Indazole, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof

53147 Β

DESCRIPTION OF THE INVENTION

This application refers to US Provisional Application Serial No. 60 / 413,151, filed September 25, 2002, and U.S. Provisional Application Serial no. 60 / 448,469, filed February 21, 2003, the entire disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to a field of nicotine acetylcholine receptor (nAChR) ligands, activation of nAChRs, and treatment of disease states associated with defective or nicotinic acetylcholine receptors that do not function, particularly the brain. Furthermore, the present invention relates to novel compounds, which act as ligands for the α7 nAChR subtype, methods for preparing such compounds, compositions containing such compounds, and methods for their use.

BACKGROUND OF THE INVENTION

There are two types of neurotransmitter receptors, acetylcholine: muscarinic receptors and nicotinic receptors, which are based on the selectivity of the action of muscarinic and nicotine, each separately. Muscarinic receptors are G-protein

53147 Β paired receptors. Nicotinic receptors are members of the ligand-bridged ion channel family. When ion conduction is activated across nicotine ion channels it increases.

Nicotinic alpha-7 receptor protein forms a homo-pentamer channel in vitro that is highly permeable to various cations (e.g., Ca⁺⁺). Each nicotinic alpha-7 receptor has four transmembrane domains, named M1, M2, MZ, and M4. The M2 domain is suggested to form a channel wall lining. Sequence alignment shows that nicotinic alpha-7 is extremely conserved during evolution. The M2 domain lining the channel is identical in protein sequence from chicken to human. For consideration of alpha-7 receptors, see, e.g., Revah et al. (1991), Nature, 353, 846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000), PNAS 97 (7), 3543-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J. Pharmacol. 290 (3), 237-246.

The nicotinic alpha-7 receptor channel is expressed in different regions of the brain and is believed to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Nicotinic alpha-7 receptors are located at both presynaptic and postsynaptic terminals and have been suggested to be involved in modulating synaptic transmission. Therefore, it is of interest to develop new compounds, which act as ligands for the α.7 nAChR subtype, for the treatment of disease states associated with defective or nicotinic acetylcholine receptors that do not function.

z

53147 Β

ESSENCE OF THE INVENTION

The present invention relates to novel compounds, which act as ligands for the α7 nAChR subtype, processes for the preparation of such compounds, compositions containing such compounds, and methods for their use.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of Formula I, II, III, or IV:

<img file="RS53147B_D0001.tif" />

IZ '

53147 Β

<img file="RS53147B_D0002.tif" />

X is O or S;

R¹ is H, F, Cl, Br, J, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het;

R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms;

R³ is H, F, Cl, Br, J, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃,

53147 Β

OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het;

R⁴ is H, F, Cl, Vg, J, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het;

R⁵ is H, F, Cl, Br, J, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (p.rg., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyakoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het;

53147 Β

Ar is an aryl group containing 6 to 10 carbon atoms which are unsubstituted or substituted once more times with alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br, or J, preferably F or Cl), dialkylamino wherein the alkyl moieties each have 1 to 8 carbon atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms. up to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulfinyl having 1 to 8 C atoms, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms 8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 C atoms and is optionally substituted, aryloxy wherein the aryl moiety contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted, arylthio at wherein the aryl moiety contains 6 to 10 carbon atoms (e.g. phenyl, naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 C atoms and is optionally substituted, sulfo, sulfonylamino, acylamido (e.g. acetamido), acyloxy (e.g. acetoxy) or a combination thereof; i

Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least one atom in the ring is an N, O or S atom, which is unsubstituted or substituted one or more times with halogen (F, Cl, Br, or J, preferably F or Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and optionally substituted, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 C

53147 Β atoms, dialkylamino wherein each alkyl group has 1 to 8 C atoms, or a combination thereof; and pharmaceutically acceptable salts thereof.

In Formula I, when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound via its 4 or 7 position. When A is a benzoisothiazolyl group of subformula (c), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position.

Similarly, in Formula II, when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound via its 4 or 7 position. When A is a benzoisothiazolyl group of subformula (c), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position.

Also, in Formula III, when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound via its 4 or 7 position. When A is a benzoisothiazolyl group of subformula (c), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position.

Further, in Formula IV, when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A

53147 The benzothiazolyl group of subformula (b) is presumably attached to the remainder of the compound via its 4 or 7 position. When A is a benzoisothiazolyl group of subformula (c), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position.

The present invention includes compounds of Formula G, 11 ', III' or IV:

<img file="RS53147B_D0003.tif" />

53147 Β

R¹ is H, F, Cl, Br, J, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ag or Het;

R² is alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms:

R³ is H, F, Cl, Br, J, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group independently has 1 to 4 carbon atoms, Ar or Het;

Ar is an aryl group containing 6 to 10 carbon atoms which are unsubstituted or substituted one or more times by alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br, or

53147 Β

J, preferably F or Cl), dialkylamino wherein the alkyl moieties each have 1 to 8 C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulfinyl having 1 to 8 C atoms, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 C atoms and is optionally substituted, aryloxy wherein the aryl moiety contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted, arylthio wherein the aryl moiety contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 C atoms and is optionally substituted, sulfo / sulfonylamino, acylamido (e.g., acetamido) , acyloxy (e.g. acetoxy) or a combination thereof; i

Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least one atom in the ring is an N, O or S atom, which is unsubstituted or substituted one or more times with halogen (F, Cl, Br, or J, preferably F or Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and optionally substituted, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each alkyl group has 1 to 8 C atoms, or a combination thereof; and pharmaceutically acceptable salts thereof.

53147 Β

In Formula Γ, when Α is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound at its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound via its 4 or 7 position.

Similarly, in Formula I, when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound via its 4 or 7 position.

Also, in Formula I, when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound via its 4 or 7 position.

Further, in Formula IV ', when A is an indazolyl group of subformula (a), it is presumably attached to the remainder of the compound via its 3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b), it is presumably attached to the remainder of the compound at its 4 or 7 position.

In Formulas 1-IV and 1'-IV ', indazolyl, benzothiazolyl and benzoisothiazolyl groups A can be attached to the rest of the structure via any suitable attachment point. The following subformulas illustrate some of the putative suspensions between the indazole and benzothiazole groups and the rest of the structure.

(la) (Ib) (lc)

53147 Β

<img file="RS53147B_D0004.tif" />

53147 Β

<img file="RS53147B_D0005.tif" />

53147 Β

The following subformulas further illustrate some of the putative suspensions between the indazolyl, benzothiazolyl and benzoisothiazolyl groups and the rest of the structure.

<img file="RS53147B_D0006.tif" />

53147 Β

<img file="RS53147B_D0007.tif" />

53147 Β

The following subformulas further illustrate some of the putative suspensions between the indazolyl, benzothiazolyl and benzoisothiazolyl groups and the rest of the structure.

<img file="RS53147B_D0008.tif" />

53147 Β

<img file="RS53147B_D0009.tif" />

(Hln)

<img file="RS53147B_D0010.tif" />

<img file="RS53147B_D0011.tif" />

(lll'a) (lll'b) (lll'c)

<img file="RS53147B_D0012.tif" />

<img file="RS53147B_D0013.tif" />

<img file="RS53147B_D0014.tif" />

<img file="RS53147B_D0015.tif" />

53147 Β

The following subformulas further illustrate some of the putative suspensions between the indazolyl, benzothiazolyl and benzoisothiazolyl groups and the rest of the structure.

<img file="RS53147B_D0016.tif" />

(IVa) (lVb) (IVc)

<img file="RS53147B_D0017.tif" />

<img file="RS53147B_D0018.tif" />

(IVf) &lt;^IV9)

<img file="RS53147B_D0019.tif" />

H (IVh) (ivi)

53147 Β

<img file="RS53147B_D0020.tif" />

53147 Β

<img file="RS53147B_D0021.tif" />

<img file="RS53147B_D0022.tif" />

In a more preferred embodiment, the following subformulas illustrate some of the more preferred moieties between the indazolyl, benzothiazolyl and benzoisothiazolyl groups and the rest of the structures of Formula I and G.

<img file="RS53147B_D0023.tif" />

<img file="RS53147B_D0024.tif" />

<img file="RS53147B_D0025.tif" />

53147 Β

<img file="RS53147B_D0026.tif" />

<img file="RS53147B_D0027.tif" />

<img file="RS53147B_D0028.tif" />

<img file="RS53147B_D0029.tif" />

<img file="RS53147B_D0030.tif" />

<img file="RS53147B_D0031.tif" />

53147 Β

According to an aspect of the method of the invention, there is provided a method of treating a patient (e.g., a mammal such as a human) suffering from a disease state (e.g., memory impairment) comprising administering to the patient a compound according to Formulas 1- IV and l'-IV '. Presumably, the disease state involves decreased activity of the nicotinic acetylcholine receptor.

According to an aspect of the method of the invention, there is provided a method of treating or prophylaxis of a disease or condition resulting from dysfunction of nicotinic acetylcholine receptor transmission in a mammal, e.g. human, which consists of administering an effective amount of a compound according to Formulas 1-IV or GIV '.

According to an aspect of the method of the invention, there is provided a method of treating or prophylaxis of a disease or condition resulting from defective or nicotinic acetylcholine receptors that do not function, in particular aJnACh receptors, in mammals, e.g. human, which consists of administering an effective amount of a compound according to Formulas l-IV or l'-IV '.

According to an aspect of the method of the invention, there is provided a method of treating or prophylaxis of a disease or condition resulting from suppressed transmission of the nicotinic acetylcholine receptor in a mammal, e.g. human, comprising administering an amount of a compound according to Formulas 1-IV or G-IV 'effective to activate cc7nACh receptors.

According to another aspect of the method of the invention, there is provided a method of treating or preventing a psychotic disorder, cognitive impairment (e.g., memory impairment), or a neurodegenerative disease.

53147 Β in mammals, e.g. human, which consists of administering an effective amount of a compound according to Formulas l-IV or l'-IV '.

According to another aspect of the method of the invention there is provided a method of treating or prophylaxis of a disease or condition resulting from the loss of cholinergic synapses in a mammal, e.g. human, which consists of administering an effective amount of a compound according to Formulas l-IV or l'-IV '.

According to another aspect of the method of the invention there is provided a method of treating or prophylaxis of a neurodegenerative disorder by activating α7nACh receptors in a mammal, e.g. human, which consists of administering an effective amount of a compound according to Formulas l-IV or l'-IV '.

According to another aspect of the method of the invention, there is provided a method of protecting neurons in a mammal, e.g. human, due to neurotoxicity induced by activation of the α7nACh receptor consisting of the administration of an effective amount of a compound according to Formulas 1-IV or 1'-IV '.

According to another aspect of the method of the invention there is provided a method of treating or prophylaxis of a neurodegenerative disorder by inhibiting the binding of Αβ peptides to cc7nACh receptors in mammals, e.g. human, which consists of administering an effective amount of a compound according to Formulas l-IV or l'-IV '.

According to another aspect of the method of the invention, there is provided a method of protecting neurons in a mammal, e.g. human, due to neurotoxicity induced by Aβ peptides consisting of administering an effective amount of a compound according to Formulas 1-IV or 1'-IV '.

53147 Β

According to another aspect of the method of the invention there is provided a method of reducing the inhibition of β-peptide-induced cholinergic function in a mammal, e.g. human, which consists of administering an effective amount of a compound according to Formulas l-IV or l'-IV '.

The compounds of the present invention are nicotinic alpha-7 ligands, preferably agonists, in particular partial agonists, for the alpha-7 nicotinic acetylcholine receptor. Experiments to determine the activity of nicotinic acetylcholine are known in science. See, e.g., Davies, AR, et al., Characterization of the binding of [3H] methyllycaconitine: a new radioligand for labeling alpha 7-type neuronal nicotinic acetylcholine receptors. Neuropharmacology, 1999, 38 (5): p. 679900. As agonists for cc-7 nAChRs, the compounds are useful in the prophylaxis and treatment of various diseases and conditions associated with the central nervous system. Nicotinic acetylcholine receptors are ligand-gastrol ion-channel receptors composed of five protein subunits that form a central ion-guided pore. Currently, there are eleven known neural nAChR subunits (a2- a9 and β2- β4). There are also five further subunits expressed in the peripheral nervous system (cd, β1, γ, b, ε).

Subtypes of nAChR receptors can be homopentameric or heteropentameric. The subtype that has received significant attention is the homopentameric α7 receptor subtype formed of five α7 subunits. cc7nAChRs show high affinity for nicotine (agonist) and for α-bungarotoxin (antagonist). Studies show that α7nAChR agonists may be useful in the treatment of psychotic illnesses, neurodegenerative illnesses, and cognitive impairments, among others. While nicotine is a known agonist, there is a need to develop other α7-nAChRs

53147 Β agonists, especially selective agonists, which are less toxic and show fewer side effects than nicotine.

The compound anabasein, i.e., 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine is a naturally occurring toxin in certain marine worms (nemertin worms) and ants. See, e.g., Kem et al., Toxicon, 9:23, 1971. Anabasein is a potent activator of mammalian nicotinic receptors. See, e.g., Kem, Amer. Zoologist, 25, 99, 1985. Certain anabasein analogs such as anabasine and DMAB (3- [4- (dimethylamino) benzylidene] -3,4,5,6-tetrahydro-2 ', 3'-bipyridine) are also known as nicotine receptor agonists. See, e.g., U.S. Pat. No. 5,602,527 and WO 92-15306. One particular anabasein analog, [E-3- [2,4-dimethoxybenzylidene] -anabasein, also known as GTS-21 and DMXB (see, e.g., U.S. Pat. No. 5,741,802), is a selective partial α7-nAChR agonist that For example, abnormal sensory inhibition is a sensory process deficit in schizophrenics and GTS-21 has been found to increase sensory inhibition through interaction with α7-nAChRs. See, e.g., Stevens et al., Psychopharmacology, 136: 320-27 (1998).

Another compound known to be a selective cz7-nAChR agonist is Tropisetron, i.e., 1aH, 5aH-tropan-3-yl indole-3-carboxylate. See JE Macor et al., The 5-HT3-Antaqonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist, Bioorg. Med. Chem. Lett. 2001, 319-321).

Alkyl throughout the text means a chain in the normal sequence or a branched chain of an aliphatic hydrocarbon radical having presumably 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

53147 Β

Alkoxy means alkyl-O- groups in which the alkyl moiety presumably has 1 to 4 carbon atoms. Suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.

Alkylthio means alkyl-S- groups in which the alkyl moiety presumably has 1 to 4 carbon atoms. Suitable alkylthio groups include methylthio and ethylthio.

Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable cycloalkyl groups include spiropentyl, bicyclo [2.1. OJpentyl, and bicyclo [3.1. Ojhexyl.

Cycloalkoxy means cycloalkyl-O- groups in which the cycloalkyl moiety is preferably a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms.

Cycloalkylalkyl groups contain 4 to 7 carbon atoms, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, and cyclopentylmethyl.

Cycloalkylalkoxy groups contain 4 to 7 carbon atoms, for example, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, and cyclopentylmethyloxy.

Cycloalkyl and cycloalkylalkyl groups may be substituted with C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and / or dialkylamino in which each alkyl group has 1 to 4 carbon atoms.

53147 Β

Arii, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical having 6 to 10 carbon atoms, unless otherwise indicated. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the aryl groups described above which are substituted one or more times with halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethyleneedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarkoxy alkylsulfinyl, alkylsulfonyl, phenoxy, and acyloxy (p.r.g., acetoxy).

Heterocyclic groups refer to saturated, partially saturated or fully unsaturated heterocyclic groups having one, two or three rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O or S atom. Preferably, the heterocyclic group contains 1 to 3 ring hetero atoms selected from N, O and S. Suitable saturated and partially saturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, isoxazolinyl, and the like. Suitable heteroaryl groups include, but are not limited to, furyl, thienyzol, pyrrolidinyl, pyrrolidine , indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like. Other examples of suitable heterocyclic groups are 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benofuranyl, 4-indoyl, 4-pyridyl, 3- quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl, 3,4-1,2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3- pyridyl, 6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3pyrazolyl, and 3-carbazolyl.

Substituted heterocyclic groups refer to the heterocyclic groups described above, which are substituted at one or more sites with, on,

53147 Β example, halogen, aryl, alkyl ,. Alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.

Radicals which are substituted one or more times presumably have 1 to 3 substituents, in particular 1 or 2 substituents of exemplary substituents. Halogenated radicals such as halogenated alkyls are presumably fluorinated and include perhalo radicals such as trifluoromethyl.

In compounds of Formula I-IV and I-IV, R¹ is preferably H, F, Cl, Br, methyl, methoxy, or amino, R²is preferably H or methyl, and R³ is preferably H, F, Cl, Br, methyl, methoxy, or amino.

Also, in the compounds of Formula l-IV and l'-IV ', R¹ it is assumed H, F, Cl, Vg,

2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl, R² preferably H, methyl 2-thiophenyl, 3thiophenyl, 3-furyl, or phenyl, and R³ it is assumed H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl,

3- furyl, or phenyl.

Also, in the compounds of Formula l-IV, R⁴ preferably H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, phenyl, iii methoxy.

Also, in the compounds of Formula l-IV, R⁵ is assumed X.

According to an aspect of a compound of the invention, the compound of formulas i-IV is selected from:

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide, N- (1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole- 3-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide hydrochloride,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride,

1-Methyl-1H-indazole-3-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl, (R) 1-Methyl-1H-indazole-3-carboxamide, N-1 -aza-bicyclo [2.2.2loct-3-yl, (S) 1-Methyl-1H-indazole-3-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (methoxy) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (cyclopropyl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

53147 Β

N- (1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (methoxy) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (cyclopropyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide,

N ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) benzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5-methoxybenzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (phenyl) -1H-indazole-3-carboxamide hydroformate,

53147 Β

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6-cyclopropylbenzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6 - (morpholin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide,

53147 Β

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) benzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (bromo) -1H-indazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-cyclopropylbenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

Ν - ((3Ή) -1-Αζ3ΝοίΜο [2.2.2] οΚί-3-ίΙ) -6- (3-ίΙυοΐΌίθηίΙ ^ θηζο [51] ίζο1ί3ΖθΙ-3carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (morpholin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (bromo) -1H-indazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-cyclopropylbenzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

53147 Β

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (morpholin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (bromo) -1H-indazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide,

53147 Β

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine,

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-4-carboxamide dihydrochloride,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-4-carboxamide dihydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-4-carboxamide dihydrochloride,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide,

N - ((3A^,-1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide,

N-CPS-N-Azabicycloxy-N-N-N-IH-indazole-N-carboxamide,

N- (1H-indazol-4-yl-1-azabicyclo [2,2,2] oct-3-ylcarboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-4-ylmethyl) amine,

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide hydrochloride,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-5-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-5-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-5-carboxamide,

N- (1H-indazol-5-yl) -1-aza-bicyclo [2.2.2] oct-3-ylcarboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -2-pyrrol-1-ylbenzothiazole-6-carboxamide hydroformate,

N- (Benzothiazol-6-yl) -N-1-Azabicyclo [2.2.2] oct-3-ylcarboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-6-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-6-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-6-carboxamide,

N - ((3P) -1-Azabicyclo [2.2.2] oct-3-yl) -3- (thiophen-3-yl) -1H-indazole-6-carboxamide hydroformate,

N- (1H-indazol-6-yl) -1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride,

N- (1-Aza bicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride,

Benzothiazole-4-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl, (R) Benzothiazole-4-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl , (S) Benzothiazole-4-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl,

-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-3-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazole -3-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-3-yl,

53147 Β

-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, Ν-1H-indazol-4-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazole -4-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-4-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-5-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H -indazol-5-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-5-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-6-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazole -6-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-6-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-7-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1 H-indazol-7-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-7-yl,

-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-4-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-4-yl, (R) 1 -Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-4-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-5-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-5-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-5-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-6-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-6-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-6-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-7-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-7-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-7-yl, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-3-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-3-ylmethyl) -amine,

53147 Β (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-3-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) ) - (1H-indazol-4-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-4-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-4-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1 H-indazol-5-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-5-ylmethyl) -amine, (R) (1- Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-5-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-6-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-6-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-6-ylmethyl) -amine, (1-Aza -bicyclo [2.2.2] oct-3-yl) - (1H-indazol-7-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H) -indazol-7-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-7-ylmethyl) -amine, (1-Aza-bicyclo [ 2.2.2] oct-3-yl) - (benzothiazol-4-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-4-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) ) - (Benzothiazol-4-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (Benzothiazol-5-ylmethyl) -amine, (S) (1-Aza-bicyclo [ 2.2.2] oct-3-yl) - (benzothiazol-5-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-5-ylmethyl) - amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-6-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (Benzothiazol-6-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-6-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - ( Benzothiazol-7-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-7-ylmethyl) -amine, (R) (1-Aza-bicyclo [ 2.2.2] oct-3-yl) - (benzothiazol-7-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-3-yl) -amine ,,

53147 Β (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-3-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct- 3-ylmethyl) - (1H-indazol-3-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-4-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-4-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-4-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-5-yl) -amine, (S) (1- Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-5-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-5-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-6-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-6-yl) -amine, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-6-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H- indazol-7-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-7-yl) -amine, (R) (1-Aza) -bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-7-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-4-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - ( Benzothiazol-4-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-4-yl) -amine, (1-Aza-bicyclo [2.2.2 ] oct-3-ylmethyl) - (benzothiazol-5-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-5-yl) -amine, ( R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-5-yl) -amine, ('1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - ( benzothiazol-6-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-6-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) ) - (Benzothiazol-6-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-7-yl) -amine, (S) (1-Aza-bicyclo [ 2.2.2] oct-3-ylmethyl) - (benzothiazol-7-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-7-yl) - amin,

53147 Β and their physiological salts.

According to another aspect of a compound of the invention, the compound of formula IIV is selected from:

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide hydrochloride,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide,

N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride,

1-Methyl-1H-indazole-3-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl, (R) 1-Methyl-1H-indazole-3-carboxamide, N-1- aza-bicyclo [2.2.2] oct-3-yl, (S) 1-Methyl-1H-indazole-3-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (methoxy) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (cyclopropyl) -1H-indazole-3-carboxamide hydroformate,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) benzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5-methoxybenzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-cyclopropylbenzo [d] isothiazole-3-carboxamide,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (morpholin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (bromo) -1H-indazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-cyclopropylbenzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate,

53147 Β

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (morpholin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) benzo [d] isothiazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) benzo [d] isothiazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (bromo) -1H-indazole-3-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole-3-carboxarnide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole-3-carboxamide hydroformate,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide,

53147 Β

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-4-carboxamide dihydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-4-carboxamide dihydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide,

N- (1H-indazol-4-yl) -1-azabicyclo [2,2,2] oct-3-ylcarboxamide,

N- (1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-4-ylmethyl) amine,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide,

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide,

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride,

Benzothiazole-4-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl, (R) Benzothiazole-4-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl , (S) Benzothiazole-4-carboxamide, N-1-aza-bicyclo [2.2.2] oct-3-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-3-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H- indazol-3-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-3-yl, (S) 1-Aza-bicyclo [2.2.2] oct- 3-ylcarboxamide, N-1H-indazol-4-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-4-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-7-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H- indazol-7-yl,

53147 Β (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, N-1H-indazol-7-yl,

1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-4-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-4-yl, (R) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-4-yl,

-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-7-yl, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-7-yl, (R) 1 -Aza-bicyclo [2.2.2] oct-3-ylcarboxamide, benzothiazol-7-yl, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-3- ylmethyl) -amine, (R) (i-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-3-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2. 2] oct-3-yl) - (1H-indazol-4-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-4-ylmethyl) ) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-5-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-5-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-5-ylmethyl) -amine, (1-Aza -bicyclo [2.2.2] oct-3-yl) - (1H-indazol-6-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1 H) -indazol-6-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-6-ylmethyl) -amine, (1-Aza-bicyclo [ 2.2.2] oct-3-yl) - (1H-indazol-7-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (1H-indazol-7-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3) -yl) - (1H-indazol-7-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-4-ylmethyl) -amine, (S) (1- Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-4-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-4) -ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-5-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct- 3-yl) - (benzothiazol-5-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-5-ylmethyl) -amine,

53147 Β (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-6-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (Benzothiazol-6-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-6-ylmethyl) -amine, (1-Aza-bicyclo [2.2. 2] oct-3-yl) - (benzothiazol-7-ylmethyl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-7-ylmethyl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-yl) - (benzothiazol-7-ylmethyl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - ( 1H-indazol-3-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-3-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3 -ylmethyl) - (1H-indazol-3-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-4-yl) -amine, (S) 1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-4-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-4-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-5-yl) -amine, (S) (1-Aza- bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-5-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-5-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-6-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-6-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-6-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H -indazol-7-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-7-yl) -amine, (R) (1-Aza) -bicyclo [2.2.2] oct-3-ylmethyl) - (1H-indazol-7-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-4-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - ( Benzothiazol-4-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-4-yl) -amine, (1-Aza-bicyclo [2.2.2 ] oct-3-ylmethyl) - (benzothiazol-5-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-5-yl) -amine,

53147 Β (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-5-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (Benzothiazol-6-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-6-yl) -amine, (R) (1-Aza-bicyclo) [2.2.2] oct-3-ylmethyl) - (benzothiazol-6-yl) -amine, (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-7-yl) -amine, (S) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) - (benzothiazol-7-yl) -amine, (R) (1-Aza-bicyclo [2.2.2] oct-3-ylmethyl) ) - (Benzothiazol-7-yl) -amine, and their physiological salts.

Preferred aspects include a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier and, optionally, the following active agent as discussed below; a method of stimulating or activating inhibiting alpha-7 nicotinic receptors, e.g., as determined by conventional assay or that described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in mammal or human); a method of treating a neurological syndrome, e.g., memory loss, especially long-term memory, cognitive impairment or impairment, memory impairment, etc., a method of treating a disease state modulated by nicotine alpha-7 activity, in a mammal, e.g., a human, p .rg., those mentioned here.

The compounds of the present invention may be prepared conventionally. Some of the known methods that can be used are described below. All starting materials are known or can be conventionally prepared and known starting materials.

Acids that can be used in the preparation of quinuclidine amides are commercially available, can be prepared by known methods that are

53147 Β described in the literature, or in the manner described below. For example, indazolecarboxylic acids can be prepared from bromo-2-methylaniline by diazotization followed by metal-halogen exchange and capture with CO₂, to give the corresponding indazole carboxylic acid (See, e.g., DeLucca, GV Substituted 2H-1,3-Diazapin-2-one Useful as an HIV Protease Inhibitor, US 6,313,110 B1, November 6, 2001; and Sun , JH; Teleha, CA; Yan, JS; Rodgers, JD; Nugiel, DA Efficient Synthesis of 5 (Bromomethyl) - and 5- (Aminomethyl) -1-THP-indazole J. Org. Chem. 1997, 62, 5627 -5629). 4-Benzothiazolecarboxylic acid can be prepared from 2 amino-4-chloro-benzothiazoles by reaction with isoamyl nitrite followed by metal halogen exchange and capture with CO₂. 5-Benzothiazolecarboxylic acid may be from 4-chloro-3-nitrobenzoic acid by reaction with Na₂S and NaOH followed by reduction with Zn in formic acid. 3-Aminoquinuclidine and its R- and

S-enantiomers are commercially available. Quinuclidine amide can be prepared by reacting acids with 3-aminoquinuclidine and HBTU or HOBt and EDCI in DMF, or converting acids to the corresponding acid chlorides and then reacting with 3-aminoquinuclidine (Macor, JE; Gurley, D .; Lanthorn, T .; Loch, J., Mack, RA, Mullen, G., Tran, O., White, N., and JE Macor et al., The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective oc- 7 Nicotinic Receptor Partial Agonist Bioorg. Med. Chem. Lett. 2001, 9, 319-321). Mating is generally performed at room temperature for 4-8 hours. Thioamide analogs can be prepared from mida by reaction with Lawesson's reagent (WWipf P .; Kim, Y .; Goldstein, DM, J. Am. Chem. Soc. 1995, 117, 11106). The resulting coupling products can be isolated and purified by standard techniques, such as chromatography or recrystallization, performed by those skilled in the art.

53147 Β

Quinuclidine amines can be prepared from quinuclidine amide by standard reduction methods as, for example, described below.

One skilled in the art will recognize that compounds of Formula l-IV and l'-IV 'may exist in different tautomeric and geometric isomeric forms. All of these compounds, including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers, are within the scope of the present invention. The substantially pure enantiomer contains not more than 5% by weight of the corresponding opposite enantiomer, preferably not more than 2%, most preferably not more than 1%.

Optical isomers can be obtained by separating racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using an optically active acid or base or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, dibenzovinic, ditoluoyltartaric and camphorsulfonic acids. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. A variety of methods for separating optical isomers involve the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional performance, optimally selected to maximize enantiomeric separation. Suitable chiral HPLC columns are produced by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all of which are routinely selectable. Enzyme separations, with or without derivation, are also useful. Optically active compounds of Formula 1-IV and 1'-IV 'can be similarly obtained

53147 Β by using starting materials in chiral synthesis processes under reaction conditions that do not cause racemization.

Additionally, one skilled in the art will recognize that the compounds can be used in a variety of enriched isotopic forms, e.g., enriched in content. ²H, ³H, ¹¹C, ¹³C and / or ¹⁴C. In one particular embodiment, the compounds are deuterium. Such deuterimizing forms can be made in the method described in U.S. Pat. 5,846,514 and 6,334,997. As described in U.S. Pat. 5,846,514 and 6,334,997, deuterium can improve efficacy and prolong the duration of action of drugs.

Deuterium-substituted compounds can be synthesized using various methods such as those described in: Dean, Dennis C .; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10)] (2000), 110 pp. CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka, George W .; Varma, Rajender S. The synthesis of radilabeled compounds via organometallic intermediates. Tetrahedron (1989), 45 (21), 6601-21, CODEN: TETRAB ISSN: 0040-4020. CAN 112: 20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64 (1-2), 9-32. CODEN: JRACBN ISSN: 0022-4081, CAN 95: 76229 AN 1981: 476229 CAPLUS.

Where applicable, the present invention also relates to useful formulations of compounds that can be prepared as shown herein, such as pharmaceutically acceptable salts or prodrugs. Pharmaceutically acceptable salts include those obtained by reacting the parent compound, which functions as a base, with an inorganic or organic acid to

53147Β forms, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those in which the parent compound functions as an acid and reacts with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of a compound for which protection is sought can be prepared by reacting the compound with an appropriate inorganic or organic acid by any of a number of methods. Alternatively, alkali and alkaline earth metal salts may be prepared by reacting a compound of the invention with an appropriate base by a variety of known methods.

The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulphates, butyrates, camphorates, digluconates, cyclopentane propionates, dodecyl sulphates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulphates, heptanoates-ethoxyates, hexanoates, hexanoates, hexanoates lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulphates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

Preferably, the formed salts are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable for intermediate products, for example, for isolating the compounds as salts and then

53147 Β converted salts back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.

The compounds of the invention may be administered alone or as an active ingredient in a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of Formula I-IV and II-IV, which contain, for example, one or more pharmaceutically acceptable carriers.

A number of standard references are available to explain methods for preparing various formulations suitable for administering the compounds of the invention. Examples of potential formulations and preparations are found, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, publishers) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, publisher), 1553-1593 (current edition).

With respect to their alpha-7 stimulating activity and, presumably, their high degree of selectivity, the compounds of the present invention may be administered to anyone in need of alpha-7 receptor stimulation. Administration can be achieved according to the patient's needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrathestally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration.

53147 Β

Various solid oral dosage forms can be used to administer the compounds of the invention including such solid forms as tablets, gel capsules, capsules, caplets, granules, lozenges and high volume powders. The compounds of the present invention may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (such as sucrose, rnanite, lactose, starches) and inert excipients known in the art, including but not limited to suspending agents, solubilizers, buffers agents, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants and the like. Time-release capsules, tablets and gels are also useful in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used to administer the compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms may also contain suitable inert diluents known in the art such as water and suitable inert fillers known in the art such as preservatives, wetting agents, sweeteners, flavoring agents, as well as emulsifying and / or suspending agents. of the invention. The compounds of the present invention may be injected intravenously, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention may be prepared by mixing the compounds with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such suitable carriers as are known in the art.

53147 Β

For topical administration, the pharmaceutical composition may be in the form of creams, ointments, coatings, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ears or nose. Topical administration may also include transdermal administration by means such as transdermal patches.

Aerosol formulations suitable for administration by inhalation may also be formulated. For example, for the treatment of respiratory tract disorders, the compounds of the invention may be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. Aerosol formulations can be placed in an acceptable pressurized reactor.

The compounds may be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and / or memory loss, e.g., other α-7 agonists, PDE4 inhibitors, calcium channel blockers , muscarinic m1 and m2 modulators, adenosine receptor modulators, amfacine NMDA-R modulators, MgluR modulators, dopamine modulators, serotonin modulators, cannabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigmine, and glantanamine). In such combinations, each active ingredient may be administered either in accordance with its usual dose range or in a dose below its usual dose range.

The compounds of the invention may be used in conjunction with positive modulators that enhance the efficacy of nicotinic receptor agonists. See, e.g., positive modulators disclosed in WO 99/56745, WO 01/32619,

53147 Β and W0 01/32622. Such combination therapy can be used in the treatment of conditions / diseases associated with reduced nicotine transmission.

Further, the compounds can be used in conjunction with compounds that bind Αβ peptides and thereby inhibit peptide binding to α7nAChR subtypes. See, e.g., WO 99/62505.

The present invention further includes treatment methods comprising activating α-7 nicotinic receptors. Thus, the present invention includes methods of selectively activating / stimulating α-7 nicotinic receptors in animals, e.g., mammals, especially humans, wherein such activation / stimulation has a therapeutic effect, such as where such activation facilitates conditions involving neurological syndromes, such as memory loss, especially long-term memory. Such methods consist of administering to an animal in need thereof, especially a mammal, most particularly a human, an effective amount of a compound of Formula I-IV or I'-IV ', alone or as part of a formulation, as disclosed herein.

Nicotine acetylcholine receptor binding agents are indicated as useful in the treatment and / or prophylaxis of various diseases and conditions, in particular psychotic diseases, neurodegenerative diseases involving cholinergic system dysfunction, and memory and / or cognitive impairment conditions, including, for example, schizophrenia, anxiety , mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative disorders], cognitive disorders (such as Alzheimer's disease, Lewy body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognition deficiency, attention deficit hyperactivity disorder)

53147 Paž attention deficit disorder), and other uses such as treating nicotine addiction, inducing smoking cessation, treating pain (i.e., analgesic use), providing neuroprotection, and treating time zone changes. See, e.g., WO 97/30998; WO 99/03850; WO 00/42044; WO 01/36417; Holladay et al., J. Med. Chem., 40:26, 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem., Chapter 5, 41-51 (2000); Stevens et al., Psychopharmatology, (1998) 136: 320-27 (1998); and Shytle et al., Molecular Psychiatry, (2002), 7, pp, 525-535.

Thus, according to the invention, there is provided a method of treating a patient, in particular a person, suffering from psychotic diseases, neurodegenerative diseases involving dysfunction of the cholinergic system, and conditions of memory impairment and / or cognition, including, for example, schizophrenia, anxiety, mania , depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative disorders], and / or cognitive disorders (such as Alzheimer's disease, Lewy body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognition deficiency, attention deficit hyperactivity disorder associated with loss of attention) consisting of giving the patient effective amounts of compounds according to Formulas 1-IV or 1'-IV '.

Neurodegenerative disorders included in the methods of the present invention include, but are not limited to, the treatment and / or prophylaxis of Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear stroke (Steel-Richardson syndrome), multisystem degeneration syndrome), motor neuronal diseases including amyotrophic lateral sclerosis, degenerative ataxia, cortical basal degeneration, ALS

53147 Β

Parkinson's-dementia Guam complex, subacute sclerosing penericephalitis, Huntington's disease, Parkinson's disease, synucleinopathy, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease / spinocerebellar ataxia type 3, Gilvoponetore de Olive diseases, bulbar, pseudobulbar drops, spinal muscular atrophies, spinobulbar muscular atrophies (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffman disease, KugelbergVelander disease, Tay-Sach disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathies such as Creon disease Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia), and neurodegenerative disorders resulting from cerebral ischemia or infarction including embolic occlusion and thrombotic occlusion as intracranial hemorrhage of any type (including, but not limited to, epidural, subdural, subarachnoid and intracerebral), and intracranial, non-limiting and non-cranial and on, contusion, penetration, cut, compression and laceration).

Additionally, α-7nAChR-1 agonists, such as the compounds of the present invention can be used to treat age-related dementia and other dementias and memory loss conditions including age-related memory loss, senility, vascular dementia, diffuse white matter disease ( Binswanger's disease), dementia of endocrine and metabolic origin, dementia of head trauma and diffuse brain damage, dementia of pugilists and frontal dementia of the lobe. See, e.g., WO 99/62505. Thus, in accordance with the invention, a method of treating a patient is provided, in particular

53147 Β a person suffering from age-related dementia and other dementias and memory loss conditions consisting of giving the patient an effective amount of a compound according to Formulas l-IV or l'-IV '.

Thus, in accordance with a further embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's diseases, Creutzfeld-Jakob diseases, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multi-infarction dementia and other neurological conditions, as well as HIV and cardiovascular diseases, consisting of administering an effective amount of a compound according to Fromulas 1-IV or 1'-IV '.

The amyloid precursor protein (APP) and the Aβ peptides derived therefrom, e.g., Armo, ARmg, and other fragments, are known to be involved in the pathology of Alzheimer's disease. Αβι_₄₂ peptides are not only involved in neurotoxicity but are also known to inhibit cholinergic transmitter function. It was further determined that Aβ peptides bind to α-7 nAChRs. Thus, agents that block the binding of Αβ peptides to cc-7 nAChRs are useful for the treatment of neurodegenerative diseases. See, e.g., WO 99/62505. Additionally, stimulation of α-7 nAChR can protect neurons from cytotoxicity associated with Aβ peptides. See, e.g., Kihara, T. et al., Ann. Neuroi., 1997, 42, 159.

Thus, in accordance with an embodiment of the invention, there is provided a method of treating and / or preventing dementia in an Alzheimer's patient comprising administering to the subject a therapeutically effective amount of a compound of Formulas 1-IV or 1'-IV 'to inhibit amyloid beta peptide binding

53147 Β (presumably, Αβ ^) with nAChRs, presumably α-7 nAChRs, most preferably human α-7 nAChRs, as well as a method of treating and / or preventing other clinical manifestations of Alzheimer's disease that include but are not limited to, cognitive and speech defects, apraxia, depression, dilusions, and other neuropsychiatric symptoms and signs, and abnormalities of movement and steps).

The present invention also provides methods for treating amyloid diseases, for example, hereditary cerebral angiopathy, non-neuropathic hereditary amyloid, Down syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardioid-associated anthropathy, and Tinske and Iowa amyloidosis.

Additionally, nicotine receptors are implied to play a role in the body's response to alcohol intake. Thus, agonists for α-7 nAChRs can be used in the treatment of alcohol withdrawal and in anti-intoxication therapy. Thus, in accordance with an embodiment of the invention, there is provided a method of treating a patient for alcohol withdrawal or treating a patient with anti-intoxication therapy comprising administering to the patient an effective amount of a compound according to Formulas 1-IV or 1'-IV '.

Agonists for α-7 nAChR subtypes can also be used for neuroprotection against damage associated with stroke and ischemia and glutamate-induced excitotoxicity. Thus, in accordance with an embodiment of the invention, a method of treating a patient is provided to provide neuroprotection against stroke-related damage and ischemia, and

53147 Β Glutamate-induced excitotoxicity consisting of administering to the patient an effective amount of a compound according to Formulas 1-IV or 1'-IV '.

As noted above, agonists for α-7 nAChR subtypes can also be used in the treatment of nicotine addiction, smoking cessation, pain treatment, and treatment of time zone change, obesity, diabetes, and inflammation. Thus, in accordance with an embodiment of the invention, there is provided a method of treating a patient suffering from nicotine dependence, pain, time zone change, obesity and / or diabetes, or a method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to Formulas 1- IV or l'-IV '.

Additionally, due to their affinity for α-7 nAChRs, labeled derivatives of the compounds of Formulas 1-IV and G-IV '(e.g., C¹¹ or F¹⁸ labeled derivatives), can be used in neuroimaging of receptors in, e.g., the brain. Thus, in vivo receptor imaging can be performed using such enhanced means using, e.g., PET imaging.

Dreams of memory impairment are manifested by a deterioration in the ability to learn new information and / or an inability to remember previously learned information. Deterioration of memory is the primary symptom of dementia and may also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.

Thus, in accordance with an embodiment of the invention, there is provided a method of treating a patient suffering from, for example, mild cognitive impairment (MCI)

53147 Β vascular dementia (VaD), age-related cognitive decline (AACD), amnesia associated with / open heart surgery, cardiac arrest, and / or general anesthesia, memory deficiency due to premature exposure to anesthetics, sleep loss caused by cognitive impairment fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy associated with cognitive impairment, Down's syndrome, alcoholism associated with dementia, a drug / substance-induced cognitive impairment, Dementia Puglistica (Boxing Syndrome) and a patient suffering from animal dementia (e.g., dogs, cats, horses, etc.) consisting of administering to the patient an effective amount of a compound according to Formulas 1-IV or l-IV.

Dosages of the compounds of the present invention depend on various factors including the particular syndrome to be treated, the severity of symptoms, the route of administration, the frequency of the dose interval, the utilization of the particular compound, efficacy, toxicological profile, pharmacokinetic profile of the compound, and the presence of adverse side effects.

The compounds of the invention may be administered to mammals, in particular Ijids, at typical dose levels common to α-7 nicotinic receptor agonists such as the known α-7 nicotinic receptor agonist compounds mentioned above. For example, the compounds may be administered, in single or multiple doses, by oral administration with a dose level of, for example, 0.0001-10 mg / kg / day, e.g., 0.01-10 mg / kg / and. Unit dosage forms may contain, for example, 1-200 mg of active compound. For intravenous administration, the compounds may be administered in single or multiple doses.

53147 Β

In carrying out the methods of the present invention, it is to be understood that references to certain buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read to include all related materials to be recognized by one skilled in the art. of interest or value in the particular context in which the consideration is presented. For example, it is often possible to replace one buffer system or culture medium with another and again achieve similar, if not identical, results. Those skilled in the art will have sufficient knowledge of such systems and methodologies to be able, without undue experimentation, to make such substitutions that will optimally serve their needs using the procedures and procedures disclosed herein.

The present invention will now be described by the following non-limiting examples. In applying the findings of these examples, it should be borne in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt recommend themselves to experts in the relevant field of science.

In the previous and subsequent examples, all temperatures were set uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications, which are cited above and below, including U.S. Provisional Patent Application Serial No. 60 / 413,151, filed September 25, 2002, and U.S. Provisional Application Serial No. 60 / 448,469, filed February 21, 2003, are incorporated herein by reference.

53147 Β

EXAMPLES

All recorded spectra are at 300 MHz on Bruker Instruments NMR unless otherwise stated. The pairing constants (J) are in hertz (Hz) and the peaks are enumerated relative to TMS (b 0.00 ppm). Microwave reactions were performed using a Personal Chemistry Optimizer ™ microwave reactor in 2.5 mL or 5 mL Personal Chemistry microwave reactor vessels. All reactions were performed at 200 ° C for 600 s with a fixed ON retention time unless otherwise indicated. Ion sulfonic acid exchange resins (SCX) were purchased from Varian Technologies. Analytical HPLC was performed on a 4.6 mm x 100 mm Xterra RP18 3.5 μ column using a gradient of 20/80 to 80/20 water (0.1% formic acid) / acetonitrile (0.1% formic acid) over 6 min.

Representative procedures.

Procedure A

Process a provides a process for pairing between 3-aminoquinuclidines and carboxylic acids to form carboxamide derivatives.

To a solution of carboxylic acid (16.1 mmol) in N / V-dimethylformamide (65 mL) was added HBTU (16.1 mmol), a catalytic amount of dimethylaminopyridine, N, N-diisopropylethylamine (96.6 mmol) and 4 A activated molecular sieves. (2.6 g). The reaction mixture was maintained at room temperature for 2 h under nitrogen and then 3-aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h, the solvent was removed under reduced pressure. The oily residue was partitioned between saturated aqueous sodium bicarbonate (25 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with 9/1 dichloromethane / methanol (5 h

53147 Β

100 mL) and the combined organic layers were concentrated. The residue was purified by chromatography using either a 90/10/1 dichloromethane / methanol / ammonium hydroxide mixture or a 70/30/1 ethyl acetate / methanol / ammonium hydroxide mixture as eluent to provide the product in 30% -70% yield. Alternatively, the products were purified by preparative HPLC using an 8 min gradient from 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid).

Procedure B

Process B provides a process for pairing between 3-aminoquinuclidine and benzisothiazole carboxylic acids to form carboxamide derivatives.

To a solution of 6-methoxybenzisothiazole-3-carboxylic acid (61 mg, 0.30 mmol) in a 5/1 mixture of tetrahydrofuran // N, N-dimethylformamide (12 mL) was added diisopropylethylamine (0.2 mL, 1.1 mmol) and (115 mg, 0.6 mmol) 3- (R) aminoquinuclidine dihydrochloride. The mixture was cooled to 0 ° C, and added in one portion to HATU (115 mg, 0.3 mmol). The reaction mixture was allowed to warm to room temperature and maintained overnight. The mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane / methanol. The aqueous layer was extracted with 95/5 dichloromethane / methanol (2X), and the combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified by chromatography (90/10/1 dichloromethane / methanol / ammonium hydroxide) to give 72 mg (75%) of the amide as a colorless solid.

53147 Β

Procedure C

Process C provides a process for pairing between 3-aminoquinuclidines and carboxylic acids to form carboxamide derivatives.

The coupling and purification reaction is carried out according to process A (indazoles, benzthiazoles) or according to process B (benzisothiazoles). The free base was dissolved in methanol (3.5 mL / mmol of starting acid) and treated with 1N hydrochloric acid in ether (3.5 mL / mmol of starting acid). The resulting suspension was diluted with ether (7 mL / mmol of starting acid) and maintained at room temperature for 2 h. The solids were collected by filtration, washed with ether, and dried under vacuum to give a yield (40-60%) of salt.

Procedure D

Process D provides a process for pairing between 3-aminoquinuclidines and carboxylic acids to form carboxamide derivatives.

To a solution of carboxylic acid (4.77 mmol) in N, N-dimethylformamide (14 mL) was added N, N-diisopropylethylamine (19 mmol) and 3-aminoquinuclidine hydrochloride (4.29 mmol). The reaction mixture was maintained at room temperature for 30 minutes under nitrogen and then HATU (4.76 mmol) was added. After 18 h, the reaction mixture was filtered through Celite (rinsing with methanol) and partitioned between 3 SCX columns. The columns were washed with methanol (100 mL each) and the base components were eluted with 2 M ammonia in methanol (100 mL each) and concentrated. The residue was purified by chromatography [1/1 to 0/1 ethyl acetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] to give the product in 15% -50% yield.

53147 Β

Procedure Ε

Process Ε provides a process for the formation of carboxamide derivatives from 3-quinuclidinecarboxylic acid methyl ester.

To a solution of the amine in toluene was added 1.0 M solution of trimethylaluminum in toluene (1.1 eq.) At 0 ° C. After 30 minutes, an additional 1.1 equivalents of trimethylaluminum was added followed by a solution of 3-quinuclidinecarboxylic acid methyl ester hydrochloride salt (1.1 eq.) In dioxane (5 mL9.) The reaction mixture was heated at 70 ° C for 10 h, allowed to cool. to room temperature, and stir in cold, (0 ° C) aqueous sodium bicarbonate solution. The aqueous layer was extracted with 5% methanol in methylene chloride (2 x 30 mL) and the combined organic layers were washed with brine and concentrated. The residue was purified by preparative HPLC using an 8 min gradient from 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid).

Procedure F

Process F provides a process for reducing carboxamides to form secondary amine derivatives.

To a solution of the amide (50 mg) in tetrahydrofuran (4 mL) was added lithium aluminum hydride (4.0 eq.). The reaction mixture was heated to reflux for 4 h, cooled to 0 ° C, and carefully quenched with ethanol. The resulting precipitate was poured onto ice water and extracted with 5% methanol in dichloromethane (Zh) and the combined organic layers were concentrated. The residue is purified

53147 Β preparative HPLC using an 8 min gradient from 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid).

Procedure G

Process G provides a coupling process between 3-aminoquinuclidine and carboxaldehyde to form secondary amine derivatives.

A suspension of 1H-indazole-4-carboxaldehyde (100 mg), 3-aminoquinuclidine dihydrochloride salt (1.0 eq.), And 4 A molecular sieves in dioxane (4 mL) was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature and treated with sodium triacetoxyborohydride (3 eq.). The reaction mixture was maintained at room temperature for 2 h and poured into water, extracted with 5% methanol in dichloromethane (2 x 30 mL), and the combined extracts were concentrated. The residue was purified by preparative HPLC using an 8 min gradient from 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid).

Procedure H

Process H provides a process for pairing between brominated and iodinated aminoquinuclidinecarboxamides and boronic acids to form aryl-substituted derivatives.

To a 5 mL microwave reaction vessel was added bromide (0.286 mmol), boronic acid (0.588 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.0289 mmol), tri-tert-butylphosphine tetrafluoroborate (0.0579 mmol), and potassium carbonate (0.810 mmol). The court is evacuated, filled from the back

53147 Β with argon gas, and dilute the contents with N, N-dimethylformamide (5.0 mL). The vessel is sealed and subjected to microwave irradiation at 200 ° C for 600 seconds. The reaction contents were filtered through celite (washing with methanol) and loaded onto a 5 g SCX column. The column was stirred with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol and concentrated. The residue was purified by preparative HPLC using an 8 min gradient from 95/5 to 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid).

Procedure I

Process I provides a process for the coupling of brominated 3-aminoquinuclidinecarboxamide and amine to form amino-substituted derivatives.

To a 5 mL microwave reaction vessel was added N - ((3R) -1-azabicyclo [2.2.2] oct-2-yl) -5- (bromo) benzo [d] isothiazole-3-carboxamide (133 mg, 0 , 37 mmol), tris (dibenzylideneacetone) dipalidium (0) (34 mg, 0.04 mmol), cesium bicarbonate (213 mg, 1.1 mmol), and (2'-dicyclohexylphosphanylbiphenyl-2yl) dimethylamine (30 mg, 0) , 07 mmol). The vessel was then evacuated and backfilled with argon gas, the solid mixture was then diluted with morpholine (0.7 mL), dioxane (1 mL), and triethylamine (0.5 mL) and the reaction vessel was sealed. The reaction mixture was subjected to microwave irradiation at 120 ° C for 1800 seconds. The reaction mixture was filtered through a plug of celite and concentrated in vacuo. The crude product was purified by chromatography (90/10/1 dichloromethane / methanol / ammonium hydroxide) to give 47 mg (34%) of 6morpholin-4-ylbenzo [d] isothiazole-3-carboxylic acid (3R) -1azabicyclo [2.2.2 Oct-3-yl) -amide as a colorless solid.

53147 Β

Procedure J.

Process J provides a process for coupling between brominated 3-aminoquinuclidinecarboxamides and Grignard reagents to form alkylsubstituted derivatives.

A 5 mL microwave reaction vessel was charged with bis (triphenylphosphine) palladium (II) chloride (0.030 mmol, 0.1 eq.) And bromide (0.30 mmol). The vessel was evacuated and filled with argon gas from the back. In a separate reaction vessel, a solution of Grignard (1.2 mmol, 4 eq.) Was added to a 0.5 M solution of zinc chloride (1.2 mmol, 4 eq.) In tetrahydrofuran at room temperature. The suspension is maintained for 30 minutes and all contents are transferred to the reaction vessel via cannula. The vessel is sealed and subjected to microwave irradiation at 100 ° C for 600 seconds with a previous mixing time of 60 seconds. The reaction was quenched with acetic acid (0.5 mL), diluted with methanol, and transferred to an SCX column. The column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol (50 mL) and concentrated. The residue was purified by chromatography [1/1 to 0/1 ethyl acetate (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] followed by preparative HPLC using a 5/95 to 80/20 gradient of acetonitrile (0.1% formic acid) / water. 0.1% formic acid) tokorn 6 minutes to obtain the product (20-50%). Alternatively, the residue is purified by chromatography (90/10/1 dichloromethane / methanol / ammonium hydroxide).

Procedure K

Process K provides a process for preparing bromoindazole from bromomethylaniline. (See, George V. DeLucca, U.S. Patent No. 6,313,110.)

53147 Β

Acetic anhydride (2.27 eq.) Was added to a cooled (0 ° C) solution of bromomethylaniline (1.00 eq.) In chloroform (1.5 mL / mol) while maintaining the temperature below 40 ° C. The reaction mixture was allowed to warm to room temperature and maintained for 1 h. Potassium acetate (0.29 eq.) And isoamyl nitrite (2.15 eq.) Were added and the reaction mixture was heated at reflux for 18 h. The volatile parts are removed under reduced pressure. Water (0.65 L / mol) was added to the residue and the mixture was concentrated. Concentrated hydrochloric acid (1 L7mol) was added to the residue and the mixture was heated at 50 ° C for 2 h. The mixture was allowed to cool to room temperature and the pH was adjusted to 10 by the slow addition of 50% aqueous sodium hydroxide solution. The mixture was diluted with water (0.65 L / mol) and extracted with ethyl acetate (2 x 1.2 L / mol) and precipitated over anhydrous sodium sulfate. The organic solution was filtered through a plug of silica gel (washed with ethyl acetate), concentrated, and the residue was triturated with heptane (1 L / mol). The solids were collected by filtration, washed with heptane, and dried in a vacuum oven.

Procedure L

Process L provides a process for preparing indazo carboxylic acid from bromoindazole.

To a solution of bromoindazole (1.00 eq.) In anhydrous tetrahydrofuran (7 L / mol) at room temperature was added sodium hydride (60% in mineral oil, 1.11 eq.) In several portions. The resulting solution was maintained at room temperature for 30 minutes and then cooled to -60 ° C. 1.3 M of sebutillithium in cyclohexane (2.1 eq.) Was added to the reaction mixture while maintaining the internal temperature below -50 ° C. The mixture is maintained extra

53147 Β h at -50 ° C. Stable stream of hydrogenated cap carbon dioxide through the reaction mixture for 1 h. The flow is continued until the reaction mixture is allowed to warm to room temperature. Saline (6 L / mol) was added and the pH of the mixture was adjusted to 5 with concentrated hydrochloric acid. The mixture was extracted with heated ethyl acetate (3x8 L / mol) and the combined extracts were washed with a small volume of brine, dried over anhydrous sodium sulfate, and concentrated. The product is purified by chromatography on silica gel or crystallization.

Procedure M

Process M provides the preparation of 1H-indazole-7-carboxylic acid from 2 amino-3-methylbenzoic acid.

To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol) in N, N-dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102 mmol,

1.5 eq.). The mixture was stirred for 30 minutes. A solution of methyl iodide 84.17 mL, 67.0 mmol, 1.0 eq.) In N, N-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at room temperature. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to give 10.2 g (92%) of methyl 2-amino-3-methylbenzoate. ¹1 H NMR (400 MHz, CDCl 3)₃) b 7.77 (d, 1H), 7.19 (d, 1H9, 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, ZN), 2.17 s, H).

To a solution of the ester (17.5 g, 106 mmol) in chloroform (300 mL) was added acetic anhydride (22.6 mL, 239 mmol, 2.3 eq.) While maintaining the temperature.

53147 Β below 40 ° C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (3.00 g, 30.6 mmol, 0.3 eq.) And isoamyl nitrite (30.6 mL, 228 mmol, 2.2 eq) were added. The reaction mixture was heated at reflux for 24 h and allowed to cool to room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100 mL) were added to the residue, and the mixture was maintained at room temperature for 18 h. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The product was isolated by filtration, washed with ethyl acetate (20 mL), and dried to give 15.3 g (68%) of methyl 1Hindazole-7-carboxylate hydrochloride.¹1 H NMR (500 MHz, DMSO-d 6)₆) b 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, ZN); MS (APCI) m / z 177 (M +)⁺+1).

A solution of indazole (8.30 g, 33.0 mmol) in methanol (100 mL) at 0 ° C was treated with 29% aqueous potassium hydroxide solution (20 mL). The reaction mixture was allowed to warm to room temperature and reflected for 18 h. The pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid and the volatiles were removed under reduced pressure. The residue was partitioned between brine (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with additional heated ethyl acetate (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solids were isolated by filtration to give 5.86 g (94%) of the acid.

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Procedure N

Process N provides for the preparation of substituted benzisothiazole-3 carboxylic acids from the corresponding thiophenols.

To a solution of 3-methoxythiophenol (3.75 g, 26.7 mmol) in ether (20 mL) was added oxalyl chloride (3.7 mL, 43 mmol) dropwise. The mixture was heated at reflux for 1.5 h, cooled to room temperature, and concentrated in vacuo. The resulting yellow oil was dissolved in dichloromethane (50 mL), cooled to 0 ° C, and treated with aluminum chloride (4.30 g, 32.0 mmol) in portions. The mixture was heated at reflux for 30 minutes, cooled to room temperature, and poured onto ice water with stirring. The organic layer was separated and washed successively with saturated, aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (4/1 ethyl acetate / hexane) to give 2.46 g (47%) of 6-methoxy-1-benzothiophene-2,3-dione as an orange solid.

To the dione mixture (86 mg, 0.44 mmol) in 30% aqueous ammonium hydroxide solution (2.0 mL) was added 35% aqueous hydrogen peroxide solution (0.2 mL) and the reaction mixture was maintained for 12 h. The precipitated pink solids were isolated by filtration, washed with water, and dried under high vacuum to give 39 mg (42%) of 6-methoxybenzisothiazole-3-carboxamide.

To a solution of the amide (1.14 g, 5.46 mmlo) in methanol (100 mL) was added 10 N sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h, cooled to room temperature, and acidified to pH &lt;2 by slow addition of concentrated hydrochloric acid. The organic layer was extracted with

53147 Β dichloromethane (2x) and dried over sodium sulfate. The crude product was purified by chromatography (300/50/1 dichloromethane / methanol / formic acid) to give 1.02 g (89%) of 6-methoxybenzisothiazole-3-carboxylic acid as a pink solid. LC / MS (EI) m.p._R 6.17 min, m / z 210 (M⁺+1).

The following acids are prepared by this procedure:

Benzisothiazole-3-carboxylic acid. ¹1 H NMR (CDCl 3)₃) b 8.86 (dd, J = 7.1,

2.5, 1H), 8.03 (dd, J = 6.3, 1.4, 1H), 7.66-7.61 (m, 2H); LC / MS (EI) m.p._R 6.75 min, m / z 180 (M⁺+1).

6- Bromobenzisothiazole-3-carboxylic acid. LC / MS (EI) m.p._R 9.95 min, m / z 258/260 (M⁺/ M⁺ +2).

5-Methoxybenzisothiazole-3-carboxylic acid. LC / MS (EI) m.p._R 6.09 min, m / z 210 (M⁺+1).

5-Bromobenzisothiazole-3-carboxylic acid. LC / MS (EI) m.p._R 9.88 min, m / z 258/260 (M7M⁺ +2).

7- Methoxybenzisothiazole-3-carboxylic acid. LC / MS (EI) m.p._R 6.49 min, m / z 210 (M⁺+1).

Procedure O

Process O provides a process for preparing 1,3-benzothiazole-5-carboxylic acid from 4-chloro-3-nitrobenzoic acid.

53147 Β

To a solution of 4-chloro-3-nitrobenzoic acid (20.0 g, 99.2 mmol) in N, N-dimethylformamide (400 mL) was added potassium carbonate (35.0 g, 254 mmol,

2.6 eq.). After 30 minutes, ethyl iodide (18.6 g, 119 mmol, 1.2 eq.) Was added and the reaction mixture was heated at 50 ° C for 4 h. Water (3 L) was added and the mixture was extracted with diethyl ether (2 x 500 mL). The organic extracts were combined, washed with brine (1 L), dried over anhydrous sodium sulfate and concentrated on a vacuum rotary evaporator. The residue was crystallized from hexane to give 19.7 g (86%) of the ester.¹1 H NMR (500 MHz, CDCl 3)₃) b

8.51 (d, 1 H), 8.17 (dd, 1 H), 7.65 (d, 1 H), 4.43 (q, 2 H), 1.42 (t, ZN).

Sulfur (1.6 g, 49.91 mmol, 0.58 eq.) Was dissolved in a solution of sodium sulfate nonahydrate (12.0 g, 49.96 mmol, 0.58 eq.) In water (60 mL). This solution was combined with a solution of ethyl 4-chloro-3-nitrobenzoate (19.6 g, 85.36 mmol, 1.00 eq.) In ethanol (100 mL) and the resulting mixture was heated at reflux for 3 h. The hot reaction mixture was poured into water (600 mL) and maintained for 15 minutes. The product was isolated by filtration and recrystallization from ethanol to give 16.5 g (77%) of disulfide.¹1 H NMR (500 MHz, CDCl 3)₃b 8.96 (d, 1 H), 8.19 (dd, 1 H),

7.88 (d, 1 H), 4.43 (q, 2 H), 1.41 (t, ZN).

A mixture of diethyl 4,4'-dithiobis (3-nitrobenzoate) (11.2 g, 24.8 mmol) and zinc granules (15.0 g, 234 mmol, 9.5 eq.) In formic acid (600 mL) was heated to reflux for 48h. The mixture was allowed to cool to room temperature and concentrated to dryness. The residue was partitioned between ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on neutral aluminum (1/1 to 0/1 hexanes / dichloromethane) to give 5.30 g (51%) of benzthiazole. ¹1 H NMR (500

53147 Β

ΜΗζ, CDCL₃) δ 9.08 (s, 1H), 8.83 (d, 1H), 8.14 (dd, 1H), 8.02 (d, 1H), 4.45 (q, 2H), 1, 44 (t, ZN); MS (EI) m / z 208 (M +)⁺+1).

To a solution of ethyl 1,3-benzothiazole-5-carboxylate (5.30 g, 25.6 mmol) in a mixture of methanol (150 mL), tetrahydrofuran (40 mL) and water (5 mL) was added a 50% aqueous solution of sodium hydroxide (10 mL). The mixture was maintained at room temperature for 18 h and concentrated. The residue was partitioned between water (300 mL) and diethyl ether (200 mL) and the organic layer was removed. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 4 and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give 4.30 g (94%) of acid.

Procedure P

Process P provides a process for preparing 1,3-benzothiazole-7-carboxylic acid from ethyl 3-aminobenzoate. (See, Kunz et al., U.S. Patent No. 5,770-758.).

A solution of 3-aminobenzoate (14.9 g, 90 mmol) in chlorobenzene (100 mL) was cooled to -10 ° C and treated with sulfuric acid (97%, 2.5 mL, 45 mmol 0.50 eq), dropwise . After 15 minutes, solid potassium thiocyanate (9.2 g, 95 mmol 1.05 eq.) Was added in several portions over 30 minutes followed by 18 crowns-6 (250 mg). The mixture was heated to 100 ° C for 10 h, allowed to cool to room temperature, and maintained for an additional 4 h. The precipitated solids were isolated by filtration and washed successively with chlorobenzene (25 mL) and hexanes (3 x 100 mL). The solid was suspended in water (300 mL) and the suspension was maintained for 30 minutes. The product is isolated by filtration and washed

53147 Β with water (2 x 100 mL). The product was dried in a vacuum oven (55 ° C) overnight to give a yield of 13.4 g (69%) of thiocarbamate.¹1 H NMR (500 MHz, DMSO-d 6)₆) b 1.32 (t, J = 7.5, ZN), 4.32 (q, J = 7, 2H), 7.44-7.47 (m, 2H), 7.68-7.76 (m, ZN) 8.05 (s, 1H), 9.86 (s, 1H); MS (APCI) m / z 225 (M⁺+1).

A solution of thiocarbamate (1.95 g, 12.2 mmol, 2.11 eq.) In chloroform (10 mL) was added dropwise over a period of 40 minutes to a vigorously maintained mixture of ethyl 3 - [(aminocarbonothioyl) amino] benzoate (1.30). g, 5.78 mmol, 1.00 eq.), glacial acetic acid (10 mL) and chloroform (10 mL). The mixture was maintained at room temperature for 30 minutes and then heated at 70 ° C for 4 h. The mixture was allowed to cool to room temperature and maintained for an additional 13 h. The volatiles were removed under reduced pressure and the solid residue was suspended in a mixture of chloroform (10 mL) and acetone (10 mL). The product was isolated by filtration, walnuts successively with acetone (5 mL) and hexanes (10 mL), and dried in a vacuum oven to give 1.65 g (95%) of the product as a mixture of ethyl 2-amino-1,3-benzothiazole. Hydrobromide 7-carboxylate and ethyl 2-amino-1,3-benzothiazole-5-carboxylate hydrobromide in a ratio of 95/5, each separately. This product was partitioned between saturated aqueous sodium bicarbonate solution (25 mL) and a mixture of ethyl acetate (70 mL) and tetrahydrofuran (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate to give pure ethyl 2 amino-1,3-benzothiazole-7-carboxylate.¹1 H NMR (500 MHz, DMSO-d 6)₆) b 1.35 (t, J = 7.5, ZN), 4.36 (q, J = 7, 2H), 7.35 (t, J = 7.5, 1H), 7.57 (d , J = 7, 1H),

7.61 (bs, 2 H), 7.65 (d, J = 8, 1 H); MS (EI) m / z 223 (M &amp; lt; + &amp; gt;)⁺+1).

Iso-amyl nitrite (7.4 mL, 53 mmol, 2.2 eq.) Was added to a solution of ethyl 2-amino-

1,3-Benzothiazole-7-carboxylate (5.40 g, 24.3 mmol) in tetrahydrofuran (70 mL) and the mixture was heated at reflux for 4 h. Volatile parts are removed from the floor

53147 Β under reduced pressure and the residue was purified by chromatography (0/100 to 5/95 methanol / dichloromethane) to give 3.56 g (71%) of the ester. ¹1 H NMR (500 MHz, CDCl 3) δ 1.47 (t, J = 7.5, ZN), 4.49 (q, J = 7, 2H), 7.62 (t, J = 8, 1H), 8.20 (d, J = 6.5, 1H), 8.33 (d, J = 8, 1H), 9.12 (s, 1H); MS (EI) m / z 208 (M +)⁺+1). Aqueous sodium hydroxide (50%, 10 mL) was added to a solution at 0 ° C of ethyl 1,3benzothiazole-7-carboxylate (3.5 g, 16.89 mmol) and a mixture of methanol (65 mL), tetrahydrofuran (20 mL) and water (5 ml_). The mixture was maintained at room temperature for 4 h and the volatiles were removed under reduced pressure. The residue was dissolved in water (100 mL) and concentrated hydrochloric acid was added to adjust the pH of the solution to 5. The mixture was cooled to 0 ° C and maintained for 30 minutes. The product was isolated by filtration, stirred with water (10 mL), and dried in a vacuum oven (70 ° C) overnight to give a yield of 2.75 g (91%) of acid. ¹1 H NMR (500 MHz, DMSO-d 6) δ 7.71 (t, J = 7.5, 1H), 8.15 (d, J = 7, 1H), 8.38 (d, J = 8, 1H) ), 9.51 (s, 1 H), 13.74 (bs, 1 H); MS (APCI) m / z 178 (M⁺-1).

Procedure Q

Process Q provides a process for the conversion of brominated isatins to the corresponding indazole-3-carboxylic acids.

Conversion of substituted isatins with the corresponding indazole-3-carboxylic acids is basically the same procedure as described with indazole-3-carboxylic acid: Snyder, HR, et. al., J. Am. Chem. Soc. 1952, 74, 2009. Substituted isatin (22.1 mmol) was diluted with 1N sodium hydroxide (24 mL) and heated at 50 ° C for 30 minutes. The reaction mixture was cooled to 0 ° C and treated with a solution at 0 ° C of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added via a pipette placed under the surface vigorously.

53147 Β A stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 ° C. The addition takes 15 minutes and the reaction is maintained for an additional 30 minutes. A cold (0 ° C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 minutes and the reaction mixture was maintained for 60 minutes. The precipitated solids were isolated by filtration, washed with water, and dried to obtain a quantitative mass balance. The material is of sufficient purity (¹1 H NMR and LC / MS) to be used in the next step without further purification.

Using the above procedures and the further procedures described below, the following compounds in Examples 1-94 were prepared:

Example 1: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0032.tif" />

Prepared from benzo [d] isothiazole-3-carboxylic acid using Method

B. Yield 42%. ¹1 H NMR (CD₃OD) b 8.73 (d, J = 8.0, 1H), 8.05 (d, J = 8.1, 1H), 7.59-7.47 (m, 2H), 4.19- 4.16 (m, 1 H), 3.37-3.28 (m, 1 H), 3.05 - 2.96 (m, 1 H), 2.86 - 2.79 (m, 2 H), 2, 07-2.04 (m, 1H), 2.02-1.80 (m, 1H), 1.78-1.74 (m, 1H), 1.56-1.52 (m, 1H); LC / MS (EI) f_R3.61 min, m / z 288 (M⁺+1).

53147 Β

Example 2: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide hydrochloride.

<img file="RS53147B_D0033.tif" />

CIH

Prepared from benzo [d] isothiazole-3-carboxylic acid using Method

C. Yield 95%. LC / MS (EI) f_R3.55 min, m / z 288 (M⁺+1).

Example 3: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0034.tif" />

Prepared from benzo [d] isothiazole-3-carboxylic acid using Method

B. Yield 44%. LC / MS (EI) 3.71 min, m / z 288 (M⁺+1).

Example 4: N - ((3S) -1-Azabicyclo [2.2.21-oct-3-yl) benzo [p] isothiazole-3-carboxamide hydrochloride.

<img file="RS53147B_D0035.tif" />

53147 Β

Prepared from benzo [d] isothiazole-3-carboxylic acid using Method

C. Yield 95%. LC / MS (EI) 3.71 min, m / z 288 (M⁺+1).

Example 5: N- (1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide.

n

Prepared from 1H-indazole-3-carboxylic acid using Method A. Yield 50%. ¹1 H NMR (CD₃OD) b 8.21 (m, 1H), 7.56 (m, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 4.19 (m, 1H), 3, 32 (m, 1 H), 2.96 (m, 5 H), 1.95 (m, 5 H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

Example 6: N4 (3RM-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride.

n

Prepared from 1H-indazole-3-carboxylic acid using Method C. Yield 76%. ¹1 H NMR (400 MHz, CD₃OD) b 8.19 (d, J = 8.4, 1H), 7.60 (d, J =

8.4, 1H), 7.43 (m, 1H), 7.26 (m, 1H), 4.55 (m, 1H), 3.85 (m, 1H), 3.50 (m 1H) , 3.34 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H); MS (APCI) m / z 271 (M⁺+1); mp 295 ° C (dec.).

53147 Β

Example 7: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-3-carboxamide hydrochloride.

<img file="RS53147B_D0036.tif" />

Prepared from 1H-indazole-3-carboxylic acid using Method C. Yield 53%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 8.19 (d, J = 8.0, 1H) 7.60 (d, J = 85, 1H), 7.43 (m, 1H), 7.26 (m, 1H), 4, 55 (m, 1 H), 3.85 (m, 1 H), 3.50 (m, 1 H), 3.34 (m, 4 H), 2.39 (m, 1 H), 2.28 (m, 1 H) ), 2.11 (m, 2 H), 1.95 (m, 1 H); MS (APCI) m / z 271 (M⁺+1); mp · 305 ° C.

Example 8: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) benzo [d] isothiazole3-carboxamide.

<img file="RS53147B_D0037.tif" />

Prepared from 5-bromobenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 5%. LC / MS (EI) m.p._R 4.7 min, m / z 365 (M⁺+1).

53147 Β

Example 9: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yn-5- (methoxy) benzo [d] isothialoyl)

3-carboxamide.

<img file="RS53147B_D0038.tif" />

Prepared from 5-methoxybenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 5%. LC / MS (EI) m.p._R 3.14 min, m / z 318 (M⁺+1).

Example 10: Nf (3R) -1-Azabicyclo [2.2.2-oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide.

5-Bromo-1H-indazole-3-carboxylic acid.

<img file="RS53147B_D0039.tif" />

n

Prepared from 5-bromoisatin using Method Q. ¹1 H NMR (DMSO-d 6)₆) b 13.9 (broad s, 1H), 8.23 ​​(d, J = 1.3, 1H), 7.67 (j, J = 8.9, 1H), 7.57 (dd, J =

8.9, 1.8, 1H).

53147 Β

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide.

<img file="RS53147B_D0040.tif" />

Prepared from 5-bromo-1H-indazole-3-carboxylic acid using Method D. Yield 32%. ¹1 H NMR (DMSO-d 6) δ 8.35 (d, J = 7.2, 1H), 8.28 (d, J = 1.4, 1H), 7.62 (d, J = 8.8, 1H), 7.52 (dd, J = 8.8, 1.8, 1H), 4.00 (m, 1H&gt;, 3.11 (m, 2H), 2.90 (m, 1H), 2.67 (m, 4H), 1.82 (m, 2H), 1.59 (t, J = 5.6, 2H), 1.30 (m, 1H); ¹1 H NMR (CD 3 OD) δ 8.37 (t, J = 1.2, 1H), 7.53 (d, J = 1.2, 2H), 4.22 (m, 1H), 3.33 (m , 1H), 3.02 (m, 1H), 2.84 (m, 4H), 2.06 (m, 1H), 194 (m, 2H), 1.80 (m, 2H), 1.58 (m, 1 H); MS (EI) m / z 349/351 (M &amp; lt; + &amp; gt;)⁺+2).

Example 11: N - ((3R, N-Azabicyclo [2.2.2] oct-3-yl) -5- (cyclopropyl-1H-indazole) -carboxamide hydroformate.

<img file="RS53147B_D0041.tif" />

Ln

Prepared from N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method J. Yield 20%. ¹1 H NMR (CD₃OD) b 789 (s, 1H), 7.48 (d, J = 8.7, 1H) 7.21 (dd, J = 8.7, 1.6, 1H), 4.54 (m, 1H) ),

53147 Β

3.82 (m, 1H), 3.42 (m, 1N), 3.35 (m, 4N), 2.38 (m, 1N), 2.28 (m, 1N), 2.11 (m, ZN), 1.92 (m, 1N), 0.98 (m, 2N), 0.73 (m, 2N); MS (EI) m / z 311 (M &amp; lt; + &amp; gt;)⁺+1).

Example 12: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (furan-3-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0042.tif" />

ou n on

Prepared from N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 3%. ¹1 H NMR (CD₃OD) b 8.47 (s, 1H) 7.93 (d, J = 0.9, 1H), 7.68 (dd, J = 8.8, 1.6, 1H), 7.59 (dd , J = 8.9, 1.7, 2H), 6.87 (m, 1H), 4.54 (m, 1H), 3.82 (m, 1H), 3.42 (m, 1H), 3.34 (m, 4H), 2.38 (m, 1H), 2.27 (m, 1H), 2.11 (m, 2H), 1.93 (m, 1H); MS (EI) m / z 337 (M +)⁺+1).

Example 13: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole-3-carboxamide.

<img file="RS53147B_D0043.tif" />

Prepared from N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 5%. ¹1 H NMR (CD₃OD) b 8.48

53147 S (s, 1 Η), 8.42 (s, 1 Η), 7.74 (dd, J = 8.7, 1.6, 1 Η), 7.67 (d, J = 7.2, 2H), 7.46 (t, J = 7.3, 2H), 7.34 (t, J = 7.4, 1H), 4.52 (m, 1H), 3.83 (m, 1H) , 3.42 (m, 1 H),

3.31 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H9, 1.92 (m, 1H); MS (EI) m / z). of 347 (M⁺+1).

Example 14: N - ((3RM-Azabicyclo [2.2.2] oct-3-yl] -5- (thiophen-2-yl) -1H-indazole3-carboxamide.

<img file="RS53147B_D0044.tif" />

Prepared from N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 85%. ¹1 H NMR (CD₃OD) b

8.46 (t, J = 0.8, 1H), 7.75 (dd, J = 8.8, 1.7, 1H), 7.61 (dd, J = 8.8, 0.7, 1H),

7.42 (dd, J = 3.6, 1.1, 1H), 7.37 (dd, J = 5.1, 1.0, 1H), 7.11 (dd, J = 5.1, 1.0, 1H), 7.10 (dd, J = 5.1, 3.6, 1H), 4.27 (m, 1H), 3.42 (m, 1H), 3.12 (m, 1H),

2.93 (m, 4H), 2.11 (m, 1H), 1.93 (m, 1H), 1.84 (m, 2H), 1.62 (m, 1H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 15: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0045.tif" />

53147 Β

Prepared from N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 20%. ¹1 H NMR (CD₃OD) b

8.45 (t, J = 0.8, 1H), 8.39 (broad s, 1H), 7.78 (dd, J = 8.8, 1.7, 1H), 7.62 (dd, 7 = 8.8, 0.8, 1H), 7.42 (dd, J = 3.6, 1.1, 1H), 7.38 (dd, 7 = 5.1, 1.0, 1H) , 7.11 (dd, J = 5.1, 3.6, 1H), 4.55 (m, 1H), 3.83 (m, 1H), 3.46 (m, 1H), 3.37 (m, 4 H),

2.40 (m, 1 H), 2.25 (m, 1 H), 2.10 (m, 2 H), 1.93 (m, 1 H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 16: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0046.tif" />

Prepared from N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 5%. ¹1 H NMR (CD₃OD) b 8.55 (broad s, 1H), 8.45 (d, J = 0.7, 1H), 7.78 (dd, J = 8.8, 1.6, 1H), 7.62 (m, 1 H),

7.51 (m, 2H), 4.52 (m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.35 (m, 4H), 2.37 (m , 1H), 2.25 (m, 1H), 2.06 (m, 2H), 1.90 (m, 1H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺-I).

53147 Β

Example 17: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -5 (bromo) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0047.tif" />

Preparation from 5-bromobenzo [d] isothiazole-3-carboxylic acid using

Procedure B. Yield 5%. LC / MS (EI) m.p._R 5.36 min, m / z 365 (M⁺+1).

Example 18: N - ((3R) -1-Azabicyclo [2.2.2] oct-341) -5-methoxybenzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0048.tif" />

o

X n on

Prepared from 5-methoxybenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 7%. LC / MS (EI) m.p._R3.38 min, m / z 318 (M⁺+1).

53147 Β

Example 19: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide.

<img file="RS53147B_D0049.tif" />

It is prepared from 5-bromo-1H-indazole-3-carboxylic acid using Method D. Yield 31%. ¹1 H NMR (DMSO-d 6) δ 8.35 (d, J = 7.2, 1H), 8.28 (d, J = 1.4, 1H), 7.62 (d, J = 8.8, 1H), 7.52 (dd, J = 8.8, 1.8, 1H), 4.00 (m, 1H), 3.11 (m, 2H), 2.90 (m, 1H), 2 , 67 (m, 4H), 1.82 (m, 2H), 1.59 (t, J = 5.6, 2H), 1.30 (m, 1H); ¹1 H NMR (CD 3 OD) δ 8.37 (t, J = 1.2, 1H), 7.53 (d, J = 1.2, 2H), 4.22 (m, 1H), 3.33 (m , 1H), 3.02 (m, 1H), 2.84 (m, 4H), 2.06 (m, 1H),

1.94 (m, 2H), 1.80 (m, 2H), 1.58 (m, 1H); MS (EI) m / z 349/351 (M &amp; lt; + &amp; gt;)⁺/ M⁺+2).

Example 20: N - ((3SM-Azabicyclo [2.2.2-oct-3-yl) -5- (furan-3-yn-1H-indazole-3-carboxamide hydroformate.

<img file="RS53147B_D0050.tif" />

<img file="RS53147B_D0051.tif" />

he

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide using Method H. Yield 11%. ¹1 H NMR (CD₃OD) b

8.47 (s, 1H), 7.93 (d, J = 0.9, 1H), 7.68 (dd, J = 8.8, 1.6, 1H), 7.59 (dd, J) =

8.9, 1.7, 2H), 6.87 (m, 1H), 4.54 (m, 1H), 3.82 (m, 1H), 3.42 (m, 1H), 3.34

<img file="RS53147B_D0052.tif" />

53147 Η (m, 4Η), 2.38 (m, 1 Η), 2.27 (m, 1 Β), 2.11 (m, 2N), 1.93 (m, 1N); MS (EI) m / z

Example 21: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (phenyl) -1H-indazole-3-carboxamide hydroformate.

<img file="RS53147B_D0053.tif" />

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (bromo) -1H-indazole-3-carboxamide using Method H. Yield 12%. ¹1 H NMR (CD₃OD) b

8.48 (s, 1H), 8.42 (s, 1H), 7.74 (dd, J = 8.7, 1.6, 1H), 7.67 (d, J = 7.2, 2H) ),

7.46 (t, J = 7.3, 2H), 7.34 (t, J = 7.4, 1H), 4.52 (m, 1H), 3.83 (m, 1H), 3, 42 (m, 1 H), 3.31 (m, 4 H), 2.39 (m, 1 H), 2.28 (m, 1 H), 2.11 (m, 2 H), 1.92 (m, 1 H) ); MS (EI) m / z 347 (M &amp; lt; + &amp; gt;)⁺+1).

Example 22: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-2-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0054.tif" />

o

X n on

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 45%. ¹1 H NMR (CD₃OD) b

53147 Β

8.45 (t, J = 0.8, 1H), 8.39 (broad s, 1H), 7.78 (dd, J = 8.8, 1.7, 1H), 7.62 (dd , d = 8.8, 0.8, 1H), 7.42 (dd, J = 3.6, 1.1, 1H), 7.38 (dd, J = 5.1, 1.0, 1H) &gt; 7.11 (dd, 5,1,3,6, 1H), 4.55 (m, 1H), 3.83 (m, 1H), 3.46 (m, 1H), 3.37 m, 4 H),

2.40 (m, 1 H), 2.25 (m, 1 H), 2.10 (m, 2 H), 1.93 (m, 1 H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 23: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5- (thiophen-3-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0055.tif" />

L_N

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -5-bromo-1H-indazole-3-carboxamide using Method H. Yield 20%. ¹1 H NMR (CD₃OD) b

8.55 (broad s, 1H), 8.45 (d, J = 0.7, 1H), 7.78 (dd, J = 8.8, 1.6, 1H), 7.62 (m, 1H), 7.51 (m, 2H), 4.52 (m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.35 (m, 4H),

2.37 (m, 1H), 2.25 (m, 1H), 2.06 (m, 2H), 1.90 (m, 1H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 24: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0056.tif" />

53147 Β

Prepared from 6-bromobenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 39%. LC / MS (EI) m.p._R 4.75 min, m / z 365 (M⁺+1).

Example 25: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-cyclopropylbenzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0057.tif" />

Prepared from N - ((3R) -1-Azabicyclo (2.2.2-oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method J. Yield 45%. LC / MS (EI) m.p._R 4.25 min, m / z 328 (M⁺+1).

Example 26: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0058.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 37%: LC / MS (EI) t_R 5.95 min, m / z 382 (M⁺+1).

53147 Β

Example 27: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0059.tif" />

Prepared from N - ((R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 8%. LC / MS (EI) m.p._R 4.52 min, m / z 382 (M⁺+1).

Example 28: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yn-6- (3-fluorophenyl) benzo [dlizothiazole-3-carboxamide.

<img file="RS53147B_D0060.tif" />

It is prepared from

N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6 bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 38%. LC / MS (EI) f_R5.92 min, m / z 382 (M⁺+1).

53147 Β

Example 29: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0061.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 10%. LC / MS (EI) m.p._R 4.56 min, m / z 382 (M⁺+1).

Example 30: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0062.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 34%. LC / MS (EI) m.p._R 5.92 min, m / z 382 (M⁺+1).

53147 Β

Example 31: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzord] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0063.tif" />

Prepared from N - ((R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 9%. LC / MS (EI) m.p._R 4.57 min, m / z 382 (M⁺+1).

Example 32: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-turan-3-yl) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0064.tif" />

Prepared from N- (3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 14%. LC / MS (EI) m.p._R 4.32 min, m / z 354 (M⁺+1).

53147 Β

Example 33: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-furan-3-yl) benzordyl] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0065.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 11%. LC / MS (EI) m.p._R 4.32 min, m / z 354 (M⁺+1).

Example 34: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0066.tif" />

Prepared from 5-methoxybenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 73%. ¹1 H NMR (CD₃OD) b 8.59 (d, J = 2.2, 1H), 7.14 (dd, J = 9.1, 2.3, 1H), 4.20 (m, 1H), 3.93 s, ZN), 3.37-3.28 (m, 1 H), 3.05-

2.96 (m, 1H), 2.86-2.79 (m, 2H), 2.07-2.04 (m, 1H), 2.02-1.80 (m, 1H), 1, 78-

1.74 (m, 1 H), 1.56-1.52 (m, 1 H); LC / MS (EI) m.p._R 4.92 min, m / z 318m / z (M⁺+1).

53147 Β

Example 35: N - ((3R) -1-Azabicyclo (2.2.2] oct-3-yl) -6- (morpholin-4-yl) benzo (d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0067.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method I. Yield 34%. ¹1 H NMR (CD₃OD) b 8.54 (d. J = 9.2, 1H), 7.45 (d, J = 2.1, 1H), 7.29 (dd, J = 9.2, 2.2, 1H) ), 4.22-4.19 (m, 1H), 3.88-3.85 (m, 2H), 3.68-3.65 (m, 2H), 3.38-3.30 (m , 5H), 3.09-3.01 (m, 2H), 2.95-2.81 (m, 4H), 2.09-2.06 (m, 1H), 1.97-1.84 (m, 1H), 1.82-1.79 (m, 2H), 1.62-1.54 (m, 1H); LC / MS (EI) m.p._R

4.77 min, m / z 373 (M⁺+1).

Example 36: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [disothiazole-3-carboxamide.

<img file="RS53147B_D0068.tif" />

It is prepared from

N - ((R) -1-azabicyclo [2.2.2] oct-3-yl) -6 bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 37%. LC / MS (EI) m.p._R 5.99 min, m / z 364 (M⁺+1).

100

53147 Β

Example 37: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzord] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0069.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 3%. LC / MS (EI) m.p._R 5.99 min, m / z 364 (M⁺+1).

Example 38: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide.

Preparation

<img file="RS53147B_D0070.tif" />

bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 19%. LC / MS (EI) m.p._R 2.94 min, m / z 365 (M⁺+1).

101

53147 Β

Example 39: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-3-yl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0071.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 5%. LC / MS (EI) m.p._R 2.94 min, m / z 365 (M⁺+1).

Example 40: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridine-4-benzonediolisolthiazole-3-carboxamide ·

Preparation

<img file="RS53147B_D0072.tif" />

are from

N - ((R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 15%. LC / MS (EI) m.p._R 2.96 min, m / z 365 (M⁺+1).

102

53147 Β

Example 41: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0073.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 2%. LC / MS (EI) fe 1.56 min, m / z 365 (M⁺+1).

Example 42: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) benzo [d] isothiazole-3-carboxamide.

Preparation

<img file="RS53147B_D0074.tif" />

are from

N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 16%. LC / MS (EI) m.p._R 4.52 min, m / z 370 (M⁺+1).

103

53147 Β

Example 43: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) benzo [dlizothiazole-3-carboxamide.

<img file="RS53147B_D0075.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 61%. ¹1 H NMR (CD₃OD) b 8.74 (d, J = 8.6, 1H), 8.36 (s, 1H), 7.85 (dd, J =

8.6, 1.4, 1H), 7.62 (d, J = 3.5, 1H), 7.51 (m, 1H), 7.17 (dd, J = 5.0, 3.7) , 1H),

4.52 (m, 1H), 3.87-3.79 (m, 1H), 3.75-3.70 (m, 1H), 3.47-3.19 (m, 4H), 2, 40 (m, 1 H), 2.26 (m, 1 H), 2.11 (m, 1 H), 1.93 (m, 1 H); LC / MS (EI) m.p._R 4.4 min, m / z 370 (M⁺+1).

Example 44: N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (bromo) -1H-indazole-3-carboxamide.

6-Bromo-1H-indazole-3-carboxylic acid are₂n

It is prepared from 6-bromoisatin using Method Q. ¹1 H NMR (DMSO-d 6)₆) b13.7 (broad s, 1H), 8.02 (d, J = 8.5, 1H), 7.60 (d, J = 1.3, 1H), 7.43 (dd, J =

8.7, 1.3, 1H).

104

53147 Β

N - {(3R) -1-azabicyclo [2.2.2] oct-3-yl) -6- (bromo-NH-indazole-3-carbosamide.

n

It is prepared from 6-bromo-1H-indazole-3-carboxylic acid using Method D. Yield 23%. ¹1 H NMR (CD₃OD) b 8.10 (d, J = 8.7, 1H), 7.78 (s, 1H), 7.37 (d, 7 = 8.7.1 H), 4.20 (m, 1H) ), 3.30 (m, 6H), 2.08 (m, 1H), 1.95 (m, 1H), 1.83 (m, 2H), 1.80 (m, 1H); MS (EI) m / z 349/351 (M7M⁺+2).

Example 45: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole · 3-carboxamide hydroformate.

he

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 12%. ¹1 H NMR (CD₃OD) b

8.49 (s, 1 H), 8.16 (m, 1 H), 8.00 (s, 1 H), 7.71 (m, 1 H), 7.59 (m, 1 H), 7.52 (m , 1H), 7.50 (m, 1H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H),

2.30 (m, 1 H), 2.10 (m, 2 H), 1.85 (m, 1 H); MS (EI) m / z 337 (M +)⁺+1).

Example 46: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate.

ΌΗ

105

53147 Β

Prepared from N - ((R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 12%. ¹1 H NMR (CD₃OD) b 8.39 (s, 1H), 8.24 (m, 1H), 7.77 (s, 1H), 7.68 (m, 2H), 7.57 (m, 1H), 7, 50 (m, 2 H),

4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m , 2H), 1.85 (m, 1H); MS (EI) m / z 347 (M &amp; lt; + &amp; gt;)⁺+1).

Example 47: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yn-6- (thiophen-2-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0076.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 13%, ¹1 H NMR (CD₃OD) b

8.49 (s, 1 H), 8.21 (m, 1 H), 7.81 (s, 1 H), 7.74 (m, 1 H), 7.64 (m, 1 H), 7.53 (m, 2 H) ), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H),

2.10 (m, 2 H), 1.85 (m, 1 H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 48: N - ((R) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0077.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 19%. ¹1 H NMR (CD₃OD) b

8.48 (s, 1 H), 8.20 (m, 1 H), 7.80 (s, 1 H), 7.62 (m, 1 H), 7.51 (m, 1 H), 7.44 , 1H), 7.13 (m, 1H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H),

2.30 (m, 1 H), 2.10 (m, 2 H), 1.85 (m, 1 H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

106

53147 Β

Example 49: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-

3-carboxamide.

<img file="RS53147B_D0078.tif" />

Prepared from 6-bromobenzo [d] isothiazole-3-carboxylic acid using

Procedure B. Yield 33%. LC / MS (EI) m.p._R 5.44 min, m / z 365 (M⁺+1).

Example 50: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6-cyclopropylbenzord] isothiazole-3-carboxamide.

<img file="RS53147B_D0079.tif" />

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method J. Yield 40%. LC / MS (EI) m.p._R 4.23 min, m / z 328 (M⁺+1).

107

53147 Β

Example 51: N - ((3S) -1-Azabicyclo (2.2.2-oct-3-yl) -6- (2-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0080.tif" />

It is prepared from

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6 bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 13%. LC / MS (EI) m.p._R 4.52 min, m / z 382 (M⁺+1).

Example 52: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (3-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate.

Preparation

<img file="RS53147B_D0081.tif" />

bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 8%. LC / MS (EI) m.p._R 4.56 min, m / z 382 (M⁺+1).

108

53147 Β

Example 53: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (4-fluorophenyl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0082.tif" />

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 15%. LC / MS (EI) m.p._R 4.56 min, m / z 382 (M⁺+1).

Example 54: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3yl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0083.tif" />

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 24%. LC / MS (EI) m.p._R 4.29 min, m / z 354 (M⁺+1).

109

53147 Β

Example 55: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-methoxybenzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0084.tif" />

Prepared from 5-methoxybenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 73%. LC / MS (EI) m.p._R 4.93 min, m / z 318 (M⁺+1).

Example 56: N - ((3S) -1-Azabicyclo [2H-2-oct-3-yl) -6- (morpholin-4-yl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0085.tif" />

o

A_he

It is prepared from

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6 bromobenzo [d] isothiazole-3-carboxamide using Method I. Yield 5%. LC / MS (EI) m.p._R 2.93 min, m / z 373 (M⁺+1).

110

53147 Β

Example 57: N - {(3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-phenylbenzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0086.tif" />

Ln

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 9%. LC / MS (EI) 4.53 min, m / z 364 (M⁺+1).

Example 58: N4 (3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridine-3-benzofundaisolthiazole-3-carboxamide hydroformate).

<img file="RS53147B_D0087.tif" />

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 8%. LC / MS (EI) m.p._R 2.72 min, m / z 365 (M⁺+1).

111

53147 Β

Example 59: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (pyridin-4yl) benzo [d] isothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0088.tif" />

It is prepared from

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6 bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 5%. LC / MS (EI) m.p._R 2.63 min, m / z 365 (M⁺+1).

Example 60: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl-6- (thiophene-2-yl) benzo [dlisothiazole-3-carboxamide hydroformate.

<img file="RS53147B_D0089.tif" />

o

<img file="RS53147B_D0090.tif" />

It is prepared from

N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6 bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 27%. LC / MS (EI) m.p._R 4.48 min, m / z 370 (M⁺+1).

112

53147 Β

Example 61: N - ((3S) -1-Azabicyclo (2.2.2-oct-3-yl) -6- (thiophen-3-yl) benzo [d] isothiazole-3-carboxamide.

<img file="RS53147B_D0091.tif" />

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 61%. LC / MS (EI) m.p._R 4.41 min, m / z 370 (M⁺+1).

Example 62: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl-6- (bromo) -1H-indazole-3-carboxamide.

<img file="RS53147B_D0092.tif" />

It is prepared from 6-bromo-1H-indazole-3-carboxylic acid using Method D. Yield 19%. ¹1 H NMR (CD₃OD) b 8.10 (d, J = 8.7, 1H), 7.78 (s, 1H), 7.37 (d, 7 = 8.7, 1H), 4.20 (m, 1H) , 3.30 (m, 6H), 2.08 (m, 1H), 1.95 (m, 1H), 1.83 (m, 2H), 1.80 (m, 1H); MS (EI) m / z 349/351 (M7M⁺+2).

113

53147 Β

Example 63: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (furan-3-yl) -1H-indazole-3-carboxamide hydroformate.

<img file="RS53147B_D0093.tif" />

o

X n on

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromobenzo [d] isothiazole-3-carboxamide using Method H. Yield 12%. ¹1 H NMR (CD₃OD) b 8.49 (s, 1H), 8.21 (m, 1H), 7.81 (s, 1H), 7.74 (m, 1H), 7.64 (m, 1H), 7, 53 (m, 2 H), 4.53 (m, 1 H), 3.35 (m, 1 H), 3.28 (m, 5 H),

2.37 (m, 1 H), 2.30 (m, 1 H), 2.10 (m, 2 H), 1.85 (m, 1 H); MS (EI) m / z 337 (M +)⁺+1).

Example 64: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (phenyl) -1H-indazole-3-carboxamide hydroformate.

<img file="RS53147B_D0094.tif" />

o

<img file="RS53147B_D0095.tif" />

he

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 13%. ¹1 H NMR (CD₃OD) b

8.49 (s, 1 H), 8.25 (m, 1 H), 7.77 (s, 1 H), 7.73 (m, 2 H), 7.64 (m, 1 H), 7.53 (m ,,

114

53147 Β

2Η), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H),

2.10 (m, 2 H), 1.85 (m, 1 H); MS (EI) m / z 347 (M &amp; lt; + &amp; gt;)⁺+1).

Example 65: N - ((3SM-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-2-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0096.tif" />

o

X n on

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 22%. ¹1 H NMR (CD₃OD) b

8.49 (s, 1 H), 8.25 (m, 1 H), 7.77 (s, 1 H), 7.73 (m, 2 H), 7.64 (m, 1 H), 7.53 (m , 2H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H),

2.10 (m, 2 H), 1.85 (m, 1 H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 66: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6- (thiophen-3-yl) -1H-indazole3-carboxamide hydroformate.

<img file="RS53147B_D0097.tif" />

o ϋ n on

115

53147 Β

Prepared from N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -6-bromo-1H-indazole-3-carboxamide using Method H. Yield 17%. 8.49 (s, 1 H), 8.21 (m, 1 H), 7.81 (s, 1 H), 7.74 (m, 2 H), 7.64 (m, 1 H), 7.53 (m , 2H), 4.53 (m, 1H),

3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m, 2H), 1.85 (m , 1H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 67: N - ((3 /^:N) -1-Azabicyclo [2.2.2] oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide.

Prepared from 7-methoxybenzo [d] isothiazole-3-carboxylic acid using Method B. Yield 7%. LC / MS (EI) m.p._R 4.00 min, m / z 318 (M⁺+1).

Example 68: N - ((3S) -1-Azabicyclo (2.2.2-oct-3-yl) -7-methoxybenzo [d] isothiazole-3-carboxamide.

Preparation from 7-methoxybenzo [d] isothiazole-3-carboxylic acid using

Procedure B. Yield4%. LC / MS (EI) m.p._R 3m76 min, m / z318 (M⁺+1).

116

53147 Β

Example 69: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine.

<img file="RS53147B_D0098.tif" />

Prepared from 3 - [(3R) -1-azabicyclo [2.2,2] oct-3-yl] -1H-indazole-3-carboxyamide using Method F. Yield 50%. ¹1 H NMR (CD₃OD) b

7.85 (m, 1 H), 7.48 (d, J = 8.4, 1 H), 7.37 (dd, J = 7.2, 8.4, 1 H), 7.14 (dd, J =

7.2, 8.4, 1H), 4.12 (m, 2H), 3.02 (m, 1H), 2.88 (m, 5H), 2.50 (m, 1H), 1.95 (m, 5 H); MS (EI) m / z 257 (M &amp; lt; + &amp; gt;)⁺+1).

Example 70: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-3-ylmethyl) amine.

<img file="RS53147B_D0099.tif" />

Prepared from 3 - [(3S) -1-azabicyclo [2.2,2] oct-3-yl] -1H-indazole-3-carboxamide using Method F. Yield 50%. ¹1 H NMR (CD₃OD) b

7.85 (m, 1 H), 7.56 (m, 1 H), 7.37 (m, 1 H), 7.11 (m, 1 H), 4.12 (m, 2 H), 3.02 (m , 1H), 2.88 (m, 5H), 2.50 (m, 1H), 1.95 (m, 5H); MS (EI) m / z 257 (M &amp; lt; + &amp; gt;)⁺+1).

117

53147 Β

Example 71: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide.

4-Bromo-1H-indazole

Br

<img file="RS53147B_D0100.tif" />

It is prepared from 3-bromo-2-methylaniline using Method K. Yield 95%. ¹1 H NMR (500 MHz, CDCl 3)₃) b 10.55 (bs, 1H), 8.12 (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 7.25 (dd, 1H).

1H-indazole-4-carboxylic acid

cn n

<img file="RS53147B_D0101.tif" />

n

It is prepared from 4-bromo-1H-indazole using Method L. Yield 55%. ¹1 H NMR (500 MHz, CDCl 3) δ 13.27 (bs, 2H), 7.85 (d, 1H), 7.84 (d, 1H), 7.49 (t, 1H); MS (EI) m / z 161 (M &amp; lt; + &amp; gt;)⁺-1).

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide.

<img file="RS53147B_D0102.tif" />

It is prepared from 1H-indazole-4-carboxylic acid using Method A.

Yield 50%. ¹1 H NMR (CD₃OD) b 8.38 (d, J = 0.9, 1H), 7.74 (d, J = 8.4, 1H),

118

53147 Β

7.62 (d, 7 = 6.9, 1H), 7.46 (dd, J = 6.9, 8.4, 1H), 4.39 (m, 1H), 3.62 (m, 1H),

3.12 (m, 5H), 1.95 (m, 5H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

Example 72: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-4-carboxamide.

<img file="RS53147B_D0103.tif" />

It is prepared from 1H-indazole-4-carboxylic acid using Method A. Yield 50%. ¹1 H NMR (CD₃OD) b 8.40 (d, J = 0.6, 1H), 7.75 (d, J = 8.4, 1H), 7.67 (d, 7 = 6.6, 1H), 7, 45 (dd, 7 = 6.6, 8.4, 1H), 4.49 (m, 1H), 3.77 (m, 1H),

3.30 (m, 5 H), 1.95 (m, 5 H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt; + 1).

Example 73: N- (1H-indazol-4-yl) -1-azabicyclo [2.2.2] oct-3-ylcarboxamide.

<img file="RS53147B_D0104.tif" />

<img file="RS53147B_D0105.tif" />

It is prepared from indazol-4-ylamine using Method E. Yield 30%. ¹H

NMR (CD₃OD) b 8.20 (s, 1H), 7.55 (m, 1H), 7.36 (m, 2H), 3.92 (m, 1H), 3.46 (m, 5H), 2, 56 (m, 1 H), 2.06 (m, 5 H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

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Example 74: N- (1-Azabicyclo [2.2.2] oct-3-yl) -N- (1H-indazol-4-ylmethyl) amine.

<img file="RS53147B_D0106.tif" />

It is prepared from indazole-4-carboxaldehyde using Method G. Yield 50%. ¹1 H NMR (CD₃OD) b 8.27 (s, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.17 (m, 1H), 4.18 (m, 2H), 3, 52 (m, 1 H), 3.30 (m, 5 H), 3.00 (m, 1 H), 1.95 (m, 5 H); MS (EI) m / z 257 (M &amp; lt; + &amp; gt;)⁺+1).

Example 61: N- (3R) -1-Azabicyclo [2.2.2] oct-3-yl) -benzothiazole-5-carboxamide hydrochloride,

1,3-Benzothiazole-5-carboxylic acid

<img file="RS53147B_D0107.tif" />

It is prepared from 4-chloro-3-nitrobenzoic acid using Method O. Yield 4.30 g (94%) of pure product. ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 13.2 (bs, 1H), 9.52 (s, 1H), 8.60 (d, 1H), 8.30 (d, 1H), 8.05 (dd, 1H); MS (ACPI) m / z 178 (M⁺-1).

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N - ((3R) -1-Azabicyclo [2.2.2-oct-3-yl) -benzothiazole-5-carboxamide hydrochloride.

<img file="RS53147B_D0108.tif" />

It is prepared from 1,3-benzothiazole-5-carboxylic acid using Method C. Yield 92%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 9.89 (s, 1 H), 8.68 (s, 1 H),

8.30 (d, J = 8.5, 1 H), 8.14 (d, J = 8.5, 1 H), 4.53 (m, 1 H), 3.87 (m, 1 H), 3, 58 (m, 1 H), 3.43 (m, 4 H), 2.42 (m, 1 H), 2.34 (m, 1 H), 2.13 (m, 2 H), 1.97 (m, 1 H) ); MS (APCI) m / z 288 (M⁺+1); mp 170-180 ° C.

Example 76: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-5-carboxamide hydrochloride.

<img file="RS53147B_D0109.tif" />

It is prepared from 1,3-benzothiazole-5-carboxylic acid using Method C. Yield 96%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 9.77 (s, 1H), 8.66 (s, 1H),

8.27 (d, J = 8.5, 1 H), 8.12 (d, J = 8.5, 1 H), 4.53 (m, 1 H), 3.87 (m, 1 H), 3, 56 (m, 1 H), 3.40 (m, 4 H), 2.42 (m, 1 H), 2.33 (m, 1 H), 2.13 (m, 2 H), 1.97 (m, 1 H) ); MS (APCI) m / z 288 (M⁺+1); mp 166-176 ° C.

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Example 77: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-5-carboxamide.

5-Bromo-1H-indazole

<img file="RS53147B_D0110.tif" />

It is prepared from 4-bromo-2-methylaniline using Method K. Yield 88%. ¹1 H NMR (500 MHz, CDCl 3)₃) b 10.4 (bs, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.47 (dd, J = 1.0, 1H), 7.39 (d, J = 8.5, 1H); MS (EI) m / z 197, 199⁺+1).

1H-indazole-5-carboxylic acid

<img file="RS53147B_D0111.tif" />

It is prepared from 5-bromo-1H-indazole using Method L. Yield 54%. ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 13.18 (bs, 2H), 8.50 (t, 1H), 8.27 (d, 1H),

7.95 (dd, 1 H), 7.63 (dt, 1 H); ¹³C NMR (125 MHz, DMSO-d 6)₆) b 167.71, 141.64, 135.20, 126.61, 123.79, 123.12, 122.60, 110.04; MS (APCI) m / z 161 (M⁺+1).

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-5-carboxamide.

<img file="RS53147B_D0112.tif" />

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It is prepared from 1H-indazole-5-carboxylic acid using Method A.

Yield 50%. ¹1 H NMR (CD₃OD) b 8.34 (s, 1H), 8.15 (s, 1H), 7.88 (d, J = 8.7,

1H), 7.59 (d, J = 8.7, 1H), 4.23 (m, 1H), 3.43 (m, 1H), 2.97 (m, 5H), 1.92 (m ,,

5H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

Example 78: N - ((3S) -1-Azabicyclo [2.2.2-oct-3-yl) -1H-indazole-5-carboxamide.

<img file="RS53147B_D0113.tif" />

o

Prepared from 1H-indazole-5-carboxylic acid using Method A. Yield 50%. ¹1 H NMR (CD₃OD) b 8.34 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.60 (d, J = 9.0, 1H) , 4.30 (m, 1H), 3.54 (m, 1H), 3.05 (m, 5H), 1.92 (m, 5H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

Example 79: N- (1H-indazol-5-yl) -1-azabicyclo [2.2.2] oct-3-ylcarboxamide.

<img file="RS53147B_D0114.tif" />

It is prepared from 1H-indazol-5-ylamine using Method E. Yield 30%. ¹1 H NMR (CD₃OD) b 8.04 (m, 2H), 7.45 (m, 2H), 3.40 (m, 1H), 2.90 (m, 5H),

2.16 (m, 1 H), 1.90 (m, 5 H); MS (Ei) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

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Example 80: N- (1-Azabicyclo (2.2.2-oct-3-yl) benzothiazole-6-carboxamide.

<img file="RS53147B_D0115.tif" />

ο

It is prepared from benzothiazole-6-carboxylic acid using Method A. Yield 60%. ¹1 H NMR (CDCl 3)₃) b 9.14 (s, 1H), 8.50 (m, 1H), 8.20 (m, 1H),

7.90 (m, 1 H), 6.47 (m, 1 H, NH), 4.25 (m, 1 H), 3.45 (m, 2 H), 2.78 (m, 4 H),

1.90 (m, 5 H); MS (EI) m / z 288 (M. +)⁺+1).

Example 81: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide hydrochloride.

<img file="RS53147B_D0116.tif" />

It is prepared from 1,3-benzothiazole-6-carboxylic acid using Method C. Yield 85%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 9.71 (s, 1H), 8.74 (t, J = 1.0, 1H), 8.16 (m, 2H), 4.51 (m, 1H), 3.85 (m , 1H), 3.53 (m, 1H), 3.37 (m, 6H), 2.39 (m, 1H), 2.30 (m, 1H), 2.11 (m, 2H), 1 , 95 (m, 1 H); MS (APCI) m / z 288 (M⁺+1); mp 285 ° C (dec.).

Example 82: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-6-carboxamide hydrochloride.

<img file="RS53147B_D0117.tif" />

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It is prepared from 1,3-benzothiazole-6-carboxylic acid using Method

C. Yield 100%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 9.75 (s, 1H), 8.75 (t, J =)

1.0, 1H), 8.17 (m, 2H), 4.50 (m, 1H), 3.85 (m, 1H), 3.51 (m, 1H), 3.37 (m,

7H), 2.40 (m, 1H), 2.31 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H); MS (APCI) m / z

288 (M⁺+1); tt dec. 287 ° C.

Example 83: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -2- (pyrrol-1-yl) benzothiazole-6-carboxamide hydroformate.

<img file="RS53147B_D0118.tif" />

<img file="RS53147B_D0119.tif" />

he

It is prepared from 2- (pyrrol-1-yl) 1,3-benzothiazole-6-carboxylic acid using Method A. Yield 75%. ¹1 H NMR (CD₃OD) b 8.45 (s, 1H), 7.99 (d, J = 8.4, 1H), 7.90 (d, J = 8.4, 1H), 7.56 (d, J = 2.1, 1H), 6.44 (d, J = 2.1, 1H), 4.47 (m, 1H), 3.87 (m, 1H), 3.40 (m, 4H), 2 .39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.96 (m, 1H); MS (EI) m / z 353 (M &amp; lt; + &amp; gt;)⁺+1).

Example 84: N- (Benzothiazol-6-yl) -1-azabicyclo [2.2.2] oct-3-ylcarboxamide ·

<img file="RS53147B_D0120.tif" />

It is prepared from benzothiazol-6-yl amine using Method E. Yield 30%. ¹1 H NMR (CD₃OD) b 9.11 (s, 1H), 8.51 (s, 1H), 7.95 (d, J = 9.0, 1H), 7.62 (d, J = 9.0.1H) , 3.44 (m, 1H), 2.88 (m, 6H), 2.13 (m, 1H), 1.74 (m, ZN), 1.46 (m, 1H); MS (EI) m / z 288 (M &amp; lt; + &amp; gt;)⁺+1).

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Example 85: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-6-carboxamide.

6-Bromo-1H-indazole

<img file="RS53147B_D0121.tif" />

It is prepared from 5-bromo-2-methylaniline using Method K. Yield 88%. ¹1 H NMR (400 MHz, CDCl 3)₃) b 13.20 (bs, 1H), 8.10 (d, 1H), 7.76 (m, 1H), 7.72 (dd, 1H), 7.24 (dd, 1H).

1H-indazole-6-carboxylic acid

<img file="RS53147B_D0122.tif" />

It is prepared from 6-bromo-1H-indazole using Method L. Yield 46%. ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 13.24 (bs, 2H), 8.20 (d, 1H), 8.19 (m, 1H),

7.87 (dd, 1 H), 7.70 (dd, 1 H); ¹³C NMR (125 MHz, DMSO-d 6)₆) b 167.53, 139.32, 133.43, 128.23, 125.08, 120.47, 120.45, 112.10; MS (APCI) m / z 161 (M⁺-1).

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-6-carboxamide.

<img file="RS53147B_D0123.tif" />

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It is prepared from 1H-indazole-6 carboxylic acid using Method A.

Yield 50%. ¹1 H NMR (CD₃OD) b 8.11 (s, 1H), 8.06 (s, 1H), 7.83 (d, J = 8.4,

1H), 7.60 (d, J = 8.4, 1H), 4.24 (m, 1H), 3.35 (m, 1H), 2.97 (m, 5H), 1.92 (m ,,

5H); MS (EI) m / z 271 (M +)⁺+1).

Example 86: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-6-carboxamide.

<img file="RS53147B_D0124.tif" />

It is prepared from 1H-indazole-6-carboxylic acid using Method A. Yield 50%. ¹1 H NMR (CD₃OD) b 8.11 (s, 1H), 8.06 (s, 1H), 7.84 (d, J = 7.8, 1H), 7.60 (d, J = 7.8, 1H) , 4.22 (m, 1H), 3.41 (m, 1H), 2.96 (m, 5H), 1.92 (m, 5H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

Example 87: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -3- (thiophen-3-yl) -1H-indazole 6-carboxamide hydroformate.

<img file="RS53147B_D0125.tif" />

Prepared from N - ((3R) -1-azabicyclo [2.2.2] oct-3-yl) -3- (iodo) -1H-indazole-6-carboxamide using Method H. Yield 28%. LC / MS (EI) m.p._R4.17 min,. m / z 353 (M⁺+1).

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Example 88: N- (1H-Indazol-6-yl) -1-azabicyclo [2.2.2] oct-3-ylcarboxamide.

<img file="RS53147B_D0126.tif" />

It is prepared from indazol-6-yl amine using Method E. Yield 30%. ¹1 H NMR (CD 3 OD) δ 8.18 (s, 1H), 7.92 (s, 1H), 7.62 (m, 1H), 7.62 (m, 1H), 3.64 (m, 1H) , 3.30 (m, 5H), 2.40 (m, 1H), 1.90 (m, 5H); MS (EI) m / z 271 (M &amp; lt; + &amp; gt;)⁺+1).

Example 89: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride.

1,3-Benzothiazole-7-carboxylic acid

<img file="RS53147B_D0127.tif" />

so₂n

It was prepared from ethyl 3-aminobenzoate using Method P. Yield 2.75 g (91%). ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 7.71 (t, J = 7.5, 1H), 8.15 (d, J = 7, 1H), 8.38 (d, 7 = 8, 1H), 9.51 (s, 1H) ), 13.74 (bs, 1H); MS (APCI) m / z 178 (M⁺-1).

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride.

<img file="RS53147B_D0128.tif" />

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It is prepared from 1,3-benzothiazole-7-carboxylic acid using Method C. ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 1.71-1.75 (m, 1H), 1.92-1.96 (m, 2H), 2.18-2.26 (m, 2H), 3.17-3.25 (m , ZN), 3.45-3.66 (m, ZN), 4.44 (d, J = 6, 1H),

7.69 (t, J = 8, 1H), 8.28 (d, J = 8, 1H), 8.54 (d, J = 8, 1H), 9.37 (d, J = 6.5) , 1H), 9.49 (s, 1H), 10.88 (bs, 1H); MS (EI) m / z 288 (M &amp; lt; + &amp; gt;)⁺+1).

Example 90: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) benzothiazole-7-carboxamide hydrochloride.

CIH ⁰

It is prepared from 1,3-benzothiazole-7-carboxylic acid using Method C. ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 1.71-1.75 (m, 1 H), 1.92-1.95 (m, 2 H),

2.17-2.26 (m, 2H), 3.17-3.24 (m, ZN), 3.44-3.55 (m, 2H), 4.44 (d, J = 6, 1H) ),

7.69 (t, J = 8, 1H), 8.29 (d, J = 8, 1H), 8.53 (d, J = 8, 1H), 9.36 (d, J = 6.5) , 1H), 9.48 (s, 1H), 10.87 (bs, 2H); MS (EI) m / z 288 (M &amp; lt; + &amp; gt;)⁺+1).

Example 91: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide.

1H-&gt; indazole-7-carboxylic acid salt, n

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It is prepared from 2-amino-3-methylbenzoic acid using Method M. Yield 5.86 g (94%). ¹1 H NMR (500 MHz, DMSO-d 6)₆) b 13.20 (bs, 2H), 8.23 ​​(s, 1H), 8.08 (dd, 1H), 8.00 (dd, 1H), 7.25 (dd, 1H); MS (APCI) m / z 161 (M⁺1).

N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide.

<img file="RS53147B_D0129.tif" />

It is prepared from 1H-indazole-7-carboxylic acid using Method A. Yield 50%. ¹1 H NMR (CD₃OD) b 8.15 (s, 1H), 7.97 (dd, J = 7.5, 7.8, 2H),

7.21 (dd, J = 7.8, 7.5, 1H), 4.30 (m, 1H), 3.43 (m, 1H), 3.06 (m, 1H), 2.85 m, 4H), 1.95 (m, 5H); MS (EI) m / z 271 (M +)⁺+1).

Example 92: N - ((3R) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride.

<img file="RS53147B_D0130.tif" />

It is prepared from 1H-indazole-7-carboxylic acid using Method C. Yield 71%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 8.61 (s, 1H), 8.32 (d, J = 7.5, 1H), 8.14 (d, J = 8.0, 1H), 7.44 (dd, J = 8.0, 7.5, 1H), 4.59 (m, 1H), 3.89 (m, 1H), 3.55 (m, 1H), 3.40 (m, 4H), 2.44 (m, 1H), 2.30 (m, 1H), 2.12 (m, 2H).

1.96 (m, 1 H); MS (APCI) m / z 271 (M⁺+1).

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Example 93: N-FOS1-1-Azabicyclo [N-loct-α-1H-indazole · carboxamide.

<img file="RS53147B_D0131.tif" />

It is prepared from 1H-indazole-7-carboxylic acid using Method A. Yield 50%. ¹1 H NMR (CD₃OD) b 8.16 (s, 1H), 8.05 (dd, J = 6.6, 0.9, 1H),

7.21 (dd, J = 0.9, 7.5, 1H), 7.21 (dd, J = 7.5, 6.6, 1H), 4.48 (m, 1H), 3.62 (m, 1 H), 3.20 (m, 1 H), 3.10 (m, 4 H), 1.95 (m, 5 H); MS (EI) m / z 271 (M +)⁺+1).

Example 94: N - ((3S) -1-Azabicyclo [2.2.2] oct-3-yl) -1H-indazole-7-carboxamide hydrochloride.

<img file="RS53147B_D0132.tif" />

It is prepared from 1H-indazole-7-carboxylic acid using Method C. Yield 71%. ¹1 H NMR (500 MHz, CD 3)₃OD) b 8.61 (s, 1H), 8.32 (d, J = 7.5, 1H), 8.14 (d, J = 8.0, 1H), 7.44 (t, J = 8.0, 1H), 4.59 (m, 1H), 3.89 (m, 1H),

3.55 (m, 1H), 3.40 (m, 4H), 2.44 (m, 1H), 2.30 (m, 1H), 2.12 (m, 2H), 1.96 (m , 1H); MS (APCI) m / z 271 (M⁺+1); mp 180-188 ° C.

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Example 95: [³Η] MLA binding

Materials:

Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2

Protease Inhibitor Cocktail Tablet: Roche, CAT No. 1697498

Membrane preparation

The rat brain in 20 volumes (w / v) of ice-cold 0.32 M sucrose with protease inhibitors (one tablet per 50 ml_) was homogenized with a polytron for 10 seconds at setting 11 and then centrifuged for 10 minutes at 1000 g, 4 ° C. . The surface layer was centrifuged again for 20 minutes at 20,000 g, 4 ° C. Granules were resuspended in binding buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO4, 2 mM CaCl 2, 0.1% (w / v ) BSA) and stored in a stored membrane at -80 ° C.

For saturation assay, 200 μΙ of the assay mixture in binding buffer contains 200 pg of membrane protein, 0.2 to 44 nM [³H] MLA. Non-specific binding is defined using 1 μΜ MLA. The competition test is performed with 2 nM [³H] MLA and the preferred range of compounds. The sample mixture was incubated at 22 ° C for 2 hours, then collected with a GF / B filter pre-soaked with 0.3% PEI in binding buffer using a Tomtec collection device. The filter is washed three times with binding buffer and the radioactivity is measured with Trilux.

The foregoing examples may be repeated with similar success by substituting the generically or specifically described reactants and / or operating conditions of the present invention for those used in the preceding examples.

132