U.S. patent application number 11/872471 was filed with the patent office on 2008-02-07 for 2, 8-disubstituted naphthyridine derivatives.
This patent application is currently assigned to Serenex, Inc.. Invention is credited to Thomas E. Barta, Gunnar J. Hanson, He Huang, Roy W. JR. Ware.
Application Number | 20080032991 11/872471 |
Document ID | / |
Family ID | 35457226 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080032991 |
Kind Code |
A1 |
Hanson; Gunnar J. ; et
al. |
February 7, 2008 |
2, 8-disubstituted Naphthyridine Derivatives
Abstract
Disclosed are compounds of formula A: ##STR1## and
pharmaceutically acceptable salts thereof, wherein R.sub.1,
R.sub.2, R.sub.2', R.sub.3, R.sub.21, A.sub.1, A.sub.2, X, and Z
are as defined herein. Compounds of formula A are useful in the
treatment of diseases and/or conditions related to cell
differentiation, such as cancer, inflammation, arthritis,
angiogenesis, or the like. Also disclosed are pharmaceutical
compositions comprising compounds of the invention and methods of
treating the aforementioned conditions using such compounds.
Inventors: |
Hanson; Gunnar J.; (Chapel
Hill, NC) ; Ware; Roy W. JR.; (Raleigh, NC) ;
Barta; Thomas E.; (Carrboro, NC) ; Huang; He;
(Chapel Hill, NC) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Serenex, Inc.
|
Family ID: |
35457226 |
Appl. No.: |
11/872471 |
Filed: |
October 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11196532 |
Aug 3, 2005 |
7282506 |
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11872471 |
Oct 15, 2007 |
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60598518 |
Aug 3, 2004 |
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Current U.S.
Class: |
514/253.04 ;
514/278; 514/300; 544/362; 546/123; 546/16 |
Current CPC
Class: |
A61P 21/00 20180101;
A61P 25/04 20180101; A61P 9/00 20180101; A61P 11/08 20180101; A61P
35/00 20180101; A61P 43/00 20180101; A61P 1/04 20180101; A61P 1/00
20180101; A61P 29/00 20180101; C07D 471/04 20130101; A61P 17/04
20180101; A61P 17/06 20180101; C07D 405/14 20130101; A61P 21/04
20180101; A61P 13/12 20180101; A61P 19/02 20180101; A61P 3/10
20180101 |
Class at
Publication: |
514/253.04 ;
514/278; 514/300; 544/362; 546/123; 546/016 |
International
Class: |
A61K 31/4375 20060101
A61K031/4375; A61K 31/4545 20060101 A61K031/4545; A61K 31/496
20060101 A61K031/496; A61P 19/02 20060101 A61P019/02; A61P 29/00
20060101 A61P029/00; A61P 35/00 20060101 A61P035/00; C07D 471/04
20060101 C07D471/04 |
Claims
1. A compound of the formula: ##STR56## or a pharmaceutically
acceptable salt thereof, wherein each independently represents a
single bond or a double bond; A.sub.1 is N, or an N-oxide; A.sub.2
is N, an N-oxide, NH, or N(C.sub.1-C.sub.6) alkyl; provided that
when is a single bond, then A.sub.2 is NH, or N(C.sub.1-C.sub.6)
alkyl; X is --NR.sub.xR.sub.y, or --C(O)R.sub.20; wherein R.sub.x,
and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
alkoxycarbonyl, arylalkoxycarbonyl, aryl, arylalkyl, --C(O)-aryl,
heteroaryl, heteroarylalkyl, or --C(O)heteroaryl; Z is a bond,
--CH.sub.2--, --NH--, --O--, --N(C.sub.1-C.sub.6 alkyl)-, --S--,
--S(O)--, --SO.sub.2--, --SO.sub.2NH--, or
--SO.sub.2N(C.sub.1-C.sub.6 alkyl)-; R.sub.1 is halogen,
C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, aryl, heteroaryl,
heterocycloalkyl, or C.sub.3-C.sub.8 cycloalkyl, each of which is
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, phenyl, or naphthyl,
wherein the phenyl and naphthyl groups are optionally substituted
with 1 or more groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, wherein each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); or
R.sub.6 and R.sub.7 and the nitrogen to which they are attached
form a ring having from 5 to 8 members, wherein the ring optionally
contains 1-3 additional heteroatoms selected from N, O, and S,
where the ring is optionally substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, amino, NH(C.sub.1-C.sub.6 alkyl), or
N(C.sub.1-C.sub.6 alkyl) (C.sub.1-C.sub.6 alkyl); R.sub.10 is
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl, heteroaryl,
or cycloalkyl, wherein the cyclic portions are optionally
substituted with 1, 2, or 3 groups that are independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN,
NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy;
wherein the heterocycloalkyl and the cycloalkyl portions of R.sub.1
and R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3; R.sub.2 and R.sub.3 are
independently H, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, --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), or aryl; R.sub.20 is H, OH,
C.sub.1-C.sub.6 alkoxy, or NR.sub.4R.sub.5; wherein R.sub.4 and
R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxy C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl,
cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl,
heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl,
heterocycloalkylalkynyl, aryl, heteroaryl, heteroarylalkyl,
heteroarylalkenyl, heteroarylalkynyl, arylalkyl, arylalkenyl, or
arylalkynyl, wherein the cyclic portion of each of the above is
unsubstituted or substituted with one or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, aryl
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 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, wherein R.sub.7 and
R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein the
alkyl is optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.6 alkoxycarbonyl, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl, 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) or CO.sub.2H; or R.sub.7 and R.sub.8 and
the nitrogen to which they are attached form a ring having from 5
to 8 members, wherein the ring optionally contains 1-3 additional
heteroatoms selected from N, O, and S, where the ring is optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, amino,
NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl); wherein the heterocycloalkyl and the
cycloalkyl portions of R.sub.4 and R.sub.5 are further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3; or
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a heterocycloalkyl ring, which is unsubstituted or substituted
with 1 or more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, aryl C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkanoyl, OH, .dbd.O, heteroaryl, heteroarylalkyl,
phenyl, naphthyl, --OCH.sub.2CH.sub.2O--, --OCH.sub.2O--, wherein
the heteroaryl, phenyl and naphthyl groups are unsubstituted or
substituted with 1 or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or
OCF.sub.3; R.sub.21 is H, CN, amino, monoalkylamino, dialkylamino,
OH, halogen, aryl, heteroaryl, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyl, --C(O)NH.sub.2,
--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); provided that R.sub.1 is halogen only when
Z is a bond; provided that when R.sub.20 is NR.sub.4R.sub.5 and
R.sub.4 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.3-7
cycloalkyl optionally substituted with OH, halogen, amino, carboxyl
or saturated or unsaturated C.sub.3-10 (carbocycle or heterocycle)
optionally substituted with OH, halogen, amino, mercapto, carboxy,
C.sub.1-4 (alkyl, alkoxy, alkylthio, acyl, acyloxy or
alkoxycarbonyl) optionally substituted with OH, halogen, amino or
C.sub.1-4 alkoxy; and C.sub.3-7 cycloalkyl fused to C.sub.6-10 aryl
optionally substituted with OH, halogen, amino, mercapto, carboxy,
C.sub.1-4 (alkyl, alkoxy, alkylthio, acyl, acyloxy or
alkoxycarbonyl) optionally substituted with OH, halogen, amino or
C.sub.1-4 alkoxy; R.sub.5 is H, or C.sub.1-4 alkyl; and (1) Z is a
bond; and R.sub.2 or R.sub.3 is H, OH, halogen, amino, cyano,
C.sub.1-6 (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl)
optionally substituted with OH, halogen, amino or C.sub.1-4 alkoxy,
and saturated or unsaturated C.sub.3-10 (carbocycle or heterocycle)
optionally substituted with OH, halogen, amino, mercapto, C.sub.1-4
alkylthio, C.sub.1-4 alkoxycarbonyl, halo substituted C.sub.1-4
alkyl or halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy or carboxy; or (2) Z is a bond; R.sub.2 or R.sub.3
is H, OH, halogen, amino, cyano, C.sub.1-6 (alkyl, alkoxy, acyl,
acyloxy or alkoxycarbonyl) optionally substituted with OH, halogen,
amino or C.sub.1-4 alkoxy, and saturated or unsaturated C.sub.3-10
(carbocycle or heterocycle) optionally substituted with OH,
halogen, amino, mercapto, C.sub.1-4 alkylthio, C.sub.1-4
alkoxycarbonyl, halo substituted C.sub.1-4 alkyl or
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4
alkoxy or carboxy; and R.sub.4 and R.sub.5 together form a
saturated or unsaturated 5 or 6 member heterocycle optionally fused
to C.sub.6-10 aryl or heteroaryl; then R.sub.1 is not OH, halogen,
amino, cyano, C.sub.1-6 (alkyl, alkoxy, acyl, acyloxy or
alkoxycarbonyl) optionally substituted with OH, halogen, amino or
C.sub.1-4 alkoxy, and saturated or unsaturated C.sub.3-10
(carbocycle or heterocycle) optionally substituted with OH,
halogen, amino, mercapto, C.sub.1-4 alkylthio, C.sub.1-4
alkoxycarbonyl, halo substituted C.sub.1-4 alkyl or
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4
alkoxy or carboxy.
2. A compound according to claim 1, wherein R.sub.1 is halogen,
C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl, thienyl,
furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl,
triazolyl, imidazolyl, oxazolyl, isoxazolyl, benzofuranyl,
3,4-dihydropyrimidin-2(1H)-onyl, piperidinyl, pyrrolidinyl,
piperazinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, or C.sub.3-C.sub.8 cycloalkyl, each of
which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, phenyl, naphthyl,
wherein the phenyl and naphthyl groups are optionally substituted
with 1 or more groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, --OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein Each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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);
R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl,
benzofuranyl, thienyl, cycloalkyl, wherein the cyclic portions are
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; wherein
the heterocycloalkyl and the cycloalkyl portions of R.sub.1 and
R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3.
3. A compound according to claim 1, wherein R.sub.20 is
NR.sub.4R.sub.5; wherein R.sub.4 and R.sub.5 are independently H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl C.sub.2-C.sub.6
alkenyl, cycloalkyl C.sub.2-C.sub.6 alkynyl, piperidinyl,
pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl,
morpholinyl C.sub.1-C.sub.6 alkyl, thiomorpholinyl C.sub.1-C.sub.6
alkyl, S,S-dioxothiomorpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl,
imidazolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, imidazolidinyl
C.sub.2-C.sub.6 alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl,
thiomorpholinyl C.sub.2-C.sub.6 alkenyl, S,S-dioxothiomorpholinyl
C.sub.2-C.sub.6 alkenyl, tetrahydrofuranyl C.sub.2-C.sub.6 alkenyl,
tetrahydrothienyl C.sub.2-C.sub.6 alkenyl, piperidinyl
C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6 alkynyl,
imidazolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, thiomorpholinyl C.sub.2-C.sub.6 alkynyl,
S,S-dioxothiomorpholinyl C.sub.2-C.sub.6 alkynyl, tetrahydrofuranyl
C.sub.2-C.sub.6 alkynyl, tetrahydrothienyl C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl, thienyl,
imidazolyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl
C.sub.1-C.sub.6 alkyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl
C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
heteroarylalkenyl, heteroarylalkynyl, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
naphthyl C.sub.2-C.sub.6 alkenyl, phenyl C.sub.2-C.sub.6 alkynyl,
naphthyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of
each of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; wherein the heterocycloalkyl
and the cycloalkyl portions of R.sub.4 and R.sub.5 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3; or R.sub.4 and R.sub.5 and the nitrogen to which
they are attached form a piperazinyl, morpholinyl, piperidinyl,
pyrrolidinyl, thiomorpholinyl, imidazolidinyl,
S,S-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, ring, which is
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, phenyl C.sub.1-C.sub.6 alkyl, naphthyl C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkanoyl, OH, .dbd.O, pyridyl, pyrimidyl,
pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, phenyl, naphthyl, --OCH.sub.2CH.sub.2O--,
--OCH.sub.2O--, wherein the pyridyl, pyrimidyl, pyrazinyl,
pyrimidyl C.sub.1-C.sub.6 alkyl, phenyl and naphthyl groups are
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, CF.sub.3 or OCF.sub.3.
4. A compound according to claim 1, wherein R.sub.1 is halogen,
C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl, thienyl,
furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl,
triazolyl, imidazolyl, oxazolyl, isoxazolyl, benzofuranyl,
3,4-dihydropyrimidin-2(1H)-onyl, piperidinyl, pyrrolidinyl,
piperazinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, or C.sub.3-C.sub.8 cycloalkyl, each of
which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, phenyl, naphthyl,
wherein the phenyl and naphthyl groups are optionally substituted
with 1 or more groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, --OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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);
R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl,
C.sub.3-C.sub.8 cycloalkyl, wherein the cyclic portions are
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; wherein
the heterocycloalkyl and the cycloalkyl portions of R.sub.1 and
R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3; and R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
alkenyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl C.sub.2-C.sub.6
alkenyl, cycloalkyl C.sub.2-C.sub.6 alkynyl, piperidinyl,
pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl,
morpholinyl C.sub.1-C.sub.6 alkyl, thiomorpholinyl C.sub.1-C.sub.6
alkyl, S,S-dioxothiomorpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl,
imidazolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, imidazolidinyl
C.sub.2-C.sub.6 alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl,
thiomorpholinyl C.sub.2-C.sub.6 alkenyl, S,S-dioxothiomorpholinyl
C.sub.2-C.sub.6 alkenyl, tetrahydrofuranyl C.sub.2-C.sub.6 alkenyl,
tetrahydrothienyl C.sub.2-C.sub.6 alkenyl, piperidinyl
C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6 alkynyl,
imidazolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, thiomorpholinyl C.sub.2-C.sub.6 alkynyl,
S,S-dioxothiomorpholinyl C.sub.2-C.sub.6 alkynyl, tetrahydrofuranyl
C.sub.2-C.sub.6 alkynyl, tetrahydrothienyl C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl, thienyl,
imidazolyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl
C.sub.1-C.sub.6 alkyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl
C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
heteroarylalkenyl, heteroarylalkynyl, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
naphthyl C.sub.2-C.sub.6 alkenyl, phenyl C.sub.2-C.sub.6 alkynyl,
naphthyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of
each of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; wherein the heterocycloalkyl
and the cycloalkyl portions of the above are further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3; or
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,
imidazolidinyl, S,S-dioxothiomorpholinyl, piperidinyl,
pyrrolidinyl, ring, which is unsubstituted or substituted with 1 or
more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, OH,
.dbd.O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6
alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl, phenyl, naphthyl,
--OCH.sub.2CH.sub.2O--, --OCH.sub.2O--, wherein the pyridyl,
pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, phenyl and
naphthyl groups are unsubstituted or substituted with 1 or more
groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or OCF.sub.3.
5. A compound according to claim 4, wherein R.sub.2 and R.sub.3 are
independently H, halogen, or C.sub.1-C.sub.6 alkyl.
6. A compound according to claim 5, wherein Z is a bond,
--CH.sub.2--, or --NH--.
7. A compound according to claim 6, wherein R.sub.1 is halogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, phenyl, thienyl,
pyridyl, triazolyl, imidazolyl, pyrazinyl, benzofuranyl,
3,4-dihydropyrimidin-2(1H)-onyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, phenyl, wherein the phenyl is optionally substituted
with 1 or more groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
haloalkoxy, --OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, or,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, wherein each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and
R.sub.10 is phenyl, pyridyl, or C.sub.3-C.sub.8 cycloalkyl, wherein
the cyclic portions are optionally substituted with halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN,
NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4
haloalkoxy.
8. A compound according to claim 7, wherein R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, piperidinyl,
pyrrolidinyl, morpholinyl, morpholinyl C.sub.1-C.sub.6 alkyl,
piperidinyl C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6
alkyl, piperidinyl C.sub.2-C.sub.6 alkenyl, pyrrolidinyl
C.sub.2-C.sub.6 alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl,
piperidinyl C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6
alkynyl, morpholinyl C.sub.2-C.sub.6 alkynyl, phenyl, furanyl,
pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl C.sub.1-C.sub.6
alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl C.sub.1-C.sub.6
alkyl, thienyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.2-C.sub.6 alkenyl, phenyl C.sub.2-C.sub.6 alkynyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, wherein R.sub.7 and
R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; wherein the heterocycloalkyl
and the cycloalkyl portions of R.sub.4 and R.sub.5 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
9. A compound according to claim 8, wherein Z is --NH-- or
--CH.sub.2--; R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, phenyl, thienyl, pyridyl, triazolyl, imidazolyl,
pyrazinyl, benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl, each of
which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, phenyl, wherein the
phenyl is optionally substituted with 1 or more groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, OH, CF.sub.3, and OCF.sub.3, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and and R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, piperidinyl,
pyrrolidinyl, morpholinyl, morpholinyl C.sub.1-C.sub.6 alkyl,
piperidinyl C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6
alkyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.4 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, wherein the cyclic portion of each of
the above is unsubstituted or substituted with one or more groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein
the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and alkanoyl,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; wherein the heterocycloalkyl
and the cycloalkyl portions of R.sub.4 and R.sub.5 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
10. A compound according to claim 9, wherein R.sub.1 is phenyl,
thienyl, pyridyl, imidazolyl, pyrazinyl, benzofuranyl, each of
which is unsubstituted or substituted with 1, 2, or 3 groups that
are independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy, OH, CN, CO.sub.2H, phenyl, wherein the phenyl is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, 2, or 3, groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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); and and R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl,
piperidinyl, pyrrolidinyl, morpholinyl C.sub.1-C.sub.4 alkyl,
piperidinyl C.sub.1-C.sub.4 alkyl, phenyl, furanyl, pyridyl,
pyrazinyl C.sub.1-C.sub.4 alkyl, pyridyl C.sub.1-C.sub.4 alkyl,
imidazolyl C.sub.1-C.sub.4 alkyl, furanyl C.sub.1-C.sub.4 alkyl,
thienyl C.sub.1-C.sub.4 alkyl, phenyl C.sub.1-C.sub.4 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.4) alkyl, CF.sub.3, OCF.sub.3, NO.sub.2,
CN, OH, NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, or 2
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; wherein the heterocycloalkyl
and the cycloalkyl portions of R.sub.4 and R.sub.5 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
11. A compound according to claim 10, wherein R.sub.4 is H or
methyl; and R.sub.5 is --CH.sub.2-furanyl.
12. A compound according to claim 11, wherein R.sub.1 is phenyl,
thienyl, pyridyl, or pyrazinyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH,
CF.sub.3, OCF.sub.3, NR.sub.6R.sub.7, --(C.sub.1-C.sub.2
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein each
R.sub.6 and R.sub.7 at each occurrence are independently H,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkoxycarbonyl.
13. A compound according to claim 6, wherein R.sub.4 and R.sub.5
and the nitrogen to which they are attached form a piperazinyl,
morpholinyl, piperidinyl, imidazolidinyl, or pyrrolidinyl ring,
each of which is unsubstituted or substituted with 1 or more groups
that are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6
alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl
C.sub.1-C.sub.4 alkyl, pyrazinyl C.sub.1-C.sub.4 alkyl, phenyl,
--OCH.sub.2CH.sub.2O--, --OCH.sub.2O--, wherein the pyridyl,
pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, and phenyl
groups are unsubstituted or substituted with 1 or more groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, CF.sub.3 or OCF.sub.3.
14. A compound according to claim 13, wherein R.sub.1 is phenyl,
thienyl, furanyl, pyridyl, pyrazinyl, triazolyl, imidazolyl,
oxazolyl, benzofuranyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, phenyl, wherein the phenyl group is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxycarbonyl, or
C.sub.1-C.sub.4 alkanoyl.
15. A compound according to claim 13, wherein R.sub.1 is phenyl,
thienyl, pyridyl, pyrazinyl, triazolyl, imidazolyl, benzofuranyl,
each of which is unsubstituted or substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, or 2 groups
that are independently halogen, OH, CF.sub.3, OCF.sub.3, 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); R.sub.10 is phenyl, naphthyl, pyridyl,
quinolinyl, pyrimidyl, furanyl, indolyl, or C.sub.3-C.sub.8
cycloalkyl, each of which is optionally substituted with halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN,
NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy;
wherein the heterocycloalkyl and the cycloalkyl portions of R.sub.1
and R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3.
16. A compound according to claim 15, wherein R.sub.4 and R.sub.5
and the nitrogen to which they are attached form a piperazinyl,
morpholinyl, piperidinyl, imidazolidinyl, or pyrrolidinyl ring,
which is unsubstituted or substituted with 1 or more groups that
are independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, phenyl C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.6 alkanoyl,
OH, pyridyl, pyrimidyl C.sub.1-C.sub.2 alkyl, phenyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--; and R.sub.2 and R.sub.3
are both H.
17. A compound according to claim 1 which is
8-Bromo-[1,6]naphthyridine-2-carboxylic acid methyl ester;
8-[5-(2-Dimethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-
-carboxylic acid (furan-2-ylmethyl)-amide;
8-[5-(2-Diethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2--
carboxylic acid (furan-2-ylmethyl)-amide;
8-[5-(2-Dimethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-
-carboxylic acid cyclopropylamide;
8-[5-(2-Diethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2--
carboxylic acid cyclopropylamide;
5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic
acid amide;
5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxyl-
ic acid methylamide;
8-[5-(3-Morpholin-4-yl-propylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-
-2-carboxylic acid methylamide;
8-Thiophen-3-yl[1,6]-naphthyridine-2-carboxylic acid;
8-Thiophen-3-yl[1,6]-naphthyridine-2-carboxylic acid
(2-oxo-cyclohexyl)amide;
8-Thiophen-3-yl-[1,6]naphthyridine-2-carboxylic acid amide;
8-Phenyl[1,6]-naphthyridine-2-carboxylic acid;
8-Phenyl[1,6]-naphthyridine-2-carboxylic acid amide;
8-Bromo[1,6]-naphthyridine-2-carboxylic acid
(2-oxo-cyclohexyl)amide; 8-Phenyl[1,6]-naphthyridine-2-carboxylic
acid (2-oxo-cyclohexyl)amide;
8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acid
cyclopropylamide;
8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acid
amide; 8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic
acid (furan-2-ylmethyl)amide;
(3-{2-[(Furan-2-ylmethyl)-carbamoyl]-[1,6]naphthyridin-8-yl}-prop-2-ynyl)-
-carbamic acid tert-butyl ester;
8-Phenylethynyl-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide; 8-Ethynyl-[1,6]naphthyridine-2-carboxylic
acid (furan-2-ylmethyl)-amide;
8-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-para-Tolylamino-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-Phenylamino-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(3-Trifluoromethyl-phenylamino-[1,6]naphthyridine-2-carboxylic
acid (furan-2-ylmethyl)-amide;
8-(4-Trifluoromethyl-phenylamino)-[1,6]naphthyridine-2-carboxylic
acid (furan-2-ylmethyl)-amide;
8-(Pyridin-3-ylamino)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(Pyridin-4-ylamino)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(Pyrazin-2-ylamino)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(3,5-Dichloro-phenylamino)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylic acid
cyclopropylamide;
8-(3,5-Dichloro-phenylamino)-[1,6]naphthyridine-2-carboxylic acid
cyclopropylamide;
8-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylic acid
amide; 8-[(Furan-2-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic
acid (furan-2-ylmethyl)-amide;
8-[(Pyridin-4-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-[(Pyridin-2-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-[(Pyridin-3-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(3-Methoxy-benzylamino)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-Cyclopropylamino-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-Prop-2-ynylamino-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide;
8-(2-Oxo-pyrrolidin-1-yl)-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide; methyl
8-bromo-1,6-naphthyridine-2-carboxylate;
8-(3-thienyl)-1,6-naphthyridine-2-carboxylic acid;
N-cyclopropyl-8-[5-({[2-(diethylamino)ethyl]amino}carbonyl)-2-thienyl]-1,-
6-naphthyridine-2-carboxamide;
8-phenyl-1,6-naphthyridine-2-carboxylic acid;
N-(2-furylmethyl)-8-{[4-(trifluoromethyl)phenyl]amino}-1,6-naphthy-
ridine-2-carboxamide;
N-(2-furylmethyl)-8-[(4-methylphenyl)amino]-1,6-naphthyridine-2-carboxami-
de; 8-anilino-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide;
N-(2-furylmethyl)-8-{[3-(trifluoromethyl)phenyl]amino}-1,6-naphthyridine--
2-carboxamide;
N-(2-furylmethyl)-8-[(4-methoxyphenyl)amino]-1,6-naphthyridine-2-carboxam-
ide;
N-(2-furylmethyl)-8-(3-hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2-ca-
rboxamide; 8-(5-carboxy-2-thienyl)-1,6-naphthyridine-2-carboxylic
acid; 8-bromo-N-(2-oxocyclohexyl)-1,6-naphthyridine-2-carboxamide;
N-(2-furylmethyl)-8-(pyridin-3-ylamino)-1,6-naphthyridine-2-carboxamide;
tert-butyl[3-(2-{[(2-furylmethyl)amino]carbonyl}-1,6-naphthyridin-8-yl)pr-
op-2-yn-1-yl]carbamate; N--
(2-furylmethyl)-8-(pyridin-4-ylamino)-1,6-naphthyridine-2-carboxamide;
8-bromo-1,6-naphthyridine-2-carboxamide;
8-[5-({[2-(diethylamino)ethyl]amino}carbonyl)-2-thienyl]-N-(2-furylmethyl-
)-1,6-naphthyridine-2-carboxamide;
8-[5-({[2-(dimethylamino)ethyl]amino]carbonyl)-2-thienyl}-N-(2-furylmethy-
l)-1,6-naphthyridine-2-carboxamide;
N-cyclopropyl-8-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-2-thienyl]-1-
,6-naphthyridine-2-carboxamide; diethyl
N-(4-{[(8-bromo-1,6-naphthyridin-2-yl)carbonyl]amino}benzoyl)glutamate
N-(2-furylmethyl)-8-(pyrazin-2-ylamino)-1,6-naphthyridine-2-carboxamide;
N-(2-oxocyclohexyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide;
N-(2-oxocyclohexyl)-8-phenyl-1,6-naphthyridine-2-carboxamide;
8-(3-hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2-carboxamide;
N-cyclopropyl-8-(3-hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2-carboxamide-
;
N-(2-furylmethyl)-8-(phenylethynyl)-1,6-naphthyridine-2-carboxamide;
8-ethynyl-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide;
N-cyclopropyl-8-[(4-methoxyphenyl)amino]-1,6-naphthyridine-2-carboxamide;
2-[(4-benzylpiperazin-1-yl)carbonyl]-8-(4-methoxyphenyl)-1,6-naphthyridi-
ne;
N-[4-(methylsulfonyl)benzyl]-8-(3-thienyl)-1,6-naphthyridine-2-carbox-
amide;
1-{[8-(3-thienyl)-1,6-naphthyridin-2-yl]carbonyl}piperidin-4-ol;
N-(2-methoxyethyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide;
8-(4-methoxyphenyl)-2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1,6-naphth-
yridine;
N-(1-benzylpiperidin-4-yl)-8-(4-methoxyphenyl)-1,6-naphthyridine-
-2-carboxamide;
8-(4-methoxyphenyl)-N-[4-(methylsulfonyl)benzyl]-1,6-naphthyridine-2-carb-
oxamide;
2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-8-phenyl-1,6-napht-
hyridine;
8-phenyl-2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1,6-naphthy-
ridine;
2-[(4-benzylpiperazin-1-yl)carbonyl]-8-phenyl-1,6-naphthyridine;
N-(1-benzylpiperidin-4-yl)-8-phenyl-1,6-naphthyridine-2-carboxamide;
N-[4-(methylsulfonyl)benzyl]-8-phenyl-1,6-naphthyridine-2-carboxamide;
2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-8-(3-thienyl)-1,6-naphthyri-
dine;
2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-8-(3-thienyl)-1,6-naphth-
yridine;
2-[(4-benzylpiperazin-1-yl)carbonyl]-8-(3-thienyl)-1,6-naphthyri-
dine;
N-(1-benzylpiperidin-4-yl)-8-(3-thienyl)-1,6-naphthyridine-2-carbox-
amide;
2-({4-[(4,6-dimethoxypyrimidin-2-yl)methyl]piperazin-1-yl}carbonyl-
)-8-(3-thienyl)-1,6-naphthyridine;
1-{[8-(1-benzofuran-2-yl)-1,6-naphthyridin-2-yl]carbonyl}piperidin-4-ol;
8-(1-benzofuran-2-yl)-N-(2-methoxyethyl)-1,6-naphthyridine-2-carboxamide;
1-[(8-phenyl-1,6-naphthyridin-2-yl)carbonyl]piperidin-4-ol;
N-(2-methoxyethyl)-8-phenyl-1,6-naphthyridine-2-carboxamide;
8-(1-benzofuran-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-1,6-n-
aphthyridine;
8-(1-benzofuran-2-yl)-2-[(4-benzylpiperazin-1-yl)carbonyl]-1,6-naphthyrid-
ine;
8-(1-benzofuran-2-yl)-N-(1-benzylpiperidin-4-yl)-1,6-naphthyridine-2-
-carboxamide;
8-(1-benzofuran-2-yl)-N-[4-(methylsulfonyl)benzyl]-1,6-naphthyridine-2-ca-
rboxamide; or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound according to
claim 1 and at least one pharmaceutically acceptable solvent,
carrier, excipient, adjuvant or a combination thereof.
19. A method of treating a disease or condition related to cell
differentiation comprising administering a therapeutically
effective amount of a compound of claim 1 to a patient in need of
such treatment.
20. The method according to claim 19, wherein the disease or
condition is cancer, inflammation, arthritis, or angiogenesis.
Description
[0001] This application claims priority from U.S. Provisional
Application No. 60/598,518, filed Aug. 3, 2004, the disclosure of
which is incorporated herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to 2,8-disubstituted naphthyridines
and more specifically to such compounds that are useful in the
treatment and/or prevention of diseases and/or conditions related
to cell differentiation, such as cancer, inflammation and
inflammation-associated disorders, and conditions associated with
angiogenesis.
[0004] 2. Description of the Related Art
[0005] Angiogenesis is a highly regulated process under normal
conditions, however many diseases are driven by persistent
unregulated angiogenesis. Unregulated angiogenesis may either cause
a particular disease directly or exacerbate an existing
pathological condition. For example, ocular neovascularization has
not only been implicated as the most common cause of blindness, but
also is believed the dominant cause of many eye diseases. Further,
in certain existing conditions, for example arthritis, newly formed
capillary blood vessels invade the joints and destroy cartilage, or
in the case of diabetes, new capillaries formed in the retina
invade the vitreous, bleed, and cause blindness. Growth and
metastasis of solid tumors are also dependent on angiogenesis
(Folkman, J., Cancer Research, 46, 467-473 (1986), Folkman, J.,
Journal of the National Cancer Institute, 82, 4-6 (1989). It has
been shown, for example, that tumors which enlarge to greater than
2 mm must obtain their own blood supply and do so by inducing the
growth of new capillary blood vessels. Once these new blood vessels
become embedded in the tumor, they provide a means for tumor cells
to enter the circulation and metastasize to distant sites such as
liver, lung or bone (Weidner, N., et al., The New England Journal
of Medicine, 324(1), 1-8 (1991). Under conditions of unregulated
angiogenesis, therapeutic methods designed to control, repress,
and/or inhibit angiogenesis could lead to the abrogation or
mitigation of these conditions and diseases.
[0006] Cancer is characterized by abnormal cellular proliferation.
Cancer cells exhibit a number of properties that make them
dangerous to the host, typically including an ability to invade
other tissues and to induce capillary ingrowth, which assures that
the proliferating cancer cells have an adequate supply of blood. A
hallmark of cancerous cells is their abnormal response to control
mechanisms that regulate cell division in normal cells and continue
to divide until they ultimately kill the host.
[0007] Inflammation is related to a variety of disorders such as
pain, headaches, fever, arthritis, asthma, bronchitis, menstrual
cramps, tendinitis, bursitis, psoriasis, eczema, burns, dermatitis,
inflammatory bowel syndrome, Crohn's disease, gastritis, irritable
bowel syndrome, ulcerative colitis, vascular diseases, Hodgkin's
disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia
gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, hypersensitivity, conjunctivitis, gingivitis,
post-injury swelling, myocardial ischemia, and the like.
[0008] Therefore, there is a continuing need in the art for new
methods of treating cancer, inflammation and
inflammation-associated disorders, and conditions or diseases
related to uncontrolled angiogenesis.
[0009] U.S. Pat. No. 5,945,431 discloses heterocyclic compounds of
the formula (I): ##STR2## wherein [0010] W is selected from CH,
CR.sub.3, CH.sub.2, C.dbd.O, CHR.sub.3, N and NR.sub.5; [0011] one
of X, Y, and Z is N or NR.sub.5 while the other two are
independently selected from CH, CR.sub.4, CH.sub.2, C.dbd.O and
CHR.sub.4; [0012] B is selected from the group consisting of
##STR3## wherein [0013] A is O or S; [0014] R.sub.1 is selected
from: [0015] C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.3-7
cycloalkyl, each of which is optionally substituted with OH,
halogen, amino, carboxyl or saturated or unsaturated C.sub.3-10
(carbocycle or heterocycle) optionally substituted with OH,
halogen, amino, mercapto, carboxy, C.sub.1-4 (alkyl, alkoxy,
alkylthio, acyl, acyloxy or alkoxycarbonyl) optionally substituted
with OH, halogen, amino or C.sub.1-4 alkoxy; and [0016] C.sub.3-7
cycloalkyl fused to C.sub.6-10 aryl optionally substituted with OH,
halogen, amino, mercapto, carboxy, C.sub.1-4 (alkyl, alkoxy,
alkylthio, acyl, acyloxy or alkoxycarbonyl) optionally substituted
with OH, halogen, amino or C.sub.1-4 alkoxy; [0017] R.sub.2 and
R'.sub.2 are independently H, C.sub.1-4 alkyl or R.sub.1 and
R.sub.2 together form a saturated or unsaturated 5 or 6 member
heterocycle optionally fused to C.sub.6-10 aryl or heteroaryl;
[0018] R.sub.3 and R.sub.4 are independently selected from H, OH,
halogen, amino, cyano, C.sub.1-6 (alkyl, alkoxy, acyl, acyloxy or
alkoxycarbonyl), where each alkyl and acyl portion is optionally
substituted with OH, halogen, amino or C.sub.1-4 alkoxy, and
saturated or unsaturated C.sub.3-C.sub.10 (carbocycle or
heterocycle) optionally substituted with OH, halogen, amino,
mercapto, C.sub.1-4 alkylthio, C.sub.1-4 alkoxycarbonyl, halo
substituted C.sub.1-4 alkyl or halo-substituted C.sub.1-4 alkoxy,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy or carboxy; [0019] R.sub.5 is H,
C.sub.1-6 alkyl or C.sub.1-6 acyl, where each of the alkyl and acyl
is optionally substituted with OH, halogen, amino or C.sub.1-4
alkoxy; and [0020] n is 0, 1 or 2.
[0021] U.S. Pat. No. 5,945,431 discloses how to make the above
compounds and how to use them allegedly as cytomegalovirus (CMV)
inhibitors for the treatment of conditions related to CMV infection
in mammals. The disclosure of U.S. Pat. No. 5,945,431 is
incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION
[0022] In a broad aspect, the invention encompasses the compounds
of formula A shown below, pharmaceutical compositions containing
those compounds and methods employing such compounds or
compositions in the treatment of diseases and/or conditions related
to cell differentiation, such as cancer, inflammation, arthritis,
angiogenesis, or the like.
[0023] The invention provides compounds of formula A, hereinafter
"Embodiment 1": ##STR4## or pharmaceutically acceptable salts
thereof, wherein each independently represents a single bond or a
double bond; [0024] A.sub.1 is N, or an N-oxide; [0025] A.sub.2 is
N, an N-oxide, NH, or N(C.sub.1-C.sub.6) alkyl; provided that when
is a single bond, then A.sub.2 is NH, or N(C.sub.1-C.sub.6) alkyl;
[0026] X is --NR.sub.xR.sub.y, or --C(O)R.sub.20; wherein [0027]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
alkoxycarbonyl, arylalkoxycarbonyl, aryl, arylalkyl, --C(O)-aryl,
heteroaryl, heteroarylalkyl, or --C(O)heteroaryl, wherein the aryl
and heteroaryl rings are optionally substituted with 1, 2, 3, 4, or
5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
-(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, C.sub.1-C.sub.4
haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; [0028] Z is a bond,
--CH.sub.2--, --NH--, --O--, --N(C.sub.1-C.sub.6 alkyl)-, --S--,
--S(O)--, --SO.sub.2--, --SO.sub.2NH--, or
--SO.sub.2N(C.sub.1-C.sub.6 alkyl)-; [0029] R.sub.1 is halogen,
C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, aryl, heteroaryl,
heterocycloalkyl, or C.sub.3-C.sub.8 cycloalkyl, each of which is
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, heteroaryl,
heterocycloalkyl, phenyl, or naphthyl, wherein the heteroaryl,
heterocycloalkyl, phenyl and naphthyl groups are optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
OH, CF.sub.3, and OCF.sub.3, wherein [0030] each R.sub.6 and
R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); or
[0031] R.sub.6 and R.sub.7 and the nitrogen to which they are
attached form a ring having from 5 to 8 members, wherein the ring
optionally contains 1-3 additional heteroatoms selected from N, O,
and S, where the ring is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, amino, NH(C.sub.1-C.sub.6
alkyl), or N(C.sub.1-C.sub.6 alkyl) (C.sub.1-C.sub.6 alkyl); [0032]
R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl,
heteroaryl, or cycloalkyl, wherein the cyclic portions are
optionally substituted with 1, 2, or 3 groups that are
independently halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, OH, CO.sub.2H, CN, NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 haloalkoxy; [0033] wherein the heterocycloalkyl and
the cycloalkyl portions of R.sub.1 and R.sub.10 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3; [0034] R.sub.2, R.sub.2', and R.sub.3 at each
occurrence are independently H, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyl, --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), or aryl; [0035] R.sub.20 is H, OH,
C.sub.1-C.sub.6 alkoxy, or NR.sub.4R.sub.5; wherein [0036] R.sub.4
and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl,
cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl,
heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl,
heterocycloalkylalkynyl, aryl, heteroaryl, heteroarylalkyl,
heteroarylalkenyl, heteroarylalkynyl, arylalkyl, arylalkenyl, or
arylalkynyl, wherein the cyclic portion of each of the above is
unsubstituted or substituted with one or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, aryl
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 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0037] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the alkyl is optionally substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.6 alkoxycarbonyl, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl, 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) or CO.sub.2H; or [0038] R.sub.7 and R.sub.8
and the nitrogen to which they are attached form a ring having from
5 to 8 members, wherein the ring optionally contains 1-3 additional
heteroatoms selected from N, O, and S, where the ring is optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH, halogen, amino,
NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl); [0039] wherein the heterocycloalkyl and
the cycloalkyl portions of R.sub.4 and R.sub.5 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3; or [0040] R.sub.4 and R.sub.5 and the nitrogen
to which they are attached form a heterocycloalkyl ring, which is
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, aryl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, OH,
.dbd.O, heteroaryl, heteroarylalkyl, phenyl, naphthyl,
--OCH.sub.2CH.sub.2O--, --OCH.sub.2O--, [0041] wherein the
heteroaryl, phenyl and naphthyl groups are unsubstituted or
substituted with 1 or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or
OCF.sub.3; [0042] R.sub.21 is H, CN, amino, monoalkylamino,
dialkylamino, OH, halogen, aryl (phenyl or naphthyl each of which
is optionally substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)), or heteroaryl
(pyridyl, pyrimidyl, indolyl, or (iso)quinolinyl, each of which is
optionally substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)),
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
alkenyl, --C(O)NH.sub.2, --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); provided
that R.sub.1 is halogen only when Z is a bond; provided that when
[0043] R.sub.20 is NR.sub.4R.sub.5 and R.sub.4 is C.sub.1-6 alkyl,
C.sub.2-6 alkenyl or C.sub.3-7 cycloalkyl optionally substituted
with OH, halogen, amino, carboxyl or saturated or unsaturated
C.sub.3-10 (carbocycle or heterocycle) optionally substituted with
OH, halogen, amino, mercapto, carboxy, C.sub.1-4 (alkyl, alkoxy,
alkylthio, acyl, acyloxy or alkoxycarbonyl) optionally substituted
with OH, halogen, amino or C.sub.1-4 alkoxy; and C.sub.3-7
cycloalkyl fused to C.sub.6-10 aryl optionally substituted with OH,
halogen, amino, mercapto, carboxy, C.sub.1-4 (alkyl, alkoxy,
alkylthio, acyl, acyloxy or alkoxycarbonyl) optionally substituted
with OH, halogen, amino or C.sub.1-4 alkoxy; [0044] R.sub.5 is H,
or C.sub.1-4 alkyl; and [0045] (1) Z is a bond; and [0046] R.sub.2
or R.sub.3 is H, OH, halogen, amino, cyano, C.sub.1-6 (alkyl,
alkoxy, acyl, acyloxy or alkoxycarbonyl) optionally substituted
with OH, halogen, amino or C.sub.1-4 alkoxy, and saturated or
unsaturated C.sub.3-10 (carbocycle or heterocycle) optionally
substituted with OH, halogen, amino, mercapto, C.sub.1-4 alkylthio,
C.sub.1-4 alkoxycarbonyl, halo substituted C.sub.1-4 alkyl or
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4
alkoxy or carboxy; or [0047] (2) Z is a bond; [0048] R.sub.2 or
R.sub.3 is H, OH, halogen, amino, cyano, C.sub.1-6 (alkyl, alkoxy,
acyl, acyloxy or alkoxycarbonyl) optionally substituted with OH,
halogen, amino or C.sub.1-4 alkoxy, and saturated or unsaturated
C.sub.3-10 (carbocycle or heterocycle) optionally substituted with
OH, halogen, amino, mercapto, C.sub.1-4 alkylthio, C.sub.1-4
alkoxycarbonyl, halo substituted C.sub.1-4 alkyl or
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4
alkoxy or carboxy; and [0049] R.sub.4 and R.sub.5 together form a
saturated or unsaturated 5 or 6 member heterocycle optionally fused
to C.sub.6-10 aryl or heteroaryl; then [0050] R.sub.1 is not OH,
halogen, amino, cyano, C.sub.1-6 (alkyl, alkoxy, acyl, acyloxy or
alkoxycarbonyl) optionally substituted with OH, halogen, amino or
C.sub.1-4 alkoxy, and saturated or unsaturated C.sub.3-10
(carbocycle or heterocycle) optionally substituted with OH,
halogen, amino, mercapto, C.sub.1-4 alkylthio, C.sub.1-4
alkoxycarbonyl, halo substituted C.sub.1-4 alkyl or
halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkyl, C.sub.1-4
alkoxy or carboxy.
[0051] The invention also includes intermediates that are useful in
making the compounds of the invention.
[0052] The invention also provides pharmaceutical compositions
comprising a compound or pharmaceutically acceptable salt of
formula A and at least one pharmaceutically acceptable carrier,
solvent, adjuvant or diluent.
[0053] The invention further provides methods of treating disease
such as cancer, inflammation, arthritis, and angiogenesis in a
patient in need of such treatment, comprising administering to the
patient a compound or pharmaceutically acceptable salt of formula
A, or a pharmaceutical composition comprising a compound or salt of
formula A.
[0054] The invention also provides the use of a compound or salt
according to formula A for the manufacture of a medicament for use
in treating cancer, inflammation, arthritis, or angiogenesis.
[0055] The invention also provides methods of preparing the
compounds of the invention and the intermediates used in those
methods.
[0056] The invention further provides a compound or pharmaceutical
composition thereof in a kit with instructions for using the
compound or composition.
DETAILED DESCRIPTION OF THE INVENTION
[0057] Preferred compounds of formula I include compounds of
embodiment 2, i.e., compounds of Formula A wherein, [0058] R.sub.1
is halogen, C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl,
thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl,
pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl,
benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl, piperidinyl,
pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, or C.sub.3-C.sub.8 cycloalkyl, each of
which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, heteroaryl selected from
pyridyl, pyrimidyl, pyrazinyl, (iso)quinolinyl, indolyl, thienyl,
furanyl, pyrrolyl, triazinyl, 1H-indazolyl, and benzimidazolyl,
heterocycloalkyl selected from piperidinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, imidazolidinyl,
piperazinyl, morpholinyl, and S,S-dioxomorpholinyl, phenyl,
naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl and
naphthyl groups are optionally substituted with 1 or more groups
that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and OCF.sub.3,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0059] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0060]
R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl,
benzofuranyl, thienyl, cycloalkyl, wherein the cyclic portions are
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; wherein
the heterocycloalkyl and the cycloalkyl portions of R.sub.1, and
R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3.
[0061] Other preferred compounds of Embodiment 1 include those
where [0062] X is --C(O)R.sub.20; [0063] R.sub.20 is
NR.sub.4R.sub.5; wherein [0064] R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
alkenyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl C.sub.2-C.sub.6
alkenyl, cycloalkyl C.sub.2-C.sub.6 alkynyl, piperidinyl,
pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl,
morpholinyl C.sub.1-C.sub.6 alkyl, thiomorpholinyl C.sub.1-C.sub.6
alkyl, S,S-dioxothiomorpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl,
imidazolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, imidazolidinyl
C.sub.2-C.sub.6 alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl,
thiomorpholinyl C.sub.2-C.sub.6 alkenyl, S,S-dioxothiomorpholinyl
C.sub.2-C.sub.6 alkenyl, tetrahydrofuranyl C.sub.2-C.sub.6 alkenyl,
tetrahydrothienyl C.sub.2-C.sub.6 alkenyl, piperidinyl
C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6 alkynyl,
imidazolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, thiomorpholinyl C.sub.2-C.sub.6 alkynyl,
S,S-dioxothiomorpholinyl C.sub.2-C.sub.6 alkynyl, tetrahydrofuranyl
C.sub.2-C.sub.6 alkynyl, tetrahydrothienyl C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl, thienyl,
imidazolyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl
C.sub.1-C.sub.6 alkyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl
C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
heteroarylalkenyl, heteroarylalkynyl, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
naphthyl C.sub.2-C.sub.6 alkenyl, phenyl C.sub.2-C.sub.6 alkynyl,
naphthyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of
each of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2-- (C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0065] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0066] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3; or [0067] R.sub.4 and R.sub.5 and the nitrogen
to which they are attached form a piperazinyl, morpholinyl,
piperidinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl,
S,S-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, ring, which is
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, phenyl C.sub.1-C.sub.6 alkyl, naphthyl C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkanoyl, OH, .dbd.O, pyridyl, pyrimidyl,
pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, phenyl, naphthyl, --OCH.sub.2CH.sub.2O--,
--OCH.sub.2O--, [0068] wherein the pyridyl, pyrimidyl, pyrazinyl,
pyrimidyl C.sub.1-C.sub.6 alkyl, phenyl and naphthyl groups are
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, CF.sub.3 or OCF.sub.3.
[0069] Other preferred compounds of Embodiment 1 include those of
embodiment 4, i.e., compounds of Embodiment 1 where [0070] R.sub.1
is halogen, C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl,
thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl,
pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl,
benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl, piperidinyl,
pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, or C.sub.3-C.sub.8 cycloalkyl, each of
which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, heteroaryl selected from
pyridyl, pyrimidyl, pyrazinyl, (iso)quinolinyl, indolyl, thienyl,
furanyl, pyrrolyl, triazinyl, 1H-indazolyl, and benzimidazolyl,
heterocycloalkyl selected from piperidinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, imidazolidinyl,
piperazinyl, morpholinyl, and S,S-dioxomorpholinyl, phenyl,
naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl and
naphthyl groups are optionally substituted with 1 or more groups
that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and OCF.sub.3,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0071] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0072]
R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl,
C.sub.3-C.sub.8 cycloalkyl, wherein the cyclic portions are
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; [0073]
wherein the heterocycloalkyl and the cycloalkyl portions of R.sub.1
and R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3; and [0074] R.sub.4 and R.sub.5
are independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6
alkenyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl C.sub.2-C.sub.6
alkenyl, cycloalkyl C.sub.2-C.sub.6 alkynyl, piperidinyl,
pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,
S,S-dioxothiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl,
morpholinyl C.sub.1-C.sub.6 alkyl, thiomorpholinyl C.sub.1-C.sub.6
alkyl, S,S-dioxothiomorpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl,
imidazolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, imidazolidinyl
C.sub.2-C.sub.6 alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl,
thiomorpholinyl C.sub.2-C.sub.6 alkenyl, S,S-dioxothiomorpholinyl
C.sub.2-C.sub.6 alkenyl, tetrahydrofuranyl C.sub.2-C.sub.6 alkenyl,
tetrahydrothienyl C.sub.2-C.sub.6 alkenyl, piperidinyl
C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6 alkynyl,
imidazolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, thiomorpholinyl C.sub.2-C.sub.6 alkynyl,
S,S-dioxothiomorpholinyl C.sub.2-C.sub.6 alkynyl, tetrahydrofuranyl
C.sub.2-C.sub.6 alkynyl, tetrahydrothienyl C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl, thienyl,
imidazolyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl
C.sub.1-C.sub.6 alkyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl
C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
heteroarylalkenyl, heteroarylalkynyl, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
naphthyl C.sub.2-C.sub.6 alkenyl, phenyl C.sub.2-C.sub.6 alkynyl,
naphthyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of
each of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0075] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0076] wherein the
heterocycloalkyl and the cycloalkyl portions of the above are
further optionally substituted with .dbd.0, .dbd.N--OH, or
.dbd.N--OCH.sub.3; or [0077] R.sub.4 and R.sub.5 and the nitrogen
to which they are attached form a piperazinyl, morpholinyl,
piperidinyl, thiomorpholinyl, imidazolidinyl,
S,S-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, ring, which is
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, phenyl C.sub.1-C.sub.6 alkyl, naphthyl C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 alkanoyl, OH, .dbd.O, pyridyl, pyrimidyl,
pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, phenyl, naphthyl, --OCH.sub.2CH.sub.2O--,
--OCH.sub.2O--, [0078] wherein the pyridyl, pyrimidyl, pyrazinyl,
pyrimidyl C.sub.1-C.sub.6 alkyl, phenyl and naphthyl groups are
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, CF.sub.3 or OCF.sub.3.
[0079] Preferred compounds of Embodiment 4 include those of
embodiment 5, i.e., compounds of Embodiment 4 where R.sub.2 and
R.sub.3 are independently H, halogen, or C.sub.1-C.sub.6 alkyl. In
another aspect, R.sub.2 and R.sub.3 are independently H or
C.sub.1-C.sub.4 alkyl.
[0080] Other preferred compounds of Embodiment 5 include those of
embodiment 6, i.e., compounds of Embodiment 5 where Z is a bond,
--CH.sub.2--, or --NH--.
[0081] Other preferred compounds of Embodiment 6 include those of
embodiment 7, i.e., compounds of Embodiment 6 where [0082] R.sub.1
is halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, phenyl,
thienyl, pyridyl, triazolyl, imidazolyl, pyrazinyl, benzofuranyl,
3,4-dihydropyrimidin-2(1H)-onyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl,
indolyl, thienyl, furanyl, pyrrolyl, and benzimidazolyl,
heterocycloalkyl selected from piperidinyl, pyrrolidinyl,
piperazinyl, morpholinyl, and S,S-dioxomorpholinyl, phenyl, or
naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl and
naphthyl groups are optionally substituted with 1 or more groups
that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and OCF.sub.3,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, or, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
wherein [0083] each R.sub.6 and R.sub.7 is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6
alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted
or substituted with 1, 2, or 3, groups that are independently
halogen, OH, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
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); and [0084] R.sub.10 is phenyl, pyridyl, or
C.sub.3-C.sub.8 cycloalkyl, wherein the cyclic portions are
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy.
[0085] Other preferred compounds of Embodiment 7 include those of
Embodiment 8, i.e., compounds of Embodiment 7 where [0086] R.sub.4
and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl
C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6 alkyl,
pyrrolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, morpholinyl
C.sub.2-C.sub.6 alkenyl, piperidinyl C.sub.2-C.sub.6 alkynyl,
pyrrolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
phenyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of each
of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0087] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0088] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0089] Other preferred compounds of Embodiment 8 include those of
Embodiment 9, i.e., compounds of Embodiment 8 where [0090] Z is
--NH-- or --CH.sub.2--; [0091] R.sub.1 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, phenyl, thienyl, pyridyl, triazolyl,
imidazolyl, pyrazinyl, benzofuranyl,
3,4-dihydropyrimidin-2(1H)-onyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, heteroaryl selected from pyridyl, pyrimidyl, indolyl,
thienyl, furanyl, and benzimidazolyl, heterocycloalkyl selected
from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and
S,S-dioxomorpholinyl, phenyl, naphthyl, wherein the heteroaryl,
heterocycloalkyl, phenyl and naphthyl groups are optionally
substituted with phenyl, wherein the phenyl is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
OH, CF.sub.3, and OCF.sub.3, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein [0092]
each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and [0093] and [0094] R.sub.4 and R.sub.5
are independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, piperidinyl,
pyrrolidinyl, morpholinyl, morpholinyl C.sub.1-C.sub.6 alkyl,
piperidinyl C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6
alkyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.4 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, wherein the cyclic portion of each of
the above is unsubstituted or substituted with one or more groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein
the phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and alkanoyl,
C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0095] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0096] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0097] Other preferred compounds of Embodiment 9 include those of
Embodiment 10, i.e., compounds of Embodiment 9 where [0098] R.sub.1
is phenyl, thienyl, pyridyl, imidazolyl, pyrazinyl, benzofuranyl,
each of which is unsubstituted or substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, pyridyl, piperidinyl,
pyrrolidinyl, piperazinyl, morpholinyl or phenyl, wherein the
pyridyl, pyrrolidinyl, morpholinyl, and phenyl groups are
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, OH, CF.sub.3, and OCF.sub.3, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein [0099]
each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 alkoxycarbonyl (in one aspect,
tert-butylalkoxycarbonyl), wherein the alkyl portion of each is
unsubstituted or substituted with 1, 2, or 3, groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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); and [0100] and [0101] R.sub.4 and R.sub.5
are independently H, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6
cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl C.sub.1-C.sub.4
alkyl, piperidinyl C.sub.1-C.sub.4 alkyl, phenyl, furanyl, pyridyl,
pyrazinyl C1-C.sub.4 alkyl, pyridyl C.sub.1-C.sub.4 alkyl,
imidazolyl C.sub.1-C.sub.4 alkyl, furanyl C.sub.1-C.sub.4 alkyl,
thienyl C.sub.1-C.sub.4 alkyl, phenyl C.sub.1-C.sub.4 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2-- (C.sub.1-C.sub.4) alkyl, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, OH, NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0102]
wherein R.sub.7 and R.sub.8 are independently H or C.sub.1-C.sub.6
alkyl, wherein the C.sub.1-C.sub.6 alkyl is optionally substituted
with 1, or 2 groups that are independently C.sub.1-C.sub.6
alkoxycarbonyl, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkanoyl, 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) or CO.sub.2H; [0103] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0104] Other preferred compounds of Embodiment 10 include those of
Embodiment 11, i.e., compounds of Embodiment 10 where [0105]
R.sub.4 is H or methyl; and [0106] R.sub.5 is
--CH.sub.2-furanyl.
[0107] Other preferred compounds of Embodiment 11 include those of
Embodiment 12, i.e., compounds of Embodiment 11 where [0108]
R.sub.1 is phenyl, thienyl, pyridyl, or pyrazinyl, each of which is
unsubstituted or substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy, OH, CF.sub.3, OCF.sub.3, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.2 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0109] each R.sub.6 and R.sub.7 at
each occurrence are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 alkoxycarbonyl.
[0110] Other preferred compounds of Embodiment 12 include those of
Embodiment 12A, i.e., compounds of Embodiment 12 where [0111]
R.sub.1 is phenyl, which is unsubstituted or substituted with 1, 2,
or 3 groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CF.sub.3, OCF.sub.3, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.2 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0112] R.sub.6 and R.sub.7 at each
occurrence are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 alkoxycarbonyl. In another aspect, R.sub.6 and
R.sub.7 are independently H or C.sub.1-C.sub.4 alkyl.
[0113] Other preferred compounds of Embodiment 12 include those of
Embodiment 12B, i.e., compounds of Embodiment 12 where [0114]
R.sub.1 is thienyl, which is unsubstituted or substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CF.sub.3, OCF.sub.3,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.2 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0115] R.sub.6 and R.sub.7 at each
occurrence are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 alkoxycarbonyl. In another aspect, R.sub.6 and
R.sub.7 are independently H or C.sub.1-C.sub.4 alkyl.
[0116] Other preferred compounds of Embodiment 12 include those of
Embodiment 12C, i.e., compounds of Embodiment 12 where [0117]
R.sub.1 is pyridyl, which is unsubstituted or substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CF.sub.3, OCF.sub.3,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.2 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0118] R.sub.6 and R.sub.7 at each
occurrence are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 alkoxycarbonyl. In another aspect, R.sub.6 and
R.sub.7 are independently H or C.sub.1-C.sub.4 alkyl.
[0119] Other preferred compounds of Embodiment 12 include those of
Embodiment 12D, i.e., compounds of Embodiment 12 where [0120]
R.sub.1 is pyrazinyl, which is unsubstituted or substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CF.sub.3, OCF.sub.3,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.2 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0121] R.sub.6 and R.sub.7 at each
occurrence are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 alkoxycarbonyl. In another aspect, R.sub.6 and
R.sub.7 are independently H or C.sub.1-C.sub.4 alkyl.
[0122] Other preferred compounds of the invention are within
Embodiment 12E, i.e., compounds of embodiments 12, 12A, 12B, 12C,
and 12D, wherein at least one of R.sub.2 and R.sub.3 is H. In
another aspect, both R.sub.2 and R.sub.3 are H.
[0123] More preferred compounds of the invention include those of
Embodiment 12F, i.e., compounds according to embodiment 12E wherein
R.sub.4 is H.
[0124] Still other preferred compounds of Embodiment 6 include
those of embodiment 13, i.e., compounds of Embodiment 6 where
[0125] R.sub.4 and R.sub.5 and the nitrogen to which they are
attached form a piperazinyl, morpholinyl, piperidinyl,
imidazolidinyl, or pyrrolidinyl ring, each of which is
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, phenyl C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkanoyl,
OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.4 alkyl,
pyrazinyl C.sub.1-C.sub.4 alkyl, phenyl, --OCH.sub.2CH.sub.2O--,
--OCH.sub.2O--, [0126] wherein the pyridyl, pyrimidyl, pyrazinyl,
pyrimidyl C.sub.1-C.sub.6 alkyl, and phenyl groups are
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, CF.sub.3 or OCF.sub.3.
[0127] Still other preferred compounds of Embodiment 13 include
those of embodiment 14, i.e., compounds of Embodiment 13 where
[0128] R.sub.1 is phenyl, thienyl, furanyl, pyridyl, pyrimidyl,
pyrazinyl, triazolyl, imidazolyl, oxazolyl, benzofuranyl, each of
which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, heteroaryl selected from
pyridyl, pyrimidyl, pyrazinyl, indolyl, thienyl, furanyl, pyrrolyl,
and benzimidazolyl, heterocycloalkyl selected from piperidinyl,
pyrrolidinyl, piperazinyl, morpholinyl, and S,S-dioxomorpholinyl,
phenyl, or naphthyl, wherein the heteroaryl, heterocycloalkyl,
phenyl and naphthyl groups are optionally substituted with 1 or
more groups that are independently selected from C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and
OCF.sub.3, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxycarbonyl, or C.sub.1-C.sub.4 alkanoyl.
[0129] Still other preferred compounds of Embodiment 13 include
those of embodiment 15, i.e., compounds of Embodiment 13 where
[0130] R.sub.1 is phenyl, thienyl, pyridyl, pyrimidyl, pyrazinyl,
triazolyl, imidazolyl, or benzofuranyl, each of which is
unsubstituted or substituted with 1, 2, or 3 groups that are
independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy, OH, --C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein [0131]
each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, or 2 groups that are independently halogen, OH, CF.sub.3,
OCF.sub.3, 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); [0132] R.sub.10 is phenyl,
naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl, or
C.sub.3-C.sub.8 cycloalkyl, each of which is optionally substituted
with halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH,
CO.sub.2H, CN, NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 haloalkoxy; [0133] wherein the heterocycloalkyl and
the cycloalkyl portions of R.sub.1 and R.sub.10 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0134] Embodiment 16 includes compounds of Embodiments 14 and 15
wherein [0135] R.sub.4 and R.sub.5 and the nitrogen to which they
are attached form a piperazinyl, morpholinyl, piperidinyl,
imidazolidinyl, or pyrrolidinyl ring, each of which is
unsubstituted or substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, phenyl C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.6 alkanoyl,
OH, pyridyl, pyrimidyl C.sub.1-C.sub.2 alkyl, phenyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--; and [0136] R.sub.2 and
R.sub.3 are both H.
[0137] Other preferred compounds of Embodiment 16 include those of
embodiment 16A, i.e., compounds of Embodiment 16 where [0138]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring,
each of which is substituted with 1 or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, phenyl C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.6 alkanoyl,
OH, pyridyl, pyrimidyl C.sub.1-C.sub.2 alkyl, phenyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--.
[0139] Embodiment 16B includes compounds of embodiments 16 and 16A
wherein [0140] R.sub.1 is phenyl, which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein [0141]
each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, 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); and [0142]
R.sub.10 is phenyl, pyridyl, or furanyl, each of which is
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2, CF.sub.3, or
OCF.sub.3.
[0143] Embodiment 16C includes compounds of embodiments 16 and 16A
wherein [0144] R.sub.1 is thienyl, triazolyl, imidazolyl, or
benzofuranyl, each of which is unsubstituted or substituted with 1,
2, or 3 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, --C(O)R.sub.10,
NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0145] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted
or substituted with 1, or 2 groups that are independently halogen,
OH, 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); and [0146] R.sub.10 is phenyl, pyridyl, or
furanyl, each of which is optionally substituted with halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN,
NO.sub.2, CF.sub.3, or OCF.sub.3.
[0147] Embodiment 16D includes compounds of embodiments 16 and 16A
wherein [0148] R.sub.1 is pyridyl, pyrimidyl, or pyrazinyl, each of
which is unsubstituted or substituted with 1, 2, or 3 groups that
are independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6
alkoxy, OH, --C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein [0149]
each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, 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); and [0150]
R.sub.10 is phenyl, pyridyl, or furanyl, each of which is
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2, CF.sub.3, or
OCF.sub.3.
[0151] Embodiment 16E includes compounds of embodiments 16, 16A,
16B, 16C, and 16D wherein Z is a bond.
[0152] Embodiment 16E includes compounds of embodiments 16, 16A,
16B, 16C, and 16D wherein Z is --CH.sub.2--.
[0153] Embodiment 16G includes compounds of embodiments 16, 16A,
16B, 16C, and 16D wherein Z is --NH--.
[0154] Embodiment 16H includes compounds of embodiments 16, 16A,
16B, 16C, and 16D wherein Z is --S-- or --SO.sub.2--.
[0155] Embodiment 16I includes compounds of embodiments 16, 16A,
16B, 16C, and 16D wherein Z is --SO.sub.2NH--, or
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)-.
[0156] In still another aspect, the invention provides compounds
according to embodiments 5, 16, and 16A-16I, wherein R.sub.21 is
H.
[0157] In yet still another aspect, the invention provides
compounds according to embodiments 5, 16, and 16A-16I, wherein
R.sub.21 is CN.
[0158] In still yet another aspect, the invention provides
compounds according to embodiments 5, 16, and 16A-16I, wherein
R.sub.21 is amino, monoalkylamino, or dialkylamino.
[0159] In yet another aspect, the invention provides compounds of
embodiments 5, 16, and 16A-16I, wherein R.sub.21 is OH.
[0160] In still another aspect, the invention provides compounds of
embodiments 5, 16, and 16A-16I, wherein R.sub.21 is phenyl.
[0161] In still another aspect, the invention provides compounds of
embodiments 5, 16, and 16A-16I, wherein R.sub.21 is pyridyl.
[0162] In still another aspect, the invention provides compounds of
embodiments 5, 16, and 16A-16I, wherein R.sub.21 is halogen.
[0163] In yet another aspect, the invention provides compounds of
embodiments 5, 16, and 16A-16I, wherein R.sub.21 is phenyl, which
is substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)).
[0164] In yet still another aspect, the invention provides
compounds of embodiments 5, 16, and 16A-16I, wherein R.sub.21 is
pyridyl, or pyrimidyl, each of which is optionally substituted with
1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0165] In yet still another aspect, the invention provides
compounds of embodiments 5, 16, and 16A-16I, wherein R.sub.21 is
indolyl or (iso)quinolinyl, each of which is optionally substituted
with 1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0166] In still another aspect, the invention provides compounds of
embodiments 5, 16, and 16A-16I, wherein R.sub.21 is C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6 alkenyl.
[0167] In still yet another aspect, the invention provides
compounds of embodiments 5, 16, and 16A-16I, wherein R.sub.21 is
--C(O)NH.sub.2, --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).
[0168] Still other preferred compounds of Embodiment 5 include
those of embodiment 17, i.e., compounds of Embodiment 5 where
[0169] R.sub.1 is halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl,
indolyl, thienyl, furanyl, pyrrolyl, and benzimidazolyl,
heterocycloalkyl selected from piperidinyl, pyrrolidinyl,
piperazinyl, morpholinyl, and S,S-dioxomorpholinyl, phenyl, or
naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl and
naphthyl groups are optionally substituted with 1 or more groups
that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and OCF.sub.3,
CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, or --C(O)NR.sub.6R.sub.7, wherein [0170]
each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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) [0171] R.sub.10 is C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, phenyl, naphthyl, pyridyl, quinolinyl,
pyrimidyl, furanyl, indolyl, C.sub.3-C.sub.8 cycloalkyl, wherein
the cyclic portions are optionally substituted with halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN,
NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy;
[0172] wherein the cycloalkyl portion of R.sub.10 is further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0173] Other preferred compounds of Embodiment 17 include those of
embodiment 18, i.e., compounds of Embodiment 17 where [0174]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,
imidazolidinyl, S,S-dioxothiomorpholinyl, piperidinyl,
pyrrolidinyl, ring, which is unsubstituted or substituted with 1 or
more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, OH,
.dbd.O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6
alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl, phenyl, naphthyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--, [0175] wherein the
pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl,
phenyl and naphthyl groups are unsubstituted or substituted with 1
or more groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or OCF.sub.3.
[0176] Other preferred compounds of Embodiment 18 include those of
embodiment 19, i.e., compounds of Embodiment 18 where [0177]
R.sub.1 is halogen.
[0178] Other preferred compounds of Embodiment 18 include those of
embodiment 20, i.e., compounds of Embodiment 18 where [0179]
R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl, pyrrolyl,
piperidinyl, pyrrolidinyl, piperazinyl morpholinyl, or phenyl,
[0180] wherein the cyclic groups are optionally substituted with 1
or more groups that are independently selected from C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and
OCF.sub.3, wherein [0181] each R.sub.6 and R.sub.7 is independently
H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxyalkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, 2, or 3, groups that are
independently halogen, OH, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, 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); [0182] R.sub.10
is phenyl or pyridyl, each of which is optionally substituted with
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH,
CO.sub.2H, CN, NO.sub.2, CF.sub.3 or OCF.sub.3.
[0183] Other preferred compounds of Embodiment 20 include those of
embodiment 21, i.e., compounds of Embodiment 20 where [0184]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, piperidinyl, or
pyrrolidinyl ring, each of which is unsubstituted or substituted
with 1 or more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, OH,
.dbd.O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6
alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl, phenyl, naphthyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--.
[0185] Other preferred compounds of Embodiment 21 include those of
embodiment 22, i.e., compounds of Embodiment 21 where [0186]
R.sub.1 is C.sub.2-C.sub.6 alkynyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0187] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, OH, CF.sub.3, and OCF.sub.3, wherein [0188] each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0189] Other preferred compounds of Embodiment 21 include those of
embodiment 23, i.e., compounds of Embodiment 21 where [0190]
R.sub.1 is C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0191] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, OH, CF.sub.3, and OCF.sub.3, wherein [0192] each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0193] Other preferred compounds of Embodiment 21 include those of
embodiment 24, i.e., compounds of Embodiment 21 where [0194]
R.sub.1 is C.sub.1-C.sub.6 alkenyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0195] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, OH, CF.sub.3, and OCF.sub.3, wherein [0196] each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0197] Embodiment 24A includes compounds of embodiments 19, 20, 21,
22, 23, and 24, wherein Z is a bond.
[0198] Embodiment 24B includes compounds of embodiments 20, 21, 22,
23, and 24, wherein Z is --CH.sub.2--.
[0199] Embodiment 24C includes compounds of embodiments 20, 21, 22,
23, and 24, wherein Z is --NH--.
[0200] Embodiment 24D includes compounds of embodiments 20, 21, 22,
23, and 24, wherein Z is --S-- or --SO.sub.2--.
[0201] Embodiment 24E includes compounds of embodiments 20, 21, 22,
23, and 24, wherein Z is --N(C.sub.1-C.sub.4 alkyl)-. In another
aspect, Z is --N(C.sub.1-C.sub.2 alkyl)-. In still another aspect,
Z is --N(C.sub.2-C.sub.3 alkyl)-.
[0202] Embodiment 24F includes compounds of embodiments 20, 21, 22,
23, and 24, wherein Z is --SO.sub.2NH--, or
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)-.
[0203] In still another aspect, the invention provides compounds
according to embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein
R.sub.21 is H.
[0204] In yet still another aspect, the invention provides
compounds according to embodiments 20, 21, 22, 23, 24, and 24A-24F,
wherein R.sub.21 is CN.
[0205] In still yet another aspect, the invention provides
compounds according to embodiments 20, 21, 22, 23, 24, and 24A-24F,
wherein R.sub.21 is amino, monoalkylamino, or dialkylamino.
[0206] In yet another aspect, the invention provides compounds of
embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R.sub.21 is
OH.
[0207] In still another aspect, the invention provides compounds of
embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R.sub.21 is
phenyl.
[0208] In still another aspect, the invention provides compounds of
embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R.sub.21 is
pyridyl.
[0209] In still another aspect, the invention provides compounds of
embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R.sub.21 is
halogen.
[0210] In yet another aspect, the invention provides compounds of
embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R.sub.21 is
phenyl, which is substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)).
[0211] In yet still another aspect, the invention provides
compounds of embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein
R.sub.21 is pyridyl, or pyrimidyl, each of which is optionally
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0212] In yet still another aspect, the invention provides
compounds of embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein
R.sub.21 is indolyl or (iso)quinolinyl, each of which is optionally
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0213] In still another aspect, the invention provides compounds of
embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R.sub.21 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6
alkenyl.
[0214] In still yet another aspect, the invention provides
compounds of embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein
R.sub.21 is --C(O)NH.sub.2, --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).
[0215] Still other preferred compounds of Embodiment 17 include
those of Embodiment 25, i.e., compounds of Embodiment 17 where
[0216] R.sub.4 and R.sub.5 are independently H, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.8 cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,
morpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6
alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.2-C.sub.6 alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl,
morpholinyl C.sub.2-C.sub.6 alkenyl, piperidinyl C.sub.2-C.sub.6
alkynyl, pyrrolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl
C.sub.2-C.sub.6 alkynyl, phenyl, furanyl, pyridyl, pyrazinyl
C.sub.1-C.sub.6 alkyl, pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl
C.sub.1-C.sub.6 alkyl, furanyl C.sub.1-C.sub.6 alkyl, thienyl
C.sub.1-C.sub.6 alkyl, phenyl C.sub.1-C.sub.6 alkyl, phenyl
C.sub.2-C.sub.6 alkenyl, phenyl C.sub.2-C.sub.6 alkynyl, wherein
the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0217] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0218] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with =.degree., .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0219] Still other preferred compounds of Embodiment 25 include
those of Embodiment 26, i.e., compounds of Embodiment 25 where
[0220] R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, [0221] wherein the pyridyl, piperidinyl and
phenyl groups are optionally substituted with 1 or more groups that
are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, OH, OH, CF.sub.3, and OCF.sub.3,
wherein [0222] each R.sub.6 and R.sub.7 is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6
alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted
or substituted with 1, 2, or 3, groups that are independently
halogen, OH, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
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); [0223] R.sub.10 is phenyl or pyridyl, each
of which is optionally substituted with halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
CF.sub.3 or OCF.sub.3.
[0224] Still other preferred compounds of Embodiment 26 include
those of Embodiment 27, i.e., compounds of Embodiment 26 where
[0225] R.sub.4 and P.sub.5 are independently H, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, piperidinyl,
pyrrolidinyl, morpholinyl, morpholinyl C.sub.1-C.sub.6 alkyl,
piperidinyl C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6
alkyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, wherein the cyclic portion of each of
the above is unsubstituted or substituted with one or more groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, NO.sub.2,
CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0226] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0227] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0228] Still other preferred compounds of Embodiment 27 include
those of Embodiment 28, i.e., compounds of Embodiment 27 where
[0229] R.sub.1 is C.sub.2-C.sub.6 alkynyl substituted with 1, 2, or
3 groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0230] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0231] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0232] Still other preferred compounds of Embodiment 27 include
those of Embodiment 29, i.e., compounds of Embodiment 27 where
[0233] R.sub.1 is C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0234] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0235] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0236] Still other preferred compounds of Embodiment 27 include
those of Embodiment 30, i.e., compounds of Embodiment 27 where
[0237] R.sub.1 is C.sub.1-C.sub.6 alkenyl substituted with 1, 2, or
3 groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
piperidinyl, piperidinyl, or phenyl, [0238] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0239] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0240] Embodiment 30A includes compounds of embodiments 27, 28, and
29, wherein R.sub.2 and R.sub.3 are independently H or methyl. In
another aspect, at least one of R.sub.2 and R.sub.3 is H.
[0241] Preferred compounds of Embodiment 30A include those of
Embodiment 30B, i.e., compounds of Embodiment 30A where wherein
R.sub.4 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl.
[0242] Preferred compounds of Embodiment 30B include those of
Embodiment 30C, i.e., compounds of Embodiment 30B where [0243]
R.sub.5 is piperidinyl, pyrrolidinyl, morpholinyl, phenyl, furanyl,
or pyridyl, wherein the cyclic portion of each of the above is
unsubstituted or substituted with one or more groups that are
independently C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.4 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0244] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0245] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0246] Preferred compounds of Embodiment 30B include those of
Embodiment 30D, i.e., compounds of Embodiment 30B where [0247]
R.sub.5 is morpholinyl C.sub.1-C.sub.4 alkyl, piperidinyl
C.sub.1-C.sub.4 alkyl, pyrrolidinyl C.sub.1-C.sub.4 alkyl,
pyrazinyl C.sub.1-C.sub.4 alkyl, pyridyl C.sub.1-C.sub.4 alkyl,
imidazolyl C.sub.1-C.sub.4 alkyl, furanyl C.sub.1-C.sub.4 alkyl,
thienyl C.sub.1-C.sub.4 alkyl, or phenyl C.sub.1-C.sub.4 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, CF.sub.3, OCF.sub.3, NO.sub.2,
CN, OH, phenyl C.sub.1-C.sub.4 alkyl wherein the phenyl is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0248] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0249] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0250] Embodiment 30E includes compounds of embodiments 30C and
30D, wherein Z is a bond.
[0251] Embodiment 30F includes compounds of embodiments 30C and
30D, wherein Z is --CH.sub.2--.
[0252] Embodiment 30G includes compounds of embodiments 30C and
30D, wherein Z is --NH--.
[0253] Embodiment 30H includes compounds of embodiments 30C and
30D, wherein Z is --S-- or --SO.sub.2--. Embodiment 30I includes
compounds of embodiments 30C and 30D, wherein Z is
--N(C.sub.1-C.sub.4 alkyl)-. In another aspect, Z is
--N(C.sub.1-C.sub.2 alkyl)-. In still another aspect, Z is
--N(C.sub.2-C.sub.3 alkyl)-. 30J. A compound according to either
embodiment 30C or 30D, wherein Z is --SO.sub.2NH--, or
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)-.
[0254] In still another aspect, the invention provides compounds
according to embodiments 27, 28, 29, 30, and 30A-30I, wherein
R.sub.21 is H.
[0255] In yet still another aspect, the invention provides
compounds according to embodiments 27, 28, 29, 30, and 30A-30I,
wherein R.sub.21 is CN.
[0256] In still yet another aspect, the invention provides
compounds according to embodiments 27, 28, 29, 30, and 30A-30I,
wherein R.sub.21 is amino, monoalkylamino, or dialkylamino.
[0257] In yet another aspect, the invention provides compounds of
embodiments 27, 28, 29, 30, and 30A-30I, wherein R.sub.21 is
OH.
[0258] In still another aspect, the invention provides compounds of
embodiments 27, 28, 29, 30, and 30A-30I, wherein R.sub.21 is
phenyl.
[0259] In still another aspect, the invention provides compounds of
embodiments 27, 28, 29, 30, and 30A-30I, wherein R.sub.21 is
pyridyl.
[0260] In still another aspect, the invention provides compounds of
embodiments 27, 28, 29, 30, and 30A-30I, wherein R.sub.21 is
halogen.
[0261] In yet another aspect, the invention provides compounds of
embodiments 27, 28, 29, 30, and 30A-30I, wherein R.sub.21 is
phenyl, which is substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)).
[0262] In yet still another aspect, the invention provides
compounds of embodiments 27, 28, 29, 30, and 30A-30I, wherein
R.sub.21 is pyridyl or pyrimidyl, each of which is optionally
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0263] In yet still another aspect, the invention provides
compounds of embodiments 27, 28, 29, 30, and 30A-30I, wherein
R.sub.21 is indolyl or (iso)quinolinyl, each of which is optionally
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0264] In still another aspect, the invention provides compounds of
embodiments 27, 28, 29, 30, and 30A-30I, wherein R.sub.21 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6
alkenyl.
[0265] In still yet another aspect, the invention provides
compounds of embodiments 27, 28, 29, 30, and 30A-30I, wherein
R.sub.21 is --C(O)NH.sub.2, --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).
[0266] Other preferred compounds of Embodiment 17 include those of
Embodiment 31, i.e., compounds of Embodiment 17 where [0267]
R.sub.4 and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.3-C.sub.6 cycloalkyl, wherein the cycloalkyl is unsubstituted
or substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0268] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0269] wherein the cycloalkyl
portion of R.sub.4 and R.sub.5 is further optionally substituted
with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0270] Other preferred compounds of Embodiment 31 include those of
Embodiment 32, i.e., compounds of Embodiment 31 where [0271]
R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, [0272] wherein the phenyl is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, wherein [0273] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0274]
R.sub.10 is phenyl or pyridyl, each of which is optionally
substituted with halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, OH, CO.sub.2H, CN, NO.sub.2, CF.sub.3 or OCF.sub.3.
[0275] Other preferred compounds of Embodiment 31 include those of
Embodiment 33, i.e., compounds of Embodiment 31 where [0276]
R.sub.1 is C.sub.2-C.sub.6 alkynyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0277] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0278] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0279] Other preferred compounds of Embodiment 31 include those of
Embodiment 34, i.e., compounds of Embodiment 31 where [0280]
R.sub.1 is C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0281] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0282] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0283] Other preferred compounds of Embodiment 31 include those of
Embodiment 35, i.e., compounds of Embodiment 31 where [0284]
R.sub.1 is C.sub.1-C.sub.6 alkenyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0285] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0286] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0287] Other preferred compounds of Embodiment 31 include those of
Embodiment 35A, i.e., compounds of Embodiment 31 where R.sub.1 is
halogen.
[0288] Embodiment 35B includes compounds of embodiments 33, 34, and
35, wherein R.sub.4 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4
alkoxy C.sub.1-C.sub.6 alkyl.
[0289] Other preferred compounds of Embodiment 35B include those of
Embodiment 35C, i.e., compounds of Embodiment 35B where [0290]
R.sub.5 is C.sub.3-C.sub.6 cycloalkyl, wherein the cycloalkyl 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, --SO.sub.2--(C.sub.1-C.sub.4) alkyl, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.4 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxycarbonyl,
C.sub.1-C.sub.4 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0291] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0292] wherein the cycloalkyl
portion of R.sub.4 and R.sub.5 is further optionally substituted
with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3; and [0293] at least
one of R.sub.2 and R.sub.3 is H.
[0294] Other preferred compounds of Embodiment 35C include those of
Embodiment 35D, i.e., compounds of Embodiment 35C where wherein Z
is a bond.
[0295] Other preferred compounds of Embodiment 35C include those of
Embodiment 35E, wherein Z is --CH.sub.2--.
[0296] Other preferred compounds of Embodiment 35C include those of
Embodiment 35F wherein Z is --NH--.
[0297] Other preferred compounds of Embodiment 35C include those of
Embodiment 35G wherein Z is --S-- or --SO.sub.2--.
[0298] Other preferred compounds of Embodiment 35C include those of
Embodiment 35H wherein Z is --N(C.sub.1-C.sub.4 alkyl)-. In another
aspect, Z is --N(C.sub.1-C.sub.2 alkyl)-. In still another aspect,
Z is --N(C.sub.2-C.sub.3 alkyl)-.
[0299] Other preferred compounds of Embodiment 35C include those of
Embodiment 35I wherein Z is --SO.sub.2NH--, or
--SO.sub.2N(C.sub.1-C.sub.4 alkyl)-.
[0300] In still another aspect, the invention provides compounds
according to embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21
is H.
[0301] In yet still another aspect, the invention provides
compounds according to embodiments 33, 34, 35, and 35A-35I, wherein
R.sub.21 is CN.
[0302] In still yet another aspect, the invention provides
compounds according embodiments 33, 34, 35, and 35A-35I, wherein
R.sub.21 is amino, monoalkylamino, or dialkylamino.
[0303] In yet another aspect, the invention provides compounds of
embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21 is OH.
[0304] In still another aspect, the invention provides compounds of
embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21 is
phenyl.
[0305] In still another aspect, the invention provides compounds of
embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21 is
pyridyl.
[0306] In still another aspect, the invention provides compounds of
embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21 is
halogen.
[0307] In yet another aspect, the invention provides compounds of
embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21 is phenyl,
which is substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)).
[0308] In yet still another aspect, the invention provides
compounds of embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21
is pyridyl or pyrimidyl, each of which is optionally substituted
with 1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0309] In yet still another aspect, the invention provides
compounds of embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21
is indolyl or (iso)quinolinyl, each of which is optionally
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0310] In still another aspect, the invention provides compounds of
embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6
alkenyl.
[0311] In still yet another aspect, the invention provides
compounds of embodiments 33, 34, 35, and 35A-35I, wherein R.sub.21
is --C(O)NH.sub.2, --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).
[0312] Other preferred compounds of Embodiment 5 include those of
Embodiment 36, i.e., compounds of Embodiment 5 where [0313] Z is a
bond; [0314] R.sub.1 is phenyl, naphthyl, thienyl, furanyl,
indolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazolyl,
imidazolyl, benzofuranyl, piperidinyl, pyrrolidinyl, piperazinyl,
or morpholinyl, each of which is unsubstituted or substituted with
1, 2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.6
alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
-(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl,
(iso)quinolinyl, indolyl, thienyl, furanyl, pyrrolyl, triazinyl,
1H-indazolyl, and benzimidazolyl, heterocycloalkyl selected from
piperidinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, imidazolidinyl, piperazinyl, morpholinyl,
and S,S-dioxomorpholinyl, phenyl, naphthyl, wherein the heteroaryl,
heterocycloalkyl, or phenyl, which is optionally substituted with
1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0315] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and
[0316] R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl,
indolyl, C.sub.3-C.sub.8 cycloalkyl, wherein the cyclic portions
are optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; [0317]
wherein the heterocycloalkyl and the cycloalkyl portions of R.sub.1
and R.sub.10 are further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3.
[0318] Other preferred compounds of Embodiment 36 include those of
Embodiment 37, i.e., compounds of Embodiment 36 where [0319]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, imidazolidinyl, or
pyrrolidinyl ring, each of which is unsubstituted or substituted
with 1 or more groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, phenyl C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl,
pyrimidyl C.sub.1-C.sub.4 alkyl, pyrazinyl C.sub.1-C.sub.4 alkyl,
phenyl, --OCH.sub.2CH.sub.2O--, --OCH.sub.2O--, [0320] wherein the
pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, and
phenyl groups are unsubstituted or substituted with 1 or more
groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or OCF.sub.3.
[0321] Other preferred compounds of Embodiment 37 include those of
Embodiment 38, i.e., compounds of Embodiment 37 where [0322]
R.sub.1 is phenyl which is unsubstituted or substituted with 1, 2,
3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, heteroaryl selected
from pyridyl, pyrimidyl, indolyl, thienyl, furanyl, and pyrrolyl,
heterocycloalkyl selected from piperidinyl, pyrrolidinyl,
piperazinyl, and morpholinyl, phenyl, wherein the heteroaryl,
heterocycloalkyl phenyl and naphthyl groups are optionally
substituted with each of which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0323] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, CF.sub.3, OCF.sub.3,
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).
[0324] Other preferred compounds of Embodiment 38 include those of
Embodiment 39, i.e., compounds of Embodiment 38 where [0325]
R.sub.2 and R.sub.3 are both H; and [0326] R.sub.4 and R.sub.5 and
the nitrogen to which they are attached form a piperazinyl,
morpholinyl, piperidinyl, or pyrrolidinyl ring, each of which is
substituted with 1 or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkanoyl, OH, pyridyl,
pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.4 alkyl, pyrazinyl
C.sub.1-C.sub.4 alkyl, phenyl, --OCH.sub.2CH.sub.2O--, or
--OCH.sub.2O--.
[0327] Preferred compounds of Embodiment 39 include those of
Embodiment 39A, i.e., compounds of Embodiment 39 where [0328]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring,
wherein the piperazinyl and piperidinyl rings are substituted at
position 4, wherein the morpholinyl, and pyrrolidinyl rings are
substituted at position 3.
[0329] Preferred compounds of Embodiment 37 include those of
Embodiment 40, i.e., compounds of Embodiment 37 where [0330]
R.sub.1 is thienyl, furanyl, indolyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, triazolyl, imidazolyl, benzofuranyl,
piperidinyl, pyrrolidinyl, piperazinyl, or morpholinyl, each of
which is unsubstituted or substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, wherein the pyridyl, piperidinyl, and
phenyl groups are optionally substituted with 1, 2, 3, 4, or 5
groups that are independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3, and OCF.sub.3, wherein
[0331] each R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and [0332] wherein the
heterocycloalkyl portion of R.sub.10 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0333] Preferred compounds of Embodiment 40 include those of
Embodiment 41, i.e., compounds of Embodiment 40 where [0334]
R.sub.2 and R.sub.3 are both H; and [0335] R.sub.4 and R.sub.5 and
the nitrogen to which they are attached form a piperazinyl,
morpholinyl, piperidinyl, or pyrrolidinyl ring, each of which is
substituted with 1 or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkanoyl, OH, pyridyl,
pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.4 alkyl, pyrazinyl
C.sub.1-C.sub.4 alkyl, phenyl, --OCH.sub.2CH.sub.2O--, or
--OCH.sub.2O--.
[0336] Preferred compounds of Embodiment 41 include those of
Embodiment 42, i.e., compounds of Embodiment 41 where [0337]
R.sub.1 is thienyl optionally substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0338] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0339] Preferred compounds of Embodiment 41 include those of
Embodiment 43, i.e., compounds of Embodiment 41 where [0340]
R.sub.1 is benzofuranyl optionally substituted with 1, 2, 3, or 4
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0341] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0342] Preferred compounds of Embodiment 36 include those of
Embodiment 44, i.e., compounds of Embodiment 36 where [0343]
R.sub.4 and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl
C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6 alkyl,
pyrrolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, morpholinyl
C.sub.2-C.sub.6 alkenyl, piperidinyl C.sub.2-C.sub.6 alkynyl,
pyrrolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
phenyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of each
of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0344] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0345] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0346] Preferred compounds of Embodiment 44 include those of
Embodiment 45, i.e., compounds of Embodiment 44 where [0347]
R.sub.1 is phenyl which is unsubstituted or substituted with 1, 2,
3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0348] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, CF.sub.3, OCF.sub.3,
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).
[0349] Preferred compounds of Embodiment 45 include those of
Embodiment 45A, i.e., compounds of Embodiment 45 where [0350] A
compound according to embodiment 36, wherein [0351] R.sub.4 is H,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6
alkyl.
[0352] Preferred compounds of Embodiment 45A include those of
Embodiment 45B, i.e., compounds of Embodiment 45A where [0353]
R.sub.5 is C.sub.3-C.sub.8 cycloalkyl, which is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0354] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0355] wherein the cycloalkyl
portion of R.sub.5 is further optionally substituted with .dbd.O,
.dbd.N--OH, or .dbd.N--OCH.sub.3.
[0356] Preferred compounds of Embodiment 45A include those of
Embodiment 45C, i.e., compounds of Embodiment 45A where [0357]
R.sub.5 is piperidinyl, pyrrolidinyl, morpholinyl, phenyl, furanyl,
or pyridyl, wherein the cyclic portion of each of the above is
unsubstituted or substituted with one or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0358] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0359] wherein the
heterocycloalkyl portion of R.sub.5 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0360] Preferred compounds of Embodiment 45A include those of
Embodiment 45D, i.e., compounds of Embodiment 45A where [0361]
R.sub.5 is morpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl,
piperidinyl C.sub.2-C.sub.6 alkenyl, pyrrolidinyl C.sub.2-C.sub.6
alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl, piperidinyl
C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6 alkynyl,
morpholinyl C.sub.2-C.sub.6 alkynyl, pyrazinyl C.sub.1-C.sub.6
alkyl, pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6
alkyl, furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6
alkyl, phenyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6
alkenyl, phenyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion
of each of the above is unsubstituted or substituted with one or
more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0362] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0363] wherein the
heterocycloalkyl portion of R.sub.5 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0364] Preferred compounds of Embodiment 45A include those of
Embodiment 45E, i.e., compounds of Embodiment 45A where [0365]
R.sub.5 is morpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl
C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl,
pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl C.sub.1-C.sub.6 alkyl,
imidazolyl C.sub.1-C.sub.6 alkyl, furanyl C.sub.1-C.sub.6 alkyl,
thienyl C.sub.1-C.sub.6 alkyl, or phenyl C.sub.1-C.sub.6 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0366] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0367] wherein the
heterocycloalkyl portion of R.sub.5 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0368] Preferred compounds of Embodiment 45A include those of
Embodiment 45F, i.e., compounds of Embodiment 45A where [0369]
R.sub.5 is piperidinyl C.sub.2-C.sub.6 alkenyl, pyrrolidinyl
C.sub.2-C.sub.6 alkenyl, morpholinyl C.sub.2-C.sub.6 alkenyl,
piperidinyl C.sub.2-C.sub.6 alkynyl, pyrrolidinyl C.sub.2-C.sub.6
alkynyl, morpholinyl C.sub.2-C.sub.6 alkynyl, phenyl
C.sub.2-C.sub.6 alkenyl, or phenyl C.sub.2-C.sub.6 alkynyl, wherein
the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0370] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0371] wherein the
heterocycloalkyl portion of R.sub.5 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0372] In still another aspect, the invention provides compounds
according to embodiments 45 and 45A-45F, wherein R.sub.21 is H.
[0373] In yet still another aspect, the invention provides
compounds according to embodiments 45 and 45A-45F, wherein R.sub.21
is CN.
[0374] In still yet another aspect, the invention provides
compounds according to embodiments 45 and 45A-45F, wherein R.sub.21
is amino, monoalkylamino, or dialkylamino.
[0375] In yet another aspect, the invention provides compounds of
embodiments 45 and 45A-45F, wherein R.sub.21 is OH.
[0376] In still another aspect, the invention provides compounds of
embodiments 45 and 45A-45F, wherein R.sub.21 is phenyl.
[0377] In still another aspect, the invention provides compounds of
embodiments 45 and 45A-45F, wherein R.sub.21 is pyridyl.
[0378] In still another aspect, the invention provides compounds of
embodiments 45 and 45A-45F, wherein R.sub.21 is halogen.
[0379] In yet another aspect, the invention provides compounds of
embodiments 45 and 45A-45F, wherein R.sub.21 is phenyl, which is
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0380] In yet still another aspect, the invention provides
compounds of embodiments 45 and 45A-45F, wherein R.sub.21 is
pyridyl or pyrimidyl, each of which is optionally substituted with
1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0381] In yet still another aspect, the invention provides
compounds of embodiments 45 and 45A-45F, wherein R.sub.21 is
indolyl or (iso)quinolinyl, each of which is optionally substituted
with 1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0382] In still another aspect, the invention provides compounds of
embodiments 45 or 45A-45F, wherein R.sub.21 is C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6 alkenyl.
[0383] In still yet another aspect, the invention provides
compounds of embodiments 45 or 45A-45F, wherein R.sub.21 is
--C(O)NH.sub.2, --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).
[0384] Preferred compounds of Embodiment 36 include those of
Embodiment 46, i.e., compounds of Embodiment 36 where R.sub.2 and
R.sub.3 are both H; and [0385] R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, piperidinyl, pyrrolidinyl, morpholinyl,
morpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6
alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl, phenyl, furanyl,
pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl C.sub.1-C.sub.6
alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl C.sub.1-C.sub.6
alkyl, thienyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.1-C.sub.6 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2-- (C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0386] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0387] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0388] Preferred compounds of Embodiment 46 include those of
Embodiment 47, i.e., compounds of Embodiment 46 where [0389]
R.sub.1 is thienyl, furanyl, indolyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, triazolyl, imidazolyl, benzofuranyl,
piperidinyl, pyrrolidinyl, piperazinyl, or morpholinyl, each of
which is unsubstituted or substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0390] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0391] Preferred compounds of Embodiment 47 include those of
Embodiment 48, i.e., compounds of Embodiment 47 where [0392]
R.sub.1 is thienyl optionally substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0393] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0394] Preferred compounds of Embodiment 47 include those of
Embodiment 49, i.e., compounds of Embodiment 47 where [0395]
R.sub.1 is benzofuranyl optionally substituted with 1, 2, 3, or 4
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, or phenyl, which is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, CF.sub.3, and OCF.sub.3, wherein [0396] each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0397] Embodiment 49A includes compounds of embodiments 47, 48 and
49, wherein, R.sub.4 is H, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl.
[0398] Preferred compounds of Embodiment 49A include those of
Embodiment 49B, i.e., compounds of Embodiment 49A where [0399]
R.sub.5 is piperidinyl, pyrrolidinyl, morpholinyl, phenyl, furanyl,
or pyridyl, wherein the cyclic portion of each of the above is
unsubstituted or substituted with one or more groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl, CF.sub.3, OCF.sub.3,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.4 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0400] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.4 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0401] wherein the
heterocycloalkyl portion of R.sub.5 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0402] Preferred compounds of Embodiment 49A include those of
Embodiment 49C, i.e., compounds of Embodiment 49A where [0403]
R.sub.5 is morpholinyl C.sub.1-C.sub.4 alkyl, piperidinyl
C.sub.1-C.sub.4 alkyl, pyrrolidinyl C.sub.1-C.sub.4 alkyl,
pyrazinyl C.sub.1-C.sub.4 alkyl, pyridyl C.sub.1-C.sub.4 alkyl,
imidazolyl C.sub.1-C.sub.4 alkyl, furanyl C.sub.1-C.sub.4 alkyl,
thienyl C.sub.1-C.sub.4 alkyl, or phenyl C.sub.1-C.sub.4 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, CF.sub.3, OCF.sub.3, NO.sub.2,
CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0404] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0405] wherein the
heterocycloalkyl portion of R.sub.5 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0406] In still another aspect, the invention provides compounds
according to embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21
is H.
[0407] In yet still another aspect, the invention provides
compounds according to embodiments 47, 48, 49, and 49A-49C, wherein
R.sub.21 is CN.
[0408] In still yet another aspect, the invention provides
compounds according to embodiments 47, 48, 49, and 49A-49C, wherein
R.sub.21 is amino, monoalkylamino, or dialkylamino.
[0409] In yet another aspect, the invention provides compounds of
embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21 is OH.
[0410] In still another aspect, the invention provides compounds of
embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21 is
phenyl.
[0411] In still another aspect, the invention provides compounds of
embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21 is
pyridyl.
[0412] In still another aspect, the invention provides compounds of
embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21 is
halogen.
[0413] In yet another aspect, the invention provides compounds of
embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21 is phenyl,
which is substituted with 1-5 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH,
hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect,
CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)).
[0414] In yet still another aspect, the invention provides
compounds of embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21
is pyridyl or pyrimidyl, each of which is optionally substituted
with 1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0415] In yet still another aspect, the invention provides
compounds of embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21
is indolyl or (iso)quinolinyl, each of which is optionally
substituted with 1-5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl
C.sub.1-C.sub.4 alkyl, haloalkyl (in one aspect, CF.sub.3), or
haloalkoxy (in one aspect, OCF.sub.3)).
[0416] In still another aspect, the invention provides compounds of
embodiments 47, 48, 49, and 49A-49C, wherein R.sub.21 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6
alkenyl.
[0417] In still yet another aspect, the invention provides
compounds of embodiments 45 and 45A-45F, wherein R.sub.21 is
--C(O)NH.sub.2, --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).
[0418] Preferred compounds of Embodiment 2 include those of
Embodiment 50, i.e., compounds of Embodiment 2 where [0419] X is
--C(O)R.sub.20, or --NR.sub.xR.sub.y; wherein [0420] R.sub.20 is OH
or C.sub.1-C.sub.6 alkoxy; and [0421] R.sub.x and R.sub.y are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, phenyl C.sub.1-C.sub.4 alkoxycarbonyl, phenyl,
naphthyl, phenyl C.sub.1-C.sub.4 alkyl, --C(O)-phenyl,
--C(O)-naphthyl, pyridyl, pyrimidyl, pyrazinyl, benzofuranyl,
indolyl, benzimidazolyl, thienyl, furanyl, quinolinyl,
isoquinolinyl, pyridyl C.sub.1-C.sub.6 alkyl, pyrimidyl
C.sub.1-C.sub.6 alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
benzofuranyl C.sub.1-C.sub.6 alkyl, indolyl C.sub.1-C.sub.6 alkyl,
benzimidazolyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6
alkyl, furanyl C.sub.1-C.sub.6 alkyl, quinolinyl C.sub.1-C.sub.6
alkyl, isoquinolinyl C.sub.1-C.sub.6 alkyl, or --C(O)-pyridyl,
--C(O)-pyrimidyl, --C(O)-pyrazinyl, --C(O)-benzofuranyl,
--C(O)-indolyl, --C(O)-benzimidazolyl, --C(O)-thienyl,
--C(O)-furanyl, --C(O)-quinolinyl, or --C(O)-isoquinolinyl, wherein
the ring portions of the above are optionally substituted with 1,
2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0422] Preferred compounds of Embodiment 50 include those of
Embodiment 51, i.e., compounds of Embodiment 50 where [0423]
R.sub.1 is halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl,
(iso)quinolinyl, indolyl, thienyl, furanyl, pyrrolyl, triazinyl,
1H-indazolyl, and benzimidazolyl, heterocycloalkyl selected from
piperidinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, imidazolidinyl, piperazinyl, morpholinyl,
and S,S-dioxomorpholinyl, phenyl, or naphthyl, wherein the
heteroaryl, heterocycloalkyl, phenyl and naphthyl groups are
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, or
--C(O)NR.sub.6R.sub.7, wherein [0424] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0425]
R.sub.10 is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl,
C.sub.3-C.sub.8 cycloalkyl, wherein the cyclic portions are
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, OH, CO.sub.2H, CN, NO.sub.2,
C.sub.1-C.sub.4 haloalkyl, or C.sub.1-C.sub.4 haloalkoxy; [0426]
wherein the cycloalkyl portion of R.sub.10 is further optionally
substituted with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0427] Preferred compounds of Embodiment 51 include those of
Embodiment 52, i.e., compounds of Embodiment 51 where [0428]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,
imidazolidinyl, S,S-dioxothiomorpholinyl, piperidinyl,
pyrrolidinyl, ring, which is unsubstituted or substituted with 1 or
more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, OH,
.dbd.O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6
alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl, phenyl, naphthyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--, [0429] wherein the
pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl,
phenyl and naphthyl groups are unsubstituted or substituted with 1
or more groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or OCF.sub.3.
[0430] Preferred compounds of Embodiment 52 include those of
Embodiment 53, i.e., compounds of Embodiment 52 where [0431]
R.sub.1 is halogen.
[0432] Preferred compounds of Embodiment 52 include those of
Embodiment 54, i.e., compounds of Embodiment 52 where [0433]
R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, [0434] wherein the phenyl is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, wherein [0435] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0436]
R.sub.10 is phenyl or pyridyl, each of which is optionally
substituted with halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, OH, CO.sub.2H, CN, NO.sub.2, CF.sub.3 or OCF.sub.3.
[0437] Preferred compounds of Embodiment 54 include those of
Embodiment 55, i.e., compounds of Embodiment 54 where [0438]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, piperidinyl, or
pyrrolidinyl ring, each of which is unsubstituted or substituted
with 1 or more groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, phenyl C.sub.1-C.sub.6 alkyl,
naphthyl C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, OH,
.dbd.O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6
alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl, phenyl, naphthyl,
--OCH.sub.2CH.sub.2O--, or --OCH.sub.2O--.
[0439] Preferred compounds of Embodiment 55 include those of
Embodiment 56, i.e., compounds of Embodiment 55 where [0440]
R.sub.1 is C.sub.2-C.sub.6 alkynyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0441] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0442] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0443] Preferred compounds of Embodiment 55 include those of
Embodiment 57, i.e., compounds of Embodiment 55 where [0444]
R.sub.1 is C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0445] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0446] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0447] Preferred compounds of Embodiment 55 include those of
Embodiment 58, i.e., compounds of Embodiment 55 where [0448]
R.sub.1 is C.sub.1-C.sub.6 alkenyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0449] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0450] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0451] Preferred compounds of Embodiment 51 include those of
Embodiment 59, i.e., compounds of Embodiment 51 where [0452]
R.sub.4 and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl
C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6 alkyl,
pyrrolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, morpholinyl
C.sub.2-C.sub.6 alkenyl, piperidinyl C.sub.2-C.sub.6 alkynyl,
pyrrolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
phenyl C.sub.2-C.sub.6 alkynyl, wherein the cyclic portion of each
of the above is unsubstituted or substituted with one or more
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6)
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
NO.sub.2, CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl
is optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0453] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0454] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0455] Preferred compounds of Embodiment 59 include those of
Embodiment 60, i.e., compounds of Embodiment 59 where [0456]
R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, [0457] wherein the phenyl is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, wherein [0458] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0459]
R.sub.10 is phenyl or pyridyl, each of which is optionally
substituted with halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, OH, CO.sub.2H, CN, NO.sub.2, CF.sub.3 or OCF.sub.3.
[0460] Preferred compounds of Embodiment 60 include those of
Embodiment 61, i.e., compounds of Embodiment 60 where [0461]
R.sub.4 and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, piperidinyl,
pyrrolidinyl, morpholinyl, morpholinyl C.sub.1-C.sub.6 alkyl,
piperidinyl C.sub.1-C.sub.6 alkyl, pyrrolidinyl C.sub.1-C.sub.6
alkyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, wherein the cyclic portion of each of
the above is unsubstituted or substituted with one or more groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, --SO.sub.2--(C.sub.1-C.sub.6) alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, NO.sub.2,
CN, OH, phenyl C.sub.1-C.sub.6 alkyl wherein the phenyl is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, CN, halogen, OH, and alkanoyl, C.sub.1-C.sub.6 alkoxy
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.7R.sub.8, or
--C(O)NR.sub.7R.sub.8, [0462] wherein R.sub.7 and R.sub.8 are
independently H or C.sub.1-C.sub.6 alkyl, wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0463] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0464] Preferred compounds of Embodiment 61 include those of
Embodiment 62, i.e., compounds of Embodiment 61 where [0465]
R.sub.1 is C.sub.2-C.sub.6 alkynyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0466] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0467] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0468] Preferred compounds of Embodiment 61 include those of
Embodiment 63, i.e., compounds of Embodiment 61 where [0469]
R.sub.1 is C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0470] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0471] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0472] Preferred compounds of Embodiment 61 include those of
Embodiment 64, i.e., compounds of Embodiment 61 where [0473]
R.sub.1 is C.sub.1-C.sub.6 alkenyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0474] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0475] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0476] Preferred compounds of Embodiment 51 include those of
Embodiment 65, i.e., compounds of Embodiment 51 where [0477]
R.sub.4 and P.sub.5 are independently H, C.sub.1-C.sub.6 alkyl, or
C.sub.3-C.sub.6 cycloalkyl, wherein the cycloalkyl is unsubstituted
or substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0478] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0479] wherein the cycloalkyl
portion of R.sub.4 and R.sub.5 is further optionally substituted
with .dbd.O, .dbd.N--OH, or .dbd.N--OCH.sub.3.
[0480] Preferred compounds of Embodiment 65 include those of
Embodiment 66, i.e., compounds of Embodiment 65 where [0481]
R.sub.1 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkenyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN,
CO.sub.2H, CF.sub.3, OCF.sub.3, --OC(O)--C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, [0482] wherein the phenyl is optionally
substituted with 1 or more groups that are independently selected
from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, wherein [0483] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); [0484]
R.sub.10 is phenyl or pyridyl, each of which is optionally
substituted with halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, OH, CO.sub.2H, CN, NO.sub.2, CF.sub.3 or OCF.sub.3.
[0485] Preferred compounds of Embodiment 66 include those of
Embodiment 67, i.e., compounds of Embodiment 66 where [0486]
R.sub.1 is C.sub.2-C.sub.6 alkynyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0487] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0488] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0489] Preferred compounds of Embodiment 66 include those of
Embodiment 68, i.e., compounds of Embodiment 66 where [0490]
R.sub.1 is C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0491] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0492] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0493] Preferred compounds of Embodiment 66 include those of
Embodiment 69, i.e., compounds of Embodiment 66 where [0494]
R.sub.1 is C.sub.1-C.sub.6 alkenyl substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
pyridyl, piperidinyl, or phenyl, [0495] wherein the phenyl is
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0496] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl portion of each
is unsubstituted or substituted with 1, or 2 groups that are
independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0497] Preferred compounds of Embodiment 65 include those of
Embodiment 70, i.e., compounds of Embodiment 65 where R.sub.1 is
halogen.
[0498] Preferred compounds of Embodiment 50 include those of
Embodiment 70A, i.e., compounds of Embodiment 50 where Z is a
bond.
[0499] Preferred compounds of Embodiment 50 include those of
Embodiment 70B, i.e., compounds of Embodiment 50 where Z is
--CH.sub.2--.
[0500] Preferred compounds of Embodiment 50 include those of
Embodiment 70C, i.e., compounds of Embodiment 50 where Z is
--NH--.
[0501] Preferred compounds of Embodiment 50 include those of
Embodiment 70D, i.e., compounds of Embodiment 50 where Z is --S--
or --SO.sub.2--.
[0502] Preferred compounds of Embodiment 50 include those of
Embodiment 70E, i.e., compounds of Embodiment 50 where Z is
--N(C.sub.1-C.sub.4 alkyl)-. In another aspect, Z is
--N(C.sub.1-C.sub.2 alkyl)-. In still another aspect, Z is
--N(C.sub.2-C.sub.3 alkyl)-.
[0503] Preferred compounds of Embodiment 50 include those of
Embodiment 70F, i.e., compounds of Embodiment 50 where Z is
--SO.sub.2NH--, or --SO.sub.2N(C.sub.1-C.sub.4 alkyl)-.
[0504] In still another aspect, the invention provides compounds
according to embodiment 50, wherein R.sub.21 is H.
[0505] In yet still another aspect, the invention provides
compounds according to embodiment 50, wherein R.sub.21 is CN.
[0506] In still yet another aspect, the invention provides
compounds according to embodiment 50, wherein R.sub.21 is amino,
monoalkylamino, or dialkylamino.
[0507] In yet another aspect, the invention provides compounds of
embodiment 50, wherein R.sub.21 is OH.
[0508] In still another aspect, the invention provides compounds of
embodiment 50, wherein R.sub.21 is phenyl.
[0509] In still another aspect, the invention provides compounds of
embodiment 50, wherein R.sub.21 is pyridyl.
[0510] In still another aspect, the invention provides compounds of
embodiment 50, wherein R.sub.21 is halogen.
[0511] In yet another aspect, the invention provides compounds of
embodiment 50, wherein R.sub.21 is phenyl, which is substituted
with 1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0512] In yet still another aspect, the invention provides
compounds of embodiment 50, wherein R.sub.21 is pyridyl or
pyrimidyl, each of which is optionally substituted with 1-5 groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in
one aspect, CF.sub.3), or haloalkoxy (in one aspect,
OCF.sub.3)).
[0513] In yet still another aspect, the invention provides
compounds of embodiment 50, wherein R.sub.21 is indolyl or
(iso)quinolinyl, each of which is optionally substituted with 1-5
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0514] In still another aspect, the invention provides compounds of
embodiment 50, wherein R.sub.21 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6 alkenyl.
[0515] In still yet another aspect, the invention provides
compounds of embodiment 50, wherein R.sub.21 is --C(O)NH.sub.2,
--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).
[0516] Preferred compounds of Embodiment 51 include those of
Embodiment 71, i.e., compounds of Embodiment 51 where Z is a bond;
[0517] R.sub.1 is phenyl, naphthyl, thienyl, furanyl, indolyl,
pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl,
benzofuranyl, piperidinyl, pyrrolidinyl, piperazinyl, or
morpholinyl, each of which is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, heteroaryl selected
from pyridyl, pyrimidyl, pyrazinyl, indolyl, thienyl, furanyl,
pyrrolyl, and benzimidazolyl, heterocycloalkyl selected from
piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and phenyl,
naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl and
naphthyl groups are optionally substituted with or phenyl, which is
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, halogen, CF.sub.3, and OCF.sub.3, wherein [0518] each
R.sub.6 and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and [0519] R.sub.10 is C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, phenyl, naphthyl, pyridyl,
quinolinyl, pyrimidyl, furanyl, indolyl, C.sub.3-C.sub.8
cycloalkyl, wherein the cyclic portions are optionally substituted
with halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, OH,
CO.sub.2H, CN, NO.sub.2, C.sub.1-C.sub.4 haloalkyl, or
C.sub.1-C.sub.4 haloalkoxy; [0520] wherein the heterocycloalkyl and
the cycloalkyl portions of R.sub.1 and R.sub.10 are further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0521] Preferred compounds of Embodiment 71 include those of
Embodiment 72, i.e., compounds of Embodiment 71 where [0522]
R.sub.4 and R.sub.5 and the nitrogen to which they are attached
form a piperazinyl, morpholinyl, piperidinyl, imidazolidinyl, or
pyrrolidinyl ring, each of which is unsubstituted or substituted
with 1 or more groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, phenyl C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl,
pyrimidyl C.sub.1-C.sub.4 alkyl, pyrazinyl C.sub.1-C.sub.4 alkyl,
phenyl, --OCH.sub.2CH.sub.2O--, --OCH.sub.2O--, [0523] wherein the
pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.6 alkyl, and
phenyl groups are unsubstituted or substituted with 1 or more
groups that are independently C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3 or OCF.sub.3.
[0524] Preferred compounds of Embodiment 72 include those of
Embodiment 73, i.e., compounds of Embodiment 72 where [0525]
R.sub.1 is phenyl which is unsubstituted or substituted with 1, 2,
3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0526] each R.sub.6 and P.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, CF.sub.3, OCF.sub.3,
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).
[0527] Preferred compounds of Embodiment 73 include those of
Embodiment 74, i.e., compounds of Embodiment 73 where [0528]
R.sub.2 and R.sub.3 are both H; and [0529] R.sub.4 and R.sub.5 and
the nitrogen to which they are attached form a piperazinyl,
morpholinyl, piperidinyl, or pyrrolidinyl ring, each of which is
substituted with 1 or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkanoyl, OH, pyridyl,
pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.4 alkyl, pyrazinyl
C.sub.1-C.sub.4 alkyl, phenyl, --OCH.sub.2CH.sub.2O--, or
OCH.sub.2O--.
[0530] Preferred compounds of Embodiment 72 include those of
Embodiment 75, i.e., compounds of Embodiment 72 where [0531]
R.sub.1 is thienyl, furanyl, indolyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, triazolyl, imidazolyl, benzofuranyl,
piperidinyl, pyrrolidinyl, piperazinyl, or morpholinyl, each of
which is unsubstituted or substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0532] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); and
[0533] wherein the heterocycloalkyl portion of R.sub.10 is further
optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0534] Preferred compounds of Embodiment 75 include those of
Embodiment 76, i.e., compounds of Embodiment 75 where [0535]
R.sub.2 and R.sub.3 are both H; and [0536] R.sub.4 and R.sub.5 and
the nitrogen to which they are attached form a piperazinyl,
morpholinyl, piperidinyl, or pyrrolidinyl ring, each of which is
substituted with 1 or more groups that are independently
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, phenyl
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 alkanoyl, OH, pyridyl,
pyrimidyl, pyrazinyl, pyrimidyl C.sub.1-C.sub.4 alkyl, pyrazinyl
C.sub.1-C.sub.4 alkyl, phenyl, --OCH.sub.2CH.sub.2O--, or
--OCH.sub.2O--.
[0537] Preferred compounds of Embodiment 76 include those of
Embodiment 77, i.e., compounds of Embodiment 76 where [0538]
R.sub.1 is thienyl optionally substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0539] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0540] Preferred compounds of Embodiment 76 include those of
Embodiment 78, i.e., compounds of Embodiment 76 where [0541]
R.sub.1 is benzofuranyl optionally substituted with 1, 2, 3, or 4
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0542] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0543] Preferred compounds of Embodiment 71 include those of
Embodiment 78, i.e., compounds of Embodiment 71 where [0544]
R.sub.4 and R.sub.5 are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl
C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6 alkyl,
pyrrolidinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.2-C.sub.6
alkenyl, pyrrolidinyl C.sub.2-C.sub.6 alkenyl, morpholinyl
C.sub.2-C.sub.6 alkenyl, piperidinyl C.sub.2-C.sub.6 alkynyl,
pyrrolidinyl C.sub.2-C.sub.6 alkynyl, morpholinyl C.sub.2-C.sub.6
alkynyl, phenyl, furanyl, pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, imidazolyl C.sub.1-C.sub.6 alkyl,
furanyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl,
phenyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.2-C.sub.6 alkenyl,
phenyl C.sub.2-C.sub.6 alkynyl, or C.sub.3-C.sub.8 cycloalkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0545] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0546] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0547] Preferred compounds of Embodiment 79 include those of
Embodiment 80, i.e., compounds of Embodiment 79 where [0548]
R.sub.1 is phenyl which is unsubstituted or substituted with 1, 2,
3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0549] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, CF.sub.3, OCF.sub.3,
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).
[0550] Preferred compounds of Embodiment 71 include those of
Embodiment 80A, i.e., compounds of Embodiment 71 where Z is a
bond.
[0551] Preferred compounds of Embodiment 71 include those of
Embodiment 80B, i.e., compounds of Embodiment 71 where Z is
--CH.sub.2--.
[0552] Preferred compounds of Embodiment 71 include those of
Embodiment 80C, i.e., compounds of Embodiment 71 where wherein Z is
--NH--.
[0553] Preferred compounds of Embodiment 71 include those of
Embodiment 80D, i.e., compounds of Embodiment 71 where Z is --S--
or --SO.sub.2--.
[0554] Preferred compounds of Embodiment 71 include those of
Embodiment 80e, i.e., compounds of Embodiment 71 where Z is
--N(C.sub.1-C.sub.4 alkyl)-. In another aspect, Z is
--N(C.sub.1-C.sub.2 alkyl)-. In still another aspect, Z is
--N(C.sub.2-C.sub.3 alkyl)-.
[0555] Preferred compounds of Embodiment 71 include those of
Embodiment 80F, i.e., compounds of Embodiment 71 where Z is
--SO.sub.2NH--, or --SO.sub.2N(C.sub.1-C.sub.4alkyl)-.
[0556] In still another aspect, the invention provides compounds
according to embodiment 71, wherein R.sub.21 is H.
[0557] In yet still another aspect, the invention provides
compounds according to embodiment 71, wherein R.sub.21 is CN.
[0558] In still yet another aspect, the invention provides
compounds according to embodiment 71, wherein R.sub.21 is amino,
monoalkylamino, or dialkylamino.
[0559] In yet another aspect, the invention provides compounds of
embodiment 71, wherein R.sub.21 is OH.
[0560] In still another aspect, the invention provides compounds of
embodiment 71, wherein R.sub.21 is phenyl.
[0561] In still another aspect, the invention provides compounds of
embodiment 71, wherein R.sub.21 is pyridyl.
[0562] In still another aspect, the invention provides compounds of
embodiment 71, wherein R.sub.21 is halogen.
[0563] In yet another aspect, the invention provides compounds of
embodiment 71, wherein R.sub.21 is phenyl, which is substituted
with 1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0564] In yet still another aspect, the invention provides
compounds of embodiment 71, wherein R.sub.21 is pyridyl or
pyrimidyl, each of which is optionally substituted with 1-5 groups
that are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in
one aspect, CF.sub.3), or haloalkoxy (in one aspect,
OCF.sub.3)).
[0565] In yet still another aspect, the invention provides
compounds of embodiment 71, wherein R.sub.21 is indolyl or
(iso)quinolinyl, each of which is optionally substituted with 1-5
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0566] In still another aspect, the invention provides compounds of
embodiment 71, wherein R.sub.21 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6 alkenyl.
[0567] In still yet another aspect, the invention provides
compounds of embodiment 71, wherein R.sub.21 is --C(O)NH.sub.2,
--C(O)NH(C.sub.2-C.sub.6 alkyl), or --C(O)N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl).
[0568] Preferred compounds of Embodiment 71 include those of
Embodiment 81, i.e., compounds of Embodiment 71 where [0569]
R.sub.2 and R.sub.3 are both H; and [0570] R.sub.4 and R.sub.5 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.6 alkyl, piperidinyl, pyrrolidinyl, morpholinyl,
morpholinyl C.sub.1-C.sub.6 alkyl, piperidinyl C.sub.1-C.sub.6
alkyl, pyrrolidinyl C.sub.1-C.sub.6 alkyl, phenyl, furanyl,
pyridyl, pyrazinyl C.sub.1-C.sub.6 alkyl, pyridyl C.sub.1-C.sub.6
alkyl, imidazolyl C.sub.1-C.sub.6 alkyl, furanyl C.sub.1-C.sub.6
alkyl, thienyl C.sub.1-C.sub.6 alkyl, phenyl C.sub.1-C.sub.6 alkyl,
wherein the cyclic portion of each of the above is unsubstituted or
substituted with one or more groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
--SO.sub.2--(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, NO.sub.2, CN, OH, phenyl
C.sub.1-C.sub.6 alkyl wherein the phenyl is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, CN, halogen, OH, and
alkanoyl, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
NR.sub.7R.sub.8, or --C(O)NR.sub.7R.sub.8, [0571] wherein R.sub.7
and R.sub.8 are independently H or C.sub.1-C.sub.6 alkyl, wherein
the C.sub.1-C.sub.6 alkyl is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkoxycarbonyl,
halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl,
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) or CO.sub.2H; [0572] wherein the
heterocycloalkyl and the cycloalkyl portions of R.sub.4 and R.sub.5
are further optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0573] Preferred compounds of Embodiment 81 include those of
Embodiment 82, i.e., compounds of Embodiment 81 where [0574]
R.sub.1 is thienyl, furanyl, indolyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, triazolyl, imidazolyl, benzofuranyl,
piperidinyl, pyrrolidinyl, piperazinyl, or morpholinyl, each of
which is unsubstituted or substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0575] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0576] Preferred compounds of Embodiment 82 include those of
Embodiment 83, i.e., compounds of Embodiment 82 where [0577]
R.sub.1 is thienyl optionally substituted with 1, 2, 3, or 4 groups
that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0578] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0579] Preferred compounds of Embodiment 82 include those of
Embodiment 84, i.e., compounds of Embodiment 82 where [0580]
R.sub.1 is benzofuranyl optionally substituted with 1, 2, 3, or 4
groups that are independently C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, CF.sub.3, OCF.sub.3,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, pyridyl,
piperidinyl, or phenyl, which is optionally substituted with 1, 2,
3, 4, or 5 groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, CF.sub.3,
and OCF.sub.3, wherein [0581] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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).
[0582] Preferred compounds of Embodiment 51 include those of
Embodiment 85, i.e., compounds of Embodiment 51 where [0583]
R.sub.4 and R.sub.5 are independently H, methyl, or --CH.sub.2--
(furan-2-yl), or C.sub.3-C.sub.6 cycloalkyl, wherein the cycloalkyl
group is optionally substituted with .dbd.O, .dbd.N--OH, or
.dbd.N--OCH.sub.3.
[0584] The invention also provides pharmaceutical compositions
comprising a compound of Formula A and at least one
pharmaceutically acceptable solvent, carrier, excipient, adjuvant
or a combination thereof.
[0585] The invention further provides packaged pharmaceutical
compositions comprising a pharmaceutical composition of the
invention in a container together with instructions on how to use
the compound or composition.
[0586] The invention further provides methods of treating a disease
or condition related to cell differentiation comprising
administering a therapeutically effective amount of a compound of
Formula A to a patient in need of such treatment. In another
embodiment, the patient is a mammal. In a more preferred
embodiment, the mammal is a human.
[0587] In preferred methods of the invention, the disease or
condition is cancer, inflammation, arthritis, or angiogenesis.
[0588] Other preferred compounds of the invention include those of
Embodiment 91, i.e., compounds of embodiments 51-85 wherein X is
--C(O)R.sub.20, and R.sub.20 is OH.
[0589] Other preferred compounds of the invention include those of
Embodiment 92, i.e., compounds of embodiments 51-85, wherein X is
--C(O)R.sub.20, and R.sub.20 is C.sub.1-C.sub.6 alkoxy (in another
aspect, C.sub.1-C.sub.4 alkoxy.)
[0590] Other preferred compounds of the invention include those of
Embodiment 93, i.e., compounds of embodiments 51-85, wherein X is
--NR.sub.xR.sub.y; wherein [0591] R.sub.x and R.sub.y are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxycarbonyl, phenyl C.sub.1-C.sub.4 alkoxycarbonyl, phenyl,
naphthyl, phenyl C.sub.1-C.sub.4 alkyl, --C(O)-phenyl, or
--C(O)-naphthyl, wherein the phenyl and naphthyl groups are
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, CO.sub.2H, NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or OCF.sub.3; wherein, within
the definition of R.sub.x and R.sub.y, [0592] R.sub.6 and R.sub.7
are independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, CF.sub.3, OCF.sub.3,
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); or [0593] R.sub.6 and R.sub.7 and the
nitrogen to which they are attached form a ring having from 5 to 6
members, wherein the ring optionally contains 1-2 additional
heteroatoms selected from N, O, and S, where the 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, OH, halogen, amino,
NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl).
[0594] Preferred compounds of Embodiment 93 include those of
Embodiment 94, i.e., compounds of Embodiment 93 where [0595]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxycarbonyl, phenyl C.sub.1-C.sub.4
alkoxycarbonyl, phenyl, phenyl C.sub.1-C.sub.4 alkyl, or
--C(O)-phenyl, wherein the phenyl group 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, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0596] Preferred compounds of Embodiment 94 include those of
Embodiment 95, i.e., compounds of Embodiment 94 where [0597]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
benzyl, or --C(O)-phenyl, wherein the phenyl groups are 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, halogen, CO.sub.2H,
NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or OCF.sub.3.
[0598] Preferred compounds of Embodiment 93 include those of
Embodiment 96, i.e., compounds of Embodiment 93 where [0599]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
pyridyl, pyrimidyl, pyrazinyl, benzofuranyl, indolyl,
benzimidazolyl, thienyl, furanyl, quinolinyl, or isoquinolinyl,
wherein the ring portions of the above are optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0600] Preferred compounds of Embodiment 96 include those of
Embodiment 96A, i.e., compounds of Embodiment 96 where [0601]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.4 alkyl,
pyridyl, pyrimidyl, pyrazinyl, thienyl, or furanyl, wherein the
ring portions of the above are optionally substituted with 1, 2, 3,
4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0602] Preferred compounds of Embodiment 96 include those of
Embodiment 96B, i.e., compounds of Embodiment 96 where [0603]
R.sub.x, and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
benzofuranyl, indolyl, benzimidazolyl, quinolinyl, or
isoquinolinyl, wherein the ring portions of the above are
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, CO.sub.2H, NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or OCF.sub.3.
[0604] Preferred compounds of Embodiment 93 include those of
Embodiment 97, i.e., compounds of Embodiment 93 where, wherein
[0605] R.sub.x, and R.sub.y are independently H, C.sub.1-C.sub.6
alkyl, pyridyl C.sub.1-C.sub.6 alkyl, pyrimidyl C.sub.1-C.sub.6
alkyl, pyrazinyl C.sub.1-C.sub.6 alkyl, benzofuranyl
C.sub.1-C.sub.6 alkyl, indolyl C.sub.1-C.sub.6 alkyl,
benzimidazolyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6
alkyl, furanyl C.sub.1-C.sub.6 alkyl, quinolinyl C.sub.1-C.sub.6
alkyl, or isoquinolinyl C.sub.1-C.sub.6 alkyl, wherein the ring
portions of the above are optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0606] Preferred compounds of Embodiment 97 include those of
Embodiment 97A, i.e., compounds of Embodiment 97 where [0607]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
pyridyl C.sub.1-C.sub.6 alkyl, pyrimidyl C.sub.1-C.sub.6 alkyl,
pyrazinyl C.sub.1-C.sub.6 alkyl, thienyl C.sub.1-C.sub.6 alkyl, or
furanyl C.sub.1-C.sub.6 alkyl, wherein the ring portions of the
above are optionally substituted with 1, 2, 3, 4, or 5 groups that
are independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, CO.sub.2H, NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or OCF.sub.3.
[0608] Preferred compounds of Embodiment 97 include those of
Embodiment 97B, i.e., compounds of Embodiment 97 where [0609]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
benzofuranyl C.sub.1-C.sub.6 alkyl, indolyl C.sub.1-C.sub.6 alkyl,
benzimidazolyl C.sub.1-C.sub.6 alkyl, quinolinyl C.sub.1-C.sub.6
alkyl, or isoquinolinyl C.sub.1-C.sub.6 alkyl, wherein the ring
portions of the above are optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0610] Preferred compounds of Embodiment 93 include those of
Embodiment 98, i.e., compounds of Embodiment 93 where [0611]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
--C(O)-pyridyl, --C(O)-pyrimidyl, --C(O)-pyrazinyl,
--C(O)-benzofuranyl, --C(O)-indolyl, --C(O)-benzimidazolyl,
--C(O)-thienyl, --C(O)-furanyl, --C(O)-quinolinyl, or
--C(O)-isoquinolinyl, wherein the ring portions of the above are
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, CO.sub.2H, NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or OCF.sub.3.
[0612] Preferred compounds of Embodiment 98 include those of
Embodiment 98A, i.e., compounds of Embodiment 98 where [0613]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
--C(O)-pyridyl, --C(O)-pyrimidyl, --C(O)-pyrazinyl, --C(O)-thienyl,
or --C(O)-furanyl, wherein the ring portions of the above are
optionally substituted with 1, 2, 3, 4, or 5 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, CO.sub.2H, NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
--(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or OCF.sub.3.
[0614] Preferred compounds of Embodiment 98 include those of
Embodiment 98B, i.e., compounds of Embodiment 98 where [0615]
R.sub.x and R.sub.y are independently H, C.sub.1-C.sub.6 alkyl,
--C(O)-benzofuranyl, --C(O)-indolyl, --C(O)-benzimidazolyl,
--C(O)-quinolinyl, or --C(O)-isoquinolinyl, wherein the ring
portions of the above are optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, CO.sub.2H, NR.sub.6R.sub.7,
--C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7,
-(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, CF.sub.3, or
OCF.sub.3.
[0616] Embodiment 99 includes compounds of embodiments 93, 94, 95,
96, 96A, 96B, 97, 97A, 97B, 98, 98A, and 98B, wherein, within the
definition of R.sub.x and R.sub.y, [0617] R.sub.6 and R.sub.7 and
the nitrogen to which they are attached form a ring having from 5
to 6 members, wherein the ring optionally contains 1-2 additional
heteroatoms selected from N, O, and S, where the 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, OH, halogen, amino,
NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl).
[0618] Preferred compounds of Embodiment 99 include those of
Embodiment 100, i.e., compounds of Embodiment 99 where, within the
definition of R.sub.1, and R.sub.y. [0619] R.sub.6 and R.sub.7 and
the nitrogen to which they are attached form a ring that is
pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, imidazolyl, imidazolidinyl, pyrrolidinyl,
pyrrolyl, piperidinyl, piperazinyl, or oxazolidinyl, 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, OH,
halogen, amino, NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6
alkyl) (C.sub.1-C.sub.6 alkyl).
[0620] Embodiment 101 includes compounds of embodiments 93, 94, 95,
96, 96A, 96B, 97, 97A, 97B, 98, 98A, and 98B, wherein, within the
definition of R.sub.x and R.sub.y, [0621] R.sub.6 and R.sub.7 are
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, or 2 groups
that are independently halogen, OH, CF.sub.3, OCF.sub.3, 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).
[0622] Embodiment 102 includes compounds of embodiments 93, 94, 95,
96, 96A, 96B, 97, 97A, 97B, 98, 98A, 98B, 99, 100, and 101 wherein,
within the definition of R.sub.x and R.sub.y. R.sub.x is H or
C.sub.1-C.sub.4 alkyl.
[0623] In another aspect, the invention provides compounds
according to any of the preceding embodiments wherein at least one
of A.sub.1 and A.sub.2 is N. In another embodiment, both A.sub.1
and A.sub.2 are N.
[0624] In yet another aspect, the invention provides compounds
according to any one of the preceding embodiments wherein at least
one of is a double bond. In a more preferred aspect, both are
double bonds.
[0625] In still another aspect, the invention provides compounds
according to any one of the preceding embodiments wherein both are
single bonds and A.sub.2 is NH or N(C.sub.1-C.sub.4 alkyl).
[0626] In yet still another aspect, at least one of R.sub.2,
R.sub.2' and R.sub.3 is hydrogen. In another aspect, two of
R.sub.2, R.sub.2' and R.sub.3 are hydrogen. In still another
aspect, R.sub.2 is methyl or halogen (in still another aspect, the
halogen is chloro or bromo.)
[0627] In another aspect, R.sub.2, R.sub.2', R.sub.21, and R.sub.3
are hydrogen.
[0628] In still another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is H.
[0629] In yet still another aspect, the invention provides
compounds of formula A, wherein R.sub.21 is CN.
[0630] In still yet another aspect, the invention provides
compounds of formula A, wherein R.sub.21 is amino, monoalkylamino,
or dialkylamino.
[0631] In yet another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is OH.
[0632] In still another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is phenyl.
[0633] In still another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is pyridyl.
[0634] In still another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is halogen.
[0635] In yet another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is phenyl, which is substituted with
1-5 groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0636] In yet still another aspect, the invention provides
compounds of formula A, wherein R.sub.21 is pyridyl or pyrimidyl,
each of which is optionally substituted with 1-5 groups that are
independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, OH, hydroxyl C.sub.1-C.sub.4 alkyl, haloalkyl (in one
aspect, CF.sub.3), or haloalkoxy (in one aspect, OCF.sub.3)).
[0637] In yet still another aspect, the invention provides
compounds of formula A, wherein R.sub.21 is indolyl or
(iso)quinolinyl, each of which is optionally substituted with 1-5
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, hydroxyl C.sub.1-C.sub.4
alkyl, haloalkyl (in one aspect, CF.sub.3), or haloalkoxy (in one
aspect, OCF.sub.3)).
[0638] In still another aspect, the invention provides compounds of
formula A, wherein R.sub.21 is C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkynyl, or C.sub.2-C.sub.6 alkenyl.
[0639] In still yet another aspect, the invention provides
compounds of formula A, wherein R.sub.21 is --C(O)NH.sub.2,
--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).
[0640] In another aspect, the invention encompasses a method of
treating cancer comprising administering to a patient in need
thereof, a pharmaceutically acceptable amount of a compound or salt
of formula A or a pharmaceutical composition comprising a compound
or salt of formula A.
[0641] The term "alkoxy" represents an alkyl group of indicated
number of carbon atoms attached to the parent molecular moiety
through an oxygen bridge. Examples of alkoxy groups include, for
example, methoxy, ethoxy, propoxy and isopropoxy.
[0642] As used herein, the term "alkyl" includes those alkyl groups
of a designed number of carbon atoms. Alkyl groups may be straight,
or branched. Examples of "alkyl" include methyl, ethyl, propyl,
isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl,
3-ethylbutyl, and the like.
[0643] The term "aryl" refers to an aromatic hydrocarbon ring
system containing at least one aromatic ring. The aromatic ring may
optionally be fused or otherwise attached to other aromatic
hydrocarbon rings or non-aromatic hydrocarbon rings.
[0644] Examples of aryl groups include, for example, phenyl,
naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred
examples of aryl groups include phenyl, naphthyl, and anthracenyl.
More preferred aryl groups are phenyl and naphthyl. Most preferred
is phenyl.
[0645] The term "cycloalkyl" refers to a C.sub.3-C.sub.8 cyclic
hydrocarbon. Examples of cycloalkyl include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
More preferred are C.sub.3-C.sub.6 cycloalkyl groups.
[0646] The terms "halogen" or "halo" indicate fluorine, chlorine,
bromine, and iodine.
[0647] The term "heterocycloalkyl" refers to a ring or ring system
containing at least one heteroatom selected from nitrogen, oxygen,
and sulfur, wherein said heteroatom is in a non-aromatic ring. The
heterocycloalkyl ring is optionally fused to or otherwise attached
to other heterocycloalkyl rings and/or non-aromatic hydrocarbon
rings and/or phenyl rings. Preferred heterocycloalkyl groups have
from 3 to 7 members. More preferred heterocycloalkyl groups have 5
or 6 members. Examples of heterocycloalkyl groups include, for
example, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl,
piperidinyl, tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and
pyrazolidinyl. Preferred heterocycloalkyl groups include
piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyridinonyl,
dihydropyrrolidinyl, and pyrrolidinonyl.
[0648] The term "heteroaryl" refers to an aromatic ring system
containing at least one heteroatom selected from nitrogen, oxygen,
and sulfur. The heteroaryl ring may be fused or otherwise attached
to one or more heteroaryl rings, aromatic or non-aromatic
hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl
groups include, for example, pyridine, furan, thienyl,
5,6,7,8-tetrahydroisoquinoline and pyrimidines.
[0649] Preferred examples of heteroaryl groups include thienyl,
benzothienyl, pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl,
benzimidazolyl, furanyl, benzofuranyl, dibenzofuranyl, thiazolyl,
benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl,
benzisothiazolyl, triazolyl, pyrrolyl, indolyl, pyrazolyl, and
benzopyrazolyl.
[0650] The compounds of this invention may contain one or more
asymmetric carbon atoms, so that the compounds can exist in
different stereoisomeric forms. These compounds can be, for
example, racemates, chiral non-racemic or diastereomers. In these
situations, the single enantiomers, i.e., optically active forms,
can be obtained by asymmetric synthesis or by resolution of the
racemates. Resolution of the racemates can be accomplished, for
example, by conventional methods such as crystallization in the
presence of a resolving agent; chromatography, using, for example a
chiral HPLC column; or derivatizing the racemic mixture with a
resolving reagent to generate diastereomers, separating the
diastereomers via chromatography, and removing the resolving agent
to generate the original compound in enantiomerically enriched
form. Any of the above procedures can be repeated to increase the
enantiomeric purity of a compound.
[0651] When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless otherwise
specified, it is intended that the compounds include the cis,
trans, Z- and E-configurations. Likewise, all tautomeric forms are
also intended to be included.
[0652] The compounds of general Formula A may be administered
orally, topically, parenterally, by inhalation or spray or rectally
in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles. The
term parenteral as used herein includes percutaneous, subcutaneous,
intravascular (e.g., intravenous), intramuscular, or intrathecal
injection or infusion techniques and the like. In addition, there
is provided a pharmaceutical formulation comprising a compound of
general Formula A and a pharmaceutically acceptable carrier. One or
more compounds of general Formula A may be present in association
with one or more non-toxic pharmaceutically acceptable carriers
and/or diluents and/or adjuvants, and if desired other active
ingredients. The pharmaceutical compositions containing compounds
of general Formula A may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0653] Compositions intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preservative agents
in order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients that are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques. In some cases such coatings may be
prepared by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monosterate or glyceryl distearate may be
employed.
[0654] Formulations for oral use may also be presented as hard
gelatin capsules, wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0655] Formulations for oral use may also be presented as
lozenges.
[0656] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone,
gum tragacanth and gum acacia; dispersing or wetting agents may be
a naturally-occurring phosphatide, for example, lecithin, or
condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate,
one or more coloring agents, one or more flavoring agents, and one
or more sweetening agents, such as sucrose or saccharin.
[0657] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
and flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the addition
of an anti-oxidant such as ascorbic acid.
[0658] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents or suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0659] Pharmaceutical compositions of the invention may also be in
the form of oil-in-water emulsions. The oily phase may be a
vegetable oil or a mineral oil or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol, anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0660] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol, glucose or
sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents. The pharmaceutical
compositions may be in the form of a sterile injectable aqueous or
oleaginous suspension. This suspension may be formulated according
to the known art using those suitable dispersing or wetting agents
and suspending agents that have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or solvent,
for example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables.
[0661] The compounds of general Formula A may also be administered
in the form of suppositories, e.g., for rectal administration of
the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter and polyethylene glycols.
[0662] Compounds of general Formula A may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0663] For disorders of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical gel, spray, ointment or cream, or as a suppository,
containing the active ingredients in a total amount of, for
example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most
preferably 0.4 to 15% w/w. When formulated in an ointment, the
active ingredients may be employed with either paraffinic or a
water-miscible ointment base.
[0664] Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane. The
transdermal patch may include the compound in a suitable solvent
system with an adhesive system, such as an acrylic emulsion, and a
polyester patch. The oily phase of the emulsions of this invention
may be constituted from known ingredients in a known manner. While
the phase may comprise merely an emulsifier, it may comprise a
mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. Preferably, a hydrophilic emulsifier is
included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make-up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others. The choice of suitable oils or fats for the
formulation is based on achieving the desired cosmetic properties,
since the solubility of the active compound in most oils likely to
be used in pharmaceutical emulsion formulations is very low. Thus,
the cream should preferably be a non-greasy, non-staining and
washable product with suitable consistency to avoid leakage from
tubes or other containers. Straight or branched chain, mono- or
dibasic alkyl esters such as di-isoadipate, isocetyl stearate,
propylene glycol diester of coconut fatty acids, isopropyl
myristate, decyl oleate, isopropyl palmitate, butyl stearate,
2-ethylhexyl palmitate or a blend of branched chain esters may be
used. These may be used alone or in combination depending on the
properties required. Alternatively, high melting point lipids such
as white soft paraffin and/or liquid paraffin or other mineral oils
can be used.
[0665] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a concentration of 0.5
to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
For therapeutic purposes, the active compounds of this combination
invention are ordinarily combined with one or more adjuvants
appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0666] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
of the above-indicated conditions (about 0.5 mg to about 7 g per
patient per day). The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient. The daily
dose can be administered in one to four doses per day. In the case
of skin conditions, it may be preferable to apply a topical
preparation of compounds of this invention to the affected area two
to four times a day.
[0667] It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, and rate of excretion, drug combination
and the severity of the particular disease undergoing therapy.
[0668] For administration to non-human animals, the composition may
also be added to the animal feed or drinking water. It may be
convenient to formulate the animal feed and drinking water
compositions so that the animal takes in a therapeutically
appropriate quantity of the composition along with its diet. It may
also be convenient to present the composition as a premix for
addition to the feed or drinking water. Preferred non-human animals
include domesticated animals.
[0669] The compounds of the present invention may be prepared by
use of known chemical reactions and procedures. Representative
methods for synthesizing compounds of the invention are presented
below. It is understood that the nature of the substituents
required for the desired target compound often determines the
preferred method of synthesis. All variable groups of these methods
are as described in the generic description if they are not
specifically defined below.
Methods of Preparation
[0670] General Procedure for Amide Coupling Reactions: ##STR5##
[0671] R.sub.6 and R.sub.7 are as defined above.
[0672] To 1 equiv. of carboxylic acid in DMF is added 1 equiv. of
the appropriate amine. The reaction mixture is stirred and cooled
to 0.degree. C. in an ice bath. 1 equiv. of diethylcyanophosphonate
and 2 equiv. of triethylamine are then added. After stirring for 10
minutes at 0.degree. C., the reaction mixture is removed from the
ice bath and stirred at room temperature for 18-24 hours. Once the
reaction was complete, as determined by LC/MS, the reaction is
concentrated to dryness. The resulting residue is dissolved in DCM
(15 mL) and washed with 0.1N HCl (1.times.15 mL) and water
(2.times.15 mL). The organic layer is then dried over sodium
sulfate, filtered, and concentrated in vacuo to afford the crude
product, which is purified via column chromatography to yield the
final product.
[0673] One of skill in the art will appreciate that other methods
of forming an amide bond are available. For example, the acid may
be converted to an acid chloride or an acid anhydride and then
treated with the amine. Or, the acid may be treated with one or
more coupling reagents, such as DCC (dicyclohexyl carbodiimide),
DIC (1,3 diisopropyl carbodiimide), EDCI
(1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride), BBC
(1-benzotriazol-1-yloxy-bis(pyrrolidino)uronium
hexafluorophosphate), BDMP
(5-(1H-benzotriazol-1-yloxy)-3,4-dihydro-1-methyl 2H-pyrrolium
hexachloroanitimonate), BOMI
(benzotriazol-1-yloxy-N,N-dimethylmethaniminium
hexachloroantimonate), HATU
(O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate),
HAPyU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium
hexafluorophosphate,
HBTU=O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate,
TAPipU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium
etrafluoroborate, AOP
(O-(7-azabenzotriazol-1-yl)-tris(dimethylamino)phosphonium
hexafluorophosphate), BDP (benzotriazol-1-yl diethyl phosphate),
BOP (1-benzotriazolyoxytris(dimethylamino)phosphonium
hexafluorophosphate), PyAOP
(7-azobenzotriazolyoxytris(pyrrolidino)phosphonium
hexafluorophosphate), PyBOP
(1-benzotriazolyoxytris(pyrrolidino)phosphonium
hexafluorophosphate), TDBTU
(2-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethylu-
ronium tetrafluoroborate), TNTU
(2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium
tetrafluoroborate), TPTU
(2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium
tetrafluoroborate), TSTU (2-succinimido-1,1,3,3-tetramethyluronium
tetrafluoroborate), BEMT (2-bromo-3-ethyl-4-methyl thiazolium
tetrafluoroborate), BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphinic
chloride), BroP (bromotris(dimethylamino)phosphonium
hexafluorophosphate), BTFFH (bis(tetramethylenefluoroformamidinium)
hexafluorophosphate), ClP (2-chloro-1,3-dimethylimidazolidinium
hexafluorophosphate), DEPBT
(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Dpp-Cl
(diphenylphosphinic chloride), EEDQ
(2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), FDPP
(pentafluorophenyl diphenylphosphinate), HOTT
(S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium
hexafluorophosphate), PyBroP (bromotris(pyrrolydino)phosphonium
hexafluorophosphate), PyCloP (chlorotris(pyrrolydino)phosphonium
hexafluorophosphate), TFFH (tetramethylfluoroformamidinium
hexafluorophosphate), TOTT
(S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium
tetrafluoroborate). General Procedure for Sonogashira Couplings:
##STR6## [0674] R carries the same definition as R.sub.4; [0675] R'
is 1, 2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.6
alkyl, halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy,
--OC(O)--C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.1-C.sub.6 alkanoyl, --C(O)R.sub.10, NR.sub.6R.sub.7,
(C.sub.1-C.sub.4 alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7,
phenyl, or naphthyl, wherein the phenyl and naphthyl groups are
optionally substituted with 1 or more groups that are independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
halogen, OH, CF.sub.3, and OCF.sub.3, wherein [0676] each R.sub.6
and R.sub.7 is independently H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl,
wherein the alkyl portion of each is unsubstituted or substituted
with 1, 2, or 3, groups that are independently halogen, OH,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); or [0677] R.sub.6 and R.sub.7 and the
nitrogen to which they are attached form a ring having from 5 to 8
members, wherein the ring optionally contains 1-3 additional
heteroatoms selected from N, O, and S, where the ring is optionally
substituted with 1, 2, or 3 groups that are independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, OH, amino,
NH(C.sub.1-C.sub.6 alkyl), or N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl).
[0678] A 8-Bromo-[1,6]naphthyridine-2-carboxylic acid amide, an
optionally substituted acetylene (2.5 equiv),
tetrakis(triphenylphosphine)palladium (0) (5 mol %), copper (I)
iodide (25 mol %), and potassium carbonate (3.0 equiv) are
dissolved in 5:1 DME:water. The reaction vessel is purged with
N.sub.2 and stirred overnight at approximately 50.degree. C. The
solvent is removed in vacuo and the residue purified by preparative
TLC, or other methods known to those skilled in the art. General
Procedure for Buchwald-Type Couplings: ##STR7## [0679] R' is 1, 2,
3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl,
halogen, C.sub.1-C.sub.6 alkoxy, OH, CN, CO.sub.2H, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, --OC(O)--C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkanoyl,
--C(O)R.sub.10, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4
alkyl)-NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, phenyl, or naphthyl,
wherein the phenyl and naphthyl groups are optionally substituted
with 1 or more groups that are independently selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halogen, OH,
CF.sub.3, and OCF.sub.3, wherein [0680] each R.sub.6 and R.sub.7 is
independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkoxyalkyl, C.sub.1-C.sub.6 alkoxycarbonyl, wherein the alkyl
portion of each is unsubstituted or substituted with 1, 2, or 3,
groups that are independently halogen, OH, C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.4 haloalkoxy, 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); or
[0681] R.sub.6 and R.sub.7 and the nitrogen to which they are
attached form a ring having from 5 to 8 members, wherein the ring
optionally contains 1-3 additional heteroatoms selected from N, O,
and S, where the ring is optionally substituted with 1, 2, or 3
groups that are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, OH, amino, NH(C.sub.1-C.sub.6
alkyl), or N(C.sub.1-C.sub.6 alkyl) (C.sub.1-C.sub.6 alkyl).
[0682] A microwave pressure vial (Personal Chemistry) is charged
with an 8-bromo-[1,6]naphthyridine-2-carboxylic acid amide (1
equiv.), an optionally substituted aniline or aminoheterocycle (4.0
equiv.), bis(dibenzylideneacetone) palladium (0) (7 mol %),
2-(dicyclohexylphosphino) biphenyl (14 mol %), and sodium
tert-butoxide (2.0 equiv). The reagents are suspended in toluene to
a concentration of 0.5 M (with regards to naphthyridine). The
vessel is purged with N.sub.2 and then the reaction mixture is
heated to 110.degree. C. via microwave radiation. After 420
seconds, the reaction vessel is allowed to cool to room temperature
and then filtered through a plug of glass wool. The resulting
filtrate is concentrated and purified by preparatory TLC, or other
methods known to those skilled in the art.
[0683] Those having skill in the art will recognize that the
starting materials and reaction conditions may be varied, the
sequence of the reactions altered, and additional steps employed to
produce compounds encompassed by the present invention, as
demonstrated by the following examples. In some cases, protection
of certain reactive functionalities may be necessary to achieve
some of the above transformations. In general, the need for such
protecting groups as well as the conditions necessary to attach and
remove such groups will be apparent to those skilled in the art of
organic synthesis.
[0684] The disclosures of all articles and references mentioned in
this application, including patents, are incorporated herein by
reference in their entirety.
[0685] Structures were named using Name Pro IUPAC Naming Software,
version 5.09, available from Advanced Chemical Development, Inc.,
90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada or with
ChemDraw v. 6.02, which is available from Cambridgesoft.com in
Cambridge, Mass.
General Procedure for Suzuki Coupling Reactions:
[0686] 1 equiv. 8-bromo-2-substituted-1,6-naphthyridine, 0.02
equiv. dichlorobis(triphenylphosphine)palladium (II), 1 equiv.
boronic acid, 1.5 equiv. sodium carbonate and 7:3:2
DME:H.sub.2O:EtOH (2-4 mL) are combined in a microwavable reaction
tube. The tube is sealed and irradiated in the microwave at
140.degree. C. for 500 seconds. The resulting reaction mixture is
cooled to room temperature and diluted with water (.about.10-15
mL).
[0687] If final compound contains an acid, the reaction mixture is
acidified to pH 6-7 with 1N HCl, and filtered. The resulting solid
is washed with water (.about.50 mL), dried, filtered, and
concentrated in vacuo to afford the crude product, which is
purified by methods known in the art.
[0688] If final compound does not contain an acid, the aqueous
layer is extracted with dichloromethane (4.times.20 mL). The
dichloromethane layers are combined, dried over sodium sulfate,
filtered and concentrated in vacuo to afford the crude product,
which is purified by methods known in the art.
CHEMISTRY EXAMPLES
[0689] The preparation of intermediates and compounds of the
invention is illustrated further by the following examples, which
are not to be construed as limiting the invention in scope or
spirit to the specific procedures and compounds described in them.
In all cases, unless otherwise specified, the column chromatography
is performed using a silica gel solid phase.
Example 1
Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid methyl
ester (2)
[0690] ##STR8##
[0691] The starting acid, 8-Bromo-[1,6]naphthyridine-2-carboxylic
acid (1), is prepared essentially according to the procedure
described in J. Med. Chem. 1999, 42, 3023-3025 and the references
cited therein.
[0692] 8-Bromo-[1,6]naphthyridine-2-carboxylic acid methyl ester
(2) is prepared by combining compound 1 (1 equiv.), cesium
carbonate (1.1 equiv.) and methyl iodide (1.1 equiv.) in DMF (10
mL) and stirring for 16 hrs. at room temperature. The reaction is
concentrated in vacuo to give a brown solid, which is dissolved in
EtOAc (50 mL) and washed with water (2.times.50 mL). The EtOAc
layer is dried over sodium sulfate, filtered, and concentrated in
vacuo to afford a purple solid.
[0693] The crude product is purified via silica gel chromatography
(EtOAc) to yield (2) as a yellow solid, 65%, LC/MS (M+H) 269.0.
Example 2
Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide (3)
[0694] ##STR9##
[0695] 8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1) is stirred
in DMF (20 mL) and furfurylamine (1 equiv.) is added. The reaction
mixture is cooled to 0.degree. C. (ice bath) and
diethylcyanophosphonate (1 equiv.) is added followed immediately by
triethylamine (2 equiv.). The reaction mixture is removed from the
ice bath and stirred at room temperature for 26 hrs. The mixture is
diluted with water (50 mL) and extracted with methylene chloride
(3.times.50 mL). The combined organic layers are dried over sodium
sulfate, filtered, and concentrated in vacuo to afford a tan solid,
which is purified via silica gel chromatography (1:1; hexanes:EtOAc
to 1:3.) LC/MS (M+H) 332.1.
Example 3
Preparation of
5-{2-[(Furan-2-ylmethyl)carbamoyl]-[1,6]naphthyridin-8-yl}thiophene-2-car-
boxylic acid (4)
[0696] ##STR10##
[0697] Compound 3 (above, 1 equiv.), 5(dihydroxylboryl)-2-thiophene
carboxylic acid (1 equiv.),
dichloro(bistriphenylphosphine)palladium (II) (0.02 equiv.), and
sodium carbonate (1.5 equiv.) are combined with 7:3:2;
DME:water:methanol (4 mL) in a microwavable reaction tube. The
reaction mixture is irradiated in the microwave at 140.degree. C.
for 300 seconds and then cooled to room temperature. The crude
mixture is concentrated in vacuo, affording a green-brown solid.
Purification via silica gel chromatography (EtOAc to 4:1;
EtOAc:methanol containing 1% acetic acid) affords a bright yellow
solid. LC/MS (M+H) 340.2.
Example 4
[0698] The following compounds are prepared essentially according
to the procedures described above. TABLE-US-00001 Ex. No. Name Data
Structure 5 8-[5-(2-Dimethylamino- ethylcarbamoyl)-thiophen-2-
yl]-[1,6]naphthyridine-2- carboxylic acid (furan-2- ylmethyl)-amide
brownish- yellow solid: LC/MS (M + H) 450.6 ##STR11## 6
8-[5-(2-Diethylamino- brownish- ethylcarbamoyl)-thiophen-2- yellow
yl]-[1,6]naphthyridine-2- solid; LC/MS carboxylic acid (furan-2- (M
+ H) ylmethyl)-amide 478.3. 7 8-Bromo-[1,6] yellow
naphthyridine-2-carboxylic solid; LC/MS acid cyclopropylamide (M +
H) 293.1 8 5-(2-Cyclopropylcarbamoyl- bright
[1,6]naphthyridin-8-yl)- yellow thiophene-2-carboxylic acid solid,
LC/MS (M + H) 340.2. 9 8-[5-(2-Dimethylamino- yellow
ethylcarbamoyl)-thiophen-2- pseudo- yl]-[1,6-naphthyridine-2-
solid, LC/MS carboxylic acid (M + H) cyclopropylamide 410.4. 10
8-[5-(2-Diethylamino- yellow ethylcarbamoyl)-thiophen-2- solid,
yl]-[1,6]naphthyridine-2- LC/MS carboxylic acid (M + H)
cyclopropylamide 438.3.
Example 11
Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid
chloride
[0699] ##STR12##
[0700] Oxalyl chloride (1.5 equiv.) is added drop wise to a slurry
of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1 equiv., in 20 mL
DMF) at 0.degree. C. (ice bath) and stirred for 30 minutes. The
reaction mixture is removed from the ice bath, stirred at room
temperature for 3 h and then concentrated in vacuo to give a
greenish colored solid, which is used immediately without further
purification.
Example 12
Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid
methylamide
[0701] ##STR13##
[0702] 2.0 M Methylamine in ethanol is added to compound 11 and the
reaction mixture is stirred for 20 h at room temperature. The
reaction is concentrated in vacuo to give a greenish-brown solid
that is purified via silica gel chromatography (EtOAc) to give
compound 12 as a yellow solid, LC/MS (M+H) 266.9.
Example 13
Preparation of
5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic
acid
[0703] ##STR14##
[0704] The desired compound is prepared essentially using the
procedure described in Example 3. The product is a yellow solid,
LC/MS (M+H) 314.16.
Example 14
Preparation of
5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic
acid chloride
[0705] ##STR15##
[0706] The desired compound is prepared essentially using the
procedure described in Example 11. The product is a yellow paste
that is used immediately without further purification.
Example 15
Preparation of
5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic
acid amide
[0707] ##STR16##
[0708] The compound is prepared by stirring compound 14 in 7N
ammonia in methanol (8 mL) at room temperature for 19 h. The
reaction mixture is concentrated in vacuo to afford a crude yellow
solid. Purification via silica gel chromatography
(CHCl.sub.3/MeOH/NH.sub.4OH 80/18/2) affords the desired compound
as a bright yellow solid, LC/MS (M+H) 313.4. Preparation 1
##STR17##
[0709] 8-Thiophen-2-yl-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide (1.0 equiv.) was stirred in methylene
chloride (2.0 mL) under nitrogen at 0.degree. C. (ice bath) and
meta-chloroperoxybenzoic acid (1.0 equiv.) was added over 10
minutes. The reaction was warmed to room temperature and stirred
for 18 hours. LC/MS indicated the N-oxide as the major product. The
reaction mixture was concentrated in vacuo to afford an orange
solid and used in the next reaction without further purification.
LC/MS (M+H) 352.2.
Preparation 2
[0710] ##STR18##
[0711] 6-A-Oxo-8-thiophen-2-yl-[1,6]naphthyridine-2-carboxylic acid
(furan-2-ylmethyl)-amide (1.0 equiv.) was combined with phosphorous
oxychloride (8.0 mL) and refluxed for 2 hours and stirred an
additional 18 hours at room temperature. The reaction mixture was
poured onto ice (25 g) and stirred for 20 minutes. The resulting
brown precipitate was filtered to yield the product as a brown
solid. LC/MS (M+H) 370.2.
Preparation 3
[0712] ##STR19##
[0713] 5-Chloro-8-thiophen-2-yl-[1,6]naphthyridine-2-carboxylic
acid (furan-2-ylmethyl)-amide (1.0 equiv.) was combined with
methylamine (10 equiv., 2.0 M in methanol) and irradiated in a
microwave at 100.degree. C. for 600 seconds. The reaction mixture
was diluted with methanol (5 mL) and sonicated. The insolubles were
filtered and the filtrate was evaporated to dryness to yield the
expected product as an orange oil. LC/MS (M+H) 365.2.
[0714] The following compounds are prepared essentially according
to the methods and procedures described above. TABLE-US-00002 Ex.
No. Name Data 16 5-(2-Methylcarbamoyl-[1, 6]naphthyridin-8-yl)-
thiophene-2-carboxylic acid methylamide bright yellow solid, LC/MS
(M + H) 327.4. ##STR20## 17 8-[5-(3-Morpholin-4-yl- yellow solid,
propylcarbamoyl)-thiophen- LC/MS 2-yl]-[1,6]naphthyridine- (M + H)
2-carboxylic acid 440.3. methylamide 18 8-Thiophen-3-yl[1,6]- tan
solid, naphthyridine-2-carboxylic LC/MS acid (M + H) 571.1 19
8-Thiophen-3-yl[1,6]- orange solid, napthyridine-2-carboxylic LC/MS
acid (furan-2-ylmethyl)- (M + H) amide 336.2. 20
8-Thiophen-3-yl[1,6]- orange solid, naphthyridine-2-carboxylic
LC/MS acid furan-2-ylmethyl- (M + H) methyl-amide 351.2. 21
8-Thiophen-3-yl[1,6]- naphthyridine-2-carboxylic acid
cyclopropylamide light, yellow solid, LC/MS (M + H) 296.2.
##STR21## 22 8-Thiophen-3-yl[1,6]- tan solid,
naphthyridine-2-carboxylic LC/MS acid methylamide (M + H) 270.1. 23
8-Thiophen-3-yl[1,6]- light, yellow naphthyridine-2-carboxylic
solid, 58% acid (2-hydroxy- LC/MS cyclohexyl)amide (M + H) 354.2.
24 8-Thiophen-3-yl[1,6]- white solid, naphthyridine-2-carboxylic
LC/MS (M + H) acid (2-oxo- 354.2. cyclohexyl)amide prepared via
Dess-Martin oxidation of compound 23 25 8-Thiophen-3-yl[1,6]-
off-white naphthyridine-2- solid, 27% carboxylic acid amide LC/MS
(M + H) 256.3. Prepared from compound 18 26 8-Thiophen-3-yl-
[1,6]naphthyridine-2- carboxylic acid (tetrahydro-furan-2-
ylmethyl)-amide off-white solid, LC/MS (M + H) 340.2. ##STR22## 27
8-Phenyl[1,6]- yellow solid, naphthyridine-2-carboxylic LC/MS (M +
H) acid 251.2. 28 8-Phenyl[1,6]- orange psuedo-
naphthyridine-2-carboxylic solid, LC/MS acid (furan-2-ylmethyl)- (M
+ H) 330.2. amide 29 8-Phenyl[1,6]- orange psuedo-
naphthyridine-2-carboxylic solid, 73%, acid furan-2-ylmethyl- LC/MS
(M + H) methyl-amide 344.3. 30 8-Phenyl[1,6]- white solid,
naphthyridine-2-carboxylic LC/MS (M + H) acid cyclopropylamide
290.2. 31 8-Phenyl[1,6]- LC/MS (M + H) naphthyridine-2-carboxylic
250.2. acid amide 32 8-Bromo[1,6]- light, yellow
naphthyridine-2-carboxylic solid, LC/MS acid (2-hydroxy- (M + H)
350.2. cyclohexyl)amide 33 8-Bromo[1,6]- naphthyridine-2-carboxylic
acid (2-oxo- cyclohexyl)amide white solid, LC/MS (M + H) 348.1.
prepared via Dess-Martin oxidation of compound 32 ##STR23## 34
8-Phenyl[1,6]- white solid, naphthyridine-2-carboxylic LC/MS (M +
H) acid (2-hydroxy- 348.3. cyclohexyl)amide 35 8-Phenyl[1,6]- off
white naphthyridine-2-carboxylic solid, LC/MS acid (2-oxo- (M + H)
346.1. cyclohexyl)amide
[0715] Example 36
Preparation of
8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acid
cyclopropylamide
[0716] ##STR24##
[0717] 8-Bromo-[1,6]naphthyridine-2-carboxylic acid
cyclopropylamide, acetylene (2.5 equiv),
tetrakis(triphenylphosphine)palladium (0) (5 mol %), copper (I)
iodide (25 mol %), and potassium carbonate (3.0 equiv) are
dissolved in 5:1 DME:water. The reaction vessel is purged with
N.sub.2 and stirred overnight at 50.degree. C. The solvent is
removed in vacuo and the residue purified by preparative TLC
(EtOAc) to afford the desired product as an off-white solid, LC/MS
(M+H) 268.2. TABLE-US-00003 Ex. No. Name Data 37
8-(3-Hydroxy-prop-1- ynyl-[1, 6]naphthyridine-2- carboxylic acid
amide off-white solid, LC/MS (M + H) 228.2. ##STR25## 38
8-(3-Hydroxy-prop-1- off-white ynyl-[1, solid, LC/MS
6]naphthyridine-2- (M + H) 308.2. carboxylic acid (furan-
2-ylmethyl)amide 39 (3-{2-[(Furan-2- off-white
ylmethyl)-carbamoyl]- solid, LC/MS [1,6]naphthyridin-8- (M + H)
407.3. yl}-prop-2-ynyl)- carbamic acid tert- butyl ester 40
8-Phenylethynyl-[1, off-white 6]naphthyridine-2- solid, LC/MS
carboxylic acid (furan- (M + H) 354.2. 2-ylmethyl)-amide 41
8-Ethynyl-[1, off-white 6]naphthyridine-2- solid, LC/MS carboxylic
acid (furan- (M + H) 278.1. 2-ylmethyl)-amide
[0718] The following compounds were prepared essentially according
to the method described for the Buchwald-type coupling.
TABLE-US-00004 Ex. No. Name Data 42 8-(4-Methoxy- phenylamino)-[1,
6]naphthyridine-2- carboxylic acid (furan-2-ylmethyl)- amide
off-white solid, LC/MS (M + H) 375.2. ##STR26## 43
8-para-Tolyamino- off-white [1,6]naphthyridine- solid, 2-carboxylic
acid LC/MS (furan-2-ylmethyl)- (M + H) amide 359.2. 44
8-Phenylamino- off-white [1,6]naphthyridine- solid, 2-carboxylic
acid LC/MS (furan-2-ylmethyl)- (M + H) amide 345.2. 45 8-(3-
off-white Trifluoromethyl- solid, phenylamino0-[1, LC/MS
6]naphthyridine-2- (M + H) carboxylic acid 413.2.
(furan-2-ylmethyl)- amide 46 8-(4- off-white Trifluoromethyl-
solid, phenylamino)-[1, LC/MS 6]naphthyridine-2- (M + H) carboxylic
acid 413.2. (furan-2-ylmethyl)- amide 47 8-(Pyridin-3- ylamino)-[1,
6]naphthyridine-2- carboxylic acid (furan-2-ylmethyl)- amide
off-white solid, LC/MS (M + H) 346.2. ##STR27## 48 8-(Pyridin-4-
off-white ylamino)-[1, solid, 6]naphthyridine-2- LC/MS carboxylic
acid (M + H) (furan-2-ylmethyl)- 346.2. amide 49 8-(Pyrazin-2-
off-white ylamino)-[1, solid, 6]naphthyridine-2- LC/MS carboxylic
acid (M + H) (furan-2-ylmethyl)- 347.2. amide 50 8-(3,5-Dichloro-
off-white phenylamino)-[1, solid, 6]naphthyridine-2- LC/MS
carboxylic acid (M + H) (furan-2-ylmethyl)- 413.2. amide 51
8-(4-Methoxy- off-white phenylamino)-[1, solid, 6]naphthyridine-2-
LC/MS carboxylic acid (M + H) cyclopropylamide 335.3. 52
8-(3,5-Dichloro- phenylamino)-[1, 6]naphthyridine-2- carboxylic
acid cyclopropylamide off-white solid, LC/MS (M + H) 373.2.
##STR28## 53 8-(4-Methoxy- off-white phenylamino)-[1, solid,
6]naphthyridine-2- LC/MS carboxylic acid (M + H) amide 291.1. 54
8-[(Furan-2- yellow ylmethyl)-amino]-[1, solid, 6]naphthyridine-2-
LC/MS carboxylic acid (M + H) (furan-2-ylmethyl)- 389.3. amide 55
8-[(Pyridin-4- yellow ylmethyl)-amino]-[1, solid,
6]naphthyridine-2- LC/MS carboxylic acid (M + H)
(furan-2-ylmethyl)- 360.3. amide 56 8-[(Pyridin-2- yellow
ylmethyl)-amino]-[1, solid, 6]naphthyridine-2- LC/MS carboxylic
acid (M + H) (furan-2-ylmethyl)- 360.3. amide 57 8-[(Pyridin-3-
ylmethyl)-amino]-[1, 6]naphthyridine-2- carboxylic acid
(furan-2-ylmethyl)- amide yellow solid, LC/MS (M + H) 360.3.
##STR29## 58 8-(3-Methoxy- yellow benzylamino)-[1, solid,
6]naphthyridine-2- LC/MS carboxylic acid (M + H)
(furan-2-ylmethyl)- 389.2. amide 59 8-Cyclopropylamino- yellow
[1,6]naphthyridine- solid, 2-carboxylic acid LC/MS
(furan-2-ylmethyl)- (M + H) amide 309.2. 60 8-Prop-2-ynylamino-
yellow [1,6]naphthyridine- solid, 2-carboxylic acid LC/MS
(furan-2-ylmethyl)- (M + H) amide 307.2. 61 8-(2-Oxo-pyrrolidin-1-
yellow yl)-[1,6]naphthyridine- solid, 2-carboxylic acid LC/MS
(furan-2-ylmethyl)- (M + H) amide 337.3.
Example 62
Preparation of (8-Bromo-[1,6]naphthyridin-2-yl)-carbamic acid
tert-butyl ester
[0719] ##STR30##
[0720] 8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1 equiv.) is
suspended in tert-butanol (20 mL). Triethylamine (1.1 equiv.) and
diphenylphosphoryl azide (1.1 equiv.) are added and the reaction is
warmed to reflux. After refluxing for 2.5 hours, the reaction is
allowed to cool and half the solvent is removed by rotary
evaporation. The residue is dissolved in ethyl acetate (200 mL) and
washed with saturated NaHCO.sub.3 (50 mL). The organic phase is
dried over magnesium sulfate, filtered and concentrated to afford
the crude product. Silica gel chromatography (1:1 EtOAc:hexanes)
affords the desired BOC amine as a solid, LC/MS (M+H) 324.1.
Example 63
Preparation of 8-Bromo-[1,6]naphthyridin-2-ylamine
dihydrochloride
[0721] ##STR31##
[0722] (8-Bromo-[1,6]naphthyridin-2-yl)-carbamic acid tert-butyl
ester (1 equiv.) is suspended in methanol (10 mL). Acetyl chloride
(ca. 1 mL) is added over 1 minute. After the reaction mixture cools
to ambient temperature, the solvent is brought briefly to reflux
using a heat gun. The heat gun is applied twice more, at which
point TLC (1:1 EtOAc:hexanes) indicated complete reaction.
Concentration, followed by trituration twice with dry methanol
affords the title compound as a white solid, LC/MS (M+H) 224.1.
Example 64
[0723] Preparation of 1,
2,3,4-Tetrahydro-[1,6]naphthyridine-2-carboxylic acid methyl ester
##STR32##
[0724] [1,6]naphthyridine-2-carboxylic acid methyl ester (1 equiv.)
and methanol (anhydrous, 5 mL) were combined in a reaction vessel
under nitrogen atmosphere. Palladium, 5% wt. on calcium carbonate
(1 equiv.) was added and hydrogen gas was bubbled through the
solution via balloon for 12 h. The reaction was passed through a
short plug of silica to remove the catalyst and the silica plug was
washed with 20% methanol in DCM. The solvent was removed in vacuo
to yield the title compound as a brown solid weighing 12 mg
(59%).
[0725] The following compounds are prepared essentially according
to the methods, examples, and procedures described above.
TABLE-US-00005 Ex. No. Structure Name 65 methyl 8-bromo-1,6-
naphthyridine-2- carboxylate 66 8-(3-thienyl)-1,6- naphthyridine-2-
carboxylic acid 67 ##STR33## N-cyclopropyl-8-[5-({[2-
(diethylamino)ethyl]amino}carbonyl)-2-thienyl]-
1,6-naphthyridine-2- carboxamide 68 8-phenyl-1,6- napthyridine-2-
carboxylic acid 69 N-(2-furylmethyl)-8-{[4-
(trifluoromethyl)phenyl]amino}- 1,6-naphthyridine- 2-carboxamide 70
N-(2-furylmethyl)-8-[(4- methylphenyl)amino]-1,6- naphthyridine-2-
carboxamide 71 8-anilino-N-(2- furylmethyl)-1,6- naphthyridine-2-
carboxamide 72 ##STR34## N-(2-furylmethyl)-8-{[3-
(trifluoromethyl)phenyl]amino}-1,6-naphthyridine- 2-carboxamide 73
N-(2-furylmethyl)-8-[(4- methylphenyl)amino]-1,6- naphthyridine-2-
carboxamide 74 N-(2-furylmethyl)-8-(3- hydroxyprop-1-yn-1-yl)-
1,6-naphthyridine-2- carboxamide 75 8-(5-carboxy-2-thienyl)-
1,6-naphthyridine-2- carboxylic acid 76 8-bromo-N-(2-
oxocyclohexyl)-1,6- naphthyridine-2- carboxamide 77 ##STR35##
N-(2-furylmethyl)-8- (pyridin-3-ylamino)-1,6- naphthyridine-2-
carboxamide 78 tert-butyl [3-(2-{[(2- furylmethyl)amino]carbonyl}-
1,6-naphthyridin-8- yl)prop-2-yn-1- yl]carbamate 79
N-(2-furylmethyl)-8- (pyridin-4-ylamino)-1,6- naphthyridine-2-
carboxamide 80 8-bromo-1,6- naphthyridine-2- carboxamide 81
8-[5-({[2- (diethylamino)ethyl]amino} carbonyl)-2-thienyl]-N-
(2-furylmethyl)-1,6- naphthyridine-2- carboxamide 82 ##STR36##
8-[5-({[2- (diethylamino)ethyl]amino}carbonyl)-2-thienyl]-N-
(2-furylmethyl)-1,6- naphthyridine-2- carboxamide 83
N-cyclopropyl-8-[5-({[2- (dimethylamino)ethyl]amino}
carbonyl)-2-thienyl]- 1,6-naphthyridine-2- carboxamide 84 diethyl
N-(4-{[(8-bromo- 1,6-naphthyridin-2- yl)carbonyl]amino}benzoyl)
glutamate 85 N-(2-furylmethyl)-8- (pyrazin-2-ylamino)-1,6-
naphthyridine-2- carboxamide 86 N-(2-oxocyclohexyl)-8-(3-
thienyl)-1,6- naphthyridine-2- carboxamide 87 ##STR37##
N-(2-oxocyclohexyl)-8- phenyl-1,6-naphthyridine- 2-carboxamide 88
8-(3-hydroxyprop-1-yn-1- yl)-1,6-naphthyridine-2- carboxamide 89
N-cyclopropyl-8-(3- hydroxyprop-1-yn-1-yl)- 1,6-naphthyridine-2-
carboxamide 90 N-(2-furylmethyl)-8- (phenylethynyl)-1,6-
naphthyridine-2- carboxamide 91 8-ethynyl-N-(2- furylmethyl)-1,6-
naphthyridine-2- carboxamide 92 ##STR38## N-cyclopropyl-8-[(4-
methoxyphenyl)amino]-1,6- naphthyridine-2- carboxamide 93
8-bromo-N-cyclopropyl- 1,6-naphthyridine-2- carboxamide 94
8-bromo-N-(2- furylmethyl)-1,6- naphthyridine-2- carboxamide 95
N-(2-furylmethyl)-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide
96 N-cyclopropyl-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide
97 ##STR39## 5-{2- [(cyclopropylamino)
carbonyl]-1,6-naphthyridin-8- yl}thiophene-2-carboxylic acid 98
5-(2-{[(2- furylmethyl)amino]carbonyl}- 1,6-naphthyridin-8-
yl)thiophene-2-carboxylic acid 99 N-methyl-8-(3-thienyl)-
1,6-naphthyridine-2- carboxamide 100 8-(4-methoxyphenyl)-N-
[(5-methylpyrazin-2- yl)methyl]-1,6- naphthyridine-2- carboxamide
101 8-(4-methoxyphenyl)-2- (morpholin-4-ylcarbonyl)-
1,6-naphthyridine 102 ##STR40## 2-[(4-benzylpiperazin-1-
yl)carbonyl]-8-(4- methoxyphenyl)-1,6- naphthyridine 103
8-phenyl-2-(piperidin-1- ylcarbonyl)-1,6- naphthyridine 104
N-(3-morpholin-4- ylpropyl)-8-(3-thienyl)- 1,6-naphthyridine-2-
carboxamide 105 2-(morpolin-4- ylcarbonyl)-8-(3- thienyl)-1,6-
naphthyridine 106 N-[4- (methylsulfonyl)benzyl]- 8-(3-thienyl)-1,6-
naphthyridine-2- carboxamide 107 ##STR41## 8-(3-thienyl)-N-{[6-
(trifluoromethyl)pyridin- 3-yl]methyl}-1,6- naphthyridine-2-
carboxamide 108 1-{[8-(3-thienyl)-1,6- naphthyridin-2-
yl]carbonyl}piperidin-4- ol 109 N-(2-methoxyethyl)-8-(3-
thienyl)-1,6- naphthyridine-2- carboxamide 110 N-cyclopropyl-8-(3-
thienyl)-1,6- naphthyridine-2- carboxamide 111
8-(4-methoxyphenyl)-N-(3- morpholin-4-ylpropyl)-
1,6-naphthyridine-2- carboxamide 112 ##STR42## N-[3-(1
H-imidazol-1- yl)propyl]-8-(4- methoxyphenyl)-1,6- naphthyridine-2-
carboxamide 113 8-(4-methoxyphenyl)-N- (pyridin-4-ylmethyl)-1,6-
naphthyridine-2- carboxamide 114 8-(4-methoxyphenyl)-2-
(piperidin-1-ylcarbonyl)- 1,6-naphthyridine 115 N-benzyl-8-(4-
methoxyphenyl)-1,6- naphthyridine-2- carboxamide 116
8-(4-methoxyphenyl)-N-(2- phenylethyl)-1,6- naphthyridine-2-
carboxamide 117 ##STR43## 8-(4-methoxyphenyl)-2- [(4-pyridin-2-
ylpiperazin-1- yl)carbonyl]-1,6- naphthyridine 118
N-(1-benzylpiperidin-4- yl)-8-(4-methoxyphenyl)-
1,6-naphthyridine-2- carboxamide 119 N-(2-methoxybenzyl)-8-(4-
methoxyphenyl)-1,6- naphthyridine-2- carboxamide 120 N-[4-
(dimethylamino)benzyl]-8- (4-methoxyphenyl)-1,6- naphthyridine-2-
carboxamide 121 8-(4-methoxyphenyl)-N-[4- (methylsulfonyl)benzyl]-
1,6-naphthyridine-2- carboxamide 122 ##STR44##
8-(4-methoxyphenyl)-N- {[6- (trifluoromethyl)pyridin-
3-yl]methyl}-1,6- naphthyridine-2- carboxamide 123
N-(3-morpholin-4- ylpropyl)-8-phenyl-1,6- naphthyridine-2-
carboxamide 124 N-[3-(1 H-imidazol-1- yl)propyl]-8-phenyl-1,6-
naphthyridine-2- carboxamide 125 N-[(5-methylpyrazin-2-
yl)methyl]-8-phenyl-1,6- naphthyridine-2- carboxamide 126 ##STR45##
2-(1,4-dioxa-8- azaspiro[4.5]dec-8-
ylcarbonyl)-8-phenyl-1,6- naphthyridine 127 8-phenyl-N-(pyridin-4-
ylmethyl)-1,6- naphthyridine-2- carboxamide 128 2-(morpholin-4-
ylcarbonyl)-8-phenyl-1,6- naphthyridine 129 N-benzyl-8-phenyl-1,6-
naphthridine-2- carboxamide 130 8-phenyl-N-(2- phenylethyl)-1,6-
naphthyridine-2- carboxamide 131 ##STR46##
8-phenyl-2-[(4-pyridin-2- ylpiperazin-1- yl)carbonyl]-1,6-
naphthyridine 132 N-(4-chlorobenzyl)-8- phenyl-1,6-naphthyridine-
2-carboxamide 133 2-[(4-benzylpiperazin-1- yl)carbonyl]-8-phenyl-
1,6-naphthyridine 134 N-(1-benzylpiperadin-4- yl)-8-phenyl-1,6-
naphthyridine-2- carboxamide 135 N-(2-methoxybenzyl)-8-
phenyl-1,6-naphthyridine- 2-carboxamide 136 ##STR47## N-[4-
(methylsulfonyl)benzyl]- 8-phenyl-1,6- naphthyridine-2- carboxamide
137 8-phenyl-N-{[6- (trifluoromethyl)pyridin- 3-yl]methyl}-1,6-
naphthyridine-2- carboxamide 138 N-(2-isopropoxybenzyl)-8-
phenyl-1,6-naphthyridine- 2-carboxamide 139 N-[3-(1 H-imidazol-1-
yl)propyl]-8-(3-thienyl)- 1,6-naphthyridine-2- carboxamide 140
2-(1,4-dioxa-8- azaspriro[4.5]dec-8- ylcarbonyl)-8-(3-
thienyl)-1,6- naphthyridine 141 ##STR48## N-(pyridin-4-ylmethyl)-8-
(3-thienyl)-1,6- naphthyridine-2- carboxamide 142 2-(piperidin-1-
ylcarbonyl)-8-(3- thienyl)-1,6- naphthyridine 143
N-benzyl-8-(3-thienyl)- 1,6-naphthyridine-2- carboxamide 144
N-(2-furylmethyl)-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide
145 2-[(4-pyridin-2- ylpiperazin-1- yl)carbonyl]-8-(3-
thienyl)-1,6- naphthyridine 146 ##STR49## N-(4-chlorobenzyl)-8-(3-
thienyl)-1,6- naphthyridine-2- carboxamide 147
2-[(4-benzylpiperazin-1- yl)carbonyl]-8-(3- thienyl)-1,6-
naphthyridine 148 N-(1-benzylpiperidin-4- yl)-8-(3-thienyl)-1,6-
naphthyridine-2- carboxamide 149 N-(2-methoxybenzyl)-8-(3-
thienyl)-1,6- naphthyridine-2- carboxamide 150 2-({4-[(4,6-
dimethoxypyrimidin-2- yl)methyl]piperazin-1- yl}carbonyl)-8-(3-
thienyl)-1,6- naphthyridine 151 ##STR50## N-(2-isopropoxybenzyl)-8-
(3-thienyl)-1,6- naphthyridine-2- carboxamide 152
1-{[8-(1-benzofuran-2- yl)-1,6-naphthyridin-2-
yl]carbonyl}piperidin-4- ol 153 8-(1-benzofuran-2-yl)-N-
(2-methoxyethyl)-1,6- naphthyridine-2- carboxamide 154
8-(1-benzofuran-2-yl)-N- cyclopropyl-1,6- naphthyridine-2-
carboxamide 155 1-[(8-phenyl-1,6- naphthyridin-2-
yl)carbonyl]piperidin-4- ol 156 ##STR51## N-(2-methoxyethyl)-8-
phenyl-1,6-naphthyridine- 2-carboxamide 157 N-cyclopropyl-8-phenyl-
1,6-naphthyridine-2- carboxamide 158 8-(1-benzofuran-2-yl)-N-
(3-morpholin-4-ylpropyl)- 1,6-naphthyridine-2- carboxamide 159
8-(1-benzofuran-2-yl)-N- [3-(1 H-imidazol-1- yl)propyl]-1,6-
naphthyridine-2- carboxamide 160 8-(1-benzofuran-2-yl)-N-
[(5-methylpyrazin-2- yl)methyl]-1,6- naphthyridine-2- carboxamide
161 ##STR52## 8-(1-benzofuran-2-yl)-2- (1,4-dioxa-8-
azaspiro[4.5]dec-8- ylcarbonyl)-1,6- naphthyridine 162
8-(1-benzofuran-2-yl)-N- (pyridin-4-ylmethyl)-1,6- naphthyridine-2-
carboxamide 163 8-(1-benzofuran-2-yl)-2- (morpholin-4-ylcarbonyl)-
1,6-naphthyridine 164 8-(1-benzofuran-2-yl)-2-
(piperidin-1-ylcarbonyl)- 1,6-naphthyridine 165
8-(1-benzofuran-2-yl)-N- benzyl-1,6-naphthyridine- 2-carboxamide
166 ##STR53## 8-(1-benzofuran-2-yl)-N- (2-furylmethyl)-1,6-
naphthyridine-2- carboxamide 167 8-(1-benzofuran-2-yl)-N-
(2-phenylethyl)-1,6- naphthyridine-2- carboxamide 168
8-(1-benzofuran-2-yl)-N- (4-chlorobenzyl)-1,6- naphthyridine-2-
carboxamide 169 8-(1-benzofuran-2-yl)-2- [(4-benzylpiperazin-1-
yl)carbonyl]-1,6- naphthyridine 170 8-(1-benzofuran-2-yl)-N-
(1-benzylpiperidin-4-yl)- 1,6-naphthyridine-2- carboxamide 171
##STR54## 8-(1-benzofuran-2-)-N- (2-methoxybenzyl)-1,6-
naphthyridine-2- carboxamide 172 8-(1-benzofuran-2-yl)-N- [4-
(methylsulfonyl)benzyl]- 1,6-naphthyridine-2- carboxamide 173
##STR55## 8-(1-benzofuran-2-yl)-N- {[6- (trifluoromethyl)pyridin-
3-yl]methyl}-1,6- naphthyridine-2- carboxamide 174
8-(1-benzofuran-2-yl)-N- (2-isopropoxybenzyl)-1,6- naphthyridine-2-
carboxamide
Biological Evaluation Endothelial Cell Activation:
[0726] Low passage normal human umbilical vein endothelial cells
(HUVEC) (Clonetics) were seeded 20,000 cells per well into 96-well
assay plates and incubated at 37.degree. C. overnight in a 5%
CO.sub.2 atmosphere. The following day, 10.times. test compounds
and controls were added to the appropriate wells and the treated
cells returned to the incubator for one hour. Cells were then
activated by adding TNF-.alpha. to a final concentration of 1 ng/ml
and incubating for an additional 4 hours. After activation, media
was removed and the cell monolayer was fixed by adding 100
.mu.l/well of 100% methanol. Expression of E-selectin was then
determined by performing an ELISA with an E-selectin-specific
primary antibody. Compound activity was determined by comparing
E-selectin expression levels to the DMSO and 10 .mu.M Actinomycin D
controls.
[0727] To test for specificity of compound action, the endothelial
cells were also activated with 1 ng/ml IL-1.beta. or LPS. 18 hour
activation was also done for all three agonist, but cell activation
for the longer activation was measured by determining expression of
ICAM using an ICAM-specific primary antibody for the ELISA
readout.
TNF-.alpha. Activation of NF.kappa.B Response Element:
[0728] 293T cells were transfected with an NF.kappa..mu.-Luc
reporter construct (BD Biosystems) using FuGENE 6 transfection
reagent (Roche). After transfection, the cells were plated into
96-well plates and incubated at 37.degree. C. overnight in a 5%
CO.sub.2 atmosphere. The following day, 10.times. concentrations of
test compounds and controls were added to the appropriate wells,
and the cells were incubated for an additional hour. TNF-.alpha.
was then added to a final concentration of 5 ng/ml, followed by
additional 4 hour incubation. After activation the media was
removed and 30 .mu.l/well of reporter lysis buffer was added
(Promega). Luciferase activity was determined by adding luciferase
reaction buffer (Promega) to the plate and measuring light output
with a Tecan GeniosPro plate reader. Compound activity was
determined by comparing light output to DMSO and 10 .mu.M
Actinomycin D controls.
LPS Activated TNF-.alpha. Release:
[0729] THP-1 cells were seeded into V-bottom 96-well plates at
5,000 cells per well. Plates were then incubated overnight at
37.degree. C., 5% CO.sub.2. Cells were then treated with 10.times.
compounds, using DMSO and 10 .mu.M Actinomycin-D as controls.
Plates were incubated for 1 hr at 37.degree. C., 5% CO.sub.2. Cells
were then activated with 10.times. LPS (final concentration: 25
ng/ml) and incubated overnight at 37.degree. C., 5% CO.sub.2. The
following day, assay plates were centrifuged, and the supernatant
transferred to ELISA plates for determination of TNF-.alpha.
secretion by sandwich ELISA (Biosource International).
TNF-.alpha. Activated IL-8 Release:
[0730] HL60 cells were seeded into V-bottom 96-well plates at
20,000 cells per well and treated with test compounds ranging in
concentration from 40 .mu.M to 64 nM, using DMSO and 10 .mu.M
Actinomycin D as the controls. Plates were incubated for 1 hour at
37.degree. C., 5% CO.sub.2. Cells were then activated by addition
of TNF-.alpha. final concentration: 12.5 ng/ml). Plates were
incubated for an additional 4 hours at 37.degree. C., 5% CO.sub.2.
Plates were then centrifuged, and supernatant transferred to ELISA
plates for determination of IL-8 secretion by sandwich ELISA.
Cell Proliferation Assays
[0731] A panel of cancer cell lines was obtained from the DCTP
Tumor Repository, National Cancer Institute (Frederick, Md.) or
ATCC (Rockville, Md.). Cell cultures were maintained in Hyclone
RPMI 1640 medium (Logan, Utah) supplemented with 10% fetal bovine
serum and 20 mM HEPES buffer, final pH 7.2, at 37.degree. C. with a
5% CO2 atmosphere. Cultures were maintained at sub-confluent
densities. Human umbilical vein endothelial cells (HUVEC) were
purchased from Clonetics, a division of Cambrex (Walkersville,
Md.). Cultures were established from cryopreserved stocks using
Clonetics EGM-2 medium supplemented with 20 mM HEPES, final pH 7.2,
at 37.degree. C. with a 5% CO.sub.2 atmosphere.
[0732] For proliferation assays, cells were seeded with the
appropriate medium into 96 well plates at 1,000-2,500 cells per
well, depending on the cell line, and were incubated overnight. The
following day, test compound, DMSO solution (negative control), or
Actinomycin D (positive control) was added to the appropriate wells
as 10.times. concentrated stocks prepared in phosphate buffered
saline. The cell plates were then incubated for an additional 2-5
days, depending on the cell line, to allow proliferation to occur.
To measure cell density, 50 .mu.L of WST-1 solution (Roche Applied
Science, IN) diluted 1:5 in phosphate buffered saline was added to
each well, and the cells incubated for an additional 1-5 hrs.,
again depending on the cell line. Optical density was determined
for each well at 450 nM using a Tecan GeniosPro plate reader (RTP,
NC). The percentage of cell growth was determined by comparing the
cell growth in the presence of test compounds to the cells treated
with DMSO vehicle (control, 100% growth) and cells treated with
Actinomycin D (10 .mu.M, 0% growth).
[0733] Immediately after the WST-1 determination, the medium was
removed from the PC-3, NCI-H460 and HUVEC cell lines, and the
plates stored at -80.degree. C. Using these assay plates, relative
amounts of DNA in each well were determined using the Cyquant DNA
assay kit from R&D Systems (Eugene, Oreg.) following the
manufacturer's directions. Results for each compound treatment were
compared to DMSO vehicle control (100%) and 10 .mu.M Actinomycin D
treated cells (0%). Table 2 contains the cell proliferation data
for several exemplary compounds useful in the methods of the
invention.
[0734] Preferred compounds of the invention have activities of less
than 20 .mu.M in all of the assays described above.
[0735] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the invention and that
modifications may be made therein without departing from the spirit
or scope of the invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *