US2011178075A1PendingUtilityA1
Indoles, 1h-indazoles, 1,2-benzisoxazoles, 1,2-benzoisothiazoles, and preparation and uses thereof
Est. expiryApr 22, 2024(expired)· nominal 20-yr term from priority
A61P 3/10A61P 9/10A61P 9/00A61P 43/00A61P 7/00A61P 29/02A61P 29/00A61P 25/16A61P 25/28A61P 25/20C07D 471/08A61P 25/04C07D 487/04A61P 25/22A61P 25/00A61P 3/04A61P 25/14A61P 25/24A61P 25/08A61P 25/18A61P 25/34C07D 451/04C07D 487/08C07D 471/04C07D 451/14
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Claims
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 (indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
Claims
exact text as granted — not AI-modified1 . A compound according to Formula I, II, or III:
wherein
X 1 to X 4 are each, independently, CH, CR 1 , or N, wherein at most one of X 1 to X 4 is N;
X 5 to X 8 are each, independently, CH, CR 2 , or N, wherein at most one of X 5 to X 8 is N;
X 9 to X 12 are each, independently, CH, CR 3 , or N, wherein at most one of X 9 to X 12 is N;
C═B is C═O, C═S, or CH 2 ;
Y is O or S;
A 1 is
and
A 2 is
wherein when A 2 is of the following formula, m is 2 or 3, and B is O, then at least one of X 5 to X 8 is CR 2 in which R 2 is other than H, CH 3 , or halogen, or R 10 is other than H, CH 3 , or C 2 H 5
wherein when A 2 is of the following formula, m is 2, and B is O, then at least one of X 5 to X 8 is CR 2 in which R 2 is other than H or CH 3 , or R 8 is other than H, CH 3 , or C 2 H 5
and
wherein when A 2 is of the following formula, m is 2 or 3, and B is O, then at least one of X 5 to X 8 is CR 2 in which R 2 is other than H or CH 3 , or R 5 is other than H, CH 3 , or C 2 H 5
A 3 is
R 1 , R 2 and R 3 are each independently,
H,
C 1-6 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 2-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 2-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Si(R 15 ) 3 , Ar, Het, or combinations thereof,
C 3-8 -cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , unsubstituted C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
halogen,
CN, NO 2 , NR 13 R 14 , SH, SR 13 , SOR 13 , SO 2 R 13 , SO 2 NR 13 R 14 , NR 13 SO 2 R 14 , CONR 13 R 14 , CSNR 13 R 14 , COOR 13 , NR 13 COR 14 , NR 13 CSR 14 , NR 13 CONR 13 R 14 , NR 13 CSNR 13 R 14 , NR 13 COOR 14 , NR 13 CSOR 14 , OCONR 13 R 14 , OCSNR 13 R 14 ,
Ar,
Het, or
R 16 O—;
R 4 to R 12 are each, independently,
H,
C 1-4 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof,
C 3-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof,
C 3-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C 1-4 -alkyl, C 1-4 -alkoxy or combinations thereof,
Ar-alkyl, or
Het-alkyl;
R 13 and R 14 are each independently
H,
Ar,
Ar-alkyl,
Het,
C 1-4 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, monoalkylamino, dialkylamino, C 3-8 -cycloalkyl, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
C 3-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof, or
C 3-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar or combinations thereof;
R 15 is C 1-6 -alkyl;
R 16 is H,
C 1-6 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 3-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 3-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 3-8 -cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , unsubstituted C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 4-8 -cycloalkylalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , unsubstituted C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
Ar, or
Het;
m is 1, 2 or 3;
o is 1 or 2;
Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by
alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 8 carbon atoms,
halogen,
amino,
cyano,
hydroxyl,
nitro,
halogenated alkyl having 1 to 8 carbon atoms,
halogenated alkoxy having 1 to 8 carbon atoms,
hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms,
alkenyloxy having 3 to 8 carbon atoms,
monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms,
carboxy,
alkoxycarbonyl,
alkylaminocarbonyl,
acylamido,
acyloxy,
alkylthio having 1 to 8 carbon atoms,
alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms,
sulfo,
sulfonylamino,
Het,
cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio, or
combinations thereof;
Ar-alkyl is an aryl-alkylene group wherein the alkylene portion contains 1 to 4 carbon atoms and is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio, and the aryl portion is Ar as defined above; and
Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by
alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 8 carbon atoms,
halogen,
amino,
cyano,
hydroxyl,
nitro,
halogenated alkyl having 1 to 8 carbon atoms,
halogenated alkoxy having 1 to 8 carbon atoms,
hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms,
alkenyloxy having 3 to 8 carbon atoms,
monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms,
carboxy,
alkoxycarbonyl,
alkoxycarbonylmethyl,
alkylaminocarbonyl,
acylamido,
acyloxy,
alkylthio having 1 to 8 carbon atoms,
alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms,
sulfo,
oxo,
sulfonylamino,
cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryl containing 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryl-alkylene group wherein the aryl portion contains 6 to 10 carbon atoms and the alkylene portion contains 1 to 4 carbon atoms and is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
heterocyclic-alkyl group, in which the heterocyclic portion is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is an alkylene group containing 1-4 carbon atoms, wherein said heterocyclic-alkyl group is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio, or
combinations thereof; and
Het-alkyl is a Het-alkylene group wherein the alkylene portion contains 1 to 4 carbon atoms, and the Het portion is Het as defined above; or
a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 , wherein said compound is a compound of Formula I or a pharmaceutically acceptable salt thereof.
3 . A compound according to claim 1 , wherein said compound is a compound of Formula II or a pharmaceutically acceptable salt thereof.
4 . A compound according to claim 1 , wherein said compound is a compound of Formula III or a pharmaceutically acceptable salt thereof
5 . (canceled)
6 . (canceled)
7 . A compound according to claim 1 , wherein R 1 , —R 2 , and R 3 are in each case H, alkyl, halogenated alkyl, OR 16 , halogen, Ar, or Het.
8 . A compound according to claim 7 , wherein Het is in each case substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted dihydropyranyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted imidazolyl, or substituted or unsubstituted isoxazolyl.
9 . A compound according to claim 7 , wherein Het is each case 2-thienyl, 3-thienyl, 2-(4-methyl)thienyl, 2-(5-methyl)thienyl), 2-oxazolyl, (trifluoromethylphenyl)thienyl, 2-(4-methyl)thiazolyl, (3,6-dihydro-2H-pyran-4-yl), (1-benzyl-1H-1,2,3-triazol-4-yl), 2-oxo-3-propylimidazolidin-1-yl), dimethylisoxazolyl, 1-benzyl-1H-pyrazol-4-yl, 2-furyl, 3-furyl, or 2-(5-methyl)furyl).
10 . A compound according to claim 1 , wherein
(a) when said compound is of formula I, X 1 to X 4 are in each case CH or CR 1 ; (b) when said compound is of formula II, X 5 to X 8 are in each case CH or CR 2 ; and (c) when said compound is of formula III, X 9 to X 12 are in each case CH or CR 3 .
11 . A compound according to claim 1 , wherein
(a) when said compound is of formula I, X 1 is CH; (b) when said compound is of formula II, X 5 is CH; and (c) when said compound is of formula III, X 9 is CH.
12 . A compound according to claim 1 , wherein
(a) when said compound is of formula I, X 4 is CH or CR 1 ; (b) when said compound is of formula II, X 8 is CH or CR 2 ; and (c) when said compound is of formula III, X 12 is CH or CR 3 ; wherein R 1 , R 2 , and R 3 are in each case alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, or halogen.
13 . A compound according to claim 1 ,
(a) when said compound is of formula I, X 2 and X 3 are in each case CH or CR 1 ; (b) when said compound is of formula II, X 6 and X 7 are in each case CH or CR 2 ; and (c) when said compound is of formula III, X 10 and X 11 are in each case CH or CR 3 ; wherein R 1 , R 2 , and R 3 are in each case alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, halogen, cyano, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylalkoxy, Ar or Het.
14 . A compound according to claim 1 , wherein R 7 , R 9 , R 11 , and R 12 are in each case H or alkyl.
15 . A compound according to claim 1 , wherein R 4 , R 5 , R 6 , R 8 , and R 10 are in each case H, alkyl, cycloalkylalkyl or Ar-alkyl.
16 . A compound according to claim 1 , wherein said compound is of formula I and A 1 is octahydropyrrolo[1,2-a]pyrazinyl, 3-methyl-3,8-diazabicyclo[3.2.1]octan-8-amino, or 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl.
17 . A compound according to claim 1 , wherein said compound is of formula II and A 2 is 8-methyl-8-azabicyclo[3.2.1]octan-3-amino (endo and/or exo).
18 . A compound according to claim 1 , wherein said compound is of formula III and A 3 is 8 methyl-3,8-diazabicyclo[3.2.1]octan-3-amino.
19 . (canceled)
20 . (canceled)
21 . A compound according to claim 1 , wherein said compound is of formula I,
A 1 is 3,8-diazabicyclo[3.2.1]octan-8-amino, 3-methyl-3,8-diazabicyclo[3.2.1]octan-8-amino or 8-methyl-3,8-diazabicyclo[3.2.1]octan-8-amino; and B is O.
22 . A compound according to claim 1 , wherein
said compound is of formula I and is selected from:
(a) a compound wherein X 1 , X 2 , and X 3 are CH, X 4 is CR 1 , and B is O,
(b) a compound wherein X 1 , X 2 , and X 4 are CH, X 3 is CR 1 , and B is O, and
(c) a compound wherein X 1 , X 3 , and X 4 are CH, X 2 is CR 1 , and B is O;
said compound is of formula II and is selected from:
(a) a compound wherein X 5 , X 6 , and X 7 are CH, X 8 is CR 2 , and B is O,
(b) a compound wherein X 5 , X 6 , and X 8 are CH, X 7 is CR 2 , and B is O, and
(c) a compound wherein X 5 , X 7 , and X 8 are CH, X 6 is CR 2 , and B is O; or
said compound is of formula III and is selected from:
(a) a compound wherein X 9 , X 10 , and X 11 are CH, X 12 is CR 3 , and B is O,
(b) a compound wherein X 9 , X 10 , and X 12 are CH, X 11 is CR 3 , and B is O, and
(c) a compound wherein X 9 , X 11 , and X 12 are CH, X 10 is CR 3 , and B is O.
23 . A compound according to claim 22 , wherein alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, or halogen.
24 . (canceled)
25 . (canceled)
26 . (canceled)
27 . (canceled)
28 . (canceled)
29 . (canceled)
30 . (canceled)
31 . (canceled)
32 . A compound according to claim 1 , wherein said compound is selected from:
3-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl)-1H-indazole hydroformate, 3-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl)-1H-indazole, 3-[(3-Methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-indazole hydroformate, 3-[(3-Methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-indazole, 3-[(8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-indazole hydroformate, 3-[(8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-indazole, 3-[(8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-5-(trifluoromethoxy)-1H-indazole hydroformate, 3-[(8-Methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-5-(trifluoromethoxy)-1H-indazole, 5-Methoxy-3-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-indazole hydroformate, 5-Methoxy-3-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-indazole, 6-Methoxy-3-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1,2-benzisothiazole hydroformate, 6-Methoxy-3-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1,2-benzisothiazole, 6-Methoxy-3-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-indazole hydroformate, 6-Methoxy-3-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-indazole, 3-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl)-6-methoxy-1H-indazole hydroformate, 3-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylcarbonyl)-6-methoxy-1H-indazole, 2-(1H-Indazol-3-ylcarbonyl)octahydro-2H-pyrido[1,2-a]pyrazine hydroformate, 2-(1H-Indazol-3-ylcarbonyl)octahydro-2H-pyrido[1,2-a]pyrazine, and pharmaceutically acceptable salts thereof.
33 . (canceled)
34 . A compound according to claim 1 , wherein said compound is selected from:
2-[(6-Methoxy-1H-indazol-3-yl)carbonyl]octahydro-2H-pyrido pyrazine hydroformate, and pharmaceutically acceptable salts thereof.
35 . (canceled)
36 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
37 . (canceled)
38 . A method of treating a patient suffering from a psychotic disease, a neurodegenerative disease involving a dysfunction of the cholinergic system, and/or a condition of memory and/or cognition impairment, comprising administering to the patient an effective amount of a compound according to according to Formula I, II, or III:
wherein
X 1 to X 4 are each, independently, CH, CR 1 , or N, wherein at most one of X 1 to X 4 is N;
X 5 to X 8 are each, independently, CH, CR 2 , or N, wherein at most one of X 5 to X 8 is N;
X 9 to X 12 are each, independently, CH, CR 3 , or N, wherein at most one of X 9 to X 12 is N;
C═B is C═O, C═S, or CH 2 ;
Y is O or S;
A 1 is
wherein when A 1 is of the following formula, m is 2 or 3, and B is O, then R 1 is other than H, CH 1 or halogen, or R 10 is other than H, CH 3 or C 2 H 5
wherein when A 1 is of the following formula, m is 1 or 2, and B is O, then R 1 is other than H or CH 3 , or R 8 is other than H, CH 3 or C 2 H 5
A 2 is
wherein when A 2 is of the following formula, m is 2 or 3, and B is O, then R 2 is other than H, CH 3 , or halogen, or R 10 is other than H, CH 3 or C 2 H 5
wherein when A 2 is of the following formula, m is 2, and B is O, then R 2 is other than H or CH 3 , or R 8 is other than H, CH 3 or C 2 H 5
wherein when A 2 is of the following formula, m is 2 or 3, and B is O, then R 2 is other than H or CH 3 , or R 5 is other than H, CH 3 or C 2 H 5
A 3 is
wherein when A 3 is of the following formula, m is 2 or 3, Y is O, and B is O, then R 3 is other than H, CH 3 , halogen, NO 2 or NH 2 , or R 10 is other than H, CH 3 or C 2 H 5
R 1 , R 2 and R 3 are each, independently,
H,
C 1-6 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 2-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 2-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Si(R 15 ) 3 , Ar, Het, or combinations thereof,
C 3-8 -cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , unsubstituted C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
halogen,
CN, NO 2 , NR 13 R 14 , SH, SR 13 , SOR B , SO 2 R 13 , SO 2 NR 13 R 14 , NR 13 SO 2 R 14 , CONR 13 R 14 , CSNR 13 R 14 , COOR 13 , NR 13 COR 14 , NR 13 CSR 14 , NR 13 CONR 13 R 14 , NR 13 CSNR 13 R 14 , NR 13 COOR 14 , NR 13 CSOR 14 , OCONR 13 R 14 , OCSNR 13 R 14 ,
Ar
Het, or
R 16 O—;
R 4 to R 12 are each, independently,
H,
C 1-4 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof,
C 3-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof,
C 3-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C 1-4 -alkyl, C 1-4 -alkoxy or combinations thereof,
Ar-alkyl, or
Het-alkyl;
R 13 and R 14 are each independently
H,
Ar,
Ar-alkyl,
Het,
C 1-4 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, monoalkylamino, dialkylamino, C 3-8 -cycloalkyl, or combinations thereof,
cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof,
C 3-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar, or combinations thereof, or
C 3-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 4 carbon atoms, Ar or combinations thereof;
R 15 is C 1-6 -alkyl;
R 16 is H,
C 1-6 -alkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 3-6 -alkenyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 3-6 -alkynyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , Ar, Het, or combinations thereof,
C 3-8 -cycloalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , unsubstituted C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , to Ar, Het, or combinations thereof,
C 4-8 -cycloalkylalkyl which is unsubstituted or substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR 13 R 14 , SH, SR 13 , SOR 13 , unsubstituted C 3-8 -cycloalkyl, SO 2 R 13 , SO 2 NR 13 R 14 , to Ar, Het, or combinations thereof,
Ar, or
Het;
m is 1, 2 or 3;
o is 1 or 2;
Ar is an aryl group containing 6 to 10 carbon atoms which is unsubstituted or substituted one or more times by
alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 8 carbon atoms,
halogen,
amino,
cyano,
hydroxyl,
nitro,
halogenated alkyl having 1 to 8 carbon atoms,
halogenated alkoxy having 1 to 8 carbon atoms,
hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms,
alkenyloxy having 3 to 8 carbon atoms,
monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms,
carboxy,
alkoxycarbonyl,
alkylaminocarbonyl,
acylamido,
acyloxy,
alkylthio having 1 to 8 carbon atoms,
alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms,
sulfo,
sulfonylamino,
Het,
cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio or
combinations thereof;
Ar-alkyl is an aryl-alkylene group wherein the alkylene portion contains 1 to 4 carbon atoms and is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio, and the aryl portion is Ar as defined above; and
Het is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 8 carbon atoms,
halogen,
amino,
cyano,
hydroxyl,
nitro,
halogenated alkyl having 1 to 8 carbon atoms,
halogenated alkoxy having 1 to 8 carbon atoms,
hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms,
alkenyloxy having 3 to 8 carbon atoms,
monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms,
carboxy,
alkoxycarbonyl,
alkoxycarbonylmethyl,
alkylaminocarbonyl,
acylamido,
acyloxy,
alkylthio having 1 to 8 carbon atoms,
alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms,
sulfo,
oxo
sulfonylamino,
cycloalkylamino wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryl containing 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryl-alkylene group wherein the aryl portion contains 6 to 10 carbon atoms and the alkylene portion contains 1 to 4 carbon atoms and is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
arylthio wherein the aryl portion contains 6 to 10 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon atoms and is optionally substituted by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio,
heterocyclic-alkyl group, in which the heterocyclic portion is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is an alkylene group containing 1-4 carbon atoms, wherein said heterocyclic-alkyl group is unsubstituted or substituted one or more times by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each have 1 to 8 carbon atoms, COR 16 , CSR 16 , cyano, hydroxyl, nitro, oxo, or thio, or
combinations thereof; or
a pharmaceutically acceptable salt thereof.
39 . A method according to claim 38 , wherein said patient is suffering from schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, and/or Attention Deficit Hyperactivity Disorder.
40 . A method of treating a patient suffering from dementia and/or another condition with memory loss, comprising administering to the patient an effective amount of a compound according to claim 1 .
41 . A method of treating a patient suffering from memory impairment due to, Alzheimer's disease, mild cognitive impairment due to aging, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV and/or cardiovascular disease comprising administering to the patient an effective amount of a compound according to claim 1 .
42 . A method of treating and/or preventing dementia in an Alzheimer's patient comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 to inhibit the binding of an amyloid beta peptide with nACh receptors.
43 . A method of treating a patient for alcohol withdrawal or treating a patient with anti-intoxication therapy comprising administering to the patient an effective amount of a compound according to claim 1 .
44 . A method of treating a patient to provide for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity comprising administering to the patient an effective amount of a compound according to claim 1 .
45 . A method of treating a patient suffering from nicotine addiction, pain, jetlag, obesity and/or diabetes, comprising administering to the patient an effective amount of a compound according to claim 1 .
46 . A method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to claim 1 .
47 . A method of treating a patient suffering from mild cognitive impairment (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated with open-heart-surgery, cardiac arrest, general anesthesia, memory deficits from exposure to anesthetic agents, sleep deprivation induced cognitive impairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive impairment, Down's syndrome, Alcoholism related dementia, drug/substance induced memory impairments, Dementia Puglistica (Boxer Syndrome), or animal dementia comprising administering to the patient an effective amount of a compound according to claim 1 .
48 . A method for treating loss of memory comprising administering to a patient in need thereof an effective amount of a compound according to claim 1 .
49 . A method for treating a patient suffering from memory impairment comprising administering to the patient a compound according to according to claim 1 .
50 . (canceled)
51 . (canceled)
52 . (canceled)
53 . (canceled)
54 . (canceled)
55 . (canceled)
56 . (canceled)
57 . A method for treating a patient suffering from an inflammatory disease, comprising administering to said patient an effective amount of a compound according to claim 1 .
58 . A method according to claim 58 , wherein said inflammatory disease is rheumatoid arthritis, diabetes or sepsis.
59 . (canceled)
60 . (canceled)
61 . A method according to claim 38 , wherein said patient is a human.Cited by (0)
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