U.S. patent application number 12/090616 was filed with the patent office on 2011-07-21 for bridged n-bicyclic sulfonamido inhibitors of gamma secretase.
This patent application is currently assigned to ELAN PHARMACEUTICALS, INC.. Invention is credited to Andrei W. Konradi, Matthew N. Mattson, Christopher M. Semko, Xiaocong Michael Ye.
Application Number | 20110178119 12/090616 |
Document ID | / |
Family ID | 37758487 |
Filed Date | 2011-07-21 |
United States Patent
Application |
20110178119 |
Kind Code |
A1 |
Konradi; Andrei W. ; et
al. |
July 21, 2011 |
Bridged N-Bicyclic Sulfonamido Inhibitors of Gamma Secretase
Abstract
The invention provides N-bicyclic sulfonamido compounds of
Formula (I) wherein A is as described in the specification and
R.sub.1 and R.sub.2 combine to form a [3.3.1] or a [3.2.1] ring
system. Compounds of Formula I are useful in treating or preventing
cognitive disorders, such as Alzheimer's Disease. The invention
also encompasses pharmaceutical compositions comprising compounds
of Formula (I) as well as methods of treating cognitive disorders,
such as Alzheimer's disease. ##STR00001##
Inventors: |
Konradi; Andrei W.;
(Burlingame, CA) ; Mattson; Matthew N.; (Santa
Clara, CA) ; Semko; Christopher M.; (Fremont, CA)
; Ye; Xiaocong Michael; (Palo Alto, CA) |
Assignee: |
ELAN PHARMACEUTICALS, INC.
South San Francisco
CA
|
Family ID: |
37758487 |
Appl. No.: |
12/090616 |
Filed: |
August 18, 2006 |
PCT Filed: |
August 18, 2006 |
PCT NO: |
PCT/US06/32261 |
371 Date: |
September 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60709961 |
Aug 19, 2005 |
|
|
|
Current U.S.
Class: |
514/299 ;
546/112; 546/183 |
Current CPC
Class: |
C07D 471/22 20130101;
A61P 25/28 20180101; C07D 451/14 20130101; C07D 498/08 20130101;
C07D 471/08 20130101; C07D 471/18 20130101; A61P 43/00
20180101 |
Class at
Publication: |
514/299 ;
546/183; 546/112 |
International
Class: |
A61K 31/439 20060101
A61K031/439; C07D 221/02 20060101 C07D221/02; A61P 25/28 20060101
A61P025/28 |
Claims
1. A compound of the formula I: ##STR00055## or a pharmaceutically
acceptable salt thereof wherein, the A-ring is aryl, cycloalkyl,
heteroaryl or heterocycloalkyl, where each ring is optionally
substituted at a substitutable position with halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl,
hydroxyalkyl, CN, phenoxy, --S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl,
C.sub.0-C.sub.3alkylCO.sub.2R', heteroaryl, heterocycloalkyl, aryl,
aralkyl, or --SO.sub.2NR.sub.10R.sub.11; R.sub.1 and R.sub.2
combine to form a [3.3.1] or a [3.2.1] ring system, where 0 or 1 of
the carbons in the ring system is optionally replaced with an
--O--, --S(O).sub.x--, or --NR.sub.15-- group; and where the
[3.3.1] or [3.2.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.16, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; where x is 0, 1, or 2; R.sub.10 and R.sub.11
at each occurrence are independently hydrogen or C.sub.1-C.sub.6
alkyl, where the alkyl is optionally substituted with an aryl,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; or R.sub.10 and R.sub.11 together may
form a 3-8 membered ring optionally including an additional
heteroatom such as N, O or S; R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-aryl, where the aryl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen
or C.sub.1-C.sub.6 alkyl optionally substituted with aryl,
hydroxyl, or halogen, where the aryl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; R.sub.15 is
hydrogen, aryl, heteroaryl, --SO.sub.2R', --C(O)R', --C(O)OR', or
C.sub.1-C.sub.6 alkyl optionally substituted with aryl, hydroxyl,
or halogen, where the aryl groups are optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; and R' and R'' are
independently hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl,
C.sub.2-C.sub.6 alkenyl or phenyl optionally substituted with 1 to
5 groups that are independently halogen, C.sub.1-C.sub.6 alkyl,
--C(O)OR', C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl,
CN, phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl,
NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
2. A compound according to claim 1, wherein the A-ring is phenyl,
C.sub.3-C.sub.8 cycloalkyl, heteroaryl that is pyridyl, pyrimidyl,
pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or
imidazolyl, or heterocycloalkyl that is pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl, or
thiomorpholinyl-S,S-dioxide, where each of the above rings is
optionally substituted at a substitutable position with halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl,
hydroxyalkyl, CN, phenoxy, --S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl,
C.sub.0-C.sub.3alkylCO.sub.2R', heteroaryl, heterocycloalkyl, aryl,
aralkyl, or --SO.sub.2NR.sub.10R.sub.11.
3. A compound according to claim 2 of formula ##STR00056## where 0
or 1 of the carbons in the [3.2.1] ring system is optionally
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group; x
is 0, 1 or 2; the [3.2.1] ring system is optionally substituted
with 1, 2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O).sub.10R.sub.11, --NR'C(O)OR''',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; R.sub.10 and R.sub.11 at
each occurrence are independently hydrogen or C.sub.1-C.sub.6
alkyl, where the alkyl is optionally substituted with an aryl,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; or R.sub.10 and R.sub.11 together may
form a 3-8 membered ring optionally including an additional
heteroatom such as N, O or S; R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-aryl, where the aryl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen
or C.sub.1-C.sub.6 alkyl optionally substituted with aryl,
hydroxyl, or halogen, where the aryl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; R.sub.15 is
hydrogen, aryl, heteroaryl, --SO.sub.2R', --C(O)R', --C(O)OR', or
C.sub.1-C.sub.6 alkyl optionally substituted with aryl, hydroxyl,
or halogen, where the aryl groups are optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; and R' and R'' are
independently hydrogen, 1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6
alkenyl or phenyl optionally substituted with 1 to 5 groups that
are independently halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR',
C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN,
phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
4. A compound according to claim 3, where the A-ring is phenyl,
which is optionally substituted at a substitutable position with
halogen 1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl,
hydroxyalkyl, CN, phenoxy, --S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl,
C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl, pyrazolyl, thiazolyl,
pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl,
pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl,
phenyl C.sub.1-C.sub.4 alkyl or --SO.sub.2NR.sub.10R.sub.11.
5. A compound according to claim 4, where 0 of the carbons in the
[3.2.1] ring system is replaced with an --O--, --S(O).sub.x--, or
--NR.sub.15-- group.
6. A compound according to claim 5, of formula ##STR00057##
wherein, the [3.2.1] ring system is optionally substituted with 1,
2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --OC(O)NR.sub.10R.sub.11,
--NR'C(O)OR'', --NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7 are independently hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, CN, hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3
alkyl-OH, --C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
R.sub.10 and R.sub.11 at each occurrence are independently hydrogen
or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally substituted
with an aryl, where the aryl is optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; or R.sub.10 and R.sub.11
together may form a 3-8 membered ring optionally including an
additional heteroatom such as N, O or S; R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl, where the aryl is
optionally substituted with 1 to 5-groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and R' and R'' are independently hydrogen,
C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl
optionally substituted with 1 to 5 groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
7. A compound according to claim 6, wherein R.sub.3, R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are hydrogen, halo, CF.sub.3,
CHF.sub.2 or methyl.
8. A compound according to claim 6, wherein R.sub.3, R.sub.5,
R.sub.6, and R.sub.7 are hydrogen and R.sub.4 is chloro.
9. A compound according to claim 8, wherein the [3.2.1] ring is
substituted with .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
R.sub.12 is C.sub.1-C.sub.6 alkyl or --SO.sub.2-- phenyl, where the
phenyl is optionally substituted with 1 to 3 groups that are
independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2; and
R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally substituted with
phenyl, hydroxyl, or halogen, where the phenyl is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
10. A compound according to claim 8, wherein the [3.2.1] ring is
not substituted.
11. A compound according to claim 8, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.2-C.sub.6 alkenyl.
12. A compound according to claim 6, where one carbon of the
[3.2.1] ring system is replaced with an --O--, --S(O).sub.x--, or
--NR.sub.15-- group; wherein x is 0, 1 or 2; the [3.2.1] ring
system is optionally substituted with 1, 2, 3, or 4 groups that are
independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; and R.sub.15 is hydrogen, C.sub.1-C.sub.6
alkyl optionally substituted with phenyl, hydroxyl, or halogen, or
phenyl, where the phenyl groups are optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
13. A compound according to claim 12, of formula: ##STR00058##
wherein. R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
R.sub.10 and R.sub.11 at each occurrence are independently hydrogen
or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally substituted
with an aryl, where the aryl is optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; or R.sub.10 and R.sub.11
together may form a 3-8 membered ring optionally including an
additional heteroatom such as N, O or S; R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; R.sub.15 is hydrogen, aryl, heteroaryl, --SO.sub.2R',
--C(O)R', --C(O)OR', or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl groups
are optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and R' and R'' are independently
hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl
or phenyl optionally substituted with 1 to 5 groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR',
C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN,
phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
14. A compound according to claim 12 of formula, ##STR00059##
wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with optionally
substituted with 1 to 5-groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
R.sub.10 and R.sub.11 at each occurrence are independently hydrogen
or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally substituted
with an aryl, where the aryl is optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; or R.sub.10 and R.sub.11
together may form a 3-8 membered ring optionally including an
additional heteroatom such as N, O or S; R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and R' and R'' are independently hydrogen,
C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl
optionally substituted with 1 to 5 groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
15. A compound according to claim 12 of formula; ##STR00060##
wherein x is 0, 1 or 2 R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7
are independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they, are attached
form a heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
R.sub.10 and R.sub.11 at each occurrence are independently hydrogen
or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally substituted
with an aryl, where the aryl is optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; or R.sub.10 and R.sub.11
together may form a 3-8 membered ring optionally including an
additional heteroatom such as N, O or S; R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and R' and R'' are independently hydrogen,
C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl
optionally substituted with 1 to 5 groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkanoyl,
pyridyl, phenyl, NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
16. A compound according to claim 3, where the A-ring is
C.sub.3-C.sub.8 cycloalkyl, which is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl or
--SO.sub.2NR.sub.10R.sub.11.
17. A compound according to claim 3, where the A-ring is heteroaryl
that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl,
furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is
optionally substituted at one or more substitutable positions with
groups that are independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl or
--SO.sub.2NR.sub.10R.sub.11.
18. A compound according to claim 3, where the A-ring is
heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where
each of the above rings is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl or
--SO.sub.2NR.sub.10R.sub.11.
19. A compound according to claim 2 of the formula ##STR00061## 0
or 1 of the carbons in the [3.3.1] ring system is optionally
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group; x
is 0, 1 or 2; the [3.3.1] ring system is optionally substituted
with 1, 2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; R.sub.10 and R.sub.11 at each occurrence are
independently hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is
optionally substituted with an aryl, where the aryl is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or S;
R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6
alkyl optionally substituted with aryl, hydroxyl, or halogen, where
the aryl is optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen, aryl, heteroaryl,
--SO.sub.2R', --C(O)R', --C(O)OR', or C.sub.1-C.sub.6 alkyl
optionally substituted with aryl, hydroxyl, or halogen, where the
aryl groups are optionally, substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and R' and R'' are independently
hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl
or phenyl optionally substituted with 1 to 5 groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR',
C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN,
phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
20. A compound according to claim 19, where the A-ring is phenyl,
which is optionally substituted at a substitutable position with
halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, haloalkyl,
haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
21. A compound according to claim 20, where 0 or 1 of the carbons
in the ring system is optionally replaced with an --O--,
--S(O).sub.x--, or --NR.sub.15-- group; and the [3.3.1] ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
O.sub.2--C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
O.sub.2--C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
22. A compound according to claim 21, of formula ##STR00062##
wherein, 0 carbons in the [3.3.1] ring system are replaced with an
--O--, --S(O)--, or --NR.sub.15-- group; R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7 are independently hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, CN, hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3
alkyl-OH, --C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with 1 to 5 groups
that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.10 and R.sub.11 at each
occurrence are independently H or C.sub.1-C.sub.6 alkyl, where the
alkyl is optionally substituted with an aryl, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; or R.sub.10 and R.sub.11 together may form a 3-8 membered
ring optionally including an additional heteroatom such as N, O or
S; R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6
alkyl optionally substituted with aryl, hydroxyl, or halogen, where
the aryl is optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and R' and R'' are independently
hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl
or phenyl optionally substituted with 1 to 5 groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR',
C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN,
phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
23. A compound according to claim 22, wherein R.sub.3, R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are hydrogen, halo, CF.sub.3,
CHF.sub.2 or methyl.
24. A compound according to 22, wherein R.sub.3, R.sub.5, R.sub.6,
and R.sub.7 are hydrogen and R.sub.4 is chloro.
25. A compound according to claim 22, wherein the [3.3.1] ring is
substituted with .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
R.sub.12 is C.sub.1-C.sub.6 alkyl or --SO.sub.2-- phenyl, where the
phenyl is optionally substituted with 1 to 3 groups that are
independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2; and
R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally substituted with
phenyl, hydroxyl, or halogen, where the phenyl is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
26. A compound according to claim 22, wherein the [3.3.1] ring is
not substituted.
27. A compound according to claim 22, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.2-C.sub.6 alkenyl.
28. A compound according to claim 22, where one carbon of the
[3.3.1] ring system is replaced with an --O--, --S(O).sub.x--, or
--NR.sub.15-- group; wherein x is 0, 1 or 2 the [3.3.1] ring system
is optionally substituted with 1, 2, 3, or 4 groups that are
independently oxo, halogen, C.sub.1-C.sub.6 alkyl-O(C.sub.1-C.sub.2
alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; and R.sub.15 is hydrogen, C.sub.1-C.sub.6
alkyl optionally substituted with phenyl, hydroxyl, or halogen, or
phenyl, where the phenyl groups are optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
29. A compound according to claim 28 of formula ##STR00063##
wherein the [3.3.1] ring system is optionally substituted with 1,
2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --OC(O)NR.sub.10R.sub.11,
--NR'C(O)OR'', --NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7 are independently hydrogen, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, CN, hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3
alkyl-OH, --C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl,
pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl,
piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl
C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or R.sub.5 and
R.sub.6 and the carbons to which they are attached form a
heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with 1 to 5 groups
that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and R.sub.10 and R.sub.11 at each
occurrence are independently H or C.sub.1-C.sub.6 alkyl, where the
alkyl is optionally substituted with an aryl, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; R.sub.10 and R.sub.11 together may form a 3-8 membered
ring optionally including an additional heteroatom such as N, O or
S; R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6
alkyl optionally substituted with aryl, hydroxyl, or halogen, where
the aryl is optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.15 is hydrogen, aryl, heteroaryl,
--SO.sub.2R', --C(O)R', --C(O)OR', or C.sub.1-C.sub.6 alkyl
optionally substituted with aryl, hydroxyl, or halogen, where the
aryl groups are optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and R' and R'' are independently
hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl
or phenyl optionally substituted with 1 to 5 groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR',
C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN,
phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
30. A compound according to claim 28, of formula ##STR00064##
wherein the [3.3.1] ring system is optionally substituted with 1,
2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7
are independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with 1 to 5 groups
that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.10 and R.sub.11 at each
occurrence are independently hydrogen or C.sub.1-C.sub.6 alkyl,
where the alkyl is optionally substituted with an aryl, where the
aryl is optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; or R.sub.12 and together may form a 3-8
membered ring optionally including an additional heteroatom such as
N, G or S; R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-aryl, where the aryl is optionally substituted with 1 to
5 groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen or
C.sub.1-C.sub.6 alkyl optionally substituted with aryl, hydroxyl,
or halogen, where the aryl is optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; and R' and R'' are
independently hydrogen-, C.sub.1-C.sub.6 alkyl, haloalkyl,
C.sub.2-C.sub.6 alkenyl or phenyl optionally substituted with 1 to
5 groups that are independently halogen, C.sub.1-C.sub.6 alkyl,
--C(O)OR', C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl,
CN, phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl,
NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
31. A compound according to claim 28 of formula ##STR00065##
wherein x is 0, 1 or 2 the [3.3.1] ring system is optionally
substituted with 1, 2, 3, or 4 groups that are independently oxo,
halogen, C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7
are independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3-C.sub.1-C.sub.3
alkyl-alkoxy, phenoxy, --SO.sub.2R', --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl,
pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl,
piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl
C.sub.1-C.sub.4 alkyl; or R.sub.4 and R.sub.5, or R.sub.5 and
R.sub.6 and the carbons to which they are attached form a
heterocycloalkyl or a heteroaryl ring which is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms; or R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with 1 to 5 groups
that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.10 and R.sub.11 at each
occurrence are independently H or C.sub.1-C.sub.6 alkyl, where the
alkyl is optionally substituted with an aryl, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; or R.sub.10 and R.sub.11 together may form a 3-8 membered
ring optionally including an additional heteroatom such as N, O or
S; R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2-aryl,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; R.sub.13 is hydrogen or C.sub.1-C.sub.6
alkyl optionally substituted with aryl, hydroxyl, or halogen, where
the aryl is optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and R' and R'' are independently
hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl
or phenyl optionally substituted with 1 to 5 groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR',
C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN,
phenoxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
32. A compound according to claim 18, where the A-ring is
C.sub.3-C.sub.8 cycloalkyl, which is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl or
--SO.sub.2NR.sub.10R.sub.11.
33. A compound according to claim 18, where the A-ring is
heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which
is optionally substituted at one or more substitutable positions
with groups that are independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl or
--SO.sub.2NR.sub.10R.sub.11.
34. A compound according to claim 18, where the A-ring is
heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where
each of the above rings is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl or
--SO.sub.2NR.sub.10R.sub.11.
35. A compound according to claim 1 that is selected from:
9-(5-chlorothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
9-(4-methylphenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
9-(5-bromothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-bromophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-bromo-3-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(3-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(3,5-dichlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-(trifluoromethoxy)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
9-(4-iodophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octane;
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octane;
8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one;
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one;
8-(4-iodophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one;
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-ol;
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one oxime;
8-(4-chlorophenylsulfonyl)-3-methylene-8-azabicyclo[3.2.1]octane;
8-(4-bromophenylsulfonyl)-3-methylene-8-azabicyclo[3.2.1]octane;
9-(4-chlorophenylsulfonyl)-3-methylene-9-azabicyclo[3.3.1]nonane;
9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]-nonan-
-3-one; diethyl
9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2,4-dicarboxyl-
ate; ethyl
9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2-ca-
rboxylate;
2-bromo-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-o-
ne;
2-amino-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane-2,4-dio-
ne;
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane;
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonan-2-one;
8-[(4-chlorophenyl)sulfonyl]-8-azabicyclo[3.2.1]octan-3-ol;
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane-2,4-dione;
(2R)-2-{9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]non-3-yl}prop-
an-1-ol;
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane;
(2S)-2-{9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]non-3-yl}prop-
an-1-ol;
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane-3-carb-
oxamide;
3-acetyl-9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nona-
ne;
9-(4-chloro-benzenesulfonyl)-3-pyridin-2-yl-9-aza-bicyclo[3.3.1]-nonan-
e; 9-(4-chlorophenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonan-2-one;
9-(4-chlorophenylsulfonyl)-3-oxa-9-azabicyclo[3.3.1]nonane;
9-(4-chlorophenylsulfonyl)-3-thia-9-azabicyclo[3.3.1]nonane;
Methanesulfonic acid
9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo-[3.3.1]non-3-yl ester;
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-ol;
[9-(4-Chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-yl]-methyl-carbam-
ic acid tert-butyl ester;
9-(4-Chloro-benzenesulfonyl)-2-(1H-pyrrol-2-ylmethylene)-9-aza-bicyclo
[3.3.1]nonan-3-one;
9-(4-Chloro-benzenesulfonyl)-3-oxo-9-aza-bicyclo[3.3.1]nonane-2-carboxyli-
c acid ethyl ester;
N-tosyl-[9-(4-Chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-ylidene]--
hydrazine; and
2-aminomethylene-9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-
-one; including steroisomers, mixtures of stereoisomers or
pharmaceutically acceptable salts thereof.
36. A method of treating Alzheimer's disease comprising
administering a therapeutically effective amount of a compound or
salt of claim 1 to a patient in need of such treatment.
37. A composition comprising a compound or salt of claim 1 and at
least one pharmaceutically acceptable solvent, adjuvant, excipient,
carrier, binder or disintegrant.
Description
[0001] This application claims priority from U.S. Provisional
application No. 60/709,961, filed Aug. 19, 2005, which is
incorporated by reference, in its entirety.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application claims the benefit under 35 U.S.C. 119(e)
to provisional application U.S. Ser. No. 60/709,961 filed Aug. 19,
2005 which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The invention relates to bridged N-bicyclic sulfonamido
compounds, which inhibit gamma secretase and .beta.-amyloid peptide
release and/or its synthesis. Therefore, the N-bicyclic sulfonamido
compounds are useful in the prevention of cognitive disorders in
patients susceptible to cognitive disorders and/or in the treatment
of patients with cognitive disorders in order to inhibit further
deterioration in their condition.
[0005] 2. State of the Art
[0006] Alzheimer's Disease (AD) is a degenerative brain disorder
characterized clinically by progressive loss of memory, cognition,
reasoning, judgment and emotional stability that gradually leads to
profound mental deterioration and ultimately death. AD is a very
common cause of progressive mental failure (dementia) in aged
humans and is believed to represent the fourth most common medical
cause of death in the United States. AD has been observed in races
and ethnic groups worldwide and presents a major present and future
public health problem. The disease is currently estimated to affect
about two to three million individuals in the United States alone.
AD is at present incurable. No treatment that effectively prevents
AD or reverses its symptoms and course is currently known.
[0007] The brains of individuals with AD exhibit characteristic
lesions termed senile (or amyloid) plaques, amyloid angiopathy
(amyloid deposits in blood vessels) and neurofibrillary tangles.
Large numbers of these lesions, particularly amyloid plaques and
neurofibrillary tangles, are generally found in several areas of
the human brain important for memory and cognitive function in
patients with AD. Smaller numbers of these lesions in a more
restrictive anatomical distribution are also found in the brains of
most aged humans who do not have clinical AD. Amyloid plaques and
amyloid angiopathy also characterize the brains of individuals with
Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage
with Amyloidosis of the Dutch Type (HCHWA-D). At present, a
definitive diagnosis of AD usually requires observing the
aforementioned lesions in the brain tissue of patients who have
died with the disease or, rarely, in small biopsied samples of
brain tissue taken during an invasive neurosurgical procedure.
[0008] The principal chemical constituent of the amyloid plaques
and vascular amyloid deposits (amyloid angiopathy) characteristic
of AD and the other disorders mentioned above is an approximately
4.2 kilodalton (kD) protein of about 39-43 amino acids designated
the .beta.-amyloid peptide (.beta.AP) or sometimes A.beta.,
A.beta.P or .beta./A4. .beta.-Amyloid peptide was first purified
and a partial amino acid sequence was provided by Glenner et al.,
Biochem. Biophys. Res. Commun., 120:885-890 (1984) The isolation
procedure and the sequence data for the first 28 amino acids are
described in U.S. Pat. No. 4,666,829.
[0009] Molecular biological and protein chemical analyses have
shown that the .beta.-amyloid peptide is a small fragment of a much
larger precursor protein termed the amyloid precursor protein
(APP), that is normally produced by cells in many tissues of
various animals, including humans. Knowledge of the formula of the
gene encoding APP has demonstrated that .beta.-amyloid peptide
arises as a peptide fragment that is cleaved from APP by protease
enzyme(s). Sequential, processing of the precursor protein by the
enzymes referred to generically as beta- and gamma-secretases, give
rise to the .beta.-amyloid peptide fragment. Both enzymes have now
been molecularly cloned, and characterized to differing levels.
[0010] Several lines of evidence indicate that progressive cerebral
deposition of .beta.-amyloid peptide plays a seminal role in the
pathogenesis of AD and can precede cognitive symptoms by years or
decades. See, for example, Selkoe, Neuron, 6:487-498 (1991). The
most important line of evidence is the discovery that missense DNA
mutations at amino acid 717 of the 770-amino acid isoform of APP
can be found in affected members but not unaffected members of
several families with a genetically determined (familial) form of
AD (Goate et al., Nature, 349:704-706 (1990); Chartier Harlan et
al., Nature, 353:844-846 (1989); and Murrell et al., Science,
254:97-99 (1991.) Another such mutation, known as the Swedish
variant, is comprised of a double mutation changing
lysine.sup.595-methionine.sup.596 to
asparagine.sup.595-leucine.sup.596 (with reference to the 695
isoform was found in a Swedish family) was reported in 1992 (Mullan
et al., Nature Genet., 1:345-347 (1992). Genetic linkage analyses
have demonstrated that these mutations, as well as certain other
mutations in the APP gene, are the specific molecular cause of AD
in the affected members of such families. In addition, a mutation
at amino acid 693 of the 770-amino acid isoform of APP has been
identified as the cause of the .beta.-amyloid peptide deposition
disease, HCHWA-D, and a change from alanine to glycine at amino
acid 692 appears to cause a phenotype that resembles AD is some
patients but HCHWA-D in others. The discovery of these and other
mutations in APP in genetically based cases of AD prove that
alteration of APP metabolism, and subsequent deposition of it
.beta.-amyloid peptide fragment, can cause AD.
[0011] Despite the progress which has been made in understanding
the underlying mechanisms of AD and other .beta.-amyloid peptide
related diseases, there remains a need to develop methods and
compositions for treatment of the disease(s). Ideally, the
treatment methods would advantageously be based on drugs which are
capable of inhibiting .beta.-amyloid peptide release and/or its
synthesis in vivo.
[0012] One approach toward inhibiting amyloid peptide synthesis in
vivo is by inhibiting gamma secretase, the enzyme responsible for
the carboxy-terminal cleavage resulting in production of
.beta.-amyloid peptide fragments of 40 or 42 residues in length.
The immediate substrates for gamma secretase are .beta.-cleaved, as
well as .alpha.-cleaved carboxy-terminal fragments (CTF) of APP.
The gamma-secretase cleavage site on .beta.- and .alpha.-CTF
fragments occurs in the predicted transmembrane domain of APP.
Inhibitors of gamma-secretase have been demonstrated to effect
amyloid pathology in transgenic mouse models (Dovey, H. F., V.
John, J. P. Anderson, L. Z. Chen, P. de Saint Andrieu, L. Y. Fang,
S. B. Freedman, B. Folmer, E. Goldbach, E. J. Holsztynska et al.
(2001). "Functional gamma-secretase inhibitors reduce beta-amyloid
peptide levels in brain." J. Neurochem 76(1): 173-81.)
[0013] Gamma secretase is recognized to be a multi-subunit complex
comprised of the presenilins (PS1 or PS2), Nicastrin, Aph-1, and
Pen 2 (De Strooper, B. (2003). "Aph-1, Pen-2, and Nicastrin with
Presenilin generate an active gamma-Secretase complex." Neuron
38(1): 9-12; Edbauer, D., E. Winkler, J. T. Regula, B. Pesold, H.
Steiner and C. Haass (2003). "Reconstitution of gamma-secretase
activity." Nat Cell Biol 5(5): 486-8; Kimberly, W. T., M. J.
LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe and D. J. Selkoe
(2003). "Gamma-secretase is a membrane protein complex comprised of
presenilin, nicastrin, Aph-1, and Pen-2." Proc Natl Acad Sci USA
100(11): 6382-7). Much evidence indicates that PS comprises the
catalytic moiety of the complex, while the other identified
subunits are necessary for proper maturation and sub-cellular
localization of the active enzyme complex (reviewed in De Strooper,
B. (2003). "Aph-1, Pen-2, and Nicastrin with Presenilin generate an
active gamma-Secretase complex." Neuron 38(1): 9-12.) Consistent
with this hypothesis: PS knock-out mice exhibit significant
reductions in .beta.-amyloid production (De Strooper, B., P.
Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K.
Von Figura and F. Van Leuven (1998). "Deficiency of presenilin-1
inhibits the normal cleavage of amyloid precursor protein." Nature
391(6665): 387-90; Haass, C. and D. J. Selkoe (1998). "Alzheimer's
disease. A technical KO of amyloid-beta peptide." Nature 391(6665):
339-40; Herreman, A., L. Serneels, W. Annaert, D. Collen, L.
Schoonjans and B. De Strooper (2000). "Total inactivation of
gamma-secretase activity in presenilin-deficient embryonic stem
cells." Nat Cell Biol 2(7): 461-2); point mutations of putative
active site aspartate residues in PS trans-membrane domains inhibit
.beta.-amyloid production in cells in a dominant negative fashion
(Wolfe, M. S., W. Xia, B. L. Ostaszewski, T. S. Diehl, W. T.
Kimberly and D. J. Selkoe (1999). "Two transmembrane aspartates in
presenilin-1 required for presenilin endoproteolysis and
gamma-secretase activity." Nature 398(6727): 513-7; Kimberly, W.
T., W. Xia, T. Rahmati, M. S. Wolfe and D. J. Selkoe (2000). "The
transmembrane aspartates in presenilin 1 and 2 are obligatory for
gamma-secretase activity and amyloid beta-protein generation." J
Biol Chem 275(5): 3173-8); active site directed substrate-based
transition state isosteres designed to inhibit gamma secretase
directly conjugate to PS (Esler, W. P., W. T. Kimberly, B. L.
Ostaszewski, T. S. Diehl, C. L. Moore, J. Y. Tsai, T. Rahmati, W.
Xia, D. J. Selkoe and M. S. Wolfe (2000). "Transition-state
analogue inhibitors of gamma-secretase bind directly to
presenilin-i." Nat Cell Biol 2(7): 428-34; Li, Y. M., M. Xu, M. T.
Lai, Q. Huang, J. L. Castro, J. DiMuzio-Mower, T. Harrison, C.
Lellis, A. Nadin, J. G. Neduvelil et al. (2000). "Photoactivated
gamma-secretase inhibitors directed to the active site covalently
label presenilin 1." Nature 405(6787): 689-94); finally, allosteric
gamma secretase inhibitors have likewise been demonstrated to bind
directly to PS (Seiffert, D., J. D. Bradley, C. M. Rominger, D. H.
Rominger, F. Yang, J. E. Meredith, Jr., Q. Wang, A. H. Roach, L. A.
Thompson, S. M. Spitz et al. (2000). "Presenilin-1 and -2 are
molecular targets for gamma-secretase inhibitors." J Biol Chem
275(44): 34086-91.)
[0014] Current evidence indicates that in addition to APP
processing leading to .beta.-amyloid synthesis, gamma-secretase
also mediates the intra-membrane cleavage of other type I
transmembrane proteins (reviewed in Fortini, M. E. (2002).
"Gamma-secretase-mediated proteolysis in cell-surface-receptor
signaling." Nat Rev Mol Cell Biol 3(9): 673-84, see also Struhl, G.
and A. Adachi (2000). "Requirements for presenilin-dependent
cleavage of notch and other transmembrane proteins." Mol Cell 6(3):
625-36.) Noteworthy among the known substrates of gamma-secretase
is mammalian Notch 1. The Notch 1 protein is important for cell
fate determination during development, and tissue homeostasis in
the adult. Upon ligand engagement via the Notch ecto-domain, Notch
undergoes sequential extra-cellular and intra-membrane processing
analogous to APP. The intra-membrane processing of Notch mediated
by gamma secretase leads to release of the Notch intracellular
domain (NICD). The NICD fragment mediates Notch signaling via
translocation to the nucleus, where it regulates expression of
genes mediating cellular differentiation in many tissues during
development, as well as in the adult.
[0015] Disruption of Notch signaling via genetic knock-out (KO)
results in embryonic lethal phenotype in mice (Swiatek, P. J., C.
E. Lindsell, F. F. del Amo, G. Weinmaster and T. Gridley (1994).
"Notch1 is essential for postimplantation development in mice."
Genes Dev 8(6): 707-19; Conlon, R. A., A. G. Reaume and J. Rossant
(1995). "Notch1 is required for the coordinate segmentation of
somites." Development 121(5): 1533-45.) The Notch KO phenotype is
very similar to the phenotype observed PS1 KO mice, and precisely
reproduced by PS1/PS2 double KO mice (De Strooper et al. (1998).
"Deficiency of presenilin-1 inhibits the normal cleavage of amyloid
precursor protein." Nature 391(6665): 387-90; Donoviel, D. B., A.
K. Hadjantonakis, M. Ikeda, H. Zheng, P. S. Hyslop and A. Bernstein
(1999). "Mice lacking both presenilin genes exhibit early embryonic
patterning defects." Genes Dev 13(21): 2801-10; Herreman, A., L.
Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper
(2000). "Total inactivation of gamma-secretase activity in
presenilin-deficient embryonic stem cells." Nat Cell Biol 2(7):
461-2.) This convergence of phenotypes observed in knock-out mice
of either the substrate (Notch) or the enzyme (PS) suggests that
inhibitors of gamma secretase that also inhibit Notch function may
be limited as therapeutic agents owing to the importance of Notch
function in adult tissues (Fortini, M. E. (2002).
"Gamma-secretase-mediated proteolysis in cell-surface-receptor
signaling." Nat Rev Mol Cell Biol 3(9): 673-84.) As APP knock-out
mice develop normally and without an overt phenotype Zheng, H., M.
Jiang, M. E. Trumbauer, R. Hopkins, D. J. Sirinathsinghji, K. A.
Stevens, M. W. Conner, H. H. Slunt, S. S. Sisodia, H. Y. Chen et
al. (1996). "Mice deficient for the amyloid precursor protein
gene." Ann N Y Aced Sci 777: 421-6; Zheng, H., M. Jiang, M. E.
Trumbauer, D. J. Sirinathsinghji, R. Hopkins, D. W. Smith, R. P.
Heavens, G. R. Dawson, S. Boyce, M. W. Conner et al. (1995).
"beta-Amyloid precursor protein-deficient mice show reactive
gliosis and decreased locomotor activity." Cell 81(4): 525-31, the
cumulative evidence, therefore, suggests that preferred gamma
secretase inhibitors would have selectivity for inhibiting gamma
secretase processing of APP over gamma secretase processing of
Notch.
SUMMARY OF THE INVENTION
[0016] In a broad aspect, the invention provides compounds of
Formula I:
##STR00002##
[0017] including stereoisomers, tautomers, mixtures of
stereoisomers and/or tautomers, or pharmaceutically acceptable
salts thereof
[0018] wherein
[0019] the A-ring is aryl, cycloalkyl, heteroaryl or
heterocycloalkyl, where each ring is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11;
[0020] R.sub.1 and R.sub.2 combine to form a [3.3.1] or a [3.2.1]
ring system, where the nitrogen is attached to the two bridgehead
carbons, where 0 or 1 of the carbons in the ring system is
optionally replaced with an --O--, --S(O).sub.x--, or --NR.sub.15--
group; where x is 0, 1 or 2; and where the [3.3.1] or [3.2.1] ring
system is optionally substituted with 1, 2, 3, or 4 groups that are
independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.4 alkyl)-O--, --S--(C.sub.1-C.sub.4 alkyl)-S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13;
[0021] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with an aryl, where the aryl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0022] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0023] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-aryl, where the aryl is optionally substituted with 1 to
5 groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2;
[0024] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2;
[0025] R.sub.15 is hydrogen, aryl, heteroaryl, --SO.sub.2R',
--C(O)R', --C(O)OR', or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl groups
are optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and
[0026] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
[0027] The compounds of Formula I inhibit .beta.-amyloid peptide
release and/or its synthesis and, therefore, are useful in the
prevention of Alzheimer's Disease (AD) in patients susceptible to
AD and/or in the treatment of patients with AD in order to inhibit
further deterioration in their condition. The invention also,
encompasses pharmaceutical compositions containing the compounds of
Formula I, and methods employing such compounds or compositions in
the treatment of cognitive diseases, including Alzheimer's
disease.
[0028] The invention also provides a method of treating a patient
who has, or in preventing a patient from getting, a disease or
condition selected from the group consisting of Alzheimer's
disease, for helping prevent or delay the onset of Alzheimer's
disease, for treating patients with mild cognitive impairment (MCI)
and preventing or delaying the onset of Alzheimer's disease in
those who would progress from MCI to AD, for treating Down's
syndrome, for treating humans who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type, for treating
cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, age related macular degeneration or diffuse Lewy body
type of Alzheimer's disease and who is in need of such treatment
which comprises administration of a therapeutically effective
amount of a compound of Formula I.
[0029] In another aspect, the invention provides methods of
preparing the compounds of interest, as well as intermediates
useful in preparing the compounds of interest.
DETAILED DESCRIPTION OF THE. INVENTION
[0030] As described above, the invention provides for compounds
according to Formula I.
[0031] In one aspect, the A-ring is phenyl, C.sub.3-C.sub.8
cycloalkyl, heteroaryl that is pyridyl, pyrimidyl, pyridazinyl,
pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, or
heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where
each of the above rings is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0032] In another aspect, the invention provides a compound of
Formula II, i.e., a compound of Formula I with the formula:
##STR00003##
[0033] where 0 or 1 of the carbons in the [3.2.1] ring system is
optionally replaced with an --O--, --S(O).sub.x--, or --NR.sub.15--
group;
[0034] x is 0, 1 or 2
[0035] the [3.2.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O--(C.sub.1-C.sub.4 alkyl)-O--, --S--(C.sub.1-C.sub.4
alkyl)-S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13;
[0036] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with an aryl, where the aryl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0037] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0038] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0039] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy; haloalkyl, haloalkoxy, CN or
NO.sub.2;
[0040] R.sub.15 is hydrogen, aryl, heteroaryl, --SO.sub.2R',
--C(O)R', --C(O)OR', or C.sub.1-C.sub.6 alkyl optionally
substituted with aryl, hydroxyl, or halogen, where the aryl groups
are optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and
[0041] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
[0042] In still another aspect, the invention provides compounds of
Formula III, i.e. compounds of Formula II having the formula:
##STR00004##
[0043] wherein
[0044] the A-ring is aryl (such as phenyl or naphthyl, preferably
phenyl), which is optionally substituted at a substitutable
position with halogen C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl,
pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl,
furanyl, thienyl, pyrrolidinyl, piperidinyl, piperazinyl,
imidazolidinyl, phenyl, or phenyl C.sub.1-C.sub.4 alkyl, or
--SO.sub.2NR.sub.10R.sub.11;
[0045] wherein 0 or 1 of the carbons in the [3.2.1] ring system is
optionally replaced with an --O--, --S(O).sub.x--, or --NR.sub.15--
group; and where the [3.2.1] ring is optionally substituted with 1,
2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.4 alkyl)-O--,
--S--(C.sub.1-C.sub.4 alkyl)-S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --OC(O)NR.sub.10R.sub.11,
--NR'C(O)OR'', --NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0046] In still another aspect, the invention provides compounds of
Formula IIIa, i.e., compounds of the Formula III having the
following formula:
##STR00005##
[0047] wherein,
[0048] 0 of the carbons in the [3.2.1] ring system are optionally
replaced with an --O--, --S(O).sub.X, or --NR.sub.15-- group;
[0049] the [3.2.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O--(C.sub.1-C.sub.4 alkyl)-O--, --S--(C.sub.1-C.sub.4
alkyl)-S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13;
[0050] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenyloxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0051] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0052] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2;
[0053] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with an phenyl, where the phenyl is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
or
[0054] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0055] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0056] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and
[0057] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy, haloalkyl
(such as CF.sub.3), haloalkoxy (such as OCF.sub.3), hydroxyl, CN,
phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl,
NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
[0058] In another aspect, the invention provides compounds of
Formula III or IIIa, wherein the [3.2.1] ring is substituted with
oxo, --O(C.sub.1-C.sub.2 alkyl)O--, or --S(C.sub.1-C.sub.2
alkyl)S--.
[0059] In another aspect the invention provides compounds of
Formula III or IIIa wherein the [3.2.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0060] In still another aspect, the invention provides compounds of
Formula III or IIIa, wherein the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0061] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0062] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0063] In yet another aspect, the invention provides compounds of
Formula III or IIIa, wherein the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0064] In yet still another aspect, the invention provides
compounds of Formula III or IIIa, wherein the [3.2.1] ring is
substituted with .dbd.N--O--R.sub.13; where R.sub.13 is
hydrogen.
[0065] In yet still another aspect, the invention provides
compounds of Formula III or IIIa, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
.dbd.N--O--R.sub.13; where R.sub.13 is C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 3 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0066] In yet still another aspect, the invention provides
compounds of Formula III or IIIa, wherein the [3.2.1] ring is not
substituted.
[0067] In yet another aspect, the invention provides compounds of
Formula III or IIIa, wherein the [3.2.1] ring is substituted with
aryl or heteroaryl, such as phenyl or pyridyl, both aryl and
heteroaryl are optionally substituted with halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0068] In yet still another aspect, the invention provides
compounds of Formula III or IIIa, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.2-C.sub.6 alkenyl.
[0069] In yet another aspect, the invention provides compounds of
Formula III or IIIa, wherein the [3.2.1] ring is substituted with 1
or 2 groups, at least one of which is hydroxyl or C.sub.1-C.sub.6
alkoxy.
[0070] In yet still another aspect, the invention provides
compounds of Formula III, wherein, 1 of the carbons in the [3.2.1]
ring system is optionally replaced with an --O--, --S(O).sub.x--,
or --NR.sub.15-- group, where R.sub.15 is hydrogen, C.sub.1-C.sub.6
alkyl optionally substituted with phenyl, hydroxyl, or halogen, or
phenyl, where the phenyl groups are optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2, and where x
is 0, 1 or 2.
[0071] In another aspect, the invention provides compounds of
Formula IIIb, i.e., compounds of Formula III having the following
formula:
##STR00006##
[0072] wherein
[0073] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0074] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0075] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2;
[0076] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0077] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0078] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0079] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2;
[0080] R.sub.15 is H, phenyl, pyridyl, pyrimidinyl, oxazolyl,
thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl,
imidazolidinyl, indolyl, --SO.sub.2R', --C(O)R', --C(O)OR', or
C.sub.1-C.sub.6 alkyl optionally substituted with phenyl, hydroxyl,
or halogen, where the cyclic groups are optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl (such as CF.sub.3), C.sub.1-C.sub.4 haloalkoxy (such as
OCF.sub.3), amino, NH(C.sub.1-C.sub.4 alkyl), N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), CN or NO.sub.2; and
[0081] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkanoyl,
pyridyl, phenyl, NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
[0082] In yet another aspect, the invention provides compounds of
Formula IIIb, wherein R.sub.15 is hydrogen.
[0083] In still another aspect, the invention provides compounds of
Formula IIIb, wherein R.sub.15 is C.sub.1-C.sub.6 alkyl.
[0084] In yet still another aspect, the invention provides
compounds of Formula IIIb, wherein R.sub.15 is C.sub.1-C.sub.6
alkyl substituted with phenyl, hydroxyl, or halogen, where the
phenyl groups are optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2.
[0085] In still yet another aspect, the invention provides
compounds of Formula IIIb, wherein R.sub.15 is phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0086] In another aspect, the invention provides compounds of
Formula III or IIIa, wherein the [3.2.1] ring is substituted with
oxo, --O(C.sub.1-C.sub.2 alkyl)O--, or --S(C.sub.1-C.sub.2
alkyl)S--.
[0087] In another aspect, the invention provides compounds of
Formula IIIc, i.e., compounds of Formula III having the following
formula:
##STR00007##
[0088] wherein
[0089] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0090] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0091] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2;
[0092] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0093] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0094] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0095] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and
[0096] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11,
[0097] In another aspect, the invention provides compounds of
Formula IIId, i.e., compounds of Formula III having the following
formula:
##STR00008##
[0098] wherein
[0099] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, ON,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --S(O.sub.2)R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0100] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0101] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2;
[0102] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0103] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0104] R.sub.12 is C.sub.1-C.sub.6 alkyl or --SO.sub.2-phenyl,
where the phenyl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2;
[0105] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and
[0106] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
[0107] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein, R.sub.3 is
hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
haloalkyl, or CN;
[0108] R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, haloalkoxy, CN,
phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and
[0109] R.sub.5 is hydrogen, C.sub.1-C.sub.6 alkyl,
--SO.sub.2--NR.sub.10R.sub.11, or halogen.
[0110] In still other aspects, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein, R.sub.4 is hydrogen,
halogen (in one aspect, I, Br, F or Cl), C.sub.1-C.sub.6 alkyl
optionally substituted with halogen or hydroxyl, C.sub.1-C.sub.6
alkoxy, OCF.sub.3, or CN.
[0111] In yet another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 is phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl,
furanyl, thienyl, or phenyl.
[0112] In still another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 is
--NR.sub.10R.sub.11.
[0113] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 is
--NR.sub.10R.sub.11, and R.sub.3, R.sub.5, R.sub.6, and R.sub.7 are
H.
[0114] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.3,
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently hydrogen,
halo, CF.sub.3, CHF.sub.2 or methyl.
[0115] In yet still another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.3,
R.sub.5, R.sub.6, and R.sub.7 are hydrogen.
[0116] In yet still another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, where R.sub.4 is
halogen, such as chloro.
[0117] In yet still another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 is
chloro, and R.sub.3, R.sub.5, R.sub.6, and R.sub.7 are H.
[0118] In another aspect, the invention provides compounds of
Formulas IIIa, IIIb, IIIc, or wherein at least one of R.sub.3,
R.sub.4, or R.sub.5 is chloro, and R.sub.6 and R.sub.7 are H.
[0119] In another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.3 is hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CF.sub.3,
or CN;
[0120] R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CF.sub.3, OCF.sub.3, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.4 alkanoyl, and
[0121] R.sub.5 is hydrogen, C.sub.1-C.sub.4 alkyl,
--SO.sub.2NR.sub.10R.sub.11 or halogen.
[0122] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or Hid, wherein R.sub.4 is
halogen (in one aspect, F or Cl), C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CF.sub.3, OCF.sub.3, or CN.
[0123] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.3,
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently hydrogen,
F, CF.sub.3, CHF.sub.2 or methyl.
[0124] In another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 are hydrogen.
[0125] In yet another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 is halogen, such
as chloro.
[0126] In another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.3 is hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CF.sub.3,
or CN;
[0127] R.sub.4 is oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl,
thienyl, or phenyl; and
[0128] R.sub.5 is hydrogen, C.sub.1-C.sub.4 alkyl, --SO.sub.2
NR.sub.10R.sub.11, or halogen.
[0129] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 is
halogen (in one aspect, F or Cl), CH.sub.3, OCH.sub.3, CF.sub.3, or
OCF.sub.3.
[0130] In another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.3 is hydrogen,
halogen, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, CF.sub.3,
or CN;
[0131] R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.2 alkyl,
C.sub.1-C.sub.2 alkoxy, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.2
haloalkoxy, CN, --NR.sub.10R.sub.11, C.sub.2-C.sub.3 alkanoyl,
oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, or thienyl;
[0132] R.sub.5 is hydrogen, CH.sub.3, or F; and
[0133] R.sub.6 and R.sub.7 are independently hydrogen or
halogen.
[0134] In still yet another aspect, the invention provides
compounds of Formula IIId, wherein R.sub.4 is CF.sub.3, or
OCF.sub.3.
[0135] In yet another aspect, the invention provides compounds of
Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 and R.sub.5, or
R.sub.5 and R.sub.6 and the carbons to which they are attached form
a benzo ring which is optionally substituted with optionally
substituted with 1 or 2 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 haloalkoxy, CN or
NO.sub.2.
[0136] In still yet another aspect, the invention provides
compounds of Formula IIIa, IIIb, IIIc, or IIId, wherein R.sub.4 and
R.sub.5, or R.sub.5 and R.sub.6 and the carbons to which they are
attached form a pyridyl, pyrrolyl, thienyl, furanyl, pyrrolidinyl,
piperidinyl ring, each of which is optionally substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, or C.sub.1-C.sub.4 alkanoyl
wherein the alkanoyl group is optionally substituted with up to 3
halogen atoms (such as F).
[0137] In one aspect, the invention provides compounds of Formula
IIIa, IIIb, IIIc, or IIId, wherein R.sub.6 and R.sub.7 are
independently hydrogen or methyl.
[0138] In one aspect, the invention provides compounds of Formula
IIIa, IIIb, IIIc, or IIId, wherein R.sub.3 and R.sub.5 are
independently hydrogen, halo, or methyl.
[0139] In another aspect, the invention provides compounds of
Formula IV, i.e., compounds of Formula II, wherein the A-ring is
C.sub.3-C.sub.8 cycloalkyl, which is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, phenyl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0140] In yet another aspect, the invention provides compounds of
Formula IV wherein
[0141] 0 or 1 of the carbons in the [3.2.1] ring system is
optionally replaced with an --O--, --S(O).sub.x, or --NR.sub.15--
group; where R.sub.15 is hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, or phenyl, where the
phenyl groups are optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2, where x is 0, 1 or 2 and
[0142] where the [3.2.1] ring system is optionally substituted with
1, 2, 3, or 4 groups that are independently oxo, halogen,
C.sub.1-C.sub.6 alkyl, --O(C.sub.1-C.sub.2 alkyl)O--,
--S(C.sub.1-C.sub.2 alkyl)S--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0143] In yet another aspect, the invention provides compounds of
Formula IVa, i.e. compounds of Formula IV having the formula:
##STR00009##
[0144] wherein no carbons in the ring system are replaced with an
--O--, --S(O).sub.x--, or --NR.sub.15-- group, and
[0145] where the [3.2.1] ring is optionally substituted 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0146] In still yet another aspect, the invention provides
compounds of Formula IV or IVa, where the [3.2.1] ring is
substituted with oxo, --O(C.sub.1-C.sub.2alkyl)O--, or
--S(C.sub.1-C.sub.2 alkyl)S--.
[0147] In another aspect the invention provides compounds of
Formula IV or IVa wherein the [3.2.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0148] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0149] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0150] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0151] In yet still another aspect, the invention provides
compounds of Formula IV or IVa, where the [3.2.1] ring is
substituted with .dbd.N--NR.sub.12, where R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or --SO.sub.2-phenyl, where the phenyl is
optionally substituted with 1 to 4 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0152] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with
.dbd.N--O--R.sub.13; where R.sub.13 is hydrogen.
[0153] In still yet another aspect, the invention provides
compounds of Formula IV or IVa, where the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
.dbd.N--O--R.sub.13; where R.sub.13 is C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 3 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0154] In another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is not substituted.
[0155] In yet another aspect, the invention provides compounds of
Formula IV or IVa, wherein the [3.2.1] ring is substituted with
aryl or heteroaryl, such as phenyl or pyridyl, both aryl and
heteroaryl are optionally substituted with halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0156] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is C.sub.2-C.sub.6 alkenyl.
[0157] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is C.sub.1-C.sub.6 alkyl.
[0158] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is phenyl.
[0159] In still another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is oxo.
[0160] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is arylalkyl; more preferably,
aryl(C.sub.1-C.sub.4)alkyl; still more preferably,
phenyl(C.sub.1-C.sub.4)alkyl; yet still more preferably,
benzyl.
[0161] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is hydroxyl or C.sub.1-C.sub.6
alkoxy.
[0162] In yet another aspect, the invention provides compounds of
Formula IVa1, i.e. compounds of Formula IV wherein,
[0163] one carbon of the [3.2.1] ring system is replaced with an
--O--, --S(O).sub.x--, or --NR.sub.15-- group, where x is 0, 1 or
2;
[0164] the [3.2.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--NR'COR'', CN, .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; and
[0165] R.sub.15 is H, phenyl, pyridyl, pyrimidinyl, oxazolyl,
thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl,
imidazolidinyl, indolyl, --SO.sub.2R', --C(O)R', --C(O)OR', or
C.sub.1-C.sub.6 alkyl optionally substituted with phenyl, hydroxyl,
or halogen, where the above cyclic groups are optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkyl (such as CF.sub.3), C.sub.1-C.sub.4
haloalkoxy (such as OCF.sub.3), CN, amino, NH(C.sub.1-C.sub.6
alkyl), N(C.sub.1-C.sub.6 alkyl) (C.sub.1-C.sub.6 alkyl), or
NO.sub.2.
[0166] In yet another aspect, the invention provides compounds of
Formula IVb, i.e., compounds of Formula IV having the following
formula:
##STR00010##
[0167] In another aspect, the invention provides compounds of
Formula IVb, wherein R.sub.15 is hydrogen.
[0168] In yet another aspect, the invention provides compounds of
Formula IVb, wherein R.sub.15 is C.sub.1-C.sub.6 alkyl.
[0169] In yet another aspect, the invention provides compounds of
Formula IVb, wherein R.sub.15 is C.sub.1-C.sub.6 alkyl substituted
with phenyl, hydroxyl, or halogen, where the phenyl groups are
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl (such as CF.sub.3), C.sub.1-C.sub.4
haloalkoxy (such as OCF.sub.3), CN or NO.sub.2.
[0170] In yet another aspect, the invention provides compounds of
Formula IVb, wherein R.sub.15 is phenyl optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl (such as CF.sub.3), C.sub.1-C.sub.4 haloalkoxy (such as
OCF.sub.3), CN or NO.sub.2.
[0171] In still another aspect, the invention provides compounds of
Formula IVb, wherein R.sub.15 is C.sub.1-C.sub.6 alkyl substituted
with hydroxyl or halogen.
[0172] In yet another aspect, the invention provides compounds of
Formula IVc, i.e., compounds of Formula IV having the following
formula:
##STR00011##
where the [3.2.1] ring is optionally substituted 1, 2, or 3 groups
that are independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0173] In yet another aspect, the invention provides compounds of
Formula IVd, i.e., compounds of Formula IV having the following
formula:
##STR00012##
where the [3.2.1] ring is optionally substituted 1, 2, or 3 groups
that are independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0174] In yet another aspect, the invention provides compounds of
Formula IV, IVa, IVb, IVc, or IVd, wherein the C.sub.3-C.sub.8
cycloalkyl group is cyclopropyl.
[0175] In still yet another aspect, the invention provides
compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the
C.sub.3-C.sub.8 cycloalkyl group is cyclobutyl.
[0176] In yet still another aspect, the invention provides
compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the
C.sub.3-C.sub.8 cycloalkyl group is cyclopentyl.
[0177] In another aspect, the invention provides compounds of
Formula IV, IVa, IVb, IVc, or IVd, wherein the C.sub.3-C.sub.8
cycloalkyl group is cyclohexyl.
[0178] In yet still another aspect, the invention provides
compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the
C.sub.3-C.sub.8 cycloalkyl group is cycloheptyl.
[0179] In still yet another aspect, the invention provides
compounds of Formula IV, IVa, IVb, IVc, or IVd, wherein the
C.sub.3-C.sub.8 cycloalkyl group is cyclooctyl.
[0180] In another aspect, the invention provides compounds of
Formula V, i.e. compounds of Formula II, wherein the A-ring is
heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which
is optionally substituted at one or more substitutable positions
with groups that are independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6-alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0181] In still another aspect, the invention provides compounds of
Formula Va, i.e. compounds of Formula V having the following
formula:
##STR00013##
[0182] wherein:
[0183] the A-ring is heteroaryl that is pyridyl, pyrimidyl,
pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or
imidazolyl, each of which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, haloalkyl, haloalkoxy, hydroxyl,
hydroxyalkyl, CN, phenoxy, --S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl,
C.sub.0-C.sub.3alkylCO.sub.2R', oxazolyl, pyrazolyl, thiazolyl,
pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl,
pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, phenyl, or
phenyl C.sub.1-C.sub.4 alkyl; or --SO.sub.2NR.sub.10R.sub.11;
[0184] zero of the carbons in the [3.2.1] ring system is replaced
with an --O--, --S(O).sub.x--, or --NR.sub.15-- group; and
[0185] the [3.2.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--NR'COR'', CN, .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0186] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with oxo,
--O(C.sub.1-C.sub.2 alkyl)O--, or --S(C.sub.1-C.sub.2
alkyl)S--.
[0187] In another aspect the invention provides compounds of
Formula V or Va wherein the [3.2.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0188] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0189] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0190] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
O.sub.1--C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0191] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0192] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with
.dbd.N--O--R.sub.13; where R.sub.13 is hydrogen.
[0193] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is .dbd.N--O--R.sub.13; where
R.sub.13 is C.sub.1-C.sub.6 optionally substituted with phenyl,
hydroxyl, or halogen, where the phenyl is optionally substituted
with 1 to 3 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
CN or NO.sub.2.
[0194] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is not substituted.
[0195] In yet another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with aryl
or heteroaryl, such as phenyl or pyridyl, both aryl and heteroaryl
optionally substituted with halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0196] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is C.sub.2-C.sub.6 alkenyl.
[0197] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is phenyl.
[0198] In yet another aspect, the invention provides compounds of
Formula IV or IVa, where the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is arylalkyl; more preferably,
aryl(C.sub.1-C.sub.4)alkyl; still more preferably,
phenyl(C.sub.1-C.sub.4)alkyl; yet still more preferably,
benzyl.
[0199] In still another aspect, the invention provides compounds of
Formula V or Va, wherein the [3.2.1] ring is substituted with 1 or
2 groups, at least one of which is hydroxyl or C.sub.1-C.sub.6
alkoxy.
[0200] In still another aspect, the invention provides compounds of
Formula V, wherein
[0201] one carbon of the [3.2.1] ring system is replaced with an
--O--, --S(O).sub.x--, or --NR.sub.15-- group;
[0202] x is 0, 1 or 2;
[0203] the [3.2.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; and
[0204] R.sub.15 is hydrogen, phenyl, pyridyl, pyrimidinyl,
oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl,
pyrrolidinyl, imidazolidinyl, indolyl, --SO.sub.2R', --C(O)R',
--C(O)OR', or C.sub.1-C.sub.6 alkyl optionally substituted with
phenyl, hydroxyl, or halogen, where the aryl, heteroaryl, or
heterocycloalkyl groups are optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2.
[0205] In still yet another aspect, the invention provides
compounds of Formula Vb, i.e., compounds of Formula V having the
following formula:
##STR00014##
[0206] In another aspect, the invention provides compounds of
Formula Vb wherein R.sub.15 is hydrogen.
[0207] In still yet another aspect, the invention provides
compounds of Formula Vb, wherein R.sub.15 is C.sub.1-C.sub.6
alkyl.
[0208] In still another aspect, the invention provides compounds of
Formula Vb, wherein R.sub.15 is C.sub.1-C.sub.6 alkyl substituted
with phenyl, hydroxyl, or halogen, where the phenyl groups are
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0209] In still yet another aspect, the invention provides
compounds of Formula Vb, wherein R.sub.15 is phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0210] In still yet another aspect, the invention provides
compounds of Formula Vc, i.e., compounds of Formula V having the
following formula:
##STR00015##
[0211] In still yet another aspect, the invention provides
compounds of Formula Vd, i.e., compounds of Formula V having the
following formula:
##STR00016##
[0212] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is pyridyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyridyl
is substituted with halogen, for example chloro.
[0213] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is pyrimidyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrimidyl
is substituted with halogen, for example chloro.
[0214] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is pyridazinyl, which is optionally substituted at one or
more substitutable positions with groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6
alkyl), --NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl,
phenyl, or --SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and
R.sub.11 is independently H or C.sub.1-C.sub.6 alkyl. In some
aspects pyridazinyl is substituted with halogen, for example
chloro.
[0215] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is pyrazinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyazinyl
is substituted with halogen, for example chloro.
[0216] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is thienyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects thienyl
is substituted with halogen, for example chloro.
[0217] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is furanyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects furanyl
is substituted with halogen, for example chloro.
[0218] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is pyrrolyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrrolyl
is substituted with halogen, for example chloro.
[0219] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is pyrazolyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrazotyl
is substituted with halogen, for example chloro.
[0220] In still yet another aspect, the invention provides
compounds of Formula V, Va, Vb, Vc or Vd, wherein the heteroaryl
group is imidazolyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects
imidazolyl is substituted with halogen, for example chloro.
[0221] In another aspect, the invention provides compounds of
Formula VI, i.e., compounds of Formula II, wherein the A-ring is
heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where
each of the above rings is optionally substituted at a
substitutable position halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0222] In another aspect, the invention provides compounds of
Formula VIa, i.e. compounds of Formula VI having the formula:
##STR00017##
[0223] wherein zero of the carbons in the [3.2.1] ring system is
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group, and
wherein the [3.2.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13,
[0224] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with
oxo, --O(C.sub.1-C.sub.2 alkyl)O--, or --S(C.sub.1-C.sub.2
alkyl)S--.
[0225] In another aspect the invention provides compounds of
Formula VI or VIa wherein the [3.2.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0226] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0227] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0228] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0229] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0230] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with
.dbd.N--O--R.sub.13; where R.sub.13 is hydrogen.
[0231] In still another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with 1
or 2 groups, at least one of which is .dbd.N--O--R.sub.13; where
R.sub.13 is C.sub.1-C.sub.6 optionally substituted with phenyl,
hydroxyl, or halogen, where the phenyl is optionally substituted
with 1 to 3 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
CN or NO.sub.2.
[0232] In yet another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is not substituted.
[0233] In yet another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with
aryl or heteroaryl, such as phenyl or pyridyl, both aryl and
heteroaryl optionally substituted with halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 1-C.sub.4 haloalkyl,
1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0234] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with 1
or 2 groups, at least one of which is C.sub.2-C.sub.6 alkenyl.
[0235] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein the [3.2.1] ring is substituted with 1
or 2 groups, at least one of which is hydroxyl or C.sub.1-C.sub.6
alkoxy.
[0236] In another aspect, the invention provides compounds of
Formula VI or VIa, wherein one carbon of the [3.2.1] ring system is
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group;
wherein,
[0237] x is 0, 1 or 2
[0238] the [3.2.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13, and
[0239] R.sub.15 is hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, or phenyl, where the
phenyl groups are optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2.
[0240] In yet another aspect, the invention provides compounds of
Formula VIb, i.e., compounds of Formula VI having the following
formula:
##STR00018##
[0241] In another aspect, the invention provides compounds of
Formula VIb, where R.sub.15 is hydrogen.
[0242] In another aspect, the invention provides compounds of
Formula VIb, where R.sub.15 is C.sub.1-C.sub.6 alkyl.
[0243] In another aspect, the invention provides compounds of
Formula VIb, where R.sub.15 is C.sub.1-C.sub.6 alkyl substituted
with phenyl, hydroxyl, or halogen, where the phenyl groups are
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0244] In another aspect, the invention provides compounds of
Formula VIb, where R.sub.15 is phenyl optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2. In yet
another aspect, the invention provides compounds of Formula VIc,
i.e., compounds of Formula VI having the following formula:
##STR00019##
[0245] In yet another aspect, the invention provides compounds of
Formula VId, i.e., compounds of Formula VI having the following
formula:
##STR00020##
[0246] In another aspect, the invention provides compounds of
Formula VI, VIa, VIb, VIc or VId, where the heterocycloalkyl group
is pyrrolidinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11 where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0247] In another aspect, the invention provides compounds of
Formula VI, VIa, VIb, VIc or VId, where the heterocycloalkyl group
is piperidinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11 where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0248] In another aspect, the invention provides compounds of
Formula VI, VIa, VIb, VIc or VId, where the heterocycloalkyl group
is piperazinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11 where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0249] In another aspect, the invention provides compounds of
Formula VI, VIa, VIb, VIc or VId, where the heterocycloalkyl group
is morpholinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11 where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0250] In another aspect, the invention provides compounds of
Formula VI, VIa, VIb, VIc or VId, where the heterocycloalkyl group
is thiomorpholinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11 where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0251] In another aspect, the invention provides compounds of
Formula VI, VIa, VIb, VIc or VId, where the heterocycloalkyl group
is thiomorpholinyl-S,S-dioxide, which is optionally substituted at
one or more substitutable positions with groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3, OCF.sub.3, hydroxyl, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11 where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0252] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with oxo, --O(C.sub.1-C.sub.2 alkyl)O--, or
--S(C.sub.1-C.sub.2 alkyl)S--.
[0253] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with --O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0254] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13;
where
[0255] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0256] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0257] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with .dbd.N--NR.sub.12, where R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or --SO.sub.2-phenyl, where the phenyl is
optionally substituted with 1 to 4 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0258] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with .dbd.N--O--R.sub.13; where R.sub.13 is
hydrogen.
[0259] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
.dbd.N--O--R.sub.13; where R.sub.13 is C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 3 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0260] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is not
substituted.
[0261] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with aryl or heteroaryl, such as phenyl or pyridyl,
both aryl and heteroaryl are optionally substituted with halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0262] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.2-C.sub.6 alkenyl.
[0263] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.1-C.sub.6 alkyl.
[0264] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is
phenyl.
[0265] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is oxo.
[0266] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is arylalkyl;
more preferably, aryl(C.sub.1-C.sub.4)alkyl; still more preferably,
phenyl(C.sub.1-C.sub.4)alkyl; yet still more preferably,
benzyl.
[0267] In another aspect, the invention provides compounds
according to any one of Formulas IIIb, IIIc, IIId, IVb, IVc, IVd,
Vb, Vc, Vd, VIb, VIc, or VId, wherein the [3.2.1] ring is
substituted with 1 or 2 groups, at least one of which is hydroxyl
or C.sub.1-C.sub.6 alkoxy.
[0268] In another aspect, the invention provides compounds of
Formula VII, i.e., compounds of Formula I, having the following
formula:
##STR00021##
[0269] 0 or 1 of the carbons in the [3.3.1] ring system is
optionally replaced with an --O--, --S(O).sub.x--, or --NR.sub.15--
group
[0270] x is 0, 1 or 2;
[0271] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13;
[0272] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0273] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0274] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; [0275] R.sub.13 is H
or C.sub.1-C.sub.6 alkyl optionally substituted with aryl (such as
phenyl or naphthyl, more preferably, phenyl), hydroxyl, or halogen,
where the aryl is optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2 [0276] R' and R'' are independently of
each other hydrogen, C.sub.1-C.sub.6 alkyl, haloalkyl,
C.sub.2-C.sub.6 alkenyl or phenyl optionally substituted with 1 to
5 groups that are independently halogen, C.sub.1-C.sub.6 alkyl,
--C(O)OR', C.sub.1-C.sub.6 alkoxy, haloalkyl (such as CF.sub.3),
haloalkoxy (such as OCF.sub.3), hydroxyl, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11; and
[0277] R.sub.15 is H, phenyl, pyridyl, pyrimidinyl, oxazolyl,
thiazolyl, imidazolyl, thienyl, furanyl, pyrrolyl, piperidinyl,
piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, quinolinyl,
--SO.sub.2R', --C(O)R'. --C(O)OR', or C.sub.1-C.sub.6 alkyl
optionally substituted with phenyl, hydroxyl, or halogen, where the
above cyclic groups are optionally substituted with 1 to 5 groups
that are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl (such as CF.sub.3
or CH.sub.2CF.sub.3), C.sub.1-C.sub.4 haloalkoxy (such as OCF.sub.3
or OCH.sub.2CF.sub.3), CN, amino, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl) (C.sub.1-C.sub.6 alkyl) or NO.sub.2.
[0278] In another aspect, the invention provides compounds of
Formula VIII, i.e. compounds VII where the A-ring is phenyl or
naphthyl (preferably phenyl), which is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R', pyridyl,
thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl,
phenyl, phenyl C.sub.1-C.sub.4 alkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0279] In another aspect, the invention provides compounds of
Formula VIII, where
[0280] 0 or 1 of the carbons in the ring system is optionally
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group,
and
[0281] the [3.3.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0282] In another aspect, the invention provides compounds of
Formula VIIIa, i.e., compounds of Formula VIII having the following
formula:
##STR00022##
[0283] wherein,
[0284] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13;
[0285] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0286] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0287] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0288] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0289] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0290] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0291] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and
[0292] R' and R'' are independently of each other hydrogen,
C.sub.1-C.sub.6 alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl
optionally substituted with 1 to 5 groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl (such as CF.sub.3), haloalkoxy (such as OCF.sub.3),
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl,
NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
[0293] In yet still another aspect, the invention provides
compounds of Formula VIII or VIIIa, wherein the [3.3.1] ring is
substituted with oxo, --O(C.sub.1-C.sub.2 alkyl)O--, or
--S(C.sub.1-C.sub.2 alkyl).
[0294] In another aspect the invention provides compounds of
Formula VIII or VIIIa wherein the [3.3.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0295] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein, the [3.3.1] ring is substituted
with .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0296] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0297] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0298] In another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein the [3.3.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-- phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0299] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein the [3.3.1] ring is substituted with
.dbd.N--O--R.sub.13; where R.sub.13 is hydrogen.
[0300] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein the [3.3.1] ring is substituted with
1 or 2 groups, at least one of which is .dbd.N--O--R.sub.13; where
R.sub.13 is C.sub.1-C.sub.6 optionally substituted with phenyl,
hydroxyl, or halogen, where the phenyl is optionally substituted
with 1 to 3 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
CN or NO.sub.2.
[0301] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein the [3.3.1] ring is not
substituted.
[0302] In yet another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein, the [3.2.1] ring is substituted
with aryl or heteroaryl, such as phenyl or pyridyl, both of which
are optionally substituted with halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0303] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein the [3.3.1] ring is substituted with
1 or 2 groups, at least one of which is C.sub.2-C.sub.6
alkenyl.
[0304] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein the [3.3.1] ring is substituted with
1 or 2 groups, at least one of which is hydroxyl or C.sub.1-C.sub.6
alkoxy.
[0305] In still another aspect, the invention provides compounds of
Formula VIII or VIIIa, wherein, one carbon of the [3.3.1] ring
system is replaced with an --O--, --S(O).sub.x, or --NR.sub.15--
group
[0306] x is 0, 1 or 2;
[0307] the [3.3.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; and
[0308] R.sub.15 is hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, or phenyl, where the
phenyl groups are optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2.
[0309] In still another aspect, the invention provides compounds of
Formula VIIIb, i.e., compounds of Formula VIII, having the
following formula:
##STR00023##
[0310] wherein
[0311] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --OC(O)NR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R''--OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13;
[0312] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0313] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0314] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; and
R.sub.10 and R.sub.11 at each occurrence are independently H or
C.sub.1-C.sub.6 alkyl, where the alkyl is optionally substituted
with phenyl, where the phenyl is optionally substituted with 1 to 5
groups that are independently halogen, hydroxyl, alkyl, alkoxy,
haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0315] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0316] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0317] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2;
[0318] R.sub.15 is hydrogen, phenyl, heteroaryl, --SO.sub.2R',
--C(O)R', --C(O)OR', or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl
groups are optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl,
haloalkoxy, CN or NO.sub.2; and
[0319] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkanoyl,
pyridyl, phenyl, NO.sub.2, or --SO.sub.2NR.sub.10R.sub.11.
[0320] In one aspect, the invention provides compounds of Formula
VIIIb, wherein R.sub.15 is C.sub.1-C.sub.6 alkyl substituted with
phenyl, hydroxyl, or halogen, where the phenyl groups are
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0321] In one aspect, the invention provides compounds of Formula
VIIIb, wherein R.sub.15 is phenyl optionally substituted with 1 to
5 groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0322] In still another aspect, the invention provides compounds of
Formula VIIIc, i.e., compounds of Formula VIII, having the
following formula:
##STR00024##
[0323] wherein
[0324] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13;
[0325] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl,
thienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,
phenyl, or phenyl C.sub.1-C.sub.4 alkyl; or
[0326] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0327] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0328] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0329] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0330] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0331] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and
[0332] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 --NR.sub.10R.sub.11, C.sub.1-C.sub.6
alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
[0333] In still another aspect, the invention provides compounds of
Formula VIIId, i.e., compounds of Formula VIII, having the
following formula:
##STR00025##
[0334] wherein
[0335] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13;
[0336] R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 are
independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, CN,
hydroxyl, C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.3 alkyl-OH,
--C.sub.1-C.sub.3 alkyl-alkoxy, phenoxy, --SO.sub.2R',
C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl,
pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, pyrrolidinyl,
piperidinyl, piperazinyl, imidazolidinyl, phenyl, or phenyl
C.sub.1-C.sub.4 alkyl; or
[0337] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a heterocycloalkyl or a heteroaryl
ring which is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is
optionally substituted with up to 3 halogen atoms; or
[0338] R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 and the carbons
to which they are attached form a benzo ring which is optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0339] R.sub.10 and R.sub.11 at each occurrence are independently
hydrogen or C.sub.1-C.sub.6 alkyl, where the alkyl is optionally
substituted with phenyl, where the phenyl is optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2; or
[0340] R.sub.10 and R.sub.11 together may form a 3-8 membered ring
optionally including an additional heteroatom such as N, O or
S;
[0341] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 5 groups that are independently halogen, hydroxyl, alkyl,
alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2;
[0342] R.sub.13 is hydrogen or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or
NO.sub.2; and
[0343] R' and R'' are independently hydrogen, C.sub.1-C.sub.6
alkyl, haloalkyl, C.sub.2-C.sub.6 alkenyl or phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, --C(O)OR', C.sub.1-C.sub.6 alkoxy,
haloalkyl, haloalkoxy, hydroxyl, CN, phenoxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, NO.sub.2, or
--SO.sub.2NR.sub.10R.sub.11.
[0344] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein,
R.sub.3 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, haloalkyl, or CN;
[0345] R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, haloalkoxy, CN,
phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and
[0346] R.sub.5 is hydrogen, C.sub.1-C.sub.6 alkyl,
--SO.sub.2--NR.sub.10R.sub.11, or halogen.
[0347] In still other aspects, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein, R.sub.4 is
hydrogen, halogen (in one aspect, I, Br, F or Cl), C.sub.1-C.sub.6
alkyl optionally substituted with halogen or hydroxyl,
C.sub.1-C.sub.6 alkoxy, OCF.sub.3, or CN.
[0348] In yet another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4 is
phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, oxazolyl, pyrazolyl,
thiazolyl, pyridyl, furanyl, thienyl, or phenyl.
[0349] In still another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4 is
--NR.sub.10R.sub.11.
[0350] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4
is --NR.sub.10R.sub.11, and R.sub.3, R.sub.5, R.sub.6, and R.sub.7
are H.
[0351] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein
R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
hydrogen, halo, CF.sub.3, CHF.sub.2 or methyl.
[0352] In yet still another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein
R.sub.3, R.sub.5, R.sub.6, and R.sub.7 are hydrogen.
[0353] In yet still another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, where R.sub.4
is halogen, such as chloro.
[0354] In yet still another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4
is chloro, and R.sub.3, R.sub.5, R.sub.6, and R.sub.7 are H.
[0355] In another aspect, the invention provides compounds of
Formulas VIIIa, VIIIb, VIIIc, or VIIId, wherein at least one of
R.sub.3, R.sub.4, or R.sub.5 is chloro, and R.sub.6 and R.sub.7 are
H.
[0356] In another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.3 is hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CF.sub.3,
or CN;
[0357] R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CF.sub.3, OCF.sub.3, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.4 alkanoyl, and
[0358] R.sub.5 is hydrogen, C.sub.1-C.sub.4 alkyl,
--SO.sub.2NR.sub.10R.sub.11 or halogen.
[0359] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4
is halogen (in one aspect, F or Cl), C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CF.sub.3, OCF.sub.3, or CN.
[0360] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein
R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
hydrogen, F, CF.sub.3, CHF.sub.2 or methyl.
[0361] In another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 are hydrogen.
[0362] In yet another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4 is halogen,
such as chloro.
[0363] In another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.3 is hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CF.sub.3,
or CN;
[0364] R.sub.4 is oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl,
thienyl, or phenyl; and
[0365] R.sub.5 is hydrogen, C.sub.1-C.sub.4 alkyl, --SO.sub.2
NR.sub.10R.sub.11, or halogen.
[0366] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4
is halogen (in one aspect, F or Cl), CH.sub.3, OCH.sub.3, CF.sub.3,
or OCF.sub.3.
[0367] In another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.3 is hydrogen,
halogen, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, CF.sub.3,
or CN;
[0368] R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.2 alkyl,
C.sub.1-C.sub.2 alkoxy, C.sub.1-C.sub.2 haloalkyl, C.sub.1-C.sub.2
haloalkoxy, CN, --NR.sub.10R.sub.11, C.sub.2-C.sub.3 alkanoyl,
oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, or thienyl;
[0369] R.sub.5 is hydrogen, CH.sub.3, or F; and
[0370] R.sub.6 and R.sub.7 are independently hydrogen or
halogen.
[0371] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIM, wherein R.sub.4
is CF.sub.3, or OCF.sub.3.
[0372] In yet another aspect, the invention provides compounds of
Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4 and R.sub.5,
or R.sub.5 and R.sub.6 and the carbons to which they are attached
form a benzo ring which is optionally substituted with optionally
substituted with 1 or 2 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 haloalkoxy, CN or
NO.sub.2.
[0373] In still yet another aspect, the invention provides
compounds of Formula VIIIa, VIIIb, VIIIc, or VIIId, wherein R.sub.4
and R.sub.5, or R.sub.5 and R.sub.6 and the carbons to which they
are attached form a pyridyl, pyrrolyl, thienyl, furanyl,
pyrrolidinyl, piperidinyl ring, each of which is optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.1-C.sub.4 alkanoyl wherein the alkanoyl group is optionally
substituted with up to 3 halogen atoms (such as F).
[0374] In one aspect, the invention provides compounds of Formula
VIIIb, wherein R.sub.6 and R.sub.7 are independently hydrogen or
methyl.
[0375] In one aspect, the invention provides compounds of Formula
VIIIb, wherein R.sub.3 and R.sub.5 are independently hydrogen,
halo, or methyl.
[0376] In one aspect, the invention provides compounds of Formula
IX, i.e., compounds of Formula VII, where the A-ring is
C.sub.3-C.sub.8 cycloalkyl, which is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0377] In one aspect, the invention provides compounds of Formula
IXa, i.e., compounds of Formula XIV having the formula:
##STR00026##
[0378] where zero of the carbons in the ring system is replaced
with an --O--, --S(O).sub.x--, or --NR.sub.15-- group, and where
the [3.3.1] ring is optionally substituted with 1, 2, 3, or 4
groups that are independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0379] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with oxo,
--O(C.sub.1-C.sub.2 alkyl)O--, or --S(C.sub.1-C.sub.2
alkyl)S--.
[0380] In another aspect the invention provides compounds of
Formula IX or IXa wherein the [3.3.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0381] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0382] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0383] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0384] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-- phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0385] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with
.dbd.N--O--R.sub.13, where R.sub.13 is hydrogen.
[0386] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is .dbd.N--O--R.sub.13; where
R.sub.13 is C.sub.1-C.sub.6 optionally substituted with phenyl,
hydroxyl, or halogen, where the phenyl is optionally substituted
with 1 to 3 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
CN or NO.sub.2.
[0387] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is not substituted.
[0388] In yet another aspect, the invention provides compounds of
Formula IX or IXa, wherein the [3.2.1] ring is substituted with
aryl or heteroaryl, such as phenyl or pyridyl, both aryl and
heteroaryl optionally substituted with halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, haloalkoxy, CN or NO.sub.2.
[0389] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is C.sub.2-C.sub.6 alkenyl.
[0390] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is C.sub.1-C.sub.6 alkyl.
[0391] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is phenyl.
[0392] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is arylalkyl. More preferably,
aryl(C.sub.1-C.sub.4)alkyl. Still more preferably,
phenyl(C.sub.1-C.sub.4)alkyl. Yet still more preferably,
benzyl.
[0393] In one aspect, the invention provides compounds of Formula
IX or IXa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is hydroxyl or C.sub.1-C.sub.6
alkoxy.
[0394] In one aspect, the invention provides compounds of Formula
IXb, i.e., compounds of Formula IX, where one carbon of the [3.3.1]
ring system is replaced with an --O--, --S(O).sub.x--, or
--NR.sub.15-- group; wherein
[0395] x is 0, 1 or 2
[0396] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12 or
.dbd.N--O--R.sub.13; and
[0397] R.sub.15 is hydrogen, aryl, heteroaryl, heterocycloalkyl,
--SO.sub.2R', --C(O)OR', or C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, where the aryl,
heteroaryl, or heterocycloalkyl groups are optionally substituted
with 1 to 5 groups that are independently halogen, hydroxyl,
alkyl-, alkoxy, haloalkyl, haloalkoxy, CN or NO.sub.2.
[0398] In another aspect, the invention provides a compound of
Formula IXb, i.e., compounds of Formula IX having the following
formula:
##STR00027##
[0399] where R.sub.15 is H, phenyl, pyridyl, pyrimidinyl, thienyl,
furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl,
imidazolidinyl, --SO.sub.2R', --C(O)R', --C(O)OR', or
C.sub.1-C.sub.6 alkyl optionally substituted with phenyl, hydroxyl,
or halogen, where the above cyclic groups are optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkyl (such as CF.sub.3), C.sub.1-C.sub.4
haloalkoxy (such as OCF.sub.3), CN, amino, NH(C.sub.1-C.sub.6
alkyl), N(C.sub.1-C.sub.6 alkyl) (C.sub.1-C.sub.6 alkyl), or
NO.sub.2.
[0400] In stilt yet another aspect, the invention provides
compounds of Formula IXb, where R.sub.15 is hydrogen.
[0401] In still another aspect, the invention provides compounds of
Formula IXb, where R.sub.15 is C.sub.1-C.sub.6 alkyl.
[0402] In still yet another aspect, the invention provides
compounds of Formula IXb, where R.sub.15 is C.sub.1-C.sub.6 alkyl
substituted with phenyl, hydroxyl, or halogen, where the phenyl
groups are optionally substituted with 1 to 5 groups that are
independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2.
[0403] In yet still another aspect, the invention provides
compounds of Formula IXb, where R.sub.15 is phenyl optionally
substituted with 1 to 5 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0404] In another aspect, the invention provides a compound of
Formula IXc, i.e., compounds of Formula IX having the following
formula:
##STR00028##
[0405] where the [33.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0406] In another aspect, the invention provides a compound of
Formula IXd, i.e., compounds of Formula IX having the following
formula:
##STR00029##
[0407] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0408] In another aspect, the invention provides compounds
according to any one of Formula IX, IXa, IXb, IXc or IXd, where the
C.sub.3-C.sub.8 cycloalkyl group is cyclopropyl.
[0409] In another aspect, the invention provides compounds
according to any one of Formula IX, IXa, IXb, IXc or IXd, where the
C.sub.3-C.sub.8 cycloalkyl group is cyclobutyl.
[0410] In another aspect, the invention provides compounds
according to any one of Formula IX, IXa, IXb, IXc or IXd, where the
C.sub.3-C.sub.8 cycloalkyl group is cyclopentyl.
[0411] In another aspect, the invention provides compounds
according to any one of Formula IX, IXa, IXb, IXc or IXd, where the
C.sub.3-C.sub.8 cycloalkyl group is cyclohexyl.
[0412] In another aspect, the invention provides compounds
according to any one of Formula IX, IXa, IXb, IXc or IXd, where the
C.sub.3-C.sub.8 cycloalkyl group is cycloheptyl.
[0413] En another aspect, the invention provides compounds
according to any one of Formula IX, IXa or IXb, where the
C.sub.3-C.sub.8 cycloalkyl group is cyclooctyl.
[0414] In another aspect, the invention provides compounds of
Formula X, i.e., compounds of Formula VII, where the A-ring is
heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which
is optionally substituted at one or more substitutable positions
with groups that are halogen, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0415] In another aspect, the invention provides compounds of
Formula Xa, i.e., compounds of Formula X having the formula:
##STR00030##
[0416] where zero of the carbons in the [3.3.1] ring system is
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group; and
where the [3.3.1] ring is optionally substituted with 1, 2, 3, or 4
groups that are independently oxo, halogen, C.sub.1-C.sub.6 alkyl,
--O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13.
[0417] In another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with oxo,
--O(C.sub.1-C.sub.2 alkyl)O--, or --S(C.sub.1-C.sub.2
alkyl)S--.
[0418] In another aspect the invention provides compounds of
Formula X or Xa wherein the [3.3.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0419] In another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; where
[0420] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or
--SO.sub.2-phenyl, where the phenyl is optionally substituted with
1 to 3 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
CN or NO.sub.2; and
[0421] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0422] In another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-- phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0423] In another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with
.dbd.N--O--R.sub.13; where R.sub.13 is hydrogen.
[0424] In yet another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is .dbd.N--O--R.sub.13; where
R.sub.13 is C.sub.1-C.sub.6 optionally substituted with phenyl,
hydroxyl, or halogen, where the phenyl is optionally substituted
with 1 to 3 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
CN or NO.sub.2.
[0425] In another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is not substituted.
[0426] In yet another aspect, the invention provides compounds of
Formula X or Xa, wherein the [3.2.1] ring is substituted with aryl
or heteroaryl, such as phenyl or pyridyl, both aryl and heteroaryl
optionally substituted with halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0427] In still another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is C.sub.2-C.sub.6 alkenyl.
[0428] In another aspect, the invention provides compounds of
Formula X or Xa, where the [3.3.1] ring is substituted with 1 or 2
groups, at least one of which is hydroxyl or C1-C6 alkoxy.
[0429] In still yet another aspect, the invention provides
compounds of Formula Xb, i.e., compounds of Formula X wherein,
[0430] one carbon of the.3.1] ring system is replaced with an
--O--, --S(O).sub.X, or --NR.sub.16-- group x is 0, 1 or 2;
[0431] the [3.3.1] ring system is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2alkyl)O--, --S(C.sub.1-C.sub.2 alkyl)S--,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy,
--C(O)OR.sub.13, --(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13,
--CONR.sub.10R.sub.11, --OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'',
--NR'S(O).sub.2R'', --OS(O).sub.2R', --NR'COR'', CN,
.dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13; and
[0432] R.sub.15 is hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, or phenyl, where the
phenyl groups are optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2.
[0433] In another aspect, the invention provides compounds of
Formula Xb, i.e., compounds of Formula X having the following
formula:
##STR00031##
[0434] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkynyl, hydroxy,
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, haloalkoxy, --C(O)OR.sub.13,
--(C.sub.1-C.sub.4 alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0435] In another aspect, the invention provides compounds of
Formula Xb where R.sub.15 is hydrogen.
[0436] In another aspect, the invention provides compounds of
Formula Xb where R.sub.15 is C.sub.1-C.sub.6 alkyl.
[0437] In another aspect, the invention provides compounds of
Formula Xb where R.sub.15 is C.sub.1-C.sub.6 alkyl substituted with
phenyl, hydroxyl, or halogen, where the phenyl groups are
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0438] In another aspect, the invention provides compounds of
Formula Xb where R.sub.15 is phenyl optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0439] In another aspect, the invention provides compounds of
Formula Xc, i.e., compounds of Formula X having the following
formula:
##STR00032##
[0440] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0441] In another aspect, the invention provides compounds of
Formula Xd, i.e., compounds of Formula X having the following
formula:
##STR00033##
[0442] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0443] In still another aspect, the invention provides compounds of
Formula X, Xa, Xb, Xc or Xd, where the heteroaryl group is pyridyl,
which is optionally substituted at one or more substitutable
positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyridyl
is substituted with halogen, for example chloro.
[0444] In still another aspect, the invention provides compounds of
Formula X, Xa, Xb, Xc or Xd, where the heteroaryl group is
pyrimidyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrimidyl
is substituted with halogen, for example chloro.
[0445] In still yet another aspect, the invention provides
compounds of Formula X, Xa, Xb, Xc or Xd, where the heteroaryl
group is pyridazinyl, which is optionally substituted at one or
more substitutable positions with groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6
alkyl), --NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl,
phenyl, or --SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and
R.sub.11 is independently H or C.sub.1-C.sub.6 alkyl. In some
aspects pyridazinyl is substituted with halogen, for example
chloro.
[0446] In yet still another aspect, the invention provides
compounds of Formula X, Xa, Xb, Xc or Xd, where the heteroaryl
group is pyrazinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrazinyl
is substituted with halogen, for example chloro.
[0447] In still yet another aspect, the invention provides
compounds of Formula X, Xa, Xb, Xc or Xd, where the heteroaryl
group is thienyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects thienyl
is substituted with halogen, for example chloro.
[0448] In still another aspect, the invention provides compounds of
Formula X, Xa, Xb, Xc or Xd, where the heteroaryl group is furanyl,
which is optionally substituted at one or more substitutable
positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects furanyl
is substituted with halogen, for example chloro.
[0449] In still another aspect, the invention provides compounds of
Formula X, Xa, Xb, Xc or Xd, where the heteroaryl group is
pyrrolyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrrolyl
is substituted with halogen, for example chloro.
[0450] In still another aspect, the invention provides compounds of
Formula X, Xa, Xb, Xc or Xd, where the heteroaryl group is
pyrazolyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects pyrazolyl
is substituted with halogen, for example chloro.
[0451] In still another aspect, the invention provides compounds of
Formula X, Xa Xb, Xc or Xd, where the heteroaryl group is
imidazolyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently H or C.sub.1-C.sub.6 alkyl. In some aspects
imidazolyl is substituted with halogen, for example chloro.
[0452] In another aspect, the invention provides compounds of
Formula XI, i.e., compounds of Formula VII where the A-ring is
heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where
each of the above rings is optionally substituted at a
substitutable position with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenoxy,
--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, C.sub.0-C.sub.3alkylCO.sub.2R',
heteroaryl, heterocycloalkyl, aryl, aralkyl, or
--SO.sub.2NR.sub.10R.sub.11.
[0453] In still yet another aspect, the invention provides
compounds of Formula XIa, i.e. compounded of Formula XI, having the
formula:
##STR00034##
[0454] wherein, zero of the carbons in the [3.3.1] ring system is
replaced with an --O--, --S(O).sub.x--, or --NR.sub.15-- group;
and
[0455] the [3.3.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0456] In still yet another aspect, the invention provides
compounds of Formula XI or XIa where the [3.3.1] ring is
substituted with oxo, --O--(C.sub.1-C.sub.2 alkyl)-O--,
--S--(C.sub.1-C.sub.2 alkyl)-S--.
[0457] In another aspect the invention provides compounds of
Formula XI or XIa wherein the [3.3.1] ring is substituted with
--O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0458] In still yet another aspect, the invention provides
compounds of Formula XI or XIa, wherein,
[0459] the [3.3.1] ring is substituted with .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13;
[0460] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0461] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0462] In still another aspect, the invention provides compounds of
Formula XI or XIa where the [3.3.1] ring is substituted with
.dbd.N--NR.sub.12, where R.sub.12 is hydrogen, C.sub.1-C.sub.6
alkyl or --SO.sub.2-- phenyl, where the phenyl is optionally
substituted with 1 to 4 groups that are independently halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, CN or NO.sub.2.
[0463] In still yet another aspect, the invention provides
compounds of Formula XI or XIa where the [3.3.1] ring is
substituted with .dbd.N--O--R.sub.13; where R.sub.13 is
hydrogen.
[0464] In still yet another aspect, the invention provides
compounds of Formula XI or XIa where the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
.dbd.N--O--R.sub.13; where R.sub.13 is C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 3 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0465] In still yet another aspect, the invention provides
compounds of Formula XI or XIa where the [3.3.1] ring is not
substituted.
[0466] In yet another aspect, the invention provides compounds of
Formula XI or Xa, wherein the [3.2.1] ring is substituted with aryl
or heteroaryl, such as phenyl or pyridyl, both aryl and heteroaryl
optionally substituted with halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0467] In still yet another aspect, the invention provides
compounds of Formula XI or XIa where the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.2-C.sub.6 alkenyl.
[0468] In still yet another aspect, the invention provides
compounds of Formula XI or XIa where the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is hydroxyl
or C.sub.1-C.sub.6 alkoxy.
[0469] In still yet another aspect, the invention provides
compounds of Formula XI where one carbon of the [3.3.1] ring system
is replaced with an --O--, --S(O).sub.x--, or --NR.sub.15--
group;
[0470] x is 0, 1 or 2
[0471] the [3.3.1] ring is optionally substituted with 1, 2, 3, or
4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13; and
[0472] R.sub.15 is hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with phenyl, hydroxyl, or halogen, or phenyl, where the
phenyl groups are optionally substituted with 1 to 5 groups that
are independently halogen, hydroxyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, CN or NO.sub.2.
[0473] In another aspect, the invention provides compounds of
Formula XIb, i.e., compounds of Formula XI having the following
formula:
##STR00035##
[0474] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0475] In still yet another aspect, the invention provides
compounds of Formula XIb, where R.sub.15 is hydrogen.
[0476] In still yet another aspect, the invention provides
compounds of Formula XIb, where R.sub.15 is C.sub.1-C.sub.6
alkyl.
[0477] In yet another aspect, the invention provides compounds of
Formula XIb, where R.sub.15 is C.sub.1-C.sub.6 alkyl substituted
with phenyl, hydroxyl, or halogen, where the phenyl groups are
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0478] In still another aspect, the invention provides compounds of
Formula XIb, where R.sub.15 is phenyl optionally substituted with 1
to 5 groups that are independently halogen, hydroxyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or NO.sub.2.
[0479] In another aspect, the invention provides compounds of
Formula XIc, i.e., compounds of Formula XI having the following
formula:
##STR00036##
[0480] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0481] In another aspect, the invention provides compounds of
Formula XId, i.e., compounds of Formula XI having the following
formula:
##STR00037##
[0482] where the [3.3.1] ring is optionally substituted with 1, 2,
3, or 4 groups that are independently oxo, halogen, C.sub.1-C.sub.6
alkyl, --O(C.sub.1-C.sub.2 alkyl)O--, --S(C.sub.1-C.sub.2
alkyl)S--, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkynyl, hydroxy, hydroxyalkyl, C.sub.1-C.sub.6
alkoxy, haloalkoxy, --C(O)OR.sub.13, --(C.sub.1-C.sub.4
alkyl)-C(O)OR.sub.13, --CONR.sub.10R.sub.11,
--OC(O)NR.sub.10R.sub.11, --NR'C(O)OR'', --NR'S(O).sub.2R'',
--OS(O).sub.2R', --NR'COR'', CN, .dbd.N--NR.sub.12, or
.dbd.N--O--R.sub.13.
[0483] In still yet another aspect, the invention provides
compounds of Formula XI, XIa or XIb, where the heterocycloalkyl
group is pyrrolidinyl, which is optionally substituted at one or
more substitutable positions with groups that are independently
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OCF.sub.3, hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6
alkyl), --NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl,
phenyl, or --SO.sub.2NR.sub.10R.sub.11'', where each R.sub.10 and
R.sub.11 is independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0484] In still yet another aspect, the invention provides
compounds of Formula XI, XIa, XIb, XIc or XId, where the
heterocycloalkyl group is piperidinyl, which is optionally
substituted at one or more substitutable positions with groups that
are independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3, OCF.sub.3, hydroxyl, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0485] In still yet another aspect, the invention provides
compounds of Formula XI, XIa, XIb, XIc or XId, where the
heterocycloalkyl group is piperazinyl, which is optionally
substituted at one or more substitutable positions with groups that
are independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3, OCF.sub.3, hydroxyl, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11'', where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0486] In still yet another aspect, the invention provides
compounds of Formula XI, XIa, XIb, XIc or XId where the
heterocycloalkyl group is morpholinyl, which is optionally
substituted at one or more substitutable positions with groups that
are independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3, OCF.sub.3, hydroxyl, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0487] In still another aspect, the invention provides compounds of
Formula XI, XIa, XIb, XIc or XId, where the heterocycloalkyl group
is thiomorpholinyl, which is optionally substituted at one or more
substitutable positions with groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3,
hydroxyl, CN, phenyloxy, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sub.10R.sub.11, C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0488] In yet another aspect, the invention provides compounds of
Formula XI, XIa, XIb, XIc or XId, where the heterocycloalkyl group
is thiomorpholinyl-S,S-dioxide, which is optionally substituted at
one or more substitutable positions with groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, CF.sub.3, OCF.sub.3, hydroxyl, CN, phenyloxy,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sub.10R.sub.11,
C.sub.1-C.sub.6 alkanoyl, pyridyl, phenyl, or
--SO.sub.2NR.sub.10R.sub.11, where each R.sub.10 and R.sub.11 is
independently hydrogen or C.sub.1-C.sub.6 alkyl.
[0489] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with oxo, --O(C.sub.1-C.sub.2 alkyl)O--, or
--S(C.sub.1-C.sub.2 alkyl)S--.
[0490] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with --O--SO.sub.2--(C.sub.1-C.sub.6 alkyl).
[0491] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with .dbd.N--NR.sub.12, or .dbd.N--O--R.sub.13;
where
[0492] R.sub.12 is hydrogen, C.sub.1-C.sub.6 alkyl or --SO.sub.2--
phenyl, where the phenyl is optionally substituted with 1 to 3
groups that are independently halogen, hydroxyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, CN or NO.sub.2;
and
[0493] R.sub.13 is hydrogen or C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 5 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0494] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with .dbd.N--NR.sub.12, where R.sub.12 is hydrogen,
C.sub.1-C.sub.6 alkyl or .dbd.SO.sub.2-phenyl, where the phenyl is
optionally substituted with 1 to 4 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0495] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with .dbd.N--O--R.sub.13; where R.sub.13 is
hydrogen.
[0496] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
.dbd.N--O--R.sub.13; where R.sub.13 is C.sub.1-C.sub.6 optionally
substituted with phenyl, hydroxyl, or halogen, where the phenyl is
optionally substituted with 1 to 3 groups that are independently
halogen, hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
CF.sub.3, OCF.sub.3, CN or NO.sub.2.
[0497] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is not
substituted.
[0498] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with aryl or heteroaryl, such as phenyl or pyridyl,
both aryl and heteroaryl are optionally substituted with halogen,
hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, CN or
NO.sub.2.
[0499] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.2-C.sub.6 alkenyl (or C.sub.2-C.sub.4 alkenyl, or C.sub.2
alkenyl).
[0500] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
C.sub.1-C.sub.6 alkyl.
[0501] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is
phenyl.
[0502] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is oxo.
[0503] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is arylalkyl;
more preferably, aryl(C.sub.1-C.sub.4)alkyl; still more preferably,
phenyl(C.sub.1-C.sub.4)alkyl; yet still more preferably,
benzyl.
[0504] In another aspect, the invention provides compounds
according to any one of Formulas VIIIb, VIIIc, VIIId, IXb, IXc,
IXd, Xb, Xc, Xd, XIb, XIc, or XId, wherein the [3.3.1] ring is
substituted with 1 or 2 groups, at least one of which is hydroxyl
or C.sub.1-C.sub.6 alkoxy.
[0505] In another aspect, the invention provides the compounds of
Formula I selected from: [0506]
9-(5-chlorothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane; [0507]
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one; [0508]
9-(4-methylphenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one; [0509]
9-(5-bromothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane; [0510]
9-(4-bromophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; [0511]
9-(4-bromo-3-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
[0512] 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; [0513]
9-(3-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; [0514]
9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
[0515] 9-(3,5-dichtorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
[0516] 9-(4-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; [0517]
9-(4-(trifluoromethoxy)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane;
[0518] 9-(4-iodophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
[0519] 8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octane; [0520]
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octane; [0521]
8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one; [0522]
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one; [0523]
8-(4-iodophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one; [0524]
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-ol; [0525]
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one oxime;
[0526]
8-(4-chlorophenylsulfonyl)-3-methylene-8-azabicyclo[3.2.1]octane;
[0527]
8-(4-bromophenylsulfonyl)-3-methylene-8-azabicyclo[3.2.1]octane;
[0528]
9-(4-chlorophenylsulfonyl)-3-methylene-9-azabicyclo[3.3.1]nonane;
[0529]
9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan--
3-one; [0530] diethyl
9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2,4-dicarboxyl-
ate; [0531] ethyl
9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2-carboxylate;
[0532]
2-bromo-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
[0533]
2-amino-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one;
[0534]
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane--
2,4-dione; [0535]
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane;
[0536]
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonan-2-one;
[0537] 8-[(4-chlorophenyl)sulfonyl-]-8-azabicyclo[3.2.1]octan-3-ol;
[0538]
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane-2,4-dio-
ne; [0539]
(2R)-2-{9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]non-
-3-yl}propan-1-01;
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane; [0540]
(2S)-2-{9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]non-3-yl}prop-
an-1-ol; [0541]
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane-3-carboxamide;
[0542]
3-acetyl-9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonan-
e; [0543]
9-(4-chloro-benzenesulfonyl)-3-pyridin-2-yl-9-aza-bicyclo[3.3.1]-
-nonane; [0544]
9-(4-chlorophenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonan-2-one;
[0545] 9-(4-chlorophenylsulfonyl)-3-oxa-9-azabicyclo[3.3.1]nonane;
[0546] 9-(4-chlorophenylsulfonyl)-3-thia-9-azabicyclo[3.3.1]nonane;
[0547] Methanesulfonic acid
9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-yl ester;
[0548] 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-ol;
[0549]
[9-(4-Chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-yl]-methyl-carbam-
ic acid tert-butyl ester
[0550]
9-(4-Chloro-benzenesulfonyl)-2-(1H-pyrrol-2-ylmethylene)-9-aza-bicy-
clo [3.3.1]nonan-3-one
[0551]
9-(4-Chloro-benzenesulfonyl)-3-oxo-9-aza-bicyclo[3.3.1]nonane-2-car-
boxylic acid ethyl ester
[0552]
N-tosyl-[9-(4-Chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-yli-
dene]-hydrazine
[0553]
2-Aminomethylene-9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]n-
onan-3-one
[0554] including steroisomers, mixtures of stereoisomers or
pharmaceutically acceptable salts thereof.
[0555] In still another aspect, the invention provides a
composition comprising a compound or salt of claim 1 and at least
one pharmaceutically acceptable solvent, adjuvant, excipient,
carrier, binder or disintegrant.
[0556] In still another aspect, the invention provides a method of
treating Alzheimer's disease comprising administering a
therapeutically effective amount of a compound or salt of Formula
Ito a patient in need of such treatment.
[0557] In another aspect, the compounds of the invention have
minimal interaction or preferably, no interaction with Notch.
DEFINITIONS
[0558] The definitions and explanations below are for the terms as
used throughout this entire document including both the
specification and the claims. Throughout the specification and the
appended claims, a given formula or name shall encompass all
isomers thereof, such as stereoisomers, geometrical isomers,
optical isomers, tautomers, and mixtures thereof where such isomers
exist, as well as pharmaceutically acceptable salts and solvates
thereof, such as for instance hydrates.
[0559] It should be noted that, as used in this specification and
the appended claims, the singular forms "a," "an," and "the"
include plural referents unless the content clearly dictates
otherwise. Thus, for example, reference to a composition containing
"a compound" includes a mixture of two or more compounds. It should
also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates
otherwise.
[0560] Where multiple substituents are indicated as being attached
to a formula, it is to be understood that the substituents can be
the same or different. Thus for example "R.sub.m optionally
substituted with 1, 2 or 3 R.sub.q groups" indicates that R.sub.m
is substituted with 1, 2, or 3 R.sub.q groups where the R.sub.q
groups can be the same or different. It will be understood by those
skilled in the art with respect to any group containing one or more
substituents that such groups are not intended to introduce any
substitution or substitution patterns that are sterically
impractical and/or synthetically non-feasable.
[0561] APP, amyloid precursor protein, is defined as any APP
polypeptide, including APP variants, mutations, and isoforms, for
example, as disclosed in U.S. Pat. No. 5,766,846.
[0562] A beta, amyloid beta peptide, is defined as any peptide
resulting from beta-secretase mediated cleavage of APP, including
peptides of 39, 40, 41, 42, and 43 amino acids, and extending from
the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or
43.
[0563] Pharmaceutically acceptable refers to those properties
and/or substances that are acceptable to the patient from a
toxicological and/or safety point of view.
[0564] A therapeutically effective amount is defined as an amount
effective to reduce or lessen at least one symptom of the disease
being treated or to reduce or delay onset of one or more clinical
markers or symptoms of the disease.
[0565] By "alkanoyl" is meant an acyl radical Alk-C(O)--, wherein
Alk is an alkyl readical as defined herein. Examples of alkanoyl
groups include acetyl, propionyl, butyryl, isobutyryl, valeryl,
isovaleryl, 2-methyl-butyryl, 2,2-dimethylpropionyl, valeryl,
hexanoyl, heptanoyl, octanoyl and the like.
[0566] By "alkyl" and "C.sub.1-C.sub.6 alkyl" in the present
invention is meant straight or branched chain alkyl groups having
1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl,
n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,
neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is
understood that in cases where an alkyl chain of a substituent
(e.g. of an alkyl, alkoxy or alkenyl group) is shorter or longer
than 6 carbons, it will be so indicated in the second "C" as, for
example, "C.sub.1-C.sub.10" indicates a maximum of 10 carbons. The
term also includes substituted alkyl groups, and refers to an
alkenyl group in which 1 or more hydrogen atoms is replaced by a
substituent independently selected from the group: acyl, acyloxy,
alkoxy, amino (wherein the amino group may be a cyclic amine),
aryl, heteroaryl, heterocyclyl, carboxyl, oxo, amido, cyano,
cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl,
sulfanyl, sulfinyl, sulfonyl, and sulfonic acid.
[0567] By "alkoxy" and "C.sub.1-C.sub.6 alkoxy" in the present
invention is meant straight or branched chain alkyl groups having
1-6 carbon atoms, attached through at least one divalent oxygen
atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,
n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy,
hexoxy, and 3-methylpentoxy.
[0568] By "alkenyl" and "C.sub.2-C.sub.6 alkenyl" is meant straight
and branched hydrocarbon radicals having from 2 to 6 carbon atoms
and from one to three double bonds and includes, for example,
ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and
the like. The term also includes substituted alkenyl groups, and
refers to an alkenyl group in which 1 or more hydrogen atoms is
replaced by a substituent independently selected from the group:
acyl, acyloxy, alkoxy, amino (wherein the amino group may be a
cyclic amine), aryl, heteroaryl, heterocyclyl, carboxyl, oxo,
amido, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro,
sulfamoyl, sulfanyl, sulfinyl, sulfonyl, and sulfonic acid, for
example 1H-pyrrol-2-ylmethylene.
[0569] By "alkylene" is meant a diradical alkyl group, whereby
alkyl is as defined above. By "alkynyl" and "C.sub.2-C.sub.6
alkynyl" is meant straight and branched hydrocarbon radicals having
from 2 to 6 carbon atoms and one or two triple bonds and includes
ethynyl, propynyl, butynyl, pentyn-2-yl and the like. The term also
includes substituted alkynyl groups, and refers to an alkynyl group
in which 1 or more hydrogen atoms is replaced by a substituent
independently selected from the group: acyl, acyloxy, alkoxy, amino
(wherein the amino group may be a cyclic amine), aryl, heteroaryl,
heterocyclyl, carboxyl, oxo, amido, cyano, cycloalkyl,
cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl, sulfanyl,
sulfinyl, sulfonyl, and sulfonic acid.
[0570] By "arylalkyl" is meant the group -alkylene-aryl, wherein
alkylene and aryl are defined herein.
[0571] By "aryl" is meant an aromatic carbocyclic group having a
single ring (e.g., phenyl) or multiple condensed rings in which at
least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl,
naphthyl), which is optionally mono-, di-, or trisubstituted.
Preferred aryl groups of the present invention are phenyl,
1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl,
fluorenyl, tetralinyl or
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein
are unsubstituted or substituted in one or more substitutable
positions with various groups. For example, such aryl groups may be
optionally substituted with, for example, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or phenyl.
[0572] By "phenoxy" is meant the group --O-aryl.
[0573] By "oxo" is meant the group .dbd.O.
[0574] By "cycloalkyl" refers to saturated carbocyclic radicals
having three to twelve carbon atoms. The cycloalkyl can be
monocyclic, a polycyclic fused system, or a bi or polycyclic
bridged system, such as adamantyl or bicyclo[2.2.1]heptyl. Examples
of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl. Preferred cycloalkyl groups are cyclopentyl,
cyclohexyl, and cycloheptyl. The cycloalkyl groups herein are
unsubstituted or, substituted in one or more substitutable
positions with various groups. For example, such cycloalkyl groups
may be optionally substituted with, for example, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxy, cyano, nitro,
amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0575] By "halogen" or "halo" is meant fluorine, bromine, chlorine,
and/or iodine.
[0576] By "haloalkyl" is meant an alkyl radical having the meaning
as defined above wherein one or more hydrogens are replaced by a
halogen. Examples of such haloalkyls include chloromethyl,
1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,
1,1,1-trifluoroethyl and the like.
[0577] By "heteroaryl" is mean at least one or more aromatic ring
systems of 5-, 6-, or 7-membered rings which includes fused ring
systems of 9-11 atoms containing at least one and up to four
heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred
heteroaryl groups of the present invention include pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl,
naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl,
imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl,
benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl,
benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl
N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl
N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl
N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,
indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,
benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,
thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,
benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The
heteroaryl groups herein are unsubstituted or substituted in one or
more substitutable positions with various groups. For example, such
heteroaryl groups may be optionally substituted with, for example,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxy,
cyano, nitro, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0578] By "heterocycle", "heterocycloalkyl" or "heterocyclyl" is
meant one or more carbocyclic ring systems of 4-, 5-, 6-, or
7-membered rings which includes fused ring systems of 9-11 atoms
containing at least one and up to four heteroatoms selected from
nitrogen, oxygen, or sulfur. Preferred heterocycles of the present
invention include morpholinyl, thiomorpholinyl, thiomorpholinyl
S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. The
heterocycle groups herein are unsubstituted or substituted in one
or more substitutable positions with various groups. For example,
such heterocycle groups may be optionally substituted with, for
example, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
hydroxy, cyano, nitro, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or oxo.
[0579] Most formulas were named using Autonom 2000 4.01.305, which
is available from Beilstein Information Systems, Inc, Englewood,
Colo. or ChemDraw v.10.0, are available from Cambridgesoft at 100
Cambridge Park Drive, Cambridge, Mass. 02140
(www.cambridgesoft.com). Alternatively, the names were generated
based on the IUPAC rules.
[0580] The compounds of this invention may contain one or more
asymmetric carbon atoms, so that the compounds can exist in
different stereoisomeric forms. These compounds can be, for
example, racemates, chiral non-racemic or diastereomers. In these
situations, the single enantiomers, i.e., optically active forms,
can be obtained by asymmetric synthesis or by resolution of the
racemates. Resolution of the racemates can be accomplished, for
example, by conventional methods such as crystallization in the
presence of a resolving agent; chromatography, using, for example a
chiral HPLC column; or derivatizing the racemic mixture with a
resolving reagent to generate diastereomers, separating the
diastereomers via chromatography, and removing the resolving agent
to generate the original compound in enantiomerically enriched
form. Any of the above procedures can be repeated to increase the
enantiomeric purity of a compound.
[0581] Non-toxic pharmaceutically acceptable salts include, but are
not limited to salts of inorganic acids such as hydrochloric,
sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or
salts of organic acids such as formic, citric, malic, maleic,
fumaric, tartaric, succinic, acetic, lactic, methanesulfonic,
p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic.
Similarly, pharmaceutically, acceptable cations include, but are
not limited to sodium, potassium, calcium, aluminum, lithium and
ammonium. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable addition salts. The invention
also encompasses prodrugs of the compounds of Formula I.
[0582] The invention also encompasses the acylated prodrugs of the
compounds of Formula I. Those skilled in the art will recognize
various synthetic methodologies, which may be employed to prepare
non-toxic pharmaceutically acceptable addition salts and acylated
prodrugs of the compounds encompassed by Formula I.
[0583] The term "acid prodrug group" denotes a moiety that is
converted in vivo into an active carboxylic acid compound of
formula I. Such prodrug groups are generally known in the art and
include ester forming groups, to form an ester prodrug, such as
benzyloxy, di(C.sub.1-C.sub.6)alkylaminoethyloxy, acetoxymethyl,
pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl,
5-methyl-2-oxo-1,3-dioxol-4-yl methyl, and (C.sub.1-C.sub.6)alkoxy
optionally substituted by N-morpholino and amide-forming groups
such as di(C.sub.1-C.sub.6)alkylamino. Preferred prodrug groups
include C.sub.1-C.sub.6 alkoxy forming an ester, and O.sup.-M.sup.+
where M.sup.+ represents a cation to form a salt of the acid.
Preferred cations include sodium, potassium, and ammonium. Other
cations include magnesium and calcium. Further preferred prodrug
groups include O.sup.=M.sup.++ where M.sup.++ is a divalent cation
such as magnesium or calcium.
[0584] When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless otherwise
specified, it is intended that the compounds include the cis,
trans, Z- and E- configurations. Likewise, all tautomeric forms are
also intended to be included.
[0585] The invention also encompasses the prodrugs of the compounds
of Formula I. Those skilled in the art will recognize various
synthetic methodologies that may be employed to prepare non-toxic
pharmaceutically acceptable prodrugs of the compounds encompassed
by Formula I. Those skilled in the art will recognize a wide
variety of non-toxic pharmaceutically acceptable solvates, such as
water, ethanol, mineral oil, vegetable oil, and
dimethylsulfoxide.
[0586] The compounds of general Formula I may be administered
orally, topically, parenterally, by inhalation or spray or rectally
in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. The
term parenteral as used herein includes percutaneous, subcutaneous,
intravascular (e.g., intravenous), intramuscular, or intrathecal
injection or infusion techniques and the like. In addition, there
is provided a pharmaceutical formulation comprising a compound of
general Formula I and a pharmaceutically acceptable carrier. One or
more compounds of general Formula I may be present in association
with one or more non-toxic pharmaceutically acceptable carriers
and/or diluents and/or adjuvants, and if desired other active
ingredients. The pharmaceutical compositions containing compounds
of general Formula I may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0587] Compositions intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preservative agents
in order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients that are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques. In some cases such coatings may be
prepared by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monosterate or glyceryl distearate may be
employed.
[0588] Formulations for oral use may also be presented as hard
gelatin capsules, wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0589] Formulations for oral use may also be presented as
lozenges.
[0590] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
[0591] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
and flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the addition
of an anti-oxidant such as ascorbic acid.
[0592] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents or suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0593] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil or a mineral oil or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0594] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol, glucose or
sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents. The pharmaceutical
compositions may be in the form of a sterile injectable aqueous or
oleaginous suspension. This suspension may be formulated according
to the known art using those suitable dispersing or wetting agents
and suspending agents that have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono-or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
[0595] The compounds of general Formula I may also be administered
in the form of suppositories, e.g., for rectal administration of
the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter and polyethylene glycols.
[0596] Compounds of general Formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle. For disorders of the eye or other external tissues,
e.g., mouth and skin, the formulations are preferably applied as a
topical gel, spray, ointment or cream, or as a suppository,
containing the active ingredients in a total amount of, for
example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most
preferably 0.4 to 15% w/w. When formulated in an ointment, the
active ingredients may be employed with either paraffinic or a
water-miscible ointment base.
[0597] Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane. The
transdermal patch may include the compound in a suitable solvent
system with an adhesive system, such as an acrylic emulsion, and a
polyester patch. The oily phase of the emulsions of this invention
may be constituted from known ingredients in a known manner. While
the phase may comprise merely an emulsifier, it may comprise a
mixture of at least one emulsifier with a fat or oil or with both a
fat and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier, which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base, which forms
the oily, dispersed phase of the cream formulations. Emulsifiers
and emulsion stabilizers suitable for use in the formulation of the
invention include Tween 60, Span 80, cetostearyl alcohol, myristyl
alcohol, glyceryl monostearate, and sodium lauryl sulfate, among
others. The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0598] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The anti-inflammatory active ingredients
are preferably present in such formulations in a concentration of
0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5%
w/w. For therapeutic purposes, the active compounds of this
combination invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. The
compounds may be admixed with lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets may contain a
controlled-release formulation as may be provided in a dispersion
of active compound in hydroxypropylmethyl cellulose. Formulations
for parenteral administration may be in the form of aqueous or
non-aqueous isotonic sterile injection solutions or suspensions.
These solutions and suspensions may be prepared from sterile
powders or granules having one or more of the carriers or diluents
mentioned for use in the formulations for oral administration. The
compounds may be dissolved in water, polyethylene glycol, propylene
glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,
benzyl alcohol, sodium chloride, and/or various buffers. Other
adjuvants and modes of administration are well and widely known in
the pharmaceutical art.
[0599] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
of the above-indicated conditions (about 0.5 mg to about 7 g per
patient per day). The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient. The daily
dose can be administered in one to four doses per day. In the case
of skin conditions, it may be preferable to apply a topical
preparation of compounds of this invention to the affected area two
to four times a day.
[0600] Formulations suitable for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable aqueous or
organic solvents, or mixtures thereof, and powders. The liquid or
solid compositions may contain suitable pharmaceutically acceptable
excipients as describe above. The compositions may be administered
by oral or nasal respiratory route for local or systemic effect.
Compositions may be nebulized by use of inert gases or vaporized,
and breathed directly from the nebulizing/vaporizing device or the
nebulizing device may be attached to a face mask tent or
intermittent positive pressure breathing machine.
[0601] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease undergoing therapy.
[0602] For administration to non-human animals, the composition may
also be added to the animal feed or drinking water. It may be
convenient to formulate the animal feed and drinking water
compositions so that the animal takes in a therapeutically
appropriate quantity of the composition along with its diet. It may
also be convenient to present the composition as a premix for
addition to the feed or drinking water.
[0603] The disclosures in this document of all articles and
references, including patents, are incorporated herein by reference
in their entirety.
[0604] The invention is illustrated further by the following
examples, which are not to be construed as limiting the invention
in scope or spirit to the specific procedures described in
them.
[0605] The starting materials and various intermediates may be
obtained from commercial sources, prepared from commercially
available compounds, and/or prepared using known synthetic
methods.
[0606] General Synthetic Procedures
[0607] The compounds of the invention can be prepared using methods
known in the art of organic synthesis. For example, the compounds
of the invention, as well as all intermediates, can be synthesized
by known processes using either solution or solid phase techniques,
as shown below. Representative procedures for preparing compounds
of the invention are outlined in the following schemes.
[0608] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions.
Suitable protecting groups for various functional groups as well as
suitable conditions for protecting and deprotecting particular
functional groups are well known in the art. For example, numerous
protecting groups are described in T. W. Greene and G. M. Wuts,
Protecting Groups in Organic Synthesis, Second Edition, Wiley, New
York, 1991, and references cited therein.
[0609] Certain compounds of this invention are prepared from other
compounds of this invention via known reactions and functional
group transformations. Examples of such transformations are ester
hydrolysis, amide formation, and reductive alkylation; with
examples of these are described in the preparations below. Starting
materials are obtained from commercial sources or prepared by known
methods as described in the examples below.
[0610] Compounds included in this invention are exemplified by the
following examples, which should not be construed as limiting the
scope of this disclosure. Analogous formulas and alternative
synthetic routes within the scope of the invention will be apparent
to those skilled in the art.
Method 1
Preparation of
9-(5-chlorothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane
##STR00038##
[0612] The cyclooctane-1,4-syn-ditosylate (45.3 mg, 0.10 mmol; from
commercial diol by literature procedure: Heterocycles, 2000, 52(2),
929-934) and the primary sulfonamide (21.7 mg, 0.11 mmol) and
tetrabutylammonium hydrogensulfate (18 mg, 0.05 mmol) were
suspended in 50% aq. KOH (0.25 mL) and toluene (0.25 mL) and
stirred evenly in a capped vial heated to 80.degree. C. Upon
complete consumption of the di-tosylate (20-100 h, LC-MS), the
reaction was diluted with dichloromethane and water. The organic
phase was separated, washed four times with brine, dried
(Na.sub.2SO.sub.4), applied to silica gel column and eluted (0-10%
EtOAc in dichloromethane) to yield the product upon evaporation. MS
(ES) m/e 306.0 (M+H).sup.+.
[0613] The following compounds were prepared essentially according
the procedures of method 1: [0614]
9-(5-bromothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS (ES)
m/e 350.0 (M+H).sup.+. [0615]
9-(4-bromophenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS (ES) m/e
344.0 (M+H).sup.+. [0616]
9-(4-bromo-3-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS
(ES) m/e 362.0 (M+H).sup.+. [0617]
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS (ES) m/e
300.0 (M+H).sup.+. [0618]
9-(3-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS (ES) m/e
300.0 (m+H).sup.+. [0619]
9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS
(ES) m/e 334.0 (M+H).sup.+.
[0620] 9-(3,5-dichlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS
(ES) m/e 334.0 (M+H).sup.+. [0621]
9-(4-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS (ES) m/e
284.0 (M+H).sup.+. [0622]
9-(4-(trifluoromethoxy)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane:
MS (ES) m/e 350.0 (M+H).sup.+. [0623]
9-(benzylsulfonyl)-9-azabicyclo[3.3.1]nonane: MS (ES) m/e 280.0
(M+H).sup.+.
Method 2
Preparation of 9-azabicyclo[3.3.1]nonan-3-one hydrochloride
##STR00039##
[0625] The pseudo-pelletierine (3.35 g, 21.9 mmol) was dissolved in
1,2-dichloroethane (18 mL) and 1-chloroethyl chloroformate (4.7 g,
33 mmol) is added all at once with good stirring. After stirring 30
min at RT, the stirred mixture is heated in a 90.degree. C. bath
for 3 h and evaporated under a stream of nitrogen. The residue is
taken up in dry MeOH (25 mL) and slowly heated to reflux for 2 h
and evaporated under a stream of nitrogen. The solids are taken up
in additional dry MeOH and heated in a 90.degree. C. bath and
evaporated again to yield 3.8 g the hydrochloride salt. MS (ES) m/e
140.0 (M+H).sup.+.
Method 3
Preparation of
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one
##STR00040##
[0627] The amine hydrochloride (2.98 g, 16.9 mmol) was dissolved in
dichloromethane (20 mL) and 4 M aq NaOH (11 mL). The
4-chlorobenzenesulfonyl chloride (5.07 g, 24 mmol) is added all at
once to the reaction mixture with good stirring. After stirring at
RT for 16 h, N,N-diethyl-ethylenediamine (1.39 g, 12 mmol) is added
and stirred for 1 h. The reaction mixture was diluted with
dichloromethane and acidified to pH 4 using aq NaHSO.sub.4. The
aqueous phase was separated and extracted once with
dichloromethane. The combined organic phases were washed with 5%
NaHSO.sub.4 (three times), water, brine, and then dried
(Na.sub.2SO.sub.4) and evaporated to yield 5.03 g of the product
upon evaporation. Further purification was optionally performed by
applying the product in dichloromethane to a silica gel column and
elution (0-10% EtOAc in dichloromethane) to yield the purified
product upon evaporation. MS (ES) m/e 314.0 (M+H).sup.+.
[0628] The following compounds were prepared essentially according
to the procedures described in methods 2 and 3. [0629]
9-(4-iodophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one: MS (ES)
m/e 406.0 (M+H).sup.+. [0630]
8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octane: MS (ES) m/e
286.0 (M+H).sup.+. [0631]
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octane: MS (ES) m/e
330.0 (M+H).sup.+. [0632]
8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one: MS (ES)
m/e 300.0 (M+H).sup.+. [0633]
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one: MS (ES)
m/e 344.0 (M+H).sup.+. [0634]
8-(4-iodophenylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one: MS (ES)
m/e 391.0 (M+H).sup.+. [0635] tert-butyl
3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate: MS (ES) m/e 262.0
(M+Na).sup.+.
Method 4
Preparation of
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-ol
##STR00041##
[0637] The ketone (31 mg, 0.10 mmol) was warmed to dissolution in
methanol (2 mL), cooled to room temperature, and excess sodium
borohydride (250 mg) was added. As the stirred reaction warmed,
vigorous hydrogen evolution occurred. Once gas evolution ceased
(.about.2 h), the reaction mixture was evaporated, aq NaHSO.sub.4
and dichloromethane were added. The aqueous phase was separated and
extracted once with dichloromethane. The combined organic phases
were washed with water, aq NaHCO.sub.3, brine, and then dried
(Na.sub.2SO.sub.4), filtered, and applied to a silica gel column
and eluted (0-25% EtOAc/MeOH (5:1) in dichloromethane) to yield the
product upon evaporation. MS (ES) m/e 316.0 (M+H).sup.+.
[0638] The following compounds were prepared essentially according
to the procedures described in method 4. [0639]
exo-8-[(4-chlorophenyl)sulfonyl]-8-azabicyclo[3.2.1]octan-3-ol MS
(ES) m/e 302.0 (M+H).sup.+. [0640]
endo-8-[(4-chlorophenyl)sulfonyl]-8-azabicyclo[3.2.1]octan-3-ol MS
(ES) m/e 302.0 (M+H).sup.+.
Method 5
Preparation of
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one oxime
##STR00042##
[0642] To a suspension of the ketone (31 mg, 0.10 mmol), sodium
acetate (41 mg, 0.5 mmol) and glacial acetic acid (0.8 mL) in a
vial was added the hydroxylamine hydrochloride (31 mg, 0.25 mmol)
with good stirring. The vial was capped and the reaction mixture
was stirred evenly and heated to 100.degree. C. Upon complete
consumption of the enol-ketone (2-18 h, LC-MS), the reaction
mixture was evaporated under a stream of nitrogen while being
warmed in a 90.degree. C. bath. The brown residue was dissolved
with dichloromethane and water. The organic phase was washed with
5% NaHSO.sub.4 (3.times.), 5% NaHCO.sub.3 (2.times.), and brine
(2.times.), dried (Na.sub.2SO.sub.4), applied to a silica gel
column and eluted (0-10% EtOAc in dichloromethane) to yield the
product upon evaporation. MS (ES) m/e 306.0 (M+H).sup.+.
Method 6
Preparation of
8-(4-chlorophenylsulfonyl)-3-methylene-8-azabicyclo[3.2.1]octane
##STR00043##
[0644] A solution of triphenylphosphonium bromide (179 mg, 0.50
mmol) in THF (2.0 mL) was placed under nitrogen and stirred in a
-78.degree. C. bath while potassium tert-butoxide in THF (0.5 mL,
1.0 M) was added all at once. After allowing the reaction mixture
to warm to 0.degree. C. for 15 min, it was recooled to -78.degree.
C., and the ketone (60 mg, 0.20 mmol) dissolved in THF (1 mL) was
added dropwise. The reaction mixture was allowed to slowly warm to
room temperature as it stirred overnight. LC-MS indicated that the
reaction was complete so methanol (0.5 mL) was added. The reaction
mixture was opened and diluted with hexanes to precipitate the
phosphorus byproducts. The organic phase was decanted from the
precipitates and evaporated. The organic residue was dissolved in
dichloromethane and EtOAc and passed through a short column of
neutral alumina and concentrated. The residue was applied to silica
gel column and eluted (chloroform, then 0-5% EtOAc in
dichloromethane) to yield the product upon evaporation. MS (ES) m/e
288.0 (M+H).sup.+.
[0645] The following compounds were prepared essentially according
to the procedure described in method 6. [0646]
8-(4-bromophenylsulfonyl)-3-methylene-8-azabicyclo[3.2.1]octane: MS
(ES) m/e 342.0 (M+H).sup.+. [0647]
9-(4-chlorophenylsulfonyl)-3-methylene-g-azabicyclo[3.3.1]nonane:
MS (ES) m/e 312.0 (M/H).sup.+.
Method 7
Preparation of
9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan--
3-one
##STR00044##
[0649] The ketone (1.88 g, 6.00 mmol) was warmed to dissolution in
ethyl formate (15 mL) and THF (4 mL), cooled to room temperature,
and dry ethanol (4 mL) was added. To the reaction mixture was added
all at once 21% sodium ethoxide in ethanol (6.72 mL, 18.0 mmol),
capped and stirred vigorously for 30 min at RT and for 1 h in a
70.degree. C. bath. The reaction mixture was evaporated under a
stream of nitrogen while being warmed in a 70.degree. C. bath. The
amber residue was dissolved with dichloromethane and water and
acidified to pH 3-4 using NaHSO.sub.4. The aqueous phase was
separated and extracted once with dichloromethane. The combined
organic phases were washed with water, brine, and then dried
(Na.sub.2SO.sub.4) and evaporated to yield 1.8 g the product upon
evaporation. MS (ES) m/e 342.0 (M+H).sup.+.
Method 8
Preparation of diethyl
3-oxo-9-azabicyclo[3.3.1]nonane-2,4-dicarboxylate
##STR00045##
[0651] The diethylacetone-1,3-dicarboxylate (60.62 g, 300 mmol) was
dissolved in ethanol (100 mL) and water (50 mL), and 50% aq
glutaraldehyde (63.32 g, 315 mmol) was added all at once with good
stirring. The reaction mixture was placed in a 48-50.degree. C.
bath and stirred while a 35.degree. C. aq ammonium chloride
solution (24.0 g, 0.460 mmol; 80 mL water) was added over 20 min.
After stirring. 2 h in the 50.degree. C. bath the starting
materials had been predominantly consumed (LC-MS), so the reaction
mixture was evaporated under a stream of nitrogen while being
warmed in a 90.degree. C. bath to yield a slurry of the
hydrochloride salt (.about.230 cc) MS (ES) m/e 284.0
(M+H).sup.+.
Method 9
Preparation of diethyl
9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2,4-dicarboxyl-
ate
##STR00046##
[0653] The slurry of amine hydrochloride from Method 8 (using
glutaraldehyde; .about.300 mmol) was suspended in dichloromethane
(150 mL) and 4 M aq NaOH (120 mL). To the well-stirred reaction
mixture was added 4-chlorobenzenesulfonyl chloride (73.14 g, 346.5
mmol) in dichloromethane (70 mL) over 10 min. After stirring at RT
for 1 h, an additional 20 mL 4M NaOH and 10 mL satd aq NaHCO.sub.3
were added to maintain the reaction mixture pH between pH 5.5-8.5.
After stirring at RT for 2 h, N,N-diethyl-ethylenediamine (13.9 g,
120 mmol) is added dropwise and stirred for 1 h. The reaction
mixture was acidified to pH 6 using aq NaHSO.sub.4. The aqueous
phase was separated and extracted once with dichloromethane. The
combined organic phases were washed with 5% NaHSO.sub.4 (three
times), water, brine, and then dried (Na.sub.2SO.sub.4) and
evaporated to yield 129 g (94% yield overall from diethyl
acetonedicarboxylate) of the enol-diester product as a semisolid
after applying full vacuum (18 h, 50.degree. C. bath). MS (ES) m/e
458.0 (M+H).sup.+.
Method 10
Preparation of ethyl
9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2-carboxylate
##STR00047##
[0655] The ketodiester (14.0 g, 30.58 mmol) was dissolved in warm
ethanol (20 mL) and 2.0 M aq NaOH (38.3 mL, 76.5 mmol). The
reaction mixture was stirred in a 100.degree. C. bath for 2 h,
where LC-MS showed consumption of the diester. After cooling to RT,
concentrated aq NaHSO.sub.4 was added cautiously (CO.sub.2
evolution) with stirring until the reaction mixture was acidified
to pH 1-2, and stirred an additional 30 min in a 50.degree. C.
bath. The reaction mixture was then extracted with dichloromethane
(3.times.), and the combined organic phases were washed with 5%
NaHCO.sub.3. (2.times.), water, brine, and then dried
(Na.sub.2SO.sub.4) and evaporated to yield 9.75 g (83% yield) of
the product which crystallized on standing. MS (ES) m/e 386.0
(M+H).sup.+.
Method 11
Preparation of
2-bromo-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one
and
2-amino-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one
##STR00048##
[0657] To a solution of the ketone
(9-[(4-chlorophenyl)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-one, 31
mg, 0.10 mmol) dissolved in ethyl acetate (0.8 mL) and chloroform
(0.4 mL) was added cupric bromide (34.6 mg, 0.12 mmol). The
reaction mixture was stirred in a 85.degree. C. bath for 4 h,
whereupon LC-MS showed nearly complete consumption of the ketone.
After cooling to RT, the reaction mixture was diluted with
dichloromethane, filtered, and washed with 10% NaHSO.sub.3, water,
brine, and then dried (Na.sub.2SO.sub.4) passed through silica gel
and evaporated to yield the crude bromide product. MS (ES) m/e
392.0 (M+H).sup.+.
[0658] The bromo-ketone (25 mg) dissolved in THF (2 mL) was added
ammonium hydroxide (2 mL), and the reaction mixture was capped
stirred in an 85.degree. C. bath for 4 h. After cooling to RT, the
reaction mixture was evaporated, diluted with dichloromethane, and
washed with water, brine, and then dried (Na.sub.2SO.sub.4) and
evaporated to yield the amino-ketone product. MS (ES) m/e 329.0
(M+H).sup.+.
[0659] The following compound was prepared essentially according to
the procedure described in method 11. [0660] tert-butyl
2-bromo-3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate; MS (ES) m/e
392.0 (M+H).sup.+.
Method 12
Preparation of
2-acetyl-9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one
##STR00049##
[0662] The ketone
(9-[(4-chlorophenyl)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-one, 94
mg, 0.30 mmol) under nitrogen was dissolved in THF (1.5 mL), and
with good stirring at room temperature, lithium diisopropylamide
(1.0 M in cyclohexane/THF, 1.0 mL, 1.0 mmol) was added all at once
by syringe. After stirring for 15 min, pyruvonitrile (140 mg, 2.0
mmol) was added all at once to the reaction mixture and stirred
vigorously for 30 min at RT and for 24 h in a 60.degree. C. bath.
The reaction mixture was partially evaporated under a stream of
nitrogen while being warmed in a 70.degree. C. bath. The black
residue was dissolved with water and dichloromethane and acidified
with aq NaHSO.sub.4. The organic phase was separated and combined
with one additional dichloromethane extraction of the aq phase. The
organic phase was washed with 0.1 M NaOH (3.times.), and the basic
washes were combined and acidified to pH 1-2 using aq NaHSO.sub.4.
The acidic phase was extracted with dichloromethane (3.times.), and
the combined dichloromethane extracts were washed with brine
(2.times.), and then dried (Na.sub.2SO.sub.4) and evaporated to
yield the brown solid product. MS (ES) m/e 356.0 (M+H).sup.+.
Method 13
Preparation of
1-(4-chlorophenylsulfonyl)piperidine-2,6-dicarboxylic acid
##STR00050##
[0664] A mixture of 10.4 g (62.1 mmol) 2,6-pyridine dicarboxylic
acid, 5.1 mL (62.1 mmol) conc. HCl, 115 mg (0.51 mmol) PtO.sub.2,
and 100 mL water, was shaken under 65 psi hydrogen in a Parr
bottle. As hydrogen was consumed during several hours of shaking,
the Parr bottle was repeatedly repressurized to 65 psi, until
hydrogen consumption ceased, indicating complete hydrogenation.
Both prior to and following complete hydrogenation, undissolved
white organic solids remained suspended in the water solvent.
Following hydrogenation, 18.6 mL (186 mmol) 10 M NaOH in water, and
6.58 g (62.1 mmol) K.sub.2CO.sub.3 were added to the mixture in the
Parr bottle, and the mixture was stirred, causing the dissolution
of all solids, except Pt(0). To the mixture were added 50 mL THF
and a magnetic stir bar, and the resulting two phases were cooled
to <3 C, by stirring and immersing the Parr bottle in an
ice-water bath. To this mixture was added 13.1 g (62.1 mmol)
4-chlorobenzenesulfonyl chloride, and the mixture was stirred
overnight, as the ice melted, and the mixture warmed to room
temperature. Approximately 25 mL THF was evaporated, by blowing air
towards the solution, causing the precipitation of a solid. 100 mL
water was added, causing the just formed precipitate to redissolve.
The mixture was filtered through filter paper to remove Pt(0), and
acidified by addition of 20 mL conc. HCl, causing the formation of
a precipitate. The precipitate was collected by filtration through
a fritted glass funnel, rinsed with water, and dried under vacuum,
to afford 8.0 g (37%)
cis-1-(4-chlorobenzenesulfonyl)-piperidine-2,6-dicarboxylic acid as
a white solid.
Method 14
Preparation of
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane-2,4-dio-
ne
##STR00051##
[0666] To a solution of 200 mg (0.575 mmol)
cis-1-(4-chlorobenzenesulfonyl)-piperidine-2,6-dicarboxylic acid,
52 uL (0.575 mmol) aniline, and 489 uL (3.45 mmol) Et.sub.3N in 2.0
mL DMF, was added 656 mg (1.72 mmol) HATU. The mixture was stirred,
generating a solution and a perceptible exotherm. After stirring
overnight, 4 mL water was added to the solution, causing the
formation of a precipitate, which was isolated by centrifugation
and decanting the supernatant solution. The precipitate was
dissolved in 6 mL CHCl.sub.3, and the resulting solution was washed
sequentially with 6 mL portions of 1 M KHSO.sub.4, water, sat.
NaHCO.sub.3, and sat NaCl. The CHCl.sub.3 solution was passed
through a plug of laboratory tissue stuffed in a pipette, and the
filtrate evaporated to afford 190 mg (82%) of the desired product
as an off-white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.79 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 7.39-7.26 (m, 3H),
6.42-6.39 (m, 2H), 4.83 (t, J=3 Hz, 2H), 2.24-2.08 (m, 4H),
2.02-1.96 (m, 1H), 1.77-1.62 (m, 1H)
Method 15
Preparation of
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane
##STR00052##
[0668] A solution of 75 mg
(9-[(4-chlorophenyl)sulfonyl]-3-phenyl-3,9-diazabicyclo[3.3.1]-nonane-2,4-
-dione, 0.185 mmol) of the imide and 176 uL (1.85 mmol) borane
dimethylsulfide complex in 2.0 mL THF was stirred and heated to
reflux under nitrogen for 90 min. The mixture was allowed to cool
to room temperature, and then opened to air, and then 2.0 mL 1 M
HCl was added carefully, causing the evolution of much gas. The THF
was evaporated, and then 4.0 mL 1 M NaOH in water was added, and
the mixture was extracted twice with 6 mL portions of Et.sub.2O.
The Et.sub.2O extracts were passed through a plug of laboratory
tissue stuffed in a pipette, and the filtrate evaporated to give a
solid white residue. The residue was recrystallized from hot
methanol, to afford the 66 mg (75%) of the desired product as
colorless crystals. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.82
(d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.26 (t, J=7.9, 2H),
6.87-6.81 (m, 3H), 4.17 (bs, 2H), 3.58 (d, J=11.4 Hz, 2H),
3.09-3.04 (m, 2H), 2.56-2.39 (m, 1H), 1.97-1.85 (m, 2H), 1.81-1.74
(m, 2H), 1.57-1.50 (m, 1H).
Method 16
Preparation of
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonan-2-one
##STR00053##
[0670] To a stirred solution of 75 mg (0.185 mmol) of the imide
(9-[(4-chlorophenyl)sulfonyl]-3-phenyl-3,9-diazabicyclo[3.3.1]nonane-2,4--
dione) in 2.0 mL MeOH and 2.0 mL THF maintained at 0 C, was added
35 mg (0.926 mmol) NaBH.sub.4. After stirring for 15 min at 0 C,
TLC of the reaction mixture directly spotted onto silica gel, and
eluted with 2:1 hexanes/EtOAc, showed complete consumption of the
starting material. The reaction mixture was quenched by addition of
2.0 mL sat. NH.sub.4Cl, causing the evolution of gas, and
generating an inorganic precipitate. To the mixture was added 2.0
mL water, dissolving the inorganic precipitate. The mixture was
extracted with 2.times.5 mL EtOAc, and the EtOAc extracts were
passed through a plug of laboratory tissue stuffed in a pipette,
and the filtrate evaporated, affording the hydroxymethyl secondary
carboxamide intermediate as a white solid. To a solution of the
entire portion of this white solid and 210 mg (0.80 mmol) PPh.sub.3
in 2.0 mL anhydrous THF maintained at 0 C under nitrogen, was added
126 uL (0.8 mmol) diethyl azodicarboxylate. The resulting mixture
was stirred at 0 C for 4 h, and then at room temperature for 44 h.
To the stirred reaction mixture was added 2.0 mL MeOH and then 4.0
mL water, generating an exotherm and a mild cloudiness. The mixture
was stirred for 24 h, generating a precipitate, which was isolated
by decanting the supernatant. TLC and 1H NMR analysis of the
precipitate indicated about 80% pure lactam. The precipitate was
purified by recrystallization from hot iPrOH/MeOH, affording 32 mg
(44%) as colorless crystals. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.88 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.35 (t,
J=7.9 Hz, 2H), 7.30-7.25 (m, 1H), 6.77 (d, J=7.2 Hz, 2H), 4.54 (bs,
1H), 4.46-4.25 (m, 1H), 3.78-3.72 (m, 1H), 3.34 (d, J=12.9 Hz, 1H),
2.20-1.82 (m, 6H).
Method 17
[0671] Preparation of:
##STR00054##
[0672] This compound can be prepared from
9-methyl-3-thia-9-azabicyclo[3.3.1]nonan-7-one (see: Zirkle,
Charles L.; Gems, Fred R.; Pavloff, Alex M.; Burger, Alfred. The
isomeric 3-oxa- and 3-thiagranatanin-7-ols and their derivatives;
reduction of bicyclic amino ketones related to tropinone. Journal
of Organic Chemistry (1961), 26 395-407) and by using methods and
procedures described herein.
BIOLOGICAL EXAMPLES
Notch Signaling Assay for Selective Inhibitors of Gamma
Secretase
[0673] A convergence of evidence indicates that the gamma secretase
complex, comprised of the presenilin subunits, mediates the
intra-membrane cleavage of Amyloid precursor protein (APP), and the
Notch family of proteins (De Strooper, B., P. Saftig, K.
Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figura
and F. Van Leuven (1998). "Deficiency of presenilin-1 inhibits the
normal cleavage of amyloid precursor protein." Nature 391(6665):
387-90; De Strooper, B., W. Annaert, P. Cupers, P. Saftig, K.
Craessaerts, J. S. Mumm, E. H. Schroeter, V. Schrijvers, M. S.
Wolfe, W. J. Ray et al. (1999). "A presenilin-1-dependent
gamma-secretase-like protease mediates release of Notch
intracellular domain."Nature 398(6727): 518-22; Mumm, J. S., E. H.
Schroeter, M. T. Saxena, A. Griesemer, X. Tian, D. J. Pan, W. J.
Ray and R. Kopan (2000). "A ligand-induced extracellular cleavage
regulates gamma-secretase-like proteolytic activation of Notch1."
Mol Cell 5(2): 197-206; Zhang, Z., P. Nadeau, W. Song, D. Donoviel,
M. Yuan, A. Bernstein and B. A. Yankner (2000). "Presenilins are
required for gamma-secretase cleavage of beta-APP and transmembrane
cleavage of Notch-1." Nat Cell Biol 2(7): 463-5). Cleavage of APP
by gamma secretase leads to beta-amyloid synthesis. Cleavage of
Notch1 by gamma secretase results in release of the Notch
intracellular domain (NICD), which translocates to the nucleus and
activates gene expression (Jarriault, S., C. Brou, F. Logeat, E. H.
Schroeter, R. Kopan and A. Israel (1995). "Signalling downstream of
activated mammalian Notch." Nature 377(6547): 355-8; Kopan, R., E.
H. Schroeter, H. Weintraub and J. S, Nye (1996). "Signal
transduction by activated Notch: importance of proteolytic
processing and its regulation by the extracellular domain." Proc
Natl Acad Sci USA 93(4): 1683-8; Schroeter, E. H., J. A. Kisslinger
and R. Kopan (1998). "Notch-1 signalling requires ligand-induced
proteolytic release of intracellular domain." Nature 393(6683):
382-6). In particular, Notch signaling activates transcription of
the mammalian homolog of the Drosophila transcription factor
hairy-enhancer of split (Hes). Transcriptional activation of Hest
is mediated by de-repression of CBF1/RBPJk upon binding by NICD in
the nucleus. These facts have been exploited to develop a reporter
gene assay for Notch Signaling Hsieh, J. J., T. Henkel, P. Salmon,
E. Robey, M. G. Peterson and S. D. Hayward (1996). "Truncated
mammalian Notch1 activates CBF1/RBPJk-repressed genes by a
mechanism resembling that of Epstein-Barr virus EBNA2." Mol Cell
Biol 16(3): 952-9; Lu, F. M. and S. E. Lux (1996). "Constitutively
active human Notch1 binds to the transcription factor CBF1 and
stimulates transcription through a promoter containing a
CBF1-responsive element." Proc Natl Acad Sci USA 93(11):
5663-7).
[0674] Gamma secretase inhibitors have been observed to block NICD
formation, and inhibit Notch signaling (De Strooper, B., W.
Annaert, P. Cupers, P. Saftig, K. Craessaerts, J. S. Mumm, E. H.
Schroeter, V. Schrijvers, M. S. Wolfe, W. J. Ray et at. (1999). "A
presenilin-1-dependent gamma-secretase-like protease mediates
release of Notch intracellular domain." Nature 398(6727): 518-22).
Due to the importance of Notch signaling in cell fate
determination, and tissue differentiation during both development
and in the adult, inhibition of Notch signaling by gamma secretase
inhibitors is postulated to be a limiting factor in their
therapeutic utility. In order to identify selective gamma secretase
inhibitors, we have employed a reporter gene based Notch signaling
assay using a constitutively active rat Notch1 construct (ZEDN1)
provided by Dr Gerry Weinmaster, who is at the University of
California at Los Angeles (UCLA) as described in Shawber, C., D.
Nofziger, J. J. Hsieh, C. Lindsell, O. Bogler, D. Hayward and G.
Weinmaster (1996). "Notch signaling inhibits muscle cell
differentiation through a CBF1-independent pathway." Development
122(12): 3765-73 in combination with the CBF1 repressible
Luciferase reporter gene 4xwtCBF.sub.1 Luc (Hsieh, J. J., T.
Henkel, P. Salmon, E. Robey, M. G. Peterson and S. D. Hayward
(1996). "Truncated mammalian Notch1 activates CBF1/RBPJk-repressed
genes by a mechanism resembling that of Epstein-Barr virus EBNA2."
Mol Cell Biol 16(3): 952-9).
[0675] When 4xwtCBF1 Luciferase is co-transfected with
Notch.delta.E (ZEDN1), gamma-secretase cleavage of Notch.delta.E
releases the Notch intracellular domain (MCD), which translocates
to the nucleus and de-represses CBF1 mediated transcriptional
repression, leading to transcription of the Luciferase reporter
gene. Luciferase activity is easily assayed in cell extracts using
commercially available kits. The activity of the reporter gene is
directly correlated with gamma secretase cleavage of Notch.delta.E,
and as such, a reduction in Luciferase activity provides a
convenient measure of inhibition of gamma secretase cleavage of
Notch.delta.E. A comparison of the IC.sub.50 values of compounds
for inhibition of Notch signaling versus inhibition of beta-amyloid
production in 293sw cells is employed to guide in the selection of
compounds that have the desired property of potent inhibition of
beta-amyloid synthesis with minimal inhibition of Notch
Signaling.
[0676] Gamma-Secretase Assay
[0677] The gamma-secretase APP enzyme assay was designed to measure
the specific proteolytic cleavage of an APP substrate (MBP-C125 Swe
fusion protein) at the A1340 site. The assay used a partially
purified extract of IMR-32 cell membranes as the gamma-secretase
enzyme preparation and a recombinant fusion protein containing the
C-terminal 125 amino acids of the Swedish variant of the APP
(MBP-C125swe) as the substrate. This assay involved two steps
beginning with the enzymatic reaction generating a cleavage product
that was captured with an immobilized antibody specific for the
neo-epitope A640 site. The captured cleavage product was then
detected in a sandwich ELISA assay with a biotinylated reporter
antibody that is specific to A.beta. (17-28). Streptavidin-linked
alkaline phosphatase was then added that would generate a
fluorescent signal proportional to the amount of cleavage product.
This assay was used to discover small molecule inhibitors of
gamma-secretase.
[0678] Materials and Methods:
[0679] Briefly, a 149 mg/ml solution of BIGCHAP detergent was made
with water at 42.degree. C. and then rotated for 30 minutes at the
same temperature. This warmed solution of BigCHAPS
(N,N-Bis(3-D-gluconamidopropyl)cholamide) detergent was used to
dissolve Brain Extract Type-V (lipid containing a minimum of 40%
phosphatidylethanolamine) from Sigma (St. Louis, Mo.) to a
concentration of 8 mg/ml. This solution containing BigCHAPS and
lipid at 8 mg/ml is then diluted to 0.53 mg/ml lipid with a
pre-warmed solution of Hepes and sodium chloride. This final
solution containing Hepes buffer, sodium chloride, BigCHAPS
detergent and lipid is used to create working solutions of both
gamma-secretase (25 Units) and the MBP-C125 substrate (0.05
mg/ml).
[0680] Gamma-secretase was then added to a 96-well micro-titre
plate and then incubated with various concentrations of inhibitor
for 30 minutes at 37.degree. C. MBP-C125 substrate was then added
to initiate the reaction that would run for two hours at 37.degree.
C. The reaction was quenched with the addition of SDS to a final
concentration of 0.1% and then 100 .mu.l of the reaction mixture
was transferred to a capture ELISA plate and incubated overnight at
4.degree. C. Detection of the cleavage product was performed using
a standard sandwich ELISA assay and quantified using a six point
standard curve.
[0681] Results
[0682] The following compounds when tested as described above
exhibited inhibition with an IC.sub.50 in a range of 2000 nM to
5000 nM (A) or in a range of 1000 nM to 2500 nM (B) and in a range
of less than 1000 nM (C).
TABLE-US-00001 Compounds .gamma.APP
9-(5-chlorothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane; A
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one; C
9-(5-bromothiophen-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane; A
9-(4-bromophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; B
9-(4-bromo-3-fluorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; A
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonane; B
9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonane; A
8-(4-chlorophenylsulfonyl)-8-azabicyclo[3.2.1]octane; A
8-(4-bromophenylsulfonyl)-8-azabicyclo[3.2.1]octane; A
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one oxime; A
9-(4-chlorophenylsulfonyl)-3-methylene-9-azabicyclo[3.3.1]nonane; C
9-(4-chlorophenylsulfonyl)-3-phenyl-3,9-diazabicyclo[3.3.1]nonane;
B
9-[(4-chlorophenyl)sulfonyl]-3,9-diazabicyclo[3.3.1]nonane-2,4-dione;
C 9-(4-chlorophenylsulfonyl)-3,9-diazabicyclo[3.3.1]nonan-2-one; A
9-(4-chlorophenylsulfonyl)-3-oxa-9-azabicyclo[3.3.1]nonane; A
9-(4-chlorophenylsulfonyl)-3-thia-9-azabicyclo[3.3.1]nonane; C
Methanesulfonic acid
9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-yl ester; B
9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-ol; A
[9-(4-Chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]non-3-yl]-methyl-carbami-
c acid tert- C butyl ester
[0683] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred aspects of the invention and that modifications
may be made therein without departing from the spirit or scope of
the invention as set forth in the claims. To particularly point out
and distinctly claim the subject matter regarded as invention, the
following claims conclude this specification.
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