U.S. patent application number 10/287367 was filed with the patent office on 2003-07-10 for amino lactam sulfonamides as inhibitors of a-beta protein production.
Invention is credited to Han, Amy Qi, Thompson, Lorin A..
Application Number | 20030130251 10/287367 |
Document ID | / |
Family ID | 22568723 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030130251 |
Kind Code |
A1 |
Thompson, Lorin A. ; et
al. |
July 10, 2003 |
Amino lactam sulfonamides as inhibitors of A-beta protein
production
Abstract
This invention relates to novel lactams having the Formula (I):
1 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: |
Thompson, Lorin A.;
(Wilmington, DE) ; Han, Amy Qi; (Hockessin,
DE) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
22568723 |
Appl. No.: |
10/287367 |
Filed: |
November 4, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10287367 |
Nov 4, 2002 |
|
|
|
09684718 |
Oct 7, 2000 |
|
|
|
6503901 |
|
|
|
|
60158565 |
Oct 8, 1999 |
|
|
|
Current U.S.
Class: |
514/183 ;
514/212.08; 514/227.8; 514/231.5; 514/253.13; 514/254.01; 514/326;
514/327; 514/422; 514/424; 540/524; 544/130; 544/141; 544/360;
544/372; 544/60; 546/207; 546/243; 548/517; 548/543 |
Current CPC
Class: |
C07D 409/14 20130101;
C07D 243/24 20130101; C07D 417/12 20130101; A61P 25/28 20180101;
C07D 405/12 20130101; C07D 413/12 20130101; C07D 409/12 20130101;
C07D 243/10 20130101; C07D 401/12 20130101 |
Class at
Publication: |
514/183 ;
514/212.08; 514/227.8; 514/231.5; 514/253.13; 514/254.01; 514/326;
514/327; 514/422; 514/424; 540/524; 544/60; 544/130; 544/141;
544/360; 544/372; 546/207; 546/243; 548/517; 548/543 |
International
Class: |
A61K 031/55; A61K
031/541; A61K 031/5377; A61K 031/496; A61K 031/4439; A61K 031/454;
C07D 417/02; C07D 413/02; C07D 43/02 |
Claims
What is claimed is:
1. A compound of the Formula (I): 32or a pharmaceutically
acceptable salt or prodrug thereof, wherein: Q is C.sub.1-C.sub.6
alkyl substituted with 0-3 R.sup.1a; C.sub.3-C.sub.10 cycloalkyl
substituted with 0-3 R.sup.1b; C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.1b; C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1b; 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.1b;
R.sup.1a, at each occurrence, is independently selected from H,
R.sup.1b, Cl, F, Br, I, OR.sup.14, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl; C.sub.2-C.sub.4
alkenyl; C.sub.2-C.sub.4 alkynyl; C.sub.1-C.sub.4 haloalkyl;
C.sub.1-C.sub.4 haloalkoxy; C.sub.3-C.sub.10 carbocycle substituted
with 0-3 R.sup.1b; C.sub.6-C.sub.10 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,
OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O, NR.sup.19R.sup.20,
CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy; --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d; C.sub.1-C.sub.6
alkyl substituted with 0-3 R.sup.1c; C.sub.2-C.sub.6 alkenyl
substituted with 0-2 R.sup.1c; C.sub.2-C.sub.6 alkynyl substituted
with 0-2 R.sup.1c; C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f; C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
5 to 14 membered heterocycle containing 1 to 4 heteroatoms selected
from nitrogen, oxygen, and sulphur, wherein said 5 to 14 membered
heterocycle is substituted with 0-3 R.sup.1f; R.sup.1c, at each
occurrence, is independently selected from H, OR.sup.14, Cl, F, Br,
I, CN, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy; --C(.dbd.O)--R.sup.1d,
--O--R.sup.1d, --S--R.sup.1d, --S(.dbd.O)--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
NR.sup.19bs(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d; C.sub.3-C.sub.10
cycloalkyl substituted with 0-3 R.sup.1f; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.1f; C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1f; 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.1f; R.sup.1d, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1e; C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.1e;
C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.1e;
C.sub.3-C.sub.10 cycloalkyl substituted with 0-3 R.sup.1f;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.1f;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; 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.1f; R.sup.1e, at each
occurrence, is independently selected from H, OR.sup.14, Cl, F, Br,
I, CN, NO.sub.2, .dbd.O, NR.sup.19R.sup.20, CF.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy; C.sub.3-C.sub.10 cycloalkyl
substituted with 0-3 R.sup.1f; C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.1f; C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1f; 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.1f;
R.sup.1f, at each occurrence, is independently selected from H,
OR.sup.14, SR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; R.sup.2 is H, C.sub.1-C.sub.6 alkyl,
(C.sub.1-C.sub.6 alkoxy) C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6
carbocycle, C.sub.6-C.sub.10 aryl, (C.sub.3-C.sub.6
carbocycle)methyl, (C.sub.6-C.sub.10 aryl)methyl, (C.sub.6-C.sub.10
aryl)ethyl, or 5 to 10 membered heterocycle; 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 cycloalkyl substituted with 0-3 R.sup.5c;
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;
acetyl, --S(C.sub.1-C.sub.4 alkyl), --S(.dbd.O)(C.sub.1-C.sub.4
alkyl), --S(.dbd.O).sub.2(C.sub.1-C.sub.4 alkyl); C.sub.3-C.sub.10
cycloalkyl substituted with 0-3 R.sup.5c; 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; 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 C.sub.6-C.sub.10 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 or 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; Ring B is a 6, 7, or 8
membered lactam, wherein the lactam is saturated, partially
saturated or unsaturated; wherein each additional lactam carbon is
substituted with 0-2 R.sup.11; and, optionally, the lactam contains
a heteroatom selected from --N.dbd., --NH--, --N(R.sup.10)--,
--O--, --S--, --S(.dbd.O)--, and --S(.dbd.O).sub.2--; additionally,
two R.sup.11 substituents on adjacent atoms may be combined to form
C.sub.3-C.sub.6 carbocycle fused radical, a benzo fused radical, or
a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6
membered heteroaryl fused radical comprises 1-2 heteroatoms
selected from N, O, and S; wherein said benzo fused radical or 5 to
6 membered heteroaryl fused radical is substituted with 0-3
R.sup.13; 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, S(.dbd.O).sub.2NR.sup.18R.sup.19,
S(.dbd.O).sub.2R.sup.17; C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.10a; C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.10b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.10b; 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.10b; 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; 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--; R.sup.11, at each occurrence, is independently
selected from 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; C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; 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.11b; 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; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.11b; 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.11b; 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; W is --(CR.sup.8R.sup.8a).sub.p--; p
is 0, 1, 2, 3, or 4; R.sup.8 and R.sup.8a, at each occurrence, are
independently selected from H, F, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl and
C.sub.3-C.sub.8 cycloalkyl; X is a bond; C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.Xb; C.sub.3-C.sub.10 cycloalkyl
substituted with 0-3 R.sup.Xb; C.sub.3-C.sub.10 carbocycle
substituted with 0-3 R.sup.Xb; 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.Xb; R.sup.Xb, 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--; Y is a bond or
--(CR.sup.9R.sup.9a).sub.t-- -V--(CR.sup.9R.sup.9a).sub.u--; t is
0, 1, 2, or 3; u is 0, 1, 2, or 3; R.sup.9 and R.sup.9a, at each
occurrence, are independently selected from H, F, C.sub.1-C.sub.6
alkyl or C.sub.3-C.sub.8 cycloalkyl; V is a bond, --C(.dbd.O)--,
--O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, --N(R.sup.19)--,
--C(.dbd.O)NR.sup.19b--, --NR.sup.19bC(.dbd.O)--,
--NR.sup.19bS(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.19b--,
--NR.sup.19bS(.dbd.O)--, --S(.dbd.O)NR.sup.19b--, --C(.dbd.O)O--,
or --OC(.dbd.O)--; Z is H; C.sub.1-C.sub.8 alkyl substituted with
0-2 R.sup.12; C.sub.2-C.sub.6 alkenyl substituted with 0-2
R.sup.12; C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
C.sub.6-C.sub.10 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 is
C.sub.6-C.sub.10 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.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, or CF.sub.3; R.sup.14, at each occurrence, is
independently selected from H, phenyl, benzyl, C.sub.1-C.sub.6
alkyl, or C.sub.2-C.sub.6 alkoxyalkyl; R.sup.15, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.16, at
each occurrence, is independently selected from H, OH,
C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); alternatively,
--NR.sup.15R.sup.16 may be a heterocyclic ring selected from the
group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,
homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R.sup.17 is
H, aryl, aryl-CH.sub.2--, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl; R.sup.18, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.19, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.19b,
at each occurrence, is independently selected from H,
C.sub.1-C.sub.4 alkyl, phenyl, benzyl, and phenethyl; and R.sup.20
and R.sup.21, at each occurrence, are independently selected from
H, C.sub.1-C.sub.4 alkyl, aryl, and aryl(C.sub.1-C.sub.2 alkyl)-;
provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl, or
octyl; R.sup.2 is H; R.sup.5 is methyl, and -WXYZ is methyl, then
Ring B is not 33 wherein R.sup.13 is H.
2. A compound of claim 1, or a pharmaceutically acceptable salt or
prodrug thereof, wherein: Q is C.sub.1-C.sub.6 alkyl substituted
with 0-3 R.sup.1a; C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1b; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b; C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; 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.1b; R.sup.1a, at each
occurrence, is independently selected from H, R.sup.1b, Cl, F, Br,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b; C.sub.6-C.sub.10 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, OR.sup.14, Cl, F, Br,
NO.sub.2, NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy; --C(.dbd.O)--R.sup.1d,
--O--R.sup.1d, --S--R.sup.1d, --S(.dbd.O)--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, --NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d; C.sub.1-C.sub.6
alkyl substituted with 0-3 R.sup.1c; C.sub.3-C.sub.10 cycloalkyl
substituted with 0-3 R.sup.1f; C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1f; and 5 to 14 membered heterocycle containing 1 to
4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 14 membered heterocycle is substituted with 0-3 R.sup.1f;
R.sup.1c, at each occurrence, is independently selected from H,
OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d; C.sub.3-C.sub.10
cycloalkyl substituted with 0-3 R.sup.1f; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.1f; C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1f; 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.1f; R.sup.1d, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, and C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1f; R.sup.1f, at each occurrence, is
independently selected from H, OR.sup.14, SR.sup.14, Cl, F, Br, I,
CN, NO.sub.2, .dbd.O, NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4 haloalkyl-S--;
R.sup.2 is H or C.sub.1-C.sub.6 alkyl; 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; or
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b; 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;
acetyl, S(C.sub.1-C.sub.4 alkyl), S(.dbd.O)(C.sub.1-C.sub.4 alkyl),
S(.dbd.O).sub.2(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.10 cycloalkyl
substituted with 0-3 R.sup.5c; 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, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S--; R.sup.6 is H, methyl, or ethyl; Ring B is a seven
membered lactam, wherein the lactam is saturated, partially
saturated or unsaturated; wherein each additional lactam carbon is
substituted with 0-2 R.sup.11; and, optionally, the lactam contains
a heteroatom selected from --N.dbd., --NH--, --N(R.sup.10)--,
--O--, --S--, --S(.dbd.O)--, and --S(.dbd.O).sub.2--; additionally,
two R.sup.11 substituents on adjacent atoms may be combined to form
C.sub.3-C.sub.6 carbocycle fused radical, a benzo fused radical, or
a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6
membered heteroaryl fused radical comprises 1-2 heteroatoms
selected from N, O, and S; wherein said benzo fused radical or 5 to
6 membered heteroaryl fused radical is substituted with 0-3
R.sup.13; 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, S(.dbd.O).sub.2NR.sup.18R.sup.19,
S(.dbd.O).sub.2R.sup.17; C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.10a; C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.10b;
C.sub.3-C.sub.10carbocycle substituted with 0-3 R.sup.10b; 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.10b; 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; 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--; R.sup.11, at each occurrence, is independently
selected from 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; C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; 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.11b; 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; C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.11b; 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.11b; 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; W is --(CR.sup.8R.sup.8a).sub.p--; p
is 0, 1, or 2; R.sup.8 and R.sup.8a, at each occurrence, are
independently selected from H, F, methyl, and ethyl; X is a bond;
phenyl substituted with 0-3 R.sup.Xb; C.sub.3-C.sub.6 cycloalkyl
substituted with 0-3 R.sup.Xb; 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 0-2 R.sup.Xb; R.sup.Xb, 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--; Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).sub.u--; t is 0,
1, or 2; u is 0, 1, or 2; R.sup.9 and R.sup.9a, at each occurrence,
are independently selected from H, F, methyl, and ethyl; V is a
bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --NHC(.dbd.O)--, or
--C(.dbd.O)NH--; Z is H; C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.12; C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12; phenyl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.6 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 is phenyl substituted with 0-4
R.sup.12b; C.sub.3-C.sub.6 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.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.4 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, at each occurrence, is
independently selected from H, phenyl, benzyl, C.sub.1-C.sub.6
alkyl, and C.sub.2-C.sub.6 alkoxyalkyl; R.sup.15, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.su- b.6 alkyl); R.sup.16,
at each occurrence, is independently selected from H, OH,
C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.su- b.6 alkyl); alternatively,
--NR.sup.15R.sup.16 may be a heterocyclic ring selected from the
group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,
homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R.sup.17 is
H, aryl, aryl-CH.sub.2--, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl; R.sup.18, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.19, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); and R.sup.20
is H or C.sub.1-C.sub.4; provided that when Q is phenyl,
3-F-phenyl, benzyl, propyl, or octyl; R.sup.2 is H; R.sup.5 is
methyl, and -WXYZ is methyl, then Ring B is not 34 wherein R.sup.13
is H.
3. A compound of claim 2 wherein Ring B is selected from: 35wherein
each benzo fused radical is substituted with 0-3 R.sup.13.
4. A compound of claim 3 of Formula (I): 36or a pharmaceutically
acceptable salt form or prodrug thereof, wherein: Q is
C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1a;
C.sub.3-C.sub.10 cycloalkyl substituted with 0-3 R.sup.1b;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; 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.1b; R.sup.1a, at each
occurrence, is independently selected from H, Cl, F, Br,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.4
haloalkyl; C.sub.6-C.sub.10 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, OR.sup.14, Cl, F, Br,
NO.sub.2, NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy; --C(.dbd.O)--R.sup.1d,
--OR.sup.1d, --S--R.sup.1d, --S(.dbd.O)--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, --NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d; C.sub.1-C.sub.6
alkyl substituted with 0-3 R.sup.1c; C.sub.3-C.sub.10 cycloalkyl
substituted with 0-3 R.sup.1f; C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1f; and 5 to 14 membered heterocycle containing 1 to
4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 14 membered heterocycle is substituted with 0-3 R.sup.1f;
R.sup.1c, at each occurrence, is independently selected from H,
OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup- .1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d; C.sub.3-C.sub.10
cycloalkyl substituted with 0-3 R.sup.1f; C.sub.3-C.sub.10
carbocycle substituted with 0-3 R.sup.1f; C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1f; 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.1f; R.sup.1d, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, and C.sub.6-C.sub.10 aryl
substituted with 0-3 R.sup.1f; R.sup.1f, at each occurrence, is
independently selected from H, Cl, F, Br, NO.sub.2, CF.sub.3,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy, and C.sub.1-C.sub.4
haloalkyl-S--; R.sup.2 is H, methyl, or ethyl; R.sup.5 is
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; or
C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b; 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,
acetyl, --S(C.sub.1-C.sub.4 alkyl), S(.dbd.O)(C.sub.1-C.sub.4
alkyl), S(.dbd.O).sub.2(C.sub.1-C.sub.4 alkyl); C.sub.3-C.sub.10
cycloalkyl 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; R.sup.6 is H; Ring B is selected
from: 37R.sup.11, at each occurrence, is independently selected
from 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; C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; 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.11b; 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, phenyl substituted with 0-3 R.sup.11b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; 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.11b; 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, C.sub.1-C.sub.4
haloalkoxy, and C.sub.1-C.sub.4 haloalkyl-S--; W is
--(CR.sup.8R.sup.8a).sub.p--; p is 0, 1, or 2; R.sup.8 and
R.sup.8a, at each occurrence, are independently selected from H, F,
methyl, and ethyl; X is a bond; phenyl substituted with 0-3
R.sup.Xb; C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
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 0-2 R.sup.Xb; R.sup.Xb, 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--; Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).sub.u--; t is 0,
1, or 2; u is 0, 1, or 2; R.sup.9 and R.sup.9a, at each occurrence,
are independently selected from H, F, methyl, and ethyl; V is a
bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--; Z is H; C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.12; C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12; phenyl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.6 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 is phenyl substituted with 0-4
R.sup.12b; C.sub.3-C.sub.6 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.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.4 alkyl,
C.sub.1-C.sub.4 alkoxy, Cl, F, Br, CN, NO.sub.2, and CF.sub.3;
R.sup.14, at each occurrence, is independently selected from H,
phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
alternatively, --NR.sup.15R.sup.16 may be a heterocyclic ring
selected from the group piperidinyl, morpholinyl, thiomorpholinyl,
pyrrolidinyl, homopiperidinyl, piperazinyl, and
N-methylpiperizinyl; R.sup.17 is H, aryl, aryl-CH.sub.2--,
C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6 alkoxyalkyl; R.sup.18, at
each occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C- .sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.19, at
each occurrence, is independently selected from H, OH,
C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); and R.sup.20 is H or
C.sub.1-C.sub.4; provided that when Q is phenyl, 3-F-phenyl,
benzyl, propyl, or octyl; R.sup.2 is H; R.sup.5 is methyl, and
-WXYZ is methyl, then Ring B is not 38 wherein R.sup.13 is H.
5. A compound of claim 4 of Formula (Ia): 39or a pharmaceutically
acceptable salt form or prodrug thereof, wherein: Ring B is 40Q is
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.1a;
C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; or 5 to 10
membered heterocycle containing 1 to 3 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, Cl, F, Br,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, and phenyl substituted with 0-3 R.sup.1b; R.sup.1b, at
each occurrence, is independently selected from H, OR.sup.14, Cl,
F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, C(.dbd.O)O--R.sup.1d,
--OC(.dbd.O)--R.sup.1d; C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1c; C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
5 to 14 membered heterocycle containing 1 to 4 heteroatoms selected
from nitrogen, oxygen, and sulphur, wherein said 5 to 14 membered
heterocycle is substituted with 0-3 R.sup.1f; R.sup.1c, at each
occurrence, is independently selected from H,
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, and --OC(.dbd.O)--R.sup.1d; R.sup.1d, at
each occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, and C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f;
R.sup.1f, at each occurrence, is independently selected from H, Cl,
F, Br, NO.sub.2, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--; R.sup.5 is OR.sup.14;
C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.5b;
C.sub.2-C.sub.6 alkenyl substituted with 0-1 R.sup.5b; or
C.sub.2-C.sub.6 alkynyl substituted with 0-1 R.sup.5b; R.sup.5a is
H or C.sub.1-C.sub.4 alkyl; 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, CN, NO.sub.2,
NR.sup.15R.sup.16; acetyl, --S(C.sub.1-C.sub.4 alkyl),
--S(.dbd.O)(C.sub.1-C.sub.4 alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.7
cycloalkyl substituted with 0-3 R.sup.5c; phenyl substituted with
0-3 R.sup.5c; and 5 to 7 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 7 membered heterocycle is substituted with 0-3 R.sup.5c;
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).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, metrhoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy; R.sup.11, at each occurrence, is independently selected
from H, --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; C.sub.1-C.sub.6
alkyl substituted with 0-1 R.sup.11a; phenyl substituted with 0-3
R.sup.11b; C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.11b; or 5 to 7 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 7 membered heterocycle is substituted with 0-3 R.sup.11b;
R.sup.11a, at each occurrence, is independently selected from H,
C.sub.1-C.sub.4 alkyl, OR.sup.14, Cl, F, Br, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, phenyl substituted with 0-3 R.sup.11b;
C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b; 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.11b; 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, C.sub.1-C.sub.4
haloalkoxy, and C.sub.1-C.sub.4 haloalkyl-S--; W is
--(CR.sup.8R.sup.8a).sub.p--; p is 0, 1, or 2; R.sup.8 and
R.sup.8a, at each occurrence, are independently selected from H, F,
methyl, and ethyl; X is a bond; phenyl substituted with 0-3
R.sup.Xb; C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
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 0-2 R.sup.Xb; R.sup.Xb, 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--; Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).sub.u--; t is 0,
1, or 2; u is 0, 1, or 2; R.sup.9 and R.sup.9a, at each occurrence,
are independently selected from H, F, methyl, and ethyl; V is a
bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--; Z is H; C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.12; C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12; phenyl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.6 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 is phenyl substituted with 0-4
R.sup.12b; C.sub.3-C.sub.6 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.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.3 alkyl,
C.sub.1-C.sub.3 alkoxy, Cl, F, Br, CN, NO.sub.2, and CF.sub.3;
R.sup.14, at each occurrence, is independently selected from H,
phenyl, benzyl, C.sub.1-C.sub.6 alkyl, and C.sub.2-C.sub.6
alkoxyalkyl; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.16, at each
occurrence, is independently selected from H, OH, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
alternatively, --NR.sup.15R.sup.16 may be a heterocyclic ring
selected from the group piperidinyl, morpholinyl, thiomorpholinyl,
pyrrolidinyl, homopiperidinyl, piperazinyl, and
N-methylpiperizinyl; R.sup.17 is H, phenyl, benzyl, C.sub.1-C.sub.4
alkyl, or C.sub.2-C.sub.4 alkoxyalkyl; R.sup.18, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl, phenyl, benzyl, phenethyl, --C(.dbd.O)--(C.sub.1-C.sub.6
alkyl) and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); R.sup.19, at
each occurrence, is independently selected from H, OH, methyl,
ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R.sup.20
is H, methyl, ethyl, propyl, or butyl.
6. A compound of claim 5 of Formula (Ia) wherein: Ring B is 41Q is
C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.1a; phenyl
substituted with 0-3 R.sup.1b; naphthyl substituted with 0-3
R.sup.1b; or 5 to 10 membered heterocycle containing 1 to 2
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, Cl,
F, Br, --NR.sup.19R.sup.20, --CF.sub.3; and phenyl substituted with
0-3 R.sup.1b; R.sup.1b, at each occurrence, is independently
selected from H, methyl, ethyl, OR.sup.14, Cl, F, Br, NO.sub.2,
NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy; --C(.dbd.O)--R.sup.1d, --O--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, --NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, --C(.dbd.O)O--R.sup.1d,
--OC(.dbd.O)--R.sup.1d; C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1c; phenyl substituted with 0-3 R.sup.1f; 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.1f; R.sup.1c, at each
occurrence, is independently selected from H,
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d, and
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d; R.sup.1d, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl; and phenyl substituted with 0-3 R.sup.1f; R.sup.1f, at each
occurrence, is independently selected from H, Cl, F, Br, NO.sub.2,
CF.sub.3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,
C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2 haloalkoxy; R.sup.5
is OR.sup.14 or C.sub.1-C.sub.4 alkyl substituted with 0-1
R.sup.5b; R.sup.5a is H; R.sup.5b, at each occurrence, is
independently selected from: H, methyl, ethyl, propyl, butyl,
--NR.sup.15R.sup.16; C.sub.3-C.sub.7 cycloalkyl substituted with
0-3 R.sup.5c; phenyl substituted with 0-3 R.sup.5c; or 5 to 7
membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered
heterocycle is substituted with 0-3 R.sup.5c; wherein said 5 to 7
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, homopiperidinyl, 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).sub.2CH.sub.3, methyl, and
methoxy; R.sup.11, at each occurrence, is independently selected
from H, NR.sup.18R.sup.19, CF.sub.3; C.sub.1-C.sub.6 alkyl
substituted with 0-1 R.sup.11a; phenyl substituted with 0-3
R.sup.11b; C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.11b; or 5 to 7 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 7 membered heterocycle is substituted with 0-3 R.sup.11b;
wherein said 5 to 7 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R.sup.11a, at
each occurrence, is independently selected from H, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, phenyl substituted with 0-3 R.sup.11b;
C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b; or 5 to
7 membered heterocycle containing 1 to 4 heteroatoms selected from
nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered
heterocycle is substituted with 0-3 R.sup.11b; wherein said 5 to 7
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, and tetrazolyl; R.sup.11b, 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; W is --(CHR.sup.8).sub.p--; p is 0 or 1; R.sup.8 is H,
methyl, or ethyl; X is a bond; phenyl substituted with 0-2
R.sup.Xb; C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
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 0-1 R.sup.Xb; R.sup.Xb, 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--; Y is a bond, --V--,
--CH.sub.2--V--, --V--CH.sub.2--, or --CH.sub.2--V--CH.sub.2--; V
is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--; Z is H; C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.12; C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12; phenyl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.6 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 is phenyl substituted with 0-4
R.sup.12b; C.sub.3-C.sub.6 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.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, methyl, ethyl, methoxy, ethoxy, Cl,
F, Br, NO.sub.2, or CF.sub.3; R.sup.14, at each occurrence, is
independently selected from 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, methyl, ethyl,
propyl, butyl, phenyl, benzyl, and phenethyl; R.sup.16, at each
occurrence, is independently selected from H, OH, methyl, ethyl,
propyl, butyl, phenyl, benzyl, phenethyl,
CH.sub.3CH.sub.2C(.dbd.O)--, CH.sub.3C(.dbd.O)--,
CH.sub.3CH.sub.2OC(.dbd.O)--, CH.sub.3OC(.dbd.O)--,
CH.sub.3CH.sub.2S(.dbd.O).sub.2-- and CH.sub.3S(.dbd.O).sub.2--;
R.sup.18, at each occurrence, is independently selected from H,
methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R.sup.19, at each occurrence, is independently selected from H, OH,
methyl, ethyl, propyl, and butyl; and R.sup.20 is H, methyl, ethyl,
propyl, or butyl.
7. A compound of claim 6 of Formula (Ia) wherein: Ring B is 42Q is
C.sub.1-C.sub.4 alkyl substituted with 0-1 R.sup.1a; phenyl
substituted with 0-3 R.sup.1b; naphthyl substituted with 0-3
R.sup.1b; or 5 to 10 membered heterocycle containing 1 to 2
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 10 membered heterocycle is substituted with 0-3 R.sup.1b;
wherein said 5 to 10 membered heterocycle is selected from
pyridinyl, quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl,
thiazolyl, imidazolyl, oxazolyl, and isoxazolyl; R.sup.1a, at each
occurrence, is independently selected from H, Cl, F, Br, CF.sub.3,
and phenyl substituted with 0-3 R.sup.1b; R.sup.1b, at each
occurrence, is independently selected from H, methyl, ethyl,
OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
OCF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, --C(.dbd.O)O--R.sup.1d,
--OC(.dbd.O)--R.sup.1d; C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1c; phenyl substituted with 0-3 R.sup.1f; 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.1f; R.sup.1c, at each occurrence, is
independently selected from H, --C(.dbd.O)--R.sup.1d,
--O--R.sup.1d, --S--R.sup.1d, --S(.dbd.O)--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d, and
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, R.sup.1d, at each
occurrence, is independently selected from H, C.sub.1-C.sub.6
alkyl; and phenyl substituted with 0-3 R.sup.1f; R.sup.1f, at each
occurrence, is independently selected from H, Cl, F, Br, NO.sub.2,
CF.sub.3, --OCF.sub.3, methyl, ethyl, methoxy, and ethoxy; R.sup.5
is methyl substituted with 0-1 R.sup.5b; ethyl substituted with 0-1
R.sup.5b; propyl substituted with 0-1 R.sup.5b; or butyl
substituted with 0-1 R.sup.5b; R.sup.5a is H; R.sup.5b, at each
occurrence, is independently selected from: H, methyl, ethyl, and
NR.sup.15R.sup.16; R.sup.11, at each occurrence, is independently
selected from H, NR.sup.18R.sup.19, CF.sub.3; C.sub.1-C.sub.4 alkyl
substituted with 0-1 R.sup.11a; phenyl substituted with 0-3
R.sup.11b; C.sub.3-C.sub.6 carbocycle substituted with 0-3
R.sup.11b; or 5 to 7 membered heterocycle containing 1 to 4
heteroatoms selected from nitrogen, oxygen, and sulphur, wherein
said 5 to 7 membered heterocycle is substituted with 0-3 R.sup.11b;
wherein said 5 to 7 membered heterocycle is selected from
pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R.sup.11a, at
each occurrence, is independently selected from H, methyl, ethyl,
propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR.sup.15R.sup.16,
CF.sub.3; phenyl substituted with 0-3 R.sup.11b; C.sub.3-C.sub.6
carbocycle substituted with 0-3 R.sup.11b; or 5 to 7 membered
heterocycle containing 1 to 4 heteroatoms selected from nitrogen,
oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is
substituted with 0-3 R.sup.11b; wherein said 5 to 7 membered
heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl,
furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl,
homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and
tetrazolyl; 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, methoxy, and ethoxy; W is a bond, --CH.sub.2--, or
--CH(CH.sub.3)--; X is a bond; phenyl substituted with 0-1
R.sup.Xb; C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms
selected from nitrogen, oxygen, and sulphur; wherein said 5 to 6
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; Y is
a bond, --V--, --CH.sub.2--V--, or --V--CH.sub.2--; V is a bond,
--C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--N(R.sup.19)--, --C(.dbd.O)NH--, or --NHC(.dbd.O)--; Z is H;
C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.12;
C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12; phenyl
substituted with 0-4 R.sup.12b; C.sub.3-C.sub.6 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 is phenyl substituted with 0-4
R.sup.12b; C.sub.3-C.sub.6 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.12b, at each occurrence, is independently selected
from H, OH, Cl, F, Br, NR.sup.15R.sup.16, CF.sub.3, OCF.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,
methyl, methoxy, Cl, F, Br, and CF.sub.3; R.sup.14, at each
occurrence, is independently selected from H, phenyl, benzyl,
methyl, ethyl, propyl, and butyl; R.sup.15, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, or butyl;
R.sup.16, at each occurrence, is independently selected from H, OH,
methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
(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--, 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.su- b.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--,(cyclo-
propyl)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--; R.sup.11, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, butyl,
phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl,
cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl,
4-CH.sub.3-phenyl, 4-CF.sub.3-phenyl, 4-CH.sub.3O-phenyl,
4-CF.sub.3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH.sub.3-phenyl,
3-CF.sub.3-phenyl, 3-CH.sub.3O-phenyl, 3-CF.sub.3O-phenyl,
2-F-phenyl, 2-Cl-phenyl, 2-CH.sub.3-phenyl, 2-CF.sub.3-phenyl,
2-CH.sub.3O-phenyl, 2-CF.sub.3O-phenyl, (4-F-phenyl)methyl-,
(4-Cl-phenyl)methyl-, (4-CH.sub.3-phenyl)methyl-,
(4-CF.sub.3-phenyl)methyl-, (4-CH.sub.3O-phenyl)methyl-,
(4-CF.sub.3O-phenyl)methyl-, (3-F-phenyl)methyl-,
(3-Cl-phenyl)methyl-, (3-CH.sub.3-phenyl)methyl-,
(3-CF.sub.3-phenyl)methyl-, (3-CH.sub.3O-phenyl)methyl-,
(3-CF.sub.3O-phenyl)methyl-, (2-F-phenyl)methyl-,
(2-Cl-phenyl)methyl-, (2-CH.sub.3-phenyl)methyl-,
(2-CF.sub.3-phenyl)methyl-, (2-CH.sub.3O-phenyl)methyl-,
(2-CF.sub.3O-phenyl)methyl-, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,
1-piperidinyl, 1-homopiperidinyl, and 1-morpholino; and R.sup.13,
at each occurrence, is independently selected from H, F, Cl, and
methoxy.
9. A compound of claim 7 wherein: Q is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, phenyl-, 2-F-phenyl-, 2-Cl-phenyl-,
2-Br-phenyl-, 2-NO.sub.2-phenyl-, 2-CH.sub.3-phenyl-,
2-CH.sub.3CH.sub.2-phenyl-, 2-CH.sub.3O-phenyl-,
2-CF.sub.3-phenyl-, 2-CF.sub.3O-phenyl-, 2-CH.sub.3CONH-phenyl, or
3,5-dimethyl-isoxazol-4-yl- -; 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,
W is a bond, --CH.sub.2--, or --CH(CH.sub.3)--; X is a bond; 43Y is
a bond, --CH.sub.2--V--, --V--, or --V--CH.sub.2--; V is a bond,
--C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--,
--NH--, --N(CH.sub.3)--, --C(.dbd.O)NH--, or --NHC(.dbd.O)--, Z is
H, --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,
--C(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,
--CH.sub.2C(CH.sub.3).sub.3, --C(CH.sub.3).sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)CH.- sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.2CH.sub- .3).sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.3, --CH(CH.sub.2CH.sub.3)CH.s-
ub.2CH.sub.2CH.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.sub.2CH.sub.2CH.sub.2CH.sub.2CF.sub.3, cyclopropyl-,
(cyclopropyl)CH.sub.2--, (cyclopropyl)CH.sub.2CH.sub.2--,
cyclobutyl-, (cyclobutyl)CH.sub.2--,
(cyclobutyl)CH.sub.2CH.sub.2--, cyclopentyl-,
(cyclopentyl)CH.sub.2--, (cyclopentyl)CH.sub.2CH.sub.2--,
cyclohexyl-, (cyclohexyl)CH.sub.2--,
(cyclohexyl)CH.sub.2CH.sub.2--, 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, morpholino, N-piperidinyl, 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-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--,
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.su- b.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--; R.sup.11, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, butyl,
phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl,
cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl,
4-CH.sub.3-phenyl, 4-CF.sub.3-phenyl, 4-CH.sub.3O-phenyl,
4-CF.sub.3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH.sub.3-phenyl,
3-CF.sub.3-phenyl, 3-CH.sub.3O-phenyl, 3-CF.sub.3O-phenyl,
2-F-phenyl, 2-Cl-phenyl, 2-CH.sub.3-phenyl, 2-CF.sub.3-phenyl,
2-CH.sub.3O-phenyl, 2-CF.sub.3O-phenyl, (4-F-phenyl)methyl-,
(4-Cl-phenyl)methyl-, (4-CH.sub.3-phenyl) methyl-,
(4CF.sub.3-phenyl) methyl-, (4-CH.sub.3O-phenyl)methyl-,
(4-CF.sub.3O-phenyl)methyl-, (3-F-phenyl)methyl-,
(3-Cl-phenyl)methyl-, (3-CH.sub.3-phenyl)methyl-,
(3-CF.sub.3-phenyl)methyl-, (3-CH.sub.3O-phenyl)methyl-,
(3-CF.sub.3O-phenyl)methyl-, (2-F-phenyl)methyl-,
(2-Cl-phenyl)methyl-, (2-CH.sub.3-phenyl)methyl-,
(2-CF.sub.3-phenyl)methyl-, (2-CH.sub.3O-phenyl)methyl-,
(2-CF.sub.3O-phenyl)methyl-, 2-pyridyl-, 3-pyridyl-, 4-pyridyl-,
1-piperidinyl, 1-homopiperidinyl, and 1-morpholino; and R.sup.13,
at each occurrence, is independently selected from H, F, Cl, and
methoxy.
10. A compound, according to claim 1, of Formula (Ic); 44or a
pharmaceutically acceptable salt form or prodrug thereof.
11. A compound, according to claim 1, of Formula (Id); 45or a
pharmaceutically acceptable salt form or prodrug thereof.
12. A compound, according to claim 1, of Formula (Ia): 46or a
pharmaceutically acceptable salt or prodrug thereof.
13. A compound of claim 1 wherein R.sup.5 is OR.sup.14.
14. A compound of claim 1 wherein R.sup.5 is C.sub.1-C.sub.4 alkoxy
substituted with 0-3 R.sup.5b.
15. A compound selected from:
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4- -methyl-pentanoic
acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,-
4]diazepin-3-yl)-amide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-me-
thyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamid-
e;
2-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(naphthalene-1-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(5-dimethylamino
naphthalene-1-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(naphthalene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
2-(2-acetamido-4-methylthiazole-5-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(thiophene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(quinoline-8-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(phenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-pheny-
l-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(2,5-dichlorophenyl sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihyd-
ro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(mesitylene-2-sulfonylamino)-4-- methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4-
]diazepin-3-yl)-amide;
2-(3-nitrophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide; 2-(4-bromophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-fluorophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-chlorophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-acetamidophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-nitrophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-methoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-tert-butylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(p-toluene-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(benzyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-pheny-
l-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide;
2-(beta-styrene-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-((2-methoxycarbonyl)phenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
2-(2-nitro-4-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
2-(3-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(2,5-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(2-methylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(3,4-dichlorophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-(trifluoromethoxy)phenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(3,4-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(2-bromophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
2-(3,5-bis(trifluoromethyl)phenyl-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide; 2-(4-ethylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-isopropylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(2,5-dichlorothiophene-3-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(2-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(3-methylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(2,3-dichlorothiophene-5-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 2-(4-bromo-5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
2-(5-[(benzoylamino)methyl]-thiophene-2-sulfonylamino)-4-methyl-pentanoi-
c acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-
-amide;
2-(4-phenylsulfonylthiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
2-(5-(phenylsulfonyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
2-[2-(1-methyl-(5-trifluoromethyl)pyrazole)thiophene-5-sulfonylamin-
o]-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e-
][1,4]diazepin-3-yl)-amide;
2-(5-(2-pyridyl)thiophene-2-sulfonylamino)-4-m- ethyl-pentanoic
acid (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-
diazepin-3-yl)-amide;
2-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methy- l-pentanoic
acid [5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[-
e][1,4]diazepin-3-yl]-amide;
N-[1-(3'-Chloro-4'-fluoro-biphenyl-3-ylmethyl-
)-2-oxo-azepan-3-yl]-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionami-
de;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[5-(4-fluoro-phenyl)-1-me-
thyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
2-(2-fluoro-benzenesulfonylamino)-N-[5-(4-fluoro-phenyl)-1-methyl-2-oxo-2-
,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-(-
2-trifluoromethyl-benzenesulfonylamino)-propionamide;
2-(2-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 4-methyl-2-(2-trifluoromethyl-benzenesulfonylamino)-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
; 4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[1-methyl-2-oxo-5-(4-triflu-
oromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
(7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3--
yl)-amide; 4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid
[5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl]-amide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl)-amide;
2-[(3,5-dimethyl-isoxazole-4-sulfonyl)-methyl-amino]-N-(1-met-
hyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide-
;
3-dimethylamino-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-methyl-2-
-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;
N-[1-methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,-
4]diazepin-3-yl]-2-(propane-1-sulfonylamino)-propionamide;
N-(7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl)-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide;
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
[5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl]-amide; and
2-methanesulfonylamino-N-[1-methyl-2-oxo-5-(4-trifluorome-
thyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide.
16. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
17. A method for the treatment of neurological disorders comprising
administering to a host in need of such treatment a therapeutically
effective amount of a compound of claim 1.
18. A method for the treatment of neurological disorders associated
with A.beta. amyloid production comprising administering to a host
in need of such treatment a therapeutically effective amount of a
compound of claim 1.
19. A method for the treatment of Alzheimer's Disease comprising
administering to a host in need of such treatment a therapeutically
effective amount of a compound of claim 1.
20. A method for the treatment of Alzheimer's Disease associated
with A.beta. amyloid production comprising administering to a host
in need of such treatment a therapeutically effective amount of a
compound of claim 1.
21. 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 claim 1 that
inhibits .gamma.-secretase activity.
Description
FIELD OF THE INVENTION
[0001] 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
[0002] 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, Dennis J. Selkoe; Cell Biology of the amyloid
(beta)-protein precursor and the mechanism of Alzheimer's disease,
Annu Rev Cell Biol, 1994, 10: 373-403).
[0003] 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).
[0004] 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.
[0005] Compelling evidence accumulated during the last decade
revealed that A.beta. is an internal polypeptide derived from a
type 1 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.
[0006] 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.
[0007] 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 AD. 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.
[0008] 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.
[0009] 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 .gamma. 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.
SUMMARY OF THE INVENTION
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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): 2
[0014] or pharmaceutically acceptable salt or prodrug forms
thereof, wherein Q, R.sup.2, R.sup.3, R.sup.5, R.sup.5a, R.sup.6,
B, W, X, Y, and Z are defined below, are effective inhibitors of
the production of A.beta..
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0015] Thus, in one embodiment, the present invention provides a
novel compound of Formula (I): 3
[0016] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0017] Q is C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1a;
[0018] C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.1a;
[0019] C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.1a;
[0020] C.sub.3-C.sub.10cycloalkyl substituted with 0-3
R.sup.1b;
[0021] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b;
[0022] C.sub.6-C.sub.10aryl substituted with 0-3 R.sup.1b; or
[0023] 5 to 10 membered heterocycle substituted with 0-3
R.sup.1b;
[0024] R.sup.1a, at each occurrence, is independently selected from
H, R.sup.1b, Cl, F, Br, I, OR.sup.14, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl; C.sub.2-C.sub.4
alkenyl; C.sub.2-C.sub.4 alkynyl; C.sub.1-C.sub.4 haloalkyl;
C.sub.1-C.sub.4 haloalkoxy;
[0025] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b;
[0026] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; and
[0027] 5 to 10 membered heterocycle substituted with 0-3
R.sup.1b;
[0028] R.sup.1b, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy;
[0029] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0030] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0031] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.1c;
[0032] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.1c;
[0033] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0034] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0035] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0036] 5 to 10 membered heterocycle substituted with 0-3
R.sup.1f;
[0037] R.sup.1c, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, NR.sup.19R.sup.20,
CF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
[0038] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0039] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0040] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0041] C.sub.6-C.sub.10aryl substituted with 0-3 R.sup.1f; and
[0042] 5 to 10 membered heterocycle substituted with 0-3
R.sup.1f;
[0043] R.sup.1d, at each occurrence, is independently selected from
H,
[0044] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1e;
[0045] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.1e;
[0046] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.1e;
[0047] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0048] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0049] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f;
[0050] 5 to 10 membered heterocycle substituted with 0-3
R.sup.1f;
[0051] R.sup.1e, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
[0052] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0053] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0054] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f;
[0055] 5 to 10 membered heterocycle substituted with 0-3
R.sup.1f;
[0056] R.sup.1f, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
haloalkoxy;
[0057] R.sup.2 is H, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6
alkoxy) C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 carbocycle,
C.sub.6-C.sub.10 aryl, (C.sub.3-C.sub.6 carbocycle)methyl,
(C.sub.6-C.sub.10 aryl)methyl, (C.sub.6-C.sub.10 aryl)ethyl, or 5
to 10 membered heterocycle;
[0058] R.sup.5 is H, OH, OR.sup.14;
[0059] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b;
[0060] C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b;
[0061] C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
[0062] C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
[0063] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.5c;
[0064] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.5c;
[0065] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or
[0066] 5 to 10 membered heterocycle substituted with
0-3R.sup.5c;
[0067] 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;
[0068] alternatively, R.sup.5 and R.sup.5a may be combined to form
.dbd.R.sup.5;
[0069] alternatively, R.sup.5 and R.sup.5a may be combined to form
a 3-7 membered cycloalkyl ring substituted with 0-3 R.sup.5c;
[0070] optionally the cycloalkyl ring formed by combining R.sup.5
and R.sup.5a may be benzo fused, wherein the benzo fused ring may
be substituted with 0-3 R.sup.5c;
[0071] R.sup.5b, at each occurrence, is independently selected
from:
[0072] 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;
[0073] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.5c;
[0074] C.sub.3-C.sub.10carbocycle substituted with 0-3
R.sup.5c;
[0075] C.sub.6-C.sub.10aryl substituted with 0-3 R.sup.5c; and
[0076] 5 to 10 membered heterocycle 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,
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
halothioalkoxy;
[0078] R.sup.6 is H;
[0079] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.6a;
[0080] C.sub.3-C.sub.10carbocycle substituted with 0-3 R.sup.6b;
or
[0081] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.6b;
[0082] 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;
[0083] 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;
[0084] Ring B is a 5 to 10 membered lactam,
[0085] wherein the lactam is saturated, partially saturated or
unsaturated;
[0086] wherein each additional lactam carbon is substituted with
0-2 R.sup.11; and,
[0087] optionally, the lactam contains a heteroatom selected from
--N--, --NH--, --N(R.sup.10)--, --O--, --S--, --S(.dbd.O)--, and
--S(.dbd.O).sub.2--;
[0088] additionally, two R.sup.11 substituents on adjacent atoms
may be combined to form C.sub.3-C.sub.6 carbocycle fused radical, a
benzo fused radical, or a 5 to 6 membered heteroaryl fused
radical,
[0089] wherein said 5 to 6 membered heteroaryl fused radical
comprises 1-2 heteroatoms selected from N, O, and S;
[0090] wherein said benzo fused radical or 5 to 6 membered
heteroaryl fused radical is substituted with 0-3 R.sup.13;
[0091] 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, S(.dbd.O).sub.2NR.sup.18R.sup.19,
S(.dbd.O).sub.2R.sup.17;
[0092] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.10a;
[0093] C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.10b;
[0094] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.10b;
or
[0095] 5 to 10 membered heterocycle optionally substituted with 0-3
R.sup.10b;
[0096] 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;
[0097] 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
halothioalkoxy;
[0098] R.sup.11, at each occurrence, is independently selected
from
[0099] 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;
[0100] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
[0101] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
[0102] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0103] 5 to 10 membered heterocycle substituted with 0-3
R.sup.11b;
[0104] 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;
[0105] 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 halothioalkoxy;
[0106] W is --(CR.sup.8R.sup.8a).sub.p--;
[0107] p is 0, 1, 2, 3, or 4;
[0108] R.sup.8 and R.sup.8a, at each occurrence, are independently
selected from H, F, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl and C.sub.3-C.sub.8 cycloalkyl;
[0109] X is a bond;
[0110] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.Xb;
[0111] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.Xb;
[0112] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.Xb;
or
[0113] 5 to 10 membered heterocycle substituted with 0-2
R.sup.Xb;
[0114] R.sup.Xb, 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
halothioalkoxy;
[0115] Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).su- b.u--;
[0116] t is 0, 1, 2, or 3;
[0117] u is 0, 1, 2, or 3;
[0118] R.sup.9 and R.sup.9a, at each occurrence, are independently
selected from H, F, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.8
cycloalkyl;
[0119] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NR.sup.19b--,
NR.sup.19bC(.dbd.O)--, --NR.sup.19bS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.19b--, --NR.sup.19bS(.dbd.O)--,
--S(.dbd.O)NR.sup.19b--, --C(.dbd.O)O--, or --OC(.dbd.O)--;
[0120] Z is H;
[0121] C.sub.1-C.sub.8 alkyl substituted with 0-2 R.sup.12;
[0122] C.sub.2-C.sub.4 alkenyl substituted with 0-2 R.sup.12;
[0123] C.sub.2-C.sub.4 alkynyl substituted with 0-2 R.sup.12;
[0124] C.sub.6-C.sub.10aryl substituted with 0-4 R.sup.12b;
[0125] C.sub.3-C.sub.10 carbocycle substituted with 0-4 R.sup.12b;
or
[0126] 5 to 10 membered heterocycle substituted with 0-3
R.sup.12b;
[0127] R.sup.12 is C.sub.6-C.sub.10aryl substituted with 0-4
R.sup.12b;
[0128] C.sub.3-C.sub.10 carbocycle substituted with 0-4 R.sup.12b;
or
[0129] 5 to 10 membered heterocycle substituted with 0-3
R.sup.12b;
[0130] 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 halothioalkoxy;
[0131] 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, or CF.sub.3;
[0132] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl;
[0133] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0134] R.sup.16, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0135] R.sup.17 is H, aryl, aryl-CH.sub.2--, C.sub.1-C.sub.6 alkyl,
or C.sub.2-C.sub.6 alkoxyalkyl;
[0136] R.sup.18, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0137] R.sup.19, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0138] R.sup.19b, at each occurrence, is independently selected
from H, C.sub.1-C.sub.4 alkyl, phenyl, benzyl, and phenethyl;
and
[0139] R.sup.20 and R.sup.21, at each occurrence, are independently
selected from H, C.sub.1-C.sub.4 alkyl, aryl, and
aryl(C.sub.1-C.sub.2 alkyl)-.
[0140] [1] In another embodiment, the present invention provides a
novel compound of Formula (I): 4
[0141] or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0142] Q is C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1a;
[0143] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1b;
[0144] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b;
[0145] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; or
[0146] 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;
[0147] R.sup.1a, at each occurrence, is independently selected from
H, R.sup.1b, Cl, F, Br, I, OR.sup.14, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl; C.sub.2-C.sub.4
alkenyl; C.sub.2-C.sub.4 alkynyl; C.sub.1-C.sub.4 haloalkyl;
C.sub.1-C.sub.4 haloalkoxy;
[0148] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b;
[0149] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; and
[0150] 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;
[0151] R.sup.1b, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy;
[0152] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0153] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0154] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.1c;
[0155] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.1c;
[0156] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0157] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0158] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0159] 5 to 14 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14
membered heterocycle is substituted with 0-3 R.sup.1f;
[0160] R.sup.1c, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, NR.sup.19R.sup.20,
CF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
[0161] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0162] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0163] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0164] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0165] 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.1f;
[0166] R.sup.1d, at each occurrence, is independently selected from
H,
[0167] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1e;
[0168] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.1e;
[0169] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.1e;
[0170] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0171] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0172] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0173] 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.1f;
[0174] R.sup.1e, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
[0175] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0176] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0177] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0178] 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.1f;
[0179] R.sup.1f, at each occurrence, is independently selected from
H, OR.sup.14, SR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--;
[0180] R.sup.2 is H, C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6
alkoxy) C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 carbocycle,
C.sub.6-C.sub.10 aryl, (C.sub.3-C.sub.6 carbocycle)methyl,
(C.sub.6-C.sub.10 aryl)methyl, (C.sub.6-C.sub.10 aryl)ethyl, or 5
to 10 membered heterocycle;
[0181] R.sup.5 is H, OR.sup.14;
[0182] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b;
[0183] C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b;
[0184] C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
[0185] C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
[0186] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.5c;
[0187] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.5c;
[0188] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or
[0189] 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;
[0190] R.sup.5a is H or C.sub.1-C.sub.4 alkyl;
[0191] R.sup.5b, at each occurrence, is independently selected
from:
[0192] 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; acetyl,
--S(C.sub.1-C.sub.4 alkyl), --S(.dbd.O)(C.sub.1-C.sub.4 alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.s- ub.4 alkyl);
[0193] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.5c;
[0194] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.5c;
[0195] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; and
[0196] 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;
[0197] 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--;
[0198] R.sup.6 is H;
[0199] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.6a;
[0200] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.6b;
or
[0201] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.6b;
[0202] 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;
[0203] 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;
[0204] Ring B is a 6, 7, or 8 membered lactam,
[0205] wherein the lactam is saturated, partially saturated or
unsaturated;
[0206] wherein each additional lactam carbon is substituted with
0-2 R.sup.11; and,
[0207] optionally, the lactam contains a heteroatom selected from
--N.dbd., --NH--, --N(R.sup.10)--, --O--, --S--, --S(.dbd.O)--, and
--S(.dbd.O).sub.2--;
[0208] additionally, two R.sup.11 substituents on adjacent atoms
may be combined to form C.sub.3-C.sub.6 carbocycle fused radical, a
benzo fused radical, or a 5 to 6 membered heteroaryl fused
radical,
[0209] wherein said 5 to 6 membered heteroaryl fused radical
comprises 1-2 heteroatoms selected from N, O, and S;
[0210] wherein said benzo fused radical or 5 to 6 membered
heteroaryl fused radical is substituted with 0-3 R.sup.13;
[0211] 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, S(.dbd.O).sub.2NR.sup.18R.sup.19,
S(.dbd.O).sub.2R.sup.17;
[0212] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.10a;
[0213] C.sub.6-C.sub.10aryl substituted with 0-4 R.sup.10b;
[0214] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.10b;
or
[0215] 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;
[0216] 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;
[0217] 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--;
[0218] R.sup.11, at each occurrence, is independently selected
from
[0219] 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;
[0220] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
[0221] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
[0222] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0223] 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;
[0224] 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;
[0225] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0226] 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;
[0227] 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--;
[0228] W is --(CR.sup.8R.sup.8a).sub.p--;
[0229] p is 0, 1, 2, 3, or 4;
[0230] R.sup.8 and R.sup.8a, at each occurrence, are independently
selected from H, F, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl and C.sub.3-C.sub.8 cycloalkyl;
[0231] X is a bond;
[0232] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.Xb;
[0233] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.Xb;
[0234] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.Xb;
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.Xb;
[0236] R.sup.Xb, 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--;
[0237] Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).su- b.u--;
[0238] t is 0, 1, 2, or 3;
[0239] u is 0, 1, 2, or 3;
[0240] R.sup.9 and R.sup.9a, at each occurrence, are independently
selected from H, F, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.8
cycloalkyl;
[0241] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NR.sup.19b--,
--NR.sup.19bC(.dbd.O)--, --NR.sup.19bS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.19b--, --NR.sup.19bS(.dbd.O)--,
--S(.dbd.O)NR.sup.19b--, --C(.dbd.O)O--, or --OC(.dbd.O)--;
[0242] Z is H;
[0243] C.sub.1-C.sub.8 alkyl substituted with 0-2 R.sup.12;
[0244] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
[0245] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
[0246] C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.12b;
[0247] C.sub.3-C.sub.10 carbocycle substituted with 0-4 R.sup.12b;
or
[0248] 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;
[0249] R.sup.12 is C.sub.6-C.sub.10 aryl substituted with 0-4
R.sup.12b;
[0250] C.sub.3-C.sub.10 carbocycle substituted with 0-4 R.sup.12b;
or
[0251] 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;
[0252] 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--;
[0253] 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, or CF.sub.3;
[0254] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl;
[0255] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0256] R.sup.16, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0257] alternatively, --NR.sup.15R.sup.16 may be a heterocyclic
ring selected from the group piperidinyl, morpholinyl,
thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and
N-methylpiperizinyl;
[0258] R.sup.17 is H, aryl, aryl-CH.sub.2--, C.sub.1-C.sub.6 alkyl,
or C.sub.2-C.sub.6 alkoxyalkyl;
[0259] R.sup.18, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0260] R.sup.19, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0261] R.sup.19b, at each occurrence, is independently selected
from H, C.sub.1-C.sub.4 alkyl, phenyl, benzyl, and phenethyl;
and
[0262] R.sup.20 and R.sup.21, at each occurrence, are independently
selected from H, C.sub.1-C.sub.4 alkyl, aryl, and
aryl(C.sub.1-C.sub.2 alkyl)-;
[0263] provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl,
or octyl; R.sup.2 is H; R.sup.5 is methyl, and -WXYZ is methyl,
then Ring B is not 5
[0264] wherein R.sup.13 is H.
[0265] [2] In an alternative embodiment of the present invention of
of Formula (I),
[0266] Q is C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1a;
[0267] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1b;
[0268] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b;
[0269] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; or
[0270] 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;
[0271] R.sup.1a, at each occurrence, is independently selected from
H, R.sup.1b, Cl, F, Br, NR.sup.19R.sup.20, CF.sub.3,
C.sub.1-C.sub.4 alkyl,
[0272] C.sub.1-C.sub.4 haloalkyl;
[0273] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1b;
[0274] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; and
[0275] 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;
[0276] R.sup.1b, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
OCF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
[0277] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0278] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0279] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0280] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0281] 5 to 14 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14
membered heterocycle is substituted with 0-3 R.sup.1f;
[0282] R.sup.1c, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0283] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0284] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0285] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0286] 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.1f;
[0287] R.sup.1d, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, and C.sub.6-C.sub.10 aryl substituted
with 0-3 R.sup.1f;
[0288] R.sup.1f, at each occurrence, is independently selected from
H, OR.sup.14, SR.sup.14, Cl, F, Br, I, CN, NO.sub.2, .dbd.O,
NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--;
[0289] R.sup.2 is H or C.sub.1-C.sub.6 alkyl;
[0290] R.sup.5 is H, OR.sup.14;
[0291] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b;
[0292] C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b;
[0293] C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
or
[0294] C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
[0295] R.sup.5a is H or C.sub.1-C.sub.4 alkyl;
[0296] R.sup.5b, at each occurrence, is independently selected
from:
[0297] 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; acetyl, S(C.sub.1-C.sub.4
alkyl), S(.dbd.O)(C.sub.1-C.sub.4 alkyl),
S(.dbd.O).sub.2(C.sub.1-C.sub.4 alkyl),
[0298] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.5c;
[0299] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.5c;
[0300] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or
[0301] 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;
[0302] 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--;
[0303] R.sup.6 is H, methyl, or ethyl;
[0304] Ring B is a seven membered lactam,
[0305] wherein the lactam is saturated, partially saturated or
unsaturated;
[0306] wherein each additional lactam carbon is substituted with
0-2 R.sup.11; and,
[0307] optionally, the lactam contains a heteroatom selected from
--N.dbd., --NH--, --N(R.sup.10)--, --O--, --S--, --S(.dbd.O)--, and
--S(.dbd.O).sub.2--;
[0308] additionally, two R.sup.11 substituents on adjacent atoms
may be combined to form C.sub.3-C.sub.6 carbocycle fused radical, a
benzo fused radical, or a 5 to 6 membered heteroaryl fused
radical,
[0309] wherein said 5 to 6 membered heteroaryl fused radical
comprises 1-2 heteroatoms selected from N, O, and S;
[0310] wherein said benzo fused radical or 5 to 6 membered
heteroaryl fused radical is substituted with 0-3 R.sup.13;
[0311] 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, S(.dbd.O).sub.2NR.sup.18R.sup.19,
S(.dbd.O).sub.2R.sup.17;
[0312] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.10a;
[0313] C.sub.6-C.sub.10 aryl substituted with 0-4 R.sup.10b;
[0314] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.10b;
or
[0315] 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;
[0316] 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;
[0317] 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--;
[0318] R.sup.11, at each occurrence, is independently selected
from
[0319] 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;
[0320] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
[0321] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
[0322] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0323] 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;
[0324] 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;
[0325] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0326] 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;
[0327] 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--;
[0328] W is --(CR.sup.8R.sup.8a).sub.p--;
[0329] p is 0, 1, or 2;
[0330] R.sup.8 and R.sup.8a, at each occurrence, are independently
selected from H, F, methyl, and ethyl;
[0331] X is a bond;
[0332] phenyl substituted with 0-3 R.sup.Xb;
[0333] C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
or
[0334] 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 0-2 R.sup.Xb;
[0335] R.sup.Xb, 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--;
[0336] Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).su- b.u--;
[0337] t is 0, 1, or 2;
[0338] u is 0, 1, or 2;
[0339] R.sup.9 and R.sup.9a, at each occurrence, are independently
selected from H, F, methyl, and ethyl;
[0340] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --NHC(.dbd.O)--, or
--C(.dbd.O)NH--;
[0341] Z is H;
[0342] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.12;
[0343] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
[0344] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
[0345] phenyl substituted with 0-4 R.sup.12b;
[0346] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0347] 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;
[0348] R.sup.12 is phenyl substituted with 0-4 R.sup.12b;
[0349] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0350] 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;
[0351] 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--;
[0352] R.sup.13, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.4 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;
[0353] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, and C.sub.2-C.sub.6
alkoxyalkyl;
[0354] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0355] R.sup.16, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0356] alternatively, --NR.sup.15R.sup.16 may be a heterocyclic
ring selected from the group piperidinyl, morpholinyl,
thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and
N-methylpiperizinyl;
[0357] R.sup.17 is H, aryl, aryl-CH.sub.2--, C.sub.1-C.sub.6 alkyl,
or C.sub.2-C.sub.6 alkoxyalkyl;
[0358] R.sup.18, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0359] R.sup.19, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); and
[0360] R.sup.20 is H or C.sub.1-C.sub.4;
[0361] provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl,
or octyl; R.sup.2 is H; R.sup.5 is methyl, and -WXYZ is methyl,
then Ring B is not 6
[0362] wherein R.sup.13 is H.
[0363] [3] In another alterantive embodiment of the present
invention of of Formula (I),
[0364] Ring B is selected from: 7
[0365] wherein each benzo fused radical is substituted with 0-3
R.sup.13.
[0366] [4] In another alternative embodiment of the present
invention of of Formula (I),
[0367] Q is C.sub.1-C.sub.6 alkyl substituted with 0-3
R.sup.1a;
[0368] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1b;
[0369] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; or
[0370] 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;
[0371] R.sup.1a, at each occurrence, is independently selected from
H, Cl, F, Br, NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl;
C.sub.1-C.sub.4 haloalkyl;
[0372] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; and
[0373] 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;
[0374] R.sup.1b, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
OCF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
[0375] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bs(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0376] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0377] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0378] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0379] 5 to 14 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14
membered heterocycle is substituted with 0-3 R.sup.1f;
[0380] R.sup.1c, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, --OC(.dbd.O)--R.sup.1d;
[0381] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.1f;
[0382] C.sub.3-C.sub.10 carbocycle substituted with 0-3
R.sup.1f;
[0383] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0384] 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.1f;
[0385] R.sup.1d, at each occurrence, is independently selected
from
[0386] H, C.sub.1-C.sub.6 alkyl, and
[0387] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f;
[0388] R.sup.1f, at each occurrence, is independently selected from
H, Cl, F, Br, NO.sub.2, CF.sub.3, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy, and C.sub.1-C.sub.4 haloalkyl-S--;
[0389] R.sup.2 is H, methyl, or ethyl;
[0390] R.sup.5 is OR.sup.14;
[0391] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.5b;
[0392] C.sub.1-C.sub.6 alkoxy substituted with 0-3 R.sup.5b;
[0393] C.sub.2-C.sub.6 alkenyl substituted with 0-3 R.sup.5b;
or
[0394] C.sub.2-C.sub.6 alkynyl substituted with 0-3 R.sup.5b;
[0395] R.sup.5a is H or C.sub.1-C.sub.4 alkyl;
[0396] R.sup.5b, at each occurrence, is independently selected
from:
[0397] 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, acetyl,
--S(C.sub.1-C.sub.4 alkyl), S(.dbd.O)(C.sub.1-C.sub.4 alkyl),
S(.dbd.O).sub.2(C.sub.1-C.sub.4 alkyl);
[0398] C.sub.3-C.sub.10 cycloalkyl substituted with 0-3
R.sup.5c;
[0399] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.5c; or
[0400] 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;
[0401] 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--;
[0402] R.sup.6 is H;
[0403] Ring B is selected from: 8
[0404] R.sup.11, at each occurrence, is independently selected
from
[0405] 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;
[0406] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
[0407] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.11b;
[0408] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0409] 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;
[0410] 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, phenyl substituted with 0-3
R.sup.11b;
[0411] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0412] 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;
[0413] 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--;
[0414] W is --(CR.sup.8R.sup.8a).sub.p--;
[0415] p is 0, 1, or 2;
[0416] R.sup.8 and R.sup.8a, at each occurrence, are independently
selected from H, F, methyl, and ethyl;
[0417] X is a bond;
[0418] phenyl substituted with 0-3 R.sup.Xb;
[0419] C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
or
[0420] 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 0-2 R.sup.Xb;
[0421] R.sup.Xb, 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--;
[0422] Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).su- b.u--;
[0423] t is 0, 1, or 2;
[0424] u is 0, 1, or 2;
[0425] R.sup.9 and R.sup.9a, at each occurrence, are independently
selected from H, F, methyl, and ethyl;
[0426] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--;
[0427] Z is H;
[0428] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.12;
[0429] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
[0430] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
[0431] phenyl substituted with 0-4 R.sup.12b;
[0432] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0433] 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;
[0434] R.sup.12 is phenyl substituted with 0-4 R.sup.12b;
[0435] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0436] 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;
[0437] 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--;
[0438] R.sup.13, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, Cl, F, Br,
CN, NO.sub.2, and CF.sub.3;
[0439] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6
alkoxyalkyl;
[0440] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0441] R.sup.16, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0442] alternatively, --NR.sup.15R.sup.16 may be a heterocyclic
ring selected from the group piperidinyl, morpholinyl,
thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and
N-methylpiperizinyl;
[0443] R.sup.17 is H, aryl, aryl-CH.sub.2--, C.sub.1-C.sub.6 alkyl,
or C.sub.2-C.sub.6 alkoxyalkyl;
[0444] R.sup.18, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0445] R.sup.19, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl); and
[0446] R.sup.20 is H or C.sub.1-C.sub.4;
[0447] provided that when Q is phenyl, 3-F-phenyl, benzyl, propyl,
or octyl; R.sup.2 is H; R.sup.5 is methyl, and -WXYZ is methyl,
then Ring B is not 9
[0448] wherein R.sup.13 is H.
[0449] [5] In another alternative embodiment of the present
invention of of Formula (I),
[0450] Ring B is 10
[0451] Q is C.sub.1-C.sub.6 alkyl substituted with 0-2
R.sup.1a;
[0452] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1b; or
[0453] 5 to 10 membered heterocycle containing 1 to 3 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.1b;
[0454] R.sup.1a, at each occurrence, is independently selected from
H, Cl, F, Br, NR.sup.19R.sup.20, CF.sub.3, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and phenyl substituted with 0-3
R.sup.1b;
[0455] R.sup.1b, at each occurrence, is independently selected from
H, OR.sup.14, Cl, F, Br, NO.sub.2, NR.sup.19R.sup.20, CF.sub.3,
OCF.sub.3, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy;
--C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d--C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, --C(.dbd.O)O--R.sup.1d,
--OC(.dbd.O)--R.sup.1d;
[0456] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0457] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f; and
[0458] 5 to 14 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 14
membered heterocycle is substituted with 0-3 R.sup.1f;
[0459] R.sup.1c, at each occurrence, is independently selected from
H, --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
--NR.sup.19bS(.dbd.O)--R.sup.1d, --S(.dbd.O)NR.sup.19b--R.sup.1d,
--C(.dbd.O)O--R.sup.1d, and --OC(.dbd.O)--R.sup.1d;
[0460] R.sup.1d, at each occurrence, is independently selected
from
[0461] H, C.sub.1-C.sub.6 alkyl, and
[0462] C.sub.6-C.sub.10 aryl substituted with 0-3 R.sup.1f;
[0463] R.sup.1f, at each occurrence, is independently selected from
H, Cl, F, Br, NO.sub.2, CF.sub.3, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy, and C.sub.1-C.sub.4 haloalkyl-S--;
[0464] R.sup.5 is OR.sup.14;
[0465] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.5b;
[0466] C.sub.2-C.sub.6 alkenyl substituted with 0-1 R.sup.5b;
or
[0467] C.sub.2-C.sub.6 alkynyl substituted with 0-1 R.sup.5b;
[0468] R.sup.5a is H or C.sub.1-C.sub.4 alkyl;
[0469] R.sup.5b, at each occurrence, is independently selected
from:
[0470] H, methyl, ethyl, propyl, butyl, CF.sub.3, OR.sup.14, Cl, F,
Br, I, .dbd.O, CN, NO.sub.2, NR.sup.15R.sup.16; acetyl,
--S(C.sub.1-C.sub.4 alkyl), --S(.dbd.O)(C.sub.1-C.sub.4 alkyl),
--S(.dbd.O).sub.2(C.sub.1-C.s- ub.4 alkyl),
[0471] C.sub.3-C.sub.7 cycloalkyl substituted with 0-3
R.sup.5c;
[0472] phenyl substituted with 0-3 R.sup.5c; and
[0473] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.5c;
[0474] 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).sub.2CH.sub.3, methyl, ethyl, propyl, butyl, metrhoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy;
[0475] R.sup.11, at each occurrence, is independently selected
from
[0476] H, --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;
[0477] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
[0478] phenyl substituted with 0-3 R.sup.11b;
[0479] C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b;
or
[0480] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.11b;
[0481] R.sup.11a, at each occurrence, is independently selected
from H, C.sub.1-C.sub.4 alkyl, OR.sup.14, Cl, F, Br, CN, NO.sub.2,
NR.sup.15R.sup.16, CF.sub.3, phenyl substituted with 0-3
R.sup.11b;
[0482] C.sub.3-C.sub.10 carbocycle substituted with 0-3 R.sup.11b;
or
[0483] 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;
[0484] 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, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.1-C.sub.4 haloalkyl-S--;
[0485] W is --(CR.sup.8R.sup.8a).sub.p--;
[0486] p is 0, 1, or 2;
[0487] R.sup.8 and R.sup.8a, at each occurrence, are independently
selected from H, F, methyl, and ethyl;
[0488] X is a bond;
[0489] phenyl substituted with 0-3 R.sup.Xb;
[0490] C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
or
[0491] 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 0-2 R.sup.Xb;
[0492] R.sup.Xb, 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--;
[0493] Y is a bond or
--(CR.sup.9R.sup.9a).sub.t--V--(CR.sup.9R.sup.9a).su- b.u--;
[0494] t is 0, 1, or 2;
[0495] u is 0, 1, or 2;
[0496] R.sup.9 and R.sup.9a, at each occurrence, are independently
selected from H, F, methyl, and ethyl;
[0497] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--;
[0498] Z is H;
[0499] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.12;
[0500] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
[0501] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
[0502] phenyl substituted with 0-4 R.sup.12b;
[0503] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0504] 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;
[0505] R.sup.12 is phenyl substituted with 0-4 R.sup.12b;
[0506] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0507] 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;
[0508] 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--;
[0509] R.sup.13, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, Cl, F, Br,
CN, NO.sub.2, and CF.sub.3;
[0510] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, C.sub.1-C.sub.6 alkyl, and C.sub.2-C.sub.6
alkoxyalkyl;
[0511] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0512] R.sup.16, at each occurrence, is independently selected from
H, OH, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0513] alternatively, --NR.sup.15R.sup.16 may be a heterocyclic
ring selected from the group piperidinyl, morpholinyl,
thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and
N-methylpiperizinyl;
[0514] R.sup.17 is H, phenyl, benzyl, C.sub.1-C.sub.4 alkyl, or
C.sub.2-C.sub.4 alkoxyalkyl;
[0515] R.sup.18, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl, phenyl, benzyl, phenethyl,
--C(.dbd.O)--(C.sub.1-C- .sub.6 alkyl) and
--S(.dbd.O).sub.2--(C.sub.1-C.sub.6 alkyl);
[0516] R.sup.19, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
and
[0517] R.sup.20 is H, methyl, ethyl, propyl, or butyl.
[0518] [6] In another alternative embodiment of the present
invention of of Formula (I),
[0519] Ring B is 11
[0520] Q is C.sub.1-C.sub.6 alkyl substituted with 0-1
R.sup.1a;
[0521] phenyl substituted with 0-3 R.sup.1b;
[0522] naphthyl substituted with 0-3 R.sup.1b; or
[0523] 5 to 10 membered heterocycle containing 1 to 2 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.1b;
[0524] R.sup.1a, at each occurrence, is independently selected
from
[0525] H, Cl, F, Br, --NR.sup.19R.sup.20, --CF.sub.3; and
[0526] phenyl substituted with 0-3 R.sup.1b;
[0527] R.sup.1b, at each occurrence, is independently selected from
H, methyl, ethyl, OR.sup.14, Cl, F, Br, NO.sub.2,
NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy;
[0528] --C(.dbd.O)--R.sup.1d, --O--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, --C(.dbd.O)O--R.sup.1d,
--OC(.dbd.O)--R.sup.1d;
[0529] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0530] phenyl substituted with 0-3 R.sup.1f; and
[0531] 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.1f;
[0532] R.sup.1c, at each occurrence, is independently selected from
H, --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d, and
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d;
[0533] R.sup.1d, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl; and phenyl substituted with 0-3
R.sup.1f;
[0534] R.sup.1f, at each occurrence, is independently selected from
H, Cl, F, Br, NO.sub.2, CF.sub.3, methyl, ethyl, propyl, methoxy,
ethoxy, propoxy, C.sub.1-C.sub.2 haloalkyl, and C.sub.1-C.sub.2
haloalkoxy;
[0535] R.sup.5 is OR.sup.14 or C.sub.1-C.sub.4 alkyl substituted
with 0-1 R.sup.5b;
[0536] R.sup.5a is H;
[0537] R.sup.5b, at each occurrence, is independently selected
from:
[0538] H, methyl, ethyl, propyl, butyl, --NR.sup.15R.sup.16;
[0539] C.sub.3-C.sub.7 cycloalkyl substituted with 0-3
R.sup.5c;
[0540] phenyl substituted with 0-3 R.sup.5c; or
[0541] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.5c; wherein said
5 to 7 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl;
[0542] 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).sub.2CH.sub.3, methyl, and methoxy;
[0543] R.sup.11, at each occurrence, is independently selected
from
[0544] H, NR.sup.18R.sup.19, CF.sub.3;
[0545] C.sub.1-C.sub.6 alkyl substituted with 0-1 R.sup.11a;
[0546] phenyl substituted with 0-3 R.sup.11b;
[0547] C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b;
or
[0548] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 7 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl;
[0549] R.sup.11a, at each occurrence, is independently selected
from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl,
F, Br, CN, NO.sub.2, NR.sup.15R.sup.16, CF.sub.3, phenyl
substituted with 0-3 R.sup.11b;
[0550] C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b;
or
[0551] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 7 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl;
[0552] R.sup.11b, 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;
[0553] W is --(CHR.sup.8).sub.p--;
[0554] p is 0 or 1;
[0555] R.sup.8 is H, methyl, or ethyl;
[0556] X is a bond;
[0557] phenyl substituted with 0-2 R.sup.Xb;
[0558] C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
or
[0559] 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 0-1 R.sup.Xb;
[0560] R.sup.Xb, 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--;
[0561] Y is a bond, --V--, --CH.sub.2--V--, --V--CH.sub.2--, or
--CH.sub.2--V--CH.sub.2--;
[0562] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--;
[0563] Z is H;
[0564] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.12;
[0565] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
[0566] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
[0567] phenyl substituted with 0-4 R.sup.12b;
[0568] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0569] 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;
[0570] R.sup.12 is phenyl substituted with 0-4 R.sup.12b;
[0571] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0572] 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;
[0573] 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--;
[0574] R.sup.13, at each occurrence, is independently selected
from
[0575] H, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, NO.sub.2, or
CF.sub.3;
[0576] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4
alkoxyalkyl;
[0577] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
[0578] R.sup.16, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,
CH.sub.3CH.sub.2C(.dbd.O)--, CH.sub.3C(.dbd.O)--,
CH.sub.3CH.sub.2OC(.dbd- .O)--, CH.sub.30C(.dbd.O)--,
CH.sub.3CH.sub.2S(.dbd.O).sub.2-- and
CH.sub.3S(.dbd.O).sub.2--;
[0579] R.sup.18, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
[0580] R.sup.19, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, and butyl; and
[0581] R.sup.20 is H, methyl, ethyl, propyl, or butyl.
[0582] [7] In another alternative embodiment of the present
invention of of Formula (I),
[0583] Ring B is 12
[0584] Q is C.sub.1-C.sub.4 alkyl substituted with 0-1
R.sup.1a;
[0585] phenyl substituted with 0-3 R.sup.1b;
[0586] naphthyl substituted with 0-3 R.sup.1b; or
[0587] 5 to 10 membered heterocycle containing 1 to 2 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10
membered heterocycle is substituted with 0-3 R.sup.1b; wherein said
5 to 10 membered heterocycle is selected from pyridinyl,
quinolinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl,
imidazolyl, oxazolyl, and isoxazolyl;
[0588] R.sup.1a, at each occurrence, is independently selected
from
[0589] H, Cl, F, Br, CF.sub.3, and
[0590] phenyl substituted with 0-3 R.sup.1b;
[0591] R.sup.1b, at each occurrence, is independently selected from
H, methyl, ethyl, OR.sup.14, Cl, F, Br, NO.sub.2,
NR.sup.19R.sup.20, CF.sub.3, OCF.sub.3, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy; --C(.dbd.O)--R.sup.1d, --O--R.sup.1d,
--S(.dbd.O).sub.2--R.sup.1d, --N(R.sup.19)--R.sup.1d,
--C(.dbd.O)NR.sup.19bR.sup.1d, --NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d,
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d, --C(.dbd.O)O--R.sup.1d,
--OC(.dbd.O)--R.sup.1d;
[0592] C.sub.1-C.sub.6 alkyl substituted with 0-3 R.sup.1c;
[0593] phenyl substituted with 0-3 R.sup.1f; and
[0594] 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.1f;
[0595] R.sup.1c, at each occurrence, is independently selected from
H, --C(.dbd.O)--R.sup.1d, --O--R.sup.1d, --S--R.sup.1d,
--S(.dbd.O)--R.sup.1d, --S(.dbd.O).sub.2--R.sup.1d,
--N(R.sup.19)--R.sup.1d, --C(.dbd.O)NR.sup.19bR.sup.1d,
--NR.sup.19bC(.dbd.O)--R.sup.1d,
--NR.sup.19bS(.dbd.O).sub.2--R.sup.1d, and
--S(.dbd.O).sub.2NR.sup.19b--R.sup.1d,
[0596] R.sup.1d, at each occurrence, is independently selected from
H, C.sub.1-C.sub.6 alkyl; and phenyl substituted with 0-3
R.sup.1f;
[0597] R.sup.1f, at each occurrence, is independently selected from
H, Cl, F, Br, NO.sub.2, CF.sub.3, --OCF.sub.3, methyl, ethyl,
methoxy, and ethoxy;
[0598] R.sup.5 is methyl substituted with 0-1 R.sup.5b;
[0599] ethyl substituted with 0-1 R.sup.5b;
[0600] propyl substituted with 0-1 R.sup.5b; or
[0601] butyl substituted with 0-1 R.sup.5b;
[0602] R.sup.5a is H;
[0603] R.sup.5b, at each occurrence, is independently selected
from:
[0604] H, methyl, ethyl, and NR.sup.15R.sup.16;
[0605] R.sup.11, at each occurrence, is independently selected
from
[0606] H, NR.sup.18R.sup.19, CF.sub.3;
[0607] C.sub.1-C.sub.4 alkyl substituted with 0-1 R.sup.11a;
[0608] phenyl substituted with 0-3 R.sup.11b;
[0609] C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b;
or
[0610] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 7 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl;
[0611] R.sup.11a, at each occurrence, is independently selected
from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl,
F, NR.sup.15R.sup.16, CF.sub.3;
[0612] phenyl substituted with 0-3 R.sup.11b;
[0613] C.sub.3-C.sub.6 carbocycle substituted with 0-3 R.sup.11b;
or
[0614] 5 to 7 membered heterocycle containing 1 to 4 heteroatoms
selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7
membered heterocycle is substituted with 0-3 R.sup.11b; wherein
said 5 to 7 membered heterocycle is selected from pyridinyl,
pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl,
piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, and tetrazolyl;
[0615] 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, methoxy, and ethoxy;
[0616] W is a bond, --CH.sub.2--, or --CH(CH.sub.3)--;
[0617] X is a bond;
[0618] phenyl substituted with 0-1 R.sup.Xb;
[0619] C.sub.3-C.sub.6 cycloalkyl substituted with 0-3 R.sup.Xb;
or
[0620] 5 to 6 membered heterocycle containing 1 to 3 heteroatoms
selected from nitrogen, oxygen, and sulphur; wherein said 5 to 6
membered heterocycle is selected from pyridinyl, pyrimidinyl,
triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl,
piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl;
[0621] Y is a bond, --V--, --CH.sub.2--V--, or --V--CH.sub.2--;
[0622] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --N(R.sup.19)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--;
[0623] Z is H;
[0624] C.sub.1-C.sub.6 alkyl substituted with 0-2 R.sup.12;
[0625] C.sub.2-C.sub.6 alkenyl substituted with 0-2 R.sup.12;
[0626] C.sub.2-C.sub.6 alkynyl substituted with 0-2 R.sup.12;
[0627] phenyl substituted with 0-4 R.sup.12b;
[0628] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0629] 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;
[0630] R.sup.12 is phenyl substituted with 0-4 R.sup.12b;
[0631] C.sub.3-C.sub.6 carbocycle substituted with 0-4 R.sup.12b;
or
[0632] 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;
[0633] R.sup.12b, at each occurrence, is independently selected
from H, OH, Cl, F, Br, NR.sup.15R.sup.16, CF.sub.3, OCF.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;
[0634] R.sup.13, at each occurrence, is independently selected from
H, methyl, methoxy, Cl, F, Br, and CF.sub.3;
[0635] R.sup.14, at each occurrence, is independently selected from
H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
[0636] R.sup.15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, or butyl;
[0637] R.sup.16, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and
phenethyl;
[0638] R.sup.18, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
[0639] R.sup.19, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, and butyl; and
[0640] R.sup.20 is H, methyl, ethyl, propyl, or butyl.
[0641] [8] In another alternative embodiment of the present
invention of of Formula (I),
[0642] Q 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(CH.sub.3).sub.2,
[0643] --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2,
[0644] --CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
[0645] phenyl-, 4-tBu-phenyl-, 4-iPr-phenyl-,4-Et-phenyl-,
2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 2-Cl-phenyl-, 3-Cl-phenyl-,
4-Cl-phenyl-, 2-Br-phenyl-, 3-Br-phenyl-, 4-Br-phenyl-,
2-NO.sub.2-phenyl-, 3-NO.sub.2-phenyl-, 4-NO.sub.2-phenyl-,
2-CH.sub.3-phenyl-, 3-CH.sub.3-phenyl-, 4-CH.sub.3-phenyl-,
2-CH.sub.3O-phenyl-, 3-CH.sub.3O-phenyl-, 4-CH.sub.3O-phenyl-,
2-CF.sub.3-phenyl-, 3-CF.sub.3-phenyl-, 4-CF.sub.3-phenyl-,
2-CF.sub.3O-phenyl-, 3-CF.sub.3O-phenyl-, 4-CF.sub.3O-phenyl-,
2-CH.sub.3CONH-phenyl, 3-CH.sub.3CONH-phenyl,
4-CH.sub.3CONH-phenyl, 2-methyoxycarbonyl-phenyl-,
4-phenyl-phenyl-,
[0646] 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-,
2,3-diMe-phenyl-, 2,4-diMe-phenyl-, 2,5-diMe-phenyl-,
2,6-diMe-phenyl-, 3,4-diMe-phenyl-, 3,5-diMe-phenyl-,
2,3-diMeO-phenyl-, 2,4-diMeO-phenyl-, 2,5-diMeO-phenyl-,
2,6-diMeO-phenyl-, 3,4-diMeO-phenyl-, 3,5-diMeO-phenyl-,
2,3-diCF.sub.3-phenyl-, 2,4-diCF.sub.3-phenyl-,
2,5-diCF.sub.3-phenyl-, 2,6-diCF.sub.3-phenyl-,
3,4-diCF.sub.3-phenyl-, 3,5-diCF.sub.3-phenyl-,
2-NO.sub.2-4-CF.sub.3-phenyl-, 2-Me-5-Cl-phenyl-,
2,4,6-triMe-phenyl,
[0647] benzyl-, naphth-1-yl-, naphth-2-yl-, beta-styrene-,
furanyl-, thienyl-, pyridyl-, thiazolyl-, imidazol-1-yl-,
oxazolyl-, isoxazolyl-, quinolin-8-yl-,
[0648] 3-methyl-isoxazol-4-yl-, 3,5-dimethyl-isoxazol-4-yl-,
3-bromo-5-chloro-thiophen-2-yl-, 2,3-dichlorothiophen-5-yl-,
4-bromo-5-chlorothiophen-2-yl-,
5-[(benzoylamino)methyl]-thiophen-2-yl-,
4-phenylsulfonylthiophen-2-yl-, 5-(phenylsulfonyl)thiophen-2-yl-,
2-(1-methyl-(5-trifluoromethyl)pyrazole)thiophen-5-yl-,
5-(2-pyridyl)thiophen-2-yl-,
1-methyl-5-(trifluoromethyl)imidazol-3-yl-,
2-(2-methylthio-pyrimdin-3-yl)-thiophen-5-yl-, or
dibenzofuran-2-yl-;
[0649] 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,
[0650] 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--,
[0651] 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--,
[0652] phenyl-CH.sub.2CH.sub.2--, (2-F-phenyl)CH.sub.2CH.sub.2--,
(3-F-phenyl)CH.sub.2CH.sub.2--,
[0653] (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--, or
isoxazolyl-CH.sub.2CH.sub.2--,
[0654] W is a bond, --CH.sub.2--, or --CH(CH.sub.3)--;
[0655] X is a bond; 13
[0656] Y is a bond, --CH.sub.2--V--, --V--, or --V--CH.sub.2--;
[0657] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NH--, --N(CH.sub.3)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--,
[0658] Z is H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
[0659] --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,
--C(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,
--CH.sub.2C(CH.sub.3).sub.3,
--C(CH.sub.3).sub.2CH.sub.2CH.sub.3,
[0660] --CH(CH.sub.3)CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.- 2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH(CH.s- ub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
[0661] --CH.sub.2CH.sub.2C(CH.sub.3).sub.3,
--CH(CH.sub.2CH.sub.3)CH.sub.2- CH.sub.2CH.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.sub.2CH.sub.2CH.sub.2CH.sub.2- CF.sub.3,
[0662] cyclopropyl-, (cyclopropyl)CH.sub.2--,
(cyclopropyl)CH.sub.2CH.sub.- 2--, cyclobutyl-,
(cyclobutyl)CH.sub.2--, (cyclobutyl)CH.sub.2CH.sub.2--,
cyclopentyl-, (cyclopentyl)CH.sub.2--,
(cyclopentyl)CH.sub.2CH.sub.2--, cyclohexyl-,
(cyclohexyl)CH.sub.2--, (cyclohexyl)CH.sub.2CH.sub.2--, 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,
morpholino, N-piperidinyl, 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-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--,
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.su- b.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--;
[0663] R.sup.11 at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl,
cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl,
4-CH.sub.3-phenyl, 4-CF.sub.3-phenyl, 4-CH.sub.3O-phenyl,
4-CF.sub.3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH.sub.3-phenyl,
3-CF.sub.3-phenyl, 3-CH.sub.3O-phenyl, 3-CF.sub.3O-phenyl,
2-F-phenyl, 2-Cl-phenyl, 2-CH.sub.3-phenyl, 2-CF.sub.3-phenyl,
2-CH.sub.3O-phenyl, 2-CF.sub.3O-phenyl, (4-F-phenyl)methyl-,
(4-Cl-phenyl)methyl-,
[0664] (4-CH.sub.3-phenyl)methyl-, (4-CF.sub.3-phenyl)methyl-,
(4-CH.sub.3O-phenyl)methyl-, (4-CF.sub.3O-phenyl)methyl-,
(3-F-phenyl)methyl-, (3-Cl-phenyl)methyl-,
(3-CH.sub.3-phenyl)methyl-, (3-CF.sub.3-phenyl)methyl-,
(3-CH.sub.3O-phenyl)methyl-, (3-CF.sub.3O-phenyl)methyl-,
(2-F-phenyl)methyl-, (2-Cl-phenyl)methyl-,
(2-CH.sub.3-phenyl)methyl-, (2-CF.sub.3-phenyl)methyl-,
(2-CH.sub.3O-phenyl)methyl-, (2-CF.sub.3O-phenyl)methyl-,
2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 1-piperidinyl,
1-homopiperidinyl, and 1-morpholino; and
[0665] R.sup.13, at each occurrence, is independently selected from
H, F, Cl, and methoxy.
[0666] [9] In another alternative embodiment of the present
invention of of Formula (I),
[0667] Q is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, phenyl-,
2-F-phenyl-, 2-Cl-phenyl-, 2-Br-phenyl-, 2-NO.sub.2-phenyl-,
2-CH.sub.3-phenyl-, 2-CH.sub.3CH.sub.2-phenyl-,
2-CH.sub.3O-phenyl-, 2-CF.sub.3-phenyl-, 2-CF.sub.3O-phenyl-,
2-CH.sub.3CONH-phenyl, or 3,5-dimethyl-isoxazol-4-yl-;
[0668] 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,
[0669] W is a bond, --CH.sub.2--, or --CH(CH.sub.3)--;
[0670] X is a bond; 14
[0671] Y is a bond, --CH.sub.2--V--, --V--, or --V--CH.sub.2--;
[0672] V is a bond, --C(.dbd.O)--, --O--, --S--, --S(.dbd.O)--,
--S(.dbd.O).sub.2--, --NH--, --N(CH.sub.3)--, --C(.dbd.O)NH--, or
--NHC(.dbd.O)--,
[0673] Z is H, --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, --C(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,
--CH.sub.2C(CH.sub.3).sub.3,
--C(CH.sub.3).sub.2CH.sub.2CH.sub.3,
[0674] --CH(CH.sub.3)CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.- 2CH.sub.2CH.sub.3,
--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH(CH.s- ub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
[0675] --CH.sub.2CH.sub.2C(CH.sub.3).sub.3,
--CH(CH.sub.2CH.sub.3)CH.sub.2- CH.sub.2CH.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.sub.2CH.sub.2CH.sub.2CH.sub.2- CF.sub.3,
[0676] cyclopropyl-, (cyclopropyl)CH.sub.2--,
(cyclopropyl)CH.sub.2CH.sub.- 2--, cyclobutyl-,
(cyclobutyl)CH.sub.2--, (cyclobutyl)CH.sub.2CH.sub.2--,
cyclopentyl-, (cyclopentyl)CH.sub.2--,
(cyclopentyl)CH.sub.2CH.sub.2--, cyclohexyl-,
(cyclohexyl)CH.sub.2--, (cyclohexyl)CH.sub.2CH.sub.2--, 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,
morpholino, N-piperidinyl, 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-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--,
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.s- ub.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--;
[0677] R.sup.11, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl,
cyclopentylethyl, cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl,
4-CH.sub.3-phenyl, 4-CF.sub.3-phenyl, 4-CH.sub.3O-phenyl,
4-CF.sub.3O-phenyl, 3-F-phenyl, 3-Cl-phenyl, 3-CH.sub.3-phenyl,
3-CF.sub.3-phenyl, 3-CH.sub.3O-phenyl, 3-CF.sub.3O-phenyl,
2-F-phenyl, 2-Cl-phenyl, 2-CH.sub.3-phenyl, 2-CF.sub.3-phenyl,
2-CH.sub.3O-phenyl, 2-CF.sub.3O-phenyl, (4-F-phenyl)methyl-,
(4-Cl-phenyl)methyl-,
[0678] (4-CH.sub.3-phenyl)methyl-, (4-CF.sub.3-phenyl)methyl-,
(4-CH.sub.3O-phenyl)methyl-, (4-CF.sub.3O-phenyl)methyl-,
(3-F-phenyl)methyl-, (3-Cl-phenyl)methyl-,
(3-CH.sub.3-phenyl)methyl-, (3-CF.sub.3-phenyl)methyl-,
(3-CH.sub.3O-phenyl)methyl-, (3-CF.sub.3O-phenyl)methyl-,
(2-F-phenyl)methyl-, (2-Cl-phenyl)methyl-,
(2-CH.sub.3-phenyl)methyl-, (2-CF.sub.3-phenyl)methyl-,
(2-CH.sub.3O-phenyl)methyl-, (2-CF.sub.3O-phenyl)methyl-,
2-pyridyl-, 3-pyridyl-, 4-pyridyl-, 1-piperidinyl,
1-homopiperidinyl, and 1-morpholino; and
[0679] R.sup.13, at each occurrence, is independently selected from
H, F, Cl, and methoxy.
[0680] [10] In another alternative embodiment, the present
invention provides a novel compound of Formula (Ic): 15
[0681] or a pharmaceutically acceptable salt form or prodrug
thereof.
[0682] [11] In another alternative embodiment, the present
invention provides a novel compound of Formula (Id): 16
[0683] or a pharmaceutically acceptable salt form or prodrug
thereof.
[0684] [12] In another alternative embodiment, the present
invention provides a novel compound of Formula (Ia); 17
[0685] or a pharmaceutically acceptable salt or prodrug
thereof.
[0686] [13] In another alternative embodiment of the present
invention of Formula (I), R.sup.5 is OR.sup.14.
[0687] [14] In another alternative embodiment of the present
invention of Formula (I), R.sup.5 is C.sub.1-C.sub.4 alkoxy
substituted with 0-3 R.sup.5b.
[0688] [15] In a preferred embodiment the present invention
provides compound of Formula (I), (Ia), (Ic), or (Id) wherein Q is
3,5-dimethyl-isoxazol-4-yl-.
[0689] In a preferred embodiment Q is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, phenyl-, 2-F-phenyl-, 2-Cl-phenyl-,
2-Br-phenyl-, 2-NO.sub.2-phenyl-, 2-CH.sub.3-phenyl-,
2-CH.sub.3CH.sub.2-phenyl-,2-CH.sub.3O-phenyl-, 2-CF.sub.3-phenyl-,
2-CF.sub.3O-phenyl-, 2-CH.sub.3CONH-phenyl, or
3,5-dimethyl-isoxazol-4-yl- -.
[0690] In a preferred embodiment Q is a substituted phenyl as
disclosed herein (preferably ortho substituted) or a 5 to 6
membered heterocyclic ring as disclosed herein (preferably
substituted); for example, 2-F-phenyl-, 2-Cl-phenyl-, 2-Br-phenyl-,
2-NO.sub.2-phenyl-, 2-CH.sub.3-phenyl-, 2-CH.sub.3CH.sub.2-phenyl-,
2-CH.sub.3O-phenyl-, 2-CF.sub.3-phenyl-, 2-CF.sub.3O-phenyl-,
2-CH.sub.3CONH-phenyl, or 3,5-dimethyl-isoxazol-4-yl-.
[0691] In a preferred embodiment Q is not a trihalomethyl group,
preferrably not trifluoromethyl.
[0692] In a preferred embodiment when R.sup.5 and/or R.sup.5a form
an alkyl or alkeneyl moiety, optionally substituted, of five
carbons or less, then Q is not a haloalkyl, preferably not
trifluoromethyl.
[0693] It is understood that any and all embodiments of the present
invention may be taken in conjunction with any other embodiment to
descibe additional even more preferred embodiments of the present
invention.
[0694] [16] In another alternative embodiment, the present
invention provides a compound selected from:
[0695]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0696]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-methyl-2-oxo-5-phen-
yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;
[0697]
2-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0698] 2-(naphthalene-1-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0699] 2-(5-dimethylamino
naphthalene-1-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0700] 2-(naphthalene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0701]
2-(2-acetamido-4-methylthiazole-5-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0702] 2-(thiophene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0703] 2-(quinoline-8-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0704] 2-(phenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0705] 2-(2,5-dichlorophenyl sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0706] 2-(mesitylene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0707] 2-(3-nitrophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0708] 2-(4-bromophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0709] 2-(4-fluorophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0710] 2-(4-chlorophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0711] 2-(4-acetamidophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0712] 2-(4-nitrophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0713] 2-(4-methoxyphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0714] 2-(4-tert-butylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0715] 2-(p-toluene-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0716] 2-(benzyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0717] 2-(beta-styrene-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0718]
2-((2-methoxycarbonyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0719]
2-(2-nitro-4-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentan-
oic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-y-
l)-amide;
[0720]
2-(3-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0721] 2-(2,5-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0722] 2-(2-methylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0723] 2-(3,4-dichlorophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0724]
2-(4-(trifluoromethoxy)phenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0725] 2-(3,4-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0726] 2-(2-bromophenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0727]
2-(3,5-bis(trifluoromethyl)phenyl-2-sulfonylamino)-4-methyl-pentano-
ic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-
)-amide;
[0728] 2-(4-ethylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0729] 2-(4-isopropylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0730] 2-(2,5-dichlorothiophene-3-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0731] 2-(5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0732]
2-(2-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0733] 2-(3-methylphenyl-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0734] 2-(2,3-dichlorothiophene-5-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0735]
2-(4-bromo-5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0736]
2-(5-[(benzoylamino)methyl]-thiophene-2-sulfonylamino)-4-methyl-pen-
tanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl)-amide;
[0737]
2-(4-phenylsulfonylthiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0738]
2-(5-(phenylsulfonyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic
acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide;
[0739]
2-[2-(1-methyl-(5-trifluoromethyl)pyrazole)thiophene-5-sulfonylamin-
o]-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e-
][1,4]diazepin-3-yl)-amide;
[0740]
2-(5-(2-pyridyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0741]
2-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic
acid
[5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diaz-
epin-3-yl]-amide;
[0742]
N-[1-(3'-Chloro-4'-fluoro-biphenyl-3-ylmethyl)-2-oxo-azepan-3-yl]-2-
-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide;
[0743]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[5-(4-fluoro-phenyl)-1-
-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
[0744]
2-(2-fluoro-benzenesulfonylamino)-N-[5-(4-fluoro-phenyl)-1-methyl-2-
-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide;
[0745]
N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-y-
l)-2-(2-trifluoromethyl-benzenesulfonylamino)-propionamide;
[0746] 2-(2-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0747]
4-methyl-2-(2-trifluoromethyl-benzenesulfonylamino)-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0748] 4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0749] 4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
;
[0750]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-[1-methyl-2-oxo-5-(4-t-
rifluoromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propiona-
mide;
[0751]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
(7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3--
yl)-amide;
[0752] 4-methyl-2-(propane-1-sulfonylamino)-pentanoic acid
[5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl]-amide;
[0753]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-
-amide;
[0754]
2-[(3,5-dimethyl-isoxazole-4-sulfonyl)-methyl-amino]-N-(1-methyl-2--
oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide;
[0755]
3-dimethylamino-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-met-
hyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide-
;
[0756]
N-[1-methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo-
[e][1,4]diazepin-3-yl]-2-(propane-1-sulfonylamino)-propionamide;
[0757]
N-(7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]dia-
zepin-3-yl)-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide;
[0758]
2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic acid
[5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl]-amide; and
[0759]
2-methanesulfonylamino-N-[1-methyl-2-oxo-5-(4-trifluoromethyl-pheny-
l)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide.
[0760] In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula (I) and
a pharmaceutically acceptable carrier.
[0761] In another embodiment, the present invention provides a
method for the treatment of neurological disorders comprising
administering to a host in need of such treatment a therapeutically
effective amount of a compound of Formula (I).
[0762] In another embodiment, the present invention provides a
method for the treatment of neurological disorders associated with
A.beta. amyloid production comprising administering to a host in
need of such treatment a therapeutically effective amount of a
compound of Formula (I).
[0763] In another embodiment, the present invention provides a
method for the treatment of Alzheimer's Disease comprising
administering to a host in need of such treatment a therapeutically
effective amount of a compound of Formula (I).
[0764] In another embodiment, the present invention provides a
method for the treatment of Alzheimer's Disease associated with
A.beta. amyloid production comprising administering to a host in
need of such treatment a therapeutically effective amount of a
compound of Formula (I).
[0765] In another embodiment, the present invention provides a
method for 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 .gamma.-secretase activity.
[0766] In another embodiment the present invention provides a
compound of Formula (I) for use in therapy of Alzheimer's
Disease.
[0767] In another 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
[0768] As used herein, the term "A.beta." 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:
1 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
[0769] 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 .gamma.
secretase, generating the N-terminus of A.beta., .gamma. 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
[0770] 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. C is 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.
[0771] 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.
[0772] When any variable (e.g., R.sup.1a, R.sup.2, R.sup.13 etc.)
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 0-3 R.sup.1a, then said group may
optionally be substituted with up to three R.sup.1a groups and
R.sup.1a at each occurrence is selected independently from the
definition of R.sup.1a. Also, combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds.
[0773] 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.
[0774] 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 to 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 is "C.sub.1-C.sub.4 alkyl"
wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl,
are specifically preferred. As used herein, "C.sub.1-C.sub.3
alkyl", whether a terminal substituent or a alkylene group linking
two substituents, is understood to specifically include both
branched and straight-chain methyl, ethyl, and propyl.
[0775] 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.
[0776] 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.
[0777] "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.
[0778] "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.
[0779] "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.
[0780] "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.
[0781] 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
example of "C.sub.3-C.sub.10carbocycle" or "C.sub.3-C.sub.6
carbocycle" is C.sub.3-C.sub.6 cycloalkyl, specifically
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0782] 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,
preferably 1, 2, or 3 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.
[0783] 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, isoxazolinyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl,
pteridinyl, 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.
[0784] As used herein, the term "aryl", "C.sub.6-C.sub.10 aryl" or
aromatic residue, is intended to mean an aromatic moiety containing
the specified number of carbon atoms; for example phenyl, pyridinyl
or naphthyl. Unless otherwise specified, "aryl" may be
unsubstituted or substituted with 0 to 3 groups selected from H,
OH, OCH.sub.3, Cl, F, Br, I, CN, NO.sub.2, NH.sub.2, N(CH.sub.3)H,
N(CH.sub.3).sub.2, CF.sub.3, OCF.sub.3, C(.dbd.O)CH.sub.3,
SCH.sub.3, S(.dbd.O)CH.sub.3, S(.dbd.O).sub.2CH.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CO.sub.2H, and CO.sub.2CH.sub.3.
[0785] The term "amino acid" as used herein, refers to natural,
modified or unnatural amino acids of either D- or L-configuration
and means an organic compound containing both a basic amino group
and an acidic carboxyl group. Natural amino acids residues are Ala,
Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, His, Hyp, Ile, Irg Leu,
Lys, Met, Orn, Phe, Phe(4-fluoro), Pro, Sar, Ser, Thr, Trp, Tyr,
and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449
(1983), Academic Press, New York, discloses numerous suitable
unnatural amino acids and is incorporated herein by reference for
that purpose.
[0786] The phrase "additional lactam carbons", as used herein, is
intended to denote the number of optional carbon atoms in the
lactam ring B of Formula (I). Formula (Ia): 18
[0787] 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 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. Examples
of lactam ring B include: 1920
[0788] 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; even more preferred examples of lactam ring B are B1 and B6.
Preferred examples of substituent R.sup.10 or R.sup.11 on lactam
ring B are methyl, ethyl, phenyl, benzyl, phenethyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,
cyclohexylethyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH.sub.3-phenyl,
4-CF.sub.3-phenyl, 4-CH.sub.3O-phenyl, 4-CF.sub.3O-phenyl,
3-F-phenyl, 3-Cl-phenyl, 3-CH.sub.3-phenyl, 3-CF.sub.3-phenyl,
3-CH.sub.3O-phenyl, 3-CF.sub.3O-phenyl, (4-F-phenyl)methyl-,
(4-Cl-phenyl)methyl-, (4-CH.sub.3-phenyl)methyl-,
(4-CF.sub.3-phenyl)methyl-, (4-CH.sub.3O-phenyl)methyl-,
(4-CF.sub.3O-phenyl)methyl-, (3-F-phenyl)methyl-,
(3-Cl-phenyl)methyl-, (3-CH.sub.3-phenyl)methyl-,
(3-CF.sub.3-phenyl)methyl-, (3-CH.sub.3O-phenyl)methyl-,
(3-CF.sub.3O-phenyl)methyl-, 2-pyridyl-, 3-pyridyl-, and
4-pyridyl-. More preferred examples of substituent R.sup.10 or
R.sup.11 on lactam ring B are methyl, ethyl, phenyl,
4-fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl,
(4-fluorophenyl)methyl, (4-chlorophenyl)methyl,
(4-trifluorophenyl)methyl, 2-pyridyl-, 3-pyridyl-, and 4-pyridyl-.
The fused rings on lactam ring B may optionally be substituted with
R.sup.13, wherein the preferred examples of substituent R.sup.13 on
fused rings of lactam B are methyl, fluoro, chloro, and
methoxy.
[0789] 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. Examples of such
configuration include, 21
[0790] but are not intended to be limited to these examples of ring
B. When required, separation of the racemic material can be
achieved by methods known in the art. Additionally, the carbon atom
to which R.sup.5 is attached may display superior biological
activity over the opposite enantiomer. For example, where R.sup.5
is not H, then the configuration of the carbon may be described as
R or S. All configurations are considered part of the
invention.
[0791] 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.
[0792] 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.
[0793] 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.
[0794] "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 or acetamide,
formamide, benzamide, and N-oxide derivatives of amine functional
groups in the compounds of Formula (I), and the like.
[0795] "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
[0796] 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.
[0797] 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.
[0798] Compounds of Formula (I) of the present invention can be
synthesized by the method of Scheme 1 comprising: step 1, an amino
acid coupling; followed by step 2, a deprotection; followed by step
3, a sulfonyl coupling (see Scheme 1). In the method of Scheme 1, a
W-X-Y-Z-substituted aminolactam, X, is coupled with a protected
natural or unnatural amino acid, XI, to form a compound, XII. The
amino protecting group of XII is then removed using a standard
deprotection procedure to give a compound XIII. The compound XIII
is coupled with an activated sulfonylating agent, XIV, preferably a
sulfonyl chloride Q-SO.sub.2Cl, XIVa, to form a compound of Formula
I. 22
[0799] In an example of the method of Scheme 1, the coupling of
Boc-Alanine to racemic
3-amino-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4- ]diazepin-2-one
followed by TFA-mediated removal of the Boc group provides the
Alanine-substituted lactam 2b (Scheme 1a). Sulfonamide formation
using 3,5-Dimethyl-isoxazole-4-sulfonyl chloride and triethylamine
as base provides the compound of Example 2. 23
[0800] Alternatively, compounds of Formula I can be prepared by the
method of Scheme 2 which comprises a sequence of sulfonyl coupling,
followed by deprotection, followed by amino acid coupling. In the
method of Scheme 2, an amino acid derivative which has a protected
carboxyl group, XV, is first coupled with a sulfonylating agent
(O)SO.sub.2Cl, XIV, or an equivalent activated sulfonylating agent,
to form a sulfonamide XVI. The carboxyl protecting group of XVI is
removed using a standard deprotection method to give a sulfonamide
carboxylic acid XVII. The W-X-Y-Z-substituted aminolactam, X, is
then coupled with the sulfonamide carboxylic acid, XVII, to form a
compound of Formula I. 24
[0801] Methods for the synthesis of lactam intermediates as
contemplated by the present invention useful in the synthesis of
compounds of Formula (I), including amino benzodiazepinones,
dibenzo azepinones and other related heterocycles, are known in the
art and are disclosed in a number of references including PCT
publication number WO 98/28268, WO 99/66934, WO 00/07995, and WO
00/38618, which are hereby incorporated by reference. Additional
references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239;
Sherrill et al, J. Org. Chem., 1995, 60, 730-734; and Walsh, D. A.,
Synthesis, September 1980, p. 677; and Brown, et al., Tetrahedron
Letters, 1971, 8, 667-670.
[0802] Synthetic approaches to substituted benzodiazepines are
widely described in the literature. The typical methods are
illustrated by, but are not limited to, the following references:
M. G. Bock et al J. Org. Chem. 1987, 52, 3232. (b) R. G. Sherrill
et al J. Org. Chem. 1995, 60, 734. (c) M. G. Bock et al J. Med.
Chem. 1989, 32, 13-16. (d) J. L. Castro et al J. Med. Chem. 1997,
40, 2491-2501. (e) M. S. Chambers et al Bioorg. & Med. Chem.
Lett. 1993, 3 (10), 1919-1924. (f) J. H. Gogerty et al J. Med.
Chem. 1977, 20 (7), 952. (g) G. Semple et al Bioorg. & Med.
Chem. Lett. 1996, 6(1), 51-54. (h) G. Semple et al J. Med. Chem.
1997, 40, 331-341. (i) G. Semple et al Bioorg. & Med. Chem.
Lett. 1996, 6 (1), 55-58. (j) G. Semple et al Synth. Commun. 1996,
26 (4), 721-727. (k) G. A. Showell et al J. Med. Chem. 1994, 37,
719-721. General synthetic descriptions of 2-aminobenzophenone with
various substitutions used in the preparation of benzodiaepines may
be found in D. A. Walsh Synthesis 1980, 677.
[0803] Incorporation of alpha-alkoxy amino acids provides access to
additional compounds. alpha-Alkoxy amino acid derivatives are
available from a number of procedures available in the art. For
instance, they may be synthesized by electrochemical oxidation of
malonic acid half esters in alcoholic solvents as shown in
Horikawa, Hiroshi; Iwasaki, Tameo; Matsumoto, Kazuo; Miyoshi,
Muneji. A new synthesis of 2-alkoxy- and 2-acetoxy-2-amino acids by
anodic oxidation. Tetrahedron Lett. 1976, (3), 191-4. Alternative
procecures include alkoxide displacement of dichloroacetic acid to
form an alpha-halo-alpha-alkoxyacetate, followed by aminolysis as
reported in Gross, Hans; Gloede, Joerg; Freiberg, Juergen.
alpha-Halo ethers. XXIX. Glyoxylic acid derivatives from
chloromethoxyacetic acid or dichloroacetic acid. Ann. Chem., Justus
Liebigs (1967), 702 68-74. and similar references.
[0804] An example of an
L-.alpha.-amino-.beta.-thio-.epsilon.-caprolactam, as shown in
Scheme 3, where ring B is the amino lactam of XVIII and J is a
sulfur atom has been reported in the literature. See S. A. Ahmed et
al, FEBS Letters, (1984), vol. 174, pages 76-9. 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. 25
[0805] Methods for the alkylation of lactams as contemplated by the
present invention in lactam ring B in Formula (I), including amino
benzodiazepines and other related heterocycles, are well known in
the art. For example, Scheme 4 demonstrates that the lactam
nitrogen of compound XIX or other lactam intermediates of the
present invention can be alkylated by generating the anion with
bases such as LDA, LiHMDS, lithium bis(trimethylsilyl)amide
potassium carbonate or sodium hydride in solvents like THF, with or
without cosolvents such as DMPU, HMPA or DMF, 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. 26
[0806] A variety of suitably protected natural and unnatural amino
acid derivatives are commercially available or can be prepared by
known procedures and can be coupled to the aminolactam of Ring B
using standard coupling procedures. Representative procedures for
preparation of amino acids include the Strecker amino acid
synthesis; the Ugi 4-component coupling reaction; alkylation of
glycine benzophenone imine, Seebach's method (reviewed in
O'Donnell, Martin J.; Fang, Zhiqiang; Seebach's "Self-Regeneration
of Chirality" and related methods for the synthesis of
.alpha.-amino acids, Hecheng Huaxue (1996), 4(4), 303-316);
Schollkopf's bislactam method, and many others. For a review, see
Duthaler, Rudolf O. Recent developments in the stereoselective
synthesis of .alpha.-amino acids. Tetrahedron (1994), 50(6),
1539-650.
[0807] Protection groups for amine funtional group 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", for example, N-Boc using di-t-butyldicarbonate
in an appropriate solvent like DMSO. Other protecting groups for
amino acids include but are not limited to Boc
(tert-butyloxycarbonyl), Fmoc (Fluorenylmethyloxycarbonyl), cBz
(Benzyloxycarbonyl), and Alloc (Allyoxycarbonyl). Methods for
removing these protecting groups are known to those skilled in the
art.
[0808] Suitable coupling agents include but are not limited to
activating agents such as dicyclohexylcarbodiimide (DCC),
diisopropylcarbodiimide (DICI), or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) with or without
the additive hydroxybenzotriazole (HOBt) or reagents such as HATU
(O-(7-azabenzotriazol-1-yl)-1,1,3,3, -tetramethyluronium
hexafluorophosphate) or PyBOP
(benzotriazole-1-yl-oxy-tris-pyrrolidino-ph- osphonium
hexafluorophosphate), which are used in a suitable solvent such as
dichloromethane or N,N-dimethylformamide with a suitable base such
as diisopropylethylamine, N-methylmorpholine, or triethylamine.
Most preferably, the couplings are run using EDC and HOBt as
coupling agents with triethylamine as a base in
dichloromethane.
EXAMPLES
[0809] Chemical abbreviations used in the Examples are defined as
follows:
[0810] "DMF" for dimethylformamide,
[0811] "THF" for tetrahydrofuran,
[0812] "DMPU" for
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone,
[0813] "HMPA" for hexamethylphosphoramide,
[0814] "TBTU" for
O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate, and
[0815] "BOP" for
benzotriazol-1-yloxytris-(dimethylamino)phosphonium
hexafluorophosphate.
[0816] "LDA" for lithium diisopropyl amide
[0817] "LiHMDS" for lithium hexamethyl disilazide or lithium
bis(trimethylsilyl) amide.
[0818] "HPLC" is an abbreviation used herein for high pressure
liquid chromatography. Compounds of the present invention are
generally purified by HPLC using conditions known to one skilled in
the art. However, unless otherwise indicated, the following
conditions are generally applicable. Reverse-phase HPLC can be
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 can be carried out using a Vydac C-18 column with gradient
elution from 10% to 90% acetonitrile in water.
Example 1
[0819]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide
[0820] Step (1a). A solution of 1.2 g (3.46 mmol) of
3-Amino-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one
and 0.818 g (3.53 mmol) of N-Boc-(L)-leucine dissolved in 50 mL of
dichloromethane at 0.degree. C. was treated sequentially with 1.2
mL (8.65 mmol) of triethylamine, 1.06 g (6.92 mmol) of
hydroxybenzotriazole, and 0.827 g (4.32 mmol) of EDC. The cooling
bath was removed and the solution was stirred for 2 h while warming
to rt. The reaction solution was then diluted with 20 mL of water
and the organic layer was separated and washed with 30 mL of 1 N
HCl solution, 30 mL of a saturated NaHCO.sub.3 solution, then dried
over Na.sub.2CO.sub.3 and concentrated in vacou. Chromatography
eluting with a gradient of 20 to 50% ethyl acetate in hexanes
provided the desired product 1a. MS (ESI) M+H=479.4.
[0821] Step (1b). The purified material 1a was dissolved in 50 mL
of a 1:1 solution of dichloroemethane and trifluoroacetic acid and
stirred for 2 h at rt. The solution was directly concentrated and
redissolved in 10 mL of toluene. After removal of the solvent 600
mg (35% for 2 steps) of the desired amine was isolated as its TFA
salt, MS (ESI) M+H=379.4. This material was then freebased by
dissolving in 20 mL of dichloromethane followed by extracting
3.times.with 10 mL of a saturated NaHCO.sub.3 solution, followed by
drying the dichloromethane solution with Na.sub.2SO.sub.4 and
concentrating to the free amine 1b.
[0822] Step (1c). The free amine 1b 200 mg, 0.528 mmol) was
dissolved in 20 mL of dichloromethane and 147 microliters (1.05
mmol) of triethylamine was added followed by 124 mg (0.63 mmol) of
3,5-dimethyl-isoxazole-4-sulf- onyl chloride. After stirring 18 h
at rt, 10 mL of water was added and the organic layer was
separated. The organic layer was washed with 10 mL of 1 N HCl, 10
mL of a saturated NaHCO.sub.3 solution, and 10 mL of brine. The
organic layer was then dried over Na.sub.2SO.sub.4 and concentrated
to an oil. Chromatography eluting with a gradient of 20 to 100%
ethyl acetate in hexanes allowed the purification of 80 mg (28%
yield) of the two diastereomers of the compound of Example 1. MS
(ESI) M+H=538.3).
Example 2
[0823]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-N-(1-methyl-2-oxo-5-phen-
yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0824] Step (2a). The compound of Example 2a was synthesized in a
manner similar to that of the compound of Example (1a), but using
N-Boc-L-Alanine as the amino acid in 50% yield. MS (ESI)
M+H=437.3
[0825] Step (2b). The purified material 2a (1.0 g) was dissolved in
50 mL of a 1:1 solution of dichloromethane and trifluoroacetic acid
and stirred for 2 h at rt. The solution was directly concentrated
and redissolved in 10 mL of toluene. After removal of the solvent
the material was then freebased by dissolving in 20 mL of
dichloromethane followed by extracting 3.times.with 10 mL of a
saturated NaHCO.sub.3 solution. The dichloromethane solution was
dried with Na.sub.2SO.sub.4 and concentrated to 0.75 g (96%) of the
free amine 2b. MS (ESI) M+H=337.2).
[0826] Step (2c). The free amine 2b 100 mg, 0.29 mmol) was
dissolved in 10 mL of dichloromethane and 83 microliters (0.6 mmol)
of triethylamine was added followed by 70 mg (0.36 mmol) of
3,5-dimethyl-isoxazole-4-sulfonyl chloride. After stirring 18 h at
rt, 10 mL of water was added and the organic layer was separated.
The organic layer was washed with 10 mL of 1 N HCl, 10 mL of a
saturated NaHCO.sub.3 solution, and 10 mL of brine. The organic
layer was then dried over Na.sub.2SO.sub.4 and concentrated to an
oil. Chromatography eluting with a gradient of 20 to 50% ethyl
acetate in hexanes allowed the purification of 30 mg (20% yield) of
the compound of Example 2. MS (ESI) M+H=496.2.
Example 3
[0827]
2-(3-Bromo-5-chloro-thiophene-2-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide
[0828] The compound of Example 3 was synthesized in a manner
similar to that of the compound of Example 1, but using
N-Boc-L-Alanine as the amino acid in Step (1a) and using
3-bromo-5-chloro-thiophene-2-sulfonyl chloride in Step (1c). MS
(ESI) M+H=597.0.
Examples 4-47
[0829] Additional Examples 4-47, listed below in Table 1, were
synthesized by the following procedure: A solution of the free
amine 1b from step (1b) (4.5 mg, 12 micromoles) was dissolved in
0.5 mL of dichloromethane and 3.3 microliters of triethylamine (25
micromoles) was added, followed by 14 micromoles of a corresponding
sulfonyl chloride. After stirring for 24 h at room temperature, 100
mg of a mixture of sulfonic acid derived silica gel and aminopropyl
derived silica gel was added with an additional 0.5 mL of
dichloromethane. After stirring for 24 h at room temperature, the
solution was collected and concentrated. HPLC eluting with a
gradient of from 10 to 100% acetonitrile/water provided purified
compounds, in a range of from 0.1 to 5 mg each.
Example 4
[0830] 2-(naphthalene-1-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=569.3.
Example 5
[0831] 2-(5-dimethylamino
naphthalene-1-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=612.4.
Example 6
[0832] 2-(naphthalene-2-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=569.3.
Example 7
[0833]
2-(2-acetamido-4-methylthiazole-5-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=597.3.
Example 8
[0834] 2-(thiophene-2-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=525.3.
Example 9
[0835] 2-(quinoline-8-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=570.3.
Example 10
[0836] 2-(phenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=519.3.
Example 11
[0837] 2-(2,5-dichlorophenyl sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=588.1.
Example 12
[0838] 2-(mesitylene-2-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=561.3.
Example 13
[0839] 2-(3-nitrophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=564.2.
Example 14
[0840] 2-(4-bromophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=598.1.
Example 15
[0841] 2-(4-fluorophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=537.2.
Example 16
[0842] 2-(4-chlorophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=553.7.
Example 17
[0843] 2-(4-acetamidophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=576.3.
Example 18
[0844] 2-(4-nitrophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=564.2.
Example 19
[0845] 2-(4-methoxyphenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=549.2.
Example 20
[0846] 2-(4-tert-butylphenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=575.3.
Example 21
[0847] 2-(p-toluene-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=533.2.
Example 22
[0848] 2-(benzyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=533.2.
Example 23
[0849] 2-(beta-styrene-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=545.3.
Example 24
[0850]
2-((2-methoxycarbonyl)phenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=577.3.
Example 25
[0851]
2-(2-nitro-4-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentan-
oic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-y-
l)-amide. MS (ESI) M+H=633.2.
Example 26
[0852]
2-(3-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=587.2.
Example 27
[0853] 2-(2,5-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=579.3.
Example 28
[0854] 2-(2-methylphenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=533.2.
Example 29
[0855] 2-(3,4-dichlorophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=588.1.
Example 30
[0856]
2-(4-(trifluoromethoxy)phenyl-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=603.2.
Example 31
[0857] 2-(3,4-dimethoxyphenyl-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=579.3.
Example 32
[0858] 2-(2-bromophenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=598.1.
Example 33
[0859]
2-(3,5-bis(trifluoromethyl)phenyl-2-sulfonylamino)-4-methyl-pentano-
ic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-
)-amide. MS (ESI) M+H=655.3.
Example 34
[0860] 2-(4-ethylphenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=547.3.
Example 35
[0861] 2-(4-isopropylphenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=561.3.
Example 36
[0862] 2-(2,5-dichlorothiophene-3-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=594.1.
Example 37
[0863] 2-(5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=559.7.
Example 38
[0864]
2-(2-(trifluoromethyl)phenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=587.2.
Example 39
[0865] 2-(3-methylphenyl-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=533.2.
Example 40
[0866] 2-(2,3-dichlorothiophene-5-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=594.1.
Example 41
[0867]
2-(4-bromo-5-chlorothiophene-2-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=639.3.
Example 42
[0868]
2-(5-[(benzoylamino)methyl]-thiophene-2-sulfonylamino)-4-methyl-pen-
tanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl)-amide. MS (ESI) M+H=658.3.
Example 43
[0869]
2-(4-phenylsulfonylthiophene-2-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=665.4.
Example 45
[0870]
2-(5-(phenylsulfonyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=665.4.
Example 46
[0871]
2-[2-(1-methyl-(5-trifluoromethyl)pyrazole)thiophene-5-sulfonylamin-
o]-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e-
][1,4]diazepin-3-yl)-amide. MS (ESI) M+H=673.4.
Example 47
[0872]
2-(5-(2-pyridyl)thiophene-2-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=602.4.
[0873] Tables 1 below provides representative Examples of the
compounds of Formula (I) of the present invention.
2TABLE 1 27 MassSpec Ex. # R--SO.sub.2-- (ESI, M + H) Found 3
3-bromo-5-chloro-2-thiophene-SO.sub.2-- 597.0 4
1-naphthalene-SO.sub.2-- 569.3 5 5-dimethylamino-naphthalene-1-SO.-
sub.2-- 612.4 6 2-naphthalene-SO.sub.2-- 569.3 7
2-acetamido-4-methyl-5-thiazole-SO.sub.2-- 597.3 8
2-thiophene-SO.sub.2-- 525.3 9 8-quinoline-SO.sub.2-- 570.3 10
phenyl-SO.sub.2-- 519.2 11 2,5-dichlorophenyl-SO.sub.2-- 588.1 12
1,3,5-trimethylphenyl-SO.sub.2-- 561.3 13 3-nitrophenyl-SO.sub.2--
564.2 14 4-bromophenyl-SO.sub.2-- 598.1 15
4-fluorophenyl-SO.sub.2-- 537.2 16 4-chlorophenyl-SO.sub.2- --
553.7 17 4-acetamidophenyl-SO.sub.2-- 576.3 18
4-nitrophenyl-SO.sub.2-- 564.2 19 4-methoxyphenyl-SO.sub.2-- 549.2
20 4-tert-butylphenyl-SO.sub.2-- 575.3 21 4-methylphenyl-SO.sub.2--
533.2 22 benzyl-SO.sub.2-- 533.2 23 beta-styrene-SO.sub.2-- 545.3
24 2-methoxycarbonylphenyl-SO.sub- .2-- 577.3 25
2-nitro-4-(trifluoromethyl)phenyl- 632.2 SO.sub.2-- 26
3-(trifluoromethyl)phenyl-SO.sub.2-- 587.2 27
2,5-dimethoxyphenyl-SO.sub.2-- 579.3 28 2-methylphenyl-SO.sub.2--
533.2 29 3,4-dichlorophenyl-SO.sub.2-- 588.1 30
4-(trifluoromethoxy)phenyl-SO.sub.2-- 603.2 31
3,4-dimethoxyphenyl-SO.sub.2-- 579.3 32 2-bromophenyl-SO.sub.2--
598.1 33 3,5-bis(trifluoromethyl)phenyl-SO.sub.2-- 655.3 34
4-ethylphenyl-SO.sub.2-- 547.3 35 4-isopropylphenyl-SO.sub.2--
561.3 36 2,5-dichlorothiophene-3-SO.sub.2-- 594.1 37
5-chlorothiophene-2-SO.sub.2-- 559.7 38 2-(trifluoromethyl)phenyl--
SO.sub.2-- 587.2 39 3-methylphenyl-SO.sub.2-- 533.2 40
2,3-dichlorothiophene-5-SO.sub.2-- 594.1 41
4-bromo-5-chlorothiophene-2-SO.sub.2-- 639.3 42
5-[(benzoylamino)methyl]-2-SO.sub.2-- 658.3 43
4-phenylsulfonylthiophene-2-SO.sub.2-- 665.4 45
5-(phenylsulfonyl)thiophene-2-SO.sub.2-- 665.4 46
2(1-methyl-(5-trifluoromethyl) 673.4 pyrazole)thiophene-5-SO.sub.-
2-- 47 5-(2-pyridyl)thiophene-2-SO.sub.2-- 602.4
Example 48
[0874]
1-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide 28
[0875] Step (48a) 1-Aminocyclohexanecarboxylic acid (1.5 grams,
10.5 mmol)was dissolved in 12.5 mL of a 1N solution of sodium
hydroxide, 6 mL of water, and 6 mL of tetrahydrofuran. To this
solution 3,5-dimethyl-isoxazole-4-sulfonyl chloride (2.45 g, 12.6
mmol) was added and the solution wsa stirred at rt for 16 hours. A
sufficient portion of 1N NaOH was then added to return the solution
to a pH of 9 or higher, and the reaction solution was extracted
2.times.with a 25 mL portion of dichloromethane and the combined
organic layers were discarded. The aqueous layer was then acidified
with 1N HCl until the pH was 3 or lower, and the aqueous layer was
extracted 3.times.with dichloromethane. The organic layers were
dried with magnesium sulfate and concentrated to a white solid 48a
which was used without further purification (234 mg, 7.4%).
[0876] Step (48b) The crude acid 48a (199 mg, 0.66 mg) was
dissolved in 8 mL of CH.sub.2Cl.sub.2 and treated with 0.25 mL (1.5
mmol) of diisopropylethylamine. The reaction solution was cooled to
0.degree. C. and stirred for 5 min. To the reaction mixture was
added 1-hydroxybenzotriazole (162 mg, 1.2 mmol) and HATU (285 mg,
0.75 mmol), and this mixture was stirred for 5 min. A 300 mg (0.60
mmol) portion of of
3-Amino-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one
was then added and the reaction solution was allowed to warm to rt
and stirred for 16 h. The reaction was quenched with 10 mL of
water, and the layers were separated. The organic layer was rinsed
with 10% citric acid, 1N Na OH, brine and then concentrated. The
resulting oil was dissolved in ethyl acetate, washed with water
(6.times.50 mL) and dried over sodium sulfate. After filtration and
concentration the compound of Example 48 was obtained as a pale
yellow solid 48 (125 mg, 38%), MS (API, MS (M+H).sup.+=551.
Example 49
[0877]
N-[1-(3'-Chloro-4'-fluoro-biphenyl-3-ylmethyl)-2-oxo-azepan-3-yl]-2-
-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide 29
[0878] Step (49a) Di-tert-butyldicarbonate (10.2 g, 46.7 mmoles)
was added portion wise to a solution of
L-(-)-.alpha.-amino-.epsilon.-caprolactam (5.0 g, 39.0 mmoles) in
dimethyl sulfoxide (30 mL). After 5 h at rt, the reaction was
partitioned between water (100 mL) and ethyl acetate. The combined
organic extracts were washed successively with 1 M HCl (50 mL),
brine, and dried (MgSO.sub.4) and concentrated in vacuo. The
residue was recrystallized in 1:1 v/v ether-hexanes, 2 crops
yielded the desired product (6.26 g, 70%) as white solid 49a. MS
(M+H-BOC).sup.+=129.
[0879] Step (49b) Boc-caprolactam 49a (5.0 g , 21.9 mmol) was
dissolved in 60 mL of THF and chilled to -78.degree. C. To the
chilled solution was added 24 mL of a 1.0 M solution of lithium
bis(trimethylsilyl)amide in THF, and the solution was brounght to
0.degree. C. and stirred for 15 min. To the anion solution was
added 6.5 g (22 mmol) of 3-iodobenzyl bromide (Aldrich) and the the
solution was allowed to warm to rt and stirred for 18 h. The
reaction solution was diluted with 50 mL of water and extracted
3.times.with ethyl acetate. The combined organic layers were dried
over MgSO.sub.4 and concentrated in vacuo. The crude product was
purified by chromatography eluting with a gradient of 5-20% ethyl
acetate/hexanes to afford 7.0 g (72%) of the alkylated
Boc-protected caprolactam as a white solid 49b. MS
(M+Na).sup.+=467.
[0880] Step (49c) The caprolactam 49b (1.1 g, 2.47 mmol) was
dissolved in 20 mL of a 50% solution of trifluoroacetic acid in
dichloromethane. After 2 h at rt, the solution was concentrated to
an oil. The oil was then dissolved in 50 mL of dichloromethane and
chilled to 0.degree. C. Boc-L-Alanine (0.47 g, 2.5 mmol) was then
added, followed by 1-hydroxybenzotriazole (0.75 g, 4.94 mmol), EDC
(0.6 g, 3.0 mmol) and triethylamine (0.86 mL, 6.2 mmol). After 16 h
at rt the reaction solution was diluted with 50 mL of 1 N HCl and
the aqueous layer was extracted with 2 30 mL portions of
dichloromethane. The organic layers were combined, dried and
concentrated and the residual oil was purified by chromatography
eluting with a gradient of 20-40% ethyl acetate/hexanes to afford
1.2 g (93%) of the desired caprolactam 49c. MS (ESI,
M+Na.sup.+)=538.2.
[0881] Step (49d) The caprolactam 49c (600 mg, 1.16 mmol) was
dissolved in 20 mL of toluene and 2 mL of methanol.
4-Fluoro-3-chlorophenylboronic acid (304 mg, 1.5 mmol) was then
added followed by tris(dibenzylideneaccetone) dipalladium (180 mg,
0.17 mmol), triphenylphosphine (184 mg, 0.7 mmol) and 1 mL of a 1M
solution of potassium carbonate. The reaction solution was heated
to reflux for 16 h and allowed to cool. The reaction solution was
then partitioned between 25 mL of ethyl acetate and 25 mL of brine
and the organic layer was removed. The aqueous layer was extracted
with 2 additional 10 mL portions of ethyl acetate and the combined
organic layers were dried and concentrated to an oil.
Chromatography eluting with a gradient of 1:5 to 2:5 ethyl
acetate/hexanes provided the desired biaryl caprolactam (500 mg,
83%) as a white solid 49d. MS (ESI, M+Na.sup.+)=540.3.
[0882] Step (49e) The biaryl caprolactam 49d (0.2 g, 0.39 mmol) was
dissolved in 20 mL of a 50% solution of trifluoroacetic acid in
dichloromethane. After 2 h at rt, the solution was concentrated to
an oil. The oil was then dissolved in 10 mL of dichloromethane and
108 .mu.L of triethylamine (0.772 mmol) and 91 mg of
3,5-dimethylisoxazole-4-sulfon- yl chloride were added. The
reaction solution was stirred at rt for 18 h , and then diluted
with 10 mL of water and extracted with 2 10 mL portions of
dichloromethane. The organic layers were dried and concentrated,
and the residual oil was purified by chromatography eluting with 5%
methanol in dichloromethane to afford 130 mg (63%) of the compound
of Example 49 as a white solid 49. MS (ESI, M+Na.sup.+)=623.4.
Example 50
[0883]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-N-[5-(4-fluoro-phenyl)-1-
-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide
[0884] Step(50a):
{1-[5-(4-Fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-be-
nzo[e][1,4]diazepin-3-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl
ester.
[0885] The compound of 50a was synthesized in a procedure analogous
to the synthesis of the compund of 1a using 0.5 g of
3-Amino-5-(4-fluoro-phenyl)-
-1-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one, and
N-Boc-(L)-alanine. In 88% yield.
[0886] Step (50b):
2-Amino-N-[5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihyd-
ro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide.
[0887] The compound of 50b was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 50a and was carried forward without purification.
[0888] Step (50c): The compound of Example 50 was synthesized from
the compound of 50b in a procedure analogous to the synthesis of
the compound of 2b using 3,5-dimethyl isoxazole-4-sulfonyl chloride
in 31% yield. MS (ESI) M+H=514.2.
Example 51
[0889]
2-2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic
Acid
[5-(4-fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diaz-
epin-3-yl]-amide
[0890] Step (51a):
{1-[5-(4-Fluoro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-b-
enzo[e][1,4]diazepin-3-ylcarbamoyl]-3-methyl-butyl}-carbamic acid
tert-butyl ester.
[0891] The compound of 51a was synthesized in a procedure analogous
to the synthesis of the compund of 1a using 0.5 g of
3-Amino-5-(4-fluoro-phenyl)-
-1-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one, and (L)-leucine.
In 92% yield.
[0892] Step (51b): 2-Amino-4-methyl-pentanoic acid
[5-(4-fluoro-phenyl)-1--
methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide.
[0893] The compound of 51b was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 51a and was carried forward without purification.
[0894] Step (51c): The compound of Example 51 was synthesized from
the compound of 50b in a procedure analogous to the synthesis of
the compound of 2b using 3,5-dimethyl isoxazole-4-sulfonyl chloride
in 36% yield. MS (ESI) M+H=556.2.
Example 52
[0895]
2-(2-Fluoro-benzenesulfonylamino)-N-[5-(4-fluoro-phenyl)-1-methyl-2-
-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide
[0896] Step (52a):
[1-(1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4-
]diazepin-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester.
[0897] The compound of 52a was synthesized in a procedure similar
to that of the compound of 1a but using N-Boc-(L)-alanine as the
amino acid in 94% yield.
[0898] Step (52b).
2-Amino-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo-
[e][1,4]diazepin-3-yl)-propionamide.
[0899] The compound of 52b was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 52a and was carried forward without purification.
[0900] Step (52c): The compound of Example 52 was synthesized from
the compound of 52b in a procedure analogous to the synthesis of
the compound of 2b using 2-fluorobenzene sulfonyl chloride in 68%
yield. MS (ESI) M+H=495.2.
Example 53
[0901]
N-(1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-y-
l)-2-(2-trifluoromethyl-benzenesulfonylamino)-propionamide
[0902] The compound of Example 53 was synthesized in a procedure
analogous to the synthesis of the compound of Example 52 using
2-trifluoromethyl benzene sulfonyl chloride in 68% yield. MS (ESI)
M+H=545.2.
Example 54
[0903] 2-(2-Fluoro-benzenesulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide
[0904] The compound of Example 54 was synthesized in a procedure
analogous to the synthesis of the compound of Example 1 using the
intermediate from 1b and 2-fluorobenzene sulfonyl chloride in 70%
yield. MS (ESI) M+H=537.2.
Example 55
[0905]
4-Methyl-2-(2-trifluoromethyl-benzenesulfonylamino)-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide
[0906] The compound of Example 55 was synthesized in a procedure
analogous to the synthesis of the compound of Example 1 using the
intermediate from 1b and 2-trifluoromethylbenzene sulfonyl chloride
in 65% yield. MS (ESI) M+H=587.2.
Example 56
[0907] 4-Methyl-2-(propane-1-sulfonylamino)-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide
[0908] The compound of Example 56 was synthesized in a procedure
analogous to the synthesis of the compound of Example 1 using the
intermediate from 1b and 1-propanesulfonyl chloride in 16% yield.
MS (ESI) M+H=485.2.
Example 57
[0909] 4-Methyl-2-(propane-1-sulfonylamino)-pentanoic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide
[0910] The compound of Example 57 was synthesized in a procedure
analogous to the synthesis of the compound of Example 1 using the
intermediate from 1b and 1-butanesulfonyl chloride. The compound
was purified by reverse-phase HLC and isolated in 1% yield. MS
(ESI) M+H=499.2.
Example 58
[0911]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-N-[1-methyl-2-oxo-5-(4-t-
rifluoromethyl-phenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propiona-
mide
[0912] Step (58a):
{1-[1-Methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dih-
ydro-1H-benzo[e][1,4]diazepin-3-ylcarbamoyl]-ethyl}-carbamic acid
tert-butyl ester.
[0913] The compound of 58a was synthesized in a procedure analogous
to the synthesis of the compund of 1a using 0.5 g of
3-Amino-1-methyl-5-(4-trifl-
uoromethyl-phenyl)-1,3-dihydro-benzo[e][1,4]diazepin-2-one, and
N-Boc-(L)-alanine. In 75% yield.
[0914] Step (58b):
3-Amino-1-methyl-5-(4-trifluoromethyl-phenyl)-1,3-dihyd-
ro-benzo[e][1,4]diazepin-2-one.
[0915] The compound of 58b was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 58a and was carried forward without purification.
[0916] Step (58c): The compound of Example 58 was synthesized from
the compound of 58b in a procedure analogous to the synthesis of
the compound of 2b using 3,5-dimethyl isoxazole-4-sulfonyl chloride
in 50% yield. MS (ESI) M+H=564.2.
Example 59
[0917]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic Acid
(7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3--
yl)-amide
[0918] Step (59a):
[1-(7-Chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-ben-
zo[e][1,4]diazepin-3-ylcarbamoyl)-3-methyl-butyl]-carbamic acid
tert-butyl ester.
[0919] The compound of 59a was synthesized in a procedure analogous
to the synthesis of the compund of 1a using 0.4 g of
3-Amino-7-chloro-1-methyl-5-
-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one, and
N-Boc-(L)-valine. In 93% yield.
[0920] Step (59b): 2-Amino-4-methyl-pentanoic acid
(7-chloro-1-methyl-2-ox-
o-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide.
[0921] The compound of 59b was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 59a and was carried forward without purification.
[0922] Step (59c): The compound of Example 59 was synthesized from
the compound of 59b in a procedure analogous to the synthesis of
the compound of 2b using 3,5-dimethyl isoxazole-4-sulfonyl chloride
in 50% yield. MS (ESI) M+H=572.2.
Example 60
[0923] 4-Methyl-2-(propane-1-sulfonylamino)-pentanoic Acid
[5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl]-amide
[0924] Step (60a):
{1-[5-(4-Chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-b-
enzo[e][1,4]diazepin-3-ylcarbamoyl]-3-methyl-butyl}-carbamic acid
tert-butyl ester.
[0925] The compound of 60a was synthesized in a procedure analogous
to the synthesis of the compund of 1a using 15.0 g of
3-Amino-5-(4-chloro-phenyl-
)-1-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one and
N-Boc-(L)-valine. in 53% yield.
[0926] Step (60b): 2-Amino-4-methyl-pentanoic acid
[5-(4-chloro-phenyl)-1--
methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-amide.
[0927] The compound of 60b was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 60a and was carried forward without purification.
[0928] Step (60c): The compound of Example 60 was synthesized from
the compound of 60b in a procedure analogous to the synthesis of
the compound of 2b using 1-propanesulfonyl chloride in 80% yield.
MS (ESI) M+H=519.2.
Example 61
[0929]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic Acid
(1-methyl-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-
-amide
[0930] Step (61a):
[3-Methyl-1-(1-methyl-2-oxo-5-pyridin-2-yl-2,3-dihydro--
1H-benzo[e][1,4]diazepin-3-ylcarbamoyl)-butyl]-carbamic acid
tert-butyl ester.
[0931] The compound of Example 61a was synthesized in a procedure
analogous to the synthesis of the compund of Example 1a using 0.31
g of
3-Amino-1-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one
and N-Boc-(L)-valine. in 50% yield.
[0932] Step (61b): 2-Amino-4-methyl-pentanoic acid
(1-methyl-2-oxo-5-pyrid-
in-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide.
[0933] The compound of Example 61b was deprotected using a
procedure analogous to the synthesis of the compound of Example 2b
but using the compound from 61a and was carried forward without
purification.
[0934] Step (61c): The compound of Example 61 was synthesized from
the compound of Example 61b in a procedure analogous to the
synthesis of the compound of Example 2b using 3,5-dimethyl
isoxazole-4-sulfonyl chloride in 39% yield. MS (ESI) M+H=539.2.
Example 62
[0935]
2-[(3,5-Dimethyl-isoxazole-4-sulfonyl)-methyl-amino]-N-(1-methyl-2--
oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0936] The compound from Example 60 (0.02 g) was dissolved in
methanol and treated with excess trimethylsilyldiazo-methane until
a yellow color persisted. The residual reagent was destroyed with
acetic acid and the solution was concentrated to provide the
compound of Example 63 in 100% yield. MS (ESI) M+H=510.2.
Example 63
[0937]
3-Dimethylamino-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(1-met-
hyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide
[0938] Step (63a):
[2-Chloro-1-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-ben-
zo[e][1,4]diazepin-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl
ester.
[0939] The compound of 63a was synthesized in a procedure analogous
to the synthesis of the compund of 1a using 0.26 g of
3-Amino-1-methyl-5-phenyl-- 1,3-dihydro-benzo[e][1,4]diazepin-2-one
and N-Boc-(L)-.-chloroalanine in 11% yield. MS (ESI)
M+Na=457.3.
[0940] Step (63b):
[2-Dimethylamino-1-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-
-1H-benzo[e][1,4]diazepin-3-ylcarbamoyl)-ethyl]-carbamic acid
tert-butyl ester.
[0941] The compound from 63a (50 mg, 0.1 mmol) was dissolved in 5
mL of acetonitrile and treated with 0.5 mL of 40% dimethylamine in
water. The reaction solution was stirred at rt for 2 h and
concentrated to provide the compound of 63b in 100% yield. MS (ESI)
M+H=480.3.
[0942] Step (63c):
2-Amino-3-dimethylamino-N-(1-methyl-2-oxo-5-phenyl-2,3--
dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide.
[0943] The compound of 63c was deprotected using a procedure
analogous to the synthesis of the compound of 2b but using the
compound from 63b and was carried forward without purification.
[0944] Step (63d): The compound of Example 63 was synthesized from
the compound of 61c in a procedure analogous to the synthesis of
the compound of 2b using 3,5-dimethyl isoxazole-4-sulfonyl chloride
in 50% yield. MS (ESI) M+H=539.2.
Example 64
[0945]
N-[1-Methyl-2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo-
[e][1,4]diazepin-3-yl]-2-(propane-1-sulfonylamino)-propionamide
[0946] The compound of Example 64 was synthesized from 0.1 g of the
compound of 58b in a procedure analogous to the synthesis of the
compound of 2b using 1-propanesulfonyl chloride in 50% yield. MS
(ESI) M+H=511.2.
Example 65
[0947]
N-(7-Chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]dia-
zepin-3-yl)-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-propionamide
[0948] The compound of Example 65 was synthesized using a procedure
analogous to the synthesis of the compound of Example 59 but using
N-Boc-(L)-alanine in the second step. MS (ESI) M+H=530.1.
Example 66
[0949]
2-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-4-methyl-pentanoic Acid
[5-(4-chloro-phenyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl]-amide
[0950] The compound of Example 66 was synthesized from 10 g of the
compound of 60b in a procedure analogous to the synthesis of the
compound of 2b using 3,5-dimethyl isoxazole-4-sulfonyl chloride in
56% yield. MS (ESI) M+H=572.2.
Example 67
[0951]
2-Methanesulfonylamino-N-[1-methyl-2-oxo-5-(4-trifluoromethyl-pheny-
l)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-propionamide
[0952] The compound of Example 67 was synthesized from 0.08 g of
the compound of 60b in a procedure analogous to the synthesis of
the compound of 58b using methanesulfonyl chloride in 60% yield. MS
(ESI) M+H=483.1.
[0953] Table 2 below provides representative Examples of the
compounds of Formula (I) of the present invention.
3TABLE 2 30 Ex. # R--SO.sub.2-- R5 R11 R13 50 3,5-dimethyl- methyl
4-F-phenyl H isoxazole-4-SO.sub.2-- 51 3,5-dimethyl- i-butyl
4-F-phenyl H isoxazole-4-SO.sub.2-- 52 2-fluorophenyl-SO.sub.2--
methyl 4-F-phenyl H 53 2-trifluoromethyl- methyl phenyl H
phenyl-SO.sub.2-- 54 2-fluorophenyl-SO.sub.2-- i-butyl phenyl H 55
2-trifluoromethyl- i-butyl phenyl H phenyl-SO.sub.2-- 56
n-propyl-SO.sub.2-- i-butyl phenyl H 57 n-butyl-SO.sub.2-- methyl
4-CF.sub.3-phenyl H 58 3,5-dimethyl- methyl 4-CF.sub.3-phenyl H
isoxazole-4-SO.sub.2-- 59 3,5-dimethyl- i-butyl phenyl Cl
isoxazole-4-SO.sub.2-- 60 n-propyl-SO.sub.2-- i-butyl 4-Cl-phenyl H
61 3,5-dimethyl- i-butyl pyridin-2-yl H isoxazole-4-SO.sub.2-- 62
3,5-dimethyl- methyl phenyl H isoxazole-4-SO.sub.2-- 63
3,5-dimethyl- (Me).sub.2N--CH.sub.2-- phenyl H
isoxazole-4-SO.sub.2-- 64 n-propyl-SO.sub.2-- methyl
4-CF.sub.3-phenyl H 65 3,5-dimethyl- methyl phenyl Cl
isoxazole-4-SO.sub.2-- 66 3,5-dimethyl- i-butyl 4-Cl-phenyl H
isoxazole-4-SO.sub.2-- 67 Methyl-SO.sub.2-- methyl
4-CF.sub.3-phenyl H
Examples 68-99
[0954] Examples 68-99 were synthesized in a manner similar to the
synthesis of the compounds of Examples 4-47, but using
1-Amino-cyclohexanecarboxylic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1-
H-benzo[e][1,4]diazepin-3-yl)-amide in a yield after RP-HPLC of
0.5-5 mg each.
[0955] The intermediate, 1-Amino-cyclohexanecarboxylic acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
, was synthesized by deprotection of
[1-(1-Methyl-2-oxo-5-phenyl-2,3-dihyd-
ro-1H-benzo[e][1,4]diazepin-3-ylcarbamoyl)-cyclohexyl]-carbamic
acid tert-butyl ester in a manner similar to the synthesis of the
compound of 1b.
[0956] The intermediate,
[1-(1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[-
e][1,4]diazepin-3-ylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl
ester, was synthesized in a manner similar to the synthesis of the
compound of 1a except using 1.5 g (10.5 mmol) of
N-Boc-1-aminocyclohexane.
Example 68
[0957] 1-(naphthalene-1-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=581.7.
Example 69
[0958] 1-(naphthalene-2-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=581.7.
Example 70
[0959] 1-(thiophene-2-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=537.7.
Example 71
[0960] 1-(phenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=531.6.
Example 72
[0961] 1-(2,5-dichlorophenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=600.5.
Example 73
[0962]
1-(2,4,6-trimethylphenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=573.7.
Example 74
[0963] 1-(3-nitrophenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=576.6.
Example 75
[0964] 1-(4-bromophenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=610.5.
Example 76
[0965] 1-(4-fluorophenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=549.6.
Example 77
[0966] 1-(4-chlorophenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=566.1.
Example 78
[0967] 1-(beta-styrene-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=557.7.
Example 79
[0968] 1-(4-nitrophenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=576.6.
Example 80
[0969] 1-(4-tert-butylphenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=587.7.
Example 81
[0970] 1-(p-toluene-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=545.7.
Example 82
[0971] 1-(benzyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=545.7.
Example 83
[0972]
1-(2-methoxycarbonylphenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=589.7.
Example 84
[0973]
1-(2-nitro-4-(trifluoromethyl)phenyl-sulfonylamino)-cyclohexanecarb-
oxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin--
3-yl)-amide. MS (ESI) M+H=644.6.
Example 85
[0974]
1-(3-(trifluoromethyl)phenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=599.6.
Example 86
[0975] 1-(2,5-dimethoxyphenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=591.7.
Example 87
[0976]
1-(2-methoxy-5chloro-1phenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=596.1.
Example 88
[0977] 1-(3,4-dichlorophenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=600.5.
Example 89
[0978]
1-(5-((benzoylamino)methyl)-thiophene-2-sulfonylamino)-cyclohexanec-
arboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazep-
in-3-yl)-amide. MS (ESI) M+H=670.8.
Example 90
[0979]
1-(4-(phenylsulfonyl)thiophene-2-sulfonylamino)-cyclohexanecarboxyl-
ic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl-
)-amide. MS (ESI) M+H=677.8.
Example 91
[0980]
1-(1-methyl-5-(trifluoromethyl)-imidazole-3-sulfonylamino)-cyclohex-
anecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]di-
azepin-3-yl)-amide. MS (ESI) M+H=685.7.
Example 92
[0981] 1-(4-phenyl-phenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=607.7.
Example 93
[0982] 1-(dibenzofuran-2-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=621.7.
Example 94
[0983] 1-(4-n-butylphenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=587.7.
Example 95
[0984]
1-(2-(2-methylthio-pyrimdin-3-yl)-thiophene-5-sulfonylamino)-cycloh-
exanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-
diazepin-3-yl)-amide. MS (ESI) M+H=661.8.
Example 96
[0985] 1-(4-phenoxy-phenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=623.7.
Example 97
[0986]
1-(3,5-dimethyl-isoxazole-4-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=550.6.
Example 98
[0987]
1-(2-(trifluoromethyl)phenyl-sulfonylamino)-cyclohexanecarboxylic
Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)--
amide. MS (ESI) M+H=599.6.
Example 99
[0988] 1-(2-methylphenyl-sulfonylamino)-cyclohexanecarboxylic Acid
(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-amide-
. MS (ESI) M+H=545.7.
[0989] Table 3 below provides representative Examples of the
compounds of Formula (I) of the present invention.
4TABLE 3 31 MassSpec Ex. # R--SO.sub.2-- (Found) 68
1-naphthalene-SO.sub.2-- 581.7 69 2-naphthalene-SO.sub.2-- 581.7 70
2-thiophene-SO.sub.2-- 537.7 71 phenyl-SO.sub.2-- 531.6 72
2,5-dichlorophenyl-SO.sub.2-- 600.5 73 2,4,6-trimethylphenyl-SO.su-
b.2-- 573.7 74 3-nitrophenyl-SO.sub.2-- 576.6 75
4-bromophenyl-SO.sub.2-- 610.5 76 4-fluorophenyl-SO.sub.2-- 549.6
77 4-chlorophenyl-SO.sub.2-- 566.1 78 beta-styrene-SO.sub.2-- 557.7
79 4-nitrophenyl-SO.sub.2-- 576.6 80 4-tert-butylphenyl-SO.sub.2--
587.7 81 4-methylphenyl-SO.sub.2-- 545.7 82 benzyl-SO.sub.2-- 545.7
83 2-methoxycarbonylphenyl-SO.sub.2-- 589.7 84
2-nitro-4-(trifluoromethyl)phenyl-SO.sub.2-- 644.6 85
3-(trifluoromethyl)phenyl-SO.sub.2-- 599.6 86
2,5-dimethoxyphenyl-SO.sub.2-- 591.7 87 2-methoxy-5-chlorophenyl-S-
O.sub.2-- 596.1 88 3,4-dichlorophenyl-SO.sub.2-- 600.5 89
5-[(benzoylamino)methyl]thiophene-2-SO.sub.2-- 670.8 90
4-(phenylsulfonyl)thiophene-2-SO.sub.2-- 677.8 91
1-methyl-5-(trifluoromethyl)imidazole-3-SO.sub.2-- 685.7 92
4-phenyl-phenyl-SO.sub.2-- 607.7 93 dibenzofuran-2-SO.sub.2-- 621.7
94 4-n-butylphenyl-SO.sub.2-- 587.7 95
2-(2-methylthio-pyrimdin-3-yl)thiophene-5-SO.sub.2-- 661.8 96
4-phenoxy-phenyl-SO.sub.2-- 623.7 97 3,5-dimethyl-isoxazole-4-SO.s-
ub.2-- 550.6 98 2-(trifluoromethyl)phenyl-SO.sub.2-- 599.6 99
2-methylphenyl-SO.sub.2-- 545.7
Utility
[0990] 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 .beta. 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.
[0991] 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 98/22493, EPO publication
number 0652009, U.S. Pat. Nos. 5,703,129 and 5,593,846; all hereby
incorporated by reference.
[0992] The compounds of the present invention have utility for the
prevention and treatment of disorders involving A.beta. production,
such as cerebrovascular disorders.
[0993] Compounds of the present invention have been shown to
inhibit A.beta. production, as determined by the secretase
inhibition assay described below.
[0994] 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.
[0995] 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.
[0996] 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.
[0997] 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.
[0998] 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.
[0999] .beta. Amyloid Precursor Protein Accumulation Assay
[1000] 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.
[1001] 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.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
150uCi 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.
[1002] 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 ul 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.
[1003] C-Terminus .beta. Amyloid Precursor Protein Accumulation
Assay
[1004] 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 1% 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
(1%) 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.
[1005] A.beta. Immunoprecipitation Assay
[1006] 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 .gamma. 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
[1007] 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.
[1008] 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.
[1009] 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.
[1010] 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.
[1011] 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.
[1012] 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.
[1013] 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.
[1014] 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.
[1015] 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.
[1016] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-ph- enol,
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.
[1017] 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.
[1018] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance. 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.
[1019] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field.
* * * * *