U.S. patent application number 12/553538 was filed with the patent office on 2009-12-31 for 1h-indazoles, benzothiazoles, 1,2-benzoisoxazoles, 1,2-benzoisothiazoles, and chromones and preparation and uses thereof.
Invention is credited to Carla Maria Gauss, Brian Herbert, Jianguo Ma, True Minh Nguyen, Richard A. Schumacher, Ashok Tehim, Wenge XIE.
Application Number | 20090325939 12/553538 |
Document ID | / |
Family ID | 34969469 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090325939 |
Kind Code |
A1 |
XIE; Wenge ; et al. |
December 31, 2009 |
1H-INDAZOLES, BENZOTHIAZOLES, 1,2-BENZOISOXAZOLES,
1,2-BENZOISOTHIAZOLES, AND CHROMONES AND PREPARATION AND USES
THEREOF
Abstract
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 (indazoles and benzothiazoles), which act as ligands for
the .alpha.7 nAChR 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) ; Ma; Jianguo;
(Montvale, NJ) ; Nguyen; True Minh; (New York,
NY) ; Gauss; Carla Maria; (New York, NY) ;
Tehim; Ashok; (New Jersey, NJ) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
34969469 |
Appl. No.: |
12/553538 |
Filed: |
September 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11123219 |
May 6, 2005 |
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12553538 |
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60568696 |
May 7, 2004 |
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60574712 |
May 27, 2004 |
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60629469 |
Nov 19, 2004 |
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Current U.S.
Class: |
514/221 ;
540/556 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 9/10 20180101; A61P 25/00 20180101; A61P 9/00 20180101; A61P
29/00 20180101; A61P 3/04 20180101; A61P 31/04 20180101; A61P 25/24
20180101; A61P 25/32 20180101; A61P 3/10 20180101; C07D 487/08
20130101; A61P 25/18 20180101; A61P 25/04 20180101; A61P 25/16
20180101; C07D 471/08 20130101; A61P 43/00 20180101; A61P 25/30
20180101; A61P 25/14 20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/221 ;
540/556 |
International
Class: |
A61K 31/551 20060101
A61K031/551; C07D 243/10 20060101 C07D243/10; A61P 25/00 20060101
A61P025/00 |
Claims
1. A compound selected from Formulas I, II, III, V, V, VI, VII and
VIII: ##STR00057## wherein X.sup.1 is CH or CR.sup.1; X.sup.2 to
X.sup.5 are each, independently, N, CH, CR.sup.1, or C--, wherein
--C represents the point of attachment of group B, and wherein at
most one of X.sup.2 to X.sup.5 is N, and one of X.sup.2 to X.sup.5
is --C; X.sup.7 to X.sup.10 are each, independently, N, CH, or
CR.sup.2, wherein at most one of X.sup.7 to X.sup.10 is N; X.sup.11
to X.sup.14 are each, independently N, CH, CR.sup.3, or C--,
wherein --C represents the point of attachment of group B, and
wherein at most one of X.sup.11 to X.sup.14 is N, and one of
X.sup.11 to X.sup.14 is --C; X.sup.15 to X.sup.17 are each,
independently N, O, S, CH, or CR.sup.4; X.sup.18 to X.sup.21 are
each, independently N, CH, or CR.sup.5, wherein at most one of
X.sup.18 to X.sup.21 is N; X.sup.22 and X.sup.23 are each,
independently, CH or CR.sup.12, wherein at least one of X.sup.22 or
X.sup.23 is CR.sup.12; X.sup.24 is either CH or N; B is CH.sub.2,
C.dbd.O, or C.dbd.S; B.sup.1 is CH; Y is O or S; Z is O or
NR.sup.11; m is 1 or 2; 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, cycloalkylalkyl having 4 to 7 carbon atoms, or
C.sub.1-6alkyl-Ar, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are each,
independently, C.sub.1-6-alkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.2-6-alkenyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7,
SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Si(R.sup.8).sub.3, Ar, Het, or
combinations thereof, C.sub.3-8-cycloalkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.16R.sup.6, SH,
SR.sup.7, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, halogen, CN, NO.sub.2, NR.sup.6R.sup.7, SR.sup.6,
SOR.sup.6, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
NR.sup.6SO.sub.2R.sup.6, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7,
COOR.sup.6, NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7,
NR.sup.6CONR.sup.6R.sup.7, NR.sup.6CSNR.sup.6R.sup.7,
NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7, OCONR.sup.6R.sup.7,
OCSNR.sup.6R.sup.7, Ar, Het, or OR.sup.9; R.sup.3 is halogen,
OR.sup.16, CN, nitro, alkyl having 1 to 4 carbon atoms, halogenated
alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon
atoms, cycloalkylalkyl having 4 to 7 carbon atoms, hydroxyalkyl
having 1 to 4 carbon atoms, NH.sub.2, monoalkylamino having 1 to 4
carbon atoms, dialkylamino wherein each alkyl group independently
has 1 to 4 carbon atoms, Ar or Het; R.sup.6 and R.sup.7 are each
independently H, C.sub.1-6-alkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, C.sub.3-6-alkenyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
C.sub.3-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Si(R.sup.8).sub.3, Ar, Het, or
combinations thereof, C.sub.3-8-cycloalkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino
having 1 to 6 carbon atoms, dialkylamino wherein each alkyl group
has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or
combinations thereof, Ar, or Het; R.sup.8 is C.sub.1-6-alkyl;
R.sup.9 is H, C.sub.1-6-alkyl which is unsubstituted or substituted
one or more by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-6-alkenyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-6-alkynyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OR.sup.16NR.sup.6R.sup.6, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.4-8-cycloalkylalkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, Ar, or Het; R.sup.10 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.sup.11 is H, alkyl having 1 to 4
carbon atoms which is unsubstituted or substituted one or more
times by halogen, OR.sup.16, C.sub.3-8 cycloalkyl, NR.sup.6R.sup.7,
Ar, or Het, cycloalkyl having 3 to 7 carbon atoms which is
unsubstituted or substituted one or more times by halogen,
OR.sup.16, NR.sup.6R.sup.7, Ar, or Het, cycloalkylalkyl having 4 to
7 carbon atoms, Ar or Het; R.sup.12 is C.sub.1-6-alkoxy which is
substituted one or more times by F, or is selected from Formulae
IX-XI ##STR00058## wherein Formula IX represents a 5-membered,
unsaturated heterocycle, Formula X represents a 5-8-membered,
heterocycle which is saturated or partially saturated and wherein
the heterocyclic ring may be bridged by a divalent alkylene group
having 1 to 3 carbon atoms, and Formula XI represents a
5-8-membered, heterocycle which is saturated, partially saturated,
or unsaturated and wherein the heterocyclic ring may be bridged by
a divalent alkylene group having 1 to 3 carbon atoms; Q.sup.1 is O,
S, N, NR.sup.13, or SO.sub.2; Q is CH, CR.sup.14, CHR.sup.14, O, S,
SO.sub.2, N, or NR.sup.13; T is O or NR.sup.10; V.sup.1 is O, S,
SO.sub.2, N, NR.sup.13, CR.sup.13, or CHR.sup.14; W.sup.1 is N;
W.sup.2 and W.sup.3 are each, independently, O, S, N, NR.sup.13,
CH, or CR.sup.1, in which the bond between W.sup.2 and W.sup.3 is a
single bond and the bond between W.sup.3 and W.sup.4 is a double
bond, or the bond between W.sup.2 and W.sup.3 is a double bond and
the bond between W.sup.3 and W.sup.4 is a single bond; W.sup.4 is
O, S, N, or NR.sup.13; V.sup.2 is C, CH, C--OH, or N; R.sup.13 is
H, C.sub.1-6-alkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Si(R.sup.8).sub.3, Ar, Het, or
combinations thereof, C.sub.3-8-cycloalkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.6, SH,
SR.sup.7, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, SO.sub.2R.sup.6, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7,
COOR.sup.6, CSOR.sup.6, COR.sup.7, CSR.sup.7, Ar, or Het; R.sup.14
is H, C.sub.1-6-alkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.7,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.7R.sup.6, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.7R.sup.6, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Si(R.sup.8).sub.3, Ar, Het, or
combinations thereof, C.sub.3-8-cycloalkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, OR.sup.9,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.6R.sup.7, SH, SR.sup.6,
SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, and/or
substituted in the alkyl portion one or more times by one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, halogen,
CN, NO.sub.2, NR.sup.6R.sup.7, SR.sup.6, SOR.sup.6,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, NR.sup.6SO.sub.2R.sup.7,
CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7,
NR.sup.6CONR.sup.6R.sup.7NR.sup.6CSNR.sup.7R.sup.6NR.sup.7COOR.sup.6,
NR.sup.7CSOR.sup.6, OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, Ar,
Het, or OR.sup.9; R.sup.15 is H, C.sub.1-6-alkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.2-6-alkenyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.2-6-alkynyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof,
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.4-10-cycloalkylalkyl which is unsubstituted or
substituted in the cycloalkyl portion one or more times by F, Cl,
Br, I, CN, OR.sup.16, NR.sup.16R.sup.6, SH, SR.sup.7, SOR.sup.6,
unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, and/or
substituted in the alkyl portion one or more times by one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-8-cycloalkyloxy which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, halogen, oxo, thio, CN, NO.sub.2, NR.sup.6R.sup.7,
SR.sup.6, SOR.sup.6, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
NR.sup.6SO.sub.2R.sup.7, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7,
COOR.sup.6, NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7,
NR.sup.6CONR.sup.6R.sup.7, NR.sup.6CSNR.sup.6R.sup.7,
NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7, OCONR.sup.6R.sup.7,
OCSNR.sup.6R.sup.7, Ar, Het, or OR.sup.9; R.sup.16 is H,
C.sub.1-6-alkyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-8-cycloalkyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, or
C.sub.4-8-cycloalkylalkyl which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR
.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.7R.sup.6, Ar,
Het, or combinations thereof; Ar is an aryl group containing 6 to
10 carbon atoms which is unsubstituted or substituted one or more
times by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8
carbon atoms, halogen, amino, cyano, hydroxyl, nitro, halogenated
alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8
carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8
carbon atoms, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, carboxy, alkoxycarbonyl, alkylaminocarbonyl, acylamido,
acyloxy, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl
having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon
atoms, sulfo, sulfonylamino, Het, cycloalkylamino wherein the
cycloalkyl group has 3 to 7 C atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, aryloxy wherein the aryl portion contains 6 to 10 carbon
atoms and is optionally substituted by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, arylthio wherein the aryl
portion contains 6 to 10 carbon atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 C atoms
and is optionally substituted by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, or combinations thereof; and
Het is a heterocyclic group, which is fully saturated, partially
saturated or fully unsaturated, having 5 to 10 ring atoms in which
at least 1 ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 8 carbon atoms, halogen, amino, cyano, hydroxyl,
nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated
alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8
carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy
having 3 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, carboxy, alkoxycarbonyl, alkylaminocarbonyl,
acylamido, acyloxy, alkylthio having 1 to 8 carbon atoms,
alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1
to 8 carbon atoms, sulfo, oxo, sulfonylamino, cycloalkylamino
wherein the cycloalkyl group has 3 to 7 carbon atoms and is
optionally substituted by halogen, alkyl having 1 to 8 carbon
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, aryl containing 6 to 10
carbon atoms and is optionally substituted by halogen, alkyl having
1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein
the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the
alkyl portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, aryl-alkylene group wherein
the aryl portion contains 6 to 10 carbon atoms and the alkylene
portion contains 1 to 4 carbon atoms and is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8 C
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, aryloxy wherein the aryl
portion contains 6 to 10 carbon atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, arylthio wherein the aryl portion contains 6 to 10 carbon
atoms and is optionally substituted by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, cycloalkyloxy wherein the
cycloalkyl group has 3 to 7 carbon atoms and is optionally
substituted by halogen, alkyl having 1 to 8 C carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, heterocyclic group, which is fully saturated,
partially saturated or fully unsaturated, having 5 to 10 ring atoms
in which at least 1 ring atom is a N, O or S atom, which is
unsubstituted or substituted one or more times by halogen, alkyl
having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, or
combinations thereof; and pharmaceutically acceptable salts
thereof; wherein when said compound is of Formulas I, II, V, VI,
VII or VII, VIII is 1.
2. A compound according to claim 1, wherein said compound is of
Formula I.
3. A compound according to claim 1, wherein said compound is of
Formula II.
4. A compound according to claim 1, wherein said compound is of
Formula III.
5. A compound according to claim 1, wherein said compound is of
Formula IV.
6. A compound according to claim 1, wherein said compound is of
Formula V.
7. A compound according to claim 1, wherein said compound is of
Formula VI.
8. A compound according to claim 1, wherein said compound is of
Formula VII.
9. A compound according to claim 1, wherein said compound is of
Formula VIII.
10. A compound according to claim 1, wherein R in Formulas I and VI
is H.
11. A compound according to claim 1, wherein said compound is
selected from Formulas I-VI in which R is H, and Het is a
heterocyclic group, which is fully saturated, partially saturated
or fully unsaturated, having 5 to 10 ring atoms in which at least 1
ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 8 carbon atoms, halogen, amino, cyano, hydroxyl,
nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated
alkoxy having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8
carbon atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy
having 3 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, carboxy, alkoxycarbonyl, alkylaminocarbonyl,
acylamido, acyloxy, alkylthio having 1 to 8 carbon atoms,
alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl having 1
to 8 carbon atoms, sulfo, sulfonylamino, cycloalkylamino wherein
the cycloalkyl group has 3 to 7 carbon atoms and is optionally
substituted by halogen, alkyl having 1 to 8 carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, aryl containing 6 to 10 carbon atoms which is
optionally substituted by halogen, alkyl having 1 to 8 carbon
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, aryl-alkylene group wherein
the aryl portion contains 6 to 10 carbon atoms and the alkylene
portion contains 1 to 4 carbon atoms and is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8 C
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, aryloxy wherein the aryl
portion contains 6 to 10 carbon atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, arylthio wherein the aryl portion contains 6 to 10 carbon
atoms and is optionally substituted by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, cycloalkyloxy wherein the
cycloalkyl group has 3 to 7 carbon atoms and is optionally
substituted by halogen, alkyl having 1 to 8 carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, heterocyclic group, which is fully saturated,
partially saturated or fully unsaturated, having 5 to 10 ring atoms
in which at least 1 ring atom is a N, O or S atom, which is
unsubstituted or substituted one or more times by halogen, alkyl
having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, or
combinations thereof; and pharmaceutically acceptable salts
thereof.
12. A compound according to claim 1, wherein said compound is
selected from Formulas I-V, wherein R is H, and R.sup.1R.sup.2,
R.sup.4 and R.sup.5 are each, independently C.sub.1-6-alkyl which
is unsubstituted or substituted one or more times by F, Cl, Br, I,
CN, OH, alkoxy having 1 to 4 carbon atoms, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.7, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.7, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.2-6-alkynyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.7,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof,
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, and/or substituted in the alkyl
portion one or more times by one or more times by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-8-cycloalkyloxy which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.7, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, halogen, CN, NO.sub.2,
NR.sup.6R.sup.7, SR.sup.6, SOR.sup.6,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7, NR.sup.6SO.sub.2R.sup.7,
CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7, NR.sup.6CONR.sup.7R.sup.6,
NR.sup.7CSNR.sup.6R.sup.7, NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, Ar, Het, or OR.sup.9;
R.sup.3 is halogen, OH, CN, nitro, alkyl having 1 to 4 carbon
atoms, halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl
having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon
atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7
carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms,
halogenated alkoxy having 1 to 4 carbon atoms, hydroxyalkyl having
1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms,
NH.sub.2, monoalkylamino having 1 to 4 carbon atoms, dialkylamino
wherein each alkyl group independently has 1 to 4 carbon atoms, Ar
or Het; R.sup.6 and R.sup.7 are each independently H,
C.sub.1-6-alkyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, C.sub.3-6-alkenyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, C.sub.3-6-alkynyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Si(R.sup.8).sub.3, Ar, Het, or combinations
thereof, C.sub.3-8-cycloalkyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, Ar, or Het;
R.sup.9 is H, C.sub.1-6-alkyl which is unsubstituted or substituted
one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.3-6-alkenyl which is
unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms, NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.3-6-alkynyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-8-cycloalkyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.7,
unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.4-8-cycloalkylalkyl which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, Ar, or Het; and R.sup.11 is H, alkyl
having 1 to 4 carbon atoms which is unsubstituted or substituted
one or more times by halogen, OH, alkoxy having 1 to 4 carbon
atoms, C.sub.3-8 cycloalkyl, NR.sup.6R.sup.7, Ar, or Het,
cycloalkyl having 3 to 7 carbon atoms which is unsubstituted or
substituted one or more times by halogen, OH, alkoxy having 1 to 4
carbon atoms, NR.sup.6R.sup.7, Ar, or Het, Ar, or Het.
13. A compound according to claim 1, wherein said compound is
selected from Formulas I, II, IV and V, and at least one of
R.sup.1, R.sup.2, R.sup.4 and R.sup.5 is C.sub.1-6-alkyl which is
substituted at least one time by OR.sup.16, C.sub.2-16-alkenyl
which is substituted at least one time by OR.sup.16,
C.sub.2-6-alkynyl which is substituted at least one time by
OR.sup.16, C.sub.3-8-cycloalkyl which is substituted at least one
time by OR.sup.16, or C.sub.4-10-cycloalkylalkyl which is
substituted at least one time by OR.sup.16, and R.sup.16 is other
than H or C.sub.1-4-alkyl.
14. A compound according to claim 1, wherein said compound is of
Formula III, R.sup.3 is OR.sup.16, and R.sup.16 is other than H,
C.sub.1-4-alkyl, halogenated C.sub.1-4-alkyl, C.sub.3-7-cycloalkyl
or C.sub.4-8-cycloalkylalkyl.
15. A compound according to claim 1, wherein said compound is
selected from Formulas I, II, IV and V, and at least one of R.sup.6
and R.sup.7 is C.sub.1-6-alkyl which is substituted at least one
time by OR.sup.16, C.sub.3-6-alkenyl which is substituted at least
one time by OR.sup.16, C.sub.3-6alkynyl which is substituted at
least one time by OR.sup.16, C.sub.3-8-cycloalkyl which is
substituted at least one time by OR.sup.16, or
C.sub.4-10-cycloalkylalkyl which is substituted at least one time
by OR.sup.16, and R.sup.16 is other than H or C.sub.1-4-alkyl.
16. A compound according to claim 1, wherein said compound is
selected from Formulas I, II, IV and V, and at least one R.sup.9 is
C.sub.1-6-alkyl which is substituted at least one time by
OR.sup.16, C.sub.3-6-alkenyl which is substituted at least one time
by OR.sup.16, C.sub.3-6-alkynyl which is substituted at least one
time by OR.sup.16, C.sub.3-8-cycloalkyl which is substituted at
least one time by OR.sup.16, or C.sub.4-10-cycloalkylalkyl which is
substituted at least one time by OR.sup.16, and R.sup.16 is other
than H or C.sub.1-4-alkyl.
17. A compound according to claim 1, wherein said compound is of
Formula IV, Z is NR.sup.11, R.sup.11 is C.sub.1-4-alkyl which is
substituted at least one time by OR.sup.16 or C.sub.3-7-cycloalkyl
which is substituted at least one time by OR.sup.16, and R.sup.16
is other than H or C.sub.1-4-alkyl.
18. A compound according to claim 1, wherein R.sup.1, R.sup.2,
R.sup.2, R.sup.4, R.sup.5, and R.sup.14 are each, independently,
halogen, nitro, NR.sup.15R.sup.16, amino, alkylamino, dialkylamino,
unsubstituted or substituted phenyl, NR.sup.6CONR.sup.6R.sup.7,
hydroxyl, alkoxy, halogenated alkoxy, or alkylsulfonamide; R.sup.3
is halogen, nitro, amino, alkylamino, dialkylamino, hydroxyl,
alkoxy, or halogenated alkoxy; and R.sup.6, R.sup.7, R.sup.9, and
R.sup.11 are each, independently, unsubstituted or substituted
phenyl.
19. A compound according to claim 1, wherein Ar is in each case
phenyl, napthyl or biphenyl, which is unsubstituted or substituted
one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, amino,
alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,
cyano, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl,
phenoxy, or acyloxy.
20. A compound according to claim 1, wherein Het is in each case
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, oxoazolinyl, isoxazolinyl, furyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, benzopyranyl, indolyl,
quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted
or substituted one or more times by halogen, aryl, alkyl, hydroxy,
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, or
dialkylamino.
21. A compound according to claim 1, wherein Het is in each case
2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 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, benzopyran-6-yl, 5-indolyl,
1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl,
2-isoimidazol-4-yl, 3-pyrazolyl, 3-carbazolyl, 2-thiazolyl,
2-oxazolyl, 1-imidazolyl, or 2-imidazolyl, which is unsubstituted
or substituted one or more times by halogen, aryl, alkyl, hydroxy,
alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, or
dialkylamino.
22. A compound according to claim 1, wherein the heterocyclic
groups of Formulas IX-XI are selected from thiazolyl, substituted
thiazolyl, thiazolylamino, substituted thiazolylamino, oxazolyl,
substituted oxazolyl, imidazolyl, substituted imidazolyl, pyranyl,
substituted pyranyl, piperidinyl, substituted piperidinyl,
pyrrolydinyl, substituted pyrrolydinyl, pyrrolydinyloxy, and
substituted pyrrolydinyloxy.
23. A compound according to claim 14, wherein the heterocyclic
groups of Formulas IX-XI are selected from
5-methyl-1,3-thiazol-2-yl, 4-methyl-1,3-thiazol-2-yl,
1,3-thiazol-2-yl, 1,3-oxazol-2-yl, 1,3-imidazol-2-yl,
5-methyl-1,3-oxazol-2-yl, 4-methyl-1,3-oxazol-2-yl, pyran-4-yl,
piperidin-4-yl, pyrrolidin-3-yl, pyrrolidin-3-yloxy,
3-hydroxypyrrolidin-1-yl, and 1,3-thiazol-2-ylamino.
24. A compound according to claim 1, wherein said compound is
selected from Formulas II and VI, and B is C.dbd.O.
25. A compound according to claim 1, wherein said compound is of
Formula V, and B is CH.sub.2 or C.dbd.O.
26. A compound according to claim 1, wherein said compound is
selected from Formulas IV and V, and Z is O or NH.
27. A compound according to claim 1, wherein said compound is of
Formula II and Y is S.
28. A compound according to claim 1, wherein m is 2.
29. A compound according to claim 1, wherein R.sup.12 is of Formula
IX, and is oxazolyl, thiazolyl, 4-methylthiazolyl, or
5-methylthiazolyl.
30. A compound according to claim 1, wherein R.sup.12 is of Formula
X and is tetrahydropyran and dihydropyran.
31. A compound according to claim 1, wherein R.sup.12 is of Formula
X and is 3-methyl-imidazolidin-2-one or
3-isopropyl-imidazolidin-2-one.
32. A compound according to claim 1, wherein R.sup.12 is
fluorinated alkoxy.
33. A compound according to claim 1, wherein R.sup.12 is OCH.sub.3,
OCF.sub.3, ethoxy, cyclopropylmethoxy, or cyclopropyl.
34. A compound according to claim 1, wherein R.sup.5 is
OCH.sub.3.
35. A compound according to claim 1, wherein said compound is of
Formula VI.
36. (canceled)
37. (canceled)
38. A compound according to claim 1, wherein said compound is
selected from:
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole,
pharmaceutically acceptable salts thereof.
39. (canceled)
40. A compound according to claim 1, wherein said compound is
selected from: 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole, 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazole,
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benzisothiazole,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazo-
le,
6-(Cyclopropylmethoxy)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-
-benzisothiazole,
6-Cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothia-
zole, pharmaceutically acceptable salts thereof.
41. A compound according to claim 1, wherein said compound is
selected from: 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-ol,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazo-
le,
6-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-
e,
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-
-3-isopropylimidazolidin-2-one,
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-
-methylimidazolidin-2-one, and pharmaceutically acceptable salts
thereof.
42. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound selected from Formulas I, II,
III, IV, V, VI, VII and VIII: ##STR00059## wherein X.sup.1 is CH or
CR.sup.1; X.sup.2 to X.sup.5 are each, independently, N, CH,
CR.sup.1, or C--, wherein --C represents the point of attachment of
group B, and wherein at most one of X.sup.2 to X.sup.5 is N, and
one of X.sup.2 to X.sup.5 is --C. X.sup.7 to X.sup.10 are each,
independently, N, CH, or CR.sup.2, wherein at most one of X.sup.7
to X.sup.10 is N; X.sup.11 to X.sup.14 are each, independently N,
CH, CR.sup.3, or C--, wherein --C represents the point of
attachment of group B, and wherein at most one of X.sup.11 to
X.sup.14 is N, and one of X.sup.11 to X.sup.14 is --C; X.sup.15 to
X.sup.17 are each, independently N, O, S, CH, or CR.sup.4; X.sup.13
to X.sup.21 are each, independently N, CH, or CR.sup.5, wherein at
most one of X.sup.18 to X.sup.21 is N; X.sup.22 and X.sup.23 are
each, independently, CH or CR.sup.12, wherein at least one of
X.sup.22 or X.sup.23 is CR.sup.12; X.sup.24 is either CH or N; B is
CH.sub.2, C.dbd.O, or C.dbd.S; B.sup.1 is CH; Y is O or S; Z is O
or NR.sup.11; m is 1 or 2; 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, cycloalkylalkyl having 4 to 7 carbon
atoms, or C.sub.1-6alkyl-Ar, R.sup.1R.sup.2R.sup.4 and R.sup.5 are
each, independently, C.sub.1-6-alkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.1SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.2-6-alkenyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16NR.sup.6R.sup.7,
SH, SR.sup.6SOR.sup.7C.sub.3-8cycloalkyl,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.2-6-alkynyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7,
SH, SR.sup.6, SOR.sup.7, C.sub.3-8cycloalkyl,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7, Si(R.sup.8).sub.3, Ar, Het,
or combinations thereof, C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16NR.sup.6R.sup.7, SH, SR.sup.6SOR.sup.6 unsubstituted
C.sub.3-8cycloalkyl, SO.sub.2R.sup.2NR.sup.6R.sup.7, Ar, Het, or
combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6, unsubstituted C.sub.3-8: cycloalkyl,
SO.sub.2R.sup.1SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof halogen, CN, NO.sub.2, NR.sup.6R.sup.7,
SR.sup.6SOR.sup.6SO.sub.2R.sup.6 SO.sub.2NR.sup.6R.sup.7,
NR.sup.6SO.sub.2R.sup.7CONR.sup.6R.sup.7,
CSNR.sup.6R.sup.7COOR.sup.6,
NR.sup.6COR.sup.7NR.sup.6CSR.sup.7NR.sup.6CONR.sup.6R.sup.7NR.sup.6CSNR.s-
up.6R.sup.7NR.sup.6COOR.sup.7NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, Ar, Het, or R.sup.3 is
halogen, OR.sup.16, CN, nitro, alkyl having 1 to 4 carbon atoms,
halogenated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3
to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,
hydroxyalkyl h having 1 to 4 carbon atoms, NH--, monoalkylamino
having 1 to 4 carbon atoms, dialkylamino wherein each alkyl group
independently has 1 to 4 carbon atoms, Ar or Het; R.sup.6 and
R.sup.7 are each independently H, C.sub.1-6-alkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
C.sub.3-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, C.sub.3-6-alkynyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino
having 1 to 6 carbon atoms, dialkylamino wherein each alkyl group
has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Si(R.sup.8).sub.3,
Ar, Het, or combinations thereof, C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN,
OR.sup.16, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, and/or
substituted in the alkyl portion one or more times by one or more
times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, Ar, or Het; R.sup.8 is C.sub.1-6-alkyl; R.sup.9 is H,
C.sub.1-6-alkyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OR.sup.16NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.2-6-alkenyl which is unsubstituted or substituted
one or more by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof C.sub.3-6-alkynyl which is unsubstituted or substituted one
or more by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-8-cycloalkyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16NR.sup.6R.sup.7,
SH, SR.sup.6SOR.sup.6, unsubstituted C.sub.3-8cycloalkyl,
SO.sub.1R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.4-8-cycloalkylalkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8cycloalkyl, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or
combinations thereof, Ar, or Het; R.sup.10 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.sup.11 is H, alkyl having 1 to 4 carbon atoms
which is unsubstituted or substituted one or more times by halogen,
OR.sup.16, C.sub.3-8cycloalkyl NR.sup.6R.sup.7, Ar, or Het,
cycloalkyl having 3 to 7 carbon atoms which is unsubstituted or
substituted one or more times by halogen, OR.sup.16,
NR.sup.6R.sup.7, Ar, or Het, cycloalkylalkyl having 4 to 7 carbon
atoms, Ar or Het; R.sup.12 is C.sub.1-6-alkoxy which is substituted
one or more times by F, or is selected from Formulae IX-XI
##STR00060## wherein Formula IX represents a 5-membered,
unsaturated heterocycle Formula X represents a 5-8-membered,
heterocycle which is saturated or partially saturated and wherein
the heterocyclic ring may be bridged by a divalent alkylene group
having 1 to 3 carbon atoms, and Formula XI represents a
5-8-membered, heterocycle which is saturated, partially saturated,
or unsaturated and wherein the heterocyclic ring may be bridged by
a divalent alkylene group having 1 to 3 carbon atoms; is O, S, N,
NR.sup.3, or SO.sub.2; is CH, CR.sup.14, CHR.sup.14, O, S,
SO.sub.2, N, or NR.sup.13. T is O or NR.sup.10; V.sup.1 is O, S,
SO.sub.2, N, NR.sup.13, CR.sup.13, or CHR.sup.14; W.sup.1 is N;
W.sup.2 and W.sup.3 are each, independently, O, S, N, NR.sup.13,
CH, or CR.sup.1, in which the bond between W.sup.2 and W.sup.3 is a
single bond and the bond between W.sup.3 and W.sup.4 is a double
bond, or the bond between W.sup.2 and W.sup.3 is a double bond and
the bond between W.sup.3 and W.sup.4 is a single bond; W.sup.4 is
O, S, N, or NR.sup.13; V.sup.2 is C, CH, C--OH, or N; R.sup.13 is
H, C.sub.1-6-alkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6C.sub.3-8cycloalkyl,
SO.sub.2R.sup.7SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-6-alkenyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7,
SH, SR.sup.6SOR.sup.6C.sub.3-8cycloalkyl,
SO.sub.2R.sup.7SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-6-alkynyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7,
SH, SR.sup.6SOR.sup.6C.sub.3-8cycloalkyl,
SO.sub.2R.sup.7SO.sub.2NR.sup.6R.sup.7, Si(R.sup.8).sub.3, Ar, Het,
or combinations thereof, C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16NR.sup.16R.sup.6, SH,
SR.sup.7SOR.sup.6 unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, SO.sub.2R.sup.6, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7,
COOR.sup.6, CSOR.sup.6, COR.sup.7, CSR.sup.7, Ar, or Het; R.sup.14
is H, C.sub.---6-alkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.7R.sup.6, SH,
SR.sup.6, SOR.sup.6C.sub.3-8-cycloalkyl, SO.sub.2R.sup.7,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.7R.sup.6, SH, SR.sup.6,
SOR.sup.6C.sub.3-8-cycloalkyl, SO.sub.2R.sup.1,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.7R.sup.6, SH, SR.sup.6,
SOR.sup.6C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.6, Si(R.sup.8).sub.3, Ar, Het,
or combinations thereof, C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.9, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2, R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Ar, Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which
is unsubstituted or substituted in the cycloalkyl portion one or
more times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6 unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16NR.sup.6R.sup.7,
SH, SR.sup.6SOR.sup.6, C.sub.3-8-cycloalkyl SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, halogen,
CN, NO.sub.2,
NR.sup.6R.sup.7SR.sup.6SOR.sup.6SO.sub.2R.sup.6SO.sub.2NR.sup.6R.sup.7,
NR.sup.6SO.sub.2R.sup.7, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7,
COOR.sup.6NR.sup.6COR.sup.7NR.sup.6CSR.sup.7NR.sup.6CONR.sup.6R.sup.7NR.s-
up.6CSNR.sup.6R.sup.7NR.sup.6COOR.sup.7NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, Ar, Het, or R.sup.15 is H,
C.sub.1-6-alkyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.6NR.sup.7R.sup.6, SH,
SR.sup.6SOR.sup.6C.sub.3-8cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.6, NR.sup.7R.sup.6, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8cycloalkyl, SO.sub.2R.sup.7,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof,
C.sub.2-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.7R.sup.6, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.16R.sup.7, Si(R.sup.8).sub.3, Ar, Het, or
combinations thereof, C.sub.3-8-cycloalkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16NR.sup.6R.sup.7, SH, SR.sup.6SOR.sup.6 unsubstituted
C.sub.3-8cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, CL, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6SOR.sup.6C.sub.3-8-cycloalkyl,
SO.sub.2, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-8-cycloalkyloxy which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16NR.sup.6R.sup.7, SH, SR.sup.6SOR.sup.6 unsubstituted
C.sub.3-8cycloalkyl, SO.sub.2, R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Ar, Het, or combinations thereof, halogen, oxo, thio, CN, NO,
NR.sup.6R.sup.7SR.sup.6SOR.sup.6SOR.sup.6S0-NR.sup.6R.sup.7NR.sup.6SO.sub-
.2R.sup.7CONR.sup.6R.sup.7CSNR.sup.6R.sup.7COOR.sup.6NR.sup.6COR.sup.7,
NR.sup.6CSR.sup.7, NR.sup.6CONR.sup.6R.sup.7,
NR.sup.6CSNR.sup.6R.sup.7, NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, Ar, Het, or R.sup.16 is H,
C.sub.1-6-alkyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, C.sub.3-8-cycloalkyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4
carbon atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, or
C.sub.4-8-cycloalkylalkyl which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof;
Ar is an aryl group containing 6 to 10 carbon atoms which is
unsubstituted or substituted one or more times by alkyl having 1 to
8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino
cyano, hydroxyl, nitro, halogenated alkyl having 1 to 8 carbon
atoms, halogenated alkoxy having 1 to 8 carbon atoms, hydroxyalkyl
having 1 to 8 carbon atoms, hydroxyalkoxy having 2 to 8 carbon
atoms, alkenyloxy having 3 to 8 carbon atoms, monoalkylamino having
1 to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, carboxy, alkoxycarbonyl
alkylaminocarbonyl, acylamido, acyloxy, alkylthio having 1 to 8
carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms, sulfo sulfonylamino,
Het, cycloalkylamino wherein the cycloalkyl group has 3 to 7 C
atoms and is optionally substituted by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, aryloxy wherein the aryl
portion contains 6 to 10 carbon atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, arylthio wherein the aryl portion contains 6 to 10 carbon
atoms and is optionally substituted by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, cycloalkyloxy wherein the
cycloalkyl group has 3 to 7 C atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, or combinations thereof; and Het is a heterocyclic group,
which is fully saturated, partially saturated or fully unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, O
or S atom, which is unsubstituted or substituted one or more times
by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon
atoms, halogen, amino cyano, hydroxyl, nitro, halogenated alkyl
having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8 carbon
atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy
having 2 to 8 carbon atoms, alkenyloxy having 3 to 8 carbon atoms,
monoalkylamino having 1 to 8 carbon atoms, dialkylamino wherein the
alkyl portions each have 1 to 8 carbon atoms, carboxy,
alkoxycarbonyl alkylaminocarbonyl, acylamido, acyloxy, alkylthio
having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8 carbon
atoms, alkylsulphonyl having 1 to 8 carbon atoms, oxo,
sulfonylamino, cycloalkylamino wherein the cycloalkyl group has 3
to 7 carbon atoms and is optionally substituted by halogen, alkyl
having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, aryl
containing 6 to 10 carbon atoms and is optionally substituted by
halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl having
1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino,
monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio,
aryl-alkylene group wherein the aryl portion contains 6 to 10
carbon atoms and the alkylene portion contains 1 to 4 carbon atoms
and is unsubstituted or substituted one or more times by halogen,
alkyl having 1 to 8 C atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, aryloxy
wherein the aryl portion contains 6 to 10 carbon atoms and is
optionally substituted by halogen, alkyl having 1 to 8 carbon
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, arylthio wherein the aryl
portion contains 6 to 10 carbon atoms and is optionally substituted
by halogen, alkyl having 1 to 8 carbon atoms, halogenated alkyl
having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms,
amino, monoalkylamino wherein the alkyl portion has 1 to 8 carbon
atoms, dialkylamino wherein the alkyl portions each have 1 to 8
carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or
thio, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 carbon
atoms and is optionally substituted by halogen, alkyl having 1 to 8
C carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein
the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the
alkyl portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, heterocyclic group, which is
fully saturated, partially saturated or fully unsaturated, having 5
to 10 ring atoms in which at least 1 ring atom is a N, O or S atom,
which is unsubstituted or substituted one or more times by halogen,
alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8
carbon atoms, alkoxy having 1 to 4 carbon atoms, amino,
monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio,
or combinations thereof; and pharmaceutically acceptable salts
thereof; wherein when said compound is of Formulas I, II, V, VI,
VII or VII, VIII is 1.
43. (canceled)
44. (canceled)
45. (canceled)
46. (canceled)
47. (canceled)
48. (canceled)
49. (canceled)
50. (canceled)
51. (canceled)
52. (canceled)
53. (canceled)
54. (canceled)
55. (canceled)
56. (canceled)
57. (canceled)
58. (canceled)
59. (canceled)
60. (canceled)
61. (canceled)
62. (canceled)
63. (canceled)
64. (canceled)
65. (canceled)
66. (canceled)
67. (canceled)
68. A compound according to claim 38, wherein said compound is a
hydrochloride salt or a hydroformate salt.
69. A compound according to claim 68, wherein said compound is
selected from:
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
hydroformate, and
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole
hydroformate.
70. A compound according to claim 40, wherein said compound is a
hydrochloride salt or a hydroformate salt.
71. A compound according to claim 70, wherein said compound is
selected from:
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole
hydroformate,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazol-
e hydroformate,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benz-
isothiazole hydroformate,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazo-
le hydroformate, and
6-Cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothia-
zole hydroformate.
72. A compound according to claim 41, wherein said compound is a
hydrochloride salt or a hydroformate salt.
73. A compound according to claim 72, wherein said compound is
selected from:
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-ol
hydroformate,
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazo-
le hydroformate,
6-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
hydroformate,
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-
-isopropylimidazolidin-2-one hydroformate, and
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-
-methylimidazolidin-2-one hydroformate.
Description
[0001] This application claims the benefit of U.S. provisional
application Ser. No. 60/568,696, filed May 7, 2004, U.S.
provisional application Ser. No. 60/574,712, filed May 27, 2004,
and U.S. provisional application Ser. No. 60/629,469, filed Nov.
10, 2004, the entire disclosures of which are hereby incorporated
by reference.
FIELD OF THE INVENTION
[0002] 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
[0003] 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.
[0004] 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.
[0005] 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.7 nAChR subtype, for the treatment of
disease conditions associated with defective or malfunctioning
nicotinic acetylcholine receptors.
SUMMARY OF THE INVENTION
[0006] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention includes compounds of Formulas I, II,
III, IV, V, VI, VII or VIII:
##STR00001##
wherein [0008] X.sup.1 is CH or CR.sup.1; [0009] X.sup.2 to X.sup.5
are each, independently, N, CH, CR.sup.1, or C--, wherein --C
represents the point of attachment of group B, and wherein at most
one of X.sup.2 to X.sup.5 is N, and one of X.sup.2 to X.sup.5 is
--C (preferably X.sup.3 or X.sup.4), preferably X.sup.1 is CH, or
CR.sup.1, X.sup.2 and X.sup.5 are N or CH, and X.sup.3 and X.sup.4
are N, CH, CR.sup.1, or C--; [0010] X.sup.7 to X.sup.1 are each,
independently, N, CH, or CR.sup.2, wherein at most one of X.sup.7
to X.sup.1 is N; [0011] X.sup.11 to X.sup.14 are each,
independently N, CH, CR.sup.3, or C--, wherein --C represents the
point of attachment of group B, and wherein at most one of X.sup.11
to X.sup.14 is N, and one of X.sup.11 to X.sup.14 is --C
(preferably X.sup.1 or X.sup.13); [0012] X.sup.15 to X.sup.17 are
each, independently N, O, S, CH, or CR.sup.4; [0013] X.sup.18 to
X.sup.21 are each, independently N, CH, or CR.sup.5, wherein at
most one of X.sup.18 to X.sup.21 is N; [0014] X.sup.22 and X.sup.23
are each, independently, CH or CR.sup.12, wherein at least one of
X.sup.22 or [0015] X.sup.23 is CR.sup.12; [0016] X.sup.24 is either
CH or N; [0017] B is CH.sub.2, C.dbd.O, or C.dbd.S; [0018] B.sup.1
is CH; [0019] Y is O or S; [0020] Z is O or NR.sup.11; [0021] m is
1 or 2; [0022] 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, cycloalkylalkyl having 4 to 7 carbon atoms, or
C.sub.1-6alkyl-Ar (e.g., benzyl), [0023] R.sup.1, R.sup.2, R.sup.4
and R.sup.5 are each, independently, [0024] C.sub.1-6-alkyl which
is unsubstituted or substituted one or more times by F, Cl, Br, I,
CN, OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., CH.sub.3, C.sub.2H.sub.5,
CF.sub.3), [0025] C.sub.2-6-alkenyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.6,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., C.sub.2H.sub.3, C.sub.3H.sub.5), [0026]
C.sub.2-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Si(R.sup.8).sub.3, Ar, Het, or
combinations thereof (e.g., C.sub.2H, C.sub.3H.sub.3), [0027]
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.6, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopropyl, cyclobutyl, cyclopentyl), [0028]
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, and/or substituted in the alkyl
portion one or more times by one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., cyclopentylmethyl,
cyclopropylmethyl, etc.), [0029] halogen (e.g., F, Cl, Br, I),
[0030] CN, NO.sub.2, NR.sup.6R.sup.7, SR.sup.6, SOR.sup.6,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, NR.sup.6SO.sub.2R.sup.7,
CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7, NR.sup.6CONR.sup.6R.sup.7,
NR.sup.6CSNR.sup.6R.sup.7, NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, [0031] Ar (e.g., phenyl),
[0032] Het (e.g., thienyl), or [0033] OR.sup.9 (e.g., hydroxyl,
alkoxy, cycloalkyloxy, cycloalkylalkoxy); [0034] R.sup.3 is halogen
(e.g., F, Cl, Br, I), OR.sup.16 (e.g., OCH.sub.3, cyclopropyloxy,
cyclopropylmethoxy, OCF.sub.3, OCHF.sub.2, hydroxyethoxy), CN,
nitro, alkyl having 1 to 4 carbon atoms (e.g., CH.sub.3,
C.sub.2H.sub.5), halogenated alkyl having 1 to 4 carbon atoms
(e.g., CF.sub.3), cycloalkyl having 3 to 7 carbon atoms (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl), cycloalkylalkyl having 4 to
7 carbon atoms (e.g., cyclopentylmethyl, cyclopropylmethyl),
hydroxyalkyl having 1 to 4 carbon atoms (e.g., hydroxymethyl,
hydroxyethyl), NH.sub.2, monoalkylamino having 1 to 4 carbon atoms
(e.g., methylamino), dialkylamino wherein each alkyl group
independently has 1 to 4 carbon atoms (e.g., dimethylamino), Ar
(e.g., phenyl) or Het; [0035] R.sup.6 and R.sup.7 are each
independently [0036] H, [0037] C.sub.1-6-alkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms (e.g.,
diethylamino), C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof (e.g., CH.sub.3, C.sub.2H.sub.5, CF.sub.3), [0038]
C.sub.3-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl, Ar, Het,
or combinations thereof (e.g., C.sub.2H.sub.3, C.sub.3H.sub.5),
[0039] C.sub.3-6-alkynyl which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino having
1 to 6 carbon atoms, dialkylamino wherein each alkyl group has 1 to
6 carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof (e.g.,
C.sub.2H, C.sub.3H.sub.3), [0040] C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.6, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms (e.g.,
diethylamino), C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof (e.g., cyclopropyl, cyclobutyl, cyclopentyl), [0041]
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN,
OR.sup.16, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms (e.g.,
diethylamino), C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.16, monoalkylamino
having 1 to 6 carbon atoms, dialkylamino wherein each alkyl group
has 1 to 6 carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl,
Ar, Het, or combinations thereof (e.g., cyclopentylmethyl,
cyclopropylmethyl, etc.), [0042] Ar, or [0043] Het; [0044] R.sup.8
is C.sub.1-6-alkyl (e.g., CH.sub.3); [0045] R.sup.9 is H, [0046]
C.sub.1-6-alkyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof (e.g.,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3), [0047] C.sub.3-6-alkenyl which
is unsubstituted or substituted one or more by F, Cl, Br, I, CN,
OR.sup.6, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., C.sub.2H.sub.3,
C.sub.3H.sub.5), [0048] C.sub.3-6-alkynyl which is unsubstituted or
substituted one or more by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., C.sub.2H, C.sub.3H.sub.3), [0049]
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OR.sup.6, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopropyl, cyclobutyl, cyclopentyl), [0050]
C.sub.4-8-cycloalkylalkyl which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), [0051]
Ar, or [0052] Het; [0053] R.sup.10 is H, alkyl having 1 to 4 carbon
atoms (e.g., CH.sub.3, C.sub.2H.sub.5), halogenated alkyl having 1
to 4 carbon atoms (e.g., CF.sub.3), cycloalkyl having 3 to 7 carbon
atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl), or
cycloalkylalkyl having 4 to 7 carbon atoms (e.g.,
cyclopentylmethyl, cyclopropylmethyl, etc.); [0054] R.sup.11 is H,
alkyl having 1 to 4 carbon atoms (which is unsubstituted or
substituted one or more times by halogen, OR.sup.16, C.sub.3-8
cycloalkyl, NR.sup.6R.sup.7, Ar, or Het), cycloalkyl having 3 to 7
carbon atoms (which is unsubstituted or substituted one or more
times by halogen, OR.sup.16, NR.sup.6R.sup.7, Ar, or Het),
cycloalkylalkyl having 4 to 7 carbon atoms (e.g.,
cyclopentylmethyl, cyclopropylmethyl, etc.), Ar or Het (e.g.,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3, cyclopropyl, cyclopentyl,
phenyl); [0055] R.sup.12 is C.sub.1-6-alkoxy which is substituted
one or more times by F, or is selected from Formulae IX-XI
##STR00002##
[0055] wherein Formula IX represents a 5-membered, unsaturated
heterocycle in which the bond between W.sup.2 and W.sup.3 is a
single bond and the, Formula X represents a 5-8-membered,
heterocycle which is saturated or partially saturated and wherein
the heterocyclic ring may be bridged by a divalent alkylene group
having 1 to 3 carbon atoms, and Formula XI represents a
5-8-membered, heterocycle which is saturated, partially saturated,
or unsaturated and wherein the heterocyclic ring may be bridged by
a divalent alkylene group having 1 to 3 carbon atoms; [0056] Q' is
O, S, N, NR.sup.13, or SO.sub.2; [0057] Q.sup.2 is CH, CR.sup.14,
CHR.sup.14, O, S, SO.sub.2, N, or NR.sup.13; [0058] T is O or
NR.sup.10; [0059] V.sup.1 is O, S, SO.sub.2, N, NR.sup.13,
CR.sup.14, or CHR.sup.14; [0060] W.sup.1 is N; [0061] W.sup.2 and
W.sup.3 are each, independently, O, S, N, NR.sup.13, CH, or
CR.sup.1, in which the bond between W.sup.2 and W.sup.3 is a single
bond and the bond between W.sup.3 and W.sup.4 is a double bond, or
the bond between W.sup.2 and W.sup.3 is a double bond and the bond
between W.sup.3 and W.sup.4 is a single bond; [0062] W.sup.4 is O,
S, N, or NR.sup.13; [0063] V.sup.2 is C, CH, C--OH, or N; [0064]
R.sup.13 is H, [0065] C.sub.1-6-alkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., CH.sub.3, C.sub.2H.sub.5, CF.sub.3), [0066]
C.sub.3-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof (e.g.,
C.sub.2H.sub.3, C.sub.3H.sub.5), [0067] C.sub.3-6-alkynyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.6, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof (e.g.,
C.sub.2H, C.sub.3H.sub.3), [0068] C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., cyclopropyl, cyclobutyl,
cyclopentyl), [0069] C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.6,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl
(e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), [0070]
SO.sub.2R.sup.6, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
CSOR.sup.6, COR.sup.7, CSR.sup.7, [0071] Ar, or [0072] Het; [0073]
R.sup.14 is H, [0074] C.sub.1-6-alkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.9,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., CH.sub.3, C.sub.2H.sub.5, CF.sub.3), [0075]
C.sub.2-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.6R.sup.7, SH, SR.sup.6,
SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof (e.g.,
C.sub.2H.sub.3, C.sub.3H.sub.5), [0076] C.sub.2-6-alkynyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.9, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Si(R.sup.1).sub.3, Ar, Het, or combinations thereof (e.g.,
C.sub.2H, C.sub.3H.sub.3), [0077] C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.9, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., cyclopropyl, cyclobutyl,
cyclopentyl), [0078] C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.9, NR.sup.6R.sup.7, SH, SR.sup.6,
SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, and/or
substituted in the alkyl portion one or more times by one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof (e.g.,
cyclopentylmethyl, cyclopropylmethyl, etc.), [0079] halogen (e.g.,
F, Cl, Br, I,), [0080] CN, NO.sub.2, NR.sup.6R.sup.7, SR.sup.6,
SOR.sup.6, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
NR.sup.6SO.sub.2R.sup.7, CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7,
COOR.sup.6, NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7,
NR.sup.6CONR.sup.6R.sup.7, NR.sup.6CSNR.sup.6R.sup.7,
NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7, OCONR.sup.6R.sup.7,
OCSNR.sup.6R.sup.7, [0081] Ar, [0082] Het, or [0083] OR.sup.9;
[0084] R.sup.5 is H, [0085] C.sub.1-6-alkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, OR.sup.16,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., CH.sub.3, C.sub.2H.sub.5, CF.sub.3), [0086]
C.sub.2-6-alkenyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof (e.g.,
C.sub.2H.sub.3, C.sub.3H.sub.5), [0087] C.sub.2-6-alkynyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof (e.g.,
C.sub.2H, C.sub.3H.sub.3), [0088] C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.16, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., cyclopropyl, cyclobutyl,
cyclopentyl), [0089] C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.8, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, OR.sup.6,
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), [0090]
C.sub.3-8-cycloalkyloxy which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OR.sup.16, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopropyloxy, cyclopentyloxy), [0091] halogen
(e.g., F, Cl, Br, I,), [0092] oxo, thio, CN, NO.sub.2,
NR.sup.6R.sup.7, SR.sup.6, SOR.sup.6, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, NR.sup.6SO.sub.2R.sup.7,
CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7, NR.sup.6CONR.sup.6R.sup.7,
NR.sup.6CSNR.sup.6R.sup.7, NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, [0093] Ar, [0094] Het, or
[0095] OR.sup.9; [0096] R.sup.16 is H, [0097] C.sub.1-6-alkyl which
is unsubstituted or substituted one or more by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms, NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof (e.g.,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3), [0098] C.sub.3-8-cycloalkyl
which is unsubstituted or substituted one or more times by F, Cl,
Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms, NR.sup.6R.sup.7,
SH, SR.sup.6, SOR.sup.6, unsubstituted C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopropyl, cyclobutyl, cyclopentyl), or [0099]
C.sub.4-8-cycloalkylalkyl which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms, NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof (e.g., cyclopentylmethyl,
cyclopropylmethyl, etc.); [0100] R.sup.17 and R.sup.18 are each
independently H, alkyl having 1 to 4 carbon atoms (e.g., CH.sub.3,
C.sub.2H.sub.5), halogenated alkyl having 1 to 4 carbon atoms
(e.g., CF.sub.3), cycloalkyl having 3 to 7 carbon atoms (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl), or cycloalkylalkyl having 4
to 7 carbon atoms (e.g., cyclopentylmethyl, cyclopropylmethyl,
etc.); [0101] R.sup.19 is H or CONH--CH.sub.2--Ar; [0102] Ar is an
aryl group containing 6 to 10 carbon atoms which is unsubstituted
or substituted one or more times by [0103] alkyl having 1 to 8
carbon atoms, [0104] alkoxy having 1 to 8 carbon atoms, [0105]
halogen (F, Cl, Br, or I, preferably F or Cl), [0106] amino, [0107]
cyano, [0108] hydroxyl, [0109] nitro, [0110] halogenated alkyl
having 1 to 8 carbon atoms, [0111] halogenated alkoxy having 1 to 8
carbon atoms, [0112] hydroxyalkyl having 1 to 8 carbon atoms,
[0113] hydroxyalkoxy having 2 to 8 carbon atoms, [0114] alkenyloxy
having 3 to 8 carbon atoms, [0115] monoalkylamino having 1 to 8
carbon atoms, [0116] dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, [0117] carboxy, [0118] alkoxycarbonyl,
[0119] alkylaminocarbonyl, [0120] acylamido (e.g., acetamido),
[0121] acyloxy (e.g., acetoxy), [0122] alkylthio having 1 to 8
carbon atoms, [0123] alkylsulphinyl having 1 to 8 carbon atoms,
[0124] alkylsulphonyl having 1 to 8 carbon atoms, [0125] sulfo,
[0126] sulfonylamino, [0127] Het, [0128] cycloalkylamino wherein
the cycloalkyl group has 3 to 7 C atoms and is optionally
substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl
having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, [0129]
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms
(e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by
halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, [0130] arylthio wherein the
aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl,
biphenyl) and is optionally substituted by halogen (F, Cl, Br, or
I, preferably F or Cl), alkyl having 1 to 8 carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, [0131] cycloalkyloxy wherein the cycloalkyl
group has 3 to 7 C atoms and is optionally substituted by halogen
(F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, or [0132] combinations
thereof; and [0133] Het is a heterocyclic group (e.g., furyl,
thienyl, methylthienyl, bithienyl, benzylprazolyl, thiazolyl,
imidazolyl, methylimidazolyl, pyrrolidinyl, morpholinyl,
thiomorpholinyl), 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 [0134] alkyl having 1 to 8 carbon
atoms, [0135] alkoxy having 1 to 8 carbon atoms, [0136] halogen (F,
Cl, Br, or I, preferably F or Cl), [0137] amino, [0138] cyano,
[0139] hydroxyl, [0140] nitro, [0141] halogenated alkyl having 1 to
8 carbon atoms, [0142] halogenated alkoxy having 1 to 8 carbon
atoms, [0143] hydroxyalkyl having 1 to 8 carbon atoms, [0144]
hydroxyalkoxy having 2 to 8 carbon atoms, [0145] alkenyloxy having
3 to 8 carbon atoms, [0146] monoalkylamino having 1 to 8 carbon
atoms, [0147] dialkylamino wherein the alkyl portions each have 1
to 8 carbon atoms, [0148] carboxy, [0149] alkoxycarbonyl, [0150]
alkylaminocarbonyl, [0151] acylamido (e.g., acetamido), [0152]
acyloxy (e.g., acetoxy), [0153] alkylthio having 1 to 8 carbon
atoms, [0154] alkylsulphinyl having 1 to 8 carbon atoms, [0155]
alkylsulphonyl having 1 to 8 carbon atoms, [0156] sulfo, [0157]
oxo, [0158] sulfonylamino, [0159] cycloalkylamino wherein the
cycloalkyl group has 3 to 7 carbon atoms and is optionally
substituted by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl
having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, [0160]
aryl containing 6 to 10 carbon atoms (e.g., phenyl, naphthyl,
biphenyl) and is optionally substituted by halogen (F, Cl, Br, or
I, preferably F or Cl), alkyl having 1 to 8 carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, [0161] aryl-alkylene group (e.g., benzyl,
phenethyl, phenpropyl) wherein the aryl portion contains 6 to 10
carbon atoms and the alkylene portion contains 1 to 4 carbon atoms
and is unsubstituted or substituted one or more times by halogen
(F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 C atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR
.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, [0162]
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms
(e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by
halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, [0163] arylthio wherein the
aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl,
biphenyl) and is optionally substituted by halogen (F, Cl, Br, or
I, preferably F or Cl), alkyl having 1 to 8 carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, [0164] cycloalkyloxy wherein the cycloalkyl
group has 3 to 7 carbon atoms and is optionally substituted by
halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8
C carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein
the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the
alkyl portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, [0165] 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), alkyl having 1 to
8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein
the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the
alkyl portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, [0166] or thio, or combinations
thereof; and pharmaceutically acceptable salts thereof.
[0167] According to a further aspect of the invention, the
compounds are selected from Formulas I-VI, wherein [0168] R is H,
and [0169] Het is a heterocyclic group (e.g., furyl, thienyl,
methylthienyl, bithienyl, benzylprazolyl, thiazolyl, imidazolyl,
methylimidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl),
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 [0170] alkyl having 1 to 8 carbon atoms, [0171] alkoxy having 1
to 8 carbon atoms, [0172] halogen (F, Cl, Br, or I, preferably F or
Cl), [0173] amino, [0174] cyano, [0175] hydroxyl, [0176] nitro,
[0177] halogenated alkyl having 1 to 8 carbon atoms, [0178]
halogenated alkoxy having 1 to 8 carbon atoms, [0179] hydroxyalkyl
having 1 to 8 carbon atoms, [0180] hydroxyalkoxy having 2 to 8
carbon atoms, [0181] alkenyloxy having 3 to 8 carbon atoms, [0182]
monoalkylamino having 1 to 8 carbon atoms, [0183] dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms, [0184]
carboxy, [0185] alkoxycarbonyl, [0186] alkylaminocarbonyl, [0187]
acylamido (e.g., acetamido), [0188] acyloxy (e.g., acetoxy), [0189]
alkylthio having 1 to 8 carbon atoms, [0190] alkylsulphinyl having
1 to 8 carbon atoms, [0191] alkylsulphonyl having 1 to 8 carbon
atoms, [0192] sulfo, [0193] sulfonylamino, [0194] cycloalkylamino
wherein the cycloalkyl group has 3 to 7 carbon atoms and is
optionally substituted by halogen (F, Cl, Br, or I, preferably F or
Cl), alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1
to 8 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino,
monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio,
[0195] aryl containing 6 to 10 carbon atoms (e.g., phenyl,
naphthyl, biphenyl) and is optionally substituted by halogen (F,
Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 carbon
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, [0196] aryl-alkylene group
(e.g., benzyl, phenethyl, phenpropyl) wherein the aryl portion
contains 6 to 10 carbon atoms and the alkylene portion contains 1
to 4 carbon atoms and is unsubstituted or substituted one or more
times by halogen (F, Cl, Br, or I, preferably F or Cl), alkyl
having 1 to 8 C atoms, halogenated alkyl having 1 to 8 carbon
atoms, alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino
wherein the alkyl portion has 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
COR.sup.9, CSR.sup.9, cyano, hydroxyl, nitro, oxo, or thio, [0197]
aryloxy wherein the aryl portion contains 6 to 10 carbon atoms
(e.g., phenyl, naphthyl, biphenyl) and is optionally substituted by
halogen (F, Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, [0198] arylthio wherein the
aryl portion contains 6 to 10 carbon atoms (e.g., phenyl, naphthyl,
biphenyl) and is optionally substituted by halogen (F, Cl, Br, or
I, preferably F or Cl), alkyl having 1 to 8 carbon atoms,
halogenated alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4
carbon atoms, amino, monoalkylamino wherein the alkyl portion has 1
to 8 carbon atoms, dialkylamino wherein the alkyl portions each
have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9, cyano, hydroxyl,
nitro, oxo, or thio, cycloalkyloxy wherein the cycloalkyl group has
3 to 7 carbon atoms and is optionally substituted by halogen (F,
Cl, Br, or I, preferably F or Cl), alkyl having 1 to 8 C carbon
atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy having
1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, [0199] 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), alkyl having 1 to
8 carbon atoms, halogenated alkyl having 1 to 8 carbon atoms,
alkoxy having 1 to 4 carbon atoms, amino, monoalkylamino wherein
the alkyl portion has 1 to 8 carbon atoms, dialkylamino wherein the
alkyl portions each have 1 to 8 carbon atoms, COR.sup.9, CSR.sup.9,
cyano, hydroxyl, nitro, oxo, or thio, or combinations thereof; and
pharmaceutically acceptable salts thereof.
[0200] According to a further aspect of the invention, the
compounds of Formulas I-VI are selected from Formulas I-V, wherein
R is H, and R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are each,
independently, [0201] C.sub.1-6-alkyl (e.g., CH.sub.3) which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, [0202] C.sub.2-6-alkenyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy
having 1 to 4 carbon atoms (e.g., OCH.sub.3), NR.sup.6R.sup.7, SH,
SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, [0203]
C.sub.2-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms
(e.g., OCH.sub.3), NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof, [0204]
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms (e.g., OCH.sub.3), NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, [0205]
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, and/or substituted in the alkyl
portion one or more times by one or more times by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), [0206]
C.sub.3-8-cycloalkyloxy which is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon
atoms (e.g., OCH.sub.3), NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
unsubstituted C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations thereof, [0207]
halogen (e.g., F, Cl, Br, I,), [0208] CN, NO.sub.2,
NR.sup.6R.sup.7, SR.sup.6, SOR.sup.6, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, NR.sup.6SO.sub.2R.sup.7,
CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7, NR.sup.6CONR.sup.6R.sup.7,
NR.sup.6CSNR.sup.6R.sup.7, NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, [0209] Ar, [0210] Het, or
[0211] OR.sup.9; [0212] R.sup.3 is halogen (e.g., F, Cl, Br, I),
OH, CN, nitro, alkyl having 1 to 4 carbon atoms, halogenated alkyl
having 1 to 4 carbon atoms (e.g., CF.sub.3), cycloalkyl having 3 to
7 carbon atoms, cycloalkylalkyl having 4 to 7 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,
halogenated alkoxy having 1 to 4 carbon atoms (e.g., OCF.sub.3,
OCHF.sub.2), hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy
having 2 to 4 carbon atoms, NH.sub.2, monoalkylamino having 1 to 4
carbon atoms, dialkylamino wherein each alkyl group independently
has 1 to 4 carbon atoms, Ar or Het; [0213] R.sup.6 and R.sup.7 are
each independently [0214] H, [0215] C.sub.1-6-alkyl (e.g.,
CH.sub.3) which is unsubstituted or substituted one or more times
by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g.,
OCH.sub.3), monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms (e.g.,
diethylamino), C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, [0216] C.sub.2-6-alkenyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy
having 1 to 4 carbon atoms (e.g., OCH.sub.3), monoalkylamino having
1 to 6 carbon atoms, dialkylamino wherein each alkyl group has 1 to
6 carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl, Ar, Het,
or combinations thereof, [0217] C.sub.2-6-alkynyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms (e.g., diethylamino),
C.sub.3-8-cycloalkyl, Si(R.sup.8).sub.3, Ar, Het, or combinations
thereof, [0218] C.sub.3-8-cycloalkyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OH, alkoxy
having 1 to 4 carbon atoms (e.g., OCH.sub.3), monoalkylamino having
1 to 6 carbon atoms, dialkylamino wherein each alkyl group has 1 to
6 carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof, [0219]
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3), monoalkylamino
having 1 to 6 carbon atoms, dialkylamino wherein each alkyl group
has 1 to 6 carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl,
Si(R.sup.8).sub.3, Ar, Het, or combinations thereof, and/or
substituted in the alkyl portion one or more times by one or more
times by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms
(e.g., OCH.sub.3), monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms
(e.g., diethylamino), C.sub.3-8-cycloalkyl, Si(R.sup.8).sub.3, Ar,
Het, or combinations thereof (e.g., cyclopentylmethyl,
cyclopropylmethyl, etc.), [0220] Ar, or [0221] Het; [0222] R.sup.9
is H, [0223] C.sub.1-6-alkyl (e.g., CH.sub.3) which is
unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar, Het, or combinations
thereof, [0224] C.sub.3-6-alkenyl which is unsubstituted or
substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to
4 carbon atoms (e.g., OCH.sub.3), NR.sup.13R.sup.14, SH, SR.sup.13,
SOR.sup.13, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.13,
SO.sub.2NR.sup.13R.sup.14, Ar, Het, or combinations thereof, [0225]
C.sub.3-6-alkynyl which is unsubstituted or substituted one or more
by F, Cl, Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g.,
OCH.sub.3), NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, [0226] C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, [0227] C.sub.4-8-cycloalkylalkyl
which is unsubstituted or substituted one or more times by F, Cl,
Br, I, CN, OH, alkoxy having 1 to 4 carbon atoms (e.g., OCH.sub.3),
NR.sup.6R.sup.7, SH, SR.sup.6, SOR.sup.6, unsubstituted
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.6, SO.sub.2NR.sup.6R.sup.7, Ar,
Het, or combinations thereof, [0228] Ar, or [0229] Het; and [0230]
R.sup.11 is H, alkyl having 1 to 4 carbon atoms (which is
unsubstituted or substituted one or more times by halogen, OH,
alkoxy having 1 to 4 carbon atoms, C.sub.3-8 cycloalkyl,
NR.sup.6R.sup.7, Ar, or Het), cycloalkyl having 3 to 7 carbon atoms
(which is unsubstituted or substituted one or more times by
halogen, OH, alkoxy having 1 to 4 carbon atoms, NR.sup.6R.sup.7,
Ar, or Het), Ar or Het.
[0231] According to a further aspect of the invention, the
compounds are selected from Formulas I, II, IV and V, and at least
one of R.sup.1, R.sup.2, R.sup.4 and R.sup.5 is C.sub.1-6-alkyl
which is substituted at least one time by OR.sup.16,
C.sub.2-6-alkenyl which is substituted at least one time by
OR.sup.16, C.sub.2-6-alkynyl which is substituted at least one time
by OR.sup.16, C.sub.3-8-cycloalkyl which is substituted at least
one time by OR.sup.16, or C.sub.4-10-cycloalkylalkyl which is
substituted at least one time by OR.sup.16, and R.sup.16 is other
than H or C.sub.1-4-alkyl.
[0232] According to a further aspect of the invention, the
compounds are selected from Formula III, R.sup.3 is OR.sup.16, and
R.sup.16 is other than H, C.sub.1-4-alkyl, halogenated
C.sub.1-4-alkyl, C.sub.3-7-cycloalkyl or
C.sub.4-8-cycloalkylalkyl.
[0233] According to a further aspect of the invention, the
compounds are selected from Formulas I, II, IV and V and at least
one of R.sup.6 and R.sup.7 is C.sub.1-6-alkyl which is substituted
at least one time by OR.sup.16, C.sub.2-6-alkenyl which is
substituted at least one time by OR.sup.16, C.sub.2-6-alkynyl which
is substituted at least one time by OR.sup.6, C.sub.3-8cycloalkyl
which is substituted at least one time by OR.sup.16, or
C.sub.4-10-cycloalkylalkyl which is substituted at least one time
by OR.sup.16, and R.sup.16 is other than H or C.sub.1-4-alkyl.
[0234] According to a further aspect of the invention, the
compounds are selected from Formulas I, II, IV and V and at least
one R.sup.9 is C.sub.1-6-alkyl which is substituted at least one
time by OR.sup.16, C.sub.2-6-alkenyl which is substituted at least
one time by OR.sup.16, C.sub.2-6-alkynyl which is substituted at
least one time by OR.sup.16, C.sub.3-8-cycloalkyl which is
substituted at least one time by OR.sup.16, or
C.sub.4-10-cycloalkylalkyl which is substituted at least one time
by OR.sup.16, and R.sup.16 is other than H or C.sub.1-4-alkyl.
[0235] According to a further aspect of the invention, the
compounds are selected from formula IV, Z is NR.sup.11, R.sup.11 is
C.sub.1-4-alkyl which is substituted at least one time by
OR.sup.16, or C.sub.3-7-cycloalkyl which is substituted at least
one time by OR.sup.16, and R.sup.16 is other than H or
C.sub.1-4-alkyl.
[0236] According to a further aspect of the invention, R.sup.12, in
addition to being C.sub.1-6-alkoxy which is substituted one or more
times by F or being selected from Formulae IX-XI, can also be
NHR.sup.8 (e.g., R.sup.8 is C.sub.2-6-alkyl),
NR.sup.17CO--R.sup.10, NR.sup.17SO.sub.2-Het,
NR.sup.17CO--O--CH.sub.2--Ar, NR.sup.17CONH--R.sup.10, or
NR.sup.17CONR.sup.18--CH.sub.2--Ar. Thus, for example, R.sup.12 can
be selected from NHR.sup.8 (e.g., R.sup.8 is C.sub.2-6-alkyl),
NR.sup.17CO--O--CH.sub.2--Ar, NR.sup.17CONH--R.sup.10, and
NR.sup.17CONR.sup.18--CH.sub.2--Ar. In addition, R.sup.12 can be
selected from NR.sup.17CO--O--CH.sub.2--Ar,
NR.sup.17CONH--R.sup.10, or NR.sup.17CONR.sup.18--CH.sub.2--Ar. In
these embodiments, R.sup.17 and R.sup.18 are each independently H,
alkyl having 1 to 4 carbon atoms (e.g., CH.sub.3, C.sub.2H.sub.5),
halogenated alkyl having 1 to 4 carbon atoms (e.g., CF.sub.3),
cycloalkyl having 3 to 7 carbon atoms (e.g., cyclopropyl,
cyclobutyl, cyclopentyl), or cycloalkylalkyl having 4 to 7 carbon
atoms (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.). Further,
R.sup.1 (in addition to being unsubstituted or substituted
C.sub.1-6-alkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.4-10-cycloalkylalkyl, halogen, CN,
NO.sub.2, NR.sup.6R.sup.7, SR.sup.6, SOR.sup.6, SO.sub.2R.sup.6,
SO.sub.2NR.sup.6R.sup.7, NR.sup.6SO.sub.2R.sup.7,
CONR.sup.6R.sup.7, CSNR.sup.6R.sup.7, COOR.sup.6,
NR.sup.6COR.sup.7, NR.sup.6CSR.sup.7, NR.sup.6CONR.sup.6R.sup.7,
NR.sup.6CSNR.sup.6R.sup.7, NR.sup.6COOR.sup.7, NR.sup.6CSOR.sup.7,
OCONR.sup.6R.sup.7, OCSNR.sup.6R.sup.7, Ar, Het, or OR.sup.9) can
also be --COR.sup.11 (e.g.,
--CO--C.sub.3-7cycloalkyl)-CONR.sup.10R.sup.11 (e.g.,
--CONHC.sub.3-8cycloalkyl) or --CONHR.sup.10(C.sub.1-6alkyl)Ar.
Compounds which have an R.sup.12 and/or R.sup.1 group in accordance
with these definitions include: [0237]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-N-(4-fluorobenzyl)-5-({[(4-fl-
uorobenzyl)amino]carbonyl}amino)-1H-indazole-1-carboxamide
hydroformate, [0238]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-N-(4-fluorobenzyl)-5-(-
{[(4-fluorobenzyl)amino]carbonyl}amino)-1H-indazole-1-carboxamide,
[0239] Benzyl [3-(1,3-diazabicyclo [3.2.2]non-3-yl
carbonyl)-1H-indazol-5-yl]carbamate hydroformate, [0240] Benzyl
[3-(1,3-diazabicyclo[3.2.2]non-3-ylcarbonyl)-1H-indazol-5-yl]carbamate,
[0241]
N-[1-(Cyclopropylcarbonyl)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbo-
nyl)-1H-indazol-5-yl]cyclopropanecarboxamide hydroformate [0242]
N-[1-(Cyclopropylcarbonyl)-3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]cyclopropanecarboxamide,
[0243]
N-[3-(1,3-Diazabicyclo[3.2.2]non-3-ylcarbonyl)-1H-indazol-5-yl]-N-7-(3-me-
thoxybenzyl)urea hydroformate, [0244] N-[3-(1,3-Diazabicyclo
[3.2.2]non-3-ylcarbonyl)-1H-indazol-5-yl]-N'-(3-methoxybenzyl)urea,
[0245] N-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]-1-methyl-1H-imidazole-4-sulfona-
mide hydroformate, [0246] N-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]-1-methyl-1H-imidazole-4-sulfona-
mide, [0247]
N-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]cyclopropa-
necarboxamide hydroformate, [0248]
N-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]cyclopropa-
necarboxamide, [0249] N-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]-N'-(4-fluorobenzyl)urea
hydroformate, [0250] N-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]-N'-(4-fluorobenzyl)urea,
[0251]
N-Cyclopentyl-N'-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol--
5-yl]urea hydroformate, [0252]
N-Cyclopentyl-N'-[3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol--
5-yl]urea, [0253] N-Cyclopentyl-5
{[(cyclopentylamino)carbonyl]amino}-3-(1,4-diazabicyclo-[3.2.2]non-4-ylca-
rbonyl)-1H-indazole-1-carboxamide hydroformate, [0254]
N-Cyclopentyl-5-{[(cyclopentylamino)carbonyl]amino}-3-(1,4-diazabicyclo-[-
3.2.2]non-4-ylcarbonyl)-1H-indazole-1-carboxamide, [0255]
N-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]pyrrolidin-
e-1-carboxamide hydroformate, [0256] N-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]pyrrolidine-1-carboxamide,
[0257] Benzyl
[1-benzyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]car-
bamate hydroformate, and [0258] Benzyl
[1-benzyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]car-
bamate. Alkyl throughout means a straight-chain or branched-chain
aliphatic hydrocarbon radical having preferably 1 to 4 carbon
atoms, unless otherwise indicated. Suitable alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
The alkyl group can also be substituted. Alkenyl throughout means a
straight-chain or branched-chain alkyl radical having preferably 2
to 6 carbon atoms, unless otherwise indicated, wherein at least one
CH.sub.2CH.sub.2 group is replaced by CH.dbd.CH. Suitable alkenyl
groups include ethenyl, propenyl, butenyl, etc. The alkenyl group
can also be substituted. Alkynyl throughout means a straight-chain
or branched-chain alkyl radical having preferably 2 to 6 carbon
atoms, unless otherwise indicated, wherein at least one
CH.sub.2CH.sub.2 group is replaced by C.ident.C. Suitable alkynyl
groups include ethynyl, propynyl, butynyl, etc. The alkynyl group
can also be substituted. Alkoxy means alkyl-O-- groups in which the
alkyl portion preferably has 1 to 4 carbon atoms, unless otherwise
indicated. Suitable alkoxy groups include methoxy, ethoxy, propoxy,
isopropoxy, isobutoxy, and sec-butoxy. The alkoxy group can also be
substituted. For example, the alkoxy group may be substituted one
or more times by F (e.g., OCF.sub.3, and OCHF.sub.2).
[0259] Cycloalkyl means a cyclic, bicyclic or tricyclic saturated
hydrocarbon radical having 3 to 8 carbon atoms, unless otherwise
indicated. Suitable cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable cycloalkyl
groups include spiropentyl, bicyclo[2.2.1]heptyl, and
bicyclo[2.2.2]octyl.
[0260] The cycloalkyl groups can be substituted by, for example, F,
Cl, Br, 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.
[0261] Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which
the cycloalkyl and alkyl portions are in accordance with previous
discussions. Suitable examples include cyclopropylmethyl and
cyclopentylmethyl.
[0262] Cycloalkyloxy refers to cycloalkyl-oxy radicals in which the
cycloalkyl portion is in accordance with previous discussions.
Suitable examples include cyclopropyloxy and cyclopentyloxy.
[0263] 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 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).
[0264] Arylalkyl refers to an aryl-alkyl radical in which the aryl
and alkyl portions are in accordance with the previous
descriptions. Suitable examples include benzyl, 1-phenethyl,
2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and
napthylmethyl.
[0265] 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 tetrahydrofuranyl,
tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, oxoazolinyl, isoxazolinyl
and the like. Suitable heteroaryl groups include but are not
limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
pyridyl, pyrimidinyl, benzopyranyl, indolyl, quinolinyl,
isoquinolinyl, naphthyridinyl and the like. Other examples of
suitable heterocyclic groups, are 2-quinolinyl, 1,3-benzodioxyl,
2-thienyl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl,
2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl,
4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl,
benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl,
6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl,
3-carbazolyl, 2-thiazolyl, 2-oxazolyl, 1-imidazolyl, and
2-imidazolyl.
[0266] Substituted heterocyclic groups refer to the heterocyclic
groups described above, which are substituted in one or more places
by, for example, halogen, aryl, alkyl, hydroxy, alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, alkylamino, and
dialkylamino.
[0267] Radicals which 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 perhalo radicals such
as trifluoromethyl.
[0268] According to a further aspect of the invention the compounds
are selected from formulas I-VIII, except that the following
compounds are excluded: [0269] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-N-(3-methoxybenzyl)-5-({[(3-methoxybenzyl)amino]-
carbonyl}amino)-1H-indazole-1-carboxamide and pharmaceutically
acceptable salts thereof, [0270]
3-(1,4-Diazabicyclo[3.2.2]non-4-yl-methyl)-8-(methoxy)-4H-chromen-4-one
and pharmaceutically acceptable salts thereof, [0271]
N,1-Dibutyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-amin-
e and pharmaceutically acceptable salts thereof, or [0272]
N-Butyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-amine
and pharmaceutically acceptable salts thereof.
[0273] According to a further aspect of the invention the compounds
are selected from formulas I-VIII, except that the following
compounds are excluded: [0274] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-methoxy-4H-chromen-4-one and
pharmaceutically acceptable salts thereof, [0275]
5-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,3-benzothiazole and
pharmaceutically acceptable salts thereof, [0276]
6-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1,3-benzothiazole and
pharmaceutically acceptable salts thereof, [0277]
6-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1H-indazole and
pharmaceutically acceptable salts thereof, [0278]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxyquinolin-4(1H)-one
and pharmaceutically acceptable salts thereof, [0279]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-methoxyquinolin-4(1H)-one
and pharmaceutically acceptable salts thereof, [0280]
N,N,1-Tributyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-a-
mine and pharmaceutically acceptable salts thereof, and [0281]
5-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazole and
pharmaceutically acceptable salts thereof.
[0282] In accordance with a further aspect of the invention,
preferred R groups include halogens (R.sup.1 to R.sup.5, R.sup.14
and R.sup.15), nitro (R.sup.1 to R.sup.5, R.sup.14 and R.sup.15),
NR.sup.6R.sup.7 (R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.4 and
R.sup.15), amino (R.sup.1 to R.sup.5, R.sup.14 and R.sup.15),
alkylamino (R.sup.1 to R.sup.5, R.sup.14 and R.sup.15),
dialkylamino (R.sup.1 to R.sup.5, R.sup.14 and R.sup.15), phenyl
which is unsubstituted or substituted (R.sup.1, R.sup.2, R.sup.4 to
R.sup.7, R.sup.9, R.sup.11, and R.sup.13 to R.sup.15),
NR.sup.6CONR.sup.6R.sup.7 such as phenylurea (R.sup.1, R.sup.2,
R.sup.4, R.sup.5, R.sup.14 and R.sup.15), hydroxyl (R.sup.1 to
R.sup.5, R.sup.14 and R.sup.15), alkoxy (R.sup.1 to R.sup.5,
R.sup.14 and R.sup.15), halogenated alkoxy (R.sup.1 to R.sup.5,
R.sup.14 and R.sup.15), and alkylsuflonamide (R.sup.1, R.sup.2,
R.sup.1, R.sup.5, R.sup.14 and R.sup.5) (e.g., bromo, nitro, amino,
phenylurea, trifluoromethoxy, methoxy, methansulfonamide, hydroxyl,
etc.)
[0283] In accordance with a further aspect of the invention,
preferred groups for the heterocyclic groups of Formulas IX to XI
include thiazolyl, substituted thiazolyl, thiazolylamino,
substituted thiazolylamino, oxazolyl, substituted oxazolyl,
imidazolyl, substituted imidazolyl, pyranyl, substituted pyranyl,
piperidinyl, substituted piperidinyl, pyrrolydinyl, substituted
pyrrolydinyl, pyrrolydinyloxy and substituted pyrrolydinyloxy
(e.g., 5-methyl-1,3-thiazol-2-yl, 4-methyl-1,3-thiazol-2-yl,
1,3-thiazol-2-yl, 1,3-oxazol-2-yl, 1,3-imidazol-2-yl,
5-methyl-1,3-oxazol-2-yl, 4-methyl-1,3-oxazol-2-yl, pyran-4-yl,
piperidin-4-yl, pyrrolidin-3-yl, pyrrolidin-3-yloxy,
3-hydroxypyrrolidin-1-yl, 1,3-thiazol-2-ylamino, etc.).
[0284] In accordance with a further aspect of the invention, R in
Formulas I and VI is preferably H.
[0285] In accordance with a further aspect of the invention, B in
Formulas II and VI is preferably C.dbd.O. In Formula V, B is
preferably CH.sub.2 or C.dbd.O.
[0286] In accordance with a further aspect of the invention, Z in
Formulas IV and V is preferably O or NH.
[0287] In accordance with a further aspect of the invention, Y in
Formula II is preferably S.
[0288] In accordance with a further aspect of the invention, the
subscript "m" is preferably 2.
[0289] In accordance with a further aspect of the invention,
preferred R.sup.12 groups of Formula IX are oxazolyl, thiazolyl,
4-methylthiazolyl, and 5-methylthiazolyl.
[0290] In accordance with a further aspect of the invention,
preferred R.sup.12 groups of Formula X are tetrahydropyran and
dihydropyran. Other preferred R.sup.12 groups of Formula X include
3-methylimidazolidin-2-one and 3-isopropyl-imidazolidin-2-one. A
further preferred R.sup.12 group is halogenated alkoxy, especially
OCF.sub.3 and OCHF.sub.2.
[0291] In accordance with a further aspect of the invention,
preferred R.sup.2 groups are OCH.sub.3, OCF.sub.3, ethoxy,
cyclopropylmethoxy, and cyclopropyl.
[0292] In accordance with a further aspect of the invention,
R.sup.5 is preferably OCH.sub.3.
[0293] In accordance with a further aspect of the invention, the
compounds of Formula VI are preferred.
[0294] According to a further compound and/or method aspect of the
invention, the compounds are selected from: [0295]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
hydroformate, [0296] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole, [0297]
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazole
hydroformate, [0298]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1-
H-indazole, [0299] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(trifluoromethoxy)-1H-indazole
hydroformate, [0300] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(trifluoromethoxy)-1H-indazole, [0301]
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole
hydroformate, [0302]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-
-indazole, [0303]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indaz-
ole hydroformate, [0304] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole, [0305]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-
-1H-indazole hydroformate, [0306]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-
-1H-indazole, [0307] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole
hydroformate, [0308] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole,
[0309] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1H-indazole
hydroformate, [0310] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1H-indazole, [0311]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole
hydroformate, [0312]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole-
, [0313] 4-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1H-indazole
hydroformate, and [0314] 4-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazole; and pharmaceutically
acceptable salts thereof.
[0315] According to a further compound and/or method aspect of the
invention, the compounds are selected from: [0316]
3-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
hydroformate, [0317] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole, [0318]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indaz-
ole hydroformate, [0319]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indaz-
ole, [0320] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(trifluoromethoxy)-1H-indazole
hydroformate, [0321] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(trifluoromethoxy)-1H-indazole, [0322]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazo-
le hydroformate, [0323]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazo-
le, [0324]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl-
)-1H-indazole hydroformate, [0325]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indaz-
ole, [0326]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-
-1H-indazole hydroformate, [0327]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-
-1H-indazole, [0328]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)-
-1H-indazole hydroformate, [0329]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)-
-1H-indazole, [0330] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1H-indazole
hydroformate, [0331]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1-
H-indazole, [0332]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole
hydroformate, [0333]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-methoxy-1,2-benzisothiazole-
, [0334] 4-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1H-indazole
hydroformate, and [0335] 4-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazole; and pharmaceutically
acceptable salts thereof.
[0336] According to a further compound and/or method aspect of the
invention, the compounds are selected from: [0337]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4H-chromen-4-one
hydroformate, [0338]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-4H-chromen-4-one,
[0339]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-pyran-4-yl)-
-1H-indazole hydroformate, and [0340] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole;
and pharmaceutically acceptable salts thereof.
[0341] According to a further compound and/or method aspect of the
invention, the compounds are selected from: [0342]
3-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole
hydroformate, [0343] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole, [0344]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indaz-
ole hydrochloride, [0345] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazole, [0346]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-pyran-4-yl)-
-1H-indazole hydroformate, [0347]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-pyran-4-yl)-
-1H-indazole, [0348] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole
hydroformate, [0349]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-
-1H-indazole, [0350]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yl)--
1H-indazole hydroformate, [0351] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indazole,
[0352]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazol-
e hydroformate, [0353]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazol-
e, [0354] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole
hydroformate, [0355]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-pyran-4-yl)--
1H-indazole, [0356] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benzisothiazole
hydroformate, [0357]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benz-
isothiazole, [0358] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazole
hydroformate, [0359] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazole, [0360]
3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chromen-4-one, [0361]
3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chromen-4-one hydroformate,
[0362] 3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chromen-4-one, [0363]
3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-one, [0364]
6-(Cyclopropylmethoxy)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-be-
nzisothiazole, [0365]
6-Cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothia-
zole hydroformate, [0366]
6-Cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothia-
zole, [0367]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)-
-1H-indazole hydroformate, and [0368] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole;
and pharmaceutically acceptable salts thereof.
[0369] According to a further compound and/or method aspect of the
invention, the compounds are selected from: [0370]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole
hydroformate, [0371]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole,
[0372]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indaz-
ole hydrochloride, [0373]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indaz-
ole, [0374]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-pyran-4-yl)-
-1H-indazole hydroformate, [0375]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-pyran-4-yl)-
-1H-indazole, [0376]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-
-1H-indazole hydroformate, [0377]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-
-1H-indazole, [0378]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yl)--
1H-indazole hydroformate, [0379]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yl)--
1H-indazole, [0380]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazol-
e hydroformate, [0381]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazol-
e, [0382]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-pyr-
an-4-yl)-1H-indazole hydroformate, [0383] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole,
[0384] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benzisothiazole
hydroformate, [0385]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benz-
isothiazole, [0386]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazo-
le hydroformate, [0387]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazo-
le, [0388] 3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chromen-4-one, [0389]
3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chromen-4-one hydroformate,
[0390] 3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chromen-4-one, [0391]
3-(1,4-Diazabicyclo[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-one,
[0392]
6-(Cyclopropylmethoxy)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-
-1,2-benzisothiazole, [0393] 6-Cyclopropyl-3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole hydroformate, [0394]
6-Cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothia-
zole, [0395]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)-
-1H-indazole hydroformate, and [0396] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole;
and pharmaceutically acceptable salts thereof.
[0397] According to a further compound and/or method aspect of the
invention, the compounds are selected from: [0398]
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazole
hydroformate, [0399] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazole, [0400]
3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chromen-4-one hydroformate,
[0401] 3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-one hydroformate,
[0402]
6-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
hydroformate, [0403]
6-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole,
[0404]
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol--
6-yl]-3-isopropylimidazolidin-2-one hydroformate, [0405]
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-
-isopropylimidazolidin-2-one, [0406]
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-
-methylimidazolidin-2-one hydroformate, [0407]
1-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-
-methylimidazolidin-2-one, [0408]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-oxazol-2-yl)-1H-indazo-
le hydroformate, [0409]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-oxazol-2-yl)-1H-indazo-
le, [0410]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-
-1H-indazole hydrochloride, [0411]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(difluoromethoxy)-1H-indazo-
le hydroformate, [0412]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(difluoromethoxy)-1H-indazo-
le, [0413]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(difluoromethoxy)-
-1H-indazole hydroformate, [0414]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(difluoromethoxy)-1H-indazo-
le, [0415]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-py-
ran-4-yloxy)-1H-indazole hydroformate, [0416] 3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole,
[0417]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-pyra-
n-4-yl)-1H-indazole hydrochloride, [0418] (3E)-3-(1,4-Diazabicyclo
[3.2.2]non-4-ylmethylene)-6-methoxy-2,3-dihydro-4H-chromen-4-one
hydroformate, [0419] (3E)-3-(1,4-Diazabicyclo
[3.2.2]non-4-ylmethylene)-6-methoxy-2,3-dihydro-4H-chromen-4-one,
[0420] (3E)-3-(1,4-Diazabicyclo
[3.2.2]non-4-ylmethylene)-5-methoxy-2,3-dihydro-4H-chromen-4-one
hydroformate, [0421] (3E)-3-(1,4-Diazabicyclo
[3.2.2]non-4-ylmethylene)-5-methoxy-2,3-dihydro-4H-chromen-4-one,
[0422] (3E)-3-(1,4-Diazabicyclo
[3.2.2]non-4-ylmethylene)-7-methoxy-2,3-dihydro-4H-chromen-4-one
hydroformate, and [0423] (3E)-3-(1,4-Diazabicyclo
[3.2.2]non-4-ylmethylene)-7-methoxy-2,3-dihydro-4H-chromen-4-one;
[0424] and pharmaceutically acceptable salts thereof.
[0425] 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.
[0426] 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.
[0427] The synthesis of similar compounds is disclosed in copending
application Ser. No. 10/669,645, filed Sep. 25, 2003, Ser. No.
11/018,429, filed Dec. 22, 2004, and Ser. No. 11/111,958, filed
Apr. 22, 2005, the entire disclosures of which are hereby
incorporated by reference.
[0428] Acids that were used in the preparation of the bicyclobase
amides were commercially available or were prepared by known
procedures described in the literature or as described below. For
example, chromone-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 (U.S. Pat.
No. 6,313,110 B1 and Sun, J. H.; Teleha, C. A.; Yan, J. S.;
Rodgers, J. D.; Nugiel, D. A. 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).
[0429] 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). 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. 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).
[0430] 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-difluoromethoxynitrobenzene 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.
[0431] The benzisoxazole- and benzisoxazolecarboxylic 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.
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.
[0432] The bicycloamines that were used in the preparation of the
bicyclobase amides were prepared by known procedures described in
the literature. For example, 1,4-diazabicyclo[3.2.2]nonane was
prepared from 3-quinuclidinone hydrochloride according to the
procedure outlined in WO 2004/076453 A1.
[0433] The bicyclobase amide was prepared by the coupling reaction
of acids with the bicycloamine and HOBt and EDCI or HBTU in DMF, or
by converting the acids to the corresponding acid chloride and then
reaction with the bicycloamine (Macor, J. E.; et. al. Bioorg. Med.
Chem. Lett. 2001, 9, 319-321). The couplings were generally
performed at room temperatures for 18-24 hours. Bicyclobase
methylenamine analogs were prepared by reductive amination using
commercially available aldehydes.
5-Methoxychromone-3-carboxaldehyde was purchased from Indofine
Chemical Company (Hillsborough, N.J.). The resultant adducts was
isolated and purified by standard techniques, such as
chromatography or recrystallization, practiced by those skilled in
the art
[0434] The nicotinic ligands were, alternatively, prepared by
modification of other nicotinic ligands. For example, the
6-(3-isopropylimidazolidin-2-one) ligand was prepared from the
corresponding bromide ligand by a palladium-catalyzed
cross-coupling reaction. Other halogen-substituted ligands served
as precursors for modified ligands where appropriate. As a final
example, urea analogs were prepared from aniline substituted
analogs.
[0435] One of ordinary skill in the art will recognize that
compounds of Formulas I-VIII 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%.
[0436] 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-VIII
can likewise be obtained by utilizing optically active starting
materials in chiral synthesis processes under reaction conditions
which do not cause racemization.
[0437] 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 H, .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.
[0438] 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.
[0439] 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 bas 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.
[0440] 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, fiunarates, 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.
[0441] 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.
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-VIII, containing, for example, one or more pharmaceutically
acceptable carriers. 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).
[0442] 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, intravenously, intramuscularly, intrasternally and
by infusion) by inhalation, rectally, vaginally, topically and by
ocular administration.
[0443] 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.
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.
[0444] 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.
[0445] 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.
[0446] 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.
[0447] 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.
[0448] 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.
[0449] 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.7nAChr subtypes. See, e.g., WO
99/62505.
[0450] 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), an effective amount of a compound of Formulas I-VIII,
alone or as part of a formulation, as disclosed herein.
[0451] 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-VIII. Preferably, the disease state involves decreased
nicotinic acetylcholine receptor activity.
[0452] 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-VIII.
[0453] 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-VIII.
[0454] 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-VIII effective to activate .alpha.7nACh receptors.
[0455] 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-VIII.
[0456] 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-VIII.
[0457] 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-VIII.
[0458] 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-VIII.
[0459] 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-VIII.
[0460] 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-VIII.
[0461] 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-VIII.
[0462] 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.
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 acetyleholine 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.).
[0463] 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.
[0464] The compound anabaseine, i.e.,
2-(3-pyridyl)-3,4,5,6-tetrahydropyridine 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).
[0465] 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.alpha.-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).
[0466] 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 dysfanction 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.
[0467] 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-VIII.
[0468] 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).
[0469] 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-VIII.
[0470] 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-VIII.
[0471] 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 .beta.-7 nAChRs are useful for
treating neurodegenerative diseases. See, e.g., WO 99/62505. In
addition, stimulation .beta.7nACh receptors can protect neurons
against cytotoxicity associated with A.beta. peptides. See, e.g.,
Kihara, T. et al., Ann. Neurol., 1997, 42, 159.
[0472] 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-VIII 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).
[0473] 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.
[0474] 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-VIII.
[0475] 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-VIII.
[0476] 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-VIII.
[0477] 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.
[0478] 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-VIII.
[0479] In addition, due to their affinity to .alpha.7nACh
receptors, labeled derivatives of the compounds of Formulas I-VIII
(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.
[0480] 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.
[0481] 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-VIII.
[0482] 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.
[0483] 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.
[0484] 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.
[0485] The compounds of the invention also are useful as
intermediates for making other compounds of the inventive genus.
Thus, for example, compounds exhibiting relatively low activity are
also useful for preparing other compounds within the inventive
genus.
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. 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.
[0486] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference.
[0487] Using the following procedures and further procedures
described below, the following compounds in Examples 1-54 were
prepared.
EXAMPLES
[0488] 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 nm in
gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile
(0.1% formic acid). Hydrochloride salts of the bicycle amides were
prepared by adding an ethereal solution of hydrochloric acid to a
methanolic solution of the bicyclic amide, followed by isolation of
the resulting precipitate.
Representative Procedures.
[0489] I. Acid Syntheses
Procedure 1
[0490] Procedure 1 provides a preparation of substituted
benzisothiazole-3-carboxylic acids from the corresponding
thiophenols.
To a solution of 3-methoxythiophenol (26.7 mmol) in ether (20 mL)
was added oxalyl chloride (43 mmol) dropwise. The mixture was
heated 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 sodium bicarbonate, water, and brine. The
organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by chromatography
(4/1 ethyl acetate/hexane) which provided
6-methoxy-1-benzothiophene-2,3-dione (47%) as an orange solid.
[0491] 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 to
afford 6-methoxybenzisothiazole-3-carboxamide (42%).
[0492] 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) to provide
6-methoxy-1,2-benzisothiazole-3-carboxylic acid (89%) as a pink
solid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane
according to procedure A.
The following acids were prepared by this method: [0493]
1,2-Benzisothiazole-3-carboxylic acid. [0494]
6-Methoxy-1,2-benzisothiazole-3-carboxylic acid. [0495]
6-Ethoxy-1,2-benzisothiazole-3-carboxylic acid [0496]
6-Trifluoromethoxy-1,2-benzisothiazole-3-carboxylic acid [0497]
6-Bromo-1,2-benzisothiazole-3-carboxylic acid [0498]
7-Methoxy-1,2-benzisothiazole-3-carboxylic acid
Procedure 2
[0499] Procedure 2 provides a method for the conversion of
substituted isatins to the corresponding indazole-3-carboxylic
acids.
[0500] 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 slurry was maintained for 60 min. The precipitated
solids were isolated by filtration, washed with water, and dried to
give a quantitative mass balance. The solid was recrystallized from
acetic acid (20 mL/g) to provide the acid as a light yellow solid.
The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according
to procedure A.
The following acids were prepared according to this method: [0501]
5-Bromo-1H-indazole-3-carboxylic acid. [0502]
5-Methoxy-1H-indazole-3-carboxylic acid. [0503]
5-(Trifluoromethoxy)-1H-indazole-3-carboxylic acid.
Procedure 3
[0504] Procedure 3 provides a method for the preparation of
5-nitroindazole-3-acid from indazole-3-acid.
[0505] The conversion of ethyl indazole-3-acid to
5-nitroindazole-3-carboxylic acid is essentially the same method as
described for methyl 3-nitrobenzoic acid: Kamm, O.; Segur, J. B.
Org. Syn. Coll. Vol 1. 1941, 372. 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 to provide ethyl
5-nitroindazole-3-carboxylate (53%) as a colorless solid. The ester
was added to a solution of 10 N sodium hydroxide and the suspension
was warmed to 60.degree. C. After 2 h the solution was allowed to
cool to room temperature and was acidified to pH .about.2. The
precipitated solids were collected by filtration, washed with
water, and dried to provide the acid as a light yellow solid. The
acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to
procedure A.
Procedure 4
[0506] Procedure 4 provides a method for the coupling between the
brominated carboxylic esters and zinc reagents to form alkyl- and
aryl-substituted derivatives.
[0507] A 5 mL microwave reaction vessel was charged with
bis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq)
and the bromo ester (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. The reaction was quenched with acetic acid (0.5 mL) and
concentrated. The residue was diluted with saturated sodium
bicarbonate and extracted with 9/1 dichloromethane/methanol
(5.times.40 mL). The combined organic layers were dried (sodium
sulfate) and concentrated. The residue was purified by
chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide the
ester. The ester was added to a solution of 2 N sodium hydroxide
and the suspension was warmed to 60.degree. C. After 2 h the
solution was allowed to cool to room temperature and was acidified
to pH .about.2. The precipitated solids were collected by
filtration, washed with water, and dried to provide the acid as an
off-white to light yellow solid. The acid was coupled with
1,4-diazabicyclo[3.2.2]nonane according to procedure A.
[0508] The Grignard reagent of thiazole is commercially available.
Alternatively, the arylithium 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, and related reagents were prepared
according to this procedure.
[0509] The following acids were prepared according to this method:
[0510] 5-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid. [0511]
6-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid. [0512]
5-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid. [0513]
6-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid. [0514]
6-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid. [0515]
6-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid. [0516]
5-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid. [0517]
5-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid. [0518]
6-Cyclopropyl-1,2-benzisothiazole-3-carboxylic acid.
Procedure 5
[0519] Procedure 5 provides a method for the preparation of
indazole carboxylic acids from bromomethylanilines. (See, George V.
DeLucca, U.S. Pat. No. 6,313,110.)
[0520] To a cooled (water/ice bath) solution of bromomethylaniline
(1.00 equiv.) in chloroform (1.5 mL/mol) was added acetic anhydride
(2.27 equiv.) maintaining the temperature below 40.degree. C. The
mixture was stirred at room temperature for 1 h. Potassium acetate
(0.29 eq) was added followed by isoamyl nitrite (2.15 equiv.). The
reaction mixture was heated overnight to reflux. Volatiles were
removed on vacuum rotary evaporator. Water (0.65 L/mol) was added
to the residue and the mixture was again concentrated in vacuum.
Hydrochloric acid (11 N, 1 L/mol) was added to the residue and the
mixture was vigorously stirred and heated to 50.degree. C. for 2 h.
The mixture was cooled to room temperature and pH was adjusted to
10 with 50% aqueous sodium hydroxide while maintaining the
temperature below 25.degree. C. The mixture was diluted with water
(0.65 L/mol) and 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. The plug was further eluted with
ethyl acetate. The solvent was removed on vacuum rotary evaporator,
and the residue was triturated with heptane (1 L/mol). The solid
material was collected by filtration, rinsed with heptane, and
dried to provide the bromoindazole in 60-70% yield.
[0521] To a solution of the bromoindazole (1.00 equiv.) in
anhydrous THF (7 L/mol) was added sodium hydride (60% in mineral
oil, 1.11 equiv.) in several portions at room temperature. The
resulting solution was stirred 30 min at room temperature then
cooled in dry ice/acetone bath. sec-Butyllithium (1.3 M in
cyclohexane, 2.11 equiv.) was added to the reaction mixture
maintaining the temperature below -50.degree. C. The mixture was
stirred 2 h at -50.degree. C. Anhydrous carbon dioxide was bubbled
through the reaction mixture at temperature below -40.degree. C.
for 1 h. The reaction was allowed to reach room temperature while
keeping steady flow of carbon dioxide through the mixture. Brine (6
L/mol) was added and pH of the mixture was adjusted to 5 with
concd. hydrochloric acid. The mixture was extracted with warm ethyl
acetate (3.times.8 L/mol). The combined extracts were washed with
small volume of brine, dried over anhydrous sodium sulfate and
concentrated. The product was purified by chromatography on silica
gel or by crystallization to provide the acid in 30-60% yield. The
acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to
procedure A.
The following acid was prepared by this method: [0522]
1H-Indazole-4-carboxylic acid.
Procedure 6:
[0523] Procedure 6 details the preparation of
benzisoxazole-3-carboxylic acid from 2,5-dibromonitrobenzene.
[0524] 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%).
[0525] 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%).
[0526] 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.
[0527] Under N.sub.2 atmosphere, sodium ethylate was formed with
sodium (33.5 g, 1.46 mol) in ethanol (1.0 L).
[0528] 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%).
[0529] 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-carboxylate (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. The acid was
coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure
A.
Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough,
P.; Deboeck, N. M.; Longstaff, T.; Swanson, S., WO 04/010995 A1 The
following acid was prepared using this method: [0530]
1,2-Benzisoxazole-3-carboxylic acid.
Procedure 7
[0531] Procedure 7 provides a method for the trapping of indazole
aryllithiums with ketones and the coupling with 3-aminoquinuclidine
to form heterocyclic derivatives.
[0532] 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.
[0533] 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%).
[0534] 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-indazole-3-carboxylic acid (60%) as a
tan solid.
[0535] The acids were coupled with 1,4-diazabicyclo[3.2.2]nonane
according to procedure A.
The following acids were prepared using this method: [0536]
5-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid. [0537]
6-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid. [0538]
5-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid. [0539]
6-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid.
Procedure 8:
[0540] Procedure 8 provides a method for the preparation of
6-nitroindazole-3-acid and the coupling with bicyclobases to form
nitro-substituted derivatives.
[0541] 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 10/1 mixture of
3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The
10/1 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 (pH=1) with 3 N
hydrochloric acid. The solid was isolated and triturated with EtOAc
to provide 51 mg of 6-nitroindazole-3-carboxylic acid as a brown
solid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane
according to procedure A.
The following acid was prepared using this method: [0542]
6-Nitro-1H-indazole-3-carboxylic acid.
Procedure 9:
[0543] Procedure 9 provides a method for the preparation of
5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.
[0544] 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.
[0545] 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.
[0546] 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.
[0547] 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.
[0548] 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.
The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according
to procedure A.
The following acids were prepared according to this method: [0549]
5-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
Procedure 10:
[0550] Procedure 10 provides a method for the preparation of
6-difluoromethoxyindazole-3-acid from 4-nitrophenol.
[0551] 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.
[0552] 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.
[0553] 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.
[0554] 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.
[0555] 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.
[0556] 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.
[0557] 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.
[0558] 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.
[0559] 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.
[0560] 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.
The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according
to procedure A.
The following acids were prepared according to this method: [0561]
6-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
Procedure 11:
[0562] Procedure 11 provides a method for the preparation of alkoxy
indazole acids from the corresponding benzyloxy indazole esters
using Mitsunobu conditions.
[0563] Diisopropyl azodicarboxylate (0.618 mmol) was added dropwise
to a solution of ethyl
5-hydroxy-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-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 with
1,4-diazabicyclo[3.2.2]nonane according to procedure A.
The following acids were prepared using this method: [0564]
5-(Tetrahydro-2H-pyran-4-yloxy)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-ind-
azole-3-carboxylic acid.
II. Coupling and Derivatization Procedures
Representative Procedure A.
[0565] Procedure A provides a method for the coupling between
bicyclobases and carboxylic acids to form carboxamide
derivatives.
Example 1
3-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-4H-chromen-4-one
Hydroformate
##STR00003##
[0566] N,N-Diisopropylethylamine (2.01 mmol) was added to a
solution of the carboxylic acid (0.502 mmol),
1,4-diazabicyclo[3.2.2]nonane (0.502 mmol) and HATU (0.603 mmol) in
N,N-dimethylformamide (5 mL) at 25.degree. C., and the reaction
mixture was maintained for 10 h. The reaction mixture was loaded on
a SCX column, washed with methanol, and the product was eluted
using a 2N solution of ammonia in methanol. The residue was
purified by preparative HPLC to provide the product in 25% yield.
.sup.1H NMR (CD.sub.3OD) .delta. 8.48 (s, 1H), 8.43 (s, 1H), 8.19
(dd, J=9.0, 1.6, 1H), 7.86 (td, J=7.2, 1.7, 1H), 7.62 (d, J=8.5,
1H), 7.56 (td, J=7.1, 1.0, 1H), 4.20 (m, 1H), 3.83 (m, 2H),
3.61-3.42 (m, 6H), 2.40-2.12 (m, 4H); LC/MS (EI) t.sub.R 1.76 min,
m/z 299 (M.sup.++1). Using this general procedure the following
compounds were prepared:
Example 2
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazole
Hydroformate
##STR00004##
[0567] Prepared by Procedure A in 29% yield. LC/MS (EI) t.sub.R 2.4
min, m/z 271 (M.sup.++1).
Example 3
6-Cyclopropyl-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiaz-
ole Hydroformate
##STR00005##
[0568] Prepared by Procedure A in 70% yield. LC/MS (EI) t.sub.R
4.75 min, m/z 328 (M.sup.++1).
Example 4
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole
Hydroformate
##STR00006##
[0569] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
2.43 min, m/z 353 (M.sup.++1).
Example 5
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole
Hydroformate
##STR00007##
[0571] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
2.42 min, m/z 353 (M.sup.++1).
Example 6
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1-
H-indazole Hydroformate
##STR00008##
[0572] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
2.41 nm, m/z 355 (M.sup.++1).
Example 7
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole
Hydroformate
##STR00009##
[0573] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
2.44 min, m/z 355 (M.sup.++1).
Example 8
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisoxazole
Hydroformate
##STR00010##
[0574] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.78 min, m/z 272 (M.sup.++1).
Example 9
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(nitro)-1H-indazole
##STR00011##
[0575] Prepared by Procedure A in 60% yield. LC/MS (EI) t.sub.R
1.33 min, m/z 316 (M.sup.++1).
Example 10
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(ethoxy)-1,2-benzisothiazole
Hydroformate
##STR00012##
[0576] Prepared by Procedure A in 70% yield. LC/MS (EI) t.sub.R
3.44 min, m/z 331 (M.sup.++1).
Example 11
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1,2-benzisothiazole
Hydroformate
##STR00013##
[0577] Prepared by Procedure A in 70% yield. LC/MS (EI) t.sub.R
4.41 min, m/z 372 (M.sup.++1).
Example 12
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-7-(methoxy)-1,2-benzisothiazole
Hydroformate
##STR00014##
[0578] Prepared by Procedure A in 66% yield. LC/MS (EI) t.sub.R
2.94 nm in, m/z 318 (M.sup.++1).
Example 13
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(methoxy)-1H-indazole Hydroformate
##STR00015##
[0579] Prepared by Procedure A in 60% yield. LC/MS (EI) t.sub.R
3.55 min, m/z 301 (M.sup.++1).
Example 14
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1H-indazole Hydroformate
##STR00016##
[0580] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.02 nm, m/z 301 (M.sup.++1).
Example 15
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(trifluoromethoxy)-1H-indazo-
le Hydroformate
##STR00017##
[0581] Prepared by Procedure A in 40% yield. LC/MS (EI) t.sub.R
4.42 min, m/z 355 (M.sup.++1).
Example 16
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(trifluoromethoxy)-1H-indazo-
le Hydroformate
##STR00018##
[0582] Prepared by Procedure A in 30% yield. LC/MS (EI) t.sub.R
4.33 min, m/z 355 (M.sup.++1).
Example 17
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(1,3-thiazol-2-yl)-1H-indazole
Hydroformate
##STR00019##
[0583] Prepared by Procedure A in 80% yield. LC/MS (EI) t.sub.R
3.18 min, m/z 354 (M.sup.++1).
Example 18
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(1,3-thiazol-2-yl)-1H-indazole
Hydroformate
##STR00020##
[0584] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
2.45 min, m/z 354 (M.sup.++1).
Example 19
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole
Hydroformate
##STR00021##
[0585] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
2.45 nm in, m/z 338 (M.sup.++1).
Example 20
4-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1H-indazole
Hydroformate
##STR00022##
[0586] Prepared by Procedure A in 74% yield. LC/MS (EI) t.sub.R
1.61 min, m/z 272 (M.sup.++1).
Example 21
3-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-5-(nitro)-1H-indazole
Hydroformate
##STR00023##
[0587] Prepared by Procedure A in 60% yield. LC/MS (EI) t.sub.R
1.32 nm in, m/z 316 (M.sup.++1).
Example 22
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-6-(5-methyl-1,3-thiazol-2-yl)--
1H-indazole Hydroformate
##STR00024##
[0588] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.55 min, m/z 368 (M.sup.++1).
Example 23
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole
Hydroformate
##STR00025##
[0589] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.20 min, m/z 368 (M.sup.++1).
Example 24
3-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
Hydroformate
##STR00026##
[0590] Prepared by Procedure A in 80% yield. LC/MS (EI) t.sub.R
2.44 min. m/z 288 (M.sup.++1).
Example 25
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(methoxy)-1,2-benzisothiazole
Hydroformate
##STR00027##
[0591] Prepared by Procedure A in 70% yield. LC/MS (EI) t.sub.R
3.82 nm in, m/z 318 (M.sup.++1).
Example 26
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(2-thienyl)-1H-indazole Hydroformate
##STR00028##
[0592] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.78 min, m/z 353 (M.sup.++1).
Example 27
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole
Hydroformate
##STR00029##
[0593] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.24 min, m/z 368 (M.sup.++1).
Example 28
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(4-methyl-1,3-thiazol-2-yl)--
1H-indazole Hydroformate
##STR00030##
[0594] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R
3.03 min, m/z 368 (M.sup.++1).
Example 29
6-Bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
Hydroformate
##STR00031##
[0595] Prepared by Procedure A in 64% yield. LC/MS (EI) t.sub.R
3.69 min, m/z 367 (M.sup.++1).
Example 30
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-5-(1,3-oxazol-2-yl)-1H-indazol-
e Hydroformate
##STR00032##
[0596] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R 2.5
min, m/z 338 (M.sup.++1).
Example 31
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(difluoromethoxy)-1H-indazole
Hydroformate
##STR00033##
[0597] Prepared by Procedure A in 6% yield. LC/MS (EI) t.sub.R 4.62
min, m/z 337 (M.sup.++1).
Example 32
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(difluoromethoxy)-1H-indazole
Hydroformate
##STR00034##
[0598] Prepared by Procedure A in 6% yield. LC/MS (EI) t.sub.R 2.13
min, m/z 337 (M.sup.++1).
Example 33
3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-5-(tetrahydro-2H-pyran-4-yloxy)-1H-indazole
Hydroformate
##STR00035##
[0599] Prepared by Procedure A, followed by exposure to aqueous
hydrochloric acid, in 17% yield. LC/MS (EI) t.sub.R 4.27 min, m/z
370 (M.sup.++1).
Representative Procedure B.
[0600] Procedure B provides a method for the coupling between
bicyclobase amines and carboxaldehydes to form tertiary amine
derivatives.
Example 34
Mixture of
3-(1,4-diazabicyclo[3.2.2]non-4-yl-methyl)-6-(methoxy)-4H-chrom-
en-4-one hydroformate and
(3E)-3-(1,4-diazabicyclo[3.2.2]non-4-ylmethylene)-6-methoxy-2,3-dihydro-4-
H-chromen-4-one Hydroformate
##STR00036##
[0601] Sodium cyanoborohydride (0.0980 mmol) was added to a
solution of 6-methoxy-4-oxo-4H-chromene-3-carbaldehyde (0.490
mmol), and 1,4-diazabicyclo[3.2.2]nonane (0.490 mmol) in methanol
(3.00 mL), and the reaction mixture was maintained for 10 h. The
reaction mixture was transferred to a SCX column, washed with
methanol, and the product was eluted using a 2N solution of ammonia
in methanol. The residue was purified by preparative HPLC to
provide the product in 4% yield, as a mixture of the 1,2 and 1,4
reduction products. .sup.1H NMR (CD.sub.3OD) .delta. 8.27 (s,
0.5H), 8.21 (s, 0.5H), 7.56 (d, J=9.0, 0.5H), 7.54 (d, J=2.9,
0.5H), 7.38 (dd, J=9.0, 3.0, 0.5H), 6.89 (d, J=2.9, 0.5H), 6.76
(dd, J=8.9, 2.9, 0.5H), 6.68 (d, J=8.9, 0.5H), 4.87 (s, 1H),
4.27-4.22 (m, 0.5H), 4.07-4.01 (m, 0.5H), 3.89 (s, 1.5H), 3.77 (s,
1.5H), 3.46-3.29 (m, 3.5H), 3.11-2.46 (m, 3.5H), 2.53-2.19 (m, 3H),
2.09-1.93 (m, 3H); LC/MS (EI) t.sub.R 1.55 min, m/z 315
(M.sup.++1). Using this general procedure the following compounds
were prepared:
Example 35
Mixture of
3-(1,4-Diazabicyclo[3.2.2]non-4-yl-methyl)-5-(methoxy)-4H-chrom-
en-4-one hydroformate and
(3E)-3-(1,4-Diazabicyclo[3.2.2]non-4-ylmethylene)-5-methoxy-2,3-dihydro-4-
H-chromen-4-one Hydroformate
##STR00037##
[0602] Prepared by Procedure B in 4% yield. LC/MS (EI) t.sub.R 1.35
min, m/z 315 (M.sup.++1).
Example 36
Mixture of 3-(1,4-Diazabicyclo
[3.2.2]non-4-yl-methyl)-7-(methoxy)-4H-chromen-4-one hydroformate
and
(3E)-3-(1,4-Diazabicyclo[3.2.2]non-4-ylmethylene)-7-methoxy-2,3-dihydro-4-
H-chromen-4-one Hydroformate
##STR00038##
[0603] Prepared by Procedure B in 3% yield. LC/MS (EI) t.sub.R 1.51
min, m/z 315 (M.sup.++1).
Representative Procedure C.
[0604] Procedure C provides a method for the reduction of nitro
bicyclobase carboxamides to form aniline derivatives.
Example 37
3-(1,4-Diazabicyclo [3.2.2]non-4-ylcarbonyl)-1H-indazol-5-amine
Dihydroformate
##STR00039##
[0605] 10% Palladium on charcoal (200 mg) was added to a solution
of
(1,4-Diazabicyclo[3.2.2]non-4-yl)-(5-nitro-1H-indazol-3-yl)-methanone
(3.8 mmol) in methanol (100 mL). The reaction mixture was
maintained under an atmosphere of hydrogen gas (60 psi) for 16 h.
The catalyst was then removed by filtration (Celite), the filter
cake was washed with methanol, and the combined filtrates were
concentrated to provide the product in 89% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.30 (s, 1H), 7.52 (s, 2H), 4.30 (m, 2H), 4.20
(m, 1H), 3.50-3.30 (m, 6H), 2.40-2.20 (m, 2H), 2.20-1.90 (m, 2H);
LC/MS (EI) t.sub.R1.53 min, m/z 286 (M.sup.++1).
Representative Procedure D.
[0606] Procedure D provides a method for the coupling between amino
bicyclobase carboxamides and isocyanates to form urea
derivatives.
Example 38
N-[3-(1,3-Diazabicyclo[3.2.2]non-3-ylcarbonyl)-1H-indazol-5-yl]-N-(3-metho-
xybenzyl)urea Hydroformate
##STR00040##
[0607] 3-Methoxybenzyl isocyanate (0.53 mmol) was added to a
solution of the amine (100 mg, 0.4 mmol) in pyridine (4 mL), and
the resulting mixture was maintained at rt for 16 h. The reaction
mixture was concentrated and the residue was purified by
preparative HPLC to provide the product in 60% yield and the
bis-acylated product in 20% yield. .sup.1H NMR (CD.sub.3OD) .delta.
8.35 (broad, 2H), 8.07 (s, 1H), 7.51 (d, J=9.0, 1H), 7.43 (d,
J=9.0, 1H), 7.24 (dd, J=6.0, 9.0, 1H), 6.92 (m, 2H), 6.79 (m, 1H),
4.55 (m, 2H), 4.35 (s, 2H), 3.75 (s, 3H), 3.60-3.40 (m, 6H),
2.50-2.30 (m, 2H), 2.30-2.10 (m, 2H); LC/MS (EI) t.sub.R3.99 min,
m/z 449 (M.sup.++1). Using this general procedure the following
compounds were prepared:
Example 39
N-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]-N'-(4-fluo-
robenzyl)urea Hydroformate
##STR00041##
[0608] Prepared by Procedure D in 30% yield. LC/MS (EI) t.sub.R
3.52 min, m/z 437 (M.sup.++1).
Example 40
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-N-(4-fluorobenzyl)-5-({[(4-fluorobenzyl)amino]ca-
rbonyl}amino)-1H-indazole-1-carboxamide Hydroformate
##STR00042##
[0609] Prepared by Procedure D in 10% yield. LC/MS (EI) t.sub.R
4.19 min, m/z 599 (M.sup.++1).
Example 41
N-Cyclopentyl-N'-[3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]urea Hydroformate
##STR00043##
[0610] Prepared by Procedure D in 40% yield. LC/MS (EI) t.sub.R
3.01 min, m/z 397 (M.sup.++1).
Example 42
N-Cyclopentyl-5-{[(cyclopentylamino)carbonyl]amino}-3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazole-1-carboxamide Hydroformate
##STR00044##
[0611] Prepared by Procedure D in 10% yield. LC/MS (EI) t.sub.R
4.16 min, m/z 508 (M.sup.++1).
Example 43
N-[3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]pyrrolidine-
-1-carboxamide Hydroformate
##STR00045##
[0612] Prepared by Procedure D in 50% yield. LC/MS (EI) t.sub.R
2.44 min, m/z 383 (M.sup.++1).
Representative Procedure E.
[0613] Procedure E provides a method for the coupling between amino
bicyclobase carboxamides and chloroformates to form carbamate
derivatives.
Example 44
Benzyl [3-(1,3-Diazabicyclo
[3.2.2]non-3-ylcarbonyl)-1H-indazol-5-yl]carbamate Hydroformate
##STR00046##
[0614] Benzyl chloroformate (0.56 mmol) was added to a solution of
the amine (0.4 mmol) in pyridine (4 mL), and the reaction mixture
was maintained at rt for 16 h. The reaction mixture was
concentrated, and the residue was purified by preparative HPLC to
provide the product in 30% yield, the bis-acylated product in 10%
yield, and the N-(1)-benzylated product (Example 45) in 5% yield.
.sup.1H NMR (CD.sub.3OD) .delta. 8.35 (broad, 2H), 7.60-7.30 (m,
7H), 5.20 (s, 1H), 4.60 (m, 2H), 4.25 (m, 1H), 3.70-3.40 (m, 6H),
2.50-2.30 (m, 2H), 2.30-2.10 (m, 2H); LC/MS (EI) t.sub.R 3.74 min,
m/z 420(M.sup.++1). Using this general procedure the following
compounds were prepared:
Example 45
Benzyl [1-benzyl-3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]carbamate Hydroformate
##STR00047##
[0615] Prepared by Procedure E in 5% yield. LC/MS (EI) t.sub.R 4.06
min, m/z 510 (M.sup.++1).
[0616] Representative Procedure F.
[0617] Procedure F provides a method for the coupling between amino
bicyclobase carboxamides and acid chlorides to form amide
derivatives.
Example 46
N-[1-(Cyclopropylcarbonyl)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H--
indazol-5-yl]cyclopropanecarboxamide Hydroformate
##STR00048##
[0618] Cyclopropanecarbonyl chloride (0.4 mmol) was added to a
solution of
3-(2-azabicyclo[3.2.2]non-2-ylcarbonyl)-1H-indazol-5-amine (0.4
mol) in pyridine (4 mL), and the reaction mixture was maintained at
rt for 16 h. The reaction mixture was concentrated, and the residue
was purified by preparative HPLC to provide the product in 50%
yield, and the bis acylated product in 20% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.31 (s, 1H), 8.29 (s, 1H), 7.55 (s, 1H), 4.50
(m, 2H), 4.30 (m, 1H), 3.70-3.50 (m, 6H), 2.50-2.30 (m, 2H),
2.30-2.10 (m, 2H), 1.85 (m, 1H), 0.97 (m, 2H), 0.88 (m, 2H); LC/MS
(EI) t.sub.R2.41 min, m/z 354 (M.sup.++1). Using this general
procedure the following compounds were prepared:
Example 47
N-[1-(Cyclopropylcarbonyl)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H--
indazol-5-yl]cyclopropanecarboxamide Hydroformate
##STR00049##
[0619] Prepared by Procedure F in 20% yield. LC/MS (EI) t.sub.R
3.60 min, m/z 423 (M.sup.++1).
Representative Procedure G.
[0620] Procedure G provides a method for the coupling between amino
bicyclobase carboxamides and sulfonyl chlorides to form sulfonamide
derivatives.
Example 48
N-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-yl]-1-methyl-1H-imidazole-4-sulfona-
mide Hydroformate
##STR00050##
[0621] 1-Methylimidazole-4-sulphonyl chloride (0.4 mmol) was added
to a solution of
3-(2-azabicyclo[3.2.2]non-2-ylcarbonyl)-1H-indazol-5-amine (0.4
mol) in pyridine (4 mL), and the reaction mixture maintained at rt
for 16 h. The reaction mixture was concentrated, and the residue
purified by preparative HPLC to provide the product in 50% yield.
.sup.1H NMR (CD.sub.3OD) .delta. 8.39 (s, 1H), 7.85 (broad, 1H),
7.67 (s, 1H), 7.58 (s, 1H), 7.28 (d, J=
[0622] 9.0, 1H), 7.27 (d, J=9.0, 1H), 4.50 (m, 2H), 4.30 (m, 1H),
3.65 (s, 3H), 3.50-3.30 (m, 6H), 2.50-2.30 (m, 2H), 2.30-2.10 (m,
2H); LC/MS (EI) t.sub.R 1.72 min, m/z 431 (M.sup.++1).
Representative Procedure H.
[0623] Procedure H provides a method for the coupling between
brominated bicyclobase carboxamides and monosubstituted cyclic
ureas to form urea derivatives.
Example 49
1-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-isopropylimidazolidin-
-2-one Hydroformate
##STR00051##
[0624] A mixture of toluene (8 mL) and
(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.2 mmol) was
degassed with nitrogen for 4 minutes, then heated at 80.degree. C.
until the (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
dissolved completely. The solution was allowed to cool to rt and
palladium acetate (0.09 mmol) was added. The mixture was stirred
until the palladium acetate completely dissolved. The resultant
yellow solution was added to a mixture of
6-bromo-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazole
(0.33 mmol), 1-isopropylimidazolidin-2-one (0.5 mmol) and cesium
carbonate (0.39 mmol) under a nitrogen atmosphere. The reaction
mixture was subjected to microwave radiation at 150.degree. C. for
360 s. The inorganic precipitates were removed by filtration, and
the filtrate was concentrated. The residue was purified by
preparative HPLC to provide the product in 75% yield. .sup.1H NMR
(CD.sub.3OD) .delta. 8.17 (s, 1H), 8.03-7.93 (m, 2H), 4.30-4.05 (m,
2H), 3.92 (t, J=7.14, 2H), 3.70 (t, J=5.7, 2H), 3.54 (t, J=7.1,
2H), 3.20-3.00 (m, 6H), 1.22 (d, J=6.78, 3 6H); LC/MS (EI) t.sub.R
3.10 min, m/z 415 (M.sup.++1). Using this general procedure the
following compounds were prepared:
Example 50
1-[3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-yl]-3-methylimidazolidin-2--
one Hydroformate
##STR00052##
[0625] Prepared by Procedure H in 69% yield. LC/MS (EI) t.sub.R
2.47 min, m/z 386 (M.sup.++1).
Representative Procedure I.
[0626] Procedure I provides a method for the coupling between
bicyclobases and carboxylic acids to form carboxamide derivatives
and the transformation of these derivatives to their hydrochloric
acid salt.
Example 51
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole
Hydrochloride
##STR00053##
[0627] N,N-Diisopropylethylamine (7.0 mL) was added to a solution
of 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid
(11.9 mmol) and 1,4-diazabicyclo[3.2.2]nonane (10.0 mmol) in
N,N-dimethylformamide (80 mL) and tetrahydrofuran (60 mL). After 15
minutes, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (12.1 mmol) was added, and the reaction mixture
was maintained at rt for 36 h, and was concentrated to a brown
sludge. The residue was diluted with 9/1 dichloromethane/methanol
(100 mL) and was washed with 2/1 saturated sodium bicarbonate/water
(25 mL). The aqueous layer was back-extracted with 9/1
dichloromethane/methanol (4.times.50 mL). The combined organic
layers were dried over sodium sulfate, treated with silica gel (15
g) and concentrated. The residue was purified by chromatography
using a gradient of 50/50 to 0/100 ethyl acetate/(70/30/1)
ethylacetate/methanol/ammonium hydroxide). The free base was
suspended in ethanol/ethyl acetate (4/1, 100 mL) and was warmed to
the boiling point. The reaction mixture was cooled to room
temperature and acetyl chloride (505 uL) was added dropwise,
resulting in the immediate formation of a precipitate. After 1 h,
the precipitated solids were collected, dried, and then
recrystallized from boiling methanol (60 mL). The product was
further purified by suspending the solid in 95/5 ethanol/water,
warming the heterogeneous mixture to 100.degree. C., and allowing
the suspension to cool to rt. The solids were isolated by
filtration, washed with cold ethanol, and dried to provide the
analytically pure product in 57% yield. .sup.1H NMR (CD.sub.3OD)
.delta. 7.57 (d, J=8.7, 1H), 7.28 (s, 1H), 7.18 (d, J=8.6, 1H),
6.06 (s, 1H), 4.76 (m, 1H), 4.14-4.05 (two m, rotomers, 4H), 3.76
(t, J=5.3, 2H), 3.54-3.34 (two m, rotomers, 6H), 2.31-1.92 (three
m, 6H); LC/MS (EI) t.sub.R 2.68 min, m/z 353 (M.sup.++1). Using
this general procedure the following compounds were prepared:
Example 52
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-6-(1,3-oxazol-2-yl)-1H-indazole
Hydrochloride
##STR00054##
[0628] Prepared by Procedure I in 20% yield. LC/MS (EI) t.sub.R
2.53 min, m/z 338 (M.sup.++1).
Representative Procedure J
[0629] Procedure J provides a method for the demethylation of aryl
ethers to provide phenols.
Example 53
3-(1,4-Diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-ol Hydroformate
##STR00055##
[0630] A 1.0 M solution of boron tribromide in dichloromethane (10
mL) was added to a suspension of
(1,4-diazabicyclo[3.2.2]non-4-yl)-(6-methoxybenzo[d]isothiazol-3-yl)metha-
none (2.06 mmol) in 1,2-dichloroethane (20 mL). The suspension was
heated at 50.degree. C. for 16 h and was allowed to cool to rt. The
reaction mixture was quenched with methanol (50 mL) and
concentrated to dryness. The residue was diluted with methanol, and
loaded on a SCX column. The column was washed with methanol (50
mL), 2 M ammonia in methanol (60 mL) and the ammonia wash was
concentrated. The residue was purified by chromotography [1/1 to
0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium
hydroxide)]followed by preparative HPLC to provide the product in
21% yield. .sup.1H NMR (CD.sub.3OD) .delta. 8.35 (s, 1H), 8.01 and
8.00 (two d, J=8.9, 1H), 7.37 (d, J=1.9, 1H), 7.05 and 7.04 (two
dd, J=8.9, 2.2, 1H), 4.99 (m, 1H), 4.47 (m, 0.3H), 4.25 (m, 0.7H),
4.07 (m, 1.3H), 3.64 (m, 0.3H), 3.53-3.34 (m, 5H), 2.45-2.27 (m,
2H), 2.26-2.04 (m, 2H); LC/MS (EI) t.sub.R 2.47 min, m/z 304
(M.sup.++1).
Representative Procedure K
[0631] Procedure K provides a method for the coupling between
phenols and alcohols to form ether analogs.
Example 54
6-(Cyclopropylmethoxy)-3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-ben-
zisothiazole Hydroformate
##STR00056##
[0632] Disopropyl azodicarboxylate (0.396 mmol) was added dropwise
to a solution of
3-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1,2-benzisothiazol-6-ol
(0.359 mmol), cyclopropyl carbinol (0.432 mmol), and
triphenylphosphine (0.541 mmol) in tetrahydrofuran (2.2 mL). The
reaction mixture was maintained at rt for 16 h, and then the
reaction mixture was concentrated. The residue was purified by
chromatography using a gradient of 50/50 to 0/100 ethyl
acetate/[(70/30/1) ethylacetate/methanol/ammonium hydroxide)]. The
compound was further purified by preparative HPLC to provide the
product in 39% yield.
[0633] .sup.1H NMR (CD.sub.3OD) .delta. 8.06 and 8.05 (two d, J=9.0
ea, 1H), 7.56 (d, J=1.8, 1H), 7.14 and 7.13 (two dd, J=8.7, 2.2 ea,
1H), 5.00 (m, 0.79H), 4.50 (m, 0.34H), 4.25 (t, J=5.6, 0.68H), 4.09
(t, J=5.6, 1.34H), 3.95 (d, J=6.9, 2H), 3.63 (t, J=5.7, 0.70 H),
3.62-3.36 (m, 5H), 2.45-2.37 (m, 2H), 2.26-2.02 (two m, 2H),
1.37-1.27 (m, 1H), 0.69-0.62 (m, 2H), 0.42-0.37 (m, 2H); LC/MS (EI)
t.sub.R 3.91 min, m/z 358 (M.sup.++1).
[0634] The following compounds could not be prepared using the
procedures set forth above. However, it is believed that these
compounds may be prepared using alternate conventional synthetic
procedures well known to those of ordinary skill in the art. [0635]
3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-N-(3-methoxybenzyl)-5-({[(3-m-
ethoxybenzyl)amino]carbonyl}amino)-1H-indazole-1-carboxamide and
pharmaceutically acceptable salts thereof, [0636]
3-(1,4-Diazabicyclo[3.2.2]non-4-yl-methyl)-8-(methoxy)-4H-chromen-4-one
and pharmaceutically acceptable salts thereof, [0637]
N,1-Dibutyl-3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-amine and pharmaceutically
acceptable salts thereof, or [0638] N-Butyl-3-(1,4-diazabicyclo
[3.2.2]non-4-ylcarbonyl)-1H-indazol-5-amine and pharmaceutically
acceptable salts thereof.
Example 55
[.sup.3H]MLA Binding
Materials:
[0639] Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2
[0640] Protease inhibitor cocktail tablet: Roche, CAT No.
1697498
Membrane Preparation
[0641] 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.
[0642] 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 times with binding buffer and the
radioactivity was counted with Trilux.
[0643] Binding affinities for the preferred compounds of the
invention were 5 nM to 21 .mu.M, especially 5 nM to 2.5 .mu.M.
[0644] 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.
[0645] While the invention has been illustrated with respect to the
production of particular compounds, it is readily apparent to those
of ordinary skill in the art that variations and modifications of
the invention can be made without departing from the spirit or
scope of the invention.
* * * * *