U.S. patent application number 11/567616 was filed with the patent office on 2007-12-27 for hydroxy alkyl amines.
This patent application is currently assigned to Elan Pharmaceuticals, Inc. and Pharmacia & Upjohn Company. Invention is credited to David L. Brown, Larry Fang, Yvette M. Fobian, John Freskos, Varghese John, Arthur Glenn Romero.
Application Number | 20070299263 11/567616 |
Document ID | / |
Family ID | 27404346 |
Filed Date | 2007-12-27 |
United States Patent
Application |
20070299263 |
Kind Code |
A1 |
Freskos; John ; et
al. |
December 27, 2007 |
Hydroxy Alkyl Amines
Abstract
Disclosed are compounds of formula X, ##STR1## which are useful
in treating Alzheimer's disease and other similar diseases.
Pharmaceutical compositions comprising compounds of formula X and
methods of preparing the compounds of formula X are also
disclosed.
Inventors: |
Freskos; John; (Clayton,
MO) ; Brown; David L.; (Chesterfield, MO) ;
Fobian; Yvette M.; (Wildwood, MO) ; Fang; Larry;
(Foster City, CA) ; Romero; Arthur Glenn;
(Kalamazoo, MI) ; John; Varghese; (San Francisco,
CA) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Elan Pharmaceuticals, Inc. and
Pharmacia & Upjohn Company
|
Family ID: |
27404346 |
Appl. No.: |
11/567616 |
Filed: |
December 6, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10160777 |
May 31, 2002 |
7144897 |
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11567616 |
Dec 6, 2006 |
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60343772 |
Dec 28, 2001 |
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60332639 |
Nov 19, 2001 |
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60295332 |
Jun 1, 2001 |
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Current U.S.
Class: |
546/226 ;
546/315; 548/333.5; 548/374.1; 549/373; 560/37; 564/162;
564/443 |
Current CPC
Class: |
C07D 211/96 20130101;
C07D 277/36 20130101; C07D 211/46 20130101; C07D 213/81 20130101;
C07C 327/32 20130101; C07D 309/12 20130101; A61P 25/16 20180101;
C07D 319/06 20130101; C07D 317/30 20130101; C07D 307/20 20130101;
C07D 231/14 20130101; C07C 2601/08 20170501; C07C 317/48 20130101;
C07D 207/28 20130101; C07D 209/08 20130101; C07D 233/64 20130101;
A61P 25/28 20180101; C07C 2601/02 20170501; C07D 277/56 20130101;
C07D 295/185 20130101; C07D 233/74 20130101; C07C 2601/14 20170501;
C07C 323/60 20130101; C07D 213/82 20130101; C07D 231/12 20130101;
C07D 241/24 20130101; A61P 43/00 20180101; C07C 317/46 20130101;
C07D 213/30 20130101; C07D 233/56 20130101; C07D 237/04 20130101;
C07D 333/48 20130101; C07C 317/50 20130101; C07D 333/32 20130101;
C07D 207/12 20130101; C07D 233/90 20130101; C07D 207/26 20130101;
C07D 261/18 20130101; C07D 249/08 20130101; C07D 333/34
20130101 |
Class at
Publication: |
546/226 ;
546/315; 548/333.5; 548/374.1; 549/373; 560/037; 564/162;
564/443 |
International
Class: |
C07D 233/22 20060101
C07D233/22; C07C 215/00 20060101 C07C215/00; C07C 229/28 20060101
C07C229/28; C07D 319/06 20060101 C07D319/06; C07C 235/02 20060101
C07C235/02; C07D 211/80 20060101 C07D211/80 |
Claims
1. A compound of the formula: ##STR352## or a pharmaceutically
acceptable salt thereof, wherein R.sub.N is: ##STR353## wherein
R.sub.4 is selected from the group consisting of H; NH.sub.2;
--NH--(CH.sub.2).sub.n6--R.sub.4-1; --NHR.sub.8;
--NR.sub.50C(O)R.sub.5; C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5;
--(CH.sub.2).sub.0-4R.sub.8; --O--C.sub.1-C.sub.4 alkanoyl; OH;
C.sub.6-C.sub.10 aryloxy optionally substituted with 1, 2, or 3
groups that are independently halogen, C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --C(O)--C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
alkoxy; C.sub.1-C.sub.6 alkoxy; aryl C.sub.1-C.sub.4 alkoxy;
--NR.sub.50CO.sub.2R.sub.51; --C.sub.1-C.sub.4
alkyl-NR.sub.50CO.sub.2R.sub.51; --C.ident.N; --CF.sub.3;
--CF.sub.2--CF.sub.3; --C.ident.CH; --CH.sub.2--CH.dbd.CH.sub.2;
--(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1;
--O--(CH.sub.2).sub.n6--R.sub.4-1;
--S--(CH.sub.2).sub.n6--R.sub.4-1;
--(CH.sub.2).sub.0-4--NHC(O)--(CH.sub.2).sub.0-6--R.sub.52;
--(CH.sub.2).sub.0-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54;
wherein n.sub.6 is 0, 1, 2, or 3; n.sub.7 is 0, 1, 2, or 3;
R.sub.4-1 is selected from the group consisting of
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), --SO--(C.sub.1-C.sub.8 alkyl),
--S--(C.sub.1-C.sub.8 alkyl), --S--CO--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; R.sub.4-2 and R.sub.4-3 are
independently H, C.sub.1-C.sub.3 alkyl, or C.sub.3-C.sub.6
cycloalkyl; R.sub.4-4 is alkyl, arylalkyl, alkanoyl, or
arylalkanoyl; R.sub.4-6 is --H or C.sub.1-C.sub.6 alkyl; R.sub.5 is
selected from the group consisting of C.sub.3-C.sub.7 cycloalkyl;
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
that are independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4
alkoxy, C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.7 cycloalkyl
C.sub.1-C.sub.4 alkyl, --S--C.sub.1-C.sub.4 alkyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, --CO.sub.2H,
--CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4 alkyl,
C.sub.6-C.sub.10 aryloxy; aryl optionally substituted with 1, 2, 3,
or 4 groups that are independently halogen, OH, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4haloalkyl; and
--NR.sub.6R.sub.7; wherein R.sub.6 and R.sub.7 are independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4
alkyl, phenyl C.sub.1-C.sub.4 alkyl; R.sub.8 is selected from the
group consisting of --SO.sub.2-aryl, --SO.sub.2--C.sub.1-C.sub.10
alkyl, --C(O)NHR.sub.9, --S--C.sub.1-C.sub.6 alkyl,
--S--C.sub.2-C.sub.4 alkanoyl, wherein R.sub.9 is aryl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkyl, or H; R.sub.50 is H
or C.sub.1-C.sub.6 alkyl; R.sub.51 is selected from the group
consisting of aryl C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently halogen, cyano, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.1-C.sub.4 alkoxy; alkenyl; alkynyl; aryl; C.sub.3-C.sub.8
cycloalkyl; and cycloalkylalkyl; wherein the aryl; C.sub.3-C.sub.8
cycloalkyl, and cycloalkylalkyl groups are optionally substituted
with 1, 2, 3, 4 or 5 groups that are independently halogen, CN,
NO.sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, hydroxy, C.sub.0-C.sub.6 hydroxyalkyl,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
thioalkoxy, C.sub.1-C.sub.6 thioalkoxy C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkoxy; R.sub.52 is aryl,
cycloalkyl, --S(O).sub.0-2--C.sub.1-C.sub.6 alkyl, CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(alkyl), --C(O)N(alkyl)(alkyl),
--CO.sub.2-alkyl, --NHS(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--N(alkyl)S(O).sub.0-2--C.sub.1-C.sub.6 alkyl, --S(O).sub.0-2-aryl,
--NH(arylalkyl), --N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each
of which is optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently alkyl, alkoxy, thioalkoxy, halogen,
haloalkyl, haloalkoxy, alkanoyl, NO.sub.2, CN, alkoxycarbonyl, or
aminocarbonyl; R.sub.53 is absent, --O--, --C(O)--, --NH--,
--N(alkyl)-, --NH--S(O).sub.0-2--, --N(alkyl)-S(O).sub.0-2--,
--S(O).sub.0-2--NH--, --S(O).sub.0-2--N(alkyl)-, --NH--C(S)--, or
--N(alkyl)-C(S)--; R.sub.54 is aryl, arylalkyl, CO.sub.2H,
--CO.sub.2-alkyl, --C(O)NH(alkyl), --C(O)N(alkyl)(alkyl),
--C(O)NH.sub.2, C.sub.1-C.sub.8 alkyl, OH, aryloxy, alkoxy,
arylalkoxy, NH.sub.2, NH(alkyl), N(alkyl)(alkyl), or
--C.sub.1-C.sub.6 alkyl-CO.sub.2--C.sub.1-C.sub.6 alkyl, each of
which is optionally substituted with 1, 2, 3, 4, or 5 groups that
are independently alkyl, alkoxy, CO.sub.2H, --CO.sub.2-alkyl,
thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl,
NO.sub.2, CN, alkoxycarbonyl, or aminocarbonyl; X is selected from
the group consisting of --C.sub.1-C.sub.6 alkylidenyl optionally
substituted with 1, 2, or 3 methyl groups; and --NR.sub.4-6--; or
R.sub.4 and R.sub.4-6 combine to form --(CH.sub.2).sub.n10--,
wherein n.sub.10 is 1, 2, 3, or 4; Z is selected from the group
consisting of a bond; SO.sub.2; SO; S; and C(O); Y is selected from
the group consisting of H; C.sub.1-C.sub.4 haloalkyl;
C.sub.5-C.sub.6 heterocycloalkyl; C.sub.6-C.sub.10 aryl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from the group consisting of halogen,
hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8
cycloalkyl optionally substituted with 1, 2, or 3 groups
independently selected from C.sub.1-C.sub.3 alkyl, and halogen;
alkoxy; aryl optionally substituted with halogen, alkyl, alkoxy, CN
or NO.sub.2; arylalkyl optionally substituted with halogen, alkyl,
alkoxy, CN or NO.sub.2; wherein Y.sub.1 and Y.sub.2 are the same or
different and are H; C.sub.1-C.sub.10 alkyl optionally substituted
with 1, 2, or 3 substituents selected from the group consisting of
halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkenyl; C2-CO alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl; or
C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or Y.sub.1,
Y.sub.2 and the nitrogen to which they are attached form a ring
selected from the group consisting of piperazinyl, piperidinyl,
morpholinyl, and pyrrolidinyl, wherein each ring is optionally
substituted with 1, 2, 3, or 4 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy C.sub.1-C.sub.6 alkyl, or halogen; R.sub.20 at each
occurrence is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, hydroxy
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkanoyl, each of which is unsubstituted or substituted with 1, 2,
3, or 4 groups independently selected from halogen, alkyl, hydroxy,
alkoxy, and NH.sub.2, and --R.sub.26-R.sub.27, wherein R.sub.26 is
selected from the group consisting of --C(O)--, --SO.sub.2--,
--CO.sub.2--, --C(O)NH--, and --C(O)N(C.sub.1-C.sub.6 alkyl)-;
R.sub.27 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6 alkyl,
heterocycloalkyl, and heteroaryl, wherein each of the above is
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, haloalkyl, hydroxyalkyl, --C(O)NH.sub.2, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); R.sub.1 is
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
--CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), or
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --F, --Cl, --Br, --I,
OH, .dbd.O, --SH, --C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3
alkoxy, amino, mono- or dialkylamino, --N(R)C(O)R'--,
--OC(.dbd.O)-amino and --OC(.dbd.O)-mono- or dialkylamino, or
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl, each of which
is optionally substituted with 1, 2, or 3 groups independently
selected from halogen, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino, and mono-
or dialkylamino, or aryl, heteroaryl, heterocyclyl,
--C.sub.1-C.sub.6 alkyl-aryl, --C.sub.1-C.sub.6 alkyl-heteroaryl,
or --C.sub.1-C.sub.6 alkyl-heterocyclyl, where the ring portions of
each are optionally substituted with 1, 2, 3, or 4 groups
independently selected from halogen, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --NR.sub.105R'.sub.105, --CO.sub.2R',
--N(R)COR', or --N(R)SO.sub.2R', --C(.dbd.O)--(C.sub.1-C.sub.4)
alkyl, --SO.sub.2-amino, --SO.sub.2-mono or dialkylamino,
--C(.dbd.O)-amino, --C(.dbd.O)-mono or dialkylamino,
--SO.sub.2--(C.sub.1-C.sub.4) alkyl, or --C.sub.1-C.sub.6 alkoxy
optionally substituted with 1, 2, or 3 groups which are
independently a selected from halogen, or C.sub.3-C.sub.7
cycloalkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino,
--C.sub.1-C.sub.6 alkyl and mono- or dialkylamino, or
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3 alkoxy,
amino, mono- or dialkylamino and --C.sub.1-C.sub.3 alkyl, or
C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, each of which
is optionally substituted with 1, 2, or 3 groups independently
selected from halogen, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino,
C.sub.1-C.sub.6 alkyl and mono- or dialkylamino; and the
heterocyclyl group is optionally further substituted with oxo; R
and R' independently are hydrogen or C.sub.1-C.sub.10 alkyl;
R.sub.2 is selected from the group consisting of H; C.sub.1-C.sub.6
alkyl, optionally substituted with 1, 2, or 3 substituents that are
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b; wherein
R.sub.1-a and R.sub.1-b are --H or C.sub.1-C.sub.6 alkyl;
--(CH.sub.2).sub.0-4-aryl; --(CH.sub.2).sub.0-4-heteroaryl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl;
--CONR.sub.N-2R.sub.N-3; --SO.sub.2NR.sub.N-2R.sub.N-3;
--CO.sub.2H; and --CO.sub.2--(C.sub.1-C.sub.4 alkyl); R.sub.3 is
selected from the group consisting of H; C.sub.1-C.sub.6 alkyl,
optionally substituted with 1, 2, or 3 substituents independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b; --(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.0-4-heteroaryl; C.sub.2-C.sub.6 alkenyl;
C.sub.2-C.sub.6 alkynyl; --CO--NR.sub.N-2R.sub.N-3;
--SO.sub.2--NR.sub.N-2R.sub.N-3; --CO.sub.2H; and
--CO--O--(C.sub.1-C.sub.4 alkyl); or R.sub.2, R.sub.3 and the
carbon to which they are attached form a carbocycle of three thru
seven carbon atoms, wherein one carbon atom is optionally replaced
by a group selected from --O--, --S--, --SO.sub.2--, or
--NR.sub.N-2--; R.sub.C is selected from the group consisting of
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of
R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S(.dbd.O).sub.0-2(C.sub.1-C.sub.6 alkyl), --SH,
--NR.sub.235C.dbd.ONR.sub.235R.sub.240,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-aryl-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-aryl-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-aryl-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl-aryl;
--[C(R.sub.255)(R.sub.260)].sub.1-3--CO--N--(R.sub.255).sub.2;
--CH(aryl).sub.2; --CH(heteroaryl).sub.2;
--CH(heterocycloalkyl).sub.2; --CH(aryl)(heteroaryl); cyclopentyl,
cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or
heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl,
or cycloheptyl is optionally replaced with NH, NR.sub.215, O, or
S(.dbd.O).sub.0-2, and wherein the cyclopentyl, cyclohexyl, or
cycloheptyl group can be optionally substituted with 1 or 2 groups
that are independently R.sub.205 or .dbd.O;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl);
C.sub.2-C.sub.10 alkenyl optionally substituted with 1, 2, or 3
R.sub.205 groups; C.sub.2-C.sub.10 alkynyl optionally substituted
with 1, 2, or 3 R.sub.205 groups; --(CH.sub.2)O--,
--CH((CH.sub.2).sub.0-6--OH)--(CH.sub.2).sub.0-1-aryl;
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1-heteroaryl;
--CH(-aryl or -heteroaryl)-CO--O(C.sub.1-C.sub.4 alkyl);
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2; (C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH;
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; --H;
and --(CH.sub.2).sub.0-6--C(.dbd.NR.sub.235)(NR.sub.235R.sub.240);
wherein each aryl is optionally substituted with 1, 2, or 3
R.sub.200; each heteroaryl is optionally substituted with 1, 2, 3,
or 4 R.sub.200; each heterocycloalkyl is optionally substituted
with 1, 2, 3, or 4 R.sub.210; R.sub.200 at each occurrence is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl optionally substituted with 1, 2, or 3 R.sub.205 groups; OH;
--NO.sub.2; halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl);
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl);
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.7 cycloalkyl);
--(CH.sub.2).sub.0-4--CO-aryl; --(CH.sub.2).sub.0-4--CO-heteroaryl;
--(CH.sub.2).sub.0-4--CO-heterocycloalkyl;
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215;
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl);
--(CH.sub.2).sub.0-4
--N(H or R.sub.215)--CO.sub.2R.sub.215; --(CH.sub.2).sub.0-4--N(H
or R.sub.215)--CO--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--N(--H or R.sub.215)--CO--R.sub.220;
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl);
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.240).sub.2;
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--(R.sub.215).sub.2--COOH;
--(CH.sub.2).sub.0-4--S--(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); C.sub.3-C.sub.7 cycloalkyl;
C.sub.2-C.sub.6 alkenyl optionally substituted with 1 or 2
R.sub.205 groups; C.sub.2-C.sub.6 alkynyl optionally substituted
with 1 or 2 R.sub.205 groups; --(CH.sub.2).sub.0-4--N(H or
R.sub.215)--SO.sub.2--R.sub.220; and
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl; wherein each aryl
group at each occurrence is optionally substituted with 1, 2, or 3
groups that are independently R.sub.205, R.sub.210 or
C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups that are
independently R.sub.205 or R.sub.210; wherein each heterocycloalkyl
group at each occurrence is optionally substituted with 1, 2, or 3
groups that are independently R.sub.210; wherein each heteroaryl
group at each occurrence is optionally substituted with 1, 2, or 3
groups that are independently R.sub.205, R.sub.210, or
C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups that are
independently R.sub.205 or R.sub.210; R.sub.205 at each occurrence
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, halogen, --OH, --O-phenyl, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); R.sub.210 at each occurrence is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
R.sub.205 groups; C.sub.2-C.sub.6 alkynyl optionally substituted
with 1, 2, or 3 R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; --CO--(C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and .dbd.O; wherein R.sub.215
at each occurrence is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.0-2-(aryl),
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7
cycloalkyl, and --(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the aryl group at
each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
R.sub.220 and R.sub.225 at each occurrence are independently
selected from the group consisting of --H, --C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, amino C.sub.1-C.sub.6 alkyl; halo
C.sub.1-C.sub.6 alkyl; --C.sub.3-C.sub.7 cycloalkyl,
--(C.sub.1-C.sub.2alkyl)-(C.sub.3-C.sub.7 cycloalkyl),
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl),
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, -aryl, -heteroaryl, and -heterocycloalkyl; wherein the aryl
group at each occurrence is optionally substituted with 1, 2, or 3
R.sub.270 groups, wherein R.sub.270 at each occurrence is
independently R.sub.205, C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
haloalkoxy; NR.sub.235R.sub.240; OH; C.ident.N; C.sub.3-C.sub.7
cycloalkyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
--CO--(C.sub.1-C.sub.4 alkyl); SO.sub.2--NR.sub.235R.sub.240;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl); and
.dbd.O; wherein the heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, or 3 R.sub.205 groups; wherein
each heteroaryl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.205 groups; R.sub.235 and R.sub.240 at each
occurrence are independently H, or C.sub.1-C.sub.6 alkyl; R.sub.245
and R.sub.250 at each occurrence are independently selected from
the group consisting of H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy,
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, aryl C.sub.1-C.sub.4 alkyl,
heteroaryl C.sub.1-C.sub.4 alkyl, and phenyl; or R.sub.245 and
R.sub.250 are taken together with the carbon to which they are
attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,
optionally where one carbon atom is replaced by a heteroatom
selected from the group consisting of --O--, --S--, --SO.sub.2--,
and --NR.sub.220--; R.sub.255 and R.sub.260 at each occurrence are
independently selected from the group consisting of H;
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; C.sub.2-C.sub.6 alkenyl optionally substituted
with 1, 2, or 3 R.sub.205 groups; C.sub.2-C.sub.6 alkynyl
optionally substituted with 1, 2, or 3 R.sub.205 groups;
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl);
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; --(C.sub.1-C.sub.4
alkyl)-aryl; --(C.sub.1-C.sub.4 alkyl)-heteroaryl;
--(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl; -aryl; -heteroaryl;
-heterocycloalkyl;
(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heteroaryl;
and;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heterocycloalkyl;
wherein R.sub.265 at each occurrence is independently --O--, --S--
or --N(C.sub.1-C.sub.6 alkyl)-; each aryl or phenyl is optionally
substituted with 1, 2, or 3 groups that are independently
R.sub.205, R.sub.210, or C.sub.1-C.sub.6 alkyl substituted with 1,
2, or 3 groups that are independently R.sub.205 or R.sub.210; each
heteroaryl is optionally substituted with 1, 2, 3, or 4 R.sub.200,
each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4
R.sub.210.
2. A compound according to claim 1 wherein R.sub.1 is
(CH.sub.2).sub.n1--(R.sub.1-aryl) where n.sub.1 is zero or one and
R.sub.1-aryl is phenyl optionally substituted with 1, 2, 3, or 4
groups independently selected from C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sup.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy; halogen; C.sub.1-C.sub.6 alkoxy; --NR.sub.N-2R.sub.N-3; and
OH; wherein R.sub.N-2 and R.sub.N-3 at each occurrence are
independently selected from the group consisting of
--C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of --OH,
--NH.sub.2, phenyl and halogen; --C.sub.3-C.sub.8 cycloalkyl;
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl);
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl);
--C.sub.2-C.sub.6 alkenyl; --C.sub.2-C.sub.6 alkynyl;
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond; aryl; heteroaryl; heterocycloalkyl; or R.sub.N-2, R.sub.N-3
and the nitrogen to which they are attached form a 5, 6, or 7
membered heterocycloalkyl or heteroaryl group, wherein said
heterocycloalkyl or heteroaryl group is optionally fused to a
benzene, pyridine, or pyrimidine ring, and said groups are
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at
each occurrence are independently C.sub.0-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, halo C.sub.0-C.sub.6 alkyl, halo
C.sub.0-C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --OH, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
thioalkoxy, and C.sub.1-C.sub.6 thioalkoxy C.sub.1-C.sub.6
alkyl.
3. A compound according to claim 2, wherein R.sub.N is: ##STR354##
wherein R.sub.4 is NH.sub.2; --NH--(CH.sub.2).sub.n6--R.sub.4-1;
--NHR.sub.8; --NR.sub.50C(O)R.sub.5; or
--NR.sub.50CO.sub.2R.sub.51; wherein n.sub.6 is 0, 1, 2, or 3;
n.sub.7 is 0, 1, 2, or 3; R.sub.4-1 is selected from the group
consisting of --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO--(C.sub.1-C.sub.8 alkyl), --S--(C.sub.1-C.sub.8 alkyl),
--S--CO--(C.sub.1-C.sub.6 alkyl), --SO.sub.2--NR.sub.4-2R.sub.4-3;
--CO--C.sub.1-C.sub.2 alkyl; --CO--NR.sub.4-3R.sub.4-4; R.sub.4-2
and R.sub.4-3 are independently H, C, C.sub.3 alkyl, or
C.sub.3-C.sub.6 cycloalkyl; R.sub.4-4 is alkyl, phenylalkyl,
C.sub.2-C.sub.4 alkanoyl, or phenylalkanoyl; R.sub.5 is selected
from the group consisting of cyclopropyl, cyclopentyl, and
cyclohexyl; C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2,
or 3 groups that are independently halogen, --NR.sub.6R.sub.7,
C.sub.1-C.sub.4 alkoxy, phenyl, C.sub.3-C.sub.7 cycloalkyl,
--S--C.sub.1-C.sub.4 alkyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4
alkyl, or phenyloxy; phenyl optionally substituted with 1, 2, 3, or
4 groups that are independently halogen, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkyl; and
--NR.sub.6R.sub.7; wherein R.sub.6 and R.sub.7 are independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4
alkyl, and phenyl C.sub.1-C.sub.4 alkyl; R.sub.8 is selected from
the group consisting of --SO.sub.2-aryl, --C(O)NHR.sub.9,
--S--C.sub.2-C.sub.4 alkanoyl, wherein R.sub.9 is phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkyl, or H; R.sub.50 is H
or C.sub.1-C.sub.6 alkyl; R.sub.51 is selected from the group
consisting of phenyl C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently halogen, cyano, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, C.sub.3-C.sub.7 or --C.sub.1-C.sub.4 alkoxy;
phenyl; C.sub.3-C.sub.8 cycloalkyl, and cycloalkylalkyl, wherein
the phenyl; C.sub.3-C.sub.8 cycloalkyl, and cycloalkylalkyl groups
are optionally substituted with 1, 2, 3, 4 or 5 groups that are
independently halogen, CN, NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, hydroxy, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 thioalkoxy, C.sub.1-C.sub.6 thioalkoxy
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkoxy.
4. A compound according to claim 3, wherein ##STR355## X is
C.sub.1-C.sub.4 alkylidenyl optionally substituted with 1, 2, or 3
methyl groups; or --NR.sub.4-6--; or R.sub.4 and R.sub.4-6 combine
to form --(CH.sub.2).sub.n10--, wherein n.sub.10 is 1, 2, 3, or 4;
Z is selected from a bond; SO.sub.2; SO; S; and C(O); Y is selected
from H; C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8 cycloalkyl optionally
substituted with 1, 2, or 3 groups independently selected from
C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; phenyl C.sub.1-C.sub.4 alkyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; wherein Y.sub.1 and Y.sub.2 are the same or
different and are H; C.sub.1-C.sub.10 alkyl optionally substituted
with 1, 2, or 3 substituents selected from the group consisting of
halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl;
and C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen; R.sub.20
at each occurrence is independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, each
of which is unsubstituted or substituted with 1, or 2 groups
independently selected from halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, NH.sub.2, and --R.sub.26-R.sub.27,
wherein R.sub.26 is selected from --C(O)--, --SO.sub.2--,
--CO.sub.2--, --C(O)NH--, and --C(O)N(C.sub.1-C.sub.6 alkyl)-;
R.sub.27 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6 alkyl,
heterocycloalkyl, and heteroaryl, wherein each of the above is
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, halo C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
--C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
5. A compound according to claim 4, wherein R.sub.1 is benzyl which
is optionally substituted with 1, 2, 3, or 4 groups independently
selected from halogen, C.sub.1-C.sub.4 alkoxy, hydroxy, and
C.sub.1-C.sub.4 alkyl optionally substituted with 1, 2, or 3
substituents halogen, OH, SH, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N--(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), C.ident.N,
CF.sub.3; R.sub.2 and R.sub.3 are independently selected from H or
C.sub.1-C.sub.4 alkyl optionally substituted with 1 substituent
selected from halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), and
NH(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); R.sub.20 at each
occurrence is independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.2 alkoxy C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.6 alkanoyl, each of which is unsubstituted or
substituted with 1 or 2 groups independently selected from halogen,
hydroxy, and NH.sub.2; R.sub.C is C.sub.1-C.sub.8 alkyl optionally
substituted with 1, 2, or 3 groups independently selected from
R.sub.205, --SH, --C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from R.sub.205, --CO.sub.2H, and
--CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl optionally substituted with
1, 2, or 3 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyridazinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrimidinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazinyl;
--(CR.sub.245R.sub.250).sub.0-3-furyl;
--(CR.sub.245R.sub.250).sub.0-3-indolyl;
--(CR.sub.245R.sub.250).sub.0-3-thienyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1, 2, 3, or 4
R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-piperazinyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl;
(CR.sub.245R.sub.250).sub.0-3-indolinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1, 2, 3, or
4 R.sub.210;
(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--(CH.sub.2).sub.0-1-phenyl-
; --(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; and
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); R.sub.205 at each occurrence is
independently C.sub.1-C.sub.6 alkyl, halogen, --OH, --O-phenyl,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); R.sub.210 at each occurrence is
independently C.sub.1-C.sub.6 alkyl optionally substituted with 1
or 2 R.sub.205 groups; halogen; C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.4 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1 or 2
R.sub.205 groups; --CO--(C.sub.1-C.sub.4 alkyl);
--SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and .dbd.O; wherein R.sub.215
at each occurrence is independently C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.6 cycloalkyl,
--(CH.sub.2).sub.0-2-(pyridyl), --(CH.sub.2).sub.0-2-(pyrrolyl),
--(CH.sub.2).sub.0-2-(imidazolyl),
--(CH.sub.2).sub.0-2-(pyrimidyl),
--(CH.sub.2).sub.0-2-(pyrrolidinyl),
--(CH.sub.2).sub.0-2-(imidazolidinyl)-(CH.sub.2).sub.0-2-(piperazinyl),
--(CH.sub.2).sub.0-2-(piperidinyl), and
--(CH.sub.2).sub.0-2-(morpholinyl); wherein the phenyl group at
each occurrence is optionally substituted with 1 or 2 groups that
are independently R.sub.205 or R.sub.210; wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1 or 2 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1 or 2 R.sub.210;
R.sub.220 and R.sub.225 at each occurrence are independently --H,
--C.sub.1-C.sub.4 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.6 cycloalkyl, and
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.2alkyl); R.sub.235 and
R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; R.sub.245 and R.sub.250 at each occurrence
are independently H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy,
or R.sub.245 and R.sub.250 are taken together with the carbon to
which they are attached to form a carbocycle of 3, 5, or 6 carbon
atoms.
6. A compound according to claim 5, wherein X is --C.sub.1-C.sub.3
alkylidenyl optionally substituted with 1 methyl group; Z is
SO.sub.2; SO; S; or C(O); Y is OH; --N(Y.sub.1)(Y.sub.2);
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or halogen; R.sub.1
is benzyl which is optionally substituted with 1, 2, or 3 groups
independently selected from methyl, ethyl, n-propyl, isopropyl,
hydroxymethyl, monohalomethyl, dihalomethyl, trihalomethyl,
--CH.sub.2CF.sub.3, methoxymethyl, halogen, methoxy, ethoxy,
n-propyloxy, isopropyloxy, and OH; R.sub.2 and R.sub.3 are
independently H or C.sub.1-C.sub.4 alkyl; R.sub.20 at each
occurrence is independently hydrogen, C.sub.1-C.sub.4 alkyl, or
C.sub.2-C.sub.4 alkanoyl; R.sub.C is C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 R.sub.205 groups;
cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl,
cyclohexyl, cyclohexylmethyl;
--(CR.sub.245R.sub.250).sub.0-3-phenyl optionally substituted with
1 or 2 R.sub.200 groups; --(CR.sub.245R.sub.250).sub.0-3-pyridyl
optionally substituted with 1 or 2 R.sub.200;
--(CR.sub.245R.sub.250).sub.0-3-piperazinyl; or
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
--(CR.sub.245R.sub.250).sub.0-3-piperidinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1 or 2
R.sub.210 groups; R.sub.200 at each occurrence is independently
selected from C.sub.1-C.sub.4 alkyl optionally substituted with 1
or 2 R.sub.205 groups; OH; and halogen; R.sub.205 at each
occurrence is independently selected from C.sub.1-C.sub.4 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, and C.sub.1-C.sub.4
alkoxy; R.sub.210 at each occurrence is independently selected from
C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2 R.sub.205
groups; halogen; C.sub.1-C.sub.4 alkoxy; OCF.sub.3; NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl); N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl); OH; and --CO--(C.sub.1-C.sub.4 alkyl); wherein R.sub.245
and R.sub.250 at each occurrence are independently selected from H,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or R.sub.245
and R.sub.250 are taken together with the carbon to which they are
attached to form a carbocycle of 3, 5, or 6 carbon atoms.
7. (canceled)
8. A compound according to claim 3 wherein R.sub.N is: ##STR356##
n.sub.7 is 0, 1, 2, or 3; R.sub.50 is H or C.sub.1-C.sub.6 alkyl;
R.sub.51 is phenyl C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently halogen, cyano, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, or --C.sub.1-C.sub.4 alkoxy; alkenyl;
alkynyl; phenyl; C.sub.3-C.sub.8 cycloalkyl; or cycloalkylalkyl;
wherein the phenyl, C.sub.3-C.sub.8 cycloalkyl, and cycloalkylalkyl
groups are optionally substituted with 1, 2, 3, 4 or 5 groups that
are independently halogen, CN, NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, hydroxy, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 thioalkoxy, C.sub.1-C.sub.6 thioalkoxy
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkoxy; R.sub.6 and R.sub.7 are independently H, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, or phenyl C.sub.1-C.sub.4 alkyl;
X is C.sub.1-C.sub.4 alkylidenyl optionally substituted with 1, 2,
or 3 methyl groups; or --NR.sub.4-6--; or R.sub.4 and R.sub.4-6
combine to form --(CH.sub.2).sub.n10--, wherein n.sub.10 is 1, 2,
3, or 4; Z is a bond; SO.sub.2; SO; S; or C(O); Y is H;
C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8 cycloalkyl optionally
substituted with 1, 2, or 3 groups independently selected from
C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; or phenyl C.sub.1-C.sub.4 alkyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; wherein Y.sub.1 and Y.sub.2 are the same or
different and are H; C.sub.1-C.sub.10 alkyl optionally substituted
with 1, 2, or 3 substituents selected from halogen, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.8 cycloalkyl, and OH; C.sub.2-C.sub.6
alkenyl; C.sub.2-C.sub.6 alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl; or
C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen; R.sub.20
at each occurrence is independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkanoyl, each of which
is unsubstituted or substituted with 1, or 2 groups independently
selected from halogen, C.sub.1-C.sub.6 alkyl, hydroxy,
C.sub.1-C.sub.6 alkoxy, NH.sub.2, and --R.sub.26-R.sub.27, wherein
R.sub.26 is --C(O)--, --SO.sub.2--, --CO.sub.2--, --C(O)NH--, or
--C(O)N(C.sub.1-C.sub.6 alkyl)-; R.sub.27 is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6 alkyl,
heterocycloalkyl, or heteroaryl, wherein each of the above is
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, halo C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
--C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
9. A compound according to claim 8, wherein X is --C.sub.1-C.sub.3
alkylidenyl; Z is SO.sub.2; SO; S; or C(O); Y is OH;
--N(Y.sub.1)(Y.sub.2); where --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1 or
2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or halogen; R.sub.1 is benzyl which is
optionally substituted with 1, 2, or 3 groups independently
selected from methyl, ethyl, n-propyl, isopropyl, hydroxymethyl,
monohalomethyl, dihalomethyl, trihalomethyl, --CH.sub.2CF.sub.3,
methoxymethyl, halogen, methoxy, ethoxy, n-propyloxy, isopropyloxy,
and OH; R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.4
alkyl; R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4 alkanoyl; R.sub.C is
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; cyclopropyl, cyclopropylmethyl, cyclopentyl,
cyclopentylmethyl, cyclohexyl, cyclohexylmethyl;
--(CR.sub.245R.sub.250).sub.0-3-phenyl optionally substituted with
1 or 2 R.sub.200 groups; or --(CR.sub.245R.sub.250).sub.0-3-pyridyl
optionally substituted with 1 or 2 R.sub.200; R.sub.200 at each
occurrence is independently C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 R.sub.205 groups; OH; or halogen; R.sub.205
at each occurrence is independently C.sub.1-C.sub.4 alkyl, halogen,
--OH, --SH, --C.ident.N, --CF.sub.3, or C.sub.1-C.sub.4 alkoxy;
R.sub.245 and R.sub.250 at each occurrence are independently H,
C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4 alkoxy, or
R.sub.245 and R.sub.250 are taken together with the carbon to which
they are attached to form a carbocycle of 3 carbon atoms.
10. (canceled)
11. (canceled)
12. A compound according to claim 8, wherein R.sub.C is
C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or
--(C.sub.1-C.sub.4)alkyl-cyclopropyl.
13. (canceled)
14. A compound according to claim 8 that is selected from
3-(butylsulfinyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-D-
-alaninamide;
S-butyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzy-
l)amino]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-D-cysteinam-
ide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(-
3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4,4,4-tr-
ifluorobutyl)sulfonyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4,4,4-trifluo-
robutyl)sulfinyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-S-(4,4,4-trifluor-
obutyl)-D-cysteinamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-D-
-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(2,2,2-trifluoroetho-
xy)carbonyl]-D-alaninamide;
N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(butylsulfo-
nyl)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[(3R)-pyrrolidin-3-y-
l]carbonyl}-D,L-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(3S)-tetrahydrofuran-
-3-yloxy]carbonyl)-D-alaninamide;
N.about.2.about.-{[2-(acetylamino)ethoxy]carbonyl}-3-(butylsulfonyl)-N.ab-
out.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hy-
droxypropyl}-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[[(pyridin-3-yl)meth-
yl]oxy]carbonyl}-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[[(pyridin-4-yl)meth-
yl]oxy]carbonyl}-D-alaninamide;
3-(butylsulfonyl)-N.about.2.about.-[(methoxy)carbonyl]-N.about.1.about.-{-
(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-D-ala-
ninamide;
3-(butylsulfonyl)-N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.-
about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydr-
oxypropyl}-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-
)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
methylbutyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(methyloxy)carbonyl]-
-D-alaninamide;
N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide;
N.about.2.about.-{[2-(acetylamino)ethoxy]carbonyl}-N.about.1.about.-{(1S,-
2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-pro-
pylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(methyloxy)carbonyl]-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide;
N.about.2.about.-{[2-(diethylamino)-2-oxoethoxy]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-3-[(1-propylbutyl)s-
ulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(isopropoxy)carbonyl]-3-[(1-propylbuty-
l)sulfonyl]-D-alaninamide;
N.about.2.about.-[(cyclopropylmethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-
-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-pr-
opylbutyl)sulfonyl]-D-alaninamide;
N.about.2.about.-[(allyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-di-
fluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)-
sulfonyl]-D-alaninamide;
N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylb-
utyl)sulfonyl]-D-alaninamide;
N.about.2.about.-{[2-(acetylamino)ethoxy]carbonyl}-N.about.1.about.-{(1S,-
2R)-1-(3,5-difluorobenzyl)-3-[(3-ethyl
benzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino-
]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[[(pyridi-
n-3-yl)methyl]oxy]carbonyl}-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[[(pyridin-
-4-yl)methyl]oxy]carbonyl}-D-alaninamide; benzyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3-(methylsulfonyl)propylcarbamate;
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-D-alaninamide trifluoroacetate;
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-L-alaninamide trifluoroacetate;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2S)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{([(1R)-2-hydroxy-1-phenylethyl]amino}propyl)-3-
-[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2S)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[(1R)-2-methoxy-1-phenylethyl]amino}propyl)-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2S)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[(1S)-2-methoxy-1-phenylethyl]amino}propyl)-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1-((1S,2R)-1-(3,5-difluoro-
benzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-[(1-pro-
pylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[(prop-2-y-
nyl)oxy]carbonyl}-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(2-methoxyethylcarbonyl)-3-[(1-propylbu-
tyl)sulfonyl]-D-alaninamide;
N.about.2.about.-{[(3R)-1-acetylpyrrolidin-3-yl]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3--
[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(cyclopropylmethyl)amino]-2-hydroxypropyl}-3-[(1-propylb-
utyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2S)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylphenyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-[(1S,2R)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-
yl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[[(pyridin-
-3-yl)methyl]oxy]carbonyl}-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}--N.about.2.about.-{[(3R)-tetrahydrofuran-3-yloxy]carbony-
l}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-hydroxypr-
opyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-prop-
ylbutyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-{[(3R)-1-acetylpyrrolidin-3-yl]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[(3R)-pyrr-
olidin-3-yl]carbonyl}-D,L-alaninamide;
N.about.2.about.-{[(3R)-1-benzylpyrrolidin-3-yl]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5difluorobenzyl)-3-[(3-ethylbenzyl)amino]--
2-hydroxypropyl}-N.about.2.about.-{[(3S)-1,1-dioxidotetrahydrothien-3-ylox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrothiophen-3-yloxy]carbo-
nyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-(cyclopentylcarbonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D, L-alaninamide;
N.about.2.about.-(cyclohexylcarbonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-di-
fluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)-
sulfonyl]-D, L-alaninamide;
N.about.1.about.-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-h-
ydroxypropyl]-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[tetrahydropyr-
an-4-yloxy]carbonyl}-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[tetrahydr-
opyran-4-yloxy]carbonyl}-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[1-(methylsulfonyl)piperidin-4-yloxy]c-
arbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-{[1-acetylpiperidin-4-yloxy]carbonyl}-N.about.1.about.-{-
(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-
-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[[(3S)-5-oxopyrrolidin-3-yl]methyl]ox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[[(3R)-5-oxopyrrolidin-3-yl]methyl]ox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[2-methoxyethyl]oxy]carbonyl}-3-[(1-p-
ropylbutyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-hydroxypr-
opyl}-N.about.2.about.-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-
, L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2R)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]amino}propyl)-3-[(1--
propylbutyl)sulfonyl]-D,L-alaninamide;
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.5.about.,-
N.about.5.about.-dipropyl-L-glutamamide; and
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.5.about.,-
N.about.5.about.-dipropyl-D-glutamamide; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3-oxoheptylcarbamate;
4-butyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzy-
l)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxycarbonyl)-D-homoserinam-
ide;
3-(2-butyl-1,3-dioxolan-2-yl)-N.about.1.about.-{(1S,2R)-1-(3,5-diflu-
orobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(met-
hoxycarbonyl)-D-alaninamide;
3-(2-butyl-1,3-dioxan-2-yl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenz-
yl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxycar-
bonyl)-D-alaninamide; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3,3-difluoroheptylcarbamate; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3-fluoroheptylcarbamate; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-4-oxooctylcarbamate; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-4-hydroxyoctylcarbamate; methyl
(1R)-3-(2-butyl-1,3-dioxolan-2-yl)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3--
[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propylcarbamate;
methyl
(1R)-3-(2-butyl-1,3-dioxan-2-yl)-1-[({(1S,2R)-1-(3,5-difluorobenzy-
l)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propylcarbamate-
; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino-
]-2-hydroxypropyl}amino)carbonyl]-4-fluorooctylcarbamate; methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-4,4-difluorooctylcarbamate;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethynylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxycarbonyl)-D-
-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydr-
oxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N.about.2.about.-(methoxyc-
arbonyl)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1--
(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(metho-
xycarbonyl)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1--
(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(met-
hoxycarbonyl)-D-alaninamide; and
3-(butylsulfonyl)-N.about.1.about.-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydr-
oxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-N.about.2.a-
bout.-(methoxycarbonyl)-D-alaninamide.
15. A compound according to claim 3, wherein R.sub.N is: ##STR357##
wherein n.sub.7 is 0, 1, 2, or 3; R.sub.50 is H or C.sub.1-C.sub.6
alkyl; R.sub.5 is selected from the group consisting of
cyclopropyl; cyclopentyl; cyclohexyl; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy,
phenyl, C.sub.3-C.sub.7 cycloalkyl, --S--C.sub.1-C.sub.4 alkyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, --CO.sub.2H,
--CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4 alkyl, or
phenyloxy; phenyl optionally substituted with 1, 2, 3, or 4 groups
that are independently halogen, OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkyl; and
--NR.sub.6R.sub.7; wherein R.sub.6 and R.sub.7 are independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4
alkyl, and phenyl C.sub.1-C.sub.4 alkyl; X is C.sub.1-C.sub.4
alkylidenyl optionally substituted with 1, 2, or 3 methyl groups;
or --NR.sub.4-6--; or R.sub.4 and R.sub.4-6 combine to form
--(CH.sub.2).sub.n10--, wherein n.sub.10 is 1, 2, 3, or 4; Z is a
bond; SO.sub.2; SO; S; or C(O); Y is C.sub.5-C.sub.6
heterocycloalkyl containing at least one N, O, or S;
--N(Y.sub.1)(Y.sub.2); wherein --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, 3, or 4 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, or halogen; and R.sub.20 at each occurrence is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkanoyl, each of which is unsubstituted or
substituted with 1, or 2 groups independently selected from
halogen, C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, and --R.sub.26-R.sub.27, wherein R.sub.26 is --C(O)--,
--SO.sub.2--, --CO.sub.2--, --C(O)NH--, or --C(O)N(C.sub.1-C.sub.6
alkyl)-; R.sub.27 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
aryl C.sub.1-C.sub.6 alkyl, heterocycloalkyl, or heteroaryl,
wherein each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, --C(O)NH.sub.2, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
16. A compound according to claim 15, wherein R.sub.1 is benzyl
which is optionally substituted with 1, 2, 3, or 4 groups
independently selected from C.sub.1-C.sub.4 alkyl optionally
substituted with 1, or 2 substituents selected from halogen, --OH,
--SH, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy; halogen; C.sub.1-C.sub.4 alkoxy; and
OH.
17. A compound according to claim 16, wherein X is C.sub.1-C.sub.3
alkylidenyl optionally substituted with 1 or 2 methyl groups; Z is
SO.sub.2; SO; S; or C(O); Y is pyrrolidinyl; piperidinyl;
imidazolidinyl; piperazinyl; --N(Y.sub.1)(Y.sub.2); wherein
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, or 3 groups that are
independently C.sub.0-C.sub.4 alkyl, C.sub.0-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl, or halogen; and
R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.4
alkyl
18. (canceled)
19. A compound according to claim 18, of the formula: ##STR358##
wherein R.sub.C is C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclopentyl,
cyclohexyl, or --(C.sub.1-C.sub.4)alkyl-cyclopropyl; A.sub.3 and
A.sub.4 are independently H, F, Cl, Br, or I; R.sub.5 is selected
from cyclopropyl; cyclopentyl; or cyclohexyl; each of which is
optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.1-C.sub.4 haloalkyl, or OH; phenyl optionally
substituted with 1, 2, 3, or 4 groups that are independently
halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.2 haloalkyl.
20. A compound according to claim 18, wherein ##STR359## wherein
A.sub.1 is H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy;
A.sub.2 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkyl or OH;
A.sub.3 and A4 are independently H, F, Cl, Br, or I; R.sub.5 is
selected from cyclopropyl; cyclopentyl; or cyclohexyl; each of
which is optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.1-C.sub.4 haloalkyl, or OH; phenyl optionally
substituted with 1, 2, 3, or 4 groups that are independently
halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.2 haloalkyl.
21. A compound according to claim 15 selected from
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(pyridin-3-ylcarbonyl-
)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(2,4-dimethyl-1,3-th-
iazol-5-yl)carbonyl]-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[3-(trifluoromethyl)-
-1H-pyrazol-4-yl]carbonyl}-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(3-methyl-1H-pyrazol-
-5-yl)carbonyl]-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(1H-imidazol-4-ylacet-
yl)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(pyrazin-2-ylcarbonyl-
)-D-alaninamide;
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(6-hydroxypyridin-3--
yl)carbonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-h-
ydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(pyridin-4-ylca-
rbonyl)-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(pyridin-4--
ylcarbonyl)-D-alaninamide;
N.about.2.about.-[(5-bromoopyridin-3-yl)carbonyl]-N.about.1.about.-{(1S,2-
R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1--
propylbutyl)sulfonyl]-D-alaninamide;
N.about.2.about.-[(5-chloropyridin-3-yl)carbonyl]-N.about.1.about.-{(1S,2-
R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1--
propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(5-methylpyridin-3-yl)carbonyl]-3-[(1--
propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[3-(triflu-
oromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(1,3-thiazo-
l-4-ylcarbonyl)-D-alaninamide;
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N.about.2.abo-
ut.-[(pyridin-3-yl)carbonyl]-D-alaninamide trifluoracetate;
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N-alaninamide-
; trifluoracetate;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2-propionyl-3-[(1-propylbutyl)sulfonyl]-D-alanin-
amide;
3-[butylsulfonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-
-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(pyridin-3-yl-
)carbonyl]-D, L-alaninamide;
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(3-hydroxybenzoyl}-3-[(1-
-propylbutyl)sulfonyl]-D,L-alaninamide trifluoracete;
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N.about.2.abo-
ut.-[(pyridin-4-yl)carbonyl]-D-alaninamide trifluoracetate;
N.about.1.about.-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(6-oxo-1,4,5,6-tetrahydropyridazin-3-y-
l)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride;
5-oxo-D-prolyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-eth-
ylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide;
5-oxo-L-prolyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-eth-
ylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide;
N.about.1.about.-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl-
)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(piperidin-4-yl)carbonyl]-3-[(1-propyl-
butyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(2,4-dimethyl-1,3-thiazol-5-yl)carbony-
l]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(2-methyl-4-(trifluoromethyl)-1,3-thia-
zol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3-
-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3--
[(1-propylbutyl)sulfonyl]-D, L-alaninamide trifluoroacetate;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(1H-pyrazol-4-yl)carbonyl]-3-[(1-propy-
lbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(1H-imidazol-5-yl)carbonyl]-3-[(1-prop-
ylbutyl)sulfonyl]-D,L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(1H-imidazol-4-ylacetyl)-3-[(1-propylbu-
tyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyrazin-2-
-yl)carbonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3,5-dihydroxypyridin-4-yl)carbonyl]---
3-[(1-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(6-hydroxypyridin-3-yl)carbonyl]-3-[(1-
-propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.2.about.-[(6-chloropyridin-3-yl)carbonyl]-N.about.1.about.-{(1S,2-
R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1--
propylbutyl)sulfonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyridin-4-
-yl)carbonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(pyridin-3-yl)carbonyl]-3-[(1-propylbu-
tyl)sulfonyl]-D,L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyridin-2-
-yl)carbonyl]-D, L-alaninamide;
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[1H-indole-6-carbonyl]-3-[(1-propylbuty-
l)sulfonyl]-D, L-alaninamide;
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2S)-2-[(-
4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide;
(2R)-2-{[(benzyloxy)carbonyl]amino}-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-m-
ethoxybenzyl)amino]propyl}-5-oxo-5-piperidin-1-ylpentanamide;
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(-
3-ethoxy-3-oxopropanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide;
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(-
4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide;
and
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(-
5-methoxy-5-oxopentanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide.
22. A compound according to claim 3, wherein R.sub.N is of the
formula: ##STR360## wherein n.sub.7 is 0, 1, or 2; R.sub.4 is
--NHR.sub.8 or NH(CH.sub.2).sub.n6--R.sub.4-1; wherein N.sub.6 is
0, 1, 2, or 3; R.sub.4-1 is selected from the group consisting of
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), --SO--(C.sub.1-C.sub.8 alkyl),
--S--(C.sub.1-C.sub.8 alkyl), --S--CO--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; R.sub.4-2 and R.sub.4-3 are
independently H, C.sub.1-C.sub.3 alkyl, or C.sub.3-C.sub.6
cycloalkyl; R.sub.4-4 is C.sub.1-C.sub.4 alkyl, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl; R.sub.8 is selected from the group
consisting of --SO.sub.2-phenyl; --C(O)NHR.sub.9;
--S--C.sub.2-C.sub.4 alkanoyl; wherein R.sub.9 is phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkyl, or H; X is
C.sub.1-C.sub.4 alkylidenyl optionally substituted with 1, 2, or 3
methyl groups; or --NR.sub.4-6--; or R.sub.4 and R.sub.4-6 combine
to form --(CH.sub.2).sub.n10--, wherein n.sub.10 is 1, 2, 3, or 4;
Z is SO.sub.2; SO; S; or C(O); Y is C.sub.5-C.sub.6
heterocycloalkyl containing at least one N, O, or S;
--N(Y.sub.1)(Y.sub.2); wherein --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, 3, or 4 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, or halogen; and R.sub.20 at each occurrence is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkanoyl, each of which is unsubstituted or
substituted with 1, or 2 groups independently selected from
halogen, C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, and --R.sub.26-R.sub.27, wherein R.sub.26 is --C(O)--,
--SO.sub.2--, --CO.sub.2--, --C(O)NH--, or --C(O)N(C.sub.1-C.sub.6
alkyl)-; R.sub.27 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
aryl C.sub.1-C.sub.6 alkyl, heterocycloalkyl, or heteroaryl,
wherein each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, --C(O)NH.sub.2, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
23. (canceled)
24. A compound according to claim 1, wherein R.sub.4 is H;
C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5; --(CH.sub.2).sub.0-4R.sub.8;
--O--C.sub.1-C.sub.4 alkanoyl; OH; C.sub.6-C.sub.10 aryloxy
optionally substituted with 1, 2, or 3 groups that are
independently halogen, C.sub.1-C.sub.4 alkyl, CO.sub.2H,
--C(O)--C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.6 alkoxy; aryl C.sub.1-C.sub.4 alkoxy;
--C.sub.1-C.sub.4 alkyl-NR.sub.50CO.sub.2R.sub.51; --C.ident.N;
--CF.sub.3; --CF.sub.2--CF.sub.3; --C.ident.CH;
--CH.sub.2--CH.dbd.CH.sub.2; --(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1;
--O--(CH.sub.2).sub.n6--R.sub.4-1;
--S--(CH.sub.2).sub.n6--R.sub.4-1;
(CH.sub.2).sub.0-4--NHC(O)--(CH.sub.2).sub.0-6--R.sub.52; or
--(CH.sub.2).sub.0-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54.
25. A compound according to claim 24, wherein R.sub.1 is
(CH.sub.2).sub.n1--(R.sub.1-aryl) where n.sub.1 is zero or one and
R.sub.1-aryl is phenyl optionally substituted with 1, 2, 3, or 4
groups independently selected from C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy; halogen; C.sub.1-C.sub.6 alkoxy; --NR.sub.N-2R.sub.N-3; and
OH; wherein R.sub.N-2 and R.sub.N-3 at each occurrence are
independently selected from the group consisting of
--C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of --OH,
--NH.sub.2, phenyl and halogen; --C.sub.3-C.sub.8 cycloalkyl;
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl);
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl);
--C.sub.2-C.sub.6 alkenyl; --C.sub.2-C.sub.6 alkynyl;
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond; aryl; heteroaryl; heterocycloalkyl; or R.sub.N-2, R.sub.N-3
and the nitrogen to which they are attached form a 5, 6, or 7
membered heterocycloalkyl or heteroaryl group, wherein said
heterocycloalkyl or heteroaryl group is optionally fused to a
benzene, pyridine, or pyrimidine ring, and said groups are
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at
each occurrence are independently C.sub.0-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --OH, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
thioalkoxy, and C.sub.1-C.sub.6 thioalkoxy C.sub.1-C.sub.6
alkyl.
26. A compound according to claim 25, wherein R.sub.20 at each
occurrence is independently selected from hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkanoyl, each of which is
unsubstituted or substituted with 1, or 2 groups independently
selected from halogen, C.sub.1-C.sub.6 alkyl, hydroxy,
C.sub.1-C.sub.6 alkoxy, NH.sub.2, and --R.sub.26-R.sub.27, wherein
R.sub.26 is selected from --C(O)--, --SO.sub.2--, --CO.sub.2--;
R.sub.27 is selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, aryl C.sub.1-C.sub.6 alkyl, piperidyl, pyrrolyl, and
pyridyl, wherein each of the above is unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, --C(O)NH.sub.2, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
27. A compound according to claim 26, wherein R.sub.4 is H;
C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5; --(CH.sub.2).sub.0-4R.sub.8;
--C.sub.1-C.sub.4 alkyl-NR.sub.50CO.sub.2R.sub.51; --C.ident.N;
--CF.sub.3; --CF.sub.2--CF.sub.3; --C.ident.CH;
--CH.sub.2--CH.dbd.CH.sub.2; --(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1;
(CH.sub.2).sub.0-4--NHC(O)--(CH.sub.2).sub.0-6--R.sub.52; or
--(CH.sub.2).sub.0-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54.
28. A compound according to claim 27, wherein X is C.sub.1-C.sub.4
alkylidenyl optionally substituted with 1, 2, or 3 methyl groups;
or --NR.sub.4-6--; or R.sub.4 and R.sub.4-6 combine to form
--(CH.sub.2).sub.n10--, wherein n.sub.10 is 1, 2, 3, or 4; Z is
selected from a bond; SO.sub.2; SO; S; and C(O); Y is
C.sub.5-C.sub.6 heterocycloalkyl containing at least one N, O, or
S; or --N(Y.sub.1)(Y.sub.2); wherein --N(Y.sub.1)(Y.sub.2) forms a
ring selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, 3, or 4 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, or halogen.
29. (canceled)
30. (canceled)
31. A compound according to claim 28 of the formula: ##STR361##
wherein A.sub.1 is H, C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4
alkoxy; A.sub.2 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkyl or
OH; A.sub.3 and A.sub.4 are independently C.sub.1-C.sub.4 alkyl,
halogen, or H.
32. A compound according to claim 28 of the formula: ##STR362##
wherein R.sub.C is C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclopentyl,
cyclohexyl, or --(C.sub.1-C.sub.4)alkyl-(C.sub.3-C.sub.6)
cycloalkyl; and A.sub.3 and A.sub.4 are independently
C.sub.1-C.sub.4 alkyl, halogen, or H.
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
Description
[0001] This application claims priority from U.S. Provisional
Application Ser. No. 60/343,772, filed Dec. 28, 2001, U.S.
Provisional Application Ser. No. 60/332,639, filed Nov. 19, 2001,
and U.S. Provisional Application Ser. No. 60/295,332, filed Jun. 1,
2001.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to hydroxy alkylamine derivates and to
such compounds that are useful in the treatment of Alzheimer's
disease and similar diseases. More specifically the invention is
directed to such compounds that are capable of inhibiting
beta-secretase, an enzyme that cleaves amyloid precursor protein to
produce amyloid beta peptide (A-beta), a major component of the
amyloid plaques found in the brains of Alzheimer's sufferers.
[0004] 2. Description of the Related Art
[0005] Alzheimer's disease (AD) is a progressive degenerative
disease of the brain primarily associated with aging. Clinical
presentation of AD is characterized by loss of memory, cognition,
reasoning, judgment, and orientation. As the disease progresses,
motor, sensory, and linguistic abilities are also affected until
there is global impairment of multiple cognitive functions. These
cognitive losses occur gradually, but typically lead to severe
impairment and eventual death in the range of four to twelve
years.
[0006] Alzheimer's disease is characterized by two major pathologic
observations in the brain: neurofibrillary tangles and beta amyloid
(or neuritic) plaques, comprised predominantly of an aggregate of a
peptide fragment know as A-beta. Individuals with AD exhibit
characteristic beta-amyloid deposits in the brain (beta amyloid
plaques) and in cerebral blood vessels (beta amyloid angiopathy) as
neurofibrillary tangles. Neurofibrillary tangles occur not only in
Alzheimer's disease but also in other dementia-inducing disorders.
On autopsy, large numbers of these lesions are generally found in
areas of the human brain important for memory and cognition.
[0007] Smaller numbers of these lesions in a more restricted
anatomical distribution are found in the brains of most aged humans
who do not have clinical AD. Amyloidogenic plaques and vascular
amyloid angiopathy also characterize the brains of individuals with
Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type (HCHWA-D), and other neurogenerative
disorders. Beta-amyloid is a defining feature of AD, now believed
to be a causative precursor or factor in the development of
disease. Deposition of A-beta in areas of the brain responsible for
cognitive activities is a major factor in the development of AD.
Beta-amyloid plaques are predominantly composed of amyloid beta
peptide (A-beta, also sometimes designated betaA4). A-beta peptide
is derived by proteolysis of the amyloid precursor protein (APP)
and is comprised of 39-42 amino acids. Several proteases called
secretases are involved in the processing of APP.
[0008] Cleavage of APP at the N-terminus of the A-beta peptide by
beta-secretase and at the C-terminus by one or more
gamma-secretases constitutes the beta-amyloidogenic pathway, i.e.
the pathway by which A-beta is formed. Cleavage of APP by
alpha-secretase and the same or a different gamma-secretase
produces alpha-sAPP, a secreted form of APP that does not result in
beta-amyloid plaque formation. This alternate pathway precludes the
formation of A-beta peptide. A description of the proteolytic
processing fragments of APP is found, for example, in U.S. Pat.
Nos. 5,441,870; 5,721,130; and 5,942,400.
[0009] An aspartyl protease has been identified as the enzyme
responsible for processing of APP at the beta-secretase cleavage
site. The beta-secretase enzyme has been disclosed using varied
nomenclature, including BACE, Asp, am Mamepsin. See, for example,
Sindha et. al., 1999, Nature 402:537-554 (p 501) and published PCT
application WO00/17369.
[0010] Several lines of evidence indicate that progressive cerebral
deposition of beta-amyloid peptide (A-beta) plays a seminal role in
the pathogenesis of AD and can precede cognitive symptoms by years
or decades. See, for example, Selkoe, 1991, Neuron 6:487. Release
of A-beta from neuronal cells grown in culture and the presence of
A-beta in cerebrospinal fluid (CSF) of both normal individuals and
AD patients has been demonstrated. See, for example, Seubert et
al., 1992, Nature 359:325-327.
[0011] It has been proposed that A-beta peptide accumulates as a
result of APP processing by beta-secretase, thus inhibition of this
enzyme's activity is desirable for the treatment of AD. In vivo
processing of APP at the beta-secretase cleavage site is thought to
be a rate-limiting step in A-beta production, and is thus a
therapeutic target for the treatment of AD. See for example,
Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.
[0012] BACE1 knockout mice fail to produce A-beta, and present a
normal phenotype. When crossed with transgenic mice that over
express APP, the progeny show reduced amounts of A-beta in brain
extracts as compared with control animals (Luo et. al., 2001 Nature
Neuroscience 4:231-232). This evidence further supports the
proposal that inhibition of beta-secretase activity and reduction
of A-beta in the brain provides a therapeutic method for the
treatment of AD and other beta amyloid disorders.
[0013] At present there are no effective treatments for halting,
preventing, or reversing the progression of Alzheimer's disease.
Therefore, there is an urgent need for pharmaceutical agents
capable of slowing the progression of Alzheimer's disease and/or
preventing it in the first place.
[0014] Compounds that are effective inhibitors of beta-secretase,
that inhibit beta-secretase-mediated cleavage of APP, that are
effective inhibitors of A-beta production, and/or are effective to
reduce amyloid beta deposits or plaques, are needed for the
treatment and prevention of disease characterized by amyloid beta
deposits or plaques, such as AD.
[0015] Various pharmaceutical agents have been proposed for the
treatment of Alzheimer's disease but without any real success.
[0016] Compounds that are effective inhibitors of beta-secretase
activity, that inhibit beta-secretase-mediated cleavage of APP, or
that are effective inhibitors of A-beta production or deposition
are needed for the treatment and prevention of disease
characterized by beta-amyloid deposits or plaques, including
AD.
[0017] At present there are no effective treatments for halting,
preventing, or reversing the progression of Alzheimer's disease.
There is an urgent need for compounds capable of slowing A-beta
peptide production and/or deposition in the brain, which presents a
therapeutic approach to treatment of Alzheimer's disease.
SUMMARY OF THE INVENTION
[0018] In a broad aspect, the invention provides compounds of the
formula X ##STR2## and the pharmaceutically acceptable salts
thereof, wherein [0019] R.sub.N is: ##STR3## wherein [0020] R.sub.4
is selected from the group consisting of H; NH.sub.2;
--NH--(CH.sub.2).sub.n6--R.sub.4-1; --NHR.sub.8;
--NR.sub.50C(O)R.sub.5; C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5;
--(CH.sub.2).sub.0-4R.sub.8; --O--C.sub.1-C.sub.4 alkanoyl; OH;
C.sub.6-C.sub.10 aryloxy optionally substituted with 1, 2, or 3
groups that are independently halogen, C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --C(O)--C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
alkoxy; C.sub.1-C.sub.6 alkoxy; aryl C.sub.1-C.sub.4 alkoxy;
--NR.sub.50CO.sub.2R.sub.51; --C.sub.1-C.sub.4
alkyl-NR.sub.50CO.sub.2R.sub.51; --C.ident.N; --CF.sub.3;
--CF.sub.2--CF.sub.3; --C.ident.CH; --CH.sub.2--CH.dbd.CH.sub.2;
--(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1;
--O--(CH.sub.2).sub.n6--R.sub.4--;
--S--(CH.sub.2).sub.n6--R.sub.4-1; --(CH.sub.2).sub.0-4--NHC(O)--
(CH.sub.2).sub.0-6--R.sub.52;
--(CH.sub.2).sub.0-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54;
[0021] wherein [0022] n.sub.6 is 0, 1, 2, or 3; [0023] n7 is 0, 1,
2, or 3; [0024] R.sub.4-1 is selected from the group consisting of
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), --SO--(C.sub.1-C.sub.8 alkyl),
--S--(C.sub.1-C.sub.8 alkyl), --S--CO--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; [0025] R.sub.4-2 and R.sub.4-3 are
independently H, C.sub.1-C.sub.3 alkyl, or C.sub.3-C.sub.6
cycloalkyl; [0026] R.sub.4-4 is alkyl, arylalkyl, alkanoyl, or
arylalkanoyl; [0027] R.sub.4-6 is --H or C.sub.1-C.sub.6 alkyl;
[0028] R.sub.5 is selected from the group consisting of
C.sub.3-C.sub.7 cycloalkyl; C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently halogen,
--NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy, C.sub.5-C.sub.6
heterocycloalkyl, C.sub.5-C.sub.6 heteroaryl, C.sub.6-C.sub.10
aryl, C.sub.3-C.sub.7 cycloalkyl C.sub.1-C.sub.4 alkyl,
--S--C.sub.1-C.sub.4 alkyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4
alkyl, C.sub.6-C.sub.10 aryloxy; heteroaryl optionally substituted
with 1, 2, or 3 groups that are independently C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halogen, C.sub.1-C.sub.4 haloalkyl,
or OH; heterocycloalkyl optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, or C.sub.2-C.sub.4 alkanoyl; aryl
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkyl; and --NR.sub.6R.sub.7;
wherein [0029] R.sub.6 and R.sub.7 are independently selected from
the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl, phenyl
C.sub.1-C.sub.4 alkyl; [0030] R.sub.8 is selected from the group
consisting of --SO.sub.2-heteroaryl, --SO.sub.2-aryl,
--SO.sub.2-heterocycloalkyl, --SO.sub.2--C.sub.1-C.sub.10 alkyl,
--C(O)NHR.sub.9, heterocycloalkyl, --S--C.sub.1-C.sub.6 alkyl,
--S--C.sub.2-C.sub.4 alkanoyl, wherein [0031] R.sub.9 is aryl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkyl, or H; [0032] R.sub.50
is H or C.sub.1-C.sub.6 alkyl; [0033] R.sub.51 is selected from the
group consisting of aryl C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.6
alkyl optionally substituted with 1, 2, or 3 groups that are
independently halogen, cyano, heteroaryl, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, C.sub.3-C.sub.7 cycloalkyl, or
--C.sub.1-C.sub.4 alkoxy; heterocycloalkyl optionally substituted
with 1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, aryl
C.sub.1-C.sub.4 alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl;
alkenyl; alkynyl; heteroaryl optionally substituted with 1, 2, or 3
groups that are independently OH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl) or N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl);
heteroarylalkyl optionally substituted with 1, 2, or 3 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); aryl; heterocycloalkyl;
C.sub.3-C.sub.8 cycloalkyl; and cycloalkylalkyl; wherein the aryl;
heterocycloalkyl, C.sub.3-C.sub.8 cycloalkyl, and cycloalkylalkyl
groups are optionally substituted with 1, 2, 3, 4 or 5 groups that
are independently halogen, CN, NO.sub.2, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, hydroxy, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 thioalkoxy, C.sub.1-C.sub.6 thioalkoxy
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkoxy; [0034] R.sub.52 is heterocycloalkyl, heteroaryl, aryl,
cycloalkyl, --S(O).sub.0-2--C.sub.1-C.sub.6 alkyl, CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(alkyl), --C(O)N(alkyl)(alkyl),
--CO.sub.2-alkyl, --NHS(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--N(alkyl)S(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--S(O).sub.0-2-heteroaryl, --S(O).sub.0-2-aryl, --NH(arylalkyl),
--N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently alkyl, alkoxy, thioalkoxy, halogen, haloalkyl,
haloalkoxy, alkanoyl, NO.sub.2, CN, alkoxycarbonyl, or
aminocarbonyl; [0035] R.sub.53 is absent, --O--, --C(O)--, --NH--,
--N(alkyl)-, --NH--S(O).sub.0-2--, --N(alkyl)-S(O).sub.0-2--,
--S(O).sub.0-2--NH--, --S(O).sub.0-2--N(alkyl)-, --NH--C(S)--, or
--N(alkyl)-C(S)--; [0036] R.sub.54 is heteroaryl, aryl, arylalkyl,
heterocycloalkyl, CO.sub.2H, --CO.sub.2-alkyl, --C(O)NH(alkyl),
--C(O)N(alkyl)(alkyl), --C(O)NH.sub.2, C.sub.1-C.sub.8 alkyl, OH,
aryloxy, alkoxy, arylalkoxy, NH.sub.2, NH(alkyl), N(alkyl)(alkyl),
or --C.sub.1-C.sub.6 alkyl-CO.sub.2--C.sub.1-C.sub.6 alkyl, each of
which is optionally substituted with 1, 2, 3, 4, or 5 groups that
are independently alkyl, alkoxy, CO.sub.2H, --CO.sub.2-alkyl,
thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl,
NO.sub.2, CN, alkoxycarbonyl, or aminocarbonyl; [0037] X is
selected from the group consisting of --C.sub.1-C.sub.6 alkylidenyl
optionally substituted with 1, 2, or 3 methyl groups; and
--NR.sub.4-6--; or [0038] R.sub.4 and R.sub.4-6 combine to form
--(CH.sub.2).sub.n10--, wherein [0039] n.sub.10 is 1, 2, 3, or 4;
[0040] Z is selected from the group consisting of a bond; SO.sub.2;
SO; S; and C(O); [0041] Y is selected from the group consisting of
H; C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl;
C.sub.6-C.sub.10 aryl; OH; --N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10
alkyl optionally substituted with 1 thru 3 substituents which can
be the same or different and are selected from the group consisting
of halogen, hydroxy, alkoxy, thioalkoxy, and haloalkoxy;
C.sub.3-C.sub.8 cycloalkyl optionally substituted with 1, 2, or 3
groups independently selected from C.sub.1-C.sub.3 alkyl, and
halogen; alkoxy; aryl optionally substituted with halogen, alkyl,
alkoxy, CN or NO.sub.2; arylalkyl optionally substituted with
halogen, alkyl, alkoxy, CN or NO.sub.2; wherein [0042] Y.sub.1 and
Y.sub.2 are the same or different and are H; C.sub.1-C.sub.10 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
the group consisting of halogen, C.sub.1-C.sub.4 alkoxy,
C.sub.3-C.sub.8 cycloalkyl, and OH; C.sub.2-C.sub.6 alkenyl;
C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; phenyl C.sub.1-C.sub.4 alkyl; or C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0043] Y.sub.1, Y.sub.2 and the nitrogen
to which they are attached form a ring selected from the group
consisting of piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, 3, or 4 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, or halogen; [0044] R.sub.20 at each occurrence is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, each of which is
unsubstituted or substituted with 1, 2, 3, or 4 groups
independently selected from halogen, alkyl, hydroxy, alkoxy, and
NH.sub.2, and --R.sub.26-R.sub.27, wherein [0045] R.sub.26 is
selected from the group consisting of --C(O)--, --SO.sub.2--,
--CO.sub.2--, --C(O)NH--, and --C(O)N(C.sub.1-C.sub.6 alkyl)-;
[0046] R.sub.27 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6
alkyl, heterocycloalkyl, and heteroaryl, wherein each of the above
is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, haloalkyl, hydroxyalkyl, --C(O)NH.sub.2, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0047] R.sub.1 is
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), or
[0048] C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or
3 groups independently selected from halogen, OH, .dbd.O, --SH,
--C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3 alkoxy, amino, mono- or
dialkylamino, --N(R)C(O)R'--, --OC(.dbd.O)-amino and
--OC(.dbd.O)-mono- or dialkylamino, or [0049] C.sub.2-C.sub.6
alkenyl or C.sub.2-C.sub.6 alkynyl, each of which is optionally
substituted with 1, 2, or 3 groups independently selected from
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, amino, and mono- or dialkylamino, or [0050] aryl,
heteroaryl, heterocyclyl, --C.sub.1-C.sub.6 alkyl-aryl,
--C.sub.1-C.sub.6 alkyl-heteroaryl, or --C.sub.1-C.sub.6
alkyl-heterocyclyl, where the ring portions of each are optionally
substituted with 1, 2, 3, or 4 groups independently selected from
halogen, --OH, --SH, --C.ident.N, --NR.sub.105R'.sub.105,
--CO.sub.2R, --N(R)COR', or --N(R)SO.sub.2R',
--C(.dbd.O)--(C.sub.1-C.sub.4) alkyl, --SO.sub.2-amino,
--SO.sub.2-mono or dialkylamino, --C(.dbd.O)-amino,
--C(.dbd.O)-mono or dialkylamino, --SO.sub.2--(C.sub.1-C.sub.4)
alkyl, or [0051] --C.sub.1-C.sub.6 alkoxy optionally substituted
with 1, 2, or 3 groups which are independently a halogen, or [0052]
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino,
--C.sub.1-C.sub.6 alkyl and mono- or dialkylamino, or [0053]
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3 alkoxy, amino, mono- or
dialkylamino and --C.sub.1-C.sub.3 alkyl, or [0054]
C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl each of which
is optionally substituted with 1, 2, or 3 groups independently
selected from halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, amino, C.sub.1-C.sub.6 alkyl and mono- or
dialkylamino; and [0055] the heterocyclyl group is optionally
further substituted with oxo; [0056] R and R' independently are
hydrogen or C.sub.1-C.sub.10 alkyl; [0057] R.sub.2 is selected from
the group consisting of H; C.sub.1-C.sub.6 alkyl, optionally
substituted with 1, 2, or 3 substituents that are independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b; wherein [0058] R.sub.1-a and
R.sub.1-b are --H or C.sub.1-C.sub.6 alkyl; [0059]
--(CH.sub.2).sub.0-4-aryl; --(CH.sub.2).sub.0-4-heteroaryl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl;
--CONR.sub.N-2R.sub.N-3; --SO.sub.2NR.sub.N-2R.sub.N-3;
--CO.sub.2H; and --CO.sub.2--(C.sub.1-C.sub.4 alkyl); [0060]
R.sub.3 is selected from the group consisting of H; C.sub.1-C.sub.6
alkyl, optionally substituted with 1, 2, or 3 substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b;
--(CH.sub.2).sub.0-4-aryl; --(CH.sub.2).sub.0-4-heteroaryl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl;
--CO--NR.sub.N-2R.sub.N-3; --SO.sub.2--NR.sub.N-2R.sub.N-3;
--CO.sub.2H; and --CO--O--(C.sub.1-C.sub.4 alkyl); [0061] or [0062]
R.sub.2, R.sub.3 and the carbon to which they are attached form a
carbocycle of three thru seven carbon atoms, wherein one carbon
atom is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, or --NR.sub.N-2--; [0063] R.sub.C is selected from
the group consisting of C.sub.1-C.sub.10 alkyl optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S(.dbd.O).sub.0-2 (C.sub.1-C.sub.6 alkyl), --SH,
--NR.sub.235C.dbd.ONR.sub.235R.sub.240,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-aryl-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-aryl-heterocycloalkyl;
(CR.sub.245R.sub.250).sub.0-4-aryl-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl-heterocycloalkyl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl-aryl;
--[C(R.sub.255)(R.sub.260)].sub.1-3--CO--N--(R.sub.255).sub.2;
--CH(aryl).sub.2; --CH(heteroaryl).sub.2;
--CH(heterocycloalkyl).sub.2; --CH(aryl)(heteroaryl); cyclopentyl,
cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or
heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl,
or cycloheptyl is optionally replaced with NH, NR.sub.215, O, or
S(.dbd.O).sub.0-2, and wherein the cyclopentyl, cyclohexyl, or
cycloheptyl group can be optionally substituted with 1 or 2 groups
that are independently R.sub.205 or .dbd.O;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl);
C.sub.2-C.sub.10 alkenyl optionally substituted with 1, 2, or 3
R.sub.205 groups; C.sub.2-C.sub.10 alkynyl optionally substituted
with 1, 2, or 3 R.sub.205 groups;
--(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-6--OH)--
(CH.sub.2).sub.0-1-aryl;
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1-heteroaryl;
--CH(-aryl or -heteroaryl)-CO--O(C.sub.1-C.sub.4 alkyl);
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2; (C.sub.1-C.sub.6
alkyl)-O-- (C.sub.1-C.sub.6 alkyl)-OH;
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; --H;
and --(CH.sub.2).sub.0-6--C(.dbd.NR.sub.235)(NR.sub.235R.sub.240);
wherein [0064] each aryl is optionally substituted with 1, 2, or 3
R.sub.200; [0065] each heteroaryl is optionally substituted with 1,
2, 3, or 4 R.sub.200; [0066] each heterocycloalkyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210; [0067] R.sub.200 at each
occurrence is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; OH; --NO.sub.2; halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.1225;
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO-- (C.sub.2-C.sub.12 alkenyl);
--(CH.sub.2).sub.0-4--CO-- (C.sub.2-C.sub.12 alkynyl);
--(CH.sub.2).sub.0-4--CO-- (C.sub.3-C.sub.7 cycloalkyl);
--(CH.sub.2).sub.0-4--CO-aryl; --(CH.sub.2).sub.0-4--CO-heteroaryl;
--(CH.sub.2).sub.0-4--CO-heterocycloalkyl;
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215;
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--SO-- (C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--SO.sub.2 (C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl);
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO.sub.2R.sub.215;
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO--N(R.sub.215).sub.2;
(CH.sub.2).sub.0-4--N--CS--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--N(--H or R.sub.215)--CO--R.sub.220;
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--O--CO-- (C.sub.1-C.sub.6 alkyl);
--(CH.sub.2).sub.0-4--O--P(O)-- (OR.sub.240).sub.2;
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--(R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O--(R.sub.215).sub.2--COOH;
--(CH.sub.2).sub.0-4--S-- (R.sub.215).sub.2;
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); C.sub.3-C.sub.7 cycloalkyl;
C.sub.2-C.sub.6 alkenyl optionally substituted with 1 or 2
R.sub.205 groups; C.sub.2-C.sub.6 alkynyl optionally substituted
with 1 or 2 R.sub.205 groups; --(CH.sub.2).sub.0-4--N(H or
R.sub.215)--SO.sub.2--R.sub.220; and
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl; [0068] wherein
each aryl group at each occurrence is optionally substituted with
1, 2, or 3 groups that are independently R.sub.205, R.sub.210 or
C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups that are
independently R.sub.205 or R.sub.210; [0069] wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 groups that are independently R.sub.210; [0070]
wherein each heteroaryl group at each occurrence is optionally
substituted with 1, 2, or 3 groups that are independently
R.sub.205, R.sub.210, or C.sub.1-C.sub.6 alkyl substituted with 1,
2, or 3 groups that are independently R.sub.205 or R.sub.210;
[0071] R.sub.205 at each occurrence is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0072] R.sub.210 at each occurrence
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; C.sub.2-C.sub.6 alkenyl optionally substituted
with 1, 2, or 3 R.sub.205 groups; C.sub.2-C.sub.6 alkynyl
optionally substituted with 1, 2, or 3 R.sub.205 groups; halogen;
C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6 haloalkoxy;
--NR.sub.220R.sub.225; OH; C.ident.N; C.sub.3-C.sub.7 cycloalkyl
optionally substituted with 1, 2, or 3 R.sub.205 groups;
--CO--(C.sub.1-C.sub.4 alkyl); SO.sub.2--NR.sub.235R.sub.240;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl); and
.dbd.O; wherein [0073] R.sub.215 at each occurrence is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(aryl), C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl, and
(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the aryl group at
each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0074] R.sub.220 and R.sub.225 at each occurrence are independently
selected from the group consisting of --H, --C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, amino C.sub.1-C.sub.6 alkyl; halo
C.sub.1-C.sub.6 alkyl; --C.sub.3-C.sub.7 cycloalkyl,
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl),
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl),
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, -aryl, -heteroaryl, and -heterocycloalkyl; wherein the aryl
group at each occurrence is optionally substituted with 1, 2, or 3
R.sub.270 groups, wherein [0075] R.sub.270 at each occurrence is
independently R.sub.205, C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
haloalkoxy; NR.sub.235R.sub.240; OH; C.ident.N; C.sub.3-C.sub.7
cycloalkyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
--CO-- (C.sub.1-C.sub.4 alkyl); SO.sub.2--NR.sub.235R.sub.240;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl); and
.dbd.O; wherein the heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, or 3 R.sub.205 groups; wherein
each heteroaryl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.205 groups; [0076] R.sub.235 and R.sub.240 at
each occurrence are independently H, or C.sub.1-C.sub.6 alkyl;
[0077] R.sub.245 and R.sub.250 at each occurrence are independently
selected from the group consisting of H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, --(CH.sub.2).sub.0-4--C.sub.3-C.sub.7
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl
C.sub.1-C.sub.4 alkyl, heteroaryl C.sub.1-C.sub.4 alkyl, and
phenyl; or [0078] R.sub.245 and R.sub.250 are taken together with
the carbon to which they are attached to form a carbocycle of 3, 4,
5, 6, or 7 carbon atoms, optionally where one carbon atom is
replaced by a heteroatom selected from the group consisting of
--O--, --S--, --SO.sub.2--, and --NR.sub.220--; [0079] R.sub.255
and R.sub.260 at each occurrence are independently selected from
the group consisting of H; C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
R.sub.205 groups;
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl);
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; --(C.sub.1-C.sub.4
alkyl)-aryl; --(C.sub.1-C.sub.4 alkyl)-heteroaryl;
--(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl; -aryl; -heteroaryl;
-heterocycloalkyl;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heteroaryl;
and;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heterocycloalkyl;
wherein [0080] R.sub.265 at each occurrence is independently --O--,
--S-- or --N(C.sub.1-C.sub.6 alkyl)-; [0081] each aryl or phenyl is
optionally substituted with 1, 2, or 3 groups that are
independently R.sub.205, R.sub.210, or C.sub.1-C.sub.6 alkyl
substituted with 1, 2, or 3 groups that are independently R.sub.205
or R.sub.210; [0082] each heteroaryl is optionally substituted with
1, 2, 3, or 4 R.sub.200, each heterocycloalkyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210.
[0083] The invention also encompasses methods for the treatment or
prevention of Alzheimer's disease, mild cognitive impairment Down's
syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the
Dutch-Type, cerebral amyloid angiopathy, other degenerative
dementias, dementias of mixed vascular and degenerative origin,
dementia associated with Parkinson's disease, dementia associated
with progressive supranuclear palsy, dementia associated with
cortical basal degeneration, diffuse Lewy body type of Alzheimer's
disease comprising administration of a therapeutically effective
amount of a compound or salt of formula X, to a patient in need
thereof.
[0084] Preferably, the patient is a human.
[0085] More preferably, the disease is Alzheimer's disease.
[0086] More preferably, the disease is dementia.
[0087] The invention also provides pharmaceutical compositions
comprising a compound or salt of formula X and at least one
pharmaceutically acceptable carrier, solvent, adjuvant or
diluent.
[0088] The invention also provides the use of a compound or salt
according to formula X for the manufacture of a medicament.
[0089] The invention also provides the use of a compound or salt of
formula X for the treatment or prevention of Alzheimer's disease,
mild cognitive impairment Down's syndrome, Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid
angiopathy, other degenerative dementias, dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, or diffuse Lewy body type of Alzheimer's disease.
[0090] The invention also provides compounds, pharmaceutical
compositions, kits, and methods for inhibiting
beta-secretase-mediated cleavage of amyloid precursor protein
(APP). More particularly, the compounds, compositions, and methods
of the invention are effective to inhibit the production of A-beta
peptide and to treat or prevent any human or veterinary disease or
condition associated with a pathological form of A-beta
peptide.
[0091] The compounds, compositions, and methods of the invention
are useful for treating humans who have Alzheimer's Disease (AD),
for helping prevent or delay the onset of AD, for treating patients
with mild cognitive impairment (MCI), and preventing or delaying
the onset of AD in those patients who would otherwise be expected
to progress from MCI to AD, for treating Down's syndrome, for
treating Hereditary Cerebral Hemorrhage with Amyloidosis of the
Dutch Type, for treating cerebral beta-amyloid angiopathy and
preventing its potential consequences such as single and recurrent
lobar hemorrhages, for treating other degenerative dementias,
including dementias of mixed vascular and degenerative origin, for
treating dementia associated with Parkinson's disease, dementia
associated with progressive supranuclear palsy, dementia associated
with cortical basal degeneration, and diffuse Lewy body type AD,
and for treating frontotemporal dementias with parkinsonism
(FTDP).
[0092] The compounds of the invention possess beta-secretase
inhibitory activity. The inhibitory activities of the compounds of
the invention is readily demonstrated, for example, using one or
more of the assays described herein or known in the art.
[0093] Unless the substituents for a particular formula are
expressly defined for that formula, they are understood to carry
the definitions set forth in connection with the preceeding formula
to which the particular formula makes reference.
[0094] The invention also provides methods of preparing the
compounds of the invention and the intermediates used in those
methods.
DETAILED DESCRIPTION OF THE INVENTION
[0095] As noted above, the invention provides compound of Formula
X.
[0096] In alternate aspects of the invention, R.sub.5 is a
C.sub.3-C.sub.8 cycloalkyl optionally substituted with one or two
groups that are C.sub.1-C.sub.6 alkyl, more preferably
C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.6 alkoxy, more preferably
C.sub.1-C.sub.2 alkoxy, CF.sub.3, OH, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), halogen,
CN, or NO.sub.2.
[0097] In this aspect, preferred R.sub.5 groups are C.sub.3-C.sub.6
cycloalkyl groups optionally substituted with 2, more preferably 1
group selected from methyl, ethyl, OH, halogen, preferably F or Cl,
methoxy or ethoxy. Other preferred R.sub.5 groups within this
aspect are C.sub.3-C.sub.6 cycloalkyl groups substituted with 1 or
2 groups that are independently CF.sub.3, Cl, F, methyl, ethyl or
cyano.
[0098] Preferred compounds of formula X include those of formula
X-I, i.e., compounds of formula X wherein [0099] R.sub.1 is
(CH.sub.2).sub.n1--(R.sub.1-aryl) where n.sub.1 is zero or one and
R.sub.1-aryl is phenyl optionally substituted with 1, 2, 3, or 4
groups independently selected from C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy; halogen; C.sub.1-C.sub.6 alkoxy; --R.sub.N-2R.sub.N-3; and
OH; wherein [0100] R.sub.N-2 and R.sub.N-3 at each occurrence are
independently selected from the group consisting of
--C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of --OH,
--NH.sub.2, phenyl and halogen; --C.sub.3-C.sub.8 cycloalkyl;
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl);
--(C.sub.1-C.sub.6 alkyl)-O-- (C.sub.1-C.sub.3 alkyl);
--C.sub.2-C.sub.6 alkenyl; --C.sub.2-C.sub.6 alkynyl;
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond; aryl; heteroaryl; heterocycloalkyl; [0101] or [0102]
R.sub.N-2, R.sub.N-3 and the nitrogen to which they are attached
form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group,
wherein said heterocycloalkyl or heteroaryl group is optionally
fused to a benzene, pyridine, or pyrimidine ring, and said groups
are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that
at each occurrence are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --OH, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
thioalkoxy, and C.sub.1-C.sub.6 thioalkoxy C.sub.1-C.sub.6
alkyl.
[0103] More preferred compounds of formula X-I include those of
formula X-II, i.e., compounds of formula X-I wherein [0104] R.sub.2
and R.sub.3 are independently selected from H or C.sub.1-C.sub.6
alkyl optionally substituted with 1, 2, or 3 substituents selected
from the group consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH,
--SH, --CH.dbd.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b.
[0105] Preferred compounds of formula X-II include those wherein
[0106] R.sub.C is selected from the group consisting of
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of
R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S--(.dbd.O).sub.0-2(C.sub.1-C.sub.6 alkyl), --SH,
--NR.sub.235C.dbd.ONR.sub.235R.sub.240,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl;
--[C(R.sub.255)(R.sub.260)].sub.1-3--CO--N--(R.sub.255).sub.2; --CH
(aryl).sub.2; --CH (heteroaryl).sub.2;
--CH(heterocycloalkyl).sub.2; --CH(aryl)(heteroaryl);
--CO--NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-6--OH)--
(CH.sub.2).sub.0-1-aryl;
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1-heteroaryl;
--CH(-aryl or -heteroaryl)-CO--O(C.sub.1-C.sub.4 alkyl);
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2; (C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH;
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; --H;
and --(CH.sub.2).sub.0-6--C(.dbd.NR.sub.235)(NR.sub.235R.sub.240);
wherein [0107] each aryl is optionally substituted with 1, 2, or 3
R.sub.200; [0108] each heteroaryl is optionally substituted with 1,
2, 3, or 4 R.sub.200; [0109] each heterocycloalkyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210; [0110] R.sub.200 at each
occurrence is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; OH; --NO.sub.2; halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; and
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0111] wherein each aryl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205, R.sub.210 or C.sub.1-C.sub.6
alkyl substituted with 1, 2, or 3 groups that are independently
R.sub.205 or R.sub.210; [0112] wherein each heterocycloalkyl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.210; [0113] wherein each heteroaryl
group at each occurrence is optionally substituted with 1, 2, or 3
groups that are independently R.sub.205, R.sub.210, or
C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups that are
independently R.sub.205 or R.sub.210; [0114] R.sub.205 at each
occurrence is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, halogen, --OH, --O-phenyl, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0115] R.sub.210 at each occurrence
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N; C.sub.3-C.sub.7
cycloalkyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
--CO-- (C.sub.1-C.sub.4 alkyl); SO.sub.2--NR.sub.235R.sub.240;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl); and
.dbd.O; wherein [0116] R.sub.215 at each occurrence is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(aryl), C.sub.3-C.sub.7 cycloalkyl, and
--(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the aryl group at
each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0117] R.sub.220 and R.sub.225 at each occurrence are independently
selected from the group consisting of --H, --C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, amino C.sub.1-C.sub.6 alkyl; halo
C.sub.1-C.sub.6 alkyl; --C.sub.3-C.sub.7 cycloalkyl,
--(C.sub.1-C.sub.6 alkyl)-O-- (C.sub.1-C.sub.3 alkyl), -aryl,
-heteroaryl, and -heterocycloalkyl; wherein the aryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.270
groups, each heteroaryl is optionally substituted with 1, 2, 3, or
4 R.sub.200, each heterocycloalkyl is optionally substituted with
1, 2, 3, or 4 R.sub.210 wherein [0118] R.sub.270 at each occurrence
is independently R.sub.205, C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; halogen;
C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6 haloalkoxy;
NR.sub.235R.sub.240; OH; C.ident.N; --CO-- (C.sub.1-C.sub.4 alkyl);
and .dbd.O; wherein the heterocycloalkyl group at each occurrence
is optionally substituted with 1, 2, or 3 R.sub.205 groups; wherein
each heteroaryl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.205 groups; [0119] R.sub.235 and R.sub.240 at
each occurrence are independently H, or C.sub.1-C.sub.6 alkyl;
[0120] R.sub.245 and R.sub.250 at each occurrence are independently
selected from the group consisting of H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, or [0121] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, 6, or 7 carbon atoms, wherein the carbocycle
is optionally substituted with 1 or 2 groups that are independently
OH, methyl, Cl, F, OCH.sub.3, CF.sub.3, NO.sub.2, or CN; [0122]
R.sub.255 and R.sub.260 at each occurrence are independently
selected from the group consisting of H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 R.sub.205 groups;
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; --(C.sub.1-C.sub.4
alkyl)-aryl; --(C.sub.1-C.sub.4 alkyl)-heteroaryl;
--(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl; aryl; heteroaryl;
heterocycloalkyl;
(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heteroaryl;
and;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heterocycloalkyl;
wherein [0123] R.sub.265 at each occurrence is independently --O--,
--S-- or --N(C.sub.1-C.sub.6 alkyl)-; [0124] each aryl or phenyl is
optionally substituted with 1, 2, or 3 groups that are
independently R.sub.205, R.sub.210, or C.sub.1-C.sub.6 alkyl
substituted with 1, 2, or 3 groups that are independently R.sub.205
or R.sub.210.
[0125] Other preferred compounds of formulas X-I and X-II include
compounds of formula X-III, i.e., those of formulas X-I or X-II
wherein [0126] R.sub.N is: ##STR4## wherein [0127] R.sub.4 is
NH.sub.2; --NH-- (CH.sub.2).sub.n6--R.sub.4-1; --NHR.sub.8;
--NR.sub.50C(O)R.sub.5; or --NR.sub.50CO.sub.2R.sub.51; wherein
[0128] n.sub.6 is 0, 1, 2, or 3; [0129] n.sub.7 is 0, 1, 2, or 3;
[0130] R.sub.4-1 is selected from the group consisting of
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), --SO--(C.sub.1-C.sub.8 alkyl),
--S--(C.sub.1-C.sub.8 alkyl), --S--CO--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; [0131] R.sub.4-2 and R.sub.4-3 are
independently H, C.sub.1-C.sub.3 alkyl, or C.sub.3-C.sub.6
cycloalkyl; [0132] R.sub.4-4 is alkyl, phenylalkyl, C.sub.2-C.sub.4
alkanoyl, or phenylalkanoyl; [0133] R.sub.5 is cyclopropyl;
cyclobutyl; cyclopentyl; and cyclohexyl; wherein each cycloalkyl
group is optionally substituted with one or two groups that are
C.sub.1-C.sub.6 alkyl, more preferably C.sub.1-C.sub.2 alkyl,
C.sub.1-C.sub.6 alkoxy, more preferably C.sub.1-C.sub.2 alkoxy,
CF.sub.3, OH, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), halogen, CN, or
NO.sub.2; or the cycloalkyl group is substituted with 1 or 2 groups
that are independently CF.sub.3, Cl, F, methyl, ethyl or cyano;
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
that are independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4
alkoxy, C.sub.5-C.sub.6 heterocycloalkyl, C.sub.5-C.sub.6
heteroaryl, phenyl, C.sub.3-C.sub.7 cycloalkyl,
--S--C.sub.1-C.sub.4 alkyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4
alkyl, or phenyloxy; heteroaryl optionally substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.1-C.sub.4 haloalkyl, or OH;
heterocycloalkyl optionally substituted with 1, 2, or 3 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.2-C.sub.4 alkanoyl; phenyl optionally substituted
with 1, 2, 3, or 4 groups that are independently halogen, OH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
haloalkyl; and --NR.sub.6R.sub.7; wherein [0134] R.sub.6 and
R.sub.7 are independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, and phenyl C.sub.1-C.sub.4
alkyl; [0135] R.sub.8 is selected from the group consisting of
--SO.sub.2-heteroaryl optionally substituted with 1 or 2 groups
that are independently C.sub.1-C.sub.4 alkyl or halogen;
--SO.sub.2-aryl, --SO.sub.2-heterocycloalkyl, --C(O)NHR.sub.9,
heterocycloalkyl, --S--C.sub.2-C.sub.4 alkanoyl, wherein [0136]
R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkyl, or
H; [0137] R.sub.50 is H or C.sub.1-C.sub.6 alkyl; [0138] R.sub.51
is selected from the group consisting of phenyl C.sub.1-C.sub.4
alkyl; C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
groups that are independently halogen, cyano, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, C.sub.3-C.sub.7 or --C.sub.1-C.sub.4 alkoxy;
heterocycloalkyl optionally substituted with 1 or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; heterocycloalkylalkyl
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl, and
--SO.sub.2C.sub.1-C.sub.4 alkyl; alkenyl; alkynyl; heteroaryl
optionally substituted with 1, 2, or 3 groups that are
independently OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); heteroarylalkyl optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); phenyl; C.sub.3-C.sub.8 cycloalkyl,
and cycloalkylalkyl, wherein the phenyl; C.sub.3-C.sub.8
cycloalkyl, and cycloalkylalkyl groups are optionally substituted
with 1, 2, 3, 4 or 5 groups that are independently halogen, CN,
NO.sub.2, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, hydroxy, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
thioalkoxy, C.sub.1-C.sub.6 thioalkoxy C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkoxy.
[0139] Preferred compounds of formula X-III include compounds
wherein [0140] R.sub.N is ##STR5## wherein [0141] X is
C.sub.1-C.sub.4 alkylidenyl optionally substituted with 1, 2, or 3
methyl groups; or --NR.sub.4-6--; or [0142] R.sub.4 and R.sub.4-6
combine to form --(CH.sub.2).sub.n10--, wherein [0143] n.sub.10 is
1, 2, 3, or 4; [0144] Z is selected from a bond; SO.sub.2; SO; S;
and C(O); [0145] Y is selected from H; C.sub.1-C.sub.4 haloalkyl;
C.sub.5-C.sub.6 heterocycloalkyl containing at least one N, O, or
S; phenyl; OH; --N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl
optionally substituted with 1 thru 3 substituents which can be the
same or different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C3-CB cycloalkyl optionally substituted
with 1, 2, or 3 groups independently selected from C.sub.1-C.sub.3
alkyl, and halogen; alkoxy; phenyl optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or
NO.sub.2; phenyl C.sub.1-C.sub.4 alkyl optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or
NO.sub.2; wherein [0146] Y.sub.1 and Y.sub.2 are the same or
different and are H; C.sub.1-C.sub.10 alkyl optionally substituted
with 1, 2, or 3 substituents selected from the group consisting of
halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl;
and C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or [0147]
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen; and
[0148] R.sub.20 at each occurrence is independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkanoyl, each of which is unsubstituted or substituted with 1, or
2 groups independently selected from halogen, C.sub.1-C.sub.6
alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, NH.sub.2, and
--R.sub.26-R.sub.27, wherein [0149] R.sub.26 is selected from
--C(O)--, --SO.sub.2--, --CO.sub.2--, --C(O)NH--, and
--C(O)N(C.sub.1-C.sub.6 alkyl)-; and [0150] R.sub.27 is selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, aryl C.sub.1-C.sub.6 alkyl, heterocycloalkyl, and
heteroaryl, wherein each of the above is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, halo
C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
--C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
[0151] More preferred compounds of formula X-III include compounds
wherein [0152] X is C.sub.1-C.sub.4 alkylidenyl optionally
substituted with 1, 2, or 3 methyl groups; [0153] Z is selected
from SO.sub.2; SO; S; and C(O); [0154] Y is selected from H;
C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from the group consisting of halogen,
hydroxy, alkoxy, thioalkoxy, and haloalkoxy; C3-CB cycloalkyl
optionally substituted with 1, 2, or 3 groups independently
selected from C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl
optionally substituted with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; phenyl C.sub.1-C.sub.4
alkyl optionally substituted with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0155] Y.sub.1 and
Y.sub.2 are the same or different and are H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
the group consisting of halogen, C.sub.1-C.sub.4 alkoxy,
C.sub.3-C.sub.8 cycloalkyl, and OH; C.sub.2-C.sub.6 alkenyl;
C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; phenyl C.sub.1-C.sub.4 alkyl; or C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0156] --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, 3, or 4 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, or halogen; [0157] R.sub.20 at each occurrence is
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkanoyl, each of which is unsubstituted or
substituted with 1 or 2 groups independently selected from halogen,
hydroxy, C.sub.1-C.sub.6 alkoxy, and NH.sub.2.
[0158] Even more preferred compounds of formula X-III include
compounds wherein [0159] R.sub.C is C.sub.1-C.sub.8 alkyl
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of R.sub.205,
--OC.dbd.ONR.sub.235R.sub.240, --S(.dbd.O).sub.0-2(C.sub.1-C.sub.6
alkyl), --SH, --C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl;
--(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--
(CH.sub.2).sub.0-1-phenyl;
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1-heteroaryl;
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2; (C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH; or
--(CH.sub.2).sub.0-6--C(.dbd.NR.sub.235)(NR.sub.235R.sub.240);
wherein [0160] each aryl is optionally substituted with 1, 2, or 3
R.sub.200; [0161] each heteroaryl is optionally substituted with 1,
2, 3, or 4 R.sub.200; [0162] each heterocycloalkyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210; [0163] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0164] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0165] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1, 2, or 3 R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and .dbd.O; wherein [0166]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.7 cycloalkyl,
and --(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the phenyl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0167] R.sub.220 and R.sub.225 at each occurrence are independently
--H, --C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl; --C.sub.3-C.sub.7 cycloalkyl, and
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl); [0168]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0169] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, or [0170] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, 6, or 7 carbon atoms.
[0171] Still yet even more preferred compounds of formula X-III
include compounds wherein [0172] R.sub.1 is benzyl which is
optionally substituted with 1, 2, 3, or 4 groups independently
selected from halogen, C.sub.1-C.sub.4 alkoxy, hydroxy, and
C.sub.1-C.sub.4 alkyl optionally substituted with 1, 2, or 3
substituents halogen, OH, SH, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N--(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), C.ident.N,
CF.sub.3; [0173] R.sub.2 and R.sub.3 are independently selected
from H or C.sub.1-C.sub.4 alkyl optionally substituted with 1
substituent selected from halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl), and NH(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl);
[0174] R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.2 alkoxy C.sub.1-C.sub.4
alkyl, halo C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkanoyl, each
of which is unsubstituted or substituted with 1 or 2 groups
independently selected from halogen, hydroxy, and NH.sub.2; [0175]
R.sub.C is C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2,
or 3 groups independently selected from R.sub.205, --SH,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from R.sub.205, --CO.sub.2H, and
--CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl optionally substituted with
1, 2, or 3 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyridazinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrimidinyl;
--(CR.sub.245R.sub.250).sub.0-3 pyrazinyl;
--(CR.sub.245R.sub.250).sub.0-3-furyl;
--(CR.sub.245R.sub.250).sub.0-3-indolyl;
--(CR.sub.245R.sub.250).sub.0-3-thienyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1, 2, 3, or 4
R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-piperazinyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl;
(CR.sub.245R.sub.250).sub.0-3-indolinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1, 2, 3, or
4 R.sub.210;
(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--(CH.sub.2).sub.0-1-phenyl-
; --(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0176] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; and
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0177] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0178] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1 or 2 R.sub.205 groups; halogen; C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.4 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1 or 2
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and .dbd.O; wherein [0179]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.6 cycloalkyl,
--(CH.sub.2).sub.0-2-(pyridyl), --(CH.sub.2).sub.0-2-(pyrrolyl),
--(CH.sub.2).sub.0-2-(imidazolyl),
--(CH.sub.2).sub.0-2-(pyrimidyl),
--(CH.sub.2).sub.0-2-(pyrrolidinyl),
--(CH.sub.2).sub.0-2-(imidazolidinyl)-(CH.sub.2).sub.0-2-(piperazinyl),
--(CH.sub.2).sub.0-2-(piperidinyl), and
--(CH.sub.2).sub.0-2-(morpholinyl); wherein the phenyl group at
each occurrence is optionally substituted with 1 or 2 groups that
are independently R.sub.205 or R.sub.210; wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1 or 2 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1 or 2 R.sub.210; [0180]
R.sub.220 and R.sub.225 at each occurrence are independently --H,
--C.sub.1-C.sub.4 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.6 cycloalkyl, and
--(C.sub.1-C.sub.4 alkyl)-O-- (C.sub.1-C.sub.2 alkyl); [0181]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0182] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, or [0183] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, or 6 carbon atoms.
[0184] Other more preferred compounds of formula X-III include
compounds wherein [0185] X is --C.sub.1-C.sub.3 alkylidenyl
optionally substituted with 1 or 2 methyl groups; [0186] Z is
SO.sub.2; SO; S; or C(O); [0187] Y is C.sub.1-C.sub.4 haloalkyl;
OH; --N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 or 2 substituents which can be the same or
different and are selected from halogen, hydroxy, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 thioalkoxy, and C.sub.1-C.sub.4 haloalkoxy;
C.sub.1-C.sub.4 alkoxy; phenyl optionally substituted with halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; and
benzyl optionally substituted with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0188] Y.sub.1 and
Y.sub.2 are the same or different and are H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
halogen, C.sub.1-C.sub.2 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; benzyl; and C.sub.3-C.sub.6 cycloalkyl C.sub.1-C.sub.2
alkyl; or [0189] --N(Y.sub.1)(Y.sub.2) forms a ring selected from
piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein
each ring is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen.
[0190] Other even more preferred compounds of formula X-III include
those of formula X-IV, i.e., compounds of formula X-III wherein
[0191] X is --C.sub.1-C.sub.3 alkylidenyl optionally substituted
with 1 methyl group; [0192] Z is SO.sub.2; SO; S; or C(O); [0193] Y
is OH; --N(Y.sub.1)(Y.sub.2); phenyl; benzyl; or C.sub.1-C.sub.10
alkyl optionally substituted with 1 or 2 substituents which can be
the same or different and are selected from halogen, hydroxy,
methoxy, ethoxy, thiomethoxy, thioethoxy, and CF.sub.3; wherein
[0194] Y.sub.1 and Y.sub.2 are the same or different and are H;
C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2
substituents selected from halogen, methoxy, ethoxy, cyclopropyl,
and OH; or [0195] --N(Y.sub.1)(Y.sub.2) forms a ring selected from
piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein
each ring is optionally substituted with 1 or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or
halogen; [0196] R.sub.1 is benzyl which is optionally substituted
with 1, 2, or 3 groups independently selected from methyl, ethyl,
n-propyl, isopropyl, hydroxymethyl, monohalomethyl, dihalomethyl,
trihalomethyl, --CH.sub.2CF.sub.3, methoxymethyl, halogen, methoxy,
ethoxy, n-propyloxy, isopropyloxy, and OH; [0197] R.sub.2 and
R.sub.3 are independently H or C.sub.1-C.sub.4 alkyl; [0198]
R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4 alkanoyl; [0199] R.sub.C
is C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; cyclopropyl, cyclopropylmethyl, cyclopentyl,
cyclopentylmethyl, cyclohexyl, cyclohexylmethyl;
--(CR.sub.245R.sub.250).sub.0-3-phenyl optionally substituted with
1 or 2 R.sub.200 groups; --(CR.sub.245R.sub.250).sub.0-3-pyridyl
optionally substituted with 1 or 2 R.sub.200;
--(CR.sub.245R.sub.250).sub.0-3-piperazinyl; or
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
--(CR.sub.245R.sub.250).sub.0-3-piperidinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1 or 2
R.sub.210 groups; [0200] R.sub.200 at each occurrence is
independently selected from C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 R.sub.205 groups; OH; and halogen; [0201]
R.sub.205 at each occurrence is independently selected from
C.sub.1-C.sub.4 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.4 alkoxy; [0202] R.sub.210 at each
occurrence is independently selected from C.sub.1-C.sub.4 alkyl
optionally substituted with 1 or 2 R.sub.205 groups; halogen;
C.sub.1-C.sub.4 alkoxy; OCF.sub.3; NH.sub.2, NH(C.sub.1-C.sub.6
alkyl); N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); OH; and
--CO--(C.sub.1-C.sub.4 alkyl); wherein [0203] R.sub.245 and
R.sub.250 at each occurrence are independently selected from H,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or [0204]
R.sub.245 and R.sub.250 are taken together with the carbon to which
they are attached to form a carbocycle of 3, 5, or 6 carbon
atoms.
[0205] Preferred compounds of formula X-IV include those of formula
X-IV-a: ##STR6## [0206] wherein X, Y, Z, R.sub.245, and R.sub.250
are as defined for formula X-IV; [0207] A.sub.1 and A.sub.2 are
independently H, methyl, ethyl, propyl, methoxy, F, Cl, Br, I, or
CF.sub.3; [0208] A.sub.3 and A.sub.4 are independently F, Cl, Br,
I, methyl, methoxy, or H; [0209] R.sub.245 and R.sub.250 are taken
together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms.
[0210] More preferred compounds of formula X-IV-a include those
wherein [0211] A.sub.2 is H; [0212] A.sub.3 and A.sub.4 are
independently H, F, Cl, Br, or I; [0213] X is C.sub.1 or C.sub.2
alkylidenyl; [0214] Z is SO.sub.2; SO; or S; and [0215] Y is
phenyl, or C.sub.1--Cl, alkyl. More preferably, Y is methyl,
propyl, n-butyl, isobutyl, isopentyl, 4-heptyl, 3-heptyl, 3-pentyl,
or 5-nonyl.
[0216] Even more preferred compounds of formula X-IV include those
of formula X-IV-b: ##STR7## [0217] wherein A.sub.1, X, Y, Z,
R.sub.245, and R.sub.250 are as defined for formula X-IV; [0218]
A.sub.3 and A.sub.4 are independently H, F, Cl, methyl, ethyl,
methoxy, ethoxy, CF.sub.3 or OCF.sub.3.
[0219] Other preferred compounds of formula X-IV include those of
formula X-V wherein ##STR8## wherein [0220] n9 is 1 or 2; [0221]
A.sub.1 and A.sub.2 are independently H, methyl, ethyl, propyl,
methoxy, ethoxy, F, Cl, Br, I, CF.sub.3, OCF.sub.3, or
C.sub.2-C.sub.6 alkynyl; and [0222] A.sub.3 and A.sub.4 are
independently F, Cl, Br, I, methyl, methoxy, or H.
[0223] Preferred compounds of formula X-V include those wherein
[0224] A.sub.1 is C.sub.1-C.sub.2 alkyl, preferably ethyl, or
C.sub.2-C.sub.3 alkynyl. More preferably A.sub.1 is ethyl, I, or
C.sub.2 alkynyl; [0225] A.sub.2 is H; [0226] A.sub.3 and A.sub.4
are independently H, F, Cl, Br, or I; [0227] X is C.sub.1 or
C.sub.2 alkylidenyl; [0228] Z is SO.sub.2; SO; or S; and [0229] Y
is phenyl, methyl, propyl, n-butyl, isobutyl, isopentyl, 4-heptyl,
3-heptyl, 3-pentyl, or 5-nonyl.
[0230] More preferred compounds of formula X-V include those of
formula X-V-a ##STR9## wherein [0231] A.sub.3 and A.sub.4 are
independently H, F, or Cl.
[0232] Other preferred compounds of formula X-IV include those of
formula X-VI, i.e., compounds of formula X-IV wherein [0233]
R.sub.C is C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or --(C.sub.1-C.sub.4 alkyl)-cyclopropyl.
Even more preferred R.sub.C is n-butyl, isobutyl, n-pentyl,
isopentyl, n-hexyl, isohexyl, cyclopropyl, or
cyclopropylmethyl.
[0234] Preferred compounds of formula X-VI include those of formula
X-VI-a: ##STR10## wherein [0235] A.sub.3 and A.sub.4 are
independently halogen, methyl, ethyl, n-propyl, iso-propyl,
methoxy, ethoxy, n-propoxy, iso-propoxy, or H; [0236] X is C.sub.1
or C.sub.2 alkylidenyl; [0237] Z is SO.sub.2; SO; or S; and [0238]
Y is phenyl, or C.sub.1-C.sub.10 alkyl. Even more preferred is when
Y is methyl, propyl, n-butyl, isobutyl, isopentyl, 4-heptyl,
3-heptyl, 3-pentyl, or 5-nonyl.
[0239] More preferred compounds of formula X-VI include those of
formula X-VI-b: ##STR11## wherein [0240] A.sub.3 and A.sub.4 are
independently H, F, Cl, methyl, or methoxy.
[0241] Representative compounds of formula X-III wherein R.sub.4 is
NH.sub.2 are [0242]
S-butyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzy-
l)amino]-2-hydroxypropyl}-D-cysteinamide; [0243]
3-(butylsulfinyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-D-alaninamide; [0244]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-D-alaninamide; [0245]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-L-alaninamide; [0246]
3-(butylsulfonyl)-N.about.1.about.-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydr-
oxy-3-(isopentylamino)propyl]-D-alaninamide; [0247]
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-D-alaninamide-
; [0248]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylben-
zyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-L-alaninamide;
[0249]
N.about.1.about.-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluoroben-
zyl)-2-hydroxypropyl]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide;
[0250]
N.about.1.about.-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxypropyl-3-(isope-
ntylamino)]-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; [0251]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; [0252]
N.about.1.about.-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide; [0253]
(2S)-2-amino-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]prop-
yl}-5-oxo-5-piperidin-1-ylpentanamide; and [0254]
(2R)-2-amino-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]prop-
yl}-5-oxo-5-piperidin-1-ylpentanamide and pharmaceutically
acceptable salts thereof.
[0255] Other preferred compounds of formula X-II include those of
formula X-VII, i.e., compounds of formula X-II wherein [0256]
R.sub.N is: ##STR12## [0257] n.sub.7 is 0, 1, 2, or 3; [0258]
R.sub.50 is H or C.sub.1-C.sub.6 alkyl; [0259] R.sub.51 is phenyl
C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.6 alkyl optionally substituted
with 1, 2, or 3 groups that are independently halogen, cyano,
--NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, or --C.sub.1-C.sub.4
alkoxy; heterocycloalkyl optionally substituted with 1 or 2 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4
alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl; heterocycloalkylalkyl
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl, and
--SO.sub.2C.sub.1-C.sub.4 alkyl; alkenyl; alkynyl; heteroaryl
optionally substituted with 1, 2, or 3 groups that are
independently OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); heteroarylalkyl optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); phenyl; C.sub.3-C.sub.8 cycloalkyl;
or cycloalkylalkyl; wherein the phenyl, C.sub.3-C.sub.8 cycloalkyl,
and cycloalkylalkyl groups are optionally substituted with 1, 2, 3,
4 or 5 groups that are independently halogen, CN, NO.sub.2,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6
alkanoyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy,
hydroxy, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 thioalkoxy, C.sub.1-C.sub.6
thioalkoxy C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkoxy; [0260] R.sub.6 and R.sub.7 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl,
phenyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl, or phenyl
C.sub.1-C.sub.4 alkyl; [0261] X is C.sub.1-C.sub.4 alkylidenyl
optionally substituted with 1, 2, or 3 methyl groups; or
--NR.sub.4-6--; or [0262] R.sub.4 and R.sub.4-6 combine to form
--(CH.sub.2).sub.n10--, wherein [0263] n.sub.10 is 1, 2, 3, or 4;
[0264] Z is a bond; SO.sub.2; SO; S; or C(O); [0265] Y is H;
C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8 cycloalkyl optionally
substituted with 1, 2, or 3 groups independently selected from
C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; or phenyl C.sub.1-C.sub.4 alkyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; wherein [0266] Y.sub.1 and Y.sub.2 are the
same or different and are H; C.sub.1-C.sub.10 alkyl optionally
substituted with 1, 2, or 3 substituents selected from halogen,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8 cycloalkyl, and OH;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl; or
C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or [0267]
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen; [0268]
R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, halo C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkanoyl,
each of which is unsubstituted or substituted with 1, or 2 groups
independently selected from halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, NH.sub.2, and --R.sub.26-R.sub.27,
wherein [0269] R.sub.26 is --C(O)--, SO.sub.2--, --CO.sub.2--,
--C(O)NH--, or --C(O)N(C.sub.1-C.sub.6 alkyl)-; [0270] R.sub.27 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6
alkyl, heterocycloalkyl, or heteroaryl, wherein each of the above
is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, halo C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
--C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
[0271] Preferred compounds of formula X-VII include those wherein:
[0272] R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.6
alkyl optionally substituted with 1, or 2 substituents selected
from halogen, --OH, --SH, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy; [0273] n.sub.7 is 0, 1, or 2; [0274]
R.sub.50 is H or C.sub.1-C.sub.4 alkyl; [0275] R.sub.51 is selected
from benzyl; phenethyl; C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently halogen,
cyano, --NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, or
--C.sub.1-C.sub.4 alkoxy; heterocycloalkyl containing at least one
N, O, or S and optionally substituted with 1 or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; heterocycloalkylalkyl
containing at least one N, O, or S and optionally substituted with
1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, phenyl
C.sub.1-C.sub.4 alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl; heteroaryl
optionally substituted with 1, 2, or 3 groups that are
independently OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); heteroarylalkyl containing at least
one N, O, or S and optionally substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); phenyl;
C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl, wherein the phenyl; C.sub.3-C.sub.6
cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl C.sub.1-C.sub.4 alkyl
groups are optionally substituted with 1, 2, or 3 groups that are
independently halogen, CN, NO.sub.2, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, hydroxy, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 thioalkoxy; [0276] R.sub.6 and
R.sub.7 are independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl or
phenethyl; [0277] X is --C.sub.1-C.sub.4 alkylidenyl optionally
substituted with 1 or 2 methyl groups; [0278] Z is SO.sub.2; SO; S;
or C(O); [0279] Y is H; C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6
heterocycloalkyl containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 thioalkoxy, and
C.sub.1-C.sub.4 haloalkoxy; C.sub.3-C.sub.6 cycloalkyl optionally
substituted with 1 group selected from C.sub.1-C.sub.3 alkyl, and
halogen; C.sub.1-C.sub.4 alkoxy; phenyl optionally substituted with
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or
NO.sub.2; or phenyl C.sub.1-C.sub.4 alkyl optionally substituted
with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or
NO.sub.2; wherein [0280] Y.sub.1 and Y.sub.2 are the same or
different and are H; C.sub.1-C.sub.10 alkyl optionally substituted
with 1, or 2 substituents selected from halogen, C.sub.1-C.sub.4
alkoxy, C.sub.3-C.sub.6 cycloalkyl, and OH; C.sub.2-C.sub.6
alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl
C.sub.1-C.sub.4 alkyl; or C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0281] --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4
alkyl, or halogen; [0282] R.sub.20 at each occurrence is
independently hydrogen, C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.4
alkyl, or C.sub.2-C.sub.4 alkanoyl, each of which is unsubstituted
or substituted with 1, or 2 groups independently selected from
halogen, C.sub.1-C.sub.4 alkyl, hydroxy, C.sub.1-C.sub.4 alkoxy,
NH.sub.2, and --R.sub.26-R.sub.27; wherein [0283] R.sub.26 is
--C(O)--, --SO.sub.2--, or --CO.sub.2--; [0284] R.sub.27 is
C.sub.1-C.sub.6 alkyl, benzyl, or phenethyl, wherein each of the
above is unsubstituted or substituted with 1, 2, or 3 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, CF.sub.3, or hydroxy C.sub.1-C.sub.4 alkyl.
[0285] More preferred compounds of formula X-VII include those
wherein: [0286] R.sub.C is C.sub.1-C.sub.8 alkyl optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S(.dbd.O).sub.0-2 (C.sub.1-C.sub.6 alkyl), --SH,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl; or
--(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-heteroaryl; wherein each aryl is
optionally substituted with 1, 2, or 3 R.sub.200; [0287] each
heteroaryl is optionally substituted with 1, 2, 3, or 4 R.sub.200;
[0288] each heterocycloalkyl is optionally substituted with 1, 2,
3, or 4 R.sub.210; [0289] R.sub.200 at each occurrence is
independently C.sub.1-C.sub.6 alkyl optionally substituted with 1,
2, or 3 R.sub.205 groups; OH; --NO.sub.2; halogen; --CO.sub.2H;
C.ident.N; --(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0290] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0291] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1, 2, or 3 R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); or .dbd.O; wherein [0292]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.7 cycloalkyl,
and --(CH.sub.2).sub.0-2-(heteroaryl), or
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the phenyl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0293] R.sub.220 and R.sub.225 at each occurrence are independently
--H, --C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.7 cycloalkyl, or
--(C.sub.1-C.sub.6 alkyl)-O-- (C.sub.1-C.sub.3 alkyl); [0294]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0295] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, or [0296] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, or 6 carbon atoms.
[0297] Even more preferred compounds of formula X-VII include those
wherein: [0298] R.sub.1 is benzyl which is optionally substituted
with 1, 2, 3, or 4 groups independently selected from
C.sub.1-C.sub.4 alkyl optionally substituted with 1, or 2
substituents selected from halogen, --OH, --SH, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy; halogen; C.sub.1-C.sub.4 alkoxy; and OH;
[0299] R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.2 alkoxy C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.6 alkanoyl, each of which is unsubstituted or
substituted with 1 or 2 groups independently selected from halogen,
hydroxy, C.sub.1-C.sub.4 alkoxy, and NH.sub.2; [0300] R.sub.C is
C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--SH, --C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl optionally substituted with
1, 2, or 3 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyridazinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrimidinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazinyl;
--(CR.sub.245R.sub.250).sub.0-3-furyl;
--(CR.sub.245R.sub.250).sub.0-3-indolyl;
--(CR.sub.245R.sub.250).sub.0-3-thienyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1, 2, 3, or 4
R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-piperazinyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl;
(CR.sub.245R.sub.250).sub.0-3-indolinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1, 2, 3, or
4 R.sub.210;
(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--(CH.sub.2).sub.0-1-phenyl-
; or --(CH.sub.2) o--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0301] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C_N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0302] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0303] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1 or 2 R.sub.205 groups; halogen; C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.4 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1 or 2
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); or .dbd.O; wherein [0304]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.6 cycloalkyl,
--(CH.sub.2).sub.0-2-(pyridyl), --(CH.sub.2).sub.0-2-(pyrrolyl),
--(CH.sub.2).sub.0-2-(imidazolyl),
--(CH.sub.2).sub.0-2-(pyrimidyl),
--(CH.sub.2).sub.0-2-(pyrrolidinyl),
--(CH.sub.2).sub.0-2-(imidazolidinyl)-(CH.sub.2).sub.0-2-(piperazinyl),
--(CH.sub.2).sub.0-2-(piperidinyl), or
--(CH.sub.2).sub.0-2-(morpholinyl); wherein the phenyl group at
each occurrence is optionally substituted with 1 or 2 groups that
are independently R.sub.205 or R.sub.210; wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1 or 2 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1 or 2 R.sub.210; [0305]
R.sub.220 and R.sub.225 at each occurrence are independently --H,
--C.sub.1-C.sub.4 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.6 cycloalkyl, or
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.2 alkyl); [0306]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0307] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, or [0308] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms.
[0309] Even more preferred compounds of formula X-VII include those
wherein: [0310] R.sub.51 is benzyl; phenethyl; C.sub.1-C.sub.6
alkyl optionally substituted with 1, 2, or 3 groups that are
independently halogen, cyano, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, or --C.sub.1-C.sub.4 alkoxy; pyrrolidinyl,
tetrahydrofuryl, tetrahydro-thienyl 1,1-dioxide, tetrahydrothienyl,
pyranyl, piperidinyl, pyrrolidinonyl, dihydropyridazinonyl,
2-thioxo-thiazolidin-4-one, each of which is optionally substituted
with 1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, benzyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; pyrrolidinonyl C.sub.1-C.sub.4
alkyl optionally substituted with 1 or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; C.sub.2-C.sub.4 alkenyl;
C.sub.2-C.sub.4 alkynyl; pyrazolyl, imidazolyl, pyrazinyl, pyridyl,
isoxazolyl, thiazolyl, indolyl, each of which is optionally
substituted with 1, 2, or 3 groups that are independently OH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); pyridinyl C.sub.1-C.sub.4 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); phenyl; cyclopropyl; cyclopentyl;
cyclohexyl; cyclopropylmethyl; wherein the phenyl; cycloalkyl, and
cycloalkylalkyl groups are optionally substituted with 1, 2, or 3
groups that are independently halogen, CN, NO.sub.2,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.6
alkanoyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
hydroxy, C.sub.1-C.sub.4 hydroxyalkyl, or C.sub.1-C.sub.4
thioalkoxy; [0311] R.sub.6 and R.sub.7 are independently H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or benzyl; [0312]
X is --C.sub.1-C.sub.3 alkylidenyl optionally substituted with 1 or
2 methyl groups; [0313] Z is SO.sub.2; SO; S; or C(O); [0314] Y is
C.sub.1-C.sub.4 haloalkyl; OH; --N(Y.sub.1)(Y.sub.2);
C.sub.1-C.sub.10 alkyl optionally substituted with 1 or 2
substituents which can be the same or different and are selected
from the group consisting of halogen, hydroxy, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 thioalkoxy, and C.sub.1-C.sub.4 haloalkoxy;
C.sub.1-C.sub.4 alkoxy; phenyl optionally substituted with halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; or
benzyl optionally substituted with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0315] Y.sub.1 and
Y.sub.2 are the same or different and are H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
halogen, C.sub.1-C.sub.2 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; benzyl; and C.sub.3-C.sub.6 cycloalkyl C.sub.1-C.sub.2
alkyl; or [0316] --N(Y.sub.1)(Y.sub.2) forms a ring selected from
piperazinyl, piperidinyl, morpholinyl, and pyrrolidinyl, wherein
each ring is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen.
[0317] Other even more preferred compounds of formula X-VII include
those wherein: [0318] X is --C.sub.1-C.sub.3 alkylidenyl; [0319] Z
is SO.sub.2; SO; S; or C(O); [0320] Y is OH; --N(Y.sub.1)(Y.sub.2);
phenyl; benzyl; or C.sub.1-C.sub.10 alkyl optionally substituted
with 1 or 2 substituents which can be the same or different and are
selected from halogen, hydroxy, methoxy, ethoxy, thiomethoxy,
thioethoxy, and CF.sub.3; wherein [0321] Y.sub.1 and Y.sub.2 are
the same or different and are H; C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 substituents selected from halogen,
methoxy, ethoxy, cyclopropyl, and OH; or [0322]
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or halogen; [0323]
R.sub.1 is benzyl which is optionally substituted with 1, 2, or 3
groups independently selected from methyl, ethyl, n-propyl,
isopropyl, hydroxymethyl, monohalomethyl, dihalomethyl,
trihalomethyl, --CH.sub.2CF.sub.3, methoxymethyl, halogen, methoxy,
ethoxy, n-propyloxy, isopropyloxy, and OH; [0324] R.sub.2 and
R.sub.3 are independently H or C.sub.1-C.sub.4 alkyl; [0325]
R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.4 alkyl, or C.sub.2-C.sub.4 alkanoyl; [0326] R.sub.C
is C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; cyclopropyl, cyclopropylmethyl, cyclopentyl,
cyclopentylmethyl, cyclohexyl, cyclohexylmethyl;
--(CR.sub.245R.sub.250).sub.0-3-phenyl optionally substituted with
1 or 2 R.sub.200 groups; or --(CR.sub.245R.sub.250).sub.0-3-pyridyl
optionally substituted with 1 or 2 R.sub.200; [0327] R.sub.200 at
each occurrence is independently C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 R.sub.205 groups; OH; or halogen; [0328]
R.sub.205 at each occurrence is independently C.sub.1-C.sub.4
alkyl, halogen, --OH, --SH, --C.ident.N, --CF.sub.3, or
C.sub.1-C.sub.4 alkoxy; [0329] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 hydroxyalkyl, or
C.sub.1-C.sub.4 alkoxy, or [0330] R.sub.245 and R.sub.250 are taken
together with the carbon to which they are attached to form a
carbocycle of 3 carbon atoms.
[0331] Additional more preferred compounds of formula X-VII include
those wherein: [0332] R.sub.51 is benzyl; phenethyl;
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
that are independently halogen, cyano, --NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, or --C.sub.1-C.sub.4 alkoxy; pyrrolidinyl,
tetrahydrofuryl, tetrahydro-thienyl 1,1-dioxide, tetrahydrothienyl,
pyranyl, piperidinyl, pyrrolidinonyl, each of which is optionally
substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
C.sub.2-C.sub.4 alkanoyl, benzyl, and --SO.sub.2C.sub.1-C.sub.4
alkyl; pyrrolidinonyl C.sub.1-C.sub.4 alkyl optionally substituted
with 1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl,
C.sub.1-C.sub.4 alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl;
C.sub.2-C.sub.4 alkenyl; C.sub.2-C.sub.4 alkynyl; pyridinyl
C.sub.1-C.sub.4 alkyl optionally substituted with 1, or 2 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); cyclopentyl;
cyclohexyl; or cyclopropylmethyl; wherein the cycloalkyl, and
cycloalkylalkyl groups are optionally substituted with 1, or 2
groups that are independently halogen, CN, NO.sub.2, methyl, ethyl,
methoxy, ethoxy, C.sub.2-C.sub.4 alkanoyl, CF.sub.3, OCF.sub.3, or
hydroxy; [0333] R.sub.6 and R.sub.7 are independently H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or benzyl; [0334]
Y is OH; --N(Y.sub.1)(Y.sub.2); phenyl; benzyl; or C.sub.1-C.sub.10
alkyl optionally substituted with 1 or 2 substituents which can be
the same or different and are selected from halogen, hydroxy,
methoxy, ethoxy, thiomethoxy, thioethoxy, and CF.sub.3; wherein
[0335] Y.sub.1 and Y.sub.2 are the same or different and are H or
C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2
substituents selected from halogen, methoxy, ethoxy, cyclopropyl,
and OH.
[0336] Even more preferred compounds of formula X-VII include those
of formula X-VIII: ##STR13## wherein [0337] A.sub.1 and A.sub.2 are
independently H, methyl, ethyl, propyl, methoxy, F, Cl, Br, I,
CF.sub.3 or C.sub.2-C.sub.6 alkynyl; and [0338] A.sub.3 and A.sub.4
are independently F, Cl, Br, I, methyl, ethyl, methoxy, ethoxy, or
H.
[0339] Preferred compounds of formulae X-VII and X-VIII include
those wherein: [0340] A.sub.1 is methyl, ethyl, methoxy, C.sub.2
alkynyl, or I; [0341] A.sub.3 and A4 are independently H, F, Cl,
Br, or I; [0342] X is C.sub.1 or C.sub.2 alkylidenyl; [0343] Z is
SO.sub.2; SO; S; or C(O); and [0344] Y is phenyl, methyl, propyl,
n-butyl, isobutyl, isopentyl, 4-heptyl, 3-heptyl, 3-pentyl, or
5-nonyl; or [0345] Y is --N(Y.sub.1)(Y.sub.2); wherein [0346]
Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0347] Preferred compounds of formula X-VIII include those of
formula X-VIII-a ##STR14## wherein [0348] A.sub.3 and A.sub.4 are
independently H, F, Cl, methyl or methoxy; and [0349] R.sub.51 is
benzyl; phenethyl; CH.sub.3; CH.sub.2CF.sub.3; CH.sub.2CH.sub.2CN;
CH.sub.2CH.sub.2NHC(O)CH.sub.3;
CH.sub.2C(O)N(CH.sub.2CH.sub.3).sub.2; isopropyl;
CH.sub.2CH.sub.2OCH.sub.3; pyrrolidinyl, tetrahydrofuryl,
tetrahydro-thienyl 1,1-dioxide, tetrahydrothienyl, pyranyl,
piperidinyl, pyrrolidinonyl, each of which is optionally
substituted with 1 or 2 groups that are independently methyl,
ethyl, methoxy, ethoxy, halogen, C.sub.2-C.sub.4 alkanoyl, benzyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; pyrrolidinonyl C.sub.1-C.sub.4
alkyl; allyl; propargyl; pyridinyl C.sub.1-C.sub.4 alkyl;
cyclopentyl; cyclohexyl; or cyclopropylmethyl.
[0350] Other preferred compounds of formula X-VII include those of
formula X-IX ##STR15## wherein [0351] n9 is 1 or 2; [0352] A.sub.1
and A.sub.2 are independently H, methyl, ethyl, propyl, methoxy, F,
Cl, Br, I, CF.sub.3 or C.sub.2-C.sub.6 alkynyl; and [0353] A.sub.3
and A.sub.4 are independently F, Cl, Br, I, methyl, methoxy, or
H.
[0354] Preferred compounds of formula X-IX include those wherein
[0355] A.sub.1 is methyl, ethyl, I, or C.sub.2 alkynyl; [0356]
A.sub.3 and A.sub.4 are independently H, F, Cl, Br, or I; [0357] X
is C.sub.1 or C.sub.2 alkylidenyl; [0358] Z is SO.sub.2; SO; S; or
C(O); and [0359] Y is phenyl, methyl, propyl, n-butyl, isobutyl,
isopentyl, 4-heptyl, 3-heptyl, 3-pentyl, or 5-nonyl; or [0360] Y is
--N(Y.sub.1)(Y.sub.2); wherein [0361] Y.sub.1 and Y.sub.2 are
independently H or C.sub.1-C.sub.4 alkyl.
[0362] More preferred compounds of formula X-IX include those of
formula X-IX-a ##STR16## wherein [0363] A.sub.3 and A.sub.4 are
both H or both F; and [0364] R.sub.51 is benzyl; phenethyl;
CH.sub.3; CH.sub.2CF.sub.3; CH.sub.2CH.sub.2CN;
CH.sub.2CH.sub.2NHC(O)CH.sub.3;
CH.sub.2C(O)N(CH.sub.2CH.sub.3).sub.2; isopropyl;
CH.sub.2CH.sub.2OCH.sub.3; pyrrolidinyl; tetrahydrofuryl;
tetrahydro-thienyl 1,1-dioxide; tetrahydrothienyl; pyranyl;
piperidinyl; pyrrolidinonyl; each of which is optionally
substituted with 1 or 2 groups that are independently methyl,
ethyl, methoxy, ethoxy, halogen, C.sub.2-C.sub.4 alkanoyl, benzyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; pyrrolidinonyl C.sub.1-C.sub.4
alkyl; allyl; propargyl; pyridinyl C.sub.1-C.sub.4 alkyl;
cyclopentyl; cyclohexyl; or
--(C.sub.1-C.sub.4)alkyl-cyclopropyl.
[0365] Preferred compounds of formula X-VII include those of
formula X-X, i.e. compounds of formula X-VII wherein [0366] R.sub.C
is C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or
--(C.sub.1-C.sub.4) alkyl-cyclopropyl.
[0367] Preferred compounds of formula X-X include those of formula
X-X-a: ##STR17## wherein [0368] A.sub.3 and A.sub.4 are
independently F, Cl, Br, I, methyl, ethyl, methoxy, ethoxy, or H;
[0369] X is C.sub.1 or C.sub.2 alkylidenyl; [0370] Z is SO.sub.2;
SO; S; or C(O); and [0371] Y is phenyl, C.sub.1-C.sub.10 alkyl.
More preferably, Y is methyl, propyl, n-butyl, isobutyl, isopentyl,
4-heptyl, 3-heptyl, 3-pentyl, or 5-nonyl. Or, [0372] Y is
--N(Y.sub.1)(Y.sub.2); wherein [0373] Y.sub.1 and Y.sub.2 are
independently H or C.sub.1-C.sub.4 alkyl.
[0374] More preferred compounds of formula X-X include those of
formula X-X-b: ##STR18## wherein [0375] A.sub.3 and A.sub.4 are
independently H, F, Cl, methyl, ethyl, methoxy, ethoxy, CF.sub.3 or
OCF.sub.3; and [0376] R.sub.51 is benzyl; phenethyl; CH.sub.3;
CH.sub.2CF.sub.3; --CH.sub.2CH.sub.2CN;
CH.sub.2CH.sub.2NHC(O)CH.sub.3;
--CH.sub.2C(O)N(CH.sub.2CH.sub.3).sub.2; isopropyl;
CH.sub.2CH.sub.2OCH.sub.3; pyrrolidinyl, tetrahydrofuryl,
tetrahydro-thienyl 1,1-dioxide, tetrahydrothienyl, pyranyl,
piperidinyl, pyrrolidinonyl, each of which is optionally
substituted with 1 or 2 groups that are independently methyl,
ethyl, methoxy, ethoxy, halogen, C.sub.2-C.sub.4 alkanoyl, benzyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; pyrrolidinonyl C.sub.1-C.sub.4
alkyl; allyl; propargyl; pyridinyl C.sub.1-C.sub.4 alkyl;
cyclopentyl; cyclohexyl; or cyclopropylmethyl.
[0377] Representative compounds of formula X-VII are [0378]
3-(butylsulfinyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-D-
-alaninamide; [0379]
S-butyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzy-
l)amino]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-D-cysteinam-
ide; [0380]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4,4,4-trifluo-
robutyl)sulfonyl]-D-alaninamide; [0381]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4,4,4-trifluo-
robutyl)sulfinyl]-D-alaninamide; [0382]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-S-(4,4,4-trifluor-
obutyl)-D-cysteinamide; [0383]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-D-
-alaninamide; [0384]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(2,2,2-trifluoroetho-
xy)carbonyl]-D-alaninamide; [0385]
N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(butylsulfo-
nyl)-D-alaninamide; [0386]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[(3R)-pyrrolidin-3-y-
l]carbonyl}-D,L-alaninamide; [0387]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofura-
n-3-yloxy]carbonyl}-D-alaninamide; [0388]
N.about.2.about.-{[2-(acetylamino)ethoxy]carbonyl}-3-(butylsulfonyl)-N.ab-
out.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hy-
droxypropyl}-D-alaninamide; [0389]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[[(pyridin-3-yl)meth-
yl]oxy]carbonyl}-D-alaninamide; [0390]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[[(pyridin-4-yl)meth-
yl]oxy]carbonyl}-D-alaninamide; [0391]
3-(butylsulfonyl)-N.about.2.about.-[(methoxy)carbonyl]-N.about.1.about.-{-
(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-D-ala-
ninamide; [0392]
3-(butylsulfonyl)-N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.ab-
out.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-
-D-alaninamide; [0393]
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-
-D-alaninamide; [0394]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
methylbutyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(methyloxy)carbonyl]-
-D-alaninamide; [0395]
N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide; [0396]
N.about.2.about.-{[2-(acetylamino)ethoxy]carbonyl}-N.about.1.about.-{(1S,-
2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-pro-
pylbutyl)sulfonyl]-D-alaninamide; [0397]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-methylbutyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(methyloxy)carbonyl]-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide; [0398]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide; [0399]
N.about.2.about.-{[2-(diethylamino)-2-oxoethoxy]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; [0400]
N.about.1.about.-{((1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino-
]-2-hydroxypropyl}-N.about.2.about.-[(methoxy)carbonyl]-3-[(1-propylbutyl)-
sulfonyl]-D-alaninamide; [0401]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(isopropoxy)carbonyl]-3-[(1-propylbuty-
l)sulfonyl]-D-alaninamide; [0402]
N.about.2.about.-[(cyclopropylmethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-
-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-pr-
opylbutyl)sulfonyl]-D-alaninamide; [0403]
N.about.2.about.-[(allyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-di-
fluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)-
sulfonyl]-D-alaninamide; [0404]
N.about.2.about.-[(2-cyanoethoxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylb-
utyl)sulfonyl]-D-alaninamide; [0405]
N.about.2.about.-{[2-(acetylamino)ethoxy]carbonyl}-N.about.1.about.-{(1S,-
2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-
-propylbutyl)sulfonyl]-D-alaninamide; [0406]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[[(pyridin-
-3-yl)methyl]oxy]carbonyl}-D-alaninamide; [0407]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[[(pyridin-
-4-yl)methyl]oxy]carbonyl}-D-alaninamide; [0408] benzyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3-(methylsulfonyl)propylcarbamate; [0409]
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-D-alaninamide trifluoroacetate; [0410]
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-L-alaninamide trifluoroacetate; [0411]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2S)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[(1R)-2-hydroxy-1-phenylethyl]amino}propyl)-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide; [0412]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2S)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[(1R)-2-methoxy-1-phenylethyl]amino}propyl)-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide; [0413]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2S)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[(1S)-2-methoxy-1-phenylethyl]amino}propyl)-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide; [0414]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide; [0415]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[(prop-2-y-
nyl)oxy]carbonyl}-D-alaninamide; [0416]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(2-methoxyethylcarbonyl)-3-[(1-propylbu-
tyl)sulfonyl]-D-alaninamide; [0417]
N.about.2.about.-{[(3R)-1-acetylpyrrolidin-3-yl]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; [0418]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-D-alaninamide; [0419]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-L-alaninamide; [0420]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide; [0421]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-L-alaninamide; [0422]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3--
[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0423]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D,L-alaninamide; [0424]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D,L-alaninamide; [0425]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-(cyclopropylamino)-2-hydroxypropyl}-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide; [0426]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(cyclopropylmethyl)amino]-2-hydroxypropyl}-3-[(1-propylb-
utyl)sulfonyl]-D,L-alaninamide; [0427]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2S)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylphenyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D,L-alaninamide; [0428]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-[(1S,2R)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-
yl]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0429]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[[(pyridin-
-3-yl)methyl]oxy]carbonyl}-D,L-alaninamide; [0430]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0431]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3R)-tetrahydrofuran-3-yloxy]carbonyl-
}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0432]
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-hydroxypr-
opyl}-N.about.2.about.-{[(3S)-tetrahydrofuran-3-yloxy]carbonyl}-3-[(1-prop-
ylbutyl)sulfonyl]-D,L-alaninamide; [0433]
N.about.2.about.-{[(3R)-1-acetylpyrrolidin-3-yl]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0434]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[(3R)-pyrr-
olidin-3-yl]carbonyl}-D,L-alaninamide; [0435]
N.about.2.about.-{[(3R)-1-benzylpyrrolidin-3-yl]carbonyl}-N.about.1.about-
.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-
}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0436]
N.about.1.about.-{(1S,2R)-1-(3,5difluorobenzyl)-3-[(3-ethylbenzyl)amino]--
2-hydroxypropyl}-N.about.2.about.-{[(3S)-1,1-dioxidotetrahydrothien-3-ylox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0437]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[(3S)-tetrahydrothiophen-3-yloxy]carbo-
nyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0438]
N.about.2.about.-(cyclopentylcarbonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D,L-alaninamide; [0439]
N.about.2.about.-(cyclohexylcarbonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-di-
fluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)-
sulfonyl]-D,L-alaninamide; [0440]
N.about.1.about.-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-h-
ydroxypropyl]-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[tetrahydropyr-
an-4-yloxy]carbonyl}-D,L-alaninamide; [0441]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[tetrahydr-
opyran-4-yloxy]carbonyl}-D,L-alaninamide; [0442]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[1-(methylsulfonyl)piperidin-4-yloxy]c-
arbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0443]
N.about.2.about.-{[1-acetylpiperidin-4-yloxy]carbonyl}-N.about.1.about.-{-
(1S,2R))-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}--
3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0444]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[[(3S)-5-oxopyrrolidin-3-yl]methyl]ox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0445]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[[(3R)-5-oxopyrrolidin-3-yl]methyl]ox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0446]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[2-methoxyethyl]oxy]carbonyl}-3-[(1-p-
ropylbutyl)sulfonyl]-D,L-alaninamide; [0447]
N.about.2.about.-[(benzyloxy)carbonyl]-3-(butylsulfonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-D,L-alaninamide; [0448]
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-hydroxypr-
opyl}-N.about.2.about.-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D-
,L-alaninamide; [0449]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-((1S,2R)-1-(3,5-d-
ifluorobenzyl)-2-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]amino}propyl)-3-[(1--
propylbutyl)sulfonyl]-D,L-alaninamide; [0450]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.5.about.,-
N.about.5.about.-dipropyl-L-glutamamide; [0451]
N.about.2.about.-[(benzyloxy)carbonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.5.about.,-
N.about.5.about.-dipropyl-D-glutamamide; [0452] methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3-oxoheptylcarbamate; [0453]
4-butyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzy-
l)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxycarbonyl)-D-homoserinam-
ide; [0454]
3-(2-butyl-1,3-dioxolan-2-yl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobe-
nzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxyc-
arbonyl)-D-alaninamide; [0455]
3-(2-butyl-1,3-dioxan-2-yl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenz-
yl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxycar-
bonyl)-D-alaninamide; [0456] methyl
(1R)-1-[([(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl]amino)carbonyl]-3,3-difluoroheptylcarbamate; [0457] methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-3-fluoroheptylcarbamate;
methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]--
2-hydroxypropyl}amino)carbonyl]-4-oxooctylcarbamate; [0459] methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-4-hydroxyoctylcarbamate; [0460] methyl
(1R)-3-(2-butyl-1,3-dioxolan-2-yl)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3--
[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propylcarbamate;
[0461] methyl
(1R)-3-(2-butyl-1,3-dioxan-2-yl)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(-
3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propylcarbamate;
[0462] methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-4-fluorooctylcarbamate; [0463] methyl
(1R)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydro-
xypropyl}amino)carbonyl]-4,4-difluorooctylcarbamate; [0464]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethynylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxycarbonyl)-D-
-alaninamide; [0465]
3-(butylsulfonyl)-N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydr-
oxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N.about.2.about.-(methoxyc-
arbonyl)-D-alaninamide; [0466]
3-(butylsulfonyl)-N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1--
(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(metho-
xycarbonyl)-D-alaninamide; [0467]
3-(butylsulfonyl)-N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1--
(3-ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(met-
hoxycarbonyl)-D-alaninamide; [0468]
3-(butylsulfonyl)-N.about.1.about.-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydr-
oxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-N.about.2.a-
bout.-(methoxycarbonyl)-D-alaninamide; and pharmaceutically
acceptable salts thereof.
[0469] Other preferred compounds of the invention include those of
formula X-XI, i.e., compounds of formula X-II wherein R.sub.N is:
##STR19## wherein [0470] n.sub.7 is 0, 1, 2, or 3; [0471] R.sub.50
is H or C.sub.1-C.sub.6 alkyl; [0472] R.sub.5 is selected from the
group consisting of cyclopropyl; cyclopentyl; cyclohexyl;
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
that are independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4
alkoxy, C.sub.5-C.sub.6 heterocycloalkyl, C.sub.5-C.sub.6
heteroaryl, phenyl, C.sub.3-C.sub.7 cycloalkyl,
--S--C.sub.1-C.sub.4 alkyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4
alkyl, or phenyloxy; heteroaryl optionally substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.1-C.sub.4 haloalkyl, or OH;
heterocycloalkyl optionally substituted with 1, 2, or 3 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.2-C.sub.4 alkanoyl; phenyl optionally substituted
with 1, 2, 3, or 4 groups that are independently halogen, OH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
haloalkyl; and --NR.sub.6R.sub.7; wherein [0473] R.sub.6 and
R.sub.7 are independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, and phenyl C.sub.1-C.sub.4
alkyl; [0474] X is C.sub.1-C.sub.4 alkylidenyl optionally
substituted with 1, 2, or 3 methyl groups; or --NR.sub.4-6--; or
[0475] R.sub.4 and R.sub.4-6 combine to form
--(CH.sub.2).sub.n10--, wherein [0476] n.sub.10 is 1, 2, 3, or 4;
[0477] Z is a bond; SO.sub.2; SO; S; or C(O); [0478] Y is H;
C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8 cycloalkyl optionally
substituted with 1, 2, or 3 groups independently selected from
C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; or phenyl C.sub.1-C.sub.4 alkyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; wherein [0479] Y.sub.1 and Y.sub.2 are the
same or different and are H; C.sub.1-C.sub.10 alkyl optionally
substituted with 1, 2, or 3 substituents selected from halogen,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8 cycloalkyl, and OH;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl; or
C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or [0480]
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen; and
[0481] R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, halo C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkanoyl,
each of which is unsubstituted or substituted with 1, or 2 groups
independently selected from halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, NH.sub.2, and --R.sub.26-R.sub.27,
wherein [0482] R.sub.26 is --C(O)--, --SO.sub.2--, --CO.sub.2--,
--C(O)NH--, or --C(O)N(C.sub.1-C.sub.6 alkyl)-; [0483] R.sub.27 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6
alkyl, heterocycloalkyl, or heteroaryl, wherein each of the above
is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, halo C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
--C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
[0484] Preferred compounds of formula X-XI include those of formula
X-XI-a, i.e., formula X-XI wherein [0485] R.sub.2 and R.sub.3 are
independently H or C.sub.1-C.sub.6 alkyl optionally 15 substituted
with 1, or 2 substituents selected from halogen, OH, SH, C.ident.N,
CF.sub.3, and C.sub.1-C.sub.3 alkoxy; and [0486] R.sub.C is
C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--OC.dbd.ONR.sub.235R.sub.240, --S(.dbd.O).sub.0-2(C.sub.1-C.sub.6
alkyl), --SH, --C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl; or
--(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-heteroaryl; wherein each aryl is
optionally substituted with 1, 2, or 3 R.sub.200; [0487] each
heteroaryl is optionally substituted with 1, 2, 3, or 4 R.sub.200;
[0488] each heterocycloalkyl is optionally substituted with 1, 2,
3, or 4 R.sub.210; [0489] R.sub.200 at each occurrence is
independently C.sub.1-C.sub.6 alkyl optionally substituted with 1,
2, or 3 R.sub.205 groups; OH; --NO.sub.2; halogen; --CO.sub.2H;
C.ident.N; --(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0490] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0491] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1, 2, or 3 R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); or .dbd.O; wherein [0492]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.7 cycloalkyl,
and --(CH.sub.2).sub.0-2-(heteroaryl), or
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the phenyl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0493] R.sub.220 and R.sub.225 at each occurrence are independently
--H, --C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.7 cycloalkyl, or
--(C.sub.1-C.sub.6 alkyl)-O-- (C.sub.1-C.sub.3 alkyl); [0494]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0495] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, or [0496] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, or 6 carbon atoms.
[0497] More preferred compounds of formula X-XI-a include those of
formula X-XI-b, i.e. X-XI-a, wherein [0498] R.sub.1 is benzyl which
is optionally substituted with 1, 2, 3, or 4 groups independently
selected from C.sub.1-C.sub.4 alkyl optionally substituted with 1,
or 2 substituents selected from halogen, --OH, --SH, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy; halogen; C.sub.1-C.sub.4 alkoxy; and
OH.
[0499] Even more preferred compounds of formula X-XI-b include
those of formula X-XI-c, i.e., X-XI-b wherein [0500] n.sub.7 is 0,
1, or 2; [0501] R.sub.5 is selected from the group consisting of
cyclopropyl; cyclopentyl; cyclohexyl; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy,
C.sub.5-C.sub.6 heterocycloalkyl, C.sub.5-C.sub.6 heteroaryl,
phenyl, C.sub.3-C.sub.7 cycloalkyl, --S--C.sub.1-C.sub.4 alkyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, --CO.sub.2H,
--CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4 alkyl, or
phenyloxy; pyridyl, thiazolyl, pyrazolyl, pyrazinyl, each of which
is optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.1-C.sub.4 haloalkyl, or OH; piperidinyl,
dihydropyridazinonyl, pyrrolidinonyl, thioxothiazolidinonyl,
isoxazolyl, imidazolyl, indolyl, each of which is optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.2-C.sub.4 alkanoyl; phenyl optionally substituted with 1, 2,
3, or 4 groups that are independently halogen, OH, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkyl; and
--NR.sub.6R.sub.7; wherein [0502] R.sub.6 and R.sub.7 are
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl, and phenethyl.
[0503] More preferred compounds of formulae X-XI, X-XI-a, X-XI-b
and X-XI-c include those wherein [0504] R.sub.20 at each occurrence
is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.2
alkoxy C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkanoyl, each of
which is unsubstituted or substituted with 1 or 2 groups
independently selected from halogen, hydroxy, C.sub.1-C.sub.4
alkoxy, tertiary-butoxy carbonyl, benzyloxycarbonyl, and NH.sub.2;
[0505] R.sub.C is C.sub.1-C.sub.8 alkyl optionally substituted with
1, 2, or 3 groups independently selected from the group consisting
of R.sub.205, --SH, --C.dbd.ONR.sub.235R.sub.240, and
--S(--O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl optionally substituted with
1, 2, or 3 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyridazinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrimidinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazinyl;
--(CR.sub.245R.sub.250).sub.0-3-furyl;
--(CR.sub.245R.sub.250).sub.0-3-indolyl;
--(CR.sub.245R.sub.250).sub.0-3-thienyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1, 2, 3, or 4
R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.1250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-piperazinyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl;
(CR.sub.245R.sub.250).sub.0-3-indolinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1, 2, 3, or
4 R.sub.210; (CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--
(CH.sub.2).sub.0-1-phenyl; or
--(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0506] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0507] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0508] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1 or 2 R.sub.205 groups; halogen; C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.4 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1 or 2
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
--SO.sub.2NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); or .dbd.O; wherein [0509]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.6 cycloalkyl,
--(CH.sub.2).sub.0-2-(pyridyl), --(CH.sub.2).sub.0-2-- (pyrrolyl),
--(CH.sub.2).sub.0-2-(imidazolyl),
--(CH.sub.2).sub.0-2-(pyrimidyl),
--(CH.sub.2).sub.0-2-(pyrrolidinyl),
--(CH.sub.2).sub.0-2-(imidazolidinyl)-(CH.sub.2).sub.0-2-(piperazinyl),
--(CH.sub.2).sub.0-2-(piperidinyl), or
--(CH.sub.2).sub.0-2-(morpholinyl); wherein the phenyl group at
each occurrence is optionally substituted with 1 or 2 groups that
are independently R.sub.205 or R.sub.210; wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1 or 2 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1 or 2 R.sub.210; [0510]
R.sub.220 and R.sub.225 at each occurrence are independently --H,
--C.sub.1-C.sub.4 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.6 cycloalkyl, or
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.2 alkyl); [0511]
R.sub.1235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0512] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, or [0513] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms.
[0514] Still other more preferred compounds of formulae X-XI,
X-XI-a, X-XI-B and X-XI-c include those wherein [0515] X is
--C.sub.1-C.sub.3 alkylidenyl optionally substituted with 1 or 2
methyl groups; [0516] Z is SO.sub.2; SO; S; or C(O); [0517] Y is H;
C.sub.1-C.sub.4 haloalkyl; pyrrolidinyl; piperidinyl;
imidazolidinyl; piperazinyl; OH; --N(Y.sub.1)(Y.sub.2);
C.sub.1-C.sub.10 alkyl optionally substituted with 1 thru 3
substituents which can be the same or different and are selected
from halogen, hydroxy, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
thioalkoxy, and C.sub.1-C.sub.4 haloalkoxy; C.sub.3-C.sub.6
cycloalkyl optionally substituted with 1, 2, or 3 groups
independently selected from C.sub.1-C.sub.3 alkyl and halogen;
C.sub.1-C.sub.4 alkoxy; phenyl, benzyl or phenethyl each of which
is optionally substituted with halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0518] Y.sub.1 and
Y.sub.2 are independently H; C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 substituents selected from halogen,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and OH;
C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; phenyl C.sub.1-C.sub.4 alkyl; or C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0519] --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4
alkyl, or halogen; and [0520] R.sub.2 and R.sub.3 are independently
H or C.sub.1-C.sub.4 alkyl.
[0521] Still other even more preferred compounds of formula X-XI
include those of formula X-XII, i.e., compounds of formula X-XI
wherein [0522] n.sub.7 is 0, or 1; [0523] R.sub.5 is selected from
the group consisting of cyclopropyl; cyclobutyl, cyclopentyl;
cyclohexyl; C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2,
or 3 groups that are independently halogen, --NR.sub.6R.sub.7,
C.sub.1-C.sub.4 alkoxy, piperidinyl, pyrrolidinyl, tetrahydrofuryl,
tetrahydrothienyl dioxide, pyranyl, pyridyl, phenyl,
C.sub.3-C.sub.6 cycloalkyl, S--C.sub.1-C.sub.4 alkyl,
SO.sub.2--C.sub.1-C.sub.4 alkyl, CO.sub.2H, CONR.sub.6R.sub.7,
CO.sub.2--C.sub.1-C.sub.4 alkyl, or phenyloxy; pyridyl, thiazolyl,
pyrazolyl, pyrazinyl, optionally substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, C.sub.1-C.sub.4 haloalkyl, or OH; piperidinyl,
dihydropyridazinonyl, pyrrolidinonyl, thioxothiazolidinonyl,
isoxazolyl, imidazolyl, indolyl, optionally substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, or C.sub.2-C.sub.4 alkanoyl;
phenyl optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.2 haloalkyl; and --NR.sub.6R.sub.7;
wherein [0524] R.sub.6 and R.sub.7 are independently selected from
the group consisting of H, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6
alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl, and benzyl;
[0525] R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, tertiary-butoxy
carbonyl, and benzyloxycarbonyl; [0526] R.sub.c is C.sub.1-C.sub.8
alkyl optionally substituted with 1 or 2 groups independently
selected from R.sub.205, and --SH;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1 R.sub.205 group;
--(CR.sub.245R.sub.250).sub.0-3-phenyl optionally substituted with
1 or 2 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1 or 2 R.sub.200;
--(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl; (CR.sub.245R.sub.250)
O.sub.3-piperidinyl; each of the above heterocycloalkyl groups is
optionally substituted with 1 or 2 R.sub.210;
(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--
(CH.sub.2).sub.0-1-phenyl; or
--(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0527] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.4 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; NO.sub.2;
halogen; CO.sub.2H; C.ident.N; or --(CH.sub.2).sub.0-4--O--
(C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, 3, or
5-F); [0528] R.sub.205 at each occurrence is independently
C.sub.1-C.sub.6 alkyl, halogen, OH, --O-phenyl, SH, C.ident.N,
CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl), or N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); [0529]
R.sub.210 at each occurrence is independently C.sub.1-C.sub.6 alkyl
optionally substituted with 1 R.sub.205 group; halogen;
C.sub.1-C.sub.4 alkoxy; C.sub.1-C.sub.4 haloalkoxy; OH; C.ident.N;
or .dbd.O; wherein [0530] R.sub.235 and R.sub.240 at each
occurrence are independently H, or C.sub.1-C.sub.6 alkyl; [0531]
R.sub.245 and R.sub.250 at each occurrence are independently H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.1-C.sub.4 alkoxy, or [0532] R.sub.245 and R.sub.250 are taken
together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms; [0533] X is
--C.sub.1-C.sub.3 alkylidenyl; [0534] Z is SO.sub.2; SO; S; or
C(O); [0535] Y is H; C.sub.1-C.sub.4 haloalkyl; pyrrolidinyl;
piperidinyl; imidazolidinyl; piperazinyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 thioalkoxy, and C.sub.1-C.sub.4 haloalkoxy;
C.sub.3-C.sub.6 cycloalkyl optionally substituted with 1, 2, or 3
groups independently selected from C.sub.1-C.sub.3 alkyl and
halogen; C.sub.1-C.sub.4 alkoxy; phenyl, benzyl or phenethyl each
of which is optionally substituted with halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0536]
Y.sub.1 and Y.sub.2 are independently H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; phenyl C.sub.1-C.sub.4 alkyl; or C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0537] --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, and pyrrolidinyl, wherein
each ring is optionally substituted with 1, or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl, or halogen; [0538]
R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.4 alkyl;
and [0539] R.sub.1 is benzyl which is optionally substituted with
1, 2, or 3 groups independently selected from C.sub.1-C.sub.4 alkyl
optionally substituted with 1 substituent selected from halogen,
--OH, NH.sub.2, NH(C.sub.1-C.sub.4 alkyl), N--(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --C-MN, CF.sub.3, and
C.sub.1-C.sub.3 alkoxy; halogen; C.sub.1-C.sub.4 alkoxy; and
OH.
[0540] More preferred compounds of formula X-XI and preferred
compounds of formula X-XII include those of formula X-XIII wherein
##STR20## wherein [0541] A.sub.1 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or C.sub.2-C.sub.6 alkynyl; [0542] A.sub.2
is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkyl or OH; [0543]
A.sub.3 and A.sub.4 are independently H, F, Cl, Br, or I; [0544]
R.sub.5 is selected from cyclopropyl; cyclobutyl, cyclopentyl;
cyclohexyl; pyridyl, thiazolyl, pyrazolyl, or pyrazinyl each of
which is optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.1-C.sub.4 haloalkyl, or OH; piperidinyl,
dihydropyridazinonyl, pyrrolidinonyl, thioxothiazolidinonyl,
isoxazolyl, imidazolyl, or indolyl each of which is optionally
substituted with 1, or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, or
C.sub.2-C.sub.4 alkanoyl; phenyl optionally substituted with 1, 2,
3, or 4 groups that are independently halogen, OH, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.2 haloalkyl; and
--NR.sub.6R.sub.7.
[0545] Preferred compounds of formula X-XIII include those wherein
[0546] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0547] X is C.sub.1 or C.sub.2 alkylidenyl;
[0548] Z is SO.sub.2; SO; S; or C(O); and [0549] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0550] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0551] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0552] More preferred compounds of formula X-XIII include those of
formula X-XIV: ##STR21##
[0553] Preferred compounds of formulas X-XIII and X-XIV include
those wherein [0554] A.sub.1 is C.sub.1-C.sub.4 alkyl, C.sub.2
alkynyl, or I; [0555] R.sub.50 is H or C.sub.1-C.sub.4 alkyl;
[0556] A.sub.2 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
OCF.sub.3, CF.sub.3 or OH; [0557] A.sub.3 and A.sub.4 are
independently H, F, Cl, Br, or I.
[0558] Even more preferred compounds of formulas X-XIII and X-XIV
include those wherein [0559] R.sub.245 and R.sub.250 are both
hydrogen or R.sub.245 and R.sub.250 form a cyclopropyl group.
[0560] Other preferred compounds of formula X-XII include those of
formula X-XV: ##STR22## wherein [0561] A.sub.1 is H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2 alkynyl, or
I; [0562] A.sub.2 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkyl or
OH; [0563] A.sub.3 and A.sub.4 are independently H, F, Cl, Br, or
I; [0564] R.sub.5 is C.sub.1-C.sub.6 alkyl optionally substituted
with 1, 2, or 3 groups that are independently halogen,
--NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy, piperidinyl,
pyrrolidinyl, pyridyl, phenyl, C.sub.3-C.sub.6 cycloalkyl,
S--C.sub.1-C.sub.4 alkyl, SO.sub.2--C.sub.1-C.sub.4 alkyl,
CO.sub.2H, CONR.sub.6R.sub.7, CO.sub.2--C.sub.1-C.sub.4 alkyl, or
phenyloxy; and --NR.sub.6R.sub.7 wherein [0565] R.sub.6 and R.sub.7
are independently selected from the group consisting of H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl, and
--SO.sub.2--C.sub.1-C.sub.4 alkyl.
[0566] Preferred compounds of formula X-XV include those wherein
[0567] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0568] X is C.sub.1 or C.sub.2 alkylidenyl;
[0569] Z is SO.sub.2; SO; S; or C(O); and [0570] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0571] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0572] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0573] More preferred compounds of formula X-XV include those of
formula X-XVI: ##STR23##
[0574] Preferred compounds of formulas X-XV and X-XVI include those
wherein [0575] A.sub.1 is C.sub.1-C.sub.4 alkyl; [0576] R.sub.50 is
H or C.sub.1-C.sub.4 alkyl; [0577] A.sub.2 is H, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, CF.sub.3 or OH; [0578]
A.sub.3 and A.sub.4 are independently H, F, Cl, Br, or I.
[0579] More preferred compounds of formulas X-XV and X-XVI include
those wherein [0580] R.sub.245 and R.sub.250 are both hydrogen or
R.sub.245 and R.sub.250 form a cyclopropyl group.
[0581] Other preferred compounds of formula X-XII include those of
formula X-XVII: ##STR24## wherein [0582] R.sub.C is C.sub.3-C.sub.8
alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or --(C.sub.1-C.sub.4)
alkyl-cyclopropyl; [0583] A.sub.3 and A.sub.4 are independently H,
F, Cl, Br, or I; [0584] R.sub.5 is selected from cyclopropyl;
cyclopentyl; cyclohexyl; pyridyl, thiazolyl, pyrazolyl, or
pyrazinyl each of which is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.1-C.sub.4 haloalkyl, or OH;
piperidinyl, dihydropyridazinonyl, pyrrolidinonyl,
thioxothiazolidinonyl, isoxazolyl, imidazolyl, or indolyl each of
which is optionally substituted with 1, or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, or C.sub.2-C.sub.4 alkanoyl; phenyl optionally substituted
with 1, 2, 3, or 4 groups that are independently halogen, OH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.2
haloalkyl; and --NR.sub.6R.sub.7.
[0585] Preferred compounds of formula X-XVII include those wherein
[0586] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0587] X is C.sub.1 or C.sub.2 alkylidenyl;
[0588] Z is SO.sub.2; SO; S; or C(O); and [0589] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0590] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0591] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0592] More preferred compounds of formula X-XVII include those of
formula X-XVIII: ##STR25##
[0593] Preferred compounds of formulas X-XVII and X-XVIII include
those wherein [0594] R.sub.50 is H or C.sub.1-C.sub.4 alkyl; [0595]
A.sub.3 and A.sub.4 are independently H, F, Cl, Br, or I.
[0596] More preferred compounds of formulas X-XVII and X-XVIII
include those wherein [0597] R.sub.245 and R.sub.250 are both
hydrogen or R.sub.245 and R.sub.250 form a cyclopropyl group.
[0598] Other preferred compounds of formula X-XII include those of
formula X-XIX: ##STR26## wherein [0599] R.sub.C is C.sub.3-C.sub.8
alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or --(C.sub.1-C.sub.4)
alkyl-cyclopropyl; [0600] A.sub.3 and A.sub.4 are independently H,
F, Cl, Br, or I; [0601] R.sub.5 is C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently halogen,
--NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy, piperidinyl,
pyrrolidinyl, pyridyl, phenyl, C.sub.3-C.sub.6 cycloalkyl,
S--C.sub.1-C.sub.4 alkyl, SO.sub.2--C.sub.1-C.sub.4 alkyl,
CO.sub.2H, CONR.sub.6R.sub.7, CO.sub.2--C.sub.1-C.sub.4 alkyl, or
phenyloxy; wherein [0602] R.sub.6 and R.sub.7 are independently
selected from the group consisting of H, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.6 alkanoyl, phenyl, and --SO.sub.2--C.sub.1-C.sub.4
alkyl.
[0603] Preferred compounds of formula X-XIX include those wherein
[0604] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0605] X is C.sub.1 or C.sub.2 alkylidenyl;
[0606] Z is SO.sub.2; SO; S; or C(O); and [0607] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0608] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0609] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0610] Preferred compounds of formula X-XIX include those of
formula X-XX: ##STR27##
[0611] Preferred compounds of formulas X-XIX and X-XX include those
wherein [0612] R.sub.50 is H or C.sub.1-C.sub.4 alkyl; [0613]
A.sub.3 and A.sub.4 are independently H, F, Cl, Br, or I.
[0614] More preferred compounds of formulas X-XIX and X-XX include
those wherein [0615] R.sub.245 and R.sub.250 are both hydrogen or
R.sub.245 and R.sub.250 form a cyclopropyl group.
[0616] Representative compounds of formula X-XI are: [0617]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(3,3,3-trifluoropropa-
noyl)-D-alaninamide; [0618]
3-(butylsulfonyl)-N.about.1.about.-{((1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-
-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(trifluoroacetyl)-D--
alaninamide; [0619]
N.about.2.about.-acetyl-3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,-
5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-D-alaninamide;
[0620]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzy-
l)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(pyridin-4-y-
lcarbonyl)-D-alaninamide; [0621]
3-(butylsulfonyl)-N.about.2.about.-(cyclopropylcarbonyl)-N.about.1.about.-
-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-
-D-alaninamide; [0622]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.(beta-alanyl)-D-alanin-
amide; [0623]
3-(butylsulfonyl)-N.about.1.about.-[(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl]-N.about.2.about.glycyl-D-alaninamide;
[0624]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl-
)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.(N,N-dimethylg-
lycyl)-D-alaninamide; [0625]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.(N,N-dimethyl-beta-ala-
nyl)-D-alaninamide; [0626]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(methoxyacetyl)-D-ala-
ninamide; [0627]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(pyridin-3-ylcarbonyl-
)-D-alaninamide; [0628]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(2,4-dimethyl-1,3-th-
iazol-5-yl)carbonyl]-D-alaninamide; [0629]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-{[3-(trifluoromethyl)-
-1H-pyrazol-4-yl]carbonyl}-D-alaninamide; [0630]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(3-methyl-1H-pyrazol-
-5-yl)carbonyl]-D-alaninamide; [0631]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(1H-imidazol-4-ylacet-
yl)-D-alaninamide; [0632]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-(pyrazin-2-ylcarbonyl-
)-D-alaninamide; [0633]
3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(6-hydroxypyridin-3--
yl)carbonyl]-D-alaninamide; [0634]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-(cyclopropylamino)-2-h-
ydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(pyridin-4-ylca-
rbonyl)-D-alaninamide; [0635]
N.about.2.about.-acetyl-3-(butylsulfonyl)-N.about.1.about.-{(1S,2R)-1-(3,-
5-difluorobenzyl)-3-[(3-methylbutyl)amino]-2-hydroxypropyl}-D-alaninamide;
[0636]
N.about.1.about.-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobe-
nzyl)-2-hydroxypropyl]-N.about.2.about.-(cyclopropylcarbonyl)-3-[(1-propyl-
butyl)sulfonyl]-D-alaninamide; [0637]
N.about.2.about.-acetyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)--
3-[(3-methylbutyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-al-
aninamide; [0638]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(pyridin-4--
ylcarbonyl)-D-alaninamide; [0639]
N.about.2.about.-[(5-bromoopyridin-3-yl)carbonyl]-N.about.1.about.-{(1S,2-
R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1--
propylbutyl)sulfonyl]-D-alaninamide; [0640]
N.about.2.about.-[(5-chloropyridin-3-yl)carbonyl]-N.about.1.about.-{(1S,2-
R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1--
propylbutyl)sulfonyl]-D-alaninamide; [0641]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-fluorobenzoyl)-3-[(1-propylbutyl)sul-
fonyl]-D-alaninamide; [0642]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(5-methylpyridin-3-yl)carbonyl]-3-[(1--
propylbutyl)sulfonyl]-D-alaninamide; [0643]
N.about.2.about.-phenylglycyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobe-
nzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl-
]-D-alaninamide; [0644]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-{[3-(triflu-
oromethyl)-1H-pyrazol-4-yl]carbonyl}-D-alaninamide; [0645]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3--
[(1-propylbutyl)sulfonyl]-D-alaninamide; [0646]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(1,3-thiazo-
l-4-ylcarbonyl)-D-alaninamide; [0647]
N.about.2.about.-[(1-acetylpiperidin-4-yl)carbonyl]-N.about.1.about.-{(1S-
,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(-
1-propylbutyl)sulfonyl]-D-alaninamide; [0648]
N.about.2.about.-[4-(acetylamino)butanoyl]-N.about.1.about.-{(1S,2R)-1-(3-
,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylb-
utyl)sulfonyl]-D-alaninamide; [0649]
N.about.2.about.-acetyl-beta-alanyl-N.about.1.about.-{(1S,2R)-1-(3,5-difl-
uorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)su-
lfonyl]-D-alaninamide; [0650]
N.about.2.about.-(chloroacetyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluoro-
benzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfon-
yl]-D-alaninamide; [0651]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(methoxyacetyl)-3-[(1-propylbutyl)sulfo-
nyl]-D-alaninamide; [0652]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-methoxypropanoyl)-3-[(1-propylbutyl)-
sulfonyl]-D-alaninamide; [0653]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(2,2-dimethylpropanoyl)-3-[(1-propylbut-
yl)sulfonyl]-D-alaninamide; [0654]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-isobutyryl-3-[(1-propylbutyl)sulfonyl]--
D-alaninamide; [0655]
N.about.2.about.-butyryl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-
-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-a-
laninamide; [0656]
N.about.2.about.-acetyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)--
3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-al-
aninamide; [0657]
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N.about.2.abo-
ut.-[(pyridin-3-yl)carbonyl]-D-alaninamide trifluoracetate; [0658]
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N.about.2.abo-
ut.-[(pyridin-4-yl)carbonyl]-D-alaninamide trifluoracetate; [0659]
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(3-hydroxybenzoyl}-3-[(1-
-propylbutyl)sulfonyl]-D-alaninamide trifluoracete; [0660]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyridin-3-
-yl)carbonyl]-D-alaninamide; [0661]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-hydroxybenzoyl}-3-[(1-propylbutyl)su-
lfonyl]-D-alaninamide; [0662]
N.about.2.about.-(cyclopropylcarbonyl)-N.about.1.about.-{(1S,2R)-1-(3,5-d-
ifluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl-
)sulfonyl]-D-alaninamide; [0663]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2-propionyl-3-[(1-propylbutyl)sulfonyl]-D-alanin-
amide; [0664]
3-[butylsulfonyl]-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-N.about.2.about.-[(pyridin-3-yl)carbon-
yl]-D,L-alaninamide; [0665]
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-N.about.2.about.-(3-hydroxybenzoyl-3-[(1--
propylbutyl)sulfonyl]-D,L-alaninamide trifluoracete; [0666]
N.about.1.about.-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyc-
lopropyl]amino}-2-hydroxypropyl)-3-[(1-propylbutyl)sulfonyl]-N.about.2.abo-
ut.-[(pyridin-4-yl)carbonyl]-D-alaninamide trifluoracetate; [0667]
N.about.1.about.-[(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl]-N.about.2.about.-[(6-oxo-1,4,5,6-tetrahydropyridazin-3-y-
l)carbonyl]-3-[(1-propylbutyl)sulfonyl]alaninamide hydrochloride;
[0668]
5-oxo-D-prolyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-eth-
ylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninamide;
[0669]
5-oxo-L-prolyl-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-
-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alanin-
amide; [0670]
N.about.1.about.-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[3-(4-oxo-2-thioxo-1,3-thiazolidin-3-yl-
)propanoyl]-3-[(1-propylbutyl)sulfonyl]alaninamide; [0671]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(piperidin-4-yl)carbonyl]-3-[(1-propyl-
butyl)sulfonyl]-D,L-alaninamide; [0672]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(2,4-dimethyl-1,3-thiazol-5-yl)carbony-
l]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0673]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(2-methyl-4-(trifluoromethyl)-1,3-thia-
zol-5-yl)carbonyl]-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide;
[0674]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3,5-dimethylisoxazol-4-yl)carbonyl]-3-
-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0675]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3-methyl-1H-pyrazol-5-yl)carbonyl]-3--
[(1-propylbutyl)sulfonyl]-D,L-alaninamide trifluoroacetate; [0676]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(1H-pyrazol-4-yl)carbonyl]-3-[(1-propy-
lbutyl)sulfonyl]-D,L-alaninamide; [0677]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(1H-imidazol-5-yl)carbonyl]-3-[(1-prop-
ylbutyl)sulfonyl]-D,L-alaninamide; [0678]
N.about.1.about.-{((1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino-
]-2-hydroxypropyl}-N.about.2.about.-(1H-imidazol-4-ylacetyl)-3-[(1-propylb-
utyl)sulfonyl]-D,L-alaninamide; [0679]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyrazin-2-
-yl)carbonyl]-D,L-alaninamide; [0680]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(3,5-dihydroxypyridin-4-yl)carbonyl]---
3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide; [0681]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(6-hydroxypyridin-3-yl)carbonyl]-3-[(1-
-propylbutyl)sulfonyl]-D,L-alaninamide; [0682]
N.about.2.about.-[(6-chloropyridin-3-yl)carbonyl]-N.about.1.about.-{(1S,2-
R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1--
propylbutyl)sulfonyl]-D,L-alaninamide; [0683]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyridin-4-
-yl)carbonyl]-D,L-alaninamide; [0684]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(pyridin-3-yl)carbonyl]-3-[(1-propylbu-
tyl)sulfonyl]-D,L-alaninamide; [0685]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-[(pyridin-2-
-yl)carbonyl]-D,L-alaninamide; [0686]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[1H-indole-6-carbonyl]-3-[(1-propylbuty-
l)sulfonyl]-D,L-alaninamide; [0687]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-N.about.2.about.-(2,3,4-trim-
ethoxybenzoyl)-D,L-alaninamide; [0688]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-[(pyridin-2-yl)carbonyl]-3-[(1-propylbu-
tyl)sulfonyl]-D,L-alaninamide; [0689]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-hydroxybenzoyl)-3-[(1-propylbutyl)su-
lfonyl]-D,L-alaninamide [0690]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-methylbenzoyl)-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide; [0691]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-ethylbenzoyl)-3-[(1-propylbutyl)sulf-
onyl]-D,L-alaninamide; [0692]
N.about.2.about.-(3-chlorobenzoyl)-N.about.1.about.-{(1S,2R)-1-(3,5-diflu-
orobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide; [0693]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(4-methylbenzoyl)-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide; [0694]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(4-methoxybenzoyl)-3-[(1-propylbutyl)su-
lfonyl]-D,L-alaninamide; [0695]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(4-trifluoromethylbenzoyl)-3-[(1-propyl-
butyl)sulfonyl]-D,L-alaninamide; [0696]
N.about.2.about.-(cyclohexylcarbonyl)-N.about.1.about.{(1S,2R)-1-(3,5-dif-
luorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)s-
ulfonyl]-D,L-alaninamide; [0697]
N.about.2.about.-(benzoyl)-N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzy-
l)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D-
,L-alaninamide; [0698] N
.about.2.about.-(benzoyl)-N.about.1.about.-[(1S,2R)-3-(cyclopropylamino)-1-
-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-[(1-propylbutyl)sulfonyl]alaninam-
ide; [0699]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(phenylacetyl)-3-[(1-propylbutyl)sulfon-
yl]-D,L-alaninamide; [0700]
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-(3-phenylpropanoyl)-3-[(1-propylbutyl)s-
ulfonyl]-D,L-alaninamide; [0701]
N-(3-({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxyp-
ropyl}amino)-3-oxo-2-{[(1-propylbutyl)sulfonyl]methyl}propyl)benzamide;
[0702]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)-
amino]propyl}-N.about.2.about.-(cyclopropylacetyl)-3-[(1-propylbutyl)sulfo-
nyl]-D,L-alaninamide; [0703]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-N.about.2.about.-[(methylsulfonyl)acetyl]-3-[(1-propylbutyl)sulfonyl-
]-D,L-alaninamide; [0704]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-N.about.2.about.-[(methylthio)acetyl]-3-[(1-propylbutyl)sulfonyl]-D,-
L-alaninamide [0705]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-N.about.2.about.-(4-hydroxy-4-oxobutanoyl)-3-[(1-propylbutyl)sulfony-
l]-D,L-alaninamide; [0706]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-N.about.2.about.-[4-(methylamino)-4-oxobutanoyl]-3-[(1-propylbutyl)s-
ulfonyl]-D,L-alaninamide; [0707]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-N.about.2.about.-(4-methoxy-4-oxobutanoyl)-3-[(1-propylbutyl)sulfony-
l]-D,L-alaninamide; [0708]
N-(methylsulfonyl)glycyl-N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[-
(3-methoxybenzyl)amino]propyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide-
; [0709]
N.about.2.about.-acetyl-N.about.1.about.-{(1S,2R)-1-benzyl-2-hy-
droxy-3-[(3-methoxybenzyl)amino]propyl}-3-(phenylsulfonyl)-D,L-alaninamide-
; [0710]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-
-(2S)-2-[(4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide-
; [0711]
(2R)-2-[[(benzyloxy)carbonyl]amino]-N-{(1S,2R)-1-benzyl-2-hydro-
xy-3-[(3-methoxybenzyl)amino]propyl}-5-oxo-5-piperidin-1-ylpentanamide;
[0712]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(-
2R)-2-[(3-ethoxy-3-oxopropanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide;
[0713]
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3-methoxybenzyl)amino]-2-h-
ydroxypropyl}-N.about.2.about.-(4-methoxy-4-oxobutanoyl)-N.about.5.about.,-
N.about.5.about.-dipropyl-D-glutamamide; [0714]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(2R)-2-[(-
4-methoxy-4-oxobutanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide;
and [0715]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-(-
2R)-2-[(5-methoxy-5-oxopentanoyl)amino]-5-oxo-5-piperidin-1-ylpentanamide
and pharmaceutically acceptable salts thereof.
[0716] Other preferred compounds of formula X-XII include those of
formula X-XXI, i.e., compounds of formula X-XII wherein [0717]
R.sub.N is of the formula: ##STR28## wherein [0718] n.sub.7 is 0,
1, or 2; [0719] R.sub.4 is --NHR.sub.8 or
--NH(CH.sub.2).sub.n6--R.sub.4-1; wherein [0720] N.sub.6 is 0, 1,
2, or 3; [0721] R.sub.4-1 is selected from the group consisting of
--SO.sub.2--(C.sub.1-C.sub.8 alkyl), --SO--(C.sub.1-C.sub.8 alkyl),
--S--(C.sub.1-C.sub.8 alkyl), --S--CO--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; [0722] R.sub.4-2 and R.sub.4-3 are
independently H, C.sub.1-C.sub.3 alkyl, or C.sub.3-C.sub.6
cycloalkyl; [0723] R.sub.4-4 is C.sub.1-C.sub.4 alkyl, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl; [0724] R.sub.8 is selected from the group
consisting of --SO.sub.2-heteroaryl optionally substituted with 1
or 2 groups that are independently C.sub.1-C.sub.4 alkyl or
halogen; --SO.sub.2-phenyl; --SO.sub.2-heterocycloalkyl;
--C(O)NHR.sub.9; heterocycloalkyl; --S--C.sub.2-C.sub.4 alkanoyl;
wherein [0725] R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 alkyl, or H; [0726] X is C.sub.1-C.sub.4
alkylidenyl optionally substituted with 1, 2, or 3 methyl groups;
or --NR.sub.4-6--; or [0727] R.sub.4 and R.sub.4-6 combine to form
--(CH.sub.2).sub.n10--, wherein [0728] n.sub.10 is 1, 2, 3, or 4;
[0729] Z is SO.sub.2; SO; S; or C(O); [0730] Y is H;
C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8 cycloalkyl optionally
substituted with 1, 2, or 3 groups independently selected from
C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; or phenyl C.sub.1-C.sub.4 alkyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; wherein [0731] Y.sub.1 and Y.sub.2 are the
same or different and are H; C.sub.1-C.sub.10 alkyl optionally
substituted with 1, 2, or 3 substituents selected from halogen,
C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8 cycloalkyl, and OH;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkanoyl; phenyl;
--SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl C.sub.1-C.sub.4 alkyl; or
C.sub.3-C.sub.8 cycloalkyl C.sub.1-C.sub.4 alkyl; or [0732]
--N(Y.sub.1)(Y.sub.2) forms a ring selected from piperazinyl,
piperidinyl, morpholinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1, 2, 3, or 4 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, or halogen; and
[0733] R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, halo C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkanoyl,
each of which is unsubstituted or substituted with 1, or 2 groups
independently selected from halogen, C.sub.1-C.sub.6 alkyl,
hydroxy, C.sub.1-C.sub.6 alkoxy, NH.sub.2, and --R.sub.26-R.sub.27,
wherein [0734] R.sub.26 is --C(O)--, --SO.sub.2--, --CO.sub.2--,
--C(O)NH--, or --C(O)N(C.sub.1-C.sub.6 alkyl)-; [0735] R.sub.27 is
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, aryl C.sub.1-C.sub.6
alkyl, heterocycloalkyl, or heteroaryl, wherein each of the above
is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, halo C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.6 alkyl,
--C(O)NH.sub.2, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
--C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
[0736] Preferred compounds of formula X-XXI include those wherein
[0737] R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.6
alkyl optionally substituted with 1, or 2 substituents selected
from halogen, OH, SH, C.ident.N, CF.sub.3, and C.sub.1-C.sub.3
alkoxy; and [0738] R.sub.C is C.sub.1-C.sub.8 alkyl optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S(.dbd.O).sub.0-2(C.sub.1-C.sub.6 alkyl), --SH,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl; or
--(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-heteroaryl; wherein each aryl is
optionally substituted with 1, 2, or 3 R.sub.200; [0739] each
heteroaryl is optionally substituted with 1, 2, 3, or 4 R.sub.200;
[0740] each heterocycloalkyl is optionally substituted with 1, 2,
3, or 4 R.sub.210; [0741] R.sub.200 at each occurrence is
independently C.sub.1-C.sub.6 alkyl optionally substituted with 1,
2, or 3 R.sub.205 groups; OH; --NO.sub.2; halogen; --CO.sub.2H;
C.ident.N; --(CH.sub.2) O.sub.4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0742] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0743] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1, 2, or 3 R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); or .dbd.O; wherein [0744]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.7 cycloalkyl,
and --(CH.sub.2).sub.0-2-(heteroaryl), or
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the phenyl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0745] R.sub.220 and R.sub.225 at each occurrence are independently
--H, --C.sub.1-C.sub.6 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.7 cycloalkyl, or
--(C.sub.1-C.sub.6 alkyl)-O-- (C.sub.1-C.sub.3 alkyl); [0746]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0747] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, or [0748] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, or 6 carbon atoms.
[0749] More preferred compounds of formula X-XXI include those
wherein [0750] R.sub.1 is benzyl which is optionally substituted
with 1, 2, 3, or 4 groups independently selected from
C.sub.1-C.sub.4 alkyl optionally substituted with 1, or 2
substituents selected from halogen, --OH, --SH, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl), --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy; halogen; C.sub.1-C.sub.4 alkoxy; and
OH.
[0751] Other more preferred compounds of formula X-XXI include
those wherein [0752] n7 is 0, 1, or 2; [0753] R.sub.4 is
--NHR.sub.8 or --NH(CH.sub.2).sub.n6--R.sub.4-1; wherein [0754]
N.sub.6 is 0, 1, or 2; [0755] R.sub.4-1 is selected from the group
consisting of --SO.sub.2--(C.sub.1-C.sub.8 alkyl), --S--CO--
(C.sub.1-C.sub.6 alkyl), --SO.sub.2--NR.sub.4-2R.sub.4-3;
--CO--C.sub.1-C.sub.2 alkyl; --CO--NR.sub.4-3R.sub.4-4; [0756]
R.sub.4-2 and R.sub.4-3 are independently H, or C.sub.1-C.sub.3
alkyl; [0757] R.sub.4-4 is C.sub.1-C.sub.4 alkyl, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl; [0758] R.sub.8 is --SO.sub.2-thienyl
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl or halogen; --SO.sub.2-phenyl,
--SO.sub.2-piperidinyl, --SO.sub.2-pyrrolidinyl, --C(O)NHR.sub.9,
morpholinyl, or --S--C.sub.2-C.sub.4 alkanoyl, wherein [0759]
R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkyl, or
H.
[0760] Even more preferred compounds of formula X-XXI include those
wherein [0761] R.sub.20 at each occurrence is independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.2 alkoxy
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkanoyl, each of which is
unsubstituted or substituted with 1 or 2 groups independently
selected from halogen, hydroxy, C.sub.1-C.sub.4 alkoxy,
tertiary-butoxy carbonyl, benzyloxycarbonyl, and NH.sub.2; [0762]
R.sub.C is C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2,
or 3 groups independently selected from the group consisting of
R.sub.205, --SH, --C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl optionally substituted with
1, 2, or 3 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyridazinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrimidinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazinyl;
--(CR.sub.245R.sub.250).sub.0-3-furyl;
--(CR.sub.245R.sub.250).sub.0-3-indolyl;
--(CR.sub.245R.sub.250).sub.0-3-thienyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1, 2, 3, or 4
R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-piperazinyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl;
(CR.sub.245R.sub.250).sub.0-3-indolinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1, 2, 3, or
4 R.sub.210; (CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--
(CH.sub.2).sub.0-1-phenyl; or
--(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0763] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO-- (C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; or
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0764] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), or N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0765] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1 or 2 R.sub.205 groups; halogen; C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.4 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1 or 2
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); or .dbd.O; wherein [0766]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.6 cycloalkyl,
--(CH.sub.2).sub.0-2-(pyridyl), --(CH.sub.2).sub.0-2-(pyrrolyl),
--(CH.sub.2).sub.0-2-(imidazolyl),
--(CH.sub.2).sub.0-2-(pyrimidyl),
--(CH.sub.2).sub.0-2-(pyrrolidinyl),
--(CH.sub.2).sub.0-2-(imidazolidinyl)-(CH.sub.2).sub.0-2-(piperazinyl),
--(CH.sub.2).sub.0-2-(piperidinyl), or
--(CH.sub.2).sub.0-2-(morpholinyl); wherein the phenyl group at
each occurrence is optionally substituted with 1 or 2 groups that
are independently R.sub.205 or R.sub.210; wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1 or 2 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1 or 2 R.sub.210; [0767]
R.sub.220 and R.sub.225 at each occurrence are independently --H,
--C.sub.1-C.sub.4 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.6 cycloalkyl, or
--(C.sub.1-C.sub.4 alkyl)-O-- (C.sub.1-C.sub.2 alkyl); [0768]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0769] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, or
C.sub.1-C.sub.4 haloalkoxy, or [0770] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms.
[0771] Still other more preferred compounds of formula X-XXI
include those wherein [0772] X is --C.sub.1-C.sub.3 alkylidenyl
optionally substituted with 1 or 2 methyl groups; [0773] Z is
SO.sub.2; SO; S; or C(O); [0774] Y is H; C.sub.1-C.sub.4 haloalkyl;
pyrrolidinyl; piperidinyl; imidazolidinyl; piperazinyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 thioalkoxy, and C.sub.1-C.sub.4 haloalkoxy;
C.sub.3-C.sub.6 cycloalkyl optionally substituted with 1, 2, or 3
groups independently selected from C.sub.1-C.sub.3 alkyl and
halogen; C.sub.1-C.sub.4 alkoxy; phenyl, benzyl or phenethyl each
of which is optionally substituted with halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0775]
Y.sub.1 and Y.sub.2 are independently H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; phenyl C.sub.1-C.sub.4 alkyl; or C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0776] --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4
alkyl, or halogen; and [0777] R.sub.2 and R.sub.3 are independently
H or C.sub.1-C.sub.4 alkyl.
[0778] Other more preferred compounds of formula X-XXI include
those wherein [0779] n.sub.7 is 0, 1, or 2; [0780] R.sub.4 is
--NHR.sub.8 or --NH(CH.sub.2).sub.n6--R.sub.4-1; wherein [0781]
N.sub.6 is 0, 1, or 2; [0782] R.sub.4-1 is selected from the group
consisting of --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; [0783] R.sub.4-2 and R.sub.4-3 are
independently H, or C.sub.1-C.sub.3 alkyl; [0784] R.sub.4-4 is
C.sub.1-C.sub.4 alkyl, phenyl C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkanoyl, or phenyl C.sub.1-C.sub.4 alkanoyl;
[0785] R.sub.8 is --SO.sub.2-thienyl optionally substituted with 1
or 2 groups that are independently C.sub.1-C.sub.4 alkyl or
halogen; --SO.sub.2-phenyl, --SO.sub.2-piperidinyl,
--SO.sub.2-pyrrolidinyl, --C(O)NHR.sub.9, or --S--C.sub.2-C.sub.4
alkanoyl, wherein [0786] R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl, or H; [0787] R.sub.20 at each occurrence is
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkanoyl, tertiary-butoxy carbonyl, and benzyloxycarbonyl; [0788]
R.sub.C is C.sub.1-C.sub.8 alkyl optionally substituted with 1 or 2
groups independently selected from R.sub.205, and --SH;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1 R.sub.205 group;
--(CR.sub.245R.sub.250).sub.0-3-phenyl optionally substituted with
1 or 2 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazolyl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1 or 2 R.sub.200;
--(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1 or 2
R.sub.210;
(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--(CH.sub.2).sub.0-1-phenyl-
; or --(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0789] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.4 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; NO.sub.2;
halogen; CO.sub.2H; C.ident.N; or --(CH.sub.2).sub.0-4--O--
(C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, 3, or
5-F); [0790] R.sub.205 at each occurrence is independently
C.sub.1-C.sub.6 alkyl, halogen, OH, --O-phenyl, SH, C.ident.N,
CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl), or N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); [0791]
R.sub.210 at each occurrence is independently C.sub.1-C.sub.6 alkyl
optionally substituted with 1 R.sub.205 group; halogen;
C.sub.1-C.sub.4 alkoxy; C.sub.1-C.sub.4 haloalkoxy; OH; C.ident.N;
or .dbd.O; wherein [0792] R.sub.235 and R.sub.240 at each
occurrence are independently H, or C.sub.1-C.sub.6 alkyl; [0793]
R.sub.245 and R.sub.250 at each occurrence are independently H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.1-C.sub.4 alkoxy, or [0794] R.sub.245 and R.sub.250 are taken
together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms; [0795] X is
--C.sub.1-C.sub.3 alkylidenyl; [0796] Z is SO.sub.2; SO; S; or
C(O); [0797] Y is H; C.sub.1-C.sub.4 haloalkyl; pyrrolidinyl;
piperidinyl; imidazolidinyl; piperazinyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 thioalkoxy, and C.sub.1-C.sub.4 haloalkoxy;
C.sub.3-C.sub.6 cycloalkyl optionally substituted with 1, 2, or 3
groups independently selected from C.sub.1-C.sub.3 alkyl and
halogen; C.sub.1-C.sub.4 alkoxy; phenyl, benzyl or phenethyl each
of which is optionally substituted with halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, CN or NO.sub.2; wherein [0798]
Y.sub.1 and Y.sub.2 are independently H; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 substituents selected from
halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.6 cycloalkyl, and
OH; C.sub.2-C.sub.6 alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4
alkyl; phenyl C.sub.1-C.sub.4 alkyl; or cyclopropyl C.sub.1-C.sub.4
alkyl; or [0799] --N(Y.sub.1)(Y.sub.2) forms a ring selected from
piperazinyl, piperidinyl, and pyrrolidinyl, wherein each ring is
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or halogen; [0800]
R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.4 alkyl;
and [0801] R.sub.1 is benzyl which is optionally substituted with
1, 2, or 3 groups independently selected from C.sub.1-C.sub.4 alkyl
optionally substituted with 1 substituent selected from halogen,
--OH, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy; halogen;
C.sub.1-C.sub.4 alkoxy; and OH.
[0802] Particularly preferred compounds of formula X-XXI include
those of formula X-XXII: ##STR29## wherein [0803] A.sub.1 is H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.6
alkynyl, or halogen; [0804] A.sub.2 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4
haloalkyl or OH; [0805] A.sub.3 and A.sub.4 are independently
C.sub.1-C.sub.4 alkyl, halogen, or H; [0806] R.sub.8 is
--SO.sub.2-thienyl optionally substituted with 1 or 2 groups that
are independently C.sub.1-C.sub.4 alkyl or halogen;
--SO.sub.2-phenyl, --SO.sub.2-piperidinyl, --SO.sub.2-pyrrolidinyl,
--C(O)NHR.sub.9, or --S--C.sub.2-C.sub.4 alkanoyl, wherein [0807]
R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl, or
H.
[0808] Preferred compounds of formulas X-XXI and X-XXII include
those wherein [0809] R.sub.20 at each occurrence is independently H
or C.sub.1-C.sub.4 alkyl; [0810] X is C.sub.1 or C.sub.2
alkylidenyl; [0811] Z is SO.sub.2; SO; S; or C(O); and [0812] Y is
phenyl; C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or
3 halogen; or OH; or [0813] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0814] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0815] Preferred compounds of formula X-XXII include those of
formula X-XXIII: ##STR30##
[0816] Preferred compounds of formulas X-XXII and X-XXIII include
those wherein [0817] A.sub.1 is C.sub.1-C.sub.4 alkyl, C.sub.2
alkynyl, or I; [0818] A.sub.2 is H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, OCF.sub.3, CF.sub.3 or OH; [0819] A.sub.3
and A.sub.4 are independently H or halogen; and [0820] R.sub.8 is
--SO.sub.2-thienyl optionally substituted with 1 or 2 groups that
are independently C.sub.1-C.sub.4 alkyl or halogen;
--SO.sub.2-phenyl; or --C(O)NHR.sub.9; wherein [0821] R.sub.9 is
phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl, or H.
[0822] Other preferred compounds of formulas X-XXII and X-XXIII
include those wherein [0823] R.sub.245 and R.sub.250 are both
hydrogen or R.sub.245 and R.sub.250 form a cyclopropyl group.
[0824] Other preferred compounds of formulas X-XXII and X-XXIII
include those wherein [0825] R.sub.20 and A.sub.2 are both
hydrogen; and [0826] A.sub.3 and A.sub.4 are independently
halogen.
[0827] Still other preferred compounds of formulas X-XXII and
X-XXIII include those wherein [0828] A.sub.3 and A.sub.4 are meta
to each other.
[0829] Other preferred compounds of formula X-XXI include those of
formula X-XXIV: ##STR31## wherein [0830] R.sub.C is C.sub.3-C.sub.8
alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or (C.sub.1-C.sub.4)
alkyl-(C.sub.3-C.sub.6) cycloalkyl.
[0831] Preferred compounds of formula X-XXIV include those wherein
[0832] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0833] X is C.sub.1 or C.sub.2 alkylidenyl;
[0834] Z is SO.sub.2; SO; S; or C(O); and [0835] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0836] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0837] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0838] More preferred compounds of formula X-XXIV include those of
formula X-XXV: ##STR32##
[0839] Preferred compounds of formulas X-XXIV and X-XXV include
those wherein [0840] R.sub.8 is --SO.sub.2-thienyl optionally
substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl or halogen; --SO.sub.2-phenyl; or
--C(O)NHR.sub.9; wherein [0841] R.sub.9 is phenyl C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl, or H.
[0842] Other preferred compounds of formulas X-XXIV and X-XXV
include those wherein [0843] R.sub.20 and A.sub.2 are both
hydrogen; and [0844] A.sub.3 and A.sub.4 are independently
halogen.
[0845] More preferred compounds of formulas X-XXIV and X-XXV
include those wherein [0846] A.sub.3 and A.sub.4 are meta to each
other. Even more preferably, A.sub.3 and [0847] A.sub.4 are at the
3 and 5 positions of the benzene ring.
[0848] Other preferred compounds of formula X-XXI include those of
formula X-XXVI: ##STR33## wherein [0849] N.sub.6 is 0, 1, or 2;
[0850] R.sub.4-1 is selected from the group consisting of
--SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--CO--NR.sub.4-3R.sub.4-4; [0851] R.sub.4-2 and R.sub.4-3 are
independently H, or C.sub.1-C.sub.3 alkyl; [0852] R.sub.4-4 is
C.sub.1-C.sub.4 alkyl, phenyl C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkanoyl, or phenyl C.sub.1-C.sub.4 alkanoyl;
[0853] A.sub.1 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen or C.sub.2-C.sub.6 alkynyl; [0854] A.sub.2 is H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy, C.sub.1-C.sub.4 haloalkyl or OH; [0855] A.sub.3 and
A.sub.4 are independently C.sub.1-C.sub.4 alkyl, halogen, or H.
[0856] Preferred compounds of formula X-XXVI include those wherein
[0857] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0858] X is C.sub.1 or C.sub.2 alkylidenyl;
[0859] Z is SO.sub.2; SO; S; or C(O); and [0860] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0861] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0862] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0863] More preferred compounds of formula X-XXVI include those of
formula X-XXVII: ##STR34## wherein [0864] A.sub.1 is
C.sub.1-C.sub.4 alkyl, C2 alkynyl or I; [0865] A.sub.2 is H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, CF.sub.3
or OH; [0866] A.sub.3 and A.sub.4 are independently H or halogen;
and [0867] N.sub.6 is 0, 1, or 2; [0868] R.sub.4-1 is selected from
the group consisting of --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--C.sub.1-C.sub.2 alkyl;
--C0-NR.sub.4-3R.sub.4-4; [0869] R.sub.4-2 and R.sub.4-3 are
independently H, or C.sub.1-C.sub.3 alkyl; [0870] R.sub.4-4 is
C.sub.1-C.sub.4 alkyl, phenyl C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkanoyl, or phenyl C.sub.1-C.sub.4 alkanoyl.
[0871] Preferred compounds of formulas X-XXVI and X-XXVII include
those wherein [0872] R.sub.245 and R.sub.250 are both hydrogen or
R.sub.245 and R.sub.250 form a cyclopropyl group.
[0873] More preferred compounds of formulas X-XXVI and X-XXVII
include those wherein [0874] R.sub.20 and A.sub.2 are both
hydrogen; and [0875] A.sub.3 and A.sub.4 are independently
halogen.
[0876] More preferred compounds of formulas X-XXVI and X-XXVII
include those wherein [0877] A.sub.3 and Aa are meta to each other.
More preferably, A.sub.3 and A.sub.4 are at the 3 and 5 positions
of the phenyl ring.
[0878] Other preferred compounds of formula X-XXI include those of
formula X-XXVIII: ##STR35## wherein [0879] R.sub.C is
C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or
--(C.sub.1-C.sub.4) alkyl-(C.sub.3-C.sub.6) cycloalkyl.
[0880] Preferred compounds of formula X-XXVIII include those
wherein [0881] R.sub.20 at each occurrence is independently H or
C.sub.1-C.sub.4 alkyl; [0882] X is C.sub.1 or C.sub.2 alkylidenyl;
[0883] Z is SO.sub.2; SO; S; or C(O); and [0884] Y is phenyl;
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
halogen; or OH; or [0885] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0886] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0887] More preferred compounds of formula X-XXVIII include those
of formula X-XXIX: ##STR36##
[0888] Preferred compounds of formulas X-XXVIII and X-XXIX include
those wherein [0889] N6 is 0, 1, or 2; [0890] R.sub.4-1 is selected
from the group consisting of --SO.sub.2--(C1-CB alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; --CO--NR.sub.4-3R.sub.4-4; [0891]
R.sub.4-2 and R.sub.4-3 are independently H, or C.sub.1-C.sub.3
alkyl; [0892] R.sub.4-4 is C.sub.1-C.sub.4 alkyl, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl;
[0893] Other preferred compounds of formulas X-XXVIII and X-XXIX
include those wherein [0894] R.sub.20 and A.sub.2 are both
hydrogen; and [0895] A.sub.3 and A.sub.4 are independently
halogen.
[0896] More preferred compounds of formulas X-XXVIII and (X-XXVIX)
include those wherein [0897] A.sub.3 and A.sub.4 are meta to each
other. More preferably, A.sub.3 and A.sub.4 are at the 3 and 5
positions of the benzene ring.
[0898] Other preferred compounds of formula X include those of
formula X-XXX, i.e., compounds of formula X wherein [0899] R.sub.4
is H; C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5;
--(CH.sub.2).sub.0-4R.sub.8; --O--C.sub.1-C.sub.4 alkanoyl; OH;
C.sub.6-C.sub.10 aryloxy optionally substituted with 1, 2, or 3
groups that are independently halogen, C.sub.1-C.sub.4 alkyl,
CO.sub.2H, --C(O)--C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
alkoxy; C.sub.1-C.sub.6 alkoxy; aryl C.sub.1-C.sub.4 alkoxy;
--C.sub.1-C.sub.4 alkyl-NR.sub.50CO.sub.2R.sub.51; --C.ident.N;
--CF.sub.3; --CF.sub.2--CF.sub.3; --C.ident.CH;
--CH.sub.2--CH.dbd.CH.sub.2; --(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1;
--O--(CH.sub.2).sub.n6--R.sub.4-1;
--S--(CH.sub.2).sub.n6--R.sub.4-1;
(CH.sub.2).sub.0-4--NHC(O)--(CH.sub.2).sub.0-6--R.sub.52; or
--(CH.sub.2).sub.0-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54.
[0900] Preferred compounds of formula X-XXX include those wherein
[0901] R.sub.1 is (CH.sub.2).sub.n1--(R.sub.1-aryl) where n.sub.1
is zero or one and R.sub.1-aryl is phenyl optionally substituted
with 1, 2, 3, or 4 groups independently selected from
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy; halogen; C.sub.1-C.sub.6
alkoxy; --NR.sub.N-2R.sub.N-3; and OH; wherein [0902] R.sub.N-2 and
R.sub.N-3 at each occurrence are independently selected from the
group consisting of --C.sub.1-C.sub.8 alkyl optionally substituted
with 1, 2, or 3 groups independently selected from the group
consisting of --OH, --NH.sub.2, phenyl and halogen;
--C.sub.3-C.sub.8 cycloalkyl; --(C.sub.1-C.sub.2
alkyl)-(C.sub.3-C.sub.8 cycloalkyl); --(C.sub.1-C.sub.6 alkyl)-O--
(C.sub.1-C.sub.3 alkyl); --C.sub.2-C.sub.6 alkenyl;
--C.sub.2-C.sub.6 alkynyl; --C.sub.1-C.sub.6 alkyl chain with one
double bond and one triple bond; aryl; heteroaryl;
heterocycloalkyl; [0903] or [0904] R.sub.N-2, R.sub.N-3 and the
nitrogen to which they are attached form a 5, 6, or 7 membered
heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl
or heteroaryl group is optionally fused to a benzene, pyridine, or
pyrimidine ring, and said groups are unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that at each occurrence are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, halo C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkoxy,
--CN, --NO.sub.2, --NH.sub.2, NH(C.sub.1-C.sub.6 alkyl),
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl), --OH,
--C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.6 alkyl),
--C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
thioalkoxy, and C.sub.1-C.sub.6 thioalkoxy C.sub.1-C.sub.6
alkyl.
[0905] More preferred compounds of formula X-XXX include those
wherein [0906] R.sub.2 and R.sub.3 are independently selected from
H or C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b; and [0907]
R.sub.C is selected from the group consisting of C.sub.1-C.sub.10
alkyl optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of R.sub.205,
--OC.dbd.ONR.sub.235R.sub.240, --S(.dbd.O).sub.0-2 (C.sub.1-C.sub.6
alkyl), --SH, --NR.sub.235C.dbd.ONR.sub.235R.sub.240,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-aryl;
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl;
--(CR.sub.245R.sub.250).sub.0-4-heterocycloalkyl;
--[C(R.sub.255)(R.sub.260)].sub.1-3--CO--N--(R.sub.255).sub.2;
--CH(aryl).sub.2; --CH(heteroaryl).sub.2;
--CH(heterocycloalkyl).sub.2; --CH(aryl)(heteroaryl);
--CO--NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-6--OH)--
(CH.sub.2).sub.0-1-aryl;
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1-heteroaryl;
--CH(-aryl or -heteroaryl)-CO--O(C.sub.1-C.sub.4 alkyl);
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2; (C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH;
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2; --H;
and
--(CH.sub.2).sub.0-6--C--(.dbd.NR.sub.235)(NR.sub.235R.sub.240);
wherein [0908] each aryl is optionally substituted with 1, 2, or 3
R.sub.200; [0909] each heteroaryl is optionally substituted with 1,
2, 3, or 4 R.sub.200; [0910] each heterocycloalkyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210; [0911] R.sub.200 at each
occurrence is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; OH; --NO.sub.2; halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225;
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; and
--(CH.sub.2).sub.0-4--O-- (C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0912] wherein each aryl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205, R.sub.210 or C.sub.1-C.sub.6
alkyl substituted with 1, 2, or 3 groups that are independently
R.sub.205 or R.sub.210; [0913] wherein each heterocycloalkyl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.210; [0914] wherein each heteroaryl
group at each occurrence is optionally substituted with 1, 2, or 3
groups that are independently R.sub.205, R.sub.210, or
C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups that are
independently R.sub.205 or R.sub.210; [0915] R.sub.205 at each
occurrence is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, halogen, --OH, --O-phenyl, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0916] R.sub.210 at each occurrence
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups; halogen; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N; C.sub.3-C.sub.7
cycloalkyl optionally substituted with 1, 2, or 3 R.sub.205 groups;
--CO--(C.sub.1-C.sub.4 alkyl); SO.sub.2--NR.sub.235R.sub.240;
--CO--NR.sub.235R.sub.240; --SO.sub.2--(C.sub.1-C.sub.4 alkyl); and
.dbd.O; wherein [0917] R.sub.215 at each occurrence is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(aryl), C.sub.3-C.sub.7 cycloalkyl, and
--(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocycloalkyl); wherein the aryl group at
each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210; wherein the
heterocycloalkyl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.210;
[0918] R.sub.220 and R.sub.225 at each occurrence are independently
selected from the group consisting of --H, --C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, amino C.sub.1-C.sub.6 alkyl; halo
C.sub.1-C.sub.6 alkyl; --C.sub.3-C.sub.7 cycloalkyl,
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), -aryl,
-heteroaryl, and -heterocycloalkyl; wherein the aryl group at each
occurrence is optionally substituted with 1, 2, or 3 R.sub.270
groups, each heteroaryl is optionally substituted with 1, 2, 3, or
4 R.sub.200, each heterocycloalkyl is optionally substituted with
1, 2, 3, or 4 R.sub.210 wherein [0919] R.sub.270 at each occurrence
is independently R.sub.205, C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; halogen;
C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6 haloalkoxy;
NR.sub.235R.sub.240; OH; C.ident.N; --CO-- (C.sub.1-C.sub.4 alkyl);
and .dbd.O; wherein the heterocycloalkyl group at each occurrence
is optionally substituted with 1, 2, or 3 R.sub.205 groups; wherein
each heteroaryl group at each occurrence is optionally substituted
with 1, 2, or 3 R.sub.205 groups; [0920] R.sub.235 and R.sub.240 at
each occurrence are independently H, or C.sub.1-C.sub.6 alkyl;
[0921] R.sub.245 and R.sub.250 at each occurrence are independently
selected from the group consisting of H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, or [0922] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 4, 5, 6, or 7 carbon atoms, [0923] R.sub.255 and
R.sub.260 at each occurrence are independently selected from the
group consisting of H; C.sub.1-C.sub.6 alkyl optionally substituted
with 1, 2, or 3 R.sub.205 groups;
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; --(C.sub.1-C.sub.4
alkyl)-aryl; --(C.sub.1-C.sub.4 alkyl)-heteroaryl;
--(C.sub.1-C.sub.4 alkyl)-heterocycloalkyl; -aryl; -heteroaryl;
-heterocycloalkyl;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heteroaryl;
and;
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heterocycloalkyl;
wherein [0924] R.sub.265 at each occurrence is independently --O--,
--S-- or --N(C.sub.1-C.sub.6 alkyl)-; [0925] each aryl or phenyl is
optionally substituted with 1, 2, or 3 groups that are
independently R.sub.205, R.sub.210, or C.sub.1-C.sub.6 alkyl
substituted with 1, 2, or 3 groups that are independently R.sub.205
or R.sub.210.
[0926] Even more preferred compounds of formula X-XXX include those
wherein [0927] R.sub.20 at each occurrence is independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy C.sub.1-C.sub.4 alkyl, halo C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.4 alkanoyl, each of which is unsubstituted or
substituted with 1, or 2 groups independently selected from
halogen, C.sub.1-C.sub.6 alkyl, hydroxy, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, and --R.sub.26-R.sub.27, wherein [0928] R.sub.26 is
selected from --C(O)--, --SO.sub.2--, --CO.sub.2--; [0929] R.sub.27
is selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
aryl C.sub.1-C.sub.6 alkyl, piperidyl, pyrrolyl, and pyridyl,
wherein each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl,
hydroxy C.sub.1-C.sub.6 alkyl, --C(O)NH.sub.2, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl), --C(O)NH(C.sub.1-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl).
[0930] Preferred compounds of formula X-XXX include those of
formula X-XXXI, i.e., compounds of formula X-XXX wherein [0931]
R.sub.4 is H; C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5;
--(CH.sub.2).sub.0-4R.sub.8; --C.sub.1-C.sub.4
alkyl-NR.sub.50CO.sub.2R.sub.51; --C.ident.N; --CF.sub.3;
--CF.sub.2--CF.sub.3; --C.ident.CH; --CH.sub.2--CH.dbd.CH.sub.2;
--(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1; (CH.sub.2).sub.0-4--NHC(O)--
(CH.sub.2).sub.0-6--R.sub.52; or
--(CH.sub.2).sub.0-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54.
[0932] Preferred compounds of formula X-XXXI include those wherein
[0933] X is C.sub.1-C.sub.4 alkylidenyl optionally substituted with
1, 2, or 3 methyl groups; or --NR.sub.4-6--; or [0934] R.sub.4 and
R.sub.4-6 combine to form --(CH.sub.2).sub.n10--, wherein [0935]
n.sub.10 is 1, 2, 3, or 4; [0936] Z is selected from a bond;
SO.sub.2; SO; S; and C(O); [0937] Y is selected from H;
C.sub.1-C.sub.4 haloalkyl; C.sub.5-C.sub.6 heterocycloalkyl
containing at least one N, O, or S; phenyl; OH;
--N(Y.sub.1)(Y.sub.2); C.sub.1-C.sub.10 alkyl optionally
substituted with 1 thru 3 substituents which can be the same or
different and are selected from halogen, hydroxy, alkoxy,
thioalkoxy, and haloalkoxy; C.sub.3-C.sub.8 cycloalkyl optionally
substituted with 1, 2, or 3 groups independently selected from
C.sub.1-C.sub.3 alkyl, and halogen; alkoxy; phenyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; phenyl C.sub.1-C.sub.4 alkyl optionally
substituted with halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN or NO.sub.2; wherein [0938] Y.sub.1 and Y.sub.2 are the
same or different and are H; C.sub.1-C.sub.10 alkyl optionally
substituted with 1, 2, or 3 substituents selected from the group
consisting of halogen, C.sub.1-C.sub.4 alkoxy, C.sub.3-C.sub.8
cycloalkyl, and OH; C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6
alkanoyl; phenyl; --SO.sub.2--C.sub.1-C.sub.4 alkyl; phenyl
C.sub.1-C.sub.4 alkyl; and C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.4 alkyl; or [0939] --N(Y.sub.1)(Y.sub.2) forms a ring
selected from piperazinyl, piperidinyl, morpholinyl, and
pyrrolidinyl, wherein each ring is optionally substituted with 1,
2, 3, or 4 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, or halogen.
[0940] More preferred compounds of formula X-XXXI include those
wherein [0941] R.sub.20 at each occurrence is independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl,
tertiary-butoxy carbonyl, and benzyloxycarbonyl; [0942] R.sub.1 is
benzyl which is optionally substituted with 1, 2, 3, or 4 groups
independently selected from halogen, C.sub.1-C.sub.4 alkoxy,
hydroxy, and C.sub.1-C.sub.4 alkyl optionally substituted with 1,
2, or 3 substituents halogen, OH, SH, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl), N--(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl),
C.ident.N, CF.sub.3; [0943] R.sub.2 and R.sub.3 are independently
selected from H or C.sub.1-C.sub.4 alkyl optionally substituted
with 1 substituent selected from halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6
alkyl), and NH(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl);
[0944] R.sub.20 at each occurrence is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.2 alkoxy C.sub.1-C.sub.4
alkyl, halo C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkanoyl, each
of which is unsubstituted or substituted with 1 or 2 groups
independently selected from halogen, hydroxy, and NH.sub.2; [0945]
R.sub.C is C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2,
or 3 groups independently selected from R.sub.205, --SH,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240;
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.6) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from R.sub.205, --CO.sub.2H, and
--CO.sub.2--(C.sub.1-C.sub.4 alkyl);
--(CR.sub.245R.sub.250).sub.0-4-phenyl optionally substituted with
1, 2, or 3 R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-pyridyl;
--(CR.sub.245R.sub.250).sub.0-3-pyridazinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrimidinyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazinyl;
--(CR.sub.245R.sub.250).sub.0-3-furyl;
--(CR.sub.245R.sub.250).sub.0-3-indolyl;
--(CR.sub.245R.sub.250).sub.0-3-thienyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrrolyl;
--(CR.sub.245R.sub.250).sub.0-3-pyrazolyl;
(CR.sub.245R.sub.250).sub.0-3-benzoxazol-yl;
--(CR.sub.245R.sub.250).sub.0-3-imidazolyl; each of the above
heteroaryl groups is optionally substituted with 1, 2, 3, or 4
R.sub.200; --(CR.sub.245R.sub.250).sub.0-3-imidazolidinyl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydrofuryl;
(CR.sub.245R.sub.250).sub.0-3-tetrahydropyranyl;
(CR.sub.245R.sub.250).sub.0-3-piperazinyl;
(CR.sub.245R.sub.250).sub.0-3-pyrrolidinyl;
(CR.sub.245R.sub.250).sub.0-3-piperidinyl;
(CR.sub.245R.sub.250).sub.0-3-indolinyl; each of the above
heterocycloalkyl groups is optionally substituted with 1, 2, 3, or
4 R.sub.210;
(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-4--OH)--(CH.sub.2).sub.0-1-phenyl-
; --(CH.sub.2).sub.0-1--CH(C.sub.1-C.sub.4
hydroxyalkyl)-(CH.sub.2).sub.0-1-pyridyl; [0946] R.sub.200 at each
occurrence is independently C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 R.sub.205 groups; OH; --NO.sub.2;
halogen; --CO.sub.2H; C.ident.N;
--(CH.sub.2).sub.0-4--CO--NR.sub.1220R.sub.225;
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.8 alkyl);
--(CH.sub.2).sub.0-4--CO.sub.2R.sub.215; and
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5-F); [0947] R.sub.205 at each
occurrence is independently C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), and N--(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); [0948] R.sub.210 at each occurrence
is independently C.sub.1-C.sub.6 alkyl optionally substituted with
1 or 2 R.sub.205 groups; halogen; C.sub.1-C.sub.4 alkoxy;
C.sub.1-C.sub.4 haloalkoxy; --NR.sub.220R.sub.225; OH; C.ident.N;
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1 or 2
R.sub.205 groups; --CO-- (C.sub.1-C.sub.4 alkyl);
SO.sub.2--NR.sub.235R.sub.240; --CO--NR.sub.235R.sub.240;
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and .dbd.O; wherein [0949]
R.sub.215 at each occurrence is independently C.sub.1-C.sub.6
alkyl, --(CH.sub.2).sub.0-2-(phenyl), C.sub.3-C.sub.6 cycloalkyl,
--(CH.sub.2).sub.0-2-(pyridyl), --(CH.sub.2).sub.0-2-(pyrrolyl),
--(CH.sub.2).sub.0-2-(imidazolyl),
--(CH.sub.2).sub.0-2-(pyrimidyl),
--(CH.sub.2).sub.0-2-(pyrrolidinyl),
--(CH.sub.2).sub.0-2-(imidazolidinyl)-(CH.sub.2).sub.0-2-(piperazinyl),
--(CH.sub.2).sub.0-2-(piperidinyl), and
--(CH.sub.2).sub.0-2-(morpholinyl); wherein the phenyl group at
each occurrence is optionally substituted with 1 or 2 groups that
are independently R.sub.205 or R.sub.210; wherein each
heterocycloalkyl group at each occurrence is optionally substituted
with 1 or 2 R.sub.210; wherein each heteroaryl group at each
occurrence is optionally substituted with 1 or 2 R.sub.210; [0950]
R.sub.220 and R.sub.225 at each occurrence are independently --H,
--C.sub.1-C.sub.4 alkyl, hydroxy C.sub.1-C.sub.4 alkyl, halo
C.sub.1-C.sub.4 alkyl; --C.sub.3-C.sub.6 cycloalkyl, and
--(C.sub.1-C.sub.4 alkyl)-O-- (C.sub.1-C.sub.2 alkyl); [0951]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0952] R.sub.245 and R.sub.250 at each
occurrence are independently H, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, or [0953] R.sub.245 and R.sub.250 are
taken together with the carbon to which they are attached to form a
carbocycle of 3, 5, or 6 carbon atoms.
[0954] Even more preferred compounds of formula X-XXXI include
those wherein [0955] R.sub.4 is H; C.sub.1-C.sub.4
alkyl-NHC(O)R.sub.5; --(CH.sub.2).sub.0-4R.sub.8; --C.sub.1-C.sub.4
alkyl-NR.sub.50CO.sub.2R.sub.51; --(CH.sub.2).sub.1-4--R.sub.4-1;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1;
(CH.sub.2).sub.1-4--NHC(O)--(CH.sub.2).sub.0-6--R.sub.52; or
--(CH.sub.2).sub.1-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54;
wherein [0956] R.sub.4-1 is --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; or --CO--NR.sub.4-3R.sub.4-4;
wherein [0957] R.sub.4-2 and R.sub.4-3 are independently H, or
C.sub.1-C.sub.3 alkyl; [0958] R.sub.4-4 is C.sub.1-C.sub.4 alkyl,
phenyl C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl; [0959] R.sub.5 is selected from the group
consisting of cyclopropyl; cyclopentyl; cyclohexyl; C.sub.1-C.sub.6
alkyl optionally substituted with 1, 2, or 3 groups that are
independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy,
C.sub.5-C.sub.6 heterocycloalkyl, C.sub.5-C.sub.6 heteroaryl,
phenyl, C.sub.3-C.sub.7 cycloalkyl, --S--C.sub.1-C.sub.4 alkyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, --CO.sub.2H,
--CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4 alkyl, or
phenyloxy; pyridyl, thiazolyl, pyrazolyl, pyrazinyl, optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
C.sub.1-C.sub.4 haloalkyl, or OH; piperidinyl,
dihydropyridazinonyl, pyrrolidinonyl, thioxothiazolidinonyl,
isoxazolyl, imidazolyl, indolyl, optionally substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, or C.sub.2-C.sub.4 alkanoyl;
phenyl optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkyl; wherein [0960] R.sub.6 and
R.sub.7 are independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl, and phenethyl; [0961]
R.sub.8 is --SO.sub.2-thienyl optionally substituted with 1 or 2
groups that are independently C.sub.1-C.sub.4 alkyl or halogen;
--SO.sub.2-phenyl, --SO.sub.2-piperidinyl, --SO.sub.2-pyrrolidinyl,
imidazolidinyl dione, --C(O)NHR.sub.9, --S--C.sub.1-C.sub.6 alkyl,
or S--C.sub.2-C.sub.4 alkanoyl, wherein [0962] R.sub.9 is phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl, or H; [0963] R.sub.50
is H or C.sub.1-C.sub.4 alkyl; [0964] R.sub.51 is selected from
benzyl; phenethyl; C.sub.1-C.sub.6 alkyl optionally substituted
with 1, 2, or 3 groups that are independently halogen, cyano,
--NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, or --C.sub.1-C.sub.4
alkoxy; heterocycloalkyl containing at least one N, O, or S and
optionally substituted with 1 or 2 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl, and
--SO.sub.2C.sub.1-C.sub.4 alkyl; heterocycloalkylalkyl containing
at least one N, O, or S and optionally substituted with 1 or 2
groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, phenyl
C.sub.1-C.sub.4 alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl; heteroaryl
optionally substituted with 1, 2, or 3 groups that are
independently OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); heteroarylalkyl containing at least
one N, O, or S and optionally substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); phenyl;
C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl, wherein the phenyl; C.sub.3-C.sub.6
cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl C.sub.1-C.sub.4 alkyl
groups are optionally substituted with 1, 2, or 3 groups that are
independently halogen, CN, NO.sub.2, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, hydroxy, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 thioalkoxy; [0965] R.sub.52 is
heterocycloalkyl, heteroaryl, phenyl, C.sub.3-C.sub.6 cycloalkyl,
--S(O).sub.0-2--C.sub.1-C.sub.6 alkyl, CO.sub.2H, --C(O)NH.sub.2,
--C(O)NH(alkyl), --C(O)N(alkyl)(alkyl), --CO.sub.2-alkyl,
--NHS(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--N(alkyl)S(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--S(O).sub.0-2-heteroaryl, --S(O).sub.0-2-aryl, --NH(arylalkyl),
--N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 thioalkoxy, halogen, C.sub.1-C.sub.4 haloalkyl,
haloalkoxy, C.sub.2-C.sub.6 alkanoyl, NO.sub.2, CN, C.sub.1-C.sub.4
alkoxycarbonyl, or aminocarbonyl; [0966] R.sub.53 is absent, --O--,
--C(O)--, --NH--, --N(alkyl)-, --NH--S(O).sub.0-2--,
--N(alkyl)-S(O).sub.0-2--, --S(O).sub.0-2--NH--, or
--S(O).sub.0-2--N(alkyl)-; [0967] R.sub.54 is pyridyl, thienyl,
imidazolyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl, piperidyl,
pyrrolidinyl, imidazolidinyl dione, CO.sub.2H, --CO.sub.2-alkyl,
--C(O)NH(alkyl), --C(O)N(alkyl) (alkyl), --C(O)NH.sub.2,
C.sub.1-C.sub.8 alkyl, OH, phenyloxy, alkoxy, phenylalkoxy,
NH.sub.2, NH(alkyl), N(alkyl)(alkyl), or --C.sub.1-C.sub.6
alkyl-CO.sub.2--C.sub.1-C.sub.6 alkyl, each of which is optionally
substituted with 1, 2, 3, 4, or 5 groups that are independently
alkyl, alkoxy, CO.sub.2H, --CO.sub.2-alkyl, thioalkoxy, halogen,
haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO.sub.2, CN,
alkoxycarbonyl, or aminocarbonyl.
[0968] Even more preferred compounds of formula X-XXXI are those of
formula X-XXXII: ##STR37## wherein [0969] A.sub.1 is H,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen or
C.sub.2-C.sub.6 alkynyl; [0970] A.sub.2 is H, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy,
C.sub.1-C.sub.4 haloalkyl or OH; [0971] A.sub.3 and A.sub.4 are
independently C.sub.1-C.sub.4 alkyl, halogen, or H.
[0972] Preferred compounds of formulas X-XXXI and X-XXXII include
those wherein [0973] R.sub.20 at each occurrence is independently H
or C.sub.1-C.sub.4 alkyl; [0974] X is C.sub.1 or C.sub.2
alkylidenyl; [0975] Z is SO.sub.2; SO; S; or C(O); and [0976] Y is
phenyl; C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or
3 halogen; or OH; or [0977] Y is --N(Y.sub.1)(Y.sub.2); wherein
[0978] Y.sub.1 and Y.sub.2 are independently H or C.sub.1-C.sub.4
alkyl.
[0979] More preferred compounds of formula X-XXXII include those of
formula X-XXXIII: ##STR38##
[0980] Preferred compounds of formulas X-XXXII and X-XXXIII include
those wherein [0981] R.sub.4 is H; or C.sub.1-C.sub.4
alkyl-NHC(O)R.sub.5; wherein [0982] R.sub.5 is selected from the
group consisting of cyclopropyl; cyclopentyl; cyclohexyl;
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
that are independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4
alkoxy, C.sub.5-C.sub.6 heterocycloalkyl, C.sub.5-C.sub.6
heteroaryl, phenyl, C.sub.3-C.sub.7 cycloalkyl,
--S--C.sub.1-C.sub.4 alkyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl,
--CO.sub.2H, --CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4
alkyl, or phenyloxy; pyridyl, thiazolyl, pyrazolyl, pyrazinyl,
optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.1-C.sub.4 haloalkyl, or OH; piperidinyl,
dihydropyridazinonyl, pyrrolidinonyl, thioxothiazolidinonyl,
isoxazolyl, imidazolyl, indolyl, optionally substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, or C.sub.2-C.sub.4 alkanoyl;
phenyl optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkyl; wherein [0983] R.sub.6 and
R.sub.7 are independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl, and phenethyl.
[0984] Other preferred compounds of formula X-XXXIII include those
wherein [0985] R.sub.4 is --(CH.sub.2).sub.0-4R.sub.8; wherein
[0986] R.sub.8 is --SO.sub.2-thienyl optionally substituted with 1
or 2 groups that are independently C.sub.1-C.sub.4 alkyl or
halogen; --SO.sub.2-phenyl, --SO.sub.2-piperidinyl,
--SO.sub.2-pyrrolidinyl, imidazolidinyl dione, --C(O)NHR.sub.9,
--S--C.sub.1-C.sub.6 alkyl, or --S--C.sub.2-C.sub.4 alkanoyl,
wherein [0987] R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl, or H;
[0988] Other preferred compounds of formula X-XXXIII include those
wherein [0989] R.sub.4 is --C.sub.1-C.sub.4
alkyl-NR.sub.50CO.sub.2R.sub.51;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1; or
(CH.sub.2).sub.1-4--NHC(O)--(CH.sub.2).sub.0-6--R.sub.52; wherein
[0990] R.sub.50 is H or C.sub.1-C.sub.4 alkyl; [0991] R.sub.51 is
selected from benzyl; phenethyl; C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently halogen,
cyano, --NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, or
--C.sub.1-C.sub.4 alkoxy; heterocycloalkyl containing at least one
N, O, or S and optionally substituted with 1 or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; heterocycloalkylalkyl
containing at least one N, O, or S and optionally substituted with
1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, phenyl
C.sub.1-C.sub.4 alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl; heteroaryl
optionally substituted with 1, 2, or 3 groups that are
independently OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); heteroarylalkyl containing at least
one N, O, or S and optionally substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); phenyl;
C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl, wherein the phenyl; C.sub.3-C.sub.6
cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl C.sub.1-C.sub.4 alkyl
groups are optionally substituted with 1, 2, or 3 groups that are
independently halogen, CN, NO.sub.2, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, hydroxy, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 thioalkoxy; [0992] R.sub.6 and
R.sub.7 are independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl, and phenethyl; [0993]
R.sub.52 is heterocycloalkyl, heteroaryl, phenyl, C.sub.3-C.sub.6
cycloalkyl, --S(O).sub.0-2--C.sub.1-C.sub.6 alkyl, CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(alkyl), --C(O)N(alkyl)(alkyl),
--CO.sub.2-alkyl, --NHS(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--N(alkyl)S(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--S(O).sub.0-2-heteroaryl, --S(O).sub.0-2-aryl, --NH(arylalkyl),
--N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 thioalkoxy, halogen, C.sub.1-C.sub.4 haloalkyl,
haloalkoxy, C.sub.2-C.sub.6 alkanoyl, NO.sub.2, CN, C.sub.1-C.sub.4
alkoxycarbonyl, or aminocarbonyl.
[0994] Still other preferred compounds of formula X-XXXIII include
those wherein [0995] R.sub.4 is --(CH.sub.2).sub.1-4--R.sub.4-1 or
--(CH.sub.2).sub.1-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54;
wherein [0996] R.sub.4-1 is --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; or --C0-NR.sub.4-3R.sub.4-4;
wherein [0997] R.sub.4-2 and R.sub.4-3 are independently H, or
C.sub.1-C.sub.3 alkyl; [0998] R.sub.4-4 is C.sub.1-C.sub.4 alkyl,
phenyl C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl; [0999] R.sub.53 is absent, --O--,
--C(O)--, --NH--, --N(alkyl)-, --NH--S(O).sub.0-2--,
--N(alkyl)-S(O).sub.0-2--, --S(O).sub.0-2--NH--, or
--S(O).sub.0-2--N(alkyl)-; [1000] R.sub.54 is pyridyl, thienyl,
imidazolyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl, piperidyl,
pyrrolidinyl, imidazolidinyl dione, CO.sub.2H, --CO.sub.2-alkyl,
--C(O)NH(alkyl), --C(O)N(alkyl) (alkyl), --C(O)NH.sub.2,
C.sub.1-C.sub.8 alkyl, OH, phenyloxy, alkoxy, phenylalkoxy,
NH.sub.2, NH(alkyl), N(alkyl)(alkyl), or --C.sub.1-C.sub.6
alkyl-CO.sub.2--C.sub.1-C.sub.6 alkyl, each of which is optionally
substituted with 1, 2, 3, 4, or 5 groups that are independently
alkyl, alkoxy, CO.sub.2H, --CO.sub.2-alkyl, thioalkoxy, halogen,
haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl, NO.sub.2, CN,
alkoxycarbonyl, or aminocarbonyl.
[1001] Other preferred compounds of formula X-XXXIII include those
of formula X-XXXIV: ##STR39## wherein [1002] R.sub.C is
C.sub.3-C.sub.8 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, or
--(C.sub.1-C.sub.4)alkyl-(C.sub.3-C.sub.6) cycloalkyl; and [1003]
A.sub.3 and A.sub.4 are independently C.sub.1-C.sub.4 alkyl,
halogen, or H.
[1004] Preferred compounds of formula X-XXXIV include [1005]
R.sub.20 at each occurrence is independently H or C.sub.1-C.sub.4
alkyl; [1006] X is C.sub.1 or C.sub.2 alkylidenyl; [1007] Z is
SO.sub.2; SO; S; or C(O); and [1008] Y is phenyl; C.sub.1-C.sub.10
alkyl optionally substituted with 1, 2, or 3 halogen; or OH; or
[1009] Y is --N(Y.sub.1)(Y.sub.2); wherein [1010] Y.sub.1 and
Y.sub.2 are independently H or C.sub.1-C.sub.4 alkyl.
[1011] More preferred compounds of formula X-XXXIV include those of
formula X-XXXV: ##STR40##
[1012] Preferred compounds of formula X-XXXV include those wherein
[1013] R.sub.4 is H; or C.sub.1-C.sub.4 alkyl-NHC(O)R.sub.5;
wherein [1014] R.sub.5 is selected from the group consisting of
cyclopropyl; cyclopentyl; cyclohexyl; C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently halogen, --NR.sub.6R.sub.7, C.sub.1-C.sub.4 alkoxy,
C.sub.5-C.sub.6 heterocycloalkyl, C.sub.5-C.sub.6 heteroaryl,
phenyl, C.sub.3-C.sub.7 cycloalkyl, --S--C.sub.1-C.sub.4 alkyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, --CO.sub.2H,
--CONR.sub.6R.sub.7, --CO.sub.2--C.sub.1-C.sub.4 alkyl, or
phenyloxy; pyridyl, thiazolyl, pyrazolyl, pyrazinyl, optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
C.sub.1-C.sub.4 haloalkyl, or OH; piperidinyl,
dihydropyridazinonyl, pyrrolidinonyl, thioxothiazolidinonyl,
isoxazolyl, imidazolyl, indolyl, optionally substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, or C.sub.2-C.sub.4 alkanoyl;
phenyl optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, or C.sub.1-C.sub.4 haloalkyl; and NR.sub.6R.sub.7 wherein
[1015] R.sub.6 and R.sub.7 are independently selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkanoyl, phenyl, --SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl, and
phenethyl.
[1016] Other preferred compounds of formula X-XXXV include those
wherein [1017] R.sub.4 is --(CH.sub.2).sub.0-4R.sub.8; wherein
[1018] R.sub.8 is --SO.sub.2-thienyl optionally substituted with 1
or 2 groups that are independently C.sub.1-C.sub.4 alkyl or
halogen; --SO.sub.2-phenyl, --SO.sub.2-piperidinyl,
--SO.sub.2-pyrrolidinyl, imidazolidinyl dione, --C(O)NHR.sub.9,
--S--C.sub.1-C.sub.6 alkyl, or S--C.sub.2-C.sub.4 alkanoyl, wherein
[1019] R.sub.9 is phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl, or H;
[1020] Other preferred compounds of formula X-XXXV include those
wherein [1021] R.sub.4 is --C.sub.1-C.sub.4
alkyl-NR.sub.50CO.sub.2R.sub.51;
--(CH.sub.2).sub.1-4--NH--R.sub.4-1; or
(CH.sub.2).sub.1-4--NHC(O)--(CH.sub.2) O.sub.6--R.sub.52; wherein
[1022] R.sub.50 is H or C.sub.1-C.sub.4 alkyl; [1023] R.sub.51 is
selected from benzyl; phenethyl; C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently halogen,
cyano, --NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, or
--C.sub.1-C.sub.4 alkoxy; heterocycloalkyl containing at least one
N, O, or S and optionally substituted with 1 or 2 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, C.sub.2-C.sub.4 alkanoyl, phenyl C.sub.1-C.sub.4 alkyl,
and --SO.sub.2C.sub.1-C.sub.4 alkyl; heterocycloalkylalkyl
containing at least one N, O, or S and optionally substituted with
1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, C.sub.2-C.sub.4 alkanoyl, phenyl
C.sub.1-C.sub.4 alkyl, and --SO.sub.2C.sub.1-C.sub.4 alkyl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl; heteroaryl
optionally substituted with 1, 2, or 3 groups that are
independently OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N(C.sub.1-C.sub.6
alkyl)(C.sub.1-C.sub.6 alkyl); heteroarylalkyl containing at least
one N, O, or S and optionally substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or
N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); phenyl;
C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl
C.sub.1-C.sub.4 alkyl, wherein the phenyl; C.sub.3-C.sub.6
cycloalkyl, and C.sub.3-C.sub.6 cycloalkyl C.sub.1-C.sub.4 alkyl
groups are optionally substituted with 1, 2, or 3 groups that are
independently halogen, CN, NO.sub.2, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, hydroxy, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 thioalkoxy; [1024] R.sub.6 and
R.sub.7 are independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkanoyl, phenyl,
--SO.sub.2--C.sub.1-C.sub.4 alkyl, benzyl, and phenethyl; [1025]
R.sub.52 is heterocycloalkyl, heteroaryl, phenyl, C.sub.3-C.sub.6
cycloalkyl, --S(O).sub.0-2--C.sub.1-C.sub.6 alkyl, CO.sub.2H,
--C(O)NH.sub.2, --C(O)NH(alkyl), --C(O)N(alkyl)(alkyl),
--CO.sub.2-alkyl, --NHS(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--N(alkyl)S(O).sub.0-2--C.sub.1-C.sub.6 alkyl,
--S(O).sub.0-2-heteroaryl, --S(O).sub.0-2-aryl, --NH(arylalkyl),
--N(alkyl)(arylalkyl), thioalkoxy, or alkoxy, each of which is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 thioalkoxy, halogen, C.sub.1-C.sub.4 haloalkyl,
haloalkoxy, C.sub.2-C.sub.6 alkanoyl, NO.sub.2, CN, C.sub.1-C.sub.4
alkoxycarbonyl, or aminocarbonyl.
[1026] Still other preferred compounds of formula X-XXXV include
those wherein [1027] R.sub.4 is --(CH.sub.2).sub.1-4--R.sub.4-1 or
--(CH.sub.2).sub.1-4--R.sub.53--(CH.sub.2).sub.0-4--R.sub.54;
wherein [1028] R.sub.4-1 is --SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; or --CO--NR.sub.4-3R.sub.4-4;
wherein [1029] R.sub.4-2 and R.sub.4-3 are independently H, or
C.sub.1-C.sub.3 alkyl; [1030] R.sub.4-4 is C.sub.1-C.sub.4 alkyl,
phenyl C.sub.1-C.sub.4 alkyl (preferably benzyl of phenethyl),
C.sub.2-C.sub.4 alkanoyl, or phenyl C.sub.1-C.sub.4 alkanoyl
(preferably benzoyl or C.sub.6H.sub.5CH.sub.2CO--); [1031] R.sub.53
is absent, --O--, --C(O)--, --NH--, --N(alkyl)-,
--NH--S(O).sub.0-2--, --N(alkyl)-S(O).sub.0-2--,
--S(O).sub.0-2--NH--, or --S(O).sub.0-2--N(alkyl)-; [1032] R.sub.54
is pyridyl, thienyl, imidazolyl, phenyl, phenyl C.sub.1-C.sub.4
alkyl, piperidyl, pyrrolidinyl, imidazolidinyl dione, CO.sub.2H,
--CO.sub.2-alkyl, --C(O)NH(alkyl), --C(O)N(alkyl) (alkyl),
--C(O)NH.sub.2, C.sub.1-C.sub.8 alkyl, OH, phenyloxy, alkoxy,
phenylalkoxy, NH.sub.2, NH(alkyl), N(alkyl)(alkyl), or
--C.sub.1-C.sub.6 alkyl-CO.sub.2--C.sub.1-C.sub.6 alkyl, each of
which is optionally substituted with 1, 2, 3, 4, or 5 groups that
are independently alkyl, alkoxy, CO.sub.2H, --CO.sub.2-alkyl,
thioalkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkanoyl,
NO.sub.2, CN, alkoxycarbonyl, or aminocarbonyl.
[1033] Other preferred compounds of formula X-XXXII include those
of formula X-XXXVI, i.e., compounds of formula X-XXXII wherein
[1034] R.sub.4 is --O--C.sub.1-C.sub.4 alkanoyl; OH;
C.sub.6-C.sub.10 aryloxy optionally substituted with 1, 2, or 3
groups that are independently halogen, C.sub.1-C.sub.4 alkyl,
CO.sub.2H, --C(O)--C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
alkoxy; C.sub.1-C.sub.6 alkoxy; aryl C.sub.1-C.sub.4 alkoxy;
--O--(CH.sub.2).sub.n6--R.sub.4-1;
--S--(CH.sub.2).sub.n6--R.sub.4-1.
[1035] Still other preferred compounds of formula X-XXXVI include
those wherein [1036] R.sub.4 is --O--C.sub.1-C.sub.4 alkanoyl; OH;
phenyloxy or napthyloxy, each of which is optionally substituted
with 1, 2, or 3 groups that are independently halogen,
C.sub.1-C.sub.4 alkyl, CO.sub.2H, --C(O)--C.sub.1-C.sub.4 alkoxy,
or C.sub.1-C.sub.4 alkoxy; C.sub.1-C.sub.6 alkoxy; phenyl
C.sub.1-C.sub.4 alkoxy; --O--(CH.sub.2).sub.n6--R.sub.4-1; or --S--
(CH.sub.2).sub.n6--R.sub.4-1 [1037] R.sub.4-1 is
--SO.sub.2--(C.sub.1-C.sub.8 alkyl),
--SO.sub.2--NR.sub.4-2R.sub.4-3; or --CO--NR.sub.4-3R.sub.4-4;
wherein [1038] R.sub.4-2 and R.sub.4-3 are independently H, or
C.sub.1-C.sub.3 alkyl; [1039] R.sub.4-4 is C.sub.1-C.sub.4 alkyl,
phenyl C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkanoyl, or phenyl
C.sub.1-C.sub.4 alkanoyl;
[1040] More preferred compounds of formula X-XXXVI include those
wherein [1041] R.sub.4 is --O--C.sub.1-C.sub.4 alkanoyl; OH;
phenyloxy optionally substituted with 1, or 2 groups that are
independently halogen, C.sub.1-C.sub.4 alkyl, CO.sub.2H,
--C(O)--C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 alkoxy; or
phenyl C.sub.1-C.sub.4 alkoxy.
[1042] Other preferred compounds of the invention are those of
formulae X-40 to X-47: ##STR41## where R.sub.N, R.sub.2, R.sub.3,
R.sub.20 and R.sub.c are as defined above for structure X.
##STR42## where R.sub.N, R.sub.2, R.sub.3, R.sub.20 and R.sub.c are
as defined above for structure X. ##STR43## where R.sub.N, R.sub.2,
R.sub.3, R.sub.20 and R.sub.c are as defined above for structure X.
##STR44## where R.sub.1, R.sub.2, R.sub.3, R.sub.20 and R.sub.c are
as defined above for structure X. ##STR45## where R.sub.N, R.sub.1,
R.sub.2, and R.sub.3 are as defined above for structure X.
##STR46## where R.sub.N, R.sub.1, R.sub.2, and R.sub.3 are as
defined above for structure X. ##STR47## where R.sub.N, R.sub.1,
R.sub.2, and R.sub.3 are as defined above for structure X.
##STR48## where R.sub.N, R.sub.2, and R.sub.3 are as defined above
for structure X.
[1043] Other representative compounds of the invention are [1044]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(ethylt-
hio)-2-{[(isobutylsulfonyl)amino]methyl}propanamide; [1045]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-N.about.2.about.-(isopentylsulfonyl)-L-methioninamide; [1046]
N.about.2.about.-[(5-chlorothien-2-yl)sulfonyl]-N.about.1.about.-{(1S,2R)-
-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-pr-
opylbutyl)sulfonyl]-D,L-alaninamide; [1047]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl-
]methyl}propanamide; [1048]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl-
]methyl}propanamide; [1049]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl-
]methyl}propanamide; and [1050]
S-{3-({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)-
-2-[(isopentylsulfonyl)methyl]-3-oxopropyl}ethanethioate and the
pharmaceutically acceptable salts thereof.
[1051] Still other representative compounds of the invention are
selected from: [1052]
4-({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxyprop-
yl}amino)-4-oxo-3-{[(1-propylbutyl)sulfonyl]methyl}butanoic acid;
[1053]
4-({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)-3--
[(isopentylsulfonyl)methyl]-4-oxobutanoic acid; [1054] methyl
4-({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)-3--
[(isopentylsulfonyl)methyl]-4-oxobutanoate; [1055]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-2-[(isopentylsulfonyl)methyl]succinamide; [1056]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]pr-
opyl}-2-[(isopentylsulfonyl)methyl]-N.about.4.about.-methylsuccinamide;
[1057]
N.about.1.about.-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)-
amino]propyl}-2-[(isopentylsulfonyl)methyl]-N.about.4.about.,N.about.4.abo-
ut.-dimethylsuccinamide; [1058]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl-
]methyl}propanamide; [1059]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl-
]methyl}propanamide; [1060]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-{[(1-propylbutyl)sulfonyl-
]methyl}propanamide; [1061]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(ethyls-
ulfonyl)-2-{[(isobutylsulfonyl)amino]methyl}propanamide; and [1062]
(2S)--N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[-
(isopentylsulfonyl)amino]-4-(methylsulfonyl)butanamide and the
pharmaceutically acceptable salts thereof.
[1063] Yet still other representative compounds of the invention
are: [1064]
2-N.about.1.about.-{((1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbe-
nzyl)amino]-2-hydroxypropyl}-1-[(butylsulfonyl)methyl]-2-oxoethyl
acetate; [1065]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}--
2-hydroxy-3-[(1-propylbutyl)sulfonyl]propanamide; [1066]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-hydroxy-
-3-(isopentylsulfonyl)propanamide; [1067]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-hydroxy-
-3-[(3-methoxyphenyl)sulfonyl]propanamide; [1068]
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropy-
l}-2-hydroxy-4-(phenylsulfonyl)butanamide; [1069]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-hydroxy-
-4-(isopentylsulfonyl)butanamide; [1070]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(isopen-
tylsulfonyl)-2-phenoxybutanamide; [1071]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(isopen-
tylsulfonyl)-2-(3-methoxyphenoxy)butanamide; [1072]
3-[1-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino-
)carbonyl]-3-(isopentylsulfonyl)propoxy]benzoic acid; [1073] methyl
3-[1-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino-
)carbonyl]-3-(isopentylsulfonyl)propoxy]benzoate; [1074]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-hydroxy-
-4-(phenylsulfonyl)butanamide; [1075]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-hydroxy-
-4-(phenylthio)butanamide; [1076]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-methoxy-
-4-(phenylsulfonyl)butanamide; [1077]
N-{(1S,2R))-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-methox-
y-4-(phenylthio)butanamide; [1078]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(phenyl-
sulfonyl)-2-propoxybutanamide; and [1079]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-(benzyl-
oxy)-4-(phenylsulfonyl)butanamide and pharmaceutically acceptable
salts thereof.
[1080] Other preferred compounds of the invention are selected
from: [1081]
N-{(1R)-3-(butylsulfonyl)-1-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[-
(3-ethynylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]propyl}-3-methyl-1H-
-pyrazole-5-carboxamide; [1082]
N-((1R)-3-(butylsulfonyl)-1-{[((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
-{[3-(trifluoromethyl)benzyl]amino}propyl)amino]carbonyl}propyl)-3-methyl--
1H-pyrazole-5-carboxamide; [1083]
N-((1R)-3-(butylsulfonyl)-1-{[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-et-
hylphenyl)cyclopropyl]amino}-2-hydroxypropyl)amino]carbonyl}propyl)-3-meth-
yl-1H-pyrazole-5-carboxamide; [1084]
N-((1R)-3-(butylsulfonyl)-1-{[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-et-
hynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)amino]carbonyl}propyl)-3-me-
thyl-1H-pyrazole-5-carboxamide; [1085]
N-[(1R)-3-(butylsulfonyl)-1-({[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]amino}carbonyl)pr-
opyl]-3-methyl-1H-pyrazole-5-carboxamide; [1086]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-2-{[(methylamino)carbonyl]amino}-4-oxooctanamide; [1087]
4-butyl-N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]--
2-hydroxypropyl}-N.sup.2-[(methylamino)carbonyl]-D-homoserinamide;
[1088]
3-(2-butyl-1,3-dioxolan-2-yl)-N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3--
[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.sup.2-[(methylamino)carbonyl]-D--
alaninamide; [1089]
3-(2-butyl-1,3-dioxan-2-yl)-N.sup.1-[(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-
-ethylbenzyl)amino]-2-hydroxypropyl]-N.about.2.about.-[(methylamino)carbon-
yl]-D-alaninamide [1090]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-4,4-difluoro-2-{[(methylamino)carbonyl]amino}octanamide;
[1091]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-4-fluoro-2-{[(methylamino)carbonyl]amino}octanamide; [1092]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-2-{[(methylamino)carbonyl]amino}-5-oxononanamide; [1093]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-5-hydroxy-2-{[(methylamino)carbonyl]amino}nonanamide;
[1094]
(2R)-4-(2-butyl-1,3-dioxolan-2-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(-
3-ethylbenzyl)amino]-2-hydroxypropyl}-2-{[(methylamino)carbonyl]amino}buta-
namide; [1095]
(2R)-4-(2-butyl-1,3-dioxan-2-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3--
ethylbenzyl)amino]-2-hydroxypropyl}-2-{[(methylamino)carbonyl]amino}butana-
mide; [1096]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-5-fluoro-2-{[(methylamino)carbonyl]amino}nonanamide; [1097]
(2R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-5,5-difluoro-2-{[(methylamino)carbonyl]amino}nonanamide;
[1098]
3-(butylsulfonyl)-N.sup.1-[(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbe-
nzyl)amino]-2-hydroxypropyl]-N.sup.2-[(methylamino)carbonyl]-D-alaninamide-
; [1099]
3-(butylsulfonyl)-N.sup.1-((1S,2R)-1-(3,5-difluorobenzyl)-2-hyd-
roxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N.sup.2-[(methylamino)car-
bonyl]-D-alaninamide; [1100]
3-(butylsulfonyl)-N.sup.1-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylp-
henyl)cyclopropyl]amino}-2-hydroxypropyl)-N.sup.2-[(methylamino)carbonyl]--
D-alaninamide; [1101]
3-(butylsulfonyl)-N.sup.1-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethyny-
lphenyl)cyclopropyl]amino}-2-hydroxypropyl)-N.sup.2-[(methylamino)carbonyl-
]-D-alaninamide; [1102]
3-(butylsulfonyl)-N.sup.1-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-
-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-N.sup.2-[(methylamin-
o)carbonyl]-D-alaninamide; [1103] 4-Methyl-pyrazole-1-carboxylic
acid
{2-(butane-1-sulfonyl)-1-[1-(3,5-difluoro-benzyl)-3-(3-ethynyl-b
enzylamino)-2-hydroxy-propylcarbamoyl]-ethyl}-amide; [1104]
4-Methyl-pyrazole-1-carboxylic acid
{2-(butane-1-sulfonyl)-1-[1-(3,5-difluoro-benzyl)-2-hydroxy-3-(3-trifluor-
omethyl-benzylamino)-propylcarbamoyl]-ethyl}-amide; [1105]
4-Methyl-pyrazole-1-carboxylic acid
(2-(butane-1-sulfonyl)-1-{1-(3,5-difluoro-benzyl)-3-[1-(3-ethyl-phenyl)-c-
yclopropylamino]-2-hydroxy-propylcarbamoyl}-ethyl)-amide; [1106]
4-Methyl-pyrazole-1-carboxylic acid
(2-(butane-1-sulfonyl)-1-{1-(3,5-difluoro-benzyl)-3-[1-(3-ethyny-1-phenyl-
)-cyclopropylamino]-2-hydroxy-propylcarbamoyl}-ethyl)-amide; [1107]
4-Methyl-pyrazole-1-carboxylic acid
(2-(butane-1-sulfonyl)-1-{1-(3,5-difluoro-benzyl)-2-hydroxy-3-[1-(3-trifl-
uoromethyl-phenyl)-cyclopropylamino]-propylcarbamoyl}-ethyl)-amide;
and pharmaceutically acceptable salts thereof. Definitions
[1108] All temperatures are in degrees Celsius.
[1109] TLC refers to thin-layer chromatography.
[1110] psi refers to pounds/in.sup.2.
[1111] HPLC refers to high pressure liquid chromatography.
[1112] THF refers to tetrahydrofuran.
[1113] DMF refers to dimethylformamide.
[1114] HOBt refers to 1-hydroxy bezotriazole hydrate.
[1115] NMM refers to N-methyl morpholine.
[1116] EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
[1117] NBS refers to N-bromosuccinimide.
[1118] TEA refers to triethylamine.
[1119] BOC refers to 1,1-dimethylethoxy carbonyl or
t-butoxycarbonyl, --CO.sub.2C(CH.sub.3).sub.3.
[1120] CBZ refers to benzyloxycarbonyl,
--CO.sub.2--CH.sub.2-phenyl.
[1121] TFA refers to trifluoracetic acid, CF.sub.3COOH.
[1122] CDI refers to 1,1'-carbonyldiimidazole.
[1123] Saline refers to an aqueous saturated sodium chloride
solution.
[1124] Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support,
eluent). It is understood that the appropriate fractions are pooled
and concentrated to give the desired compound(s).
[1125] CMR refers to C-13 magnetic resonance spectroscopy, chemical
shifts are reported in ppm (.delta.) downfield from TMS.
[1126] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (d) downfield
from TMS.
[1127] -.phi. refers to phenyl (C.sub.6H.sub.5)
[1128] MS refers to mass spectrometry expressed as m/e, m/z or
mass/charge unit. MH.sup.+ refers to the positive ion of a parent
plus a hydrogen atom. EI refers to electron impact. CI refers to
chemical ionization. FAB refers to fast atom bombardment.
[1129] HRMS refers to high resolution mass spectrometry.
[1130] Ether refers to diethyl ether.
[1131] When solvent pairs are used, the ratios of solvents used are
volume/volume (v/v).
[1132] When the solubility of a solid in a solvent is used the
ratio of the solid to the solvent is weight/volume (wt/v).
[1133] BOP refers to
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate.
[1134] TBDMSCl refers to t-butyldimethylsilyl chloride.
[1135] TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acid
ester.
[1136] Trisomy 21 refers to Down's Syndrome.
[1137] EDC refers to 1-[3-(dimethylamino)propyl]-3-ethyl
carbodiimide.
[1138] DIPMAP refers to
(R,R)-1,2-bis[(o-methoxyphenyl)-phenylphosphinp]ethane.
[1139] MeDuPhos refers to
1,2-bis((2S,5S)-2,5-dimethylphospholano)benzene.
[1140] EtDuPhos refers to
1,2-bis((2S,5S)-2,5-diethylphospholano)benzene.
[1141] Binaphane refers to
(S,S)-1,2-Bis{S)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]phosphepino}benze-
ne.
[1142] f-Binaphane refers to
(R,R)-1,1'-Bis{R)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]phosphepino}ferr-
ocene.
[1143] Me-KetalPhos refers to
1,2-Bis-[(2S,3S,4S,5S)-3,4-O-isopropylidene-3,4-dihydroxy-2,5-dimethyl]be-
nzene.
[1144] Me-f-KetalPhos refers to
1,1'-Bis-[(2S,3S,4S,5S)-2,5-dimethyl-3,4-O-isopropylidene-3,4-dihydroxyph-
ospholanyl]ferrocene.
[1145] Et-f-KetalPhos refers to
1,1'-Bis-[(2S,3S,4S,5S)-2,5-diethyl-3,4-O-isopropylidene-3,4-dihydroxypho-
spholanyl]ferrocene
[1146] BINAP refers to
R-2,2'-bis(diphenylphosphino)-1,1'binaphthyl.
[1147] DIOP refers to
(R,R)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-butan-
e.
[1148] BPPFA refers to
R-1-[(S)-1,2-bisdiphenylphospino)ferrocenyl]-ethyldimethylamine.
[1149] BPPM refers to
(2S,4S)-1-tert-butoxycarbonyl-4-diphenylphosphino-2-(diphenylphosphinomet-
hyl)pyrrolidine.
[1150] CHIRAPHOS refers to
(S,S)-2,3-bis(diphenylphosphino)butane.
[1151] PROPHOS refers to (S)-1,2-bis(diphenylphosphino)propane.
[1152] NORPHOS refers to
(R,R)-5,6-bis(diphenylphosphino)-2-norbornene.
[1153] CYCLOPHOS refers to
R-1-cyclohexyl-1,2-bis(diphenylphosphino)ethane.
[1154] BDPP refers to (2S,4S)-bis(diphenylphosphine) pentane.
[1155] DEGPHOS refers to 1-substituted
(S,S)-3,4-bis-(diphenylphosphino)-pyrrolidine.
[1156] PNNP refers to
N,N'-bis(diphenylphosphino)-N,N'-bis[(R)-1-phenyl]ethylenediamine.
[1157] LDA refers to lithium diisopropylamide.
[1158] LiHMDS refers to lithium hexamethyldisilazane.
[1159] KHMDS refers to potassium hexamethyldisilazane.
[1160] By the terms "alkyl" and "C.sub.1-C.sub.6 alkyl" is meant
straight or branched chain alkyl groups having 1-6 carbon atoms,
such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,
3-hexyl, and 3-methylpentyl. It is understood that in cases where
an alkyl chain of a substituent (e.g. of an alkyl, alkoxy or
alkenyl group) is shorter or longer than 6 carbons, it will be so
indicated in the second "C" as, for example, "C.sub.1-C.sub.10"
indicates a maximum of 10 carbons.
[1161] By the terms "alkoxy" and "C.sub.1-C.sub.6 alkoxy" is meant
straight or branched chain alkyl groups having 1-6 carbon atoms,
attached through at least one divalent oxygen atom, such as, for
example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy,
and 3-methylpentoxy.
[1162] By the term "halogen" is meant fluorine, bromine, chlorine,
and/or iodine.
[1163] The terms "alkenyl" and "C.sub.2-C.sub.6 alkenyl" refer to
straight and branched hydrocarbon radicals having from 2 to 6
carbon atoms and from one to three double bonds and includes, for
example, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl,
1-hex-5-enyl and the like.
[1164] The terms "alkynyl" and "C.sub.2-C.sub.6 alkynyl" means
straight and branched hydrocarbon radicals having from 2 to 6
carbon atoms and one or two triple bonds and includes ethynyl,
propynyl, butynyl, pentyn-2-yl and the like.
[1165] As used herein, the term "cycloalkyl" refers to saturated
carbocyclic radicals having three to twelve carbon atoms. The
cycloalkyl can be monocyclic, or a polycyclic fused system.
Examples of such radicals include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl groups
herein are unsubstituted or, as specified, substituted in one or
more substitutable positions with various groups. For example, such
cycloalkyl groups may be optionally substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxy,
cyano, nitro, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6) alkylamino(C.sub.1-C.sub.6) alkyl.
[1166] By "aryl" is meant an aromatic carbocyclic group having a
single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or
multiple condensed rings in which at least one is aromatic, (e.g.,
1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-,
di-, or trisubstituted. Preferred aryl groups of the invention are
phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl,
tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. Even
more preferred aryl groups are phenyl and napthyl. The most
preferred aryl group is phenyl.
[1167] The aryl groups herein are unsubstituted or, as specified,
substituted in one or more substitutable positions with various
groups. For example, such aryl groups may be optionally substituted
with, for example, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl, --COOH,
--C(.dbd.O)O(C.sub.1-C.sub.6 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)N(mono- or di-C.sub.1-C.sub.6 alkyl),
--S(C.sub.1-C.sub.6 alkyl), --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--O--C(.dbd.O)(C.sub.1-C.sub.6 alkyl),
--NH--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--(C.sub.1-C.sub.6 alkyl),
--NH--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)-SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NH--C(.dbd.O)NH.sub.2,
--NH--C(.dbd.O)N(mono- or di-C.sub.1-C.sub.6 alkyl),
--NH(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--NH.sub.2 or
--NH(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--N-(mono- or
di-C.sub.1-C.sub.6 alkyl).
[1168] By "heteroaryl" is meant one or more aromatic ring systems
of 5-, 6-, or 7-membered rings which includes fused ring systems of
9-11 atoms containing at least one and up to four heteroatoms
selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl
groups of the invention include pyridinyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl,
carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl
N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl
N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl
N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,
indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,
benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,
thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,
benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.
[1169] The heteroaryl groups herein are unsubstituted or, as
specified, substituted in one or more substitutable positions with
various groups. For example, such heteroaryl groups may be
optionally substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6) alkyl or
di(C.sub.1-C.sub.6) alkylamino(C.sub.1-C.sub.6) alkyl, --COOH,
--C(.dbd.O)O(C.sub.1-C.sub.6 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)N(mono- or di-C.sub.1-C.sub.6 alkyl),
--S(C.sub.1-C.sub.6 alkyl), --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--O--C(.dbd.O)(C.sub.1-C.sub.6 alkyl),
--NH--C(.dbd.O)--(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)-C(.dbd.O)--(C.sub.1-C.sub.6 alkyl),
--NH--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl)-SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NH--C(.dbd.O)NH.sub.2,
--NH--C(.dbd.O)N(mono- or di-C.sub.1-C.sub.6 alkyl),
--NH(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--NH.sub.2 or
--NH(C.sub.1-C.sub.6 alkyl)-C(.dbd.O)--N-(mono- or
di-C.sub.1-C.sub.6 alkyl).
[1170] By the terms "heterocycle", "heterocycloalkyl" and
"heterocyclyl" is meant one or more carbocyclic ring systems of 4-,
5-, 6-, or 7-membered rings which includes fused ring systems of
9-11 atoms containing at least one and up to four heteroatoms
selected from nitrogen, oxygen, or sulfur. Preferred heterocycles
of the invention include morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.
[1171] The heterocycle groups herein are unsubstituted or, as
specified, substituted in one or more substitutable positions with
various groups. For example, such heterocycle groups may be
optionally substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or .dbd.O.
[1172] APP, amyloid precursor protein, is defined as any APP
polypeptide, including APP variants, mutations, and isoforms, for
example, as disclosed in U.S. Pat. No. 5,766,846.
[1173] A-beta, amyloid beta peptide, is defined as any peptide
resulting from beta-secretase mediated cleavage of APP, including
peptides of 39, 40, 41, 42, and 43 amino acids, and extending from
the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or
43.
[1174] Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl
protease that mediates cleavage of APP at the amino-terminal edge
of A-beta. Human beta-secretase is described, for example, in
WO00/17369.
[1175] Pharmaceutically acceptable refers to those properties
and/or substances that are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
[1176] A therapeutically effective amount is defined as an amount
effective to reduce or lessen at least one symptom of the disease
being treated or to reduce or delay onset of one or more clinical
markers or symptoms of the disease.
Pharmaceutical Compositions
[1177] Compositions containing therapeutically effective amounts of
the compounds are provided of the invention. The compounds are
preferably formulated into suitable pharmaceutical preparations
such as tablets, capsules or elixirs, for oral administration or in
sterile solutions or suspensions for parenteral administration.
Typically the compounds described above are formulated into
pharmaceutical compositions using techniques and procedures known
in the art.
[1178] A unit dose of about 0.1 to 1000 mg of a compound or mixture
of compounds of the invention or a physiologically acceptable salt
is compounded with a physiologically acceptable vehicle, carrier,
excipient, binder, preservative, stabilizer, flavor, etc., in a
unit dosage form as called for by accepted pharmaceutical practice.
The amount of active substance in those compositions or
preparations is such that a suitable dosage in the range indicated
is obtained. The compositions are preferably formulated in a unit
dosage form, each dosage containing from about 0.1 to about 1000 mg
the desired amount of the active ingredient. The term "unit dosage
form" refers to physically discrete units suitable as unitary
dosages for human subjects and other mammals, each unit containing
a predetermined quantity of active material calculated to produce
the desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Preferably, the compound of the invention
is employed at no more than about 20 weight percent of the
pharmaceutical composition, more preferably no more than about 15
weight percent, with the balance being pharmaceutically inert
carrier(s).
[1179] To prepare compositions, one or more compounds of the
invention are mixed with a suitable pharmaceutically acceptable
carrier. Upon mixing or addition of the compound(s), the resulting
mixture may be a solution, suspension, emulsion or the like.
Liposomal suspensions may also be suitable as pharmaceutically
acceptable carriers. These may be prepared according to methods
known to those skilled in the art. The form of the resulting
mixture depends upon a number of factors, including the intended
mode of administration and the solubility of the compound in the
selected carrier or vehicle. The effective concentration is
sufficient for ameliorating at least one symptom of the disease,
disorder, or condition treated and may be empirically
determined.
[1180] Pharmaceutical carriers or vehicles suitable for
administration of the compounds provided herein include any such
carriers known to those skilled in the art to be suitable for the
particular mode of administration. In addition, the active
materials can also be mixed with other active materials that do not
impair the desired action, or with materials that supplement the
desired action or have other action. The compounds may be
formulated as the sole pharmaceutically active ingredient in the
composition or may be combined with other active ingredients.
[1181] In instances in which the compounds exhibit insufficient
solubility, methods for solubilizing compounds may be used. Such
methods are known to those of skill in this art, and include, but
are not limited to, using cosolvents, such as dimethylsulfoxide
(DMSO), using surfactants, such as Tween.RTM., or dissolution in
aqueous sodium bicarbonate. Derivatives of the compounds, such as
salts of the compounds or prodrugs of the compounds may also be
used in formulating effective pharmaceutical compositions.
[1182] The concentration of the compounds in the composition is
effective for delivery of an amount that, upon administration,
ameliorates one or more symptoms of the disorder for which the
compound is administered. Typically, the compositions are
formulated for single dosage administration.
[1183] The compounds of the invention may be prepared with carriers
that protect them against rapid elimination from the body, such as
time-release formulations or coatings. Such carriers include
controlled release formulations, such as, but not limited to,
microencapsulated delivery systems. The active compound is included
in the pharmaceutically acceptable carrier in an amount sufficient
to exert a therapeutically useful effect in the absence of
undesirable side effects on the patient treated. The
therapeutically effective concentration may be determined
empirically by testing the compounds in known in vitro and in vivo
model systems for the treated disorder.
[1184] The compositions can be enclosed in ampoules, disposable
syringes, or multiple or single dose vials made of glass, plastic,
or other suitable material. Such enclosed compositions can be
provided in kits.
[1185] The concentration of active compound in the drug composition
will depend on absorption, inactivation, and excretion rates of the
active compound, the dosage schedule, and amount administered, as
as other factors known to those of skill in the art.
[1186] The active ingredient may be administered at once, or may be
divided into a number of smaller doses to be administered at
intervals of time. It is understood that the precise dosage and
duration of treatment is a function of the disease being treated
and may be determined empirically using known testing protocols or
by extrapolation from in vivo or in vitro test data. It is to be
noted that concentrations and dosage values may also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens may be adjusted over time according to the individual need
and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
compositions.
[1187] If oral administration is desired, the compound may be
provided in a composition that protects it from the acidic
environment of the stomach. For example, the composition can be
formulated in an enteric coating that maintains its integrity in
the stomach and releases the active compound in the intestine. The
composition may also be formulated in combination with an antacid
or other such ingredient.
[1188] Oral compositions will generally include an inert diluent or
an edible carrier and may be compressed into tablets or enclosed in
gelatin capsules. For the purpose of oral therapeutic
administration, the active compound or compounds can be
incorporated with excipients and used in the form of tablets,
capsules or troches. Pharmaceutically compatible binding agents and
adjuvant materials can be included as part of the composition.
[1189] The tablets, pills, capsules, troches, and the like can
contain any of the following ingredients or compounds of a similar
nature: a binder, such as, but not limited to, gum tragacanth,
acacia, corn starch, or gelatin; an excipient such as
microcrystalline cellulose, starch, or lactose; a disintegrating
agent such as, but not limited to, alginic acid or corn starch; a
lubricant such as, but not limited to, magnesium stearate; a
gildant, such as, but not limited to, colloidal silicon dioxide; a
sweetening agent such as sucrose or saccharin; and a flavoring
agent such as peppermint, methyl salicylate, or fruit
flavoring.
[1190] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials that modify the physical form of the dosage unit, for
example, coatings of sugar or other enteric agents. The compounds
can also be administered as a component of an elixir, suspension,
syrup, wafer, chewing gum, or the like. A syrup may contain, in
addition to the active compounds, sucrose as a sweetening agent or
certain preservatives, dyes and colorings, and flavors.
[1191] The active materials can also be mixed with other active
materials that do not impair the desired action, or with materials
that supplement the desired action.
[1192] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include any of the
following components: a sterile diluent, such as water for
injection, saline solution, fixed oil, a naturally occurring
vegetable oil such as sesame oil, coconut oil, peanut oil,
cottonseed oil, and the like, or a synthetic fatty vehicle such as
ethyl oleate or the like, polyethylene glycol, glycerine, propylene
glycol, or other synthetic solvent; antimicrobial agents, such as
benzyl alcohol or methyl parabens; antioxidants, such as ascorbic
acid or sodium bisulfite; chelating agents, such as
ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,
citrates, or phosphates; and agents for the adjustment of tonicity,
such as sodium chloride or dextrose. Parenteral preparations can be
enclosed in ampoules, disposable syringes, or multiple dose vials
made of glass, plastic, or other suitable material. Buffers,
preservatives, antioxidants, and the like can be incorporated as
required.
[1193] If administered intravenously, suitable carriers include
physiological saline or phosphate buffered saline (PBS), and
solutions containing thickening and solubilizing agents, such as
glucose, polyethylene glycol, polypropyleneglycol, and mixtures
thereof. Liposomal suspensions, including tissue-targeted
liposomes, may also be suitable as pharmaceutically acceptable
carriers. These may be prepared according to methods known to those
skilled in the art. For example, liposome formulations may be
prepared as described in U.S. Pat. No. 4,522,811.
[1194] The active compounds may be prepared with carriers that
protect the compound against rapid elimination from the body, such
as time release formulations or coatings. Such carriers include
controlled release formulations, such as, but not limited to,
implants and microencapsulated delivery systems, and biodegradable,
biocompatible polymers, such as collagen, ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, polyorthoesters, polylactic
acid, and others. Methods for preparation of such formulations are
known to those skilled in the art.
Methods of the Invention
[1195] The compounds of the invention, and pharmaceutically
acceptable salts thereof, are useful for treating humans or animals
suffering from a condition characterized by a pathological form of
beta-amyloid peptide, such as beta-amyloid plaques, and for helping
to prevent or delay the onset of such a condition. For example, the
compounds are useful for treating Alzheimer's disease, for helping
prevent or delay the onset of Alzheimer's disease, for treating
patients with MCI (mild cognitive impairment) and preventing or
delaying the onset of Alzheimer's disease in those who would
progress from MCI to AD, for treating Down's syndrome, for treating
humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of
the Dutch-Type, for treating cerebral amyloid angiopathy and
preventing its potential consequences, i.e. single and recurrent
lobal hemorrhages, for treating other degenerative dementias,
including dementias of mixed vascular and degenerative origin,
dementia associated with Parkinson's disease, dementia associated
with progressive supranuclear palsy, dementia associated with
cortical basal degeneration diffuse Lewy body type Alzheimer's
disease. The compounds and compositions of the invention are
particularly useful for treating Alzheimer's disease. When treating
these diseases, the compounds of the invention can either be used
individually or in combination, as is best for the patient.
[1196] As used herein, the term "treating" means that the compounds
of the invention can be used in humans with at least a tentative
diagnosis of disease. The compounds of the invention will delay or
slow the progression of the disease thereby giving the individual a
longer and more useful life span.
[1197] The term "preventing" means that the compounds of the
invention are useful when administered to a patient who has not
been diagnosed as having or possibly having the disease at the time
of administration, but who would normally be expected to develop
the disease or be at increased risk for the disease. The compounds
of the invention will slow the development of disease symptoms,
delay the onset of the disease, or prevent the individual from
developing the disease. Preventing thus includes administration of
the compounds of the invention to those individuals thought to be
predisposed to the disease due to age, familial history, genetic or
chromosomal abnormalities, and/or due to the presence of one or
more biological markers for the disease, such as a known genetic
mutation of APP or APP cleavage products in brain tissues or
fluids.
[1198] In treating or preventing the above diseases, the compounds
of the invention are administered in a therapeutically effective
amount. The therapeutically effective amount will vary depending on
the particular compound used and the route of administration, as is
known to those skilled in the art.
[1199] In treating a patient displaying any of the diagnosed above
conditions a physician may administer a compound of the invention
immediately and continue administration indefinitely, as needed. In
treating patients who are not diagnosed as having Alzheimer's
disease, but who are believed to be at substantial risk for
Alzheimer's disease, the physician should preferably start
treatment when the patient first experiences early pre-Alzheimer's
symptoms such as, memory or cognitive problems associated with
aging. In addition, there are some patients who may be determined
to be at risk for developing Alzheimer's through the detection of a
genetic marker such as APOE4 or other biological indicators that
are predictive for Alzheimer's disease. In these situations, even
though the patient does not have symptoms of the disease,
administration of the compounds of the invention may be started
before symptoms appear, and treatment may be continued indefinitely
to prevent or delay the outset of the disease.
Modes of Administration, Dosage Forms and Amounts
[1200] The compounds of the invention can be administered orally,
parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually,
intranasally (inhalation), intrathecally, topically and rectally.
Dosage forms known to those skilled in the art are suitable for
delivery of the novel substituted amines X of the invention.
[1201] Compositions are provided that contain therapeutically
effective amounts of the compounds of the invention. The compounds
are preferably formulated into suitable pharmaceutical preparations
such as tablets, capsules, or elixirs for oral administration or in
sterile solutions or suspensions for parenteral administration.
Typically the compounds described above are formulated into
pharmaceutical compositions using techniques and procedures known
in the art.
[1202] About 1 to 500 mg of a compound or mixture of compounds of
the invention or a physiologically acceptable salt or ester is
compounded with a physiologically acceptable vehicle, carrier,
excipient, binder, preservative, stabilizer, flavor, etc., in a
unit dosage form as called for by accepted pharmaceutical practice.
The amount of active substance in those compositions or
preparations is such that a suitable dosage in the range indicated
is obtained. The compositions are preferably formulated in a unit
dosage form, each dosage containing from about 2 to about 100 mg,
more preferably about 10 to about 30 mg of the active ingredient.
The term "unit dosage from" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
[1203] To prepare compositions, one or more compounds of the
invention are mixed with a suitable pharmaceutically acceptable
carrier. Upon mixing or addition of the compound(s), the resulting
mixture may be a solution, suspension, emulsion, or the like.
Liposomal suspensions may also be suitable as pharmaceutically
acceptable carriers. These may be prepared according to methods
known to those skilled in the art. The form of the resulting
mixture depends upon a number of factors, including the intended
mode of administration and the solubility of the compound in the
selected carrier or vehicle. The effective concentration is
sufficient for lessening or ameliorating at least one symptom of
the disease, disorder, or condition treated and may be empirically
determined.
[1204] Pharmaceutical carriers or vehicles suitable for
administration of the compounds provided herein include any such
carriers known to those skilled in the art to be suitable for the
particular mode of administration. In addition, the active
materials can also be mixed with other active materials that do not
impair the desired action, or with materials that supplement the
desired action, or have another action. The compounds may be
formulated as the sole pharmaceutically active ingredient in the
composition or may be combined with other active ingredients.
[1205] Where the compounds exhibit insufficient solubility, methods
for solubilizing may be used. Such methods are known and include,
but are not limited to, using cosolvents such as dimethylsulfoxide
(DMSO), using surfactants such as Tween.RTM., and dissolution in
aqueous sodium bicarbonate. Derivatives of the compounds, such as
salts or prodrugs may also be used in formulating effective
pharmaceutical compositions.
[1206] The concentration of the compound is effective for delivery
of an amount upon administration that lessens or ameliorates at
least one symptom of the disorder for which the compound is
administered. Typically, the compositions are formulated for single
dosage administration.
[1207] The compounds of the invention may be prepared with carriers
that protect them against rapid elimination from the body, such as
time-release formulations or coatings. Such carriers include
controlled release formulations, such as, but not limited to,
microencapsulated delivery systems. The active compound is included
in the pharmaceutically acceptable carrier in an amount sufficient
to exert a therapeutically useful effect in the absence of
undesirable side effects on the patient treated. The
therapeutically effective concentration may be determined
empirically by testing the compounds in known in vitro and in vivo
model systems for the treated disorder.
[1208] The compounds and compositions of the invention can be
enclosed in multiple or single dose containers. The enclosed
compounds and compositions can be provided in kits, for example,
including component parts that can be assembled for use. For
example, a compound inhibitor in lyophilized form and a suitable
diluent may be provided as separated components for combination
prior to use. A kit may include a compound inhibitor and a second
therapeutic agent for co-administration. The inhibitor and second
therapeutic agent may be provided as separate component parts. A
kit may include a plurality of containers, each container holding
one or more unit dose of the compound of the invention. The
containers are preferably adapted for the desired mode of
administration, including, but not limited to tablets, gel
capsules, sustained-release capsules, and the like for oral
administration; depot products, pre-filled syringes, ampules,
vials, and the like for parenternal administration; and patches,
medipads, creams, and the like for topical administration.
[1209] The concentration of active compound in the drug composition
will depend on absorption, inactivation, and excretion rates of the
active compound, the dosage schedule, and amount administered as
other factors known to those of skill in the art.
[1210] The active ingredient may be administered at once, or may be
divided into a number of smaller doses to be administered at
intervals of time. It is understood that the precise dosage and
duration of treatment is a function of the disease being treated
and may be determined empirically using known testing protocols or
by extrapolation from in vivo or in vitro test data. It is to be
noted that concentrations and dosage values may also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
compositions.
[1211] If oral administration is desired, the compound should be
provided in a composition that protects it from the acidic
environment of the stomach. For example, the composition can be
formulated in an enteric coating that maintains its integrity in
the stomach and releases the active compound in the intestine. The
composition may also be formulated in combination with an antacid
or other such ingredient.
[1212] Oral compositions will generally include an inert diluent or
an edible carrier and may be compressed into tablets or enclosed in
gelatin capsules. For the purpose of oral therapeutic
administration, the active compound or compounds can be
incorporated with excipients and used in the form of tablets,
capsules, or troches. Pharmaceutically compatible binding agents
and adjuvant materials can be included as part of the
composition.
[1213] The tablets, pills, capsules, troches, and the like can
contain any of the following ingredients or compounds of a similar
nature: a binder such as, but not limited to, gum tragacanth,
acacia, corn starch, or gelatin; an excipient such as
microcrystalline cellulose, starch, or lactose; a disintegrating
agent such as, but not limited to, alginic acid and corn starch; a
lubricant such as, but not limited to, magnesium stearate; a
gildant, such as, but not limited to, colloidal silicon dioxide; a
sweetening agent such as sucrose or saccharin; and a flavoring
agent such as peppermint, methyl salicylate, or fruit
flavoring.
[1214] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials, which modify the physical form of the dosage unit, for
example, coatings of sugar and other enteric agents. The compounds
can also be administered as a component of an elixir, suspension,
syrup, wafer, chewing gum or the like. A syrup may contain, in
addition to the active compounds, sucrose as a sweetening agent and
certain preservatives, dyes and colorings, and flavors.
[1215] The active materials can also be mixed with other active
materials that do not impair the desired action, or with materials
that supplement the desired action.
[1216] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include any of the
following components: a sterile diluent such as water for
injection, saline solution, fixed oil, a naturally occurring
vegetable oil such as sesame oil, coconut oil, peanut oil,
cottonseed oil, and the like, or a synthetic fatty vehicle such as
ethyl oleate, and the like, polyethylene glycol, glycerine,
propylene glycol, or other synthetic solvent; antimicrobial agents
such as benzyl alcohol and methyl parabens; antioxidants such as
ascorbic acid and sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid (EDTA); buffers such as acetates,
citrates, and phosphates; and agents for the adjustment of tonicity
such as sodium chloride and dextrose. Parenteral preparations can
be enclosed in ampoules, disposable syringes, or multiple dose
vials made of glass, plastic, or other suitable material. Buffers,
preservatives, antioxidants, and the like can be incorporated as
required.
[1217] Where administered intravenously, suitable carriers include
physiological saline, phosphate buffered saline (PBS), and
solutions containing thickening and solubilizing agents such as
glucose, polyethylene glycol, polypropyleneglycol, and mixtures
thereof. Liposomal suspensions including tissue-targeted liposomes
may also be suitable as pharmaceutically acceptable carriers. These
may be prepared according to methods known for example, as
described in U.S. Pat. No. 4,522,811.
[1218] The active compounds may be prepared with carriers that
protect the compound against rapid elimination from the body, such
as time-release formulations or coatings. Such carriers include
controlled release formulations, such as, but not limited to,
implants and microencapsulated delivery systems, and biodegradable,
biocompatible polymers such as collagen, ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, polyorthoesters, polylactic
acid, and the like. Methods for preparation of such formulations
are known to those skilled in the art.
[1219] The compounds of the invention can be administered orally,
parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually,
intranasally (inhalation), intrathecally, topically, or rectally.
Dosage forms known to those skilled in the art are suitable for
delivery of the compounds of the invention.
[1220] Compounds of the invention may be administered enterally or
parenterally. When administered orally, compounds of the invention
can be administered in usual dosage forms for oral administration
as is known to those skilled in the art. These dosage forms include
the usual solid unit dosage forms of tablets and capsules as as
liquid dosage forms such as solutions, suspensions, and elixirs.
When the solid dosage forms are used, it is preferred that they be
of the sustained release type so that the compounds of the
invention need to be administered only once or twice daily.
[1221] The oral dosage forms are administered to the patient 1, 2,
3, or 4 times daily. It is preferred that the compounds of the
invention be administered either three or fewer times, more
preferably once or twice daily. Hence, it is preferred that the
compounds of the invention be administered in oral dosage form. It
is preferred that whatever oral dosage form is used, that it be
designed so as to protect the compounds of the invention from the
acidic environment of the stomach. Enteric coated tablets are known
to those skilled in the art. In addition, capsules filled with
small spheres each coated to protect from the acidic stomach, are
also known to those skilled in the art.
[1222] When administered orally, an administered amount
therapeutically effective to inhibit beta-secretase activity, to
inhibit A-beta production, to inhibit A-beta deposition, or to
treat or prevent AD is from about 0.1 mg/day to about 1,000 mg/day.
It is preferred that the oral dosage is from about 1 mg/day to
about 100 mg/day. It is more preferred that the oral dosage is from
about 5 mg/day to about 50 mg/day. It is understood that while a
patient may be started at one dose, that dose may be varied over
time as the patient's condition changes.
[1223] Compounds of the invention may also be advantageously
delivered in a nano crystal dispersion formulation. Preparation of
such formulations is described, for example, in U.S. Pat. No.
5,145,684. Nano crystalline dispersions of HIV protease inhibitors
and their method of use are described in U.S. Pat. No. 6,045,829.
The nano crystalline formulations typically afford greater
bioavailability of drug compounds.
[1224] The compounds of the invention can be administered
parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When
administered parenterally, a therapeutically effective amount of
about 0.5 to about 100 mg/day, preferably from about 5 to about 50
mg daily should be delivered. When a depo formulation is used for
injection once a month or once every two weeks, the dose should be
about 0.5 mg/day to about 50 mg/day, or a monthly dose of from
about 15 mg to about 1,500 mg. In part because of the forgetfulness
of the patients with Alzheimer's disease, it is preferred that the
parenteral dosage form be a depo formulation.
[1225] The compounds of the invention can be administered
sublingually. When given sublingually, the compounds of the
invention should be given one to four times daily in the amounts
described above for IM administration.
[1226] The compounds of the invention can be administered
intranasally. When given by this route, the appropriate dosage
forms are a nasal spray or dry powder, as is known to those skilled
in the art. The dosage of the compounds of the invention for
intranasal administration is the amount described above for IM
administration.
[1227] The compounds of the invention can be administered
intrathecally. When given by this route the appropriate dosage form
can be a parenteral dosage form as is known to those skilled in the
art. The dosage of the compounds of the invention for intrathecal
administration is the amount described above for IM
administration.
[1228] The compounds of the invention can be administered
topically. When given by this route, the appropriate dosage form is
a cream, ointment, or patch. Because of the amount of the compounds
of the invention to be administered, the patch is preferred. When
administered topically, the dosage is from about 0.5 mg/day to
about 200 mg/day. Because the amount that can be delivered by a
patch is limited, two or more patches may be used. The number and
size of the patch is not important, what is important is that a
therapeutically effective amount of the compounds of the invention
be delivered as is known to those skilled in the art. The compounds
of the invention can be administered rectally by suppository as is
known to those skilled in the art. When administered by
suppository, the therapeutically effective amount is from about 0.5
mg to about 500 mg.
[1229] The compounds of the invention can be administered by
implants as is known to those skilled in the art. When
administering a compound of the invention by implant, the
therapeutically effective amount is the amount described above for
depot administration.
[1230] The invention here is the new compounds of the invention and
new methods of using the compounds of the invention. Given a
particular compound of the invention and a desired dosage form, one
skilled in the art would know how to prepare and administer the
appropriate dosage form.
[1231] The compounds of the invention are used in the same manner,
by the same routes of administration, using the same pharmaceutical
dosage forms, and at the same dosing schedule as described above,
for treating patients with MCI (mild cognitive impairment) and
preventing or delaying the onset of Alzheimer's disease in those
who would progress from MCI to AD, for treating Down's syndrome,
for treating humans who have Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type, for treating cerebral amyloid
angiopathy and preventing its potential consequences, i.e. single
and recurrent lobar hemorrhages, for treating other degenerative
dementias, including dementias of mixed vascular and degenerative
origin, dementia associated with Parkinson's disease, dementia
associated with progressive supranuclear palsy, dementia associated
with cortical basal degeneration, diffuse Lewy body type of
Alzheimer's disease.
[1232] The compounds of the invention can be used in combination,
with each other or with other therapeutic agents or approaches used
to treat or prevent the conditions listed above. Such agents or
approaches include: acetylcholine esterase inhibitors such as
tacrine (tetrahydroaminoacridine, marketed as COGNEX.RTM.),
donepezil hydrochloride, (marketed as Aricept.RTM. and rivastigmine
(marketed as Exelon.RTM.); gamma-secretase inhibitors;
anti-inflammatory agents such as cyclooxygenase II inhibitors;
anti-oxidants such as Vitamin E and ginkolides; immunological
approaches, such as, for example, immunization with A-beta peptide
or administration of anti-A-beta peptide antibodies; statins; and
direct or indirect neurotropic agents such as Cerebrolysin.RTM.,
AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and other
neurotropic agents of the future.
[1233] In addition, the compounds of the invention can also be used
with inhibitors of P-glycoprotein (P-gp). The use of P-gp
inhibitors is known to those skilled in the art. See for example,
Cancer Research, 53, 4595-4602 (1993), Clin. Cancer Res., 2, 7-12
(1996), Cancer Research, 56, 4171-4179 (1996), International
Publications WO99/64001 and WO01/10387. The important thing is that
the blood level of the P-gp inhibitor be such that it exerts its
effect in inhibiting P-gp from decreasing brain blood levels of the
compounds of the invention. To that end the P-gp inhibitor and the
compounds of the invention can be administered at the same time, by
the same or different route of administration, or at different
times. The important thing is not the time of administration but
having an effective blood level of the P-gp inhibitor.
[1234] Suitable P-gp inhibitors include cyclosporin A, verapamil,
tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate,
progesterone, rapamycin, 10,11-methanodibenzosuberane,
phenothiazines, acridine derivatives such as GF120918, FK506,
VX-710, LY335979, PSC-833, GF-102,918 and other steroids. It is to
be understood that additional agents will be found that do the same
function and are also considered to be useful.
[1235] The P-gp inhibitors can be administered orally,
parenterally, (IV, IM, IM-depo, SQ, SQ-depo), topically,
sublingually, rectally, intranasally, intrathecally and by
implant.
[1236] The therapeutically effective amount of the P-gp inhibitors
is from about 0.1 to about 300 mg/kg/day, preferably about 0.1 to
about 150 mg/kg daily. It is understood that while a patient may be
started on one dose, that dose may have to be varied over time as
the patient's condition changes.
[1237] When administered orally, the P-gp inhibitors can be
administered in usual dosage forms for oral administration as is
known to those skilled in the art. These dosage forms include the
usual solid unit dosage forms of tablets and capsules as liquid
dosage forms such as solutions, suspensions and elixirs. When the
solid dosage forms are used, it is preferred that they be of the
sustained release type so that the P-gp inhibitors need to be
administered only once or twice daily. The oral dosage forms are
administered to the patient one thru four times daily. It is
preferred that the P-gp inhibitors be administered either three or
fewer times a day, more preferably once or twice daily. Hence, it
is preferred that the P-gp inhibitors be administered in solid
dosage form and further it is preferred that the solid dosage form
be a sustained release form which permits once or twice daily
dosing. It is preferred that what ever dosage form is used, that it
be designed so as to protect the P-gp inhibitors from the acidic
environment of the stomach. Enteric coated tablets are known to
those skilled in the art. In addition, capsules filled with small
spheres each coated to protect from the acidic stomach, are also
known to those skilled in the art.
[1238] In addition, the P-gp inhibitors can be administered
parenterally. When administered parenterally they can be
administered IV, IM, depo-IM, SQ or depo-SQ.
[1239] The P-gp inhibitors can be given sublingually. When given
sublingually, the P-gp inhibitors should be given one thru four
times daily in the same amount as for IM administration.
[1240] The P-gp inhibitors can be given intranasally. When given by
this route of administration, the appropriate dosage forms are a
nasal spray or dry powder as is known to those skilled in the art.
The dosage of the P-gp inhibitors for intranasal administration is
the same as for IM administration.
[1241] The P-gp inhibitors can be given intrathecally. When given
by this route of administration the appropriate dosage form can be
a parenteral dosage form as is known to those skilled in the
art.
[1242] The P-gp inhibitors can be given topically. When given by
this route of administration, the appropriate dosage form is a
cream, ointment or patch. Because of the amount of the P-gp
inhibitors needed to be administered the patch is preferred.
However, the amount that can be delivered by a patch is limited.
Therefore, two or more patches may be required. The number and size
of the patch is not important, what is important is that a
therapeutically effective amount of the P-gp inhibitors be
delivered as is known to those skilled in the art.
[1243] The P-gp inhibitors can be administered rectally by
suppository as is known to those skilled in the art.
[1244] The P-gp inhibitors can be administered by implants as is
known to those skilled in the art.
[1245] There is nothing novel about the route of administration nor
the dosage forms for administering the P-gp inhibitors. Given a
particular P-gp inhibitor, and a desired dosage form, one skilled
in the art would know how to prepare the appropriate dosage form
for the P-gp inhibitor.
[1246] It should be apparent to one skilled in the art that the
exact dosage and frequency of administration will depend on the
particular compound administered, the particular condition being
treated, the severity of the condition being treated, the age,
weight, general physical condition of the particular patient, other
medication the individual may be taking as is known to those
skilled in the art.
[1247] The invention provides compounds, compositions, and methods
for inhibiting beta-secretase enzyme activity and A-beta peptide
production. Inhibition of beta-secretase enzyme activity halts or
reduces the production of A-beta from APP and reduces or eliminates
the formation of beta-amyloid deposits in the brain.
[1248] The invention provides compounds, compositions, kits, and
methods for inhibiting beta-secretase enzyme activity and A-beta
peptide production. Inhibition of beta-secretase enzyme activity
halts or reduces the production of A-beta from APP and reduces or
eliminates the formation of beta-amyloid deposits in the brain.
[1249] The invention provides compounds that are useful in treating
and preventing Alzheimer's disease. The compounds of the invention
are made by methods known to those skilled in the art from starting
materials either known to those skilled in the art, commercially
available and/or that can be prepared readily using literature
methods. The process chemistry is known to those skilled in the
art. A general process to prepare the compounds of formula X is set
forth in SCHEME A. The chemistry is straight forward and in summary
involves the steps of N-protecting the amino acid (I) starting
material to produce the corresponding protected amino acid (II),
reaction of the protected amino acid (II) with diazomethane
followed by work-up as described below to add a carbon atom to
produce the corresponding protected compound (III), reduction of
the protected halide to the corresponding alcohol (IV), formation
of the corresponding epoxide (V), opening of the epoxide (V) with a
C-terminal amine, R.sub.C--NH.sub.2 (VI) to produce the
corresponding protected alcohol (VII) which then has the nitrogen
protecting group removed to produce the corresponding amine (VIII),
which is then reacted with an amide forming agent such as, for
example, (R.sub.N--).sub.2O or R.sub.N--X or R.sub.N--OH (IX) to
produce the compounds of formula X. One skilled in the art will
appreciate that these are all known reactions in organic chemistry.
A chemist skilled in the art, knowing the chemical structure of the
biologically active substituted amine end product X of the
invention would be able to prepare them by known methods from known
starting materials without any additional information. The
explanation below therefore is not necessary but is deemed helpful
to those skilled in the art who desire to make the compounds of the
invention.
[1250] The backbone of the compounds of the invention can be
considered a hydroxyethylamine moiety, --NH--CH(R)--CH(OH)--. It
can be prepared by methods disclosed in the literature and known to
those skilled in the art. For example, J. Med. Chem., 36, 288-291
(1993), Tetrahedron Letters, 28, 5569-5572 (1987), J. Med. Chem.,
38, 581-584 (1995) and Tetrahedron Letters, 38, 619-620 (1997) and
WO 02/02506 all disclose processes to prepare hydroxyethylamine
type compounds and/or their intermediates.
[1251] SCHEME A sets forth a general method used in the invention
to prepare the appropriately substituted amines X. The compounds of
the invention are prepared by starting with the corresponding amino
acid (I). The amino acids (I) are known to those skilled in the art
or can be readily prepared by methods known to those skilled in the
art. The compounds of the invention have at least two chiral
centers, which give 2 sets of diastereomers, each of which is
racemic for a total of at least four stereoisomers. While
biologically active end products result from all stereoisomers, the
(S,R) configuration is preferred. The first of these chiral centers
(the carbon carrying R.sub.1) derives from the amino acid starting
material (I). It is preferred to commercially obtain or produce the
desired enantiomer rather than produce an enantiomerically impure
mixture and then have to separate out the desired enantiomer. Thus
it is preferred to start the process with enantiomerically pure
(S)-amino acid (I) of the same configuration as that of the desired
X product.
[1252] In Scheme A, the protection of free amine (I) to produce the
(S)-protected amino acid (II) is depicted. Amino protecting groups
are known to those skilled in the art. See for example, "Protecting
Groups in Organic Synthesis", John Wiley and sons, New York, N.Y.,
1981, Chapter 7; "Protecting Groups in Organic Chemistry", Plenum
Press, New York, N.Y., 1973, Chapter 2. The function of the amino
protecting group is to protect the free amino functionality
(--NH.sub.2) during subsequent reactions on the (S)-amino acid (I)
which would not proceed either because the amino group would react
and be functionalized in a way that is inconsistent with its need
to be free for subsequent reactions or the free amino group would
interfere in the reaction. When the amino protecting group is no
longer needed, it is removed by methods known to those skilled in
the art. By definition the amino protecting group must be readily
removable as is known to those skilled in the art by methods known
to those skilled in the art. Suitable amino PROTECTING GROUPs
include t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,
phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,
iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,
4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,
4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,
2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,
4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,
2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,
1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,
2-(p-toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,
1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,
1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl,
2-(4-toluoylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobrornyloxycarbonyl, 1-piperidyloxycarbonyl, 9-fluoroenylmethyl
carbonate, --CH--CH.dbd.CH.sub.2 and phenyl-C--(.dbd.N--)--H.
[1253] It is preferred that the protecting group be
t-butoxycarbonyl (BOC) and/or benzyloxycarbony (CBZ), it is more
preferred that the protecting group be t-butoxycarbonyl. One
skilled in the art will understand the preferred methods of
introducing a t-butoxycarbonyl or benzyloxycarbonyl protecting
group and may additionally consult T. W. Green and P. G. M. Wuts in
"Protective Groups in Organic Chemistry, John Wiley and Sons, 1991
for guidance.
[1254] The (S)-protected amino acid (II) is transformed to the
corresponding (S)-protected compound (III) by two different methods
depending on nature of R.sub.2 and R.sub.3.
[1255] R.sub.2 and R.sub.3 can be the same or different. It is
preferred that R.sub.2 and R.sub.3 both be --H. If R.sub.2 and
R.sub.3 are not the same, an additional chiral or stereogenic
center is added to the molecule. To produce compounds of formula
(III) where R.sub.2 and R.sub.3 are both --H, the (S)-protected
amino acid (II) is reacted with diazomethane, as is known to those
skilled in the art, followed by reaction with a compound of the
formula H--X.sub.1 to produce the (S)-protected compound (III).
X.sub.1 includes --Cl, --Br, --I, --O-tosylate, --O-mesylate,
--O-nosylate and --O-brosylate. It is preferred that --X.sub.1 be
--Br or --Cl. Suitable reaction conditions include running the
reaction in inert solvents, such as but not limited to ether,
tetrahydrofuran and the like. The reactions from the (S)-protected
amino acid (II) to the (S)-protected compound (III) are carried out
for a period of time between 10 minutes and 1 day and at
temperatures ranging from about -78.degree. to about 20-25.degree..
It is preferred to conduct the reactions for a period of time
between 1-4 hours and at temperatures between -30.degree. to
-10.degree.. This process adds one methylene group.
[1256] Alternatively, the (S)-protected compounds of formula (III)
can be prepared by first converting the (S)-protected amino acid
(II) to a corresponding methyl or ethyl ester, according to methods
established in the art, followed by treatment with a reagent of
formula X.sub.1--C(R.sub.2)(R.sub.3)--X.sub.1 and a strong metal
base. The base serves to affect a halogen-metal exchange, where the
--X.sub.1 undergoing exchange is a halogen selected from chlorine,
bromine or iodine. The nucleophilic addition to the ester
derivative gives directly the (S)-protected compound (III).
Suitable bases include, but are not limited to the alkyllithiums
including, for example, sec-butyllithium, n-butyllithium, and
t-butyllithium. The reactions are preferably conducted at low
temperature, such as -78.degree.. Suitable reaction conditions
include running the reaction in inert solvents, such as but not
limited to, ether, tetrahydrofuran and the like. Where R.sub.2 and
R.sub.3 are both hydrogen, then examples of
X.sub.1--C(R.sub.2)(R.sub.3)--X.sub.1 include dibromomethane,
diiodomethane, chloroiodomethane, bromoiodomethane and
bromochloromethane. One skilled in the art knows the preferred
conditions required to conduct this reaction. Furthermore, if
R.sub.2 and/or R.sub.3 are not --H, then by the addition of
--C(R.sub.2)(R.sub.3)--X.sub.1 to esters of the (S)-protected amino
acid (II) to produce the (S)-protected compound (III), an
additional chiral center will be incorporated into the product,
provided that R.sub.2 and R.sub.3 are not the same.
[1257] The (S)-protected compound (III) is then reduced by means
known to those skilled in the art for reduction of a ketone to the
corresponding secondary alcohol affording the corresponding alcohol
(IV). The means and reaction conditions for reducing the
(S)-protected compound (III) to the corresponding alcohol (IV)
include, for example, sodium borohydride, lithium borohydride,
borane, diisobutylaluminum hydride, and lithium aluminium hydride.
Sodium borohydride is the preferred reducing agent. The reductions
are carried out for a period of time between 1 hour and 3 days at
temperatures ranging from -78.degree. to elevated temperature up to
the reflux point of the solvent employed. It is preferred to
conduct the reduction between -78.degree. and 0.degree.. If borane
is used, it may be employed as a complex, for example,
borane-methyl sulfide complex, borane-piperidine complex, or
borane-tetrahydrofuran complex. The preferred combination of
reducing agents and reaction conditions needed are known to those
skilled in the art, see for example, Larock, R. C. in Comprehensive
Organic Transformations, VCH Publishers, 1989. The reduction of the
(S)-protected compound (III) to the corresponding alcohol (IV)
produces the second chiral center (third chiral center if R.sub.2
and R.sub.3 are not the same). The reduction of the (S)-protected
compound (III) produces a mixture of enantiomers at the second
center, (S, R/S)-alcohol (IV). This enantiomeric mixture is then
separated by means known to those skilled in the art such as
selective low-temperature recrystallization or chromatographic
separation, for example by HPLC, employing commercially available
chiral columns. The enantiomer that is used in the remainder of the
process of SCHEME A is the (S,S)-alcohol (IV) since this enantiomer
will give the desired biologically active anti-Alzheimer
(S,R)-substituted amine X.
[1258] The (S,S)-alcohol (IV) is transformed to the corresponding
epoxide (V) by means known to those skilled in the art. The
stereochemistry of the (S)-(IV) center is maintained in forming the
epoxide (V). A preferred means is by reaction with base, for
example, but not limited to, hydroxide ion generated from sodium
hydroxide, potassium hydroxide, lithium hydroxide and the like.
Reaction conditions include the use of C.sub.1-C.sub.6 alcohol
solvents; ethanol is preferred. A common co-solvent, such as for
example, ethyl acetate may also be employed. Reactions are
conducted at temperatures ranging from -45.degree. up to the reflux
temperature of the alcohol employed; preferred temperature ranges
are between -20.degree. and 40.degree..
[1259] An alternative, and preferable process for preparing the
epoxide (V) when R.sub.1 is 3,5-difluorobenzyl, is set forth in
SCHEME E. The first step of the process is to protect the free
amino group of the (S)-amino acid (I) with an amino protecting
group, PROTECTING GROUP, as previously discussed to produce the
(S)-protected amino acid (II).
[1260] In the alternative process, the (S)-protected amino acid (I)
is transformed to the corresponding (S)-protected ester (XVII) in
one of a number of ways. One method involves the use of lithium
hydroxide. Using lithium hydroxide, the (S)-protected amino acid
(I) and the lithium hydroxide are mixed and cooled to from about
-20.degree. to about 10.degree.. Next a methylating agent, selected
from the group consisting of dimethylsulfate, methyl iodide and
methyl triflate, is added. It is more preferred that the
methylating agent is dimethylsulfate. This is followed by heating
to from about 20.degree. to about 50.degree..
[1261] Alternatively, the (S)-protected amino acid (I) is contacted
with a weak base such as bicarbonate or preferably carbonate. This
is followed by addition of the methylating agent. Heat is not
necessary but can be used to facilitate the reaction. The carbonate
method is known to those skilled in the art. For those
(S)-protected esters (XVII) where Z.sub.1 is not methyl, one
skilled in the art knowing the chemical structure would know how to
prepare the desired compounds from known starting materials. In one
known method the (S)-protected amino acid (I) is contacted with an
activating agent, such as DCC, followed addition of the appropriate
alcohol, Z.sub.1-OH. This method is operable when Z.sub.1 is
C.sub.1-C.sub.4 alkyl (optionally substituted),
--CH.sub.2--CH.dbd.CH.sub.2 or phenyl (optionally substituted).
[1262] SCHEME F and PREPARATIONS 10 and 11 set forth an alternative
process for the preparation of the ester (II). In the process of
SCHEME F, the aldehyde (XX), which is known to those skilled in the
art, is reacted with the phosphorous compound (XXI), where X.sub.3
is a good leaving group, to produce the olefin (XXI). The
phosphorous compounds (XXI) are known to those skilled in the art.
It is preferred that X.sub.3 is C.sub.1-C.sub.3 alkyl; it is more
preferred that X.sub.3 is C.sub.1 alkyl. The aldehyde (XX) and the
phosphate (XXI) are combined in an organic solvent then cooled to
about 0.degree.. A base such as DBU or TMG is added and the
contents of the reaction mixture are warmed to about 20-25.degree.
and stirred until the reaction is complete. Once the reaction is
complete, it is preferred to separate the E- and Z-olefin isomers
(XXII). The separation is done by methods known to those skilled in
the art, such as by silica gel chromatography. Next the olefin
(XXII) is hydrogenated with a suitable hydrogenation catalyst to
obtain the desired ester (II). Some hydrogenation reactions will
give racemic ester (II). The desired stereochemistry of the ester
(II) is (S)--, and therefore it is preferable to use the Z-olefin
(XXII) with a hydrogenation catalyst. It is preferred that the
hydrogenation catalyst is a compound of the formula
[Rh(diene)L].sup.+X.sup.-
[1263] where Rh is rhodium;
[1264] where diene is cyclootediene and nonbornadiene;
[1265] where L is DIPMAP, MeDuPhos, EtDuPhos, Binaphane,
f-Binaphane, Me-KetalPhos, Me-f-KetalPhos, BINAP, DIOP, BPPFA,
BPPM, CHIRAPHOS, PROPHOS, NORPHOS, CYCLOPHOS, BDPP, DEGPHOS, PNNP
and where X.sup.- is ClO.sub.4.sup.-, BF.sub.4.sup.-,
CF.sub.3--SO.sub.3.sup.-, Cl.sup.-, Br.sup.-, PF.sub.6.sup.- and
SbF.sub.6.sup.-. It is preferred that the hydrogenation catalyst be
either DIPMAP or EtDuPhos. Suitable solvents include polar solvents
such as alcohols, preferably C.sub.1-C.sub.5 alcohols and THF, more
preferably methanol, ethanol, isopropanol and THF. The chiral
hydrogenation is performed in a temperature range of from about
-20.degree. to about reflux. It is preferred that the reaction be
performed in the temperature range from about 0.degree. to about
room temperature (25.degree.). The chiral hydrogenation is
performed under a pressure of from about one atmosphere to about
100 psig; it is more preferred that the chiral hydrogenation be
performed under a pressure of from about 10 psig to about 40
psig.
[1266] The (S)-protected ester (II) is then transformed to the
corresponding (S)-protected ketone (III) by reaction with a slight
excess of a compound of the formula CH.sub.2ClX.sup.2 where X.sup.2
is --Br and --I in one of two different ways. In one process, no
exogenous nucleophile is used. That process requires (1) the
presence of three or more equivalents of strong base which has a
pK.sub.b of greater than about 30 followed by (2) adding acid. The
other process requires (1) the presence of about 2 to about 2.5
equivalents of strong base which has a pK.sub.b of greater than
about 30, (2) contacting the mixture of step (1) with about 1 to
about 1.5 equivalents of an exogenous nucleophile and (3) adding
acid. Suitable strong bases are those which has a pK.sub.b of
greater than about 30. It is preferred that the strong base be
selected from the group consisting of LDA, LiHMDS and KHMDS; it is
more preferred that the strong base be LDA. Suitable acids are
those, which have a pk.sub.a of less than about 10. It is preferred
the acid be selected from the group consisting of acetic, sulfuric,
hydrochloric, citric, phosphoric and benzoic acids; it is more
preferred that the acid be acetic acid. The preferred solvent for
the process is THF. The reaction can be performed in the
temperature range from about -80.degree. to about -50.degree.; it
is preferred to perform the reaction in the temperature range of
from about -75.degree. to about -65.degree.. Suitable nucleophiles
include alkyl lithium, aryl lithium, alkyl-Grignard and
aryl-Grignard reagents. It is preferred that the nucleophile be
selected from the group consisting of phenyl lithium, n-butyl
lithium, methyl magnesium bromide, methyl magnesium chloride,
phenyl magnesium bromide, phenyl magnesium chloride; it is more
preferred that the nucleophile be n-butyl lithium. PREPARATION 2
discloses the process with no nucleophile and PREPARATION 16
discloses the process with an exogenous nucleophile.
[1267] The (S)-protected ketone (III) is then reduced to the
corresponding (S)-alcohol (IV) by means known to those skilled in
the art for reduction of a ketone to the corresponding secondary
alcohol. The means and reaction conditions for reducing the
(S)-protected compound (III) to the corresponding alcohol (IV)
include, for example, sodium borohydride, lithium borohydride,
borane, diisobutylaluminum hydride, zinc borohydride and lithium
aluminium hydride. Sodium borohydride is the preferred reducing
agent. The reductions are carried out for a period of time between
about 1 hour and about 3 days at temperatures ranging from about
-78.degree. to elevated temperature up to the reflux point of the
solvent employed. It is preferred to conduct the reduction between
about -78.degree. and about 0.degree.. If borane is used, it may be
employed as a complex, for example, borane-methyl sulfide complex,
borane-piperidine complex, or borane-tetrahydrofuran complex. The
preferred combination of reducing agents and reaction conditions
needed are known to those skilled in the art, see for example,
Larock, R. C. in Comprehensive Organic Transformations, VCH
Publishers, 1989. The reduction of the (S)-protected compound (III)
to the corresponding alcohol (IV) produces a second chiral center.
The reduction of the (S)-protected compound (III) produces a
mixture of diastereomers at the second center, (S, R/S)-alcohol
(IV). This diastereomeric mixture is then separated by means known
to those skilled in the art such as selective low-temperature
recrystallization or chromatographic separation, most preferably by
recrystallization or by employing commercially available chiral
columns. The diastereomer that is used in the remainder of the
process of SCHEME A is the (S,S)-alcohol (IV) since this
stereochemistry will give the desired epoxide (V).
[1268] The alcohol (IV) is transformed to the corresponding epoxide
(V) by means known to those skilled in the art. The stereochemistry
of the (S)-(IV) center is maintained in forming the epoxide (V). A
preferred means is by reaction with base, for example, but not
limited to, hydroxide ion generated from sodium hydroxide,
potassium hydroxide, lithium hydroxide and the like. Reaction
conditions include the use of C.sub.1-C.sub.6 alcohol solvents;
ethanol is preferred. A common co-solvent, such as for example,
ethyl acetate may also be employed. Reactions are conducted at
temperatures ranging from about -45.degree. up to the reflux
temperature of the alcohol employed; preferred temperature ranges
are between about -20.degree. and about 40.degree.. The epoxide (V)
is then reacted with the appropriately substituted C-terminal
amine, R.sub.C--NH.sub.2 (VI) by means known to those skilled in
the art which opens the epoxide to produce the desired
corresponding enantiomerically pure (S,R)-protected alcohol (VII).
The substituted C-terminal amines, R.sub.C--NH.sub.2 (VI) of this
invention are commercially available or are known to those skilled
in the art and can be readily prepared from known compounds. It is
preferred that when R.sub.C is phenyl, it is substituted in the
3-position or 3,5-positions.
[1269] Suitable reaction conditions for opening the epoxide (V)
include running the reaction in a wide range of common and inert
solvents. C.sub.1-C.sub.6 alcohol solvents are preferred and
isopropyl alcohol most preferred. The reactions can be run at
temperatures ranging from 20-25.degree. up to the reflux
temperature of the alcohol employed. The preferred temperature
range for conducting the reaction is between 50.degree. up to the
reflux temperature of the alcohol employed. When the substituted
C-terminal amine (VI) is a 1-amino-3,5-cis-dimethyl
cyclohexyldicarboxylate it is preferably prepared as follows. To
dimethyl-5-isophthalate in acetic acid and methanol, is added
rhodium in alumina in a high-pressure bottle. The bottle is
saturated with hydrogen at 55 psi and shaken for one week of time.
The mixture is then filtered through a thick layer of celite cake
and rinsed with methanol three times, the solvents are removed
under reduced pressure (with heat) to give a concentrate. The
concentrate is triturated with ether and filtered again to give the
desired C-terminal amine (VI). When the substituted C-terminal
amine (VI) is 1-amino-3,5-cis-dimethoxy cyclohexane it is
preferably following the general procedure above and making
non-critical variations but starting with 3,5-dimethoxyaniline.
[1270] When the substituted C-terminal amine (VI) is an aminomethyl
group where the substituent on the methyl group is an aryl group,
for example NH.sub.2--CH.sub.2-aryl, is not commercially available
it is preferably prepared as follows. A suitable starting material
is the (appropriately substituted) aralkyl compound. The first step
is bromination of the alkyl substituent via methods known to those
skilled in the art, see for example R. C. Larock in Comprehensive
Organic Transformations, VCH Publishers, 1989, p. 313. Next the
alkyl halide is reacted with azide to produce the
aryl-(alkyl)-azide. Last the azide is reduced to the corresponding
amine by hydrogen/catalyst to give the C-terminal amine (VI) of
formula NH.sub.2--CH.sub.2--R.sub.C-aryl.
[1271] SCHEME B discloses an alternative process for production of
the enantiomerically pure (S,R)-protected alcohol (VII) from the
(S)-protected compound (III). In the alternative process, the
(S)-protected compound (III) is first reacted with the
appropriately substituted C-terminal amine R.sub.C--NH.sub.2 (VI)
using the preferred conditions described above to produce the
corresponding (S)-protected ketone (XI) which is then reduced using
the preferred conditions described above to produce the
corresponding (S,R)-protected alcohol (VII).
[1272] SCHEME C discloses another alternative process for
production of enantiomerically pure (S,R)-protected alcohol (VII)
but this time from the epoxide (V). In the process of SCHEME C, the
epoxide (V) is reacted with azide to produce the corresponding
enantiomerically pure (S,R)-protected azide (XII). Conditions to
conduct the azide mediated epoxide opening are known to those
skilled in the art, see for example, J. March, Advanced Organic
Chemistry, 3.sup.rd Edition, John Wiley & Sons Publishers,
1985, p. 380. Next, the (S,R)-protected azide (XII) is reduced to
the corresponding protected amine (XIII) by methods known to those
skilled in the art. Preferred reducing conditions to reduce the
(S,R)-protected azide (XII) in the presence of a t-butoxycarbonyl
N-protecting group include catalytic hydrogenation, the conditions
for which are known to those skilled in the art. Alternative
reducing conditions which may be used to avoid N-deprotection with
protecting groups other than t-butoxycarbonyl are known to those
skilled in the art, see for example, R. C. Larock in Comprehensive
Organic Transformations, VCH Publishers, 1989, p. 409.
[1273] The (S,R)-protected alcohol (VII) is deprotected to the
corresponding (S,R)-amine (VIII) by means known to those skilled in
the art for removal of amine protecting group. Suitable means for
removal of the amine protecting group depends on the nature of the
protecting group. Those skilled in the art, knowing the nature of a
specific protecting group, know which reagent is preferable for its
removal. For example, it is preferred to remove the preferred
protecting group, BOC, by dissolving the (S,R)-protected alcohol
(VII) in a trifluoroacetic acid/dichloromethane (1/1) mixture. When
complete, the solvents are removed under reduced pressure to give
the corresponding (S,R)-amine (as the corresponding salt, i.e.
trifluoroacetic acid salt) which is used without further
purification. However, if desired, the (S,R)-amine can be purified
further by means known to those skilled in the art, such as for
example, recrystallization. Further, if the non-salt form is
desired that also can be obtained by means known to those skilled
in the art, such as for example, preparing the free base amine via
treatment of the salt with mild basic conditions. Additional BOC
deprotection conditions and deprotection conditions for other
protecting groups can be found in T. W. Green and P. G. M. Wuts in
"Protective Groups in Organic Chemistry, John Wiley and Sons, 1991,
p. 309. Suitable chemically suitable salts include
trifluoroacetate, and the anion of mineral acids such as chloride,
sulfate, phosphate; preferred is trifluoroacetate.
[1274] The (S,R)-amine (VIII) is then reacted with an appropriately
substituted amide forming agent (IX) such as, for example, an
anhydride, acyl halide, or acid of the formulas (R.sub.N).sub.2O or
R.sub.NX or R.sub.NOH (IX) respectively, by means known to those
skilled in the art to produce the corresponding (S,R)-substituted
amine X. Nitrogen acylation conditions for reaction of the
(S,R)-amine (VIII) with an amide forming agent (IX) to produce the
corresponding (S,R)-substituted amine X are known to those skilled
in the art and can be found in R. C. Larock in Comprehensive
Organic Transformations, VCH Publishers, 1989, p. 981, 979, and
972.
[1275] The nitrogen-acylation of primary amines to produce
secondary amides is a known reaction. Amide forming agents,
(R.sub.N).sub.2O, R.sub.NX, and R.sub.NOH (IX) (which are acid
anhydrides, acid halides and acids respectively) are known to those
skilled in the art and are commercially available or can be readily
prepared from known starting materials by methods known in the
literature.
[1276] SCHEME D sets forth an alternative processes for production
of the (S,R)-substituted amine X from the (S,R)-protected azide
(XII), which is produced from the corresponding epoxide (V) in
SCHEME C. The amino protecting group is removed to produce the
corresponding unprotected azide (XIV) by methods previously
described in SCHEME A for the conversion of (S,R)-protected alcohol
(VII) to the corresponding (S,R)-amine (VIII). The
(S,R)-unprotected azide (XIV) is then acylated on nitrogen to
produce the corresponding (S,R)-azide (XV). Next, the azide
functionality is reduced as previously discussed for the conversion
of the (S,R)-protected azide (XII) to the corresponding
(S,R)-protected amine (XIII) to give the (S,R)-free amine (XVI).
Last, the (S,R)-free amine (XVI) is transformed to the
corresponding (S,R)-substituted amine X by nitrogen alkylation with
a compound of the formula R.sub.C--X.sub.3 to give the
corresponding (S,R)-substituted amine X. X.sub.3 is an appropriate
leaving group, such as but not limited to, --Cl, --Br, --I,
--O-mesylate, --O-tosylate, O-triflate, etc. X.sub.3 may also be an
aldehyde; the corresponding coupling with (XVI) via the known
reductive amination procedure gives the (S,R)-substituted amine
X.
[1277] SCHEME G discloses an alternative, and preferable, process
for preparing the substituted amines X from the corresponding
protected alcohol (VII). The corresponding protected alcohol (VII)
which then has the unprotected amino group protected with an amino
PROTECTING GROUP, as previously discussed, to form the diprotected
diamine (XXXIV). The diprotected diamine (XXXIV) has the protecting
group at the N-terminal end then removed, as previously discussed,
to form the monoprotected diamine (XXXV) which is then reacted with
an amide forming agent (IX), as discussed above to produce the
coupled product (XXXVI). Upon removal of the remaining protecting
group from the coupled product (XXXVI), the desired
(S,R)-substituted amine X is produced.
[1278] SCHEME H discloses a process for the preparation of a
racemic amide forming agent (IX-XLI) where for R.sub.N, R.sub.4 is
--NH--R.sub.4-1, n.sub.7 is 0; X is --CH.sub.2--; Z is either
--SO-- or --SO.sub.2-- and ultimately the substituted amines
(X-XLV) and (X-XLVI). The process of SCHEME H begins with the
alcohol (XXXVII) where X.sub.4 is C.sub.1-C.sub.4 alkyl or phenyl.
The alcohol (XXXVII) has the alcohol group converted to a good
LEAVING GROUP which includes tosylate, mesylate, nosylate and other
groups known to those skilled in the art as "leaving groups" to
produce the LEAVING GROUP-alcohol compound (XXXVIII). The LEAVING
GROUP is replaced by the group Y--S-- by reaction with a mercaptan
to prepare the thiol ether (XXXIX) by means known to those skilled
in the art. The thiol ether (XXXIX) is then converted to the
corresponding sulfone acid (XL) by hydrolysis of the ester group.
The thiol acid is then oxidized to the corresponding sulfone acid
(XLI). Should it be desired that Z be --SO-- rather than
--SO.sub.2--, only one equivalent of oxidizing agent, rather than
two equivalents, is used to produce the sulfoxide (--SO--) rather
then the sulfone (--SO.sub.2--) as is known to those skilled in the
art. Since the remainder of the process chemistry for SCHEME H is
the same regardless of whether Z is --SO-- or --SO.sub.2-- for
simplicity, only --SO.sub.2-- will be illustrated and referred to.
However, the explanation is equally relevant for --SO-- as is
apparent to one skilled in the art. Next, the sulfone acid (XLI) is
reacted with the monoprotected diamine (XXXV of SCHEME G) to
produce the diprotected coupled intermediate (XLII). The
diprotected coupled product (XLII) then has the PROTECTING GROUP on
the R.sub.N group (preferably BOC) selectively removed to give the
monoprotected compound (XLIII). This selective removal of a
PROTECTING GROUP is known to those skilled in the art and is
referred to as "orthonigally protected". The monoprotected compound
(XLIII) then can be selectively deprotected to give the
corresponding --NH--R.sub.4-1. To give the corresponding amine
substituted intermediate (XLIV). The amine substituted intermediate
(XLIV) is then has the remaining PROTECTING GROUP (preferrably CBZ)
removed by hydrogenation to give the substituted amine (X-XLV).
Alternatively, the diprotected coupled intermediate (XLII) can have
both PROTECTING GROUPS removed to produce the corresponding sulfone
substituted amine (X-XLVI) by heating in a strong acid such as
hydrochloric acid.
[1279] SCHEME I discloses a process for the preparation of
enantiomerically pure thiol acid (XLIX) whereas SCHEME H disclosed
a process to produce racemic thiol acid (XL). The stereoselective
process of SCHEME I begins with the optically pure acid (XLVII)
which is coverted to the lactone (XLVIII) by Mitsunobu dehydration.
The lactone (XLVII) is converted to the corresponding optically
pure thiol (XLIX) by reaction of the thiol with sodium hydride in
THF. The optically pure thiol (XLIX) is then oxidized as explained
in SCHEME H to produce the corresponding sulfoxide (--SO--) or
sulfone (--SO.sub.2--). As with SCHEME H, only the sulfone has been
carried thru by exemplification. However, the exact same process
chemistry would be used to prepare the corresponding sulfoxide
substitutes amines (X-LIV) as was explained with regards to SCHEME
H.
[1280] SCHEME J discloses a process for the preparation of
substituted amines X where in the variable substitutent R.sub.N,
R.sub.4 is (III), --(CH.sub.2).sub.1-4--R.sub.4-1, where only one
methylene group is present and R.sub.4 is (G) giving for R.sub.4,
--CH.sub.2--CO--NR.sub.4-3R.sub.4-4 or (M) --CH.sub.2--CO--OH. The
process of SCHEME J begins with the cyclic compound (LV) which is
opened by the appropriate alcohol, as is known to those skilled in
the art, to give the olefin acid (LVI) where X.sub.4 is as defined
above. The olefin acid (LVI) is then transformed to the
corresponding diester, preferably the activated ester (LVII) by
means known to those skilled in the art. Next the Y--S-- group is
added to the double bond producing the thiol ester (LVIII) by
Michael reaction with the appropriate thiol in methanol with
triethylamine. The thiol ester (LVIII) is then converted to the
corresponding acid and then reacted with the appropriate amine
(VIII) to produce the protected thiol (LIX) as previously
explained. This diester (LVIII) can be selectively coupled with the
amine to give the protected sulfide ester (LIX). This sulfide ester
(LIX) can be hydrolyzed under standard conditions (lithium
hydroxide/THF/water) to give the sulfide acid (LX). Oxidation of
the sulfide acid (LX) to the sulfoxide or sulfone is performed as
previously stated to give the protected sulfone acid (LXI). If
desired, the protected sulfone acid (LXI) can be converted to an
amide by simple peptide coupling with the desired amine to give the
sulfone amide (LXII). The sulfone amide (LXII) illustrates the
methylamine. Simple deprotection of the R.sub.C protecting group
with an appropriate deprotecting agent is know by one skilled in
the art and gives the sulfone-amide substituted amine
(X-LXIII).
[1281] SCHEME K discloses an alternative and preferred process to
transform the cyclic compound (LV) to the corresponding protected
sulfone acid (LXI). The process of SCHEME K replaces the X.sub.4
protecting group with a specific protecting group p-methoxybenzyl.
The advantage of this group is that it, as as the PROTECTING GROUP
on the amine nitrogen, both can be removed in one step, by
hydrogenation, when the PROTECTING GROUP is CBZ.
[1282] Scheme L discloses a process to prepare aminomethylene
derivatives. The allylic halide (LXXI), preferably bromide, is
reacted with a protected amine like phthalimide to give the
N-protected amino acrylate (LXXII). The acrylate (LXXII) is reacted
with the appropriate thiol, as previously described, to give the
Michael product (LXXIII). Base hydrolysis of the sulfide ester
(LXXIII) gives the acid (LXXIV) which is reacted with the amine
(IX) as previously described to give the orthogonally protected
compound (LXXV). The protecting group is removed from the protected
compound (LXXV) with hydrazine to give the free amine (LXXVI) which
is either acylated, X is --C(O)R to give an amide, or reacted with
a mixed carbonate, X is --C(O)OR to give a carbamate (LXXVII). The
sulfide (LXXVII) is oxidized as previously described to give the
protected sulfone (LXXVIII). Simple de-protection of the protected
sulfone (LXXVIII), as previously described, gives the target
sulfone substituted amine (X-LXXIX).
[1283] Scheme M discloses the preparation of a series of racemic
substituted alpha amino sulfones while Scheme N discloses the
preparation of the active enantiomer. In SCHEME M, the first step
discloses the Michael reaction of an appropriate thiol with a
protected dehydroalanine methyl ester (LXXX) to give the thio
compound (LXXXI). Oxidation as previously described gives the
corresponding sulfone (LXXXII). Hydrolysis of the ester group and
amino protecting group, such as acetate (--CO--CH.sub.3) can be
accomplished with strong acid, such as 6N hydrochloric acid--acetic
acid at elevated temperature, to give the free amino acid
hydrochloride salt (LXXXIII). Amino acid (LXXXIII) is reacted, as
the free amine or salt, with the appropriate protecting group
(preferably either CBZ or BOC) to give the protected amine
(IX-LXXXIV). Standard peptide coupling of the protected amine
(IX-LXXXIV) preferentially gives the protected sulfone (LXXXV)
which is orthogonally protected to give the diprotected sulfone
(LXXXVI). Selective removal of the R.sub.N protecting group gives
the monoprotected sulfone (LXXXVII). This monoprotected sulfone
(LXXXVII) can be converted as previously described, into amides,
carbamates and also into ureas (by reaction of the amine with the
appropriate isocyanide) and into sulfonamides by reaction with the
appropriate sulfonyl chlorides. The final step is removal of the
R.sub.C protecting group to give the corresponding desired amide
(X-LXXXIX). SCHEME N is identical to SCHEME M except it discloses
that one can separate the isomers of (IX-LXXXIV) either by
chemical, enzymatic or by chiral chromatography to yield the single
isomer acid (XC) which is transformed to final product (X-XCV) as
described above.
[1284] Scheme O illustrates several alcohols that can be used to
prepare the carbamates of the instant invention.
[1285] Scheme P illustrates one method for preparing the compounds
of the invention, starting with an enantiomerically enriched amino
acid. One of ordinary skill in the art will readily recognize that
the method described in Scheme P is equally as useful for preparing
compounds with the opposite stereochemistry or for preparing
racemic compounds.
[1286] In Scheme P, cysteine is alkylated using a base an
alkylating agent. One of ordinary skill in the art will readily
recognize that other amino acids and other methods for generating
the thioether can be used. The free amine is then converted into a
carbamate using a chloroformate. One of skill in the art will
readily recognize that the free amine may be converted into an
amide, alkylated, sulfonylated, or protected rather than being
converted into an carbamate. The carbamate nitrogen can optionally
be alkylated using a base and an alkylating agent to generate a
tertiary nitrogen. In Scheme P, the carbamate nitrogen is alkylated
with a base and an alkyl halide.
[1287] The carboxyl moiety of the starting amino acid is then
reacted with an amino compound to generate the coupled compound.
The amino compound can be achiral, a single enantiomer, racemic or
a mixture of diastereomers. The coupled product may be further
manipulated to convert the thiol into a sulfoxide, which can then
be converted into a sulfone or the thiol can be directly converted
into a sulfone. Other groups in the coupled product can, if
desired, be manipulated using methods known in the art of organic
synthesis. For example, nitrogens can be alkylated, acylated or
sulfonylated. Alcohols can be converted into esters or oxidized
into aldehydes or acids. Aryl groups can be acylated and halides
can be coupled.
[1288] One skilled in the art will appreciate that these are all
known reactions in organic chemistry. A chemist skilled in the art,
knowing the chemical structure of the biologically active end
product X of the invention would be able to prepare them by known
methods from known starting materials without any additional
information. The explanation below therefore is not necessary but
is deemed helpful to those skilled in the art who desire to make
the compounds of the invention.
[1289] The backbone of the compounds of the invention is a
hydroxyethylamine moiety, --NH--CH(R.sub.1)--CH(OH)--. It can be
readily prepared by methods disclosed in the literature and known
to those skilled in the art. For example, J. Med. Chem., 36,
288-291 (1993), Tetrahedron Letters, 28, 5569-5572 (1987), J. Med.
Chem., 38, 581-584 (1995) and Tetrahedron Letters, 38, 619-620
(1997), and WO 02/02506 all disclose processes to prepare
hydroxyethylamine type compounds and/or their intermediates.
[1290] The compounds of the invention may contain geometric or
optical isomers as tautomers. Thus, the invention includes all
tautomers and pure geometric isomers, such as the E and Z geometric
isomers, as mixtures thereof. Further, the invention includes pure
enantiomers and diastereomers as mixtures thereof, including
racemic mixtures. The individual geometric isomers, enantiomers or
diastereomers may be prepared or isolated by methods known to those
skilled in the art, including but not limited to chiral
chromatography; preparing diastereomers, separating the
diastereomers and converting the diastereomers into enantiomers
through the use of a chiral resolving agent.
[1291] Compounds of the invention with the stereochemistry
designated in formula X can be included in mixtures, including
racemic mixtures, with other enantiomers, diastereomers, geometric
isomers or tautomers. Compounds of the invention with the (S,R)
stereochemistry are typically present in these mixtures in excess
of 50 percent. Preferably, compounds of the invention with the
stereochemistry designated in formula X are present in these
mixtures in excess of 80 percent. More preferably, compounds of the
invention with the stereochemistry designated in formula X are
present in these mixtures in excess of 90 percent. Even more
preferably, compounds of the invention with the stereochemistry
designated in formula X are present in these mixtures in excess of
99 percent.
[1292] Where the compounds of formula X are amines, they form salts
when reacted with acids. Pharmaceutically acceptable salts are
preferred over the corresponding free amines since they produce
compounds which are generally more water soluble, stable and/or
more crystalline. Pharmaceutically acceptable salts are any salt
which retains the activity of the parent compound and does not
impart any deleterious or undesirable effect on the subject to whom
it is administered and in the context in which it is administered.
Pharmaceutically acceptable salts include salts of both inorganic
and organic acids. The preferred pharmaceutically acceptable salts
include salts of the following acids acetic, aspartic,
benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric,
butyric, calcium edetate, camsylic, carbonic, chlorobenzoic,
citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric,
gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic,
hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric,
hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic,
maleic, malic, malonic, mandelic, methanesulfonic, methylnitric,
methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,
p-nitromethanesulfonic, pamoic, pantothenic, phosphoric,
monohydrogen phosphoric, dihydrogen phosphoric, phthalic,
polygalactouronic, propionic, salicylic, stearic, succinic,
succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic,
tartaric, teoclic and toluenesulfonic. For other acceptable salts,
see Int. J. Pharm., 33, 201-217 (1986) and J. Pharm. Sci., 66(1),
1, (1977).
Inhibition of APP Cleavage
[1293] The compounds of the invention are believed to inhibit
cleavage of APP between Met595 and Asp596 numbered for the APP695
isoform, or a mutant thereof, or at a corresponding site of a
different isoform, such as APP751 or APP770, or a mutant thereof
(sometimes referred to as the "beta secretase site". While not
wishing to be bound by a particular theory, inhibition of
beta-secretase activity is thought to inhibit production of beta
amyloid peptide (A-beta). Inhibitory activity is demonstrated in
one of a variety of inhibition assays, whereby cleavage of an APP
substrate in the presence of a beta-secretase enzyme is analyzed in
the presence of the inhibitory compound, under conditions normally
sufficient to result in cleavage at the beta-secretase cleavage
site. Reduction of APP cleavage at the beta-secretase cleavage site
compared with an untreated or inactive control is correlated with
inhibitory activity. Assay systems that can be used to demonstrate
efficacy of the compound inhibitors of the invention are known.
Representative assay systems are described, for example, in U.S.
Pat. Nos. 5,942,400, 5,744,346, as in the Examples below.
[1294] The enzymatic activity of beta-secretase and the production
of A-beta can be analyzed in vitro or in vivo, using natural,
mutated, and/or synthetic APP substrates, natural, mutated, and/or
synthetic enzyme, and the test compound. The analysis may involve
primary or secondary cells expressing native, mutant, and/or
synthetic APP and enzyme, or may utilize transgenic animal models
expressing the substrate and enzyme. Detection of enzymatic
activity can be by analysis of one or more of the cleavage
products, for example, by immunoassay, fluorometric or chromogenic
assay, HPLC, or other means of detection. Inhibitory compounds are
determined as those having the ability to decrease the amount of
beta-secretase cleavage product produced in comparison to a
control, where beta-secretase mediated cleavage in the reaction
system is observed and measured in the absence of inhibitory
compounds.
Beta-Secretase
[1295] Various forms of beta-secretase enzyme are known, and are
available and useful for assay of enzyme activity and inhibition of
enzyme activity. These include native, recombinant, and synthetic
forms of the enzyme. Human beta-secretase is known as Beta Site APP
Cleaving Enzyme (BACE), Asp2, and memapsin 2, and has been
characterized, for example, in U.S. Pat. No. 5,744,346 and
published PCT patent applications WO98/22597, WO00/03819,
WO01/23533, and WO00/17369, as in literature publications (Hussain
et. al., 1999, Mol. Cell. Neurosci. 14:419-427; Vassar et. al.,
1999, Science 286:735-741; Yan et. al., 1999, Nature 402:533-537;
Sinha et. al., 1999, Nature 40:537-540; and Lin et. al., 2000, PNAS
USA 97:1456-1460). Synthetic forms of the enzyme have also been
described (WO98/22597 and WO00/17369). Beta-secretase can be
extracted and purified from human brain tissue and can be produced
in cells, for example mammalian cells expressing recombinant
enzyme.
[1296] Preferred compounds are effective to inhibit 50% of
beta-secretase enzymatic activity at a concentration of less than
about 50 micromolar, preferably at a concentration of less than
about 10 micromolar, more preferably less than about 1 micromolar,
and most preferably less than about 10 nanomolar.
APP Substrate
[1297] Assays that demonstrate inhibition of
beta-secretase-mediated cleavage of APP can utilize any of the
known forms of APP, including the 695 amino acid "normal" isotype
described by Kang et. al., 1987, Nature 325:733-6, the 770 amino
acid isotype described by Kitaguchi et. al., 1981, Nature
331:530-532, and variants such as the Swedish Mutation (KM670-1NL)
(APP-SW), the London Mutation (V7176F), and others. See, for
example, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature
Genet. 1:233-234, for a review of known variant mutations.
Additional useful substrates include the dibasic amino acid
modification, APP-KK disclosed, for example, in WO 00/17369,
fragments of APP, and synthetic peptides containing the
.theta.-secretase cleavage site, wild type (WT) or mutated form,
e.g., SW, as described, for example, in U.S. Pat. No. 5,942,400 and
WO00/03819.
[1298] The APP substrate contains the beta-secretase cleavage site
of APP (KM-DA or NL-DA) for example, a complete APP peptide or
variant, an APP fragment, a recombinant or synthetic APP, or a
fusion peptide. Preferably, the fusion peptide includes the
beta-secretase cleavage site fused to a peptide having a moiety
useful for enzymatic assay, for example, having isolation and/or
detection properties. A useful moiety may be an antigenic epitope
for antibody binding, a label or other detection moiety, a binding
substrate, and the like.
Antibodies
[1299] Products characteristic of APP cleavage can be measured by
immunoassay using various antibodies, as described, for example, in
Pirttila et. al., 1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No.
5,612,486. Useful antibodies to detect A-beta include, for example,
the monoclonal antibody 6E10 (Senetek, St. Louis, Mo.) that
specifically recognizes an epitope on amino acids 1-16 of the
A-beta peptide; antibodies 162 and 164 (New York State Institute
for Basic Research, Staten Island, N.Y.) that are specific for
human A-beta 1-40 and 1-42, respectively; and antibodies that
recognize the junction region of beta-amyloid peptide, the site
between residues 16 and 17, as described in U.S. Pat. No.
5,593,846. Antibodies raised against a synthetic peptide of
residues 591 to 596 of APP and SW192 antibody raised against
590-596 of the Swedish mutation are also useful in immunoassay of
APP and its cleavage products, as described in U.S. Pat. Nos.
5,604,102 and 5,721,130.
Assay Systems
[1300] Assays for determining APP cleavage at the beta-secretase
cleavage site are known in the art. Exemplary assays, are
described, for example, in U.S. Pat. Nos. 5,744,346 and 5,942,400,
and described in the Examples below.
Cell Free Assays
[1301] Exemplary assays that can be used to demonstrate the
inhibitory activity of the compounds of the invention are
described, for example, in WO00/17369, WO 00/03819, and U.S. Pat.
Nos. 5,942,400 and 5,744,346. Such assays can be performed in
cell-free incubations or in cellular incubations using cells
expressing a beta-secretase and an APP substrate having a
beta-secretase cleavage site.
[1302] An APP substrate containing the beat-secretase cleavage site
of APP, for example, a complete APP or variant, an APP fragment, or
a recombinant or synthetic APP substrate containing the amino acid
sequence: KM-DA or NL-DA, is incubated in the presence of
beta-secretase enzyme, a fragment thereof, or a synthetic or
recombinant polypeptide variant having beta-secretase activity and
effective to cleave the beta-secretase cleavage site of APP, under
incubation conditions suitable for the cleavage activity of the
enzyme. Suitable substrates optionally include derivatives that may
be fusion proteins or peptides that contain the substrate peptide
and a modification useful to facilitate the purification or
detection of the peptide or its beta-secretase cleavage products.
Useful modifications include the insertion of a known antigenic
epitope for antibody binding; the linking of a label or detectable
moiety, the linking of a binding substrate, and the like.
[1303] Suitable incubation conditions for a cell-free in vitro
assay include, for example: approximately 200 nanomolar to 10
micromolar substrate, approximately 10 to 200 picomolar enzyme, and
approximately 0.1 nanomolar to 10 micromolar inhibitor compound, in
aqueous solution, at an approximate pH of 4-7, at approximately 37
degrees C., for a time period of approximately 10 minutes to 3
hours. These incubation conditions are exemplary only, and can be
varied as required for the particular assay components and/or
desired measurement system. Optimization of the incubation
conditions for the particular assay components should account for
the specific beta-secretase enzyme used and its pH optimum, any
additional enzymes and/or markers that might be used in the assay,
and the like. Such optimization is routine and will not require
undue experimentation.
[1304] One useful assay utilizes a fusion peptide having maltose
binding protein (MBP) fused to the C-terminal 125 amino acids of
APP-SW. The MBP portion is captured on an assay substrate by
anti-MBP capture antibody. Incubation of the captured fusion
protein in the presence of beta-secretase results in cleavage of
the substrate at the beta-secretase cleavage site. Analysis of the
cleavage activity can be, for example, by immunoassay of cleavage
products. One such immunoassay detects a unique epitope exposed at
the carboxy terminus of the cleaved fusion protein, for example,
using the antibody SW192. This assay is described, for example, in
U.S. Pat. No. 5,942,400.
Cellular Assay
[1305] Numerous cell-based assays can be used to analyze
beta-secretase activity and/or processing of APP to release A-beta.
Contact of an APP substrate with a beta-secretase enzyme within the
cell and in the presence or absence of a compound inhibitor of the
invention can be used to demonstrate beta-secretase inhibitory
activity of the compound. Preferably, assay in the presence of a
useful inhibitory compound provides at least about 30%, most
preferably at least about 50% inhibition of the enzymatic activity,
as compared with a non-inhibited control.
[1306] In one embodiment, cells that naturally express
beta-secretase are used. Alternatively, cells are modified to
express a recombinant beta-secretase or synthetic variant enzyme as
discussed above. The APP substrate may be added to the culture
medium is preferably expressed in the cells. Cells that naturally
express APP, variant or mutant forms of APP, or cells transformed
to express an isoform of APP, mutant or variant APP, recombinant or
synthetic APP, APP fragment, or synthetic APP peptide or fusion
protein containing the beta-secretase APP cleavage site can be
used, provided that the expressed APP is permitted to contact the
enzyme and enzymatic cleavage activity can be analyzed.
[1307] Human cell lines that normally process A-beta from APP
provide a useful means to assay inhibitory activities of the
compounds of the invention. Production and release of A-beta and/or
other cleavage products into the culture medium can be measured,
for example by immunoassay, such as Western blot or enzyme-linked
immunoassay (EIA) such as by ELISA.
[1308] Cells expressing an APP substrate and an active
beta-secretase can be incubated in the presence of a compound
inhibitor to demonstrate inhibition of enzymatic activity as
compared with a control. Activity of beta-secretase can be measured
by analysis of one or more cleavage products of the APP substrate.
For example, inhibition of beta-secretase activity against the
substrate APP would be expected to decrease release of specific
beta-secretase induced APP cleavage products such as A-beta.
[1309] Although both neural and non-neural cells process and
release A-beta, levels of endogenous beta-secretase activity are
low and often difficult to detect by EIA. The use of cell types
known to have enhanced beta-secretase activity, enhanced processing
of APP to A-beta, and/or enhanced production of A-beta are
therefore preferred. For example, transfection of cells with the
Swedish Mutant form of APP (APP-SW); with APP-KK; or with APP-SW-KK
provides cells having enhanced .theta.-secretase activity and
producing amounts of A-beta that can be readily measured.
[1310] In such assays, for example, the cells expressing APP and
beta-secretase are incubated in a culture medium under conditions
suitable for beta-secretase enzymatic activity at its cleavage site
on the APP substrate. On exposure of the cells to the compound
inhibitor, the amount of A-beta released into the medium and/or the
amount of CTF99 fragments of APP in the cell lysates is reduced as
compared with the control. The cleavage products of APP can be
analyzed, for example, by immune reactions with specific
antibodies, as discussed above.
[1311] Preferred cells for analysis of beta-secretase activity
include primary human neuronal cells, primary transgenic animal
neuronal cells where the transgene is APP, and other cells such as
those of a stable 293 cell line expressing APP, for example,
APP-SW.
In Vivo Assays: Animal Models
[1312] Various animal models can be used to analyze beta-secretase
activity and/or processing of APP to release A-beta, as described
above. For example, transgenic animals expressing APP substrate and
beta-secretase enzyme can be used to demonstrate inhibitory
activity of the compounds of the invention. Certain transgenic
animal models have been described, for example, in U.S. Pat. Nos.
5,877,399; 5,612,486; 5,387,742; 5,720,936; 5,850,003; 5,877,015,
and 5,811,633, and in Ganes et. al., 1995, Nature 373:523.
Preferred are animals that exhibit characteristics associated with
the pathophysiology of AD. Administration of the compound
inhibitors of the invention to the transgenic mice described herein
provides an alternative method for demonstrating the inhibitory
activity of the compounds. Administration of the compounds in a
pharmaceutically effective carrier and via an administrative route
that reaches the target tissue in an appropriate therapeutic amount
is also preferred.
[1313] Inhibition of beta-secretase mediated cleavage of APP at the
beta-secretase cleavage site and of A-beta release can be analyzed
in these animals by measure of cleavage fragments in the animal's
body fluids such as cerebral fluid or tissues. Analysis of brain
tissues for A-beta deposits or plaques is preferred.
[1314] On contacting an APP substrate with a beta-secretase enzyme
in the presence of an inhibitory compound of the invention and
under conditions sufficient to permit enzymatic mediated cleavage
of APP and/or release of A-beta from the substrate, the compounds
of the invention are effective to reduce .theta.-secretase-mediated
cleavage of APP at the beta-secretase cleavage site and/or
effective to reduce released amounts of A-beta. Where such
contacting is the administration of the inhibitory compounds of the
invention to an animal model, for example, as described above, the
compounds are effective to reduce A-beta deposition in brain
tissues of the animal, and to reduce the number and/or size of beta
amyloid plaques. Where such administration is to a human subject,
the compounds are effective to inhibit or slow the progression of
disease characterized by enhanced amounts of A-beta, to slow the
progression of AD in the, and/or to prevent onset or development of
AD in a patient at risk for the disease.
[1315] Unless defined otherwise, all scientific and technical terms
used herein have the same meaning as commonly understood by one of
skill in the art to which this invention belongs. All patents and
publications referred to herein are hereby incorporated by
reference for all purposes.
BIOLOGY EXAMPLES
Example A
Enzyme Inhibition Assay
[1316] The compounds of the invention are analyzed for inhibitory
activity by use of the MBP-C125 assay. This assay determines the
relative inhibition of beta-secretase cleavage of a model APP
substrate, MBP-C125SW, by the compounds assayed as compared with an
untreated control. A detailed description of the assay parameters
can be found, for example, in U.S. Pat. No. 5,942,400. Briefly, the
substrate is a fusion peptide formed of maltose binding protein
(MBP) and the carboxy terminal 125 amino acids of APP-SW, the
Swedish mutation. The beta-secretase enzyme is derived from human
brain tissue as described in Sinha et. al, 1999, Nature 40:537-540)
or recombinantly produced as the full-length enzyme (amino acids
1-501), and can be prepared, for example, from 293 cells expressing
the recombinant cDNA, as described in WO00/47618.
[1317] Inhibition of the enzyme is analyzed, for example, by
immunoassay of the enzyme's cleavage products. One exemplary ELISA
uses an anti-MBP capture antibody that is deposited on precoated
and blocked 96-high binding plates, followed by incubation with
diluted enzyme reaction supernatant, incubation with a specific
reporter antibody, for example, biotinylated anti-SW192 reporter
antibody, and further incubation with streptavidin/alkaline
phosphatase. In the assay, cleavage of the intact MBP-C125SW fusion
protein results in the generation of a truncated amino-terminal
fragment, exposing a new SW-192 antibody-positive epitope at the
carboxy terminus. Detection is effected by a fluorescent substrate
signal on cleavage by the phosphatase. ELISA only detects cleavage
following Leu 596 at the substrate's APP-SW 751 mutation site.
[1318] Specific Assay Procedure
[1319] Compounds are diluted in a 1:1 dilution series to a
six-point concentration curve (two wells per concentration) in one
96-plate row per compound tested. Each of the test compounds is
prepared in DMSO to make up a 10 millimolar stock solution. The
stock solution is serially diluted in DMSO to obtain a final
compound concentration of 200 micromolar at the high point of a
6-point dilution curve. Ten (10) microliters of each dilution is
added to each of two wells on row C of a corresponding V-bottom
plate to which 190 microliters of 52 millimolar NaOAc, 7.9% DMSO,
pH 4.5 are pre-added. The NaOAc diluted compound plate is spun down
to pellet precipitant and 20 microliters/well is transferred to a
corresponding flat-bottom plate to which 30 microliters of ice-cold
enzyme-substrate mixture (2.5 microliters MBP-C125SW substrate,
0.03 microliters enzyme and 24.5 microliters ice cold 0.09% TX100
per 30 microliters) is added. The final reaction mixture of 200
micromolar compound at the highest curve point is in 5% DMSO, 20
millimolar NaAc, 0.06% TX100, at pH 4.5.
[1320] Warming the plates to 37 degrees C. starts the enzyme
reaction. After 90 minutes at 37 degrees C., 200 microliters/cold
specimen diluent is added to stop the reaction and 20
microliters/was transferred to a corresponding anti-MBP antibody
coated ELISA plate for capture, containing 80 microliters/specimen
diluent. This reaction is incubated overnight at 4 degrees C. and
the ELISA is developed the next day after a 2 hour incubation with
anti-192SW antibody, followed by Streptavidin-AP conjugate and
fluorescent substrate. The signal is read on a fluorescent plate
reader.
[1321] Relative compound inhibition potency is determined by
calculating the concentration of compound that showed a
fifty-percent reduction in detected signal (IC.sub.50) compared to
the enzyme reaction signal in the control s with no added compound.
In this assay, the compounds of the invention exhibited an
IC.sub.50 of less than 50 micromolar.
Example B
Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate
[1322] A synthetic APP substrate that can be cleaved by
beta-secretase and having N-terminal biotin and made fluorescent by
the covalent attachment of oregon green at the Cys residue is used
to assay beta-secretase activity in the presence or absence of the
inhibitory compounds of the invention. Useful substrates include
the following: TABLE-US-00001 [SEQ ID NO: 1]
Biotin-SEVNL-DAEFRC[oregon green]KK [SEQ ID NO: 2]
Biotin-SEVKM-DAEFRC[oregon green]KK [SEQ ID NO: 3]
Biotin-GLNIKTEEISEISY-EVEFRC[oregon green]KK [SEQ ID NO: 4]
Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEFRC [oregon green]KK [SEQ ID
NO: 5] Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKAC [oregon
green]KK
[1323] The enzyme (0.1 nanomolar) and test compounds (0.001-100
micromolar) are incubated in pre-blocked, low affinity, black
plates (384) at 37 degrees for 30 minutes. The reaction is
initiated by addition of 150 millimolar substrate to a final volume
of 30 microliter per. The final assay conditions are: 0.001-100
micromolar compound inhibitor; 0.1 molar sodium acetate (pH 4.5);
150 nanomolar substrate; 0.1 nanomolar soluble beta-secretase;
0.001% Tween 20, and 2% DMSO. The assay mixture is incubated for 3
hours at 37.degree. C., and the reaction is terminated by the
addition of a saturating concentration of immunopure streptavidin.
After incubation with streptavidin at room temperature for 15
minutes, fluorescence polarization is measured, for example, using
a LJL Acqurest (Ex485 nm/Em530 nm). The activity of the
beta-secretase enzyme is detected by changes in the fluorescence
polarization that occur when the substrate is cleaved by the
enzyme. Incubation in the presence or absence of compound inhibitor
demonstrates specific inhibition of beta-secretase enzymatic
cleavage of its synthetic APP substrate. In this assay, compounds
of the invention exhibited an IC50 of less than 50 micromolar.
Example C
Beta-Secretase Inhibition: P26-P4'SW Assay
[1324] Synthetic substrates containing the .theta.-secretase
cleavage site of APP are used to assay beta-secretase activity,
using the methods described, for example, in published PCT
application WO00/47618. The P26-P4'SW substrate is a peptide of the
sequence: TABLE-US-00002 [SEQ ID NO: 6]
(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF
[1325] The P26-P1 standard has the sequence: TABLE-US-00003 [SEQ ID
NO: 7] (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL
[1326] Briefly, the biotin-coupled synthetic substrates are
incubated at a concentration of from about 0 to about 200
micromolar in this assay. When testing inhibitory compounds, a
substrate concentration of about 1.0 micromolar is preferred. Test
compounds diluted in DMSO are added to the reaction mixture, with a
final DMSO concentration of 5%. Controls also contain a final DMSO
concentration of 5%. The concentration of beta secretase enzyme in
the reaction is varied, to give product concentrations with the
linear range of the ELISA assay, about 125 to 2000 picomolar, after
dilution.
[1327] The reaction mixture also includes 20 millimolar sodium
acetate, pH 4.5, 0.06% Triton X100, and is incubated at 37 degrees
C. for about 1 to 3 hours. Samples are then diluted in assay buffer
(for example, 145.4 nanomolar sodium chloride, 9.51 millimolar
sodium phosphate, 7.7 millimolar sodium azide, 0.05% Triton X405, 6
g/liter bovine serum albumin, pH 7.4) to quench the reaction, then
diluted further for immunoassay of the cleavage products.
[1328] Cleavage products can be assayed by ELISA. Diluted samples
and standards are incubated in assay plates coated with capture
antibody, for example, SW192, for about 24 hours at 4 degrees C.
After washing in TTBS buffer (150 millimolar sodium chloride, 25
millimolar Tris, 0.05% Tween 20, pH 7.5), the samples are incubated
with strepavidin-AP according to the manufacturer's instructions.
After a one hour incubation at room temperature, the samples are
washed in TTBS and incubated with fluorescent substrate solution A
(31.2 g/liter 2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5).
Reaction with streptavidin-alkaline phosphate permits detection by
fluorescence. Compounds that are effective inhibitors of
.theta.-secretase activity demonstrate reduced cleavage of the
substrate as compared to a control.
Example D
Assays Using Synthetic Oligopeptide-Substrates
[1329] Synthetic oligopeptides are prepared that incorporate the
known cleavage site of beta-secretase, and optionally detectable
tags, such as fluorescent or chromogenic moieties. Examples of such
peptides, as their production and detection methods are described
in U.S. Pat. No. 5,942,400, herein incorporated by reference.
Cleavage products can be detected using high performance liquid
chromatography, or fluorescent or chromogenic detection methods
appropriate to the peptide to be detected, according to methods
known in the art.
[1330] By way of example, one such peptide has the sequence
SEVNL-DAEF [SEQ ID NO: 8], and the cleavage site is between
residues 5 and 6. Another preferred substrate has the sequence
ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO: 9], and the cleavage
site is between residues 26 and 27.
[1331] These synthetic APP substrates are incubated in the presence
of beta-secretase under conditions sufficient to result in
beta-secretase mediated cleavage of the substrate. Comparison of
the cleavage results in the presence of the compound inhibitor to
control results provides a measure of the compound's inhibitory
activity.
Example E
Inhibition of Beta-Secretase Activity-Cellular Assay
[1332] An exemplary assay for the analysis of inhibition of
beta-secretase activity utilizes the human embryonic kidney cell
line HEKp293 (ATCC Accession No. CRL-1573) transfected with APP751
containing the naturally occurring double mutation Lys651Met52 to
Asn651Leu652 (numbered for APP751), commonly called the Swedish
mutation and shown to overproduce A-beta (Citron et. al., 1992,
Nature 360:672-674), as described in U.S. Pat. No. 5,604,102.
[1333] The cells are incubated in the presence/absence of the
inhibitory compound (diluted in DMSO) at the desired concentration,
generally up to 10 micrograms/ml. At the end of the treatment
period, conditioned media is analyzed for beta-secretase activity,
for example, by analysis of cleavage fragments. A-beta can be
analyzed by immunoassay, using specific detection antibodies. The
enzymatic activity is measured in the presence and absence of the
compound inhibitors to demonstrate specific inhibition of
beta-secretase mediated cleavage of APP substrate.
Example F
Inhibition of Beta-Secretase in Animal Models of AD
[1334] Various animal models can be used to screen for inhibition
of beta-secretase activity. Examples of animal models useful in the
invention include, but are not limited to, mouse, guinea pig, dog,
and the like. The animals used can be wild type, transgenic, or
knockout models. In addition, mammalian models can express
mutations in APP, such as APP695-SW and the like described herein.
Examples of transgenic non-human mammalian models are described in
U.S. Pat. Nos. 5,604,102, 5,912,410 and 5,811,633.
[1335] PDAPP mice, prepared as described in Games et. al., 1995,
Nature 373:523-527 are useful to analyze in vivo suppression of
A-beta release in the presence of putative inhibitory compounds. As
described in U.S. Pat. No. 6,191,166, 4 month old PDAPP mice are
administered compound formulated in vehicle, such as corn oil. The
mice are dosed with compound (1-30 mg/ml; preferably 1-10 mg/ml).
After time, e.g., 3-10 hours, the animals are sacrificed, and
brains removed for analysis.
[1336] Transgenic animals are administered an amount of the
compound inhibitor formulated in a carrier suitable for the chosen
mode of administration. Control animals are untreated, treated with
vehicle, or treated with an inactive compound. Administration can
be acute, i.e., single dose or multiple doses in one day, or can be
chronic, i.e., dosing is repeated daily for a period of days.
Beginning at time 0, brain tissue or cerebral fluid is obtained
from selected animals and analyzed for the presence of APP cleavage
peptides, including A-beta, for example, by immunoassay using
specific antibodies for A-beta detection. At the end of the test
period, animals are sacrificed and brain tissue or cerebral fluid
is analyzed for the presence of A-beta and/or beta-amyloid plaques.
The tissue is also analyzed for necrosis.
[1337] Animals administered the compound inhibitors of the
invention are expected to demonstrate reduced A-beta in brain
tissues or cerebral fluids and reduced beta amyloid plaques in
brain tissue, as compared with non-treated controls.
Example G
Inhibition of A-Beta Production in Human Patients
[1338] Patients suffering from Alzheimer's Disease (AD) demonstrate
an increased amount of A-beta in the brain. AD patients are
administered an amount of the compound inhibitor formulated in a
carrier suitable for the chosen mode of administration.
Administration is repeated daily for the duration of the test
period. Beginning on day 0, cognitive and memory tests are
performed, for example, once per month.
[1339] Patients administered the compound inhibitors are expected
to demonstrate slowing or stabilization of disease progression as
analyzed by changes in one or more of the following disease
parameters: A-beta present in CSF or plasma; brain or hippocampal
volume; A-beta deposits in the brain; amyloid plaque in the brain;
and scores for cognitive and memory function, as compared with
control, non-treated patients.
Example H
Prevention of A-Beta Production in Patients at Risk for AD
[1340] Patients predisposed or at risk for developing AD are
identified either by recognition of a familial inheritance pattern,
for example, presence of the Swedish Mutation, and/or by monitoring
diagnostic parameters. Patients identified as predisposed or at
risk for developing AD are administered an amount of the compound
inhibitor formulated in a carrier suitable for the chosen mode of
administration. Administration is repeated daily for the duration
of the test period. Beginning on day 0, cognitive and memory tests
are performed, for example, once per month.
[1341] Patients administered the compound inhibitors are expected
to demonstrate slowing or stabilization of disease progression as
analyzed by changes in one or more of the following disease
parameters: A-beta present in CSF or plasma; brain or hippocampal
volume; amyloid plaque in the brain; and scores for cognitive and
memory function, as compared with control, non-treated
patients.
EXAMPLES
[1342] The following detailed examples describe how to prepare the
various compounds and/or perform the various processes of the
invention and are to be construed as merely illustrative, and not
limitations of the preceding disclosure in any way whatsoever.
Those skilled in the art will promptly recognize appropriate
variations from the procedures both as to reactants and as to
reaction conditions and techniques.
Preparation 1 tert-Butyl
(1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III)
[1343] N-methyl-morpholine (5.83 Ml, 53 mmole, 1.05 eq.) is added
to
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic
acid (II, 15 g, 50 mmole) in THF (100 mL) and the reaction is
cooled to -78.degree.. Isobutyl chloroformate (6.87 mL, 53 mmole,
1.05 eq.) is added rapidly. The cold bath is then removed and the
mixture stirred for 1 hr. The reaction was monitored by TLC to
insure completion of the reaction and the mixture is then filtered
and washed with dry THF (50 ml) and kept cold in the filtered flask
at -20.degree..
[1344] In a ice-salt bath is placed a 500 ml graduate cylinder
containing ether (200 mL) and aqueous potassium hydroxide (40%, 60
ml). 1-methyl-3-nitro-1-nitrosoguanidine (5.6 g, 106 mmole, 2.1
eq.) is added slowly with stirring and temperature kept below zero
degree. The mixture turned yellow and the bubbling lasted for 10
minutes. The stirring is stopped and without mixing the layers, the
top diazomethane ethereal layer is transferred with non-ground tip
pipette into the stirred mixed anhydride mixture at -20.degree..
The reaction is monitored by TLC (ethyl acetate/hexane, 50/50;
R.sub.f=0.69). After 1 hour nitrogen is then bubbled into the
mixture. The solvent is removed under reduced pressure (with heat)
and the mixture is partitioned between ether and water. The phases
are separated, the organic phase is washed with bicarbonate,
saline, dried over anhydrous sodium sulfate, filtered, and solvent
removed under reduced pressure (with heat). The residue is
dissolved in ether (100 mL) and hydrobromous acid (48%, 15 mL, 135
mmole, 2.7 eq,) is added at -20.degree., the cold bath is removed
and the mixture is stirred for another half hour. The reaction is
monitored by TLC (ethyl acetate/hexane, 50/50; R.sub.f=0.88). The
mixture is partitioned between ether and water, washed with
bicarbonate, saline, dried over anhydrous sodium sulfate, filtered,
and the solvent removed. The residue is recrystallized from ethanol
to give the title compound, TLC (ethyl acetate/hexane, 50/50)
R.sub.f=0.88; MS (MH.sup.+)=379.3
Preparation 2 tert-Butyl
(1S,2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate
(IV)
[1345] Sodium borohydride (1.32 g, 34.9 mmole, 1.1 eq.) is added to
tert-Butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate
(III, PREPARATION 1, 12 g, 31.75 mmole) dissolved in absolute
alcohol (500 mL)-78.degree.. The reaction mixture is stirred for 30
minutes and monitored by TLC (ethyl acetate/hexane, 20/80;
R.sub.f=0.2). The mixture is quenched with water (10 mL) and the
solvent removed under reduced pressure with heat (not exceeding
30.degree.) to dryness. The solid is partitioned between
dichloromethane and water, washed with saline, dried over anhydrous
sodium sulfate. The solvent is removed under reduced pressure to
give the title compound, TLC (ethyl acetate/hexane, 20/80)
R.sub.f=0.2; MS (MH.sup.+)=381.2
Preparation 3 tert-Butyl
(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V)
[1346] tert-Butyl
(1S,2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate
(IV, PREPARATION 2) is dissolved in absolute alcohol (150 mL) and
ethyl acetate (100 mL) and potassium hydroxide (2.3 g, 34.9 mmole,
1.1 eq.) in ethyl alcohol (85%, 5 mL) is added at -20.degree.. The
cold bath is then removed and the mixture stirred for 30 minutes.
The reaction is monitored by TLC (ethyl acetate/hexane, 20/80).
When the reaction is complete, it is diluted with dichloromethane
and extracted, washed with water, saline, dried over anhydrous
sodium sulfate and the solvent removed under reduced pressure. The
crude material is purified by flash chromatography on silica gel to
give the title compound, TLC (ethyl acetate/hexane, 20/80)
R.sub.f=0.3; MS (MH.sup.+)=300.4.
Preparation 4 Benzyl
(1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III)
[1347] Following the general procedure of PREPARATION 1 and making
non critical variations but starting with the CBZ protecting group
and using hydrochloric acid, the title compound is obtained.
Preparation 5 Benzyl
(1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate
(IV)
[1348] Following the general procedure of PREPARATION 2 and making
non critical variations but starting with benzyl
(1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III,
PREPARATION 4), the title compound is obtained.
Preparation 6 Benzyl
(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V)
[1349] Following the general procedure of PREPARATION 3 and making
non critical variations but starting with benzyl (1S,
2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV,
PREPARATION 5), the title compound is obtained.
Preparation 7 tert-Butyl
(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl-
carbamate (VII)
[1350] tert-Butyl
(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V,
PREPARATION 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol
(6 mL) and 3-methoxybenzylamine (160 .mu.L, 1.22 mmol) is added
with stirring at 20-25.degree.. This mixture is heated to gentle
reflux (bath temp 850) under nitrogen for 2 hr, whereupon the
resulting mixture is concentrated under reduced pressure to give
the title compound. The title compound is purified by flash
chromatography (2-5% methanol/methylene chloride; gradient elution)
to give purified title compound.
Preparation 8 tert-Butyl
(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate
(VII)
[1351] ##STR49##
[1352] tert-Butyl 1-(2-oxiranyl)-2-phenylethylcarbamate (V,
commercially available, 20 g, 76 mmole) is dissolved in i-propanol
(380 ml). To this mixture is added 3-methoxybenzyl amine (49 ml,
380 mmole). The reaction mixture is heated to reflux for 1 hr (when
HPLC indicated complete reaction). The reaction mixture is
concentrated under reduced pressure and the residue is treated with
hexane (500 ml). The product is isolated by filtration. The mother
liquors are concentrated under reduced pressure to give additional
crude material which is partitioned between ethyl acetate (50 ml)
and water (50 ml). The mixture is acidified with concentrated
hydrochloric acid (to pH=4), the organic phase is separated and
washed with water, saline, dried over sodium sulfate and then
concentrated under reduced pressure to give additional title
compound, M+H 401.
Preparation 9 Benzyl
(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]ethyl
carbamate (VII)
[1353] Following the general procedure of PREPARATION 7 and making
non-critical variations but using benzyl 1-(2-oxiranyl)-2-phenyl
carbamate (V), as the epoxide, the title compound is obtained.
Preparation 10 Methyl
(2Z)-2-[[(benzyloxy)carbonyl]-3-(3,5-difluorophenyl)-2-propenonate
(XXII)
[1354] ##STR50##
[1355] 3,5-Difluorobenzaldehyde (XX, 2.87 g, 0.02 moles, 1 eq) and
THF (100 mL) are mixed and cooled to about 00.
N-(Benzyloxycarbonyl)phosphonyl-glycinetrimethylester (XXI, 8.7 g,
0.026 moles, 1.3 eq) is added to the 3,5-difluorobenzaldehyde
(XX)/THF mixture. This is followed by 1,1,3,3-tetramethyl quanidine
(4.0 mL, 0.032 moles, 1.56 eq) added dropwise. The reaction is
stirred for 5 min at 0.degree. then allowed to warm to
20-25.degree.. After 2 hr, the reaction is complete (by TLC
analysis) at which time water (100 mL) and ethyl acetate (100 mL)
are added. The phases are separated and the aqueous phase is
extracted with ethyl acetate (100 mL) and the combined organic
phases are washed with saline (100 mL), dried over sodium sulfate,
filtered and concentrated under reduced pressure to give a crude
solid. The solid is purified by silica gel chromatography (ethyl
acetate/hexanes; 15/85) to give the title compound, mp=112.degree.;
NMR (CDCl.sub.3) .delta. 7.19, 7.06, 6.86, 6.15, 6.43, 4.97 and
3.69; CMR (CDCl.sub.3) .delta. 165.56, 164.54, 164.41, 162.07,
137.39, 136.02, 128.97, 128.80, 128.62, 128.57, 128.47, 126.25,
112.57, 112.38, 105.22, 104.97, 104.72, 68.17 and 53.33. Additional
material is recovered that is a mixture of E and Z olefins.
Preparation 11 methyl
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(3,5-difluorophenyl)propanoate
(II)
[1356] ##STR51##
[1357] Methyl
(2Z)-2-[[(benzyloxy)carbonyl]-3-(3,5-difluorophenyl)-2-propenonate
(XXII, PREPARATION 10, 0.100 g, 0.228 mmol) and degassed methanol
(10 ml) are mixed in a 100 mL Hastelloy bomb. The reaction mixture
is purged three times with hydrogen (60 psig) and then stirred at
60 psig hydrogen for 60 min at 20-25.degree.. Then (R,R)-DIPAP)Rh
(5.2 mg, 3 mole %) is dissolved in methanol (1 mL, degassed) is
added and the system purged with hydrogen (3.times.60 psig). The
contents are then stirred at 20 psig hydrogen at 25.degree.
overnight at which time the reaction is complete as determined by
HPLC. The system is then purged and filtered to remove the catalyst
and the solvent is removed under reduced pressure to give the title
compound.
Preparation 12 1-tert-butyl
(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propylcar-
bamate (VII)
[1358] ##STR52##
[1359] tert-Butyl
(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V,
PREPARATION 3, 1.75 g, 5.8 mmole) is mixed with isopropanol (30
ml). The reaction flask is charged with 3-iodobenzylamine (VI). The
reaction mixture is heated to reflux for 45 minutes, HPLC analysis
indicates complete disappearance of the epoxide (V). The reaction
mixture is concentrated under reduced pressure and the residue is
partitioned between ethyl acetate (150 ml) and aqueous hydrochloric
acid (3%, 35 ml). The organic phase is separated and washed with
aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline and
dried over sodium sulfate. Concentration under reduced pressure
gives the title compound, M+H=535.
Preparation 13 1-9H-fluoren-9-ylmethyl
(2R,3S)-3-(3-t-butyloxycarbonyl)amino-4-(3,5-difluorophenyl)-2-hydroxybut-
yl(3'-iodobenzyl)carbamate hydrochloride (XXXIV)
[1360] ##STR53##
[1361] 1-tert-butyl
(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propylcar-
bamate (VII, PREPARATION 12, 2.5 g, 4.7 mmole) and triethylamine
(0.72 ml, 5.1 mmole) in THF (10 ml) are mixed. The reaction is
cooled to 0.degree. and treated with FMOC (1.2 g, 4.7 mmole) in THF
(2 ml) via addition funnel. After 15 minutes HPLC indicates
complete disappearance of starting material. The reaction is
diluted with ethyl acetate and washed with aqueous potassium
bisulfate, saturated aqueous bicarbonate, saline and dried over
sodium sulfate. Concentration under reduced pressure gives crude
product which is purified by flash chromatography, eluting with
ethyl acetate/hexane (20/80) followed by ethyl acetate to give the
title compound, M+H=757.
Preparation 14 1-9H-fluoren-9-ylmethyl
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3-iodobenzyl)carbam-
ate hydrochloride (XXXV)
[1362] ##STR54##
[1363] 1-9H-fluoren-9-ylmethyl
(2R,3S)-3-(3-t-butyloxycarbonyl)amino-4-(3,5-difluorophenyl)-2-hydroxybut-
yl(3'-iodobenzyl)carbamate hydrochloride (XXXIV, PREPARATION 13,
2.9 g) in hydrochloric acid/dioxane (4N, 10 ml). The mixture is
stirred 1 hour then slowly poured into rapidly stirring ether (200
ml). The product is filtered and dried to give the title compound,
M+H=657.
Preparation 15 1-9H-fluoren-9-ylmethyl
(2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3-{[5-oxo-5-(1-piperidinyl)penta-
noyl]amino}butyl(3-iodobenzyl)carbamate (XXXVI)
[1364] ##STR55##
[1365] HOBt (81 mg, 0.6 mmole) and EDC (105 mg, 0.55 mmole) are
added to 1-carboxy-5-piperidinylglutaramide (IX, 100 mg, 0.5 mmole)
in DMF (2 ml). The acid is activated 60 minutes then treated with
1-9H-fluoren-9-ylmethyl
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3-iodobenzyl)carbam-
ate hydrochloride (XXXV, PREPARATION 14, 300 mg, 0.43 mmole) and
NMM (0.19 ml, 1.72 mmole). The reaction is stirred 3 hrs then
concentrated under reduced pressure. The residue is partitioned
between ethyl acetate and saturated aqueous bicarbonate. The
organic phases are washed with aqueous potassium bisulfate, saline,
dried over sodium sulfate and finally concentrated under reduced
pressure to give crude product. Purification via flash
chromatography with ethyl acetate/hexane (50/50) then
methanol/ethyl acetate (10/90) gives the title compound, M+H=838
g/m.
Preparation 16
1-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]prop-
yl}-5-oxo-5-(1-piperidinyl)pentanamide trifluoroacetate X
[1366] ##STR56##
[1367]
1-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)ami-
no]propyl}-5-oxo-5-(1-piperidinyl)pentanamide trifluoroacetate
(XXXVI, PREPARATION 15, 240 mg, 0.29 mmole is dissolved in
diethylamine (10%, 9 ml) in methylene chloride. The reaction is
stirred at 20-25.degree. overnight. Next morning the reaction is
concentrated under reduced pressure and the residue is redissolved
in methylene chloride and purified by preparative reverse phase
HPLC. The appropriate fractions are pooled and concentrated under
reduced pressure and partitioned between ethyl acetate and saline.
The organic phase is separated and dried over sodium sulfate and
concentrated to give the title compound, M+H=614.
Preparation 17 1-tert-butyl
(2R,3S)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)
carbamate (XXXIV)
[1368] ##STR57##
[1369] 1-benzyl
(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate
hydrochloride (VII, PREPARATION 9, 8.16 g, 18.8 mmole) is mixed
with THF (150 ml). The reaction mixture is cooled to 0.degree. and
treated with tri-ethylamine (2.9 ml, 20.6 mmole) and di-t-butyl
pyrocarbonate (4.1 g, 18.8 mmole). The reaction mixture is stirred
at 20-25.degree. for 3 hours. The reaction mixture is concentrated
under reduced pressure and the residue is partitioned between ethyl
acetate and aqueous citric acid (5%). The organic phase is
separated and washed with saturated aqueous bicarbonate, saline,
dried over sodium sulfate and concentrated to give the title
compound (96% purity by HPLC).
Preparation 18 1-tert-butyl
(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate
(XXXV)
[1370] ##STR58##
[1371] 1-tert-butyl
(2R,3S)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)-
carbamate (XXXIV, EXAMPLE 1, 9.47 g), palladium-on-carbon (wet, 5%,
1.9 g) and methanol (95 ml) are added to a 300 ml Fisher Porter
bottle. The reaction mixture is charged with hydrogen (50 psi) and
hydrogenated for 1.2 hours until gas uptake ceased. The reaction
mixture is filtered thru celite and concentrated under reduced
pressure to give the title compound, M+H=401.
Preparation 19
1-Benzyl(1s)-1-[({(1S,2R)-1-benzyl-3-[(tert-butoxycarbonyl)(3-methoxybenz-
yl)amino]-2-hydroxypropyl}amino)carbonyl]-4-oxo-4-(1-piperidinyl)butylcarb-
amate (XXXVI)
[1372] ##STR59##
[1373]
1-(2S)-2-{[(Benzyloxy)carbonyl]amino}-5-oxo-5-(1-piperidinyl)penta-
noic (IX, 1.1 g), HOBt (0.64 g, 1.5 eq) and EDC (700 mg, 1.15 eq)
and DMF (4 ml) are mixed. The acid is activated for 20 minutes and
then treated with 1-tert-butyl
(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(3-methoxybenzyl) carbamate
(XXXV, EXAMPLE 2, 1.3 g) and NMM (0.65 g, 2 eq) in DMF (4 ml). The
reaction mixture is stirred 14 hours then concentrated under
reduced pressure. The residue is partitioned between ethyl acetate
and saturated aqueous bicarbonate. The organic phase is separated
and washed with aqueous potassium bisulfate, saline, dried over
sodium sulfate and concentrated under reduced pressure to give
crude product. The crude product is purified via flash
chromatography eluting with ethyl acetate (100%) to give the title
compound, M+H 731.
Preparation 20
(2R)-2-Carbobenzyloxyamino-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxyben-
zyl)amino]propyl}-5-oxo-5-piperidin-1-ylpentanamide hydrochloride
X
[1374] ##STR60##
[1375] A 50 ml round bottom flask was charged with 1-benzyl
(1S)-1-[({(1S,2R)-1-benzyl-3-[(tert-butoxycarbonyl)(3-methoxybenzyl)amino-
]-2-hydroxypropyl}amino)carbonyl]-4-oxo-4-(1-piperidinyl)butylcarbamate
(XXXVI, EXAMPLE 3, 100 mg) in dioxane/hydrochloric acid (4 N, 4
ml). The reaction is stirred 15 minutes when HPLC analysis
indicates complete de-protection. The reaction mixture is
concentrated under reduced pressure. The crude product is chased
with acetonitrile (5 ml) then methylene chloride (5 ml). The
resulting hydrochloride salt is dried under reduced pressure, to
give the title compound, M+H=631.
Preparation 21 1-tert-butyl
(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate
(XXXIV)
[1376] ##STR61##
[1377] tert-Butyl
(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate
(VII, PREPARATION 8, 19.2 g, 48 mmole) in THF (100 ml). The
reaction mixture is cooled to 0.degree. and treated with
N-benzyloxy carbonyloxysuccinamide (11.9 g, 48 mmole) while
maintaining temperature<50. The reaction mixture is stirred
overnight and in the morning is concentrated under reduced
pressure. The residue is partitioned between ethyl acetate and
saturated aqueous bicarbonate. The organic phase is separated and
washed with citric acid (5%), saline, dried over sodium sulfate and
concentrated. The crude product is purified by preparatory HPLC
eluting with a gradient of from 20/80-50/50 ethyl acetate. To give
the title compound, M+H=534.
Preparation 22
(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate
hydrochloride. (XXXV)
[1378] ##STR62##
[1379] 1-tert-butyl
(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate
(XXXIV, EXAMPLE 5, 5.4 g) and dioxane-hydrochloric acid (20 ml, 4
N) are mixed. The reaction mixture is stirred at 20-25.degree. for
30 minutes then poured into stirred ether (300 ml). The product is
filtered and dried under reduced pressure to give the title
compound, M+H=435.
Preparation 23 tert-butyl
(2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3-({3-[(1-propylbutyl)sulfonyl]a-
lanyl}amino)butyl(3-ethylbenzyl)carbamate (LXXXVII)
[1380] ##STR63##
[1381] Methyl 2-acetamidoacrylate (LXXX, 5.0 g, 34 mmole) and
4-mercaptoheptane (4.6 g, 34 mmole) in methanol (50 ml) are mixed.
Triethylamine (3.6 g, 36 mmole) is added and the mixture is stirred
at 20-25.degree. for 45 minutes. The reaction vessel is then
treated with oxone (47.2 g, 77 mmole). After 90 minutes HPLC
indicated complete oxidation to the desired sulfone (LXXXII). The
reaction mixture is filtered and concentrated under reduced
pressure. The residue is partitioned between ethyl acetate and
water and the organic phase is separate and is washed with saline,
dried over sodium sulfate, and concentrated under reduced pressure
to give methyl N-acetyl-3-[(1-propylbutyl)sulfonyl]alaninate
(LXXXII), M+H=308 g/m.
[1382] Methyl N-acetyl-3-[(1-propylbutyl)sulfonyl]alaninate
(LXXXII, 9.2 g) in acetic acid (50 ml) and concentrated
hydrochloric acid (50 ml). The mixture is refluxed for 4 hours then
concentrated under reduced pressure. The residue is chased with
toluene (2.times.) then vacuum dried overnight to give
3-[(1-propylbutyl)sulfonyl]alanine hydrochloride salt
(LXXXIII).
[1383] 3-[(1-Propylbutyl)sulfonyl]alanine (LXXXIII, 7.8 g, 27
mmole) and N-CBZ succinamide (7.4 g, 30 mmole) are mixed in
methylene chloride (100 ml). The reaction is cooled to 00, and NMM
(6.9 g) is added dropwise. The reaction is allowed to warm to
20-25.degree. and stirred for 4 hours at which point HPLC analysis
indicated complete reaction. The reaction mixture is concentrated
under reduced pressure and partitioned between ethyl acetate and
hydrochloric acid (1 N). The organic phase is washed with water,
saline, dried over sodium sulfate, and concentrated under reduced
pressure to give
N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine (LXXXIV)
that is used without further purification, M+H 386.
[1384] N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine
(LXXXIV, 4.0 g, 10 mmole) and
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol
dihydrochloride (1.2 g, 12 mmole) are mixed in anhydrous methylene
chloride (50 ml). To the reaction mixture is added NMM (5.6 ml, 51
mmole), hydroxybenzotriazole (1.7 g, 13 mmole) and lastly
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g
(16 mmole). After stirring at 20-25.degree. for 3 hours, HPLC
analysis indicates complete reaction. The reaction mixture is
diluted with methylene chloride and washed with saturated sodium
bicarbonate solution, citric acid (0.5 M), and saline. The organic
phase is dried over sodium sulfate, filtered, and concentrated
under reduced pressure to give
N.sup.2-[(benzyloxy)carbonyl]-N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[-
(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]alaninam-
ide (LXXXV).
[1385]
N.sup.2-[(benzyloxy)carbonyl]-N.sup.1-{(1S,2R)-1-(3,5-difluorobenz-
yl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]a-
laninamide (LXXXV) is dissolved in anhydrous methylene chloride.
The mixture is cooled to O.sub.2 and di-tert-butyl dicarbonate (2.5
g, 12 mmole) and N-methyl morpholine (1.2 ml, 11 mmole) are added.
The reaction mixture is allowed to warm to 20-25.degree. and
stirred for 18 hours at which point HPLC analysis indicates
complete reaction. The reaction mixture is diluted with methylene
chloride and washed with saturated sodium bicarbonate solution, and
saline. The phases are separated and the organic phase is dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The concentrate is purified on silica gel by flash
chromatography using a gradient solvent of ethyl acetate/hexane
(5/94 to 40/60) to give
N.sup.2-[(benzyloxy-)carbonyl]-N.sup.1-{(1S,2R)-N-[(t-butyloxy)carbonyl]--
1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-pro-
pylbutyl)sulfonyl]-D,L-alaninamide (LXXXVI), M+Na=824.
[1386]
N.sup.2-[(benzyloxy-)carbonyl]-N.sup.1-{(1S,2R)-N-[(t-butyloxy)car-
bonyl]-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3--
[(1-propylbutyl)sulfonyl]-D,L-alaninamide (LXXXVI, 3.4 g, 4.2
mmole) in methanol (50 ml) is added to a Fisher-Porter bottle.
After degassing with nitrogen, palladium on carbon (5% Pd/C, 1.6 g,
Degussa E101 50% water) is added. The reaction vessel is purged
with nitrogen (40 psi, 4.times.) then pressurized to 50 psi with
hydrogen. After 15 minutes, HPLC analysis indicates complete
reaction. The catalyst is removed by filtration through celite, and
the filtrate concentrated under reduced pressure to give
N.sup.1-{(1S,2R)-N-[(t-butyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-[-
(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D,L-ala-
nine (LXXXVII), M+H=668.
Preparation 24
N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydrox-
ypropyl}-N.sup.2-{[tetrahydropyran-4-yloxy]carbonyl}-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide trifluoroacetate (X-LXXXIX)
[1387] ##STR64##
[1388] Tetrahydro-4H-pyran-4-ol (1.0 g, 9.8 mmole) is mixed with
acetonitrile (50 ml). Di-(N-succinimidyl)carbonate (3.5 g, 13.5
mmole) is then added and stirred for 42 hours at 20-25.degree.. The
reaction mixture is then concentrated under reduced pressure,
redissolved in ethyl acetate, and washed with aqueous hydrochloric
acid (1 N), saturated sodium bicarbonate solution, and saline. The
phases are separated and the organic phase is dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude material is recrystallized from hot ethyl acetate and hexane
to give
1-{[(tetrahydro-2H-pyran-4-yloxy)carbonyl]oxy}pyrrolidine-2,5-dione,
M+Na=266.
[1389]
N.sup.1-{(1S,2R)-N-[(benzyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3--
[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D,L-al-
anine (LXXXVII, EXAMPLE 101, 251 mg, 0.31 mmole) is mixed with
1-{[(tetrahydro-2H-pyran-4-yloxy)carbonyl]-oxy}pyrrolidine-2,5-dione
(100 mg) in methylene chloride (3 ml). Triethylamine (70 .mu.l,
0.51 mmole) is added and the mixture stirred at 20-25.degree.
overnight. The reaction mixture is diluted with ethyl acetate and
washed with citric acid (5%), saturated sodium bicarbonate
solution, and saline. The phases are separated and the organic
phase is dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The crude material is purified by reverse
phase HPLC using a gradient solvent of acetonitrile in water with
0.5% trifluoroacetic acid to give of
N.sup.1-{(1S,2R)-N-[(benzyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-[(3-eth-
ylbenzyl)amino]-2-hydroxypropyl}-N.sup.2-{[tetrahydropyran-4-yloxy]carbony-
l}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide (LXXXVIII,
M+H=830.
[1390]
N.sup.1-{(1S,2R)-N-[(benzyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3--
[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.sup.2-{[tetrahydropyran-4-yloxy]-
carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide (LXXXVIII,
163 mg, 0.20 mmole) in methanol/tetrahydrofuran (1/1, 10 ml) is
added to a Fisher-Porter bottle. After degassing with nitrogen,
palladium on carbon (5% Pd/C, 88 mg, Degussa E101 50% water) is
added. The reaction vessel is purged with 40 psi nitrogen
(4.times.) then pressurized to 50 psi with hydrogen. After 25
minutes, HPLC analysis indicates the reaction is complete. The
catalyst is removed by filtration through celite, and the filtrate
concentrated under reduced pressure. The crude material is purified
by reverse phase HPLC using a gradient solvent of acetonitrile in
water with 0.5% trifluoroacetic acid to give
N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydrox-
ypropyl}-N.sup.2-{[tetrahydropyran-4-yloxy]carbonyl}-3-[(1-propylbutyl)sul-
fonyl]-D,L-alaninamide trifluoroacetate (X-LXXXIX), M+H=696.
Preparation 25
N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydrox-
ypropyl}-N.sup.2-(4-methoxybenzoyl)-3-[(1-propylbutyl)sulfonyl]-D,L-alanin-
amide hydrochloride (X-LXXXIX)
[1391] ##STR65##
[1392]
N.sup.1-{(1S,2R)-N-[(t-benzyloxy)carbonyl]-1-(3,5-difluorobenzyl)--
3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1-propylbutyl)sulfonyl]-D,L--
alanine (LXXXVII, EXAMPLE 101, 150 mg, 0.22 mmole) in methylene
chloride (1 ml). p-anisoyl chloride (32 .mu.l, 0.22 mmole) and
4-methylmorpholine (60 .mu.l, 0.55 mmole) are added. After stirring
at 20-25.degree. for 10 minutes, HPLC indicates the reaction is
complete. The reaction mixture is diluted with ethyl acetate and
washed with saturated sodium bicarbonate solution, citric acid (5%)
and saline. The phases are separated and the organic phase is dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude material is purified on silica gel using flash
chromatography (ethyl acetate 20-50% in hexane as eluant to give
N.sup.1-{(1S,2R)-N-[(t-butyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-[-
(3-ethylbenzyl)-amino]-2-hydroxypropyl}-N.sup.2-(4-methoxybenzoyl)-3-[(1-p-
ropylbutyl)sulfonyl]-D,L-alaninamide, (LXXXVIII) M+H=802.
[1393]
N.sup.1-{(1S,2R)-N-[(t-butyloxy)carbonyl]-1-(3,5-difluorobenzyl)-3-
-[(3-ethylbenzyl)-amino]-2-hydroxypropyl}-N.sup.2-(4-methoxybenzoyl)-3-[(1-
-propylbutyl)sulfonyl]-D,L-alaninamide, (LXXXVIII, 114 mg, 0.14
mmole) in hydrochloric acid (4 N, 1 ml) in dioxane. After stirring
for 10 minutes at 20-25.degree., the solvent is removed under
reduced pressure to give
N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydrox-
ypropyl}-N.sup.2-(4-methoxybenzoyl)-3-[(1-propylbutyl)sulfonyl]-D,L-alanin-
amide hydrochloride,
Preparation 26
N.about.1.about.-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-
-2-hydroxypropyl}-N.about.2.about.-{[[[(3R)-5-oxopyrrolidin-3-yl]methyl]ox-
y]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide
hydrochloride (X-LXXXIX)
[1394] ##STR66##
[1395] Di-(N-succinimidyl)carbonate (3.1 g, 12.3 mmole) and
pyridine (1.7 ml, 21.1 mmole) pyridine is added to
(R)-(-)-5-(hydroxymethyl)-2-pyrrolidinone (1.0 g, 8.8 mmole) in
acetonitrile (50 ml). After stirring for 18 hours at 20-25.degree.,
the reaction mixture is concentrated under reduced pressure,
redissolved in ethyl acetate, and washed with saturated sodium
bicarbonate solution and saline. The organic phase is dried over
sodium sulfate, filtered, and concentrated under reduced pressure
to give
1-[({[(2S)-5-oxopyrrolidin-2-yl]methoxy}carbonyl)oxy]pyrrolidine-2,5-dion-
e, M+H 257.
[1396] The compound of example 101 (200 mg, 0.30 mmole) and
1-[({[(2S)-5-oxopyrrolidin-2-yl]methoxy}carbonyl)oxy]pyrrolidine-2,5-dion-
e (108 mg, 0.45 mmole) are mixed in methylene chloride (5 ml). To
the reaction mixture is added triethylamine (60 .mu.l, 0.45 mmole)
and stirred at 20-252 overnight. The reaction mixture is diluted
with ethyl acetate and washed with citric acid (5%), saturated
sodium bicarbonate solution, and saline. The organic phase is dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude material was purified by reverse phase HPLC
using a gradient solvent of acetonitrile in water with 0.5%
trifluoroacetic acid to give
N.sup.1-{(1S,2R)-]-1-(3,5-difluorobenzyl)-3-[(N-[(t-butyloxy)carbonyl])-(-
3-ethylbenzyl)amino]-2-hydroxypropyl}-N.sup.2-{[[[(3R)-5-oxopyrrolidin-3-y-
l]methyl]oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide,
M+H=809.
[1397]
N.sup.1-{(1S,2R)-]-1-(3,5-difluorobenzyl)-3-[(N-[(t-butyloxy)carbo-
nyl])-(3-ethylbenzyl)amino]-2-hydroxypropyl}-N.sup.2-{[[[(3R)-5-oxopyrroli-
din-3-yl]methyl]-oxy]carbonyl}-3-[(1-propylbutyl)sulfonyl]-D,L-alaninamide
(247 mg, 0.31 mmole) is mixed with dioxane (2 ml, 4 N hydrochloic
acid). After stirring for 10 minutes at 20-25.degree., the solvent
was removed under reduced pressure to give the title compound,
M+H=709.
[1398] The following compounds in table 1 are prepared essentially
according to the procedures described in the schemes, examples and
preparations set forth herein. The names in table 1 were generated
at least in part by using the Advanced Chemistry Development Inc.
(ACD) nomenclature program, IUPAC Name Batch Version 4, 4.5 or 5,
or Chemdraw Ultra versions 6.0 or 6.02. TABLE-US-00004 TABLE 1 Low
Res Mass Spec Structure Compound Name(s) M + H ##STR67##
3-(butylsulfinyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- [(methoxy)carbonyl]-D- alaninamide
568 ##STR68## S-butyl-N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- [(methoxy)carbonyl]-D-
cysteinamide 552 ##STR69## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(4,4,4-
trifluorobutyl)sulfonyl]-D- alaninamide hydrochloride 714 ##STR70##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(4,4,4-
trifluorobutyl)sulfinyl]-D- alaninamide hydrohloride 698 ##STR71##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-S-(4,4,4-
trifluorobutyl)-D-cysteinamide 682 ##STR72##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- [(methoxy)carbonyl]-D- alaninamide
hydrochloride 584 ##STR73## 3-(butylsulfonyl)-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-[(2,2,2-
trifluoroethoxy)carbonyl]-D- alaninamide hydrochloride 652
##STR74## N.about.2.about.-[(2-
cyanoethoxy)carbonyl]-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-
(butylsulfonyl)-D-alaninamide hydrochloride 623 ##STR75##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[(3R)-
pyrrolidin-3-yl]carbonyl}-D,L- alaninamide dihydrochloride 639
##STR76## 3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[(3S)- tetrahydrofuran-3-
yloxy]carbonyl}-D-alaninamide hydrochloride 640 ##STR77##
N.about.2.about.-{[2- (acetylamino)ethoxy]carbonyl}-
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-D-alaninamide trifluoroacetate 655 ##STR78##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- {[[(pyridin-3-
yl)methyl]oxy]carbonyl}-D- alaninamide hydrochloride 661 ##STR79##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- {[[(pyridin-4-
yl)methyl]oxy]carbonyl}-D- alaninamide hydrochloride 661 ##STR80##
3-(butylsulfonyl)-N+113 2.about.-
[(methoxy)carbonyl]-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3- (cyclopropylamino)-2-
hydroxypropyl}-D-alaninamide hydrochloride 506 ##STR81##
3-(butylsulfonyl)-N.about.2.about.-[(2-
cyanoethoxy)carbonyl]-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3- (cyclopropylamino)-2-
hydroxypropyl}-D-alaninamide hydrochloride 545 ##STR82##
N.about.2.about.-[(benzyloxy)carbonyl]-3-
(butylsulfonyl)-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- methylbutyl)amino]-2-
hydroxypropyl}-D-alaninamide hydrochloride 612 ##STR83##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- methylbutyl)amino]-2-
hydroxypropyl}-N.about.2.about.- [(methyloxy)carbonyl]-D-
alaninamide hydrochloride 536 ##STR84## N.about.2.about.-[(2-
cyanoethoxy)carbonyl]-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3- (cyclopropylamino)-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 587 ##STR85##
N.about.2.about.-{[2- (acetylamino)ethoxy]carbonyl}-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-
(cyclopropylamino)-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 619 ##STR86##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
methylbutyl)amino]-2- hydroxypropyl}-N.about.2.about.-
[(methyloxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 578 ##STR87## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
methylbutyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 654 ##STR88##
N.about.2.about.-{[2-(diethylamino)-2-
oxoethoxy]carbonyl}-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 725 ##STR89##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
[(methoxy)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 626 ##STR90## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- [(isopropoxy)carbonyl]-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 654 ##STR91##
N.about.2.about.- [(cyclopropylmethoxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 666 ##STR92##
N.about.2.about.-[(allyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide trifluoroacetate 652 ##STR93##
N.about.2.about.-[(2- cyanoethoxy)carbonyl]-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
trifluoroacetate 665 ##STR94## N.about.2.about.-{[2-
(acetylamino)ethoxy]carbonyl}- N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 697 ##STR95##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[[(pyridin-3-
yl)methyl]oxy]carbonyl}-D- alaninamide hydrochloride 703 ##STR96##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[[(pyridin-4-
yl)methyl]oxy]carbonyl}-D- alaninamide hydrochloride 703 ##STR97##
benzyl(1R)-1-[({(1S,2R)-1- (3,5-difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}amino)carbonyl]-3-
(methylsulfonyl)propylcarbamate 632 ##STR98##
N.about.2.about.-[(benzyloxy)carbonyl]-3-
(butylsulfonyl)-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-D-alaninamide trifluroacetate 660 ##STR99##
N.about.2.about.-[(benzyloxy)carbonyl]-3-
(butylsulfonyl)-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-L-alaninamide trifluroacetate 660 ##STR100##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-((1S,2S)-1-(3,5- difluorobenzyl)-2-hydroxy-3-
{[(1R)-2-hydroxy-1- phenylethyl]amino}propyl)-3-
[(1-propylbutyl)sulfonyl]-D- alaninamide 704 ##STR101##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-((1S,2S,)-1-(3,5- difluorobenzyl)-2-hydroxy-3-
{[(1R)-2-methoxy-1- phenylethyl]amino}propyl)-3-
[(1-propylbutyl)sulfonyl]-D- alaninamide 718 ##STR102##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-((1S,2S)-1-(3,5- difluorobenzyl)-2-hydroxy-3-
{[(1S)-2-methoxy-1- phenylethyl]amino}propyl)-3-
[(1-propylbutyl)sulfonyl]-D- alaninamide 718 ##STR103##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-((1S,2R)-1-(3,5- difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopropyl]amino}- 2-hydroxypropyl)-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide 728 ##STR104##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.-
{[(prop-2-ynyl)oxy]carbonyl}- D-alaninamide trifluoroacetate 650
##STR105## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(2-
methoxyethylcarbonyl)-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 670 ##STR106## N.about.2.about.-{[(3R)-1-
acetylpyrrolidin-3- yl]carbonyl}-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 723 ##STR107## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[(3S)- tetrahydrofuran-3-
yloxy]carbonyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
trifluoroacetate 682 ##STR108## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[(3S)- tetrahydrofuran-3-
yloxy]carbonyl}-3-[(1- propylbutyl)sulfonyl]-L- alaninamide
trifluoroacetate 682 ##STR109##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide trifluoroacetate 702
##STR110## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-L- alaninamide trifluoroacetate 702
##STR111## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-((1S,2R)-1-(3,5- difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopropyl]amino}- 2-hydroxypropyl)-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 728
##STR112## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 702
##STR113## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
methylbutyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide 654 ##STR114##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-
(cyclopropylamino)-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 624
##STR115## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-
[(cyclopropylmethyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl}-D,L- alaninamide trifluoroacetate 638
##STR116## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2S)-1-(3,5- difluorobenzyl)-3-[(3-
ethylphenyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 688
##STR117## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-[(1S,2R)-1-(3,5- difluorobenzyl)-2-hydroxy-3-
({2-[3- (trifluoromethyl)phenyl]ethyl}amino)propyl]-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 756
##STR118## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[[(pyridin-3-
yl)methyl]oxy]carbonyl}-D,L- alaninamide hydrochloride 703
##STR119## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[(3S)-
tetrahydrofuran-3- yloxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 682
##STR120## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[(3R)-
tetrahydrofuran-3- yloxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 682
##STR121## N.about.1.about.-{(1S,2R)-1-benzyl-3-[3-
methoxybenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[(3S)-
tetrahydrofuran-3- yloxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 648
##STR122## N.about.2.about.-{[(3R)-1- acetylpyrrolidin-3-
yl]carbonyl}-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
trifluoroacetate 723 ##STR123## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[(3R)-pyrrolidin-3-
yl]carbonyl}-D,L-alaninamide dihydrochloride 681 ##STR124##
N.about.2.about.-{[(3R)-1- benzylpyrrolidin-3-
yl]carbonyl}-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 771 ##STR125## N.about.1.about.-{(1S,2R)-1-
(3,5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[(3S)-
1,1-dioxidotetrahydrothien-3- yloxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 730
##STR126## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[(3S)-
tetrahydrothiophen-3- yloxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 698
##STR127## N.about.2.about.-(cyclopentylcarbonyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 680 ##STR128##
N.about.2.about.-(cyclohexylcarbonyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 694 ##STR129##
N.about.1.about.-[(1S,2R)-3- (cyclopropylamino)-1-(3,5-
difluorobenzyl)-2- hydroxypropyl]-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[tetrahydropyran-4-
yloxy]carbonyl}-D,L- alaninamide hydrochloride 618 ##STR130##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[tetrahydropyran-4-
yloxy]carbonyl}-D,L- alaninamide trifluoroacetate 696 ##STR131##
N.about.1.about.-{(1S,2R)-1-(3,5- diflourobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[1-
(methylsulfonyl)piperidin-4- yloxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 773
##STR132## N.about.2.about.-{[1-acetylpiperidin-4-
yloxy]carbonyl}-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
trifluoroacetate 737 ##STR133## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[[[(3S)- 5-oxopyrrolidin-3-
yl]methyl]oxy]carbonyl}-3-[(1- propylbutyl)sulfonyl]-D,L-
alaninamide hydrochloride 709 ##STR134##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[[[(3R)-
5-oxopyrrolidin-3- yl]methyl]oxy]carbonyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoroacetate 709
##STR135## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-{[[2-
methoxyethyl]oxy]carbonyl}-3- [(1-propylbutyl)sulfonyl]D,L-
alaninamide hydrochloride 670 ##STR136##
N.about.2.about.-[(benzyloxy)carbonyl]-3-
(butylsulfonyl)-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-D,L-alaninamide 660 ##STR137##
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3- methoxybenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- [(benzyloxy)carbonyl]-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 668 ##STR138##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-((1S,2R)-1-(3,5- difluorobenzyl)-2-hydroxy-3-
{[2-(3- methoxyphenyl)ethyl]amino}propyl)- 3-[(1-
propylbutylsulfonyl]-D,L- alaninamide trifluoroacetate 718
##STR139## N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.5.about.,N.about.5.about.-
dipropyl-L-glutamamide trifluoroacetate 681 ##STR140##
N.about.2.about.-[(benzyloxy)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.5.about.,N.about.5.about.-
dipropyl-D-glutamamide 681 ##STR141##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(3,3,3- trifluoropropanoyl)-D-
alaninamide hydrochloride 636 ##STR142##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- (trifluoroacetyl)-D- alaninamide
hydrochloride 622 ##STR143##
N.about.2.about.-acetyl-3-(butylsulfonyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-D-alaninamide hydrochloride
568 ##STR144## 3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(pyridin-
4-ylcarbonyl)-D-alaninamide dihydrochloride 631 ##STR145##
3-(butylsulfonyl)-N.about.2.about.-
(cyclopropylcarbonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-D-alaninamide hydrochloride 594 ##STR146##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.(beta- alanyl)-D-alaninamide
dihydrochloride 597 ##STR147## 3-(butylsulfonyl)-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.glycyl-D- alaninamide
dihydrochloride 583 ##STR148## 3-(butylsulfonyl)-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.(N,N- dimethylglycyl)-D-alaninamide
dihydrochloride 611 ##STR149## 3-(butylsulfonyl)-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.(N,N- dimethyl-beta-alanyl)-D-
alaninamide dihydrochloride 625 ##STR150##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- (methoxyacetyl-D-alaninamide 598
##STR151## 3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(pyridin-
3-ylcarbonyl)-D-alaninamide dihydrochloride 631 ##STR152##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-[(2,4- dimethyl-1,3-thiazol-5-
yl)carbonyl]-D-alaninamide hydrochloride 665 ##STR153##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-{[3- (trifluoromethyl)-1H-pyrazol-
4-yl]carbonyl}-D-alaninamide hydrochloride 688 ##STR154##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-[(3- methyl-1H-pyrazol-5-
yl)carbonyl]-D-alaninamide hydrochloride 634 ##STR155##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(1H- imidazol-4-ylacetyl)-D-
alaninamide dihydrochloride 620 ##STR156##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(pyrazin-
2-ylcarbonyl)-D-alaninamide dihydrochloride 632 ##STR157##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-[(6- hydroxypyridin-3-yl)carbonyl]-
D-alaninamide dihydrochloride 647 ##STR158##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-
(cyclopropylamino)-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- (pyridin-4-ylcarbonyl)-D-
alaninamide dihydrochloride 553 ##STR159##
N.about.2.about.-acetyl-3-(butylsulfonyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
methylbutyl)amino]-2- hydroxypropyl}-D-alaninamide hydrochloride
520 ##STR160## N.about.1.about.-[(1S,2R)-3-
(cyclopropylamino)-1-(3,5- difluorobenzyl)-2-
hydroxypropyl]-N.about.2.about.- (cyclopropylcarbonyl)-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 558 ##STR161##
N.about.2.about.-acetyl-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- methylbutyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 562 ##STR162## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- (pyridin-4-ylcarbonyl)-D-
alaninamide dihydrochloride 673 ##STR163##
N.about.2.about.-[(5-bromoopyridin-3-
yl)carbonyl]-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide 751
##STR164## N.about.2.about.-[(5-chloropyridin-3-
yl)carbonyl]-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 707 ##STR165## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.(3- fluorobenzoyl)-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 690 ##STR166##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(5-
methylpyridin-3-yl)carbonyl]- 3-[(1-propylbutyl)sulfonyl]-D-
alaninamide dihydrochloride 687
##STR167## N.about.2.about.-phenylglycyl-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide 701
##STR168## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- {[3-(trifluoromethyl)-1H-
pyrazol-4-yl]carbonyl}-D- alaninamide hydrochloride 730 ##STR169##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(3-
methyl-1H-pyrazol-5- yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D-
alaninamide hydrochloride 676 ##STR170##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.-
(1,3-thiazol-4-ylcarbonyl)-D- alaninamide hydrochloride 679
##STR171## N.about.2.about.-[(1-acetylpiperidin-4-
yl)carbonyl]-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 721 ##STR172## N.about.2.about.-[4-
(acetylamino)butanoyl]-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 695 ##STR173##
N.about.2.about.-acetyl-beta-alanyl-N.about.1.about.-
{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 681 ##STR174##
N.about.2.about.-(chloroacetyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 644 ##STR175##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
(methoxyacetyl)-3-[(1- propylbutyl)sulfonyl]-D- alaninamide 640
##STR176## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(3-
methoxypropanoyl)-3-[(1- propylbutyl)sulfonyl]-D- alaninamide 654
##STR177## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(2,2-
dimethylpropanoyl)-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 652 ##STR178## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- isobutyryl-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 638 ##STR179##
N.about.2.about.-butyryl-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 638 ##STR180##
N.about.2.about.-acetyl-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
hydrochloride 610 ##STR181## N.about.1.about.-((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-3-[(1- propylbutyl)sulfonyl]-N.about.2.about.-
[(pyridin-3-yl)carbonyl]-D- alaninamide trifluoracetate 699
##STR182## N.about.1.about.-((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-3-[(1- propylbutyl)sulfonyl]-
N.about.2.about.-[(pyridin-4-yl)carbonyl]-D- alaninamide
trifluoracetate 699 ##STR183## N.about.1.about.-((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-N.about.2.about.-(3- hydroxybenzoyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide trifluoracete 714 ##STR184##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- [(pyridin-3-yl)carbonyl]-D-
alaninamide 673 ##STR185## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(3- hydroxybenzoyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide 688 ##STR186##
N.about.2.about.-(cyclopropylcarbonyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide hydrochloride 636 ##STR187##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-propionyl-
3-[(1-propylbutyl)sulfonyl]-D- alaninamide 624 ##STR188##
3-[butylsulfonyl]-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-[(pyridin-
3-yl)carbonyl]-D,L-alaninamide hydrochloride 631 ##STR189##
N.about.1.about.-((1S,2R)-1-(3,5- difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-N.about.2.about.-(3- hydroxybenzoyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide trifluoracete 714 ##STR190##
N.about.1.about.-((1S,2R)-1-(3,5- difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopropyl]amino}- 2-hydroxypropyl)-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.- [(pyridin-4-yl)carbonyl]-D-
alaninamide trifluoracetate 699 ##STR191##
N.about.1.about.-{(1S,2S)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(6-oxo-
1,4,5,6-tetrahydropyridazin-3- yl)carbonyl]-3-[(1-
propylbutyl)sulfonyl]alaninamide hydorchloride 692 ##STR192##
5-oxo-D-prolyl-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]alaninamide
hydrochloride 679 ##STR193##
5-oxo-L-prolyl-N.about.1.about.-{(1S,2R)-
1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]alaninamide
hydrochloride 679 ##STR194## N.about.1.about.-{(1S,2S)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-[3-(4-oxo-
2-thioxo-1,3-thiazolidin-3- yl)propanoyl]-3-[(1-
propylbutyl)sulfonyl]alaninamide 755 ##STR195##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
[(piperidin-4-yl)carbonyl]-3- [(1-propylbutyl)sulfonyl]-D,L-
alaninamide dihydrochloride 679 ##STR196##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(2,4-
dimethyl-1,3-thiazol-5- yl)carbonyl]-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 707 ##STR197##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(2-
methyl-4-(trifluoromethyl)- 1,3-thiazol-5-yl)carbonyl]-3-
[(1-propylbutyl)sulfonyl]-D,L- alaninamide 761 ##STR198##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(3,5-
dimethylisoxazol-4- yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L-
alaninamide hydrochloride 691 ##STR199##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(3-
methyl-1H-pyrazol-5- yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L-
alaninamide triflouroacetate 676 ##STR200##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(1H-
pyrazol-4-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L-
alaninamide hydrochloride 662 ##STR201##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(1H-
imidazol-5-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L-
alaninamide hydrochloride 662 ##STR202##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(1H-
imidazol-4-ylacetyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
dihydrochloride 676 ##STR203## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.-
[(pyrazin-2-yl)carbonyl]-D,L- alaninamide 674 ##STR204##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(3,5-
dihydroxypyridin-4- yl)carbonyl]--3-[(1- propylbutyl)sulfonyl]-D,L-
alaninamide hydrochloride 705 ##STR205##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(6-
hydroxypyridin-3-yl)carbonyl]- 3-[(1-propylbutyl)sulfonyl]-
D,L-alaninamide trifluoroacetate 689 ##STR206##
N.about.2.about.-[(6-chloropyridin-3-
yl)carbonyl]-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 707 ##STR207## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.-
[(pyridin-4-yl)carbonyl]-D,L- alaninamide dihydrochloride 673
##STR208## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(pyridin-
3-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide 673
##STR209## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.-
[(pyridin-2-yl)carbonyl]-D,L- alaninamide hydrochloride 673
##STR210## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[1H-
indole-6-carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 711 ##STR211## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-N.about.2.about.-
(2,3,4-trimethoxybenzoyl)-D,L- alaninamide hydrochloride 762
##STR212## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-[(pyridin-
2-yl)carbonyl]-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 686 ##STR213## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(3- hydroxybenzoyl)-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide 688 ##STR214##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(3-
methylbenzoyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 686 ##STR215## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(3- ethylbenzoy)-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide 700 ##STR216##
N.about.2.about.-(3-chlorobenzoyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 706 ##STR217##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(4-
methylbenzoyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 686 ##STR218## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(4- methylbenzoyl)-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 702 ##STR219##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(4-
triflluoromethylbenzoyl)-3- [(1-propylbutyl)sulfonyl]-D,L-
alaninamide hydrochloride 740
##STR220## N.about.2.about.-(cyclohexylcarbonyl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 678 ##STR221##
N.about.2.about.(benzoyl)- N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide 672 ##STR222##
N.about.2.about.(benzoyl)- N.about.1.about.-{(1S,2R)-3-
(cyclopropylamino)-1- (3,5- difluorobenzyl)-2-
hydroxypropyl]-3-[(1- propylbutyl)sulfonyl]alaninamide
hydrochloride 594 ##STR223## N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- (phenylacetyl)-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide 686 ##STR224##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-(3-
phenylpropanoyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
trifluoroacetate 700 ##STR225## N-(3-({(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)-3-oxo-2- {[(1-
propylbutyl)sulfonyl]methyl}propyl)benzamide 686 ##STR226##
N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-
N.about.2.about.-(cyclopropylacetyl)-3-
[(1-propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 616
##STR227## N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-
N.about.2.about.-[(methylsulfonyl)acetyl]-
3-[(1-propylbutyl)sulfonyl]- D,L-alaninamide trifluoroacetate 654
##STR228## N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-
N.about.2.about.-[(methylthio)acetyl]-3-
[(1-propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 622
##STR229## N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}- N.about.2.about.-(4-hydroxy-4-
oxobutanoyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 634 ##STR230## N.about.1.about.-{(1S,2R)-1-benzyl-2-
hydroxy-3-[(3- methoxybenzyl)amino]propyl}-
N.about.2.about.-[4-(methylamino)-4- oxobutanoyl]-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 647 ##STR231##
N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-](3-
methoxybenzyl)amino]propyl}- N.about.2.about.-(4-methoxy-4-
oxobutanoyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide
hydrochloride 648 ##STR232##
N-(methylsulfonyl)glycyl-N.about.1.about.-
{(1S,2R)-1-benzyl-2-hydroxy-3- [(3- methoxybenzyl)amino]propyl}-3-
[(1-propylbutyl)sulfonyl]-D,L- alaninamide hydrochloride 669
##STR233## N.about.2.about.-acetyl-N.about.1.about.-{(1S,2R)-1-
benzyl-2-hydroxy-3-[(3- methoxybenzyl)amino]propyl}-3-
(phenylsulfonyl)-D,L- alaninamide hydrochloride 554 ##STR234##
N-{(1S,2R)-1- benzyl-2-hydroxy-3-[(3- methoxybenzyl)amino]propyl}-
(2S)-2-[(4-methoxy-4- oxobutanoyl)amino]-5-oxo-5-
piperidin-1-ylpentanamide hydrochloride 611 ##STR235## (2R)-2-
{[(benzyloxy)carbonyl]amino}- N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-5- oxo-5-piperidin-1- ylpentanamide
hydrochloride 631 ##STR236## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]-propyl}- (2R)-2-[(3-ethoxy-3-
oxopropanoyl)amino].5-oxo-5- piperidin-1-ylpentanamide
hydrochloride 611 ##STR237##
N.about.1.about.-{(1S,2R)-1-benzyl-3-[(3- methoxybenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.-(4- methoxy-4-oxobutanoyl)-
N.about.5.about.,N.about.5.about.-dipropyl-D- glutamamide
hydrochloride 627 ##STR238## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}- (2R)-2-[(4-methoxy-4-
oxobutanoyl)amino]-5-oxo-5- piperidin-1-ylpentanamide hydrochloride
611 ##STR239## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}- (2R)-2-[5-methoxy-5-
oxopentanoyl)amino]-5-oxo-5- piperidin-1-ylpentanamide
hydrochloride 625 ##STR240## 2-N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-1-
[(butylsulfonyl)methyl]-2- oxoethyl acetate 569 ##STR241##
S-butyl-N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-D-cysteinamide dihydrochloride
494 ##STR242## 3-(butylsulfinyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-D-alaninamide 510 ##STR243##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-D-alaninamide bis(trifluoroacetate) 526 ##STR244##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-L-alaninamide dihydrochloride 526 ##STR245##
3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3- (isopentylamino)propyl]-D- alaninamide
dihydrochloride 478 ##STR246## N.about.1.about.-((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-3-[(1- propylbutyl)sulfonyl]-D- alaninamide
bis(trifluoroacetate 594 ##STR247##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-L- alaninamide dihydrochloride 568 ##STR248##
N.about.1.about.-[(1S,2R)-3- cyclopropylamino)-1-(3,5-
difluorobenzyl)-2- hydroxypropyl]-3-[(1- propylbutyl)sulfonyl]-D-
alaninamide dihydrochloride 490 ##STR249##
N.about.1.about.-[(1S,2R)-1-(3,5- difluorobenzyl)-2-
hydroxypropyl-3- (isopentylamino)]-3-[(1- propylbutyl)sulfonyl]-D-
alaninamide dihydrochloride 520 ##STR250##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D- alaninamide dihydrochloride 568 ##STR251##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]alaninamide hydrochloride 568 ##STR252##
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
(phenoxyacetyl)-3-[(1- propylbutyl)sulfonyl]alaninamide
hydrochloride 702 ##STR253## N.about.2.about.-[(5-chlorothien-2-
yl)sulfonyl]-N.about.1.about.-{(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide 748
##STR254## N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
(phenylsulfonyl)-3-[(1- propylbutyl)sulfonyl]-D,L- alaninamide 708
##STR255## N.about.2.about.-[(benzylamino)carbonyl]-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-[(1-
propylbutyl)sulfonyl]-D,L- alaninamide 701 ##STR256##
4-({(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)-4-oxo-3- {[(1-
propylbutyl)sulfonyl]methyl}butanoic acid trifluoroacetate 611
##STR257## 4-({(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}amino)-3- [(isopentylsulfonyl)methyl]-4-
oxobutanoic acid hydrochloride 549 ##STR258## methyl
4-({(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}amino)-3- [(isopentylsulfonyl)methyl]-4-
oxobutanoate hydrochloride 563 ##STR259##
N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-2-
[(isopentylsulfonyl)methyl]succinamide hydrochloride 548 ##STR260##
N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-2- [(isopentylsulfonyl)methyl]-
N.about.4.about.-methylsuccinamide hydrochloride 562 ##STR261##
N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-2-
[(isopentylsulfonyl)methyl]N.about.4.about.,N.about.4.about.-dimethylsucc-
inamide hydrochloride 576 ##STR262## N-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-(4,4-
dimethyl-2,5- dioxoimidazolidin-1-yl)-2- {[(1-
propylbutyl)sulfonyl]methyl}propanamide 693 ##STR263##
N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-3-(4,4- dimethyl-2,5- dioxoimidazolidin-1-yl)-2-
{[(1- propylbutyl)sulfonyl]methyl}propanamide (first isomer) 693
##STR264## N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-3-(4,4- dimethyl-2,5-
dioxoimidazolidin-1-yl)-2- {[(1-
propylbutyl)sulfonyl]methyl}propanamide (second isomer) 693
##STR265## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-3- (ethylsulfonyl)-2-
{[(isobutylsulfonyl)amino]methyl}propanamide hydrochloride 598
##STR266## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-3- (ethylthio)-2-
{[(isobutylsulfonyl)amino]methyl}propanamide hydrochloride 566
##STR267## (2S)-N-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-2- [(isopentylsulfonyl)amino]-4-
(methylsulfonyl)butanamide hydrochloride 598 ##STR268##
N.about.1.about.-{(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-
N.about.2.about.-(isopentylsulfonyl)-L- methioninamide
hydrochloride 566 ##STR269## S-{3-({(1S,2R)-1-benzyl-2-
hydroxy-3-[(3- methoxybenzyl)amino]propyl}amino)-2-
[(isopentylsulfonyl)Methyl]-3- oxopropyl}ethanethioate
hydrochloride 579 ##STR270## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- hydroxy-3-[(1-
propylbutyl)sulfonyl]propanamide 535 ##STR271##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- hydroxy-3-
(isopentylsulfonyl)propanamide hydrochloride 507 ##STR272##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- hydroxy-3-[(3-
methoxyphenyl)sulfonyl]propanamide hydrochloride 543 ##STR273##
N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-2-hydroxy-4- (phenylsulfonyl)butanamide 561
##STR274## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- hydroxy-4-
(isopentylsulfonyl)butanamide hydrochloride 521 ##STR275##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-4- (isopentylsulfonyl)-2-
phenoxybutanamide hydrochloride 597 ##STR276##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-4- (isopentylsulfonyl)-2-(3-
methoxyphenoxy)butanamide hydrochloride 627 ##STR277##
3-[1-[({(1S,2R)-1-benzyl-2- hydroxy-3-[(3-
methoxybenzyl)amino]propyl}amino) carbonyl]-3-
(isopentylsulfonyl)propoxy]benzoic acid trifluoroacetate 641
##STR278## methyl 3-[1-[({(1S,2R)-1- benzyl-2-hydroxy-3-[(3-
methoxybenzyl)amino]propyl}amino)carbonyl]-3-
(isopentylsulfonyl)propoxy]benzoate hydrochloride 655 ##STR279##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- hydroxy-4-
(phenylsulfonyl)butanamide hydrochloride 527 ##STR280##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- hydroxy-4- (phenylthio)butanamide
hydrochloride 495 ##STR281## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- methoxy-4-
(phenylsulfonyl)butanamide hydrochloride 541 ##STR282##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- methoxy-4- (phenylthio)butanamide
hydrochloride 509 ##STR283## N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-4- (phenylsulfonyl)-2-
propoxybutanamide hydrochloride 569 ##STR284##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3-
methoxybenzyl)amino]propyl}-2- (benzyloxy)-4-
(phenylsulfonyl)butanamide hydrochloride 617 ##STR285##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3- methoxybenzyl)amino]propyl}-
N.about.2.about.-[(benzyloxy)carbonyl]- D,L-methioninamide
hydrochloride 566 ##STR286## (2S)-2-amino-N-{(1S,2R)-1-
benzyl-2-hydroxy-3-[(3- methoxybenzyl)amino]propyl}-5-
oxo-5-piperidin-1- ylpentanamide dihydrochloride 497 ##STR287##
N-{(1S,2R)-1-benzyl-2-hydroxy- 3-[(3- methoxybenzyl)amino]propyl}-
(2S)-2-[(2-ethoxy-2- oxoethanyl)amino]-5-oxo-5-
piperidin-1-ylpentanamide dihydrochloride 569 ##STR288##
(2R)-2-amino-N-{(1S,2R)-1- benzyl-2-hydroxy-3-[(3-
methoxybenzyl)amino]propyl}-5- oxo-5-piperidin-1- ylpentanamide
dihydrochloride 497 ##STR289## N-{(1S,2R)-1-benzyl-2-hydroxy-
3-[(3- methoxybenzyl)amino]propyl}- (2R)-2-[(2-ethoxy-2-
oxoethanyl)amino]-5-oxo-5- piperidin-1-ylpentanamide
dihydrochloride 583 ##STR290## N-{(1S,2R)-1-benzyl-2-hydroxy-
3-[(3- methoxybenzyl)amino]propyl}- (2R)-2-[(4-ethoxy-4-
oxobutanyl)amino]-5-oxo-5- piperidin-1-ylpentanamide
ditrifluoroacetate 611 ##STR291## methyl (1R)-[({(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]- 3-oxoheptylcarbamate ##STR292##
4-butyl-N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
(methoxycarbonyl)-D- homoserinamide ##STR293##
3-(2-butyl-1,3-dioxolan-2-yl)- N.about.1.about.-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.about.2.about.- (methoxycarbonyl)-D- alaninamide
##STR294## 3-(2-butyl-1,3-dioxan-2-yl)-
N.about.1.about.-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.about.2.about.-
(methoxycarbonyl)-D- alaninamide ##STR295## methyl
(1R)-1-[({(1S,2R)-1- (3,5-difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}amino)carbonyl]-
3,3-difluoroheptylcarbamate ##STR296## methyl (1R)-1-[({(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]- 3-fluoroheptylcarbamate ##STR297##
methyl (1R)-1-[({(1S,2R)-1- (3,5-difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}amino)carbonyl]-
4-oxooctylcarbamate ##STR298## methyl (1R)-1-[({(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]- 4-hydroxyoctylcarbamate ##STR299##
methyl (1R)-3-(2-butyl-1,3- dioxolan-2-yl)-1-[({(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]propylcarbamate ##STR300## methyl
(1R)-3-(2-butyl-1,3- dioxan-2-yl)-1-[({(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]propylcarbamate ##STR301## methyl
(1R)-1-[({(1S,2R)-1- (3,5-difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}amino)carbonyl]-
4-fluorooctylcarbamate ##STR302## methyl (1R)-1-[({(1S,2R)-1-
(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]- 4,4-difluorooctylcarbamate
##STR303## 3-(butylsulfonyl)-N.about.1.about.- {(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethynylbenzyl)amino]-2- hydroxypropyl}-
N.about.2.about.(methoxycarbonyl)-D- alaninamide ##STR304##
3-(butylsulfonyl)-N.about.1.about.- ((1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3- {[3-
(trifluoromethyl)benzyl]amino}propyl)-N.about.2.about.(methoxycarbonyl)-
D-alaninamide ##STR305## 3-(butylsulfonyl)-N.about.1.about.-
((1S,2R)-1-(3,5- difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopropyl]amino}- 2-hydroxypropyl)-
N.about.2.about.(methoxycarbonyl)-D- alaninamide ##STR306##
3-(butylsulfonyl)-N.about.1.about.- ((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)- N.about.2.about.(methoxycarbonyl)-D- alaninamide
##STR307## 3-(butylsulfonyl)-N.about.1.about.- [(1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3- ({1-[3-
(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-
N.about.2.about.(methoxycarbonyl)-D- alaninamide ##STR308##
N-{(1R)-3-(butylsulfonyl)-1- [({(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethynylbenzyl)amino]-2-
hydroxypropyl}amino)carbonyl]propyl}-3-methyl-1H-pyrazole-5-
carboxamide ##STR309## N-((1R)-3-(butylsulfonyl)-1-
{[((1S,2R)-1-(3,5- difluorobenzyl)-2-hydroxy-3- {[3-
(trifluoromethyl)benzyl]amino}propyl)amino]carbonyl}propyl)-
3-methyl-1H-pyrazole-5- carboxamide ##STR310##
N-((1R)-3-(butylsulfonyl)-1- {[((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-2-
hydroxypropyl)amino]carbonyl}propyl)-3-methyl-1H-pyrazole-5-
carboxamide ##STR311## N-((1R)-3-(butylsulfonyl)-1-
{[((1S,2R)-1-(3,5- difluorobenzyl)-3-{[1-(3-
ethynylphenyl)cyclopropyl]amino}-2-
hydroxypropyl)amino]carbonyl}propyl)-3-methyl-1H-pyrazole-5-
carboxamide ##STR312## N-[(1R)-3-(butylsulfonyl)-1-
({[(1S,2R)-1-(3,5- difluorobenzyl)-2-hydroxy-3- ({1-[3-
(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]amino}carbonyl)propyl]-3-
-methyl-1H- pyrazole-5-carboxamide ##STR313##
(2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-2-
{[(methylamino)carbonyl]amino}- 4-oxooctanamide ##STR314##
4-butyl-N.sup.1-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-N.sup.2-
[(methylamino)carbonyl]-D- homoserinamide ##STR315##
3-(2-butyl-1,3-dioxolan-2-yl)- N.sup.1-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.sup.2- [(methylamino)carbonyl]-D- alaninamide
##STR316## 3-(2-butyl-1,3-dioxan-2-yl)- N.sup.1-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-
hydroxypropyl}-N.sup.2- [(methylamino)carbonyl]-D- alaninamide
##STR317## (2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-4,4-difluoro-2-
{[(methylamino)carbonyl]amino}octanamide ##STR318##
(2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-4-fluoro-2-
{[(methylamino)carbonyl]amino}octanamide ##STR319##
(2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-2-
{[(methylamino)carbonyl]amino}- 5-oxononanamide ##STR320##
(2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-5-hydroxy-2-
{[(methylamino)carbonyl]amino}nonanamide ##STR321##
(2R)-4-(2-butyl-1,3-dioxolan- 2-yl)-N-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-
{[(methylamino)carbonyl]amino}butanamide ##STR322##
(2R)-4-(2-butyl-1,3-dioxan- 2-yl)-N-{(1S,2R)-1-(3,5-
difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-
{[(methylamino)carbonyl]amino}butanamide ##STR323##
(2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-5-fluoro-2-
{[(methylamino)carbonyl]amino}nonanamide ##STR324##
(2R)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2- hydroxypropyl}-5,5-difluoro-2-
{[(methylamino)carbonyl]amino}nonanamide ##STR325##
3-(butylsulfonyl)-N.sup.1-{(1S,2R)- 1-(3,5-difluorobenzyl)-3-[(3-
ethynylbenzyl)amino]-2- hydroxypropyl}-N.sup.2-
[(methylamino)carbonyl]-D- alaninamide ##STR326##
3-(butylsulfonyl)-N.sup.1-((1S,2R)- 1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[3- (trifluoromethyl)benzyl]amino}propyl)-N.sup.2-
[(methylamino)carbonyl]-D- alaninamide ##STR327##
3-(butylsulfonyl)-N.sup.1-((1S,2R)-
1-(3,5-difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-N.sup.2- [(methylamino)carbonyl]-D- alaninamide
##STR328## 3-(butylsulfonyl)-N.sup.1-((1S,2R)-
1-(3,5-difluorobenzyl)-3-{[1-(3- ethylphenyl)cyclopropyl]amino}-
2-hydroxypropyl)-N.sup.2- [(methylamino)carbonyl]-D- alaninamide
##STR329## 3-(butylsulfonyl)-N.sup.1-[(1S,2R)-
1-(3,5-difluorobenzyl)-2- hydroxy-3-({1-[3-
(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-N.sup.2-
[(methylamino)carbonyl]-D- alaninamide ##STR330##
4-Methyl-pyrazole-1-carboxylic acid {2-(butane-1-sulfonyl)-1-
[1-(3,5-difluoro-benzyl)-3-(3- ethynyl- benzylamino)-2-hydroxy-
propylcarbamoyl]-ethyl}-amide ##STR331##
4-Methyl-pyrazole-1-carboxylic acid {2-(butane-1-sulfonyl)-1-
[1-(3,5-difluoro-benzyl)-2- hydroxy-3-(3-
trifluoromethyl-benzylamino)- propylcarbamoyl]-ethyl}-amide
##STR332## 4-Methyl-pyrazole-1-carboxylic acid
(2-(butane-1-sulfonyl)-1- {1-(3,5-difluoro-benzyl)-3-[1- (3-ethyl-
phenyl)-cyclopropylamino]-2- hydroxy-propylcarbamoyl}- ethyl)-amide
##STR333## 4-Methyl-pyrazole-1-carboxylic acid
(2-(butane-1-sulfonyl)-1- {1-(3,5-difluoro-benzyl)-3-[1-
(3-ethynyl- phenyl)-cyclopropylamino]-2- hydroxy-propylcarbamoyl}-
ethyl)-amide ##STR334## 4-Methyl-pyrazole-1-carboxylic acid
(2-(butane-1-sulfonyl)-1- {1-(3,5-difluoro-benzyl)-2- hydroxy-3-[1-
(3-trifluoromethyl-phenyl)- cyclopropylamino]-
propylcarbamoyl}-ethyl)-amide
[1399] ##STR335## ##STR336## ##STR337## ##STR338## ##STR339##
##STR340## ##STR341## ##STR342## ##STR343## ##STR344## ##STR345##
##STR346## ##STR347## ##STR348## ##STR349## ##STR350##
##STR351##
* * * * *