U.S. patent application number 12/913986 was filed with the patent office on 2011-11-03 for pyrimidine compounds as delta opioid receptor modulators.
Invention is credited to Haiyan BIAN, Chaozhong CAI, Steven J. COATS, Peter J. CONNOLLY, Scott L. DAX, Bart L. DECORTE, Wei HE, Li LIU, Mark J. MACIELAG, Philip M. PITIS.
Application Number | 20110269759 12/913986 |
Document ID | / |
Family ID | 43447850 |
Filed Date | 2011-11-03 |
United States Patent
Application |
20110269759 |
Kind Code |
A1 |
COATS; Steven J. ; et
al. |
November 3, 2011 |
PYRIMIDINE COMPOUNDS AS DELTA OPIOID RECEPTOR MODULATORS
Abstract
Disclosed are compounds, compositions and methods for treating
various diseases, syndromes, conditions and disorders, including
pain. Such compounds are represented by Formula I as follows:
##STR00001## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.a, and Y are
defined herein.
Inventors: |
COATS; Steven J.;
(McDonough, GA) ; BIAN; Haiyan; (Princeton,
NJ) ; CAI; Chaozhong; (North Wales, PA) ;
DECORTE; Bart L.; (Southampton, PA) ; LIU; Li;
(Germantown, MD) ; MACIELAG; Mark J.; (Branchburg,
NJ) ; DAX; Scott L.; (Landenberg, PA) ; PITIS;
Philip M.; (North Wales, PA) ; CONNOLLY; Peter
J.; (New Providence, NJ) ; HE; Wei; (Audubon,
PA) |
Family ID: |
43447850 |
Appl. No.: |
12/913986 |
Filed: |
October 28, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61256405 |
Oct 30, 2009 |
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Current U.S.
Class: |
514/235.8 ;
514/252.18; 514/269; 544/123; 544/295; 544/296; 544/319 |
Current CPC
Class: |
C07D 401/14 20130101;
A61P 1/00 20180101; C07D 401/04 20130101; A61P 25/06 20180101; A61P
25/32 20180101; A61P 29/00 20180101; C07D 403/12 20130101; A61P
1/12 20180101; A61P 25/00 20180101; C07D 403/14 20130101; C07D
403/04 20130101; A61P 11/02 20180101; A61P 25/28 20180101; A61P
17/02 20180101; A61P 25/30 20180101; A61P 15/00 20180101; A61P
17/04 20180101; A61P 21/00 20180101; A61P 35/00 20180101; A61P
11/04 20180101; A61P 25/16 20180101; A61P 25/24 20180101; C07D
409/14 20130101; A61P 13/02 20180101; A61P 13/10 20180101; A61P
13/00 20180101; A61P 15/12 20180101; A61P 17/00 20180101; A61P
19/02 20180101; A61P 11/00 20180101; A61P 19/00 20180101; C07D
405/14 20130101; A61P 25/04 20180101; C07D 413/14 20130101; A61P
9/10 20180101; A61P 25/02 20180101; C07D 239/47 20130101; C07D
401/12 20130101; A61P 9/00 20180101; A61P 13/08 20180101; C07D
417/14 20130101; A61P 1/16 20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/235.8 ;
544/319; 514/269; 544/296; 544/295; 514/252.18; 544/123 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/506 20060101 A61K031/506; C07D 413/14
20060101 C07D413/14; C07D 403/14 20060101 C07D403/14; A61K 31/496
20060101 A61K031/496; A61P 19/02 20060101 A61P019/02; A61P 25/06
20060101 A61P025/06; A61P 25/04 20060101 A61P025/04; A61P 13/10
20060101 A61P013/10; A61P 17/00 20060101 A61P017/00; A61P 1/00
20060101 A61P001/00; A61P 35/00 20060101 A61P035/00; A61P 29/00
20060101 A61P029/00; A61P 25/16 20060101 A61P025/16; A61P 25/24
20060101 A61P025/24; A61P 25/32 20060101 A61P025/32; A61P 9/00
20060101 A61P009/00; C07D 401/14 20060101 C07D401/14 |
Claims
1. A compound of Formula I ##STR00049## wherein R.sub.1 is selected
from the group consisting of i) phenyl optionally substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy, chloro, and fluoro;
in addition, phenyl is optionally substituted with a single amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylaminocarbonyl,
hydroxy(C.sub.1-4)alkyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkoxycarbonylamino, ureido,
C.sub.1-4alkylureido, di(C.sub.1-4alkyl)ureido, cyano,
trifluoromethoxy, C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl,
bromo, piperazin-1-yl optionally substituted with 4-C.sub.1-4alkyl,
morpholin-4-yl, phenyl, formamido, or pyridinyl substituent; and
wherein the phenyl and pyridinyl substituents of the R.sub.1-phenyl
are each optionally substituted with one substituent selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, fluoro, chloro, cyano, amino, and hydroxy; ii)
pyrimidinyl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, and hydroxy; in addition,
pyrimidinyl is optionally substituted with a single amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylaminocarbonyl,
hydroxy(C.sub.1-4)alkyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkoxycarbonylamino, ureido,
C.sub.1-4alkylureido, di(C.sub.1-4alkyl)ureido, cyano,
trifluoromethoxy, C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl,
bromo, piperazin-1-yl optionally substituted with 4-C.sub.1-4alkyl,
morpholin-4-yl, formamido, pyrrol-1-yl, phenyl, pyridinyl or
piperidin-1-yl substituent; and wherein the phenyl and pyridinyl
substituents of the R.sub.1-pyrimidinyl are each optionally
substituted with one substituent selected from the group consisting
of C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro,
chloro, cyano, amino, and hydroxy; iii) pyridinyl optionally
substituted with one to two substituents independently selected
form the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in
addition, pyridinyl is optionally substituted with a single
hydroxymethyl, amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
C.sub.1-4alkylsulfonyl, aminocarbonyl, C.sub.1-4alkylaminocarbonyl,
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkoxyaminocarbonyl, ureido, C.sub.1-4alkylureido,
di(C.sub.1-4alkyl)ureido, piperazin-1-yl, morpholin-4-yl, phenyl,
or pyridinyl; and, wherein the phenyl and pyridinyl substituents of
the R.sub.1-pyridinyl are optionally independently substituted with
one to two substituents selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro,
chloro, cyano, amino, and hydroxy; and iv) a G-substituent selected
from the group consisting of naphthyl, pyrazolyl, thienyl,
benzothiazolyl, benzimidazolyl, quinolinyl, indolyl, thiazolyl,
furanyl, dihydrobenzofuranyl, pyrazinyl, isoquinolinyl,
quinoxalinyl, quinazolinyl, isoxazolyl, oxazolyl, pyrrolopyridinyl,
benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,
4H-[1,2,4]oxadiazol-5-on-yl, benzothiophenyl, indazolyl, and
2,3-dihydrobenzo[1,4]dioxinyl; wherein G is optionally
independently substituted with one to two substituents selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
fluoro, chloro, bromo, cyano, C.sub.1-4alkylcarbonyl, amino,
C.sub.1-4alkylamino, and di(C.sub.1-4alkyl)amino; R.sub.2 is (i)
phenyl optionally substituted with one to three substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro, chloro, and hydroxy;
in addition, phenyl of R.sub.2 is optionally substituted with a
single amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, di(C.sub.1-4)alkylaminocarbonyl,
C.sub.1-4alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano,
C.sub.3-7cycloalkylcarbonylamino, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy(C.sub.1-4)alkyl, C.sub.1-4alkoxy-(C.sub.1-4)alkoxy,
C.sub.1-4alkylcarbonyloxy, C.sub.1-4alkylsulfonylamino,
C.sub.1-4alkylsulfonyl, pyridinyl(C.sub.1-4)alkyl,
benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl,
morpholin-4-ylcarbonyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-(C.sub.1-3)alkyl, or
C.sub.3-7cycloalkyl-(C.sub.1-3)alkoxy substituent; (ii)
1,2-dihydrobenzofuranyl; provided that 1,2-dihydrobenzofuranyl is
bound to O of Formula (I) at the benzo portion of the ring; and
wherein the benzo portion of 1,2-dihydrobenzofuranyl is optionally
independently substituted with one to two substituents selected
from the group consisting of C.sub.1-4alkyl, fluoro, chloro, bromo,
cyano, C.sub.1-4alkylcarbonyl, amino, C.sub.1-4alkylamino, and
di(C.sub.1-4alkylamino; or (iii) heteroaryl selected from the group
consisting of benzothiazolyl, benzooxazolyl, pyridinyl,
pyrimidinyl, indazolyl, quinolinyl, quinazolinyl, benzimidazolyl,
pyrazinyl, triazinyl, benzothiophenyl, benzofuranyl, and
isoquinolinyl; wherein heteroaryl of R.sub.2 is optionally
independently substituted with one to two substituents selected
from the group consisting of C.sub.1-4alkyl, fluoro, chloro, bromo,
cyano, C.sub.1-4alkylcarbonyl, amino, C.sub.1-4alkylamino, and
di(C.sub.1-4alkylamino; A-L- is selected from the group consisting
of a.sup.1-L.sub.1-; a.sub.2-L.sub.2-; a.sub.3-L.sub.3-;
a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein L.sub.1 is absent
or C.sub.1-4alkyl; a.sub.1 is bound through a carbon atom to
L.sub.1 and is selected from the group consisting of i)
pyrrolidinyl optionally substituted at carbon with C.sub.1-4alkyl,
amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, aminomethyl,
hydroxy, cyano, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, or one to
two fluoro substituents; and wherein pyrrolidinyl is optionally
substituted at nitrogen with C.sub.1-4alkyl,
phenyl(C.sub.1-4)alkyl, C.sub.1-4alkylcarbonyl,
C.sub.1-4alkoxycarbonyl, or phenyl(C.sub.1-4)alkoxycarbonyl; ii)
piperidinyl optionally substituted with C.sub.1-4alkyl, phenyl,
amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, aminomethyl,
hydroxy, cyano, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl,
phenyl(C.sub.1-4)alkyl, C.sub.1-4alkylcarbonyl, or
phenyl(C.sub.1-4)alkoxycarbonyl; and iii) azetidinyl optionally
substituted with 3-amino, 3-hydroxy, 3-C.sub.1-4alkoxy,
C.sub.1-4alkyl, or aminomethyl; provided that when L.sub.1 is
absent, a.sub.1 is attached to N(R.sub.a) via a carbon atom other
than that which is alpha to a nitrogen atom of a.sub.1; and
provided that when a.sub.1 is substituted with a substituent
containing an oxygen or nitrogen radical as a point of attachment
to a.sub.1, the substitution is at a carbon atom other than that
alpha to a nitrogen atom of a.sub.1; L.sub.2 is C.sub.1-4alkyl;
a.sub.2 is bound through a carbon atom to L.sub.2 and is selected
from the group consisting of i) piperazinyl optionally substituted
at carbon with C.sub.1-4alkyl, aminomethyl, cyano, or
C.sub.1-4alkoxycarbonyl; and wherein piperazinyl is optionally
substituted at nitrogen with C.sub.1-4alkyl,
phenyl(C.sub.1-4)alkyl, C.sub.1-4alkylcarbonyl,
C.sub.1-4alkoxycarbonyl, or phenyl(C.sub.1-4)alkoxycarbonyl; and
iii) morpholinyl optionally independently substituted with
phenyl(C.sub.1-4)alkyl or one to two C.sub.1-4alkyl substituents;
L.sub.3 is methylene; a.sub.3 is imidazolyl optionally
independently substituted with one to two C.sub.1-4alkyl
substituents; L.sub.4 is (C.sub.2-6)alkyl; and when L.sub.4 is
C.sub.3-6alkyl, L.sub.4 is optionally substituted with chloro,
hydroxy or C.sub.1-4alkoxy; provided that the chloro, hydroxy, and
C.sub.1-4alkoxy substituents are not alpha to a nitrogen-bearing
carbon atom; a.sub.4 is selected from the group consisting of amino
and C.sub.1-4alkylamino; provided that a.sub.4 is attached at a
carbon atom other than that alpha to N(R.sub.a); L.sub.5 is absent
or C.sub.1-4alkyl; a.sub.5 is C.sub.3-7cycloalkyl substituted with
R.sub.B; wherein R.sub.B is selected from the group consisting of
amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, aminomethyl,
C.sub.1-4alkylamino-methyl, and di(C.sub.1-4alkyl)amino-methyl;
provided that when R.sub.B contains a nitrogen radical as the point
of attachment to C.sub.3-7cycloalkyl, the attachment is at a carbon
atom other than that alpha to N(R.sub.a); or, A-L- is taken with
R.sub.a and the nitrogen atom to which they are both attached to
form a nitrogen-bound heterocyclyl selected from the group
consisting of i) pyrrolidinyl wherein pyrrolidinyl is optionally
substituted with C.sub.1-4alkyl, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, aminomethyl, cyano, C.sub.1-4alkoxy,
C.sub.1-4alkoxycarbonyl, or phenyl; ii) piperazinyl optionally
substituted with 4-C.sub.1-4alkyl; and wherein piperazinyl is
optionally independently substituted at carbon with one to two
C.sub.1-4alkyl substituents, 2-oxo, 3-oxo, trifluoromethyl,
aminomethyl, or hydroxymethyl iii) piperidinyl optionally
substituted with one to two C.sub.1-4alkyl substituents, amino,
C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, aminomethyl, hydroxy,
cyano, C.sub.1-4alkoxy, C.sub.1-4alkoxycarbonyl, phenyl,
phenyl(C.sub.1-4)alkyl, or one to two fluoro substituents; and,
wherein the phenyl and the phenyl portion of phenyl(C.sub.1-4)alkyl
are optionally substituted with C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, fluoro, chloro, cyano, amino, or hydroxy; iv)
azetidinyl optionally substituted with 3-amino or 3-aminomethyl; v)
[1,4]diazepan-1-yl optionally substituted with one to two
C.sub.1-4alkyl substituents; and vi)
3,6-diazoabicyclo[3.1.1]hept-3-yl optionally substituted with one
to two C.sub.1-4alkyl substituents; R.sub.a is hydrogen or
C.sub.1-4alkylcarbonyl; provided that a compound of Formula (I) is
other than a compound selected from the group consisting of a
compound wherein R.sub.1 is 4-fluoro-phenyl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sup.1-L.sub.1, a.sub.1 is
(S)-pyrrolidin-2-yl, L.sub.1 is methyl, R.sub.a is H, and X is O; a
compound wherein R.sub.1 is pyrimidin-5-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.2-L.sub.2, a.sub.2 is
(S)-morpholin-3-yl, L.sub.2 is methyl, R.sub.a is H, and X is O; a
compound wherein R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a.sup.1-L.sub.1, a.sub.1
is (S)-pyrrolidin-2-yl, L.sub.1 is methyl, R.sub.a is H, and X is
O; a compound wherein R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.B is 2-amino,
R.sub.a is H, and X is O; and a compound wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-diethylaminocarbonyl-phenyl,
A-L- is a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is
methyl, R.sub.a is H, and X is O; and enantiomers, diastereomers,
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein R.sub.1 is selected from the
group consisting of i) phenyl optionally substituted with one to
two substituents independently selected from the group consisting
of C.sub.1-4alkyl, C.sub.1-4alkoxy, hydroxy, chloro, and fluoro; in
addition, phenyl is optionally substituted with a single amino,
di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl,
hydroxy(C.sub.1-4)alkyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, cyano, trifluoromethoxy,
C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl
substituent; ii) pyrimidinyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkoxy, C.sub.1-4alkylthio, and hydroxy; in addition,
pyrimidinyl is optionally substituted with a single cyano,
morpholin-4-yl, amino, di(C.sub.1-4alkyl)amino, or piperazin-1-yl
optionally substituted with 4-C.sub.1-4alkyl substituent; iii)
pyridinyl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and
cyano; in addition, pyridinyl is optionally substituted with a
single hydroxymethyl, amino, aminocarbonyl, C.sub.1-4alkylsulfonyl,
or pyridinyl substituent; wherein the pyridinyl substituent of the
R.sub.1-pyridinyl is optionally independently substituted with one
to two substituents selected from the group consisting of chloro
and methyl; and iv) a G-substituent selected from the group
consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl,
quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl,
pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl,
benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,
4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl; wherein G is
optionally independently substituted with one to two substituents
selected from the group consisting of C.sub.1-4alkyl, fluoro, and
chloro.
3. The compound of claim 2 wherein R.sub.1 is selected from the
group consisting of i) phenyl optionally substituted with one to
two substituents independently selected from the group consisting
of C.sub.1-4alkyl, C.sub.1-4alkoxy, hydroxy, chloro, and fluoro; in
addition, phenyl is optionally substituted with a single amino,
di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl,
hydroxy(C.sub.1-4)alkyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, cyano, trifluoromethoxy,
C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl
substituent; ii) pyrimidinyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkoxy, C.sub.1-4alkylthio, and hydroxy; in addition,
pyrimidinyl is optionally substituted with a single cyano,
morpholin-4-yl, amino, di(C.sub.1-4alkyl)amino, or piperazin-1-yl
optionally substituted with 4-C.sub.1-4alkyl substituent; iv)
pyridinyl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and
cyano; in addition, pyridinyl is optionally substituted with a
single hydroxymethyl, amino, C.sub.1-4alkylsulfonyl, or pyridinyl
substituent; wherein the pyridinyl substituent of the
R.sub.1-pyridinyl is optionally independently substituted with one
to two substituents selected from chloro and methyl; and iv) a
G-substituent selected from the group consisting of naphthyl,
pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl,
furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl, oxazolyl,
pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,
dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and
benzothiophenyl; wherein G is optionally independently substituted
with one to two C.sub.1-4alkyl substituents.
4. The compound of claim 3 wherein R.sub.1 is selected from the
group consisting of i) phenyl optionally substituted with one to
two substituents independently selected from the group consisting
of C.sub.1-4alkyl, C.sub.1-2alkoxy, hydroxy, chloro, and fluoro; in
addition, phenyl is optionally substituted with a single amino,
di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl,
hydroxy(C.sub.1-4)alkyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, cyano, trifluoromethoxy,
C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl, or phenyl
substituent; ii) pyrimidinyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkoxy and C.sub.1-4alkylthio; in addition, pyrimidinyl is
optionally substituted with a single cyano, morpholin-4-yl,
di(C.sub.1-4alkyl)amino, or piperazin-1-yl optionally substituted
with 4-C.sub.1-4alkyl substituent; iii) pyridinyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in
addition, pyridinyl is optionally substituted with a single
hydroxymethyl, amino, C.sub.1-4alkylsulfonyl, or pyridinyl
substituent; wherein the pyridinyl substituent of the
R.sub.1-pyridinyl is optionally independently substituted with one
to two substituents selected from chloro and methyl; and iv) a
G-substituent selected from the group consisting of naphthyl,
pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl,
furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl,
pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,
dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and
benzothiophenyl; wherein G is optionally substituted with one
C.sub.1-4alkyl substituent.
5. The compound of claim 4 wherein R.sub.1 is selected from the
group consisting of i) phenyl optionally substituted with one to
two substituents independently selected from the group consisting
of C.sub.1-4alkyl, C.sub.1-2alkoxy, hydroxy, and fluoro; in
addition, phenyl is optionally substituted with a single amino,
di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl,
hydroxy(C.sub.1-4)alkyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, cyano, trifluoromethoxy,
C.sub.1-4alkylsulfonyl, nitro, or trifluoromethyl substituent; ii)
pyrimidinyl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkoxy
and C.sub.1-4alkylthio; in addition, pyrimidinyl is optionally
substituted with a single cyano, morpholin-4-yl,
di(C.sub.1-4alkyl)amino, or piperazin-1-yl optionally substituted
with 4-C.sub.1-4alkyl substituent; iii) pyridinyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in
addition, pyridinyl is optionally substituted with a single
hydroxymethyl or amino substituent; and iv) a G-substituent
selected from the group consisting of pyrazolyl, thienyl,
benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl,
dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and
benzo[1,2,5]oxadiazolyl; wherein G is optionally substituted with
one C.sub.1-4alkyl substituent;
6. The compound of claim 5 wherein R.sub.1 is selected from the
group consisting of i) phenyl optionally substituted with a
substituent selected from the group consisting of C.sub.1-2alkyl,
C.sub.1-2alkoxy, hydroxy, and fluoro; or, phenyl is optionally
substituted with one substituent selected from the group consisting
of amino, di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl,
hydroxymethyl, aminocarbonyl, C.sub.1-4alkylcarbonylamino, cyano,
trifluoromethoxy, C.sub.1-2alkylsulfonyl, nitro, and
trifluoromethyl; ii) pyrimidinyl optionally substituted with one to
two substituents selected from the group consisting of
C.sub.1-4alkoxy and C.sub.1-4alkylthio; or, pyrimidinyl is
optionally substituted with one substituent selected from the group
consisting of morpholin-4-yl, di(C.sub.1-4alkyl)amino, and
piperazin-1-yl optionally substituted with 4-methyl; iii) pyridinyl
optionally substituted with one to two substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, hydroxy, fluoro, and chloro; or, pyridinyl
optionally substituted with one substituent selected from the group
consisting of cyano, hydroxymethyl, and amino; iv) a G-substituent
selected from the group consisting of pyrazolyl, thienyl,
benzothiazolyl, quinolinyl, indolyl, thiazolyl, furanyl,
dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and
benzo[1,2,5]oxadiazolyl; wherein G is optionally substituted with
one C.sub.1-4alkyl substituent.
7. The compound of claim 1 wherein R.sub.2 is (i) phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, one to two fluoro substituents, chloro, and
hydroxy; in addition, phenyl is optionally substituted with a
single amino, fluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl,
di(C.sub.1-4)alkylaminocarbonyl, C.sub.1-4alkylcarbonylamino,
2,2,2-trifluoroethoxy, cyano, C.sub.3-7cycloalkylcarbonylamino,
hydroxy(C.sub.1-4)alkyl, C.sub.1-4alkoxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy-(C.sub.1-4)alkoxy, C.sub.1-4alkylcarbonyloxy,
C.sub.1-4alkylsulfonylamino, C.sub.1-4alkylsulfonyl,
pyridinyl(C.sub.1-4)alkyl, benzyloxycarbonylamino,
4-methyl-piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, carboxy,
piperidin-1-ylcarbonyl, or morpholin-4-ylcarbonyl substituent; or,
(ii) heteroaryl selected from the group consisting of
benzothiazolyl, benzooxazolyl, and pyridinyl; wherein heteroaryl is
optionally independently substituted with one to two C.sub.1-4alkyl
substituents.
8. The compound of claim 7 wherein R.sub.2 is (i) phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-2alkoxy,
C.sub.1-4alkylthio, one to two fluoro substituents, chloro, and
hydroxy; in addition, phenyl is optionally substituted with a
single amino, fluoromethyl, trifluoromethyl, fluoromethoxy,
difluoromethoxy, trifluoromethoxy, formamidino, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkylcarbonyloxy,
2,2,2-trifluoroethoxy, benzyloxycarbonylamino,
hydroxy(C.sub.1-4)alkyl, or C.sub.1-4alkoxy(C.sub.1-4)alkyl
substituent; or, (ii) heteroaryl selected from the group consisting
of benzothiazolyl and benzooxazolyl; wherein heteroaryl is
optionally independently substituted with one to two C.sub.1-4alkyl
substituents.
9. The compound of claim 8 wherein R.sub.2 is (i) phenyl optionally
substituted with one to two substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-2alkoxy, C.sub.1-4alkylthio,
one to two fluoro substituents, chloro, and hydroxy; in addition,
phenyl is optionally substituted with a single amino,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino,
aminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or
C.sub.1-4alkoxy(C.sub.1-4)alkyl substituent; or, (ii) heteroaryl
selected from the group consisting of benzothiazolyl and
benzooxazolyl; wherein heteroaryl is optionally independently
substituted with one to two C.sub.1-4alkyl substituents.
10. The compound of claim 9 wherein R.sub.2 is phenyl optionally
substituted with one to two substituents selected from the group
consisting of C.sub.1-2alkyl, C.sub.1-2alkoxy, C.sub.1-2alkylthio,
fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is optionally
substituted with one substituent selected from the group consisting
of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkylcarbonyloxy, and
2,2,2-trifluoroethoxy; or, R.sub.2 is a heteroaryl selected from
the group consisting of benzothiazolyl and benzooxazolyl; wherein
heteroaryl of R.sub.2 is optionally independently substituted with
one to two C.sub.1-2alkyl substituents.
11. The compound of claim 10 wherein R.sub.2 is (i) phenyl
optionally substituted with one substituent selected from the group
consisting of C.sub.1-2alkyl, C.sub.1-2alkoxy, C.sub.1-2alkylthio,
one to two fluoro substituents, 3-chloro, 4-chloro, and hydroxy;
or, phenyl is optionally substituted with one substituent selected
from the group consisting of amino, difluoromethoxy,
trifluoromethoxy, aminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy; or, (ii)
heteroaryl selected from the group consisting of benzothiazolyl and
benzooxazolyl; wherein heteroaryl of R.sub.2 is optionally
independently substituted with one to two C.sub.1-2alkyl
substituents.
12. A compound of claim 1 wherein A-L- is selected from the group
consisting of a.sub.1-L.sub.1-; a.sub.2-L.sub.2-; a.sub.3-L.sub.3-;
a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein L.sub.1 is absent
or C.sub.1-4alkyl; a.sub.1 is bound through a carbon atom to
L.sub.1 and is selected from the group consisting of i)
pyrrolidinyl optionally substituted at carbon with amino, hydroxy,
or one to two fluoro substituents; ii) piperidinyl; and iii)
azetidinyl; provided that when L.sub.1 is absent, a.sub.1 is
attached to N(R.sub.a) via a carbon atom other than that which is
alpha to a nitrogen atom of a.sub.1; and provided that when a.sub.1
is substituted with a substituent containing an oxygen or nitrogen
radical as a point of attachment to a.sub.1, the substitution is at
a carbon atom other than that alpha to a nitrogen atom of a.sub.1;
L.sub.2 is C.sub.1-4alkyl; a.sub.2 is bound through a carbon atom
to L.sub.2 and a.sub.2 is morpholinyl; L.sub.3 is methylene;
a.sub.3 is imidazolyl optionally independently substituted with one
to two C.sub.1-4alkyl substituents; L.sub.4 is (C.sub.2-6)alkyl;
a.sub.4 is selected from the group consisting of amino and
C.sub.1-4alkylamino; provided that a.sub.4 is attached at a carbon
atom of (C.sub.2-6)alkyl other than that alpha to N(R.sub.a);
L.sub.5 is absent or C.sub.1-4alkyl; a.sub.5 is C.sub.3-7cycloalkyl
substituted with R.sub.B; wherein R.sub.B is amino; provided that
when R.sub.B contains a nitrogen radical as a point of attachment
to C.sub.3-7cycloalkyl, the attachment is at a carbon atom other
than that alpha to N(R.sub.a); or, A-L- is taken with R.sub.a and
the nitrogen atom to which they are both attached to form a
nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl wherein pyrrolidin-1-yl is optionally
substituted with C.sub.1-4alkyl, amino, or aminomethyl; ii)
piperazin-1-yl optionally substituted with 4-C.sub.1-4alkyl; and
wherein piperazin-1-yl is optionally independently substituted at
carbon with one to two C.sub.1-4alkyl substituents, 2-oxo, or
3-oxo; iii) piperidin-1-yl optionally substituted with one to two
C.sub.1-4alkyl substituents or amino; iv) azetidin-1-yl optionally
substituted with 3-amino or 3-aminomethyl; v) [1,4]diazepan-1-yl;
and vi) 3,6-diazoabicyclo[3.1.1]hept-3-yl.
13. The compound of claim 12 wherein A-L- is selected from the
group consisting of a.sup.1-L.sub.1-; a.sub.2-L.sub.2-;
a.sub.3-L.sub.3-; a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein
L.sub.1 is absent or C.sub.1-2alkyl; a.sub.1 is bound through a
carbon atom to L.sub.1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or
one to two fluoro substituents; ii) piperidin-3-yl; and iii)
azetidinyl; provided that when L.sub.1 is absent, a.sub.1 is
attached to N(R.sub.a) via a carbon atom other than that which is
alpha to a nitrogen atom of a.sub.1; and provided that when a.sub.1
is substituted with a substituent containing an oxygen or nitrogen
radical as a point of attachment to a.sub.1, the substitution is at
a carbon atom other than that alpha to a nitrogen atom of a.sub.1;
L.sub.2 is C.sub.1-2alkyl; a.sub.2 is bound through a carbon atom
to L.sub.2 and a.sub.2 is morpholinyl; L.sub.3 is methylene;
a.sub.3 is imidazolyl optionally independently substituted with one
to two C.sub.1-2alkyl substituents; L.sub.4 is (C.sub.2-4)alkyl;
a.sub.4 is selected from the group consisting of amino and
C.sub.1-4alkylamino; provided that a.sub.4 is attached at a carbon
atom other than that alpha to N(R.sub.a); L.sub.5 is absent or
C.sub.1-4alkyl; a.sub.5 is C.sub.4-6cycloalkyl substituted with
R.sub.B; wherein R.sub.B is amino; provided that when R.sub.B
contains a nitrogen radical as the point of attachment to
C.sub.5-6cycloalkyl, the attachment is at a carbon atom other than
that alpha to N(R.sub.a); or, A-L- is taken with R.sub.a and the
nitrogen atom to which they are both attached to form a
nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino or
aminomethyl; ii) piperazin-1-yl optionally substituted with
4-C.sub.1-4alkyl; and wherein piperazin-1-yl is optionally
independently substituted at carbon with one to two C.sub.1-4alkyl
substituents; iii) piperidin-1-yl optionally substituted with
amino; iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
and v) [1,4]diazepan-1-yl; provided that the position of a
substituent containing a nitrogen radical as a point of attachment
to the nitrogen-bound heterocyclyl is at a carbon atom other than
that alpha to a heterocyclyl nitrogen atom.
14. The compound of claim 13 wherein A-L- is selected from the
group consisting of a.sub.1-L.sub.1-; a.sub.2-L.sub.2-;
a.sub.3-L.sub.3-, a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein
L.sub.1 is absent or C.sub.1-2alkyl; a.sub.1 is bound through a
carbon atom to L.sub.1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or
one to two fluoro substituents; and ii) piperidin-3-yl provided
that when L.sub.1 is absent, a.sub.1 is attached to N(R.sub.a) via
a carbon atom other than that which is alpha to a nitrogen atom of
a.sub.1; and provided that when a.sub.1 is substituted with a
substituent containing an oxygen or nitrogen radical as a point of
attachment to a.sub.1, the substitution is at a carbon atom other
than that alpha to a nitrogen atom of a.sub.1; L.sub.2 is
methylene; a.sub.2 is bound through a carbon atom to L.sub.2 and
a.sub.2 is morpholinyl; L.sub.3 is methylene; a.sub.3 is imidazolyl
optionally substituted with one to two methyl substituents; L.sub.4
is (C.sub.2-3)alkyl; a.sub.4 is amino, provided that a.sub.4 is
attached at a carbon atom other than that alpha to N(R.sub.a);
L.sub.5 is absent or C.sub.1-2alkyl; a.sub.5 is C.sub.4-6cycloalkyl
substituted with R.sub.B; wherein R.sub.B is amino; provided that
when R.sub.B contains a nitrogen radical as the point of attachment
to C.sub.5-6cycloalkyl, the attachment is at a carbon atom other
than that alpha to N(R.sub.a); or, A-L- is taken with R.sub.a and
the nitrogen atom to which they are both attached to form a
nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino; ii)
piperazin-1-yl optionally independently substituted at carbon with
one to two C.sub.1-4alkyl substituents; iii) piperidin-1-yl
optionally substituted with amino; and iv) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen
radical as a point of attachment to the nitrogen-bound heterocyclyl
is at a carbon atom other than that alpha to the heterocyclyl
nitrogen atom.
15. The compound of claim 14 wherein A-L- is selected from the
group consisting of a.sup.1-L.sub.1-; a.sub.2-L.sub.2-;
a.sub.3-L.sub.3-, a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein
L.sub.1 is absent or C.sub.1-2alkyl; a.sub.1 is bound through a
carbon atom to L.sub.1 and is selected from the group consisting of
i) pyrrolidinyl optionally substituted at carbon with hydroxy or
one to two fluoro substituents; and ii) piperidin-3-yl provided
that when L.sub.1 is absent, a.sub.1 is attached to N(R.sub.a) via
a carbon atom other than that which is alpha to a nitrogen atom of
a.sub.1; and provided that when a.sub.1 is substituted with a
substituent containing an oxygen or nitrogen radical as a point of
attachment to a.sub.1, the substitution is at a carbon atom other
than that alpha to a nitrogen atom of a.sub.1; L.sub.2 is
methylene; a.sub.2 is bound through a carbon atom to L.sub.2 and
a.sub.2 is morpholinyl; L.sub.3 is methylene; a.sub.3 is imidazolyl
optionally substituted with one to two methyl substituents; L.sub.4
is (C.sub.2-3)alkyl; a.sub.4 is amino, provided that a.sub.4 is
attached at a carbon atom other than that alpha to N(R.sub.a);
L.sub.5 is absent or C.sub.1-2alkyl; a.sub.5 is C.sub.4-6cycloalkyl
substituted with R.sub.B; wherein R.sub.B is amino; provided that
when R.sub.B contains a nitrogen radical as the point of attachment
to C.sub.5-6cycloalkyl, the attachment is at a carbon atom other
than that alpha to N(R.sub.a); or, A-L- is taken with R.sub.a and
the nitrogen atom to which they are both attached to form a
nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino; ii)
piperazin-1-yl optionally independently substituted at carbon with
one to two C.sub.1-2alkyl substituents; iii) piperidin-1-yl
optionally substituted with amino; and iv) [1,4]diazepan-1-yl;
provided that the position of a substituent containing an nitrogen
radical as a point of attachment to the nitrogen-bound heterocyclyl
is at a carbon atom other than that alpha to the heterocyclyl
nitrogen atom.
16. The compound of claim 1 wherein R.sub.a is hydrogen.
17. A compound of Formula (I) ##STR00050## wherein R.sub.1 is
selected from the group consisting of i) phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
hydroxy, chloro, and fluoro; in addition, phenyl is optionally
substituted with a single amino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, hydroxy(C.sub.1-4)alkyl,
aminocarbonyl, C.sub.1-4alkylcarbonylamino, cyano,
trifluoromethoxy, C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl,
or phenyl substituent; ii) pyrimidinyl optionally substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkoxy, C.sub.1-4alkylthio, and hydroxy; in
addition, pyrimidinyl is optionally substituted with a single
cyano, morpholin-4-yl, amino, di(C.sub.1-4alkyl)amino, or
piperazin-1-yl optionally substituted with 4-C.sub.1-4alkyl
substituent; iii) pyridinyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy,
fluoro, chloro, and cyano; in addition, pyridinyl is optionally
substituted with a single hydroxymethyl, amino, aminocarbonyl,
C.sub.1-4alkylsulfonyl, or pyridinyl substituent; wherein the
pyridinyl substituent of the R.sub.1-pyridinyl is optionally
independently substituted with one to two substituents selected
from chloro and methyl; and iv) a G-substituent selected from the
group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl,
quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl,
pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl,
benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,
4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl; wherein G is
optionally independently substituted with one to two substituents
selected from the group consisting of C.sub.1-4alkyl, fluoro, and
chloro; R.sub.2 is phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, one to two
fluoro substituents, chloro, and hydroxy; in addition, phenyl is
optionally substituted with amino, fluoromethyl, trifluoromethyl,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino,
aminocarbonyl, di(C.sub.1-4)alkylaminocarbonyl,
C.sub.1-4alkylcarbonylamino, 2,2,2-trifluoroethoxy, cyano,
C.sub.3-7cycloalkylcarbonylamino, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy(C.sub.1-4)alkyl, C.sub.1-4alkoxy-(C.sub.1-4)alkoxy,
C.sub.1-4alkylcarbonyloxy, C.sub.1-4alkylsulfonylamino,
C.sub.1-4alkylsulfonyl, pyridinyl(C.sub.1-4)alkyl,
benzyloxycarbonylamino, 4-methyl-piperazin-1-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, carboxy, piperidin-1-ylcarbonyl, or
morpholin-4-ylcarbonyl; or, R.sub.2 is a heteroaryl selected from
the group consisting of benzothiazolyl, benzooxazolyl, and
pyridinyl; wherein heteroaryl is optionally independently
substituted with one to two C.sub.1-4alkyl substituents; A-L- is
selected from the group consisting of a.sup.1-L.sub.1-;
a.sub.2-L.sub.2-; a.sub.3-L.sub.3-; a.sub.4-L.sub.4-; and
a.sub.5-L.sub.5-; wherein L.sub.1 is absent or C.sub.1-4alkyl;
a.sub.1 is bound through a carbon atom to L.sub.1 and is selected
from the group consisting of i) pyrrolidinyl optionally substituted
at carbon with amino, hydroxy, or one to two fluoro substituents;
ii) piperidinyl; and iii) azetidinyl; provided that when L.sub.1 is
absent, a.sub.1 is attached to N(R.sub.a) via a carbon atom other
than that which is alpha to a nitrogen atom of a.sub.1; and
provided that when a.sub.1 is substituted with a substituent
containing an oxygen or nitrogen radical as a point of attachment
to a.sub.1, the substitution is at a carbon atom other than that
alpha to a nitrogen atom of a.sub.1; L.sub.2 is C.sub.1-4alkyl;
a.sub.2 is bound through a carbon atom to L.sub.2 and a.sub.2 is
morpholinyl; L.sub.3 is methylene; a.sub.3 is imidazolyl optionally
independently substituted with one to two C.sub.1-4alkyl
substituents; L.sub.4 is (C.sub.2-6)alkyl; a.sub.4 is selected from
the group consisting of amino and C.sub.1-4alkylamino; provided
that a.sub.4 is attached at a carbon atom of (C.sub.2-6)alkyl other
than that alpha to N(R.sub.a); L.sub.5 is absent or C.sub.1-4alkyl;
a.sub.5 is C.sub.3-7cycloalkyl substituted with R.sub.B; wherein
R.sub.B is amino; provided that when R.sub.B contains a nitrogen
radical as a point of attachment to C.sub.3-7cycloalkyl, the
attachment is at a carbon atom other than that alpha to N(R.sub.a);
or, A-L- is taken with R.sub.a and the nitrogen atom to which they
are both attached to form a nitrogen-bound heterocyclyl selected
from the group consisting of i) pyrrolidin-1-yl wherein
pyrrolidin-1-yl is optionally substituted with C.sub.1-4alkyl,
amino, or aminomethyl; ii) piperazin-1-yl optionally substituted
with 4-C.sub.1-4alkyl; and wherein piperazin-1-yl is optionally
independently substituted at carbon with one to two C.sub.1-4alkyl
substituents, 2-oxo, or 3-oxo; iii) piperidin-1-yl optionally
substituted with one to two C.sub.1-4alkyl substituents or amino;
iv) azetidin-1-yl optionally substituted with 3-amino or
3-aminomethyl; v) [1,4]diazepan-1-yl; and vi)
3,6-diazoabicyclo[3.1.1]hept-3-yl; R.sub.a is hydrogen or
methylcarbonyl; provided that a compound of Formula (I) is other
than a compound selected from the group consisting of a compound
wherein R.sub.1 is 4-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is
methyl, R.sub.a is H, and X is O; a compound wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is (S)-morpholin-3-yl, L.sub.2 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is
4-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a.sup.1-L.sub.1, a.sub.1
is (S)-pyrrolidin-2-yl, L.sub.1 is methyl, R.sub.a is H, and X is
O; a compound wherein R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; and a compound wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.B is 2-amino,
R.sub.a is H, and X is O; and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
18. A compound of Formula (I) ##STR00051## wherein R.sub.1 is
selected from the group consisting of i) phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
hydroxy, chloro, and fluoro; in addition, phenyl is optionally
substituted with a single amino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, hydroxy(C.sub.1-4)alkyl,
aminocarbonyl, C.sub.1-4alkylcarbonylamino, cyano,
trifluoromethoxy, C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl,
or phenyl substituent; ii) pyrimidinyl optionally substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkoxy, C.sub.1-4alkylthio, and hydroxy; in
addition, pyrimidinyl is optionally substituted with a single
cyano, morpholin-4-yl, amino, di(C.sub.1-4alkyl)amino, or
piperazin-1-yl optionally substituted with 4-C.sub.1-4alkyl
substituent; iii) pyridinyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy,
fluoro, chloro, and cyano; in addition, pyridinyl is optionally
substituted with a single hydroxymethyl, amino,
C.sub.1-4alkylsulfonyl, or pyridinyl substituent; wherein the
pyridinyl substituent of the R.sub.1-pyridinyl is optionally
independently substituted with one to two substituents selected
from chloro and methyl; and v) a G-substituent selected from the
group consisting of naphthyl, pyrazolyl, thienyl, benzothiazolyl,
quinolinyl, indolyl, thiazolyl, furanyl, dihydrobenzofuranyl,
pyrazinyl, quinoxalinyl, oxazolyl, pyrrolopyridinyl,
benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl, dibenzothiophenyl,
4H-[1,2,4]oxadiazol-5-on-yl, and benzothiophenyl; wherein G is
optionally independently substituted with one to two C.sub.1-4alkyl
substituents; R.sub.2 is (i) phenyl optionally substituted with one
to two substituents independently selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-2alkoxy, C.sub.1-4alkylthio,
one to two fluoro substituents, chloro, and hydroxy; in addition,
phenyl is optionally substituted with amino, fluoromethyl,
trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
formamidino, aminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy,
benzyloxycarbonylamino, hydroxy(C.sub.1-4)alkyl, or
C.sub.1-4alkoxy(C.sub.1-4)alkyl; or, (ii) heteroaryl selected from
the group consisting of benzothiazolyl and benzooxazolyl; wherein
heteroaryl is optionally independently substituted with one to two
C.sub.1-4alkyl substituents; A-L- is selected from the group
consisting of a.sup.1-L.sub.1-; a.sub.2-L.sub.2-; a.sub.3-L.sub.3-;
a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein L.sub.1 is absent
or C.sub.1-2alkyl; a.sub.1 is bound through a carbon atom to
L.sub.1 and is selected from the group consisting of i)
pyrrolidinyl optionally substituted at carbon with hydroxy or one
to two fluoro substituents; ii) piperidin-3-yl; and iii)
azetidinyl; provided that when L.sub.1 is absent, a.sub.1 is
attached to N(R.sub.a) via a carbon atom other than that which is
alpha to a nitrogen atom of a.sub.1; and provided that when a.sub.1
is substituted with a substituent containing an oxygen or nitrogen
radical as a point of attachment to a.sub.1, the substitution is at
a carbon atom other than that alpha to a nitrogen atom of a.sub.1;
L.sub.2 is C.sub.1-2alkyl; a.sub.2 is bound through a carbon atom
to L.sub.2 and a.sub.2 is morpholinyl; L.sub.3 is methylene;
a.sub.3 is imidazolyl optionally independently substituted with one
to two C.sub.1-2alkyl substituents; L.sub.4 is (C.sub.2-4)alkyl;
a.sub.4 is selected from the group consisting of amino and
C.sub.1-4alkylamino; provided that a.sub.4 is attached at a carbon
atom other than that alpha to N(R.sub.a); L.sub.5 is absent or
C.sub.1-4alkyl; a.sub.5 is C.sub.4-6cycloalkyl substituted with
R.sub.B; wherein R.sub.B is amino; provided that when R.sub.B
contains a nitrogen radical as the point of attachment to
C.sub.5-6cycloalkyl, the attachment is at a carbon atom other than
that alpha to N(R.sub.a); or, A-L- is taken with R.sub.a and the
nitrogen atom to which they are both attached to form a
nitrogen-bound heterocyclyl selected from the group consisting of
i) pyrrolidin-1-yl optionally substituted with amino or
aminomethyl; ii) piperazin-1-yl optionally substituted with
4-C.sub.1-4alkyl; and wherein piperazin-1-yl is optionally
independently substituted at carbon with one to two C.sub.1-4alkyl
substituents; iii) piperidin-1-yl optionally substituted with
amino; iv) azetidin-1-yl optionally substituted with 3-aminomethyl;
and v) [1,4]diazepan-1-yl; provided that the position of a
substituent containing a nitrogen radical as a point of attachment
to the nitrogen-bound heterocyclyl is at a carbon atom other than
that alpha to a heterocyclyl nitrogen atom; R.sub.a is hydrogen;
provided that a compound of Formula (I) is other than a compound
selected from the group consisting of a compound wherein R.sub.1 is
4-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is (S)-morpholin-3-yl, L.sub.2 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; and a compound wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.B is 2-amino,
R.sub.a is H, and X is O; and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
19. A compound of Formula (I) ##STR00052## wherein R.sub.1 is
selected from the group consisting of i) phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-2alkoxy,
hydroxy, chloro, and fluoro; in addition, phenyl is optionally
substituted with a single amino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, hydroxy(C.sub.1-4)alkyl,
aminocarbonyl, C.sub.1-4alkylcarbonylamino, cyano,
trifluoromethoxy, C.sub.1-4alkylsulfonyl, nitro, trifluoromethyl,
or phenyl substituent; ii) pyrimidinyl optionally substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkoxy and C.sub.1-4alkylthio; in addition,
pyrimidinyl is optionally substituted with a single cyano,
morpholin-4-yl, di(C.sub.1-4alkyl)amino, or piperazin-1-yl
optionally substituted with 4-C.sub.1-4alkyl substituent; iii)
pyridinyl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and
cyano; in addition, pyridinyl is optionally substituted with a
single hydroxymethyl, amino, C.sub.1-4alkylsulfonyl, or pyridinyl
substituent; wherein the pyridinyl substituent of the
R.sub.1-pyridinyl is optionally independently substituted with one
to two substituents selected from chloro and methyl; and iv) a
G-substituent selected from the group consisting of naphthyl,
pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl, thiazolyl,
furanyl, dihydrobenzofuranyl, pyrazinyl, quinoxalinyl,
pyrrolopyridinyl, benzo[1,3]dioxol-5-yl, benzo[1,2,5]oxadiazolyl,
dibenzothiophenyl, 4H-[1,2,4]oxadiazol-5-on-yl, and
benzothiophenyl; wherein G is optionally substituted with one
C.sub.1-4alkyl substituent; R.sub.2 is (i) phenyl optionally
substituted with one to two substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-2alkoxy, C.sub.1-4alkylthio,
one to two fluoro substituents, chloro, and hydroxy; in addition,
phenyl is optionally substituted with a single amino,
fluoromethoxy, difluoromethoxy, trifluoromethoxy, formamidino,
aminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyloxy, 2,2,2-trifluoroethoxy, or
C.sub.1-4alkoxy(C.sub.1-4)alkyl substituent; (ii) or heteroaryl
selected from the group consisting of benzothiazolyl and
benzooxazolyl; wherein heteroaryl is optionally independently
substituted with one to two C.sub.1-4alkyl substituents; A-L- is
selected from the group consisting of a.sup.1-L.sub.1-;
a.sub.2-L.sub.2-; a.sub.3-L.sub.3-; a.sub.4-L.sub.4-; and
a.sub.5-L.sub.5-; wherein L.sub.1 is absent or C.sub.1-2alkyl;
a.sub.1 is bound through a carbon atom to L.sub.1 and is i)
pyrrolidinyl optionally substituted at carbon with hydroxy or one
to two fluoro substituents; ii) piperidin-3-yl or iii) azetidinyl;
provided that when L.sub.1 is absent, a.sub.1 is attached to
N(R.sub.a) via a carbon atom other than that which is alpha to a
nitrogen atom of a.sub.1; and provided that when a.sub.1 is
substituted with a substituent containing a nitrogen radical as a
point of attachment to a.sub.1, the substitution is at a carbon
atom other than that alpha to a nitrogen atom of a.sub.1; L.sub.2
is methylene; a.sub.2 is bound through a carbon atom to L.sub.2 and
a.sub.2 is morpholinyl; L.sub.3 is methylene; a.sub.3 is imidazolyl
optionally independently substituted with one to two C.sub.1-4alkyl
substituents; L.sub.4 is (C.sub.2-3)alkyl; a.sub.4 is amino,
provided that a.sub.4 is attached at a carbon atom other than that
alpha to N(R.sub.a); L.sub.5 is absent or C.sub.1-2alkyl; a.sub.5
is C.sub.4-6cycloalkyl substituted with R.sub.B; wherein R.sub.B is
amino; provided that when R.sub.B contains a nitrogen radical as
the point of attachment to C.sub.5-6cycloalkyl, the attachment is
at a carbon atom other than that alpha to N(R.sub.a); or, A-L- is
taken with R.sub.a and the nitrogen atom to which they are both
attached to form a nitrogen-bound heterocyclyl selected from the
group consisting of i) pyrrolidin-1-yl optionally substituted with
amino or aminomethyl; ii) piperazin-1-yl optionally independently
substituted at carbon with one to two C.sub.1-4alkyl substituents;
iii) piperidin-1-yl optionally substituted with amino; iv)
azetidin-1-yl optionally substituted with 3-aminomethyl; and v)
[1,4]diazepan-1-yl; provided that the position of a substituent
containing an nitrogen radical as a point of attachment to the
nitrogen-bound heterocyclyl is at a carbon atom other than that
alpha to the heterocyclyl nitrogen atom; R.sub.a is hydrogen;
provided that a compound of Formula (I) is other than a compound
selected from the group consisting of a compound wherein R.sub.1 is
4-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is (S)-morpholin-3-yl, L.sub.2 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; and a compound wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.B is 2-amino,
R.sub.a is H, and X is O; and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
20. A compound of Formula (I) ##STR00053## wherein R.sub.1 is
selected from the group consisting of i) phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-2alkoxy,
hydroxy, and fluoro; in addition, phenyl is optionally substituted
with a single amino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, hydroxy(C.sub.1-4)alkyl,
aminocarbonyl, C.sub.1-4alkylcarbonylamino, cyano,
trifluoromethoxy, C.sub.1-4alkylsulfonyl, nitro, or trifluoromethyl
substituent; ii) pyrimidinyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkoxy and C.sub.1-4alkylthio; in addition, pyrimidinyl is
optionally substituted with a single cyano, morpholin-4-yl,
di(C.sub.1-4alkyl)amino, or piperazin-1-yl optionally substituted
with 4-C.sub.1-4alkyl substituent; iii) pyridinyl optionally
substituted with one to two substituents independently selected
form the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and cyano; in
addition, pyridinyl is optionally substituted with hydroxymethyl or
amino; and iv) a G-substituent selected from the group consisting
of pyrazolyl, thienyl, benzothiazolyl, quinolinyl, indolyl,
thiazolyl, furanyl, dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, and
benzo[1,2,5]oxadiazolyl; wherein G is optionally substituted with
one C.sub.1-4alkyl substituent; R.sub.2 is (i) phenyl optionally
substituted with one to two substituents selected from the group
consisting of C.sub.1-2alkyl, C.sub.1-2alkoxy, C.sub.1-2alkylthio,
fluoro, 3-chloro, 4-chloro, and hydroxy; or phenyl is optionally
substituted with one substituent selected from the group consisting
of amino, difluoromethoxy, trifluoromethoxy, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkylcarbonyloxy, and
2,2,2-trifluoroethoxy; or, (ii) heteroaryl selected from the group
consisting of benzothiazolyl and benzooxazolyl; wherein heteroaryl
of R.sub.2 is optionally independently substituted with one to two
C.sub.1-2alkyl substituents; A-L- is selected from the group
consisting of a.sup.1-L.sub.1-; a.sub.2-L.sub.2-; a.sub.3-L.sub.3-,
a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein L.sub.1 is absent
or C.sub.1-2alkyl; a.sub.1 is bound through a carbon atom to
L.sub.1 and is i) pyrrolidinyl optionally substituted at carbon
with hydroxy or one to two fluoro substituents; or ii)
piperidin-3-yl provided that when L.sub.1 is absent, a.sub.1 is
attached to N(R.sub.a) via a carbon atom other than that which is
alpha to a nitrogen atom of a.sub.1; and provided that when a.sub.1
is substituted with a substituent containing an oxygen or nitrogen
radical as a point of attachment to a.sub.1, the substitution is at
a carbon atom other than that alpha to a nitrogen atom of a.sub.1;
L.sub.2 is methylene; a.sub.2 is bound through a carbon atom to
L.sub.2 and a.sub.2 is morpholinyl; L.sub.3 is methylene; a.sub.3
is imidazolyl optionally substituted with one to two methyl
substituents; L.sub.4 is (C.sub.2-3)alkyl; a.sub.4 is amino,
provided that a.sub.4 is attached at a carbon atom other than that
alpha to N(R.sub.a); L.sub.5 is absent or C.sub.1-2alkyl; a.sub.5
is C.sub.4-6cycloalkyl substituted with R.sub.B; wherein R.sub.B is
amino; provided that when R.sub.B contains a nitrogen radical as
the point of attachment to C.sub.5-6cycloalkyl, the attachment is
at a carbon atom other than that alpha to N(R.sub.a); or, A-L- is
taken with R.sub.a and the nitrogen atom to which they are both
attached to form a nitrogen-bound heterocyclyl selected from the
group consisting of i) pyrrolidin-1-yl optionally substituted with
amino; ii) piperazin-1-yl optionally independently substituted at
carbon with one to two C.sub.1-4alkyl substituents; iii)
piperidin-1-yl optionally substituted with amino; and iv)
[1,4]diazepan-1-yl; provided that the position of a substituent
containing an nitrogen radical as a point of attachment to the
nitrogen-bound heterocyclyl is at a carbon atom other than that
alpha to the heterocyclyl nitrogen atom; R.sub.a is hydrogen;
provided that a compound of Formula (I) is other than a compound
selected from the group consisting of a compound wherein R.sub.1 is
4-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is (S)-morpholin-3-yl, L.sub.2 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; and a compound wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.B is 2-amino,
R.sub.a is H, and X is O; and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
21. A compound of Formula (I) ##STR00054## wherein R.sub.1 is
selected from the group consisting of i) phenyl optionally
substituted with a substituent selected from the group consisting
of C.sub.1-2alkyl, C.sub.1-2alkoxy, hydroxy, and fluoro; or, phenyl
is optionally substituted with one substituent selected from the
group consisting of amino, di(C.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminocarbonyl, hydroxymethyl, aminocarbonyl,
C.sub.1-4alkylcarbonylamino, cyano, trifluoromethoxy,
C.sub.1-2alkylsulfonyl, nitro, and trifluoromethyl; ii) pyrimidinyl
optionally substituted with one to two substituents selected from
the group consisting of C.sub.1-4alkoxy and C.sub.1-4alkylthio; or,
pyrimidinyl is optionally substituted with one substituent selected
from the group consisting of morpholin-4-yl,
di(C.sub.1-4alkyl)amino, and piperazin-1-yl optionally substituted
with 4-methyl; iii) pyridinyl optionally substituted with one to
two substituents selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy,
fluoro, and chloro; or, pyridinyl optionally substituted with one
substituent selected from the group consisting of cyano,
hydroxymethyl, and amino; and iv) a G-substituent selected from the
group consisting of pyrazolyl, thienyl, benzothiazolyl, quinolinyl,
indolyl, thiazolyl, furanyl, dihydrobenzofuranyl,
benzo[1,3]dioxol-5-yl, and benzo[1,2,5]oxadiazolyl; wherein G is
optionally substituted with one C.sub.1-4alkyl substituent; R.sub.2
is (i) phenyl optionally substituted with one to two substituents
selected from the group consisting of C.sub.1-2alkyl,
C.sub.1-2alkoxy, C.sub.1-2alkylthio, one to two fluoro
substituents, 3-chloro, 4-chloro, and hydroxy; or, phenyl is
optionally substituted with one substituent selected from the group
consisting of amino, difluoromethoxy, trifluoromethoxy,
aminocarbonyl, C.sub.1-4alkylcarbonylamino,
C.sub.1-4alkylcarbonyloxy, and 2,2,2-trifluoroethoxy; or (ii)
heteroaryl selected from the group consisting of benzothiazolyl and
benzooxazolyl; wherein heteroaryl of R.sub.2 is optionally
independently substituted with one to two C.sub.1-2alkyl
substituents; A-L- is selected from the group consisting of
a.sup.1-L.sub.1-; a.sub.2-L.sub.2-; a.sub.3-L.sub.3-,
a.sub.4-L.sub.4-; and a.sub.5-L.sub.5-; wherein L.sub.1 is absent
or C.sub.1-2alkyl; a.sub.1 is bound through a carbon atom to
L.sub.1 and is i) pyrrolidinyl optionally substituted at carbon
with hydroxy or one to two fluoro substituents; or ii)
piperidin-3-yl provided that when L.sub.1 is absent, a.sub.1 is
attached to N(R.sub.a) via a carbon atom other than that which is
alpha to a nitrogen atom of a.sub.1; and provided that when a.sub.1
is substituted with a substituent containing an oxygen or nitrogen
radical as a point of attachment to a.sub.1, the substitution is at
a carbon atom other than that alpha to a nitrogen atom of a.sub.1;
L.sub.2 is methylene; a.sub.2 is bound through a carbon atom to
L.sub.2 and a.sub.2 is morpholinyl; L.sub.3 is methylene; a.sub.3
is imidazolyl optionally substituted with one to two methyl
substituents; L.sub.4 is (C.sub.2-3)alkyl; a.sub.4 is amino,
provided that a.sub.4 is attached at a carbon atom other than that
alpha to N(R.sub.a); L.sub.5 is absent or C.sub.1-2alkyl; a.sub.5
is C.sub.4-6cycloalkyl substituted with R.sub.B; wherein R.sub.B is
amino; provided that when R.sub.B contains a nitrogen radical as
the point of attachment to C.sub.5-6cycloalkyl, the attachment is
at a carbon atom other than that alpha to N(R.sub.a); or, A-L- is
taken with R.sub.a and the nitrogen atom to which they are both
attached to form a nitrogen-bound heterocyclyl selected from the
group consisting of i) pyrrolidin-1-yl optionally substituted with
amino; ii) piperazin-1-yl optionally independently substituted at
carbon with one to two C.sub.1-2alkyl substituents; iii)
piperidin-1-yl optionally substituted with amino; and iv)
[1,4]diazepan-1-yl; provided that the position of a substituent
containing an nitrogen radical as a point of attachment to the
nitrogen-bound heterocyclyl is at a carbon atom other than that
alpha to the heterocyclyl nitrogen atom; R.sub.a is hydrogen;
provided that a compound of Formula (I) is other than a compound
selected from the group consisting of a compound wherein R.sub.1 is
4-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is (S)-morpholin-3-yl, L.sub.2 is methyl,
R.sub.a is H, and X is O; a compound wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-phenyl, A-L- is
a.sup.1-L.sub.1, a.sub.1 is (S)-pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is H, and X is O; and a compound wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.B is 2-amino,
R.sub.a is H, and X is O; and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof.
22. A compound of Formula (I) ##STR00055## selected from the group
consisting of: a compound of Formula (I) wherein R.sub.1 is
4-methoxy-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is 3-methoxy-phenyl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 2-methoxy-phenyl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is naphth-1-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is naphth-2-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-4-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is thien-3-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is furan-3-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-trifluoromethoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methylcarbonylamino-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl,
L.sub.1 is methyl, and R.sub.a is H; (2S) a compound of Formula (I)
wherein R.sub.1 is 3-hydroxy-phenyl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is quinolin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
quinolin-8-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2-methyl-quinolin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
4-biphenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is quinolin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is dibenzothiophen-2-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 6-methoxy-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl, R.sub.2
is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 2-fluoro-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 6-fluoro-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 2-methoxy-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is
2,6-dihydroxy-pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-cyano-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-nitro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-aminocarbonyl-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-N,N-diethylaminocarbonyl-phenyl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.i is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 3-methanesulfonyl-phenyl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 4-hydroxy-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
indol-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
4H-[1,2,4]oxadiazol-5-on-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-fluoro-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
6-methoxy-pyridin-3-yl, R.sub.2 is 4-fluoro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-methoxy-pyridin-3-yl, R.sub.2 is 2-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 2-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
3-diethylamino-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-methylcarbonylamino-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
4-methylcarbonylamino-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-methoxy-pyridin-3-yl, R.sub.2 is 4-amino-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-amino-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-amino-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
benzothiazol-2-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
thiazol-2-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
benzothiophen-2-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-trifluoromethyl-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-trifluoromethoxy-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2-methylthio-pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2-methoxy-pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3,5-difluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3,4-difluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3,5-difluoro-4-hydroxymethyl-phenyl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 2,4-dimethoxy-pyrimidin-5-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 6-methoxy-pyridin-3-yl,
R.sub.2 is 4-hydroxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 2-ethoxy-pyrimidin-5-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrazol-5-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is
3,5-dimethyl-isoxazol-4-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2,3-dihydrobenzofuran5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-fluoro-4-methoxy-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrazol-4-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
2-methylthio-pyrimidin-4-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
1-methyl-pyrazol-4-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-fluoro-5-methoxy-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-fluoro-5-methyl-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-amino-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-6-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-hydroxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-hydroxy-pyridin-3-yl, R.sub.2 is 4-hydroxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
quinoxalin-6-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
1H-pyrrolo[2,3-ID]pyridin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
benzo[1,2,5]oxadiazol-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4,4-difluoro-pyrrolidin-2-yl, L.sub.1
is methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is pyrimidin-5-yl, R.sub.2
is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
4-fluoro-pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S,4R) a compound of Formula (I) wherein R.sub.1 is
2-amino-pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2-dimethylamino-pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2-(morpholin-4-yl)-pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 2-(4-methyl-pyrazin-1-yl)-pyrimidin-5-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is benzothiazol-6-yl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl, R.sub.2
is 2-methyl-benzoxazol-6-yl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 2-methyl-benzoxazol-6-yl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
4-fluoro-pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S,4S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-methyl-benzothiazol-6-yl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3,5-dimethyl-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
benzo[1,3]dioxol-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3,5-dichloro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 3,5-difluoro-4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is pyrimidin-5-yl, R.sub.2 is
3,5-difluoro-4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 3-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl, R.sub.2
is 3-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
3-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 2,3-difluoro-4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 2,3-difluoro-4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is pyrimidin-5-yl, R.sub.2 is
2,3-difluoro-4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-ethoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl, R.sub.2
is 4-ethoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 4-ethoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is
5-methylthio-pyridin-3-y, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methanesulfonyl-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent, and
R.sub.a is H; (racemic) a compound of Formula (I) wherein R.sub.1
is 5-cyano-pyridin-3-yl, R.sub.2 is 4-difluoromethoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-difluoromethoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-difluoromethoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-n-propyloxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-n-propyloxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-n-propyloxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
indol-4-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is indol-6-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is indol-7-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrazin-2-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 2-cyano-pyrimidin-5-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-(2,2,2-trifluoro-ethoxyl)-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is
4-(2,2,2-trifluoro-ethoxy)-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1
is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-n-butoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl, R.sub.2
is 4-n-butoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 4-n-butoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 4-chloro-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-chloro-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl, R.sub.2
is 4-chloro-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 3-fluoro-4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 3-fluoro-4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 3-fluoro-4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is pyridin-3-yl, R.sub.2 is 3-cyano-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-cyano-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-cyclopropylcarbonylamino-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-isopropyloxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-isopropyloxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-isopropyloxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
3-cyano-5-fluoro-phenyl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-hydroxymethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-hydroxymethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-hydroxymethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-fluoro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methyl-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methylthio-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methylthio-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methylthio-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxymethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxymethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxymethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-hydroxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-diethylaminocarbonyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-pyrrolidin-1-ylcarbonyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-carboxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-piperidin-1-ylcarbonyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-(morpholin-4-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S)
a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2
is 4-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-carboxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 3-carboxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-carboxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is
3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 3-diethylaminocarbonyl-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
3-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is
3-(piperidin-1-ylcarbonyl)-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1
is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 3-(morpholin-4-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is
3-(4-methyl-piperazin-1-ylcarbonyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-diethylaminocarbonyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is
4-(pyrrolidin-1-ylcarbonyl)-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-benzyloxycarbonylamino-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-ethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-chloro-pyridin-3-yl, R.sub.2 is 4-ethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-aminocarbonyl-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
R.sub.a is methylcarbonyl; (2S) a compound of Formula (I) wherein
R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is 4-ethyl-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 3-fluoro-4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-ethyl-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 3-fluoro-4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-chloro-pyridin-3-yl, R.sub.2 is 3-fluoro-4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-fluoro-4-methyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-benzyloxycarbonylamino-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2,3-difluoro-4-methyl-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-chloro-pyridin-3-yl, R.sub.2 is 2,3-difluoro-4-methyl-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
2,3-difluoro-4-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
2,3-difluoro-4-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
4-fluoro-pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S,4R) a compound of Formula (I) wherein R.sub.1 is
5-chloro-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is 4-ethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
4-benzyloxycarbonylamino-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1
is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 4-amino-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
piperidin-3-yl, L.sub.1 is absent, and R.sub.a is H; (3S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 3-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-chloro-pyridin-3-yl,
R.sub.2 is 3-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-fluoro-pyridin-3-yl,
R.sub.2 is 3-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
3-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 3-methyl-4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 3-methyl-4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-fluoromethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent, and
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-4-yl, L.sub.1 is absent, and
R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-(pyridin-3-ylmethyl)-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-chloro-pyridin-3-yl, R.sub.2 is 3-methyl-4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 3-methyl-4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-methylcarbonylamino-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 5-fluoro-pyridin-3-yl, R.sub.2 is
4-methanesulfonylamino-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methanesulfonylamino-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
azetidin-3-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a compound
of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-formamido-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-fluoromethyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 3-methyl-4-fluoro-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 3-methyl-4-fluoro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-trifluoromethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-trifluoromethyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-methanesulfonyl-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-formamido-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-3-yl, L.sub.1 is absent, and R.sub.a is H;
(3R) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
piperidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
azetidin-3-yl, L.sub.1 is absent, and R.sub.a is H; a compound of
Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-chloro-pyridin-3-yl,
R.sub.2 is 2-methyl-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 3-methylcarbonyloxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-chloro-pyridin-3-yl, R.sub.2 is 2-chloro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 2-chloro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 3-hydroxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methoxy-pyridin-3-yl, R.sub.2 is 2-chloro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methylthio-pyridin-3-y, R.sub.2 is 2-chloro-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methylthio-pyridin-3-y, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is 5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a
.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent, and
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-3-yl, L.sub.1 is absent, and R.sub.a is H;
(3S) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4R) a compound of Formula (I) wherein
R.sub.1 is 5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S,4S) a compound of Formula (I) wherein
R.sub.1 is 5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is 4-fluoro-pyrrolidin-2-yl,
L.sub.1 is methyl, and R.sub.a is H; (2S,4S) a compound of Formula
(I) wherein R.sub.1 is 5-methylthio-pyridin-3-y, R.sub.2 is
4-(2-methoxy-ethoxy)-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-methyl-pyridin-3-yl,
R.sub.2 is 4-(2-methoxy-ethoxy)-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-methoxy-pyridin-3-yl, R.sub.2 is 4-(2-methoxy-ethoxy)-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is pyridin-3-yl, R.sub.2 is 4-(2-methoxy-ethoxy)-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is
methyl, and R.sub.a is H; (2S) a compound of Formula (I) wherein
R.sub.1 is 5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is
absent, and R.sub.a is H; (3S) a compound of Formula (I) wherein
R.sub.1 is 5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is
absent, and R.sub.a is H; (3R) a compound of Formula (I) wherein
R.sub.1 is 5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl,
A-L- is a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is
absent, R.sub.a is H; (3S) a compound of Formula (I) wherein
R.sub.1 is 5-methylthio-pyridin-3-y, R.sub.2 is
3-methylcarbonyloxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-methoxy-pyridin-3-yl,
R.sub.2 is 3-hydroxy-phenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-methoxy-pyridin-3-yl,
R.sub.2 is 3-methylcarbonyloxy-phenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 3-methylcarbonyloxy-phenyl, A-L-
is a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl,
and R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methylthio-pyridin-3-y, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent, and
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-methylthiopyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent,
R.sub.a is H; (3R) a compound of Formula (I) wherein R.sub.1 is
5-methylthiopyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-3-yl, L.sub.1 is absent,
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-methoxypyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-3-yl, L.sub.1 is absent,
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-3-yl, L.sub.1 is absent,
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent,
R.sub.a is H; (3R) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is piperidin-3-yl, L.sub.1 is absent,
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-fluoromethoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is piperidin-3-yl, L.sub.1 is absent, R.sub.a is H; (3R) a
compound of Formula (I) wherein R.sub.1 is
6-fluoro-5-methylpyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
2,5-dimethyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6'-chloro-3,5'-dimethyl-[2,3']bipyridinyl-5-yl, R.sub.2 is
4-methoxyphenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is
6-chloro-4-methylpyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
6-chloro-5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is piperidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(2R) a compound of Formula (I) wherein R.sub.1 is
2-chloro-5-methylpyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-hydroxymethyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is pyrrolidin-2-yl, L.sub.1 is methyl, and
R.sub.a is H; (2S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is 4-hydroxy-pyrrolidin-2-yl, L.sub.1 is methyl, R.sub.a is
H; (trans 2S,4R) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.1-L.sub.1,
a.sub.1 is -hydroxypyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a
is H; (cis 2R,4R) a compound of Formula (I) wherein R.sub.1 is
5-methoxypyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.1-L.sub.1, a.sub.1 is 4-hydroxy-pyrrolidin-2-yl, L.sub.1 is
methyl, R.sub.a is H, (trans 2S,4R) a compound of Formula (I)
wherein R.sub.1 is 5-methoxypyridin-3-yl, R.sub.2 is
4-methoxyphenyl, A-L- is a.sub.1-L.sub.1, a.sub.1 is
4-hydroxy-pyrrolidin-2-yl, L.sub.1 is methyl, and R.sub.a is H;
(cis 2R,4R) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-2-yl, L.sub.2 is methyl, and
R.sub.a is H; (racemic) a compound of Formula (I) wherein R.sub.1
is 5-fluoro-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-2-yl, L.sub.2 is methyl, and
R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-2-yl, L.sub.2 is methyl, and
R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-3-yl, L.sub.2 is methyl, and
R.sub.a is H; (racemic) a compound of Formula (I) wherein R.sub.1
is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-3-yl, L.sub.2 is methyl, and
R.sub.a is H; (racemic) a compound of Formula (I) wherein R.sub.1
is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-3-yl, L.sub.2 is methyl, and
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
5-fluoro-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.2-L.sub.2, a.sub.2 is morpholin-3-yl, L.sub.2 is methyl, and
R.sub.a is H; (3S) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.2-L.sub.2,
a.sub.2 is morpholin-3-yl, L.sub.2 is methyl, and R.sub.a is H;
(3S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.3-L.sub.3, a.sub.3 is imidazol-2-yl, L.sub.3 is methyl, and
R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.3-L.sub.3, a.sub.3 is 3H-imidazol-4-yl, L.sub.3 is methyl,
and R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.3-L.sub.3, a.sub.3 is 5-methyl-3H-imidazol-4-yl, L.sub.3 is
methyl, R and R.sub.a is H; a compound of Formula (I) wherein
R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.3-L.sub.3, a.sub.3 is 3-methyl-3H-imidazol-4-yl, L.sub.3
is methyl, and R.sub.a is H; a compound of Formula (I) wherein
R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.3-L.sub.3, a.sub.3 is 2-ethyl-5-methyl-3H-imidazol-4-yl,
L.sub.3 is methyl, and R.sub.a is H; a compound of Formula (I)
wherein R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.3-L.sub.3, a.sub.3 is 3H-imidazol-4-yl, L.sub.3 is methyl,
and R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
5-methylthio-pyridin-3-y, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.3-L.sub.3, a.sub.3 is 3H-imidazol-4-yl, L.sub.3 is methyl,
and R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.3-L.sub.3, a.sub.3 is 3H-imidazol-4-yl, L.sub.3 is methyl,
and R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.3-L.sub.3, a.sub.3 is 3H-imidazol-4-yl, L.sub.3 is methyl,
and R.sub.a is H; a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.4-L.sub.4, a.sub.4 is 2-amino, L.sub.4 is propyl, and R.sub.a
is H; (2S) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.4-L.sub.4, a.sub.4 is 2-amino, L.sub.4 is ethyl, and R.sub.a
is H; a compound of Formula (I) wherein R.sub.1 is pyrimidin-5-yl,
R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.4-L.sub.4, a.sub.4 is
2-amino, L.sub.4 is 4-methyl-pentyl, and R.sub.a is H; (2S) a
compound of Formula (I) wherein R.sub.1 is 5-methyl-pyridin-3-yl,
R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.4-L.sub.4, a.sub.4 is
2-amino, L.sub.4 is ethyl, and R.sub.a is H; a compound of Formula
(I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxyphenyl,
A-L- is a.sub.4-L.sub.4, a.sub.4 is 2-methylamino, L.sub.4 is
ethyl, and R.sub.a is H; a compound of Formula (I) wherein R.sub.1
is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (cis/trans mixture) a compound of Formula (I) wherein
R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is methyl, and
R.sub.a is H; (2S,1R) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is methyl, and
R.sub.a is H; (2S,1R) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclobutyl, L.sub.5 is methyl, and
R.sub.a is H; (trans) a compound of Formula (I) wherein R.sub.1 is
pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclobutyl, L.sub.5 is methyl, and
R.sub.a is H; (trans) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclobutyl, L.sub.5 is absent, and
R.sub.a is H; (cis/trans mixture) a compound of Formula (I) wherein
R.sub.1 is pyrimidin-5-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclobutyl, L.sub.5 is absent, and
R.sub.a is H; (cis/trans mixture) a compound of Formula (I) wherein
R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (cis) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, and R.sub.a is H;
(racemic, cis/trans mixture) a compound of Formula (I) wherein
R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (1RS,3SR racemic cis) a compound of Formula (I)
wherein R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L-
is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (1RS,2SR racemic single stereoisomer, unknown
cis/trans) a compound of Formula (I) wherein R.sub.1 is
5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; racemic, mixture of cis/trans) a compound of Formula
(I) wherein R.sub.1 is 5-methylthiopyridin-3-yl, R.sub.2 is
4-methoxyphenyl, A-L- is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl,
L.sub.5 is absent, and R.sub.a is H; (racemic, mixture of cis and
trans) a compound of Formula (I) wherein R.sub.1 is
5-methoxypyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (cis 1R,3S) a compound of Formula (I) wherein R.sub.1
is 5-methoxypyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, R.sub.a
is H; (cis 1S,3R) a compound of Formula (I) wherein R.sub.1 is
5-methoxypyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (trans, one enantiomer, absolute unknown) a compound
of Formula (I) wherein R.sub.1 is 5-methoxypyridin-3-yl, R.sub.2 is
4-methoxyphenyl, A-L- is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl,
L.sub.5 is absent, and R
.sub.a is H; (trans, one enantiomer, absolute unknown) a compound
of Formula (I) wherein R.sub.1 is 5-methyl-pyridin-3-yl, R.sub.2 is
4-methoxyphenyl, A-L- is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl,
L.sub.5 is absent, and R.sub.a is H; (racemic, mixture of cis and
trans) a compound of Formula (I) wherein R.sub.1 is
5-methylthiopyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (cis 1S,3R) a compound of Formula (I) wherein R.sub.1
is 5-methylthiopyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is
a.sub.5-L.sub.5, a.sub.5 is cyclohexyl, L.sub.5 is absent, and
R.sub.a is H; (trans, one enantiomer, absolute unknown) a compound
of Formula (I) wherein R.sub.1 is 5-methylthiopyridin-3-yl, R.sub.2
is 4-methoxyphenyl, A-L- is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl,
L.sub.5 is absent, and R.sub.a is H; (trans, one enantiomer,
absolute unknown) a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-cyclopropylphenyl, and A-L- and R.sub.a
are taken together with the atoms to which they are attached to
form piperazin-1-yl; a compound of Formula (I) wherein R.sub.1 is
pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.5-L.sub.5,
a.sub.5 is cyclohexyl, L.sub.5 is absent, and R.sub.a is H; (cis
1S,3R) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-methoxyphenyl, A-L- is a.sub.5-L.sub.5, a.sub.5 is
cyclohexyl, L.sub.5 is absent, and and R.sub.a is H; (cis 1R,3S) a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxyphenyl, A-L- is a.sub.5-L.sub.5, a.sub.5 is cyclohexyl,
L.sub.5 is absent, and R.sub.a is H; (trans, one enantiomer,
absolute unknown) a compound of Formula (I) wherein R.sub.1 is
phenyl, R.sub.2 is 4-methoxy-phenyl, and A-L- and R.sub.a are taken
together with the atoms to which they are attached to form
piperazin-1-yl; a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form piperazin-1-yl; a compound of Formula (I) wherein
R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and
A-L- and R.sub.a are taken together with the atoms to which they
are attached to form 3-aminopyrrolidin-1-yl; a compound of Formula
(I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl,
and A-L- and R.sub.a are taken together with the atoms to which
they are attached to form piperazin-1-yl; a compound of Formula (I)
wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, A-L- is , A-L- and R.sub.a are taken to form,
3-aminopyrrolidin-1-yl 3S a compound of Formula (I) wherein R.sub.1
is 5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 3-aminopiperidin-1-yl; (3S) a compound of Formula
(I) wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-aminopiperidin-1-yl;
(3R) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 3-aminomethylazetidin-1-yl; a compound of Formula
(I) wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form
2-aminomethylpyrrolidin-1-yl; (2R) a compound of Formula (I)
wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 4-aminopiperidin-1-yl; a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, and A-L- and R.sub.a are taken
together with the atoms to which they are attached to form
2-aminomethylpyrrolidin-1-yl; (2R) a compound of Formula (I)
wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-oxopiperazin-1-yl; a
compound of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form [1,4]diazepan-1-yl; a
compound of Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl,
R.sub.2 is 4-methoxy-phenyl, and A-L- and R.sub.a are taken
together with the atoms to which they are attached to form
2-oxopiperazin-1-yl; a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 3,6-diaza-bicyclo[3.1.1]hept-3-ylamino; a compound
of Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, v 3-aminopyrrolidin-1-yl; (3R) a compound of
Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-amino-azetidin-1-yl; a
compound of Formula (I) wherein R.sub.1 is
5-methylthio-pyridin-3-y, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form piperazin-1-yl; a compound of Formula (I) wherein
R.sub.1 is 5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and
A-L- and R.sub.a are taken together with the atoms to which they
are attached to form piperazin-1-yl; a compound of Formula (I)
wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-methyl-piperazin-1-yl;
(racemic) a compound of Formula (I) wherein R.sub.1 is
5-cyano-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 2-methyl-piperazin-1-yl; (2R) a compound of
Formula (I) wherein R.sub.1 is 5-cyano-pyridin-3-yl, R.sub.2 is
4-methoxy-phenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 2-methyl-piperazin-1-yl;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-methoxy-pyridin-3-yl, R.sub.2 is 4-methoxy-phenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form [1,4]-diazepan-1-yl; a compound of Formula (I)
wherein R.sub.1 is 5-methylthiopyridin-3-yl, R.sub.2 is
4-methoxyphenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form [1,4]-diazepan-1-yl; a
compound of Formula (I) wherein R.sub.1 is
5-methylthiopyridin-3-yl, R.sub.2 is 4-methoxyphenyl and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 3-amino-pyrrolidin-1-yl; (3R) a compound of
Formula (I) wherein R.sub.1 is 5-methoxypyridin-3-yl, R.sub.2 is
4-methoxyphenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-amino-pyrrolidin-1-yl;
(3R) a compound of Formula (I) wherein R.sub.1 is
5-methylthiopyridin-3-yl, R.sub.2 is 4-methoxyphenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 3,3-dimethyl-piperazin-1-yl; a compound of Formula
(I) wherein R.sub.1 is 5-methyl-pyridin-3-yl, R.sub.2 is
4-methoxyphenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form piperazin-1-yl; a compound
of Formula (I) wherein R.sub.1 is 5-methyl-pyridin-3-yl, R.sub.2 is
4-methoxyphenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-amino-pyrrolidin-1-yl;
(3R) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-methoxyphenyl, and A-L- and R.sub.a are taken together
with the atoms to which they are attached to form
4-methyl-piperazin-1-yl; a compound of Formula (I) wherein R.sub.1
is pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, and A-L- and R.sub.a
are taken together with the atoms to which they are attached to
form 2-methyl-piperazin-1-yl; (2S) a compound of Formula (I)
wherein R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, and
A-L- and R.sub.a are taken together with the atoms to which they
are attached to form 3,3-dimethyl-piperazin-1-yl; a compound of
Formula (I) wherein R.sub.1 is pyridin-3-yl, R.sub.2 is
4-methoxyphenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 3-methyl-piperazin-1-yl;
(3S) a compound of Formula (I) wherein R.sub.1 is pyridin-3-yl,
R.sub.2 is 4-methoxyphenyl, and A-L- and R.sub.a are taken together
with the atoms to which they are attached to form
3-methyl-piperazin-1-yl; (3R) a compound of Formula (I) wherein
R.sub.1 is 5-methyl-pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, and
A-L- and R.sub.a are taken together with the atoms to which they
are attached to form [1,4]diazepan-1-yl; a compound of Formula (I)
wherein R.sub.1 is pyridin-3-yl, R.sub.2 is 4-methoxyphenyl, and
A-L- and R.sub.a are taken together with the atoms to which they
are attached to form 3,5-dimethyl-piperazin-1-yl; (cis) a compound
of Formula (I) wherein R.sub.1 is 5-methoxypyridin-3-yl, R.sub.2 is
4-methoxyphenyl, and A-L- and R.sub.a are taken together with the
atoms to which they are attached to form 2-ethyl-piperazin-1-yl;
(2S) a compound of Formula (I) wherein R.sub.1 is
5-methoxypyridin-3-yl, R.sub.2 is 4-methoxyphenyl, and A-L- and
R.sub.a are taken together with the atoms to which they are
attached to form 3-ethyl-piperazin-1-yl; (3R); and pharmaceutically
acceptable salts thereof.
23. A pharmaceutical composition comprising a compound of claim 1
and at least one of a pharmaceutically acceptable carrier, a
pharmaceutically acceptable excipient, and a pharmaceutically
acceptable diluent.
24. The pharmaceutical composition of claim 23, wherein the
composition is a solid, oral dosage form.
25. The pharmaceutical composition of claim 23, wherein the
composition is a syrup, an elixir, or a suspension.
26. A method for treating mild to severe pain in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of a compound of claim 1.
27. The method of claim 26 wherein the mild to severe pain is due
to a disease or condition selected from the group consisting of
osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine,
headache, toothache, burn, sunburn, snake bite, spider bite, insect
sting, neurogenic bladder, benign prostatic hypertrophy,
interstitial cystitis, rhinitis, contact
dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,
enteritis, cellulites, causalgia, sciatic neuritis, mandibular
joint neuralgia, peripheral neuritis, polyneuritis, stump pain,
phantom limb pain, post-operative ileus, cholecystitis,
postmastectomy pain syndrome, oral neuropathic pain, Charcot's
pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, cluster headache,
migraine headache, peripheral neuropathy, bilateral peripheral
neuropathy, diabetic neuropathy, optic neuritis, postfebrile
neuritis, migrating neuritis, segmental neuritis, Gombault's
neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,
geniculate neuralgia, glossopharyngial neuralgia, migrainous
neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary
neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital
neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine
neuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory
bowel disease, irritable bowel syndrome, sinus headache, tension
headache, labor, childbirth, menstrual cramps, and cancer.
28. The method of claim 26 wherein the pain is selected from the
group consisting of inflammatory pain, centrally mediated pain,
peripherally mediated pain, visceral pain, structural related pain,
cancer pain, soft tissue injury related pain, progressive disease
related pain, neuropathic pain and acute pain from acute injury,
acute pain from trauma, acute pain from surgery, chronic pain from
headache, chronic pain from neuropathic conditions, chronic pain
from post-stroke conditions and chronic pain from migraine.
29. A method for treating or preventing a disease or condition
selected from the group consisting of depression, Parkinson's
disease, drug abuse, alcohol abuse, gastritis, urinary
incontinence, premature ejaculation, diarrhea, cardiovascular
disease, and respiratory diseases, said method comprising the step
of administering to a mammal in need of such treatment a
therapeutically effective amount of a compound, or salt of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 61/256,412, filed on Oct. 30, 2009, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to novel opioid receptor
modulators of Formula (I). The invention further relates to methods
for preparing such compounds, pharmaceutical compositions
containing them, and their use in the treatment of opioid modulated
disorders.
BACKGROUND OF THE INVENTION
[0003] The term "opiate" has been used to designate
pharmacologically active alkaloids derived from opium, e.g.,
morphine, codeine, and many semi-synthetic congeners of morphine.
After the isolation of peptide compounds with morphine-like
actions, the term opioid was introduced to refer generically to all
drugs with morphine-like actions. Included among opioids are
various peptides that exhibit morphine-like activity, such as
endorphins, enkephalins and dynorphins. However, some sources use
the term "opiate" in a generic sense, and in such contexts, opiate
and opioid are interchangeable. Additionally, the term opioid has
been used to refer to antagonists of morphine-like drugs as well as
to characterize receptors or binding sites that combine with such
agents.
[0004] Opioids are generally employed as analgesics, but they may
have many other pharmacological effects as well. Morphine and
related opioids produce certain of their major effects on the
central nervous and digestive systems. The effects are diverse,
including analgesia, drowsiness, mood changes, respiratory
depression, dizziness, mental clouding, dysphoria, pruritus,
increased pressure in the biliary tract, decreased gastrointestinal
motility, nausea, vomiting, and alterations of the endocrine and
autonomic nervous systems.
[0005] When therapeutic doses of morphine are given to patients
with pain, they report that the pain is less intense, less
discomforting, or entirely gone. In addition to experiencing relief
of distress, some patients experience euphoria. However, when
morphine in a selected pain-relieving dose is given to a pain-free
individual, the experience is not always pleasant; nausea is
common, and vomiting may also occur. Drowsiness, inability to
concentrate, difficulty in mentation, apathy, lessened physical
activity, reduced visual acuity, and lethargy may ensue.
[0006] Two distinct classes of opioid molecules can bind opioid
receptors: the opioid peptides (e.g., the enkephalins, dynorphins,
and endorphins) and the alkaloid opiates (e.g., morphine,
etorphine, diprenorphine and naloxone). Subsequent to the initial
demonstration of opiate binding sites (Pert, C. B. and Snyder, S.
H., Science (1973) 179:1011-1014), the differential pharmacological
and physiological effects of both opioid peptide analogues and
alkaloid opiates served to delineate multiple opioid receptors.
Accordingly, three molecularly and pharmacologically distinct
opioid receptor types have been described: delta, kappa and mu.
Furthermore, each type is believed to have sub-types (Wollemann,
M., J Neurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature
(1977) 267:495-499).
[0007] All three of these opioid receptor types appear to share the
same functional mechanisms at a cellular level. For example, the
opioid receptors cause inhibition of adenylate cyclase, and
inhibition of neurotransmitter release via both potassium channel
activation and inhibition of Ca.sup.2+ channels (Evans, C. J., In:
Biological Basis of Substance Abuse, S. G. Korenman & J. D.
Barchas, eds., Oxford University Press (in press); North, A. R., et
al., Proc Natl Acad Sci USA (1990) 87:7025-29; Gross, R. A., et
al., Proc Natl Acad Sci USA (1990) 87:7025-29; Sharma, S. K., et
al., Proc Natl Acad Sci USA (1975) 72:3092-96). Although the
functional mechanisms are the same, the behavioral manifestations
of receptor-selective drugs differ greatly (Gilbert, P. E. &
Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82). Such
differences may be attributable in part to the anatomical location
of the different receptors.
[0008] Delta receptors have a more discrete distribution within the
mammalian CNS than either mu or kappa receptors, with high
concentrations in the amygdaloid complex, striatum, substantia
nigra, olfactory bulb, olfactory tubercles, hippocampal formation,
and the cerebral cortex (Mansour, A., et al., Trends in Neurosci
(1988) 11:308-14). The rat cerebellum is remarkably devoid of
opioid receptors including delta opioid receptors.
[0009] There is a continuing need for new delta opioid receptor
modulators as analgesics. There is a further need for delta opioid
receptor selective agonists as analgesics having reduced side
effects. There is also a need for delta opioid receptor antagonists
as immunosuppressants, antiinflammatory agents, agents for the
treatment of neurological and psychiatric conditions, agents for
the treatment of urological and reproductive conditions,
medicaments for drug and alcohol abuse, agents for treating
gastritis and diarrhea, cardiovascular agents and agents for the
treatment of respiratory diseases, having reduced side effects.
[0010] There is a continuing need for new opioid receptor
modulators as analgesics. There is a further need for delta and mu
opioid receptor agonists as analgesics having reduced side effects.
There is a further need for mu opioid receptor agonists as
analgesics having reduced side effects for the treatment of pain,
immune function, esophageal reflux, and cough. There is also a need
for delta opioid receptor agonists as analgesic agents, agents for
the treatment of respiratory diseases, cardiovascular agents,
agents for treating urological dysfunction, and agents for the
treatment of neurological and psychiatric conditions. There is
further need for dual delta opioid receptor/mu opioid receptor
agonists.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to a compound of Formula
I
##STR00002##
wherein [0012] R.sub.1 is selected from the group consisting of
[0013] i) phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy,
di(C.sub.1-4alkyl)aminocarbonyl, chloro, and fluoro; such that only
one di(C.sub.1-4alkyl)aminocarbonyl is present; [0014] ii)
naphthyl; [0015] iii) pyridinyl optionally substituted with one
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, hydroxy, fluoro, chloro, and
cyano; [0016] iv) pyrimidin-5-yl; [0017] v) furanyl; [0018] vi)
thienyl; [0019] vii) 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; and
[0020] viii) di(C.sub.1-2alkyl)aminocarbonyl; [0021] with the
proviso that when R.sub.1 is
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, Y is a bond; [0022] Y is
ethyl, vinyl, or a bond; [0023] or, Y is O when R.sub.1 is an
optionally substituted phenyl; [0024] R.sub.2 is phenyl optionally
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
fluoro, chloro, cyano, trifluoromethoxy, and hydroxy; [0025] or,
R.sub.2 is phenyl substituted with one aminocarbonyl,
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkoxycarbonyl, or
carboxy substituent; [0026] R.sub.3 is selected from the group
consisting of [0027] i) 3-amino-cyclohexyl; [0028] ii)
4-amino-cyclohexyl; [0029] iii) piperidin-3-yl; [0030] iv)
piperidin-4-yl; [0031] v) pyrrolidin-2-ylmethyl wherein
pyrrolidin-2-yl is optionally substituted at the 3- or 4-position
with one to two fluoro substituents; [0032] vi)
azetidin-3-ylmethyl; [0033] vii) 2-(N-methylamino)ethyl; [0034]
viii) 3-hydroxy-2-amino-propyl; [0035] ix) piperidin-3-ylmethyl;
[0036] x) 1-azabicyclo[2.2.2]octan-3-yl; and [0037] xi)
8-azabicyclo[3.2.1]octan-3-yl;
[0038] or, R.sub.3 is taken with R.sub.a and the nitrogen atom to
which they are both attached to form piperazinyl optionally
substituted with 4-C.sub.1-4alkyl; [0039] R.sub.a is hydrogen,
2-(N-methylamino)ethyl, or C.sub.1-2alkyl optionally substituted
with azetidin-3-yl; and enantiomers, diastereomers, solvates, and
pharmaceutically acceptable salts thereof.
[0040] The present invention is also directed to a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
compound of Formula (I) or a pharmaceutically acceptable salt form
thereof.
[0041] Also provided are processes for making a pharmaceutical
composition comprising mixing a compound of Formula (I) and a
pharmaceutically acceptable carrier.
[0042] The present invention is further directed to methods for
treating or ameliorating an opioid receptor-modulated disorder. In
particular, the methods of the present invention are directed to
treating or ameliorating an opioid receptor-modulated disorder
including, but not limited to, inflammatory pain, centrally
mediated pain, peripherally mediated pain, visceral pain,
structural related pain, cancer/pain, soft tissue injury related
pain, progressive disease related pain, neuropathic pain and acute
pain from acute injury, acute pain from trauma, acute pain from
surgery, chronic pain from headache, chronic pain from neuropathic
conditions, chronic pain from post-stroke conditions and chronic
pain from migraine.
[0043] The present invention also provides methods for producing
the instant compounds and pharmaceutical compositions and
medicaments thereof.
[0044] As used herein, the following terms are intended to have the
following meanings:
[0045] "C.sub.a-b" (where a and b are integers) refers to a radical
containing from a to b carbon atoms inclusive. For example,
C.sub.1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
[0046] With reference to substituents, the term "independently"
means that when more than one of such substituent is possible, such
substituents may be the same or different from each other.
Therefore, designated numbers of carbon atoms (e.g. C.sub.1-8)
shall refer independently to the number of carbon atoms in an alkyl
or cycloalkyl moiety or to the alkyl portion of a larger
substituent in which alkyl appears as its prefix root.
[0047] As used herein, unless otherwise noted, "alkyl" whether used
alone or as part of a substituent group refers to straight and
branched carbon chains having 1 to 8 carbon atoms or any number
within this range. The term "alkoxy" refers to an --Oalkyl
substituent group, wherein alkyl is as defined supra. Similarly,
the terms "alkenyl" and "alkynyl" refer to straight and branched
carbon chains having 2 to 8 carbon atoms or any number within this
range, wherein an alkenyl chain has at least one double bond in the
chain and an alkynyl chain has at least one triple bond in the
chain. An alkyl and alkoxy chain may be substituted on a carbon
atom. In substituent groups with multiple alkyl groups such as
(C.sub.1-6alkyl).sub.2amino- the C.sub.1-6alkyl groups of the
dialkylamino may be the same or different.
[0048] "Halogenated alkyl" refers to a saturated branched or
straight chain alkyl radical derived by removal of 1 hydrogen atom
from the parent alkane; the parent alkyl chain contains from 1 to 8
carbon atoms with 1 or more hydrogen atoms replaced with halogen
atoms up to and including replacement of all hydrogen atoms with
halogen. Preferred halogenated alkyl groups include trifluoromethyl
substituted alkyls, difluoromethyl substituted alkyls, and
perfluorinated alkyls; more preferred fluorinated alkyls include
trifluoromethyl and difluoromethyl.
[0049] "Halogenated alkoxy" refers to a radical derived from a
halogenated alkyl, radical attached to an oxygen atom with the
oxygen atom having one open valence for attachment to a parent
structure.
[0050] The term "cycloalkyl" refers to saturated or partially
unsaturated, moncyclic or polycyclic hydrocarbon of from 3 to 20
carbon atom members (preferably from 3 to 14 carbon atom members).
Examples of such groups include, and are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
adamantyl. The term cycloalkyl includes a cycloalkyl ring fused to
a benzene ring (benzo fused cycloalkyl), or a 5 or 6 membered
heteroaryl ring (containing one of O, S or N and, optionally, one
additional nitrogen) to form a heteroaryl fused cycloalkyl.
[0051] The term "heterocyclyl" refers to a nonaromatic monocyclic
ring of 5 to 10 members in which 1 to 4 members are nitrogen or a
nonaromatic monocyclic ring of 5 to 10 members in which zero, one
or two members are nitrogen and up to two members are oxygen or
sulfur; wherein, optionally, the ring contains zero, one or two
unsaturated bonds. The term heterocyclyl includes a heterocyclyl
ring fused to a benzene ring (benzo fused heterocyclyl), a 5 or 6
membered heteroaryl ring (containing one of O, S or N and,
optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl
or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the
same definition as above but absent the option of a further fused
ring) or fused with the carbon of attachment of a cycloalkyl,
cycloalkenyl or heterocyclyl ring to form a spiro moiety. For
instant compounds of the invention, the carbon atom ring members
that form the heterocyclyl ring are fully saturated. Other
compounds of the invention may have a partially saturated
heterocyclyl ring. Additionally, heterocyclyl includes a
heterocyclic ring bridged to form bicyclic rings. Preferred
partially saturated heterocyclyl rings may have from one to two
double bonds. Such compounds are not considered to be fully
aromatic and are not referred to as heteroaryl compounds. Examples
of heterocyclyl groups include, and are not limited to, pyrrolinyl
(including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl,
2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.
[0052] The term "aryl" refers to an unsaturated, aromatic
monocyclic ring of 6 carbon members or to an unsaturated, aromatic
polycyclic ring of from 10 to 14 carbon members. Examples of such
aryl rings include, and are not limited to, phenyl, naphthalenyl or
anthracenyl. Preferred aryl groups for the practice of this
invention are phenyl and naphthalenyl.
[0053] The term "heteroaryl" refers to an aromatic ring of 5 or 6
members wherein the ring consists of carbon atoms and has at least
one heteroatom member. Suitable heteroatoms include nitrogen,
oxygen or sulfur. In the case of 5 membered rings, the heteroaryl
ring contains one member of nitrogen, oxygen or sulfur and, in
addition, may contain up to three additional nitrogens. In the case
of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 membered ring has
three nitrogens, at most two nitrogen atoms are adjacent. The term
heteroaryl includes a heteroaryl ring fused to a benzene ring
(benzofused heteroaryl), a 5 or 6 membered heteroaryl ring
(containing one of O, S or N and, optionally, one additional
nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered
heterocyclic ring (as defined supra but absent the option of a
further fused ring). Examples of heteroaryl groups include, and are
not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or
pyrazinyl; fused heteroaryl groups include indolyl, isoindolyl,
benzofuryl, benzothienyl, indazolyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,
benzotriazolyl, quinoxalinyl, quinolinyl, isoquinolinyl or
quinazolinyl.
[0054] The term "arylalkyl" means an alkyl group substituted with
an aryl group (e.g., benzyl, phenethyl). Similarly, the term
"arylalkoxy" indicates an alkoxy group substituted with an aryl
group (e.g., benzyloxy).
[0055] The term "halogen" refers to fluorine, chlorine, bromine and
iodine. Substituents that are substituted with multiple halogens
are substituted in a manner that provides compounds, which are
stable.
[0056] The term "vinyl" refers to a two-carbon unsaturated linker
in which the unsaturation is a double bond between said two carbon
atoms. When two substituents occur on the vinyl linker, the
substituents are understood to be bound on adjacent carbon atoms,
such that the substituents are 1,2-configured.
[0057] The term "oxo" whether used alone or as part of a
substituent group refers to an O.dbd. to either a carbon or a
sulfur atom. For example, phthalimide and saccharin are examples of
compounds with oxo substituents.
[0058] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl,
alkylamino) it shall be interpreted as including those limitations
given above for "alkyl" and "aryl." Designated numbers of carbon
atoms (e.g., C.sub.1-C.sub.6) shall refer independently to the
number of carbon atoms in an alkyl moiety or to the alkyl portion
of a larger substituent in which alkyl appears as its prefix root.
For alkyl, and alkoxy substituents the designated number of carbon
atoms includes all of the independent member included in the range
specified individually and all the combination of ranges within in
the range specified. For example C.sub.1-6 alkyl would include
methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well
as sub-combinations thereof (e.g. C.sub.1-2, C.sub.1-3, C.sub.1-4,
C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6, C.sub.5-6, C.sub.2-5,
etc.).
[0059] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0060] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated.
[0061] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0062] As used herein, the term "acyl" refers to alkylcarbonyl
substituents.
[0063] Throughout this disclosure, the terminal portion of the
designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenyl(C.sub.1-6)alkylaminocarbonyl(C.sub.1-6)alkyl" substituent
refers to a group of the formula
##STR00003##
[0064] Unless otherwise noted, it is intended that the definition
of any substituent or variable at a particular location in a
molecule be independent of its definitions elsewhere in that
molecule. It is understood that substituents and substitution
patterns on the compounds of formula (I) can be selected by one of
ordinary skill in the art to provide compounds that are chemically
stable and that can be readily synthesized by techniques known in
the art as well as those methods set forth herein.
[0065] For purposes of the present invention, the term "opioid
receptor-modulated" is used to refer to the condition of being
affected by the modulation of an opioid receptor, including but not
limited to, the state of being mediated by the opioid receptor.
[0066] Embodiments of the present invention include those compounds
of Formula (I)
##STR00004##
wherein [0067] a) R.sub.1 is selected from the group consisting of
[0068] i) phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkoxy, di(C.sub.1-4alkyl)aminocarbonyl, and fluoro; such
that only one di(C.sub.1-4alkyl)aminocarbonyl is present; [0069]
ii) naphthyl; [0070] iii) pyridinyl optionally substituted with one
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro, and cyano; [0071] iv)
pyrimidin-5-yl; [0072] v) furanyl; [0073] vi) thienyl; and [0074]
vii) di(C.sub.1-2alkyl)aminocarbonyl; [0075] b) R.sub.1 is selected
from the group consisting of [0076] i) phenyl optionally
substituted with one substituent selected from the group consisting
of C.sub.1-4alkoxy, di(C.sub.1-4alkyl)aminocarbonyl, and fluoro;
[0077] ii) pyridinyl optionally substituted with one substituent
selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro, and cyano; [0078] iii)
pyrimidin-5-yl; and [0079] iv) di(C.sub.1-2alkyl)aminocarbonyl;
[0080] c) R.sub.1 is selected from the group consisting of [0081]
i) phenyl optionally substituted with one methoxy substituent;
[0082] ii) pyridinyl optionally substituted with one substituent
selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro, and cyano; [0083] iii)
pyrimidin-5-yl; and [0084] iv) di(C.sub.1-2alkyl)aminocarbonyl;
[0085] d) Y is vinyl or a bond; or, Y is O when R.sub.1 is an
optionally substituted phenyl; [0086] e) Y is vinyl or a bond;
[0087] f) R.sub.2 is phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, fluoro, chloro, and hydroxy;
[0088] or, R.sub.2 is phenyl substituted with one aminocarbonyl or
di(C.sub.1-4alkyl)aminocarbonyl substituent; [0089] g) R.sub.2 is
phenyl optionally substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, and hydroxy; [0090] or, R.sub.2 is phenyl
substituted with one aminocarbonyl or
di(C.sub.1-4alkyl)aminocarbonyl substituent; [0091] h) R.sub.2 is
phenyl optionally substituted with one substituent independently
selected from the group consisting of methoxy, hydroxy,
aminocarbonyl, and di(C.sub.1-4alkyl)aminocarbonyl; [0092] i)
R.sub.3 is selected from the group consisting of [0093] i)
3-amino-cyclohexyl; [0094] ii) 4-amino-cyclohexyl; [0095] iii)
pyrrolidin-2-ylmethyl wherein pyrrolidin-2-yl is optionally
substituted at the 3- or 4-position with one to two fluoro
substituents; [0096] iv) 2-(N-methylamino)ethyl; [0097] v)
piperidin-3-ylmethyl; and [0098] vi) 1-azabicyclo[2.2.2]octan-3-yl;
[0099] or, R.sub.3 is taken with R.sub.a and the nitrogen atom to
which they are both attached to form piperazinyl; [0100] j) R.sub.3
is selected from the group consisting of [0101] i)
3-amino-cyclohexyl; [0102] ii) 4-amino-cyclohexyl; and [0103] iii)
pyrrolidin-2-ylmethyl wherein pyrrolidin-2-yl is optionally
substituted at the 3- or 4-position with one fluoro substituent;
[0104] or, R.sub.3 is taken with R.sub.a and the nitrogen atom to
which they are both attached to form piperazinyl; [0105] k) R.sub.a
is hydrogen or C.sub.1-2alkyl; [0106] l) R.sub.a is hydrogen;
[0107] and any combination of embodiments a) through l) above,
provided that it is understood that combinations in which different
embodiments of the same substituent would be combined are excluded;
and enantiomers, diastereomers, solvates, and pharmaceutically
acceptable salts thereof.
[0108] A further embodiment of the present invention includes
compounds of Formula (I)
##STR00005##
wherein [0109] R.sub.1 is selected from the group consisting of
[0110] i) phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkoxy, di(C.sub.1-4alkyl)aminocarbonyl, and fluoro; such
that only one di(C.sub.1-4alkyl)aminocarbonyl is present; [0111]
ii) naphthyl; [0112] iii) pyridinyl optionally substituted with one
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro, and cyano; [0113] iv)
pyrimidin-5-yl; [0114] v) furanyl; [0115] vi) thienyl; and [0116]
vii) di(C.sub.1-2alkyl)aminocarbonyl; [0117] Y is vinyl or a bond;
or, Y is O when R.sub.1 is an optionally substituted phenyl; [0118]
R.sub.2 is phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, fluoro, chloro, and hydroxy;
[0119] or, R.sub.2 is phenyl substituted with one aminocarbonyl or
di(C.sub.1-4alkyl)aminocarbonyl substituent; [0120] R.sub.3 is
selected from the group consisting of [0121] i) 3-amino-cyclohexyl;
[0122] ii) 4-amino-cyclohexyl; [0123] iii) pyrrolidin-2-ylmethyl
wherein pyrrolidin-2-yl is optionally substituted at the 3- or
4-position with one to two fluoro substituents; [0124] v)
2-(N-methylamino)ethyl; [0125] vi) piperidin-3-ylmethyl; and [0126]
vii) 1-azabicyclo[2.2.2]octan-3-yl; [0127] or, R.sub.3 is taken
with R.sub.a and the nitrogen atom to which they are both attached
to form piperazinyl; [0128] R.sub.a is hydrogen or C.sub.1-2alkyl;
and enantiomers, diastereomers, solvates, and pharmaceutically
acceptable salts thereof.
[0129] A further embodiment of the present invention includes
compounds of Formula (I)
##STR00006##
wherein [0130] R.sub.1 is selected from the group consisting of
[0131] i) phenyl optionally substituted with one substituent
selected from the group consisting of C.sub.1-4alkoxy,
di(C.sub.1-4alkyl)aminocarbonyl, and fluoro; [0132] ii) pyridinyl
optionally substituted with one substituent selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylthio,
fluoro, and cyano; [0133] iii) pyrimidin-5-yl; and [0134] iv)
di(C.sub.1-2alkyl)aminocarbonyl; [0135] Y is vinyl or a bond;
[0136] R.sub.2 is phenyl optionally substituted with one to two
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, and hydroxy; [0137] or, R.sub.2 is
phenyl substituted with one aminocarbonyl or
di(C.sub.1-4alkyl)aminocarbonyl substituent; [0138] R.sub.3 is
selected from the group consisting of [0139] i) 3-amino-cyclohexyl;
[0140] ii) 4-amino-cyclohexyl; [0141] iii) pyrrolidin-2-ylmethyl
wherein pyrrolidin-2-yl is optionally substituted at a carbon atom
with one to two fluoro substituents; [0142] v)
2-(N-methylamino)ethyl; [0143] vi) piperidin-3-ylmethyl; and [0144]
vii) 1-azabicyclo[2.2.2]octan-3-yl;
[0145] or, R.sub.3 is taken with R.sub.a and the nitrogen atom to
which they are both attached to form piperazinyl; [0146] R.sub.a is
hydrogen; and enantiomers, diastereomers, solvates, and
pharmaceutically acceptable salts thereof.
[0147] A further embodiment of the present invention includes
compounds of Formula (I)
##STR00007##
wherein [0148] R.sub.1 is selected from the group consisting of
[0149] i) phenyl optionally substituted with one methoxy
substituent; [0150] ii) pyridinyl optionally substituted with one
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylthio, fluoro, and cyano; [0151] iii)
pyrimidin-5-yl; and [0152] iv) di(C.sub.1-2alkyl)aminocarbonyl;
[0153] Y is vinyl or a bond; [0154] R.sub.2 is phenyl optionally
substituted with one substituent independently selected from the
group consisting of methoxy, hydroxy, aminocarbonyl, and
di(C.sub.1-4alkyl)aminocarbonyl; [0155] R.sub.3 is selected from
the group consisting of [0156] i) 3-amino-cyclohexyl; [0157] ii)
4-amino-cyclohexyl; [0158] iii) pyrrolidin-2-ylmethyl wherein
pyrrolidin-2-yl is optionally substituted at a carbon atom with one
fluoro substituent;
[0159] or, R.sub.3 is taken with R.sub.a and the nitrogen atom to
which they are both attached to form piperazinyl; [0160] R.sub.a is
hydrogen; and enantiomers, diastereomers, solvates, and
pharmaceutically acceptable salts thereof.
[0161] A further embodiment of the present invention includes
compounds of Formula (I)
##STR00008##
selected from the group consisting of [0162] a compound wherein
R.sub.1 is 2-(N,N-diethylaminocarbonyl), Y is (E)-vinyl, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0163] a compound wherein R.sub.1 is
2-(N,N-diethylaminocarbonyl), Y is ethyl, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0164] a compound wherein R.sub.1 is 2-(4-methoxy-phenyl),
Y is ethyl, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0165] a compound
wherein R.sub.1 is 2-(3-methoxy-phenyl), Y is ethyl, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0166] a compound wherein R.sub.1 is 2-phenyl, Y is ethyl,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0167] a compound wherein R.sub.1 is
2-(4-fluoro-phenyl), Y is ethyl, R.sub.2 is 4-methoxy-phenyl,
R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0168] a
compound wherein R.sub.1 is 2-(3-fluoro-phenyl), Y is ethyl,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0169] a compound wherein R.sub.1 is
2-[3-(N,N-diethylaminocarbonyl)phenyl], Y is ethyl, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0170] a compound wherein R.sub.1 is
N,N-diethylaminocarbonyl, Y is a bond, R.sub.2 is phenyl, R.sub.3
is pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0171] a compound
wherein R.sub.1 is N,N-diethylaminocarbonyl, Y is a bond, R.sub.2
is 4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a
is H; (2S) [0172] a compound wherein R.sub.1 is
N,N-diethylaminocarbonyl, Y is a bond, R.sub.2 is 2-methoxy-phenyl,
R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0173] a
compound wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-cyano-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is H;
(2S) [0174] a compound wherein R.sub.1 is phenyl, Y is a bond,
R.sub.2 is 3-cyano-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0175] a compound wherein R.sub.1 is phenyl, Y
is a bond, R.sub.2 is phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0176] a compound wherein R.sub.1 is phenyl, Y
is a bond, R.sub.2 is 3-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0177] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is 4-fluoro-phenyl,
R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0178] a
compound wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-trifluoromethoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0179] a compound wherein R.sub.1 is phenyl, Y
is a bond, R.sub.2 is 2,6-dichloro-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0180] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is 2-(N-methylamino)ethyl, and R.sub.a is
H; [0181] a compound wherein R.sub.1 is phenyl, Y is a bond,
R.sub.2 is 4-methoxycarbonyl-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0182] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
3-methoxycarbonyl-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0183] a compound wherein R.sub.1 is phenyl, Y
is a bond, R.sub.2 is 2,4-dichloro-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0184] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is piperidin-4-yl, and R.sub.a is H;
[0185] a compound wherein R.sub.1 is 5-cyano-pyridin-3-yl, Y is a
bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
4-fluoro-pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S,4R) [0186] a
compound wherein R.sub.1 is 5-fluoro-pyridin-3-yl, Y is a bond,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
4-fluoro-pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S,4R) [0187] a
compound wherein R.sub.1 is 5-methylthio-pyridin-3-yl, Y is a bond,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
4-fluoro-pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S,4R) [0188] a
compound wherein R.sub.1 is 5-methoxy-pyridin-3-yl, Y is a bond,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
4-fluoro-pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S,4R) [0189] a
compound wherein R.sub.1 is 5-methyl-pyridin-3-yl, Y is a bond,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
4-fluoro-pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S,4R) [0190] a
compound wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-aminocarbonyl-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0191] a compound wherein R.sub.1 is phenyl, Y
is a bond, R.sub.2 is 3-aminocarbonyl-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0192] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-carboxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0193] a compound wherein R.sub.1 is phenyl, Y is a bond,
R.sub.2 is 3-carboxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and
R.sub.a is H; (2S) [0194] a compound wherein R.sub.1 is phenyl, Y
is a bond, R.sub.2 is 4-(N,N-diethylaminocarbonyl)phenyl, R.sub.3
is pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0195] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
3-(N,N-diethylaminocarbonyl)phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0196] a compound
wherein R.sub.1 is phenyl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0197] a compound wherein R.sub.1 is naphthalen-2-yl, Y is
a bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0198] a compound
wherein R.sub.1 is naphthalen-1-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0199] a compound wherein R.sub.1 is pyridin-4-yl, Y is a
bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0200] a compound
wherein R.sub.1 is pyridin-3-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0201] a compound wherein R.sub.1 is furan-3-yl, Y is a
bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0202] a compound
wherein R.sub.1 is thiophen-3-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0203] a compound wherein R.sub.1 is pyrimidin-5-yl, Y is a
bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0204] a compound
wherein R.sub.1 is 5-fluoro-pyridin-3-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0205] a compound wherein R.sub.1 is 5-cyano-pyridin-3-yl,
Y is a bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0206] a compound
wherein R.sub.1 is pyridin-3-yl, Y is a bond, R.sub.2 is
4-hydroxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0207] a compound wherein R.sub.1 is phenyl, Y is a bond,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is taken with R.sub.a and the
nitrogen atom to which they are both attached to form
piperazin-1-yl; [0208] a compound wherein R.sub.1 is phenyl, Y is a
bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is taken with R.sub.a
and the nitrogen atom to which they are both attached to form
4-methyl-piperazin-1-yl; [0209] a compound wherein R.sub.1 is
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
H; (2S) [0210] a compound wherein R.sub.1 is pyridin-3-yl, Y is a
bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is ethyl; (2S) [0211] a compound
wherein R.sub.1 is 5-fluoro-pyridin-3-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
ethyl; (2S) [0212] a compound wherein R.sub.1 is pyrimidin-5-yl, Y
is a bond, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is ethyl; (2S) [0213] a compound
wherein R.sub.1 is 5-cyano-pyridin-3-yl, Y is a bond, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is pyrrolidin-2-ylmethyl, and R.sub.a is
ethyl; (2S) [0214] a compound wherein R.sub.1 is 4-methoxy-phenyl,
Y is O, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
pyrrolidin-2-ylmethyl, and R.sub.a is H; (2S) [0215] a compound
wherein R.sub.1 is 4-methoxy-phenyl, Y is O, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is piperidin-3-yl, and R.sub.a is H;
racemic [0216] a compound wherein R.sub.1 is 4-methoxy-phenyl, Y is
O, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
3-hydroxy-2(R)-amino-propyl, and R.sub.a is H; [0217] a compound
wherein R.sub.1 is 4-methoxy-phenyl, Y is O, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is piperidin-4-yl, and R.sub.a is H;
[0218] a compound wherein R.sub.1 is 4-methoxy-phenyl, Y is O,
R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
8-azabicyclo[3.2.1]octan-3-yl, and R.sub.a is H; mixture of
endo/exo isomers [0219] a compound wherein R.sub.1 is
4-methoxy-phenyl, Y is O, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
azetidin-3-yl-methyl, and R.sub.a is H; [0220] a compound wherein
R.sub.1 is 4-methoxy-phenyl, Y is O, R.sub.2 is 4-methoxy-phenyl,
R.sub.3 is azetidin-3-yl-methyl, and R.sub.a is
azetidin-3-yl-methyl; [0221] a compound wherein R.sub.1 is
4-methoxy-phenyl, Y is O, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
1-azabicyclo[2.2.2]octan-3-yl, and R.sub.a is H; mixture of
endo/exo isomers [0222] a compound wherein R.sub.1 is
4-methoxy-phenyl, Y is O, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
piperidin-3-ylmethyl, and R.sub.a is H; racemic [0223] a compound
wherein R.sub.1 is 4-methoxy-phenyl, Y is O, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is 3-amino-cyclohexyl, and R.sub.a is H;
mixture of 4 isomers [0224] a compound wherein R.sub.1 is
4-methoxy-phenyl, Y is O, R.sub.2 is 4-methoxy-phenyl, R.sub.3 is
2-(N-methylamino)ethyl, and R.sub.a is H; and [0225] a compound
wherein R.sub.1 is 4-methoxy-phenyl, Y is O, R.sub.2 is
4-methoxy-phenyl, R.sub.3 is 2-(N-methylamino)ethyl, and R.sub.a is
2-(N-methylamino)ethyl; and pharmaceutically acceptable salts
thereof.
[0226] For use in medicine, salts of compounds of formula (I) refer
to non-toxic "pharmaceutically acceptable salts." Other salts may,
however, be useful in the preparation of compounds of formula (I)
or of their pharmaceutically acceptable salts thereof. Suitable
pharmaceutically acceptable salts of compounds of formula (I)
include acid addition salts which can, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid.
[0227] Furthermore, where the compounds of formula (I) carry an
acidic moiety, suitable pharmaceutically acceptable salts thereof
may include alkali metal salts, e.g., sodium or potassium salts;
alkaline earth metal salts, e.g., calcium or magnesium salts; and
salts formed with suitable organic ligands, e.g., quaternary
ammonium salts. Thus, representative pharmaceutically acceptable
salts include the following: acetate, benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, calcium
edetate, camsylate, carbonate, chloride, clavulanate, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate,
N-methylglucamine ammonium salt, oleate, pamoate (embonate),
palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide and valerate.
[0228] Representative acids and bases which may be used in the
preparation of pharmaceutically acceptable salts include the
following: acids including acetic acid, 2,2-dichloroacetic acid,
acylated amino acids, adipic acid, alginic acid, ascorbic acid,
L-aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucoronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid;
[0229] and bases including ammonia, L-arginine, benethamine,
benzathine, calcium hydroxide, choline, deanol, diethanolamine,
diethylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole,
L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine,
piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine,
sodium hydroxide, triethanolamine, tromethamine and zinc
hydroxide.
[0230] Embodiments of the present invention include prodrugs of
compounds of formula (I). In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of embodiments of the present invention, the
term "administering" encompasses the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
a patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in
[0231] "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0232] Where the compounds according to embodiments of this
invention have at least one chiral center, they may accordingly
exist as enantiomers. Where the compounds possess two or more
chiral centers, they may additionally exist as diastereomers. It is
to be understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention. Furthermore,
some of the crystalline forms for the compounds may exist as
polymorphs and as such are intended to be included in the present
invention. In addition, some of the compounds may form solvates
with water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention. The skilled artisan will understand that the term
compound as used herein, is meant to include solvated compounds of
Formula I.
[0233] Where the processes for the preparation of the compounds
according to certain embodiments of the invention give rise to a
mixture of stereoisomers, these isomers may be separated by
conventional techniques such as preparative chromatography. The
compounds may be prepared in racemic form, or individual
enantiomers may be prepared either by enantiospecific synthesis or
by resolution. The compounds may, for example, be resolved into
their component enantiomers by standard techniques, such as the
formation of diastereomeric pairs by salt formation with an
optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid
and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional
crystallization and regeneration of the free base. The compounds
may also be resolved by formation of diastereomeric esters or
amides, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be resolved
using a chiral HPLC column.
[0234] One embodiment of the present invention is directed to a
composition comprising the (+)-enantiomer of a compound of formula
(I) wherein said composition is substantially free from the
(-)-isomer of said compound. In the present context, substantially
free means less than 25%, preferably less than 10%, more preferably
less than 5%, even more preferably less than 2% and even more
preferably less than 1% of the (-)-isomer calculated as.
% ( + ) - enantiomer = ( mass ( + ) - enantiomer ) ( mass ( + ) -
enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100
##EQU00001##
[0235] Another embodiment of the present invention is a composition
comprising the (-)-enantiomer of a compound of formula (I) wherein
said composition is substantially free from the (+)-isomer of said
compound. In the present context, substantially free from means
less than 25%, preferably less than 10%, more preferably less than
5%, even more preferably less than 2% and even more preferably less
than 1% of the (+)-isomer calculated as
% ( - ) - enantiomer = ( mass ( - ) - enantiomer ) ( mass ( + ) -
enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.
##EQU00002##
[0236] During any of the processes for preparation of the compounds
of embodiments of the present invention, it may be necessary and/or
desirable to protect sensitive or reactive groups on any of the
molecules concerned. This may be achieved by means of conventional
protecting groups, such as those described in Protective Groups in
Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T.
W. Greene & P. G. M. Wuts, Protective Groups in Organic
Synthesis, John Wiley & Sons, 1991. The protecting groups may
be removed at a convenient subsequent stage using methods known
from the art.
[0237] Even though the compounds of embodiments of the present
invention (including their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates) can be administered alone,
they will generally be administered in admixture with a
pharmaceutical carrier, excipient or diluent selected with regard
to the intended route of administration and standard pharmaceutical
practice. Thus, particular embodiments of the present invention are
directed to pharmaceutical compositions comprising compounds of
formula (I) and one or more than one pharmaceutically acceptable
carrier, excipient or diluent.
[0238] By way of example, in the pharmaceutical and veterinary
compositions of embodiments of the present invention, the compounds
of formula (I) may be admixed with any suitable binder(s),
lubricant(s), suspending agent(s), coating agent(s), and/or
solubilizing agent(s).
[0239] Tablets or capsules of the compounds may be administered one
or two or more at a time, as appropriate. It is also possible to
administer the compounds in sustained release formulations.
[0240] Alternatively, compounds of formula (I) can be administered
by inhalation (intratracheal or intranasal) or in the form of a
suppository or pessary, or they may be applied topically in the
form of a lotion, solution, cream, ointment or dusting powder. For
example, they can be incorporated into a cream consisting of an
aqueous emulsion of polyethylene glycols or liquid paraffin. They
can also be incorporated, at a concentration of between 1% and 10%
by weight, into an ointment consisting of a white wax or white soft
paraffin base together with such stabilizers and preservatives as
may be required. An alternative means of transdermal administration
is by use of a skin patch.
[0241] For some applications, preferably the compositions are
administered orally in the form of tablets containing excipients
such as starch or lactose, or in capsules or ovules either alone or
in admixture with excipients, or in the form of elixirs, solutions
or suspensions containing flavoring or coloring agents.
[0242] The compositions (as well as the compounds alone) can also
be injected parenterally, for example intracavernosally,
intravenously, intramuscularly, subcutaneously, intradermally or
intrathecally. In this case, the compositions will comprise a
suitable carrier or diluent.
[0243] For parenteral administration, the compositions are best
used in the form of a sterile aqueous solution which may contain
other substances, for example, enough salts or monosaccharides to
make the solution isotonic with blood.
[0244] For buccal or sublingual administration, the compositions
may be administered in the form of tablets or lozenges, which can
be formulated in a conventional manner.
[0245] By way of further example, pharmaceutical and veterinary
compositions containing one or more of the compounds of formula (I)
as the active ingredient can be prepared by intimately mixing the
compound or compounds with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques. The carrier may
take a wide variety of forms depending upon the desired route of
administration (e.g., oral, parenteral, etc.). Thus for liquid oral
preparations such as suspensions, elixirs and solutions, suitable
carriers and additives include water, glycols, oils, alcohols,
flavoring agents, preservatives, stabilizers, coloring agents and
the like; for solid oral preparations, such as powders, capsules
and tablets, suitable carriers and additives include starches,
sugars, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like. Solid oral preparations also
may be coated with substances such as sugars or be
enterically-coated so as to modulate the major site of absorption.
For parenteral administration, the carrier will usually consist of
sterile water, and other ingredients may be added to increase
solubility or preservation. Injectable suspensions or solutions may
also be prepared utilizing aqueous carriers along with appropriate
additives.
[0246] A therapeutically effective amount of compounds of formula
(I) or a pharmaceutical composition thereof comprises a dose range
from about 0.1 mg to about 3000 mg, in particular from about 1 mg
to about 1000 mg or, more particularly, from about 10 mg to about
500 mg of active ingredient in a regimen of about 1 to 4 times per
day for an average (70 kg) human; although, it is apparent to one
skilled in the art that the therapeutically effective amount for
active compounds of the invention will vary as will the conditions
being treated.
[0247] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing 0.01, 10.0,
50.0, 100, 150, 200, 250, and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
subject to be treated.
[0248] Advantageously, compounds of formula (I) may be administered
in a single daily dose, or the total daily dosage may be
administered in divided doses of two, three or four times daily.
Furthermore, compounds of formula (I) can be administered in
intranasal form via topical use of suitable intranasal vehicles, or
via transdermal skin patches well known to those skilled in that
art.
[0249] It is also apparent to one skilled in the art that the
therapeutically effective dose for active compounds of formula (I)
or a pharmaceutical composition thereof will vary according to the
desired effect. Therefore, optimal dosages to be administered may
be readily determined and will vary with the particular compound
used, the mode of administration, the strength of the preparation,
and the advancement of the disease condition. In addition, factors
associated with the particular subject being treated, including
subject age, weight, diet and time of administration, will result
in the need to adjust the dose to achieve an appropriate
therapeutic level. The above dosages are thus exemplary of the
average case. There can be, of course, individual instances wherein
higher or lower dosage ranges are merited, and such are within the
scope of this invention.
[0250] Compounds of formula (I) may be administered in any of the
foregoing compositions and dosage regimens or by means of those
compositions and dosage regimens established in the art whenever
use of the compounds of formula (I) as analgesics is required for a
subject in need thereof.
[0251] Examples of pain intended to be within the scope of the
present invention include, but are not limited to, inflammatory
pain, centrally mediated pain, peripherally mediated pain, visceral
pain, structural or soft tissue injury related pain, progressive
disease related pain, neuropathic pain and acute pain such as
caused by acute injury, trauma or surgery and chronic pain such as
headache and that caused by neuropathic conditions, post-stroke
conditions, cancer, and migraine.
[0252] Compounds of the present invention are also useful as
immunosuppressants, antiinflammatory agents, agents for the
treatment and prevention of neurological and psychiatric
conditions, for instance, depression and Parkinson's disease,
agents for the treatment of urological and reproductive conditions,
for instance, urinary incontinence and premature ejaculation,
medicaments for drug and alcohol abuse, agents for treating
gastritis and diarrhea, cardiovascular agents and cardioprotective
agents and agents for the treatment of respiratory diseases.
[0253] The compounds of the present invention are also useful in
treating pain caused by osteoarthritis, rheumatoid arthritis,
fibromyalgia, migraine, headache, toothache, burn, sunburn, snake
bite (in particular, venomous snake bite), spider bite, insect
sting, neurogenic bladder, benign prostatic hypertrophy,
interstitial cystitis, rhinitis, contact
dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,
enteritis, cellulitis, causalgia, sciatic neuritis, mandibular
joint neuralgia, peripheral neuritis, polyneuritis, stump pain,
phantom limb pain, post-operative ileus, cholecystitis,
postmastectomy pain syndrome, oral neuropathic pain, Charcot's
pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, cluster headache,
migraine headache, peripheral neuropathy, bilateral peripheral
neuropathy, diabetic neuropathy, optic neuritis, postfebrile
neuritis, migrating neuritis, segmental neuritis, Gombault's
neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia,
geniculate neuralgia, glossopharyngial neuralgia, migrainous
neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary
neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital
neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine
neuralgia, supraorbital neuralgia, vidian neuralgia, inflammatory
bowel disease, irritable bowel syndrome, sinus headache, tension
headache, labor, childbirth, menstrual cramps, and cancer.
[0254] In regard to the use of the present compounds in treatment
of the diseases or conditions such as those listed above, a
therapeutically effective dose can be determined by persons skilled
in the art by the use of established animal models. The
therapeutically effective dose of the compounds of Formula (I)
exemplified in such a treatment is from about 0.001 mg/kg/day to
about 300 mg/kg/day. Particularly, the range is from about 0.5 to
about 5.0 mg/kg of body weight per day; and more particularly, from
about 1.0 to about 3.0 mg/kg of body weight per day. The compounds
may be administered on a regimen of 1 to 4 times per day.
General Synthetic Methods
[0255] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and illustrated in the schemes and examples that
follow. Since the schemes are an illustration, the invention should
not be construed as being limited by the chemical reactions and
conditions described in the schemes. The various starting materials
used in the schemes and examples are commercially available or may
be prepared by methods well within the skill of persons versed in
the art. The variables are as defined herein.
[0256] Abbreviations used in the instant specification,
particularly the schemes and examples, are as follows: [0257] AcCl
acetyl chloride [0258] AcOH glacial acetic acid [0259] aq. aqueous
[0260] Bn or Bzl benzyl [0261] CDI N,N'-carbonyldiimidazole [0262]
conc. concentrated [0263] DAMGO Tyr-D-Ala-Gly-(methyl)Phe-Gly-ol
[0264] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene [0265] DCE
1,2-dichloroethane [0266] DCM dichloromethane [0267] DIEA
diisopropylethylamine [0268] DMF N,N-dimethylformamide [0269] DMSO
dimethylsulfoxide [0270] DPDPE [D-Pen2,D-Pen5]-enkephalin [0271]
dppf 1,1'-bis(diphenylphosphino)ferrocene [0272] EDC
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0273] ESI
electron-spray ionization [0274] EtOAc ethyl acetate [0275] EtOH
ethanol [0276] h or hrs hour(s) [0277] HATU
O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium-hexafluorophosp-
hate [0278] HBTU
O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0279] HEPES
2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid [0280] HOBt
N-hydroxybenzotriazole [0281] HPLC high performance liquid
chromatography [0282] Me methyl [0283] MeOH methanol [0284] MHz
megahertz [0285] min minutes [0286] MPLC medium pressure liquid
chromatography [0287] MS mass spectrometry [0288] NMR nuclear
magnetic resonance [0289] NT not tested [0290] Ph phenyl [0291]
Pd/C palladium on activated carbon [0292] Ph.sub.3P
triphenylphosphine [0293] PPA polyphosphoric acid [0294] PyBOP
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
[0295] rt room temperature [0296] TBDMS tert-butyldimethylsilyl
[0297] TEA/Et.sub.3N triethylamine [0298] TFA trifluoroacetic acid
[0299] THF tetrahydrofuran [0300] TLC thin layer chromatography
[0301] TMS tetramethylsilane or trimethylsilyl
[0302] Scheme A illustrates the preparation of compounds of Formula
(I)-A and Formula (I)-A1 wherein Y is vinyl or ethyl, respectively,
R.sub.1 is di(C.sub.1-2alkyl)aminocarbonyl, and R.sub.3 is as
defined herein. R.sub.3a of compound A5 is defined as
(N-methylamino)methyl, pyrrolidin-2-yl, azetidin-3-yl, or
piperidin-3-yl. Ring A of compound A5-1 is defined as 3- or
4-amino-cyclohexyl, piperidin-3-yl, piperidin-4-yl,
##STR00009##
[0303] Compound A1 is either commercially available or can be made
by known methods described in the scientific literature. Reaction
with an appropriately substituted alcohol of formula A2, optionally
in the presence of a base, affords a compound of formula A3. The
nitro group of a compound of formula A3 may be reduced to the
corresponding amino group by the action of a reducing agent such as
zinc metal in the presence of acetic acid in an organic solvent
such as methanol, or by the action of sodium borohydride in the
presence of nickel chloride or a catalytic hydrogenation. The
resultant aniline of formula A4 may be alkylated with an
R.sub.3a-substituted aldehyde (A5) or a ketone of formula A5-1, in
the presence of a reducing agent such as sodium
triacetoxyborohydride in acetic acid to afford a compound of
formula A6. A palladium catalyzed coupling with a compound of
formula A7, wherein R is C.sub.1-4alkyl, in the presence or absence
of added ligands for palladium such as dppf or
tri-o-tolylphosphine, affords an alkene of formula A8. The
alkoxycarbonyl group of a compound of formula A8 may be saponified
in the presence of hydroxide ion to form its corresponding
carboxylic acid, which may then be coupled with a di(C.sub.1-4
alkyl)amine, in the presence of an appropriate coupling agent such
as EDCI, and an activating agent such as HOBt, to form an amide of
formula (I)-A. Reduction of the alkenyl group of a compound of
formula (I)-A with a reducing agent such as catalytic hydrogenation
affords a compound of formula (I)-A1. One skilled in the art will
recognize that certain compounds of formula A5 and A5-1 may require
an amino protecting group (P), which may be carried through
subsequent chemical steps of the synthetic scheme. Conventional
chemical methods may be used for amino deprotection at a later
stage. For example, a Boc group may be removed by the action of a
mineral acid or by an organic acid such as trifluoroacetic
acid.
[0304] Scheme B illustrates the preparation of compounds of Formula
(I)-B wherein Y is ethyl, and R.sub.1a is optionally substituted
phenyl, naphthyl, optionally substituted pyridinyl, pyrimidin-5-yl,
furanyl, or thienyl.
##STR00010##
A compound of formula A6 may be coupled with a compound of formula
B1 wherein R.sub.1a is defined herein, in the presence of a
palladium catalyst and in the presence or absence of added ligands
for palladium, and in the presence of an organic base such as TEA
to afford an alkene of formula B2. Reduction of the alkenyl
functionality may be achieved by a transition metal-catalyzed
hydrogenation to afford, upon optional amino deprotection, a
compound of formula (I)-B.
[0305] Scheme C illustrates the preparation of compounds of Formula
(I)-C wherein Y is a bond and R.sub.1 is
di(C.sub.1-2alkyl)aminocarbonyl.
##STR00011##
The compound C1 is either commercially available or can be made by
known methods described in the scientific literature. The compound
C1 may be coupled with an amine of formula C2 in the presence of an
appropriate coupling agent such as EDCI, and an activating agent
such as HOBt, to afford an amide of formula C3. Aromatic
nucleophilic substitution with a compound of formula A2 in the
presence of a base affords a compound of formula C4. The nitro
group of a compound of formula C4 may be reduced to the
corresponding amino group by the action of a reducing agent such as
zinc metal in the presence of acetic acid in an organic solvent
such as methanol, or by the action of sodium borohydride in the
presence of nickel chloride, or a catalytic hydrogenation. The
resultant aniline of formula C5 may be alkylated with an
R.sub.3a-substituted aldehyde (A5) or ketone of formula A5-1, in
the presence of a reducing agent such as sodium
triacetoxyborohydride in acetic acid to afford, upon optional amino
deprotection, a compound of formula (I)-C.
[0306] Scheme D illustrates the preparation of compounds of Formula
(I)-D wherein Y is a bond and R.sub.1 is optionally substituted
phenyl, naphthyl, optionally substituted pyridinyl, pyrimidin-5-yl,
furanyl, or thienyl (represented as R.sub.1a).
##STR00012##
The R.sub.1a group may be introduced into a compound of formula A6
through a palladium catalyzed cross-coupling reaction with an
appropriately substituted boronic acid or boronate ester (D1), in
the presence of a suitable base such as potassium carbonate. The
reaction also may be carried out in the presence or absence of
added ligands for palladium which, when used, include one or more
than one of triphenylphosphine, tri-O-tolylphosphine,
tri(tert-butyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene,
bis[2-(diphenyl-phosphino)phenyl]ether,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl,
1-butyl-3-methylimidazolium hexafluorophosphate, and the like.
Useful solvents include ethanol, THF, DMF, toluene, DME, dioxane,
or benzene. Upon optional amino deprotection, a compound of formula
(I)-D may be prepared.
[0307] Scheme E illustrates the preparation of compounds of Formula
(I)-E wherein Y is a bond, R.sub.1 is optionally substituted
phenyl, naphthyl, optionally substituted pyridinyl, pyrimidin-5-yl,
furanyl, or thienyl (represented as R.sub.1a); and R.sub.3 is taken
with --N--R.sub.a to form piperazin-1-yl.
##STR00013##
The R.sub.1a group may be introduced into a compound of formula A1
through a palladium catalyzed cross-coupling reaction with an
appropriately substituted boronic acid or boronate ester (D1), in
the presence of a suitable base such as potassium carbonate, as
further described herein. A compound of formula E1 may be reacted
with a compound of formula A2 in the presence of a suitable base to
form a compound of formula E2. The nitro group of a compound of
formula E2 may be reduced to the corresponding aniline as previous
described herein to form a compound of formula E3. Treatment with a
protected amine of formula E4 in the presence of a suitable base
such as potassium carbonate affords a compound of formula E5.
Removal of amino protecting group (P) affords a compound of formula
(I)-E.
[0308] Scheme F illustrates the preparation of compounds of Formula
(I)-F wherein Y is O, R.sub.1 is optionally substituted phenyl
(pictured as R.sub.1f), and R.sub.3 is as defined by the
invention.
##STR00014##
A difluoro compound of formula F1 is either commercially available
or readily synthesized according to methods described in the
scientific literature. Upon nucleophilic aromatic substitution with
a compound of formula A2, optionally in the presence of a base, a
compound of formula F2 may be prepared. Subsequent reaction with an
R.sub.1f-substituted phenol of formula F3, optionally in the
presence of a base, affords a compound of formula F4. Reduction of
the nitro group as previously described affords a compound of
formula F5. Treatment with an aldehyde of formula A5 or a ketone of
formula A5-1 in the presence of a hydride source followed by
conventional amino deprotection if R.sub.3 contains an amino
protecting group provides compounds of formula (I)-F.
[0309] Scheme G illustrates the preparation of certain useful
R.sub.3 intermediates of the present invention, useful for the
synthesis of compounds of Formula (I) wherein R.sub.3 is
pyrrolidin-2-yl methyl substituted at the 3- or 4-position with one
to two fluoro substituents.
##STR00015##
[0310] such that no more than two can be F
A compound of formula G1 is either commercially available or can be
prepared according to known methods described in the scientific
literature. A compound of formula G1 (wherein G.sup.1, G.sup.1a,
G.sup.2, and G.sup.2a are each hydrogen or fluoro, such that no
more than two of said G.sup.1, G.sup.1a, G.sup.2, and G.sup.2a can
be fluoro) may be treated with N,O-dimethylhydroxylamine
hydrochloride, in the presence of a peptide coupling agent such as
HBTU and an organic base such as DIEA, in an organic solvent such
as DMF, to afford a compound of formula G2. A compound of formula
G2 may be converted to its corresponding aldehyde of formula G3 by
the action of lithium aluminum hydride. A compound of formula G3
may be used in an analogous manner to a compound of formula A5 to
form compounds of Formula (I).
[0311] Scheme H describes the preparation of compounds of Formula
(I)-H wherein R.sub.1 is optionally substituted phenyl, naphthyl,
optionally substituted pyridinyl, pyrimidin-5-yl, furanyl, or
thienyl (represented as R.sub.1a); Y is a bond, and R.sub.3 is
taken with --N--R.sub.a to form piperazin-1-yl substituted with
4-C.sub.1-4alkyl.
##STR00016##
A compound of Formula (I)-E may be reacted with a compound of
formula H1 wherein R.sub.H is hydrogen or C.sub.1-3alkyl, in the
presence of a hydride source such as sodium cyanoborohydride, to
form an alkylated product of formula (I)-H.
[0312] Scheme I illustrates the preparation of compounds of Formula
(I)-I wherein Y is a bond, R.sup.1 is
5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, and R.sup.3 is as defined
herein.
##STR00017##
A compound of formula A6 may be prepared by the synthetic methods
described in the schemes provided herein. A compound of formula A6
may be treated with zinc cyanide in the presence of a palladium
catalyst such as Pd(PPh.sub.3).sub.4 to afford a cyanide of formula
I1. Reaction of the cyano group with hydroxylamine hydrochloride in
the presence of a base affords a compound of formula I3.
Condensation of a compound of formula I2 with CDI in the presence
of a base such as DBU gives a compound of formula (I)-I. Compounds
of formula (I)-I wherein R.sub.3 contains an amino protecting group
may require conventional removal of the group.
[0313] Scheme J illustrates the preparation of compounds of formula
(I)-J and (I)-J1 wherein R.sub.3 is 2-(N-methylamino)ethyl or
azetidin-3-ylmethyl, and R.sub.a is hydrogen or
2-(N-methylamino)ethyl, respectively. R.sub.3J is defined as
N-protected methylaminomethyl or N-protected azetidin-3-yl.
##STR00018##
A compound of formula C5, E3, or F5 may undergo a reductive
alkylation with an aldehyde of formula J1 in the presence of a
hydride source such as sodium triacetoxyborohydride, followed by
conventional amino deprotection, to afford a mixture of compounds
of formula (I)-J and formula (I)-J1. Products of formula (I)-J and
formula (I)-J1 may be separated using conventional separation
methods known to those skilled in the art.
[0314] Scheme K illustrates the preparation of compounds of formula
(I)-K, formula (I)-K1, and formula (I)-K2, wherein R.sub.1, Y, and
R.sub.3 are as defined herein and R.sub.a is optionally substituted
C.sub.1-2alkyl as defined herein.
##STR00019##
A compound of formula A6 may undergo a reductive alkylation with an
aldehyde of formula K1 in the presence of a hydride source such as
sodium cyanoborohydride or sodium triacetoxyborohydride to afford a
compound of formula K2. A compound of formula K2 may be coupled
with a compound of formula D1 which, upon removal of any chemically
necessary protecting groups, may afford, upon optional amino
deprotection, a compound of formula (I)-K wherein Y is a bond.
Similarly, a compound of formula K1 may be coupled with a compound
of formula B1 to afford a compound of formula (I)-K1 wherein Y is
vinyl. Conventional reduction of the vinyl group as described in
Scheme B affords, upon optional amino deprotection, a compound of
formula (I)-K2 wherein Y is ethyl.
[0315] Scheme L illustrates the preparation of compounds of formula
(I)-L, wherein R.sub.1L is di(C.sub.1-2alkyl)aminocarbonyl or
--OR.sub.1f, R.sub.3 is defined herein, and R.sub.a is optionally
substituted C.sub.1-2alkyl as defined herein.
##STR00020##
A compound of formula (I)-C or formula (I)-F may undergo a
reductive alkylation with an aldehyde of formula K1 in the presence
of a hydride source such as sodium cyanoborohydride or sodium
triacetoxyborohydride to afford, upon optional amino deprotection,a
compound of formula (I)-L.
[0316] Scheme M illustrates the preparation of compounds of Formula
(I)-M wherein Y and R.sub.1 are as defined herein, and R.sub.3 is
taken with --N--R.sub.a to form piperazin-1-yl.
##STR00021##
[0317] A compound of formula A4 may be treated with a protected
amine of formula E4 in the presence of a suitable base such as
potassium carbonate to afford a compound of formula M1. Suitable Y
and R.sub.1 groups of the present invention may be installed by
reaction with a compound of formula A7, B1, or F3, for example, as
taught in the schemes provided herein, to afford a compound of
formula M2. Amino deprotection using conventional chemistry affords
a compound of formula (I)-M.
SPECIFIC EXAMPLES
[0318] Reagents were purchased from commercial sources. Nuclear
magnetic resonance (NMR) spectra for hydrogen atoms were measured
in the indicated solvent with tetramethylsilane (TMS) as the
internal standard on a Bruker Avance or Varian (300 or 400 MHz)
spectrometer. The values are expressed in parts per million
downfield from TMS. The mass spectra (MS) were determined on a
Micromass Platform LC or Agilent 1100 LCMS spectrometer as (ESI)
m/z (M+H.sup.+) using an electrospray technique. Microwave
accelerated reactions were performed using a CEM Discover or
Biotage microwave instrument, and were contained in a sealed
pressure vessel unless otherwise noted. Stereoisomeric compounds
may be characterized as racemic mixtures or as separate
diastereomers and enantiomers thereof using X-ray crystallography
and other methods known to one skilled in the art. Unless otherwise
noted, the materials used in the examples were obtained from
readily available commercial suppliers or synthesized by standard
methods known to one skilled in the art of chemical synthesis. The
substituent groups, which vary between examples, are hydrogen
unless otherwise noted.
Example 1
##STR00022## ##STR00023##
[0320] A. 4-Bromo-2-(4-methoxy-phenoxy)nitrobenzene (1c). A mixture
of Compound 1a (2.20 g, 10.0 mmol), 4-methoxyphenol (Compound 1b,
1.32 g, 10.5 mmol), K.sub.2CO.sub.3 (1.52 g, 11.0 mmol), and 6 mL
of DMF was stirred at 75.degree. C. for 3 h. The mixture was
concentrated in vacuo and the residue was partitioned between EtOAc
and water. The organic layer was washed successively with 2N
aqueous NaOH, 2N aqueous HCl, saturated aqueous NaHCO.sub.3, and
brine, dried over Na.sub.2SO.sub.4, and concentrated to give
Compound 1c as a brown gel (2.95 g, 91%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 7.11-7.84 (d, 1H), 7.24-7.27 (m, 1H),
7.01-7.06 (m, 3H), 6.93-6.97 (m, 2H), 3.71 (s, 3H).
[0321] B. 4-Bromo-2-(4-methoxy-phenoxy)-aniline (1d). A mixture of
Compound 1c (1.64 g, 5.06 mmol), zinc (1.98 g, 30.4 mmol), 15 mL of
HOAc, and 50 mL of MeOH was stirred at 20.degree. C. for 20 h.
After removal of solvents, the residue was partitioned between
EtOAc and 3N aqueous NaOH. The organic phase was washed with brine,
dried over Na.sub.2SO.sub.4, and concentrated to give Compound 1d
as a brown oil (1.54 g, 103% yield). MS: m/z 294.0 (M+H).sup.+.
[0322] C.
2-(S)-{[4-Bromo-2-(4-methoxy-phenoxy)-phenylamino]-methyl}-pyrro-
lidine-1-carboxylic acid tert-butyl ester (1f). NaBH.sub.3CN (0.67
mmol, 10.1 mmol) was added to a mixture of Compound 1d (1.45 g,
5.06 mmol) and Boc-L-prolinal (Compound 1e, 1.04 g, 5.06 mmol) in
20 mL of MeOH and 2.5 mL of HOAc. The mixture was stirred at
20.degree. C. for 1.5 h. After evaporation of solvent, the residue
was extracted with EtOAc. The organic layer was washed successively
with 1N aqueous NaOH, 1N aqueous HCl, and brine and was dried over
Na.sub.2SO.sub.4. Concentration and purification by flash column
chromatography (SiO.sub.2), eluting with a hexanes-ether gradient,
afforded Compound 1f as a yellow oil (2.36 g, 98% yield) MS: m/z
476.9, 478.8 (M+H).sup.+.
[0323] D.
(E)-2-(S)-{[4-(2-Ethoxycarbonyl-ethenyl)-2-(4-methoxy-phenoxy)-p-
henylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
(1h). A mixture of Compound 1f (0.19 g, 0.4 mmol), ethyl acrylate
(1g, 0.43 g, 0.045 mL, 0.5 mmol), Pd(OAc).sub.2 (0.0009 g, 0.004
mmol), tri-o-tolylphosphine (0.0049 g, 0.016 mmol), and 0.4 mL of
DMF was irradiated in a microwave reactor for 10 min at 160.degree.
C. Purification by preparative TLC, eluting with 3:7 EtOAc:hexanes,
gave Compound 1h as a yellow solid (0.15 g, 78% yield). MS: m/z
483.2 (M+H).sup.+.
[0324] E.
(E)-2-(S)-{[4-(2-Carboxy-ethenyl)-2-(4-methoxy-phenoxy)-phenylam-
ino]-methyl}-pyrrolidine-1-carboxylic acid tent-butyl ester (1i). A
mixture of Compound 1h (0.15 g, 0.31 mmol), 1 mL of 3N aqueous NaOH
(3 mmol), and 1 mL of MeOH was stirred at 20.degree. C. for 20 h.
After evaporation of the MeOH, the aqueous phase was acidified with
1N aqueous HCl and extracted with EtOAc. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to
give Compound 1i (0.18 g, 124% yield). MS: m/z 469.3
(M+H).sup.+.
[0325] F.
2-(S)-{[4-(2-Diethylcarbamoyl-ethenyl)-2-(4-methoxy-phenoxy)-phe-
nylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
(1k). A mixture of Compound 1i (0.18 g, 0.38 mmol),
N,N-diethylamine (Compound 1j, 0.04 mL, 0.38 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide monohydrochloride
(EDC-HCl, 0.095 g, 0.49 mmol), and HOBt (0.10 g, 0.76 mmol) was
stirred in 3 mL of DMF at 20.degree. C. for 20 h. Water was added
and the mixture was extracted with EtOAc. The organic phase was
washed successively with 1N aqueous HCl, brine, saturated aqueous
NaHCO.sub.3, and brine and was dried over MgSO.sub.4. Evaporation
of the solvent and purification by preparative TLC, eluting with
1:1 ether:hexanes, gave Compound 1k (0.100 g, 50% yield). MS: m/z
524.2 (M+H).sup.+.
[0326] G. Cpd 1:
(2E)-N,N-Diethyl-3-[3-(4-methoxyphenoxy)-4-{[(2S)-pyrrolidin-2-ylmethyl]a-
mino}phenyl]prop-2-enamide. A mixture of Compound 1k (0.026 g,
0.050 mmol), TFA, and CH.sub.2Cl.sub.2 was stirred at 20.degree. C.
for 4 h. After concentration, the residue was purified by reverse
phase HPLC to afford Cpd 1 as a TFA salt (0.0063 g, 19% yield). MS:
m/z 424.2 (M+H).sup.+.
Example 2
##STR00024##
[0328] A.
2-(S)-{[4-(2-Diethylcarbamoyl-ethyl)-2-(4-methoxy-phenoxy)-pheny-
lamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester
(2a). A mixture of compound 1k (0.050 g, 1.0 mmol) and 10%
palladium on carbon in MeOH was shaken under a hydrogen atmosphere
(34 psi) at 20.degree. C. for 4 h. The catalyst was filtered and
solvent was removed by evaporation to give Compound 2a. MS: m/z
526.3 (M+H).sup.+.
[0329] B. Cpd 2:
N,N-Diethyl-3-[3-(4-methoxyphenoxy)-4-{[(2S)-pyrrolidin-2-ylmethyl]amino}-
phenyl]propanamide. A mixture of Compound 2a (0.050 g, 0.095 mmol),
TFA, and CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 4 h.
After concentration, the residue was purified by reverse phase HPLC
to afford Cpd 2 as a TFA salt (0.022 g, 36% yield). .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 6.87-6.91 (m, 5H), 6.78 (d, 1H),
6.60 (d, 1H), 3.90 (m, 1H), 3.79 (s, 3H), 3.42-3.48 (m, 2H)
3.24-3.34 (m, 6H), 2.77 (t, 2H), 2.53 (t, 2H), 2.18-2.28 (m, 1H),
2.00-2.14 (m, 2H), 1.73-1.86 (m, 1H), 1.03-1.08 (m, 6H); MS: m/z
426.3 (M+H).sup.+.
Example 3
##STR00025## ##STR00026##
[0331] A. 4-Chloro-2-(4-methoxy-phenoxy)nitrobenzene (3b).
4-Chloro-2-fluoronitrobenzene (Compound 3a, 1.76 g, 10 mmol),
Compound 1b (1.30 g, 10.5 mmol), and K.sub.2CO.sub.3 (1.52 g, 11
mmol) were heated in 6 mL of DMF at 75.degree. C. for 3 h. The
mixture was concentrated in vacuo and the residue was partitioned
between EtOAc and water. The organic layer was washed successively
with 1N aqueous NaOH, 1N aqueous HCl, saturated aqueous
NaHCO.sub.3, and brine and dried over Na.sub.2SO.sub.4.
Concentration and purification by flash column chromatography
(SiO.sub.2), eluting with a hexanes-EtOAc gradient, afforded
Compound 3b as a yellow solid (2.75 g, 98% yield) MS: m/z 279.9
(M+H).sup.+.
[0332] B. 4-Chloro-2-(4-methoxy-phenoxy)-aniline (3c). A mixture of
Compound 3b (2.47 g, 8.83 mmol), zinc (3.46 g, 53 mmol), 60 mL of
HOAc, 5 mL of THF, and 36 mL of MeOH was stirred at 20.degree. C.
for 20 h. The solid material was filtered and washed with MeOH. The
filtrate was partitioned between EtOAc and 1N aqueous NaOH. The
organic phase was washed with brine, dried over Na.sub.2SO.sub.4,
and concentrated to give Compound 3c as a black gel that was used
without purification (1.80 g, 82% yield). MS: m/z 249.9
(M+H).sup.+.
[0333] C.
2-(S)-{[4-Chloro-2-(4-methoxy-phenoxy)-phenylamino]-methyl}-pyrr-
olidine-1-carboxylic acid tert-butyl ester (3d). NaBH.sub.3CN (0.95
g, 14.4 mmol) was added to a mixture of Compound 3c (1.80 g, 7.2
mmol) and Compound 1e (1.48 g, 7.2 mmol) in 28 ml, of MeOH and 3.5
mL of HOAc. The mixture was stirred at 20.degree. C. for 1 h. After
evaporation of solvent, the residue was extracted with EtOAc. The
organic layer was washed successively with saturated aqueous
NaHCO.sub.3 and brine and was dried over Na.sub.2SO.sub.4.
Concentration and purification by flash column chromatography
(SiO.sub.2), eluting with 3:7 EtOAc:hexanes, afforded Compound 3d
as a brown oil (2.84 g, 91% yield). MS: m/z 433.1 (M+H).sup.+.
[0334] D.
(E)-2-(S)-({2-(4-Methoxy-phenoxy)-4-[2-(4-methoxy-phenyl)-etheny-
l]-phenylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl
ester (3f). A mixture of Compound 3d (0.11 g, 0.254 mmol),
4-vinylanisole (Compound 3e, 0.042 g, 0.042 mL, 0.305 mmol),
Pd.sub.2(dba).sub.3 (0.035 g, 0.038 mmol), P(t.sup.-Bu).sub.3
(0.032 g, 0.04 mL, 0.152 mmol), Cs.sub.2CO.sub.3 (0.091 g, 0.279
mmol), and 0.2 mL of dioxane was irradiated in a microwave reactor
at 180.degree. C. for 30 min. Brine was added and the mixture was
extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated, and the residue was purified by
preparative TLC to give Compound 3f (0.05 g, 51% yield). MS: m/z
531.4 (M+H).sup.+.
[0335] E.
(E)-2-(S)-({2-(4-Methoxy-phenoxy)-4-[2-(4-methoxy-phenyl)-ethyl]-
-phenylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl
ester (3g). A mixture of compound 3f (0.050 g, 0.094 mmol) and 10%
palladium on carbon in MeOH was shaken under a hydrogen atmosphere
(38 psi) at 20.degree. C. The catalyst was filtered and solvent was
removed by evaporation to give Compound 3g (0.05 g, 100%
yield).
[0336] F. Cpd 3:
(S)-{2-(4-Methoxy-phenoxy)-4-[2-(4-methoxy-phenyl)-ethyl]-phenyl}-pyrroli-
din-2-ylmethyl-amine. A mixture of Compound 3g (0.050 g, 0.094
mmol), TFA, and CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 2
h. After concentration, the residue was dissolved in CH.sub.3CN and
purified by reverse phase HPLC to afford Cpd 3 as a TFA salt (0.018
g, 29% yield). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 6.72-6.94
(m, 10H), 6.38 (m, 1H), 3.81-3.92 (m, 1H), 3.76 (s, 3H), 3.74 (s,
3H), 3.21-3.44 (m, 4H), 2.69-2.71 (m, 4H), 1.98-2.28 (m, 3H),
1.71-1.82 (m, 1H); MS: m/z 432.9 (M+H).sup.+.
[0337] Following the procedure described above for Example 3 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00001 MS Cpd (M + H).sup.+ .sup.1H NMR 4 433.2 .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 7.05-7.11 (m, 1H), 6.49-6.90 (m,
9H), 6.42 (m, 1H), 3.80-3.92 (m, 1H), 3.75 (s, 3H), 3.70 (s, 3H),
3.21-3.52 (m, 4H), 2.73-2.79 (m, 4H), 1.91-2.28 (m, 3H), 1.72-1.80
(m, 1H) 5 402.9 .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.05-7.18 (m, 5H), 6.52-6.86 (m, 6H), 6.44 (m, 1H), 3.80-3.90 (m,
1H), 3.78 (s, 3H), 3.26-3.45 (m, 4H), 2.73-2.77 (m, 4H), 1.92-2.26
(m, 3H), 1.72-1.80 (m, 1H) 6 421.2 .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 6.72-7.08 (m, 10H), 6.38 (m, 1H), 3.81-3.91
(m, 1H), 3.79 (s, 3H), 3.24-3.46 (m, 4H), 2.77-2.79 (m, 4H),
1.96-2.28 (m, 3H), 1.73-1.81 (m, 1H) 7 421.2 .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.14-7.22 (m, 1H), 6.72-6.89 (m, 9H), 6.42 (m,
1H), 3.80-3.92 (m, 1H), 3.78 (s, 3H), 3.25-3.46 (m, 4H), 2.75-2.82
(m, 4H), 1.94-2.25 (m, 3H), 1.72-1.79 (m, 1H)
Example 4
##STR00027##
[0339] A.
2-(S)-{[4-[2-(3-Carboxy-phenyl)-ethyl]-2-(4-methoxy-phenoxy)-phe-
nylamino]-methyl}-pyrrolidine-1-carboxylic acid tent-butyl ester
(4a). Compound 4a was prepared according to the method used to
prepare Compound 3g described in Example 3 above, substituting
3-ethenylbenzoic acid for Compound 3e. MS: m/z 547.2
(M+H).sup.+.
[0340] B.
2-(S)-{[4-[2-(3-Diethylcarbamoyl-phenyl)-ethyl]-2-(4-methoxy-phe-
noxy)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl
ester (4b). A mixture of Compound 4b (0.016 g, 0.029 mmol),
Compound 1j (0.0021 g, 0.003 mL, 0.029 mmol), PyBOP (0.030 g, 0.058
mmol), HOBt (0.0059 g, 0.044 mmol), DIEA (0.0075 g, 0.010 mL, 0.058
mmol), and 1 mL of DMF was stirred at 20.degree. C. for 3 h. Water
was added and the mixture was extracted with EtOAc. The organic
layer was washed successively with 1N aqueous HCl, saturated
aqueous NaHCO.sub.3, and brine and was dried over Na.sub.2SO.sub.4.
Evaporation of solvent and purification by preparative TLC, eluting
with 3:7 EtOAc:hexanes, afforded Compound 4b. MS: m/z 602.3
(M+H).sup.+.
[0341] C. Cpd 8:
(S)-N,N-Diethyl-3-(2-{3-(4-methoxy-phenoxy)-4-[(pyrrolidin-2-ylmethyl)-am-
ino]-phenyl}-ethyl)-benzamide. A mixture of Compound 4b, TFA, and
CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 1.5 h. After
concentration, the residue was dissolved in CH.sub.3CN and purified
by reverse phase HPLC to afford Cpd 8 as a TFA salt (0.002 g, 9%
yield, steps B and C). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.25-7.33 (m, 2H), 7.12-7.17 (m, 2H), 7.03 (m, 1H), 6.74-6.86 (m,
5H), 6.43 (m, 1H), 3.82-3.90 (m, 1H), 3.77 (s, 3H), 3.38-3.57 (m,
4H), 3.13-3.31 (m, 4H), 2.76-2.86 (m, 4H), 2.00-2.28 (m, 3H),
1.75-1.82 (m, 1H), 1.21-1.26 (m, 3H), 0.98-1.04 (m, 3H); MS: m/z
502.4 (M+H).sup.+.
Example 5
##STR00028## ##STR00029##
[0343] A. N,N-Diethyl-4-nitro-3-fluoro-benzamide (5b). A mixture of
Compound 5a (0.50 g, 2.7 mmol), Compound 1j (0.20 g, 0.28 mL, 2.7
mmol), PyBOP (2.81 g, 5.4 mmol), HOBt (0.55 g, 4.05 mmol), DIEA
(0.70 g, 0.94 mL, 5.4 mmol), and 8 mL of DMF was stirred at
20.degree. C. for 3 h. Water was added and the mixture was
extracted with EtOAc. The organic layer was washed successively
with 1N aqueous HCl, saturated aqueous NaHCO.sub.3, and brine and
was dried over Na.sub.2SO.sub.4. Evaporation of solvent and
purification by preparative TLC, eluting with 4:6 EtOAc:hexanes,
afforded Compound 5b (0.67 g, 103% yield). MS: m/z 240.9
(M+H).sup.+.
[0344] B. N,N-Diethyl-4-nitro-3-phenoxy-benzamide (5d). Compound 5b
(0.22 g, 0.92 mmol), phenol (Compound 5c, 0.10 g, 1.1 mmol),
Cs.sub.2CO.sub.3 (0.90 g, 2.7 mmol), and 4 mL of DMF were heated
with stirring at 120.degree. C. for 3 h. Water was added and the
resulting mixture was extracted with EtOAc. The organic layer was
washed successively with 3N aqueous NaOH, 2N aqueous HCl, and
brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue
was purified by preparative TLC to provide Compound 5d as a brown
oil. MS: m/z 315.0 (M+H).sup.+.
[0345] C. 4-Amino-N,N-diethyl-3-phenoxy-benzamide (5e). A mixture
of compound 5d, prepared in Step B, and 10% palladium on carbon in
MeOH was shaken under a hydrogen atmosphere (30 psi) at 20.degree.
C. for 3 h. The catalyst was collected by filtration and the
solvent was removed by evaporation to give Compound 5e (0.19 g, 73%
yield, steps B and C).
[0346] D.
2-[(4-Diethylcarbamoyl-2-phenoxy-phenylamino)-methyl]-pyrrolidin-
e-1-carboxylic acid tert-butyl ester (5f). NaBH.sub.3CN (0.025
mmol, 0.4 mmol) was added to a mixture of Compound 5e (0.063 g, 0.2
mmol) and Compound 1e (0.04 g, 0.2 mmol) in 5 mL of MeOH and 0.4 mL
of HOAc. The mixture was stirred at 20.degree. C. for 1.5 h. After
evaporation of solvent, the residue was extracted with EtOAc. The
organic layer was washed successively with saturated aqueous
NaHCO.sub.3 and brine and was dried over MgSO.sub.4. Concentration
and purification by preparative TLC afforded Compound 5f (0.07 g,
75% yield) MS: m/z 468.3 (M+H).sup.+.
[0347] E. Cpd 9:
(S)-N,N-Diethyl-3-phenoxy-4-[(pyrrolidin-2-ylmethyl)-amino]-benzamide.
A mixture of Compound 5f (0.07 g, 0.15 mmol), TFA, and
CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 1.5 h. After
concentration, the residue was dissolved in CH.sub.3CN and purified
by reverse phase HPLC to afford Cpd 9 as a TFA salt (0.044 g, 49%
yield). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.33-7.39 (m,
2H), 7.10-7.15 (m, 2H), 7.00-7.03 (m, 2H), 6.89-6.92 (m, 1H), 6.77
(m, 1H), 3.88-3.93 (m, 1H), 3.26-3.55 (m, 8H), 1.99-2.25 (m, 3H),
1.74-1.81 (m, 1H), 1.03-1.17 (m, 6H); MS: m/z 368.0
(M+H).sup.+.
[0348] Following the procedure described above for Example 5 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00002 MS Cpd (M + H).sup.+ .sup.1H NMR 10 398.0 .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 6.66-7.05 (m, 6H), 6.66 (m, 1H),
3.89-3.92 (m, 1H), 3.76 (s, 3H), 3.28-3.56 (m, 8H), 1.99-2.26 (m,
3H), 1.02-1.17 (m, 6H) 11 398.0 .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 7.11-7.21 (m, 2H), 6.97-7.06 (m, 3H), 6.84-6.86 (m, 1H),
6.48 (m, 1H), 3.88-4.00 (m, 1H), 3.77 (s, 3H), 3.54-3.58 (m, 2H),
3.28-3.38 (m, 6H), 2.00-2.27 (m, 3H), 1.81-1.86 (m, 1H), 0.95-1.18
(m, 6H)
Example 6
##STR00030## ##STR00031##
[0350] A. 3-Fluoro-4-nitrobiphenyl (6b).
4-Chloro-2-fluoronitrobenzene (Compound 3a, 3.51 g, 20 mmol),
phenylboronic acid (Compound 6a, 3.77 g, 30 mmol), potassium
fluoride (3.49 g, 60 mmol), Pd(OAc).sub.2 (0.045 g, 0.2 mmol), and
2-(di-t-butylphosphino)biphenyl (0.12 g, 0.4 mmol) were added to a
dry, nitrogen-swept flask. The flask was evacuated and flushed with
nitrogen three times, and THF (25 mL) was added. The reaction
mixture was stirred at ambient temperature for 20 h. EtOAc was
added and the organic solution was washed successively with 1N
aqueous NaOH and brine, dried over MgSO.sub.4, and concentrated.
The crude product was purified by flash column chromatography
(SiO.sub.2), eluting with a hexanes-EtOAc gradient to afford pure
Compound 6b (1.27 g, 30% yield) and an additional quantity of less
pure Compound 6b (3.66 g). .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 8.12-8.18 (m, 1H), 7.47-7.62 (m, 7H).
[0351] B. 4-(4-Nitro-biphenyl-3-yloxy)-benzonitrile (6d). Compound
6b (0.22 g, 1.0 mmol), 4-hydroxybenzonitrile (Compound 6c, 0.19 g,
1.5 mmol), Cs.sub.2CO.sub.3 (0.98 g, 3.0 mmol), and 4 ml, of DMF
were heated with stirring at 120.degree. C. for 3.5 h. The reaction
mixture was poured onto water and extracted with EtOAc. The organic
layer was washed successively with 3N aqueous NaOH, 2N aqueous HCl,
and brine and dried over Na.sub.2SO.sub.4. After removal of
solvent, crude Compound 6d was isolated and used without
purification (0.263 g, 83% yield). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 8.12-8.16 (m, 1H), 7.38-7.66 (m, 9H),
7.06-7.09 (m, 2H).
[0352] C. 4-(4-Amino-biphenyl-3-yloxy)-benzonitrile (6e). A mixture
of compound 6d (1.0 mmol) and tin (II) chloride dihydrate (1.13 g,
5 mmol) in 10 mL of MeOH was refluxed for 2.5 h. After cooling to
room temperature, solvent was removed by evaporation and the
residue was mixed with water. The aqueous solution was adjusted to
pH 9 using saturated aqueous NaHCO.sub.3 and the mixture was
extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4 and evaporated to give Compound 6e as a brown
solid that was used without purification. MS: m/z 287.2
(M+H).sup.+.
[0353] D.
2-(S)-{[3-(4-Cyano-phenoxy)-biphenyl-4-ylamino]-methyl}-pyrrolid-
ine-1-carboxylic acid tert-butyl ester (6f). NaBH.sub.3CN (0.066 g,
1.0 mmol) was added to a mixture of Compound 6e (0.14 g, 0.50 mmol)
and Compound 1e (0.10 g, 0.50 mmol) in 4 mL of MeOH and 0.3 mL of
HOAc. The mixture was stirred at 20.degree. C. for 1.5 h. After
evaporation of solvent, the residue was extracted with EtOAc. The
organic layer was washed successively with saturated aqueous
NaHCO.sub.3 and brine and was dried over MgSO.sub.4. Concentration
and purification by preparative TLC afforded Compound 6f as a brown
oil (0.167 g, 71% yield). MS: m/z 470.2 (M+H).sup.+.
[0354] E. Cpd 12.
(S)-4-{4-[(Pyrrolidin-2-ylmethyl)-amino]-biphenyl-3-yloxy}-benzonitrile.
A mixture of Compound 6f (0.167 g, 0.36 mmol), TFA, and
CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 2 h. After
concentration, the residue was dissolved in CH.sub.3CN and purified
by reverse phase HPLC to afford Cpd 12 as a TFA salt (0.029 g, 13%
yield). MS: m/z 370.2 (M+H).sup.+.
[0355] Following the procedure described above for Example 6 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00003 MS Cpd (M + H).sup.+ .sup.1H NMR 13 370.2 .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.18-7.52 (m, 11H), 7.00-7.03
(m, 1H), 3.80-3.90 (m, 1H), 3.48-3.52 (m, 2H), 3.26-3.31 (m, 2H),
2.02-2.24 (m, 3H), 1.75-1.82 (m, 1H) 14 345.1 .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.03-7.48 (m, 7H), 7.07-7.12 (m, 1H),
6.95-7.04 (m, 5H), 3.85-3.96 (m, 1H), 3.48-3.54 (m, 2H), 3.26-3.31
(m, 2H), 2.03-2.30 (m, 3H), 1.70-1.84 (m, 1H) 15 375.1 .sup.1H NMR
(300 MHz, CD.sub.3OD): .delta. 7.44-7.46 (m, 2H), 7.32-7.38 (m,
3H), 7.21-7.24 (m, 2H), 7.10 (m, 1H), 6.95-6.98 (m, 1H), 6.56-6.69
(m, 3H), 3.85-3.96 (m, 1H), 3.76 (s, 3H), 3.48-3.53 (m, 2H),
3.26-3.30 (m, 2H), 1.97-2.30 (m, 3H), 1.73-1.86 (m, 1H) 16 363.0
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.42-7.45 (m, 2H),
7.30-7.37 (m, 3H), 7.21-7.24 (m, 1H), 6.94-7.22 (m, 6H), 3.85-3.96
(m, 1H), 3.48-3.54 (m, 2H), 3.27-3.33 (m, 2H), 1.99-2.32 (m, 3H),
1.74-1.87 (m, 1H) 17 428.9 .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 6.97-7.50 (m, 12H), 3.83-3.95 (m, 1H), 3.40-3.53 (m, 2H),
3.27-3.31 (m, 2H), 2.00-2.28 (m, 3H), 1.77-1.82 (m, 2H) 18 412.8
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.53-7.55 (m, 2H),
7.23-7.32 (m, 7H), 6.93-6.96 (m, 1H), 6.46 (m, 1H), 3.95-4.08 (m,
1H), 3.59-3.63 (m, 2H), 3.31-3.36 (m, 2H), 2.09-2.38 (m, 3H),
1.82-1.93 (m, 1H) 19 348.9 .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 7.18-7.40 (m, 6H), 6.89-7.02 (m, 6H), 3.79 (s, 3H),
3.56-3.60 (m, 2H), 3.26-3.30 (m, 2H), 2.74 (s, 3H) 20 402.9 .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.98-8.02 (m, 2H), 7.43-7.50 (m,
3H), 7.35-7.37 (m, 2H), 7.19-7.23 (m, 2H), 6.99-7.06 (m, 3H),
3.82-3.94 (m, 1H), 3.87 (s, 3H), 3.48-3.52 (m, 2H), 3.25-3.31 (m,
2H), 1.93-2.28 (m, 3H), 1.71-1.83 (m, 1H) 21 402.9 .sup.1H NMR (300
MHz, CD.sub.3OD): .delta. 7.73-7.76 (m, 1H), 7.60 (m, 1H),
7.23-7.50 (m, 8H), 7.13 (m, 1H), 6.99-7.02 (m, 1H), 3.84-3.95 (m,
1H), 3.88 (s, 3H), 3.49-3.54 (m, 2H), 3.26-3.30 (m, 2H), 1.98-2.29
(m, 3H), 1.75-1.83 (m, 1H) 22 412.8 .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.56 (m, 1H), 7.18-7.40 (m, 7H), 6.91-6.99 (m,
3H), 3.89-3.95 (m, 1H), 3.53-3.56 (m, 2H), 3.28-3.34 (m, 2H),
2.00-2.27 (m, 3H), 1.76-1.83 (m, 1H) 23 375.0 .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.23-7.44 (m, 6H), 6.93-7.10 (m, 6H),
3.76-3.88 (m, 1H), 3.79 (s, 3H), 3.44-3.48 (m, 2H), 3.14-3.18 (m,
2H), 2.25-2.32 (m, 2H), 1.70-1.84 (m, 2H)
Example 7
##STR00032##
[0357] A.
(2S,4R)-4-Fluoro-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carb-
oxylic acid tert-butyl ester (7b). HBTU (12.3 g, 32.3 mmol) was
added in portions to a solution of Compound 7a (6.26 g, 26.9 mmol),
N,O-dimethylhydroxylamine hydrochloride (3.15 g, 32.3 mmol), and
DIEA (5.62 mL, 4.17 g, 32.3 mmol) in 60 mL of DMF at 0.degree. C.
After 15 min, the cooling bath was removed and the mixture was
stirred 16 h at 20.degree. C. EtOAc (200 mL) and saturated aqueous
NH.sub.4Cl (100 mL) were added. The organic layer was separated,
washed with saturated aqueous NaHCO.sub.3 (100 mL), and brine (100
mL), and dried over MgSO.sub.4. The solution was concentrated to
give 7.7 g of off-white oil that was purified by flash column
chromatography (SiO.sub.2), eluting with 10% MeOH/CH.sub.2Cl.sub.2,
to yield Compound 7b (5.47 g, 74% yield). .sup.1H-NMR
(DMSO-d.sub.6): .delta. 5.29 (1H, dt), 4.70 (1H, dd), 3.50 (2H, m),
3.13 (3H, s), 2.69 (3H, s), 2.00 (2H, m), 1.34 (9H, s).
[0358] B. (2S,4R)-4-Fluoro-2-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (7c). A 1M solution of LiAlH4 in Et.sub.2O (19.2
mL, 19.2 mmol) was added in dropwise to a solution of Compound 7b
(3.54 g, 12.8 mmol) in 10 mL of Et.sub.2O at 0.degree. C. The
mixture was stirred for 1.5 h at 20.degree. C. 10 mL of 0.5 N
saturated aqueous KHSO.sub.4 was added, followed by 25 mL of
Et.sub.2O. The organic layer was separated and washed with 1N
aqueous NaOH to break up the aluminum complex. The organic layer
was separated, dried over MgSO4, and concentrated to provide
Compound 7c as an oil (1.33 g, 48% yield). .sup.1H-NMR
(DMSO-d.sub.6): .delta. 9.45 (1H, s) 5.10 (1H, m), 4.20 (1H, m),
3.50 (2H, m), 2.20 (2H, m), 1.48 (9H, s).
Example 8
##STR00033##
[0360] A.
(2S,4R)-2-{[4-Bromo-2-(4-methoxy-phenoxy)-phenylamino]-methyl}-4-
-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (8a). A
mixture of Compound 1d (1.18 g, 4.0 mmol), Compound 7c (1.33 g, 6.1
mmol), and 5 drops of HOAc in 10 mL of DCE was stirred for 5 min at
20.degree. C. NaBH(OAc).sub.3 (2.54 g, 12 mmol) was added in
portions over a 5 min period and the mixture was stirred at
20.degree. C. for 20 h. Saturated aqueous NH.sub.4Cl (25 mL) was
added to the stirring mixture, followed by 100 mL of
CH.sub.2Cl.sub.2 and 10 mL of water. The organic layer was
separated and the aqueous layer was extracted with 50 mL of
CH.sub.2Cl.sub.2. The combined organic layers were dried over
Na2SO4 and concentrated to give 2 g of crude product. This material
was purified by flash column chromatography (SiO.sub.2), eluting
with a hexanes-EtOAc gradient, to yield Compound 8a (0.496 g, 25%
yield). MS: m/z 495.0/497.0 (M+H).sup.+.
[0361] B.
(2S,4R)-2-{[4-(5-Cyano-pyridin-3-yl)-2-(4-methoxy-phenoxy)-pheny-
lamino]-methyl}-4-fluoro-pyrrolidine-1-carboxylic acid tent-butyl
ester (8c). A mixture of Compound 8a (0.124 g, 0.30 mmol), Compound
8b (0.096 g, 0.65 mmol), Pd(dppf)Cl.sub.2 (0.055 g, 0.075 mmol),
Cs.sub.2CO.sub.3 (0.244 g, 0.75 mmol), 0.25 mL of EtOH, and 1 mL of
dioxane was irradiated in a microwave reactor at 140.degree. C. for
15 min. The reaction mixture was filtered and the solid was washed
with 100 mL of EtOAc. The filtrate was washed with saturated
aqueous K.sub.2CO.sub.3 dried over Na.sub.2SO.sub.4 and charcoal,
and concentrated to afford 0.32 g of crude residue containing
Compound 8c.
[0362] C. Cpd 24:
(2S,4R)-5-[4-[(4-Fluoro-pyrrolidin-2-ylmethyl)-amino]-3-(4-methoxy-phenox-
y)-phenyl]-nicotinonitrile. TFA (5 mL) was added dropwise to a
solution of the residue from Step B above in 10 mL of
CH.sub.2Cl.sub.2 The mixture was stirred for 4 h at 20.degree. C.
and was then evaporated. The residue was purified by reverse phase
HPLC to afford Cpd 24 as a TFA salt (0.058 g, 36% yield for 2
steps). .sup.1H NMR (300 MHz, CD.sub.3OD): 8.76 (1H, d), 8.63 (1H,
d), 8.14 (1H, d), 7.31 (1H, dd), 6.98-6.82 (6H, m), 5.37 (1H, d),
4.12 (1H, m), 3.65-3.40 (5H, m), 2.50 (1H, m), 1.95 (1H, m); MS:
m/z 419.1 (M+H).sup.+.
[0363] Following the procedure described above for Example 8 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00004 MS Cpd (M + H).sup.+ .sup.1H NMR 25 412.0 26 440.1
27 424.3 .sup.1H NMR (400-MHz, CDCl.sub.3): .delta. 8.44 (s 1H);
8.33 (s, 1H); 7.86 (s, 1H); 7.33 (s, 1H); 6.95 (m, 1H); 4.11 (m,
2H); 3.8 (s, 6H); 3.4 (m, 1H); 255 (m, 2H); 2.24-2.01 (m, 2H); 1.24
(m, 1H) 28 408.3 .sup.1H NMR (400-MHz, CDCl.sub.3): .delta. 8.7 (s,
1H); 8.5 (m, 2H); 7.5 (s, 1H); 7.2-6.9 (m, 6H); 4.2 (m, 1H); 3.7
(s, 3H); 3.7 (m, 3H); 3.5 (m, 1H); 2.85 (m, 3H); 2.56 (s, 3H)
Example 9
##STR00034##
[0365] A.
2-(S)-{[3-(4-Carbamoyl-phenoxy)-biphenyl-4-ylamino]-methyl}-pyrr-
olidine-1-carboxylic acid tent-butyl ester (9a). 20% aqueous NaOH
(0.5 mL) and 30% aqueous H.sub.2O.sub.2 (0.4 mL) were added to a
solution of compound 6f (0.040 g, 0.085 mmol) in 1.5 mL of EtOH and
1.5 mL of dioxane. The mixture was heated at 60.degree. C. for 2
days. The reaction mixture was extracted with EtOAc, dried over
MgSO.sub.4, and concentrated to give Compound 9a. MS: m/z 488.3
(M+H).sup.+.
[0366] B. Cpd 29:
(S)-4-{4-[(Pyrrolidin-2-ylmethyl)-amino]-biphenyl-3-yloxy}-benzamide.
A mixture of Compound 9a, TFA, and CH.sub.2Cl.sub.2 was stirred at
20.degree. C. for 2 h. After concentration, the residue was
dissolved in CH.sub.3CN and purified by reverse phase HPLC to
afford Cpd 29 as a TFA salt (0.015 g, 29% yield for 2 steps).
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.87-7.89 (m, 2H),
7.33-7.49 (m, 5H), 7.18-7.19 (m, 2H), 7.00-7.06 (m, 3H), 3.84-3.95
(m, 1H), 3.44-3.57 (m, 2H), 3.28-3.35 (m, 2H), 1.98-2.28 (m, 3H),
1.72-1.82 (m, 1H); MS: m/z 387.9 (M+H).sup.+.
[0367] Following the procedure described above for Example 9 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compound of the present invention was prepared:
TABLE-US-00005 MS Cpd (M + H).sup.+ .sup.1H NMR 30 387.9 .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.55-7.58 (m, 1H), 7.31-7.49 (m,
7H), 7.14-7.23 (m, 3H), 6.98-7.00 (m, 1H), 3.85-3.96 (m, 1H),
3.43-3.58 (m, 2H), 3.25-3.31 (m, 2H), 1.98-2.27 (m, 3H), 1.73-1.84
(m, 1H)
Example 10
##STR00035##
[0369] A.
2-(S)-{[3-(4-Methoxycarbonyl-phenoxy)-biphenyl-4-ylamino]-methyl-
}-pyrrolidine-1-carboxylic acid tert-butyl ester (10a). Compound
10a was prepared according to the method used to prepare Compound
6f described in Example 6 above, substituting methyl
4-hydroxybenzoate for Compound 6c. MS: m/z 503.2 (M+H).sup.+.
[0370] B.
2-(S)-{[3-(4-Carboxy-phenoxy)-biphenyl-4-ylamino]-methyl}-pyrrol-
idine-1-carboxylic acid tert-butyl ester (10b). A mixture of
Compound 10a (0.034 g, 0.068 mmol), 20% aqueous NaOH, and MeOH was
stirred at 20.degree. C. for 20 h. After evaporation of the MeOH,
the aqueous phase was acidified and extracted with EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and concentrated to give Compound 10b (0.032 g, 95% yield). MS: m/z
489.2 (M+H).sup.+.
[0371] C. Cpd 31:
(S)-4-{4-[(Pyrrolidin-2-ylmethyl)-amino]-biphenyl-3-yloxy}-benzoic
acid. A mixture of Compound 10b (0.032 g, 0.065 mmol), TFA, and
CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 2 h. After
concentration, the residue was dissolved in CH.sub.3CN and purified
by reverse phase HPLC to afford Cpd 31 as a TFA salt (0.019 g, 47%
yield). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.98-8.13 (m,
2H), 7.43-7.50 (m, 3H), 7.32-7.37 (m, 2H), 7.20-7.25 (m, 2H),
6.99-7.05 (m, 3H), 3.83-3.96 (m, 1H), 3.42-3.58 (m, 2H), 3.25-3.30
(m, 2H), 1.95-2.28 (m, 3H), 1.70-1.83 (m, 1H) : MS: m/z 389.0
(M+H).sup.+.
[0372] Following the procedure described above for Example 10 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compound of the present invention was prepared:
TABLE-US-00006 MS Cpd (M + H).sup.+ .sup.1H NMR 32 389.0 .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.74-7.79 (m, 1H), 7.61-7.62 (m,
1H), 7.14-7.48 (m, 9H), 6.97-7.00 (m, 1H), 3.87-3.90 (m, 1H),
3.49-3.53 (m, 2H), 3.25-3.32 (m, 2H), 1.99-2.22 (m, 3H), 1.73-1.80
(m, 1H)
Example 11
##STR00036##
[0374] A.
2-(S)-{[3-(4-Diethylcarbamoyl-phenoxy)-biphenyl-4-ylamino]-methy-
l}-pyrrolidine-1-carboxylic acid tert-butyl ester (11a). A mixture
of Compound 10b (0.021 g, 0.043 mmol), Compound 1j (0.0094 g,
0.0013 mL, 0.129 mmol), PyBOP (0.045 g, 0.086 mmol), HOBt (0.0087
g, 0.065 mmol), DIEA (0.011 g, 0.015 mL, 0.086 mmol), and 1 mL of
DMF was stirred at 20.degree. C. for 3 h. Water was added and the
mixture was extracted with EtOAc. The organic layer was washed
successively with 1N aqueous HCl, saturated aqueous NaHCO.sub.3,
and brine and was dried over MgSO.sub.4. Evaporation of solvent and
purification by reverse phase HPLC gave Compound 11a. MS: m/z 544.3
(M+H).sup.+.
[0375] B. Cpd 33:
(S)-N,N-Diethyl-4-{4-[(pyrrolidin-2-ylmethyl)-amino]-biphenyl-3-yloxy}-be-
nzamide. A mixture of Compound 11a, TFA, and CH.sub.2Cl.sub.2 was
stirred at 20.degree. C. for 2 h. After concentration, the residue
was dissolved in CH.sub.3CN and purified by reverse phase HPLC to
afford Cpd 33 as a TFA salt (0.016 g, 55% yield for 2 steps).
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 7.32-7.50 (m, 7H),
7.23-7.25 (m, 1H), 7.16 (m, 1H), 7.05-7.09 (m, 2H), 6.98-7.01 (m,
1H), 3.87-3.91 (m, 1H), 3.44-3.56 (m, 4H), 3.26-3.35 (m, 4H),
2.02-2.23 (m, 3H), 1.74-1.81 (m, 1H), 1.09-1.28 (m, 6H) ; MS: m/z
444.0 (M+H).sup.+.
[0376] Following the procedure described above for Example 11 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compound of the present invention was prepared:
TABLE-US-00007 MS Cpd (M + H).sup.+ .sup.1H NMR 34 444.0 .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.31-7.48 (m, 6H), 6.88-7.24 (m,
6H), 3.87-3.92 (m, 1H), 3.42-3.58 (m, 4H), 3.22-3.32 (m, 4H),
2.19-2.25 (m, 1H), 2.01-2.08 (m, 2H), 1.73-1.80 (m, 1H), 1.17-1.22
(m, 3H), 1.00-1.04 (m, 3H)
Example 12
##STR00037##
[0378] A.
2-(S)-{[3-(4-Methoxy-phenoxy)-biphenyl-4-ylamino]-methyl}-pyrrol-
idine-1-carboxylic acid tent-butyl ester (12b). A microwave
reaction vessel containing a mixture of Compound 3d (0.070 g, 0.16
mmol), Compound 6a (0.030 g, 0.24 mmol), Pd(OAc).sub.2 (0.0034 g,
0.015 mmol), Compound 12a (0.016 g, 0.039 mmol), and
K.sub.3PO.sub.4 (0.064 g, 0.30 mmol) was evacuated and flushed with
nitrogen three times. Toluene (0.5 mL) and THF (0.3 mL) were added
and the mixture was irradiated in a microwave reactor at
160.degree. C. for 30 min. The reaction mixture was filtered and
the concentrated filtrate was purified by preparative TLC to give
Compound 12b (0.050 g, 66% yield). MS: m/z 475.2 (M+H).sup.+.
[0379] B. Cpd 35:
(S)-[3-(4-Methoxy-phenoxy)-biphenyl-4-yl]-pyrrolidin-2-ylmethyl-amine.
A mixture of Compound 12b (0.050 g, 0.11 mmol), TFA, and
CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 1 h. After
concentration, the residue was dissolved in CH.sub.3CN and purified
by reverse phase HPLC to afford Cpd 35 as a TFA salt (0.0063 g, 9%
yield). .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 6.68-7.50 (m,
12H), 4.08-4.14 (m, 1H), 3.78-3.83 (m, 1H), 3.80 (s, 3H), 3.56-3.61
(m, 1H), 3.32-3.41 (m, 2H), 2.00-2.27 (m, 3H), 1.77-1.88 (m, 1H);
MS m/z 375.1 (M+H).sup.+.
Example 13
##STR00038##
[0381] A.
2-(S)-{[2-(4-Methoxy-phenoxy)-4-naphthalen-2-yl-phenylamino]-met-
hyl}-pyrrolidine-1-carboxylic acid tent-butyl ester (13b). A
mixture of Compound 1f (0.14 g, 0.30 mmol), Compound 13a (0.077 g,
0.45 mmol), Pd.sub.2(dba).sub.3 (0.0011 g, 0.012 mmol), Compound
12a (0.010 g, 0.024 mmol), K.sub.3PO.sub.4 (0.13 g, 0.60 mmol), and
0.6 mL of toluene was irradiated in a microwave reactor at
160.degree. C. for 30 min. The reaction mixture was filtered and
the concentrated filtrate was purified by preparative TLC to give
Compound 13b. MS: m/z 425.2 (M-Boc).
[0382] B. Cpd 36:
(S)-[2-(4-Methoxy-phenoxy)-4-naphthalen-2-yl-phenyl]-pyrrolidin-2-ylmethy-
l-amine. A mixture of Compound 13b, TFA, and CH.sub.2Cl.sub.2 was
stirred at 20.degree. C. for 1.5 h. After concentration, the
residue was dissolved in CH.sub.3CN and purified by reverse phase
HPLC to afford Cpd 36 as a TFA salt (0.0084 g, 3% yield for 2
steps). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.78-7.81 (m,
4H), 7.32-7.55 (m, 4H), 7.11 (m, 1H), 6.83-6.99 (m, 5H), 3.84-3.95
(m, 1H), 3.7 (s, 3H), 3.50-3.70 (m, 2H), 3.26 (m, 2H), 1.98-2.23
(m, 3H), 1.73-1.83 (m, 1H); MS: m/z 425.0 (M+H).sup.+.
[0383] Following the procedure described above for Example 13 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00008 MS Cpd (M + H).sup.+ .sup.1H NMR 37 424.9 .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 7.75-7.92 (m, 3H), 7.28-7.47 (m,
4H), 7.09-7.25 (m, 1H), 6.68-6.78 (m, 6H), 3.84-3.95 (m, 1H), 3.73
(s, 3H), 3.53-3.67 (m, 2H), 3.18-3.26 (m, 2H), 1.79-2.23 (m, 4H).
38 375.9 1H NMR (300 MHz, CDCl.sub.3): .delta. 8.44-8.47 (m, 2H),
7.45-7.48 (m, 2H), 7.25-7.29 (m, 1H), 6.75-6.91 (m, 6H), 3.74-4.10
(m, 5H), 3.34-3.61 (m, 3H), 2.13-2.30 (m, 3H), 1.84-1.93 (m, 1H).
39 375.9 1H NMR (300 MHz, CDCl.sub.3): .delta. 8.59-8.69 (m, 2H),
8.14-8.17 (m, 1H), 7.74-7.79 (m, 1H), 7.12-7.16 (m, 1H), 6.83 (s,
4H), 6.68-6.75 (m, 2H), 3.97-4.09 (m, 1H), 3.78 (s, 3H), 3.30-3.70
(m, 4H), 2.07-2.28 (m, 3H), 1.84-1.88 (m, 1H). 40 365.0 1H NMR (300
MHz, CDCl.sub.3): .delta. 6.50-7.54 (m, 10H), 4.02-4.18 (m, 1H),
3.80 (s, 3H), 3.74-3.79 (m, 1H), 3.26-3.58 (m, 3H), 2.02-2.26 (m,
3H), 1.79-1.84 (m, 1H). 41 380.9 1H NMR (300 MHz, CDCl.sub.3):
.delta. 7.17-7.30 (m, 4H), 6.77-6.96 (m, 6H), 3.82-3.94 (m, 1H),
3.77 (s, 3H), 3.43-3.63 (m, 2H), 3.14-3.26 (m, 2H), 1.94-21.9 (m,
3H), 1.70-1.82 (m, 1H). 42 377.2 43 394.2 44 401.1
Example 14
##STR00039##
[0385] A.
2-{[2-(4-methoxy-phenoxy)-4-pyridin-3-yl-phenylamino]-methyl}-py-
rrolidine-1-carboxylic acid tert-butyl ester (14a). Compound 14a
was prepared according to the method described in Example 13 above,
substituting pyridine-3-boronic acid for Compound 13a. MS: m/z
476.3 (M+H).sup.+.
[0386] B. Cpd 45:
(S)-4-{5-Pyridin-3-yl-2-[(pyrrolidin-2-ylmethyl)-amino]-phenoxy}-phenol.
A mixture of Compound 14a (0.18 g, 0.38 mmol), 2 mL of concentrated
(12 N) HCl, and 2 mL of MeOH was stirred at 20.degree. C. for 3 h.
After concentration, the residue was purified by preparative TLC,
eluting with MeOH:CH.sub.2Cl.sub.2. The product was taken up in
MeOH, filtered, and concentrated to give a yellow solid. This
material was neutralized with saturated aqueous NaHCO.sub.3 and
extracted into EtOAc. The organic phase was washed with water,
concentrated to a small volume, filtered through a 0.4 .mu.m filter
disk, and acidified with 2N aqueous HCl. The EtOAc was evaporated
and the residue was dissolved in water, filtered, and lyophilized.
The resulting material was purified by reverse phase HPLC. The
fractions containing Cpd 39 were concentrated, neutralized with
saturated aqueous NaHCO.sub.3, and extracted with EtOAc. The
organic phase was washed with water and concentrated; the residue
was dissolved in dilute aqueous HCl, filtered, and lyophilized to
give Cpd 39 as an HCl salt (0.195 g). The fractions containing Cpd
45 were concentrated and lyophilized to give Cpd 45 as a TFA salt
(0.013 g). MS: m/z 362.2 (M+H).sup.+.
Example 15
##STR00040##
[0388] A. 3-(4-Methoxy-phenoxy)-4-nitrobiphenyl (15a). Compound 6b
(0.22 g, 1.0 mmol), Compound 1b (0.19 g, 1.5 mmol),
Cs.sub.2CO.sub.3 (0.98 g, 3.0 mmol), and 4 mL of DMF were heated
with stirring at 120.degree. C. for 3 h. The reaction mixture was
poured onto ice water and the resulting solid was collected by
filtration. The solid was dissolved in EtOAc and dried over
Na.sub.2SO.sub.4. After removal of solvent, Compound 15a was
isolated as a brown oil that was used without purification (0.45 g,
.about.140% yield). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.02
(m, 1H), 7.32-7.47 (m, 6H), 7.06-7.10 (m, 3H), 6.91-6.94 (m, 2H),
3.82 (s, 3H).
[0389] B. 3-(4-Methoxy-phenoxy)-biphenyl-4-ylamine (15b). A mixture
of compound 15a (.about.1.0 mmol) and 10% palladium on carbon in
MeOH was shaken under a hydrogen atmosphere (34 psi) at 20.degree.
C. for 3 h. The catalyst was filtered and solvent was removed by
evaporation to give Compound 15b as a brown oil that was used
without purification (0.33 g, 113% yield). MS: m/z 292.2
(M+H).sup.+.
[0390] C. Cpd 46: 1-[3-(4-Methoxy-phenoxy)biphenyl-4-yl]piperazine.
A mixture of Compound 15b (0.16 g, 0.55 mmol),
bis-(2-chloroethyl)ammonium chloride (Compound 15c, 0.10 g, 0.55
mmol), K.sub.2CO.sub.3 (0.038 g, 0.275 mmol) and 2 mL of n-butanol
was heated at reflux for 42 h. After cooling to room temperature,
brine was added and the mixture was extracted with EtOAc. The
organic layer was dried over MgSO.sub.4 and concentrated to give
crude residue that was purified by reverse phase HPLC to afford Cpd
46 as a TFA salt. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
7.47-7.50 (m, 2H), 7.37-7.41 (m, 3H), 7.28-7.31 (m, 1H), 7.12-7.19
(m, 2H), 6.92-6.94 (m, 4H), 3.77 (s, 3H), 3.35-3.39 (m, 4H),
3.18-3.22 (m, 4H); MS: m/z 360.9 (M+H).sup.+.
Example 16
##STR00041##
[0392] Cpd 47:
1-[3-(4-Methoxy-phenoxy)biphenyl-4-yl]-4-methyl-piperazine. To a
stirring solution of Cpd 46 (0.090 g, 0.25 mmol) and 37% aqueous
formaldehyde (0.5 mL) in 0.5 mL of acetonitrile was added sodium
cyanoborohydride (0.06 g, 0.9 mmol) and 0.5 mL of acetic acid. The
resulting mixture was stirred at 20.degree. C. for 3 h, and then
was quenched by adding saturated aqueous NaHCO.sub.3. Solvent was
removed by evaporation and the aqueous residue was extracted with
EtOAc. The organic layer was washed successively with 1N aqueous
NaOH, 1N aqueous HCl, and brine, dried over Na.sub.2SO.sub.4, and
concentrated. The resulting crude residue was purified by reverse
phase HPLC to afford Cpd 47 as a TFA salt. .sup.1H NMR (300 MHz,
CD.sub.3OD): .delta. 7.16-7.48 (m, 7H), 7.09 (m, 1H), 6.92 (m, 4H),
3.77 (s, 3H), 3.68-3.72 (m, 2H), 3.52-3.55 (m, 2H), 3.07-3.13 (m,
4H), 2.90 (s, 3H); MS: m/z 374.9 (M+H).sup.+.
Example 17
##STR00042## ##STR00043##
[0394] A.
2-(S)-{[4-Cyano-2-(4-methoxy-phenoxy)-phenylamino]-methyl}-pyrro-
lidine-1-carboxylic acid tert-butyl ester (17a). A mixture of
Compound 1f (0.13 g, 0.30 mmol), zinc (II) cyanide (0.036 mmol,
0.30 mmol), and Pd(PPh.sub.3).sub.4 (0.017 g, 0.015 mmol) in 1.2 mL
of DMF was irradiated in a microwave reactor at 160.degree. C. for
6 min. The residue was purified by preparative TLC, eluting with
1:1 EtOAc:hexanes, to give Compound 17a (0.080 g, 63% yield). MS:
m/z 426.2 (M+H).sup.+.
[0395] B.
2-(S)-{[4-(N-Hydroxycarbamimidoyl)-2-(4-methoxy-phenoxy)-phenyla-
mino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (17b).
Hydroxylamine hydrochloride (0.023 g, 0.32 mmol), NaHCO.sub.3
(0.040 g, 0.48 mmol), and 0.2 mL of water were stirred until
CO.sub.2 evolution ceased. A suspension of compound 17a (0.069 g,
0.16 mmol) in 0.5 mL of EtOH was added. The mixture was irradiated
in a microwave reactor at 160.degree. C. for 16 min. After
evaporation of the solvent, the residue was dissolved in EtOAc and
purified by preparative TLC, eluting with 1:1 EtOAc:hexanes, to
give Compound 17b (0.038 g, 52% yield). MS: m/z 459.3
(M+H).sup.+.
[0396] C.
2-(S)-{[2-(4-Methoxy-phenoxy)-4-(5-oxo-4,5-dihydro-[1,2,4]oxadia-
zol-3-yl)-phenylamino]-methyl}-pyrrolidine-1-carboxylic acid
tert-butyl ester (17c). DBU (0.071 g, 0.069 mL, 0.464 mmol) was
added to a stirring solution of Compound 17b (0.053 g, 0.116 mmol)
and 1,1'-carbonyldiimidazole (0.021 g, 0.128 mmol) in 1 mL of
CH.sub.3CN. The mixture was stirred under N.sub.2 for 2 days and
was then purified by filtration through a solid-phase extraction
(SPE) column. Evaporation of the solvent afforded Compound 17c. MS:
m/z 483.2 (M+H).sup.+.
[0397] D. Cpd 48:
(S)-3-{3-(4-Methoxy-phenoxy)-4-[(pyrrolidin-2-ylmethyl)-amino]-phenyl}-4H-
-[1,2,4]oxadiazol-5-one. A mixture of Compound 17c (0.048 g, 0.099
mmol), TFA, and CH.sub.2Cl.sub.2 was stirred at 20.degree. C. for 4
h. After concentration, the residue was purified by reverse phase
HPLC to afford Cpd 48 as a TFA salt (0.018 g, 30% yield. .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 7.39 (d, 1H), 6.92-7.07 (m, 6H),
3.88-3.98 (m, 1H), 3.80 (s, 3H), 3.53-3.60 (m, 2H) 3.30-3.33 (m,
2H), 2.23-2.31 (m, 1H), 2.05-2.13 (m, 2H), 1.75-1.88 (m, 1H); MS:
m/z 383.1 (M+H).sup.+.
Example 18
##STR00044##
[0399] A.
2-(S)-({[4-Bromo-2-(4-methoxy-phenoxy)-phenyl]-ethyl-amino}-meth-
yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (18a). A mixture
of Compound 1d (11.8 g, 40 mmol) and Compound 1e in 5 mL of HOAc
and 60 mL of 1,2-dichloroethane was stirred for 1 h at 20.degree.
C. NaBH(OAc).sub.3 was added in portions over a 15 min period, and
the mixture was allowed to stir at 20.degree. C. for 21/2 days.
Saturated aqueous K.sub.2CO.sub.3 (200 mL) was added slowly,
followed by CH.sub.2Cl.sub.2 (500 mL). The organic layer was
separated, and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.200 mL). The combined organic fractions
were dried over MgSO.sub.4, treated with charcoal, filtered over
Celite, and evaporated to yield 26.9 g of a dark brown oil. The
residue was purified via flash column chromatography (SiO.sub.2),
eluting with a hexanes-EtOAc gradient to yield Compound 1f (6.93 g,
36% yield) and Compound 18a (6.63 g, 33% yield). MS: m/z
505.1/507.1 (M+H).sup.+.
[0400] B.
2-(S)-({Ethyl-[2-(4-methoxy-phenoxy)-4-pyridin-3-yl-phenyl]-amin-
o}-methyl)-pyrrolidine-1-carboxylic acid tent-butyl ester (18c). A
mixture of Compound 18a (0.51 g, 1 mmol), Compound 18b (0.307 g,
2.5 mmol), Pd(dppf)Cl.sub.2 (0.183 g, 0.25 mmol), Cs.sub.2CO.sub.3
(0.977 g, 3.0 mmol), 0.5 mL of EtOH, and 2.5 mL of dioxane was
irradiated in a microwave reactor at 140.degree. C. for 15 min. The
reaction mixture was filtered and the solid was washed with 100 mL
of EtOAc. The filtrate was washed with 30 mL of saturated aqueous
K.sub.2CO.sub.3 dried over Na.sub.2SO.sub.4 and charcoal, and
concentrated to afford 0.36 g of crude residue containing Compound
18c.
[0401] C. Cpd 49:
(S)-Ethyl-[2-(4-methoxy-phenoxy)-4-pyridin-3-yl-phenyl]-pyrrolidin-2-ylme-
thyl-amine. TFA (5 mL) was added dropwise to a solution of the
residue from Step B above in 10 mL of CH.sub.2Cl.sub.2 The mixture
was stirred for 4 h at 20.degree. C. and was then evaporated. The
residue was dissolved in 100 mL of CH.sub.2Cl.sub.2 and washed with
20 mL of 1N aqueous NaOH. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
reverse phase HPLC. Fractions containing the desired product were
concentrated, dissolved in 100 mL of CH.sub.2Cl.sub.2, and washed
with 10 mL of 1N aqueous NaOH. The organic layer was dried over
Na.sub.2SO.sub.4, concentrated redissolved in CH.sub.2Cl.sub.2,
treated with 6 mL of 1N HCl in Et.sub.2O, and evaporated to afford
a lightly yellow solid, Cpd 49, as an HCl salt (0.130 g, 27% yield
for 2 steps). .sup.1H NMR (300 MHz, DMSO-d.sub.6): 9.64 (1H, s,
broad), 9.20 (1H, d), 8.93, 1H, s, broad), 8.84 (1H, d), 8.78 (1H,
d), 8.07 (1H, dd), 7. 71 (1H, dd), 7.46 (1H, d), 7.42 (1H, d), 7.00
(4H, m), 3.79 (3H, s), 3.7-3.1 (7H, m), 2.0-1.75 (3H, m), 1.55 (1H,
m), 1.02 (3H, t); MS: m/z 404.2 (M+H).sup.+.
[0402] Following the procedure described above for Example 18 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00009 MS Cpd (M + H).sup.+ 50 422.2 51 405.1 52 429.1
Example 19
##STR00045## ##STR00046##
[0404] A. 2,4-Bis-(4-methoxy-phenoxy)-nitrobenzene (19b). A
solution of 2,4-difluoronitrobenzene (Compound 19a, 0.5 g, 3.1
mmol) in 15 mL of acetone was added to a mixture of Compound 1b
(0.86 g, 6.9 mmol) and 6.9 mL of 1N aqueous NaOH in 5 mL of
acetone. The mixture was heated at 55.degree. C. for 3 days and
then at 80.degree. C. for 5 h. The reaction mixture was
concentrated to remove acetone and the residue was loaded onto a 10
mL solid-phase extraction (SPE) column. Elution with
CH.sub.2Cl.sub.2 and concentration of the eluent yielded 1.5 g of a
1:4 mixture of Compound 19c and Compound 19b that was used without
purification. MS: m/z 368 (M+H).sup.+.
[0405] B. 2,4-Bis-(4-methoxy-phenoxy)-aniline (19d). The mixture
containing Compounds 19b and 19c prepared in Step A were combined
with 50 mg of 10% Pd--C in 50 mL of EtOH/EtOAc and stirred at
20.degree. C. under a hydrogen atmosphere (14.7 psi) for 17 h. The
mixture was filtered through Celite and concentrated. The residue
was taken up in MeOH, filtered through a 0.4 .mu.m filter disk, and
concentrated to give Compound 19d. MS: m/z 338.1 (M+H).sup.+.
[0406] C.
(S)-2-{[2,4-Bis-(4-methoxy-phenoxy)-phenylamino]-methyl}-pyrroli-
dine-1-carboxylic acid tert-butyl ester (19e). A mixture of
Compound 19d (0.051 g, 0.15 mmol), Compound 1e (0.033 g, 0.31 mL,
0.17 mmol), HOAc (0.017 mL, 0.3 mmol), and 0.4 mL of DCE was
stirred at 20.degree. C. for 2.5 h. NaBH(OAc).sub.3 (0.089 g, 0.42
mmol) was added and the mixture was stirred at 20.degree. C. for 20
h. The reaction mixture was purified using a 1 mL SPE column,
eluting with CH.sub.2Cl.sub.2, to give Compound 19e.
[0407] D. Cpd 53:
(S)-[2,4-Bis-(4-methoxy-phenoxy)-phenyl]-pyrrolidin-2-ylmethyl-amine.
Compound 19e was dissolved in 50% TFA/CH.sub.2Cl.sub.2 and stirred
at 20.degree. C. for 45 min. After concentration, the residue was
purified by reverse phase HPLC to afford Cpd 53 as a TFA salt
(0.082 g, 84% yield). MS: m/z 421.2 (M+H).sup.+.
[0408] Following the procedure described above for Example 19 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00010 Cpd MS (M + H).sup.+ 54 421.1 55 411.1 56 421.1 57
447.0 60 447.2 61 435.2 62 435.2
Example 20
##STR00047##
[0410] A.
{2-[2,4-Bis-(4-methoxy-phenoxy)-phenylamino]-ethyl}-methyl-carba-
mic acid tert-butyl ester (20b); and
(2-{[2,4-Bis-(4-methoxy-phenoxy)-phenyl]-[2-(tert-butoxycarbonyl-methyl-a-
mino)-ethyl]-amino}-ethyl)-methyl-carbamic acid tert-butyl ester
(20c). HOAc (0.034 mL, 0.59 mmol) and NaBH(OAc).sub.3 (0.175 g,
0.83 mmol) were added to a solution of Compound 19d (0.102 g, 0.30
mmol) and Compound 20a (0.112 g, 0.32 mL, 0.17 mmol) in DCE and the
mixture was stirred at 20.degree. C. for 18 h. Water (0.2 mL) was
added and the reaction mixture was purified using a 3 mL SPE
column, eluting with CH.sub.2Cl.sub.2, to give a mixture of
Compound 20b and Compound 20c.
[0411] B. Cpd 63:
N-[2,4-Bis-(4-methoxy-phenoxy)-phenyl]-N'-methyl-ethane-1,2-diamine;
and Cpd 64:
N-[2,4-Bis-(4-methoxy-phenoxy)-phenyl]-N'-methyl-N-(2-methylamino-
-ethyl)-ethane-1,2-diamine.
[0412] The mixture of Compound 20b and Compound 20c prepared in
Step A was dissolved in TFA/CH.sub.2Cl.sub.2 and stirred at
20.degree. C. After concentration, the residue was purified by
reverse phase HPLC to afford Cpd 63 (0.139 g, 62% yield) and Cpd 64
(0.013 g, 5.6% yield), each as a TFA salt. Cpd 63: MS: m/z 395.2
(M+H).sup.+. Cpd 64: MS: m/z 452.3 (M+H).sup.+.
[0413] Following the procedure described above for Example 20 and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00011 Cpd MS (M + H).sup.+ 58 407.1 59 476.3
[0414] Compounds 1 through 64 of Formula (I) in the table below
were synthesized using the procedures described above.
TABLE-US-00012 TABLE 1 Formula (I) ##STR00048## R.sub.3 Cpd stereo
No. R.sub.1 Y R.sub.2 R.sub.3 R.sub.a R.sub.3--N--R.sub.a chem 1
2-(N,N- (E)- 4-methoxy- pyrrolidin-2-yl H 2S diethyl vinyl- phenyl
methyl amino carbonyl) 2 2-(N,N- ethyl 4-methoxy- pyrrolidin-2-yl H
2S diethyl phenyl methyl amino carbonyl) 3 2-(4- ethyl 4-methoxy-
pyrrolidin-2- H 2S methoxy- phenyl ylmethyl phenyl 4 2-(3- ethyl
4-methoxy- pyrrolidin-2-yl H 2S methoxy- phenyl methyl phenyl) 5
2-phenyl ethyl 4-methoxy- pyrrolidin-2-yl H 2S phenyl methyl 6
2-(4-fluoro- ethyl 4-methoxy- pyrrolidin-2-yl H 2S phenyl) phenyl
methyl 7 2-(3-fluoro- ethyl 4-methoxy- pyrrolidin-2-yl H 2S phenyl)
phenyl methyl 8 2-[3-(N,N- ethyl 4-methoxy- pyrrolidin-2-yl H 2S
diethyl phenyl methyl amino carbonyl) phenyl] 9 N,N-diethyl a bond
phenyl pyrrolidin-2-yl H 2S amino methyl carbonyl 10 N,N-diethyl a
bond 4-methoxy- pyrrolidin-2-yl H 2S amino phenyl methyl carbonyl
11 N,N-diethyl a bond 2-methoxy- pyrrolidin-2-yl H 2S amino phenyl
methyl carbonyl 12 phenyl a bond 4-cyano- pyrrolidin-2-yl H 2S
phenyl methyl 13 phenyl a bond 3-cyano- pyrrolidin-2-yl H 2S phenyl
methyl 14 phenyl a bond phenyl pyrrolidin-2-yl H 2S methyl 15
phenyl a bond 3-methoxy- pyrrolidin-2-yl H 2S phenyl methyl 16
phenyl a bond 4-fluoro- pyrrolidin-2-yl H 2S phenyl methyl 17
phenyl a bond 4-trifluoro pyrrolidin-2-yl H 2S methoxy- methyl
phenyl 18 phenyl a bond 2,6-dichloro- pyrrolidin-2-yl H 2S phenyl
methyl 19 phenyl a bond 4-methoxy- 2-(N- H phenyl methylamino)
ethyl 20 phenyl a bond 4-methoxy pyrrolidin-2-yl H 2S carbonyl-
methyl phenyl 21 phenyl a bond 3-methoxy pyrrolidin-2- H 2S
carbonyl- ylmethyl phenyl 22 phenyl a bond 2,4-dichloro-
pyrrolidin-2-yl H 2S phenyl methyl 23 phenyl a bond 4-methoxy-
piperidin-4-yl H 2S phenyl 24 5-cyano- a bond 4-methoxy- 4-fluoro-
H 2S,4R pyridin-3-yl phenyl pyrrolidin-2-yl methyl 25 5-fluoro- a
bond 4-methoxy- 4-fluoro- H 2S,4R pyridin-3-yl phenyl
pyrrolidin-2-yl methyl 26 5- a bond 4-methoxy- 4-fluoro- H 2S,4R
methylthio- phenyl pyrrolidin-2-yl pyridin-3-yl methyl 27
5-methoxy- a bond 4-methoxy- 4-fluoro- H 2S,4R pyridin-3-yl phenyl
pyrrolidin-2-yl methyl 28 5-methyl- a bond 4-methoxy- 4-fluoro- H
2S,4R pyridin-3-yl phenyl pyrrolidin-2-yl methyl 29 phenyl a bond
4-amino pyrrolidin-2-yl H 2S carbonyl- methyl phenyl 30 phenyl a
bond 3-amino pyrrolidin-2-yl H 2S carbonyl- methyl phenyl 31 phenyl
a bond 4-carboxy- pyrrolidin-2-yl H 2S phenyl methyl 32 phenyl a
bond 3-carboxy- pyrrolidin-2-yl H 2S phenyl methyl 33 phenyl a bond
4-(N,N- pyrrolidin-2-yl H 2S diethylamino methyl carbonyl) phenyl
34 phenyl a bond 3-(N,N- pyrrolidin-2-yl H 2S diethylamino methyl
carbonyl) phenyl 35 phenyl a bond 4-methoxy- pyrrolidin-2-yl H 2S
phenyl methyl 36 naphthalen- a bond 4-methoxy- pyrrolidin-2-yl H 2S
1-yl phenyl methyl 37 naphthalen- a bond 4-methoxy- pyrrolidin-2-yl
H 2S 1-yl phenyl methyl 38 pyridin-3-yl a bond 4-methoxy-
pyrrolidin-2-yl H 2S phenyl methyl 39 pyridin-3-yl a bond
4-methoxy- pyrrolidin-2-yl H 2S phenyl methyl 40 furan-3-yl a bond
4-methoxy- pyrrolidin-2-yl H 2S phenyl methyl 41 thiophen-3- a bond
4-methoxy- pyrrolidin-2-yl H 2S yl phenyl methyl 42 pyrimidin-5- a
bond 4-methoxy- pyrrolidin-2-yl H 2S yl phenyl methyl 43 5-fluoro-
a bond 4-methoxy- pyrrolidin-2-yl H 2S pyridin-3-yl phenyl methyl
44 5-cyano- a bond 4-methoxy- pyrrolidin-2-yl H 2S pyridin-3-yl
phenyl methyl 45 pyridin-3-yl a bond 4-methoxy- pyrrolidin-2-yl H
2S phenyl methyl 46 phenyl a bond 4-methoxy- piperazin- 2S phenyl
1-yl 47 phenyl a bond 4-methoxy- 4-methyl- 2S phenyl piperazin 1-yl
48 5-oxo- a bond 4-methoxy- pyrrolidin-2-yl H 2S dihydro- phenyl
methyl [1,2,4]oxa diazol-3-yl 49 pyridin-3-yl a bond 4-methoxy-
pyrrolidin-2-yl ethyl 2S phenyl methyl 50 5-fluoro- a bond
4-methoxy- pyrrolidin-2-yl ethyl 2S pyridin-3-yl phenyl methyl 51
pyrimidin-5- 4-methoxy- pyrrolidin-2-yl ethyl 2S yl phenyl methyl
52 5-cyano- a bond 4-methoxy- pyrrolidin-2-yl ethyl 2S pyridin-3-yl
phenyl methyl 53 4-methoxy- O 4-methoxy- pyrrolidin-2-yl H 2S
phenyl phenyl methyl 54 4-methoxy- O 4-methoxy- piperidin-3-yl H
racemic phenyl phenyl 55 4-methoxy- O 4-methoxy- 3-hydroxy- H 2R
phenyl phenyl 2(R)-amino- propyl 56 4-methoxy- O 4-methoxy-
piperidin-4-yl H phenyl phenyl 57 4-methoxy- O 4-methoxy- 8- H
mixture phenyl phenyl azabicyclo[3.2. of endo/ 1]octan-3-yl exo
isomers 58 4-methoxy- O 4-methoxy- axetidin-3-yl H phenyl phenyl
methyl 59 4-methoxy- O 4-methoxy- azetidin-3-yl azetidin- phenyl
phenyl methyl 3-yl- methyl 60 4-methoxy- O 4-methoxy- 1- H mixture
phenyl phenyl azabicyclo[2.2. of endo/ 2]octan-3-yl exo isomers 61
4-methoxy- O 4-methoxy- piperidin-3-yl H racemic phenyl phenyl
methyl mixture 62 4-methoxy- O 4-methoxy- 3-amino- H of 4 phenyl
phenyl cyclohexyl isomers 63 4-methoxy- O 4-methoxy- 2-(N- H phenyl
phenyl methylamino) ethyl 64 4-methoxy- O 4-methoxy- 2-(N- 2-(N-
phenyl phenyl methylamino) methyl ethyl amino) ethyl
BIOLOGICAL EXAMPLES
In Vitro Assays
Example 1
NG108-15, 24-Well Delta Opioid Receptor Binding Assay
[0415] Methods: NG108-15 cell membranes were purchased from Applied
Cell Sciences (Rockville, Md.). 5 mg/mL of membrane protein
suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose. With
several brief pulses from a Polytron homogenizer, each vial was
homogenized in 5 mls of 50 mM Tris Buffer, pH 7.4. The homogenate
was diluted in 50 mM Tris Buffer containing 5 mM MgCl.sub.2 to 330
ug/ml in the working solution for a final concentration of 133
ug/well. This particulate preparation was used for the 24-well
delta opioid binding assay.
[0416] Following incubation with the delta selective peptide ligand
.about.0.2 nM [.sup.3H]naltrindole at 25.degree. C. for 2.5 h in a
24-well plate with total volume of 1 mL, the plate contents were
filtered through a UniFilter24, GF/B. This plate was presoaked in
0.3% PEI and filtered through a 24-well Harvester. The UniFilter24
was rinsed three times with 2 mL of 10 mM HEPES (pH 7.4), and dried
in an oven at 37.degree. C. for 1.5 hours. To each well, was added
150 .mu.L of Scint0 (PerkinElmer, Cat #6013611). The plates were
then read on a TopCount.
[0417] Analysis: The data from the scintillation counter were used
to calculate either the % inhibition compared to control binding
(when only a single concentration of test compound was evaluated)
or a K.sub.i value (when a range of concentrations was tested).
Non-specific binding (N.S.-1 mM naloxone) was used as the negative
control, while the Total Binding (T.B.-Membrane and ligand only)
was used as the positive control. If one concentration was
screened, the % inhibition was calculated as (cpms of total binding
minus cpms of compound) divided by (cpms of T.B.minus cpms of N.S).
The triplicate % Inhibitions were averaged and reported. If
multiple concentrations were generated, the values were analyzed
using the one-site binding non-linear regression program in Prism
to determine K.sub.i values. The bottom and top values are globally
shared. The triplicate K.sub.i values are then averaged and
reported.
[0418] The data obtained are shown in Table 2, below.
Example 2
Rat Brain Delta Opioid Receptor Binding Assay
[0419] Procedure: Male, Wistar rats (150-250 g, VAF, Charles River,
Kingston, N.Y.) were killed by CO.sub.2, and their brains were
removed and placed immediately in ice cold Tris HCl buffer (50 mM,
pH 7.4). The forebrains were separated from the remainder of the
brain by a coronal transection, beginning dorsally at the colliculi
and passing ventrally through the midbrain-pontine junction. After
dissection, the forebrains were homogenized in Tris buffer in a
Teflon.RTM.-glass homogenizer. The homogenate was diluted to a
concentration of 1 g of forebrain tissue per 80 mL Tris and
centrifuged at 39,000.times.g for 10 min. The pellet was
resuspended in the same volume of Tris buffer containing 5 mM
MgCl.sub.2 with several brief pulses from a Polytron homogenizer.
This particulate preparation was used for the delta opioid binding
assays. Following incubation with the delta selective peptide
ligand .about.4 nM [.sup.3H]DPDPE or 0.25 nM [.sup.3H]naltrindole
at 25.degree. C. for 2.5 h in a 96-well plate with total volume of
1 mL, the plate contents were filtered through Wallac filtermat B
sheets on a Tomtec 96-well harvester. The filters were rinsed three
times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650 W
microwave oven for 1.75 min twice. To each sample area 2.times.50
.mu.L of Betaplate Scint scintillation fluid (LKB) was added and
the radioactivity was quantified on a LKB (Wallac) 1205 BetaPlate
liquid scintillation counter.
[0420] Analysis: The data from the scintillation counter were used
to calculate either the % inhibition compared to control binding
(when only a single concentration of test compound was evaluated)
or a K.sub.i value (when a range of concentrations was tested).
Percent inhibition was calculated as: [(total dpm-test compound
dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were
calculated using GraphPad PRISM data analysis program. The data
obtained are shown in Table 2, below.
Example 3
Rat Brain Mu Opioid Receptor Binding Assay
[0421] Procedure: Male, Wistar rats (150-250 g, VAF, Charles River,
Kingston, N.Y.) were killed by CO.sub.2, and their brains were
removed and placed immediately in ice cold Tris HCl buffer (50 mM,
pH 7.4). The forebrains were separated from the remainder of the
brain by a coronal transection, beginning dorsally at the colliculi
and passing ventrally through the midbrain-pontine junction. After
dissection, the forebrains were homogenized in Tris buffer in a
Teflon.RTM.-glass homogenizer. The homogenate was diluted to a
concentration of 1 g of forebrain tissue per 80 mL Tris and
centrifuged at 39,000.times.g for 10 min. The pellet was
resuspended in the same volume of Tris buffer containing 5 mM
MgCl.sub.2 with several brief pulses from a Polytron homogenizer.
This particulate preparation was used for the mu opioid binding
assays. Following incubation with the mu selective peptide ligand,
.about.0.8 nM [.sup.3H]DAMGO, at 25.degree. C. for 2.5 h in a
96-well plate with total assay volume of 1 mL, the plate contents
were filtered through Wallac filtermat B sheets on a Tomtec 96-well
harvester. The filters were rinsed three times with 2 mL of 10 mM
HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 min
twice. To each sample area 2.times.40 .mu.L of Betaplate Scint
scintillation fluid (LKB) was added and the radioactivity was
quantified on a LKB (Wallac) 1205 BetaPlate liquid scintillation
counter.
[0422] Analysis: The data from the scintillation counter were used
to calculate either the % inhibition compared to control binding
(when only a single concentration of test compound was evaluated)
or a K.sub.i value (when a range of concentrations was tested).
Percent inhibition was calculated as: [(total dpm-test compound
dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were
calculated using GraphPad PRISM data analysis program. The data
obtained are shown in Table 2, below.
TABLE-US-00013 TABLE 2 Delta and Mu Opioid Receptor Binding Data
.delta.-binding .delta.-binding .delta.-binding NG108 cell (DPDPE
(Naltrindole Cpd membrane ligand) ligand) .mu.-binding No. K.sub.i
(.mu.M) K.sub.i (.mu.M) K.sub.i (.mu.M) K.sub.i (.mu.M) 1 0.006081
3.3659 2 0.02641 >100 3 0.1197 >10 4 0.21 >10 5 0.2395
>10 6 0.6836 >10 7 0.2288 >10 8 0.1269 9.00119 9 1.023
>10 10 0.9356 0.9356 11 0.1053 >10 12 0.9959 >10 13 0.4018
>10 14 0.1131 >10 15 0.2886 >10 16 0.4191 >10 17 1.472
>10 18 0.1075 >10 19 0.192 >10 20 0.7789 >10 21 0.8869
>10 22 0.6978 >10 23 0.4615 >10 27 1.001 >10 28
0.006814 4.673 29 0.1467 >10 30 0.1265 5.7956 31 7.691 >10 32
2.667 >10 33 0.2843 9.30465 34 0.3095 >10 35 0.02885 >10
36 0.2905 >10 37 0.3009 >10 38 0.0155 4.3621 39 0.001646
0.02213 3.1067 40 0.2051 >10 41 0.2896 >10 42 0.001388 43
0.00076 44 0.000436 45 0.00542 4.4555 46 0.07971 >10 47 2.223
>10 48 0.492 9.705 49 0.02897 50 0.02303 51 0.077 52 0.009328 53
0.1053 >10 54 0.492 9.705 55 1.367 >10 56 1.729 >10 57
1.43 >10 58 0.7027 >10 59 2.275 >10 60 0.1577 >10 61
0.111 >10 62 0.04088 1.6417 63 0.02374 >10 64 1.536
>10
Example 4
[.sup.35S]GTP.gamma.S Binding Assay in NG108-15 Cell Membranes
(Delta Opioid Functional Assay)-200 nM Screen
[0423] Methods: NG108-15 cell membranes were purchased from Applied
Cell Sciences (Rockville, Md.). 5 mg/mL of membrane protein
suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose.
Membranes were maintained at 4-8.degree. C. A 1 mL volume of
membranes was added into 10 mL cold binding assay buffer. The assay
buffer contained 50 mM Tris, pH 7.6, 5 mM MgCl.sub.2, 100 mM NaCl,
1 mM DTT and 1 mM EGTA. The membrane suspension was homogenized
twice with a Polytron, and centrifuged at 3000 rpm for 10 min. The
supernatant was then centrifuged at 18,000 rpm for 20 min. Ten mL
assay buffer was added into the pellet containing tube. The pellet
and buffer were mixed with a Polytron.
[0424] Incubation procedure: The pellet membranes (75 .mu.g/mL)
were preincubated with SPA (10 mg/mL) at 25.degree. C. for 45 min
in the assay buffer. The SPA (5 mg/mL) coupled with membranes (37.5
.mu.g/mL) was then incubated with 0.1 nM [.sup.35S]GTP.gamma.S in
the same Tris buffer containing 100 .mu.M GDP in total volume of
200 .mu.L. 200 nM of receptor agonists was used to stimulate
[.sup.35S]-GTP.gamma.S binding. The basal binding was tested in the
absence of agonists and non-specific binding was tested in the
presence of 10 .mu.M unlabeled GTP.gamma.S. The data were analyzed
on a Packard Top Count and are shown in Table 3, below.
Data
[0425] % of Basal=(stimulated-non specific)*100/(basal-non
specific).
Relative Efficacy of a compound at 200 nM
=(% of Basal of test compound at 200 nM)/(Calculated Max of SNC80
dose response. Curve in prism).
Example 5
[.sup.35S]GTP.gamma.S Binding Assays in CHO-hMOR Cell Membranes (Mu
Opioid Functional Assay)
[0426] Methods: CHO-hMOR cell membranes were purchased from
Receptor Biology, Inc. (Baltimore, Md.). About 10 mg/mL of membrane
protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10%
sucrose, and the suspension kept on ice. A 1 mL volume of membranes
was added to 15 mL cold binding assay buffer containing 50 mM
HEPES, pH 7.6, 5 mM MgCl.sub.2, 100 mM NaCl, 1 mM DTT and 1 mM
EDTA. The membrane suspension was homogenized with a Polytron and
centrifuged at 3,000 rpm for 10 min. The supernatant can then be
centrifuged at 18,000 rpm for 20 min. The pellet was resuspended in
10 mL assay buffer with a Polytron. The membranes were preincubated
with wheat germ agglutinin coated SPA beads (Amersham) at
25.degree. C. for 45 min in the assay buffer. The SPA bead (5
mg/mL) coupled membranes (10 .mu.g/mL) were then incubated with 0.5
nM [.sup.35S]GTP.gamma.S in the assay buffer. The basal binding was
that taking place in the absence of added test compound; this
unmodulated binding was considered as 100%, with agonist stimulated
binding rising to levels significantly above this value. A range of
concentrations of receptor agonist was used to stimulate
[.sup.35S]GTP.gamma.S binding. Both basal and non-specific binding
were tested in the absence of agonist; non-specific binding
determination included 10 .mu.M unlabeled GTP.gamma.S.
[0427] Compounds were tested for function as antagonists by
evaluating their potential to inhibit agonist-stimulated
GTP.gamma.S binding. Radioactivity was quantified on a Packard
TopCount. The following parameters were calculated:
% stimulation = ( test compound cpm - non - specific cpm ( basal
cpm - non - specific cpm ) . .times. 100 ##EQU00003## % inhibition
= ( % stimulation by 1 .mu. M DAMGO - % stimulation by test
compound ) ( % stimulation by 1 .mu. M DAMGO - 100 ) .times. 100
##EQU00003.2##
EC.sub.50 values were calculated using GraphPad Prism and are shown
in Table 3, below.
TABLE-US-00014 TABLE 3 Delta Opioid Receptor Functional Data
GTP.gamma.S GTP.gamma.S GTP.gamma.S .delta.-opioid .delta.-opioid
GTP.gamma.S .delta.-opioid receptor receptor Cpd
.delta.-RelEfficacy receptor Rel % Inh No. @200 nM EC.sub.50
(.mu.M) Efficacy @10 .mu.M 1 0.1093 0.8328 2.2554 2 0.0391 0.8333
22.78 11 0.3194 18 1.0428 0.763 23.395 24 1.01 0.0461 1.0158 25
0.78 0.0924 1.0217 26 0.7 0.1873 1.0716 28 0.1651 0.8756 30 1.0245
0.2668 36.491 35 1.4612 1 38 0.4782 0.8323 16.36 39 0.1114 0.9245
13.425 42 0.39 43 0.43 0.218 1.0908 44 0.45 0.1176 1.1554 45 0.0408
0.627 35.642 53 0.3194 28.165 61 4.0729 16.134 62 0.3811 1.733 63
3.1067 25.97
In Vivo Assay
Example 6
Mouse Graded Abdominal Irritant Test (GrAIT)
[0428] Test compound or vehicle was administered s.c. or p.o. to
mice. Following the pretreatment time, an i.p. injection of 0.6% of
acetic acid in 0.5 mL was administered. Five min after acetic acid
administration, mice were placed into clear chambers and were
continuously observed for 5 min. Behavioral responses including
twisting and elongation of the body that extended through the
hindlimbs were counted and averaged for the group of animals over
the observation period. The results are shown in Table 4 below.
TABLE-US-00015 TABLE 4 route # abdominal # abdominal dose of no. of
pretreatment stretches stretches Cpd (mg/kg) vehicle admin. animals
(min) (vehicle) (cpd) 1 30 10% s.c. 5 30 14.1 10.9 Solutol 10 30
10% s.c. 10 30 16.7 11 Solutol 10 30 10% p.o. 5 30 19.8 19 Solutol
10 100 10% p.o. 10 30 19.8 17.9 Solutol 10 300 10% p.o. 5 30 19.8
21.2 Solutol
* * * * *