d, J= 8.6 Hz, 1 H), 7.89 (d, J=1.2 Hz, 1 H), 8.82 - 8.90 (m, 2 H) ppm; MS (DCI/NH3): 351 (M+H)+.
Example 35B
15 (3R)-3-[5-(2-Methvl-benzooxazol-5-vl)-pyrimidin-2-vloxvl-1-aza-bicvclo[2.2.2]octane
bis(hydroqen 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
20 MHz, CD3-OD) δ 1.46 (t, J=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, J=7.6 Hz, 2 H), 3.22 - 3.56 (m, 5 H), 3.92 (dd, J=13.6, 8.7 Hz, 1 H), 4.99 - 5.63 (m, 1 H), 7.63 (d, J=8.5 Hz, 1 H), 7.71 (d, J=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,
25 13.13.
Example 36
(3R)-3-[5-(2-Phenyl-benzooxazol-5-yl)-pvrimidin-2-vloxy]-1-aza-bicyclo[2.2.2]octane
bishydroqen chloride)
30
-92-

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 urn, 30 x 100 mm. Eluting
5 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 (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)+.
10
Example 37B
(R)-5-[2-(1-Aza-bicvclo[2.2.2]oct-3-vloxv)-pvrimidin-5-yl-3H-benzooxazol-2-one
bis(hydrochloride)
The product of Example 37A (60 mg, 0.18 mmol) was treated with HCI
15 (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) δ 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 C18H18N403 20 -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.
Example 38
(R)-3-[6-M-Aza-bicyclo[2.2.2]oct-3-yloxy)-pvridazin-3-yl]-9H-carbazole
25
Example 38A
3-(4.4.5.5-Tetramethyl-[1,3,2]dioxaborolan-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
30 [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,
-94-

(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 (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
5 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/z321(M+H)+.
Example 39B 3-f6-(1H-lndol-3-vl)-pvridazin-3-vloxv1-1-aza-bicyclo[2.2.21octane hemifumarate
10 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-D4l 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 -
15 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 for C19H2oN400.5 C4O4H40.35 H20: C, 65.56; H, 5.95; N, 14.56. Found: C, 65.49; H, 6.21; N, 14.34.
20 Example 40
(R)-3-r6-(1H-lndol-3-vn-pvridazin-3-yloxv1-1-aza-bicvclor2.2.2loctanefumarate The product of Example 4A (127 mg, 1 mmol) was coupled with 3-(6-chloro-pyridazin-3-yl)-1/-/-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
25 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, J=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, J=7.1 Hz, 1 H), 7.90 (s, 1 H), 8.07 (d, J=9.2 Hz, 1 H), 8.30 (d, J=7.1 Hz, 1 H) ppm. MS (DCI/NH3) m/z 321(M+H)+. Anal. Calculated for C19H20N4O-2.1 C4O4H40.35 EtOAc: C, 58.14; H, 5.29; N, 9.42.
30 Found: C, 57.91; H, 5.35; N, 9.42.
-96-

(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 CaCI2/2 mM MgCI2). Packard MicroScint-20® scintillation cocktail (40 µL) was added to each well and radioactivity determined using a
5 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 Kj = IC5o/1+[Ligand]/KD].
[3H1-Methvllvcaconitine (MLA) binding
10 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 ug of protein, 5 nM [3H]-MLA (25 Cj/mmol; Perkin
15 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 uL 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 uM MLA. Bound radioactivity was isolated by vacuum filtration onto glass fiber filter plates
20 prewetted with 2% BSA using a 96-well filtration apparatus (Packard Instruments, Meriden, CT) and were then rapidly rinsed with 2 mL of ice-cold BSS. Packard MicroScint-20® scintillation cocktail (40 uL) 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
25 calculated from the IC50S using the Cheng-Prusoff equation, where Kj = • IC50/1+[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
30 about 50 nanomolar to at least 100 micromolar. The determination of preferred compounds typically considered the Ki value as measured by MLA assay in view of
-98-

1. A compound of the formula (I):

or a pharmaceutical^ acceptable salt, ester, amide, or prodrug thereof, wherein:
n is 0, 1, or 2;
A is N or N+-CT;
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:

Z1, 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;
-100-

R3b and R3c 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.
2. The compound of claim 1, wherein Ar1 is a group of the formula:

wherein:
X1, X2, X3, and X are each independently selected from the group consisting of N and -CR10; and
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:
-102-

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, R3b, R8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, and Z16 are as defined in claim 1.
5. The compound of claim 1, or a pharmaceutically acceptable salt, ester, amide, or prodrug 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;
-104-

5-{6-[(3R)-1-oxy-1-Aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro-
indol-2-one;
5-{6-[(3R)-1-aza-bicyclo[2.2.2]oct-3-yloxy]-pyridazin-3-yl}-1,3-dihydro-
benzoimidazol-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-(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;
(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-bicyclo[2.2.2]octane.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
7. A method of selectively modulating the effects of a.7 nicotinic acetylcholine receptors in a mammal comprising administering an effective amount of a compound of claim 1.
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ABSTRACT
Compounds of formula (I)
wherein n is 0,1, or 2; A is N or N+-0"; X is O, S, -NH-, and -N-alkyl-; Ar1 is a 6-membered aromatic ring; and Ar2 is a fused bicycloheterocycle. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.
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FUSED BICYCLOHETEROCYCLE SUBSTITUTED QUINUCLIDINE COMPOUND

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