KR20080048550A - Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazoloryridines, and preparation and uses thereof - Google Patents

Abstract

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the E7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

Description

Indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolopyridine, isothiazolopyridine, and their preparation and use

This application is directed to U.S. Provisional Application No. 60 / 791,881 filed Apr. 14, 2006 and U.S. Provisional Application No. 60 / 719,552, Sept. 23, 2005, the entire disclosures of which are incorporated herein by reference. Claim).

This application also discloses US patent application Ser. No. 11 / 089,533 filed March 25, 2005 (US Provisional Application No. 60 / 555,951 filed March 25, 2004) and US Provisional Application No. 60 / 616,033 (10 October 2004). Claiming the benefit of the 6/6/6) and U.S. Patent Application No. 10 / 669,645 filed Sep. 25, 2003 (US Provisional Application No. 60 / 413,151 filed September 25,2002) and U.S. Provisional Application No. 60 / 448,469, filed February 21, 2003), each of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION The present invention generally relates to the field of treatment of a disease condition associated with a ligand for nicotinic acetylcholine receptor (nAChR), activation of nAChR, and a deficiency or dysfunction of nicotinic acetylcholine receptors, especially nicotinic acetylcholine receptors in the brain. will be. The present invention also relates to novel compounds that act as ligands for the α7 nAChR subtype, methods of making such compounds, compositions comprising such compounds, and methods of using them.

There are two types of receptors for the neurotransmitter acetylcholine, based on selectivity for muscarinic and nicotine action, respectively. Muscarinic receptors are G-protein coupled receptors. Nicotinic receptors are members of the ligand-gated ion channel class. Upon activation, ionic conductivity through nicotinic ion channels increases.

Nicotinic α-7 receptor proteins form highly permeable homotrimeric channels for various cations (eg Ca ⁺⁺ ) in vitro. The nicotinic α-7 receptor has four transmembrane domains called M1, M2, M3 and M4, respectively. The M2 domain has been proposed to form walls in which the channels line up. Sequence alignment shows that nicotinic α-7 is highly conserved during evolution. The M2 domains that line the channels have the same protein sequence from chicken to human. A discussion of the α-7 receptor is described, for example, in 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.

Nicotinic α-7 receptor channels are expressed in various brain regions and are believed to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Nicotinic α-7 receptors are located at the ends before and after synapses and have been suggested to be involved in regulating synaptic transmission. Accordingly, there is interest in the development of novel compounds that act as ligands for the α7nACh receptor subtype for the treatment of disease symptoms associated with deficiency or dysfunction of nicotinic acetylcholine receptors.

Summary of the Invention

The present invention relates to novel compounds that act as ligands for the α7 nACh receptor subtype, methods of making such compounds, compositions comprising such compounds, and methods of using them.

The present invention provides solvates of the compounds of formulas (I), (II), (III) or (IV) below, and their pharmaceutically acceptable salts or solvates (e.g. Or pharmaceutically acceptable salts or solvates of these N-oxides.

Where

A is

이고;

ego;

X is O or S;

X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, where C— represents the point where the A group is attached to the rest of the structure of formula (I), (II), (III) or (IV) (eg, X ¹ , X ² , X ³ and X ⁴ are each CH or CR ¹ , and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹ , X ² And X ³ Are each CH or CR ¹ , X ⁴ is N, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹ , X ² and X ⁴ are each CH or CR ¹ , X ³ is N, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹ , X ³ and X ⁴ are each CH or CR ¹ , and X ² is N and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV);

X ⁵ to X ⁸ are each independently N, CH, CR ³ or C-, wherein C- represents the point where the A group is attached to the rest of the structure of formula (I), (II), (III) or (IV) (eg, X ⁵ , X ⁶ and X ⁸ are each CH or CR ³ and X ⁷ is C-, wherein the A group is attached at the 5-position to the remainder of the structure of Formula I, II, III or IV, or X ⁵ , X ⁷ and X ⁸ are each CH or CR ³ and X ⁶ is C—, wherein the A group is attached at the 6-position to the rest of the structure of formula (I), (II), (III) or (IV);

X ⁹ And X ¹² are each independently N, CH, CR ⁴ or C-, wherein C- represents the point at which the A group is attached to the remainder of the structure of formula (I), (II), (III) or (IV) (eg, X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is CH or CR ⁴ , respectively, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ⁹ , X ¹⁰ and X ¹¹ are each CH or CR ⁴ , and X is ¹² is N, the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), X ⁹ , X ¹⁰ and X ¹² are each CH or CR ⁴ , X ¹¹ is N, The A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ⁹ , X ¹¹ and X ¹² are each CH or CR ⁴ , X ¹⁰ is N and the A group is Attached at the 3-position to the rest of the structure of II, III or IV);

X ¹³ to X ¹⁶ are each independently N, CH, CR or C—, where C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV) (eg, X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ are each CH or CR, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹³ , X ¹⁴ and X ¹⁵ are each CH or CR, X ¹⁶ is N, the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹³ , X ¹⁴ and X ¹⁶ are each CH or CR, X ¹⁵ is N, The A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹³ , X ¹⁵ and X ¹⁶ are each CH or CR, X ¹⁴ is N, and the A group is of formula (I) Attached in the 3-position to the rest of the structure of II, III or IV);

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

R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e. g., CF _3), Alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated alkyl, alkenyl or alkyn) The niyl group in each case is unsubstituted or substituted by Ar or Het; for example phenylacetylene C ₆ H ₅ -C = C -), cycloalkenyl having a cycloalkyl of 5 to 8 carbon atoms having from 3 to 7 carbon atoms (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6-alkoxy,} NR ⁶ R ^{7, CO-NR 6 R 7} , C 2 -6 - alkoxycarbonyl or substituted by -CO-R ^10), cycloalkyl having cycloalkylalkyl, 6 to 9 carbon atoms having 4 to 7 carbon atoms Alkenylalkyl, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclo Propylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), 1 to Hydroxyalkyl having 4 carbon atoms, fluorinated hydroxide having 1 to 4 carbon atoms Cyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to 4 carbons Fluorinated hydroxyalkoxy having atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, and 2 to 6 carbon atoms alkoxycarbonyl, Ar, Het, OAr, OHet , carbonate -O, Ar-C _{1 -6} having -alkyl -O-, Het-C _{1 -6-alkyl,} -O-, Het-CO-Het-, Het -C _{1 -6} - alkyl -Het-O-, - alkyl, -NR ² - or Ar-C _{1 -6}

Provided that R is not NH ₂ ; or

(여기서, n은 2 내지 4이고; m은 3 내지 5임) 중 하나의 기이거나; 또는R is of the formula

Wherein n is 2 to 4; m is 3 to 5; or

Two R's together may form a fused five-membered ring structure containing one or more N atoms;

R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, a fluorinated alkyl (e.g., having from 1 to 4 carbon atoms CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het; for example phenyla Ethylene _{C 6 H 5 -C = C-)} , 3 cycloalkenyl to the cycloalkyl having 5 to 8 carbon atoms having 7 carbon atoms (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6-alkoxy,} NR ⁶ R ^7, CO-NR ⁶ R ^7, C ₂ - ₆ - alkoxycarbonyl or substituted by -CO-R ^10), 4 to a cycloalkyl alkyl having 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, having 4 to 7 carbon atoms Cycloalkylalkoxy (eg, cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg, OCF ₃ , OCHF ₂ ), hydroxyalkyl having 1 to 4 carbon atoms, flu having 1 to 4 carbon atoms Orated hydroxyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to Fluorinated hydroxyalkoxy having 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, 2 to 6 carbon atoms alkoxycarbonyl having a carbon atoms, Ar, Het, OAr, OHet , carbonate -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-O-, or -Het; or

중 하나의 기이거나; 또는R ¹ is a chemical formula

One of the groups; or

Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms;

R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4 - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO- (e.g., (a [2.2, l-azabicyclo .2] oct-3-yl) -NH-CO-);

R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, a fluorinated alkyl (e.g., having from 1 to 4 carbon atoms CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het; for example phenyla Ethylene _{C 6 H 5 -C = C-)} , 3 to cycloalkenyl (wherein the cycloalkenyl having a cycloalkyl of 5 to 8 carbon atoms having a 7 carbon atom is unsubstituted or HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl or substituted by -CO-R ^10), 4 to a cycloalkyl alkyl having 7 carbon atoms , Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 carbon atoms Cycloalkylalkoxy having (eg cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg , OCF _3, OCHF _2), having a flat hydroxyalkyl, from 1 to 4 carbon atoms having 1 to 4 carbon atoms Orated hydroxyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to Fluorinated hydroxyalkoxy having 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, 2 to 6 carbon atoms alkoxycarbonyl having a carbon atoms, Ar, Het, OAr, OHet , carbonate -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-O-, or -Het; or

중 하나의 기이거나; 또는R ³ is a chemical formula

One of the groups; or

Two R ³ together may form a fused five-membered ring structure containing one or more N atoms;

R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, a fluorinated alkyl (e.g., having from 1 to 4 carbon atoms CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het; for example phenyla Ethylene _{C 6 H 5 -C = C-)} , 3 cycloalkenyl to the cycloalkyl having 5 to 8 carbon atoms having 7 carbon atoms (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6-alkoxy,} NR ⁶ R ^7, CO-NR ⁶ R ^7, C ₂ - ₆ - alkoxycarbonyl or substituted by -CO-R ^10), 4 to a cycloalkyl alkyl having 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, having 4 to 7 carbon atoms Cycloalkylalkoxy (eg, cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg, OCF ₃ , OCHF ₂ ), hydroxyalkyl having 1 to 4 carbon atoms, flu having 1 to 4 carbon atoms Orated hydroxyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to Fluorinated hydroxyalkoxy having 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, 2 to 6 carbon atoms alkoxycarbonyl having a carbon atoms, Ar, Het, OAr, OHet , carbonate -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-O-, or -Het; or

중 하나의 기이거나; 또는R ⁴ is a chemical formula

One of the groups; or

Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms;

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 , alkyl with 1 to 4 carbon atoms, 1 to 4 Fluorinated alkyl having 2 carbon atoms (eg CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg ethynyl, propynyl, Pentenyl) wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl group in each occurrence is unsubstituted or substituted by Ar or Het; for example phenylacetylene C ₆ H ₅ -C = C- ), Cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, 1 to 4 Alkoxy having carbon atoms (e.g., OCH _3), 3 to 7 cycloalkyl alkoxy having cycloalkoxy, 4 to 7 carbon atoms, having a carbon atom (e.g., cyclopropylmethoxy), 1 to Alkylthio having 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxide having 1 to 4 carbon atoms Hydroxyalkyl, fluorinated hydroxyalkyl having 1 to 4 carbon atoms (eg, 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), 2 to Hydroxyalkoxy having 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups are each independently 1 to Having 4 carbon atoms), 2 to 6 carbons Having from alkoxycarbonyl, Ar, Het, OAr, or OHet gt;

R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Is cycloalkylalkyl or R ⁶ and R ⁷ are alkylene groups containing 4 to 6 carbon atoms together and forming a ring together with N atoms (eg, piperidinyl, pyrrolidinyl);

R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (eg CF ₃ ), alkenyl having 3 to 6 carbon atoms, 3 to 6 Alkynyl (eg, propynyl, pentenyl) having 3 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Phenylacetylene C ₆ H ₅ -C = C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkyl having 4 to 7 carbon atoms, for example Alkyl, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, having 1 to 4 carbon atoms Monoalkylamino, dialkylamino, wherein Skill groups each independently of 1 to 4 having a carbon atom), and Ar or Het;

R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het;

R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (eg CF ₃ ), alkenyl having 3 to 6 carbon atoms, 3 to 6 carbons Alkynyl having an atom (eg, propynyl, pentenyl), wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group is in each case unsubstituted or substituted by Ar or Het; Phenylacetylene C ₆ H ₅ -C = C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms, monoalkyl having 1 to 4 carbon atoms Amino, dialkylamino (wherein Each kill group independently has 1 to 4 carbon atoms), NR ⁶ R ⁷ , NR ² R ⁸ , Ar, or Het;

Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen (F, Cl, Br or I, preferably Preferably F or Cl), dialkylamino, wherein the alkyl moiety has 1 to 8 carbon atoms each, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, 1 Halogenated alkoxy having from 8 to 8 carbon atoms, hydroxyalkyl having from 1 to 8 carbon atoms, hydroxyalkoxy having from 2 to 8 carbon atoms, alkenyloxy having from 3 to 8 carbon atoms, 1 to 8 Alkylthio having 1 carbon atom, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino (where city Chloalkyl groups have 3 to 7 carbon atoms and are optionally substituted, aryloxy (where the aryl moiety has 6 to 10 carbon atoms (eg, phenyl, naphthyl, biphenyl), optionally substituted ), Arylthio (where the aryl moiety has 6 to 10 carbon atoms (eg, phenyl, naphthyl, biphenyl), optionally substituted), cycloalkyloxy (where the cycloalkyl group is 3 to 7 carbon atoms) One or more times by carbon atoms, optionally substituted), sulfo, sulfonylamino, acylamido (eg acetamido), acyloxy (eg acetoxy) or combinations thereof ;

Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are N, O or S atoms, which is unsubstituted or halogen ( F, Cl, Br or I, preferably F or Cl), optionally substituted aryl having 6 to 10 carbon atoms (eg phenyl, naphthyl, biphenyl), having 1 to 8 carbon atoms Alkyl, alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms (eg cyclopropylmethyl), 1 to 8 carbon atoms Halogenated alkoxy (eg OCHF ₂ ) with cycloalkyl, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), 2 to 8 Carbons Alkoxyalkyl having an atom (eg CH ₃ OCH ₂ ), Alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms; for example methyl (trifluoromethyl) amino , Di (halogenated alkyl) amino (where the alkyl groups each have 1 to 8 carbon atoms), (halogenated alkyl) amino having 1 to 8 carbon atoms, cyano, having 1 to 8 carbon atoms Halogenated alkyl (eg fluorinated alkyl such as trifluoromethyl, trifluoroethyl), nitro, oxo, OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino, 1 to 8 Monoalkylamino having a carbon atom, dialkylamino, wherein the alkyl group has 1 to 8 carbon atoms each, at least one substitution by SO ₂ R ¹¹ , -CXR ¹¹ , piperidinylethyl or a combination thereof Become;

Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof (eg, indanyl, tetrahydronaphthenyl, etc.);

R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms (eg CF ₃ ), alkenyl having 3 to 6 carbon atoms, 3 to 6 carbon atoms Alkynyl (eg, propynyl, pentenyl), wherein the alkyl, halogenated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted by Ar or Het; for example Phenylacetylene C ₆ H ₅ -C = C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, 6 to Cycloalkenylalkyl having 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, Dialkylamino (where an alkyl group Each independently has 1 to 4 carbon atoms) or Ar.

According to another compound and / or method aspect of the invention, the compound is a compound according to formula (I), (II), (III) or (IV) below, and a pharmaceutically acceptable salt or solvate (eg hydrate) or N-jade thereof Seeds, or solvates of pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts or solvates of N-oxides thereof.

<Formula I>

<Formula II>

<Formula III>

<Formula IV>

Where

A is

이고;

ego;

X is O or S;

X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, where C— represents the point where the A group is attached to the rest of the structure of formula (I), (II), (III) or (IV) (eg, X ¹ , X ² , X ³ and X ⁴ are each CH or CR ¹ , and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹ , X ² and X ³ Are each CH or CR ¹ , X ⁴ is N, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹ , X ² and X ⁴ are each CH or CR ¹ , X ³ is N, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹ , X ³ and X ⁴ are each CH or CR ¹ , and X ² is N and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV);

X ⁵ to X ⁸ are each independently N, CH, CR ³ or C-, wherein C- represents the point where the A group is attached to the rest of the structure of formula (I), (II), (III) or (IV) (eg, X ⁵ , X ⁶ and X ⁸ are each CH or CR ³ and X ⁷ is C-, wherein the A group is attached at the 5-position to the remainder of the structure of Formula I, II, III or IV, or X ⁵ , X ⁷ and X ⁸ are each CH or CR ³ and X ⁶ is C—, wherein the A group is attached at the 6-position to the rest of the structure of formula (I), (II), (III) or (IV);

X ⁹ to X ¹² are each independently N, CH, CR ⁴ or C—, where C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV) (eg, X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is CH or CR ⁴ , respectively, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ⁹ , X ¹⁰ and X ¹¹ are each CH or CR ⁴ , and X is ¹² is N, the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), X ⁹ , X ¹⁰ and X ¹² are each CH or CR ⁴ , X ¹¹ is N, The A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ⁹ , X ¹¹ and X ¹² are each CH or CR ⁴ , X ¹⁰ is N and the A group is Attached at the 3-position to the rest of the structure of II, III or IV);

X ¹³ to X ¹⁶ are each independently N, CH, CR or C—, where C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV) (eg, X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ are each CH or CR, and the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹³ , X ¹⁴ and X ¹⁵ are each CH or CR, X ¹⁶ is N, the A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹³ , X ¹⁴ and X ¹⁶ are each CH or CR, X ¹⁵ is N, The A group is attached at the 3-position to the rest of the structure of formula (I), (II), (III) or (IV), or X ¹³ , X ¹⁵ and X ¹⁶ are each CH or CR, X ¹⁴ is N, and the A group is of formula (I) Attached in the 3-position to the rest of the structure of II, III or IV);

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

R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e. g., CF _3), Alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated alkyl, alkenyl or alkyn) The niyl group in each case is unsubstituted or substituted by Ar or Het; for example phenylacetylene C ₆ H ₅ -C = C -), cycloalkenyl having a cycloalkyl of 5 to 8 carbon atoms having from 3 to 7 carbon atoms (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6-alkoxy,} NR ⁶ R ^{7, CO-NR 6 R 7} , C 2 -6 - alkoxycarbonyl or substituted by -CO-R ^10), cycloalkyl having cycloalkylalkyl, 6 to 9 carbon atoms having 4 to 7 carbon atoms Alkenylalkyl, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclo Propylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), 1 to Hydroxyalkyl having 4 carbon atoms, fluorinated hydroxide having 1 to 4 carbon atoms Cyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to 4 carbons Fluorinated hydroxyalkoxy having atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, and 2 to 6 carbon atoms alkoxycarbonyl, Ar, Het, OAr, OHet , carbonate -O, Ar-C _{1 -6} having -alkyl -O-, Het-C _{1 -6-alkyl,} -O-, Het-CO-Het-, Het -C _{1 -6} - alkyl -Het-O-, - alkyl, -NR ² - or Ar-C _{1 -6}

Provided that R is not NH ₂ ; or

(여기서, n은 2 내지 4이고; m은 3 내지 5임) 중 하나의 기이거나; 또는R is of the formula

Wherein n is 2 to 4; m is 3 to 5; or

Two R's together may form a fused five-membered ring structure containing one or more N atoms;

R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, a fluorinated alkyl (e.g., having from 1 to 4 carbon atoms CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het; for example phenyla Ethylene _{C 6 H 5 -C = C-)} , 3 cycloalkenyl to the cycloalkyl having 5 to 8 carbon atoms having 7 carbon atoms (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6-alkoxy,} NR ⁶ R ^7, CO-NR ⁶ R ^7, C ₂ - ₆ - alkoxycarbonyl or substituted by -CO-R ^10), 4 to a cycloalkyl alkyl having 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, having 4 to 7 carbon atoms Cycloalkylalkoxy (eg, cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg, OCF ₃ , OCHF ₂ ), hydroxyalkyl having 1 to 4 carbon atoms, flu having 1 to 4 carbon atoms Orated hydroxyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to Fluorinated hydroxyalkoxy having 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, 2 to 6 carbon atoms alkoxycarbonyl having a carbon atoms, Ar, Het, OAr, OHet , carbonate -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-O-, or -Het; or

중 하나의 기이거나; 또는R ¹ is a chemical formula

One of the groups; or

Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms;

R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4 - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO- (e.g., (a [2.2, l-azabicyclo .2] oct-3-yl) -NH-CO-);

R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, a fluorinated alkyl (e.g., having from 1 to 4 carbon atoms CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het; for example phenyla Ethylene _{C 6 H 5 -C = C-)} , 3 to cycloalkenyl (wherein the cycloalkenyl having a cycloalkyl of 5 to 8 carbon atoms having a 7 carbon atom is unsubstituted or HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl or substituted by -CO-R ^10), 4 to a cycloalkyl alkyl having 7 carbon atoms , Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 carbon atoms Cycloalkylalkoxy having (eg cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg , OCF _3, OCHF _2), having a flat hydroxyalkyl, from 1 to 4 carbon atoms having 1 to 4 carbon atoms Orated hydroxyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to Fluorinated hydroxyalkoxy having 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, 2 to 6 carbon atoms alkoxycarbonyl having a carbon atoms, Ar, Het, OAr, OHet , carbonate -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-O-, or -Het; or

중 하나의 기이거나; 또는R ³ is a chemical formula

One of the groups; or

Two R ³ together may form a fused five-membered ring structure containing one or more N atoms;

R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 alkyl of the carbon atoms, a fluorinated alkyl (e.g., having from 1 to 4 carbon atoms CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg, ethynyl, propynyl, pentenyl) (wherein the alkyl, fluorinated Alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het; for example phenyla Ethylene _{C 6 H 5 -C = C-)} , 3 cycloalkenyl to the cycloalkyl having 5 to 8 carbon atoms having 7 carbon atoms (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6-alkoxy,} NR ⁶ R ^7, CO-NR ⁶ R ^7, C ₂ - ₆ - alkoxycarbonyl or substituted by -CO-R ^10), 4 to a cycloalkyl alkyl having 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, having 4 to 7 carbon atoms Cycloalkylalkoxy (eg, cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg, OCF ₃ , OCHF ₂ ), hydroxyalkyl having 1 to 4 carbon atoms, flu having 1 to 4 carbon atoms Orated hydroxyalkyl (eg 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), hydroxyalkoxy having 2 to 4 carbon atoms, 2 to Fluorinated hydroxyalkoxy having 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino where the alkyl groups each independently have 1 to 4 carbon atoms, 2 to 6 carbon atoms alkoxycarbonyl having a carbon atoms, Ar, Het, OAr, OHet , carbonate -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-O-, or -Het; or

중 하나의 기이거나; 또는R ⁴ is a chemical formula

One of the groups; or

Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms;

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 , alkyl with 1 to 4 carbon atoms, 1 to 4 Fluorinated alkyl having 2 carbon atoms (eg CF ₃ ), alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (eg ethynyl, propynyl, Pentenyl) wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl group in each occurrence is unsubstituted or substituted by Ar or Het; for example phenylacetylene C ₆ H ₅ -C = C- ), Cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, 1 to 4 Alkoxy having carbon atoms (e.g., OCH _3), 3 to 7 cycloalkyl alkoxy having cycloalkoxy, 4 to 7 carbon atoms, having a carbon atom (e.g., cyclopropylmethoxy), 1 to Alkylthio having 4 carbon atoms (eg SCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxide having 1 to 4 carbon atoms Hydroxyalkyl, fluorinated hydroxyalkyl having 1 to 4 carbon atoms (eg, 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl), 2 to Hydroxyalkoxy having 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups are each independently 1 to Having 4 carbon atoms), 2 to 6 carbons Having from alkoxycarbonyl, Ar, Het, OAr, or OHet gt;

R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Is cycloalkylalkyl or R ⁶ and R ⁷ are alkylene groups containing 4 to 6 carbon atoms together and forming a ring together with N atoms (eg, piperidinyl, pyrrolidinyl);

R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (eg CF ₃ ), alkenyl having 3 to 6 carbon atoms, 3 to 6 Alkynyl (eg, propynyl, pentenyl) having 3 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Phenylacetylene C ₆ H ₅ -C = C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkyl having 4 to 7 carbon atoms, for example Alkyl, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, having 1 to 4 carbon atoms Monoalkylamino, dialkylamino, wherein Skill groups each independently of 1 to 4 having a carbon atom), and Ar or Het;

R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het;

R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (eg CF ₃ ), alkenyl having 3 to 6 carbon atoms, 3 to 6 carbons Alkynyl having an atom (eg, propynyl, pentenyl), wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group is in each case unsubstituted or substituted by Ar or Het; Phenylacetylene C ₆ H ₅ -C = C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon atoms, monoalkyl having 1 to 4 carbon atoms Amino, dialkylamino (wherein Each kill group independently has 1 to 4 carbon atoms), NR ⁶ R ⁷ , NR ² R ⁸ , Ar, or Het;

Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen (F, Cl, Br or I, preferably Preferably F or Cl), dialkylamino, wherein the alkyl moiety has 1 to 8 carbon atoms each, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon atoms, 1 Halogenated alkoxy having from 8 to 8 carbon atoms, hydroxyalkyl having from 1 to 8 carbon atoms, hydroxyalkoxy having from 2 to 8 carbon atoms, alkenyloxy having from 3 to 8 carbon atoms, 1 to 8 Alkylthio having 1 carbon atom, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino (where city Chloalkyl groups have 3 to 7 carbon atoms and are optionally substituted, aryloxy (where the aryl moiety has 6 to 10 carbon atoms (eg, phenyl, naphthyl, biphenyl), optionally substituted ), Arylthio (where the aryl moiety has 6 to 10 carbon atoms (eg, phenyl, naphthyl, biphenyl), optionally substituted), cycloalkyloxy (where the cycloalkyl group is 3 to 7 carbon atoms) One or more times by carbon atoms, optionally substituted), sulfo, sulfonylamino, acylamido (eg acetamido), acyloxy (eg acetoxy) or combinations thereof ;

Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein one or more ring atoms are N, O or S atoms, which is unsubstituted or halogen ( F, Cl, Br or I, preferably F or Cl), optionally substituted aryl having 6 to 10 carbon atoms (eg phenyl, naphthyl, biphenyl), having 1 to 8 carbon atoms Alkyl, alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms (eg cyclopropylmethyl), 1 to 8 carbon atoms Halogenated alkoxy (eg OCHF ₂ ) with cycloalkyl, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), 2 to 8 Carbons Alkoxyalkyl having an atom (eg CH ₃ OCH ₂ ), Alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms; for example methyl (trifluoromethyl) amino , Di (halogenated alkyl) amino (where the alkyl groups each have 1 to 8 carbon atoms), (halogenated alkyl) amino having 1 to 8 carbon atoms, cyano, having 1 to 8 carbon atoms Halogenated alkyl (eg fluorinated alkyl such as trifluoromethyl, trifluoroethyl), nitro, oxo, OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino, 1 to 8 Monoalkylamino having a carbon atom, dialkylamino, wherein the alkyl group has 1 to 8 carbon atoms each, at least one substitution by SO ₂ R ¹¹ , -CXR ¹¹ , piperidinylethyl or a combination thereof Become;

Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof (eg, indanyl, tetrahydronaphthenyl, etc.);

R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms (eg CF ₃ ), alkenyl having 3 to 6 carbon atoms, 3 to 6 carbon atoms Alkynyl (eg, propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl group is in each case unsubstituted or substituted by Ar or Het; Phenylacetylene C ₆ H ₅ -C = C-), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, 6 Cycloalkenylalkyl having from 9 to 9 carbon atoms, hydroxyalkyl having from 2 to 4 carbon atoms, fluorinated hydroxyalkyl having from 2 to 4 carbon atoms, monoalkylamino having from 1 to 4 carbon atoms , Dialkylamino (where alkyl Each group independently has 1 to 4 carbon atoms) or Ar;

의 4급 암모늄 염의 형태이고,Provided that the 1-azabicyclo group is a partial chemical formula

In the form of a quaternary ammonium salt of

Wherein Z is alkyl having 1 to 4 carbon atoms (eg methyl, ethyl, propyl), halogenated alkyl having 1 to 4 carbon atoms (eg chloromethyl, chloroethyl), 4 to 7 Cycloalkylalkyl (e.g. cyclopropylmethyl) with 7 carbon atoms or arylalkyl (e.g. benzyl) with 7 to 16 carbon atoms and anion A is e.g. iodide, bromide, chloride , Triflate, tosylate or mesylate.

According to another compound and / or method aspect of the invention, the compound

In the case where the R ² there H, 1-4 alkyl having a carbon atom, a fluorinated alkyl, cycloalkyl, 4 to 7 carbon atoms having from 3 to 7 carbon atoms having from 1 to 4 carbon atoms cycloalkylalkyl having, fluorinated C _{1 -4} - alkyl, -CO-, C _3-7 - cycloalkyl, -CO-, C _{1 -4} - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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- _{(e.g., CH 2 CH 2 -O-CH} 3) , or Ar-C _{1 -4-alkyl} and -NH-CO-;

Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen; Optionally substituted aryl having 6 to 10 carbon atoms, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, 1 to 8 carbon atoms Halogenated alkoxy having 3,7 cycloalkylalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms ), Di (halogenated alkyl) amino (where the alkyl groups each have 1 to 8 C atoms), (halogenated alkyl) amino having 1 to 8 carbon atoms, cyano, 1 Halogenated alkyl, nitro, oxo, OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino having from 8 to 8 carbon atoms (where The alkyl group is selected from compounds of formula (I) to formula (IV) wherein each alkyl group is substituted one or more times by each having 1 to 8 C atoms), SO ₂ R ¹¹ , -CXR ¹¹ , piperidinylethyl or a combination thereof.

In formulas (I) to (IV), groups A, for example indazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrazolo [3,4-b] pyridinyl, pyrazolo [4,3-c] pyri Dinyl or isothiazolo [5,4-b] pyridinyl groups may be attached to the rest of the structure via any suitable point of attachment.

In formula (I), when A is part of a group of formula (a), for example indazolyl, it is preferably attached to the rest of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is part of a group of formula (b), for example benzothiazolyl, it is preferably attached to the rest of the compound via the 4 or 7 position. If A is a group of the partial formula (c), for example benzoisothiazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is a group of partial formula (d), for example benzisoxazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position.

Likewise, in formula II, when A is a group of the partial formula (a), for example indazolyl, it is preferably attached to the rest of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is a group of the partial formula (b), for example benzothiazolyl, it is preferably attached to the rest of the compound via the 4 or 7 position. If A is a group of the partial formula (c), for example benzoisothiazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is a group of partial formula (d), for example benzisoxazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position.

In addition, in formula (III), when A is a group of the partial formula (a), for example indazolyl, it is preferably attached to the rest of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is part of a group of formula (b), for example benzothiazolyl, it is preferably attached to the rest of the compound via the 4 or 7 position. If A is a group of the partial formula (c), for example benzoisothiazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is a group of partial formula (d), for example benzisoxazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position.

In addition, in formula (IV), when A is a group of the partial formula (a), for example indazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is part of a group of formula (b), for example benzothiazolyl, it is preferably attached to the rest of the compound via the 4 or 7 position. If A is a group of the partial formula (c), for example benzoisothiazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position. If A is a group of partial formula (d), for example benzisoxazolyl, it is preferably attached to the remainder of the compound via the 3, 4 or 7 position, in particular the 3-position.

The partial formulas shown below are A groups such as indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, pyra Some of the preferred attachments between zolo [4,3-c] pyridinyl and isothiazolo [5,4-b] pyridinyl and the rest of the structure to formula (I) are shown. In each partial formula below, the R, R ¹ , R ³ and / or R ⁴ substituents are generally present 1, 2 or 3 times, preferably 1 or 2 times, more preferably once.

The partial formulas below also show A groups such as indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, Some of the preferred attachments between the pyrazolo [4,3-c] pyridinyl and isothiazolo [5,4-b] pyridinyl groups and the rest of the structure to formula (II) are shown. In each partial formula below, the R, R ¹ , R ³ and / or R ⁴ substituents are generally present 1, 2 or 3 times, preferably 1 or 2 times, more preferably once.

The partial formulas below also show A groups such as indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, Some of the preferred attachments between pyrazolo [4,3-c] pyridinyl and isothiazolo [5,4-b] pyridinyl and the rest of the structure for formula (III) are shown. In each partial formula below, the R, R ¹ , R ³ and / or R ⁴ substituents are generally present 1, 2 or 3 times, preferably 1 or 2 times, more preferably once.

The partial formulas below also show A groups such as indazole, benzothiazole, benzoisothiazole, benzisoxazole, pyrazolo [3,4-b] pyridinyl, pyrazolo [3,4-c] pyridine, Some of the preferred attachments between pyrazolo [4,3-c] pyridinyl and isothiazolo [5,4-b] pyridinyl and the rest of the structure to formula (IV) are shown. In each partial formula below, the R, R ¹ , R ³ and / or R ⁴ substituents are generally present 1, 2 or 3 times, preferably 1 or 2 times, more preferably once.

In all cases X is preferably O.

In all cases R 'is preferably H, cyclopropylmethyl or CH ₃ , in particular H.

Alkyl means a straight or branched chain aliphatic hydrocarbon radical having all 1 to 8 carbon atoms, preferably 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 all preferably mean straight or branched chain aliphatic hydrocarbon radicals having 2 to 6 carbon atoms. Suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl and pentenyl.

Alkynyl means all straight or branched aliphatic hydrocarbon radicals, preferably having 2 to 6 carbon atoms. Suitable alkynyl groups include, but are not limited to, ethyne (ethynyl), propyne (propynyl), butyne (butynyl), and the like.

Alkoxy means an alkyl-O- group, wherein the alkyl moiety has 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and sec-butoxy.

Alkoxyalkyl means an alkyl-O-alkyl- group wherein the alkyl moieties each independently have 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. Suitable alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl and methoxyethyl.

Alkylthio means an alkyl-S- group, wherein 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 cyclic, bicyclic or tricyclic saturated hydrocarbon radical 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 where the cycloalkyl moiety is preferably a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms.

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

Cycloalkylalkoxy groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkoxy groups include, but are not limited to, for example, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy and cyclopentylmethyloxy.

Cycloalkyl and cycloalkylalkyl structure is, for example, C _{1 -4} - alkyl, C _{1 -4} - alkoxy, hydroxyl, amino, monoalkylamino and / or dialkylamino having 1 to 4 carbon atoms (wherein , Alkyl groups each having 1 to 4 carbon atoms).

Aryl as part of a substituent group, or its own, or a group or substituent (e. G., Ar, OAr, Ar-C _{1 -6} - alkyl, -O- or Ar-C _{1 -6} - alkyl, -Het-O-), as opposed Unless indicated, they represent aromatic carbocyclic radicals having 6 to 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl and biphenyl. Substituted aryl groups are halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl , Aryl groups described above substituted one or more times with alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy and / or acyloxy (eg, acetoxy).

A heterocyclic group (for example, Het, OHet, Het-C _{1 -6} - alkyl, -O-, Het-CO-Het-, and Het-C _1-6 - Het portion of the alkyl -NR ²⁾ is 1, A saturated, partially saturated and fully unsaturated heterocyclic group having 2 or 3 rings and a total of 5 to 10 ring atoms, wherein one or more ring atoms are N, O or S atoms. Preferably, the heterocyclic group contains 1 to 3 hetero-ring atoms selected from N, O and S. Suitable saturated and partially saturated heterocyclic groups include dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, bisulfate Sazolinyl and the like, but are not limited to these. Suitable heteroaryl groups include furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like. However, it is not limited to these. Other examples of suitable heterocyclic groups include 2-furyl, 3-furyl, 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 3-thienyl, 1,3-thiazolyl-2- 1,3-oxazol-2-yl, pyrrolidin-1-yl, 6-pyrrolidin-1-yl, piperidin-1-yl, 6-piperazin-1-yl, morpholine -4-yl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indolyl, 4-pyridyl, 3-quinolinyl , 4-quinolinyl, 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, 5-benzofuranyl, 2-isoimidazol-4-yl, 3- Pyrazolyl, 3-carbazolyl, hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl, octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl and 1 , 4-diazepan-1-yl.

Heterocyclic groups are also substituted and unsubstituted azabicyclo and oxaazabicyclo groups such as 2,5-diazabicyclo [2.2.1] hept-2-yl, methyl-2,5- Diazabicyclo [2.2.1] hept-2-yl, trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, 2-oxa-5-azabicyclo [2.2 .1] hept-5-yl, 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl, 1,4-diazabicyclo [3.2.2] non-4-yl , 5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl, 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl, 5-cyclo Propyl-2,5-diazabicyclo [2.2.1] hept-2-yl and 5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl do.

Substituted heterocyclic groups are described above substituted at one or more positions, for example by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino and / or dialkylamino. Heterocyclic group. Suitable substituted heterocyclic groups include 2-methylpiperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 3,4-dimethylpiperazin-1-yl, 4-methyl-1,4-diazepan-1-yl, 3-methoxypyrrolidin-1-yl, 1-methylpyrrolidin-3-yl, 1-methyl-4,5-dihydro-1H- Imidazol-2-yl, 3- (cyclopropylmethoxy) pyrrolidin-1-yl, 6-chloroisothiazolo [5,4-b] pyridinyl, 4- (cyclopropylcarbonyl) piperazin- 1-yl and 1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl.

Substituted radicals are substituted one or more times in each case and preferably have 1 to 3 substituents, in particular 1 or 2 substituents, among the exemplified substituents. These substituents are independently selected in each case. Thus, the substituents can be the same or different. Halogenated radicals such as halogenated alkyls are preferably fluorinated and include perhalo radicals such as trifluoromethyl and the like.

According to another compound and / or method aspect of the invention, R is not NH ₂ or NHCH ₃ . According to another aspect of the invention, R is not NH ₂ , NHCH ₃ or N (CH ₃ ) ₂ . According to another aspect of the invention, R is not NH ₂ , monoalkylamino or dialkylamino.

According to a compound and / or method aspect of the invention, R ² is Het-NH-CO-. According to another compound and / or method aspect of the invention, when R ² is Het-NH-CO-, the Het group is preferably an azabicyclo group, for example 1-azabicyclo [2.2.2] oct- 3- days.

According to a compound and / or method aspect of the invention, Het is substituted by cycloalkylalkyl (eg cyclopropylmethyl) having 4 to 7 carbon atoms. According to another compound and / or method aspect of the invention, when Het is substituted by cycloalkylalkyl, the cycloalkyl moiety preferably has 3 to 5 carbon atoms (eg cyclopropyl), alkyl moiety Preferably has 1 to 2 carbon atoms. In addition, the Het group is preferably an azabicyclo group, for example 2,5-diazabicyclo [2.2.1] hept-2-yl.

According to other compounds and / or methods of the invention, Het is a fully saturated, partially saturated or fully unsaturated hetero having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom. Cyclic group, which is substituted, wherein at least one of the substituents is alkoxy having 1 to 8 carbon atoms halogenated (eg OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, 4 to Cycloalkylalkoxy having 7 carbon atoms (eg cyclopropylmethyloxy), cycloalkylalkyl having 4-7 carbon atoms (eg cyclopropylmethyl), halogenated alkyl (except trifluoromethyl ) (Eg, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms, such as trifluoroethyl and trifluoropropyl), alkoxy having 2 to 8 carbon atoms Alkyl (e.g., CH ₃ OCH _2), alkyl (halogenated alkyl) amino (where the alkyl group are each 1 to having 8 carbon atoms), di (halogenated alkyl) amino (where the alkyl group are each 1 to Having 8 carbon atoms) or (halogenated alkyl) amino having 1 to 8 carbon atoms.

According to another compound and / or method aspect of the invention, the compound is at least one of R, R ¹ , R ³ , R ⁴ and R ⁵ groups Het or OHet, wherein the Het group is in each case substituted or unsubstituted , Azabicyclooctyl (eg 1-azabicyclo [2.2.2] oct-3-yl), oxa-azabicycloheptyl (eg 2-oxa-5-azabicyclo [2.2. 1] heptyl), diazabicycloheptyl (eg, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diazabicyclo [2.2.1 ] Hept-2-yl, trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, 5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2 .1] hept-2-yl), diazabicyclononyl (eg, 1,4-diazabicyclo [3.2.2] non-4-yl), diazabicyclooctyl (eg, 5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl and 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl), pyrazole , Dihydroimidazolyl, 1,4-diazepanyl (eg, 1,4-diazepan-1-yl and 4-methyl-1,4-diazepan-1-yl), hexahydropyrrolo Pyrazinyl (eg, hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) and octahydropyrrolopyridinyl (eg, 1- (cyclopropylcarbonyl) -octahydro -6H-pyrrolo [3,4-b] pyridin-6-yl).

According to another compound and / or method aspect of the invention, at least one of X ¹ , X ² , X ³ and X ⁴ is N; At least one of X ⁵ , X ⁶ , X ⁷ and X ⁸ is N; At least one of X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is N; ^At least one of X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ is N. According to another embodiment of this aspect of the invention, at least one of X ¹ , X ² , X ³ and X ⁴ is N and one or two of the remaining X ¹ to X ⁴ is CR ¹ . According to another embodiment of this aspect of the invention, at least one of X ⁵ , X ⁶ , X ⁷ and X ⁸ is N and one or both of the remaining X ⁵ to X ⁸ is CR ³ . According to another embodiment of this aspect of the invention, at least one of X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is N and one or two of the remaining X ⁹ to X ¹² is CR ⁴ . According to another embodiment of this aspect of the invention, at least one of X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ is N and one or two of the remaining X ¹³ to X ¹⁶ is CR.

According to another compound and / or method aspect of the invention, X ⁴ is N and X ¹ , X ² and X ³ are each CH or CR ¹ . According to another compound and / or method aspect of the invention, X ³ is N and X ¹ , X ² and X ⁴ are each CH or CR ¹ .

According to another compound and / or method aspect of the invention, X ¹² is N and X ⁹ , X ¹⁰ and X ¹¹ are each CH or CR ⁴ .

According to another compound and / or method aspect of the invention, Het is a fully saturated, partially saturated or fully unsaturated having from 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom Heterocyclic group, which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (eg OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, 4 Cycloalkylalkoxy having 7 to 7 carbon atoms (e.g. cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl) (e.g. halogenating having 2 to 8 or 3 to 8 carbon atoms alkyl, such as methyl and propyl trifluoromethyl trifluoromethyl), for alkoxyalkyl (for example, having 2 to 8 carbon atoms, CH ₃ OCH _2), alkyl (halogenated alkyl) amino (where the alkyl Are each having 1 to 8 carbon atoms), di (halogenated alkyl) amino (where the alkyl groups each have 1 to 8 C atoms) or (halogenated alkyl) amino having 1 to 8 carbon atoms .

According to another compound and / or method aspect of the invention, Het is a fully saturated heterocyclic group, which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 C atoms (e.g. For example, OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl) ( For example, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoropropyl, alkoxyalkyl having 2 to 8 carbon atoms (eg CH ₃ OCH ₂ ), alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, di (halogenated alkyl) amino, where the alkyl groups each have 1 to 8 C atoms) or 1 to 8 Of a carbon atom having a (halogenated alkyl) amino.

According to another compound and / or method aspect of the invention, Het is a fully saturated, partially saturated or fully unsaturated having from 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom Heterocyclic group, which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (eg OCHF ₂ ), cycloalkylalkoxy having 4 to 7 carbon atoms ( For example, cyclopropylmethyloxy) halogenated alkyl (except trifluoromethyl) (eg, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoro propyl), 2 to 8 alkoxy al keel having a carbon atom (for example, CH ₃ OCH ₂₎ or alkyl (halogenated alkyl) amino (where the alkyl group has from 1 to 8 carbon atoms) The.

According to another compound and / or method aspect of the invention, Het is a fully saturated heterocyclic group, which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (e.g. For example, OCHF ₂ ), cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl) (eg 2 to 8 or 3 to Halogenated alkyl having 8 carbon atoms such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms (eg CH ₃ OCH ₂ ) or alkyl (halogenated alkyl) amino Wherein the alkyl groups each have 1 to 8 carbon atoms.

According to another compound and / or method aspect of the invention, A is a group of formula (a) and has one or more R ¹ substituents, wherein R ¹ is 5 to 10 ring atoms, wherein at least one ring atom is N, A fully saturated, partially saturated, or fully unsaturated heterocyclic group having 0 or S atoms, which is substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms ( For example, OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl (Eg, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms, such as trifluoroethyl and trifluoropropyl), alkoxyalkyl having 2 to 8 carbon atoms ( For example, CH ₃ OCH ₂ ), alkyl (halogenated alkyl) amino, wherein the alkyl groups have from 1 to 8 carbon atoms each, and di (halogenated alkyl) amino (where the alkyl groups are each from 1 to 8 carbon atoms) Having carbon atoms) or (halogenated alkyl) amino having 1 to 8 C atoms.

According to another compound and / or method aspect of the invention, A is a group of formula (a) and has one or more R ¹ substituents, wherein R ¹ is a fully saturated heterocyclic group, which is substituted, and One or more of the substituents when used is halogenated alkoxy having 1 to 8 C atoms (eg OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms ( For example, cyclopropylmethyloxy, halogenated alkyl (except trifluoromethyl) (eg, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoro Ropropyl), alkoxyalkyl having 2 to 8 carbon atoms (eg CH ₃ OCH ₂ ) or alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms.

According to another compound and / or method aspect of the invention, A is a group of formula (c) and has one or more R ⁴ substituents, wherein R ⁴ is 5 to 10 ring atoms, wherein at least one ring atom is N , O or S atoms), a fully saturated, partially saturated or fully unsaturated heterocyclic group, which is substituted, wherein at least one of the substituents is halogenated having from 1 to 8 carbon atoms Alkoxy (eg OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (trifluoro Except methyl) (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms, such as trifluoroethyl and trifluoropropyl), alkoxy having 2 to 8 carbon atoms Alkyl (eg, CH ₃ OCH ₂ ), alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms), di (halogenated alkyl) amino, wherein the alkyl groups are each 1- Having 8 carbon atoms) or (halogenated alkyl) amino having 1 to 8 carbon atoms.

According to another compound and / or method aspect of the invention, A is a group of formula (c) and has one or more R ⁴ substituents, wherein R ⁴ is a fully saturated heterocyclic group, which is substituted, where At least one of the substituents is halogenated alkoxy having 1 to 8 carbon atoms (eg OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg For example, cyclopropylmethyloxy, halogenated alkyl (except trifluoromethyl) (e.g., halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl and trifluoro Propyl), alkoxyalkyl having 2 to 8 carbon atoms (eg CH ₃ OCH ₂ ) or alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms.

According to a further compound and / or method aspect of the invention, A is a group of formula (d), has one or more substituents R, wherein R is OH, O- (C _{1 -6} - alkyl -O) _{1- 2} -C _{1 -6} - alkyl, -OC _{1 -6} - alkyl, -NR ⁶ R ^7, 1 alkoxy having to 4 carbon atoms (e.g., OCH _{3), 3} to cycloalkoxy having 7 carbon atoms , Cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethoxy), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), 1 to 4 Hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms alkyl, -Het-O- -, OAr, OHet , carbonate -O, Ar-C _{1 -6} - alkyl, -O-, Het-C _{1 -6} - alkyl, -O- or Ar-C _{1 -6.}

According to a further compound and / or method aspect of the invention, A is a group of formula (d), has one or more substituents R, wherein R is OH, O- (C _{1 -6} - alkyl -O) _{1- 2} -C _{1 -6} - alkyl, 1-alkoxy having to 4 carbon atoms (e.g., OCH _{3), 3} to cycloalkyl alkoxy having cycloalkoxy, 4 to 7 carbon atoms having 7 carbon atoms ( For example, cyclopropylmethoxy), fluorinated alkoxy having 1 to 4 carbon atoms (e.g. OCF ₃ , OCHF ₂ ), hydroxyalkoxy or fluorinated having 2 to 4 carbon atoms Hydroxyalkoxy.

According to another compound and / or method aspect of the invention, A is a group of formula (d) and has one or more R substituents, wherein R is OH, alkoxy having 1 to 4 carbon atoms (eg, OCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxyalkoxy having 2 to 4 carbon atoms or fluorinated hydroxyalkoxy.

According to another compound and / or method aspect of the invention, A is a group of formula (a) and has one or more R ¹ substituents, where R ¹ is dihydroimidazolyl.

According to another compound and / or method aspect of the invention, A is a group of formula (a) and has one or more R ¹ substituents, wherein R ¹ is Het (excluding thiazolyl), wherein R ² is 2 to Alkyl having 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, fluorinated C _{1 − 4-alkyl,} -CO-, C _{3 -7-cycloalkyl,} -CO-, C _{1 -4-alkyl,} -NH-CO-, C _{3 -7} - cycloalkyl, -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} (for example, CH ₂ CH ₂ -O-CH _3), or Ar-C _{1 -4} - alkyl, -NH-CO-.

According to another compound and / or method aspect of the invention, A is a group of formula (c) and has one or more R ⁴ substituents, wherein R ⁴ is imidazolyl (eg, imidazol-1-yl) , pyrrolyl, pyrazolyl, C _{1 - 8} alkyl-pyrazolyl (e.g., 3-methyl -1H- pyrazol-1-yl, 5-methyl -1H- pyrazol-1-yl), oxa-aza Bicycloheptyl (eg 2-oxa-5-azabicyclo [2.2.1] heptyl), diazabicycloheptyl (eg 2,5-diazabicyclo [2.2.1] hept- 2-1), C _{1 - 8} alkyl-for-heptyl (such as diazabicyclo, 5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl), halogenated C _{1 - 8} alkyl-diazabicycloheptyl (eg, trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, piperidinyl, monoalkylamino (substituted by amino) C _{1 - 8} alkyl, -NH-), or dialkylamino ((C _{1 - 8} alkyl) ₂ N-) (e.g., (4-dimethylamino) piperidin 1-yl) or a hydroxy-pyrrolidinyl substituted by hydroxy, halogenated alkoxy, cycloalkyl, alkoxy, amino, monoalkylamino (C _{1 - 8} alkyl, -NH-), dialkylamino ((C _{1 - 8} Alkyl) ₂ N-), alkoxyalkyl or alkyl (fluorinated alkyl) amino (eg, 3- (cyclopropylmethoxy) pyrrolidin-1-yl, 3- (hydroxy) pyrrolidine-1 -(Eg, 3- (3R) -hydroxypyrrolidin-1-yl, 3- (3S) -hydroxypyrrolidin-1-yl), 3- (difluoromethoxy) pyrrolidine- 1-yl), 3- (dimethylamino) pyrrolidin-1-yl (eg 3- (3S)-(dimethylamino) pyrrolidin-1-yl, 3- (3R)-(dimethylamino) py Ralidin-1-yl), 3-methylaminopyrrolidin-1-yl, 3- (methoxymethyl) pyrrolidin-1-yl, 3- [methyl (2,2,2-trifluoroethyl ) Amino] pyrrolidin-1-yl).

(식 중, Z는 1 내지 4개의 탄소 원자를 갖는 알킬 (예를 들면, 메틸, 에틸, 프로필), 1 내지 4개의 탄소 원자를 갖는 할로겐화된 알킬 (예를 들면, 클로로메틸, 클로로에틸), 4 내지 7개의 탄소 원자를 갖는 시클로알킬알킬 (예를 들면, 시클로프로필메틸) 또는 7 내지 16개의 탄소 원자를 갖는 아릴알킬 (예를 들면, 벤질)이고, 음이온 A는, 예를 들면 요오다이드, 브로마이드, 클로라이드, 트리플레이트, 토실레이트 또는 메실레이트임)의 4급 암모늄 염의 형태이다. 상기 실시양태에서, A 기는 바람직하게는 부분 화학식 (a) 또는 (c)의 기이다. 또한, X¹ 내지 X⁴는 각각 바람직하게는 CH 또는 CR¹이고, X⁹ 내지 X¹²는 각각 바람직하게는 CH 또는 CR⁴이다.According to another aspect of the invention, the compound is a compound of Formulas I-IV, but the 1-azabicyclo group is a partial

Wherein Z is alkyl having 1 to 4 carbon atoms (eg methyl, ethyl, propyl), halogenated alkyl having 1 to 4 carbon atoms (eg chloromethyl, chloroethyl), Cycloalkylalkyl having 4 to 7 carbon atoms (eg cyclopropylmethyl) or arylalkyl having 7 to 16 carbon atoms (eg benzyl) and the anion A being iodide, for example , Bromide, chloride, triflate, tosylate or mesylate). In this embodiment, the A group is preferably a group of partial formula (a) or (c). Further, X ¹ to X ⁴ are each preferably CH or CR ¹ , and X ⁹ to X ¹² are each preferably CH or CR ⁴ .

According to another aspect of the invention, the compound is selected from compounds of formula (Ip) according to the following subclasses:

(i) X ¹³ to X ¹⁶ are independently CH or CR, wherein at least one of X ¹³ to X ¹⁶ is not CH;

X is O;

R 'is H, alkyl (eg CH ₃ or C ₂ H ₅ , in particular CH ₃ ) or cycloalkylalkyl (eg cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopropylethyl, in particular Cyclopropylmethyl);

At least one R is alkoxy (eg OCH ₃ ) or Het (eg 3-methoxy-pyrrolidin-1-yl [eg, (3R) -3-methoxypyrrolidin-1-yl, (3S) -3-methoxypyrrolidin-1-yl].

According to another aspect of the invention, the compound is selected from compounds of formula la or ij according to the following subclasses:

(i) X is O;

One of X ¹ to X ⁴ is N, or one of X ⁹ to X ¹² is N, and the remaining X ¹ to X ⁴ or X ⁹ to X ¹² are CH, CR ¹ or CR ⁴ ;

R 'is H, alkyl (eg CH ₃ or C ₂ H ₅ , in particular CH ₃ ) or cycloalkylalkyl (eg cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopropylethyl, especially cyclo Propylmethyl);

R ² is H;

R ¹ and R ⁴ are independently selected from H, halogen (eg Cl or F), Ar (eg phenyl) or Het (eg 3-dimethylaminopyrrolidin-1-yl) Compound.

According to other compounds and / or method aspects of the invention, the compounds are selected from compounds according to the following subclasses:

(a) a compound according to formula I, wherein at least one of X ¹ , X ² , X ³ and X ⁴ is N;

(b) X ¹ , X ² , X ³ and X ⁴ A compound according to formula Ia, wherein at least one of is N;

(c) a compound according to formula Ij, wherein at least one of X ¹ , X ² , X ³ and X ⁴ is N;

(d) X ⁵ , X ⁶ , X ⁷ and X ⁸ A compound according to formula I, wherein at least one of is N;

(e) X ⁹ , X ¹⁰ , X ¹¹ and X ¹² A compound according to formula I, wherein at least one of is N;

(f) X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ A compound according to formula I, wherein at least one of is N;

(g) X ¹ , X ² , X ³ and X ⁴ One or more of N is N, and one or two of the remaining X ¹ to X ⁴ is CR ¹ ;

(h) X ¹ , X ² , X ³ and X ⁴ One or more of N is N, and one or two of the remaining X ¹ to X ⁴ is CR ¹ ;

(i) X ¹ , X ² , X ³ and X ⁴ One or more of N is N, and one or two of the remaining X ¹ to X ⁴ is CR ¹ ;

(j) X ⁵ , X ⁶ , X ⁷ and X ⁸ One or more of N is N, and one or two of the remaining X ⁵ to X ⁸ is CR ³ ;

(k) X ⁹ , X ¹⁰ , X ¹¹ and X ¹² One or more of N is N, and one or two of the remaining X ⁹ to X ¹² is CR ⁴ ;

(l) X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ One or more of N is N, and one or both of X ¹³ to X ¹⁶ are CR;

(m) a compound according to formula (I), wherein X ⁴ is N and X ¹ , X ² and X ³ are each CH or CR ¹ ;

(n) a compound according to formula (Ia), wherein X ⁴ is N and X ¹ , X ² and X ³ are each CH or CR ¹ ;

(o) a compound according to formula (Ij), wherein X ¹² is N and X ⁹ , X ¹⁰ and X ¹¹ are each CH or CR ⁴ ;

(p) a compound according to formula (Ia), wherein X ³ is N and X ¹ , X ² and X ⁴ are each CH or CR ¹ ;

(q) at least one R ¹ or R ⁴ , wherein R ¹ or R ⁴ is substituted Het, wherein at least one Het substituent is halogenated alkoxy having 1 to 8 carbon atoms (eg, OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl) (eg For example, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (eg CH ₂ OCH ₃ ), alkyl (halogenated) Alkyl) amino (where the alkyl groups each have 1 to 8 carbon atoms), di (halogenated alkyl) amino (where the alkyl groups each have 1 to 8 carbon atoms) or 1 to 8 C atoms Having (halogenated alkyl) The compounds according to formula Ia or Ij elderly;

(r) at least one R ¹ or R ⁴ , wherein R ¹ or R ⁴ is substituted Het, wherein at least one Het substituent is halogenated alkoxy having 1 to 8 carbon atoms (eg, OCHF ₂ ), cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl) (eg 2 to 8 or 3 to 8 carbons Halogenated alkyls having an atom such as trifluoroethyl), alkoxyalkyls having 2 to 8 carbon atoms (eg CH ₂ OCH ₃ ) or alkyl (halogenated alkyl) amino (where the alkyl groups are each 1 to Having 8 carbon atoms); a compound according to formula la or ij;

(s) has one or more R ¹ or R ⁴ , wherein R ¹ or R ⁴ is a fully saturated substituted Het group (eg, pyrrolidinyl or piperidinyl), wherein one or more Het substituents Halogenated alkoxy having 1 to 8 carbon atoms (eg OCHF ₂ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyl Oxy), halogenated alkyl (except trifluoromethyl) (eg, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms, such as trifluoroethyl), having 2 to 8 carbon atoms Alkoxyalkyl (eg, CH ₂ OCH ₃ ), alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms, and di (halogenated alkyl) amino, wherein the alkyl groups are each 1 To 8 carbon atoms Or (halogenated alkyl) amino having from 1 to 8 carbon atoms;

(t) has at least one R ¹ or R ⁴ , wherein R ¹ or R ⁴ is a fully saturated substituted Het group (eg pyrrolidinyl), wherein at least one Het substituent is 1-8 Halogenated alkoxy with carbon atoms (eg OCHF ₂ ), cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethyloxy), halogenated alkyl (except trifluoromethyl) (eg For example, halogenated alkyl having 2 to 8 or 3 to 8 carbon atoms such as trifluoroethyl), alkoxyalkyl having 2 to 8 carbon atoms (eg CH ₂ OCH ₃ ) or alkyl ( Halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 carbon atoms;

(u) has at least one substituent R, wherein R is OH, O- (C _{1 -6} - alkyl -O) _1-2 -C _{1 -6} - alkyl, -OC _{1 -6} - alkyl, -NR ⁶ R ⁷ , alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylme Oxy), fluorinated alkoxy having 1 to 4 carbon atoms (eg OCF ₃ , OCHF ₂ ), hydroxyalkyl having 1 to 4 carbon atoms, fluorinated having 1 to 4 carbon atoms hydroxyalkyl of 2 to 4 carbon atoms and having a hydroxy-alkoxy, 2 to 4 fluorinated carbon atoms having a hydroxy-alkoxy, OAr, OHet, carbonate -O, Ar-C _{1 -6} - alkyl -O -, Het-C _{1 -6} - alkyl, -O- or Ar-C _{1 -6} - alkyl, -Het-O- a compound according to formula Ip;

(v) having one or more substituents R, wherein R is OH, O- alkoxy (e.g., alkyl having 1 to 4 carbon atoms, - (C _{1 -6} - alkyl -O) _1-2 -C _{1 -6} For example, OCH ₃ ), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (eg cyclopropylmethoxy), fluorinating having 1 to 4 carbon atoms Compounds according to formula Ip, which are alkoxy (eg OCF ₃ , OCHF ₂ ), hydroxyalkoxy having 2 to 4 carbon atoms or fluorinated hydroxyalkoxy;

(w) has one or more R substituents, wherein R is OH, alkoxy having 1 to 4 carbon atoms (eg OCH ₃ ), fluorinated alkoxy having 1 to 4 carbon atoms (eg , OCF ₃ , OCHF ₂ ), a compound according to formula Ip which is hydroxyalkoxy or fluorinated hydroxyalkoxy having 2 to 4 carbon atoms;

(x) a compound according to formula la, having one or more R substituents, wherein R is dihydroimidazolyl;

(y) has one or more R ¹ substituents, wherein R ¹ is Het (excluding thiazolyl), wherein R ² is alkyl having 2 to 4 carbon atoms, fluorinated having 1 to 4 carbon atoms the cycloalkylalkyl having a cycloalkyl, 4 to 7 carbon atoms having the alkyl, 3 to 7 carbon atoms, fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4-alkyl -NH-CO-, C _{3 -7} - cycloalkyl, -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 (e.g., CH 2 CH 2 -O-CH} 3) , or Ar-C _1-4 - alkyl - A compound according to formula (Ia), which is NH-CO-;

(z) has at least one substituent R ^4, wherein R ⁴ is imidazolyl (e.g., imidazol-1-yl), pyrrolyl, pyrazolyl, C _{1 - 8} alkyl-pyrazolyl (e. g. , 3-methyl-1H-pyrazol-1-yl, 5-methyl-1H-pyrazol-1-yl), oxo-azabicycloheptyl (eg, 2-oxo-5-azabicyclo [2.2 0.1] heptyl), 2,5-diazabicyclo [2.2.1] hept-2-yl, C _{1 - 8} alkyl-for-heptyl (such as diazabicyclo, 5-methyl-2,5-dia Here bicyclo [2.2.1] hept-2-yl), halogenated C _{1 - 8} alkyl-a-heptyl (such as diazabicyclo by example, trifluoro ethyl-2,5-diazabicyclo [2.2. ] hept-2-yl), a piperazinyl substituted by amino-piperidinyl, monoalkylamino (C _{1 - 8} alkyl, -NH-), or dialkylamino ((C _{1 - 8} alkyl) ₂ N-) (e.g. , (4-dimethylamino) piperidin-1-yl) or pyrrolidinyl substituted by hydroxy, halogenated alkoxy, cycloalkylalkoxy, amino, parent No alkylamino (C _{1 - 8} alkyl, -NH-), dialkylamino ((C _{1 -8-alkyl) 2} N-), alkoxyalkyl, or alkyl (fluorinated alkyl) amino (e.g., 3- (bicyclo Propylmethoxy) pyrrolidin-1-yl, 3- (hydroxy) pyrrolidin-1-yl (eg, 3- (3R) -hydroxypyrrolidin-1-yl, 3- (3S)- Hydroxypyrrolidin-1-yl), 3- (difluoromethoxy) pyrrolidin-1-yl), 3- (dimethylamino) pyrrolidin-1-yl (eg, 3- (3S)- (Dimethylamino) pyrrolidin-1-yl, 3- (3R)-(dimethylamino) pyrrolidin-1-yl), 3-methylaminopyrrolidin-1-yl, 3- (methoxymethyl) Pyrrolidin-1-yl, 3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl); a compound according to formula Ij;

(aa) a compound of the subclass according to any one of the subclasses (a) to (z), wherein X is O; And

(ab) A compound of subclass according to any of the above subclasses (a) to (aa), wherein R 'is H or alkyl, in particular H.

According to compounds and / or process aspects of the invention, the compounds of formulas (I) to (IV)

1) (3S) -3-({[6- (cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azo Niabicyclo [2.2.2] octane bromide or formate,

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

3) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate,

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

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

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

7) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide hydroformate,

8) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3 Carboxamide hydroformate,

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

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

11) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazole-3-carboxamide hydro Formate,

12) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroxy-1,2-benziso thiazole-3-carboxamide hydroformate,

13) (3S) -3-{[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] Octane iodide or formate,

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

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

16) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate,

17) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

18) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-methyl-6-{[(propylamino) carbonyl] amino} -1 H-indazol-3 Carboxamide hydroformate,

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

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

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

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

23) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-car Voxamide hydroformate,

24) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H- Sol-3-carboxamide hydroformate,

25) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-{[(propylamino) carbonyl] amino} -1 H Indazole-3-carboxamide hydroformate,

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

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

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

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

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

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

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

33) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide,

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

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

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

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

38) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-[(cyclopropylcarbonyl) amino] -1 H-indazol-3- Carboxamide,

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

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

41) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4S) -4-hydroxy-2-oxopyrrolidin-1-yl]- 1H-indazole-3-carboxamide hydroformate,

42) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

43) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate,

44) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate,

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

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

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

48) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydro Formate,

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

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

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

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

53) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride,

54) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide hydrochloride,

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

56) 6-methoxy-N-[(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -1,2-benzisothiazole-3-carboxamide Is selected from,

Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts,

The compounds listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of solvates (eg hydrates),

The compounds listed above (in free base form or in the form of pharmaceutically acceptable salts) may also be in the form of N-oxides,

The compounds listed above (in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof) may also be in polymorphic form,

Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers (eg racemates) or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer.

According to other compounds and / or method aspects of the invention, the compounds of formulas (I) to (IV)

1) (3S) -3-({[6- (cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azo Niabicyclo [2.2.2] octane bromide or formate,

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

3) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate,

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

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

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

7) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide hydroformate,

8) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3 Carboxamide hydroformate,

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

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

11) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazole-3-carboxamide hydro Formate,

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

13) (3S) -3-{[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] Octane iodide or formate,

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

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

16) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate,

17) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

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

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

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

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

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

23) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-car Voxamide hydroformate,

24) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H- Sol-3-carboxamide hydroformate,

25) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-{[(propylamino) carbonyl] amino} -1 H Indazole-3-carboxamide hydroformate,

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

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

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

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

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

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

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

33) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide,

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

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

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

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

38) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-[(cyclopropylcarbonyl) amino] -1 H-indazole- 3-carboxamide,

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

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

41) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4S) -4-hydroxy-2-oxopyrrolidin-1-yl]- 1H-indazole-3-carboxamide hydroformate,

42) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

43) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate,

44) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate,

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

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

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

48) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide Hydroformate,

49) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide hydrochloride, and

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

Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts,

The compounds listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of solvates (eg hydrates),

The compounds listed above (in the form of free base or solvates thereof, or in the form of pharmaceutically acceptable salts or solvates thereof) may also be in polymorphic form,

Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers (eg racemates) or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer.

According to other compounds and / or method aspects of the invention, the compounds of formulas (I) to (IV)

57) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide hydro Formate,

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

59) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide,

60) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate,

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

62) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazole-3-carbox Amide hydroformate,

63) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazole 3-carboxamide hydroformate,

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

65) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benz Isothiazole-3-carboxamide,

66) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrrol-1-yl) -1,2-benzisothiazole-3-carbox Voxamide,

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

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

69) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazole-3 Carboxamide,

70) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide,

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

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

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

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

75) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

76) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

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

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

79) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

80) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3- Carboxamide,

81) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3- Carboxamide,

82) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide,

83) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide,

84) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

85) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

86) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazole-3-carboxamide,

87) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2- Benzisothiazole-3-carboxamide,

88) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide,

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

90) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3 , 4-b] pyridine-3-carboxamide,

91) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1 H-pyrazolo [3 , 4-b] pyridine-3-carboxamide,

92) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide,

93) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide,

94) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

95) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

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

97) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide,

98) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

99) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

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

101) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

102) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide,

103) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide,

104) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide,

105) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide,

106) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate,

107) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate,

108) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide,

109) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide,

110) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate,

111) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

112) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate,

113) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate,

114) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide ,

115) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide ,

116) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

117) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

118) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide,

119) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide,

120) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide,

121) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide,

122) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (2,2,2-trifluoroethyl)- 2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

123) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide,

124) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide,

125) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

126) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

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

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

129) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, and

130) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide,

Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts,

The compounds listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of solvates (eg hydrates),

The compounds listed above (in free base form or in the form of pharmaceutically acceptable salts) may also be in the form of N-oxides,

The compounds listed above (in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof) may also be in polymorphic form,

Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers (eg racemates) or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer.

According to another compound and / or method aspect of the invention, the compounds of formulas (I) to (IV)

131) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, or a pharmaceutically acceptable salt thereof,

Wherein the compounds listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of solvates (eg hydrates),

The compounds listed above (in free base form or in the form of pharmaceutically acceptable salts) may also be in the form of N-oxides,

The compounds listed above (in the form of the free base or solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof) may also be in polymorphic form.

According to other compounds and / or method aspects of the invention, the compounds of formulas (I) to (IV)

132) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate,

133) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate,

134) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

135) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

136) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate,

137) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate,

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

139) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide,

140) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide,

141) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide,

142) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide,

143) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide,

144) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide,

145) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Yl) -1,2-benzisothiazole-3-carboxamide,

146) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Yl) -1,2-benzisothiazole-3-carboxamide,

147) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide,

148) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide,

149) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

150) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

151) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

152) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

153) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepane-1-yl) -1,2-benz Isothiazole-3-carboxamide,

154) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

155) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

156) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

157) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide,

158) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide,

159) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide,

160) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide,

161) N, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-1,3-dicarboxamide,

162) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide,

163) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide,

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

165) (3S) -1- (chloromethyl) -3-[(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride,

166) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1 H-indazol- 3-carboxamide dihydroformate,

167) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide,

168) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide,

169) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide,

170) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide,

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

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

173) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl)-1,2-benzisothiazole- 3-carboxamide,

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

175) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide,

176) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide,

177) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

178) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

179) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide,

180) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide,

181) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

182) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide,

183) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole -3-carboxamide,

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

185) 3-[(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride,

186) N (3)-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-3,6- Dicarboxamide,

187) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4-methylpiperazin-1-yl) carbonyl] -1 H-indazol-3 Carboxamide,

188) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H- Sol-3-carboxamide,

189) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide,

190) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Selected from voxamides,

Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts,

The compounds listed above (in free base form or in the form of a pharmaceutically acceptable salt) may also be in the form of solvates (eg hydrates),

The compounds listed above (in free base form or in the form of pharmaceutically acceptable salts) may also be in the form of N-oxides,

The compounds listed above (in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof) may also be in polymorphic form,

Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers (eg racemates) or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer.

The table below shows the structures for the compounds of the formulas I to IV selected according to the invention:

Further aspects include pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, optionally other active agents discussed below; Methods for stimulating or activating α-7 nicotinic receptor inhibition (eg, in vitro or in vivo (in animals, for example in animal models, or in mammals or humans) in conventional assays or assays described herein Determined); Neurological syndromes such as memory loss, especially long term memory loss, cognitive impairment or decline, memory impairment, etc .; Methods of treating disease states, such as the conditions mentioned herein, which are regulated by nicotinic α-7 activity in mammals, such as humans.

The compounds of the present invention can be prepared conventionally. Some of the known procedures that can be used are described below. All starting materials are known or can be prepared conventionally from known starting materials by those skilled in the art.

Acids used in the preparation of bicyclobase amides are commercially available or are prepared by known procedures described in the literature or as described below. For example, indazole-3-carboxylic acid is commercially available. Various simple substituted indazole-3-acids, such as bromoindazole acid, are prepared from the corresponding isatins by basic hydrolysis, diazotization and reduction (Snyder, HR et al., J. Am. Chem. Soc 1952, 74, 2009].

Some substituted indazole-3-acids are prepared by modifying existing indazole acids or esters. For example, N (1)-and N (2) -protected indazole acids can be prepared from esters of methoxyethoxy methyl chloride (MEM-Cl) or trimethylsilylethoxymethyl chloride (SEM-Cl) and sodium hydride or Prepared via reaction with di-isopropylethylamine. N (1) -alkylated indazole-3-carboxylic acids are prepared from the corresponding indazole esters by standard alkylation or Mitsunobu procedures. N (1) -arylated indazole-3-carboxylic acids are prepared by copper-mediated cross coupling with boronic acid from the corresponding indazole esters. Non-aromatic heterocyclic derivatives are prepared by metal-halogen exchange from the corresponding bromide, capture of indazole aryl lithium into ketones followed by reduction or acid mediated removal. Aromatic substituted indazole-3-acids are prepared from the corresponding bromide via palladium-mediated cross-coupling with boronic acid or aryl zinc reagents (Reeder, MR; et. Al. Org. Proc. Res. Devel. 2003, 7, 696]. Amino indazole acid is prepared using a palladium-mediated cross-coupling reaction with a secondary amine. Phenolic derivatives are prepared from boron tribromide from the corresponding methoxy acids. 6-amino- and 6-phenyl-7-azindazol-3-carboxylic acids are reacted with secondary amines from commercially available 6-fluoro materials or nickel-mediated cross-linking with aryl Grignard reagents. It is made by coupling.

Some substituted indazole-3-acids are prepared from benzene derivatives. For example, 5-difluoromethoxyindazol-3-acid is reacted with 3-dibromo-4-nitrophenol with ethyl difluoroacetate, with diethyl malonate, decarboxylated saponification, ester By nitrification, reduction of nitro groups and diazotization. 6-difluoromethoxyindazol-3-acid is prepared in a similar manner from 2-bromo-5-difluoromethoxynitrobenzene. 2-bromo-5-difluoromethoxynitrobenzene is a nitro reduction, nitration, amide hydrolysis, accompanied by ether formation from 4-nitrophenol, protection with amides, and Sandmeyer with copper bromide (I) ) Reaction. 6-benzyloxyindazole-3-carboxylic acids and esters are subjected to nitro reduction, nitration, amide hydrolysis, sandmeier reaction with copper (I) and debromination with protection of 4-methoxynitrobenzene from amides Prepared by methylation. Phenol is alkylated with benzyl bromide, arylbromide reacts with diethyl malonate, decarboxylated saponified, esterified, reduced to nitro group, and diazotized. 5-benzyloxy analogs are prepared in a similar manner from 4-benzyloxy-2-bromonitrobenzene (Parker, K.A .; Mindt, T.L. Org. Lett. 2002, 4, 4265). Benzyl groups are removed by hydrocracking and the resulting phenols are transformed into ether derivatives via alkylation or Mitsunobu reaction conditions. 4-Methoxyindazole acid is hydrolyzed bromine following amide formation, nitration, amide hydrolysis from 4-methoxyaniline, sandmeier reaction with copper bromide, nitro reduction, isatin formation and rearrangement to indazole Prepared by removal. 5-Azaindazol-3-acid is prepared by metallization from 4-chloropyridine and entrapment with diethyloxalate, cyclization with hydrazine and saponification. 6-Azaindazol-3-acid is prepared by reaction of 4-chloro-3-nitropyridine with malonate anion, decarboxylation, nitro reduction, diazotization and saponification.

Benzisoxazole esters are prepared from simple benzene derivatives using similar techniques. For example, ethyl 6-bromobenzisoxazole-3-carboxylate can be prepared by reaction of 2-nitro-1,4-dibromobenzene with dimethylmalonate, continuous saponification / decarboxylation, esterification and It is prepared by reaction with isoamyl nitrite under basic conditions. The 6-methoxybenzisoxazole ester compound is similarly prepared from 2,4-dinitrochlorobenzene. From the reduction of the resulting 6-nitro group and subsequent diazotization and oxidation, a 6-hydroxy compound is provided. The ether is obtained by simple alkylation.

Benzisothiazole carboxylic acids are also prepared using a strategy similar to the strategy outlined for indazole acid. For example, 6-methoxybenzisothiazole-3-carboxylic acid is prepared by the reaction of 3-methoxythiophenol with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide and sodium hydroxide. do. Amino substituted benzisothiazole acids are prepared by palladium-mediated cross-coupling reactions from essential bromide with secondary amines or benzophenone imines. Primary and secondary amines produced in this way are used as intermediates for other redands. For example, amines are modified to tertiary amines and amides using standard reduction amination and acylation reactions, which are carried out by those skilled in the art. 7-Azabenzisothiazole-3-carboxylic acid was reacted with diethylmalonate anion and decarboxylation from 2-chloronicotinoyl chloride followed by reaction of ketone with sulfur, ammonium hydroxide and ammonia. Prepared by producing the aza-3-methylbenzisothiazole core. The acid is located using benzyl oxidation and hydrolysis with N-bromosuccinamide followed by basic permanganate oxidation of the alcohol. The 7-aza-6-chlorobenzisothiazole-3-acid is used to form a 6-chlorine atom by a rearrangement reaction mediated by triphosgene following the oxidation of the pyridine ring nitrogen from the 7-aza-3-methylbenzisothiazole core. Synthesized by positioning in position. The synthesis is completed by benzyl oxidation in a similar manner to unsubstituted azabenzisothiazolic acid.

Bicycloamines, 3-aminoquinuclidines and their R- and S-enantiomers used in the preparation of bicyclobase amides are commercially available. N-alkylated quinuclidines are prepared by acylation of 3-aminoquinuclidines followed by amide reduction.

Bicyclobase amides are standard peptide coupling agents from acids and bicycloamines, such as O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU). , O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), O- (benzotriazol-1-yl)- N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), hydroxybenztriazole (HOBt) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDCI ), Carbonyl diimidazole (CDI) and 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), or after conversion of the acid to the corresponding acid chloride with bicycloamine Prepared by reaction (Macor, JE; Gurley, D .; Lanthorn, T .; Loch, J .; Mack, RA; Mullen, G .; Tran, O .; Wright, N .; and JE Macor et al ., "The 5-HT3-Antagonist Tropisetron (ICS 205-930) wa s a Potent and Selective α-7 Nicotinic Receptor Partial Agonist, "Bioorg. Med. Chem. Lett. 2001, 9, 319-321). Coupling is generally carried out at room temperature for 18 to 24 hours. The resulting adduct is isolated and purified by standard techniques performed by those skilled in the art such as chromatography and recrystallization.

Nicotinic ligands are otherwise prepared by modifying other nicotinic ligands. For example, cyclic urea ligands are prepared by palladium-catalytic cross-coupling reactions from the corresponding bromide ligands. Amino-substituted ligands are prepared by similar palladium-mediated coupling reactions with secondary amines or benzophenone imines. Primary and secondary amines produced in this manner are used as intermediates for other ligands, as those skilled in the art will understand. 5-alkoxybenzisothiazole ligands are prepared by palladium-mediated cross-coupling with panacolborane dimers followed by oxidation and alkylation. In some cases, the indazole quinuclidin carboxamides are derivatized at indazole nitrogen under Mitsunobu conditions or via copper-mediated coupling with boronic acid. Quaternary quinuclidin salts are prepared by reacting the final product with an alkylating agent. N-oxides are prepared by reacting the final product with an oxidant.

Those skilled in the art will appreciate that compounds of Formulas (I) through (IV) may exist in different tautomeric and geometric isomeric forms. Such compounds (including cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers) are all within the scope of the present invention. Substantially pure enantiomers contain up to 5% w / w, preferably up to 2%, most preferably up to 1% of the corresponding opposite enantiomers.

Optical isomers can be obtained by dividing the racemate mixture according to conventional procedures, for example by forming diastereomeric salts or forming covalent diastereomers with an optically active acid or base. can do. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, dytoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical and / or chemical differences by methods known to those skilled in the art, for example by chromatography or fractional crystallization. The optically active base or acid is then liberated from the separated diastereomeric salts. Several procedures for the separation of optical isomers include the use of chiral chromatography (eg, chiral HPLC columns) most suitably selected to maximize separation of enantiomers with or without conventional derivatization. Suitable chiral HPLC columns are made of Diacel, for example Chilacel OD and Chilacel OJ, among many others, all of which are generally selectable. Separation by enzymes with or without derivatization is also useful. Optically active compounds of formulas (I) to (IV) can likewise be obtained using optically active starting materials in the course of chiral synthesis under reaction conditions which do not result in racemization.

Those skilled in the art will also recognize that the compounds can be used in different isotope-rich forms, for example in rich forms of contents of ² H, ³ H, ¹¹ C, ¹³ C and / or ¹⁴ C. In one particular embodiment, the compound is deuterated. Such deuterated forms can be prepared by the procedures described in US Pat. No. 5,846,514 and 6,334,997. As described in US Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve efficacy and increase the duration of action of the drug.

Deuterium substituted compounds are described in Dean, Dennis C .; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. In: Curr., Pharm. Des., 2000; 6 (10)] (2000), 110 pp. CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka, George W .; Varma, Rajender S. The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45 (21), 6601-21, CODEN: TETRAB ISSN: 0040-4020. CAN 112: 20527 AN 1990: 20527 CAPLUS and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64 (1-2), 9-32. CODEN: JRACBN ISSN: 0022-4081, CAN 95: 76229 AN 1981: 476229 CAPLUS] can be synthesized using various methods.

Where applicable, the invention also relates to useful forms of the compounds disclosed herein, including pharmaceutically acceptable salts or prodrugs and free base forms of all compounds of the invention from which salts or prodrugs may be prepared. Pharmaceutically acceptable salts may be reacted with a major compound that functions as a base and an inorganic or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, brominated Hydrogen acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid and salts of carbonic acid). Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and reacts with the appropriate base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts can be prepared by reacting the compounds of the present invention with the appropriate base through various known methods.

Further examples of acid salts obtainable by reaction with inorganic or organic acids include acetates, adipates, alginates, citrate, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, Cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxy Ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, Propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

For example, the pharmaceutically acceptable salt can be hydrochloride, hydrobromide, hydroformate or maleate.

Salts of the present invention also include quaternary ammonium salts obtained by reacting a major compound that functions as a nucleophile with an agent bearing a nucleofugal group. Examples of such agents are methyl iodide, methyl bromide, methyl chloride, methyl triflate, methyl tosylate, methyl mesylate, ethyl iodide, ethyl bromide, ethyl chloride, ethyl triflate, ethyl tosylate, ethyl mesyl Latex, propyl iodide, propyl bromide, propyl chloride, cyclopropylmethyl bromide, benzyl bromide, methylene chloride and dichloroethane. Those skilled in the art will appreciate that the list of exemplary agents presented is non-limiting and may be reasonably extended.

For example, quaternary ammonium salts can be formed at the N atom of the azabicyclo structure shown in the formula below.

Where

Z is for example methyl, chloromethyl, ethyl, chloroethyl, propyl, cyclopropylmethyl or benzyl and the corresponding anion A is for example iodide, bromide, chloride, triflate, tosylate or mesylate to be. See, eg, compounds 1, 13 and 165.

Preferably, the salt formed is pharmaceutically acceptable when administered to a mammal. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates which are used, for example, after the compounds have been isolated as salts, which are then treated with alkaline reagents and converted back to the free base compound. For example, alkyl halide addition salts (eg salts formed by reaction with methyl iodide) can be observed. The free base can then be converted to pharmaceutically acceptable acid addition salts, if desired.

Those skilled in the art will also recognize that some of the compounds of Formulas (I), (II), (III) and (IV) may exist in different polymorphic forms. As is known in the art, polymorphism is the ability of a compound to crystallize into more than one discrete crystal or “polymorphic” species. Polymorphs are solid crystalline forms of compounds having polymorphic forms of compound molecules in two or more different alignments or solid states. Polymorphic forms of any given compound are defined by the same chemical formula or composition and the chemical structure is distinguished by the crystalline structure of two different chemical compounds.

Those skilled in the art will also recognize that compounds of formulas (I), (II), (III) and (IV) may exist in different solvate forms. Solvates of the compounds of the present invention may also be formed when solvent molecules are incorporated into the crystalline lattice structure of the compound molecules during the crystallization process.

The compounds of the present invention can be administered alone or as active ingredients of the formulation. Accordingly, the present invention also encompasses pharmaceutical compositions of the compounds of formulas (I) to (IV) containing, for example, one or more pharmaceutically acceptable carriers.

A number of standard references are available describing the procedures used to prepare various formulations suitable for administering the compounds according to the invention. Examples of potential agents and medicaments are described, for example, in 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., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition). .

The compounds of the present invention can be administered to anyone in need of stimulation of the α-7 receptor in terms of their α-7 stimulatory activity, preferably their high selectivity. Depending on the needs of the patient, it may be administered orally, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and infusion), for example by inhalation, rectal, vaginal, topical route and ocular administration.

When administering a compound of the present invention, various solid oral dosage forms can be used, including solid forms such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. Compounds of the present invention may be used alone or in various pharmaceutically acceptable carriers, diluents (eg, sucrose, mannitol, lactose, starch) and excipients (suspending agents, solubilizers, buffers, binders, disintegrants, preservatives known in the art). , Colorants, flavors, lubricants, and the like). Time release capsules, tablets and gels are also advantageous for administering the compounds of the present invention.

When administering a compound of the present invention, various liquid oral dosage forms may be employed including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such dosage forms also include suitable inert diluents and preservatives known in the art such as water, wetting agents, sweeteners, flavoring agents, as well as suitable excipients known in the art such as formulations used for emulsifying and / or suspending the compounds of the present invention. It may contain. The compounds of the invention can be injected (eg, intravenous) in the form of isotonic sterile solutions. Other agents are also possible.

Suppositories for rectal administration of a compound of the present invention may be prepared by mixing the compound with suitable excipients such as cocoa butter, salicylate and polyethylene glycol. Formulations for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations, which contain, in addition to the active ingredient, suitable carriers as known in the art.

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

Aerosol formulations suitable for administration via inhalation may also be prepared. For example, when treating a respiratory disorder, the compounds according to the invention can be administered by inhalation in the form of a powder (eg finely divided powder) or in the form of a nebulized solution or suspension. Aerosol formulations may be placed in an acceptable pressurized propellant.

The compound may be administered alone or used in the treatment of cognitive impairment and / or memory loss, for example other α-7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic m1 and m2 modulators, Other pharmaceutical preparations such as adenosine receptor modulators, ampacins, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, cannabinoid modulators and cholinesterase inhibitors (e.g., donepezil, rivastigimin and glantanamin) It can be administered together with. In such combinations, the active ingredients may each be administered according to their usual dosage range or below their conventional dosage range.

Compounds of the invention can be used in conjunction with "positive modulators" that enhance the efficacy of nicotinic receptor agonists. See, for example, the positive regulators disclosed in WO 99/56745, WO 01/32619 and WO 01/32622. Such combination therapy can be used to treat symptoms / diseases associated with reduced nicotine delivery.

In addition, the compounds can be used with compounds that bind to Aβ peptides and inhibit the peptides from binding to the α7nACh receptor subtype. See, eg, WO 99/62505.

The invention also encompasses methods of treatment comprising activation of the α-7 nicotinic receptor. Thus, the present invention relates to patients (eg, mammals such as humans) where the selective activation / stimulation of α-7 nicotinic receptors has a therapeutic effect, such as neurological syndromes such as memory loss, especially long term memory loss. And selectively activating / stimulating α-7 nicotinic receptors in patients capable of alleviating the symptoms associated with the disease. Such methods include administering an effective amount of a compound of Formulas I to IV to a patient (eg, a mammal, such as a human), either alone or as part of a formulation, as disclosed herein.

According to a method aspect of the invention, said patient comprising administering a compound according to Formulas I to IV to a patient (eg, a mammal such as a human) suffering from a disease state (eg, memory impairment) The treatment method of is provided. Preferably, the disease state is associated with reduced nicotinic acetylcholine receptor activity.

A disease resulting from dysfunction of nicotinic acetylcholine receptor delivery in a patient (eg, a mammal, such as a human), comprising administering an effective amount of a compound according to Formulas (I) through (IV) according to a method aspect of the invention Or a method of treating or preventing a symptom is provided.

In accordance with a method aspect of the invention, a deficiency or function of nicotinic acetylcholine receptors, in particular α7nACh receptors, in a patient (eg, a mammal, such as a human), comprising administering an effective amount of a compound according to Formulas I to IV Methods of treating or preventing a disease or condition resulting from failure are provided.

Nicotinic acetylcholine inhibited in a patient (eg, a mammal, such as a human), comprising administering an amount of a compound according to Formulas (I) to (IV) effective to activate the α7nACh receptor according to the method aspect of the present invention Methods of treating or preventing a disease or condition resulting from receptor delivery are provided.

According to another method aspect of the invention, a psychotic disorder, cognitive impairment (eg, memory) in a patient (eg, a mammal such as a human), comprising administering an effective amount of a compound according to Formulas I-IV Injury) or neurodegenerative diseases are provided.

According to another method aspect of the invention, a disease or condition resulting from the loss of cholinergic synapses in a patient (eg, a mammal, such as a human), comprising administering an effective amount of a compound according to Formulas I-IV Methods of treating or preventing the present are provided.

According to another method aspect of the invention, a neurodegenerative disorder is treated by activation of the α7nACh receptor in a patient (eg, a mammal, such as a human), comprising administering an effective amount of a compound according to Formulas I to IV or A method of prevention is provided.

According to another method aspect of the invention, neurons from neurotoxicity induced by activation of the α7nACh receptor in a patient (eg, a mammal, such as a human), comprising administering an effective amount of a compound according to Formulas I to IV A method of protecting the protection is provided.

According to another method aspect of the invention, a neuron is inhibited by inhibiting the binding of the Aβ peptide to the α7nACh receptor in a patient (eg, a mammal such as a human), comprising administering an effective amount of a compound according to Formulas (I) to (IV). Methods of treating or preventing degenerative disorders are provided.

In accordance with another method aspect of the invention, neurons are protected from neurotoxicity induced by Aβ peptides in a patient (eg, a mammal such as a human), comprising administering an effective amount of a compound according to Formulas (I) to (IV). A method is provided.

According to another method aspect of the invention, inhibition of cholinergic function induced by Aβ peptides in a patient (eg, a mammal, such as a human), comprising administering an effective amount of a compound according to Formulas I-IV Methods of mitigation are provided.

The subject or patient to which the therapeutic compound, which is a therapeutic regimen effective for a disease or disorder, is preferably a human or any animal, including laboratory animals associated with clinical trials or screenings or actual experiments. Thus, as one of ordinary skill in the art will readily appreciate, the methods, compounds and compositions of the present invention may be applied to any animal, particularly a mammal, such as a human, a domestic animal such as a cat or a dog subject, a farm animal such as a cow, a horse, a goat, To wild animals (wild or zoological animals), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., bird species such as chickens, turkeys, songbirds, etc. Particularly suitable for administration for veterinary use.

The compounds of the invention are agonists, in particular partial agonists, for the nicotinic α-7 ligand, preferably the α-7 nicotinic acetylcholine receptor. Assays for determining nicotinic acetylcholine activity are known in the art. See, for example, Davides, A.R., et al., Characterization of the binding of [3H] methyllycaconitine: a new radioligand for labeling alpha 7-type neuronal nicotinic acetylcholine receptors. Neuropharmacology, 1999. 38 (5): p. 679-90. As agonists for the α7nACh receptor, the compounds are useful for the prevention and treatment of various diseases and conditions associated with the central nervous system. The nicotinic acetylcholine receptor is a ligand-gastrol ion-channel receptor and consists of five subunit proteins that form central ion-conducting pores. Currently, 11 neuron nACh receptor subunits (α2-α9 and β2-β4) are known. In addition, there are five additional subunits (α1, β1, γ, δ, ε) that are expressed in the peripheral nervous system.

The nACh receptor subtypes can be homomers or heteromers. Subtypes of considerable attention are homopenta α7 receptor subtypes formed from five α7 subunits. The α7nACh receptor exhibits high affinity for nicotine (agonist) and α- bungarotoxin (antagonist). Studies have shown that a7nACh receptor agonists may be useful for the treatment of mental illness, neurodegenerative disorders and cognitive impairment. Nicotine is a known agonist, but there is a need to develop other α7nACh receptor agonists, particularly selective agonists, which are less toxic or have fewer side effects than nicotine.

The compound anabasein (ie 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine is a toxin produced naturally in certain marine worms (nemertine worms) and ants. See, eg, Kem et al., Toxicon, 9:23, 1971. Anabasein is a potent activator of mammalian nicotinic receptors, see, eg, Kem, Amer. Zoologist, 25 , 99, 1985. Certain anabasein analogs, such as anabacin 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. One particular anabasein analog, also known as GTS-21 and DMXB, is E-3- [2. , 4-dimethoxy-benzylidene] -anabasane (see, eg, US 5,741,802) is an optional partial α7nACh receptor agonist under intensive study. For example, abnormal sensory suppression is a sensory processing deficiency in schizophrenia and GTS-21 has been shown to increase sensory suppression through interaction with the α7nACh receptor, see, eg, Stevens et al., Psychopharmacology, 136 : 320-27 (1998).

Another compound known as the selective α7nACh receptor agonist is Tropisetron, ie 1αH, 5αH-tropan-3α-yl indole-3-carboxylate. J.E. Macor et al., The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selective A7 Nicotinic Receptor Partial Agonist. Bioorg. Med. Chem. Lett. 2001, 319-321.

Agents that bind to nicotinic acetylcholine receptors can be used to treat a variety of diseases and conditions, particularly mental disorders, neurodegenerative diseases associated with dysfunction of the cholinergic system, and symptoms of memory and / or cognitive impairment, such as schizophrenia, anxiety, mania , Depression, mood swings [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], cognitive disorders (eg Alzheimer's disease) , Lewy Body dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficit, attention deficit, attention deficit hyperactivity disorder, etc. It is also known to have other uses such as pain treatment (ie, analgesic use), neuroprotection and treatment of jet lag. For example, 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, an effective amount of a compound according to formulas (I) to (IV) is used to treat mental disorders, neurodegenerative diseases associated with dysfunction of the cholinergic system, and memory and / or cognitive impairment symptoms such as schizophrenia, anxiety Mania, depression, mood swings [examples of psychotic disorders], Tourette syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative disorders], and / or cognitive disorders (eg Alzheimer's disease, Lewy body dementia, amyotrophic lateral sclerosis, memory impairment, Methods of treating such patients, including administration to a patient suffering from memory loss, cognitive deficit, attention deficit, attention deficit hyperactivity disorder, in particular human, are provided.

Neurodegenerative disorders encompassed within the methods of the present invention include Alzheimer's disease, Pick's disease, diffuse Lewis body disease, progressive nuclear palsy (Steel-Richardson syndrome), systemic degeneration (Shy-Dragger syndrome). (Shy-Drager syndrome)), motor neuron disease, e.g., atrophic lateral sclerosis, degenerative ataxia, cortical basal degeneration, ALS-Parkinson-dementia complications in Guam, subacute scleroderma, Huntington's disease, Parkinson's disease, Synucleinopathy, primary progressive aphasia, striatal melanoma, Macado-Joseph disease / spinal cerebellar ataxia type 3, olive cerebellar degeneration, Gilles de La Tourette disease, soft palsy, pseudoparesis, spinal muscular atrophy, spinal muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paralysis, Wedni-Hoffmann disease, Kugelberg- bell Kuelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spasm disease, Wohlfart-Kügelberg-Welder disease, spastic paraplegia , Advanced multifocal encephalopathy, prion diseases (e.g. Creutzfeldt-Jakob's disease, Gerstmann-Straeussler-Scheinker's disease, Kuru) ) And lethal family insomnia), and cerebral ischemia or cerebral infarction (e.g., embolic and thrombotic occlusion), as well as any type of intracranial hemorrhage (including epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, and intracranial hemorrhage), and Treatment and / or prevention of neurodegenerative disorders resulting from intracranial and spinal lesions (including bruises, penetrating, amputation, compression and laceration, etc.).

In addition, age-related dementia and other memory loss-related dementia and symptoms, such as age-related memory loss, aging, vascular dementia, interspersed white matter disease (Binswanger's), using α7nACh receptor agonists such as the compounds of the invention. disease)), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain injury, boxer dementia and prefrontal dementia. See, eg, WO 99/62505. Thus, according to the present invention there is provided a method of treatment of a patient comprising administering to a patient suffering from age-related dementia and other memory loss-related dementia symptoms, in particular an effective amount of a compound according to formulas (I) to (IV). do.

Thus, according to another embodiment, the present invention comprises administering an effective amount of a compound according to formulas (I) to (IV), for example Alzheimer's disease, mild cognitive impairment by aging, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Methods for treating patients suffering from memory impairments caused by HIV and cardiovascular disease, as well as Creutzent-Jacob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiple infarct dementia and other neurological symptoms.

Amyloid precursor protein (APP) and Aβ peptides derived therefrom such as Aβ _1-40 , Aβ _1-42 and other fragments are known to be associated with the pathology of Alzheimer's disease. Aβ _1-42 peptides are known to be involved in neurotoxicity as well as inhibit cholinergic transporter function. In addition, it was determined that the Αβ peptide binds to the α7nACh receptor. Thus, agents that block the binding of Aβ peptides to α-7 nAChR are useful for treating neurodegenerative diseases. See, eg, WO 99/62505. It can also stimulate the α7nACh receptor to protect neurons from cytotoxicity associated with Aβ peptides. See, eg, Kihara, T. et al., Ann. Neurol., 1997, 42, 159.

Thus, according to an embodiment of the invention, a therapeutically effective amount of a compound according to formulas (I) to (IV) is administered to a subject to provide amyloid beta peptides (preferably Aβ _1-42 ) and nACh receptors, preferably α7nACh receptors Methods of treating and / or preventing dementia in Alzheimer's patients, preferably comprising inhibiting binding of human α7nACh receptors, as well as cognitive and speech deficits, behavioral disorders, depression, delusions and other neuropsychiatric signs and conditions And other clinical signs of Alzheimer's disease, including dyskinesia and gait dysfunction).

The invention also includes other amyloidosis diseases, such as congenital cerebrovascular disease, congenital non-neuropathy amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreas. Methods of treating related and heart-related amyloidosis, chronic hemodialysis arthrosis and amyloidosis in Finland and Iowa.

Nicotinic receptors are also known to play an important role in the body's response to alcohol intake. Thus, agonists for the α7nACh receptor can be used for the treatment and detoxification therapy of alcohol withdrawal. Thus, in accordance with an embodiment of the present invention, there is provided a method of treating a patient comprising administering an effective amount of a compound according to Formulas I to IV to a patient with alcohol withdrawal or a patient having detoxification therapy.

Agonists for the α7nACh receptor subtype may also be used for neuroprotection from damage and glutamate-induced excitatory toxicity associated with stroke and ischemia. Thus, in accordance with an embodiment of the present invention, administering an effective amount of a compound according to Formulas I to IV to a patient for providing neuroprotection against damage associated with stroke and ischemia and glutamate-induced excitatory toxicity. The treatment method of is provided.

As mentioned above, agonists for the α7nACh receptor subtype can also be used to treat nicotine addiction, induce smoking cessation, to treat pain, and to treat jet lag, obesity, diabetes and inflammation. Thus, according to an embodiment of the present invention, administering to a patient suffering from nicotine intoxication, pain, jet lag, obesity, diabetes and / or inflammation an effective amount of a compound according to formulas (I) to (IV) A method of treatment or a method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to Formulas I to IV is provided.

Inflammatory reflexes are autonomic nervous system responses to inflammatory signals. When detecting inflammatory stimuli, the autonomic nervous system responds by releasing acetylcholine through the vagus nerve and activating nicotinic α7 receptors in macrophages. These macrophages then release cytokines. Dysfunction in this pathway is associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. Macrophages express nicotinic α7 receptors, which are thought to mediate cholinergic anti-inflammatory responses. Thus, compounds having affinity for the α7nACh receptor on macrophages may be useful for human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. See, eg, Czura, C J et al., J. Intern. Med., 2005, 257 (2), 156-66.

Thus, in accordance with an embodiment of the present invention, an effective amount of a compound according to formulas (I) to (IV) is administered to a patient (eg, a mammal such as a human) suffering from an inflammatory disease or disorder, such as rheumatoid arthritis, diabetes or sepsis, and the like. Provided is a method of treating said patient, including.

In addition, labeled derivatives of the compounds of formulas (I) to (IV), such as C ¹¹ or F ¹⁸ labeled derivatives, have affinity for the α7nACh receptor and therefore may be used, for example, for neuroimaging of receptors in the brain. Thus, using such labeled agents, the receptor can be imaged in vivo, for example by PET imaging.

Symptoms of memory impairment are evidenced by impairment in the ability to learn new information and / or lack of recall of previously learned information. Memory impairment is a primary sign of dementia and may also be related to diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease, and head trauma, as well as age-related cognitive decline. Can be.

Thus, according to embodiments of the present invention, forgetfulness associated with, for example, minor cognitive impairment (MCI), vascular dementia (VaD), age-related cognitive decline (AACD), cardiac incision, heart failure and / or general anesthesia Premature exposure to memory, lack of sleep-induced cognitive impairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive impairment, Down syndrome, alcoholism-related dementia, drug / substance-induced memory impairment A method of treating a patient comprising administering to a patient suffering from boxer dementia (Boxer syndrome) and animal dementia (eg, dog, cat, horse, etc.) an effective amount of a compound according to formulas (I) to (IV). This is provided.

Dosages of the compounds of the present invention may, among other considerations, include the specific syndrome being treated, the severity of the indication, the route of administration, the frequency of the interval of administration, the specific compound used, the efficacy, the toxicity profile, the pharmacokinetic profile of the compound and any deleterious side effects. It depends on many factors, including its existence.

Compounds of the present invention may be administered to patients (eg, mammals, especially humans) at dosage levels typical of the α-7 nicotinic receptor agonists, such as the above-mentioned known α-7 nicotinic receptor agonist compounds. May be administered. For example, the compound may be administered orally in single or multiple doses at a dosage level of, for example, 0.0001 to 10 mg / kg / day, for example 0.01 to 10 mg / kg / day. The unit dosage form may contain, for example, 1 to 200 mg of active compound. For intravenous administration, the compounds may be administered in single or multiple doses.

In carrying out the procedures of the present invention, references to particular buffers, media, reagents, cells, culture conditions, etc., are not intended to be limiting, of course, but are all relevant to those of ordinary skill in the art that are of interest or value in the particular context under discussion. It is to be understood to include the substance. For example, one buffer system or culture medium may be replaced with another, but not identical, but still achieve similar results. Those skilled in the art will have sufficient knowledge of the systems and methods that can be substituted to optimally serve their purposes without undue experimentation in using the methods and procedures disclosed herein.

The present invention will now be described in more detail with the following non-limiting examples. In applying the disclosures of these examples, it should be clearly noted that many other embodiments of the methods disclosed in accordance with the present invention will of course be proposed to those skilled in the art as such.

In the above and the following examples, all temperatures are described in degrees Celsius in an uncalibrated state, and all parts and percentages are by weight unless otherwise indicated.

The entire disclosures of all applications, patents, and publications cited above and below are incorporated herein by reference in their entirety.

Using the following procedure and the additional procedure described below, the following compounds were prepared. The synthesis of related compounds is also described in US Patent Application Nos. 11 / 089,533 and 10 / 669,645, the entirety of which is incorporated herein by reference in its entirety.

All spectra were recorded at 300 MHz on a Bruker Instruments NMR unless otherwise noted. Coupling constants (J) are expressed in hertz (Hz) and peaks are listed for 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 (TM) microwave reactor. All reactions were performed at 200 ° C. for 600 seconds with a fixed hold time ON unless otherwise stated. Sulfonic acid ion exchange resins (SCX) were purchased from Varian Technologies. Analytical HPLC was performed for 6 minutes using a gradient of 20/80 → 80/20 acetonitrile (0.1% formic acid) / water (0.1% formic acid) on a 4.6 mm × 100 mm Xterra RP ₁₈ 3.5 μ column. It was. For compound 57, a gradient of 5/95 to 60/40 acetonitrile (0.1% formic acid) / water (0.1% formic acid) was used. For compounds 116-130, a gradient of 10/90 → 80/20 acetonitrile (0.1% formic acid) / water (0.1% formic acid) was used for 8 minutes.

Preparative HPLC was obtained using a gradient of (i) 20/80 → 80/20 acetonitrile (0.1% formic acid) / water (0.1% formic acid) on a 30 mm × 100 mm Xterra Prep RP ₁₈ 5 μ column (8 Min) (compounds 1-50, 54-57, 59, 60, 63-77, 79-131 and 149-185), (ii) 5 / 95-> 95/5 acetonitrile (0.05% trifluoroacetic acid) / Gradient of water (0.05% trifluoroacetic acid) (30 minutes) (compounds 51 to 53), (iii) gradient of 10/90 to 60/40 acetonitrile (0.1% formic acid) / water (0.1% formic acid) (8 Min) (compounds 58, 61, 62, 78, and 132 to 137), (iv) gradient of 5/95 to 60/40 acetonitrile (0.1% formic acid) / water (0.1% formic acid) (8 min) (compound 186 to 190), or (v) a gradient of 10/90 to 80/20 acetonitrile (0.1% formic acid) / water (0.1% formic acid) (8 minutes) (compounds 138 to 148).

Acid manufacturing

The following procedures (1 to 29) describe in detail the preparation of indazole, benzisoxazole and benzisothiazole acids and esters which are not commercially available.

Procedure 1

Procedure 1 provides a method for preparing substituted benzisothiazole-3-carboxylic acids from the corresponding thiophenols.

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

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

To a solution of amide (5.46 mmol) in methanol (100 mL) was added 10N sodium hydroxide (12 mL). The mixture was heated at reflux for 12 h, cooled to rt and acidified to less than pH 2 by the slow addition of concentrated hydrochloric acid. The organic layer was extracted with dichloromethane (2 ×) and dried over sodium sulfate. The crude product was purified by chromatography (300/50/1 dichloromethane / methanol / formic acid) to give acid (89%) as a pink solid.

The following acids were prepared using this method:

6-bromobenzisothiazole-3-carboxylic acid.

5-bromobenzisothiazole-3-carboxylic acid.

6-methoxybenzisothiazole-3-carboxylic acid.

7-bromobenzisothiazole-3-carboxylic acid.

The following esters were prepared from acids using ethanol and sulfuric acid:

Ethyl 6-bromobenzisothiazole-3-carboxylate.

Ethyl 6-methoxybenzisothiazole-3-carboxylate.

tert-butyl 5-bromo-1,2-benzisothiazole-3-carboxylate.

Benzisothiazole tert-butyl ester was prepared using the following procedure:

Di-tert-butyldicarbonate (128 mmol) was converted to 6-bromo-1,2-benzisothiazole-3-carboxylic acid in tert-butyl alcohol (40.0 mL) and tetrahydrofuran (40.0 mL). 46.5 mmol) and 4-dimethylaminopyridine (4.26 mmol), and the reaction mixture was heated at 65 ° C. for 16 h. Carbon dioxide was released vigorously and gradually quenched, resulting in a homogeneous mixture. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The dichloromethane solution was filtered through silica gel (ca 50 g) and the eluate was concentrated to give ester product (99% yield).

Using this method the following esters were prepared:

tert-butyl 6-bromo-1,2-benzisothiazole-3-carboxylate.

Procedure 2

Procedure 2 provides a process for preparing isatin from aniline and a process for converting the isatin to the corresponding indazole-3-carboxylic acid.

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

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

The method for converting substituted isatin to the corresponding indazole-3-carboxylic acid is essentially the same as described for indazole-3-carboxylic acid (Snyder, HR, et. Am. Chem. Soc. 1952, 74, 2009]. Substituted isatin (22.1 mmol) was diluted with 1N sodium hydroxide (24 mL) and heated at 50 ° C. for 30 minutes. The Burgundy solution was cooled to room temperature and maintained 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 pipette at 0 ° C. under a surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL). It took 15 minutes to add and the reaction was held for 30 more minutes. A cold (0 ° C.) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 minutes and the reaction mixture was maintained for 60 minutes. The precipitated solid was isolated by filtration, washed with water and dried to achieve quantitative mass balance. This substance is then purified without further purification Have sufficient purity to use ( ¹ H NMR and LC / MS). Alternatively, the acid was recrystallized from acetic acid to give pure material.

The following acids were prepared using this method:

6-bromo-1H-indazol-3-acid.

5-methoxy-1H-indazol-3-acid.

6-methoxy-1H-indazol-3-acid.

Procedure 3

Procedure 3 provides a method of capturing indazole aryl lithium with ketones and coupling with 3-aminoquinuclidines to form heterocyclic derivatives.

tert-butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with 2-fold excess di-tert-butyldicarbonate followed by treatment with sodium hydroxide. To a suspension of sodium hydride (60% mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) tert-butyl 6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL) Solution was added slowly at 0 ° C. After stirring for 0.5 h at 0 ° C, 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 h 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. The residue was purified by chromatography (70/30 ethyl acetate / hexanes) to give 6- (4-hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (68 %) Was obtained as a colorless solid.

6- (4-hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) is dissolved in trifluoroacetic acid (3 mL) and the mixture is allowed to room temperature. Was maintained for 16 hours. The solvent is removed in vacuo and the residue is triturated with ethyl acetate to give 6- (3,6-dihydro-2H-pyran-4-yl) -1H-indazole-3-carboxylic acid (76%). It was. The acid was coupled with quinuclidin amine according to Procedure A.

6- (4-hydroxytetrahydropyran-4-yl) -1H-indazole-3-carboxylic acid tert-butyl ester (1.0 mmol) with trifluoroacetic acid (5 mL), triethylsilane (2 mL ) And dichloromethane (3 mL) and the mixture was refluxed for 16 h. 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 and esters were prepared using this method:

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

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

tert-butyl 6-formyl-1H-indazole-3-carboxylic acid.

tert-butyl 6-formyl-1H-indazole-3-carboxylate.

Procedure 4

Procedure 4 provides a process for preparing an N-1-alkylated indazole-3-carboxylic acid from the corresponding indazole ester.

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 h, 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 hexanes / ethyl acetate) to yield 2-substituted indazole (17%) and 1-substituted indazole (44%). . 1-Substituted indazole (61 mg, 0.26 mmol) was suspended in ethanol (5.0 mL) and warmed to facilitate dissolution. An aliquot of a 5.0 M solution of sodium hydroxide in water (2.00 mL) was added and the reaction mixture was kept at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and acidified with 6.0 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 × 50 mL) and the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated to give an acid (95% yield).

The following acids were prepared using this method:

6-bromo-1-methyl-1H-indazole-3-carboxylic acid.

6-bromo-1-ethyl-1H-indazole-3-carboxylic acid.

1-ethyl-6-methoxy-1H-indazole-3-carboxylic acid.

Procedure 5

Procedure 5 provides a method for preparing 5-difluoromethoxyindazol-3-acid from 3-bromo-4-nitrophenol.

3-bromo-4-nitrophenol (10.0 mmol) was added to a suspension of sodium hydroxide (29.0 mmol) in N, N-dimethylformamide (15 mL) and the suspension was kept at room temperature for 15 minutes. 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 h and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give difluoromethyl ether as a yellow oil (75% yield).

Diethyl malonate (328 mmol) was added dropwise at 0 ° C. to a suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40 mL). The reaction mixture was warmed to 60 ° C. and maintained for 0.5 h. A solution of difluoromethyl ether (149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the reaction mixture was heated at 100 ° C for 5 h. The cooled solution was poured into ice water and the aqueous layer was extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give crude diester as an oil (112% yield). Diester (167 mmol), sodium hydroxide (500 mmol) and water (335 mL) were combined and heated at 60 ° C. for 1 h. The reaction mixture was cooled to rt and the aqueous layer was washed with dichloromethane (3 × 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 solids collected by filtration and dried to give an acid (61% yield).

Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0 ° C. After 0.5 h, acid (101 mmol) was added and the reaction mixture was heated at reflux for 15 h. 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 give ester as a brown oil (60% yield).

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 at reflux for 10 minutes, the suspension was filtered through celite and the filter cake was washed three times with ethanol. The filtrate was concentrated and the residue suspended in 2N hydrochloric acid and stirred vigorously for 0.5 h. The aqueous layer was washed with ethyl acetate (3 × 50 mL) and the pH was adjusted to 9-10 with 5M sodium hydroxide. The aqueous layer was extracted with chloroform (3 × 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 at reflux for 16 h. 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 × 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to give N-acetylindazole ester as a brown oil (79% yield).

Ester (63.8 mmol), sodium hydroxide (193 mmol) and water (65 mL) were combined and the reaction was maintained 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 an acid (27% yield).

The following acids were prepared according to this method:

5- (difluoromethoxy) -1 H-indazole-3-carboxylic acid.

Procedure 6

Procedure 6 provides a process for preparing 6-difluoromethoxyindazol-3-acid from 4-nitrophenol.

4-nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in N, N-dimethylformamide (150 mL) and the suspension was kept 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 h and concentrated. The residue was diluted with ice water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give difluoromethyl ether as a yellow oil (59% yield).

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 at reflux for 30 minutes and the suspension was filtered through celite. The filter cake was washed three 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 × 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 kept at rt for 16 h. 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 light yellow solid (62% yield).

Acetic anhydride (19.6 mmol) was added to a solution of acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 minutes. The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give nitro-amide (83% yield).

Amide (11.0 mmol), sodium hydroxide (43.8 mmol) and water (10 mL) were combined, the reaction mixture was maintained at 60 ° C. for 1.5 h, the reaction was cooled to room temperature, the precipitated solid was isolated by filtration, Washed with water and dried to give aniline as a light yellow solid (98% yield).

Aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90 ° C. to completely dissolve 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 for 15 minutes. The solution was kept at 0-5 ° C. for 40 minutes and filtered. Copper bromide (I) (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and cooled to 0 ° C. The solution of diazo salt was slowly added to the copper solution and the mixture was held at 0-10 ° C. for 30 minutes. The reaction mixture was heated at 60 ° C. for 30 minutes and then at 100 ° C. for 10 minutes to complete the reaction. The reaction mixture was cooled to rt and extracted with dichloromethane (3 × 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 nitro bromide as a light yellow solid (76% yield).

Diethyl malonate (25.7 mmol) was added dropwise at 0 ° C. to a suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5 mL). The reaction mixture was warmed to 60 ° C and held for 30 minutes. A solution of nitro bromide (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 × 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give crude diester as an oil. Diester (11.7 mmol), sodium hydroxide (35 mmol) and water (20 mL) were combined and heated at 60 ° C for 1 h. The reaction mixture was cooled to rt and the aqueous layer was washed with dichloromethane (3 × 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 solids collected by filtration and dried to give an acid (64% yield).

Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 ° C. After 30 minutes, acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. 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 × 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to give ester as a brown oil (94% yield).

Acetic anhydride (6.0 mL) was added to the ester (3.64 mmol) and acetic acid (7.0 mL) suspension at 0 ° C. Zinc dust (14.6 mmol) was added in portions for 15 minutes and the reaction mixture was kept at 0 ° C. for 30 minutes and then at room temperature for 1.5 hours. Additional zinc powder (6.15 mmol) was added and the reaction maintained 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 × 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to give acetamide as a brown oil (92% yield).

Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol) and potassium acetate (2.04 mmol) were added to a solution of acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was heated at reflux for 16 h. . 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 × 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to give crude N-acetylindazole ester as a brown oil.

Ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was maintained at 60 ° C. for 24 hours. After cooling to rt, the aqueous layer was washed with dichloromethane (3 × 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 an acid (26% yield).

The following acids were prepared according to this method:

6- (difluoromethoxy) -1H-indazole-3-carboxylic acid.

Procedure 7

Procedure 7 provides a method of coupling a brominated benzisothiazole-3-carboxylic acid ester and a brominated indazole-3-carboxylic acid ester and a Grignard reagent to form a heteroaromatic-substituted acid.

A 0.5 M solution of Grignard reagent (75.0 mmol) in tetrahydrofuran was diluted with tetrahydrofuran (150 mL), cooled to 5 ° C. and treated with solid zinc chloride (165 mmol). The reaction mixture was allowed to warm to room temperature and brominated ester (28.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.64 mmol) were added. The suspension was heated at 65 ° C. for 16 h and concentrated. The reaction was partitioned between ethyl acetate (250 mL) and 7M ammonium chloride (500 mL). The aqueous layer was extracted with ethyl acetate (3 × 250 mL) and the combined extracts were dried over sodium sulphate and concentrated to dryness. The residue was purified by chromatography (using a gradient of 100/0 to 97/3 chloroform / methanol) to give an ester (80% yield). The ester was suspended in methanol (100 mL) and treated with 8M sodium hydroxide (30 mL). The mixture was heated at 60 ° C. for 3 h, cooled to rt, filtered and acidified to less than pH 2 by the slow addition of concentrated hydrochloric acid. The aqueous layer was concentrated and the residue triturated with water. The resulting solid was recrystallized from water to give an acid (81% yield).

Grignard reagents for thiazoles are commercially available. Alternatively, aryl lithium and the corresponding aryl zinc reagents are described in Reeder, M.R .; et. al., Org. Proc. Res. Devel. 2003, 7, 696] can be prepared according to the procedure outlined. Zinc reagent of oxazole was prepared according to the above procedure.

The following acids were prepared using this method:

6- (1,3-thiazol-2-yl) -1H-indazol-3-carboxylic acid.

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

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

Procedure 8

Procedure 8 provides a process for preparing N-methoxyethoxymethyl and N-trimethylsilylethoxymethyl protected indazole acids and esters from the corresponding indazole esters using alkylation conditions.

Representative procedure for N (1) -alkylation : A solution of ethyl 5- (benzyloxy) -1H-indazole-3-carboxylate (2.70 mmol) in tetrahydrofuran (10 mL) was added to tetrahydrofuran (54.0 mL). ) Was added dropwise to a 0 ° C. suspension of sodium hydride (60% mineral oil dispersion, 8.1 mmol). The reaction was kept at 0 ° C for 1 hour. [β- (trimethylsilyl) ethoxy] methyl chloride (3.2 mmol) was added and the reaction mixture was maintained for 1 hour. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 → 85/15 hexanes / ethyl acetate) to give protected indazole (89% yield).

Representative procedure for N (2) -alkylation : 2-methoxyethoxy methyl chloride (48.0 mmol) was added ethyl 6-bromo-1H-indazol-3-carboxylate (40.0 mmol) in methylene chloride (80.0 mL). ) And a suspension of N, N-diisopropylethylamine (80.0 mmol). The reaction became homogeneous and kept at room temperature for 4 hours. The reaction mixture was concentrated and the residue was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated to give a sufficiently pure product of a 2/1 mixture of N (2)-regioisomers and N (1)-regioisomers. (89%) was obtained as a yellow oil.

5.0 M sodium hydroxide (52 mL) is added to a solution of ethyl 6-bromo-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylate (18.2 mmol), The reaction mixture was maintained for 16 hours. The solution was diluted with water (50 mL) and acidified with 6.0N hydrochloric acid. The slurry was extracted with ethyl acetate (50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was recrystallized from toluene to give a colorless solid (82%) as a regioisomer mixture.

Using this method the following esters and acids were prepared:

6-bromo-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylic acid.

Ethyl 6-bromo-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylate.

Ethyl 6-benzyloxy-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylate.

6-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid.

Ethyl 6-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid.

5-Bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole-3-carboxylic acid.

6-bromo-2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole-3-carboxylic acid.

5-Bromo-2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole-3-carboxylic acid.

Ethyl 6-bromo-2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole-3-carboxylic acid.

Ethyl 5-bromo-2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole-3-carboxylic acid.

Ethyl 5-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid.

Procedure 9

Procedure 9 provides a process for preparing alkoxy indazole acid from the corresponding benzyloxy indazole ester using Mitsunobu conditions.

Ethyl 6-benzyloxy-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylate (9.38 mmol) in 10% palladium on carbon (249 mg) in ethanol (66.7 mL) To the suspension of. The reaction was shaken for 4.0 hours under hydrogen atmosphere (50 psi). The reaction was filtered through celite and concentrated to give phenol as a white solid (87% yield).

Diisopropyl azodicarboxylate (0.841 mmol) was added ethyl 6-hydroxy-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxyl in tetrahydrofuran (4.6 mL). To a solution of rate (0.765 mmol), 1-methyl-3-pyrrolidinol (0.917 mmol) and triphenylphosphine (1.15 mmol) was added dropwise. The reaction was maintained for 16 hours and concentrated. The residue was purified by chromatography (100/0 → 90/10 ethyl acetate / [70/30/2 ethyl acetate / methanol / dimethylethylamine]) to give the ether product (28% yield). Saponification of the ester gave an acid, which was coupled to the bicyclobase using Procedure C.

The following acids were prepared using this method:

Ethyl 6-hydroxy-1-[(2-methoxyethoxy) methyl] -1H-indazole-3-carboxylate.

1-[(2-methoxyethoxy) methyl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3-carboxylic acid.

1-[(2-methoxyethoxy) methyl] -6- (tetrahydrofuran-3-yloxy) -1H-indazole-3-carboxylic acid.

1-[(2-methoxyethoxy) methyl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazole-3-carboxylic acid.

6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benzisothiazole-3-carboxylic acid.

6- (1-Azabicyclo [2.2.2] oct-3-yloxy) -1,2-benzisothiazole-3-carboxylic acid.

Procedure 10

Procedure 10 provides a method for preparing 4-methoxyindazole acid from 4-methoxyaniline.

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

Concentrated nitric acid (210 mL) was added dropwise to a solution of acetamide (1.52 mol) in dichloromethane (1.5 L) at room temperature. The reaction mixture was heated at 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 (83% yield).

A solution of 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 nitroaniline as an orange solid (85% yield).

A solution of sodium nitrite (1.48 mol) in water (250 mL) was prepared by heating a cold (0-5 ° C.) solution of nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (reaction mixture heated at 90 ° C. for 2 hours. Is added). The reaction mixture was maintained for 40 minutes and filtered. The filtrate was added dropwise to a cold (0-5 ° C.) solution of copper bromide (I) (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 minutes. The reaction mixture was warmed to 60 ° C. and maintained for 30 minutes. The reaction mixture was warmed to reflux and maintained for 1 hour. The reaction mixture was diluted with water (2 L) and extracted with dichloromethane (3 × 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 bromide as a yellow solid (50% yield).

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

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

α-oxime amide (58.6 mmol) was added to warm (40 ° C.) 90% sulfuric acid (16 mL) in one portion 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 give isatin as a yellow solid (57% yield).

Isatin (20.7 mmol) was mixed with 1M sodium hydroxide (23 mL) and the reaction mixture was heated to 30-40 ° C. for 30 minutes. The reaction mixture was cooled to 0 ° C. and treated with a solution of sodium nitrite (20.7 mmol) in water (5.1 mL) and maintained for 20 minutes. This solution was added dropwise to a cold (0-5 ° C.) solution of concentrated sulfuric acid (2.24 mL) in water (43.3 mL) and the reaction mixture was maintained 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 maintained at 0-5 ° C. for 1 h. The precipitated solid was isolated by filtration and dried to give indazole acid as a yellow solid (100 mass%).

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

Indazole ester (1.02 mmol) was combined with carbonic phase 10% palladium (30 mg) and methanol (20 mL) at room temperature under hydrogen gas atmosphere for 30 minutes. The catalyst was removed by filtration and the eluate was concentrated to give the de-brominated indazole ester as an orange solid (24% yield).

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

The following acid was prepared using this procedure:

4-methoxy-1H-indazole-3-carboxylic acid.

Procedure 11

Procedure 11 provides a process for preparing benzyloxy-substituted indazole-3-carboxylic acids and esters from the corresponding bromo nitrobenzene.

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

65% nitric acid (22 mL) was added dropwise to a solution of acetamide (200 mmol) in dichloromethane (200 mL) over 0.5 h. The reaction mixture was kept at room temperature for 1 hour and heated at 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 nitro acetamide (90%) as a yellow solid.

Nitroacetamide (180 mmol) was added to 4M sodium hydroxide (180 mL) and the reaction mixture was maintained 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 (70% yield).

A solution of sodium nitrite (11.8 g) in water (28 mL) was added dropwise to a solution of nitroaniline (125 mmol) in 40% hydrobromic acid (110 g) at 10 ° C. over 0.5 h. The reaction mixture was maintained at 0-10 ° C. for 40 minutes and filtered. The filtrate was added dropwise over 1 hour to a 0 ° C. purple solution of copper bromide (I) (209 mmol) in hydrobromic acid (74 mL). The reaction mixture was warmed to room temperature, held at room temperature for 30 minutes, held at 60 ° C. for 0.5 hours, and heated at reflux for 1 hour. The reaction mixture was partitioned between water (2.0 L) and dichloromethane (600 mL) and the aqueous layer 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 nitrobromide with a yellow oil. Obtained (83% yield).

A solution of boron tribromide (250 mmol) in dichloromethane (200 mL) was added dropwise to a solution of nitrobromide (100 mmol) in dichloromethane (250 mL) at -78 ° C over 1 hour. The reaction mixture was allowed to warm to room temperature and maintained 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 × 300 mL). The combined organic layers were washed with saturated sodium bicarbonate (2 × 300 mL), dried (magnesium sulfate) and concentrated to give nitrophenol as a brown crystalline solid (87% yield).

Benzyl bromide (131 mmol) and potassium carbonate (130 mmol) were added to a solution of nitrophenol (87.0 mmol) in 2/1 acetonitrile / acetone (840 mL). The reaction mixture was heated at reflux for 17 h 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 (2x567 mL) and brine (567 mL). The organic layer was dried (magnesium sulfate) and concentrated to give benzyl ether (78% yield).

Diethyl malonate (890 mmol) was added dropwise to a suspension of sodium hydride (520 mmol) in dimethylsulfoxide (100 mL) at 0 ° C. over 1 hour. Benzyl ether (44.0 mmol) was added and the reaction mixture was heated at 100 ° C for 5 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 × 70 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to afford the diethylmalonate addition product. The diethylmalonate addition product was diluted with 4M solution of sodium hydroxide (100 mL) and the reaction mixture was heated at 60 ° C for 6 h. 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 rt and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give phenyl acetic acid as a solid (78% yield).

Phenylacetic acid (350 mmol) was added to a freshly prepared solution of ethanol hydrochloric acid [adding acetyl chloride (5 mL) to ethanol (100 mL)] and the reaction mixture was heated at reflux for 20 h. 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 × 50 mL) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to give an ester (77% yield).

Nitro ester (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 maintained for 2 hours. An additional amount of zinc dust (2 × 45.9 mmol) was added over the course of 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 × 50 mL) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to give acetamide (82% yield).

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

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 h. 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 (28% yield).

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

The following acids were prepared using this method:

6-benzyloxy-1H-indazole-3-carboxylic acid.

5-benzyloxy-1H-indazole-3-carboxylic acid (obtained from 4-benzyloxy-2-bromonitrobenzene: Parker, KA; Mindt, TL Org. Lett., 2002, 4, 4265 ] Reference).

Ethyl 6-benzyloxy-1H-indazole-3-carboxylate.

Ethyl 5-benzyloxy-1H-indazole-3-carboxylate.

Procedure 12

Procedure 12 provides a process for preparing N (1) -difluoromethylindazole acid from the corresponding indazole-3-carboxylic acid.

Acetyl chloride (141 mmol) was added dropwise to a solution of 6-methoxy-3-indazole-carboxylic acid (26.0 mmol) in ethanol (200 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt and concentrated. The residue was dissolved in ethyl acetate (300 mL) and washed with aqueous sodium bicarbonate (2 × 50 mL). The combined aqueous layers were extracted again with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (50 mL), dried (sodium sulfate), concentrated and dried under vacuum to give 4.91 g (86%) of ester as a solid.

A solution of ethyl 6-methoxy-1H-indazole-3-carboxylate (4.54 mmol) in N, N-dimethylformamide (6.11 mL) was dissolved in sodium hydride (5.45 mmol) and N, N-dimethylformamide ( 12.2 mL), and the reaction mixture was kept at room temperature for 30 minutes. Chlorodifluoromethane (17.0 mol) was bubbled into the reaction and the mixture was warmed to 80 ° C. and maintained for 2 hours. The mixture was diluted with water (200 mL) and the precipitate collected to yield a white solid. The solid was dissolved in ethanol (20.0 mL) and 5.0M solution of sodium hydroxide (3.6 mL) was added. The reaction mixture was kept at room temperature for 2 hours, diluted with water (50 mL) and acidified with 6.0N hydrochloric acid. The precipitate was collected and dried to give an acid (65% yield).

The following acids were prepared using this method:

1- (difluoromethyl) -6-methoxy-1H-indazole-3-carboxylic acid.

6-bromo-1- (difluoromethyl) -1H-indazole-3-carboxylic acid.

Procedure 13

Procedure 13 provides a method for preparing 5-azidazol-3-carboxylic acid from 4-chloropyridine.

Saturated aqueous sodium bicarbonate solution was carefully added to a solution of 4-chloropyridine hydrochloride (56.7 mmol) in water (20 mL) until the solution became basic. The mixture was extracted with hexane (3 × 25 mL). The combined organic layers were dried over magnesium sulfate and concentrated to a volume of about 25 mL to give a solution of free base.

n-butyllithium (2.0 M in pentane, 68 mmol) was added dropwise to a solution of N, N-diisopropylamine (62.3 mmol) in tetrahydrofuran (61.6 mmol) at 0 ° C. and the reaction mixture was maintained for 30 minutes I was. The reaction mixture was cooled to -78 ° C, a hexane solution of 4-chloropyridine was added dropwise and the mixture was maintained for 1 hour. Diethyl oxalate (56.7 mmol) was added to the orange homogeneous solution and the mixture was allowed to warm to room temperature. Analysis by LC / MS showed that the main product was N, N-diisopropylamide rather than ethyl oxalate. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organics washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was dissolved in ethanol (50.0 mL), treated with hydrazine (160 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was concentrated and the residue triturated with dichloromethane to give 1.20 g (8.6%) of hydrazone product.

A mixture of N, N-diisopropyl-1H-pyrazolo [4,3-c] pyridine-3-carboxamide (0.800 g, 0.00325 mol) and aqueous hydrogen chloride (10M, 3.00 mL) was added in a microwave reaction vessel. Heated at 120 ° C. for minutes. The mixture should be heated on high adsorption conditions to avoid pressure build up. The reaction was diluted with water and neutralized with 3N sodium hydroxide. The resulting white precipitate was collected and found to be a mixture of acid (47%) and mono-isopropyl amide (25%). The mixture was used without further purification.

The following acids were prepared using this method:

1H-pyrazolo [4,3-c] pyridine-3-carboxylic acid.

Procedure 14

Procedure 14 provides a process for preparing 6-azindazol-3-carboxylic acid from 4-chloro-3-nitropyridine.

tert-Butyl ethyl propane-1,3-dioate (26.6 mmol) was added to a suspension of sodium hydride (1.11 g) in tetrahydrofuran (50.0 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature and held for 30 minutes. The reaction mixture was then cooled to 0 ° C. and a solution of 4-chloro-3-nitropyridine (12.6 mmol) in tetrahydrofuran / N, N-dimethylformamide (9/1, 10 mL) was added dropwise. The mixture was warmed to room temperature and kept for 1 hour. The reaction was quenched with water (50 mL) and neutralized to pH 5 with acetic acid (the color changed from dark brown to yellow upon neutralization). The mixture was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated to give the product (94% yield).

Crude tert-butyl ethyl (3-nitropyridin-4-yl) malonate (12.6 mmol) was dissolved in 4/1 dichloromethane / trifluoroacetic acid (25.0 mL) and the mixture was heated at reflux for 2 hours. . The reaction mixture was concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The layers were separated and the ethyl acetate layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 dichloromethane / ethyl acetate) to give the product (77% yield).

Ethyl (3-nitropyridin-4-yl) acetate (9.66 mmol) and 10% palladium on carbon (2.10 g) were diluted with ethanol (25.0 mL) in a Parr pressure reactor. The reaction mixture was shaken for 3 hours under hydrogen atmosphere (30 psi). The reaction mixture was filtered (celite) and concentrated to give the product (97% yield).

Amyl nitrite (18.9 mmol) is added to a solution of ethyl (3-aminopyridin-4-yl) acetate (9.43 mmol), potassium acetate (11.3 mmol) and acetic anhydride (28.3 mmol) in chloroform (10.0 mL), and the reaction Heated at 60 ° C. for 16 h. The cooled reaction mixture was carefully diluted with aqueous sodium bicarbonate and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (50/50 → 0/100 hexanes / ethyl acetate) in advance to give a complex mixture of products. The mixture was dissolved in ethanol (10.0 mL), diluted with 5.0 M sodium hydroxide (5.00 mL) and the reaction mixture was maintained for 16 hours. The reaction mixture was concentrated to about 5 mL, diluted with water (20 mL) and neutralized with acetic acid. The yellow solid was collected by filtration to give the desired product (18% yield).

The following acids were prepared using this method:

1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid.

Procedure 15

Procedure 15 provides a method for preparing aminobenzisothiazole-3-carboxylic acid from esters.

Cesium carbonate (3.18 mmol), palladium (II) acetate (0.24 mmol) and 2-dicyclohexylphosphino-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (0.24 mmol ) Were combined in a microwave vessel and the vessel was flushed with nitrogen. (R)-(+)-3-pyrrolidinol (3.18 mol) and tert-butyl 6-bromo-1,2-benzisothiazole-3-carboxylate (1.59) in tetrahydrofuran (20.0 mL) mol) solution was added. The vessel was sealed and heated at 135 ° C. for 30 minutes. The reaction mixture was filtered through celite (ethyl acetate) and the filtrate was concentrated. The residue was purified by chromatography (70/30 → 50/50 hexanes / ethyl acetate) to give purified ester. The ester was dissolved in dichloromethane / trifluoroacetic acid (4: 1, 2.00 mL) and maintained for 16 hours. The reaction mixture was concentrated to give the product (23% yield). The product was used without further purification.

Alternatively, when ethyl 6-bromo-1,2-benzisothiazole-3-carboxylate is used, the solution of ester in ethanol is saponified with 5N sodium hydroxide. The acid was diluted with water and neutralized with acetic acid and then collected by filtration.

The following acids and esters were prepared using this method:

6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6-[(3S) -3-Dimethylaminopyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(3R) -3-Dimethylaminopyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (3-ethoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-yl] -1,2-benzisothiazole-3-carboxylic acid.

tert-butyl 7-bromo-1,2-benzisothiazole-3-carboxylate.

7-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

7-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S) -5- (tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3 -Carboxylic acid.

6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [3-[(tert-butoxycarbonyl) (methyl) amino] pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [4- (dimethylamino) piperidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (pyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (4-methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl) -1,2-benzisothiazole-3-carboxylic acid.

5- (4-Methyl-1,4-diazepan-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

5-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

5-[(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl] -2-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazol-3-carboxylic acid .

5-[(3S) -3- (methoxy) pyrrolidin-1-yl] -2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole-3-carboxylic acid.

5-((3R) -3-{[2- (trimethylsilyl) ethoxy] methoxy} pyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

5-((3S) -3-{[2- (trimethylsilyl) ethoxy] methoxy} pyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

6- [4- (tert-butoxycarbonyl) -3-methylpiperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [1- (tert-butoxycarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxylic acid.

5-[(3S) -3-methoxypyrrolidin-1-yl] -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-3-carboxylic acid.

6- [4- (tert-butoxycarbonyl) -3-methylpiperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [1- (tert-butoxycarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [4- (tert-butoxycarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

Ethyl 6- [4- (tert-butoxycarbonyl) -1,4-diazepan-1-yl] -1,2-benzisothiazole-3-carboxylate.

6- [4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

Ethyl 6- [3-[(tert-butoxycarbonyl) (methyl) amino] pyrrolidin-1-yl] -1,2-benzisothiazole-3-carboxylate.

The following esters were prepared from N-Boc intermediates using trifluoroacetic acid:

Ethyl 6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylate.

Ethyl 6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl) -1,2-benzisothiazole-3-carboxylate.

Ethyl 6-piperazin-1-yl-1,2-benzisothiazole-3-carboxylate.

Procedure 16

Procedure 16 describes a process for preparing 6-amino-7-azidazol-3-carboxylic acid from tert-butyl 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxylate. to provide.

3-pyrrolidinol (24.7 mmol) was added to tert-butyl 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (4.22 mmol) in toluene (4.00 mL) in a microwave reaction vessel. Was added to the solution. The reaction mixture was microwaved at 120 ° C. for 300 seconds. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL) and the layers separated. The organic layer was washed with water (2 × 50 mL) and brine (25 mL) and filtered through silica gel (50 g). The silica was washed with 100 mL of EtOAc and the combined EtOAc solutions were concentrated to give the product (63% yield).

Methanesulfonyl chloride (5.52 mmol) was converted to tert-butyl 6- (3-hydroxypyrrolidin-1-yl) -1H-pyrazolo [3,4-b] pyridine-3- in dichloromethane (2.7 mL). To a cold (0 ° C.) solution of carboxylate (2.63 mmol) and triethylamine (6.57 mmol) was added dropwise. The reaction mixture was kept at rt for 16 h and diluted with water (25 mL). The dichloromethane layer was separated and transferred to a silica gel column. The column was eluted using a gradient of 90/10 to 0/100 hexanes / ethyl acetate to afford bis-mesylate (60% yield) and monomesylate (28% yield).

tert-butyl 1- (methylsulfonyl) -6-3-[(methylsulfonyl) oxy] pyrrolidin-1-yl-1H-pyrazolo [3,4-b] pyridine-3-carboxylate ( 0.380 mmol) was diluted with a 2.0 M solution of dimethylamine in tetrahydrofuran (5.0 mL) in a microwave vessel. Microwaves were irradiated to the reaction mixture at 135 ° C. for 80 minutes. The reaction mixture was concentrated and the residue was purified by chromatography {100/0 → 90/10 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]} to give the purified ester. . The ester was dissolved in 4/1 dichloromethane / trifluoroacetic acid (5.00 mL) and the mixture was kept at rt for 16 h. The volatiles were removed and the residue was dissolved in water. The mixture was neutralized with half-saturated sodium bicarbonate and the solid precipitate was collected by filtration to give the product (79% yield).

The following acids were prepared using this method:

6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid.

Procedure 17

Procedure 17 provides a process for preparing fluorinated benzisothiazole-3-carboxylic acids from esters of the corresponding benzisothiazole-3-carboxylic acids.

1-fluoro-2,6-dichloropyridinium triflate (2.25 mmol) was converted to ethyl 6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole in dichloromethane (20.0 mL). To a solution of -3-carboxylate (1.87 mmol) was added and the reaction mixture was kept at room temperature for 6 hours. The reaction mixture was filtered through silica gel (10 g, dichloromethane wash) and the eluate was concentrated. The residue was purified by chromatography (90/10 → 70/30 hexanes / ethyl acetate) to give the product (22% yield).

A solution of ethyl 7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylate (0.177 mmol) in ethanol (1.5 mL) was dissolved in sodium hydroxide. (3.0 mmol) in a 5.0 M solution. Within minutes, a gelatinous solid precipitated out. The reaction mixture was diluted with water (50 mL) and acidified with 6.0N hydrochloric acid. The precipitate was collected by filtration to give the product (80% yield). The acid was used without further purification.

The following acids were prepared using this method:

7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

7-fluoro-6- (3-ethoxypyrrolidin-1-yl) -1,2-benzisothiazole-3-carboxylic acid.

7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxylic acid.

Procedure 18

Procedure 18 was performed from tert-butyl 6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylate to 6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxyl. Provided are methods for preparing acids.

[1,3-bis (diphenylphosphino) propane] nickel (II) chloride (0.0999 mmol) and tert-butyl 6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (0.999 mmol) was dissolved in tetrahydrofuran (20.0 mL) and the reaction mixture was cooled to 0 ° C. A 1.00M solution of phenylmagnesium bromide in tetrahydrofuran (2.40 mL) was added and the reaction mixture was allowed to warm to room temperature and maintained for 4 hours. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organics washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 → 85/15 hexanes / ethyl acetate) to give the product (56% yield).

tert-butyl 6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylate (0.555 mmol) is dissolved in 4/1 dichloromethane / trifluoroacetic acid solution (2.00 mL) and the reaction Was maintained at room temperature for 16 hours. The reaction mixture was concentrated and the residue was diluted with water (5 mL). The reaction mixture was neutralized to pH 5-7, stirred vigorously for 1 hour, and the precipitated solid was collected by filtration to give an acid (92% yield).

The following acids were prepared using this method:

6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid.

Procedure 19

Procedure 19 describes in detail the preparation of ethyl 6-bromobenzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.

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

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

Sulfuric acid (1 mL) was added to a solution of acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained 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 (sodium sulfate) and concentrated to give 8.00 g (98%) of ester as a liquid.

Isoamyl nitrite (225 mL) was added to a solution of ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L 3-neck round bottom flask and the mixture was warmed to 60 ° C. A solution of sodium ethoxide (prepared from sodium metal) (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained 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 × 2 L) and the combined organic layers were washed with water (2 × 1 L) and brine (2 × 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 → 0/1 hexanes / ethyl acetate) to give 110 g (28%) of product.

See, eg, international application number WO 2004/010995.

Using this method the following esters were prepared:

Ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate.

Procedure 20

Procedure 20 describes in detail the preparation of ethyl 6-methoxybenzisoxazole-3-carboxylate from 1-chloro-2,4-dinitrobenzene.

Sodium hydride (417 mmol) was added to a solution of ethyl 3-oxobutanoate (129 mmol) in tetrahydrofuran (350 mL). 1-chloro-2,4-dinitrobenzene (123 mmol) was added and the resulting suspension was kept at room temperature for 24 hours. The pH was adjusted to 5 by addition of 3M hydrochloric acid and the resulting solution was extracted with diethyl ether (300 mL). The organic layer was washed with water (3 × 300 mL), dried (magnesium sulfate) and concentrated to give ethyl 2- (2,4-dinitrophenyl) -3-oxobutanoate as a brown solid (98% yield).

Propan-1-amine (136 mmol) was added to a solution of ethyl 2- (2,4-dinitrophenyl) -3-oxobutanoate (135 mmol) in chloroform (500 mL). The reaction mixture was kept at rt for 12 h and concentrated. The residue was purified by chromatography (20/1 hexanes / ethyl acetate) to give ethyl 2- (2,4-dinitrophenyl) acetate as a brown oil (99% yield).

A solution of ethyl 2- (2,4-dinitrophenyl) acetate (18.1 mmol) and nitrite 3-methylbutanyl (73.5 mmol) in ethanol (70 mL) was warmed to 60 ° C. A solution of sodium ethoxide (prepared from sodium) (21.7 mmol) and ethanol (70 mL) was added and the reaction mixture was maintained for 1 hour. The reaction mixture was cooled to 0 ° C and the pH was adjusted to 7 by addition of 5% hydrochloric acid. The resulting solution was diluted with water (500 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (4 x 200 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (30/1 petroleum ether / ethyl acetate) to give 6-nitrobenzo [d] isoxazole-3-carboxylate as an orange solid (70% yield).

Combine ethyl 6-nitrobenzo [d] isoxazole-3-carboxylate (12.7 mmol), iron (53.6 mmol) and ammonium chloride (56.1 mmol) and dilute with ethanol (150 mL) and water (20 mL). It was. The resulting suspension was heated with vigorous stirring at reflux for 2 hours. The reaction mixture was filtered through celite, diluted with brine (200 mL) and the resulting solution extracted with ethyl acetate (200 mL). The organic layer was washed with brine (3 × 200 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (20/1 petroleum ether / ethyl acetate) to give ethyl 6-aminobenzo [d] isoxazole-3-carboxylate as an orange solid (49.6% yield).

Ethyl 6-aminobenzo [d] isoxazole-3-carboxylate (2.43 mmol) was diluted with a solution of sulfuric acid (2.5 mL) in water (2.5 mL) and the resulting mixture was maintained at room temperature for 30 minutes. A solution of sodium nitrite (2.67 mmol) in water (2.5 ml) was added dropwise at 0 ° C. and the resulting mixture was kept at 0 ° C. for 30 minutes. The aqueous solution was added to a cold (0 ° C.) solution of copper (II) nitrate (149 mmol) in water (80 mL) and the reaction mixture was allowed to warm to room temperature. After 5 minutes, copper (I) (2.78 mmol) was added to the mixture and the reaction mixture was kept at room temperature for 1 hour. The reaction mixture is extracted with ethyl acetate (3 × 100 mL) and the combined organic layers are dried (magnesium sulfate) and concentrated to give crude ethyl 6-hydroxybenzo [d] isoxazole-3-carboxylate as a brown oil. (99% yield).

Potassium carbonate (9.42 mmol) and iodomethane (8.45 mmol) were dissolved in crude ethyl 6-hydroxybenzo [d] isoxazole-3-carboxylate (2.42 mmol) in N, N-dimethylformamide (30 mL). To the solution was added and the reaction mixture was kept at room temperature for 48 hours in the dark. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (30/1 petroleum ether / ethyl acetate) to give ethyl 6-methoxybenzo [d] isoxazole-3-carboxylate as a yellow solid (19% yield).

Using this method the following esters were prepared:

Ethyl 6-methoxybenzo [d] isoxazole-3-carboxylate.

Procedure 21

Procedure 21 provides a method for preparing 7-azabenzisothiazole-3-carboxylic acid from 2-chloronicotinic acid.

2-Chloronicotinic acid (317 mmol) was diluted with oxalyl chloride (130 mL) and the resulting solution was heated at reflux for 18 h. The volatiles were removed by evaporation to give 2-chloronicotinoyl chloride as a white solid (98% yield).

Magnesium chloride (221 mmol) and triethylamine (752 mmol) were added to a solution of diethyl malonate (375 mmol) in toluene (250 ml) and the reaction mixture was maintained at 25 ° C. for 1 hour. A solution of 2-chloronicotinoyl chloride (313 mmol) in toluene (80 mL) was added dropwise over a 2 hour course. The reaction mixture was kept at rt for 3.5 h and quenched with cold (0 ° C.) water (500 mL). The resulting solution was extracted with ethyl acetate (500 mL) and the organic layers combined. The organic layer was washed with brine (3 × 300 mL), dried (sodium sulfate) and concentrated to give diethyl 2- (2-chloronicotinoyl) malonate as a brown oil (85% yield).

A solution of diethyl 2- (2-chloronicotinoyl) malonate (267 mmol) in dimethyl sulfoxide (100 ml) was added to a 130 ° C. solution of water (10 mL) in dimethyl sulfoxide (260 mL) at 1.5 h. Dropwise over. The reaction mixture was further maintained at 130 ° C. for 2 hours and cooled to room temperature. The reaction mixture was diluted with cold (0 ° C.) water (500 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (5 × 200 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (10/1 petroleum ether / ethyl acetate) to give 1- (2-chloropyridin-3-yl) ethanone as a yellow oil (52% yield).

A solution of 1- (2-chloropyridin-3-yl) ethanone (129 mmol) in ammonium hydroxide (130 mL) and ethanol (500 mL) was added to a 1 L high pressure steel vessel under ammonia atmosphere. Sulfur (129 mmol) was added to the reaction mixture, the vessel was sealed and the reaction mixture was heated at 130 ° C for 16 h. The reaction mixture was filtered through celite and the eluate was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (20/1 petroleum ether / ethyl acetate) to give 3-methylisothiazolo [5,4-b] pyridine as a white solid (22% yield).

N-bromosuccinamide (10.7 mmol) was added to a solution of 3-methylisothiazolo [5,4-b] pyridine (10.0 mmol) in carbon tetrachloride (20 mL). Benzoyl peroxide (0.82 mmol) was added and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered through celite (ethyl acetate) and the eluate was concentrated to give crude 3- (bromomethyl) isothiazolo [5,4-b] pyridine as a yellow solid.

A solution of crude 3- (bromomethyl) isothiazolo [5,4-b] pyridine (3.49 mmol) in dimethylsulfoxide (20 mL) was treated with water (4 mL) and the reaction mixture was 1.5 at 80 ° C. Heated for hours. The reaction mixture was diluted with water (100 mL), filtered through celite and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water, dried (magnesium sulfate) and concentrated to give isothiazolo [5,4-b] pyridin-3-ylmethanol as a yellow oil (31% yield).

Potassium permanganate (2.25 mmol) and potassium hydroxide (1.79 mmol) are added to a solution of isothiazolo [5,4-b] pyridin-3-ylmethanol (1.08 mmol) in water (4 mL), and the resulting solution is The reaction was carried out at room temperature for 3 hours. The reaction mixture was filtered through celite and extracted with ethyl acetate (3 × 10 mL). The pH of the combined aqueous layers was adjusted to 2 by addition of 0.6 M hydrochloric acid. The slurry was stirred for 5 minutes and the solids were collected by filtration to give isothiazolo [5,4-b] pyridine-3-carboxylic acid as a light yellow solid (42% yield).

The following acids were prepared using this method:

Isothiazolo [5,4-b] pyridine-3-carboxylic acid.

step  22

The following procedure provides a process for the preparation of 2,2,2-trifluoroethyl substituted acid.

Ethyl 6-[(1S, 4S) -5- (tert-butoxycarbonyl) -2,5-diazabicyclo [2.2.1] hept in 4/1 methylene chloride / trifluoroacetic acid (10.00 mL) The mixture of 2-yl] -1,2-benzisothiazol-3-carboxylate (1.16 mmol) was maintained at room temperature for 16 hours. The reaction mixture was concentrated and the residue was loaded on an SCX column (10 g) and flushed with 5 volumes of methanol. The partially purified product was then eluted with 2.0 M ammonia in methanol to give an amine (68% yield).

2,2,2-trifluoroethylmethanesulfonate (0.330 mmol) was converted to ethyl 6-[(1S, 4S) -2 in N, N-diisopropylethylamine (0.20 mL) and acetonitrile (15 mL). To a solution of, 5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylate (0.165 mmol), and the resulting mixture was added for 16 hours. Kept at room temperature. The reaction mixture was concentrated and the residue was purified by chromatography (90/10 → 70/30 hexanes / ethyl acetate) to give purified ester. The ester was dissolved in ethanol (5.0 mL) and aqueous sodium hydroxide solution (5.0M, 2.0 mL) was added. The reaction was kept at rt for 4 h before diluted with water (50 mL) and neutralized with acetic acid. The precipitate was collected by filtration to give 6-[(1S, 4S) -5- (2,2,2-trifluoroethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid was obtained (29% yield).

The following acid was prepared using a similar procedure:

6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidin-1-yl} -1,2-benzisothiazole-3-carboxylic acid

Procedure 23

Procedure 23 provides a method for preparing amidine substituted indazole-3-carboxylic acid from the corresponding aldehyde.

N-methyl-1,2-ethanediamine (4.7 mmol) was added to a solution of tert-butyl 6-formyl-1H-indazole-3-carboxylate (4.2 mmol) in tert-butanol (40 mL) and The reaction mixture was kept for 30 minutes. Potassium carbonate (10 mmol) and iodine (5.3 mmol) were added and the slurry was heated at 70 ° C. for 3 hours. The reaction mixture was cooled to rt and quenched with aqueous sodium thiosulfate (40 mL). The aqueous layer was extracted with 9/1 dichloromethane / methanol, and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography [100/0 → 60/40 dichloromethane / (7M ammonia in 8/1/1 dichloromethane / methanol / methanol)] to give amidine (51% yield).

tert-butyl 6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazole-3-carboxylate (2.2 mmol) in trifluoroacetic acid (3.7 mL) Diluted, and the reaction mixture was kept at room temperature for 16 hours. The precipitated product was isolated by filtration to give an acid (93% yield).

The following acids were prepared using this method:

6- (1-Methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxylic acid.

Procedure 24

Procedure 24 provides a process for preparing N-alkyl aminobenzisothiazole-3-carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic acid esters.

Sodium cyanoborohydride (8.57 mmol) was diluted with ethyl 6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2 in ethanol (11.2 mL). -Benzisothiazole-3-carboxylate (0.260 g, 0.857 mmol) and 1-ethoxy-1- (trimethylsilyloxy) cyclopropane (8.57 mmol) were added to a solution and the reaction mixture was added at 60 ° C. Heated for hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (ethyl acetate) to give ester. A 5.0 M solution of sodium hydroxide in water (4.00 mL) was added to a solution of ester in ethanol (10.0 mL) and the reaction mixture was maintained for 16 hours. The reaction was neutralized with acetic acid and loaded on an SCX column. The column was flushed with water (200 mL) and methanol (100 mL) and the product eluted with 2.0M ammonia (60 mL) in methanol to give an acid (56% yield). The acid was used without further purification.

The following acids were prepared using this method:

6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxylic acid.

Procedure 25

Procedure 25 provides a process for preparing N-alkyl aminobenzisothiazole-3-carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic acid esters.

Cyclopropylmethyl bromide (1.71 mmol) was diluted with ethyl 6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2- in acetonitrile (10.0 mL). To a suspension of benzisothiazole-3-carboxylate (0.857 mmol) and sodium bicarbonate (3.43 mmol), the reaction mixture was heated at 60 ° C. for 6 hours. Acetonitrile was decanted from the solid and the solid was washed with acetonitrile (2 x 5 mL). The acetonitrile solution was transferred to a silica gel column and the mixture was purified by chromatography {9/1 → 7/3 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]} to purify the ester. Obtained. A 5.0 M solution of sodium hydroxide in water (2.00 mL) was added to a solution of ester in ethanol (5.0 mL) and the reaction mixture was maintained for 16 h. The reaction was neutralized with acetic acid and the reaction mixture was transferred to an SCX column (10 g). The column was flushed with water (200 mL) and methanol (100 mL) and the product eluted with 2.0 M ammonia in methanol to give the product (50% yield). The acid was used without further purification.

The following acids were prepared using this method:

6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxyl mountain.

Procedure 26

Procedure 26 provides a process for preparing 6-hydroxybenzisothiazole-3-carboxylic acid and ester from the corresponding anisole.

1.0 M solution of boron tribromide in methylene chloride (20.00 mL) to 0 ° C. solution of ethyl 6-methoxy-1,2-benzisothiazole-3-carboxylate (12.6 mmol) in methylene chloride (30.0 mL) Dropped in The reaction mixture was allowed to warm to room temperature and maintained for 16 hours. The reaction mixture was poured into 100 mL of ice cold 2N sodium hydroxide and the mixture was stirred vigorously for 20 minutes. The precipitated solid was removed by filtration and the eluate was washed with ethyl acetate (2 x 50 mL). The aqueous layer was neutralized with 6N hydrochloric acid and the precipitated tan solid was collected by filtration to give a mixture of methoxy (about 48% yield) and hydroxy acid (about 37% yield).

Thionyl chloride (27.0 mmol) was added dropwise at 0 ° C. to a round bottom flask containing ethanol (50.0 mL). The reaction mixture is allowed to warm to room temperature and a mixture of hydroxy and methoxy acid is added after 30 minutes. The reaction mixture was heated at 95 ° C for 4 h and concentrated to about 25 mL. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL), and the organic layer was washed with brine and concentrated. The residue was purified by chromatography (using a gradient of 80/20 to 60/40 hexanes / ethyl acetate) to give the product (82% yield).

The following acids and esters were prepared using this method:

6-hydroxy-1,2-benzisothiazole-3-carboxylic acid.

6-methoxybenzo [d] isothiazole-3-carboxylic acid.

Ethyl 6-hydroxy-1,2-benzisothiazole-3-carboxylate.

Procedure 27

Procedure 27 provides a method for preparing 7-aza-6-chlorobenzisothiazole-3-carboxylic acid from 2-chloronicotinoyl chloride.

Magnesium metal (1.25 mol) was diluted with ethanol (250 mL) and carbon tetrachloride (5 mL) and the suspension was heated at 70 to 80 ° C for 1 hour. A solution of diethylmalonate (1.21 mol) in toluene (200 mL) was added dropwise and the reaction mixture was maintained for 2 hours. The reaction mixture was cooled to 0 ° C and a solution of 2-chloronicotinoyl chloride (313 mmol) in toluene (200 mL) was added dropwise while maintaining a temperature of 0-5 ° C. The resulting solution was allowed to warm to room temperature and maintained for 2 hours. The reaction mixture was diluted with 50 mL of water and the precipitated solid was collected by filtration to give 104 g of crude diethyl 2- (2-chloronicotinoyl) malonate as a pink solid.

Water (1.3 mL) was added to a solution of diethyl 2- (2-chloronicotinoyl) malonate (31.7 mmol) in dimethylsulfoxide (50 mL). Hydrochloric acid was added to adjust the pH of the reaction mixture to 5-6, and the reaction mixture was heated at 130 ° C. for 2 hours. The reaction mixture was then quenched with ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (1/20 ethyl acetate / petroleum ether) to give 1- (2-chloropyridin-3-yl) ethanone as a light yellow oil (56% yield).

Ammonium hydroxide (368 mL) was added to a mixture of sulfur (386 mmol) and 1- (2-chloropyridin-3-yl) ethanone (350 mmol) and the slurry was diluted with methanol (960 mL). Ammonia gas was bubbled through the reaction mixture for 10 minutes and the reaction mixture was heated at 110 ° C. for 24 hours. The reaction mixture was concentrated to dryness and the residue was extracted with water (3 × 500 mL). The aqueous layer was extracted with ethyl acetate (5 x 500 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/25 ethyl acetate / petroleum ether) to give 3-methylisothiazolo [5,4-b] pyridine as a light yellow solid (67% yield).

A solution of m-chloroperbenzoic acid (160 mmol) in acetic acid (200 mL) was added dropwise to a solution of 3-methylisothiazolo [5,4-b] pyridine (107 mmol) in dichloromethane (200 mL). The reaction mixture was kept at 25 ° C. for 6 hours. The reaction mixture was diluted with water (100 mL), the pH was adjusted to 8 with 10% sodium hydroxide and the layers separated. The aqueous layer was extracted with ethyl acetate (10 × 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to afford 3-methylisothiazolo [5,4-b] pyridine-N-oxide as a yellow solid. (62% yield).

Solution of triphosphogen (190 mmol) in dichloromethane (200 mL) to a solution of 3-methylisothiazolo [5,4-b] pyridine-N-oxide (47.4 mmol) in dichloromethane (150 mL)- Dropwise at 20 ° C. over 20 minutes. A solution of diisopropylamine (190 mmol) in dichloromethane (200 mL) was added dropwise over 1 hour. The reaction mixture was allowed to warm to room temperature and maintained for 16 hours. The reaction mixture was quenched with water (40 mL) and the pH was adjusted to 7 by addition of 10% sodium hydroxide. The organic layer was washed with water (100 mL). The combined aqueous layers were extracted with dichloromethane (10 × 100 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/80 ethyl acetate / petroleum ether) to give 6-chloro-3-methylisothiazolo [5,4-b] pyridine as a colorless solid (46% yield).

AIBN (1.35 mmol) was added to a solution of 6-chloro-3-methylisothiazolo [5,4-b] pyridine (13.5 mmol) and N-bromosuccinamide (27.1 mmol) in carbon tetrachloride (25 mL). It was. The reaction mixture was heated at 80 ° C. for 6 hours, cooled to room temperature and the precipitated solid was removed by filtration. The filtrate was concentrated to give crude 3- (bromomethyl) -6-chloroisothiazolo [5,4-b] pyridine as a yellow oil.

Water (8 mL) is added to a solution of 3- (bromomethyl) -6-chloroisothiazolo [5,4-b] pyridine (19.0 mmol) in dimethylsulfoxide (40 mL) and the reaction mixture is 80 Heat at 1.5 ° C. for 1.5 h. The reaction mixture was then quenched with water (50 mL) and the resulting solution was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to afford crude (6-chloroisothiazolo [5,4-b] pyridin-3-yl) methanol as a yellow solid.

Potassium permanganate (1.69 mmol) was added to a solution of (6-chlorobenzo [d] isothiazol-3-yl) methanol (2.50 mmol) in several batches of water (3 mL). Potassium carbonate (2.90 mmol) was added and the reaction mixture was kept at 25 ° C for 30 minutes. Insoluble matter was removed by filtration and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). 1N hydrochloric acid was added to adjust the pH of the aqueous layer to 3-4 and the reaction mixture was maintained for 10 minutes. The solid was collected by filtration to give 6-chlorobenzo [d] isothiazole-3-carboxylic acid as a white solid (15% yield).

The following acids were prepared using this method:

6-chloroisothiazolo [5,4-b] pyridine-3-carboxylic acid.

step  28

Procedure 28 provides a process for preparing N-acylated aminobenzisothiazole-3-carboxylic acids from the corresponding aminobenzisothiazole-3-carboxylic acid esters.

Cyclopropanecarbonyl chloride (0.37 mmol) and N, N-diisopropylethylamine (0.49 mmol) were added to ethyl 6-piperazin-1-yl-1,2-benzisothiazole- in methylene chloride (3.0 mL). To a solution of 3-carboxylate (0.12 mmol) was added and the reaction mixture was kept at room temperature for 1 hour. The reaction mixture was quenched with methanol (10 mL) and the mixture was held for 30 more minutes. The reaction mixture was poured into a 5 g SCX column and the product eluted with methanol (20 mL). A 5.0 M solution of sodium hydroxide in water (1.2 mL) was added to the methanol solution and the mixture was maintained for 2 hours. The reaction mixture was diluted with water (50 mL) and neutralized with 6N solution of hydrochloric acid (1.5 mL). The pH was further adjusted to 5-7 using acetic acid. The precipitated solid was collected by filtration to give an acid (88% yield).

The following acids were prepared using this method:

6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benzisothiazole-3-carboxylic acid.

6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl] -1,2-benzisothiazole-3-carboxylic acid.

6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carbox Acid.

Procedure 29

Procedure 29 provides a process for preparing nitrile substituted indazole-3-carboxylic acids from the corresponding bromoindazole-3-carboxylic acid esters.

Zinc cyanide (1.00 mmol) was diluted with ethyl 6-bromo-1H-indazole-3-carboxylate (0.502 mmol) and tetrakis (triphenylphosphine) palladium in N, N-dimethylformamide (5.00 mL). 0) (0.0502 mmol) was added and the reaction mixture was heated at 100 ° C. for 16 h. The reaction mixture was diluted with ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate (2 ×) and the combined organic layers were washed with brine and dried (sodium sulfate). The residue was purified by chromatography (70/30 → 50/50 hexanes / ethyl acetate) to give nitrile (65% yield). The ester was hydrolyzed with sodium hydroxide in ethanol to give an acid.

This procedure was used to prepare the following acids and esters:

Ethyl 6-cyano-1H-indazole-3-carboxylate.

6-cyano-1H-indazole-3-carboxylic acid.

Base manufacturing

The following procedures (30 to 35) describe in detail the preparation of bicyclobases and amines which are not commercially available.

Procedure 30

Procedure 30 provides a process for preparing N-alkylated 3-aminoquinuclidines from 3-aminoquinuclidines.

Acetyl chloride (12 mmol) was added dropwise to a solution of (R) -3-aminoquinuclidin (10 mmol) and N, N-diisopropylethylamine (30 mmol) in dichloromethane (100 mL). The resulting solution was kept at room temperature for 4 hours and evaporated to dryness. The crude amide was dissolved in tetrahydrofuran (150 mL) and treated with a small portion of lithium aluminum hydride (66 mmol). The reaction mixture was quenched with sodium sulfate decahydrate and the resulting slurry was diluted with tetrahydrofuran and filtered through celite. After concentration of the filtrate, the residue was diluted with freshly prepared methanolic hydrogen chloride (produced by dropwise addition of 3 mL of acetyl chloride to 30 mL of methanol) and held at room temperature for 15 minutes. The residue obtained by removing volatiles was recrystallized (2-propanol / methanol) to give a secondary amine as a colorless solid (41% yield).

The following bases were prepared using this method:

(3R) -N- (methyl) quinucridin-3-amine dihydrochloride.

(3S) -N- (methyl) quinucridin-3-amine dihydrochloride.

Procedure 31

Procedure 31 provides a method of preparing cyclic urea from diamines.

Carbonic acid, dimethyl ester (10.0 mmol) was added dropwise to a mixture of N-propyl-1,2-ethanediamine (10.0 mmol) and cesium carbonate (2.00 mmol) and the reaction mixture was heated at 70 ° C for 1 hour. The reaction mixture was concentrated and the residue was heated at 130 ° C for 3 hours. The reaction mixture was concentrated and the residue was purified by chromatography [(50/50 → 0/100) hexanes / ethyl acetate] to give the product (60%) as an oil.

The following cyclic ureas were prepared using this method:

1-propylimidazolidin-2-one.

1-ethylimidazolidin-2-one.

Procedure 32

Procedure 32 provides a method for preparing 3-alkoxypyrrolidine from N-Boc-3-hydroxypyrrolidine.

1-Boc-3-hydroxypyrrolidine (16.1 mmol) was added in portions at 0 ° C. to a suspension of sodium hydride (22.0 mmol) in tetrahydrofuran (40 mL). The reaction mixture was diluted with tetrahydrofuran (60 mL) and warmed to room temperature. Methyl iodide (21.0 mmol) was added to the cloudy suspension after 1 hour and the reaction mixture was kept at room temperature for 6 hours. The reaction mixture was concentrated and dissolved again in ethyl acetate (100 mL). The extract was washed with saturated ammonium chloride (20 mL), water (20 mL) and brine (20 mL) and dried (sodium sulfate). The residue was purified by chromatography (1/4 ethyl acetate / hexanes) to give ether. The N-Boc product was dissolved in tetrahydrofuran (30 mL) and 6N hydrochloric acid (20 mL) was added. The resulting mixture was stirred for 1 hour and concentrated to give an oil. Toluene (10 mL) and ethanol (10 mL) were added and the mixture was concentrated to give 1.79 g of a high hygroscopic brown solid. The solid was suspended in ethyl acetate and stirred vigorously for 12 hours. The solid was quickly collected by filtration and dried under high vacuum to afford the product (81%) as a colorless solid.

Another procedure used for N-Boc group removal involves concentrating the reaction mixture after 4 hours of exposure to trifluoroacetic acid. This procedure may be useful for the production of amines as free base.

This procedure was used to prepare the following amines:

3-methoxypyrrolidine hydrochloride.

The salt residue is neutralized with saturated sodium carbonate (5 mL), extracted with 9/1 dichloromethane / methanol (3 × 20 mL), dried (potassium carbonate) and concentrated, then the amine is captured on an SCX column, Elution with 2M ammonia in methanol gave the free base:

3-methoxypyrrolidine.

3-ethoxypyrrolidine.

(3R) -3-methoxypyrrolidine.

(3S) -3-methoxypyrrolidine.

3- (methoxymethyl) pyrrolidine.

Procedure 33

Procedure 33 provides a method for preparing SEM protected hydroxypyrrolidine from hydroxypyrrolidine.

A solution of 1-Boc-3-hydroxy-pyrrolidine (26.7 mmol) in tetrahydrofuran (20 mL) is added slowly to a suspension of sodium hydride (30.8 mmol) in tetrahydrofuran (78 mL) and the reaction mixture Was held for 30 minutes. A solution of [β- (trimethylsilyl) ethoxy] methyl chloride (30.7 mmol) in tetrahydrofuran (4.4 mL) was added and the reaction mixture was maintained for 18 hours. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the layers separated. The organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 → 80/20 hexanes / ethyl acetate) to give Boc-protected product. The residue was heated at 350 ° C for 3 h. The resulting brown oil was purified by chromatography [100/0 → 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] to give a brown oil after concentration. The oil was dissolved in ethanol and the solution was treated with activated carbon, filtered and concentrated to give the product (52% yield).

The following amines were prepared using this method:

3-{[2- (trimethylsilyl) ethoxy] methoxy} pyrrolidine.

Procedure 34

Procedure 34 provides a method for preparing 3-trifluoromethoxypyrrolidine from hydroxypyrrolidine.

A solution of 1-Boc-3-hydroxypyrrolidine (26.7 mmol) in tetrahydrofuran (20 mL) was added slowly to a suspension of sodium hydride (30.8 mmol) in tetrahydrofuran (78 mL) at 0 ° C. Chlorodifluoromethane (30.7 mmol) was added to the reaction and the reaction mixture was allowed to warm to room temperature and maintained for 18 hours. The reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the layers separated. The organic layer was washed with brine (25 mL), dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (95/5 → 80/20 hexanes / ethyl acetate) to give Boc-protected product. The purified product (about 2 g) was dissolved in a 4/1 mixture of dichloromethane / trifluoroacetic acid (20.0 mL) and maintained for 4 hours. The solvent was removed and the residue was purified by chromatography [100/0 → 90/10 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)]. The product was surprisingly volatile and lost much in concentration. Final product yield was 2%.

The following amines were prepared using this method:

3- (difluoromethoxy) pyrrolidine.

Procedure 35

Procedure 35 provides a method for preparing 3-cyclopropylmethoxypyrrolidine from hydroxypyrrolidine.

A solution of 3-hydroxy-pyrrolidine-hydrochloride (162 mmol) in tetrahydrofuran (100 mL) was diluted with potassium carbonate (210 mmol) and benzyl chloroformate (210 mmol) in tetrahydrofuran (50 mL). Treated with solution. The resulting solution was kept at room temperature for 16 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with brine (3 × 100 mL), dried (magnesium sulfate) and concentrated to afford the protected amine as a yellow liquid (90% yield).

Sodium hydride (280 mmol) was added in portions to a cold (0 ° C.) solution of benzyl 3-hydroxypyrrolidine-1-carboxylate (76.9 mmol) in N, N-dimethylformamide (100 mL). The mixture was held for 60 minutes, then treated with a solution of (bromomethyl) cyclopropane (231 mmol) in N, N-dimethylformamide (100 mL) and potassium iodide (0.66 mmol). The reaction mixture was allowed to warm up to room temperature and held for 30 minutes. The reaction mixture was microwaved at 90 ° C. for 2 hours. The reaction mixture was concentrated, the residue was diluted with ethyl acetate (200 mL) and water (200 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (3 × 200 mL) and the combined organic layers were washed with brine (2 × 200 mL) and dried (magnesium sulfate). The residue was purified by chromatography (20/1 petroleum ether / ethyl acetate) to give the product (81% yield).

A suspension of benzyl 3- (cyclopropylmethoxy) pyrrolidine-1-carboxylate (17.4 mmol) and 10% palladium on carbon (600 mg) in ethyl acetate (20 mL) and methanol (20 mL) was added with hydrogen gas. Placed in the atmosphere. The reaction mixture was maintained for 16 hours and filtered through celite. The filtrate was concentrated to give the product as a yellow liquid (86% yield).

The following amines were prepared using this method:

3- (cyclopropylmethoxy) pyrrolidine.

Representative Procedure

The following procedures (A to AA) describe in detail the preparation of bicyclobase analogs.

Procedure A

Procedure A provides a method of coupling 3-aminoquinuclidine and benzisoxazole carboxylic acid ester to form carboxamide derivatives.

A suspension of (S) -3-aminoquinuclidin hydrochloride (3.50 mmol) in ethanol (5 mL) was treated with N, N-diisopropylethylamine (4.00 mmol). Ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate (1.86 mmol) was added and the suspension was heated at 85 ° C. for 3 days. The reaction mixture was cooled to rt, diluted with dichloromethane (30 mL) and washed with 10 mL saturated sodium bicarbonate. The aqueous layer was extracted again with dichloromethane (30 mL) and the combined organic layers were washed with brine and dried (sodium sulfate). The organic layer was loaded on a 10 g SCX column. The column was washed with methanol (50 mL), 2M ammonia in methanol (60 mL) and the ammonia wash was concentrated. The residue was purified by chromatography [40/60 → 0/100 ethyl acetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] to give the product as a colorless oil (63% yield).

Using this method the following compounds were prepared:

86) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazole-3-carboxamide

;

;

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

Procedure B

Procedure B provides a method of coupling 3-aminoquinuclidine and benzisothiazole carboxylic acid to form carboxamide derivatives.

To a solution of benzisothiazole-3-carboxylic acid (0.30 mmol) in a 5/1 mixture (12 mL) of tetrahydrofuran / N, N-dimethylformamide, diisopropylethylamine (1.1 mmol) and (R ) -3-aminoquinuclidin dihydrochloride (0.6 mmol) was added. The mixture was cooled to 0 ° C and HATU (0.3 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and maintained for 16 hours. The mixture was partitioned between a saturated aqueous potassium carbonate solution and a 95/5 mixture of dichloromethane / methanol. The aqueous layer was extracted with 95/5 dichloromethane / methanol (2 ×) and the combined organic layers were washed with brine and dried over sodium sulfate. Alternatively, the reaction mixture was loaded into a 10 g SCX column, the column was washed with methanol (50 mL), 2M ammonia in methanol (60 mL), and the ammonia wash was concentrated. The crude product was purified by chromatography (100/0 → 30/70 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]) or preparative HPLC to give the amide as a colorless solid ( 75% yield).

Using this method the following compounds were prepared:

84) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide,

;

;

85) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.91, m / z 387.2 (M ⁺⁺ 1);

87) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.82, m / z 419.1 (M ⁺⁺ 1);

92) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 5.11, m / z 405.2 (M ⁺⁺ 1);

93) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 5.08, m / z 405.2 (M ⁺⁺ 1);

94) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.25, m / z 373.1 (M ⁺⁺ 1);

95) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.23, m / z 373.1 (M ⁺⁺ 1);

96) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.92, m / z 400.2 (M ⁺⁺ 1);

97) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.26, m / z 385.1 (M ⁺⁺ 1);

98) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.27, m / z 373.1 (M ⁺⁺ 1);

99) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.23, m / z 373.1 (M ⁺⁺ 1);

100) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.89, m / z 400.2 (M ⁺⁺ 1);

101) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.27, m / z 373.1 (M ⁺⁺ 1);

102) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.26, m / z 373.1 (M ⁺⁺ 1);

103) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.92, m / z 400.2 (M ⁺⁺ 1);

104) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.36, m / z 385.1 (M ⁺⁺ 1);

105) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.81, m / z 400.2 (M ⁺⁺ 1);

106) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, LC / MS (EI) t _R 2.71, m / z 289.1 (M ⁺ +1);

107) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, LC / MS ( EI) t _R 2.48, m / z x 289.1 (M ⁺⁺ l);

114) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide , LC / MS (EI) t _R 3.8, m / z 336.1 (M ⁺⁺ l);

115) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide , LC / MS (EI) t _R 3.81, m / z 336.1 (M ⁺⁺ l);

116) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.84, m / z 398.2 (M ⁺⁺ 1);

117) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.87, m / z 398.2 (M ⁺⁺ 1);

122) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (2,2,2-trifluoroethyl)- 2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.69, m / z 466.1 (M ⁺ +1);

123) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.77, m / z 468.1 (M ⁺⁺ 1);

124) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.75, m / z 468.1 (M ⁺⁺ 1);

125) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 4.98, m / z 401.1 (M ⁺⁺ 1);

126) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 4.94, m / z 401.1 (M ⁺⁺ 1);

127) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.55, m / z 400.2 (M ⁺⁺ 1);

128) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.55, m / z 400.1 (M ⁺⁺ 1);

129) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, LC / MS (EI) t _R 1.59, m / z 414.1 (M ⁺⁺ 1);

130) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, LC / MS (EI) t _R 1.61, m / z 414.2 (M ⁺⁺ 1);

177) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.30, m / z 440 (M ⁺ +1);

178) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.30, m / z 440 (M ⁺ +1);

179) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.81, m / z 480 (M ⁺ +1);

180) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.85, m / z 480 (M ⁺ +1);

181) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.97, m / z 452 (M ⁺⁺ 1);

182) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.04, m / z 452 (M ⁺⁺ 1);

183) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole -3-carboxamide, LC / MS (EI) t _R 1.30, m / z 400 (M ⁺⁺ 1);

132) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Ro [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate, LC / MS (EI) t _R 3.27, m / z 412.2 (M ⁺ + One);

133) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Ro [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate, LC / MS (EI) t _R 3.19, m / z 412.2 (M ⁺ + One);

134) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.26, m / z 398.2 (M ⁺⁺ 1);

135) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.2, m / z 398.2 (M ⁺⁺ 1);

136) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate, LC / MS (EI) t _R 1.61, m / z 412.2 (M ⁺⁺ 1);

137) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate, LC / MS (EI) t _R 3.51, m / z 412.1 (M ⁺⁺ 1);

138) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carbox Amide, LC / MS (EI) t _R 4.66, m / z 357.2 (M ⁺⁺ l);

139) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 -Carboxamide, LC / MS (EI) t _R 1.67, m / z 386.2 (M ⁺ +1);

140) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 -Carboxamide, LC / MS (EI) t _R 1.63, m / z 386.2 (M ⁺ +1);

141) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 1.8, m / z 400.2 (M ⁺⁺ 1);

142) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 1.84, m / z 400.2 (M ⁺⁺ 1);

143) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.79, m / z 412.1 (M ⁺⁺ 1);

144) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.81, m / z 412.2 (M ⁺⁺ 1);

145) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Il) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.88, m / z 412.2 (M ⁺⁺ 1);

146) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Il) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.88, m / z 412.2 (M ⁺⁺ 1);

147) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.95, m / z 412.2 (M ⁺⁺ 1);

148) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Il) -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.93, m / z 412.2 (M ⁺⁺ 1);

149) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.08, m / z 424.1 (M ⁺⁺ 1);

150) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.24, m / z 424.1 (M ⁺⁺ 1);

151) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.31, m / z 438.2 (M ⁺⁺ 1);

152) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.31, m / z 438.2 (M ⁺⁺ 1);

153) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 2.14, m / z 400.2 (M ⁺⁺ 1);

154) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.57, m / z 387.2 (M ⁺⁺ 1);

155) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.57, m / z 387.2 (M ⁺⁺ 1);

156) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.56, m / z 387.2 (M ⁺⁺ l);

157) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide, LC / MS (EI) t _R 1.25, m / z 387.2 (M ⁺⁺ 1);

158) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide, LC / MS (EI) t _R 1.25, m / z 387.2 (M ⁺⁺ 1);

159) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.33, m / z 413.2 (M ⁺⁺ 1);

160) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.32, m / z 413.2 (M ⁺⁺ 1);

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-[(3R) -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] -6- (methoxy) -1,2-benzisothiazole-3-carboxamide.

Using the above procedure, treatment with trifluoroacetic acid, isolation by ion exchange, and purification by chromatography or preparative HPLC as described above gave the following compounds:

118) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.87, m / z 384.1 (M ⁺⁺ 1);

119) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.87, m / z 384.1 (M ⁺⁺ 1);

120) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, LC / MS (EI) t _R 1.96, m / z 386.1 (M ⁺⁺ 1);

121) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, LC / MS (EI) t _R 1.94, m / z 386.2 (M ⁺⁺ 1);

168) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3 -Carboxamide, LC / MS (EI) t _R 1.28, m / z 386.2 (M ⁺⁺ l);

169) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.33, m / z 412.2 (M ⁺⁺ 1);

170) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.35, m / z 412.2 (M ⁺⁺ 1);

171) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.29, m / z 372 (M ⁺⁺ l);

172) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazole-3-carboxamide, LC / MS (EI) t _R 1.47, m / z 372 (M ⁺⁺ l);

173) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl) -1,2-benzisothiazole- 3-carboxamide, LC / MS (EI) t _R 1.74, m / z 386 (M ⁺ +1);

174) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl) -1,2-benzisothiazole- 3-carboxamide, LC / MS (EI) t _R 1.70, m / z 386 (M ⁺ +1);

175) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 -Carboxamide, LC / MS (EI) t _R 1.57, m / z 386 (M ⁺ +1);

176) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 -Carboxamide, LC / MS (EI) t _R 1.55, m / z 386 (M ⁺ +1).

Procedure C

Procedure C provides a method of coupling 3-aminoquinuclidines and carboxylic acids to form carboxamide derivatives.

HBTU (16.1 mmol), catalytic amount of dimethylaminopyridine, N, N-diisopropylethylamine (96.6 mmol) and 4 ′ activation in a solution of carboxylic acid (16.1 mmol) in N, N-dimethylformamide (65 mL) Molecular sieves (2.6 g) were added. The reaction mixture was kept at room temperature under nitrogen for 2 hours before 3-aminoquinuclidin 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 × 100 mL) and the combined organic layers were concentrated. The residue is chromatographed [90/10/1 dichloromethane / methanol / ammonium hydroxide or 1/1 → 0/1 ethyl acetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] or by preparative HPLC. Purification gave the product (30% to 70% yield).

Using this method the following compounds were prepared:

42) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate,

;

;

43) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, LC / MS (EI) t _R 2.82, m / z 351 (M ⁺ +1);

44) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, LC / MS (EI) t _R 2.9, m / z 351 (M ⁺ +1);

45) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, LC / MS (EI) t _R 2.55, m / z 369 (M ⁺ +1);

46) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, LC / MS (EI) t _R 2.89, m / z 369 (M ⁺ +1);

47) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide hydroformate, LC / MS (EI) t _R 3.33, m / z 368 (M ⁺ +1);

48) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydro Formate, LC / MS (EI) t _R 3.21, m / z 348 (M ⁺⁺ l);

N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1 H-indazol-3-carboxamide.

Procedure D

Procedure D provides a method of coupling 3-aminoquinuclidines and carboxylic acids to form carboxamide derivatives.

To a solution of carboxylic acid (4.77 mmol) in N, N-dimethylformamide (14 mL) was added N, N-diisopropylethylamine (19 mmol) and 3-aminoquinuclidin dihydrochloride (4.29 mmol). Added. The reaction mixture was kept at room temperature under nitrogen for 30 minutes before HATU (4.76 mol) was added. After 18 hours, the reaction mixture was filtered through celite (methanol wash) and distributed equally over three SCX columns. The column was washed with methanol (100 mL each) and the basic component eluted with 2M ammonia in methanol (100 mL each) and concentrated. The residue was purified by chromatography [1/1 → 0/1 ethyl acetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] or preparative HPLC to give the product (15% to 50% yield). ).

Using this method the following compounds were prepared:

3) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate,

;

;

17) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, LC / MS (EI) t _R 2.53, m / z 315 (M ⁺⁺ l);

19) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, LC / MS ( EI) t _R 3.55, m / z 329 (M ⁺⁺ l);

20) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, LC / MS ( EI) t _R 3.54, m / z 329 (M ⁺⁺ l);

21) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazole-3-carboxamide , LC / MS (EI) t _R 3.75, m / z 351 (M ⁺ +1);

28) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, LC / MS (EI) t _R 3.09, m / z 352 (M ⁺ +1);

29) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazol- 3-carboxamide, LC / MS (EI) t _R 3.33, m / z 368 (M ⁺ +1);

34) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, LC / MS (EI) t _R 2.52, m / z 369 (M ⁺ +1);

35) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, LC / MS (EI) t _R 2.85, m / z 369 (M ⁺ +1);

36) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, LC / MS (EI) t _R 3.4, m / z 351 (M ⁺ +1);

37) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, LC / MS (EI) t _R 3.48, m / z 351 (M ⁺ +1);

40) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazole-3-carboxamide, LC / MS ( EI) t _R 2.51, m / z 315 (M ⁺ +1);

57) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide hydro Formate, LC / MS (EI) t _R 2.47, m / z 290 (M ⁺⁺ 1);

59) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide, LC / MS (EI ) t _R 1.29, m / z 272.2 (M ⁺⁺ l);

60) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate, LC / MS (EI) t _R 1.59, m / z 272.2 (M ⁺⁺ l);

73) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide hydroformate, LC / MS (EI) t _R 3.13, m / z 366 (M ⁺⁺ 1);

88) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, LC / MS (EI) t _R 4.18, m / z 348.1 (M ⁺⁺ 1);

90) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3 , 4-b] pyridine-3-carboxamide, LC / MS (EI) t _R 2.64, m / z 384.2 (M ⁺⁺ 1);

91) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1 H-pyrazolo [3 , 4-b] pyridine-3-carboxamide, LC / MS (EI) t _R 2.62, m / z 384.2 (M ⁺⁺ 1);

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

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

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

N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-methyl-1H-indazol-3-carboxamide;

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

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- (1,3-oxazol-2-yl) -1H-indazole-3-carboxamide;

N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-[(2-methoxyethoxy) methyl] -1 H-indazol-3- Carboxamides;

N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole- 3-carboxamide;

N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-bromo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole- 3-carboxamide;

N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6-bromo-2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole- 3-carboxamide;

N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-bromo-2-{[2- (trimethylsilyl) ethoxy] methyl} -1 H-indazole- 3-carboxamide.

Using the above procedure, the protecting group was removed using 6N hydrochloric acid, isolated by ion exchange, and purified by preparative HPLC to prepare the following compounds:

6) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazole-3-carboxamide hydro Formate, LC / MS (EI) t _R 2.68, m / z 357 (M ⁺⁺ 1);

7) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide hydroformate, LC / MS (EI) t _R 2.73, m / z 371 (M ⁺⁺ 1);

8) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3 -Carboxamide hydroformate, LC / MS (EI) t _R 1.4, m / z 370 (M ⁺ +1).

Using the above procedure, the following compounds were prepared by treatment with tetrabutylammonium fluoride:

164) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl]- 1H-indazol-3-carboxamide, LC / MS (EI) t _R 3.67, m / z 410 (M ⁺ +1);

166) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1 H-indazol- 3-carboxamide dihydroformate, LC / MS (EI) t _R 2.44, m / z 369 (M ⁺⁺ 1).

Procedure E

Procedure E provides a method of coupling 3-aminoquinuclidines and carboxylic acids, amines, and indazoles to form amide and urea derivatives.

6- (1-Methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-indazol-3-carboxylic acid (0.500 mmol), TBTU (0.624 mmol) and (3R) -quinu A mixture of clidin-3-amine dihydrochloride (0.706 mmol) was diluted with N, N-dimethylformamide (4 mL) and N, N-diisopropylethylamine (2.34 mmol) was added. The reaction mixture was kept at rt for 16 h. The reaction mixture was loaded on an SCX column (10 g) and washed with methanol (100 mL). The partially purified product was then eluted with 2.0 M ammonia (60 mL) in methanol. Solvent was removed and the residue was purified by preparative HPLC to give product (20% yield).

Using this method the following compounds were prepared:

162) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide,

;

;

163) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazol-3-carboxamide, LC / MS (EI) t _R 1.26, m / z 352 (M ⁺⁺ 1);

167) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide, LC / MS (EI) t _R 2.46, m / z 322 (M ⁺ +1);

184) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1H-indazol-3-carboxamide, LC / MS (EI) t _R 2.50, m / z 2.96 (M ⁺ +1).

Procedure F

Procedure F provides a method of coupling 3-aminoquinuclidines and carboxylic acids, amines, and indazoles to form amide and urea derivatives.

N, N-carbonyldiimidazole (0.62 mmol) was added to a solution of (S) 3-aminoquinuclidin hydrochloride (0.500 mmol) in N, N-dimethylformamide (3.0 mL). N, N-diisopropylethylamine (1.48 mmol) was added dropwise and the reaction mixture was kept at room temperature for 2 hours. N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-indazole-3-carboxamide (0.370 mmol) was added and the reaction mixture was maintained for 16 hours. . The reaction mixture was transferred to an SCX column (10 g) and the column was flushed with 5 volumes of methanol. The partially purified product was then eluted with 5% dimethylethylamine in methanol. The residue was purified by chromatography (using 50/50 → 30/70 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]) to give urea (61% yield).

Using this method the following compounds were prepared:

161) N, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-1,3-dicarboxamide,

;

;

N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -6- (bromo) -1,2-benzisothiazole-3-carboxamide.

N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1- [2- (trimethylsilyl) Methoxy] methyl-1H-indazole-3-carboxamide;

Using the above procedure, the following compounds were prepared by treatment with tetrabutylammonium fluoride:

190) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Boxamide; LC / MS (EI) t _R 4.46, m / z 370.4 (M ⁺ +1).

Procedure G

Procedure G provides a method of coupling 3-aminoquinuclidines and carboxylic acids to form carboxamide derivatives.

Coupling reactions and purification were performed according to Procedure A (benzisoxazole), Procedure B, E or F (benzisothiazole) or Procedure C, D, E or F (indazole). 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 ether (7 mL / mmol starting acid) and kept at room temperature for 2 hours. The solid was collected by filtration, washed with ether and dried to give the hydrochloride salt (40-60% yield).

Using this method the following compounds were prepared:

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

;

;

74) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide hydrochloride, LC / MS (EI) t _R 3.07, m / z 366 (M ⁺⁺ l);

51) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, LC / MS (EI) t _R 14.4, m / z 318 (M ⁺⁺ l);

52) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, LC / MS (EI) t _R 14.35, m / z 318 (M ⁺⁺ l);

53) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, LC / MS (EI) t _R 15.36, m / z 318 (M ⁺⁺ l).

Procedure H

Procedure H provides a method of coupling the brominated 3-aminoquinuclidincarboxamide and Grignard reagent to form alkyl-substituted derivatives.

A 5 mL microwave reaction vessel was charged with bis (triphenylphosphine) palladium (II) chloride (0.030 mmol, 0.1 equiv) and bromide (0.30 mmol). The vessel was emptied and refilled under argon gas. In a separate reaction vessel, a solution of Grignard (1.2 mmol, 4 equiv) was added to a 0.5M solution of zinc chloride (1.2 mmol, 4 equiv) in tetrahydrofuran at room temperature. The suspension was maintained for 30 minutes and the entire contents were transferred through the cannula to the reaction vessel. The vessel was sealed and irradiated with microwave at 100 ° C. for 600 seconds (pre-stirred for 60 seconds). The reaction was quenched with acetic acid (0.5 mL), diluted with methanol and transferred to an SCX column. The column was washed with methanol (50 mL) and the product eluted with 2M ammonia (50 mL) in methanol and concentrated. The residue is chromatographed [90/10/1 dichloromethane / methanol / ammonium hydroxide or 1/1 → 0/1 ethyl acetate / (70/30/1 ethyl acetate / methanol / ammonium hydroxide)] or by preparative HPLC. Purification gave the product (20-50% yield).

Using this method the following compounds were prepared:

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

.

.

Procedure I

Procedure I provides a method of coupling an aniline or phenol bearing aminoquinuclidincarboxamide with an alkylating agent to form secondary aniline- or ether-substituted derivatives.

N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole- in N, N-dimethylformamide (6 mL) To a solution of 3-carboxamide (0.400 mol) was added potassium carbonate (2.00 mol) and cyclopropylmethyl bromide (0.47 mmol). The reaction was kept for 16 hours and the solvent was removed in vacuo. The residue was extracted with 10/1 dichloromethane / methanol (3 ×) and the combined extracts were concentrated. The residue was purified by preparative HPLC (95/5 → 20/80 water (0.1% formic acid) / acetonitrile (0.1% formic acid) using a gradient of 8 minutes) to give the product (32% yield).

Using this method the following compounds were prepared:

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

13) (3S) -3-{[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] Octane iodide or formate, LC / MS (EI) t _R 2.55, m / z 318 (M ⁺⁺ 1);

N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -5-methoxy-1,2-benzisothiazole-3-carboxamide hydroformate.

Using this method the following compounds were prepared:

1) (3S) -3-({[6- (cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azo Niabicyclo [2.2.2] octane bromide or formate, LC / MS (EI) t _R 5.76, m / z 412 (M ⁺⁺ 1).

Procedure J

Procedure J provides a method of coupling a brominated 3-aminoquinuclidin benzisothiazole and a cyclic amine to form an aniline derivative.

Pyrrolidine (0.361 mmol), N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1,2-benzisothiazole-3-carbox Amide (0.259 mmol), palladium acetate (0.021 mmol), 2-dicyclohexylphosphino-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (0.049 mmol) and cesium carbonate (0.586 mmol) was combined in a microwave vessel. The vessel was emptied and refilled under argon atmosphere. Tetrahydrofuran (3.7 mL) was added and the vessel sealed. The reaction was microwaved at 135 ° C. for 30 minutes. The reaction mixture was filtered through celite and the residue was purified by chromatography [100/0 → 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] or by preparative HPLC. The product was obtained (34% yield).

Using this method the following compounds were prepared:

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

;

;

64) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide , LC / MS (EI) t _R 4.13, m / z 357.2 (M ⁺⁺ l);

66) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrrol-1-yl) -1,2-benzisothiazole-3-carbox Voxamide, LC / MS (EI) t _R 4.04, m / z 353.1 (M ⁺⁺ 1);

68) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.31, m / z 427.2 (M ⁺⁺ 1);

69) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazole-3 -Carboxamide, LC / MS (EI) t _R 3.57, m / z 371.2 (M ⁺ +1);

70) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, LC / MS (EI) t _R 3.83, m / z 387.2 (M ⁺⁺ l);

72) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, LC / MS (EI) t _R 3.8, m / z 387.2 (M ⁺ +1);

75) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.74, m / z 387.2 (M ⁺⁺ 1);

76) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.77, m / z 387.2 (M ⁺⁺ l);

79) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 4.22, m / z 423.2 (M ⁺⁺ 1);

108) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide, LC / MS (EI) t _R 4.5, m / z 371.1 (M ⁺⁺ 1);

109) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide, LC / MS (EI) t _R 4.5, m / z 371.1 (M ⁺⁺ 1);

110) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, LC / MS (EI) t _R 3.92, m / z 387.1 (M ⁺⁺ 1);

111) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 3.91, m / z 387.1 (M ⁺⁺ 1);

112) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, LC / MS (EI) t _R 3.91, m / z 387.1 (M ⁺⁺ 1);

113) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, LC / MS (EI) t _R 3.94, m / z 387.1 (M ⁺⁺ 1).

The following compounds were prepared by using the above method from 3-[(2-trimethylsilylethoxy) methoxy] pyrrolidine, treated with 6N hydrochloric acid, purified by preparative HPLC, and isolated using SCX ion exchange. Was:

78) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxypyrrolidin-1-yl) -1,2-benzisothiazole -3-carboxamide, LC / MS (EI) t _R 4.44, m / z 373.1 (M ⁺⁺ 1).

Procedure K

Procedure K provides a method of coupling a brominated 3-aminoquinuclidin indazole with a cyclic amine to form an aniline derivative.

2-dicyclohexylphosphino-2 ', 4', 6'-tri-isopropyl-1,1'-biphenyl (0.0450 mmol), palladium (II) acetate (0.0150 mmol), cesium carbonate (2.25 mmol) And 3- (cyclopropylmethoxy) pyrrolidine (2.25 mmol) were combined in vials. N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-2- [2- (trimethylsilyl) ethoxy] methyl-1H in toluene (6.36 mL) A solution of -indazole-3-carboxamide (0.751 mmol) was added and the mixture was heated at 80 ° C for 3 days. The reaction mixture was filtered through celite, loaded onto a RediSep column (silica gel) and using a gradient of 100/0 → 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine) Eluted. The residue was transferred to an SCX column (10 g), the column was washed with methanol (5 vol), 2.0 M ammonia in methanol (most SEM removed in this process), and the ammonia eluate was concentrated. The residue was purified by preparative HPLC [90/10-&gt; 50/50 water (0.1% formic acid) / acetonitrile (0.1% formic acid); 10 min] to afford the desired product (7% yield).

The following acids were prepared using this method:

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

;

;

61) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazole 3-carboxamide hydroformate, LC / MS (EI) t _R 4.49, m / z 410.2 (M ⁺⁺ 1);

62) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazole-3-carbox Amide hydroformate, LC / MS (EI) t _R 4.1, m / z 370.3 (M ⁺⁺ 1).

Procedure L

Procedure L provides a method of coupling a brominated aminoquinuclidincarboxamide and a cyclic amine to form an aniline derivative.

3-methoxypyrrolidine hydrochloride (6.27 mmol), N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1,2-benzisothiazole 3-carboxamide (4.42 mmol), 2-dicyclohexylphosphino-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (0.845 mmol), palladium acetate (0.363 mmol) and cesium carbonate (9.97 mmol) were withdrawn and charged again under an argon atmosphere. Tetrahydrofuran (60 mL) was added and the reaction heated at reflux for 67 h. The reaction mixture was cooled to rt, filtered through celite (MeOH) and concentrated. The residue was partitioned between 9/1 dichloromethane / methanol (100 mL) and saturated sodium bicarbonate (40 mL) and the layers separated. The aqueous layer was extracted with 9/1 dichloromethane / methanol (3 × 50 mL) and the combined organic layers were washed with brine and dried (sodium sulfate). The residue was purified by chromatography (70/30/1 ethyl acetate / methanol / ammonium hydroxide) to give free base (84%) as a yellow foam. The mono-hydrochloride salt was prepared from methanolic hydrogen chloride [acetyl chloride (0.95 equiv) in methanol (5 mL)] and recrystallized from methanol / ethyl acetate.

Using this procedure the following compounds were prepared:

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

.

.

Procedure M

Procedure M provides a method of coupling a brominated aminoquinuclidincarboxamide with benzophenone imine to form an aniline derivative.

Eject a mixture of bromide (6.30 mmol), palladium acetate (1.00 mmol) and 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos) (0.700 mmol), argon Under charge again. 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 at reflux for 16 h. The reaction mixture was concentrated and again dissolved in a mixture of tetrahydrofuran (90 mL) and 3N hydrochloric acid (30 mL). The reaction mixture was maintained for 2 hours and concentrated. The residue was purified by chromatography (using a mixture of 70/30/1 ethyl acetate / methanol / ammonium hydroxide) to give aniline (79% yield). Aniline was used directly in the subsequent reaction.

Using this method the following compounds were prepared:

6-amino-N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (methyl) -1H-indazole-3-carboxamide;

6-amino-N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -1H-indazole-3-carboxamide;

6-amino-N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-1H-indazole-3-carboxamide.

Procedure N

Procedure N provides a method of coupling an amino aminoquinuclidincarboxamide and an acylating agent to form a carboxamide derivative.

Acid chloride (0.55 mmol) was added to a solution of aniline (0.42 mmol) in pyridine (2 mL) and N, N-dimethylformamide (2 mL). The mixture was kept at ambient temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to give the product (30-80% yield).

Using this method the following compounds were prepared:

23) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-car Voxamide hydroformate,

;

;

24) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H- Sol-3-carboxamide hydroformate, LC / MS (EI) t _R 3.79, m / z 404 (M ⁺⁺ 1);

38) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-[(cyclopropylcarbonyl) amino] -1 H-indazol-3- Carboxamide, LC / MS (EI) t _R 3.65, m / z 394 (M ⁺⁺ 1).

Procedure O

Procedure O provides a method of coupling an amino aminoquinuclidincarboxamide and an isocyanate to form urea derivatives.

Isocyanate (0.53 mmol) was added to aniline (0.40 mmol) in a mixture of pyridine (2 mL) and N, N-dimethylformamide (1 mL). The reaction mixture was kept at ambient temperature for 16 hours and concentrated in vacuo. The residue was purified by preparative HPLC to give the product (50-80% yield).

Using this method the following compounds were prepared:

18) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-methyl-6-{[(propylamino) carbonyl] amino} -1 H-indazol-3 Carboxamide hydroformate,

;

;

25) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-{[(propylamino) carbonyl] amino} -1 H -Indazole-3-carboxamide hydroformate, LC / MS (EI) t _R 3.81, m / z 421 (M ⁺⁺ 1);

39) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-{[(propylamino) carbonyl] amino} -1 H-indazole- 3-carboxamide, LC / MS (EI) t _R 3.71, m / z 411 (M ⁺ +1).

Procedure P

Procedure P provides a method of demethylating methoxy-substituted quinuclidincarboxamides to form phenol derivatives.

Boron tribromide (20.0 mmol) was dissolved in N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benziso in dichloromethane (100 mL). To a solution of thiazole-3-carboxamide (3.80 mmol) was added at 0 ° C. The reaction mixture was allowed to warm up to room temperature and maintained for 3 days. The reaction mixture was quenched with saturated potassium carbonate solution (50 mL) and the layers were separated. The aqueous layer was further extracted with dichloromethane / methanol (10/1) (50 mL) and the organic layers combined and concentrated. The residue was purified by chromatography [(70/30/1) ethyl acetate / methanol / ammonium hydroxide] to give the product (70% yield).

Using this procedure the following compounds were prepared:

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

;

;

10) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazole-3-carboxamide hydroformate, LC / MS (EI) t _R 3.9, m / z 365/367 (M ⁺⁺ 1);

11) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazole-3-carboxamide hydro Formate, LC / MS (EI) t _R 4.26, m / z 443/445/447 (M ⁺⁺ 1);

16) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate, LC / MS (EI ) t _R 2.48, m / z 287 (M ⁺⁺ l);

50) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide, LC / MS ( EI) t _R 2.58, m / z 304 (M ⁺ +1).

Procedure Q

Procedure Q provides a method for preparing cyclic amide derivatives from the corresponding brominated quinuclidin derivatives.

Palladium (II) acetate (0.09 mmol) is added to a solution of 2,2'-bis (diphenylphosphino) -1,1'-binafphyl (0.14 mmol) in toluene (10 mL) and the reaction mixture is The contents were held until complete dissolution. The resulting yellow solution was transferred to a mixture of bromide (0.33 mmol), cesium carbonate (0.60 mmol) and amide (1.00 mmol) under a nitrogen gas atmosphere and the reaction mixture was heated at 100 ° C. for 16 h. The reaction mixture was filtered through celite and concentrated. The residue was purified by HPLC to give the product (72% yield).

Using this method the following compounds were prepared:

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

;

;

65) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benz Isothiazole-3-carboxamide, LC / MS (EI) t _R 2.93, m / z 385.2 (M ⁺⁺ 1).

Using the above procedure, the protecting group was removed using 6N hydrochloric acid to prepare the following compound:

41) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4S) -4-hydroxy-2-oxopyrrolidin-1-yl]- 1H-indazol-3-carboxamide hydroformate, LC / MS (EI) t _R 1.39, m / z 370 (M ⁺⁺ 1).

Procedure R

Procedure R provides a method of coupling an aminoquinuclidincarboxamide with an alcohol via Mitsunobu conditions to form an N (1) -alkylated derivative.

Diisopropyl azodicarboxylate (0.212 mmol) to N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl Dropwise to a solution of) -1H-indazole-3-carboxamide (0.141 mmol), cyclopropyl carbinol (0.283 mmol), triphenylphosphine (0.283 mmol) and N, N-dimethylformamide (1.00 mL). It was. The reaction mixture was kept at room temperature for 16 hours and loaded onto a column of silica gel. The mixture was purified by chromatography {95/5-&gt; 85/15 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]} to give the product (20%) as a solid. The product contained about 7% 2-cyclopropylmethyl isomer.

Using this procedure the following compounds were prepared:

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

;

;

5) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, LC / MS (EI) t _R 3.9, m / z 396 (M ⁺⁺ 1);

30) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, LC / MS (EI) t _R 3.61, m / z 366 (M ⁺ +1);

31) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) -1H -Indazole-3-carboxamide, LC / MS (EI) t _R 3.88, m / z 392 (M ⁺⁺ 1);

32) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1 H-indazole- 3-carboxamide, LC / MS (EI) t _R 3.79, m / z 380 (M ⁺ +1);

33) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H -Indazole-3-carboxamide, LC / MS (EI) t _R 3.79, m / z 380 (M ⁺ +1).

Procedure S

Procedure S provides a method for forming ether derivatives using Mitsunobu reactions from the corresponding phenols.

Diisopropyl azodicarboxylate (0.618 mmol) in N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6 in N, N-dimethylformamide (3.40 mL) -Added dropwise to a solution of hydroxy-1,2-benzisothiazole-3-carboxamide (0.594 mmol), 3-furanmethanol (0.594 mmol) and triphenylphosphine (0.594 mmol). The reaction mixture was maintained for 16 hours and concentrated. The residue was purified by chromatography {100/0 → 90/10 ethyl acetate / [(70/30/2) ethyl acetate / methanol / dimethylethylamine]} to give the product (26% yield).

Using this procedure the following compounds were prepared:

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

.

.

Procedure T

Procedure T provides a method for preparing phenol-substituted quinuclidincarboxamides from bromide derivatives.

Potassium acetate (0.600 mmol), palladium acetate (0.060 mmol), bis (pinacolato) diboron (0.800 mmol) and 2-dicyclohexylphosphino-2 ', 4', 6'-tri-i-propyl- 1,1'-biphenyl (0.200 mmol) was dissolved in N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-1,2 in toluene (8 mL) -To a suspension of benzisothiazole-3-carboxamide (0.500 mmol). The reaction mixture was microwaved for 5 minutes (150 ° C.). The reaction mixture was cooled to rt, filtered through celite (methanol) and the filtrate was concentrated. The residue was purified by preparative HPLC to give the product (60% yield).

Hydrogen peroxide (0.500 mmol) was added to N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4,4,5,5-tetramethyl- in acetone (3 mL). To a solution of 1,3,2-dioxarobolan-2-yl) -1,2-benzisothiazole-3-carboxamide (0.200 mmol). The reaction mixture was kept at rt for 2 h and diluted with water (2 mL). The product was extracted with dichloromethane / methanol (9/1) and the extract was concentrated to give the product (70% yield). Phenol was used directly in the subsequent reaction.

Using this procedure the following compounds were prepared:

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

;

;

(3-[(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1,2-benzisothiazol-5-yl) boronic acid;

(3-[(3S) -1-Azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1,2-benzisothiazol-6-yl) boronic acid.

Procedure U

Procedure U provides a method of forming aromatic aniline derivatives via coupling between 3-aminoquinuclidine benzisothiazole boronic acid.

(3-[(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1,2-benzisothiazol-6-yl) boronic acid (0.604 mmol), 1H- Imidazole (1.8 mmol), copper (II) acetate (1.21 mmol), triethylamine (3.0 mmol), pyridine (4.8 mmol) and tetrahydrofuran (8.5 mL) were combined in a microwave vessel. Microwaves were irradiated to the reaction mixture at 140 ° C. for 600 seconds. The reaction mixture was concentrated and the residue was purified by chromatography [95/5-&gt; 85/15 ethyl acetate / (1/1 / 0.1 ethyl acetate / methanol / dimethylethylamine)] to give the pre-purified product as a yellow oil. Obtained. The residue was further purified by preparative HPLC, fractions containing the desired product were collected and loaded on a 5 g SCX column. The column was washed with methanol (120 mL), 2.0 M ammonia in methanol, and the ammonia eluate was concentrated to give the product as a white solid (14% yield).

Using this method the following compounds were prepared:

80) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3- Carboxamide,

;

;

81) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3- Carboxamide, LC / MS (EI) t _R 3.27, m / z 354.1 (M ⁺⁺ l);

82) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide, LC / MS (EI) t _R 3.85, m / z 368.1 (M ⁺⁺ 1);

83) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide, LC / MS (EI) t _R 3.47, m / z 368.1 (M ⁺⁺ 1).

Procedure V

Procedure V provides a method of coupling indazole quinuclidincarboxamide with boronic acid to form N (1) -alkylated and arylated carboxamide derivatives.

N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1H-indazole-3-carboxamide ( 0.280 mmol), cyclopropylboronic acid (0.840 mmol) and a mixture of copper (II) acetate (5.60 mmol) were diluted with triethylamine (1.40 mmol), pyridine (2.2 mmol) and tetrahydrofuran (3.00 mL). Microwaves were irradiated to the reaction mixture at 140 ° C. for 600 seconds. The reaction mixture was filtered and transferred to an SCX column. The column was washed with methanol (5 vol) and then the product was eluted with 2.0 M ammonia in methanol to give a light yellow solid. The residue was purified by chromatography {90/10-&gt; 80/20 ethyl acetate / [(50/50/2) ethyl acetate / methanol / dimethylethylamine]} to give the product (22% yield). The final product contained about 3% regioisomer.

Using this method the following compounds were prepared:

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

;

;

27) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl)- 1H-indazol-3-carboxamide LC / MS (EI) t _R 4.28, m / z 436 (M ⁺⁺ 1);

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

Procedure W

Procedure W provides a method of coupling a bromo aminoquinuclidin benzisothiazole and cyclic urea to form urea derivatives.

1-propylimidazolidin-2-one (19.0 mmol), N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-1,2-benz Isothiazole-3-carboxamide (10.0 mmol), palladium (II) acetate (1.00 mmol) and di-tert-butyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) force The mixture of pins (2.00 mmol) was diluted with toluene (100 mL) and tetrahydrofuran (50 mL). The reaction mixture was heated at 100 ° C. for 16 h, and the reaction mixture was filtered through celite (methanol) and concentrated. The residue was transferred to an SCX column and washed with methanol (100 mL). The crude product was eluted with 7M ammonia in methanol (100 mL) and the combined product fractions were concentrated. The residue was purified by chromatography [(70/35/1) ethyl acetate / methanol / ammonium hydroxide] to give the product (90% yield). The mono-hydrochloride salt was prepared from methanolic hydrogen chloride [acetyl chloride (0.95 equiv) in methanol (5 mL)] and recrystallized from methanol / ethyl acetate.

Alternative method: 1-ethylimidazolidin-2-one (41.2 mg, 0.000361 mol), N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo -1,2-benzisothiazole-3-carboxamide (95.0 mg, 0.000259 mol), palladium (II) acetate (4.8 mg, 0.000021 mol), 2-dicyclohexylphosphino-2 ', 4', A mixture of 6'-tri-i-propyl-1,1'-biphenyl (23.2 mg, 0.0000488 mol) and cesium carbonate (191 mg, 0.000586 mol) was withdrawn from the microwave tube and recharged under an argon atmosphere. Tetrahydrofuran (3.7 mL, 0.045 mol) was added, the vessel was sealed and the reaction mixture was microwaved at 135 ° C. for 30 minutes. The reaction mixture was filtered through celite and concentrated. The residue was purified by chromatography [100/0 → 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] to give the product (24% yield).

Using this method the following compounds were prepared:

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

;

;

131) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, LC / MS (EI) t _R 3.76, m / z 414.2 (M ⁺⁺ 1);

54) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide hydrochloride, LC / MS (EI) t _R 3.68, m / z 414 (M ⁺⁺ 1).

Procedure X

Procedure X provides a method of coupling a bromo aminoquinuclidin indazole and a cyclic urea to form a urea derivative.

1-propylimidazolidin-2-one (0.5684 mmol), N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-bromo-2- [2- (Trimethylsilyl) ethoxy] methyl-1H-indazol-3-carboxamide (0.409 mmol), palladium acetate (0.034 mmol), 2-dicyclohexylphosphino-2 ', 4', 6'-tri- A mixture of i-propyl-1,1'-biphenyl (0.0768 mmol) and cesium carbonate (0.924 mmol) was withdrawn from the microwave tube and recharged under argon atmosphere. Tetrahydrofuran (5.8 mL) was added and the vessel sealed. Microwaves were irradiated to the reaction mixture at 135 ° C. for 30 minutes. The reaction mixture was filtered through celite and concentrated. The residue was purified by chromatography [100/0 → 80/20 ethyl acetate / (50/50/2 ethyl acetate / methanol / dimethylethylamine)] to give a purified SEM protected product. The residue was dissolved in tetrahydrofuran (5 mL) and 6N hydrochloric acid (5 mL), and the reaction mixture was microwaved at 140 ° C. for 600 seconds. The reaction mixture was transferred to an SCX column (10 g) and the column was flushed with methanol (120 mL) and 2.0 M ammonia in methanol (60 mL) and the ammonia eluate was concentrated. The residue was purified by preparative HPLC, fractions containing the desired product were collected and transferred to SCX column (10 g). The column was flushed with methanol (120 mL) and 2.0 M ammonia (60 mL) in methanol and the ammonia eluate was concentrated to give the product (28% yield).

Using this method the following compounds were prepared:

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

;

;

63) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazole -3-carboxamide, LC / MS (EI) t _R 4.14, m / z 397.3 (M ⁺⁺ 1).

Procedure Y

Procedure Y provides a method of oxidizing quinuclidincarboxamide to form an N-oxide derivative.

m-chloroperbenzoic acid (0.266 mmol) was added in portions to a -78 ° C suspension of quinuclidinamide (0.21 mmol) in dichloromethane (3 mL) and the reaction mixture was allowed to warm to room temperature and maintained for 16 h. The reaction mixture was diluted with methanol and loaded on an SCX column. The column was washed with methanol (50 mL), 2M ammonia in methanol (60 mL) and the ammonia wash was concentrated. The crude product was purified by preparative HPLC to give 26.5 mg (38%) of product.

Using this method the following compounds were prepared:

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

;

;

56) 6-methoxy-N-[(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -1,2-benzisothiazole-3-carboxamide , LC / MS (EI) t _R 3.65, m / z 334 (M ⁺ +1).

step  Z

Procedure Z provides a method for converting aminoquinuclidincarboxamide nitrile to dihydroimidazole derivatives using diamines.

Hydrogen sulfide was added 6-cyano-N- (quinuclindin-3-yl) -1H-indazole-3-carboxamide (90 mg, 0.31 mmol) in ethanol (6 mL) at 0 ° C. in a pressure tube for 30 minutes. Bubbling through a solution. The vessel was sealed and the reaction mixture heated at 80 ° C. for 16 h and concentrated. The residue was diluted with ethylenediamine (4 mL) and heated at 100 ° C for 16 h. The reaction mixture was concentrated to give 110 mg (94%) of dihydroimidazole as a brown solid.

Using this method the following compounds were prepared:

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

.

.

step AA

Procedure AA provides a method for reacting 3-aminoquinuclidine carboxamide with an electrophile to form quaternary ammonium salt derivatives.

N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-indazol-3-carboxamide (3.26 mmol) is dissolved in dichloromethane (50.0 mL) and reacted The mixture was kept at room temperature for 3 days. After a few minutes the mixture became cloudy and after 1 hour a white precipitate appeared. The precipitated solid was collected by filtration, washed with dichloromethane and ethyl acetate and dried to give the product as a colorless solid (92% yield). Analysis by analytical LC / MS showed the product was contaminated with a small amount of starting material (about 5%).

(3S) -1- (chloromethyl) -3-[(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride (0.999) in methanol (10.0 mL) To a solution of mmol) was added MP-diisopropylethylamine (415 mmol / g loading; 41.5 mol) and MP-carbonate (3.5 mmol / g loading; 0.050 mmol). The reaction mixture was shaken for 24 hours and the solid support reagent was removed by filtration. The solvent was evaporated to about 3 mL and ethyl acetate (15 mL) was added. The precipitated solid was collected to give the product (94% yield).

Using this method the following compounds were prepared:

165) (3S) -1- (chloromethyl) -3-[(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride,

.

.

step AB

Procedure AB provides a method of hydrolyzing 3-aminoquinuclidine nitrile to carboxylic acid followed by coupling with an amine to form an amide derivative.

Potassium hydroxide (7.0 mmol) is N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1H- in 1,2-ethanediol (6 mL) To a solution of sol-3-carboxamide (2.3 mmol) was added and the reaction mixture was heated at 140 ° C. for 7 hours. The reaction was cooled to rt and treated with 6 mL of 1 M hydrochloric acid. The precipitate formed was isolated by filtration and dried in vacuo to give the product as HCl salt (45% yield).

In vial 3-[(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride (0.3 mmol), TBTU (0.4 mmol) ) And dimethylamine (0.432 mmol). N, N-dimethylformamide (2 mL) and N, N-diisopropylethylamine (0.249 mL, 1.43 mmol) were added and the reaction mixture was kept at room temperature for 16 hours. The reaction mixture was loaded into an SCX column (10 g) and flushed with methanol (200 mL). The partially purified product was then eluted with 7.0 M ammonia (60 mL) in methanol. The residue was purified by preparative HPLC, product fractions were collected and loaded on SCX column (10 g). The column was flushed with methanol (200 mL) and then flushed with 7.0 M ammonia (60 mL) in methanol. The ammonia layer was evaporated to give an amide (30% yield).

Using this method the following compounds were prepared:

185) 3-[(3S) -1-Azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride, LC / MS (EI) t _R 1.50, m / z 315 (M ⁺⁺ l);

186) N (3)-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-3,6- Dicarboxamide,

;

;

187) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4-methylpiperazin-1-yl) carbonyl] -1 H-indazol-3 -Carboxamide, LC / MS (EI) t _R 2.40, m / z 397 (M ⁺ +1);

188) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H- Sol-3-carboxamide, LC / MS (EI) t _R 2.50, m / z 398 (M ⁺⁺ 1).

step AC

Procedure AC provides a method for producing ether derivatives of 7-azabenzisothiazole from the corresponding chlorides.

Sodium methoxide (30.0 mmol) was dissolved in N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b in methanol (2 mL). ] Was added to a solution of pyridine-3-carboxamide (0.3 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt, quenched with methanol and concentrated. The residue was purified by preparative HPLC, product fractions were collected and loaded on SCX column (10 g). The column was flushed with methanol (200 mL) and then flushed with 7.0 M ammonia (60 mL) in methanol. The ammonia layer was evaporated to give the product (30% yield).

The following compound was prepared using this method.

189) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide, LC / MS (EI) t _R 3.25, m / z 319 (M ⁺ +1).

Binding Example: [ ³ H] MLA Binding

material:

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

Protease Inhibitor Cocktail Tablets: Roche, Catalog No. 1697498

Just ready

Ice-cold 0.32M sucrose 20 volumes (weight / volume) of the rat brain with protease inhibitor (one tablet per 50 ml) were homogenized with polytron for 10 seconds at setting 11 and then centrifuged at 1000 g, 4 ° C. for 10 minutes. Separated. The supernatant was again centrifuged at 20,000 g, 4 ° C. for 20 minutes. 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% (weight / volume) BSA). The membrane formulations were stored at -80 ° C.

For the saturation assay, 200 μl of the assay mixture in binding buffer contains 200 μg of membrane protein, 0.2 to 44 nM [ ³ H] MLA. 1 μM MLA was used to define nonspecific binding. Competition assays were performed using 2 nM [ ³ H] MLA and a preferred range of compounds. The assay mixture was incubated at 22 ° C. for 2 hours and then harvested with a GF / B filter pre-soaked in 0.3% PEI in binding buffer using a Tomtec harvester. The filter was washed three times with binding buffer and radioactivity counted with Trilux.

The binding affinity for the preferred compounds of the invention is 2 nM to 25 μM, in particular 2 nM to 2.5 μM.

The above examples can be repeated in a similar process by replacing the reactants described generally or specifically and / or by implementing the conditions of the present invention for those used in the above examples.

While the invention has been described with reference to specific compounds and their production, it is clear that changes and modifications of the invention can be made without departing from the spirit or scope of the invention.

Claims (65)

Or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a N-oxide thereof, in accordance with Formula I, II, III or IV Phase acceptable salts or solvates. <Formula I>

<Formula II>

<Formula III>

<Formula IV>

Where A is

ego; X is O or S; X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ⁵ to X ⁸ are each independently N, CH, CR ³ or C—, wherein C— represents the point at which the A group is attached to the remainder of the structure of Formula (I), (II), (III) or (IV); X ⁹ to X ¹² are each independently N, CH, CR ⁴ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ¹³ to X ¹⁶ are each independently N, CH, CR or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); R 'is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms ; R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxy, 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 having 1 to 4 carbon atoms and 1 to 4 carbon atoms, fluorinated alkyl having 2 to 6 carbon atoms having the Alkenyl, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, 3 to 7 Cycloalkyl having 5 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms ( , Where the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R ¹⁰ or a Substituted), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, having 3 to 7 carbon atoms Cycloalkoxy, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms Fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 carbon atoms Monoalkylamino having dialkyl Diamino (wherein the alkyl group each independently having one to four carbon atoms), alkoxycarbonyl of 2 to 6, Ar, Het having carbon atoms, OAr, OHet, carbonate -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-O} -Het -ego, Provided that R is not NH ₂ ; or R is of the formula

Wherein n is 2 to 4; m is 3 to 5; or Two R's together may form a fused five-membered ring structure containing one or more N atoms; R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where the alkyl groups each independently have 1 to 4 carbon atoms), alkoxy carbonyl having 2 to 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 R ¹ is a chemical formula

One of the groups; or Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , a fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _{1 -4} - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO-; R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Alkyl having 6 carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ³ is a chemical formula

One of the groups; or Two R ³ together may form a fused five-membered ring structure containing one or more N atoms; R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Substituted), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ⁴ is a chemical formula

One of the groups; or Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms; 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 , alkyl with 1 to 4 carbon atoms, 1 to 4 Fluorinated alkyl having 2 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups Unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 carbons Cycloalkylalkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino Wherein the alkyl groups each independently have 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr or OHet; R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Have cycloalkylalkyl or R ⁶ And R ⁷ is an alkylene group containing 4 to 6 carbon atoms together and forming a ring together with the N atom; R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms ( Wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, 5 to 8 carbon atoms Cycloalkenyl having 1 to 4 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups each independently have 1 to 4 carbon atoms, Ar or Het; R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het; R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (where Said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorine having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar Or Het And; Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino (where the alkyl moiety is Each having 1 to 8 C atoms), amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, 1 to 8 C Hydroxyalkyl having 2 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, having 1 to 8 C atoms Alkylsulfinyl, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino, wherein the cycloalkyl group has 3 to 7 C atoms and 1 to 4 Alkyl with carbon atoms, 1 By alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino having 1 to 4 carbon atoms, wherein the alkyl groups each have 1 to 4 carbon atoms, or a combination thereof Optionally substituted), aryloxy (where the aryl moiety has 6 to 10 carbon atoms, halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylene Dioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms , Hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, 1 to 8 carbons Alkylsulfinyl having an atom, optionally substituted by alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyloxy or a combination thereof, arylthio (where the aryl moiety is 6-10 carbon atoms) Halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, Dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl, Alkoxycarbonyl (where the alkoxy group has 1 to 8 carbon atoms), alkylthio, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, phenoxy or Optionally substituted by acyloxy, or a combination thereof, cycloalkyloxy, wherein the cycloalkyl group has 3 to 7 C atoms, alkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Having alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each have 1 to 4 carbon atoms, or combinations thereof, sulfo , Sulfonylamino, acyl amido, acyloxy or a combination thereof one or more times; Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen, Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, alkyl having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to Cycloalkylalkoxy having 7 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, di (halogenated alkyl) Amino (where the alkyl groups each have 1 to 8 C atoms), (halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo , OH, 3 Alkoxycarbonylalkyl having 1 to 8 carbon atoms, amino, monoalkylamino having 1 to 8 C atoms, dialkylamino, wherein the alkyl groups each have 1 to 8 C atoms, SO ₂ R ¹¹ , -CXR ^11, ethyl-piperidinyl, or it is substituted one or more times with a combination thereof; Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof; R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms, wherein Alkyl, halogenated alkyl, alkenyl or alkynyl groups in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloal having 5 to 8 carbon atoms Kenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, or Ar, Wherein the compound may also be in polymorphic form, Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer, At least one of the R, R ¹ , R ³ , R ⁴ and R ⁵ groups is Het or OHet, wherein the Het group is in each case substituted or unsubstituted, azabicyclooctyl, oxa-azabicycloheptyl, diaza Bicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepane, hexahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. The compound of claim 1, wherein at least one of the R, R ¹ , R ³ , R ^4, and R ⁵ groups is 1-azabicyclo [2.2.2] oct-3-yloxy, 2-oxa-5-azabicyclo [2.2.1] heptyl, diazabicycloheptyl (eg, 2,5-diazabicyclo [2.2.1] hept-2-yl, 5-methyl-2,5-diazabicyclo [2.2 .1] hept-2-yl, trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl, 5- (cyclopropylcarbonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl, 1,4-diazabicyclo [3.2.2] non-4-yl, 5-methyl-2,5-diazabicyclo [2.2.2] oct-2 -Yl, 8-methyl-3,8-diazabicyclo [3.2.1] oct-3-yl, pyrazolyl, dihydroimidazolyl, 1,4-diazepane-1-yl, 4-methyl- 1,4-diazepane-1-yl, hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl or 1- (cyclopropylcarbonyl) -octahydro-6H-pyrrolo [3, 4-b] pyridin-6-yl. The method of claim 1, Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen; Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, alkyl having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkyl alkoxy having 4 to 7 carbon atoms, 2 to 8 Alkoxyalkyl, alkyl (halogenated alkyl) amino having 3 carbon atoms, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino, wherein the alkyl groups are each 1 to 8 C atoms ), (Halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, alkoxycar having 3 to 8 carbon atoms Bonil Kill, amino, monoalkylamino with 1 to 8 C atoms, dialkylamino where the alkyl groups each have 1 to 8 C atoms, SO ₂ R ¹¹ , -CXR ¹¹ , piperidinylethyl or these Is substituted one or more times by a combination of; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , a fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _{1 -4} - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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-; A compound in which at least one of the R, R ¹ , R ³ , R ⁴ and R ⁵ groups is substituted or unsubstituted diazabicycloheptyl or oxazabicycloheptyl. 4. A compound according to claim 3, wherein at least one of the R, R ¹ , R ³ , R ⁴ and R ⁵ groups is 2,5-diazabicyclo [2.2.1] hept-2-yl, methyl-2,5-dia Jabacyclo [2.2.1] hept-2-yl, trifluoroethyl-2,5-diazabicyclo [2.2.1] hept-2-yl or 2-oxa-5-azabicyclo [2.2. 1] hept-5-yl. Or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a N-oxide thereof, in accordance with Formula I, II, III or IV Phase acceptable salts or solvates. <Formula I>

<Formula II>

<Formula III>

<Formula IV>

Where A is

ego; X is O or S; X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ⁹ to X ¹² are each independently N, CH, CR ⁴ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); R 'is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms ; R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ¹ is a chemical formula

One of the groups; or Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4 - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO-; R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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-; R ⁴ is a chemical formula

One of the groups; or Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms; R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Or cycloalkylalkyl having R ⁶ and R ⁷ together are alkylene groups containing 4 to 6 carbon atoms and forming a ring together with N atoms; R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms ( Wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, 5 to 8 carbon atoms Cycloalkenyl having 1 to 4 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups each independently have 1 to 4 carbon atoms, Ar or Het; R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het; R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (where Said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorine having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar Or Het And; Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino (where the alkyl moiety is Each having 1 to 8 C atoms), amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, 1 to 8 C Hydroxyalkyl having 2 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, having 1 to 8 C atoms Alkylsulfinyl, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino, wherein the cycloalkyl group has 3 to 7 C atoms and 1 to 4 Alkyl with carbon atoms, 1 Optionally by alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino having 1 to 4 carbon atoms, wherein the alkyl groups each have 1 to 4 carbon atoms, or a combination thereof having 4 carbon atoms Substituted), aryloxy (where the aryl moiety has 6 to 10 carbon atoms, halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedi Oxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl having 1 to 8 carbon atoms, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, 1 to 8 carbons Alkylsulfinyl having an atom, optionally substituted by alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyloxy or a combination thereof, arylthio (where the aryl moiety is 6-10 carbon atoms) Halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, Dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl, Alkoxycarbonyl (where the alkoxy group has 1 to 8 carbon atoms), alkylthio, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyl Optionally substituted by oxy or a combination thereof, cycloalkyloxy, wherein the cycloalkyl group has 3 to 7 C atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, Hydroxyl, amino, monoalkylamino, having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each have 1 to 4 carbon atoms or optionally substituted thereof, sulfo, sulfonyl Substituted one or more times with amino, acylamido, acyloxy or a combination thereof; Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen, Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, alkyl having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 Cycloalkylalkoxy having 2 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino Wherein each alkyl group has 1 to 8 C atoms, (halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, 3 Alkoxycarbonylalkyl having 1 to 8 carbon atoms, amino, monoalkylamino having 1 to 8 C atoms, dialkylamino, wherein the alkyl groups each have 1 to 8 C atoms, SO ₂ R ¹¹ , -CXR ^11, ethyl-piperidinyl, or it is substituted one or more times with a combination thereof; Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof; R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms, wherein Alkyl, halogenated alkyl, alkenyl or alkynyl groups in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloal having 5 to 8 carbon atoms Kenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms) or Ar; Wherein the compound may also be in polymorphic form, Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer, Provided that A is a group of formula (a) and has one or more R ¹ substituents, wherein R ¹ is Het excluding thiazolyl, R ² is alkyl having 2 to 4 carbon atoms, 1 to 4 carbon atoms fluorinated alkyl, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, a fluorinated C _{1 -4} having -alkyl -CO-, C _{3 -7-cycloalkyl} -CO-, C _{1 -4-alkyl,} -NH-CO-, C _{3 -7} - cycloalkyl, -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 or -NH-CO-; A is a group of formula (c), has at least one R ⁴ substituent, and where R ⁴ is imidazolyl, pyrrolyl, pyrazolyl, C _{1 - 8} alkyl-pyrazolyl, oxazolyl-to-azabicyclo heptyl, diaza bicycloalkyl as heptyl, C _{1 - 8} alkyl-heptyl in diazabicyclo, halogenated C _{1 - 8} alkyl-heptyl in diazabicyclo, piperidinyl (amino, C _{1 - 8} alkyl or -NH- (C _{1 - 8} alkyl) substituted by ₂ N-), or pyrrolidinyl (hydroxy, halogenated alkoxy, cycloalkyl, alkoxy, amino, monoalkylamino (C _{1 - 8} alkyl, -NH-), dialkylamino ((C _{1 - 8} alkyl) ₂ N-), alkoxyalkyl or alkyl (fluorinated alkyl) amino). The method of claim 5, Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen; Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, alkyl having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, 2 to 8 Alkoxyalkyl, alkyl (halogenated alkyl) amino having 3 carbon atoms, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino, wherein the alkyl groups are each 1 to 8 C atoms ), (Halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, alkoxycar having 3 to 8 carbon atoms Bonil , Monoalkylamino, dialkylamino having amino, 1 to 8 C atoms (wherein the alkyl group having 1 to 8 C atoms, ^{_{respectively), SO 2 R 11, -CXR}} 11, piperidinyl ethyl or a Substituted one or more times by a combination; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , a fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _{1 -4} - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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-. 7. Compounds according to claim 5 or 6, having formula (I). 7. Compounds according to claim 5 or 6, having formula II. 7. Compounds according to claim 5 or 6, having formula III. 7. Compounds according to claim 5 or 6, having formula IV. The compound of any one of claims 5-10, wherein A is a group of partial formula (a) and is attached to the remainder of the compound via the 3, 4 or 7 position. The compound of any one of claims 5-11, wherein A is a group of partial formula (c) and is attached to the remainder of the compound via the 3, 4 or 7 position. 12. The compound of claim 11, wherein A is a group of partial formula (a) and is attached to the rest of the compound via the 3 position. The compound of claim 12, wherein A is a group of partial formula (c) and is attached to the remainder of the compound via the 3 position. Or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a N-oxide thereof, in accordance with Formula I, II, III or IV Phase acceptable salts or solvates. <Formula I>

<Formula II>

<Formula III>

<Formula IV>

Where A is

ego; X is O or S; X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ⁵ to X ⁸ are each independently N, CH, CR ³ or C—, wherein C— represents the point at which the A group is attached to the remainder of the structure of Formula (I), (II), (III) or (IV); X ⁹ to X ¹² are each independently N, CH, CR ⁴ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ¹³ to X ¹⁶ are each independently N, CH, CR or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); R 'is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms ; R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxy, 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 having 1 to 4 carbon atoms and 1 to 4 carbon atoms, fluorinated alkyl having 2 to 6 carbon atoms having the Alkenyl, alkynyl having 2 to 6 carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl group is in each case unsubstituted or substituted by Ar or Het, 3 to 7 Cycloalkyl having 5 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms (Wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R ^10, or their Substituted by a combination of; cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, and 3 to 7 carbon atoms Cycloalkoxy having, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxy having 1 to 4 carbon atoms Alkyl, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 carbon atoms Monoalkylamino, dial with Amino (wherein the alkyl group each independently having one to four carbon atoms), alkoxycarbonyl of 2 to 6, Ar, Het having carbon atoms, OAr, OHet, carbonate -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-O} -Het -ego, Provided that R is not NH ₂ ; or R is of the formula

Wherein n is 2 to 4; m is 3 to 5; or Two R's together may form a fused five-membered ring structure containing one or more N atoms; R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 - 6 -} ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ¹ is a chemical formula

One of the groups; or Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkyl having 4 to 7 carbon atoms alkyl, fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4 - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO-; R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 - 6 -} ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ³ is a chemical formula

One of the groups; or Two R ³ together may form a fused five-membered ring structure containing one or more N atoms; R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ⁴ is a chemical formula

One of the groups; or Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms; 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 , alkyl with 1 to 4 carbon atoms, 1 to 4 Fluorinated alkyl having 2 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups Unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 carbons Cycloalkylalkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino Wherein the alkyl groups each independently have 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr or OHet; R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Or cycloalkylalkyl having R ⁶ and R ⁷ together are alkylene groups containing 4 to 6 carbon atoms and forming a ring together with N atoms; R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms ( Wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, 5 to 8 carbon atoms Cycloalkenyl having 1 to 4 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups each independently have 1 to 4 carbon atoms, Ar or Het; R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het; R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (where Said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorine having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar Or Het And; Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino (where the alkyl moiety is Each having 1 to 8 C atoms), amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, 1 to 8 C Hydroxyalkyl having 2 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, having 1 to 8 C atoms Alkylsulfinyl, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino, wherein the cycloalkyl group has 3 to 7 C atoms and 1 to 4 Alkyl with carbon atoms, 1 Optionally by alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino having 1 to 4 carbon atoms, wherein the alkyl groups each have 1 to 4 carbon atoms, or a combination thereof having 4 carbon atoms Substituted), aryloxy (where the aryl moiety has 6 to 10 carbon atoms, halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedi Oxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl having 1 to 8 carbon atoms, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, 1 to 8 carbons Alkylsulfinyl having an atom, optionally substituted by alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyloxy or a combination thereof, arylthio (where the aryl moiety is 6-10 carbon atoms) Halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, Dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl, Alkoxycarbonyl (where the alkoxy group has 1 to 8 carbon atoms), alkylthio, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyl Optionally substituted by oxy or a combination thereof, cycloalkyloxy, wherein the cycloalkyl group has 3 to 7 C atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, Hydroxyl, amino, monoalkylamino, having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each have 1 to 4 carbon atoms or optionally substituted thereof, sulfo, sulfonyl Substituted one or more times with amino, acylamido, acyloxy or a combination thereof; Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen, Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylene dioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, al having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 Cycloalkylalkoxy having 2 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino Wherein each alkyl group has 1 to 8 C atoms, (halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, 3 Alkoxycarbonylalkyl having 1 to 8 carbon atoms, amino, monoalkylamino having 1 to 8 C atoms, dialkylamino, wherein the alkyl groups each have 1 to 8 C atoms, SO ₂ R ¹¹ , -CXR ^11, ethyl-piperidinyl, or it is substituted one or more times with a combination thereof; Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof; R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms, wherein Alkyl, halogenated alkyl, alkenyl or alkynyl groups in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloal having 5 to 8 carbon atoms Kenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms) or Ar; Wherein the compound may also be in polymorphic form, Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer, The compound has one or more Het groups, wherein Het is a fully saturated, partially saturated or fully unsaturated group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom , Wherein at least one of the substituents is halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, 4 to Cycloalkylalkyl having 7 carbon atoms, halogenated alkyl having 2 to 8 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups are each 1-8 Having C atoms, di (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms) or having 1 to 8 C atoms (halogenated) A keel) amino. 16. The fully saturated, partially saturated or fully aromatic group of claim 15 having at least one Het group, wherein the Het group has 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom. Unsaturated groups, which are substituted, wherein at least one of the substituents is halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkyl having 4 to 7 carbon atoms Alkoxy, halogenated alkyl having 2 to 8 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms), di ( Halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, or (halogenated alkyl) amino having 1 to 8 C atoms. The compound of claim 15, wherein R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, 17. to cycloalkyl-alkyl having 7 carbon atoms, a fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _{1 -4} - alkyl, -NH-CO-, C _{3 - 7-cycloalkyl,} -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- of the compound. Or a pharmaceutically acceptable salt or solvate or N-oxide thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a N-oxide thereof, in accordance with Formula I, II, III or IV Phase acceptable salts or solvates. <Formula I>

<Formula II>

<Formula III>

<Formula IV>

Where A is

ego; X is O or S; X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ⁵ to X ⁸ are each independently N, CH, CR ³ or C—, wherein C— represents the point at which the A group is attached to the remainder of the structure of Formula (I), (II), (III) or (IV); X ⁹ to X ¹² are each independently N, CH, CR ⁴ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ¹³ to X ¹⁶ are each independently N, CH, CR or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); R 'is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms ; R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxy, 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 having 1 to 4 carbon atoms and 1 to 4 carbon atoms, fluorinated alkyl having 2 to 6 carbon atoms having the Alkenyl, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, 3 to 7 Cycloalkyl having 5 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms (Wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R ^10, or their Substituted by a combination of; cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, and 3 to 7 carbon atoms Cycloalkoxy having, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxy having 1 to 4 carbon atoms Alkyl, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 carbon atoms Monoalkylamino, dial with Amino (wherein the alkyl group each independently having one to four carbon atoms), alkoxycarbonyl of 2 to 6, Ar, Het having carbon atoms, OAr, OHet, carbonate -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-O} -Het -ego, Provided that R is not NH ₂ ; or R is of the formula

Wherein n is 2 to 4; m is 3 to 5; or Two R's together may form a fused five-membered ring structure containing one or more N atoms; R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to Monoal with 4 carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ¹ is a chemical formula

One of the groups; or Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4 - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO-; R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ³ is a chemical formula

One of the groups; or Two R ³ together may form a fused five-membered ring structure containing one or more N atoms; R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het ), Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where the alkyl groups each independently have 1 to 4 carbon atoms), alkoxy carbonyl having 2 to 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 R ⁴ is a chemical formula

One of the groups; or Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms; 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 , alkyl with 1 to 4 carbon atoms, 1 to 4 Fluorinated alkyl having 2 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups Unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 carbons Cycloalkylalkoxy with atoms, alkylthio with 1 to 4 carbon atoms, fluorinated alkoxy with 1 to 4 carbon atoms, hydroxyalkyl with 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having 2 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkyl Amino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr or OHet; R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Or cycloalkylalkyl having R ⁶ and R ⁷ together are alkylene groups containing 4 to 6 carbon atoms and forming a ring together with N atoms; R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms ( Wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, 5 to 8 carbon atoms Cycloalkenyl having 1 to 4 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups each independently have 1 to 4 carbon atoms, Ar or Het; R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het; R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (where Said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorine having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar Or Het And; Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino (where the alkyl moiety is Each having 1 to 8 C atoms), amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, 1 to 8 C Hydroxyalkyl having 2 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, having 1 to 8 C atoms Alkylsulfinyl, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino, wherein the cycloalkyl group has 3 to 7 C atoms and 1 to 4 Alkyl with carbon atoms, 1 By alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino having 1 to 4 carbon atoms, wherein the alkyl groups each have 1 to 4 carbon atoms, or a combination thereof Optionally substituted), aryloxy (where the aryl moiety has 6 to 10 carbon atoms, halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylene Dioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms , Hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, 1 to 8 carbons Alkylsulfinyl having an atom, optionally substituted by alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyloxy or a combination thereof, arylthio (where the aryl moiety is 6-10 carbon atoms) Halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, Dialkylamino (where the alkyl groups each have 1 to 8 carbon atoms), hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl , Alkoxycarbonyl (where the alkoxy group has 1 to 8 carbon atoms), alkylthio, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, a Optionally substituted by oxy or a combination thereof, cycloalkyloxy, wherein the cycloalkyl group has 3 to 7 C atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, Hydroxyl, amino, monoalkylamino, having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each have 1 to 4 carbon atoms or optionally substituted thereof, sulfo, sulfonyl Substituted one or more times with amino, acylamido, acyloxy or a combination thereof; Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen, Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has from 1 to 8 carbon atoms, alkyl thio, al having from 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 Cycloalkylalkoxy having 2 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino Wherein each alkyl group has 1 to 8 C atoms, (halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, 3 Alkoxycarbonylalkyl having 1 to 8 carbon atoms, amino, monoalkylamino having 1 to 8 C atoms, dialkylamino, wherein the alkyl groups each have 1 to 8 C atoms, SO ₂ R ¹¹ , -CXR ^11, ethyl-piperidinyl, or it is substituted one or more times with a combination thereof; Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof; R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms, wherein Alkyl, halogenated alkyl, alkenyl or alkynyl groups in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloal having 5 to 8 carbon atoms Kenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms) or Ar; Wherein the compound may also be in polymorphic form, Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer, At least one of X ¹ , X ² , X ³ and X ⁴ is N; At least one of X ⁵ , X ⁶ , X ⁷ and X ⁸ is N; At least one of X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is N; ^At least one of X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ is N. The method of claim 18, Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen; Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, alkyl having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, 2 to 8 Alkoxyalkyl, alkyl (halogenated alkyl) amino having 3 carbon atoms, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino, wherein the alkyl groups are each 1 to 8 C atoms ), (Halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, alkoxycar having 3 to 8 carbon atoms Bonil , Monoalkylamino, dialkylamino having amino, 1 to 8 C atoms (wherein the alkyl group having 1 to 8 C atoms, ^{_{respectively), SO 2 R 11, -CXR}} 11, piperidinyl ethyl or a Substituted one or more times by a combination; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , a fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _{1 -4} - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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-. The method of claim 18 or 19, At least one of X ¹ , X ² , X ³ and X ⁴ is N and one or two of the remaining X ¹ to X ⁴ is CR ¹ ; At least one of X ⁵ , X ⁶ , X ⁷ and X ⁸ is N and one or two of the remaining X ⁵ to X ⁸ is CR ³ ; At least one of X ⁹ , X ¹⁰ , X ¹¹ and X ¹² is N and one or two of the remaining X ⁹ to X ¹² is CR ⁴ ; or ^At least one of X ¹³ , X ¹⁴ , X ¹⁵ and X ¹⁶ is N and at least one of the remaining X ¹³ to X ¹⁶ is CR. The method according to any one of claims 1 to 20, A is a group of partial formula (a) and is attached to the remainder of the compound via the 3, 4 or 7 position, or A is a group of partial formula (b) and is attached to the remainder of the compound via the 4 or 7 position, or A is a group of partial formula (c) and is attached to the remainder of the compound via the 3, 4 or 7 position, or A is a group of partial formula (d) and is attached to the remainder of the compound via the 3, 4 or 7 position. The compound of claim 21 having formula (I). The compound of claim 21 having formula II. The compound of claim 21, having formula III. The compound of claim 21 having formula IV. The compound of any one of claims 1-25, wherein A is a group of partial formula (a) and is attached to the remainder of the compound via the 3, 4 or 7 position. The compound of any one of claims 1-25, wherein A is a group of partial formula (c) and is attached to the remainder of the compound via the 3, 4 or 7 position. The compound of claim 26, wherein A is a group of partial formula (a) and is attached to the remainder of the compound via the 3 position. The compound of claim 27, wherein A is a group of partial formula (c) and is attached to the remainder of the compound via the 3 position. The compound of claim 21, wherein A is a group of partial formula (a), (c) or (d) and is attached to the remainder of the compound via the 3-position. Solvates of compounds according to formula (I), (II), (III) or (IV), and their pharmaceutically acceptable salts (including quaternary ammonium salts) or solvates or N-oxides, or their pharmaceutically acceptable salts, or these Pharmaceutically acceptable salts or solvates of N-oxides. <Formula I>

<Formula II>

<Formula III>

<Formula IV>

Where A is

ego; X is O or S; X ¹ to X ⁴ are each independently N, CH, CR ¹ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ⁵ to X ⁸ are each independently N, CH, CR ³ or C—, wherein C— represents the point at which the A group is attached to the remainder of the structure of Formula (I), (II), (III) or (IV); X ⁹ to X ¹² are each independently N, CH, CR ⁴ or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); X ¹³ to X ¹⁶ are each independently N, CH, CR or C—, wherein C— represents the point where the A group is attached to the rest of the structure of Formula (I), (II), (III) or (IV); R 'is H, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms ; R is H, F, Cl, Br, I, OH, CN, COH, NR ⁶ R ⁷ , carboxy, 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 having 1 to 4 carbon atoms and 1 to 4 carbon atoms, fluorinated alkyl having 2 to 6 carbon atoms having the Alkenyl, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het, 3 to 7 Cycloalkyl having 5 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms ( Wherein said cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R ¹⁰ or a Substituted), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, having 3 to 7 carbon atoms Cycloalkoxy, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms , Fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 carbon atoms Monoalkylamino, dial with Amino (wherein the alkyl group each independently having one to four carbon atoms), alkoxycarbonyl of 2 to 6, Ar, Het having carbon atoms, OAr, OHet, carbonate -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-O} -Het -ego, Provided that R is not NH ₂ ; or R is of the formula

Wherein n is 2 to 4; m is 3 to 5; or Two R's together may form a fused five-membered ring structure containing one or more N atoms; R ¹ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ¹ is a chemical formula

One of the groups; or Two R ¹ together may form a fused five-membered ring structure containing one or more N atoms; R ² is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms , fluorinated C _{1 -4} - alkyl, -CO-, C _{3 -7} - cycloalkyl, -CO-, C _1-4 - alkyl, -NH-CO-, C _{3 -7} - cycloalkyl, -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 _{(e.g., CH 2 CH 2 -O-CH} 3), Ar-C 1 -4 - alkyl or -NH-CO- Het-NH-CO-; R ³ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or substituted by Ar or Het ), Cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where the alkyl groups each independently have 1 to 4 carbon atoms), alkoxy carbonyl having 2 to 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 R ³ is a chemical formula

One of the groups; or Two R ³ together may form a fused five-membered ring structure containing one or more N atoms; R ⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH ₂ , COH, NR ⁶ R ⁷ , carboxy, 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, 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, fluorinated alkyl having 2 to Alkenyl having 6 carbon atoms, alkynyl having 2 to 6 carbon atoms (wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl groups are in each case unsubstituted or by Ar or Het Substituted), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl (wherein the cycloalkenyl is unsubstituted or substituted by HCO-, C _{1 -6} - ^{alkoxy, NR 6 R 7, CO-} NR 6 R 7, C 2 -6 - alkoxycarbonyl, -CO-R Substituted by ¹⁰ or a combination thereof), cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, 3 to 7 carbon atoms Cycloalkoxy having carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, 1 to 4 carbon atoms Hydroxyalkyl having 1, fluorinated hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, 1 to 4 Monovalent carbon atoms Amino, dialkylamino (where each alkyl group independently has 1 to 4 carbon atoms), alkoxycarbonyl having 2 to 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 R ⁴ is a chemical formula

One of the groups; or Two R ⁴ together may form a fused five-membered ring structure containing one or more N atoms; 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 , alkyl with 1 to 4 carbon atoms, 1 to 4 Fluorinated alkyl having 2 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein the alkyl, fluorinated alkyl, alkenyl or alkynyl groups Unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, Cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 carbons Cycloalkylalkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino Wherein the alkyl groups each independently have 1 to 4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr or OHet; R ⁶ and R ⁷ each independently represent H, alkyl having 1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or 4 to 7 carbon atoms Or cycloalkylalkyl having R ⁶ and R ⁷ together are alkylene groups containing 4 to 6 carbon atoms and forming a ring together with N atoms; R ⁸ is H, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms ( Wherein said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, 5 to 8 carbon atoms Cycloalkenyl having 1 to 4 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, 1 to 4 carbon atoms Fluorinated hydroxyalkyl having, monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein the alkyl groups each independently have 1 to 4 carbon atoms, Ar or Het; R ⁹ is alkyl having 1 to 4 carbon atoms, Ar, Ar-alkyl, wherein the alkyl moiety has 1 to 4 carbon atoms or Het; R ¹⁰ is alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (where Said alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, having 5 to 8 carbon atoms Cycloalkenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorine having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, NR ⁶ R ⁷ , NR ² R ⁸ , Ar Or Het And; Ar is an aryl group having 6 to 10 carbon atoms, which is unsubstituted or alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen, dialkylamino (where the alkyl moiety is Each having 1 to 8 C atoms), amino, cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, 1 to 8 C Hydroxyalkyl having 2 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, having 1 to 8 C atoms Alkylsulfinyl, alkylsulfonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino, wherein the cycloalkyl group has 3 to 7 C atoms and 1 to 4 Alkyl with carbon atoms, 1 Optionally by alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino having 1 to 4 carbon atoms, wherein the alkyl groups each have 1 to 4 carbon atoms, or a combination thereof having 4 carbon atoms Substituted), aryloxy (where the aryl moiety has 6 to 10 carbon atoms, halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedi Oxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl having 1 to 8 carbon atoms, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, 1 to 8 carbons Alkylsulfinyl having an atom, optionally substituted by alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyloxy or a combination thereof, arylthio (where the aryl moiety is 6-10 carbon atoms) Halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino having 1 to 8 carbon atoms, Dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano, acyl, Alkoxycarbonyl (where the alkoxy group has 1 to 8 carbon atoms), alkylthio, alkylsulfinyl having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, phenoxy, acyl Optionally substituted by oxy or a combination thereof, cycloalkyloxy, wherein the cycloalkyl group has 3 to 7 C atoms, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, Hydroxyl, amino, monoalkylamino, having 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each have 1 to 4 carbon atoms or optionally substituted thereof, sulfo, sulfonyl Substituted one or more times with amino, acylamido, acyloxy or a combination thereof; Het is a fully saturated, partially saturated or fully unsaturated heterocyclic group having 5 to 10 ring atoms, wherein at least one ring atom is an N, O or S atom, which is unsubstituted or halogen, Aryl having 6 to 10 carbon atoms, wherein the aryl is halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro, methylenedioxy, ethylenedioxy, Amino, alkylamino having 1 to 8 carbon atoms, dialkylamino where the alkyl groups each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms, 1 to 8 carbon atoms Hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, wherein the alkoxy group has 1 to 8 carbon atoms, alkylthio, alkyl having 1 to 8 carbon atoms Sulfinyl, optionally substituted by alkylsulfonyl, phenoxy, acyloxy, or a combination thereof, having 1 to 8 carbon atoms), alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms , Cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, halogenated alkoxy having 1 to 8 C atoms, cycloalkoxy having 3 to 7 carbon atoms, 4 to 7 Cycloalkylalkoxy having 2 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, alkyl (halogenated alkyl) amino, wherein the alkyl groups each have 1 to 8 C atoms, and di (halogenated alkyl) amino Wherein each alkyl group has 1 to 8 C atoms, (halogenated alkyl) amino having 1 to 8 C atoms, cyano, halogenated alkyl having 1 to 8 carbon atoms, nitro, oxo, OH, 3 Alkoxycarbonylalkyl having 1 to 8 carbon atoms, amino, monoalkylamino having 1 to 8 C atoms, dialkylamino, wherein the alkyl groups each have 1 to 8 C atoms, SO ₂ R ¹¹ , -CXR ^11, ethyl-piperidinyl, or it is substituted one or more times with a combination thereof; Carbo is a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or halogen, alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, hydroxy, Substituted one or more times with nitro, cyano, oxo, or a combination thereof; R ¹¹ is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkenyl having 3 to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms, wherein Alkyl, halogenated alkyl, alkenyl or alkynyl groups in each case unsubstituted or substituted by Ar or Het), cycloalkyl having 3 to 7 carbon atoms, cycloal having 5 to 8 carbon atoms Kenyl, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, hydroxyalkyl having 2 to 4 carbon atoms, fluorinated having 2 to 4 carbon atoms Hydroxyalkyl, monoalkylamino with 1 to 4 carbon atoms, dialkylamino, wherein the alkyl groups each independently have 1 to 4 carbon atoms, or Ar; Wherein the compound may also be in polymorphic form, Where the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer, Provided that the 1-azabicyclo group is a partial formula

In the form of quaternary ammonium, wherein Z is alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms or 7 to 16 carbons Arylalkyl with an atom, and anion A is iodide, bromide, chloride, triflate, tosylate or mesylate. <Claim 31> The compound of claim 30, wherein the A group is a group of formula (a) or (c). The compound of claim 31, wherein X ¹ to X ⁴ are each CH or CR ¹ , or X ⁹ to X ¹² are each CH or CR ⁴ . 33. The compound of any one of the preceding claims, wherein X is O. 34. The compound of any one of claims 1-33, wherein R 'is H, cyclopropylmethyl or CH ₃ . 1) (3S) -3-({[6- (cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azo Niabicyclo [2.2.2] octane bromide or formate, 2) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 3) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate, 4) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1 H-indazole- 3-carboxamide, 5) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, 6) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazole-3-carboxamide hydro Formate, 7) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide hydroformate, 8) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3 Carboxamide hydroformate, 9) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazole-3-carboxamide hydroformate, 10) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazole-3-carboxamide hydroformate, 11) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazole-3-carboxamide hydro Formate, 12) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroxy-1,2-benzisothiazole-3-carboxamide hydroformate, 13) (3S) -3-{[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] Octane iodide or formate, 14) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-furylmethoxy) -1,2-benzisothiazole-3-carboxamide Hydroformate, 15) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin-1-yl) -1 H-indazole- 3-carboxamide hydroformate, 16) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate, 17) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, 18) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-methyl-6-{[(propylamino) carbonyl] amino} -1 H-indazol-3 Carboxamide hydroformate, 19) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 20) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 21) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazole-3-carboxamide , 22) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- (1,3-thiazol-2-yl)- 1H-indazole-3-carboxamide, 23) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-car Voxamide hydroformate, 24) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H- Sol-3-carboxamide hydroformate, 25) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-{[(propylamino) carbonyl] amino} -1 H Indazole-3-carboxamide hydroformate, 26) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, 27) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl)- 1H-indazole-3-carboxamide, 28) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, 29) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide, 30) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, 31) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide, 32) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1 H-indazole- 3-carboxamide, 33) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide, 34) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, 35) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, 36) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, 37) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, 38) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-[(cyclopropylcarbonyl) amino] -1 H-indazol-3- Carboxamide, 39) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-{[(propylamino) carbonyl] amino} -1 H-indazole- 3-carboxamide, 40) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide, 41) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4S) -4-hydroxy-2-oxopyrrolidin-1-yl]- 1H-indazole-3-carboxamide hydroformate, 42) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, 43) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, 44) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, 45) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, 46) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, 47) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide hydroformate, 48) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydro Formate, 49) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide hydrochloride, 50) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide, 51) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, 52) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, 53) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, 54) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide hydrochloride, 55) N-[(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -5- (trifluoromethoxy) -1H-indazole-3-carboxamide , 56) 6-methoxy-N-[(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -1,2-benzisothiazole-3-carboxamide , 57) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide hydro Formate, 58) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1 H-indazole 3-carboxamide hydroformate, 59) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide, 60) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate, 61) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1H-indazole 3-carboxamide hydroformate, 62) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazole-3-carbox Amide hydroformate, 63) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazole 3-carboxamide hydroformate, 64) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide , 65) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benz Isothiazole-3-carboxamide, 66) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrrol-1-yl) -1,2-benzisothiazole-3-carbox Voxamide, 67) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethyl-2-oxoimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 68) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 69) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazole-3 Carboxamide, 70) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 71) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazole-3-carboxamide hydrochloride, 72) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 73) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide hydroformate, 74) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide hydrochloride, 75) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 76) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 77) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazole -3-carboxamide, 78) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxypyrrolidin-1-yl) -1,2-benzisothiazole -3-carboxamide, 79) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 80) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3- Carboxamide, 81) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3- Carboxamide, 82) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide, 83) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide, 84) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 85) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 86) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazole-3-carboxamide, 87) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2- Benzisothiazole-3-carboxamide, 88) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, 89) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4,5-dihydro-1H-imidazol-2-yl) -1H-indazole -3-carboxamide, 90) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3 , 4-b] pyridine-3-carboxamide, 91) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1 H-pyrazolo [3 , 4-b] pyridine-3-carboxamide, 92) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 93) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 94) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 95) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 96) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 97) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide, 98) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 99) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 100) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 101) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 102) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 103) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 104) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide, 105) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 106) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, 107) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, 108) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide, 109) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide, 110) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, 111) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 112) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, 113) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, 114) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide , 115) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide , 116) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 117) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 118) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide, 119) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide, 120) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, 121) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, 122) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (2,2,2-trifluoroethyl)- 2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 123) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide, 124) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide, 125) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 126) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 127) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1 , 2-benzisothiazole-3-carboxamide, 128) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 129) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, 130) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, 131) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 132) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate, 133) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate, 134) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 135) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 136) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate, 137) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate, 138) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide , 139) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 140) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 141) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, 142) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, 143) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide, 144) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide, 145) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Yl) -1,2-benzisothiazole-3-carboxamide, 146) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Yl) -1,2-benzisothiazole-3-carboxamide, 147) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide, 148) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide, 149) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 150) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 151) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 152) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 153) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, 154) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 155) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 156) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 157) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide, 158) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide, 159) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide, 160) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide, 161) N, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-1,3-dicarboxamide, 162) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide, 163) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide, 164) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl]- 1H-indazole-3-carboxamide, 165) (3S) -1- (chloromethyl) -3-[(1H-indazol-3-ylcarbonyl) amino] -1-azonia bicyclo [2.2.2] octane chloride, 166) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1 H-indazol- 3-carboxamide dihydroformate, 167) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide, 168) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 169) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide, 170) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide, 171) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazole-3-carboxamide, 172) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazole-3-carboxamide, 173) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl) -1,2-benzisothiazole- 3-carboxamide, 174) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl) -1,2-benzisothiazole- 3-carboxamide, 175) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 176) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 177) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 178) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 179) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide, 180) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide, 181) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 182) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 183) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole -3-carboxamide, 184) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1H-indazole-3-carboxamide, 185) 3-[(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride, 186) N (3)-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-3,6- Dicarboxamide, 187) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4-methylpiperazin-1-yl) carbonyl] -1 H-indazol-3 Carboxamide, 188) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H- Sol-3-carboxamide, 189) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide, and 190) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide Is selected from, Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of solvates, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of N-oxides, The compounds listed above in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof may also be in polymorphic form, When the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer. 36. The method of claim 35 wherein 2) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 3) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazol-3-carboxamide hydroformate, 4) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1 H-indazole- 3-carboxamide, 5) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, 6) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazole-3-carboxamide hydro Formate, 7) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide hydroformate, 8) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3 Carboxamide hydroformate, 9) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazole-3-carboxamide hydroformate, 10) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazole-3-carboxamide hydroformate, 11) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazole-3-carboxamide hydro Formate, 12) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroxy-1,2-benzisothiazole-3-carboxamide hydroformate, 13) (3S) -3-{[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1-methyl-1-azoniabicyclo [2.2.2] Octane iodide or formate, 14) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-furylmethoxy) -1,2-benzisothiazole-3-carboxamide Hydroformate, 15) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin-1-yl) -1 H-indazole- 3-carboxamide hydroformate, 16) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate, 17) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, 18) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-methyl-6-{[(propylamino) carbonyl] amino} -1 H-indazol-3 Carboxamide hydroformate, 19) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 20) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 21) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazole-3-carboxamide , 22) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- (1,3-thiazol-2-yl)- 1H-indazole-3-carboxamide, 23) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3-car Voxamide hydroformate, 24) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H- Sol-3-carboxamide hydroformate, 25) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-{[(propylamino) carbonyl] amino} -1 H Indazole-3-carboxamide hydroformate, 26) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, 27) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl)- 1H-indazole-3-carboxamide, 28) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, 29) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide, 30) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, 31) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide, 32) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1 H-indazole- 3-carboxamide, 33) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide, 34) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, 35) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, 36) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, 37) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, 38) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-[(cyclopropylcarbonyl) amino] -1 H-indazol-3- Carboxamide, 39) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-{[(propylamino) carbonyl] amino} -1 H-indazole- 3-carboxamide, 40) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide, 41) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4S) -4-hydroxy-2-oxopyrrolidin-1-yl]- 1H-indazole-3-carboxamide hydroformate, 42) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, 43) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, 44) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, 45) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, 46) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, 47) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide hydroformate, 48) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydro Formate, 49) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide hydrochloride, 50) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide, 51) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, 52) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, 53) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-methoxy-1,2-benzisothiazole-3-carboxamide hydrochloride, 54) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide hydrochloride, 55) N-[(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -5- (trifluoromethoxy) -1H-indazole-3-carboxamide , And 56) 6-methoxy-N-[(3S) -1-oxido-1-azabicyclo [2.2.2] oct-3-yl] -1,2-benzisothiazole-3-carboxamide Is selected from, Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of solvates, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of N-oxides, The compounds listed above in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof may also be in polymorphic form, When the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer. 36. The method of claim 35 wherein 2) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 3) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,6-dimethoxy-1H-indazole-3 -carboxamide hydroformate, 4) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -1-propyl-6- (1,3-thiazol-2-yl) -1 H-indazole- 3-carboxamide, 5) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-isopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, 6) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydrofuran-3-yloxy) -1H-indazole-3-carboxamide hydro Formate, 7) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide hydroformate, 8) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1 H-indazol-3 Carboxamide hydroformate, 9) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -4-hydroxy-1H-indazole-3-carboxamide hydroformate, 10) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-bromo-4-hydroxy-1H-indazole-3-carboxamide hydroformate, 11) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5,7-dibromo-4-hydroxy-1H-indazole-3-carboxamide hydro Formate, 12) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-hydroxy-1,2-benzisothiazole-3-carboxamide hydroformate, 13) (3S) -3-{[(5-hydroxy-1,2-benzisothiazol-3-yl) carbonyl] amino} -1- methyl-1-azoniabicyclo [2.2.2] Octane iodide or formate, 14) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-furylmethoxy) -1,2-benzisothiazole-3-carboxamide Hydroformate, 15) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (2-oxopyrrolidin-1-yl) -1 H-indazole- 3-carboxamide hydroformate, 16) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-hydroxy-1H-indazol-3-carboxamide hydroformate, 17) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, 18) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-methyl-6-{[(propylamino) carbonyl] amino} -1 H-indazol-3 Carboxamide hydroformate, 19) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 20) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6-methoxy-1H-indazol-3-carboxamide, 21) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-methoxy-1H-indazole-3-carboxamide , 22) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6- (1,3-thiazol-2-yl)- 1H-indazole-3-carboxamide, 23) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1-methyl-1H-indazol-3- Carboxamide hydroformate, 24) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(cyclopropylcarbonyl) amino] -1- (difluoromethyl) -1H- Sol-3-carboxamide hydroformate, 25) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (difluoromethyl) -6-{[(propylamino) carbonyl] amino} -1 H Indazole-3-carboxamide hydroformate, 26) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6- (1,3-thiazol-2-yl) -1H-indazole -3-carboxamide, 27) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-thiazol-2-yl) -1- (3-thienyl)- 1H-indazole-3-carboxamide, 28) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, 29) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide, 30) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide, 31) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1- (cyclopropylmethyl) -6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide, 32) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,3-oxazol-2-yl) -1-propyl-1 H-indazole- 3-carboxamide, 33) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-N-methyl-6- (1,3-oxazol-2-yl) -1H Indazole-3-carboxamide, 34) N-[(3S) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, 35) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide, 36) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, 37) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide, 38) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-[(cyclopropylcarbonyl) amino] -1 H-indazol-3- Carboxamide, 39) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-cyclopropyl-6-{[(propylamino) carbonyl] amino} -1 H-indazole- 3-carboxamide, 40) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide, 41) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4S) -4-hydroxy-2-oxopyrrolidin-1-yl]- 1H-indazole-3-carboxamide hydroformate, 42) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-methoxy-N-methyl-1H-indazol-3-carboxamide hydroformate, 43) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, 44) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (difluoromethoxy) -N-methyl-1H-indazol-3-carboxamide hydro Formate, 45) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, 46) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-5- (tetrahydro-2H-pyran-4-yl) -1H-indazole- 3-carboxamide hydroformate, 47) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -N-methyl-6- (1,3-thiazol-2-yl) -1H-indazole- 3-carboxamide hydroformate, 48) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-N-methyl-1,2-benzisothiazole-3-carboxamide hydro Formate, 49) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide hydrochloride, and 50) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-hydroxy-1,2-benzisothiazole-3-carboxamide Is selected from, Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of solvates, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of N-oxides, The compounds listed above in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof may also be in polymorphic form, When the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer. 36. The method of claim 35 wherein 57) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carboxamide hydro Formate, 58) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1 H-indazole 3-carboxamide hydroformate, 59) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [4,3-c] pyridine-3-carboxamide, 60) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1H-pyrazolo [3,4-c] pyridine-3-carboxamide hydroformate, 61) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1 H-indazole 3-carboxamide hydroformate, 62) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1H-indazole-3-carbox Amide hydroformate, 63) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazole 3-carboxamide hydroformate, 64) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide , 65) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-2-oxopyrrolidin-1-yl) -1,2-benz Isothiazole-3-carboxamide, 66) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrrol-1-yl) -1,2-benzisothiazole-3-carbox Voxamide, 67) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethyl-2-oxoimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 68) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (cyclopropylmethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 69) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisoxazole-3 Carboxamide, 70) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 71) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazole sol-3-carboxamide hydrochloride, 72) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methoxypyrrolidin-1-yl) -1,2-benzisothiazole- 3-carboxamide, 73) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide hydroformate, 74) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -1-ethyl-6- (1,3-oxazol-2-yl) -1 H-indazole- 3-carboxamide hydrochloride, 75) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 76) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 77) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1H-indazole -3-carboxamide, 78) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-hydroxypyrrolidin-1-yl) -1,2-benzisothiazole -3-carboxamide, 79) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (difluoromethoxy) pyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 80) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-imidazol-1-yl) -1,2-benzisothiazole-3- Carboxamide, 81) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1H-pyrazol-1-yl) -1,2-benzisothiazole-3- Carboxamide, 82) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide, 83) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-1H-pyrazol-1-yl) -1,2-benzisothia Sol-3-carboxamide, 84) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 85) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 86) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxy-1,2-benzisoxazole-3-carboxamide, 87) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-ethoxypyrrolidin-1-yl) -7-fluoro-1,2- Benzisothiazole-3-carboxamide, 88) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-phenyl-1H-pyrazolo [3,4-b] pyridine-3-carboxamide, 89) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4,5-dihydro-1H-imidazol-2-yl) -1H-indazole -3-carboxamide, 90) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3 , 4-b] pyridine-3-carboxamide, 91) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (dimethylamino) pyrrolidin-1-yl] -1H-pyrazolo [3, 4-b] pyridine-3-carboxamide, 92) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 93) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6- (3-methoxypyrrolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, 94) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 95) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 96) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 97) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide, 98) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 99) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 100) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 101) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 102) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-hydroxypyrrolidin-1-yl] -1,2- Benzisothiazole-3-carboxamide, 103) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 104) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept -5-yl] -1,2-benzisothiazole-3-carboxamide, 105) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 106) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, 107) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] isothiazolo [5,4-b] pyridine-3-carboxamide hydroformate, 108) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide, 109) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benzi Soxazole-3-carboxamide, 110) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, 111) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 112) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, 113) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide hydroformate, 114) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide , 115) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -7-fluoro-6-methoxy-1,2-benzisothiazole-3-carboxamide , 116) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 117) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 118) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide, 119) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -2,5-diazabicyclo [2.2.1] hept- 2-yl] -1,2-benzisothiazole-3-carboxamide, 120) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, 121) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methylamino) pyrrolidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, 122) N-[(3R) -1-Azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (2,2,2-trifluoroethyl)- 2,5-diazabicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 123) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide, 124) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- {3- [methyl (2,2,2-trifluoroethyl) amino] pyrrolidine -1-yl} -1,2-benzisothiazole-3-carboxamide, 125) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 126) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [3- (methoxymethyl) pyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 127) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 128) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3- (dimethylamino) pyrrolidin-1-yl] -1, 2-benzisothiazole-3-carboxamide, 129) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide, and 130) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (dimethylamino) piperidin-1-yl] -1,2-benziso Thiazole-3-carboxamide Is selected from, Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of solvates, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of N-oxides, The compounds listed above in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof may also be in polymorphic form, When the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer. 36. The method of claim 35 wherein 131) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-oxo-3-propylimidazolidin-1-yl) -1,2- Benzisothiazole-3-carboxamide, and pharmaceutically acceptable salts thereof, Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of solvates, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of N-oxides, The compounds listed above in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof may also be in polymorphic form, When the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer. 36. The method of claim 35 wherein 1) (3S) -3-({[6- (cyclopropylmethoxy) -1,2-benzisothiazol-3-yl] carbonyl} amino) -1- (cyclopropylmethyl) -1-azo Niabicyclo [2.2.2] octane bromide or formate, 132) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate, 133) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -N-methyl-6-[(1S, 4S) -5-methyl-2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide dihydroformate, 134) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 135) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1R, 4R) -5-methyl-2,5-diazabicyclo [2.2. 1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 136) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate, 137) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazabicyclo [3.2.2] non-4-yl) -1 , 2-benzisothiazole-3-carboxamide dihydroformate, 138) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-pyrrolidin-1-yl-1,2-benzisothiazole-3-carboxamide , 139) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 140) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 141) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, 142) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (4-methyl-1,4-diazepane-1-yl) -1,2-benz Isothiazole-3-carboxamide, 143) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide, 144) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl)- 1,2-benzisothiazole-3-carboxamide, 145) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Yl) -1,2-benzisothiazole-3-carboxamide, 146) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (5-methyl-2,5-diazabicyclo [2.2.2] oct-2- Yl) -1,2-benzisothiazole-3-carboxamide, 147) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide, 148) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (8-methyl-3,8-diazabicyclo [3.2.1] oct-3- Yl) -1,2-benzisothiazole-3-carboxamide, 149) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 150) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5-cyclopropyl-2,5-diazabicyclo [2.2 .1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 151) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 152) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylmethyl) -2,5-diazabicycle Rho [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 153) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5- (4-methyl-1,4-diazepan-1-yl) -1,2-benz Isothiazole-3-carboxamide, 154) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 155) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3R) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 156) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 157) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide, 158) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1-methylpyrrolidin-3-yl) oxy] -1,2-benziso Thiazole-3-carboxamide, 159) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide, 160) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-azabicyclo [2.2.2] oct-3-yloxy) -1,2 Benzisothiazole-3-carboxamide, 161) N, N'-di- (3S) -1-azabicyclo [2.2.2] oct-3-yl-1H-indazole-1,3-dicarboxamide, 162) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide, 163) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl)- 1H-indazole-3-carboxamide, 164) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3- (cyclopropylmethoxy) pyrrolidin-1-yl]- 1H-indazole-3-carboxamide, 165) (3S) -1- (chloromethyl) -3-[(1H-indazol-3-ylcarbonyl) amino] -1-azoniabicyclo [2.2.2] octane chloride, 166) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -5-[(3S) -3-methoxypyrrolidin-1-yl] -1 H-indazol- 3-carboxamide dihydroformate, 167) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-chloroisothiazolo [5,4-b] pyridine-3-carboxamide, 168) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 169) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide, 170) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl)- 1,2-benzisothiazole-3-carboxamide, 171) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazole-3-carboxamide , 172) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-piperazin-1-yl-1,2-benzisothiazole-3-carboxamide, 173) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl) -1,2-benzisothiazole- 3-carboxamide, 174) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (1,4-diazepane-1-yl) -1,2-benzisothiazole- 3-carboxamide, 175) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 176) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- (2-methylpiperazin-1-yl) -1,2-benzisothiazole-3 Carboxamide, 177) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 178) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [4- (cyclopropylcarbonyl) piperazin-1-yl] -1,2-benz Isothiazole-3-carboxamide, 179) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide, 180) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6- [1- (cyclopropylcarbonyl) octahydro-6H-pyrrolo [3,4-b ] Pyridin-6-yl] -1,2-benzisothiazole-3-carboxamide, 181) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 182) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(1S, 4S) -5- (cyclopropylcarbonyl) -2,5-diaza Bicyclo [2.2.1] hept-2-yl] -1,2-benzisothiazole-3-carboxamide, 183) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -6- (3,4-dimethylpiperazin-1-yl) -1,2-benzisothiazole -3-carboxamide, 184) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-cyano-1H-indazole-3-carboxamide, 185) 3-[(3S) -1-azabicyclo [2.2.2] oct-3-ylamino] carbonyl-1H-indazol-6-carboxylic acid hydrochloride, 186) N (3)-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -N (6), N (6) -dimethyl-1H-indazol-3,6- Dicarboxamide, 187) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(4-methylpiperazin-1-yl) carbonyl] -1 H-indazol-3 Carboxamide, 188) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-[(3R) -3-methoxypyrrolidin-1-yl] carbonyl-1H- Sol-3-carboxamide, 189) N-[(3S) -1-azabicyclo [2.2.2] oct-3-yl] -6-methoxyisothiazolo [5,4-b] pyridine-3-carboxamide, and 190) N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -5- (tetrahydro-2H-pyran-4-yloxy) -1H-indazol-3-car Voxamide Is selected from, Wherein the salts listed above may also be in free base form or in the form of other pharmaceutically acceptable salts, the free base forms listed above may also be in the form of pharmaceutically acceptable salts, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of solvates, The compounds listed above in free base form or in the form of a pharmaceutically acceptable salt may also be in the form of N-oxides, The compounds listed above in free base form or in the form of solvates or N-oxides thereof, or pharmaceutically acceptable salts or solvates thereof may also be in polymorphic form, When the compound exhibits chiral properties, it may be in the form of a mixture of enantiomers or a mixture of diastereomers or in the form of a single enantiomer or a single diastereomer. 41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier. 42. The method of claim 41, wherein the other α-7 agonist, PDE4 inhibitor, calcium channel blocker, muscarinic m1 modulator, muscarinic m2 modulator, adenosine receptor modulator, ampakin, NMDA-R modulator, mGluR modulator, dopamine modulator, A pharmaceutical composition further comprising one or more additional pharmaceutical agents selected from serotonin modulators, cannabinoid modulators and cholinesterase inhibitors. Α- in patients with selective activation / stimulation of α-7 nicotinic receptors comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a patient in need thereof 7 Method of selectively activating / stimulating nicotinic receptors. 41. A method comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a patient suffering from mental disorders, neurodegenerative diseases associated with cholinergic dysfunction and / or memory and / or cognitive impairment symptoms. The treatment method of said patient. 45. The method of claim 44, wherein the patient has schizophrenia, anxiety, mania, depression, mood swings, Tourette's syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, Lewy body Lewy Body) Dementia, amyotrophic lateral sclerosis, memory impairment, memory loss, cognitive deficit, attention deficit and / or attention deficit hyperactivity disorder. 41. A method of treating a patient, comprising administering to a patient suffering from dementia and / or other memory loss related symptoms an effective amount of a compound according to any one of claims 1-40. Memory impairment due to minor cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia A method of treating a patient, comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a patient suffering from cerebral senility, multiple infarction dementia, HIV and / or cardiovascular disease. 41. Treating and / or preventing dementia in Alzheimer's patients comprising administering to the Alzheimer's patient a therapeutically effective amount of a compound according to any one of claims 1 to 40 to inhibit the binding of amyloid beta peptides to the nACh receptor. Way. 41. A method of treating a patient comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a patient exhibiting symptoms of alcohol withdrawal or to a patient undergoing detoxification treatment. The treatment of a patient, comprising administering an effective amount of a compound according to any one of claims 1 to 40 to the patient for providing neuroprotection against damage associated with seizures and ischemia and glutamate-induced excitatory toxicity. Way. A method of treating a patient, comprising administering to a patient suffering from nicotine intoxication, pain, jet lag, obesity, and / or diabetes. 41. A method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1-40. Minor cognitive impairment (MCI), vascular dementia (VaD), age-related cognitive decline (AACD), cardiac surgery, forgetfulness associated with heart attack or general anesthesia, memory deficiency due to exposure to anesthetics, sleep deprivation-induced cognitive impairment Patients with chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive impairment, Down syndrome, alcoholism-related dementia, drug / substance-induced memory impairment, boxer dementia (Boxer syndrome) or animal dementia 41. A method of treating a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1-40. A method of treating memory loss comprising administering an effective amount of a compound according to any one of claims 1 to 40 to a patient in need thereof. 41. A method of treating a patient, comprising administering a compound according to any one of claims 1 to 40 to a patient suffering from memory impairment. The method of claim 55, wherein said memory damage is due to reduced nicotinic acetylcholine receptor activity. A method of treating or preventing a disease or condition resulting from a dysfunction of nicotinic acetylcholine receptor delivery in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. A method of treating or preventing a disease or condition resulting from a deficiency or malfunction of nicotinic acetylcholine receptor in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. . An effective amount of a compound according to any one of claims 1 to 40 to a patient A method of treating or preventing a disease or condition resulting from inhibited nicotinic acetylcholine receptor delivery in said patient, comprising administering. A method of treating or preventing a disease or condition resulting from a loss of cholinergic synapses in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. A method for protecting neurons from neurotoxicity induced by activation of the α7nACh receptor in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. A method of treating or preventing a neurodegenerative disorder by inhibiting the binding of Aβ peptides to α7nACh receptors in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 40. 41. A method of treating a patient, comprising administering a compound according to any one of claims 1 to 40 to a patient suffering from an inflammatory disease. 64. The method of claim 63, wherein the inflammatory disease is rheumatoid arthritis, diabetes or sepsis. 65. The method of any one of claims 40-64, wherein said patient is a human.