U.S. patent application number 12/254431 was filed with the patent office on 2009-03-12 for succinoylamino benzodiazepines as inhibitors of ab protein production.
This patent application is currently assigned to Bristol-Myers Squibb Pharma Company. Invention is credited to Richard E. Olson.
Application Number | 20090069293 12/254431 |
Document ID | / |
Family ID | 22350336 |
Filed Date | 2009-03-12 |
United States Patent
Application |
20090069293 |
Kind Code |
A1 |
Olson; Richard E. |
March 12, 2009 |
SUCCINOYLAMINO BENZODIAZEPINES AS INHIBITORS OF AB PROTEIN
PRODUCTION
Abstract
This invention relates to novel lactams having the formula (I):
##STR00001## to their pharmaceutical compositions and to their
methods of use. These novel compounds inhibit the processing of
amyloid precursor protein and, more specifically, inhibit the
production of A.beta.-peptide, thereby acting to prevent the
formation of neurological deposits of amyloid protein. More
particularly, the present invention relates to the treatment of
neurological disorders related to .beta.-amyloid production such as
Alzheimer's disease and Down's Syndrome.
Inventors: |
Olson; Richard E.;
(Wilmington, DE) |
Correspondence
Address: |
KELLEY DRYE & WARREN LLP
400 ALTLANTIC STREET , 13TH FLOOR
STAMFORD
CT
06901
US
|
Assignee: |
Bristol-Myers Squibb Pharma
Company
Princeton
NJ
|
Family ID: |
22350336 |
Appl. No.: |
12/254431 |
Filed: |
October 20, 2008 |
Related U.S. Patent Documents
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Application
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12061227 |
Apr 2, 2008 |
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12254431 |
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12045126 |
Mar 10, 2008 |
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12061227 |
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11331791 |
Jan 13, 2006 |
7456172 |
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12045126 |
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11230203 |
Sep 19, 2005 |
7304049 |
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11331791 |
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09505788 |
Feb 17, 2000 |
7053084 |
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11230203 |
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09469939 |
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Current U.S.
Class: |
514/212.04 ;
540/522 |
Current CPC
Class: |
C07D 223/16 20130101;
A61P 25/28 20180101; A61P 25/00 20180101; C07D 401/04 20130101;
C07D 243/24 20130101; C07D 243/14 20130101; A61P 43/00 20180101;
C07D 243/12 20130101 |
Class at
Publication: |
514/212.04 ;
540/522 |
International
Class: |
A61K 31/55 20060101
A61K031/55; C07D 223/18 20060101 C07D223/18 |
Claims
1-24. (canceled)
25. A process for preparing a compound of Formula (I), ##STR00200##
or a stereoisomer or a pharmaceutically acceptable salt thereof,
comprising the steps of: coupling a solid phase bound succinic acid
derivative by amide bond synthesis to an aminolactam mediated by
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
benzotriazol-1-yloxytris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP), EDC, CDI, or DCC, the product being
liberated from the solid phase by employing dilute trifluoroacetic
acid in CH.sub.2Cl.sub.2; and purified by chromatography to obtain
a structure; wherein: A is O; Q is --NR.sup.1R.sup.2; R.sup.1 is
selected from: H; C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1a; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b; aryl substituted with 0-3 R.sup.1b; and 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.1b; R.sup.1a, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.1b; aryl substituted with 0-3
R.sup.1b; and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.1b;
R.sup.1b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.4 haloalkoxy; R.sup.2 is selected from
H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 carbocycle,
C.sub.6-C.sub.10 aryl, and 5 to 10 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R.sup.3 is --(CR.sup.7R.sup.7a)--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4,
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4,
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).sub.m---
R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)--(CR.sup.7R.sup.7a).sub.m---
R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)C(.dbd.O)--(CR.sup.7R.sup.-
7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.-
m--R.sup.4,
(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).-
sub.m--R.sup.4, or
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2N(R.sup.7b)--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4; n is 0, 1, 2, or 3; m is 1, 2, or 3; R.sup.3a is
H, OH, C.sub.1-C.sub.4 alkyl C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkenyloxy; R.sup.4 is
H, OH, OR.sup.14a, C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.4a, C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a,
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a,
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b, aryl
substituted with 0-3 R.sup.4b, or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.4b; R.sup.4a, at each occurrence, is independently
selected from H, F, Cl, Br, I, CF.sub.3, C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.4b, aryl substituted with 0-3
R.sup.4b, and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S--; R.sup.5 is H, OR.sup.14; C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.5b; C.sub.1-C.sub.6 alkoxy substituted
with 0-3 R.sup.5b; C.sub.2-C.sub.6 alkenyl substituted with 0-3
R.sup.5b; C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c; aryl
substituted with 0-3 R.sup.5c; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.5c; R.sup.5a is H, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyl, or C.sub.2-C.sub.4
alkenyloxy; R.sup.5b, at each occurrence, is independently selected
from: H, C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.5c; aryl substituted with 0-3
R.sup.5c; and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.5c.
R.sup.5c, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S; R.sup.6 is H; C.sub.1-C.sub.6 alkyl substituted with
0-3 R.sup.6a; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.6b; or aryl substituted with 0-3 R.sup.6b; R.sup.6a, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, OR.sup.14, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16, aryl and CF.sub.3; R.sup.6b, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
R.sup.7, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4
alkyl; R.sup.7a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; R.sup.7b is selected from H and CJ-C4 alkyl; Ring B is
##STR00201## Z is H; C.sub.1-C.sub.8 alkyl substituted with 1-3
R.sup.12; C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a; aryl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10 carbocycle
substituted with 0-4 R.sup.2b; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.12b; R.sup.12, at each occurrence, is independently
selected from aryl substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10
carbocycle substituted with 0-4 R.sup.12b; and 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.12b; R.sup.12a, at each occurrence, is
independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S; R.sup.12b, at each occurrence, is independently
selected from H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S; R.sup.13, at each occurrence, is
independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, T, CN, NO.sub.2,
NR.sup.15R.sup.16, and CF.sub.3; R.sup.14 is H, phenyl, benzyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, or
C.sub.3-C.sub.6 cycloalkyl; R.sup.14a is H, phenyl, benzyl, or
C.sub.1-C.sub.4 alkyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(O).sub.2--; R.sup.6, at each occurrence,
is independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
benzyl, phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, aryl
substituted by 0-4 R.sup.17a, or --CH.sub.2-aryl substituted by 0-4
R.sup.17a; and R.sup.17a, at each occurrence, is independently
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy,
--OH, F, Cl, Br, I, CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3,
SO.sub.2CH.sub.3, --NH.sub.2, --N(CH.sub.3).sub.2, and
C.sub.1-C.sub.4 haloalkyl; provided, when R.sup.13 is H. then Z is
H; C.sub.4-C.sub.8 alkyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12,
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a; or
C.sub.2-C.sub.4 alkynyl substituted with 3 R.sup.12a.
26. The process according to claim 25, for preparing a compound of
Formula (Ia), or a stereoisomer or a pharmaceutically acceptable
salt thereof comprising the scheme: ##STR00202## wherein a succinic
derivative (11) is coupled to an aminolactam (27) using a coupling
agent comprising HATU, TBTU, BOP, pyBOP, EDC, CDI, DCC,
hydroxysuccinimide, mixed carboxylic anhydride, or phenyl ester;
the product being liberated from the solid phase by employing
dilute trifluoroacetic acid in CH.sub.2Cl.sub.2; and purified by
chromatography to obtain a structure of aid formula (Ia); wherein:
A is O; R.sup.1 is selected from: H; C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.10a; C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.1b; aryl substituted with 0-3 R.sup.1b;
and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.1b; R.sup.1s at
each occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl Cl, F. Br, I, .dbd.O, CN, NO.sub.2, NR.sup.5R.sup.6,
CF.sub.3; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b; aryl substituted with 0-3 R.sup.1b; and 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.1b; R.sup.1b, at each occurrence, is
independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
R.sup.2 is selected from H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10
carbocycle, C.sub.6-C.sub.10 aryl, and 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur; R.sup.3 is --(CR.sup.7R.sup.7a).sub.n--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
(CR.sup.7R.sup.7a).sub.n
N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).sub.m--R.-
sup.4,
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.-
sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)C(.dbd.O)--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.-
m--R.sup.4,
(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).-
sub.m--R.sup.4, or
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2N(R.sup.7b)--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; R.sup.3a
is H, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkenyloxy; R.sup.4 is
H, OH, OR.sup.14a, C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.4a, C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a,
C.sub.2-C.sub.6 alknynl substituted with 0-3 R.sup.4a,
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b, aryl
substituted with 0-3 R.sup.4b, or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.4b; R.sup.4a, at each occurrence, is independently
selected from H, F, Cl, Br, I, CF.sub.3, C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.4b, aryl substituted with 0-3
R.sup.4b, and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S--; R.sup.5 is H, OR.sup.14; C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.5b; C.sub.1-C.sub.6 alkoxy substituted
with 0-3 R.sup.5b; C.sub.2-C.sub.6 alkenyl substituted with 0-3
R.sup.5b; C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c; aryl
substituted with 0-3 R.sup.5c; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.5c; R.sup.5a is H, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyl, or C.sub.2-C.sub.4
alkenyloxy; R.sup.5b, at each occurrence, is independently selected
from: H, C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.5c; aryl substituted with 0-3
R.sup.5c; and to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.5c;
R.sup.5c, at each occurrence, is independently selected from H, OH,
Cl, F. Br, I, CN, NO.sub.2 NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S; R.sup.6 is H; C.sub.1-C.sub.6 alkyl substituted with
0-3 R.sup.6a; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.6b; or aryl substituted with 0-3 R.sup.6b; R.sup.6a, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, OR.sup.14, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16, aryl and CF.sub.3; R.sup.6b, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
R.sup.7, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4
alkyl; R.sup.7a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; R.sup.7b is selected from H and C.sub.1-C.sub.4 alkyl; Ring
B is ##STR00203## Z is H; C.sub.1-C.sub.8 alkyl substituted with
1-3 R.sup.12; C.sub.2-C.sub.4 alkenyl substituted with 1-3
R.sup.12; C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a; aryl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10 carbocycle
substituted with 0-4 R.sup.12b; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.12b; R.sup.12, at each occurrence, is independently
selected from aryl substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10
carbocycle substituted with 0-4 R.sup.12b; and 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.12b: R.sup.12a, at each occurrence, is
independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy and C.sub.1-C.sub.4
haloalkyl-S; R.sup.12b, at each occurrence, is independently
selected from H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S; R.sup.13, at each occurrence, is
independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, and CF.sub.3; R.sup.14 is H, phenyl, benzyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, or
C.sub.3-C.sub.6 cycloalkyl; R.sup.14a is H, phenyl, benzyl, or
C.sub.1-C.sub.4 alkyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, aryl
substituted by 0-4 R.sup.17a, or --CH.sub.2-aryl substituted by 0-4
R.sup.17a; and R.sup.17a, at each occurrence, is independently
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy,
--OH, F, Cl, Br, I, CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3,
SO.sub.2CH.sub.3, --NH.sub.2, --N(CH.sub.3).sub.2, and
C.sub.1-C.sub.4 haloalkyl; provided, when R.sup.13 is H, then Z is
H; C.sub.4-C.sub.8 alkyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a; or
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a.
27. A process according to claim 25, for preparing a compound of
Formula (Ia'): ##STR00204## a stereoisomer, or a pharmaceutically
acceptable salt thereof, wherein: A is O; R.sup.3 is
--(CR.sup.7R.sup.7a).sub.n--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--, --(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4,
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4,
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).sub.m---
R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)--(CR.sup.7R.sup.7a).sub.m---
R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)C(.dbd.O)--(CR.sup.7R.sup.-
7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.-
m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)S(.dbd.O).sub.2--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4, or
--(CR.sup.7R.sup.7a).sub.n--S(O).sub.2N(R.sup.7b)--(CR.sup.7R.sup.7a).sub-
.m--R.sup.4; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; R.sup.3a is H,
OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4
alkenyl or C.sub.2-C.sub.4 alkenyloxy; R.sup.4 is H, OH,
OR.sup.14a, C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.4a,
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a,
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.4a,
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b, aryl
substituted with 0-3 R.sup.4b, or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.4b; R.sup.4a, at each occurrence, is independently
selected from H, F, Cl, Br, I, CF.sub.3, C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.4b, aryl substituted with 0-3
R.sup.4b, and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S--; R.sup.5 is H, OR.sup.14; C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.5b; C.sub.1-C.sub.6 alkoxy substituted
with 0-3 R.sup.5b; C.sub.2-C.sub.6 alkenyl substituted with 0-3
R.sup.5b; C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c; aryl
substituted with 0-3 R.sup.5c; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.5c; R.sup.5a is H, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyl, or C.sub.2-C.sub.4
alkenyloxy; R.sup.5b, at each occurrence, is independently selected
from: H, C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.5c; aryl substituted with 0-3
R.sup.5c; and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.5c;
R.sup.5c, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S; R.sup.6 is H; C.sub.1-C.sub.6 alkyl substituted with
0-3 R.sup.6a; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.6b; or aryl substituted with 0-3 R.sup.6b; R.sup.6a, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, OR.sup.14, Cl, F, Br, I, --O, CN, NO.sub.2,
NR.sup.15R.sup.16, aryl and CF.sub.3; R.sup.6b, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
R.sup.7, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4
alkyl; R.sup.7a, at each occurrence, is independently selected from
H, OH, Cl, F. Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; R.sup.7b is selected from H and C.sub.1-C.sub.4 alkyl; Ring
B is ##STR00205## Z is H; C.sub.1-C.sub.8 alkyl substituted with
1-3 R.sup.12; C.sub.2-C.sub.4 alkenyl substituted with 113
R.sup.12; C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a; aryl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10 carbocycle
substituted with 0-4 R.sup.12b; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.12b; R.sup.12, at each occurrence, is independently
selected from aryl substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10
carbocycle substituted with 0-4 R.sup.12b; and 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.12b; R.sup.12a, at each occurrence, is
independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S; R.sup.12b, at each occurrence, is independently
selected from H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S; R.sup.13 at each occurrence is
independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, and CF.sub.3; R.sup.14 is H, phenyl, benzyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, or
C.sub.3-C.sub.6 cycloalkyl; R.sup.14a is H, phenyl, benzyl, or
C.sub.1-C.sub.4 alkyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, aryl
substituted by 0-4 R.sup.17a, or --CH.sub.2-aryl substituted by 0-4
R.sup.17a; and R.sup.17a, at each occurrence, is independently
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy,
--OH, F, Cl, Br, I, CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3,
SO.sub.2CH.sub.3, --NH.sub.2, --N(CH.sub.3).sub.2, and
C.sub.1-C.sub.4 haloalkyl; provided, when R.sup.13 is H, then Z is
H; C.sub.4-C.sub.8 alkyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a; or
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a.
28. A process according to claim 27, for preparing a compound of
Formula (Ia'): ##STR00206## a stereoisomer, or a pharmaceutically
acceptable salt thereof, wherein: Z is H; C.sub.1-C.sub.8 alkyl
substituted with 0-3 R.sup.12a; C.sub.2-C.sub.4 alkenyl substituted
with 0-3 R.sup.12a; or C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.12a.
29. A process according to claim 27 for preparing a compound, of
Formula (Ia'): ##STR00207## a stereoisomer, or a pharmaceutically
acceptable salt thereof, wherein: Ring B is ##STR00208## Z is
C.sub.1-C.sub.8 alkyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12; aryl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10 carbocycle
substituted with 0-4 R.sup.12b; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.12b; provided, when R.sup.13 is H, then Z is
C.sub.4-C.sub.8 alkyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12; or
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12.
30. A process according to claim 27 for preparing a compound, of
Formula (Ia'): ##STR00209## a stereoisomer, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.5 is
--(C.sup.7R.sup.7a)--R.sup.4, --(CR.sup.7R.sup.7a),
--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4, or
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4; n is 0, 1, or 2; m is 0, 1, or 2; R.sup.3a is H, OH, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, allyl, or
3-buten-1-yl; R.sup.4 is H, OH, OR.sup.14a, C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.4a, C.sub.2-C.sub.6 alkenyl substituted
with 0-3 R.sup.4a, C.sub.2-C.sub.6 alkynyl substituted with 0-3
R.sup.4a, C.sub.3-C.sub.1 carbocycle substituted with 0-3 R.sup.4b,
aryl substituted with 0-3 R.sup.4b, or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur wherein said 5 to 11 membered heterocycle is substituted
with 0-3 R.sup.4b; R.sup.4a, at each occurrence, is independently
selected from H, F, Cl, Br, I, CF.sub.3, C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.4b, aryl substituted with 0-3
R.sup.4b, and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, and C.sub.1-C.sub.4 haloalkoxy; R.sup.5 is H, OR.sup.14;
C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b;
C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b;
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c; aryl
substituted with 0-3 R.sup.5c; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.5c; R.sup.5a is H or C.sub.1-C.sub.4 alkyl;
R.sup.5b, at each occurrence, is independently selected from: H,
C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I, .dbd.O,
CN, NO.sub.2, NR.sup.15R.sup.16; C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.5c; aryl substituted with 0-3 R.sup.5c;
and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.5c; R.sup.5c, at
each occurrence, is independently selected from H, OH, Cl, F, Br,
I, CN, NO.sub.2, N.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; R.sup.6 is H, methyl, or ethyl;
R.sup.7, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3 phenyl, and C.sub.1-C.sub.4
alkyl; R.sup.7a, at each occurrence, is independently selected from
H, OH, Cl, F. Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; R.sup.7b is selected from H, methyl, ethyl, propyl, and
butyl; Ring B is ##STR00210## Z is C.sub.1-C.sub.6 alkyl
substituted with 1-3 R.sup.12; C.sub.2-C.sub.4 alkenyl substituted
with 1-3 R.sup.12; C.sub.2-C.sub.4 alkynyl substituted with 1-3
R.sup.12; aryl substituted with 0-4 R.sup.12b; C.sub.3-C.sub.10
carbocycle substituted with 0-4 R.sup.12b; or 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.12b; R.sup.12, at each occurrence, is
independently selected from aryl substituted with 0-4 R.sup.12b;
C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b; and 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.12b; R.sup.12b, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy;
R.sup.13, at each occurrence, is independently selected from H, OH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3; R.sup.14 is, at each
occurrence, H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or
C.sub.2-C.sub.6 alkoxyalkyl; R.sup.14a is H, phenyl, benzyl,
methyl, ethyl, propyl, or butyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2; R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkyoxyalkyl, aryl
substituted by 0-4 R.sup.17a, or --CH.sub.2-aryl substituted by 0-4
R.sup.17a; R.sup.17a is, at each occurrence, H, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, propoxy, butoxy, --OH, F, Cl, Br,
I, CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3,
--NH.sub.2, --N(CH.sub.3).sub.2, or C.sub.1-C.sub.4 haloalkyl;
provided, when R.sup.13 is H, then Z is C.sub.4-C.sub.6 alkyl
substituted with 1-3 R.sup.12; C.sub.2-C.sub.4 alkenyl substituted
with 1-3 R.sup.12.
31. A process according to claim 27 for preparing a compound, of
Formula (Ia'): ##STR00211## a stereoisomer, or a pharmaceutically
acceptable salt thereof wherein: R.sup.3 is
--(CR.sup.7R.sup.7a).sub.n--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
or
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4; n is 0, 1, or 2; n is 0, 1, or 2; R.sup.3a is H, OH, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, allyl, or
3-buten-1-yl; R.sup.4 is H, OH, OR.sup.14a, C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.4a, alkenyl substituted with 0-3
R.sup.4a, C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.4a,
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b, aryl
substituted with 0-3 R.sup.4b, or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.4b; R.sup.4a, at each occurrence, is independently
selected from H, F, Cl, Br, I, CF.sub.3, C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.4b, aryl substituted with 0-3
R.sup.4b, and 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, and C.sub.1-C.sub.4 haloalkoxy; R.sup.5 is H OR.sup.14;
C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b;
C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c: aryl
substituted with 0-3 R.sup.5c; or 5 to 10 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 10 membered heterocycle is substituted
with 0-3 R.sup.5c; R.sup.5a is H or C.sub.1-C.sub.4 alkyl;
R.sup.5b, at each occurrence, is independently selected from: H,
C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I, .dbd.O,
CN, NO.sub.2, NR.sup.15R.sup.16; C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.5c; aryl substituted with 0-3 R.sup.5c;
and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.5c; R.sup.5c, at
each occurrence, is independently selected from H, OH, Cl, F, Br,
I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; R.sup.6 is H, methyl, or ethyl;
R.sup.7, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, phenyl, and C.sub.1-C.sub.4
alkyl; R.sup.7a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; R.sup.7b is selected from H, methyl, ethyl, propyl, and
butyl; Ring B is ##STR00212## R.sup.12, at each occurrence, is
independently selected from aryl substituted with 0-4 R.sup.12b;
C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b; and 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 11 membered
heterocycle is substituted with 0-3 R.sup.12b; R.sup.12b, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy;
R.sup.13, at each occurrence, is independently selected from H, OH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3; R.sup.14 is, at each
occurrence, H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or
C.sub.2-C.sub.6 alkoxyalkyl; R.sup.14a is H, phenyl, benzyl,
methyl, ethyl, propyl, or butyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--, R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, aryl
substituted by 0-4 R.sup.17a, or --CH.sub.2-aryl substituted by 0-4
R.sup.17a; R.sup.17a is, at each occurrence, H, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, propoxy, butoxy, --OH, F, Cl, Br,
I, CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3,
--NH.sub.2, --N(CH.sub.3).sub.2, or C.sub.1-C.sub.4 haloalkyl; and
provided, when R.sup.13 is H, then Z is C.sub.4-C.sub.6 alkyl
substituted with 1-3 R.sup.12; C.sub.2-C.sub.4 alkenyl substituted
with 1-3 R.sup.12; or C.sub.2-C.sub.4 alkynyl substituted with 1-3
R.sup.12.
32. A process according to claim 27 for preparing a compound of
Formula (Ia'), ##STR00213## a stereoisomer, or pharmaceutically
acceptable salt thereof wherein: R.sup.3 is --(CR.sup.7R.sup.7a),
--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
or --(CR.sup.7R.sup.7a).sub.n
N(R.sup.7b)--(CR.sup.7R.sup.7a)--R.sup.4; n is 0, 1, or 2; m is 0,
1, or 2; R.sup.3a is H, OH, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, butoxy, allyl, or 3-buten-1-yl; R.sup.4 is H, OH,
OR.sup.14a, C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.4a,
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a,
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.4a,
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b,
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.4b, or 5 to 10
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.4b; R.sup.4a, at each
occurrence, is independently selected from is H, F, Cl, Br, I,
CF.sub.3, C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.4b, C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.4b, or 5
to 10 membered heterocycle containing 1 to 4 heteroatoms selected
from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.4b; R.sup.4b, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; R.sup.5 is H, OR.sup.4;
C.sub.1-C.sub.6) alkyl substituted with 0-3 R.sup.5b;
C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b;
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or 5 to 10
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.5c; R.sup.5a is H or
C.sub.1-C.sub.4 alkyl; R.sup.5b, at each occurrence, is
independently selected from: H, C.sub.1-C.sub.6 alkyl, CF.sub.3,
OR.sup.14, Cl, F, Br, I, .dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or 5 to 10
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.5c; R.sup.5c, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; R.sup.6 is H, methyl, or ethyl;
R.sup.7, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4
alkyl; R.sup.7a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; R.sup.7b is independently selected from H, methyl, ethyl,
propyl, and butyl; Ring B is ##STR00214## Z is H; C.sub.1-C.sub.6
alkyl substituted with 0-3 R.sup.12a; C.sub.2-C.sub.4 alkenyl
substituted with 0-3 R.sup.12a; or C.sub.2-C.sub.4 alkynyl
substituted with 0-3 R.sup.12a; R.sup.12a, at each occurrence, is
independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S; R.sup.13, at each occurrence, is independently
selected from H, OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy,
Cl, F. Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3;
R.sup.14 is H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or
C.sub.2-C.sub.6 alkoxyalkyl; R.sup.14a is H, phenyl, benzyl,
methyl, ethyl, propyl, or butyl; R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, aryl
substituted by 0-4 R.sup.17a, or --CH.sub.2-aryl substituted by 0-4
R.sup.17a; and R.sup.17a is H, methyl, ethyl, propyl, butyl,
methoxy, ethoxy, propoxy, butoxy, --OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, or C.sub.1-C.sub.4 haloalkyl.
33. The process according to claim 25 to prepare a compound of
Formula (Ib), ##STR00215## a stereoisomer, or a pharmaceutically
acceptable salt thereof wherein: R.sup.3 is
--(CHR.sup.7).sub.n--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7).sub.m--R.sup.4, or
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4; n is 0 or 1; m is 0 or 1; R.sup.4 is H, OH, OR.sup.14a,
C.sub.1-C.sub.4 alkyl substituted with 0-2 R.sup.4a,
C.sub.2-C.sub.4 alkenyl substituted with 0-2 R.sup.4a,
C.sub.2-C.sub.4 alkenyl substituted with 0-2 R.sup.4a,
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, aryl
substituted with 0-3 R.sup.4b, or 5 to 6 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 6 membered heterocycle is substituted
with 0-3 R.sup.4b; R.sup.4a, at each occurrence, is independently
selected from H, F, Cl, Br, T, CF.sub.3, C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.4b, phenyl substituted with 0-3
R.sup.4b, and 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.4b,
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16. CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; R.sup.5 is H, OR.sup.14;
C.sub.1-C.sub.4 alkyl substituted with 0-3 R.sup.5b;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.5b; or
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.5b; R.sup.5b, at
each occurrence, is independently selected from: H, methyl, ethyl,
propyl, butyl, CF.sub.3, OR.sup.14, Cl, F, Br, I, .dbd.O;
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.5c; phenyl
substituted with 0-3 R.sup.5c; and 5 to 6 membered heterocycle
containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and
sulphur, wherein said 5 to 6 membered heterocycle is substituted
with 0-3 R.sup.5c; R.sup.5c, at each occurrence, is independently
selected from H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy;
R.sup.6 is H: R.sup.7, at each occurrence, is independently
selected from H, F, CF.sub.3, methyl, and ethyl; R.sup.7a, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4 alkyl; R.sup.7b is selected
from H and C.sub.1-C.sub.4 alkyl; Ring B is ##STR00216## Z is H;
C.sub.1-C.sub.4 alkyl substituted with 0-3 R.sup.12a;
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a; or
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a R.sup.12a at
each occurrence, is independently selected from H, OH, Cl, F, Br,
I, CN, NO.sub.2, NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S; R.sup.13, at each occurrence, is
independently selected from H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, and CF.sub.3; R.sup.14 is H, phenyl, benzyl,
C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4 alkoxyalkyl; R.sup.15, at
each occurrence, is independently selected from H, C.sub.1-C.sub.4
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.4 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.4 alkyl)-S(.dbd.O).sub.2--; R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.4
alkyl, benzyl, phenethyl, (C.sub.1-C.sub.4 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.4 alkyl)-S(.dbd.O).sub.2--; R.sup.17 is H, methyl,
ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl,
ethoxyethyl, phenyl substituted by 0-3 R.sup.17a, or
--CH.sub.2-phenyl substituted by 0-3 R.sup.17a; R.sup.17a, at each
occurrence, is independently selected from H., methyl, methoxy,
--OH, F, Cl, CF.sub.3, and OCF.sub.3.
34. The process according to claim 25 to prepare a compound of
Formula (If), ##STR00217## a stereoisomer, or a pharmaceutically
acceptable salt thereof wherein: R.sup.3 is R.sup.4, R.sup.4 is
C.sub.1-C.sub.4 alkyl substituted with 0-1 R.sup.4a,
C.sub.2-C.sub.4 alkenyl substituted with 0-1 R.sup.4a, or
C.sub.2-C.sub.4 alkynyl substituted with 0-1 R.sup.4a; R.sup.4a, at
each occurrence, is independently selected from H, F, CF.sub.3,
carbocycle substituted with 0-3 R.sup.4b, phenyl substituted with
0-3 R.sup.4b, or 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.4b;
wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl oxazolyl,
isoxazolyl, and tetrazolyl; R.sup.4b, at each occurrence, is
independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
--F.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; R.sup.5 is C.sub.1-C.sub.4 alkyl substituted with 0-1
Rb C.sub.2-C.sub.4 alkenyl substituted with 0-1 R.sup.5b;
C.sub.2-C.sub.4 alkyl substituted with 0-1 R.sup.5b; R.sup.5b, at
each occurrence, is independently selected from: H, methyl, ethyl,
propyl, butyl, CF.sub.3, OR.sup.14, .dbd.O; C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c; phenyl substituted with
0-3 R.sup.5c; or 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.5c;
wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; R.sup.5c, at each occurrence,
is independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; Z is C.sub.1-C.sub.3 alkyl substituted with 1-3
R.sup.12; C.sub.2-C.sub.3 alkenyl substituted with 1-3 R.sup.12;
C.sub.2-C.sub.3 alkynyl substituted with 1-3 R.sup.12;
C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12b;
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.12b; or 5 to
6 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered
heterocycle is substituted with 0-3 R.sup.12b; wherein said 5 to 6
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and
tetrazolyl; R.sup.12, at each occurrence, is independently selected
from C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12b;
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.12b; or 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.12b; wherein said 5 to 6
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and
tetrazolyl; R.sup.12b, at each occurrence, is independently
selected from H, OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; R.sup.13, at each
occurrence, is independently selected from H, OH, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR.sup.15R.sup.16,
and CF.sub.3; R.sup.14 is H, phenyl, benzyl, methyl, ethyl, propyl,
or butyl; R.sup.15, at each occurrence, is independently selected
from H, methyl, ethyl, propyl, and butyl; R.sup.16, at each
occurrence, is independently selected from H, OH, methyl, ethyl,
propyl, butyl, benzyl, phenethyl, methyl-C(.dbd.O)--,
ethyl-C(.dbd.O)--, methyl-S(.dbd.O).sub.2--, and
ethyl-S(.dbd.O).sub.2--; R.sup.18, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, butyl,
phenyl, benzyl, and phenethyl; and R.sup.19, at each occurrence, is
independently selected from H, methyl, and ethyl. provided, when
R.sup.13 is H, then Z is C.sub.2-C.sub.3 alkenyl substituted with
1-3 R.sup.12; or C.sub.2-C.sub.3 alkynyl substituted with 1-3
R.sup.12.
35. The process according to claim 34, to prepare a compound of
Formula (If), ##STR00218## a stereoisomer, or a pharmaceutically
acceptable salt thereof wherein: R.sup.3 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2(CH.sub.3).sub.2,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.dbd.CH.sub.2, --CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CH(CH.sub.3),
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3); --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
cyclopropyl-CH.sub.2--, cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
cyclopropyl-CH.sub.2CH.sub.2--, cyclobutyl-CH.sub.2CH.sub.2--,
cyclopentyl-CH.sub.2CH.sub.2--, cyclohexyl-CH.sub.2CH.sub.2--,
phenyl-CH.sub.2--, (2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, (2-C.sub.1-phenyl)CH.sub.2--,
(3-C.sub.1-phenyl)CH.sub.2--, (4-C.sub.1-phenyl)CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2--, (2,4-diF-phenyl)CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2--, (2,6-diF-phenyl)CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2--, (3,5-diF-phenyl)CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2--, (2,4-diCl-phenyl)CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2--, (2,6-diCl-phenyl)CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2--, (3,5-diCl-phenyl)CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2--, (3-F-5-Cl-phenyl)CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--, (2-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-Cl-phenyl)CH.sub.2CH.sub.2--, (4-Cl-phenyl)CH.sub.2CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--, or
(3-F-5-Cl-phenyl)CH.sub.2CH.sub.2--, R.sup.5 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.2CH.sub.3).sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3, --CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
cis-CH.sub.2CH.dbd.CH(CH.sub.3), trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(C.sub.6H.sub.5),
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
trans-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CHCH.sub.2 (C.sub.6H.sub.5) --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2C.ident.C(C.sub.6H.sub.5) --CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
--CH.sub.2CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
cyclopropyl-CH.sub.2--, cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2-cyclopropyl-CH.sub.2CH.sub.2--,
cyclobutyl-CH.sub.2CH.sub.2--, cyclopentyl-CH.sub.2CH.sub.2--,
cyclohexyl-CH.sub.2CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2CH.sub.2--, phenyl-CH.sub.2--,
(2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, furanyl-CH.sub.2--, thienyl-CH.sub.2--,
pyridyl-CH.sub.2--, 1-imidazolyl-CH.sub.2--, oxazolyl-CH.sub.2--,
isoxazolyl-CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--, furanyl-CH.sub.2CH.sub.2--,
thienyl-CH.sub.2CH.sub.2--, pyridyl-CH.sub.2CH.sub.2--,
1-imidazolyl-CH.sub.2CH.sub.2--, oxazolyl-CH.sub.2CH.sub.2--,
isoxazolyl-CH.sub.2CH.sub.2--, Z is phenyl, 2-F-phenyl, 3-F-phenyl,
4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,
2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl,
3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,
2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,
3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl,
4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl,
3-MeS-phenyl, 4-MeS-phenyl, 2-CF.sub.3O-phenyl, 3-CF.sub.3O-phenyl,
4-CF.sub.3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl,
3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,
1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
morpholino, N-piperinyl, phenyl-CH.sub.2--, (2-F-phenyl)CH.sub.2--,
(3-F-phenyl)CH.sub.2--, (4-F-phenyl)CH.sub.2--,
(2-Cl-phenyl)CH.sub.2--, (3-Cl-phenyl)CH.sub.2--,
14-Cl-phenyl)CH.sub.2--, (2,3-diF-phenyl)CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2--, (2,5-diF-phenyl)CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2--, (3,4-diF-phenyl)CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2--, (2,3-diCl-phenyl)CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2--, (2,5-diCl-phenyl)CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2--, (3,4-diCl-phenyl)CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2--, (3-F-4-Cl-phenyl)CH.sub.2--,
(3-F-5-Cl-phenyl)CH.sub.2--, (3-Cl-4-F-phenyl)CH.sub.2--,
(2-MeO-phenyl)CH.sub.2--, (3-MeO-phenyl)CH.sub.2--,
(4-MeO-phenyl)CH.sub.2--, (2-Me-phenyl)CH.sub.2--,
(3-Me-phenyl)CH.sub.2--, (4-Me-phenyl)CH.sub.2--,
(2-MeS-phenyl)CH.sub.2--, (3-MeS-phenyl)CH.sub.2--,
4-MeS-phenyl)CH.sub.2--, (2-CF.sub.3O-phenyl)CH.sub.2--,
(3-CF.sub.3O-phenyl)CH.sub.2--, (4-CF.sub.3O-phenyl)CH.sub.2--,
(furanyl)CH.sub.2--, (thienyl)CH.sub.2--, (pyridyl)CH.sub.2--,
(2-Me-pyridyl)CH.sub.2--, (3-Me-pyridyl)CH.sub.2--,
(4-Me-pyridyl)CH.sub.2--, (1-imidazolyl)CH.sub.2--,
(oxazolyl)CH.sub.2--, (isoxazolyl)CH.sub.2--,
(1-benzimidazolyl)CH.sub.2--, (cyclopropyl)CH.sub.2--,
(cyclobutyl)CH.sub.2--, (cyclopentyl) CH.sub.2--,
(cyclohexyl)CH.sub.2--, (morpholino)CH.sub.2--,
(N-piperidinyl)CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(phenyl).sub.2CHCH.sub.2--, (2-F-phenyl)CH.sub.2CH.sub.2--,
(3-F-phenyl)CH.sub.2CH.sub.2--, (4-F-phenyl, CH.sub.2CH.sub.2--,
(2-Cl-phenyl)CH.sub.2CH.sub.2--, (3-Cl-phenyl)CH.sub.2CH.sub.2--,
(4-Cl-phenyl)CH.sub.2CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-F-5-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2CH.sub.2--,
(2-MeO-phenyl)CH.sub.2CH.sub.2--, (3-MeO-phenyl)CH.sub.2CH.sub.2--,
(4-MeO-phenyl)CH.sub.2CH.sub.2--, (2-Me-phenyl)CH.sub.2CH.sub.2--,
(3-Me-phenyl)CH.sub.2CH.sub.2--, (4-Me-phenyl)CH.sub.2CH.sub.2--,
(2-MeS-phenyl)CH.sub.2CH.sub.2--, (3-MeS-phenyl)CH.sub.2CH.sub.2--,
(4-MeS-phenyl)CH.sub.2CH.sub.2--,
(2-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(3-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(4-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(furanyl)CH.sub.2CH.sub.2--, (thienyl)CH.sub.2CH.sub.2--,
(pyridyl)CH.sub.2CH.sub.2--, (2-Me-pyridyl)CH.sub.2CH.sub.2--,
(3-Me-pyridyl)CH.sub.2CH.sub.2--, (4-Me-pyridyl)CH.sub.2CH.sub.2--,
(imidazolyl)CH.sub.2CH.sub.2--, (oxazolyl)CH.sub.2CH.sub.2--,
(isoxazolyl)CH.sub.2CH.sub.2--, (benzimidazolyl)CH.sub.2CH.sub.2,
(cyclopropyl)CH.sub.2CH.sub.2--, (cyclobutyl)CH.sub.2CH.sub.2--,
(cyclopentyl)CH.sub.2CH.sub.2--, (cyclohexyl)CH.sub.2CH.sub.2--,
(morpholino)CH.sub.2CH.sub.2--, or
(N-pipridinyl)CH.sub.2CH.sub.2--; and R.sup.13, at each occurrence,
is independently selected from H, F, Cl, OH, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, and --CF.sub.3.
36. The process according to claim 25 to prepare a compound of
formula (If'). ##STR00219## or a stereoisomer or pharmaceutically
acceptable salt thereof R.sup.3 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2(CH.sub.3).sub.2, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2C(CH.sub.3).sub.3,
--CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3, --CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CH(CH.sub.3),
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3); --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
cyclopropyl-CH.sub.2--, cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
cyclopropyl-CH.sub.2CH.sub.2--, cyclobutyl-CH.sub.2CH.sub.2--,
cyclopentyl-CH.sub.2CH.sub.2--, cyclohexyl-CH.sub.2CH.sub.2--,
phenyl-CH.sub.2--, (2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, (2-Cl-phenyl)CH.sub.2--,
(3-Cl-phenyl)CH.sub.2--, (4-Cl-phenyl)CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2--, (2,4-diF-phenyl)CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2--, (2,6-diF-phenyl)CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2--, (3,5-diF-phenyl)CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2--, (2,4-diCl-phenyl)CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2--, (2,6-diCl-phenyl)CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2--, (3,5-diCl-phenyl)CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2--, (3-F-5-C.sub.1-phenyl)CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--, (2-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-Cl-phenyl)CH.sub.2CH.sub.2--, (4-Cl-phenyl)CH.sub.2CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--, or
(3-F-5-Cl-phenyl)CH.sub.2CH.sub.2--, R.sup.5 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.2CH.sub.3).sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3, --CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
cis-CH.sub.2CH.dbd.CH(CH.sub.3), trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(C.sub.6H.sub.5),
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
trans-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CHCH.sub.2(C.sub.6H.sub.5), --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2C.ident.C(C.sub.6H.sub.5) --CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
--CH.sub.2CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
cyclopropyl-CH.sub.2--, cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2--, cyclopropyl-CH.sub.2CH.sub.2--,
cyclobutyl-CH.sub.2CH.sub.2--, cyclopentyl-CH.sub.2CH.sub.2--,
cyclohexyl-CH.sub.2CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2CH.sub.2--, phenyl-CH.sub.2--,
(2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, furanyl-CH.sub.2--, thienyl-CH.sub.2--,
pyridyl-CH.sub.2--, 1-imidazolyl-CH.sub.2--, oxazolyl-CH.sub.2--,
isoxazolyl-CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--, furanyl-CH.sub.2CH.sub.2--,
thienyl-CH.sub.2CH.sub.2--, pyridyl-CH.sub.2CH.sub.2--,
1-imidazolyl-CH.sub.2CH.sub.2--, oxazolyl-CH.sub.2CH.sub.2--,
isoxazolyl-CH.sub.2CH.sub.2--, Z is phenyl, 2-F-phenyl, 3-F-phenyl,
4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,
2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl,
3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl,
2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,
3-F-5-Cl-phenyl, 3-Cl-4F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl,
4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl,
3-MeS-phenyl, 4-MeS-phenyl, 2-CF.sub.3O-phenyl, 3-CF.sub.3O-phenyl,
4-CF.sub.3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl,
3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,
1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
morpholino, N-piperinyl, phenyl-CH.sub.2--, (2-F-phenyl)CH.sub.2--,
(3-F-phenyl)CH.sub.2--, (4-F-phenyl)CH.sub.2--,
(2-Cl-phenyl)CH.sub.2--, (3-C.sub.1-phenyl)CH.sub.2--,
(4-Cl-phenyl)CH.sub.2--, (2,3-diF-phenyl)CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2--, (2,5-diF-phenyl)CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2--, (3,4-diF-phenyl)CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2--, (2,3-diCl-phenyl)CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2--, (2,5-diCl-phenyl)CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2--, (3,4-diCl-phenyl)CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2--, (3-F-4-Cl-phenyl)CH.sub.2--,
(3-F-5-Cl-phenyl)CH.sub.2--, (3-Cl-4-F-phenyl)CH.sub.2--,
(2-MeO-phenyl)CH.sub.2--, (3-MeO-phenyl)CH.sub.2--,
(4-MeO-phenyl)CH.sub.2--, (2-Me-phenyl)CH.sub.2--,
(3-Me-phenyl)CH.sub.2--, (4-Me-phenyl)CH.sub.2--,
(2-MeS-phenyl)CH.sub.2--, (3-MeS-phenyl)CH.sub.2--,
4-MeS-phenyl)CH.sub.2--, (2-CF.sub.3O-phenyl)CH.sub.2--,
(3-CF.sub.3O-phenyl)CH.sub.2--, (4-CF.sub.3O-phenyl)CH.sub.2--,
(furanyl)CH.sub.2--, (thienyl)CH.sub.2--, (pyridyl)CH.sub.2--,
(2-Me-pyridyl)CH.sub.2--, (3-Me-pyridyl)CH.sub.2--,
(4-Me-pyridyl)CH.sub.2--, (1-imidazolyl)CH.sub.2--,
(oxazolyl)CH.sub.2--, (isoxazolyl)CH.sub.2--,
(1-benzimidazolyl)CH.sub.2--, (cyclopropyl)CH.sub.2--,
(cyclobutyl)CH.sub.2--, (cyclopentyl)CH.sub.2--,
(cyclohexyl)CH.sub.2--, (morpholino)CH.sub.2--,
(N-piperidinyl)CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(phenyl).sub.2CHCH.sub.2--, (2-F-phenyl)CH.sub.2CH.sub.2--,
(3-F-phenyl)CH.sub.2CH.sub.2--, (4-F-phenyl)CH.sub.2CH.sub.2--,
(2-Cl-phenyl)CH.sub.2CH.sub.2--, (3-Cl-phenyl)CH.sub.2CH.sub.2--,
(4-Cl-phenyl)CH.sub.2CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-F-5-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2CH.sub.2--,
(2-MeO-phenyl)CH.sub.2CH.sub.2--, (3-MeO-phenyl)CH.sub.2CH.sub.2--,
(4-MeO-phenyl)CH.sub.2CH.sub.2--, (2-Me-phenyl)CH.sub.2CH.sub.2--,
(3-Me-phenyl)CH.sub.2CH.sub.2--, (4-Me-phenyl)CH.sub.2CH.sub.2--,
(2-MeS-phenyl)CH.sub.2CH.sub.2--, (3-MeS-phenyl)CH.sub.2CH.sub.2--,
(4-MeS-phenyl)CH.sub.2CH.sub.2--,
(2-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(3-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(4-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(furanyl)CH.sub.2CH.sub.2--, (thienyl)CH.sub.2CH.sub.2--,
(pyridyl)CH.sub.2CH.sub.2--, (2-Me-pyridyl)CH.sub.2CH.sub.2--,
(3-Me-pyridyl)CH.sub.2CH.sub.2--, (4-Me-pyridyl)CH.sub.2CH.sub.2--,
(imidazolyl)CH.sub.2CH.sub.2--, (oxazolyl)CH.sub.2CH.sub.2--,
(isoxazolyl)CH.sub.2CH.sub.2--, (benzimidazolyl)CH.sub.2CH.sub.2,
(cyclopropyl)CH.sub.2CH.sub.2--, (cyclobutyl)CH.sub.2CH.sub.2--,
(cyclopentyl)CH.sub.2CH.sub.2--, (cyclohexyl)CH.sub.2CH.sub.2--,
(morpholino)CH.sub.2CH.sub.2--, or
(N-piperidinyl)CH.sub.2CH.sub.2--.
37. The process according to claim 25 to prepare Example Compound
47, (2R,3S) N1
[6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-
-3 allyl-butanediamide, or a stereoisomer, or a pharmaceutically
acceptable salt thereof, comprising: step 1, according to a scheme
for preparing intermediate Compound (47'), ##STR00220## comprising:
(i) adding 2.29 mmol HATU and 7.05 mmol DIPEA to a solution of 1.76
mmol amine 31, 1.94 mmol succinate 9, and DMF at 0.degree. C.; (ii)
allowing the solution to warm to room temperature while stirring
for 18 h; (iii) removing the DMF under reduced pressure; and (iv)
dissolving the residue in ethyl acetate, washing with 0.1 N HCl
(2.times.100 mL) and 5% aqueous NaHCO.sub.3 (2.times.100 mL),
drying over anhydrous Na.sub.2SO.sub.4, and concentrating to a
brown oil; and (v) purifying the crude product further via silica
gel column chromatography (1% MeOH, 99% CH.sub.2Cl.sub.2) to yield
47' (70.5%) as a pale yellow solid; characterized by .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 0.87-1.42 (m, 9H), 1.48 (d, 9H),
2.21-2.79 (m, 4H), 3.38 (s, 3H), 4.92-5.11 (m, 3H), 5.41 (d, 1H),
5.72 (m, 1H), 7.29-7.65 (m, 8H). CT MS m/z=491
[C.sub.30H.sub.38N.sub.2O.sub.4.sup.+H].sup.+; step 2: according to
a scheme for preparing intermediate Compound 47'' ##STR00221##
comprising: (i) dissolving 1.24 mmol t-Butyl ester 47' in TFA (ii)
stirring for 4 h at room temperature under N.sub.2; (iii) removing
the TFA under reduced pressure, and (iv) dissolving the residue in
ethyl acetate, washing with a saturated solution of aqueous
NaHCO.sub.3 (2.times.50 mL), drying over anhydrous
Na.sub.2SO.sub.4, and concentrating to yield 47'' (71%) as a pale
yellow foam; characterized by: .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 0.8-1.82 (m, 9H), 2.25-2.55 (m, 4H), 3.28 (s, 3H),
4.91-5.20 (m, 3H), 5.48 (s, 1H), 5.7-5.9 (m, 1H), 7.35-7.76 (m,
8H); and step 3, according to a scheme for preparing Example
Compound 47: ##STR00222## comprising (i) bubbling ammonia gas
through a solution of 0.88 mmol 47'' in DMF in the presence of 1.1
mmol HATU, and 4.3 mmol DIPEA at 0.degree. C. for 10 mm, stirring
the solution for 18 h to while warming to room temperature; (ii)
removing the DMF tinder reduced pressure, dissolving the resulting
residue in ethyl acetate, followed by washing with 0.1 N HCI
(2.times.100 mL), brine (2.times.100 mL), drying over anhydrous
Na.sub.2SO.sub.4, and concentrating to yield a light brown oil; and
(iii) purifying the crude material further via silica gel
chromatography (2% MeOH, 98% CH.sub.2Cl.sub.2) to yield the title
compound, Example 47, as an off-white solid (55%): mp
137-145.degree. C., characterized by: .sup.1H NMR (500 MHz,
CDCl.sub.3) 60.82-1.08 (m, 6H), 1.22-1.79 (m, 3H) 2.13-2.82 (m, 4H)
3.35 (s, 3H) 4.94-5.12 (m, 3H), 5.36 (d, 1H), 5.52 (d, 1H),
5.67-5.81 (m, 1H), 7.30-7.63 (m, 8H); IR (KBr) 3334, 2955, 1654,
1498, 1386 cm.sup.-1; CI MS m/z=434
[C.sub.26H.sub.31N.sub.3O.sub.3+H]; HPLC 95.4% tr=17.65 min. Anal.
Calcd. for C.sub.26H.sub.31N.sub.3O.sub.3 0.25 H.sub.2O: C, 72.29;
H. 7.25; N 9.59, Found: C, 71.22; H, 7.13; N, 9.32.
38. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 25, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
39. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 26, a stereoisomer, or
a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
40. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 27, a stereoisomer, or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
41. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 28, a stereoisomer, or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
42. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 29, a stereoisomer, or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
43. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 30, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
44. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 31, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
45. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 32, a stereoisomer, or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
46. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 33, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
47. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 34, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
48. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 35, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
49. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 36, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
50. A process for preparing a pharmaceutical composition combining
a compound according to the process of claim 37, a stereoisomer, or
a pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional application of U.S. patent application
Ser. No. 12/061,227, filed Apr. 2, 2008, which is a divisional of
U.S. patent application Ser. No. 12/045,126, filed Mar. 10, 2008,
which is a divisional of U.S. patent application Ser. No.
11/331,791, filed Jan. 13, 2006, which is a divisional application
of U.S. patent application Ser. No. 11/230,203, filed Sep. 19,
2005, (now U.S. Pat. No. 7,304,049), which is a continuation
application of U.S. patent application Ser. No. 09/505,788, filed
Feb. 17, 2000, (now U.S. Pat. No. 7,053,084), which is a continua
ion-in-part of U.S. patent application Ser. No. 09/469,939, filed
Dec. 24, 1999, abandoned, which claims benefit of U.S. Provisional
application Ser. No. 60/113,588, filed Dec. 24, 1998, the contents
of which are incorporated herein in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to novel lactams having drug and
bio-affecting properties, their pharmaceutical compositions and
methods of use. These novel compounds inhibit the processing of
amyloid precursor protein and, more specifically, inhibit the
production of A.beta.-peptide, thereby acting to prevent the
formation of neurological deposits of amyloid protein. More
particularly, the present invention relates to the treatment of
neurological disorders related to .beta.-amyloid production such as
Alzheimer's disease and Down's Syndrome.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) is a degenerative brain disorder
characterized clinically by progressive loss of memory, temporal
and local orientation, cognition, reasoning, judgment and
emotionally stability. AD is a common cause of progressive dementia
in humans and is one of the major causes of death in the United
States. AD has been observed in all races and ethnic groups
worldwide, and is a major present and future health problem. No
treatment that effectively prevents AD or reverses the clinical
symptoms and underlying pathophysiology is currently available (for
review, Selkoe, 1994).
[0004] Histopathological examination of brain tissue derived upon
autopsy or from neurosurgical specimens in effected individuals
revealed the occurrence of amyloid plaques and neurofibrillar
tangles in the cerebral cortex of such patients. Similar
alterations were observed in patients with Trisomy 21 (Down's
syndrome), and hereditary cerebral hemorrhage with amyloidosis of
the Dutch-type. Neurofibrillar tangles are nonmembrane-bound
bundles of abnormal proteinaceous filaments and biochemical and
immunochemical studies led to the conclusion that their principle
protein subunit is an altered phosphorylated form of the tau
protein (reviewed in Selkoe, 1994).
[0005] Biochemical and immunological studies revealed that the
dominant proteinaceous component of the amyloid plaque is an
approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino
acids. This protein was designated A.beta., .beta.-amyloid peptide,
and sometimes .beta./A4; referred to herein as A.beta.. In addition
to its deposition in amyloid plaques, A.beta. is also found in the
walls of meningeal and parenchymal arterioles, small arteries,
capillaries, and sometimes, venules. A.beta. was first purified and
a partial amino acid reported in 1984 (Glenner and Wong, Biochem.
Biophys. Res. Commun. 120: 885-890). The isolation and sequence
data for the first 28 amino acids are described in U.S. Pat. No.
4,666,829.
[0006] Compelling evidence accumulated during the last decade
revealed that A.beta. is an internal polypeptide derived from a
type I integral membrane protein, termed .beta. amyloid precursor
protein (APP). .beta. APP is normally produced by many cells both
in vivo and in cultured cells, derived from various animals and
humans. A.beta. is derived from cleavage of .beta. APP by as yet
unknown enzyme (protease) system(s), collectively termed
secretases.
[0007] The existence of at least four proteolytic activities has
been postulated. They include .beta. secretase(s), generating the
N-terminus of A.beta., .alpha. secretase(s) cleaving around the
16/17 peptide bond in A.beta., and .gamma. secretases, generating
C-terminal A.beta. fragments ending at position 38, 39, 40, 42, and
43 or generating C-terminal extended precursors which are
subsequently truncated to the above polypeptides.
[0008] Several lines of evidence suggest that abnormal accumulation
of A.beta. plays a key role in the pathogenesis of AD. Firstly,
A.beta. is the major protein found in amyloid plaques. Secondly,
A.beta. is neurotoxic and may be causally related to neuronal death
observed in AD patients. Thirdly, missense DNA mutations at
position 717 in the 770 isoform of .beta. APP can be found in
effected members but not unaffected members of several families
with a genetically determined (familiar) form of A.beta.. In
addition, several other .beta. APP mutations have been described in
familiar forms of AD. Fourthly, similar neuropathological changes
have been observed in transgenic animals overexpressing mutant
forms of human .beta. APP. Fifthly individuals with Down's syndrome
have an increased gene dosage of .beta. APP and develop early-onset
AD. Taken together, these observations strongly suggest that
A.beta. depositions may be causally related to the AD.
[0009] It is hypothesized that inhibiting the production of A.beta.
will prevent and reduce neurological degeneration, by controlling
the formation of amyloid plaques, reducing neurotoxicity and,
generally, mediating the pathology associated with A.beta.
production. One method of treatment methods would therefore be
based on drugs that inhibit the formation of A.beta. in vivo.
[0010] Methods of treatment could target the formation of A.beta.
through the enzymes involved in the proteolytic processing of
.beta. amyloid precursor protein. Compounds that inhibit .beta. or
.gamma. secretase activity, either directly or indirectly, could
control the production of A.beta.. Advantageously, compounds that
specifically target, secretases, could control the production of
A.beta.. Such inhibition of .beta. or .gamma. secretases could
thereby reduce production of A.beta., which, thereby, could reduce
or prevent the neurological disorders associated with A.beta.
protein.
[0011] PCT publication number WO 96/29313 discloses the general
formula:
##STR00002##
covering metalloprotease inhibiting compounds useful for the
treatment of diseases associated with excess and/or unwanted matrix
metalloprotease activity, particularly collagenase and or
stromelysin activity.
[0012] Compounds of general formula:
##STR00003##
are disclosed in PCT publication number WO 95/22966 relating to
matrix metalloprotease inhibitors. The compounds of the invention
are useful for the treatment of conditions associated with the
destruction of cartilage, including corneal ulceration,
osteoporosis, periodontitis and cancer.
[0013] European Patent Application number EP 0652009A1 relates to
the general formula:
##STR00004##
and discloses compounds that are protease inhibit that A.beta.
production.
[0014] U.S. Pat. No. 5,703,129 discloses the general formula:
##STR00005##
which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives
that inhibit A.beta. production and are useful in the treatment of
Alzheimer's disease.
[0015] Copending, commonly assigned U.S. patent application Ser.
No. 09/370,089 filed Aug. 7, 1999 (equivalent to international
application PCT US99/17717) discloses lactams of general
formula:
##STR00006##
wherein the lactam ring B is substituted by succinamide and a
carbocyclic, aryl, or heteroaryl group. These compounds inhibit the
processing of amyloid precursor protein and, more specifically,
inhibit the production of A.beta.-peptide, thereby acting to
prevent the formation of neurological deposits of amyloid
protein.
[0016] None of the above references teaches or suggests the
compounds of the present invention which are described in detail
below.
SUMMARY OF THE INVENTION
[0017] One object of the present invention is to provide novel
compounds which are useful as inhibitors of the production of
A.beta. protein or pharmaceutically acceptable salts or prodrugs
thereof.
[0018] It is another object of the present invention to provide
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of at
least one of the compounds of the present invention or a
pharmaceutically acceptable salt or prodrug form thereof.
[0019] It is another object of the present invention to provide a
method for treating degenerative neurological disorders comprising
administering to a host in need of such treatment a therapeutically
effective amount of at least one of the compounds of the present
invention or a pharmaceutically acceptable salt or prodrug form
thereof.
[0020] These and other objects, which will become apparent during
the following detailed description, have been achieved by the
inventors' discovery that compounds of Formula (I):
##STR00007##
or pharmaceutically acceptable salt or prodrug forms thereof,
wherein R.sup.3, R.sup.3a, R.sup.5, R.sup.5a, R.sup.6, A, Q, B, and
Z are defined below, are effective inhibitors of the production of
A.beta..
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0021] Thus, in a first embodiment, the present invention provides
a novel compound of Formula (I):
##STR00008##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0022] A is selected from O and S; [0023] Q is --NR.sup.1R.sup.2;
[0024] R.sup.1, at each occurrence, is independently selected from:
[0025] H; [0026] C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1a; [0027] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b: [0028] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.1b; and [0029] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.1b;
[0030] R.sup.1a, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3; [0031] C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.1b; [0032] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1b; and [0033] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.1b; [0034] R.sup.1b, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16. CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
[0035] R.sup.2 is independently selected from H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.10 carbocycle, C.sub.6-C.sub.10 aryl, and 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur; [0036] R.sup.3 is
--(CR.sup.7R.sup.7a).sub.n--R.sup.4, [0037]
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a)--R.sup.4, [0038]
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0039]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--R.sup.-
4, [0040]
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--
-R.sup.4, [0041]
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).sub.m--R.-
sup.4, [0042] --(C
R.sup.7R.sup.7a).sub.n--C(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0043]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)C(.dbd.O)--(CR.sup.7R.sup.7-
a).sub.m--R.sup.4, [0044]
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.-
m--R.sup.4,
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)S(.dbd.O).sub.2--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4, or [0045]
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2N(R.sup.7b)--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4; [0046] n is Q, 1, 2, or 3; [0047] m is 0, 1, 2,
or 3; [0048] R.sup.3a is H, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4
alkenyloxy; [0049] R.sup.4 is H, OH, OR.sup.14a, [0050]
C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.4a, [0051]
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a, [0052]
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.4a, [0053]
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b, [0054]
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.4b, or [0055] 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.4b; [0056] R.sup.4a, at
each occurrence, is independently selected from is H, F, Cl, Br, I,
CF.sub.3, [0057] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.4b, [0058] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.4b, or [0059] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 11 membered heterocycle is substituted with 0-3 R.sup.4b;
[0060] R.sup.4b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
[0061] C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkyl, [0062] C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 halothioalkyl-S--; [0063] R.sup.5 is H, OR.sup.14;
[0064] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b; [0065]
C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b; [0066]
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b; [0067]
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b; [0068]
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c; [0069]
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or [0070] 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.5c; [0071] R.sup.5a is H,
OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4
alkenyl, or C.sub.2-C.sub.4 alkenyloxy; [0072] R.sup.5b, at each
occurrence, is independently selected from: [0073] H,
C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I, .dbd.O,
CN, NO.sub.2, NR.sup.15R.sup.16; [0074] C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.5c; [0075] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.5c; or [0076] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.5c; [0077] R.sup.5c, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, [0078] C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, [0079]
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 halothioalkyl-S--;
[0080] R.sup.6 is H; [0081] C.sub.1-C.sub.6 alkyl substituted with
0-3 R.sup.6a; [0082] C.sub.3-C.sub.10 carbocycle substituted with
0-3 R.sup.6b; or [0083] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.6b; [0084] R.sup.6a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, aryl or CF.sub.3; [0085]
R.sup.6b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
C.sub.1-C.sub.6 alkyl C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, and C.sub.1-C.sub.4 haloalkoxy; [0086] R.sup.7, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4 alkyl; [0087]
R.sup.7a, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4 alkyl;
[0088] R.sup.7b is independently selected from H and
C.sub.1-C.sub.4 alkyl [0089] Ring B is a 7 membered lactam or
thiolactam, [0090] wherein the lactam or thiolactam is saturated,
partially saturated or unsaturated; [0091] wherein each additional
lactam carbon or thiolactam carbon is substituted with 0-2
R.sup.11; and, [0092] optionally, the lactam or thiolactam contains
a heteroatom selected from --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N.dbd., --NH--, and --N(R.sup.10)--; [0093]
additionally, two R.sup.11 substituents on adjacent atoms may be
combined to form a benzo fused radical; wherein said benzo fused
radical is substituted with 0-4 R.sup.13; [0094] additionally, two
R.sup.11 substituents on adjacent atoms may be combined to form a 5
to 6 membered heteroaryl fused radical, wherein said 5 to 6
membered heteroaryl fused radical comprises 1 or 2 heteroatoms
selected from N, O, and S; wherein said 5 to 6 membered heteroaryl
fused radical is substituted with 0-3 R.sup.13; [0095]
additionally, two R.sup.11 substituents on the same or adjacent
carbon atoms may be combined to form a C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.3; [0096] R.sup.10 is H,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.18R.sup.19,
[0097] S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.17;
[0098] C.sub.1-C.sub.6 alkyl optionally substituted with 0-3
R.sup.10a; [0099] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.10a; [0100] C.sub.3-C.sub.1 carbocycle substituted with 0-3
R.sup.10b; or [0101] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.10b; [0102] R.sup.10a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, or aryl
substituted with 0-4 R.sup.10b; [0103] R.sup.10b, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; [0104] R.sup.11, at each occurrence,
is independently selected from [0105] H, C.sub.1-C.sub.4 alkoxy,
Cl, F. Br, I, .dbd.O, CN, NO.sub.2, NR.sup.18R.sup.19,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.18R.sup.19,
S(.dbd.O).sub.2NR.sup.18R.sup.19, CF.sub.3; [0106] C.sub.1-C.sub.6
alkyl optionally substituted with 0-3 R.sup.11a; [0107]
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b; [0108]
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; or
[0109] 5 to 10 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.11b; [0110]
R.sup.11a, at each occurrence, is independently selected from
[0111] H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I, .dbd.O,
CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3; [0112] phenyl
substituted with 0-3 R.sup.11b; [0113] C.sub.3-C.sub.6 cycloalkyl
substituted with 0-3 R.sup.11b; and [0114] 5 to 6 membered
heterocycle containing 1 to 3 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.11b; [0115] R.sup.11b, at each
occurrence, is independently selected from H, OH, Cl, F. Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, [0116] C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, [0117]
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 halothioalkyl-S--;
[0118] Z is H; [0119] C.sub.1-C.sub.8 alkyl substituted with 1-3
R.sup.12; [0120] C.sub.2-C.sub.4 alkenyl substituted with 1-3
R.sup.12; [0121] C.sub.2-C.sub.4 alkynyl substituted with 1-3
R.sup.12; [0122] C.sub.1-C.sub.8 alkyl substituted with 0-3
R.sup.12a; [0123] C.sub.2-C.sub.4 alkenyl substituted with 0-3
R.sup.12a; [0124] C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.12a; [0125] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.2b; [0126] C.sub.3-C.sub.10 carbocycle substituted with 0-4
R.sup.12b; or [0127] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.12b; [0128] R.sup.12, at each occurrence, is independently
selected from [0129] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.2b; [0130] C.sub.3-C.sub.10 carbocycle substituted with 0-4
R.sup.12b; or [0131] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.12b; [0132] R.sup.12a, at each occurrence, is independently
selected from [0133] H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, [0134] S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
[0135] C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkyl, [0136] C.sub.1-C.sub.4 haloalkoxy, or
C.sub.1-C.sub.4 halothioalkyl-S--; [0137] R.sup.12b, at each
occurrence, is independently selected from [0138] H, OH, Cl, F, Br,
I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, [0139] C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, [0140]
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 halothioalkyl-S--;
[0141] R.sup.13, at each occurrence, is independently selected from
[0142] H, OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F,
Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3; [0143]
R.sup.14 is H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkoxyalkyl, or C.sub.3-C.sub.6 cycloalkyl; [0144]
R.sup.14a is H, phenyl, benzyl, or C.sub.1-C.sub.4 alkyl; [0145]
R.sup.15, at each occurrence, is independently selected from H,
C.sub.1-C.sub.6 alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--;
[0146] R.sup.16, at each occurrence, is independently selected from
[0147] H, OH, C.sub.1-C.sub.6 alkyl, benzyl, phenethyl, [0148]
(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--; [0149] R.sup.7 is H, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkoxyalkyl, [0150] aryl substituted by 0-4
R.sup.17a, or [0151] --CH.sub.2-aryl substituted by 0-4 R.sup.17a;
[0152] R.sup.17a is H, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, butoxy, --OH, F, Cl, Br, I, CF.sub.3, OCF.sub.3,
SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, or C.sub.1-C.sub.4 haloalkyl; [0153] R.sup.18,
at each occurrence, is independently selected from [0154] H,
C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl, [0155]
(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--; and [0156] R.sup.19, at each occurrence,
is independently selected from [0157] H, OH, C.sub.1-C.sub.6 alkyl,
phenyl, benzyl, phenethyl, [0158] (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--;
provided, when R.sup.3 is H. [0159] then Z is H; [0160]
C.sub.4-C.sub.8 alkyl substituted with 1-3 R.sup.12; [0161]
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12; [0162]
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12; [0163]
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a; [0164]
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a; or [0165]
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a; and
provided, when ring B is a
1,3,4,5-tetrahydro-1-(Z)-5-(R.sup.10)-6,6,7,7-tetra(R.sup.11)-2,4-dioxo-2-
H-1,5-diazepin-3-yl core, and R.sup.13 is H; then [0166] R.sup.10
is H, C(.dbd.O)R.sup.7, C(.dbd.O)OR.sup.17,
C(.dbd.O)NR.sup.18R.sup.19, [0167]
S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.7; or [0168]
C.sub.1-C.sub.6 alkyl optionally substituted with 0-3 R.sup.10a;
[0169] R.sup.10a, at each occurrence, is independently selected
from [0170] H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3.
[0171] [2] In a preferred embodiment the present invention provides
for a compound of Formula (Ia):
##STR00009##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0172] Z is H; [0173] C.sub.1-C.sub.8 alkyl substituted with 0-3
R.sup.12a; [0174] C.sub.2-C.sub.4 alkenyl substituted with 0-3
R.sup.12a; or [0175] C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.12a.
[0176] [3] In a more preferred embodiment the present invention
provides for a compound of Formula (Ia):
wherein: [0177] R.sup.3 is --(CR.sup.7R.sup.7a).sub.n--R.sup.4,
[0178]
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0179]
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
or [0180]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--
-R.sup.4; [0181] n is 0, 1, or 2; [0182] m is 0, 1, or 2; [0183]
R.sup.3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, butoxy, allyl, or 3-buten-1-yl; [0184] R.sup.4 is H, OH,
OR.sup.14a, [0185] C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.4a, [0186] C.sub.2-C.sub.6 alkenyl substituted with 0-3
R.sup.4a, [0187] C.sub.2-C.sub.6 alkynyl substituted with 0-3
R.sup.4a, [0188] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.4b, [0189] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.4b, or [0190] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b.
[0191] R.sup.4a, at each occurrence, is independently selected from
is H, F, Cl, Br, I, CF.sub.3, [0192] C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.4h, [0193] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.4b, or [0194] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.4b; [0195] R.sup.4b, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
[0196] R.sup.5 is H, OR.sup.14; [0197] C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.5b; [0198] C.sub.1-C.sub.6 alkoxy
substituted with 0-3 R.sup.5b; [0199] C.sub.2-C.sub.6 alkenyl
substituted with 0-3 R.sup.5b; [0200] C.sub.2-C.sub.6 alkynyl
substituted with 0-3 R.sup.5b; [0201] C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.5c; [0202] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.5c; or [0203] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.5c; [0204] R.sup.5a is H or
C.sub.1-C.sub.4 alkyl; [0205] R.sup.5b, at each occurrence, is
independently selected from: [0206] H, C.sub.1-C.sub.6 alkyl,
CF.sub.3, OR.sup.14, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16; [0207] C.sub.3-C.sub.10 carbocycle substituted
with 0-3 R.sup.5c; [0208] C.sub.6-C.sub.10 aryl substituted with
0-3 R.sup.5c; or [0209] 5 to 10 membered heterocycle containing 1
to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.5c; [0210] R.sup.5c, at each occurrence, is independently
selected from H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
[0211] R.sup.6 is H, methyl, or ethyl; [0212] R.sup.7, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4 alkyl; [0213]
R.sup.7a, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4 alkyl;
[0214] R.sup.7b is independently selected from H, methyl, ethyl,
propyl, and butyl; [0215] Ring B is a 7 membered lactam or
thiolactam, [0216] wherein the lactam or thiolactam is saturated,
partially saturated or unsaturated; [0217] wherein each additional
lactam carbon or thiolactam carbon is substituted with 0-2
R.sup.11; and, [0218] optionally, the lactam or thiolactam contains
a heteroatom selected from, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N.dbd., --NH--, and --N(R.sup.10)--; [0219]
additionally, two R.sup.11 substituents on adjacent atoms may be
combined to form a benzo fused radical; wherein said benzo fused
radical is substituted with 0-3 R.sup.13; [0220] additionally, two
R.sup.11 substituents on adjacent atoms may be combined to form a 5
to 6 membered heteroaryl fused radical, wherein said 5 to 6
membered heteroaryl fused radical comprises 1 or 2 heteroatoms
selected from N, O, and S; wherein said 5 to 6 membered heteroaryl
fused radical is substituted with 0-3 R.sup.13; [0221]
additionally, two R.sup.11 substituents on the same or adjacent
carbon atoms may be combined to form a C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.13; [0222] R.sup.10 is H,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.18R.sup.19,
[0223] S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.17;
[0224] C.sub.1-C.sub.6 alkyl optionally substituted with 0-2
R.sup.10a; [0225] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.11b; [0226] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.10b; or [0227] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.10b; [0228] R.sup.10a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, or phenyl
substituted with 0-4 R.sup.10b; [0229] R.sup.10b, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, or CF.sub.3; [0230] R.sup.11, at each
occurrence, is independently selected from [0231] H,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.18R.sup.19, C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17,
C(.dbd.O)NR.sup.18R.sup.19, S(.dbd.O).sub.2NR.sup.18R.sup.19,
CF.sub.3; [0232] C.sub.1-C.sub.6 alkyl optionally substituted with
0-3 R.sup.11a; [0233] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.11b; [0234] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.11b; or [0235] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.11b; [0236] R.sup.11a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl. OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, or phenyl
substituted with 0-3 R.sup.11b. [0237] R.sup.11b, at each
occurrence, is independently selected from [0238] H, OH, Cl, F, Br,
I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; [0239] Z is H; [0240] C.sub.1-C.sub.6
alkyl substituted with 0-3 R.sup.12a; [0241] C.sub.2-C.sub.4
alkenyl substituted with 0-3 R.sup.12a; or [0242] C.sub.2-C.sub.4
alkynyl substituted with 0-3 R.sup.12a; [0243] R.sup.12a, at each
occurrence, is independently selected from [0244] H, OH, Cl, F, Br,
I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl. SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; [0245] R.sup.13, at each occurrence, is
independently selected from [0246] H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, and CF.sub.3; [0247] R.sup.14 is H, phenyl,
benzyl, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6 alkoxyalkyl;
[0248] R.sup.14a is H, phenyl, benzyl, methyl, ethyl, propyl, or
butyl; [0249] R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, benzyl, phenethyl,
(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--; [0250] R.sup.16 at each occurrence, is
independently selected from [0251] H, OH, C.sub.1-C.sub.6 alkyl,
benzyl, phenethyl, [0252] (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; [0253] R.sup.17 is H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkoxyalkyl, [0254] aryl
substituted by 0-4 R.sup.17a, or [0255] --CH.sub.2-aryl substituted
by 0-4 R.sup.17a; [0256] R.sup.17a is H, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, butoxy, --OH, F, Cl, Br, I,
CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3,
--NH.sub.2, --N(CH.sub.3).sub.2, or C.sub.1-C.sub.4 haloalkyl;
[0257] R.sup.18, at each occurrence, is independently selected from
[0258] H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl, [0259]
(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--; and [0260] R.sup.19, at each occurrence,
is independently selected from [0261] H, OH, C.sub.1-C.sub.6 alkyl,
phenyl, benzyl, phenethyl, [0262] (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--.
[0263] [4] In a further more preferred embodiment the present
invention provides for a compound of Formula (Ia) wherein: [0264]
R.sup.3 is --(CHR.sup.7), --R.sup.4, [0265] n is 0 or 1; [0266]
R.sup.3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, butoxy, allyl, or 3-buten-1-yl: [0267] R.sup.4 is H, OH,
OR.sup.14a, [0268] C.sub.1-C.sub.4 alkyl substituted with 0-2
R.sup.4a. [0269] C.sub.2-C.sub.4 alkenyl substituted with 0-2
R.sup.4a, [0270] C.sub.2-C.sub.4 alkynyl substituted with 0-1
R.sup.4a, [0271] C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.4b. [0272] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.4h, or [0273] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.4b;
[0274] R.sup.4a, at each occurrence, is independently selected from
is H, F, Cl, Br, I, CFI, [0275] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.4b, [0276] phenyl substituted with 0-3
R.sup.4b, or [0277] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.4b;
[0278] R.sup.4b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0279] R.sup.5 is H,
OR.sup.14; [0280] C.sub.1-C.sub.4 alkyl substituted with 0-3
R.sup.5b; [0281] C.sub.2-C.sub.4 alkenyl substituted with 0-3
R.sup.5b; [0282] C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.5b; [0283] R.sup.5a is H, methyl, ethyl, propyl, or butyl;
[0284] R.sup.5b, at each occurrence, is independently selected
from: [0285] H, methyl, ethyl, propyl, butyl, CF.sub.3, OR.sup.14,
Cl, F, Br, I, .dbd.O; [0286] C.sub.3-C.sub.6 carbocycle substituted
with 0-3 R.sup.5c; [0287] phenyl substituted with 0-3 R.sup.5c; or
[0288] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.5c; [0289]
R.sup.5c, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0290] R.sup.6 is H;
[0291] R.sup.7, at each occurrence, is independently selected from
H, F, CF.sub.3, methyl, and ethyl; [0292] Ring B is a 7 membered
lactam or thiolactam, [0293] wherein the lactam or thiolactam is
saturated, partially saturated or unsaturated; [0294] wherein each
additional lactam carbon or thiolactam carbon is substituted with
O-2 R.sup.11; and, [0295] optionally, the lactam or thiolactam
contains a heteroatom selected from --N.dbd., --NH--, and
--N(R.sup.10)--; [0296] additionally, two R.sup.11 substituents on
adjacent atoms may be combined to form a benzo fused radical;
wherein said benzo fused radical is substituted with 0-2 R.sup.13;
[0297] additionally, two R.sup.11 substituents on adjacent atoms
may be combined to form a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1
or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6
membered heteroaryl fused radical is substituted with 0-2 R.sup.13:
[0298] additionally, two R.sup.11 substituents on the same or
adjacent carbon atoms may be combined to form a C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.13: [0299] R.sup.10 is H,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17; [0300] C.sub.1-C.sub.4 alkyl
optionally substituted with 0-1 R.sup.10a; [0301] phenyl
substituted with 0-4 R.sup.10b; [0302] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.10b; or [0303] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.10b; [0304] R.sup.10a, at each
occurrence, is independently selected from H, C.sub.1-C.sub.4
alkyl, OR.sup.14, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, or phenyl substituted with 0-4
R.sup.10b; [0305] R.sup.10b, at each occurrence, is independently
selected from H, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, or CF.sub.3; [0306]
R.sup.11, at each occurrence, is independently selected from [0307]
H, C.sub.1-C.sub.4 alkoxy, Cl, F, .dbd.O, NR.sup.18R.sup.19,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, CF.sub.3; [0308]
C.sub.1-C.sub.6 alkyl optionally substituted with 0-3 R.sup.11a;
[0309] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b; [0310]
C.sub.3-6 carbocycle substituted with 0-3 R.sup.11b; or [0311] 5 to
6 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered
heterocycle is substituted with 0-3 R.sup.11b; [0312] R.sup.1a, at
each occurrence, is independently selected from H, C.sub.1-C.sub.4
alkyl, OR.sup.14, F, .dbd.O, NR.sup.15R.sup.15R.sup.16, CF.sub.3,
or phenyl substituted with 0-3 R.sup.11b; [0313] R.sup.11b, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy;
[0314] Z is H; [0315] C.sub.1-C.sub.4 alkyl substituted with 0-3
R.sup.12a; [0316] C.sub.2-C.sub.4 alkenyl substituted with 0-3
R.sup.12a; or [0317] C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.12a; [0318] R.sup.12a, at each occurrence, is independently
selected from [0319] H, OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3,
acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0320] R.sup.13, at each
occurrence, is independently selected from [0321] H, OH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3; [0322] R.sup.14 is H,
phenyl, benzyl, C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4
alkoxyalkyl; [0323] R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-C.sub.4 alkyl, benzyl, phenethyl,
(C.sub.1-C.sub.4 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.4
alkyl)-S(.dbd.O).sub.2--; [0324] R.sup.16, at each occurrence, is
independently selected from [0325] H, OH, C.sub.1-C.sub.4 alkyl,
benzyl, phenethyl, [0326] (C.sub.1-C.sub.4 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.4 alkyl)-S(.dbd.O).sub.2--; [0327] R.sup.17 is H,
methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl,
methoxyethyl, ethoxyethyl, [0328] phenyl substituted by 0-3
R.sup.17a, or [0329] --CH.sub.2-phenyl substituted by 0-3
R.sup.17a; [0330] R.sup.17a is H, methyl, methoxy, --OH, F, Cl,
CF.sub.3, or OCF.sub.3; [0331] R.sup.18, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, butyl,
phenyl, benzyl, and phenethyl; [0332] R.sup.19, at each occurrence,
is independently selected from [0333] H, methyl, and ethyl.
[0334] [5] In an even more preferred embodiment the present
invention provides for a compound of Formula (Ib):
##STR00010##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0335] Ring B is selected from:
##STR00011##
[0336] [6] In an even further more preferred embodiment the present
invention provides for a compound of Formula (Ic):
##STR00012##
or a pharmaceutically acceptable salt or prodrug thereof wherein
[0337] R.sup.3 is R.sup.4, [0338] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0339] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0340] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0341] R.sup.4a, at each occurrence,
is independently selected from [0342] H, F, CF.sub.3, [0343]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0344]
phenyl substituted with 0-3 R.sup.4b, or [0345] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0346]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0347] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0348] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0349] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0350] R.sup.5b, at each occurrence,
is independently selected from: [0351] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0352] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c; [0353] phenyl substituted
with 0-3 R.sup.5c; or [0354] 5 to 6 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 6 membered heterocycle is substituted with 0-3
R.sup.5c; wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0355] R.sup.5c, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0356] R.sup.11, at each occurrence, is independently
selected from [0357] H, .dbd.O, NR.sup.18R.sup.19, CF.sub.3; [0358]
C.sub.1-C.sub.4 alkyl optionally substituted with 0-1 R.sup.11a;
[0359] phenyl substituted with 0-3 R.sup.11b; [0360]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b; and
[0361] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0362] R.sup.11a, at each occurrence,
is independently selected from H, C.sub.1-C.sub.4 alkyl, OR.sup.14,
F, Cl, .dbd.O, NR.sup.15R.sup.16, CF.sub.3, or phenyl substituted
with 0-3 R.sup.11b; [0363] R.sup.11b, at each occurrence, is
independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0364] Z
is HT [0365] C.sub.1-C.sub.4 alkyl substituted with 0-3 R.sup.12a;
[0366] C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a or
[0367] C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a;
[0368] R.sup.12a, at each occurrence, is independently selected
from [0369] H, OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0370] R.sup.13, at each
occurrence, is independently selected from [0371] H, OH, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN,
NR.sup.15R.sup.16, and CF.sub.3; [0372] R.sup.14 is H, phenyl,
benzyl, methyl, ethyl, propyl, or butyl; [0373] R.sup.15, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; [0374] R.sup.16, at each occurrence, is
independently selected from [0375] H, OH, methyl, ethyl, propyl,
butyl, benzyl, phenethyl, methyl-C(.dbd.O)--, ethyl-C(.dbd.O)--,
methyl-S(.dbd.O).sub.2--, and ethyl-S(.dbd.O).sub.2--; [0376]
R.sup.18, at each occurrence, is independently selected from [0377]
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0378] R.sup.19, at each occurrence, is independently selected from
[0379] H, methyl, and ethyl.
[0380] [7] In another even further more preferred embodiment the
present invention provides for a compound of Formula (Id):
##STR00013##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0381] R.sup.3 is R.sup.4, [0382] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0383] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0384] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0385] R.sup.4a, at each occurrence,
is independently selected from [0386] H, F, CF.sub.3, [0387]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0388]
phenyl substituted with 0-3 R.sup.4b, or [0389] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0390]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0391] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0392] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0393] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0394] R.sup.5b, at each occurrence,
is independently selected from: [0395] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0396] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c; [0397] phenyl substituted
with 0-3 R.sup.5c; or [0398] 5 to 6 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 6 membered heterocycle is substituted with 0-3
R.sup.5c; wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0399] R.sup.5, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0400] R.sup.11, at each occurrence, is independently
selected from [0401] H, .dbd.O, NR.sup.18R.sup.19, CF.sub.3; [0402]
C.sub.1-C.sub.4 alkyl optionally substituted with 0-1 R.sup.11a;
[0403] phenyl substituted with 0-3 R.sup.11b; [0404]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b; or
[0405] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0406] R.sup.11a, at each occurrence,
is independently selected from H, C.sub.1-C.sub.4 alkyl, OR.sup.14,
F, Cl, .dbd.O, NR.sup.15R.sup.16, CF.sub.3, or phenyl substituted
with 0-3 R.sup.11b; [0407] R.sup.11b, at each occurrence, is
independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0408] Z
is H; [0409] C.sub.1-C.sub.4 alkyl substituted with 0-3 R.sup.12a;
[0410] C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a; or
[0411] C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a;
[0412] R.sup.12a, at each occurrence, is independently selected
from [0413] H, OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0414] R.sup.13, at each
occurrence, is independently selected from [0415] H, OH, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN,
NR.sup.15R.sup.16 and CF.sub.3; [0416] R.sup.14 is H, phenyl,
benzyl, methyl, ethyl, propyl, or butyl; [0417] R.sup.15, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; [0418] R.sup.16, at each occurrence, is
independently selected from [0419] H, OH, methyl, ethyl, propyl,
butyl, benzyl, phenethyl, methyl-C(.dbd.O)--, ethyl-C(.dbd.O)--,
methyl-S(.dbd.O).sub.2--, and ethyl-S(.dbd.O).sub.2--; [0420]
R.sup.18, at each occurrence, is independently selected from [0421]
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0422] R.sup.19, at each occurrence, is independently selected from
[0423] H, methyl, and ethyl.
[0424] [8] In another even further more preferred embodiment the
present invention provides for a compound of Formula (Ie):
##STR00014##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0425] R.sup.3 is R.sup.4, [0426] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0427] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0428] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0429] R.sup.4a, at each occurrence,
is independently selected from [0430] H, F, CF.sub.3, [0431]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0432]
phenyl substituted with 0-3 R.sup.4b, or [0433] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0434]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0435] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0436] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0437] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0438] R.sup.5b, at each occurrence,
is independently selected from: [0439] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0440] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c; [0441] phenyl substituted
with 0-3 R.sup.5c; or [0442] 5 to 6 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 6 membered heterocycle is substituted with 0-3
R.sup.5c; wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0443] R.sup.5c, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0444] R.sup.10 is H, C(.dbd.O)R.sup.17,
C(.dbd.O)OR.sup.17; [0445] C.sub.1-C.sub.4 alkyl optionally
substituted with 0-1 R.sup.10a; [0446] phenyl substituted with 0-4
R.sup.10b; [0447] C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.10b; or [0448] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.10b
wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0449] R.sup.10a, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, butyl, OR.sup.14, C, F, O, NR.sup.15R.sup.16, CF.sub.3, or
phenyl substituted with 0-4 R.sup.10b; [0450] R.sup.10b, at each
occurrence, is independently selected from H, OH, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR.sup.15R.sup.16,
and CF.sub.3; [0451] Z is H, [0452] C.sub.1-C.sub.4 alkyl
substituted with 0-3 R.sup.12a; [0453] C.sub.2-C.sub.4 alkenyl
substituted with 0-3 R.sup.12a; or [0454] C.sub.2-C.sub.4 alkynyl
substituted with 0-3 R.sup.12a: [0455] R.sup.12a, at each
occurrence, is independently selected from [0456] H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0457] R.sup.13, at each occurrence, is independently
selected from [0458] H, OH, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, Cl, F, Br, CN, NR.sup.15R.sup.16, and CF.sub.3; [0459]
R.sup.14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
[0460] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl; [0461] R.sup.16, at each
occurrence, is independently selected from [0462] H, OH, methyl,
ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(.dbd.O)--,
ethyl-C(.dbd.O)--, methyl-S(.dbd.O).sub.2--, and
ethyl-S(.dbd.O).sub.2--; [0463] R.sup.17 is H, methyl, ethyl,
propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl,
ethoxyethyl, [0464] phenyl substituted by 0-3 R.sup.17a, or [0465]
--CH.sub.2-phenyl substituted by 0-3 R.sup.17a; [0466] R.sup.17a is
H, methyl, methoxy, --OH, F, Cl, CF.sub.3, or OCF.sub.3; [0467]
R.sup.18, at each occurrence, is independently selected from [0468]
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0469] R.sup.19, at each occurrence, is independently selected from
[0470] H, methyl, and ethyl.
[0471] [9] In another even further more preferred embodiment the
present invention provides for a compound of Formula (If):
##STR00015##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0472] R.sup.3 is R.sup.4, [0473] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0474] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0475] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0476] R.sup.4a, at each occurrence,
is independently selected from [0477] H, F, CF.sub.3, [0478]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0479]
phenyl substituted with 0-3 R.sup.4b, or [0480] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0481]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0482] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0483] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0484] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b: [0485] R.sup.5b, at each occurrence,
is independently selected from: [0486] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0487] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c; [0488] phenyl substituted
with 0-3 R.sup.5c, or [0489] 5 to 6 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 6 membered heterocycle is substituted with 0-3
R.sup.5c; wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0490] R.sup.5c, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0491] Z is H; [0492] C.sub.1-C.sub.4 alkyl substituted
with 0-3 R.sup.12a; [0493] C.sub.2-C.sub.4 alkenyl substituted with
0-3 R.sup.12a; or [0494] C.sub.2-C.sub.4 alkynyl substituted with
0-3 R.sup.12a; [0495] R.sup.12a at each occurrence, is
independently selected from [0496] H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, acetyl. SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0497] R.sup.13, at each occurrence, is independently
selected from [0498] H, OH, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, Cl, F. Br, CN, NR.sup.15R.sup.16 and CF.sub.3; [0499]
R.sup.14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
[0500] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl; [0501] R.sup.16, at each
occurrence, is independently selected from [0502] H, OH, methyl,
ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(.dbd.O)--,
ethyl-C(.dbd.O)--, methyl-S(.dbd.O).sub.2--, and
ethyl-S(.dbd.O).sub.2--; [0503] R.sup.18 at each occurrence, is
independently selected from [0504] H, methyl, ethyl, propyl, butyl,
phenyl, benzyl, and phenethyl; and [0505] R.sup.19, at each
occurrence, is independently selected from [0506] H, methyl, and
ethyl.
[0507] [10] In another even further more preferred embodiment the
present invention provides for a compound of one of Formulas (Ic),
(Id), (Ie), or (If), wherein: [0508] R.sup.3 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2(CH.sub.3).sub.2,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3, --CF.sub.3,
--CH.sub.2CF.sub.3--CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3, --CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CH(CH.sub.3)
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH--CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3); --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
cyclopropyl-CH.sub.2--, Cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
cyclopropyl-CH.sub.2CH.sub.2--, cyclobutyl-CH.sub.2CH.sub.2--,
cyclopentyl-CH.sub.2CH.sub.2--, cyclohexyl-CH.sub.2CH.sub.2--,
phenyl-CH.sub.2--, (2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, (2-C.sub.1-phenyl)CH.sub.2--,
(3-C.sub.1-phenyl)CH.sub.2--, (4-C.sub.1-phenyl)CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2--, (2,4-diF-phenyl)CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2--, (2,6-diF-phenyl)CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2--, (3,5-diF-phenyl)CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2--, (2,4-diCl-phenyl)CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2--, (2,6-diCl-phenyl)CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2--, (3,5-diCl-phenyl)CH.sub.2--,
(3-F-4-C.sub.1-phenyl)CH.sub.2--, (3-F-5-C.sub.1-phenyl)CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--, (2-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-C.sub.1-phenyl)CH.sub.2CH.sub.2--,
(4-C.sub.1-phenyl)CH.sub.2CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--, or
(3-F-5-C.sub.1-phenyl)CH.sub.2CH.sub.2--, [0509] R.sup.5 is
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3--CH.sub.2CH(CH.sub.3)CH.sub.2CH.su-
b.3, --CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH(CH.sub.2CH.sub.3).sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3, --CH.dbd.CH.sub.2,
--CH.sub.2CH--CH.sub.2, --CH.dbd.CHCH.sub.3,
cis-CH.sub.2CH--CH(CH.sub.3), trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(C.sub.6H.sub.5)--CH.sub.2CH.dbd.C(CH.sub.3).sub.2-
, cis-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3
trans-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH--CH(CH.sub.3),
trans-CH.sub.2CH--CHCH.sub.2(C.sub.6H.sub.5), --C.ident.CH,
--CH.sub.2C.ident.C.dbd.H, --CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2C.ident.C(C.sub.6H.sub.5) --CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
--CH.sub.2CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(CH.sub.3)--CH.sub.2CH.sub.2CH.sub.2C.-
ident.C(C.sub.6H.sub.5) cyclopropyl-CH.sub.2--
cyclobutyl-CH.sub.2--, cyclopentyl-CH.sub.2--,
cyclohexyl-CH.sub.2--, (2-CH.sub.3-cyclopropyl)CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2--, cyclopropyl-CH.sub.2CH.sub.2--,
cyclobutyl-CH.sub.2CH.sub.2--, cyclopentyl-CH.sub.2CH.sub.2--,
cyclohexyl-CH.sub.2CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2CH.sub.2--
(3-CH.sub.3-cyclobutyl)CH.sub.2CH.sub.2--, phenyl-CH.sub.2--,
(2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, furanyl-CH.sub.2--, thienyl-CH.sub.2--,
pyridyl-CH.sub.2--, 1-imidazolyl-CH.sub.2--, oxazolyl-CH.sub.2--,
isoxazolyl-CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2
(4-F-phenyl)CH.sub.2CH.sub.2--, furanyl-CH.sub.2CH.sub.2--,
thienyl-CH.sub.2CH.sub.2--, pyridyl-CH.sub.2CH.sub.2--,
1-imidazolyl-CH.sub.2CH.sub.2--, oxazolyl-CH.sub.2CH.sub.2--,
isoxazolyl-CH.sub.2CH.sub.2--, [0510] Z is methyl, ethyl, i-propyl,
n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, or allyl; [0511]
R.sup.10 is H, methyl, ethyl, phenyl, benzyl, phenethyl,
4-F-phenyl, (4-F-phenyl)CH.sub.2--, (4-F-phenyl)CH.sub.2CH.sub.2--,
4-Cl-phenyl, (4-Cl-phenyl)CH.sub.2--,
(4-Cl-phenyl)CH.sub.2CH.sub.2--, 4-CH.sub.3-phenyl
(4-CH.sub.3-phenyl)CH.sub.2--,
(4-CH.sub.3-phenyl)CH.sub.2CH.sub.2--, 4-CF.sub.3-phenyl,
(4-CF.sub.3-phenyl)CH.sub.2--, or
(4-CF.sub.3-phenyl)CH.sub.2CH.sub.2--; [0512] R.sup.11, at each
occurrence, is independently selected from [0513] H, .dbd.O,
methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,
(4-F-phenyl)CH.sub.2--, (4-F-phenyl)CH.sub.2CH.sub.2--, 3-F-phenyl,
(3-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--, 2-F-phenyl,
(2-F-phenyl)CH.sub.2--, (2-F-phenyl)CH.sub.2CH.sub.2--,
4-C.sub.1-phenyl, (4-C.sub.1-phenyl)CH.sub.2--,
(4-C.sub.1-phenyl)CH.sub.2CH.sub.2--, 3-C.sub.1-phenyl,
(3-C.sub.1-phenyl)CH.sub.2--, (3-C.sub.1-phenyl)CH.sub.2CH.sub.2--,
4-CH.sub.3-phenyl (4-CH.sub.3-phenyl)CH.sub.2--,
(4-CH.sub.3-phenyl)CH.sub.2CH.sub.2--, 3-CH.sub.3-phenyl,
(3-CH.sub.3-phenyl)CH.sub.2--,
(3-CH.sub.3-phenyl)CH.sub.2CH.sub.2--, 4-CF.sub.3-phenyl,
(4-CF.sub.3-phenyl)CH.sub.2--,
(4-CF.sub.3-phenyl)CH.sub.2CH.sub.2--, pyrid-2-yl, pyrid-3-yl, or
pyrid-4-yl and [0514] R.sup.13, at each occurrence, is
independently selected from H, F, Cl, OH, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, or --CF.sub.3.
[0515] [11] In another even further more preferred embodiment the
present invention provides for a compound selected from: [0516]
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-allyl-butanediamide; [0517] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-propyl-butanediamide; [0518] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-allyl-butanediamide; [0519] (2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-allyl-butanediamide; [0520] (2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-propyl-butanediamide; [0521] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-propyl-butanediamide; [0522] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-meth-
yl-3-allyl-butanediamide; [0523] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-methyl-3-allyl-butanediamide; [0524] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-methyl-3-propyl-butanediamide; [0525] (2R)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-meth-
yl-butanediamide; [0526] (2R,3S)
N1-[1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-methylprop-
yl)-3-allyl-butanediamide; [0527] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzodiazepin-3-y-
l]-2-(2-methylpropyl)-3-allyl-butanediamide; [0528] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzodiazepi-
n-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0529] (2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzodiazepi-
n-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0530] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-1,4-benzodi-
azepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0531]
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0532]
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0533]
(2S,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-allyl-butanediamide; [0534] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzodiazepi-
n-3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide; [0535] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide; [0536]
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(4-fluorophenyl)-2H-1,4-benzodia-
zepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0537]
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-fluorophenyl)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0538] (2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(4-fluorophenyl)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0539] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(pyrid-2-yl)-2H-1,4-benzodiazepin-3-yl]--
2-(2-methylpropyl)-3-allyl-butanediamide; [0540] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-morpholino)-2H-1,4-benzodiazepin-3-yl-
]-2-(2-methylpropyl)-3-allyl-butanediamide; [0541] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(dimethylamino)-2H-1,4-benzodiazepin-3-y-
l]-2-(2-methylpropyl)-3-allyl-butanediamide; [0542] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-methyl-N-phenylamino)-2H-1,4-benzodia-
zepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0543]
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-piperidinyl)-2H-1,4-benzodiazepin-3-y-
l]-2-(2-methylpropyl)-3-allyl-butanediamide; [0544] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-homopiperidinyl)-2H-1,4-benzodiazepin-
-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0545] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(3-methoxyphenyl)-2H-1,4-benzodiazepin-3-
-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0546] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(pyrid-4-yl)-2H-1,4-benzodiazepin-3-yl]--
2-(2-methylpropyl)-3-allyl-butanediamide; [0547] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-methoxy-2H-1,4-benzodiazepin-3--
yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0548] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(pyrid-3-yl)-2H-1,4-benzodiazepin-3-yl]--
2-(2-methylpropyl)-3-allyl-butanediamide; [0549] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-(cyclopropylmethyl)-butanediamide; [0550] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-3--
yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0551] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(3-fluorophenyl)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0552] (2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(3-fluorophenyl)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0553] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide; [0554] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-(cyclopentylethyl)-butanediamide; [0555]
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide;
[0556] (2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide;
[0557] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-benzodi-
azepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0558]
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0559]
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0560]
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-be-
nzodiazepin-3-yl]-2-(2-methylpropyl)-3-n-butyl-butanediamide;
[0561] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2-
H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide
[0562] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide; [0563]
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-n-butyl-butanediamide; [0564] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-allyl-N-4-[benzyl]-butanediamide; [0565]
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-methyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-allyl-butanediamide; [0566] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-n-butyl-2H-1,4-benzodiazepin-3-yl]-2-(2--
methylpropyl)-3-allyl-butanediamide; [0567] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(2-methylpropyl)-2H-1,4-benzodiazepin-3--
yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0568] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-3--
yl]-2-(2-methylpropyl)-3-allyl-butanediamide; [0569] (2R,3S)
N1-[1,3-dihydro-1-ethyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-me-
thylpropyl)-3-allyl-butanediamide; [0570] (2R,3S)
N1-[1,3-dihydro-1-propyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-allyl-butanediamide; [0571] (2R,3S)
N1-[1,3-dihydro-1-(isopropyl)-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3-allyl-butanediamide; [0572] (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-
-(2-methylpropyl)-3,3-diallyl-butanediamide; [0573] (2R,3S)
N1-[6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylprop-
yl)-3-allyl-butanediamide; and [0574] (2R,3S)
N1-[1,3,4,5-tetrahydro-1,5-dimethyl-2,4-dioxo-2H-1,5-benzodiazepin-3-yl]--
2-(2-methylpropyl)-3-allyl-butanediamide.
[0575] [12] In a preferred embodiment the present invention
provides for a compound of Formula (Ia):
##STR00016##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0576] Z is C.sub.1-C.sub.8 alkyl substituted with 1-3 R.sup.12;
[0577] C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12;
[0578] C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12;
[0579] C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12; [0580]
C.sub.3-C.sub.10 carbocycle substituted with 0-4 R.sup.12b or
[0581] 5 to 10 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.12b; provided,
when R.sup.13 is H, [0582] then Z is C.sub.4-C.sub.8 alkyl
substituted with 1-3 R.sup.12; [0583] C.sub.2-C.sub.4 alkenyl
substituted with 1-3 R.sup.12; or [0584] C.sub.2-C.sub.4 alkynyl
substituted with 1-3 R.sup.12; and provided, when ring B is a
1,3,4,5-tetrahydro-1-(Z)-5-(R.sup.10)-6,6,7,7-tetra(R.sup.11)-2,4-dioxo-2-
H-1,5-diazepin-3-yl core, and R.sup.13 is H; then [0585] R.sup.10
is H, C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17,
C(.dbd.O)NR.sup.18R.sup.19, [0586]
S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.17; or
[0587] C.sub.1-C.sub.6 alkyl optionally substituted with 0-3
R.sup.10a; [0588] R.sup.10a, at each occurrence, is independently
selected from [0589] H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F,
Br, I, .dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3.
[0590] [13] In a more preferred embodiment the present invention
provides for a compound of Formula (Ia): [0591] R.sup.3 is
(CR.sup.7R.sup.7a).sub.n--R.sup.4, [0592]
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0593]
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
or [0594]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--
-R.sup.4; [0595] n is 0, 1, or 2; [0596] m is 0, 1, or 2; [0597]
R.sup.3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, butoxy, allyl, or 3-buten-1-yl; [0598] R.sup.4 is H, OH,
OR.sup.14a, [0599] C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.4a, [0600] C.sub.2-C.sub.6 alkenyl substituted with 0-3
R.sup.4a, [0601] C.sub.2-C.sub.6 alkynyl substituted with 0-3
R.sup.4a, [0602] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.4b, [0603] C.sub.6-C.sub.11 aryl substituted with 0-3
R.sup.4b, or [0604] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
[0605] R.sup.4a, at each occurrence, is independently selected from
is H, F, Cl, Br, I, CF.sub.3, [0606] C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.4b, [0607] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.4b, or [0608] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.4b; [0609] R.sup.4b, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
[0610] R.sup.5 is H, OR.sup.14; [0611] C.sub.1-C.sub.6 alkyl
substituted with 0-3 R.sup.5b; [0612] C.sub.1-C.sub.6 alkoxy
substituted with 0-3 R.sup.5b; [0613] C.sub.2-C.sub.6 alkenyl
substituted with 0-3 R.sup.5b; [0614] C.sub.2-C.sub.6 alkynyl
substituted with 0-3 R.sup.5b; [0615] C.sub.3-C.sub.11 carbocycle
substituted with 0-3 R.sup.5c: [0616] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.5c; or [0617] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.5c; [0618] R.sup.5a is H or
C.sub.1-C.sub.4 alkyl; [0619] R.sup.5b, at each occurrence, is
independently selected from: [0620] H, C.sub.1-C.sub.6 alkyl,
CF.sub.3, OR.sup.4, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16; [0621] C.sub.3-C.sub.10 carbocycle substituted
with 0-3 R.sup.5c; [0622] C.sub.6-C.sub.10 aryl substituted with
0-3 R.sup.5c; or [0623] 5 to 10 membered heterocycle containing 1
to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.5c; [0624] R.sup.5c, at each occurrence, is independently
selected from H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 haloalkoxy;
[0625] R.sup.6 is H, methyl, or ethyl; [0626] R.sup.7, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, CF.sub.3, phenyl, and C.sub.1-C.sub.4 alkyl; [0627]
R.sup.7a, at each occurrence, is independently selected from [0628]
H, OH, Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4
alkyl; [0629] R.sup.7b is independently selected from H, methyl,
ethyl, propyl, and butyl; [0630] Ring B is a 7 membered lactam,
[0631] wherein the lactam is saturated, partially saturated or
unsaturated; [0632] wherein each additional lactam carbon is
substituted with 0-2 R.sup.11; and, [0633] optionally, the lactam
contains a heteroatom selected from --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N.dbd., --NH--, and --N(R.sup.10)--; [0634]
additionally, two R.sup.11 substituents on adjacent atoms may be
combined to form a benzo fused radical; wherein said benzo fused
radical is substituted with 0-3 R.sup.13; [0635] additionally, two
R.sup.11 substituents on adjacent atoms may be combined to form a 5
to 6 membered heteroaryl fused radical, wherein said 5 to 6
membered heteroaryl fused radical comprises 1 or 2 heteroatoms
selected from N, O, and S; wherein said 5 to 6 membered heteroaryl
fused radical is substituted with 0-3 R.sup.13, [0636]
additionally, two R.sup.11 substituents on the same or adjacent
carbon atoms may be combined to form a C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.13; [0637] R.sup.10 is H,
C.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.18R.sup.19,
[0638] S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.17;
[0639] C.sub.1-C.sub.6 alkyl optionally substituted with 0-2
R.sup.10a; [0640] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.10b; [0641] C.sub.3-C.sub.11 carbocycle substituted with 0-3
R.sup.10b; or [0642] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.10b; [0643] R.sup.10a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, or phenyl
substituted with 0-4 R.sup.10b; [0644] R.sup.10b, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, or CF.sub.3; [0645] R.sup.11, at each
occurrence, is independently selected from [0646] H,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.18R.sup.19, C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17,
C(.dbd.O)NR.sup.18R.sup.19, S(.dbd.O).sub.2NR.sup.18R.sup.19,
CF.sub.3; [0647] C.sub.1-C.sub.6 alkyl optionally substituted with
0-3 R.sup.11a; [0648] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.11b; [0649] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.11b; or [0650] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.11b; [0651] R.sup.11a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, or phenyl
substituted with 0-3 R.sup.11b [0652] R.sup.11b, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 haloalkoxy; [0653] Z is C.sub.1-C.sub.6 alkyl
substituted with 1-3 R.sup.12; [0654] C.sub.2-C.sub.4 alkenyl
substituted with 1-3 R.sup.12; [0655] C.sub.2-C.sub.4 alkynyl
substituted with 1-3 R.sup.12; [0656] C.sub.6-C.sub.10 aryl
substituted with 0-4 R.sup.12b, [0657] C.sub.3-C.sub.10 carbocycle
substituted with 0-4 R.sup.12b; or [0658] 5 to 11 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.12b; [0659] R.sup.12, at each
occurrence, is independently selected from [0660] C.sub.6-C.sub.10
aryl substituted with 0-4 R.sup.12b; [0661] C.sub.3-C.sub.10
carbocycle substituted with 0-4 R.sup.12b; or [0662] 5 to 10
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.12b; [0663] R.sup.12b, at
each occurrence, is independently selected from [0664] H, OH, Cl,
F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, and C.sub.1-C.sub.4 haloalkoxy; [0665] R.sup.13, at each
occurrence, is independently selected from [0666] H, OH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F. Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3; [0667] R.sup.14 is H,
phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl; [0668] R.sup.14a is H, phenyl, benzyl, methyl, ethyl,
propyl, or butyl; [0669] R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-C.sub.6 alkyl, benzyl,
phenethyl, (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; [0670] R.sup.16, at each
occurrence, is independently selected from [0671] H, OH,
C.sub.1-C.sub.6 alkyl, benzyl, phenethyl, [0672] (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--;
[0673] R.sup.17 is H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkoxyalkyl, [0674] aryl substituted by 0-4 R.sup.17a, or [0675]
--CH.sub.2-aryl substituted by 0-4 R.sup.17a; [0676] R.sup.17a is
H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy,
--OH, F, Cl, Br, I, CF.sub.3, OCF.sub.3, SCH.sub.3, S(O)CH.sub.3,
SO.sub.2CH.sub.3, --NH.sub.2, --N(CH.sub.3).sub.2, or
C.sub.1-C.sub.4 haloalkyl; [0677] R.sup.18, at each occurrence, is
independently selected from [0678] H, C.sub.1-C.sub.6 alkyl,
phenyl, benzyl, phenethyl, [0679] (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--;
and [0680] R.sup.9, at each occurrence, is independently selected
from [0681] H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl,
phenethyl, [0682] (C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and
(C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--; provided, when R.sup.13
is H, [0683] then Z is C.sub.4-C.sub.6 alkyl substituted with 1-3
R.sup.12; [0684] C.sub.2-C.sub.4 alkenyl substituted with 1-3
R.sup.12; or [0685] C.sub.2-C.sub.4 alkynyl substituted with 1-3
R.sup.12.
[0686] [14] In a further more preferred embodiment the present
invention provides for a compound of Formula (Ia) wherein: [0687]
R.sup.3 is --(CHR.sup.7).sub.n--R.sup.4, [0688] n is 0 or 1; [0689]
R.sup.3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,
propoxy, butoxy, allyl, or 3-buten-1-yl; [0690] R.sup.4 is H, OH,
OR.sup.14a, [0691] C.sub.1-C.sub.4 alkyl substituted with 0-2
R.sup.4a, [0692] C.sub.2-C.sub.4 alkenyl substituted with 0-2
R.sup.4a, [0693] C.sub.2-C.sub.4 alkynyl substituted with 0-1
R.sup.4a, [0694] C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.4b, [0695] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.4b or [0696] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.4b;
[0697] R.sup.4a, at each occurrence, is independently selected from
is H, F, Cl, Br, I, CF.sub.3, [0698] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.4b, [0699] phenyl substituted with 0-3
R.sup.4b, or [0700] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.4b;
[0701] R.sup.4b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0702] R.sup.5 is H,
OR.sup.14; [0703] C.sub.1-C.sub.4 alkyl substituted with 0-3
R.sup.5b; [0704] C.sub.2-C.sub.4 alkenyl substituted with 0-3
R.sup.5b; [0705] C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.5b; [0706] R.sup.5a is H, methyl, ethyl, propyl, or butyl;
[0707] R.sup.5b, at each occurrence, is independently selected
from: [0708] H, methyl, ethyl, propyl, butyl, CF.sub.3, OR.sup.14,
Cl, F, Br, I, .dbd.O; [0709] C.sub.3-C.sub.6 carbocycle substituted
with 0-3 R.sup.5c: [0710] phenyl substituted with 0-3 R.sup.5c; or
[0711] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.5c; [0712]
R.sup.5c, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0713] R.sup.6 is H;
[0714] R.sup.7, at each occurrence, is independently selected from
H, F, CF.sub.3, methyl, and ethyl; [0715] Ring B is a 7 membered
lactam, [0716] wherein the lactam is saturated, partially saturated
or unsaturated; [0717] wherein each additional lactam carbon is
substituted with 0-2 R.sup.11; and, [0718] optionally, the lactam
contains a heteroatom selected from --N--, --NH--, and
--N(R.sup.10)--; [0719] additionally, two R.sup.11 substituents on
adjacent atoms may be combined to form a benzo fused radical;
wherein said benzo fused radical is substituted with 0-2 R.sup.13;
[0720] additionally, two R.sup.11 substituents on adjacent atoms
may be combined to form a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1
or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6
membered heteroaryl fused radical is substituted with 0-2 R.sup.3;
[0721] additionally, two R.sup.11 substituents on the same or
adjacent carbon atoms may be combined to form a C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.13, [0722] R.sup.10 is H,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17: [0723] C.sub.1-C.sub.4 alkyl
optionally substituted with 0-1 R.sup.10a: [0724] phenyl
substituted with 0-4 R.sup.10b. [0725] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.10b; or [0726] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.10b; [0727] R.sup.10a, at each
occurrence, is independently selected from H, C.sub.1-C.sub.4
alkyl, OR.sup.14, Cl, F, Br, I, .dbd.O, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, or phenyl substituted with 0-4
R.sup.10b; [0728] R.sup.10b, at each occurrence, is independently
selected from H, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkoxy,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, or CF.sub.3; [0729]
R.sup.11, at each occurrence, is independently selected from [0730]
H, C.sub.1-C.sub.4 alkoxy, Cl, F, .dbd.O, NR.sup.18R.sup.19,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, CF.sub.3; [0731]
C.sub.1-C.sub.6 alkyl optionally substituted with 0-3 R.sup.11a;
[0732] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b; [0733]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b; or
[0734] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.11b; [0735]
R.sup.11a, at each occurrence, is independently selected from H,
C.sub.1-C.sub.4 alkyl, OR.sup.14, F, .dbd.O, NR.sup.15R.sup.16,
CF.sub.3, or phenyl substituted with 0-3 R.sup.11b; [0736]
R.sup.11b, at each occurrence, is independently selected from H,
OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0737] Z is C.sub.1-C.sub.4 alkyl
substituted with 1-3 R.sup.12; [0738] C.sub.2-C.sub.4 alkenyl
substituted with 1-3 R.sup.12; [0739] C.sub.2-C.sub.4 alkynyl
substituted with 1-3 R.sup.12; [0740] C.sub.6-C.sub.10 aryl
substituted with 0-4 R.sup.12b; [0741] C.sub.3-C.sub.6 carbocycle
substituted with 0-4 R.sup.12b; or [0742] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.12b, [0743] R.sup.12, at each
occurrence, is independently selected from [0744] C.sub.6-C.sub.10
aryl substituted with 0-4 R.sup.12b, [0745] C.sub.3-C.sub.6
carbocycle substituted with 0-4 R.sup.12b; or [0746] 5 to 10
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.12b; [0747] R.sup.12b, at
each occurrence, is independently selected from [0748] H, OH, Cl,
F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0749] R.sup.13, at each occurrence, is
independently selected from [0750] H, OH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, and CF.sub.3; [0751] R.sup.14 is H, phenyl,
benzyl, C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4 alkoxyalkyl;
[0752] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-C.sub.4 alkyl, benzyl, phenethyl, (C.sub.1-C.sub.4
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.4 alkyl)-S(.dbd.O).sub.2--;
[0753] R.sup.16, at each occurrence, is independently selected from
[0754] H, OH, C.sub.1-C.sub.4 alkyl, benzyl, phenethyl, [0755]
(C.sub.1-C.sub.4 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.4
alkyl)-S(.dbd.O).sub.2--; [0756] R.sup.7 is H, methyl, ethyl,
propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl,
ethoxyethyl, [0757] phenyl substituted by 0-3 R.sup.11a, or [0758]
--CH.sub.2-phenyl substituted by 0-3 R.sup.17a; [0759] R.sup.17a is
H, methyl, methoxy, --OH, F, Cl, CF.sub.3, or OCF.sub.3; [0760]
R.sup.18, at each occurrence, is independently selected from [0761]
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0762] R.sup.19, at each occurrence, is independently selected from
[0763] H, methyl and ethyl; provided, when R.sup.13 is H, [0764]
then Z is butyl substituted with 1-3 R.sup.12, [0765]
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12; or [0766]
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.2.
[0767] [15] In an even more preferred embodiment the present
invention provides for a compound of Formula (Ib):
##STR00017##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0768] Ring B is selected from:
##STR00018##
[0769] [16] In an even further more preferred embodiment the
present invention provides for a compound of Formula (Ic):
##STR00019##
or a pharmaceutically acceptable salt or prodrug thereof wherein
[0770] R.sup.3 is R.sup.4, [0771] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0772] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0773] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0774] R.sup.4a, at each occurrence,
is independently selected from [0775] H, F, CF.sub.3, [0776]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, phenyl
substituted with 0-3 R.sup.4b, or [0777] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0778]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0779] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0780] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0781] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0782] R.sup.5b, at each occurrence,
is independently selected from: [0783] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, --O; [0784] C.sub.3-C.sub.6 carbocycle
substituted with 0-2 R.sup.5c; [0785] phenyl substituted with 0-3
R.sup.5c; or [0786] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.5c;
wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0787] R.sup.5c, at each occurrence, is
independently selected from H, OH, Cl, F NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3.
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0788] R.sup.11, at each occurrence, is independently
selected from [0789] H, .dbd.O, NR.sup.18R.sup.19, CF.sub.3; [0790]
C.sub.1-C.sub.4 alkyl optionally substituted with 0-1 R.sup.11a;
[0791] phenyl substituted with 0-3 R.sup.11b; [0792]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b; or
[0793] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0794] R.sup.11a, at each occurrence,
is independently selected from H, C.sub.1-C.sub.4 alkyl, OR.sup.14,
F, Cl, .dbd.O, NR.sup.15R.sup.16, CF.sub.3, or phenyl substituted
with 0-3 R.sup.11b, [0795] R.sup.11b, at each occurrence, is
independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0796] Z
is C.sub.1-C.sub.3 alkyl substituted with 1-3 R.sup.12; [0797]
C.sub.2-C.sub.3 alkenyl substituted with 1-3 R.sup.12; [0798]
C.sub.2-C.sub.3 alkynyl substituted with 1-3 R.sup.12; [0799]
C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12b; [0800]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.12b; or
[0801] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.12b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0802] R.sup.12, at each occurrence, is
independently selected from [0803] C.sub.6-C.sub.10 aryl
substituted with 0-4 R.sup.12b: [0804] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.2b; or [0805] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.12b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0806]
R.sup.12b, at each occurrence, is independently selected from
[0807] H, OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2
haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0808] R.sup.13, at each
occurrence, is independently selected from [0809] H, OH, methyl,
ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN,
NR.sup.15R.sup.16 and CF.sub.3; [0810] R.sup.14 is H, phenyl,
benzyl, methyl, ethyl, propyl, or butyl; [0811] R.sup.15, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, and butyl; [0812] R.sup.16, at each occurrence, is
independently selected from [0813] H, OH, methyl, ethyl, propyl,
butyl, benzyl, phenethyl, methyl-C(.dbd.O)--, ethyl-C(.dbd.O)--,
methyl-S(.dbd.O).sub.2--, and ethyl-S(.dbd.O).sub.2--; [0814]
R.sup.18, at each occurrence, is independently selected from [0815]
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0816] R.sup.19, at each occurrence, is independently selected from
[0817] H, methyl, and ethyl. provided, when R.sup.13 is H, [0818]
then Z is C.sub.2-C.sub.3 alkenyl substituted with 1-3 R.sup.12; or
[0819] C.sub.2-C.sub.3 alkynyl substituted with 1-3 R.sup.12.
[0820] [17] In another even further more preferred embodiment the
present invention provides for a compound of Formula (Id):
##STR00020##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0821] R.sup.3 is R.sup.4. [0822] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a. [0823] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0824] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0825] R.sup.4a, at each occurrence,
is independently selected from [0826] H, F, CF.sub.3, [0827]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0828]
phenyl substituted with 0-3 R.sup.4b, or [0829] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0830]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0831] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0832] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0833] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0834] R.sup.5b, at each occurrence,
is independently selected from: [0835] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0836] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c-- [0837] phenyl
substituted with 0-3 R.sup.5c; or [0838] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.5c; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0839]
R.sup.5c, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0840] R.sup.11, at each occurrence, is
independently selected from [0841] H, .dbd.O, NR.sup.18R.sup.19.
CF.sub.3; [0842] C.sub.1-C.sub.4 alkyl optionally substituted with
0-1 R.sup.11a; [0843] phenyl substituted with 0-3 R.sup.11b; [0844]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b; or
[0845] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0846] R.sup.11a, at each occurrence,
is independently selected from H, C.sub.1-C.sub.4 alkyl, OR.sup.14,
F, Cl, .dbd.O, NR.sup.15R.sup.16, CF.sub.3, or phenyl substituted
with 0-3 R.sup.11b; [0847] R.sup.11b, at each occurrence, is
independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; [0848] Z
is C.sub.1-C.sub.3 alkyl substituted with 1-3 R.sup.12; [0849]
C.sub.2-C.sub.3 alkenyl substituted with 1-3 R.sup.12; [0850]
C.sub.2-C.sub.3 alkynyl substituted with 1-3 R.sup.12. [0851]
C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12b; [0852]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.12b; or
[0853] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.12b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0854] R.sup.12, at each occurrence, is
independently selected from [0855] C.sub.6-C.sub.10 aryl
substituted with 0-4 R.sup.12b; [0856] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.12b; or [0857] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.12b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0858]
R.sup.12b, at each occurrence, is independently selected from
[0859] H, OH, Cl F. NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0860] R.sup.13, at each occurrence, is
independently selected from [0861] H, OH, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, Cl, F, Br, CN, NR.sup.15R.sup.16 and
CF.sub.3; [0862] R.sup.14 is H, phenyl, benzyl, methyl, ethyl,
propyl, or butyl; [0863] R.sup.15, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, and butyl;
[0864] R.sup.16, at each occurrence, is independently selected from
[0865] H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl,
methyl-C(.dbd.O)--, ethyl-C(.dbd.O)--, methyl-S(.dbd.O).sub.2--,
and ethyl-S(.dbd.O).sub.2--; [0866] R.sup.18, at each occurrence,
is independently selected from H, methyl, ethyl, propyl, butyl,
phenyl, benzyl, and phenethyl; and [0867] R.sup.19, at each
occurrence, is independently selected from H, methyl, and ethyl.
provided, when R.sup.13 is H, [0868] then Z is C.sub.2-C.sub.3
alkenyl substituted with 1-3 R.sup.12; or [0869] C.sub.2-C.sub.3
alkynyl substituted with 1-3 R.sup.12.
[0870] [18] In another even further more preferred embodiment the
present invention provides for a compound of Formula (Ie):
##STR00021##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0871] R.sup.3 is R.sup.4, [0872] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0873] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0874] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0875] R.sup.4a, at each occurrence,
is independently selected from [0876] H, F, CF.sub.3, [0877]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0878]
phenyl substituted with 0-3 R.sup.4b, or [0879] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0880]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0881] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0882] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0883] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0884] R.sup.5b, at each occurrence,
is independently selected from: [0885] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0886] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c; [0887] phenyl substituted
with 0-3 R.sup.5c; or [0888] 5 to 6 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 6 membered heterocycle is substituted with 0-3
R.sup.5c; wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl, [0889] R.sup.5c, at each
occurrence, is independently selected from H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0890] R.sup.10 is H, C(.dbd.O)R.sup.17,
C(.dbd.O)OR.sup.17; [0891] C.sub.1-C.sub.4 alkyl optionally
substituted with 0-1 R.sup.10a; [0892] phenyl substituted with 0-4
R.sup.10b; [0893] C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.10b; or [0894] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.10b;
wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0895] R.sup.10a, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, butyl, OR.sup.4, Cl, F, .dbd.O, NR.sup.15R.sup.16,
CF.sub.3, or phenyl substituted with 0-4 R.sup.10b; [0896]
R.sup.10b, at each occurrence, is independently selected from H,
OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F,
NR.sup.15R.sup.16, and CF.sub.3; [0897] Z is C.sub.1-C.sub.3 alkyl
substituted with 1-3 R.sup.12; [0898] C.sub.2-C.sub.3 alkenyl
substituted with 1-3 R.sup.12; [0899] C.sub.2-C.sub.3 alkynyl
substituted with 1-3 R.sup.12; [0900] C.sub.6-C.sub.10 aryl
substituted with 0-4 R.sup.12b; [0901] C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.12b; or [0902] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.12b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0903]
R.sup.12, at each occurrence, is independently selected from [0904]
C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12b; [0905]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.12b; or
[0906] 5 to 6 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6
membered heterocycle is substituted with 0-3 R.sup.12b; wherein
said 5 to 6 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0907] R.sup.12b, at each occurrence,
is independently selected from [0908] H, OH, Cl, F,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0909] R.sup.13, at each occurrence, is independently
selected from [0910] H, OH, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, Cl, F, Br, CN, NR.sup.15R.sup.16, and CF.sub.3; [0911]
R.sup.14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
[0912] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl; [0913] R.sup.16, at each
occurrence, is independently selected from [0914] H, OH, methyl,
ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(.dbd.O)--,
ethyl-C(.dbd.O)--, methyl-S(.dbd.O).sub.2--, and
ethyl-S(.dbd.O).sub.2--; [0915] R.sup.17 is H, methyl, ethyl,
propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl,
ethoxyethyl, [0916] phenyl substituted by 0-3 R.sup.17a, or [0917]
--CH.sub.2-phenyl substituted by 0-3 R.sup.17a; [0918] R.sup.17a is
H, methyl, methoxy, --OH, F, Cl, CF.sub.3, or OCF.sub.3; [0919]
R.sup.18, at each occurrence, is independently selected from [0920]
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0921] R.sup.19, at each occurrence, is independently selected from
[0922] H, methyl, and ethyl. provided, when R.sup.13 is H, [0923]
then Z is C.sub.2-C.sub.3 alkenyl substituted with 1-3 R.sup.12; or
[0924] C.sub.2-C.sub.3 alkynyl substituted with 1-3 R.sup.12
[0925] [19] In another even further more preferred embodiment the
present invention provides for a compound of Formula (If):
##STR00022##
or a pharmaceutically acceptable salt or prodrug thereof wherein:
[0926] R.sup.3 is R.sup.4, [0927] R.sup.4 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.4a, [0928] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.4a, or [0929] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.4a; [0930] R.sup.4a, at each occurrence,
is independently selected from [0931] H, F, CF.sub.3, [0932]
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.4b, [0933]
phenyl substituted with 0-3 R.sup.4b, or [0934] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.4b; wherein said 5 to 6 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; [0935]
R.sup.4b, at each occurrence, is independently selected from H, OH,
Cl, F, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl,
butyl, methoxy, ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and
C.sub.1-C.sub.2 haloalkoxy; [0936] R.sup.5 is C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.5b; [0937] C.sub.2-C.sub.4 alkenyl
substituted with 0-1 R.sup.5b; [0938] C.sub.2-C.sub.4 alkynyl
substituted with 0-1 R.sup.5b; [0939] R.sup.5b, at each occurrence,
is independently selected from: [0940] H, methyl, ethyl, propyl,
butyl, CF.sub.3, OR.sup.14, .dbd.O; [0941] C.sub.3-C.sub.6
carbocycle substituted with 0-2 R.sup.5c, [0942] phenyl substituted
with 0-3 R.sup.5c; or [0943] 5 to 6 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur,
wherein said 5 to 6 membered heterocycle is substituted with 0-3
R.sup.5c; wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl piperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; [0944] R.sup.5c, at each occurrence, is
independently selected from H, OH, Cl, F, NR.sup.15R.sup.16,
CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; [0945] Z is C.sub.1-C.sub.3 alkyl substituted with 1-3
R.sup.12; [0946] C.sub.2-C.sub.3 alkenyl substituted with 1-3
R.sup.12; [0947] C.sub.2-C.sub.3 alkynyl substituted with 1-3
R.sup.12; [0948] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.12b, [0949] C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.12b; or [0950] 5 to 6 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 6 membered heterocycle is substituted with 0-3 R.sup.12;
wherein said 5 to 6 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl; [0951] R.sup.12, at each
occurrence, is independently selected from [0952] C.sub.6-C.sub.10
aryl substituted with 0-4 R.sup.12b; [0953] C.sub.3-C.sub.6
carbocycle substituted with 0-3 R.sup.12b; or [0954] 5 to 10
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.12b; wherein said 5 to 6
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and
tetrazolyl; [0955] R.sup.12b, at each occurrence, is independently
selected from [0956] H, OH, Cl, F, NR.sup.15R.sup.16, CF.sub.3,
acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy;
[0957] R.sup.13, at each occurrence, is independently selected from
[0958] H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F
Br, CN, NR.sup.15R.sup.16, and CF.sub.3; [0959] R.sup.4 is HK
phenyl, benzyl, methyl, ethyl, propyl, or butyl; [0960] R.sup.15,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl and butyl; [0961] R.sup.6, at each occurrence, is
independently selected from [0962] H, OH, methyl ethyl propyl,
butyl, benzyl, phenethyl, methyl-C(.dbd.O)--, ethyl-C(.dbd.O)--,
methyl-S(.dbd.O).sub.2 and ethyl-S(.dbd.O).sub.2--; [0963] R.sup.18
at each occurrence, is independently selected from [0964] H,
methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
[0965] R.sup.19, at each occurrence, is independently selected from
[0966] H, methyl, and ethyl. provided, when R.sup.13 is H, [0967]
then Z is C.sub.2-C.sub.3 alkenyl substituted with 1-3 R.sup.12; or
[0968] C.sub.2-C.sub.3 alkynyl substituted with 1-3 R.sup.12.
[0969] [20] In another even further more preferred embodiment the
present invention provides for a compound of one of Formulas (II),
(Id), (le), or (If), wherein: [0970] R.sup.3 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2(CH.sub.3).sub.2,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3-- --CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.dbd.CH.sub.2, --CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.dbd.CH.sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CH(CH.sub.3),
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3); --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
cyclopropyl-CH.sub.2--, cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
cyclopropyl-CH.sub.2CH.sub.2--, cyclobutyl-CH.sub.2CH.sub.2--,
cyclopentyl-CH.sub.2CH.sub.2--, cyclohexyl-CH.sub.2CH.sub.2--,
phenyl-CH.sub.2-(2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.12--, (2-C.sub.1-phenyl)CH.sub.2--,
(3-C.sub.1-phenyl)CH.sub.2--, (4-C.sub.1-phenyl)CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2-- (2,4-diF-phenyl)CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2--,
(2,6-diF-phenyl)CH.sub.12-(3,4-diF-phenyl)CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2--, (2,3-diCl-phenyl)CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2-(2,5-diCl-phenyl)CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2--, (3,4-diCl-phenyl)CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2--, (3-F-4-C.sub.1-phenyl)CH.sub.2--,
(3-F-5-C.sub.1-phenyl)CH.sub.2--, (3-Cl-4F-phenyl)CH.sub.2--,
phenyl-CH.sub.2CH.sub.2--, (2-F-phenyl)CH.sub.2CH.sub.12--
(3-F-phenyl)CH.sub.2 CH.sub.2--, (4-F-phenyl)CH.sub.2CH.sub.2--,
(2-Cl-phenyl)CH.sub.2CH.sub.2--, (3-Cl-phenyl)CH.sub.2CH.sub.2--,
(4-Cl-phenyl)CH.sub.2CH.sub.2-(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--, or
(3-F-5-Cl-phenyl)CH.sub.2CH.sub.2--, [0971] R.sup.5 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.2CH.sub.3).sub.2,
--CF.sub.3, --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3, --CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
cis-CH.sub.2CH.dbd.CH(CH.sub.3), trans-CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CH(C.sub.6H.sub.5),
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2,
cis-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
trans-CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
cis-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.sub.2CH.dbd.CH(CH.sub.3),
trans-CH.sub.2CH.dbd.CHCH.sub.2(C.sub.6H.sub.5), --C.ident.CH,
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2C.ident.C(C.sub.6H.sub.5), --CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
--CH.sub.2CH.sub.2CH.sub.2C.ident.CH,
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(CH.sub.3),
--CH.sub.2CH.sub.2CH.sub.2C.ident.C(C.sub.6H.sub.5)
cyclopropyl-CH.sub.2--, cyclobutyl-CH.sub.2--,
cyclopentyl-CH.sub.2--, cyclohexyl-CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2--, cyclopropyl-CH.sub.2CH.sub.2--,
cyclobutyl-CH.sub.2CH.sub.2--, cyclopentyl-CH.sub.2CH.sub.2--,
cyclohexyl-CH.sub.2CH.sub.2--,
(2-CH.sub.3-cyclopropyl)CH.sub.2CH.sub.2--,
(3-CH.sub.3-cyclobutyl)CH.sub.2CH.sub.2--, phenyl-CH.sub.2--,
(2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, furanyl-CH.sub.2--, thienyl-CH.sub.2--,
pyridyl-CH.sub.2--, 1-imidazolyl-CH.sub.2--, oxazolyl-CH.sub.2--,
isoxazolyl-CH.sub.2--, phenyl-CH.sub.2CH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2-- (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--, furanyl-CH.sub.2CH.sub.2--,
thienyl-CH.sub.2CH.sub.2--, pyridyl-CH.sub.2CH.sub.2--,
1-imidazolyl-CH.sub.2CH.sub.2--, oxazolyl-CH.sub.2CH.sub.2--,
isoxazolyl-CH.sub.2CH.sub.2--, [0972] Z is phenyl, 2-F-phenyl,
3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl,
2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl,
3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl,
2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl,
3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl,
3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl,
2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF.sub.30-phenyl,
3-CF.sub.30-phenyl, 4-CF.sub.30-phenyl, [0973] furanyl, thienyl,
pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl,
oxazolyl, isoxazolyl, 1-benzimidazolyl, [0974] cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,
phenyl-CH.sub.2--, (2-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2--,
(4-F-phenyl)CH.sub.2--, (2-C.sub.1-phenyl)CH.sub.2--,
(3-C.sub.1-phenyl)CH.sub.2--, (4-C.sub.1-phenyl)CH.sub.2--,
(2,3-diF-phenyl)CH.sub.2--, [0975] (2,4-diF-phenyl)CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2--, (2,6-diF-phenyl)CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2--, (3,5-diF-phenyl)CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2--, (2,4-diCl-phenyl)CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2--, (2,6-diCl-phenyl)CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2--, (3,5-diCl-phenyl)CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2--, (3-F-5-Cl-phenyl)CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2--, (2-MeO-phenyl)CH.sub.2--,
(3-MeO-phenyl)CH.sub.2--, (4-MeO-phenyl)CH.sub.2--,
(2-Me-phenyl)CH.sub.2--, (3-Me-phenyl)CH.sub.2--,
(4-Me-phenyl)CH.sub.2--, (2-MeS-phenyl)CH.sub.2--,
(3-MeS-phenyl)CH.sub.2--, 4-MeS-phenyl)CH.sub.2--,
(2-CF.sub.3O-phenyl)CH.sub.2--, (3-CF.sub.3O-phenyl)CH.sub.2--,
(4-CF.sub.30-phenyl)CH.sub.2--, (furanyl)CH.sub.2--,
(thienyl)CH.sub.2--, (pyridyl)CH.sub.2--, (2-Me-pyridyl)CH.sub.2--,
(3-Me-pyridyl)CH.sub.2--, (4-Me-pyridyl)CH.sub.2--,
(1-imidazolyl)CH.sub.2--, (oxazolyl)CH.sub.2--,
(isoxazolyl)CH.sub.2--, (1-benzimidazolyl)CH.sub.2--,
(cyclopropyl)CH.sub.2--, (cyclobutyl)CH.sub.2--,
(cyclopentyl)CH.sub.2--, (cyclohexyl)CH.sub.2--,
(morpholino)CH.sub.2--, (N-piperidinyl)CH.sub.2--,
phenyl-CH.sub.2CH.sub.2--, (phenyl).sub.2CHCH.sub.2--,
(2-F-phenyl)CH.sub.2CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--,
(4-F-phenyl)CH.sub.2CH.sub.2--,
(2-C.sub.1-phenyl)CH.sub.2CH.sub.2--,
(3-C.sub.1-phenyl)CH.sub.2CH.sub.2--,
(4-C.sub.1-phenyl)CH.sub.2CH.sub.2--
(2,3-diF-phenyl)CH.sub.2CH.sub.2--,
(2,4-diF-phenyl)CH.sub.2CH.sub.2--,
(2,5-diF-phenyl)CH.sub.2CH.sub.2-(2,6-diF-phenyl)CH.sub.2CH.sub.2--,
(3,4-diF-phenyl)CH.sub.2CH.sub.2--,
(3,5-diF-phenyl)CH.sub.2CH.sub.2--,
(2,3-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(2,6-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,4-diCl-phenyl)CH.sub.2CH.sub.2--,
(3,5-diCl-phenyl)CH.sub.2CH.sub.2--,
(3-F-4-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-F-5-Cl-phenyl)CH.sub.2CH.sub.2--,
(3-Cl-4-F-phenyl)CH.sub.2CH.sub.2-(2-MeO-phenyl)CH.sub.2CH.sub.2--
(3-MeO-phenyl)CH.sub.2CH.sub.2--, (4-MeO-phenyl)CH.sub.2CH.sub.2--,
(2-Me-phenyl)CH.sub.2CH.sub.2--, (3-Me-phenyl)CH.sub.2CH.sub.2--,
(4-Me-phenyl)CH.sub.2CH.sub.2--, (2-MeS-phenyl)CH.sub.2CH.sub.2--,
(3-MeS-phenyl)CH.sub.2CH.sub.2--, (4-MeS-phenyl)CH.sub.2CH.sub.2--
(2-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--, [0976]
(3-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--,
(4-CF.sub.3O-phenyl)CH.sub.2CH.sub.2--, (furanyl)CH.sub.2CH.sub.2,
(thienyl)CH.sub.2CH.sub.2--, (pyridyl)CH.sub.2CH.sub.2--, [0977]
(2-Me-pyridyl)CH.sub.2CH.sub.2--, (3-Me-pyridyl)CH.sub.2CH.sub.2--,
[0978] (4-Me-pyridyl)CH.sub.2CH.sub.2--,
(imidazolyl)CH.sub.2CH.sub.2--, (oxazolyl)CH.sub.2CH.sub.2--,
(isoxazolyl)CH.sub.2CH.sub.2--, (benzimidazolyl)CH.sub.2CH.sub.2--,
(cyclopropyl)CH.sub.2CH.sub.2--, (cyclobutyl)CH.sub.2CH.sub.2,
(cyclopentyl)CH.sub.2CH.sub.2--, (cyclohexyl)CH.sub.2CH.sub.2--,
(morpholino)CH.sub.2CH.sub.2--, or [0979]
(N-piperidinyl)CH.sub.2CH.sub.2--; [0980] R.sup.10 is H, methyl,
ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,
(4-F-phenyl)CH.sub.2--, (4-F-phenyl)CH.sub.2CH.sub.2--,
4-C.sub.1-phenyl, (4-Cl-phenyl)CH.sub.2--,
(4-Cl-phenyl)CH.sub.2CH.sub.2--, 4-CH.sub.3-phenyl
(4-CH.sub.3-phenyl)CH.sub.2--,
(4-CH.sub.3-phenyl)CH.sub.2CH.sub.2--, 4-CF.sub.3-phenyl,
(4-CF.sub.3-phenyl)CH.sub.2--, or
(4-CF.sub.3-phenyl)CH.sub.2CH.sub.2--; [0981] R.sup.11, at each
occurrence, is independently selected from [0982] H, .dbd.O,
methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,
(4-F-phenyl)CH.sub.2--, (4-F-phenyl)CH.sub.2CH.sub.2--, 3-F-phenyl,
(3-F-phenyl)CH.sub.2--, (3-F-phenyl)CH.sub.2CH.sub.2--, 2-F-phenyl,
(2-F-phenyl)CH.sub.2--, (2-F-phenyl)CH.sub.2CH.sub.2--,
4-Cl-phenyl, (4-Cl-phenyl)CH.sub.2--,
(4-Cl-phenyl)CH.sub.2CH.sub.2--, 3-Cl-phenyl,
(3-Cl-phenyl)CH.sub.2--, (3-Cl-phenyl)CH.sub.2CH.sub.2--,
4-CH.sub.3-phenyl, (4-CH.sub.3-phenyl)CH.sub.2--,
(4-CH.sub.3-phenyl)CH.sub.2CH.sub.2--, 3-CH.sub.3-phenyl,
(3-CH.sub.3-phenyl)CH.sub.2--,
(3-CH.sub.3-phenyl)CH.sub.2CH.sub.2--, 4-CF.sub.3-phenyl,
(4-CF.sub.3-phenyl)CH.sub.2--,
(4-CF.sub.3-phenyl)CH.sub.2CH.sub.2--, pyrid-2-yl, pyrid-3-yl, or
pyrid-4-yl, and [0983] R.sup.13, at each occurrence, is
independently selected from [0984] H, F, Cl, OH, --CH.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, or --CF.sub.3.
[0985] [21] In another embodiment the present invention provides
for a method for the treatment of neurological disorders associated
with .beta.-amyloid production comprising administering to a host
in need of such treatment a therapeutically effective amount of a
compound of Formula (I):
##STR00023##
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
[0986] A is O or S; [0987] Q is --NR.sup.1R.sup.2; [0988] R.sup.1
is OR.sup.14; [0989] R.sup.2 is independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 carbocycle,
C.sub.6-C.sub.10 aryl, and 5 to 10 membered heterocycle containing
1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
[0990] R.sup.3 is --(CR.sup.7R.sup.7a).sub.n--R.sup.4, [0991]
--(CR.sup.7R.sup.7a).sub.n--S--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0992]
--(CR.sup.7R.sup.7a).sub.n--O--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0993]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.m--
-R.sup.4, [0994]
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0995]
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2--(CR.sup.7R.sup.7a).su-
b.m--R.sup.4, [0996]
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)--(CR.sup.7R.sup.7a).sub.m--R.sup.4,
[0997]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)C(.dbd.O)--(CR.sup.7R.sup.7-
a).sub.m--R.sup.4, [0998]
--(CR.sup.7R.sup.7a).sub.n--C(.dbd.O)N(R.sup.7b)--(CR.sup.7R.sup.7a).sub.-
m--R.sup.4, [0999]
--(CR.sup.7R.sup.7a).sub.n--N(R.sup.7b)S(.dbd.O).sub.2--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4, or [1000]
--(CR.sup.7R.sup.7a).sub.n--S(.dbd.O).sub.2N(R.sup.7b)--(CR.sup.7R.sup.7a-
).sub.m--R.sup.4. [1001] n is 0, 1, 2, or 3; [1002] m is 0, 1, 2,
or 3; [1003] R.sup.3a is H, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4
alkenyloxy: [1004] R.sup.4 is H, OH, OR.sup.14a, [1005]
C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.4a, [1006]
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.4a, [1007]
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.4a, [1008]
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.4b, [1009]
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.4b, or [1010] 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.4b; [1011] R.sup.4a, at
each occurrence, is independently selected from is H, F, Cl, Br, I,
CF.sub.3, [1012] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.4b, [1013] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.4b, or [1014] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.4b;
[1015] R.sup.4b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3,
[1016] C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkyl, [1017] C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 halothioalkyl-S--; [1018] R.sup.5 is H, OR.sup.14;
[1019] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b; [1020]
C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b; [1021]
C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b; [1022]
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b; [1023]
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.5c; [1024]
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or [1025] 5 to
10 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered
heterocycle is substituted with 0-3 R.sup.5c; [1026] R.sup.5a is H,
OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4
alkenyl, or C.sub.2-C.sub.4 alkenyloxy; [1027] R.sup.5b, at each
occurrence, is independently selected from: [1028] H,
C.sub.1-C.sub.6 alkyl, CF.sub.3, OR.sup.14, Cl, F, Br, I, --O, CN,
NO.sub.2, NR.sup.15R.sup.16; [1029] C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.5c; [1030] C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.5c; or [1031] 5 to 10 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is
substituted with 0-3 R.sup.5c; [1032] R.sup.5c, at each occurrence,
is independently selected from H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, [1033] C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, [1034]
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 halothioalkyl-S--;
[1035] R.sup.6 is H; [1036] C.sub.1-C.sub.6 alkyl substituted with
0-3 R.sup.6a; [1037] C.sub.3-C.sub.10 carbocycle substituted with
0-3 R.sup.6b; or [1038] C.sub.6-C.sub.10 aryl substituted with 0-3
R.sup.6b; [1039] R.sup.6a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, aryl or CF.sub.3; [1040]
R.sup.6b, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, and C.sub.1-C.sub.4 haloalkoxy; [1041] R.sup.7, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, CF.sub.3, phenyl and C.sub.1-C.sub.4 alkyl; [1042]
R.sup.7a, at each occurrence, is independently selected from H, OH,
Cl, F, Br, I, CN, NO.sub.2, CF.sub.3, and C.sub.1-C.sub.4 alkyl;
[1043] R.sup.7b is independently selected from H and
C.sub.1-C.sub.4 alkyl; [1044] Ring B is a 7 membered lactam or
thiolactam, [1045] wherein the lactam or thiolactam is saturated,
partially saturated or unsaturated; [1046] wherein each additional
lactam carbon or thiolactam carbon is substituted with 0-2
R.sup.11; and, [1047] optionally, the lactam or thiolactam contains
a heteroatom selected from --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N.dbd., --NH--, and --N(R.sup.10)--; [1048]
additionally, two R.sup.11 substituents on adjacent atoms may be
combined to form a benzo fused radical; wherein said benzo fused
radical is substituted with 0-4 R.sup.13; [1049] additionally, two
R.sup.11 substituents on adjacent atoms may be combined to form a 5
to 6 membered heteroaryl fused radical, wherein said 5 to 6
membered heteroaryl fused radical comprises 1 or 2 heteroatoms
selected from N, O, and S; wherein said 5 to 6 membered heteroaryl
fused radical is substituted with 0-3 R.sup.13; [1050]
additionally, two R.sup.11 substituents on the same or adjacent
carbon atoms may be combined to form a C.sub.3-C.sub.6 carbocycle
substituted with 0-3 R.sup.13; [1051] R.sup.10 is H,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.18R.sup.19,
[1052] S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.17;
[1053] C.sub.1-C.sub.6 alkyl optionally substituted with 0-3
R.sup.10a; [1054] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.10b; [1055] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.10b; or [1056] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.10b; [1057] R.sup.10a, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I,
.dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, or aryl
substituted with 0-4 R.sup.10b; [1058] R.sup.10b, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3, S(.dbd.O)CH.sub.3,
S(.dbd.O).sub.2CH.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; [1059] R.sup.11, at each occurrence,
is independently selected from [1060] H, C.sub.1-C.sub.4 alkoxy,
Cl, F. Br, I, .dbd.O, CN, NO.sub.2, NR.sup.18R.sup.19,
C(.dbd.O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.11R.sup.19,
S(.dbd.O).sub.2NR.sup.18R.sup.19, CF.sub.3: [1061] C.sub.1-C.sub.6
alkyl optionally substituted with 0-3 R.sup.11a; [1062]
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b; [1063]
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; or
[1064] 5 to 10 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.11b; [1065]
R.sup.11a, at each occurrence, is independently selected from
[1066] H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F, Br, I, .dbd.O,
CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3; [1067] phenyl
substituted with 0-3 R.sup.11b; [1068] C.sub.3-C.sub.6 cycloalkyl
substituted with 0-3 R.sup.11b; and [1069] 5 to 6 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is
substituted with 0-3 R.sup.11b; [1070] R.sup.11b, at each
occurrence, is independently selected from H, OH, Cl, F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, [1071] C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, [1072]
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 halothioalkyl-S--;
[1073] Z is H. [1074] C.sub.1-C.sub.8 alkyl substituted with 1-3
R.sup.12; [1075] C.sub.2-C.sub.4 alkenyl substituted with 1-3
R.sup.12; [1076] C.sub.2-C.sub.4 alkynyl substituted with 1-3
R.sup.12; [1077] C.sub.1-C.sub.8 alkyl substituted with 0-3
R.sup.12a; [1078] C.sub.2-C.sub.4 alkenyl substituted with 0-3
R.sup.12a; [1079] C.sub.2-C.sub.4 alkynyl substituted with 0-3
R.sup.12a; [1080] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.12b; [1081] C.sub.3-C.sub.10 carbocycle substituted with 0-4
R.sup.12b; or [1082] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.12b; [1083] R.sup.12, at each occurrence, is independently
selected from [1084] C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.12b, [1085] C.sub.3-C.sub.10 carbocycle substituted with 0-4
R.sup.12b; or [1086] 5 to 10 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3
R.sup.12b: [1087] R.sup.12a, at each occurrence, is independently
selected from [1088] H, OH, Cl, F, Br, I, CN, NO.sub.2,
NR.sup.15R.sup.16, --C(.dbd.O)NR.sup.15R.sup.16, CF.sub.3, acetyl,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, [1089]
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkyl, [1090] C.sub.1-C.sub.4 haloalkoxy, or C.sub.1-C.sub.4
halothioalkyl-S--; [1091] R.sup.12b, at each occurrence, is
independently selected from [1092] H, OH, Cl. F, Br, I, CN,
NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, acetyl, SCH.sub.3,
S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, [1093] C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, [1094]
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 halothioalkyl-S--;
[1095] R.sup.13, at each occurrence, is independently selected from
[1096] H, OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F,
Br, I, CN, NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3; [1097]
R.sup.14 is H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl.
C.sub.2-C.sub.6 alkoxyalkyl, or C.sub.3-C.sub.6 cycloalkyl; [1098]
R.sup.14a is H, phenyl, benzyl, or C.sub.1-C.sub.4 alkyl; [1099]
R.sup.15, at each occurrence, is independently selected from H,
C.sub.1-C.sub.6 alkyl, benzyl, phenethyl, (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--;
[1100] R.sup.16, at each occurrence, is independently selected from
[1101] H, OH, C.sub.1-C.sub.6 alkyl, benzyl, phenethyl, [1102]
(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--; [1103] R.sup.17 is H, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkoxyalkyl, [1104] aryl substituted by 0-4
R.sup.17a, or [1105] --CH.sub.2-aryl substituted by 0-4 R.sup.17a;
[1106] R.sup.17a is H, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, butoxy, --OH, F, Cl, Br, I, CF.sub.3, OCF.sub.3,
SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, or C.sub.1-C.sub.4 haloalkyl; [1107] R.sup.18,
at each occurrence, is independently selected from [1108] H,
C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl, [1109]
(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6
alkyl)-S(.dbd.O).sub.2--; and [1110] R.sup.19, at each occurrence,
is independently selected from [1111] H, OH, C.sub.1-C.sub.6 alkyl,
phenyl, benzyl, phenethyl, [1112] (C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--, and (C.sub.1-C.sub.6 alkyl)-S(.dbd.O).sub.2--;
provided, when R.sup.13 is H, [1113] then Z is H; [1114]
C.sub.4-C.sub.8 alkyl substituted with 1-3 R.sup.2; [1115]
C.sub.2-C.sub.4 alkenyl substituted with 1-3 R.sup.12; [1116]
C.sub.2-C.sub.4 alkynyl substituted with 1-3 R.sup.12: [1117]
C.sub.1-C.sub.8 alkyl substituted with 0-3 R.sup.12a; [1118]
C.sub.2-C.sub.4 alkenyl substituted with 0-3 R.sup.12a, or [1119]
C.sub.2-C.sub.4 alkynyl substituted with 0-3 R.sup.12a; and
provided, when ring B is a
1,3,4,5-tetrahydro-1-(Z)-5-(R.sup.10)-6,6,7,7-tetra(R.sup.11)-2,4-dioxo-2-
H-1,5-diazepin-3-yl core, and R.sup.13 is H; then [1120] R.sup.10
is H, C(O)R.sup.17, C(.dbd.O)OR.sup.17, C(.dbd.O)NR.sup.18R.sup.19,
[1121] S(.dbd.O).sub.2NR.sup.18R.sup.19, S(.dbd.O).sub.2R.sup.17;
or [1122] C.sub.1-C.sub.6 alkyl optionally substituted with 0-3
R.sup.10a; [1123] R.sup.10a, at each occurrence, is independently
selected from [1124] H, C.sub.1-C.sub.6 alkyl, OR.sup.14, Cl, F,
Br, I, .dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16, and CF.sub.3.
[1125] In a more preferred embodiment of the present invention, Q
is NH.sub.2.
[1126] In a most preferred embodiment the total number of carbon
atoms in R.sup.3, R.sup.3a, R.sup.5, and R.sup.5a equals seven or
more.
[1127] It is understood that any and all embodiments of the present
invention may be taken in conjunction with any other embodiment to
describe additional even more preferred embodiments of the present
invention.
[1128] In a second embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I) and
a pharmaceutically acceptable carrier.
[1129] In a third embodiment, the present invention provides a
method for the treatment of neurological disorders associated with
.beta.-amyloid production comprising administering to a host in
need of such treatment a therapeutically effective amount of a
compound of Formula (I).
[1130] In a preferred embodiment the neurological disorder
associated with .beta.-amyloid production is Alzheimer's
Disease.
[1131] In a fourth embodiment, the present invention provides a
method for inhibiting .gamma.-secretase activity for the treatment
of a physiological disorder associated with inhibiting
.gamma.-secretase activity comprising administering to a host in
need of such inhibition a therapeutically effective amount of a
compound of Formula (I) that inhibits .gamma.-secretase
activity.
[1132] Thus, the present invention provides a method for inhibiting
.gamma.-secretase activity comprising administering to a host in
need of such inhibition a therapeutically effective amount of a
compound of Formula (I) that inhibits I-secretase activity.
[1133] In a preferred embodiment the physiological disorder
associated with inhibiting .gamma.-secretase activity is
Alzheimer's Disease.
[1134] In a fifth embodiment, the present invention provides a
compound of Formula (I) for use in therapy.
[1135] In a preferred embodiment the present invention provides a
compound of Formula (I) for use in therapy of Alzheimer's
Disease.
[1136] In a sixth embodiment, the present invention provides for
the use of a compound of Formula (I) for the manufacture of a
medicament for the treatment of Alzheimer's Disease.
DEFINITIONS
[1137] As used herein, the term "A" denotes the protein designated
A.beta., .beta.-amyloid peptide, and sometimes .beta./A4, in the
art. A.beta. is an approximately 4.2 kilodalton (kD) protein of
about 39 to 43 amino acids found in amyloid plaques, the walls of
meningeal and parenchymal arterioles, small arteries, capillaries,
and sometimes, venules. The isolation and sequence data for the
first 28 amino acids are described in U.S. Pat. No. 4,666,829. The
43 amino acid sequence is:
TABLE-US-00001 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val
His His Gln Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys
Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala
Thr
[1138] The term "APP", as used herein, refers to the protein known
in the art as .beta. amyloid precursor protein. This protein is the
precursor for A.beta. and through the activity of "secretase"
enzymes, as used herein, it is processed into A.beta.. Differing
secretase enzymes, known in the art, have been designated .beta.
secretase, generating the N-terminus of A.beta., .alpha. secretase
cleaving around the 16/17 peptide bond in A.beta., and ".gamma.
secretases", as used herein, generating C-terminal A.beta.
fragments ending at position 38, 39, 40, 42, and 43 or generating
C-terminal extended precursors which are subsequently truncated to
the above polypeptides.
[1139] The compounds herein described may have asymmetric centers.
Compounds of the present invention containing an asymmetrically
substituted atom may be isolated in optically active or racemic
forms. It is well known in the art how to prepare optically active
forms, such as by resolution of racemic forms or by synthesis from
optically active starting materials. Many geometric isomers of
olefins, C.dbd.N double bonds, and the like can also be present in
the compounds described herein, and all such stable isomers are
contemplated in the present invention. Cis and trans geometric
isomers of the compounds of the present invention are described and
may be isolated as a mixture of isomers or as separated isomeric
forms. All chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
[1140] The term "substituted," as used herein, means that any one
or more hydrogens on the designated atom is replaced with a
selection from the indicated group, provided that the designated
atom's normal valency is not exceeded, and that the substitution
results in a stable compound. When a substituent is keto (i.e.,
.dbd.O), then 2 hydrogens on the atom are replaced.
[1141] When any variable (e.g., R.sup.5b) occurs more than one time
in any constituent or formula for a compound, its definition at
each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-2 R.sup.5b, then said group may optionally be
substituted with up to two R.sup.5b groups and R.sup.5b at each
occurrence is selected independently from the definition of
R.sup.5b. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
[1142] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may
be bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[1143] As used herein, "alkyl" or "alkylene" is intended to include
both branched and straight-chain saturated aliphatic hydrocarbon
groups having the specified number of carbon atoms; for example,
"C.sub.1-C.sub.6 alkyl" denotes alkyl having 1, 2, 3, 4, 5, or 6
carbon atoms. Examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,
t-butyl, pentyl, and hexyl. Preferred "alkyl" group, unless
otherwise specified, is "C.sub.1-C.sub.4 alkyl". Additionally,
unless otherwise specified, "propyl" denotes n-propyl or i-propyl;
"butyl" denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
[1144] As used herein, "alkenyl" or "alkenylene" is intended to
include hydrocarbon chains of either a straight or branched
configuration and one or more unsaturated carbon-carbon bonds which
may occur in any stable point along the chain. Examples of
"C.sub.2-C.sub.6 alkenyl" include, but are not limited to, ethenyl,
1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the
like.
[1145] As used herein, "alkynyl" or "alkynylene" is intended to
include hydrocarbon chains of either a straight or branched
configuration and one or more carbon-carbon triple bonds which may
occur in any stable point along the chain, such as ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the
like.
[1146] "Alkoxy" or "alkyloxy" represents an alkyl group as defined
above with the indicated number of carbon atoms attached through an
oxygen bridge. Examples of alkoxy include, but are not limited to,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,
t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy,
t-butoxy. Similarly, "alkylthio" or "thioalkoxy" is represents an
alkyl group as defined above with the indicated number of carbon
atoms attached through a sulphur bridge.
[1147] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo. Unless otherwise specified, preferred halo is
fluoro and chloro. "Counterion" is used to represent a small,
negatively charged species such as chloride, bromide, hydroxide,
acetate, sulfate, and the like.
[1148] "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogen (for example --C.sub.vF.sub.w where v=1 to 3 and w=1 to
(2v+1)). Examples of haloalkyl include, but are not limited to,
trifluoromethyl, trichloromethyl, pentafluoroethyl,
pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl,
heptafluoropropyl, and heptachloropropyl. "Haloalkoxy" is intended
to mean a haloalkyl group as defined above with the indicated
number of carbon atoms attached through an oxygen bridge; for
example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy,
and the like. "Halothioalkoxy" is intended to mean a haloalkyl
group as defined above with the indicated number of carbon atoms
attached through a sulphur bridge.
[1149] "Cycloalkyl" is intended to include saturated ring groups,
having the specified number of carbon atoms. For example,
"C.sub.3-C.sub.6 cycloalkyl" denotes such as cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl.
[1150] As used herein, "carbocycle" is intended to mean any stable
3- to 7-membered monocyclic or bicyclic or 7- to 13-membered
bicyclic or tricyclic, any of which may be saturated, partially
unsaturated, or aromatic. Examples of such carbocycles include, but
are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, adamantyl, cyclooctyl.
[3.3.0]bicyclooctane. [4.3.0]bicyclononane, [4.4.0]bicyclodecane
(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,
indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred
"carbocycle" are cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
[1151] As used herein, the term "heterocycle" or "heterocyclic
ring" is intended to mean a stable 5- to 7-membered monocyclic or
bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is
saturated partially unsaturated or unsaturated (aromatic), and
which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms
independently selected from the group consisting of N, O and S and
including any bicyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The nitrogen and
sulfur heteroatoms may optionally be oxidized. The heterocyclic
ring may be attached to its pendant group at any heteroatom or
carbon atom which results in a stable structure. The heterocyclic
rings described herein may be substituted on carbon or on a
nitrogen atom if the resulting compound is stable. If specifically
noted, a nitrogen in the heterocycle may optionally be quaternized.
It is preferred that when the total number of S and O atoms in the
heterocycle exceeds 1, then these heteroatoms are not adjacent to
one another. It is preferred that the total number of S and O atoms
in the heterocycle is not more than 1.
[1152] Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,
b-carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthrdinyl,
phenanthrolinyl phenarsazinyl, phenazinyl, phenothiazinyl,
phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, pteridinyl piperdonyl, 4-piperdonyl, ptendinyl
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl pyrazolyl
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl pyrrolidinyl, pyrrolinyl, pyrrolyl,
quinazolinyl, quinolinyl, 4H-quinolizinyl quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl. 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10
membered heterocycles include, but are not limited to, pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl,
benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl,
1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl,
benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and
isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but
are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl,
thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6
membered heterocycles include, but are not limited to pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl,
piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[1153] As used herein, the term "aryl", "C.sub.6-C.sub.1 aryl" or
aromatic residue, is intended to mean an aromatic moiety containing
the specified number of carbon atoms; for example phenyl, pyridinyl
or naphthyl. Preferred "aryl" is phenyl. Unless otherwise
specified, "aryl" may be unsubstituted or substituted with 0 to 3
groups selected from H, methyl, ethyl, propyl, butyl, methoxy,
ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF.sub.3,
SCH.sub.3, S(O)CH.sub.3, SO.sub.2CH.sub.3, --N(CH.sub.3).sub.2,
N(CH.sub.3)H, CN, NO.sub.2, OCF.sub.3, C(.dbd.O)CH.sub.3,
CO.sub.2H, CO.sub.2CH.sub.3, or C.sub.1-C.sub.4 haloalkyl.
[1154] The phrase "additional lactam or thiolactam carbons", as
used herein, is intended to denote the number of optional carbon
atoms in the lactam or thiolactam ring B of Formula (I). Formula
(I''):
##STR00024##
represents the lactam ring B of Formula (I). Additional lactam
carbons are carbons in lactam ring B other than the carbons
numbered 2 and 3 in the backbone of the formula. The same numbering
applies to the carbons in the analogous thiolactam ring B. The
additional lactam carbons may be optionally replaced by a
heteroatom selected from oxygen nitrogen and sulfur. Lactam ring B
contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one
optional carbon may optionally be replaced by a heteroatom, such
that the total number of members of lactam ring B, including atoms
numbered 1, 2 and 3 in the backbone, does not exceed 10. It is
preferred that the total number of atoms of lactam ring B is 6, 7
or 8; it is more preferred that the total number of atoms of lactam
ring B is seven. It is further understood that lactam ring B may
optionally be unsaturated or partially unsaturated (i.e. two
adjacent atoms in the ring form a double bond) wherein the backbone
of lactam ring B may contain one, two or three double bonds.
Examples of lactam ring B include:
##STR00025## ##STR00026##
but are not intended to limit the invention. Preferred examples of
lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more
preferred examples of lactam ring B are B1, B6, B8, B9, and B13.
Preferred examples of substituent R.sup.10 or R.sup.11 on lactam B
are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl,
4-trifluoromethylphenyl, (4-fluorophenyl)methyl,
(4-chlorophenyl)methyl, (4-trifluoromethylphenyl)methyl, and 2-,
3-, and 4-pyridinyl. Preferred examples of R.sup.13 on lactam B are
F, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.
[1155] The compounds herein described may have asymmetric centers.
One enantiomer of a compound of Formula (I) may display superior
biological activity over the opposite enantiomer. For example
carbon 3 of lactam ring B Formula (I'') may exist in either an S or
R configuration. Thus, an R or S configuration at carbon 3 in
Formula (I'') is considered part of the invention. An example of
such configuration includes,
##STR00027##
but is not intended to be limited to this example of ring B. When
required, separation of the racemic material can be achieved by
methods known in the art. Additionally, the carbon atoms to which
R.sup.3 and R.sup.5 are attached may describe chiral carbons which
may display superior biological activity over the opposite
enantiomer. For example, where R.sup.3 and R.sup.5 are not H, then
the configuration of the two centers may be described as (2R,3R),
(2R,3S), (2S,3R), or (2S,3S). All configurations are considered
part of the invention; however, the (2R,3S) and the (2S,3R) are
preferred and the (2R,3S) is more preferred.
[1156] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[1157] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane
disulfonic, oxalic, isethionic, and the like.
[1158] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[1159] "Prodrugs" are intended to include any covalently bonded
carriers which release the active parent drug according to formula
(I) in vivo when such prodrug is administered to a mammalian
subject. Prodrugs of a compound of formula (I) are prepared by
modifying functional groups present in the compound in such a way
that the modifications are cleaved, either in routine manipulation
or in vivo, to the parent compound. Prodrugs include compounds of
formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded
to any group that, when the prodrug or compound of formula (I) is
administered to a mammalian subject, cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to acetate,
formate and benzoate derivatives of alcohol and amine functional
groups in the compounds of formula (I), and the like.
[1160] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
Synthesis
[1161] The compounds of the present invention can be prepared in a
number of ways well known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or variations thereon as appreciated by those skilled in the art.
Preferred methods include, but are not limited to, those described
below. All references cited herein are hereby incorporated in their
entirety herein by reference.
[1162] The novel compounds of this invention may be prepared using
the reactions and techniques described in this section. The
reactions are performed in solvents appropriate to the reagents and
materials employed and are suitable for the transformations being
effected. Also, in the description of the synthetic methods
described below, it is to be understood that all proposed reaction
conditions, including choice of solvent, reaction atmosphere,
reaction temperature, duration of the experiment and workup
procedures, are chosen to be the conditions standard for that
reaction, which should be readily recognized by one skilled in the
art. It is understood by one skilled in the art of organic
synthesis that the functionality present on various portions of the
molecule must be compatible with the reagents and reactions
proposed. Such restrictions to the substituents which are
compatible with the reaction conditions will be readily apparent to
one skilled in the art and alternate methods must then be used.
[1163] Methods for the synthesis of succinylamino lactams are known
in the art and are disclosed in a number of references including
PCT publication number WO 96/29313, which is hereby incorporated by
reference.
[1164] Disubstituted succinate derivatives can be prepared by a
number of known procedures. The procedure of Evans (D. A. Evans et
al, Org. Synth. 86, p 83 (1990)) is outlined in Scheme 1 where
acylation of an oxazolidinone with an acylating agent such as an
acid chloride provides structures 1. Alkylation to form 2 followed
by cleavage of the chiral auxiliary and subsequent alkylation of
the dianion of the carboxylic acid 3 provides a variety of
disubstituted succinates which can be separated and incorporated
into structures of formula (I) by those skilled in the art.
Additional examples are found in P. Becket, M. J. Crimmin, M. H.
Davis, Z. Spavold, Synlett, (1993), 137-138, incorporated herein by
reference.
##STR00028##
[1165] Diastereomerically pure succinate derivatives can be
accessed using the chemistry outlined below, adapted from P.
Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993),
137-138 incorporated herein by reference. This reference provides
the synthesis below to obtain compound 9, Scheme 2. Compound II,
Scheme 2, is used as an intermediate and is prepared from 9 by
hydrogenation of the allyl group followed by coupling of
9-fluorenemethanol under standard conditions using DCC and DMAP in
CH.sub.2Cl.sub.2. Deprotection of the tert-butyl ester is
accomplished by treatment with 50% trifluoroacetic acid.
[1166] Additional methods useful for the preparation of succinate
derivatives are known by those skilled in the art. Such references
include, McClure and Axt, Bioorganic & Medicinal Chemistry
Letters, 8 (1998) 143-146; Jacobson and Reddy, Tetrahedron Letters,
Vol 37, No. 46, 8263-8266 (1996); Pratt et al., SYNLETT, May 1998,
p. 531; WO 97/18207; and WO 98/51665. The synthetic disclosures of
WO97/18207 and WO 98/51665 are hereby incorporated by
reference.
##STR00029## ##STR00030##
[1167] A variety of compounds of Formula (I) can be prepared by
methods described in Scheme 4. The protected .alpha.-amine 3 of the
.alpha.-amino-.epsilon.-caprolactam can be prepared by methods well
known in the literature for amino protecting groups as discussed in
Theodora W. Greene's book "Protective Groups in Organic Synthesis",
like NV-Boc using di-t-butyldicarbonate in an appropriate solvent
like DMSO. A sulfur atom can be introduced into the ring providing
L-.alpha.-amino-.beta.-thio-.epsilon.-caprolactam according to the
procedure in S. A. Ahmed et al. FEBS Letters, (1984), vol. 174,
pages 76-9 (Scheme 3). One skilled in the art can extend this
methodology to the synthesis of .beta.-amino and oxygen containing
rings by analogy. The sulfur-containing molecules can also be
oxidized to the sulfoxide and sulfone by methods known to one
skilled in the art.
##STR00031##
[1168] The lactam nitrogen of compound 13 can be alkylated by
generating the anion with bases such as LDA, lithium
bis(trimethylsilyl)amide or sodium hydride in solvents like THF,
with or without cosolvents such as DMPU or HMPA and reacting this
with a variety of groups containing leaving groups (X'') like
bromide, iodide, mesylate or tosylate. Alkylating agents such as
.alpha.-bromo amides, ketones and acids can be prepared by a number
of literature methods including halogenation of amino acids by
diazotization or are commercially available. Other suitable
alkylating agents such as alkyl, allylic and benzylic halides can
be formed form a variety of precursors such as free-radical
addition of halides or activation of alcohols, and other
chemistries known to those skilled in the art. For discussion of
these types of reactions, see Carey, F. A. and Sundberg, R. J.,
Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990,
pages 304-305, 342-347, 695-698.
[1169] The N-Boc protecting group can be removed by any number of
methods well known in the literature like TFA in methylene chloride
to give the compound 15. The amine 15 can be coupled to an
appropriately substituted carboxylic acid or acid chloride by
methods well described in the literature for making amide bonds,
like TBTU in DMF with a base like NMM to give the elaborated
compound 16. Compounds 16 can be alkylated using standard bases
like LDA, NaH, or NaHMDS to deprotonate the amide followed by
addition of an alkylating agent with an appropriate leaving group
like halide, mesylate, or triflate in an appropriate solvent to
provide compounds 17 with an R.sup.6 substituent. The t-butyl ester
is then removed by treatment with TFA in methylene chloride to give
the carboxylic acid 17.
##STR00032##
The final compounds 18 were prepared by treating the activated
carboxylic acid of 17 with an appropriately substituted amine. For
instance, activation of the carboxylic acid with HATU
(O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium
hexafluorophosphate) or PyBOP
(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate) or other coupling agents known to those
skilled in the art allows condensation with ammonia to form primary
amides. Similarly, condensation of the activated acid with
hydroxylamine hydrochloride provides the hydroxamic acid, or
reaction with a primary or secondary amine provides the substituted
amine derivative. Activation of the acid with PyBroP
(bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) followed
by addition of an alcohol and 4-dimethylaminopyridine allows
formation of the ester directly. For additional acylation reactions
see for example Carey, F. A. and Sundberg, R. J., Advanced Organic
Chemistry, Part A, New York: Plenum Press, 1990, pages 475-479.
[1170] Additional intermediates in the synthesis of compounds of
formula (I) can be prepared as shown in Scheme 5. A suitable resin
for solid phase synthesis such as Fmoc
(Fluorenylmethylcarbonyl)-protected hydroxylamine bound to
polystyrene beads can be purchased from Novabiochem, Inc.
Deprotection of the Fmoc group under standard conditions using 20%
piperidine in DMF provides trityl-linked hydroxylamine resin.
Coupling of a fluorenylmethyl-protected succinic acid derivative
such as 20 with a coupling agent such as HATU in a suitable solvent
like DMF or N-methylpyrrolidinone provides the support-bound
hydroxamate 21. The Fluorenylmethyl ester can be removed using 20%
piperidine in DMF to provide the free carboxylic acid which can be
coupled to amines like the caprolactam 22 (which is available using
chemistry outlined in Scheme 4) using PyBOP
(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate) and a suitable base like DIEA in DMF or NMP.
The support-bound intermediate 23 can then be elaborated to biaryl
structures of the type 24 using typical Suzuki coupling conditions
employing a catalyst such as Palladium complexes like
tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium
carbonate as a base in a suitable solvent like THF or DME and an
excess of a boronic acid. The final compounds are liberated from
the support employing dilute (5%) trifluoroacetic acid in
CH.sub.2Cl.sub.2 and purified by conventional chromatography.
##STR00033##
[1171] The compounds of formula (I) of the present invention can
also be prepared from aminolactams and aminothiolactams (27) and
succinic acid derivatives (11) using amide bond syntheses known in
the art, including methods commonly used in peptide syntheses, such
as HATU, TBTU. BOP, pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed
carboxylic anhydride, and phenyl ester mediated couplings, as
illustrated in Scheme 6 for the synthesis of (Ia), a particular
embodiment of (I). Depending on the structure of
##STR00034##
the final product, it will be appreciated by those skilled in the
art that protecting groups or precursor functionality convertable
to the desired groups may be desirable. Protecting groups and their
use in synthesis are described in Green and Wuts, Protective Groups
in Organic Synthesis, (Wiley 1991). This is further illustrated in
Scheme 6a, in which the succinate half-ester (9) (Becket et al.,
Synlett 1993, 137-138) is coupled to the aminobenzodiazepine (30)
(Sherrill and Sugg, J. Org. Chem. 1995, 60, 730-734; Bock et al.,
J. Med. Chem., 1993, 36, 4276-4292) to give ester (Ib), followed by
conversion of the ester group to the primary amide (Ic).
[1172] The synthesis of the thiolactams of the present invention
(Formula (I), A=S) can be carried out using thiolactam
intermediates (27, A=S), using the methods described above. The
thiolactam intermediates may be prepared from suitably protected
aminolactams employing methods known to those skilled in the art,
using, for example, Lawessson's reagent, P4S10, or related methods
(see Taylor et al., Bioorg. Med. Chem. Lett. 1997, 7 (4), 453-456;
Schwarz et al., Tetrahedron, 1997, 53 (26), 8795-8806; Achour et
al., Synth. Commun. 1994, 24 (20), 2899-2905; Buege et al., Arch.
Pharm. 1994, 327 (2), 99-103; Levai, et al., Arch. Pharm. 1992 (325
(11), 721-726; Duhammel et al., Tetrahedron Asymmetry 1991, 2 (3),
203-206; Bodine et al., Synth. Commun. 1982, 12, 787). Deprotection
of the amine, coupling to an appropriate succinate derivative and
elaboration of the distal succinic acid derivative provides the
desired thiolactams of the present invention.
##STR00035##
[1173] Methods for the synthesis of lactams, including amino
benzodiazapines, are known in the art and are disclosed in a number
of references including PCT publication number WO 98/28268, which
is hereby incorporated by reference. Additional examples of the
synthesis of ring B lactams within the scope of the invention are
shown below in Schemes 7, 8, 9, and 10.
##STR00036##
Step 1: Preparation of 72;
[1174] Following the literature procedures: Stanetty, P.; Koller,
H.; Mihovilovic, M. J. Org. Chem., 1992, 57, 6833-6837; Muchowski,
J. M.; Venuti, M. D. J. Org. Chem., 1980, 57, 4798-4801.
[1175] A stirred mixture of 71 (13.0 g, 67.3 mmol) in diether ether
(100 mL) under nitrogen was cooled to below -50.degree. in a dry
ice/acetone bath. A solution of t-butyl lithium in hexanes (2.5 M,
90 mL) was added dropwise. The cooling bath was removed and the
reaction allowed to warm to approximately -25.degree. C. and then
the temperature was maintained between -20.degree. C. and
-10.degree. C. for 3.25 hours with a dry ice/ethylene glycol
cooling bath. The reaction was cooled again to below -50.degree. C.
and 4-pyridine carboxaldehyde (8.3 mL, 87.5 mmol) was added and the
reaction stirred at approximately -15.degree. C. for 1.25 hours.
The reaction was quenched with a saturated solution of ammonium
chloride and the mixture stirred overnight. Hexanes (100 mL) was
added. The reaction was filtered, washed with water and dried in
vacuo to give 72.degree. C. (15.0 g, 74% as a tan solid: .sup.1HNMR
(300 MHz, DMSO-d.sub.6 .delta. 8.55 (s, 1H), 8.48 (d, 2H), 7.50 (d,
1H), 7.36 (d, 1H), 7.24 (d, 2H), 7.23 (m, 1H) 7.09 (t of d, 1H0,
6.68 (d, 1H), 5.93 (d, 1H), 1.38 (s, 9H; API MS m/z=301
[C.sub.17H.sub.20N.sub.2O.sub.3--H].sup.+.
Step 2: Preparation of 73;
[1176] To a vigorously stirred solution of 72 (1.21 g, 4.03 mmol)
in methylene chloride (45 mL) was added manganese oxide (5.2 g,
59.8 mmol). After 5 hours the reaction was filtered over celite and
the celite washed with methylene chloride. The filtrate was
concentrated to an oil and triturated with hexanes. The hexanes
were removed via pipette and the solid was dried in vacuo to give a
73 (1.01 g, 84%) as a tan solid: .sup.1HNMR (300 MHz, CDCl.sub.3)
.delta. 10.25 (s, 1H), 8.80 (d, 2H). 8.50 (d. 1H). 7.48 (t, 1H),
7.47 (d, 2H), 7.43 (d, 1H), 7.00 (t, 1H), 1.53 (s, 9H); API MS
m/z=299 [C.sub.17H.sub.18N.sub.2O.sub.3+H].sup.+.
Step 3: Preparation of 74;
[1177] Following the literature procedure; Nudelman, Ayetlet;
Bechor, Y.; Falb, E.; Fischer, B.; Wexler, B. A.; Nudelman,
Abraham; Syn. Com., 1998, 28(3), 471-474.
[1178] Acetyl chloride (57 mL, 801 mmol) was added to ice cold
methanol (280 mL) with vigorous stirring. Solid 73 (9.0 g., 30.2
mmol) was added and the reaction stirred overnight. The methanol
was evaporated in vacuo and the residue dissolved in water and
cooled in an ice bath. The pH was adjusted to approximately 9 with
6N NaOH. The resulting yellow precipitate was collected by vacuum
filtration and washed with water and dried in vacuo at 40.degree.
C. to give 74 (5.71 g, 95%) as a yellow solid: .sup.1HNMR (300 MHz,
CDCl.sub.3) .delta. 8.77 (d, 2H), 7.43 (d, 2H), 7.33 (m, 2H), 6.74
(d, 1H), 6.49 (t, 1H), 6.30 (broad s, 2H). CI MS m/z=199
[C.sub.12H.sub.10N.sub.2O.sub.1+H].sup.+
Step 4: Preparation of 76;
[1179] The benzotriazole acid 75 (13.6 g, 41.7 mmol) and a
catalytic amount of DMF were dissolved in dry THF (130 mL.) The
reaction was cooled in an ice/salt bath. Oxalyl chloride (3.6 mL,
41.2 mmol) was added dropwise over 1 hour. The reaction was stirred
an additional 2.5 hours. A solution of 74 (5.5 g, 27.7 mmol) in THF
(50 mL) was added dropwise forming a thick precipitate. Water and
ether were added and the layers separated. The aqueous layer was
extracted with methylene chloride. The combined organics were
washed with saturated sodium bicarbonate, dried over magnesium
sulfate and concentrated. The resulting oil was chromotographed
over silica gel (1:1 methyl acetate/methylene chloride) to provide
76 (12.2 g. 86%) as a yellow solid: .sup.1HNMR (300 MHz,
CDCl.sub.3) .delta. 11.62 (s, 1H); 8.78 (d, 2H), 8.63 (d, 1H), 8.08
(d, 1H), 7.71 (broad s, 1H), 7.63 (t, 1H). 7.54 (m, 1H), 7.44 (d,
1H), 7.40-7.19 (m, 11H), 7.17 (t, 1H), 7.02 (broad s, 1H),
5.24-5.07 (m, 2H); API MS m/z=5.07
[C.sub.28H.sub.22N.sub.6O.sub.4.sup.+H].sup.+.
Step 5: Preparation of 77;
[1180] Based on the literature procedures; Semple, G.; Ryder, H.;
Ohta, M.; Satoh, M. Syn. Comm., 1996, 26(4), 721-727. Semple. G.;
Ryder, H.; Rooker, D. P. Batt, A. R. Kendrick, D. A.; Szelke, M.;
Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. J. Med.
Chem., 1997, 40, 331-341.
[1181] To stirred ice cold methanol (40 mL) was added 76 (4.0 g,
7.9 mmol) and ammonium hydroxide (20 mL.) The reaction was stirred
for 2.5 hours forming a heavy precipitate. The reaction mixture was
added slowly to cold acetic acid (40 mL) and stirred overnight at
room temperature. The reaction mixture was evaporated and water
added. The solution was adjusted to pH 9 with concentrated ammonium
hydroxide and stirred 0.5 hour. The resulting tan solid was
collected by vacuum filtration and dried in vacuo. The solid was
stirred in ethyl acetate (20 mL) and heated under reflux for 1
hour. The mixture was cooled in ice and filtered. The product was
washed with cold ethyl acetate and dried in vacuo to give 77 (2.2
g, 72%) as a white solid: .sup.1HNMR (300 MHz. DMSO-d.sub.6)
.delta. 10.94 (s, 1H), 8.68 (d, 2H), 8.51 (d, 1H), 7.57 (t, 1H),
7.43-7.25 (m, 10H), 5.10 (d, 2H); CI MS m/z=387
[C.sub.22H.sub.18N.sub.4O.sub.3+H].sup.+.
Step 6: Preparation of 78;
[1182] Following the literature procedures; Semple, G.; Ryder, H.;
Ohta, M.; Satoh, M. Syn. Comm., 1996, 26(4), 721-727. Semple, G.;
Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D. A.; Szelke, M.;
Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. J. Med.
Chem., 1997, 40, 331-341.
[1183] A stirred solution of 77 (1.0 g, 2.59 mmol) in DMF (10 mL)
under nitrogen was cooled in ice. Sodium hydride (62 mg, 2.59 mmol)
was added and the reaction stirred 2 hours. Methyl iodide (0.16 mL,
2.59 mmol) was added and the reaction stirred 2 hours at room
temperature. The reaction was evaporated and chloroform and water
were added. The layers were separated and the aqueous extracted
with chloroform. The combined organics were washed with brine,
dried over sodium sulfate, decanted, evaporated and dried in vacuo.
The crude product was passed through a pad a silica gel (1:1 ethyl
acetate/methylene chloride) and evaporated to give 78 (934 mg, 90%)
was a tan solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.59 (d,
2H), 7.62 (t, 1H), 7.52 (d, 1H), 7.42-7.25 (m, 9H), 6.72 (d, 1H),
5.38-5.30 (m, 1H), 5.15 (s, 2H), 3.48 (s, 3H); CI MS m/z 401
[C.sub.23H.sub.20N.sub.4O.sub.3+H].sup.+.
##STR00037##
Using the procedures described in Scheme 7 the 3-pyridyl isomer can
be prepared. The following data characterizes the individual
intermediates.
Intermediate 82;
[1184] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.61 (broad s,
1H), 8.49 (s, 1H), 8.42 (d, 1H), 7.61 (d, 1H), 7.49 (d, 1H) 7.40
(d, 1H), 7.34-7.21 (m, 2H), 7.40 (t, 1H), 6.51 (broad s, 1H), 6.00
(s, 1H), 1.39 (s, 9H).
Intermediate 83;
[1185] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.11 (s, 1H) 8.92
(s, 1H), 8.80 (d, 1H), 8.48 (d, 1H), 8.02 (d, 1H), 7.59 (t, 1H),
7.52-7.42 (m, 2H). 7.05 (t, 1H), 1.54 (s, 9 h).
Intermediate 84;
[1186] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.84 (s, 1H). 8.73
(d, 1H), 7.93 (d, 1H), 7.44-7.37 (m, 2H), 7.32 (t, 1H), 6.75 (d,
1H), 6.60 (t, 1H), 6.22 (broad s, 2H); CI MS m/z=199
[C.sub.12H.sub.10N.sub.2O.sub.1+H].sup.+.
Intermediate 86;
[1187] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 11.51 (s, 1H),
8.81-8.75 (m, 2H), 8.60 (d, 1H), 8.07 (d, 1H), 7.89 (d of t, 1H),
7.80 (broad s, 1H), 7.63 (t, 1H), 7.52 (d, 2H), 7.42-7.15 (m, 9H),
6.94 (broad s, 1H), 5.22-5.02 (m, 2H); API MS m/z=507
[C.sub.28H.sub.22N.sub.6O.sub.4.sup.+H].sup.+.
Intermediate 87;
[1188] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.69 (s, 2H), 8.24
(broad s, 1H), 7.98 (d, 1H), 8.48 (t, 1H), 7.42-7.25 (m, 8H), 7.17
(d, 1H), 6.60 (d, 1H), 5.47 (d, 1H), 5.18 (s, 2H); CIMS m/z=387
[C.sub.22H.sub.18N.sub.4O.sub.3+H].sup.+.
Intermediate 88;
[1189] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (d, 2H), 8.25
(d, 1HO, 7.62 (t, 1H), 7.40-7.24 (m, 9H), 6.68 (d, 1H), 5.33 (d,
1H), 5.14 (s, 2H), 3.46 (s, 3H).
##STR00038##
Step 1: Preparation of 2-Amino-3'-met oxybenzophenone 93
[1190] Following the literature precedent: Walsh, D. A. Synthesis,
1980, 677-688.
[1191] To a solution of bromoanisole 91 (1.38 mL, 10.7 mmol) in THF
(5 mL) at 78.degree. C. and under nitrogen atmosphere, was added
1.2 M t-BuLi in pentane (18.2 mL, 21.9 mmol) dropwise. After
stirring for 20 min, anthranilonitile 92 (0.63 g, 5.3 mmol) was
added. The reaction was warmed to rt and stirred overnight. The
reaction was cooled to 0.degree. C. and quenched with 3N HCl. After
stirring 30 min at rt, the acidic extracts were washed with EtOAc
(3.times.12 mL). The aqueous layer was made basic (pH>10) using
6N NaOH and extracted with CH.sub.2Cl.sub.2. The organic extracts
were washed with sat. NaCl, dried over NaSO.sub.4, filtered, and
concentrated to give a crude mixture containing 93. The crude oil
was purified by chromatography on silica to provide pure 93 (0.17
g, 14%) as a yellow oil; .sup.1H NMR (500 MHz, DMSO-d6) .delta.
7.40-7.43 (m, 1H), 7.27-7.30 (m, 1H), 7.07-7.17 (m, 4H). 6.86-6.88
(m, 1H). 6.49-6.52 (m, 1H), 3.81 (s, 3H); CI MS m/z=228
[C.sub.14H.sub.13NO.sub.2+H].sup.+.
Step 2: Preparation of 95;
[1192] Based on the literature procedures; Semple, G,; Ryder, H.;
Ohta, M.; Satoh, M. Syn. Comm., 1996, 26(4), 721-727. Semple, G.;
Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D. A.; Szelke, M.;
Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. J. Med.
Chem., 1997, 40, 331-341.
[1193] To a solution of benzotriazole acid 94 (16.47 g, 50.5 mmol)
in THF (101 mL) at 0.degree. C. under a nitrogen atmosphere was
added oxalyl chloride (4.84 mL, 55.5 mmol) and a catalytic amount
of DMF (1.0 mL). After stirring for 1 h, a solution of 93 (11.47 g,
50.5 mmol) and N-methylmorpholine (12.25 mL, 111 mmol) in THF (51
mL) was added dropwise via dropping funnel. The reaction was
allowed to warm to rt and stirred overnight. The solids were
removed by filtration. The filtrate was diluted with MeOH (62 mL),
and NH.sub.3 gas was condensed into the solution for 15 min, the
reaction vessel was sealed and stirred at rt for 2 h. After
concentration, the crude oil was dissolved in EtOAc, washed with 3N
NaOH (3.times.20 mL). The organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The resultant crude
oil was dissolved in AcOH (121 mL), and NH.sub.4OAc (7.17 g) was
added. After stirring at rt overnight (16 h), the reaction was
concentrated and diluted with water and made basic with 50% NaOH.
The basic aqueous solution was extracted with EtOAc (3.times.150
mL). The combined organic extracts were washed with sat. NaCl,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
product was purified by chromatography on silica to provide 95
(6.96 g, 33%) as a solid; .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
7.50 (t, 1 HO, 7.10-7.40 (m, 9H), 7.05 (d, 1H), 6.97 (dd, 1 HO,
6.63 (d, 1H0, 5.30 (d, 1H), 5.20 (s, 2 HO, 3.77 (s, 3H).
Step 3: Preparation of 96;
[1194] To a solution of 95 (2.07 g, 5.4 mmol) and K2CO3 (3.71 g,
26.8 mmol) in DMF (9.7 mL), was added MeI (0.50 mL, 8.1 mmol).
After stirring 1 h at rt, the reaction was poured into water (100
mL) and stirred overnight. The solid was collected by filtration,
rinsed with water and Et2O. This was dried in a vacuum oven at
55.degree. C. to provide 96 (1.5 g, 3.5 mmol) as a red solid; 1H
NMR (300 MHz, CDCl3) .delta. 7.58 (t, 1H), 7.19-7.42 (m, 9H), 7.07
(d, 1 HO, 7.00 (dd, 1H), 6.69 (d, 1H), 5.32 (d, 1HO, 5.15 (s, 2 HO,
3.83 (s, 3 HO, 3.45 (s, 3H).
Step 3: Preparation of 97; Cbz Deprotection to Free Amine.
[1195] To protected amine 96 (2.13 g, 4.9 mmol) was added 30% HBr
in AcOH (50 mL). This was stirred at rt for 1 h. The reaction was
poured into water (200 mL) and washed with EtOAc (200 mL). The
aqueous layer was made basic with 50% NaOH and extracted with EtOAc
(2.times.200 mL). The extracts were concentrated to give crude 97
(1.14 g, 78%) as a yellow solid; .sup.1H NMR (300 MHz. CDCl.sub.3)
.delta. 7.58 (t, 1H), 7.17-7.40 (m, 5H), 7.12 (d, 1H0, 7.00 (dd,
1H) 3.83 (s, 3H), 3.48 (s, 3H); CI MS m/z=296
[C.sub.17H.sub.17N.sub.3O2+H].sup.+.
##STR00039##
Step 1: Preparation of 102;
[1196] To a stirred mixture of p-anisidine (6 g, 48.7 mmol) in
methylene chloride (170 mL) under nitrogen was added DMAP (5.0 mg,
mmol) and triethylamine (13.9 mL, 99.7 mmol.) Ethyl chloroformate
(4.85 mL, 50.7 mmol) was added and the reaction stirred for 2.5
hours. Dilute phosphoric acid (0.5 N) was added and the mixture
stirred for 15 minutes. The aqueous layer was neutralized with
sodium bicarbonate and then extracted with methylene chloride. The
methylene chloride solution was dried over sodium sulfate, filtered
and concentrated. Purification by column chromatography (gradient
ethyl acetate hexanes) provided 102 (7.2 g, 75% q) as a solid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.27 (d, 2H), 6.82 (d,
2H0, 6.45 (broad s, 1H), 4.20 (q, 2H), 3.77 (s, 3H0, 1.31 (t,
3H).
Step 2: Preparation of 103;
[1197] To a stirred suspension of lithium aluminum hydride (1.8 g,
47.4 mmol) in THF (95 mL) was added 102 (3.0 g, 15.4 mmol.) The
reaction was heated at reflux for 2 hours. The reaction was cooled
and quenched with ethyl acetate (150 mL). Solid sodium sulfate was
added and the mixture filtered. The clear solution was evaporated
and dried to give 103 (2.1 g, 100%); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 6.79 (d, 2H). 6.56 (d, 2H). 3.74 (s, 3H), 2.78
(s, 3H).
Step 3: Preparation of 105;
[1198] Based on the following literature references: Sugasawa, T.,
Toyoda. T.; Adachi, M.; Sasakura. K. J Chem. Soc., 1978, 100,
4842-4852. Houpis, I. N.; Moline, A.; Douglas, A. W.; Xavier, L.;
Lynch, J.; Volante, R. P.; Reider, P. J. Tet Lett., 1994, 35,
6811-6814. Adachi, M.; Sasukura, K.; Sugasawa, T. Chem. Pharm.
Bull., 1985, 33, 1826-1835. Sugasawa, T.; Adachi, M.; Sasakura, K.;
Kitagawa, A. J. Org. Chem., 1979, 44, 578-586.
[1199] To a stirred solution of boron trichloride (1 M in
CH.sub.2Cl.sub.2, 29.9 mL) at 0.degree. C. was added toluene (15
mL.) A solution of 103 (3.42 g, 24.9 mmol) in toluene (40 mL) was
added dropwise over 0.5 h. The reaction was stirred at 0.degree. C.
for 20 minutes and then heated under reflux for 1 h.
Anthranilonitrile (25.7 g, 249 mmol) was added and the reaction
heated under reflux for 6.5 h. 2N HCl (1.5 mL) was added and the
reaction heated at 80.degree. C. for 0.5 h. Water was added and the
reaction was neutralized with solid sodium carbonate and extracted
with methylene chloride. The combined organics were dried over
magnesium sulfate, filtered and concentrated. Purification by
column chromatography gave 105 (1.3 g, 33%) as a yellow solid.
.sup.1H NMR (300 MHz. CDCl.sub.3) .delta. 9.98 (broad s, 1H), 7.61
(d. 2 HO, 7.55-7.4 (m, 3 HO, 7.1 (d of d, 1H), 7.02 (d, 1H), 6.72
(d, 1H0, 3.64 (s. 3H), 2.93 (d, 3H).
Step 4: Preparation of 107;
[1200] Based on the following literature references: Semple, G.;
Ryder, H.; Ohta, M.; Satoh, M. Syn. Comm. 1996, 26(4), 721-727.
Semple, G.; Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick D. A.;
Szelke, M., Ohta, M.; Satoh, M., Nishida. A.; Akuzawa, S.; Miyata,
K. J. Med. Chem., 1997, 40, 331-341.
[1201] To a stirred solution of benzotriazole acid 106 in THF (3
mL) at 0.degree. C. was added oxalyl chloride (0.95 mL, 1.1 mmol)
and a catalytic amount of DIMF and the reaction stirred 1 h. A
solution of 105 (240 mg, 1 mmol) and N-methyl morpholine (0.24 mL.
2.2 mmol) in THF 1.5 mL) was added dropwise. The reaction was
stirred overnight at room temperature. The solution was filtered
and concentrated. Methanol (3 mL) was added ammonia gas was bubbled
into the reaction for 25 minutes. The reaction was stirred at room
temperature for 1.5 h and then evaporated in vacuo and diluted with
ethyl acetate. The solution was washed with 1 N NaOH. The aqueous
layer was extracted with ethyl acetate and the combined organics
were dried over magnesium sulfate and concentrated. The residue was
dissolved in acetic acid (2.4 mL) and ammonium acetate (140 mg) was
added and the reaction stirred for 16 h. The reaction was
concentrated in vacuo and diluted with 1 N NaOH and extracted with
ethyl acetate. The organic layer was dried over sodium sulfate,
filtered and concentrated. The residue was chromatographed on
silica gel (ethyl acetate/hexanes) to give 107 (98 mg, 45%) as a
yellow solid); .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.63 (d, 2
HO. 7.45 (t, 1 HO, 7.34-7.23 (m, 8H), 7.13 (d, 1H), 6.79 (s, 1H),
6.67 (d, 1H), 5.34 (d, 1H), 5.14 (q, 2H), 3.73 (s, 3 HO. 3.40 (s,
3H0; API MS m/z=430 [C.sub.25H.sub.23N.sub.3O.sub.4+H].sup.+; mp.
71-73.degree. C.; IR (thin film) 3410, 1724, 1678, 1498, 1289,
1231, 1039, 699 cm.sup.-1.
EXAMPLES
[1202] Chemical abbreviations used in the Examples are defined as
follows: "DMPU" for
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, "TBTU" for
O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate, "BOP" for
benzotriazol-1-yloxytris-(dimethylamino)-phosphonium
hexafluorophosphate, and "HATU" for
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate. "HPLC" is an abbreviation used herein for high
pressure liquid chromatography. Reverse-phase HPLC was carried out
using a Vydac C-18 column with gradient elution from 10% to 100%
buffer B in buffer A (buffer A: water containing 0.1%
trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile
containing 0.1% trifluoroacetic acid). Alternatively, reverse-phase
HPLC was carried out using a Vydac C-18 column with gradient
elution from 10% to 90% acetonitrile in water.
Example 1
[1203] (2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-m-
ethylpropyl)-3-allyl-butanediamide
##STR00040##
Step 1
##STR00041##
[1205] A solution of tert-butyl succinate ester (9) (1.0 eq.) in
DMF (0.25 M) under N.sub.2 at 0.degree. C. was added HATU (1.1
eq.), then Hunig's base (4.0 eq.). The mixture was stirred at
0.degree. C. for 10 mins. A solution of
1,3-dihydro-1-methyl-3-amino-5-phenyl-2H-1,4-benzodiazepin-2-one
(30) in DMF (0.8 M) (1.0 eq.) was added to this solution. The
reaction mixture was stirred overnight at room temperature and then
transferred to a separatory funnel containing water. 30% n-Hexane
in ethyl acetate was added which gave a clear organic layer. The
aqueous solution was extracted twice with 30% n-hexane in ethyl
acetate. The combined organic layers were washed with water and
brine, dried over magnesium sulfate, and concentrated in vacuo. The
residue was purified by chromatography on flash grade silica gel
using 20-30% ethyl acetate in n-hexane; preferably 30% ethyl
acetate in n-hexane. Compound, 1', was isolated as an amorphous
white solid (85%). Rf=0.25 (7:3 n-hexane:ethyl acetate).
[1206] .sup.1H-NMR: (CDCl.sub.3): .delta.7.61-7.21 (m, 10H);
5.77-5.73 (m, 1H); 5.57-5.54 (d, 1H); 5.20-4.97 (m, 2H); 3.47 (s,
3H); 2.63-2.33 (m, 4H); 1.80-1.76 (m, 2H); 1.47-1.46 (d, 9H);
1.43-1.11 (m, 1H); 1.01-0.86 (m, 6H).
[1207] MS: C.sub.3H.sub.39N.sub.3O.sub.4 (M+H) 518.3 (M+Na)
540.3.
Step 2
##STR00042##
[1209] A solution of (1') in 50% TFA in methylene chloride (0.15M)
was stirred at room temperature overnight. The solution was
concentrated in vacuo, washed and concentrated four times with
toluene in vacuo to give compound (1'') as an amorphous solid
(95%). Rf=0.64 (9.5:0.5 methylene chloride:methanol). MS:
C.sub.27H.sub.31N.sub.3O.sub.4 (M+H) 462.
Step 3
##STR00043##
[1211] To a solution of (1'') (1.0 eq.) in DMF (0.25 M) under
N.sub.2 at 0.degree. C. was added HATU (1.1 eq.), and then Hunig's
base (4.0 eq.). The mixture was stirred at 0.degree. C. for 10
mins, and then anhydrous ammonia bubbled through the solution for
two minutes. The reaction mixture was stirred overnight at room
temperature and then transferred to a separatory funnel containing
water and diluted with 30% n-hexane in ethyl. The aqueous solution
was extracted twice with 30% n-hexane in ethyl acetate. The
combined organic layers were washed with water and brine, dried
over magnesium sulfate, and concentrated in vacuo. The residue was
purified by chromatography on flash grade silica gel using 4%
methanol in methylene chloride. The title compound. Example 1, was
isolated as an amorphous white solid (87%). Rf=0.43 (9:1 methylene
chloride:methanol).
[1212] .sup.1H NMR: (CDCl.sub.3): .delta. 7.63-7.22 (m, 10H);
6.25-6.13 (d, 1H); 5.88-5.73 (m, 1H); 5.53-5.51 (dd, 1H); 5.44-5.41
(d, 1H); 5.22-5.04 (m, 2H); 3.47-3.46 (d, 3H); 2.74-2.31 (m, 4H);
1.81-1.61 (m, 2H); 1.34-1.22 (m, 1H); 0.99-0.87 (m, 6H).
[1213] MS: C.sub.27H.sub.32N.sub.4O.sub.3 (M+H) 461.
Example 2
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-
-2-(2-methylpropyl)-3-allyl-N-4-[3,5-difluorobenzyl]-butanediamide
##STR00044##
[1215] Following a procedure analogous to the preparation of
Example 1 using 3,5-difluorobenzylamine in place of ammonia in Step
3, the title compound was prepared. MS (M+H).sup.+=587.
Example 3
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-
-2-(2-methylpropyl)-3-propyl-butanediamide
##STR00045##
[1217] Following a procedure analogous to the preparation of
Example 1 using succinate ester (10) (Scheme 2) in place of
succinate ester (9) in Step 1, as well as reagents known to one
skilled in the art, the title compound was prepared. MS
(M+H)=463.0.
Example 4a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00046##
[1219] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepi-
ne-2-one in place of (30) in Step 1, the mixture of benzodiazepine
diastereomers of the title compound was prepared, The isomers were
separated using reverse phase chromatography (C-18 column,
isocratic eluent composed of 65% 90:10 water:acetonitrile and 35%
10:90 water:acetonittile). The first eluting isomer was assigned
the (S)-benzodiazepine configuration using the H-NMR method
described for Example 112a. The required aminobenzodiazepine was
prepared using the method of Sherrill and Sugg (J. Org. Chem. 1995,
60, 730-734). MS (M+H).sup.+=479.4; (M+Na).sup.+=501.4.
Example 4b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
[1220] Following the procedure of Example 4a, the second eluting
isomer was isolated and assigned the (R)-benzodiazepine
configuration using the H-NMR method described for Example 12b. MS
(M+H).sup.+=479.4; (M+Na).sup.+=501.4.
Example 5
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00047##
[1222] Following a procedure analogous to the preparation of
Example 1 using (S) isomer of benzodiazepinone (30) in Step 1 in
place of racemic benzodiazepinone (30), and reducing the amount of
Hunig's base in Step 1 to 2.2 eq., the title compound was
prepared.
[1223] .sup.1H-NMR for product of Step 1: (CDCl.sub.3): 7.61-7.21
(m. 10H); 5.77-5.73 (m, 1H); 5.57-5.54 (d, 1H); 5.20-5.00 (m, 2H);
3.46 (s, 3H); 2.63-2.33 (m, 4H); 1.80-1.76 (m, 2H); 1.46 (s, 9H);
1.43-1.11 (m, 1H); 0.97-0.95 (d, 3H); 0.88-0.85 (d, 3H).
[1224] .sup.1H-NMR for product of Step 3: (CDCl.sub.3): 7.65-7.00
(m, 1H); 6.10-6.00 (s, 1H); 5.85-5.65 (m, 1H); 5.54-5.52 (d, 1H);
5.40-5.30 (s, 1H); 5.23-5.00 (m, 2H); 3.47 (s, 3H); 2.80-2.20 (m,
4H); 1.85-1.60 (m, 2H); 1.40-1.20 (m, 1H), 0.98-0.95 (d, 3H);
0.90-0.87 (d, 3H). MS (M+H).sup.+ 461.3; MS (M+H).sup.+=483.3.
Example 6
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00048##
[1226] Using the method of Example 5, but replacing the (S) isomer
of benzodiazepinone (30) with (R) isomer of benzodiazepinone (30)
in Step 1, the title compound was prepared. Alternatively, the (R)-
and (S)-benzodiazepine diastereomers may be separated using a
Chiralpack AD column, eluting with 0.1 diethylamine in 1:1
n-hexane/1-propanol. Under these conditions, the compound of
Example 6 [(R)-benzodiazepine diastereomer] elutes first.
[1227] .sup.1H-NMR: (CDCl.sub.3): 7.65-7.00 (m, 10H); 6.10-6.00 (s,
1H); 5.85-5.65 (m, 1H); 5.54-5.52 (d, 1H); 5.40-5.30 (s, 1H);
5.23-5.00 (m, 2H); 3.47 (s, 3H); 2.80-2.20 (m, 4H); 1.85-1.60 (m,
2H); 1.40-1.20 (m, 1H), 0.99-0.95 (apparent t, 6Hf). MS
(M+H).sup.+=461.3; MS (M+Na).sup.+=483.3.
Example 7
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide
##STR00049##
[1229] The product of Example 6 was hydrogenated by dissolution in
methanol (0.25M), addition of an equal amount by weight of
Pearlman's catalyst [Pd(OH).sub.2/C (20% Wt, Water %.ltoreq.50)]
and 30 eq. of 1,4-cyclohexadiene at room temperature. The solution
was heated to reflux for 1 hr, then cooled to room temperature.
Removal of volatiles and purification by flash chromatography using
4% methanol in CH.sub.2Cl.sub.2 gave the title compound. MS
(M+H).sup.+=463.3; MS (M+Na).sup.+=485.3.
Example 8
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide
##STR00050##
[1231] Using the product of Example 5 as starting material, and
following the method of Example 7, the title compound was prepared.
MS (Mt H).sup.+=463.3; MS (M+Na).sup.+=485.3.
Example 9a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-methyl-3-allyl-butanediamide
##STR00051##
[1233] Following a procedure analogous to the preparation of
Example 5, coupling the appropriate succinate ester, prepared using
the method disclosed in PCT publication WO 98/51665, in place of
(9), with (S)isomer of benzodiazepinone-(30) in Step 1, the title
compound was prepared. MS (M+H).sup.+=419.1;
(M+Na).sup.+=441.1.
Example 10
(2R)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2--
methyl-butanediamide
##STR00052##
[1235] Following a procedure analogous to the preparation of
Example 1 using the appropriate succinate ester (prepared by
methods disclosed in Becket et al. (Synlett, 1993, pp. 137-138) and
shown in Scheme 1), in place of ester (9) in Step 1, the title
compound was prepared. MS (M+H).sup.+=379.0
Example 11
(2R,3S)
N1-[1,3-dihydro-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-2-(2-met-
hylpropyl)-3-allyl-butanediamide
##STR00053##
[1237] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepine-2-one in place
of (30) in Step 1, the title compound was prepared. MS
(M+H).sup.+=447.2.
Example 12
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzodiaze-
pin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00054##
[1239] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-phenyl-7-chloro-2H-1,4-benzodiazepin-
e-2-one in place of (30) in Step 1, the title compound was
prepared. MS (M+H).sup.+=495.0.
Example 12a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzo-
diazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00055##
[1241] The product of Example 12 was separated into the (S)-- and
(R)-benzodiazepine diastereomers using a Chiralpack A.beta. column,
eluting with 1:1 n-hexane-1-propanol. The diastereomers were
assigned on the basis of the elution order ((S)-diastereomer elutes
second under these conditions) and the i-butyl signals in the H-NMR
spectra, consistent with the elution order and H-NMR spectra of the
products of Examples 5 and 6. In CDCl.sub.3 the (S)-diastereomer
shows two doublets (6H total) above 1 ppm and the (R)-diastereomer
shows an apparent triplet (6H) above 1 ppm. MS (M+H).sup.+=495.2;
MS (M+Na).sup.+=517.1.
Example 12b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzo-
diazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00056##
[1243] As described for Example 12a, the product of Example 12 was
separated into the (S)- and (R)-benzodiazepine diastereomers using
a Chiralpack AD column, eluting with 1:1 n-hexane-1-propanol, with
the (R)-diastereomer eluting first under these conditions. In
CDCl.sub.3 the i-butyl signals for the (R)-diastereomer appear as
an apparent triplet (6H) above 1 ppm. MS (M+H).sup.+=495.2; MS
(M+Na).sup.+=517.1.
Example 13
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-1,4--
benzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00057##
[1245] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(2-fluorophenyl)-7-chloro-2H-1,4-ben-
zodiazepine-2-one prepared by methods known by one skilled in the
art, in place of (30) in Step 1, the title compound was prepared.
MS (M-H).sup.+=513.3; MS (M+Na).sup.+=535.2.
Example 13a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-
-[4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00058##
[1247] Following a procedure analogous to the preparation of
Examples 12a and 12b, the (S)-benzodiazepine diastereomer of
Example 13 was isolated. MS (M+H).sup.+=513.3; MS
(M+Na).sup.+=535.2.
Example 13b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00059##
[1249] Following a procedure analogous to the preparation of
Examples 12a and 12b, the (R)-benzodiazepine diastereomer of
Example 13 was isolated. MS (M+H).sup.+=513.3; MS
(M+Na).sup.+=535.2.
Example 14
(2S,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl]-
-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00060##
[1251] Following a procedure analogous to the preparation of
Example 1 using the appropriate syn-succinate ester (prepared by
methods disclosed in Becket et al. (Synlett, 1993, pp. 137-138) and
shown in Scheme 1), in place of ester (9) in Step 1, the title
compound was prepared. MS (M+H).sup.+=461.4;
(M+Na).sup.+=483.4.
Example 15
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzo-
diazepin-3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide
##STR00061##
[1253] Using the product of Example 12a as starting material, and
following the reduction procedure of Example 7, the title compound
was prepared. MS (M+H).sup.+=497.2; MS (M+Na).sup.+=519.1
Example 16
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(2-fluorophenyl)-7-chloro-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide
##STR00062##
[1255] Using the product of Example 13a as starting material, and
following the reduction procedure of Example 7, the title compound
was prepared, MS (M+H).sup.+=515.3; MS (M+Na).sup.+=537.2
Example 17
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(4-fluorophenyl)-2H-1,4-benzodiaz-
epin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00063##
[1257] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(4-fluorophenyl)-2H-1,4-benzodiazepi-
ne-2-one, prepared by methods known to one skilled in the art, in
place of (30) in Step 1, the title compound was prepared. MS
(M+H).sup.+ 479.3.
Example 17a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-fluorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00064##
[1259] Following a procedure analogous to the preparation of
Examples 112a and 12b, the (S)-benzodiazepine diastereomer of
Example 13 was isolated. MS (M+H).sup.+=479.3; MS
(M+Na).sup.+=501.2.
Example 17b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(4-fluorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00065##
[1261] Following a procedure analogous to the preparation of
Examples 12a and 12b, the (R)-benzodiazepine diastereomer of
Example 13 was isolated. MS (M+H).sup.+=479.3; MS
(M+Na).sup.+=501.2.
Example 18
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(pyrid-2-yl)-2H-1,4-benzodiazepin-
-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00066##
[1263] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(pyrid-2-yl)-2H-1,4-benzodiazepine-2-
-one, prepared by methods known to one skilled in the art, in place
of (30) in Step 1, the title compound was prepared. MS (2M
Na).sup.+=945.6.
Example 19
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-morpholino)-2H-1,4-benzodiazep-
in-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00067##
[1265] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(N-morpholinyl)-2H-1,4-benzodiazepin-
e-2-one, prepared by methods known to one skilled in the art, in
place of (30) in Step 1, the title compound was prepared. Mp
145-151.degree. C.; MS (M+H).sup.+=470.
Example 20
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(dimethylamino)-2H-1,4-benzodiaze-
pin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00068##
[1267] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(dimethylamino)-2H-1,4-benzodiazepin-
e-2-one, prepared by methods known to one skilled in the art, in
place of (30) in Step 1, the title compound was prepared. Mp
230-232.degree. C.; MS (M+H).sup.+=428.
Example 21
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-methyl-N-phenylamino)-2H-1,4-b-
enzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00069##
[1269] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(N-methyl-N-phenylamino)-2H-1,4-benz-
odiazepine-2-one, prepared by methods known to one skilled in the
art, in place of (30) in Step 1, the title compound was prepared,
melting point 266.6-267.8.degree. C.; MS (M+H).sup.+=490.
Example 22
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-piperidinyl)-2H-1,4-benzodiaze-
pin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00070##
[1271] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(N-piperidinyl)-2H-1,4-benzodiazepin-
e-2-one, prepared by methods known to one skilled in the art, in
place of (30) in Step 1, the title compound was prepared, melting
point 231-238.degree. C.; MS (M+H).sup.+=468.
Example 23
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(N-homopiperidinyl)-2H-1,4-benzod-
iazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00071##
[1273] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(N-homopiperidinyl)-2H-1,4-benzodiaz-
epine-2-one, prepared by methods known to one skilled in the art,
in place of (30) in Step 1, the title compound was prepared,
melting point 232-237.degree. C.; MS (M+H).sup.+=482.
Example 24
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(3-methoxyphenyl)-2H-1,4-benzodia-
zepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00072##
[1275] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(3-methoxyphenyl)-2H-1,4-benzodiazep-
ine-2-one, prepared by methods known to one skilled in the art, in
place of (30) in Step 1, the title compound was prepared, melting
point 225-230.degree. C.; MS (M+H).sup.+=491
Step 1: Preparation of 24';
[1276] This was prepared using the standard HATU coupling
conditions with 97 (1.03 g, 3.5 mmol) to give 24' (0.48 g, 25%) as
a colorless oil (mixture of diastereomers): .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.63 (t, 1H), 7.33-7.38 (m, 2 HO, 7.24-7.30 (m,
2H), 7.05 (d, 1H), 7.00 (dd, 1H), 5.65-5.8 (m, 1H), 5.57 (d, 1H),
4.92-5.20 (m, 2 HO, 3.80 (s, 3H), 3.77 (s, 3H), 3.48 (s, 3H)
2.27-2.67 (m, 3H), 1.75-1.80 (m, 1H0, 1.60-1.63 (m, 1H), 1.48 (s,
9H), 1.46 (s, 9H), 1.22-1.26 (m, 1 HO, 0.88-1.00 (m, 3H), 0.80 (d,
3H).
Step 2: Preparation of 24'':
[1277] This was prepared using the standard t-Bu ester deprotection
with TFA. The acid intermediate 24'' is a mixture of diastereomers:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.75 (bs, 1H), 7.75-7.85
(m, 1H), 7.00-7.51 (m, 7H.), 5.70-5.80 (m, 2H), 5.05-5.15 (m, 2H),
3.80 (s, 3H), 3.53, 3.50 (s, 3H), 5.74-2.93 (m, 1 HO, 2.25-2.53 (m,
1H), 1.53-1.80 (m, 1H), 1.25-1.30 (m, 1H0, 0.93 (d, 3H), 0.89 (d,
3H); API MS m/z=492 [C.sub.28H.sub.33N.sub.3O.sub.5+H].sup.+.
Step 3: Preparation of Example 24;
[1278] This was prepared using the HATU mediated amide formation.
mp 225-230.degree. C.; .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
7.55-7.70 (m, 2H), 7.27-7.33 (m, 3H), 7.24 (s, 1H), 7.0-7.07 (m,
2H) 5.70-5.77 (m, 1H), 5.45 (d, 1H), 4.93-5.10 (m, 2H0, 3.78, 3.76
(s, 3 HO, 3.48 (s, 3H), 2.75-2.85 (m, 1H), 2.27-2.50 (m, 2H),
1.53-1.71 (m, 2H), 1.10-1.25 (m, 1H), 0.80-1.00 (m, 6H); IR (KBr)
3423, 2956, 1655, 1601, 1326 cm.sup.-1; API MS m/z=491
[C.sub.2H.sub.34N.sub.4O.sub.4.sup.+H]; Anal. Calcd. For
C.sub.28H.sub.34N.sub.4O.sub.4-0.5H.sub.2O: C, 67.3; H, 7.06; N,
11.21. Found: C, 67.52; H. 6.85; N, 11.21.
Example 25
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(pyrid-4-yl)-2H-1,4-benzodiazepin-
-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00073##
[1280] Following a procedure analogous to the preparation of
Example 1 using methods known to one skilled in the art, the title
compound was prepared. MS (M+H).sup.+=462.
Example 26
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-methoxy-2H-1,4-benzodiaz-
epin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00074##
[1282] Following a procedure analogous to the preparation of
Example 1 using reagents known to one skilled in the art, the title
compound was prepared, m.pt. 244-255.degree. C.; MS
(M+H).sup.+=491.
Example 27
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(pyrid-3-yl)-2H-1,4-benzodiazepin-
-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00075##
[1284] Following a procedure analogous to the preparation of
Example 1 using reagents known to one skilled in the art, the title
compound was prepared, m.pt. 251-253.degree. C., MS
(M+H).sup.+=462.
Example 28a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-(cyclopropylmethyl)-butanediamide
##STR00076##
[1286] A procedure analogous to the preparation of Example 5 was
followed. The appropriate succinate ester was prepared using the
method disclosed in PCT publication WO 98/51665, using
cyclopropylmethyl iodide for reagent R.sup.3--X in place of allyl
bromide (see Scheme 2). This succinate half-ester, a mixture of
syn- and anti-isomers, was coupled to the (S) benzodiazepinone-(30)
using the procedures of Example 1, Step 1. After Steps 2 and 3, the
mixture of butanediamide isomers was separated using silica gel
chromatography to provide Example 28a. MS (M+H).sup.+=475.
Example 28b
(2R,3R)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-(cyclopropylmethyl)-butanediamide
##STR00077##
[1288] From the product of Step 3 of Example 28a, the other
succinate isomer, Example 2-b, was isolated. Np 146-148.degree. C.;
MS (M+H).sup.+=475
Example 29
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(3-fluorophenyl)-2H-1,4-benzodiaz-
epin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00078##
[1290] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(3-fluorophenyl)-2H-1,4-benzodiazepi-
ne-2-one, prepared by methods known to one skilled in the art, in
place of (30) in Step 1, the title compound was prepared. MS
(M+H).sup.+=479.3.; (M+Na).sup.+=501.3.
Example 29a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(3-fluorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00079##
[1292] Following a procedure analogous to the preparation of
Examples 12a and 12b, the (S)-benzodiazepine diastereomer of
Example 29 was isolated. MS (M+H)=479.3.
Example 29b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(3-fluorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00080##
[1294] Following a procedure analogous to the preparation of
Examples 12a and 12b, the (R)-benzodiazepine diastereomer of
Example 29 was isolated. MS (M+H).sup.+=479.3.
Example 30
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide
##STR00081##
[1296] A procedure analogous to the preparation of Example 5 was
followed. The appropriate succinate ester was prepared using the
method disclosed in PCT publication WO 98/51665), using 3-butenyl
bromide for R.sup.3-X in place allyl bromide (see Scheme 2). The
anti-succinate half-ester was coupled to (S)-isomer benzodiazepine
(330) using the procedures of Step 1. After Steps 2 and 3, the
title compound was isolated. MS (M+H).sup.+=475.3;
(M+Na).sup.+=497.3.
Example 31
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-(cyclopentylethyl)-butanediamide
##STR00082##
[1298] A procedure analogous to the preparation of Example 5 was
followed. The appropriate succinate ester was prepared using the
method disclosed in PCT publication WO 98/51665, using
2-(cyclopentyl)ethyl iodide for R.sup.3-X in place of allyl bromide
(see Scheme 2). The anti-succinate half-ester was coupled to
(S)-isomer benzodiazepine (30) using the procedures of Step 1.
After Steps 2 and 3, the title compound was isolated. MS
(M+H).sup.+=475; (M+Na).sup.+=497.2.
Example 32a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide
##STR00083##
[1300] A procedure analogous to the preparation of Example 5 was
followed. The succinate ester of Example 30 was employed. The
anti-succinate half-ester was coupled to
(S)-1,3-dihydro-1-methyl-3-amino-5-(4-trifluoromethylphenyl)-2H-1,4-benzo-
diazepine-2-one using the procedures of Step 1. The required
(S)-3-aminobenzodiazepine was prepared by HBr deprotection of the
corresponding benzyloxycarbonyl derivative, which was separated
from the (R)-isomer using chiral chromatography. The racemic
Cbz-aminobenzodiazepine was prepared using the method of Sherrill
and Sugg (J. Org. Chem. 1995, 60, 730-734). After Steps 2 and 3,
the title compound was isolated. The stereochemical assignment of
Examples 32a and 32b was performed following the H-NMR method of
Examples 12a and 12b. MS (M+H).sup.+=543.2; (M+Na).sup.+=565.3.
Example 32b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide
##STR00084##
[1302] A procedure analogous to the preparation of Example 32a was
followed using (R) --
1,3-dihydro-1-methyl-3-amino-5-(4-trifluoromethylphenyl)-2H-1,4-benzodiaz-
epine-2-one in Step 1. MS (M+H).sup.+=543.2;
(M+Na).sup.+=565.3.
Example 33
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4--
benzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00085##
[1304] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(4-fluoromethylphenyl)-2H-1,4-benzod-
iazepine-2-one, prepared by methods known to one skilled in the
art, in place of (30) in Step 1 the title compound was prepared. MS
(M+H).sup.+=529.2.
Example 33a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00086##
[1306] Following a procedure analogous to the preparation of
Examples 12a and 12b, the (S)-benzodiazepine diastereomer of
Example 33 was isolated. MS (M+H).sup.+=529.2.
Example 33b
(2R,3S)
N1-[(3R)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00087##
[1308] Following a procedure analogous to the preparation of
Examples 12a and 112b, the (S)-benzodiazepine diastereomer of
Example 33 was isolated. MS (M+H).sup.+=529.2;
(M+Na).sup.+=551.2.
Example 34
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3,3-diallyl-butanediamide
##STR00088##
[1310] A procedure analogous to the preparation of Example 5 was
followed, The diallyl succinate ester was prepared using the method
of Curtin et al. (Biorg. Med. Chem. Lett., 8, 1998, 1443-8). The
succinate half-ester was coupled to the (S)isomer of
benzodiazepinone (30) using the procedures of Step 1. After Steps 2
and 3, the title compound was isolated. MS (M+Na).sup.+=523.2.
Example 35a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-n-butyl-butanediamide
##STR00089##
[1312] Following the reduction procedure of Example 7, the product
of Example 32a was converted to the title compound. MS
(M+H).sup.+=545.2; (M+Na).sup.+=567.3.
Example 36
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-
-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-propyl-butanediamide
##STR00090##
[1314] Following the reduction procedure of Example 7, the product
of Example 33a was converted to the title compound. MS
(M#H).sup.+=531.2; (M+Na)=553.2.
Example 37
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-(3-buten-1-yl)-butanediamide
##STR00091##
[1316] A procedure analogous to the preparation of Example 5 was
followed. The succinate ester of Example 30 was employed and was
coupled to
(S)-2,3-dihydro-1-methyl-3-amino-5-(4-chlorophenyl)-1H-1,4-benzodiazepine-
-2-one using the procedures of Step 1. The required
(S)-3-aminobenzodiazepine was prepared by HBr deprotection of the
corresponding benzyloxycarbonyl derivative, which was separated
from the (R)-isomer using chiral chromatography. The racemic
Cbz-aminobenzodiazepine was prepared using the method of Sherrill
and Sugg (J. Org. Chem. 1995, 60, 730-734). After Steps 2 and 3,
the title compound was isolated. The stereochemical assignment was
performed following the H-NMR method of Example 12a. MS
(M#H).sup.+=509.2.
Example 38
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-n-butyl-butanediamide
##STR00092##
[1318] The product of Example 37 was taken up in ethanol (0.25M)
together with 10% by weight Wilkinson's catalyst
(chlorotris(triphenylphosphine)rhodium(I)). The mixture was shaken
under 50 psi hydrogen overnight. The reaction mixture was filtered
through a layer of celite and the solvent was evaporated. The
residue was purified by flash chromatography on silica gel using 4%
methanol in CH.sub.2Cl.sub.2 to provide the title compound. MS
(M+H).sup.+=511.2; (M+Na).sup.+=533.2.
Example 39
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-allyl-N-4-[benzyl]-butanediamide
##STR00093##
[1320] Following a procedure analogous to the preparation of
Example 5 using benzylamine in place of ammonia in Step 3, the
title compound was prepared. MS (M+H).sup.+=551.2;
(M+Na).sup.+=565.3.
Example 40
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-methyl-2H-1,4-benzodiazepin-3-yl]-
-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00094##
[1322] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-methyl-2H-1,4-benzodiazepine-2-one
in place of (30) in Step 1, the title compound was prepared. MS
(M+H).sup.+=399.1.
Example 41
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-n-butyl-2H-1,4-benzodiazepin-3-yl-
]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00095##
[1324] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(n-butyl)-2H-1,4-benzodiazepine-2-on-
e in place of (30) in Step 1, the title compound was prepared. The
benzodiazepine diastereomers, Example 41a (3S) isomer and 41b (3R)
isomer, were separated by silica gel chromatography. MS
(M+H).sup.+=441.2.
Example 42
(2R,3S)
N1-[1,3-dihydro-1-methyl-2-oxo-5-(2-methylpropyl)-2H-1,4-benzodiaz-
epin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00096##
[1326] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(1-butyl)-2H-1,4-benzodiazepine-2-on-
e in place of (30) in Step 1, the title compound was prepared. MS
(M+H).sup.+=441.2.
Example 43a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benz-
odiazepin-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00097##
[1328] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-methyl-3-amino-5-(4-chlorophenyl)-2H-1,4-benzodiazepi-
ne-2-one in place of (30) in Step 1, the mixture of benzodiazepine
diastereomers of the title compound was prepared. The isomers were
separated using reverse phase chromatography (C-18 column,
isocratic eluent composed of 65% 90:10 water:acetonitrile and 35%
10:90 water:acetonitrile). The first eluting isomer was assigned
the (S)-benzodiazepine configuration using the H-NMR method
described for Example 12a. The required aminobenzodiazepine was
prepared using the method of Sherrill and Sugg (J. Org. Chem. 1995,
60, 730-734). MS (M+H).sup.+=495.
Example 44a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-ethyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-
-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00098##
[1330] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-ethyl-3-amino-5-phenyl-2H-1,4-benzodiazepine-2-one in
place of (30) in Step 1, the title compound was prepared. The
required aminobenzodiazepine was prepared using the method of
Sherrill and Sugg (J. Org. Chem. 1995, 60, 730-734). The
benzodiazepine diastereomers of the product were separated using
reverse phase HPLC as described for Example 43a. The first eluting
isomer was assigned the (S)-benzodiazepine configuration using the
H-NMR method described for Example 12a. MS (M+H).sup.+=475.
Example 45a
(2R,3S)
N1-[(3S)-1,3-dihydro-1-propyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00099##
[1332] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-(n-propyl)-3-amino-5-phenyl-2H-1,4-benzodiazepine-2-o-
ne in place of (30) in Step 1, the title compound was prepared as a
mixture of benzodiazepine diastereomers, which were separated using
reverse phase HPLC as described for Example 43a. The first eluting
isomer was assigned the (S)-benzodiazepine configuration using the
H-NMR method described for Example 12a. The required
aminobenzodiazepine was prepared using the method of Sherrill and
Sugg (J. Org. Chem. 1995, 60, 730-734. MS (M+H).sup.+=489.
Example 45b
2R,3S)
N1-[(3R)-1,3-dihydro-1-propyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-
-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
[1333] Following the procedure of Example 45a, the second eluting
isomer was isolated and assigned the (R)-benzodiazepine
configuration using the H-NMR method described for Example 12b. MS
(M+H).sup.+=489.
Example 46
(2R,3S)
N1-[1,3-dihydro-1-(isopropyl)-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00100##
[1335] Following a procedure analogous to the preparation of
Example 1 using
1,3-dihydro-1-(i-propyl)-3-amino-5-phenyl-2H-1,4-benzodiazepine-2-o-
ne in place of (30) in Step 1, the title compound was prepared. The
required aminobenzodiazepine was prepared using the method of
Sherrill and Sugg (J. Org. Chem. 1995, 60, 730-734). MS
(M+H).sup.+=489.
Example 47
(2R,3S)
N1-[6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-met-
hylpropyl)-3-allyl-butanediamide
Step 1: Preparation of Compound 47';
##STR00101##
[1337] To a solution of amine 31, (for preparation see Audia, J.
E., PCT patent application WO 99/32453) (0.42 g 1.76 mmol),
succinate 9, (0.52 g, 1.94 mmol), and DMF (50 mL) at 0.degree. C.
was added HATU (0.87 g, 2.29 mmol), and finally DIPEA (1.23 mL.
7.05 mmol). The solution was allowed to warm to room temperature
while stirring for 18 h. The DMF was removed under reduced pressure
and the residue was dissolved in ethyl acetate (200 mL), washed
with 0.1 N HCl (2.times.100 mL), 5% aqueous NaHCO.sub.3
(2.times.100 mL), dried over anhydrous Na.sub.2SO.sub.4O and
concentrated to yield a brown oil. The crude material was further
purified via silica gel column chromatography (1% MeOH, 99%
CH.sub.2Cl.sub.2) to yield 47' (0.61 g, 70.5%) as a pale yellow
solid.
[1338] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.87-1.42 (m, 9H)
1.48 (d, 9H) 2.21-2.79 (m, 4H), 3.38 (s, 3H), 4.92-5.11 (m, 3H),
5.41 (d, 1H), 5.72 (m, 1H), 7.29-7.65 (m, 8H). CI MS m z 491
[C.sub.30H.sub.38N.sub.2O.sub.4+H].sup.+.
Step 2: Preparation of Compound 47'';
##STR00102##
[1340] t-Butyl ester 47' (0.61 g, 1.24 mmol) was dissolved in TFA
(15 mL) and stirred for 4 h at room temperature under N.sub.2. The
TFA was removed under reduced pressure, the residue was dissolved
in ethyl acetate (50 mL), washed with a saturated solution of
aqueous NaHCO.sub.3 (2.times.50 mL), dried over anhydrous
Na.sub.2SO.sub.4, and concentrated to yield 47'' (0.38 g, 71%) as a
pale yellow foam.
[1341] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.8-1.82 (m, 9H),
2.25-2.55 (m, 4H), 3.28 (s, 3H), 4.91-5.20 (m, 3H), 5.48 (s, 1H),
5.7-5.9 (m, 1H), 7.35-7.76 (m, 8H).
Step 3: Preparation of Example 47;
##STR00103##
[1343] Ammonia gas was bubbled through as a solution of 47'' (0.38
g, 0.88 mmol), DMF (15 mL), HATU (0.4 g, 1.1 mmol), and DIPEA (4.3
mmol, 0.76 mL) at 0.degree. C. for 10 min. The solution was allowed
to warm to room temperature while stirring for 18 h. The DMF was
removed under reduced pressure and the resulting residue was
dissolved in ethyl acetate (200 mL), washed with 0.1 N HCl
(2.times.100 mL), brine (2.times.100 mL), dried over anhydrous
Na.sub.2SO.sub.4, and concentrated to yield a light brown oil. The
crude material was further purified via silica gel chromatography
(2% MeOH. 98% CH.sub.2Cl.sub.2) to yield the title compound,
Example 47, as an off-white solid (0.21 g, 55%): mp 137-145.degree.
C.
[1344] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 0.82-1.08 (m, 6H),
1.22-1.79 (m, 3H) 2.13-2.82 (m, 4H) 3.35 (s, 3H) 4.94-5.12 (m, 3H),
5.36 (d, 1H), 5.52 (d, 1H), 5.67-5.81 (m, 1H), 7.30-7.63 (m, 8H);
IR (KBr) 3334, 2955, 1654, 1498, 1386 cm.sup.-1; CI MS m/z=434
[C.sub.26H.sub.31N.sub.3O.sub.3+H]; HPLC 95.4% tr=17.65 min. Anal.
Calcd. for C.sub.26H.sub.31N.sub.3O.sub.3 0.25H.sub.2O: C, 72.29;
H, 7.25; N, 9.59, Found: C, 71.22; H, 7.13; N, 9.32.
Example 48
(2R,3S)
N1-[1,3,4,5-tetrahydro-1,5-dimethyl-2,4-dioxo-2H-1,5-benzodiazepin-
-3-yl]-2-(2-methylpropyl)-3-allyl-butanediamide
##STR00104##
[1345] Step 1: Preparation of Compound 48';
##STR00105##
[1347] To a solution of tert-butyl succinate ester (9) (1.0 eq) in
DMF (0.25 M) at zero degrees was added HATU (1.1 eq), then Hunig's
base (4.0 eq). The mixture was stirred at zero degrees for 10 mins.
A solution of 3
amino-1,3,4,5-tetrahydro-1,5-dimethyl-2H-1,5-benzodiazepin-2,4-dione
(32) in DIMF (0.8 M) (1.0 eq) was added to this solution. The
reaction mixture was stirred overnight at RT and then transferred
to a separatory funnel containing water. 30% N-hexane in ethyl
acetate was added which gave a clear organic layer. The aqueous
solution was extracted twice with 30% n-hexane in ethyl acetate.
The combined organic layers were washed with water and brine, dried
over magnesium sulfate, and concentrated in vacuo. The residue was
purified by chromatography on flash grade silica gel using 30%
ethyl acetate in n-hexane. Compound 48' was isolated as an
amorphous white solid (92%). Rf=0.15 (7:3 n-hexane:ethyl
acetate).
[1348] .sup.1H-NMR (CDCl.sub.3): .delta. 7.34 (s, 4H); 6.97-6.94
(d. 1H); 5.8-5.60 (m, 1H). 5.15-4.95 (m, 3H); 3.45 (s, 6H);
2.65-2.20 (m, 4H); 1.80-1.50 (m, 2H); 1.18-1.00 (m, 1H); 0.95-0.92
(d 3H); 0.87-0.84 (d, 3H); MS (M+H).sup.+ 472.2.
Step 2: Preparation of Compound 48'':
##STR00106##
[1350] Following a procedure analogous to the procedure of Step 2
in Example 1, compound 48'' was prepared.
Step 3: Preparation of Example 48;
##STR00107##
[1352] Following a procedure analogous to the procedure of Step 3
in Example 1, the title compound, Example 48, was prepared.
[1353] .sup.1H-NMR (CDCl.sub.3): .delta. 7.36 (s, 4H); 7.10-7.00
(d, 1H); 6.44 (s, 1H); 5.85-5.75 (m, 1H); 5.40 (m, 1H). 5.19-5.00
(m, 3H); 3.50-3.45 (d, 6H); 2.70-2.33 (m, 4H); 1.60-1.40 (m, 2H);
1.30-1.20 (m, 1H); 0.90-0.85 (q, 6H).
[1354] MS (M-H)+=415.4, (M+Na)+=437.4.
Example 49
(2R,3S)
N1-[1,3,4,5-tetrahydro-1-methyl-2-oxo-2H-benzoazepin-3-yl]-2-(2-me-
thylpropyl)-3-allyl-butanediamide
##STR00108##
[1356] Following a procedure analogous to the preparation of
Example 1 using
3-amino-1,3,4,5-tetrahydro-1-methyl-2-2H-benzoazepine-2-one,
prepared by methods known to one skilled in the art, in place of
(30) in Step 1, the title compound was prepared. MS
(M+H).sup.+=408.3.
Example 50
(2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin--
3-yl]-2-methyl-3-propyl-butanediamide
##STR00109##
[1358] Using the product of Example 9a as starting material, and
following the reduction procedure of Example 7, the title compound
was prepared. MS (M+Na).sup.+=443.2.
[1359] Table 2 demonstrates representative compounds envisaged
within the scope of the present invention. Each formulae at the
start of Table 2 are intended to be paired with each entry in the
table which follows.
[1360] For example the compound (2R,3)
N1-[6,7-dihydro-5-methyl-6-oxo-dibenz[b,d]azepin-7-yl]-(2-methylpropyl)-3-
-(allyl)-butanediamide is represented by Example #500-B-j, which
cores the core B, succinate j, and entry #500.
[1361] For example the compound (2R,3S)
N1-[(3S)-1,3-dihydro-1-methyl-2-oxo-5-phenyl-7-chloro-2H-1,4-benzodiazepi-
n-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide, is represented
by Example #502-D-ab, which comprises the core D, succinate ab, and
entry #502.
TABLE-US-00002 TABLE 2 ##STR00110## ##STR00111## ##STR00112##
##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117##
##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122##
##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127##
wherein R.sup.3 and R.sup.5 are: ##STR00128## ##STR00129##
##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134##
##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139##
##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144##
##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149##
##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154##
##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159##
##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164##
##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##
##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174##
##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179##
##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184##
##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189##
##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194##
##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## Ex
# core R3/R5 R13 Z 500 A-S a-bt H methyl 501 A-S a-bt F methyl 502
A-S a-bt Cl methyl 503 A-S a-bt OH methyl 504 A-S a-bt --CH.sub.3
methyl 505 A-S a-bt --CH.sub.2CH.sub.3 methyl 506 A-S a-bt
--OCH.sub.3 methyl 507 A-S a-bt --CF.sub.3 methyl 508 A-S a-bt H
ethyl 509 A-S a-bt F ethyl 510 A-S a-bt Cl ethyl 511 A-S a-bt OH
ethyl 512 A-S a-bt --CH.sub.3 ethyl 513 A-S a-bt --CH.sub.2CH.sub.3
ethyl 514 A-S a-bt --OCH.sub.3 ethyl 515 A-S a-bt --CF.sub.3 ethyl
516 A-S a-bt H i-propyl 517 A-S a-bt F i-propyl 518 A-S a-bt Cl
i-propyl 519 A-S a-bt OH i-propyl 520 A-S a-bt --CH.sub.3 i-propyl
521 A-S a-bt --CH.sub.2CH.sub.3 i-propyl 522 A-S a-bt --OCH.sub.3
i-propyl 523 A-S a-bt --CF.sub.3 i-propyl 524 A-S a-bt H n-propyl
525 A-S a-bt F n-propyl 526 A-S a-bt Cl n-propyl 527 A-S a-bt OH
n-propyl 528 A-S a-bt --CH.sub.3 n-propyl 529 A-S a-bt
--CH.sub.2CH.sub.3 n-propyl 530 A-S a-bt --OCH.sub.3 n-propyl 531
A-S a-bt --CF.sub.3 n-propyl 532 A-S a-bt H n-butyl 533 A-S a-bt F
n-butyl 534 A-S a-bt Cl n-butyl 535 A-S a-bt OH n-butyl 536 A-S
a-bt --CH.sub.3 n-butyl 537 A-S a-bt --CH.sub.2CH.sub.3 n-butyl 538
A-S a-bt --OCH.sub.3 n-butyl 539 A-S a-bt --CF.sub.3 n-butyl 540
A-S a-bt H i-butyl 541 A-S a-bt F i-butyl 542 A-S a-bt Cl i-butyl
543 A-S a-bt OH i-butyl 544 A-S a-bt --CH.sub.3 i-butyl 545 A-S
a-bt --CH.sub.2CH.sub.3 i-butyl 546 A-S a-bt --OCH.sub.3 i-butyl
547 A-S a-bt --CF.sub.3 i-butyl 548 A-S a-bt H s-butyl 549 A-S a-bt
F s-butyl 550 A-S a-bt Cl s-butyl 551 A-S a-bt OH s-butyl 552 A-S
a-bt --CH.sub.3 s-butyl 553 A-S a-bt --CH.sub.2CH.sub.3 s-butyl 554
A-S a-bt --OCH.sub.3 s-butyl 555 A-S a-bt --CF.sub.3 s-butyl 556
A-S a-bt H t-butyl 557 A-S a-bt F t-butyl 558 A-S a-bt Cl t-butyl
559 A-S a-bt OH t-butyl 560 A-S a-bt --CH.sub.3 t-butyl 561 A-S
a-bt --CH.sub.2CH.sub.3 t-butyl 562 A-S a-bt --OCH.sub.3 t-butyl
563 A-S a-bt --CF.sub.3 t-butyl
564 A-S a-bt H allyl 565 A-S a-bt F allyl 566 A-S a-bt Cl allyl 567
A-S a-bt OH allyl 568 A-S a-bt --CH.sub.3 allyl 569 A-S a-bt
--CH.sub.2CH.sub.3 allyl 570 A-S a-bt --OCH.sub.3 allyl 571 A-S
a-bt --CF.sub.3 allyl 572 A-S a-bt H cyclopropyl 573 A-S a-bt F
cyclopropyl 574 A-S a-bt Cl cyclopropyl 575 A-S a-bt OH cyclopropyl
576 A-S a-bt --CH.sub.3 cyclopropyl 577 A-S a-bt --CH.sub.2CH.sub.3
cyclopropyl 578 A-S a-bt --OCH.sub.3 cyclopropyl 579 A-S a-bt
--CF.sub.3 cyclopropyl 580 A-S a-bt --CF.sub.3 cyclopropyl 581 A-S
a-bt H cyclopropyl-CH.sub.2-- 582 A-S a-bt F cyclopropyl-CH.sub.2--
583 A-S a-bt Cl cyclopropyl-CH.sub.2-- 584 A-S a-bt OH
cyclopropyl-CH.sub.2-- 585 A-S a-bt --CH.sub.3
cyclopropyl-CH.sub.2-- 586 A-S a-bt --CH.sub.2CH.sub.3
cyclopropyl-CH.sub.2-- 587 A-S a-bt --OCH.sub.3
cyclopropyl-CH.sub.2-- 588 A-S a-bt --CF.sub.3
cyclopropyl-CH.sub.2-- 589 A-S a-bt H cyclobutyl 590 A-S a-bt F
cyclobutyl 591 A-S a-bt Cl cyclobutyl 592 A-S a-bt OH cyclobutyl
593 A-S a-bt --CH.sub.3 cyclobutyl 594 A-S a-bt --CH.sub.2CH.sub.3
cyclobutyl 595 A-S a-bt --OCH.sub.3 cyclobutyl 596 A-S a-bt
--CF.sub.3 cyclobutyl 597 A-S a-bt H cyclobutyl-CH.sub.2-- 598 A-S
a-bt F cyclobutyl-CH.sub.2-- 599 A-S a-bt Cl cyclobutyl-CH.sub.2--
600 A-S a-bt OH cyclobutyl-CH.sub.2-- 601 A-S a-bt --CH.sub.3
cyclobutyl-CH.sub.2-- 602 A-S a-bt --CH.sub.2CH.sub.3
cyclobutyl-CH.sub.2-- 603 A-S a-bt --OCH.sub.3
cyclobutyl-CH.sub.2-- 604 A-S a-bt --CF.sub.3 cyclobutyl-CH.sub.2--
605 A-S a-bt H cyclopentyl 606 A-S a-bt F cyclopentyl 607 A-S a-bt
Cl cyclopentyl 608 A-S a-bt OH cyclopentyl 609 A-S a-bt --CH.sub.3
cyclopentyl 610 A-S a-bt --CH.sub.2CH.sub.3 cyclopentyl 611 A-S
a-bt --OCH.sub.3 cyclopentyl 612 A-S a-bt --CF.sub.3 cyclopentyl
613 A-S a-bt H cyclopentyl-CH.sub.2-- 614 A-S a-bt F
cyclopentyl-CH.sub.2-- 615 A-S a-bt Cl cyclopentyl-CH.sub.2-- 616
A-S a-bt OH cyclopentyl-CH.sub.2-- 617 A-S a-bt --CH.sub.3
cyclopentyl-CH.sub.2-- 618 A-S a-bt --CH.sub.2CH.sub.3
cyclopentyl-CH.sub.2-- 619 A-S a-bt --OCH.sub.3
cyclopentyl-CH.sub.2-- 620 A-S a-bt --CF.sub.3
cyclopentyl-CH.sub.2-- 621 A-S a-bt H cyclohexyl 622 A-S a-bt F
cyclohexyl 623 A-S a-bt Cl cyclohexyl 624 A-S a-bt OH cyclohexyl
625 A-S a-bt --CH.sub.3 cyclohexyl 626 A-S a-bt --CH.sub.2CH.sub.3
cyclohexyl 627 A-S a-bt --OCH.sub.3 cyclohexyl 628 A-S a-bt
--CF.sub.3 cyclohexyl 629 A-S a-bt H cyclohexyl-CH.sub.2-- 630 A-S
a-bt F cyclohexyl-CH.sub.2-- 631 A-S a-bt Cl cyclohexyl-CH.sub.2--
632 A-S a-bt OH cyclohexyl-CH.sub.2-- 633 A-S a-bt --CH.sub.3
cyclohexyl-CH.sub.2-- 634 A-S a-bt --CH.sub.2CH.sub.3
cyclohexyl-CH.sub.2-- 635 A-S a-bt --OCH.sub.3
cyclohexyl-CH.sub.2-- 636 A-S a-bt --CF.sub.3 cyclohexyl-CH.sub.2--
637 A-S a-bt H phenyl 638 A-S a-bt F phenyl 639 A-S a-bt Cl phenyl
640 A-S a-bt OH phenyl 641 A-S a-bt --CH.sub.3 phenyl 642 A-S a-bt
--CH.sub.2CH.sub.3 phenyl 643 A-S a-bt --OCH.sub.3 phenyl 644 A-S
a-bt --CF.sub.3 phenyl 645 A-S a-bt H 2-F-phenyl 646 A-S a-bt F
2-F-phenyl 647 A-S a-bt Cl 2-F-phenyl 648 A-S a-bt OH 2-F-phenyl
649 A-S a-bt --CH.sub.3 2-F-phenyl 650 A-S a-bt --CH.sub.2CH.sub.3
2-F-phenyl 651 A-S a-bt --OCH.sub.3 2-F-phenyl 652 A-S a-bt
--CF.sub.3 2-F-phenyl 653 A-S a-bt H 3-F-phenyl 654 A-S a-bt F
3-F-phenyl 655 A-S a-bt Cl 3-F-phenyl 656 A-S a-bt OH 3-F-phenyl
657 A-S a-bt --CH.sub.3 3-F-phenyl 658 A-S a-bt --CH.sub.2CH.sub.3
3-F-phenyl 659 A-S a-bt --OCH.sub.3 3-F-phenyl 660 A-S a-bt
--CF.sub.3 3-F-phenyl 661 A-S a-bt H 4-F-phenyl 662 A-S a-bt F
4-F-phenyl 663 A-S a-bt Cl 4-F-phenyl 664 A-S a-bt OH 4-F-phenyl
665 A-S a-bt --CH.sub.3 4-F-phenyl 666 A-S a-bt --CH.sub.2CH.sub.3
4-F-phenyl 667 A-S a-bt --OCH.sub.3 4-F-phenyl 668 A-S a-bt
--CF.sub.3 4-F-phenyl 669 A-S a-bt H 3-Cl-phenyl 670 A-S a-bt F
3-Cl-phenyl 671 A-S a-bt Cl 3-Cl-phenyl 672 A-S a-bt OH 3-Cl-phenyl
673 A-S a-bt --CH.sub.3 3-Cl-phenyl 674 A-S a-bt --CH.sub.2CH.sub.3
3-Cl-phenyl 675 A-S a-bt --OCH.sub.3 3-Cl-phenyl 676 A-S a-bt
--CF.sub.3 3-Cl-phenyl 677 A-S a-bt H 4-Cl-phenyl 678 A-S a-bt F
4-Cl-phenyl 679 A-S a-bt Cl 4-Cl-phenyl 680 A-S a-bt OH 4-Cl-phenyl
681 A-S a-bt --CH.sub.3 4-Cl-phenyl 682 A-S a-bt --CH.sub.2CH.sub.3
4-Cl-phenyl 683 A-S a-bt --OCH.sub.3 4-Cl-phenyl 684 A-S a-bt
--CF.sub.3 4-Cl-phenyl 685 A-S a-bt H 3-Me-phenyl 686 A-S a-bt F
3-Me-phenyl 687 A-S a-bt Cl 3-Me-phenyl 688 A-S a-bt OH 3-Me-phenyl
689 A-S a-bt --CH.sub.3 3-Me-phenyl 690 A-S a-bt --CH.sub.2CH.sub.3
3-Me-phenyl 691 A-S a-bt --OCH.sub.3 3-Me-phenyl 692 A-S a-bt
--CF.sub.3 3-Me-phenyl 693 A-S a-bt H 4-Me-phenyl 694 A-S a-bt F
4-Me-phenyl 695 A-S a-bt Cl 4-Me-phenyl 696 A-S a-bt OH 4-Me-phenyl
697 A-S a-bt --CH.sub.3 4-Me-phenyl 698 A-S a-bt --CH.sub.2CH.sub.3
4-Me-phenyl 699 A-S a-bt --OCH.sub.3 4-Me-phenyl 700 A-S a-bt
--CF.sub.3 4-Me-phenyl 701 A-S a-bt H 3-MeO-phenyl 702 A-S a-bt F
3-MeO-phenyl 703 A-S a-bt Cl 3-MeO-phenyl 704 A-S a-bt OH
3-MeO-phenyl 705 A-S a-bt --CH.sub.3 3-MeO-phenyl 706 A-S a-bt
--CH.sub.2CH.sub.3 3-MeO-phenyl 707 A-S a-bt --OCH.sub.3
3-MeO-phenyl 708 A-S a-bt --CF.sub.3 3-MeO-phenyl 709 A-S a-bt H
4-MeO-phenyl 710 A-S a-bt F 4-MeO-phenyl 711 A-S a-bt Cl
4-MeO-phenyl 712 A-S a-bt OH 4-MeO-phenyl 713 A-S a-bt --CH.sub.3
4-MeO-phenyl 714 A-S a-bt --CH.sub.2CH.sub.3 4-MeO-phenyl 715 A-S
a-bt --OCH.sub.3 4-MeO-phenyl 716 A-S a-bt --CF.sub.3 4-MeO-phenyl
717 A-S a-bt H 3-F.sub.3C-phenyl 718 A-S a-bt F 3-F.sub.3C-phenyl
719 A-S a-bt Cl 3-F.sub.3C-phenyl 720 A-S a-bt OH 3-F.sub.3C-phenyl
721 A-S a-bt --CH.sub.3 3-F.sub.3C-phenyl 722 A-S a-bt
--CH.sub.2CH.sub.3 3-F.sub.3C-phenyl 723 A-S a-bt --OCH.sub.3
3-F.sub.3C-phenyl 724 A-S a-bt --CF.sub.3 3-F.sub.3C-phenyl 725 A-S
a-bt H 4-F.sub.3C-phenyl 726 A-S a-bt F 4-F.sub.3C-phenyl 727 A-S
a-bt Cl 4-F.sub.3C-phenyl 728 A-S a-bt OH 4-F.sub.3C-phenyl 729 A-S
a-bt --CH.sub.3 4-F.sub.3C-phenyl 730 A-S a-bt --CH.sub.2CH.sub.3
4-F.sub.3C-phenyl 731 A-S a-bt --OCH.sub.3 4-F.sub.3C-phenyl 732
A-S a-bt --CF.sub.3 4-F.sub.3C-phenyl
Utility
[1362] A.beta. production has been implicated in the pathology of
Alzheimer's Disease (AD). The compounds of the present invention
have utility for the prevention and treatment of AD by inhibiting
A.beta. production. Methods of treatment target formation of
A.beta. production through the enzymes involved in the proteolytic
processing of c amyloid precursor protein. Compounds that inhibit
.beta. or .gamma. secretase activity, either directly or
indirectly, control the production of A.beta.. Such inhibition of
.beta. or .gamma. secretases reduces production of A.beta., and is
expected to reduce or prevent the neurological disorders associated
with A.beta. protein, such as Alzheimer's Disease.
[1363] Cellular screening methods for inhibitors of A.beta.
production, testing methods for the in vivo suppression of A.beta.
production, and assays for the detection of secretase activity are
known in the art and have been disclosed in numerous publications,
including PCT publication number WO 98/12493, EPO publication
number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat. No.
5,593,846; all hereby incorporated by reference.
[1364] The compounds of the present invention have utility for the
prevention and treatment of disorders involving A.beta. production,
such as cerebrovascular disorders.
[1365] Compounds of the present invention have been shown to
inhibit A.beta. production, as determined by the secretase
inhibition assay described below.
[1366] Compounds of the present invention have been shown to
inhibit A.beta. production, utilizing the C-terminus .beta. amyloid
precursor protein accumulation assay described below.
[1367] Compounds of Formula (I) are expected to possess
.gamma.-secretase inhibitory activity. The .gamma.-secretase
inhibitory activity of the compounds of the present invention is
demonstrated using assays for such activity, for example, using the
assay described below. Compounds of the present invention have been
shown to inhibit the activity of .gamma.-secretase, as determined
by the A.beta. immunoprecipitation assay.
[1368] Compounds provided by this invention should also be useful
as standards and reagents in determining the ability of a potential
pharmaceutical to inhibit A.beta. production. These would be
provided in commercial kits comprising a compound of this
invention.
[1369] As used herein ".mu.g" denotes microgram, "mg" denotes
milligram, "g" denotes gram, ".mu.L" denotes microliter, "mL"
denotes milliliter. L'' denotes liter, "nM" denotes nanomolar,
".mu.M" denotes micromolar, "mM" denotes millimolar, "M" denotes
molar, "nm" denotes nanometer, "SDS" denotes sodium dodecyl
sulfate, and "DMSO" denotes dimethyl sulfoxide, and "EDTA" denotes
ethylenediaminetetraacetato.
[1370] A compound is considered to be active if it has an IC.sub.50
or K.sub.i value of less than about 100 .mu.M for the inhibition of
A.beta. production.
.beta. Amyloid Precursor Protein Accumulation Assay
[1371] A novel assay to evaluate the accumulation of A.beta.
protein was developed to detect potential inhibitors of secretase.
The assay uses the N 9 cell line, characterized for expression of
exogenous APP by immunoblotting and immunoprecipitation.
[1372] The effect of test compounds on the accumulation of A.beta.
in the conditioned medium is tested by immunoprecipitation.
Briefly, N 9 cells are grown to confluency in 6-well plates and
washed twice with 1.times..times. Hank's buffered salt solution.
The cells are starved in methionine/cysteine deficient media for 30
min, followed by replacement with fresh deficient media containing
150 uCi S35 Translabel (Amersham). Test compounds dissolved in DMSO
(final concentration 1%) are added together with the addition of
radiolabel. The cells are incubated for 4 h at 37.degree. C. in a
tissue culture incubator.
[1373] At the end of the incubation period, the conditioned medium
is harvested and pre-cleared by the addition of 5 .mu.l normal
mouse serum and 50 .mu.l of protein A Sepharose (Pharmacia), mixed
by end-over-end rotation for 30 minutes at 4.degree. C., followed
by a brief centrifugation in a microfuge. The supernatant is then
harvested and transferred to fresh tubes containing 5 ug of a
monoclonal antibody (clone 1101.1; directed against an internal
peptide sequence in A.beta.) and 50 .mu.l protein A Sepharose.
After incubation overnight at 4.degree. C., the samples are washed
three times with high salt washing buffer (50 mM Tris, pH 7.5, 500
mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt
wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5%
Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet
after the last wash is resuspended in SDS sample buffer (Laemmli,
1970) and boiled for 3 minutes. The supernatant is then
fractionated on either 10-20% Tris, Tricine SDS gels or on 16.5%
Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film
or analyzed by phosphorimaging. The resulting image is analyzed for
the presence of A.beta. polypeptides. The steady-state level of
A.beta. in the presence of a test compound is compared to wells
treated with DMSO (1%) alone. A typical test compound blocks
A.beta. accumulation in the conditioned medium, and is therefore
considered active, with an IC.sub.50 less than 100 .mu.M.
C-Terminus .beta. Amyloid Precursor Protein Accumulation Assay
[1374] The effect of test compounds on the accumulation of
C-terminal fragments is determined by immunoprecipitation of APP
and fragments thereof from cell lysates. N 9 cells are
metabolically labeled as above in the presence or absence of test
compounds. At the end of the incubation period, the conditioned
medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH
8.0 containing 11 Triton X-100, 1% deoxycholate. 0.1% SDS, 150 mM
NaCl, 0.125% NaN.sub.3). Again, lysates are precleared with 5 ul
normal rabbit serum 50 ul protein A Sepharose, followed by the
addition of BC-1 antiserum (15 .mu.l) and 50 .mu.l protein A
Sepharose for 16 hours at 4.degree. C. The immunoprecipitates are
washed as above, bound proteins eluted by boiling in SDS sample
buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to
X-ray film or phosphorimager, the resulting images are analyzed for
the presence of C-terminal APP fragments. The steady-state level of
C-terminal APP fragments is compared to wells treated with DMSO
(11%) alone. A typical test compound stimulates C-terminal fragment
accumulation in the cell lysates, and is therefore considered
active, with an IC.sub.50 less than 100 .mu.M.
A.beta. Immunoprecipitation Assay
[1375] This immunoprecipitation assay is specific for .gamma.
secretase (i.e., proteolytic activity required to generate the
C-terminal end of A.beta. either by direct cleavage or generating a
C-terminal extended species which is subsequently further
proteolyzed). N 9 cells are pulse labeled in the presence of a
reported 7 secretase inhibitor (MDL 28170) for 1 h, followed by
washing to remove radiolabel and MDL 28170. The media is replaced
and test compounds are added. The cells are chased for increasing
periods of times and A.beta. is isolated from the conditioned
medium and C-terminal fragments from cell lysates (see above). The
test compounds are characterized whether a stabilization of
C-terminal fragments is observed and whether A.beta. is generated
from these accumulated precursor. A typical test compound prevents
the generation of A.beta. out of accumulated C-terminal fragments
and is considered active with an IC.sub.50 less than 100 .mu.M.
Dosage and Formulation
[1376] The compounds of the present invention can be administered
orally using any pharmaceutically acceptable dosage form known in
the art for such administration. The active ingredient can be
supplied in solid dosage forms such as dry powders, granules,
tablets or capsules, or in liquid dosage forms, such as syrups or
aqueous suspensions. The active ingredient can be administered
alone, but is generally administered with a pharmaceutical carrier.
A valuable treatise with respect to pharmaceutical dosage forms is
Remington's Pharmaceutical Sciences, Mack Publishing.
[1377] The compounds of the present invention can be administered
in such oral dosage forms as tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixirs, tinctures, suspensions, syrups, and
emulsions. Likewise, they may also be administered in intravenous
(bolus or infusion), intraperitoneal, subcutaneous, or
intramuscular form, all using dosage forms well known to those of
ordinary skill in the pharmaceutical arts. An effective but
non-toxic amount of the compound desired can be employed to prevent
or treat neurological disorders related to .beta.-amyloid
production or accumulation, such as Alzheimer's disease and Down's
Syndrome.
[1378] The compounds of this invention can be administered by any
means that produces contact of the active agent with the agent's
site of action in the body of a host, such as a human or a mammal.
They can be administered by any conventional means available for
use in conjunction with pharmaceuticals, either as individual
therapeutic agents or in a combination of therapeutic agents. They
can be administered alone, but generally administered with a
pharmaceutical carrier selected on the basis of the chosen route of
administration and standard pharmaceutical practice.
[1379] The dosage regimen for the compounds of the present
invention will, of course, vary depending upon known factors, such
as the pharmacodynamic characteristics of the particular agent and
its mode and route of administration; the species, age, sex,
health, medical condition, and weight of the recipient; the nature
and extent of the symptoms; the kind of concurrent treatment; the
frequency of treatment; the route of administration, the renal and
hepatic function of the patient, and the effect desired. An
ordinarily skilled physician or veterinarian can readily determine
and prescribe the effective amount of the drug required to prevent,
counter, or arrest the progress of the condition.
[1380] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three, or four times
daily.
[1381] The compounds for the present invention can be administered
in intranasal form via topical use of suitable intranasal vehicles,
or via transdermal routes, using those forms of transdermal skin
patches wall known to those of ordinary skill in that art. To be
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittant throughout the dosage regimen.
[1382] In the methods of the present invention, the compounds
herein described in detail can form the active ingredient, and are
typically administered in admixture with suitable pharmaceutical
diluents, excipients, or carriers (collectively referred to herein
as carrier materials) suitably selected with respect to the
intended form of administration, that is, oral tablets, capsules,
elixirs, syrups and the like, and consistent with conventional
pharmaceutical practices.
[1383] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable, inert carrier such
as lactose, starch, sucrose, glucose, methyl callulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like; for oral administration in liquid form, the oral drug
components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water, and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents, and coloring
agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars such as glucose or
.beta.-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, and the like.
[1384] The compounds of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamallar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[1385] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacylates, and crosslinked or
amphipathic block copolymers of hydrogels.
[1386] Gelatin capsules may contain the active ingredient and
powdered carriers, such as lactose, starch, cellulose derivatives,
magnesium stearate, stearic acid, and the like. Similar diluents
can be used to make compressed tablets. Both tablets and capsules
can be manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any unpleasant
taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract.
[1387] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
[1388] In general, water, a suitable oil, saline, aqueous dextrose
(glucose), and related sugar solutions and glycols such as
propylene glycol or polyethylene glycols are suitable carriers for
parenteral solutions. Solutions for parenteral administration
preferably contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer substances.
Antioxidizing agents such as sodium bisulfite, sodium sulfite, or
ascorbic acid, either alone or combined, are suitable stabilizing
agents. Also used are citric acid and its salts and sodium EDTA. In
addition, parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propyl-paraben, and
chlorobutanol.
[1389] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
* * * * *