CN101001856A - Indazole, benzothiazole, benzisothiazole, benzisoxazole, preparation and use thereof - Google Patents

Abstract

In general, the present invention relates to the following fields: ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and treatment of disease states associated with defective or malfunctioning nicotinic acetylcholine receptors, particularly of the brain. In addition, the present invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the α 7nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

Description

Indazole, benzothiazole, benzisothiazole, benzisoxazole, preparation and use thereof

This application claims priority to US Provisional Application 60/555,951, filed March 25, 2004, and US Provisional Application 60/616,033, filed October 6, 2004, the entire disclosures of which are incorporated herein by reference.

This application is also related to U.S. Patent Application 10/669,645, filed September 25, 2003, which claims U.S. Provisional Application 60/413,151, filed September 25, 2002, and U.S. Provisional Application 60/ 448,469, the disclosure of which is incorporated herein by reference in its entirety.

technical field

The present invention generally relates to the field of ligands for nicotinic acetylcholine receptors (nAChRs), activation of nAChRs and treatment of conditions associated with deficiency or dysfunction of nicotinic acetylcholine receptors, particularly those of the brain. Furthermore, the present invention relates to novel compounds that are ligands for the α7 nAChR subtype, methods for preparing these compounds, compositions containing these compounds, and methods for their use.

Background technique

There are two types of neurotransmitters, acetylcholine: muscarinic receptors and nicotinic receptors, which are based on the selectivity of muscarinic and nicotinic action, respectively. Muscarinic receptors are G-protein coupled receptors. Nicotinic receptors are members of the ligand-gated ion channel family. When activated, the conductance of ions across the nicotinic ion channel is increased.

Nicotinic alpha-7 receptor proteins form homopentameric channels in vitro that are highly permeable to various cations (eg, Ca ⁺⁺ ). Each nicotinic alpha-7 receptor has four transmembrane domains, termed M1, M2, M3 and M4. The M2 domain has been proposed to line the walls of this channel. Sequence alignment shows that nicotine α-7 is highly conserved during evolution. The M2 domain covering the inner layer of the channel is the same in protein sequences from chicken to human. For a discussion of the alpha-7 receptor, see, eg, Revah et al. (1991), Nature, 353, 846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000), PNAS 97 (7), 3643-3648; 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 multiple brain regions 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 on presynaptic and postsynaptic terminals and have been proposed to be involved in the regulation of synaptic transmission. Therefore, it is of interest to develop new compounds that are ligands of the α7nACh receptor subtype for the treatment of conditions associated with nicotinic acetylcholine receptor deficiency or dysfunction.

Contents of the invention

The present invention relates to novel compounds that are ligands for the α7 nACh receptor subtype, methods of making these compounds, compositions comprising these compounds and methods of their use.

Detailed ways

The present invention includes compounds of formula I, II, III or IV and their pharmaceutically acceptable salts:

in

A is

或

or

X is O or S;

R' is H, alkyl having 1-4 carbon atoms, haloalkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms, or cycloalkyl having 4-7 carbon atoms alkyl;

R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , -O-(C _{1- 6} -Alkyl-O) _1-2 -C _1-6 -Alkyl, NR ² -C _1-6 -Alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 -Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -alkyl-Ar, NR ² -C _1-6 -alkyl-CO-OR ² , NR ² -C _1-6 -alkyl-NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , alkyl with 1-4 carbon atoms, fluorinated alkanes with 1-4 carbon atoms (eg CF ₃ ), alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms (eg ethynyl, propynyl, pentynyl), wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het (eg phenylacetylene C ₆ H ₅ -C≡C-), cycloalkyl having 3-7 carbon atoms, unsubstituted or substituted by Cycloalkenes with 5-8 carbon atoms substituted by HCO-, C _1-6 -alkoxy, NR ⁶ R ⁷ , CO-NR ⁶ R ⁷ , C _2-6 -alkoxycarbonyl or -CO-R ¹⁰ radical, cycloalkylalkyl having 4-7 carbon atoms, cycloalkenylalkyl having 6-9 carbon atoms, alkoxy having 1-4 carbon atoms (eg OCH ₃ ), having 3- Cycloalkoxy with 7 carbon atoms, cycloalkylalkoxy with 4-7 carbon atoms (eg cyclopropylmethoxy), alkylthio with 1-4 carbon atoms (eg SCH ₃ ) , Fluorinated alkoxides with 1-4 carbon atoms

(eg OCF ₃ , OCHF ₂ ), hydroxyalkyl groups with 1-4 carbon atoms, fluorinated hydroxyalkyl groups with 1-4 carbon atoms (eg 2,2,2-trifluoro-1-hydroxy- 1-(trifluoromethyl)ethyl), hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 2-4 carbon atoms, monoalkane with 1-4 carbon atoms Dialkylamino, wherein each alkyl group independently has 1-4 carbon atoms, alkoxycarbonyl with 2-6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -Alkyl-O-, Het-C _1-6 -Alkyl-O-, Het-CO-Het-, Het-C _1-6 -Alkyl-NR ² - or Ar-C _1-6 -Alkyl-Het-O-,

with the proviso that R is not _NH2 ; or

R is one of

n is 2-4;

m is 3-5; or

Two Rs can form together a 5-membered fused ring structure containing at least one N atom;

R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR _{2 R 9 , SO 2} ^{R 10 ,} SOR ^{10 ,} -O-(C _1-6 -alkyl-O) _1-2 -C _1-6 -alkyl, NR ² -C _1-6 -alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 - Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -Alkyl-Ar, NR ² -C _1-6 -Alkyl-CO-OR ² , NR ² -C _1-6 -Alkyl- NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , with 1-4 carbon atoms, with 1-4 A fluorinated alkyl group of carbon atoms (such as CF ₃ ), an alkenyl group with 2-6 carbon atoms, an alkynyl group with 2-6 carbon atoms (such as ethynyl, propynyl, pentynyl), wherein The alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het (for example, phenylacetylene C ₆ H ₅ -C≡C-), a cycloalkane with 3-7 carbon atoms _5- ^{_ _ _ _} _{_} ^_ Cycloalkenyl with 8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms (e.g. OCH ₃ ), cycloalkoxy having 3-7 carbon atoms, cycloalkylalkoxy having 4-7 carbon atoms (eg cyclopropylmethoxy), alkane having 1-4 carbon atoms Thio group (eg SCH ₃ ), fluorinated alkoxy group with 1-4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxyalkyl group with 1-4 carbon atoms, fluorinated alkoxy group with 1-4 carbon atoms Fluorinated hydroxyalkyl groups (such as 2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), hydroxyalkoxy groups with 2-4 carbon atoms, 2-4 Fluorinated hydroxyalkoxy groups of carbon atoms, monoalkylamino groups having 1-4 carbon atoms, dialkylamino groups wherein each alkyl group independently has 1-4 carbon atoms, having 2-6 carbon atoms Alkoxycarbonyl, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _1-6 -alkyl-O-, Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-; or

^R1 is one of

或者

or

Two R ¹ can form together a 5-membered fused ring structure containing at least one N atom;

^R is H, alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms, ring having 4-7 carbon atoms Alkylalkyl, fluorinated C _1-4 -alkyl-CO-, C _3-7 -cycloalkyl-CO-, C _1-4 -alkyl-NH-CO-, C _3-7 -cycloalkane -NH-CO-, Het, Ar-C _1-4 -alkyl-, Ar-C _1-4 -alkyl-CO-, Ar-C _1-4 -alkyl-SO ₂ -, C _{1- 4} -Alkyl-OC _1-4 -alkyl- (eg CH ₂ CH ₂ -O-CH ₃ ) or Ar-C _1-4 -alkyl-NH-CO-;

R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR ₂ R ⁹ , SO ² R ¹⁰ , SOR ^{10 ,} -O-(C _1-6 -alkyl-O) _1-2 -C _1-6 -alkyl, NR ² -C _1-6 -alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 - Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -Alkyl-Ar, NR ² -C _1-6 -Alkyl-CO-OR ² , NR ² -C _1-6 -Alkyl- NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , with 1-4 carbon atoms, with 1-4 A fluorinated alkyl group of carbon atoms (such as CF ₃ ), an alkenyl group with 2-6 carbon atoms, an alkynyl group with 2-6 carbon atoms (such as ethynyl, propynyl, pentynyl), wherein The alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het (for example, phenylacetylene C ₆ H ₅ -C≡C-), a cycloalkane with 3-7 carbon atoms _5- ^{_ _ _ _} _{_} ^_ Cycloalkenyl with 8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms (e.g. OCH ₃ ), cycloalkoxy having 3-7 carbon atoms, cycloalkylalkoxy having 4-7 carbon atoms (eg cyclopropylmethoxy), alkane having 1-4 carbon atoms Thio group (eg SCH ₃ ), fluorinated alkoxy group with 1-4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxyalkyl group with 1-4 carbon atoms, fluorinated alkoxy group with 1-4 carbon atoms Fluorinated hydroxyalkyl groups (such as 2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), hydroxyalkoxy groups with 2-4 carbon atoms, 2-4 Fluorinated hydroxyalkoxy groups of carbon atoms, monoalkylamino groups having 1-4 carbon atoms, dialkylamino groups wherein each alkyl group independently has 1-4 carbon atoms, having 2-6 carbon atoms Alkoxycarbonyl, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _1-6 -alkyl-O-, Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-; or

^R3 is one of

或者

or

Two ^R3 can together form a 5-membered fused ring structure containing at least one N atom;

R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR ₂ R ⁹ , SO ² R ¹⁰ , SOR ^{10 ,} -O-(C _1-6 -alkyl-O) _1-2 -C _1-6 -alkyl, NR ² -C _1-6 -alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 - Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -Alkyl-Ar, NR ² -C _1-6 -Alkyl-CO-OR ² , NR ² -C _1-6 -Alkyl- NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , with 1-4 carbon atoms, with 1-4 A fluorinated alkyl group of carbon atoms (such as CF ₃ ), an alkenyl group with 2-6 carbon atoms, an alkynyl group with 2-6 carbon atoms (such as ethynyl, propynyl, pentynyl), wherein The alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het (for example, phenylacetylene C ₆ H ₅ -C≡C-), a cycloalkane with 3-7 carbon atoms _5- ^{_ _ _ _} _{_} ^_ Cycloalkenyl with 8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms (e.g. OCH ₃ ), cycloalkoxy having 3-7 carbon atoms, cycloalkylalkoxy having 4-7 carbon atoms (eg cyclopropylmethoxy), alkane having 1-4 carbon atoms Thio group (for example SCH ₃ ), fluorinated alkoxy group with 1-4 carbon atoms (for example OCF ₃ , OCHF ₂ ), hydroxyalkyl group with 1-4 carbon atoms, fluorinated alkoxy group with 1-4 carbon atoms Fluorinated hydroxyalkyl groups (such as 2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), hydroxyalkoxy groups with 2-4 carbon atoms, 2-4 Fluorinated hydroxyalkoxy groups of carbon atoms, monoalkylamino groups having 1-4 carbon atoms, dialkylamino groups wherein each alkyl group independently has 1-4 carbon atoms, having 2-6 carbon atoms Alkoxycarbonyl, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _1-6 -alkyl-O-, Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-; or

^R4 is one of

或者

or

Two R ⁴ can together form a 5-membered condensed ring structure containing at least one N atom;

R ⁵ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , carboxy, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , ^{NR 2} CSNR ⁶ R ⁷ , NR 2 R 9 , SO ² _R ¹⁰ , SOR ¹⁰ , an alkyl group having 1 to 4 carbon atoms, having Fluorinated alkyl groups with 1-4 carbon atoms (for example CF ₃ ), alkenyl groups with 2-6 carbon atoms, alkynyl groups with 2-6 carbon atoms (for example ethynyl, propynyl, pentynyl ), wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups are each unsubstituted or substituted by Ar or Het (eg phenylacetylene C ₆ H ₅ -C≡C-), having 3-7 carbon atoms Cycloalkyl, cycloalkenyl with 5-8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, cycloalkenylalkyl with 1-4 Alkoxy with carbon atoms (for example OCH ₃ ), cycloalkoxy with 3-7 carbon atoms, cycloalkylalkoxy with 4-7 carbon atoms (for example cyclopropylmethoxy), with Alkylthio with 1-4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy with 1-4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxyalkyl with 1-4 carbon atoms, Fluorinated hydroxyalkyl groups having 1 to 4 carbon atoms (e.g. 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl), hydroxyalkanes having 2 to 4 carbon atoms Oxygen, fluorinated hydroxyalkoxy groups having 2-4 carbon atoms, monoalkylamino groups having 1-4 carbon atoms, dialkylamino groups wherein each alkyl group independently has 1-4 carbon atoms , an alkoxycarbonyl group having 2-6 carbon atoms, Ar, Het, OAr or OHet;

Each R ^{and R} is independently H, alkyl having 1-4 carbon atoms, alkoxyalkyl having 2-8 carbon atoms, cycloalkyl having 3-7 carbon atoms, or having Cycloalkylalkyl with 4-7 carbon atoms, or ^R6 and ^R7 together are an alkylene group containing 4-6 carbon atoms and forming a ring with said N atom (e.g. piperidinyl, pyrrolidinyl) ;

R ⁸ is H, alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms (eg CF ₃ ), alkenyl having 3-6 carbon atoms, Alkynyl of carbon atoms (such as propynyl, pentynyl), wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl is unsubstituted or substituted by Ar or Het (such as phenylacetylene C ₆ H ₅ -C≡C-), cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkylalkyl having 4-7 carbon atoms, cycloalkylalkyl having 6-9 Cycloalkenylalkyl with carbon atoms, hydroxyalkyl with 1-4 carbon atoms, fluorinated hydroxyalkyl with 1-4 carbon atoms, monoalkylamino with 1-4 carbon atoms, wherein each Each alkyl group independently has dialkylamino, Ar or Het of 1-4 carbon atoms;

^R is Ar, Ar-alkyl wherein the alkyl moiety has 1-4 carbon atoms, or Het;

R ¹⁰ is an alkyl group having 1-4 carbon atoms, a fluorinated alkyl group having 1-4 carbon atoms (eg CF ₃ ), an alkenyl group having 3-6 carbon atoms, an alkenyl group having 3-6 carbon atoms alkynyl (such as propynyl, pentynyl), wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl is unsubstituted or substituted by Ar or Het (such as phenylacetylene C ₆ H ₅ -C ≡C-), cycloalkyl with 3-7 carbon atoms, cycloalkenyl with 5-8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, cycloalkyl with 6-9 carbon atoms Cycloalkenylalkyl, hydroxyalkyl having 2-4 carbon atoms, fluorinated hydroxyalkyl having 2-4 carbon atoms, monoalkylamino having 1-4 carbon atoms, wherein each alkane The group independently has a dialkylamino group of 1-4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar or Het;

Ar is an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted one or more times by: alkyl group having 1-8 carbon atoms, alkoxy group having 1-8 carbon atoms , halogen (F, Cl, Br or I, preferably F or Cl), dialkylamino, amino, cyano, hydroxyl, nitro, wherein the alkyl moieties each have 1-8 carbon atoms, have 1-8 Haloalkyl with carbon atoms, haloalkoxy with 1-8 carbon atoms, hydroxyalkyl with 1-8 carbon atoms, hydroxyalkoxy with 2-8 carbon atoms, hydroxyalkoxy with 3-8 carbon atoms Alkenyloxy, alkylthio with 1-8 carbon atoms, alkylsulfinyl with 1-8 carbon atoms, alkylsulfonyl with 1-8 carbon atoms, alkylsulfonyl with 1-8 carbon atoms Atomic monoalkylamino, wherein the cycloalkyl is optionally substituted and has 3-7 carbon atoms cycloalkylamino, wherein the aryl moiety is optionally substituted and contains 6-10 carbon atoms (e.g. phenyl, Naphthyl, biphenyl) aryloxy, wherein the aryl moiety is optionally substituted and contains 6-10 carbon atoms (e.g. phenyl, naphthyl, biphenyl) arylthio, wherein cycloalkyl is optionally Cycloalkoxy, sulfo, sulfonylamino, amido (such as acetamido), acyloxy (such as acetoxy) or combinations thereof that are substituted and have 3-7 carbon atoms; and

Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, has 5-10 ring atoms, wherein at least one ring atom is a N, O or S atom, and the heterocyclic group is unsubstituted or replaced by The following groups are substituted one or more times: halogen (F, Cl, Br or I, preferably F or Cl), optionally substituted aryl having 6-10 carbon atoms (e.g. phenyl, naphthyl, biphenyl radical), alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, cycloalkyl having 3-7 carbon atoms, cyano, trifluoromethyl, nitro, oxygen Substitute, OH, alkoxycarbonylalkyl having 3-8 carbon atoms, amino, monoalkylamino having 1-8 carbon atoms, dialkylamino wherein each alkyl group has 1-8 carbon atoms , SO ₂ R ¹¹ , -CXR ¹¹ , piperidinylethyl, or combinations thereof;

Carbo is a partially unsaturated carbocyclic group having 5-14 carbon atoms which is unsubstituted or substituted one or more times by: halogen, alkyl having 1-8 carbon atoms, having 1- Alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., indanyl, tetralinyl, etc.) of 8 carbon atoms; and

R ¹¹ is alkyl having 1-4 carbon atoms, haloalkyl having 1-4 carbon atoms (eg CF ₃ ), alkenyl having 3-6 carbon atoms, alkyne having 3-6 carbon atoms (e.g. propynyl, pentynyl), wherein each of the alkyl, haloalkyl, alkenyl or alkynyl groups is unsubstituted or substituted by Ar or Het (e.g. phenylacetylene C ₆ H ₅ -C≡C-) , cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkylalkyl having 4-7 carbon atoms, cycloalkenyl having 6-9 carbon atoms Alkyl, hydroxyalkyl having 2-4 carbon atoms, fluorinated hydroxyalkyl having 2-4 carbon atoms, monoalkylamino having 1-4 carbon atoms, wherein each alkyl independently has Dialkylamino of 1 to 4 carbon atoms or Ar.

In formula I, when A is indazolyl of subformula (a), it is preferably linked to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzothiazolyl of subformula (b), it is preferably linked to the rest of the compound via its 4 or 7 position. When A is benzisothiazolyl of subformula (c), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzisoxazolyl of subformula (d), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position.

Similarly, in formula II, when A is indazolyl of subformula (a), it is preferably linked to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzothiazolyl of subformula (b), it is preferably linked to the rest of the compound via its 4 or 7 position. When A is benzisothiazolyl of subformula (c), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzisoxazolyl of subformula (d), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position.

Likewise, in formula III, when A is indazolyl of subformula (a), it is preferably linked to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzothiazolyl of subformula (b), it is preferably linked to the rest of the compound via its 4 or 7 position. When A is benzisothiazolyl of subformula (c), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzisoxazolyl of subformula (d), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position.

Furthermore, in formula IV, when A is indazolyl of sub-formula (a), it is preferably linked to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzothiazolyl of subformula (b), it is preferably linked to the rest of the compound via its 4 or 7 position. When A is benzisothiazolyl of subformula (c), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position. When A is benzisoxazolyl of subformula (d), it is preferably attached to the rest of the compound via its 3, 4 or 7 position, especially via the 3 position.

In Formulas I-IV, the indazolyl, benzothiazolyl, benzisothiazolyl and benzisoxazolyl groups of A may be attached to the remainder of the structure via any suitable point of attachment. The following sub-formulas illustrate some preferred linkages between the indazolyl, benzothiazolyl, benzisothiazolyl and benzisoxazolyl groups and the rest of the structure.

Some preferred linkages between indazolyl, benzothiazolyl, benzisothiazolyl and benzisoxazolyl and the rest of the structure are further exemplified by the following sub-formulae.

Some preferred linkages between indazolyl, benzothiazolyl, benzisothiazolyl and benzisoxazolyl and the rest of the structure are further exemplified by the following sub-formulae.

Some preferred linkages between indazolyl, benzothiazolyl, benzisothiazolyl and benzisoxazolyl and the rest of the structure are further exemplified by the following sub-formulae.

X is preferably O.

R' is preferably H or _CH3 , especially H.

Alkyl here means a linear or branched aliphatic hydrocarbon group preferably having 1 to 4 carbon atoms. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

Alkenyl here means a linear or branched aliphatic hydrocarbon group preferably having 2 to 6 carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl and pentenyl.

Alkynyl here means a straight-chain or branched aliphatic hydrocarbon group preferably having 2 to 6 carbon atoms. Suitable alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

Alkoxy means an alkyl-O-group in which the alkyl moiety preferably has 1 to 4 carbon atoms. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and sec-butoxy.

Alkylthio means an alkyl-S-group in which the alkyl moiety preferably has 1 to 4 carbon atoms. Suitable alkylthio groups include, but are not limited to, methylthio and ethylthio.

Cycloalkyl means a monocyclic, bicyclic or tricyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo[2.1.0]pentyl and bicyclo[3.1.0]hexyl.

Cycloalkoxy means a cycloalkyl-O- group, wherein the cycloalkyl moiety is preferably a monocyclic, bicyclic or tricyclic saturated hydrocarbon group having 3 to 7 carbon atoms.

Cycloalkylalkyl groups contain 4-7 carbon atoms. Suitable cycloalkylalkyl groups include, but are not limited to, eg, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and cyclopentylmethyl.

Cycloalkylalkoxy groups contain 4-7 carbon atoms. Suitable cycloalkylalkoxy groups include, but are not limited to, eg cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy and cyclopentylmethoxy.

Cycloalkyl and cycloalkylalkyl groups may be substituted by C _1-4 -alkyl, C _1-4 -alkoxy, hydroxy, amino, monoalkylamino having 1 to 4 carbon atoms and /or a dialkylamino group in which each alkyl group has 1 to 4 carbon atoms.

Aryl, by itself or as part of a group or substituent, unless otherwise indicated, means an aromatic carbocyclic group containing 6 to 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl and biphenyl. Substituted aryl groups include the above aryl groups substituted one or more times by: halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino , dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxyl, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy and acyloxy (e.g. Acetoxy).

Heterocyclyl means saturated, partially saturated and fully unsaturated heterocyclic groups having 1, 2 or 3 rings and a total of 5-10 ring atoms, at least one of which is a N, O or S atom . The heterocyclic group preferably contains 1-3 heterocyclic atoms selected from N, O and S. Suitable saturated and partially saturated heterocyclic groups include, but are not limited to, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Isoxazolinyl, etc. Suitable heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolyl , naphthyridyl, etc. Other examples of suitable heterocyclic groups are 2-furyl, 3-furyl, 2-quinolyl, 1,3-benzodioxyl (1,3-benzodioxyl), 2-thienyl, 3-thiophene Base, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 2-benzofuryl , 2-benzothienyl, 3-thienyl, 2,3-dihydro-5-benzofuryl, 4-indolyl, 4-pyridyl, 3-quinolyl, 4-quinolyl, 1,4-benzodioxan-6-yl, 3-indolyl, 2-pyrrolyl, tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4 -yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl (6-coumarinyl), 5-benzofuryl, 2-isoimidazol-4-yl , 3-pyrazolyl and 3-carbazolyl.

Substituted heterocyclic group means the above-mentioned heterocyclic group substituted at one or more positions by, for example, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxygen Substitute, amino, alkylamino and dialkylamino.

Groups which are substituted one or more times preferably have 1 to 3 substituents, in particular 1 or 2 of the substituents exemplified. Halo groups such as haloalkyl groups are preferably fluorinated and include but are not limited to perhalo groups such as trifluoromethyl.

According to another aspect of the present invention, in the compound of formula I-IV, when R is NR ⁶ R ⁷ , at least one of R ⁶ and R ⁷ is an alkyl group with 2-4 carbon atoms, an alkyl group with 2-8 alkoxyalkyl with 3-7 carbon atoms, cycloalkyl with 3-7 carbon atoms or cycloalkylalkyl with ^4-7 carbon atoms, or R and ^R together are 4-6 carbon atom and form a ring with said N atom.

According to another aspect of the invention, in the compounds of formulas I-IV, R is not NR ⁶ R ⁷ .

According to another aspect of the invention, in the compound of formulas I-IV, A is a group according to formula (a), (b) or (c), and at least one of R ¹ , R ³ or R ⁴ is H , F, Cl, Br, I, OH, CN, Nitro, NH ₂ , COH, NR ⁶ R ⁷ , Carboxyl, CONR ⁶ R ⁷ , NR ² COR ^{8 , NR 2 COOR 8 , NR 2 CSR 8 ,} NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , with 1-4 Alkyl with 1-4 carbon atoms, fluorinated alkyl with 1-4 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkenyl having 4-7 carbon atoms Cycloalkylalkyl, cycloalkenylalkyl having 6-9 carbon atoms, alkoxy having 1-4 carbon atoms, cycloalkoxy having 3-7 carbon atoms, cycloalkoxy having 4-7 Cycloalkylalkoxy with 1-4 carbon atoms, alkylthio with 1-4 carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, Fluorinated hydroxyalkyl groups with 1-4 carbon atoms, hydroxyalkoxy groups with 2-4 carbon atoms, fluorinated hydroxyalkoxy groups with 2-4 carbon atoms, one Alkylamino, dialkylamino wherein each alkyl independently has 1-4 carbon atoms, alkoxycarbonyl having 2-6 carbon atoms, Ar, Het, OAr or OHet; or one of the following formulae:

和/或

and / or

^R is H, alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms or ring having 4-7 carbon atoms Alkylalkyl; and/or

Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, has 5-10 ring atoms, wherein at least one ring atom is a N, O or S atom, and the heterocyclic group is unsubstituted or replaced by The following groups are substituted one or more times: halogen, optionally substituted aryl having 6-10 carbon atoms, alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, Cyano, trifluoromethyl, nitro, oxo, OH, alkoxycarbonylalkyl having 3-8 carbon atoms, amino, an alkylamino having 1-8 carbon atoms, wherein each alkyl Dialkylamino having 1-8 carbon atoms, SO ₂ R ¹¹ , —CXR ¹¹ , piperidinylethyl, or combinations thereof.

According to another aspect of the present invention, in the compound of formula I-IV, at least one of R ¹ , R ³ or R ⁴ is COH, NR ⁶ R ⁷ wherein at least one of R ⁶ and R ⁷ is not an alkyl group, carboxyl , CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , alkyl having 1-4 carbon atoms substituted by Ar or Het, having 1-4 carbon atoms substituted by Ar or Het Fluorinated alkyl, alkenyl optionally substituted by Ar or Het having 2-6 carbon atoms, alkynyl optionally substituted by Ar or Het having 2-6 carbon atoms, alkynyl optionally substituted by Ar or Het having 5-8 carbon atoms cycloalkenyl, cycloalkenylalkyl having 6-9 carbon atoms, fluorinated hydroxyalkyl having 1-4 carbon atoms, alkoxycarbonyl having 2-6 carbon atoms, OAr, OHet or Het substituted by SO ₂ R ¹¹ or CXR ¹¹ , or selected from the following formulae:

和/或

and / or

R ⁵ is carboxyl, alkoxycarbonyl having 2-6 carbon atoms, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , alkenyl having 2-6 carbon atoms, alkyne having 2-6 carbon atoms Group (such as ethynyl, propynyl), alkyl substituted by Ar or Het, alkenyl substituted by Ar or Het, alkynyl substituted by Ar or Het (such as phenylacetylene), having 5-8 carbon atoms cycloalkenyl, cycloalkenylalkyl having 6-9 carbon atoms, fluorinated hydroxyalkyl having 1-4 carbon atoms (such as 2,2,2-trifluoro-1-hydroxyl-1-( Trifluoromethyl)ethyl), fluorinated hydroxyalkoxy with 2-4 carbon atoms, OAr, OHet or Het substituted by SO ₂ R ¹¹ or CXR ¹¹ .

According to another aspect of the present invention, in the compound of formula I-IV, at least one of R ¹ , R ³ , R ⁴ and R ⁵ is a carboxyl group, an alkoxycarbonyl group with 2-6 carbon atoms, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , ^{NR 2 CSNR 6} R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms (eg ethynyl, propynyl), alkyl substituted by Ar or Het, alkyl substituted by Alkenyl substituted by Ar or Het, alkynyl substituted by Ar or Het (such as phenylacetylene), cycloalkenyl with 5-8 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, cycloalkenylalkyl with 1 - Fluorinated hydroxyalkyl groups with 4 carbon atoms (for example 2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), fluorinated hydroxyalkanes with 2-4 carbon atoms Oxygen, OAr, OHet or Het substituted by SO ₂ R ¹¹ or CXR ¹¹ (preferably, at least one of R ¹ , R ³ , R ⁴ and R ⁵ is an alkynyl group having 2-6 carbon atoms, having 1 - fluorinated hydroxyalkyl or Ar-alkynyl groups of 4 carbon atoms (eg phenylacetylene), especially R ¹ or R ⁴ );

R and R are ^each independently H, alkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms ^, or cycloalkylalkyl having 4-7 carbon atoms, or R ⁶ and ^R together are an alkylene group containing 4-6 carbon atoms and forming a ring with said N atom;

^R9 is Ar or Het; and

Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, has 5-10 ring atoms, wherein at least one ring atom is a N, O or S atom, and the heterocyclic group is unsubstituted or replaced by The following groups are substituted one or more times: halogen (F, Cl, Br or I, preferably F or Cl), optionally substituted aryl having 6-10 carbon atoms (e.g. phenyl, naphthyl, biphenyl group), alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, 1-8 carbon atoms Monoalkylamino, dialkylamino wherein each alkyl group has 1-8 carbon atoms, SO ₂ R ¹¹ , —CXR ¹¹ , or combinations thereof.

According to another aspect of the present invention, the compound is selected from formula I, wherein A is a group of formula (a) or (c), X is O, R ² is H or alkyl (eg CH ₃ ), and R ¹ and R ⁴ are each F, Cl, CN, NO ₂ , NH ₂ , fluorinated alkyl (eg CF ₃ ), alkoxy (eg OCH ₃ ), fluorinated alkoxy (eg OCF ₃ ), fluorinated hydroxy Alkyl (e.g. 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl), alkynyl (e.g. ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy radical, Ar, Ar-alkynyl (eg phenylacetylene) or Het. For example, R ¹ and R ⁴ are each selected from F, Cl, CN, NO ₂ , NH ₂ , CF ₃ , OCH ₃ , OC ₂ H ₅ , OCF ₃ , 2,2,2-trifluoro-1-hydroxyl-1- (Trifluoromethyl)ethyl, ethynyl, propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl, phenylethynyl, dihydropyranyl (e.g. 3, 6-dihydro-2H-pyran-4-yl), thiazolyl (such as 1,3-thiazol-2-yl), oxazolyl (such as 1,3-oxazol-2-yl), pyrrolidinyl (eg pyrrolidin-1-yl), piperidinyl (eg piperidin-1-yl) or morpholinyl (eg morpholin-4-yl). R ⁴ may also be selected from CN, alkoxy, fluorinated alkoxy and cycloalkylalkoxy, eg CN, OCH ₃ , OC ₂ H ₅ , OCF ₃ and cyclopropylmethoxy.

According to another aspect of the invention, the compound is selected from formula Ia or Ij, wherein R ² is H or alkyl (eg CH ₃ ), and R ¹ and R ⁴ are each F, Cl, CN, NO ₂ , NH ₂ , fluorinated alkyl (such as CF ₃ ), alkoxy (such as OCH ₃ ), fluorinated alkoxy (such as OCF ₃ ), fluorinated hydroxyalkyl (such as 2,2,2-trifluoro-1-hydroxy -1-(trifluoromethyl)ethyl), alkynyl (eg ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl (eg phenylacetylene) or Het. For example, R ¹ and R ⁴ are each selected from F, Cl, CN, NO ₂ , NH ₂ , CF ₃ , OCH ₃ , OC ₂ H ₅ , OCF ₃ , 2,2,2-trifluoro-1-hydroxyl-1- (Trifluoromethyl)ethyl, ethynyl, propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl, phenylethynyl, dihydropyranyl (e.g. 3, 6-dihydro-2H-pyran-4-yl), thiazolyl (such as 1,3-thiazol-2-yl), oxazolyl (such as 1,3-oxazol-2-yl), pyrrolidinyl (eg pyrrolidin-1-yl), piperidinyl (eg piperidin-1-yl) or morpholinyl (eg morpholin-4-yl). R ⁴ may also be selected from CN, alkoxy, fluorinated alkoxy and cycloalkylalkoxy, eg CN, OCH ₃ , OC ₂ H ₅ , OCF ₃ and cyclopropylmethoxy.

According to another aspect of the invention, in the compound of formula I-IV, at least one of R ¹ , R ³ or R ⁴ is COH, NR ⁶ R 7 ^or NR wherein at least one of R ⁶ and R ⁷ is not an alkyl group ² COOR ⁸ .

According to another aspect of the present invention, in the compound of formula I-IV, at least one of R ¹ , R ³ or R ⁴ is selected from the following formulae:

According to another aspect of the invention, the compounds of formulas I-IV have 2-3 substituents R ¹ , R ³ or R ⁴ .

According to another aspect of the present invention, in the compounds of formulas I-IV, R ² is a fluorinated alkyl group having 1-4 carbon atoms.

According to another aspect of the present invention, in the compound of formulas I-IV, at least one of ^R6 and ^R7 is an alkoxyalkyl group having 2-8 carbon atoms.

According to another aspect of the invention, in the compound of formulas I-IV, the compound has at least one ^R group which is Ar-alkyl in which the alkyl moiety has 1-4 carbon atoms.

According to another aspect of the present invention, in the compound of formula I-IV, the compound has at least one Het, which is a fully saturated, partially saturated or fully unsaturated heterocyclic group with 5-10 ring atoms, wherein At least one ring atom is a N, O or S atom, and it is substituted by at least one substituent selected from OH, alkoxycarbonylalkyl having 3-8 carbon atoms, and piperidinylethyl.

According to another compound and/or method aspect of the present invention, the compound of formula I-IV is selected from (wherein the compound in salt form can also be its non-salt form):

3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic acid formate,

3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic acid,

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt,

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamide salt,

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide ,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide ,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydrochloride Salt,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amides,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-formamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide formic acid Salt,

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

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide formic acid Salt,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide,

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide trifluoroacetate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide,

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

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

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

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide,

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

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

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

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

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

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide,

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

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide ,

N-[(3S)-1-azabicyclo[2-2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide hydrochloride,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydrochloride Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amides,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide formic acid Salt,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide formic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl Base] -1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide,

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

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

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

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

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide,

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

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

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

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

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide, and their physiologically acceptable salts.

According to another compound and/or method aspect of the present invention, the compound of formula I-IV is selected from (wherein the compound in salt form can also be its non-salt form):

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

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

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3 - Formamide,

N-[(3S-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3- Formamide,

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

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

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

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

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

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-formamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxamide,

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(hydroxyl)-1,2-benzisothiazole-3-carboxamide,

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

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide ,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide ,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole -3-Carboxamide,

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamide salt,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamide salt,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3- formamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3- formamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide salt,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indazole- 3-formamide,

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

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

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

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

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

6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide,

6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide,

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl]amino}carbonyl) Amino]-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1,2-benzene and isothiazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-fluorophenyl)ethyl]amino}carbonyl)amino]- 1,2-Benzisothiazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino]carbonyl}amino)-1, 2-Benzisothiazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbonyl}amino)-1, 2-Benzisothiazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}amino)-1,2-benzene and isothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]amino}carbonyl)amino] -1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino}carbonyl)amino ]-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino}-1,2-benzisothiazole-3 - Formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3- Formamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - Formamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole -3-Carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole -3-Carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - Formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3- formamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide formic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide formic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-indazole-3 - carboxamide dicarboxylate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1H-1,2,3 -triazol-4-yl]-1H-indazole-3-carboxamide dicarboxylate,

[4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)-1H-1,2,3 -Triazol-1-yl] ethyl acetate formate,

Benzyl (3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate,

(3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)vinylcarbamate, and

their physiologically acceptable salts.

According to another compound and/or method aspect of the present invention, the compound of formula I-IV is selected from (wherein the compound in salt form can also be its non-salt form):

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indazole-3-carboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1H-indazole-3-carboxamide salt,

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

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-3-carboxamide formate,

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

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1H-indazol-3- formamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - formamide hydrochloride,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(methoxy)pyrrolidin-1-yl]-1H-indazol-3- formamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)oxy]-1H-indazole-3 - carboxamide dicarboxylate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - formamide hydrochloride,

N-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formate,

N-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide formate,

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole-3- formamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-yloxy)-1H-indazole -3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazole-3-carboxamide diformate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-indazole-3-carboxamide diformate,

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

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3 - Formamide,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazole-3-carboxamide dicarboxylic acid Salt,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-indazole-3-carboxamide dicarboxylic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxamide di formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)oxy]-1H-indazole-3 - carboxamide dicarboxylate,

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy-1H-indazole-3-carboxamide formic acid Salt,

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - formamide hydrochloride,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-cyclopropylmethyl-5-(1,3-thiazol-2-yl)-1H-ind Azole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3-thiazole-2 -yl)-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H-indazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-1,2-benzene Isothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-1,2-benzene Isothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole- 3-formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole- 3-formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-benzisothiazole- 3-formamide,

6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide,

5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-(2,2,2-trifluoroethyl)-1H-indazole-3-methanol amides,

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

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

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

Dimethyl 4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)amino]butanoate salt,

Dimethyl 4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)amino]butanoate salt,

{2-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,2-benzisothiazol-6-yl)amino]ethyl tert-butyl propyl carbamate formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)amino]-1H-indazole-3 - carboxamide formate,

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

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-methoxyethyl)amino ]-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amino}-1, 2-Benzisothiazole-3-carboxamide formate,

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-benzisothiazole-3-methyl amide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisothiazole-3-carboxamide formate ,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole-3-carboxamide formate ,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-(cyclopropylmethyl)-1H-ind azole-3-carboxamide,

5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indazole-3-carboxamidedicarboxylic acid Salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cyclopropylcarbonyl)amino]-1H-indazole -3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5-{[(4-methoxy phenyl)acetyl]amino}-1H-indazole-3-carboxamide formate,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1,2-benzisothiazole-3-carboxamide formate,

6-(Acetamido)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide formate,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]amino}-1,2-benzisothiazole- 3-Carboxamide formate,

5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H-indazole-3-carboxamide dicarboxylate ,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(propylamino)carbonyl]amino}-1H -indazole-3-carboxamide,

N(3)-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzyl)-5-({[(3 -methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,

N(3)-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[(4-fluoro Benzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,

N(3)-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentylamino)carbonyl]amino }-1H-indazole-1,3-dicarboxamide formate,

N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carbonyl]amino}- 1H-indazole-1,3-dicarboxamide,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]thiocarbonyl}amino)-1H-indazole- 3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]thiocarbonyl}amino)-1,2-benzene Isothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)thiocarbonyl]amino}-1,2-benzisothiazole -3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)thiocarbonyl]amino}-1,2-benzisothiazole- 3-Carboxamide formate,

N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbonyl]amino}-1H-indazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(propylamino)carbonyl]amino}-1H -Indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propylamino)carbonyl ]amino}-1H-indazole-3-carboxamide formate,

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole -3-Carboxamide formate,

{3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl}carbamate isopropyl formate,

{3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(isopropylamino)carbonyl]-1H-indazol-5-yl } isopropyl carbamate formate,

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

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

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

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]amino}-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazole-3-carboxamide salt,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin-1-yl)-1H-indazole- 3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2-benzisothiazole -3-Carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2- Benzisothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzene and isothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2- Benzisothiazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzene and isothiazole-3-carboxamide,

6-[acetyl(methyl)amino]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzisothiazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H- Indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethyl-1H-indazole-3-methyl amides,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cyclopropylmethyl-1H-indazole- 3-formamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2,2-trifluoroethyl )-1H-indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thiazol-2-yl) -1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazol-2-yl)-1H -Indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiazol-2-yl)-1H -Indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-(cyclopropylmethyl Base)-1H-indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H- Indazole-3-carboxamide formate,

3-[3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole -1-yl]pyrrolidine-1-carboxylic acid tert-butyl formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thienylmethyl)- 1H-Indazole-3-carboxamide formate,

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazol-2-yl) -1H-indazole-3-carboxamide formate,

and their physiologically acceptable salts.

Preferred aspects include pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier and optionally another active agent as discussed below; methods of stimulating or activating the inhibition of alpha-7 nicotinic receptors, for example by conventional assays Or the assay method described herein is determined in vitro or in vivo (in animals, such as in animal models, or in mammals, or in humans); treatment of neurological syndromes, such as memory, especially long-term memory loss, cognitive Methods of disorders or decline, memory impairment, etc.; methods of treating diseases modulated by nicotine alpha-7 activity in mammals, such as humans, such as those mentioned herein.

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

The acids used to prepare the bicyclic base amides are commercially available or can be prepared by known methods described in the literature or as described below. For example, indazole-3-carboxylic acid is commercially available. Positional isomers of indazole carboxylic acids can be prepared from the requisite bromo-2- _{methylaniline} by diazotization followed by metal-halogen exchange and trapping with CO (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). Many simply substituted indazole-3-acids such as bromoindazole acids are prepared from the corresponding indoline diones by base hydrolysis, diazotization and reduction (Snyder, HR et al., J. Am. Chem. Soc. 1952, 74, 2009).

Some substituted indazole-3-acids are prepared by modification of existing indazole acids or esters. For example 5-nitroindazole-3-oic acid can be prepared by nitration of indazole-3-oic acid (Kamm, O.; Segur, J.B.Org. Syn. Coll. Vol 1.1941, 372). 6-Nitroindazole-3-oic acid is prepared from 3-iodo-6-nitroindazole with copper(I) cyanide followed by hydrolysis. Some non-aromatic heterocyclic derivatives are prepared from bromides by metal-halogen exchange, ketone trapping of indazolaryllithium, followed by reduction or acid-mediated elimination. Trapping indazolaryllithiums with amides provides ketones and aldehydes, which serve as useful precursors for reductive aminations, among others. Aromatically substituted indazol-3-acids are prepared from bromides via palladium-mediated cross-coupling with boronic acid or aryl zinc reagents (Reeder, M.R. et al., Org. Proc. Res. Devel. 2003, 7, 696 ). 4-Bromo-5-methoxyindazole- and 7-bromo-6-methoxyindazole-3-carboxylic acids were prepared from the corresponding methoxyindazole-3-carboxylates by bromination and saponification. 4-Fluoro-5-methoxyindazole- and 7-fluoro-6-methoxyindazole-3-carboxylic acids were prepared from the corresponding methoxyindazole-3-carboxylates by fluorination and saponification. 5-Bromo-4-nitroindazole- and 6-bromo-7-nitroindazole-3-carboxylic acids were prepared from the corresponding bromoindazole-3-carboxylates by nitration and saponification. Hydrogenolysis of the nitro bromide affords 4-aminoindazole- and 7-aminoindazole-3-carboxylic acids. Aminoindazole esters are converted to additional useful acid analogs by reductive amination, alkylation and acylation methods. N-1-Alkylated indazole-3-carboxylic acids are prepared from the corresponding indazole esters by standard alkylation procedures. N-1-arylated indazole-3-carboxylic acids were prepared from the corresponding indazole esters by copper-mediated cross-coupling with boronic acid. Phenol derivatives are prepared from the corresponding methoxy acids using boron tribromide.

Some substituted indazole-3-acids are prepared from simple benzene derivatives. For example, 5-difluoromethoxyindazole-3-acid is reacted by 3-bromo-4-nitrophenol with ethyl difluoroacetate, reacted with diethyl malonate, decarboxylated saponification, esterification, nitro reduction and diazotization preparation. 6-Difluoromethoxyindazole-3-oic acid was prepared in a similar manner from 2-bromo-5-difluoromethoxynitrobenzene. 2-Bromo-5-difluoromethoxynitrobenzene used in the preparation by ether formation with reduction of the nitro group protected in the amide form, nitration, amide hydrolysis and Sandmeyer reaction with copper(I) bromide From 4-nitrophenol preparation. 6-Benzyloxyindazole-3-carboxylic acids and esters were converted from 4- Preparation of methoxynitrobenzene. Alkylation of phenol with benzyl bromide and reaction of aryl bromide with diethyl malonate, decarboxylation saponification, esterification, nitro reduction and diazotization. The 5-benzyloxy analog was prepared in a similar manner from 4-benzyloxy-2-bromonitrobenzene (Parker, K.A.; Mindt, T.L.Org. Lett. 2002, 4, 4265). The benzyl group is removed by hydrogenolysis and the resulting phenol is converted to the ether derivative via alkylation or Mitsunobu reaction conditions. Debromination of 4-methoxyindazole acid by amide formation, nitration, amide hydrolysis, Sandmeyer reaction with copper(I) bromide, nitro reduction, indoline dione formation and indazole rearrangement, followed by hydrogenolysis Prepared from 4-methoxyaniline.

Benzisoxazole-, benzisoxazole- and benzothiazolecarboxylic acids were prepared using methods similar to those described for indazole acids. For example, ethyl 6-bromobenzisoxazole-3-carboxylate is prepared from 2,5-dibromonitrobenzene by reaction with diethylmalonate, saponification and decarboxylation, reaction with isoamyl nitrite. Benzisoxazole-3-carboxylic acid ethyl ester prepared by hydrogenolysis of 6-bromo derivative. 4-Benzothiazole carboxylic acid was prepared from 2-amino-4-chloro-benzothiazole by reacting 2-amino-4-chloro-benzothiazole with isoamyl nitrite, followed by metal-halogen exchange, and using _CO2 capture. 5-Benzothiazolecarboxylic acid was prepared from 4-chloro-3-nitrobenzoic acid by reaction of 4-chloro-3-nitrobenzoic acid with _Na2S and NaOH followed by reduction with Zn in formic acid. 3-Benzisothiazolecarboxylic acid is prepared from thiophenol by reaction of thiophenol with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide and sodium hydroxide.

The bicyclic amines, 3-aminoquinuclidine and their R- and S-enantiomers used in the preparation of the bicyclic base amides are commercially available. N-Alkylated quinuclidines are prepared by acylation of 3-aminoquinuclidine followed by reduction of the amide. 3-Aminomethylquinuclidine is prepared from 3-quinuclidinone by the action of p-toluenesulfonylmethylisonitrile followed by hydrogenation of the nitrile.

Bicyclic base amides are prepared from acids and bicyclic amines by coupling with EDCI using standard peptide coupling reagents such as HBTU, HATU or HOBt, or by converting the acid into the corresponding acid chloride and subsequent reaction with the bicyclic amine (Macor, J.E. ; Gurley, D.; Lanthorn, T.; Loch, J.; Mack, R.A.; Mullen, G.; Tran, O.; Wright, N.; 205-930) was a Potent and Selective α-7 Nicotinic Receptor Partial Agonist," Bioorg. Med. Chem. Lett. 2001, 9, 319-321). Couplings are typically performed at room temperature for 18-24 hours. The resulting adducts can be isolated and purified by those skilled in the art using standard techniques such as chromatography or recrystallization.

Those of ordinary skill in the art will recognize that compounds of Formulas I-IV may exist in different tautomeric and geometric isomeric forms. Includes cis isomers, trans isomers, diastereomeric mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure and pure enantiomers in All such compounds within are within the scope of the invention. A substantially pure enantiomer contains no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.

Optical isomers can be obtained by resolution of racemic mixtures according to conventional methods, for example, by formation of diastereomeric salts with optically active acids or bases, or by formation of covalent diastereoisomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Diastereomeric mixtures can be separated into their individual diastereoisomers 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 base or acid is then liberated from the separated diastereoisomeric salts. Different methods of separation of optical isomers include the use of chiral chromatography (eg chiral HPLC columns), with or without conventional derivatization, optimally chosen to obtain maximum separation of the enantiomers. Suitable chiral HPLC columns are produced by Diacel, such as Chiracel OD and Chiracel OJ, etc., which can be routinely selected. Enzyme isolation with or without derivatization is also useful. Optically active compounds of the formulas I-IV can likewise be obtained using optically active starting materials in chiral synthetic methods under reaction conditions which do not cause racemization.

In addition, one of ordinary skill in the art will recognize that the compounds may be used in different isotopically enriched forms, such as ² H, ³ H, ¹¹ C, ¹³ C and/or ¹⁴ C enriched forms. In a particular embodiment, the compound is deuterated. This deuterated form can be prepared according to the methods described in US Patent Nos. 5,846,514 and 6,334,997. As described in US Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy of drugs and increase the duration of action of drugs.

Deuterated compounds can be synthesized by various methods, as described in: Dean, DennisC.; Editor. Recent Advances in the Synthes is 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 radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45 (21), 6601-21, CODEN: TETRAB ISSN: 0040-4020. CAN 112: 20527 AN1990: 20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64 (1 -2), 9-32. CODEN: JRACBNISSN: 0022-4081, CAN 95: 76229 AN 1981: 476229 CAPLUS.

Where applicable, the invention also relates to useful forms of the compounds disclosed herein, such as all pharmaceutically acceptable salts or prodrugs of the compounds of the invention for which salts or prodrugs can be prepared. Pharmaceutically acceptable salts include salts obtained by reacting the main compound as a base with an inorganic or organic acid to form a salt, such as hydrochloride, sulfate, phosphate, methanesulfonate, camphorsulfonate, oxalate , maleate, succinate, citrate, formate, hydrobromide, benzoate, tartrate, fumarate, salicylate, almondate and carbonate. Pharmaceutically acceptable salts also include salts wherein the principal compound is formed as an acid and reacted with a suitable base, such as sodium, potassium, calcium, magnesium, ammonium and choline salts. Those skilled in the art will further recognize that acid addition salts of claimed compounds may be prepared by reacting the compounds with a suitable inorganic or organic acid by any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting the compounds of the invention with a suitable base by a variety of known methods.

The following are further examples of acid salts which may be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonic acid Salt, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, lauryl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate salt, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, Methanesulfonate, Nicotinate, 2-Naphthalenesulfonate, Oxalate, Palmitate, Pectinate, Persulfate, 3-Phenylpropionate, Picrate, Pivalate , propionate, succinate, tartrate, thiocyanate, tosylate, methanesulfonate and undecanoate.

Preferably the salt formed is pharmaceutically acceptable for administration to a mammal. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, eg, as the compounds are isolated in salt form and subsequently converted back to the free base compound by treatment with a basic reagent. The free base can then be converted, if desired, into a pharmaceutically acceptable acid addition salt.

The compounds of the present invention can be administered alone, or as active ingredients of formulations. Accordingly, the present invention also includes pharmaceutical compositions of compounds of formulas I-IV containing, for example, one or more pharmaceutically acceptable carriers.

There are numerous standard documents describing methods for the preparation of various formulations suitable for administration of the compounds of the invention. Examples of possible formulations are described in, for example, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors), current edition, published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

Due to the alpha-7 stimulating activity of the compounds of the present invention, and preferably their high selectivity, they can be administered to anyone in need of alpha-7 receptor stimulation. Administration can be carried out according to the needs of the patient, such as oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and infusion), inhalation, rectal, vaginal, topical and intraocular administration.

Various solid oral dosage forms can be used for administering the compounds of the invention, including the following solid dosage forms: tablets, gelcaps, capsules, caplets, granules, lozenges and powders. The compounds of the present invention can be administered alone or with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannose, lactose, starch) and excipients known in the art, including but not limited to suspending agents, Solubilizers, buffers, binders, disintegrants, preservatives, coloring agents, flavoring agents, lubricants, etc. are administered together. Time-release capsules, tablets and gels are also advantageous in administering the compounds of the invention.

Various liquid oral dosage forms can also be used for administration of the compounds of this invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. These dosage forms may also contain suitable inert diluents known in the art, such as water, and suitable excipients known in the art, such as preservatives, wetting agents, sweeteners, flavoring agents and agents for emulsification. and/or reagents for suspending the compounds of the invention. For example, the compounds of the invention can be injected intravenously as sterile isotonic solutions. Other formulations are also possible.

Suppositories for rectal administration of a compound of this invention may be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration may be in the form of a pessary, tampon, cream, gel, paste, foam or spray containing the active ingredient and suitable carriers known in the art.

For topical administration, the pharmaceutical composition may be a cream, ointment, liniment, lotion, emulsion, suspension, gel, solution, paste, powder suitable for administration to the skin, eyes, ears or nose , spray and drop forms. Topical administration may also include transdermal administration via devices such as transdermal patches.

Aerosol formulations suitable for administration by inhalation may also be prepared. For example, for the treatment of respiratory diseases, the compounds of the invention may be administered in the form of powders (eg micronized) or nebulized solutions or suspensions by inhalation. Aerosol formulations can be placed in a pressurizable propellant.

The compound may also be administered as the sole active agent or in combination with other drugs such as other drugs used in the treatment of cognitive impairment and/or memory loss, such as other alpha-7 agonists, PDE4 inhibitors, calcium channel blockers, mushroom Muscarpine m1 and m2 modulators, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g. donepezil, Rivastigmine (rivastigimine) and glanthanamine) are given together. In these combinations, each active ingredient can be administered according to its usual dosage range, or according to a dosage lower than its usual dosage range.

The compounds of the present invention may be used in combination with "positive modulators" that potentiate the efficacy of nicotinic receptor agonists. See, e.g., the positive modulators disclosed in WO 99/56745, WO 01/32619 and WO 01/32622. Such combination therapy is useful in the treatment of conditions/diseases associated with decreased nicotinic transmission.

In addition, the compounds may be used in combination with compounds that bind to the Aβ peptide thereby inhibiting the binding of the peptide to the α7 nACh receptor subtype. See, for example WO 99/62505.

The invention also includes methods of treatment involving activation of alpha-7 nicotinic receptors. Accordingly, the present invention includes methods of selectively activating/stimulating alpha-7 nicotinic receptors in a patient (e.g., a mammal such as a human), wherein such activation/stimulation has a therapeutic effect, such as the activation may alleviate neurologically related syndromes. disorders such as loss of memory, especially long-term memory. These methods comprise administering to a patient (eg, a mammal such as a human) in need thereof an effective amount of a compound of Formulas I-IV disclosed herein, alone or as part of a formulation.

According to a method aspect of the invention there is provided a method of treating a patient (eg a mammal such as a human) suffering from a disease (eg memory impairment) comprising administering to said patient a compound of formulas I-IV. Preferably, the disease is associated with decreased activity of nicotinic acetylcholine receptors.

According to the method aspects of the present invention there is provided a method of treating or preventing a disease or condition in a patient (eg a mammal such as a human) caused by a dysfunction of nicotinic acetylcholine receptor transmission comprising administering an effective amount of a compound of formulas I-IV.

According to the method aspect of the present invention, there is provided a method of treating or preventing a disease or condition caused by a deficiency or dysfunction of nicotinic acetylcholine receptors, particularly α7 nACh receptors, in a patient (e.g. a mammal such as a human), comprising administering an effective amount of Compounds of formula I-IV.

According to the method aspect of the present invention, there is provided a method of treating or preventing a disease or condition caused by inhibition of nicotinic acetylcholine receptor transmission in a patient (e.g., a mammal such as a human), comprising administering an amount of formula I effective to activate an α7 nACh receptor - Compounds of IV.

According to another method aspect of the present invention, there is provided a method of treating or preventing a mental disorder, a cognitive disorder (such as a memory disorder) or a neurodegenerative disease in a patient (e.g., a mammal such as a human), comprising administering an effective amount of the formula I- Compounds of IV.

According to another method aspect of the present invention, there is provided a method of treating or preventing a disease or condition caused by loss of cholinergic synapses in a patient (eg, a mammal such as a human), comprising administering an effective amount of a compound of formulas I-IV.

According to another method aspect of the present invention, there is provided a method of treating or preventing a neurodegenerative disorder caused by α7 nACh receptor activation in a patient (e.g., a mammal such as a human), comprising administering an effective amount of a compound of formulas I-IV.

According to another method aspect of the present invention, there is provided a method of protecting neurons in a patient (e.g., a mammal such as a human) from neurotoxicity caused by activation of α7 nACh receptors, comprising administering an effective amount of a compound of Formulas I-IV.

According to another method aspect of the present invention, there is provided a method for treating or preventing a neurodegenerative disorder in a patient (e.g., a mammal such as a human) by inhibiting the binding of Aβ peptide to the α-7 nACh receptor, comprising administering an effective amount of a formula I-IV compound of.

According to another method aspect of the present invention, there is provided a method of protecting neurons from A[beta] peptide-induced neurotoxicity in a patient (eg, a mammal such as a human), comprising administering an effective amount of a compound of formulas I-IV.

According to another method aspect of the present invention, there is provided a method of alleviating A[beta] peptide-induced inhibition of cholinergic function in a patient (eg, a mammal such as a human), comprising administering an effective amount of a compound of formulas I-IV.

The subject or patient in which administration of a therapeutic compound is an effective treatment regimen for a disease or condition is preferably a human, but can be any animal, including experimental animals in the context of clinical trials or screening or activity assays. Accordingly, those of ordinary skill in the art will readily appreciate that the methods, compounds and compositions of the present invention are particularly suitable for administration to any animal, particularly mammals, including but not limited to humans, domestic animals such as feline or canine subjects, farm Animals such as but not limited to cattle, horses, goats, sheep and pig subjects, wild animals (wild or zoo), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., Birds such as chicks, flamingos, songbirds, etc. are used in veterinary applications.

The compounds of the invention are nicotinic alpha7 ligands, preferably agonists, especially partial agonists of the alpha7 nicotinic acetylcholine receptor. Assays for determining nicotine acetylcholine activity are known in the art. See, for example, 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):679-90. As an agonist of the α7 nACh receptor, this compound is useful in the prevention and treatment of a number of diseases or conditions related to the central nervous system. The nicotinic acetylcholine receptor is a ligand-gastrol ion channel receptor composed of 5 protein subunits that form a central ion-conducting pore. Currently, there are 11 known neuronal nACh receptor subunits (α2-α9 and β2-β4). Five other subunits (α1, β1, γ, δ, ε) are also expressed in the peripheral nervous system.

nACh receptor subtypes can be homo-pentameric or heteropentameric. The subtype that has received major attention is the homopentameric α7 receptor subtype, which is formed by 5 α7 subunits. The α7 nACh receptor exhibits high affinity for nicotine (agonist) and α-bungarotoxin (antagonist). Studies have shown that α7 nACh receptor agonists can be used to treat mental diseases, neurodegenerative diseases and cognitive disorders. Although nicotine is a known agonist, there is still a need to develop other α7 nACh receptor agonists, especially selective agonists with less toxicity or side effects than nicotine.

The compound aniseicine, ie 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine, is a naturally occurring toxin in certain marine worms (Neutralis worms) and in ants. See, eg, Kem et al., Toxicon, 9:23,1971. Aniseine is a potent agonist of mammalian nicotinic receptors. See, eg, Kem, Amer. Zoologist, 25, 99, 1985. Certain anisepine analogues such as anonicotinoids and DMAB (3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2',3'-bipyridine ) is also a known nicotinic receptor agonist. See, for example, US 5,602,257 and WO 92/15306. A specific aniseedine analogue, E-3-[2,4-dimethoxy-benzylidene]-aniseedine, also known as GST-21 and DMXB (see, e.g., US 5,741,802), is a widely studied selective partial α7 nACh receptor agonist. For example, abnormal sensory inhibition is a sensory processing deficit in schizophrenia, and GST-21 has been found to increase sensory inhibition by interacting with α7 nACh receptors. See, eg, Stevens et al., Psychopharmacology, 136:320-27 (1998).

Another known selective α7 nACh receptor agonist compound is tropisetron, 1αH,5αH-tropane-3α-ylindole-3-carboxylate. See JEMacor et al., 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist . Bioorg. Med. Chem. Lett. 2001, 319-321).

Drugs that bind to nicotinic acetylcholine receptors have been indicated for the treatment and/or prevention of a variety of diseases and conditions, in particular psychiatric disorders, neurodegenerative diseases associated with dysfunction of the cholinergic system, and memory and/or cognitive impairments. Disorders, including, for example, schizophrenia, anxiety, mania, depression, manic depression [example of a psychiatric disorder], Tourette's syndrome, Parkinson's disease, Huntington's disease [example of a neurodegenerative disorder], cognitive Conditions (such as Alzheimer's disease, Lewy Body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficits, attention deficit, attention deficit disorder) and other uses, such as the treatment of nicotine Addiction, including smoking cessation, treating pain (ie, analgesic use), providing neuroprotection, and treating jetlag. 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; and Shytle et al., Molecular Psychiatry, (2002), 7, pp.525-535.

Thus, according to the present invention, there is provided the treatment of conditions suffering from psychiatric diseases, neurodegenerative diseases associated with dysfunction of the cholinergic system, and memory and/or cognitive disorders, including for example schizophrenia, anxiety, mania, depression manic depression [examples of psychiatric 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, A method for a patient, especially a human, of amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficit, attention deficit, attention deficit disorder), comprising administering to said patient an effective amount of a compound of formulas I-IV.

Neurodegenerative disorders included in the methods of the invention include, but are not limited to, treatment and/or prevention of Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multiple Systemic degeneration (Shadow-Dement syndrome), motor neuron disease including amyotrophic lateral sclerosis, degenerative ataxia, corticobasal degeneration, ALS-Parkinson's-Demenia complex of Guam (ALS-Parkinson's-Demenia complex of Guam), subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Ma-Joe disease/spinocerebellar ataxia type 3 , olivopontocerebellar degeneration, Tourette's disease, bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy (Kennedy disease), primary lateral sclerosis, familial spastic paraplegia, Weilhardt disease, Kugelberg-Welander disease, Tay-Sachs familia, Sandhoff disease, familial spasticity, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy , prion diseases (such as Creutzfeldt-Jakob disease, Ger-Sch-Sarrah disease, Kuru disease, and fatal familial insomnia), and disorders resulting from cerebral ischemia or infarction, including embolic and thrombotic occlusions neurodegenerative diseases, and any type of intracranial hemorrhage (including but not limited to epidural, subdural, subarachnoid and intracerebral), and intracranial and spinal injuries (including but not limited to contusion, penetration, shear cut, compress and tear).

Additionally, α7 nACh receptor agonists, such as the compounds of the present invention, are useful in the treatment of age-related dementia and other dementias and conditions associated with memory loss, including age-related memory loss, aging, vascular dementia, diffuse White matter disease (Binswanger disease), dementia of endocrine or metabolic origin, head trauma and diffuse brain injury dementia, dementia pugilistica and frontal lobe dementia. See, for example WO 99/62505. Thus, according to the present invention there is provided a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and disorders with memory loss, comprising administering to said patient an effective amount of a compound of formulas I-IV.

Thus, according to another embodiment, the present invention includes a method of treating a patient suffering from memory impairment caused by: mild cognitive impairment caused by aging, Alzheimer's disease, schizophrenia, Parkinson's disease , Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, central nervous system hypoxia, brain aging, multi-infarct dementia and other neurological disorders as well as HIV and cardiovascular disease, It involves administering an effective amount of a compound of formulas I-IV.

Amyloid precursor protein (APP) and Aβ peptides derived therefrom, such as Aβ _1-40 , Aβ _1-42 and other fragments, are known to be involved in the pathology of Alzheimer's disease. The Aβ _1-42 peptide is not only associated with neurotoxicity, but it is also known to inhibit cholinergic transmitter function. Furthermore, it has been determined that Aβ peptide binds to the α7 nACh receptor. Therefore, drugs that block the binding of Aβ peptides to α-7 nACh receptors are useful in the treatment of neurodegenerative diseases. See, eg WO 99/62505. In addition, stimulation of α7 nACh receptors protects neurons from Aβ peptide-associated cytotoxicity. See, eg Kihara T. et al., Ann. Neurol, 1997, 42, 159.

Therefore, according to an embodiment of the present invention, there is provided a method for treating and/or preventing dementia in a patient with Alzheimer's disease, comprising administering to the patient an effective amount of a compound of formulas I-IV to inhibit amyloid beta peptide ( Preferably Aβ _1-42 ) binds to an nACh receptor, preferably an α7 nACh receptor, most preferably a human α7 nACh receptor (as well as methods of treating and/or preventing other clinical manifestations of Alzheimer's disease, including but not Limited to cognitive and language deficits, apraxia, depression, delusions and other neuropsychiatric symptoms and signs, and movement and gait abnormalities).

The present invention also provides the treatment of other amyloidosis diseases, such as hereditary cerebrovascular disease, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever , Moore-Wei syndrome, multiple myeloma, amyloidosis associated with the pancreas and heart, chronic hemodialysis anthropathy, and approaches to Finnish and Iowa amyloidosis.

It has also been pointed out that nicotinic receptors play a role in the body's response to alcohol intake. Therefore, α7 nACh receptor agonists are useful in the treatment of alcohol withdrawal and in anti-intoxication therapy. Accordingly, according to an embodiment of the present invention there is provided a method of treating alcohol withdrawal in a patient or treating a patient with anti-intoxication therapy comprising administering to said patient an effective amount of a compound of formulas I-IV.

Agonists of the α7 nACh receptor subtype may also be used for neuroprotection against injuries associated with stroke, ischemia, and glutamate-induced excitotoxicity. Therefore, according to an embodiment of the present invention, there is provided a method of treating a patient to provide neuroprotection against damage associated with stroke, ischemia, and glutamate-induced excitotoxicity, comprising administering to said patient an effective amount of formulas I-IV compound of.

As noted above, agonists of the α7 nACh receptor subtype may also be useful in treating nicotine addiction, inducing smoking cessation, treating pain and treating jet lag, obesity, diabetes and inflammation. Thus, according to an embodiment of the present invention there is provided a method of treating a patient suffering from nicotine addiction, pain, jet lag, obesity and/or diabetes, or a method of inducing smoking cessation in a patient comprising administering to said patient an effective Quantities of compounds of formula I-IV.

The inflammatory reflex is an automatic nervous system response in response to inflammatory signals. Upon sensing an inflammatory stimulus, the autonomic nervous system responds via the vagus nerve by releasing acetylcholine and activating nicotinic α7 receptors on macrophages. These macrophages in turn release cytokines. Dysfunction of this pathway has been implicated in human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. Macrophages express the nicotinic α7 receptor, and it may be this receptor that mediates cholinergic anti-inflammatory responses. Therefore, compounds with affinity for the α7 nACh receptor on macrophages may be useful in human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. See, eg, Czura, C J et al., J. Intern. Med., 2005, 257(2), 156-166.

Thus, according to an embodiment of the present invention there is provided a method of treating a patient (eg mammal such as a human) suffering from an inflammatory disease such as but not limited to rheumatoid arthritis, diabetes or sepsis comprising administering to said patient An effective amount of a compound of formulas I-IV.

In addition, due to the affinity of the compounds of formulas I-IV for the α7 nACh receptors, their labeled derivatives (eg C ¹¹ or F ¹⁸ labeled derivatives) are useful eg in neuroimaging of the receptors in the brain. Thus, in vivo imaging of receptors can be performed using such labeled drugs, for example, using PET imaging.

The condition of memory impairment is manifested by an impairment of the ability to learn new information and/or an inability to recall previously learned information. Memory impairment is a major symptom of dementia and may also be a symptom associated with: Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease, and Head trauma and age-related cognitive decline.

Accordingly, according to embodiments of the present invention, there is provided a method of treating a patient suffering from, for example, mild cognitive impairment (MCI), vascular dementia (VaD), age-related cognitive decline (AACD), cardiac Orthopedic surgery, amnesia associated with cardiac arrest and/or general anesthesia, memory deficits induced by early exposure to anesthetics, cognitive impairment induced by sleep deprivation, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, Cognitive impairment associated with epilepsy, Down syndrome, dementia associated with alcoholism, drug/substance-induced memory impairment, dementia of boxers (boxer syndrome), and dementia of animals (eg, dogs, cats, horses, etc.), which comprising administering to said patient an effective amount of a compound of Formulas I-IV.

The dosage of the compounds of this invention will depend on many factors including the particular syndrome to be treated, the severity of the syndrome, the route of administration, the number of dose intervals, the particular compound being used, the efficacy of the compound, the toxicological profile , pharmacokinetic characteristics, and the presence of any adverse side effects.

The compounds of the present invention may be administered to a patient, such as a mammal, especially a human, at dosage levels conventional for alpha-7 nicotinic receptor agonists such as the known alpha-7 nicotinic receptor agonist compounds described above. For example, the compound may be administered in one or more doses, for oral administration at dosage levels such as 0.0001-10 mg/kg/day, such as 0.01-10 mg/kg/day. Unit dosage forms may contain, for example, 1-200 mg of active compound. For intravenous administration, the compound may be administered in one or more doses.

In practicing the methods of the present invention, it should of course be understood that references to specific buffers, media, reagents, cells, culture conditions, etc. are not intended to be limiting, but are to be understood to include those considered by those of ordinary skill in the art to be discussed. All relevant material that is of interest or value to a particular aspect of the problem. For example, it is often possible to substitute another buffer system or medium and still obtain similar, if not identical, results. Those skilled in the art are well aware of these systems and methods to be able, without undue experimentation, to make such substitutions in using the methods disclosed herein that best serve their purposes.

The invention will now be further described by the following non-limiting examples. In carrying out the teachings of these examples, it should be clearly understood that they will undoubtedly suggest other and different embodiments to those skilled in the art with respect to the methods disclosed in accordance with the present invention.

In the foregoing and following examples, all temperatures are given uncorrected in degrees Celsius; and unless otherwise indicated, all parts and percentages are by weight.

All applications, patents and publications cited above and below are hereby incorporated by reference in their entirety.

The following compounds in Examples 1-315 were prepared using the following methods and methods described further below. Additional synthetic examples are described in US patent application Ser. No. 10/669,645, which is incorporated herein by reference.

Example

All spectra were recorded by Bruker Instruments NMR at 300 MHz unless otherwise noted. Coupling constants (J) are in Hertz (Hz) and peaks are listed relative to TMS (δ 0.00 ppm). Microwave reactions were performed in 2.5 mL or 5 mL Personal Chemistry microwave reactor vials using a Personal Chemistry Optimizer ^™ Microwave Reactor. Unless otherwise noted, all reactions were performed at 200 °C for 600 s with a fixed hold time ON. Sulfonic acid ion exchange resin (SCX) was purchased from Varian Technologies. Analytical HPLC was performed on a 4.6mm x 100mm Xterra RP ₁₈ 3.5μ column using a gradient of 20/80 to 80/20 water (0.1% formic acid)/acetonitrile (0.1% formic acid) over 6 minutes. Preparative HPLC was performed on a 30mm x 100mm Xterra RP ₁₈ 5[mu] column using a gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid) over 8 minutes.

acid preparation

The following methods (1-27) detail the preparation of indazoles, benzothiazoles, benzisothiazoles and benzisoxazole acids which are not commercially available.

method 1

Method 1 provides a method for preparing 1,3-benzothiazolecarboxylic acid from chloronitrobenzoic acid.

To a solution of 4-chloro-3-nitrobenzoic acid (99.2 mmol) in N,N-dimethylformamide (400 mL) was added potassium carbonate (254 mmol). After 30 minutes, ethyl iodide (119 mmol) was added and the reaction mixture was heated at 50 °C for 4 hours. Water (3 L) was added and the mixture was extracted with ether (2 x 500 mL). The organic extracts were combined, washed with brine (1 L), dried over anhydrous sodium sulfate, and concentrated. The residue was crystallized from hexane, thus giving the ester in 86% yield. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.51 (d, 1H), 8.17 (dd, 1H), 7.65 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).

Sulfur (49.91 mmol) was dissolved in a solution of anhydrous sodium sulfide (49.96 mmol) in water (60 mL). This solution was combined with a solution of ethyl 4-chloro-3-nitrobenzoate (85.36 mmol) in ethanol (100 mL), and the resulting mixture was heated to reflux for 3 hours. The hot reaction mixture was poured into water (600 mL) and left for 15 minutes. The product was isolated by filtration and recrystallized from ethanol, whereby the disulfide was obtained in 77% yield. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H).

A mixture of diethyl 4,4'-dithiobis(3-nitrobenzoate) (24.8 mmol) and zinc particles (234 mmol) in formic acid (600 mL) was heated at reflux for 48 hours. The mixture was cooled 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. Chromatography of the residue on neutral alumina (1/1 to 0/1 hexane/dichloromethane) afforded the thiazole in 51% yield. ¹ H NMR (500MHz, CDCl ₃ ) δ9.08(s, 1H), 8.83(d, 1H), 8.14(dd, 1H), 8.02(d, 1H), 4.45(q, 2H), 1.44(t, 3H); MS (EI) m/z 208 (M ⁺ +1).

To a solution of ethyl 1,3-benzothiazole-5-carboxylate (25.6 mmol) in a mixture of methanol (150 mL), tetrahydrofuran (40 mL) and water (5 mL) was added 50% aqueous sodium hydroxide (10 mL) . The mixture was left at room temperature for 18 hours and concentrated. The residue was partitioned between water (300 mL) and 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 the acid in 94% yield.

The following acids were prepared using this method:

1,3-Benzothiazole-5-carboxylic acid

1,3-Benzothiazole-6-carboxylic acid

Method 2

Method 2 provides a method for the preparation of 1,3-benzothiazole-7-carboxylic acid from ethyl 3-aminobenzoate.

A solution of ethyl 3-aminobenzoate (90 mL) in chlorobenzene (100 mL) was cooled to -10°C and treated dropwise with sulfuric acid (45 mmol). After 15 minutes, solid potassium thiocyanate (95 mmol) was added in portions over 30 minutes, followed by 18-crown-6 (250 mg). The mixture was heated at 100°C for 10 hours, cooled to room temperature, and left for a further 4 hours. The precipitated solid was isolated by filtration and washed sequentially with chlorobenzene (25 mL) and hexane (3 x 100 mL). The solid was suspended in water (300 mL), and the suspension was left for 30 minutes. The product was isolated by filtration and washed with water (2 x 100 mL). The product was dried in a vacuum oven (55° C.) for 16 hours, thereby obtaining the thiocarbamate in a yield of 69%. ¹ HNMR (500MHz, Me ₂ SO-d ₆ ) δ1.32(t, J=7.5, 3H), 4.32(q, J=7, 2H), 7.44-7.47(m, 2H), 7.68-7.76(m , 3H), 8.05(s, 1H), 9.86(s, 1H); MS (APCI) m/z 225 (M ⁺⁺ 1).

A solution of thiocarbamate (12.2 mmol) in chloroform (10 mL) was added dropwise to ethyl 3-[(aminothiocarbonyl)amino]benzoate (5.78 mmol), glacial acetic acid (10 mL) and Chloroform (10 mL) was placed in the vigorously stirred mixture. The mixture was left at room temperature for 30 minutes, then heated at 70°C for 4 hours. The mixture was cooled to room temperature and left for another 13 hours. 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, washed sequentially with acetone (5 mL) and hexane (10 mL), and dried in a vacuum oven to give the product as ethyl 2-amino-1,3-benzothiazole-7-carboxylate hydrogen A 95/5 mixture of bromate and ethyl 2-amino-1,3-benzothiazole-5-carboxylate hydrobromide in a ratio of 95% yielded 95%. The product was partitioned between saturated aqueous sodium bicarbonate (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, whereby pure ethyl 2-amino-1,3-benzothiazole-7-carboxylate was obtained. ¹ H NMR (500 MHz, Me ₂ SO-d ₆ ) δ 1.35 (t, J=7.5, 3H), 4.36 (q, J=7, 2H), 7.35 (t, J=7.5, 1H), 7.57 ( d, J = 7, 1H), 7.61 (bs, 2H), 7.65 (d, J = 8, 1H); MS (EI) m/z 223 (M ⁺ +1).

To a solution of ethyl 2-amino-1,3-benzothiazole-7-carboxylate (5.40 g) in tetrahydrofuran (70 mL) was added isoamyl nitrite (53 mmol), and the mixture was heated under reflux for 4 hrs. The volatiles were removed under reduced pressure and the residue was purified by chromatography (0/100 to 5/95 methanol/dichloromethane) to afford the ester in 71% yield. ¹ H NMR (500MHz, CDCl ₃ ) δ1.47(t, J=7.5, 3H), 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). To a 0° C. solution of ethyl 1,3-benzothiazole-7-carboxylate (16.89 mmol) in a mixture of methanol (65 mL), tetrahydrofuran (20 mL) and water (5 mL) was added 50% aqueous sodium hydroxide ( 10mL). The mixture was left at room temperature for 4 hours, 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 left for 30 minutes. The product was isolated by filtration, washed with water (10 mL), and dried in a vacuum oven (70° C.) for 16 hours, whereby the acid was obtained in 91% yield. ¹ H NMR (500 MHz, Me ₂ SO-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, 1H), 13.74 (bs, 1H); MS (APCI) m/z 178 (M ⁺ -1).

References: Kunz et al., US Patent 5,770,758.

Method 3

Method 3 provides the preparation of substituted benzisothiazole-3-carboxylic acids from the corresponding thiophenols.

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

To a mixture of the diketone (0.44 mmol) in 30% aqueous ammonium hydroxide (2.0 mL) was added 35% aqueous hydrogen peroxide (0.2 mL), and the reaction mixture was left for 12 hours. The precipitated pink solid was isolated by filtration, washed with water, and dried under high vacuum to afford the amide in 42% yield.

To a solution of the amide (5.46 mmol) in methanol (100 mL) was added 10N sodium hydroxide (12 mL). The mixture was heated to reflux for 12 hours, cooled to room temperature, and acidified to pH <2 by slow addition of concentrated hydrochloric acid. The organic layer was extracted with dichloromethane (2x) and dried over sodium sulfate. The product was purified by chromatography (300/50/1 dichloromethane/methanol/formic acid) to give the acid as a pink solid in 89% yield. LC/MS (EI) t _R 6.17 min, m/z 210 (M ⁺ +1).

The following acids were prepared by this method:

Benzisothiazole-3-carboxylic acid

6-Bromobenzisothiazole-3-carboxylic acid

5-Bromobenzisothiazole-3-carboxylic acid

6-Methoxybenzisothiazole-3-carboxylic acid

7-Methoxybenzisothiazole-3-carboxylic acid

6-Trifluoromethoxybenzisothiazole-3-oic acid

6-Ethoxybenzisothiazole-3-acid

6-Cyclopropylmethoxybenzisothiazole-3-oic acid

Method 4

Method 4 provides a method for the preparation of indoline diones from anilines and the conversion of indoline diones to the corresponding indazole-3-carboxylic acids.

A solution of substituted aniline (565 mL) in 6N hydrochloric acid (106 mL) was added to a solution of 2,2,2-trichloro-1-ethoxyethanol (678 mL) and sodium sulfate (3.15 mol) in water (1.4 L) suspension, and the reaction mixture was stirred vigorously for 1 hour. A solution of hydroxylamine hydrochloride (2.08 mol) in water (650 mL) was added in one portion and the reaction mixture was heated at 80°C for 1.5 hours. The reaction mixture was cooled to 10 °C, and the precipitated solid was collected by filtration, washed with water, and dried to give the amide in 91% yield.

The amide was added to sulfuric acid (1.9 L) and the reaction mixture was heated at 60 °C for 6 hours. The reaction mixture was cooled to room temperature and poured carefully onto ice (7 kg). The precipitated solid was collected by filtration, washed with water, and dried to give indolindione in 61% yield.

The conversion of substituted indoline diones to the corresponding indazole-3-carboxylic acids is the same as described for indazole-3-carboxylic acids (Snyder, HR et al., J.Am.Chem.Soc.1952, 74, 2009.) are essentially the same. The substituted indoline dione (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and heated at 50° C. for 30 minutes. The burgundy solution was cooled to room temperature and left for 1 hour. The reaction mixture was cooled to 0°C and treated with a 0°C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added via a dropper submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0°C. The addition took 15 minutes and the reaction was allowed to stand 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 left for 60 minutes. The precipitated solid was isolated by filtration, washed with water, and dried to give a quantitative remainder. The material was of sufficient purity ( ^1HNMR and LC/MS) to be used in the next step without further purification. Alternatively, recrystallization of the acid from acetic acid afforded the pure material.

The following acids were prepared using this method:

5-Chloro-1H-indazole-3-acid

7-Methoxy-1H-indazole-3-oic acid

5-Fluoro-1H-indazole-3-acid

6-Fluoro-1H-indazole-3-acid

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

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

5-Trifluoromethoxy-1H-indazole-3-oic acid

6-Trifluoromethyl-1H-indazole-3-oic acid

5-methoxy-1H-indazole-3-oic acid

6-methoxy-1H-indazole-3-oic acid

5-Methyl-1H-indazole-3-carboxylic acid

Method 5

Method 5 provides a method for the preparation of bromoindazole from bromomethylaniline.

Acetic anhydride (2.27 equiv) was added to a cold (0 °C) solution of bromomethylaniline (1.00 equiv) in chloroform (1.5 mL/mmol) while maintaining the temperature below 40 °C. The reaction mixture was warmed to room temperature and left for 1 hour. Potassium acetate (0.29 equiv) and isoamyl nitrite (2.15 equiv) were added and the reaction mixture was heated to reflux for 18 hours. Volatiles were removed under reduced pressure. Water (0.65 L/mol) was added to the residue and the mixture was concentrated. Concentrated hydrochloric acid (1 L/mol) was added to the residue, and the mixture was heated at 50°C for 2 hours. The mixture was cooled to room temperature and the pH was adjusted to 10 by 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). The combined extracts were washed with brine (1 L/mol) and dried over anhydrous sodium sulfate. The organic solution was filtered through a short plug of silica gel (washed with ethyl acetate), concentrated, and the residue was triturated with heptane (1 L/mol). The solid was collected by filtration, rinsed with heptane, and dried in a vacuum oven to give indazole bromide in 60-80% yield.

References: George V. DeLucca, US Patent 6,313,110.

This method was used to prepare the following indazoles:

5-Bromo-1H-indazole

6-Bromo-1H-indazole

Method 6

Method 6 provides a method for the preparation of indazole carboxylic acids from bromoindazole.

To a solution of bromoindazole (1.00 equiv) in anhydrous tetrahydrofuran (7 L/mol) was added sodium hydride (60% in mineral oil, 1.11 equiv) in several portions at room temperature. The resulting solution was left at room temperature for 30 minutes and then cooled to -60°C. A 1.3 M solution of sec-butyllithium in cyclohexane (2.1 eq.) was added to the reaction mixture while maintaining the internal temperature below -50°C. The mixture was left at -50°C for another 2 hours. A steady stream of _anhydrous CO was bubbled through the reaction mixture for 1 h. The sparging was continued while the reaction mixture was allowed to warm to room temperature. Brine (6 L/mol) was added and the pH of the mixture was adjusted to 5 with concentrated hydrochloric acid. The mixture was extracted with warm ethyl acetate (3 x 8 mL), the combined extracts were washed with a small amount of brine, dried over anhydrous sodium sulfate, and concentrated. Purification of the residue by chromatography on silica gel or by crystallization affords the acid in 30-60% yield.

This method was used to prepare the following indazoles:

1H-Indazole-5-carboxylic acid

1H-Indazole-6-carboxylic acid

Method 7

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

To a solution of 2-amino-3-methylbenzoic acid (66.9 mmol) in N,N-dimethylformamide (200 mL) was added cesium carbonate (102 mmol). The mixture was stirred for 30 minutes. A solution of methyl iodide (67.0 mmol) in N,N-dimethylformamide (50 mL) was added dropwise, and the reaction mixture was left at room temperature for 18 hours. The reaction mixture was partitioned between water (1 L) and ether (200 mL), and the aqueous layer was extracted with additional ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated to give methyl 2-amino-3-methylbenzoate in 92% yield. ¹ HNMR (400MHz, CDCl ₃ ) δ7.77(d, 1H), 7.19(d, 1H), 6.59(t, 1H), 5.82(bs, 2H), 3.86(s, 3H), 2.17(s, 3H) ).

To a solution of the ester (106 mmol) in chloroform (300 mL) was added acetic anhydride (239 mmol) while maintaining the temperature below 40°C. The reaction mixture was left at room temperature for 1 hour while potassium acetate (30.6 mmol) and isoamyl nitrite (228 mmol) were added. The reaction mixture was heated to reflux for 24 hours and cooled to room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated. To the residue were added methanol (100 mL) and 6N hydrochloric acid (100 mL), and the mixture was left at room temperature for 18 hr. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The residue was separated by filtration, washed with ethyl acetate (20 mL), and dried, whereby methyl 1H-indazole-7-carboxylate hydrochloride was obtained in a yield of 68%. ¹ H NMR (500MHz, Me ₂ SO-d ₆ ) δ13.3(bs, 1H), 8.26(d, 1H), 8.12(d, 1H), 8.25(dd, 1H), 7.27(t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177 (M ⁺ +1).

A solution of indazole (33.0 mmol) in methanol (100 mL) was treated with 29% aqueous potassium hydroxide (20 mL) at 0°C. The reaction mixture was warmed to room temperature and left for 18 hours. 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 warm ethyl acetate (200 mL). The combined extracts were dried over anhydrous sodium sulfate, and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solid was isolated by filtration to afford the acid in 94% yield.

Method 8

Method 8 provides a method for the preparation of 5-nitroindazole-3-acid from ethyl indazole-3-carboxylate.

Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL of concentrated sulfuric acid, and the reaction mixture was cooled to 0°C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over 1 hour. The mixture was stirred for a further 1 hour at 0°C and poured onto crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water, and dried in vacuo. The dried solid was suspended in 250 mL of acetonitrile, and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature, the solid was collected and dried in vacuo, thus giving ethyl 5-nitroindazole-3-carboxylate as a colorless solid in 53% yield and 7-nitroindazole- Ethyl 3-carboxylate (5%) as a colorless solid. Saponification of the ester with sodium hydroxide affords the acid.

References: Org.Synthesis.Coll.Vol.1 , 372 pages.

The following acids were prepared using this method:

5-nitro-1H-indazole-3-carboxylic acid

7-nitro-1H-indazole-3-carboxylic acid

5-Nitro-1H-indazole-3-carboxylic acid ethyl ester

7-Nitro-1H-indazole-3-carboxylic acid ethyl ester

Method 9

Method 9 provides a method for the preparation of 6-nitroindazole-3-oic acid from 3-iodo-6-nitroindazole.

Into a 5 mL microwave reaction vessel was added 3-iodo-6-nitroindazole (1 mmol), copper(I) cyanide (2 mmol) and N,N-dimethylformamide (3 mL). The container was sealed and microwaved at 185°C for 600 seconds. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10:1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. A 10:1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole was dissolved in 10N sodium hydroxide and the light orange solution was heated at 100°C for 1 hour. The mixture was cooled to room temperature and carefully acidified to pH 1 with 3N hydrochloric acid. The solid was isolated and triturated with ethyl acetate to give 51 mg of 6-nitroindazole-3-carboxylic acid as a brown solid.

3-iodo-6-nitroindazole was prepared from 6-nitroindazole by the method of Collot, V. et al., Tetrahedron 1999, 55, 6917.

Method 10

Method 10 provides a method for trapping indazole aryllithium with ketone and coupling with 3-aminoquinuclidine to form heterocyclic derivatives.

6-Bromoindazole-3-carboxylic acid tert-butyl ester was prepared from the acid by reaction with a 2-fold excess of di-tert-butyl dicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% dispersion in mineral oil) (4.8 mmol) in tetrahydrofuran (40 mL) was slowly added tert-butyl 6-bromoindazole-3-carboxylate (4.0 mmol) at 0 °C. Solution in tetrahydrofuran (4 mL). After stirring at 0 °C for 0.5 h, the mixture was cooled to -78 °C and a 1.7 M solution of tert-butyllithium in pentane (5.1 mmol) was added. After 0.5 h at -78°C, a solution of tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at -78°C for 1 hour and warmed to 0°C. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with brine (50 mL), dried (magnesium sulfate), and concentrated. Purification of the residue by chromatography (70/30 ethyl acetate/hexanes) gave tert-butyl 6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylate (68% ), which is a colorless solid.

6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL), and the mixture was left at room temperature 16 hours. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to give 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%). The acid was coupled with quinuclidine according to Method A.

6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (1.0mmol) was placed (take up) in trifluoroacetic acid (5mL), triethyl Silane (2 mL) and dichloromethane (3 mL), and the mixture was refluxed for 16 hours. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to give 6-(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tan solid.

The following acids were prepared using this method:

6-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxylic acid

5-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid

6-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid

5-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid

6-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid

5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid

6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid

5-Formyl-1H-indazole-3-carboxylic acid

6-Formyl-1H-indazole-3-carboxylic acid

Method 11

Method 11 provides a method for the preparation of 4-bromo-5-methoxyindazole-3-carboxylic acid from ethyl 5-methoxyindazole-3-carboxylate and describes further modifications to prepare 4-substituted 5 - Methoxyindazole-3-acid.

N-Bromosuccinimide (24.0 mmol) was added to a solution of ethyl 5-methoxyindazole-3-carboxylate (20.0 mmol) in acetonitrile (200 mL). The reaction mixture was left for 16 hours and partitioned between water (150 mL) and ethyl acetate (250 mL). The layers were separated and the organic layer was washed with brine (50 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography using a gradient of 90/10 to 70/30 hexane/ethyl acetate to afford the 4-brominated product in 57% yield and traces of the 6-brominated product. The 4-brominated product was further derivatized using the Suzuki (Method G; yield 60-70%) or Negishi (Method H; yield 20-40%) reaction conditions described below. The ester (3.82 mmol) was diluted with ethanol (10.0 mL) and 5M sodium hydroxide (10.0 mL), and the reaction mixture was left at room temperature for 4 hours. The reaction mixture was diluted with water (50 mL), acidified to pH 1 with 6N hydrochloric acid. The solid was collected by filtration, whereby the acid was obtained in 80-95% yield.

The following compounds were prepared by this method:

4-Bromo-5-methoxy-1H-indazole-3-carboxylic acid

6-Bromo-5-methoxy-1H-indazole-3-carboxylic acid

7-Bromo-6-methoxy-1H-indazole-3-carboxylic acid

5-Bromo-6-methoxy-1H-indazole-3-carboxylic acid

5-Methoxy-4-(thiophen-2-yl)-1H-indazole-3-carboxylic acid

5-Methoxy-4-(thiophen-3-yl)-1H-indazole-3-carboxylic acid

6-Methoxy-5-(thiophen-3-yl)-1H-indazole-3-carboxylic acid

5-cyclopropyl-6-methoxy-1H-indazole-3-carboxylic acid

Method 12

Method 12 provides a method for the preparation of 5-bromo-4-nitroindazole-3-carboxylic acid from ethyl 5-bromoindazole-3-carboxylate.

5-Bromo-1H-indazole-3-carboxylic acid ethyl ester (5.02 mmol) was dissolved in sulfuric acid (20.0 mL) and cooled to 0°C. A mixture of 70% nitric acid (7/3, nitric acid/water, 1.0 mL) and sulfuric acid (2.0 mL) was added dropwise and the reaction was left at 0 °C for 1 hour. The reaction mixture was poured into 100 mL of ice water, and the solid was collected by filtration, thereby obtaining the product in a yield of 86%. The ester (3.82 mmol) was diluted with ethanol (10.0 mL) and 5M sodium hydroxide (10.0 mL), and the reaction mixture was left at room temperature for 4 hours. The reaction mixture was diluted with water (50 mL), and acidified to pH 1 with 6N hydrochloric acid. The solid was collected by filtration, whereby the acid was obtained in 82% yield.

Method 13

Method 13 provides a method for the preparation of N-1-alkylated indazole-3-carboxylic acids from the corresponding indazole esters.

To a solution of ethyl 5-methoxyindazole-3-carboxylate (1.50 mmol) in acetonitrile (15 mL) was added potassium carbonate (5.99 mmol) and methyl iodide (3.00 mol). The reaction was heated at 60°C for 4 hours, cooled to room temperature, and partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography using a gradient of 95/5 to 80/20 hexane/ethyl acetate to afford 2-substituted indazoles (17%) and 1-substituted indazoles (44%). The 1-substituted indazole (61 mg, 0.26 mmol) was suspended in ethanol (5.0 mL) and heated to aid dissolution. An aliquot of a 5.0 M solution of sodium hydroxide in water (2.00 mL) was added and the reaction mixture was left at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL), and acidified with 6.0N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 50 mL), the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate), and concentrated to afford the acid in 95% yield.

The following compounds were prepared by this method:

5-Methoxy-1-methyl-1H-indazole-3-carboxylic acid

5-methoxy-1-ethyl-1H-indazole-3-carboxylic acid

5-Methoxy-1-cyclopentyl-1H-indazole-3-carboxylic acid

5-Methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic acid

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

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

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

5-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic acid

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

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

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

6-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic acid

1-Benzyl-6-difluoromethoxy-1H-indazole-3-carboxylic acid

1-Benzyl-5-difluoromethoxy-1H-indazole-3-carboxylic acid

Method 14

Method 14 provides a method for the demethylation of methoxyindazole acid and coupling with 3-aminoquinuclidine to form the hydroxy-substituted derivative.

Methoxyindazole acid (10.4 mmol) was diluted with dichloromethane (100 mL), and the solution was cooled to -78°C. A 1.0 M solution of boron tribromide in dichloromethane (52 mmol, 5 equiv) was added dropwise over 30 minutes. The reaction mixture was warmed to room temperature and left for 24 hours. The reaction was quenched slowly with methanol (100 mL), and the reaction was concentrated to dryness. The residue was purified by chromatography using a gradient of hexane/ethyl acetate (100/0 to 80/20) followed by a mixture of ethyl acetate/methanol/triethylamine (70/30/1) to obtain This gave phenol (60-80%) as a brown solid. This method was also successfully used for N-(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide, N-(3R) -1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide and benzisothiazole analogs.

This method was used to prepare the following compounds:

5-Hydroxy-1H-indazole-3-carboxylic acid

6-Hydroxy-1H-indazole-3-carboxylic acid

5-Hydroxy-1,2-benzisothiazole-3-carboxylic acid

6-Hydroxy-1,2-benzisothiazole-3-carboxylic acid

Method 15

Method 15 provides the preparation of 7-fluoro-6-methoxy-1H-indazole-3-carboxylic acids and 4-fluoro-5-methoxy-1H-indazole-3-carboxylic acids from the corresponding methoxyindazole acids carboxylic acid method.

1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.00 g, 2.82 mmol) was added to 6-methoxy-1H - A solution of ethyl indazole-3-carboxylate (500 mg, 2.27 mmol) in acetonitrile (15.0 mL), and the reaction mixture was left at room temperature for 18 hours. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL), the separated organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (95/5 to 80/20 hexane/ethyl acetate) to yield 541 mg (23%) of the fluorinated ester. A solution of the ester (124 mg, 0.520 mmol) in ethanol (5.00 mL) was diluted with 5.0 M sodium hydroxide (2.00 mL), and the mixture was left at room temperature for 18 hours. The reaction was acidified with 6N hydrochloric acid and partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated in vacuo to afford 109 mg (84%) of the acid. The acid was coupled with the bicyclic base according to Method A.

The following acids were prepared using this method:

7-Fluoro-6-methoxy-1H-indazole-3-carboxylic acid

4-fluoro-5-methoxy-1H-indazole-3-carboxylic acid

Method 16

Method 16 details the preparation of ethyl benzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.

Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 mL) over 30 minutes. The reaction temperature rose to 60°C, and the mixture became clear. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added, and the solution was left at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into ice (300g-400g). The precipitated solid was isolated by filtration and dried to give 11.0 g of product (89%).

The ester (11.0 g, 32.0 mmol) was diluted with 2N sodium hydroxide solution (32 mL, 63 mmol), and the reaction mixture was left at room temperature for 16 hours. The aqueous layer was extracted with dichloromethane (20 mL) and acidified. The precipitated solid was isolated by filtration and dried to yield 7.00 g of acid (89%).

Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 mL). The reaction mixture was heated to reflux for 2 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL), and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (magnesium sulfate) and concentrated to give 8.00 g (98%) of the ester as a liquid.

To a solution of this ester (420 g, 1.46 mol) in ethanol (3 L) was added isoamyl nitrite (225 mL) in a 10 L three necked round bottom flask and the mixture was warmed to 60 °C. A sodium ethoxide solution prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was left for 2 hours. The reaction mixture was cooled to room temperature and neutralized with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2 L), the combined organic layers were washed with water (2 x 1 L), brine (2 x 1 L), and dried (magnesium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to afford 110 g of product (28%).

To a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300 mL) was added 10% palladium on carbon (1.5 g) and tris Ethylamine (7.5 g, 82.4 mmol). The nitrogen atmosphere was removed by evacuation, replaced by hydrogen, and the reaction mixture was left for 1 hour. The hydrogen atmosphere was removed by evacuation, replaced by nitrogen, and filtered through celite to remove palladium. The filter cake was washed with ethanol (3 x 50 mL), and the filtrate was concentrated. The residue was dissolved in dichloromethane (200 mL), the solution was washed with water (4 x 50 mL), dried (sodium sulfate), and evaporated to give 13.0 g of product as a yellow solid (96%). Saponification of the ester with sodium hydroxide afforded the acid, which was coupled according to Method A with the bicyclic base.

References: Angell, R.M.; Baldwin, I.R.; Bamborough, P.; Deboeck, N.M.; Longstaff, T.;

The following acids and esters were prepared using this method:

6-Bromo-1,2-benzisoxazole-3-carboxylic acid ethyl ester

1,2-Benzisoxazole-3-carboxylic acid ethyl ester

1,2-Benzisoxazole-3-carboxylic acid

Method 17

Method 17 provides a method for the preparation of 5-difluoromethoxyindazole-3-oic acid from 3-bromo-4-nitrophenol.

To a suspension of sodium hydroxide (29.0mmol) in N,N-dimethylformamide (15mL) was added 3-bromo-4-nitrophenol (10.0mmol), and the suspension was left at room temperature for 15 minute. The reaction mixture was cooled to 0 °C and treated with ethyl chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated at 70 °C for 16 hours and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the difluoromethyl ether as a yellow oil in 75% yield.

To a suspension of sodium hydride (328 mmol) in dimethyl sulfoxide (40 mL) was added diethyl malonate (328 mmol) dropwise at 0°C. The reaction mixture was warmed to 60°C and allowed to stand for 0.5 hours. A solution of difluoromethyl ether (149 mmol) in dimethyl sulfoxide (80 mL) was added dropwise, and the reaction mixture was heated at 100° C. for 5 hours. The cooled solution was poured into ice water, and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil in 112% yield. The diester (167 mmol), sodium hydroxide (500 mmol) and water (335 mL) were combined and heated at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and the aqueous layer was washed with dichloromethane (3 x 100 mL). The pH of the aqueous layer was carefully adjusted to 1 with concentrated hydrochloric acid, and the reaction mixture was heated at 60 °C for 1 hour. The suspension was cooled to 5°C and the solid was collected by filtration and dried to give the acid in 61% yield.

Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0°C. After 0.5 hours, the acid (101 mmol) was added and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane (200 mL) and saturated sodium bicarbonate (100 mL). The aqueous layer was further extracted with dichloromethane (2 x 200 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated to afford the ester as a brown oil in 60% yield.

The ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted with water (71 mL), and treated with ammonium chloride (243 mmol) and iron powder (301 mmol). The reaction mixture was heated to reflux for 10 minutes, the suspension was filtered through celite, and the filter cake was washed 3 times with ethanol. The filtrate was concentrated, and the residue was suspended in 2N hydrochloric acid and stirred vigorously for 0.5 hours. The aqueous layer was washed with ethyl acetate (3 x 50 mL), and the pH was adjusted to 9-10 with 5M sodium hydroxide. The aqueous layer was extracted with chloroform (3 x 100 mL), and the combined organic layers were dried (magnesium sulfate). Acetic anhydride (392 mmol), isoamyl nitrite (291 mmol) and potassium acetate (51.0 mmol) were added to the organic layer, and the suspension was heated to reflux for 16 hours. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with dichloromethane (2 x 100 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated to afford N-acetylindazole ester as a brown oil in 79% yield.

The ester (63.8 mmol), sodium hydroxide (193 mmol) and water (65 mL) were combined and the reaction was left at 60 °C for 24 hours. After cooling to room temperature, the aqueous layer was washed with dichloromethane (3 x 50 mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dichloromethane, and dried to give the acid in 27% yield.

The following acids were prepared according to this method:

5-(Difluoromethoxy)-1H-indazole-3-carboxylic acid

Method 18

Method 18 provides a method for the preparation of 6-difluoromethoxyindazole-3-oic acid from 4-nitrophenol.

To a suspension of sodium hydroxide (485 mmol) in N,N-dimethylformamide (150 mL) was added 4-nitrophenol (162 mmol), and the suspension was left at room temperature for 15 minutes. The reaction mixture was cooled to 0°C and treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated at 70 °C for 16 hours and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the difluoromethyl ether as a yellow oil in 59% yield.

The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated to reflux for 30 minutes, and the suspension was filtered through celite. The filter cake was washed 3 times with ethanol, and the combined filtrates were concentrated. The residue was dissolved in water and the pH was adjusted to 9-10 with 5M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was left at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and neutralized with solid sodium bicarbonate. The precipitated solid was isolated by filtration, washed with water, and dried to give acetamide as a pale yellow solid in 62% yield.

To a solution of acetamide (19.6 mmol) in chloroform (20 mL) was added acetic anhydride (19.6 mmol), and the reaction mixture was heated to reflux. Fuming nitric acid (16.0 mmol) was added dropwise, and the reaction mixture was refluxed for 30 minutes. The cooled solution was diluted with water (20 mL), and the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the nitroamide in 83% yield.

The amide (11.0 mmol), sodium hydroxide (43.8 mmol) and water (10 mL) were combined and the reaction mixture was left at 60° C. for 1.5 hours. The reaction was cooled to room temperature, and the precipitated solid was isolated by filtration, washed with water, and dried to afford aniline as a pale yellow solid in 98% yield.

Aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL), and the reaction mixture was heated at 80-90° C. to completely dissolve the aniline. The reaction mixture was cooled to 0 °C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added within 15 minutes. The solution was left at 0-5°C for 40 minutes and filtered. Copper(I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and cooled to 0°C. The azide salt solution was slowly added to the copper solution, and the mixture was left at 0-10°C for 30 minutes. The reaction mixture was heated at 60°C for 30 minutes followed by 100°C for 10 minutes to ensure completion of the reaction. The reaction mixture was cooled to room temperature and extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with 1M sodium hydroxide, water, 1N hydrochloric acid and water. The organic layer was dried (magnesium sulfate) and concentrated to give the nitrobromide as a pale yellow solid in 76% yield.

To a suspension of sodium hydride (25.8 mL) in dimethylsulfoxide (5 mL) was added diethyl malonate (25.7 mmol) dropwise at 0°C. The reaction mixture was heated to 60 °C and allowed to stand for 30 minutes. A solution of nitrobromide (11.7 mmol) in dimethylsulfoxide (7 mL) was added dropwise, and the reaction mixture was heated at 100° C. for 5 hours. The cooled solution was poured into ice water, and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol) and water (20 mL) were combined and heated at 60 °C for 1 hour. The reaction mixture was cooled to room temperature, and the aqueous layer was washed with dichloromethane (3 x 100 mL). The pH of the aqueous layer was carefully adjusted to 1 with concentrated hydrochloric acid, and the reaction mixture was heated at 60 °C for 1 hour. The suspension was cooled to 0°C and the solid was collected by filtration and dried to give the acid in 64% yield.

Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0°C. After 30 minutes, the acid (7.69 mmol) was added and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated to afford the ester as a brown oil in 94% yield.

To a suspension of this ester (3.64 mmol) and acetic acid (7.0 mL) was added acetic anhydride (6.0 mL) at 0°C. Zinc powder (14.6 mmol) was added in portions over 15 minutes and the reaction mixture was left at 0° C. for 30 minutes and then at room temperature for 1.5 hours. Additional zinc dust (6.15 mmol) was added and the reaction mixture was left for 3 hours. The suspension was filtered through celite, and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20 mL). The aqueous layer was further extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated to give acetamide as a brown oil in 92% yield.

To a solution of this acetamide (3.92 mmol) in chloroform (20 mL) was added acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol) and potassium acetate (2.04 mmol), and the suspension was heated at reflux for 16 hours . The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (10 mL) and dichloromethane (20 mL). The aqueous layer was further extracted with dichloromethane (2 x 20 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated to give crude N-acetylindazole ester as a brown oil.

The ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was left at 60 °C for 24 hours. After cooling to room temperature, the aqueous layer was washed with dichloromethane (3 x 30 mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dichloromethane, and dried to give the acid in 26% yield.

The following acids were prepared according to this method:

6-(Difluoromethoxy)-1H-indazole-3-carboxylic acid

Method 19

Method 19 provides a method for coupling brominated benzisothiazole-3-carboxylates with brominated indazole-3-carboxylates and Grignard reagents to form alkyl-substituted and heterocyclic-substituted acids.

A 0.5 M solution of Grignard reagent (25.0 mmol, 3.7 equiv) in THF was diluted with THF (60 mL) at room temperature and treated with a 0.5 M solution of zinc chloride (25.0 mmol, 3.7 equiv) in THF. After 10 minutes, the brominated ester (0.30 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.95 mmol, 0.1 equiv) were added to the suspension. The reaction mixture was left at room temperature for 1 hour, followed by 1 hour at 65°C. The reaction was quenched with saturated ammonium chloride and the reaction was extracted with dichloromethane (3x). The extract was dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography using a gradient of 100/0 to 90/10 dichloromethane/methanol to afford the alkyl- and aryl-substituted amides. The amide was dissolved in a mixture of methanol/tetrahydrofuran/water (90/10/20) and treated with sodium hydroxide (5.8 g). The mixture was heated to reflux for 12 hours, cooled to room temperature, filtered and acidified to pH <2 by slow addition of concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2x) and dried over sodium sulfate. The extract was concentrated to give the acid in 38% yield. The acid was coupled with the bicyclic base according to Method A.

With minor modifications, this method was used to derivatize brominated indazole-3-piperidinamides with various Grignard reagents. Grignard reagents for thiazoles are commercially available. Alternatively, aryllithium and corresponding arylzinc reagents can be prepared according to the method described by Reeder, M.R. et al., Org.Proc.Res.Devel.2003, 7, 696. Zinc reagents for oxazole, 4-methylthiazole, and 5-methylthiazole were prepared according to this method.

The following acids were prepared using this method:

6-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid

5-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid

5-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid

5-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid

6-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid

6-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid

5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxylic acid

6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxylic acid

Method 20

Method 20 provides the preparation of alkoxyindazole acids from the corresponding benzyloxyindazole esters using alkylation conditions.

To a suspension of sodium hydride (60% dispersion in mineral oil, 8.1 mmol) in tetrahydrofuran (54.0 mL) at 0 °C was added dropwise 5-(benzyloxy)-1H-indazole-3-carboxylic acid (2.70 mmol) Solution in tetrahydrofuran (10 mL). The reaction was left at 0°C for 1 hour. [β-(Trimethylsilyl)ethoxy]methyl chloride (3.2 mmol) was added and the reaction mixture was left for 1 hour. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL), the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (95/5 to 85/15 hexane/ethyl acetate) to afford the protected indazole in 89% yield.

To a suspension of 10% palladium on carbon (249 mg) in ethanol (66.7 mL) was added 5-(benzyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H - Ethyl indazole-3-carboxylate (9.38 mmol). The reaction was shaken under a hydrogen atmosphere (50 psi) for 4.0 hours. The reaction was filtered through celite and concentrated to give phenol as a white solid in 87% yield.

To a solution of ethyl 5-hydroxy-1-(2-trimethylsilylethoxymethyl)-1H-indazole-3-carboxylate (5.94 mmol) in acetonitrile (10.0 mL) was added cyclopropane methyl bromide (1.19 mmol) and potassium carbonate (2.38 mmol). The suspension was heated at 60°C for 4.0 hours. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL), the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (100/0 to 85/15 hexane/ethyl acetate) to afford the purified ethyl ester. The ester was dissolved in ethanol (10 mL), and 5N sodium hydroxide (3 mL) was added. The mixture was left overnight, diluted with water (20 mL), and acidified to pH 1 with 3N hydrochloric acid. The solid was collected by vacuum filtration to afford the acid as a white solid in 72% yield.

The following acids were prepared using this method:

5-(cyclopropylmethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1-1H-indazole-3-carboxylic acid

6-(cyclopropylmethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1-1H-indazole-3-carboxylic acid

5-(cyclopentyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

6-(cyclopentyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-(2,2,2-Trifluoroethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

6-(2,2,2-Trifluoroethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

Method 21

Method 21 provides the preparation of alkoxyindazole acids from the corresponding benzyloxyindazole esters using Mitsunobu conditions.

To 5-hydroxy-1-(2-trimethylsilylethoxymethyl)-1H-indazole-3-carboxylic acid ethyl ester (0.594mmol), 1-methyl-3-pyrrolidinol (0.594 mmol) and triphenylphosphine (0.594 mmol) in tetrahydrofuran (3.6 mL) was added dropwise diisopropyl azadicarboxylate (0.618 mmol). The reaction was left for 16 hours and concentrated. Purification of the residue by chromatography (100/0 to 90/10 ethyl acetate/[70/30/2 ethyl acetate/methanol/dimethylethylamine] afforded the ether product in 49% yield. The ester Saponification provides the acid, which is coupled with the bicyclic base using Method C.

The following acids were prepared using this method:

5-[(1-Methylpyrrolidin-3-yl)oxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic acid

5-[(1-Benzylpyrrolidin-3-yl)oxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxylic acid

5-[2-(Dimethylamino)ethoxy]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-(2-Pyrrolidin-1-ylethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-(2,3-Dihydro-1H-inden-2-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-(tetrahydro-2H-pyran-4-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

Method 22

Method 22 provides a method for the preparation of 1-(3-thienyl)-1H-indazole-3-carboxylic acids from the corresponding indazole esters.

1H-Indazole-3-carboxylic acid ethyl ester (5.50mmol), 3-thienylboronic acid (7.50mmol), copper (II) acetate (5.01mmol), triethylamine (24.7mmol) and pyridine (40.4mmol) Dissolve in 1,4-dioxane (39.8 mL). The reaction was left at room temperature for 16 hours and diluted with water (50 mL) and ethyl acetate (50 mL). The reaction mixture was filtered through celite, the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (90/10 to 70/30 hexane/ethyl acetate) to afford N-arylindazole esters in 35% yield. The ester was saponified using standard conditions and the resulting acid was used in Method A.

Method 23

Method 23 provides a method for the preparation of 1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylic acid from ethyl 6-bromo-7-nitro-1H-indazole-3-carboxylate.

To a 0.50 M solution of (1,3-dioxan-2-ylmethyl)magnesium bromide in THF (11 mL) was added a 0.50 M solution of zinc chloride in THF (11 mL), and the reaction mixture was placed 20 minutes. To 4 microwave tubes containing ethyl 6-bromo-7-nitro-1H-indazole-3-carboxylate (143 mmol) and bis(tri-tert-butylphosphine)palladium(0) (26 mg, 0.051 mmol) Aliquots (5.5 mL) of the zinc reagent solution were added to each. The reaction was heated at 160° C. for 10 minutes in a microwave reactor. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL), filtered through celite, and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (80/20 to 60/40 hexane/ethyl acetate) to afford the dioxane product in 46% yield.

To a suspension of 10% palladium on carbon (100 mg) in ethanol (30 mL) was added 6-(1,3-dioxan-2-ylmethyl)-7-nitro-1H-indazole-3- Ethyl carboxylate (0.657 mmol). The reaction mixture was shaken under hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite and concentrated to afford the amine as an oil in 94% yield.

7-Amino-6-(1,3-dioxan-2-ylmethyl)-1H-indazole-3-carboxylic acid ethyl ester (0.371 mmol) was dissolved in tetrahydrofuran (30 mL), and washed with 6M hydrochloric acid ( 5mL) treatment. The reaction mixture was left for 16 hours and partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (90/10 to 70/30 hexane/ethyl acetate) to afford pyrrolidine in 72% yield.

1,8-Dihydropyrrolo[3,2-g]indazole-3-carboxylic acid ethyl ester (0.266mmol) was dissolved in ethanol (2mL) and 5.0M sodium hydroxide (1.00mL), and the reaction Set aside for 16 hours. The reaction mixture was neutralized with 3N hydrochloric acid and partitioned between water (30 mL) and ethyl acetate (30 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated in vacuo to give the acid in 41% yield. The acid was used without further purification.

Method 24

Method 24 provides a method for the preparation of alkoxypyrrolidine substituted indazole-3-carboxylic acids from the corresponding nitro-1H-indazole-3-carboxylates.

To a suspension of ethyl 5-nitro-1H-indazole-3-carboxylate (8.50mmol) and N,N-diisopropylethylamine (25.5mmol) in dichloromethane (20.0mL) dropwise [β-(Trimethylsilyl)ethoxy]methyl chloride (10.2 mmol) was added. The heterogeneous reaction mixture was left at room temperature for 16 hours, at which point the reaction mixture gradually became homogeneous. The reaction mixture was filtered through silica gel (about 40 g), and concentrated. The residue was diluted with ethanol (50.0 mL), and 10% palladium on carbon (200 mg) was added under nitrogen flow. The reaction was shaken under hydrogen atmosphere for 4 hours, the reaction mixture was filtered through celite and concentrated. The residue was purified by chromatography (70/30 to 50/50 hexane/ethyl acetate) to afford the aniline as a 2/1 mixture of the 1- and 2-SEM regioisomers in 60% yield.

5-Amino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid ethyl ester (3.61mmol) and 1,4-dibromo-2- Butanol (3.80 mmol) and potassium carbonate (3.47 mmol) were combined in triethyl phosphate (10.0 mL) and the reaction was heated at 120°C for 2 hours. The reaction mixture was loaded onto an SCX cartridge (3 x 10 g) and the cartridge was washed with 5 mL of methanol. The partially purified product was then eluted with 2.0M aqueous ammonia in methanol and the product fractions were combined and concentrated. The residue was purified by chromatography (90/10 to 70/30 hexane/ethyl acetate) to afford pyrrolidine in 55% yield.

5-(3-Hydroxypyrrolidin-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid ethyl ester (0.493mmol) The solution in tetrahydrofuran (20.0 mL) was cooled to -78°C. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (1.18 mL) was added dropwise and the reaction mixture was left for 30 minutes. 2,2,2-Trifluoroethyl nonafluorobutanesulfonate (0.493 mmol) was added and the reaction mixture was allowed to warm to room temperature and allowed to stand for 4 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (90/10 to 80/20 hexane/ethyl acetate) to afford the alkoxypyrrolidine in 42% yield.

The ester (0.172 mmol) was dissolved in ethanol (5.0 mL) with slight heating. 5.0M sodium hydroxide (2.00 mL) was added and the reaction mixture was left overnight. The reaction mixture was diluted with water (50 mL), neutralized to pH 6-7 with 3.0 N hydrochloric acid, and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated to give the acid in 89% yield. The acid was used without further purification.

The following acids were prepared by this method:

5-[3-(Hydroxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-[3-(Methoxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-[3-(Benzyloxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carboxylic acid

5-[3-(2,2,2-Trifluoroethyl)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole- 3-Carboxylic acid

Method 25

Method 25 provides a method for the preparation of aminomethyl substituted indazole-3-carboxylic acids from the corresponding bromides.

At 60°C, to a mixture of 5-bromo-1H-indazole-3-carboxylic acid (62.2mmol) and 4-dimethylaminopyridine (19.0mmol) in tert-butanol (150mL) and tetrahydrofuran (150mL) A solution of di-tert-butyl dicarboxylate (188 mmol) in tetrahydrofuran (50 mL) was added carefully in medium. The mixture was left at 60° C. until gas evolution ceased (approximately 4 hours). The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, sodium bicarbonate and brine, dried (sodium sulfate), and concentrated. The residue was dissolved in 1/1 hexane/ethyl acetate (-300 mL) and filtered through silica gel (ca. 40 g). The silica gel was washed with additional 1/1 hexane/ethyl acetate (500 mL), and the combined eluents were concentrated. The residue was dissolved in methanol (100 mL) and tetrahydrofuran (100 mL), and treated with 2.0 M sodium hydroxide (100 mL). The reaction mixture was left at room temperature for 2 hours and partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried (magnesium sulfate), and concentrated. The residue was triturated with hexanes to give the ester in 80% yield.

Sodium hydride (60% dispersion in mineral oil) (6.00 mmol) and tetrahydrofuran (90 mL) were added to a single neck round bottom flask. The reaction was cooled to -78°C and a solution of tert-butyl 5-bromo-lH-indazole-3-carboxylate (4.00 mL) in tetrahydrofuran (10.0 mL) was added. The reaction was heated and left at 25°C for 30 minutes. The reaction was cooled to -78°C and tert-butyllithium in pentane (1.7M, 3.6 mL) was added dropwise. The reaction was placed at -78°C for 15 minutes and N,N-dimethylformamide (20 mmol) was added. The reaction was held at -78°C for 30 minutes, then quenched with methanol (0.5 mL) and allowed to warm to room temperature. The reaction was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (80/20 to 60/40 hexane/ethyl acetate) to afford benzaldehyde in 52% yield.

To a suspension of 5-formyl-1H-indazole-3-carboxylic acid tert-butyl ester (2.03mmol) and dimethylamine hydrochloride (4.74mmol) in 1,2-dichloroethane (50.0mL) Sodium triacetoxyborohydride (4.74 mmol) was added. The reaction mixture was left at room temperature for 3 days. The reaction mixture was washed with water (50 mL) and brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was loaded onto an SCX cartridge (10 g) and the cartridge was washed with 5 volumes of methanol. The purified product was then eluted with 2.0M aqueous ammonia in methanol to afford the amine in 86% yield.

5-[(Dimethylamino)methyl]-1H-indazole-3-carboxylic acid tert-butyl ester (1.74 mmol) was dissolved in trifluoroacetic acid (3.00 mL), and the reaction mixture was left for 16 hours. The reaction mixture was concentrated and loaded onto an SCX cartridge (10 g) and the cartridge was washed with 5 volumes of methanol. The purified product was then eluted with 2.0M aqueous ammonia in methanol to afford the acid in 90% yield.

This method was used to prepare the following compounds:

5-[(Dimethylamino)methyl]-1H-indazole-3-carboxylic acid

5-[(Diethylamino)methyl]-1H-indazole-3-carboxylic acid

5-[(Pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxylic acid

5-Bromo-1H-indazole-3-carboxylic acid tert-butyl

Method 26

Method 26 provides a method for the preparation of 4-methoxyindazoles from 4-methoxyanilines.

A solution of 4-methoxyaniline (1.63 mol) in acetic acid (244 mL) was treated with acetic anhydride (244 mL) and zinc dust (30.8 mmol), and the reaction mixture was heated to reflux for 30 minutes. The suspension was cooled to room temperature, filtered, and concentrated. The residue was diluted with water (200 mL), and the pH of the solution was adjusted to 8 with 10% sodium hydroxide. The precipitated solid was collected by filtration, washed with water (1 L), and dried to give acetamide as a purple solid in 94% yield.

To a solution of this acetamide (1.52 mol) in dichloromethane (1.5 L) was added concentrated nitric acid (210 mL) dropwise at room temperature. The reaction mixture was heated to reflux for 1 hour and cooled to room temperature. The reaction mixture was washed with water (1.0 L), saturated sodium carbonate (1.0 L) and water (1.0 L). The organic layer was dried over anhydrous sodium sulfate and concentrated to give nitroacetamide as an orange solid in 83% yield.

A solution of the nitroacetamide (1.27 mol) in water (1.27 L) was treated with sodium hydroxide (5.07 mol) and the reaction mixture was heated at 60°C for 2 hours. The precipitated solid was collected by filtration, washed with water, and dried to give the nitroaniline as an orange solid in 85% yield.

To a cold (0-5° C.) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90° C. for 2 hours) was added sodium nitrite (1.48 mol) Solution in water (250 mL). The reaction mixture was left for 40 minutes and filtered. The filtrate was added dropwise to a cold (0-5° C.) solution of copper(I) bromide (1.81 mol) in hydrobromic acid (640 mL), and the reaction mixture was left for 30 minutes. The reaction mixture was heated to 60 °C and allowed to stand for 30 minutes. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was diluted with water (2 L) and extracted with dichloromethane (3 x 1 L). The combined organic layers were washed with 10% sodium hydroxide (1.0 L), water (2.0 L), 10% hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate), and concentrated. The residue was recrystallized from ethanol to give the bromide as a yellow solid in 50% yield.

To a solution of this bromide (216 mmol) in ethanol (200 mL) and water (140 mL) were added iron powder (1.08 mol) and ammonium chloride (862 mmol), and the reaction mixture was heated to reflux for 1 hour. The suspension was filtered and concentrated, and the residue was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried (sodium sulfate) and concentrated to give the bromoaniline as a yellow liquid in 96% yield.

To a solution of chloral hydrate (312 mmol) and sodium sulfate (967 mmol) in water (450 mL) was added a solution of the bromoaniline (208 mmol) in 50% hydrochloric acid (40 mL) and the reaction mixture was left for 1 hour . A solution of hydroxylamine hydrochloride (793 mmol) in water (240 mL) was added and the reaction mixture was heated at 60° C. for 2 hours. The aqueous layer was decanted and the residual red oil was purified by chromatography (6/6/1 petroleum ether/dichloromethane/ethyl acetate), which solidified on standing to give the α-oxime amide as a pale yellow solid , the yield was 29%.

The α-oxime amide (58.6 mmol) was added in one portion to warm (40° C.) 90% sulfuric acid (16 mL) and the reaction mixture was heated at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature and poured into ice water. The precipitated orange solid was collected by filtration and dried. The crude product was purified by chromatography (15/1 petroleum ether/ethyl acetate) to afford indolindione as a yellow solid in 57% yield.

The indolindione (20.7 mmol) was mixed with 1M sodium hydroxide (23 mL), and the reaction mixture was heated at 30-40° C. for 30 minutes. The reaction mixture was cooled to 0 °C, treated with a solution of sodium nitrite (20.7 mmol) in water (5.1 mL) and left for 20 min. To a cold (0-5 °C) solution of concentrated sulfuric acid (2.24 mL) in water (43.3 mL) was added dropwise the solution and the reaction mixture was left for 0.5 h. A solution of tin(II) chloride (50.5 mmol) in concentrated hydrochloric acid (19.6 mL) was added dropwise and the reaction mixture was left at 0-5°C for 1 hour. The precipitated solid was isolated by filtration and dried to give indazole acid as a yellow solid (100% by mass).

To methanol (180 mL) was added acetyl chloride (18 mL) at 0°C, and the reaction mixture was left for 1 hr. Indazole acid (21.8 mmol) was added and the reaction mixture was heated to reflux for 3 hours. The solution was concentrated to dryness, the residue was suspended in water, and the pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 100 mL), the combined organic layers were dried (magnesium sulfate), and concentrated. The crude product was purified by chromatography (2/1 petroleum ether/ethyl acetate) to afford the indazole ester as a yellow solid in 5% yield (two steps).

Under a hydrogen atmosphere, the indazole ester (1.02 mmol) was combined with 10% palladium on carbon (30 mg) and methanol (20 mL), and left at room temperature for 30 minutes. The catalyst was removed by filtration and the eluate was concentrated to afford the debrominated indazole ester as an orange solid in 24% yield.

To a solution of the debrominated indazole ester (0.243 mmol) in methanol (3.0 mL) was added 1M sodium hydroxide (1.5 mL) and the reaction mixture was heated at 60° C. for 3 hours. The solution was concentrated, the pH was adjusted to 1-2, and the solid was collected by filtration to give indazole acid as a yellow solid in 100% yield.

Method 27

Method 27 provides a method for the preparation of benzyloxy substituted indazole-3-carboxylic acids from the corresponding bromides.

To a solution of 4-methoxynitrobenzene (230 mmol) in glacial acetic acid (34 mL) was added acetic anhydride (34 mL) and zinc powder (4.59 mmol), and the reaction mixture was heated to reflux for 0.5 h. The reaction mixture was poured into water (340 mL), and the pH of the solution was adjusted to 8 with 10% sodium hydroxide. The precipitated solid was isolated by filtration, washed with water (100 mL), and dried to give acetamide in 88% yield.

To a solution of this acetamide (200 mmol) in dichloromethane (200 mL) was added 65% nitric acid (22 mL) dropwise over 0.5 h. The reaction mixture was left at room temperature for 1 hour and heated to reflux for 1 hour. The reaction mixture was washed with water (200 mL), saturated sodium carbonate solution (100 mL) and water (200 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the nitroacetamide as a yellow solid in 90% yield.

To 4M sodium hydroxide (180 mL) was added the nitroacetamide (180 mmol), and the reaction mixture was left at 60° C. for 2 hours. The precipitated solid was isolated by filtration, washed with water, and dried to give nitroaniline as a red solid in 70% yield.

To this solution of nitroaniline (125 mmol) in 40% hydrobromic acid (110 g) was added dropwise a solution of sodium nitrite (11.8 g) in water (28 mL) at 10° C. over 0.5 h. The reaction mixture was placed at 0-10°C for 40 minutes and filtered. The filtrate was added dropwise to a 0° C. purple solution of copper(I) bromide (209 mmol) in hydrobromic acid (74 mL) over 1 hour. The reaction mixture was warmed to room temperature, left at room temperature for 30 minutes, at 60°C for 0.5 hours, and heated to reflux for 1 hour. The reaction mixture was partitioned between water (2.0 L) and dichloromethane (600 mL), and the aqueous layer was further extracted with dichloromethane (300 mL). The combined organic layers were washed with 10% sodium hydroxide (200 mL), water (600 mL), 10% hydrochloric acid (300 mL) and water (600 mL), dried (magnesium sulfate), and concentrated to give the nitro bromide as a yellow Oil, 83% yield.

To this solution of nitrobromide (100 mmol) in dichloromethane (250 mL) was added a solution of boron tribromide (250 mmol) in dichloromethane (200 mL) dropwise at -78°C over 1 hour. The reaction mixture was warmed to room temperature and left for 30 hours. The reaction mixture was cooled to 0 °C, quenched with water (300 mL), and the aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with saturated sodium bicarbonate (2 x 300 mL), dried (magnesium sulfate), and concentrated to afford nitrophenol as a brown crystalline solid in 87% yield.

To a solution of this nitrophenol (87.0 mmol) in 2/1 acetonitrile/acetone (840 mL) was added benzyl bromide (131 mmol) and potassium carbonate (130 mmol). The reaction mixture was heated to reflux for 17 hours and concentrated to dryness. The residue was suspended in ethyl acetate (756 mL), filtered, and the organic layer was washed with water (567 mL), 1M hydrochloric acid (2 x 567 mL) and brine (567 mL). The organic layer was dried (magnesium sulfate) and concentrated to give the benzyl ether in 78% yield.

To a suspension of sodium hydride (520 mmol) in dimethyl sulfoxide (100 mL) was added diethyl malonate (890 mol) dropwise at 0°C. The benzyl ether (44.0 mmol) was added and the reaction mixture was heated at 100°C for 5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 x 70 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the diethyl malonate addition product. The diethyl malonate addition product was diluted with 4 M sodium hydroxide (100 mL), and the reaction mixture was heated at 60° C. for 6 hours. The solution was extracted with dichloromethane (3 x 50 mL), and the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. The reaction mixture was heated at 60 °C for 1 h, cooled to room temperature, and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to afford phenylacetic acid as a solid in 78% yield.

To a fresh ethanolic hydrochloric acid solution [acetyl chloride was added to ethanol (100 mL)] was added the phenylacetic acid (350 mmol) and the reaction mixture was heated to reflux for 20 hours. The reaction mixture was concentrated to dryness, and the residue was partitioned between saturated sodium bicarbonate (200 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to give the ester in 77% yield.

The nitroester (27.0 mmol) was dissolved in acetic acid (60 mL) and acetic anhydride (44 mL) and cooled to 0°C. Zinc dust (153 mmol) was added and the reaction mixture was allowed to warm to room temperature and allowed to stand for 2 hours. An additional amount of zinc powder (2 x 45.9 mmol) was added over 3 hours. After 1 hour, the reaction mixture was filtered, and the filter cake was washed with ethanol (100 mL). The combined filtrates were concentrated, and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate (50 mL). The solution was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (magnesium sulfate), filtered, and concentrated to give acetamide in 82% yield.

To a solution of acetamide (21.0 mmol) in chloroform (80 mL) and acetic anhydride (45 mL) was added isoamyl nitrite (47.2 g) dropwise over 30 minutes. Solid potassium acetate (7.13 mmol) was added in portions and the reaction mixture was heated to reflux for 1.5 hours. The reaction mixture was washed with water (2 x 80 mL) and brine (80 mL), dried (magnesium sulfate), and concentrated to give the acetylated indazole ester in 68% yield.

The acetylated indazole ester (15.0 mmol) was suspended in 2M sodium hydroxide (35 mL), and the reaction mixture was heated at 60° C. for 24 hours. The pH of the solution was adjusted to 1-2 with concentrated hydrochloric acid, and the solid was collected by filtration and dried to give 6-benzyloxy-1H-indazole-3-carboxylic acid as a yellow solid in 28% yield.

To a fresh ethanolic hydrochloric acid solution [prepared from ethanol (20 mL) and acetyl chloride (5 mL)] was added 6-benzyloxy-1H-indazole-3-carboxylic acid (1.85 mmol), and the reaction mixture was heated to reflux for 25 hours, and concentrated. The residue was partitioned between saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL), the combined organic layers were dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (300/1 dichloromethane/methanol) to give the product in 36.4% yield. Alternatively, the ester can be obtained from the acetylated indazole ester by dissolving the acetylated material in 2M ammonia in methanol for 30 minutes.

The following acids were prepared using this method:

6-Benzyloxy-1H-indazole-3-carboxylic acid

5-Benzyloxy-1H-indazole-3-carboxylic acid (from 4-benzyloxy-2-bromonitrobenzene: Parker, K.A.; Mindt, T.L.Org.Lett. 2002, 4, 4265)

6-Benzyloxy-1H-indazole-3-carboxylic acid ethyl ester

5-Benzyloxy-1H-indazole-3-carboxylic acid ethyl ester

Alkali preparation

The following methods (28-29) detail the preparation of bicyclic bases that are not commercially available.

Method 28

Method 28 provides a method for the preparation of N-alkylated 3-aminoquinuclidines from 3-aminoquinuclidines.

To a solution of (R)-3-aminoquinuclidine (10 mmol) and N,N-diisopropylethylamine (30 mmol) in dichloromethane (100 mL) was added cyclopropanecarbonyl chloride (12 mmol) dropwise. The resulting solution was left at room temperature for 4 hours and evaporated to dryness. The crude amide was dissolved in tetrahydrofuran (150 mL) and treated in small portions with lithium aluminum hydride (66 mol). The reaction mixture was quenched with sodium sulfate decahydrate and the resulting slurry was diluted with tetrahydrofuran and filtered through celite. The filtrate was concentrated, and the residue was diluted with fresh methanolic hydrochloric acid (generated by dropping 3 mL of acetyl chloride into 30 mL of methanol) and left at room temperature for 15 minutes. The residue obtained by removal of volatiles was recrystallized (2-propanol/methanol) to afford the secondary amine as a colorless solid in 41% yield.

This method was used to prepare the following bases:

(3R)-N-(Cyclopropylmethyl)quinuclidin-3-amine dihydrochloride

(3S)-N-(Cyclopropylmethyl)quinuclidin-3-amine dihydrochloride

(3R)-N-(methyl)quinuclidin-3-amine dihydrochloride

(3S)-N-(methyl)quinuclidin-3-amine dihydrochloride

(3R)-N-(Ethyl)quinuclidin-3-amine dihydrochloride

(3S)-N-(Ethyl)quinuclidin-3-amine dihydrochloride

Method 29

Method 29 provides a method for the preparation of 1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride from quininone.

To a suspension of quinuclidone (40 mmol) in ethylene glycol dimethyl ether (155 mL) was added a solution of p-toluenesulfonylmethylisonitrile (50 mmol) in ethanol at -5°C. Solid potassium tert-butoxide (130 mmol) was added portionwise over 20 minutes. The reaction mixture was held at -5°C for 30 minutes, then allowed to warm to room temperature and left for an additional 3 hours. The reaction mixture was filtered and diluted with saturated hydrochloric acid in isopropanol. The reaction mixture was filtered and diluted with ether. The resulting precipitate was collected by filtration to afford the nitrile as a yellow solid in 88% yield.

A solution of the nitrile (35 mmol) in methanol (720 mL) was cooled to 5°C and treated with concentrated hydrochloric acid (12 mL) and 10% palladium on carbon (9.6 g). The reaction mixture was left at room temperature under hydrogen atmosphere for 4.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give a yellow solid. The solid was dissolved in methanol and diluted with ether. The resulting precipitate was collected by filtration to afford the nitrile as a yellow solid in 32% yield.

representative method

The following methods (A-AG) describe the preparation of bicyclic base analogs in detail.

Method A

Method A provides the coupling of 3-aminoquinuclidine with a carboxylic acid to form an amide derivative.

To a solution of carboxylic acid (16.1 mmol) in N,N-dimethylformamide (65 mL) was added HBTU (16.1 mmol), catalytic amount of dimethylaminopyridine, N,N-diisopropylethylamine (96.6 mmol) and 4 A activated molecular sieves (2.6 g). The reaction mixture was left at room temperature under nitrogen for 2 hours, then 3-aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 hours, 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 x 100 mL), and the combined organic layers were concentrated. By chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparing The residue was purified by HPLC, whereby the product was obtained in 30%-70% yield.

Example 1: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide formate

Prepared by Method A in 29% yield. ¹ H NMR (CD ₃ OD) δ8.52 (s, 1H), 8.18 (s, 1H), 7.59 (d, J=8.9, 1H), 7.41 (dd, J=8.9, 1.9, 1H), 4.51 ( m,1H),3.80(m,1H),3.44(m,5H),2.36(m,1H),2.24(m,1H),2.09(m,2H),1.86(m,1H); (EI)t _R 2.75, m/z 305 (M ⁺ +1).

Example 2: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide formate

Prepared by Method A in 15% yield. LC/MS (EI) t _R 2.86, m/z 289 (M ⁺ +1).

Example 3: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide formate

Prepared by method A, the yield is 30%. LC/MS (EI) t _R 2.76, m/z 305 (M ⁺ +1).

Example 4: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide formate

Prepared by Method A in 27% yield. LC/MS (EI) t _R 2.53, m/z 289 (M ⁺ +1).

Example 5: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formic acid Salt

Prepared by Method A in 32% yield. LC/MS (EI) t _R 5.15, m/z 335 (M ⁺ +1).

Example 6: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide formate

Prepared by method A, the yield is 38%. LC/MS (EI) t _R 2.53, m/z 301 (M ⁺ +1).

Example 7: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formic acid Salt

Prepared by Method A in 27% yield. LC/MS (EI) t _R 5.13, m/z 355 (M ⁺ +1).

Example 8: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide formate

Prepared by Method A in 34% yield. LC/MS (EI) t _R 2.53, m/z 301 (M ⁺ +1).

Example 9: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide

Prepared by Method A in 43% yield. LC/MS (EI) t _R 5.06, m/z 339 (M ⁺ +1).

Example 10: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide

Prepared by Method A in 45% yield. LC/MS (EI) t _R 5.06, m/z 339 (M ⁺ +1).

Example 11: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide

Prepared by method A, the yield is 63%. LC/MS (EI) t _R 2.53, m/z 301 (M ⁺ +1).

Example 12: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide

Prepared by Method A in 57% yield. LC/MS (EI) t _R 2.53, m/z 301 (M ⁺ +1).

Example 13: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide

Prepared by Method A in 62% yield. LC/MS (EI) t _R 2.53, m/z 289 (M ⁺ +1).

Example 14: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide

Prepared by Method A in 62% yield. LC/MS (EI) t _R 2.53, m/z 289 (M ⁺ +1).

Example 15: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carboxamide

Prepared by Method A in 14% yield. LC/MS (EI) t _R 2.50, m/z 301 (M ⁺ +1).

Example 16: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide formate

Prepared by method A, the yield is 20%. LC/MS (EI) t _R 3.09, m/z 272 (M ⁺ +1).

Example 17: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide formate

Prepared by method A, the yield is 20%. LC/MS (EI) t _R 3.12, m/z 272 (M ⁺ +1).

Example 18: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared by method A, the yield is 30%. LC/MS (EI) t _R 3.40, m/z 355 (M ⁺ +1).

Example 19: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxyl-1-(trifluoro Methyl)ethyl]-1H-indazole-3-carboxamide

Prepared by Method A in 9% yield. LC/MS (EI) t _R 4.94, m/z 437 (M ⁺ +1).

Example 20: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H -Indazole-3-carboxamide formate

Prepared by Method A in 24% yield. LC/MS (EI) t _R 3.62, m/z 353 (M ⁺ +1).

Example 21: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H -Indazole-3-carboxamide formate

Prepared by Method A in 23% yield. LC/MS (EI) t _R 3.50, m/z 353 (M ⁺ +1).

Example 22: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1-methyl-1H-indazole-3-carboxamide

Prepared by method A, the yield is 40%. LC/MS (EI) t _R 3.03, m/z 315 (M ⁺ +1).

Example 23: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H-indazole-3-carboxamide

Prepared by method A, the yield is 63%. LC/MS (EI) t _R 3.26, m/z 329 (M ⁺ +1).

Example 24: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-cyclopentyl-1H-indazole-3-carboxamide

Prepared by method A, the yield is 87%. LC/MS (EI) t _R 5.45, m/z 369 (M ⁺ +1).

Example 25: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carboxamide

Prepared by Method A in 12% yield. LC/MS (EI) t _R 4.36, m/z 379/381 (M ⁺ +1).

Example 26: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indazole-3-carba Amide

Prepared by method A, the yield is 35%. LC/MS (EI) t _R 2.20, m/z 310 (M ⁺ +1).

Example 27: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1H-indazole-3 - Formamide formate

Prepared by Method A in 18% yield. LC/MS (EI) t _R 5.27, m/z 427 (M ⁺ +1).

Example 28: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-carboxamide formate

Prepared by Method A in 16% yield. LC/MS (EI) t _R 5.10, m/z 353 (M ⁺ +1).

Example 29: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared by method A, the yield is 30%. LC/MS (EI) t _R 4.41, m/z 337 (M ⁺ +1).

Example 30: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared by Method A in 16% yield. LC/MS (EI) t _R 4.27, m/z 337 (M ⁺ +1).

Example 31: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide formate

Prepared by method A, the yield is 5.3%. LC/MS (EI) t _R 2.93, m/z 368 (M ⁺ +1).

Example 32: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carboxamide formate

Prepared by Method A in 12% yield. LC/MS (EI) t _R 2.43, m/z 301 (M ⁺ +1).

Example 33: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-3-carboxamide formic acid Salt

Prepared by method A, the yield is 20%. LC/MS (EI) t _R 268.00, m/z 319 (M ⁺ +1).

Example 34: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-3-carboxamide formic acid Salt

Prepared by Method A in 29% yield. LC/MS (EI) t _R 2.40, m/z 319 (M ⁺ +1).

Example 35: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared by Method A in 34% yield. LC/MS (EI) t _R 3.71, m/z 337 (M ⁺ +1).

Example 36: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide

Prepared by Method A in 22% yield. LC/MS (EI) t _R 3.72, m/z 337 (M ⁺ +1).

Example 37: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide formate

Prepared by Method A in 24% yield. LC/MS (EI) t _R 4.34, m/z 368 (M ⁺ +1).

Example 38: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide formate

Prepared by Method A in 21% yield. LC/MS (EI) t _R 4.50, m/z 368 (M ⁺ +1).

Example 39: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-indazole-3-carboxamide Formate

Prepared by method A, the yield is 10%. LC/MS (EI) t _R 4.66, m/z 341 (M ⁺ +1).

Example 40: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole-3 - Formamide formate

Prepared by Method A in 13% yield. LC/MS (EI) t _R 5.10, m/z 383 (M ⁺ +1).

Example 41: N-[(3Sz)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(Benzyloxy)pyrrolidin-1-yl]-1H-ind Azole-3-carboxamide formate

Prepared by Method A in 4% yield. LC/MS (EI) t _R 5.26, m/z 446 (M ⁺ +1).

Example 42: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(methoxy)pyrrolidin-1-yl]-1H-ind Azole-3-carboxamide formate

Prepared by Method A in 46% yield. LC/MS (EI) t _R 2.39, m/z 370 (M ⁺ +1).

Example 43: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-1H-indazole- 3-Carboxamide formate

Prepared by Method A in 13% yield. LC/MS (EI) t _R 2.39, m/z 356 (M ⁺ +1).

Example 44: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)oxy]-1H- Indazole-3-carboxamide dicarboxylate

Prepared by method A, the yield is 40%. LC/MS (EI) t _R 1.89, m/z 370 (M ⁺ +1).

Example 45: N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formate

Prepared by Method A in 25% yield. LC/MS (EI) t _R 5.15, m/z 369 (M ⁺ +1).

Example 46: N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide formate

Prepared by Method A in 25% yield. LC/MS (EI) t _R 2.80, m/z 315 (M ⁺ +1).

Example 47: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-1H-indazole-3-carboxamide salt

Prepared by Method A in 37% yield. LC/MS (EI) t _R 4.66, m/z 341 (M ⁺ +1).

Example 48: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentyloxy)-1H-indazole-3-carboxamide formate

Prepared by method A, the yield is 30%. LC/MS (EI) t _R 4.90, m/z 355 (M ⁺ +1).

Example 49: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazole- 3-Carboxamide formate

Prepared by method A, the yield is 40%. LC/MS (EI) t _R 4.70, m/z 369 (M ⁺ +1).

Example 50: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1H-indazole-3-carboxamide salt

Prepared by method A, the yield is 36%. LC/MS (EI) t _R 4.59, m/z 341 (M ⁺ +1).

Example 51: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazole- 3-Carboxamide formate

Prepared by Method A in 78% yield. LC/MS (EI) t _R 4.75, m/z 369 (M ⁺ +1).

Example 52: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benzyloxy)-1H-indazole-3-carboxamide formate

Prepared by Method A in 33% yield. LC/MS (EI) t _R 5.09, m/z 377 (M ⁺ +1).

Example 53: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-ind Azole-3-carboxamide formate

Prepared by Method A in 67% yield. LC/MS (EI) t _R 2.79, m/z 371 (M ⁺ +1).

Example 54: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-yloxy)- 1H-Indazole-3-carboxamide formate

Prepared by Method A in 37% yield. LC/MS (EI) t _R 4.26, m/z 403 (M ⁺ +1).

Example 55: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazole- 3-Carboxamide dicarboxylate

Prepared by Method A in 24% yield. LC/MS (EI) t _R 1.90, m/z 358 (M ⁺ +1).

Example 56: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-indazole- 3-Carboxamide dicarboxylate

Prepared by Method A in 49% yield. LC/MS (EI) t _R 1.88, m/z 384 (M ⁺ +1).

Example 57: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamide salt

Prepared by Method A in 12% yield. LC/MS (EI) t _R 2.52, m/z 315 (M ⁺ +1).

Method B

Method B provides the coupling of 3-aminoquinuclidine with benzisothiazole carboxylic acid to form an amide derivative.

To a solution of 6-methoxybenzisothiazole-3-carboxylic acid (61 mg, 0.30 mmol) in a 5/1 tetrahydrofuran/N,N-dimethylformamide mixture (12 mL) was added diisopropylethyl Amine (0.2 mL, 1.1 mmol) and 3-(R)-aminoquinuclidine dihydrochloride (115 mg, 0.6 mmol). The mixture was cooled to 0 °C and HATU (115 mg, 0.3 mmol) was added in one portion. The reaction mixture was warmed to room temperature and left overnight. The mixture was partitioned between saturated aqueous potassium carbonate and a 95/5 dichloromethane/methanol mixture. 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) or by preparative HPLC to afford the amide as a colorless solid in 75% yield.

This method was used to prepare the following compounds:

Example 58: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3- Formamide formate

Prepared by method B in 17% yield. ¹ H NMR (CD ₃ OD) δ8.85 (d, J=9.0, 1H), 8.49 (s, 1H), 8.13 (s, 1H), 7.48 (d, J=9.0, 1H), 4.55 (m, 1H), 3.88-3.80(m, 1H), 3.53-3.30(m, 5H), 2.40(m, 1H), 2.32-2.27(m, 1H), 2.16-2.10(m, 2H), 1.99-1.91( m, 1H); LC/MS (EI) t _R 4.58, m/z 372 (M ⁺⁺ 1).

Example 59: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide formic acid Salt

Prepared by Method B in 37% yield. LC/MS (EI) t _R 4.42, m/z 332 (M ⁺ +1).

Example 60: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide formic acid Salt

Prepared by Method B in 12% yield. LC/MS (EI) t _R 4.31, m/z 332 (M ⁺ +1).

Example 61: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3- Formamide formate

Prepared by Method B in 41% yield. LC/MS (EI) t _R 4.62, m/z 372 (M ⁺ +1).

Example 62: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3 -Formamide

Prepared by Method B in 36% yield. LC/MS (EI) t _R 4.34, m/z 358 (M ⁺ +1).

Example 63: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3 -Formamide

Prepared by Method B in 53% yield. LC/MS (EI) t _R 4.33, m/z 358 (M ⁺ +1).

Method C

Method C provides a method for coupling 3-aminoquinuclidine with a carboxylic acid to form an amide derivative.

To a solution of the carboxylic acid (4.77 mmol) in N,N-dimethylformamide was added N,N-diisopropylethylamine (19 mmol) and 3-aminoquinuclidine dihydrochloride (4.29 mmol) . The reaction mixture was left at room temperature under nitrogen for 30 minutes, and then HATU (4.76 mol) was added. After 18 hours, the reaction mixture was filtered through celite (methanol rinse) and split between 3 SCX cartridges. The cartridge was eluted with 2M ammonia in methanol (100 mL each), the basic components were eluted with 2M ammonia in methanol (100 mL each), and concentrated. Purification of the residue by chromatography [1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC gave the product in 15-50% yield .

This method was used to prepare the following compounds:

Example 64: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole- 3-formamide

Prepared using Method C in 22% yield. ¹ H NMR (CD ₃ OD) δ8.07(s, 1H), 7.53(d, J=8.4, 1H), 7.38(d, J=8.4, 1H), 4.25(m, 1H), 4.08(m, 2H), 3.60(m, 2H), 3.36(m, 1H), 3.15(m, 1H), 3.0-2.8(m, 5H), 2.11(m, 1H), 2.05(m, 1H), 2.0-1.7 (m, 6H), 1.62 (m, 1H); LC/MS (EI) _tR 3.44, m/z 355 (M ⁺⁺ 1).

Example 65: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxyl)-1H-indazole-3-carboxamide

Prepared using Method C or Method AA. ¹ H NMR (400MHz, Me ₂ SO-d ₆ ) δ13.30(s, 1H), 9.32(s, 1H), 8.07(d, J=7.6, 1H), 7.43(m, 1H), 6.94(m , 1H), 4.01(m, 1H), 3.12(m, 1H), 2.93(m, 1H), 2.72(m, 4H), 1.89(m, 1H), 1.80(m, 1H), 1.61(m, 2H), 1.33 (m, 1H); LC/MS (EI) m/z 288 (M ⁺ +1).

Example 66: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide formate

Prepared using Method C or Method AA in 11% yield. LC/MS (EI) t _R 2.35, m/z 288 (M ⁺ +1).

Example 67: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide formate

Prepared using Method C or Method AA in 11% yield. LC/MS (EI) t _R 2.37, m/z 287 (M ⁺ +1).

Example 68: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamide formic acid Salt

Prepared using Method C in 17% yield. LC/MS (EI) t _R 4.85, m/z 355 (M ⁺ +1).

Example 69: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamide formic acid Salt

Prepared using method C in 14% yield. LC/MS (EI) t _R 4.84, m/z 355 (M ⁺ +1).

Example 70: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide formic acid Salt

Prepared using Method C in 41% yield. LC/MS (EI) t _R 4.71, m/z 355 (M ⁺ +1).

Example 71: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide formic acid Salt

Prepared using Method C in 41% yield. LC/MS (EI) t _R 4.73, m/z 355 (M ⁺ +1).

Example 72: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide

Prepared using Method C in 73% yield. LC/MS (EI) t _R 3.43, m/z 316 (M ⁺ +1).

Example 73: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(hydroxyl)-1,2-benzisothiazole-3-carboxamide

Prepared using Method C or Method AA in 70% yield. LC/MS (EI) t _R 2.75, m/z 304 (M ⁺ +1).

Example 74: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide

Prepared using method C in 18% yield. LC/MS (EI) t _R 2.42, m/z 316 (M ⁺ +1).

Example 75: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide

Prepared using Method C in 31% yield. LC/MS (EI) t _R 3.18, m/z 316 (M ⁺ +1).

Example 76: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole- 3-formamide

Prepared using method C in 23% yield. LC/MS (EI) t _R 3.33, m/z 355 (M ⁺ +1).

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

Prepared using Method C in 28% yield. LC/MS (EI) t _R 2.43, m/z 316 (M ⁺ +1).

Example 78: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H- Indazole-3-carboxamide

Prepared by method C in 20% yield. LC/MS (EI) t _R 2.39, m/z 371 (M ⁺ +1).

Example 79: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H- Indazole-3-carboxamide

Prepared by method C in 30% yield. LC/MS (EI) t _R 2.39, m/z 371 (M ⁺ +1).

Example 80: N-[(3S)-1-Azabicyclo[2-2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carboxamide

Prepared using Method C in 17% yield. LC/MS (EI) t _R 2.99, m/z 316 (M ⁺ +1).

Example 81: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H -Indazole-3-carboxamide formate

Prepared using Method C in 15% yield. LC/MS (EI) t _R 3.20, m/z 353 (M ⁺ +1).

Example 82: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H -Indazole-3-carboxamide

Prepared using method C in 21% yield. LC/MS (EI) t _R 3.90, m/z 353 (M ⁺ +1).

Example 83: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide formic acid Salt

Prepared using method C in 26% yield. LC/MS (EI) t _R 2.54, m/z 381/383 (M ⁺ +1).

Example 84: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide formic acid Salt

Prepared using method C in 12% yield. LC/MS (EI) t _R 2.54, m/z 383 (M ⁺ +1).

Example 85: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxamide

Prepared using Method C in 25% yield. LC/MS (EI) t _R 4.73, m/z 394/396 (M ⁺ +1).

Example 86: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carboxamide formate

Prepared using Method C in 51% yield. LC/MS (EI) t _R 2.35, m/z 299 (M ⁺ +1).

Example 87: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole- 3-formamide

Prepared using Method C in 59% yield. LC/MS (EI) t _R 2.37, m/z 355 (M ⁺ +1).

Example 88: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole- 3-formamide

Prepared using Method C in 52% yield. LC/MS (EI) t _R 3.22, m/z 355 (M ⁺ +1).

Example 89: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroethyl)- 1H-Indazole-3-carboxamide

Prepared by method C in 81% yield. LC/MS (EI) t _R 5.02, m/z 383 (M ⁺ +1).

Example 90: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(ethyl)-1H-indazole-3-carboxamide

Prepared using Method C in 64% yield. LC/MS (EI) t _R 3.94, m/z 377/379 (M ⁺ +1).

Example 91: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-(ethyl)-1H-indazole-3-carboxamide

Prepared using Method C in 72% yield. LC/MS (EI) t _R 3.90, m/z 377/379 (M ⁺ +1).

Example 92: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl)-1H-indazole-3- Formamide

Prepared by method C in 70% yield. LC/MS (EI) t _R 4.20, m/z 403/405 (M ⁺ +1).

Example 93: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethyl)-1H- Indazole-3-carboxamide

Prepared using Method C in 61% yield. LC/MS (EI) t _R 4.10, m/z 431/433 (M ⁺ +1).

Example 94: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazole-3-methan Amidodiformate

Prepared using Method C in 35% yield. LC/MS (EI) t _R 1.30, m/z 328 (M ⁺ +1).

Example 95: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-indazole-3-methan Amidodiformate

Prepared using method C in 29% yield. LC/MS (EI) t _R 1.32, m/z 356 (M ⁺ +1).

Example 96: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indazole-3 - Formamide diformate

Prepared using Method C in 39% yield. LC/MS (EI) t _R 1.34, m/z 354 (M ⁺ +1).

Example 97: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)oxy]-1H- Indazole-3-carboxamide dicarboxylate

Prepared using Method C in 33% yield. LC/MS (EI) t _R 2.35, m/z 446 (M ⁺ +1).

Example 98: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole-3-carboxamide

Prepared using Method C in 7% yield. LC/MS (EI) t _R 2.78, m/z 329 (M ⁺ +1).

Example 99: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1H-indazole-3-methan Amide

Prepared using Method C in 1% yield. LC/MS (EI) t _R 3.83, m/z 383 (M ⁺ +1).

Example 100: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy-1H-indazole-3- Formamide formate

Prepared using Method C in 7% yield. LC/MS (EI) t _R 3.56, m/z 355 (M ⁺ +1).

Example 101: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazole-3-carboxamide formate

Prepared by method C in 8% yield. LC/MS (EI) t _R 3.42, m/z 325 (M ⁺ +1).

Example 102: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-5-trifluoromethoxy-1H-indazole- 3-Carboxamide formate

Prepared using Method C in 5% yield. LC/MS (EI) t _R 3.99, m/z 409 (M ⁺ +1).

Example 103: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxyl)-1H-indazole-3-carboxamide

Prepared by method C in 40% yield. LC/MS (EI) t _R 9.80 [95/5 to 5/95 water (0.1% formic acid)/acetonitrile (0.1% formic acid)], m/z 287 (M ⁺ +1).

Example 104: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole-3-carboxamide

Prepared from Example 86 by reduction with sodium borohydride in 12% yield. LC/MS (EI) t _R 1.99, m/z 301 (M ⁺ +1).

Example 105: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-indazole-3-carboxamide

Prepared using Method C. The acid was prepared in 46% yield from ethyl 5-nitro-1H-indazole-3-carboxylate by reduction, reductive amination and saponification. LC/MS (EI) t _R 1.92, m/z 354 (M ⁺ +1).

Method D

Method D provides a method for coupling 3-aminoquinuclidine with a carboxylic acid to form an amide derivative.

Coupling reactions and purifications were performed according to methods A and C (indazole, benzothiazole) or according to method B (benzisothiazole). The free base was dissolved in methanol (3.5 mL/mmol starting acid) and treated with 1N hydrochloric acid in ether (3.5 mL/mmol starting acid). The resulting suspension was diluted with diethyl ether (7 mL/mmol starting acid) and left at room temperature for 2 hours. The solid was collected by filtration, rinsed with ether, and dried to give the hydrochloride salt in 40-60% yield.

This method was used to prepare the following compounds:

Example 106: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide hydrochloride

Prepared by method D in 42% yield. ¹ H NMR (500MHz, Me ₂ SO-d ₆ ) δ14.02(s, 1H), 10.42(s, 1H), 8.89(d, J=7.0, 1H), 8.27(s, 1H), 7.67(d , J=8.5, 1H), 7.49(dd, J=8.0, 1.0, 1H), 4.44(m, 1H), 3.62(m, 1H), 3.34(m, 2H), 3.21(m, 4H), 2.21 (m, 1H), 2.09 (m, 1H), 1.93 (m, 2H), 1.73 (m, 1H); LC/MS (EI) _tR 2.61, m/z 295 (M ⁺ +1).

Example 107: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide hydrochloride

Prepared by method D in 56% yield. LC/MS (EI) t _R 5.53, m/z 368 (M ⁺ +1).

Example 108: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H -Indazole-3-carboxamide hydrochloride

Prepared by method D in 29% yield. LC/MS (EI) t _R 3.20, m/z 353 (M ⁺ +1).

Example 109: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide hydrochloride

Prepared by Method D. LC/MS (EI) t _R 13.28 [on a 4.6mm×250mm YMC ODS-AQS-5 120m column using 05/95 to 95/05 acetonitrile (0.05% trifluoroacetic acid)/water (0.05% trifluoroacetic acid) gradient for analytical HPLC], m/z 368 (M ⁺ +1).

Example 110: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide hydrochloride

Prepared by method D in 57% yield. LC/MS (EI) _tR 14.00, m/z 367 (ES-Neg) (M ⁺ ).

Example 111: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide hydrochloride Salt

Prepared by Method D in 60% yield. LC/MS (EI) t _R 5.13, m/z 355 (M ⁺ +1).

Example 112: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3- Formamide hydrochloride

Prepared by Method D in 68% yield. LC/MS (EI) t _R 2.58, m/z 354 (M ⁺ +1).

Example 113: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3- Formamide hydrochloride

Prepared by method D in 38% yield. LC/MS (EI) t _R 2.58, m/z 354 (M ⁺ +1).

Example 114: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide hydrochloride

Prepared by Method D in 68% yield. LC/MS (EI) t _R 2.53, m/z 301 (M ⁺ +1).

Method E

Method E provides a method for the formation of amide derivatives from methyl 3-quinuclidine carboxylates.

To the amine solution in toluene was added 1.0 M trimethylaluminum solution in toluene (1.1 equiv) at 0°C. After 30 minutes, an additional 1.1 equivalents of trimethylaluminum was added, followed by a solution of methyl-3-quinuclidinecarboxylate hydrochloride (1.1 equivalents) in dioxane (5 mL). The reaction mixture was heated at 70°C for 10 hours, cooled to room temperature, and poured into cold (0°C) aqueous sodium bicarbonate solution. The aqueous layer was extracted with 5% methanol in dichloromethane (2 x 30 mL), the combined organic layers were washed with brine, and concentrated. The residue was purified by preparative HPLC.

Method F

Method F provides the reduction of amides to form secondary amine derivatives.

To a solution of the amide (50 mg) in tetrahydrofuran (4 mL) was added lithium aluminum hydride (4.0 equiv). The reaction mixture was heated to reflux for 4 hours, cooled to 0°C, and carefully quenched with ethanol. The resulting slurry was poured into ice water, extracted with 5% methanol in dichloromethane (3x), and the combined organic layers were concentrated. The residue was purified by preparative HPLC.

Method G

Method G provides a method for coupling brominated and iodinated aminoquinuclidine amides with boronic acids to form aryl-substituted derivatives.

Into 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 (0.810mmol). The vessel was evacuated, backfilled with argon, and the contents were diluted with N,N-dimethylformamide (5.0 mL). The container was sealed and irradiated with microwaves at 200°C for 600 seconds. The reaction contents were filtered through celite (methanol wash) and loaded onto a 5 g SCX cartridge. The column was washed with methanol (50 mL), the product was eluted with 2M ammonia in methanol, and concentrated. The residue was purified by preparative HPLC whereby the product was obtained in 15-40% yield.

This method was used to prepare the following compounds:

Example 115: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1H-indazole-3 - Formamide formate

Prepared using methods G or C in 37% yield. ¹ H NMR (CD ₃ OD) δ8.39 (s, 1H), 7.57 (d, J=9.1, 1H), 7.46 (m, 1H), 7.39 (d, J=9.1, 1H), 7.36 (m, 1H), 7.23(m, 1H), 4.03(m, 1H), 3.79(s, 3H), 3.59(m, 1H), 3.3-3.2(m, 5H), 2.81(m, 1H), 2.10(m , 1H), 1.97 (m, 2H), 1.79 (m, 1H); LC/MS (EI) t _R 2.60, m/z 383 (M ⁺ +1).

Example 116: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3 - Formamide formate

Prepared using methods G or C in 12% yield. LC/MS (EI) t _R 2.62, m/z 383 (M ⁺ +1).

Example 117: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3 - Formamide formate

Prepared using methods G or C in 16% yield. LC/MS (EI) t _R 2.37, m/z 383 (M ⁺ +1).

Method H

Method H provides a method for coupling 3-aminoquinuclidine bromide with a Grignard reagent to form an alkyl substituted derivative.

Into a 5 mL microwave reaction vessel was added bis(triphenylphosphine)palladium(II) dichloride (0.030 mmol, 0.1 equiv) and bromide (0.30 mmol). The vessel was evacuated and backfilled with argon. In a separate reaction vessel, to a solution of 0.5M zinc chloride (1.2 mmol, 4 equiv) in tetrahydrofuran was added a solution of Grignard reagent (1.2 mmol, 4 equiv) at room temperature. The suspension was left for 30 minutes and the entire contents were cannula transferred to the reaction vessel. The vessel was sealed, pre-stirred for 60 seconds, and microwaved at 100°C for 600 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), the product was eluted with 2M ammonia in methanol (50 mL), and concentrated. By chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparing The residue was purified by HPLC to give the product in 20-50% yield.

Grignard reagents for thiazoles are commercially available. Alternatively, aryllithium and corresponding arylzinc reagents can be prepared according to the method listed by Reeder, M.R. et al., Org.Proc.Res.Devel.2003, 7, 696. Zinc reagents for oxazoles, 1-methylimidazole and related reagents were prepared according to this method.

This method was used to prepare the following compounds:

Example 118: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Method H in 21% yield. ¹ H NMR (CD ₃ OD) δ 8.07(s, 1H), 7.50(d, J=8.7, 1H), 7.36(d, J=8.7, 1H), 4.21(m, 1H), 3.36(m, 1H ), 3.15(m, 1H), 3.02(m, 1H), 3.0-2.8(m, 4H), 2.2-2.0(m, 3H), 2.0-1.5(m, 10H); LC/MS(EI)t _R 5.11, m/z 339 (M ⁺ +1).

Example 119: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3- Formamide formate

Prepared using Method H in 37% yield. LC/MS (EI) t _R 4.28, m/z 354 (M ⁺ +1).

Example 120: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3- Formamide formate

Prepared using Method H in 18% yield. LC/MS (EI) t _R 2.54, m/z 354 (M ⁺ +1).

Example 121: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3- Formamide formate

Prepared using Method H in 18% yield. LC/MS (EI) t _R 2.58, m/z 354 (M ⁺ +1).

Example 122: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3- Formamide formate

Prepared using Method H in 12% yield. LC/MS (EI) t _R 3.96, m/z 354 (M ⁺ +1).

Example 123: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazol-3- Formamide formate

Prepared using Method H in 24% yield. LC/MS (EI) t _R 4.97, m/z 309 (M ⁺ +1).

Example 124: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3 -Formamide

Prepared using Method H in 71% yield. LC/MS (EI) t _R 2.58, m/z 338 (M ⁺ +1).

Example 125: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3 -Formamide

Prepared using Method H in 85% yield. LC/MS (EI) t _R 2.61, m/z 338 (M ⁺ +1).

Example 126: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3 -Formamide

Prepared using Method H in 55% yield. LC/MS (EI) t _R 3.12, m/z 338 (M ⁺ +1).

Example 127: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3 -Formamide

Prepared using Method H in 72% yield. LC/MS (EI) t _R 2.64, m/z 338 (M ⁺ +1).

Example 128: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole -3-Carboxamide formate

Prepared using Method H in 11% yield. LC/MS (EI) t _R 1.21, m/z 351 (M ⁺ +1).

Example 129: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole -3-Carboxamide formate

Prepared using Method H in 18% yield. LC/MS (EI) t _R 1.23, m/z 351 (M ⁺ +1).

Example 130: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Method H in 25% yield. LC/MS (EI) t _R 5.27, m/z 339 (M ⁺ +1).

Example 131: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Method H in 30% yield. LC/MS (EI) t _R 5.11, m/z 339 (M ⁺ +1).

Example 132: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide

Prepared using Method H in 38% yield. LC/MS (EI) t _R 5.10, m/z 339 (M ⁺ +1).

Example 133: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide formate

Prepared using Method H in 11% yield. LC/MS (EI) t _R 5.37, m/z 353 (M ⁺ +1).

Example 134: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide formate

Prepared using Method H in 12% yield. LC/MS (EI) t _R 5.33, m/z 353 (M ⁺ +1).

Example 135: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide

Prepared using Method H in 32% yield. LC/MS (EI) t _R 5.37, m/z 353 (M ⁺ +1).

Example 136: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide

Prepared using Method H in 10% yield. LC/MS (EI) t _R 5.39, m/z 353 (M ⁺ +1).

Example 137: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(propyl)-1H-indazole-3-carboxamide formate

Prepared using Method H in 6% yield. LC/MS (EI) t _R 4.84, m/z 315 (M ⁺ +1).

Example 138: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(ethyl)-1H-indazole-3-carboxamide formate

Prepared using Method H in 19% yield. LC/MS (EI) t _R 4.48, m/z 299 (M ⁺ +1).

Example 139: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide

Prepared using Method H in 43% yield. LC/MS (EI) t _R 4.98, m/z 368 (M ⁺ +1).

Example 140: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide

Prepared using Method H in 30% yield. LC/MS (EI) t _R 4.96, m/z 368 (M ⁺ +1).

Example 141: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide

Prepared using Method H in 30% yield. LC/MS (EI) t _R 5.01, m/z 368 (M ⁺ +1).

Example 142: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide

Prepared using Method H in 56% yield. LC/MS (EI) t _R 4.59, m/z 368 (M ⁺ +1).

Example 143: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carboxamide formate

Prepared using Method H in 15% yield. LC/MS (EI) t _R 5.41, m/z 327 (M ⁺ +1).

Example 144: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-indazole-3-carboxamide Formate

Prepared using Method H in 20% yield. LC/MS (EI) t _R 2.73, m/z 341 (M ⁺ +1).

Example 145: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole-3-carboxamide salt

Prepared using Method H in 10% yield. LC/MS (EI) t _R 2.42, m/z 329 (M ⁺ +1).

Example 146: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide formate

Prepared using Method H in 24% yield. LC/MS (EI) t _R 4.98, m/z 368 (M ⁺ +1).

Example 147: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide formate

Prepared using Method H in 61% yield. LC/MS (EI) t _R 3.63, m/z 382 (M ⁺ +1).

Example 148: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropylmethyl-5-(1,3-thiazol-2-yl) -1H-Indazole-3-carboxamide formate

Prepared using Method H in 10% yield. LC/MS (EI) t _R 3.97, m/z 408 (M ⁺ +1).

Example 149: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3 -Thiazol-2-yl)-1H-indazole-3-carboxamide formate

Prepared using Method H in 18% yield. LC/MS (EI) t _R 3.87, m/z 436 (M ⁺ +1).

Example 150: N-[(3S-1-Azabicyclo[2.2.2]oct-3-yl)-1-ethyl-6-(1,3-thiazol-2-yl)-1H-ind Azole-3-carboxamide formate

Prepared using Method H in 32% yield. LC/MS (EI) t _R 3.67, m/z 382 (M ⁺ +1).

Example 151: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benziso Thiazole-3-carboxamide formate

Prepared using Method H in 16% yield. LC/MS (EI) t _R 5.20, m/z 371 (M ⁺ +1).

Example 152: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benziso Thiazole-3-carboxamide formate

Prepared using Method H in 36% yield. LC/MS (EI) t _R 5.16, m/z 371 (M ⁺ +1).

Example 153: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(methyl)-1H-indazole-3-carboxamide formate

Prepared using methods H or C in 13% yield. LC/MS (EI) t _R 3.18, m/z 285 (M ⁺ +1).

Method I

Method I provides the coupling of 3-aminoquinuclidinamide bromide with acetylene to form the alkynyl substituted derivative.

Add bis(triphenylphosphine)palladium(II) dichloride (0.0597mmol, 0.1 equivalent), copper(I) iodide (0.0719mmol, 0.12 equivalent), triphenylphosphine (0.124mmol , 0.2 eq) and bromide (0.578 mmol). The vessel was evacuated and backfilled with argon. Alkyne (0.71 mmol, 1.2 equiv), diethylamine (3.5 mL) and N,N-dimethylformamide (1.5 mL) were added, the vessel was sealed and microwave irradiated at 120 °C for 1500 sec. The reaction was reduced to ~1.5 mL under vacuum and transferred to an SCX column. The column was washed with methanol (50 mL), the product was eluted with 2M 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)] to give silyleacetylene in 90-95% yield. The silane was dissolved in tetrahydrofuran (2.5 mL) and treated with tetrabutylammonium fluoride (0.6 mL of a 1 M solution in tetrahydrofuran). The reaction mixture was left for 11 hours and transferred to an SCX column. The column was washed with methanol (50 mL), the product was eluted with 2M ammonia in methanol (50 mL), and concentrated. The residue was purified by preparative HPLC whereby the product was obtained in 40-60% yield.

This method was used to prepare the following compounds:

Example 154: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide formate

Prepared by method I, the yield is 36%. ¹ H NMR (CD ₃ OD) δ8.41 (s, 1H), 8.33 (s, 1H), 7.58 (d, J=8.7, 1H), 7.49 (dd, J=8.7, 1.4, 1H), 4.53 ( m, 1H), 3.82(m, 1H), 3.47(s, 1H), 3.31(m, 5H), 2.38(m, 1H), 2.27(m, 1H), 2.10(m, 2H), 1.93(m , 1H); LC/MS (EI) t _R 2.61, m/z 295 (M ⁺⁺ 1).

Example 155: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide formate

Prepared by method I, the yield is 40%. LC/MS (EI) t _R 2.73, m/z 295 (M ⁺ +1).

Example 156: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide formate

Prepared by method I, the yield is 29%. LC/MS (EI) t _R 2.73, m/z 295 (M ⁺ +1).

Example 157: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide formate

Prepared by method I, the yield is 30%. LC/MS (EI) t _R 2.63, m/z 295 (M ⁺ +1).

Example 158: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazol-3- Formamide formate

Prepared by method I, the yield is 37%. LC/MS (EI) t _R 5.28, m/z 337 (M ⁺ +1).

Example 159: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide formate

Prepared by method I, the yield is 36%. LC/MS (EI) t _R 5.46, m/z 371 (M ⁺ +1).

Example 160: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide formate

Prepared by method I, the yield is 9%. LC/MS (EI) t _R 4.24, m/z 312 (M ⁺ +1).

Example 161: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide formate

Prepared by method I, the yield is 5%. LC/MS (EI) t _R 5.22, m/z 312 (M ⁺ +1).

Method J

Method J provides a method for coupling 3-aminoquinuclidine bromide with cyclic olefins to form cycloalkenyl substituted derivatives.

Into a 5 mL microwave reaction vessel was added palladium(II) acetate (0.012 mmol, 0.04 equiv), tri-o-tolylphosphine (0.030 mmol, 0.1 equiv) and bromide (0.358 mmol). The vessel was evacuated and backfilled with argon. Olefin (0.30 mmol), diisopropylethylamine (63 μL) and N,N-dimethylformamide (2.8 mL) were added, the vessel was sealed and microwave irradiated at 220° C. for 300 seconds. The reaction was transferred to an SCX cartridge and the cartridge was washed with methanol (50 mL). The product was eluted with 2M aqueous ammonia in methanol (50 mL) and concentrated. Purification of the residue by chromatography [1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] and further purification by preparative HPLC gave the product in yield 7-40%.

This method was used to prepare the following compounds:

Example 162: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3 - Formamide formate

Prepared using Method J in 7% yield. ¹ H NMR (CD ₃ OD) δ8.48(s, 1H), 8.05(s, 1H), 7.53(d, J=8.7, 1H), 7.37(dd, J=8.7, 1.6, 1H), 5.77( m, 1H), 4.52(m, 1H), 3.81(m, 1H), 3.35(m, 5H), 2.38(m, 1H), 2.27(m, 1H), 2.10(m, 2H), 1.93(m , 1H); LC/MS (EI) t _R 5.14, m/z 351 (M ⁺⁺ 1).

Example 163: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H- Indazole-3-carboxamide formate

Prepared using Method J in 1% yield. LC/MS (EI) t _R 4.91, m/z 379 (M ⁺ +1).

Example 164: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yl)-1H-indazole-3-carboxamide formic acid Salt

Prepared using Method J followed by hydrogenation in 2% yield. LC/MS (EI) t _R 3.59, m/z 341 (M ⁺ +1).

Method K

Method K provides the coupling of 3-aminoquinuclidinamide bromide with nickel(II) cyanide to form the cyano-substituted derivative.

Into a 5 mL microwave reaction vessel was added nickel(II) cyanide (3.11 mmol, 5.4 equiv) and bromide (0.578 mmol). The vessel was evacuated, backfilled with argon, and diluted with N-methylpyrrolidone (5.0 mL). The container was sealed and microwaved at 200°C for 2400 seconds. The reaction was transferred to an SCX cartridge and the cartridge was washed with methanol (50 mL). The product was eluted with 2M aqueous ammonia in methanol (50 mL) and concentrated. The residue was purified by preparative HPLC whereby the product was obtained in 10-40% yield.

References: Arvella, R.K.; Leadbeater, N.E.J. Org. Chem. 2003, 68, 9122.

This method was used to prepare the following compounds:

Example 165: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide formate

Prepared using Method K in 41% yield. ¹ H NMR (CD ₃ OD) δ8.94 (d, J=8.5, 1H), 8.63 (s, 1H), 7.83 (d, J=8.5, 1H), 4.55 (m, 1H), 3.89-3.81 ( LC/ MS (EI) t _R 3.68, m/z 313 (M ⁺ +1).

Example 166: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide formate

Prepared using Method K in 39% yield. LC/MS (EI) t _R 2.59, m/z 296 (M ⁺ +1).

Example 167: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide formate

Prepared using Method K in 52% yield. LC/MS (EI) t _R 2.55, m/z 296 (M ⁺ +1).

Example 168: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide formate

Prepared using Method K in 18% yield. LC/MS (EI) t _R 2.47, m/z 296 (M ⁺ +1).

Example 169: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide formate

Prepared using Method K in 42% yield. LC/MS (EI) t _R 2.47, m/z 296 (M ⁺ +1).

Example 170: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide formate

Prepared using Method K in 48% yield. LC/MS (EI) t _R 2.99, m/z 313 (M ⁺ +1).

Example 171: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide Trifluoroethyl salt

Prepared using Method K in 41% yield. LC/MS (EI) t _R 3.68, m/z 313 (M ⁺ +1).

Example 172: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide Trifluoroethyl salt

Prepared using Method K in 48% yield. LC/MS (EI) t _R 2.99, m/z 313 (M ⁺ +1).

Method L

Method L provides a method for coupling 3-aminoquinuclidine bromide with phenol to form diaryl ether derivatives.

Into a 2.5 mL microwave reaction vessel was added copper(II) triflate (0.144 mmol, 0.5 equiv), cesium carbonate (0.565 mmol, 2 equiv), benzoic acid (0.402 mmol, 1.4 equiv) and bromide (0.284 mmol ). The vessel was evacuated and backfilled with argon. Add a 0.5M solution of phenol in N,N-dimethylformamide (1.2mL, 0.60mmol, 2.1 equivalents) and N,N-dimethylformamide (1.3mL), seal the container, and place at 200°C Under microwave irradiation for 2400 seconds. The reaction was transferred to an SCX cartridge and the cartridge was washed with methanol (50 mL). The product was eluted with 2M aqueous ammonia in methanol (50 mL) and concentrated. Purification of the residue by chromatography [1/1 to 0/1 ethyl acetate (70/30/1 ethyl acetate/methanol/ammonium hydroxide)] and further purification by preparative HPLC gave the product in yield of 10-40%.

This method was used to prepare the following compounds:

Example 173: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide formate

Prepared using Method L in 2% yield. ¹ H NMR (CD ₃ OD) δ8.53 (s, 1H), 7.71 (d, J=1.8, 1H), 7.63 (d, J=9.0, 1H), 7.37 (dd, J=8.4, 7.5, 2H ), 7.23 (dd, J=9.0, 2.3, 1H), 7.12 (t, J=7.4, 2H), 7.01 (d, J=8.8, 1H), 4.52 (m, 1H), 3.81 (m, 1H) , 3.35(m, 5H), 2.38(m, 1H), 2.27(m, 1H), 2.10(m, 2H), 1.93(m, 1H); LC/MS(EI)t _R 5.02, m/z 363 (M ⁺⁺ 1).

Method M

Method M provides a method for coupling aniline or phenol-bearing aminoquinuclidine amides with alkylating reagents to form secondary aniline or ether substituted derivatives.

To N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxyl-1,2-benzisothiazole-3-carboxamide (0.400mol) in N, Potassium carbonate (2.00 mol) and cyclopropylmethyl bromide (0.47 mmol) were added to a solution in N-dimethylformamide (6 mL). The reaction was left for 16 hours and the solvent was removed in vacuo. The residue was extracted with 10/1 dichloromethane/methanol (3x), and the combined extracts were concentrated. The residue was purified by preparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid) to give the product in 32% yield.

The following compounds were prepared by this method:

Example 174: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-1 , 2-Benzisothiazole-3-carboxamide formate

Prepared using Method M in 30% yield. ¹ H NMR (CD ₃ OD) δ8.55 (d, J=9.0, 1H), 8.38 (broad, 1H), 7.37 (s, 1H), 7.05 (d, J=9.0, 1H), 4.55 (m, 1H), 3.95(t, J=9.0, 1H), 3.70-3.45(m, 11H), 3.31(s, 3H), 2.40(m, 1H), 2.30(m, 1H), 2.15(m, 2H) , 2.05 (m, 2H), 1.30 (t, J=6.0, 2H); LC/MS (EI) t _R 2.88, m/z 420 (M ⁺ +1).

Example 175: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3 - Formamide formate

Prepared using Method M in 32% yield. LC/MS (EI) t _R 3.48, m/z 358 (M ⁺ +1).

Method N

Method N provides a method for hydrolyzing a nitrile-substituted 3-aminoquinuclidinamide to form a carboxy-substituted derivative.

Into a 2.5 mL microwave reaction vessel was added nitrile (0.195 mmol), water (2.0 mL) and 2N sodium hydroxide (0.5 mL). The container was sealed and microwaved at 200°C for 1800 seconds. The reaction was acidified with acetic acid (-1.5 mL) and transferred to an SCX column. The column was washed with methanol (50 mL), the product was eluted with 2M ammonia in methanol (50 mL), and concentrated. The residue was purified by preparative HPLC whereby the product was obtained in 5-30% yield.

This method was used to prepare the following compounds:

Example 176: 3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic acid formate

Prepared using Method N in 3% yield. ¹ H NMR (CD ₃ OD) δ8.39 (s, 1H), 8.25 (s, 1H), 8.21 (d, J=8.6, 1H), 7.89 (dd, J=8.6, 1.2, 1H), 4.53 ( m, 1H), 3.84(m, 1H), 3.37(m, 5H), 2.39(m, 1H), 2.28(m, 1H), 2.11(m, 2H), 1.94(m, 1H); LC/MS (EI)t _R 2.37, m/z 315 (M ⁺ +1).

Method O

Method O provides a method for coupling 3-aminoquinuclidinamide bromide with an amine to form an amino-substituted derivative.

Into a 5 mL microwave reaction vessel was added bromide (133 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.04 mmol), cesium bicarbonate (213 mg, 1.1 mmol) and (2'- Dicyclohexylphosphinobiphenyl-2-yl)dimethylamine ((2'-dicyclohexylphosphanylbiphenyl-2-yl)dimethylamine (30 mg, 0.07 mmol). The bottle was then evacuated and backfilled with argon. The solid mixture was then diluted with amine (0.7 mL), dioxane (1 mL) and triethylamine (0.5 mL), and the vessel was sealed. The reaction mixture was microwave irradiated at 120 °C for 1800 sec. The reaction mixture was filtered through a short plug of celite and concentrated in vacuo. The crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) to obtain the product as a colorless solid in 34% yield.

This method was used to prepare the following compounds:

Example 177: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,5-Dimethyl-1H-pyrrol-1-yl)-1H -Indazole-3-carboxamide

Prepared using Method O in 13% yield. ¹ H NMR (CD ₃ OD) δ8.09 (dd, J=1.9, 0.7, 1H), 7.55 (dd, J=8.8, 0.7, 1H), 7.41 (dd, J=8.8, 1.9, 1H), 5.82 (s, 2H), 4.22(m, 1H), 3.35(m, 1H), 3.03(m, 1H), 3.0-2.8(m, 4H), 2.06(m, 1H), 2.00(m, 1H), 1.99 (s, 6H), 1.79 (m, 2H), 1.55 (m, 1H); LC/MS (EI) _tR 5.00, m/z 364 (M ⁺ +1).

Example 178: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide

Prepared using Method O in 7% yield. LC/MS (EI) t _R 4.94, m/z 336 (M ⁺ +1).

Example 179: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide

Prepared using Method O in 26% yield. LC/MS (EI) t _R 4.79, m/z 336 (M ⁺ +1).

Method P

Method P provides a method for coupling 3-aminoquinuclidinamide bromide with a cyclic secondary amine to form an amino-substituted derivative.

Into a 2.5 mL microwave reaction vessel was added tris(dibenzylideneacetone)dipalladium(0) (0.060 mmol, 0.1 equiv), [2'-(dimethylamino)biphenyl-2-yl]dicyclohexylphosphine (0.060mmol, 0.1 equiv) and bromide (0.550mmol). The vessel was evacuated and backfilled with argon. The amine (0.66 mmol, 1.2 eq) and a 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (1.7 mmol, 3 eq) were added, the vessel was sealed and heated at 65°C for 15 hours. The reaction was transferred to an SCX cartridge and the cartridge was washed with methanol (50 mL). The product was eluted with 2M aqueous ammonia in methanol (50 mL) and concentrated. The residue was purified by preparative HPLC whereby the product was obtained in 30-50% yield.

References: Harris, M.C.; Huang, X.; Buchwald, S.L., Org. Lett. 2002, 4, 2885.

This method was used to prepare the following compounds:

Example 180: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-pyrrole-3-carboxamide

Prepared using Method P in 24% yield. ¹ H NMR (CD ₃ OD) δ7.43 (d, J=9.1, 1H), 7.20 (s, 1H), 6.98 (d, J=9.1, 1H), 4.20 (m, 1H), 3.5-3.2 ( m, 5H), 3.15(m, 1H), 3.0-2.8(m, 4H), 2.2-2.0(m, 6H), 1.79(m, 2H), 1.55(m, 1H); LC/MS(EI) t _R 2.53, m/z 340 (M ⁺ +1).

Example 181: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared using Method P in 52% yield. LC/MS (EI) t _R 2.40, m/z 454 (M ⁺ +1).

Example 182: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared using Method P in 51% yield. LC/MS (EI) t _R 1.57, m/z 400 (M ⁺ +1).

Example 183: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-1 , 2-Benzisothiazole-3-carboxamide formate

Prepared by Method P in 50% yield. LC/MS (EI) t _R 4.61, m/z 466 (M ⁺ +1).

Example 184: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide

Prepared using Method P in 58% yield. LC/MS (EI) t _R 3.87, m/z 401 (M ⁺ +1).

Example 185: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide

Prepared using Method P in 41% yield. LC/MS (EI) t _R 3.67, m/z 401 (M ⁺ +1).

Example 186: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide

Prepared using Method P in 19% yield. LC/MS (EI) t _R 3.63, m/z 387 (M ⁺ +1).

Example 187: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carboxamide

Prepared using Method P in 24% yield. LC/MS (EI) t _R 4.63, m/z 340 (M ⁺ +1).

Example 188: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide Trifluoroethyl salt

Prepared using Method P in 51% yield. LC/MS (EI) t _R 1.88, m/z 354 (M ⁺ +1).

Example 189: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide formate

Prepared using Method P in 26% yield. LC/MS (EI) t _R 1.60, m/z 354 (M ⁺ +1).

Example 190: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide

Prepared using Method P in 25% yield. LC/MS (EI) t _R 2.60, m/z 356 (M ⁺ +1).

Example 191: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide

Prepared using Method P in 16% yield. LC/MS (EI) t _R 2.42, m/z 356 (M ⁺ +1).

Example 192: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethane Amyl-1H-indazole-3-carboxamide formate

Prepared using Method P in 24% yield. LC/MS (EI) t _R 4.53, m/z 474 (M ⁺ +1).

Example 193: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethane Amyl-1H-indazole-3-carboxamide formate

Prepared using Method P in 48% yield. LC/MS (EI) t _R 4.55 min, m/z 474 (M ⁺ +1).

Example 194: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-( Cyclopropylmethyl)-1H-indazole-3-carboxamide formate

Prepared using Method P in 51% yield. LC/MS (EI) t _R 4.67 min, m/z 500 (M ⁺ +1).

Method Q

Method Q provides a method for coupling brominated aminoquinuclidines with benzophenone imines to form aniline derivatives.

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide (6.30mmol), palladium acetate (1.00 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (Xantphos) (0.700 mmol) was evacuated and backfilled with argon. The solid was diluted with tetrahydrofuran (150 mL) and treated with cesium carbonate (7.00 mmol) and benzophenone imine (6.80 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was concentrated and redissolved in a mixture of tetrahydrofuran (90 mL) and 3N hydrochloric acid (30 mL). The reaction mixture was left for 2 hours and concentrated. The residue was purified by chromatography using 70/30/1 ethyl acetate/methanol/ammonium hydroxide to give the aniline in a yield of 79%. This aniline was used directly in the subsequent reaction.

The following compounds were prepared by this method:

Example 195: 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide

Prepared using Method Q in 72% yield. LC/MS (EI) t _R 2.44, m/z 287 (M ⁺ +1).

Example 196: 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide

Prepared by Method Q in 69% yield. LC/MS (EI) t _R 2.86, m/z 303 (M ⁺ +1).

Example 197: 6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide

Prepared by Method Q in 73% yield. LC/MS (EI) t _R 2.84, m/z 303 (M ⁺ +1).

Example 198: 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-1H- Indazole-3-carboxamide

Prepared by Method Q in 64% yield. LC/MS (EI) t _R 1.43, m/z 368 (M ⁺ +1).

Example 199: 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-1H-indazole-3- Formamide

Prepared using method Q in 67% yield. LC/MS (EI) t _R 1.43, m/z 340 (M ⁺ +1).

Example 200: 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide

Prepared by Method Q in 68% yield. LC/MS (EI) t _R 1.34, m/z 314 (M ⁺ +1).

Example 201: 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide

Prepared using method Q in 61% yield. LC/MS (EI) t _R 1.36, m/z 314 (M ⁺ +1).

Method R

Method R provides a method for the reduction of nitroaminoquinuclidinamides to form aniline derivatives.

A mixture of nitro compound (1.06 mmol) and 10% palladium on carbon (100 mg) was diluted with methanol (100 mL) in a Parr mixing bottle. The reaction vessel was pressurized to 30 psi with hydrogen and left for 3 hours. The reaction was evacuated, backfilled with nitrogen, and filtered through celite to remove the catalyst. The organic layer was concentrated to give the amine product (91%). This aniline was used directly in the subsequent reaction.

The following compounds were prepared by this method:

Example 202: 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Method R in 4% yield. LC/MS (EI) t _R 1.85, m/z 386 (M ⁺ +1).

Example 203: 5-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Method R in 91% yield. LC/MS (EI) t _R 1.36, m/z 286 (M ⁺ +1).

Example 204: 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared using Method R in 95% yield. LC/MS (EI) t _R 1.30, m/z 286 (M ⁺ +1).

Example 205: 4-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared from Example 87 using Procedure R in 97% yield. LC/MS (EI) t _R 2.53, m/z 286 (M ⁺ +1).

Example 206: 7-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared by Method R from the corresponding 6-bromo-7-nitro analog in 11% yield. LC/MS (EI) t _R 1.79, m/z 286 (M ⁺ +1).

Method S

Method S provides a method for coupling 3-aminoquinuclidine with an aldehyde to form a secondary amine derivative.

A suspension of 1H-indazole-4-carbaldehyde (100 mg), 3-aminoquinucidine dihydrochloride (1.0 equiv) and 4 A molecular sieves in dioxane (4 mL) was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and treated with sodium triacetoxyborohydride (3 equiv). The reaction mixture was left at room temperature for 2 hours 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.

This method was used to prepare the following compounds:

Example 207: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-indazole-3 - Formamide diformate

Prepared using Method S in 48% yield. ¹ H NMR (CD ₃ OD) δ7.42 (d, J=9.0, 1H), 7.37 (s, 1H), 7.0 (d, J=9.0, 1H), 4.55 (m, 1H), 4.05 (m, 1H), 3.85(m, 2H), 3.61-3.50(m, 8H), 3.35(s, 3H), 2.49-3.0(m, 2H), 2.20(m, 2H), 2.05(m, 1H); LC /MS(EI) _tR 1.65, m/z 344 (M ⁺⁺ 1).

Example 208: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylmethyl)amino]-1H-indazole-3-methan Amidodiformate

Prepared using Method S in 42% yield. LC/MS (EI) t _R 1.77, m/z 340 (M ⁺ +1).

Example 209: 4-[(3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)amino]butanoic acid methyl ester diformate

Prepared using Method S in 62% yield. LC/MS (EI) t _R 1.36, m/z 386 (M ⁺ +1).

Example 210: 4-[(3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)amino]butanoic acid methyl ester diformate

Prepared using Method S in 55% yield. LC/MS (EI) t _R 2.62, m/z 403 (M ⁺ +1).

Example 211: {2-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,2-benzisothiazol-6-yl )amino]ethyl}propylcarbamate tert-butyl dicarbamate

Prepared using Method S in 63% yield. LC/MS (EI) t _R 5.59, m/z 488 (M ⁺ +1).

Example 212: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)amino]-1H- Indazole-3-carboxamide dicarboxylate

Prepared using Method S in 30% yield. LC/MS (EI) t _R 2.84, m/z 383 (M ⁺ +1).

Example 213: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole-3-carboxamidedicarboxylic acid Salt

Prepared using Method S in 52% yield. LC/MS (EI) t _R 1.68, m/z 314 (M ⁺ +1).

Example 214: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-methoxy Ethyl)amino]-1H-indazole-3-carboxamide dicarboxylate

Prepared using Method S in 9% yield. LC/MS (EI) t _R 2.84, m/z 402 (M ⁺ +1).

Example 215: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amino }-1,2-Benzisothiazole-3-carboxamide dicarboxylate

Prepared using Method S in 67% yield. LC/MS (EI) t _R 3.67, m/z 416 (M ⁺ +1).

Example 216: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-carboxamide dicarboxylate

Prepared using Method S in 47% yield. LC/MS (EI) t _R 2.38, m/z 342 (M ⁺ +1).

Example 217: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-benzisothiazole -3-Carboxamide dicarboxylate

Prepared using Method S in 45% yield. LC/MS (EI) t _R 4.50, m/z 357 (M ⁺ +1).

Example 218: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisothiazole-3-methan Amidodiformate

Prepared using Method S in 51% yield. LC/MS (EI) t _R 2.53, m/z 331 (M ⁺ +1).

Example 219: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole-3-methan Amidodiformate

Prepared using Method S in 60% yield. LC/MS (EI) t _R 1.36, m/z 342 (M ⁺ +1).

Method T

Method T provides a method for coupling an aminoaminoquinuclidine amide and an acylating reagent to form an amide derivative.

To 5-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide (0.42mmol) in pyridine (2mL) and N , to a solution in N-dimethylformamide (2 mL) was added trifluoroacetic anhydride (0.55 mmol). The mixture was left at room temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to give the product in 30% yield and the diacylated product in 5% yield.

The following compounds were prepared by this method:

Example 220: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H- Indazole-3-carboxamide formate

Prepared by method T in 31% yield. ¹ H NMR (CD ₃ OD) δ8.52(s, 1H), 8.42(s, 1H), 7.64-7.43(m, 6H), 5.32(s, 2H), 4.72(m, 1H), 3.94(m , 1H), 3.70-3.40(m, 4H), 2.51(m, 1H), 2.50(m, 1H), 2.20(m, 2H), 2.06(m, 1H); LC/MS(EI)t _R 4.94 , m/z 434 (M ⁺⁺ 1).

Example 221: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-(cyclopropylmethyl) -1H-Indazole-3-carboxamide

Prepared by method T in 45% yield. LC/MS (EI) t _R 4.77, m/z 408 (M ⁺ +1).

Example 222: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H-indazole-3-carboxamide Formate

Prepared by method T in 30% yield. LC/MS (EI) t _R 3.28, m/z 382 (M ⁺ +1).

Example 223: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamide Formate

Prepared by method T in 30% yield. LC/MS (EI) t _R 2.61, m/z 354 (M ⁺ +1).

Example 224: 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indazole-3-methan Amidodiformate

Prepared by method T in 30% yield. LC/MS (EI) t _R 2.92, m/z 382 (M ⁺ +1).

Example 225: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cyclopropylcarbonyl)amino]- 1H-Indazole-3-carboxamide formate

Prepared by method T in 30% yield. LC/MS (EI) t _R 5.09, m/z 422 (M ⁺ +1).

Example 226: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5-{[( 4-Methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamide formate

Prepared by method T in 31% yield. LC/MS (EI) t _R 5.44, m/z 583 (M ⁺ +1).

Example 227: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1,2-benzisothiazole- 3-Carboxamide formate

Prepared by method T in 60% yield. LC/MS (EI) t _R 3.66, m/z 371 (M ⁺ +1).

Example 228: 6-(Acetamido)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide salt

Prepared by method T in 60% yield. LC/MS (EI) t _R 2.42, m/z 345 (M ⁺ +1).

Example 229: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethyl-1H-indazole -3-Carboxamide

Prepared by method T in 33% yield. LC/MS (EI) t _R 3.44, m/z 382 (M ⁺ +1).

Example 230: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cyclopropylmethyl-1H -Indazole-3-carboxamide

Prepared by method T in 44% yield. LC/MS (EI) t _R 3.68, m/z 408 (M ⁺ +1).

Example 231: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2,2- Trifluoroethyl)-1H-indazole-3-carboxamide

Prepared by method T in 47% yield. LC/MS (EI) t _R 3.66, m/z 436 (M ⁺ +1).

Method U

Method U provides a method for coupling an aminoaminoquinuclidine amide and a sulfonylation reagent to form a sulfonamide derivative.

To a solution of the amine (0.20 mmol) in a mixture of pyridine (2 mL) and N,N-dimethylformamide (1 mL) was added ethanesulfonyl chloride (0.25 mmol). The mixture was left at room temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to give the product in 60% yield and the disulfonylated product in 20% yield.

The following compounds were prepared by this method:

Example 232: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide salt

Prepared by Method U in 32% yield. ¹ H NMR (CD ₃ OD) δ8.09(s, 1H), 7.55(d, J=8.9, 1H), 7.41(d, J=8.9, 1H), 4.20(m, 1H), 3.35(m, 1H), 3.08(q, J=7.4, 2H), 3.02(m, 1H), 3.0-2.8(m, 4H), 2.06(m, 1H), 2.00(m, 1H), 1.79(m, 2H) , 1.55 (m, 1H), 1.32 (t, J=7.4, 3H); LC/MS (EI) t _R 2.37, m/z 378 (M ⁺ +1).

Example 233: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3 -Formamide

Prepared by Method U in 74% yield. LC/MS (EI) t _R 2.85, m/z 395 (M ⁺ +1).

Example 234: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3 -Formamide

Prepared by method U in 73% yield. LC/MS (EI) t _R 2.82, m/z 395 (M ⁺ +1).

Example 235: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3 -Formamide

Prepared by method U in 71% yield. LC/MS (EI) t _R 2.84, m/z 381 (M ⁺ +1).

Example 236: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3 -Formamide

Prepared by Method U in 69% yield. LC/MS (EI) t _R 2.82, m/z 381 (M ⁺ +1).

Example 237: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-H-indazole-3-carboxamide salt

Prepared by Method U in 35% yield. LC/MS (EI) t _R 4.64, m/z 440 (M ⁺ +1).

Example 238: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]amino}-1,2-benzene Isothiazole-3-carboxamide formate

Prepared by Method U in 48% yield. LC/MS (EI) t _R 3.53, m/z 410 (M ⁺ +1).

Example 239: 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H-indazole-3-carboxamide Diformate

Prepared by Method U in 35% yield. LC/MS (EI) t _R 4.29, m/z 440 (M ⁺ +1).

Example 240: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide salt

Prepared by Method U in 19% yield. LC/MS (EI) t _R 1.61, m/z 364 (M ⁺ +1).

Example 241: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide salt

Prepared by Method U in 10% yield. LC/MS (EI) t _R 2.43, m/z 378 (M ⁺ +1).

Example 242: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide

Prepared by Method U in 9% yield. LC/MS (EI) t _R 3.96, m/z 364 (M ⁺ +1).

Method V

Method V provides a method for coupling aminoaminoquinuclidine amides with isocyanates to form urea derivatives.

To the amine (0.40 mmol) in a mixture of pyridine (2 mL) and N,N-dimethylformamide (1 mL) was added 5-chloro-2-methylphenylisocyanate (0.53 mmol). The reaction mixture was left at room temperature for 16 hours and concentrated in vacuo. The residue was purified by chromatography (70/30/1 ethyl acetate/methanol/ammonium hydroxide) whereby the product was obtained in 78% yield.

The following compounds were prepared by this method:

Example 243: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl] Amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared by Method V in 70% yield. ¹ H NMR (CD ₃ OD) δ8.68 (d, J=9.0, 1H), 8.46 (s, 1H), 7.47-7.30 (m, 3H), 7.33 (d, J=9.0, 1H), 3.97 ( m, 1H), 3.96(t, J=12.0, 1H), 3.64(t, J=6.0, 2H), 3.50-3.30(m, 6H), 2.52(m, 1H), 2.40(m, 1H), 2.20 (m, 2H), 2.10 (m, 1H); LC/MS (EI) t _R 5.55, m/z 518 (M ⁺ +1).

Example 244: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(propylamino)carbonyl] Amino}-1H-indazole-3-carboxamide

Prepared by Method V in 32% yield. LC/MS (EI) t _R 4.88, m/z 425 (M ⁺ +1).

Example 245: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1 , 2-Benzisothiazole-3-carboxamide

Prepared by Method V in 40% yield. LC/MS (EI) t _R 5.74, m/z 447 (M ⁺ +1).

Example 246: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-fluorophenyl)ethyl]amino}carbonyl )amino]-1,2-benzisothiazole-3-carboxamide

Prepared by Method V in 50% yield. LC/MS (EI) t _R 5.42, m/z 454 (M ⁺ +1).

Example 247: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino]carbonyl}amino )-1,2-benzisothiazole-3-carboxamide

Prepared by Method V in 76% yield. LC/MS (EI) t _R 5.79, m/z 450 (M ⁺ +1).

Example 248: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbonyl}amino )-1,2-benzisothiazole-3-carboxamide

Prepared by Method V in 78% yield. LC/MS (EI) t _R 5.92, m/z 470 (M ⁺ +1).

Example 249: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}amino)-1 , 2-Benzisothiazole-3-carboxamide

Prepared by Method V in 40% yield. LC/MS (EI) t _R 5.78, m/z 450 (M ⁺ +1).

Example 250: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]amino} Carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared by Method V in 71% yield. LC/MS (EI) t _R 5.54, m/z 450 (M ⁺ +1).

Example 251: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino }carbonyl)amino]-1,2-benzisothiazole-3-carboxamide

Prepared by Method V in 74% yield. LC/MS (EI) t _R 5.37, m/z 466 (M ⁺ +1).

Example 252: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino}-1,2-benzo Isothiazole-3-carboxamide

Prepared by Method V in 63% yield. LC/MS (EI) t _R 5.34, m/z 414 (M ⁺ +1).

Example 253: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benziso Thiazole-3-carboxamide

Prepared by Method V in 70% yield. LC/MS (EI) t _R 4.40, m/z 388 (M ⁺ +1).

Example 254: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H- Indazole-3-carboxamide

Prepared by Method V in 65% yield. LC/MS (EI) t _R 5.03, m/z 397 (M ⁺ +1).

Example 255: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)- 1H-Indazole-3-carboxamide

Prepared by Method V in 68% yield. LC/MS (EI) t _R 5.02, m/z 449 (M ⁺ +1).

Example 256: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3 -Formamide

Prepared by Method V in 54% yield. LC/MS (EI) t _R 4.24, m/z 397 (M ⁺ +1).

Example 257: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)- 1H-Indazole-3-carboxamide

Prepared by Method V in 64% yield. LC/MS (EI) t _R 4.75, m/z 434 (M ⁺ +1).

Example 258: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H- Indazole-3-carboxamide

Prepared by Method V in 57% yield. LC/MS (EI) t _R 5.03, m/z 397 (M ⁺ +1).

Example 259: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benziso Thiazole-3-carboxamide formate

Prepared by Method V in 70% yield. LC/MS (EI) t _R 4.78, m/z 388 (M ⁺ +1).

Example 260: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3- Formamide formate

Prepared by Method V in 35% yield. LC/MS (EI) t _R 2.87, m/z 371 (M ⁺ +1).

Example 261: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3- Formamide formate

Prepared by Method V in 30% yield. LC/MS (EI) t _R 2.91, m/z 371 (M ⁺ +1).

Example 262: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-difluorobenzyl)amino]carbonyl}amino)-1H -Indazole-3-carboxamide formate

Prepared by Method V in 41% yield. LC/MS (EI) t _R 5.03, m/z 397 (M ⁺ +1).

Example 263: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H- Indazole-3-carboxamide formate

Prepared by Method V in 36% yield. LC/MS (EI) t _R 5.02, m/z 437 (M ⁺ +1).

Example 264: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3 - Formamide formate

Prepared by Method V in 34% yield. LC/MS (EI) t _R 4.24, m/z 397 (M ⁺ +1).

Example 265: N(3)-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-(3-methoxybenzyl)-5-({[(3- Methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide

Prepared by Method V in 14% yield. LC/MS (EI) t _R 5.74, m/z 612 (M ⁺ +1).

Example 266: N(3)-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[ (4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide

Prepared by Method V in 13% yield. LC/MS (EI) t _R 5.81, m/z 588 (M ⁺ +1).

Example 267: N(3)-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentylamino )carbonyl]amino}-1H-indazole-1,3-dicarboxamide formate

Prepared by Method V in 13% yield. LC/MS (EI) t _R 5.51, m/z 508 (M ⁺ +1).

Example 268: N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carbonyl ]Amino}-1H-indazole-1,3-dicarboxamide

Prepared by Method V in 9.4% yield. LC/MS (EI) t _R 5.24, m/z 456 (M ⁺ +1).

Example 269: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]thiocarbonyl}amino)-1H -Indazole-3-carboxamide formate

Prepared by Method V in 47% yield. LC/MS (EI) t _R 2.75, m/z 399 (M ⁺ +1). Example 270: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]thiocarbonyl}amino)-1 , 2-Benzisothiazole-3-carboxamide formate

Prepared by Method V in 26% yield. LC/MS (EI) t _R 3.98, m/z 416 (M ⁺ +1).

Example 271: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)thiocarbonyl]amino}-1,2- Benzisothiazole-3-carboxamide formate

Prepared by Method V in 60% yield. LC/MS (EI) t _R 3.01, m/z 404 (M ⁺ +1).

Example 272: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)thiocarbonyl]amino}-1,2-benzene Isothiazole-3-carboxamide formate

Prepared by Method V in 47% yield. LC/MS (EI) t _R 3.65, m/z 385 (M ⁺ +1).

Example 273: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}-1H-indazole-3 - Formamide formate

Prepared by Method V in 43% yield. LC/MS (EI) t _R 2.46, m/z 385 (M ⁺ +1).

Example 274: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbonyl]amino}-1H- Indazole-3-carboxamide formate

Prepared by Method V in 11% yield. LC/MS (EI) t _R 3.50, m/z 399 (M ⁺ +1).

Example 275: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(propylamino)carbonyl] Amino}-1H-indazole-3-carboxamide formate

Prepared by Method V in 56% yield. LC/MS (EI) t _R 3.74, m/z 425 (M ⁺ +1).

Example 276: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propane Amino)carbonyl]amino}-1H-indazole-3-carboxamide formate

Prepared by Method V in 40% yield. LC/MS (EI) t _R 3.72, m/z 453 (M ⁺ +1).

Example 277: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]amino}- 1H-Indazole-3-carboxamide formate

Prepared by Method V in 37% yield. LC/MS (EI) t _R 3.44, m/z 399 (M ⁺ +1).

Method W

Method W provides a method for coupling aminoaminoquinuclidine amides with halogenated heterocycles to form N-heteroarylaniline derivatives.

To 6-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide (0.175mmol) in toluene ( 0.5 mL) and a mixture of 2-propanol (0.5 mL) were added 2-bromothiazole (0.18 mmol) and potassium carbonate (0.21 mmol). The reaction mixture was microwave irradiated at 180 °C for 600 s and concentrated. The residue was resuspended in 95/5 dichloromethane/methanol, filtered and concentrated. The residue was purified by preparative HPLC, whereby the product was obtained in 10% yield.

This method was used to prepare the following compounds:

Example 278: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared by Method W in 10% yield. LC/MS (EI) t _R 4.78, m/z 386 (M ⁺ +1).

Method X

Method X provides a method for coupling acetylenic aminoquinuclides with azides to form triazole derivatives.

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide (0.300mol) and azidotrimethyl Silane (0.30 mmol) was suspended in water (0.6 mL) and tert-butanol (0.6 mL). Sodium ascorbate (0.20 mol) was added to the reaction mixture, followed by a solution of copper(II) sulfate pentahydrate (0.030 mmol) in water (30 μL). The reaction was stirred vigorously for 12 hours and concentrated. The residue was redissolved in methanol, filtered and concentrated. The residue was purified by preparative HPLC, whereby the product was obtained in 6% yield.

The following compounds were prepared by this method:

Example 279: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H- Indazole-3-carboxamide dicarboxylate

Prepared using Method X in 6% yield. ¹ H NMR (CD ₃ OD) δ8.69(s, 1H), 8.27(s, 1H), 7.97(d, 1H, J=8.8), 7.72(d, J=8.8), 4.58-4.43(m, 1, 3.91-3.84 (m, 1, 3.49-3.38 (m, 4, 2.43-1.97 (m, 6; LC/MS (EI) t _R 2.77, m/z 338 (M ⁺⁺ 1).

Example 280: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1H-1 , 2,3-triazol-4-yl]-1H-indazole-3-carboxamide dicarboxylate

Prepared using Method X in 55% yield. LC/MS (EI) t _R 2.04, m/z 449 (M ⁺ +1).

Example 281: [4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)-1H-1 , 2,3-triazol-1-yl] ethyl acetate dicarboxylate

Prepared using Method X in 20% yield. LC/MS (EI) t _R 3.15, m/z 424 (M ⁺ +1).

Method Y

Method Y provides a method for coupling an aminoaminoquinuclidinamide with a chloroformate to form a carbamate derivative.

To a solution of the amine (0.52 mmol) in N,N-dimethylformamide (1 mL) and pyridine (2 mL) was added benzyl chloroformate (0.58 mmol) and the reaction mixture was left for 16 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the product in 54% yield and the dicarbamate in 12% yield.

The following compounds were prepared by this method:

Example 279: Benzyl (3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate

Prepared by method Y in 54% yield. ¹ H NMR (CD ₃ OD) δ8.59(s, 1H), 8.51(s, 1H), 7.65(s, 1H), 7.41(d, J=9.0, 1H), 7.19(d, J=9.0, 1H), 7.05(d, J=9.0, 1H), 7.05(d, J=9.0, 1H), 6.94(d, J=9.0, 1H), 4.62(m, 1H), 3.95(m, 1H), 3.87(s, 3H), 3.50-3.30(m, 4H), 2.48(m, 1H), 2.37(m, 1H), 2.20(m, 2H), 2.02(m, 1H); LC/MS(EI) t _R 5.33, m/z 420 (M ⁺ +1).

Example 283: Vinyl (3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)carbamate

Prepared by method Y in 50% yield. LC/MS (EI) t _R 3.30, m/z 356 (M ⁺ +1).

Example 284: Isopropyl {3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl}carbamate

Prepared by method Y in 36% yield. LC/MS (EI) t _R 2.90, m/z 372 (M ⁺ +1).

Example 285: {3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(isopropylamino)carbonyl]-1H-indazole -5-yl}carbamate isopropyl formate

Prepared by method Y in 18% yield. LC/MS (EI) t _R 5.16, m/z 458 (M ⁺ +1).

Method Z

Method Z provides the oxidation of quinuclides to form N-oxide derivatives.

To a solution of quinuclidine (4.44 mmol) in dichloromethane (40 mL) was added dropwise a 0° C. solution of m-chloroperbenzoic acid (6.66 mmol) in dichloromethane (30 mL), and the reaction mixture was left for 3 Hour. The reaction mixture was concentrated and the residue was purified by chromatography on neutral alumina using a gradient of 100/0 to 90/10 dichloromethane/methanol to give the product in 58% yield.

The following compounds were prepared by this method:

Example 286: N-[(3S)-1-Oxo-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide

Prepared by Method Z in 58% yield. ¹ H NMR (CD ₃ OD, 500MHz) δ8.21 (d, J=8.0, 1H), 7.59 (d, J=9.0, 1H), 7.42 (dt, Jt=7.5, Jd=1.0, 1H), 7.26 (dt, Jt=7.5, Jd=1.0, 1H), 4.65(m, 1H), 3.83(m, 1H), 3.42(m, 5H), 2.37(m, 4H), 2.27(m, 1H), 2.17 (m, 2H), 2.02 (m, 1H); LC/MS (EI) t _R 12.4 [on a 4.6mm x 250mm YMC ODS-AQ S-5 120m column, using 05/95 to 95/05 in 35 minutes Gradient of acetonitrile (0.05% trifluoroacetic acid)/water (0.05% trifluoroacetic acid), analytical HPLC], m/z 287 (M ⁺ +1).

Method AA

Method AA provides a method for the demethylation of methoxy-substituted quinuclidinamides to form phenol derivatives.

To a solution of quinuclidine (4.44 mmol) in dichloromethane (40 mL) was added dropwise a 0° C. solution of m-chloroperbenzoic acid (6.66 mmol) in dichloromethane (30 mL), and the reaction mixture was left for 3 Hour. The reaction mixture was concentrated and the residue was purified by chromatography on neutral alumina using a gradient of 100/0 to 90/10 dichloromethane/methanol to give the product in 58% yield.

The following compounds were prepared by this method:

Example 287: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide hydrobromide

Prepared using Method AA in 32% yield. ¹ H NMR (Me ₂ SO-d ₆ ) δ 13.43 (s, 1H), 9.49 (br s, 1H), 9.35 (s, 1H), 8.62 (d, J=5.9, 1H), 4.46-7.44 ( m, 1H), 6.95(d, J=6.5, 1H), 4.41(br s, 1H), 3.68-3.63(m, 1H), 3.33-3.18(m, 7H), 2.22-2.20(m, 1H) , 2.09-2.08 (m, 1H), 1.94-1.93 (m, 1H), 1.75-1.70 (m, 1H); LC/MS (EI) t _R 10.72, m/z 287 (M ⁺ +1).

Example 288: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide hydrobromide

Prepared using Method AA in 39% yield. LC/MS (EI) t _R 10.32 [on a 4.6mm×250mmYMC ODS-AQ S-5 120m column using 05/95 to 95/05 acetonitrile (0.05% trifluoroacetic acid)/water (0.05% trifluoroacetic acid), analytical HPLC], m/z 287 (M ⁺ +1).

Method AB

Methods AB provide methods for the preparation of urea using phosgene equivalents.

To a solution of quinuclidine (4.44 mmol) in dichloromethane (40 mL) was added dropwise a 0° C. solution of m-chloroperbenzoic acid (6.66 mmol) in dichloromethane (30 mL), and the reaction mixture was left for 3 Hour. The reaction mixture was concentrated and the residue was purified by chromatography on neutral alumina using a gradient of 100/0 to 90/10 dichloromethane/methanol to give the product in 58% yield.

The following compounds were prepared by this method:

Example 289: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]amino}-1H-indazole-3 - Formamide formate

Prepared using Method AB in 55% yield. ¹ H NMR (CD ₃ OD) δ8.40(s, 1H), 8.10(s, 1H), 7.51(s, 1H), 4.52(m, 1H), 3.83(t, J=15.0, 1H), 3.37 (t, J=9.0, 4H), 3.36-3.30(m, 4H), 2.30(m, 1H), 2.15(m, 2H), 1.95(m, 1H), 1.19(t, J=6.0, 6H) ; LC/MS (EI) t _R 2.45, m/z 385 (M ⁺ +1).

Example 290: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3 - Formamide formate

Prepared using Method AB in 57% yield. LC/MS (EI) t _R 2.47, m/z 383 (M ⁺ +1).

Example 291: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3 - Formamide formate

Prepared using Method AB in 69% yield. LC/MS (EI) t _R 3.35, m/z 400 (M ⁺ +1).

Method AC

Methods AC provide methods for the preparation of cyclic amide derivatives from the corresponding brominated quinuclidine derivatives.

To a solution of (S)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthalene (0.14 mmol) in toluene (10 mL) was added palladium(II) acetate (0.09 mmol), and place the reaction mixture until the contents are completely dissolved. The resulting yellow solution was transferred to N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-yl under nitrogen atmosphere formamide (0.33mmol), cesium carbonate (0.60mmol) and 2-pyrrolidone (1.00mmol), and the reaction mixture was heated at 100°C for 16 hours. The reaction mixture was filtered through celite and concentrated. The residue was purified by HPLC, whereby the product was obtained in 72% yield.

This method was used to prepare the following compounds:

Example 292: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared using Methods AC in 72% yield. ¹ H NMR (CD ₃ OD) δ8.78 (d, J=9.0, 1H), 8.53 (broad, 1H), 8.81 (s, 1H), 7.63 (d, J=9.0, 1H), 4.5 (m, 1H), 4.07(t, J=6.0, 2H), 3.76(t, J=12.0, 1H), 3.50-3.30(m, 4H), 2.35(t, J=6.0, 2H), 2.35(m, 1H ), 2.20 (m, 3H), 2.10 (m, 2H), 1.90 (m, 1H); LC/MS (EI) t _R 2.43, m/z 371 (M ⁺ +1).

Example 293: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared using Methods AC in 40% yield. LC/MS (EI) t _R 2.11, m/z 354 (M ⁺ +1).

Example 294: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1-yl)-1 , 2-Benzisothiazole-3-carboxamide formate

Prepared using Methods AC in 50% yield. LC/MS (EI) t _R 5.17, m/z 447 (M ⁺ +1).

Method AD

Methods AD provide methods for the preparation of cyclic urea derivatives from the corresponding aminoquinuclidine derivatives.

To 6-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide (0.400mmol) in methanol ( 5 mL) were added tert-butyl N-(2-oxoethyl)carbamate (0.56 mmol), sodium cyanoborohydride (1.00 mmol) and acetic acid (0.4 mL), and the reaction mixture was left for 4 h . The reaction mixture was diluted with 3N hydrochloric acid (5 mL), and the reaction mixture was left for 2 hrs. The reaction mixture was concentrated, and the residue was purified by HPLC to obtain the reducing amine in 63% yield.

To a solution of the reducing amine (0.100 mmol) in N,N-dimethylformamide (4 mL) was added N,N-carbonyldiimidazole (0.150 mmol) and the reaction mixture was heated at 100° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by HPLC, thereby obtaining a cyclic urea in a yield of 60%.

This method was used to prepare the following compounds:

Example 295: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-benzo Isothiazole-3-carboxamide formate

Prepared using Methods AD in 60% yield. ¹ H NMR (CD ₃ OD) δ8.67 (d, J=9.0, 1H), 8.51 (broad, 1H), 8.18 (s, 1H), 7.96 (d, J=9.0, 1H), 4.48 (d, 1H), 4.08(dd, J=6.0, 6.0, 2H), 3.79(t, J=12.0, 1H), 3.60(dd, J=6.0, 6.0, 2H), 3.5-3.3(m, 4H), 2.38 (m, 1H), 2.22 (m, 1H), 2.08 (m, 2H), 1.90 (m, 1H); LC/MS (EI) t _R 2.43, m/z 372 (M ⁺ +1).

Example 296: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazole-3 - Formamide formate

Prepared using Methods AD in 60% yield. LC/MS (EI) t _R 1.26, m/z 355 (M ⁺ +1).

Example 297: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin-1-yl)-1H -Indazole-3-carboxamide formate

Prepared using Methods AD in 40% yield. LC/MS (EI) t _R 3.27, m/z 397 (M ⁺ +1).

Example 298: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2- Benzisothiazole-3-carboxamide formate

Prepared using Methods AD in 35% yield. LC/MS (EI) t _R 1.47, m/z 303 (M ⁺ +1).

Method AE

Methods AE provide methods for the preparation of cyclic urea derivatives from the corresponding brominated quinuclidine derivatives.

Palladium(II) acetate (0.09 mmol), and place the reaction mixture until the contents are completely dissolved. The resulting yellow solution was transferred to N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-yl under nitrogen atmosphere amide (0.33mmol), cesium carbonate (0.39mmol) and 1-methyl-2-imidazolidinone (0.500mmol), and the reaction mixture was heated at 100°C for 16 hours. The reaction mixture was filtered through celite and concentrated. The residue was purified by HPLC, whereby the product was obtained in 70% yield.

This method was used to prepare the following compounds:

Example 299: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1 , 2-Benzisothiazole-3-carboxamide formate

Prepared using Methods AE in 70% yield. ¹ H NMR (CD ₃ OD) δ8.64 (d, J=9.0, 1H), 8.55 (s, 1H), 8.18 (d, J=9.0, 1H), 4.20 (m, 1H), 3.95 (dd, J=6.0, 6.0, 2H), 3.51(dd, J=6.0, 6.0, 2H), 3.35(s, 3H), 3.45-3.30(m, 4H), 2.10(m, 1H), 1.95(m, 1H ), 1.80 (m, 2H), 1.60 (m, 1H); LC/MS (EI) t _R 2.73, m/z 386 (M ⁺ +1).

Example 300: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolidin-1-yl)- 1,2-Benzisothiazole-3-carboxamide formate

Prepared using Methods AE in 65% yield. LC/MS (EI) t _R 3.65, m/z 414 (M ⁺ +1).

Example 301: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)-1 , 2-Benzisothiazole-3-carboxamide formate

Prepared using Methods AE in 67% yield. LC/MS (EI) t _R 4.61, m/z 414 (M ⁺ +1).

Example 302: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1-yl)-1 , 2-Benzisothiazole-3-carboxamide

Prepared using Methods AF in 27% yield. LC/MS (EI) t _R 3.07, m/z 387 (M ⁺ +1).

Example 303: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolidin-1-yl)- 1,2-Benzisothiazole-3-carboxamide

Prepared using Methods AF in 31% yield. LC/MS (EI) t _R 3.70, m/z 414 (M ⁺ +1).

Example 304: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-1 , 2-Benzisothiazole-3-carboxamide

Prepared using Methods AF in 24% yield. LC/MS (EI) t _R 3.66, m/z 414 (M ⁺ +1).

Method AF

Methods AF provide methods for the preparation of benzisoxazolequinuclidines from ethyl benzisoxazole-3-carboxylates.

(S)-3-Aminoquinuclidine hydrochloride (3.52 mmol) was dissolved in N,N-diisopropylethylamine (0.5 mL) and ethanol (3 mL) under heating. Ethyl 5-bromo-1,2-benzisoxazole-3-carboxylate (1.86 mmol) was added and the reaction mixture was heated at 85°C for 72 hours. The reaction mixture was diluted with dichloromethane (30 mL) and washed with 10 mL of saturated sodium carbonate. The aqueous layer was extracted with dichloromethane (30 mL), and the combined organic layers were washed with brine and dried (sodium sulfate). The organic layer was loaded onto a 10 g SCX cartridge, and the cartridge was washed with methanol (50 mL). The crude product was eluted with 2M aqueous ammonia in methanol (60 mL) and concentrated. Purification of the residue by chromatography [40/60 to 0/100 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] afforded the amide as a light yellow oil in yield of 59%.

This method was used to prepare the following compounds:

Example 305: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisoxazole-3-carboxamide

Prepared using Methods AF in 59% yield. ¹ H NMR (CD ₃ OD) δ8.16 (d, J=0.6, 1H), 7.71 (dd, J=8.9, 0.6, 1H), 7.59 (d, J=8.9, 1H), 4.21 (m, 1H ), 3.37(m, 1H), 3.02(m, 1H), 2.84(m, 4H), 2.08(m, 1H), 1.96(m, 1H), 1.78(m, 2H), 1.55(m, 1H) ; LC/MS (EI) t _R 2.33, m/z 350/352 (M ⁺ /M ⁺ +2).

Example 306: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-carboxamide

Prepared using Methods AF in 63% yield. LC/MS (EI) t _R 2.22, m/z 350/352 (M ⁺ +1).

Method AG

Methods AG provide methods for the preparation of acyclic amide derivatives from the corresponding brominated quinuclidine derivatives.

Palladium(II) acetate (0.040 mmol), and place the reaction mixture until the contents are completely dissolved. The resulting yellow solution was transferred to N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-yl under nitrogen atmosphere formamide (0.30mmol), cesium carbonate (0.50mmol) and N-methylacetamide (0.500mmol), and the reaction mixture was microwave irradiated at 200°C for 300 seconds. The reaction mixture was filtered through celite and concentrated. The residue was purified by HPLC, whereby the product was obtained in 50% yield.

This method was used to prepare the following compounds:

Example 307: 6-[Acetyl(methyl)amino]-oxaN-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole -3-Carboxamide formate

Prepared using Methods AG in 50% yield. ¹ H NMR (CD ₃ OD) δ8.85 (d, J=9.0, 2H), 8.40 (broad, 1H), 8.13 (s, 1H), 7.53 (d, J=9.0, 1H), 4.43 (m, 1H), 3.85(m, 1H), 3.5-3.2(m, 7H), 2.45(m, 1H), 2.30(m, 1H), 2.10(m, 3H), 1.95(m, 3H); LC/MS (EI)t _R 2.40, m/z 359 (M ⁺ +1).

Example 308: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzisothiazole- 3-Carboxamide formate

Prepared using Methods AG in 60% yield. LC/MS (EI) t _R 2.42, m/z 373 (M ⁺ +1).

Example 309: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazole-2- base)-1H-indazole-3-carboxamide formate

Prepared using Method AH in 31% yield. ¹ H NMR (CD ₃ OD) δ8.43(s, 1H), 8.28(d, J=8.4, 1H), 8.27(s, 1H), 7.94(d, J=3.3, 1H), 7.85(d, J=8.3, 1H), 7.68(d, J=3.3, 1H), 4.55(m, 1H), 4.46(d, J=7.0, 2H), 3.84(m, 1H), 3.6-3.3(m, 5H ), 2.41(m, 1H), 2.29(m, 1H), 2.15(m, 2H), 1.95(m, 1H), 1.45(m, 1H), 0.62(m, 2H), 0.53(m, 2H) ; LC/MS (EI) t _R 3.99 min, m/z 408 (M ⁺ +1).

Example 310: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiazole-2- base)-1H-indazole-3-carboxamide formate

Prepared using Method AH in 40% yield. LC/MS (EI) t _R 3.68 min, m/z 424 (M ⁺ +1).

Example 311: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thiazole- 2-yl)-1H-indazole-3-carboxamide formate

Prepared using Method AH in 27% yield. LC/MS (EI) t _R 3.64 min, m/z 412 (M ⁺ +1).

Example 312: 3-[3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-thiazol-2-yl)- 1H-Indazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl formate

Prepared using Method AH in 38% yield. LC/MS (EI) t _R 4.30 min, m/z 523 (M ⁺ +1).

Example 313: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-yl )-1H-indazole-3-carboxamide

Prepared from EXAMPLE 312 by exposure to trifluoroacetic acid in 88% yield. LC/MS (EI) t _R 2.41 min, m/z 423 (M ⁺ +1).

Example 314: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thienyl Methyl)-1H-indazole-3-carboxamide formate

Prepared using Method AH in 11% yield. LC/MS (EI) t _R 4.15 min, m/z 450 (M ⁺ +1).

Example 315: N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazole- 2-yl)-1H-indazole-3-carboxamide formate

Prepared using Method AH in 54% yield. LC/MS (EI) t _R 4.33 min, m/z 474 (M ⁺ +1).

Example 316: [ ³ H]MLA Binding

Material:

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

Protease inhibitor cocktail tablet (cocktail tablet): Roche, CAT No.1697498 film preparation

Rat brain and protease inhibitors (1 tablet/50ml) in 20 volumes (w/v) of ice-cold 0.32 M sucrose were homogenized with a polytron at setting 11 for 10 seconds, followed by centrifugation at 4°C and 1000g 10 minutes. The supernatant was centrifuged again at 20000g for 20 minutes at 4°C. The pellet was resuspended in binding buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO ₄ , 2 mM CaCl ₂ , 0.1% (w/v) BSA), and Membrane preparations were stored at -80°C.

For saturation analysis, 200 μl assay mix contained 200 μg membrane protein, 0.2-44 nM [ ³ H]MLA in binding buffer. Non-specific binding was defined using 1 μM MLA. Competition assays were performed with 2 nM [ ^3H ]MLA and the desired range of compounds. The assay mixture was incubated at 22°C for 2 hours, followed by harvesting using a Tomtec harvester with GF/B filters pre-soaked with 0.3% PEI in binding buffer. Filters were washed three times with binding buffer and radioactivity was recorded with Trilux.

Preferred compounds of the invention have a binding affinity of 2 nM to 25 μM, especially 2 nM to 2.5 μM.

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

While specific compounds and preparations have been illustrated, it will be evident that changes and modifications may be made without departing from the spirit or scope of the invention.

Claims (69)

1. A compound of formula I, II, III or IV or a pharmaceutically acceptable salt thereof:

in A is

or

X is O or S; R' is H, alkyl having 1-4 carbon atoms, haloalkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms, or cycloalkyl having 4-7 carbon atoms alkyl; R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , -O-(C _{1- 6} -Alkyl-O) _1-2 -C _1-6 -Alkyl, NR ² -C _1-6 -Alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 -Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -alkyl-Ar, NR ² -C _1-6 -alkyl-CO-OR ² , NR ² -C _1-6 -alkyl-NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , alkyl with 1-4 carbon atoms, fluorinated alkanes with 1-4 carbon atoms A group, an alkenyl group having 2-6 carbon atoms, an alkynyl group having 2-6 carbon atoms, wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl groups is unsubstituted or substituted by Ar or Het , cycloalkyl with 3-7 carbon atoms, unsubstituted or replaced by HCO-, C _1-6 -alkoxy, NR ⁶ R ⁷ , CO-NR ⁶ R ⁷ , C _2-6 -alkoxycarbonyl Or -CO-R ¹⁰ substituted cycloalkenyl with 5-8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, with 1 - alkoxy with 4 carbon atoms, cycloalkoxy with 3-7 carbon atoms, cycloalkylalkoxy with 4-7 carbon atoms, alkylthio with 1-4 carbon atoms, Fluorinated alkoxy groups having 1-4 carbon atoms, hydroxyalkyl groups having 1-4 carbon atoms, fluorinated hydroxyalkyl groups having 1-4 carbon atoms, hydroxyalkanes having 2-4 carbon atoms Oxygen, fluorinated hydroxyalkoxy groups having 2-4 carbon atoms, monoalkylamino groups having 1-4 carbon atoms, dialkylamino groups wherein each alkyl group independently has 1-4 carbon atoms , alkoxycarbonyl having 2-6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _1-6 -alkyl-O- , Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-, with the proviso that R is not _NH2 ; or R is one of

n is 2-4; m is 3-5; or Two Rs can form together a 5-membered fused ring structure containing at least one N atom; R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR _{2 R 9 , SO 2} ^{R 10 ,} SOR ^{10 ,} -O-(C _1-6 -alkyl-O) _1-2 -C _1-6 -alkyl, NR ² -C _1-6 -alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 - Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -Alkyl-Ar, NR ² -C _1-6 -Alkyl-CO-OR ² , NR ² -C _1-6 -Alkyl- NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , with 1-4 carbon atoms, with 1-4 fluorinated alkyl with 2-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl is not Substituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, unsubstituted or substituted by HCO-, C _1-6 -alkoxy, NR ⁶ R ⁷ , CO-NR ⁶ R ⁷ , C _2-6 -Alkoxycarbonyl or -CO-R ¹⁰ substituted cycloalkenyl with 5-8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, ring with 6-9 carbon atoms Alkenylalkyl, alkoxy having 1-4 carbon atoms, cycloalkoxy having 3-7 carbon atoms, cycloalkylalkoxy having 4-7 carbon atoms, having 1-4 Alkylthio with carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, fluorinated hydroxyalkyl with 1-4 carbon atoms, 2- Hydroxyalkoxy with 4 carbon atoms, fluorinated hydroxyalkoxy with 2 to 4 carbon atoms, monoalkylamino with 1 to 4 carbon atoms, wherein each alkyl group independently has 1 to 4 Dialkylamino with carbon atoms, alkoxycarbonyl with 2-6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _{1- 6} -Alkyl-O-, Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-; or ^R1 is one of

or Two R ¹ can form together a 5-membered fused ring structure containing at least one N atom; ^R is H, alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms, ring having 4-7 carbon atoms Alkylalkyl, fluorinated C _1-4 -alkyl-CO-, C _3-7 -cycloalkyl-CO-, C _1-4 -alkyl-NH-CO-, C _3-7 -cycloalkane -NH-CO-, Het, Ar-C _1-4 -alkyl-, Ar-C _1-4 -alkyl-CO-, Ar-C _1-4 -alkyl-SO ₂ -, C _{1- 4} -Alkyl-OC _1-4 -alkyl- or Ar-C _1-4 -alkyl-NH-CO-; R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR ₂ R ⁹ , SO ² R ¹⁰ , SOR ^{10 ,} -O-(C _1-6 -alkyl-O) _1-2 -C _1-6 -alkyl, NR ² -C _1-6 -alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 - Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -Alkyl-Ar, NR ² -C _1-6 -Alkyl-CO-OR ² , NR ² -C _1-6 -Alkyl- NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , with 1-4 carbon atoms, with 1-4 fluorinated alkyl with 2-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl is not Substituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, unsubstituted or substituted by HCO-, C _1-6 -alkoxy, NR ⁶ R ⁷ , CO-NR ⁶ R ⁷ , C _2-6 -Alkoxycarbonyl or -CO-R ¹⁰ substituted cycloalkenyl with 5-8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, ring with 6-9 carbon atoms Alkenylalkyl, alkoxy having 1-4 carbon atoms, cycloalkoxy having 3-7 carbon atoms, cycloalkylalkoxy having 4-7 carbon atoms, having 1-4 Alkylthio with carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, fluorinated hydroxyalkyl with 1-4 carbon atoms, 2- Hydroxyalkoxy with 4 carbon atoms, fluorinated hydroxyalkoxy with 2 to 4 carbon atoms, monoalkylamino with 1 to 4 carbon atoms, wherein each alkyl group independently has 1 to 4 Dialkylamino with carbon atoms, alkoxycarbonyl with 2-6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _{1- 6} -Alkyl-O-, Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-; or ^R3 is one of

or Two ^R3 can together form a 5-membered fused ring structure containing at least one N atom; R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR ₂ R ⁹ , SO ² R ¹⁰ , SOR ^{10 ,} -O-(C _1-6 -alkyl-O) _1-2 -C _1-6 -alkyl, NR ² -C _1-6 -alkyl-NR ⁶ R ⁷ , NR ² -C _1-6 - Alkyl-CONR ⁶ R ⁷ , NR ² -CO-C _1-6 -Alkyl-Ar, NR ² -C _1-6 -Alkyl-CO-OR ² , NR ² -C _1-6 -Alkyl- NR ² (CO-OR ² ), -C _1-6 -alkyl-NR ² , -OC _1-6 -alkyl-NR ⁶ R ⁷ , with 1-4 carbon atoms, with 1-4 fluorinated alkyl with 2-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl is not Substituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, unsubstituted or substituted by HCO-, C _1-6 -alkoxy, NR ⁶ R ⁷ , CO-NR ⁶ R ⁷ , C _2-6 -Alkoxycarbonyl or -CO-R ¹⁰ substituted cycloalkenyl with 5-8 carbon atoms, cycloalkylalkyl with 4-7 carbon atoms, ring with 6-9 carbon atoms Alkenylalkyl, alkoxy having 1-4 carbon atoms, cycloalkoxy having 3-7 carbon atoms, cycloalkylalkoxy having 4-7 carbon atoms, having 1-4 Alkylthio with carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, fluorinated hydroxyalkyl with 1-4 carbon atoms, 2- Hydroxyalkoxy with 4 carbon atoms, fluorinated hydroxyalkoxy with 2 to 4 carbon atoms, monoalkylamino with 1 to 4 carbon atoms, wherein each alkyl group independently has 1 to 4 Dialkylamino with carbon atoms, alkoxycarbonyl with 2-6 carbon atoms, Ar, Het, OAr, OHet, Carbo-O, Ar-C _1-6 -alkyl-O-, Het-C _{1- 6} -Alkyl-O-, Het-CO-Het-, Het-C _1-6 -alkyl-NR ² - or Ar-C _1-6 -alkyl-Het-O-; or ^R4 is one of or Two R ⁴ can together form a 5-membered condensed ring structure containing at least one N atom; R ⁵ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , carboxy, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , ^{NR 2} CSNR ⁶ R ⁷ , NR 2 R 9 , SO ² _R ¹⁰ , SOR ¹⁰ , an alkyl group having 1 to 4 carbon atoms, having Fluorinated alkyl with 1-4 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkylalkyl having 4-7 carbon atoms, having Cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms, cycloalkoxy with 3-7 carbon atoms, cycloalkylalkane with 4-7 carbon atoms Oxygen, alkylthio with 1-4 carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, fluorine with 1-4 carbon atoms Hydroxyalkyl, hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 2-4 carbon atoms, monoalkylamino with 1-4 carbon atoms, wherein each alkane The group independently has a dialkylamino group with 1-4 carbon atoms, an alkoxycarbonyl group with 2-6 carbon atoms, Ar, Het, OAr or OHet; R ^and R are ^each independently H, an alkyl group with 1-4 carbon atoms, an alkoxyalkyl group with 2-8 carbon atoms, a cycloalkyl group with 3-7 carbon atoms, or a cycloalkyl group with 4 -Cycloalkylalkyl with 7 carbon atoms, or ^R6 and ^R7 together are an alkylene group containing 4-6 carbon atoms and forming a ring with the N atom; ^R is H, alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, alkenyl having 3-6 carbon atoms, alkynyl having 3-6 carbon atoms , wherein each of the alkyl, fluorinated alkyl, alkenyl or alkynyl is unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkene having 5-8 carbon atoms radical, cycloalkylalkyl having 4-7 carbon atoms, cycloalkenylalkyl having 6-9 carbon atoms, hydroxyalkyl having 1-4 carbon atoms, hydroxyalkyl having 1-4 carbon atoms Fluorinated hydroxyalkyl, monoalkylamino with 1-4 carbon atoms, dialkylamino with each alkyl independently having 1-4 carbon atoms, Ar or Het; ^R is Ar, Ar-alkyl wherein the alkyl moiety has 1-4 carbon atoms, or Het; R is ^alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, alkenyl having 3-6 carbon atoms, alkynyl having 3-6 carbon atoms, wherein The alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, Cycloalkylalkyl with 4-7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, hydroxyalkyl with 2-4 carbon atoms, fluorinated Hydroxyalkyl, monoalkylamino having 1-4 carbon atoms, dialkylamino wherein each alkyl independently has 1-4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar or Het ; Ar is an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted one or more times by: alkyl group having 1-8 carbon atoms, alkoxy group having 1-8 carbon atoms , halogen, dialkylamino, amino, cyano, hydroxyl, nitro, haloalkyl having 1 to 8 carbon atoms, dialkylamino having 1 to 8 carbon atoms, wherein the alkyl moiety each has 1 to 8 carbon atoms Haloalkoxy, hydroxyalkyl having 1-8 carbon atoms, hydroxyalkoxy having 2-8 carbon atoms, alkenyloxy having 3-8 carbon atoms, alkane having 1-8 carbon atoms Thio group, an alkylsulfinyl group having 1-8 carbon atoms, an alkylsulfonyl group having 1-8 carbon atoms, an alkylamino group having 1-8 carbon atoms, wherein the cycloalkyl group is optionally Cycloalkylamino substituted and having 3-7 carbon atoms, aryloxy group wherein the aryl part is optionally substituted and containing 6-10 carbon atoms, wherein the aryl part is optionally substituted and containing 6-10 Arylthio of carbon atoms, cycloalkoxy, sulfo, sulfonylamino, amido, acyloxy, or combinations thereof, wherein cycloalkyl is optionally substituted and has 3-7 carbon atoms; and Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, has 5-10 ring atoms, wherein at least one ring atom is a N, O or S atom, and the heterocyclic group is unsubstituted or replaced by The following groups are substituted one or more times: halogen, optionally substituted aryl having 6-10 carbon atoms, alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, Cycloalkyl with 3-7 carbon atoms, cyano, trifluoromethyl, nitro, oxo, OH, alkoxycarbonylalkyl with 3-8 carbon atoms, amino, with 1-8 carbons Atomic monoalkylamino, wherein each alkyl group has 1-8 carbon atoms dialkylamino, SO ₂ R ¹¹ , -CXR ¹¹ , piperidinylethyl or combinations thereof; Carbo is a partially unsaturated carbocyclic group having 5-14 carbon atoms which is unsubstituted or substituted one or more times by: halogen, alkyl having 1-8 carbon atoms, having 1- 8-carbon alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof; and R is ^alkyl having 1-4 carbon atoms, haloalkyl having 1-4 carbon atoms, alkenyl having 3-6 carbon atoms, alkynyl having 3-6 carbon atoms, wherein said Alkyl, haloalkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkenyl having 4-7 Cycloalkylalkyl with 6-9 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, hydroxyalkyl with 2-4 carbon atoms, fluorinated hydroxyalkyl with 2-4 carbon atoms, A monoalkylamino group having 1-4 carbon atoms, a dialkylamino group wherein each alkyl group independently has 1-4 carbon atoms, or Ar. 2. The compound according to claim 1, wherein when R is NR ⁶ R ⁷ , at least one of R ⁶ and R ⁷ is an alkyl group with 2-4 carbon atoms, an alkoxy group with 2-8 carbon atoms Alkyl, cycloalkyl having 3-7 carbon atoms or cycloalkylalkyl having 4-7 carbon atoms, or R ⁶ and R ⁷ together are 4-6 carbon atoms and with said N atom An alkylene group forming a ring. 3. The compound according to claim 1, wherein R is ^other than ^NR6R7 . 4. The compound according to claim 1, wherein R' is H or _CH3 . 5. The compound according to claim 1, wherein R' is H; A is a group according to formula (a), (b) or (c); R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR _{2 R 9 , SO 2} ^{R 10 ,} SOR ^{10 ,} Alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, wherein the alkane Alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkenyl having 4- Cycloalkylalkyl with 7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms, cycloalkoxy with 3-7 carbon atoms, Cycloalkylalkoxy with 4-7 carbon atoms, alkylthio with 1-4 carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyl with 1-4 carbon atoms Alkyl, fluorinated hydroxyalkyl with 1-4 carbon atoms, hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 1-4 Monoalkylamino of carbon atoms, dialkylamino of which each alkyl independently has 1-4 carbon atoms, alkoxycarbonyl of 2-6 carbon atoms, Ar, Het, OAr or OHet; or ^R1 is one of

^R is H, alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms or ring having 4-7 carbon atoms alkyl alkyl; R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR _{2 R 9 , SO 2} ^{R 10 ,} SOR ^{10 ,} Alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, wherein the alkane Alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkenyl having 4- Cycloalkylalkyl with 7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms, cycloalkoxy with 3-7 carbon atoms, Cycloalkylalkoxy with 4-7 carbon atoms, alkylthio with 1-4 carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyl with 1-4 carbon atoms Alkyl, fluorinated hydroxyalkyl with 1-4 carbon atoms, hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 1-4 Monoalkylamino of carbon atoms, dialkylamino of which each alkyl independently has 1-4 carbon atoms, alkoxycarbonyl of 2-6 carbon atoms, Ar, Het, OAr or OHet; or ^R3 is one of

R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ^8. NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR 2 CONR ⁶ R ⁷ , NR ^{2 CSNR 6} R 7 , NR _{2 R 9 , SO 2} ^{R 10 ,} SOR ^{10 ,} Alkyl having 1-4 carbon atoms, fluorinated alkyl having 1-4 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, wherein the alkane Alkyl, fluorinated alkyl, alkenyl or alkynyl are each unsubstituted or substituted by Ar or Het, cycloalkyl having 3-7 carbon atoms, cycloalkenyl having 5-8 carbon atoms, cycloalkenyl having 4- Cycloalkylalkyl with 7 carbon atoms, cycloalkenylalkyl with 6-9 carbon atoms, alkoxy with 1-4 carbon atoms, cycloalkoxy with 3-7 carbon atoms, Cycloalkylalkoxy with 4-7 carbon atoms, alkylthio with 1-4 carbon atoms, fluorinated alkoxy with 1-4 carbon atoms, hydroxyl with 1-4 carbon atoms Alkyl, fluorinated hydroxyalkyl with 1-4 carbon atoms, hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 2-4 carbon atoms, fluorinated hydroxyalkoxy with 1-4 Monoalkylamino of carbon atoms, dialkylamino of which each alkyl independently has 1-4 carbon atoms, alkoxycarbonyl of 2-6 carbon atoms, Ar, Het, OAr or OHet; or ^R4 is one of

and Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, has 5-10 ring atoms, wherein at least one ring atom is a N, O or S atom, and the heterocyclic group is unsubstituted or replaced by The following groups are substituted one or more times: halogen, optionally substituted aryl having 6-10 carbon atoms, alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, Cyano, trifluoromethyl, nitro, oxo, OH, alkoxycarbonylalkyl having 3-8 carbon atoms, amino, an alkylamino having 1-8 carbon atoms, wherein each alkyl Dialkylamino having 1-8 carbon atoms, SO ₂ R ¹¹ , —CXR ¹¹ , piperidinylethyl, or combinations thereof. 6. The compound according to claim 1, wherein at least one of R ¹ , R ³ or R ⁴ is COH, wherein R ⁶ and R ⁷ are not alkyl NR ⁶ R ⁷ , carboxyl, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² COOR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ² R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , an alkyl group having 1-4 carbon atoms substituted by Ar or Het, a fluorinated alkyl group having 1-4 carbon atoms substituted by Ar or Het, optionally Alkenyl having 2-6 carbon atoms substituted by Ar or Het, alkynyl having 2-6 carbon atoms optionally substituted by Ar or Het, cycloalkenyl having 5-8 carbon atoms, having 6 -Cycloalkenylalkyl with 9 carbon atoms, fluorinated hydroxyalkyl with 1-4 carbon atoms, alkoxycarbonyl with 2-6 carbon atoms, OAr, OHet or by SO ₂ R ¹¹ or -CXR ¹¹ substituted Het, or selected from the following formula:

and / or R ⁵ is carboxyl, alkoxycarbonyl having 2-6 carbon atoms, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ¹⁰ , NR ² CONR ⁶ R ⁷ , NR ² CSNR ⁶ R ⁷ , NR ₂ R ⁹ , SO ₂ R ¹⁰ , SOR ¹⁰ , alkenyl having 2-6 carbon atoms, alkyne having 2-6 carbon atoms group, alkyl group substituted by Ar or Het, alkenyl group substituted by Ar or Het, alkynyl group substituted by Ar or Het, cycloalkenyl group with 5-8 carbon atoms, ring with 6-9 carbon atoms Alkenylalkyl, fluorinated hydroxyalkyl with 1-4 carbon atoms, fluorinated hydroxyalkoxy with 2-4 carbon atoms, OAr, OHet or Het substituted by SO ₂ R ¹¹ or -CXR ¹¹ . 7. The compound according to claim 1, wherein at least one of R ¹ , R ³ , R ⁴ and R ⁵ is carboxyl, an alkoxycarbonyl group with 2-6 carbon atoms, CONR ⁶ R ⁷ , NR ² COR ⁸ , NR ² CSR ⁸ , NR ² CONR ² R ⁹ , NR ² CSNR ² R ⁹ , NR ² SO ₂ R ^{10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6} R ⁷ , NR ₂ R ⁹ , SO ² R ¹⁰ , SOR ^10. Alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, alkyl substituted by Ar or Het, alkenyl substituted by Ar or Het, alkynyl substituted by Ar or Het , cycloalkenyl having 5-8 carbon atoms, cycloalkenylalkyl having 6-9 carbon atoms, fluorinated hydroxyalkyl having 1-4 carbon atoms, fluorine having 2-4 carbon atoms Hydroxyalkoxy, OAr, OHet, or Het substituted by SO ₂ R ¹¹ or -CXR ¹¹ ; R and R are ^each independently H, alkyl having 1-4 carbon atoms, cycloalkyl having 3-7 carbon atoms ^, or cycloalkylalkyl having 4-7 carbon atoms, or R ⁶ and ^R together are an alkylene group containing 4-6 carbon atoms and forming a ring with said N atom; ^R9 is Ar or Het; and Het is a heterocyclic group, which is fully saturated, partially saturated or completely unsaturated, has 5-10 ring atoms, wherein at least one ring atom is a N, O or S atom, and the heterocyclic group is unsubstituted or replaced by The following groups are substituted one or more times: halogen, optionally substituted aryl having 6-10 carbon atoms, alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, Cyano, trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1-8 carbon atoms, dialkylamino wherein each alkyl group has 1-8 carbon atoms, _SO2R ^11. -CXR ¹¹ or a combination thereof. 8. The compound according to claim 7, wherein at least one of R ¹ , R ³ , R ⁴ and R ⁵ is an alkynyl group having 2-6 carbon atoms, a fluorinated hydroxyalkyl group having 1-4 carbon atoms or Ar-alkynyl. 9. The compound according to claim 1, wherein said compound is a compound of formula I, A is a group of formula (a) or (c), X is O, ^R is H or an alkyl group, and R and ^{R 4} are each F, Cl, CN, NO ₂ , NH ₂ , fluorinated alkyl, alkoxy, fluorinated alkoxy, fluorinated hydroxyalkyl, alkynyl, cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl or Het. 10. The compound according to claim 9, wherein R ¹ and R ⁴ are each selected from F, Cl, CN, NO ₂ , NH ₂ , CF ₃ , OCH ₃ , OC ₂ H ₅ , OCF ₃ , 2,2,2- Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl, ethynyl, propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl, phenylethynyl , dihydropyranyl, thiazolyl, oxazolyl, pyrrolidinyl, piperidinyl or morpholinyl. 11. The compound according to claim 9, wherein A is a group of formula (c), and ^R4 is CN, alkoxy, fluorinated alkoxy and cycloalkylalkoxy. 12. The compound according to claim 1, wherein said compound is a compound of formula Ia or Ij, R ² is H or alkyl, and R ¹ and R ⁴ are each F, Cl, CN, NO ₂ , NH ₂ , fluorine fluorinated alkyl, alkoxy, fluorinated alkoxy, fluorinated hydroxyalkyl, alkynyl, cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl or Het. 13. The compound according to claim 1 , wherein at least one of R ¹ , R ³ or R ⁴ is COH, NR ⁶ R ⁷ or NR ² COOR ⁸ wherein at least one of R ⁶ and R ⁷ is not an alkyl group. 14. The compound according to claim 1, wherein at least one of R ¹ , R ³ or R ⁴ is selected from the following formulae:

15. The compound according to claim 1, wherein said compound has 2 or 3 substituents ^R1 , ^R3 or ^R4 . 16. The compound according to claim 1, wherein ^R2 is a fluorinated alkyl group having 1-4 carbon atoms. 17. The compound according to claim 1, wherein at least one of ^R6 and ^R7 is an alkoxyalkyl group having 2-8 carbon atoms. 18. The compound according to claim 1, wherein said compound has at least one ^R9 group which is Ar-alkyl, wherein said alkyl moiety has 1-4 carbon atoms. 19. The compound according to claim 1, wherein said compound has at least one Het that is a heterocyclic group that is fully saturated, partially saturated or fully unsaturated with 5-10 ring atoms, wherein at least One ring atom is a N, O or S atom, and the heterocyclic group is substituted with at least one substituent selected from OH, alkoxycarbonylalkyl having 3-8 carbon atoms, and piperidinylethyl. 20. The compound according to claim 1, wherein said compound is a compound of formula I, and A is a group of subformula (a) attached via its 3, 4 or 7 position to the rest of said compound. 21. The compound according to claim 1, wherein said compound is a compound of formula I, and A is a group of subformula (b) attached via its 4 or 7 position to the rest of said compound. 22. The compound according to claim 1, wherein said compound is a compound of formula I, and A is a group of subformula (c) attached via its 3, 4 or 7 position to the rest of said compound. 23. The compound according to claim 1, wherein said compound is a compound of formula I, and A is a group of subformula (d) attached via its 3, 4 or 7 position to the rest of said compound. 24. The compound according to claim 1, wherein said compound is a compound of formula II and A is a group of subformula (a) attached via its 3, 4 or 7 position to the rest of said compound. 25. The compound according to claim 1, wherein said compound is a compound of formula II and A is a group of subformula (b) attached via its 4 or 7 position to the rest of said compound. 26. The compound according to claim 1, wherein said compound is a compound of formula II and A is a group of subformula (c) attached via its 3, 4 or 7 position to the rest of said compound. 27. The compound according to claim 1, wherein said compound is a compound of formula II and A is a group of subformula (d) attached via its 3, 4 or 7 position to the rest of said compound. 28. The compound according to claim 1, wherein said compound is a compound of formula III and A is a group of subformula (a) attached via its 3, 4 or 7 position to the rest of said compound. 29. The compound according to claim 1, wherein said compound is a compound of formula III, and A is a group of subformula (b) attached via its 4 or 7 position to the rest of said compound. 30. The compound according to claim 1, wherein said compound is a compound of formula III and A is a group of subformula (c) attached via its 3, 4 or 7 position to the rest of said compound. 31. The compound according to claim 1, wherein said compound is a compound of formula III and A is a group of subformula (d) attached via its 3, 4 or 7 position to the rest of said compound. 32. The compound according to claim 1, wherein said compound is a compound of formula IV and A is a group of subformula (a) attached via its 3, 4 or 7 position to the rest of said compound. 33. The compound according to claim 1, wherein said compound is a compound of formula IV and A is a group of subformula (b) attached via its 4 or 7 position to the rest of said compound. 34. The compound according to claim 1, wherein said compound is a compound of formula IV and A is a group of subformula (c) attached via its 3, 4 or 7 position to the rest of said compound. 35. The compound according to claim 1, wherein said compound is a compound of formula IV and A is a group of subformula (d) attached via its 3, 4 or 7 position to the rest of said compound. 36. The compound according to claim 1, wherein X is O. 37. Compounds according to claim 1, wherein alkyl is in each case methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl. 38. Compounds according to claim 1, wherein alkoxy is in each case methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and sec-butoxy. 39. Compounds according to claim 1, wherein cycloalkyl is in each case cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 40. The compound according to claim 1, wherein Ar is in each case phenyl, naphthyl or biphenyl, which is unsubstituted or substituted one or more times by: halogen, alkyl, hydroxy, alkane Oxygen, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxyl, cyano, acyl, alkoxycarbonyl, alkane Thio, alkylsulfinyl, alkylsulfonyl, phenoxy or acyloxy. 41. The compound according to claim 1, wherein Het is in each case dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, morphine Linyl, isoxazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolyl or naphthyridinyl, which in each case is unsubstituted or substituted in one or more positions by: halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro , oxo, amino, alkylamino or dialkylamino. 42. The compound according to claim 1, wherein Het is in each case 2-furyl, 3-furyl, 2-quinolyl, 1,3-benzodioxanyl, 2-thienyl, 3 -Thienyl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 2-benzo Furyl, 2-benzothienyl, 3-thienyl, 2,3-dihydro-5-benzofuryl, 4-indolyl, 4-pyridyl, 3-quinolyl, 4-quinoline Base, 1,4-benzodioxan-6-yl, 3-indolyl, 2-pyrrolyl, tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran -4-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumaryl, 5-benzofuryl, 2-isoimidazol-4-yl, 3- Pyrazolyl or 3-carbazolyl, which is in each case unsubstituted or substituted in one or more positions by: halogen, aryl, alkyl, alkoxy, cyano, trifluoro Methyl, nitro, oxo, amino, alkylamino or dialkylamino. 43. The compound according to claim 1, wherein said compound is selected from the group consisting of: 3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic acid formate, 3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxylic acid, 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt, N[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamide salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide , N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide , N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2-2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide hydrochloride, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydrochloride Salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amides, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide formic acid Salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide formic acid Salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide trifluoroacetate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide hydrochloride, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide trifluoroacetate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H)indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide , N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H)indazole-3-carboxamide hydrochloride, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydrochloride Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-methyl amides, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl Base] -1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide, and their physiologically acceptable salts. 44. The compound according to claim 1, wherein said compound is selected from the group consisting of: N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-methyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-cyclopentyl-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3 - Formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3 - Formamide, N-[(3S-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(hydroxyl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(hydroxyl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(hydroxyl)-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide , N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide , N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole- 3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole -3-Carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole-3-carboxamide, N-[(3S)- 1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1 indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy.4-(2-thienyl)-1H-indazole-3-carboxamide salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(propyl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3- formamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3- formamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(ethyl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - Formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(methyl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide salt, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indazole- 3-formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carboxamide, 5-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide, 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide, 4-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide, 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide, 6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide, 7-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylmethyl)amino]-1H-indazole-3-carboxamide formate , N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-[(methylsulfonyl)amino]-1H-indazole-3 carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl]amino}carbonyl) Amino]-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1,2-benzene and isothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-fluorophenyl)ethyl]amino}carbonyl)amino]- 1,2-Benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino]carbonyl}amino)-1, 2-Benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbonyl}amino)-1, 2-Benzisothiazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}amino)-1,2-benzene and isothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]amino}carbonyl)amino] -1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino}carbonyl)amino ]-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino}-1,2-benzisothiazole-3 - Formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3- Formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)nitro]carbonyl}amino)-1H-indazole- 3-formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-("(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole- 3-formamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole -3-Carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - Formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3- formamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-3 - carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-indazole-3 - carboxamide dicarboxylate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1H-1,2,3 -triazol-4-yl]-1H-indazole-3-carboxamide dicarboxylate, [4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)-1H-], 2,3 -Triazol-1-yl] ethyl acetate formate, Benzyl (3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)-carbamate, (3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)-carbamic acid vinyl ester, and their physiologically acceptable salts. 45. The compound according to claim 1, wherein said compound is selected from the group consisting of: N-[(3-1-azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indazole-3-carboxamide, N-[(3R))-1-azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1H-indazole-3-carboxamide formate, N-[(3-1-azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-carboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1H-indazol-3- formamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - formamide hydrochloride, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(methoxy)pyrrolidin-1-yl]-1H-indazol-3- formamide formate, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)oxy]-1H-indazole-3 - carboxamide dicarboxylate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - formamide hydrochloride, N-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide formate, N-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentyloxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(benzyloxy)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole-3- formamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-yloxy)-1H-indazole -3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazole-3-carboxamide diformate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-indazole-3-carboxamide diformate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(ethyl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-(ethyl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3 - Formamide, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazole-3-carboxamide dicarboxylic acid Salt, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-indazole-3-carboxamide dicarboxylic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxamide di formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)oxy]-1H-indazole-3 - carboxamide dicarboxylate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy-1H-indazole-3-carboxamide formic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazole-3-carboxamide formate, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-5-trifluoromethoxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3 - formamide hydrochloride, H-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate, H-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-cyclopropylmethyl-5-(1,3-thiazol-2-yl)-1H-ind Azole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3-thiazole-2 -yl)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-thiazol-2-yl)-1H-indazole-3 - carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-1,2-benzene Isothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-1,2-benzene Isothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole- 3-formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole- 3-formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-benzisothiazole- 3-formamide, 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide, 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-(2,2,2-trifluoroethyl)-1H-indazole-3-methanol amides, 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide, 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide, 6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carboxamide, Dimethyl 4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)amino]butanoate salt, Dimethyl 4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6-yl)amino]butanoate salt, {2-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,2-benzisothiazol-6-yl)amino]ethyl tert-butyl propyl carbamate formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)amino]-1H-indazole-3 - carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-methoxyethyl)amino ]-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amino}-1, 2-Benzisothiazole-3-carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-benzisothiazole-3-methyl amide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisothiazole-3-carboxamide formate , N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole-3-carboxamide formate , N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-(cyclopropylmethyl)-1H-ind azole-3-carboxamide, 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indazole-3-carboxamidedicarboxylic acid Salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cyclopropylcarbonyl)amino]-1H-indazole -3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5-{[(4-methoxy phenyl)acetyl]amino}-1H-indazole-3-carboxamide formate, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1,2-benzisothiazole-3-carboxamide formate, 6-(Acetamido)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide formate, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]amino}-1,2-benzisothiazole- 3-Carboxamide formate, 5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H-indazole-3-carboxamide dicarboxylate , N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(propylamino)carbonyl]amino}-1H -indazole-3-carboxamide, N(3)-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzyl)-5-({[(3 -methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide, N(3)-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[(4-fluoro Benzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide, N(3)-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentylamino)carbonyl]amino }-1H-indazole-1,3-dicarboxamide formate, N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carbonyl]amino}- 1H-indazole-1,3-dicarboxamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]thiocarbonyl}amino)-1H-indazole- 3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]thiocarbonyl}amino)-1,2-benzene Isothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)thiocarbonyl]amino}-1,2-benzisothiazole -3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)thiocarbonyl]amino}-1,2-benzisothiazole- 3-Carboxamide formate, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbonyl]amino}-1H-indazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(propylamino)carbonyl]amino}-1H -Indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propylamino)carbonyl ]amino}-1H-indazole-3-carboxamide formate, N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]amino}-1H-indazole -3-Carboxamide formate, {3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl}carbamate isopropyl formate, {3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(isopropylamino)carbonyl]-1H-indazol-5-yl } isopropyl carbamate formate, N-[(3S)-1-oxo-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide hydrobromide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]amino}-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3 - carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazole-3-carboxamide salt, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin-1-yl)-1H-indazole- 3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2-benzisothiazole -3-Carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2- Benzisothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzene Isothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzene and isothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2- Benzisothiazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-1,2-benzene and isothiazole-3-carboxamide, 6-[acetyl(methyl)amino]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzisothiazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H- Indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethyl-1H-indazole-3-methyl amides, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cyclopropylmethyl-1H-indazole- 3-formamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2,2-trifluoroethyl )-1H-indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thiazol-2-yl) -1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazol-2-yl)-1H -Indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiazol-2-yl)-1H -Indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-(cyclopropylmethyl Base)-1H-indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-yl]-1-ethyl-1H- Indazole-3-carboxamide formate, 3-[3-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-thiazol-2-yl)-1H-indazole -1-yl]pyrrolidine-1-carboxylic acid tert-butyl formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-yl)-1H- Indazole-3-carboxamide, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thienylmethyl)- 1H-Indazole-3-carboxamide formate, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazol-2-yl) -1H-indazole-3-carboxamide formate, and their physiologically acceptable salts. 46. A pharmaceutical composition comprising a compound according to any one of claims 1-45 and a pharmaceutically acceptable carrier. 47. A method of selectively activating/stimulating alpha-7 nicotinic receptors in a patient, wherein such activation/stimulation has a therapeutic effect, said method comprising administering to a patient in need thereof an effective amount of the α-7 nicotinic receptor according to claims 1-45. any compound. 48. A method of treating a patient suffering from psychosis, a neurodegenerative disease associated with dysfunction of the cholinergic system and/or memory and/or cognitive impairment disorders, comprising administering to said patient an effective amount of any of claims 1-45 any compound. 49. The method according to claim 48, wherein said patient suffers from schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease Haimer's disease, Lewy body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficits, attention deficits, and/or attention deficit disorder 50. A method of treating a patient suffering from dementia and/or other conditions with memory loss comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 51. Method of treating a patient suffering from memory impairment caused by: mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Gram - Ya disease, depression, aging, head trauma, stroke, central nervous system hypoxia, brain aging, multi-infarct dementia, HIV and/or cardiovascular disease, which includes administering to said patient an effective amount of the claim The compound of any one of 1-45. 52. A method for treating and/or preventing dementia in an Alzheimer's patient, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1-45 to inhibit amyloid beta peptide and nACh receptors combination. 53. A method of treating alcohol withdrawal in a patient or treating a patient with anti-intoxication therapy comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 54. A method of treating a patient to provide neuroprotection against stroke and ischemia-related injury and glutamate-induced excitotoxicity, comprising administering to said patient an effective amount of a compound according to any one of claims 1-45 . 55. A method of treating a patient suffering from nicotine addiction, pain, jet lag, obesity and/or diabetes comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 56. A method of inducing smoking cessation in a patient comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 57. Treatment of patients with mild cognitive impairment (MCI), vascular dementia (VaD), age-related cognitive decline (AACD), amnesia associated with open heart surgery, cardiac arrest, general anesthesia, exposure to anesthetics memory deficits, cognitive impairment due to sleep deprivation, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive impairment, Down syndrome, alcoholism-related dementia, drug/substance-induced memory impairment, A method for a patient with dementia pugilistica (boxer syndrome) or animal dementia, comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 58. A method of treating memory loss comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-45. 59. A method of treating a patient suffering from memory impairment comprising administering to said patient a compound according to any one of claims 1-45. 60. The method according to claim 59, wherein said memory impairment is caused by decreased activity of nicotinic acetylcholine receptors. 61. A method of treating or preventing a disease or condition in a patient caused by a dysfunction of nicotinic acetylcholine receptor transmission comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 62. A method of treating or preventing a disease or condition caused by nicotinic acetylcholine receptor deficiency or dysfunction in a patient comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 63. A method of treating or preventing a disease or condition in a patient caused by inhibition of nicotinic acetylcholine receptor transmission comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 64. A method of treating or preventing a disease or condition caused by loss of cholinergic synapses in a patient comprising administering to said patient an effective amount of a compound according to any one of claims 3 1-45. 65. A method of protecting neurons in a patient from neurotoxicity caused by activation of a7nACh receptors, comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 66. A method of treating or preventing a neurodegenerative disorder by inhibiting the binding of A[beta] peptides to [alpha]7nACh receptors in a patient, comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 67. A method of treating a patient suffering from an inflammatory disease comprising administering to said patient an effective amount of a compound according to any one of claims 1-45. 68. The method according to claim 67, wherein said inflammatory disease is rheumatoid arthritis, diabetes or sepsis. 69. The method according to any one of claims 47-68, wherein said patient is a human.