Cns active fused bicycloheterocycle substituted azabicyclic alkane derivatives

Technical Field The present invention relates to fused azabicyclic alkane derivatives substituted with a bicycloheterocycle, compositions containing such compounds and methods of treating conditions and disorders using such compounds and compositions.

Description of the Related Art [0003] Nicotinic acetylcholine receptors (nicotinic acetylcholine receptors) are widely distributed in the central (CNS) and peripheral nervous system (PNS). Such receptors play an important role in regulating the function of the CNS (CNS, central nervous system), especially by modulating the release of many different neurotransmitters including, but not limited to, acetylcholine, noradrenaline, dopamine, serotonin and GABA. As a result, nicotinic receptors mediate a wide variety of physiological effects and are a target, among others, for the therapeutic treatment of disorders related to cognitive function, learning and memory, neurodegeneration, pain and inflammation, psychosis and sensory gating, mood and emotions.

[0004] There are many nAChR subtypes in the CNS and peripheral nervous system. Each of the subtypes has a different effect on the regulation of general physiological functions. Typically, nAChRs are ion channels that are built of pentameric protein subunit assemblies. At least 12 protein subunits, α2-α10 and β2-β4 have been identified in the neural tissue. These subunits provide a large variety of homomeric and heteromeric combinations that constitute different receptor subtypes. For example, the dominant receptor, which is responsible for high nicotine binding affinity in brain tissue, has the structure (α4) 2 (β2) 3 (α4β2 subtype), while the other major receptor population consists of homomeric (α7) 5 receptors (α7 subtype ).

[0005] Certain compounds, such as the nicotine plant alkaloid, interact with all nAChR subtypes, explaining the physiological effects of this compound. Although nicotine has many biological activities, not all of these nicotine-mediated activities are desirable. For example, nicotine has gastrointestinal and cardiovascular side effects that overlap at therapeutic doses, and its addictive nature is well known. Ligands that are selective for interaction only with certain nAChR subtypes offer the potential to achieve beneficial therapeutic effects with an increased safety margin.

[0006] α7 and α4β2 nAChRs have been found to play a significant role in increasing function

Cognitive aspects, including aspects of learning, memory and attention (Levin, ED, J. Neurobiol. 53: 633-640, 2002). For example, among other systemic activities, α7 nAChRs are associated with conditions and disorders associated with attention deficit disorder, attention deficit hyperactivity disorder (ADHD), and Alzheimer's disease (AD: Alzheimer's disease), mild cognitive impairment, senile dementia, Lewy body dementia, Down syndrome-related dementia, AIDS-related dementia, Pick's disease, as well as schizophrenia-related cognitive disorders. The α4β2 receptor subtype is involved in the control of attention, cognition, schizophrenia, epilepsy and pain (Paterson and Norberg, Progress in Neurobiology 61 75-111, 2000).

[0007] The activity of both α7 and α4β2 nAChRs can be changed or regulated by administration of subtype selective nAChR ligands. Ligands may exhibit antagonist, agonist or partial agonist properties. Compounds that act as positive allosteric modulators are also known.

[0008] Although compounds that are non-selective in the activity of nicotinic receptor subtypes, including α4β2 and α7 nAChR are known, it would be beneficial to provide compounds that, when compared to other subtypes, would interact selectively with neuronal nAChR containing α7, α4β2 nAChR or both α7 and α4β2 nAChR.

[0009] International Patent Application No. WO 00/44755, assigned to Abbott Laboratories, relates to diazabicyclic derivatives of formula (A), which are ligands of nicotinic acetylcholine receptors.

<img file="PL2018380T3_D0001.tif" />

SUMMARY OF THE INVENTION [0010] The invention relates to fused bicycloheterocycle substituted azabicyclic compounds as well as compositions containing such compounds and the method of their use.

[0011] In one aspect, the present invention relates to a compound of formula (I)

<img file="PL2018380T3_D0002.tif" />

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2 or 3;

A is N or N⁺-ABOUT^-;

EP 2 018 380 B1

R represents a hydrogen atom, an alkyl, cycloalkylalkyl and arylalkyl group;

L is selected from the group consisting of O, S and -N (Ra) -;

ar¹ is a 6-membered aryl ring or a 6-membered heteroaryl ring; ar² is a fused nine-membered bicyclic heteroaryl; and

Ra is selected from the group consisting of hydrogen, alkyl and alkylcarbonyl;

wherein if Ar¹ means

<img file="PL2018380T3_D0003.tif" />

then L is O or S.

[0012] Another aspect of the invention relates to pharmaceutical compositions containing compounds of the invention. Such compositions may be administered in accordance with the method of the invention, usually as part of a treatment regimen for the treatment or prevention of conditions or disorders associated with nAChR activity, and more specifically α7 nAChR activity.

[0013] Still another aspect of the present invention relates to the use of compounds of the invention in the manufacture of a medicament for selectively modulating nAChR activity, for example α7 nAChR activity. The use is useful in the manufacture of a medicament for the treatment and / or prevention of conditions and disorders associated with the modulation of α7 nAChR activity in mammals. More specifically, the application is useful for conditions or disorders associated with attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, and dementia associated with

AIDS, Pick disease, Lewy body dementia, Down syndrome dementia, amyotrophic lateral sclerosis, Huntington's disease, reduced CNS function associated with traumatic brain injury, acute pain, postoperative pain, chronic pain, inflammatory pain, neuropathic pain, infertility, the need to create new blood vessels related to wound healing, the need for new blood vessels associated with vascularization of the skin graft and lack of circulation, more specifically circulation around vascular occlusion, among other systemic activities, e.g. TNF-mediated inflammatory response.

[0014] Compounds, compositions containing compounds and uses of the compounds for the preparation of a medicament for treating or preventing conditions and disorders by administration of the compounds will be further described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions of terms [0015] Certain terms used in the specification are intended to refer to the following definitions, as detailed below.

[0016] 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 the acyl group include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

[0017] 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 the acyloxy group include, but are not limited to, acetyloxy, propionyloxy and isobutyryloxy.

[0018] The term "alkenyl", as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond, formed by the removal of two hydrogen atoms. Representative examples of the alkenyl group include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,

2-methyl-1-heptenyl and 3-decenyl.

[0019] 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 the alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0020] 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 the alkoxyalkoxy group include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy and methoxymethoxy.

[0021] The term "alkoxyalkyl", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of the alkoxyalkyl group include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.

[0022] The term "alkoxycarbonyl" as used herein, means an alkoxy group as defined herein, appended to the parent molecular moiety through a carbonyl group represented by -C (O) - as defined herein. Representative examples of the alkoxycarbonyl group include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.

[0023] 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 the alkoxyimino group include, but are not limited to, ethoxy (imino) methyl and methoxy (imino) methyl.

[0024] The term "alkoxysulfonyl", as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as

EP 2 018 380 B1 is here defined. Representative examples of the alkoxysulfonyl group include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.

[0025] The term "alkyl" as used herein means a straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms. Representative examples of the alkyl group 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 nhexyl.

[0026] As used herein, the term "alkylcarbonyl" means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of the alkylcarbonyl group include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

[0027] 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 the alkylcarbonyloxy group include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy.

[0028] 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 the alkylsulfonyl group include, but are not limited to, methylsulfonyl and ethylsulfonyl.

[0029] The term "alkylthiol", as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of the alkylthiol group include, but are not limited to, methylthiol, ethylthiol, tert-butylthiol and hexylthiol.

[0030] The term "alkynyl" as used herein means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of the alkynyl group include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

[0031] The term "amide" as used herein means an amino, alkylamino or dialkylamino group attached to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of the amide group include, but are not limited to, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and ethylmethylaminocarbonyl.

[0032] The term "aryl", as used herein, means a monocyclic or bicyclic aromatic ring system. Representative examples of the aryl group include, but are not limited to, phenyl and naphthyl.

[0033] The aryl groups of the present invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the acyl, acyloxy, alkenyl, alkoxy group,

Alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amino, carboxylic, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxy, hydroxyalkyl, hydroxyalkyl (NRgRj) alkyl, (NRgRj) alkoxy, (NRgRj) carbonyl and (NRgRj) sulfonyl, wherein Rg and Rj are each independently selected from the group consisting of hydrogen and alkyl.

[0034] The term "arylcarbonyl" as used herein means an aryl group as defined herein, or a benzyl group attached to the parent molecular moiety through a carbonyl group represented by -C (O) - as defined herein. Representative examples of the arylcarbonyl group include, but are not limited to, phenylcarbonyl and benzylcarbonyl.

[0035] The term "aryloxycarbonyl" as used herein means an aryl-O- group where the aryl or aryl-O- group is as defined herein, or the benzyloxy group attached to the parent molecular moiety through a carbonyl group represented by -C (O) - as defined here. Representative examples of the aryloxycarbonyl group include, but are not limited to, phenoxycarbonyl and benzyloxycarbonyl.

[0036] The term "arylsulfonyl", as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of the arylsulfonyl group include, but are not limited to, phenylsulfonyl, (methylaminophenyl) sulfonyl, (dimethylaminophenyl) sulfonyl and (naphthyl) sulfonyl.

[0037] The term "carbonyl", as used herein, means a -C (O) - group.

[0038] The term "carboxy", as used herein, means a -CO2H group.

[0039] The term "cyano", as used herein, means a -CN group.

[0040] The term "formyl", as used herein, means a -C (O) H group.

[0041] The term "halo" or "halogen" as used herein means -Cl, -Br, -I or -F.

[0042] 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.

[0043] The term "haloalkyl", as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.

[0044] The term "heteroaryl" means a five- or six-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and

Sulfur. Heteroaryl groups are attached to the parent molecular moiety through a carbon or nitrogen atom. Representative examples of the heteroaryl group include, but are not limited to, furyl, imidazolyl, indazolyl, benzothiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, triazolyl, tetiazolyl and triazolyl.

[0045] The heteroaryl groups of the invention are substituted with 0, 1, 2 or 3 substituents independently selected from the alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthiolate, alkynyl, alkynyl , haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercaptan, nitro, -NRgRj, (NRgRj) alkyl, (NRgRj) alkoxy, (NRgRj) carbonyl and (NRgRj) sulfonyl, wherein Rg and Rj are each independently selected from the group consisting of hydrogen and alkyl.

[0046] The term "bicyclic heteroaryl ring" refers to fused nine- and ten-membered bicyclic aromatic rings containing 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. Bicyclic heteroaryl groups are attached 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. The bicyclic heteroaryl groups of the invention are substituted with 0, 1, 2 or 3 substituents independently selected from the alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthiol, alkynyl, alkynyl , haloalkyl, halogen, hydroxyl, hydroxyalkyl, mercaptan, nitro, -NRgRj, (NRgRj) alkyl, (NRgRj) alkoxy, (NRgRj) carbonyl and (NRgRj) sulfonyl, where Rg and Rj are each independently selected from the group consisting of hydrogen and alkyl.

[0047] As used herein, the term "heterocycle" or "heterocyclic" means a monocyclic heterocyclic ring or bicyclic heterocyclic ring. A monocyclic heterocyclic ring means a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of nitrogen, oxygen and sulfur. A 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. A 5 membered ring contains 0 or one double bond and one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. A 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The monocyclic heterocyclic ring is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the monocyclic heterocyclic ring. Representative examples of the monocyclic heterocyclic ring include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithanyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,

Thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxydothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and trithanyanyl. A bicyclic heterocyclic ring is a monocyclic heterocyclic ring that is either fused to a cycloalkyl ring, heteroaryl ring or other heterocyclic ring, or is formed by an alkyl chain attached to two non-adjacent carbon atoms contained in the monocyclic heterocyclic ring. The bicyclic heterocyclic ring is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the monocyclic heterocyclic ring. Representative examples of a bicyclic heterocyclic ring include, but are not limited to, azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1, 4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl and 1,2,3,4-tetrahydroquinolinyl.

[0048] The heterocyclic groups of the invention are substituted with 0, 1, 2 or 3 substituents independently selected from the alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthiol, alkynyl, formyl, carboxylate , haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercaptan, nitro, -NRgRj, (NRgRj) alkyl, (NRgRj) alkoxy, (NRgRj) carbonyl and (NRgRj) sulfonyl, where Rg and Rj are each independently selected from the group consisting of hydrogen and alkyl.

[0049] The term "hydroxyl", as used herein, means a -OH group.

[0050] The term "hydroxyalkyl", as used herein, means that at least one hydroxyl group, as defined herein, is attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of the hydroxyalkyl group include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl and 2-ethyl-4-hydroxyheptyl.

[0051] The term "mercaptan" as used herein means a -SH group.

[0052] The term "nitro", as used herein, means a -NO2 group.

As used herein, the term "-NRgRj" means two groups, Rg and Rj, which are attached to the parent molecular moiety through a nitrogen atom. Rg and Rj are each independently hydrogen or an alkyl group. Representative examples of -NRgRj include, but are they are not limited to amino, methylamino, dimethylamino and methylethylamino.

[0054] The term "(NRgRj) alkyl," as used herein, means a -NRgRj group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of the (NRgRj) alkyl group include, but are not limited to , (amino) methyl, (dimethylamino) methyl and (ethylamino) methyl.

The term "(NRgRj) alkoxy", as used herein, means a -NRgRj group, as defined herein, attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of the (NRgRj) alkoxy group include, but are not limited to , (amino) methoxy, (dimethylamino) methoxy and (diethylamino) ethoxy. [0056] The term "(NRgRj) carbonyl" as used herein means a -NRgRj as defined herein,

EP 2 018 380 B1 attached to the parent molecular moiety through a carbonyl group as defined herein. Representative examples of (NRgRj) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl and (ethylmethylamino) carbonyl.

The term "(NRgRj) sulfonyl" as used herein means a -NRgRj group, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of the (NRgRj) sulfonyl group include, but are not limited to, , aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl and (ethylmethylamino) sulfonyl.

[0058] The term "sulfonyl" as used herein means a -S (O) 2- group.

The term "thioalkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of a thioalkoxy group include, but are not limited to, methylthiol, ethylthiol and propylthiol.

[0060] Although it can usually be seen that an asterisk is used to indicate that the exact subunit of the receptor composition is undefined, for example a3b4 * indicates a receptor that contains α3 and β4 proteins in combination with other subunits, the term α7 as used herein is intended to include receptors where the exact composition subunit is both defined and indefinite. For example, α7 as used herein includes homomeric (α7) 5 receptors and α7 * receptors, which means nAChRs containing at least one α7 subunit.

Compounds of the Invention [0061] The compounds of the invention have formula (I) as defined above. More specifically, compounds of formula (I) may include, but are not limited to, compounds where A is N, and n is 1 or 2. There are some preferred compounds wherein A is N; L is O; n means 2.

[0062] More specifically, in the compounds of formula (I) Ar¹ chooses from:

<img file="PL2018380T3_D0004.tif" />

EP 2 018 380 B1

<img file="PL2018380T3_D0005.tif" />

where R1, R2, R3, R4 and R5 independently represent an acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amino, carboxyl, cyano, haloalkyl, formyl, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercaptan, nitro, thioalkoxy, -NRgRj, (NRgRj) alkyl, (NRgRj) alkoxy, (NRgRj) carbonyl or (NRgRj) sulfonyl; Rg and Rj are each independently a hydrogen atom or a group

<img file="PL2018380T3_D0006.tif" />

In particular, the invention includes, but is not limited to, compounds of formula (I) wherein A is N; R represents a methyl group; L is O; n is 2; ar¹ means

<img file="PL2018380T3_D0007.tif" />

[0063] In compounds of formula (I) Ar² chooses from:

<img file="PL2018380T3_D0008.tif" />

<img file="PL2018380T3_D0009.tif" />

wherein each Z1, Z2, Z3 and Z4 independently is a nitrogen atom or a carbon atom, where the carbon atom is

Optionally substituted with a substituent selected from the group consisting of hydrogen, halogen, alkyl, -ORc, -alkyl-ORc, -NRdRe and -alkyl-NRdRe; Rb is selected from the group consisting of hydrogen, alkyl and alkylcarbonyl; Rc is an alkyl group; each Rd and Re is independently selected from the group consisting of hydrogen and alkyl, each R6 and R7 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydrogen, hydroxyl, hydroxyalkyl, mercaptan, nitro, thioalkoxy, -NRgRj, (NRgRj) alkyl, (NRgRj) alkoxy, (NRgRj) carbonyl and (NRgRj) sulfonyl; Rg and Rj are each independently selected from the group consisting of hydrogen and alkyl.

[0064] R is selected from hydrogen, alkyl, cycloalkylalkyl and arylalkyl. Preferred compounds are disclosed wherein R is hydrogen and an alkyl group. Preferably R is methyl and hydrogen.

[0065] Preferred compounds are disclosed wherein Ar² means

<img file="PL2018380T3_D0010.tif" />

More preferably Ar² means

<img file="PL2018380T3_D0011.tif" />

In particular, the invention relates to compounds of formula (I) wherein A is N; R is selected from methyl and hydrogen; L is O; n is 2; and Ar² are selected from the group consisting of:

<img file="PL2018380T3_D0012.tif" />

More preferably, the invention relates to compounds of formula (I) wherein A is N; R represents a methyl group or a hydrogen atom; L is O; n is 2; ar¹ means

EP 2 018 380 B1

<img file="PL2018380T3_D0013.tif" />

and

ar² means

<img file="PL2018380T3_D0014.tif" />

[0066] The compounds for the method of the invention include, but are not limited to, those specified in the examples or otherwise specifically (explicitly named), they can modulate and often have affinity for nAChR, especially α7 nAChR. As α7 nAChR ligands, compounds of the invention may be useful for treating or preventing many of α7 nAChR-mediated diseases or conditions.

[0067] Specific examples of compounds that may be useful for treating or preventing diseases or conditions mediated by α7 nAChR include, but are not limited to, the compounds described in the Compounds of the Invention as well as in the Examples, as well as compounds such as:

5- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridazin-3-yl} -1H-indole;

(Endo) -3- (6-benzo [b] thiophen-5-yl-pyridazin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane;

(Endo) -3- [6- (benzofuran-5-yl) -pyridazin-3-yloxy] -8-methyl-8-aza-bicyclo [3.2.1] octane;

6- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridazin-3-yl} -1H-indole; 5- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridazin-3-yl} -1H-indazole; 1-methyl-5- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridazin-3-yl} -1H-indole; 5- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -2-trifluoromethyl-1H20 indole;

5- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3--yloxy] pyridazin-3-yl} -1H-indole;

5- {5 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-2-yl} -1H-indole;

(Endo) -3- (6-benzo [b] thiophen-5-yl-pyridin-3-yloxy) -8-aza-bicyclo [3.2.1] octane;

5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-2-yl} -1H-indole;

(Exo) -3- [6- (benzofuran-5-yl) -pyridin-3-yloxy] -8-methyl-8-aza-bicyclo [3.2.1] octane;

5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-2-yl} -1H-indazole; 5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-2-yl} -2-trifluoromethyl-1H-indole;

4- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-2-yl} -1H-indole;

5- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole;

(Endo) -3- (5-benzo [b] thiophen-5-yl-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane;

EP 2 018 380 B1

5- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole;

[6- (1H-indol-5-yl) -pyridin-3-yl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[6- (benzofuran-5-yl) -pyridin-3-yl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[(Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] - [6- (2-trifluoromethyl-1H-indol-5-yl) -pyridin-3-yl] -amine ;

[6- (1H-indazol-5-yl) -pyridin-3-yl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[6- (1H-indol-4-yl) -pyridin-3-yl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[(Endo) -8-aza-bicyclo [3.2.1] oct-3-yl] - [6- (1H-indol-5-yl) -pyridin-3-yl] -amine;

[4- (1H-indol-5-yl) -phenyl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[4- (1H-indazol-5-yl) -phenyl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[(Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] - [4- (1-methyl-1H-indol-5-yl) -phenyl] -amine;

(4-benzo [b] thiophen-5-yl-phenyl) - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[4- (benzofuran-5-yl) -phenyl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[4- (1H-indol-4-yl) -phenyl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[3- (1H-indol-5-yl) -phenyl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

[3- (1H-indol-4-yl) -phenyl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

5- {6 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridazin-3-yl} -2-trifluoromethyl-1H-indol;

4- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole;

5- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole;

5- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -2-trifluoromethyl-1H-indole;

4- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole;

6- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole;

5- {5 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl] -1H-indole;

4- {5 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl] -1H-indole;

6- {5 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl] -1H-indole;

[6- (1H-indol-6-yl) -pyridin-3-yl] - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine;

5- {6 - [(endo) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yloxy] pyridazin-3-yl} -1H-indole; (Endo) -3- [6- (benzo [b] thiophen-5-yl) pyridazin-3-yloxy] -9-methyl-9-azabicyclo [3.3.1] nonane; 5- {5 - [(endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-pyrrolo [2,3-b] pyridine; 5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2,3-b] pyridine; 5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole;

5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole;

4- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole;

6- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole;

(Endo) -N- (5- (1H-indol-5-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine;

(Endo) -N- (5- (1H-indol-4-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine;

(Endo) -N- (5- (1H-indol-6-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine;

(Endo) -N- {5- [2- (trifluoromethyl) -1H-indol-5-yl] pyridin-3-yl} -8-methyl-8-azabicyclo [3.2.1] octane-3-amine;

5- {5 - [(endo) -8-methyl-8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2.3.b] pyridine;

EP 2 018 380 B1

5- {5 - [(endo) -8-methyl-8-azabicyclo [3.2.1] octan-3-yloxy] pyridin-2-yl} indolin-2-one;

5- {5 - [(endo) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H- indole;

(1R, 3r, 5S, 8s) -3- (6- (1H-indol-5-yl) pyridin-3-yloxy) -8-methyl-8-azabicyclo [3.2.1] octane 8-oxide; (1R, 3R, 5S, 8R-) - 3- (6- (1H-indol-5-yl) pyridin-3-yloxy) -8-methyl-8-azabicyclo [3.2.1] octane 8-oxide;

4- {5 - [(endo) -8-azabicyclo [3.2.1] octan-3-yloxy] pyridin-2-yl} -1H-indole;

5- {5 - [(exo) -8-azabicyclo [3.2.1] octan-3-yloxy] pyridin-2-yl} -1H-indole; 5- {5 - [(endo) -8-azabicyclo [3.2.1] octan-3-yloxy] pyridin-2-yl} indolin-2-one; 5- {5 - [(endo) -8-azabicyclo [3.2.1] octan-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2,3-b] pyridine; 5- {5 - [(exo) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2,3-b] pyridine, or pharmaceutically acceptable salts thereof.

[0068] The compound names were determined using AUTONOM name determination software, which is provided by MDL Information Systems GmbH (formerly known as Beilstein Informationssysteme) Frankfurt, Germany and is part of the CHEM-DRAW® ULTRA version 6.0.2 software package.

[0069] The compounds of the invention may exist as stereoisomers in which asymmetric or chiral centers are present. Depending on the configuration of the substituents around the chiral element, these stereoisomers are "R" and "S". The terms "R" and "S" used herein mean the configuration as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976.45: 13-30.

<img file="PL2018380T3_D0015.tif" />

[0070] Attachment of L to an azabicyclic alkane can be considered to include both endo and exo geometry such as the (Ia) and (Ib) isomer. As described in Stereochemistry of Organic Compounds, EL Eliel, SH Wilen; John Wiley and Sons, Inc. 1994, the term structure configuration of formula (Ia) is termed endo. Using the same methods, structures of formula (Ib) were designated as exo.

<img file="PL2018380T3_D0016.tif" />

[0071] Parts N⁺ABOUT^- isomer (Ic) and isomer (Id) are distereoisomers. As described in Synthesis, 1992, 1080, Becker, DP; Flynn, DL and as defined in Stereochemistry of Organic Compounds, EL Eliel, SH Wilen; John Wiley and Sons, Inc. 1994, the term structure configuration of formula (Ic) is defined as (r). Using the same methods, the structure configuration of formula (Id) was further specified as (s).

[0072] The invention contemplates various stereoisomers and mixtures thereof and are in particular included in

Within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the 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 followed by resolution well known to the skilled person. These separation methods are illustrated by (1) attaching a mixture of enantiomers to a chiral helper, separating the resulting mixture of diastereomers by recrystallization or chromatography and optionally releasing the optically pure product from the helper 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 a mixture of optical enantiomers on chiral chromatographic columns or (3) fractional crystallization method.

Methods for making compounds of the invention [0073] The reactions illustrated in the schemes were carried out in a solvent suitable for the reagents and materials used and suitable for carrying out the transformations. Depending on the functional group present in the molecule, in order to obtain the desired compound of the invention, the transformations described may require changing the order of the synthetic steps or selecting one particular process scheme instead of another.

[0074] The methods described below may require the use of different enantiomers. Where stereochemistry is shown in the diagrams, it is for illustrative purposes only.

<img file="PL2018380T3_D0017.tif" />

[0075] Compounds of formula (8), where Ar, Ar have the meanings as defined in formula (I), can be prepared as described in Scheme 1. Compounds of formula (I) when treated with a compound of formula (2a), wherein halogen means bromide, chloride or iodide, in the presence of CuI, 1,10-phenanthroline and Cs2CO3 in a solvent such as, but not limited to, toluene as described in Org. Lett. 2002, 4, 973, provide compounds of formula (3). Compounds of formula (3) can also be prepared by reacting compounds of formula (1) with compounds of formula (2b) in the presence of a base such as but not

Limited to this, KHMDS, in a solvent such as, but not limited to, THF, DME and toluene. Compounds of formula (3) when treated with hexamethyldicine or an organo-boron compound of formula (4) such as bis (pinacolano) dibor or bis (catecholan) dibor, where R is a hydrogen atom, an alkyl or aryl group, will provide a palladium catalyst in the presence of the corresponding tin compound or boronic acid of formula (5), where M is -Sn- (Me) 3 or B (OR) 2. Compounds of formula (5) when treated with compounds of formula (6), Ar²-halo, where Ar² means a bicyclic heteroaryl ring and halo means bromide, chloride or iodide, in the presence of a palladium catalyst provides a compound of formula (8). Optionally, compounds of formula (6) when treated with hexamethyldicine or diborane including a compound of formula (4), such as bis (pinacolano) dibor and bis (catecholan) dibor, in the presence of a palladium catalyst provide a suitable tin compound or boronic acid comprising a compound of formula (7), where Ar² is a bicyclic heteroaryl ring, and where M is -Sn- (Me) 3 or -B (OR) 2. Compounds of formula (7) when treated with a compound of formula (3) in the presence of a palladium catalyst will provide a compound of formula (8).

<img file="PL2018380T3_D0018.tif" />

[0076] Compounds of formula (13), wherein Ar¹ is nitrogen-containing heteroaryl, for example pyridazine, pyrimidine, pyrazine, 2-pyridyl, and Ar² has the meaning as defined in formula (I), can be prepared as shown in scheme 2. Compounds of formula (9), where R^from represents an alkoxyalkyl, alkyl, alkyloxycarbonyl, alkylcarbonyl, aryl, arylalkyloxycarbonyl, cycloalkylalkyl, arylcarbonyl and aryloxycarbonyl group and K is potassium which is prepared from hydroxyl group heterocycles of a similar formula by treatment with potassium tert-butoxide in solvents such as doing this, THF or DMF to obtain potassium oxide comprising compounds of formula (9). Compounds of formula (9) when treated with compounds of formula (10), wherein Y¹ and halo are both bromo, chloro and iodo, and X², X³, X⁴ and X⁵independently are either carbon or nitrogen, for example dichloropyridazine, will provide compounds of formula (11). Compounds of formula (11), when treated with hexamethyldicine or diborane comprising a compound of formula (4) in the presence of a palladium catalyst, according to the procedure outlined in Scheme 1, provide compounds of formula (12). Compounds of formula (12)

Treated with compounds of formula 6 in the presence of a palladium catalyst will provide compounds of formula (13). Optionally, compounds of formula (11) when treated with an organotin compound or organoboronic acid, including compounds of formula (7) as described in Scheme 1, in the presence of a palladium catalyst will provide a compound of formula (13).

Diagram 3

<img file="PL2018380T3_D0019.tif" />

[0077] Optionally, compounds of formula (8) can be prepared as outlined in Scheme 3. Compounds of formula (1) when treated with a compound of formula (14), where Z³ is bromo, chloro or iodo or Ar², in the presence of diethyl azodicarboxylate or di (isopropyl) azodicarboxylate and a phosphine such as triphenylphosphine, will provide compounds of formula (15). When Z³means Ar², compounds of formula (15) are representative compounds of the present invention. When Z³is halogen, further treatment of the compound according to the conditions outlined in Schemes 1-2 depicting Suzuki coupling, provides compounds of formula (8) which are representatives of the compounds of the present invention.

<img file="PL2018380T3_D0020.tif" />

[0078] Another method for preparing compounds of formula (8) is described in Scheme 4. Activated tin compounds or boronic acid compounds of formula (7) can be coupled with various aryl halides, which will provide a process for producing biaryl compounds with formula (17) and formula (20). For example, compounds of formula (7), when treated with diiodobenzene of formula (16) in the presence of a palladium catalyst, provide compounds of formula (17). Compounds of formula (17), when treated with compounds of formula (1) in the presence of cuprous iodide and cesium carbonate and 1,10-phenanthroline as described in Scheme 1, provide compounds of formula (8). Optionally, compounds of formula (7) when treated with a compound of formula (18), wherein R^and is benzyl or other suitable alcohol protecting group, will provide compounds of formula (19) in the presence of a palladium catalyst. Deprotection of the alcohol protecting group, for example when R^and is a benzyl group, deprotection is usually achieved using palladium on carbon and a hydrogen atmosphere, will provide compounds of formula (20). Compounds of formula (20), when treated with compounds of formula (1) in the presence of triphenylphosphine and diethyldiazodicarboxylate or similar agent, will provide compounds of formula (8).

<img file="PL2018380T3_D0021.tif" />

[0079] Compounds of formula (25) which are representatives of compounds of formula (I) where L is -NH- can be prepared as shown in Scheme 5. Compounds of formula (21) when treated with compounds of formula (22) , wherein halo is bromide, chloride or iodide, together with sodium triacetoxy borohydride and Na2SO4 in acetic acid will provide compounds of formula (23).

Optionally, a compound of formula (23) can be obtained by treating compounds of formula (24) with a compound of formula (2), wherein Y is bromo or iodo, in the presence of a palladium catalyst, preferably in toluene. Compounds of formula (23) when further treated with tin or diborane of formula (4), such as bis (pinacolano) dibor and bis (catecholano) dibor, under the conditions described in Scheme 2, will provide suitable tin compound or boronic acid compounds of formula (26). Compounds of formula (26), when treated with a compound of formula (6) in the presence of a palladium catalyst, will provide a compound of formula (25). Optionally, a compound of formula (23) when treated with a tin compound or boronic acid comprising a compound of formula (7) in the presence of a catalyst

EP 2 018 380 B1 will also provide compounds of formula (25).

Scheme 6 (22) + (7)

<img file="PL2018380T3_D0022.tif" />

(21) (27) (25) [0080] In addition, compounds of formula (25) can be prepared as shown in Scheme 6. Ketone 5 comprising compounds of formula (21) when treated with compounds of formula (27) prepared by reaction coupling a haloarylamine of formula (22) and the corresponding tin or boron agent of formula (7) in the presence of a palladium catalyst, and then treated with sodium borohydride triacetate and Na2SO4 in acetic acid to provide compounds of formula (25) as described in Tetrahedron Lett.

1996, 37, 6045.

<img file="PL2018380T3_D0023.tif" />

[0081] Compounds of formula (31) wherein L is S and Ar¹ and Ar² have the meanings as defined in formula (I), can be prepared as shown in Scheme 7. Compounds of formula (29) wherein halo is bromide, chloride or iodide when pre-treated with sodium hydride in a solvent such as but not limited to of this, DMF and then by treatment with compounds of formula (28) provide compounds of formula (30). Compounds of formula (30), when treated with a compound of formula (7) as described in Scheme 1, provide compounds of formula (31) which are representatives of compounds of formula (I), where L is S. Optionally a compound of formula (30) ) when treated with hexamethyldicin or a diboron reagent of formula (4) such as bis (pinacolano) dibor and bis (catecholano) diboron, in the presence of a palladium catalyst provides a compound of formula (32). Compounds of formula (32) when treated with compounds of formula (6), where halo is bromo, chloro or iodo, in the presence of a palladium catalyst provide compounds of formula (31).

EP 2 018 380 B1

<img file="PL2018380T3_D0024.tif" />

[0082] Compounds of formula (35) which are representatives of compounds of formula (I) wherein L is O, S or -N (Ra) -, Ar¹ has the meaning as previously defined in formula (I) and Ar² is amino-substituted benzothiazole, prepared according to the conditions outlined in Scheme 8. Compounds of formula (33) which were prepared using the methods described in Schemes 1-7, wherein Ar² is substituted with a -NH2 group when treated with bromine or KSCN in acetic acid to provide compounds of formula (34). Compounds of formula (34) can be further treated with the desired R group halide^gwhere R^g has the meaning as defined in the scope of the compounds of the present invention, to provide compounds of formula (35).

<img file="PL2018380T3_D0025.tif" />

[0083] Compounds of formula (39) wherein L is O, NH or S; ar¹ has the meaning as previously defined in formula (I), Ar² is benzimidazole as defined for compounds of formula (I), prepared as outlined in Scheme 9. Compounds of formula (36) are prepared by treating compounds of formula (33) from Scheme 8, using conditions known to the skilled person who introduce a group protecting nitrogen to nitrogen Ar²where P is the tert20 group

Butyloxycarbonyl, benzyloxycarbonyl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl or trialkylsilane. Compounds of formula (36) when treated with nitric acid in sulfuric acid will provide compounds of formula (37). Compounds of formula (37) when subjected to reducing conditions such as, but not limited to, treatment with a palladium catalyst and a hydrogen atmosphere, will reduce the nitro group to the appropriate amine, which is subjected to conditions known to the skilled person that will remove the protecting group nitrogen to provide compounds of formula (38). The compounds of formula (38) are then subjected to further treatment with an excess of the orthoester of formula (EtO) 3CR^m providing compounds of formula (39), wherein R^m is an alkyl or aryl group.

<img file="PL2018380T3_D0026.tif" />

[0084] Compounds of formula (44) containing a benzooxazole group, wherein L is O, NH or S; ar¹has the meaning as previously defined in formula (I), and Rⁿ is an alkyl group, a hydrogen atom or an aryl group, can be prepared as outlined in Scheme 10. Compounds of formula (40) can be treated with a dicin or diboron reagent of formula (4), such as hexamethyldicine, bis (pinacolano) diboron and bis ( catecholane) diboron, in the presence of a palladium catalyst, to provide the corresponding tin compound or boronic acid of formula (41). Compounds of formula (41) when treated with a halogen containing compound of formula (42) in the presence of a palladium catalyst will provide compounds of formula (43). Compounds of formula (43) when treated under conditions known to the skilled person which reduce nitro groups to the corresponding amino group and then treated with an R-substituted orthoesterⁿwhere Rⁿ represents a hydrogen atom, an alkyl or aryl group, provide compounds of formula (44).

[0085] In addition, compounds of formula (I) where A is N can be converted to compounds of formula (I) where A is N⁺-ABOUT^- by treatment with an oxidizing agent. Examples of the oxidizing agent include, but are not limited to, aqueous hydrogen peroxide m-chloroperbenzoic acid. The reaction is usually 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, at a temperature from about 0 ° C to about 80 ° C, for a period of about 1 hours to about 4 days.

[0086] The compounds and intermediates of the invention can be isolated and purified using methods well known to those skilled in the art of organic synthesis. Examples of traditional methods for isolating and purifying compounds may include, but are not limited to, chromatography on solid supports such as silica gel, alumina or silica

EP 2 018 380 B1 derivatized with alkyl silicon groups, by recrystallization at high or low temperature with optional pre-treatment with activated carbon, thin layer chromatography, distillation under different pressures, sublimation under reduced pressure and trituration as described for example in "Vogel's Textbook of Practical Organic Chemistry ", 5th Edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific &amp; Technical, Essex CM20 2JE, England.

[0087] The compounds of the invention have at least one basic nitrogen atom, whereby the compounds can be treated with an acid to form the desired salt. For example, the compound may be reacted with an acid at or above room temperature to provide the desired salt, which is precipitated and collected after cooling by filtration. Examples of suitable acids for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic, atromylic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbon, fumaric, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, lemon or hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, glutamic and the like.

[0088] Nitrogen protecting groups can be used to protect the amino groups present in the compounds described. Such methods and some suitable nitrogen protecting groups are described in Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999). For example, suitable nitrogen protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), acetyl and trifluoroacetyl. More specifically, the Boc protecting group can be removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid. The Cbz and Bn protecting groups can be removed by catalytic hydrogenation. The acetyl and trifluoroacetyl protecting group can be removed with hydroxide ion.

[0089] The compounds and methods of the invention will be better understood by reference to the following examples, which are intended to illustrate and not limit the scope of the invention.

Example 1 5- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole trifluoroacetate

Example 1A (ene) -3- (6-chloro-pyridazin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0090] Mixture (endo) -tropine (Aldrich, 706 mg, 5.0 mmol), 3,6-dichloropyridazine (Aldrich, 745 mg, 5.0 mmol) and potassium t-butoxide (Aldrich, 1.12 g, 10 mmol) in THF (anhydrous, Aldrich, 25 ml) was stirred in 60 ° C under nitrogen for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography (150 g SiO2 EtOAc: MeOH: ΝΗ₃· Η₂Ο, 90: 10: 1, R._f. 0.20) to obtain the title compound.¹H NMR (300 MHz, CD₃OD) δ 2.03 - 2.36 (m, 8H), 2.45 (s, 3H), 3.38 [s (br), 2H], 5.40 (t, J = 5.09 Hz , 1H), 7.20 (d, J = 9.16 Hz, 1H), 7.66 (d, J = 9.16 Hz, 1H) ppm; MS (DCI / NH3) m / z 254 (M + H)⁺,

EP 2 018 380 B1

Example 1B 5- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole trifluoroacetate [0091] A mixture of Example 1A (112 mg, 0.44 mmol), 5- (4,4,5,5-tetramethyl [1.3.2] dioxaborolan-2-yl) -1H-indole (Aldrich, 232 mg, 0.954 mmol), chloride bis (triphenylphosphine) palladium (II) (Aldrich, 7.02 mg, 0.01 mmol) and biphenyl-2-yl-dicyclohexyl phosphate (Strem Chemicals, 10.5 mg, 0.03 mmol) in a dioxane / EtOH mixture / Na2CO3 (aqueous, 1 M) (vol. 1/1/1, 3 ml) was heated and irradiated with microwave radiation to 150 ° C and 300 watts for 15 minutes in the Emry ™ Creator microwave reactor. The solid was filtered off through the syringe filter and the organic solution was purified immediately using preparative HPLC (Gilson, column, Xterra® 5 μm, 40 x 100 mm. Elution solvent, MeCN / H₂O containing 0.1% vol. TFA (90% to 10% for 25 minutes. Flow rate 40 ml / minute, UV detector set at 254 nm). Fractions containing the desired product were collected and concentrated under reduced pressure, and the residue was stirred in an ether / ethanol mixture (vol. 10/1, 5 mL) at ambient temperature for 16 hours to give the title compound.¹H NMR (300 MHz, CD3OD) δ 2.31 - 2.60 (m, 8 H), 2.85 (s, 3 H), 3.97 [s (br), 2 H], 5.53 - 5.62 (m, 1H), 6.56 (d, J = 3.05 Hz, 1H), 7.24 - 7.34 (m, 2H), 7.51 (d, J = 8 , 48 Hz, 1H), 7.74 (dd, J = 8.65, 186 Hz, 1H), 8.09 - 8.17 (m, 2H) ppm; MS (DCI / NH3) m / z 335 (M + H)⁺. Anal. Calculated for C20H22N4O-1.05 CF₃CO2HO, 50 C2H₅OH: C, 58.14; H, 5.50; N, 11.74. Found: C, 58.07; H, 5.44; N, 11.75.

Example 2 (ene) -3- (6-benzo [b] thiophen-5-yl-pyridazin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane trifluoroacetate [0092] Product of example 1A (121 mg, 0.48 mmol) and 2-benzo [b] thiophen-5-yl-4,4,5,5-tetramethyl [1.3.2] dioxaborolane (Maybridge, 219 mg, 0.84 mmol) were treated according to the procedure outlined in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.33 - 2.58 (m, 8H), 2.86 (s, 3H), 3.94 - 4.02 (m, 2H), 5.57 - 5.64 (m, 1H), 7.34 (d, J = 9.15 Hz, 1H), 7.50 (d, J = 5.42 Hz, 1H), 7.67 (d , J = 5.42 Hz, 1H), 7.98 (dd, J = 8.48, 1.70 Hz, 1H), 8.06 (d, J = 8.48 Hz, 1H), 8.20 (d, J = 9.15 Hz, 1H), 8.44 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH3): m / z 352 (M + H)⁺. Anal. Calculated for C.₂₀H₂₁N₃OS1,10 CF₃WHAT₂H: C, 55.91; H, 4.67; N, 8.81, Found: C, 55.90; H, 4.41; N, 8.59.

Example 3 (enfo) -3- [6- (benzofuran-5-yl) -pyridazin-3-yloxy] -8-methyl-8-aza-bicyclo [3.2.1] octane trifluoroacetate [3.2.1] octane [0093] The product of example 1A ( 131 mg, 0.52 mmol) and 1-benzofuran-5-ylboronic acid (Apollo, 166 mg, 1.02 mol) were treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.33 - 2.64 (m, 8H), 2.86 (s, 3H), 3.94 - 4.02 (m, 2H), 5.56 5.63 (m, 1H), 6.96 (d, J = 1.36 Hz, 1H), 7.32 (d, J = 9.16 Hz, 1H), 7.65 (d, J = 8.82 Hz, 1H), 7.84 (d, J = 2.37 Hz, 1H), 7.93 (dd, J = 8.82, 2.03 Hz, 1H), 8 , (D, J = 9.49 Hz, 1H), 8.22 (d, J = 1.36 Hz, 1H) ppm; MS (DCI / NH₃): m / z 3.36 (M + H) +. Anal. Calculated for C.₂₀H₂₁N₃ABOUT₂H, 1 CF₃WHAT₂H: C, 57.86; H, 4.83; N, 9.12. Found: C, 58.10; H, 4.54; N, 9.06.

EP 2 018 380 B1

Example 4 6- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole trifluoroacetate [0094] The product of the example 1A (158 mg, 0.62 mmol) was coupled to indole-6-boronic acid (Frontier, 162 mg, 1.01 mol), treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.33 - 2.59 (m, 8 H), 2.85 (s, 3 H), 3.93 - 4.01 (m, 2

H), 5.58 (t, J = 3.05 Hz, 1H), 6.51 (d, J = 3.05 Hz, 1H), 7.29 (d, J = 9.16 Hz, 1H), 7.35 (d, J = 3.05 Hz, 1

H), 7.58 - 7.64 (m, 1H), 7.66 - 7.73 (m, 1H), 8.01 (s, 1H), 8.13 (d, J = 9 , 49 Hz, 1H) ppm. MS (DCI / NH 3): m / z 335 (M + H) +. Anal. Calculated for C2oH2iN4O-1.10 CF₃WHAT₂H: C, 57.99; H, 5.06; N, 12.18. Found: C, 58.09; H, 4.95; N, 11.97.

Example 5 5- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indazole fumarate

Example 5A

5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole [0095] To a flask containing 5-bromo-1H-indazole (reference: US 2003199511, 9 , 45 g, 48 mmol) and bis (pinacolano) diboron (Aldrich, 15.5 g, 61 mmol) in dry DMF (160 mL) was added KOAc (16.7 g, 170 mmol). The mixture was degassed and flushed with N2 three times, then PdCl was added₂(Dppf) OH₂cl₂ (Aldrich, 985 mg, 1.21 mmol). The mixture was heated to 90 ° C and stirred for 24 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (250 mL), washed with water (2 x 50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by chromatography (400 g SiO2 hexane: EtOAc 90:10, Rf = 0.6) to afford the title compound.¹H NMR (300 MHz, CD3OD) δ 1.36 (s, 12H), 7.51 (dt, J = 8.48, 1.02 Hz, 1H), 7.73 (dd, J = 8, 48, 1.02 Hz, 1H), 8.08 (d, J = 1.02 Hz, 1H), 8.23 ​​(t, J = 1.02 Hz, 1H) ppm. MS (DCI / NH3): m / z 245 (M + H)⁺.

Example 5B

5- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indazole [0096] A mixture of the compound of Example 1A ( 158 mg, 0.62 mmol) and the product of Example 5A (308 mg, 1.26 mol) treated with bis (triphenylphosphine) palladium (II) chloride (Aldrich, 7.02 mg, 0.01 mmol) and biphenyl-2-yl dicyclohexyl phosphate (Strem Chemicals, 10.5 mg, 0.03 mmol) in a mixture of dioxane / EtOH / Na2CO3 (aqueous, 1 M) (vol. 1/1/1, 3 ml) was heated and irradiated with microwave radiation to 150 ° C and 300 watts for 15 minutes in the Emry ™ Creator microwave reactor. The mixture was cooled to ambient temperature, the solid was filtered through a syringe filter and the organic solution was immediately purified by chromatography (40 g SiO2 EtOAc: MeOH: NH3-H2O, 90: 10: 1, Rf = 0.10) to afford the title compound.¹H NMR (300 MHz, CD3OD) δ 2.02 - 2.33 (m, 8H), 2.36 (s, 3H), 3.25 [s (br), 2H], 5.47 ( t, J = 4.92 Hz, 1H), 7.23 (d, J = 9.16 Hz, 1

EP 2 018 380 B1

H), 7.67 (dt, J = 8.82, 0.85 Hz, 1H), 8.07 (dd, J = 8.82, 1.70 Hz, 1H), 8.10 - 8 , 19 (m, 2H), 8.36 (dd, J = 1.53, 0.85 Hz, 1H) ppm; MS (DCI / NH3): m / z 336 (M + H)⁺.

Example 5C 5- {6 - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indazole fumarate [0097] Example product 5B (128 mg, 0.38 mmol) was treated with fumaric acid (46 mg, 0.40 mmol) in a mixture of EtOAc / EtOH (vol. 1: 1, 5 mL) at ambient temperature for 15 hours. To obtain the title compound, the mixture was filtered.¹H NMR (300 MHz, CD3OD) δ 2.29 - 2.61 (m, 8H), 2.86 (s, 3H), 3.90 - 3.99 (m, 2H), 5.59 (t, J = 4.92 Hz, 1H), 6.69 (s, 2H), 7.32 (d, J = 9.16 Hz, 1H), 7.68 (d, J = 8 , 82 Hz, 1H), 8.08 (dd, J = 8.82, 1.70 Hz, 1H), 8.15 - 8.21 (m, 2H), 8.38 (dd, J = 1.70,

0.68 Hz, 1H) ppm; MS (DCI / NH₃): m / z 336 (M + H) +. Anal. Calc. for C.₁₉H₂₁N₅O-1.20 C₄H₄ABOUT₄: C, 60.22;

H, 5.48; N, 14.75. Found: C, 60.03; H, 5.17; N, 14.85.

Example 6 1-methyl-5- {6 - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1-indole trifluoroacetate [0098] Product of Example 1A (121 mg, 0.48 mmol) and N-methylindole-5-boronic acid (Frontier, 175 mg, 1.0 mol) were treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.22 - 2.70 (m, 8H), 2.86 (s, 3H), 3.93 - 4.03 (m, 2H), 5.53 - 5.62 (m, 1H), 6.57 (d, J = 3.05 Hz, 1H), 7.26 (d, J = 3.39 Hz, 1H), 7.37 (d , J = 9.49 Hz, 1H), 7.54 (d, J = 8.82 Hz, 1H), 7.80 (dd, J = 8.65, 1.87 Hz, 1H), 8.16 (d, J = 1.70 Hz, 1H), 8.21 (d, J = 9.16 Hz, 1H) ppm; MS (DCI / NH₃): m / z 349 (M + H) +. Anal. Calculated for C.₂₁H₂₄N₄O-1.60 CF₃WHAT₂H: C, 54.75; H, 4.86; N

10.55. Found: C, 54.69; H, 4.80; N, 10.58.

Example 7 trifluoroacetate_5- {6 - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -2-trifluoromethyl-1H-indole

Example 7A

5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -2-trifluoromethyl-1H-indole [0099] A mixture of 5-bromo-2-trifluoromethyl-1H-indole ( reference: US 2005043347, 6.05 g, 22.9 mmol), bis (pinacolano) diboron (7.74 g, 30.5 mmol), KOAc (8.05 g, 82 mmol) and PdCl2 (dppf) -CH2Cl2 (901 mg, 1.1 mmol) in anhydrous DMF (242 mL) was processed according to the procedure described in Example

5A to obtain the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.36 (s, 12H), 6.91 (s, 1H), 7.43 (d,

J = 8.48 Hz, 1H), 7.64 (d, J = 8.14 Hz, 1H), 8.11 (s, 1H) ppm; MS (DCI / NH3): 312 (M + H)⁺.

Example 7B

EP 2 018 380 B1

(Eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl 4-nitro-benzoate [0100] To the (endo) -tropine mixture (2.82 g, 20.0 mmol), 4-nitrobenzoic acid (3.34 g, 20.0 mmol) and triphenylphosphine (5.24 g, 20.0 mmol) in dry THF (100 mL) at diisopropyl azodicarboxylate (4.04 g, 20.0) mmol) and the resulting mixture was stirred for 40 hours.

The mixture was concentrated under reduced pressure and the residue was purified by chromatography (140 g SiO2, EtOAc: MeOH: NH3-H2O, 90: 10: 1, Rf = 0.30) to afford the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.74 - 2.23 (m, 8H), 2.38 (s, 3H), 3.32 - 3.38 (m, 2H), 5.23 - 5.38 (m, 1H), 8.21 (d, J = 8.82 Hz, 2H), 8.32 (d, J = 8.82 Hz, 2H) ppm; MS (DCI / NH3): 291 (M + H)⁺.

Example 7C (eqzq) -8-methyl-8-aza-bicyclo [3.2.1] octane-3-ol [0101] The product of example 7B (5.0 g, 0.017 mol) in ethanol (10 ml) was treated with NaOH ( 1N, 200 ml) at room temperature for 40 hours. The mixture was extracted with a mixture of 10% isopropanol in chloroform (3 X 100 mL) and the combined extracts concentrated under reduced pressure to afford the title compound.¹H NMR (300 MHz, CD3OD) δ 1.55 - 1.69 (m, 4 H), 1.80 (m, 2 H), 1.99 - 2.09 (m, 2

H), 2.28 (s, 3H), 3.14-3.21 (m, 2H), 3.79-3.93 (m, 1H) ppm. MS (DCI / NH3): 142 (M + H)⁺.

Example 7D (eqzq) -3- (6-chloro-pyridazin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0102] The product of example 7C (721 mg, 5.1 mmol ) and 3,6-dichloropyridazine (1.04 g, 7.0 mmol) were treated according to the procedure described in Example 1A to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.87 - 2.07 (m, 4H), 2.23 - 2.31 (m, 2H), 2.37 (m, 2H), 3.60 - 3.69 (m, 2H),

5.54 (m, 1H), 7.15 (d, J = 9.16 Hz, 1H), 7.64 (d, J = 9.16 Hz, 1H) ppm; MS (DCI / NH3): 254 (M + H)⁺.

Example 7E Trifluoroacetate_5- {6 - [(enrfq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -2-trifluoromethyl-IH-indole [0103] The product of Example 7D (128 mg, 0.5 mmol) and the product of Example 7A (311 mg, 1.0 mmol) were treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.01 - 2.73 (m, 8H), 2.85 (s, 3H), 4.01 - 4.10 (m, 2H), 5.64 - 5.80 (m, 1H), 7.02 (s, 1H), 7.23 (d, J = 9.15 Hz, 1H), 7.60 (d, J = 8.48 Hz , 1H), 7.95 (dd, J = 8.48, 1.70 Hz, 1H), 8.13 (d, J = 9.49 Hz, 1H), 8.26 (d, J = 1.02 Hz, 1H) ppm; MS (DCI / NH3): m / z 403 (M + H)⁺. Anal. Calculated for

C21H21F3N4O-1.55 CF3CO2H: C, 49.98; H, 3.92; N, 9.67. Found: C, 49.93; H, 4.09; N, 9.69.

Example 8

5- {6 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole fumarate [0104] The product of Example 7D ( 154 mg, 0.61 mmol) and 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-226

EP 2 018 380 B1) -1H-indole (Aldrich, 243 mg, 1.0 mmol) was treated with bis (triphenylphosphine) palladium (II) chloride (Aldrich, 7.02 mg, 0.01 mmol) and biphenyl-2- il-dicyclohexyl phosphene (Strem Chemicals, 10.5 mg, 0.03 mmol) in a mixture of dioxane / EtOH / aqueous 1M Na2CO3 (vol. 1/1/1, 3 ml) was heated and irradiated with microwave radiation to 150 ° C and 300 watts for 15 minutes in the Emry ™ Creator microwave reactor. The mixture was cooled to ambient temperature, the solid was filtered through a syringe filter and the organic solution was immediately purified using preparative HPLC (Gilson, Xterra® column, 7 μm, 40 x 100 mm, elution solvent, MeCN / H2O with 0.1 M NH4HCO3 / NH4OH, PH = 10) (vol. 90/10 to 10/90 for 25 minutes), flow rate, 40 ml / min, uv, 254 nm) to obtain the free base of the title compound. The free base was treated with fumaric acid (65 mg, 0.57 mmol) according to the procedure of Example 5C to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.04 - 2.50 (m, 6H), 2.57 - 2.69 (m, 2H), 2.85 (s, 3H), 3.99 - 4.05 (m, 2H), 5.63 - 5.78 (m, 1H), 6.56 (d, J = 3.05 Hz, 1H), 6.69 (s, 2H ), 7.20 (d, J = 9.15 Hz, 1H), 7.31 (d, J = 3.39 Hz, 1H), 7.51 (d, J = 8.48 Hz, 1 H), 7.74 (dd, J = 8.48, 1.70 Hz, 1H), 8.09 (d, J = 9.49 Hz, 1H), 8.14 (d, J = 1 , 02 Hz, 1H) ppm; MS (DCI / NH3): m / z 335 (M + H)⁺; Anal. Calculated for C.₂₀H₂₂N₄OH, 20 C.₄H₄ABOUT₄: C, 62.88; H, 5.70; N, 11.83. Found: C, 62.63; H, 5.70; N, 11.96.

Example 9 5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole ditosylate

Example 9A (ene) -3- (6-chloro-pyridin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0105] Mixture (endo) -tropine (Aldrich, 2.82 g, 20 mmol), 2-chloro-5-iodo-pyridine (Aldrich, 2.39 g, 24 mmol), CuI (Strem Chemicals, 0.19 g, 1 mmol) and 1,10-phenanthroline (Aldrich, 0 , 36 g, 2 mmol), Cs 2 CO 3 (Aldrich, 6.52 g, 20 mmol) in toluene (anhydrous, Aldrich, 25 ml) was stirred at 110 ° C for 40 hours. The mixture was allowed to cool to ambient temperature and diluted with CH 2 Cl 2 (100 mL) and washed with water (2 x 10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO₂, CH₂cl₂: MeOH: NH₃n₂O, 90: 10: 1, R._f 0.10) to obtain the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.97 - 2.08 (d, J = 14.5 Hz,, 2 H), 2.13 - 2.18 (d, J = 2.37 Hz, 2 H ), 2.45 (s, 3H), 3.35 - 3.41 (m, 2H), 4.66 (t, J = 4.8 Hz, 1H), 7.35 - 7.42 (m, 2H), 7.96 - 8.04 (dd, J = 2.3, 1.0 Hz, 1H) ppm. MS (DCI / NH3) m / z 255 (M + H)⁺. 253 (M + H)⁺.

Example 9B

5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole [0106] The product mixture of Example 9A ( 150 mg, 0.59 mmol), 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol), Pd (PPh3) 4 (Aldrich, 6.8 mg, 0.006 mmol) and K2CO3 (2 M, 1 ml) was heated to 85 ° C in dioxane (4 ml) for 12 hours. The mixture was cooled to ambient temperature, filtered and purified using preparative HPLC [Waters XTerra RP 18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate,

Adjusted to pH 10 with ammonium hydroxide) (vol. 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm] to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.94 - 2.06 (m, 2H), 2.06 - 2.27 (m, 6H), 2.34 (s, 3H), 3.21 [s (br,), 2H], 4.67 (t, J = 4.75 Hz, 1H), 6.52 (dd, J = 3.05, 1.00 Hz, 1H), 7 , 26 (d, J = 3.39 Hz, 1H), 7.40 (dd, J = 8.82, 3.05 Hz, 1H), 7.45 (dt,

J = 8.48, 0.7 Hz, 1H), 7.63 (dd, J = 8.65, 1.87 Hz, 1H), 7.77 (dd, J = 8.82, 0, 70 Hz, 1H), 7.99 - 8.08 (m, 1H), 8.18 (d, J = 3.05 Hz, 1H) ppm. MS (DCI / NH3) m / z 3:34 (M + H)⁺.

Example 9C 5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole ditosylate [0107] Product of example 9B (40 mg, 0.12 mmol) was treated with p-toluenesulfonic acid monohydrate TsOHHO (Aldrich, 38 mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate (5 mL) at ambient temperature for 10 hours. The mixture was filtered to give the title compound.¹H NMR (300 MHz, CD3OD) δ 2.25-2.56 (m, 13 H), 2.77 - 2.89 (m, 4 H), 3.87 - 4.03 (m, 2 H) , 4.90-2.04 (m, 1H), 6.66 (dd, J = 3.1, 0.7 Hz, 1H), 7.19 (d, J = 8.10 Hz, 4H) , 7.43 (d, J = 3.39 Hz, 1H), 7.55 - 7.65 (m, 2H), 7.68 (d, J = 8.14 Hz, 4H), 8 , 10 - 8.17 (m, 1H), 8.22 - 8.38 (m, 2H), 8.46 (d,

J = 2.03 Hz, 1H) ppm. MS (DCI / NH₃): m / z 334 (M + H) +. Anal. Calculated for C.₂₁H₂₃N₃O ^ 2.05

C₇H₈SO₃^ 2.00H₂O: C, 57.52; H, 6.17; N, 5.72. Found: C, 57.88; H, 5.99; N, 5.33.

Example 10 (ene) -3- (6-benzo [b] thiophen-5-yl-pyridin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane ditosylate

Example 10A

2-benzo [b] thiophen-5-yl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane [0108] A mixture of 5-bromo-benzo [b] thiophene (Maybridge, 4.26 g , 0.0200 mol), bis (pinacolano) diboron (Aldrich, 6.09 g, 0.0240 mol) and potassium acetate (Aldrich, 2.94 g, 0.0300 mol) in 1,4-dioxane (Aldrich, 50 ml) was degassed and N2 was passed through three times. [1,1'-Bis (diphenylphosphine) ferrocene] dichloropalladium (II) PdCl was added₂(Dppf) OH₂cl₂ (300 mg, 0.4 mmol, Aldrich) and the solution was heated to 100 ° C for 20 hours. The mixture was then cooled to room temperature, diluted with 300 mL EtOAc and washed with brine (2 x 20 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound.¹H NMR (300 MHz, CDCl3) δ 1.36 - 1.41 (S, 12H), 7.35 (d, J = 5.50 Hz, 1H), 7.42 (d, J = 5, 70 Hz, 1H), 7.75 (d, J = 8.14 Hz, 1H), 7.89 (d, J = 8.14 Hz, 1H), 8.31 (s, 1H) ppm. MS (DCI / NH3) m / z 278 (M + H)⁺.

Example 10B (ene) -3- (6-benzo [b] thiophen-5-yl-pyridin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0109] The product of example 9A (150 mg, 0.59 mmol) and the product of Example 10A (231.6 mg, 0.89 mmol) were treated with Pd (PPh3) 4 (Aldrich, 6.8 mg, 0.006 mmol) according to the procedure described in Example 9B.

EP 2 018 380 B1

The title product was purified using preparative HPLC [Waters XTerra RP18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol. 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm]. ¹H NMR (300 MHz, CD3OD) δ 1.93 - 2.07 (m, 2H), 2.06 5 2.28 (m, 6H), 2.34 (s, 3H), 3.21 [s (br,), 2H], 4.70 (t, J = 5.26 Hz, 1H), 7.37 - 7.50 (m, 2H), 7.61 (d,

J = 5.43 Hz, 1H), 7.80 - 7.92 (m, 2H), 7.94 - 8.02 (m, 1H), 8.25 (d, J = 2.71 Hz, 1H), 8.34 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH3) m / z 351 (M + H)⁺.

Example 10C (ene) -3- (6-benzo [b] thiophen-5-yl-pyridin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane ditosylate [0110] Product from example 10B (70 mg, 0.20 mmol) treated with p-toluenesulfonic acid monohydrate TsOHH₂O (Aldrich, 38 mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate as shown in Example 9C. The mixture was filtered to give the title compound.¹H NMR (300 MHz, CD3OD) δ 2.35 (s, 6H), 2.48-2.62 (m, 8H), 2.78 (s, 3H), 3.88 - 4.05 ( m, 2H), 5.02 (t, J = 4.58 Hz, 1H), 7.22 (d, J = 7.80 Hz, 4H), 7.55 (d, J = 5, 76 Hz, 1H), 7.70 (d, J = 8.48 Hz, 4H), 7.75 15 7.84 (m, 2H), 8.12 - 8.22 (m, 2H ), 8.29 (d, J = 9.20 Hz, 1H) 8.37 (d, J = 1.70 Hz, 1H), 8.56 (d, J = 3.05

Hz, 1H) ppm. MS (DCI / NH₃): m / z 351 (M + H) +. Anal. Calculated for C.₂₁H₂₃N₂OSZ, 00 C.₇H₈SO₃d, 00 H2O: C, 58.97; H, 5.66; N, 3.93. Found: C, 58.86; H, 5.61; N, 5.71.

Example 11 5- {5 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole tosylate

Example 11A (Exo) -3- (6-chloro-pyridin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane tosylate [0111] To (endo) -tropine mixture (Aldrich, 2 , 82 g, 20 mmol), 2-chloro-5-hydroxypyridine (Aldrich, 1.29 g, 10 mmol) and Ph3P (Aldrich, 5.24 g, 20 mmol) diisopropyl azadicarboxylate (Aldrich, 4.04 g, 20 mmol) in THF (anhydrous, Aldrich, 100 ml) and the mixture was stirred for two days.

The mixture was concentrated under reduced pressure and the title product was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3-H2O, 90: 10: 1, Rf 0.40) as a solid (1.98 g, yield, 78.3%) . ¹H NMR (300 MHz, CD3OD) δ 1.63 - 1.92 (m, 4H), 1.97 - 2.20 (m, 4H), 2.33 (s, 3H), 3.34 (s, 2H), 4.51 - 4.75 (m, 1H), 7.27 - 7.37 (dd, J = 8.80, 0.7 Hz, 1H), 7.37 - 7.49 (dd, J = 8.80, 3.00 Hz, 1H), 8.01 (d, J = 3.05 Hz, 1H) ppm. MS (DCI / NH3) m / z 255 (M + 11)⁺, 253 (M + H)⁺.

Example 11B

5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole [0112] The product mixture of Example 11A ( 150 mg, 0.59 mmol), 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol) and Pd (PPh3) 4 (Aldrich, 6.8 mg, 0.006 mmol) and K2CO3 (2 M, 1 ml) in

Dioxane (4 mL) was stirred at 85 ° C for 12 hours according to the procedure described in Example 9B. The title product was purified using preparative HPLC [Waters XTerra RP18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) (vol. 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm].¹H NMR (300 MHz, CD3OD) δ 1.61 - 1.97 (m, 4H), 2.00 2.23 (m, 4H), 2.35 (s, 3H), 3.22 - 3.38 (m, 2H), 4.56 - 4.78 (m, 1H), 6.51 (d, J = 4.07 Hz, 1H), 7.26 (d, J = 3 , 39 Hz, 1H), 7.40 - 7.52 (m, 2H), 7.62 (dd, J = 8.48, 1.70 Hz, 1H), 7.75 (d, J = 8.82 Hz, 1H), 8.03 (s, 1H), 8.21 (d, J = 2.37 Hz, 1H) ppm. MS (DCI / NH3) m / z 334 (M + H)⁺.

Example 11C 5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole tosylate [0113] The product of the example 11B (50 mg, 0.15 mmol) treated with p-toluenesulfonic acid monohydrate TsOHU₂O (Aldrich, 38 mg, 0.2 mmol) in a mixture of 25% isopropanol in ethyl acetate (5 mL) at ambient temperature for 10 hours according to the procedure of Example 9C. The mixture was filtered to give the title compound.¹H NMR (300 MHz, CD3OD) δ 1.90 - 2.13 (m, 2H), 2.17 2.31 (m, 2H), 2.33-2.42 (m, 5H), 2 , 44 - 2.58 (m, 2H), 2.83 (s, 3H), 4.02 [s (br,), 2H], 4.86 - 5.03 (m, 1H) , 6.53 (dd, J = 3.22; 0.85 Hz, 1H), 7.22 (d, J = 8.14 Hz, 1H), 7.26 - 7.32 (m, 1 H), 7.47 (d, J = 8.48 Hz, 1H), 7.56 - 7.66 (m, 2H), 7.70 (dt, J = 8.10, 1.80 Hz, 2H), 7.82 (d, J = 8.82 Hz, 1H), 8.05 (d, J = 1.36 Hz, 1H), 8.28 (d, J = 3.05 Hz , 1H) ppm. MS (DCI / NH3): m / z 334 (M + H)⁺. Anal. Calculated for C.₂₁H₂₃N₃OH, 00 C.₇H₈SQ₃-1.00 H₂O: C, 64.22; H, 6.35; N, 8.02. Found: C, 64.07; H, 6.16; N, 7.69.

Example 12 (eqzo) -3- [6- (benzofuran-5-yl) -pyridin-3-yloxy] -8-methyl-8-aza-bicyclo [3.2.1] octane ditrifluoroacetate [3.21] octane [0114] The product of example 11A ( 1.30 mg, 0.52 mmol) and 1-benzofuran-5-ylboronic acid (Maybridge, 166 mg, 1.0 mmol) were treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.98 - 2.58 (m, 8H), 2.84 (s, 3H), 3.98 4.09 (m, 2H), 4.93 - 5.07 (m, 1H), 6.94 (d, J = 1.36 Hz, 1H), 7.62 (d, J = 8.81 Hz, 1H), 7.73 (dd, J = 8.81, 3.05 Hz, 1H), 7.80 - 7.86 (m, 2H), 7.92 (d, J = 8.48 Hz, 1H), 8.13 ( d, J = 1.36 Hz, 1H), 8.38 (d, J = 2.37 Hz, 1H) ppm; MS (DCI / NH₃): m / z 335 (M + H) +. Anal. Calculated for C.₂₁H₂₂N₂ABOUT₂^ 2.00 CF₃WHAT₂H: C, 53.39; H, 4.30; N, 4.98. Found: C, 53.28; H, 4.04; N, 4.95.

Example 13 5- {5 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indazole hemifumarate [0115] Example product 11A (139 mg, 0.55 mmol) and the product of Example 5A (325 mg, 1.3 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.97 - 2.45 (m, 8 H), 2.73 (s, 3 H), 3.80 - 3.89 (m, 2 H), 4.84 - 4.96 (m, 1H), 6.68 (s, 1H), 7.56 (dd, J = 8.82, 3.05 Hz, 1H), 7.62 (d, J = 8.82 Hz, 1H), 7.84 (d, J = 8.82 Hz, IH), 7.97 (dd, J = 8.82, 1.70 Hz, IH), 8.12 (d , J = 1.02 Hz, 1H), 8.27 (dd, J = 1.53, 0.85 Hz, 1H), 8.32 (d, J = 3.05 Hz, 1

EP 2 018 380 B1

H) ppm; MS (DCI / NH3): m / z 335 (M + H)⁺.

Example 14 5- {5 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -2-trifluoromethyl-1-indole fumarate [0116] Product of Example 11A (130 mg, 0.52 mmol) and the product of Example 7A (319 mg, 1.0 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.99 - 2.53 (m, 8H), 2.83 (s, 3H), 3.96 - 4.03 (m, 2H), 4.85 - 5.02 (m, 1H), 6.69 (s, 2H), 6.97 (s, 1H), 7.50 - 7.62 (m, 2H), 7.78 - 7 , 88 (m, 2H), 8.16 (d, J = 1.36 Hz, 1H), 8.31 (d, J = 2.71 Hz, 1H) ppm; MS (DCI / NH₃): m / z 402 (M + H) +. Anal. Calculated for C.₂₂H₂₂F₃N₃1.20 C.₄ABOUT₄H₄: C,

59.53; H, 5.00; N, 7.77. Found: C, 59.26; H, 5.06; N, 7.86.

Example 15 4- {5 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole bistrifluoroacetate [0117] The product of the example 11A (130 mg, 0.52 mmol) and indole-4-boronic acid (Apollo, 165 mg, 1.0 mmol) were treated according to the procedure described in Example 1B to give the title compound.

¹H NMR (300 MHz, CD3OD) δ 2.03 - 2.64 (m, 8H), 2.85 (s, 3H), 4.00 - 4.10 (m, 2H), 5.02 - 5.16 (m,

H), 6.70 (d, J = 2.37 Hz, IH), 7.25 - 7.40 (m, 2H), 7.44 (d, J = 3.05 Hz, 1H), 7.59 (d, J = 7.80 Hz, 1H), 8.01 - 8.17 (m, 2H), 8.50 (d, J = 2.71 Hz, 1H) ppm; MS (DCI / NH3): m / z 334 (M + H)⁺; Anal. Calculated for C.₂₁H₂₃N₃O ^ 2.00 C.₂F₃ABOUT₂H: C, 53.48; H, 4.49; N, 7.48. Found: C, 53.29; H, 4.17; N, 7.35.

Example 16 4- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -phenylamine bistrifluoroacetate

Example 16A

4- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -phenylamine [0118] The product of Example 11A (379 mg, 1.5 mmol) and 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenylamine (Aldrich, 552 mg, 2.5 mmol) were processed according to the procedure in Example 5B .

The mixture was purified by chromatography (140 g SiO2 EtOAc: MeOH: NH₃^ H₂O, 90: 10: 1), receiving the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.76 - 1.91 (m, 4H), 2.08 - 2.21 (m, 4H), 3.35 - 3.42 [s (br,) , 2H], 4.62 -4.76 (m, 1H), 6.73 - 6.81 (m, 2H), 7.42 (dd, J = 8.81, 3.05 Hz, 1H), 7.57 - 7.68 (m, 3H), 8.15 (d, J = 2.37 Hz, 1H) ppm; MS (DCI / NH3): m / z 310 (M + H)⁺.

Example 16B 4- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -phenylamine bistrifluoroacetate [0119] The product of Example 16A ( 1.35 mg, 0.44 mmol) was again purified using

Preparative HPLC (Gilson column, Xterra®, 5 μm, 40 x 100 mm. Elution solvent, MeCN / H2O (with 0.1% by volume TFA) (vol. 90/10 to 10/90 for 25 min.) Flow rate, 40 ml / min, uv, 254 nm). The desired product fractions were collected and concentrated under reduced pressure, and the residue was stirred in an ether / ethanol mixture (10/1 volume, 5 mL) at room temperature for 16 hours. The mixture was filtered to give the bistrifluoroacetate salt.¹H NMR (300 MHz, CD3OD) δ 1.99 2.56 (m, 8H), 4.03 [s (br,), 2H], 4.93 - 5.07 (m, 1H), 6.96 - 7.07 (m, 2H), 7.73 - 7.86 (m, 3H), 7.88 7.98 (m, 1H), 8.32 (d, J = 3 , 05 Hz, 1H) ppm; MS (DCI / NH3) m / z 310 (M + H)⁺; Anal. Calculated for C.₁₉H₂₃N₃O ^ 2.30 CF₃WHAT₂H: C, 49.58; H, 4.46; N, 7.53. Found: C, 49.58; H, 4.36; N, 7.44.

Example 17 5- {6 - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole tosylate

Example 17A (ene) -3- (5-bromo-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0120] (endo) -Tropine (Aldrich, 282 mg, 2 mmol) treated ^tBuOK (Aldrich, 224 mg, 2 mmol) in THF (20 mL) at ambient temperature for 1 hour, followed by the addition of 3,6-dibromopyridine (Aldrich, 569 mg, 2.4 mmol). The mixture was stirred at 60 ° C for an additional 10 hours and then concentrated under reduced pressure. The residue was dissolved in CHCl3 / isopropanol (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 (SiO₂ CH₂cl₂ MeOH: NH₃^ H₂O, 90: 10: 1, R._f 0,10). ¹H NMR (300 MHz, CD3OD) δ 1.93 (d, J = 14.50 Hz, 2H), 2.02 - 2.23 (m, 6H), 2.31 (s, 3H), 3.17 [s (br,), 2H], 5.16 (t, J = 5.26 Hz, 1H), 6.70 (d, J = 8.82 Hz, 1H), 7, 77 (dd, J = 8.81, 2.71 Hz, 1H), 8.16 (d, J = 2.71 Hz, 1H) ppm, MS (DCI / NH3): 299 (M + H)⁺, 297 (M + H)⁺.

Example 17B

5- {6 - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole [0121] The product mixture of example 17A ( 150 mg, 0.50 mmol), 5-indolylboronic acid (Rsycor, 121.9 mg, 0.75 mmol), Pd (PPh3) 4 (Aldrich, 6.8 mg, 0.006 mmol) and K2CO3 (2 M, 1 ml) in dioxane (4 ml) was stirred at 85 ° C for 12 hours according to the procedure described in Example 9B. The title product was purified using preparative HPLC [Waters XTerra RP18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol. 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm]. ¹H NMR (300 MHz, CD3OD) δ 2.01 (d, J = 14.30 Hz, 2H), 2.06-2.28 (m, 6H), 2.34 (s, 3H), 3.17 - 3.26 (m, 2H), 5.19 (t, J = 5.26 Hz, 1H), 6.49 (d, J = 2.37 Hz, 1H), 6, 82 (d, J = 8.48 Hz, 1H), 7.26 (d, J = 3.05 Hz, 1H), 7.31 (dd, J = 8.48, 1.70 Hz, 1 H), 7.45 (d, J = 8.48 Hz, 1H), 7.73 (s, 1H), 7.96 (dd, J = 8.65, 2.54 Hz, 1H) , 8.35 (d, J = 2.03 Hz, 1H) ppm. MS (DCI / NH3) m / z 334 (M + H)⁺.

Example 17C

5- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole bistosylate [0122] The product of Example 11B (40 mg, 0.15 mmol) was treated with p-toluenesulfonic acid monohydrate TsOH ^ H₂O (Aldrich, 38 mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate (5 ml) at ambient temperature for 10 hours according to the procedure described in Example 9C. The mixture was filtered to give the title compound.¹H NMR (300 MHz, CD3OD) δ 2.32-2.58 (m, 14H), 2.81 - 2.88 (s, 3H), 3.89 - 4.01 (m, 2H) , 5.27 - 5.41 (m, 1H), 6.52 (d, J = 3.39 Hz, 1H), 7.13 (d, J = 8.48 Hz, IH), 7, 23 (d, J = 7.80 Hz, 4 H), 7.35 (dd, J = 8.48, 2.03 Hz, 1H), 7.49 (d, J = 8.48 Hz, 1 H), 7.70 (d, J = 8.14 Hz, 4 H), 7.79 (s, 1H), 8.24 (dd, J = 8.65, 2.54 Hz, 1H) , 8.47 (d, J = 2.71 Hz, 1H) ppm. MS (DCI / NH₃): m / z 334 (M + H) +. Anal. Calculated for C.₂₁H₂₃N₃O ^ 2.20 C₇H₈SO₃^ 2.00H₂O: C, 58.42; H, 6.01; N, 5.62. Found: C, 58.02; H, 5.84; N, 5.31.

Example 18 (enfo) -3- (5-benzo [b] thiophen-5-yl-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane tosylate

Example 18A (enfo) -3- (5-benzo [b] thiophen-5-yl-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] acetate [0123] A mixture of the compound of the example 17A (150 mg, 0.50 mmol), the product of Example 10A (197.0 mg, 0.75 mmol), Pd (PPh3) 4 (Aldrich, 6.8 mg, 0.006 mmol) and K2CO3 (2 M, 1 ml) in dioxane (4 ml) was processed according to the procedure described in example 9B. The title product was purified using preparative HPLC [Waters XTerra RP18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol. 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm]. ¹H NMR (300 MHz, CD3OD) δ 1.99 (d, J = 14.50 Hz, 1H), 2.03 - 2.28 (m, 6H), 2.33 (s, 3H), 3.14 3.25 (m, 2H), 5.23 (t, J = 5.26 Hz, 1H), 6.86 (d, J = 8.48 Hz, 1H), 7.43 (d, J = 5.43 Hz, 1H), 7.57 (dd, J = 8.48, 1.70 Hz, 1H), 7.61 (d, J = 5.43 Hz, 1H ), 7.91 - 8.09 (m, 3H), 8.42 (d, J = 1.70 Hz, 1H) ppm. MS (DCI / NH3) m / z 351 (M + H)⁺.

Example 18B (ENFO) -3- (5-benzo [b] thiophen-5-yl-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane tosylate [0124] Product of example 18A (60 mg, 0.17 mmol) was treated with p-toluenesulfonic acid monohydrate TsOH ^ H₂O (Aldrich, 38 mg, 0.2 mmol) in a mixture of 25% isopropanol in isopropyl acetate (5 ml) at ambient temperature for 10 hours according to the procedure described in Example 9C. The mixture was filtered to give the title compound.¹H NMR (300 MHz, CD3OD) δ 2.34-2.45 (m, 9H), 2.48-2.55 (m, 2H), 2.84 (s, 3H), 3.88 - 4.00 (m, 2H), 5.39 (t, J = 4.41 Hz, 1H), 7.06 (d, J = 8.82 Hz, 1H), 7.23 (d , J = 7.80 Hz, 2 H), 7.45 (d, J = 5.43 Hz, 1 H), 7.59 (dd, J = 8.48, 1.70 Hz, 1 H), 7.64 (d, J = 5.76 Hz, 1H), 7.70 (d, J = 8.48 Hz, 2H), 8.00 (d, J = 8.48 Hz, 1H) , 8.08 (d, J = 1.36 Hz, 1H), 8.18 (dd, J = 8.82, 2.37 Hz, 1H), 8.51 (d, J = 2.03 Hz, 1H) ppm, MS (DCI / NH3): m / z 351 (M + H)⁺. Anal. Calculated for C.₂1H₂₃N₂OSd, 10 C7HeSO3-1.00 H₂O: C, 61.79; H, 5.93; N, 5.02. Found: C,

EP 2 018 380 B1

61.44; H, 5.63; N, 4.68.

Example 19 5- {6 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyridin-3-yl} -1H-indole fumarate

Example 19A (eqzq) -3- (5-bromo-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0125] The product of example 7C (721 mg, 5.1 mmol ) and 2,5-dibromopyridine (1.66 g, 7.0 mmol) were treated according to the procedure described in Example 1A to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.88 - 2.47 (m, 8 H), 2.74 (s, 3 H), 3.82 - 3.90 (m, 2 H), 5.34 - 5.48 (m, 1H), 6.71 (d, J = 8.82 Hz, 1H), 7.78 (dd, J = 8.82, 2.71 Hz, 1H), 8 , 20 (d, J = 2.37 Hz, 1H) ppm; MS (DCI / NH3):

2997 (M + H)⁺, 297 (M + H)⁺.

Example 19B 5- {6 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole fumarate [0126] Example product 19A (129 mg, 0.434 mmol) and 5-indolylboronic acid (165 mg, 1.02 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H

NMR (300 MHz, CD3OD) δ 1.97 - 2.12 (m, 2H), 2.20 - 2.46 (m, 4H), 2.48 - 2.60 (m, 2H), 2.84 (s, 3H), 3.96 - 4.07 (m, 2H), 5.43 - 5.60 (m, 1H), 6.49 (d, J = 3.05 Hz , 1H), 6.70 (s, 2H), 6.82 (d, J = 8.48 Hz, 1H), 7.23 - 7.35 (m, 2H), 7.46 ( d, J = 8.14 Hz, 1H), 7.73 (d, J = 1.70 Hz, 1H), 7.95 (dd, J = 8.65, 2.54 Hz, 1H) , 8.37 (d, J = 2.03 Hz, 1H) ppm; MS DCI / NH3): m / z 334 (M + H)⁺; Anal. Calculated for C.₂₁H₂₃N₃O-1.00 C.₄ABOUT₄-1.00 H₂O: C, 63.67; H, 6.18; N, 8.77. Found: C, 63.77; H, 6.26; N, 8.64.

Example 20 bis (hydrochloride) [6- (1H-indol-5-yl) -pyridin-3-yl] - [(entfq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3- yl] -amine

Example 20A (6-chloro-pyridin-3-yl) - [(entfq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine [0127] Tropinone mixture (Aldrich, 2 , 78 g, 20 mmol), 6-chloro-pyridin-3-ylamine (Aldrich, 2.83 g, mmol), Na2SO4 (anhydrous, Aldrich, 21.3 g, 150 mmol) and NaBH (OAc) 3 (Aldrich , 8.48 g, 40 mmol) in HOAc (50 mL) at ambient temperature was stirred for 15 hours. The mixture was filtered and the filtrate washed with EtOH (2 x 10 mL). The organic solution was concentrated under reduced pressure, and the title compound was obtained by purification by chromatography (SiO2,

CH₂cl₂: MeOH: NH₃AT₂O, 90: 10: 2, R, 0.10). ¹H NMR (300 MHz, CD₃OD) δ 2.16 (d, J = 15.26 Hz, 2H),

2.25 - 2.35 (m, 2H), 2.37 - 2.60 (m, 4H), 2.81 (s, 3H), 3.65 (t, J = 5.93 Hz , 1H), 3.79 - 3.98 (m, J = 2.71 Hz, 1H), 7.09 (dd, J = 8.50, 3.00 Hz, 1H), 7.21 (d, J = 8.80 Hz, 1H), 7.73 (d, J = 2.71 Hz, 1H) ppm. MS

EP 2 018 380 B1 (DCI / NH3) m / z 254 (M + H)⁺, 252 (M + H)⁺.

Example 20B [6- (1H-indol-5-yl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine [0128] A mixture of the compound of Example 20A (250 mg, 1.0 mmol), 5-indolylboronic acid (Rsycor, 241.0 mg, 1.50 mmol), bis (triphenylphosphine) palladium (II) chloride (Aldrich, 10, 0 mg, 0.01 mmol) and biphenyl-2-yl-dicyclohexyl phosphate (Strem Chemicals, 11.0 mg, 0.03 mmol) in a mixture of dioxane / EtOH / 1M aqueous Na2CO3 (vol. 1/1/1 (3 ml) was heated and irradiated with microwave radiation to 130 ° C and 300 watts for 15 minutes in the Emry ™ Creator microwave reactor. The mixture was filtered through a syringe filter and the liquid was purified using preparative HPLC [Waters XTerra RP18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol. 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm], obtaining the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.88 (d, J = 15.20 Hz, 2H) 2.05 - 2.18 (m, 4H), 2.18 - 2.31 (m, 2 H), 2.37 (s, 3H), 3.26 [s (br,), 2H)], 3.60 (t, J = 6.44 Hz, 1H), 6.49 (d , J = 3.05 Hz, 1H), 7.05 (dd, J = 8.82, 2.71 Hz, 1H), 7.24 (d, J = 3.05 Hz, 1H), 7.42 (d, J = 8.48 Hz, 1H), 7.49 - 7.64 (m, 2H), 7.95 (s, 1H) ppm. MS (DCI / NH3) m / z 333 (M + H)⁺.

Example 20C bis (hydrochloride) [6- (1H-indol-5-yl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl ] amines [0129] A solution of the compound of Example 20B (160 mg, 0.48 mmol) in EtOAc (10.0 mL) was treated at room temperature with 4M hydrochloric acid in dioxane (0.5 mL, 2.0 mmol) for 10 hours . The title compound was obtained by filtration.¹H NMR (300 MHz, CD3OD) δ 2.25 (d, J = 15.65 Hz, 2H), 2.32 - 2.53 (m, 4H), 2.54 - 2.64 (m, 2H), 2.84 (s, 3H), 3.83 (t, J = 6.14 Hz, 1H), 3.97 [s (br,), 2H], 6.63 (d , J = 3.07 Hz, 1H), 7.40-7.41 (m, 1H), 7.54 (dd, J = 8.60, 1.90Hz, 1H), 7.62 ( d, J = 8.60 Hz, 1H), 7.83 - 7.95 (m, 2H), 8.06 (d, J = 1.53 Hz, 1H), 8.12 (d, J = 8.90 Hz, 1H) ppm. MS (DCI / NH3): m / z 333 (M + H)⁺. Anal. Calculated for C21H24N4 2.30 HCl 3.35 H2O: C, 52.92; H, 6.98; N, 11.75. Found: C, 52.87; H, 6.78; N, 11.35.

Example 21 [6- (Benzofuran-5-yl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0130 ] The product of example 20A (136 mg, 0.54 mmol) and 1-benzofuran-5-ylboronic acid (Aldrich, 185 mg, 1.14 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.14 - 2.57 (m, 8H), 2.83 (s, 3H), 3.74 (t, J = 5.93 Hz, 1H), 3.90 [s (br,), 2H], 6.9 (s, 2H), 6.89 (d, J = 1.36 Hz, 1H), 7.13 (dd, J = 8 , 65, 2.88 Hz, 1H), 7.54 (d, J = 8.82 Hz, 1H), 7.68 (d, J = 8.82 Hz, 1H), 7.72 - 7.79 (m, 2H), 7.99- 8.07 (m, 2H) ppm; MS DCI / NH3): m / z 334 (M + H)⁺.

EP 2 018 380 B1

Example 22 bistrifluoroacetate [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] - [6- (2-trifluoromethyl-1H-indol-5-yl) pyridin-3-yl ] -amines [0131] The product of Example 20A (1.30 mg, 0.52 mmol) and the product of Example 7A (262 mg, 0.84 mmol) were treated according to the procedure described in Example 1B to give the title compound . ¹H NMR (300 MHz, CD3OD) δ 2.17 - 2.62 (m, 8H), 2.84 (s, 3H), 3.82 (t, J = 5.93 Hz,

H), 3.96 [s (br,), 2H], 7.06 (s, 1H), 7.63 - 7.80 (m, 3H), 7.95 (d, J = 2 , 71 Hz, 1H), 8.06 (d, J = 9.16 Hz, 1H), 8.15 (d, J = 1.36 Hz, 1H) ppm; MS DCI / NH3): m / z 401 (M + H)⁺; Anal. Calculated for C22H22F3N3O · 2.00 CF3CO2H 0.70 NH4OH: C, 47.75; H, 4.24; N, 7.92. Found: C, 47.69; H, 3.91;

N, 8.14.

Example 23

[6- (1H-Indazol-5-yl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0132 ] The product of Example 20A (128 mg, 0.51 mmol) and the product of Example 5A (205 mg, 0.84 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.11 - 2.55 (m, 8H), 2.79 (s, 3H), 3.73 (t, J = 5.93 Hz, 1H), 3.85 [s (br,), 2H],

6.67 (s, 3H), 7.13 (dd, J = 8.65, 2.88 Hz, 1H), 7.59 (d, J = 8.82 Hz, 1H), 7.70 ( d, J = 8.82 Hz, 1H), 7.90 (dd, J = 8.82, 1.70 Hz, 1H), 8.04 (d, J = 2.71 Hz, 1H) , 8.09 (s, 1H), 8.18 (s, 1H) ppm; MS DCI / NH3): m / z 3.34 (M + H) +; Anal. Calculated for C.₂₀H₂₃N₅-1.50 C₄ABOUT₄H &lt;1.00 NH4OH: C, 57.55; H, 6.32; N, 15.49. Found: C, 57.46; H, 6.26; N, 15.55.

Example 24 [6- (1H-indol-4-yl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0133] The product of example 20A (130 mg, 0.52 mmol) and indole-4-boronic acid (Apollo, 165 mg, 1.0 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.16 - 2.60 (m, 8H), 2.84 (s, 3H), 3.76 (t, J = 5.76 Hz, 1H), 3.88 - 3.95 [s (br,), 2H], 6.69 (s, 2H), 6.70 (d, J = 3.39 Hz, 1H), 7.14 - 7 , 32 (m, 4H), 7.40 (d, J = 7.80 Hz, 1H),

7.68 (d, J = 8.48 Hz, 1H), 8.06 (d, J = 2.71 Hz, 1H) ppm; MS DCI / NH3): m / z 333 (M + H)⁺; Anal. Calculated for C.₂₁H₂₄N₄-1.40 C₄ABOUT₄H₄Oh, 90H₂O: C, 62.50; H, 6.19; N, 10.96. Found: C, 62.40; H, 6.17; N, 11.04.

Example 25 [(enfo) -8-aza-bicyclo [3.2.1] oct-3-yl] - [6- (1H-indol-5-yl) -pyridin-3-yl] -amine

Example 25A (Enfo) -3- (6-chloro-pyridin-3-ylamino) -8-aza-bicyclo [3.2.1] octane] -8-carboxylic acid tert-butyl ester

[0134] Mixture of 3-oxo-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (Fluka, 3.50 g, 15.50 mmol), -chloro-pyridin-3-ylamine (Aldrich, 2.20 g, 17.1 mmol), Na2SO4 (anhydrous, Aldrich, 16.6 g, 116 mmol) and NaBH (OAc) 3 (Aldrich, 6.59 g, 31.1 mmol) in HOAc (40 mL) was stirred at ambient temperature for 15 hours according to the procedure described in Example 20A. The title compound was purified by chromatography (SiO2, hexane: EtOAc, 50:50, Rf 0.40).¹H NMR (300 MHz, CD3OD) δ 1.41 - 1.56 (m, 9H), 1.58 - 2.90 (m, 8H) 4.13 - 4.33 (m, 1H), 4.37 4.54 (m, 2 H), 7.00 (dd, J = 8.81, 3.05 Hz, 0.5 H), 7.15 (d, J = 8.14 Hz, 0 , 5 H), 7.26 (dd, J = 8.30, 3.10 Hz, 0.5 H) 7.41 (d, J = 8.48 Hz, 0.5 H), 7.68 ( d, J = 3.05 Hz, 0.5 H) 7.84 (d, J = 2.37 Hz, 0.5 H) ppm. MS (DCI / NH3) m / z 340 (M + H)⁺, 338 (M + H)⁺.

Example 25B [(enfo) -8-aza-bicyclo [3.2.1] oct-3-yl] - (6-chloro-pyridin-3-yl) -amine [0135] The product of example 25A (2.92 g, 8.7 mmol) was treated with trifluoroacetic acid (5 ml) in dichloromethane (20 ml) at ambient temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by chromatography (SiO2, CH₂cl₂: MeOH: NH₂AT₂O, 90: 10: 2, R._f 0.10) to obtain the title compound. ¹H NMR (300 MHz, CD₃OD) δ 1.71 - 1.94 (m, 4H) 2.03 - 2.22 (m, 4H), 3.42 - 3.64 (m, 3H), 6.98 (dd, J = 8.82, 3.05 Hz, 1H), 7.14 (d, J = 8.14 Hz, 1H), 7.65 (d, J = 3.05 Hz, 1H) ppm. MS (DCI / NH3) m / z 238 (M + H)⁺, 240 (M + H)⁺.

Example 25C [(enfo) -8-aza-bicyclo [3.2.1] oct-3-yl] - [6- (1H-indol-5-yl) -pyridin-3-yl] -amine [0136] Product from Example 20A (250 mg, 1.0 mmol), 5-indolylboronic acid (Rsycor, 241.0 mg, 1.50 mmol), bis (triphenylphosphine) palladium (II) chloride (Aldrich, 10.0 mg, 0.01 mmol) and biphenyl-2-yl-dicyclohexyl phosphate (Strem Chemicals, 11.0 mg, 0.03 mmol) in a mixture of dioxane / EtOH / 1M aqueous Na2CO3 (1/1/1 3 ml) was heated and irradiated with microwave radiation to 130 ° C and 300 watts for 15 minutes in the Emry ™ Creator microwave reactor. The solid was filtered off using a syringe filter and the liquid was purified using preparative HPLC [Waters XTerra RP18 column, 30x100 mm, elution solvents, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol . 90/10 to 10/90 for 20 min), flow rate 40 ml / min, uv, 250 nm], receiving the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.96 - 2.17 (m, 4H), 2.20 - 2.52 (m, 4H), 3.71 (t, J = 6.1 Hz, 1H) 3.80 - 3.92 (m, 2H), 6.49 (d, J = 2.37 Hz, 1H), 7.10 (dd, J = 8.82, 3.05 Hz , 1H), 7.25 (d, J = 3.05 Hz, 1H), 7.42 (d, J = 8.48 Hz, 1H), 7.56 (dd, J = 8.48 , 1.70 Hz, 1H), 7.63 (d, J = 8.48 Hz, 1H), 7.92 - 8.00 (s, 1H) ppm. MS (DCI / NH3) m / z 319 (M + H)⁺.

Example 26 [6- (4-Amino-3-methyl-phenyl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] fumarate amine

EP 2 018 380 B1

Example 26A [2-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -trifluoroacetamide [0137] Mixture N- (4-bromo-2 -methyl-phenyl) -2,2,2-trifluoro-acetamide (US reference 20050043347, 4.23 g, 15.0 mmol), bis (pinacolano) diboron (Aldrich, 5.07 g, 20 mmol), KOAc ( Aldrich, 5.27 g,

53.7 mmol) and PdCl2 (dppf): CH2Cl2 (Aldrich, 203 mg, 0.25 mmol) in anhydrous dioxane (50 mL) in

100 ° C for 72 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (150 mL), washed with water (2 x 25 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by chromatography (140 g SiO2 hexane: EtOAc, 80:20, Rf 0.6) to afford the title compound.¹H NMR (300 MHz, CDCl3) δ 1.35 (s, 12H), 2.31 (s, 3H), 7.66 - 7.80 (m,

3 H), 7.90 (d, J = 8.14 Hz, 1H) ppm; MS (DCI / NH3): 347 (M + NH4)⁺.

Example 26B [6- (4-Amino-3-methyl-phenyl) -pyridin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] fumarate amines [0138] The product of Example 20A (130 mg, 0.52 mmol) and the product of Example 26A (277 mg, 0.84 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.12 - 2.57 (m, 11H), 2.82 (s, 3H), 3.71 (t, J = 6.10 Hz, 1H), 3.85 - 3.94 (m, 2H),

6.69 (s, 2H), 6.77 (d, J = 8.14 Hz, 1H), 7.10 (dd, J = 8.65, 2.88 Hz, 1H), 7, 42 (dd, J = 8.14, 2.37 Hz, 1H), 7.47 (s, 1H), 7.53 (d, J = 8.82 Hz, 1H), 7.92 ( d, J = 2.71 Hz, 1H) ppm; MS DCI / NH3): m / z 323 (M + H)⁺.

Example 27 [4- (1H-indol-5-yl) -phenyl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate

Example 27A (4-bromo-phenyl) - (3-endo-8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -amine [0139] Tropinon (Aldrich, 2.78 g, 20 mmol) and p-bromoaniline (Aldrich, 3.78 g, 22 mmol) were treated according to the procedure described in Example 20A to give the title compound. The title compound was purified by chromatography (140 g SiO2, EtOAc: MeOH (vol. 2% NH3, H2O), 50:50, Rf 0.25).¹H NMR (300 MHz, MeOH-D4) δ 1.71 - 1.82 (m, 2H), 2.00 - 2.22 (m, 6H), 2.29 (s, 3H), 3 , 14 [s (br,), 2H], 3.46 (t, J = 6.61 Hz, 1H), 6.46 (d, J = 8.81 Hz, 2H), 7.17 (d, J = 9.15 Hz, 2H) ppm; MS (DCI / NH3): 297 (M + H)⁺ 295 (M + H)⁺.

Example 27B [4- (1H-indol-5-yl) -phenyl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0140] Product from Example 27A (134 mg, 0.45 mmol) and 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-238

E1) -1H-indole (Aldrich, 198 mg, 0.81 mmol) was treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.16 - 2.60 (m, 8H), 2.82 (s, 3H), 3.72 (t, J = 5.76 Hz, 1H), 3.89 [s (br,), 2 H], 6.44 (d, J = 2.37 Hz, 1H), 6.66 - 6.74 (m, 5.3 H), 7.21 (d, J = 3.39 Hz, 1H), 7.26 - 7.32 (m, 1H), 7.35 - 7.41 (m, 1H), 7.46 (d, J = 8.82 Hz, 2H), 7.67 (d, J = 1.02 Hz, 1H) ppm; MS DCI / NH₃): m / z 332 (M + H) +; Anal. Calculated for C.₂₂H₂₅N₃1.65 C.₄ABOUT₄H₄: C, 65.68; H, 6.09; N, 8.03. Found: C, 65.62; H, 6.40; N, 8.14.

Example 28 [4- (1H-indazol-5-yl) -phenyl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0141] Product of Example 27A (134 mg, 0.45 mmol) and the product of Example 5A (265 mg, 1.08 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.14 - 2.61 (m, 8H), 2.82 (s, 3H), 3.72 (t, J = 5.93 Hz, 1H), 3.89 [s (br,), 2 H], 6.67 - 6.77 (m, 5 H), 7.45 - 7.52 (m, 2 H), 7.52 - 7.58 ( m, 1H), 7.59 - 7.65 (m, 1H), 7.87 (s, 1H), 8.04 (s, 1H) ppm; MS DCI / NH₃): m / z 333 (M + H) +; Anal. Calculated for C.₂₁H₂₄N &lt;1.48 C₄ABOUT₄H₄: C, 64.12; H, 5.98; N, 11.11. Found: C, 64.00; H, 5.98; N, 11.22.

Example 29 [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] - [4- (1-methyl-1H-indol-5-yl) -phenyl] -amine fumarate [0142] The product of example 27A (128 mg, 0.43 mmol) and N-methylindole-5-boronic acid (Frontier, 142 mg, 0.81 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.12 - 2.63 (m, 8H), 2.82 (s, 3H), 3.72 (t, J = 5.93 Hz, 1H),

3.80 (s, 3H), 3.88 [s (br,), 2H], 6.42 (d, J = 3.05 Hz, 1H), 6.66 - 6.74 (m , 4H), 7.13 (d, J = 3.05 Hz, 1

H), 7.36 (d, J = 1.0 Hz, 2 H), 7.46 (d, J = 8.48 Hz, 2 H), 7.67 (t, J = 1.20 Hz, 1H) ppm; MS DCI / NH3): m / z 346 (M + H) +. Anal. Calculated for C.₂₃H₂₇N₃1.0 C₄ABOUT₄H₄: C, 69.55; H, 6.69; N, 8.88. Found: C, 69.29; H, 6.76; N, 8.85.

Example 30 (4-benzo [b] thiophen-5-yl-phenyl) - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine trifluoroacetate [0143] Product of the example 27A (129 mg, 0.44 mmol) and 2-benzo [b] thiophen-5-yl-4,4,5,5-tetramethyl [1,3,2] dioxaborolane (Maybridge, 189 mg, 0.73 mmol ) was treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.17 - 2.60 (m, 8H), 2.82 (s, 3H), 3.73 (t, J = 5.76 Hz, 1H), 3.90 [s (br), 2H], 6.73 (d, J = 8.82 Hz, 2H), 7.38 (d, J = 5.76 Hz, 1H),

7.48 - 7.59 (m, 4H), 7.88 (d, J = 8.48 Hz, 1H), 7.97 (d, J = 1.70 Hz, 1H) ppm; MS DCI / NH3): m / z 349 (M + H) +; Anal. Calculated for C.₂₂H₂₄N₂S1.10 C.₂F₃ABOUT₂H: C, 61.33; H, 5.34; N, 5.91. Found: C, 61.03; H, 5.34; N, 5.76.

Example 31 [4- (Benzofuran-5-yl) -phenyl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate

[0144] The product of example 27A (135 mg, 0.46 mmol) and 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzofuran (Maybridge , 189 mg, 0.77 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.15 - 2.60 (m, 8H), 2.82 (s, 3H), 3.72 (t, J = 5.93 Hz, 1H), 3.88 [s (br), 2H], 6.65 - 6.76 (m, 4H), 6.83 (d, J = 2.71 Hz, 1H), 7.40

- 7.52 (m, 4H), 7.69 - 7.75 (m, 2H) ppm; MS DCI / NH3): m / z 333 (M + H)⁺; Anal. Calculated for

C₂₂H₂₄N₂O-1.15 C₄ABOUT₄H₄: C, 68.57; H, 6.19; N, 6.01. Found: C, 68.42; H, 6.17; N, 6.02.

Example 32 [4- (1H-indol-4-yl) -phenyl] - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0145] Product of Example 27A (125 mg, 0.42 mmol) and indole-4-boronic acid (Apollo, 131 mg, 0.81 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.11 - 2.68 (m, 8H), 2.83 (s, 3H), 3.74 (t, J = 8.31 Hz, 1H), 3.89 [s (br,), 2H] 6.58 (dd, J = 3.39, 1.02 Hz, 1H), 6.68 (s, 2H), 6.74 (d, J = 8.82 Hz, 2H), 6.99 (dd, J = 7.12, 1.02 Hz, 1H), 7.08 - 7.15 (m, 1H), 7.23 ( d, J = 3.39 Hz, 1H), 7.29 (d, J = 8.14 Hz, 1H), 7.51 (d, J = 8.81 Hz, 2H) ppm; MS DCI / NH3): m / z 332 (M + H) +; Anal. Calculated for C.₂₂H₂₅N₃d, 00 C.₄ABOUT₄H₄: C, 69.78; H, 6.53; N

9.39. Found: C, 70.17; H, 6.69; N, 9.58.

Example 33 [3- (1H-Indol-5-yl) -phenyl] - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate

Example 33A (3-bromo-phenyl) - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine [0146] Tropinone (696 mg, 5.0 mmol) and m-bromoaniline (946 mg, 5.5 mmol) was treated according to the procedure described in Example 20A to give the title compound. The title compound was purified by chromatography [140 g SiO2, EtOAc: MeOH (vol. 2% NH3.H2O), 50:50, Rt = 0.25].¹H NMR (300 MHz, MeOH-D4) δ 1.72 - 2.23 (m, 8H), 2.29 (s, 3H), 3.14 [s (br,), 2H], 3 , 47 (t, J = 6.44 Hz, 1H),

6.46 - 6.52 (ddd, J = 8.20, 2.00, 1.00 Hz, 1H), 6.64 - 6.72 (m, 2H), 6.92 - 7.02 (t , J = 8.10 Hz, 1H) ppm;

MS (DCI / NH3): 297 (M + H)⁺, 295 (M + H)⁺.

Example 33B [3- (1H-indol-5-yl) -phenyl] - [(enoo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine fumarate [0147] Product of Example 33A (128 mg, 0.43 mmol) and indole-5-boronic acid (165 mg, 1.0 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.19 - 2.61 (m, 8H), 2.81 (s, 3H), 3.75 (t, J = 5.76 Hz, 1H), 3.83 - 3.92 (m, 2H),

6.47 (dd, J = 3.05, 0.70 Hz, 1H), 6.55 (ddd, J = 7.14, 2.60, 0.70 Hz, 1H), 6.68 (s, 2H), 6.89 (t, J = 2.03 Hz, 1H), 6.96 (ddd, J = 7.80, 1.70, 1.00 Hz, 1H), 7.20 ( t, J = 7.80 Hz, 1H), 7.24 (d, J = 7.10 Hz, 1H), 7.34 (dd, J = 8.50, 1.70 Hz, 1H), 7.39 (t, J = 8.40 Hz, 1H), 7.74 (dd, J = 1.70, 0.70 Hz 1H) ppm; MS

EP 2 018 380 B1

DCI / NH3): m / z 332 (M + H) +; Anal. Calculated for C.₂₂H₂₅N₃d, C4H4O4OA0 C4H8O2: C, 68.03; H, 6.65; N, 8.50. Found: C, 67.68; H, 6.85; N, 8.78.

Example 34 [3- (1H-indol-4-yl) -phenyl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] -amine trifluoroacetate [0148] Product of Example 33A (128 mg, 0.43 mmol) and indole-4-boronic acid (Apollo, 168 mg, 1.0 mmol) were treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.22 - 2.64 (m, 8H), 2.81 (s, 3H), 3.74 (t, J = 5.42 Hz, 1H), 3.87 - 3.93 (m, 2H), 6.57 - 6.67 (m, 2H), 6.92 (t, J = 2.10 Hz, 1H), 6.99 (dt , J = 7.80, 1.00 Hz, 1H) 7.14 (t, J = 7.56 Hz, 1H), 7.21 - 7.28 (m, 2H), 7.35 ( d, J = 8.14 Hz, 1H) ppm; MS DCI / NH3): m / z 332 (M + H)⁺; Anal.

Calculated for C.₂₂H₂₅N₃-1.10 CF₃WHAT₂H 0.60 EtOH: C, 62.96; H, 6.18; N, 8.67. Found: C, 62.85; H, 5.98; N, 8.65.

Example 35 trifluoroacetate_5- {6 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -2-trifluoromethyl-1H-indole [0149] The product of Example 1A (89 mg, 0.35 mmol) and the product of Example 7A (299 mg, 0.96 mmol) were treated according to the procedure described in Example 1B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.22 - 2.67 (m, 8H), 2.86 (s, 3H), 3.93 - 4.01 [s (br), 2H], 5.55 - 5.62 (m, 1H), 7.02 (t, J = 1.02 Hz, 1H), 7.32 (d, J = 9.15 Hz, 1H), 7, 60 (d, J = 8.81 Hz, 1H), 7.94 (dd, J = 8.82, 1.70 Hz, 1H), 8.16 (d, J = 9.49 Hz, 1 H), 8.26 (d, J = 1.36 Hz, 1H) ppm; MS DCI / NH3): m / z 403 (M + H)⁺; Anal.

Calculated for C ^ Fs ^ From ^ CF₃WHAT₂H: C, 50.09; H, 3.94; N, 9.71. Found: C, 50.07; H, 3.94; N, 9.66.

Example 36 4- {6 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole fumarate [0150] The product of the example 7D (129 mg, 0.51 mmol) and indole-4-boronic acid (Apollo, 161 mg, 1.0 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.05 - 2.50 (m, 6H), 2.66 (ddd, J = 14.92, 5.76, 3.05 Hz, 2H), 2, 85 (s, 3H), 4.03 (dd, J = 3.73, 3.05 Hz, 2H), 5.67 - 5.83 (m, 1H), 6.79 (dd, J = 3.22, 0.85 Hz, 1H), 7.22 - 7.30 (m, 2H), 7.37 (d, J = 3.05 Hz, 1H), 7.41 (dd , J = 7.29, 0.85 Hz, 1H), 7.54 (d, J = 8.14 Hz, 1H), 8.08 (d, J = 9.15 Hz, 1H) ppm ; MS DCI / NH₃): m / z 335 (M + H) +; Anal. Calculated for C.₂₀H₂₂N₄From, 20 C.₄H₄ABOUT₄: C,

62.88; H, 5.70; N, 11.83. Found: C, 62.90; H, 5.53; N, 11.79.

Example 37 5- {6 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole fumarate

Example 37A

(Eqzq) -3- (5-bromo-pyridin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0151] The product of example 7C (721 mg, 5 , 1 mmol) and 2,5-dibromo-pyridine (Aldrich, 1.66 g, 7.0 mmol) were treated according to the procedure described in Example 1A to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.90 - 2.46 (m, 8H), 2.74 (s, 3H), 3.81 - 3.90 (m, 2H), 5.34 - 5.48 (m, 1H), 6.71 (d, J = 8.82 Hz, 1H), 7.78 (dd, J = 8.82, 2.71 Hz, 1H), 8 , 20 (d, J = 2.37 Hz, 1H) ppm; MS DCI / NH3): m / z 299 (M + H)⁺ 297 (M + H)⁺.

Example 37B 5- {6 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole fumarate [0152] The product of the example 37A (129 mg, 0.43 mmol) and indole-5-boronic acid (Ryscor Inc., 165 mg, 1.0 mmol) were treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.96 - 2-62 (m, 8 H), 2.84 (s, 3 H), 3.97 - 4.04 (m, 2 H), 5.44 - 5.58 (m, 1H), 6.49 (dd, J = 3.22, 0.85 Hz, 1H), 6.70 (s, 2H), 6.82 (d, J = 8.48 Hz, 1H), 7.27 (d, J = 3.05 Hz, 1H), 7.30 (dd, J = 8.48, 1.70 Hz, 1H), 7.46 (d, J = 8.14 Hz, 1H), 7.73 (d, J = 1.70 Hz, 1H), 7.95 (dd, J = 8.65, 2.54 Hz, 1H ), 8.37 (d, J = 2.03 Hz, 1H) ppm; MS DCI / NH3): m / z 334 (M + H)⁺; Anal. Calculated for C.₂₁H₂₃N₃Q-1.10 C.₄H₄ABOUT₄d, 00H₂O: C, 63.67; H, 6.18; N, 8.77. Found: C, 63.77; H, 6.26; N, 8.64.

Example 38 5- {6 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -2-trifluoromethyl-1Hindole [0153] product from Example 37A (129 mg, 0.43 mmol) and 5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -2-trifluoromethyl-1H-indole (Aldrich, 319 mg , 1.02 mmol) was treated according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.92 - 2.63 (m, 8H), 2.85 (s, 3H), 4.02 [s (br), 2H], 5.46 - 5.61 (m, 1H), 6.71 (s, 4H), 6.84 (d, J = 8.48 Hz, 1H), 6.95 (s, 1H), 7.47 - 7.59 (m, 2H), 7.85 (s, 1H), 7.97 (dd, J = 8.65, 2.54 Hz, 2H), 8.40 (d, J = 2.03 Hz, 1H) ppm; MS DCI / NH3): m / z 402 (M + H) +. Anal. Calculated for C.₂₂H₂₂F₃N₃Q-2.00 C.₄H₄Q₄: C, 56.87; H, 4.77; N, 6.63. Found: C, 56.98; H, 5.09; N, 6.29.

Example 39 4- {6 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridazin-3-yl} -1H-indole fumarate [0154] Example product 7D (129 mg, 0.51 mmol) was coupled to indole-4-boronic acid (Apollo, 161 mg, 1.0 mmol) to obtain the free base of the title compound (150 mg, 0.45 mmol). It was then treated with fumaric acid (52.0 mg, 0.45 mmol) according to the procedure of Example 5C to give the title compound as a white solid.¹H NMR (300 MHz, CD3OD) δ 2.05 - 2.49 (m, 6H) 2.60 - 2.71 (m, 2H) 2.85 (s, 3H) 4.01 - 4, 07 (m, 2H) 5.69 - 5.81 (m, 1H) 6.69 (s, 2H) 6.79 (dd, J = 3.22, 0.85 Hz, 1H) 7 , 23 - 7.29 (m, 2H) 7.37 (d, J = 3.05 Hz, 1H) 7.41 (dd, J = 7.29, 0.85 Hz, 1H) 7, 54 (d, J = 8.14 Hz, 1H) 8.08 (d, J = 9.15 Hz, 1H) ppm. MS (DCI / NH 3): m / z 335 (M + H) +. Anal. Calculated for C.₂₀H₂₂N₄Q-1.2 C.₄ABOUT₄H₄: C, 62.88; H, 5.70; N, 11.83. Found: C, 62.90;

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H, 5.53; N, 11.79.

Example 40 6- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole hydrochloride

Example 40A

6- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-indole [0155] Under N2, the product mixture from Example 11A (240 mg, 0.95 mmol) was coupled to 6-indolylboronic acid (Frontier Scientific, 229 mg, 1.42 mmol) according to the procedure described in Example 11B to give the title product. ¹H NMR (300 MHz, CD3OD) δ 1.72 - 1.93 (m, 4H), 2.00 - 2.25 (m, 4H), 2.39 (s, 3H), 3.23 -3.35 (m, 2H), 4.56 - 4.82 (m, 1H), 7.29 (d, J = 3.05 Hz, 1H), 7.46 (d,

J = 2.71 Hz, 1H), 7.47 - 7.51 (m, 1H), 7.53 (d, J = 1.36 Hz, 1H), 7.60 (d, J = 8.52 Hz, 1H), 7.76 (d,

J = 8.82 Hz, 1H), 7.88 (s, 1H), 8.22 (d, J = 3.05 Hz, 1H) ppm; MS (DCI / NH3) m / z 334 (M + H)⁺.

Example 40B 6- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxyl] -pyridin-2-yl} -1H-indole hydrochloride [0156] The product of example 40A (210 mg, 0.63 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) EtOAc (10 mL) at ambient temperature for 10 hours and concentrated under reduced pressure to give the title compound . ¹H NMR (300 MHz, CD3OD) δ 2.14-2.32 (m, 2H), 2.26 2.49 (m, 4H), 2.49-2.65 (m, 2H), 2.85 (s, 3H), 3.99 - 4.18 (m, 2H), 5.07 - 5.31 (m, 1H), 6.60 (d, J = 4.07 Hz , 1H), 7.46 - 7.56 (m, 2H), 7.82 (d, J = 8.48 Hz, 1H), 7.98 (s, 1H), 8.34 ( s, 1H), 8.35 (d, J = 2.71 Hz, 1H), 8.55 (d, J = 2.37 Hz, 1H) ppm. MS (DCI / NH3): m / z 334 (M + H)⁺. Anal. Calculated for

C₂H₂₃N₃O-1.00 HCl-1.20 H₂O: C, 64.42; H, 6.80; N, 10.73. Found: C, 64.54; H, 6.61; N, 10.89.

Example 41 5- {5 - [(enoq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl) -1H-indole tosylate

Example 41A

5-bromo-pyrazin-2-ylamine [0157] To a solution of 2-aminopyrazine (Aldrich, 4.75 g, 50 mmol) in anhydrous MeCN (Aldrich, 50 mL) was slowly added a solution of N-bromo succinic acid (Aldrich, 8, 90 g, 50 mmol) in MeCN (anhydrous, 50 ml) at 0-10 ° C. The reaction mixture was then stirred at ambient temperature and quenched with saturated Na2S2O3 (5.0 mL). The mixture was concentrated and the residue was extracted with EtOAc (3 x 50 mL). The combined extracts were concentrated and the title compound was purified by chromatography (SiO2, EtOAc / hexane = 1/1, vol. Rf = 0.50). ¹H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 1.36 Hz, 1H), 8.09 (d, J = 1.36 Hz, 1H) ppm; m / z 174 (M + H)⁺, 174 (M + H)⁺.

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Example 41B

5-bromo-2-iodopyrazine [0158] Under N2, to a mixture of the product of example 41 A (7.50 g, 43 mmol) in DME (anhydrous, Aldrich, 200 ml) was added at ambient temperature CsI (Aldrich, 11.20 g, 43 mmol), iodine (Aldrich, 5.52 g, 21.6 mmol), CuI (Stream, 2.52 g, 13.2 mmol) and isoamyl nitrite (34.8 mL, 259.2 mmol). It was then heated to 60 ° C and stirred for 30 min until no more gas evolution was observed. After cooling to room temperature, the dark mixture was poured into a flask containing EtOAc (200 mL) and saturated NH4Cl (200 mL), stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 1000 mL). The combined organic solution was washed with 5% aqueous Na2S2O3 (2 x 50 mL), brine (50 mL) and dried over MgSO4. The drying agents were filtered off and the organic solution was concentrated to give the title compound.¹H NMR (300 MHz, CDCl3) δ 8.50 (d, J = 1.36 Hz, 1H), 8.62 (d, J = 1.36 Hz, 1H) ppm; m / z 284 (M + H)⁺, 286 (M + H)⁺.

Example 41C (ene) -3- (5-iodo-pyrazin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0159] Under N2, a mixture of (endo) -tropine (Aldrich, 1.54 g, 11 mmol) were treated with potassium t-butoxide (Aldrich, 0.96 g, 10 mmol) in THF (anhydrous, Aldrich, 50 ml) at ambient temperature for 1

h. The product of Example 41B (2.85 g, 10.0 mmol) and added. The brown mixture was stirred at ambient temperature for 4 hours and quenched with water (5 mL). The mixture was concentrated and the residue was purified by chromatography (150 g SiO₂, EtOAc: MeOH: NH₃^ H₂O, 90: 10: 1, R._f 0.20) to obtain the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.16 - 2.60 (m, 8H), 2.84 (s, 3H), 3.78 4.05 (m, 2H), 5.17 - 5.40 (m, 1H), 8.14 (d, J = 1.36 Hz, 1H), 8.42 (d, J = 1.36 Hz, 1H) ppm; MS (DCI / NH3) m / z 346 (M + H)⁺.

Example 41D

5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl] -1H-indole [0160] The product of example 41C (200 mg, 0.58 mmol) was coupled to 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol) according to the procedure of Example 9B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.94 - 2.05 (m, 2H), 2.07 - 2.29 (m, 6H), 2.34 (s, 3H), 3.15 - 3.27 (m, 2H), 5.29 (t, J = 5.09 Hz, 1H), 6.53 (d, J = 2.37 Hz, 1H), 7.27 (d , J = 3.39 Hz, 1H), 7.47 (d, J = 8.48 Hz, 1H), 7.68 (dd, J = 8.48, 1.70 Hz, 1H), 8.11 (s, 1H), 8.17 (d, J = 1.70 Hz, 1H), 8.58 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Example 41E 5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole tosylate [0161] The product of Example 41D (90 mg, 0.27 mmol) was treated with p-toluenesulfonic acid monohydrate TsOH ^ H₂O (Aldrich, 57 mg, 0.3 mmol) in a mixture of EtOAc / EtOH (4: 1 volume, 5 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to give

Title compound. ¹H NMR (300 MHz, CD3OD) δ 2.36 (s, 3H), 2.38 - 2.48 (m, 4H), 2.48 - 2.61 (m, 4H), 2.84 (s, 3H), 3.84 - 4.05 (m, 2H), 5.41 (t, J = 4.41 Hz, 1H), 7.23 (d, J = 7.80 Hz , 2H), 7.30 (s, 1H), 7.49 (d, J = 8.48 Hz, 1H), 7.65 - 7.77 (m, 4H), 8.13 ( d, J = 1.70 Hz, 1H), 8.29 (s, 1H) ppm. MS (DCI / NH 3): m / z 335 (M + H) +. Anal. Calculated for C.₂0H₂₂N4O ^ 1.38 C₇H₈SO3-0.80 H₂O: C, 60.74; H

5.95; N, 9.55. Found: C, 61.00; H, 5.63; N, 9.17.

Example 42 4- {5 - [(enqq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole bistosylate

Example 42A

4- {5 - [(enrfq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole [0162] The product of example 41C (200 mg, 0.58 mmol) was coupled to 4-indolylboronic acid (Apollo, 143.3 mg, 0.89 mmol) according to the procedure of Example 9B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.97 - 2.06 (m, 2H), 2.08 - 2.30 (m, 6H), 2.34 (s, 3H), 3.16 - 3.28 (m, 2H), 5.33 (t, J = 5.09 Hz, 1H), 6.82 (d, J = 3.39 Hz, 1H), 7.22 (t , J = 7.50 Hz, 1H), 7.34 (d, J = 3.05 Hz, 1H), 7.40 (d, J = 7.46 Hz, 1H), 7.47 ( d, J = 8.14 Hz, 1H), 8.27 (d, J = 1.36 Hz, 1H), 8.61 (d, J = 1.36 Hz, 1

H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Example 42B 4- {5 - [(enrfq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-indole bistosylate [0163] The product of the example 42A (40 mg, 0.12 mmol) was treated with p-toluenesulfonic acid monohydrate TsOHH₂O (Aldrich, 27 mg, 0.15 mmol) in a mixture of EtOAc / EtOH (4: 1 volume, 5 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.36 (s, 6H) 2.40-2.48 (m, 4H), 2.50-2.64 (m, 2H), 2.85 ( s, 3H), 3.87 - 4.04 (m, 2H), 5.26 - 5.63 (m, 1H), 7.19 - 7.29 (m, 6H), 7, 35 (s, 1H), 7.42 (d, J = 6.44 Hz, 1H), 7.49 (d, J = 8.14 Hz, 1H), 7.71 (d, J = 8.48 Hz, 4H), 8.38 (d, J = 1.36 Hz, 1H), 8.68 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH₃): m / z 335 (M + H) +. Anal. Calculated for C.₂₀H₂₂N₄OZ 00

C₇H₈SO₃Oh, 50H₂O: C, 59.37; H, 5.71; N, 8.15. Found: C, 59.56; H, 6.10; N, 8.17.

Example 43 6- {5 - [(enrfq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole tosylate

Example 43A

6- {5 - [(enqf) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole [0164] The product of example 41C (200 mg, 0.58 mmol) was coupled to 6-indolylboronic acid (Frontier Scientific, 143.3 mg, 0.89 mmol) according to the procedure described in Example 9B to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.93 - 2.05 (m, 2H), 2.08 - 2.28 (m, 6H), 2.33 (s, 3

EP 2 018 380 B1

H), 3-13 - 3.26 (m, 2H), 5.29 (t, J = 4.92 Hz, 1H), 6.47 (d, J = 3.05 Hz, 1H) , 7.30 (d, J = 3.39 Hz, 1H), 7.54 - 7.68 (m, 2H), 7.96 (s, 1H), 8.19 (d, J = 1.36 Hz, 1H), 8.60 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Example 43B 6- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-indole tosylate [0165] Example product 43A (80 mg, 0.24 mmol) was treated with p-toluenesulfonic acid monohydrate TsOH ^ H₂O (Aldrich, 57 mg, 0.30 mmol) in a mixture of EtOAc / EtOH (vol. 4: 1, 5 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.36 (s, 3H), 2.37 - 2.48 (m, 6H), 2.47 - 2.63 (m, 2

H), 2.84 (s, 3H), 3.83 - 4.02 (m, 2H), 5.27 - 5.50 (m, 1H), 6.48 (d, J = 2 , 37 Hz, 1H), 7.32 (t, J = 1.70

Hz, 1H), 7.53 - 7.67 (m, 2H), 7.71 (d, J = 8.14 Hz, 2H), 7.99 (s, 1H), 8.29 (d, J = 1.36 Hz, 1H), 8.64 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH₃): m / z 335 (M + H) +. Anal. Calculated for C.₂₀H₂₂N₄From, 15 C.₇H₈SO₃Oh, 75H₂O: C, 61.71; H, 6.04; N, 10.26. Found: C, 61.74; H, 5.72; N, 9.87.

Example 44 trifluoroacetate [6- (1H-indol-6-yl) -pyrazin-3-yl] - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl] - amines [0166] The product of example 20A (139 mg, 0.55 mmol) was coupled to indole-6-boronic acid (Frontier Scientific, 165 mg, 1.02 mmol) according to the procedure described in Example 8 to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.18 - 2.63 (m, 8 H) 2.84 (s, 3 H) 3.82 (t, J = 6.10 Hz, 1 H) 3.96 (s, 2H) 6.57 (dd, J = 3.05, 0.68 Hz, 1H) 7.41 - 7.47 (m, 2H) 7.74 - 7.93 (m, 4 H) 8.10 (d,

J = 9.16 Hz, 1H) ppm. MS (DCI / NH₃): m / z 333 (M + H) +. Anal. Calculated for C.₂₁H₂₄N &lt;2.45 CF₃CO 2 H:

C, 50.85; H, 4.36; N, 9.16. Found: C, 50.72; H, 4.43; N, 9.25.

Example 45 5- {6 - [(enfo) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yloxy] pyridazin-3-yl} -1H-indole trifluoroacetate

Example 45A (ene) -9-methyl-9-azabicyclo [3.3.1] nonan-3-ol [0167] (endo) -9-methyl-9-azabicyclo [3,3,1] nonan-3-ol was prepared according to the procedure as described in International Patent Application No. WO 03062235. ¹H NMR (300 MHz, CD3OD) δ 1.22 1.32 (m, 2H), 1.35 - 1.47 (m, 3H), 1.98 (tt, J = 13.60, 5, 21 Hz, 2H), 2.30 - 2.56 (m, 6H), 2.87 - 2.96 (m, 2H), 4.04 - 4.15 (m, 1H) ppm. MS (DCI / NH3): m / z 156 (M + H)⁺.

Example 45B (enfo) -3- (6-chloropyridazin-3-yloxy) -9-methyl-9-azabicyclo [3.3.1] nonane

[0168] The product of example 45A (467 mg, 3.0 mmol) was coupled to 3,6-dichloropyridazine (614 mg, 3.3 mmol) according to the procedure of Example 1A. ¹H NMR (300 MHz, CD3OD) δ 1.59 (ddd, J = 14.41, 6.27, 6.10 Hz, 1H), 1.77 (dd, J = 14.92, 5.76 Hz , 2H), 2.06 - 2.28 (m, 4H), 2.52 - 2.82 (m, 3H), 2.90 (s, 3H), 3.51 (t, J = 5.76 Hz, 2H), 5.55 (tt, J = 6.91, 1.74 Hz, 1H), 7.26 (d, J = 9.16 Hz, 1H),

7.69 (d, J = 9.16 Hz, 1H) ppm. MS (DCI / NH3): m / z 268 (M + H)⁺.

Example 45C 5- {6 - [(ene) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yloxy] pyridazin-3-yl} -1H-indole trifluoroacetate [0169] The product of Example 45B (145 mg, 0.54 mmol) was coupled to indole-5-boronic acid (Ryscor, 165 mg, 1.02 mmol) according to the procedure of Example 1B to give the title compound. ¹H

NMR (300 MHz, CD3OD) δ 1.57 - 1.81 (m, 2H) 1.95 - 2.47 (m, 5H) 2.67 - 2.92 (m, 3H) 2.98 - 3.06 (m, 3H) 3.65 (t, J = 5.09 Hz, 2H) 5.61 (t, J = 6.95 Hz, 1H) 6.59 (d, J = 3.05 Hz, 1H) 7.34 (d, J = 3.05 Hz, 1H) 7.37 - 7.43 (m, 1H) 7.55 (d, J = 8.48 Hz, 1H) 7.74 (dd, J = 8.65, 1.86 Hz, 1H) 8.18 (d, J = 1.70 Hz, 1H) 8.20 - 8.27 (m, 1 H) ppm. MS (DCI / NH₃): m / z 349 (M + H) +. Anal. Calculated for C.₂₁H₂₄N₄O ^ 2.10 CF3CO2H: C, 51.48; H, 4.47; N, 9.53. Found: C, 51.31; H, 4.33; N, 9.36.

Example 46 trifluoroacetate (enfo) -3- [6- (benzo [b] thiophen-5-yl) pyridazin-3-yloxy] -9-methyl-9-azabicyclo [3.3.1] nonane [0170] The product of example 45B (145 mg, 0.54 mmol) was coupled to the product of Example 10A (280 mg, 1.02 mmol) according to the procedure of Example 1B to give the title compound. ¹H NMR (300 MHz,

CD3OD) δ 1.56 - 1.81 (m, 2H), 1.94 - 2.48 (m, 5H), 2.68 - 2.92 (m, 3H), 2.98 - 3 , 08 (m, 3H), 3.65 (t, J = 5.09 Hz, 2H), 5.66 (t, J = 6.95 Hz, 1H), 7.34 (d, J = 9.16 Hz, 1H), 7.50 (d, J = 5.76 Hz, 1H), 7.68 (d, J = 5.76 Hz, 1H), 7.96 - 8, 02 (m, 1H), 8.04 - 8.10 (m, 1H), 8.20 (d, J = 9.49 Hz, 1H), 8.45 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH₃): m / z 366 (M + H) +. Anal. Calculated for C.₂₁H₂₃N₃OS1,13 CF₃WHAT₂H: C, 56.51; H, 4.92; N, 8.50. Found: C, 56.56; H, 4.75; N, 8.44.

Example 47 bistosylate_5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-pyrrolo [2,3-b] pyridine

Example 47A

5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrrolo [2,3-b] pyridine [0171] 5-Bromo-1H-pyrrolo [2 , 3-b] pyridine (Chemgenx, 0.90 g, 4.57 mmol) was coupled to bis (pinacolano) diboron (Aldrich, 1.27 g, 5.0 mmol) according to the procedure of Example 10A. ¹H NMR (300 MHz, CDCl3) δ 1.37 (s, 12H) 6.52 (d, J = 3.73 Hz, 1H), 7.38 (d, J = 3.73 Hz, 1H ), 8.34 (d, J = 1.36 Hz, 1H), 8.49 (d, J = 1.70 Hz, 1H) ppm; m / z 245 (M + H)⁺.

EP 2 018 380 B1

Example 47B 5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-pyrrolo [2,3-b] tosylate ] pyridine [0172] The product of example 41C (207 mg, 0.60 mmol) was coupled with the product of example 47A (200.0 mg, 0.82 mmol) according to the procedure of Example 10B. ¹H NMR (300 MHz, CD3OD) δ 1.98 - 2.09 (m, 2

H), 2.10 - 2.32 (m, 6H), 2.40 (s, 3H), 5.32 (t, J = 5.09 Hz, 1H), 6.58 (d, J = 3.39 Hz, 1H), 7.44 (d,

J = 3.73 Hz, 1H), 8.25 (d, J = 1.36 Hz, 1H), 8.53 (d, J = 2.03 Hz, 1H), 8.65 (d , J = 1.36 Hz, 1H), 8.78 (d, J = 2.03 Hz, 1H) ppm. MS (DCI / NH3) m / z 336 (M + H)⁺.

Example 47C bistosylate_5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} 1H-pyrrolo [2,3-b] 10 pyridine [0173] The product of example 47B (90 mg, 0.27 mmol) was treated with p-toluenesulfonic acid monohydrate TsOUH₂O (Aldrich, 95 mg, 0.5 mmol) in a mixture of EtOAc / EtOH (4: 1 volume, 10 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.35 (s, 6H), 2.38 - 2.45 (m, 2H), 2.45 - 2.61 (m, 6

H), 2.85 (s, 3H), 3.85 - 4.07 (m, 2H), 5.46 (t, J = 4.75 Hz, 1H), 6.97 (d, J = 3.39 Hz, 1H), 7.22 (d,

J = 7.80 Hz, 4 H) 7.70 (d, J = 8.14 Hz, 4 H), 7.76 (d, J = 3.73 Hz, 1 H), 8.42 (d, J = 1.36 Hz, 1H), 8.85 (d, J = 1.36 Hz, 1H), 9.04 (d, J = 1.70 Hz, 1H), 9.27 (d , J = 1.70 Hz, 1H) ppm. MS (DCI / NH 3): m / z 336 (M + H) +. Anal. Calculated for C1₉H₂1N₅O ^ 2.17 C.₇HeSO3-1.00 H₂O: C, 56.48; H, 5.59; N, 9.63. Found: C, 56.48; H, 5.37; N, 9.67.

Example 48 bistosylate_5- {5 - [(eqzo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} 1H-pyrrolo [2,3-b] pyridine

Example 48A

5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-pyrrolo [2,3-b] pyridine [ [0174] The product of Example 11A (152 mg, 0.60 mmol) was coupled to the product of Example 47A (200.0 mg, 0.82 mmol) according to the procedure of Example 9B. ¹H NMR (300 MHz, CD3OD) δ 1.76 - 1.92 (m, 4H), 2.06 - 2.20 (m, 4H), 2.36 (s, 3H), 3.18 - 3.31 (m, 2H), 4.64 - 4.79 (m, 1H), 6.57 (d, J = 3.39 Hz, 1H), 7.43 (d, J = 3.73 Hz, 1H), 7.81 (d, J = 8.82 Hz, 1H), 8.29 (d, J = 3.05 Hz, 1H), 8.45 (d, J = 2.03 Hz, 1H), 8.72 (d, J = 2.03 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Example 48B 5- {5 - [(exo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} 1H-pyrrolo [2,3-b] bistosylate pyridine [0175] The product of example 48A (100 mg, 0.30 mmol) was treated with p-toluene 48 monohydrate

Sulfonic acid TsOH-H₂O (Aldrich, 95 mg, 0.5 mmol) in a mixture of EtOAc / EtOH (4: 1 volume, 10 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.18 - 2.47 (m, 2H), 2.15-2.40 (m, 10H), 2.46 - 2.60 (m, 2H), 2.85 (s, 3H), 3.99 - 4.06 (m, 2H), 4.95 - 5.19 (m, 1H), 6.83 (d, J = 3.39 Hz , 1H), 7.22 (d,

J = 8.14 Hz, 4 H), 7.66 (d, J = 3.39 Hz, 1 H), 7.70 (d, J = 8.48 Hz, 4 H), 8.09 (d , J = 8.82 Hz, 1H), 8.48 (d,

J = 2.71 Hz, 1H), 8.87 (d, J = 2.03 Hz, 1H), 8.91 (d, J = 2.03 Hz, 1H) ppm. MS (DCI / NH 3): m / z 335 (M + H) +. Anal. Calcd for ^ 22 ^ 0-2.14 C7H8SO₃-0.50 H₂O: C, 59.01; H, 5.68; N, 7.87. Found: C, 58.88; H, 5.63; N, 7.47.

Example 49 Tri (hydrochloride) 5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-3-yl} 1H-indole

Example 49A (eqzq) -3- (5-chloro-pyridin-3-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0176] (endo) -Tropine (Aldrich, 0.56 g , 4.0 mmol) was coupled to 3-chloro-5-hydroxy-pyridine (Aldrich, 0.26 g, 2.0 mmol) in the presence of DIAD (diisopropyl azadicarboxylate, Aldrich, 0.81 g, 4.0 mmol) and Ph3P (Aldrich, 1.14 g, 4.0 mmol) in THF (anhydrous, Aldrich, 20 ml) at ambient temperature for two days. The reaction mixture was concentrated. The title product was purified by chromatography (SiO2, CH₂cl₂: MeOH: NH₃-H₂O, 90: 10: 1, R._f 0,45). ¹H NMR (300 MHz, CD₃OD) δ 1.66 - 1.91 (m, 4H), 1.98 2.19 (m, 4H), 2.33 (s, 3H), 3.22 - 3.28 (m, 2H), 4.58 - 4.79 (m, 1H), 7.49 (dd, J = 2.37, 1.70 Hz, 1H), 8.11 (d, J = 1.70 Hz, 1H), 8.15 (d, J = 2.37 Hz, 1H) ppm. MS (DCI / NH3) m / z 255 (M + H)⁺, 253 (M + H)⁺.

Example 49B

5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-3-yl} -1H-indole [0177] Under N2, the product mixture from Example 49A (250 mg, 1.00 mmol) was coupled to 5-indolylboronic acid (Rsycor, 240.0 mg, 1.50 mmol) according to the procedure of Example 9B. ¹H NMR (300 MHz, CD3OD) δ 1.71 - 1.92 (m, 4H), 2.02 - 2.21 (m, 4H), 2.34 (s, 3H), 3.23 - 3.30 (m, 2H), 4.63

- 4.80 (m, 1H), 6.54 (d, J = 3.05 Hz, 1H), 7.29 (d, J = 3.39 Hz, 1H), 7.38 (dd , J = 8.48, 2.03 Hz, 1H),

7.47 - 7.53 (m, 1H), 7.58 - 7.64 (m, 1H), 7.83 (d, J = 1.36 Hz, 1H), 8.15 (d , J = 2.71 Hz, 1H), 8.39 (d, J = 1.70 Hz, 1H) ppm. MS (DCI / NH3) m / z 334 (M + H)⁺.

Example 49C Tri (hydrochloride) 5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole [0178] The product of example 49B (90 mg, 0.27 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.25 mL, 1.0 mmol) in a mixture ^andPrOAc /^andPrOH (vol. 4: 1, 5 mL) at ambient temperature for 2 hours to give the title compound. ¹H NMR (300 MHz, CD3OD) δ 2.01 - 2.66 (m, 8H), 2.83 (s, 3H), 3.92 4.09 (m, 2H), 4.98 - 5.15 (m, 1H), 6.61 (d, J = 3.05 Hz, 1H), 7.33 - 7.40 (m, 1H), 7.50 - 7.63 (m , 2H),

EP 2 018 380 B1

8.04 - 8.10 (m, 2H), 8.44 (d, J = 1.70 Hz, 1H), 8.80 (s, 1H) ppm. MS (DCI / NH3): m / z 334 (M + H)⁺. Anal. Calculated for C.₂₁H₂₃N3O-3.00 HCl · 4.60 H₂O: C, 47.98; H, 6.14; N, 7.85. Found: C, 47.62; H, 6.38; N, 7.62.

Example 50 5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole tosylate

Example 50A (eqzq) -3- (5-iodo-pyrazin-2-yloxy) -8-methyl-8-aza-bicyclo [3.2.1] octane [0179] Under N2, the product mixture of Example 7C (0.42 g, 3.0 mmol) was treated with potassium t-butoxide (Aldrich, 0.32 g, 3.3 mmol) in THF (anhydrous, Aldrich, 50 ml) at ambient temperature for

1 hour. The product of example 41B (1.00 g, 3.5 mmol) and added. The mixture was stirred at ambient temperature for 4 hours and quenched with water (5 mL). The mixture was concentrated and the residue was purified by chromatography (150 g SiO₂, EtOAc: MeOH: NH₃^ H₂O, 90: 10: 1, R._f 0.40) to obtain the title compound. ¹H NMR (300 MHz, CD3OD) δ 1.90 - 2.25 (m, 4H), 2.31 - 2.60 (m, 4H),

2.84 (s, 3H), 3.94 - 4.11 (m, 2H), 5.32 - 5.57 (m, 1H), 8.06 (d, J = 1.36 Hz , 1H), 8.42 (d, J = 1.36 Hz, 1

H) ppm; MS (DCI / NH3) m / z 346 (M + H)⁺.

Example 50B

5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl] -1H-indole [0180] The product of example 50A (200 mg, 0.58 mmol) was coupled to 5-indolylboronic acid (Rsycor, 143.3 mg, 0.89 mmol) according to the procedure of Example 9B. ¹H NMR (300 MHz, CD3OD) δ

1.95 - 2.17 (m, 2H), 2.16 - 2.31 (m, 2H), 2.36 - 2.47 (m, 2H), 2.48 - 2.67 ( m, 2H), 2.85 (s, 3H), 3.90

- 4.17 (m, 1H), 5.36 - 5.69 (m, 1H), 6.53 (d, J = 3.39 Hz, 1H), 7.29 (d, J = 3.05 Hz, 1H), 7.48 (d, J = 8.48 Hz, 1H) 7.69 (dd, J = 8.48, 1.70 Hz, 1H), 8.13 ( s, 1H) 8.20 (d, J = 1.36 Hz, 1H), 8.62 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Product 50C 5- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-indole tosylate [0181] Product of example 50B (170 mg, 0.50 mmol) was treated with p-toluenesulfonic acid monohydrate TsOHH₂O (Aldrich, 100 mg, 0.51 mmol) in a mixture of EtOAc / EtOH (vol. 4: 1, 5 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.01 - 2.15 (m, 2H), 2.16 - 2.30 (m, 2H), 2.36 (s, 3

H), 2.39 - 2.49 (m, 2H), 2.52 - 2.67 (m, 2H), 2.84 (s, 3H), 3.96 - 4.13 (m , 2H), 5.43 - 5.70 (m, 1H),

7.23 (d, J = 8.14 Hz, 2H), 7.30 (s, 1H), 7.49 (d, J = 8.48 Hz, 1H), 7.62 - 7, 75 (m, 4H), 8.12 (s, 1H), 8.22 (d, J = 1.36 Hz, 1H), 8.68 (d, J = 1.36 Hz, 1H ) ppm. MS (DCI / NH3): m / z 335 (M + H)⁺.

Example 51

4- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-indole tosylate

Example 51A

4- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole [0182] The product of example 50A (200 mg, 0.58 mmol) was coupled to 4-indolylboronic acid (Apollo, 143.3 mg, 0.89 mmol) according to the procedure of Example 9B. ¹H NMR (300 MHz, CD3OD) δ 2.02 - 2.28 (m, 4H), 2.34 - 2.48 (m, 2H), 2.50 - 2.65 (m, 2H) , 2.86 (s, 3H), 3.96 - 4.07 (m, 2H), 5.45 - 5.68 (m, 1H), 6.82 (d, J = 4.07 Hz, 1H), 7.23 (t, J = 7.60 Hz 1H), 7.35 (d, J = 3.39 Hz, 1H), 7.41 (d, J = 6.44 Hz, 1H), 7.48 (d, J = 8.14 Hz, 1H), 8.29 (d, J = 1.36 Hz, 1H), 8.65 (d, J = 1, 36 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Example 51B 4- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-indole tosylate [0183] The product of the example 51A (120 mg, 0.36 mmol) was treated with p-toluenesulfonic acid monohydrate TsOUH₂O (Aldrich, 68 mg, 0.36 mmol) in a mixture of EtOAc / EtOH (vol. 4: 1, 5 mL) at ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.02 - 2.17 (m, 2H), 2.18 - 2.32 (m, 2H), 2.36 (s, 3H), 2.38 - 2.50 (m, 2H), 2.52 - 2.69 (m, 2H), 2.85 (s, 3H), 4.00 - 4.11 (m, 2H), 7 , 17 - 7.28 (m, 1H), 7.35 (s, 1H), 7.42 (d, J = 7.12 Hz, 1H), 7.49 (d, J = 8, 14 Hz, 1H), 7.70 (d, J = 8.14 Hz, 1H), 8.30 (d, J = 1.70 Hz, 1H), 8.67 (d, J = 1 , 36 Hz, 1H) ppm. MS (DCI / NH3): m / z 335 (M + H)⁺.

Example 52 6- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole tosylate

Example 52A

6- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] pyrazin-2-yl} -1H-indole [0184] The product of example 41C (200 mg, 0.58 mmol) was coupled to 6-indolylboronic acid (Frontier Scientific, 143.3 mg, 0.89 mmol) according to the procedure of Example 9B. ¹H NMR (300 MHz,

CD3OD) δ 1.97 - 2.16 (m, 2H), 2.14 - 2.26 (m, 2H), 2.31 - 2.65 (m, 4H), 2.81 (s , 3H), 3.84 - 4.05 (m, 2H), 5.33 - 5.71 (m, 1H), 6.47 (d, J = 3.05 Hz, 1H), 7.31 (d, J = 3.05 Hz, 1H), 7.48 - 7.73 (m, 2H), 7.99 (s, 1H), 8.20 (d, J = 1 , 36 Hz, 1H), 8.63 (d, J = 1.36 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺. Example 52B 6- {5 - [(eqzq) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyrazin-2-yl} -1H-indole tosylate [0185] The product of the example 52A (90 mg, 0.27 mmol) was treated with p-toluensulfonic acid monohydrate TsOHU₂O (Aldrich, 57 mg, 0.30 mmol) in a mixture of EtOAc / EtOH (volume 4: 1, 5 ml) in

At ambient temperature for 10 hours. The mixture was concentrated under reduced pressure to obtain the title compound.¹H NMR (300 MHz, CD3OD) δ 2.01 - 2.14 (m, 2H), 2.16 - 2.31 (m, 2H), 2.36 (s, 3H), 2.39 - 2.51 (m, 2H), 2.50 - 2.65 (m, 2H), 2.84 (s, 3H), 3.98 - 4.08 (m, 2H), 5 , 41 - 5.68 (m, 1H), 6.48 (d, J = 2.37 Hz, 1H), 7.23 (d, J = 7.80 Hz, 2H), 7.32 (s, 1H), 7.55 - 7.67 (m, 2H), 7.71 (d, J = 8.48

Hz, 2H), 7.99 (s, 1H), 8.22 (d, J = 1.36 Hz, 1H), 8.65 (d, J = 1.36 Hz, 1H) ppm . MS (DCI / NH3): m / z 335 (M + H)⁺.

Example 53 (endo) -N- (5- (1H-indol-5-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine

Example 53A (endo) -N- (5-bromopyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine [0186] 8-Methyl-8-azabicyclo [3.2, 1] octane-3-one (Aldrich, 695 mg, 5.0 mmol) was reacted with bromopyridine-3-amine (950 mg, 5.5 mmol) according to the procedure of Example 20A to give the title compound (650 mg, yield , 44%). ¹H NMR (300 MHz, CD3OD) δ 1.54 - 2.25 (m, 8H), 2.29 (s, 3H), 3.16 [s (wide), 2H], 3.50 ( t, J = 6.61 Hz, 1H), 7.08 (t, J = 2.20 Hz, 1H), 7.79 (d, J = 1.70 Hz, 1H), 7.85 (d, J = 2.37 Hz, 1H) ppm; MS (DCI / NH3): m / z 298 (M + H)⁺, 296 (M + H)⁺.

Example 53B (endo) -N- (5- (1H-indol-5-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine p-tosylate [0187 ] The product of example 53A (150 mg, 0.5 mmol) was coupled to indole-5-boronic acid (Frontier, 150 mg, 0.93 mmol) according to the procedure of Example 9B to obtain the free base of the title compound (82 mg, yield , 50%), which was treated with p-toluenesulfonic acid hydrate (Aldrich, 47 mg, 0.25 mmol) in a mixture of EtOAc / EtOH (vol. 10: 1, 5 mL) at room temperature for 16 hours. The precipitate was collected and dried to give the title compound (99.3 mg, yield, 67.2%). ¹H NMR (300 MHz, CD3OD) δ 2.15 - 2.30 (m, 2H), 2.30 - 2.42 (m, 5.5H), 2.42 - 2.63 (m, 4 H), 2.82 (s, 3H), 3.81 (t, J = 5.9 Hz, 1H), 3.93 [s (wide), 2H), 6.54 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.1

Hz, 3H), 7.32 (d, J = 3.1 Hz, 1H), 7.39 (dd, J = 8.4, 1.7 Hz, 1H), 7.47 - 7, 59 (m, 2H), 7.70 (d, J = 8.5 Hz, 3H); 7.86 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 8.23 ​​(d, J = 1.7 Hz, 1H) ppm. MS DCI / NH3): m / z 333 (M + H) +. Anal. Calculated for C.₂₁H₂₄N4-1.50 C.₇H₈ABOUT₃S-1.20 H₂O: C, 61.78; H, 6.32; N, 9.15. Found: C, 61.78; H, 6.19; N, 8.99.

Example 54 (endo) -N- (5- (1H-indol-4-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine p-tosylate

Example 54A (endo) -N- (5- (1H-indol-4-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine

[0188] The product of example 53A (150 mg, 0.5 mmol) was coupled with indole-4-boronic acid (Frontier, 150 mg, 0.93 mmol) according to the procedure of Example 9B to give the title compound (80 mg, yield, 48%). ¹H NMR (300 MHz, CD3OD) δ 1.78 - 1.96 (m, 2H), 2.05 - 2.16 (m, 4H), 2.17 2.30 (m, 2H), 2.33 (s, 3H), 3.21 [s (wide), 2H], 3.63 (t, J = 6.8 Hz, 1H), 6.57 (d, J = 3, 4 Hz, 1H),

7.08 (d, J = 7.1 Hz, 1H), 7.15 - 7.26 (m, 2H), 7.31 (d, J = 3.1 Hz, 1H), 7, 42 (d, J = 7.8 Hz, 1H), 7.89 (d,

J = 2.7 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H) ppm; MS DCI / NH3): m / z 3.33 (M + H)⁺.

Example 54B (endq) -N- (5- (1H-indol-4-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] acetate-3-amine p-tosylate [3.2.1] acetate-3-amine [0189 ] The product of Example 54A (80 mg, 0.24 mmol) was treated with p-toluene sulfonic acid hydrate (Aldrich, 47 mg, 0.25 mmol) in a mixture of EtOAc / EtOH (10: 1, 5 mL volume) at room temperature for 16 hours. The precipitate was collected and dried to give the title compound (85.3 mg, yield, 58.5%).¹H NMR (300 MHz, CD3OD) δ 2.17 - 2.31 (m, 2H), 2.31 - 2.41 (m, 5.8H), 2.41 2.60 (m, 4H ), 2.82 (s, 3H), 3.79 (t, J = 5.9 Hz, 1H), 3.93 [s (wide), 2H), 7.16 (dd, J = 7.5, 1.0 Hz, 1H), 7.21-7.27 (m, 5.2H), 7.37 (d, J = 3.1 Hz, 1H), 7.50 ( d, J = 8.1 Hz, 1.0 H), 7.62 - 7.66 (m, 1.0 H), 7.70 (d, J = 8.1 Hz, 3.2 H), 7.99 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 1.4 Hz, 1H) ppm. MS DCI / NH3): m / z 333 (M + H) +. Anal. Calculated for C.₂₁H₂₄N &lt;1.60 C₇H₈ABOUT₃SH, 20H₂O: C, 61.43; H, 6.28; N, 8.90. Found: C, 61.72; H, 6.26; N, 8.64.

Example 55 (endq) -N- (5- (1H-indol-6-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine p-tosylate

Example 55A (endq) -N- (5- (1H-indol-6-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine [0190] Product from Example 53A (150 mg, 0.5 mmol) was coupled with indole-6-boronic acid (Frontier, 150 mg, 0.93 mmol) according to Example 9B to give the free base of the title compound (102 mg, yield, 60%). ¹H NMR (300 MHz, CD3OD) δ 1.80 - 1.98 (m, 2H), 2.06 - 2.19 (m, 4H),

2.19-2.32 (m, 2H), 2.35 (s, 3H), 3.24 [s (wide), 2H), 3.64 (t, J = 6.8 Hz, 1H), 6.47 (d, J = 3.4 Hz, 1

H), 7.16 - 7.21 (m, 1H), 7.22 - 7.34 (m, 2H), 7.57 - 7.67 (m, 2H), 7.83 (d , J = 2.7 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H) ppm; MS DCI / NH3): m / z 333 (M + H)⁺.

Example 55B (endq) -N- (5- (1H-indol-6-yl) pyridin-3-yl) -8-methyl-8-azabicyclo [3.2.1] octane-3-amine p-tosylate [3.2.1] octane-3-amine ] The product of example 55A (102 mg, 0.3 mmol) was treated with p-toluenesulfonic acid hydrate (Aldrich, 57 mg, 0.30 mmol) in a mixture of EtOAc / EtOH (volume 10: 1, 5 mL) at room temperature for 16 hours. The precipitate was collected and dried to give the title compound (1.3.2mg, yield, 59.4%).¹H NMR (300 MHz, CD3OD) 2.16 - 2.64 (m, 12.2 H), 2.82 (s, 3 H), 3.78 (t, J = 6.3

EP 2 018 380 B1

Hz, 1H), 3.92 [s (wide), 2H), 6.48 (d, J = 4.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2 , 8 H), 7.27 (dd, J = 8.1, 1.7 Hz, 1H), 7.30 (d, J = 3.1 Hz, 1H), 7.31 - 7.34 (m, 1H), 7.61 - 7.66 (m, 2H), 7.70 (d, J = 8.1 Hz, 2.8 H), 7.88 (d, J = 2, 4 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H) ppm. MS DCI / NH3): m / z 333 (M + H)⁺. Anal. Calculated for C.₂₁H₂4N₄-1.40 C₇H₈ABOUT₃SO, 70H₂O: C, 63.11; H, 6.29; N, 9.56. Found: C, 63.17; H, 6.61; N

9,43.

Example 56 (enfo) -N- {5- [2- (trifluoromethyl) -1H-indol-5-yl] pyridin-3-yl} -8-methyl-8-azabicyclo [3.2.1] octane-3- fumarate amines [0192] The product of Example 9A (110 mg, 0.4 mmol) was coupled with the product of Example 7A (300 mg,

0.97 mmol) according to the procedure described in Example 9B to obtain the free base of the title compound (38 mg, yield, 22.5%), which (38 mg, 0.09 mmol) was then treated with fumaric acid (12 mg, 0, 1 mmol) in a mixture of EtOAc / EtOH (10: 1.5 vol.) At room temperature for 16 hours. The precipitate was filtered off and dried to give the title compound (50.4 mg, yield, 99%).¹H NMR (300 MHz, CD3OD) δ 2.28 - 2.37 (m, 4H), 2.42-2.57 (m, 4H), 2.84 (s, 3H),

3.02 [s (wide), 2H], 4.80-4.90 (m, 1H) 6.72 (s, 2.6H), 6.97 (s, 1H), 7, 47 - 7.57 (m, 2H), 7.85 (d,

J = 8.8 Hz, 2H), 8.17 (s, 1H) 8.30 (s, 1H) ppm. MS DCI / NH3): m / z 402 (M + H)⁺. Anal. Calculated for C.₂₂H₂₂F₃N₄1.30 C.₄ABOUT₄H₄: C, 59.15; H, 4.96; N, 7.61. Found: C, 59.29; H, 5.07; N, 7.37.

Example 57 5- {5 - [(ene) -8-methyl-8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2,3-b] pyridine tosylate

Example 57A

5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-pyrrolo [2.3-b] pyridine [0193] The product of Example 9A (200 mg, 0.80 mmol) was coupled with the product of Example 47A (244.0 mg, 1.0 mmol) according to the procedure of Example 9B to give the title compound (190 mg, yield, 71%). ¹H NMR (300 MHz, CD3OD) δ 1.93 - 2.27 (m, 8H), 2.33 (s, 3H), 3.20 [s (wide), 2H], 4.69 ( t

J = 5.1 Hz, 1H), 6.57 (d, J = 3.4 Hz, 1H), 7.39 - 7.48 (m, 2H), 7.83 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 2.7

Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H) ppm. MS (DCI / NH3) m / z 335 (M + H)⁺.

Example 57B 5- {5 - [(enfo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yloxy] -pyridin-2-yl} -1H-pyrrolo [2.3-b] pyridine tosylate [0194] The product of example 48A (80 mg, 0.24 mmol) was treated with p-toluene sulfonic acid monohydrate TsOHH₂O (Aldrich, 57 mg, 0.3 mmol) in a mixture of EtOAc / EtOH (vol. 4: 1, 10 mL) at ambient temperature for 10 hours. The precipitate was filtered off and dried to give the title compound (100 mg, yield, 79.6%).¹H NMR (300 MHz, CD3OD) δ 2.27 - 2.69 (m, 11H),

2.84 (s, 3H), 3.84 - 4.08 (m, 2H), 4.84 - 4.94 (m, 1H), 6.62 (d, J = 3.4 Hz , 1H), 7.23 (d, J = 8.1 Hz, 2

EP 2 018 380 B1

H), 7.47 (d, J = 3.7 Hz, 1H), 7.56 (dd, J = 8.8, 3.1 Hz, 1H), 7.71 (d, J = 8 , 1 Hz, 2 H), 7.92 (d, J = 8.8 Hz, 1 H), 8.36 (d, J = 2.7 Hz, 1 H), 8.56 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H) ppm. MS (DCI / NH 3): m / z 335 (M + H) +. Anal. Calculated for C.₂₀H₂₂N₄At 1.10 C.₇H₈SO₃Oh, 80H₂O: C, 61.81; H, 6.07; N, 10.41. Found: C, 62.15; H, 5.92; N, 10.05.

Example 58 bis (hydrochloride) 5- {5 - [(enfo) -8-methyl-8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} indolin-2one

Example 58A

5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolin-2-one [0195] Under N2, 5-bromoindolin-2-one (Aldrich, 2.11 g , 10.0 mmol) coupled to bis (pinacolano) diboron (Frontier Scientific, 3.05 g, 12 mmol) in the presence of KOAc (Aldrich, 1.50 g, 15.0 mmol) under catalysis with PdCl2 (dppf) CH2Cl2 ( Aldrich, 163 mg, 0.2 mmol) in anhydrous dioxane (Aldrich, 50 ml) at 85 ° C for 15 hours. After completion of the reaction, it was cooled to ambient temperature and diluted with EtOAc (100 mL). The mixture was then washed with brine (2 x 10 mL) and concentrated. The residue was purified by silica gel chromatography (EtOAc / hexanes, vol. 1: 1, Rf = 0.5) to give the title compound (2.43 g, yield, 93.8%).¹H NMR (300 MHz, CD3OD) δ 1.24 (s, 12H), 3.51 (s, 2H), 6.88 (d, J = 8.5 Hz, 1H), 7.52 - 7.75 (m, 2H) ppm. MS (DCI / NH3): m / z 260 (M + H)⁺. Example 58B

5- {5 - [(enfo) -8-methyl-8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} indolin-2-one [0196] The product of Example 9A (200 mg, 0.80 mmol) was coupled to the product of Example 58A (260 mg, 1.0 mmol) according to the procedure of Example 9B to give the title compound (130 mg, yield, 46.4%). ¹H NMR (300 MHz, CD3OD) δ 1.93 - 2.04 (m, 2H), 2.06 - 2.15 (m, J = 2.4 Hz, 4H), 2.14 - 2, 25 (m, 2H), 2.33 (s, 3H), 3.20 [s (wide), 2H], 4.67 (t, J = 5.1 Hz, 1H), 6, 96 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.8, 3.1 Hz, 1H), 7.69 - 7.80 (m, 3H), 8.18 (d, J = 3.1 Hz, 1H) ppm. MS (DCI / NH3) m / z 350 (M + H)⁺.

Example 58C Bis (hydrochloride) 5- {5 - [(enfo) -8-methyl-8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} indolin-2one [0197] The product of example 48A (80 mg, 0.24 mmol) was treated with p-toluenesulfonic acid monohydrate TsOH ^ H₂O (Aldrich, 57 mg, 0.3 mmol) in a mixture of EtOAc / EtOH (vol. 4: 1, 10 mL) at ambient temperature for 10 hours. The precipitate was filtered off and dried to give the title compound (100 mg, yield, 79.6%).¹H NMR (300 MHz, CD3OD) δ 2.31 - 2.67 (m, 8H),

2.85 (s, 3H), 3.68 (s, 2H), 3.90 - 4.08 (m, 2H), 5.03 (t, J = 4.6 Hz, 1H) , 7.14 (d, J = 9.2 Hz, 1H), 7.73 7.82 (m, 2H), 8.22 - 8.34 (m, 2H), 8.53 (d , J = 2.4 Hz, 1H) ppm. MS (DCI / NH3) m / z 350 (M + H)⁺ Anal.

EP 2 018 380 B1

Calculated for C21H2₃N₃O2 ^, 00 HCl-3.0 H₂O: C, 52.95; H, 6.56; N, 8.82. Found: C, 52.67; H, 6.47; N, 8.62.

Example 59 bis (hydrochloride) 5- {5 - [(enefo) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole

Example 59A (ene) -3- (6-chloropyridin-3-yloxy) -8-azabicyclo [3.2.1] octane [0198] To a solution of the product of Example 9A (25.3 mg, 1.0 mmol) in anhydrous 1 , 2-dichloroethane (Aldrich, 10 ml) 1-chloroethyl chloroformate (Aldrich, 286 mg, 2.0 mmol) was added. The mixture was heated to reflux for 15 hours. Then concentrated, the residue was diluted with 5 mL methanol. The solution was stirred at 65 ° C for 1 h and then concentrated. The residue was purified using silica gel chromatography (CH₂cl₂: MeOH: NH₃^ H₂Oh, vol. 90: 10: 2, R._f= 0.1) to give the title compound (180 mg, yield, 75%). ¹H NMR (300 MHz, CD3OD) δ 2.03 - 2.62 (m, 8H), 4.01 - 4.14 (m, 2H), 4.75 - 4.82 (m, 1H) , 7.37 - 7.42 (m, 1H), 7.44 (d, J = 3.1 Hz, 1H), 8.03 8.13 (m, 1H) ppm. MS (DCI / NH3) m / z 241 (M + H)⁺, 239 (M + H)⁺.

Example 59B

5- {5 - [(enefo) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole [0199] The product of example 59A (180 mg, 0.75 mmol) coupled with 1H-indol-5-ylboronic acid (160 mg, 1.0 mmol) according to the procedure of Example 9B to give the title compound (120 mg, yield, 50.1%). ¹H NMR (300 MHz, CD3OD) δ 1.77 - 1.94 (m, 2H), 1.96 - 2.07 (m, 2H), 2.07 20 2.30 (m, 4H) , 3.46 - 3.59 (m, 2H), 4.73 (t, J = 4.9 Hz, 1H), 6.51 (d, J = 4.1 Hz, 1H), 7 , 26 (d, J = 3.1 Hz,

H), 7.39 (dd, J = 8.8, 3.1 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.62 (dd, J = 8 , 5, 1.7 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 8.17 ( d, J = 2.7 Hz, 1H) ppm. MS (DCI / NH3) m / z 320 (M + H)⁺.

Example 59C bis (hydrochloride) 5- {5 - [(enefo) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole [0200] The product of example 59B (120 mg , 0.38 mmol) was treated with HCl (4 M, in dioxane, 0.2 mL, 0.8 mmol) in EtOAc (5.0 mL) at ambient temperature for 10 hours. The precipitate was filtered off and dried to give the title compound (130 mg, yield, 79.6%).¹H NMR (300 MHz, CD3OD) δ 2.09 - 2.26 (m, 2H), 2.28 - 2.43 (m, 2H), 2.40 - 2.59 (m, 4H) , 4.02 - 4.23 (m, 2H), 5.02 (t, J = 4.4 Hz, 1H), 6.65 (d, J = 3.1 Hz, 1H), 7 , 42 (d, J = 3.4 Hz, 1H), 7.57 - 7.71 (m, 2H), 8.15 (s, 1H), 8.19 (dd,

J = 9.1, 2.7 Hz, 1H), 8.29 (d, J = 9.1 Hz, 1H), 8.44 (d, J = 2.7 Hz, 1H) ppm. MS (DCI / NH 3) m / z 320 (M + H) +. Anal. Calculated for C.₂₀H₂₁N₃O ^ 2.00 HCl-1.18 H₂O: C, 58.08; H, 6.18; N, 10.16. Found: C, 57.73; H, 6.37; N, 9.95.

Example 60

EP 2 018 380 B1

(1f, 3 /; 5S, 8s) -3- (6- (1H-indol-5-yl) pyridin-3-yloxy) -8-methyl-8-azabicyclo [3.2.1] octane 8-oxide ] 3-Chloroperbenzoic acid (Aldrich, 70-75%, 240 mg, 1.0 mmol) was added to a solution of the product of Example 9B (333 mg, 1.0 mmol) in MeOH (10 mL). It was then stirred at ambient temperature for 4 hours. The solution was purified immediately using preparative HPLC [Gilson, Xterra® 5 μm column, 40 x 100 mm, elution solvent, MeCN / H₂O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol. 10/90 to 75/25 for 20 minutes, flow rate 40 ml / minute, UV detector set at 250 nm]. lower retention time was collected and concentrated under reduced pressure to give the title compound (130 mg, yield, 37.2%). ¹H NMR (300 MHz, CD3OD) δ 2.19 - 2.42 (m, 4H), 2.45 - 2.74 (m, 4H), 3.34 (s, 3H), 3.57 - 3.70 (m, 2H), 4.72 (t, J = 5.3 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 7.27 (d , J = 3.1 Hz, 1H), 7.40 - 7.52 (m, 2H), 7.64 (dd, J = 8.5, 1.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 8.23 ​​(d, J = 3.1 Hz, 1H) ppm; MS (DCI / NH3) m / z 350 (M + H)⁺.

Example 61

(1f, 3 / ', 5S, 3 /') 8-oxide - 3- (6- (1H-indol-5-yl) pyridin-3-yloxy) -8-methyl-8-azabicyclo [3.2.1] octane [0202] 3-Chloroperbenzoic acid (Aldrich, 70-75%, 240 mg, 1.0 mmol) was added to a solution of the product of Example 9B (333 mg, 1.0 mmol) in MeOH (10 mL). It was then stirred at ambient temperature for 4 hours. The solution was immediately purified using preparative HPLC [Gilson, Xterra® 5 μm column, 40 x 100 mm. Elution solvent, MeCN / H2O (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 using ammonium hydroxide) (vol. 10/90 to 75/25 for 20 minutes, flow rate 40 ml / minute, UV detector set to 250 nm. Fractions with higher retention time were collected and concentrated under reduced pressure to give the title compound (110 mg, yield, 31.5%). ¹H NMR (300 MHz, CD3OD) δ 1.96 - 2.07 (m, 2H), 2.19 - 2.37 (m, 2H), 2.44 - 2.59 (m, 2H) , 3.06 (dt, J = 15.3, 4.2 Hz, 2H), 3.24 (s, 3H), 3.47 - 3.59 (m, 2H), 4.71 4 , 81 (m, 1H), 6.52 (d, J = 3.1 Hz, 1H), 7.27 (d, J = 3.4 Hz, 1H), 7.42 - 7.50 (m, 2H), 7.64 (dd, J = 8.5, 1.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 8.05 (d , J = 1.7 Hz, 1H), 8.24 (d, J = 3.1 Hz, 1H) ppm; MS (DCI / NH3) m / z 350 (M + H)⁺.

Example 62 4- {5 - [(enrfq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole trifluoroacetate [0203] The product of Example 59A (120 mg, 0, 50 mmol) was coupled to 1H-indol-4-ylboronic acid (Frontier, 121 mg, 0.75 mmol) according to the procedure described in Example 9B. The crude mixture was purified using preparative HPLC (Gilson, Xterra® 5 μm column, 40 x 100 mm. Elution solvent, MeCN / H2O containing 0.1 vol% TFA (90% to 10% for 25 minutes). Flow rate 40 ml / minute, UV detector set at 254 nm). Fractions containing the desired product were collected and concentrated under reduced pressure, and the residue was stirred in an ether / ethanol mixture (vol. 10/1, 5 mL) at neutral temperature for 16 hours to give the title compound. (80 mg, yield, 29.2%).¹H NMR (300 MHz, CD3OD) δ 2.06 - 2.24 (m, 2H), 2.25 - 2.60 (m, 6H), 4.00 - 4.33 (m, 2H) , 4.90 - 5.02 (m, 1H), 6.72 (dd, J = 3.39, 1.02 Hz, 1H), 7.25 - 7.32 (m, 1H), 7.34 57

EP 2 018 380 B1

7.39 (m, 1H), 7.43 (d, J = 3.05 Hz, 1H), 7.58 (dt, J = 7.80, 1.02 Hz, 1H), 7, 93 (dd, J = 8.99, 2.88 Hz, 1H), 8.11 1 (d, J = 8.82 Hz, 1H), 8.46 (d, J = 2.71 Hz, 1H) ppm. MS (DCI / NH3) m / z 320 (M + H)⁺Anal. Calc. for C.₂₀H₂₁N₃O ^ 2.00 CF₃WHAT₂HO, 50H₂O: C, 51.80; H, 4.35; N, 7.55. Found: C, 51.84; H, 4.28; N, 7.30.

Example 63 bis (hydrochloride) 5- {5 - [(eqzq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole

Example 63A (eqzq) -3- (6-chloropyridin-3-yloxy) -8-azabicyclo [3.2.1] octane [0204] To the solution of the product of Example 11A (2.52 g, 9.97 mmol) in 1, 2-dichloroethane (25 mL) (anhydrous) 1-chloroethyl chloroformate (5.54 mL, 49.9 mmol) was added. The mixture was then heated to 100 ° C for 50 h. Then it was cooled to ambient temperature, 25 ml MeOH was added. The mixture was then heated to reflux for 1 hour. The mixture was concentrated and the crude product was purified using silica gel chromatography (CH₂cl₂: MeOH: NH₃AT₂Oh, vol. 90: 10: 2, R._f= 0.15) to obtain the title compound (180 mg, yield,

75%). ¹H NMR (300 MHz, CD3OD) δ 1.56 - 1.71 (m, 2H), 1.74 - 1.94 (m, 4H), 2.01 - 2.26 (m, 2H) .

3.46 - 3.73 (m, 2H), 4.58 - 4.76 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.43 (dd , J = 8.8, 3.0 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H) ppm. MS (DCI / NH3) m / z 241 (M + H)⁺, 239 (M + H)⁺.

Example 63B

5- {5 - [(eqzq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole [0205] The product of example 63A (0.24 g, 1.0 mmol) was coupled to 1H-indol-5-ylboronic acid (Frontier, 0.241 g, 1.50 mmol) according to the procedure of Example 9B to give the title compound (0.25 g, yield, 79%). ¹H NMR (300 MHz, CD3OD) δ 1.69 - 1.83 (m, 2H), 1.86 - 1.99 (m, 4H), 2.18 2.32 (m, 2H), 3.67 - 3.87 (m, 2H), 4.69 - 4.82 (m, 1H), 6.52 (d, J = 2.37 Hz, 1H), 7.27 (d , J = 3.05 Hz, 1H), 7.45 (dt, J = 8.48, 0.85 Hz, 1H), 7.49 (dd, J = 8.82, 3.05 Hz, 2H), 7.62 (dd, J = 8.48, 1.70 Hz, 2H),

7.76 (d, J = 8.14 Hz, 2H), 8.03 (d, J = 1.36 Hz, 2H), 8.22 (d, J = 2.37 Hz, 1H) ppm; MS (DCI / NH3) m / z

320 (M + H)⁺.

Example 63C Bis (hydrochloride) 5- {5 - [(eqzq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-indole [0206] The product of Example 63B (0, 25 g, 0.79 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) in a mixture of EtOAc / EtOH (10/1 volume, 10 mL). The precipitate was filtered off and dried to obtain the title compound (0.20 g, yield, 64.9%).¹H NMR (300 MHz, CD3OD) δ 1.94 - 2.13 (m, 2H), 2.12 - 2.35 (m, 4H), 2.42 - 2.68 (m, 2H) , 4.09 - 4.37 (m, 2H), 5.05 - 5.28 (m, 1H), 6.67 (d, J = 3.39 Hz, 1H), 7.43 ( d, J = 3.05 Hz, 1H), 7.57 - 7.72 (m, 2H), 8.16 (s, 1H), 8.27 - 8.39 (m, 2H) , 8.52

EP (018 380 B1 (d, J = 2.37 Hz, 1H) ppm; MS (DCI / NH 3) m / z 320 (M + H) +. Anal. Calc. for C._{2 O}H21N3O-2.00 HCl-0.90 H₂O: C, 58.80; H, 6.12; N, 10.29. Found: C, 58.50; H, 5.86; N, 10.08.

Example 64

5- {5 - [(endq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} indolin-2-one [0207] The product of example 59A (119 mg, 0.50 mmol ) was coupled with the product of Example 58A (194 mg, 0.75 mmol) according to the procedure of Example 9B to give the title compound (150 mg, yield, 89.0%). ¹H NMR (300 MHz, DMSO-D6) δ 1.86 - 2.42 (m, 8 H), 3.54 (s, 2 H), 3.89 - 4.06 (m, 2 H), 4 , 83 (t, J = 4.07 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 7.47 (dd, J = 8.82, 3.05 Hz, 1H), 7.78 - 7.94 (m, 3H), 8.32 (d, J = 2.71 Hz, 1H), 10.50 (s, 1H) ppm; MS (DCI / NH3) m / z 336 (M + H)⁺.

Example 65

5- {5 - [(endq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2,3-b] pyridine [0208] The product of example 59A ( 200 mg, 0.80 mmol) was coupled to the product of Example 47A (183 mg, 0.75 mmol) according to the procedure of Example 9B to give the title compound (80 mg, yield, 49.9%).¹H NMR (300 MHz, DMSO-D6) δ 1.89 - 2.16 (m, 4H), 2.17 - 2.40 (m, 4H), 3.78 - 4.26 (m, 2

H), 4.86 (t, J = 4.24 Hz, 1H), 6.51 (dd, J = 3.39, 1.70 Hz, 1H), 7.46 - 7.58 (m , 2H), 7.97 (d, J = 8.82 Hz, 1

H), 8.39 (d, J = 2.71 Hz, 1H), 8.52 (d, J = 2.03 Hz, 1H), 8.88 (d, J = 2.03 Hz, 1H), 11.70 (s, 1H) ppm; MS (DCI / NH3) m / z 321 (M + H)⁺.

Example 66

5- {5 - [(eqzq) -8-azabicyclo [3.2.1] octane-3-yloxy] pyridin-2-yl} -1H-pyrrolo [2,3-b] pyridine [0209] The product of example 63A ( 200 mg, 0.80 mmol) was coupled with the product of Example 47A (183 mg, 0.75 mmol) according to the procedure of Example 9B to give the title compound (120 mg, yield, 74.9%). ¹H NMR (300 MHz, DMSO-D6) δ 1.82 - 2.18 (m, 6H), 2.18 - 2.40 (m, 2H), 3.91 4.30 (m, 2H ), 4.71 - 5.30 (m, 1H), 6.51 (dd, J = 3.39, 1.70 Hz, 1H), 7.47 - 7.55 (m, 1H) , 7.61 (dd, J = 8.82, 3.05 Hz, 1H), 7.94 (d, J = 8.82 Hz, 1H), 8.42 (d, J = 2.71 Hz, 1H), 8.52 (d, J = 2.03 Hz, 1H),

8.88 (d, J = 2.03 Hz, 1H), 11.71 (s, 1H) ppm; MS (DCI / NH3) m / z 321 (M + H)⁺.

Compositions of the Invention [0210] The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in association with a pharmaceutically acceptable carrier. The compositions contain compounds of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. Pharmaceutical compositions may be formulated for oral administration in solid or liquid form, for parenteral injection or rectal administration.

[0211] The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or any

EP 2 018 380 B1 type auxiliary formulation. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic brine; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic miscible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavors and flavors, preservatives and antioxidants. also be present in the composition according to the judgment of a specialist in the field of formulation.

[0212] The pharmaceutical compositions of the present invention may be administered to humans or other mammals orally, rectally, parenterally, intrathecal, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccal or in the form of a mouth or nose spray. The term "parenteral" as used herein refers to modes of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intra-articular injection and infusion.

[0213] Pharmaceutical compositions for parenteral injection contain pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or carrier liquids include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like and mixtures thereof), vegetable oils (such as olive oil) and organic esters for injection such as ethyl oleate or their respective mixtures. The proper fluidity of the composition can be maintained, for example, by the use of a coating such as lecithin, while maintaining the required particle size in the case of dispersions, or by the use of surfactants.

[0214] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and fungicidal agents, for example parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be obtained by the use of absorption retarding agents, for example aluminum monostearate and gelatin.

[0215] In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a drug may depend on its dissolution rate, which in turn may depend on the size of the crystals and the crystal form. Alternatively, dissolving

For example, or by suspending the drug in an oil carrier, the drug may be administered for parenteral administration.

[0216] In addition to the active compounds, suspensions may contain suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite, agar and tragacanth and mixtures thereof.

[0217] If desired and for more efficient distribution, the compounds of the invention may be incorporated into slow-release or target delivery systems, such as polymer matrices, liposomes and microspheres. They can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents into sterile solid compositions that can be dissolved in sterile water or other sterile injectable medium just before use.

[0218] Injectable depot forms are made by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0219] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just before use.

[0220] 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. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally-acceptable diluent or solvent such as a solution in 1,3-butanediol. Acceptable carrier liquids and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile vegetable oils may traditionally be used as a solvent or suspending agent. For this purpose, any mild vegetable oil can be used, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0221] 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 are mixed with at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and salicylic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerin; d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as alcohol

Cetyl and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0222] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0223] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as gastric coatings and other coatings well known in the art of pharmaceutical formulations. They may optionally contain opacifying agents and may also be formulated to release the active ingredient (s) only, or preferably, in a certain part of the gastrointestinal tract in a delayed manner. Examples of materials useful for delayed release of the active agent may include polymeric substances and waxes.

[0224] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of the present invention with suitable non-irritating carriers such as cocoa butter, polyethylene glycol or suppository wax which are solid at room temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity and release the active compound.

[0225] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the pharmaceutical field, such as, for example, water or other solvents, dissolving agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoate benzyl, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oil, peanut, corn, germ, olive oil, castor oil and sesame), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids with sorbitan and mixtures thereof.

[0226] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

[0227] Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays (aerosols), inhalants and patches. The desired compound of the invention is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers that may be needed. Eye formulations, ear drops, eye ointments, powders and solutions are also anticipated to be within the scope of the present invention.

[0228] In addition to the active compound of the present invention, ointments, pastes, creams and gels may contain animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,

EP 2 018 380 B1 polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

[0229] In addition to the active compounds of the present invention, powders and sprays may contain lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorocarbons.

[0230] The compounds of the invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compound of the invention, the present compositions in liposome form may contain stabilizers, preservatives and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together.

[0231] Methods for producing liposomes are known in the art. See, for example, Prescott, ed., Methods in Cell Biology, vol. XIV, Academic Press, New York, NY (1976), p. 33 et seq.

[0232] Dosage forms for topical administration of a compound of the present invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants. Eye formulations, eye ointments, powders and solutions are also anticipated to be within the scope of the present invention. Aqueous liquid compositions are also particularly useful.

[0233] The compounds of the invention may 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 compounds of formula (I) that fall within the scope of sound medical judgment, suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic response and the like, and are commensurate with the rational benefit-risk balance and effective in their intended use.

[0234] The term "pharmaceutically acceptable salts" refers to those salts that are within reasonable medical judgment, suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic response and the like, and are commensurate with rational benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. 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 functional group with the appropriate organic acid.

[0235] Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspargate, benzoate, benzenesulfonate, bisulfate, butyrate, campforate, camphorsulfonate, digluconate, fumarate, glycerophosphate, hemisulfate, heptate fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate

EP 2 018 380 B1 (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, peroxodisulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, phosphate , p-toluenesulfonate and undecanoate.

[0236] Furthermore, basic nitrogen-containing groups can be quaternized using agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenylethyl bromides and others. In this way, products soluble or dispersible in water or oil are obtained.

[0237] Examples of acids that can be used to prepare pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid .

[0238] Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the present invention by reacting the carboxylic acid-containing moiety with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia or an organic primary amine , secondary or tertiary. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like, and non-toxic quaternary ammonia and amine cations, including an ammonium cation, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

[0239] The term "pharmaceutically acceptable ester" as used herein refers to esters of compounds of the present invention that hydrolyze in vivq and subtract those that cleave readily in the human body, releasing the parent compound or a salt thereof. Examples of the pharmaceutically acceptable, non-toxic esters of the present invention include C1-to-C6 alkyl esters and C5-to-C7 cycloalkyl esters, although C1-to-C4 alkyl esters are preferred. Esters of compounds of formula (I) can be prepared according to traditional methods. Pharmaceutically acceptable esters can be attached to hydroxyl groups by reacting a compound that contains a hydroxyl group with an acid and an alkylcarboxylic acid such as acetic acid, or with an acid and arylcarboxylic acid such as benzoic acid. For compounds containing carboxylic acid groups, pharmaceutically acceptable esters are prepared from compounds containing carboxylic acid groups by reacting the compound with a base such as triethylamine and an alkyl halide, alkyl triflate, for example with methyl iodide, benzyl iodide, cyclopentyl iodide. They can also be prepared by reacting the compound with an acid such as hydrochloric acid and an alkylcarboxylic acid such as acetic acid, or with an acid and arylcarboxylic acid such as

Benzoic acid.

[0240] The term "pharmaceutically acceptable amide" as used herein refers to non-toxic amides of the invention obtained from ammonia, primary C1-to-C6 alkyl amines and secondary dial-alkyl amines. In the case of secondary amines, the amines may also be in the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom. Preferred are amides obtained from ammonia, primary C1-to-C3 alkyl amides and secondary dialkyl C1-to-C2 amides. Amides of compounds of formula (I) can be prepared according to traditional methods. Pharmaceutically acceptable amides can be prepared from compounds having primary or secondary amine groups by reacting a compound that contains an amino group 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 reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and alkylamine, dialkylamine, for example with methylamine, diethylamine, piperidine. They can also be prepared by reacting the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with an acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions, such as with the addition of molecular sieves. The composition may contain a compound of the present invention in the form of a pharmaceutically acceptable prodrug.

[0241] The term "pharmaceutically acceptable prodrug" or "prodrug" as used herein means those prodrugs of the compounds of the invention that are within reasonable medical judgment, suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic response and the like, commensurate with the rational benefit-risk balance, and effective for their intended use. Prodrugs of the invention can be rapidly converted in vivq to the parent compound of formula (I), for example by hydrolysis in blood. Detailed discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, volume 14 ACS Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987 ).

[0142] The invention contemplates pharmaceutically acceptable compounds either chemically synthesized or produced by biological conversion in vivq to compounds of formula (I).

Determination of biological activity [0243] To determine the efficacy of representative compounds of the present invention as α7 nAChR, compounds of the invention were evaluated by binding [³H] -DPPB or binding assay [³H] -methyllicaconitin (MLA) (both measure α7 NNR binding) and the binding assay [³H] -cytisine (measurement of α4β2 interactions), which was carried out as described below. Binding [³H] -cytisines [0244] Binding conditions were modified relative to the procedures described in Pabreza LA, Dhawan, S, Kellar KJ, [3H] -Citisine Binding to Nicotinic Cholinergic Receptors in Brain, Mol. Pharm. 39: 9-12

EP 2 018 380 B1

1991. Enriched membrane fractions from cerebellar rat rat (ABS Inc., Wilmington, DE) were slowly thawed at 4 ° C, washed and resuspended in 30 volumes of BSS-Tris buffer (120 mM NaCl / 5 mM KCl / 2 mM CaCl₂/ 2 mM MgCl₂/ 50 mM Tris-Cl, pH 7.4, 4 ° C). Samples containing 100-200 μg protein and 0.75 nM [3H] -cytisine (30 Ci / mmol; Perkin Elmer / NEN Life Science Products, Boston, MA) were incubated in a final volume of 500 μl for 75 minutes at 4 ° C. Seven diluted logarithmic concentrations of each compound were tested in two embodiments. Non-specific binding was determined in the presence of 10 μM (-) - nicotine. Bound radioactivity was separated by vacuum filtration on previously wetted glass fiber filter plates (Millipore, Bedford, MA) using a 96-well filtration device (Packard Instruments, Meriden, CT) followed by rapid washing with 2 ml ice-cold BSS buffer (120 mM NaCl / 5 mM KCl / 2 mM CaCl₂/ 2 mM MgCl₂). To each well, a Packard MicroScint-20® scintillation cocktail (40 μL) was added and radioactivity was determined using a Packard TopCount® instrument. IC50 values ​​were determined using non-linear regression in Microsoft Excel® software. Ki values ​​were calculated from IC50 values ​​using the Cheng-Prusoff equation. where Ki = IC50 / 1 + [Ligand] / KD].

Binding [³H] -Methylolaconacon (MLA) [0245] Binding conditions were similar for those for [3H] -cytisine binding. Enriched membrane fractions of rat cerebellum (ABS Inc., Wilmington, DE) were slowly thawed at 4 ° C, washed and resuspended in 30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl₂, and 50 mM Tris-Cl, pH 7.4, 22^::C). Samples containing 100-200 μg protein, 5 nM [3H] -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 log diluted concentrations of each compound were tested in duplicate. Non specific binding was determined in the presence of 10 μM MLA. Bound radioactivity was separated by suction filtration on glass fiber filter plates previously wetted with 2% BSA using a 96-well filtration device (Packard Instruments, Meriden, CT) followed by rapid washing with 2 ml of ice-cold BSS. To each well, a Packard MicroScint-20® scintillation cocktail (40 μL) was added and the radioactivity determined using a Packard TopCount® instrument. IC50 values ​​were determined using non-linear regression in Microsoft Excel® software. Ki values ​​were calculated from IC50 using the Cheng-Prusoff equation, where Ki = IC50 / 1 + [Ligand] / KD].

Binding [³H] -DPPB [0246] Binding [³H] -DPPB, iodide [³H] - (S, S) -2,2-dimethyl-5- (6-phenyl-pyridazin-3-yl) -5-aza-2-azonia-bicyclo [2.2.1] heptane, for the subtype α7 nAChR was determined using enriched membrane fractions from rat cerebellum or human cortex (ABS Inc., Wilmington, DE). The pellets were thawed at 4 ° C, washed and resuspended using Polytron at setting 7 in 30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2 and 50 mM Tris-Cl, pH 7, 4, 47C). Seven log diluted concentrations of test compounds containing 100-200 μg protein and 0.5 nM [3H] -DPPB (62.8 Ci / mmol; R46V, Abbott Labs) were incubated in a final volume of 500 μl for 75 minutes at 4'C in two copies. Non specific binding was determined in the presence of 10

EP 2 018 380 B1 μΜ methyl lycaconitin. Bound radioactivity was collected on Millipore MultiScreen® FB collection plates pre-soaked in 0.3% PEI, using a Packard cell harvester, washed with 2.5 ml ice-cold buffer and radioactivity determined using a Packard TopCount Microplate beta particle counter. IC50 values ​​were determined using nonlinear regression in Microsaft® Excel or Assay Explorer software. Ki values ​​were calculated from the IC50 using the Cheng-Prusoff equation, where Ki = IC50 / 1 + [Ligand] / KD]. [³H] -DPPB was prepared according to the preparation procedures described below.

iodide production [Methyl-³H] 2,2-dimethyl-5- (6-phenyl-pyridazin-3-yl) -5-aza-2-azonia-bicyclo [2.2.1] heptane [0247] Iodide [methyl-³H] 2,2-dimethyl-5- (6-phenyl-pyridazin-3-yl) -5-aza-2-azonia-bicyclo [2.2.1] heptane; used in the above binding designation [³H] -DPPB was prepared according to the following procedures.

Step 1: Preparation of t-butyl (S, S) -5- (6-phenyl-pyridazin-3-yl) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylate [0248] For suspension ( S, S) -2,5-diazabicyclo [2.2.1] t-butyl heptane-2-carboxylate (3.43 g, 17.3 mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine (3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL), triethylamine (20 mL) was added and the mixture was heated under nitrogen at 100 ° C for 7 days. The dark mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration, washed with toluene (15 mL) and dried under reduced pressure to give the title compound as an off-white solid (3.00 g). The filtrate was concentrated and the residue was purified by silica gel column chromatography, eluting with ethyl acetate to give additional product (0.41 g, total yield 3.41 g, 56%): MS (DCI / NH3) m / z 353 (M + H)⁺.

Step 2: Preparation of (S, S) -2-methyl 5- (6-phenyl-pyridazin-3-yl) -2,5-diaza-bicyclo [2.2.1] heptane [0249] The product obtained in step 1 (3 , 41 g, 9.7 mmol) was dissolved in formic acid (20 ml) and treated with formalin (37% by weight, 1.0 g, 12.3 mmol). The mixture was heated at 100 ° C for 1 h and the brown solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a mixture of CH2Cl2 - CH3OH - NH4OH (95: 5: 1) to give the title compound as an off-white solid (2.50 g, 96%): MS (DCI / NH3) m / z 267 (M + H)⁺.

Step 3: Iodide production [³H] - (S, S) -2,2-dimethyl-5- (6-phenyl-pyridazin-3-yl) -5-aza-2-azoniabicyclo [2.2.1] heptane ([³H] -DPPB) [0250] Iodide [³H] methyl in toluene (250 mCi in 0.1 mL, 85 Ci / mmol, American Radiolabeled Chemicals, Inc.) was combined with a solution of the product obtained in step 2 in dichloromethane (0.788 mg, 2.96 mmol in 0.45 mL) . The vial was capped and the mixture allowed to react overnight at room temperature. Methanol was added and the solvents evaporated to give 42 mCi. The product was dissolved in methanol for purification by HPLC.

EP 2 018 380 B1

Purification using high performance liquid chromatography (HPLC) [0251] About 7 mCi [³H] -DPPB was evaporated to dryness and the residue was dissolved in a total volume of about 4.5 ml of acetonitrile: water: TFA (15: 85: 0.1). Approximately 0.9 ml per injection was applied to a Phenomenex Luna C18 (2) column (5 microns, 250 mm x 4.6 mm ID), using an Agilent HPLC system. [³H] -DPPB was eluted using a gradient of mobile phase flow from 10% B to 20% B over 20 min, where mobile phase A = 0.1% trifluoroacetic acid in water and mobile phase B = 0.1% trifluoroacetic acid in acetonitrile at a flow rate of approximately 1 ml / min. Peak detection and chromatograms were obtained using Agilent with a variable wavelength UV detector set at 275 nm. [3H] -DPPB containing fractions were collected for approximately 14 minutes using an Agilent fraction collector. The fractions were combined and the solvents evaporated under reduced pressure. The residue was dissolved in absolute (200 proof) ethanol (2 mL) to obtain 0.7 mCi.

Step 5: Determination of purity and specific activity [0252] [³H] -DPPB was analyzed using an Agilent 1100 series HPLC system consisting of a four-component pump, an autosampler and a UV detector with a photodiode matrix. The Packard Radiomatic A 500 radioactivity detector was connected to the HPLC system. For radiodetection, a 500 ml flow cell and 3: 1 Ultima-Flo M scintillation cocktail in the HPLC mobile phase were used. Analyzes were performed using a Phenomenex Luna C18 (2) column (5 microns, 250 mm x 4.6 mm ID). The mobile phase consisting of a gradient starts at 10% B and increases to 20% B in 20 minutes, then increases to 90% B in 1 minute and holds at 90% B for 9 minutes, where mobile phase A = 0.1% trifluoroacetic acid in water and mobile phase B = 0.1% trifluoroacetic acid in acetonitrile. The flow rate was set to approximately 1 ml / min, and UV detection was set to 275 nm.

[0253] Radiochemical purity has been found [³H] -DPPB was&gt; 98%. Specific activity was determined to be 62.78 Ci / mmol using mass spectroscopy.

[0254] The compounds of the invention had Ki values ​​from about 1 nanomolar to about 10 micromolar when tested using the [³H] -MLA, many have Ki lower than 1 micromolar. Binding values ​​[³H] -cytisines of the compounds of the invention ranged from about 1 nanomolar to at least 100 micromolar. Optionally, a Ki value as measured using the [³H] -DPPB can be used instead of KiMLA.

[0255] The compounds and compositions of the invention are useful for modulating nAChR activities, and more specifically α7 nAChRs. In particular, the compounds and compositions of the invention can be used to treat and prevent disorders that are modulated by α7 nAChR. Typically, such disorders can be alleviated by selectively modulating α7 nAChR 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 treatment regimen. Furthermore, some compounds of the invention in addition to affinity for α7 nAChR have affinity for α4β2 nAChR, and selective compounds with dual affinity for the two receptor subtypes are also thought to have beneficial effects.

[0256] The compounds of the invention, including but not limited to those specified in the examples, have an affinity for nAChR, and more specifically α7 nAChR. As α7 nAChR ligands, compounds of the invention may be useful for the treatment and prevention of many α7 nAChR-mediated diseases or conditions.

[0257] For example, α7 nAChRs have been shown to play a significant role in enhancing cognitive function, including aspects of learning, memory and attention (Levin, ED, J. Neurobiol. 53: 633-640, 2002). As such, α7 ligands are suitable for the treatment of cognitive disorders including, for example, attention disorder syndrome, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS-related dementia, disease Pick, dementia associated with Lewy bodies and dementia associated with Down syndrome, as well as cognitive impairment associated with schizophrenia.

[0258] In addition, α7-containing nAChRs have been shown to be involved in the neuroprotective effects of nicotine, both in vitro (Jonnala, RB and Buccafusco, JJ, J. Neurosci. Res. 66: 565-572,2001) and in vivo (Shimohama, S. et al., Brain Res. 779: 359-363, 1998). More specifically, 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 reduced CNS function resulting from traumatic brain injury. For example, the attenuated action of α7 nAChR by β-amyloid proteins associated with Alzheimer's disease can be considered a key factor in the development of disease-related cognitive defects (Liu, Q.-S., Kawai, H., Berg, DK, PNAS 98: 4734-4739, 2001). Activation of α7 nAChR has been demonstrated to block this neurotoxicity (Kihara, T. et al., J. Biol. Chem. 276: 13541-13546, 2001). As such, selective ligands that increase α7 activity can counteract deficits due to Alzheimer's disease and other neurodegenerative diseases.

[0259] Schizophrenia is a complex disease that is characterized by abnormalities in perception, comprehension, and feelings. Significant evidence indicates the involvement of α7 nAChR in this disease, including measured deficiency of these receptors in patients after death (Leonard, S. Eur. J. Pharmacol. 393: 237-242, 2000). Deficiencies in sensory processing (gating) are one of the characteristic features of schizophrenia. These deficiencies can be normalized using nicotinic ligands that act at α7 nAChR (Adler LE et al., Schizophrenia Bull. 24: 189-202, 1998; Stevens, KE et al., Psychopharmacology 1.36: 320-327, 1998). Thus, α7 ligands have the potential to treat schizophrenia.

[0260] Angiogenesis, a process associated with the growth of new blood vessels, is important in beneficial systemic effects such as wound healing, vascularization of skin grafts, and improved circulation, for example, increased circulation around vascular occlusion. Non-selective nAChR agonists such as nicotine have been found to stimulate angiogen (Heeschen, C. et al., Nature Medicine 7: 833-839, 2001). Improved angiogenesis has been found to involve activation of α7 nAChR (Heeschen, C. et al., J. Clin. Invest., 110: 527-536, 2002). Thus, nAChR ligands that are selective for the α7 subtype offer improved potential for stimulating angiogenesis with an improved side effect profile.

[0261] The α7 nAChR population in the spinal cord modulates serotonergic transmission, which

EP 2 018 380 B1 is associated with pain-relieving effects of nicotine compounds (Cordero-Erausquin, M. and Changeux, J.-P. PNAS 98: 280.3-2807, 2001). Α7 nAChR ligands have therapeutic potential to treat pain conditions including acute pain, postoperative pain as well as chronic pain conditions including inflammatory pain and neuropathic pain. In addition, α7 nAChRs are expressed on the surface of primary macrophages that are involved in the inflammatory response, and this activation of the α7 receptor inhibits the release of TNF and other cytokines that elicit an inflammatory response (Wang, H. et al., Nature 421: 384388, 2003). Thus, selective α7 ligands have the potential to treat conditions including TNF-mediated diseases, for example, rheumatoid arthritis, Crohn's disease, ulcerative colitis, enteritis, organ rejection after transplantation, acute organ transplant related immune disease, chronic immune related disease with organ transplant, septic shock, toxic shock syndrome, sepsis syndrome, depression and ankylosing spondylitis.

[0262] The acrosomal reaction of a mammalian sperm is an exocytosis process important for fertilization of the egg by the sperm. Activation of α7 nAChR in the sperm cell has been found to be important for the acrosomal reaction (Son, J.-H. and Meizel, S. Biol. Reproduct. 68: 1348-1353 2003). Consequently, selective α7 agents are useful in the treatment of fertility disorders.

[0263] The compounds of the invention are particularly useful in the treatment and prevention of cognition, neurodegenerative and schizophrenia condition or disorder.

[0264] Cognitive impairment associated with schizophrenia often limits patients' ability to function properly, a symptom inadequately treated with commonly available therapies, for example, atypical antipsychotic treatment. (Rowley, M. et al., J. Med. Chem. 44: 477-501, 2001). Such cognitive deficiency is associated with dysfunction of the nicotinic cholinergic system, in particular with reduced activity of α7 receptors. (Friedman, JI et al., Biol Psychiatry, 51: 349-357, 2002). Thus, α7 receptor activators may provide useful treatment for enhancing cognitive function in schizophrenic patients who are treated with atypical antipsychotics. Accordingly, the combination of α7 nAChR ligand and atypical antipsychotics may offer improved therapeutic utility. Specific examples of suitable atypical antipsychotics include, but are not limited to, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, zotepine, iloperidone and the like.

[0265] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of active compound (s) that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration. The dosage level chosen will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and medical history of the patient being treated. However, it is known in the art to start with lower doses of the compound than required to obtain a therapeutic effect and gradually increase the dose to obtain the desired effect.

[0266] When used in the above or other therapies, a pharmaceutically effective amount of one of the compounds of the present invention can be used in pure form or, where such forms exist, in the form of a pharmaceutically acceptable salt, ester, amide or prodrug.

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Optionally, the compound may be administered in the form of a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers. The expression "therapeutically effective amount" of a compound of the invention means a sufficient amount of the compound for treating disorders, suitable for use at a reasonable benefit-risk ratio in any medical treatment. It should be understood, however, that the total daily use of the compounds and compositions of the invention will depend on the decision of the attending physician regarding 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; activity of the specific compound employed; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; drugs used in combination or concurrently with the specific compound employed; and similar factors known in the medical field. For example, it is well known in the art that it is good to start with lower doses of the compound than required to obtain a therapeutic effect and gradually increase the dose to obtain the desired effect.

[0267] The total daily dose of the compounds of the present invention administered to a human or lower animal ranges from about 0.010 mg / kg body weight to about 1 g / kg body weight. More preferably, the dose may range from about 0.010 mg / kg body weight to about 100 mg / kg body weight. If desired, the effective daily dose can be divided into several doses for administration purposes. As a result, a single dose of the composition may contain such amounts or aliquot thereof adding up to the daily dose.

[0268] The compounds of the invention are α7 nAChR ligands that modulate the action of α7 nAChR by altering receptor activity or signal transduction. The compounds may be inverse agonists that inhibit the basic activity of the receptor or antagonists that completely block the action of the receptor-activating agonist. The compounds may also be partial agonists that partially block or partially activate the α7 nAChR receptor or agonists that activate the receptor. Binding to the α7 receptor also triggers signaling processes involving various kinases and phosphatases, and protein-protein interactions that are important for memory effects, cell protective effects, gene transcription and disease modification. Thus, administering a therapeutically effective amount of a compound of formula (I) to a mammal provides a method of selectively modulating the effects of nicotinic α4β2, α7 or both α4β2 and α7 nicotinic receptors.

[0269] In addition, administering a therapeutically effective amount of a compound of formula (1) to a mammal provides a method of treating or preventing a condition or disorder selected from the group consisting of attention disorders, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild impairment of function cognitive, senile dementia, AIDS-related dementia, Pick's disease, Lewy-related dementia, Down's syndrome dementia, amyotrophic lateral sclerosis, Huntington's disease, reduced CNS effects associated with traumatic brain injury, acute pain, postoperative pain, chronic pain, inflammatory pain, neuropathic pain, infertility, need for new blood vessels associated with wound healing, need for new blood vessels associated with skin graft vascularization and

Lack of circulation, more specifically circulation around vascular occlusion, rheumatoid arthritis, Lesniowski and Crohn's disease, ulcerative colitis, enteritis, organ rejection after transplantation, acute organ transplant related immune disease, chronic organ transplant related immune disease , septic shock, toxic shock syndrome, sepsis syndrome, depression and ankylosing spondylitis. More preferably, administering a therapeutically effective amount of a compound of formula (I) to a mammal provides a method of treating cognitive, neurodegenerative and schizophrenia. In addition, the compounds of formula (I) may also be administered in combination with atypical antipsychotics.

[0270] It should be understood that the above detailed description and accompanying examples are for illustrative purposes only and should not be construed as limiting the scope of the invention, which is defined only by the appended claims and their equivalents. The person skilled in the art will appreciate various changes and modifications to the disclosed embodiments. Such changes and modifications, including without limitation those associated with chemical structures, substituents, derivatives, intermediates, syntheses, formulations or methods of using the invention, may be made without departing from the scope of the claims.

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