MXPA06007189A

MXPA06007189A - Fused bicycloheterocycle substituted quinuclidine derivatives

Info

Publication number: MXPA06007189A
Application number: MXPA/A/2006/007189A
Authority: MX
Inventors: L Nersesian Diana; Ji Jianguo; H Mortell Kathleen; R Schrimpf Michael; Li Tao; Pan Liping
Original assignee: Abbott Laboratories; Ji Jianguo; Li Tao; H Mortell Kathleen; L Nersesian Diana; Pan Liping; R Schrimpf Michael
Priority date: 2003-12-22
Filing date: 2006-06-22
Publication date: 2006-12-13

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 ar e pharmaceutical compositions having compounds of formula (I) and methods for using such compounds and compositions.

Description

QUINUCLIDINE DERIVATIVES REPLACED WITH FUSED BICICLOHETEROCICLO Technical Field The invention relates to quinuclidine derivatives substituted with fused bicycloheterocycle, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions.

Description of Related Technology Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central (CNS) and peripheral (SNP) nervous systems. Such receptors play an important role in regulating CNS function, particularly by modulating the release of a wide range of neurotransmitters, including, but not necessarily limited to acetylcholine, norepinephrine, dopamine, serotonin and GABA. Consequently, nicotinic receptors mediate a wide range of physiological effects, and have been oriented to the therapeutic treatment of disorders related to cognitive function, learning and memory, neurodegeneration, pain and inflammation, psychosis and sensory block, mood and emotion, among others. Many sub-types of nAChR exist in the CNS and the periphery. Each sub-type has a different effect in regulating the total physiological function. Normally, nAChRs are ion channels that are constructed from a pentameric subunit protein assembly. At least 12 subunit proteins, a2-a10 and ß2-ßA, have been identified in neuronal tissue. These subunits provide a wide variety of homomeric and heteromeric combinations that determine the various receptor subtypes. For example, the predominant receptor that is responsible for the high-affinity binding of nicotine in brain tissue has composition (a4) 2 (/? 2) 3 (subtype a4 /? 2), while another larger population of receptors is comprised of (a7) 5 homomeric (subtype a7). Certain compounds, similar to the alkaloid nicotine of plants, interact with all subtypes of the nAChRs, being responsible for the deep physiological effects of this compound. Although nicotine has been shown to have many beneficial properties, not all effects mediated by nicotine are desirable. For example, nicotine exerts gastrointestinal and cardiovascular side effects that interfere with the therapeutic dose, and its addictive nature and acute toxicity are well known. Ligands that are selective for interaction with only certain nAChR subtypes offer firmness to achieve beneficial therapeutic effects with an improved margin for safety. It has been shown that the nAChRs of a7 play a notable role in improving cognitive function, including aspects of learning, memory and attention (Levin, E.D., J. Neurobiol, 53: 633-640, 2002). For example, nAChRs of a7 have been linked to conditions and disorders related to attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), moderate cognitive impairment, senile dementia, dementia associated with Lewy bodies, dementia associated with Down syndrome, AIDS dementia, Pick disease, as well as cognitive deficit with schizophrenia, among other systemic activities. The activity in nAChRs of a7 can be modified or regulated by the administration of ligands of nAChR of a7. The ligands may exhibit antagonist, agonist, partial agonist or inverse agonist properties. Thus, a7 ligands are strong in the treatment of various cognitive disorders. Although several classes of compounds demonstrating that the a7 nAChR modulation activity exists, it would be beneficial to provide additional compounds demonstrating the activity in nAChRs of a7 that can be incorporated into pharmaceutical compositions useful for therapeutic methods. Specifically, it would be beneficial to provide compounds that interact selectively with the neuronal nAChRs containing a7 compared to other subtypes.

BRIEF DESCRIPTION OF THE INVENTION The invention is directed to quinuclidine compounds substituted with fused bicycloheterocycle as well as to compositions comprising such compounds, and to a method for using same. The compounds of the invention have the formula: 0) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein: n is 0, 1 or 2; A is N or N + -O; X is selected from the group consisting of O, S and -N (R1) -; Ar1 is a 6-membered aromatic ring which contains 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: (a) (b) or (c) Z Z2, Z3 and Z4 are independently selected from the group consisting of C and -C (R3b); as long as zero or one of Z \ Z2, Z3 and Z4 is C; Z5, Z6, Z7 and Z8 are independently selected from the group consisting of C and -C (R3); as long as 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); as long as one of Z9, Z10, Z11, Z12, Z13, Z14, Z15 and Z16 is C and the group of formula (c) is linked to Ar1 through the C atom; Y1 in each case 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 -C (R3) (R3a); Y3 is selected from the group consisting of -N (R2), -C (R3) and -C (R3) (R3a); provided that zero or one of Y1, Y2 and Y3 is -C (R3) in a group of the formula (a); wherein when one of Y1, Y2 and Y3 is -C (R3) in a group of the formula (a), then Z1, Z2, Z3 and Z4 are each -C (R3b) and the group of the formula (a ) binds to Ar through the C atom of -C (R3) of Y1, Y2 or Y3; and also when one of Z1, Z2, Z3 and Z4 is C, then Y1, Y2 and Y3 are different from -C (R3) and the group of the formula (a) is attached to Ar through the C atom of Z1 , Z2, Z3 or Z4; 2a and 3a are independent of the group consisting of N, C and -C (R3a); as long as Y1 is -C (R3) in a group of the formula (b), Y2a and Y3a are selected from the group consisting of N and -C (R3a), and when one of Y2a and Y3a is C, then Y1 in a group of the formula (b) is O, S, -N (R2) or -C (R3) (R3a); wherein, when one of Z5, Z6, Z7 and Z8 is C, then Y1 in a group of formula (b) is selected from the group consisting of O, S, -N (R2) and -C (R3 ) (R3a); Y2a and Y3a are each independently selected from the group consisting of N and -C (R3a); and the group of the formula (b) is attached to Ar1 through the C of Z5, Z6, Z7 or Z8; and also where when Y1 in a group of the formula (b) is -C (R3) or one of Y2a and Y3a is C, then Z5, Z6, Z7 and Z8 are each -C (R3b) and the group of Formula (b) binds Ar1 through the C-atom of -C (R3) of Y1 in the group of formula (b) or through the C atom of Y2a or Y3a. R1 and R2 in each case are each independently selected from the group consisting of hydrogen and alkyl; R and R in each case are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4, -NR5R6, -alkyl-OR4 and -alkyl-NR5R6; R 3b R | 3cC in each case are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR 4, -NR 5 R 6, -alkyl-OR 4, -alkyl-NR 5 R 6 and -SCN; R 4 is selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl and arylcarbonyl; R5 and R6 in each case are independently selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl and arylcarbonyl, provided that at least one of R5 and R6 is hydrogen or alkyl; and R8 is selected from the group consisting of hydrogen and alkyl. Another aspect of the invention relates to pharmaceutical compositions comprising compounds of the invention. Such compositions can be administered according to a method of the invention, normally as part of the therapeutic regimen for the treatment or prevention of conditions and disorders related to the activity of the nAChR, and more particularly the activity of the nAChR of a7. Yet another aspect of the invention relates to a method for selectively modulating nAChR activity, e.g., nAChR activity of a7. The method is useful for treating and / or preventing conditions and disorders related to the modulation of nAChR activity of a7 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), moderate cognitive impairment, senile dementia, AIDS dementia, Pick, dementia associated with Lewy bodies, dementia associated with Down syndrome, amyotrophic lateral escolerosis, Huntington's disease, decreased CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, neuropathic pain, infertility, need for new blood vessel development associated with wound healing, need for new blood vessel development associated with vascularization of skin grafts, and lack of circulation, more particularly circulation around vascular occlusion, among other systemic activities . The compounds, compositions comprising the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms Certain terms as used in the specification are intended to refer to the following definitions, as detailed below. The term "acyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of acyl include, but are not limited to acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl. The term "acyloxy," as used herein, means an acyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of acyloxy include, but are not limited to acetyloxy, propionyloxy and isobutyryloxy. The term "alkenyl", as used herein, means a straight or branched chain hydrocarbon which contains from 2 to 10 carbon atoms and which contains at least one carbon-carbon double bond formed by the removal of two carbon atoms. hydrogens. Representative examples of alkenyl include, but are not limited to ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and -Decenl The term "alkoxy," as used herein, means an alkyl group as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy. The term "alkoxyalkoxy", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy and methoxymethoxy. The term "alkoxyalkyl", as defined herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl. The term "alkoxycarbonyl", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C (O) -, as defined at the moment. Representative examples of alkoxycarbonyl include, but are not limited to methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl. The term "alkoxyimino," as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative examples of alkoxyimino include, but are not limited to, ethoxy (imino) methyl and methoxy (imino) methyl. The term "alkoxysulfonyl", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxlsulfonyl. The term "alkyl", as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl . The term "alkylcarbonyl", as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl. The term "alkylcarbonyloxy", as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy. The term "alkylsulfonyl", as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to methylsulfonyl and ethylsulfonyl. The term "alkylthio", as used herein, means an alkyl group, as defined herein, attached to the progenitor molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited to methylthio, ethylthio, tert-butylthio and hexylthio. The term "alkynyl", as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propylene, 2-propynyl, 3-butynyl, 2-pentynyl. and 1-butinyl. The term "amido", as used herein, means an am alkylamor dialkylamgroup attached to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of amido include, but are not limited to amarbonyl, methylamarbonyl, dialkyl amarbonyl and ethylmethylamarbonyl. The term "aryl", as used herein, means a monocyclic or bicyclic aromatic ring system. Representative examples of aryl include, but are not limited to phenyl and naphthyl. The aryl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyim alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, am carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy, -NRARB. (NRARB) alkyl, (NRARB) alkoxy, (NRARB) carbonyl and (NRARB) sulfonyl.

The term "arylcarbonyl", as used herein, means an aryl group, as defined herein, or a benzyl group attached to the progenitor molecular moiety through a carbonyl group, represented by -C (O) - , as defined herein. Representative examples of arylcarbonyl include, but are not limited to, phenylcarbonyl and benzylcarbonyl. The term "aryloxycarbonyl", as used herein, means an aryl-O- group, wherein the aryl-aryl-O- is as defined herein, or a benzyloxy group attached to the parent molecular moiety through of a carbonyl group, represented by -C (O) -, as defined herein. Representative examples of aryloxycarbonyl include, but are not limited to, phenoxycarbonyl and benzyloxycarbonyl. The term "aryisulfonyl", as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to phenylsulfonyl, (methylamhenyl) sulfonyl, (dimethylamhenyl) sulfonyl and (naphthyl) sulfonyl. The term "carbonyl", as used herein, means a group -C (O) -. The term "carboxy", as used herein, means a group -CO2H. The term "cyano", as used herein, means a -CN group. The term "formyl," as used herein, means a group -C (0) H. The term "halo" or "halogen", as used herein, means -Cl, -Br, -I or -F.

The term "haloalkoxy", as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to chloromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy. The term "haloalkyl" as defined herein, means at least one halogen, as defined herein, attached to the progenitor molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl. The term "heteroaryl" means a five or six membered aromatic ring, which contains 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, thiazolyl, thienyl, triazinyl and triazolyl. The heteroaryl groups of the invention are substituted with 0, 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl , haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB) alky, (NRARB) alkoxy, (NRARB) carbonyl and (NRARB) sulfonyl. The term "bicyclic heteroaryl" refers to aromatic 9- and 10-membered aromatic rings, which contain 1, 2 3 or 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a tautomer thereof. The bicyclic heteroaryl groups are connected to the parent molecular moiety through a carbon or nitrogen atom. Representative examples of bicyclic heteroaryl rings include, but are not limited to indolyl, benzothiazolyl, benzofuranyl, isoquinolinyl and quinolinyl. Bicyclic heteroaryl groups of the invention are substituted with 0, 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB) alkyl, (NRARB) alkoxy, (NRARB) carbonyl and (NRARB) sulfonyl. The term "hydroxy", as used herein, means an -OH group. The term "hydroxyalkyl," as used herein, means at least one hydroxy group, as defined herein, is attached to the progenitor molecular moiety through an alkyl group as defined herein. Representative examples of hydroalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl and 2-ethyl-4-hydroxyheptyl. The term "mercapto", as used herein, means a -SH group. The term "nitro" as used herein, means a group -N02. The term "-NRARB", as used herein, means two groups, RA and RB, which are attached to the parent molecular moiety through a nitrogen atom. RA and RB are each independently hydrogen, alkyl, alkylcarbonyl or formyl. Representative examples of -NRARB include, but are not limited to amino, methylamino, acetylamino and acetylmethylamino. The term "(NRARB) alkyl", as used herein, means a group -NRARB, as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein. Representative examples of (NRARB) akyl include, but are not limited to, (amino) methyl, (dimethylamino) methyl and (ethylamino) methyl. The term "(NRARB) alkoxy," as used herein, means a group -NRAR8, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of (NRARB) alkoxy include, but are not limited to (amino) methoxy, (dimethylamino) methoxy and (diethylamino) ethoxy.

The term "(NRARB) carbonyl", as used herein, means a group -NRARB, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRARB) carbonyl include, but are not limited to aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl and (ethylmethylamino) carbonyl. The term "(NRARB) suphonyl", as used herein, means a group -NRARB, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of (NRARB) sulfonyl include, but are not limited to, aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl and (ethylmethylamino) sulfonyl. The term "sulfonyl", as used herein, means a group -S (0) 2-. The term "thioalkoxy," as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of thioalkoxy include, but are not limited to methylthio, ethylthio and propylthio. Although it can be normally recognized that an asterisk is used to indicate that the exact subunit composition of a receptor is uncertain, for example, a3b4 * denotes a receptor that contains the a3 and ßA proteins in combination with other subunits, the term a7 as used herein, it is intended to include receptors in which the exact subunit composition is both true and uncertain. For example, as used herein a7 includes homomeric receptors (a7) 5 and a7 * receptors, which denote a nAChR containing at least one a7 subunit.

Compounds of the Invention The compounds of the invention may have the formula (I) as described above. More particularly, the compounds of the formula (I) may include, but are not limited to, compounds wherein Ar 1 is a group of the formula: (b) In a group of the formula (b), X1, X2, X3 and X4 are each independently selected from the group consisting of N and -CR10, wherein R10 in each case is independently selected from the group consisting of hydrogen and I rent. Preferably, at least one of X1, X2, X3 and X4 is -CR10, so that the group of formula (b) contains 0, 1, 2 or 3 nitrogen atoms. Specific examples of the groups for Ar1 are for example, and the like.

Specific examples of the groups for Ar2 in a compound of formula (I) are, for example, Vii) (V) (vi) ((viii) (ix) wherein: Z1, Z2, Z3 and Z4 are independently selected from the group consisting of C and -C (R3); as long as one of Z1, Z2, Z3 and Z4 is C and formula (ix) binds 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); as long as zero or one of Z5, Z6, Z7 and Z8 is C; ? 2a and? 3a are independently selected from the group consisting of C and -C (R3a); where when one of Z5, Z6, Z7 and Z8 is C, then Y2a and Y3a in the group of formulas (i) - (vii) are each -C (R3a); and each of the group of formulas (i) - (vii) is joined to Ar1 through the C of Z5, Z6, Z7 or Z8; and also where, when one of Y2a and Y3a is C in the group of formulas (¡) - (vii), then Z5, Z6, Z7 and Z8 are each -C (R3b) and each of the group of formulas (i) - (vii) binds Ar1 through the C atom of Y2a or Y3a; and R2, R3, R3a and R3b are as defined for a compound of the formula (I). Also, other specific examples of the groups for Ar2 in a compound of the formula (I) are, for example, wherein Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16 and R8 are as defined for the compounds of the formula (I). Specific embodiments contemplated as part of the invention include, but are not limited to, compounds of the formula (I), as defined, wherein: 3- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 4- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 5- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 5-. { 4 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy) phenyl} -1H-indole; 6- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 2- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; - [6- (1-azaiciclo [2.2.2] oct-3-yloxy) pyridazin-3-yl] -1 H-indole; 4- [6- (1-azabicyclo [2.2.2] oct-3-yloxy) pyridazin-3-yl] -1H-indole; 5-. { 6 - [. (3R) -1-azabicyclo [2.2.2] oct-3-yloxy] pyridazin-3-yl} -1H-indole; 5-. { 6 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] pyridazin-3-yl} -3-methyl-1H-indole; 5-. { 2 - [(3R) -1-azabicynic [2.2.2] oct-3-yloxy] pyrimidin-5-yl} -1H-indole; 4-. { 2 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] irimidin-5-yl} -1H-indole; 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; 6- { 4 - [(3 R) -1-aza bicyclo [2.2.2] oct-3-i I oxijf in i l} -4-thiocyanato-1,3-benzothiazol-2-amine; 6- { 4 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] pheniI} -4-bromo-1,3-benzothiazol-2-amine; N- [4- (3-methyl-1 H -indazol-5-yl) phenyl] quinuclidin-3-amine; (R) -3- [6- (3-Methyl-1 H -indazol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -3- [6- (1-Methyl-1 H -indol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -. { 5- [6- (1-Azabicicio [2.2.2] oct-3-yloxy) -pyridazin-3-yl] -1H-indol-3-ylmethyl} -dimet i I-amine; 1-R (R) -3- [6- (1H-indol-5-yl) -pyridazin-3-yloxy] -1-aza bicyclo [2.2.2] octane oxide; 6- { 6 - [(3 R) -1-aza bicyclo [2.2.2] oct-3-yloxy] -p i rid azi n-3-il} -benzothiazo I-2-ilamine; (3R) -3- [6- (3-Bromo-1H-indol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; 5-. { 6 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] -? Iridazin-3-iI} -1,3-dihydro-indole-2-one; 5-. { 6 - [(3R) -1-oxy-1-azabicyclo [2.2.2] oct-3-lloxy] -pyridazin-3-yl} -1,3-dihydroindol-2-one; 5-. { 6 - [(3 R) -1-aza bicyclo [2.2.2] oct-3-i I oxy] -p i rid azi n-3-il} -1, 3-dihi dro-benzoimidazol-2-one; (R) -3- [6- (1 H -benzoimidazol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (S) -3- [6- (1H-indol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -3- [5- (1H-indol-5-yl) -pyridin-2-yloxy] -1-azabicyclo [2.2.2] octane; 1-Oxide of (3R) -3- [5- (1 H -indol-4-yl) -pyrimidin-2-yloxy] -1-azabicyclo [2.2.2] octane; (3R) -3- (5-Benzooxazol-5-yl-pyrimidin-2-yloxyl) -1-azabicyclo [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; (3 R) - 3- [5- (2-f in yl-benzooxazol-5-yl) -pyrim id i n-2-i loxi] -1-azabicyclo [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-azabicyclo [2.2.2] oct-3-yloxy) -pipdazin-3-yl] -9H-carbazole; 3- [6- (1H-indol-3-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -3- [6- (1 H -indol-3-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; and (S) -3- [6- (1H-indol-3-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; or pharmaceutically acceptable salts, esters, amides and prodrugs thereof. Compound names are assigned using the software named AUTONOM, which is provided by MDL Information Systems GMBH (formally known as Beilstein Informationssysteme) in Frankfurt, Germany, and is part of the CHEMDRAW® ULTRA v. Software package. 6.0.2. The compounds of the invention can exist as stereoisomers in which asymmetric or chiral centers occur. These stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral element. The terms "R" and "S" used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Puré Appl. Chem, 1976, 45: 13-30. The invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and distereomers, and mixtures of enantiomers or diastereomers. The individual stereoisomers of compounds of the invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by the preparation of racemic mixtures after resolution well known to those of ordinary skill in the art. These resolution methods are exemplified by (1) inclusion of a mixture of enantiomers to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography, and optional release of the optically pure product from the auxiliary as described in Furniss. , Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & amp;; Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers in chiral chromatographic columns or (3) methods of fractional recrystallization. The compounds of the invention demonstrate beneficial linkage in a7 neuronal nicotinic receptors. In addition, such compounds generally demonstrate more beneficial binding at a7 neuronal nicotinic receptors when compared to a less desirable effect of binding to the ion channel of the gene related to ether to human go-go (hERG). As such, the compounds of the invention demonstrate an improved cardiovascular profile, ie, less similar to induce cardiovascular complications associated with hERG, than other amphiphilic molecules that are demonstrated in the neuronal nicotinic receptor link a7.Methods for Preparing Compounds of the Invention As used in the description of the schemes and examples, certain abbreviations are intended to have the following meanings: Ac for acetyl; Bu for butyl; dba for dibenzylidene acetone; DEAD for diethyl azodicarboxylate; DMSO for dimethylsulfonic; EtoAc for ethyl acetate; EtOH for ethanol; Et 3 N for triethylamine; Et2O for diethyl ether; HPLC for high pressure liquid chromatography; 'Pr for isopropyl; I stop methyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc for acetoxy; o-tol. for o-toluene; Ph for phenyl; t-Bu for tert-butyl; TFA for trifluoroacetic acid; and THF for tetrahydrofuran. The reactions exemplified in the schemes are carried out in a solvent appropriate to the reagents and materials used and suitable for the transformations that are carried out. The transformations described may require modifying the order of the synthetic steps or selecting a particular process scheme over another in order to obtain a desired compound of the invention, depending on the functionality present in the molecule.

Nitrogen protection groups can be used to protect amine groups present in the described compounds. Such methods, and some suitable nitrogen protection groups, are described in Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999). For example, suitable nitrogen protection groups include, but are not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), acetyl and trifluoroacetyl. More particularly, the protection group Boc can be removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid. The Cbz and Bn protection groups can be removed by catalytic hydrogenation. The acetyl and trifluoroacetyl protection groups can be removed by a hydroxide ion. The methods described below may involve the use of several enantiomers. Where the stereochemistry is shown in the Schemes, this is intended for illustrative purposes only.

Scheme 1 l = Sn, B X '= Br, CI, I (8) (5) The quinuclidine ethers of the general formula (8), wherein Ar1 and Ar2 are as defined in the formula (I), can be prepared as is described in Scheme 1. The 3-quinuclidinol of the formula (1) is treated with a halophenyl iodide of the formula (2), wherein X 'is bromide, chloride or iodide, with Cul and Cs2CO3 at 1.10. - phenanthroline as described in Org. Lett., 2002, 4, 973, to obtain a halofenoxi quinuclidine of the formula (4). Alternatively, a compound of the formula can be obtained by treating 3-quinuclidinol with a halophenyl alcohol of the formula (3), wherein X 'is bromide, chloride or iodide, and diethyl azodicarboxylate in the presence of a phosphine, such as triphenylphosphine. The compounds of the formula (4) can be treated with hexamethyldithine or diboro of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboro, wherein R is hydrogen, alkyl, butyloxycarbonyl or benzyloxycarbonyl, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of the formula (5), which is reacted with a desired halide of a fused bicycloheterocycle represented by Ar 2 of the formula (6), wherein X 'is bromide , chloride or iodide, to provide compounds of the formula (8). Alternatively, halides of a desired Ar2 group can be treated with hexamethyldistane or diboro of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboron, in the presence of a palladium catalyst to provide a tin reagent of corresponding boronic acid which is a with a compound of the formula (4) in the presence of a palladium catalyst to provide a compound of the formula (8).

Scheme 2 Me3SnSnMe3 (14) The quinuclidine ethers of the formula (14), wherein Ar 1 is a heteroaryl containing nitrogen, for example, pyrazidine, and Ar2 is as defined in formula (I), can be ared as shown in Scheme 2. Potassium quinuclidinoxide (10) can be reacted with a dihaloaromatic ring, for example, dichloropyridazine of the formula (11) to obtain a quinuclidine ether of the formula (12). The quinuclidine ether can be reacted with a suitable tin or boron reagent, as described in Scheme 1, to provide a quinuclidine ether substituted with fused bicycloheterocycle of the formula (14). Alternatively, the quinuclidine ether of the formula (12) can be treated with hexamethylditin or diboro of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboro, to activate the aromatic group to provide (13), wherein M is tin or an ester of boronic acid, and further treated with a halide of a desired Ar2 group in the ence of a palladium catalyst that provides compounds of the formula (14).

Scheme 3 The quinuclidine ethers of the formula (8), wherein Ar 1 and Ar 2 are as defined by the formula (I) can also be obtained by the methods described in Scheme 3. The activated tin or boronic acid reagent of the formula (7) can be coupled with the diiodoaromatic ring of formula (17) in the presence of a palladium catalyst to provide a compound of formula (18). The compounds of the formula (18) can be reacted with 3-quinuclidinoI and Cul with Cs2CO3 in 1, 10-phenanthroline as described in Org. Lett. 2002, 4, 973, to provide a desired compound of the formula (8). Alternatively, the compound of the formula (7) is treated with a compound of the formula (19), wherein Ra is benzyl, in the presence of a palladium catalyst to provide a compound of the formula (20). The compounds of the formula (20), wherein Ra is benzyl, are hydrogenated to provide compounds of the formula (21) under standard hydrogenation conditions, for example, Pd / C, and are further treated with 3-quinuclidinol in the presence of a phosphine, for example, triphenylphosphine, and diethyl azodicarboxylate to provide compounds of the formula (8).

Scheme 4 (27) (28)? '= Br, CU Pd / Ligand Cs2C03, tol.

The compounds of the formula (31), wherein X is -NH- and Ar1 and Ar2 are as described for the compounds of the formula (I), can be prepared as shown in Scheme 4. The 3-quinuclidinone (25) ) and the haloarylamine of the formula (26), wherein X 'is bromide, chloride or iodide, can be treated with sodium trlethoxyborohydride and acetic acid in Na 2 SO 4 to provide a compound of the formula (29). Alternatively, a compound of formula (29) can be obtained by treating 3-aminoquinuclidine (27) with a heteroaromatic group as described in formula (28) with Cs 2 C 0 in the presence of a palladium catalyst, preferably in toluene. A compound of the formula (29) can be treated with a tin or diboro of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboron, under conditions previously described to provide the corresponding tin reagent or boronic acid of the formula (30), which can be reacted with the halide of a desired group represented by Ar2 in a compound of the formula (I) to provide a compound of the formula (31). Alternatively, the compound of the formula (29) is treated with a tin or a boronic acid ester of the desired group Ar2 in the presence of a palladium catalyst to provide a compound of the formula (31).

Scheme 5 Me3SnSnMe3 The compounds of the formula (39), wherein X is S and Ar1 and Ar2 are as defined in a compound of the formula (I), can be prepared as shown in Scheme 5. It can be reacted 3- chloroquinuclidine (35) with a haloarylthio of the formula (36), wherein X 'is bromide, chloride or iodide, to provide a compound of the formula (37). The compound of the formula (37) can be treated with a tin or boron reagent of a desired group for Ar2 as described for a compound of the formula (I) to provide a compound of the formula (39). Alternatively, the compound of the formula (37) can be reacted with a hexamethyl distiller or diboro reagent of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboron, in the presence of a palladium catalyst for providing a compound of the 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 the formula (39).

Scheme 6 Me3SpSnMe3 X '= Br, CI, i (5) (4) M = Sn, B Pd (0) / L. Pd (0) / L. X'-Ar2-NHRb M'-Ar2-NHRb (41) (40) X '= Br, Cl, I' = Sn, B, Zn, Mg, Rb = H, alkyl, Boc, Cbz The compounds of the formula (42), wherein X is O, R3 is NHRb, and Ar1, Ar2 are defined as in the compounds of the formula (I), they can be prepared as shown in Scheme 6. The compounds of the Formula (4) obtained as shown in Scheme 1 can be treated with a metal of the group Ar2 substituted with desired amino, as described for the compounds of the formula (I) to provide compounds of the formula (42), wherein Rb is hydrogen, alkyl, butyloxycarbonyl or benzyloxycarbonyl. The compounds of the formula (4) can be treated with a hexamethylditin or diboro reagent of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboron, in the presence of a palladium catalyst to provide the tin or corresponding boronic acid of the formula (5), which is reacted with a desired halide of a fused bicycloheterocycle, substituted with amine represented by Ar2 of the formula (41), wherein X 'is bromide, chloride or iodide to provide compounds of the formula (42).

Scheme 7 Me3SnSnMe3 (12) R = alkyl, aryl M = Sn, B (13) X1, X2 ', X3 = N, CHY = Br, Cl, I Pd (0) / L. Pd (0) / L. X'-Ar2-NHRb M'-Ar2-NHRb (45) (46) M '= Sn, B, Zn, Mg, X' = Br, Cl, I R = H, Boc, Cbz, alkyl, aryl (47) The compounds of the formula (47), wherein X is O, Ar1 is a nitrogen containing an aromatic group, for example, pyridazine, R3 is NHRb, as previously defined, and Ar2 is defined as in the compounds of the 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 or the group Ar2 substituted with desired amino, as is described for the compounds of the formula (I), of the formula (45) to provide compounds of the formula (47). The compounds of the formula (12) can also be treated with a hexamethylditin or diboro reagent in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of the formula (9), such as bis (pinacolato) diborium and bis (catecholate) diboro, in the presence of a palladium catalyst to provide the tin or boronic acid of the formula (13) which is reacted with a desired halide of a fused bicycloheterocycle substituted with amine represented by Ar 2 of the formula (46) ), wherein X 'is bromide, chloride or iodide, to provide compounds of the formula (47).

Scheme 8 AV- Ar2- X "+ GT X" = Br, CI, l, N02, NR'R "(51) Cul, Cs2C03 1,10-phenanthroline Tol reflux (50)? "= Br, CI, l, N02, NR'R" " R ', R'-H, alkyl, aryl, RCO, Boc, Cbz The quinuclidine ethers of the formula (56) and (57), wherein Ar 1 is as defined by the formula (I) and Ar 2 is substituted with a group NR 5 R 6 can be obtained by the methods described in Scheme 8. The compounds of Formula (50) can be treated with 3-quinuclidinol in the presence of a phosphine, for example, triphenylphosphine and diethyl azodicarboxylate to provide compounds of formula (52). Alternatively, compounds of the formula (51), wherein X "is bromide, chloride or iodide, can be reacted with Cul, Cs2C03 in 1, 10-phenanthroline as described in Org Lett, 2002, 4, 973, to provide a desired compound of the formula (52) The compounds of the formula (52), wherein X "is N02, can be reduced with hydrogen in the presence of a palladium catalyst and reacted with a chloride or bromide of a group R of the formula (53), wherein R 'is hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl or aryloxycarbonyl, to provide compounds of the formula (56). The compounds of the formula (52), wherein X "is bromide, chloride or iodide, can be treated with a compound R'NHR" of the formula (54), wherein R 'and R "are as previously described for R 'in the compounds of the formula (53) to provide a corresponding compound of the formula (57).

Scheme 9 (60) X "= Br, CI, l, N02, NHR'R" , Cbz I ¡YJ YH R '(63) The compounds of the formulas (63) and (64) can be prepared as shown in Scheme 9. The 3-quinuclidinone and a halobarylamine of the formula (60), wherein X 'is bromide, chloride or iodide, can be treated with sodium borohydride-triacetate and Na2SO4 in acetic acid to provide a compound of the formula (61) as described in Tetrahedron Lett. 1996, 37, 6045. The compounds of the formula (61), wherein X 'is bromide, chloride or iodide, can be treated with a compound R'NHR "of the formula (54), wherein R' and R" are as previously described for R 'in compounds of the formula (53), to provide a corresponding compound of the formula (64). The compounds of the formula (61), wherein x is N02, can be reduced with hydrogen in the presence of a palladium catalyst and reacted with a chloride or bromide of a desired R 'group of the formula (53), in where R 'is hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl or aryloxycarbonyl, to provide compounds of the formula (63).

Scheme 10 Me3SnSpMe3 X '= Br, Cl, l Pd (0) / L. P (0) / L X-Ar2-NHRb M'-Ar2-NHRb (46) (45) X = Br, Cl, I M '= Sn, B, Zp, Mg, Rb = H, Boc.Cbz, alkyl artt (69) The compounds of the formula (69), wherein X is -NH-, R3 is NHRb, and Ar1, Ar2 are as defined in the compounds of the formula (I), they can be prepared as shown in Scheme 10. The compounds of the formula (29) obtained as shown in Scheme 7 can be treated with a metal of the group Ar2 substituted with desired amino, as described for the compounds of the formula (I), of the formula (45) to provide compounds of the formula (69). The compounds of the formula (29) can also be treated with a hexamethyl diamine or diboro reagent of the formula (9), such as bis (pinacolato) diboro and bis (catecholate) diboron, in the presence of a palladium catalyst to provide the corresponding tin or the boronic acid of the formula (30), which is reacted with a desired halide of a fused bicycloheterocycle substituted with amine represented by Ar 2 of the formula (46), wherein X 'is bromide, chloride or iodide , to provide compounds of the formula (69).

Scheme 11 X "= Br, Cl, IN02, NHR'R" X = N02 X = Br, CI, l -,) Pd / C, H2 2) R'Clo R'Br (53) Pd / Ligand | R'NHR "(54) (73) The quinuclidine biarylsulfides of the formulas (72) and (73), wherein Ar1 is as defined for the formula (I) and Ar2 is substituted with a group NR'R "can be obtained by the methods described in Scheme 11. 3-Cyanoquinuclidine can be reacted with a halobarylthiol of the formula (70), wherein X "is bromide, chloride, iodide, N02 or NHR'R", as described in Tetrahedron Lett, 1996, 37, 6045, to provide a compound of the formula (71) The compounds of the formula (71), wherein X "is N02, can be reduced with hydrogen in the presence of a palladium catalyst and reacted with a chloride or bromide of a group R ' of the formula (53), wherein R 'is hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl or aryloxycarbonyl, to provide compounds of the formula (72). The compounds of the formula (71), wherein X "is bromide, chloride or iodide, can be treated with a compound R'NHR" of the formula (54), wherein R 'and R "are as previously described for R 'in compounds of the formula (53), to provide a corresponding compound of the formula (73).

Scheme 12 Me3SnSnMe3 B X '= Br, CI, l (38) Pd (0) / L Pd (0) / L M'-Ar -NHRb X'-Ar2-NHRb (75) (76) M '= Sn, B, Zn, Mg, X' = Br, Cl, I Rb = H, Boc.Cbz, alkyl (77) The compounds of the formula (77), wherein X is S, R3 is NHRb, and Ar1, Ar2 are as defined in the compounds of the formula (I) can be prepared as shown in Scheme 12. The compounds of the Formula (37) obtained as shown in Scheme 5 can be treated with a metal of the group Ar2 substituted with desired amino, as described for the compounds of the formula (I), of the formula (75) to provide compounds of the formula (77). The compounds of the formula (37) can also be treated with a hexamethylditin or diboro reagent of the formula (9) such as bis (pinacolato) diboro and bis (catecholate) diboron, in the presence of a palladium catalyst to provide the tin or corresponding boronic acid of the formula (38), which is reacted with a desired halide of a fused bicycloheterocycle substituted with amine represented by Ar2 of the formula (76), wherein X 'is bromide, chloride or iodide, to provide compounds of the formula (77).

Scheme 13 The aminobenzothiazole substituted quinuclidines of the formula (82) can be obtained as shown in Scheme 13. The quinuclidine ethers substituted with amino, thioethers and amines of the formula (80) are obtained by methods described in Schemes 6-12. The compounds of the formula (80) are reacted with bromide and KSCN in acetic acid to provide aminobenzothiazole substituted quinuclidines of the formula (81).

The compounds of the formula (81) can be further treated with the halide of a desired Rc group, wherein R ° as defined for R5 or R6 in compounds of the formula (I) provides the derivative (82) of quinuclidine substituted with aminobenzothiazole . The compounds of the formula (82) can be further treated to obtain compounds of the formulas (84), (86) and (88). Bromination of the compounds of the formula (82) provides compounds of the formula (83). The compounds of the formula (83) are reacted with a nucleophilic agent, for example, KSCN to give compounds of the formula (84). The compounds of the formula (83) can be treated with a metal of a suitable aryl group, as described for the compounds of the formula (I), of the formula (85), in the presence of a palladium catalyst to provide the corresponding compounds of the formula (86). The compounds of the formula (83) can also be treated with an alcohol of the formula (87) or an amine of the formula (87a), wherein R4, R5 and R6 are as defined for the compounds of the formula (I) , in the presence of the palladium catalyst to provide the corresponding compounds of the formula (88).

Scheme 14 1) H2, Pd / C2) (EtO) 3CR MeOH DMF R3 = alkyl, aryl Quinuclidines substituted with benzoimidazole of the formula (92), wherein Y 'is O, NH or S and Ar1 is as defined for the compounds of the formula (I), can be obtained as shown in Scheme 14. The compounds of the formula (89), the which are obtained by treating compounds of the formula (80), in Scheme 13 under standard nitrogen protection conditions, are reacted with nitric acid in sulfuric acid to provide compounds of the formula (90). The compounds of the formula (90) are hydrogenated by palladium catalysis and treated with excess triethyl orthoformate to obtain compounds of the formula (91). The compounds of the formula (91) are deprotected under standard nitrogen deprotection conditions to obtain compounds of the formula (92).

Scheme 15 I, S 1) H2, Pd / C 2) (EtO) 3CRJ MeOH DMF (99) Quinuclidines substituted with benzooxazole of the formula (99), where Y 'is O, NH or S and Ar1 and R3 are as defined for the compounds of the formula (I), they can be obtained as shown in Scheme 14. The compounds of the formula (95) they can be treated with a diboro reagent of the formula (9), such as a bis (pinacolato) diboro and bis (catecholate) diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of the formula (96). ). The compounds of the formula (96) are reacted with a desired halide of a heteroaromatic group Ar1 substituted with quinuclidine as represented by the compounds of the formula (97), wherein X 'is bromide, chloride or iodide, to provide compounds of the formula (98). The compounds of the formula (98) are hydrogenated by palladium catalysis and treated with excess triethyl orthoformate to obtain compounds of the formula (99). The compounds of the formula (I) wherein A is N can be converted to compounds of the formula (I), wherein A is N + -0"by the treatment with an oxidizing agent Examples of the oxidizing agent include, but are not they are limited to aqueous acid peroxide and m-chloroperbenzoic acid The reaction is generally carried out in a solvent such as, but not limited to acetonitrile, water, dichloromethane, acetone or a mixture thereof, preferably a mixture of acetonitrile and water, in a temperature from about room temperature to about 80 ° C, for a period of about 1 hour to about 4 days The compounds and intermediates of the invention can 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 may include, but are not limited to, chromatography on solid supports such as silica gel, alumina. or silica derived from alkylsilane groups, by recrystallization at elevated and low temperature with optional pretreatment with activated carbon, thin layer chromatography, distillation at various pressures, sublimation under vacuum and grinding, as described for example in "Vogel's Texbook of Practical Organic Chemistry ", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific &; Technical, Essex CM20 2JE, England. The compounds of the invention have at least one basic nitrogen so that the compound can be treated with an acid to form a desired salt. For example, a compound can be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolytic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric or hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, glutamic and the like.

Compositions of the Invention The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the formula (I) in combination with a pharmaceutically acceptable carrier. The compositions comprise compounds of the invention formulated together with one or more pharmaceutically acceptable non-toxic carriers. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The term "pharmaceutically acceptable carrier", as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, a diluent, an encapsulating material or a formulation aid of any type. Some examples of materials which serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; ph regulatory agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and ph-phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium laurisulfate and magnesium stearate, as well as coloring agents, release agents, coating agents; Sweetening, flavoring and perfume agents, preservatives and antioxidants may also be present in the composition, according to the judgment of one skilled in the art of formulations. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally or as an oral or nasal spray. The term "parenterally" as used herein, refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous or intraarticular injection or infusion. Pharmaceutical compositions for parenteral injection comprise sterile, pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like, and suitable mixtures thereof), vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate or suitable mixtures thereof. The proper fluidity of the composition can 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 may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by various antibacterial and anti-fungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. This may be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can occur through the use of agents that delay absorption, for example, aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is often desired to decrease the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor aqueous solubility. The rate of absorption of the drug may depend on its rate of dissolution, which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, a parenterally administered drug form can be administered by dissolving or suspending the drug in an oily vehicle. The suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof. If desired, and for a more effective distribution, the compounds of the invention can be incorporated into slow delivery or targeted delivery systems such as polymer matrices, liposomes and microspheres. These can be sterilized, for example by filtration through a filter that retains bacteria or by the incorporation of sterilization agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer and the nature of the polymer employed, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or suspended in sterile water or other sterile injectable medium just before use.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion, in a non-toxic, parenterally-acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P, and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally employed as a solvent or a suspending medium. For this purpose, any soft fixed oil can be employed including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, one or more compounds of the invention is mixed with at least one inert pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate and / or to) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and salicyclic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polivilpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbers such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise pH regulating agents. Solid compositions of a similar type can also be used as fillers in filled, soft and hard gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. These may optionally contain opacifying agents and may also be of a composition that releases the ingredient (s) only, or preferably, in a certain part of the gastrointestinal tract in a delayed manner. Examples of materials used to retard the release of the active agent may include polymeric substances and waxes. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at room temperature. body and therefore melt in the rectum or vaginal cavity and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art., such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils ( in particular, cottonseed, peanut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and pefume agents. Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. A desired compound of the invention is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary pH regulators or preservatives as may be required. Ophthalmic formulation, eye drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, animal and vegetable fats, oils, paraffin waxes, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and sodium oxide. zinc, or mixtures thereof. The powders and sprays may contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may also contain customary propellants such as chlorofluorohydrocarbons. The compounds of the invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phosphoiipids or their lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to the compounds of the invention, stabilizers, preservatives and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods for forming liposomes are known in the art. See for example, Prescott, Ed., Methods in Cell Bioiogy, Volume XIV, Academic Press, New York, N.Y., (1976), p 33 et seq. Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalers. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, pH regulators or propellants. Ophthalmic formulations, ointments for eyes, powders and solutions are also contemplated as being within the scope of this invention. The aqueous liquid compositions of the invention are also particularly useful. The compounds of the invention can be used in the form of pharmaceutically acceptable salts, esters or amides derived from inorganic or organic acids. The term "pharmaceutically acceptable salts, esters or amides" as used herein, includes salts, zwitterions, esters and amides of the compounds of formula (I) which are within the scope of sound medical judgment, suitable for the use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, are in proportion to a reasonable benefit / risk ratio and are effective for their intended use. The term "pharmaceutically acceptable salt" refers to those salts which are within the scope of successful 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 in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base function with a suitable organic acid. Salts Representative acid addition 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-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nlcotlnato, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphonate, glutamate , bicarbonate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized with such agents as lower alkylhalides 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. The soluble or dispersible products in water or oil are obtained accordingly. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include such inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. The basic addition salts can be prepared in situ during the isolation and final purification of compounds of this invention by reacting a carboxylic acid-containing portion with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia. or a primary or secondary tertiary amine. The pharmaceutically acceptable salts include, but are not limited to cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like, and non-toxic ammonium and quaternary amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and others. Other representative organic amines useful for the formation of base addition salts include ethylene diamine, ethanolamine, diethanolamine, piperidine and piperazine.

The term "pharmaceutically acceptable ester", as used herein, refers to esters of compounds of the invention which hydrolyze in vivo and include those which readily disintegrate in the human body to leave a parent compound or a salt thereof. . Examples of non-toxic, pharmaceutically acceptable esters of the invention include alkyl esters of C, to C6 and cycloalkyl esters of C5 to C7, although alkyl esters of Ci to C4 are preferred. The esters of the compounds of the formula (I) can be prepared according to conventional methods. The pharmaceutically acceptable esters can be attached on hydroxyl groups by the reaction of the hydroxyl group-containing compound with acid and an alkylcarboxylic acid such as acetic acid, or with an acid and an arylcarboxylic acid such as benzoic acid. In the case of the compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by the reaction of the base compound such as triethylamine and an alkylhalide, alkyl triflate, by example, with methyl iodide, benzyl iodide, cyclopentyl iodide. These can also be prepared by the reaction of the compound with an acid such as hydrochloric acid and an alkylcarboxylic acid such as acetic acid, or with an acid and an arylcarboxylic acid such as benzoic acid. The term "pharmaceutically acceptable amide" as used herein, refers to non-toxic amides of the invention derived from ammonia, primary alkylamines of C-i to C6 and secondary dialkylamines of C-i to C6. In the case of the secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing a nitrogen atom. The amides are derived from ammonia, primary alkylamides of C are preferred; to C3 and secondary dialkylamides of C-, to C2. The amides of the compounds of the formula (I) can be prepared according to conventional methods. The pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reacting the amino group-containing compound with an alkyl anhydride, aryl anhydride, acyl halide or aroyl halide. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable esters are prepared from compounds containing carboxylic acid groups by the reaction of the base compound such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazo, and an alkylamine, dialkylamine, for example, with methylamine, diethylamine, piperidine. These can be prepared by the reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an alkylcarboxylic acid such as benzoic acid under dehydration conditions as with aggregated molecular sieves. The composition may contain a compound of the invention in the form of a pharmaceutically acceptable prodrug. The term "pharmaceutically acceptable pro-drug" or "pro-drug", 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 tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, in proportion to a reasonable benefit / risk ratio, and effective for their intended use. The pro-drugs of the invention can be rapidly transformed in vivo to a parent compound of the formula (I), for example, by hydrolysis in blood. A direct discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A. C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). The invention contemplates pharmaceutically active compounds synthesized either chemically or formed by biotransformation in vivo to compounds of the formula (I).

Methods of the Invention The compounds and compositions of the invention are useful for modulating the effects of nAChRs, and more particularly nAChRs of al. In particular, the compounds and compositions of the invention can be used to treat and prevent disorders modulated by nAChRs of a7. Typically, such disorders can be ameliorated by selectively modulating the nAChRs of a.7 in a mammal, preferably by administering a compound or composition of the invention, either alone or in combination with another active agent, for example, as part of a therapeutic regimen. . The compounds of the invention, including, but not limited to, those specified in the examples, possess an affinity for nAChRs, and more particularly nAChRs of a7. As ligands of nAChRs of a.7, the compounds of the invention may be useful for the treatment and prevention of a number of diseases or conditions mediated by nAChR of a7. For example, it has been shown that nAChRs from al play a notable role in improving cognitive function, including aspects of learning, memory and attention (Levin, E.D., J. Neurobiol, 53: 633-640, 2002). Such as, a7 ligands are suitable for the treatment of cognitive disorders including for example, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), moderate cognitive impairment, senile dementia, dementia. AIDS, Pick's disease, dementia associated with Lewy bodies, and dementia associated with Down syndrome, as well as cognitive deficit associated with schizophrenia. In addition, it has been shown that nAChRs containing a.7 are involved in the neuroprotective effects of nicotine both in vivo (Shimohama, S. et al., Brain Res. 779: 359-363, 1998). More particularly, neurodegeneration is the basis of several progressive CNS disorders, including, but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, as well as decreased function of the CNS that results from traumatic brain damage. For example, the impaired function of nAChRs of al for peptides - amyloids linked to Alzheimer's disease has been implicated as a key factor in the development of cognitive deficits associated with the disease (Liu, Q.-S., Hawaii, H. , Berg, DK, PNAS 98: 4734-4739, 2001). Activation of nAChRs from al has been shown to block this neurotoxity (Kihara, T. et al., J. Biol. Chem. 276: 13541-13456, 2001). Such as, the selective ligands that improve the activity of al can counteract the deficiencies of Alzheimer's and other neurodegenerative diseases. Schizophrenia is a complex disease characterized by abnormalities in perception, cognition and emotions. The remarkable evidence implies the intervention of nAChRs of a.7 in this disease, including a measured deficit of these receptors in post-mortem patients (Leonard, S. Eur. J. Pharmacol. 393: 237-242, 2000). Deficiencies in sensory processing (periodic activation) are some of the hallmarks of schizophrenia. These deficiencies can be normalized by nicotinic ligands operating in the nAChR of al (Adier L.E. et al., Schizophrenia Bull.24: 189-202, 1998, Stevens, K. E. et al., Psychopharmacology 136: 320-327, 1998). Thus, a.7 ligands demonstrate potential in the treatment of 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 improvement of circulation, for example, increased circulation around a vascular occlusion. Non-selective nAChR agonists such as 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 nAChR of a7 (Heeschen, C. et al., J. Clin.Research 110: 527-536, 2002). Therefore, nAChR ligands that are selective for the subtype offer enhanced potential to stimulate angiogenesis with an improved side effect profile.

A population of nAChRs of al in the spinal cord modulates the serotonergic transmission that has been associated with pain relieving effects of nicotinic compounds (Cordero-Erausquin, M. and Changeux, J.-P.PNAS 98: 2803-2807, 2001 ). The nACHR ligands of al demonstrate therapeutic potential for the treatment of pain states, including acute pain, post-surgical pain, as well as chronic pain states including inflammatory pain and neuropathic pain. In addition, nAChRs of α are expressed on the surface of primary macrophages that are involved in the inflammation response, and that activation of the receptor to inhibit the release of TNF and other cytokines that activate the inflammation response (Wang, H. et al. »Nature 421: 384-388, 2003). Therefore, ligands to the selective demonstrate potential to treat conditions involving inflammation and pain.

The acrosome reaction of mammalian sperm is a process of exocytosis important in the fertilization of the ovum by sperm. The activation of a nAChR of a7 in the sperm has shown that it is essential for the acrosome reaction (Son, J.-H. and Meizel, S. Biol. Reproduct. 68: 1348-1353 2003). As a result, the selective agents show utility for the treatment of fertility disorders. The compounds of the invention are particularly useful for treating and preventing a condition or disorders that affects cognition, neurodegeneration and schizophrenia. Cognitive impairment associated with schizophrenia often limits the ability of patients to function normally, a symptom not adequately treated by commonly available treatments, for example, treatment with atypical anti-psychotic. (Rowley, M. et al., J. Med. Chem. 44: 477-501, 2001). Such cognitive deficit has been linked to dysfunction of the cholinergic nicotinic system, in particular with the activity decreases in the al receptors (Friedman, J.l. et al., Biol Psychiatry, 51: 349-357, 2002). Thus, activators of the al receptors can provide useful treatment to improve cognitive function in schizophrenic patients who are being treated with atypical antipsychotics. Accordingly, the combination of a nAChR ligand of al and an atypical anti-psychotic would offer improved therapeutic utility. Specific examples of suitable atypical anti-psychotics include, but are not limited to clozapine, risperidone, olanzapine, quitapine, ziprasidone, zotepine, iloperidone and the like. The current dose levels of active ingredients in the pharmaceutical compositions of this invention can be varied such that an amount of the active compound or compounds that are effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration is obtained. The dose level selected will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the ability of the art to start the dose of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. When used in the foregoing and other treatments, a therapeutically effective amount of one of the compounds of the invention may be employed in pure form, or where such forms exist, in the form of a pharmaceutically acceptable salt, ester, amide or prodrug. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit / risk ratio applicable to any medical treatment.

It will be understood, however, that the total daily use of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; age, body weight, general health, sex and the patient's diet; the administration time, the route of administration and the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical arts. For example, it is suitable within the skill of the art to initiate dose of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a human or animal varies from about 0.10 mg / kg of body weight to about 1 g / kg of body weight. More preferable doses may be in the range from about 0.01 mg / kg of body weight to about 100 mg / kg of body weight. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Consequently, single dose compositions may contain such amounts or submultiples thereof to compose the daily dose. The compounds and processes of the invention will be better understood for reference to the following examples and reference examples, which are intended as an illustration and not a limitation on the scope of the invention.

EXAMPLES Example 1 3-r4- (1-Azabicyclo2.2.21oct-3-yloxy) fenip-1H-indole Example 1A 3- (4-Iodophenoxy) quinuclidine Under N2, the mixture of 3-hydroxyquinuclidine (Aldrich, 2.54 g, 20 mmol), 1, 4-dlyodobenzene. (Aldrich, 7. 9 g, 24 mmol) CuL (Strem Chemicals, 0.38 g, 2 mmol) and 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol) in toluene (anhydrous, Aldrich, 50 ml) was stirred at 110 ° C for 40 hours. After the reaction proceeded to completion, the reaction mixture was diluted with chloroform (100 ml) and washed with water (2 x 10 ml). The organic solution was concentrated and the title compound was purified by 1 H NMR chromatography (300 MHz, CD3OD) d 1.40-1.56 (m, 1H), 1.64-1.80 (m, 2H), 1.90-2.08 (m, 1H), 2.10-2.21 (m, 1H), 2.60-3.00 (m, 5H), 3.34-3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8, Hz, 2H), ppm. MS (DCl / NH3) m / z 330 (M + H) 0 Example 1 B 3.r4- (1-Azabicyclo2.2.21oct-3-yloxy) fenip-1H-indole The product mixture of Example 1A (330 mg , 1 mmol), N- (2-ethynyl-phenyl) -2,2,2-trifluoroacetamide (ref Tetrahedron Lett, 1992, 33, 3915; 280 mg, 1.3 mmol), Pd2 (dba) 3 (Aldrich , 19 mg, 0.02 mmol) and K2CO3 (180 mg, 1.3 mmol) in DMSO (3 mL) was stirred at 40 ° C under N2 for 2 hours. The reaction was monitored with TLC. After the reaction was complete, it was cooled to room temperature and diluted with EtOAc (50 ml). This was then washed with brine (3 x 5 ml). The organic solution was concentrated and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 mm Elution Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 for 20 minutes), flow rate, 75 ml / minute, uv, 250 nm) as a solid (113 mg, 36% yield). 1 H NMR (300 MHz, CD 3 OD) d 1.43-1.57 (m, 1 H), 1.62-1.89 (m, 2 H), 2.01-2.15 (m, 1 H), 2.16-2.23 (m, 1 H), 2.73-3.03 (m , 5H), 3.28-3.40 (m, 1H), 4.51-4.58 (m, 1H), 6.97 (dt, J = 8.8, 2.1 Hz, 2H), 7.03-7.17 (m, 2H), 7.36 (s, 1H) ), 7.37-7.42 (m, 1H), 7.57 (dt, J = 8.8, 2.0 Hz, 2H), 7.81 (dt, J = 7.8, 1.2 Hz, 1H) ppm. MS (DCI / NH3) m / z 319 (M + H) +.

Example 1C Hemifumarate of 3-f4- (1-Azabiciciof2.2.21oct-3-yloxy) phen.p-1 H-indole The product of Example 1B (113 mg, 0.36 mmole) was treated with fumaric acid (46 mg, 0.4 mmoles) in EtOAc / EtOH (v. 1: 1, 4 ml) at room temperature for 10 hours. The title compound was obtained as a solid (131 mg, 89% yield). 1H NMR (300 MHz, CD3OD) d 1.73-2.13 (m, 3H), 2.23-2.37 (m, 1H), 2.43-2.51 (m, 1H), 3.12-3.43 (m, 5H), 3.64-3.76 (m , 1H), 4.77-4.88 (m, 1H), 6.67 (s, 1.4H), 6.99-7.18 (m, 4H), 7.38 (s, 1H), 7.39-7.43 (m, 1H), 7.61 (dt, J = 8.8, 2.0 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H) ppm. MS (DCI / NH3): m / z 319 (M + H) 0 Anal. Calculated for C21H22N2O-0.85 C4H404: C, 70.27; H, 6.14; N, 6.72. Found: C, 70.20; H, 6.35; N, 6.88.

EXAMPLE 2 4-r4- (1-Azabicyclo2.2.21oct-3-yloxy) fenip-1H-indole Example 2A 3-r4- (trimethylstannyl) phenoxyquinuclidine The mixture of the product from Example 1A ( 330 mg, 1 mmol), hexamethylditin (Aldrich, 654 mg, 2 mmol) and Pd (PPh3) 4 (Aldrich, 116 mg, 0.1 mmol) in toluene (10 ml) was stirred at 110 ° C under N2 for 2 hours. The reaction was monitored with TLC. After the reaction was complete, it was cooled to room temperature and diluted with EtOAc (50 ml). This was then washed with brine (2 x 5 ml). The organic solution was concentrated under reduced pressure and the title compound was purified by flash chromatography (Si02, CH2Cl2: MeOH: NH3 H20, 90: 10: 1, Rf. 0.35) as a solid (300 mg, yield, 82%) . 1H NMR (300 MHz, CD3OD) d 0.25 (s, 9H), 1.79-2.16 (m, 3H), 2.23-2.36 (m, 1H), 2.45-2.52 (m, 1H), 3.17-3.43 (m, 5H ), 3.73-3.83 (m, 1H), 4.84-4.92 (m, 1H), 6.96 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H) ppm. MS (DCI / NH3): m / z 364 (M + H) +, 366 (M + H) \ 368 (M + H) +.

Example 2B 4-r4- (1-Azabicicior2.2.21oct-3-yloxy) phen.p-1H-indole The product of 2A (300 mg, 0.8 mmol), 4-bromoindole (Aldrich, 196 mg, 1 mmol), Pd2 (dba) 3 (Aldrich, 27 mg, 0.03 mmol) and (o-tol.) 3P (Aldrich, 27 mg, 0.09 mmol) in DMF (Aldrich, anhydrous, 5 ml) were heated at 80 ° C under N2 and They stirred during the night. This was then cooled to room temperature and diluted in EtOAc (50 ml). The mixture was washed with brine (2 x 5 ml). The organic solution was concentrated under reduced pressure and the title compound was purified by flash chromatography (Si02, CH2Cl2: MeOH; NH3.H20, 90: 10: 1, Rf 0.30) as a solid, (48 mg, yield, 19% ). 1H NMR (300 MHz, CD3OD) d 1.46-1.58 (m, 1H), 1.64-1.91 (m, 2H), 2.01-2.17 (m, 1H), 2.19-2.26 (m, 1H), 2.75-3.03 (m , 5H), 3.32-3.42 (m, 1H), 4.55-4.63 (m, 1H), 6.58 (dd, J = 3.4, 1.0 Hz, 1H), 6.98-7.04 (m, 3H), 7.14 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 3.1 Hz, 1H), 7.33 (dt, J = 8.1, 1.0 Hz, 1H), 7.59 (dt, J = 9.2, 2.7 Hz, 2H) ppm. MS (DCI / NH3): m / z 319 (M + H) +.

Example 2C Fumarate of 4-r4- (1-Azabiciclof2.2.21oct-3-yloxy) fenip-1 H -indole The product of Example 2B (48 mg, 0.16 mmol) was treated with fumaric acid (23 mg, 0.2 mmol) in EtOAc / EtOH (v. 1: 1, 3 mL) at room temperature for 15 hours. The title compound was obtained as a solid (60.2 mg, yield, 90%). 1 H NMR (300 MHz, CD 3 OD) d 1.82-2.19 (m, 3 H), 2.29-2.42 (m, 1 H), 2.51-2.58 (m, 1 H), 3.16-3.46 (m, 5 H), 3.75-3.85 (m , 1H), 4.89-4.96 (m, 1H), 6.56 (dd, J = 3.4, 1.0 Hz, 1H), 6.69 (s, 2.2H), 7.02 (dd, J = 7.1, 1.0 Hz, 1H), 7.08 (dt, J = 8.8, 2.5 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.26 (d, J = 3.4 Hz, 1H), 7.35 (dt, J = 8.1, 1.0 Hz, 1H) , 7.64 (dt, J = 8.8, 2.6 Hz, 2H) ppm. MS (DCI / NH3): m / z 319 (M + H) +. Anal. Calculated for C21H22N20-1.12 C4H404: C, 68.25; H, 5.95; N, 6.25. Found: C, 68.43; H, 5.58; N, 6.20.

Example 3 5-r4- (1-Azabiciclof2.2.21oct-3-yloxy) phenyl-1H-indole Example 3A 5-r4-M-Azabicylchlor2.2.21oct-3 -loxy) phen.p-1H-indole Under N2, the product of Example 1A (329 mg, 1 mmol), 5-indolylboronic acid (Frontier, 193 mg, 1.2 mmol), Pd2 (dba) 3 (Aldrich, 24 mg, 0.025 mmol), ('Bu3P) 2Pd (26 mg, 0.05 mmol), K2C03 (276 mg, 2 mmol) and KF (80 mg, 1.4 mmol) in THF (8 mL) was stirred at 60 ° C overnight. The reaction was monitored with TLC. After the reaction was completedThis was diluted with EtOAc (30 ml) and washed with brine (2 x 5 ml). The organic solution was concentrated under reduced pressure and the title product was purified by preparative HPLC (Gilson, column, Symmetry® C-87 μm, 40 x 100 mm Solvent eluent, MeCN / H20 (with 0.2% v. TFA) ( v 90/10 to 10/90 for 20 minutes), flow rate, 75 ml / minute, UV, 250 nm) as a solid (80 mg, yield 25%). 1H NMR (300 MHz, CD3OD) d 1.44-1.58 (m, 1H), 1.62-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m , 5H), 3.27-3.40 (m, 1-H), 4.51-4.59 (m, 1H), 6.46 (dd, J = 3.4, 1.1 Hz, 1H), 6.95 (dt, J = 8.8, 2.6 Hz, 2H ), 7.22 (d, J = 3.1 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.40 (dt, J = 8.5, 1.0 Hz, 1H), 7.54 (dt, J = 9.2, 2.6 Hz, 2H), 7.71 (dd, J = 1.7, 0.7 Hz, 1H) ppm. MS (DCI / NH3): m / z 319 (M + H) \ Example 3B 5-T4- (1-azabicyclochloride.2.21oct-3-yloxy) fenip-1 H-indole fumarate The product of Example 3A (80 mg, 0.25 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc / EtOH (v. 1: 1, 4 ml) at room temperature for 10 hours. The title compound was obtained as a solid (57 mg, yield, 52%). 1H NMR (300 MHz, CD3OD) d 1.78-2.16 (m, 3H), 2.25-2.39 (m, 1H), 2.46-2.54 (m, 1H), 3. 14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80-4.89 (m, 1H), 6.46 (dd, J = 3.0, 1.0, 1H), 6.68 (s, 2H), 7.02 (dt) , J = 8.8, 2.5 Hz, 2H), 7.23 (d, J = 3.1 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.43 (dt, J = 8.4, 0.8 Hz, 1H), 7.58 (dt, J = 9.2, 2.6 Hz, 2H), 7.71 (dd, J = 1.7, 1.0 Hz, 1H) ppm.

MS (DCI / NH3): m / z 319 (M + H) 0 Anal. Calculated for C2? H22N20-C4H404: C, 69.11; H, 6.03; N, 6.45. It was found: C, 69.23; H, 5.81; N, 6.59.

Example 4 5-. { 4-r (3R) -1-Azabicyclo2.2.21oct-3-yloxy1phenyl > -1H-indole Example 4A (3R) -3-Quinuclidinol (3R) -3-Quinuclidinol hydrochloride (Aldridh, 20 g, 12. 2 mmole) with aqueous NaOH solution (20%, 50 ml) at room temperature for 10 minutes. This was then extracted with CHC / 'PrOH (v. 10: 1, 3 x 200 ml). The extracts were combined, washed with brine (50 ml) and dried over MgSO4. The drying agents were removed by filtration and the filtrates were concentrated under reduced pressure to give the title compound as a white solid (15.5 g, 99% yield). 1H NMR (300 MHz, CD3OD) d 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 2.50-2.95 (m , 5H), 3.10 (ddd, J = 14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCI / NH3): m / z 128 (M + H) +.

Example 4B (3R) -3- (4-Bromophenoxy) quinuclidine The product of Example 4A (1.27 g, 10 mmol) was coupled with 1-iodo-4-bromobenzene (Aldridh, 2.83 g, 10 mol) according to the procedure of Example 1A The title product was purified by chromatography (Si02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, R, 0.30) as a solid (400 mg, yield, 14%). 1H NMR (300 MHz, CD3OD) d 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 (DC1 / NH3): m / z 282 (M + H) +, 284 (M + H) 0 Example 4C 5-4-r (3R) -1-Azabicycloi2.2.21oct-3-yloxy1phenyl > -1H-indole The product of 4C (282 mg, 1 mmol) coupled with 5-indolylboronic acid (Frontier, 190 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by chromatography (Si02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf. 0.35) as a solid (50 mg, yield, 16%). 1H NMR (300 MHz, CD3OD) d 1.44-1.58 (m, 1H), 1.62-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.16-2.24 (m, 1H), 2.74-3.04 (m , 5H), 3.27-3.40 (m, 1H), 4.51-4.59 (m, 1H), 6.46 (dd, J = 3.4, 1.1 Hz, 1H), 6.95 (dt, J = 8.8, 2.6 Hz, 2H), 7.22 (d, J = 3.1 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.40 (dt, J = 8.5, 1.0 Hz, 1H), 7.54 (dt, J = 9.2, 2.6 Hz , 2H), 7.71 (dd, J = 1.7, 0.7 Hz, 1H) ppm. MS (DCI / NH3): m / z 319 (M + H) \ Example 4D Fumarate of 5- (4-r (3R) -1-azabicyclo2.2.21oct-3-yloxy-phenyl} -1-H-indole The product of Example 4C (50 mg, 0.25 mmol) was treated with fumaric acid ( 29 mg, 0.25 mmol) in EtOAc / EtOH (v. 1: 1.4 ml) at room temperature for 10 hours.The title compound was obtained as a solid (56.9 mg, 52% yield) .1H NMR (300 MHz, CD3OD) d 1.78-2.16 (m, 3H), 2.25-2.39 (m, 1H), 2.46-2.54 (m, 1H), 3.14-3.45 (m, 5H), 3.69-3.81 (m, 1H), 4.80- 4.89 (m, 1H), 6.46 (dd, J = 3.0, 1.0, 1H), 6.68 (s, 2.2H), 7.02 (dt, J = 8.8, 2.5 Hz, 2H), 7.23 (d, J = 3.1 Hz , 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.43 (dt, J = 8.4, 0.8 Hz, 1H), 7.58 (dt, J = 9.2, 2.6 Hz, 2H), 7.71 (dd, J = 1.7, 1.0 Hz, 1H) ppm MS (DCI / NH3): m / z 319 (M + H) Anal 0. Calculated for C21H22N20-1.14 C4H404: C, 68.11; H, 5.94; N, 6.21. found: C, 68.12; H, 6.04; N, 6.18.

Example 5 6-r4- (1-azabicic [or2.2.21oct-3-yloxy) phen.p-1H-indole Example 5A 6-r4- (1-Azabicyclo2.2.21oct-3-yloxy) phenin-1H-indole The product of Example 2A (300 mg, 0.8 mmol) was coupled with 6-bromoindole (Aldrich, 196 mg, 1 mmol) according to the procedure in 2B. The title compound was purified by chromatography (Si02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.20) as a solid (30 mg, yield 12%). 1H NMR (300 MHz, CD3OD) d 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 (, 4H) ppm. MS (DCI / NH3): m / z 319 (M + H) \ Example 5B Fumarate of 6-f4- (1-azabiciclof 2.2.21 oct-3-yloxy) feni 11-1 H-indole 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 room temperature for 15 hours. The title compound was obtained as a solid (38.4 mg, 79% yield), 1 H NMR (300 MHz, CD3OD) d 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. Cale, for C19H20N4O-1.3 C4H404: C, 67.05; H, 5.84; N, 5.97. It was found: C, 67.15; H, 5.99; N, 5.95.

Example 6 2-r4- (1-Azabicyclo2.2.21oct-3-yloxy) phenyH-1H-indole Example 6A 3- (4-Ethylphenyloxy) quinuclidine Under N2, the mixture of the product from Example 1A (800 mg, 2.4 mmoles), 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 room temperature. Atmosphere during the night. DMF was then removed under reduced pressure. The residue was treated with tetrabutylammonium fluoride (Aldrich, in THF, 1M, 5 ml) at room temperature for 3 hours. The reaction was monitored with TLF. After the reaction was complete, it was diluted with EtOAc (50 ml) and washed with brine (2 x 10 ml). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf. 0. 30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) d 1.42-1.54 (m, 1H), 1.61-1.87 (m, 2H), 1.93-2.07 (m, 1H), 2.10-2.18 (m, 1H), 2.71-3.00 (m , 5H), 3.19-3.37 (m, 2H), 4.49-4.56 (m, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H) ppm. MS (DCI / NH3): m / z 228 (M + H) 0 Example 6B 2,2,2-Trifluoro-N- (2-iodophenyl) acetamide 2-iodo-phenylamine (Aldrich, 1.09 g, 5 mmol) was treated with trifluoroacetic anhydride (Aldrich, 1.26 g, 6 mmol) and 2.6 -di-tert-butyl-4-methyl-pyridine (Aldrich, 1.23 g, 6 mmol) in CH2CI2 (10 ml) at room temperature overnight. This was then quenched with water (5 ml) and extracted with EtOAc (3 x 10 ml). The extracts were combined and washed with brine (5 ml). The organic solution was concentrated and the title compound was purified by flash chromatography (S02, Hexanes / EtOAc, 80:20, Rf. 0.50) as a solid (1.1 g, yield, 70%). 1H NMR (300 MHz, CD3OD) d 7.07-7.12 (m, 1H), 7.39-7.47 (m, 2H), 7.95 (dd, J = 7.8, 1.3 Hz, 1H) ppm. MS (INN): m / z 316 (M + H) 0 Example 6C 2-r 4 - (1-Azabicyclochloride.2.21oct-3-yloxy) phenyl-1H-indole Under N 2, the mixture of the product from Example 6A (114 mg, 0.5 mmol), the product of Example 6B (157 mg, 0.5 mmol), Cul (Strem Chemicals, 14 mg, 0.075 mmol), PPh3 (Aldrich, 39 mg, 0.15 mmol) and K3P04 (212 mg, 1 mmol) in dioxane (5 mL) was stirred at 80 ° C for 20 hours. After the reaction was complete, it was diluted with EtOAc (30 ml) and washed with brine (2 x 5 ml). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO 2, CH 2 Cl 2: MeOH: NH 3 H 20, 90: 10: 1, Rf 0.30) as a solid (70 mg, yield 44%). 1H NMR (300 MHz, CD3OD) d 1.45-1.59 (m, 1H), 1.65-1.91 (m, 2H), 2.00-2.14 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.01 (m , 5H), 3.31-3.42 (m, 1H), 4.54-4.62 (m, 1H), 6.66 (d, J = 0.7 Hz, 1H), 6.93-7.00 (m, 3H), 7.01-7.08 (m, 1H ), 7.35 (dq, J = 8.2, 1.0 Hz, 1H), 7.48 (dq, J = 7.8, 0.7 Hz, 1H), 7.71 (dt, J = 8.8, 2.6 Hz, 2H) ppm. MS (DCI / NH3): m / z 319 (M + H) 0 Example 6D Fumarate of 2-r4- (1-azabicyclo2.2.21oct-3-yloxy) fe nyl1-1H-indole 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 room temperature for 10 hours. The title compound was obtained as a solid (87 mg, yield, 89%). 1 H NMR (300 MHz, CD 3 OD) d 1.81-2.18 (m, 3 H), 2.25-2.39 (m, 1 H), 2.48-2.56 (m, 1 H), 3.19-3.48 (m, 5 H), 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 C2? H22N20-1.1 C4H404: C, 68.39; H, 5.96; N, 6.28. Found: C, 68.10; H, 6.22; N, 6.25.

Example 7 5-r6- (1-Azabicyclor2.2.21oct-3-yloxy) pyridazin-3-n-1H-indole Example 7A 3-r (6-chloropyridazin-3-yl) oxy-1-quinuclidine tried 3-q ui nucí id inol (Aldrich, 508 mg, 4 mmoles) with 'BuOK (Aldrich, 448 mg, 4 mmol) in THF (20 ml) at room temperature for 1 hour. 3,6-Dichloropyradazine (Aldrich, 740 mg, 5 mmol) was then added. The mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored with TLC. After the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in CHCl3 / 'ProH (v.10: 1, 50 ml) and washed with brine (2 x 5 ml). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO 2, CH 2 Cl 2: MeOH: NH 3 H 20, 90: 10: 1, Rf 0.45) as a solid (780 mg, yield, 82%) . 1H NMR (300 MHz, CD3OD) d 1.48-1.61 (m, 1H), 1.65-1.90 (m, 2H), 1.94-2.08 (, 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) 0 Example 7B 5-r6- (1-Azabicyclo2.2.21oct-3-yloxy) pyridazin-3-yl1-1H-indole The product of Example 7A (200 mg, 0.8 mmol) was coupled with 5-indolylboronic acid (161 mg, 1 mmole) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-87 μm, 40 x 100 mm Eluent solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 for 20 minutes), flow rate, 75 ml / minute, uv, 250 nm) as a solid (35 mg, yield 14%). 1H NMR (300 MHz, CD3OD) d 1.50-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.00--2.16 (m, 1H), 2.29-2.37 (m, 1H), 2.78-3.05 (m , 5H), 3.44-3.55 (m, 1H), 5.26-5.35 (m, 1H), 6.56 (dd, J = 3.3, 1.1 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.31 ( d, J = 3.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.5, 1.7 Hz, 1H), 8.08, (d, J = 9.5 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H) ppm. MS (DCI / NH3): m / z 321 (M + H) +.

Example 7C 5-R6- (1-azabiciclof2.2.21oct-3-yloxy) pyridazin-3-ylMH-indole hemifumarate The product of Example 7B (35 mg, 0.11 mmol) was treated with fumaric acid (23 mg, 0.2 mmol). ) in EtOAc / EtOH (v. 1: 1, 3 ml) at room temperature for 10 hours. The title compound was obtained as a solid (42 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) d 1.76-1.91 (m, 1H), 1.92-2.13 (m, 2H), 2.22-2.36 (m, 1H), 2.51-2.59 (m, 1H), 3.12-3.40 (m , 5H), 3.77-3.88 (m, 1H), 5.42-5.51 (m, 1H), 6.56 (dd, J = 2.0, 1.0Hz, 1H), 6.67 (s, 1H), 7.27-7.33 (m, 2H ), 7.52 (dt, J = 8.5, 1.0 Hz, 1H), 7.74 (dd, J = 8.8, 1.7 Hz, 1H), 8.10-8.16 (m, 2H) ppm. MS (DC1 / NH3): m / z 321 (M + H) 0 Anal. Calculated for C19H20N4O-0.55 C4H404: C, 66.27; H, 5.82; N, 14.58. Found: C, 66.12; H, 5.53; N, 14.63.

Example 8 4-r6- (1-Azabicyclo2.2.2.1oct-3-yloxy) pyridazin-3-yl) -1H-indole Example 8A 4-r6- (1-Azabiciclof2.2.21oct-3-yloxy) pyr dazin-3-ip-1H-indole Under N2, the mixture of Example 7A (168 mg, 0.7 mmol), 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2) -iI) -1H-indole (ref.

WO02055517, 170 mg, 0.7 mmol), Pd2 (dba) 3 (Aldrich, 19 mg, 0.02 mmol), 1,3-bis (2,6-iso-propylphenyl) imidazolium chloride (Strem Chemicals, 26 mg, 0.06 mmol ) and aqueous Na 2 CO 3 (2 M, 1 ml) in toluene (10 ml) was stirred at 110 ° C overnight. After the reaction was complete, it was cooled to room temperature and diluted with EtOAc (30 ml). The mixture was then washed with brine (2 x 5 ml) and the title compound was purified by chromatography (Sio2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf 0.10) as a solid (45 mg, yield, twenty%). 1H NMR (300 MHz, CD3OD) d 1.51-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.01-2.16 (m, 1H), 2.31-2.39 (m, 1H), 2.78-3.09 (m , 5H), 3.45-3.56 (m, 1H), 5.30-5.38 (m, 1H), 6.78 (dd, J = 3.4, 1.0 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.30 ( d, J = 9.5 Hz, 1H), 7.36 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 7.5, 1.0 Hz, 1H), 7.52 (dt, J = 8.1, 1.0 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): m / z 321 (M + H) 0 EXAMPLE 8B 4-r6- (1-Azab i cyclola.2.21 oct-3-i I oxy) pyridazin-3-i 11-1 H-indole fumarate The product of Example 8A (45 mg0.14 mmol) was treated with fumaric acid (23 mg, 0.2 mmol) in EtOAc / EtOH (v. 1: 1, 3 mL) at room temperature for 10 hours. The title compound was obtained as a solid (56 mg, 85% yield). 1H NMR (300 MHz, CD3OD) d 1.90-2.23 (m, 3H), 2.33-2.48 (m, 1H), 2.62-2.70 (m, 1H), 3.21-3.54 (m, 5H), 3.92-4.03 (m , 1H), 5.54-5.62 (m, 1H), 6.69 (s, 2.5H), 6.78 (dd, J = 3.4, 1.0 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.35-7.44 (m, 3H), 7.55 (dt, J = 8.1, 1.1 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): m / z 321 (M + H) 0 Anal. Calculated for C19H20N4O-1.3 C4H404: C, 61.67; H, 5.39; N, 11.89. Found: C, 61.49; H, 5.52; N, 12.17.

Example 9 5-. { 5-f (3R) -1-Azabiciclof 2.2.21 oct-3-yloxy-1-pyridazin-3-yl > -1H-indole Example 9A (3R) -3-f (6-Chloro iridazin-3-yl) oxpquinuclidine The product of Example 4A (635 mg, 5 mmol) was coupled with 3,6-dichloropyridazine (Aldrich, 925 mg , 6.25 mmole) according to the procedure of Example 7A. The title compound was purified by chromatography (Si02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.45) as a solid (750 mg, 63% yield). H NMR (300 MHz, CD3OD) d 1.54-1.68 (m, 1H), 1.71-1.95 (m, 2H), 2.00-2.14 (m, 1H), 2.28-2.36 (m, 1H), 2.83-3.08 (m , 5H), 3.44-3.56 (m, 1H), 5.23-5.30 (m, 1H), 7.24 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): 240 (M + H) +, 242 (M + H) +.

Example 9B 5-. { 6-r (3R) -1-Azabicylchlor2.2.21oct-3-yloxy-1-pyridazin-3-yl-1H-indole The product of Example 9A (480mg, 2 mmole) was coupled with 5-indolylboronic acid (Frontier, 403 mg , 2.5 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 mm Solvent Eluent, MeCN / H20 (with 0.2% v. TFA (v. 90/10 a /90 for 20 minutes). Flow rate, 75 ml / min. uv., 250 nm) as a solid (240 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) d 1.49-1.64 (m, 1H), 1.68-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.05 (m, 5H), 3.43- 3.55 (m, 1H), 5.26-5.34 (m, 1H), 6.56 (dd, J = 3.4, 1.0 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 3.1 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 8.08 (d, J = 9.5 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H) ppm. MS (DCI / NH3): m / z 321 (M + H) +.

Example 9C Fumarate of 5-f6-T (3R) -1-Azabicyclo-2.2.21-oct-3-yloxylpihydraz -3- il > -1H-indole The product of Example 9B (240 mg, 0.75 mmol) was treated with fumaric acid (93 mg, 0.8 mmol) in EtOAc / EtOH (v. 1: 1, 10 mL) at room temperature for 15 hours. The title compound was obtained as a solid (247 mg, 72% yield). 1H NMR (300 MHz, CD3OD) d 1.88-2.22 (m, 3H), 2.31-2.47 (m, 1H), 2.59-2.68 (m, 1H), 3.23-3.50 (m, 5H), 3.89-4.00 (m , 1H), 5.49-5.57 (m, 1H), 6.56 (dd, J = 3.0, 1.0 Hz, 1H), 6.69 (s, 2H), 7.29-7.35 (m, 2H), 7.52 (dt, J = 8.5 , X0 Hz, 1H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 8.12-8.17 (m, 2H) ppm. MS (DCI / NH3): m / z 321 (M + H) +. Anal. Cale, for C19H20N4O-1.1 C4H404-0.4 H20: C, 61.73; H, 5.58; N, 12.31. It was found: C, 61.67; H, 5.52; N, 12.33.

Example 10 5-. { 6-r (3R) -1-Azabicyclo2.2.21oct-3-yloxy-1-pyridazin-3-yl > -3-methyl-1H-indole Example 10A 3-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-d-oxaborolan-2-yl) -1H-indole Under N 2, a mixture of 5-bromo-3-methyl-1 H-indole (Aldrich, 1.05 mg, 5 mmol) bis (pinacolato) diboro (Aldrich, 1.40 g, 5.5 mmol) PdCI2 (dppf) .CH2Cl2 (Aldrich, 122 mg, 0.15 mmol) and KOAc (Aldrich, 1.47 g, 15 mmol) in DMSO (20 ml) was stirred at 90 ° C for 1 hour. The reaction was monitored with TLC. After the reaction was complete, it was then diluted with EtOAc (100 ml) and washed with brine (3 x 10 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 a solid (510 mg, yield, 40%). 1 H NMR (300 MHz, CDCl 3) d 1.38 (s, 12 H), 2.35 (s, 3 H), 6.98 (s, 1 H), 7.34 (dd, J = 8.1, 0.7, Hz, 1 H), 7.65 (dd, J = 8.1, 1.0 Hz, 1H), 8.12 (s, 1H) ppm. MS (DCI / NH3): m / z 258 (M + H) 0 EXAMPLE 10 B 5- (6-R (3R) -1-Azabicyclo2.2.21oct-3-yloxypyridazin-3-yl -3-methyl-1H-indole The product of Example 10A (240 mg, 1 mmol) was coupled with the product of Example 9A (250 mg, 1 mmol) according to the procedure in Example 8 A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, x 100 mm Solvent Eluent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 for 20 minutes, flow rate, 75 ml / min., UV 250 nm) as a solid ( 40 mg, yield, 12%) .1H NMR (300 MHz, CD3OD) d 1.50-1.64 (m, 1H), 1.69-1.92 (m, 2H), 2.01-2.14 (m, 1H), 2.29-2.35 (m , 1H), 2.37 (s, 3H), 2.81-3.04 (m, 5H), 3.43-3.55 (m, 1H), 5.27-5.34 (m, 1H), 7.06 (d, J = 1.4 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 7.44 (dd, J = 8.5, 0.7 Hz, 1H), 7.71 (dd, J = 8.8, 2.0, Hz, 1H), 8.07-8.12 (m, 2H) ppm MS (DCI / NH3): m / z 335 (M + H) 0 Example 10C Fumarate of 5-. { 6-f (3R) -1-Azabicyclo \ 2.2.21 oct-3-i loxylpyridazin-3-yl-3-methyl-1H-indole The product of Example 10B (40 mg, 0.12 mmol) was treated with fumaric acid (23 mg , 0.2 mmol) in EtOAc / EtOH (v. 1: 1, 5 ml) at room temperature for 10 hours. The title compound was obtained as a solid (40 mg, yield, 62%). 1 H NMR (300 MHz, CD 3 OD) d 1.90-2.24 (m, 3 H), 2.33-2.48 (m, 4 H), 2.61-2.68 (m, 1 H), 3.22-3.53 (m, 5 H), 3.93-4.03 (m , 1H), 5.51-5.58 (m, 1H), 6.70 (s, 3.6 H), 7.08 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 9.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.8, 1.7 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 8.17 (d, J = 9.5 Hz, 1H) ppm. MS (DCI / NH3): m / z 335 (M + H) \ Anal. Calculated for C20H22N4O-1.8 C4H404: C, 60.13; H, 5.42; N, 10.31. Found: C, 60.02; H, 5.53; N, 10.27.

Example 11 5-. { 2-r (3R) -1-Azabicyclo2.2.2loct-3-yloxy-1-pyrimidin-5-yl > -1H-indole Example 11 A (3R) -3-f (5-Bromopyrimidin-2-yl) oxyquinuclidine The product of Example 4A (508 mg, 4 mmol) was coupled with 5-bromo-2-iodo-pyrimidine (Aldrich , 1.42 g, 5 mmol) according to the procedure of Example 7A. The title compound was purified by chromatography (S02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf 0.40) as a solid (760 mg, yield, 67%). 1H NMR (300 MHz, CD3OD) d 1.54-1.68 (m, 1H), 1.68-1.95 (m, 2H), 2.03-2.16 (m, 1H), 2.24-2.33 (m, 1H), 2.82-3.11 (m , 5H), 3.41-3.52 (m, 1H), 5.09-5.17 (m, 1H), 8.65 (s, 2H). MS (DCI / NH3): 284 (M + H) + 286 (M + H) +.

Example 11 B 5-. { 2-r (3R) -1-Azab.c.sup.c [or2.2.21oct-3-yloxy-1-pyrimidin-5-yl > -1H-indole The product of Example 11A (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (Aldrich, 193 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by Preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 mm Solvent Eluent, MeCN / H20 (0.2% v.TFA) (v. 90/10 a /90 for 20 minutes. Flow rate, 75 ml / min., UV, 250 nm) as a solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) d 1.50-1.63 (m, 1H), 1.67-1.93 (m, 2H), 2.04-2.17 (m, 1H), 2. 24-2.31 (m, 1H), 2.75-3.05 (, 5H), 3.38-3.48 (m, 1H), 5.14-5.21 (m, 1H), 6.53 (dd, J = 3.1, 0.7 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 7.35 (dd, J = 8.5, 1.7 Hz, 1H), 7.51 (dt, J = 8.5, 0.7 Hz, 1H), 7.80 (dd, J = 1.7, 0. 7 Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI / NH3): m / z 321 (M + H) +.

Example 11 C 5- Hemifumarate. { 2-r (3R) -1-Azabicyclo2.2.21oct-3-yloxy-1-pyrimidin-5-yl) -1H-indole 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 room temperature for 10 hours. The title compound was obtained as a solid (42 mg, yield, 88%). 1H NMR (300 MHz, CD3OD) d 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) 0 Anal. Cale, for C19H20N4O-0.6 C4H404: C, 65.90; H, 5.79; N, 14.36. Found: C, 65.65; H, 5.24; N, 14.41.

Example 12 4-. { 2-r (3R) -1-Azabicylchlor2.2.21oct-3-ylylpyrimidin-5-yl-1H-indole Example 12A 4-. { 2-r (3R) -1-Azabicylchlor2.2.21oct-3-ylylpyrimidin-5-yl > -1H-indole The product of Example 11A (170 mg, 0.6 mmol) was coupled with 4- (4,4,5,5-tetra-methyl- [1,3,2] dioxaborolan-2-yl) -1H-indole ((ref.

WO02055517, 146 mg, 0.6 mmol) according to the procedure in Example 8A. The title compound was purified by chromatography (SiO 2, CH 2 Cl 2: MeOH: NH 3 H 20, 90: 10: 1, Rf. 0.10) as a solid (76 mg, yield, 40%). 1H NMR (300 MHz, CD3OD) d 1.50-1.64 (m, 1H), 1.67-1.93 (m, 2H), 2.05-2.19 (m, 1H), 2.25-2.33 (m, 1H), 2.73-3.12 (m , 5H), 3.39-3.50 (m, 1H), 5.17-5.25 (m, 1H), 6, .55 (dd, J = 3.4, 1.0 Hz, 1H), 7.11 (dd, J = 7.1, 1.0, Hz , 1H), 7.23 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 3.1 Hz, 1H), 7.44-7.49 (m, 1H), 8.85 (s, 2H) ppm. MS (DCI / NH3): m / z 321 (M + H) +.

Example 12B Fumarate of 4-f 2-f (3R) -1-Azabi cid of2.2.21 oct-3-i 1-oxyl pyrimidin-5-ylf-1H-indole The product of Example 12A (76 mg, 0.24 mmol) was treated with fumaric acid (29 mg, 0.25 mmol) in EtOAc / EtOH (v. 1: 1, 4 mL) at room temperature for 10 hours. The title compound was obtained as a solid (94.6 mg, 90% yield). 1H NMR (300 MHz, CD3OD) d 1.88-2.21 (m, 3H), 2.33-2.48 (m, 1H), 2.59-2.66 (m, 1H), 3. 22-3.50 (m, 5H), 3.84-3.95 (m, 1H), 5.41-5.49 (m, 1H), 6.55 (dd, J = 3.4, 1.0 Hz, 1H), 6.68 (s, 2H), 7.11 ( dd, J = 7.5, 1.0 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 3.1 Hz, 1H), 7.48 (dt, J = 8.1, 0.7 Hz, 1H), 8.89 (s, 2H) ppm. MS (DCI / NH3): m / z 321 (M + H) 0 Anal.

Calculated for C19H20N40-C4H4O4: C, 63.29; H, 5.54; N, 12.84. Found: C, 62.95; H, 5.85; N, 12.61.

Example 13 5-. { 2-r (3S) -1-Azabicylchlor2.2.21oct-3-yloxy-1-pyrimidin-5-yl-1H-indole Example 13A (3R) -1-Azabicyclochloride (L) -tartrate 2.2.21oct-3 -yl It was treated (+/-) - 3-quinuclidinol (Sigma, 17.9 g, 77. 5 mmole) with L-tartaric acid (Aldrich, 99% ee, 11.63 g, 77.5 mmol) in EtOH (80%, 222 ml) at room temperature for 1 week. The white solid was removed by filtration and dried under reduced pressure. 6.5 g of benzoate (L) -tartrate of 3- (R) -quinuclidinol was obtained with -80% ee (tested by HPLC) HPLC conditions: chiralpak column AD 25 cm x 4 mm ID. Solvent, EtOH: hexanes = 15: 85. Flow rate, 1 ml / minute, uv, 220 nm. Retention time: (S) -3-quinuclidinol benzoate, 7.87 min; (R) -3-quinuclidinol benzoate 13.3 min.) Recrystallization from the above solid in EtOH (80%, 35 ml) gave the title product (4.5 g, 15%, > 98% ee). MS (DCL / NH3) m / z 232 (M + H) +.

Example 13B (3R) Quinuclidin-3-ol The product of Example 13A (4.5 g, 11.8 mmol) was treated with hydrolysis was NaOH (15%, 40 mL) MeOH (40 mL) at 50 ° C for 10 hours. 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 MgSO4 (anhydrous). The drying agents were removed by filtration and the filtrate was concentrated to give the title product as a white solid (1.35 g, yield, 90%). MS (DCL / NH3) m / z 128 (M + H) 0 Example 13C (3S) -1-Azabicyclo2.2.21oct-3-yl benzoate (D) -tartrate The mother liquor 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 minutes. This was extracted with chloroform (3 x ml). The extracts were combined and dried (MgSO4). The drying agents were removed by filtration. The filtrates were concentrated to give 3-quinuclidinol benzoate (15.25 g, 66 mmol) which was then treated with (D) -tartaric acid (Aldrich, 97% ee, 9.9 g, 66 mmol), in EtOH (80%, 190 mi) at room temperature for 3 days according to the procedure of Example 1A. The title product was obtained (7.0 g, yield, 28%, 92.3% ee).

Example 13D (3S) -Quinuclidin-3-ol The product of Example 13C (7.0 g, 18.4 mmol) was treated with NaOH (aqueous) according to the procedure of Example 1B. The title product was obtained as a white solid (2.0 g, 86% yield) MS (DCI / NH3) m / z 128 (M + H) \ Example 13E (3S) -3-r (5-Bromopyrimidin-2-yl) oxyquinuclidine The product of Example 13D (508 mg, 4 mmol) was coupled with 2-iodo-5-bromo-pyridymine (1.42 g, 5 mmol) according to the procedure of Example 7A. The title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.20) as a solid (780 mg, yield, 69%) as a solid. 1 H NMR (300 MHz, CD 3 OD) d 1.47-1.61 (m, 1 H), 1.63-1.90 (m, 2 H), 1.96-2.12 (m, 1 H), 2.19-2.27 (m, 1 H), 2.73-3.03 (m , 5H), 3.33-3.45 (m, 1H), 5.05-5.14 (m, 1H), 8.64 (s, 2H) ppm. MS (DCI / NH3): 284 (M + H) + 286 (M + H) 0 Example 13F 5-f 2 -R (3S) -1-Azabicyclochlorothiochlorothioxy-2-yl-2-yl-2-yl-2-yl-yl -1 H -indole The product of Example 13E (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (193 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by Preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 m, Eluent Solvent, MeCN / H20 (with 0.2% v. TFA) (v. 90/10 to 10/90 for 20 minutes). of flow, 75 ml / min., UV, 250 nm) as a solid (120 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) d 1.50-1.63 (m, 1H), 1.66-1.92 (m, 2H), 2.03-2.18 (m, 1H), 2.24-2.32 (m, 1H), 2.75-3.07 (m, 5H), 3.38-3.49 (m, 1H), 5.13-5.21 (m, 1H), 6. 53 (dd, J = 3.0, 0.7 Hz, 1H), 7.30 (d, J = 3.4 Hz, 1H), 7.35 (dd, J = 8.5, 1. 7 Hz, 1H), 7.51 (dt, J = 9.2, 0.7 Hz, 1H), 7.80 (dd, J = 1.7, 0.7 Hz, 1H), 8.81 (s, 2H) ppm. MS (DCI / NH3): m / z 321 (M + H) +.

Example 13G Hemifumarate of 5-. { 2-r / (3S) -1-Azabicyclo2.2.21oct-3-ylxylpyrimidin-5-yl} -1H-indole The product of Example 13F (120 mg, 0.38 mmol) was treated with fumaric acid (44 mg, 0.38 mmol) in EtOAc / EtOH (v. 1: 1, 10 mL). The title compound was obtained as a solid (123 mg, yield, 84%). 1H NMR (300 MHz, CD3OD) d 1.75-2.13 (m, 3H), 2.22-2.37 (m, 1H), 2.46-2.54 (m, 1H), 3.03-3.45 (m, 5H), 3.68-3.79 (m , 1H), 5.30- 5.38 (m, 1H), 6.52 (dd, J = 3.1, 1.1 Hz, 1H), 6.67 (s, 1.2H), 7.30 (d, J = 3.1 Hz, 1H), 7.35 (dd) , J = 8.5, 1.7 Hz, 1H), 7.51 (dt, J = 8.5, 0.7 Hz, 1H), 7.80 (d, J = 1.7, 0.7 Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI / NH3): m / z 321 (M + H) \ Anal. Calculated for C19H20N4O-0.6 C4H404: C, 65.90; H, 5.79; N, 14.36. It was found: C, 65.62; H, 5.76; N, 14.40.

Example 14 5-T4- (1-Azabicyclochloride.2.2.1.oct-3-yloxy) phen.p -3-methyl-1 H-indazole trifluoroacetate The product of Example 1A (200 mg, 0.61 mmol) was coupled with t- butyl- (3-methyl-5-trimethylstannanyl-indazole) -1-carboxylate (reference 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 μm, 40 x 100 mm Solvent Eluent, MeCN / H20 (with 0.2% v. TFA) (see 90/10 to 10 / 90 for 20 minutes Flow rate, 75 ml / min., UV, 250 nm) as a solid (70 mg, yield, 26%). 1 H NMR (300 MHz, CD3OD) d 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) 0 Anal Calculated for C21H23N30-1.0 CF3CO2H-0.5 H20: C, 60.52; H, 5.52; N, 9.21 Found: C, 60.79; H, 5.39; N, 9.17 .

Example 15 6-r4- (1-Azabicyclo2.2.21oct-3-yloxy) phenyl-1, 3-benzothiazol-2-amine Example 15A 3-f (4'-Nitro-1,1'-biphenyl-4-yl ) oxyquinuclidine 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 azodicarboxylate, Aldrich 0.81 g, 4 mmol) and Ph3P (Aldrich, 1.04 g, 4 mmol) in THF (anhydrous, Aldrich, 40 ml) at room temperature for two days. The reaction mixture was concentrated. The title product was purified by chromatography ((Si02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf 0.20) as a solid (400 mg, yield, 62%). 1H NMR (300 MHz, CD3OD) d 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H), 2.17-2.24 (m, 1H), 2.66-3.00 (m, 5H), 3.30-3.41 (m , 1H), 4.56-4.64 (ni, 1H), 7.05 (dt, J = 8.8, 2.6 Hz, 2H), 7.68 (dt, J = 9.2, 2.6 Hz, 2H), 7.82 (dt, J = 8.8, 2.7 Hz, 2H), 8.28 (dt, J = 8.8, 2.8 Hz, 2H) ppm MS (DCI / NH3) m / z 325 (M + H) +.

Example 15B 4 '- (1-Azabiciclof2.2.21oct-3-yloxy) -1,1'-biphenyl-4-amine The product of Example 15A (300 mg, 0.92 mmol) was treated with Pd / C (Aldrich, % by weight, 30 mg) in methanol (20 ml) under H2 at room temperature for 30 minutes. After the reaction was completed, the catalyst was removed through a short column of diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the title compound (200 mg, yield, 74%). 1H NMR (300 MHz, CD3OD) d 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m , 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J = 8.8, 2.5 Hz, 2H), 6.91 (dt, J = 8.8, 2.4 Hz, 2H), 7.32 (dt, J = 8.5, 2.5 Hz, 2H), 7.43 (dt, J = 9.2, 2.8 Hz, 2H) ppm. MS (DCI / NH3) m / z 295 (M + H) \ Example 15C 6-T4- (1-Azabicyclor2.2.21oct-3-yloxy) phenyl-1,3-benzothiazol-2-amine The product of Example 15B (200 mg, 0.68 mmol) and KSCN (Aldrich, 140 mg, 1.52 mmoles) were dissolved in HOAc (5 ml). Bromide [Aldrich, 99%, 40 μL, 0.76 mmol, in HOAc (1 mL) was added slowly to the previous solution for 5 minutes. The mixture was stirred at room temperature for an additional 1 hour, and then quenched with aqueous NaOH (10%, 20 ml) at 5-10 ° C. This was then extracted with CHCl3 / 'PrOH (v. 10: 1.2 x 50 ml). The extracts were combined and concentrated under reduced pressure. The title compound was purified by chromatography ((Si02, CH2Cl2: MeOH: NH3.H2O, 90: 10: 1, Rf.0.10) as solid (140 mg, yield, 59%). H NMR (300 MHz, CD3OD) d 1.27-1.37 (m, 1H), 1.51-1.72 (m, 2H), 1.79-1.88 (m, 1H), 2.02-2.07 (m, 1H), 2.51-2.84 (m, 5H), 3.21-3.39 (m, m, 1H), 4.45-4.52 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.5 Hz, 7.45 (dd, J = 8.5, 2.1 Hz, 1H), 7.55 (d, J = 8.5, 2H), 7.90 (d, J = 2.0 Hz, 1H) ppm MS (DCI / NH3) m / z 352 (M + H) 0 Example 15D Bis trifluoroacetate 6-T4- ( 1 -AzabIcichlor2.2.21oct-3-yloxy) phenyl-1,3-benzothiazol-2-amine The product of Example 15C (140 mg, 0.4 mmol) was treated with trifluoroacetic acid (Aldrich, 99%, 114 mg, 80 μl, 1 mmol) in 'ProH (5 ml) at room temperature for 15 hours. The title compound was obtained as a solid (90 mg, yield, 39%). 1H NMR (300 MHz, DMSO-D6) 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 (d, J = 8.5, 2.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.76 [s (broad.), 2H], 7.96 (d, J = 1.7 Hz, 1H) ppm. MS (DCI / NH3): m / z 352 (M + H) +. Anal. Calculated for C20H21N3OS-2.08 CF3C02H C, 49.30; H, 3.95; N, 7.14. Found: C, 49.70; H, 3.42; N, 7.03.

Example 16 6-. { 4-r (3R) -1-Azabicyclo2.2.21oct-3-yloxy1phenyl > -1,3-benzothiazol-2-amine Example 16A (3R) -3-r (4, -N-thre-1,1'-biphenyl-4-yl) oxyquinuclidine The product of Example 4A (1.28 g, 10 mmol) it was coupled with 4-iodo-4'-nitro-biphenyl (TCI, 1.62 g, 5 mmol) according to the procedure of Example 1A. The title product was purified by chromatography (Si02, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.20) as a solid (930 mg, yield, 57%). 1H NMR (300 MHz, CD3OD) d 1.45-1.57 (m, 1H), 1.63-1.91 (m, 2H), 1.97-2.12 (m, 1H), 2.17-2.24 (m, 1H), 2.66-3.00 (m , 5H), 3.30-3.41 (m, 1H), 4.56-4.64 (m, 1H), 7.05 (dt, J = 8.8, 2.6 Hz, 2H), 7.68 (dt, J = 9.2, 2.6 Hz, 2H), 7.82 (dt, J = 8.8, 2.7 Hz, 2H), 8.28 (dt, J = 8.8, 2.8 Hz, 2H) ppm. MS (DCI / NH3) m / z 325 (M + H) 0 Example 16B 4'-r (3R) -1-Azabiciclof2.2.21oct-3-ylox1-1.1'-biphenyl-4-amine The product of Example 16A (580 mg, 1.79 mmol) was treated with Pd / C ( Aldrich, 10% by weight, 100 mg) in ethanol (50 ml) under H2 at room temperature for 30 minutes. After the reaction was completed, 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, 99% yield). H NMR (300 MHz, CD3OD) d 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m , 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J = 8.8, 2.5 Hz, 2H), 6.91 (dt, J = 8.8, 2.4 Hz, 2H), 7.32 (dt, J = 8.5, 2.5 Hz, 2H), 7.43 (dt, J = 9.2, 2.8 Hz, 2H) ppm. MS (DCI / NH3) m / z 295 (M + H) +.

Example 16C Tri (6-f4K3R) -1-Azabicyclochloride2.2.21oct-3-loxi-phenyl > -1,3-benzothiazol-2-amine 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 slowly added to the above solution for 5 minutes. The mixture was stirred at room temperature for an additional 2 hours, and quenched with aqueous NaOH (10%, 20 ml) at 5-10 ° C. This was extracted with CHCl3 / 'ProH (v. 10: 1, 2 x 50 ml). The extracts were combined and concentrated under reduced pressure. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 mm. Solvent Eluent, MeCN / H20 (with 0.2%, v. TFA) (v. 90/10 to 10/90 for 20 minutes). Flow rate, 75 ml / min., UV, 250 nm) as a solid (150 mg, yield, 19%). 1 H NMR (300 MHz, DMSO-D6) d 1.84-2.20 (m, 3 H), 2.22-2.44 (m, 1 H), 2.47-2.69 (m, 1 H), 3.32-3.51 (m, 5 H), 3.74 -3.93 (m, 1H), 4.89-5.02 (m, 1H), 7.01-7.15 (m, 2 H), 7.53 (d, J = 8.5 Hz, 1H), 7.59-7.66 (m, 2 H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H) ppm. MS (DCI / NH3): m / z 352 (M + H) 0 Anal. Calculated for C20H2? N3OS-3.00 CF3C02H C, 45.03; H, 3.49; N, 6.06. Found: C, 44.70; H, 3.42; N, 6.00.

Example 17 Trifluoroacetate of 6-. { 4-r (3R) -1-Azabicyclochlor2.2.21oct-3-yloxy-phenyl > 4-thiocyanato-1,3-benzothiazol-2-amine 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 slowly added to the above solution for 5 minutes, according to the procedure of Example 16C. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 m Solvent Eluent, MeCN / H20 (with 0.2% v. TFA) (see 90/10 to 10 / 90 for 20 minutes) Flow rate 75 ml / min., UV, 250 nm) as a solid (55 mg, yield, 12%). 1 H NMR (300 MHz, MeOH-D 4) d 1.79-2.24 (m, 3 H), 2.22-2.44 (m, 1 H), 2.46-2.65 (m, 1 H), 3.30-3.52 (m, 5 H), 3.74-3.90 (m, 1H), 4.93 (dd, J = 9.2, 5.1 Hz, 1H), 6.96-7.23 (m, 2H) 7.48-7.70 (m, 3H) 7.88 (d, J = 1.7 Hz, 1H) ppm. MS (DCI / NH3): m / z 409 (M + H) +.

EXAMPLE 18 Bis (6-f4-r (3R) -1-Azabicyclochloride.2.2-octyl-3-yloxyl-1-phenyl} -1,4-bromo-1,3-benzothiazole-2-amine The product of Example 16B (250 mg, 0.85 mmol) and KSCN (Aldrich, 165 mg, 1.70 mmol) was dissolved in HOAc (5 mL). Bromine [Aldrich, 99%, 47 μL, 0.90 mmol, in HOAc (1 ml) to the above solution for 5 minutes, according to the procedure of Example 16C. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40 x 100 mm, Eluent Solvent, MeCN / H20 (0.2% v TFA) (see 90/10 to 10 / 90 for 20 minutes), flow rate, 75 ml / min, UV, 250 nm) as a solid (50 mg, yield, 9%). 1 H NMR (300 MHz, MeOH-D 4) d 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, 1H), 4.88-5.03 (m, 1H), 6.96-7.22 (m, 2H), 7.52-7.65 (m, 2 H), 7.68 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H) ppm. MS (DCl / NHs): m / z 430 (M + H) +, 432 (M + H) 0 Anal. Calculated for C2oH2oBrN3OS-2.00 CF3C02H C, 43.78; H, 3.37; N, 6.38. Found: C, 44.70; H, 3.42; N, 6.32.

EXAMPLE 19 N-r4- (3-Methyl-1H-indazol-5-yl) phenyl-quinuclidin-3-arnine Example 19A N- (4-iodophenyl) quinucl-ddin-3-amine 3-quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) with 4-iodo-aniline (Aldrich, 2.19, 10 mmol), Na 2 SO 4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH (OAc) 3 (Aldrich, 3.16 g, 15 mmol) in HOAc (25 ml) at room temperature for 15 hours. After the reaction was completed, the reaction mixture was slowly poured into a flask containing 75 ml of saturated NaHCO 3 and stirred for 20 minutes. This was extracted with EtOAc (3 x 100 ml). The extracts were combined and washed with brine (2 x 20 ml). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO 2, CH 2 Cl 2: MeOH: NH3.H20, 90: 10: 2, Rf.0.10) as oil (3.24 g, yield, 98%). 1H NMR (300 MHz, CD3OD,) d 1.70-1.81 (m, 1H), 1.93-2.04 (m, 2H), 2.08-2.24 (m, 2H), 2.89 (ddd, J = 12.9, 5.1, 2.7 Hz, 1H), 3.12-3.28 (m, 4H), 3.64 (ddd, J = 12.9, 9.5, 2.4 Hz, 1H), 3.79-3.85 (m, 1H), 6.46 (dt, J = 9.0, 2.7 Hz, 2H) , 7.39 (dt, J = 9.1, 2.7 Hz, 2H) ppm. MS (DCI / NH3) m / z 329 (M + H) +.

Example 19B N-f4- (3-Met il-1 H-indazol-5-yl) faith nillquinuclidin-3-amine trifluoroacetate The product of Example 19A (200 mg, 0.61 mmol) was coupled with t-Butyl- (3 - Methyl L-5-trimethylstantan i lidazol) -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 μm, 40 x 100 mm Solvent Eluent, MeCN / H20 (0.2%, v. TFA) (v. 90/10 to 10 / 90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (28 mg, yield, 10%). 1H NMR (300 MHz, CD3OD) d 1.85-1.96 (m, 1H), 2.08-2.15 (m, 2H), 2.24-2.40 (m, 2H), 2.59 (s, 3H), 3.02-3.15 (m, 1H ), 3.20-3.45 (m, 4H), 3.78-3.88 (m, 1H), 3.98-4.06 (m, 1H), 6.77 (dt, J = 8.8, 2.0 Hz, 2H), 7.46-7.52 (m, 3H) ), 7.59 (dd, J = 8.9, 1.6 Hz, 1H), 7.78 (s, 1H) ppm. MS (DCI / NH3): m / z 333 (M + H) +. Anal. Calculated for C2? H2 N4-1.25 CF3C02H: C, 59.43; H, 5.36; N, 11.80. It was found: C, 59.20; H, 4.96; N, 11.62.

EXAMPLE 20 (R) -3-R6- (3-MetHl-1H-indazol-5-yl) -pyridazin-3-yloxy-1-aza-bicyclo2.2.2-octane fumarate Example 20A-3-tert-butylester of acid 3 -methyl-5-trimethylstannyl-indazole-1-carboxylic acid The tert-butyl ester of 5-bromo-3-methyl-indazole was coupled (3.0 g, 9.6 mmol) with hexamethylditin (Aldrich, 4.73 g, 14.4 mmol) catalyzed by Pd (PPh3) 4 (Aldrich, 1.1 g, 0.96 mmol) in anhydrous toluene (Aldrich, 50 ml) at 115 ° C (oil bath ) under N2 for 2 hours. After the reaction proceeded to completion, the black reaction mixture was cooled to room temperature and loaded directly onto a column of flash silica gel (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, 9H) 1.71 (s, 9H) 2.59 (s, 3H) 7.67 (d, J = 8.1 Hz, 1H) 7. 87 (s, 1H) 8.06 (d, J = 8.5 Hz, 1H) ppm. MS (DCI / NH3) m / z 397 (M + H) \ Example 20B (R) -3-r6- (3-Methyl-1H-indazol-5-yl) -pyridazin-3-yloxy-1-azabicyclof2.2.21octane The title product of Example 9A (120 mg, 0.5 mmoles) was coupled with the product of Example 20A (278 mg, 0.7 mmol) under the catalysis of Pd2 (dba) 3 (Aldrich, 24 mg, 0.025 mmol) and ('Bu3P) 2Pd (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 15 hours. After the reaction proceeded to completion, it was diluted with EtOAc (50 ml) and washed with brine (2 x 10 ml). The organic solution was concentrated under vacuum and the residue treated with TFA (1 ml) in CH2Cl2 (5 ml) at room temperature for 2 hours. This one concentrated then. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18 5 μm, 30 x 100 m, eluent solvent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10) (see 90/10 a) 10/90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (68 mg, 41%). 1H NMR (MeOH-D4, 300 MHz) 1.50-1.66 (m, 1H) 1.70-1.94 (m, 2H) 2.01-2.15 (m, 1H) 2.29-2.37 (m, 1H) 2.62 (s, 3 H) 2.81 -3.04 (m, 5H) 3.44-3.56 (m, 1H) 5.28-5.36 (m, 1H) 7.28 (d, J = 9.2 Hz, 1H) 7.59 (d, J = 8.8 Hz, 1H) 8.05 (dd, J = 8.8, 1.4 Hz, 1H) 8.16 (d, J = 9.2 Hz, 1H) 8.31 (s, 1H) ppm. MS (DCI / NH3) m / z 336 (M + H) 0 Example 20C Fumarate of (R) -3-f6- (3-Methyl-1 H -indazol-5-yl) -pyridazin-3-yloxy-1-aza-bicyclo2.2.21 octane 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, ml) to provide the title compound as a solid (59.1 mg, 65%). 1H NMR (MeOH-D4, 300 MHz) 1.82-2.18 (m, 3H) 2.27-2.42 (m, 1H) 2.55-2.66 (m, 4H) 3.21-3.43 (m, 5H) 3.82-3.95 (m, 1H) 5.47- 5.57 (m, 1H) 6.68 (s, 2H) 7.34 (d, J = 9.2 Hz, 1H) 7.60 (d, J = 8.8 Hz, 1H) 8.06 (dd, J = 8.8, 1.7 Hz, 1H) 8.21 (d, J = 9.2 Hz, 1H) 8.32 (s, 1H) ppm. MS (DCI / NH3) m / z 336 (M + H) 0 Anal. Calculated for C19H21N5O-1.0 C4H4O4'0.35 H20: C, 60.35; H, 5.66; N, 15.30. Found: C, 60.06; H, 5.40; N, 15.56.

EXAMPLE 21 Trifluoroacetate of (R) -3-f6- (1-methyl-1H-quinol-5-i) - i -idazin-3-yloxy-1-aza-bicyclof2.2.21-octane The product of Example 4A (120 mg, 0.5 mmol) was coupled with N-methyI-indole-5-boronic acid (Aldrich, 250 mg, 1.5 mmol) catalysed by Pd2 (dba) 3 (24 mg, 0.025 mmol) and ('Bu3P) Pd ( 26 mg, 0.05 mmol) with CsF (Strem Chemicals, 228 mg, 1.5 mmol) in dioxane (8 ml) at 80 ° C under N2 for 16 hours according to the procedure of Example 20B. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18 5 μm, 30 x 100 m Solvent Eluent, MeCN / H20 (with 0.2% v. TFA) (see 90/10 to 10 / 90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (109.9 mg, 49%). 1 H NMR (MeOH-D 4, 300 MHz) 1.91-2.25 (m, 3 H), 2.34-2.48 (m, 1 H), 2.61-2.70 (m, 1 H), 3.33-3.56 (m, 5 H), 3.86 (s) , 3H), 3.94-4.04 (m, 1H), 5.50-5.59 (m, 1H), 6.56 (d, J = 3.1 Hz, 1H), 7.25 (d, J = 3.1 Hz, 1H), 7.29-7.36 ( m, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 8.6, 1.9 Hz, 1H), 8.10-8.19 (m, 2 H) ppm. MS (DCI / NH3) m / z 335 (M + H) +. Anal. Calculated for C20H22N4O-1.075 C2F302H: C, 58.22; H, 5.09; N, 12.26. It was found: C, 58.21; H, 5.00; N, 12.30.

EXAMPLE 22 (R) - (5-r6- (1-Aza-bicyclo2.2.21oct-3-yloxy) -pyridazin-3-yn-1H-indol-3-ylmethyl bis-dimethoxy-dimethylamine Example 22A (R) -f5-f6- (1-Azabicyclo2.2.21oct-3-yloxy) -pyridazin-3-yn-1H-indol-3-ylmethyl-dimethyl-amine The product of Example 9B (150 mg, 0.47 mmol) was treated with HCHO (Aldrich, 37%, 76 mg, 0.94 mmol) and dimethylamine (Aldrich, 42 mg, 0.94 mmol) in dioxane / HOAc (v.1: 1.5 ml) at room temperature for 16 hours. It was then concentrated and the title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18 5 μm, 30 x 100 mm Solvent Eluent, MeCN / H20 (NH4HC03, 0. 1 M, pH = 10) (v. 90/10 to 10/90 for 20 minutes). Flow rate, 75 ml / min., UV, 250 nm) as a solid (80 mg, 45%). 1H NMR (MeOH-D4, 300 MHz) 1.59-1.75 (m, 1H), 1.77-1.99 (m, 2H), 2.07-2.23 (m, 1H), 2.36-2.44 (m, 1H), 2.60-2.69 (m, 6 H), 2.91-3.13 (m, 5H), 3.52-3.65 (m, 1H), 4.22 (s, 2 H) , 5.32-5.40 (m, 1H), 7.30 (d, J = 9.5 Hz, 1H), 7.49 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.81 (dd, J = 8.5, 1.7 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H), 8.29 (s, 1H) ppm. MS (DCI / NH3) m / z 378 (M + H) 0 Example 22B Bis ((R) - (5-T6- (1-Azabicyclo r2.2.21oct-3-i I oxy) pyridazin-3-yl-1H-indol-3-ylmethyl fumarate .) - dimethyl amine 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 a white solid (74.8 mg, 53%) .1H NMR (MeOH-D4, 300 MHz) 1.79-2.17 (m, 3 H), 2.25-2.41 (m, 1H), 2.54-2.61 (m, 1H), 2.84. (s, 6 H), 3.19-3.42 (m, 5H), 3.78-3.90 (m, 1H), 4.50 (s, 2H), 5.45-5.54 (m, 1H), 6.66 (s, 5H), 7.34 ( d, J = 9.2 Hz, 1H), 7.54-7.63 (m, 2H), 7.84 (dd, J = 8.5, 1.7 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.35 (s, 1H) ) ppm MS (DCI / NH3) m / z 378 (M + H) 0 Anal.Calcd for C22H27N50-2.5 C4H404-0.5 H20: C, 56.80; H, 5.66; N, 10.35 Found: C, 56.62; H, 5.78; N, 10.09.

EXAMPLE 23 (1 R) -3-f6- (1 H -indol-5-yl) -pyridazin-3-yloxy-1-aza-bicyclo-2.2-octane-1-oxide trifluoroacetate The product of Example 9B was treated with H202 (Aldrich, 30% aqueous, 1 ml, 8.8 mmol) in acetonitrile (3 ml) for 5 hours. The mixture was quenched by Na 2 SO 3 solution carefully until no more peroxide was observed, and it was then concentrated under vacuum. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 m Solvent Eluent, MeCN / H20 (0.2% v TFA), (v. 90/10 a 10/90 for 20 minutes), flow rate, 75 m! / 7min., UV, 250 nm) as a solid (15.6 mg, 13%). 1H NMR (MeOH-d4, 300 MHz) 2.14-2.38 (m, 3H) 2.55-2.71 (m, 2H) 3.68-3.92 (m, 5H) 4.37-4.47 (m, J = 8.5 Hz, 1H) 5.62-5.70 (m, J = 4.4 Hz, 1H) 6.57 (d, J = 2.0 Hz, 1H) 7.30-7.38 (m, 2 H) 7.52 (d, J = 8.5 Hz, 1H) 7.74 (dd, J = 8.6, 1.9 Hz, 1H) 8.13-8.20 (m, 2H) ppm. MS (ESI) m / z 337 (M + H) \ Anal. Calculated for C19H20N4O2-1.15 CF3C02H: C, 54.72; H, 4.56; N, 11.98. Found: C, 54.72; H, 4.07; N, 12.08.

EXAMPLE 24 Tri (Acid chloride of 6- { Β-f (3R) -1-Aza-bicyclo2.2.21oct-3-yloxy-1-pyridazin-3-yl-benzothiazol-2-ylamine Example 24A 6- (4- Bromo-phenyl) -4,5-dihydro-2H-pyridazin-3-one 4- (4-Bromo-phenyl) -4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) was treated with NH2NH2.H20 ( Aldrich, 55%, 9.1 ml, 156 mmol) in EtOH (Aldrich, 100 ml) was refluxed for 2 hours, which was cooled to room temperature and the white solid was filtered off to give the title compound (24.2 g, 98%). %) .1H NMR (CDCl3, 300 MHz) d 2.50-2.76 (m, 2H), 2.85-3.09 (m, 2H), 7.43-7.71 (m, 4H), 8.55 (s, 1H) ppm MS (DCI) NH 3) m / z 253 (M + H) +, 255 (M + H) +, 270 (M + NH 4) + 272 (M + NH 4) +.

Example 24B 6- (4-Bromo-phenyl) -4,5-dihydro-2H-pyridazin-3-one The product of Example 24A (24.0 g, 95 mmol) was oxidized with bromine (Aldrich, 18.81 g, 6.1 ml, 104.5 mmole) in HOAc (Aldrich, 200 ml) at 100 ° C for 1 hour. The brown mixture was then cooled to room temperature. The white solid was removed by filtration and the filtrate was washed with water (2 x 20 ml). The solid was collected and dried under vacuum to give the title compound (25.0 g, 100%). 1 H NMR (CDCl 3, 300 MHz) d 7.07 (d, J = 10.2 Hz, 1 H), 7.55-7.69 (m, 4 H), 7.72 (d, J = 9.8 Hz, 1 H) ppm. MS (DCI / NH3) m / z 251 (M + H) \ 253 (M + H) +, 268 (M + NH4) +, 270 (M + NH4) 0 Example 24C 3- (4-Bromo-phenyl) -6-chloro-pyridazine The product from Example 24B (25.0 g, 100 mmol) was stirred in POC (Aldrich, 200 ml) at 100 ° C for 18 hours. The majority of POCL3 was extracted by filtration (about 150 ml was collected). The residue was then poured into 300 ml of ice / water and stirred vigorously for 1 hour. The solid was removed by filtration. The filtrate was washed with water (2 x 50 ml) and dried under vacuum to give the title compound (26.2 g, 98%). 1 H NMR (MeOH-D 4, 300 MHz) d 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, 1H) ppm. MS (DCI / NH3) m / z 269 (M + H) +, 271 (M + H) +, 273 (M + H) +.

Example 24D (3R) -3-r6- (4-Bromo-phenyl) pyridazin-3-yloxy-1-aza-bicyclo2.2.21 octane The product of Example 24C (2.43 g, 9 mmol) was coupled with the product of Example 4A (1.27 g, 10 mmol) using í-BuOK (Aldrich, 1.12 g, 10 mmol) as the base in THF (anhydrous, Aldrich, 50 ml) according to the procedure of Example 7A. The title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3H20, 90: 10: 2, Rf.0.30) as a light yellow solid (3.30 g, 100%). 1 H NMR (MeOH-D 4, 300 MHz) 1.47-1.66 (m, 1H), 1.66-1.93 (m, 2 H), 1. 96-2.18 (m, 1H), 2.23-2.42 (m, 1H), 2.71-3.06 (m, 5 H), 3.38-3.58 (m, 1H), 5.17-5.47 (m, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.59-7.78 (m, 2H), 7.82-7.99 (m, 2H), 8.06 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3) m / z 360 (M + H) +, 362 (M + H) 0 Example 24E. { 4-r6-r (3R) -1-Aza-bicyclo2.2.21oct-3-yloxy-1-pyridazin-3-in-phenyl-benzhydryleideamine The product of Example 24D (360 mg, 1 mmol) was coupled with benzhydryl amine (Aldrich, 270 mg, 1.5 mmol) under the catalysis of Pd2 (dba) 3 (Aldrich, 18.3 mg, 0.02 mmol) and Xantphos (Strem Chemicals, 36 mg, 0.06 mmol) with t-BuONa (Aldrich, 150 mg, 1.5 mmol) in toluene (anhydrous, Aldrich, 10 ml) at 100 ° C for 2 hours. The mixture was then cooled to room temperature and diluted with EtOAc (50 ml), washed with water (2 x 5 ml). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.4) as a solid (360 mg, yield 78%). H NMR (300 MHz, CD3OD) d 1.45-1.63 (m, 1H), 1.64-1.94 (m, 2H), 1.94-2.13 (m, 1H), 2.23-2.41 (m, 1H), 2.71-3.06 (m , 5 H), 3.39-3.55 (m, 1H), 5.10-5.37 (m, 1H), 6.82-6.93 (m, 2 H), 7.12-7.23 (m, 3H), 7.25-7.35 (m, 3H) , 7.39-7.57 (m, 3H), 7.67-7.74 (m, 2H), 7.74-7.83 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): 461 (M + H) 0 Example 24F 4-. { 6-r (3R) -1-Aza-bichloro2.2.21oct-3-yloxy-1-pyridazin-3-yl > phenylamine The product of Example 24E (360 mg, 0.78 mmol) was treated with HCl (10% aqueous, 5 ml) in THF (5 ml) at room temperature for 4 hours. This was then concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.1) as a solid (210 mg, yield, 90%). H NMR (300 MHz, CD3OD) d 1.44-1.66 (m, 1H), 1.65-1.94 (m, 2H), 1.95-2.16 (m, 1H), 2.20-2.40 (m, 1H), 2.68-3.06 (m , 5 H), 3.37-3.57 (m, 1H), 5.15-5.37 (m, 1H), 6.65-6.89 (m, 2 H), 7.18 (d, J = 9.5 Hz, 1H), 7.55-7.81 (m , 2H), 7.93 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): 297 (M + H) +.

Example 24G 6- 6-T (3 R) -1-Aza-bi-cyclole .2.21 Oct-3-i Ixyl-p-ridyl-3-i-P-benzothiazole -2 -lamin The product of Example 24F (150 mg, 0.5 mmol) was treated with KSCN (Aldrich, 97 mg, 1 mmol) and bromine (Aldrich, 96 mg, 0.6 mmol) in HOAc (5 mL) at room temperature for 0.5 hours. This was quenched with Na 2 SO 3 (10% aqueous, 1 ml) and concentrated. The title compound was purified by chromatography (SiO 2, CH 2 Cl 2: MeOH: NH 3 H 20, 90: 10: 2, Rf 0.1) as a solid (170 mg, yield, 80%). 1H NMR (300 MHz, CD3OD) • 1.60-1.70 (m, 1H), 1.72-1.98 (m, 2 H), 2.02-2.19 (m, 1H), 2.23-2.42 (m, 1H), 2.82-3.13 ( m, 5H), 3.42-3.68 (m, 1H), 5.15-5.54 (m, 1H), 7.26 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.87 (dd , J = 8.6, 1.9 Hz, 1H), 8.07 (d, J = 9.5 Hz, 1H), 8.23 (d, J = 1.4 Hz, 1H) ppm. MS (DCI / NH3): 354 (M + H) +.

Example 24H Tri (acid chloride) of 6-. { 6-f (3R) -1-Aza-bicyclo2.2.21oct-3-yloxy-pyridazin-3-yl} -benzothiazole-2-ylamine The product of Example 24G (170 mg, 0.48 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2 mmol) in EtOAc (anhydrous, Aldrich, 5 mL) at room temperature. environment for 0.5 hour to give the title compound as a yellow solid (170 mg, yield, 77%). H NMR d 1.88-2.29 (m, 3 H) 2.30-2.42 (m, 1H) 2.57-2.75 (m, 1H), 3.33-3.60 (m, 5H), 3.99 (dd, J = 14.2, 8.1 Hz, 1H ), 5.41-5.71 (m, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 8.16 (dd, J = 8.5, 1.7 Hz, 1H), 8.26 (d, J = 9.2 Hz, 1H), 8.48 (d, J = 1.4 Hz, 1H) ppm; MS (DCI / NH3): 354 (M + H) +. Anal. Calculated for C15H19N5OS-3.00 HCM.00 H20: C, 44.96; H, 5.03; N, 14.56. Found: C, 44.70; H, 5.17; N, 14.24.

Example 25 Tri (acid chloride) of (3R) -3-r6- (3-Bromo-1 H -indol-5-yl) -pyridazin-3-yloxy-1-aza-bicyclo2.2.21octane Example 25A ( 3R) -3 -T6- (3-B rom Q-1 H -indole -5-i I) -pi ridazin-3-i I oxyl-1-azabicyclo r2.2.21octane The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10 ml) and treated with HOAc (Sigma, 60 mg, 1 mmol) for 10 minutes. N-Bromosuccinimide (Aldrich, 110 mg, 0.6 mmol) was added slowly in MeCN (Aldrich, 5 ml) for 5 minutes. The mixture was stirred for 1 hour at room temperature and concentrated in vacuo. The title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf.0.15) as a solid (70 mg, 35% yield). 1H NMR (300 MHz, CD3OD) d 1.55-1.62 (m, 1H), 1.70-1.96 (m, 2H), 2.05-2.20 (m, 1H), 2.29-2.43 (m, 1H), 2.74-3.13 (m , 5 H), 3.42-3.66 (m, 1H) 5.24-5.46 (m, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.38 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.82 (dd, J = 8.5, 1.7 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J = 9.5 Hz, 1H) ppm. MS (DCI / NH3): 399 (M + H) +, 401 (M + H) +.

Example 25B Tri (acid chloride) of (3R) -3-rß- (3-Bromo-1 H -indol-5-yl) -pyridazin-3-yloxy-1-aza-bicyclo2.2.21octane The product of Example 25A (50 mg, 0.125 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.25 mL, 1 mmol) in EtOAc (anhydrous, 5 mL) at room temperature for 1 h to give the title compound as a yellow solid (60 mL). mg, yield, 95%). 1 H NMR (300 MHz, CD 3 OD) d 1.89-2.28 (m, 3 H), 2.29-2.56 (m, 1 H), 2. 63-2.80 (m, 1H), 3.35-3.71 (m, 5H), 3.81-4.10 (m, 1H), 5.37-5.74 (m, 1H), 7.56 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H) 7.80 (dd, J = 8.5, 1.8 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H) 8.21 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 9.5 Hz, 1H) ppm; MS (DCI / NH3): 399 (M + H) \ 401 (M + H) +. Anal. Calculated for C19H19BrN4O-3.00 HCI-1.50 H20: C, 42.60; H, 4.70; N, 10.46. It was found: C, 42.59; H, 4.79; N, 10.09.

Example 26 Bis (acid chloride) of 5-. { 6-r (3R) -1-Aza-bicyclo2.2.21oct-3-yloxyl-pyridazin-3-ylf-1,3-dihydro-indol-2-one Example 26A 5- (4,4,5, 5-tetramethyl-ri, 3,21-dioxaborolan-2-yl) -1,3-dihydro-indol-2-one. 5-Bromo-1,3-dihydro-indol-2-one (Aldrich, 1.06 g, 5%) was coupled. mmoles) with bis (pinacolato) diboro (Aldrich, 1.52 g, 6 mmol) catalyzed by PdCI2 (dppf92.CH2CI2 (Aldrich, 82 mg, 0.1 mmol) using KOAc (Aldrich, 0.98 g, 10 mmol) as the base in dioxane (anhydrous) , Aldrich, 50 ml) at 80 ° C for 10 hours.After cooling to room temperature, the mixture was diluted with EtOAc (50 ml) and washed with brine (2 x 10 ml) .The organic solution was then concentrated under The title compound was purified by chromatography (Si02, hexane: EtOAc, 70:30, Rf.0.5) as a solid (0.96 g, yield, 74%). 1 H NMR (300 MHz, CDCl 3) • 1.24 (s) , 3H), 1.28 (s, 3H), 1.34 (s, 6H), 3.69 (s, 2H), 6.86 (d, J = 7.8 Hz, 1H), 7.57-7.78 (m, 2 H) ppm MS ( DCI / NH3): 260 (M + H) 0 Example 26B 5- (6-r (3R) -1-Aza-bicyclo2.2.21oct-3-yloxy-1-pyridazin-3-yl-1,3-dihydro-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 / Na 2 CO 3 (aq, 1 M) (v 1/1/1, 4.5 ml) at 130 ° C at 330 watts for 15 minutes in a microwave Emry ™ Creator. The inorganic solid was removed by filtration with a syringe filter and the mixture was purified directly by chromatography (Si02, EtOAc: MeOH (v. 2% NH3.H2O), 50:50, Rf.0.2) to give the compound of the title (240 mg, 71%). 1 H NMR (300 MHz, MeOH-D 4) d 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, 2H), 3.47-3.65 (m, 1H), 5.16-5.49 (m, 1H), 7.02 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.73-7.90 (m, 2 H), 8.01 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): 337 (M + H) 0 Example 26C Bis (acid chloride) of 5-6-r (3R) -1-Aza-bicyclo2.2.21oct-3-yloxy-1-pyridazin-3-yl) -1,3-dihydro-indol-2-one The product of Example 26B (80 mg, 0.24 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.25 mL, 1 mmol) in ETOAc (anhydrous, 5 mL) at room temperature for 1 hour to give the title compound as a solid. yellow (100 mg, yield, 100%). 1 H NMR (300 MHz, MeOH-D 4) d 1.89-2.28 (m, 3 H), 2.29-2.49 (m, 1 H), 2.60-2.72 (m, 1 H), 3.34-3.63 (m, 5 H), 3.67 (s) , 2H), 3.81-4.10 (m, 1H), 5.45-5.71 (m, 1H), 7.12 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.82-7.97 ( m, 1H), 8.46 (d, J = 9.5 Hz, 1H) ppm; MS (DCI / NH3): 337 (M + H) 0 Anal. Calculated for C19H20N4O-22.00 HCI-2.00 H20: C, 51.24; H, 5.88; N, 12.58. It was found: C, 51.34; H, 5.75; N, 12.62.

Example 27 Bis (acid chloride) of 5- (6-r (3R) -1-Oxi-1-Aza-bichloride.2.21-oct-3-yloxyl-pyridazin-3-yl) -1,3-dihydro- indole-2-one Example 27A 5-. { 6-r (3R) -1-Oxy-1-Aza-bicyclo2.2.21oct-3-yloxy-iridazin-3-yl-1,3-dihydro-indol-2-one The product of Example 26B (100 mg, 0.30 mmol) was treated with H202 (Aldrich, 30%, 0.5 ml, 1.3 mmol) in MeCN / H20 (v. 4/1, 10 ml) at 60 ° C for 70 hours according to the procedure of Example 23. The compound The title was purified by chromatography (SiO 2, EtOAc: MeOH (v. 2% of NH.sub.3 H20), 50:50, Rf.0.1) as a solid (80 mg, 76%). 1 H NMR (300 MHz, MeOH-D 4) d 1.89-2.28 (m, 3 H), 2.29-2.49 (m, 1 H), 2.60-2.72 (m, 1 H), 3.34-3.63 (m, 5 H), 3.67 (s) , 2H), 3.81-4.10 (m, 1H), 5.45-5.71 (m, 1H), 7.12 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.82-7.97 ( m, 1H), 8.46 (d, J = 9.5 Hz, 1H) ppm; MS (DCI / NH3): 337 (M + H) +. Anal. Calculated for C19H20N4O-22.00 HCI-2.00 H20: C, 51.24; H, 5.88; N, 12.58. It was found: C, 51.34; H, 5.75; N, 12.62.

Example 27B Bis (acid chloride) of 5-. { 6-f (3R) -1-Oxi-1-Aza-bicyclo2.2.21oct-3-yloxy-1-pyridazin-3-ylf-1,3-dihydro-indol-2-one The product of Example 27A (80 mg, 0.23 mmol) was treated with HCl (Aldrich, 4M in dioxane, 0.25 ml, 1 mmol) in / -ProH (5 ml) at room temperature for 1 hour to give the title compound as a yellow solid (90 mg, yield, 93%). 1H NMR d 2.10-2.50 (m, 3H), 2.54-2.81 (m, 2H), 3.35 (s, 2H), 3.71-3.94 (m, 4H), 4.02 (d, J = 13.2 Hz, 1H), 4.30 -4.58 (m, 1H), 5.51-5.86 (m, 1H), 7.18 (d, J = 8.9 Hz, 1H), 7.84-8.00 (m, 2 H), 7.99 (d, J = 9.2 Hz, 1H) , 8.63 (d, J = 9.2 Hz, 1H) ppm; MS (DCI / NH3): 353 (M + H) 0 Anal. Calculated for C19H20N403-2.00 HCI-1.65 H20: C, 50.15; H, 5.60; N, 12.31. Found: C, 49.77; H, 5.29; N, 12.03.

Example 28 Trifluoroacetate of 5-. { 6-r (3R) -1-Aza-bicyclo2.2.2loct-3-yloxyl-pyridazin-3-yl} -1,3-D-Hydro-benzoimidazol-2-one Example 28A (4-Bromo-2-nitro-phenyl) -carbamic acid tert-butylester 4-Bromo-2-nitro-phenylamine (Aldrich, 10.8 g , 50 mmol) with di (tert-butyl) dicarbonate (Aldrich, 11.99 g, 55 mmol) in THF (Aldrich, 100 ml) at reflux for 6 hours. This was then concentrated and the title compound was purified by recrystallization from EtOH as a white solid (12.8 g, yield, 81%). 1 H NMR (300 MHz, MeOH-D 4) d 1.40 (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, 1H) ppm. MS (DCI / NHs): 334 (M + H) +, 336 (M + H) +.

Example 28B r2-Nitro-4- (4,4,5,5-tetramethyl-1,3,31-dioxaborolan-2-yl) -phene-carbamic acid tert-butylester The product of Example 28A (10.05 g, 30 mmol) was coupled with bis (pinacolato) diboro (Aldrich, 9.14 g, 36 mmol) under the catalysis of PdCI2 (dppf) 2.CH2CI2 (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 (SiO2, hexane: EtOAc, 70:30, Rf 0.5) as a solid (9.0 g, yield, 83%). 1 H NMR (300 MHz, CDCl 3) 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 Hz, 1 H), 8.45 (d, J = 1.4 Hz, 1H) ppm. MS (DCI / NHs): 382 (M + NH4) 0 Example 28C Ter-Butylester of the acid. { 4-. { 6-f (3R) -1-Aza-bicyclo2.2.21oct-3-yloxyl-pyridazin-3-yl} -2-nitro-phenyl > -carbamic 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 ('Bu3P) 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 chromatography (SiO2, EtOAc: MeOH (v.2% NH3.H20), 50:50, Rf. 0. 3) as a yellow solid (350 mg, 79%). 1 H NMR (300 MHz, MeOH-D 4) d 1.40 (s, 9 H), 1.51-1.70 (m, 1 H), 1.70-1.98 (m, 2 H), 2.00-2.23 (m, 1H), 2.37-2.51 (m, 1H), 2.71-3.18 (m, 5H), 3.47-3.69 (m, 1H), . 33-5.49 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7. 62 (s, 1H), 8.14 (d, J = 9.5 Hz, 1H), 8.37 (dd, J = 8.1, 2.0 Hz, 1H), 8. 80 (d, J = 2.0 Hz, 1H) ppm. MS (DCI / NH3): 442 (M + H) 0 Example 28D 4-. { 6-r (3R) -1-Aza-bicyclo2.2.21oct-3-yloxy-1-pyridazin-3-yl > -2-nitro-phenylamine The product of Example 28C (350 mg, 0.79 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 2 mL, 8 mmol) in EtOH (5 mL) at room temperature for 1 hour. The mixture was concentrated and the title compound was purified by chromatography (Si02, EtOAc: MeOH (v.2% NH3.H20), 50:50, Rf. 0.1) as a white solid (250 mg, 93%). 1 H NMR (300 MHz, MeOH-D 4) d 1.54-1.66 (m, 1H), 1.72-2.02 (m, 2H), 2.07-2.24 (m, 1H), 2.35-2.57 (m, 1H), 2.79-3.18 (m, 5H), 3.48-3.69 (m, 1H), 5.27-5.47 (m, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 9.5 Hz, 1H), 7.66 ( s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 8.08 (dd, J = 9.0, 2.2 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H) ppm. MS (DC1 / NH3): 342 (M + H) +.

Example 28E 4-. { 6-r (3R) -1-Aza-biciclof2.2.21oct-3-yloxy-1-pyridazin-3-yl > -benzene-1,2-diamine The product of Example 28D (200 mg, 0.59 mmol) was hydrogenated under the catalysis of Pd / C (Aldrich, 10% by weight, 50 mg) in EtOH (10 ml) under hydrogen at room temperature. environment for 10 hours. After the reaction proceeded to completion, the catalyst was removed through a short column of diatomaceous earth (~ 2g) and the filtrate was washed with EtOH (2 x 5 ml). The ethanol solution was concentrated to give the title compound (180 mg, yield, 98%). 1H NMR (500 MHz, CD3-OD) d 1.58-1.73 (m, 1H), 1.76-2.00 (m, 2H), 2.06-2.27 (m, 1H), 2.29-2.47 (m, 1H), 2.81- 3.20 (m, 5 H), 3.52-3.68 (m, 1H), 5.11-5.57 (m, 1H), 6.78 (d, J = 8.2 Hz, 1H), 7.12-7.26 (m, 2H), 7.32 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H) ppm. MS (DCI / NH3): 312 (M + H) \ Example 28F 5- (6-r (3R) -1-Aza-bi cyclone.2.21 oct-3 -i loxyl-pyridazin-3-alpha-trifluoroacetate 1,3-dihydro-benzoimidazol-2-one The product of Example 28E (62 mg, 0.2 mmo!) Was treated with 1,1'-carbonyldiimidazole (Aldrich, 50 mg, 0.31 mmol) in THF / DMF (v. : 1.5 ml) at room temperature for 10 hours, which was then concentrated.The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 mm Solvent Eluent, MeCN / H20 (with 0.2% v. TFA), (v. 90/10 to 10/90 for 20 minutes), flow rate, 75 ml / min, uv, 250 nm) as a solid (20.0 mg, 22%). 1H NMR (500 MHz, CD3-OD) d 1.94-2.33 (m, 3 H), 2.30-2.48 (m, 1H), 2.65-2.79 (m, 1H), 3.38-3.70 (m, 6H), 3.94- 4.06 (m, 1H), 5.41-5.73 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.62-7.78 (m, 2 H), 8.00 (d, J = 7.0 Hz, 1H), 8.65 (d, J = 7.3 Hz, 1H) ppm; MS (DCI / NH3): 338 (M + H) + Anal Calculated for C13H19N502- 1.15 CF3CO2H-2.30 H20: C, 47.81; H, 4.89; N, 13.73. It was found: C, 47.69; H, 5.27; N, 14.09.

Example 29 (R) -3-r6- (1H-Benzoimidazol-5-yl) -pyridazin-3-yloxy1-1-azabicycloi2.2.21octane Example 29A (R) -N- (4-r6- (1- Aza-biciclof 2.2.21 oct-3-yloxy) -pyridazi n-3-H-phenyl-acetamide The product of Example 9A (182 mg, 0.76 mmol), N- [4- (4,4,5,5 - tetramethyl I- [1, 3,2] dioxaborolan-2-yl) -phenyl] -acetamide (Aldrich, 500 mg, 1.9 mmol), dichlorobis (triphenylphosphine) palladium (II) (Aldrich, 53 mg, 0.076 mmol) and 2- (Dicyclohexylphosphino) biphenyl (Strem Chemicals, 6.5 mg, 0.019 mmol) were combined with 1 ml each of ethanol, p-dioxane and 1M aqueous sodium carbonate.The mixture was heated in a sealed tube at 150 ° C to 330 watts for 10 minutes in an Emry ™ Creator microwave The mixture was cooled to room temperature, filtered through Celite®, and concentrated on silica. The product was purified by column chromatography (SiO2, 5% methanol containing 1% NH4OH-CH2Cl2) to give the title compound (203 mg, 79%). 1H NMR (300 MHz, CD3OD) • 1.96 (m, 1H), 2.09 (m, 1H), 2.16 (m, 1H), 2.16 (s, 3 H), 2.38 (m, 1H), 2.64 (td, J = 6.5, 3.6 Hz, 1H), 3.33-3.53 (m, 6H), 3.97 (dd, J = 13.9, 8.1 Hz, 1H), 5.54 (m, 1H), 7.32 (d, J = 9.4 Hz, 1H) , 7.69-7.78 (m, 2 H), 7.91-7.98 (m, 2 H), 8.11 (d, J = 9.3 Hz, 1H) ppm; MS (DCI / NH3): m / z 339 (M + H) +.

Example 29B 4- (6-F (3R) -1-Aza-bichloro2.2.21oct-3-yloxy-pyridazin-3-ylph-2-nitro-phenylamine trifluoroacetate To an ice-cooled solution of Example 29A ( 160 mg, 0. 47 mmol) in concentrated sulfuric acid (5 ml) was added 90% nitric acid (0.02 ml, 0.47 mmol). After 2 hours at 4 ° C, the mixture was poured onto ice and neutralized with ice-cooled NaOH (1N aqueous). The mixture was concentrated and the residue was dissolved in MeOH and filtered to give an unpurified red solid. The product was purified by preparative RP HPLC (Symmetry® C-8, 7 μm, 40 x 100 mm, 10-90% MeCN / H20 with 0.2% v TFA) to give the title compound (54 mg, 0.11 mmol , 2. 3%). 1H NMR (400 MHz, CD3OD) d 1.97 (m, 1H), 2.03-2.23 (m, 2H), 2.39 (m, 1H), 2.65 (td, J = 6.5, 3.6 Hz, 1H), 3.35-3.47 ( m, 4 H), 3.49 (m, 1H), 3.85 (m, 1H), 3.97 (dd, J = 14.0, 8.4 Hz, 1H), 5.54 (m, 1H), 7.12 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 9.2 Hz, 1H), 8.04 (dd, J = 8.9, 2.1 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H) ppm. MS (ESI): m / z 342 (M + H) +.

Example 29C (R) -3-r6- (1H-Benzoimidazol-5-yl) -pyridazin-3-yloxy) -1-azabicyclo2.2.21octane The product of Example 29B (29 mg, 0.064 mmol) was dissolved in 2.0 ml of methanol and 6 mg of Pd (OH) 2 / C (Aldrich, 10% by weight) was added. The mixture was stirred under 50 psi of H2 for 30 minutes. The solution was filtered through a nylon membrane and concentrated.

The residue was dissolved in DMF (0.25 ml) and treated with excess triethyl orthoformate (0.1 ml). The solution was heated at 80 ° C for 2 hours, then cooled to room temperature and stirred for 4 hours. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-185 μm, 30 x 100 mm.

Eluent solvent, MeCN / H20 (NH4HC03, 0.1M, pH = 10) (v. 40/60 a 70/30 for 20 minutes). Flow rate, 75 ml / min., UV, 250 nm) as a solid (13 mg, 0.04 mmol, 63%). 1 H NMR (300 MHz, CD 3 OD) d 1.57 (m, 1 H), 1.73-1.94 (m, 2 H), 2.08 (m, 1 H), 2.34 (td, J = 6.4, 3.6 Hz, 1 H), 2.80-3.03 (m, 6 H), 3.50 (ddd, J = 14.5, 8.1, 1.5 Hz, 1H), 5.32 (m, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 8.5 Hz , 1H), 7.91 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.22 (s, 1H), 8.25 (s, 1H) ppm; MS (DCI / NH3): m / z 322 (M + H) 0 EXAMPLE 30 (S) -3-f6- (1 H-lndol-5-yl) -pyridazin-3-yloxy-1-azabicyclo2.2.2-octane fumarate Example 30A (S) -3- (6-chloro- pyridazin-3-yloxy) -1-aza-bicyclo2.2.2-octane 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, CH2Cl2: MeOH: NH3.H20, 90: 10: 2, Rf.0.30) as a solid (346 mg, 72%). 1 H NMR (300 MHz, MeOH-D 4) d 1. 47-1.63 (m, J = 12.9 Hz, 1H), 1.65-1.92 (m, 2H), 1.94-2.10 (m, J = 5.9, 3.6 Hz, 1H), 2.22-2.32 (m, J = 2.7 Hz, 1H), 2.72-3.02 (m, 5H), 3. 36-3.49 (m, 1H), 5.17-5.28 (m, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 9.5 Hz, 1H) ppm. MS (DCI / NH3) m / z 240 (M + H) +, 242 (M + H) 0 Example 30B (S) -3-r6- (1H-lndol-5-yl) pyridazin-3-yloxy1-1-aza-bicyclo2.2.21octane The product of Example 30A (270 mg, 1.1 mmol) was coupled with 5-indoylboronic acid (215 mg, 1.4 mmol) according to the procedure of Example 20B. The title compound was purified by preparative HPLC (Xterra ™, column, Xterra RP-18 5 μm, 30 x 100 m, Eluent Solvent, MeCN / H20 (NH4HC03, 0.1M, PH = 10) (v. 90/10 a 10/90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (200 mg, 57%). 1 H NMR (300 MHz, MeOH-D 4) d 1.49-1.63 (m, 1H), 1.67-1.92 (m, 2H), 1.99-2.14 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.04 (m, 5 H), 3.48 (ddd, J = 14.7, 8.2, 1.9 Hz, 1H), 5.24-5.34 (m, 1H), 6.56 (d, J = 4.1 Hz, 1H), 7.24 (d, J = 9.5 Hz, 1H), 7.30 (d, J = 3.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 8.6, 1.9 Hz, 1H), 8.07 (d, J = 9.5 Hz, 1H), 8.13 (s, 1H) ppm. MS (DC1 / NH3) m / z 321 (M + H) +.

Example 30C (S) -3-R6- (1H-indol-5-yl) -p-ridazin-3-yloxy-1-azabicyclo2.2.21octane fumarate The product of Example 30B (200 mg, 0.625 mmol) was treated with fumaric acid (Aldrich, 73 mg, 0.63 mmol) in EtOAc / MeOH (v.10: 1, 10 mL) at room temperature for 10 hours to give the title compound (240.2 mg, 85% ). 1 H NMR (300 MHz, MeOH-D 4) d 1.87-2.22 (m, 3 H), 2.31-2.45 (m, 1 H), 2.60-2.67 (m, 1 H), 3.30-3.50 (m, 5 H), 3.89-4.00 (m, 1H), 5.49-5.57 (m, 1H), 6.57 (d, J = 3.1 Hz, 1H), 6.68 (s, 2 H), 7.28-7.35 (m, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 8.6, 1.9 Hz, 1H), 8.11-8.19 (m, J = 9.5 Hz, 2H) ppm. MS (DCI / NH3) m / z 321 (M + H) 0 Anal. Calculated for C19H20N4O-1.0 C4O4H4-0.50 H20: C, 62.01; H, 5.66; N, 12.58. Found: C, 61.79; H, 5.46; N, 12.43.

Example 31 Trifluoroacet ato of (R) -3-f5- (1 H-lndol-5-yl) -pyridin-2-yloxyl-1-azabicyclo.2.2.21octane Example 31A (R) -3- (5-Bromo- pyridin-2-yloxy) -1-aza-biciclof2.2.21octane The product of Example 4A (1.27 g, 10 mmol) was coupled with 5-bromo-2-chloro-pyridine (Aldrich, 1.54 g, 8 mmol) according to to the procedure of Example 7A. The title compound was purified by column chromatography (SiO2, CH2Cl2: MeOH: NH3.H20, 90: 10: 1, Rf 0.2) as a solid (2.0 g, yield, 88%). 1 H NMR (MeOH-d, 300 MHz) 1.49-1.64 (m, 1H), 1.66-1.91 (m, 2H), 1.97-2.11 (m, 1H), 2.17-2.26 (m, 1H), 2.77-3.05 ( m, 5H), 3.36-3.47 (m, 1H), 5.02-5.10 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.8, 2.7 Hz, 1H), 8.16 (t, J = 2.5 Hz, 1H) ppm. MS (DCI / NH3) m / z 283 (M + H) +, 285 (M + H) +.

EXAMPLE 31B Trifluoroacetate of (R) -3.r5- (1H-lndol-5-yl) -pyr i din -2 -iloxyl-1-azabicyclo 2.2.2] octane The product of Example 31A (140 mg, 0.5 mmol) was coupled with 5-indolylboronic acid (Ryscor Science, 161 mg, 1.0 mmol) according to the procedure of Example 29A. The title compound by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 mm Solvent Eluent, MeCN / H20 (with 0.2% v. TFA), (see 90/10 to 10 / 90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (72.9 mg, 32%). 1 H NMR (MeOH-d 4, 300 MHz) 1.86-2.22 (m, 3H), 2.31-2.46 (m, 1H), 2.52-2.63 (, 1H), 3.29-3.50 (m, 5H), 3.85-3.97 (m , 1H), 5.34-5.42 (m, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 7.24-7.35 (m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 8.00 (dd, J = 8.6, 2.5 Hz, 1H), 8.38 (d, J = 2.7 Hz, 1H) ppm. MS (DCI / NH3) m / z 320 (M + H) +. Anal. Calculated for C2oH2? N30-1.14 CF3C02H: C, 59.55; H, 4.97; N, 9.35. It was found: C, 59.59; H, 4.99; N, 9.03.

EXAMPLE 32 1-(3R) -3-f5- (1 H -indol ^ -in-pyrimidin ^ -yloxyl-1-azabicyclol ^^^ loctane) The product of Example 12A (10 mg, 0.03 mol) was oxidized with H202 (Aldrich, 30% aqueous) according to the procedure of Example 23. The title compound was purified by chromatography [Si02, CH2Ci2: MeOH (v. 5% NH3-H20) 90:10]. 1H NMR (300 MHz, CD3OD) d 2.01-2.32 (m, 3H), 2.42-2.64 (m, 2H), 3.41-3.70 (m, 5H), 3.91-4.24 (m, 1H), 5.39-5.59 (m , 1H), 6.55 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 3.0 Hz, 1H ), 7.47 (d, J = 8.0 Hz, 1H), 8.96 (s, 2 H) ppm.

EXAMPLE 33 Bis (Acid Chloride) of (3R) -3- (5-Benzooxazol-5-yl-pyridimin-2-yloxy) -1-aza-bicyclo2.2.21octane Example 33A 1 -Benzyloxy-4-bromo -2- Nitro-benzene 4-Bromo-2-nitro-phenol (Aldrich, 2.18 g, 10 mmol) was treated with K2C03 (Aldrich, 2.76 g, 20 mmol) in DMF (Aldrich, 100 ml) at room temperature for 20 minutes. Benzyl chloride (Aldrich, 1.52 g, 12 mmol) was added. The mixture was stirred at 100 ° C for 6 hours. This was then poured into ice / water (200 ml) and stirred at room temperature for 10 hours. The white solid was filtered and dried to give the title compound (3.0 g, yield, 100%). 1 H NMR (300 MHz, CDCl 3) d 5.23 (s, 2 H), 7.01 (d, J = 9.2 Hz, 1 H), 7.31-7.49 (m, 5 H), 7.58 (dd, J = 9.0, 2.5 Hz, 1 H) , 7.98 (d, J = 2.7 Hz, 1H) ppm. MS (DCI / NH3): 325 (M + H) +, 327 (M + H) 0 Example 33B f2-Nitro-4- (4,4,5,5-tetramethyl-ri, 3,21-, dioxaborolan-2-yl) -phenocarbamic acid tert-butylester The product of Example 33A (3.0 g, 10 mmol) was coupled with bis (pinacolato) diboron (Aldrich, 3.04 g, 12 mmol) according to the procedure of Example 28B. The title compound was purified by chromatography (Si02: hexane: EtOAc, 70:30, Rf 0.5) as a solid (3.05 g, yield, 86%). 1 H NMR (300 MHz, MEOH-D 4) 6 1.34 (s, 12 H), 5.30 (s, 2 H), 7.27-7.43 (, 4 H), 7.42-7.51 (m, 2 H), 7.89 (dd, J = 8.3, 1.5 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H) ppm. MS (DCI / NH3): 373 (M + NH4) 0 EXAMPLE 33C (3R) -3-r5- (4-Benzyloxy-3-nitro-phenyl) -pyrimidin-2-yloxy-1-azabicyclo.2.21octum The product of Example 11A (1.42 g, 5 mmol. ) was coupled with the product of Example 33B (2.50 g, 7.0 mmole) according to the procedure of Example 20B. The title compound was purified by chromatography (Si02, EtOAc: MeOH (v. 2% of NH3.H20) 50:50, Rf.0.3) as a solid (1.75 g, 81%). 1 H NMR (300 MHz, MeOH-D 4) d 1.46-1.61 (m, 1H), 1.63-1.92 (m, 2H), 1.97-2.15 (m, 1H), 2.17-2.33 (m, 1H), 2.69-3.04 (m, 5 H), 3.35-3.49 (m, 1H), 5.11-5.22 (, 1H), 5.34 (s, 2 H), 7.25-7.55 (m, 5 H), 7.85 (dd, J = 8.8, 2.4 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H), 8.82 (s, 2 H) ppm. MS (DCI / NH3): 433 (M + H) \ Example 33D 2-A ino-4-. { 2-r (3R) -1-aza-bicyclo2.2.21oct-3-yloxy-1-pyrimidin-5-yl > - phenol The product of Example 33C (380 mg, 0.88) was hydrogenated under the catalysis of Pd / C (Aldrich, 10% by weight, 100 mg) according to the procedure of Example 28E. The title compound was obtained as a yellow solid (220 mg, yield, 92%). 1H NMR (300 MHz, CD3OD) d 1.47-1.93 (m, 3 H), 1.95-2.35 (m, 2H) 2.70-3.05 (, 5H), 3.33-3.48 (m, 1H), 5.04-5.30 (m, J = 8.8 Hz, 1H), 6.72-6.88 (m, 2H), 6.98 (d, J = 1.7 Hz, 1H), 8.70 (s, 2 H) ppm. MS (DCI / NH3): 313 (M + H) +.

Example 33E (3R) -3- (5-Benzooxazol-5-yl-pyrimidin-2-yloxy) -1-azabicyclo2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthoformate (Aldrich, 0.5 ml) in DMF (1 ml) at 100 ° C for 10 hours. This one concentrated then. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 m Solvent Eluent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10) (see 90/10 at 10/90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (50.0 mg, 78%). 1H NMR (300 MHz, CD3-OD) d 1.46-1.64 (m, 1H), 1.64-1.93 (m, 2H), 2.00-2.19 (m, 1H), 2.19-2.39 (m, 1H), 2.67-3.13 (m, 5H), 3.36-3.51 (m, 1H), 5.09-5.38 (m, 1H), 7.72 (dd, J = 8.5, 2.0 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 8.53 (s, 1H), 8.87 (s, 2 H) ppm; MS (DCI / NH3): 323 (M + H) +.

Example 33F Bis (acid chloride) of (3R) -3- (5-Benzooxazol-5-yl-pyrimidin-2-yloxy) -1-aza-bicyclo2.2.21octane The product of Example 33E (50 mg, 0.15 mmol) was dealt with HCl (Aldrich, 4M in dioxane, 0.50 mL, 2.0 mmol) in EtOAc (5 mL) at room temperature for 1 hour to yield the title compound as a yellow solid (55.0 mg, 93%). 1H NMR (300 MHz, CD3-OD) d 1.83-2.28 (m, 3H), 2.30-2.50 (m, 1H), 2.58-2.75 (m, 1H), 3.34-3.51 (m, 5H), 3.84-3.97 (m, 1H), 5.33-5.52 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.51-7.67 (m, 1H), 7.80 (s, 1H), 8.09 (s, 1H), 8.81 (s, 2 H) ppm; MS (DCI / NH3): 323 (M + H) 0 Anal. Calculated for C18H18N402 • 2.38 HCI-2.60 H20: C, 47.41; H, 5.65; N, 12.29. It was found: C, 47.33; H, 5.25; N, 11.92.

EXAMPLE 34 (3R) -3-R5- (2-Methyl-benzooxazol-5-yl) -pyridin-2-yloxy-1-aza-bicyclo2.2.2-octane acid chloride Example 34A (3R) -3-r5 - (2-Methyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-1-azabicyclo2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthoacetate (Aldrich, 0.5 ml. ) in DMF (1 ml) at 100 ° C for 10 hours. This one concentrated then. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μ, 30 x 100 mm, eluent solvent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10) (see 90/10). at 10/90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (20.0 mg, 30%). 1H NMR (500 MHz, CD3OD) d 1.51-1.64 (m, 1H), 1.66-1.77 (m, 1H), 1.78-1.91 (m, 1H), 2.02-2.16 (m, 1H), 2.19-2.36 (m , 1H), 2.67 (s, 3H), 2.74-3.07 (m, 5H), 3.37-3.48 (m, 1H), 5.07-5.39 (m, 1H), 7.62 (dd, J = 8.5, 1.3 Hz, 1H ), 7.68 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 8.79-8.93 (s, 2 H) ppm; MS (DCI / NH3): 327 (M + H) 0 EXAMPLE 34B (3R) -3-R5- (2-Methyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-1-aza-bichloride.2.21-octane acid chloride The product of Example 34A (20) mg, 0.06 mmol) was treated with HCl (Aldrich, 4M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (3 mL) at room temperature for 1 hour to yield the title compound as a yellow solid (20.0 mg, 92%). . 1 H NMR (500 MHz, CD 3 OD) d 1.92-2.25 (m, 3 H), 2.33-2.47 (m, 1 H), 2.59-2.65 (m, 1 H), 2.65-2.71 (s, 3 H), 3.33-3.54 (m m, 5H), 3.87-4.00 (m, 1H), 5.34-5.54 (m, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.88 (s) , 1 H), 8.90 (s, 2 H) ppm; MS (DCI / NH3): 327 (M + H) +. Anal. Calculated for C19H2ON402-1.20 HCI-1.50 H20: C, 56.39; H, 5.60; N, 13.45. Found: C, 56.05; H, 5.99; N, 13.76.

Example 35 Bis (acid chloride) of (3R) -3-f5- (2-Ethyl-benzooxazol-5-yl) -pyrimidin-2-yloxy1-1-aza-bicyclo2.2.21 octane Example 35A (3R) - 3-r5- (2-Ethyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-1-azabicyclo2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthopropionate (Aldrich, 0.5 ml) in DMF (1 ml) at 100 ° C for 10 hours. This one concentrated then. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 mm Solvent Eluent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10), (v. 90 / 10 to 10/90 for 20 minutes), flow rate, 75 ml / min, uv, 250 nm) as a solid (20.0 mg, 30%). 1H NMR (500 MHz, CD3OD) d 1.45 (t, J = 7.6 Hz, 3H), 1.49-1.64 (m, 1H), 1.66-1.78 (m, 1H), 1.79-1.94 (m, 1H), 2.04- 2.16 (m, 1H), 2.21-2.36 (m, 1H), 2.72-3.11 (m, 7H), 3.37-3.53 (m, 1H), 5.07-5.31 (m, 1H), 7.62 (dd, J = 8.5 , 1.7 Hz, 1H) 7.69 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 1.2 Hz, 1H), 8.82-8.90 (m, 2 H) ppm; MS (DCI / NH3): 351 (M + H) 0 EXAMPLE 35B Bis (Acid Chloride) of (3R) -3-f5- (2-Methyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-aza-bicyclo2.2.21octane The product of Example 35A ( 20 mg, 0.06 mmol) was treated with HCl (Aldrich, 4M in dioxane, 0.25 ml, 1.0 mmol) in EtOAc (3 ml) at room temperature for 1 hour to yield the title compound as a yellow solid (15.0 mg, 92%). 1H NMR (500 MHz, CD3-OD) d 1.46 (t, J = 7.6 Hz, 3H), 1.89-2.25 (m, 3H), 2.28-2.52 (m, 1H), 2.54-2.72 (m, 1H), 3.02 (q, J = 7.6 Hz, 2H), 3.22-3.56 (m, 5H), 3.92 (dd, J = 13.6, 8.7 Hz, 1H), 4.99-5.63 (m, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 8.90 (s, 2 H) ppm; MS (DCI / NH3): 351 (M + H) 0 Anal. Calculated for C20H22N4O2-2.00 HCl: C, 56.74; H, 5.71; N, 13.23. Found: C, 56.82; H, 5.69; N, 13.13.

EXAMPLE 36 Bis (Acid Chloride) of (3R) -3-r5- (2-Phenyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-1-aza-bicyclof2.2.21-octane Example 36A (3R) - 3-r5- (2-Phenyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-1-azabicyclo2.2.21octane The product of Example 33D (62 mg, 0.2 mmol) was treated with triethyl orthobenzoate (Aldrich , 0.5 ml) in DMF (1 ml) at 100 ° C for 10 hours. This one concentrated then. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 mm Solvent solvent, MeCN / H20 (NH4HC03, 0.1 M, pH = 1), (v. 90 / 10 to 10/90 for 20 minutes), flow rate 75 ml / min., UV, 250 nm) as a solid (40.0 mg, 50%). 1H NMR (500 MHz, CD3OD) d 1.52-1.64 (m, 1H), 1.68-1.80 (m, 1H), 1.80-1.92 (m, 1H), 2.06-2.18 (m, 1H), 2.25-2.31 (m, 1H), 2.75- 3.10 (m, 5 H), 3.39-3.49 (m, 1H), 5.14-5.27 (m, 1H), 7.55-7.66 (m, 3H), 7.69 (dd, J = 8.5, 1.8 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 8.27 (dd, J = 8.1, 1.7 Hz, 2H), 8.89 (s, 2H) ppm; MS (DCI / NH3): 399 (M + H) 0 Example 36B Bis (acid chloride) of (3R) -3-r5- (2-Phenyl-benzooxazol-5-yl) -pyrimidin-2-yloxy-1-aza-biciclof2.2.21octane The product of Example 36A (40 mg, 0.10 mmol) was treated with HCl (Aldrich, 4M in dioxane, 0.25 ml, 1.0 mmol) in EtOAc (3 ml) at room temperature for 1 hour to yield the title compound as a yellow solid (20.0 mg, 92%). 1 H NMR (500 MHz, CD 3 OD) d 1.93-2.23 (m, 3 H), 2.33-2.48 (m, 1 H), 2.60-2.71 (m, 1 H), 3.34-3.57 (m, 5 H), 3.90-3.99 (m. m, 1H), 5.35-5.61 (m, 1H), 7.54-7.68 (m, 3H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 8.21-8.37 (m, 2 H), 8.98 (s, 2H) ppm; MS (DCI / NH3): 399 (M + H) 0 Anal. Calculated for C24H22N402-1.40 HCM.50 H20: C, 60.49; H, 5.58. Found: C, 60.12; H, 5.72.

EXAMPLE 37 Bis (hydrochloride) of (R) -5-T2- (1-Aza-bicyclo2.2.21oct-3-yloxy) -pyridimidin-5-n-3H-benzooxazol-2-one Example 37A (R) -5-r2- (1-Aza-bicichlor2.2.2lot-3-yloxy) -pyrimidin-5-in-3H-benzooxazol-2-one The product of Example 33D (62 mg, 0.2 mmol) was treated with 1, 1'-carbonyldiimidazole (Aldrich, 50 mg, 0.31 mmol) in THF / DMF (v. 1: 1, 5 ml) at room temperature for 10 hours. This one concentrated then. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 mm Solvent Eluent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10), (v. 90 / 10 to 10/90 for 20 minutes), flow rate, 75 ml / min, uv, 250 nm) as a solid (60.0 mg, 34%). 1H NMR (500 MHz, CD3-OD) d 1.46-1.96 (m, 3H), 2.02-2.18 (m, 1H), 2.19-2.38 (m, 1H), 2.70-3.11 (m, 5H), 3.37-3.51 (m, 1H), 5.08-5.29 (m, 1H), 7.14-7.60 (m, 3 H), 8.79 (s, 2 H) ppm; MS (DCI / NH3): 338 (M + H) 0 Example 37B Bis (R) -5-r2- (1-Aza-bicyclo2.2.21oct-3-yloxy) -pyrimidin-5-yl-3H hydrochloride -benzooxazol-2-one The product of Example 37A (60 mg, 0.18 mmol) was treated with HCl (Aldrich, 4M in dioxane, 0.25 mL, 1.0 mmol) in EtOAc (3 mL) at room temperature for 1 hour to produce the Composition of the title as yellow solid (60.0 mg, 83%) .1H NMR (500 MHz, CD3OD) d 1.89-2.28 (m, 3H), 2.30: 2.54 (m, 1H), 2.61-2.76 (m, 1H), 3.36-3.52 (m, 5H), 3.82-3.99 (m, 1H), 5.40-5.52 (m, 1H) 7.20-7.47 (m, 2H), 7.68 (s, 1H), 8.80 (s, 2H) ppm; MS (DCI / NH3): 338 (M + H) \ Anal. Calc'd for C18H18N4O3-2.00 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-r6- (1-Aza-bicyclo2.2.21oct-3-yloxy) -pyridazin-3-n-9H-carbazole Example 38A 3- (4,4,5, 5-Tetramethyl-ri, 3,21-dioxoborolan-2-yl) -9H-carbazole. 3-Bromo-9H-carbazole (Aldrich, 0.97 g, 3.96 mmol) was coupled with bis (pinacolato) diboro (Aldrich, 1.13 g, 4.46 mmol. ) under the catalysis of dichloro [1,1'-bis-8-diphenylphosphino) ferrocene] palladium (II) dichloromethane (Aldrich, 103 mg, 0.125 mmol) with KOAc (Aldrich, 1.21 g, 12.3 mmol) in DMF (anhydrous, Aldrich, 25 ml ) at 80 ° C overnight according to the procedure of Example 26A. The title compound was purified by chromatography (Si02, gradient 5 to 50% EtOAc-hexanes) to give 0.80 g (2.73 mmol, 69% yield). 1 H NMR (300 MHz, CDCl 3) d 1.40 (s, 12 H), 7.26 (s, 1 H), 7.40-7.47 (m, 3 H), 7.88 (d, J = 7.0 Hz, 1 H), 8.11 (d, J = 7.0 Hz, 2 H), 8.58 (s, 1H) ppm. MS (DCI / NH3) m / z 294 (M + H) 0 Example 38B (R) -3-r6- (1-Aza-bicyclo2.2.21oct-3-yloxy) -pyridazin-3-n-9H-carbazole The product of Example 9A (0.173 g, 0.72 mmol) was coupled with the product of Example 38A (0.267 g, 0.91 mmol) under the catalysis of dichlorobis (triphenyl-phosphine) palladium (II) (Aldrich, 5.3 mg, 0.007 mmol) and 2- (dicyclohexylphosphino) biphenyl (Strem Chemicals, 7.3 mg, 0.021) mmoles) at 150 ° C for 10 minutes, according to the procedure of Example 29A. The title product was purified by preparative HPLC (Xterra ™, column, Xterra RP-18 5 μm, 30 x 100 mm Solvent Eluent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10) (v. 40/60 a 70/30 for 20 minutes), flow rate, 75 ml / min, uv, 250 nm) as a solid. H NMR (300 MHz, CD3OD) d 1.45-1.62 (m, 1H), 1.68-1.92 (m, 2H), 2.00-2.15 (m, 1H), 2.27-2.40 (m, Hz, 1H), 2.75-3.05 (m, 5H), 3.43-3.59 (m, Hz, 1H), 5.22-5.42 (m, Hz, 1H), 7.16-7.24 (m, 1H), 7.28 (d, J = 9 Hz, 1H), 7.36 -7.44 (m, 1H), 7.45-7.52 (m, 1H), 7.57 (d, J = 8 Hz, 1H), 8.02 (dd, J = 9, 2 Hz, 1H), 8.17 (t, J = 9 Hz, 2 H), 8.67 (s, 1 H) ppm; MS (DCI / NH3) m / z 371 (M + H) +.

Example 39 Hemifumarate of 3-r6- (1H-indol-3-yl) -pyridazin-3-yloxyl-1-azabicyclo2.2.21octane Example 39A 3-r6- (1H-lndol-3-yl) -pyridazine- 3-Iloxy1-1-aza-bicichlor2.2.21octane 3-quinuclidinol (Aldrich, 254 mg, 2 mmol) was coupled with 3- (6-chloro-pyridazin-3-yl) -1 H-indole (Bionet, 458 mg , 2 mmoles) at 60 ° C for 16 hours according to the procedure of Example 7A. The title compound was purified by preparative HPLC (Xterra ™, column, Xterra RP-18, 5 μm, 30 x 100 mm Eluent solvent, MeCN / H20 (NH4HC03, 0.1 M, pH = 10), (v. 90 / 10 to 10/90 for 20 minutes), flow rate, 75 ml / min., UV, 250 nm) as a solid (400 mg, 63%). 1 H NMR (MeOH-D 4, 300 MHz) 1.50-1.64 (m, 1H), 1.71-1.93 (m, 2H), 2.00-2.15 (, 1H), 2.29-2.36 (m, 1H), 2.78-3.04 (m , 5H), 3.43-3.55 (m, 1H), 5.24-5.32 (m, 1H), 7.12-7.25 (m, 3 H), 7.42-7.48 (m, 1H), 7.87 (s, 1H), 8.01 ( d, J = 9.2 Hz, 1H), 8.26-8.33 (m, 1H) ppm. MS (DCI / NHg) m / z 321 (M + H) 0 Example 39B 3- [6- (1 H-lndol-3-yl) -pyridazin-3-yloxy-1-azabicyclo [2.2.21 octane] Hemifumarate The product of Example 39A (200 mg, 0.63 mmol) was treated with fumaric acid (Aldrich, 73 mg, 0.63 mmol) in EtOAc / MeOH (v. 10: 1, ml) at room temperature overnight to give the title compound (247.3 mg, 100%). 1H NMR (MeOH-D4, 300 MHz) 1.76-1.91 (m, 1H), 1.92-2.14 (m, 2H), 2.22-2.37 (m, 1H), 2.51-2.58 (m, 1H), 3.16-3.39 ( m, 5 H), 3.82 (ddd, J = 14.0, 8.2, 1.9 Hz, 1H), 5.40-5.49 (m, 1H), 6.67 (s, 1H), 7.12-7.26 (m, 3H), 7.42-7.49 (m, 1H), 7.89 (s, 1H), 8.05 (d, J = 9.5 Hz, 1H), 8.26-8.32 (m, 1H) ppm. MS (DCI / NH3) m / z 321 (M + H) 0 Anal. Calculated for C19H20N4O-0.5 C404H4-0.35 H20: C, 65.56; H, 5.95; N, 14.56. Found: C, 65.49; H, 6.21; N, 14.34.

Example 40 Fumarate of (R) -3-f6- (1 H -indol-3-yl) -pyridazin-3-yloxy-1-azabicyclo2.2.21octane The product of Example 4A (127 mg, 1 mmol) was coupled with 3- (6-chloro-pyridazin-3-yl) -1 W-indole (Bionet, 229 mg, 1 mmol) according to the procedure of Example 39. The title compound was obtained as a solid (208.3 mg, yield , 35%). 1H NMR (MeOH-d4, 300 MHz) 1.90-2.24 (m, 3H), 2.33-2.48 (m, 1H), 2.61-2.69 (m, 1H), 3.32-3.55 (m, 5H), 3.98 (dd, J = 13.7, 8.3 Hz, 1H), 5.49-5.57 (m, 1H), 6.71 (s, 4H), 7.13-7.28 (m, 3H), 7.46 (d, J = 7.1 Hz, 1H), 7.90 (s) , 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 7.1 Hz, 1H) ppm. MS (DCI / NH3) m / z 321 (M + H) 0 Ana). Calculated for C19H2oN40-2.1 C4O4H4-0.35 EtOAc: C, 58.14; H, 5.29; N, 9.42. Found: C, 57.91; H, 5.35; N, 9.42.

EXAMPLE 41 (S) -3-T6- (1 H -indol-3-yl) -pyridazin-3-yloxy-1-azabicyclo2.2.21octane fumarate The product of Example 13D (127 mg, 1 mmol ) was coupled with 3- (6-chloro-pyridazin-3-yl) -1 H-indole (Bionet, 229 g, 1 mmol) according to the procedure of Example 39. The title compound was obtained as a solid (239 mg , yield, 39%). 1 H NMR (MeOH-d 4, 300 MHz) 1.90-2.24 (m, 3 H), 2.33-2.48 (m, 1 H), 2.61-2.69 (m, 1 H), 3.33-3.55 (m, 5 H), 3.93-4.04 (m, 1H), 5.49-5.57 (m, 1H), 6.72 (s, 4H), 7.13-7.28 (m, 3H), 7.46 (d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 7.1 Hz, 1H) ppm. MS (DC1 / NH3) m / z 321 (M + H) +. Anal. Calculated for C19H2oN40-2.1 C4O4H4-0.5 EtOAc: C, 58.06; H, 5.37; N, 9.21. Found: C, 57.81; H, 5.54; N, 9.53.

Example 42 DETERMINATION OF BIOLOGICAL ACTIVITY To determine the effectiveness of the representative compounds of this invention as nAChRs of al, the compounds of the invention were evaluated according to the [3 H] -methyl-licaconitine (MLA) binding assay and the binding assay [3H] -cystisine, which was performed as described in the following.

Linkage of [3H1-cystisine The binding conditions were modified from the procedures described in Pabreza LA, Dhawan.S, Kellar KJ, [3H] -Cystisine Binding to Nicotinic Cholinergic Receptors in Brain, Mol. Pharm. 39: 9-12, 1991. Fractions enriched with membranes from the rat brain cerebellum negative (ABS Inc., Wilmington, DE) were slowly thawed at 4 ° C, washed and resuspended in 30 volumes of pH buffer of BSS-Tris (120 mM NaCl / 5 mM KCI / 2 mM CaCl2 / 2 mM MgCl2 / 50 mM Tris-Cl, pH 7.4, 4 ° C). Samples containing 100-200 μg of protein and 0.75 nM of [3 H] -cystisine (30 CJmmol, Perkin Elmer / NEN Life Science Products, Boston, MA) were incubated in a final volume of 500 μl for 75 minutes at 4 ° C. C. Seven logarithm dilution concentrations of each compound were tested in duplicate. The non-specific binding was determined in the presence of 10 μM of (-) - nicotine. Binding radioactivity was isolated by vacuum filtration on pre-moistened glass fiber filter plates (Millipore, Bedford, MA) using a 96-well filtration apparatus (Packard Instruments, Meriden, CT) and quickly wiped with water. my BSS ph regulator cooled with ice (120 mM NaCl / 5 mM KCI / 2 mM CaCl2 / 2 mM MgCl2). A Packard MicroScint-20® scintillation cocktail (40 μl) was added to each well and the radioactivity was determined using a Packard TopCount® instrument. The IC50 values were determined by non-linear regression in Microsoft Excel® software. The K i values were calculated from IC50s using the Cheng-Prusoff equation, where K i = IC50 / 1 + [Ligand] / KD].

Linkage of r3H1-Methyl-licaconitine (MLA) The binding conditions were similar to those for [3H] -cystisine binding. Fractions enriched with membranes from rat brain cerebellum negative (ABS Inc., Wilmington, DE) were thawed slowly at 4 ° C, washed and resuspended in 30 volumes of pH regulator BSS-Tris (120 mM NaCl, 5 mM KCl, 2 mM CaCl 2, 2 mM MgCl 2, and 50 mM Tris-Cl, pH 7.4, 22 ° C). Samples containing 100-200 μg of protein, 5 nM [3 H] -MLA (25 C./mmol, Perkin Elmer / NEN Life Science Products, Boston, MA) and 0.1% bovine serum albumin (BSA, Millipore , Bedford, MA) were incubated in a final volume of 500 μl for 60 minutes at 22 ° C. Seven concentrations of logarithm dilutions of each compound were tested in duplicate. The non-specific binding was determined in the presence of 10 μM MLA. Binding radioactivity was isolated by vacuum filtration on glass fiber filter plates pre-moistened with 2% BSA using a 95-well filtration apparatus (Packard Instruments, Meriden, CT) and then rinsed rapidly with 2 ml of BSS cooled with ice. The Packard MicroScint-20® scintillation cocktail (40 μl) was added to each well and the radioactivity was determined using a Packard TopCount® instrument. The IC5Q values were determined by non-linear regression in Microsoft Excel® software. The K values were calculated from IC50s using the Cheng-Prusoff equation, where K, = IC50 / I + [Ligand] / KD].

The compounds of the invention had K i values from about 1 nanomolar to about 10 micromolar when tested by the MLA assay, many having a K i of less than 1 micromolar. Enzyme values of [3 H] -cystisine of the compounds of the invention ranged from about 50 nanomolar to at least 100 micromolar. The determination of the preferred compounds normally considered the value K i as measured by the MLA test in view of the value K i as measured by the [3 H] -cystine linkage, so that in the formula D = K 3 H- cyst / KiM A, D is approximately 50. Preferred compounds normally exhibit higher potency at receptors compared to aAβ2 receptors. The compounds of the invention are nAChRs ligands that modulate the function of nAChRs by alternating the activity of the receptor. The compounds can be inverse agonists that inhibit the basal activity of the receptor or antagonists that completely block the action of the agonists that activate the receptor. The compounds may also be partial agonists that partially block or partially activate the nAChR receptor of al or agonists that activate the receptor. Some compounds of the invention have also been evaluated for potential binding to the hERG ion channel. Blockage of the hERG ion channel has been associated with the interference of cardiac muscle repolarization, which presents a cardiovascular risk. The binding affinities to the hERG channel were measured by displacement of the radioligand [3 H] -dofetilide and expressed in the K i value, ie, K, ERG- The compounds of the invention demonstrate a higher ratio of a receptor binding to the to the link relationship hERG ie, (K¡ MLA) / (, HERG) > were considered to demonstrate a better cardiovascular risk profile. The compounds of the invention that were tested all showed a beneficial cardiovascular risk profile for ligands of the al receptor. It is understood that the above detailed description and the appended examples are illustrative only and are not construed as limitations to the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the embodiments described will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use of the invention, can be made without departing from the spirit and scope thereof.

Claims

A compound of the formula (I): ) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein: n is 0, 1 or 2; A is N or N + -0; X is selected from the group consisting of O, S and -N (R1) -; Ar1 is a 6-membered aromatic ring which contains 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: (a) (b) or (o) Z, Z, Z and Z are independently selected from the group consisting of C and -C (R3b); as long as 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); as long as zero or one of Z5, Z6, Z7 and Z8 is C; • 11 • \ 2 13 -14 -15 and z • 16 are independently selected from the group consisting of C and -C (R3c); as long as one of Z9, Z10, Z11, Z12, Z13, Z14, Z15 and Z16 is C and the group of formula (c) is linked to Ar1 through the C atom; Y1 in each case 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 (= 0), -C (R3) and -C (R3) (R3a); Y3 is selected from the group consisting of -N (R2), -C (R3) and -C (R3) (R3a); provided that zero or one of Y1, Y2 and Y3 is -C (R3) in a group of the formula (a); wherein when one of Y1, Y2 and Y3 is -C (R3) in a group of the formula (a), then Z1, Z2, Z3 and Z4 are each -C (R3b) and the group of the formula (a ) binds Ar1 through the C-atom of -C (R3) of Y1, Y2 or Y3; and also when one of Z1, Z2, Z3 and Z4 is C, then Y1, Y2 and Y3 are different from -C (R3) and the group of the formula (a) is attached to Ar1 through the C atom of Z1 , Z2, Z3 or Z4; 2a and 3a are independent of the group consisting of N, C and -C (R3a); as long as Y1 is -C (R3) in a group of the formula (b), Y2a and Y3a are selected from the group consisting of N and -C (R3a), and when one of Y2a and Y3a is C, then Y1 in a group of the formula (b) is O, S, -N (R2) or -C (R3) (R3a); wherein, when one of Z5, Z6, Z7 and Z8 is C, then Y1 in a group of formula (b) is selected from the group consisting of O, S, -N (R2) and -C (R3 ) (R3a); Y2a and Y3a are each independently selected from the group consisting of N and -C (R3a); and the group of the formula (b) is attached to Ar1 through the C of Z5, Z6, Z7 or Z8; and also where when Y1 in a group of the formula (b) is -C (R3) or one of Y2a and Y3a is C, then Z5, Z6, Z7 and Z8 are each -C (R3b) and the group of Formula (b) binds Ar1 through the C-atom of -C (R3) of Y1 in the group of formula (b) or through the C atom of Y2a or Y3a. R1 and R2 in each case are each independently selected from the group consisting of hydrogen and alkyl; R3 and R3a in each case are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR4, -NR5R6, -alkyl-OR4 and -alkyl-NR5R6; > 3b R 3c in each case are each independently selected from the group consisting of hydrogen, halogen, alkyl, aryl, -OR 4, -NR 5 R 6, -alkyl-OR 4, -alkyl-NR 5 R 6 and -SCN; R 4 is selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl and arylcarbonyl; R5 and R6 in each case are 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 according to claim 1, wherein Ar1 is a group of the formula: (b) wherein X1, X2, X3 and X4 are each independently selected from the group consisting of N and -CR10; and R10 in each case is independently selected from the group consisting of hydrogen and alkyl. 3. The compound according to claim 1, wherein Ar1 is selected from the group consisting of: wherein R10 in each case is independently selected from the group consisting of hydrogen and alkyl. 4. The compound according to claim 1, wherein Ar2 is selected from the group consisting of: (ü) (v) (vi) (viii) (ix) - (x) wherein: Z1, Z2, Z3 and Z4 are independently selected from the group consisting of C and -C (R3); as long as one of Z1, Z2, Z3 and Z4 is C and formula (ix) binds 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 (R3); as long as zero or one of Z5, Z6, Z7 and Z8 is C; ? 2a and? 3a are independently selected from the group consisting of C and -C (R3a); wherein when one of Zd, Z6, Z7 and Z8 is C, then Y2a and Y3a in the group of formulas (i) - (vii) are each -C (R3a); and each of the group of formulas (i) - (vii) joins Ar1 through the C of Z5, Z6, Z7 or Z8; and also where, when one of Y2a and Y3a is C in the group of the formulas (i) - (vii), then Z5, Z6, Z7 and Z8 are each -C (R3) and each of the group of the formulas (i) - (vii) is linked to Ar1 through the C atom of Y2a or Y3a; Y R2, R3, R3a, R3, R8, Z10, Z11, Z12, Z13, Z14, Z15, and Z16 are as defined in claim 1. 5. The compound according to claim 1, or a salt, ester, amide, or pharmaceutically acceptable prodrug thereof, selected from the group consisting of: 3- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 4- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 5- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 5-. { 4 - [(3R) -1-azabicic or [2.2.2] oct-3-yloxy) fenii} -1H-indole; 6- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 2- [4- (1-azabicyclo [2.2.2] oct-3-yloxy) phenyl] -1H-indole; 5- [6- (1-azabicyclo [2.2.2] oct-3-yloxy) pyridazin-3-yl] -1H-indole; 4- [6- (1-azabicyclo [2.2.2] oct-3-yloxy) pyridazin-3-yl] -1H-indole; 5-. { 6 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] pyridazin-3-yl} -1H-indole; 5-. { 6 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] pyridazin-3-yl} -3-methyl-1H-indole; 5-. { 2 - [(3R) -1-Azacyclo [2.2.2] oct-3-yloxy] pyrimidin-5-yl} -1H-indole; 4-. { 2 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] pyrimidin-5-yl} -1H-indole; 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-azabicicio [2.2.2] oct-3-yloxy] phenyl} -1,3-benzothiazol-2-amine; 6- { 4 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] phenyl} -4-thiocyanato-1,3-benzothiazol-2-amine; 6- { 4 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] phenyl} -4-bromo-1,3-benzothiazol-2-amine; N- [4- (3-methyl-1 H -indazol-5-yl) phenyl] quinuclidin-3-amine; (R) -3- [6- (3-Methyl-1H-indazol-5-yl) -pyridazin-3-yloxy] -1-azabicicio [2.2.2] octane; (R) -3- [6- (1-methyl-1 H-indo l-5-i I) -p i ridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -. { 5- [1- (1-Aza-bicyclo [2.2.2] oct-3-yloxy) -p] ridazin-3-yl] -1 H-in dol-3-ylmethyl} dimethyl amine; 1-R (R) -3- [6- (1H-indol-5-yl) -p i ridazin-3-yloxy] -1-aza bicyclo [2.2.2] octane oxide; 6- { 6 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] -pyridazin-3-yl} -benzothiazole-2- plate; (3R) -3- [6- (3-Bromo-1 H -indol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; 5-. { 6 - [(3R) -1-azabicyclo [2.2.2] oct-3-yloxy] -pyridazin-3-yl} -1,3-dihydro-indol-2-one; 5-. { 6 - [(3R) -1-oxy-1-azabicynic [2.2.2] oct-3-yloxy] -pyridazin-3-yl} -1,3-dihydroindol-2-one; 5-. { 6 - [(3R) -1-azabicyclo [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-azabicyclo [2.2.2] octane; (S) -3- [6- (1H-indol-5-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -3- [5- (1H-indol-5-yl) -pyridin-2-yloxy] -1-azabicyclo [2.2.2] octane; 1-Oxide of (3R) -3- [5- (1 H -indol-4-yl) -pyrimidin-2-yloxy] -1-azabicyclo [2.2.2] octane; (3R) -3- (5-Benzooxazol-5-yl-pyrimidin-2-yloxy) -1-azabicyclo [2.2.2] octane; (3R) -3- [5- (2-Methyl-benzooxazoI-5-yl) -pyrimidin-2-yloxy] -1-azabicyclo [2.2.2] octane; (3R) -3- [5- (2-Ethyl-benzooxazol-5-yl) -pyrimidin-2-yloxy] -1-azabicynic [2.2.2] octane; (3R) -3- [5- (2-phenyl-benzooxazol-5-yl) -pyrimidin-2-yloxy] -1-azabicyclo [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-Azabicyclo [2.2.2] oct-3-yloxy) -pyridazin-3-yl] -9H-carbazole;
3- [6- (1H-indol-3-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; (R) -3- [6- (1 H -indol-3-yl) -pyridazin-3-yloxy] -1-azabicyclo [2.2.2] octane; and (S) -3- [6- (1 H -indole-3-yl) -pyridazin-3-yloxy] -1-azabicyclo [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 for selectively modulating Iso effects of nicotinic acetylcholine receptors of a7 in a mammal, comprising administering an effective amount of a compound of claim 1. 8. A method for treating or preventing a condition or disorder selected from the group consisting of of attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), moderate cognitive impairment, senile dementia, AIDS dementia, Pick's disease, dementia associated with Lewy bodies, dementia associated with syndrome of Down, amyotrophic lateral escolerosis, Huntington's disease, decreased CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, neuropathic pain, infertility, need for new blood vessel development associated with scarring of wounds, need for new blood vessel development associated with vascular grafting of skin grafts, and lack of circulation, more particularly circulation around vascular occlusion, comprising the step of administering a compound of claim 1. 9. The method according to claim 1, wherein the condition or The disorder is selected from the group consisting of a cognitive disorder, neurodegeneration and schizophrenia. The method according to claim 1, further comprising administering a compound of claim 1 in combination with an atypical antipsychotic.