U.S. patent application number 11/089533 was filed with the patent office on 2005-10-20 for indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof.
Invention is credited to Gauss, Carla Maria, Herbert, Brian, Ma, Jianguo, Nguyen, Truc Minh, Schumacher, Richard A., Tehim, Ashok, Xie, Wenge.
Application Number | 20050234095 11/089533 |
Document ID | / |
Family ID | 34968660 |
Filed Date | 2005-10-20 |
United States Patent
Application |
20050234095 |
Kind Code |
A1 |
Xie, Wenge ; et al. |
October 20, 2005 |
Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and
preparation and uses thereof
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 .alpha.7 nACh receptor subtype, methods of
preparing such compounds, compositions containing such compounds,
and methods of use thereof.
Inventors: |
Xie, Wenge; (Mahwah, NJ)
; Herbert, Brian; (Stockholm, NJ) ; Schumacher,
Richard A.; (Monroe, NY) ; Nguyen, Truc Minh;
(New York, NY) ; Ma, Jianguo; (Montvale, NJ)
; Gauss, Carla Maria; (New York, NY) ; Tehim,
Ashok; (Ridgewood, NJ) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
34968660 |
Appl. No.: |
11/089533 |
Filed: |
March 25, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60555951 |
Mar 25, 2004 |
|
|
|
60616033 |
Oct 6, 2004 |
|
|
|
Current U.S.
Class: |
514/305 ;
546/135 |
Current CPC
Class: |
A61P 19/08 20180101;
A61P 25/32 20180101; A61P 13/12 20180101; A61P 9/00 20180101; A61P
25/30 20180101; A61P 3/04 20180101; A61P 7/04 20180101; A61P 31/18
20180101; A61P 21/02 20180101; A61P 25/02 20180101; A61P 25/18
20180101; A61P 25/16 20180101; A61P 43/00 20180101; A61P 3/10
20180101; A61P 25/00 20180101; A61P 25/28 20180101; A61P 25/04
20180101; A61P 25/26 20180101; A61P 25/14 20180101; A61P 19/02
20180101; A61P 25/34 20180101; A61P 25/22 20180101; A61P 35/00
20180101; A61P 9/10 20180101; A61P 29/00 20180101; A61P 25/24
20180101; A61P 31/04 20180101; C07D 453/02 20130101 |
Class at
Publication: |
514/305 ;
546/135 |
International
Class: |
C07D 453/02; A61K
031/4745 |
Claims
1. A compound according to Formula I, II, III, or IV 337wherein
338A is X is O or S; 339R' 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.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6- -alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7, NR.sup.2--C.sub.1-6-alk-
yl-CONR.sup.6R.sup.7, NR.sup.2--CO--C.sub.1-6-alkyl-Ar,
NR.sup.2--C.sub.1-6-alkyl-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.su- p.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sub.1-6-alkyl-NR.s- up.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
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 are in each unsubstituted or substituted by Ar or
Het, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5
to 8 carbon atoms which is unsubstituted or substituted by HCO--,
C.sub.1-6-alkoxy, NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7,
C.sub.2-6-alkoxycarbonyl, or --CO--R.sup.10, 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, 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, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein 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.sub.1-6-alkyl-O--, Het-C.sub.1-6-alkyl-O--,
Het-CO-Het-, Het-C.sub.1-6-alkyl-NR.sup.2--, or
Ar--C.sub.1-6-alkyl-Het-O--, with the proviso that R is not
NH.sub.2; or R is of one of the following formulas 340n is 2 to 4;
m is 3 to 5; or two R can together form a 5-membered fused ring
structure containing at least one N atom; R.sup.1 is H, F, Cl, Br,
I, OH, CN, nitro, NH.sub.2, COH, NR.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6-alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7,
NR.sup.2--C.sub.1-6-alkyl-CONR- .sup.6R.sup.7,
NR.sup.2--CO--C.sub.1-6-alkyl-Ar, NR.sup.2--C.sub.1-6-alkyl-
-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sub.1-6-alkyl-NR.sup.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
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 are in each unsubstituted or substituted by Ar or
Het, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5
to 8 carbon atoms which is unsubstituted or substituted by HCO--,
C.sub.1-6-alkoxy, NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7,
C.sub.2-6-alkoxycarbonyl, or --CO--R.sup.10, 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, 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, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein 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.sub.1-6-alkyl-O--, Het-C.sub.1-6-alkyl-O--,
Het-CO-Het-, Het-C.sub.1-6-alkyl-NR.sup.2--, or
Ar--C.sub.1-6-alkyl-Het-O--; or R.sup.1 is of one of the following
formulas 341two R.sup.1 can together form a 5-membered fused ring
structure containing at least one N atom; R.sup.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.sub.1-4-alkyl-CO--,
C.sub.3-7-cycloalkyl-CO--, C.sub.1-4-alkyl-NH--CO--,
C.sub.3-7-cycloalkyl-NH--CO--, Het, Ar--C.sub.1-4-alkyl-,
Ar--C.sup.1-4-alkyl-CO--, Ar--C.sup.1-4-alkyl-SO.su- b.2--,
C.sup.1-4-alkyl-O--C.sub.1-4-alkyl-, or
Ar--C.sub.1-4-alkyl-NH--CO-- -; R.sup.3 is H, F, Cl, Br, I, OH, CN,
nitro, NH.sub.2, COH, NR.sup.6R.sup.7, carboxy, CONR.sup.6R.sup.7,
NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8, NR.sup.2CSR.sup.8,
NR.sup.2CONR.sup.2R.sup.9, NR.sup.2CSNR.sup.2R.sup.9,
NR.sup.2SO.sub.2R.sup.10, NR.sup.2CONR.sup.6R.sup.7,
NR.sup.2CSNR.sup.6R.sup.7, NR.sup.2R.sup.9, SO.sub.2R.sup.10,
SOR.sup.10, --O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6- -alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7, NR.sup.2--C.sub.1-6-alk-
yl-CONR.sup.6R.sup.7, NR.sup.2--CO--C.sub.1-6-alkyl-Ar,
NR.sup.2--C.sub.1-6-alkyl-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.su- p.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sup.1-6-alkyl-NR.s- up.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
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 are in each unsubstituted or substituted by Ar or
Het, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5
to 8 carbon atoms which is unsubstituted or substituted by HCO--,
C.sub.1-6-alkoxy, NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7,
C.sub.2-6-alkoxycarbonyl, or --CO--R.sup.10, 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, 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, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein 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.sub.1-6-alkyl-O--, Het-C.sub.1-6-alkyl-O--,
Het-CO-Het-, Het-C.sub.1-6-alkyl-NR.sup.2--, or
Ar--C.sub.1-6-alkyl-Het-O--; or R.sup.3 is of one of the following
formulas 342two R.sup.3 can together form a 5-membered fused ring
structure containing at least one N atom; R.sup.4 is H, F, Cl, Br,
I, OH, CN, nitro, NH.sub.2, COH, NR.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6- -alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7, NR.sup.2--C.sub.1-6-alk-
yl-CONR.sup.6R.sup.7, NR.sup.2--CO--C.sub.1-6-alkyl-Ar,
NR.sup.2--C.sub.1-6-alkyl-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.su- p.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sub.1-6-alkyl-NR.s- up.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
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 are in each unsubstituted or substituted by Ar or
Het, cycloalkyl having 3 to 7 carbon atoms, cycloalkenyl having 5
to 8 carbon atoms which is unsubstituted or substituted by HCO--,
C.sub.1-6-alkoxy, NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7,
C.sub.2-6-alkoxycarbonyl, or --CO--R.sup.10, 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, 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, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein 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.sub.1-6-alkyl-O--, Het-C.sub.1-6-alkyl-O--,
Het-CO-Het-, Het-C.sub.1-6-alkyl-NR.sup.2--, or
Ar--C.sub.1-6-alkyl-Het-O--; or R.sup.4 is of one of the following
formulas 343two R.sup.4 can together form a 5-membered fused ring
structure containing at least one N atom; R.sup.5 is H, F, Cl, Br,
I, OH, CN, nitro, NH.sub.2, carboxy, CONR.sup.6R.sup.7,
NR.sup.2COR.sup.8, NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkyl having 1 to 4
carbon atoms, fluorinated alkyl having 1 to 4 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
are in each 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,
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,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein
each alkyl group independently has 1 to 4 carbon atoms,
alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, or OHet;
R.sup.6 and R.sup.7 are each, independently, H, alkyl having 1 to 4
carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl
having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon
atoms, or R.sup.6 and R.sup.7 together are an alkylene group
containing 4-6 carbon atoms which forms a ring with the N atom;
R.sup.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 the alkyl, fluorinated
alkyl, alkenyl, or alkynyl groups are in each 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,
hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkyl
having 1 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon
atoms, dialkylamino wherein each alkyl group independently has 1 to
4 carbon atoms, Ar, or Het; R.sup.9 is Ar, Ar-alkyl wherein the
alkyl portion has 1 to 4 carbon atoms, or Het; R.sup.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, wherein the alkyl, fluorinated alkyl, alkenyl, or
alkynyl groups are in each 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, hydroxyalkyl having 2
to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon
atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein each alkyl group independently has 1 to 4 carbon atoms,
NR.sup.6R.sup.7, NR.sup.2R.sup.8, Ar, or Het; 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 C atoms,
alkoxy having 1 to 8 C atoms, halogen, dialkylamino wherein the
alkyl portions each have 1 to 8 C atoms, amino, cyano, hydroxyl,
nitro, halogenated alkyl having 1 to 8 C atoms, halogenated alkoxy
having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 C atoms,
hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C
atoms, alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to
8 C atoms, alkylsulphonyl having 1 to 8 C atoms, monoalkylamino
having 1 to 8 C atoms, cycloalkylamino wherein the cycloalkyl group
has 3 to 7 C atoms and is optionally substituted, aryloxy wherein
the aryl portion contains 6 to 10 carbon atoms and is optionally
substituted, arylthio wherein the aryl portion contains 6 to 10
carbon atoms and is optionally substituted, cycloalkyloxy wherein
the cycloalkyl group has 3 to 7 C atoms and is optionally
substituted, sulfo, sulfonylamino, acylamido, acyloxy or
combinations thereof; 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 halogen, aryl
having 6 to 10 carbon atoms which is optionally substituted, alkyl
having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, cycloalkyl
having 3 to 7 carbon atoms, cyano, trifluoromethyl, nitro, oxo, OH,
alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino,
monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each
alkyl group has 1 to 8 C atoms, SO.sub.2R.sup.11, --CXR.sup.11,
piperidinylethyl or combinations thereof; Carbo is a partially
unsaturated carbocyclic group having 5 to 14 carbon atoms, which is
unsubstituted or substituted one or more times by halogen, alkyl
having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, hydroxy,
nitro, cyano, oxo, or combinations thereof; and R.sup.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 the alkyl, halogenated alkyl, alkenyl, or
alkynyl groups are in each 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, hydroxyalkyl having 2
to 4 carbon atoms, fluorinated hydroxyalkyl having 2 to 4 carbon
atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein each alkyl group independently has 1 to 4 carbon atoms, or
Ar; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein when R is
NR.sup.6R.sup.7, at least one of R.sup.6 and R.sup.7 is alkyl
having 2 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms,
cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4
to 7 carbon atoms, or R.sup.6 and R.sup.7 together are an alkylene
group containing 4-6 carbon atoms which forms a ring with the N
atom.
3. A compound according to claim 1, wherein R is not
NR.sup.6R.sup.7.
4. A compound according to claim 1, wherein R' is H or
CH.sub.3.
5. A compound according to claim 1, wherein R' is H; A is a radical
according to formulas (a), (b) or (c); R.sup.1 is H, F, Cl, Br, I,
OH, CN, nitro, NH.sub.2, COH, NR.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkyl having 1 to 4
carbon atoms, fluorinated alkyl having 1 to 4 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
are in each 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,
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,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein
each alkyl group independently has 1 to 4 carbon atoms,
alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, or OHet;
or R.sup.1 is of one of the following formulas 344R.sup.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, or
cycloalkylalkyl having 4 to 7 carbon atoms; R.sup.3 is H, F, Cl,
Br, I, OH, CN, nitro, NH.sub.2, COH, NR.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkyl having 1 to 4
carbon atoms, fluorinated alkyl having 1 to 4 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
are in each 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,
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,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein
each alkyl group independently has 1 to 4 carbon atoms,
alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, or OHet;
or R.sup.3 is of one of the following formulas 345R.sup.4 is H, F,
Cl, Br, I, OH, CN, nitro, NH.sub.2, COH, NR.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkyl having 1 to 4
carbon atoms, fluorinated alkyl having 1 to 4 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
are in each 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,
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,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein
each alkyl group independently has 1 to 4 carbon atoms,
alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, or OHet;
or R.sup.4 is of one of the following formulas 346Het 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 halogen, aryl having 6 to 10
carbon atoms and is optionally substituted, alkyl having 1 to 8 C
atoms, alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl, nitro,
oxo, OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms, amino,
monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each
alkyl group has 1 to 8 C atoms, SO.sub.2R.sup.11, --CXR.sup.11,
piperidinylethyl or combinations thereof.
6. A compound according to claim 1, wherein at least one of
R.sup.1, R.sup.3, or R.sup.4 is COH, NR.sup.6R.sup.7 wherein at
least one of R.sup.6 and R.sup.7 is other than alkyl, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkyl having 1 to 4
carbon atoms which is substituted by Ar or Het, fluorinated alkyl
having 1 to 4 carbon atoms which is substituted by Ar or Het,
alkenyl having 2 to 6 carbon atoms which is optionally substituted
by Ar or Het, alkynyl having 2 to 6 carbon atoms which is
optionally substituted by Ar or Het, cycloalkenyl having 5 to 8
carbon atoms, cycloalkenylalkyl having 6 to 9 carbon atoms,
fluorinated hydroxyalkyl having 1 to 4 carbon atoms, alkoxycarbonyl
having 2 to 6 carbon atoms, OAr, OHet, or Het which is substituted
by SO.sub.2R.sup.11 or --CXR.sup.11, or is selected from the
following formulas 347R.sup.5 is carboxy, alkoxycarbonyl having 2
to 6 carbon atoms, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkenyl having 2 to
6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkyl
substituted by Ar or Het, alkenyl substituted by Ar or Het, alkynyl
substituted by Ar or Het, cycloalkenyl having 5 to 8 carbon atoms,
cycloalkenylalkyl having 6 to 9 carbon atoms, fluorinated
hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, OAr, OHet, or Het which is substituted
by SO.sub.2R.sup.11 or --CXR.sup.11.
7. A compound according to claim 1, wherein at least one of
R.sup.1, R.sup.3, R.sup.4, and R.sup.5 is carboxy, alkoxycarbonyl
having 2 to 6 carbon atoms, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkenyl having 2 to
6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkyl
substituted by Ar or Het, alkenyl substituted by Ar or Het, alkynyl
substituted by Ar or Het, cycloalkenyl having 5 to 8 carbon atoms,
cycloalkenylalkyl having 6 to 9 carbon atoms, fluorinated
hydroxyalkyl having 1 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, OAr, OHet, or Het which is substituted
by SO.sub.2R.sup.11 or --CXR.sup.11; R.sup.6 and R.sup.7 are each,
independently, H, alkyl having 1 to 4 carbon atoms, cycloalkyl
having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon
atoms, or R.sup.6 and R.sup.7 together are an alkylene group
containing 4-6 carbon atoms which forms a ring with the N atom;
R.sup.9 is Ar or Het; 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 halogen,
aryl having 6 to 10 carbon atoms and is optionally substituted,
alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, cyano,
trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 C
atoms, dialkylamino wherein each alkyl group has 1 to 8 C atoms,
SO.sub.2R.sup.11, --CXR.sup.11, or combinations thereof.
8. A compound according to claim 7, wherein at least one of
R.sup.1, R.sup.3, R.sup.4, and R.sup.5 is alkynyl having 2 to 6
carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon atoms,
or Ar-alkynyl.
9. A compound according to claim 1, wherein said compound is of
formula I, A is of formulae (a) or (c), X is O, R.sup.2 is H or
alkyl, and R.sup.1 and R.sup.4 are each F, Cl, CN, NO.sub.2,
NH.sub.2, fluorinated alkyl, alkoxy, fluorinated alkoxy,
fluorinated hydroxyalkyl, alkynyl, cycloalkyl, cycloalkylalkoxy,
Ar, Ar-alkynyl, or Het.
10. A compound according to claim 9, wherein R.sup.1 and R.sup.4
are each selected from F, Cl, CN, NO.sub.2, NH.sub.2, CF.sub.3,
OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethy- l)ethyl, ethynyl,
propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy,
phenyl, phenylethynyl, dihydropyranyl, thiazolyl, oxazolyl,
pyrrolidinyl, piperidinyl, or morpholinyl.
11. A compound according to claim 9, wherein A is of formulae (c)
and R.sup.4 is CN, alkoxy, fluorinated alkoxy, and
cycloalkylalkoxy.
12. A compound according to claim 1, wherein said compound is of
formulae Ia or Ij, R.sup.2 is H or alkyl, and R.sup.1 and R.sup.4
are each F, Cl, CN, NO.sub.2, NH.sub.2, fluorinated alkyl, alkoxy,
fluorinated alkoxy, fluorinated hydroxyalkyl, alkynyl, cycloalkyl,
cycloalkylalkoxy, Ar, Ar-alkynyl or Het.
13. A compound according to claim 1, wherein at least one R.sup.1,
R.sup.3 or R.sup.4 is COH, NR.sup.6R.sup.7 wherein at least one of
R.sup.6 and R.sup.7 is other than alkyl, or NR.sup.2COOR.sup.8.
14. A compound according to claim 1, wherein at least one R.sup.1,
R.sup.3 or R.sup.4 is selected from the following formulas 348
15. A compound according to claim 1, wherein said compound exhibits
2 or 3 of substituents R.sup.1, R.sup.3, or R.sup.4.
16. A compound according to claim 1, wherein R.sup.2 is fluorinated
alkyl having 1 to 4 carbon atoms.
17. A compound according to claim 1, wherein at least one R.sup.6
and R.sup.7 is alkoxyalkyl having 2 to 8 carbon atoms.
18. A compound according to claim 1, wherein said compound exhibits
at least one R.sup.9 group that is Ar-alkyl wherein the alkyl
portion has 1 to 4 carbon atoms.
19. A compound according to claim 1, wherein said compound exhibits
at least one Het that 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, and
which is substituted by at least one substituent selected from OH,
alkoxycarbonylalkyl having 3 to 8 carbon atoms, and
piperidinylethyl.
20-35. (canceled)
36. A compound according to claim 1, wherein X is O.
37-42. (canceled)
43. A compound according to claim 1, wherein said compound is
selected from:
3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-c-
arboxylic acid hydroformate,
3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]car-
bonyl}-1H-indazole-6-carboxylic acid,
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]o-
ct-3-yl]-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-
-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]o-
ct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-c-
arboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-
-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-
-5-(cyclohex-1-en-1-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.-
2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluorometho-
xy)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-
-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-
-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-c-
arboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-i-
ndazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl--
1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl--
1H-indazole-3-carboxamide hydrochloride,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3--
yl]-5-ethynyl-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-
-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1-
H-indazole-3-carboxamide,
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1-
H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl-
]-5-hydroxy-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl-
]-5-methoxy-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole--
3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-in-
dazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5--
piperidin-1-yl-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-
-yl]-5-pyrrolidin-1-yl-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2-
.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-c-
arboxamide hydrochloride,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thia-
zol-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2-
.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-ind-
azole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(-
1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl
1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisoth-
iazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1--
yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-
-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carb-
oxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethyny-
l)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trif-
luoromethoxy)-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothia-
zole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethy-
l)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-
-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.-
2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxamide
hydrotrifluoroacetate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-b-
enzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-
-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-cyano-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl-
]-6-cyclohexyl-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxami-
de,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carbo-
xamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole--
3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy--
1,2-benzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6--
ethynyl-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2-
]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2-
]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]-
oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide
hydrochloride,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-
-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-i-
ndazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1--
yl-1H-indazole-3-carboxamide hydrotrifluoroacetate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carbo-
xamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-
-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1-
H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thia-
zol-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2-
.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluorometho-
xy)-1H-indazole-3-carboxamide hydrochloride,
N-[(3S)-1-Azabicyclo[2.2.2]oc-
t-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-c-
arboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-ca-
rboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-i-
ndazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-ind-
azole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-c-
yano-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyc-
lopentyl-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-
-ethynyl-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.-
2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.-
2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole--
3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3--
carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-i-
ndazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-
-2-yl)-1H-indazole-3-carboxamide hydrochloride,
N-[(3S)-1-Azabicyclo[2.2.2-
]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-c-
arboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-
-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oc-
t-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-ind-
azole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(-
3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisoth-
iazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4--
yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pro-
p-1-yn-1-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-car-
boxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-be-
nzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-
-yl]-6-(trifluoromethoxy)-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-ca-
rboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydro-
xy-1-(trifluoromethyl)ethyl]-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carbox-
amide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzi-
sothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-
-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cya-
no-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct--
3-yl]-6-cyano-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-cyclohexyl-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxami-
de,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carbox-
amide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-ca-
rboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazo-
le-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-etho-
xy-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-
-6-ethynyl-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.-
2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.-
2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2-
.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2-
.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide, and physiologically
acceptable salts thereof.
44. A compound according to claim 1, wherein said compound is
selected from:
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-methyl-1H-indazole-
-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H--
indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-c-
yclopentyl-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-
-5-(nitro)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-
-6-(4-hydroxytetrahydro-2H-pyran-4-yl 1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl-
)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifl-
uoromethoxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-c-
arboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoro-
methoxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.-
2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1H-indazole-3-carboxamid-
e,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxy)-1H-indazole-3-carboxam-
ide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carboxam-
ide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-
-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-
-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carb-
oxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-metho-
xy-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct--
3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.-
2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.-
2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.-
2]oct-3-yl]-6-(hydroxy)-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-
-4-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(-
tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-ind-
azole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-m-
ethoxy-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole-3-carb-
oxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-inda-
zole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-th-
ienyl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]-
oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole--
3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(propyl-
)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-
-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothia-
zole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(e-
thyl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]o-
ct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-ind-
azole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3--
thiazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methox-
y-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-
-yl]-4-ethyl-5-methoxy-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-ind-
azole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(-
methyl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2-
]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carb-
oxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofu-
ran-3-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2-
.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)ami-
no]-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-
-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-car-
boxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indaz-
ole-3-carboxamide,
5-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazol-
e-3-carboxamide,
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole--
3-carboxamide,
4-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3--
carboxamide,
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiaz-
ole-3-carboxamide,
6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzis-
othiazole-3-carboxamide,
7-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-i-
ndazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropy-
lmethyl)amino]-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1-
H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl-
]-5-[(trifluoroacetyl)amino]-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-in-
dazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5--
[(ethylsulfonyl)amino]-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazol-
e-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(eth-
ylsulfonyl)amino]-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benziso-
thiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulf-
onyl)amino]-1,2-benzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]-
oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benzis-
othiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-[(methylsu-
lfonyl)amino]-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3--
yl]-5-[(benzylsulfonyl)amino]-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl]am-
ino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}a-
mino)-1,2-benzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-[({[2-(4-florophenyl)ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-
-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphe-
nyl)amino]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbo-
nyl}amino)-1,2-benzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]o-
ct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}amino)-1,2-benzisothiazole-3--
carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)-
ethyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino-
}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino-
}-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]--
6-{[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}-
amino)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(-
{[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino-
}-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3--
methoxybenzyl)amino]carbonyl}amino)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}-
amino)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{-
[(propylamino)carbonyl]amino}-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbo-
nyl]amino}-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.-
2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)a-
mino]carbonyl}amino)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}-
amino)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]-
oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylami-
no)-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-indazol-
e-3-carboxamide dihydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1--
(2-piperidin-1-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazole-3-carboxamide
dihydroformate,
Ethyl[4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbon-
yl}-1H-indazol-6-yl 1H-1,2,3-triazol-1-yl]acetate hydroformate,
Benzyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-y-
l)carbamate,
Vinyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H--
indazol-5-yl)carbamate, and physiologically acceptable salts
thereof.
45. A compound according to claim 1, wherein said compound is
selected from:
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carbox-
amide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamid-
e hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-c-
arboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazo-
l-2-yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carb-
oxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]ind-
azole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difl-
uoromethoxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-carboxam-
ide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-
-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluo-
romethoxy)-1H-indazole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-
-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H--
indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]--
4-fluoro-5-methoxy-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-ca-
rboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-ind-
azole-3-carboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3--
thiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-ind-
azole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-c-
yclopropyl-6-methoxy-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole--
3-carboxamide hydroformate,
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(ben-
zyloxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-ind-
azole-3-carboxamide hydrochloride,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5--
[3-(methyloxy)pyrrolidin-1-yl]-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-1H-in-
dazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5--
[(1-methylpyrrolidin-3-yl)oxy]-1H-indazole-3-carboxamide
dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-ind-
azole-3-carboxamide hydrochloride,
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-
-(trifluoromethoxy)-1H-indazole-3-carboxamide hydroformate,
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-
-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3--
yl]-5-(cyclopentyloxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazol-
e-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cycl-
opropylmethoxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazol-
e-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benz-
yloxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]-
oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inde-
n-2-yloxy)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.-
2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazole-3-carboxamide
dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-yl-
ethoxy)-1H-indazole-3-carboxamide dihydroformate,
N-[(3S)-1-Azabicyclo[2.2- .2]oct-3-yl]-5-bromo-1-(ethyl
1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-(ethyl)-1H-indazole-3-carb-
oxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl-
)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo--
1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazol-
e-3-carboxamide dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(d-
iethylamino)methyl]-1H-indazole-3-carboxamide dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indaz-
ole-3-carboxamide dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[-
(1-benzylpyrrolidin-3-yl)oxy]-1H-indazole-3-carboxamide
dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole-3-carb-
oxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1-
H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cycloprop-
ylmethyl-6-methoxy-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazole-3-ca-
rboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropyl-
methyl-5-trifluoromethoxy-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl]-1H-ind-
azole-3-carboxamide hydrochloride,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1--
ethyl-5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclorpopylmethyl-5-(1,3-thiazol-2-
-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oc-
t-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3-thiazol-2-yl)-1H-indazole-3-carbox-
amide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-th-
iazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H-in-
dazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6--
[3-(2-methoxyethoxy)propoxy]-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperaz-
in-1-yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benzis-
othiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-
-6-[4-(3-furoyl)piperazin-1-yl]-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin--
1-yl)-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-ben-
zisothiazole-3-carboxamide,
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-
,2-benzisoxazole-3-carboxamide,
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-y-
l]-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-1H-ind-
azole-3-carboxamide,
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl-
)-1H-indazole-3-carboxamide,
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]--
1-(ethyl)-1H-indazole-3-carboxamide, Methyl
4-[(3-{[(3S)-1-azabicyclo[2.2.-
2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl)amino]butanoate
dihydroformate, Methyl
4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-
-6-yl)amino]butanoate dihydroformate, tert-Butyl
{2-[(3-{[(3S)-1-azabicycl-
o[2.2.2]oct-3-ylamino]carbonyl}-1,2-benzisothiazol-6-yl)amino]ethyl}propyl-
carbamate hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiaz-
ol-2-ylmethyl)amino]-1H-indazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole-3-carb-
oxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyeth-
yl)-5-[(2-methoxyethyl)amino]-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amin-
o}-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.-
2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-ben-
zisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3--
yl]-6-(dimethylamino)-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole-
-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cycl-
opropylcarbonyl)amino]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide,
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indaz-
ole-3-carboxamide dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(-
cyclopropylcarbonyl)-5-[(cyclopropylcarbonyl)amino]-1H-indazole-3-carboxam-
ide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl-
)acetyl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbony-
l)amino]-1,2-benzisothiazole-3-carboxamide hydroformate,
6-(Acetylamino)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole--
3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dime-
thylamino)sulfonyl]amino}-1,2-benzisothiazole-3-carboxamide
hydroformate,
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl
1H-indazole-3-carboxamide dihydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct--
3-yl]-1-(cyclopropylmethyl)-6-{[(propylamino)carbonyl]amino}-1H-indazole-3-
-carboxamide,
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzy-
l)-5-({[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxami-
de,
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[(4--
fluorobenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,
N(3)-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentyl-
amino)carbonyl]amino}-1H-indazole-1,3-dicarboxamide hydroformate,
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carb-
onyl]amino}-1H-indazole-1,3-dicarboxamide,
N-[(3R)-1-Azabicyclo[2.2.2]oct--
3-yl]-5-({[(cyclopropylmethyl)amino]carbonothioyl}amino)-1H-indazole-3-car-
boxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopro-
pylmethyl)amino]carbonothioyl}amino)-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino-
)carbonothioyl]amino}-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonothioyl]a-
mino}-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}--
1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-y-
l]-1-ethyl-6-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)--
5-{[(propylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propyl-
amino)carbonyl]amino}-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]-
amino}-1H-indazole-3-carboxamide hydroformate, Isopropyl
{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl}carb-
amate hydroformate, Isopropyl
{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]c-
arbonyl}-1-[(isopropylamino)carbonyl]-1H-indazol-5-yl}carbamate
hydroformate,
N-[(3S)-1-Oxido-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3--
carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3--
carboxamide hydrobromide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1-
H-indazole-3-carboxamide hydrobromide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl-
]-5-{[(diethylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcar-
bonyl)amino]-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1-
H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl-
]-6-(2-oxopyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benziso-
thiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]--
6-(2-oxo-4-phenylpyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-
-yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazo-
le-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-o-
xo-3-propylimidazolidin-1-yl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2--
benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-
-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxami-
de hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxo-
imidazolidin-1-yl 1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)--
1,2-benzisothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2-
]oct-3-yl]-5-bromo-1,2-benzisoxazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-carboxam-
ide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1--
yl)-1,2-benzisothiazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl-
]-5-(3-isopropyl-2-oxoimidazolidin-1-yl)-1,2-benzisothiazole-3-carboxamide-
,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-
-1,2-benzisothiazole-3-carboxamide,
6-[Acetyl(methyl)amino]-N-[(3S)-1-azab-
icyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzi-
sothiazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl-
]-6-methoxy-N-methyl-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-e-
thyl-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oc-
t-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethyl-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cyc-
lopropylmethyl-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-
-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazole-3-
-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1-
,3-thiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazol-
-2-yl)-1H-indazole-3-carboxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]-
oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiazol-2-yl)-1H-indazole-3-carb-
oxamide hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy-
)pyrrolidin-1-yl]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrol-
idin-1-yl]-1-ethyl-1H-indazole-3-carboxamide hydroformate,
tert-Butyl
3-[3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-thiazol-2-y-
l)-1H-indazol-1-yl]pyrrolidine-1-carboxylate hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-y-
l)-1H-indazole-3-carboxamide,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3--
thiazol-2-yl)-1-(2-thienylmethyl)-1H-indazole-3-carboxamide
hydroformate,
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazol-2--
yl)-1H-indazole-3-carboxamide hydroformate, and physiologically
acceptable salts thereof.
46. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
47. A method of selectively activating/stimulating .alpha.-7
nicotinic receptors in a patient wherein such
activation/stimulation has a therapeutic effect, comprising
administering to the patient in need thereof an effective amount of
a compound according to claim 1.
48. 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 claim 1.
49. A method according to claim 48, 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.
50. 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.
51. A method of treating a patient suffering from memory impairment
due to mild cognitive impairment due to aging, Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeld-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.
52. 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.
53. 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.
54. 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.
55. 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.
56. A method of inducing smoking cessation in a patient comprising
administering to the patient an effective amount of a compound
according to claim 1.
57. 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.
58. 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.
59. A method for treating a patient suffering from memory
impairment comprising administering to the patient a compound
according to according to claim 1.
60. A method according to claim 59, wherein said memory impairment
is due to decreased nicotinic acetylcholine receptor activity.
61. A method for the treatment or prophylaxis of a disease or
condition resulting from dysfunction of nicotinic acetylcholine
receptor transmission in a patient comprising administering to the
patient an effective amount of a compound according to claim 1.
62. A method for the treatment or prophylaxis of a disease or
condition resulting from defective or malfunctioning nicotinic
acetylcholine receptors in a patient comprising administering to
the patient an effective amount of a compound according to claim
1.
63. A method for the treatment or prophylaxis of a disease or
condition resulting from suppressed nicotinic acetylcholine
receptor transmission in a patient comprising administering to the
patient an effective amount of a compound according to claim 1.
64. A method for the treatment or prophylaxis of a disease or
condition resulting from loss of cholinergic synapses in a patient
comprising administering to the patient an effective amount of a
compound according to claim 1.
65. A method for protecting neurons in a patient from neurotoxicity
induced by activation of .alpha.7nACh receptors comprising
administering to said patient an effective amount of a compound
according to claim 1.
Description
[0001] This application claims the benefit of U.S. Provisional
application Ser. No. 60/555,951, filed Mar. 25, 2004, and U.S.
Provisional application Ser. No. 60/616,033, filed Oct. 6, 2004,
the entire disclosures of which are hereby incorporated by
reference.
[0002] This application is also related to U.S. patent application
Ser. No. 10/669,645, filed Sep. 25, 2003, which claims the benefit
of U.S. Provisional application Ser. No. 60/413,151, filed Sep. 25,
2002, and U.S. Provisional application Ser. No. 60/448,469, filed
Feb. 21, 2003, the entire disclosures of which are hereby
incorporated by reference.
FIELD OF THE INVENTION
[0003] The present invention relates generally to the field of
ligands for nicotinic acetylcholine receptors (nAChR), activation
of nAChRs, 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, which act as ligands for the .alpha.7 nAChR subtype,
methods of preparing such compounds, compositions comprising such
compounds, and methods of use thereof.
BACKGROUND OF THE INVENTION
[0004] There are two types of receptors for the neurotransmitter,
acetylcholine: muscarinic receptors and nicotinic receptors, based
on the selectivity of action of muscarine and nicotine,
respectively. Muscarinic receptors are G-protein coupled receptors.
Nicotinic receptors are members of the ligand-gated ion channel
family. When activated, the conductance of ions across the
nicotinic ion channels increases.
[0005] Nicotinic alpha-7 receptor protein forms a homo-pentameric
channel in vitro that is highly permeable to a variety of cations
(e.g., Ca.sup.++). Each nicotinic alpha-7 receptor has four
transmembrane domains, named M1, M2, M3, and M4. The M2 domain has
been suggested to form the wall lining the channel. Sequence
alignment shows that nicotinic alpha-7 is highly conserved during
evolution. The M2 domain that lines the channel is identical in
protein sequence from chicken to human. For discussions of the
alpha-7 receptor, see, e.g., Revah et al. (1991), Nature, 353,
846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al.
(2000), PNAS 97(7), 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.
[0006] The nicotinic alpha-7 receptor channel is expressed in
various brain regions and is believed to be involved in many
important biological processes in the central nervous system (CNS),
including learning and memory. Nicotinic alpha-7 receptors are
localized on both presynaptic and postsynaptic terminals and have
been suggested to be involved in modulating synaptic transmission.
It is therefore of interest to develop novel compounds, which act
as ligands for the .alpha.7nACh receptor subtype, for the treatment
of disease conditions associated with defective or malfunctioning
nicotinic acetylcholine receptors.
SUMMARY OF THE INVENTION
[0007] This invention relates to novel compounds, which act as
ligands for the .alpha.7 nACh receptor subtype, methods of
preparing such compounds, compositions comprising such compounds,
and methods of use thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The present invention includes compounds of Formulas I, II,
III, or IV: 1
[0009] wherein
[0010] A is 2
[0011] X is O or S;
[0012] 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;
[0013] R is H, F, Cl, Br, I, OH, CN, COH, NR.sup.6R.sup.7, carboxy,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6-alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7,
NR.sup.2--C.sub.1-6-alkyl-CONR- .sup.6R.sup.7,
NR.sup.2CO--C.sub.1-6alkyl-Ar, NR.sup.2--C.sub.1-6-alkyl-CO-
--O--R.sup.2, NR.sup.2--C.sub.1-6-alkyl-NR.sup.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sub.1-6-alkyl-NR.sup.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms (e.g., CF.sub.3), alkenyl having 2 to 6 carbon atoms,
alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl,
pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or
alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.5--C C--), cycloalkyl
having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms
which is unsubstituted or substituted by HCO--, C.sub.1-6-alkoxy,
NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7, C.sub.2-6-alkoxycarbonyl, or
--CO--R.sup.10, cycloalkylalkyl having 4 to 7 carbon atoms,
cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4
carbon atoms (e.g., OCH.sub.3), cycloalkoxy having 3 to 7 carbon
atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,
SCH.sub.3), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,
OCF.sub.3, OCHF.sub.2), hydroxyalkyl having 1 to 4 carbon atoms,
fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),
hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon
atoms, dialkylamino wherein each alkyl group independently has 1 to
4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het,
OAr, OHet, Carbo-O, Ar--C.sub.1-6-alkyl-O--,
Het-C.sub.1-6-alkyl-O--, Het-CO-Het-,
Het-C.sub.1-6-alkyl-NR.sup.2--, or Ar--C.sub.1-6-alkyl-Het-O--,
[0014] with the proviso that R is not NH.sub.2; or
[0015] R is of one of the following formulas 3
[0016] n is 2 to 4;
[0017] m is 3 to 5; or
[0018] two R can together form a 5-membered fused ring structure
containing at least one N atom;
[0019] R.sup.1 is H, F, Cl, Br, I, OH, CN, nitro, NH.sub.2, COH,
NR.sup.6R.sup.7, carboxy, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8,
NR.sup.2COOR.sup.8, NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6- -alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7, NR.sup.2--C.sub.1-6-alk-
yl-CONR.sup.6R.sup.7, NR.sup.2--CO--C.sub.1-6-alkyl-Ar,
NR.sup.2--C.sub.1-6-alkyl-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.su- p.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sub.1-6-alkyl-NR.s- up.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms (e.g., CF.sub.3), alkenyl having 2 to 6 carbon atoms,
alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl,
pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or
alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.5--C C--), cycloalkyl
having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms
which is unsubstituted or substituted by HCO--, C.sub.1-6-alkoxy,
NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7, C.sub.2-6-alkoxycarbonyl, or
--CO--R.sup.10, cycloalkylalkyl having 4 to 7 carbon atoms,
cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4
carbon atoms (e.g., OCH.sub.3), cycloalkoxy having 3 to 7 carbon
atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,
SCH.sub.3), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,
OCF.sub.3, OCHF.sub.2), hydroxyalkyl having 1 to 4 carbon atoms,
fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),
hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon
atoms, dialkylamino wherein each alkyl group independently has 1 to
4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het,
OAr, OHet, Carbo-O, Ar--C.sub.1-6-alkyl-O--,
Het-C.sub.1-6-alkyl-O--, Het-CO-Het-,
Het-C.sub.1-6-alkyl-NR.sup.2--, or Ar--C.sub.1-6-alkyl-Het-O--;
or
[0020] R.sup.1 is of one of the following formulas 4
[0021] two R.sup.1 can together form a 5-membered fused ring
structure containing at least one N atom;
[0022] R.sup.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.sub.1-4-alkyl-CO--, C.sub.3-7-cycloalkyl-CO--,
C.sub.1-4-alkyl-NH--CO--- , C.sub.3-7-cycloalkyl-NH--CO--, Het,
Ar--C.sub.1-4-alkyl-, Ar--C.sub.1-4-alkyl-CO--,
Ar--C.sub.1-4-alkyl-SO.sub.2--, C.sub.1-4-alkyl-O--C.sub.1-4-alkyl-
(e.g., CH.sub.2CH.sub.2--O--CH.sub.3)- , or
Ar--C.sub.1-4-alkyl-NH--CO--;
[0023] R.sup.3 is H, F, Cl, Br, I, OH, CN, nitro, NH.sub.2, COH,
NR.sup.6R.sup.7, carboxy, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8,
NR.sup.2COOR.sup.8, NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6- -alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7, NR.sup.2--C.sub.1-6-alk-
yl-CONR.sup.6R.sup.7, NR.sup.2--CO--C.sub.1-6-alkyl-Ar,
NR.sup.2--C.sub.1-6-alkyl-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.su- p.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR.sup.2, --O--C.sub.1-6-alkyl-NR.s- up.6R.sup.7,
alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4
carbon atoms (e.g., CF.sub.3), alkenyl having 2 to 6 carbon atoms,
alkynyl having 2 to 6 carbon atoms (e.g., ethynyl, propynyl,
pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl, or
alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.5--C.ident.C--), cycloalkyl
having 3 to 7 carbon atoms, cycloalkenyl having 5 to 8 carbon atoms
which is unsubstituted or substituted by HCO--, C.sub.1-6-alkoxy,
NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7, C.sub.2-6-alkoxycarbonyl, or
--CO--R.sup.10, cycloalkylalkyl having 4 to 7 carbon atoms,
cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4
carbon atoms (e.g., OCH.sub.3), cycloalkoxy having 3 to 7 carbon
atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,
SCH.sub.3), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,
OCF.sub.3, OCHF.sub.2), hydroxyalkyl having 1 to 4 carbon atoms,
fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),
hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon
atoms, dialkylamino wherein each alkyl group independently has 1 to
4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het,
OAr, OHet, Carbo-O, Ar--C.sub.1-6-alkyl-O--,
Het-C.sub.1-6-alkyl-O--, Het-CO-Het-,
Het-C.sub.1-6-alkyl-NR.sup.2--, or Ar--C.sub.6-alkyl-Het-O--;
or
[0024] R.sup.3 is of one of the following formulas 5
[0025] two R.sup.3 can together form a 5-membered fused ring
structure containing at least one N atom;
[0026] R.sup.4 is H, F, Cl, Br, I, OH, CN, nitro, NH.sub.2, COH,
NR.sup.6R.sup.7, carboxy, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8,
NR.sup.2COOR.sup.8, NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10,
--O--(C.sub.1-6-alkyl-O).sub.1-2--C.sub.1-6- -alkyl,
NR.sup.2--C.sub.1-6-alkyl-NR.sup.6R.sup.7, NR.sup.2--C.sub.1-6-alk-
yl-CONR.sup.6R.sup.7, NR.sup.2--CO--C.sub.1-6-alkyl-Ar,
NR.sup.2--C.sub.1-6-alkyl-CO--O--R.sup.2,
NR.sup.2--C.sub.1-6-alkyl-NR.su- p.2(CO--O--R.sup.2),
--C.sub.1-6-alkyl-NR, --O--C.sub.1-6-alkyl-NR.sup.6R.- sup.7, alkyl
having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon
atoms (e.g., CF.sub.3), alkenyl having 2 to 6 carbon atoms, alkynyl
having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, pentenyl),
wherein the alkyl, fluorinated alkyl, alkenyl, or alkynyl groups
are in each unsubstituted or substituted by Ar or Het (e.g.,
phenylacetylene C.sub.6H.sub.5--C C--), cycloalkyl having 3 to 7
carbon atoms, cycloalkenyl having 5 to 8 carbon atoms which is
unsubstituted or substituted by HCO--, C.sub.1-6-alkoxy,
NR.sup.6R.sup.7, CO--NR.sup.6R.sup.7, C.sub.2-6-alkoxycarbonyl, or
--CO--R.sup.10, cycloalkylalkyl having 4 to 7 carbon atoms,
cycloalkenylalkyl having 6 to 9 carbon atoms, alkoxy having 1 to 4
carbon atoms (e.g., OCH.sub.3), cycloalkoxy having 3 to 7 carbon
atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,
SCH.sub.3), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,
OCF.sub.3, OCHF.sub.2), hydroxyalkyl having 1 to 4 carbon atoms,
fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),
hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon
atoms, dialkylamino wherein each alkyl group independently has 1 to
4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het,
OAr, OHet, Carbo-O, Ar--C.sub.1-6-alkyl-O--,
Het-C.sub.1-6-alkyl-O--, Het-CO-Het-,
Het-C.sub.1-6-alkyl-NR.sup.2--, or Ar--C.sub.1-6-alkyl-Het-O--;
or
[0027] R.sup.4 is of one of the following formulas 6
[0028] two R.sup.4 can together form a 5-membered fused ring
structure containing at least one N atom;
[0029] R.sup.5 is H, F, Cl, Br, I, OH, CN, nitro, NH.sub.2,
carboxy, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2CSR.sup.8,
NR.sup.2CONR.sup.2R.sup.9, NR.sup.2CSNR.sup.2R.sup.9,
NR.sup.2SO.sub.2R.sup.10, NR.sup.2CONR.sup.6R.sup.7,
NR.sup.2CSNR.sup.6R.sup.7, NR.sup.2R.sup.9, SO.sub.2R.sup.10,
SOR.sup.10, alkyl having 1 to 4 carbon atoms, fluorinated alkyl
having 1 to 4 carbon atoms (e.g., CF.sub.3), alkenyl having 2 to 6
carbon atoms, alkynyl having 2 to 6 carbon atoms (e.g., ethynyl,
propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl,
or alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.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, alkoxy having 1 to 4
carbon atoms (e.g., OCH.sub.3), cycloalkoxy having 3 to 7 carbon
atoms, cycloalkylalkoxy having 4 to 7 carbon atoms (e.g.,
cyclopropylmethoxy), alkylthio having 1 to 4 carbon atoms (e.g.,
SCH.sub.3), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,
OCF.sub.3, OCHF.sub.2), hydroxyalkyl having 1 to 4 carbon atoms,
fluorinated hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl),
hydroxyalkoxy having 2 to 4 carbon atoms, fluorinated hydroxyalkoxy
having 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon
atoms, dialkylamino wherein each alkyl group independently has 1 to
4 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het,
OAr, or OHet;
[0030] R.sup.6 and R.sup.7 are each, independently, H, alkyl having
1 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms,
cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4
to 7 carbon atoms, or R.sup.6 and R.sup.7 together are an alkylene
group containing 4-6 carbon atoms which forms a ring with the N
atom (e.g., piperidinyl, pyrrolidinyl);
[0031] R.sup.8 is H, alkyl having 1 to 4 carbon atoms, fluorinated
alkyl having 1 to 4 carbon atoms (e.g., CF.sub.3), alkenyl having 3
to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g.,
propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl,
or alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.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 1
to 4 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein each alkyl group independently has 1 to 4 carbon atoms, Ar,
or Het;
[0032] R.sup.9 is Ar, Ar-alkyl wherein the alkyl portion has 1 to 4
carbon atoms, or Het;
[0033] R.sup.10 is alkyl having 1 to 4 carbon atoms, fluorinated
alkyl having 1 to 4 carbon atoms (e.g., CF.sub.3), alkenyl having 3
to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g.,
propynyl, pentenyl), wherein the alkyl, fluorinated alkyl, alkenyl,
or alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.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, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein each alkyl group independently has 1 to 4 carbon atoms,
NR.sup.6R.sup.7, NR.sup.2R.sup.8, Ar, or Het;
[0034] 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 C atoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br, or I,
preferably F or Cl), dialkylamino wherein the alkyl portions each
have 1 to 8 C atoms, amino, cyano, hydroxyl, nitro, halogenated
alkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C
atoms, hydroxyalkyl having 1 to 8 C atoms, hydroxyalkoxy having 2
to 8 C atoms, alkenyloxy having 3 to 8 C atoms, alkylthio having 1
to 8 C atoms, alkylsulphinyl having 1 to 8 C atoms, alkylsulphonyl
having 1 to 8 C atoms, monoalkylamino having 1 to 8 C atoms,
cycloalkylamino wherein the cycloalkyl group has 3 to 7 C atoms and
is optionally substituted, aryloxy wherein the aryl portion
contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl)
and is optionally substituted, arylthio wherein the aryl portion
contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl, biphenyl)
and is optionally substituted, cycloalkyloxy wherein the cycloalkyl
group has 3 to 7 C atoms and is optionally substituted, sulfo,
sulfonylamino, acylamido (e.g., acetamido), acyloxy (e.g., acetoxy)
or combinations thereof;
[0035] 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 halogen (F, Cl,
Br, or I, preferably F or Cl), aryl having 6 to 10 carbon atoms
(e.g., phenyl, naphthyl, biphenyl) which is optionally substituted,
alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms,
cycloalkyl having 3 to 7 carbon atoms, cyano, trifluoromethyl,
nitro, oxo, OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms,
amino, monoalkylamino having 1 to 8 C atoms, dialkylamino wherein
each alkyl group has 1 to 8 C atoms, SO.sub.2R.sup.11,
--CXR.sup.11, piperidinylethyl or combinations thereof;
[0036] Carbo is a partially unsaturated carbocyclic group having 5
to 14 carbon atoms, which is unsubstituted or substituted one or
more times by halogen, alkyl having 1 to 8 C atoms, alkoxy having 1
to 8 C atoms, hydroxy, nitro, cyano, oxo, or combinations thereof
(e.g., indanyl, tetrahydronaphthenyl, etc.); and
[0037] R.sup.11 is alkyl having 1 to 4 carbon atoms, halogenated
alkyl having 1 to 4 carbon atoms (e.g., CF.sub.3), alkenyl having 3
to 6 carbon atoms, alkynyl having 3 to 6 carbon atoms (e.g.,
propynyl, pentenyl), wherein the alkyl, halogenated alkyl, alkenyl,
or alkynyl groups are in each unsubstituted or substituted by Ar or
Het (e.g., phenylacetylene C.sub.6H.sub.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, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein each alkyl group independently has 1 to 4 carbon atoms, or
Ar; and
[0038] pharmaceutically acceptable salts thereof.
[0039] In Formula I, when A is an indazolyl group of subformula
(a), it is preferably attached to the remainder of the compound via
its 3, 4 or 7 position, particularly via the 3-position. When A is
a benzothiazolyl group of subformula (b), it is preferably attached
to the remainder of the compound via its 4 or 7 position. When A is
a benzoisothiazolyl group of subformula (c), it is preferably
attached to the remainder of the compound via its 3, 4 or 7
position, particularly via the 3-position. When A is a
benzisoxazolyl group of subformula (d), it is preferably attached
to the remainder of the compound via its 3, 4 or 7 position,
particularly via the 3-position.
[0040] Similarly, in Formula II, when A is an indazolyl group of
subformula (a), it is preferably attached to the remainder of the
compound via its 3, 4 or 7 position, particularly via the
3-position. When A is a benzothiazolyl group of subformula (b), it
is preferably attached to the remainder of the compound via its 4
or 7 position. When A is a benzoisothiazolyl group of subformula
(c), it is preferably attached to the remainder of the compound via
its 3, 4 or 7 position, particularly via the 3-position. When A is
a benzisoxazolyl group of subformula (d), it is preferably attached
to the remainder of the compound via its 3, 4 or 7 position,
particularly via the 3-position.
[0041] Also, in Formula III, when A is an indazolyl group of
subformula (a), it is preferably attached to the remainder of the
compound via its 3, 4 or 7 position, particularly via the
3-position. When A is a benzothiazolyl group of subformula (b), it
is preferably attached to the remainder of the compound via its 4
or 7 position. When A is a benzoisothiazolyl group of subformula
(c), it is preferably attached to the remainder of the compound via
its 3, 4 or 7 position, particularly via the 3-position. When A is
a benzisoxazolyl group of subformula (d), it is preferably attached
to the remainder of the compound via its 3, 4 or 7 position,
particularly via the 3-position.
[0042] Further, in Formula IV, when A is an indazolyl group of
subformula (a), it is preferably attached to the remainder of the
compound via its 3, 4 or 7 position, particularly via the
3-position. When A is a benzothiazolyl group of subformula (b), it
is preferably attached to the remainder of the compound via its 4
or 7 position. When A is a benzoisothiazolyl group of subformula
(c), it is preferably attached to the remainder of the compound via
its 3, 4 or 7 position, particularly via the 3-position. When A is
a benzisoxazolyl group of subformula (d), it is preferably attached
to the remainder of the compound via its 3, 4 or 7 position,
particularly via the 3-position.
[0043] In Formulas I-IV, the indazolyl, benzothiazolyl,
benzoisothiazolyl, and benzisoxazolyl groups of A can be attached
to the remainder of the structure via any suitable attachment
point. The following subformulas illustrate some of the preferred
attachments between the indazole, benzothiazole, benzoisothiazole,
and benzisoxazole groups and the remainder of the structure.
789
[0044] The following subformulas further illustrate some of the
preferred attachments between the indazolyl, benzothiazolyl,
benzoisothiazolyl and benzisoxazolyl groups and the remainder of
the structure. 101112
[0045] The following subformulas further illustrate some of the
preferred attachments between the indazolyl, benzothiazolyl,
benzoisothiazolyl and benzisoxazolyl groups and the remainder of
the structure. 131415
[0046] The following subformulas further illustrate some of the
preferred attachments between the indazolyl, benzothiazolyl,
benzoisothiazolyl and benzisoxazolyl groups and the remainder of
the structure. 161718
[0047] X is preferably O.
[0048] R' is preferably H or CH.sub.3, particularly H.
[0049] Alkyl throughout means a straight-chain or branched-chain
aliphatic hydrocarbon radical having 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.
[0050] Alkenyl throughout means a straight-chain or branched-chain
aliphatic hydrocarbon radical having preferably 2 to 6 carbon
atoms. Suitable alkenyl groups include but are not limited to
ethenyl, propenyl, butenyl, and pentenyl.
[0051] Alkynyl throughout means a straight-chain or branched-chain
aliphatic hydrocarbon radical having preferably 2 to 6 carbon
atoms. Suitable alkynyl groups include but are not limited to
ethyne, propyne, butyne, etc.
[0052] Alkoxy means alkyl-O-- groups in which the alkyl portion
preferably has 1 to 4 carbon atoms. Suitable alkoxy groups include
but are not limited to methoxy, ethoxy, propoxy, isopropoxy,
isobutoxy, and sec-butoxy.
[0053] Alkylthio means alkyl-S-- groups in which the alkyl portion
preferably has 1 to 4 carbon atoms. Suitable alkylthio groups
include but are not limited to methylthio and ethylthio.
[0054] 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.
[0055] Cycloalkoxy means cycloalkyl-O-- groups in which the
cycloalkyl portion preferably is a cyclic, bicyclic or tricyclic
saturated hydrocarbon radical having 3 to 7 carbon atoms.
[0056] Cycloalkylalkyl groups contain 4 to 7 carbon atoms. Suitable
cycloalkylalkyl groups include but are not limited to, for example,
cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, and
cyclopentylmethyl.
[0057] Cycloalkylalkoxy groups contain 4 to 7 carbon atoms.
Suitable cycloalkylalkoxy groups include but are not limited to,
for example, cyclo-propylmethyloxy, cyclopropylethyloxy,
cyclobutylmethyloxy, and cyclo-pentylmethyloxy.
[0058] The cycloalkyl and cycloalkylalkyl groups can be substituted
by C.sub.1-4-alkyl, C.sub.1-4-alkoxy, hydroxyl, amino,
monoalkylamino having 1 to 4 carbon atoms, and/or dialklyamino in
which each alkyl group has 1 to 4 carbon atoms.
[0059] Aryl, as a group or substituent per se or as part of a group
or substituent, refers to an aromatic carbocyclic radical
containing 6 to 10 carbon atoms, unless indicated otherwise.
Suitable aryl groups include but are not limited to phenyl, napthyl
and biphenyl. Substituted aryl groups include the above-described
aryl groups which are substituted one or more times by halogen,
alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,
amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy,
carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl,
alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy).
[0060] Heterocyclic groups refer to saturated, partially saturated
and fully unsaturated heterocyclic groups having one, two or three
rings and a total number of 5 to 10 ring atoms wherein at least one
of the ring atoms is an N, O or S atom. Preferably, the
heterocyclic group contains 1 to 3 hetero-ring atoms selected from
N, O and S. Suitable saturated and partially saturated heterocyclic
groups include, but are not limited to dihydropyranyl,
tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl
and the like. Suitable heteroaryl groups include but are not
limited to furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl,
pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl,
isoquinolinyl, naphthyridinyl and the like. Other examples of
suitable heterocyclic groups, are 2-furyl, 3-furyl, 2-quinolinyl,
1,3-benzodioxyl, 2-thienyl, 3-thienyl, 1,3-thiazoly-2-yl,
1,3-oxazol-2-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,
2-benzofuranyl, 2-benzothiophenyl, 3-thienyl,
2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl,
4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 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, and 3-carbazolyl.
[0061] Substituted heterocyclic groups refer to the heterocyclic
groups described above, which are substituted in one or more places
by, for example, halogen, aryl, alkyl, alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, alkylamino, and
dialkylamino.
[0062] Radicals that are substituted one or more times preferably
have 1 to 3 substituents, especially 1 or 2 substituents of the
exemplified substituents. Halogenated radicals such as halogenated
alkyls are preferably fluorinated and include but are not limited
to perhalo radicals such as trifluoromethyl.
[0063] According to a further aspect of the invention, in the
compounds of Formulas I-IV, when R is NR.sup.6R.sup.7, at least one
of R.sup.6 and R.sup.7 is alkyl having 2 to 4 carbon atoms,
alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7
carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms, or
R.sup.6 and R.sup.7 together are an alkylene group containing 4-6
carbon atoms which forms a ring with the N atom.
[0064] According to a further aspect of the invention, in the
compounds of Formulas I-IV, R is not NR.sup.6R.sup.7.
[0065] According to a further aspect of the invention, in the
compounds of Formulas I-IV, A is a radical according to formulas
(a), (b) or (c), and at least one of R.sup.1, R.sup.3, or R.sup.4
is H, F, Cl, Br, I, OH, CN, nitro, NH.sub.2, COH, NR.sup.6R.sup.7,
carboxy, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8,
NR.sup.2CSR.sup.8, NR.sup.2CONR.sup.2R.sup.9,
NR.sup.2CSNR.sup.2R.sup.9, NR.sup.2SO.sub.2R.sup.10,
NR.sup.2CONR.sup.6R.sup.7, NR.sup.2CSNR.sup.6R.sup.7,
NR.sup.2R.sup.9, SO.sub.2R.sup.10, SOR.sup.10, alkyl having 1 to 4
carbon atoms, fluorinated alkyl having 1 to 4 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
are in each 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,
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,
monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein
each alkyl group independently has 1 to 4 carbon atoms,
alkoxycarbonyl having 2 to 6 carbon atoms, Ar, Het, OAr, or OHet;
or is of one of the following formulas 19
[0066] R.sup.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, or cycloalkylalkyl having 4 to 7 carbon atoms; and/or
[0067] 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 halogen, aryl
having 6 to 10 carbon atoms and is optionally substituted, alkyl
having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, cyano,
trifluoromethyl, nitro, oxo, OH, alkoxycarbonylalkyl having 3 to 8
carbon atoms, amino, monoalkylamino having 1 to 8 C atoms,
dialkylamino wherein each alkyl group has 1 to 8 C atoms,
SO.sub.2R.sup.11, --CXR.sup.11, piperidinylethyl or combinations
thereof.
[0068] According to a further aspect of the invention, in the
compounds of Formulas I-IV, at least one of R.sup.1, R.sup.3, or
R.sup.4 is
[0069] COH, NR.sup.6R.sup.7 wherein at least one of R.sup.6 and
R.sup.7 is other than alkyl, carboxy, CONR.sup.6R.sup.7,
NR.sup.2COR.sup.8, NR.sup.2COOR.sup.8, NR.sup.8 CSR.sup.8,
NR.sup.2CONR.sup.2R.sup.9, NR.sup.2CSNR.sup.2R.sup.9,
NR.sup.2SO.sub.2R.sup.10, NR.sup.2CONR.sup.6R.sup.7
NR.sup.2CSNR.sup.6R.sup.7, NR.sup.2R.sup.9, SO.sub.2R.sup.10,
SOR.sup.10, alkyl having 1 to 4 carbon atoms which is substituted
by Ar or Het, fluorinated alkyl having 1 to 4 carbon atoms which is
substituted by Ar or Het, alkenyl having 2 to 6 carbon atoms which
is optionally substituted by Ar or Het, alkynyl having 2 to 6
carbon atoms which is optionally substituted by Ar or Het,
cycloalkenyl having 5 to 8 carbon atoms, cycloalkenylalkyl having 6
to 9 carbon atoms, fluorinated hydroxyalkyl having 1 to 4 carbon
atoms, alkoxycarbonyl having 2 to 6 carbon atoms, OAr, OHet, or Het
which is substituted by SO.sub.2R.sup.11 or --CXR.sup.11, or
[0070] is selected from the following formulas 20
[0071] R.sup.5 is carboxy, alkoxycarbonyl having 2 to 6 carbon
atoms, CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2CSR.sup.8,
NR.sup.2CONR.sup.2R.sup.9, NR.sup.2CSNR.sup.2R.sup.9,
NR.sup.2SO.sub.2R.sup.10, NR.sup.2CONR.sup.6R.sup.7,
NR.sup.2CSNR.sup.6R.sup.7, NR.sup.2R.sup.9, SO.sub.2R.sup.10,
SOR.sup.10, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to
6 carbon atoms (e.g., ethynyl, propynyl), alkyl substituted by Ar
or Het, alkenyl substituted by Ar or Het, alkynyl substituted by Ar
or Het (e.g., phenylacetylene), cycloalkenyl having 5 to 8 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, fluorinated
hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluor- omethyl)ethyl),
fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, OAr, OHet, or
Het which is substituted by SO.sub.2R.sup.11 or --CXR.sup.11.
[0072] According to a further aspect of the invention, in the
compounds of Formulas I-IV, at least one of R.sup.1, R.sup.3,
R.sup.4, and R.sup.5 is
[0073] carboxy, alkoxycarbonyl having 2 to 6 carbon atoms,
CONR.sup.6R.sup.7, NR.sup.2COR.sup.8, NR.sup.2CSR.sup.8,
NR.sup.2CONR.sup.2R.sup.9, NR.sup.2CSNR.sup.2R.sup.9,
NR.sup.2SO.sub.2R.sup.10, NR.sup.2CONR.sup.6R.sup.7,
NR.sup.2CSNR.sup.6R.sup.7, NR.sup.2R.sup.9, SO.sub.2R.sup.10,
SOR.sup.10, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to
6 carbon atoms (e.g., ethynyl, propynyl), alkyl substituted by Ar
or Het, alkenyl substituted by Ar or Het, alkynyl substituted by Ar
or Het (e.g., phenylacetylene), cycloalkenyl having 5 to 8 carbon
atoms, cycloalkenylalkyl having 6 to 9 carbon atoms, fluorinated
hydroxyalkyl having 1 to 4 carbon atoms (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluor- omethyl)ethyl),
fluorinated hydroxyalkoxy having 2 to 4 carbon atoms, OAr, OHet, or
Het which is substituted by SO.sub.2R.sup.11 or --CXR.sup.11
(Preferably, at least one of R.sup.1, R.sup.3, R.sup.4, and R.sup.5
is alkynyl having 2 to 6 carbon atoms, fluorinated hydroxyalkyl
having 1 to 4 carbon atoms, or Ar-alkynyl (e.g., phenylacetylene),
especially R.sup.1 or R.sup.4);
[0074] R.sup.6 and R.sup.7 are each, independently, H, alkyl having
1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or
cycloalkylalkyl having 4 to 7 carbon atoms, or R.sup.6 and R.sup.7
together are an alkylene group containing 4-6 carbon atoms which
forms a ring with the N atom;
[0075] R.sup.9 is Ar or Het; and
[0076] 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 halogen (F, Cl,
Br, or I, preferably F or Cl), aryl having 6 to 10 carbon atoms
(e.g., phenyl, naphthyl, biphenyl) and is optionally substituted,
alkyl having 1 to 8 C atoms, alkoxy having 1 to 8 C atoms, cyano,
trifluoromethyl, nitro, oxo, amino, monoalkylamino having 1 to 8 C
atoms, dialkylamino wherein each alkyl group has 1 to 8 C atoms,
SO.sub.2R.sup.11, --CXR.sup.11, or combinations thereof.
[0077] According to a further aspect of the invention, the
compounds are selected from formula I in which A is of formulae (a)
or (c), X is O, R.sup.2 is H or alkyl (e.g., CH.sub.3), and R.sup.1
and R.sup.4 are each F, Cl, CN, NO.sub.2, NH.sub.2, fluorinated
alkyl (e.g., CF.sub.3), alkoxy (e.g., OCH.sub.3), fluorinated
alkoxy (e.g., OCF.sub.3), fluorinated hydroxyalkyl (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl)- , alkynyl
(e.g., ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar,
Ar-alkynyl (e.g., phenylacetylene), or Het. For example, R.sup.1
and R.sup.4 are each selected from F, Cl, CN, NO.sub.2, NH.sub.2,
CF.sub.3, OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3,
2,2,2,-trifluoro-1-hydroxyl-1-(tri- fluoromethyl)ethyl, ethynyl,
propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy,
phenyl, phenylethynyl, dihydropyranyl (e.g.,
3,6-dihydro-2H-pyran-4-yl), thiazolyl (e.g., 1,3-thiazol-2-yl),
oxazolyl (e.g., 1,3-oxazol-2-yl), pyrrolidinyl (e.g.,
pyrrolidin-1-yl), piperidinyl (e.g. piperidin-1-yl), or morpholinyl
(e.g. morpholin-4-yl). R.sup.4 can also be selected from CN,
alkoxy, fluorinated alkoxy, and cycloalkylalkoxy, such as CN,
OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3, and cyclopropylmethoxy.
[0078] According to a further aspect of the invention, the
compounds are selected from formulae Ia or Ij wherein R.sup.2 is H
or alkyl (e.g., CH.sub.3), and R.sup.1 and R.sup.4 are each F, Cl,
CN, NO.sub.2, NH.sub.2, fluorinated alkyl (e.g., CF.sub.3), alkoxy
(e.g., OCH.sub.3), fluorinated alkoxy (e.g., OCF.sub.3),
fluorinated hydroxyalkyl (e.g.,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), alkynyl
(e.g., ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar,
Ar-alkynyl (e.g., phenylacetylene), or Het. For example, R.sup.1
and R.sup.4 are each selected from F, Cl, CN, NO.sub.2, NH.sub.2,
CF.sub.3, OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3,
2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethy- l)ethyl, ethynyl,
propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy,
phenyl, phenylethynyl, dihydropyranyl (e.g.,
3,6-dihydro-2H-pyran55-4-yl), thiazolyl (e.g., 1,3-thiazol-2-yl),
oxazolyl (e.g., 1,3-oxazol-2-yl), pyrrolidinyl (e.g.,
pyrrolidin-1-yl), piperidinyl (e.g. piperidin-1-yl), or morpholinyl
(e.g. morpholin-4-yl). R.sup.4 can also be selected from CN,
alkoxy, fluorinated alkoxy, and cycloalkylalkoxy, such as CN,
OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3, and cyclopropylmethoxy.
[0079] According to a further aspect of the invention, in the
compounds of Formulas I-IV, at least one R.sup.1, R.sup.3 or
R.sup.4 is COH, NR.sup.6R.sup.7 wherein at least one of R.sup.6 and
R.sup.7 is other than alkyl, or NR.sup.2COOR.sup.8.
[0080] According to a further aspect of the invention, in the
compounds of Formulas I-IV, at least one R.sup.1, R.sup.3 or
R.sup.4 is selected from the following formulas 21
[0081] According to a further aspect of the invention, the
compounds of Formulas I-IV, exhibit 2-3 of substituents R.sup.1,
R.sup.3, or R.sup.4.
[0082] According to a further aspect of the invention, in the
compounds of Formulas I-IV, R.sup.2 is fluorinated alkyl having 1
to 4 carbon atoms.
[0083] According to a further aspect of the invention, in the
compounds of Formulas I-IV, at least one R.sup.6 and R.sup.7 is
alkoxyalkyl having 2 to 8 carbon atoms.
[0084] According to a further aspect of the invention, in the
compounds of Formulas I-IV, the compound exhibits at least one
R.sup.9 group that is Ar-alkyl wherein the alkyl portion has 1 to 4
carbon atoms.
[0085] According to a further aspect of the invention, in the
compounds of Formulas I-IV, the compound exhibits at least one Het
that 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, and which is substituted
by at least one substituent selected from OH, alkoxycarbonylalkyl
having 3 to 8 carbon atoms, and piperidinylethyl.
[0086] According to a further compound and/or method aspect of the
invention, the compound of formulas I-IV is selected from (wherein
compounds in their salt forms can also be in their non-salt
forms):
[0087]
3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-c-
arboxylic acid hydroformate,
[0088]
3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-c-
arboxylic acid,
[0089]
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxam-
ide,
[0090]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazol-
e-3-carboxamide,
[0091]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide hydroformate,
[0092]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide,
[0093]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-inda-
zole-3-carboxamide hydroformate,
[0094]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-inda-
zole-3-carboxamide,
[0095]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1-
H-indazole-3-carboxamide,
[0096]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1-
H-indazole-3-carboxamide,
[0097]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydroformate,
[0098]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide,
[0099]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxa-
mide hydroformate,
[0100]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxa-
mide,
[0101]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxam-
ide hydroformate,
[0102]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxam-
ide,
[0103]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-ca-
rboxamide,
[0104]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carbox-
amide hydrochloride,
[0105]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carbox-
amide hydroformate,
[0106]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carbox-
amide hydroformate,
[0107]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxa-
mide hydroformate,
[0108]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxa-
mide,
[0109]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carbox-
amide hydroformate,
[0110]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carbox-
amide,
[0111]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carbox-
amide hydroformate,
[0112]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carbox-
amide,
[0113]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carbox-
amide hydroformate,
[0114]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carbox-
amide,
[0115]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-
-carboxamide hydroformate,
[0116]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-
-carboxamide,
[0117]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-indazole--
3-carboxamide,
[0118]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazol-
e-3-carboxamide,
[0119]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide hydrochloride,
[0120]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide hydroformate,
[0121]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide,
[0122]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)--
1H-indazole-3-carboxamide hydroformate,
[0123]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)--
1H-indazole-3-carboxamide,
[0124]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide hydroformate,
[0125]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide,
[0126]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-ben-
zisothiazole-3-carboxamide,
[0127]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-
-3-carboxamide hydroformate,
[0128]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-
-3-carboxamide,
[0129]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole--
3-carboxamide hydroformate,
[0130]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole--
3-carboxamide,
[0131]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzi-
sothiazole-3-carboxamide hydroformate,
[0132]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzi-
sothiazole-3-carboxamide,
[0133]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazol-
e-3-carboxamide,
[0134]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3--
carboxamide hydroformate,
[0135]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3--
carboxamide hydrotrifluoroacetate,
[0136]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3--
carboxamide,
[0137]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxam-
ide hydroformate,
[0138]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxam-
ide,
[0139]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-car-
boxamide hydroformate,
[0140]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-car-
boxamide,
[0141]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-ca-
rboxamide,
[0142]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-
-carboxamide hydroformate,
[0143]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-
-carboxamide,
[0144]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carbox-
amide hydroformate,
[0145]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carbox-
amide,
[0146]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxa-
mide,
[0147]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carbox-
amide hydroformate,
[0148]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carbox-
amide,
[0149]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carbox-
amide hydrochloride,
[0150]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carbox-
amide,
[0151]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-
-carboxamide,
[0152]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-
-carboxamide hydrotrifluoroacetate,
[0153]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-
-carboxamide,
[0154]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole--
3-carboxamide,
[0155]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazol-
e-3-carboxamide,
[0156]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide hydroformate,
[0157]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide,
[0158]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1-
H-indazole-3-carboxamide,
[0159]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydrochloride,
[0160]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydroformate,
[0161]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide,
[0162]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxa-
mide hydroformate,
[0163]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxa-
mide,
[0164]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxam-
ide hydroformate,
[0165]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxam-
ide,
[0166]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-ca-
rboxamide,
[0167]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carbox-
amide hydroformate,
[0168]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carbox-
amide,
[0169]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxa-
mide hydroformate,
[0170]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxa-
mide,
[0171]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carbox-
amide hydroformate,
[0172]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carbox-
amide,
[0173]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxam-
ide,
[0174]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazol-
e-3-carboxamide,
[0175]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide hydrochloride,
[0176]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide hydroformate,
[0177]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazo-
le-3-carboxamide,
[0178]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)--
1H-indazole-3-carboxamide hydroformate,
[0179]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)--
1H-indazole-3-carboxamide,
[0180]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide hydroformate,
[0181]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide,
[0182]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-ben-
zisothiazole-3-carboxamide,
[0183]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-
-3-carboxamide,
[0184]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-
-3-carboxamide hydroformate,
[0185]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-
-3-carboxamide,
[0186]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzi-
sothiazole-3-carboxamide hydroformate,
[0187]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzi-
sothiazole-3-carboxamide,
[0188]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazol-
e-3-carboxamide,
[0189]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxy-1-
-(trifluoromethyl)ethyl]-1H-indazole-3-carboxamide,
[0190]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3--
carboxamide hydroformate,
[0191]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3--
carboxamide,
[0192]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3--
carboxamide,
[0193]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxam-
ide hydroformate,
[0194]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxam-
ide,
[0195]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-car-
boxamide hydroformate,
[0196]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-car-
boxamide,
[0197]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-car-
boxamide,
[0198]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-ca-
rboxamide,
[0199]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-
-carboxamide hydroformate,
[0200]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-
-carboxamide,
[0201]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carbox-
amide hydroformate,
[0202]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carbox-
amide,
[0203]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxa-
mide,
[0204]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carbox-
amide,
[0205]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxam-
ide,
[0206] and physiologically acceptable salts thereof.
[0207] According to a further compound and/or method aspect of the
invention, the compound of formulas I-IV is selected from (wherein
compounds in their salt forms can also be in their non-salt
forms):
[0208]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-methyl-1H-indazole-
-3-carboxamide,
[0209]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H-indazole--
3-carboxamide,
[0210]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-cyclopentyl-1H-ind-
azole-3-carboxamide,
[0211]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carbox-
amide,
[0212]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyra-
n-4-yl)-1H-indazole-3-carboxamide,
[0213]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyra-
n-4-yl)-1H-indazole-3-carboxamide,
[0214]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydroformate,
[0215]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydroformate,
[0216]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydroformate,
[0217]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazo-
le-3-carboxamide hydroformate,
[0218]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1H-indazole-3-carb-
oxamide,
[0219]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxy)-1H-indazole-3-carb-
oxamide,
[0220]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carbox-
amide,
[0221]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide hydroformate,
[0222]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide,
[0223]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole--
3-carboxamide hydroformate,
[0224]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole--
3-carboxamide hydroformate,
[0225]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3--
carboxamide,
[0226]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carbox-
amide,
[0227]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carbox-
amide,
[0228]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1,2-benzisothiazol-
e-3-carboxamide,
[0229]
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carbo-
xamide hydroformate,
[0230]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1-
H-indazole-3-carboxamide,
[0231]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1-
H-indazole-3-carboxamide,
[0232]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)--
1H-indazole-3-carboxamide hydroformate,
[0233]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroet-
hyl)-1H-indazole-3-carboxamide,
[0234]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole--
3-carboxamide,
[0235]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-indazo-
le-3-carboxamide,
[0236]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1H-ind-
azole-3-carboxamide hydroformate,
[0237]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-ind-
azole-3-carboxamide hydroformate,
[0238]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-ind-
azole-3-carboxamide hydroformate,
[0239]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(propyl)-1H-indazole-3-carbo-
xamide hydroformate,
[0240]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzi-
sothiazole-3-carboxamide hydroformate,
[0241]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzi-
sothiazole-3-carboxamide hydroformate,
[0242]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(ethyl)-1H-indazole-3-carbox-
amide hydroformate,
[0243]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide,
[0244]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide,
[0245]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide,
[0246]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide,
[0247]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carbox-
amide hydroformate,
[0248]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-ind-
azole-3-carboxamide hydroformate,
[0249]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole--
3-carboxamide hydroformate,
[0250]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydroformate,
[0251]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(methyl)-1H-indazole-3-carbo-
xamide hydroformate,
[0252]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole--
3-carboxamide hydroformate,
[0253]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole--
3-carboxamide hydroformate,
[0254]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yl)-1H-in-
dazole-3-carboxamide hydroformate,
[0255]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-ben-
zisothiazole-3-carboxamide hydroformate,
[0256]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-i-
ndazole-3-carboxamide hydroformate,
[0257]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl-
)-1H-indazole-3-carboxamide,
[0258]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-
-3-carboxamide,
[0259]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-
-3-carboxamide,
[0260]
5-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxam-
ide,
[0261]
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxam-
ide,
[0262]
4-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxam-
ide,
[0263]
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3--
carboxamide,
[0264]
6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3--
carboxamide,
[0265]
7-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxam-
ide,
[0266]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylmethyl)amino]-1-
H-indazole-3-carboxamide hydroformate,
[0267]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]am-
ino}-1H-indazole-3-carboxamide hydroformate,
[0268]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H--
indazole-3-carboxamide hydroformate,
[0269]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-
-1H-indazole-3-carboxamide hydroformate,
[0270]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-in-
dazole-3-carboxamide hydroformate,
[0271]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-i-
ndazole-3-carboxamide hydroformate,
[0272]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-in-
dazole-3-carboxamide hydroformate,
[0273]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-b-
enzisothiazole-3-carboxamide,
[0274]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-b-
enzisothiazole-3-carboxamide,
[0275]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2--
benzisothiazole-3-carboxamide,
[0276]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2--
benzisothiazole-3-carboxamide,
[0277]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-[(methylsulfonyl)amino]-1H-i-
ndazole-3-carboxamide,
[0278]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-1H-i-
ndazole-3-carboxamide hydroformate,
[0279]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)et-
hyl]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
[0280]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carb-
onyl}amino)-1,2-benzisothiazole-3-carboxamide,
[0281]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-florophenyl)ethyl]a-
mino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
[0282]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino-
]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,
[0283]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino-
]carbonyl}amino)-1,2-benzisothiazole-3-carboxamide,
[0284]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]car-
bonyl}amino)-1,2-benzisothiazole-3-carboxamide,
[0285]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]-
amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
[0286]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl-
]amino}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide,
[0287]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl-
]amino}-1,2-benzisothiazole-3-carboxamide,
[0288]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amin-
o}-1,2-benzisothiazole-3-carboxamide,
[0289]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]car-
bonyl}amino)-1H-indazole-3-carboxamide,
[0290]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]ca-
rbonyl}amino)-1H-indazole-3-carboxamide,
[0291]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl-
]amino}-1H-indazole-3-carboxamide,
[0292]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]ca-
rbonyl}amino)-1H-indazole-3-carboxamide,
[0293]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]car-
bonyl}amino)-1H-indazole-3-carboxamide,
[0294]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amin-
o}-1,2-benzisothiazole-3-carboxamide hydroformate,
[0295]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amin-
o}-1H-indazole-3-carboxamide hydroformate,
[0296]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amin-
o}-1H-indazole-3-carboxamide hydroformate,
[0297]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]car-
bonyl}amino)-1H-indazole-3-carboxamide hydroformate,
[0298]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]car-
bonyl}amino)-1H-indazole-3-carboxamide hydroformate,
[0299]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl-
]amino}-1H-indazole-3-carboxamide hydroformate,
[0300]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2--
benzisothiazole-3-carboxamide hydroformate,
[0301]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-i-
ndazole-3-carboxamide dihydroformate,
[0302]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1-
H-1,2,3-triazol-4-yl]-1H-indazole-3-carboxamide dihydroformate,
[0303]
Ethyl[4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-ind-
azol-6-yl)-1H-1,2,3-triazol-1-yl]acetate hydroformate,
[0304]
Benzyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indaz-
ol-5-yl)carbamate,
[0305]
Vinyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazo-
l-5-yl)carbamate, and
[0306] physiologically acceptable salts thereof.
[0307] According to a further compound and/or method aspect of the
invention, the compound of formulas I-IV is selected from (wherein
compounds in their salt forms can also be in their non-salt
forms):
[0308]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carbox-
amide,
[0309]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamid-
e hydroformate,
[0310]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamid-
e hydroformate,
[0311]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzis-
othiazole-3-carboxamide hydroformate,
[0312]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole--
3-carboxamide,
[0313]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indaz-
ole-3-carboxamide,
[0314]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1-
H-indazole-3-carboxamide hydroformate,
[0315]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-ca-
rboxamide hydroformate,
[0316]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazol-
e-3-carboxamide,
[0317]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazol-
e-3-carboxamide,
[0318]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydroformate,
[0319]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carbox-
amide hydroformate,
[0320]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-
-3-carboxamide hydroformate,
[0321]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-
-3-carboxamide hydroformate,
[0322]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazol-
e-3-carboxamide,
[0323]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazol-
e-3-carboxamide,
[0324]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydroformate,
[0325]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydroformate,
[0326]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-ind-
azole-3-carboxamide hydroformate,
[0327]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-ind-
azole-3-carboxamide hydroformate,
[0328]
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-y-
l]-1H-indazole-3-carboxamide hydroformate,
[0329]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydrochloride,
[0330]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(methyloxy)pyrrolidin-1-y-
l]-1H-indazole-3-carboxamide hydroformate,
[0331]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-
-1H-indazole-3-carboxamide hydroformate,
[0332]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)ox-
y]-1H-indazole-3-carboxamide dihydroformate,
[0333]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydrochloride,
[0334]
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indaz-
ole-3-carboxamide hydroformate,
[0335]
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carbo-
xamide hydroformate,
[0336]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-1H-inda-
zole-3-carboxamide hydroformate,
[0337]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentyloxy)-1H-indazole-
-3-carboxamide hydroformate,
[0338]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-i-
ndazole-3-carboxamide hydroformate,
[0339]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1H-inda-
zole-3-carboxamide hydroformate,
[0340]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-i-
ndazole-3-carboxamide hydroformate,
[0341]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benzyloxy)-1H-indazole-3-ca-
rboxamide hydroformate,
[0342]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy-
)-1H-indazole-3-carboxamide hydroformate,
[0343]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-ylox-
y)-1H-indazole-3-carboxamide hydroformate,
[0344]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-
-indazole-3-carboxamide dihydroformate,
[0345]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-
-indazole-3-carboxamide dihydroformate,
[0346]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(ethyl)-1H-indazole--
3-carboxamide,
[0347]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-(ethyl)-1H-indazole--
3-carboxamide,
[0348]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl)--
1H-indazole-3-carboxamide,
[0349]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethy-
l)-1H-indazole-3-carboxamide,
[0350]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-i-
ndazole-3-carboxamide dihydroformate,
[0351]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-in-
dazole-3-carboxamide dihydroformate,
[0352]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-
-indazole-3-carboxamide dihydroformate,
[0353]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)ox-
y]-1H-indazole-3-carboxamide dihydroformate,
[0354]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole--
3-carboxamide,
[0355]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1H--
indazole-3-carboxamide,
[0356]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy--
1H-indazole-3-carboxamide hydroformate,
[0357]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazol-
e-3-carboxamide hydroformate,
[0358]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-5-trifluor-
omethoxy-1H-indazole-3-carboxamide hydroformate,
[0359]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)--
1H-indazole-3-carboxamide hydrochloride,
[0360]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1-
H-indazole-3-carboxamide hydroformate,
[0361]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclorpopylmethyl-5-(1,3-thi-
azol-2-yl)-1H-indazole-3-carboxamide hydroformate,
[0362]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,-
3-thiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
[0363]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-thiazol-2-yl)-1-
H-indazole-3-carboxamide hydroformate,
[0364]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-
-1H-indazole-3-carboxamide hydroformate,
[0365]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-
-1,2-benzisothiazole-3-carboxamide hydroformate,
[0366]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-
-1,2-benzisothiazole-3-carboxamide hydroformate,
[0367]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2--
benzisothiazole-3-carboxamide hydroformate,
[0368]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-
-1,2-benzisothiazole-3-carboxamide hydroformate,
[0369]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,-
2-benzisothiazole-3-carboxamide,
[0370]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,-
2-benzisothiazole-3-carboxamide,
[0371]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1-
,2-benzisothiazole-3-carboxamide,
[0372]
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-ca-
rboxamide,
[0373]
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethy-
l)-1H-indazole-3-carboxamide,
[0374]
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)--
1H-indazole-3-carboxamide,
[0375]
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole--
3-carboxamide,
[0376]
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole--
3-carboxamide,
[0377] Methyl
4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-i-
ndazol-5-yl)amino]butanoate dihydroformate,
[0378] Methyl
4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-i-
ndazol-6-yl)amino]butanoate dihydroformate,
[0379] tert-Butyl
{2-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-
-1,2-benzisothiazol-6-yl)amino]ethyl}propylcarbamate
hydroformate,
[0380]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)ami-
no]-1H-indazole-3-carboxamide hydroformate,
[0381]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole--
3-carboxamide hydroformate,
[0382]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-metho-
xyethyl)amino]-1H-indazole-3-carboxamide hydroformate,
[0383]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethy-
l]amino}-1,2-benzisothiazole-3-carboxamide hydroformate,
[0384]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-c-
arboxamide hydroformate,
[0385]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1-
,2-benzisothiazole-3-carboxamide hydroformate,
[0386]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisot-
hiazole-3-carboxamide hydroformate,
[0387]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisoth-
iazole-3-carboxamide hydroformate,
[0388]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-
-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide,
[0389]
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-
-indazole-3-carboxamide dihydroformate,
[0390]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cy-
clopropylcarbonyl)amino]-1H-indazole-3-carboxamide
hydroformate,
[0391]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5--
{[(4-methoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamide
hydroformate,
[0392]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-
-1,2-benzisothiazole-3-carboxamide hydroformate,
[0393]
6-(Acetylamino)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothi-
azole-3-carboxamide hydroformate,
[0394]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]am-
ino}-1,2-benzisothiazole-3-carboxamide hydroformate,
[0395]
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H--
indazole-3-carboxamide dihydroformate,
[0396]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(pro-
pylamino)carbonyl]amino}-1H-indazole-3-carboxamide,
[0397]
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzyl)-5-({-
[(3-methoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,
[0398]
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(4-fluorobenzyl)-5-({[-
(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide,
[0399]
N(3)-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclo-
pentylamino)carbonyl]amino}-1H-indazole-1,3-dicarboxamide
hydroformate,
[0400]
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamin-
o)carbonyl]amino}-1H-indazole-1,3-dicarboxamide,
[0401]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]-
carbonothioyl}amino)-1H-indazole-3-carboxamide hydroformate,
[0402]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]-
carbonothioyl}amino)-1,2-benzisothiazole-3-carboxamide
hydroformate,
[0403]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)carbono-
thioyl]amino}-1,2-benzisothiazole-3-carboxamide hydroformate,
[0404]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonoth-
ioyl]amino}-1,2-benzisothiazole-3-carboxamide hydroformate,
[0405]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]a-
mino}-1H-indazole-3-carboxamide hydroformate,
[0406]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbo-
nyl]amino}-1H-indazole-3-carboxamide hydroformate,
[0407]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(pro-
pylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
[0408]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(-
propylamino)carbonyl]amino}-1H-indazole-3-carboxamide
hydroformate,
[0409]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)car-
bonyl]amino}-1H-indazole-3-carboxamide hydroformate,
[0410] Isopropyl
{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-i-
ndazol-5-yl}carbamate hydroformate,
[0411] Isopropyl
{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(-
isopropylamino)carbonyl]-1H-indazol-5-yl}carbamate
hydroformate,
[0412]
N-[(3S)-1-Oxido-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxam-
ide,
[0413]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carbox-
amide hydrobromide,
[0414]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carbox-
amide hydrobromide,
[0415]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]ami-
no}-1H-indazole-3-carboxamide hydroformate,
[0416]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)am-
ino]-1H-indazole-3-carboxamide hydroformate,
[0417]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)am-
ino]-1H-indazole-3-carboxamide hydroformate,
[0418]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-b-
enzisothiazole-3-carboxamide hydroformate,
[0419]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-b-
enzisothiazole-3-carboxamide hydroformate,
[0420]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1--
yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
[0421]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-
-benzisothiazole-3-carboxamide hydroformate,
[0422]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H--
indazole-3-carboxamide hydroformate,
[0423]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin--
1-yl)-1H-indazole-3-carboxamide hydroformate,
[0424]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino-
}-1,2-benzisothiazole-3-carboxamide hydroformate,
[0425]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin--
1-yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
[0426]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolid-
in-1-yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
[0427]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin--
1-yl)-1,2-benzisothiazole-3-carboxamide hydroformate,
[0428]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisoxazole-3-ca-
rboxamide,
[0429]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-ca-
rboxamide,
[0430]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin--
1-yl)-1,2-benzisothiazole-3-carboxamide,
[0431]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolid-
in-1-yl)-1,2-benzisothiazole-3-carboxamide,
[0432]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin--
1-yl)-1,2-benzisothiazole-3-carboxamide,
[0433]
6-[Acetyl(methyl)amino]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-be-
nzisothiazole-3-carboxamide hydroformate,
[0434]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-
-benzisothiazole-3-carboxamide hydroformate,
[0435]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-
-3-carboxamide hydroformate,
[0436]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-y-
l]-1-ethyl-1H-indazole-3-carboxamide hydroformate,
[0437]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-
-1-ethyl-1H-indazole-3-carboxamide,
[0438]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-
-1-cyclopropylmethyl-1H-indazole-3-carboxamide,
[0439]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-
-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxamide,
[0440]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thia-
zol-2-yl)-1H-indazole-3-carboxamide hydroformate,
[0441]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-t-
hiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
[0442]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,-
3-thiazol-2-yl)-1H-indazole-3-carboxamide hydroformate,
[0443]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-y-
l]-1-(cyclopropylmethyl)-1H-indazole-3-carboxamide
hydroformate,
[0444]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-y-
l]-1-ethyl-1H-indazole-3-carboxamide hydroformate,
[0445] tert-Butyl
3-[3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-
-(1,3-thiazol-2-yl)-1H-indazol-1-yl]pyrrolidine-1-carboxylate
hydroformate,
[0446]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiaz-
ol-2-yl)-1H-indazole-3-carboxamide,
[0447]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thie-
nylmethyl)-1H-indazole-3-carboxamide hydroformate,
[0448]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thia-
zol-2-yl)-1H-indazole-3-carboxamide hydroformate, and
[0449] physiologically acceptable salts thereof.
[0450] Preferred aspects include pharmaceutical compositions
comprising a compound of this invention and a pharmaceutically
acceptable carrier and, optionally, another active agent as
discussed below; a method of stimulating or activating inhibiting
alpha-7 nicotinic receptors, e.g., as determined by a conventional
assay or one described herein, either in vitro or in vivo (in an
animal, e.g., in an animal model, or in a mammal or in a human); a
method of treating a neurological syndrome, e.g., loss of memory,
especially long-term memory, cognitive impairment or decline,
memory impairment, etc. method of treating a disease state
modulated by nicotinic alpha-7 activity, in a mammal, e.g., a
human, e.g., those mentioned herein.
[0451] The compounds of the present invention may be prepared
conventionally. Some of the known processes that can be used are
described below. All starting materials are known or can be
conventionally prepared from known starting materials.
[0452] Acids that were used in the preparation of the bicyclobase
amide were commercially available or were prepared by known
procedures described in the literature or as described below. For
example, indazole-3-carboxylic acid was commercially available.
Positional isomers of indazole carboxylic acid were prepared from
the requisite bromo-2-methylanilines by diazotization followed by
metal-halogen exchange and trapping with carbon dioxide (Se e.g.,
DeLucca, G. V. Substituted 2H-1,3-Diazapin-2-one Useful as an HIV
Protease Inhibitor, U.S. Pat. No. 6,313,110 B1, Nov. 6, 2001; and
Sun, J. H.; Teleha, C. A.; Yan, J. S.; Rodgers, J. D.; Nugiel, D.
A. Efficient Synthesis of 5-(Bromomethyl)- and
5-(Aminomethyl)-1-THP-Indazole. J. Org. Chem. 1997, 62, 5627-5629).
A variety of the simple substituted indazole-3-acids, such as the
bromoindazole acids, were prepared from the corresponding isatins
by basic hydrolysis, diazotization, and reduction (Snyder, H. R.;
et al. J. Am. Chem. Soc. 1952, 74, 2009).
[0453] Some substituted indazole-3-acids were prepared by modifying
existing indazole acids or esters. For example,
5-nitroindazole-3-acid was prepared by nitration of indazole-3-acid
(Kamm, O.; Segur, J. B. Org. Syn. Coll. Vol 1. 1941, 372).
6-Nitroindazole-3-acid was prepared from 3-iodo-6-nitroindazole
using copper (I) cyanide followed by hydrolysis. Some non-aromatic
heterocyclic derivatives were prepared from the bromides by
metal-halogen exchange, trapping of indazole aryllithiums with
ketones, followed by reduction or acid mediated elimination.
Trapping of the indazole aryllithiums with amides provided ketones
and aldehydes that served as useful precursors for, among other
things, reductive aminations. Aromatic substituted indazole-3-acids
were prepared from the bromides via palladium mediated
cross-coupling with boronic acids or aryl zinc reagents (Reeder, M.
R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696).
4-Bromo-5-methoxyindazole- and
7-bromo-6-methoxyindazole-3-carboxylic acids were prepared from the
corresponding methoxyindazole-3-carboxylates by bromination and
saponification. 4-Fluoro-5-methoxyindazole- and
7-fluoro-6-methoxyindazol- e-3-carboxylic acids were prepared from
the corresponding methoxyindazole-3-carboxylates by fluorination
and saponification. 5-Bromo-4-nitroindazole- and
6-bromo-7-nitroindazole-3-carboxylic acids were prepared from the
corresponding bromoindazole-3-carboxylates by nitration and
saponification. Subjecting the nitro bromides to hydrogenolysis
provided 4-aminoindazole- and 7-aminoindazole-3-carboxylic acids.
The aminoindazole esters were transformed to additional useful acid
analogs by reductive amination, alkylation, and acylation
strategies. N-1-Alkylated indazole-3-carboxylic acids were prepared
from the corresponding indazole esters by standard alkylation
procedures. N-1-Arylated indazole-3-carboxylic acids were prepared
from the corresponding indazole esters by copper mediated cross
couplings with boronic acids. Phenol derivatives were prepared from
the corresponding methoxy acids using boron tribromide.
[0454] Some substituted indazole-3-acids were prepared from simple
benzene derivatives. For example, 5-difluoromethoxyindazole-3-acid
was prepared from 3-bromo-4-nitrophenol by reaction with ethyl
difluoroacetate, reaction with diethyl malonate, decarboxylative
saponification, esterification, reduction of the nitro group, and
diazotization. 6-Difluoromethoxyindazole-3-acid was prepared in a
similar manner from 2-bromo-5-difluoromethoxynitrobenzene. The
2-bromo-5-difluoromethoxynitro- benzene used in that preparation
was prepared from 4-nitrophenol by ether formation, nitro reduction
with concomitant protection as the amide, nitration, amide
hydrolysis, and a Sandmeyer reaction with copper (I) bromide.
6-Benzyloxyindazole-3-carboxylic acid and ester was prepared from
4-methoxynitrobenzene by nitro reduction with concomitant
protection as the amide, nitration, amide hydrolysis, Sandmeyer
reaction with copper (I) bromide, and demethylation. The phenol was
alkylated with benzyl bromide and the arylbromide was subjected to
reaction with diethyl malonate, decarboxylative saponification,
esterification, reduction of the nitro group, and diazotization.
The 5-benzyloxy analog was prepared in a similar manner from
4-benzyloxy-2-bromonitrobenzene (Parker, K. A.; Mindt, T. L. Org.
Lett. 2002, 4, 4265.) The benzyl group was removed by
hydrogenolysis and the resulting phenol was transformed to ether
derivatives via either alkylation or Mitsunobu reaction conditions.
4-Methoxyindazole acid was prepared from 4-methoxyaniline by amide
formation, nitration, amide hydrolysis, Sandmeyer reaction with
copper (I) bromide, nitro reduction, isatin formation and
rearrangement to the indazole, followed by hydrogenolytic removal
of the bromine.
[0455] The benzisoxazole-, benzisoxazole-, and
benzothiazolecarboxylic acids were prepared using similar
strategies outlined for the indazole acids. For example, ethyl
6-bromobenzisoxazole-3-carboxylate was prepared from
2,5-dibromonitrobenzene by reaction with diethyl malonate,
saponification and decarboxylation, and reaction with
isoamylnitrite. Ethyl benzisoxazole-3-carboxylate was obtained by
hydrogenolysis of the 6-bromo derivative. 4-Benzothiazolecarboxylic
acid was prepared from 2-amino-4-chloro-benzothiazole by reaction
with isoamyl nitrite followed by metal-halogen exchange and
trapping with carbon dioxide. 5-Benzothiazolecarboxylic acid was
prepared from 4-chloro-3-nitrobenzoic acid by reaction with
Na.sub.2S and sodium hydroxide followed by reduction with zinc in
formic acid. 3-Benzisothiazolecarboxylic acid was prepared from
thiophenol by reaction with oxalyl chloride and aluminum chloride
followed by treatment with hydroxylamine, hydrogen peroxide, and
sodium hydroxide.
[0456] The bicycloamines, 3-aminoquinuclidine and the R- and
S-enantiomers thereof, used in the preparation of the bicyclobase
amides were commercially available. The N-alkylated quinuclidines
were prepared by acylation of 3-aminoquinuclidine followed by
reduction of the amide. 3-Aminomethylquinuclidine was prepared from
3-quinuclidinone by the action of p-tolylsulfonylmethyl isocyanide
followed by hydrogenation of the nitrile.
[0457] The bicyclobase amides were prepared from the acids and the
bicycloamines using standard peptide coupling agents, such as HBTU,
HATU, or HOBt and EDCI, or by converting the acids to the
corresponding acid chloride and then reaction with the bicycloamine
(Macor, J. E.; Gurley, D.; Lanthom, T.; Loch, J.; Mack, R. A.;
Mullen, G.; Tran, O.; Wright, N.; and J. E. Macor et al., "The
5-HT3-Antagonwast Tropisetron (ICS 205-930) was a Potent and
Selective .alpha.-7 Nicotinic Receptor Partial Agonist," Bioorg.
Med. Chem. Lett. 2001, 9, 319-321). The couplings were generally
performed at room temperatures for 18-24 hours. The resultant
adducts were isolated and purified by standard techniques, such as
chromatography or recrystallization, practiced by those skilled in
the art.
[0458] One of ordinary skill in the art will recognize that
compounds of Formulas I-IV can exist in different tautomeric and
geometrical isomeric forms. All of these compounds, including cis
isomers, trans isomers, diastereomic mixtures, racemates,
nonracemic mixtures of enantiomers, substantially pure, and pure
enantiomers, are within the scope of the present invention.
Substantially pure enantiomers contain no more than 5% w/w of the
corresponding opposite enantiomer, preferably no more than 2%, most
preferably no more than 1%.
[0459] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, for example,
by the formation of diastereoisomeric salts using an optically
active acid or base or formation of covalent diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual
diastereomers on the basis of their physical and/or chemical
differences by methods known to those skilled in the art, for
example, by chromatography or fractional crystallization. The
optically active bases or acids are then liberated from the
separated diastereomeric salts. A different process for separation
of optical isomers involves the use of chiral chromatography (e.g.,
chiral HPLC columns), with or without conventional derivation,
optimally chosen to maximize the separation of the enantiomers.
Suitable chiral HPLC columns are manufactured by Diacel, e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely
selectable. Enzymatic separations, with or without derivitization,
are also useful. The optically active compounds of Formulas I-IV
can likewise be obtained by utilizing optically active starting
materials in chiral synthesis processes under reaction conditions
which do not cause racemization.
[0460] In addition, one of ordinary skill in the art will recognize
that the compounds can be used in different enriched isotopic
forms, e.g., enriched in the content of .sup.2H, .sup.3H, .sup.11C,
.sup.13C and/or .sup.14C. In one particular embodiment, the
compounds are deuterated. Such deuterated forms can be made the
procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As
described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration
can improve the efficacy and increase the duration of action of
drugs.
[0461] Deuterium substituted compounds can be synthesized using
various methods such as 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.
[0462] Where applicable, the present invention also relates to
useful forms of the compounds as disclosed herein, such as
pharmaceutically acceptable salts or prodrugs of all the compounds
of the present invention for which salts or prodrugs can be
prepared. Pharmaceutically acceptable salts include those obtained
by reacting the main compound, functioning as a base, with an
inorganic or organic acid to form a salt, for example, salts of
hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic
acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic
acid, citric acid, formic acid, hydrobromic acid, benzoic acid,
tartaric acid, fumaric acid, salicylic acid, mandelic acid, and
carbonic acid. Pharmaceutically acceptable salts also include those
in which the main compound functions as an acid and is reacted with
an appropriate base to form, e.g., sodium, potassium, calcium,
magnesium, ammonium, and choline salts. Those skilled in the art
will further recognize that acid addition salts of the claimed
compounds may be prepared by reaction of 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 invention with the
appropriate base via a variety of known methods.
[0463] The following are further examples of acid salts that can be
obtained by reaction with inorganic or organic acids: acetates,
adipates, alginates, citrates, aspartates, benzoates,
benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates, cyclopentanepropionates- , dodecylsulfates,
ethanesulfonates, glucoheptanoates, glycerophosphates,
hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,
palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,
pivalates, propionates, succinates, tartrates, thiocyanates,
tosylates, mesylates and undecanoates.
[0464] Preferably, the salts formed are pharmaceutically acceptable
for administration to mammals. However, pharmaceutically
unacceptable salts of the compounds are suitable as intermediates,
for example, for isolating the compound as a salt and then
converting the salt back to the free base compound by treatment
with an alkaline reagent. The free base can then, if desired, be
converted to a pharmaceutically acceptable acid addition salt.
[0465] The compounds of the invention can be administered alone or
as an active ingredient of a formulation. Thus, the present
invention also includes pharmaceutical compositions of compounds of
Formulas I-IV, containing, for example, one or more
pharmaceutically acceptable carriers.
[0466] Numerous standard references are available that describe
procedures for preparing various formulations suitable for
administering the compounds according to the invention. Examples of
potential formulations and preparations are contained, for example,
in the 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).
[0467] In view of their alpha-7 stimulating activity and,
preferably their high degree of selectivity, the compounds of the
present invention can be administered to anyone needing stimulation
of alpha-7 receptors. Administration may be accomplished according
to patient needs, for example, orally, nasally, parenterally
(subcutaneously, intraveneously, intramuscularly, intrasternally
and by infusion) by inhalation, rectally, vaginally, topically and
by ocular administration.
[0468] Various solid oral dosage forms can be used for
administering compounds of the invention including such solid forms
as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk
powders. The compounds of the present invention can be administered
alone or combined with various pharmaceutically acceptable
carriers, diluents (such as sucrose, mannitol, lactose, starches)
and excipients known in the art, including but not limited to
suspending agents, solubilizers, buffering agents, binders,
disintegrants, preservatives, colorants, flavorants, lubricants and
the like. Time release capsules, tablets and gels are also
advantageous in administering the compounds of the present
invention.
[0469] Various liquid oral dosage forms can also be used for
administering compounds of the inventions, including aqueous and
non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
Such dosage forms can also contain suitable inert diluents known in
the art such as water and suitable excipients known in the art such
as preservatives, wetting agents, sweeteners, flavorants, as well
as agents for emulsifying and/or suspending the compounds of the
invention. The compounds of the present invention may be injected,
for example, intravenously, in the form of an isotonic sterile
solution. Other preparations are also possible.
[0470] Suppositories for rectal administration of the compounds of
the present invention can be prepared by mixing the compound with a
suitable excipient such as cocoa butter, salicylates and
polyethylene glycols. Formulations for vaginal administration can
be in the form of a pessary, tampon, cream, gel, paste, foam, or
spray formula containing, in addition to the active ingredient,
such suitable carriers as are known in the art.
[0471] For topical administration the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the skin, eye, ear or
nose. Topical administration may also involve transdermal
administration via means such as transdermal patches.
[0472] Aerosol formulations suitable for administering via
inhalation also can be made. For example, for treatment of
disorders of the respiratory tract, the compounds according to the
invention can be administered by inhalation in the form of a powder
(e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
[0473] The compounds can be administered as the sole active agent
or in combination with other pharmaceutical agents such as other
agents used in the treatment of cognitive impairment and/or memory
loss, e.g., other .alpha.-7 agonists, PDE4 inhibitors, calcium
channel blockers, muscarinic m1 and m2 modulators, adenosine
receptor modulators, amphakines NMDA-R modulators, mGluR
modulators, dopamine modulators, serotonin modulators, canabinoid
modulators, and cholinesterase inhibitors (e.g., donepezil,
rivastigimine, and glanthanamine). In such combinations, each
active ingredient can be administered either in accordance with
their usual dosage range or a dose below their usual dosage
range.
[0474] The compounds of the invention can be used in conjunction
with "positive modulators" which enhance the efficacy of nicotinic
receptor agonists. See, e.g., the positive modulators disclosed in
WO 99/56745, WO 01/32619, and WO 01/32622. Such combinational
therapy can be used in treating conditions/diseases associated with
reduced nicotinic transmission.
[0475] Further the compounds may be used in conjunction with
compounds that bind to A.beta. peptides and thereby inhibit the
binding of the peptides to .alpha.7nACh receptor subtypes. See,
e.g., WO 99/62505.
[0476] The present invention further includes methods of treatment
that involve activation of .alpha.-7 nicotinic receptors. Thus, the
present invention includes methods of selectively
activating/stimulating .alpha.-7 nicotinic receptors in a patient
(e.g., a mammal such as a human) wherein such
activation/stimulation has a therapeutic effect, such as where such
activation may relieve conditions involving neurological syndromes,
such as the loss of memory, especially long-term memory. Such
methods comprise administering to a patient (e.g., a mammal such as
a human) in need thereof, an effective amount of a compound of
Formulas I-IV, alone or as part of a formulation, as disclosed
herein.
[0477] In accordance with a method aspect of the invention, there
is provided a method of treating a patient (e.g., a mammal such as
a human) suffering from a disease state (e.g., memory impairment)
comprising administering to the patient a compound according to
Formulas I-IV. Preferably, the disease state involves decreased
nicotinic acetylcholine receptor activity.
[0478] In accordance with a method aspect of the invention there is
provided a method for the treatment or prophylaxis of a disease or
condition resulting from dysfunction of nicotinic acetylcholine
receptor transmission in a patient (e.g., a mammal such as a human)
comprising administering an effective amount of a compound
according to Formulas I-IV.
[0479] In accordance with a method aspect of the invention there is
provided a method for the treatment or prophylaxis of a disease or
condition resulting from defective or malfunctioning nicotinic
acetylcholine receptors, particularly .alpha.7nACh receptors, in a
patient (e.g., a mammal such as a human) comprising administering
an effective amount of a compound according to Formulas I-IV.
[0480] In accordance with a method aspect of the invention there is
provided a method for the treatment or prophylaxis of a disease or
condition resulting from suppressed nicotinic acetylcholine
receptor transmission in a patient (e.g., a mammal such as a human)
comprising administering an amount of a compound according to
Formulas I-IV effective to activate .alpha.7nACh receptors.
[0481] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
psychotic disorder, a cognition impairment (e.g., memory
impairment), or neurodegenerative disease in a patient (e.g., a
mammal such as a human) comprising administering an effective
amount of a compound according to Formulas I-IV.
[0482] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
disease or condition resulting from loss of cholinergic synapses in
a patient (e.g., a mammal such as a human) comprising administering
an effective amount of a compound according to Formulas I-IV.
[0483] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
neurodegenerative disorder by activation of .alpha.7nACh receptors
in a patient (e.g., a mammal such as a human) comprising
administering an effective amount of a compound according to
Formulas I-IV.
[0484] In accordance with another method aspect of the invention
there is provided a method for protecting neurons in a patient
(e.g., a mammal such as a human) from neurotoxicity induced by
activation of .alpha.7nACh receptors comprising administering an
effective amount of a compound according to Formulas I-IV.
[0485] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
neurodegenerative disorder by inhibiting the binding of A.beta.
peptides to .alpha.7nACh receptors in a patient (e.g., a mammal
such as a human) comprising administering an effective amount of a
compound according to Formulas I-IV.
[0486] In accordance with another method aspect of the invention
there is provided a method for protecting neurons in a patient
(e.g., a mammal such as a human) from neurotoxicity induced by
A.beta. peptides comprising administering an effective amount of a
compound according to Formulas I-IV.
[0487] In accordance with another method aspect of the invention
there is provided a method for alleviating inhibition of
cholinergic function induced by A.beta. peptides in a patient
(e.g., a mammal such as a human) comprising administering an
effective amount of a compound according to Formulas I-IV.
[0488] A subject or patient in whom administration of the
therapeutic compound is an effective therapeutic regimen for a
disease or disorder is preferably a human, but can be any animal,
including a laboratory animal in the context of a clinical trial or
screening or activity experiment. Thus, as can be readily
appreciated by one of ordinary skill in the art, the methods,
compounds and compositions of the present invention are
particularly suited to administration to any animal, particularly a
mammal, and including, but by no means limited to, humans, domestic
animals, such as feline or canine subjects, farm animals, such as
but not limited to bovine, equine, caprine, ovine, and porcine
subjects, wild animals (whether in the wild or in a zoological
garden), research animals, such as mice, rats, rabbits, goats,
sheep, pigs, dogs, cats, etc., avian species, such as chickens,
turkeys, songbirds, etc., i.e., for veterinary medical use.
[0489] The compounds of the present invention are nicotinic alpha-7
ligands, preferably agonists, especially partial agonists, for the
alpha-7 nicotinic acetylcholine receptor. Assays for determining
nicotinic acetylcholine activity are known within the art. See,
e.g., Davies, A. R., et al., Characterisation of the binding of
[3H]methyllycaconitine: a new radioligand for labelling alpha
7-type neuronal nicotinic acetylcholine receptors.
Neuropharmacology, 1999. 38(5): p. 679-90. As agonists for
.alpha.7nACh receptors, the compounds are useful in the prophylaxis
and treatment of a variety of diseases and conditions associated
with the central nervous system. Nicotinic acetylcholine receptors
are ligand-gastrol ion-channel receptors that are composed of five
subunit proteins which form a central ion-conducting pore.
Presently, there are eleven known neuronal nACh receptor subunits
(.alpha.2-.alpha.9 and .beta.2-.beta.4). There are also five
further subunits expressed in the peripheral nervous system
(.alpha.1, .beta.1, .gamma., .delta., .epsilon.).
[0490] The nACh receptor subtypes can be homopentameric or
heteropentameric. The subtype which has received considerable
attention is the homopentameric .alpha.7 receptor subtype formed
from five .alpha.7 subunits. The .alpha.7nACh receptors exhibit a
high affinity for nicotine (agonist) and for .alpha.-bungarotoxin
(antagonist). Studies have shown the .alpha.7nACh receptor agonists
can be useful in the treatment of psychotic diseases,
neurodegenerative diseases, and cognitive impairments, among other
things. While nicotine is a known agonist, there is a need for the
development of other .alpha.7nACh receptor agonists, especially
selective agonists, which are less toxic or exhibit fewer side
effects than nicotine.
[0491] The compound anabaseine, i.e.,
2-(3-pyridyl)-3,4,5,6-tetrahydropyri- dine is a naturally occurring
toxin in certain marine worms (nemertine worms) and ants. See,
e.g., Kem et al., Toxicon, 9:23, 1971. Anabaseine is a potent
activator of mammalian nicotinic receptors. See, e.g., Kem, Amer.
Zoologist, 25, 99, 1985. Certain anabaseine analogs such as
anabasine and DMAB
(3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2-
',3'-bipyridine) are also known nicotinic receptor agonists. See,
e.g., U.S. Pat. No. 5,602,257 and WO 92/15306. One particular
anabaseine analog, (E-3-[2,4-dimethoxy-benzylidene]-anabaseine,
also known as GTS-21 and DMXB (see, e.g., U.S. Pat. No. 5,741,802),
is a selective partial .alpha.7nACh receptor agonist that has been
studied extensively. For example, abnormal sensory inhibition is a
sensory processing deficit in schizophrenics and GTS-21 has been
found to increase sensory inhibition through interaction with
.alpha.7nACh receptors. See, e.g., Stevens et al.,
Psychopharmacology, 136: 320-27 (1998).
[0492] Another compound which is known to be a selective
.alpha.7nACh receptor agonist is Tropisetron, i.e., 1.alpha.H,
5.alpha.H-tropan-3.alph- a.-yl indole-3-carboxylate. See 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).
[0493] Agents that bind to nicotinic acetylcholine receptors have
been indicated as useful in the treatment and/or prophylaxis of
various diseases and conditions, particularly psychotic diseases,
neurodegenerative diseases involving a dysfunction of the
cholinergic system, and conditions of memory and/or cognition
impairment, including, for example, schizophrenia, anxiety, mania,
depression, manic depression [examples of psychotic disorders],
Tourette's syndrome, Parkinson's disease, Huntington's disease
[examples of neurodegenerative diseases], cognitive disorders (such
as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral
Sclerosis, memory impairment, memory loss, cognition deficit,
attention deficit, Attention Deficit Hyperactivity Disorder), and
other uses such as treatment of nicotine addiction, inducing
smoking cessation, treating pain (i.e., analgesic use), providing
neuroprotection, and treating jetlag. See, e.g., WO 97/30998; WO
99/03850; WO 00/42044; WO 01/36417; Holladay et al., J. Med. Chem.,
40:26, 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem.,
Chapter 5, 41-51 (2000); Stevens et al., Psychopharmatology, (1998)
136: 320-27; and Shytle et al., Molecular Psychiatry, (2002), 7,
pp. 525-535.
[0494] Thus, in accordance with the invention, there is provided a
method of treating a patient, especially a human, suffering from
psychotic diseases, neurodegenerative diseases involving a
dysfunction of the cholinergic system, and conditions of memory
and/or cognition impairment, including, for example, schizophrenia,
anxiety, mania, depression, manic depression [examples of psychotic
disorders], Tourette's syndrome, Parkinson's disease, Huntington's
disease [examples of neurodegenerative diseases], and/or cognitive
disorders (such as Alzheimer's disease, Lewy Body Dementia,
Amyotrophic Lateral Sclerosis, memory impairment, memory loss,
cognition deficit, attention deficit, Attention Deficit
Hyperactivity Disorder) comprising administering to the patient an
effective amount of a compound according to Formulas I-IV.
[0495] Neurodegenerative disorders included within the methods of
the present invention include, but are not limited to, treatment
and/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse
Lewy Body disease, progressive supranuclear palsy (Steel-Richardson
syndrome), multisystem degeneration (Shy-Drager syndrome), motor
neuron diseases including amyotrophic lateral sclerosis,
degenerative ataxias, cortical basal degeneration,
ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing
panencephalitis, Huntington's disease, Parkinson's disease,
synucleinopathies, primary progressive aphasia, striatonigral
degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,
olivopontocerebellar degenerations, Gilles De La Tourette's
disease, bulbar, pseudobulbar palsy, spinal muscular atrophy,
spinobulbar muscular atrophy (Kennedy's disease), primary lateral
sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease,
Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,
familial spastic disease, Wohlfart-Kugelberg-Welander disease,
spastic paraparesis, progressive multifocal leukoencephalopathy,
prion diseases (such as Creutzfeldt-Jakob,
Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial
insomnia), and neurodegenerative disorders resulting from cerebral
ischemia or infarction including embolic occlusion and thrombotic
occlusion as well as intracranial hemorrhage of any type
(including, but not limited to, epidural, subdural, subarachnoid
and intracerebral), and intracranial and intravertebral lesions
(including, but not limited to, contusion, penetration, shear,
compression and laceration).
[0496] In addition, .alpha.7nACh receptor agonists, such as the
compounds of the present invention can be used to treat age-related
dementia and other dementias and conditions with memory loss
including age-related memory loss, senility, vascular dementia,
diffuse white matter disease (Binswanger's disease), dementia of
endocrine or metabolic origin, dementia of head trauma and diffuse
brain damage, dementia pugilistica and frontal lobe dementia. See,
e.g., WO 99/62505. Thus, in accordance with the invention, there is
provided a method of treating a patient, especially a human,
suffering from age-related dementia and other dementias and
conditions with memory loss comprising administering to the patient
an effective amount of a compound according to Formulas I-IV.
[0497] Thus, in accordance with a further embodiment, the present
invention includes methods of treating patients suffering from
memory impairment due to, for example, mild cognitive impairment
due to aging, Alzheimer's disease, schizophrenia, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob
disease, depression, aging, head trauma, stroke, CNS hypoxia,
cerebral senility, multiinfarct dementia and other neurological
conditions, as well as HIV and cardiovascular diseases, comprising
administering an effective amount of a compound according to
Formulas I-IV.
[0498] Amyloid precursor protein (APP) and A.beta. peptides derived
therefrom, e.g., A.beta..sub.1-40, A.beta..sub.1-42, and other
fragments, are known to be involved in the pathology of Alzhemier's
disease. The A.beta..sub.1-42 peptides are not only implicated in
neurotoxicity but also are known to inhibit cholinergic transmitter
function. Further, it has been determined that A.beta. peptides
bind to .alpha.7nACh receptors. Thus, agents which block the
binding of the A.beta. peptides to .alpha.-7 nAChRs are useful for
treating neurodegenerative diseases. See, e.g., WO 99/62505. In
addition, stimulation .alpha.7nACh receptors can protect neurons
against cytotoxicity associated with A.beta. peptides. See, e.g.,
Kihara, T. et al., Ann. Neurol., 1997, 42, 159.
[0499] Thus, in accordance with an embodiment of the invention
there is provided a method of treating and/or preventing dementia
in an Alzheimer's patient which comprises administering to the
subject a therapeutically effective amount of a compound according
to Formulas I-IV to inhibit the binding of an amyloid beta peptide
(preferably, A.beta..sub.1-42) with nACh receptors, preferable
.alpha.7nACh receptors, most preferably, human .alpha.7nACh
receptors (as well as a method for treating and/or preventing other
clinical manifestations of Alzheimer's disease that include, but
are not limited to, cognitive and language deficits, apraxias,
depression, delusions and other neuropsychiatric symptoms and
signs, and movement and gait abnormalities).
[0500] The present invention also provides methods for treating
other amyloidosis diseases, for example, hereditary cerebral
angiopathy, normeuropathic hereditary amyloid, Down's syndrome,
macroglobulinemia, secondary familial Mediterranean fever,
Muckle-Wells syndrome, multiple myeloma, pancreatic- and
cardiac-related amyloidosis, chronic hemodialysis anthropathy, and
Finnish and Iowa amyloidosis.
[0501] In addition, nicotinic receptors have been implicated as
playing a role in the body's response to alcohol ingestion. Thus,
agonists for .alpha.7nACh receptors can be used in the treatment of
alcohol withdrawal and in anti-intoxication therapy. Thus, in
accordance with an embodiment of the invention there is provided a
method of treating a patient for alcohol withdrawal or treating a
patient with anti-intoxication therapy comprising administering to
the patient an effective amount of a compound according to Formulas
I-IV.
[0502] Agonists for the .alpha.7nACh receptor subtypes can also be
used for neuroprotection against damage associated with strokes and
ischemia and glutamate-induced excitotoxicity. Thus, in accordance
with an embodiment of the invention there is provided 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 Formulas I-IV.
[0503] As noted above, agonists for the .alpha.7nACh receptor
subtypes can also be used in the treatment of nicotine addiction,
inducing smoking cessation, treating pain, and treating jetlag,
obesity, diabetes, and inflammation. Thus, in accordance with an
embodiment of the invention there is provided a method of treating
a patient suffering from nicotine addiction, pain, jetlag, obesity
and/or diabetes, or a method of inducing smoking cessation in a
patient comprising administering to the patient an effective amount
of a compound according to Formulas I-IV.
[0504] The inflammatory reflex is an autonomic nervous system
response to an inflammatory signal. Upon sensing an inflammatory
stimulus, the autonomic nervous system responds through the vagus
nerve by releasing acetylcholine and activating nicotinic .alpha.7
receptors on macrophages. These macrophages in turn release
cytokines. Dysfunctions in this pathway have been linked to human
inflammatory diseases including rheumatoid arthritis, diabetes and
sepsis. Macrophages express the nicotinic .alpha.7 receptor and it
is likely this receptor that mediates the cholinergic
anti-inflammatory response. Therefore, compounds with affinity for
the .alpha.7nACh receptor on macrophages may be useful for human
inflammatory diseases including rheumatoid arthritis, diabetes and
sepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005,
257(2), 156-66.
[0505] Thus, in accordance with an embodiment of the invention
there is provided a method of treating a patient (e.g., a mammal,
such as a human) suffering from an inflammatory disease, such as,
but not limited to, rheumatoid arthritis, diabetes or sepsis,
comprising administering to the patient an effective amount of a
compound according to Formulas I-IV.
[0506] In addition, due to their affinity to .alpha.7nACh
receptors, labeled derivatives of the compounds of Formulas I-IV
(e.g., C.sup.11 or F.sup.18 labeled derivatives), can be used in
neuroimaging of the receptors within, e.g., the brain. Thus, using
such labeled agents in vivo imaging of the receptors can be
performed using, e.g., PET imaging.
[0507] The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. Memory
impairment is a primary symptom of dementia and can also be a
symptom associated with such diseases as Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and
head trauma as well as age-related cognitive decline.
[0508] Thus, in accordance with an embodiment of the invention
there is provided a method of treating a patient suffering from,
for example, mild cognitive impairment (MCI), vascular dementia
(VaD), age-associated cognitive decline (AACD), amnesia associated
w/open-heart-surgery, cardiac arrest, and/or general anesthesia,
memory deficits from early exposure of 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), and animal dementia (e.g., dogs, cats, horses,
etc.) comprising administering to the patient an effective amount
of a compound according to Formulas I-IV.
[0509] The dosages of the compounds of the present invention depend
upon a variety of factors including the particular syndrome to be
treated, the severity of the symptoms, the route of administration,
the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile
of the compound, and the presence of any deleterious side-effects,
among other considerations.
[0510] The compounds of the invention can be administered to
patients, e.g., mammals, particularly humans, at typical dosage
levels customary for .alpha.-7 nicotinic receptor agonists such as
the known .alpha.-7 nicotinic receptor agonist compounds mentioned
above. For example, the compounds can be administered, in single or
multiple doses, by oral administration at a dosage level of, for
example, 0.0001-10 mg/kg/day, e.g., 0.01-10 mg/kg/day. Unit dosage
forms can contain, for example, 1-200 mg of active compound. For
intravenous administration, the compounds can be administered in
single or multiple dosages.
[0511] In carrying out the procedures of the present invention it
is of course to be understood that reference to particular buffers,
media, reagents, cells, culture conditions and the like are not
intended to be limiting, but are to be read so as to include all
related materials that one of ordinary skill in the art would
recognize as being of interest or value in the particular context
in which that discussion is presented. For example, it is often
possible to substitute one buffer system or culture medium for
another and still achieve similar, if not identical, results. Those
of skill in the art will have sufficient knowledge of such systems
and methodologies so as to be able, without undue experimentation,
to make such substitutions as will optimally serve their purposes
in using the methods and procedures disclosed herein.
[0512] The present invention will now be further described by way
of the following non-limiting examples. In applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods disclosed according to the
present invention will no doubt suggest themselves to those of
skill in the relevant art.
[0513] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0514] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference.
[0515] Using the following procedures and further procedures
described below, the following compounds in Examples 1-315 were
prepared. Other synthesis examples are described in U.S. patent
application Ser. No. 10/669,645, hereby incorporated by
reference.
EXAMPLES
[0516] All spectra were recorded at 300 MHz on a Bruker Instruments
NMR unless otherwise stated. Coupling constants (J) are in Hertz
(Hz) and peaks are listed relative to TMS (.delta. 0.00 ppm).
Microwave reactions were performed using a Personal Chemistry
Optimizer.TM. microwave reactor in 2.5 mL or 5 mL Personal
Chemistry microwave reactor vials. All reactions were performed at
200.degree. C. for 600 s with the fixed hold time ON unless
otherwise stated. Sulfonic acid ion exchange resins (SCX) were
purchased from Varian Technologies. Analytical HPLC was performed
on 4.6 mm.times.100 mm Xterra RP.sub.18 3.5.mu. columns using a
gradient of 20/80 to 80/20 water (0.1% formic acid)/acetonitrile
(0.1% formic acid) over 6 min. Preparative HPLC was performed on 30
mm.times.100 mm Xtera Prep RP.sub.18 5.mu. columns using an 8 min
gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile
(0.1% formic acid).
[0517] Acid Preparations.
[0518] The following procedures (1-27) detail the preparation of
the indazole, benzothiazole, benzisothiazole, and benzisoxazole
acids that were not commercially available.
[0519] Procedure 1
[0520] Procedure 1 provides a method of preparation of
1,3-benzothiazole carboxylic acids from chloro nitrobenzoic
acids.
[0521] To a solution of 4-chloro-3-nitrobenzoic acid (99.2 mmol) in
N,N-dimethylformamide (400 mL) was added potassium carbonate (254
mmol). After 30 min, ethyl iodide (119 mmol) was added and the
reaction mixture was heated at 50.degree. C. for 4 h. Water (3 L)
was added and the mixture was extracted with diethyl ether
(2.times.500 mL). The organic extracts were combined, washed with
brine (1 L), dried over anhydrous sodium sulfate and concentrated.
The residue was crystallized from hexanes, thus providing the ester
in 86% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.51 (d,
1H), 8.17 (dd, 1H), 7.65 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).
[0522] Sulfur (49.91 mmol) was dissolved in a solution of sodium
sulfide nonahydrate (49.96 mmol) in water (60 mL). This solution
was combined with a solution of ethyl 4-chloro-3-nitrobenzoate
(85.36 mmol) in ethanol (100 mL) and the resulting mixture was
heated at reflux for 3 h. The hot reaction mixture was poured into
water (600 mL) and maintained for 15 min. The product was isolated
by filtration and recrystallized from ethanol, thus providing the
disulfide in 77% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H), 1.41 (t,
3H).
[0523] A mixture of diethyl 4,4'-dithiobis(3-nitrobenzoate) (24.8
mmol) and zinc granules (234 mmol) in formic acid (600 mL) was
heated to reflux for 48 h. The mixture was allowed to cool to room
temperature and concentrated to dryness. The residue was
partitioned between ethyl acetate (500 mL) and saturated aqueous
sodium bicarbonate (500 mL). The organic layer was separated, dried
over anhydrous sodium sulfate and concentrated. The residue was
chromatographed on neutral Alumina (1/1 to 0/1
hexanes/dichloromethane), thus providing the thiazole in 51% yield.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.08 (s, 1H), 8.83 (d,
1H), 8.14 (dd, 1H), 8.02 (d, 1H), 4.45 (q, 2H), 1.44 (t, 3H); MS
(EI) m/z 208 (M.sup.++1).
[0524] To a solution of ethyl 1,3-benzothiazole-5-carboxylate (25.6
mmol) in a mixture of methanol (150 mL), tetrahydrofuran (40 mL)
and water (5 mL) was added a 50% aqueous solution of sodium
hydroxide (10 mL). The mixture was maintained at rt for 18 h and
was concentrated. The residue was partitioned between water (300
mL) and diethyl ether (200 mL) and the organic layer was removed.
Concentrated hydrochloric acid was added to the aqueous layer to
adjust the pH to 4 and the mixture was extracted with ethyl acetate
(3.times.300 mL). The combined extracts were washed with brine (200
mL), dried over anhydrous sodium sulfate, and concentrated thus
providing the acid in 94% yield.
[0525] The following acids were prepared using this method:
[0526] 1,3-benzothiazole-5-carboxylic acid
[0527] 1,3-benzothiazole-6-carboxylic acid
[0528] Procedure 2
[0529] Procedure 2 provides a method for the preparation of
1,3-benzothiazole-7-carboxylic acid from ethyl 3-aminobenzoate.
[0530] A solution of ethyl 3-aminobenzoate (90 mmol) in
chlorobenzene (100 mL) was cooled to -10.degree. C. and treated
with sulfuric acid (45 mmol), dropwise. After 15 min, solid
potassium thiocyanate (95 mmol) was added in several portions over
30 min followed by 18-crown-6 (250 mg). The mixture was heated at
100.degree. C. for 10 h, allowed to cool to rt, and was maintained
for an additional 4 h. The precipitated solids were isolated by
filtration and were washed successively with chlorobenzene (25 mL)
and hexanes (3.times.100 mL). The solid was suspended in water (300
mL) and the suspension was maintained 30 min. The product was
isolated by filtration and washed with water (2.times.100 mL). The
product was dried in a vacuum oven (55.degree. C.) for 16 h, thus
providing the thiocarbamate in 69% yield. .sup.1H NMR (500 MHz,
Me.sub.2SO-d.sub.6) .delta. 1.32 (t, J=7.5, 3H), 4.32 (q, J=7, 2H),
7.44-7.47 (m, 2H), 7.68-7.76 (m, 3H), 8.05 (s, 1H), 9.86 (s, 1H);
MS (APCI) m/z 225 (M.sup.++1).
[0531] A solution of thiocarbamate (12.2 mmol) in chloroform (10
mL) was added dropwise over a period of 40 min to a vigorously
maintained mixture of ethyl 3-[(aminocarbonothioyl)amino]benzoate
(5.78 mmol), glacial acetic acid (10 mL) and chloroform (10 mL).
The mixture was maintained 30 min at rt and then was heated at
70.degree. C. for 4 h. The mixture was allowed to cool to room
temperature and maintained for an additional 13 h. The volatiles
were removed under reduced pressure and the solid residue was
suspended in a mixture of chloroform (10 mL) and acetone (10 mL).
The product was isolated by filtration, washed successively with
acetone (5 mL) and hexanes (10 mL), and dried in a vacuum oven,
thus providing the product in 95% yield as a mixture of ethyl
2-amino-1,3-benzothiazole-7-carboxylate hydrobromide and ethyl
2-amino-1,3-benzothiazole-5-carboxylate hydrobromide in a ratio of
95/5, respectively. This product was partitioned between saturated
aqueous solution of sodium bicarbonate (25 mL) and a mixture of
ethyl acetate (70 mL) and tetrahydrofuran (30 mL). The organic
layer was separated, dried over anhydrous sodium sulfate and
concentrated. The residue was crystallized form ethyl acetate, thus
providing pure ethyl 2-amino-1,3-benzothiazole-7-carboxylate.
.sup.1H NMR (500 MHz, Me.sub.2SO-d.sub.6) .delta. 1.35 (t, J=7.5,
3H), 4.36 (q, J=7, 2H), 7.35 (t, J=7.5, 1H), 7.57 (d, J=7, 1H),
7.61 (bs, 2H), 7.65 (d, J=8, 1H); MS (EI) m/z 223 (M.sup.++1).
[0532] iso-Amylnitrite (53 mmol) was added to a solution of ethyl
2-amino-1,3-benzothiazole-7-carboxylate (5.40 g) in tetrahydrofuran
(70 mL) and the mixture was heated at reflux for 4 h. The volatiles
were removed under reduced pressure and the residue was purified by
chromatography (0/100 to 5/95 methanol/dichloromethane), thus
providing the ester in 71% yield. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 1.47 (t, J=7.5, 3H), 4.49 (q, J=7, 2H), 7.62 (t, J=8, 1H),
8.20 (d, J=6.5, 1H), 8.33 (d, J=8, 1H), 9.12 (s, 1H); MS (EI) m/z
208 (M.sup.++1). A 50% aqueous sodium hydroxide (10 mL) was added
to a 0.degree. C. solution of ethyl 1,3-benzothiazole-7-carboxylate
(16.89 mmol) in a mixture of methanol (65 mL), tetrahydrofuran (20
mL) and water (5 mL). The mixture was maintained at room
temperature for 4 h and the volatiles were removed under reduced
pressure. The residue was dissolved in water (100 mL) and
concentrated hydrochloric acid was added to adjust the pH of the
solution to 5. The mixture was cooled to 0.degree. C. and
maintained for 30 min. The product was isolated by filtration,
washed with water (10 mL), and dried in vacuum oven (70.degree. C.)
for 16 h, thus providing the acid in 91% yield. .sup.1H NMR (500
MHz, Me.sub.2SO-d.sub.6) .delta. 7.71 (t, J=7.5, 1H), 8.15 (d, J=7,
1H), 8.38 (d, J=8, 1H), 9.51 (s, 1H), 13.74 (bs, 1H); MS (APCI) m/z
178 (M.sup.+-1).
[0533] Literature reference: Kunz et. al. U.S. Pat. No.
5,770,758.
[0534] Procedure 3
[0535] Procedure 3 provides a preparation of substituted
benzisothiazole-3-carboxylic acids from the corresponding
thiophenols.
[0536] To a solution of 3-methoxythiophenol (26.7 mmol) in ether
(20 mL) was added oxalyl chloride (43 mmol) dropwise. 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.degree. C., and was treated with aluminum
chloride (32.0 mmol) in portions. The mixture was heated at reflux
for 30 min, cooled to rt, and poured onto ice water with stirring.
The organic layer was separated and successively washed with
saturated, aqueous sodum bicarbonate, water, and brine. The organic
layer was dried over magnesium sulfate, filtered and concentrated
in vacuo. The residue was purified by chromatography (4/1 ethyl
acetate/hexane), thus providing
6-methoxy-1-benzothiophene-2,3-dione in 47% yield as an orange
solid.
[0537] To a mixture of the dione (0.44 mmol) in 30% aqueous
solution of ammonium hydroxide (2.0 mL) was added 35% aqueous
solution hydrogen peroxide (0.2 mL) and the reaction mixture was
maintained for 12 h. The precipitated pink solids were isolated by
filtration, washed with water, and dried under high vacuum, thus
providing the amide in 42% yield.
[0538] To a solution of the amide (5.46 mmol) in methanol (100 mL)
was added 10 N sodium hydroxide (12 mL). The mixture was heated at
reflux for 12 h, cooled to rt, and was acidified to pH<2 by the
slow addition of conc. hydrochloric acid. The organic layer was
extracted with dichloromethane (2.times.) and was dried over sodium
sulfate. The crude product was purified by chromatography (300/50/1
dichloromethane/methanol- /formic acid), thus providing the acid in
89% as a pink solid. LC/MS (EI) t.sub.R 6.17 min, m/z 210
(M.sup.++1).
[0539] The following acids were prepared by this method:
[0540] Benzisothiazole-3-carboxylic acid.
[0541] 6-Bromobenzisothiazole-3-carboxylic acid.
[0542] 5-Bromobenzisothiazole-3-carboxylic acid.
[0543] 6-Methoxybenzisothiazole-3-carboxylic acid
[0544] 7-Methoxybenzisothiazole-3-carboxylic acid.
[0545] 6-Trifluoromethoxybenzisothiazole-3-acid.
[0546] 6-Ethoxybenzisothiazole-3-acid.
[0547] 6-Cyclopropylmethoxybenzisothiazole-3-acid.
[0548] Procedure 4
[0549] Procedure 4 provides a method for the preparation of isatins
from anilines and the conversion of the isatins to the
corresponding indazole-3-carboxylic acids.
[0550] A solution of the substituted aniline (565 mL) in 6N
hydrochloric acid (106 mL) was added to a suspension of
2,2,2-trichloro-1-ethoxyethano- l (678 mL) and sodium sulfate (3.15
mol) in water (1.4 L) and the reaction mixture was stirred
vigorously for 1 h. A solution of hydroxylamine hydrochloride (2.08
mol) in water (650 mL) was added in one portion and the reaction
mixture was heated at 80.degree. C. for 1.5 h. The reaction mixture
was cooled to 10.degree. C. and the precipitated solids were
collected by filtration, washed with water, and dried to provide
the amide in 91% yield.
[0551] The amide was added to sulfuric acid (1.9 L) and the
reaction mixture was heated at 60.degree. C. for 6 h. The reaction
mixture was allowed to cool to room temperature and was cautiously
poured onto ice (7 kg). The precipitated solids were collected by
filtration, washed with water, and dried to provide the isatin in
61% yield.
[0552] The conversion of the substituted isatins to the
corresponding indazole-3-carboxylic acids is essentially the same
method as described for indazole-3-carboxylic acid: Snyder, H. R.,
et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin
(22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was
heated at 50.degree. C. for 30 min. The burgundy solution was
allowed to cool to rt and was maintained for 1 h. The reaction
mixture was cooled to 0.degree. C. and was treated with a 0.degree.
C. solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This
solution was added through a pipet submerged below the surface of a
vigorously stirred solution of sulfuric acid (2.3 mL) in water (45
mL) at 0.degree. C. The addition took 15 min and the reaction was
maintained for an additional 30 min. A cold (0.degree. C.) solution
of tin (II) chloride dihydrate (52.7 mmol) in concentrated
hydrochloric acid (20 mL) was added to the reaction mixture over 10
min and the reaction mixture was maintained for 60 min. The
precipitated solids were isolated by filtration, washed with water,
and dried to give a quantitative mass balance. This material was of
sufficient purity (.sup.1H NMR and LC/MS) to use in the next step
without further purification. Alternatively, the acid was
recrystallized from acetic acid to provide pure material.
[0553] The following acids were prepared using this method:
[0554] 5-Chloro-1H-indazole-3-acid.
[0555] 7-Methoxy-1H-indazole-3-acid.
[0556] 5-Fluoro-1H-indazole-3-acid.
[0557] 6-Fluoro-1H-indazole-3-acid.
[0558] 5-Bromo-1H-indazole-3-acid.
[0559] 6-Bromo-1H-indazole-3-acid.
[0560] 5-Trifluoromethoxy-1H-indazole-3-acid.
[0561] 6-Trifluoromethyl-1H-indazole-3-acid.
[0562] 5-Methoxy-1H-indazole-3-acid.
[0563] 6-Methoxy-1H-indazole-3-acid.
[0564] 5-Methyl-1H-indazole-3-carboxylic acid.
[0565] Procedure 5
[0566] Procedure 5 provides a method for the preparation of
bromoindazoles from bromomethylanilines.
[0567] Acetic anhydride (2.27 equiv.) was added to a cooled
(0.degree. C.) solution of bromomethylaniline (1.00 equiv.) in
chloroform (1.5 mL/mmol) while maintaining the temperature below
40.degree. C. The reaction mixture was allowed to warm to room
temperature and was maintained for 1 h. Potassium acetate (0.29 eq)
and isoamyl nitrite (2.15 equiv.) was added and the reaction
mixture was heated at reflux for 18 h. The volatiles were removed
under reduced pressure. Water (0.65 L/mol) was added to the residue
and the mixture was concentrated. Concentrated hydrochloric acid (1
L/mol) was added to the residue and the mixture was heated at
50.degree. C. for 2 h. The mixture was allowed to cool to room
temperature and the pH was adjusted to 10 by the slow addition of a
50% aqueous sodium hydroxide solution. The mixture was diluted with
water (0.65 L/mol) and was extracted with ethyl acetate
(2.times.1.2 L/mol). The combined extracts were washed with brine
(1 L/mol) and dried over anhydrous sodium sulfate. The organic
solution was filtered through a plug of silica gel (ethyl acetate
wash), concentrated, and the residue was triturated with heptane (1
L/mol). The solids were collected by filtration, rinsed with
heptane, and dried in a vacuum oven, thus providing the brominated
indazole in 60-80% yield.
[0568] Literature reference: George V. DeLucca, U.S. Pat. No.
6,313,110.
[0569] The following indazoles were prepared using this method:
[0570] 5-Bromo-1H-indazole.
[0571] 6-Bromo-1H-indazole.
[0572] Procedure 6
[0573] Procedure 6 provides a method for the preparation of
indazole carboxylic acid from bromoindazole.
[0574] To a solution of bromoindazole (1.00 equiv.) in anhydrous
tetrahydrofuran (7 L/mol) at room temperature was added sodium
hydride (60% in mineral oil, 1.11 equiv.) in several portions. The
resulting solution was maintained for 30 min at room temperature
and was then cooled to -60.degree. C. A 1.3 M solution of
sec-butyllithium in cyclohexane (2.1 equiv.) was added to the
reaction mixture while maintaining the internal temperature below
-50.degree. C. The mixture was maintained for an additional 2 h at
-50.degree. C. A steady stream of anhydrous carbon dioxide was
bubbled through the reaction mixture for 1 h. The flow was
continued while the reaction mixture was allowed to warm to room
temperature. Brine (6 L/mol) was added and the pH of the mixture
was adjusted to 5 with concentrated hydrochloric acid. The mixture
was extracted with warm ethyl acetate (3.times.8 L/mol) and the
combined extracts were washed with small volume of brine, dried
over anhydrous sodium sulfate, and concentrated. The residue was
purified by chromatography on silica gel or by crystallization,
thus providing the acid in 30-60% yield.
[0575] The following indazoles were prepared using this method:
[0576] 1H-Indazole-5-carboxylic acid.
[0577] 1H-Indazole-6-carboxylic acid.
[0578] Procedure 7
[0579] Procedure 7 provides a preparation of
1H-indazole-7-carboxylic acid from 2-amino-3-methylbenzoic
acid.
[0580] To a solution of 2-amino-3-methylbenzoic acid (66.9 mmol) in
N,N-dimethylformamide (200 mL) was added cesium carbonate (102
mmol). The mixture was stirred for 30 min.
[0581] A solution of methyl iodide (67.0 mmol) in
N,N-dimethylformamide (50 mL) was added dropwise and the reaction
mixture was maintained for 18 h at rt. The reaction mixture was
partitioned between water (1 L) and ether (200 mL) and the water
layer was extracted with an additional volume of ether (100 mL).
The combined extracts were washed with brine (500 mL), dried over
anhydrous potassium carbonate, and concentrated, thus providing
methyl 2-amino-3-methylbenzoate in 92% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82
(bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H).
[0582] To a solution of the ester (106 mmol) in chloroform (300 mL)
was added acetic anhydride (239 mmol) while maintaining the
temperature below 40.degree. C. The reaction mixture was maintained
at room temperature for 1 h when potassium acetate (30.6 mmol) and
isoamyl nitrite (228 mmol) was added. The reaction mixture was
heated at reflux for 24 h and was allowed to cool to room
temperature. The reaction mixture was washed with a saturated,
aqueous solution of sodium bicarbonate, dried over sodium sulfate,
and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100
mL) were added to the residue and the mixture was maintained for 18
h at rt. The volatiles were removed under reduced pressure and the
residue was triturated with ethyl acetate (100 mL). The product was
isolated by filtration, washed with ethyl acetate (20 mL), and
dried, thus providing methyl 1H-indazole-7-carboxylate
hydrochloride in 68% yield. .sup.1H NMR (500 MHz,
Me.sub.2SO-d.sub.6) .delta. 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d,
1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177
(M.sup.++1).
[0583] A solution of the indazole (33.0 mmol) in methanol (100 mL)
at 0.degree. C. was treated with an 29% aqueous solution of
potassium hydroxide (20 mL). The reaction mixture was allowed to
warm to rt and was maintained for 18 h. The pH of the solution was
adjusted to 5.5 by the addition of concentrated hydrochloric acid
and the volatiles were removed under reduced pressure. The residue
was partitioned between brine (100 mL) and ethyl acetate (200 mL)
and the aqueous layer was extracted with additional warm ethyl
acetate (200 mL). The combined organic extracts were dried over
anhydrous sodium sulfate and concentrated. The residue was
triturated with ethyl acetate (30 mL) and the solids were isolated
by filtration, thus providing the acid in 94% yield.
[0584] Procedure 8
[0585] Procedure 8 provides a method for the preparation of
5-nitroindazole-3-acid from ethyl indazole-3-carboxylate.
[0586] Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20
mL concentrated sulfuric acid and the reaction mixture was cooled
to 0.degree. C. A mixture of concentrated sulfuric acid (12 mL) and
70% nitric acid (12 mL) was added dropwise over the course of 1 h.
The mixture was stirred for an additional 1 h at 0.degree. C. and
was poured onto of crushed ice (200 g). The solid was collected by
vacuum filtration, washed with several portions of water and dried
in vacuo. The dried solid was suspended in 250 mL acetonitrile and
the mixture was heated at reflux for 2 h. The mixture was allowed
to cool to room temperature and the solid was collected and dried
in vacuo, thus providing ethyl 5-nitroindazole-3-carboxylate in 53%
yield as a colorless solid and ethyl 7-nitroindazole-3-carboxylate
(5%) as a colorless solid. The esters were saponified using sodium
hydroxide to provide the acids.
[0587] Literature reference: Org. Synthesis, Coll. Vol. 1, page
372.
[0588] The following acids were prepared using this method:
[0589] 5-Nitro-1H-indazole-3-carboxylic acid.
[0590] 7-Nitro-1H-indazole-3-carboxylic acid.
[0591] Ethyl 5-nitro-1H-indazole-3-carboxylate.
[0592] Ethyl 7-nitro-1H-indazole-3-carboxylate.
[0593] Procedure 9
[0594] Procedure 9 provides a method for the preparation of
6-nitroindazole-3-acid from 3-iodo-6-nitroindazole.
[0595] A 5 mL microwave reaction vessel was charged with
3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and
N,N-dimethylformamide (3 mL). The vessel was sealed and subjected
to microwave irradiation at 185.degree. C. for 600 sec. The
reaction mixture was partitioned between ethyl acetate (100 mL) and
water (100 mL) and the mixture was filtered through Celite. The
organic layer was collected, washed with brine, dried (magnesium
sulfate), and concentrated to give 122 mg of a 10 to 1 mixture of
3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The
10 to 1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole was
dissolved in 10 N sodium hydroxide and the bright orange solution
was heated at 100.degree. C. for 1 h. The mixture was allowed to
cool to room temperature and carefully acidified to pH 1 with 3 N
hydrochloric acid. The solid was isolated and triturated with
EtOAc, thus providing 51 mg of 6-nitroindazole-3-carboxyl- ic acid
as a brown solid.
[0596] 3-Iodo-6-nitroindazole was prepared from 6-nitroindazole
using the method of Collot, V.; et. al. Tetrahedron 1999, 55,
6917.
[0597] Procedure 10
[0598] Procedure 10 provides a method for the trapping of indazole
aryllithiums with ketones and the coupling with 3-aminoquinuclidine
to form heterocyclic derivatives.
[0599] tert-Butyl 6-bromoindazole-3-carboxylate was prepared from
the acid by reaction with a 2-fold excess of
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) at 0.degree. C.
was slowly added a solution of tert-butyl
6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL).
After stirring for 0.5 h at 0.degree. C., the mixture was cooled to
-78.degree. C. and a 1.7 M solution of tert-butyllithium in pentane
(5.1 mmol) was added. After 0.5 h at -78.degree. C., a solution of
tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added
dropwise. The mixture was stirred at -78.degree. C. for 1 h and
warmed to 0.degree. 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 yield
6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid
tert-butyl ester (68%) as a colorless solid.
[0600] 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic
acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic
acid (3 mL) and the mixture was maintained at room temperature for
16 h. The solvent was removed in vacuo and the residue was
triturated with ethyl acetate to provide
6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%).
The acids were coupled with quinuclidine amine according to
procedure A.
[0601] 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic
acid tert-butyl ester (1.0 mmol) was taken up in 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 provide
6-(tetrahydropyran-4-yl)-1H-inda- zole-3-carboxylic acid (60%) as a
tan solid.
[0602] The following acids were prepared using this method:
[0603]
6-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H-indazole--
3-carboxylic acid.
[0604]
5-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
[0605]
6-(4-Hydroxytetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
[0606] 5-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
[0607] 6-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
[0608] 5-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
[0609] 6-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
[0610] 5-Formyl-1H-indazole-3-carboxylic acid.
[0611] 6-Formyl-1H-indazole-3-carboxylic acid.
[0612] Procedure 11
[0613] Procedure 11 provides a method for the preparation of
4-bromo-5-methoxyindazole-3-carboxylic acid from ethyl
5-methoxyindazole-3-carboxylate and describes further modifications
to produce 4-substituted 5-methoxyindazole-3-acids.
[0614] N-Bromosuccinimide (24.0 mmol) was added to a solution of
ethyl 5-methoxyindazole-3-carboxylate (20.0 mmol) in acetonitrile
(200 mL). The reaction mixture was maintained for 16 h and was
partitioned between water (150 mL) and ethyl acetate (250 mL). The
layers were separated and the organic layer was washed with brine
(50 mL), dried (magnesium sulfate), and concentrated. The residue
was purified by chromatography using a gradient of 90/10 to 70/30
hexanes/ethyl acetate, thus providing the 4-brominated product in
57% yield and trace quantities of the 6-brominated product. The
4-brominated ester was further derivatized using Suzuki (procedure
G; 60-70% yields) or Negishi (procedure H; 20-40% yields) reaction
conditions described below. The ester (3.82 mmol) was diluted with
ethanol (10.0 mL) and 5 M sodium hydroxide (10.0 mL) and the
reaction mixture was maintained for 4 h at ambient temperature. The
reaction mixture was diluted with water (50 mL) and acidified to pH
1 with 6 N hydrochloric acid. The solids were collected by
filtration, thus providing the acids in 80-95% yield.
[0615] The following compounds were prepared by this method:
[0616] 4-Bromo-5-methoxy-1H-indazole-3-carboxylic acid.
[0617] 6-Bromo-5-methoxy-1H-indazole-3-carboxylic acid.
[0618] 7-Bromo-6-methoxy-1H-indazole-3-carboxylic acid.
[0619] 5-Bromo-6-methoxy-1H-indazole-3-carboxylic acid.
[0620] 5-Methoxy-4-(thiophen-2-yl)-1H-indazole-3-carboxylic
acid.
[0621] 5-Methoxy-4-(thiophen-3-yl)-1H-indazole-3-carboxylic
acid.
[0622] 6-Methoxy-5-(thiophen-3-yl)-1H-indazole-3-carboxylic
acid.
[0623] 5-Cyclopropyl-6-methoxy-1H-indazole-3-carboxylic acid.
[0624] Procedure 12
[0625] Procedure 12 provides a method for the preparation of
5-bromo-4-nitroindazole-3-carboxylic acid from ethyl
5-bromoindazole-3-carboxylate.
[0626] Ethyl 5-bromo-1H-indazole-3-carboxylate (5.02 mmol) was
dissolved in sulfuric acid (20.0 mL) and was cooled to 0.degree. C.
A mixture of 70% nitric acid (7/3, nitric acid/water, 1.0 mL) and
sulfuric acid (2.0 mL) was added dropwise and the reaction was
maintained for 1 hour at 0.degree. C. The reaction mixture was
poured onto 100 mL of ice water and the solids collected by
filtration, thus providing the product in 86% yield. The ester
(3.82 mmol) was diluted with ethanol (10.0 mL) and 5 M sodium
hydroxide (10.0 mL) and the reaction mixture was maintained for 4 h
at ambient temperature. The reaction mixture was diluted with water
(50 mL) and acidified to pH 1 with 6 N hydrochloric acid. The
solids were collected by filtration, thus providing the acid in 82%
yield
[0627] Procedure 13
[0628] Procedure 13 provides a method for the preparation of
N-1-alkylated indazole-3-carboxylic acids from the corresponding
indazole ester.
[0629] 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.degree. C. for 4 hours, allowed to cool to ambient temperature,
and was partitioned between water (50 mL) and ethyl acetate (50
mL). The layers were separated and the organic later 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 provide the 2-substituted
indazole (17%) and the 1-substituted indazole (44%). The
1-substituted indazole (61 mg, 0.26 mmol) was suspended in ethanol
(5.0 mL) and was 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 maintained at ambient temperature for 16
h. The reaction mixture was diluted with water (50 mL) and was
acidified with 6.0 N hydrochloric acid. The aqueous layer was
extracted with ethyl acetate (3.times.50 mL) and the combined
organic layers were washed with brine (25 mL), dried (magnesium
sulfate), and concentrated, thus providing the acid in 95%
yield.
[0630] The following compounds were prepared by this method:
[0631] 5-Methoxy-1-methyl-1H-indazole-3-carboxylic acid.
[0632] 5-Methoxy-1-ethyl-1H-indazole-3-carboxylic acid.
[0633] 5-Methoxy-1-cyclopentyl-1H-indazole-3-carboxylic acid.
[0634] 5-Methoxy-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic
acid.
[0635] 5-Bromo-1-methyl-1H-indazole-3-carboxylic acid.
[0636] 5-Bromo-1-ethyl-1H-indazole-3-carboxylic acid.
[0637] 5-Bromo-1-cyclopropylmethyl-1H-indazole-3-carboxylic
acid.
[0638] 5-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic
acid.
[0639] 6-Bromo-1-methyl-1H-indazole-3-carboxylic acid.
[0640] 6-Bromo-1-ethyl-1H-indazole-3-carboxylic acid.
[0641] 6-Bromo-1-cyclopropylmethyl-1H-indazole-3-carboxylic
acid.
[0642] 6-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carboxylic
acid.
[0643] 1-Benzyl-6-difluoromethoxy-1H-indazole-3-carboxylic
acid.
[0644] 1-Benzyl-5-difluoromethoxy-1H-indazole-3-carboxylic
acid.
[0645] Procedure 14
[0646] Procedure 14 provides a method for the demethylation of
methoxyindazole acids and the coupling with 3-aminoquinuclidine to
form hydroxy-substituted derivatives.
[0647] The methoxy indazole acid (10.4 mmol) was diluted with
dichloromethane (100 mL) and the solution was cooled to -78.degree.
C. A 1.0 M solution of boron tribromide in dichloromethane (52
mmol, 5 eq.) was added dropwise over 30 min. The reaction mixture
was allowed to warm to room temperature and was maintained for 24
h. The reaction was slowly quenched with MeOH (100 mL) and
concentrated to dryness. The residue was purified by chromatography
using a gradient of hexane/ethyl acetate (100/0 to 80/20) followed
by elution with a mixture of ethyl acetate/methanol/triethylamine
(70/30/1), thus providing the phenol (60-80%) as a brown solid.
This procedure was also applied to
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide,
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide,
and the benzisothiazole analogs with success.
[0648] The following compounds were prepared using this method:
[0649] 5-Hydroxy-1H-indazole-3-carboxylic acid.
[0650] 6-Hydroxy-1H-indazole-3-carboxylic acid.
[0651] 5-Hydroxy-1,2-benzisothiazole-3-carboxylic acid.
[0652] 6-Hydroxy-1,2-benzisothiazole-3-carboxylic acid
[0653] Procedure 15:
[0654] Procedure 15 provides a method for the preparation of
7-fluoro-6-methoxy-1H-indazole-3-carboxylic acid and
4-fluoro-5-methoxy-1H-indazole-3-carboxylic acid from the
corresponding methoxyindazole acids.
[0655] 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (1.00 g, 2.82 mmol) was added to a solution
of ethyl 6-methoxy-1H-indazole-3-carboxylate (500 mg, 2.27 mmol) in
acetonitrile (15.0 mL) and the reaction mixture was maintained at
rt for 18 h. The reaction was partitioned between water (50 mL) and
ethyl acetate (50 mL) and the separated organic layer was washed
with brine (25 mL), dried (magnesium sulfate), and concentrated.
The residue was purified by chromatography (95/5 to 80/20
hexanes/ethyl acetate) to yield 541 mg (23%) of the fluorinated
ester. A solution of the ester (124 mg, 0.520 mmol) in ethanol
(5.00 mL) was diluted with 5.0 M of sodium hydroxide (2.00 mL) and
the mixture was maintained at rt for 18 h. The reaction was
acidified with 6 N hydrochloric acid and partitioned between water
(50 mL) and ethyl acetate (50 mL). The layers were separated and
the organic washed with brine (25 mL), dried (magnesium sulfate),
and concentrated in vacuo to yield 109 mg (84%) of the acid.
[0656] The acid was coupled with the bicyclobase according to
procedure A.
[0657] The following acid was prepared using this method:
[0658] 7-Fluoro-6-methoxy-1H-indazole-3-carboxylic acid.
[0659] 4-Fluoro-5-methoxy-1H-indazole-3-carboxylic acid.
[0660] Procedure 16:
[0661] Procedure 16 details the preparation of ethyl
benzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.
[0662] Diethyl malonate (12.6 g, 79 mmol) was added to a suspension
of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml)
over 30 min. The temperature of the reaction rose to 60.degree. C.
and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0
mmol) was added and the solution was maintained for 2 h at
100.degree. C. The reaction mixture was allowed to cool to rt and
was poured into ice (300 g-400 g). The precipitated solids were
isolated by filtration and dried to provide 11.0 g of the product
(89%).
[0663] The ester (11.0 g, 32.0 mmol) was diluted with a 2 N
solution of sodium hydroxide (32 mL, 63 mmol) and the reaction
mixture was maintained at room temperature for 16 h. The aqueous
layer was extracted with dichloromethane (20 mL) and was acidified.
The precipitated solids were isolated by filtration and dried to
provide 7.00 g of the acid (89%).
[0664] Sulfuric acid (1 mL) was added to a solution of the acid
(7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was
warmed to reflux, maintained for 2 h, and was concentrated under
reduce 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 provide 8.00 g (98%) of the ester as a liquid.
[0665] Isoamylnitrite (225 mL) was added to a solution of the ester
(420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round
bottom flask and the mixture was warmed to 60.degree. 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 h. The reaction mixture was allowed to cool to rt
and was neutralized with 2 N hydrochloric acid. The reaction
mixture was extracted with ethyl acetate (4.times.2 L) and the
combined organic layers were washed with water (2.times.1 L) and
brine (2.times.1 L) and dried (sodium sulfate). The residue was
purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to
provide 110 g of the product (28%).
[0666] 10% Palladium on carbon (1.5 g) and triethylamine (7.5 g,
82.4 mmol) were added to a solution of ethyl
6-bromobenzisoxazole-3-carboxylat- e (20 g, 0.081 mol) in ethanol
(300 ml) at 0.degree. C. under an atmosphere of nitrogen. The
nitrogen atmosphere was removed by evacuation and replaced with
hydrogen gas, and the reaction mixture was maintained for 1 hour.
The hydrogen atmosphere was removed by evacuation and replaced with
nitrogen gas, and the palladium removed by filtration through
Celite. The filter cake was washed with ethanol (3.times.50 mL) and
the filtrates were concentrated. The residue was dissolved in
dichloromethane (200 mL) and the solution was washed with water
(4.times.50 mL), dried (sodium sulfate) and evaporated to provide
13.0 g of the product as a yellow solid (96%). The ester was
saponified using sodium hydroxide to provide the acid which was
coupled with the bicyclobase according to procedure A.
[0667] Literature reference: Angell, R. M.; Baldwin, I. R.;
Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S.
WO04010995A1
[0668] The following acid and esters were prepared using this
method:
[0669] Ethyl 6-bromo-1,2-benzisoxazole-3-carboxylate.
[0670] Ethyl 1,2-benzisoxazole-3-carboxylate.
[0671] 1,2-Benzisoxazole-3-carboxylic acid.
[0672] Procedure 17:
[0673] Procedure 17 provides a method for the preparation of
5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.
[0674] 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 maintained for 15 min at rt. The reaction
mixture was cooled to 0.degree. C. and was treated with ethyl
chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated
at 70.degree. C. for 16 h and was concentrated. The residue was
diluted with ice water (200 mL) and was extracted with ethyl
acetate (3.times.100 mL). The combined organic layers were dried
(magnesium sulfate) and concentrated to provide the difluoromethyl
ether in 75% yield as a yellow oil.
[0675] Diethyl malonate (328 mmol) was added dropwise to a
suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40
mL) at 0.degree. C. The reaction mixture was warmed to 60.degree.
C. and maintained for 0.5 h. A solution of the difluoromethyl ether
(149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the
reaction mixture was heated at 100.degree. C. for 5 h. The cooled
solution was poured onto ice water, and the aqueous layer was
extracted with dichloromethane (3.times.100 mL). The combined
organic layers were dried (magnesium sulfate) and concentrated to
give the crude diester in 112% yield as an oil. The diester (167
mmol), sodium hydroxide (500 mmol), and water (335 mL) were
combined and heated at 60.degree. C. for 1 h. The reaction mixture
was allowed to cool to rt and the aqueous layer was washed with
dichloromethane (3.times.100 mL). The pH of the aqueous layer was
cautiously adjusted to 1 with concentrated hydrochloric acid and
the reaction mixture was heated at 60.degree. C. for 1 h. The
suspension was cooled to 5.degree. C. and the solids were collected
by filtration and dried to provide the acid in 61% yield.
[0676] Acetyl chloride (203 mmol) was added dropwise to ethanol
(300 mL) at 0.degree. C. After 0.5 h, the 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.times.200 mL) and the combined organic layers
were dried (magnesium sulfate) and concentrated to provide the
ester in 60% yield as a brown oil.
[0677] The ester (60.4 mmol) was dissolved in ethanol (103 mL),
diluted with water (71 mL), and was treated with ammonium chloride
(243 mmol) and iron powder (301 mmol). The reaction mixture was
heated at reflux for 10 minutes and the suspension was filtrated
through Celite and the filter cake was washed with ethanol three
times. The filtrate was concentrated, the residue was suspended in
2 N hydrochloric acid and was stirred vigorously for 0.5 h. The
aqueous layer was washed with ethyl acetate (3.times.50 mL) and the
pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer
was extracted with chloroform (3.times.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.times.100 mL) and the combined organic
layers were dried (magnesium sulfate) and concentrated to provide
the N-acetylindazole ester in 79% yield as a brown oil.
[0678] The ester (63.8 mmol), sodium hydroxide (193 mmol), and
water (65 mL) were combined and the reaction was maintained for 24
h at 60.degree. C. After cooling to rt, the aqueous layer was
washed with dichloromethane (3.times.50 mL). The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid. The
precipitated solids were collected by filtration, washed with water
and dichloromethane, and dried to provide the acid in 27%
yield.
[0679] The following acids were prepared according to this
method:
[0680] 5-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
[0681] Procedure 18:
[0682] Procedure 18 provides a method for the preparation of
6-difluoromethoxyindazole-3-acid from 4-nitrophenol.
[0683] 4-Nitrophenol (162 mmol) was added to a suspension of sodium
hydroxide (485 mmol) in N,N-dimethylformamide (150 mL) and the
suspension was maintained for 15 min at rt. The reaction mixture
was cooled to 0.degree. C. and was treated with ethyl
chlorodifluoroacetate (329 mmol). The reaction mixture was heated
at 70.degree. C. for 16 h and was concentrated. The residue was
diluted with ice water (200 mL) and was extracted with ethyl
acetate (3.times.100 mL). The combined organic layers were dried
(magnesium sulfate) and concentrated to provide the difluoromethyl
ether in 59% yield as a yellow oil.
[0684] The nitro ether (149 mmol) was dissolved in ethanol (37.5
mL), diluted with water (25 mL), and was 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 with ethanol
three times and the combined filtrates were concentrated. The
residue was dissolved in water and the pH adjusted to 9-10 with 5 M
sodium hydroxide. The aqueous layer was extracted with ethyl
acetate (3.times.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 maintained at rt for 16 h. The reaction mixture was diluted
with water (50 mL) and was neutralized with solid sodium
bicarbonate. The precipitated solids were isolated by filtration,
washed with water, and dried to provide the acetamide in 62% yield
as a light yellow solid.
[0685] Acetic anhydride (19.6 mmol) was added to a solution of the
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 min. The cooled solution was diluted with water (20 mL) and
the aqueous layer was extracted with dichloromethane (3.times.10
mL). The combined organic layers were dried (magnesium sulfate) and
concentrated to provide the nitro-amide in 83% yield.
[0686] The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and
water (10 mL) were combined and the reaction mixture was maintained
for 1.5 hour at 60.degree. C. the reaction was allowed to cool to
rt and the precipitated solids were isolated by filtration, and
washed with water, and dried to provide the aniline in 98% yield as
a light yellow solid.
[0687] The 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.degree. C. in order to completely dissolve the aniline. The
reaction mixture was cooled to 0.degree. C. and a solution of
sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15
min period. The solution was maintained for 40 minutes at
0-5.degree. C. and filtered. Copper (I) bromide (18.8 mmol) was
dissolved in 40% hydrobromic acid (21 mL) and was cooled to
0.degree. C. The solution of the diazo salt was added slowly to the
copper solution and the mixture was maintained for 30 min at
0-10.degree. C. The reaction mixture was heated at 60.degree. C.
for 30 min and then at 100.degree. C. for 10 min to ensure
completion. The reaction mixture was allowed to cool to rt and was
extracted with dichloromethane (3.times.40 mL). The combined
organic layers were washed with 1 M sodium hydroxide, water, 1 N
hydrochloric acid, and water. The organic layer was dried
(magnesium sulfate) and concentrated to provide the nitro bromide
in 76% yield as a light yellow solid.
[0688] Diethyl malonate (25.7 mmol) was added dropwise to a
suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5
mL) at 0.degree. C. The reaction mixture was warmed to 60.degree.
C. and maintained for 30 min. A solution of the nitro bromide (11.7
mmol) in dimethylsulfoxide (7 mL) was added dropwise and the
reaction mixture was heated at 100.degree. C. for 5 h. The cooled
solution was poured onto ice water and the aqueous layer was
extracted with dichloromethane (3.times.100 mL). The combined
organic layers were dried (magnesium sulfate) and concentrated to
give the crude diester as an oil. The diester (11.7 mmol), sodium
hydroxide (35 mmol), and water (20 mL) were combined and heated at
60.degree. C. for 1 h. The reaction mixture was allowed to cool to
rt and the aqueous layer was washed with dichloromethane
(3.times.100 mL). The pH of the aqueous layer was cautiously
adjusted to 1 with concentrated hydrochloric acid and the reaction
mixture was heated at 60.degree. C. for 1 h. The suspension was
cooled to 0.degree. C. and the solids were collected by filtration
and dried to provide the acid in 64% yield.
[0689] Acetyl chloride (15.3 mmol) was added dropwise to ethanol
(50 mL) at 0.degree. C. After 30 min, the 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.times.20 mL) and the combined organic layers
were dried (magnesium sulfate) and concentrated to provide the
ester in 94% yield as a brown oil.
[0690] Acetic anhydride (6.0 mL) was added to a suspension of the
ester (3.64 mmol), and acetic acid (7.0 mL) at 0.degree. C. Zinc
dust (14.6 mmol) was added in portions over 15 min and the reaction
mixture was maintained for 30 min at 0.degree. C. and then for 1.5
h at rt. Additional zinc powder (6.15 mmol) was added and the
reaction maintained for 3 h. 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.times.20 mL) and the combined organic layers were dried
(magnesium sulfate) and concentrated to provide the acetamide in
92% yield as a brown oil.
[0691] Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol),
and potassium acetate (2.04 mmol) were added to a solution of the
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.times.20 mL) and the combined
organic layers were dried (magnesium sulfate) and concentrated to
provide the crude N-acetylindazole ester as a brown oil.
[0692] The ester (3.36 mmol), sodium hydroxide (10 mmol) and water
(5 mL) were combined and the reaction was maintained for 24 h at
60.degree. C. After cooling to rt, the aqueous layer was washed
with dichloromethane (3.times.30 mL). The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid and the
precipitated solids were collected by filtration, washed with water
and dichloromethane, and dried to provide the acid in 26%
yield.
[0693] The following acids were prepared according to this
method:
[0694] 6-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
[0695] Procedure 19:
[0696] Procedure 19 provides a method for the coupling between
brominated benzisothiazole-3-carboxylic esters and brominated
indazole-3-carboxylic esters and Grignard reagents to form alkyl-
and heterocycle-substituted acids.
[0697] A 0.5 M solution of Grignard reagent (25.0 mmol, 3.7 eq) in
tetrahydrofuran was diluted with tetrahydrofuran (60 mL) and
treated with a 0.5 M solution of zinc chloride (25.0 mmol, 3.7 eq)
in tetrahydrofuran at rt. After 10 min, the brominated ester (0.30
mmol) and bis(triphenylphosphine)palladium (II) chloride (0.95
mmol, 0.1 eq) were added to the suspension. The reaction mixture
was maintained for 1 h at ambient temperature then at 65.degree. C.
for 1 h. The reaction was quenched with saturated ammonium chloride
and was extracted with dichloromethane (3.times.). The extracts
were dried over sodium sulfate and concentrated to dryness. The
residue was purified by chromatography using a gradient of 100/0 to
90/10 dichloromethane/methanol to provide the alkyl- or
aryl-substituted amide. The amide was dissolved in a mixture of
methanol/tetrahydrofuran/water (90/10/20 mL) and was treated with
sodium hydroxide (5.8 g). The mixture was heated at reflux for 12
h, cooled to rt, filtered, and was acidified to pH<2 by the slow
addition of conc. hydrochloric acid. The aqueous layer was
extracted with ethyl acetate (2.times.) and was dried over sodium
sulfate. Concentration of the extracts gave the acid in 38% yield.
The acid was coupled to the bicyclobases according to procedure
A.
[0698] This procedure was used, with slight modifications, to
derivatize brominated indazole-3-piperidine carboxamides with
various Grignard reagents. The Grignard reagent of thiazole is
commercially available. Alternatively, the aryllithium and the
corresponding arylzinc reagent can be generated according to the
procedure outlined by Reeder, M. R.; et. al. Org. Proc. Res. Devel.
2003, 7, 696. The zinc reagents of oxazole, 4-methylthiazole, and
5-methylthiazole were prepared according to this procedure.
[0699] The following acids were prepared using this method:
[0700] 6-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid.
[0701] 5-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid.
[0702] 5-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic
acid.
[0703] 5-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic
acid.
[0704] 6-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic
acid.
[0705] 6-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic
acid.
[0706] 5-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid.
[0707] 6-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid.
[0708] Procedure 20:
[0709] Procedure 20 provides a method for the preparation of alkoxy
indazole acids from the corresponding benzyloxy indazole esters
using alkylation conditions.
[0710] A solution of ethyl 5-(benzyloxy)-1H-indazole-3-carboxylate
(2.70 mmol) in tetrahydrofuran (10 mL) was added dropwise to a
0.degree. C. suspension of sodium hydride (60% mineral oil
dispersion, 8.1 mmol) in tetrahydrofuran (54.0 mL). The reaction
was maintained at 0.degree. C. for 1 h.
[.beta.-(Trimethylsilyl)ethoxy]methyl chloride (3.2 mmol) was added
and the reaction mixture was maintained for 1 h. 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 to 85/15 hexanes/ethyl acetate to provide the
protected indazole in 89% yield.
[0711] Ethyl
5-(benzyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole--
3-carboxylate (9.38 mmol) was added to a suspension of 10%
palladium on carbon (249 mg) in ethanol (66.7 mL). The reaction was
shaken under an atmosphere of hydrogen (50 psi) for 4.0 h. The
reaction was filtered through Celite and concentrated to give the
phenol in 87% yield as a white solid.
[0712] Cyclopropylmethyl bromide (1.19 mmol) and potassium
carbonate (2.38 mmol) was added to a solution of
5-hydroxy-1-(2-trimethylsilanylethoxymet-
hyl)-1H-indazole-3-carboxylic acid ethyl ester (5.94 mmol) in
acetonitrile (10.0 mL) The suspension was heated at 60.degree. C.
for 4.0 h. 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 (100/0 to 85/15 hexanes/ethyl
acetate) to yield the purified ethyl ester. The ester was dissolved
in ethanol (10 mL) and 5 N sodium hydroxide (3 mL) was added. The
mixture was allowed to stand overnight and was diluted with water
(20 mL) and acidified to pH 1 with 3 N hydrochloric acid. The solid
was collected by vacuum filtration to give the acid in 72% yield as
a white solid.
[0713] The following acids were prepared using this method:
[0714]
5-(Cyclopropylmethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazo-
le-3-carboxylic acid.
[0715]
6-(Cyclopropylmethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazo-
le-3-carboxylic acid.
[0716]
5-(Cyclopentyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-
-carboxylic acid.
[0717]
6-(Cyclopentyloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-
-carboxylic acid.
[0718]
5-(2,2,2-Trifluoroethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-ind-
azole-3-carboxylic acid.
[0719]
6-(2,2,2-Trifluoroethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-ind-
azole-3-carboxylic acid.
[0720] Procedure 21:
[0721] Procedure 21 provides a method for the preparation of alkoxy
indazole acids from the corresponding benzyloxy indazole esters
using Mitsunobu conditions.
[0722] Diisopropyl azodicarboxylate (0.618 mmol) was added dropwise
to a solution of ethyl
5-hydroxy-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-
e-3-carboxylate (0.594 mmol), 1-methyl-3-pyrrolidinol (0.594 mmol),
and triphenylphosphine (0.594 mmol) in tetrahydrofuran (3.6 mL).
The reaction was maintained for 16 h and was concentrated. The
residue was purified by chromatography (100/0 to 90/10 ethyl
acetate/[70/30/2 ethyl acetate/methanol/dimethylethylamine] to
provide the ether product in 49% yield. The ester was saponified to
provide the acid which was coupled to the bicyclobase using
Procedure C.
[0723] The following acids were prepared using this method:
[0724]
5-[(1-Methylpyrrolidin-3-yl)oxy]-1-{[2-(trimethylsilyl)ethoxy]methy-
l}-1H-indazole-3-carboxylic acid.
[0725]
5-[(1-Benzylpyrrolidin-3-yl)oxy]-1-{[2-(trimethylsilyl)ethoxy]methy-
l}-1H-indazole-3-carboxylic acid.
[0726]
5-[2-(Dimethylamino)ethoxy]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-i-
ndazole-3-carboxylic acid.
[0727]
5-(2-Pyrrolidin-1-ylethoxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-i-
ndazole-3-carboxylic acid.
[0728]
5-(2,3-Dihydro-1H-inden-2-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-
-1H-indazole-3-carboxylic acid.
[0729]
5-(Tetrahydro-2H-pyran-4-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl--
1H-indazole-3-carboxylic acid.
[0730] Procedure 22:
[0731] Procedure 22 provides a method for the preparation of
1-(3-thienyl)-1H-indazole-3-carboxylic acid from the corresponding
indazole ester.
[0732] Ethyl 1H-indazole-3-carboxylate (5.50 mmol),
3-thienylboronic acid (7.50 mmol), copper (II) acetate (5.01 mmol),
triethylamine (24.7 mmol), and pyridine (40.4 mmol) were dissolved
in 1,4-dioxane (39.8 mL). The reaction was maintained at rt for 16
h and was diluted with water (50 mL) and ethyl acetate (50 mL). The
reaction mixture was filtered through Celite and the organic layer
was washed with brine (25 mL), dried (magnesium sulfate), and
concentrated. The residue was purified by chromatography (90/10 to
70/30 hexanes/ethyl acetate) to yield the N-arylindazole ester in
35% yield. The ester was saponified using standard conditions and
the resultant acid was used in Procedure A.
[0733] Procedure 23:
[0734] Procedure 23 provides a method for the preparation of
1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylic acid from ethyl
6-bromo-7-nitro-1H-indazole-3-carboxylate.
[0735] A 0.50 M solution of zinc chloride in tetrahydrofuran (11
ml) was added to a 0.50 M solution of
(1,3-dioxolan-2-ylmethyl)magnesium bromide in tetrahydrofuran (11
mL) and the reaction mixture was maintained for 20 min. An aliquot
(5.5 mL) of the zinc reagent solution was added to each of 4
microwave tubes containing ethyl
6-bromo-7-nitro-1H-indazole-3-carbo- xylate (143 mmol) and
bis(tri-t-butylphosphine)palladium(0) (26 mg, 0.051 mmol). The
reaction was heated in a microwave reactor at 160.degree. C. for 10
min. The reaction was partitioned between water (50 mL) and ethyl
acetate (50 mL), filtered through Celite and the organic layer was
washed with brine (25 mL), dried (magnesium sulfate), and
concentrated. The residue was purified by chromatography (80/20 to
60/40 hexanes/ethyl acetate) to yield the dioxolane product in 46%
yield.
[0736] Ethyl
6-(1,3-dioxolan-2-ylmethyl)-7-nitro-1H-indazole-3-carboxylate
(0.657 mmol) was added to a suspension of 10% palladium on carbon
(100 mg) in ethanol (30 mL). The reaction mixture was shaken under
an atmosphere of hydrogen gas for 4 h. The reaction mixture was
filtered through Celite and concentrated to give the amine in 94%
yield as an oil.
[0737] Ethyl
7-amino-6-(1,3-dioxolan-2-ylmethyl)-1H-indazole-3-carboxylate
(0.371 mmol) was dissolved in tetrahydrofuran (30 mL) and treated
with 6 M hydrogen chloride (5 mL). The reaction mixture was
maintained for 16 h and was partitioned between water (30 mL) and
ethyl acetate (30 mL). The organic layer was washed with brine (25
mL), dried (magnesium sulfate), and concentrated. The residue was
purified by chromatography (90/10 to 70/30 hexanes/ethyl acetate)
to yield the pyrrolidine in 72% yield.
[0738] Ethyl 1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylate (0.266
mmol) was dissolved in ethanol (2 mL) and 5.0 M of sodium hydroxide
(1.00 mL) and the reaction was maintained for 16 h. The reaction
mixture was neutralized with 3 N hydrochloric acid and was
partitioned between water (30 mL) and ethyl acetate (30 mL). The
layers were separated and the organic layer was washed with brine
(25 mL), dried (magnesium sulfate), and concentrated in vacuo to
provide the acid in 41% yield. The acid was used without further
purification.
[0739] Procedure 24:
[0740] Procedure 24 provides a method for the preparation of
alkoxypyrrolidine substituted indazole-3-carboxylic acids from the
corresponding nitro-1H-indazole-3-carboxylates.
[0741] [.beta.-(Trimethylsilyl)ethoxy]methyl chloride (10.2 mmol)
was added dropwise to a suspension of ethyl
5-nitro-1H-indazole-3-carboxylate (8.50 mmol) and
N,N-diisopropylethylamine (25.5 mmol) in dichloromethane (20.0 mL).
The heterogeneous reaction mixture was maintained at rt for 16 h
whereupon the reaction mixture gradually became homogeneous. The
reaction mixture was filtered through silica gel (ca. 40 g) and
concentrated. The residue was diluted with ethanol (50.0 mL) and
10% palladium on carbon (200 mg) was added under a flow of nitrogen
gas. The reaction was shaken under an atmosphere of hydrogen for 4
h and the reaction mixture was filtered through Celite and
concentrated. The residue was purified by chromatography (70/30 to
50/50 hexanes/ethyl acetate) to yield the aniline in 60% yield as a
2/1 mixture of 1- and 2-SEM regioisomers.
[0742] Ethyl
5-amino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-indazole-3-carb-
oxylate (3.61 mmol) was combined with 1,4-dibromo-2-butanol (3.80
mmol) and potassium carbonate (3.47 mmol) in triethyl phosphate
(10.0 mL) and the reaction was heated at 120.degree. C. for 2 h.
The reaction mixture was loaded onto a SCX column (3.times.10 g)
and flushed with 5 volumes of methanol. The partially purified
product was then eluted using 2.0 M ammonia in methanol and the
product fractions were combined and concentrated. The residue was
purified by chromatography (90/10 to 70/30 hexanes/ethyl acetate)
to provide the pyrrolidine in 55% yield.
[0743] A solution of ethyl
5-(3-hydroxypyrrolidin-1-yl)-1-[2-(trimethylsil-
yl)ethoxy]methyl-1H-indazole-3-carboxylate (0.493 mmol) in
tetrahydrofuran (20.0 mL) was cooled to -78.degree. C. A 0.5 M
solution of potassium bis(trimethylsilyl)amide in toluene (1.18 mL)
was added dropwise and the reaction mixture was maintained for 30
min. 2,2,2-Trifluoroethyl nonafluorobutanesulfonate (0.493 mmol)
was added and the reaction mixture was allowed to warm to room
temperature and was maintained for 4 h. The reaction mixture 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 (90/10 to 80/20 hexanes/ethyl acetate) to yield the
alkoxypyrrolidine in 42% yield.
[0744] The ester (0.172 mmol) was dissolved in ethanol (5.0 mL) by
warming slightly. A 5.0 M of sodium hydroxide (2.00 mL) was added
and the reaction mixture was maintained overnight. The reaction
mixture was diluted with water (50 mL), neutralized to pH 6-7 with
3.0 N hydrochloric acid, and was extracted with ethyl acetate
(2.times.25 mL). The organic layer was washed with brine (25 mL),
dried (magnesium sulfate), and concentrated to provide the acid in
89% yield. The acid was used with no further purification.
[0745] The following acids were prepared by this method:
[0746]
5-[3-(Hydroxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1-
H-indazole-3-carboxylic acid.
[0747]
5-[3-(Methoxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1-
H-indazole-3-carboxylic acid.
[0748]
5-[3-(Benzyloxy)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-
-1H-indazole-3-carboxylic acid.
[0749]
5-[3-(2,2,2-Trifluoroethyl)pyrrolidin-1-yl]-1-[2-(trimethylsilyl)et-
hoxy]methyl-1H-indazole-3-carboxylic acid.
[0750] Procedure 25:
[0751] Procedure 25 provides a method for the preparation of
aminomethyl substituted indazole-3-carboxylic acids from the
corresponding bromides.
[0752] A solution of di-tert-butyldicarbonate (188 mmol) in
tetrahydrofuran (50 mL) was cautiously added to a mixture of
5-bromo-1H-indazole-3-carboxylic acid (62.2 mmol) and
4-dimethylaminopyridine (19.0 mmol) in tert-butyl alcohol (150 mL)
and tetrahydrofuran (150 mL) at 60.degree. C. The mixture was
maintained at 60.degree. C. until gas evolution ceased (approx. 4
h). The reaction mixture was allowed to cool to rt, diluted with
ethyl acetate, washed with water, sodium bicarbonate, and brine,
dried (sodium sulfate) and concentrated. The residue was dissolved
in 1/1 hexanes/ethyl acetate (.about.300 mL) and filtered through
of silica gel (approx. 40 g). The silica was washed with additional
1/1 hexanes/ethyl acetate (500 mL) and the combined eluant was
concentrated. The residue was dissolved in methanol (100 mL) and
tetrahydrofuran (100 mL) and was treated with 2.0 M sodium
hydroxide (100 mL). The reaction mixture was maintained for 2 h at
rt and was partitioned between water (200 mL) and ethyl acetate
(200 mL). The organic layer was washed with brine (50 mL), dried
(magnesium sulfate), and concentrated. The residue was triturated
with hexanes to provide the ester in 80% yield.
[0753] Into a 1-Neck round-bottom flask was added sodium hydride
(60% mineral oil dispersion) (6.00 mmol) and tetrahydrofuran (90
mL) The reaction was cooled to -78.degree. C. and a solution of
tert-butyl 5-bromo-1H-indazole-3-carboxylate (4.00 mmol) in
tetrahydrofuran (10.0 mL) was added. The reaction was heated at
25.degree. C. and was maintained for 30 min. The reaction was
cooled to -78.degree. C. and tert-butyllithium in pentane (1.7 M,
3.6 mL) was added dropwise. The reaction was maintained at
-78.degree. C. for 15 minutes and N,N-dimethylformamide (20 mmol)
was added. The reaction was maintained at -78.degree. C. for 30
minutes, then quenched with methanol (0.5 mL) and allowed to warm
to room temperature. The reaction was partitioned between water
(100 mL) and ethyl acetate (100 mL) and the organic layer was
washed with brine (25 mL), dried (magnesium sulfate), and
concentrated. The residue was purified by chromatography (80/20 to
60/40 hexanes/ethyl acetate) to yield the benzaldehyde in 52%
yield.
[0754] Sodium triacetoxyborohydride (4.74 mmol) was added to a
suspension of tert-butyl 5-formyl-1H-indazole-3-carboxylate (2.03
mmol) and dimethylamine hydrochloride (4.74 mmol) in
1,2-dichloroethane (50.0 mL). The reaction mixture was maintained
for 3 days at rt. The reaction mixture was washed with water (50
mL) and brine (25 mL), dried (magnesium sulfate), and concentrated.
The residue was loaded onto a SCX column (10 g) and washed with 5
volumes of methanol. The purified product was then eluted using 2.0
M ammonia in methanol to provide the amine in 86% yield
[0755] tert-Butyl
5-[(dimethylamino)methyl]-1H-indazole-3-carboxylate (1.74 mmol) was
dissolved in trifluoroacetic acid (3.00 mL) and the reaction
mixture was maintained for 16 h. The reaction mixture was
concentrated and was loaded onto a SCX column (10 g) and flushed
with 5 volumes of methanol. The purified product was then eluted
using 2.0 M ammonia in methanol to provide the acid in 90%
yield.
[0756] The following compounds were prepared using this method:
[0757] 5-[(Dimethylamino)methyl]-1H-indazole-3-carboxylic acid.
[0758] 5-[(Diethylamino)methyl]-1H-indazole-3-carboxylic acid.
[0759] 5-[(Pyrrolidin-1-yl)methyl]-1H-indazole-3-carboxylic
acid.
[0760] tert-Butyl 5-bromo-1H-indazole-3-carboxylate.
[0761] Procedure 26:
[0762] Procedure 26 provides a method for the preparation of
4-methoxyindazole acid from 4-methoxyaniline.
[0763] 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
min. The suspension was allowed to cool to rt and was filtered and
concentrated. The residue was diluted with water (200 mL) and the
pH of the solution was adjusted to 8 with 10% sodium hydroxide. The
precipitated solids were collected by filtration, washed with water
(1 L), and dried to give the acetamide in 94% yield as a purple
solid.
[0764] Concentrated nitric acid (210 mL) was added dropwise to a
solution of the acetamide (1.52 mol) in dichloromethane (1.5 L) at
rt. The reaction mixture was heated at reflux for 1 h and was
allowed to cool to rt. 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 provide the nitroacetamide in 83% yield as an
orange solid.
[0765] A solution of the nitroacetamide (1.27 mol) in water (1.27
L) was treated with sodium hydroxide (5.07 mol) and the reaction
mixture was heated at 60.degree. C. for 2 h. The precipitated
solids were collected by filtration, washed with water, and dried
to provide the nitroaniline in 85% yield as an orange solid.
[0766] A solution of sodium nitrite (1.48 mol) in water (250 mL)
was added to a cold (0-5.degree. C.) solution of the nitroaniline
(1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the
reaction mixture at 90.degree. C. for 2 h). The reaction mixture
was maintained for 40 min and was filtered. The filtrate was added
dropwise to a cold (0-5.degree. C.) solution of copper (I) bromide
(1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture
was maintained for 30 min. The reaction mixture was warmed to
60.degree. C. and was maintained for 30 min. The reaction mixture
was warmed to reflux and was maintained for 1 h. The reaction
mixture was diluted with water (2 L) and was extracted with
dichloromethane (3.times.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 provide the bromide in 50% yield as a yellow solid.
[0767] Iron powder (1.08 mol) and ammonium chloride (862 mmol) were
added to a solution of the bromide (216 mmol) in ethanol (200 mL)
and water (140 mL) and the reaction mixture was heated at reflux
for 1 h. The suspension was filtered and concentrated and the
residue was extracted with ethyl acetate (3.times.200 mL). The
combined organic layers were dried (sodium sulfate) and
concentrated to give the bromoaniline in 96% yield as a yellow
liquid.
[0768] A solution of the bromoaniline (208 mmol) in 50%
hydrochloric acid (40 mL) was added to a solution of
trichloroacetaldehyde hydrate (312 mmol) and sodium sulfate (967
mmol) in water (450 mL) and the reaction mixture was maintained for
1 h. A solution of hydroxylamine hydrochloride (793 mmol) in water
(240 mL) was added and the reaction mixture was heated at
60.degree. C. for 2 h. The aqueous layer was decanted and the
residual red oil, which solidifies upon standing, was purified by
chromatography (6/6/1 petroleum ether/dichloromethane/ethyl
acetate) to provide the .alpha.-oxime amide in 29% yield as a light
yellow solid.
[0769] The .alpha.-oxime amide (58.6 mmol) was added in one portion
to warm (40.degree. C.) 90% sulfuric acid (16 mL) and the reaction
mixture was heated at 60.degree. C. for 30 min. The reaction
mixture was allowed to cool to rt and was poured into ice water.
The precipitated orange solids were collected by filtration and
dried. The crude product was purified by chromatography (15/1
petroleum ether/ethyl acetate) to provide the isatin in 57% yield
as a yellow solid.
[0770] The isatin (20.7 mmol) was mixed with 1 M sodium hydroxide
(23 mL) and the reaction mixture was heated to 30-40.degree. C. for
30 min. The reaction mixture was cooled to 0.degree. C. and treated
with a solution of sodium nitrite (20.7 mmol) in water (5.1 mL) and
was maintained for 20 min. That solution was added dropwise to a
cold (0-5.degree. 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.degree. C. for 1 h. The precipitated
solids were isolated by filtration and dried to provide the
indazole acid as a yellow solid (100% by mass).
[0771] Acetylchloride (18 mL) was added to methanol (180 mL) at
0.degree. C. and the reaction mixture maintained for 1 h. The
indazole acid (21.8 mmol) was added and the reaction mixture was
heated at reflux for 3 h. The solution was concentrated to dryness
and the residue was suspended in water and the pH adjusted to 7
with saturated sodium hydrogen carbonate. The mixture was extracted
with ethyl acetate (3.times.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 provide the indazole ester in 5% yield (two steps) as a
yellow solid.
[0772] The indazole ester (1.02 mmol) was combined with 10%
palladium on carbon (30 mg) and methanol (20 mL) under an
atmosphere of hydrogen gas for 30 min at rt. The catalyst was
removed by filtration and the eluent was concentrated to afford the
de-brominated indazole ester in 24% yield as an orange solid.
[0773] 1 M Sodium hydroxide (1.5 mL) was added to a solution of the
de-brominated indazole ester (0.243 mmol) in methanol (3.0 mL) and
the reaction mixture was heated at 60.degree. C. for 3 h. The
solution was concentrated, the pH adjusted to 1-2, and the solids
collected by filtration to provide the indazole acid in 100% yield
as a yellow solid.
[0774] Procedure 27:
[0775] Procedure 27 provides a method for the preparation of
benzyloxy-substituted indazole-3-carboxylic acids and esters from
the corresponding bromides.
[0776] 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 with 10% sodium hydroxide.
The precipitated solids were isolated by filtration, washed with
water (100 mL), and dried to provide the acetamide in 88%
yield.
[0777] 65% Nitric acid (22 mL) was added dropwise over 0.5 h to a
solution of the acetamide (200 mmol) in dichloromethane (200 mL).
The reaction mixture was maintained for 1 h at rt and was heated at
reflux for 1 h. 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 provide the nitro acetamide in 90% as a yellow
solid.
[0778] The nitroacetamide (180 mmol) was added to 4 M sodium
hydroxide (180 mL) and the reaction mixture was maintained for 2 h
at 60.degree. C. The precipitated solids were isolated by
filtration, washed with water, and dried to provide the
nitroaniline in 70% yield as a red solid.
[0779] A solution of sodium nitrite (11.8 g) in water (28 mL) was
added dropwise over 0.5 h to a solution of the nitroaniline (125
mmol) in 40%. hydrobromic acid (110 g) at 10.degree. C. The
reaction mixture was maintained for 40 min at 0-10.degree. C. and
was filtered. The filtrate was added dropwise over 1 h to a
0.degree. C., purple solution of copper (I) bromide (209 mmol) in
hydrobromic acid (74 mL). The reaction mixture was allowed to warm
to and maintained at rt for 30 min, was maintained at 60.degree. C.
for 0.5 h, and was heated at reflux for 1 h. The reaction mixture
was partitioned between water (2.0 L) and dichloromethane (600 mL)
and the aqueous layer was further extracted with dichloromethane
(300 mL). The combined organic layers were washed with 10% sodium
hydroxide (200 mL), water (600 mL), 10% hydrochloric acid (300 mL),
and water (600 mL), dried (magnesium sulfate) and concentrated to
provide the nitrobromide in 83% yield as a yellow oil.
[0780] A solution of boron tribromide (250 mmol) in dichloromethane
(200 mL) was added drop wise over 1 h to a solution of the
nitrobromide (100 mmol) in dichloromethane (250 mL) at -78.degree.
C. The reaction mixture was allowed to warm to rt and was
maintained for 30 h. The reaction mixture was cooled to 0.degree.
C., quenched with water (300 mL) and the aqueous layer was
extracted with ethyl acetate (2.times.300 mL). The combined organic
layers were washed with saturated sodium bicarbonate (2.times.300
mL), dried (magnesium sulfate), and concentrated to provide the
nitrophenol in 87% yield as a brown crystalline solid.
[0781] Benzyl bromide (131 mmol) and potassium carbonate (130 mmol)
were added to a solution of the nitrophenol (87.0 mmol) in 2/1
acetonitrile/acetone (840 mL). The reaction mixture was heated at
reflux for 17 h and was concentrated to dryness. The residue was
suspended in ethyl acetate (756 mL), filtered, and the organic
layer was washed with water (567 mL), 1 M hydrochloric acid
(2.times.567 mL), and brine (567 mL). The organic layer was dried
(magnesium sulfate) and concentrated to the benzyl ether in 78%
yield.
[0782] Diethyl malonate (890 mmol) was added drop wise over 1 h to
a suspension of sodium hydride (520 mmol) in dimethylsulfoxide (100
mL) at 0.degree. C. The benzyl ether (44.0 mmol) was added and the
reaction mixture was heated at 100.degree. C. for 5 h. The reaction
mixture was poured into ice water and was extracted with ethyl
acetate (3.times.70 mL). The combined organic layers were dried
(magnesium sulfate) and concentrated to provide the diethylmalonate
addition product. The diethylmalonate addition product was diluted
with a 4 M solution of sodium hydroxide (100 mL) and the reaction
mixture was heated at 60.degree. C. for 6 h. The solution was
extracted with dichloromethane (3.times.50 mL) and the aqueous
layer was adjusted to pH 1 with concentrated hydrochloric acid. The
reaction mixture was heated at 60.degree. C. for 1 h, allowed to
cool to rt, and was extracted with ethyl acetate (3.times.50 mL).
The combined organic layers were dried (magnesium sulfate) and
concentrated to provide the phenylacetic acid in 78% yield as a
solid.
[0783] The phenylacetic acid (350 mmol) was added to a freshly
prepared solution of ethanolic hydrochloric acid [acetyl chloride
(5 mL) was added 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.times.50 mL) and the combined
organic layers were dried (magnesium sulfate), filtered and
concentrated to provide the ester in 77% yield.
[0784] The nitro ester (27.0 mmol) was dissolved in acetic acid (60
mL) and acetic anhydride (44 mL) and was cooled to 0.degree. C.
Zinc dust (153 mmol) was added and the reaction mixture was allowed
to warm to rt and was maintained for 2 h. Additional quantities of
zinc dust (2.times.45.9 mmol) were added during a 3 h course of
time. After 1 h, 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.times.50 mL) and the combined
organic layers were dried (magnesium sulfate), filtered and
concentrated to provide the acetamide in 82% yield.
[0785] Isoamyl nitrite (47.2 g) was added dropwise over 30 min to a
solution of the acetamide (21.0 mmol) in chloroform (80 mL) and
acetic anhydride (45 mL). 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.times.80 mL) and brine (80 mL), dried (magnesium sulfate), and
concentrated to provide the acetylated indazole ester in 68%
yield.
[0786] The acetylated indazole ester (15.0 mmol) was suspended in 2
M sodium hydroxide (35 mL) and the reaction mixture was heated at
60.degree. C. for 24 h. The pH of the solution was adjusted to 1-2
with concentrated hydrochloric acid and the solids were collected
by filtration and dried to provide
6-benzyloxy-1H-indazole-3-carboxylic acid in 28% yield as a yellow
solid.
[0787] 6-Benzyloxy-1H-indazole-3-carboxylic acid (1.85 mmol) was
added to a freshly prepared solution of ethanolic hydrochloric acid
[prepared from ethanol (20 mL) and acetyl chloride (5 mL)] and the
reaction mixture was heated at reflux for 25 h and was
concentrated. The residue was partitioned between saturated sodium
bicarbonate (20 mL) and ethyl acetate (20 mL) and the layers were
separated. The aqueous layer was extracted with ethyl acetate
(2.times.20 mL) and the combined organic layers were dried
(magnesium sulfate) and concentrated. The residue was purified by
chromatography (300/1 dichloromethane/methanol) to provide the
product in 36.4% yield. Alternatively, the ester can be obtained
from the acetylated indazole ester by maintaining the acetylated
material in 2 M ammonia in methanol for 30 min.
[0788] The following acids were prepared using this method:
[0789] 6-Benzyloxy-1H-indazole-3-carboxylic acid.
[0790] 5-Benzyloxy-1H-indazole-3-carboxylic acid (from
4-benzyloxy-2-bromonitrobenzene: Parker, K. A.; Mindt, T. L. Org.
Lett. 2002, 4, 4265.).
[0791] Ethyl 6-benzyloxy-1H-indazole-3-carboxylate.
[0792] Ethyl 5-benzyloxy-1H-indazole-3-carboxylate.
[0793] Base Preparations.
[0794] The following procedures (28-29) detail the preparation of
the bicyclobases that were not commercially available.
[0795] Procedure 28:
[0796] Procedure 28 provides a method for the preparation of
N-alkylated 3-aminoquinuclidines from 3-aminoquinuclidine.
[0797] Cyclopropanecarbonyl chloride (12 mmol) was added dropwise
to a solution of (R)-3-aminoquinuclidine (10 mmol) and
N,N-diisopropylethylami- ne (30 mmol) in dichloromethane (100 mL).
The resulting solution was maintained at rt for 4 h and was
evaporated to dryness. The crude amide was dissolved in
tetrahydrofuran (150 mL) and was treated with lithium aluminum
hydride (66 mmol) in small portions. The reaction mixture was
quenched with sodium sulfate decahydrate and the resulting slurry
was diluted with tetrahydrofuran and filtered through Celite. The
filtrate was concentrated and the residue was then diluted with
freshly prepared methanolic hydrogen chloride (generated by the
dropwise addition of 3 mL of acetyl chloride into 30 mL of
methanol) and maintained at rt for 15 min. The residue obtained by
the removal of the volatiles was recrystallized
(2-propanol/methanol) to provide the secondary amine in 41% yield
as a colorless solid.
[0798] The following bases were prepared using this method:
[0799] (3R)-N-(Cyclopropylmethyl)quinuclidin-3-amine
dihydrochloride.
[0800] (3S)-N-(Cyclopropylmethyl)quinuclidin-3-amine
dihydrochloride.
[0801] (3R)-N-(Methyl)quinuclidin-3-amine dihydrochloride.
[0802] (3S)-N-(Methyl)quinuclidin-3-amine dihydrochloride.
[0803] (3R)-N-(Ethyl)quinuclidin-3-amine dihydrochloride.
[0804] (3S)-N-(Ethyl)quinuclidin-3-amine dihydrochloride.
[0805] Procedure 29:
[0806] Procedure 29 provides a method for the preparation of
1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride from
quinuclidinone.
[0807] A solution of p-tolylsulfonylmethyl isocyanide (50 mmol) in
ethanol (4 mL) was added to a suspension of quinuclidone (40 mmol)
in ethylene glycol dimethyl ether (155 mL) at -5.degree. C. Solid
potassium tert-butoxide (130 mmol) was added in portions over 20
min. The Reaction mixture was maintained for 30 min at -5.degree.
C. and was then allowed to warm to the rt and maintained for an
additional 3 h. The reaction mixture was filtered and was diluted
with saturated hydrochloric acid in isopropanol. The reaction
mixture was filtered and diluted with ether. The resulting
precipitate was collected by filtration to provide the nitrile in
88% yield as a yellow solid.
[0808] The solution of the nitrile (35 mmol) in methanol (720 mL)
was cooled to 5.degree. C. and was treated with concentrated
hydrochloric acid (12 mL) and 10% palladium on carbon (9.6 g). The
reaction mixture was maintained under an atmosphere of hydrogen gas
for 4.5 h at the rt. The catalyst was removed by filtration and the
filtrate was concentrated to afford a yellow solid. The solid was
dissolved in methanol and was diluted with ethyl ether. The
resulting precipitate was collected by filtration to provide the
nitrile in 32% yield as a yellow solid.
[0809] Representative Procedures.
[0810] The following procedures (A-AG) detail the preparation of
the bicyclobase analogs.
[0811] Procedure A.
[0812] Procedure A provides a method for the coupling between
3-aminoquinuclidine and carboxylic acids to form carboxamide
derivatives.
[0813] To a solution of the carboxylic acid (16.1 mmol) in
N,N-dimethylformamide (65 mL) was added HBTU (16.1 mmol), catalytic
amount of dimethylaminopyridine, N,N-diisopropylethylamine (96.6
mmol) and 4 .ANG. activated molecular sieves (2.6 g). The reaction
mixture was maintained at room temperature for 2 h under nitrogen
and then 3-aminoquinuclidine dihydrochloride (16.1 mmol) was added.
After 18 h, the solvent was removed under reduced pressure. The
oily residue was partitioned between saturated, aqueous sodium
bicarbonate (25 mL) and dichloromethane (100 mL). The aqueous layer
was further extracted with 9/1 dichloromethane/methanol
(5.times.100 mL) and the combined organic layers were concentrated.
The residue was purified by chromatography [90/10/1
dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl
acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by
preparative HPLC, thus providing the product in 30%-70% yield.
[0814] The following compounds were prepared using this method:
Example 1
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide
hydroformate
[0815] 22
[0816] Prepared using Procedure A in 29% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.52 (s, 1H), 8.18 (s, 1H), 7.59 (d, J=8.9,
1H), 7.41 (dd, J=8.9, 1.9, 1H), 4.51 (m, 1H), 3.80 (m, 1H), 3.44
(m, 5H), 2.36 (m, 1H), 2.24 (m, 1H), 2.09 (m, 2H), 1.86 (m, 1H);
LC/MS (EI) t.sub.R 2.75, m/z 305 (M.sup.++1).
Example 2
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide
hydroformate
[0817] 23
[0818] Prepared using Procedure A in 15% yield. LC/MS (EI) t.sub.R
2.86, m/z 289 (M.sup.++1).
Example 3
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-chloro-1H-indazole-3-carboxamide
hydroformate
[0819] 24
[0820] Prepared using Procedure A in 30% yield. LC/MS (EI) t.sub.R
2.76, m/z 305 (M.sup.++1).
Example 4
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-fluoro-1H-indazole-3-carboxamide
hydroformate
[0821] 25
[0822] Prepared using Procedure A in 27% yield. LC/MS (EI) t.sub.R
2.53, m/z 289 (M.sup.++1).
Example 5
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydroformate
[0823] 26
[0824] Prepared using Procedure A in 32% yield. LC/MS (EI) t.sub.R
5.15, m/z 355 (M.sup.++1).
Example 6
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide
hydroformate
[0825] 27
[0826] Prepared using Procedure A in 38% yield. LC/MS (EI) t.sub.R
2.53, m/z 301 (M.sup.++1).
Example 7
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydroformate
[0827] 28
[0828] Prepared using Procedure A in 27% yield. LC/MS (EI) t.sub.R
5.13, m/z 355 (M.sup.++1).
Example 8
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1H-indazole-3-carboxamide
hydroformate
[0829] 29
[0830] Prepared using Procedure A in 34% yield. LC/MS (EI) t.sub.R
2.53, m/z 301 (M.sup.++1).
Example 9
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-car-
boxamide
[0831] 30
[0832] Prepared using Procedure A in 43% yield. LC/MS (EI) t.sub.R
5.06, m/z 339 (M.sup.++1).
Example 10
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethyl)-1H-indazole-3-car-
boxamide
[0833] 31
[0834] Prepared using Procedure A in 45% yield. LC/MS (EI) t.sub.R
5.06, m/z 339 (M.sup.++1).
Example 11
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide
[0835] 32
[0836] Prepared using Procedure A in 63% yield. LC/MS (EI) t.sub.R
2.53, m/z 301 (M.sup.++1).
Example 12
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide
[0837] 33
[0838] Prepared using Procedure A in 57% yield. LC/MS (EI) t.sub.R
2.53, m/z 301 (M.sup.++1).
Example 13
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide
[0839] 34
[0840] Prepared using Procedure A in 62% yield. LC/MS (EI) t.sub.R
2.53, m/z 289 (M.sup.++1).
Example 14
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1H-indazole-3-carboxamide
[0841] 35
[0842] Prepared using Procedure A in 62% yield. LC/MS (EI) t.sub.R
2.53, m/z 289 (M.sup.++1).
Example 15
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-methoxy-1H-indazole-3-carboxamide
[0843] 36
[0844] Prepared using Procedure A in 14% yield. LC/MS (EI) t.sub.R
2.50, m/z 301 (M.sup.++1).
Example 16
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide
hydroformate
[0845] 37
[0846] Prepared using Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.09, m/z 272 (M.sup.++1).
Example 17
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxamide
hydroformate
[0847] 38
[0848] Prepared using Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.12, m/z 272 (M.sup.++1).
Example 18
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1,2-benzisothiazo-
le-3-carboxamide hydroformate
[0849] 39
[0850] Prepared using Procedure A in 30% yield. LC/MS (EI) t.sub.R
3.40, m/z 355 (M.sup.++1).
Example 19
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[2,2,2-trifluoro-1-hydroxy-1-(trifl-
uoromethyl)ethyl]-1H-indazole-3-carboxamide
[0851] 40
[0852] Prepared using Procedure A in 9% yield. LC/MS (EI) t.sub.R
4.94, m/z 437 (M.sup.++1).
Example 20
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide hydroformate
[0853] 41
[0854] Prepared using Procedure A in 24% yield. LC/MS (EI) t.sub.R
3.62, m/z 353 (M.sup.++1).
Example 21
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide hydroformate
[0855] 42
[0856] Prepared using Procedure A in 23% yield. LC/MS (EI) t.sub.R
3.50, m/z 353 (M.sup.++1).
Example 22
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-methyl-1H-indazole-3-carb-
oxamide
[0857] 43
[0858] Prepared using Procedure A in 40% yield. LC/MS (EI) t.sub.R
3.03, m/z 315 (M.sup.++1).
Example 23
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-ethyl-1H-indazole-3-carbo-
xamide
[0859] 44
[0860] Prepared using Procedure A in 63% yield. LC/MS (EI) t.sub.R
3.26, m/z 329 (M.sup.++1).
Example 24
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-cyclopentyl-1H-indazole-3-
-carboxamide
[0861] 45
[0862] Prepared using Procedure A in 87% yield. LC/MS (EI) t.sub.R
5.45, m/z 369 (M.sup.++1).
Example 25
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-6-methoxy-1H-indazole-3-carbo-
xamide
[0863] 46
[0864] Prepared using Procedure A in 12% yield. LC/MS (EI) t.sub.R
4.36, m/z 379/381 (M.sup.++1).
Example 26
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1,8-dihydropyrrolo[3,2-g]indazole-3-c-
arboxamide
[0865] 47
[0866] Prepared using Procedure A in 35% yield. LC/MS (EI) t.sub.R
2.20, m/z 310 (M.sup.++1).
Example 27
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzyl-6-(difluoromethoxy)-1H-indaz-
ole-3-carboxamide hydroformate
[0867] 48
[0868] Prepared using Procedure A in 18% yield. LC/MS (EI) t.sub.R
5.27, m/z 427 (M.sup.++1).
Example 28
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(3-thienyl)-1H-indazole-3-carboxami-
de hydroformate
[0869] 49
[0870] Prepared using Procedure A in 16% yield. LC/MS (EI) t.sub.R
5.10, m/z 353 (M.sup.++1).
Example 29
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-car-
boxamide
[0871] 50
[0872] Prepared using Procedure A in 30% yield. LC/MS (EI) t.sub.R
4.41, m/z 337 (M.sup.++1).
Example 30
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(difluoromethoxy)-1H-indazole-3-car-
boxamide
[0873] 51
[0874] Prepared using Procedure A in 16% yield. LC/MS (EI) t.sub.R
4.27, m/z 337 (M.sup.++1).
Example 31
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydroformate
[0875] 52
[0876] Prepared using Procedure A in 5.3% yield. LC/MS (EI) t.sub.R
2.93, m/z 368 (M.sup.++1).
Example 32
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-methoxy-1H-indazole-3-carboxamide
hydroformate
[0877] 53
[0878] Prepared using Procedure A in 12% yield. LC/MS (EI) t.sub.R
2.43, m/z 301 (M.sup.++1).
Example 33
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-fluoro-6-methoxy-1H-indazole-3-carb-
oxamide hydroformate
[0879] 54
[0880] Prepared using Procedure A in 20% yield. LC/MS (EI) t.sub.R
268.00, m/z 319 (M.sup.++1).
Example 34
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-fluoro-5-methoxy-1H-indazole-3-carb-
oxamide hydroformate
[0881] 55
[0882] Prepared using Procedure A in 29% yield. LC/MS (EI) t.sub.R
2.40, m/z 319 (M.sup.++1).
Example 35
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-car-
boxamide
[0883] 56
[0884] Prepared using Procedure A in 34% yield. LC/MS (EI) t.sub.R
3.71, m/z 337 (M.sup.++1).
Example 36
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(difluoromethoxy)-1H-indazole-3-car-
boxamide
[0885] 57
[0886] Prepared using Procedure A in 22% yield. LC/MS (EI) t.sub.R
3.72, m/z 337 (M.sup.++1).
Example 37
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydroformate
[0887] 58
[0888] Prepared using Procedure A in 24% yield. LC/MS (EI) t.sub.R
4.34, m/z 368 (M.sup.++1).
Example 38
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydroformate
[0889] 59
[0890] Prepared using Procedure A in 21% yield. LC/MS (EI) t.sub.R
4.50, m/z 368 (M.sup.++1).
Example 39
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopropyl-6-methoxy-1H-indazole-3-
-carboxamide hydroformate
[0891] 60
[0892] Prepared using Procedure A in 10% yield. LC/MS (EI) t.sub.R
4.66, m/z 341 (M.sup.++1).
Example 40
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-5-(3-thienyl)-1H-indazole-3-
-carboxamide hydroformate
[0893] 61
[0894] Prepared using Procedure A in 13% yield. LC/MS (EI) t.sub.R
5.10, m/z 383 (M.sup.++1).
Example 41
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1H-i-
ndazole-3-carboxamide hydroformate
[0895] 62
[0896] Prepared using Procedure A in 4% yield. LC/MS (EI) t.sub.R
5.26, m/z 446 (M.sup.++1).
Example 42
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(methyloxy)pyrrolidin-1-yl]-1H-i-
ndazole-3-carboxamide hydroformate
[0897] 63
[0898] Prepared using Procedure A in 46% yield. LC/MS (EI) t.sub.R
2.39, m/z 370 (M.sup.++1).
Example 43
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(hydroxy)pyrrolidin-1-yl]-1H-ind-
azole-3-carboxamide hydroformate
[0899] 64
[0900] Prepared using Procedure A in 13% yield. LC/MS (EI) t.sub.R
2.39, m/z 356 (M.sup.++1).
Example 44
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-methylpyrrolidin-3-yl)oxy]-1H-i-
ndazole-3-carboxamide dihydroformate
[0901] 65
[0902] Prepared using Procedure A in 40% yield. LC/MS (EI) t.sub.R
1.89, m/z 370 (M.sup.++1).
Example 45
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-(trifluoromethoxy)-1H-indazole-3-c-
arboxamide hydroformate
[0903] 66
[0904] Prepared using Procedure A in 25% yield. LC/MS (EI) t.sub.R
5.15, m/z 369 (M.sup.++1).
Example 46
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide
hydroformate
[0905] 67
[0906] Prepared using Procedure A in 25% yield. LC/MS (EI) t.sub.R
2.80, m/z 315 (M.sup.++1).
Example 47
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopropylmethoxy)-1H-indazole-3--
carboxamide hydroformate
[0907] 68
[0908] Prepared using Procedure A in 37% yield. LC/MS (EI) t.sub.R
4.66, m/z 341 (M.sup.++1).
Example 48
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentyloxy)-1H-indazole-3-carb-
oxamide hydroformate
[0909] 69
[0910] Prepared using Procedure A in 30% yield. LC/MS (EI) t.sub.R
4.90, m/z 355 (M.sup.++1).
Example 49
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,2,2-trifluoroethoxy)-1H-indazole-
-3-carboxamide hydroformate
[0911] 70
[0912] Prepared using Procedure Amod in 40% yield. LC/MS (EI)
t.sub.R 4.70, m/z 369 (M.sup.++1).
Example 50
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1H-indazole-3--
carboxamide hydroformate
[0913] 71
[0914] Prepared using Procedure A in 36% yield. LC/MS (EI) t.sub.R
4.59, m/z 341 (M.sup.++1).
Example 51
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2,2,2-trifluoroethoxy)-1H-indazole-
-3-carboxamide hydroformate
[0915] 72
[0916] Prepared using Procedure A in 78% yield. LC/MS (EI) t.sub.R
4.75, m/z 369 (M.sup.++1).
Example 52
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(benzyloxy)-1H-indazole-3-carboxami-
de hydroformate
[0917] 73
[0918] Prepared using Procedure A in 33% yield. LC/MS (EI) t.sub.R
5.09, m/z 377 (M.sup.++1).
Example 53
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yloxy)-1H-in-
dazole-3-carboxamide hydroformate
[0919] 74
[0920] Prepared using Procedure A in 67% yield. LC/MS (EI) t.sub.R
2.79, m/z 371 (M.sup.++1).
Example 54
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dihydro-1H-inden-2-yloxy)-1H-i-
ndazole-3-carboxamide hydroformate
[0921] 75
[0922] Prepared using Procedure A in 37% yield. LC/MS (EI) t.sub.R
4.26, m/z 403 (M.sup.++1).
Example 55
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[2-(dimethylamino)ethoxy]-1H-indazo-
le-3-carboxamide dihydroformate
[0923] 76
[0924] Prepared using Procedure Amod in 24% yield. LC/MS (EI)
t.sub.R 1.90, m/z 358 (M.sup.++1).
Example 56
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-pyrrolidin-1-ylethoxy)-1H-indazo-
le-3-carboxamide dihydroformate
[0925] 77
[0926] Prepared using Procedure A in 49% yield. LC/MS (EI) t.sub.R
1.88, m/z 384 (M.sup.++1).
Example 57
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-N-methyl-1H-indazole-3-carb-
oxamide hydroformate
[0927] 78
[0928] Prepared using Procedure A in 12% yield. LC/MS (EI) t.sub.R
2.52, m/z 315 (M.sup.++1).
[0929] Procedure B.
[0930] Procedure B provides a method for the coupling between
3-aminoquinuclidine and benzisothiazole carboxylic acids to form
carboxamide derivatives.
[0931] To a solution of 6-methoxybenzisothiazole-3-carboxylic acid
(61 mg, 0.30 mmol) in a 5/1 mixture of
tetrahydrofuran/N,N-dimethylformamide (12 mL) was added
diisopropylethylamine (0.2 mL, 1.1 mmol) and (115 mg, 0.6 mmol)
3-(R)-aminoquinuclidine dihydrochloride. The mixture was cooled to
0.degree. C., and HATU (115 mg, 0.3 mmol) was added in one portion.
The reaction mixture was allowed to warm to rt and was maintained
overnight. The mixture was partitioned between saturated aqueous
potassium carbonate solution and a 95/5 mixture of
dichloromethane/methanol. The aqueous layer was extracted with 95/5
dichloromethane/methanol (2.times.), and the combined organic
layers were washed with brine and dried over sodium sulfate. The
crude product was purified by chromatography (90/10/1
dichloromethane/methanol/ammonium hydroxide) or by preparative
HPLC, thus providing the amide in 75% yield as a colorless
solid.
[0932] The following compounds were prepared using this method:
Example 58
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiaz-
ole-3-carboxamide hydroformate
[0933] 79
[0934] Prepared using Procedure B in 17% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.85 (d, J=9.0, 1H), 8.49 (s, 1H), 8.13 (s,
1H), 7.48 (d, J=9.0, 1H), 4.55 (m, 1H), 3.88-3.80 (m, 1H),
3.53-3.30 (m, 5H), 2.40 (m, 1H), 2.32-2.27 (m, 1H), 2.16-2.10 (m,
2H), 1.99-1.91 (m, 1H); LC/MS (EI) t.sub.R 4.58, m/z 372
(M.sup.++1).
Example 59
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carbox-
amide hydroformate
[0935] 80
[0936] Prepared using Procedure B in 37% yield. LC/MS (EI) t.sub.R
4.42, m/z 332 (M.sup.++1).
Example 60
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethoxy-1,2-benzisothiazole-3-carbox-
amide hydroformate
[0937] 81
[0938] Prepared using Procedure B in 12% yield. LC/MS (EI) t.sub.R
4.31, m/z 332 (M.sup.++1).
Example 61
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1,2-benzisothiaz-
ole-3-carboxamide hydroformate
[0939] 82
[0940] Prepared using Procedure B in 41% yield. LC/MS (EI) t.sub.R
4.62, m/z 372 (M.sup.++1).
Example 62
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothi-
azole-3-carboxamide
[0941] 83
[0942] Prepared using Procedure B in 36% yield. LC/MS (EI) t.sub.R
4.34, m/z 358 (M.sup.++1).
Example 63
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothi-
azole-3-carboxamide
[0943] 84
[0944] Prepared using Procedure B in 53% yield. LC/MS (EI) t.sub.R
4.33, m/z 358 (M.sup.++1).
[0945] Procedure C.
[0946] Procedure C provides a method for the coupling between
3-aminoquinuclidine and carboxylic acids to form carboxamide
derivatives.
[0947] To a solution of the carboxylic acid (4.77 mmol) in
N,N-dimethylformamide (14 mL) was added N,N-diisopropylethylamine
(19 mmol) and 3-aminoquinuclidine dihydrochloride (4.29 mmol). The
reaction mixture was maintained at room temperature for 30 min
under nitrogen and then HATU (4.76 mol) was added. After 18 h, the
reaction mixture was filtered through Celite (methanol rinse) and
was divided equally amongst 3 SCX columns. The columns were washed
with methanol (100 mL each) and the basic components were eluted
with 2 M ammonia in methanol (100 mL each) and concentrated. The
residue was purified by chromatography [1/1 to 0/1 ethyl
acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by
preparative HPLC, thus providing the product in 15%-50% yield.
[0948] The following compounds were prepared using this method:
Example 64
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indaz-
ole-3-carboxamide
[0949] 85
[0950] Prepared using Procedure C in 22% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.07 (s, 1H), 7.53 (d, J=8.4, 11H), 7.38 (d,
J=8.4, 11H), 4.25 (m, 1H), 4.08 (m, 2H), 3.60 (m, 2H), 3.36 (m,
1H), 3.15 (m, 1H), 3.0-2.8 (m, 5H), 2.11 (m, 1H), 2.05 (m, 1H),
2.0-1.7 (m, 6H), 1.62 (m, 1H); LC/MS (EI) t.sub.R 3.44, m/z 355
(M.sup.++1).
Example 65
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxy)-1H-indazole-3-carboxamide
[0951] 86
[0952] Prepared using Procedure C or Procedure AA. .sup.1H NMR (400
MHz, Me.sub.2SO-d.sub.6) .delta. 13.30 (s, 1H), 9.32 (s, 1H), 8.07
(d, J=7.6, 11H), 7.43 (m, 1H), 6.94 (m, 1H), 4.01 (m, 1H), 3.12 (m,
1H), 2.93 (m, 1H), 2.72 (m, 4H), 1.89 (m, 1H), 1.80 (m, 1H), 1.61
(m, 2H), 1.33 (m, 1H); LC/MS (EI) m/z 288 (M.sup.++1).
Example 66
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide
hydroformate
[0953] 87
[0954] Prepared using Procedure C or Procedure AA in 11% yield.
LC/MS (EI) t.sub.R 2.35, m/z 288 (M.sup.++1).
Example 67
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide
hydroformate
[0955] 88
[0956] Prepared using Procedure C or Procedure AA in 11% yield.
LC/MS (EI) t.sub.R 2.37, m/z 287 (M.sup.++1).
Example 68
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydroformate
[0957] 89
[0958] Prepared using Procedure C in 17% yield. LC/MS (EI) t.sub.R
4.85, m/z 355 (M.sup.++1).
Example 69
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydroformate
[0959] 90
[0960] Prepared using Procedure C in 14% yield. LC/MS (EI) t.sub.R
4.84, m/z 355 (M.sup.++1).
Example 70
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydroformate
[0961] 91
[0962] Prepared using Procedure C in 41% yield. LC/MS (EI) t.sub.R
4.71, m/z 355 (M.sup.++1).
Example 71
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydroformate
[0963] 92
[0964] Prepared using Procedure C in 41% yield. LC/MS (EI) t.sub.R
4.73, m/z 355 (M.sup.++1).
Example 72
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide
[0965] 93
[0966] Prepared using Procedure C in 73% yield. LC/MS (EI) t.sub.R
3.43, m/z 316 (M.sup.++1).
Example 73
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1,2-benzisothiazole-3-car-
boxamide
[0967] 94
[0968] Prepared using Procedure C or Procedure AA in 70% yield.
LC/MS (EI) t.sub.R 2.75, m/z 304 (M.sup.++1).
Example 74
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1H-indazole-3-carboxamide
[0969] 95
[0970] Prepared using Procedure C in 18% yield. LC/MS (EI) t.sub.R
2.42, m/z 316 (M.sup.++1).
Example 75
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-nitro-1H-indazole-3-carboxamide
[0971] 96
[0972] Prepared using Procedure C in 31% yield. LC/MS (EI) t.sub.R
3.18, m/z 316 (M.sup.++1).
Example 76
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(tetrahydro-2H-pyran-4-yl)-1H-indaz-
ole-3-carboxamide
[0973] 97
[0974] Prepared using Procedure C in 23% yield. LC/MS (EI) t.sub.R
3.33, m/z 355 (M.sup.++1).
Example 77
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(nitro)-1H-indazole-3-carboxamide
[0975] 98
[0976] Prepared using Procedure C in 28% yield. LC/MS (EI) t.sub.R
2.43, m/z 316 (M.sup.++1).
Example 78
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-
-1H-indazole-3-carboxamide
[0977] 99
[0978] Prepared using Procedure C in 20% yield. LC/MS (EI) t.sub.R
2.39, m/z 371 (M.sup.++1).
Example 79
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-hydroxytetrahydro-2H-pyran-4-yl)-
-1H-indazole-3-carboxamide
[0979] 100
[0980] Prepared using Procedure C in 30% yield. LC/MS (EI) t.sub.R
2.39, m/z 371 (M.sup.++1).
Example 80
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-7-(nitro)-1H-indazole-3-carboxamide
[0981] 101
[0982] Prepared using Procedure C in 17% yield. LC/MS (EI) t.sub.R
2.99, m/z 316 (M.sup.++1).
Example 81
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide hydroformate
[0983] 102
[0984] Prepared using Procedure C in 15% yield. LC/MS (EI) t.sub.R
3.20, m/z 353 (M.sup.++1).
Example 82
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3,6-dihydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide
[0985] 103
[0986] Prepared using Procedure C in 21% yield. LC/MS (EI) t.sub.R
3.90, m/z 353 (M.sup.++1).
Example 83
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carbo-
xamide hydroformate
[0987] 104
[0988] Prepared using Procedure C in 26% yield. LC/MS (EI) t.sub.R
2.54, m/z 381/383 (M.sup.++1).
Example 84
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-bromo-5-methoxy-1H-indazole-3-carbo-
xamide hydroformate
[0989] 105
[0990] Prepared using Procedure C in 12% yield. LC/MS (EI) t.sub.R
2.54, m/z 381/383 (M.sup.++1).
Example 85
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-4-nitro-1H-indazole-3-carboxa-
mide
[0991] 106
[0992] Prepared using Procedure C in 25% yield. LC/MS (EI) t.sub.R
4.73, m/z 394/396 (M.sup.++1).
Example 86
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(formyl)-1H-indazole-3-carboxamide
hydroformate
[0993] 107
[0994] Prepared using Procedure C in 51% yield. LC/MS (EI) t.sub.R
2.35, m/z 299 (M.sup.++1).
Example 87
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indaz-
ole-3-carboxamide
[0995] 108
[0996] Prepared using Procedure C in 59% yield. LC/MS (EI) t.sub.R
2.37, m/z 355 (M.sup.++1).
Example 88
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1H-indaz-
ole-3-carboxamide
[0997] 109
[0998] Prepared using Procedure C in 52% yield. LC/MS (EI) t.sub.R
3.22, m/z 355 (M.sup.++1).
Example 89
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-1-(2,2,2-trifluoroethyl)-1H-
-indazole-3-carboxamide
[0999] 110
[1000] Prepared using Procedure C in 81% yield. LC/MS (EI) t.sub.R
5.02, m/z 383 (M.sup.++1).
Example 90
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(ethyl)-1H-indazole-3-carbo-
xamide
[1001] 111
[1002] Prepared using Procedure C in 64% yield. LC/MS (EI) t.sub.R
3.94, m/z 377/379 (M.sup.++1).
Example 91
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-(ethyl)-1H-indazole-3-carbo-
xamide
[1003] 112
[1004] Prepared using Procedure C in 72% yield. LC/MS (EI) t.sub.R
3.90, m/z 377/379 (M.sup.++1).
Example 92
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(cyclopropylmethyl)-1H-inda-
zole-3-carboxamide
[1005] 113
[1006] Prepared using Procedure C in 70% yield. LC/MS (EI) t.sub.R
4.20, m/z 403/405 (M.sup.++1).
Example 93
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-(2,2,2-trifluoroethyl)-1H-i-
ndazole-3-carboxamide
[1007] 114
[1008] Prepared using Procedure C in 61% yield. LC/MS (EI) t.sub.R
4.10, m/z 431/433 (M.sup.++1).
Example 94
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(dimethylamino)methyl]-1H-indazole-
-3-carboxamide dihydroformate
[1009] 115
[1010] Prepared using Procedure C in 35% yield. LC/MS (EI) t.sub.R
1.30, m/z 328 (M.sup.++1).
Example 95
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(diethylamino)methyl]-1H-indazole--
3-carboxamide dihydroformate
[1011] 116
[1012] Prepared using Procedure C in 29% yield. LC/MS (EI) t.sub.R
1.32, m/z 356 (M.sup.++1).
Example 96
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-yl)methyl]-1H-indazo-
le-3-carboxamide dihydroformate
[1013] 117
[1014] Prepared using Procedure C in 39% yield. LC/MS (EI) t.sub.R
1.34, m/z 354 (M.sup.++1).
Example 97
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1-benzylpyrrolidin-3-yl)oxy]-1H-i-
ndazole-3-carboxamide dihydroformate
[1015] 118
[1016] Prepared using Procedure C in 33% yield. LC/MS (EI) t.sub.R
2.35, m/z 446 (M.sup.++1).
Example 98
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-6-methoxy-1H-indazole-3-carbo-
xamide
[1017] 119
[1018] Prepared using Procedure C in 7% yield. LC/MS (EI) t.sub.R
2.78, m/z 329 (M.sup.++1).
Example 99
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-ethyl-5-trifluoromethoxy-1H-indazol-
e-3-carboxamide
[1019] 120
[1020] Prepared using Procedure C in 1% yield. LC/MS (EI) t.sub.R
3.83, m/z 383 (M.sup.++1).
Example 100
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-6-methoxy-1H-inda-
zole-3-carboxamide hydroformate
[1021] 121
[1022] Prepared using Procedure C in 7% yield. LC/MS (EI) t.sub.R
3.56, m/z 355 (M.sup.++1).
Example 101
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-1H-indazole-3-car-
boxamide hydroformate
[1023] 122
[1024] Prepared using Procedure C in 8% yield. LC/MS (EI) t.sub.R
3.42, m/z 325 (M.sup.++1).
Example 102
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N-cyclopropylmethyl-5-trifluoromethox-
y-1H-indazole-3-carboxamide hydroformate
[1025] 123
[1026] Prepared using Procedure C in 5% yield. LC/MS (EI) t.sub.R
3.99, m/z 409 (M.sup.++1).
Example 103
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(hydroxy)-1H-indazole-3-carboxamide
[1027] 124
[1028] Prepared using Procedure C in 40% yield. LC/MS (EI) t.sub.R
9.80 [95/5 to 5/95 water (0.1% formic acid)/acetonitrile (0.1%
formic acid)], m/z 287 (M.sup.++1).
Example 104
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(hydroxymethyl)-1H-indazole-3-carbo-
xamide
[1029] 125
[1030] Prepared from Example 86 by sodium borohydride reduction in
12% yield. LC/MS (EI) t.sub.R 1.99, m/z 301 (M.sup.++1).
Example 105
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclopentylamino)-1H-indazole-3-ca-
rboxamide
[1031] 126
[1032] Prepared using Procedure C. The acid was prepared from ethyl
5-nitro-1H-indazole-3-carboxylate via reduction, reductive
amination, and saponification in 46% yield. LC/MS (EI) t.sub.R
1.92, m/z 354 (M.sup.++1).
[1033] Procedure D.
[1034] Procedure D provides a method for the coupling between
3-aminoquinuclidine and carboxylic acids to form carboxamide
derivatives.
[1035] The coupling reaction and purification was performed
according to procedures A and C (indazoles, benzthiazoles) or
according to procedure B (benzisothiazoles). 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 was maintained at room temperature for 2 h. The solids
were collected by filtration, rinsed with ether, and dried, thus
providing the hydrochloride salt in 40-60% yield.
[1036] The following compounds were prepared using this method:
Example 106
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide
hydrochloride
[1037] 127
[1038] Prepared using Procedure D in 42% yield. .sup.1H NMR (500
MHz, Me.sub.2SO-d.sub.6) .delta. 14.02 (s, 1H), 10.42 (s, 1H), 8.89
(d, J=7.0, 1H), 8.27 (s, 1H), 7.67 (d, J=8.5, 1H), 7.49 (dd, J=8.0,
1.0, 1H), 4.44 (m, 1H), 3.62 (m, 1H), 3.34 (m, 2H), 3.21 (m, 4H),
2.21 (m, 1H), 2.09 (m, 1H), 1.93 (m, 2H), 1.73 (m, 1H); LC/MS (EI)
t.sub.R 2.61, m/z 295 (M.sup.++1).
Example 107
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(5-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydrochloride
[1039] 128
[1040] Prepared using Procedure D in 56% yield. LC/MS (EI) t.sub.R
5.53, m/z 368 (M.sup.++1).
Example 108
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3,6-dihydro-2H-pyran-4-yl)-1H-inda-
zole-3-carboxamide hydrochloride
[1041] 129
[1042] Prepared using Procedure D in 29% yield. LC/MS (EI) t.sub.R
3.20, m/z 353 (M.sup.++1).
Example 109
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydrochloride
[1043] 130
[1044] Prepared using Procedure D. LC/MS (EI) t.sub.R 13.28
[Analytical HPLC was performed on 4.6 mm.times.250 mm YMC 0DS-AQ
S-5 120 m columns using a gradient of 05/95 to 95/05 acetonitrile
(0.05% trifluoroacetic acid)/water (0.05% trifluoroacetic acid)
over 35 min], m/z 368 (M.sup.++1).
Example 110
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydrochloride
[1045] 131
[1046] Prepared using Procedure D in 57% yield. LC/MS (EI) t.sub.R
14.00, m/z 367 (ES-Neg) (M.sup.+).
Example 111
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(trifluoromethoxy)-1H-indazole-3-ca-
rboxamide hydrochloride
[1047] 132
[1048] Prepared using Procedure D in 60% yield. LC/MS (EI) t.sub.R
5.13, m/z 355 (M.sup.++1).
Example 112
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-ca-
rboxamide hydrochloride
[1049] 133
[1050] Prepared using Procedure D in 68% yield. LC/MS (EI) t.sub.R
2.58, m/z 354 (M.sup.++1).
Example 113
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-ca-
rboxamide hydrochloride
[1051] 134
[1052] Prepared using Procedure D in 38% yield. LC/MS (EI) t.sub.R
2.58, m/z 354 (M.sup.++1).
Example 114
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-methoxy-1H-indazole-3-carboxamide
hydrochloride
[1053] 135
[1054] Prepared using Procedure D in 68% yield. LC/MS (EI) t.sub.R
2.53, m/z 301 (M.sup.++1).
[1055] Procedure E
[1056] Procedure E provides a method for the formation of
carboxamide derivatives from methyl 3-quinuclidinecarboxylic acid
ester.
[1057] To a solution of the amine in toluene was added 1.0 M
solution of trimethylaluminum in toluene (1.1 eq) at 0.degree. C.
After 30 min, an additional 1.1 eq of trimethylaluminum was added
followed by a solution of methyl 3-quinuclidinecarboxylic acid
ester hydrochloride salt (1.1 eq) in dioxane (5 mL). The reaction
mixture was heated at 70.degree. C. for 10 h, allowed to cool to
rt, and was poured onto a cold (0.degree. C.), aqueous solution of
sodium bicarbonate. The aqueous layer was extracted with 5%
methanol in methylene chloride (2.times.30 mL) and the combined
organic layers were washed with brine and concentrated. The residue
was purified by preparative HPLC.
[1058] Procedure F
[1059] Procedure F provides a method for the reduction of the
carboxamide to form secondary amine derivatives.
[1060] To a solution of the amide (50 mg) in tetrahydrofuran (4 mL)
was added lithium aluminum hydride (4.0 eq). The reaction mixture
was heated at reflux for 4 h, was cooled to 0.degree. C., and was
cautiously quenched with ethanol. The resultant slurry was poured
onto ice water and extracted with 5% methanol in dichloromethane
(3.times.) and the combined organic layers were concentrated. The
residue was purified by preparative HPLC.
[1061] Procedure G.
[1062] Procedure G provides a method for the coupling between
brominated and iodinated aminoquinuclidinecarboxamides and boronic
acids to form aryl-substituted derivatives.
[1063] In a 5 mL microwave reaction vessel was added the bromide
(0.286 mmol), the boronic acid (0.588 mmol),
tris(dibenzylideneacetone)dipalladi- um (0) (0.0289 mmol),
tri-tert-butylphosphine tetrafluoroborate (0.0579 mmol), and
potassium carbonate (0.810 mmol). The vessel was evacuated,
back-filled with argon gas, and the contents diluted with
N,N-dimethylformamide (5.0 mL). The vessel was sealed and subjected
to microwave irradiation at 200.degree. C. for 600 s. The contents
of the reaction were filtered through Celite (methanol wash) and
loaded on a 5 g SCX column. The column was washed with methanol (50
mL) and the product was eluted with 2 M ammonia in methanol and
concentrated. The residue was purified by preparative HPLC, thus
providing the product in 15-40% yield.
[1064] The following compounds were prepared using this method:
Example 115
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(3-thienyl)-1H-indazole-3-
-carboxamide hydroformate
[1065] 136
[1066] Prepared using Procedure G or C in 37% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.39 (s, 1H), 7.57 (d, J=9.1, 1H), 7.46 (m,
1H), 7.39 (d, J=9.1, 1H), 7.36 (m, 1H), 7.23 (m, 1H), 4.03 (m, 1H),
3.79 (s, 3H), 3.59 (m, 1H), 3.3-3.2 (m, 5H), 2.81 (m, 1H), 2.10 (m,
1H), 1.97 (m, 2H), 1.79 (m, 1H). LC/MS (EI) t.sub.R 2.60, m/z 383
(M.sup.++1).
Example 116
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-
-carboxamide hydroformate
[1067] 137
[1068] Prepared using Procedure G or C in 12% yield. LC/MS (EI)
t.sub.R 2.62, m/z 383 (M.sup.++1).
Example 117
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-methoxy-4-(2-thienyl)-1H-indazole-3-
-carboxamide hydroformate
[1069] 138
[1070] Prepared using Procedure G or C in 16% yield. LC/MS (EI)
t.sub.R 2.37, m/z 383 (M.sup.++1).
[1071] Procedure H.
[1072] Procedure H provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and Grignard reagents to
form alkyl-substituted derivatives.
[1073] A 5 mL microwave reaction vessel was charged with
bis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq)
and the bromide (0.30 mmol). The vessel was evacuated and
back-filled with argon gas. In a separate reaction vessel, solution
of the Grignard (1.2 mmol, 4 eq) was added to a 0.5 M solution of
zinc chloride (1.2 mmol, 4 eq) in tetrahydrofuran at rt. The
suspension was maintained for 30 min and the entire contents were
transferred to the reaction vessel via cannula. The vessel was
sealed and subjected to microwave irradiation at 100.degree. C. for
600 sec with a pre-stir time of 60 s. The reaction was quenched
with acetic acid (0.5 mL), diluted with methanol, and was
transferred to a SCX column. The column was washed with methanol
(50 mL) and the product was eluted with 2 M ammonia in methanol (50
mL) and concentrated. The residue was purified by chromatography
[90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1
ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)]
or by preparative HPLC, thus providing the product in 20-50%
yield.
[1074] The Grignard reagent of thiazole is commercially available.
Alternatively, the aryllithium and the corresponding arylzinc
reagent can be generated according to the procedure outlined by
Reeder, M. R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696. The
zinc reagents of oxazole, 1-methylimidazole, and related reagents
were prepared according to this procedure.
[1075] The following compounds were prepared using this method:
Example 118
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxami-
de
[1076] 139
[1077] Prepared using Procedure H in 21% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.07 (s, 1H), 7.50. (d, J=8.7, 1H), 7.36 (d,
J=8.7, 1H), 4.21 (m, 1H), 3.36 (m, 1H), 3.15 (m, 1H), 3.02 (m, 1H),
3.0-2.8 (m, 4H), 2.2-2.0 (m, 3H), 2.0-1.5 (m, 10H). LC/MS (EI)
t.sub.R 5.11, m/z 339 (M.sup.++1).
Example 119
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-ca-
rboxamide hydroformate
[1078] 140
[1079] Prepared using Procedure H in 37% yield. LCMS (EI) t.sub.R
4.28, m/z 354 (M.sup.++1).
Example 120
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-ca-
rboxamide hydroformate
[1080] 141
[1081] Prepared using Procedure H in 18% yield. LC/MS (EI) t.sub.R
2.54, m/z 354 (M.sup.++1).
Example 121
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1H-indazole-3-ca-
rboxamide hydroformate
[1082] 142
[1083] Prepared using Procedure H in 18% yield. LC/MS (EI) t.sub.R
2.58, m/z 354 (M.sup.++1).
Example 122
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-thiazol-2-yl)-1H-indazole-3-ca-
rboxamide hydroformate
[1084] 143
[1085] Prepared using Procedure H in 12% yield. LC/MS (EI) t.sub.R
3.96, m/z 354 (M.sup.++1).
Example 123
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(prop-1-yn-1-yl)-1H-indazole-3-carb-
oxamide hydroformate
[1086] 144
[1087] Prepared using Procedure H in 24% yield. LC/MS (EI) t.sub.R
4.97, m/z 309 (M.sup.++1).
Example 124
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-car-
boxamide
[1088] 145
[1089] Prepared using Procedure H in 71% yield. LC/MS (EI) t.sub.R
2.58, m/z 338 (M.sup.++1).
Example 125
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-car-
boxamide
[1090] 146
[1091] Prepared using Procedure H in 85% yield. LC/MS (EI) t.sub.R
2.61, m/z 338 (M.sup.++1).
Example 126
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1,3-oxazol-2-yl)-1H-indazole-3-car-
boxamide
[1092] 147
[1093] Prepared using Procedure H in 55% yield. LC/MS (EI) t.sub.R
3.12, m/z 338 (M.sup.++1).
Example 127
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-oxazol-2-yl)-1H-indazole-3-car-
boxamide
[1094] 148
[1095] Prepared using Procedure H in 72% yield. LC/MS (EI) t.sub.R
2.64, m/z 338 (M.sup.++1).
Example 128
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-inda-
zole-3-carboxamide hydroformate
[1096] 149
[1097] Prepared using Procedure H in 11% yield. LC/MS (EI) t.sub.R
1.21, m/z 351 (M.sup.++1).
Example 129
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1-methyl-1H-imidazol-2-yl)-1H-inda-
zole-3-carboxamide hydroformate
[1098] 150
[1099] Prepared using Procedure H in 18% yield. LC/MS (EI) t.sub.R
1.23, m/z 351 (M.sup.++1).
Example 130
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyclopentyl-1H-indazole-3-carboxami-
de
[1100] 151
[1101] Prepared using Procedure H in 25% yield. LC/MS (EI) t.sub.R
5.27, m/z 339 (M.sup.++1).
Example 131
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxami-
de
[1102] 152
[1103] Prepared using Procedure H in 30% yield. LC/MS (EI) t.sub.R
5.11, m/z 339 (M.sup.++1).
Example 132
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclopentyl-1H-indazole-3-carboxami-
de
[1104] 153
[1105] Prepared using Procedure H in 38% yield. LC/MS (EI) t.sub.R
5.10, m/z 339 (M.sup.++1).
Example 133
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamid-
e hydroformate
[1106] 154
[1107] Prepared using Procedure H in 11% yield. LC/MS (EI) t.sub.R
5.37, m/z 353 (M.sup.++1).
Example 134
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamid-
e hydroformate
[1108] 155
[1109] Prepared using Procedure H in 12% yield. LC/MS (EI) t.sub.R
5.33, m/z 353 (M.sup.++1).
Example 135
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamid-
e
[1110] 156
[1111] Prepared using Procedure H in 32% yield. LC/MS (EI) t.sub.R
5.37, m/z 353 (M.sup.++1).
Example 136
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyclohexyl-1H-indazole-3-carboxamid-
e
[1112] 157
[1113] Prepared using Procedure H in 10% yield. LC/MS (EI) t.sub.R
5.39, m/z 353 (M.sup.++1).
Example 137
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(propyl)-1H-indazole-3-carboxamide
hydroformate
[1114] 158
[1115] Prepared using Procedure H in 6% yield. LC/MS (EI) t.sub.R
4.84, m/z 315 (M.sup.++1).
Example 138
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(ethyl)-1H-indazole-3-carboxamide
hydroformate
[1116] 159
[1117] Prepared using Procedure H in 19% yield. LC/MS (EI) t.sub.R
4.48, m/z 299 (M.sup.++1).
Example 139
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide
[1118] 160
[1119] Prepared using Procedure H in 43% yield. LC/MS (EI) t.sub.R
4.98, m/z 368 (M.sup.++1).
Example 140
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide
[1120] 161
[1121] Prepared using Procedure H in 30% yield. LC/MS (EI) t.sub.R
4.96, m/z 368 (M.sup.++1).
Example 141
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(5-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide
[1122] 162
[1123] Prepared using Procedure H in 30% yield. LC/MS (EI) t.sub.R
5.01, m/z 368 (M.sup.++1).
Example 142
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide
[1124] 163
[1125] Prepared using Procedure H in 56% yield. LC/MS (EI) t.sub.R
4.59, m/z 368 (M.sup.++1).
Example 143
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butyl)-1H-indazole-3-carboxamide
hydroformate
[1126] 164
[1127] Prepared using Procedure H in 15% yield. LC/MS (EI) t.sub.R
5.41, m/z 327 (M.sup.++1).
Example 144
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-cyclopropyl-5-methoxy-1H-indazole-3-
-carboxamide hydroformate
[1128] 165
[1129] Prepared using Procedure H in 20% yield. LC/MS (EI) t.sub.R
2.73, m/z 341 (M.sup.++1).
Example 145
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-ethyl-5-methoxy-1H-indazole-3-carbo-
xamide hydroformate
[1130] 166
[1131] Prepared using Procedure H in 10% yield. LC/MS (EI) t.sub.R
2.42, m/z 329 (M.sup.++1).
Example 146
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-methyl-1,3-thiazol-2-yl)-1H-inda-
zole-3-carboxamide hydroformate
[1132] 167
[1133] Prepared using Procedure H in 24% yield. LC/MS (EI) t.sub.R
4.98, m/z 368 (M.sup.++1).
Example 147
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-5-(1,3-thiazol-2-yl)-1H-indaz-
ole-3-carboxamide hydroformate
[1134] 168
[1135] Prepared using Procedure H in 61% yield. LC/MS (EI) t.sub.R
3.63, m/z 382 (M.sup.++1).
Example 148
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-cyclopropylmethyl-5-(1,3-thiazol-2--
yl)-1H-indazole-3-carboxamide hydroformate
[1136] 169
[1137] Prepared using Procedure H in 10% yield. LC/MS (EI) t.sub.R
3.97, m/z 408 (M.sup.++1).
Example 149
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-(1,3-thiaz-
ol-2-yl)-1H-indazole-3-carboxamide hydroformate
[1138] 170
[1139] Prepared using Procedure H in 18% yield. LC/MS (EI) t.sub.R
3.87, m/z 436 (M.sup.++1).
Example 150
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-(1,3-thiazol-2-yl)-1H-indaz-
ole-3-carboxamide hydroformate
[1140] 171
[1141] Prepared using Procedure H in 32% yield. LC/MS (EI) t.sub.R
3.67, m/z 382 (M.sup.++1).
Example 151
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiaz-
ole-3-carboxamide hydroformate
[1142] 172
[1143] Prepared using Procedure H in 16% yield. LC/MS (EI) t.sub.R
5.20, m/z 371 (M.sup.++1).
Example 152
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1,2-benzisothiaz-
ole-3-carboxamide hydroformate
[1144] 173
[1145] Prepared using Procedure H in 36% yield. LC/MS (EI) t.sub.R
5.16, m/z 371 (M.sup.++1).
Example 153
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(methyl)-1H-indazole-3-carboxamide
hydroformate
[1146] 174
[1147] Prepared using Procedure H or C in 13% yield. LC/MS (EI)
t.sub.R 3.18, m/z 285 (M.sup.++1).
[1148] Procedure I.
[1149] Procedure I provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and acetylenes to form
alkynyl-substituted derivatives.
[1150] A 5 mL microwave reaction vessel was charged with
bis(triphenylphosphine)palladium (II) chloride (0.0597 mmol, 0.1
eq), copper (I) iodide (0.0719 mmol, 0.12 eq.), triphenylphosphine
(0.124 mmol, 0.2 eq.), and the bromide (0.578 mmol). The vessel was
evacuated and back-filled with argon gas. The alkyne (0.71 mmol,
1.2 eq), diethylamine (3.5 mL), and N,N-dimethylformamide (1.5 mL)
were added and the vessel was sealed and subjected to microwave
irradiation at 120.degree. C. for 1500 sec. The reaction was
reduced under vacuum to .about.1.5 mL and was transferred to a SCX
column. The column was washed with methanol (50 mL) and the product
was eluted with 2 M ammonia in methanol (50 mL) and concentrated.
The residue was purified by chromatography [1/1 to 0/1 ethyl
acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to
provide the silylacetylene in 90-95% yield. The silane was
dissolved in tetrahydrofuran (2.5 mL) and was treated with
tetrabutylammonium fluoride (0.6 mL of a 1 M solution in
tetrahydrofuran). The reaction mixture was maintained for 11 h and
was transferred to a SCX column. The column was washed with
methanol (50 mL) and the product was eluted with 2 M ammonia in
methanol (50 mL) and concentrated. The residue was purified by
preparative HPLC, thus providing the product in 40-60% yield.
[1151] The following compounds were prepared using this method:
Example 154
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide
hydroformate
[1152] 175
[1153] Prepared using Procedure I in 36% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.41 (s, 1H), 8.33 (s, 1H), 7.58 (d, J=8.7,
1H), 7.49 (dd, J=8.7, 1.4, 1H), 4.53 (m, 1H), 3.82 (m, 1H), 3.47
(s, 1H), 3.31 (m, 5H), 2.38 (m, 1H), 2.27 (m, 1H), 2.10 (m, 2H),
1.93 (m, 1H); LC/MS (EI) t.sub.R 2.61, m/z 295 (M.sup.++1).
Example 155
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide
hydroformate
[1154] 176
[1155] Prepared using Procedure I in 40% yield. LC/MS (EI) t.sub.R
2.73, m/z 295 (M.sup.++1).
Example 156
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carboxamide
hydroformate
[1156] 177
[1157] Prepared using Procedure I in 29% yield. LC/MS (EI) t.sub.R
2.73, m/z 295 (M.sup.++1).
Example 157
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-ethynyl-1H-indazole-3-carboxamide
hydroformate
[1158] 178
[1159] Prepared using Procedure I in 30% yield. LC/MS (EI) t.sub.R
2.63, m/z 295 (M.sup.++1).
Example 158
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(pent-1-yn-1-yl)-1H-indazole-3-carb-
oxamide hydroformate
[1160] 179
[1161] Prepared using Procedure I in 37% yield. LC/MS (EI) t.sub.R
5.28, m/z 337 (M.sup.++1).
Example 159
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(phenylethynyl)-1H-indazole-3-carbo-
xamide hydroformate
[1162] 180
[1163] Prepared using Procedure I in 36% yield. LC/MS (EI) t.sub.R
5.46, m/z 371 (M.sup.++1).
Example 160
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carbo-
xamide hydroformate
[1164] 181
[1165] Prepared using Procedure I in 9% yield. LC/MS (EI) t.sub.R
4.24, m/z 312 (M.sup.++1).
Example 161
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1,2-benzisothiazole-3-carbo-
xamide hydroformate
[1166] 182
[1167] Prepared using Procedure I in 5% yield. LC/MS (EI) t.sub.R
5.22, m/z 312 (M.sup.++1).
[1168] Procedure J.
[1169] Procedure J provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and cyclic alkenes to
form cycloalkenyl-substituted derivatives.
[1170] A 5 mL microwave reaction vessel was charged with palladium
(II) acetate (0.012 mmol, 0.04 eq), tri-o-tolylphosphine (0.030
mmol, 0.1 eq.), and the bromide (0.358 mmol). The vessel was
evacuated and back-filled with argon gas. The alkene (0.30 mmol),
diisopropylethylamine (63 .mu.L), and N,N-dimethylformamide (2.8
mL) were added and the vessel was sealed and subjected to microwave
irradiation at 220.degree. C. for 300 sec. The reaction was
transferred to a SCX column and the column was washed with methanol
(50 mL). The product was eluted with 2 M ammonia in methanol (50
mL) and concentrated. The residue was purified by chromatography
[1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium
hydroxide)] and was further purified by preparative HPLC, thus
providing the product in 7-40% yield.
[1171] The following compounds were prepared using this method:
Example 162
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(cyclohex-1-en-1-yl)-1H-indazole-3--
carboxamide hydroformate
[1172] 183
[1173] Prepared using Procedure J in 7% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.48 (s, 1H), 8.05 (s, 1H), 7.53 (d, J=8.7,
1H), 7.37 (dd, J=8.7, 1.6, 1H), 5.77 (m, 1H), 4.52 (m, 1H), 3.81
(m, 1H), 3.35 (m, 5H), 2.38 (m, 1H), 2.27 (m, 1H), 2.10 (m, 2H),
1.93 (m, 1H); LC/MS (EI) t.sub.R 5.14, m/z 351 (M.sup.++1).
Example 163
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-formylcyclohex-1-en-1-yl)-1H-ind-
azole-3-carboxamide hydroformate
[1174] 184
[1175] Prepared using Procedure J in 1% yield. LC/MS (EI) t.sub.R
4.91, m/z 379 (M.sup.++1).
Example 164
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(tetrahydrofuran-3-yl)-1H-indazole--
3-carboxamide hydroformate
[1176] 185
[1177] Prepared using Procedure J followed by hydrogenation in 2%
yield. LC/MS (EI) t.sub.R 3.59, m/z 341 (M.sup.++1).
[1178] Procedure K.
[1179] Procedure K provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and nickel (II) cyanide
to form cyano-substituted derivatives.
[1180] A 5 mL microwave reaction vessel was charged with nickel
(II) cyanide (3.11 mmol, 5.4 eq) and the bromide (0.578 mmol). The
vessel was evacuated, back-filled with argon gas, and diluted with
N-methylpyrrolidinone (5.0 mL). The vessel was sealed and subjected
to microwave irradiation at 200.degree. C. for 2400 sec. The
reaction was transferred to a SCX column and the column was washed
with methanol (50 mL). The product was eluted with 2 M ammonia in
methanol (50 mL) and concentrated. The residue was purified by
preparative HPLC, thus providing the product in 10-40% yield.
[1181] Literature Reference: Arvella, R. K.; Leadbeater, N. E. J.
Org. Chem. 2003, 68, 9122.
[1182] The following compounds were prepared using this method:
Example 165
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxa-
mide hydroformate
[1183] 186
[1184] Prepared using Procedure K in 41% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.94 (d, J=8.5, 1H), 8.63 (s, 1H), 7.83 (d,
J=8.5, 1H), 4.55 (m, 1H), 3.89-3.81 (m, 1H), 3.53-3.31 (m, 5H),
2.42 (m, 1H), 2.26-2.16 (m, 1H), 2.14-2.03 (m, 2H), 1.99-1.91 (m,
1H); LC/MS (EI) t.sub.R 3.68, m/z 313 (M.sup.++1).
Example 166
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide
hydroformate
[1185] 187
[1186] Prepared using Procedure K in 39% yield. LC/MS (EI) t.sub.R
2.59, m/z 296 (M.sup.++1).
Example 167
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide
hydroformate
[1187] 188
[1188] Prepared using Procedure K in 52% yield. LC/MS (EI) t.sub.R
2.55, m/z 296 (M.sup.++1).
Example 168
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-cyano-1H-indazole-3-carboxamide
hydroformate
[1189] 189
[1190] Prepared using Procedure K in 18% yield. LC/MS (EI) t.sub.R
2.47, m/z 296 (M.sup.++1).
Example 169
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1H-indazole-3-carboxamide
hydroformate
[1191] 190
[1192] Prepared using Procedure K in 42% yield. LC/MS (EI) t.sub.R
2.47, m/z 296 (M.sup.++1).
Example 170
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxa-
mide hydroformate
[1193] 191
[1194] Prepared using Procedure K in 48% yield. LC/MS (EI) t.sub.R
2.99, m/z 313 (M.sup.++1).
Example 171
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxa-
mide hydrotrifluoroacetate
[1195] 192
[1196] Prepared using Procedure K in 41% yield. LC/MS (EI) t.sub.R
3.68, m/z 313 (M.sup.++1).
Example 172
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-cyano-1,2-benzisothiazole-3-carboxa-
mide hydrotrifluoroacetate
[1197] 193
[1198] Prepared using Procedure K in 48% yield. LC/MS (EI) t.sub.R
2.99, m/z 313 (M.sup.++1).
[1199] Procedure L.
[1200] Procedure L provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and phenols to form
biaryl ether derivatives.
[1201] A 2.5 mL microwave reaction vessel was charged with copper
(II) triflate (0.144 mmol, 0.5 eq.), cesium carbonate (0.565 mmol,
2 eq.), benzoic acid (0.402 mmol, 1.4 eq.), and the bromide (0.284
mmol). The vessel was evacuated and back-filled with argon gas. A
0.5 M solution of the phenol in N,N-dimethylformamide (1.2 mL, 0.60
mmol, 2.1 eq), and N,N-dimethylformamide (1.3 mL) were added and
the vessel was sealed and subjected to microwave irradiation at
200.degree. C. for 2400 sec. The reaction mixture was transferred
to a SCX column and the column was washed with methanol (50 mL).
The product was eluted with 2 M ammonia in methanol (50 mL) and
concentrated. The residue was purified by chromatography [1/1 to
0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium
hydroxide)] and was further purified by preparative HPLC, thus
providing the product in 10-40% yield.
[1202] The following compounds were prepared using this method:
Example 173
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-1H-indazole-3-carboxamide
hydroformate
[1203] 194
[1204] Prepared using Procedure L in 2% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.53 (s, 1H), 7.71 (d, J=1.8, 1H), 7.63 (d,
J=9.0, 1H), 7.37 (dd, J=8.4, 7.5, 2H), 7.23 (dd, J=9.0. 2.3, 1H),
7.12 (t, J=7.4, 2H), 7.01 (d, J=8.8, 1H), 4.52 (m, 1H), 3.81 (m,
1H), 3.35 (m, 5H), 2.38 (m, 1H), 2.27 (m, 1H), 2.10 (m, 2H), 1.93
(m, 1H); LC/MS (EI) t.sub.R 5.02, m/z 363 (M.sup.++1).
[1205] Procedure M.
[1206] Procedure M provides a method for the coupling between
aniline or phenol bearing aminoquinuclidinecarboxamides and
alkylating agents to form secondary aniline- or ether-substituted
derivatives.
[1207] To a solution of
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1,2-
-benzisothiazole-3-carboxamide (0.400 mol) in N,N-dimethylformamide
(6 mL) was added potassium carbonate (2.00 mol) and
cyclopropylmethyl bromide (0.47 mmol). The reaction was maintained
for 16 h and the solvent was removed in vacuo. The residue was
extracted with 10/1 dichloromethane/methanol (3.times.) and the
combined extracts were concentrated. The residue was purified by
preparative HPLC using an 8 min gradient of 95/5 to 20/80 water
(0.1% formic acid)/acetonitrile (0.1% formic acid), thus providing
the product in 32% yield.
[1208] The following compounds were prepared by this method:
Example 174
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(2-methoxyethoxy)propoxy]-1,2-be-
nzisothiazole-3-carboxamide hydroformate
[1209] 195
[1210] Prepared using Procedure M in 30% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.55 (d, J=9.0, 1H), 8.38 (broad, 1H), 7.37
(s, 1H), 7.05 (d, J=9.0, 1H), 4.55 (m, 1H), 3.95 (t, J=9.0, 1H),
3.70-3.45 (m, 1H), 3.31 (s, 3H), 2.40 (m, 1H), 2.30 (m, 1H), 2.15
(m, 2H), 2.05 (m, 2H), 1.30 (t, J=6.0, 2H). LC/MS (EI) t.sub.R
2.88, m/z 420 (M.sup.++1).
Example 175
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(cyclopropylmethoxy)-1,2-benzisothi-
azole-3-carboxamide hydroformate
[1211] 196
[1212] Prepared using Procedure M in 32% yield. LC/MS (EI) t.sub.R
3.48, m/z 358 (M.sup.++1).
[1213] Procedure N.
[1214] Procedure N provides a method for the hydrolysis of
nitrile-substituted 3-aminoquinuclidinecarboxamides to form
carboxyl-substituted derivatives.
[1215] A 2.5 mL microwave reaction vessel was charged with the
nitrile (0.195 mmol), water (2.0 mL), and 2 N sodium hydroxide (0.5
mL). The vessel was sealed and subjected to microwave irradiation
at 200.degree. C. for 1800 sec. The reaction was acidified with
acetic acid (.about.1.5 mL) and was transferred to a SCX column.
The column was washed with methanol (50 mL) and the product was
eluted with 2 M ammonia in methanol (50 mL) and concentrated. The
residue was purified by preparative HPLC, thus providing the
product in 5-30% yield.
[1216] The following compounds were prepared using this method:
Example 176
3-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazole-6-carboxyl-
ic acid hydroformate
[1217] 197
[1218] Prepared using Procedure N in 3% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.39 (s, 1H), 8.25 (s, 1H), 8.21 (d, J=8.6,
1H), 7.89 (dd, J=8.6, 1.2, 1H), 4.53 (m, 1H), 3.84 (m, 1H), 3.37
(m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.94 (m, 1H);
LC/MS (EI) t.sub.R 2.37, m/z 315 (M.sup.++1).
[1219] Procedure O.
[1220] Procedure O provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and amines to form
amino-substituted derivatives.
[1221] In a 5 mL microwave reaction vessel was added the bromide
(133 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (34
mg, 0.04 mmol), cesium bicarbonate (213 mg, 1.1 mmol), and
(2'-dicyclohexylphosphanylbiph- enyl-2-yl)dimethylamine (30 mg,
0.07 mmol). The vial was then evacuated and back-filled with argon
gas. The mixture of solids was then diluted with the amine (0.7
mL), dioxane (1 mL), and triethylamine (0.5 mL) and the reaction
vessel was sealed. The reaction mixture was subjected to microwave
irradiation at 120.degree. C. for 1800 s. The reaction mixture was
filtered through a plug of Celite and concentrated in vacuo. The
crude product was purified by chromatography (90/10/1
dichloromethane/methanol/ammonium hydroxide), thus providing the
product in 34% yield as a colorless solid.
[1222] The following compounds were prepared using this method:
Example 177
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-in-
dazole-3-carboxamide
[1223] 198
[1224] Prepared using Procedure O in 13% yield. .sup.1H NMR
(CD.sub.3OD) .delta. d 8.09 (dd, J=1.9, 0.7, 1H), 7.55 (dd, J=8.8,
0.7, 1H), 7.41 (dd, J=8.8, 1.9, 1H), 5.82 (s, 2H), 4.22 (m, 1H),
3.35 (m, 1H), 3.03 (m, 1H), 3.0-2.8 (m, 4H), 2.06 (m, 1H), 2.00 (m,
1H), 1.99 (s, 6H), 1.79 (m, 2H), 1.55 (m, 1H); LC/MS (EI) t.sub.R
5.00, m/z 364 (M.sup.++1).
Example 178
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carb-
oxamide
[1225] 199
[1226] Prepared using Procedure O in 7% yield. LC/MS (EI) t.sub.R
4.94, m/z 336 (M.sup.++1).
Example 179
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(1H-pyrrol-1-yl)-1H-indazole-3-carb-
oxamide
[1227] 200
[1228] Prepared using Procedure O in 26% yield. LC/MS (EI) t.sub.R
4.79, m/z 336 (M.sup.++1).
[1229] Procedure P.
[1230] Procedure P provides a method for the coupling between
brominated 3-aminoquinuclidinecarboxamides and cyclic, secondary
amines to form amino-substituted derivatives.
[1231] A 2.5 mL microwave reaction vessel was charged with
tris(dibenzylideneacetone)dipalladium (0) (0.060 mmol, 0.1 eq),
[2'-(dimethylamino)biphenyl-2-yl]dicyclohexylphosphine (0.060 mmol,
0.1 eq), and the bromide (0.550 mmol). The vessel was evacuated and
back-filled with argon gas. The amine (0.66 mmol, 1.2 eq) and a 1 M
solution of lithium hexamethyldisilazide in tetrahydrofuran (1.7
mmol, 3 eq) were added and the vessel was sealed and heated at
65.degree. C. for 15 h. The reaction was transferred to a SCX
column and the column was washed with methanol (50 mL). The product
was eluted with 2 M ammonia in methanol (50 mL) and concentrated.
The residue was purified by preparative HPLC, thus providing the
product in 30-50% yield.
[1232] Literature reference: Harris, M. C.; Huang, X.; Buchwald, S.
L. Org. Lett. 2002, 4, 2885.
[1233] The following compounds were prepared using this method:
Example 180
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-pyrrolidin-1-yl-1H-indazole-3-carbo-
xamide
[1234] 201
[1235] Prepared using Procedure P in 24% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 7.43 (d, J=9.1, 1H), 7.20 (s, 1H), 6.98 (d,
J=9.1, 1H), 4.20 (m, 1H), 3.5-3.2 (m, 5H), 3.15 (m, 1H), 3.0-2.8
(m, 4H), 2.2-2.0 (m, 6H), 1.79 (m, 2H), 1.55 (m, 1H); LC/MS (EI)
t.sub.R 2.53, m/z 340 (M.sup.++1).
Example 181
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-cyclohexylpiperazin-1-yl)-1,2-be-
nzisothiazole-3-carboxamide hydroformate
[1236] 202
[1237] Prepared using Procedure P in 52% yield. LC/MS (EI) t.sub.R
2.40, m/z 454 (M.sup.++1).
Example 182
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(4-ethylpiperazin-1-yl)-1,2-benziso-
thiazole-3-carboxamide hydroformate
[1238] 203
[1239] Prepared using Procedure P in 51% yield. LC/MS (EI) t.sub.R
1.57, m/z 400 (M.sup.++1).
Example 183
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[4-(3-furoyl)piperazin-1-yl]-1,2-be-
nzisothiazole-3-carboxamide hydroformate
[1240] 204
[1241] Prepared using Procedure P in 50% yield. LC/MS (EI) t.sub.R
4.61, m/z 466 (M.sup.++1).
Example 184
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-ethoxypyrrolidin-1-yl)-1,2-benzi-
sothiazole-3-carboxamide
[1242] 205
[1243] Prepared using Procedure P in 58% yield. LC/MS (EI) t.sub.R
3.87, m/z 401 (M.sup.++1).
Example 185
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-ethoxypyrrolidin-1-yl)-1,2-benzi-
sothiazole-3-carboxamide
[1244] 206
[1245] Prepared using Procedure P in 41% yield. LC/MS (EI) t.sub.R
3.67, m/z 401 (M.sup.++1).
Example 186
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxypyrrolidin-1-yl)-1,2-benz-
isothiazole-3-carboxamide
[1246] 207
[1247] Prepared using Procedure P in 19% yield. LC/MS (EI) t.sub.R
3.63, m/z 387 (M.sup.++1).
Example 187
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-pyrrolidin-1-yl-1H-indazole-3-carbo-
xamide
[1248] 208
[1249] Prepared using Procedure P in 24% yield. LC/MS (EI) t.sub.R
4.63, m/z 340 (M.sup.++1).
Example 188
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-piperidin-1-yl-1H-indazole-3-carbox-
amide hydrotrifluoroacetate
[1250] 209
[1251] Prepared using Procedure P in 51% yield. LC/MS (EI) t.sub.R
1.88, m/z 354 (M.sup.++1).
Example 189
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-piperidin-1-yl-1H-indazole-3-carbox-
amide hydroformate
[1252] 210
[1253] Prepared using Procedure P in 26% yield. LC/MS (EI) t.sub.R
1.60, m/z 354 (M.sup.++1).
Example 190
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-morpholin-4-yl-1H-indazole-3-carbox-
amide
[1254] 211
[1255] Prepared using Procedure P in 25% yield. LC/MS (EI) t.sub.R
2.60, m/z 356 (M.sup.++1).
Example 191
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(morpholin-4-yl)-1H-indazole-3-carb-
oxamide
[1256] 212
[1257] Prepared using Procedure P in 16% yield. LC/MS (EI) t.sub.R
2.42, m/z 356 (M.sup.++1).
Example 192
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-et-
hyl-1H-indazole-3-carboxamide hydroformate
[1258] 213
[1259] Prepared using Procedure P in 24% yield. LC/MS (EI) t.sub.R
4.53, m/z 474 (M.sup.++1).
Example 193
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[3-(benzyloxy)pyrrolidin-1-yl]-1-et-
hyl-1H-indazole-3-carboxamide hydroformate
[1260] 214
[1261] Prepared using Procedure P in 48% yield. LC/MS (EI) t.sub.R
4.55 min, m/z 474 (M.sup.++1).
Example 194
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[3-(benzyloxy)pyrrolidin-1-yl]-1-(c-
yclopropylmethyl)-1H-indazole-3-carboxamide hydroformate
[1262] 215
[1263] Prepared using Procedure P in 51% yield. LC/MS (EI) t.sub.R
4.67 min, m/z 500 (M.sup.++1).
[1264] Procedure Q
[1265] Procedure Q provides a method for the coupling between
brominated aminoquinuclidinecarboxamides and benzophenone imine to
form aniline derivatives.
[1266] The mixture of
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-ben-
zisothiazole-3-carboxamide (6.30 mmol), palladium acetate (1.00
mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene
(Xantphos) (0.700 mmol) was evacuated and back-fill with Ar gas.
The solids were 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 redissolved in a mixture of
tetrahydrofuran (90 mL) and 3 N hydrochloric acid (30 mL). The
reaction mixture was maintained for 2 h and was concentrated. The
residue was purified by chromatography using a mixture of 70/30/1
ethyl acetate/methanol/ammonium hydroxide, thus providing the
aniline in 79% yield. The aniline was used directly in subsequent
reactions.
[1267] The following compounds were prepared by this method:
Example 195
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoxazole-3-carboxami-
de
[1268] 216
[1269] Prepared using Procedure Q in 72% yield. LC/MS (EI) t.sub.R
2.44, m/z 287 (M.sup.++1).
Example 196
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxa-
mide
[1270] 217
[1271] Prepared using Procedure Q in 69% yield. LC/MS (EI) t.sub.R
2.86, m/z 303 (M.sup.++1).
Example 197
6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-carboxa-
mide
[1272] 218
[1273] Prepared using Procedure Q in 73% yield. LC/MS (EI) t.sub.R
2.84, m/z 303 (M.sup.++1).
Example 198
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-1H-i-
ndazole-3-carboxamide
[1274] 219
[1275] Prepared using Procedure Q in 64% yield. LC/MS (EI) t.sub.R
1.43, m/z 368 (M.sup.++1).
Example 199
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-1H-inda-
zole-3-carboxamide
[1276] 220
[1277] Prepared using Procedure Q in 67% yield. LC/MS (EI) t.sub.R
1.43, m/z 340 (M.sup.++1).
Example 200
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carbo-
xamide
[1278] 221
[1279] Prepared using Procedure Q in 68% yield. LC/MS (EI) t.sub.R
1.34, m/z 314 (M.sup.++1).
Example 201
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-1H-indazole-3-carbo-
xamide
[1280] 222
[1281] Prepared using Procedure Q in 61% yield. LC/MS (EI) t.sub.R
1.36, m/z 314 (M.sup.++1).
[1282] Procedure R
[1283] Procedure R provides a method for the reduction of nitro
aminoquinuclidinecarboxamides to form aniline derivatives.
[1284] A mixture of the nitro compound (1.06 mmol) and 10%
palladium on carbon (100 mg) in a Parr shaker bottle was diluted
with methanol (100 mL). The reaction vessel was pressurized to 30
psi with hydrogen gas and was maintained for 3 h. The reaction was
evacuated, back-filled with nitrogen gas, and the catalyst removed
by filtration through Celite. The organic layer was concentrated to
provide the amine product (91%). The aniline was used directly in
subsequent reactions.
[1285] The following compounds were prepared by this method:
Example 202
6-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide
[1286] 223
[1287] Prepared using Procedure R in 4% yield. LC/MS (EI) t.sub.R
1.85, m/z 386 (M.sup.++1).
Example 203
5-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide
[1288] 224
[1289] Prepared using Procedure R in 91% yield. LC/MS (EI) t.sub.R
1.36, m/z 286 (M.sup.++1).
Example 204
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide
[1290] 225
[1291] Prepared using Procedure R in 95% yield. LC/MS (EI) t.sub.R
1.30, m/z 286 (M.sup.++1).
Example 205
4-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide
[1292] 226
[1293] Prepared from Example 87 using Procedure R in 97% yield.
LC/MS (EI) t.sub.R 2.53, m/z 286 (M.sup.++1).
Example 206
7-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide
[1294] 227
[1295] Prepared from the corresponding 6-bromo-7-nitro analog using
Procedure R in 11% yield. LC/MS (EI) t.sub.R 1.79, m/z 286
(M.sup.++1).
[1296] Procedure S.
[1297] Procedure S provides a method for the coupling between
3-aminoquinuclidine and carboxaldehydes to form secondary amine
derivatives.
[1298] The suspension of 1H-indazole-4-carboxaldehyde (100 mg),
3-aminoquinuclidine dihydrocloride salt (1.0 eq), and 4 .ANG.
molecular sieves in dioxane (4 mL) was heated at reflux for 4 h.
The reaction mixture was allowed to cool to rt and was treated with
sodium triacetoxyborohydride (3 eq). The reaction mixture was
maintained at rt for 2 h and was poured into water, extracted with
5% methanol in dichloromethane (2.times.30 mL), and the combined
extracts were concentrated. The residue was purified by preparative
HPLC.
[1299] The following compounds were prepared using this method:
Example 207
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(2-methoxyethyl)amino]-1H-indazole-
-3-carboxamide dihydroformate
[1300] 228
[1301] Prepared using Procedure S in 48% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 7.42 (d, J=9.0, 1H), 7.37 (s, 1H), 7.0 (d,
J=9.0, 1H), 4.55 (m, 1H), 4.05 (m, 1H), 3.85 (m, 2H), 3.61-3.50 (m,
8H), 3.35 (s, 3H), 2.49-3.0 (m, 2H), 2.20 (m, 2H), 2.05 (m, 1H).
LC/MS (EI) t.sub.R 1.65, m/z 344 (M.sup.++1).
Example 208
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylmethyl)amino]-1H-indaz-
ole-3-carboxamide dihydroformate
[1302] 229
[1303] Prepared using Procedure S in 42% yield. LC/MS (EI) t.sub.R
1.77, m/z 340 (M.sup.++1).
Example 209
Methyl
4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol--
5-yl)amino]butanoate dihydroformate
[1304] 230
[1305] Prepared using Procedure S in 62% yield. LC/MS (EI) t.sub.R
1.36, m/z 386 (M.sup.++1).
Example 210
Methyl
4-[(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol--
6-yl)amino]butanoate dihydroformate
[1306] 231
[1307] Prepared using Procedure S in 55% yield. LC/MS (EI) t.sub.R
2.62, m/z 403 (M.sup.++1).
Example 211
tert-Butyl
{2-[(3-{1[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1,2-b-
enzisothiazol-6-yl)amino]ethyl}propylcarbamate dihydroformate
[1308] 232
[1309] Prepared using Procedure S in 63% yield. LC/MS (EI) t.sub.R
5.59, m/z 488 (M.sup.++1).
Example 212
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(1,3-thiazol-2-ylmethyl)amino]-1H--
indazole-3-carboxamide dihydroformate
[1310] 233
[1311] Prepared using Procedure S in 30% yield. LC/MS (EI) t.sub.R
2.84, m/z 383 (M.sup.++1).
Example 213
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(dimethylamino)-1H-indazole-3-carbo-
xamide dihydroformate
[1312] 234
[1313] Prepared using Procedure S in 52% yield. LC/MS (EI) t.sub.R
1.68, m/z 314 (M.sup.++1).
Example 214
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-5-[(2-methoxyethyl-
)amino]-1H-indazole-3-carboxamide dihydroformate
[1314] 235
[1315] Prepared using Procedure S in 9% yield. LC/MS (EI) t.sub.R
2.84, m/z 402 (M.sup.++1).
Example 215
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(diethylamino)-2-oxoethyl]amino-
}-1,2-benzisothiazole-3-carboxamide dihydroformate
[1316] 236
[1317] Prepared using Procedure S in 67% yield. LC/MS (EI) t.sub.R
3.67, m/z 416 (M.sup.++1).
Example 216
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(butylamino)-1H-indazole-3-carboxam-
ide dihydroformate
[1318] 237
[1319] Prepared using Procedure S in 47% yield. LC/MS (EI) t.sub.R
2.38, m/z 342 (M.sup.++1).
Example 217
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylmethyl)amino]-1,2-benz-
isothiazole-3-carboxamide dihydroformate
[1320] 238
[1321] Prepared using Procedure S in 45% yield. LC/MS (EI) t.sub.R
4.50, m/z 357 (M.sup.++1).
Example 218
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(dimethylamino)-1,2-benzisothiazole-
-3-carboxamide dihydroformate
[1322] 239
[1323] Prepared using Procedure S in 51% yield. LC/MS (EI) t.sub.R
2.53, m/z 331 (M.sup.++1).
Example 219
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(diethylamino)-1,2-benzisothiazole--
3-carboxamide dihydroformate
[1324] 240
[1325] Prepared using Procedure S in 60% yield. LC/MS (EI) t.sub.R
1.36, m/z 342 (M.sup.++1).
[1326] Procedure T.
[1327] Procedure T provides a method for the coupling between amino
aminoquinuclidinecarboxamides and acylating agents to form
carboxamide derivatives.
[1328] To a solution of
5-amino-N-[(3S)-1-azabicyclo[2,2,2]oct-3-yl]-1H-in-
dazole-3-carboxamide (0.42 mmol) in pyridine (2 mL) and
N,N-dimethylformamide (2 mL) was added the trifluoroacetic
anhydride (0.55 mmol). The mixture was maintained at ambient
temperature for 16 h and was concentrated in vacuo. The residue was
purified by preparative HPLC, thus providing the product in 30%
yield and the bis-acylated product in 5% yield.
[1329] The following compounds were prepared by this method:
Example 220
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(4-methoxyphenyl)acetyl]amino}-1H-
-indazole-3-carboxamide hydroformate
[1330] 241
[1331] Prepared using Procedure T in 31% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.52 (s, 1H), 8.42 (s. 1H), 7.64-7.43 (m, 6H),
5.32 (s, 2H), 4.72 (m, 1H), 3.94 (m, 1H), 3.70-3.40 (m, 4H), 2.51
(m, 1H), 2.50 (m, 1H), 2.20 (m, 2H), 2.06 (m, 1H). LC/MS (EI)
t.sub.R 4.94, m/z 434 (M.sup.++1).
Example 221
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-(cyc-
lopropylmethyl)-1H-indazole-3-carboxamide
[1332] 242
[1333] Prepared using Procedure T in 45% yield. LC/MS (EI) t.sub.R
4.77, m/z 408 (M.sup.++1).
Example 222
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(trifluoroacetyl)amino]-1H-indazol-
e-3-carboxamide hydroformate
[1334] 243
[1335] Prepared using Procedure T in 30% yield. LC/MS (EI) t.sub.R
3.28, m/z 382 (M.sup.++1).
Example 223
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1H-ind-
azole-3-carboxamide hydroformate
[1336] 244
[1337] Prepared using Procedure T in 30% yield. LC/MS (EI) t.sub.R
2.61, m/z 354 (M.sup.++1).
Example 224
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(trifluoroacetyl)-1H-indazo-
le-3-carboxamide dihydroformate
[1338] 245
[1339] Prepared using Procedure T in 30% yield. LC/MS (EI) t.sub.R
2.92, m/z 382 (M.sup.++1).
Example 225
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylcarbonyl)-5-[(cycloprop-
ylcarbonyl)amino]-1H-indazole-3-carboxamide hydroformate
[1340] 246
[1341] Prepared using Procedure T in 30% yield. LC/MS (EI) t.sub.R
5.09, m/z 422 (M.sup.++1).
Example 226
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-[(4-methoxyphenyl)acetyl]-5-{[(4-me-
thoxyphenyl)acetyl]amino}-1H-indazole-3-carboxamide
hydroformate
[1342] 247
[1343] Prepared using Procedure T in 31% yield. LC/MS (EI) t.sub.R
5.44, m/z 583 (M.sup.++1).
Example 227
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1,2-be-
nzisothiazole-3-carboxamide hydroformate
[1344] 248
[1345] Prepared using Procedure T in 60% yield. LC/MS (EI) t.sub.R
3.66, m/z 371 (M.sup.++1).
Example 228
6-(Acetylamino)-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-3-
-carboxamide hydroformate
[1346] 249
[1347] Prepared using Procedure T in 60% yield. LC/MS (EI) t.sub.R
2.42, m/z 345 (M.sup.++1).
Example 229
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(cyclopropylcarbonyl)amino]-1-ethy-
l-1H-indazole-3-carboxamide
[1348] 250
[1349] Prepared using Procedure T in 33% yield. LC/MS (EI) t.sub.R
3.44, m/z 382 (M.sup.++1).
Example 230
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-cycl-
opropylmethyl-1H-indazole-3-carboxamide
[1350] 251
[1351] Prepared using Procedure T in 44% yield. LC/MS (EI) t.sub.R
3.68, m/z 408 (M.sup.++1).
Example 231
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(cyclopropylcarbonyl)amino]-1-(2,2-
,2-trifluoroethyl)-1H-indazole-3-carboxamide
[1352] 252
[1353] Prepared using Procedure T in 47% yield. LC/MS (EI) t.sub.R
3.66, m/z 436 (M.sup.++1).
[1354] Procedure U.
[1355] Procedure U provides a method for the coupling between amino
aminoquinuclidinecarboxamides and sulfonylating agents to form
sulfonamide derivatives.
[1356] Ethanesulfonyl chloride (0.25 mmoL) was added to a solution
of the amine (0.20 mmol) in a mixture of pyridine (2 mL) and
N,N-dimethylformamide (1 mL). The mixture was maintained at ambient
temperature for 16 h and was concentrated in vacuo. The residue was
purified by preparative HPLC, thus providing the product in 60%
yield and the bis-sulfonylated product in 20% yield.
[1357] The following compounds were prepared by this method:
Example 232
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole--
3-carboxamide hydroformate
[1358] 253
[1359] Prepared using Procedure U in 32% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.09 (s, 1H), 7.55 (d, J=8.9, 1H), 7.41 (d,
J=8.9, 1H), 4.20 (m, 1H), 3.35 (m, 1H), 3.08 (q, J=7.4, 2H), 3.02
(m, 1H), 3.0-2.8 (m, 4H), 2.06 (m, 1H), 2.00 (m, 1H), 1.79 (m, 2H),
1.55 (m, 1H), 1.32 (t, J=7.4, 3H); LC/MS (EI) t.sub.R 2.37, m/z 378
(M.sup.++1).
Example 233
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisot-
hiazole-3-carboxamide
[1360] 254
[1361] Prepared using Procedure U in 74% yield. LC/MS (EI) t.sub.R
2.85, m/z 395 (M.sup.++1).
Example 234
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(ethylsulfonyl)amino]-1,2-benzisot-
hiazole-3-carboxamide
[1362] 255
[1363] Prepared using Procedure U in 73% yield. LC/MS (EI) t.sub.R
2.82, m/z 395 (M.sup.++1).
Example 235
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benziso-
thiazole-3-carboxamide
[1364] 256
[1365] Prepared using Procedure U in 71% yield. LC/MS (EI) t.sub.R
2.84, m/z 381 (M.sup.++1).
Example 236
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(methylsulfonyl)amino]-1,2-benziso-
thiazole-3-carboxamide
[1366] 257
[1367] Prepared using Procedure U in 69% yield. LC/MS (EI) t.sub.R
2.82, m/z 381 (M.sup.++1).
Example 237
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(benzylsulfonyl)amino]-1H-indazole-
-3-carboxamide hydroformate
[1368] 258
[1369] Prepared using Procedure U in 35% yield. LC/MS (EI) t.sub.R
4.64, m/z 440 (M.sup.++1).
Example 238
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(dimethylamino)sulfonyl]amino}-1,-
2-benzisothiazole-3-carboxamide hydroformate
[1370] 259
[1371] Prepared using Procedure U in 48% yield. LC/MS (EI) t.sub.R
3.53, m/z 410 (M.sup.++1).
Example 239
5-Amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1-(benzylsulfonyl)-1H-indazol-
e-3-carboxamide dihydroformate
[1372] 260
[1373] Prepared using Procedure U in 35% yield. LC/MS (EI) t.sub.R
4.29, m/z 440 (M.sup.++1).
Example 240
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(methylsulfonyl)amino]-1H-indazole-
-3-carboxamide hydroformate
[1374] 261
[1375] Prepared using Procedure U in 19% yield. LC/MS (EI) t.sub.R
1.61, m/z 364 (M.sup.++1).
Example 241
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(ethylsulfonyl)amino]-1H-indazole--
3-carboxamide hydroformate
[1376] 262
[1377] Prepared using Procedure U in 10% yield. LC/MS (EI) t.sub.R
2.43, m/z 378 (M.sup.++1).
Example 242
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-4-[(methylsulfonyl)amino]-1H-indazole-
-3-carboxamide
[1378] 263
[1379] Prepared using Procedure U in 9% yield. LC/MS (EI) t.sub.R
3.96, m/z 364 (M.sup.++1).
[1380] Procedure V.
[1381] Procedure V provides a method for the coupling between amino
aminoquinuclidinecarboxamides and isocyanates to form urea
derivatives.
[1382] To the amine (0.40 mmol) in a mixture of pyridine (2 mL) and
N,N-dimethylformamide (1 mL) was added 5-chloro-2-methylphenyl
isocyanate (0.53 mmol). The reaction mixture was maintained at
ambient temperature for 16 h and was concentrated in vacuo. The
residue was purified by chromatography (70/30/1 ethyl
acetate/methanol/ammonium hydroxide), thus providing the product in
78% yield.
[1383] The following compounds were prepared by this method:
Example 243
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(2,6-dichlorophenyl)ethyl]ami-
no}carbonyl)amino]-1,2-benzisothiazole-3-carboxamide
[1384] 264
[1385] Prepared using Procedure V in 70% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.68 (d, J=9.0, 1H), 8.46 (s, 1H), 7.47-7.30
(m, 3H), 7.33 (d, J=9.0, 1H), 3.97 (m, 1H), 3.96 (t, J=12.0, 1H),
3.64 (t, J=6.0, 2H), 3.50-3.30 (m, 6H), 2.52 (m, 1H), 2.40 (m, 1H),
2.20 (m, 2H), 2.10 (m, 1H). LC/MS (EI) t.sub.R 5.55, m/z 518
(M.sup.++1).
Example 244
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-{[(propylamin-
o)carbonyl]amino}-1H-indazole-3-carboxamide
[1386] 265
[1387] Prepared using Procedure V in 32% yield. LC/MS (EI) t.sub.R
4.88, m/z 425 (M.sup.++1).
Example 245
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}am-
ino)-1,2-benzisothiazole-3-carboxamide
[1388] 266
[1389] Prepared using Procedure V in 40% yield. LC/MS (EI) t.sub.R
5.74, m/z 447 (M.sup.++1).
Example 246
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-fluorophenyl)ethyl]amino}c-
arbonyl)amino]-1,2-benzisothiazole-3-carboxamide
[1390] 267
[1391] Prepared using Procedure V in 50% yield. LC/MS (EI) t.sub.R
5.42, m/z 454 (M.sup.++1).
Example 247
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4-dimethylphenyl)amino]carbon-
yl}amino)-1,2-benzisothiazole-3-carboxamide
[1392] 268
[1393] Prepared using Procedure V in 76% yield. LC/MS (EI) t.sub.R
5.79, m/z 450 (M.sup.++1).
Example 248
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,5-dimethylphenyl)amino]carbon-
yl}amino)-1,2-benzisothiazole-3-carboxamide
[1394] 269
[1395] Prepared using Procedure V in 78% yield. LC/MS (EI) t.sub.R
5.92, m/z 470 (M.sup.++1).
Example 249
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methylbenzyl)amino]carbonyl}a-
mino)-1,2-benzisothiazole-3-carboxamide
[1396] 270
[1397] Prepared using Procedure V in 40% yield. LC/MS (EI) t.sub.R
5.78, m/z 450 (M.sup.++1).
Example 250
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(4-methylphenyl)ethyl]amino}c-
arbonyl)amino]-1,2-benzisothiazole-3-carboxamide
[1398] 271
[1399] Prepared using Procedure V in 71% yield. LC/MS (EI) t.sub.R
5.54, m/z 450 (M.sup.++1).
Example 251
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[2-(3-methoxyphenyl)ethyl]amino}-
carbonyl)amino]-1,2-benzisothiazole-3-carboxamide
[1400] 272
[1401] Prepared using Procedure V in 74% yield. LC/MS (EI) t.sub.R
5.37, m/z 466 (M.sup.++1).
Example 252
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclopentylamino)carbonyl]amino}-
-1,2-benzisothiazole-3-carboxamide
[1402] 273
[1403] Prepared using Procedure V in 63% yield. LC/MS (EI) t.sub.R
5.34, m/z 414 (M.sup.++1).
Example 253
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2--
benzisothiazole-3-carboxamide
[1404] 274
[1405] Prepared using Procedure V in 70% yield. LC/MS (EI) t.sub.R
4.40, m/z 388 (M.sup.++1).
Example 254
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}a-
mino)-1H-indazole-3-carboxamide
[1406] 275
[1407] Prepared using Procedure V in 65% yield. LC/MS (EI) t.sub.R
5.03, m/z 397 (M.sup.++1).
Example 255
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}-
amino)-1H-indazole-3-carboxamide
[1408] 276
[1409] Prepared using Procedure V in 68% yield. LC/MS (EI) t.sub.R
5.02, m/z 449 (M.sup.++1).
Example 256
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-
-1H-indazole-3-carboxamide
[1410] 277
[1411] Prepared using Procedure V in 54% yield. LC/MS (EI) t.sub.R
4.24, m/z 397 (M.sup.++1).
Example 257
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(3-methoxybenzyl)amino]carbonyl}-
amino)-1H-indazole-3-carboxamide
[1412] 278
[1413] Prepared using Procedure V in 64% yield. LC/MS (EI) t.sub.R
4.75, m/z 434 (M.sup.++1).
Example 258
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}a-
mino)-1H-indazole-3-carboxamide
[1414] 279
[1415] Prepared using Procedure V in 57% yield. LC/MS (EI) t.sub.R
5.03, m/z 397 (M.sup.++1).
Example 259
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylamino)carbonyl]amino}-1,2--
benzisothiazole-3-carboxamide hydroformate
[1416] 280
[1417] Prepared using Procedure V in 70% yield. LC/MS (EI) t.sub.R
4.78, m/z 388 (M.sup.++1).
Example 260
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-i-
ndazole-3-carboxamide hydroformate
[1418] 281
[1419] Prepared using Procedure V in 35% yield. LC/MS (EI) t.sub.R
2.87, m/z 371 (M.sup.++1).
Example 261
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(propylamino)carbonyl]amino}-1H-i-
ndazole-3-carboxamide hydroformate
[1420] 282
[1421] Prepared using Procedure V in 30% yield. LC/MS (EI) t.sub.R
2.91, m/z 371 (M.sup.++1).
Example 262
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}a-
mino)-1H-indazole-3-carboxamide hydroformate
[1422] 283
[1423] Prepared using Procedure V in 41% yield. LC/MS (EI) t.sub.R
5.03, m/z 397 (M.sup.++1).
Example 263
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(4-fluorobenzyl)amino]carbonyl}a-
mino)-1H-indazole-3-carboxamide hydroformate
[1424] 284
[1425] Prepared using Procedure V in 36% yield. LC/MS (EI) t.sub.R
5.02, m/z 437 (M.sup.++1).
Example 264
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(cyclopentylamino)carbonyl]amino}-
-1H-indazole-3-carboxamide hydroformate
[1426] 285
[1427] Prepared using Procedure V in 34% yield. LC/MS (EI) t.sub.R
4.24, m/z 397 (M.sup.++1).
Example 265
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-(3-methoxybenzyl)-5-({[(3-met-
hoxybenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide
[1428] 286
[1429] Prepared using Procedure V in 14% yield. LC/MS (EI) t.sub.R
5.74, m/z 612 (M.sup.++1).
Example 266
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl-N(1)-(4-fluorobenzyl)-5-({[(4-fluor-
obenzyl)amino]carbonyl}amino)-1H-indazole-1,3-dicarboxamide
[1430] 287
[1431] Prepared using Procedure V in 13% yield. LC/MS (EI) t.sub.R
5.81, m/z 588 (M.sup.++1).
Example 267
N(3)-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-cyclopentyl-5-{[(cyclopentyla-
mino)carbonyl]amino}-1H-indazole-1,3-dicarboxamide hydroformate
[1432] 288
[1433] Prepared using Procedure V in 13% yield. LC/MS (EI) t.sub.R
5.51, m/z 508 (M.sup.++1).
Example 268
N(3)-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-N(1)-propyl-5-{[(propylamino)carbo-
nyl]amino}-1H-indazole-1,3-dicarboxamide
[1434] 289
[1435] Prepared using Procedure V in 9.4% yield. LC/MS (EI) t.sub.R
5.24, m/z 456 (M.sup.++1).
Example 269
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-({[(cyclopropylmethyl)amino]carbono-
thioyl}amino)-1H-indazole-3-carboxamide hydroformate
[1436] 290
[1437] Prepared using Procedure V in 47% yield. LC/MS (EI) t.sub.R
2.75, m/z 399 (M.sup.++1).
Example 270
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(cyclopropylmethyl)amino]carbono-
thioyl}amino)-1,2-benzisothiazole-3-carboxamide hydroformate
[1438] 291
[1439] Prepared using Procedure V in 26% yield. LC/MS (EI) t.sub.R
3.98, m/z 416 (M.sup.++1).
Example 271
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(propylmethylamino)carbonothioyl]-
amino}-1,2-benzisothiazole-3-carboxamide hydroformate
[1440] 292
[1441] Prepared using Procedure V in 60% yield. LC/MS (EI) t.sub.R
3.01, m/z 404 (M.sup.++1).
Example 272
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonothioyl]am-
ino}-1,2-benzisothiazole-3-carboxamide hydroformate
[1442] 293
[1443] Prepared using Procedure V in 47% yield. LC/MS (EI) t.sub.R
3.65, m/z 385 (M.sup.++1).
Example 273
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(sec-butylamino)carbonyl]amino}-1-
H-indazole-3-carboxamide hydroformate
[1444] 294
[1445] Prepared using Procedure V in 43% yield. LC/MS (EI) t.sub.R
2.46, m/z 385 (M.sup.++1).
Example 274
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-ethyl-6-{[(propylamino)carbonyl]ami-
no}-1H-indazole-3-carboxamide hydroformate
[1446] 295
[1447] Prepared using Procedure V in 11% yield. LC/MS (EI) t.sub.R
3.50, m/z 399 (M.sup.++1).
Example 275
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-5-{[(propylamin-
o)carbonyl]amino}-1H-indazole-3-carboxamide hydroformate
[1448] 296
[1449] Prepared using Procedure V in 56% yield. LC/MS (EI) t.sub.R
3.74, m/z 425 (M.sup.++1).
Example 276
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2,2,2-trifluoroethyl)-5-{[(propyla-
mino)carbonyl]amino}-1H-indazole-3-carboxamide hydroformate
[1450] 297
[1451] Prepared using Procedure V in 40% yield. LC/MS (EI) t.sub.R
3.72, m/z 453 (M.sup.++1).
Example 277
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(ethyl)-5-{[(propylamino)carbonyl]a-
mino}-1H-indazole-3-carboxamide hydroformate
[1452] 298
[1453] Prepared using Procedure V in 37% yield. LC/MS (EI) t.sub.R
3.44, m/z 399 (M.sup.++1).
[1454] Procedure W
[1455] Procedure W provides a method for the coupling between amino
aminoquinuclidinecarboxamides and halogenated heterocycles to form
N-heteroarylaniline derivatives.
[1456] To a solution of
6-amino-N-[(3S)-1-azabicyclo[2.2.2]octy-3-yl]-1,2--
benisothiazole-3-carboxamide (0.175 mmol) in a mixture of toluene
(0.5 mL) and 2-propanol (0.5 mL) was added 2-bromothiazole (0.18
mmol) an potassium carbonate (0.21 mmol). The reaction mixture was
subjected to microwave irradiation at 180.degree. C. for 600 s, and
was concentrated. The residue was resuspended in 95/5
dichloromethane/methanol and was filtered and concentrated. The
residue was purified by preparative HPLC, thus providing the
product in 10% yield.
[1457] The following compounds were prepared using this method:
Example 278
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-ylamino)-1,2-benziso-
thiazole-3-carboxamide hydroformate
[1458] 299
[1459] Prepared using Procedure W in 10% yield. LC/MS (EI) t.sub.R
4.78, m/z 386 (M.sup.++1).
[1460] Procedure X
[1461] Procedure X provides a method for the coupling between
acetylenic aminoquinuclidinecarboxamides and azides to form
triazole derivatives.
[1462]
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-ethynyl-1H-indazole-3-carbox-
amide (0.300 mol) and azidotrimethylsilane (0.30 mmol) were
suspended in water (0.6 mL) and tert-butyl alcohol (0.6 mL). Sodium
ascorbate (0.20 mol) was added to the reaction mixture followed by
a solution of copper(II)sulfate pentahydrate (0.030 mmol) in water
(30 .mu.L). The reaction was stirred vigorously for 12 hours, and
was concentrated. The residue was redissolved in methanol and was
filtered and concentrated. The residue was purified by preparative
HPLC, thus providing the product in 6% yield.
[1463] The following compounds were prepared by this method:
Example 279
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1H-1,2,3-triazol-4-yl)-1H-indazole-
-3-carboxamide dihydroformate
[1464] 300
[1465] Prepared using Procedure X in 6% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.69 (s, 1H), 8.27 (s, 1H), 7.97 (d, 1H,
J=8.8), 7.72 (d, J=8.8), 4.58-4.43 (m, 1, 3.91-3.84 (m, 1,
3.49-3.38 (m, 4, 2.43-1.97 (m, 6. LC/MS (EI) t.sub.R 2.77, m/z 338
(M.sup.++1).
Example 280
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[1-(2-piperidin-1-ylethyl)-1H-1,2,3-
-triazol-4-yl]-1H-indazole-3-carboxamide dihydroformate
[1466] 301
[1467] Prepared using Procedure X in 55% yield. LC/MS (EI) t.sub.R
2.04, m/z 449 (M.sup.++1).
Example 281
Ethyl[4-(3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-6--
yl)-1H-1,2,3-triazol-1-yl]acetate dihydroformate
[1468] 302
[1469] Prepared using Procedure X in 20% yield. LC/MS (EI) t.sub.R
3.15, m/z 424 (M.sup.++1).
[1470] Procedure Y.
[1471] Procedure Y provides a method for the coupling between amino
aminoquinuclidinecarboxamides and chloroformates to form carbamate
derivatives.
[1472] Benzyl chloroformate (0.58 mmoL) was added to a solution of
the amine (0.52 mmol) in N,N-dimethylformamide (1 mL) and pyridine
(2 mL) and the reaction mixture was maintained for 16 h. The
reaction mixture was concentrated and the residue was purified by
preparative HPLC, thus providing the product in 54% yield and the
bis-carbamate in 12% yield.
[1473] The following compounds were prepared by this method:
Example 282
Benzyl(3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl-
)carbamate
[1474] 303
[1475] Prepared using Procedure Y in 54% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.59 (s, 1H), 8.51 (s, 1H), 7.65 (s, 1H), 7.41
(d, J=9.0, 1H), 7.19 (d, J=9.0, 1H), 7.05 (d, J=9.0, 1H), 7.05 (d,
J=9.0, 1H), 6.94 (d, J=9.0, 1H), 4.62 (m, 1H), 3.95 (m, 1H), 3.87
(s, 3H), 3.50-3.30 (m, 4H), 2.48 (m, 1H), 2.37 (m, 1H), 2.20 (m,
2H), 2.02 (m, 1H). LC/MS (EI) t.sub.R 5.33, m/z 420
(M.sup.++1).
Example 283
Vinyl(3-{1[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol-5-yl-
)carbamate
[1476] 304
[1477] Prepared using Procedure Y in 50% yield. LC/MS (EI) t.sub.R
3.30, m/z 356 (M.sup.++1).
Example 284
Isopropyl
{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1H-indazol--
5-yl}carbamate hydroformate
[1478] 305
[1479] Prepared using Procedure Y in 36% yield. LC/MS (EI) t.sub.R
2.90, m/z 372 (M.sup.++1).
Example 285
Isopropyl
{3-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-[(isoprop-
ylamino)carbonyl]-1H-indazol-5-yl}carbamate hydroformate
[1480] 306
[1481] Prepared using Procedure Y in 18% yield. LC/MS (EI) t.sub.R
5.16, m/z 458 (M.sup.++1).
[1482] Procedure Z.
[1483] Procedure Z provides a method for the oxidation of
quinuclidinecarboxamides to form N-oxide derivatives.
[1484] A 0.degree. C. solution of m-chloroperbenzoic acid (6.66
mmoL) in dichloromethane (30 mL) was added dropwise to a solution
of the quinuclidine amide (4.44 mmol) in dichloromethane (40 mL)
and the reaction mixture was maintained for 3 h. The reaction
mixture was concentrated and the residue was purified by
chromatography on neutral alumina using a gradient of 100/0 to
90/10 dichloromethane/methanol, thus providing the product in 58%
yield.
[1485] The following compounds were prepared by this method:
Example 286
N-[(3S)-1-Oxido-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide
[1486] 307
[1487] Prepared using Procedure Z in 58% yield. .sup.1H NMR
(CD.sub.3OD, 500 MHz) .delta. 8.21 (d, J=8.0, 1H), 7.59 (d, J=9.0,
1H), 7.42 (dt, Jt=7.5, Jd=1.0, 1H), 7.26 (dt, Jt=7.5, Jd=1.0, 1H),
4.65 (m, 1H), 3.83 (m, 1H), 3.42 (m, 5H), 2.37 (m, 4H), 2.27 (m,
1H), 2.17 (m, 2H), 2.02 (m, 1H); LC/MS (EI) t.sub.R 12.4
[Analytical HPLC was performed on 4.6 mm.times.250 mm YMC 0DS-AQ
S-5 120 m columns using a gradient of 05/95 to 95/05 acetonitrile
(0.05% trifluoroacetic acid)/water (0.05% trifluoroacetic acid)
over 35 min], m/z 287 (M.sup.++1).
[1488] Procedure AA.
[1489] Procedure AA provides a method for the demethylation of
methoxy-substituted quinuclidinecarboxamides to form phenol
derivatives.
[1490] A 0.degree. C. solution of m-chloroperbenzoic acid (6.66
mmoL) in dichloromethane (30 mL) was added dropwise to a solution
of the quinuclidine amide (4.44 mmol) in dichloromethane (40 mL)
and the reaction mixture was maintained for 3 h. The reaction
mixture was concentrated and the residue was purified by
chromatography on neutral alumina using a gradient of 100/0 to
90/10 dichloromethane/methanol, thus providing the product in 58%
yield.
[1491] The following compounds were prepared by this method:
Example 287
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-hydroxy-1H-indazole-3-carboxamide
hydrobromide
[1492] 308
[1493] Prepared using Procedure AA in 32% yield. .sup.1H NMR
(Me.sub.2SO-d.sub.6) .delta. 13.43 (s, 1H), 9.49 (br s, 1H), 9.35
(s, 1H), 8.62 (d, J=5.9, 1H), 7.46-7.44 (m, 1H), 6.95 (d, J=6.5,
1H), 4.41 (br s, 1H), 3.68-3.63 (m, 1H), 3.33-3.18 (m, 7H),
2.22-2.20 (m, 1H), 2.09-2.08 (m, 1H), 1.94-1.93 (m, 1H), 1.75-1.70
(M, 1H). LC/MS (EI) t.sub.R 10.72, m/z 287 (M.sup.++1).
Example 288
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-hydroxy-1H-indazole-3-carboxamide
hydrobromide
[1494] 309
[1495] Prepared using Procedure AA in 39% yield. LC/MS (EI) t.sub.R
10.32 [Analytical HPLC was performed on 4.6 mm.times.250 mm YMC
0DS-AQ S-5 120 m columns using a gradient of 05/95 to 95/05
acetonitrile (0.05% trifluoroacetic acid)/water (0.05%
trifluoroacetic acid) over 35 min], m/z 287 (M.sup.++1).
[1496] Procedure AB.
[1497] Procedure AB provides a method for the preparation of urea
derivatives using phosgene equivalents.
[1498] A 0.degree. C. solution of m-chloroperbenzoic acid (6.66
mmoL) in dichloromethane (30 mL) was added dropwise to a solution
of the quinuclidine amide (4.44 mmol) in dichloromethane (40 mL)
and the reaction mixture was maintained for 3 h. The reaction
mixture was concentrated and the residue was purified by
chromatography on neutral alumina using a gradient of 100/0 to
90/10 dichloromethane/methanol, thus providing the product in 58%
yield.
[1499] The following compounds were prepared by this method:
Example 289
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[(diethylamino)carbonyl]amino}-1H--
indazole-3-carboxamide hydroformate
[1500] 310
[1501] Prepared using Procedure AB in 55% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.40 (s, 1H), 8.10 (s, 1H), 7.51 (s, 1H), 4.52
(m, 1H), 3.83 (t, J=15.0, 1H), 3.37 (t, J=9.0, 4H), 3.36-3.30 (m,
4H), 2.30 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H), 1.19 (t, J=6.0, 6H).
LC/MS (EI) t.sub.R 2.45, m/z 385 (M.sup.++1).
Example 290
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-[(pyrrolidin-1-ylcarbonyl)amino]-1H-
-indazole-3-carboxamide hydroformate
[1502] 311
[1503] Prepared using Procedure AB in 57% yield. LC/MS (EI) t.sub.R
2.47, m/z 383 (M.sup.++1).
Example 291
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[(pyrrolidin-1-ylcarbonyl)amino]-1H-
-indazole-3-carboxamide hydroformate
[1504] 312
[1505] Prepared using Procedure AB in 69% yield. LC/MS (EI) t.sub.R
3.35, m/z 400 (M.sup.++1).
[1506] Procedure AC.
[1507] Procedure AC provides a method for the preparation of cyclic
amide derivatives from the corresponding brominated quinuclidine
derivatives.
[1508] Palladium (II) acetate (0.09 mmol) was added to a solution
of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.14 mmol)
in toluene (10 mL) and the reaction mixture was maintained until
the contents completely dissolved. The resultant yellow solution
was transferred to a mixture of
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo--
1,2-benzisothiazole-3-carboxamide (0.33 mmol), cesium carbonate
(0.60 mmol) and 2-pyrrolidinone (1.00 mmol) under an atmosphere of
nitrogen gas and the reaction mixture was heated at 100.degree. C.
for 16 h. The reaction mixture was filtered through Celite and
concentrated. The residue was purified by HPLC, thus providing the
product in 72% yield.
[1509] The following compounds were prepared using this method:
Example 292
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxopyrrolidin-1-yl)-1,2-benzisot-
hiazole-3-carboxamide hydroformate
[1510] 313
[1511] Prepared using Procedure AC in 72% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.78 (d, J=9.0, 1H), 8.53 (broad, 1H), 8.81
(s, 1H), 7.63 (d, J=9.0, 1H), 4.5 (m, 1H), 4.07 (t, J=6.0, 2H),
3.76 (t, J=12.0, 1H), 3.50-3.30 (m, 4H), 2.35 (t, J=6.0, 2H), 2.35
(m, 1H), 2.20 (m, 3H), 2.10 (m, 2H), 1.90 (m, 1H). LC/MS (EI)
t.sub.R 2.43, m/z 371 (M.sup.++1).
Example 293
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxopyrrolidin-1-yl)-1,2-benzisot-
hiazole-3-carboxamide hydroformate
[1512] 314
[1513] Prepared using Procedure AC in 40% yield. LC/MS (EI) t.sub.R
2.11, m/z 354 (M.sup.++1).
Example 294
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxo-4-phenylpyrrolidin-1-yl)-1,2-
-benzisothiazole-3-carboxamide hydroformate
[1514] 315
[1515] Prepared using Procedure AC in 50% yield. LC/MS (EI) t.sub.R
5.17, m/z 447 (M.sup.++1).
[1516] Procedure AD.
[1517] Procedure AD provides a method for the preparation of cyclic
urea derivatives from the corresponding amino quinuclidine
derivatives.
[1518] To a solution of
6-amino-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-b-
enzisothiazole-3-carboxamide (0.400 mmol) in methanol (5 mL) was
added tert-butyl N-(2-oxoethyl)carbamate (0.56 mmol), sodium
cyanoborohydride (1.00 mmol) and acetic acid (0.4 mL) and the
reaction mixture was maintained for 4 h. The reaction mixture was
diluted with 3 N hydrochloric acid (5 mL) and the reaction mixture
was maintained for 2 h. The reaction mixture was concentrated and
the residue was purified by HPLC, thus providing the reduced amine
in 63% yield.
[1519] To solution of the reduced amine (0.100 mmol) in
N,N-dimethylformamide (4 mL) was added N,N-carbonyldiimidazole
(0.150 mmol) and the reaction mixture was heated at 100.degree. C.
for 3 h. The reaction mixture was concentrated and the residue was
purified by HPLC, thus providing the cyclic urea in 60% yield.
[1520] The following compounds were prepared using this method:
Example 295
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(2-oxoimidazolidin-1-yl)-1,2-benzis-
othiazole-3-carboxamide hydroformate
[1521] 316
[1522] Prepared using Procedure AD in 60% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.67 (d, J=9.0, 1H), 8.51 (broad, 1H), 8.18
(s, 1H), 7.96 (d, J=9.0, 1H), 4.48 (d, 1H), 4.08 (dd, J=6.0, 6.0,
2H), 3.79 (t, J=12.0, 1H), 3.60 (dd, J=6.0, 6.0, 2H), 3.5-3.3 (m,
4H), 2.38 (m, 1H), 2.22 (m, 1H), 2.08 (m, 2H), 1.90 (m, 1H). LC/MS
(EI) t.sub.R 2.43, m/z 372 (M.sup.++1).
Example 296
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxoimidazolidin-1-yl)-1H-indazol-
e-3-carboxamide hydroformate
[1523] 317
[1524] Prepared using Procedure AD in 60% yield. LC/MS (EI) t.sub.R
1.26, m/z 355 (M.sup.++1).
Example 297
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(2-oxo-3-propylimidazolidin-1-yl)-1-
H-indazole-3-carboxamide hydroformate
[1525] 318
[1526] Prepared using Procedure AD in 40% yield. LC/MS (EI) t.sub.R
3.27, m/z 397 (M.sup.++1).
Example 298
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[2-(propylamino)ethyl]amino}-1,2-b-
enzisothiazole-3-carboxamide hydroformate
[1527] 319
[1528] Prepared using Procedure AD in 35% yield. LC/MS (EI) t.sub.R
1.47, m/z 303 (M.sup.++1).
[1529] Procedure AE.
[1530] Procedure AE provides a method for the preparation of cyclic
urea derivatives from the corresponding brominated quinuclidine
derivatives.
[1531] Palladium (II) acetate (0.09 mmol) was added to a solution
of (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.14 mmol)
in toluene (8 mL) and the reaction mixture was maintained until the
contents completely dissolved. The resultant yellow solution was
transferred to a mixture of
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazo-
le-3-carboxamide (0.33 mmol), cesium carbonate (0.39 mmol) and
1-methyl-2-imidazolidinone 2-pyrrolidinone (0.500 mmol) under an
atmosphere of nitrogen gas and the reaction mixture was heated at
100.degree. C. for 16 h. The reaction mixture was filtered through
Celite and concentrated. The residue was purified by HPLC, thus
providing the product in 70% yield.
[1532] The following compounds were prepared using this method:
Example 299
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methyl-2-oxoimidazolidin-1-yl)-1-
,2-benzisothiazole-3-carboxamide hydroformate
[1533] 320
[1534] Prepared using Procedure AE in 70% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.64 (d, J=9.0, 1H), 8.55 (s, 1H), 8.18 (d,
J=9.0, 1H), 4.20 (m, 1H), 3.95 (dd, J=6.0, 6.0, 2H), 3.51 (dd,
J=6.0, 6.0, 2H), 3.35 (s, 3H), 3.45-3.30 (m, 4H), 2.10 (m, 1H),
1.95 (m, 1H), 1.80 (m, 2H), 1.60 (m, 1H). LC/MS (EI) t.sub.R 2.73,
m/z 386 (M.sup.++1).
Example 300
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-isopropyl-2-oxoimidazolidin-1-yl-
)-1,2-benzisothiazole-3-carboxamide hydroformate
[1535] 321
[1536] Prepared using Procedure AE in 65% yield. LC/MS (EI) t.sub.R
3.65, m/z 414 (M.sup.++1).
Example 301
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-propyl-2-oxoimidazolidin-1-yl)-1-
,2-benzisothiazole-3-carboxamide hydroformate
[1537] 322
[1538] Prepared using Procedure AE in 67% yield. LC/MS (EI) t.sub.R
4.61, m/z 414 (M.sup.++1).
Example 302
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-methyl-2-oxoimidazolidin-1-yl)-1-
,2-benzisothiazole-3-carboxamide
[1539] 323
[1540] Prepared using Procedure AF in 27% yield. LC/MS (EI) t.sub.R
3.07, m/z 387 (M.sup.++1).
Example 303
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-isopropyl-2-oxoimidazolidin-1-yl-
)-1,2-benzisothiazole-3-carboxamide
[1541] 324
[1542] Prepared using Procedure AF in 31% yield. LC/MS (EI) t.sub.R
3.70, m/z 414 (M.sup.++1).
Example 304
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-(3-propyl-2-oxoimidazolidin-1-yl)-1-
,2-benzisothiazole-3-carboxamide
[1543] 325
[1544] Prepared using Procedure AF in 24% yield. LC/MS (EI) t.sub.R
3.66, m/z 414 (M.sup.++1).
[1545] Procedure AF.
[1546] Procedure AF provides a method for the preparation of
benzisoxazole quinuclidine amides from ethyl
benzisoxazole-3-carboxylates.
[1547] (S)-3-aminoquinuclidine hydrochloride (3.52 mmol) was
dissolved in N,N-diisopropylethylamine (0.5 mL) and ethanol (3 mL)
with warming. Ethyl 5-bromo-1,2-benzisoxazole-3-carboxylate (1.86
mmol) was added and the reaction mixture was heated at 85.degree.
C. for 72 h. The reaction mixture was diluted with dichloromethane
(30 mL) and washed with 10 mL of saturated sodium carbonate. The
aqueous layer was extracted with dichloromethane (30 mL) and the
combined organic layers were washed with brine and dried (sodium
sulfate). The organic layer was loaded on a 10 g SCX column and the
column was washed with methanol (50 mL). The crude product was
eluted with 2 M ammonia in methanol (60 mL) and concentrated. The
residue was purified by chromatography [40/60 to 0/100 ethyl
acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)], thus
providing the amide in 59% yield as a light yellow oil.
[1548] The following compounds were prepared using this method:
Example 305
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-5-bromo-1,2-benzisoxazole-3-carboxami-
de
[1549] 326
[1550] Prepared using Procedure AF in 59% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.16 (d, J=0.6, 1H), 7.71 (dd, J=8.9, 0.6,
1H), 7.59 (d, J=8.9, 1H), 4.21 (m, 1H), 3.37 (m, 1H), 3.02 (m, 1H),
2.84 (m, 4H), 2.08 (m, 1H), 1.96 (m, 1H), 1.78 (m, 2H), 1.55 (m,
1H); LC/MS (EI) t.sub.R 2.33, m/z 350/352 (M+/M++2).
Example 306
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisoxazole-3-carboxami-
de
[1551] 327
[1552] Prepared using Procedure AF in 63% yield. LC/MS (EI) t.sub.R
2.22, m/z 350/352 (M.sup.++1).
[1553] Procedure AG.
[1554] Procedure AG provides a method for the preparation of
acyclic amide derivatives from the corresponding brominated
quinuclidine derivatives.
[1555] Palladium (II) acetate (0.040 mmol) was added to a solution
of (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.050 mmol)
in toluene (6 mL) and the reaction mixture was maintained until the
contents completely dissolved. The resultant yellow solution was
transferred to a mixture of
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazo-
le-3-carboxamide (0.30 mmol), cesium carbonate (0.50 mmol) and
N-methylacetamide (0.500 mmol) under an atmosphere of nitrogen gas
and the reaction mixture was subjected to microwave irradiation at
200.degree. C. for 300 s. The reaction mixture was filtered through
Celite and concentrated. The residue was purified by HPLC, thus
providing the product in 50% yield.
[1556] The following compounds were prepared using this method:
Example 307
6-[Acetyl(methyl)amino]-N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisoth-
iazole-3-carboxamide hydroformate
[1557] 328
[1558] Prepared using Procedure AG in 50% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.85 (d, J=9.0, 2H), 8.40 (broad, 1H), 8.13
(s, 1H), 7.53 (d, J=9.0, 1H), 4.43 (m, 1H), 3.85 (m, 1H), 3.5-3.2
(m, 7H), 2.45 (m, 1H), 2.30 (m, 1H), 2.10 (m, 3H), 1.95 (m, 3H).
LC/MS (EI) t.sub.R 2.40, m/z 359 (M.sup.++1).
Example 308
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[methyl(propionyl)amino]-1,2-benzis-
othiazole-3-carboxamide hydroformate
[1559] 329
[1560] Prepared using Procedure AG in 60% yield. LC/MS (EI) t.sub.R
2.42, m/z 373 (M.sup.++1).
Example 309
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(cyclopropylmethyl)-6-(1,3-thiazol--
2-yl)-1H-indazole-3-carboxamide hydroformate
[1561] 330
[1562] Prepared using Procedure AH in 31% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.43 (s, 1H), 8.28 (d, J=8.4, 1H), 8.27 (s,
1H), 7.94 (d, J=3.3, 1H), 7.85 (d, J=8.3, 1H), 7.68 (d, J=3.3, 1H),
4.55 (m, 1H), 4.46 (d, J=7.0, 2H), 3.84 (m, 1H), 3.6-3.3 (m, 5H),
2.41 (m, 1H), 2.29 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H), 1.45 (m,
1H), 0.62 (m, 2H), 0.53 (m, 2H); LC/MS (EI) t.sub.R 3.99 min, m/z
408 (M.sup.++1).
Example 310
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(tetrahydrofuran-3-yl)-6-(1,3-thiaz-
ol-2-yl)-1H-indazole-3-carboxamide hydroformate
[1563] 331
[1564] Prepared using Procedure AH in 40% yield. LC/MS (EI) t.sub.R
3.68 min, m/z 424 (M.sup.++1).
Example 311
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-methoxyethyl)-6-(1,3-thiazol-2-y-
l)-1H-indazole-3-carboxamide hydroformate
[1565] 332
[1566] Prepared using Procedure AH in 27% yield. LC/MS (EI) t.sub.R
3.64 min, m/z 412 (M.sup.++1).
Example 312
tert-Butyl
3-[3-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-6-(1,3-t-
hiazol-2-yl)-1H-indazol-1-yl]pyrrolidine-1-carboxylate
hydroformate
[1567] 333
[1568] Prepared using Procedure AH in 38% yield. LC/MS (EI) t.sub.R
4.30 min, m/z 523 (M.sup.++1).
Example 313
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-pyrrolidin-3-yl-6-(1,3-thiazol-2-yl-
)-1H-indazole-3-carboxamide
[1569] 334
[1570] Prepared from Example 312, by exposure to trifluoroacetic
acid, in 88% yield. LC/MS (EI) t.sub.R 2.41 min, m/z 423
(M.sup.++1).
Example 314
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(1,3-thiazol-2-yl)-1-(2-thienylmeth-
yl)-1H-indazole-3-carboxamide hydroformate
[1571] 335
[1572] Prepared using Procedure AH in 11% yield. LC/MS (EI) t.sub.R
4.15 min, m/z 450 (M.sup.++1).
Example 315
N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1-(2-phenoxyethyl)-6-(1,3-thiazol-2-y-
l)-1H-indazole-3-carboxamide hydroformate
[1573] 336
[1574] Prepared using Procedure AH in 54% yield. LC/MS (EI) t.sub.R
4.33 min, m/z 474 (M.sup.++1).
Example 316
[.sup.3H] MLA Binding
[1575] Materials:
[1576] Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2
[1577] Protease inhibitor cocktail tablet: Roche, CAT No.
1697498
[1578] Membrane Preparation
[1579] Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose with
protease inhibitors (one tablet per 50 ml,) were homogenized with a
polytron for 10 sec at setting 11, then centrifuged 10 min at 1000
g, 4.degree. C. The supernatant was centrifuged again for 20 min at
20,000 g, 4.degree. C. The pellets were resuspended in binding
buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM
KCl, 1 mM MgSO.sub.4, 2 mM CaCl.sub.2, 0.1% (w/v) BSA) and stored
membrane prep at -80.degree. C.
[1580] For saturation assay, the 200 .mu.l assay mixture in binding
buffer contains 200 .mu.g of membrane protein, 0.2 to 44 nM of
[.sup.3H] MLA. The nonspecific binding was defined using 1 .mu.M
MLA. Competition assay was carried out with 2 nM [.sup.3H] MLA and
a desirable range of compounds. The assay mixture was incubated at
22.degree. C. for 2 hours, then harvested with GF/B filter
presoaked with 0.3% PEI in binding buffer using Tomtec harvester.
The filter was washed three time with binding buffer and the
radioactivity was counted with Trilux.
[1581] Binding affinities for the preferred compounds of the
invention are 2 nM to 25 .mu.M, especially 2 nM to 2.5 .mu.M.
[1582] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[1583] While the invention has been illustrated with respect to the
production and of particular compounds, it is apparent that
variations and modifications of the invention can be made without
departing from the spirit or scope of the invention.
* * * * *