SUBSTITUTED PYRIMIDINONE AND PYRIDINONE COMPOUNDS AND THEIR USE

COMPOSES SUBSTITUES A BASE DE PYRIMIDONE ET DE PYRIDONE ET PROCEDES D'UTILISATION

English Abstract

Selected novel substituted pyrimidinone and pyridone compounds are effective
for prophylaxis
and treatment of diseases, such as TNF-.alpha., IL-.beta., IL-6 and/or IL-8
mediated diseases, and other
maladies, such as pain and diabetes. The invention encompasses novel compounds
of the
following general formula:
(see formula I)
analogs, prodrugs and pharmaceutically acceptable salts thereof,
pharmaceutical compositions
and methods for phrophylaxis and treatment of diseases and other maladies or
conditions
involving inflammation, pain, diabetes and the like. The subject invention
also relates to
processes for making such compounds as well as to intermediates useful in such
processes.

French Abstract

Cette invention concerne de nouveaux composés substitués sélectionnés, à base de pyrimidone et de pyridone, qui s'avèrent efficaces s'agissant de la prophylaxie et du traitement de maladies, telles que les maladies induites par le TNF- alpha , IL-1 beta , IL-6 et/ou IL-8, et d'autres maladies, telles que le diabète, ou de symptômes du type douleur. L'invention se rapporte à de nouveaux composés, à des analogues, à des promédicaments et à des sels pharmaceutiquement acceptables de ces composés, à des compositions pharmaceutiques et à des procédés de prophylaxie et de traitement de maladies et autres symptômes ou troubles liés à une inflammation, à une douleur, au diabète ou analogue. La présente invention se rapporte également à des procédés de fabrication de tels composés ainsi qu'à des intermédiaires utiles à ces procédés.

Claims

223
WHAT IS CLAIMED IS:
1. ~A compound of formula
<IMG>
or a pharmacutically acceptable salt thereof, wherein
X is O, S Or NR5;
<IMG>
provided
that the combined total number of aryl; heteroaryl,
cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-3;
U is NR21 or CHR21; and n is an integer of 1-3;
R1 and R2 are each independently -Y or -Z-Y, and R3 and
R4 are each independently -Z-Y; provided that R4 is
other than substituted-aryl, (substituted-
aryl)methyl or (substituted-aryl)ethyl radical, and the
total number of aryl, heteroaryl, cycloalkyl and
heterocyclyl radicals in each -Y and -Z-Y is 0-3;

224
wherein each Z is independently a
(1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical
optionally substituted by (a) 1-3 radicals of amino, C1-
C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano or halo and (b) 1-2 radicals of
heterocyclyl, aryl or heteroaryl optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (Cl-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,

225
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo. C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3
radicals- of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-
C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo. C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
each Y is independently a
(1) hydrogen radical;
(2) halo, cyano or nitro radical;
(3) -C(O) -R20, -C(O)-OR21, -C(O)-NR5R21 or -C(NR5)-NR5R21-
radical;
(4) -OR21, -O-C(O)-R21, -O-C(O)-NR5R21 or -O-C(O)-NR22-
S(O)2-R21 radical;
(5) -SR21, -S(O)-R20, -S(O)2-R20, -S(O)2-NR5R21, -S(O)2-
NR22-C(O)-R21, -S(O)2-NR22-C(O)-OR20 or -S(O)2-NR22-C(O)-
NR5R21 radical; or
(6) -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)-
NR5R21, -NR22-C(NR5)-NR5R21, -NR22-S(O)2-R20 or -NR22-
S(O)2-NR5R21 radical;
wherein each R5 is independently
(1) hydrogen radicals;
(2) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, cyano or halo; or

226
(3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-
C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-C8
cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radicals
optionally substituted by-1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; and
wherein each R20 is independently
(1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radicals
optionally substituted by 1-3 radicals of -CO2R23,
amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4
alkoxy)carbonyl)-N-(C1-C4 alkyl)amino,
aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo or aryl-C1-C4-alkoxy, aryl-
C1-C4-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8
cycloalkyl, heterocyclyl, aryl or heteroaryl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
C1-C4 alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo
radicals; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4

227
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-
3 halo radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by a
radical of heterocyclyl, aryl or heteroaryl optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C2-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or
(3) heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-
alkyl optionally substituted by 1-3 radicals of amino,
C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl,
cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo
radicals;

228
R11 is an aryl radical and R12 is a heteroaryl radical, wherein the
aryl and heteroaryl radicals are optionally substituted by 1-2
radicals of;
(1) R30;
(2) halo or cyano radicals;
(3) -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 or -C(NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32, -NR31R32 or
-NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each of
R11 and R12 is 0 - 1;
wherein each R30 is independently
(1) C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl radicals
optionally substituted by 1-3 radicals of -NR31R31, -
CO2R23, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4
alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo or aryl-
C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-
alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4
alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4
alkyl or C1-C4 haloalkyl of 1-3 halo radicals;

229
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-
C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
each R29 is independently hydrogen radical or R30:
each R31 and R32 are each independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by an C3-
C8 cycloalkyl, aryl, heterocyclyl ar heteroaryl radical
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4
alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-C8 cycloalkyl
radical optionally substituted by 1-3 radicals of amino,
C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3
halo radicals; and
wherein each R33 is independently
(1) hydrogen radical; or

230
(2) C1-C4 alkyl radical optionally substituted by a
radical of heterocyclyl, aryl or heteroaryl optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-
C4 haloalkyl of 1-3 halo radicals; and
wherein heterocyclyl is a radical of a monocyclic or
bicyclic saturated heterocyclic ring system having 5-8
ring members per ring, wherein 1-3 ring members are
oxygen, sulfur or nitrogen heteroatoms, which is
optionally partially unsaturated or benzo-fused and
optionally substituted by 1-2 oxo or thioxo radicals;
aryl is a phenyl or naphthyl radical; and heteroaryl is
radical of a monocyclic or bicyclic aromatic
heterocyclic ring system having 5-6 ring members per
ring, wherein 1-3 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused or
saturated C3-C4-carbocyclic-fused.
2. A compound of formula
<IMG>
or a pharmacutically acceptable salt thereof, wherein
X is O, S or NR5;

230a
<IMG>
provided
that the combined total number of aryl; heteroaryl,
cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-3;
U is NR21 or CHR21; and n is an integer of 1-3;
R1 and R2 are each independently -Y or -Z-Y, and R3 and
R4 are each independently -Z-Y; provided that R4 is
other than substituted-aryl, (substituted-
aryl)methyl or (substituted-aryl)ethyl radical, and the
total number of aryl, heteroaryl, cycloalkyl and
heterocyclyl radicals in each -Y and -Z-Y is 0-3;
each Z is independently a
(1) C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl radical
optionally substituted by (a) 1-3 radicals of amino, C1-
C4 alkylamino, di-(C1-C4 alkyl)amino; C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or halo and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C1-C5 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,

231
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
each Y is independently a
(1) hydrogen radical;
(2) halo, cyano or nitro radical;
(3) -C(O)-R20, -C(O)-OR21, -C(O)-NR5R21 or -C(NR5)-NR5R21
radical;
(4) -OR21, -O-C(O)-R21, -O-C(O)-NR5R21 or -O-C(O)-NR22-
S(O)2-R20 radical;
(5) -SR21, -S(O)-R20, -S(O)2-R20, -S(O)2-NR5R21, -S(O)2-
NR22-C(O)-R21, -S(O)2-NR22-C(O)-OR20 or -S(O)2-NR22-C(O)-
NR5R21 radical; or
(6) -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)-
NR5R21, -NR22-C(NR5)-NR5R21, -NR22-S(O)2-R20 or -NR22-
S(O)2-NR5R21 radical;

231a
each R5 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio or halo; or
(3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-
C4-alkyl, heterocyclyl, heterocyclyl-C2-C4-alkyl, C3-C8
cycloalkyl or C3-C8-cycloalkyl-C1-C4-alkyl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4
alkoxy, -C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;
each R20 is independently
(1) C1-C8 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals
optionally substituted by 1-3 radicals of -CO2R23,
amino, C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, N-((C1-C4
alkoxy)carbonyl)-N-(C1-C4 alkyl)amino,

232
aminocarbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C8 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl-radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C2-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of
1-3 halo radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by a
radical of heterocyclyl, aryl or heteroaryl optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or

232a
(3) heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
aryl, heteroaryl, -aryl-C1-C4-alkyl or heteroaryl-C1-C4-
alkyl optionally substituted by 1-3 radicals of amino,
C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4~alkoxy, C1-C4
alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl,
cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of 1-3 halo
radicals;
R11 is an aryl radical and R12 is a heteroaryl radical, wherein the
aryl and heteroaryl radicals are optionally substituted by 1-2
radicals of
(1) R30;
(2) halo or cyano radicals;
(3) -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 or -C(NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32, -NR31R32 or
-NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each of
R11 and R12 is 0 - 1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by 1-3
radicals of
(a) -NR31R31:
(b) C1-C4 alkoxy-carbonyl or phenoxycarbonyl or
phenylmethoxycarbonyl optionally substituted by 1-3
radicals of amino, alkylamino, di-(C1-C4-alkyl)amino,

233
C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl;
or
(c) hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl-C1-
C4-alkoxy, phenyl-C1-C4-alkylthio, heterocyclyl, phenyl
or heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl
of 1-3 halo radicals;
(2) C1-C4 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
each R31 is independently
(1) hydrogen radicals; or
(2) C1-C4 alkyl radical optionally substituted by an
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, C1-C4 alkyl or trifluoromethyl
radicals; and
each R32 is independently
(1) hydrogen radicals;

234
(2) C1-C4 alkyl radical optionally substituted by an C3-
C6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4
alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-C6 cycloalkyl
radical optionally substituted by 1-3 radicals of amino,
C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3
halo radicals; and
each R33 is independently hydrogen or C1-C4 alkyl
radical, and
wherein heterocyclyl is a radical of a monocyclic or
bicyclic saturated heterocyclic ring system having 5-8
ring-members per ring, wherein 1-3 ring members are
oxygen, sulfur or nitrogen heteroatoms, which is
optionally partially unsaturated or benzo-fused and
optionally substituted by 1-2 oxo or thioxo radicals;
aryl is a phenyl or naphthyl radical; and heteroaryl is
radical of a monocyclic or bicyclic aromatic
heterocyclic ring system having 5-6 ring members per
ring, wherein 2-3 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused or
saturated C3-C4-carbocyclic-fused.

234a
3. The compound of Claim 2 or a pharmaceutically
acceptable salt thereof, wherein
X is O or S;
<IMG>
provided that the. combined total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in -VC(R)W- is 0-2;
wherein R1, is -Y or -Z-Y, provided that (1) the total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in R1 is 0-3;

235
Z is a
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or halo and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl
of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C2 haloalkyl of 1-3 halo radicals;
Y is a
(1) hydrogen radical;
(2) halo radical;
(3) -C(O)-R20, -C(O)-OR21, -C(O)-NR5R21 or -C(NR5)-NR5R21
radical;
(4) -OR21, -O-C(O)-R21 or -O-C(O)-NR5R21 radical;
(5) -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21 radical;
or
(6) -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)-
NR5R21, -NR22-C(NR5)-NR5R21, -NR22-S(O)2-R20 or -NR22-
S(O)2-NR5R21 radical;

236
each R5 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of amino, di-(C1-C4-
alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or
halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl,
heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl
radicals optionally substituted by 1-3 radicals of
amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-
C4 alkylthio, cyano, C1-C4 alkyl or C1-C2 haloalkyl of 1-
3 halo radicals;
each R24 is independently
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of -CO2R23, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C2-C5
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or

237
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or C1-C2 haloalkyl of 1-
3 halo radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently
(1) hydrogen radical; or
(2) C1-C4 alkyl radical optionally substituted by a
radical of phenyl or heteroaryl optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C2-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-
C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or
C1-C2 haloalkyl of 1-3 halo radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-
C2-alkyl optionally substituted by 1-3 radicals of
amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl
of 1-3 halo radicals;
R2 is a radical of hydrogen, C1-C4 alkyl, halo, cyano,
hydroxy, C1-C4 alkoxy, C1-C2 haloalkoxy of 1-3 halo
radicals, C1-C4 alkylthio, amino, C1-C4 alkylamino, di-
(C1-C4 alkyl)amino or C1-C2 haloalkyl of 1-3 halo
radicals;

238
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b)
1-2 radicals of heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4
alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl,
trifluoromethoxy or trifluoromethyl radicals;
R11 is an aryl radical and R12 is a heteroaryl radical, wherein the aryl
and heteroaryl radicals are optionally substituted by 1-2 radicals of
(1) R30:
(2) halo or cyano radicals;
(3) -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 or -C(NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32,
-NR31R32, or -NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each of
R11 and R12 is 0-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by

239
(a) amino, C1-C4 alkylamino or di-(C1-C4-alkyl)amino
radicals; or
(b) hydroxy, C1-C4 alkoxy, heterocyclyl, phenyl or
heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) C1-C2 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
each R31 is independently hydrogen or C1-C4 alkyl
radicals; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by phenyl
or heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; and

240
each R33 is independently hydrogen or methyl radical;
and
wherein heterocyclyl is a radical of a monocyclic
saturated heterocyclic ring system having 5-6 ring
members, wherein 1-3 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused
and optionally substituted by 1-2 oxo or thioxo
radicals; aryl is a phenyl or naphthyl radical; and
heteroaryl is radical of a monocyclic aromatic
heterocyclic ring system having 5-6 ring members,
wherein 1-3 ring members are oxygen, sulfur or nitrogen
heteroatoms, which is optionally benzo-fused or
saturated C3-C4-carbocyclic-fused.
4. The compound of Claim 3 or a pharmaceutically
acceptable salt thereof, wherein
Z is a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, di-(C1-C2
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio or halo and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C2
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio or C1-C4 alkyl radicals; or

241
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-
C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3
radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2
alkoxy, C1-C2 alkylthio or halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl,
heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl
radicals optionally substituted by 1-3 radicals of
amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-
C2 alkylthio, methoxy, methylthio, cyano, C1-C4 alkyl or
trifluoromethyl radicals;
each R22 is independently hydrogen or C1-C4 alkyl
radical;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-
C2-alkyl optionally substituted by 1-3 radicals of
amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
R3 is
(1) C1-C8 alkyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4

242
alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or
trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo,
C1-C4 alkyl, trifluoromethoxy or trifluoromethyl
radicals;
R11 is an aryl radical and R12 is a heteroaryl radical,
wherein the aryl and heteroaryl radicals are optionally
substituted by 1-2 radicals of
(1) R30:
(2) halo or cyano radicals;
(3) -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 or -C(NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32,
-NR31R32 or -NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino,
acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R29 is independently hydrogen radical or R30; and
each R32 is independently

243
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, C1-C4
alkyl or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino-,
acetamido, hydroxy, C1-C2 alkoxy, C1-C4 alkyl or
trifluoromethyl radicals; and
wherein heterocyclyl is a radical of a monocyclic
saturated heterocyclic ring system having 5-6 ring
members, wherein 1-2 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused
and optionally substituted by 1-2 oxo or thioxo
radicals; aryl is a phenyl or naphthyl radical; and
heteroaryl is radical of a monocyclic aromatic
heterocyclic ring system having 5-6 ring members,
wherein 1-2 ring members are oxygen, sulfur or nitrogen
heteroatoms, which is optionally benzo-fused.
5. The compound of Claim 4 or a pharmaceutically
acceptable salt thereof, wherein
wherein R1 is -Y or -Z-Y, provided that (1) the total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in R1 is 0-2;
Z is a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, di-(C1-C2
alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2
alkoxy, C1-C2 alkylthio or halo and (b) 1-2 radicals of
aryl or heteroaryl optionally substituted by 1-2

244
radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals; or
(2) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
Y is a
(1) hydrogen radical;
(2) -C(O)-R20, -C(O)-OR21 or -C(O)-NR5R21 radical;
(3) -OR21, -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21
radical; or
(4) -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)-
NR5R21, -NR22-S(O)2-R20 or -NR22-S(O)2-NR5R21 radical;
each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3
halo radicals; or
(3) phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl,
radicals optionally substituted by 1-3 radicals of
amino, dimethylamino, hydroxy, methoxy, methylthio,
methyl or trifluoromethyl radicals;
each R20 is independently
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of -CO2R23, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,

245
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5-
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4-alkoxy,
C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, C1-
C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4
alkyl or trifluoromethyl radicals;
each R21 is independently hydrogen radical or R20;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino,
hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-
C4 alkyl or trifluoromethyl radicals;
R2 is a radical of hydrogen, C1-C4 alkyl, halo, cyano,
hydroxy, C1-C4 alkoxy, trifluoromethoxy or
trifluoromethyl;
R3 is C1-C8 alkyl radical
optionally substituted by 1-2 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy
or aryl or heteroaryl optionally substituted by 1-3

246
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4
alkyl, trifluoromethoxy or trifluoromethyl radicals;
R11 is an aryl radical and R12 is a heteroaryl radical,
wherein the aryl and heteroaryl radicals are optionally
substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals; or
-C(O)-NR31R32, -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -
S(O)2-NR31R32, -NR31R32 or -NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
each R31 is independently hydrogen, methyl or ethyl
radicals; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally

247
substituted by 1-3 radicals of amino, dimethylamino,
acetamido, hydroxy, methoxy, methyl on trifluoromethyl
radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals.
6. The compound of Claim 5 or a pharmaceutically
acceptable salt thereof, wherein
R3 is a C1-C4 alkyl radial;
R11 is an aryl radical optionally substituted by 1-2
radicals of
(1) R30;
(2) halo or cyano radicals; or
(3) -C(O)-NR31R32, -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -
S(O)2-NR31R32, -NR31R32 or -NR33-C(O)-R29 radicals; and
R12 is a heteroaryl radical optionally substituted by 1-
2 radicals of
(1) R30;
(2) halo or cyano radicals;
(3) -C(O)-NR31R32, -OR29, -SR29, -NR33R32 or -NR33-C(O)-
R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-2;
R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;

248
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
R29 is an aryl or heteroaryl radicals optionally
substituted by 1-2 radicals of amino, dimethylamino,
acetamido, hydroxy, halo, methoxy, methyl or
trifluoromethyl radicals; and
R32 is independently
(1) hydrogen or C1-C4 alkyl radical; or
(2) phenyl or heteroaryl radical optionally substituted
by 1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals.
7. The compound of Claim 6 or a pharmaceutically
acceptable salt thereof, wherein
wherein R1 is -Y or -Z-Y, provided that (1) the total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in R1 is 0-1;
Z is a C1-C4 alkyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, halo, or aryl or heteroaryl optionally
substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy,
C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R5 is independently hydrogen or C1-C4 alkyl
radical;

249
each R20 is independently
(1) C1-C8 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-
C4 alkyl)amino, aminocarbonylamino; hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl,
aryl or heteroaryl radicals optionally substituted by 1-
2 radicals of amino, di- (C1-C4 alkyl) amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-
C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of (C1-C4 alkoxy)carbonyl, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl
or trifluoromethyl radicals;
each R21 is independently hydrogen radical or R20:
each R23 is independently. hydrogen or C1-C4 alkyl, or
phenyl-C1-C2-alkyl optionally substituted by 1-2
radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio,
cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
R2 is a hydrogen radical;
R3 is a methyl or ethyl radical;

250
R11 is an aryl radical optionally substituted by 1-2
radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methylthio, methylsulfinyl,
methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl
radicals; and
R12 is a heteroaryl radical optionally substituted by 1-
2 radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methyl or trifluoromethyl
radicals.
8. The compound of Claim 7 or a pharmaceutically
acceptable salt thereof, wherein
Z is C1-C4 alkyl radical optionally substituted by 1-2
radicals of amino, t-butoxycarbonylamino, dimethylamino,
hydroxy, methoxy, methylthio or halo radicals;
Y is a
(1) hydrogen radical;
(2) -C(O)-R20, -C(O)-OR21 or -C(O)-NR5R21 radical;
(3) -OR21, -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21
radical; or
(4) -NR5R21, -NR22-C(O)-R21 or -NR22-S(O)2-R20 radical;
R5 is a hydrogen radical;
each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, methylamino, dimethylamino,
t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl,
phenyl or heteroaryl radicals optionally substituted by

251
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals:
(2) heterocyclyl radical optionally substituted by 1-2
radicals of t-butoxycarbonyl, hydroxy, or C1-C4 alkyl;
or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently hydrogen or methyl radical;
each R23 is independently hydrogen or C1-C4 alkyl
radicals;
R11 is an unsubstituted phenyl,or naphthyl radical or a
phenyl radical substituted by 1-2 radicals of amino,
dimethylamiao, acetamido, hydroxy, halo, cyano, methoxy,
methylthio, methylsulfinyl, methylsulfonyl,
aminocarbonyl, methyl or trifluoromethyl radicals; and
R12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-
pyrimidinyl radical optionally substituted by a radical
of amino, dimethylamino, acetamido, hydroxy, halo,
cyano, methoxy, methyl or trifluoromethyl radicals.
g. The compound of Claim 8 or a pharmaceutically
acceptable salt thereof, wherein
Y is a
(1) -C(O)-R2 p or -C(O)-NR5R21 radical;
(2) -OR21, -SR21, -S (O) -R20, -S(O)2-R20 or -S(O)2-NR5R21
radical; or

252
(3) -NR5R21, -NR22-C(O)-R21 or -NR22-S(O)2-R20 radical ;
each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, methylamino, dimethylamino,
t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl,
phenyl or heteroaryl radicals optionally substituted by
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by t-
butoxycarbonyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals; and
each R21 is independently hydrogen radical or R20
10. The compound of Claim 9 or a pharmaceutically
acceptable salt thereof, wherein
Y is a -OR21, -SR21 or -NR5R21 radical;
each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of amino, methylamino, dimethylamino, hydroxy
or phenyl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
(2) heterocyclyl radical; or

253
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
each R21 is independently hydrogen radical or R20;
R11 is an unsubstituted phenyl radical or a phenyl
radical substituted by 1-2 radicals of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,
methylthio, methylsulfonyl, methyl or trifluoromethyl
radicals; and
R12 is a 4-pyridyl radical optionally substituted by a
radical of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methyl or trifluoromethyl
radicals.
11. The compound of Claim 2 or a pharmaceutically
acceptable salt thereof, wherein
X is O or S;
<IMG>
provided that
the combined total number of aryl, heteroaryl, cycloalkyl
and heterocyclyl radicals in -VC(R)W- is 0-2;
wherein R1 is -Y or -Z-Y, provided that (1) the total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in R1 is 0-3;
Z is a

254
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, halo, or heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl
of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C2 haloalkyl of 1-3 halo radicals;
Y is a
(1) hydrogen radical;
(2) halo radical;
(3) -C(O)-R20, -C(O)-OR21, -C(O)-NR5R21 or -C(NR5)-NR5R21
radical;
(4) -OR21, -O-C(O)-R21 or -O-C(O)-NR5R21 radical;
(5) -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21 radical;
or
(6) -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)-
NR5R21, -NR22-C(NR5) -NR5R21, -NR22-S(O)2-R20 or -NR22-
S(O)2-NR5R21 radical;
each R5 is independently
(1) hydrogen radicals;

255
(2) C1-C4 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of amino, di-(C1-C4-
alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or
halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl,
heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl
radicals optionally substituted by 1-3 radicals of
amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy, C1-
C4 alkylthio, cyano, C1-C4 alkyl or C1-C2 haloalkyl of 1-
3 halo radicals;
each R20 is independently
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of -CO2R23, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C5
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4

256
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or Cl-C2 haloalkyl of 1-
3 halo radicals;
each R21 is independently hydrogen radical or R2o:
each R22 is independently
(1) hydrogen radical; or
(2) C1-C4 alkyl radical optionally substituted by a
radical of phenyl or heteroaryl optionally substituted
by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-
C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or
C1-C2 haloalkyl of 1-3 halo radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-
C2-alkyl optionally substituted by 1-3 radicals of
amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl
of 1-3 halo radicals;
R4 is
(1) C1-C8 alkyl or C2-C8 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b)
1-2 radicals of heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,

257
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4
alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) heteroaryl radical optionally substituted by 2-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl,
trifluoromethoxy or trifluoromethyl radicals;
R11 is an aryl radical and R12 is a heteroaryl radical, wherein the aryl
and heteroaryl radicals are optionally substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals;
(3 ) -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 or -C(NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32,
-NR31R32 or -NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each of
R11 and R12 i s 0-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by
(a) amino, C1-C4 alkylamino or di-(C1-C4-alkyl)amino
radicals; or
(b) hydroxy, C1-C4 alkoxy, heterocyclyl, phenyl or
heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;

258
(2) C1-C2 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
each R31 is independently hydrogen or C1-C4 alkyl
radicals; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by phenyl
or heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; and
each R33 is independently hydrogen or methyl radical;
and
wherein heterocyclyl is a radical of a monocyclic
saturated heterocyclic ring system having 5-6 ring
members, wherein 1-3 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused
and optionally substituted by 1-2 oxo or thioxo
radicals; aryl is a phenyl or naphthyl radical; and

259
heteroaryl is radical of a monocyclic aromatic
heterocyclic ring system having 5-6 ring members,
wherein 1-3 ring members are oxygen, sulfur or nitrogen
heteroatoms, which is optionally benzo-fused or
saturated C3-C4-carbocyclic-fused.
12. The compound of Claim 11 or a pharmaceutically
acceptable salt thereof, wherein
Z is a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, halo, or heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-
C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3
radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2
alkoxy, C1-C2 alkylthio or halo; or

260
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl,
heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl
radicals optionally substituted by 1-3 radicals of
amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-
C2 alkylthio, methoxy, methylthio, cyano, C1-C4 alkyl or
trifluoromethyl radicals;
each R22 is independently hydrogen or C1-C4 alkyl
radical;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-
C2-alkyl optionally substituted by 1-3 radicals of
amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
R4 is
(1) C1-C8 alkyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or
trifluoromethyl radicals; or
(2) heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo,
C1-C4 alkyl, trifluoromethoxy or trifluoromethyl
radicals;
R11 is an aryl radical and R12 is a heteroaryl radical,
wherein the aryl and heteroaryl radicals are optionally
substituted by 1-2 radicals of

261
(1) R30:
(2) halo or cyano radicals;
(3) -C(O)-R30, -C(O)-OR29, -C(O)-NR31R32 or -C(NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -S(O)2-NR31R32,
-NR31R32 or NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino,
acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R29 is independently hydrogen radical or R30; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, C1-C4
alkyl or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino,
acetamido, hydroxy, C1-C2 alkoxy, C1-C4 alkyl or
trifluoromethyl radicals; and

262
wherein heterocyclyl is a radical of a monocyclic
saturated heterocyclic ring system having 5-6 ring
members, wherein 1-2 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused
and optionally substituted by 1-2 oxo or thioxo,
radicals; aryl is a phenyl or naphthyl radical; and
heteroaryl is radical of a monocyclic aromatic
heterocyclic ring system having 5-6 ring members,
wherein 1-2 ring members are oxygen, sulfur or nitrogen
heteroatoms, which is optionally benzo-fused.
13. The compound of Claim 12 or a pharmaceutically
acceptable salt thereof, wherein
wherein R1 is -Y or -Z-Y, provided that (1) the total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in R1 is 0-2;
Z is a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2
alkoxy, C1-C2 alkylthio, halo, or aryl or heteroaryl
optionally substituted by 1-2 radicals of amino, di-(C1-
C2 alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino,
hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-
C4 alkyl or trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
Y is a
(1) hydrogen radical;

263
(2) -C(O)-R20, -C(O)-OR21 or -C(O)-NR5R21 radical;
(3) -OR21, -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21
radical; or
(4) -NR5R21, -NR22-C(O)-R21, -NR22-C(O)-OR20, -NR22-C(O)-
NR5R21, -NR22-S(O)2-R20 or -NR22-S(O)2-NR5R21 radical;
each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3
halo radicals; or
(3) phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl,
radicals optionally substituted by 1-3 radicals of
amino, dimethylamino, hydroxy, methoxy, methylthio,
methyl or trifluoromethyl radicals;
each R20 is independently
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of -CO2R23, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted. by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or

264
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, C1-
C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4
alkyl or trifluoromethyl radicals;
each R21 is independently hydrogen radical or R20;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino,
hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-
C4 alkyl or trifluoromethyl radicals;
R4 is a C1-C8 alkyl radical optionally substituted by 1-
2 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or
trifluoromethyl radicals;
R11 is an aryl radical and R12 is a heteroaryl radical,
wherein the aryl and heteroaryl radicals are optionally
substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals; or
(3) -C(O)-NR31R32, -OR29, -SR29, -S(O)-R30, -S(O)2-R30,
S(O)2-NR31R32, -NR31R32 or NR33-C(O)-R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1;

265
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
each R31 is independently hydrogen, methyl or ethyl
radicals; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally
substituted by 1-3 radicals of amino, dimethylamino,
acetamido, hydroxy, methoxy, methyl or trifluoromethyl
radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals.
14. The compound of Claim 13 or a pharmaceutically
acceptable salt thereof, wherein
R4 is a C1-C4 alkyl radical;
R11 is an aryl radical optionally substituted by 1-2
radicals of

266
(1) R30;
(2) halo or cyano radicals; or
(3) -C(O)-NR31R32, -OR29, -SR29, -S(O)-R30, -S(O)2-R30, -
S(O)2-NR31R32, -NR31R32 or NR33-C(O)-R29 radicals; and
R12 is a heteroaryl radical optionally substituted by 1-
2 radicals of
(1) R30;
(2) halo or cyano radicals; or
(3) -C(O)-NR31R32, -OR29, -SR29, -NR31R32 or -NR33-C(O)-
R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1;
R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
R32 is independently
(1) hydrogen or C1-C4 alkyl radical; or

267
(2) phenyl or heteroaryl radical optionally substituted
by 1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals.
15. The compound of Claim 14 or a pharmaceutically
acceptable salt thereof, wherein
wherein R1 is -Y or -Z-Y, provided that (1) the total
number of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in R1 is 0-1;
Z is a C1-C4 alkyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, halo, or aryl or heteroaryl optionally
substituted by 1-2 radicals of hydroxy, C1-C2 alkoxy,
C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R5 is independently hydrogen or C1-C4 alkyl
radical;
each R20 is independently
(1) C1-C8 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-
C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl,
aryl or heteroaryl radicals optionally substituted by 1-
2 radicals of amino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-

268
C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of (C1-C4 alkoxy)carbonyl, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl
or trifluoromethyl radicals;
each R21 is independently hydrogen radical or R20;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl-C1-C2-alkyl optionally substituted by 1-2
radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio,
cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;
R4 is a methyl or ethyl radical;
R11 is an aryl radical optionally substituted by 1-2
radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methylthio, methylsulfinyl,
methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl
radicals; and
R12 is a heteroaryl radical optionally substituted by 1-
2 radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methyl or trifluoromethyl
radicals.
16. The compound of Claim 15 or a pharmaceutically
acceptable salt thereof, wherein

269
Z is C1-C4 alkyl radical optionally substituted by 1-2
radicals of amino, t-butoxycarbonylamino, dimethylamino,
hydroxy, methoxy, methylthio or halo radicals;
Y is a
(1) hydrogen radical;
(2) -C(O)-R20, -C(O)-OR21 or -C(O)-NR5R21 radical;
(3) -OR21, -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21
radical; or
(4) -NR5R21, -NR22-C(O)-R21 or -NR22-S(O)2-R20 radical;
R5 is a hydrogen radical;
each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, methylamino, dimethylamino,
t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl,
phenyl or heteroaryl radicals optionally substituted by
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of t-butoxycarbonyl, hydroxy, or C1-C4 alkyl;
or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
each R21 is independently hydrogen radical or R20;
each R22 is independently hydrogen or methyl radical;

270
each R23 is independently hydrogen or C1-C4 alkyl
radicals;
R11 is an unsubstituted phenyl or naphthyl radical or a
phenyl radical substituted by 1-2 radicals of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,
methylthio, methylsulfinyl, methylsulfonyl,
aminocarbonyl, methyl or trifluoromethyl radicals; and
R12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-
pyrimidinyl radical optionally substituted by a radical
of amino, dimethylamino, acetamido, hydroxy, halo,
cyano, methoxy, methyl or trifluoromethyl radicals.
17. The compound of Claim 16 or a pharmaceutically
acceptable salt thereof, wherein
Y is a
(1) -C(O)-R20 or -C(O)-NR5R21 radical;
(2) -OR21, -SR21, -S(O)-R20, -S(O)2-R20 or -S(O)2-NR5R21
radical; or
(3) -NR5R21, -NR22-C(O)-R21 or -NR22-S(O)2-R20 radical;
each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, methylamino, dimethylamino,
t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl,
phenyl or heteroaryl radicals optionally substituted by
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by t-
butoxycarbonyl; or

271
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals; and
each R21 is independently hydrogen radical or R20.
18. The compound of Claim 17 or a pharmaceutically
acceptable salt thereof, wherein
Y is a -OR21, -SR21 or -NR5R21 radical;
each R20 is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of amino, methylamino, dimethylamino, hydroxy
or phenyl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
(2) heterocyclyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
each R21 is independently hydrogen radical or R20;
R11 is an unsubstituted phenyl radical or a phenyl
radical substituted by 1-2 radicals of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,
methylthio, methylsulfonyl, methyl or trifluoromethyl
radicals; and
R12 is a 4-pyridyl radical optionally substituted by a
radical of amino, dimethylamino, acetamido, hydroxy,

272
halo, cyano, methoxy, methyl or trifluoromethyl
radicals.
19. The compound of Claim 2 or a pharmaceutically
acceptable salt thereof, wherein
X is O or S;
<IMG>
provided that the
combined total number of aryl, heteroaryl, cycloalkyl and
heterocyclyl radicals in -VC(R)W- is 0-2;
each R21 is independently a hydrogen radical or
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of -CO2R23, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5

273
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl,-hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or C1-C2 haloalkyl of 1-
3 halo radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl, heteroaryl; phenyl-C1-C2-alkyl or heteroaryl-C1-
C2-alkyl optionally substituted by 1-3 radicals of
amino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C2 haloalkyl
of 1-3 halo radicals;
R11 is an aryl radical and R12 is a heteroaryl radical, wherein the aryl
and heteroaryl radicals are optionally substituted by 1-2 radicals of
(1) R30;
(2) halo or cyano radicals;
(3) -C (O) R30, -C (O) -OR29, -C (O) -NR31R32 or -C (NR31) -
NR31R32 radicals; or
(4) -OR29, -SR29, -S (O) -R30, -S (O) 2-R30, -S (O) 2-NR31R32,
-NR31R32 or -NR33-C (O) -R29 radicals;
provided that the

274
total number of aryl, heteroaryl, cycloalkyl and
heterocyclyl radicals substituted on each of R11 and R12
is 0-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by
(a) amino, C1-C4 alkylamino or di-(C1-C4-alkyl)amino
radicals; or
(b) hydroxy. C1-C4 alkoxy, heterocyclyl, phenyl or
heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl) amino, C1-C5 alkanoylamino, (-C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) C1-C2 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30
each R31, is independently hydrogen or C1-C4 alkyl-
radicals; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by phenyl
or heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; or

275
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; and
each R33 is independently hydrogen or methyl radical;
and
wherein heterocyclyl is a radical of a monocyclic
saturated heterocyclic ring system having 5-6 ring
members, wherein 1-3 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused
and optionally substituted by 1-2 oxo or thioxo
radicals; aryl is a phenyl or naphthyl radical; and
heteroaryl is radical of a monocyclic aromatic
heterocyclic ring system having 5-6 ring members,
wherein 1-3 ring members are oxygen, sulfur or nitrogen
heteroatoms, which is optionally benzo-fused or
saturated C3-C4-carbocyclic-fused.
20. The compound of Claim 19 or a pharmaceutically
acceptable salt thereof, wherein
U is NR21;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-
C2-alkyl optionally substituted by 1-3 radicals of
amino, di-(C1-C2 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;

276
R11 is an aryl radical and R12 is a heteroaryl radical,
wherein the aryl and heteroaryl radicals are optionally
substituted by 1-2 radicals of
(1) R30:
(2) halo or cyano radicals;
(3) -C (0) -R30 -C (O) -OR29 , -C (O) -NR31R32 or -C (NR31)-
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30, -S (O) 2-R30. -S (O) 2-NR31R32.
-NR31R32 or NR33-C (O) -R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 4-1;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino,
acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
each R29 is independently hydrogen radical or R30; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally
substituted by 1-3 radicals of amino; di-(C1-C2
alkyl)amino, acetamido, hydroxy, C1-C2 alkoxy, C1-C4
alkyl or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted
-by 1-3 radicals of amino, di-(C1-C2 alkyl)amino,

277
acetamido, hydroxy, C1-C2 alkoxy, C1-C4 alkyl or
trifluoromethyl radicals; and
wherein heterocyclyl is a radical of a monocyclic
saturated heterocyclic ring system having 5-6 ring
members, wherein 1-2 ring members are oxygen, sulfur or
nitrogen heteroatoms, which is optionally benzo-fused
and optionally substituted by 1-2 oxo or thioxo
radicals; aryl is a phenyl or naphthyl radical; and
heteroaryl is radical of a monocyclic aromatic
heterocyclic ring system having 5-6 ring members,
wherein 1-2 ring members are oxygen, sulfur or nitrogen
heteroatoms, which is optionally benzo-fused.
21. The compound of Claim 20 or a pharmaceutically
acceptable salt thereof, wherein
<IMG>
each R21 is independently a hydrogen radical or
(1) C1-C8 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of -CO2R23, amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4

278
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5
alkanoyl, (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or C1-C2
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
alkoxy)carbonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, C1-
C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4
alkyl or trifluoromethyl radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl optionally
substituted by 1-3 radicals of amino, di-(C1-C2
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino,
hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-
C4 alkyl or trifluoromethyl radicals;
each R24 is independently a hydrogen or C1-C4 alkyl
radical;
R11 is an aryl radical and R12 is a heteroaryl radical,
wherein the aryl and heteroaryl radicals are optionally
substituted by 1-2 radicals of
(1) R30:
(2) halo or cyano radicals; or

279
(3) -C(O)-NR31R32, -OR29, -SR29; -S(O)-R30, -S(O)2-R30,-
S (O) 2-NR31R32. NR31R32 or -NR33-C (O) -R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1%;
each R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
each R31 is independently hydrogen, methyl or ethyl
radicals; and
each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally
substituted by 1-3 radicals of amino, dimethylamino,
acetamido, hydroxy, methoxy, methyl or trifluoromethyl
radicals; -or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals.
22. The compound of Claim 21 or a pharmaceutically
acceptable salt thereof, wherein

280
R11 is an aryl radical optionally substituted by 1-2
radicals of
(1) R30;
(2) halo or cyano radicals; or
(3) -C (O) -NR31R32, -OR29. -SR29, -S (O) -R30, -S (O) 2-R30,-
S(O) 2-NR31R32, -NR31R32 or -NR33-C (O) -R29 radicals; and
R12 is a heteroaryl radical optionally substituted by 1-
2 radicals of
(1) R30:
(2) halo or cyano radicals; or
(3) -C (O) -NR31R32, -OR29, -SR29. -NR31R32 or -NR33-C (O) -
R29 radicals;
provided that the total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals substituted on each
of R11 and R12 is 0-1;
R30 is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
each R29 is independently hydrogen radical or R30;
R32 is independently

281
(1) hydrogen or C1-C4 alkyl radical; or
(2) phenyl or heteroaryl radical optionally substituted
by 1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals
23. The compound of Claim 22 or a pharmaceutically
acceptable salt thereof, wherein
each R21 is independently a hydrogen radical or
(1) C1-C8 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-
C4 alkyl)amino, aminocarbonylamino, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl,
aryl or heteroaryl radicals optionally substituted by 1-
2 radicals of amino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy, C1-
C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of (C1-C4 alkoxy)carbonyl, hydroxy, C1-C4
alkoxy, C1-C4 alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of (C1-C4 alkoxy)carbonyl, amino, C1-C4
alkylamino, di- (C1-C4 alkyl ) amino, hydroxy, C1-C4,
alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl
or trifluoromethyl radicals;
each R23 is independently hydrogen or C1-C4 alkyl, or
phenyl-C1-C2-alkyl optionally substituted by 1-2
radicals of hydroxy, C1-C2 alkoxy, C1-C2 alkylthio,
cyano, halo, C1-C4 alkyl or trifluoromethyl radicals;

282
R11 is an aryl radical optionally substituted by 1-2
radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methylthio, methylsulfinyl,
methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl
radicals; and
R12 is a heteroaryl radical optionally substituted by 1-
2 radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methyl or trifluoromethyl
radicals.
24. The compound of Claim 23 or a pharmaceutically
acceptable salt thereof, wherein
<IMG>
each R21 is independently a hydrogen radical or
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of -CO2R23, amino, methylamino, dimethylamino,
t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl,
phenyl or heteroaryl radicals optionally substituted by
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals;
(2) heterocyclyl radical optionally substituted by t-
butoxycarbonyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,

283
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
each R23 is independently hydrogen or C1-C4 alkyl
radicals;
R11 is an unsubstituted phenyl or naphthyl radical or a
phenyl radical substituted by 1-2 radicals of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,
methylthio, methylsulfinyl, methylsulfonyl,
aminocarbonyl, methyl or trifluoromethyl radicals; and
R12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-
pyrimidinyl radical optionally substituted by a radical
of amino, dimethylamino, acetamido, hydroxy, halo,
cyano, methoxy, methyl or trifluoromethyl radicals.
25. The compound of Claim 24 or a pharmaceutically
acceptable salt thereof, wherein
each R21 is independently a hydrogen radical or
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of amino, methylamino, dimethylamino, hydroxy
or phenyl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino,-hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
(2) heterocyclyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
R11 is an unsubstituted phenyl radical or a phenyl
radical substituted by 1-2 radicals of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,

284
methylthio, methylsulfonyl, methyl or trifluoromethyl
radicals; and
R12 is a 4-pyridyl radical optionally substituted by-a
radical of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methyl or trifluoromethyl
radicals.
26. The compound of Claim 1 which is:
2-(2,6-Dichlorobenzyl)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone,
2-(Butylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone,
2-(Benzylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-((R-1-phenylethyl)amino)-(4-
pyridyl)-4(3H)-pyrimidinone,
2-(2-(2-Chlorophenyl)-ethylamino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(8H)-pyrimidinone,
5-(4-Fluorophenyl)-2-(2-(4-fluorophenyl)-ethylamino)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-2-((2-hydroxy-2-phenyl)-ethylamino)-
3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-amino)-
6-(4-pyridyl) -4 (3H) -pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-((1-methyl-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-((R-1-methyl-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-((2-phenylaminoethyl)-
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-2-((3-imidazolylpropyl).-amino)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone.
5-(4-Fluorophenyl)-3-methyl-6-t4-pyridyl)-2-(3-
(pyrrolidin-1-yl)-propylamino)-4(3H)-pyrimidinone,
3,6-biphenyl-4-(4-pyridyl)-2(1H)-pyridone,
6-(4-Methylphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-
pyridone,
6-(4-Ethyiphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-pyridone,
6-(2,4-Dimethylphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-
pyridone,

285
3-Phenyl-4-(4-pyridyl)-6-(2-thienyl)-2(1H)-pyridone,
6-(2-Furyl)-3-phenyl-4-(4-pyridyl)-2(1H)-pyridone,
2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-(((R)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-(((S)-2-N-Ethyl-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-((2-Amino-2-methy-3-phehylpropyl)amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-((2-Aminomethy-3-phenylpropyl)-amino)-5-(4-
fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-((3-Amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-(3-(2- .
methylphenyl)propyl)-amino)-6.-(4-pyridyl)-4(3H)-
pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-((R,S)-2-amino-3-(2'-
fluorophenyl)-propyl-amino)-6-(4-pyridyl)-4(3H)-
pyrimidinone,
2-(((S)-2-Acetamido-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone,
2-(((S)-2-N-N-Butylamino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-ethyl-5-(4-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Ethyl-5-(4-fluorophenyl)-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone,
2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-4-(4-pyridyl)-pyrimidine,
2-((2-(3-trifluoromethylphenyl)phenylmethyl)amino)-3-
methyl-5-(4-fluorophenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(4-tolyl)-
6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(4-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,

286
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
isopropylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-chloro-
4-fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3,5-
bis(trifluoromethyl)phenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3,4-
dichlorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(1-
naphthyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(3-phenylpropylamino)-5-(3,5-dichlorophenyl)-
6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(3-phenylpropylamino)-5-(4-tolyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(3-phenylpropylamino)-5-(3-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(3-phenylpropylamino)-5-(4-methoxyphenyl)-6-
(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(3-phenylpropylamino)-5-(4-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2-methyl-3-phenylpropylamino)-5-(3-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
3-Methyl-2-(2-methyl-3-phenylpropylamino)-5-(1-
naphthyl)-6-(4-pyridyl)-4(3H)-pyrimidinone,
5-(4-Fluorophenyl)-2-(((S)-2-N-glycylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-N-Glycylamino-3-phenylpropyl)-amino)-3-methyl-
5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone,
5-(4-Fluorophenyl)-2-(((S)-2-hydroxyacetamido-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
5-(4-Fluorophenyl)-2-(((S)-2-pyrrolidinyl-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H-)-
pyrimidinone,
2-((S)-3-Benzylpiperazinyl)-5-(4-fluorophenyl)-3-methyl-
6-(4-pyridyl)-4-(3H)-pyrimidinone,
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,

287
2-((3-Amino-3-(2-methylphenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-3-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((R)-3-Amino-3-phenylpropyl}-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone,
2-(((R)-3-Amino-3-phenylpropyl)-amino)-3-methyl-5-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone,
2-((3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone,
2-((3-Amino-3-(2-methylphenyl)propyl)-amino)-3-methyl-6-
(4-pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone;
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-6-
(4-pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone,
2-((3-Amino-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone,
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone,
2-((3-Amino-3-(2-chlorophenyl)propyl)-amino)-3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone,
2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3,4-dimethylphenyl)-4-(3H)-pyrimidinone,
2-(((2R,3R)-3-Amino-2-methyl-3-phenylpropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((2S,3S)-3-Amino-2-methyl-3-phenylpropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
5-(4-Fluorophenyl)-2-(((S)-3-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
5-(4-Fluorophenyl)-2-(((R)-3-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
5-(4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-((S)-
tetrahydroisoguinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone,
3-Methyl-6-(4-pyridyl)-2-((S)-tetrahydroisoquinol-3-
ylmethylenamino)- 5-(3-trifluoromethylphenyl)-4-(3H}-
pyrimidinone,

288
3-Methyl-5-(3-methylphenyl)-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone,
3-Methyl-5-(4-methylthiophenyl)-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone,
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone,
5-(4-Fluorophenyl)-2-((3-hydroxy-3-phenylpropyl)-amino)-
3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone,
2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone,
2-(((S)-2-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-Amino-3-(4-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-Amino-3-(2-chlorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-N-Isopropylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-N-Isopropylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
5-(3-Chlorophenyl-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-chlorophenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone,
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-5-(3-trifluorophenyl)-4-(3H)-
pyrimidinone or
5-(4-Fluorophenyl)-3-methyl-2-(((S)-2-N-methylamino-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4-(3H)-pyrimidinone
or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a
compound of any one of Claims 1 to 26 and a pharmaceutically
acceptable carrier.

289
28. A use of an effective amount of a compound of
any one of Claims 1 to 26 for prophylaxis or treatment of
inflammation.
29. A use of an effective amount of a compound of
any one of Claims 1 to 26 for the production of a medicament for
prophylaxis or treatment of inflammation.
30. A use of an effective amount of a composition of
Claim 27 for prophylaxis or treatment of inflammation.
31. A use of an effective amount of a composition of
Claim 27 for the production of a medicament for
prophylaxis or treatment of inflammation.

290
32. A use of an effective amount of a compound of
any one of Claims 1 to 26 for lowering plasma concentrations of
either or both TNF-.alpha.-wand IL-1.
33. A use of an effective amount of a compound of
any one of Claims 1 to 26 for the production of a medicament for
lowering plasma concentrations of either or both TNF-.alpha. and
IL-1.
34. A use of an effective amount of a composition of
Claim 27 for lowering plasma concentrations of either or
both TNF-.alpha. and IL-1.
35. A use of an effective amount of a composition of
Claim 27 for the production of a medicament for lowering
plasma concentrations of either or both TNF-.alpha. and IL-1.
36. A use of an effective amount of a compound of
any one of Claims 1 to 26 for lowering plasma concentrations of
either or both IL-6 and IL-8.
37. A use of an effective amount of a compound of
any one of Claims 1 to 26 for the production of a medicament for
lowering plasma concentrations of either or both IL-6 and
IL-8.

291
38. A use of an effective amount of a composition of
Claim 27 for lowering plasma concentrations of either or
both-IL-6 and IL-8.
39. A use of an effective amount of a composition of
Claim 27 for the production of a medicament for lowering
plasma concentrations of either or both IL-6 and IL-8.
40. A use of an effective amount of a compound
according to any one of Claims 1 to 26 to produce a glucagon
antagonist effect for prophylaxis or treatment of diabetes
disease in a mammal in need thereof.
41. A use of an effective amount of a compound
according to any one of Claims 1 to 26 to produce a glucagon
antagonist effect for the production of a medicament for
prophylaxis or treatment of diabetes disease in a mammal
in need thereof.
42. A use of an effective amount of a pharmaceutical
composition according to Claim 27 to produce a glucagon
antagonist effect for prophylaxis or treatment of diabetes
disease in a mammal.
43. A use of an effective amount of a pharmaceutical
composition according to Claim 27 to produce a glucagon
antagonist effect for the production of a medicament for
prophylaxis or treatment of diabetes disease in a mammal.
44. A use of an effective amount of a compound
according to any one of Claims 1 o 26 for prophylaxis or treatment
of a pain disorder in a mammal in need thereof.
45. A use of an effective amount of a compound
according to any one of Claims 1 to 26 for the production of a
medicament for prophylaxis or treatment of a pain disorder
in a mammal in need thereof.
46. A use of an effective amount of a pharmaceutical
composition according to Claim 27 for prophylaxis or
treatment of a pain disorder in a mammal in need thereof.

292
47. A use of an effective amount of a pharmaceutical
composition according to Claim 27 for the production of a
medicament for prophylaxis or treatment of a pain disorder
in a mammal in need thereof.
48. A use of an effective amount of a compound
according to any one of Claims 1 to 26 for decreasing prostaglandins
production in a mammal in need thereof.
49. A use of an effective amount of a compound
according to any one of Claims 1 to 26 for the production of a
medicament for decreasing prostaglandins production in a
mammal in need thereof.
50. A use of an effective amount of a pharmaceutical
composition according to Claim 27 for decreasing
prostaglandins production in a mammal in need thereof.
51. A use of an effective amount of a pharmaceutical
composition according to Claim 27 for the production of a
medicament for decreasing prostaglandins production in a
mammal in need thereof.
52. A use of an effective amount of a compound
according to any one of Claims 1 to 26 for decreasing cyclooxygenase
enzyme activity in a mammal in need thereof.
53. A use of an effective amount of a compound
according to any one of Claims 1 to 26 for the production of a
medicament for decreasing cyclooxygenase enzyme activity
in a mammal in need thereof.
54. The use of Claim 52 or 53 wherein the
cyclooxygenase enzyme is COX-2.
55. A use of an effective amount of a pharmaceutical
composition according to Claim 27 for decreasing
cyclooxygenase enzyme activity in a mammal in need
thereof.
56. A use of an effective amount of a pharmaceutical
composition according to Claim 27 for the production of a

293
medicament for decreasing cyclooxygenase enzyme activity
in a mammal in need thereon.
57. ~The use of Claim 55 or 56 wherein the
cyclooxygenase enzyme is COX-2.

Description

CA 02274093 2003-02-20
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WO 98/24780 PCT/US9'712Z949
1
SUBSTITUTED PYRIMIDINONE AND PYRIDONE COMPOUNDS AND
METHODS OF USE
BACKGROUND OF THE INVENTION
The present invention comprises a new class of compounds
useful in treating diseases, such as TNF-a, IL-lei, IL-6
and/or IL-8 mediated diseases and other maladies, such
as pain and diabetes. In particular, the compounds of
the invention are useful for the prophylaxis and
treatment of diseases or conditions involving
inflammation. This invention also relates to
intermediates and processes useful in the preparation of
such compounds.
Interleukin-1 (IL-1) and Tumor Necrosis Factor Oc
(TNF-a) are pro-inflammatory cytokines secreted by a ,
variety of cells, including monocytes and macrophages,
in response to many inflammatory stimuli (e. g.,
lipopolysaccharide - LPS) or external cellular stress
~(e.g.; osmotic shock and geroxide).
Elevated levels of TNF-a andJor IL-l over basal
levels have been implicated in mediating or exacerbating
3C a number of disease states including rheumatoid
arthritis; Pagets disease; osteophorosis; multiple
myeloma; uveititis; acute and chronic myelogenous ,
leukemia; pancreatic i~ cell destruction; osteoarthriti.s;
rheumatoid sgondylitis; gouty arthritis; inflammatory
bowel disease; adult respiratory distress syndrome
CARDS); psoriasis; Crohn's disease; allergic rhinztis;
ulcerative colitis; anaphylaxis; contact dermatitis;

CA 02274093 1999-06-03
WO 98/24780 PCT/US97/22949
2
asthma; muscle degeneration; cachexia; Reiter's
syndrome; type I and type II diabetes; bone resorption
diseases; graft vs. host reaction; ischemia reperfusion
injury; atherosclerosis; brain trauma; multiple
sclerosis; cerebral malaria; sepsis; septic shock; toxic
shock syndrome; fever, and myalgias due to infection.
HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,
adenovirus, the herpes viruses (including HSV-1, HSV-2),
and herpes zoster are also exacerbated by TNF-a.
It has been reported that TNF-a plays a role in
head trauma, stroke, and ischemia. For instance, in
animal models of head trauma (rat), TNF-a levels
increased in the contused hemisphere (Shohami et al., J.
Cereb. Blood Flow Metab. 14, 615 (1994)). In a rat
model of ischemia wherein the middle cerebral artery was
occluded, the levels of TNF-a mRNA of TNF-a increased
(Feurstein et al., Neurosci. Lett. 164, 125 (1993)).
Administration of TNF-a into the rat cortex has been
reported to result in significant neutrophil
accumulation in capillaries and adherence in small blood
vessels. TNF-a promotes the infiltration of other
cytokines (IL-lei, IL-6) and also chemokines, which
promote neutrophil infiltration into the infarct area
(Feurstein, Stroke 25, 1481 (1994)). TNF-a has also
been implicated to play a role in type II diabetes
(Endocrinol. 130, 43-52, 1994; and Endocrinol. 13~,
1474-1481, 1995).
TNF-a appears to play a role in promoting certain
viral life cycles and disease states associated with
them. For in-stance, TNF-a secreted by monocytes induced
elevated levels of HIV expression in a chronically
infected T cell clone (Clouse et al., J. Immunol. 142,
431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289
(1988)) discussed the role of TNF-a in the HIV
associated states of cachexia and muscle degradation.

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WO 98/24780 PCT/tJS97122949
3
TNF-oc is upstream in the cytokine cascade of
infla_mrnation. As a results elevated levels of TNF-a may
7.ead to elevated levels of other inflammatory and
proinflammatory cytokines, such as IL-1, IL-6, and IL-8.
Llevated levels of IL-1 over basal levels have been
implicated in mediating or exacerbating a number of
disease states including rheumatoid arthritis;
osteoarthritis; rheumatoid spondylitis; gouty arthritis;
inflammatory bowel disease; adult respiratory distress
syndrome CARDS); psoriasis; Crohn's disease; ulcerative
colitis; anaphylaxis; muscle degeneration; cachexia;
Reiter's syndrome; type I and type II diabetes; bone
resorption diseases; ischemia reperfusion injury;
atherosclerosis; brain trauma; multiple sclerosis;
sepsis; septic shock; and toxic shock syndrome. Viruses
sensitive to TNF-OC inhibition, e.g., HIV-l, HIV-2, HIV-
3, are also affected by IL-1.
TNF-oc and IL-1 appear to play a role in pancreatic
f~ cell destruction and diabetes. Pancreatic i3 cells
produce insulin which helps mediate blood glucose
homeostasis. Deterioration of pancreatic i3 cells often
accompanies type I diabetes. Pancreatic Q cell
functional abnormalities may occur in patients with type
II diabetes. Type II diabetes is characterized by.a
functional resistance to insulin: Further, type II
diabetes is also often accompanied by elevated levels of
piasna glucagon and increased rates of hepatic glucose
production. Glucagon is a regulatory hormone that
attenuates Liver gluconeogenesis inhibition by insulin.
Glucagon receptors have been fcund in the liver, kidney
and adipose Tissue. Thus glucagon antagonists are
useful for attenuating plasma glucose levels (WO
97 / 16442).
By antagonizing the glucagon receptors, it
is thought that insulin responsiveness in the liver will

CA 02274093 1999-06-03
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4
improve, thereby decreasing gluconeogenesis and lowering
the rate of hepatic glucose production.
In rheumatoid arthritis models in animals, multiple
intra-articular injections of IL-1 have led to an acute
and destructive form of arthritis (Chandrasekhar et al.,
Clinical Immunol Immunopathol. 55, 382 (1990)). In
studies using cultured rheumatoid synovial cells, IL-1
is a more potent inducer of stromelysin than is TNF-a
(Firestein, Am. J. Pathol. 140; 1309 (1992)). At sites
of local injection, neutrophil, lymphocyte, and monocyte
emigration has been observed. The emigration is
attributed to the induction of chemokines (e.g., IL-8),
and the up-regulation of adhesion molecules (Dinarello,
Eur. Cytokine Netw. 5, 517-531 (1994))
IL-1 also appears to play a role in promoting
certain viral life cycles. For example, cytokine-
induced increase of HIV expression in a chronically
infected macrophage line has been associated with a
concomitant and selective increase in IL-1 production
(Folks et al., J. Immunol. 136, 40 (1986)). Beutler et
al. (J. Immunol. 135, 3969 (1985)) discussed the role of
IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308,
553 (1983)) discussed the role of IL-1 in muscle
degeneration.
In rheumatoid arthritis, both IL-1 and TNF-a induce
synoviocytes and chondrocytes to produce collagenase and
neutral proteases, which leads to tissue destruction
within the arthritic joints. In a model of arthritis
(collagen-induced arthritis (CIA) in rats and mice),
intra-articular administration of TNF-a either prior to
or after the induction of CIA led to an accelerated
onset of arthritis and a more severe course of the
disease (Brahn et al., Lymphokine Cytokine Res. 11, 253
- (1992); and Cooper, Clin. Exp. Immunol. 898, 244
(1992)).
IL-8 has been implicated in exacerbating and/or
causing many disease states in which massive neutrophil

CA 02274093 2003-02-20
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infiltration into sites of inflammation or injury (e. g.,
ischemia) is mediated by the chemotactic nature of IL-8,
including, but not limited to, the following: asthma,
inflammatory bowel disease, psoriasis, adult respiratory
5 distress syndrome, cardiac and renal reperfusion injury,
thrombosis and glomerulonephritis. In addition to the
chemotaxis effect on neutrophils, IL-8 also has the
ability to activate neutrophils. Thus, reduction in IL-
8 levels may lead to diminished neutrophil infiltration.
Several approaches have been taken to block the
effect of TNF-oc. One approach involves using soluble
receptors for TNF-a (e. g., TNFR-55 or TNFR-?5), which
have demonstrated efficacy in animal models of TNF-oc-
mediated disease states. A second approach to
neutralizing TNF-of using a monoclonal antibody specific ,
to TNF-a, cA2, has demonstrated improvement in swollen
joint count in a Phase II human trial of rheumatoid
arthritis tFeldmann et al., Immunological Reviews, pp.
195-223 (1995)). These approaches block the effects of
TNF-a and IL-1 by either protein sequestration or
receptor antagonism.
US 5,100,897 describes pyrimidinone compounds useful as
angiotensin II antagonists wherein one of the
pyrimidinone ring nitrogen atoms is substituted with a
substituted phenylmethyl or pherethyl radical.
US 5,162,325 describes pyrimidinone compounds useful as
angiotensin II antagonists wherein one of the
pyrimidinone ring nitrogen atoms is substituted with a
substituted phenylmethyl radical.
EP 481448 describes pyrimidinone compounds useful as
angiotensin II antagonists wherein one of the
pyrimidinone ring nitrogen atoms is substituted with a
substituted phenyl, phenylmethyl or phenethyl radical.

CA 02274093 2003-02-20
WO 98/24780 PCTlUS97lZ2949
6
CA 2,020,370 describes pyrimidinone compounds useful as
angiotensin II antagonists wherein one of the
pyrimidinone ring nitrogen atoms is substituted with a
substituted biphenylaliphatic hydrocarbon radical.
BRIEF DESCRIPTION OF THE INVENTION
The present invention comprises a new class of
compounds useful in the prophylaxis and treatment of
diseases, such as TNF-OC, IL-1~, IL-6 and/or IL-8
mediated diseases and other maladies, such as pain and
diabetes. In particular, the compounds of the invention
are useful for the prophylaxis and treatment of diseases
or conditions involving inflammation. Accordingly, the
invention also comprises pharmaceutical compositions
comprising the compounds, methods for the prophylaxis
and treatment of TNF-OC, IL-lei, IL-6 and/or IL-8 mediated
diseases, such as inflammatory, pain and diabetes
diseases, using the compounds and compositions of the
invention, and intermediates and processes useful for
the preparation of the compounds of the invention.
The compounds of the invention are represented by
the following general structure:
X
R11
V
~~'
R12 W R
wherein the dashed lines represent a double bond between
C(R) and V or W (i.e., -V=C(R)- or -W=C(R)-) and V, W,
X, R, R" and R'~ are defined below.
.The foregoing merely summarizes certain aspects of
the invention and is not intended, nor should it be
construed, as limiting the invention in any way.

CA 02274093 1999-06-03
WO 98!24780 PCT/US97/22949
7
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is
provided compounds of the formula:
X
R1l
V
R12 W R
(I)
or a pharmaceutically acceptable salt thereof, wherein
X is 0, S or NRS; preferably, X is O or S; and most
preferably, X is O;
V
' is
\y~ ~, R
\N~R3 \N
\N~ R4 \ ~ \N
\Rl \ ~ ~ Rl \ ~ ~R21
R2 N R1 Rq N U
\ N \N
\ \ \N
N U N N-R21
\ ~ R21
.'' N
n N \
R2i, R2i or R2i ; provided
that the combined total number of aryl, heteroaryl,
cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-3,
preferably, 0-2, most preferably, 0-1;
a first preferred subgroup of

CA 02274093 1999-06-03
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8
\ / R3
N
V
1S R1
\W . R R2
a second preferred subgroup of
\
N
\V \N~R9 \
; is
J\ J\ I R
\W ' R \N R1 or R4 -
a third preferred subgroup of
N
\V \N N U
is ' ~R21
\ \
W R N R21
\N
\ \N
N N -R21
\ ~ R21
N N
R21 or R21
more preferably,
N
\N \N I
\
~1 \ N N"R21
\ ~N N N_R21
N
R21 ~ R
29 or
\N ~ _
R29
\N N
R2 i .
most preferably,

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WO 98/24780 PCT/US97/22949
9
\N \N
/~ /~ R2a
_N ~ i 'N
N ~ N
R2i or R2i
- U is NRz1 or CHR~1; preferably, U is NRzl;
n is an integer of 1-3;
R1 and R~ are each independently -Y or -Z-Y, and R3 and
R~ are each independently -Z-Y; provided that R4 is
other than a substituted-aryl, (substituted-aryl)methyl
or lsubstituted-aryl)ethyl radical, and the total number
of aryl, heteroaryl, cycloalkyl and heterocyclyl
radicals in each -Y and -Z-Y is 0-3; preferably, 0-2;
more preferably, 0-1;
preferably, R2 is a radical of hydrogen, C1-C,q alkyl,
halo, cyano, hydroxy, CZ-C4 alkoxy, C1-C2 haloalkoxy of
1-3 halo radicals, C1-Cq alkylthio, amino, C1-Cq
alkylamino, di-(C1-C4 alkyl)amino or C1-C2 haloalkyl of
1-3 halo radicals; more preferably, R2 is a radical of
hydrogen, C1-C4 alkyl, halo, cyano, hydroxy, C1-C4
a'~icoxy, trifluoromethoxy or trifluoromethyl; most
preferably, R2 is a hydrogen radical;
preferably, R3 is a hydrogen radical or
(1) C1-Cg alkyl or C2-Cg alkenyl radical optionally
substituted. by (a) 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b)
1-2 radicals of heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-Cq alkyl)amino, C1-C5 alkanoylamino,

CA 02274093 1999-06-03
WO 98/24780 PCT/US97/22949
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4
alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by
5 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, Cl-C4 alkylthio, cyano, halo, C1-C4 alkyl,
trifluoromethoxy or trifluoromethyl radicals;
more preferably, R3 is a hydrogen radical or
(1) C1-Cg alkyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-Cq
alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or
trifluoromethyl radicals; or
(2) aryl or heteroaryl radical optionally substituted by-
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C2-C4 alkoxy, C~-C4 alkylthio, cyano, halo,
C1-C4 alkyl, trifluoromethoxy or trifluoromethyl
radicals;
more preferably, R3 is a hydrogen radical or C1-Cg alkyl
'radical optionally substituted by 1-2 radicals of amino,
C1-C4 alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4
alkoxy or aryl or heteroaryl optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C2-C4
alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4
alkyl, trifluoromethoxy or trifluoromethyl radicals;
more preferably, R3 is a radical of hydrogen or C1-C4
alkyl; more preferably, R3 is a hydrogen, methyl or
ethyl radical;

CA 02274093 1999-06-03
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11
preferably, R4 is
(1) C1-Cg alkyl or C2-Cg alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or halo, and (b)
1-2 radicals of heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4
alkyl, trifluoromethoxy or trifluoromethyl radicals; or
(2) heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-Cq
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl,
trifluoromethoxy or trifluoromethyl radicals;
more preferably, R4 is
(1) C1-Cg alkyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, hydroxy, C1-C4 alkoxy or aryl or heteroaryl
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl, trifluoromethoxy or
trifluoromethyl radicals; or
(2) heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, -
Cl-C4 alkyl, trifluoromethoxy or trifluoromethyl
radicals;

CA 02274093 1999-06-03
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12
more preferably, Rg is a C1-Cg alkyl radical optionally
substituted by 1-2 radicals of amino, C1-Cg alkylamino,
di-(C1-Cg alkyl)amino, hydroxy, C1-Cg alkoxy or aryl or
heteroaryl optionally substituted by 1-3 radicals of
amino, C1-Cg alkylamino, di-(C1-Cg alkyl)amino, C1-Cg
alkoxy, Cz-Cg alkylthio, halo, Cl-Cg alkyl,
trifluoromethoxy or trifluoromethyl radicals;
more preferably, Rg is a C1-Cg alkyl radical; most
preferably, Rg is a methyl or ethyl radical;
wherein each Z is independently a
(1) alkyl, alkenyl or alkynyl radical optionally
substituted by (a) 1-3 radicals of amino, alkylamino,
dialkylamino, alkanoylamino, alkoxycarbonylamino,
alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo,
and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl
optionally substituted by 1-3 radicals of amino,
alkylamino, dialkylamino, alkanoylamino,
alkoxycarbonylamino, alkylsulfonylamino, hydroxy,
alkoxy, alkylthio, halo, alkyl or haloalkyl;
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or
haloalkyl;
preferably, each Z is independently a
(1) C1-Cg alkyl, C2-Cg alkenyl or C2-C8 alkynyl radical
optionally substituted by (a) 1-3 radicals of amino, C1-
C4 alkylamino, di-(C1-Cg alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-Cg

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13
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or halo, and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
. alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-Cq
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-Cq alkylthio, cyano, halo, C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each Z is independently a
(1) C1-Cg alkyl, C2-Cg alkenyl or C2-Cg alkynyl radical
optionally substituted by (a) 1-3 radicals of amino, C1-
C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4_
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or halo, and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
. alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals;

CA 02274093 1999-06-03
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14
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C2-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-CQ alkylthio, cyano, halo, C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each Z is independently a
(1) C1-Cg alkyl or C2-Cg alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or halo, and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C2-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl or C1-C2 haloalkyl of 1-3
halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
_ alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4 -
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C2 haloalkyl of 1-3 halo radicals;

CA 02274093 1999-06-03
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- . 15
more preferably, each Z is independently a
(1) C1-C4 alkyl or C2-C5 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, di-(C1-CZ
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio or halo, and (b) 1-2 radicals of heterocyclyl,
aryl or heteroaryl optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(Cz-C2
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C2 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio or C1-C4 alkyl radicals; or
(3) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-
C2 alkoxy, C1-C2 alkylthio, cyano, halo, C1-C4 alkyl or
trifluoromethyl radicals;
more preferably, each Z is independently a
(1) C1-C4 alkyl or C?-C5 alkenyl radical optionally
substituted by (a) 1-3 radicals of amino, di-(C1-C2
alkyl)amino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2
alkoxy, C1-C2 alkylthio or halo, and (b) 1-2 radicals of
aryl or heteroaryl optionally substituted by 1-2
radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2
alkylthio, halo, C1-C4 alkyl or trifluoromethyl
radicals; or
(2) aryl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
(C1-C4 alkoxy)carbonylamino, hydroxy, C1-C2 alkoxy, C1-C2

CA 02274093 1999-06-03
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16
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
more preferably, each Z is independently a C1-Cq alkyl
radical optionally substituted by 1-2 radicals of amino,
di-(C1-C2 alkyl)amino, (C1-C4 alkoxy)carbonylamino,
hydroxy, C1-C2 alkoxy, C1-C2 alkylthio, halo or aryl or
heteroaryl optionally substituted by 1-2 radicals of
hydroxy, C1-C2 alkoxy, C1-C2 al~ylthio, halo, C1-C4 alkyl
or trifluoromethyl radicals; and
most preferably, each Z is independently a C1-C4 alkyl
radical optionally substituted by 1-2 radicals of amino,
t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy,
methylthio or halo radicals;
each Y is independently a
(1) hydrogen radical;
(2) halo or nitro radical;
(3) -C(O)-R2p or -C(NR5)-NR5R21 radical;
4 ) -OR21, -O-C ( O ) -R21, -O-C ( O ) -NR5R21 or -O-C ( O ) -NR22 -
S(O)2-R2p radical;
(5) -SR21, -S (O) -R2p, -S (0) 2-R20, -S (0) 2-NR5R21, -S (0) 2-
NR22-C (O) -R21, -S (O) 2-NR22-C (O) -OR20 or -S (O) 2-NR22-C (O) -
NR5R21 radical; or
( 6 ) -NR5R21, -NR22-C (O) -R21, -NR22-C (O) -OR20, -NR22-C (O) -
NR5R21~ -NR22-C (NR5) -NR5R21, -NR22-S (0) 2-R20 or -NR22-
S(0)2-NR5R21 radical;
preferably, each Y is independently a
(1) hydrogen radical;
(2) halo radical;
(3) -C(O)-R20 or -C(NR5)-NR5R21 radical;
(4) -OR21, -O-C(O)-R21 or -0-C(O)-NR5R21 radical;
(5) -SR21, -S(O)-R2p, -S{0)2-R2p or -S(O)2-NR5R21 radical;
or

CA 02274093 1999-06-03
WO 98124780 PCT/US97/22949
17
( 6 ) -NR5R21, -NR22-C (O) -R21. -NR22-C (O) -OR20. -NR22-C (0) -
NR5R21. -NR22-C (NR5 } -NR5R21. -NR22-S (O) 2-R2p or -NR22-
S(O)2-NR5R21 radical;
more preferably, each Y is independently a
(1) hydrogen radical;
(2 ) -C (O) -R2p radical;
(3) -OR21. -SR21. -S(0)-R2o. -S(O)2-R2p or -S(O)2-NR5R21
radical; or
( 4 ) -NR5R21, -NR22 -C ( O ) -R21. -NR22 -C ( O ) -OR2 0 , -NR22 -C ( O )
NR5R21, -NR22-S(O)2-R20 or -NR22-S(O)2-NR5R21 radical;
more preferably, each Y is independently a
(1) hydrogen radical;
(2) -C(O)-R2p radical;
(3) -OR21, -SR21. -S(O)-R20. -S(O)2-R2p or -S(O)2-NR5R21
radical; or
(~) -NR5R21, -NR22-C(O)-R21 or -NR22-S(O)2-R20 radical;
more preferably, each Y is independently a
(1) -C(O)-R2p radical;
(~) -OR21, -SR21. -S(O)-R2p, -S(O)2-R20 or -S(O)2-NR5R21
:adical; or
i'r -NR5R21, -NR22-C(O)-R21 or -NR22-S(O)2-R2p radical.
most preferably, each Y is independently a -OR21, -SR21
or -NR5R21 radical;
wherein each R5 is independently
(1) hydrogen radicals;
(2) alkyl, alkenyl or alkynyl radicals optionally
substituted by 1-3 radicals of amino, alkylamino,
dialkylamino, hydroxy, alkoxy, alkylthio, -S03H or halo;
or
(3) aryl, heteroaryl, aralkyl, heteroaralkyl,
heterocyclyl, heterocyclylalkyl, cycloalkyl or

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18
cycloalkylalkyl radicals optionally substituted by 1-3
radicals of amino, alkylamino, dialkylamino, hydroxy,
alkoxy, alkylthio, alkyl or haloalkyl;
preferably, each R5 is independently
(1) hydrogen radicals;
(2) C2-Cg alkyl, C2-Cg alkenyl or C2-Cg alkynyl radicals
optionally substituted by 1-3 radicals of amino, Cl-Cg
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, -S03H or halo; or -
(3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-
alkyl, heterocyclyl; heterocyclyl-C1-C4-alkyl, C3-Cg
cycloalkyl or C3-Cg-cycloalkyl-C1-C4-alkyl radicals
optionally substituted by 2-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, C1-C4 alkyl or C1-Cq haloalkyl of 1-3
halo radicals;
more preferably, each R5 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals
optionally subs-tituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, -S03H or halo; or
(3) aryl, heteroaryl, aryl-C1-C4-alkyl, heteroaryl-C1-C4-
alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, C3-Cg
cycloalkyl or C3-Cg-cycloalkyl-C1-C4-alkyl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, C1-C4 alkyl or C1-C4 haloalkyl of 1-3
halo radicals;
more preferably, each R5 is independently
(1) hydrogen radicals;

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19
(2) C1-C4 alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of amino, di-(C1-C4-
alkyl)amino, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, -
S03H or halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl,
heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl
radicals optionally substituted by 1-3 radicals of
amino, di-(C1-C4-alkyl)amino, hydroxy, C1-C4 al~coxy, C1-
C4 alkylthio, C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo
radicals;
more preferably, each R5 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by 1-3
radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2
alkoxy, C1-C2 alkylthio or halo; or
(3) phenyl-C1-C2-alkyl, heteroaryl-C1-C2-alkyl,
heterocyclyl-C1-C2-alkyl or C3-C6-cycloalkyl-C1-C2-alkyl
radicals optionally substituted by 1-3 radicals of
amino, di-(C1-C2-alkyl)amino, hydroxy, C1-C2 alkoxy, C1-
CZ alkylthio, methoxy, methylthio, C1-C4 alkyl or
trifluoromethyl radicals;
more preferably, each R5 is independently
(1) hydrogen radical;
'(2) C1-C4 alkyl radical optionally substituted by 1-3
halo radicals; or
(3) phenyl-C1-C2-alkyl or heteroaryl-C1-CZ-alkyl,
radicals optionally substituted by 1-3 radicals of
amino, dimethylamino, hydroxy, methoxy, methylthio,
methyl or trifluoromethyl radicals;
more preferably, each R5 is independently hydrogen or
C1-C4 alkyl radical; and most preferably, each R5 is a
hydrogen radical;

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wherein each R2p is independently
(1) alkyl, alkenyl or alkynyl radicals optionally
substituted by 1-3 radicals of amino, alkylamino,
5 dialkylamino, alkanoylamino, alkoxycarbonylamino, N-
(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino,
alkylsulfonylamino, hydroxy, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, halo or aralkoxy,
aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl,
10 aryl or heteroaryl radicals optionally substituted by 1-
3 radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino,_alkylsulfonylamino,
alkanoyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, halo, alkyl or haloalkyl;
15 (2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or
(3) aryl or heteroaryl radicals optionally substituted
20 by 1-3 radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo,
azido, alkyl or haloalkyl;
preferably, each R2p is independently
(1) C1-Cg alkyl, CZ-Cg alkenyl or C2-Cg alkynyl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-Cg alkyl)amino, C1-C5 alkanoylamino,
(Cl-C4 alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-
N-(C1-C4 alkyl)amino, aminocarbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo
or aryl-C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-
alkylsulfonyl, C3-Cg cycloalkyl, heterocyclyl, aryl or
heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4

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21
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5
alkanoyl, hydroxy, C1-Cq alkoxy, C1-Cq alkylthio, C1-Cq
alkylsulfinyl, C1-Cq alkylsulfonyl, halo, C1-Cq alkyl or
C1-Cq haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, C1-Cq alkylamino, di-(Cl-Cq
alkyl)amino, C1-C5 alkanoylamino, (C1-Cq
alkoxy)carbonylamino, C1-Cq alkylsulfonylamino, hydroxy,
C1-Cq alkoxy, C1-Cq alkylthio, C1-C4 alkyl or C1-Cq
haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-Cq
alkyl)amino, C1-C5 alkanoylamino, (C1-Cq
alkoxy)carbonylamino, C1-Cq alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-Cq alkoxy, Cl-Cq alkylthio,
cyano, halo, azido, C1-Cq alkyl or C1-Cq haloalkyl of 1-3
halo radicals;
more preferably, each R2p is independently
(1) C~-Cg alkyl, C2-C5 alkenyl or C2-C5 alkynyl radicals
optionally substituted by 1-3 radicals of amino, C1-Cq
alkylamino, di-(Cl-Cq alkyl)amino, C1-C5 alkanoylamino,
(C;-Cq alkoxy)carbonylamino, N-((C1-Cq alkoxy)carbonyl)-
N-(C1-Cq alkyl)amino, aminocarbonylamino, C1-Cq
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, halo
or aryl-C1-C4-alkoxy, aryl-Cz-Cq-alkylthio, aryl-C1-C4-
alkylsulfonyl, C3-Cg cycloalkyl, heterocyclyl, aryl or
- 30 heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1
alkoxy)carbonylamino, C1-Cq alkylsulfonylamino, C1-C5
' alkanoyl, hydroxy, C1-C4 alkoxy, Cl-C4 alkylthio, C1-C4

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22
alkylsulfinyl, C1-C4 alkylsulfonyl, halo, C1-C4 alkyl or
C1-C4 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, C1-C4-alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted
by 1--3 radicals of amino, C1-C4 alkylamino, di-(C1-Cq
alkyl)amino, C1-C5 alkanoylamino, (Cl-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or C1-C4 haloalkyl of 1-
3 halo radicals;
more preferably, each RZp is independently
(1) C1-Cg alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4
alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, halo or aryl-C1-CQ-alkoxy, aryl-C1-C4-
-alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkyisulfonylamino, C1-C5
alkanoyl, hydroxy, C1-Cq alkoxy, C1-C4 alkylthio, halo,
C1-C4 alkyl or C1-CZ haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4

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23
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, (C1-C4
alkoxy)carbonyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio,
cyano, halo, azido, C1-C4 alkyl or C1-C2 haloalkyl of 1-3
halo radicals;
more preferably, each R2p is independently
(1) C1-Cg alkyl or C2-C5 alkenyl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-Cq
alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-Cq
alkylsulfonyl, halo or aryl-C1-C4-alkoxy, aryl-C1-C4-
alkylthio, aryl-C1-C4-alkylsulfonyl, C3-C6 cycloalkyl,
heterocyclyl, aryl, or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, C1-C5
alkanoyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, halo,
C1-C4 alkyl or C1-C2 haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of amino, di-(C1-C4 alkyl)amino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, acetamido, (C1-C4 alkoxy)carbonylamino, C1-
C4 alkylsulfonylamino, (C1-C4 alkoxy)carbonyl, hydroxy,
- C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, azido, C1-C4
alkyl or trifluoromethyl radicals;

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24
more preferably, each R2p is independently
(1) C1-Cg alkyl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, N-((C1-C4 alkoxy)carbonyl)-N-(C1-C4
alkyl)amino, aminocarbonylamino, hydroxy, C1-C4 alkoxy,
Cl-C4 alkylthio, C1-Cq alkylsulfinyl, C2-C4
alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl,
aryl or heteroaryl radicals optionally substituted by 1-
2 radicals of amino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C~ alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) heterocyclyl radical optionally substituted by 1-2
radicals of hydroxy, C1-C4 alkoxy, C1-C4 alkylthio or C1-
C4 alkyl; or -
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of (C1-C4 alkoxy)carbonyl, amino, C2-C4
alkylamino, di-(C1-C4 alkyl)amino, hydroxy, C1-C4 alkoxy,
C1-C4 alkylthio, cyano, halo, azido, C1-C4 alkyl or
trifluoromethyl radicals;
more preferably, each R2p is independently
(1) C1-C6 alkyl radicals optionally-substituted by 1-3
radicals of amino, methylamino, dimethylamino, t-
butoxycarbonylamino, N-((t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl, heterocyclyl,
phenyl or heteroaryl radicals optionally substituted by
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals;

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(2) heterocyclyl radical optionally substituted by 1-2
radicals of hydroxy or C1-C4 alkyl; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
5 methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
more preferably, each R2o is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
10 radicals of amino, methylamino, dimethylamino, t-
butoxycarbonylamino, N-{(t-butoxy)carbonyl)-N-
(methyl)amino, aminocarbonylamino, hydroxy, butoxy,
methoxy, butylthio, methylthio, methylsulfinyl,
methylsulfonyl, halo or C5-C6 cycloalkyl., heterocyclyl,
15 phenyl or heteroaryl radicals optionally substituted by
1-2 radicals of amino, dimethylamino, acetamino,
hydroxy, methoxy, methylthio, halo, methyl or
trifluoromethyl radicals;
(2) heterocyclyl radical; or
20 (3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
25 most preferably, each R2p is independently
(1) C1-C6 alkyl radicals optionally substituted by 1-3
radicals of amino, methylamino, dimethylamino, hydroxy
or phenyl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;
(2) heterocyclyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-2 radicals of amino, dimethylamino, hydroxy,
methoxy, methylthio, halo, methyl or trifluoromethyl
radicals;

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26
each R21 is independently hydrogen radical or R2o: ,
each R22 is independently
(1) hydrogen radical;
(2) alkyl radical optionally substituted by a radical of
heterocyclyl, aryl or heteroaryl optionally substituted
by 1-3 radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
hydroxy, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or
(3) heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, alkylamino,
dialkylamino, alkanoylamino, alkoxycarbonylamino,
alkylsulfonylamino, hydroxy, alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or
haloalkyl; provided when Z is a bond and Y is -NR22-
C(O)-NH2, then R22 is other then an optionally
substituted aryl radical;
preferably, each R22 is independently
(1) hydrogen radical;
(2) C1-C4 alkyl radical optionally substituted by a
radical of heterocyclyl, aryl or heteroaryl optionally
substituted by 1-3 radicals of amino, C1-Cq alkylamino,
di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino, (Cl-Cq
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C2-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of 1-3 halo radicals; or
(3) heterocyclyl, aryl or heteroaryl radicals optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-C4 alkyl)amino, Cl-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4
alkylsulfonyl, cyano, halo, C1-C4 alkyl or C1-C4
haloalkyl of-1-3 halo radicals; provided when Z is a

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27
bond and Y is -NR22-C(O)-NH2, then R22 is other then an
optionally substituted aryl radical;
more preferably, each R22 is independently
(1) hydrogen radical; or
(2) C1-Cq alkyl radical optionally substituted by a
radical of phenyl or heteroaryl optionally substituted
by 1-3 radicals of amino, di-(C1-C2 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, hydroxy, C1-
C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl or
C1-C2 haloalkyl of 1-3 halo radicals;
more preferably, each R22 is independently hydrogen or
C1-C4 alkyl radical; and most preferably, each R22 is
independently hydrogen or methyl radical;
R11 and R12 are each independently an aryl or heteroaryl
radical optionally substituted by 1-3 radica-is of
(1) R3p;
(2) halo or cyano radicals;
(3 ) -C (O) -R3p, -C (O) -OR2g, -C (O) -NR31R32 or -C (NR31) -
NR31R32 radicals;
( 4 ) -OR2 g , -O-C ( 0 ) -R2 g , -O-C ( O ) -NR31R3 2 or -O-C ( O ) -NR3 3 -
S(O)2-R3p radicals;
(5) -SR2g, -S(O)-R30~ -S(O)2-R30~ -S(O)2-NR31R32~ -S(0)2-
NR33-C (O) -R3o, -S (O) 2-NR33-C (O) -OR3p or -S {O) 2-NR33-C (O) -
NR31R32 radicals; or
(6) -NR31R32, -NR33-C(0)-R2g, -NR33-C(O)-OR3p. -NR33-C(O)-
NR31R32, -NR33-C(NR31)-NR31R32, -NR33-S(0)2-R3p or -NR33-
S{O)2-NR31R32 radicals;
provided that (1) R11 is other than a 4-pyridyl, 4-
- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical
optionally substituted by 1-2 substituents; and (2) the
_ total number of aryl, heteroaryl, cycloalkyl and
heterocyclyl radicals substituted on each of R11 and R12
is 0-1;

CA 02274093 1999-06-03
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28
preferably, R11 and R12 are each independently an aryl or
heteroaryl radical optionally substituted by 1-2
radicals of
(1) R3o;
(2) halo or cyano radicals;
(3 ) -C (O) -R3p, -C (0) -OR29, -C (O) -NR31R32 or -C (NR31) -
NR31R32 radicals;
( 4 ) -OR2 g , -O-C ( O ) -R2 g , -O-C ( O ) -NR31R32 or -O-C ( O ) -NR3 3 -
S(O)2-R3p radicals;
(5) -SR29. -S(O)-R30. -S(O)2-R30. -S(O)2-NR31R32. -S(0)2-
NR33-C (O) -R3p, -S (0) 2-NR33-C (O) -OR3p or -S (O) 2-NR33-C (0) -
NR31R32 radicals; or
( 6 ) -NR31R32. -NR33-C (0) -R29. -NR33-C (O) -OR30. -NR33-C (O) _
NR31R32. -NR33-~C(NR31)-NR31R32. -NR33-S(O)2-R30 or -NR33-
S(O)2-NR31R32 radicals;
provided that (1) R11 is other than a 4-pyridyl, 4-
pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical
optionally substituted by 1-2 substituents; and (2) the
total number of aryl, heteroaryl, cycloalkyl and
heterocyclyl radicals substituted on each of R11 and R12
is 0-1;
more preferably, R11 and R12 are each independently an
aryl or heteroaryl radical optionally substituted by 1-2
radicals of
(1) R30;
(2) halo or cyano radicals;
( 3 ) -C (O) -R3p, -C (O) -OR29, -C (O) -NR31R32 or -C (NR~~ ) -
NR31R32 radicals; or
(4) -OR2g, -SR29. -S (O) -R30. -S (O) 2-R30. -S (0) 2-NR31R32.
-NR31R32. -NR33-C (O) -R29 or -NR33-C (O) -OR30 radicals;
more preferably, Rll is an aryl radical and R12 is a
heteroaryl radical, wherein the aryl and heteroaryl
--radicals are optionally substituted by 1-2 radicals of

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29
(1) R30%
(2) halo or cyano radicals;
( 3 ) -C ( O ) -R3 0 , -C ( O ) -OR2 g , -C ( O ) -NR31R32 or -C ( NR31 ) -
NR31R32 radicals; or
(4) -OR29, -SR29, -S(O)-R30. -S(O)2-R30, -S(O)2-NR31R32.
-NR31R32 or -NR33-C(O)-R2g radicals;
more preferably, R11 is an aryl radical and R12 is a
heteroaryl radical, wherein the aryl and heteroaryl
radicals are optionally substituted by 1-2 radicals of
(1) R30%
(2) halo or cyano radicals; or
(3) -C(O)-NR31R32~ -OR29, -SR29~ -S(O)-R30. -S(0)2-R3p, _
S(O)2-NR31R32, -NR31R32 or -NR33-C(O)-R2g radicals;
more preferably, R11 is an aryl radical optionally
substituted by 1-2 radicals of (1) R30; (2) halo or
cyano radicals; or (3) -C(O)-NR31R32~ -OR29. -SR2g, -
S (O) -R30 ~ -S (O) 2-R30. -S (O) 2-NR31R32 ~ -NR31R32 fir' -NR33-
C(O)-R2g radicals; more preferably, Rll is an aryl
radical optionally substituted by 1-2 radicals of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,
methylthio, methylsulfinyl, methylsulfonyl,
aminocarbonyl, methyl or trifluoromethyl radicals; more
preferably, R11 is an unsubstituted phenyl or naphthyl
radical or a phenyl radical substituted by 1-2 radicals
of amino, dimethylamino, acetamido, hydroxy, halo,
cyano, methoxy, methylthio, methylsulfinyl,
methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl
radicals; and most preferably, R11 is an unsubstituted
phenyl radical or a phenyl radical substituted by 1-2
radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methylthio, methylsulfonyl, methyl
or trifluoromethyl radicals;

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more preferably, R12 is a heteroaryl radical optionally
substituted by 1-2 radicals of (1) R3p; (2) halo or
cyano radicals; or (3) -C(O)-NR31R32, -OR2g, -SR2g,
-NR31R32 or -NR33-C(O)-R2g radicals; more preferably, R12
5 is a heteroaryl radical optionally substituted by 1-2
radicals of amino, dimethylamino, acetamido, hydroxy,
halo, cyano, methoxy, methyl or trifluoromethyl
radicals; more preferably, R12 is a 4-pyridyl, 4-
quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical
10 optionally substituted by a radical of amino,
dimethylamino, acetamido, hydroxy, halo, cyano, methoxy,
methyl or trifluoromethyl radicals; and most preferably,
R12 is a 4-pyridyl radical optionally substituted by a
radical of amino, dimethylamino, acetamido, hydroxy,
15 halo, cyano, methoxy, methyl or trifluoromethyl
radicals;
wherein each R3p is independently
(1) alkyl, alkenyl or alkynyl radicals optionally
20 substituted by 1-3 radicals of -NR31R31~ -C~2R23.
hydroxy, alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio,
aralkylsulfonyl, heterocyclyl, aryl or heteroaryl
radicals optionally substituted by 1-3 radicals of
25 amino, alkylamino, dialkylamino, alkanoylamino,
alkoxycarbonylamino, alkylsulfonylamino, hydroxy,
alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano,
halo, alkyl or haloalkyl;
(2) heterocyclyl radical optionally substituted by 1-3
30 radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, alkylamino, dialkylamino,
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,

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hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or
haloalkyl;
preferably, each R3p is-independently
(1) C1-C4 alkyl, C2-Cq alkenyl or C2-C4 alkynyl radicals
- optionally substituted by 1-3 radicals of -NR31R31, -
C02R23, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4
alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo or aryl-
C1-C4-alkoxy, aryl-C1-C4-alkylthio, aryl-C1-C4-
alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C1-C4 alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-Cq alkoxy, C1-C4 alkylthio, C1-C4
alkylsulfinyl, C1-C4 alkylsulfonyl, cyano, halo, C1-C4
alkyl or C1-C.~ haloalkyl of 1-3 halo radicals;
(2) heterocyclyl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-Cq -
alkoxy)carbonylamino, C1-C~ alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4 alkyl or C1-
C4 haloalkyl of 1-3 halo radicals; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-Cq
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, halo, C1-C4 alkyl
or C1-C4 haloalkyl of 1-3 halo radicals;
more preferably, each R3p is independently
-- (1) C1-C4 alkyl radical optionally substituted by 1-3
radicals of
(a) -NR31R31;
(b) C1-C4 alkoxy-carbonyl or phenoxycarbonyl or
phenylmethoxycarbonyl optionally substituted by 1-3

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32
radicals of amino, alkylamino, di-(C1-C4-alkyl)amino,
C1-C5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, CZ-C4 alkyl or trifluoromethyl;
or
(c) hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, or phenyl-C1-
C4-alkoxy, phenyl-C1-C4-alkylthio, heterocyclyl, phenyl
or heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or C1-C4 haloalkyl of
1-3 halo radical;
(2) C1-Cq haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (Cl-C4
alkoxy)carbonylamino, hydroxy, C1-Cq alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
more preferably, each R3p is independently
i:) C,-C4 alkyl radical optionally substituted by
~G) amino, C1-Cq alkylamino or di-(C1-C4-alkyl)amino
radicals; or
(b) hydroxy, C1-C4 alkoxy, heterocyclyl, phenyl or
heteroaryl radicals optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
(2) Cl-C2 haloalkyl of 1-3 halo radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, C1-C~ alkylamino, di-(C1-C4

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alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, halo, C1-C4 alkyl or trifluoromethyl
radicals;
more preferably, each R3p is independently
(1) C1-C, alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, di-(C1-C2 alkyl)amino, acetamido,
hydroxy, C1-CZ alkoxy, halo, C1-C4 alkyl or
trifluoromethyl radicals;
(2) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by I-3 radicals of amino, di-(C1-C2 alkyl)amino,
acetamido, hydroxy, C1-C2 alkoxy, halo, C1-C4 alkyl or
tr~~luoromethyl radicals;
more preferably, each R3p is independently
(1) C1-Cq alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(~) trifluoromethyl radical; or
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
most preferably, R3p is independently
(1) C1-C4 alkyl radical optionally substituted by a
phenyl or heteroaryl radical optionally substituted by
1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl
radicals;
(2) trifluoromethyl radical; or

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34 '
(3) aryl or heteroaryl radicals optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, halo, methoxy, methyl or trifluoromethyl -
radicals;
each R2g is independently hydrogen radical or R3p; and
most preferably, R29 is an aryl or heteroaryl radicals
optionally substituted by 1-2 radicals of amin6,
dimethylamino, acetamido, hydroxy, halo, methoxy, methyl
or trifluoromethyl radicals;
each R31 is independently
(1) hydrogen radicals;
(2) alkyl radical optionally substituted by an
cycloalkyl, aryl, heterocyclyl or heteroaryl radical
optionally substituted by 1-3 radicals of amino,
alkylamino, dialkylamino, alkanoylamino,
alkoxycarbonylamino, alkylsulfonylamino, hydroxy,
alkoxy, alkylthio, cyano, alkyl or haloalkyl; or
(3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical
optionally substituted by 1-3 radicals of amino,
alkylamino, dialkylamino, alkanoylamino,
alkoxycarbonylamino, alkylsulfonylamino, hydroxy,
alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R31 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical optionally substituted by an C3-
Cg cycloalkyl, aryl, heterocyclyl or heteroaryl radical
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-CQ alkyl)amino, Cl-C5 alkanoylamino,
(C1-Cq alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C~-C4 alkylthio, cyano, C1-C4
alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-Cg cycloalkyl
radical optionally substituted by 1-3 radicals of amino,

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Cl-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyorno, C1-C4 alkyl or C1-C4 haloalkyl of 1-3
5 halo radicals;
more preferably, each R31 is independently
(1) hydrogen radicals; or
(2) C1-C4 alkyl radical optionally substituted by an
10 phenyl or heteroaryl radical optionally substituted by
1-3 radicals of amino, C1-C4 alkylamino, di-(C2-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-Cq
alkylthio, cyorno, C1-C4 alkyl or trifluoromethyl
15 radicals;
more preferably, each R31 is independently hydrogen or
C1-C4 alkyl radicals; and most preferably, each R31 is
independently hydrogen, methyl or ethyl radicals;
each R32 is independently
(1) hydrogen radicals;
(2) alkyl radical optionally substituted by an
cycloalkyl, aryl, heterocyclyl or heteroaryl radical
optionally substituted by 1-3 radicals of amino,
alkylamino, dialkylamino, alkanoylamino,
alkoxycarbonylamino, alkylsulfonylamino, hydroxy,
alkoxy, alkylthio, cyorno, alkyl or haloalkyl; or
(3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical
optionally substituted by 1-3 radicals of amino,
alkylamino, dialkylamino, alkanoylamino,
alkoxycarbonylamino, alkylsulfonylamino, hydroxy,
alkoxy, alkylthio, cyorno, alkyl or haloalkyl;
preferably, each R32 is independently
(1) hydrogen radicals;

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(2) C1-C4 alkyl radical optionally substituted by an C3-
Cg cycloalkyl, aryl, heterocyclyl or heteroaryl radical
optionally substituted by 1-3 radicals of amino, Cl-C4
alkylamino, di-(C1-Cq alkyl)amino, C1-C5 alkanoylamino~
(C1-Cq alkoxy)carbonylamino, C1-C4 alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-C4
alkyl or C1-Cq haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyl or C3-Cg cycloalkyl
radical optionally substituted by 1-3 radicals of amino,
C1-Cq alkylamino, di-(C1-Cg alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C1-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-C4
alkylthio, cyano, C1-Cq alkyl or C1-C4 haloalkyl of 1-3
halo radicals;
more preferably, each R32 is independently
(1) hydrogen radicals;
~2) C1-C4 alkyl radical optionally substituted by an C3-
C6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical
optionally substituted by 1-3 radicals of amino, C1-C4
alkylamino, di-(C1-C4 alkyl)amino, C1-C5 alkanoylamino,
(C~-Cq alkoxy)carbonylamino, C1-Cq alkylsulfonylamino,
hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C1-Cq
alkyl or C1-C4 haloalkyl of 1-3 halo radicals; or
(3) aryl, heteroaryl, heterocyclyi or C3-C6 cycloalkyl
radical optionally substituted by 1-3 radicals of amino,
C1-C4 alkylamino, di-(C1-C4 alkyl)amino, C1-C5
alkanoylamino, (C1-C4 alkoxy)carbonylamino, C~-C4
alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C1-Cq
- 30 alkylthio, cyano, C1-C4 alkyl or C1-C4 haloalkyl of 1-3
halo radicals;
more preferably, each R32 is independently
(1) hydrogen radicals;

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37
(2) C1-C4 alkyl radical optionally substituted by phenyl
or heteroaryl radical optionally substituted by 1-3
radicals of amino, C1-C4 alkylamino, di-(C1-Cq
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-C4 alkoxy, C1-C4 alkyl
or trifluoromethyl radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, C1-C4 alkylamino, di-(C1-C4
alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, hydroxy, C1-Cq alkoxy, C1-C4 alkyl
or trifluoromethyl radicals;
more preferably, each R32 is independently
(1) hydrogen radicals;
(2) C1-C4 alkyl radical or C1-C2 alkyl radical
substituted by phenyl or heteroaryl radical optionally
substituted by 1-3 radicals of amino, dimethylamino,
acetamido, hydroxy, methoxy, methyl or trifluoromethyl
radicals; or
(3) phenyl or heteroaryl radical optionally substituted
by 1-3 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals;
most preferably, R32 is independently
(1) hydrogen or C1-C4 alkyl radical; or
(2) phenyl or heteroaryl radical optionally substituted
by 1-2 radicals of amino, dimethylamino, acetamido,
hydroxy, methoxy, methyl or trifluoromethyl radicals;
and
wherein each_R33 is independently
(1) hydrogen radical; or
(2) alkyl radical optionally substituted by a radical of
heterocyclyl, aryl or heteroaryl optionally substituted
by 1-3 radicals of amino, alkylamino, dialkylamino,

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38
alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,
hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;
preferably, each R33 is independently
(1) hydrogen radical; or
(2) C1-C4 alkyl radical optionally substituted by a
radical of heterocyclyl, aryl or heteroaryl optionally
substituted by 1-3 radicals of amino, C1-C4 alkylamino,
di-(C1-Cq alkyl)amino, C1-C5 alkanoylamino, (C1-C4
alkoxy)carbonylamino, C1-C4 alkylsulfonylamino, hydroxy,
C1-C4 alkoxy, C1-C4 alkylthio, cyano, Cl-C4 alkyl or C1-
C4 haloalkyl of 1-3 halo radicals;
more preferably, each R33 is independently hydrogen or
C1-C4 alkyl radical; and most preferably, eachR33 is
independently hydrogen or methyl radical.
The compounds of this invention may have in general
several asymmetric centers and are typically depicted in
the form of racemic mixtures. This invention is
intended to encompass racemic mixtures, partially
racemic mixtures and separate enantiomers and
diasteromers.
Compounds of interest include the following:
O
R11 ~CH3
2 5 R12 N R1
wherein Rll, R12, and Rl are one of the combinations given
in the following table:
R R R _
Phen 1 4- rid 1 1- i erazin 1
4-fluoro henyl 4- _ 1 1- i erazin 1
rid
3-fluoro hen 1 4- rid 1 1- i erazin 1
2-fluoro hen 1 4- rid 1 1- i erazin 1
4-chlorophen 1 4- rid 1 1- i erazin 1
3-chloro hen 1 4- rid 1 1- iperazinyl

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2-chloro hen 1 4- rid 1 1- i erazin 1
4-tol 1 4- ridyl.., 1- i erazin 1
3-tol 1 4- rid 1 1- i erazin 1
2-tol 1 4- rid 1 1- i erazin 1
4-trifluoro- 4-pyridyl 1-piperazinyl
meth 1 hen 1
3-trifluoro- 4-pyridyl 1-piperazinyl
meth 1 hen 1
2,6- 4-pyridyl 1-piperazinyl
dichloro hen 1
2,6-dimethyl 4-pyridyl 1-piperazinyl -
hen 1
3,4- 4-pyridyl 1-piperazinyl
dichloro hen 1
3,4-dimethyl 4-pyridyl 1-piperazinyl
hen 1
2,4- 4-pyridyl 1-piperazinyl
dichloro hen 1
2,4-dimethyl 4-pyridyl 1-piperazinyl
hen 1
Phenyl 2-amino-4- 1-piperazinyl
rid 1
4-fluorophenyl 2-amino-4- 1-piperazinyl
rid 1
3-fluorophenyl 2-amino-4- 1-piperazinyl
ridyl
2-fluorophenyl 2-amino-4- 1-piperazinyl
ridyl
4-chlorophenyl 2-amino-4- 1-piperazinyl
rid 1
3-chlorophenyl 2-amino-4- 1-piperazinyl
rid 1
2-chlorophenyl 2-amino-4- 1-piperazinyl
rid 1
4-tolyl 2-amino-4- 1-piperazinyl
rid 1
3-tolyl 2-amino-4- 1-piperazinyl
rid 1
~2-tolyl 2-amino-4- 1-piperazinyl
rid 1
4-trifluoro- 2-amino-4- 1-piperazinyl
meth 1 hen 1 rid 1
3-trifluoro- 2-amino-4- 1-piperazinyl
meth 1 hen 1 rid 1
2,6- 2-amino-4- 1-piperazinyl
dichloro hen 1 rid 1
2,6-dimethyl 2-amino-4- 1-piperazinyl
hen 1 rid 1
3,4- 2-amino-4- 1-piperazinyl
dichloro hen 1 rid 1
3,4-dimethyl 2-amino-4- 1-piperazinyl
hen 1 rid 1
2,4- 2-amino-4- 1-piperazinyl
dichloro hen 1 rid 1

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2,4-dimethyl 2-amino-4- 1-piperazinyl
~
hen 1 rid 1
Phenyl 2-acetamido- 1-piperazinyl
4- rid 1
4-fluorophenyl 2-acetamido- 1-piperazinyl
4- ridyl
3-fluorophenyl 2-acetamido- 1-piperazinyl
4- rid 1
2-fluorophenyl 2-acetamido- 1-piperazinyl
4- rid 1
4-chlorophenyl 2-acetamido- 1-piperazinyl
4- rid 1
3-chlorophenyl 2-acetamido- 1-piperazinyl
4- rid 1
2-chlorophenyl 2-acetamido- 1-piperazinyl
4- rid 1
4-tolyl 2-acetamido- 1-piperazinyl
4- yrid 1
3-tolyl 2-acetamido- 1-piperazinyl
4- rid 1
2-tolyl 2-acetamido- 1-piperazinyl
4-p rid 1
4-trifluoro- 2-acetamido- 1-piperazinyl
meth 1 hen 1 4- rid 1
3-trifluoro- 2-acetamido- 1-piperazinyl
meth 1 hen 1 4- rid 1
2,6- 2-acetamido- 1-piperazinyl
dichloro hen 1 4-pyrid 1
2,6-dimethyl 2-acetamido- 1-piperazinyl
hen 1 4- rid 1
3,4- 2-acetamido- 1-piperazinyl
dichloro hen 1 4- rid 1
3,4-dimethyl 2-acetamido- 1-piperazinyl
hen 1 4- yrid 1
..,4- 2-acetamido- 1-piperazinyl
,d:chloro hen 4- rid 1
1
4-dimethyl 2-acetamido- 1-piperazinyl
4
hen 1 4- rid 1
Phenyl 2-amino-4- 1-piperazinyl
rimidin 1
4-fluorophenyl 2-amino-4- 1-piperazinyl
rimidin 1
3-fluorophenyl 2-amino-4- 1-piperazinyl
rimidin 1
2-fluorophenyl 2-amino-4- 1-piperazinyl
rimidin 1
4-chlorophenyl 2-amino-4- 1-piperazinyl
rimidin 1
3-chlorophenyl 2-amino-4- 1-piperazinyl
rimidin 1
2-chlorophenyl 2-amino-4- 1-piperazinyl
rimidin 1
4-tolyl 2-amino-4- 1-piperazinyl
rimidin 1

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41
3-tolyl 2-amino-4- 1-piperazinyl _
rimidin 1
_
2-tolyl 2-amino-4- 1
-piperazinyl
rimidin1
4-trifluoro- 2-amino-4- 1-piperazinyl
meth 1 hen 1 rimidin 1
3-trifluoro- 2-amino-4- 1-piperazinyl
meth 1 hen 1 rimidin 1
2 ri 1 piperazinyl
dichloro hen 1 midin 1
2,6-dimethyl 2-amino-4- 1-piperazinyl
hen 1 rimidin 1
3,4- 2-amino-4- 1-piperazinyl
dichloro hen 1 rimidin 1
3,4-dimethyl 2-amino-4- 1-piperazinyl
phen 1 rimidin 1
2,4- 2-amino-4- 1-piperazinyl
dichloro hen 1 rimidin 1
2,4-dimethyl 2-amino-4- 1-piperazinyl
hen 1 rimidin 1
Phenyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
4-fluorophenyl 4-pyridyl 2-(2-chlorophenyl)
ethylamino
3-fluorophenyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
2-fluorophenyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
4-chlorophenyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
3-chlorophenyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
2-chlorophenyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
4-tolyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
3-tolyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
2-tolyl 4-pyridyl 2-(2-chlorophenyl)
eth lamino
4-trifluoro- 4-pyridyl 2-(2-chlorophenyl)
meth 1 hen 1 eth lamino
3-trifluoro- 4-pyridyl 2-(2-chlorophenyl)
meth 1 hen 1 eth lamino
2,6- 4-pyridyl 2-(2-chlorophenyl)
dichloro hen 1 eth lamino
2,6-dimethyl 4-pyridyl 2-(2-chlorophenyl)
hen 1 eth lamino
3,4- 4-pyridyl 2-(2-chlorophenyl)
dichloro hen 1 eth lamino
3,4-dimethyl 4-pyridyl 2-(2-chlorophenyl)
hen 1 eth lamino
2;4- 4-pyridyl 2-(2-chlorophenyl)
dichloro hen 1 eth lamino

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42
2,4-dimethyl 4-pyridyl 2-(2-chlorophenyl)
henyl eth lamino
4-fluorophenyl 4-pyridyl 3-(3-fluorophenyl)
ro ylamino
4-fluorophenyl 2-amino-4- 3-(3-fluorophenyl)
rimidin 1 pro lamino
Benz 1 4- rid 1 3-phen 1 ro ylamino
benzyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
2-thienyl 4- rid 1 3-phen 1 ro lamino
2-thienyl 4-pyridyl 2-(4-fluorophenyl)
ethylamino
c clohexyl 4-p rid 1 3- hen lpro lamino
cyclohexyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
tert-but 1 4-p rid 1 3- hen lpro lamino
tert-butyl 4-pyridyl 2-(4-fluorophenyl)
ethylamino
4-fluorophenyl 4- 3-phenylpropylamino
iperidinyl
4-fluorophenyl 4- 2-(4-fluorophenyl)
pi eridin 1 ethylamino
4-fluoro henyl 4- yran 1 3-phen lpro ylamino
4-fluorophenyl 4-pyranyl 2-(4-fluorophenyl)
eth lamino
Phenyl 2-amino-4- 2-(2-chlorophenyl)
yrid 1 ethylamino
4-fluorophenyl 2-amino-4- 2-(2-chlorophenyl)
p ridyl eth lamino
3-fluorophenyl 2-amino-4- 2-(2-chlorophenyl)
pyrid 1 ethylamino
2-fluorophenyl 2-amino-4- 2-(2-chlorophenyl)
rid 1 eth lamino
4-chlorophenyl 2-amino-4- 2-(2-chlorophenyl)
rid 1 eth lamino
3-chlorophenyl 2-amino-4- 2-(2-chlorophenyl)
pyridyl eth lamino
2-chlorophenyl 2-amino-4- 2-(2-chlorophenyl)
rid 1 eth lamino
4-tolyl 2-amino-4- 2-(2-chlorophenyl)
rid 1 ethylamino
3-tolyl 2-amino-4- 2-(2-chlorophenyl)
p rid 1 eth lamino
_
2-tolyl 2-amino-4- 2-(2-chlorophenyl)
rid 1 eth 1amino
4-trifluoro- 2-amino-4- 2-(2-chlorophenyl)
meth 1 hen 1 rid 1 eth lamino
3-trifluoro- 2-amino-4- 2-(2-chlorophenyl)
methyl hen 1 rid 1 eth lamino
2,6- 2-amino-4- 2-(2-chlorophenyl~
dichloro hen 1 rid 1 eth lamino
2,6-dimethyl 2-amino-4- 2-(2-chlorophenyl)
phen 1 p ridyl eth lamino

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43
3,4- 2-amino-4- 2-(2-chlorophenyl)
dichloro hen 1 rid 1 eth lamino
3,4-dimethyl 2-amino-4- 2-(2-chlorophenyl)
hen 1 rid 1 eth lamino
2,4- 2-amino-4- 2-(2-chlorophenyl)
dichlor o eth lamino
hen 1 yrid 1
2,4-dimethyl 2-amino-4- 2-(2-chlorophenyl)
hen 1 rid 1 eth lamino
Phenyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
4-fluorophenyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
3-fluorophenyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 ethlamino
2-fluorophenyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
4-chlorophenyl 2-acetamido- 2-(2-.chlorophenyl)
4- rid 1 eth lamino
3-chlorophenyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
2-chlorophenyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
4-tolyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
3-tolyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
2-tolyl 2-acetamido- 2-(2-chlorophenyl)
4- rid 1 eth lamino
4-trifluoro- 2-acetamido- 2-(2-chlorophenyl)
meth 1 hen 1 4- rid 1 eth lamino
3-trifluoro- 2-acetamido- 2-(2-chlorophenyl)
meth 1 hen 1 4- rid 1 eth lamino
2,6- 2-acetamido- 2-(2-chlorophenyl)
d:chloro hen 1 4- ridyl eth lamino
-dimethyl 2-acetamido- 2-(2-chlorophenyl)
'paeny? 4- rid 1 th lamino
e
~.4- 2-acetamido- 2-(2-chlorophenyl)
dichloro hen 1 4- rid 1 eth lamino
3,4-dimethyl 2-acetamido- 2-(2-chlorophenyl)
hen 1 4- rid 1 eth lamino
2,4- 2-acetamido- 2-(2-chlorophenyl)
dichloro hen 1 4- rid 1 eth lamino
2,4-dimethyl 2-acetamido- 2-(2-chlorophenyl)
hen 1 4- rid 1 eth lamino
Phenyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
4-fluorophenyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
3-fluorophenyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
2-fluorophenyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
4-chlorophenyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino

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44
3-chlorophenyl 2-amino-4- 2-(2-chloropheny~)
rimidinrl ethylamino
2-chlorophenyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
4-tolyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
3-tolyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 ethylamino
2-tolyl 2-amino-4- 2-(2-chlorophenyl)
rimidin 1 eth lamino
4-trifluoro- 2-amino-4- 2-(2-chlorophenyl)
meth lphen 1 p rimidin 1 eth lamino
3-trifluoro- 2-amino-4- 2-(2-chlorophenyl)
meth 1 henyl rimidin 1 eth lamino
2,6- 2-amino-4- 2-(2-chlorophenyl)
dichlorophen 1 rimidinyl eth lamino
2,6-dimethyl 2-amino-4- 2-(2-chlorophenyl)
phen 1 rimidin 1 ethylamino
3,4- 2-amino-4- 2-(2-chlorophenyl)
dichlorophen 1 rimidin 1 ethylamino
3,4-dimethyl 2-amino-4- 2-(2-chlorophenyl)
henyl rimidin 1 eth lamino
2,4- 2-amino-4- 2-(2-chlorophenyl)
dichloro henyl rimidin 1 eth lamino
2,4-dimethyl 2-amino-4- 2-(2-chlorophenyl)
henyl rimidin 1 eth lamino
Phenyl 4- rid 1 3-imidazol lpropylamino
4-fluorophen 1 4- yrid 1 3-imidazol 1 ro lamino
3-fluoro hen 1 4- rid 1 3-imidazol 1 ro lamino
2-fluoro hen 1 4- rid 1 3-imidazol 1 ro lamino
4-chloro hen 1 4- rid 1 3-imidazol lpro lamino
3-chloro hen 1 4- yrid 1 3-imidazolyl ro lamino
2-chlorophenyl 4-pyridyl 3-imidazol 1 ro lamino
4-tol 1 4- rid 1 3-imidazol 1 ro lamino
3-tol 1 4- rid 1 3-imidazol lpro lamino
2-tol 1 4- rid 1 3-imidazolyl ro lamino
4-trifluoro- 4-pyridyl 3-imidazolylpropylamino
meth 1 hen 1
3-trifluoro- 4-pyridyl 3-imidazolylpropylamino
meth 1 hen 1
2,6- 4-pyridyl 3-imidazolylpropylamino
dichloro hen 1
2,6-dimethyl 4-pyridyl 3-imidazolylpropylamino
hen 1
3,4- 4-pyridyl 3-imidazolylpropylamino
dichloro hen 1
3,4-dimethyl 4-pyridyl 3-imidazolylpropylamino
hen 1
2,4- 4-pyridyl 3-imidazolylpropylamino
dichloro hen 1
2,4-dimethyl 4-pyridyl 3-imidazolylpropylamino
hen 1
Phenyl 2-amino-4- 3-imidazolylpropylamino
rid 1

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4-fluorophenyl 2-amino-4- 3-imidazolylpropylamino
~
rid 1
3-fluorophenyl 2-amino-4- 3-imidazolylpropylamino
rid 1
2-fluorophenyl 2-amino-4- 3-imidazolylpropylamino
rid 1
4-chlorophenyl 2-amino-4- 3-imidazolylpropylamino
rid 1
3-chlorophenyl 2-amino-4- 3-imidazolylpropylamino
rid 1
2-chlorophenyl 2-amino-4- 3-imidazolylpropylamino
rid 1
4-tolyl 2-amino-4- 3-imidazolylpropylamino
rid 1
3-tolyl 2-amino-4- 3-imidazolylpropylamino
rid 1
2-tolyl 2-amino-4- 3-imidazolylpropylamino
rid 1
4-trifluoro- 2-amino-4- 3-imidazolylpropylamino
meth 1 hen 1 rid 1
3-trifluoro- 2-amino-4- 3-imidazolylpropylamino
meth 1 hen 1 ridyl
2,6- 2-amino-4- 3-imidazolylpropylamino
dichloro hen 1 rid 1
2,6-dimethyl 2-amino-4- 3-imidazolylpropylamino
hen 1 yrid 1
3,4- 2-amino-4- 3-imidazolylpropylamino
dichloro hen 1 rid 1
3,4-dimethyl 2-amino-4- 3-imidazolylpropylamino
phenyl rid 1
2,4- 2-amino-4- 3-imidazolylpropylamino
dichloro hen 1 rid 1
2,4-dimethyl 2-amino-4- 3-imidazolylpropylamino
henyl rid 1
Phenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
4-fluorophenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
3-fluorophenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
2-fluorophenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
4-chlorophenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
3-chlorophenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
2-chlorophenyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
4-tolyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
3-tolyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1
2-tolyl 2-acetamido- 3-imidazolylpropylamino
4- rid 1

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4-trifluoro- 2-acetamido- 3-imidazolylpropylamino
meth 1 hen 1 4- rid 1
3-trifluoro- 2-acetamido- 3-imidazolylpropylamino
meth 1 hen 1 4- rid 1
2,6- 2-acetamido- 3-imidazolylpropylamino
dichlorophen 1 4- rid 1
2,6-dimethyl 2-acetamido- 3-imidazolylpropylamino
phen 1 4- rid 1
3,4- 2-acetamido- 3-imidazolylpropylamino
dichlorophen 1 4- yrid 1
3,4-dimethyl 2-acetamido- 3-imidazolylpropylamino
hen 1 4- rid 1
2,4- 2-acetamido- 3-imidazolylpropylamino
dichloro hen 1 4- yrid 1
2,4-dimethyl 2-acetamido- 3-imidazolylpropylamino
hen 1 4- yrid 1
Phenyl 2-amino-4- 3-imidazolylpropylamino
rimidin 1
4-fluorophenyl 2-amino-4- 3-imidazolylpropylamino
rimidin 1
3-fluorophenyl 2-amino-4- 3-imidazolylpropylamino
rimidin 1
2-fluorophenyl 2-amino-4- 3-imidazolylpropylamino
yrimidin 1
4-chlorophenyl 2-amino-4- 3-imidazolylpropylamino
pyrimidinyl
3-chlorophenyl 2-amino-4- 3-imidazolylpropylamino
pyrimidinyl
2-chlorophenyl 2-amino-4- 3-imidazolylpropylamino
rimidin 1
4-tolyl 2-amino-4- 3-imidazolylpropylamino
yrimidin 1
3-tolyl 2-amino-4- 3-imidazolylpropylamino
rimidin 1
..-tolyl 2-amino-4- 3-imidazolylpropylamino
pyrimid_in
1
4-trifluoro- 2-amino-4- 3-imidazolyipropylamino
meth 1 hen 1 rimidin 1
3-trifluoro- 2-amino-4- 3-imidazolylpropylamino
meth 1 hen 1 rimidin 1
2,6- 2-amino-4- 3-imidazolylpropylamino
dichloro henyl rimidin 1
2,6-dimethyl 2-amino-4- 3-imidazolylpropylamino
hen 1 rimidin 1
3,4- 2-amino-4- 3-imidazolylpropylamino
dichloro hen 1 rimidin 1
3,4-dimethyl 2-amino-4- 3-imidazolylpropylamino
hen 1 rimidin 1
2,4- 2-amino-4- 3-imidazolylpropylamino
dichloro hen 1 rimidin 1
2,4-dimethyl 2-amino-4- 3-imidazolylpropylamino
hen 1 rimidin 1
4-fluorophenyl 4-pyridyl 2-(2-chlorophenyl-1-
meth 1)eth 1)amino

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4-fluorophenyl 2-acetamido- 2-(2-chlorophenyl-1-
4- rid 1 meth 1)eth 1)amino
4-fluorophenyl 2-amino-4- 2-(2-chlorophenyl-1-
rimidin 1 meth 1)eth 1)amino
3-fluorophenyl 4-pyridyl (S)-tetrahydroisoquinol-
3- lmeth lenamino
2-fluorophenyl 2-amino-4- (S)-3-benzylpiperazinyl
rid 1
3-chlorophenyl 2-acetamido- (S)-2-N-isopropylamino-3-
4- rid 1 hen 1 ro lamino
2-chlorophenyl 2-amino-4- (S)-2-N-glycylamino-3-
rimidin 1 hen 1 ro lamino
4-tolyl 4-pyridyl (S)-2-amino-3-
hen 1 rop lamino
3-tolyl 2-amino-4- (R)-2-amino-3-
rid 1 hen 1 ro lamino
2-tolyl 2-acetamido- 3-amino-3- -
4- rid 1 hen 1 ro lamino
4-trifluoro- 2-amino-4- (S)-2-amino-3-(2-
meth 1 hen 1 rimidin 1 fluoro hen 1) ro lamino
3-trifluoro- 4-pyridyl (S)-2-amino-3-(2-
meth 1 henyl meth 1 hen 1) ro lamino
2,6- 2-amino-4- 3-amino-3-(2-
dichloro hen 1 rid 1 fluoro hen 1) ro lamino
2,6-dimethyl 2-acetamido- 3-amino-3-(2-
hen 1 4- rid 1 meth 1 hen 1) ro lamino
3,4- 2-amino-4- 2-amino-2-methyl-3-
dichloro hen 1 rimidin 1 phenyl ro lamino
3,4-dimethyl 4-pyridyl 3-amino-2-methyl-3-
hen 1 phen 1 ro lamino
3-fluorophenyl 2-amino-4- (S)-2-amino-3-
rid 1 hen 1 ro lamino
2-fluorophenyl 2-acetamido- (S)-2-amino-3-(2-
4- rid 1 fluoro hen 1) ro lamino
3-chlorophenyl 2-amino-4- (S)-2-amino-3-(2-
rimidin 1 meth 1 hen 1) ro lamino
2-chlorophenyl 4-pyridyl (S)-2-N-isopropylamino-3-
hen 1 ro lamino
4-tolyl 2-amino-4- (S)-2-N-glycylamino-3-
rid 1 hen 1 ro lamino
3-tolyl 2-acetamido- 2-amino-2-methyl-3-
4- rid 1 hen 1 ro lamino
2-tolyl 2-amino-4- (R)-2-amino-3-
rimidin 1 hen 1 ro lamino
4-trifluoro- 4-pyridyl 3-amino-3-
meth 1 hen 1 hen 1 ro lamino-
3-trifluoro- 2-amino-4- 3-amino-3-(2-
meth 1 hen 1 rid 1 fluoro hen 1) ro lamino
2,6- 2-acetamido- 3-amino-3-(2-
dichloro hen 1 4- rid 1 meth 1 hen 1) ro lamino
2,6-dimethyl 2-amino-4- 3-amino-2-methyl-3-
hen 1 rimidin 1 hen 1 ro lamino
3,4- 4-pyridyl (S)-tetrahydroisoquinol-
dichloro hen 1 3- lmeth lenamino

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1 3, 4-dimethyl 1 4-pyridyl (S) -3-benzylpiperazinyl
phenyl
O
R11 ~CH3
I N
R12 N R1
wherein R1', R'', and R' are one of the coribinations given
in the following table:
R.. R.~ R
Phen 1 4- ridyl 4-pyrid 1
4-fluoro hen 1 4- rid 1 4- ridyl
3-fluoro hen 1 4- rid 1 4- rid 1
2-fiuoro hen 1 4- rid 1 4- rid 1
4-chloro hen 1 4- ridyl 4- yrid 1
3-chloro hen 1 4- rid 1 4-pyrid 1
2-chloro hen 1 4- rid 1 4- rid 1
4-tol 1 4- rid 1 4- rid 1
3-tol 1 4- rid 1 4- ridyl
2-tol 1 4- rid 1 4- rid 1
4-trifluoro- 4-pyridyl 4-pyridyl
meth 1 hen 1
3-trifluoro- 4-pyridyl 4-pyridyl
meth 1 hen 1
2,6- 4-pyridyl 4-pyridyl
dichloro hen 1
2,6-dimethyl 4-pyridyl 4-pyridyl
hen 1
dichloro hen 1 4 pyridyl 4-pyridyl
3,4-dimethyl 4-pyridyl 4-pyridyl
hen 1
2,4- 4-pyridyl 4-pyridyl
dichloro hen 1
2,4-dimethyl 4-pyridyl 4-pyridyl
hen 1
Phenyl 2-amino-4- 4-pyridyl
rid 1
4-fluorophenyl 2-amino-4- 4-pyridyl
_ rid 1
3-fluorophenyl 2-amino-4- 4-pyridyl
rid 1
2-fluorophenyl 2-amino-4- 4-pyridyl
rid 1
4-chlorophenyl 2-amino-4- 4-pyridyl
rid 1
3-chlorophenyl 2-amino-4- 4-pyridyl
rid 1

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2-chlorophenyl 2-amino-4- 4-pyridyl
~ridyl
4-tolyl 2-amino-4- 4-pyridyl
rid 1
3-tolyl 2-amino-4- 4-pyridyl
rid 1
2-tolyl 2-amino-4- 4-pyridyl
rid 1
4-trifluoro- 2-amino-4- 4-pyridyl
meth 1 hen 1 rid 1
3-trifluoro- 2-amino-4- 4-pyridyl
meth 1 hen 1 rid 1
2,6- 2-amino-4- 4-pyridyl
dichloro hen 1 rid 1
2,6-dimethyl 2-amino-4- 4-pyridyl
hen 1 p rid 1
3,4- 2-amino-4- 4-pyridyl
dichloro hen 1 rid 1
3,4-dimethyl 2-amino-4- 4-pyridyl
hen 1 rid 1
2,4- 2-amino-4- 4-pyridyl
dichloro hen 1 rid 1
2,4-dimethyl 2-amino-4- 4-pyridyl
hen 1 rid 1
Phenyl 2-acetamido- 4-pyridyl
4- rid 1
4-fluorophenyl 2-acetamido- 4-pyridyl
4- rid 1
3-fluorophenyl 2-acetamido- 4-pyridyl
4- rid 1
2-fluorophenyl 2-acetamido- 4-pyridyl
4- rid 1
4-chlorophenyl 2-acetamido- 4-pyridyl
4- rid 1
3-chlorophenyl 2-acetamido- 4-pyridyl
4- ridyl
2-chlorophenyl 2-acetamido- 4-pyridyl
4- rid 1
4-tolyl 2-acetamido- 4-pyridyl
4- rid 1
-
3-tolyl 2-acetamido- 4-pyridyl
4- rid 1
2-tolyl 2-acetamido- 4-pyridyl
4- rid 1
4-trifluoro- 2-acetamido- 4-pyridyl
meth 1 hen 1_ 4- rid 1
3-trifluoro- 2-acetamido- 4-pyridyl
meth 1 hen 1 4- rid 1
2,6- 2-acetamido- 4-pyridyl
dichloro hen 1 4- rid 1
2,6-dimethyl 2-acetamido- 4-pyridyl
hen 1 4- rid 1
3,4- 2-acetamido- 4-pyridyl
dichloro hen 1 4- rid 1

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3,4-dimethyl 2-acetamido- 4-pyridyl
hen 1 4- rid 1
2,4- 2-acetamido- 4
-pyridyl
dichloro hen 1 4- rid 1
2,4-dimethyl 2-acetamido- 4-pyridyl
hen 1 4- rid 1
Phenyl 2-amino-4- 4-pyridyl
rimidin 1
4-fluorophenyl 2-amino-4- 4-pyridyl
rimidinyl
3-fluorophenyl 2-amino-4- 4-pyridyl
rimidin 1
2-fluorophenyl 2-amino-4- 4-pyridyl
rimidin 1
4-chlorophenyl 2-amino-4- 4-pyridyl
rimidin 1
3-chlorophenyl 2-amino-4- 4-pyridyl
rimidin 1
2-chlorophenyl 2-amino-4- 4-pyridyl
yrimidin 1
4-tolyl 2-amino-4- 4-pyridyl
rimidinyl
3-tolyl 2-amino-4- 4-pyridyl
rimidin 1
2-tolyl 2-amino-4- 4-pyridyl
rimidinyl
4-trifluoro- 2-amino-4- 4-pyridyl
meth 1 hen 1 rimidin 1
3-trifluoro- 2-amino-4- 4-pyridyl
meth 1 hen 1 rimidin 1
2,6- 2-amino-4- 4-pyridyl
dichloro hen 1 yrimidin 1
2,6-dimethyl 2-amino-4- 4-pyridyl
hen 1 rimidin 1
3,4- 2-amino-4- 4-pyridyl
dichlorophenyl rimidin 1
3,4-dimethyl 2-amino-4- 4-pyridyl
hen 1 rimidin 1
2,4- 2-amino-4- 4-pyridyl
dichloro hen 1 rimidin 1
2,4-dimethyl 2-amino-4- 4-pyridyl
hen l rimidin 1
Phen 1 4- rid 1 4-meth 1 sulfin 1 hen 1
4-fluoro henyl 4- rid 1 4-meth 1 sulfin 1 hen 1
3-fluoro hen 1 4- rid 1 4-meth 1 sulfin 1 hen 1
2-fluoro hen 1 4- rid 1 4-meth 1 sulfin 1 hen 1
4-chloro hen 1 4- rid 1 4-methyl sulfin 1 hen 1
3-chloro hen 1 4- rid 1 4-meth 1 sulfin 1 hen 1
2-chloro hen 1 4- rid 1 4-meth 1 sulfin 1 hen 1
4-tol 1 4- ridyl 4-meth 1 sulfin 1 hen 1
3-tol 1 4- rid 1 4-meth 1 sulfin 1 hen 1
2-tol 1 4- rid 1 4-meth 1 sulfin 1 hen 1
4-trifluoro- 4-pyridyl 4-methyl sulfinylphenyl
meth 1 hen 1 -

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3-trifluoro- 4-pyridyl 4-methyl sulfinylphenyl
meth 1 hen 1
2,6- 4-pyridyl 4-methyl sulfinylphenyl
dichloro hen 1
2,6-dimethyl 4-pyridyl 4-methyl sulfinylphenyl
hen 1
3,4- 4-pyridyl 4-methyl sulfinylphenyl
dichloro hen 1
3,4-dimethyl 4-pyridyl 4-methyl sulfinylphenyl
phen 1
2,4- 4-pyridyl 4-methyl sulfinylphenyl
dichloro hen 1
2,4-dimethyl 4-pyridyl 4-methyl sulfinylphenyl
hen 1
Phenyl 2-amino-4- 4-methyl sulfinylphenyl
grid 1
4-fluorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
3-fluorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
2-fluorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
4-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
3-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
2-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl
yrid 1
4-tolyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
3-tolyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
2-tolyl 2-amino-4- 4-methyl sulfinylphenyl
rid 1
4-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl
imeth 1 hen 1 rid 1
3-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl
meth 1 hen 1 rid 1
2,6- 2-amino-4- 4-methyl sulfinylphenyl
dichloro hen 1 rid 1
2,6-dimethyl 2-amino-4- 4-methyl sulfinylphenyl
phen 1 rid 1
3,4- 2-amino-4- 4-methyl sulfinylphenyl
dichloro hen 1 rid 1
3,4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl
hen 1 rid 1
2,4- 2-amino-4- 4-methyl sulfinylphenyl
dichloro hen 1 rid 1
2,4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl
hen 1 rid 1
Phenyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1
4-fluorophenyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1

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3-fluorophenyl 2-acetamido- 4~-methyl sulfinylphenyl
4- rid 1
2-fluorophenyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1
4-chlorophenyl 2-acetamido- 4-methyl sulfinylphenyl
4- ridyl
3-chlorophenyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1
2-chlorophenyl 2-acetamido- 4-methyl sulfinylphenyl
4- yridyl
4-tolyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1
3-tolyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1
2-tolyl 2-acetamido- 4-methyl sulfinylphenyl
4- rid 1
4-trifluoro- 2-acetamido- 4-methyl sulfinylphenyl
meth lphenyl 4-p rid 1
3-trifluoro- 2-acetamido- 4-methyl sulfinylphenyl
methylphenyl 4- rid 1
2,6- 2-acetamido- 4-methyl sulfinylphenyl
dichloro hen 1 4- ridyl
2,6-dimethyl 2-acetamido- 4-methyl sulfinylphenyl
henyl 4- yrid 1
3,4- 2-acetamido- 4-methyl sulfinylphenyl
dichloro hen 1 4- rid 1
3,4-dimethyl 2-acetamido- 4-methyl sulfinylphenyl
phen 1 4-p ridyl
2,4- 2-acetamido- 4-methyl sulfinylphenyl
dichlorophenyl 4- rid 1
2,4-dimethyl 2-acetamido- 4-methyl sulfinylphenyl
hen 1 4-p ridyl
Phenyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
4-fluorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
3-fluorophenyl 2-amino-4- 4-methyl sulfinylphenyl
p rimidin 1
2-fluorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1 -
4-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rimidinyl
3-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
2-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
4-tolyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
3-tolyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
2-tolyl 2-amino-4- 4-methyl sulfinylphenyl
rimidin 1
4-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl
-meth 1 hen 1 rimidinyl

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3-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl
meth 1 hen 1 rimidin 1
_
2,6- 2-amino-4- 4-methyl~sulfinylphenyl
dichloro hen 1 rimidin 1
2,6-dimethyl 2-amino-4- 4-methyl sulfinylphenyl
hen 1 rimidin 1
3,4- 2-amino-4- 4-methyl sulfinylphenyl
dichloro hen 1 rimidin 1
3,4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl
hen 1 rimidin 1
2,4- 2-amino-4- 4-methyl sulfinylphenyl
dichloro hen 1 rimidin 1
2,4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl
hen 1 rimidin 1
Phen 1 4- rid 1 2,6-dichlorobenz 1
4-fluorophen 1 4- rid 1 2,6-dichlorobenz 1
3-fluoro hen 1 4- rid 1 2,6-dichlorobenz 1
2-fluoro henyl 4- rid 1 2,6-dichlorobenz 1
4-chloro hen 1 4- rid 1 2,6-dichlorobenz 1
3-chloro hen 1 4- ridyl 2,6-dichlorobenz 1
2-chloro hen 1 4- yrid 1 2,6-dichlorobenz 1
4-tol 1 4- rid 1 2,6-dichlorobenz 1
3-tol 1 4- rid 1 2,6-dichlorobenz 1
2-tol 1 4- rid 1 2,6-dichlorobenz 1
4-trifluoro- 4-pyridyl 2,6-dichlorobenzyl
meth 1 hen 1
3-trifluoro- 4-pyridyl 2,6-dichlorobenzyl
meth 1 hen 1
2,6- 4-pyridyl 2,6-dichlorobenzyl
dichloro hen 1
2,6-dimethyl 4-pyridyl 2,6-dichlorobenzyl
hen 1
3,4- 4-pyridyl 2,6-dichlorobenzyl
dichloro hen 1
3,4-dimethyl 4-pyridyl 2,6-dichlorobenzyl
hen 1
2,4- 4-pyridyl 2,6-dichlorobenzyl
dichloro hen 1
2,4-dimethyl 4-pyridyl 2,6-dichlorobenzyl
hen 1
Phenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
4-fluorophenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
3-fluorophenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
2-fluorophenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
4-chlorophenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
3-chlorophenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
2-chlorophenyl 2-amino-4- 2,6-dichlorobenzyl
rid 1

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54
4-tolyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
3-tolyl 2-amino-4- 2,6-dichlorobenzyl
rid 1
2-tolyl 2-amino-4- 2,6-dichlorobenzyl
p rid 1
4-trifluoro- 2-amino-4- 2,6-dichlorobenzyl
meth lphen 1 rid 1
3-trifluoro- 2-amino-4- 2,6-dichlorobenzyl
meth lphen 1 rid 1
2,6- 2-amino-4- 2,6-dichlorobenzyl
dichloro hen 1 rid 1
2,6-dimethyl 2-amino-4- 2,6-dichlorobenzyl
hen 1 yridyl
3,4- 2-amino-4- 2,6-dichlorobenzyl
dichloro hen 1 yridyl
3,4-dimethyl 2-amino-4- 2,6-dichlorobenzyl
henyl rid 1
2,4- 2-amino-4- 2,6-dichlorobenzyl
dichloro hen 1 rid 1
2,4-dimethyl 2-amino-4- 2,6-dichlorobenzyl
phen 1 p rid 1
Phenyl 2-acetamido- 2,6-dichlorobenayl
4- yridyl
4-fluorophenyl 2-acetamido- 2,6-dichlorobenzyl
4- yridyl
3-fluorophenyl 2-acetamido- 2,6-dichlorobEnzyl
4-p rid 1
2-fluorophenyl 2-acetamido- 2,6-dichlorobenzyl
4- yrid 1
4-chlorophenyl 2-acetamido- 2,6-dichlorobenzyl
4- rid 1
3-chlorophenyl 2-acetamido- 2,6-dichlorobenzyl
4- rid 1
2-chlorophenyl 2-acetamido- 2,6-dichlorobenzyl
4- rid 1
4-tolyl 2-acetamido- 2,6-dichlorobenzyl
4- rid 1
3-tolyl 2-acetamido- 2,6-dichlorobenzyl
4- rid 1
2-tolyl 2-acetamido- 2,6-dichlorobenzyl
4- rid 1
4-trifluoro- 2-acetamido- 2,6-dichlorobenzyl
meth 1 henyl 4- rid 1
3-trifluoro- 2-acetamido- 2,6-dichlorobenzyl
methyl hen 1 4- rid 1
2,6- 2-acetamido- 2,6-dichlorobenzyl
dichloro henyl 4- rid 1
2,6-dimethyl 2-acetamido- 2,6-dichlorobenzyl
hen 1 4- rid 1
3,4- 2-acetamido- 2,6-dichlorobenzyl
dichloro hen 1 4- rid 1
3,4-dimethyl 2-acetamido- 2,6-dichlorobenzyl
hen 1 4- rid 1

CA 02274093 1999-06-03
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2,4- 2-acetamido- 2,6-dichlorobenzyl
dichloro hen 1 4- ridyl
2,4-dimethyl 2-acetamido- 2,6-dichlorobenzyl
phen 1 4- rid 1
Phenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
4-fluorophenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
3-fluorophenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
2-fluorophenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
4-chlorophenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
3-chlorophenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
2-chlorophenyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
4-tolyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
3-tolyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
2-tolyl 2-amino-4- 2,6-dichlorobenzyl
rimidin 1
4-trifluoro- 2-amino-4- 2,6-dichlorobenzyl-
meth 1 hen 1 rimidin 1
3-trifluoro- 2-amino-4- 2,6-dichlorobenzyl
meth 1 hen 1 rimidinyl
2,6- 2-amino-4- 2,6-dichlorobenzyl
dichloro hen 1 rimidin 1
2,6-dimethyl 2-amino-4- 2,6-dichlorobenzyl
hen 1 rimidin 1
3,4- 2-amino-4- 2,6-dichlorobenzyl
dichloro hen 1 rimidin 1
3,4-dimethyl 2-amino-4- 2,6-dichlorobenzyl
hen 1 rimidin 1
2;4- 2-amino-4- 2,6-dichlorobenzyl
dichloro hen 1 rimidin 1
2,4-dimethyl 2-amino-4- 2,6-dichlorobenzyl
hen 1 rimidin 1
Phenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
4-fluorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
3-fluorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
2-fluorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
4-chlorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
3-chlorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
2-chlorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino

CA 02274093 1999-06-03
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4-tolyl 4-pyridyl 2-(4-fluorophenyl)
eth !amino
3-tolyl 4-pyridyl 2-(4-fluorophenyl)
eth !amino
2-tolyl 4-pyridyl 2-(4-fluorophenyl)
eth !amino
4-trifluoro- 4-pyridyl 2-(4-fluorophenyl)
meth 1 hen 1 eth !amino
3-trifluoro- 4-pyridyl 2-(4-fluorophenyl)
meth 1 hen 1 eth !amino
2,6- 4-pyridyl 2-(4-fluorophenyl)
dichloro hen 1 eth !amino
2,6-dimethyl 4-pyridyl 2-(4-fluorophenyl)
hen 1 eth !amino
3,4- 4-pyridyl 2-(4-fluorophenyl)
dichlorophen 1 eth !amino
3,4-dimethyl 4-pyridyl 2-(4-fluorophenyl)
hen 1 ethylamino
2,4- 4-pyridyl 2-(4-fluorophenyl)
dichloro hen 1 eth !amino
2,4-dimethyl 4-pyridyl 2-(4-fluorophenyl)
hen 1 eth !amino
Phenyl 2-amino-4- 2-(4-fluorophenyl)
rid 1 eth !amino
4-fluorophenyl 2-amino-4- 2-(4-fluorophenyl)
rid 1 ethylamino
3-fluorophenyl 2-amino-4- 2-(4-fluorophenyl)
p ridyl ethylamino
2-fluorophenyl 2-amino-4- 2-(4-fluorophenyl)
ridyl eth !amino
4-chlorophenyl 2-amino-4- 2-(4-fluorophenyl)
yrid 1 eth !amino
3-chlorophenyl 2-amino-4- 2-(4-fluorophenyl)
yrid 1 eth !amino
2-chlorophenyl 2-amino-4- 2-(4-fluorophenyl)
rid 1 ethylamino
4-tolyl 2-amino-4- 2-(4-fluorophenyl)
rid 1 eth !amino
3-tolyl 2-amino-4- 2-(4-fluorophenyl)
rid 1 eth !amino
2-tolyl 2-amino-4- 2-(4-fluorophenyl)
rid 1 eth !amino
4-trifluoro- 2-amino-4- 2-(4-fluorophenyl)
meth lphen 1 rid 1 eth !amino
3-trifluoro- 2-amino-4- 2-(4-fluorophenyl)
meth 1 hen 1 ridyl eth !amino
2;6- 2-amino-4- 2-(4-fluorophenyl)
dichloro hen 1 rid 1 eth !amino
2,6-dimethyl 2-amino-4- 2-(4-fluorophenyl)
hen 1 rid 1 eth !amino
3:4- 2-amino-4- 2-(4-fluorophenyl)
dichloro hen 1 rid 1 eth !amino
3,4-dimethyl 2-amino-4- 2-(4-fluorophenyl)
hen 1 rid 1 eth !amino

CA 02274093 1999-06-03
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2,4- 2-amino-4- 2-(4-fluorophenyl)
dichloro hen 1 ridrl eth lamino
2,4-dimethyl 2-amino-4- 2-(4-fluorophenyl)
hen 1 rid 1 eth lamino
Phenyl 2-acetamido- 2-(4-fluorophenyl)
4- rid l eth lamino
4-fluorophenyl 2-acetamido- 2-(4-fluorophenyl)
4- ridyl eth lamino
3-fluorophenyl 2-acetamido- 2-(4-fluorophenyl)
4- grid 1 eth lamino
2-fluorophenyl 2-acetamido- 2-(4-fluorophen_yl)
4- rid 1 eth lamino
4-chlorophenyl 2-acetamido- 2-(4-fluorophenyl}
4- rid 1 eth lamino
3-chlorophenyl 2-acetamido- 2-(4-fluorophenyl)
4- rid 1 eth lamino
2-chlorophenyl 2-acetamido- 2-(4-fluorophenyl)
4- rid 1 eth lamino
4-tolyl 2-acetamido- 2-(4-fluorophenyl)
4- rid 1 eth lamino
3-tolyl 2-acetamido- 2-(4-fluorophenyl)
4- rid 1 eth lamino
2-tolyl 2-acetamido- 2-(4-fluorophenyl)
4- rid 1 eth lamino
4-trifluoro- 2-acetamido- 2-(4-fluorophenyl)
meth 1 hen 1 4- rid 1 ethylamino
3-trifluoro- 2-acetamido- 2-(4-fluorophenyl)
meth 1 hen 1 4- rid 1 eth lamino
2,6- 2-acetamido- 2-(4-fluorophenyl)
dichloro hen 1 4- rid 1 eth lamino
2,6-dimethyl 2-acetamido- 2-(4-fluorophenyl)
hen 1 4- rid 1 eth lamino
3,4- 2-acetamido- 2-(4-fluorophenyl)
dichloro hen 1 4- rid 1 eth lamino
3,4-dimethyl 2-acetamido- 2-(4-fluorophenyl)
hen 1 4- rid 1 eth lamino
2,4- 2-acetamido- 2-(4-fluorophenyl}
dichloro hen 1 4- rid 1 eth lamino
2,4-dimethyl 2-acetamido- 2-(4-fluorophenyl)
phen 1 4- rid 1 eth lamino
Phenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
4-fluorophenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
3-fluorophenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
2-fluorophenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
4-chlorophenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
3-chlorophenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
2-chlorophenyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino

CA 02274093 1999-06-03
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4-tolyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
3-tolyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
2-tolyl 2-amino-4- 2-(4-fluorophenyl)
rimidin 1 eth lamino
4-trifluoro- 2-amino-4- 2-(4-fluorophenyl)
meth 1 hen 1 rimidin 1 eth lamino
3-trifluoro- 2-amino-4- 2-(4-fluorophenyl)
methyl hen 1 yrimidin 1 eth lamino
-
2,6- 2-amino-4- 2-(4-fluorophenyl)
dichlorophen 1 rimidinyl eth lamino
2,6-dimethyl 2-amino-4- 2-(4-fluorophenyl)
phenyl rimidin 1 eth lamino
3,4- 2-amino-4- 2-(4-fluorophenyl)
dichlorophen 1 rimidinyl eth lamino
3,4-dimethyl 2-amino-4- 2-(4-fluorophenyl)
phen 1 rimidin 1 eth lamino
2,4- 2-amino-4- 2-(4-fluorophenyl)
dichloro hen 1 rimidin 1 eth lamino
2,4-dimethyl 2-amino-4- 2-(4-fluorophenyl)
hen 1 rimidin 1 eth lamino
Phen 1 4- ridyl 3- henyl- ro lamino
4-fluoro hen 1 4- rid 1 3- hen 1-pro ylamino
3-fluoro hen 1 4- ridyl 3-phenyl- ro lamino
2-fluoro hen 1 4- rid 1 3- hen 1-pro lamino
4-chloro hen 1 4-pyridyl 3-phen 1-pro lamino
3-chloro hen 1 4- rid 1 3- henyl- rop lamino
2-chloro hen 1 4- yrid 1 3- hen 1-pro lamino
4-tol 1 4- ridyl 3-phen 1- ro lamino
3-tol 1 4- rid 1 3- hen 1- ro lamino
2-tol 1 4- rid 1 3-phen 1- ro lamino
4-trifluoro- 4-pyridyl 3-phenyl-propylamino
meh 1 henyl
_-t:ifluoro- 4-pyridyl 3-phenyl-propylamino
meth1 hen 1
?.,6- 4-pyridyl 3-phenyl-propylamino
dichloro henyl
2,6-dimethyl 4-pyridyl 3-phenyl-propylamino
hen 1
3,4- 4-pyridyl 3-phenyl-propylamino
dichloro hen 1
3,4-dimethyl 4-pyridyl 3-phenyl-propylamino
hen 1
2,4- 4-pyridyl 3-phenyl-propylamino
dichloro hen 1
2,4-dimethyl 4-pyridyl 3-phenyl-propylamino
hen 1
Phenyl 2-amino-4- 3-phenyl-propylamino
rid 1
4-fluorophenyl 2-amino-4- 3-phenyl-propylamino
rid 1
3-fluorophenyl 2-amino-4- 3-phenyl-propylamino
rid 1

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2-fluorophenyl 2-amino-4- 3-phenyl-propylamino
rid 1
_
4-chlorophenyl 2-amino-4- 3-phenyl-propylamino
rid 1
3-chlorophenyl 2-amino-4- 3-phenyl-propylamino
rid 1
2-chlorophenyl 2-amino-4- 3-phenyl-propylamino
rid 1
4-tolyl 2-amino-4- 3-phenyl-propylamino
rid 1
3-tolyl 2-amino-4- 3-phenyl-propylamino
ridyl
2-tolyl 2-amino-4- 3-phenyl-propylamino
rid 1
4-trifluoro- ?.-amino-4- 3-phenyl-propylamino
meth 1 hen 1 rid 1
3-trifluoro- 2-amino-4- 3-phenyl-propylamino
meth 1 hen 1 rid 1
2,6- 2-amino-4- 3-phenyl-propylamino
dichloro hen 1 rid 1
2,6-dimethyl 2-amino-4- 3-phenyl-propylamino
hen 1 rid 1
3,4- 2-amino-4- 3-phenyl-propylamino
dichloro hen 1 rid 1
3,4-dimethyl 2-amino-4- 3-phenyl-propylamino
hen 1 rid 1
2,4- 2-amino-4- 3-phenyl-propylamino
dichloro hen 1 rid 1
2,4-dimethyl 2-amino-4- 3-phenyl-propylamino
hen 1 rid 1
Phenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
4-fluorophenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
3-fluorophenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
2-fluorophenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
4-chlorophenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
3-chlorophenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
2-chlorophenyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
4-tolyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
3-tolyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
2-tolyl 2-acetamido- 3-phenyl-propylamino
4- rid 1
4-trifluoro- 2-acetamido- 3-phenyl-propylamino
meth 1 hen 1 4- rid 1
3-trifluoro- 2-acetamido- 3-phenyl-propylamino
meth 1 hen 1 4- rid 1

CA 02274093 1999-06-03
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2,6- 2-acetamido- 3-phenyl-propylamino
dichloro henyl 4- rid 1
2,6-dimethyl 2-acetamido- 3-phenyl-propylamino
phen 1 4- ridyl
3,4- 2-acetamido- 3-phenyl-propylamino
dichloro henyl 4- rid l
3,4-dimethyl 2-acetamido- 3-phenyl-propylamino
hen 1 4- rid 1
2,4- 2-acetamido- 3-phenyl-propylamino
dichloro hen 1 4- rid 1
2,4-dimethyl 2-acetamido- 3-phenyl-propylamino
hen 1 4-pyrid 1
Phenyl 2-amino-4- 3-phenyl-propylamino
rimidinyl
4-fluorophenyl 2-amino-4- 3-phenyl-propylamino
rimidin 1
3-fluorophenyl 2-amino-4- 3-phenyl-propylamino
rimidin 1
2-fluorophenyl 2-amino-4- 3-phenyl-propylamino
rimidin 1
4-chlorophenyl 2-amino-4- 3-phenyl-propylamino
p rimidin 1
3-chlorophenyl 2-amino-4- 3-phenyl-propylamino
yrimidin 1
2-chlorophenyl 2-amino-4- 3-phenyl-propylamino
rimidin 1
4-tolyl 2-amino-4- 3-phenyl-propylamino
rimidin 1
3-tolyl 2-amino-4- 3-phenyl-propylamino
rimidinyl
2-tolyl 2-amino-4- 3-phenyl-propylamino
rimidin 1
4-trifluoro- 2-amino-4- 3-phenyl-propylamino
methylphen 1 yrimidin 1
3-trifluoro- 2-amino-4- 3-phenyl-propylamino
methylphen 1 pyrimidin 1
2,6- 2-amino-4- 3-phenyl-propylamino
dichloro hen 1 rimidin 1
2,6-dimethyl 2-amino-4- 3-phenyl-propylamino
hen 1 rimidin 1
3,4- 2-amino-4- 3-phenyl-propylamino
dichloro henyl rimidin 1
3,4-dimethyl 2-amino-4- 3-phenyl-propylamino
hen 1 rimidin 1
2,4- 2-amino-4- 3-phenyl-propylamino
dichloro hen 1 rimidin 1
2,4-dimethyl 2-amino-4- 3-phenyl-propylamino
henyl rimidin 1
Phenyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
4-fluorophenyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
3-fluorophenyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino

CA 02274093 1999-06-03
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2-fluorophenyl 4-pyridyl (1-methyl-3-
henyl)propylamino
4-chlorophenyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
3-chlorophenyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
2-chlorophenyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
4-tolyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
3-tolyl 4-pyridyl (1-methyl-3-
hen 1)pro lamino
2-tolyl 4-pyridyl (1-methyl-3-
hen 1) ro lamino
4-trifluoro- 4-pyridyl (1-methyl-3-
meth 1 hen 1 hen 1) ro lamino
3-trifluoro- 4-pyridyl (1-methyl-3-
meth 1 hen 1 hen 1) ro lamino
4 pyridyl (1-methyl-3-
dichloro hen 1 hen 1) ro lamino
2,6-dimethyl 4-pyridyl (1-methyl-3-
hen 1 hen 1) ro lamino
3,4- 4-pyridyl (1-methyl-3-
dichloro hen 1 hen 1) ro lamino
3,4-dimethyl 4-pyridyl (1-methyl-3-
hen 1 hen 1) ro lamino
2,4- 4-pyridyl (1-methyl-3-
dichloro hen 1 hen 1) ro lamino
2,4-dimethyl 4-pyridyl (1-methyl-3-
hen 1 hen 1) ro lamino
Phenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
4-fluorophenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
3-fluorophenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
2-fluorophenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
4-chlorophenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
3-chlorophenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
2-chlorophenyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
4-tolyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
3-tolyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
2-tolyl 2-amino-4- (1-methyl-3-
rid 1 hen 1) ro lamino
4-trifluoro- 2-amino-4- (1-methyl-3-
meth 1 hen 1 rid 1 hen 1) ro lamino
3-trifluoro- 2-amino-4- (1-methyl-3-
meth 1 hen 1 rid 1 hen 1) ro lamino

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2,6- 2-amino-4- (1-methyl-3-
dichlorophen 1 yridyl hen 1) ro lamino
2,6-dimethyl 2-amino-4- (1-methyl-3-
phen 1 yrid 1 hen 1) ro lamino
3,4- 2-amino-4- (1-methyl-3-
dichloro hen 1 rid 1 phen 1) ro lamino
3,4-dimethyl 2-amino-4- (1-methyl-3-
phen 1 rid 1 hen 1) ro lamino
2,4- 2-amino-4- (1-methyl-3-
dichloro hen 1 rid 1 hen 1) ro lamino
2,4-dimethyl 2-amino-4- (1-methyl-3-
hen 1 rid 1 hen 1) rop lamino
Phenyl 2-acetamido- (1-methyl-3-
4- yrid 1 phen 1) ro lamino
4-fluorophenyl 2-acetamido- (1-methyl-3-
4- rid 1 hen 1) ro ylamino
3-fluorophenyl 2-acetamido- (1-methyl-3-
4- rid 1 phen 1) rop lamino
2-fluorophenyl 2-acetamido- (1-methyl-3-
4- rid 1 hen 1) ro lamino
4-chlorophenyl 2-acetamido- (1-methyl-3-
4- rid 1 phen 1) ro lamino
3-chlorophenyl 2-acetamido- (1-methyl-3-
4- rid 1 phenyl) ro lamino
2-chlorophenyl 2-acetamido- (1-methyl-3-
4- rid 1 hen 1) ro lamino
4-tolyl 2-acetamido- (1-methyl-3-
4-p ridyl phen 1) ro lamino
3-tolyl 2-acetamido- (1-methyl-3-
4- rid 1 hen 1) ro lamino
2-tolyl 2-acetamido- (1-methyl-3-
4- rid 1 henyl) ro lamino
4-trifluoro- 2-acetamido- (1-methyl-3-
meth 1 hen 1 4- rid 1 phen 1) ro lamino
3-trifluoro- 2-acetamido- (1-methyl-3-
meth 1 hen 1 4- rid 1 phen 1) ro lamino
2,6- 2-acetamido- (1-methyl-3-
dichloro hen 1 4- rid 1 hen 1) ro lamino
2,6-dimethyl 2-acetamido- (1-methyl-3-
hen 1 4- rid 1 hen 1) ro lamino
3,4- 2-acetamido- (1-methyl-3-
dichloro hen 1 4- rid 1 hen 1) ro lamino
3,4-dimethyl 2-acetamido- (1-methyl-3-
hen 1 4- rid 1 hen 1) ro lamino
2,4- 2-acetamido- (1-methyl-3-
dichlorophen 1 4- rid 1 hen 1) ro lamino
2,4-dimethyl 2-acetamido- (1-methyl-3-
hen 1 4- rid 1 hen 1) ro lamino
Phenyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
4-fluorophenyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
3-fluorophenyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino

CA 02274093 1999-06-03
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2-fluorophenyl 2-amino-4- (1-methyl-3-
rimidinyl hen 1) ro lamino
_
4-chlorophenyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
3-chlorophenyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
2-chlorophenyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
4-tolyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
3-tolyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
2-tolyl 2-amino-4- (1-methyl-3-
rimidin 1 hen 1) ro lamino
4-trifluoro- 2-amino-4- (1-methyl-3-
meth 1 hen 1 rimidin 1 hen 1) ro lamino
3-trifluoro- 2-amino-4- (1-methyl-3-
meth 1 hen 1 rimidin 1 hen 1) ro lamino
2,6- 2-amino-4- (1-methyl-3-
dichloro hen 1 rimidin 1 hen 1) ro lamino
2,6-dimethyl 2-amino-4- (1-methyl-3-
hen 1 rimidin 1 hen 1) ro lamino
3,4- 2-amino-4- (1-methyl-3-
dichloro hen 1 rimidin 1 hen 1) ro lamino
3,4-dimethyl 2-amino-4- (1-methyl-3-
hen 1 rimidin 1 hen 1) ro ylamino
2,4- 2-amino-4- (1-methyl-3- -
dichloro hen 1 rimidin 1 hen 1) ro lamino
2,4-dimethyl 2-amino-4- (1-methyl-3-
hen 1 rimidin 1 hen 1) ro lamino
4-fluoro hen 1 4- rid 1 4-fluorobenz lamino
4-fluorophenyl 2-acetamido- 4-fluorobenzylamino
4-p rid 1
4-fluorophenyl 2-amino-4- 4-fluorobenzylamino
rimidin 1
4-fluorophenyl 4-pyridylnyl (2-(4-fluorophenyl)-1-
meth 1-eth 1)amino
4-fluorophenyl 2-acetamido- (2-(4-fluorophenyl)-1-
4- rid 1 meth 1-eth 1)amino
4-fluorophenyl 2-amino-4- (2-(4-fluorophenyl)-1-
rimidin 1 meth 1-eth 1)amino
4-fluorophenyl 4-pyridyl (1,1-dimethyl-2-(4-
fluoro hen 1)-eth 1)amino
4-fluorophenyl _ (1,1-dimethyl-2-(4-
2-acetamido-
4- rid 1 fluoro hen 1)-eth 1)amino
4-fluorophenyl 2-amino-4- (1,1-dimethyl-2-(4-
rimidin 1 fluoro hen 1)-eth 1)amino
4-fluorophenyl 4-pyridyl 2-(4-fluorophenyl)-2-
meth 1-eth lamino
4-fluorophenyl 2-acetamido- (2-(4-fluorophenyl)-2-
4- rid 1 meth 1-eth 1)amino
4-fluorophenyl 2-amino-4- (2-(4-fluorophenyl)-2-
rimidin 1 meth 1-eth 1)amino

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4-fluorophenyl 4-pyridyl (2-methyl-2-
~hen leth 1)amino
4-fluorophenyl 2-acetamido- (2-methyl-2-
4- rid 1 hen leth 1)amino
4-fluorophenyl 2-amino-4- (2-methyl-2-
rimidin 1 hen leth 1)amino
4-fluorophenyl 4-pyridyl methyl-(2-
hen leth 1)amino
4-fluorophenyl 2-acetamido- methyl-(2-
4- rid 1 hen leth 1)amino
4-fluorophenyl 2-amino-4- methyl-(2-
rimidin 1 henyleth 1)amino
4-fluorophenyl 4-pyridyl (2-(4-trifluoromethyl
hen 1)ethyl)amino
4-fluorophenyl 2-acetamido- (2-(4-trifluoromethyl
4- rid 1 hen 1)eth 1)amino
4-fluorophenyl 2-amino-4- (2-(4-trifluoromethyl
rimidin 1 hen 1)eth 1)amino
4-fluoro hen 1 4-p ridyl 2-(4-tol 1)eth lamino
4-fluorophenyl 2-acetamido- 2-(4-tolyl)ethylamino
4- rid 1
4-fluorophenyl 2-amino-4- 2-(4-tolyl)ethylamino
rimidin 1
4-fluorophenyl 4-pyridyl (2-(3-fluorophenyl)
eth 1)amino
4-fluorophenyl 2-acetamido- (2-(3-fluorophenyl)
4- rid 1 ethyl)amino
4-fluorophenyl 2-amino-4- (2-(3-fluorophenyl)
p rimidinyl ethyl)amino
4-fluorophenyl 4-pyridyl (2-(2-fluorophenyl)
eth 1)amino
4-fluorophenyl 2-acetamido- (2-(2-fluorophenyl)
4-pyrid 1 eth 1)amino
4-fluorophenyl 2-amino-4- (2-(2-fluorophenyl)
rimidin 1 eth 1)amino
4-fluorophenyl 4-pyridyl methyl-(2-(2-
rid 1)eth 1)amino
4-fluorophenyl 2-acetamido- methyl-(2-(2-
4- rid 1 rid 1)eth 1)amino
4-fluorophenyl 2-amino-4- methyl-(2-(2-
rimidin 1 rid 1)eth 1)amino
4-fluorophenyl 4-pyridyl (1,1-dimethyl-3-phenyl-
ro 1)amino
4-fluorophenyl 2-acetamido- (1,1-dimethyl-3-phenyl-
4- rid 1 ro 1)amino
4-fluorophenyl 2-amino-4- (1,1-dimethyl-3-phenyl-
rimidin 1 ro 1)amino
4-fluorophenyl 4-pyridyl (3-(4-fluorophenyl)-
ro 1)amino
4-fluorophenyl 2-acetamido- (3-(4-fluorophenyl)-
4- rid 1 ro 1)amino
4-fluorophenyl 2-amino-4- (3-(4-fluorophenyl)-
rimidin 1 pro 1)amino

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4-fluorophenyl 4-pyridyl (3-(4-fluorophenyl)-1-
meth l~ropyl)amino
4-fluorophenyl 2-acetamido- (3-(4-fluorophenyl)-1-
4- rid 1 meth 1- ro 1)amino
-
4-fluorophenyl 2-amino-4- (3-(4-fluorophenyl)-1-
rimidin 1 meth 1- ro 1)amino
4-fluorophenyl 4-pyridyl (1,1-dimethyl-3-(4-fluoro
hen 1)- ro 1)amino
4-fluorophenyl 2-acetamido- (1,1-dimethyl-3-(4-fluoro
4- rid 1 hen 1)- ro 1)amino
4-fluorophenyl 2-amino-4- (1,1-dimethyl-3-(4-fluoro
rimidin 1 hen 1)- ro 1)amino
4-fluorophenyl 4-pyridyl (3-(2-fluorophenyl)-
ro 1)amino
4-fluorophenyl 2-acetamido- (3-(2-fluorophenyl)-
4- rid 1 ro 1)amino
4-fluorophenyl 2-amino-4- (3-(2-fluorophenyl)-
rimidin 1 ro 1)amino
4-fluorophenyl 4-pyridyl (3-methyl-3-phenyl-
ro 1)amino
4-fluorophenyl 2-acetamido- (3-methyl-3-phenyl-
4- rid 1 ro 1)amino
4-fluorophenyl 2-amino-4- (3-methyl-3-phenyl-
rimidin 1 ro 1)amino
4-fluorophenyl 4-pyridyl (2-methyl-3-phenyl-
ro 1)amino
4-fluorophenyl 2-acetamido- (2-methyl-3-phenyl-
4- rid 1 ro 1)amino
4-fluorophenyl 2-amino-4- (2-methyl-3-phenyl-
rimidin 1 ro 1)amino
4-fluoro hen 1 4- rid 1 (3,3-dimeth lbut 1)amino
4-fluorophenyl 2-acetamido- (3,3-dimethylbutyl)amino
4- rid 1
4-fluorophenyl 2-amino-4- (3,3-dimethylbutyl)amino
rimidin 1
4-fluoro hen 1 4- rid 1 isoam lamino
4-fluorophenyl 2-acetamido- isoamylamino
4- rid 1
4-fluorophenyl 2-amino-4- isoamylamino
rimidin 1
4-fluoro hen 1 4- rid 1 am lamino
4-fluorophenyl 2-acetamido- amylamino
4- rid 1
4-fluorophenyl 2-amino-4- amylamino
rimidin 1
4-fluoro hen 1 4- rid 1 (2,5-dimeth 1) ent lamino
4-fluorophenyl 2-acetamido- (2,5-dimethyl)pentylamino
4- rid 1
4-fluorophenyl 2-amino-4- (2,5-dimethyl)pentylamino
rimidin 1
4-fluoro hen 1 4- rid 1 i erazin 1
4-fluorophenyl 2-acetamido- piperazinyl
4- rid 1

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4-fluorophenyl 2-amino-4- piperazinyl
rrimidin 1
4-fluorophenyl 4-pyridyl (3-(3-fluorophenyl)-
ro 1 ) amino
4-fluorophenyl 2-acetamido- (3-(3-fluorophenyl)-
4- rid 1 ro 1)amino
4-fluorophenyl 2-amino-4- (3-(3-fluorophenyl)-
yrimidinyl ro 1)amino
benz 1 4- rid 1 3- hen 1 ro ylamino
benzyl 4-pyridyl 2-(4-fluorophenyl)
eth laming
2-thienyl 4- rid 1 3- hen 1 rop laming
2-thienyl 4-pyridyl 2-(4-fluorophenyl)
eth laming
cyclohe 1 4- rid 1 3-phenyl ro laming
cyclohexyl 4-pyridyl 2-(4-fluorophenyl)
ethylamino
tert-but 1 4- rid 1 3-phen lpro ylamino
tert-butyl 4-pyridyl 2-(4-fluorophenyl)
-- eth laming
4-fluorophenyl 4- 3-phenylpropylamino
i eridin 1
4-fluorophenyl 4- 2-(4-fluorophenyl)
iperidin 1 eth laming
4-fluoro hen 1 4- yranyl 3-phen lpro ylamino
4-fluorophenyl 4-pyranyl 2-(4-fluorophenyl)
eth laming
Phenyl 4-pyridyl 3-phenyl-2-amino-
pro laming
4-fluorophenyl 4-pyridyl 3-phenyl-2-amino-
ro laming
3-fluorophenyl 4-pyridyl 3-phenyl-2-amino-
ro laming
2-fluorophenyl 4-pyridyl 3-phenyl-2-amino-
rop laming
4-chlorophenyl 4-pyridyl 3-phenyl-2-amino-
ro laming
3-chlorophenyl 4-pyridyl 3-phenyl-2-amino-
ro laming
2-chlorophenyl 4-pyridyl 3-phenyl-2-amino-
ro laming
4-tolyl 4-pyridyl 3-phenyl-2-amino-
ro laming
3-tolyl 4-pyridyl 3-phenyl-2-amino-
ro laming
2-tolyl 4-pyridyl 3-phenyl-2-amino-
pro ylamino
4-trifluoro- 4-pyridyl 3-phenyl-2-amino-
meth 1 hen 1 ro laming
3-trifluoro- 4-pyridyl 3-phenyl-2-amino-
meth 1 hen 1 ro laming
2,6- 4-pyridyl - 3-phenyl-2-amino-
dichloro hen 1 ro laming

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2,6-dimethyl 4-pyridyl 3-phenyl-2-amino-
hen 1 ro lamino
3,4- 4-pyridyl 3-phenyl-2-amino-
dichloro hen 1 ro lamino
3,4-dimethyl 4-pyridyl 3-phenyl-2-amino-
hen 1 ro lamino
2,4- 4-pyridyl 3-phenyl-2-amino-
dichloro hen 1 ro lamino
2,4-dimethyl 4-pyridyl 3-phenyl-2-amino-
hen 1 pro lamino
Phenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
4-fluorophenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
3-fluorophenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
2-fluorophenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
4-chlorophenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
3-chlorophenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
2-chlorophenyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
4-tolyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
3-tolyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
2-tolyl 4-pyridyl 3-phenyl-3-amino-
ro lamino
4-trifluoro- 4-pyridyl 3-phenyl-3-amino-
meth 1 hen 1 ro lamino
3-t:ifluoro- 4-pyridyl 3-phenyl-3-amino-
methvl hen 1 ro lamino
_,6- 4-pyridyl 3-phenyl-3-amino-
d:chloro hen 1 ro lamino
~,6-dimethyl 4-pyridyl 3-phenyl-3-amino-
hen 1 ro lamino
3,4- 4-pyridyl 3-phenyl-3-amino-
dichloro hen 1 ro lamino
3,4-dimethyl 4-pyridyl 3-phenyl-3-amino-
hen 1 ro lamino
2,4- 4-pyridyl 3-phenyl-3-amino-
dichloro hen 1 ro lamino
2,4-dimethyl 4-pyridyl 3-phenyl-3-amino-
hen 1 ro lamino
ana

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- ~ 68
O
R11 N~CH2CH3
R12 N R1
wherein Rll, Rlz, and Rl are one of the combinations given
in the following table:
R R1 R
4-fluorophenyl 4-pyridyl (2-(4-fluorophenyl)
eth 1)amino
4-fluorophenyl 2-acetamido- (2-(4-fluorophenyl)
4- yrid 1 eth 1)amino
4-fluorophenyl 2-amino-4- (2-(4-fluorophenyl)
rimidin 1 eth 1)amino
4-fluoro hen 1 4- rid 1 (3- hen lpro 1)amino
4-fluorophenyl 2-acetamido- (3-phenylpropyl)amino
4- rid 1
4-fluorophenyl 2-amino-4- (3-phenylpropyl)amino
rimidin 1
4-fluorophenyl 4-pyridyl (S)-2-amino-3-
hen 1 ro lamino
4-fluorophenyl 2-acetamido- (S)-2-amino-3-
4- rid 1 hen 1 ropylamino
4-fluorophenyl 2-amino-4- (S)-2-amino-3-
rimidinyl hen 1 ro lamino
4-fluorophenyl 4-pyridyl 3-amino-3-
hen 1 ro lamino
4-fluorophenyl 2Tacetamido- 3-amino-3-
4- rid 1 hen 1 ro lamino
4-fluorophenyl 2-amino-4- 3-amino-3-
yrimidin 1 hen 1 ro lamino
4-fluorophenyl 4-pyridyl 3-amino-2-methyl-3-
hen 1 ro lamino
4-fluorophenyl 2-acetamido- 3-amino-2-methyl-3-
4- rid 1 hen lpro lamino
4-fluorophenyl 2-amino-4- 3-amino-2-methyl-3-
rimidin 1 hen 1 ro lamino
4-fluorophenyl 4-pyridyl (S)-tetrahydroisoquinol-
3- lmeth lenamino
4-fluorophenyl 2-acetamido- (S)-tetrahydroisoquinol-
4- rid 1 3- lmeth lenamino
4-fluorophenyl 2-amino-4- (S)-tetrahydroisoquinol-
rimidin 1 3- lmeth lenamino
4-fluoro hen 1 4- rid 1 (S)-3-Benz 1 i erazin 1
4-fluorophenyl 2-acetamido- (S)-3-benzylpiperazinyl
4- rid 1
4-fluorophenyl 2-amino-4- (S)-3-benzylpiperazinyl
p rimidin 1

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69 '
O
R1:
Ri:
R2
in which RZ is H, methyl or benzyl, and R11, Rlz, and R1
are one of the combinations given in the_ following
table:
R w-~- -~,..
Phen 1 4- rid 1 he_n 1
4-fluoro hen 1 4- rid 1 hen 1
Phenyl 2-acetamido- phenyl
rid 1
4-fluorophenyl 2-acetamido- phenyl
rid 1
Phen 1 4- rid 1 4-eth 1 hen 1
4-fluoro hen 1 4- rid 1 4-ethyl hen 1
Phenyl 2-acetamido- 4-ethylphenyl
rid 1
4-fluorophenyl 2-acetamido- 4-ethylphenyl
rid 1
Phen 1 4- rid 1 2,4-dimeth 1 henyl
4-fluoro hen 1 4-pyridyl 2,4-dimeth 1 hen 1
Phenyl 2-acetamido- 2,4-dimethylphenyl
rid 1
4-fluorophenyl 2-acetamido- 2,4-dimethylphenyl
ridyl
Phen 1 4- rid 1 2,6-dichlorobenz 1
4-fluorophen 1 4- yrid 1 2,6-dichlorobenz 1
Phenyl 2-acetamido- 2,6-dichlorobenzyl
rid 1
4-fluorophenyl 2-acetamido- 2,6-dichlorobenzyl
rid 1
Phenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
4-fluorophenyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
Phenyl 2-acetamido- 2-(4-fluorophenyl)
rid 1 eth lamino
4-fluorophenyl 2-acetamido- 2-(4-fluorophenyl)
rid 1 eth lamino
-- Phen 1 4- rid 1 3- hen 1 ro lamino
4-fluorophen 1 4- rid 1 3- hen 1 ro lamino
Phenyl 2-acetamido- 3-phenylpropylamino
rid 1
4-fluorophenyl 2-acetamido- 3-phenylpropylamino
rid 1
Phen 1 4- rid 1 1- i erazin 1
p4-fluorophenyl 4-pyridyl 1-piperazinvl
~

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Phenyl 2-acetamido- 1
-piperazinyl
yrid 1
4-fluorophenyl 2-acetamido- 1-piperazinyl
pyrid 1
benz 1 4- rid 1 3- hen 1 ro lamino
benzyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
2-thien 1 4- rid 1 3- hen 1 ro lamino
2-thienyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
c clohex 1 4- rid 1 3- hen 1 ro ylamino
cyclohexyl 4-pyridyl 2-(4-fluorophenyl)
eth lamino
tert-but 1 4- rid 1 3- hen lpro lamino
tert-butyl 4-pyridyl 2-(4-fluorophenyl)
ethylamino
4-fluorophenyl 4- 3-phenylpropylamino
i eridin 1
4-fluorophenyl 4- 2-(4-fluorophenyl)
iperidin 1 eth lamino
4-fluoro hen 1 4- ran 1 3- hen 1 ro lamino
4-fluorophenyl 4-pyranyl 2-(4-fluorophenyl)
eth lamino
Phenyl 4-pyridyl (S)-2-amino-3-
hen lpro lamino
4-fluorophenyl 4-pyridyl (S)-2-amino-3-
hen lpro lamino
Phenyl 2-acetamido- (S)-2-amino-3-
ridyl hen 1 ro lamino
9-fluorophenyl 2-acetamido- (S)-2-amino-3-
rid 1 phen lprop lamino
Phenyl 4-pyridyl 3-amino-3-
hen 1 ro lamino
4-fluorophenyl 4-pyridyl 3-amino-3-
hen
1 ro ylamino
;Pnenyl 2-acetamido- _
3-amino-3-
rid 1 phen 1 ropylamino
4-fluorophenyl 2-acetamido- 3-amino-3-
rid 1 hen 1 ro lamino
Phenyl 4-pyridyl 3-amino-2-methyl-3-
hen 1 ro lamino
4-fluorophenyl 4-pyridyl 3-amino-2-methyl-3-
hen 1 ro lamino
Phenyl 2-acetamido- 3-amino-2-methyl-3-
rid 1 hen 1 ro lamino
4-fluorophenyl 2-acetamido- 3-amino-2-methyl-3-
rid 1 hen 1 ro lamino
Phenyl 4-pyridyl (S)-tetrahydroisoquinol-
3- lmeth lenamino
4-fluorophenyl 4-pyridyl (S)-tetrahydroisoquinol-
3- lmeth lenamino
Phenyl 2-acetamido- (S)-tetrahydroisoquinol-
rid 1 3- lmeth lenamino

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4-fluorophenyl 2-acetamido- (S)-tetrahydroisoquinol-
rid 1 3-ylmethylenamino
Phen 1 4- rid 1 (S)-3-benz 1 i erazin 1
4-fluoro hen 1 4- rid 1 S)-3-benz 1 i erazin 1
Phenyl 2-acetamido- S)-3-benzylpiperazinyl
rid 1
4-fluorophenyl 2-acetamido- S)-3-benzylpiperazinyl
rid 1
Additional preferred compounds are listed in the
Examples, infra.
As utilized herein, the following terms shall have
the following meanings:
"Alkyl", alone or in combination, means a straight-chain
or branched-chain alkyl radical containing preferably 1-
carbon atoms (C1-C15), more preferably 1-8 carbon
10 atoms (C1-Cg), even more preferably 1-6 carbon atoms
(C1-C6), yet more preferably 1-4 carbon atoms (C1-Cq),
still more preferably 1-3 carbon atoms (C1-C3), and most
preferably 1-2 carbon atoms (C1-C2). Examples of such
radicals include methyl, ethyl, n-propyl, isopropyl,
15 n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-
amyl, hexyl, octyl and the like.
"Hydroxyalkyl", alone or in combination, means an alkyl
radical as defined above wherein at least one hydrogen
radical is replaced with a hydroxyl radical, preferably
1-3 hydrogen radicals are replaced by hydroxyl radicals,
more preferably 1-2 hydrogen radicals are replaced by
hydroxyl radicals, and most preferably one hydrogen
radical is replaced by a hydroxyl radical. Examples of
such radicals include hydroxymethyl, 1-, 2-hydroxyethyl,
1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-
dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the
like.
"Alkenyl", alone or in combination, means a straight-
chain or branched-chain hydrocarbon radical having one

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or more double bonds, preferably 1-2 double bonds and
more preferably one double bond, and containing
preferably 2-15 carbon atoms (C2-C15), more preferably
2-8 carbon atoms (C2-Cg), even more preferably 2-6
carbon atoms (C2-C6), yet more preferably 2-4 carbon
atoms (C2-C4), and still more preferably 2-3 carbon
atoms (C2-C3). Examples of such alkenyl radicals
include ethenyl, propenyl, 2-methylpropenyl, 1,4-
butadienyl and the like.
"Alkoxy", alone or in combination, means a radical of
the type "R-O-" wherein "R" is an alkyl radical as
defined above and "O" is an oxygen atom. Examples of
such alkoxy radicals include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-
butoxy and the like.
"Alkoxycarbonyl", alone or in combination, means a
radical of the type "R-O-C(O)-" wherein "R-O-" is an
alkoxy radical as defined above and "C(O)" is a carbonyl
radical.
"Alkoxycarbonylamino", alone or in combination, means a
radical of the type "R-O-C(O)-NH-" wherein "R-O-C(O)" is
an alkoxycarbonyl radical as defined above, wherein the
amino radical may optionally be substituted, such as
with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl
and the like.
"Alkylthio", alone or in combination, means a radical of
the type "R-S-" wherein "R" is an alkyl radical as
defined above and "S" is a sulfur atom. Examples of
such alkylthio radicals include methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio, iso-butylthio,
sec-butylthio, tert-butylthio and the like.

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"Alkylsulfinyl", alone or in combination, means a
radical of the type "R-S(O)-" wherein "R" is an alkyl
- radical as defined above and "S(0)" is a mono-oxygenated
sulfur atom. Examples of such alkylsulfinyl radicals
_ 5 include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,
isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl,
sec-butylsulfinyl, tert-butylsulfinyl and the like.
"Alkylsulfonyl", alone or in combination, means a
radical of the type "R-S(O)z-" wherein "R" is an alkyl
radical as defined above and "S(O)z" is a di-oxygenated
sulfur atom. Examples of such alkylsulfonyl radicals
include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl and the like.
"Aryl", alone or in combination, means a phenyl or
biphenyl radical, which is optionally benzo fused or
heterocyclo fused and which is optionally substituted
with one or more substituents selected from alkyl,
alkoxy, halogen, hydroxy, amino, azido, nitro, cyano,
haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl,
alkanoylamino, amido, amidino, alkoxycarbonylamino, N-
alkylamidino, alkylamino, dialkylamino, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N,N-
dialkylamido, aralkoxycarbonylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, oxo and the like.
Examples of aryl radicals are phenyl, o-tolyl, 4-
methoxyphenyl, 2-(tert-butoxy)phenyl, 3-methyl-4-
methoxyphenyl, 2-CF3-phenyl, 2-fluorophenyl, 2-
chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-
acetamidophenyl, 2-amino-3-(aminomethyl)phenyl, 6-
methyl-3-acetamidophenyl, 5-methyl-2-aminophenyl, 6-
methyl-2,3-diaminophenyl, 2-amino-3-methylphenyl, 4,6-
dimethyl-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-
hydroxyphenyl, 4-(2-methoxyphenyl)phenyl, 2-amino-1-
naphthyl, 2-naphthyl, 3-amino-2-naphthyl, 1-methyl-3-

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amino-2-naphthyl, 2,3-diamino-1-naphthyl, 4,8-dimethoxy-
2-naphthyl and the Like.
"Aralkyl" and "arylalkyl", alone or in combination,
means an alkyl radical as defined above in which at
least one hydrogen atom, preferably 1-2, is replaced by
an aryl radical as defined above, such as benzyl, 1-, 2-
phenylethyl, dibenzylmethyl, hydroxyphenylmethyl,
methylphenylmethyl, diphenylmethyl,
dichlorophenylmethyl, 4-methoxyphenylmethyl and the
like.
"Aralkoxy", alone or in combination, means an alkoxy
radical as defined above in which at least one hydrogen
atom, preferably 1-2, is replaced by an aryl radical as
defined above, such as benzyloxy, 1-, 2-phenylethoxy,
dibenzylmethoxy, hydroxyphenylmethoxy,
methylphenylmethoxy, dichlorophenylmethoxy, 4-
methoxyphenylmethoxy and the like.
"Aralkoxycarbonyl", alone or in combination, means a
radical of the type "R-O-C(O)-" wherein "R-O-" is an
aralkoxy radical as defined above and "-C(O)-" is a
carbonyl radical.
"Alkanoyl", alone or in combination, means a radical of
the type "R-C(O)-" wherein "R" is an alkyl radical as
defined above and "-C(O)-" is a carbonyl radical.
Examples of such alkanoyl radicals include acetyl,
trifluoroacetyl, hydroxyacetyl, propionyl; butyryl,
valeryl, 4=methylvaleryl, and the like.
"Alkanoylamino", alone or in combination, means a
radical of the type "R-C(O)-NH-" wherein "R-C(O)-" is an
alkanoyl radical as defined above, wherein the amino
radical may optionally be substituted, such as with

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alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and
the like.
"Aminocarbonyl", alone or in combination, means an amino
5 substituted carbonyl (carbamoyl) radical, wherein the
amino radical may optionally be mono- or di-substituted,
such as with alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, alkanoyl, alkoxycarbonyl;
aralkoxycarbonyl and the like.
"Aminosulfonyl", alone or in combination, means an amino
substituted sulfonyl radical.
"Benzo", alone or in combination, means the divalent
radical C6H4= derived from benzene. "Benzo fused" forms
a ring system in which benzene and a cycloalkyl or aryl
group have two carbons in common, for example
tetrahydronaphthylene and the like.
"Bicyclic" as used herein is intended to include both
fused ring systems, such as naphthyl and i3-carbolinyl,
and substituted ring systems, such as biphenyl,
phenylpyridyl and diphenylpiperazinyl.
"Cycloalkyl", alone or in combination, means a saturated
or partially saturated, preferably one double bond,
monocyclic, bicyclic or tricyclic carbocyclic alkyl
radical, preferably monocyclic, containing preferably 5-
12 carbon atoms (C5-C12), more preferably 5-10 carbon
atoms (C5-Clp), even more preferably 5-7 carbon atoms
(C5-C~), which is optionally benzo fused or heterocyclo
fused and which is optionally substituted as defined
herein with respect to the definition of aryl. Examples
of such cycloalkyl radicals include cyclopentyl,
cyclohexyl, dihydroxycyclohexyl,
ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl,
--tetrahydronaphthyl, octahydroquinolinyl,

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dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl,
azabicyclo[3.2.1]octyl and the like.
"Heteroatoms" means nitrogen, oxygen and sulfur
heteroatoms.
"Heterocyclo fused" forms a ring system in which a
heterocyclyl or heteroaryl group of 5-6 ring members and
a cycloalkyl or aryl group have two carbons in common,
for example indole, isoquinoline, tetrahydroquinoline,
methylenedioxybenzene and the like.
"Heterocyclyl" means a saturated or partially
unsaturatEd, preferably one double bond, monocyclic or
bicyclic, preferably monocyclic, heterocycle radical
containing at least one, preferably 1 to 4, more
preferably 1 to 3, even more preferably 1-2, nitrogen,
oxygen or sulfur atom ring member and having preferably
3-8 ring members in each ring, more preferably 5-8 ring
members in each ring and even more preferably 5-6 ring
members in each ring. "Heterocyclyl" is intended to
include sulfone and sulfoxide derivatives of sulfur ring
members and N-oxides of tertiary nitrogen ring members,
and carbocyclic fused, preferably 3-6 ring carbon atoms
and more preferably 5-6 ring carbon atoms, and benzo
fused ring systems. "Heterocyclyl" radicals may
optionally be substituted on at least one, preferably 1-
4, more preferably 1-3, even more preferably 1-2, carbon
atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo,
aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-
alkylamidino, alkoxycarbonylamino, alkylsulfonylamino
and the like, and/or on a secondary nitrogen atom by
hydroxy, alkyl, aralkoxycarbonyl, alkanoyl,
alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals.
More preferably, "heterocyclyl", alone or in
combination, is a radical of a monocyclic or bicyclic
saturated heterocyclic ring system having 5-8 ring

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members per ring, wherein 1-3 ring members are oxygen,
sulfur or nitrogen heteroatoms, which is optionally
- partially unsaturated or benzo-fused and optionally
substituted by 1-2 oxo or thioxo radicals. Examples of
such heterocyclyl radicals include pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,
4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl,
pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl,
tetrahydrothienyl and its sulfQxide and sulfone
derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-
oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl,
methylenedioxyphenyl, ethylenedioxyphenyl and the like.
"Heteroaryl" means a monocyclic or bicyclic, preferably
monocyclic, aromatic heterocycle radical, having at
least one, preferably 1 to 4, more preferably 1 to 3,
even more preferably 1-2, nitrogen, oxygen or sulfur
atom ring members and having preferably 5-6 ring members
in each ring, which is optionally saturated carbocyclic
fused, preferably 3-4 carbon atoms (C3-C4) to form 5-6
ring membered rings and which is optionally substituted
as defined above with respect to the definitions of
aryl. Examples of such heteroaryl groups include
imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl,
pyrazolyl, pyridyl, 3-(2-methyl)pyridyl, 3-(4-
trifluoromethyl)pyridyl, pyrimidinyl, 5-(4-
trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl,
furyl, thienyl, oxazolyl, thiazolyl, indolyl,
quinolinyl, 5,6,7,8-tetrahydroquinolyl,
5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl,
benzothiazolyl, benzofuryl, benzimidazolyl, benzoxazolyl
and the like.
"Heteroaralkyl" and "heteroarylalkyl," alone or in
combination, means an alkyl radical as defined above in
which at least one hydrogen atom, preferably 1-2, is

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78
replaced by a heteroaryl radical as defined above, such
as 3-furylpropyl, 2-pyrrolyl propyl,
chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl,
1-imidazolylethyl and the like.
"Halogen" and "halo", alone or in combination, means
fluoro, chloro, bromo or iodo radicals.
"Haloalkyl", alone or in combination, means an alkyl
radical as defined above in which at least one hydrogen
atom, preferably 1-3, is replaced by a halogen radical,
more preferably fluoro or chloro radicals. Examples of
such haloalkyl radicals include 1,1,1-trifluoroethyl,
chloromethyl, 1-bromoethyl, fluoromethyl,
difluoromethyl, trifluoromethyl,
bis(trifluoromethyl)methyl and the like.
"Pharmacologically acceptable salt" means a salt
prepared by conventional means, and are well known by
those skilled in the art. The "pharmacologically
acceptable salts" include basic salts of inorganic and
organic acids, including but not limited to hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, ethanesulfonic acid, malic acid,
acetic acid, oxalic acid, tartaric acid, citric acid,
lactic acid, fumaric acid, succinic acid, malefic acid,
salicylic acid, benzoic acid, phenylacetic acid,
mandelic acid and the like. When compounds of the
invention include an acidic function such as a carboxy
group, then suitable pharmaceutically acceptable cation
pairs for the carboxy group are well known to those
skilled in tl~e art and include alkaline, alkaline earth,
ammonium, quaternary ammonium cations and the like. For
additional examples of "pharmacologically acceptable
salts," see infra and Berge et al,- J. Pharm. Sci. 66, 1
( 1977 ) .

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"Cytokine" means a secreted protein that affects the
functions of other cells, particularly as it relates to
' the modulation of interactions between cells of the
immune system or cells involved in the inflammatory
response. Examples of cytokines include but are not
limited to interleukin 1 (IL-1), preferably IL-1i3,
interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF,
preferably TNF-a (tumor necrosis factor-oc).
"TNF, IL-1, IL-6, and/or IL-8 mediated disease or
disease state" means all disease states wherein TNF, IL-
1, IL-6, and/or IL-8 plays a role, either directly as
TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1,
IL-6, and/or IL-8 inducing another cytokine to be
released. For example, a disease state in which IL-1
plays a major role, but in which the production of or
action of IL-1 is a result of TNF, would be considered
mediated by TNF.
"Leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol
or an alcohol nucleophile. Such leaving groups are well
known in the art. Examples of such leaving groups
include, but are not limited to, N-hydroxysuccinimide,
N-hydroxybenzotriazole, halides, triflates, tosylates
and the like. Preferred leaving groups are indicated
herein where appropriate.
"Protecting group" generally refers to groups well known
in the art which are used to prevent selected reactive
groups, such as carboxy, amino, hydroxy, mercapto and the
like, from undergoing undesired reactions, such as
nucleophilic, electrophilic, oxidation, reduction and the
like. Preferred protecting groups are indicated herein
where appropriate. Examples of amino protecting groups
include, but are not limited to, aralkyl, substituted
aralkyl, cycloalkenylalkyl and substituted cycloalkenyl

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alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl,
aralkoxycarbonyl, silyl and the like. Examples of
aralkyl include, but are not limited to, benzyl, ortho-
methylbenzyl, trityl and benzhydryl, which can be
optionally substituted with halogen, alkyl, alkoxy,
hydroxy, nitro, acylamino, acyl and the like, and salts,
such as phosphonium and ammonium salts. Examples of aryl
groups include phenyl, naphthyl, indanyl, anthracenyl, 9-
(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
Examples of cycloalkenylalkyl or substituted
cycloalkylenylalkyl radicals, preferably have 6-10 carbon
atoms, include, butare not limited to, cyclohexenyl
methyl and the like. Suitable acyl, alkoxycarbonyl and
aralkoxycarbonyl groups include benzyloxycarbonyl, t-
butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted
benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro
acetyl, phthaloyl and the like. A mixture of protecting
groups can be used to protect the same amino group, such
as a primary amino group can be protected by both an
aralkyl group and an aralkoxycarbonyl group. Amino
protecting groups can also form a heterocyclic ring with
the nitrogen to which they are attached, for example,
1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,
maleimidyl and the like and where these heterocyclic
groups can further include adjoining aryl and cycloalkyl
rings. In addition, the heterocyclic groups can be
mono-, di- or tri-substituted, such as nitrophthalimidyl.
Amino groups may also be protected against undesired
reactions, such as oxidation, through the formation of an
addition salt, such as hydrochloride, toluenesulfonic
acid, trifluoroacetic acid and the like. Many of the
amino protecting groups are also suitable for protecting
carboxy, hydroxy and mercapto groups. For example,
aralkyl groups. Alkyl groups are also sutiable groups
for protecting hydroxy and mercapto groups, such as tert-
butyl.

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81 '
Silyl protecting groups are silicon atoms
optionally substituted by one or more alkyl, aryl and
aralkyl groups. Suitable silyl protecting groups
include,. but are not limited to, trimethylsilyl,
. 5 triethylsilyl, tri-isopropylsilyl, tert-
butyldimethylsilyl, dimethylphenylsilyl, 1,2-
bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane
and diphenylmethylsilyl. Silylation of an amino groups
provide mono- or di-silylamino groups. Silylation of
aminoalcohol compounds can lead to a N,N,O-tri-silyl
derivative. Removal of the silyl function from a silyl
ether function is readily accomplished by treatment
with, for example, a metal hydroxide or ammonium
flouride reagent, either as a discrete reaction step or
in situ during a reaction with the alcohol group.
Suitable silylating agents are, for example,
trimethylsilyl chloride, tert-butt'-dimethylsilyl
chloride, phenyldimethylsilyl chloride, diphenylmethyl
silyl chloride or their combination products with
imidazole or DMF. Methods for silylation of amines and
removal of silyl protecting groups are well known to
those skilled in the art. Methods of preparation of
these amine derivatives from corresponding amino acids,
amino acid amides or amino acid esters are also well
known to those skilled in the art of organic chemistry
including amino acid/amino acid ester or aminoalcohol
'chemistry.
Protecting groups are removed under conditions
which will not affect the remaining portion of the
molecule. These methods are well known in the art and
include acid hydrolysis, hydrogenolysis and the like. A
preferred method involves removal of a protecting group,
such as removal of a benzyloxycarbonyl group,by
hydrogenolysis utilizing palladium on carbon in a
suitable solvent system such as an alcohol, acetic acid,
and the like or mixtures thereof. A t-butoxycarbonyl
protecting group can be removed utilizing an inorganic

CA 02274093 1999-06-03
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82
or organic acid, such as HC1 or trifluoroacetic acid, in
a suitable solvent system, such as dioxane or methylene
chloride. The resulting amino salt can readily be
neutralized to yield the free amine. Carboxy protecting
group, such as methyl, ethyl, benzyl, tert-butyl, 4-
methoxyphenylmethyl and the like, can be removed under
hydroylsis and hydrogenolysis conditions well known to
those skilled in the art.
The symbols used above have the following meanings:
Rx Ry 0
-CRxRy- _ -C(0)- -
R
Rx I
-NRxRy - ~-N\ -C (NR) - - N
Ry
R
-NR- - ~~N~~ -S (O) 2- _
,f~ '~~ s~.~
to
Prodrugs of the compounds of this invention are
also contemplated by this invention. A prodrug is an
active or inactive compound that is modified chemically
through in vivo physicological action, such as
hydrolysis, metabolism and the like, into a compound of
this invention following adminstration of the prodrug to
a patient. The suitability and techniques involved in
making and usingprodrugs are well known by those
skilled in the art. For a general discussion of
20 prodrugs involving esters see Svensson and Tunek Drug
Metabolism Reviews 165 (1988) and Bundgaard Design of
Prodrugs, Elsevier (1985). Examples of a masked
carboxylate anion include a variety of esters, such as
alkyl (for example, methyl, ethyl), cycloalkyl (for
25 example, cyclohexyl), aralkyl (for example, benzyl, p-
methoxybenzyl), and alkylcarbonyloxyalkyl (for example,
pivaloyloxymethyl). Amines have been masked as

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83
arylcarbonyloxymethyl substituted derivatives which are
cleaved by esterases in vivo releasing the free drug and
- formaldehyde (Bungaard J. Med. Chem. 2503 (1989)).
Also, drugs containing an acidic NH group, such as
imidazole, imide, indole and the like, have been masked
with N-acyloxymethyl groups (Bundgaard Design of
Prodrugs, Elsevier (1985)). Hydroxy groups have been
masked as esters and ethers. EP 039,051 (Sloan and
Little, 4/11/81) discloses Mannich-base hydroxamic acid
prodrugs, their preparation and use.
Compounds according to the invention can be
synthesized according to one or more of the following
methods. It should be noted that the general procedures
are shown as it relates to preparation of compounds
having unspecified stereochemistry. However, such
procedures are generally applicable to those compounds
of a specific stereochemistry, e.g., where the
stereochemistry about a group is (S) or (R). In
addition, the compounds having one stereochemistry
(e. g., (R)) can often be utilized to produce those
having opposite stereochemistry (i.e., (S)) using well-
known methods, for example, by inversion.
~ ( 3 H) -Pyrimidinones
For the synthesis of 4(3H)-pyrimidinones II (or its
tautomer, 4-hydroxy-pyrimidines), the approach displayed
in Scheme 1 may be followed (for a review of synthetic
methods see: D.J. Brown, Heterocyclic Compounds: the
Pyrimidines, supra). This approach involves the
cyclization reaction between an acrylic acid ester XII
and an amidine V followed by oxidation of the resulting
- dihydropyrimidinone XIII to give II.

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84 '
Scheme 1
O H2N R1 si O
R11 ~ R
FOR NH NH
R12 v R12 N~R1
XII
XIII
OH O
R11 R11
N _ ~ \NH
R12 N~R1 R12 N~R1
II
For the synthesis of 2-substituted 5-(4-
fluorophenyl)-6-(4-pyridyl)-4-hydroxy-pyrimidines II
(Scheme 2), the disubstituted acrylic acid ester XII may
be prepared conveniently by condensation of pyridine-4-
carboxaldehyde with 4-fluorophenylacetic acid followed
by esterification. XII may be reacted with a variety of
amidines V at elevated temperature. As a
dehydrogenating agent for the conversion of XIII to II,
sodium nitrite/acetic acid is suitable.

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Scheme 2
0
F
~H
N
' F ~ / OR
. O
OH
H2N XI I
.i R1
HN
F y ~ F
Rm--~,. R1
XIII II
Accordingly, further compounds of formula II may be
obtained in which R1z is any other heteroaryl ring within
5 the definition of R'2 by the appropriate choice of
starting material. Such starting materials include but
are not limited to 2-methylpyridine-4-carboxaldehyde,
2,6-dimethylpyridine-4-carboxaldehyde (Mathes and
Sauermilch, Chem. Ber. 88, 1276-1283 (1955)), quinoline-
10 4-carboxaldehyde, pyrimidine-4-carboxaldehyde, 6-
methylpyrimidine-4-carbox-aldehyde, 2-methylpyrimidine-
4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxalde-
hyde (Bredereck et al., Chem. Ber. 97, 3407-3417
(1964)). The use of 2-nitropyridine-4-carboxaldehyde
15 would lead to a derivative of formula II with R1Z
represented by a 2-vitro-4-pyridyl group. Catalytic
reduction of the vitro to an amino group would provide
_ the 2-amino-4-pyridyl derivative of II. The approach
displayed in Scheme 2 is applicable to the use of other
20 aryl acetic acids leading to compounds of formula II
with different aryl groups as R1'.

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86
Pyrimidinone II (R'= H) may be substituted at the
N-3 position by reaction with e.g, an alkyl halide, such
as methyl iodide or ethyl bromide in the presence of an
appropriate base such as potassium carbonate and the
like.
Scheme 3
O
I F I H2
OEt \ O S
F I \ 0 N / / OE t H2N
'OE t ~ ~ \ O
N /
XIV
F \ O F \ O F \
I/ ~ I/ ~ I/ o
I --~- I ~ --.~. I '~ 21
N~SH ~ \ N~SMe I \ N~N~R
N / N / NJ R5
XV
XVI
II
F \ 0
/
I
\ N~R1
N /
II R1 _ SR2i
Another approach (Scheme 3) leading to 5,6-diaryl-
4-hydroxy-pyrimidines involves the cyclization of the b-
keto ester XIV with thiourea to give the thiouracil
derivative XV. XV can be S-monomethylated to XVI.
Reaction of_XVI with primary and secondary amines leads
to 2-amino substituted 4-hydroxy-pyrimidines II.
Further 2-thioether derivatives of II with R1 - SRzI can
be obtained, for example by alkylation of XV with alkyl
halides. Treatment of XV or XVI with Raney nickel and
H2 provides compounds of structure II wherein R1 is H.
Although Scheme 3 illustrates syntheses in which R12
is 4-pyridyl, this approach may be equally applied to

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87
any other heteroaryl ring within the definition of R'z by
the appropriate choice of the starting material. Such
starting materials include but are not limited to ethyl
2-methyl isonicotinate (E~imovsky and Rumpf, Bull. Soc.
Chim. FR. 648-649 (1954)), methyl pyrimidine-4-
carboxylate, methyl 2-methylpyrimidine-4-carboxylate,
methyl 6-methylpyrimidine-4-carboxylate and methyl 2,6-
dimethylpyrimidine-4-carboxylate (Sakasi et al.,
Heterocycles 13, 235 (1978)). Likewise, methyl 2-
nitroisonicotinate (Stanonis, J. Org. Chem. 22, 475
(1957)) may be reacted with an aryl acetic acid ester
followed by cyclization of the resultant b-keto ester
with thiourea analogously to Scheme 3. Subsequent
catalytic reduction of the nitro group to an amino group
would give a pyrimidinone II in which R12 is represented
by a 2-amino-4-pyridyl group (Scheme 4).
Scheme 4
\ O F I \ O 4
/ .R4 / ~R
N N
\ I N~R1 \ I N~Ri
N~ N
NT02 TNH2 =_
Furthermore, methyl 2-acetamido isonicotinate
2~ (Scheme 5) may be reacted analogously to Scheme 3 after
appropriate protection of the amide nitrogen with e.g. a
tert-butyldimethylsilyloxymethyl group (Benneche et al.,
Acta Chem. Scand. B 42 384-389 (1988)), a tert-
butyldimethylsilyl group, a benzyloxymethyl group, a
benzyl group or the like (P1}.
Scheme 5
C02Me ~ ~ C02Me ~ .\ C02Me
N~ ~ N~ ~ N
NH2 NHAc i Ac
P1

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_ , 88
Removal of the protecting group P1 of the resulting
pyrimidine II with a suitable reagent (e. g.,
tetrabutylammonium fluoride in the case where P1 is t-
butyldimethyl-silyloxymethyl) would then lead to a
pyrimidinone II with R12 represented by a 2-acetamido-4-
pyridyl group. Needless to say, ethyl p-fluorophenyl
acetate may be substituted by any alkyl arylacetate in
the procedure illustrated in Scheme 3 thus providing
compounds of formula II with different R1' aryl
substituents.
In a further process, pyrimidinones II may be
prepared by coupling_a suitable derivative of XVIII (L
is a leaving group, such as halogen radical and the
like) with an appropriate aryl equivalent.
O
L ~ R4
N
R12 N~R1
XVIII
Such aryl/heteroaryl couplings are well known to
those skilled in the art and involve an organic-metallic
component for reaction with a reactive derivative, e.g.,
a halogeno derivative, of the second compound in the
presence of a catalyst. The metallo-organic species may
be provided either by the pyrimidinone in which case the
aryl component provides the reactive halogen equivalent
or the pyrimidinone may be in the form of a reactive 5-
halogeno derivative for reaction with a metallo organic
aryl compound. Accordingly, 5-bromo and 5-iodo
derivatives of XVIII (L = Br, I) may be treated with
arylalkyl tin compounds, e.g., trimethylstannylbenzene,
in an inert solvent such as tetrahydrofuran in the
presence of a palladium catalyst, such as
di(triphenylphosphine)palladium(II)dichloride.~ (Peters
et al., J. Heterocyclic Chem. 27, 2165-2173, (1990).
Alternatively, the halogen derivative of XVIII may be
converted into a trialkyltin derivative (L = Bu3Sn) by

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89
reaction with e.g. tributylstannyl chloride following
lithiation with butyllithium and may then be reacted
' with an aryl halide in the presence of a catalyst.
(Sandosham and Undheim, Acta Chem. Stand. 43, 684-689
(1989). Both approaches would lead to pyrimidines II in
which R11 is represented by aryl and heteroaryl groups.
As reported in the literature (Kabbe, Lieb. Ann.
Chem. 704, 144 (1967}; German Patent 1271116 (1968)) and
displayed in Scheme 6, 5-aryl-2,6-dipyridyl-4(3H)-
pyrimidinones II may be prepared in a one step synthesis
by reaction of the cyanopyridine with an arylacetyl
ester, such as ethyl phenylacetate in the presence of
sodium methoxide.
Scheme 6
O
CN Rm~C02Et
N
J
N
II
In Scheme 7, compounds of the present invention of
formula XXX can be readily prepared by reacting the
methylthio intermediate XXXI with the amine NHRSR21, for
example by heating the mixture preferably at a
temperature greater than 100°C, more preferably 150-
210°C. Alternatively, compounds of formula XXX can be
readily prepared by reacting the methylsulfonyl
intermediate XXXII with the amine NHRSRZ1, for example by
heating the mixture preferably at a temperature greater
than 40°C, more preferably 50-210°C.
Scheme 7
O O O
Rll Rll 11
NH R NH
12 ~ ~ . R21
R12 N SMe R N N R12 N~S02Me
R5
XXXI ~ XXXII

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Amines of formula NHRSR21 are commercially available
or can be readily prepared by those skilled in the art
from commercially available starting materials. For
example, an amide, nitro or cyano group can be reduced
5 under reducing conditions, such as in the prescence of a
reducing agent like lithium aluminum hydride and the
like, to form the corresponding amine. Alkylation and
acylation of amino groups are well known in the art.
Chiral and achiral substituted amines can be prepared
10 from chiral amino acids and amino acid amides (for
example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl and the like
substituted glycine, i3-alanine and the like) using
methods well known in the art, such as H. Brunner, P.
15 Hankofer, U. Holzinger, B. Treittinger and H.
Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M.
Freiberger and R. B. Hasbrouck, J. Am. Chem. Soc. 82,
696-698, 1960; Dornow and Fust, Chem. Ber. 87, 984,
1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55,
20 1454-1459, 1982; W. Wheeler and D. O'Bannon, Journal of
Labelled Compounds and Radiopharmaceuticals XXXI, 306,
1992; and S. Davies, N. Garrido, O. Ichihara and I.
Walters, J. Chem. Soc., Chem. Commun. 1153, 1993.
25 Pvridones:
As displayed in Scheme 8, a suitable route to
2(1H)-pyridones III involves the cyclization reaction
between an a,b-unsaturated ketone XXII and a
sufficiently reactive, substituted acetamide in the
30 presence of base (E1-Rayyes and A1-Hajjar, J.
Heterocycl. Chem. 21, 1473 (1984)) and subsequent
dehydrogenation.

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_ , 91
Scheme 8 -
O
R12~H O
0
_ ~ 1 ~ R12!~R1
R O NH2
' XXII ii
R
O
R11 _ O
NH R11
~ NH
Ri2 ~ R1
R1z ~ R1
III
Scheme 9
O
0 ~ i 0
R
~ ~H -' ~ ~ ~~Rl
N / N /
XXII ~ j~2
0
R1
R1
_~~ t
Accordingly (Scheme 9), pyridine-4-carboxaldehyde
or other heteroaromatic carboxaldehyde-like pyrimidine-
4-carboxaldehydes or quinoline-4-carboxyaldehydes may be
reacted with acetyl aryl, acetyl heteroaryl or acetyl
cycloalkyl derivatives in the presence of piperidine/
' 10 acetic acid at elevated temperature (Bayer and Hartmann,
Arch. Pharm. (Weinheim) 324, 815 (1991)) as well as
pinacolone (CH3-CO-C(CH~)3) in the presence of sodium
hydroxide to provide the unsaturated ketone XXII (or the

CA 02274093 1999-06-03
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92
analogous ketone from the corresponding heteroaromatic-
4-carboxyaldehyde). The reaction of XXII with
phenylacetamide in the presence of sodium ethoxide then
may lead via the 3,4-dihydropyridone to 6-substituted 3-
phenyl-4-(heteroaryl)-2(1H)-pyridones of structure III.
In Scheme 10, a feasible route is illustrated
leading to 6-chloro-2(1H)-pyridone XXIV, a versatile
intermediate for further modifications at the 6-
position. This approach (G. Simchen, Chem. Ber. 103,
389-397 (1970) is based on the conversion of the
unsaturated g-cyanocarboxylic acid chloride XXIII into
XXIV in the presence of hydrogen chloride.
Scheme 10
Eton / o
11 O P\OEt R11 O
R
OR
OEt CN
R12 ~ R12 ~ CN _
O
R = Et
XII R = H
R11
R11
~C 1
12~ ~~ 12 ~ CN
R C1 R
XXIV XXIII
Reaction of XXIV with ammonia (Katritzky and
Rachwal, J. Heterocylic Chem. 32, 1007 (1995)), primary
and secondary amines would lead to 2-amino substituted
pyridones III. Furthermore, XXIV may be reacted in a
palladium or nickel catalyzed cross-coupling reaction
with an alkyl or aryl boronic acid or an alkyl or aryl
zinc halide to provide pyridone III wherein R' is alkyl
or aryl or heteroaryl.
In addition, pyridone III may be substituted at the
N-1 position by reaction with, e.g., an alkyl halide in

CA 02274093 1999-06-03
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93
the presence of an appropriate base such as potassium
carbonate.
An approach that may lead to a pyrimidinone of the
general formula III is illustrated in Scheme 11.
- 5 Scheme 11
R11 O R11 O R4NH 11 O S
C1 I NCS 2 R N~~Rq
R12 OEt ~ R12 OEt ~ ( H
R12 OEt
XXVI
XXVII
R11 ~ R11
1 N I NH
12~~ ~ ~ 12~~
R N SMe R N S
R4 R4
XXVIII XXIX
According to this approach (Shaw and Warrener, J.
Chem. Soc. 153-156 (1958); Hronowski and Szarek, Can. J.
Chem. 63, 2787 (1985); Agathocleous and Shaw, J. Chem.
Soc. Perkin Trans. I, 2555 (1993)), an ethoxyacryloyl
iscthiocyanate XXVI is reacted with a primary amine to
give as an addition product the acylthiourea XXVII which_
can be cyclized under basic or acidic conditions to the
thiouracil compound XXVIII. XXVIII may be methylated to
the methylthio derivative XXIX, a versatile intermediate
for further transformations at the 2-position.
Fused 4(3H)-Pvrimidinones:
As displayed in Schemes 12 and 13, introduction of
a suitable R' group through the alkylation of XXXIII
affords an intermediate to the fused 5, 6, or 7 membered
_ ring systems of Formula I wherein Rl and V or W are
joined. The synthesis utilizes a haloalkylamine in
which the amino group is protected through reaction with
1,2-bis(chlorodimethylsilyl)ethane affording the cyclic

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- ~ 94
stabase derivative (see:Basha and Debernardis _
Tetrahedron Lett 5271, 1984) which protects the amine in
the subsequent alkylation step (sodium hydride, DMF).
Scheme 12
O iS, O
R11 Br~N' R11 ~ ,S
NH S ~ N
N' \ / v .
m S
R12 N SMe NaH R12 N~SMe
m = 2-4
XXXIII
xxxlv '
T8AF
THF / H20
O 0
Rll R11
N ) - Heat N'~H2
m 1 ~ ~ m
R12 N' N 12
H R N SMe
XXXVI XXXV
Scheme 13
R11
R11
N i N
12 ~ ~ 12
R N ~ R N SMe
NH
m_1 ~ 2
m
Deprotection of the amine can be accomplished with acid
treatment (p-toluenesulfonic acid) or tetrabutylammonium
fluoride treatment. The free amine can then be cyclized
in an intramolecular fashion by warming to high
temperatures. The bromoalkylamines are either
commercially available (eg. 3-bromopropylamine
hydrobromide, 2-bromoethylamine hydrobromide) or they
can be synthesized from the corresponding
haloalkylazide followed by reduction of the azide to the
amine (see: Hendry et al Tetrahedron Lett 4597 (1987)).
More functionalized haloalkylamines can be used as long
as the functional groups are tolerated in the

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transformations shown in scheme 12 including the bromo
derivatives obtained from amino acid precursors as
' described by Baldwin et al (Synlett. 51-53, 1993) and
Leanna et al (Tetrahedron Lett. 4485, 1993).
5 Alternatively, the fused ring system can be made
through the addition of a hydroxyalkylamine as outlined
in Scheme 14. Initially, the amine component of the
hydroxyalkylamine displaces the 2-methylthio group to
afford compound XXXVII which is followed by conversion
10 of the alcohol to a suitable leaving group (eg.
methanesulfonate or trifluoromethanesulfonate). Closure
of the ring can be accomplished by treatment with an
excess of sodium hydride in DMF to afford XXXVI.
Scheme 14
O O
1 i OH
R ~ ~NH HO m NHz Rll NH
R1z N~SMe 1z ~ ~ m-1
R N N
H
XXXIII XXXVII
MeS02C1
Et3N
O
0
R11 OMs
N 11
m-1 R NH
Rlz N~N
H Riz N~N ~ m-1
H
XXXYI
15 xxxvIII
The 6,5 fused ring systems can be obtained as
outlined in Scheme 15. Alkylation of the N-3 nitrogen
with 3-bromo-1-trimethylsilylpropyne can be followed by
a displacement of the 2-methylthio group with the
20 appropriate amine component exemplified but not limited
to a phenylalkylamine. The 2-amino group under the
reaction conditions cyclizes onto the acetylene as shown
with a loss of the trimethylsilyl group as well. This
transformation is illustrated in the examples below

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wherein 3-phenyl-1-propylamine and benzylamine are
reacted with 3-(3-trimethylsilyl-2-propynyl)-5-(4-
fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)- -
pyrimidinone to afford the corresponding 6, 5 fused
system.
Scheme 15
TMS
Br i
R11 R11
'NH ~ N ~ TMS
s2 ~SMe NaH Ri2 N~SMe
R N
XXXIX
XXXIII
R21NH2
Rll
~N~
R12 N NN
R21
XXXX
Scheme 16
F
R2i
OR H2N ~L
N J HN R21
L* N n
NH ~n ~ R2i
R21
R21 R21
Compounds of the invention when U is CHRZ1 can be
prepared according to Scheme 2 above wherein R1 contains
an leaving group or a group which can be converted into
a leaving group (L*) which can be reacted with a

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primidine nitrogen atoms to form the fused ring (see
Scheme 16).
- The following Examples are presented for
illustrative purposes only and are not intended, nor
should they be construed, as limiting the invention in
any manner. Those skilled in the art will appreciate
that modifications and variations of the compounds
disclosed herein can be made without violating the
spirit or scope of the present invention.
EXAMPLES
Exa~qple 1
General procedure for the preparation of 2-substituted
5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3X) -pyrimidones
O
I
I \ H F I \ O
F N ~ / OR
\ 0 --s
I\
OH N
H2N a. R = H
b. R = Et
R
HN
F F
O
I
I~N~Rl
N
a. 2-l4-Fluorophenvl)-3-(4-pyridvl)-acrylic acid A
mixture of 4-fluorophenylacetic acid (9 g, 58.4 mmol},
4-pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine
(6 ml) and acetic anhydride (6 ml) was heated at 150°C
for 1 h followed by evaporation and co-distillation with _
water. The resulting material crystallized on addition
of ethanol. The solids were filtered and washed with
ethanol and ethyl acetate to provide the title compound.
- MS (m/z) : 244.0 (M+H)'; ClaHIOFN02 requir. 243.2 'H-NMR

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(DMSO-d6): d 8.43, 6.98 (2d, each 2H, Pyrid.), 7.73 (s,
2H, CH=), 7.21 (d, 4H, PhF).
b. Ethvl 2-(4-fluorophenyl)-3-(4-pyridyl)-acrvlate~
Conc. sulfuric acid (2.2 ml) was added carefully to a
suspension of 2-(4-fluorophenyl)-3-(4-pyridyl}-acrylic
acid (6.7 g, 27.5 mmol) in ethanol (120 ml) and the
mixture was heated at reflux for 24 h. The solvent was
evaporated, the remainder was taken up in
dichloromethane and the organic solution was washed with
aqueous sodium hydrogencarbonate and water, followed by
drying and evaporation. Flash column chromatography on
silica gei (hexane-acetone = 2:1) provided the pure
title compound. MS (m/z) : 271.8 (M+H)'; C1fiH14FN02 requir.
271.3 'H-NMR (CDC1~): 8.44, 6.88 (2m, each 2H, Pyrid.),
7.72 (s, 1H, CH=), 7.16, 7.06 (2m, each 2H, PhF), 4.28
(q, 2H, CH2) , 1.28 (t, 3H, CH3) .
c. General procedure: A stirred mixture of ethyl 2-(4-
fluorophenyl)-3-(4-pyridyl)-acrylate (357 mg, 1.38
mmol), the amidine hydrochloride (2.61 mmol) and sodium
methoxide (250 mg, 4.62 mmol) in ethanol (5 ml) was
heated in a sealed tube at 120°C for 3 h. It was
neutralized with 2N hydrochloric acid prior to
evaporation. The residue was taken up in acetic acid
(25 ml) and treated with sodium nitrite (670 mg, 9.71
mmol) at 44°C for 20 min. After evaporation, the
resultant product was taken up in dichloromethane and
the solution was washed with aqueous sodium
hydrogencarbonate and water before drying and
evaporation. The product was purified by
recrystallization from methanol. If the crude product
of nitrite oxidation was water soluble, as was found for
5-(4-fluorophenyl)-2-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone, then no aqueous work up was done, but the
material obtained on evaporation was applied to a column
of silica gel (5~ methanol/dichloromethane) prior to
recrystallization.

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The following compounds were prepared accordingly
using the appropriate amidine hydrochloride:
1-1 5-(4-Fluorophenyl)-2-methyl-6-(4-pyridyl)-4(3H)-
_ pvrimidinone: MS (m/z) : 282.2 (M+H)'; C16H1zFN30 requir.
- 5 281.3 1H-NMR (DMSO-ds): d 8.46 (m 2H, Pyrid.), 7.2-7.03
- (m, 6H, PhF, Pyrid. ) . 2.38 (s, 3H, CH3) .
R1 = CH3-
1-2 5-(4-Fluorophenyl)-2-isopropyl-6-(4-pyridyl)-4(3H)=
pyrimidinone: MS (m/z) : 310.0 (M+H)'; C18H16FN30 requir.
309.4 1H-NMR (DMSO-ds): 8.45 (m, 2H, Pyrid.), 7.21-7.03
(m, 6H, PhF, Pyrid.), 2.90 (m, 1H, CH(CH3)2,) 1.26, 1.24
(2s, each 3H, 2CHj) .
R1 = ( CH3 ) ZCH-
1-3 2-(2,6-Dichlorobenzvl)-5-(4-fluorophenvl)-6-(4-
pyridyl)-4(3H)-pyrimidinone: MS (m/z): 426.0 (M)';
Cz~H14C12FN~0 requir. 426.3 1H-NMR (DMSO-d6) : d 8.37 (m, 2H,
Pyrid.), 7.50 (d, 2H, PhCl2), 7.35 (t, 1H, PhCl2), 7.18-
7.08 (m, 4H, PhF), 6.96 (m, 2H, Pyrid.), 4.36 (s, 2H,
CHZ ) .
Cl
R1 =
2 0 / Cl
1-4 5-(4-Fluorophenyl)-2-phenyl-6-(4-pyridvl)-4(3H)=
pyrimidinone: MS (m/z) : 344.2 (M+H)'; CZ1H14FN30 requir.
343.4 1H-NMR (DMSO-ds): d 8.49 (d, 2H, Pyrid.), 8,20 (d,
2H, Ph), 7.66-7.50 (m, 3H, Pyrid., Ph), 7.32-7.11 (m,
6H, PhF, Ph).
R1 = I

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Example 2
General procedure for the preparation of 2-N substituted
2-amino-5- (4-fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -
pyrimidinones
Step A. 5-(4-Fluorophenyl)-3-methyl-2-methylthio-6-(4-
pyridyl)-4(3H)-pyrimidinone:
F
NH ~CH3
~SH ~SCH3
Methyl iodide (418 ml, 6.67 mmol) was added to a
stirred mixture of 5-(4-fluorophenyl)-6-(4-pyridyl)-2-
thiouracil (1.0 g, 3.34 mmol) and potassium carbonate
(923 mg, 6.68 mmol) in N, N-dimethylformamide (30 ml) at
room temperature. Stirring was continued for 3 h-,
followed by evaporation and flash chromatography on a
column of silica gel (hexane-acetone = 3:1, 2:1, 1:1) or
IatrobeadsR (chloroform-methanol = 90:7; chloroform-
methanol-triethylamine = 90:7:3). The second main
fraction provided the title compound as a solid. MS
(m/z) : 328.0 (M+H)'; Cl~HIaFN30S requir. 327.4. 1H-NMR
(DMSO-db): d 8.50, 7.26 (2m, each 2H, Pyrid.), 7.18,
7.14 (2m, each 2H, PhF), 3.52 (s, 3H, NCH3), 2.65 (s,
3H, SCH3 ) . _
Step B. General procedure:
F ~ O F
_ ~ / N~CH3 .CH3
i
N ~SCH3 NR5R21
N /
A mixture of 5-(4-fluorophenyl)-3-methyl-2-
methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (103 mg,
0 . 32 mmol ) and the amine HNRSR21 ( 1. 2-3 . 2 mmol ) was
heated at 190-200°C for 2-48 h. The resulting product

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was purified by flash chromatography on a column of
silica gel (hexane-acetone or methanol-dichloromethane
- or methanol-dichloromethane-conc. ammonium hydroxide) to
provide the target compound.
The following compounds were prepared using the
above procedure outlined above and an appropriate amine:
2-1 2-(n-Butylamino)-5-(4-fluorophenyl)-3-methyl-6 (4
pyridyl)-4(3H)-pyrimidinone:
The reaction was done in a sealed tube at 190°C for 5 h.
MS (m/z) : 353 .0 (M+H)';
C2oH21FN40 requir. 352.4.
Rl - CHI ( CHz ) 3NH-
2-2 5-(4-Fluorophenyl)-3-methyl-2-(pentylamino)-6-(4
pyridyl)-4(3H)-pyrimidinone: The reaction was done in a
sealed tube at 190°C for 2.5 h. MS (m/z): 366.8 (M+H)';
Cz1H23FN40 requir . 3 6 6 . 4 .
R1 - CHI ( CHZ ) QNH-
2-3 2-(3,3-Dimethylbutylamino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone: The reaction
was done in a sealed tube at 190°C for 5 h. MS (m/z):
3 81. 2 ( M+H ) ' ; CzzHz5FNa0 requir . 3 8 0 . 5 .
Rl - ( CHI ) 3C ( CHZ ) zNH-
2-4 2-(Benzylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone: The reaction was done at
185°C for 6h. MS (m/z) : 387.2 (M+H)'; Cz3H19FNq0 requir.
386.4
i
-N
H
R~ _
2-5 2-(4-Fluorobenzvlamino)-5-(4-fluorophenvl) 3
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone: The reaction
was done at 190°C for 24 h. MS (m/z): 405.2 (M+H)';
CZ,H,BF2Na0 requir. 404.4.
~ ~ N~
H
Rl _ F

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2-6 2-(3-Fluorobenzylamino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone: The reaction
was done at 195°C for 40 h. MS (m/z): 405.0 (M+H)';
C23H18FZN40 requir . 404 . 4 .
\ ~ N~
H
I
Rl - F
2-7 5-(4-Fluorophenvl)-3-methyl-((R-1-
phenylethyl)amino)-(4-pyridyl)-4(3H)-pyrimidinone: The
reaction was done at 180°C for 4 days. MS (m/z): 401.0
(M+H)~; CZQHZ1FN40 requir. 400.5
3
N~
H
I
Rl - F -
2-8 2-(2-(2-Chlorophenyl)-ethylamino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone:
The reaction was done at 190°C for 5 h. MS (mlz): 435.2
(M+H)'; Cz4HZOC1FNa0 requir. 434.9.
H
N~
R~ -
C1
2-9 5-(4-Fluorophenyl)-2-(2-(4-fluorophenyl)-
ethylamino)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone:
The reaction was done at 190°C for 5 h. MS (m/z): 419.2
(M+H) ~; CZaH2oF2Nd0 requir. 418. 5
H
\~N~
Rl _ I
2-10 5-(2-Fluorot~henyl)-2-(2-(3-fluorophenyl)-
ethylamino)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone:
The reaction was done at 190°C for 24 h. MS (m/z):
419 . 2 ( M+H ) ' ; C,QHZpFzNdO requir . 418 . 5

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H
~~N~
Rl - I
F
. 2-11 5-(2-Fluorophenyl)-2-(2-(2-fluorophenyl)-
ethylamino)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone:
The reaction was done at 190°C for 12 h. MS (m/z):
419 . 0 (M+H ) ' ; Cz4H2oF,N40 requir . 418 . 5
H
N~
R' -
F
2-12 5-(2-Fluorophenyl)-2-((2-hvdroxv-2-phenyl)-
ethvlamino)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone:
The reaction was done at 190°C for 1.5 h. MS (m/z):
417 . 0 ( M+H ) ' ; C2aHzIFNaOz requir . 416 . 5 .
OH H
N~
R' _ I
2-13 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-pyridyl)-4(3H) pyrimidinone: The reaction
was done at 190°C for 6 h. MS (m/z): 415.0 (M+H)';
C~;Hz~FNaO requir . 414 . 5 . 'H-NMR ( CDC13 ) : d 8 . 49 , 7 . 2 0 ( 2m,
each 2H, Pyrid.), 7.35 (t, 2H, Ph), 7.30-7.25 (m, 3H,
Ph), 7.12, 6.97 (2m, each 2H, PhF), 4.61 (t, 1H, NH),
3.67 (q, 2H, CHZN), 3.28 (s, 3H, CH3), 2.82 (t, 2H,
CH2Ph) , 2 . 12 (m, 2H, CHZ) .
v
R~ _ I _ H
2-14 5-(4-F'luoronhenyl)-3-methyl-2-((1-methyl-3-
_ phenvlprotwl)-amino)-6-(4-pyridvl)-4(3H)-pyrimidinone:
The reaction was done at 200°C for 48h. MS (m/z): 429.0
(M+H) f ; CZ6H25FNa0 requir. 428 . 5 .

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CH3
Rl - I v v H
2-15 5-(4-Fluorophenyl)-3-methyl-2-((R-1-methyl-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)-pyrimidinone:
The reaction was done at 200°C for 48 h. MS (m/z):
429.0 (M+H)'; CZ6HzsFNqO requir. 428.5. _
CH3
Rl I v v H
2-16 2-((3,3-Diphenylpropyl)-amino)-5-(4-fluorophenyl)-
3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone: The reaction
was done at 190°C for 6 h. MS (m/z): 490.8 (M+H)';
C31HZ,FNqO requir . 4 9 0 . 6 .
Rl -
i
N
H
2-17 5-(4-Fluorophenyl)-3-methyl-2-((2-
phenylaminoethyl)-amino)-6-(4-pyridvl)-4(3H)=
pyrimidinone: The reaction was done at 190°C for 4 h.
MS (m/z) : 416.2 (M+H)'; C~QH"FN,O requir. 415.5.
H
N~ N
w
Rl - ~ H
2-18 5-(4-Fluorophenvl)-2-((3-imidazolvlpropyl)-amino)-
3-methyl-6-(4-pvridyl)-4(3H)-pvrimidinone: The reaction
was done at 190°C for 2 h. MS (m/z): 405.0 (M+H)';
2 0 CZZH21FN60 requ i r . 4 0 4 . 5 .
~N~N/
R - N~ H
2-19 5-(4-Fluorophenvl)-3-methyl-2-(2-(piperazin-1-yl)-
et~lamino ) -6- ( 4-pyridyl ) -4 ( 3H) -pyrimidinone : The

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reaction was done at 190°C for 30 min. MS (m/z): 409.2
(M+H) '; CZZH25FNs0 requir. 408 . 5 .
R -
HN NN~N~
- 2-20 5-(4-Fluorophenvl)-3-methyl-6-(4-pvridvl)-2-(3-
_ 5 (pyrrolidin-1-yl)-propylamino)-4(3H)-pyrimidinone: The
reaction was done at 190°C for 2 h. MS (mlz): 408.2
(M+H}'; Cz~Hz~FNsO requir. 407.5.
Rl - N/~N~
H
2-21 2-(((S)-2-Amino-3-phenylpropvl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: The reaction was done at 190°C for 2.5 h.
MS (m/z): 430.1 (M+H)+; C25H24FN50 requir. 429.5 (free
base).
_ i
R - H
I ~ N
NH2
2-22 2-(((S)-2-N-Ethyl-3-phenvlpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: The reaction was done at 190°C for 4 h.
MS (m/z): 458.3 (M+H)+; C27H28FN50 requir. 457.6 (free
base).
i
N
H
R~ - HN
1
2-23 2-((2-Amino-2-methy-3-phenylpropvl) amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridvl)-4(3H)-pvrimidinone
hydrochloride: The reaction was done at 190°C for 4 h.
MS (m/z): 444.0 (M+H)+; C26H26FN50 requir. 443.5 (free
base) .
-N
R _ H
~NH
_ ~ 2
2-24 2-((2-Aminomethv-3-phenylpro~yl)-amino)-5-(4
fluorophenvl-3-methyl-6-(4-pyridyl)-4(3H)-bvrimidinone

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hydrochloride: The reaction was done at 190°C for 1 h.
MS (m/z): 444.0 (M+H)+; C2(H26FN40 requir. 443.5 (free
base) .
N
H
NH2
Rl _
2-25 2-((3-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: The reaction was done at 190°C for 2.5
h. MS (m/z): 430.0 (M+H)+; C25H24FN50 requir. 429.5
(free base) .
NH2 -
\ Ni
H
R1 -
2-26 5-(4-Fluorophenyl)-3-methyl-2-(3-(2-
methvlphenvl)propvl)-amino)-6-(4-pvridvl)-4(3H)-
pyrimidinone: The reaction was done at 190°C for 4 h.
MS (m/z): 429.5 (M+H)+; C26H25FN40 requir. 428.5.
\ ~ N/
H
Rl - / \ CH3
2-27 5-(4-Fluorophenyl)-3-methyl-2-((R,S)-2-amino-3-(2-
fluorophenyl)-propyl-amino)-6-(4-pyridyl)-4(3H)-
pyrimidinone Hydrochloride: The reaction was done at
190°C for 7 h. MS (m/z): 448(M+H)'.
N
NH2 H
2 0 Rl - F
2-28 2-(((R)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: The reaction was done at 190°C for 2 h.
MS (mlz): 430.2 (M+H)+; C25H24FN50 requir. 429.5 (free
base).

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i
I ~ ~ N
R - ~2 H
2-29 2-(((S)-2-N-Methyl-3-phenvlpropvl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pvridyl)-4(3H)-pyrimidinone
hydrochloride: The reaction was done at 190°C for 4 h.
MS (m/z): 444.0 (M+H)+; C26H26FN50 requir. 443.5 (free
base). -
N~
R~ _ I I H
~~ CH
3
2-30 2-((2-phenylthioethyl)-amino)-5-(4-fluorot~henyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone: The reaction
was done at 190°C for 16 h. MS (m/z): 433 (M+H1+_
N~
( H
Rl
2-31 2-((2-hydroxyethyl)-amino)-5-(4-fluorot~henyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone: The reaction
was done at 190°C for 16 h. MS (m/z): 341 (M+H)+.
HO~ N ~
R' - H
2-32 2-((2,2-dimethyl-3-hydroxypropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridvl)-4(3H)-pyrimidinone:
The reaction was done at 190°C for 16 h. MS (m/z): 383
(M+H)+.
/~
R' -HO
2-33 2-((2,2-dimethyl-3-phenylthiopropyl)-amino)-5-(4-
fluorophenvl)-3-methyl-6-(4-pvridvl)-4(3H)-pyrimidinone:
To a solution of triphenylphosphine (262 mg, 0.29 mmol)
in tetrahydofuran (2 mL) at 0 C was added diisopropyl
azodicarboxylate (DIAD) (56 ml, 0.29 mmol). After 30
min at 0 C, 2-((2,2-dimethyl-3-hydroxypropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone (50 mg, 0.14 mmol) and 2,6-
dichlorothiophenol in tetrahydrofuran (2 mL) was added.

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After 16 h, the reaction was concentrated under a stream
of nitrogen. The reaction mixture was applied directly
to purification via flash chromatography (step gradient
ethyl acetate:CHCl3 1:3 then 1:2 then 1:1 then 2:1 then
3:1) to afford the title compound: MS (m/z) 544 (M+H)+.
R~ _ HO ~~ H
2-34 2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
was prepared from 5-(4-fluorophenyl)-3-methyl-2-
methylthio-6-(4-pyridyl)- 4(3H)-pyrimidinone and 1-(2-
fluorophenyl)-1,3-propanediamine according to the
General Procedure. The reaction was done at 190°C for 3
h. MS (m/z) : 448.1 (M+H)'; Cz5HZ3F2N50 requir. 447.5 (free
base).
F NH2
R1 - / I \/\N/
~ H
2-35 2-((3-Amino-3-(2-methyl~henyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
hvdrochloridewas prepared from 5-(4-fluorophenyl)-3-
methyl-2-methylthio-6-(4-pyridyl)- 4(3X)-pyrimidinone
and 1-(2-methylphenyl)-1,3-propanediamine according to
tae General Procedure. The reaction was done at 185°C ---
for 4 h. MS (m/z) : 444.5 (M+H)'; Cz6HzcFN50 requir. 443.5
(free base) .
CH3 ~2
Rl _ ' I \/\N/
H
2-36 2-(((S)-3-amino-3-phenylnropyl)-amino)-5-(4-
fluorophenvl)-3-methyl-6-(4-pyridvl)-4(3H)-pvrimidinone
hydrochloride was prepared from 5-(4-fluorophenyl)-3-
methyl-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone and
(S)-1-phenyl-1,3-propanediamine according to the General
Procedure. The reaction was done at 190°C for 2.5 h. MS
(m/z) : 430.2 {M+H)'; CZSH2aFN50 requir. 429. 5 (free base) .

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NH2
R1 _ / I ~N/
H
2-37 2-(((R)-3-amino-3-phenylpropvl)-amino)-5-(4-
fluoronhenyl)-3-methyl-6-(4-pvridyl)-4(3H)-pyrimidinone
hydrochloride was prepared from 5-(4-fluorophenyl)-3-
methyl-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone and
(R)-1-phenyl-1,3-propanediamine according to the General
Procedure. The reaction was done at 190°C for 3.5 h. MS
(m/~) : 430.7 (M+H)'; CZSHZ4FN50 requir. 429.5 (free base) .
NH~
Ri _ / I /
N
H
2-38 2-(((2R,3R)-3-Amino-2-methyl-3-phenylpropyl)-
amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride was prepared from 5-(4-
fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-
4(3H)-pyrimidinone and (2R,3R)-2-methyl-3-phenyl-1,3-
propanediamine according to the General Procedure. The
reaction was done at 190°C for 3 h. MS (m/z): 444.5
(M+H ) ' ; CZ6H26FN50 requir . 443 . 5 ( free base ) .
NHZ
Fi _ / I /
N
H
2-39 2-(((2S,3S)-3-Amino-2-methyl-3-phenylpropvl)-
amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-
pvrimidinone hydrochloride was prepared from 5-(4-
fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-
4(3H)-pyrimidinone and (2S,3S)-2-methyl-3-phenyl-1,3-
propanediamine according to the General Procedure. The
reaction was done at 190°C for 2 h. MS (m/z): 444.4
(M+H)'; C26HzcFNsO requir. 443.5 (free base) .
NH2
Ri - / I N/
- H

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Analogously, the isomers 2-(((2S,3R)-3-Amino-2-methyl-3-
phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone and 2-(((2R,3S)-3-amino-2-
methvl-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pvridyl)-4(3H)-pvrimidinone may be prepared
from the corresponding diamines.
2-40 5-(4-Fluorophenyl)-2-((-3-hydroxy-3-phenylpropyl)-
amino)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone~ The
reaction was done at 190°C for 3 h. MS (m/z): 431.2
(M+H)+; C25H23FN4Oz requir. 430.5.
HO
RZ - / ~ ~N/
H
Example 3
Procedure for the preparation of N-substituted
pyrimidinones
F ~ I O F ~ I O
NH ~ I N~CH3
i ~ i
~N ~N
N~ ~ N
C1 I ~ C1 C1 I ~ C1
2-(2,6-Dichlorobenzyl)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone: Methyl iodide (41 ml, 0.65
-.mmol) was added to a stirring mixture of 2-(2,6-
dichlorobenzyl}-5-(4-fluorophenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone (280 mg, 0.61 mmol) and potassium carbonate
(181 mg, 1.30 mmol) in N,N-dimethylformamide (2 ml).
Stirring was continued for 2 h, followed by evaporation
and flash chromatography of the resulting product on a
- 25 column of silica gel (hexane-acetone = 3:1} to yield the
title compound as a white solid. MS (m/z): 440.2
(M+H) '; Cz3H1sC12FN30 requir . 440 . 3 .

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Example 4
General procedure for the preparation of 2-N and 2'-N
substi tuted 2-amino-5- (4-fluorophenyl) -3-methyl-6- (4- (2
amino)pyridyl) ) -4 (3H) -pyrimidinones
F
' I O
/ ,t.CH3
N~NR5R21
N
NR31R32
Step A. 5-(4-Fluorophenyl)-3-methyl-2-methylthio-6-(4-
(2-acetamido)pvridvl))-4(3H)-pyrimidinone: To a
solution of 5-(4-fluorophenyl)-6-(4-(2-
acetamido)pyridyl)-2-thiouracil (600 mg, 1.68 mmol) in
DMF (35 mL) was added powdered sodium hydride (60~ oil
dispersion, 221 mg, 5.56 mmol) over 1 minute at 23°C.
After 45 min, iodomethane (210 ml, 3.37 mmo1) was added
dropwise. After 45 min, the reaction was concentrated
in vacuo (rotovap connected to high vac with a bath
temperature no greater than 40°C). The residue was
applied immediately to flash chromatography purification
(step gradient hexane: acetone 4:1; then 3:1; then 2:1;
the 1:1) to afford the desired product.
Step B. 5-!4-Fluorophenyl)-3-methyl-2-((3-phenvlpropvl
amino)-6-(4-(2-amino)pyridyl))-4(3H) pyrimidinone: A
neat mixture of 5-(4-Fluorophenyl)-3-methyl-2-
methylthio-6-(4-(2-acetamido)pyridyl))-4(3H)-
pyrimidinone (50 mg, 0.13 mmol) and 3-phenyl-1-
propylamine (88 mg, 0.65 mmol) was warmed to 190°C for
17 h. After cooling to 23°C, the reaction mixture was
applied directly to purification via flash
chromatography (step gradient l~MeOH:CHC13 then 2~, then
3~; then 4~; then 5~) to afford the desired product: MS
(m/z) 430 (M+H)+.

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N
R - I H
R31 _ H
R'z - H
The following compounds were prepared using the
above procedure outlined above and an appropriate amine:
4-1 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-acetamido)pyridyl))-4(3H)-pyrimidinone:
To a solution of 5-(4-Fluorophenyl)-3-methyl-2-((3-
phenylpropyl)-amino)-6-(4-(2-amino)pyridyl))-4(3H)-
pyrimidinone (11 mg, 0.026 mmol) in 600 ~,1 of pyridine
was added (5 EL1, 0.064 mmol) of acetyl chloride at 23 C.
After 2 h, the reaction was quenched with water (5 ~1)
and the reaction was concentrated under a stream of
nitrogen. The reaction mixture was applied directly to
purification via flash chromatography (step gradient
l~MeOH:CHC13 then 2~, then 3~) to afford the title
compound: MS (m/z) 472 (M+H)+.
v
R~ _ I _ H
R'z - H
R'1 - Ac
4-2 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-methoxyacetamido)pyridvl))-4(3H)=
pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3-
methyl-2-((3-phenylpropyl)-amino)-6-(4-(2-
amino)pyridyl))-4(3H)-pyrimidinone (11 mg, 0.026 mmol)
in 600 ~.l of pyridine was added (5 ~,1, 0.064 mmol) of
methoxyacetyl chloride at 23 C. After 2 h, the reaction
was quenched with water (5 ~.1) and the reaction was
concentrated under a stream of nitrogen. The reaction
mixture was applied directly to purification via flash
chromatography (step gradient l~MeOH:CHCl3 then 2~, then
3~) to afford the title compound: MS (m/z) 502 (M+H)+.

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N~
R _ I H
R'~ - H
- R'1 - C ( O ) CHZOMe
4-3 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylnropyl)-
- 5 amino)-6-(4-(2-acetoxyacetamido)pyridyl))-4(3H)=
pyrimidinone: The reaction was done in the manner of the
above substituting acetoxyacetyl chloride for acetyl
chloride to afford the title compound after
chromatography: MS (m/z) 530 (M+H)+.
v
R~ _ I _ H
R3z - H
R" - C ( O ) CH20Ac
4-4 5-(4-Fluorophenyl)-3-methyl-2-((3-phenvlpropyl)-
amino)-6-(4-(2-hydroxyacetamido)pyridyl))-4(3H)=
pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3-
methyl-2-((3-phenylpropyl)-amino)-6-(4-(2-
acetoxyacetamido)pyridyl))-4(3H)-pyrimidinone ( 2 mg,
0.003 mmol) in 900 ~.1 methanol: 100 ~,1 water was added
potassium carbonate ( 4 mg, 0.032 mmol) as a solid at 23
C. After 3 h, the reaction was concentrated under a
stream of nitrogen. The reaction mixture was diluted
with chloroform (20 mL), dried (Na2S04), and
concentrated to afford the title compound: MS (m/z) 488
(M+H)+.
R~ _ I w v _ H
Rsa _ H
R'1 - C ( O ) CHZOH
4-5 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpro~wl)-
- amino)-6-(4-(2-methvlsulfonamido)pvridvl))-4(3H)-
pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3-
methyl-2-((3-phenylpropyl)-amino)-6-(4-(2-

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amino)pyridyl))-4(3H)-pyrimidinone (11 mg, 0.026 mmol)
in 600 )1.1 of pyridine was added methanesulfonyl
chloride (4 ~.1, 0.051 mmol) at 23 C. After 2 h, the
reaction was quenched with water (5 ~.1} and the reaction
was concentrated under a stream of nitrogen. The
reaction mixture was applied directly to purification
via flash chromatography (step gradient l~MeOH:CHC13
then 2~) to afford the title compound: MS (m/z} 508
(M+H)+.
R1 - I \ v H
R'z - H
R" - SOzMe
4-6 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
aminoL-6-(4-(2-benzylamino)pyridyl))-4(3H)-pyrimidinone:
To a solution of 5-(4-Fluorophenyl)-3-methyl-2-{(3-
phenylpropyl)-amino)-6-(4-{2-amino)pyridyl))-4(3H)-
pyrimidinone (11 mg, 0.026 mmol) in 600 ~.1 of 1,2-
dichloroethane was added benzaldehyde (8.9 mg, 0.084
mmol) and sodium triacetoxyborohydride (14.8 mg, 0.070
mmol) at 23 C. After 16 h, the reaction was quenched
with water (15 ~,1) and the reaction was concentrated
under a stream of nitrogen. The reaction mixture was
applied directly to purification via flash
chromatography (step gradient l~MeOH:CHC13 then 2~~,
then 3~; then 4~; then 5~) to afford the title compound:
MS (m/z) 458 (M+H)+.
Rl - ~ ~ H
R'2 - H
R'1 - CHZPh
4-7 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-(2-methoxvphenvl)met~lamino)pvridvl))-
4(3H}-pyrimidinone: The reaction was done in the manner

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of the above substituting 2-methoxybenzaldehyde_.for
benzaldehyde to afford the title compound after
chromatography: MS (m/z) 550 (M+H)+,
v
. R~ - ~ H
R'z - H
R'1 _ ~OMe
4-8 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-ethylamino)pyridyl))-4(3H)-pyrimidinone:
The reaction was done in the manner of the above
substituting acetaldehyde for benzaldehyde to afford the
title compound after chromatography: MS (mlz): 458
(M+H)+.
v
R1 - I H
R'z - H
R" - Et
4-9 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-(di-(3-methvlbutyl)amino)pyridyl))-4(3H)=
pyrimidinone: The reaction was done in the manner of
the above substituting isovaleradehyde for benzaldehyde
to afford the title compound after chromatography: MS
(m/z) : 570 (M+H)+.
R~ - ~ v H
R32 - CHZCHZCH ( CH3 ) 2
R'1 - CHZCHzCH ( CH3 ) 2
4-10 5-(4-Fluorophenvl)-3-methyl-2-((3-phenvlpropvl)-
amino)-6-(4-(2-diethvlamino)pvridvl))-413H)=
pvrimidinone: The reaction was done in the manner of
the above substituting acetaldehyde for benzaldehyde to

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afford the title compound after chromatography: MS
(m/z): 486 (M+H)+.
v
R~ _ I _ H
R'2 - Et
R31 - Et
4-11 5-(4-Fluorophenvl)-3-methyl-2-((3-phenvlpropyl)-
amino)-6-(4-(2-phenylaminocarbonvl-amino)pyridyl))-
4(3H)-twrimidinone: To a solution of 5-(4-Fluorophenyl)-
3-methyl-2-((3-phenylpropyl)-amino)-6-{4-(2-
amino)pyridyl))-4(3H)-pyrimidinone (.11 mg, 0.026 mmol)
in 600 ~,l of dioxane was added phenyl isocyanate (3.3
mg, 0.03 mmol) at 23°C. After 16 h, the reaction was
quenched with water (15 ~.1) and the reaction was
concentrated under a stream of nitrogen. The reaction
mixture was applied directly to purification via flash
chromatography (step gradient l~MeOH:CHCl3 then 20, then
3~; then 4%; then 5o) to afford the title compound: MS
(m/z) 549 {M+H) +.
N
R _ I H
R'~ - H
R" - NH(CO)NHPh
4-12 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-methylaminocarbonvl-amino)pyridvl))-
4(3H)-pyrimidinone: The reaction was done in the manner
of the above substituting methylisocyanate for
phenylisocyanate to afford the title compound after
chromatography: MS (m/z): 487 (M+H)+.
N
R1 - ~ H
R32 - H
3 0 R'1 - NH ( CO ) NHMe

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4-13 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylprotwl)-
amino)-6-(4-(2-(2'amino-1'-oxo-ethylamino)pyridyl))-
- 4(3H)-pyrimidinone: General Procedure for mixed
anhydride coupling - Isobutyl chloroformate (32 ml, 0.24
mmol) was added dropwise to a -20-30 oC solution of N-a-
t-Boc-glycine (5.6 mg, 0.05 mmol) and pyridine (0.6 mL).
After 20 min at -20-30°C, 5-(4-fluorophenyl)-3-methyl-2-
((3-phenylpropyl)-amino)-6-(4-(2-amino)pyridyl))-4(3H)-
pyrimidinone (11 mg, 0.026 mmol) and pyridine (0.6 mL)
was added in one portion. The reaction was allowed to
warm to 23°C. After 16 h at 23°C, the reaction was
poured into saturated bicarbonate (20 mL), extracted
with ethyl acetate (2 x 50 mL), washed with brine (1 x
50 mL), and dried (Na2S04). The reaction mixture was
applied to purification via flash chromatography (step
gradient l~MeOH:CHC13 then 2~~, then 3~; then 4~; then
5~) to afford the N-Boc protected title compound. The
crude title compound was obtained after treatment with
50~ trifluoroacetic acid:chloroform (1 mL) for 16 h.
After concentration with a stream of nitrogen, the
reaction mixture was applied to purification via flash
chromatography (step gradient l~MeOH:CHC13 then 2~, then
3~e; then 4~; then 5~) to afford the title compound: MS
;m ~~) : 487 (M+H)+.
' ~ N
- H
R'~ - H
R" - NH { CO ) CHZNH2
4-14 5-(4-Fluoroohenyl)-3-methyl-2-((3-phenvlpropyl)-
amino)-6-(4-(2-(4'amino-1'-oxo-butylamino)pyridyl))-
4(3H)-pvrimidinone: The reaction was done in the manner
of the above with the following substitution: N-t-Boc-g
- aminobutyric acid was used in place of N-a-t-Boc-glycine
which after deprotection as above afforded the title
compound: MS (m/z): 515 (M+H)+

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N~ _
R - H
R'2 - H
R31 - NH ( CO ) CHZCHzCHZNH2
4-15 5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-
amino)-6-(4-(2-(3'-amino-1'-oxo-propylamino)pyridyl))-
4(3H)--pyrimidinone: The reaction was done in the manner
of tY~e above with the following substitution: N-t-Boc-~i-
alanine was used in place of N-o~-t-Boc-glycine which -
afterdeprotection as above afforded the title compound:
MS (m/z): 501 (M+H)+:
v
R~ - I H
R'2 - H
R'1 - NH ( CO ) CH2CHZNH2
-16 2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-(2-aminopyridyl))-4(3H)-
pyrimidinone hydrochloride: The reaction was done at
190°C for 6 h in the above manner with the following
substitution of (S)-1, 2-diamino-3-phenylpropane for
3-phenyl-1-propylamine: MS (m/z): 445 (M+H)+;
i
i ~ ~ N
R - H
NH2
2 0 R,~ - H -
R'2 - H
4-17 2-(((S)-2-Dimethylamino-3-phenylpropyl)-amino)-5-
(4-fluorophenvl)-3-methyl-6-(4-(2-aminopvridyl))-4(3H)-
pyrimidinone hydrochloride: The reaction was done at
190°C for 6 h in the above manner with the following
substitution of 1-amino- 2(S)-dirnethylamino-3-
phenylpropane for 3-phenyl-1-propylamine: MS (~m/z): 473
(M+H) +;

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N/
R~ = I I H
/ N
R'2 - H
- Rsi _ H
4-18 2-(((S)-2-Dimethvlamino-3-phenvlpropvl) amino) 5
- 5 (4-fluorophenyl)-3-methyl-6-(4-(2-acetamidopyridyl))
4(3H)-pyrimidinone hydrochloride: The reaction was done
in the manner of example XX substituting 2-(((S)-2-
Dimethylamino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-
3-methyl-6-(4-(2-aminopyridyl))-4(3H)-pyrimidinone
hydrochloride for 5-(4-Fluorophenyl)-3-methyl-2-((3-
phenylpropyl)-amino)-6-(4-(2-amino)pyridyl))-4(3H)-
pyrimidinone which afforded the title compound: MS
(m/z): 515 (M+H)+;
N/
R~ = I ~ H
/
R'z - H
R'1 - Ac
4-19 2-(((R,S)-3-Amino-3-phenvlpropvl)-amino)-5-(4-
fluorophenvl)-3-methyl-6-(4-(2-aminopyridvl)) 4(3H)=
pyrimidinone hydrochloride~ The reaction was done at
190°C for 12 h in the above manner with the following
substitution of (3 R,S)-1,3-diamino-3-phenylpropane for
3-phenyl-1-propylamine: MS (m/z): 445 (M+H)+;
NH2 _
~ N~
H
R~ _ /
Rsz - H
R'1 - H
4-20 5-(4-Fluorophenvl)-3-methyl-2-(phenvlmethvlamino)
6-(4-(2-(3'-phenyl-1'-oxo-propvlamino)pvridvl)) (4 (2
amino)pvridvl))-413H)-pyrimidinone: A neat mixture of
5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-(2-
-acetamido)pyridyl))-4(3H)-pyrimidinone (260 mg, 0.13

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120
mmol) and benzylamine (88 mg, 2.71 mmol} was warmed to
190 C for 17 h. After cooling to 23 C, the reaction
mixture was applied directly to purification via flash
chromatography {step gradient l~MeOH:CHC13 then 2~, then
3~; then 4~; then 5~) to afford 5-(4-Fluorophenyl)-3-
methyl-2-(phenylmethylamino)-6-{4-(2-amino)pyridyl))-
4(3H)-pyrimidinone. The 5-(4-fluorophenyl)-3-methyl-2-
(phenylmethylamino)-6-(4-(2-amino)pyridyl))-4(3H)-
pyrimidinone was converted in the manner of the above
substituting hydrocinnamoyl chloride for acetyl chloride
and 5-(4-fluorophenyl)-3-methyl-2-(phenylmethylamino)-6-
(4-(2-amino)pyridyl})-4(3H)-pyrimidinone for 5-(4-
fluorophenyl)-3-methyl-2-((3-phenylpropyl)-amino)-6-(4-
(2-amino)pyridyl))-4(3H)-pyrimidinone to afford the
title compound after chromatography: MS (m/z) 534
(M+H)+.
R1 - NHCHZPh
R'2 - H
R'1 - ( CO ) CH2CHzPh
Example 5
General procedure for the preparation of
5-(4-fluorophenyl)-6-(4-pyridyl)-2-thioalkyl-4(3H)
pyrimidinones
Step A. Ethvl 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl)-
propionate:
F
0
OEt ~ OEt
F ~ 0 N
----
OEt N /
(According to: Legrand and Lozac~h, Bul~. Soc. Chim. _
Fr., 79-81 (1955)).
A mixture of ethyl 4-fluorophenylacetate (13 g,
71.35 mmol), ethyl isonicotinate (10.7 ml, 71.4 mmol)
and sodium spheres (1.64 g, 71.34 mmol) was heated at
90-95°C under argon. The mixture started to reflux and

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gradually turned into a solid. After 2.5 h, the mixture
was neutralized with dil. acetic acid with cooling
followed by extraction with dichloromethane. The
organic solution was washed with water, dried and
evaporated. Flash chromatography on a column of silica
gel (hexane-acetone = 4:1, 3:1, 2:1) provided the title
compound as an oil . MS (m/z) : 287 . 8 (M+H) i; C16H1aFN03
requir. 287.3 1H-NMR (CDC13), (ketone . mole = 1 .
0.33): d 13.50 (s, 0.3H, OH-E), 8.81 (m, 2H, Pyrid.-K),
8.48 (m, 0.66 H, Pyrid.-E), 7.72 (m, 2H, Pyrid.-K), 7.38
(m, 2H, PhF-K), 7.14-7.04 (m, 2H, PhF-K; ~0.65H, Pyrid.-
E; -0.65H, PhF-E), 6.96 (t, 0.64H, PhF-E), 5.51 (s, 1H,
CH-K), 4.23-4.2- (m, CHz-K, E), 1.26 (t, CHI-K, E).
Step B. 5-(4-fluoronhenyl)-6-(4-pyridyl)-2-thiouracil-
F H2N F
~S
OEt H2N NH
~SH
A stirred mixture of ethyl 2-(4-fluorophenyl)-3-
oxo-3-(4-pyridyl)-propionate (22.3 g, 77.6 mmol) and
thiourea (5.9 g, 77.6 mmol) was reacted at 190°C under
argon for 40 min. The reaction mixture was allowed to
reach room temperature, taken up in acetone and the
precipitate was filtered to provide the title compound.
MS ( m/z ) : 3 0 0 . 2 (M+H ) '; C15H1oFN30S requir . 2 9 9 . 3 1H-NMR
(DMSO-d6): d 12.74, 12.65 (2s, 2H), 8.51 (m, 2H,
Pyrid.), 7.26 (m, 2H, Pyrid.), 7.09 and 7.03 (2m, each
2H, PhF).
Alternatively, ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-
pyridyl)-propionate (2.87 g, 10 mmol) and thiourea (2.28
g, 30 mmol) were suspended in anhydrous p-xylene (50 ml)
with very efficient stirring. To the mixture pyridinium
p-toluenesulfonate (100 mg) was added and refluxed for
12-16 h using a Dean-Stark apparatus with continuous
removal of water (0.2 ml). Reaction mixture was cooled

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and a dark brown solid was filtered using a Buchner
funnel. The collected solid. was suspended in acetone
(25 ml) and filtered. The acetone washed product
contained a trace of thiourea, which was removed by
trituration with hot water (20-30 ml). The product was
filtered and airdried.
Step C. General procedure:
The arylalkyl bromide (0.36 mmol) was added
dropwise to a stirring mixture of 5-(4-fluorophenyl)-6-
(4-pyridyl)-2-thiouracil (100 mg, 0.33 mmol) and
potassium carbonate (46 mg, 0.33 mmol) in N,N-
dimethylformamide (4.6 ml). Stirring was continued for
3h followed by evaporation. Flash chromatography on a
column of silica gel (hexane-acetone = 3:1, 2:1, 1:1)
and recrystallization from hot methanol provided the
target compound.
The following compounds were obtained using the
appropriate arylalkyl bromide according to the above
procedure:
5-1 5-(4-Fluorophenyl)-2-(2-phenylethyl)thio-6-(4-
pyridyl) -4 (3H) -pyrimidinone: MS (m/z) : 404.2 (M+H)';
C23H18FN30S requir. 403.4. 1H-NMR (DMSO-ds) : d 13.08 (bs,
0.7H), 8.49 (m, 2H, Pyrid.), 7.30-7.06 (m, 11H, Pyrid.,
Ph, PhF), 3.41 (dd, 2H, CH2S), 3.00 (t, 2H, CH2).
R1- I
'
5-2 5-(4-Fluorophenyl)-2-(3-phenvlpropvl)thio-6-f4-
pyridyl)-4(3H)-pyrimidinone: MS (m/z): 418.0 (M+H).';
C24HZOFN30S requir . 417 . 5 . 1H-NMR ( DMSO-ds ) : d 13 . 10 (bs ,
0.7H), 8.47 (m, 2H, Pyrid.), 7.29-7.06 (m, 11H, Pyrid., Ph,
PhF), 3.18 (t, 2H, CHZS), 2.71 (t, 2H, CHZPh), 2.03 (m, 2H,
CHz ) .
_ S~
R~ - I

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5-3 5-(4-Fluoronhenyl)-2-(2-phenoxyethvl)thio-6-(4-
pyridyl,Z 4 (3H) -pyrimidinone: MS (m/z) : 420. 0 (M+H)~;
Cz3H1eFN302S requir . 419 . 5 . 1H-NMR ( DMSO-ds ) : d 13 . 2 0 ( bs ,
0.7H), 8.46 (m, 2H, Pyrid.), 7.24-7.07 (m, 8H, Pyrid.,
PhF, Ph), 6.95 (d, 2H, Ph), 6.92 (t, overlapped, 1H,
Ph) , 4.30 (t, 2H,_ CHzO) , 3.58 (t, 2H, CHzS) .
o~ ~
R~ -
5-4 5-(4-Fluorophenyl)-2-(2-phenylaminoethvl)thio-6-(4-
pyridyl)-4(3H)-pyrimidinone: MS (m/z): 419.0 (M+H)';
C23H19FNaOS requir . 418 : 5 . 1H-NMR ( DMSO-d6 ) : d 13 . 2 0 ( bs ,
0.8H), 8.48, 7.22 (2m, each 2H, Pyrid.), 7.16, 7.10 (2m,
each 2H, PhF), 6.89 (t, 2H, Ph), 6.54 (d, 2H, Ph), 6.48 (t,
1H, Ph), 5.90 (bs, 0.6H, NH), 3.43-3.25 (m, 2CH2).
H
N~S~
R - I
Example 6
General procedure for the preparation of 2-N substituted
2-amino-5- (4-fluorophenyl ) -6- (4-pyridyl ) -4 (3H)
pyrimidinones:
Step A. 5-(4-Fluorophenyl)-2-methylthio-6-(4-pyridyl)-
4 ( 3H) -pyrimidinone
F F
NH
SH
~SCH3
Methyl iodide (90 ml, 1.44 mmol) was added dropwise
to a stirred mixture of 5-(4-fluorophenyl)-6-(4-
pyridyl)-2-thiouracil (430 mg, 1.44 mmol) and potassium
carbonate (198 mg, 1.43 mmol) in N,N-dimethylformamide
(13 ml) at ice-bath temperature. After 40 min, it was
evaporated and the crude product purified by flash
chromatography on a column of silica gel (hexane-acetone

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- 2:1, 1:1, 1:2) to provide the title compound as a
solid. MS (m/z) : 314.2 (M+H)'; C16H1zFN30S requir. 313 .3 .
1H-NMR (DMSO-db): d 13.10 (bs), 8.47, 7.22 (2m, each 2H,
Pyrid.), 7.16, 7.10 (2m, each 2H, PhF), 2.56 (s, 3H,
CH3 ) .
Step B. General procedure'
F F
NH
SCH3 ~NR5R21
A mixture of 5-(4-fluorophenyl)-2-methylthio-6-(4-
pyridyl)-4(3H)-pyrimidinone (100 mg, 0.32 mmol) and an
amine HNR'R2' (1 mmol) was heated at 180°C for 2 h. The
resulting product was purified by flash chromatography
on a column of silica gel (hexane-acetone or methanol-
dichloromethane or dichloromethane-methanol-conc.
ammonium hydroxide) to provide the target compound.
The following compounds were prepared using the
general procedure outlined above and an appropriate
amine:
6-1 2-(2-(2-Chlorophenyl)ethyl-amino)-5-(4-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone: MS
(m/z) : 421 .2 (M+H) ~; C23H18C1FNa0 requir. 420 . 9 . 1H-NMR
(DMSO-d6): d 11.24 (bs), 8.44, 7.16 (2m, each 2H,
Pyrid.), 7.43, 7.38 (2dd, each 1H, PhCl), 7.30, 7.26
(2dt, each 1H, PhCl), 7.10-7.00 (m, 2H, PhF), 6.74 (bs,
1H, NH), 3.60 {q, 2H, CH2N), 3.03 (t, 2H, CHZ).
H
N~
R1 -
2 5 ~ C1
6-2 5-(4-Fluorophenyl)-2-((3-phenylpropyl)-amino) 6 (4
pyridvl) -4 (3H) -pyrimidinone: MS (m/z) : 401.2 (M+H)';
CzaH21FNa0 requir . 4 0 0 . 5 . 1H-NMR ( DMSO-d6 ) : d 11.16 ( bs ) ,
8.44, 7.14 (2m, each 2H, Pyrid.), 7.32-7.01 (m, 9H, Ph,

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PhF), 6.78 (bs, NH), 3.36 (q, 2H, CHZN), 2.67 (t, 2H,
CH2Ph) , 1.89 (m, 2H, CHZ) .
- ~ i
Rl - I v v H
. /
6-3 5-(4-Fluorophenyl)-2-((1-methyl-3-phenylpropyl)-
amino)-6-(4-pvridvl)-4(3H)-pvrimidinone: A reaction
time of 15 h at 180_ C was required. MS (mlz): 415.0
( M+H ) ' ; CZSHZ~FN40 requir . 414 . 5 . 1H-NMR ( CDC 13 ) : d 8 . 4 8
(m, 2H, Pyrid.), 7.28-7.08 (m, 9H, Pyrid., Ph, PhF),
6.94 (m, 2H, PhF), 5.67 (bs, 1H, NH), 4.08 (m, 1H,
CHCH~), 2.61 (t, 2H, CHzPh), 1.67 (m, 2H, CHZ), 1.08 (d,
3H, CHI ) .
CH3
i
1 ~ N
R - ~ H
6-4 5-(4-Fluorophenyl)-2-((3-imidazolylpropyl)-amino)-
6-(4-pyridyl)-4(3H)-pyrimidinone: MS (m/z): 391.0
( M+H ) ' ; CZ1H19FN60 requir . 3 9 0 . 4 . 1H-NMR ( DMSO-db ) : d 11. 2 4
(bs), 8.42, 7.12 (2m, each 2H, Pyrid.), 7.62, 7.18 (2s,
each 1H, Imid.), 7.08-6.99 (m, 4H, PhF), 6.88 (s, 1H,
Imid.), 4.02 (t, 2H, CHZN), 3.28 (overlapped by water
signal, CHZNH) , 2.00 (m, 2H, CHz) .
R~ - ~N~N~
N' H
6-5 2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4=
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: The reaction was done at 170°C for 7 h.
MS (m/z): 416.1 (M+H)+; C26H22FN50 requir. 415.5.
Ri _ / I N/
' NH2 H

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Example 7
5- (4-Fluorophenyl) -2-hydrazino-6- (4-pyridyl) -4 (3H) -
pyrimidinone
A mixture of 5-(4-fluorophenyl)-6-(4-pyridyl)-2-
thiouracil (500 mg, 1.66 mmol) and hydrazine hydrate
(800 ml, ~14 mmol) was heated at 120°C for 60 min. It
was evaporated and the reaction product was
recrystallized from hot methanol to provide the title
compound. MS (m/z) : 298.0 (M+H)~; C15H1zFN50 requir.
297.3. 1H-NMR (DMSO-d6): d 8.41, 7.12 (2m, each 2H,
Pyrid.), 7.05, 7.00 (2m, each 2H, PhF).
R1 = NH-NHZ
Example 8
General procedure for the preparation of 5-aryl-2,6-
dipyridyl- (3H) -pyrimidinones
s-i
H /
I O
/ CN H ~ ~
2 N~~ + I / O ~ ~ NH
OEt N~ ~N
J iN
8-2
F
r/ CN F
2 N~~ + ( / O
~/
OEt
N J ~~ N
8-3 N ,
O
/ CN N ~ O
2 N~ + I / ~ ~ NH
OEt I ~ N
N / ~N
8_4 F
~~CN F ~ _
+ ~ / O
N OEt

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These compounds were prepared according to_the
literature (Kabbe, supra; German Patent 1271116 (1968))
- as follows:
A stirred mixture of the ethyl phenylacetate (3.13
mmol), cyanopyridine (6.24 mmol) and sodium methoxide
(3.5 mmol) in n-butanol (1.2 ml) was heated at 110°C for
' 2h. The reaction mixture was concentrated and dissolved
in water (4 ml), followed by the addition of aqueous
sat. ammonium chloride (2 ml). The precipitate was
filtered and recrystallized from hot methanol.
The following compounds were prepared according to
this procedure using the appropriate starting materials:
8-1 5-Phenvl-2,6-bis-(4-pyridyl)-4-(3H)pyrimidinone: MS
(m/z) : 327.2 (M+H)~; C2oH1aN40 requir. 326.4. 1H-NMR (DMSO-
ds): d 8.78, 8.47, 8.13 (3m, each 2H, Pyrid.), 7.40-7.14
(m, 7H, Ph, Pyrid.).
8-2 5-(4-Fluorophenvl)-2,6-bis-(4-pyridvl)-4(3H)=
pyrimidinone : MS (m/z) : 345 . 2 (M+H) r; CzoH13F1Va0 requir .
344.4 1H-NMR (DMSO-d6): d 8.80, 8.49, 8.13 (3m, each 2H,
Pyrid.), 7.40-7.08 (m, 6H, PhF, Pyrid.).
8-3 2,5,6-Tris-l4-pyridyl)-4(3H)-pyrimidinone was
prepared according to the general procedure by reacting
ethyl 4-pyridylacetate and 4-cyanopyridine in the
presence of sodium methoxide. MS (m/z): 328.2 (M+H)';
C19H~~N50 requir. 327.4 1H-NMR (DMSO-db) : 8.65, 8.45, 8.35,
8.18, 7.25, 7.13 (6m, each 2H, Pyrid.).
8-4 5-(4-Fluorophenyl)-2,6-bis-(3-pvridvl)-4(3H~=
pyrimidinone: MS (m/z) : 345.2 (M+H)~; C2oH13FN,0 requir.
344.4 1H-NMR (DMSO-ds): d 9.34, 8.77, 8.54, 8.48, 7.78,
7.60, 7.34 (7m, 3xlH, 2H, 3xlH, Pyrid.), 7.26, 7.15 (2m,
each 2H, PhF).

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Example 9
3- (3-trimethylsilyl-2-propynyl) -5- (4-fluorophenyl) -2
methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone
F
~\~~ TMS
SMe
The preparation of the tile compound was carried
out in the same manner as 3-ethyl-5-(4-fluorophenyl)-2-
methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone with the
following substitution: 3-bromo-1-(trimethylsilyl)-1-
propyne was used in place of ethyl bromide.
Example 10
6-(4-Fluorophenyl)-2-methyl-1-(3-phenylpropyl)-7
pyridin-4-y1-1H-imidazo(1,2-a)pyrimidin-5-one
F
N
--N
Ph
A neat mixture of 3-(3-trimethylsilyl-2-propynyl)-
5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-
pyrimidinone (50 mg, 0.12 mmol) and 3-phenyl-1-
propylamine (67 mg, 0.47 mmol) was warmed to 190°C for
17 h. After cooling to 23°C, the reaction mixture was
applied directly to purification via flash
chromatography (step gradient l~MeOH:CHC13 then 2~, then
3~; ) to afford the desired product: MS (m/z) 439
(M+H)+.

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Example 11
6-(4-Fluorophenyl)-2-methyl-1-benzyl-7-pyridin-4-yl-1H
- imidazo(1,2-a)pyrimidin-5-one
F ~ I. o
\ ~N~
I \ N~N
N J '~" Ph
The preparation of the title compound was carried
out in the same manner as 6-(4-Fluorophenyl)-2-methyl-1-
(3-phenyl propyl)-7-pyridin-4-yl-1H-imidazo(1,2-
a)pyrimidin-5-one with the following substitution:
benzylamine for 3-phenyl-1-propylamine; MS (mlz): 411
(M+H)+.
Example 12
General procedure for the preparation of 6-substituted
3-phenyl-4- (4-pyridyl) -2 (1H) -pyridones
Step A. General procedure for the preparation of 1-
aryl-3-(4-pyridyl)-2-propene-1-one
H O
I \ O + O ~ ' Rl
N / ~R1 N
At ice-bath temperature, piperidine (206 ml),
acetic acid (206 ml) and 4-pyridinecarboxaldehyde (1.6
mi, 16.6 mmol) were mixed. Then the acetophenone (12.0
mmol) was added at rom temperature and the mixture was
heated at 130°C for 1.5 h. The reaction mixture was
diluted with dichloromethane, washed with aqueous sodium
hydrogencarbonate and water followed by drying and
evaporation. The crude product was purified by column
chromatography on silica gel (hexane-acetone = 3:1).
The following compounds were prepared according to
this procedure using the apropriate acetophenone
derivative:
1-Phenyl-3-(4-pyridyl)-2-propene-1-one: MS (m/z): 210.1
(M+H)'; ClaHiiNO requir. 209.3.

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1-(4-Methylphenyl)-3-(4-pyridyl)-2-propene-1-one_: MS -
(m/z) : 224.2 (M+H)'; C15H13N0 requir. 223 .3 .
1-(4-Ethylphenyl)-3-(4-pyridyl}-2-propene-1-one: MS
(m/z) : 237.8 (M+H)'; C16H15N0 requir. 237.3 .
1-(4-Isopropylphenyl)-3-(4-pyridyl)-2-propene-1-one: MS
(m/z) : 252.0 (M+H)'; C1~H1~N0 requir. 251.3 .
1-(2-Methylphenyl)-3-(4-pyridyl)-3-propene-1-one: MS
(m/z) : 223 . 8 (M+H)'; C15H13N0 requir. 223 .3 .
1-(2,4-Dimethylphenyl)-3-(4-pyridyl)-2-propene-1-one: MS
(mlz) : 238. 0 (M+H)'; C16H15N0 requir. 237.3 . _
1-(2-Methoxyphenyl)-3-(4-pyridyl)-2-propene-1-one: MS
(m/z) : 240.0 (M+H)'; C15H13N02 requir._ 239.3
1-(4-Chlorophenyl}-3-(4-pyridyl)-2-propene-1-one: MS
(m/z) : 244. 0 (M+H)'; ClaHIOCINO requir. 243 :7.
1-(4-Cyanophenyl)-3-(4-pyridyl)-2-propene-1-one: MS
(mlz) : 235.1 (M+H)'; C15H1oN20 requir. 234.3 .
1-(a-Naphthyl)-3-(4-pyridyl)-2-propene-1-one: MS (m/z):
260.0 (M+H)'; C18H13N0 requir. 259.3.
1,3-Bis-(4-pyridyl)-2-propene-1-one: MS (m/z): 211.0
(M+H)': C13H1oNZ0 requir. 210.2.
3-(4-Pyridy-1-(2-thienyl)-2-propene-1-one: MS (m/z):
216. 0 (M+H)'; ClzH9NOS requir. 215.3.
1-(2-Furyl-3-(4-pyridyl)-2-propene-1-one: MS (mlz):
200.0 (M+H)'; C12H9N02 requir. 199.2.
1-Cyclohexyl-3-(4-pyridyl)-2-propene-1-one was prepared
in the same way using acetylcyclohexane: MS (m/z):
216.2 (M+H)'; C14H1~N0 requir. 215.3.
1-tert-Butyl-3-(4-pyridyl)-2-propene-1-one: A mixture of
3,3-dimethyl-2-butanone (2.5 ml, 20.0 mmol), 4-
pyridinecarboxaldehyde (2.15 ml, 22.3 mmol), ethanol
(7.6 ml), and 4.5~ aqueous sodium hydroxide (4.6 ml) was
kept at room temperature for 12 h. It was diluted with
dichloromethane, washed with aqueous hydrochloric acid
and water, dried and evaporated. Subsequent column
chromatography (hexane - ethyl acetate = 3:1) provided
the title compound. MS (m/z) : 190.4 (M+H)'; C1zH15N0
requir.189.3.

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Step B. General procedure for the preparation of 6-
substituted 3-phenyl-4-(4-pyridyl)-2(1H)-pyridones:
- O
\ \ Ri
NJ
1 1
\ NH2 R
I I
/ O -
Sodium (40 mg, 1.74 mmol) was dissolved in a
stirring mixture of phenylacetamide (880 mg, 6.51 mmol)
and ethanol (5m1). If solubility allowed, the 1-
substituted 3-(4-pyridyl)-2-propene-1-one (5.4 mmol) was
added portionwise as an ethanolic solution (20 ml) to
the refluxing phenylacetamide solution or it was added
at room temperature as a solid. The mixture was kept
under reflux for 1.5 h and was then allowed to reach
room temperature. 2N Hydrochloric acid was added to a
pH value of 5 followed by the addition of a few ml of
water. The product that crystallized from this mixture
was filtered, washed subsequently with ethanol, water,
ethanol and recrystallized from methanol. If the
product did not crystallize from the reaction mixture on
addition of hydrochloric acid, then the mixture was
evaporated and the remainder taken up in
dichloromethane. The organic solution was washed with
water, dried and evaporated. The resultant product was
crystallized from hot acetone and recrystallized from
methanol.
The following compounds were prepared according to
this procedure using the 2-(4-pyridyl)-2-propene-1-one
derivatives described in Example 12.a:
- 12-1 3,6-Diphenvl-4-(4-pyridyl)-2(1H)-pyridone: MS
(m/z) : 325.4 (M+H)~; CZZH16Nz0 requir. 324.4. 1H-NMR (DMSO-
d6): d 8.63 (m, 2H, Pyrid.), 7.86 (m, 2H), 7.58-7.45,
7.29-7.08 (2m).

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R~ - I \ /
12-2 6-(4-Methylphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-
pyridone: MS (m/z) : 339.2 (M+H)'; Cz3H18N20 requir. 338.4.
1H-NMR (DMSO-d6): d 8.44 (m, 2H, Pyrid.), 7.79 (d, 2H),
7.32 (d, 2H), 7.26-7.01 (m, 7H, Ph, Pyrid.), 6.67 (bs,
1H ) .
R~ ~ /
H3C
12-3 6-(4-Ethvlphenvl)-3-phenyl-4-(4-pvridvl)-2(1H)-
pyridone: MS (m/z) : 353.0 (M+H)'; CZ9HzoN20 requir. 352.4.
1H-NMR (DMSO-db): d 8.42 (m, 2H, Pyrid.), 7.79 (d, 2H),
7.33 (d, 2H), 7.24-7.06 (m, 7H, Ph, Pyrid.), 6.65 (bs,
1H, CH=), 2.66 (q, 2H, CHZ), 1.21 (t, 3H, CH3).
R1 -
Et
12-4 6-(4-Isopropylphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-
pyridone: MS (m/z) : 367.0 (M+H)'; CZSHZZN20 requir. 366.5.
iH-NMR (DMSO-d6): d 8.45 (m, 2H, Pyrid.), 7.82 (d, 2H),
7.39 (d, 2H), 7.28-7.10 (m, 7H, Ph, Pyrid.), 6.67 (bs,
1H. CH=), 2.98 (m, 1H, CH(CH3)2), 1.27, 1.25 (2s, each
3H, 2CH3) .
i
Rl - H3C
2 0 H3C
12-5 6-(2-Methylphenvl)-3-phenyl-4-(4-pvridvl)-2(1H)-
pyridone: MS (m/z) : 339.2 {M+H)'; C23H18N20 requir. 338.4.
1H-NMR {DMSO-ds): d 8.40 (m, 2H, Pyrid.), 7.45-7.09 (m,
11H, Ph, Pyrid.), 6.21 (bs, 1H, CH=), 2.39 (s, 3H, CH3).
R1 _ I
2 5 \ CH3
12-6 ~2,4-Dimethvlphenyl)-3-phenyl-4-(4-twridyl)-
2 (1H) -pyridone: MS (m/z) : 353 . 0 (M+H)'; C24HZON20 requir.
352.4. 1H-NMR (DMSO-ds): d 8.42 (m, 2H, Pyrid.), 7.29

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(d, 1H), 7.23-7.06 (m, 9H, Ph, Pyrid.), 6.17 (bs, 1H,
CH=), 2.34, 2.31 (2s, each 3H, 2CH3).
R~ - I ~
HOC CH3
12-7 6-(2-Methoxyphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-
pyridone: MS (m/z) : 355.0 (M+H)'; Cz3H18NzO2 requir. 354.4.
1H-NNiR (DMSO-db) : d 8.41 (m, 2H, Pyrid. ) , 7.49 (bd, 1H) ,
7.44 (m, 1H), 7.24-7.06 (m, 8H, Ph, Pyrid.), 7.02 (dt,
1H), 6.32 (bs, 1H, CH=), 3.82 (s, 3H, CH3).
R1 _ I
OCH~
12-8 6-(4-Chlorophenyl)-3-phenyl-4-(4-pvridvl)-2(1H
pyridone: MS (m/z) : 359.2 (M+H)'; Cz2H15C1N20 requir.
358.8. 'H-NMR (DMSO-db): d 8.42 (m, 2H, Pyrid.), 7.93
(bd, 2H), 7.54 (m, 2H), 7.26-7.08 (m, 7H, Ph, Pyrid.),
6.80 (bs, 1H, CH=).
R' -
Cl
12-9 6-(4-Cyanophenyl)-3-phenyl-4-(4-pyridyl)-2(1HL
pyridone: MS (m/z) : 350.2 (M+H)+; C23H15N30 requir. 349.4.
1H-NMR (DMSO-db): d 8.45 (m, 2H, Pyrid.), 8.16 (bd, 2H),
7.98 (d, 2H), 7.32-7.00 (m, 8H, Ph, Pyrid., CH=).
R' -
2 0 NC
12-10 6-(a-Naphthvl)-3-phenyl-4-(4-pvridyl)-2(1H)-
pyridone: MS (m/z) : 375.0 (M+H)'; CZ6H18N20 requir. 374.5.
1H-NMR (DMSO-ds): d 8.38 (m, 2H, Pyrid.), 8.06-7.98 (m,
3H), 7.67 (dd, 1H), 7.62-7.54 (m, 3H), 7.25-7.11 (m, 7H,
Ph, Pyrid.), 6.38 (bs, 1H, CH=).
R1- ~ I
12-11 3-Phenyl-4,6-bis-(4-pvridvl)-2(1H)-~vridone~
MS (m/z) : 326.0 (M+H)'; CZIH1sN30 requir. 325.4. 1H-NMR

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134 '
(DMSO-ds: d 8.69, 8.43 (2m, each 2H, Pyrid.), 7.92 (bs,
2H), 7.28-7.05 (m, 8H).
R1
N
12-12 3-Phenyl-4-(4-pyridyl)-6-(2-thienyl)-2(1H)
pyridone: MS (m/z) : 331.0 (M+H)'; CzoH1aN20S requir. 330.4.
1H-NMR (DMSO-ds): d 8.44 (m, 2H, Pyrid.), 7.90, 7.70
(2bd, each 1H), 7.28-7.08 (m, 9H).
S
R~ ~ /\
12-13 6-(2-Furyl)-3-phenyl-4-(4-pyridvl)-2(1H
pyridone: MS (m/z) : 315.0 (M+H)'; CzoH1aN202 requir. 314.4.
1H-NMR (DMSO-ds): d 8.44 (m, 2H, Pyrid.), 7.90 (s, 1H),
7.43 {bs, 1H), 7.27-7.08 (m, 7H, Ph, Pyrid.), 6.71 (m,
2H).
RI - I O\-
12-14 6-Cvclohexvl-3-phenyl-4-(4-pvridvl)-2(1H)-
pyridone: MS (m/z) : 331.2 (M+H)'; CZZHZZN20 requir. 330.4.
1H-NMR (DMSO-d6): d 8.40 (m, 2H, Pyrid.), 7.22-7.13,
7.10-7.03 (2m, 7H, Ph, Pyrid.), 6.04 (bs, 1H, CH=),
1.95-1.15 (m, 11H, cyclohex.).
R' -
'12-15 6-tent-Butyl-3-phenyl-4-(4-pyridyl)-2(1H)-
pyridone: MS (m/z) : 305. 0 (M+H)'; CzoHzoN20 requir. 304.4.
1H-NMR (DMSO-ds): d 8.39 (m, 2H, Pyrid.), 7.20-7.12,
7.10-7.02 (2m, 7H, Ph, Pyrid.), 6.02 (bs, 1H, CH=), 1.31
(s, 9H, 3CH3) .
Rl - ( CH3 ) 3C-

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Example 13
Procedure for the preparation of (S)-2,2
Benzylethylendiamine
NH2
NH2
- 5 (S)-1,2-Benzvlethylendiamine: The diamine was prepared
according to the literature (H. Brunner, P. Hankofer, U.
Holzinger, B. Treittinger and H. Schoenenberger, Eur. J.
Med. Chem. 25, 35-44, (1990)) by reduction of L-
phenylalanine amide with lithium aluminium hydride. The
(R)-enantiomer was prepared in the same manner from D-
phenylalanine amide.
Example 14
Procedure for the preparation of 2-(((S)-2-Acetamido-3
phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4
pyridyl ) -4 (3H) -pyrimidinone
F ~ O F /
O
\ I N/ \ I N/
I I
J. \ -.,.~ J~ \
N H __ ( / ~ \ N N _ I /
N / NHz N / H NHAc
2-(((S)-2-Acetamido-3-phenvlpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pvrimidinone:
A solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone (25 mg, 0.058 mmol) and acetic anhydride
(200 ml) in methanol (2 ml) was kept at room temperature
for 1 h. Evaporation followed by chromatography of the
resultant product on a column of silica gel (10~
methanol/dichloromethane) provided the title compound.
MS (m/z): 472.3 (M+H)+; C27H26FN502 requir. 471.5.

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Example 15
Procedure for the preparation of 5-(4-Fluorophenyl)-2-
(((S)-2-N-isopropylamino-3-phenylpropyl)-amino)-3-
methyl-6- (4-pyridyl ) -4 (3H) -pyrimidinone hydrochloride
F F /
\ I 0 , \ I ON/
N
I
I \ I NJ~N I \ I \ N~N I /
N J H IVH ~ N / H NH
2
5-(4-Fluorophenyl)-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride~ Sodium
triacetoxyborohydride (23 mg, 0.109 mmol) was added to a
strirring mixture of 2-(((S)-2-amino-3-phenylpropyl)-
amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride (50 mg, 0.107 mmol),
triethylamine (15 ml, 0.108 mmol) and acetone (7.9 ml,
0.108 mmol) in 1,2-dichloroethane (0.8 ml). _ After 4h,
the reaction was quenched by the addition of sat. aqu.
sodium hydrogencarbo-nate, followed by extraction with
dichloromethane, drying of the organic solution and
evaporation. Chromatography on a column of silica gel
(10o methanol/chloroform) provided the title compound as
a free base which was converted into the
monohydrochloride by the addition of 4N hydrochloric
acid/dioxane (21 mml, 0.08 mmol) to its methanolic
solution (1 ml) and subsequent evaporation. MS (m/z):
472.1 (M+H)+; C28H30FN50 requir. 471.6 (free base).

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Example 16
Procedure for the preparation of 5-(4-Fluorophenyl)-2-
- (((S)-2-N-cyclohexylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride
F / O F / I O
\ I / \ N/
I N~N I \ ~.I \ I NON I \
I - ~ N / H NH
N J H NH2
5-(4-Fluorophenvl)-2-(((S)-2-N-cvclohexvlamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride: Utilizing cyclohexanone, 5-
(4-fluorophenyl)-2-(((S)-2-N-cyclohexylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone was prepared in the same manner as 5-(4-
fluorophenyl)-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone: MS (m/z): 511.6 (M)+; C31H34FN50 requir.
511.6 (free base).
Example 17
Procedure for the preparation of 2-(((S)-2-N-n
Butylamino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride
F ~ 0
F / O \ I N/
I
---~ I
\ I J' _ \ I \ NJ'N - I \
N N = ~ NJ H
N / H NH2
2-(((S)-2-N-n-Butylamino-3-phenvlpropvl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pvridvl)-4(3H)-pyrimidinone
hydrochloride: Sodium triacetoxyborohydride (28 mg,
0.13 mmol) was added to a strirring mixture of 2-(((S)-
2-amino-3-phenylpropyl)-amino}-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (41 mg, 0.095

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mmol) and butyraldehyde (8.5 ml, 0.094 mmol) in 1,2-
dichloroethane (0.8 ml). After 2 h, the reaction was
quenched by the addition of sat. aqu, sodium
hydrogencarbonate, followed by extraction with
dichloromethane, drying of the organic solution and
evaporation. Chromatography on a column of silica gel
(5~ methanol/chloroform) provided the title compound as
a free base which was converted into the
monohydrochloride by the addition of 4N hydrochloric
acid/dioxane (12 mml, 0.048 mmol) to its methanolic
solution (1 ml) and subsequent evaporation. MS (m/z):
486.2 (M+H)+; C2gH32FN50 requir. 485.6 (free base).
Example 18
Procedure for the preparation of (S)-2-N,N-
Dimethylamino-3-phenylpropylamine
O
O
\ H2N ~ \ H2N
H2N ~/ ~ --~ _- / ~ N
N
NH2
(S)-2-N,N-Dimethylamino-3-phenvlpropylamine: Sodium
triacetoxyhydride (13.0 g, 61.3 mmol) was added to a
stirring mixture of phenylalanine amide (3.6 g, 21.9
mmol) and 37~ formaldehyde solution (4.4 ml, 58.7 mmol)
in 1,2-dichloroethane (77 ml). After stirring for 2 h,
the reaction was quenched by the addition of sat. aqu.
sodium hydrogencarbonate. Then potassium hydroxide
pellets were added followed by extraction with
dichloromethane, drying of the organic solution and
evaporation. The resulting (S)-2-N,N-dimethylamino-3-
phenylpropylamide was reduced with lithium aluminium
hydride according to the literature (H. Brunner, P.
Hankofer, U. Holzinger, B. Treittinger and H. _
Schoenenberger, Eur. J. Med. Chem. 25, 35-44, (1990)) to
provide the title compound.

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Exaraple 19
Procedure for the preparation of 2-(((S)-2-N,N
Dimethylamino-3-phenylpropyl)-amino)-5-(4-fluorophenyl
3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride
_ F ~ I ~ ~ F ~I 0
I 'N \
I \ N~S~CH3 '~ \ I N~~~CHg
N J -
O
F
I ° \
\ I N/ H2N __
I \ N~N I \ /N\
H
NJ__ ~N~\
Step A. 5-(4-Fluorophenyl)-3-methyl-.2-methvlsulfonvl-6-
~4-pyridyl)-4(3H)-pyrimidinone: A mixture of 5-(4-
fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-4(3H)-
pyrimidinone (400 mg, 1.22 mmol) and OxoneR (potassium
peroxymonosulfate, 2.3 g, 3.74 mmol) in methanol (100
ml) and water (45 ml) was stirred for 13 h. The solvent
was concentrated to about 50 ml, followed by extraction
with dichloromethane, drying of the organic solution and
evaporation. The resulting white solid was used without
purification in the next step.
Step B. 2-(((S)-2-N N-Dimethvlamino-3-phenylpropvl)-
amino)-5-(4-fluoromhenyl-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride: A mixture of crude 5-(4-
fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-
4(3H)-pyrimidinone (430 mg g, 1.19 mmol) and (S)-2-N,N-
dimethylamino-3-phenylpropylamine (600 mml, ~3.4 mmol)
was stirred at room temperature for 1h and then briefly
0
warmed at 50 C. Column chromatography on silica gel (3-
5~ methanol/chloroform) provided the title compound as a
free base which was converted into the monohydrochloride
by the addition of 4N hydrochloric acid/dioxane (160
mml, 0.64 mmol) to its methanolic solution (4 ml) and

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subsequent evaporation. MS (m/z): 458.0 (M+H)+;
C27H28~50 requir. 457.5 (free base).
Example 20
5- (4-fluorophenyl) -&- (4- (2-acetami do) -pyridyl) -2-
thioalkyl-4 (3H) -pyrimidinones
Step A. Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4 (2
acetamido)-pyridyl))-propionate
A solution of 2-chloroisonicotinic acid (25.Og, 0.16
mol) in 65 mL of concentrated ammonium hydroxide was
warmed to 205 Celsius in a steel bomb for 72 h. After
cooling to 23 C, the solution was acidified to a pH of 1
using 6N HC1 and subsequently filtered to remove
unreacted starting material. The solution was
concentrated to one fourth the original volume (approx
200 mL) in vacuo, and carefully adjusted to a pH of 6
using 1 N NaOH. After storing the cloudy solution at 0
C for 20 h, the desired 2-aminoisonicotinic acid was
filtered off. To a suspension of 2-aminoisonicotinic
acid in ethanol (600 mL) was added 47.1 mL of 4 N
anhdrous HC1 in dioxane. After warming to achieve
reflux for 20 h, an additional 47.1 mL of 4 N anhdrous
HC1 in dioxane was added and the reaction was warmed to
reflux for an additional 20 h. Concentration with a
stream of nitrogen in the hood was followed by further
concentration in vacuo, the remaining solid was diluted
with saturated bicarbonate (200 mL), extracted with
ethyl acetate (2 x 200mL), dried (Na2S04). After
concentration in vacuo, the desired ethyl 2-
aminoisonicotinate was obtained. To a solution of ethyl
2-aminoisonicotinic acid in pyridine (45 mL) at 0 C
undr an argon atmosphere was added acetyl chloride
dropwise over 5 min. After 2 h at 0 C, the reaction was
pored into over ice 300 g, extracted with ethyl acetate
(2 x300 mL), washed with water (2 x100 ml) followed by
brine ( 2 x 100 mL), and dried (Na2S04). After
concentration in vacuo, the residue was purified by

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application of flash chromatography ( step gradient
ethyl acetate: hexane 1:4 then ethyl acetate: hexane
1:1) to afford ethyl 2-acetamidoisonicotinate.
To a solution of diisopropylamine (14.15 mL, 101
mmol) and THF (40 mL) at -78 C was added n-butyl
lithium (38.1 mL, 95 mmol) dropwise over 5 min. After
- 10 min, ethyl 4-fluorophenylacetate (17.3 g, 95 mmol)
was added in 40 mL of dry THF. After 10 min, ethyl 2-
acetamidoisonicotinate (6.0 g, 29 mmol) was added in 20
ml of dry THF. The reaction was allowed to warm to 23 G
overnight, and then acetic acid (95 mmol) was added in
one portion. The reaction was concentrated in vacuo,
then partitioned repeatedly between saturated
bicarbonate (200 ml) and ether (300 mL), the combined
bicarbonate layers were neutralized with 10~ citric
acid, and extracted with ethyl acetate (2 x 300 mL).
The organic layers were dried (Na2S04), concentrated in
vacuo to afford the Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-
(2-acetamido)-pyridyl)-propionate.
Step B. 5-(4-fluorophenyl)-6-(4-(2-acetamido)pyridyl))-
2-thiouracil:
Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2-
acetamido)pyridyl)-propionate (1.3 g, 3.78 mmol) and
thiourea (863 mg, 11.3 mmol) were suspended in
anhydrous p-xylene (15 ml) with very efficient stirring.
To the mixture pyridinium p-toluenesulfonate (38 mg) was
added and refluxed for 12-16 h using a Dean-Stark
apparatus with continuous removal of water (0.1 ml).
Reaction mixture was cooled and a dark brown solid was
filtered using a Buchner funnel. The collected solid
was suspended in acetone (25 ml) and filtered. The
acetone washed product contained a trace of thiourea,
- which was removed by trituration with hot water (20-30
ml). The product was filtered and air dried followed by
azeotroping with toluene.

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Example 21
Procedure for the preparation of (S)-2-N-Ethylamino-3-
phenylpropylamine
O
O
\ H2N __ ~ / H2N ~ \
H2N ~_ ~ / ~ O NH ~ - /
NH 2
~S)-2-N-Ethylamino-3-phenylpropylamine: Acetic
anhydride (1.2 ml, 12.7 mmol) was added to a stirring
solution of L-phenylalanine amide (1.0 g, 6.10 mmol) in
methanol (25 ml). After 1.5 h at room temperature, it
was evaporat-ed followed by drying in an oil pump vacuum.
The resultant L-N-ethylphenylalanine amide (6.1 mmol)
was reduced with lithium aluminium hydride (570 mg, 15.0
mmol ) in tetrahydrofuran ( 65 mml ) at 55°C for 4 h. The
reaction mixture was poured into sat. aqu. sodium
hydrogencarbonate followed by extraction with
dichloromethane, drying and evaporation. Column
chromatography on silica gel (chloroform . methanol .
triethylamine = 90:7:3) provided the amine as a
yellowish oil. MS (mlz): 179.1 (M+H)+; C11H18N2 requir.
178.3.
Exat~ple 22
Procedure for the preparation of 2-Amino-2-methyl-3-
phenylpropylamine
/~ 'NH2
/ NH2
2-Amino-2-methyl-3-phenylpropylamine: A solution of
commercially available D,L-a-methyl phenylalanine methyl
ester (5.0 g, 25.7 mmol) in aqu. 28~ ammonium hydroxide
(50 ml) was kept at room temperature for 3 d. The
resulting white precipitate of D,L-a-methyl
phenylalanine amide was filtered and dried (2.5 g).

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This material (2.0 g, 11.22 mmol) was reduced with
lithium aluminium hydride (1.3 g, 34.26 mmol) in boiling
tetrahydrofuran for 24 h. The reaction was quenched by
the addition of sodium sulfate decahydrate at ice-bath
temperature. The salts were filtered off, followed by
evaporation to leave the title compound as an oil. MS
(m/z): 165.1 (M+H)+; C1pH16N2 requir. 164.2. An
alternative preparation was reported by M. Freiberger
and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698
(1960).
Example 23
Procedure for the preparation of 2-Methyl-3-
phenylpropylamine
~NH2
/ CH3
2-Methyl-3-phenvlpropylamine: A mixture of commercially
available 2-methyl-3-phenylpropylamide (4.32 g, 26.5
mmol) and lithium aluminium hydride (1.3 g, 34.3 mmol)
in tetrahydrofuran (184 ml) was stirred at room
temperature for 5 h. It was poured into aqu. sat.
sodium sulfate and extracted with dichloromethane
followed by drying of the organic solution and
evaporation to provide the amine as an oil. Other
syntheses have been reported, e.g. Dornow and Fust,
Chem. Ber. 87, 984 (1954).

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Example 24
Procedure for the preparation of 5-(4-Fluorophenyl)-3
methyl-2-((2-methy-3-phenylpropyl) amino)-6-(4-pyridyl)
4 (3H) -pyrimidinone hydrochloride
F ~ O
\ I i
N O
N~S~CH3 F / 0
N / O \ I N/
+ --w ~\ ~ N~N ~\
H2N ~ NJ H CH
/ 3
CH3
5-(4-Fluorophenvl)-3-methvl-2-((2-methv-3-phenvlpropvl)
amino)-6-(4-pvridyl)-4(3H)-pyrimidinone hydrochloride:
A mixture of crude 5-(4-fluorophenyl)-3-methyl-2-
methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (520 mg
g, 1.45 mmol) and 2-methyl-3-phenylpropylamine (1.5 g,
10.1 mmol) was heated at 50°C for 30 min. Column
chromatography on silica gel (2-5~
methanol/dichloromethane; hexane-acetone= 2 . 1)
provided the title compound. MS (mlz): 429.4 (M+H)+;
C26H25FN40 requir. 428.5 (free base).
Example 25
Procedure for the preparation of 1-Phenyl-1,3
propanediamine
NH2
1-Phenvl-1,3-propanediamine: 3-Phenyl-3-aminopropionic
acid (S. G. Cohen and S. Y. Weinstein, J. Am. Chem. Soc.
86, 725-728, 1964) was converted into 1-phenyl-1,3-
propanediamine as reported in the literature (M. Kojima
and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459
(1982)),

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Analogously, 1-(2-fluorophenyl)-1,3-propanediamine, 1-
(2-methylphenvl)-1,3-propanediamine and 1-(2-
- chlorophenyl)-1,3-propanediamine have been prepared.
- Example 26
Procedure for the preparation of 3-Ethyl-5-(4
fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H)
pyrimidinone
F / ( O F / I O
NH ' N~
N~S~CH3 ----~ I ~ I N~S~CH3
N / N
3-Ethvl-5-(4-fluorophenyl)-2-methylthio-6-(4-pvridvl
4(3H)~wrimidinone: Ethyl bromide (600 ml, 8.03 mmol)
was added to a stirred mixture of 5-(4-fluorophenyl)-2-
methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (1.8 g, 5.97
mmol) and sodium hydride (60~ oily suspension, 320 mg, 8
mmol) in N,N-dimethylformamide (60 ml) at room
temperature. More ethyl bromide (2x 600 ml, 2x8.03
mmol) was added after 2 and 3.5 h. After 8 h, the
reaction mixture was neutralized with acetic acid and
evaporated. The remainder was taken up in
d;chloromethane, the organic solution was washed with
water, dried and evaporated. Flash chromatography on a
column of silica gel (hexane-acetone = 3:1, 2:1).
provided in the second main fraction the title compound
as a solid.
Example 27
Procedure for the preparation of 3-Ethyl-5-(4-
fluorophenyl) -2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -
' pyrimidinone
F / O F / O
__ ~ I N~ ~ I N~
I
N~S~CH3 '.~' I ' I N J\p~CH3
N / N J il
O

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3-Ethyl-5-(4-fluorophenyl)-2-methvlsulfonyl-6 (4
pvridvl)-4(3H)-pyrimidinone: A mixture of 3-ethyl-5-(4-
fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-
pyrimidinone (300 mg, 0.88 mmol) and OxoneR (potassium
peroxymonosulfate, 2.54 g, 4.14 mmol) in methanol (71
ml) and water (33 ml) was stirred for 14 h. The solvent
was concentrated to about 35 ml, followed by extraction
with dichloromethane, drying and evaporation. The
resulting white solid was used without purification in
the next step.
Example 28
Procedure for the preparation of 2-(((S)-2-Amino-3
phenylpropyl) -amino) -3-ethyl-5- (4-fluorophenyl) -6- (4
pyridyl)-4(3H)-pyrimidinone hydrochloride
O
N
NJwN - ~ \
NJ H ~2
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-ethyl-5-(4
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: A mixture of 3-ethyl-5-(4-fluorophenyl)-
2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (150 mg,
0.44 mmol) and (S)-1,2-benzylethylendiamine (200 ml,
~1.3 mmol) was heated at 190-C for 4.5 h. Column
-.chromatography on IatrobeadsR (chloroform . methanol .
triethylamine = 90 . 7 . 3) provided the title compound
as a free base which was converted into the
crystallizing monohydrochloride by the addition of 2N
hydrochloric acid (165 ml, 0.33 mmol) and methanol (1.5
ml). Filtration provided the title compound. MS (m/z):
444.0 (M+H)+; C265H27FN50 requir. 443.5 (free, base).

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Txample 29
Procedure for the preparation of 3-Ethyl-5-(4
fluorophenyl) -2- ( (2-methy-3-phenylpropyl) amino) -6- (4
pyridyl)-4(3H)-pyrimidinone hydrochloride
F / 0
\ I N~
\ I NJ~N I \
NJ H CH3 U
3-Ethyl-5-(4-fluorophenyl)-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride:
A mixture of crude 3-ethyl-5-(4-fluorophenyl)-2-
methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (320 mg
g, 0.89 mmol) and 2-methyl-3-phenylpropylamine (600 ml,
~4 mmol) was heated at 60°C for 2 h. Column
chromatography on silica gel (hexane-acetone= 2 . 1; 2-
5~ methanol/dichloromethane) provided the title
compound. MS (m/z): 443.2 (M+H)+; C27H27FN40 requir.
442.5.
Example 30
Procedure for the preparation of 3-(2-
Methylphenyl)propylamine
~ ~NHZ
CH3
3-(2-Methvlphenvl)propvlamine: Diethyl
cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to'
a stirring suspension of sodium hydride (60~ oily
suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml)
under argon. After 3o min, 2-methylbenzaldehyde (3.6
ml, 31.1 mmol) was added and stirring continued for 1 h.
The reaction was quenched by the addition of water and
' extracted with dichloromethane followed by drying and
evaporation of the organic solution. Column
chromatography (hexane; hexane . ethylacetate = 3 . 1)

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provided 2-(2-methylphenyl)acrylonitrile as an oil.
This material (3.8 g), 10~ palladium on carbon (3.8 g)
and 12 N hydrochloric acid (11.8 ml, 142 mmol) in
methanol (125 ml) were hydrogenated with hydrogen at
atmospheric pressure for 2 d. The catalyst was removed
by filtration and the solvent was evaporated. The
resultant material was partitioned between
dichloromethane and water. The aqueous layer was made
basic with 10 N sodium hydroxide and extracted with
dichloromethane, followed by drying and evaporation.
The resultant material was purified on a silica gel
column (chloroform . methaol . triethylamine = 85 . 10 .
5) to provide the title compound as an oil.
Example 31
Procedure for the preparation of 2-amino-3-(2-
fluorophenyl)-propylamine
\NH2
/ F NH2
Step A. Methyl 2-amino-3-(2-fluorophenyl)propionate:
5g (27.3 mmol) of (D,L)-(2-fluoro-phenyl)alanine was
suspended in 50 ml methanolic HC1 and stirred at room
temperature for 3 days. The reaction mixture was
concentrated in vacuo and dried to give a yellow oil.
MS (m/z) : 198 (M+H)' ; CloHIZFN02 requir. 297.2.
Step B. 2-Amino-3-(2-fluorophenyl)propionamide: Methyl
2-amino-3-(2-fluorophenyl) propionate was suspended in
50 ml 30~ ammonium hydroxide and stirred at room
temperature-for 18 hrs. The mixture was filtered,
washed with cold water and 2-amino-3-(2-fluorophenyl)
propionamide was collected as a white solid. MS (m/z):
183.1 (M+H)' ; C9H11FN20 requir. 182.2.
Step C. 2-Amino-3-(2-fluoronhenvl)-propvlamine: 2-
Amino-3-{2-fluorophenyl)propionamide was added carefully
to a chilled (5°) mixture of LAH (l.Og, 26.3 mmol) and

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20 ml THF under argon. The reaction was then heated at
reflux for 10 hrs. The reaction was cooled to 5°C and
carefully treated with Na2S04~10 H20. The resulting
mixture was stirred for 18 hrs, then filtered to remove
the solids. The filtrate was concentrated in vacuo to
give an amber oil. MS (m/z) : 169 (M+H)' ; C9H13FN2
requir. 168.19
Example 32
Procedure for the preparation of 5-(4-Fluorophenyl)-2
(((S)-2-N-glycylamino-3-phenylpropyl)-amino)-3-methyl-6
(4-pyridyl ) -4 (3H) -pyrimidinone hydrochloride
F ~ O
N~N I \
N ~ _ H NH
0 "NH2
5-(4-Fluorophenvl).-2-(((S)-2-N-ctlvcvlamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)
pyrimidinone hydrochloride: Ethyl chloroformate (56.8
~1, 0.59 mmol) was added at ice-bath temperature to a
stirring mixture of N-(tert.-butoxycarbonyl)glycine (104
mg, 0.59 mmol) and 4-methylmorpholine (65.3 ~1, 0.59
mmol) in tetrahydrofuran (9 ml). After 50 min, a
solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
(250 mg, 0.58 mmol) in tetrahydrofuran (9 ml) was added
at ice-bath temperature. Within 2 h, the mixture was
allowed to reach room temperature. It was diluted with
dichloromethane, washed with aqueous sodium
hydrogencarbonate, followed by drying of the organic
solution and evaporation. The resulting material was
- dissolved in methanol (1.2 ml) and 4N hydrogen
chloride/dioxane (1.2 ml) was added. After 1 h at room
temperature, it was evaporated and the remainder taken
up in dichloromethane followed by washing with aqueous

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sodium hydrogencarbonate, drying of the organic solution
and evaporation. Column chromatography on silica gel
(dichloromethane - methanol - conc. ammonium hydroxide =
93 . 7 . 0.7) provided the title compound as the free
base which was converted into the hydrochloride by the
addition of 4N hydrogen chloride/dioxane (112 ~.I,1, 0.45
mmol) to its methanolic solution (3 ml) followed by
evaporation. MS (m/z) : 487.1 (M+H)'; Cz~H2~FN60z requir.
486.6 (free base).
Accordingly, 2-(((S)-2-N-alycylamino-3-phenylpropyl)-
amino)-3-methyl-5-(3-methylphenyl)-6-(4-pvridvl)-4(3H)
pyrimidinone hydrochloride was prepared from 2-(((S)-2-
amino-3-phenylpropyl)-amino))-3-methyl-5-(3-methylphenyl
6-(4-pyridyl)-4(3H)-pyrimidinone.
Example 33
Procedure for the preparation of 5-(4-Fluorophenyl)-2
(((S)-2-hydroxyacetamido-3-phenylpropyl)-amino)-3
methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone
F ~ O
I N
N~N
N ~ H NH
O~ OH
5-(4-Fluorophenvl)-2-(((S)-2-hydroxyacetamido-3-
phenvlpropvl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone: Acetoxyacetyl chloride (55 ~.1, 0.51 mmol)
was added at ice-bath temperature to a stirring solution
of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-fluoro
phenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (200
mg, 0.466 mmol) and triethylamine (130 ~1, 0.93 mmol) in
dichloromethane (4 ml). After 50 min, the reaction was
quenched by the addition of a drop of methanol followed
by evaporation. The resultant material was taken up in a
1:1:1 mixture of methanol/water/triethylamine (3 ml) and

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left overnight. Evaporation and subsequent column
chromatography (3-7~ methanol/chloroforme) provided the
title compound. MS (m/z) : 488.3 (M+H)~; CZ,HZ6FN503 requir.
487.5.
Example 34
- Procedure for the preparation of 5-(4-fluorophenyl)-2
(2-((3-N-methylureido)-3-phenylpropyl)-amino)-3-methyl
6- (4-pyridyl) -4 (3H) -pyrimidinone
F / O
~' /
I N
N~N _
I - /
N ~ H NH
O' NHCH3
5-(4-Fluorot~henyl)-2-(2-((3-N-methvlureido)-3-
phenvlpropyl)-amino)-3-methvl-6-(4-pyridvl)-4(3H)-
pyrimidinone: Methyl isocyanate (6 ~1, 0.102 mmol) was
added to a solution of 2-(((S)-2-amino-3-phenylpropyl)-
amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone (43.6 mg, 0.102 mmol) in dioxane (1.5 ml)
at 15°C. After 15 min, the solvent was evaporated and
the reaction product applied to a silica gel column (5-
7~ methanol/chloroform) to provide the title compound.
MS (m/z) : 486.6 (M+H)'; C~,HZ~FN602 requir. 486.6.
Example 35
Procedure for the preparation of 5-(4-fluorophenyl)-3
methyl-6-(4-pyridyl)-2-((2-pyrrolidinyl-3-phenylpropyl)
amino)-4(3H)-pyrimidinone hydrochloride
F / O
. ~I /
N
_ I ~ I N~N I ~
NJ H N
U

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5-(4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-(((S)-2-
pyrrolidinyl-3-phenylprotwl)-amino)-4(3H)-pvrimidinone
hydrochloride: Sodium hydride (60~ oily suspension, 84
mg, 2.1 mmol> was added to a solution of 2-(((S)-2-
amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (300 mg, 0.70
mmol) in N,N-dimethylformamide (8 ml) at ice-bath
temperature. After 30 min, 1,4-dibromobutane (108 ~1,
0.91 mmol) was added. Stirring was continued for 30 min
at ice-bath temperature, then 20 h at room temperature.
It was neutralized with acetic acid, followed by
evaporation. The crude product was--purified on a column
of silica gel (dichloromethane - methanol = 93 . 7;
dichloromethane - methanol - conc. ammonium hydroxide =
93 . 7 . 0.7). The resultant product was converted into
the hydrochloride by the addition of 4N hydrogen
chloride/dioxane (37 ~.l) to its methanolic solution (2
ml) and subsequent evaporation. MS (m/z): 484.6 (M+H)';
C~9H~oFN~O requir . 483 . 6 ( free base ) .
Example 36
Procedure for the preparation of 5-(4-fluorophenyl)-2
(((S)-3-N-isopropylamino-3-phenylpropyl)-amino)-3
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride
F ~ O
NH
I N
~ N~N
H
5-(4-Fluorophenvl)-2-(((S)-3-N-isopropvlamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride~ Sodium triacetoxyborohydride
(12.9 mg, 0.061 mmol) was added to a strirring mixture
of 2-(((S)-3-amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
(21.8 mg, 0.051 mmol) and acetone (4.5 ~.1, 0.061 mmol)

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in 1,2-dichloroethane (0.4 ml). After 2.5 h, the
reaction was quenched by the addition of sat. aqu.
- sodium hydrogencarbonate, followed by extraction with
dichloromethane, drying of the organic solution and
evaporation. Chromatography on a column of silica gel
(10~ methanol/chloroform) provided the title compound as
- a free base which was converted into the
monohydrochloride by the addition of 4N hydrochloric
acid/dioxane (12.2 E11) to its methanolic solution (1 ml)
and subsequent evaporation. MS (m/z): 472.0 (M+H)+;
C2gH3pFN50 requir. 471.6 (free base).
Example 37
Procedure for the preparation of 5-(4-fluorophenyl)-2
(((R)-3-N-isopropylamino-3-phenylpropyl)-amino)-3
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride
F / O
/ NH
N
I ~ I N J.N
N ~ H
5-(4-Fluorophenyl)-2-(((R)-3-N-isopropvlamino-3
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone hydrochloride was prepared from 5-(4-
fluorophenyl)-2-(((R)-3-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone as described above for its S-enantiomer. MS
(m/z): 472.1 (M+H}+; CZgH3pFN50 requir. 471.6 (free
base).
Exaa~le 38
Procedure for the preparation of 2-(((S)-3-acetamido-3-
- phenylpropyl)-amino)-5-(4-fluorophenyl)- 3-methyl-6-(4-
- pyridyl ) -4 (3H) -pyrimidino.ne

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F / 0 O' \
NH
I ~N -
N~N
N J H U
2-(((S)-3-Acetamido-3-phenylpropyl)-amino)-5 (4
fluorophenyl)- 3-methyl-6-(4-pyridyl)-4(3H)
pyrimidinone: A solutiont of 2=(((S)-3-amino-3-
phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone (23.8 mg, 0.055 mmol) and
acetic anhydride (20 E1.1, 0.21 mmol) in methanol(1 ml)
was kept for 30 min at room temperature. Evaporation
was followed by column chromatography (dichloromethane -
methanol - ammonium hydroxide = 93 . 7 . 0.7) to provide
the title compound. MS (m/z): 472.2 (M+H)+; C2~I-i26FN502
requir. 471.5.
Example 39
Procedure for the preparation of(S)-1-Phenyl-1,3-
propanediamine
NH-tBOC NHZ
N --~ \ I v wNH2
(S)-1-Phenyl-1 3-propanediamine~ S-3-N-tert.--
Butoxycarbonylamino-3-phenylpropionitrile was prepared
according to the literature (W. J. Wheeler and D.D.
O'Bannon, J. Label.Compds. Radiopharm. XBXI (4), 305-
315, 1992) from D-(-)-a-phenylglycinol. For reduction
(D. Mitchell and T.M. Koenig, Synth. Comm. 25 (8), 1231-
1238, 1995), borane-methyl sulfide complex (2N, 3 ml, 5
mmol) was added dropwise to a solution of the nitrile (1
g, 4.06 mmol) in tetrahydrofuran (6 ml). Methyl sulfide
was distilled off and the resulting solution refluxed
for 2.5 h. With ice-cooling, methanolic hydrogen
chloride (1N, 3 ml) was added followed by evaporation.

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The remainder was taken up in methanol (10 ml) and 4N
hydrogen chloride/dioxane (10 ml) was added. After 1 h
at room temperature, it was evaporated and the aqueous
solution of the resultant-product was washed with
,~ 5 dichloromethane. The aqueous solution was made basic by
the addition of solid potassium hydroxide followed by
repeated dichloromethane extractions. Drying and
evaporation of the dichloromethane solution left the
crude diamine as an oil. MS (m/z) : 150.8 (M+H)'; C9H1aN2
requir. 150.2.
Enantiomeric fR)-1-phenyl-1,3-propanediamine was
prepared analogously from L-(+)-o~,-phenylglycinol. MS
(m/z) : 150.9 (M+H)'; C9HlaNz requir. 150.2.
Example 40
Procedure for the preparation of (2R,3R)-2-methyl-3-
phenyl-1,3-propanediamine
_ Ph NH2
NJ o 0
Phi
--~. ( ~ OMe
-OMe ~
NH2 ~2 0
NH2 1; ~ , ~2
Step A: Methyl f2S,3R,aS)-3-(N-benzvl-N-a
methvlbenzylamino)-2-methyl-3-phenylpropionate was
prepared as reported for the 2R,3S,ocR-enantiomer (S. G.
Davies and I.A.S. Walters, J. Chem. Soc. Perkin Trans.I,
- 1129-1139 (1994).
' Step B: Methyl (2S,3R)-3-amino-2-methyl-3-
phenvlpropionate: A mixturte of methyl (2S,3R,ocS)-3-
(N-benzyl-N-a-methylbenzylamino)-2-methyl-3-
phenylpropionate (13.0 g, 33.55 mmol) and 10~ palladium-

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on-carbon (13.0 g) in glacial acetic acid (260 ml) was
hydrogenated under a balloon of hydrogen for 24 h. The
catalyst was removed by filtration followed by
evaporation and co-distillation with toluene to provide
the title compound as a white solid. MS (mlz): 194.2
(M+H)'; C11H1sNCz requir. 193.3.
Step C: (2S,3R)-3-Amino-2-methyl-3-phenylpropionamide
A solution of methyl (2S,3R)-3-amino-2-methyl-3-
phenylpropionate (6.3 g, 33 mmol) in 2N methanolic
ammonia (20 ml) and ammonium hydroxide (28-30~, 40 ml)
was stirred at room temperature. After 4d, it was
evaporated followed by chromatography on a short column
of silica gel (dichloromethane - methanol - conc.
ammonium hydroxide = 93 . 7 . 0.7; 90 . 10 . 0.8) to
provide the amide as a white solid. MS (m/z): 179.2
(M+H)'; CloH1qN20 requir. 178.2 .
Step D: (2R,3R)-2-methyl-3-phenyl-1 3-propanediamine:
Lithium aluminium hydride (2.3 g, 60.60 mmol) was added
in portions to a stirring solution of (2S,3R)-3-amino-2-
methyl-3-phenylpropionamide (2.6 g, 14.59 mmol) in
tetrahydrofuran (54 ml) at ice-bath temperature. After
45 min, the mixture was heated at reflux for 16 h. With
ice-bath cooling, the reaction was quenched by the
portionwise addition of sodium sulfate decahydrate and
some methanol until hydrogen evolution ceased. The
solids were removed by filtration and washed with
dichloromethane. The combined filtrates were evaporated
to provide the title compound. MS (m/z): 165.2 (M+H)';
CloH16N2 requir . 164 . 3 .
Accordingly, the enantiomer (2S,3S)-2-methyl-3-phenyl-
1s3-propanediamine was prepared from methyl (2R,3S,aR)-
3-(N-benzyl-N-a-methylbenzylamino)-2-methyl-3-
phenylpropionate . MS (m/z) : 165 . 3 (M+H) '; C1oH16Nz requir.
164.3.

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Analogously, the enantiomers (2R,3S)-2-methyl-3-phenvl-
1,3-prot~anediamine and (2S,3R)-2-methyl-3-phenyl-1 3-
propanediamine may be prepared from tert.butyl
(2S, 3S, ocR) - and - (2R, 3R, otS) -3- (N-benzyl-N-a-
methylbenzylamino)-2-methyl-3-phenylpropionate (S.
Davies et al., J. Chem. Soc. Chem. Commun. 1153-1155,
1993 ) .
Example 41
Procedure for the preparation of 2-((S)-3-
Benzylpiperaziny)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone hydrochloride
O F ~ ~ O
\ /
\ \ N
HN ~ I / ,~ H ~~ ' / + \ I N~,O,/
S
O N ~ 0
F
\ ~ O /
I N
\ N ~N I \
N / ~ NH
Step A: (S)-2-Benzylpiperazine~ At ice-bath
temperature, lithium aluminium hydride (1.6 g, 42.16
mmol) was added in portions to a stirring mixture of
(S)-2-benzylpiperazine-3,6-dione (3.0 g, 14.70 mmol)
,.(comm. avail.) and tetrahydrofuran (80 ml). After 30
min at ice-bath temperature, the mixture was refluxed
for 4 h with stirring. The reaction was quenched by the
portionwise addition of sodium sulfate decahydrate and
some methanol until hydrogen evolution ceased. It was
filtered and the solids were washed several times with
- dichloromethane. The combined filtrates were evaporated
" , to leave a white solid.MS (m/z) : 177.1 (M+H)'; CI1H16Nz
requir. 176.3.
Step B: 2-((S)-3-Benzvlpiperaziny)-5-(4-fluorophenvl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride:

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A mixture of crude 5-(4-fluorophenyl)-3-methyl-2-
methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (434 mg,
1.21 mmol) and (S)-2-benzylpiperazine_(426 mg, 2.42
mmol) was heated at 105°C for 1 h. The crude reaction
product was purified by column chromatography on silica
gel (dichloromethane - methane = 93 . 7; dichloromethane
methanol - conc. ammonium hydroxide = 93 . 7: 0.7).
The resulting material was converted into its
hydrochloride by the addition of 4N hydrogen
chloride/dioxane (75 ~.1) to its methanolic solution (3
ml) followed by evaporation. MS (m/z): 456.5 (M+H)';
Cz.,Hz6FN50 requir. 455.5 (free base) .
Example 42
Procedure for the preparation of 5-(4-fluorophenyl)-3-
methyl-2- (3-phenylpropoxy) -6- (4-pyridyl) -4 (3H) -
pyrimidinone
F
0
\ I
I N
N ~0 \
N
5-(~-fluorophenyl)-3-methyl-2-(3-phenylpropoxy) 6 (4
~~,~-idyl)-4(3H)-pyrimidinone: Sodium hydride (60~ oily __
suspension, 111 mg, 2.79 mmol) was added to a stirred
solution of 3-phenylpropanol (387 mg, 2.85 mmol) in
tetrahydrofuran (1 ml). After gas evolution ceased, 5-
(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-
pyridyl)-4(3H)-pyrimidinone (100 mg, 0.279 mmol) was
added and the mixture was heated at 60°C for 30 min.
The reaction mixture was partitioned between
dichloromethane and water. The organic solution was
washed with brine, dried and evaporated. Column
chromatography on silica gel (hexane - ethyl acetate = 2
. 1) provided the title compound. MS (m/z): 416.1
(M+H)+; C25H22FN302 requir. 415.5.

CA 02274093 1999-06-03
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Example 43
Procedure for the preparation of 5-(4-fluorophenyl)-3
methyl-2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H)
pyrimidinone
F
/
Step A: 5-(4-Fluorophenvl)-2-(4-phenylbutyl)-6-(4-
pyridyl)-4~3H)-pyrimidinone: Ethyl 2-(4-fluorophenyl)-
3-oxo-3-(4-pyridyl)-propionate (293 mg, 1.02 mmol), 4-
phenylbutanecarboxamidine (315 mg, 1.79 mmol) and
pyridinium p-toluenesulfonate (10 mg) were suspended in
p-xylene (10 ml). With efficient stirring, the mixture
was heated to reflux using a Dean-Stark apparatus with
continuous removal of water. After 16 h, the solvent
was evaporated and the product purified by column
chromatography on silica gel (3~
methanol/dichloromethane) followed by recrystallization
from acetone. MS (m/z): 400.3 (M+H)+; C25H22FN30 requir.
399.5.
Step B: 5-(4-Fluorophenyl)-3-methyl-2-(4-phenylbutyl)-6-
(4-pyridyl)-4(3H)-pyrimidinone: Methyl iodide (22 ~,1,
0.351 mmol) was added to a stirring mixture of 5-(4-
fluorophenyl)-2-(4-phenylbutyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone (140 mg, 0.351 mmol) and potassium
carbonate (49 mg, 0.351 mmol) in N,N-dimethylformamide
(5 ml). After 75 min, it was evaporated and the
resultant product purified on a silica gel column
(hexane - acetone = 3 . 1; 2 . 1) to provide the title -
compound. MS (m/z): 414.3 (M+H)+; C26H24FN30 requir.
413.5.

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Example 44
The compounds shown in Table I were prepared using
the procedures of Examples 1-43.
TABLE I
F
O F I \ O
/ N
C 1 / I N'
I \ N N I \ I \ N~N ./
N / H NH2 / NJ H NH I
2
MS (m/~): 464.0 (M)+; MS (m/z): 479.7 (M)+;
C25H23FN50 requir. 463.9 C2gH26FN50 requir. 479.6
F \ O F I \ O
N' / N
I \ N~N \ Cl \ ~ N~N
N / H NH2 ~Cl N ~ H NH2
MS (m/z): 498.0 (M)+; MS (m/z): 416.1 (M+H)+;
C25H2~FN50 requir. 498.4
C24H22FN50 requir. 415
F
O F ( ~ O
N~ / N
N~N ~ I \ N~N~Sw
N H NH2 ~Cl N J H NH
2
MS (m/z): 464.1 (M)+; MS (m/z): 414.0 (M+H)+;
C25H~3C1FN50 requir. 463.9 C21H24FN50S requir. 413.5
F
O F I \ O
/ N
F / N
N~N _ ~ \ I \ I N~N _
N / H NH2 ~ N / H NH2
MS (m/z): 448.3 (M+H)+; MS (m/z): 436.2 (M+H)+;
C25H23FzN502 requir. 447.5 C25H3pFN50 requir. 435.6
F
0 F ~ \ O
/ N, / N
N~N ~ I \ N~N ' \
N H ~2 ~F N / H HN--
MS (m/z): 448.2 (M+H)+; MS (m/z): 428.1 (M+H)+;
C25H22FZN50 requir. 447.3 C25H22FN50 requir. 427.5

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F I \ O F I \ 0
/ N~ / N
I \ I N~N~ I I \ I \ I N~N \
N / H~~ N / H ~ I /
2 S
MS (m/z): 486.1 (M+H)+; MS (m/z): 442.1 (M+H)+;
C2~H24FN50S requir. 485.4 C26H24FN50 requir. 413.5
Example 45
The compounds shown in Table II can be prepared
using the procedures of Examples 1-43, wherein R11
represents 3-methylphenyl, 3-chlorophenyl, 3-
trifluoromethylphenyl, 4-fluorophenyl, 4-methylphenyl,
4-chlorophenyl and 3,4-dimethylphenyl.
TABLE II
O O
11 11
R N~ C1 R N
i \ I NON _ I ~ I \ I NON _ I
N ~ H NH2 / N ~ H NH2
Rll ONE R110N~
I \ I N~.N I \ Cl I \ I N~.N~ \
N / H NH2 / Cl N / H NH
2 N
R11 ~ ~ R11 ~ i
I N ~N
I \ N~N \ C1 \ I N~N \
N ~ H NH2 ~ N / H NH2 I N
11 ~ 11
\ I J~~ \ R I JL
I~ N N __ ~ I \ N N _= I \
N / H NH2 / N / HN
Rll O ~ Rll
I N I ~N
I \ N~N I \ I \ N~~N I \
N / H NH' ~F N / H HN--

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11 O R11 O i
R I N~ F N
I \ N~N -_ ~I ~\ I \ I N~N I \
N ~ H NH2 " F N / H NH I /
2 S
R11 O ~ R11 O ~
I N _ I ~IV
I \ N~N lI \ I \ N~N _
N / H NH2 ~CN N / H NH2
R11 O R11
\ I N J~ N _ \ I JL _
I = - I N N _ I S
N / H NH2 NHS N / H
2
O R11
\ INS . \ I ~ _
I N I N N _
N / H ~2 N y NH N / H NH
2
O O
Rll ~ Rll
\ I N~N \ \ I \ I N~N _
I
N / H ~2 I / / N / H
2
Example 46
Procedure for the preparation of 3-methyl-2-(2(S)-amino-
3-phenylpropylamino)-5-(3-trifluoromethyl phenyl)-6-(4-
pyridyl ) -4 (3H) -pyrimidinone
F
Stets A. 6-(4-pyridyl)-2-thiouracil: Ethyl
isonicotinoylacetate (5g, 25.89 mmol) and thiourea (5.94
g, 77.64 mmol) were suspended in anhydrous p-xylene
(100m1) with vigorous stirring. To the mixture,
pyridinium p-toluenesulfonate (150mg) was added and
refluxed for 12-16 h using a Dean-Stark apparatus with

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continuous removal of water (0.5m1). The reaction
mixture was cooled and a dark brown solid was filtered.
The collected solid was suspended in acetone (25 ml) and
filtered. The acetone washed product contain trace of
thiourea, which was removed by trituration with hot
water (20-30m1). The title compound was isolated by
filtration. MS (m/z): 206.2 C9H~N30S requir. 205.3. 1H-
NMR (DMSO-d6): d 12.65 (bm, 2H, NH and SH), 8.71(m, 2H,
pryid.), 7.66(m, 2H, Pyrid.), 6:25 (s, 1H, H-5).
Step B. 3-Methyl-6-(4-pyridyl)-2-methylthio-4(3H)-
pvrimidinone: 6-(4-Pyridyl)-2-thiouracil (1.5g 7.299
mmol) was dissolved in DMF (50 ml) and the mixture was
cooled to 0°C. Sodium hydride (0.437 g, 0.7308 60~ in
oil, 18.25 mmol) was added and the reaction mixture was
stirred for 30 minutes. Methyl iodide (1.2 ml, 2.68,
18.25 mmol) was added dropwise over 15 minutes.
Formation of dimethyl compound was monitored by TLC.
Reaction mixture was concentrated and the residue
chromatographed on silica gel column using hexane:
acetone (9:1, 4:1 and 2:1) to obtain the title compound
as a solid: MS (m/z) :234.1 CIlHmN30S requir. 233 .2; 1H-
NMR(CDCls):d 8.75 (m, 2H, pyridyl), 7.8 (m, 2H,
pyridyl), 6.75 (s, 1H), 3.58 (s, 3H, N-CH3), 2.72 (s,
3H, S-CHI) .
Stets C. 3-Methyl-5-bromo-6-(4-pyridyl)-2-methylthio-
4(3H)-pvrimidinone: 3-Methyl-6-!4-pyridyl)-2-methylthio-
4(3H)-pyrimidinone (1.008 4.29 mmol) was dispersed in
acetic acid (24 ml) and to the clear solution Bromine
(0.5m1, 1.58 9.38 mmol) was added. The reaction mixture
stirred at room temperature for 24 h. The mixture was
concentrated and the residue was co-evaporated with
toluene until all bromine is removed. The crude
_ compound is ready to use in next step. MS(m/z): 312 and
314 . C11H1oBrN30S requir . 311 and 313 . 1H-NMR ( DMSO-d6 ) : d
8.75 (m, 2H, pyridyl) 8.19 (m, 2H, pyridyl), 3.67 (s,
3H, N-CH3) , 2.80 (s, 3H, S-CH3) .

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Step D. 3-Methyl-5-(3-trifluoromethylphenyl)-6-(4-
pyridyl)-2-thiomethyl-4(3H)-pvrimidinone: 3-Methyl-5-
bromo-6-(4-pyridyl)-2-methylthio-4(3H)-pyrimidinone
(1.2g, 3.8 mmol) was dipersed in 2M sodium carbonate
solution (30 ml) and the pale yellow colour of the
adhered bromine disappeared to give colourless
precipitate in the reaction mixture. 3-
Trifluromethylbenzene boronic acid (1.00 g, 5.27 mmol)
and toluene (30m1) were added to the above mixture and
the reaction mixture was degassed. Tetrakis triphenyl
phosphine Pd(0) {350 mg) was added. The reaction mixture
was refluxed for 8-12h. The formation of the product
was monitored by TLC. The mixture was cooled, diluted
with toluene(20m1) and washed with water. The organic
layer was dried over sodium sulfate, concentrated and
product isolated by silica gel chromatgraphy to give the
titled compoud. MS (m/z) : 378.4 C18H14F3N30S requir.
377.39; 1H-NMR(CDCl~):d 8.5 (m, 2H, pyridyl), 7.45
(s,lH), 7.17-7.25 (m, 3H, pyridyl and Ph-CF3), 6.95 (d,
2 0 1H, Ph-CF3 ) , 3 . 67 (N-CH3 ) , 2 . 8 ( S-CH3 ) .
Step E. 3-methyl-2-(2(S)-amino-3-phenylpropylamino)-5-
(3-trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone: 3-Methyl-5-(3-trifluoromethylphenyl)-6-(4-
pyridyl)-2-thiomethyl-4(3H)-pyrimidinone (0.7g, 1.85
mmol) and (S)-2-amino-3-phenyl-1-propylamine {0.9 ml,
6.00 mmol) were mixed in a round bottom flask and heated
at 185°C for 3h. The mixture was separated on silica
gel (dichloromethane: methanol: ammonium hydroxide
92:7:1) to obtain compound titled compound. MS(m/z):
480, CZ6HZaF3N50 requir 479.51; 1H-NMR(CDC13) :d 8.49 (m,
2H, pyridyl), 7.51-7.17 (m, 11H, Ph and pyridyl), 5.81
{bm, 1H, NH), 3.91 (m, 1H, CH), 3.53 (s, 3H, N-CHI),
3 .35 (m, 2H, CHz) , 2.94 {dd, 1H, CHZ) , 2.82 (dd, 1H,
CHZ ) .

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Exa~m~ple 47
Using the corresponding starting materials, the
following compounds of Table III were prepared using the
procedure for 3-methyl-2-(2(S)-amino-3-
phenylpropylamino)-5-(3-trifluoromethylphenyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone.
TABLE III
1
MS (m/z)
4-tolyl 2(S)-amino-3-phenyl-propyl 426
4-trifluoromethyl 2(S)-amino-3-phenyl-propyl 480
phenyl
3-isopropylphenyl 2(S)-amino-3-phenyl-propyl 454
3-chloro-4-fluoro 2(S)-amino-3-phenyl-propyl 464
phenyl
3,5-bis(trifluoro 2(S)-amino-3-phenyl-propyl 548
methyl)phenyl
3,4-dichloro 2(S)-amino-3-phenyl-propyl 482
phenyl
1-naphthyl 2(S)-amino-3-phenyl-propyl 462
3-fluorophenyl 2(S)-amino-3-phenyl-propyl 430
3-chlorophenyl 2(S)-amino-3-phenyl-propyl
3-methylphenyl 2(S)-amino-3-phenyl-propyl
4-chlorophenyl 2(S)-amino-3-phenyl-propyl
2-chlorophenyl 2(S}-amino-3-phenyl-propyl
2-thienyl 2(S)-amino-3-phenyl-propyl
3,4-dimethylphenyl 2(S)-amino-3-phenyl-propyl 440.6
3,5-dichloro 3-phenylpropyl 467
phenyl
4-tolyl 3-phenylpropyl 411
3-trifluoromethyl 3-phenylpropyl 465
. phenyl
4-methoxyphenyl 3-phenylpropyl 427
4-trifluoromethyl 3-phenylpropyl 465
phenyl
3-chlorophenyl 3-phenyl-propyl
3-methylphenyl 3-phenyl-propyl
4-chlorophenyl 3-phenyl-propyl
2-chlorophenyl 3-phenyl-propyl
3-nitrophenyl 3-phenyl-propyl

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3-methoxyphenyl 3-phenyl-propyl
2-fluorophenyl 3-phenyl-propyl
benzothienyl 3-phenyl-propyl
3-fluorophenyl 2-methyl-3-phenyl-propyl 429
1-naphthyl 2-methyl-3-phenyl-propyl 461
3-trifluoromethyl 2(S)-dimethylamino-
phenyl 3-phenylpropyl
3-methylphenyl 2(S)-dimethylamino-
3-phenylpropyl
3-chlorophenyl 2(S)-N,N-dimethylamino-
3-phenylpropyl
3-nitrophenyl 2(S)-N,N-dimethylamino-
3-phenylpro~yl
3-methoxyphenyl 2(S)-N,N-dimethylamino-
3-phenylpropyl
2-fluorophenyl 2(S)-N,N-dimethylamino-
3-phenylpropyl
3-trifluoromethyl (S)-tetrahydroisoquinol-3- 492.1
phenyl ylmethylenamino
3-methylphenyl (S)-tetrahydroisoquinol-3- 438
ylmethylenamino
3,4-dimethylphenyl 3-amino-3-phenylpropylamine 440.6
3-methylphenyl 3-amino-3-phenylpropylamine
benzothienyl 3-amino-3-phenylpropylamine
benzofuranyl 3-amino-3-phenylpropylamine
Example 48
3-Methyl-5-(4-methylsulfinylphenyl)-6-(4-pyridyl) 2
thiomethvl-4(3H)-pyrimidinone: The title compound was
prepared in the ng
manner of example 4-
34-D substituti
methylsulfinylbenzene
boronic acid for
3-
trifluoromethylbenzene
boronic.
Example 4s
3-methyl-2-(3(S)-(1 2 3 4-tetrahydroisoctuinolinyl)methyl
amino)-5-(4-methvlthiophenvl)-6-(4-pvridvl)-4(3H)
pyrimidinone: The title compound was prepared in the
manner of example 34 step D with the following
substitutions of 3-methyl-5-(4-methylsulfinylphenyl)-6-
(4-pyridyl)-2-thiomethyl-4(3H)-pyrimidinone for 3-
methyl-5-(3-trifluoromethylphenyl)-6-(4-pyridyl)-2-
thiomethyl-4(3H)-pyrimidinone and 3(S)-(1,2,3,4-
tetrahydroisoquinolinyl)methylamine for (S)-2-amino-3-
phenyl-1-propylamine: MS (m/z) 470 (M+H)+.

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Example 50
3-methyl-2-(3(S)-(1.2,3,4-tetrahvdroisoauinolinvl)methvl
- amino)-5-(4-methylsulfonvlphenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone: To a solution of 3-methyl-2-(3(S)-
(1,2,3,4-tetrahydroisoquinolinyl)methylamino)-5-(4-
methylthiophenyl).-6-(4-pyridyl)-4(3H)-pyrimidinone (50
' mg, 0.11 mmol) in methanol: water (15 mL:lO mL) was added
oxone (127 mg, 0.21 mmol) as a solid in one portion at
23°C. After 16 h, the reaction was concentrated under a
stream of nitrogen. The reaction mixture was applied
directly to purification via preparative plate
chromatography (3 silica gel 2mm thick plates; 5~
methanol in methylene chloride) to afford the title
compound . MS (m/z) 502 (M+H)+.
Example 51 -
2-(((S)-3-Amino-3-phenvlpropvl)-amino)-3-methyl-6=l4-
pyridyl)-5-(3-trifluoromethylphenyl)-4(3H)-pyrimidinone
hydrochloride was prepared from 3-methyl-2-methylthio-6-
(4-pyridyl)-5-(3-trifluoromethylphenyl)-4(3H)-
pyrimidinone and (S)-1-phenyl-1,3-propanediamine
according to the General Procedure. The reaction was at
190°C for 1 h. MS (m/z) : 480.0 (M+H)'; CZ6HZaF~NsO requir.
479.5 (free base).
Example 52
2-(((R)-3-Amino-3-phenvlpropvl)-amino)-3-methyl-6-~4-
pyridvl)-5-(3-trifluoromethvlphenyl)-4(3H)-pyrimidinone
hydrochloride was prepared from 3-methyl-2-methylthio-
6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4(3H)-
pyrimidinone and (R)-1-phenyl-1,3-propanediamine
according to the General Procedure. The reaction was
done at 190°C for 3.5 h. MS (m/z) : 480.4 (M+H)'; CZ6Hz4F,N50
requir. 479.5 (free base).

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Exaanple 53
Procedure for the preparation of 2-chloro-3-methyl-5-(3
methylphenyl ) -6- (4-pyridyl ) -4 (3H) -pyrimidinone
O / I O / I O
N~ ~ i ~ i
---~ N ~N
N~S/ I ~ I N~OH ~ I ~ I N~C1
N / N~ NJ
Step A: 3-Methyl-5-(3-methylphenyl)-6-(4-pyridyl)
2,4(1H,3H)-pyrimidindione: 10 N Sodium hydroxide (25
ml) and water (50 ml) was added to a solution of 3-
methyl-5-(3-methylphenyl)-2-methylthio-6-(4-pyridyl)-
4(3H)-pyrimidindione (16.17 g, 0.05 mol) in dixoxane (65
ml). The mixture was heated at 80°C for 16 h under
argon. The mixture was allowed to reach room
temperature and the pH value was adjusted to 9 with 1 N
hydrochloric acid. The precipitate was filtered, washed
with water and dried to give the title compound. MS
(m/z) : 292 (M-H)+; C1~H15N302 requir. 293.3.
Step B: 2-Chloro-3-methyl-5-(3-methylphenyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone: A mixture of 3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-2,4(1H,3H)-pyrimidindione
(12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml)
was refluxed for 16 h. The excess of phosphorus
oxychloride was evaporated followed by co-distillation
with toluene. The remainder was carefully partitioned
between dichloromethane and aqueous sodium
hydrogencarbonate. The organic solution was washed with
water, dried and evaporated to leave the title compound.
- MS (m/z) : 312 (M)+; C1~H14C1N30 requir. 311.8.
2-Chloro-3-methyl-6-(4-pvridyl)-5-(3-
trifluoromethylphenyl)-4(3H)-pyrimidinone was prepared
according to the same procedure.

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Example 54
Procedure for the preparation of 2-(((S)-2-amino-3-
- phenylpropyl) -amino) -3-methyl-5- (3-methylphenyl) -6- (4-
pyridyl) -4 (3H) -pyrimidinone hydrochloride
1 NH2 \ I
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
hydrochloride: A solution of 2-chloro-3-methyl-5-(3-
methylphenyl}-6-(4-pyridyl)-4(3H)-pyrimidinone (3.34 g,
10.71 mmol) and (S)-1-benzyl-1,2-ethanediamine (2.3 g,
15.31 mmol} in ethanol (50 ml) was stirred at room
temperature for 16 h. The solvent was evaporated and
the crude product recrystallized from methanol. MS
(m/z) : 426 (M+H)+; C26H2~N5O requir. 425.5 (free base) .
Example 55
Procedure for the preparation of 2-((3-amino-2,2-
dimethyl-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone
hydrochloride
O
\I
I N ~2
N ~ H
2-((-3-.Amino-2 2-dimethyl-3-phenylpropvl)-amino)-3-
- methyl-5-(3-methvlphenyl)-6-(4-pvridvl)-4(3H)-
pvrimidinone hydrochloride: A solution of 2-chloro-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone (228 mg, 0.73 mmol) and 3-phenyl-2,2-
' dimethyl-1,3-propanediamine (178 mg, 1 mmol} (prepared
according to: W. Ten Hoeve and H. Wynberg, Synth. Commun.

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24 (15), 2215-2221, 1994) in ethanol (4 ml) was stirred
at room temperature for 16 h. The solvent was
evaporated and the crude product purified by column
chromatography on silica gel. MS (m/z): 454 (M+H)+;
C2gH31N50 requir. 453.6 (free base).
Accordingly, 2-((-3-Amino-2 2-dimethyl-3-phenylpropyl)
amino)-3-methyl-6-(4-pyridyl)-5-(3-trifluoromethyl
phenyl)-4(3H)-pyrimidinone hydrochloride was prepared.
MS {m/z) : 508 (M+H)'; CzeHz8F3N50 requir. 507. 6 (free base) .
Example 56
Procedure for the preparation of ~-(((S)-3-amino-3-
phenylpropyl ) -amino) -3-methyl-6- (4-pyridyl ) -5- (3-
trifluoromethylphenyl)-4(3H)-pyrimidinone hydrochloride
CF3
O
N~ NH2
N~N
N / H \ I
2-(((S)-3-Amino-3-phenvlpropyl)-amino)-3-methyl-6-(4
pyridvl)-5-(3-trifluoromethvlphenvl)-4(3H)-pyrimidinone
hydrochloride: Aqueous sat. sodium carbonate (2 ml) was
ad~ed to a solution of 2-chloro-3-methyl-6-(4-pyridyl)-
_-c3-trifluoromethylphenyl)-4(3H)-pyrimidinone
hydrochloride (730 mg, 2 mmol) and (S)-1-phenyl-1,3-
propanediamine {360 mg, 2.4 mmol) in ethanol (10 ml).
The mixture was stirred for 4 h at room temperature. It
was evaporated and the remainder partitioned between
dichloromethane and water. The organic solution was
dried and evaporated followed by column chroatography on
silica gel (dichloromethane . methanol . conc. ammonium
hydroxide = 93 . 7 . 0.7). MS (m/z): 480 (M+H)';
C26HZQF3N5O requir. 479.5 (free base) .

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Examwple 57
Procedure for the preparation of 3-methyl-2-methylthio
5- (3-methylphenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone
_ ~ O
\I
_ I N
N~SCH3
N
3-Methyl-2-methvlthio-5-(3-methylphenyl)-6-(4-pyridyl)-
4(3Fi)-pyrimidinone: A solution of potassium t-butoxide
(1M in t-butanol, 11, 1 mol) was added dropwise to a
stirring solution of ethyl 3-methylphenyl acetate (178
g, 1 mol) in N,N-dimethylformamide (2 1). A solution of
4-cyanopyridine (104.11 g, 1 mol) in N,N-
dimethylformamide (1 1) was pumped into the reaction
mixture over a period of about 4.5 h. The mixture was
then stirred at room temperature for 3 h, before the
dropwise addition of a solution of methyl isothiocyanate
(68.4 ml, 1 mol) in N,N-dimethylformamide (50 ml) over a
period of 10 min. After stirring for 1 h at room
temperature, the reaction mixture was cooled to 3 C and
methyl iodide (62.3 ml, 1 mol) was added dropwise over a
period of 10 min. Stirring was continued at room
temperature overnight. The mixture was cooled to 3 C
and water (4 1) was pumped into the reaction mixture
over a period of 6 h. The precipitate was removed by
filtration, washed with water and dried in a vacuum oven
to give the title compound. MS (m/z): 324 (M+H)';
C18H1~N30S requir. 323.4.
~xaa~ple 58
Using the corresponding starting materials, the
following compounds of Table IV may be prepared using
the procedure for 6-(4-fluorophenyl)-2-methyl-1-(3-
phenylpropyl)-7-pyridin-4-yl-1H-imidazo(1,2-a)pyrimidin-
5-one. The required pyrimidinones with the varied R'~

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substituents can be prepared using the general
procedures described above.
TABLE IV
O
R11 ~ ''N[ /
N~N
N, J R21
Rll
3,5-dichlorophenyl 2(S)-amino-3-phenyl-propyl
4-methoxyphenyl 2(S)-amino-3-phenyl-propyl
3-tolyl 2(S)-amino-3-phenyl-propyl
3-chlorophenyl 2(S)-amino-3-phenyl-propyl
4-fluorophenyl 2(S)-amino-3-phenyl-propyl
2-naphthyl 2(S)-amino-3-phenyl-propyl
n-butyl 2(S)-amino-3-phenyl-propyl
2-thiophene 2(S)-amino-3-phenyl-propyl
3-thiophene 2(S)-amino-3-phenyl-propyl
3-aminophenyl 2(S)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(S)-amino-3-phenyl-propyl
3-isopropylphenyl 3-phenylpropyl
3-tolyl 3-phenylpropyl
3-chlorophenyl 3-phenylpropyl
3-chloro-4-fluorophenyl 3-phenylpropyl
3,5-Ditrifluoromethylphenyl 3-phenylpropyl
4-fluorophenyl 3-phenylpropyl
3,4-dichlorophenyl 3-phenylpropyl
1-naphthyl 3-phenylpropyl
3-fluorophenyl 3-phenylpropyl
2-naphthyl 3-phenylpropyl
n-butyl 3-phenylpropyl
'2-thiophene 3-phenylpropyl
3-thiophene 3-phenylpropyl
3-aminophenyl 3-phenylpropyl
2-(5-chlorothiophene) 3-phenylpropyl
3,5-dichlorophenyl 3-methyl-3-phenyl-propyl
4-tolyl 3-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-methoxyphenyl 3-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
3-isopropylphenyl 3-methyl-3-phenyl-propyl
3-tolyl 3-methyl-3-phenyl-propyl
3-chlorophenyl 3-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-fluorophenyl 3-methyl-3-phenyl-propyl
3,4-dichlorophenyl 3-methyl-3-phenyl-propyl

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2-naphthyl 3-methyl-3-phenyl-propyl
n-butyl 3-methyl-3-phenyl-propyl
2-thiophene 3-methyl-3-phenyl-propyl
3-thiophene 3-methyl-3-phenyl-propyl
3-aminophenyl 3-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 3-methyl-3-phenyl-propyl
3,5-dichlorophenyl 3-amino-3-phenyl-propyl
4-tolyl 3-amino-3-phenyl-propyl
3-trifluoromethylphenyl 3-amino-3-phenyl-propyl
' 10 4-methoxyphenyl 3-amino-3-phenyl-propyl
4-trifluoromethylphenyl 3-amino-3-phenyl-propyl
3-isopropylphenyl 3-amino-3-phenyl-propyl
3-tolyl 3-amino-3-phenyl-propyl
3-chlorophenyl 3-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-amino-3-phenyl-propyl
4-fluorophenyl 3-amino-3-phenyl-propyl
3,4-dichlorophenyl 3-amino-3-phenyl-propyl
1-naphthyl 3-amino-3-phenyl-propyl
3-fluorophenyl 3-amino-3-phenyl-propyl
2-naphthyl 3-amino-3-phenyl-propyl
n-butyl 3-amino-3-phenyl-propyl
2-thiophene 3-amino-3-phenyl-propyl
3-thiophene 3-amino-3-phenyl-propyl
3-aminophenyl 3-amino-3-phenyl-propyl
2-(5-chlorothiophene) 3-amino-3-phenyl-propyl
3,5-dichlorophenyl 2(R)-amino-3-phenyl-propyl
4-tolyl 2(R)-amino-3-phenyl-propyl
3-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-methoxyphenyl 2(R)-amino-3-phenyl-propyl
4-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
3-isopropylphenyl 2(R)-amino-3-phenyl-propyl
3-tolyl 2(R)-amino-3-phenyl-propyl
3-chlorophenyl 2(R)-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,4-dichlorophenyl 2(R)-amino-3-phenyl-propyl
1-naphthyl 2(R)-amino-3-phenyl-propyl
3-fluorophenyl 2(R)-amino-3-phenyl-propyl
2-naphthyl 2(R)-amino-3-phenyl-propyl
n-butyl 2(R)-amino-3-phenyl-propyl
2-thiophene 2(R)-amino-3-phenyl-propyl
3-thiophene 2(R)-amino-3-phenyl-propyl
3-aminophenyl 2(R)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(R)-amino-3-phenyl-propyl
3,5-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
4-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-methoxyphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
_ propyl

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3-isopropylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-chlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3-chloro-4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,5-Ditrifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,4-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
1-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
3-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
n-butyl 2-methyl-2-amino-3-phenyl-
propyl
2-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-aminophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-(5-chlorothiophene) 2-methyl-2-amino-3-phenyl-
propyl
3,5-dichlorophenyl 2-methyl-3-phenyl-propyl
4-tolyl 2-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-methoxyphenyl 2-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
3-isopropylphenyl 2-methyl-3-phenyl-propyl
3-tolyl 2-methyl-3-phenyl-propyl
3-chlorophenyl 2-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 2-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-fluorophenyl 2-methyl-3-phenyl-propyl
3,4-dichlorophenyl 2-methyl-3-phenyl-propyl
1-naphthyl 2-methyl-3-phenyl-propyl
3-fluorophenyl 2-methyl-3-phenyl-propyl
2-naphthyl 2-methyl-3-phenyl-propyl
n-butyl ~ 2-methyl-3-phenyl-propyl
2-thiophene 2-methyl-3-phenyl-propyl
3-thiophene 2-methyl-3-phenyl-propyl
3-aminophenyl 2-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 2-methyl-3-phenyl-propyl
3,5-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-tolyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N,N-dimethylamino}-3-
phenyl-propyl

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4-methoxyphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-isopropylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-tolyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-chlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-chloro-4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
1-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
n-butyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-thiophene 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-thiophene 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-aminophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-dichlorophenyl 2-(N-methylamino)-3-
phenyl-propyl
4-tolyl 2-(N-methylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N-methylamino)-3-
phen 1
y -propyl
4-methoxyphenyl 2-(N-methylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N-methylamino)-3-
h
y
3-isopropylphenyl 2
(N
mephylamino)-3-
phenyl-propyl
3-tolyl 2-(N-methylamino)-3-
phenyl-propyl
3-chlorophenyl 2-(N-methylamino)-3-
phenyl-propyl
3-chloro-4-fluorophenyl 2-(N-methylamino)-3-
h
y
3,5-Ditrifluoromethylphenyl 2
(N
mephylamino)-3-
h
y
3,4-dichlorophenyl 2
(N
methylamino)-3-
phenyl-propyl

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4-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
1-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
3-fluorophenyl 2-(N-methylamino)-3-
h
y
2-naphthyl 2
(N
mephypamino)-3-
phenyl-propyl
n-butyl 2-(N-methylamino)-3-
h
y
2-thiophene . p
(N
mephypamino)-3-
phenyl-propyl
3-thiophene 2-(N-methylamino)-3-
phenyl-propyl
3-aminophenyl 2-(N-methylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N-methylamino)-3-
phenyl-propyl
Exaraple 59
The compounds in table V can be prepared using the
appropriate starting materials and the following
procedures: The required pyrimidinones with the varied
R11 substituents can be prepared using the general
procedures described above. The fused 6, 5 ring system
can be prepared as described above affording R~1 as a
hydrogen radical. Other R21 groups can be introduced
through a reductive amination process using the
corresponding aldehyde with appropriate amino protection
(Boc group). For example, N-Boc-phenylalanal can be
prepared from the corresponding Weinreb amide through
reduction with lithium aluminum hydride as described in
the literature (Konieczny and Cushman Tetrahedron Lett
6939, 1992). The N-Boc-phenylalanal can then be reacted
with the amino group using sodium triacetoxyborohydride.
Alternatively, the alcohol of N-Boc-phenylalanol can be
activated under Mitsunobu conditions
(triphenylphosphine, diiisopropyl azodicarboxylate) and
reacted with the amino group of the 6, 5 fused system
followed by removal of the Boc group (trifluoroacetic
acid).

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TABLE V
O
R11 WN
N~N
1
V J R21
Rll Rz i
3,5-dichlorophenyl 2(S)-amino-3-phenyl-propyl
4-methoxyphenyl 2(S)-amino-3-phenyl-propyl
3-tolyl 2(S)-amino-3-phenyl-propyl
3-chlorophenyl 2(S)-amino-3-phenyl-propyl
4-fluorophenyl 2(S)-amino-3-phenyl-propyl
2-naphthyl 2(S)-amino-3-phenyl-propyl
n-butyl 2(S)-amino-3-phenyl-propyl
2-thiophene 2(S)-amino-3-phenyl-propyl
3-thiophene 2(S)-amino-3-phenyl-propyl
3-aminophenyl 2(S)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(S)-amino-3-phenyl-propyl
3-isopropylphenyl 3-phenylpropyl
3-tolyl 3-phenylpropyl
3-chlorophenyl 3-phenylpropyl
3-chloro-4-fluorophenyl 3-phenylpropyl
3,5-Ditrifluoromethylphenyl 3-phenylpropyl
4-fluorophenyl 3-phenylpropyl
3,4-dichlorophenyl 3-phenylpropyl
1-naphthyl 3-phenylpropyl
3-fluorophenyl 3-phenylpropyl
2-naphthyl 3-phenylpropyl
n-butyl 3-phenylpropyl
2-thiophene 3-phenylpropyl
3-thiophene 3-phenylpropyl
3-aminophenyl 3-phenylpropyl
2-(5-chlorothiophene) 3-phenylpropyl
3,5-dichlorophenyl 3-methyl-3-phenyl-propyl
4-tolyl 3-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-methoxyphenyl 3-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
3-isopropylphenyl 3-methyl-3-phenyl-propyl
3-tolyl 3-methyl-3-phenyl-propyl
3-chlorophenyl 3-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-fluorophenyl 3-methyl-3-phenyl-propyl
3,4-dichlorophenyl 3-methyl-3-phenyl-propyl
2-naphthyl 3-methyl-3-phenyl-propyl
n-butyl 3-methyl-3-phenyl-propyl
2-thiophene 3-methyl-3-phenyl-propyl
3-thiophene 3-methyl-3-phenyl-propyl
3-aminophenyl 3-methyl-3-phenyl-propyl

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2-(5-chlorothiophene) 3-methyl-3-phenyl-propyl
3,5-dichlorophenyl 3-amino-3-phenyl-propyl
4-tolyl 3-amino-3-phenyl-propyl
3-trifluoromethylphenyl 3-amino-3-phenyl-propyl
4-methoxyphenyl 3-amino-3-phenyl-pro 1
PY
4-trifluoromethylphenyl 3-amino-3-phenyl-propyl
3-isopropylphenyl 3-amino-3-phenyl-propyl
3-tolyl 3-amino-3-phenyl-propyl
3-chlorophenyl 3-amino-3-phenyl-pro 1
PY
3-chloro-4-fluorophenyl 3-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-amino-3-phenyl-propyl
4-fluorophenyl 3-amino-3-phenyl-pro 1
PY
3,4-dichlorophenyl 3-amino-3-phenyl-propyl
1-naphthyl 3-amino-3-phenyl-propyl
3-fluorophenyl 3-amino-3-phenyl-pro 1
y
2-naphthyl 3-amino-3-phenyl-pro
l
PY
n-butyl 3-amino-3-phenyl-propyl
2-thiophene 3-amino-3-phenyl-propyl
3-thiophene 3-amino-3-phenyl-pro 1
pY
3-aminophenyl 3-amino-3
propyl
P
y
2-(5-chlorothiophene) 3-amino-3
hen
l
-p y -propyl
3,5-dichlorophenyl 2(R)-amino-3-phenyl-propyl
4-tolyl 2(R)-amino-3 hen 1
P Y Propyl
3-trifluoromethylphenyl 2(R)-amino-3
propyl
P
Y
4-methoxyphenyl l_
2(R)-amino-3
hen
propyl
p
y
4-trifluoromethylphenyl 2(R)-amino-3
hen
l
-p y -propyl
3-isopropylphenyl 2(R)-amino-3-phenyl-propyl
3-tolyl 2(R)-amino-3-phenyl-pro 1
PY
3-chlorophenyl 2(R)-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,4-dichlorophenyl 2(R)-amino-3-phenyl-propyl
1-naphthyl 2(R)-amino-3-phenyl-propyl
3-fluorophenyl 2(R)-amino-3-phenyl-propyl
2-naphthyl 2(R)-amino-3-phenyl-propyl
n-butyl 2(R)-amino-3-phenyl-propyl
2-thiophene 2(R)-amino-3-phenyl-pro 1
PY
3-thiophene 2(R)-amino-3-phenyl-propyl
3-aminophenyl 2(R)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(R)-amino-3-phenyl-propyl
3,5-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
4-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-methoxyphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-isopropylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-tolyl 2-methyl-2-amino-3-phenyl-
propyl

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3-chlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3-chloro-4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl.
3,5-Ditrifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,4-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
1-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
3-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
n-butyl 2-methyl-2-amino-3-phenyl-
propyl
2-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-aminophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-(5-chlorothiophene) 2-methyl-2-amino-3-phenyl-
propyl
3,5-dichlorophenyl 2-methyl-3-phenyl-propyl
4-tolyl 2-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-methoxyphenyl 2-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
3-isopropylphenyl 2-methyl-3-phenyl-propyl
3-tolyl 2-methyl-3-phenyl-propyl
3-chlorophenyl 2-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 2-methyl-3-phenyl-propyl
i,5-Ditrifluoromethylphenyl 2-methyl-3-phenyl-propyl
_
4-fluorophenyl 2-methyl-3-phenyl-propyl
3,4-dichlorophenyl 2-methyl-3-phenyl-propyl
1-naphthyl 2-methyl-3-phenyl-propyl
3-fluorophenyl 2-methyl-3-phenyl-propyl
2-naphthyl 2-methyl-3-phenyl-propyl
n-butyl 2-methyl-3-phenyl-propyl
2-thiophene 2-methyl-3-phenyl-propyl
3-thiophene 2-methyl-3-phenyl-propyl
3-aminophenyl 2-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 2-methyl-3-phenyl-propyl
3,5-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-tolyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-methoxyphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl

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3-isopropylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-tolyl
2-(N,N-dimethylamino)-3-
phenyl-propyl
3-chlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-chloro-4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N;N-dimethylamino)-3-
h
4-fluorophenyl p
(NyN-dimethylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
1-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
n-butyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-thiophene 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-thiophene 2-(N,N-dimethylamino)-3-
h
3-aminophenyl p
(NyN-dimethylamino)-3-
2-(5-chlorothiophene) ph(NyN-dimethylamino)-3-
phenyl-propyl
3,5-dichlorophenyl 2-(N-methylamino)-3-
phenyl-propyl
4-tolyl 2-(N-methylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N-methylamino)-3-
h
y
4-methoxyphenyl p
(N
mephylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3-isopropylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3-tolyl 2-(N-methylamino)-3-
3-chlorophenyl ph(Nymephypamino)-3-
phenyl-propyl
3-chloro-4-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N-methylamino)-3-
phenyl-propyl
4-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
1-naphthyl - 2-(N-methylamino)-3-
phenyl-propyl

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3-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
2-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
n-butyl 2-(N-methylamino)-3-
phenyl-propyl
_ 2-thiophene 2-(N-methylamino)-3-
phenyl-propyl
3-thiophene 2-(N-methylamino)-3-
' 10 phenyl-propyl
3-aminophenyl 2-(N-methylamino
)-3-
_
phenyl-propyl
2-(5-chlorothiophene) 2-(N-methylamino)-3-
phenyl-propyl
Example 60
The compounds in table VI can be prepared using the
appropriate starting materials and procedures as
described above.
TABLE VI
O
R11 I wN
N~N
N J R2i
R11 R21
3,5-dichlorophenyl 2(S)-amino-3-phenyl-propyl
4-methoxyphenyl 2(S)-amino-3-phenyl-propyl
3-tolyl 2(S)-amino-3-phenyl-propyl
3-chlorophenyl 2(S)-amino-3-phenyl-propyl
4-fluorophenyl 2(S)-amino-3-phenyl-propyl
2-naphthyl 2(S)-amino-3-phenyl-propyl
n-butyl 2(S)-amino-3-phenyl-propyl
2-thiophene 2(S)-amino-3-phenyl-propyl
3-thiophene 2(S)-amino-3-phenyl-propyl
3-aminophenyl 2(S)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(S)-amino-3-phenyl-propyl
3-isopropylphenyl 3-phenylpropyl
3-tolyl 3-phenylpropyl
3-chlorophenyl 3-phenylpropyl
_ 3-chloro-4-fluorophenyl 3-phenylpropyl
3,5-Ditrifluoromethylphenyl 3-phenylpropyl
4-fluorophenyl 3-phenylpropyl
3,4-dichlorophenyl 3-phenylpropyl
1-naphthyl 3-phenylpropyl
3-fluorophenyl 3-phenylpropyl
2-naphthyl 3-phenylpropyl
n-butyl 3-phenylpropyl

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2-thiophene 3-phenylpropyl
3-thiophene 3-phenylpropyl
3-aminophenyl 3-phenylpropyl
2-(5-chlorothiophene) 3-phen-ylpropyl
3,5-dichlorophenyl 3-methyl-3-phenyl-propyl
4-tolyl 3-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-methoxyphenyl 3-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
3-isopropylphenyl 3-methyl-3-phenyl-propyl
3-tolyl 3-methyl-3-phenyl-propyl
3-chlorophenyl 3-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-fluorophenyl 3-methyl-3-phenyl-propyl
3,4-dichlorophenyl 3-methyl-3-phenyl-propyl
2-naphthyl 3-meth 1-3
Propyl
y
P
y
n-butyl 3-meth
l-3
hen
l
Y -P y -propyl
2-thiophene 3-methyl-3-phenyl-propyl
3-thiophene 3-meth 1-3
phenyl-propyl
y
3-aminophenyl 3-meth
l-3
phenyl-propyl
y
2-(5-chlorothiophene) l-3
3-meth
l propyl
n
3,5-dichlorophenyl 3-amino-3 hen
l
-p y -propyl
4-tolyl 3-amino-3-phenyl-pro 1
PY
3-trifluoromethylphenyl 3-amino-3-phenyl-propyl
4-methoxyphenyl 3-amino-3-phenyl-propyl
4-trifluoromethylphenyl 3-amino-3-phenyl-propyl
3-isopropylphenyl 3-amino-3-phenyl-propyl
3-tolyl 3-amino-3-phenyl-propyl
3-chlorophenyl 3-amino-3-phenyl-pro 1
y
3-chloro-4-fluorophenyl 3-amino-3-phenyl-pro
l
PY
3,5-Ditrifluoromethylphenyl 3-amino-3-phenyl-propyl
4-fluorophenyl 3-amino-3-phenyl-pro 1
PY
3,4-dichlorophenyl 3-amino-3-phenyl-propyl
:-naphthyl 3-amino-3-phenyl-pro 1
py
?-fluorophenyl 3-amino-3
Propyl
P
y
..-naphthyl _._
3-amino-3
hen
l
-p y -propyl
n-butyl 3-amino-3-phenyl-propyl
2-thiophene 3-amino-3-phenyl-propyl
3-thiophene 3-amino-3-phenyl-propyl
3-aminophenyl 3-amino-3-phenyl-propyl
2-(5-chlorothiophene) 3-amino-3-phenyl-propyl
3,5-dichlorophenyl 2(R}-amino-3-phenyl-propyl
4-tolyl 2(R}-amino-3-phenyl-propyl
3-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-methoxyphenyl 2(R)-amino-3-phenyl-propyl
4-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
3-isopropylphenyl 2(R)-amino-3-phenyl-propyl
3-tolyl 2(R)-amino-3-phenyl-propyl
3-chlorophenyl 2(R)-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,4-dichlorophenyl 2(R)-amino-3-phenyl-propyl
1-naphthyl 2(R)-amino-3-phenyl-propyl
3-fluorophenyl 2(R)-amino-3-phenyl-propyl

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2-naphthyl 2(R)-amino-3-phenyl-propyl
n-butyl 2(R)-amino-3-phenyl-propyl
2-thiophene 2(R)-amino-3-phenyl-propyl
a 3-thiophene 2(R)-amino-3-phenyl-propyl
3-aminophenyl 2(R)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(R)-amino-3-phenyl-propyl
3,5-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
4-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
Px'oPYl
4-methoxyphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-isopropylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-chloroghenyl 2-methyl-2-amino-3-phenyl-
propyl
3-chloro-4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,5-Ditrifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,4-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
1-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
3-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
n-butyl 2-methyl-2-amino-3-phenyl-
propyl
2-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-aminophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-(5-chlorothiophene) 2-methyl-2-amino-3-phenyl-
propyl
3,5-dichlorophenyl 2-methyl-3-phenyl-propyl
- 4-tolyl 2-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-methoxyphenyl 2-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
3-isopropylphenyl 2-methyl-3-phenyl-propyl
3-tolyl 2-methyl-3-phenyl-propyl
3-chlorophenyl 2-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 2-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-methyl-3-phenyl-propyl

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4-fluorophenyl 2-methyl-3-phenyl-propyl
3,4-dichlorophenyl 2-methyl-3-phenyl-propyl
1-naphthyl 2-methyl-3-phenyl-propyl
3-fluorophenyl 2-methyl-3-phenyl-propyl
2-naphthyl 2-methyl-3-phenyl-propyl
n-butyl 2-methyl-3-phenyl-propyl
2-thiophene 2-methyl-3-phenyl-propyl
3-thiophene 2-meth 1-3
y -phenyl-propyl
3-aminophenyl 2-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 2-methyl-3-phenyl-propyl
3,5-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-tolyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
h
4-methoxyphenyl p
(NyN-dimethylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-isopropylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-tolyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-chlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-chloro-4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
1-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-naphthyl 2-(N,N-dimethylamino)-3-
phen 1
n-butyl 2-(NyN-dimethylami~no)-3-
phenyl-propyl
2-thiophene 2-(N,N-dimethylamino)-3-
h
3-thiophene 2
(NyN-dimethylamino)-3-
h
3-aminophenyl 2
(NYN-dimethylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-dichlorophenyl 2-(N-methylamino)-3-
n
y
4-tolyl 2
(N
mephylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N-methylamino)-3-
--
phenyl-propyl

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4-methoxyphenyl 2-(N-methylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N-methylamino)-3-
- phenyl-propyl
3-isopropylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3-tolyl 2-(N-methylamino)-3-
phenyl-propyl
3-chlorophenyl ~ 2-(N-methylamino)-3-
- 10 phenyl-propyl
3-chloro-4-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N-methylamino)-3-
h
y
4-fluorophenyl p
(N
mephylamino)-3-
phenyl-propyl
1-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
3-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
2-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
n-butyl 2-(N-methylamino)-3-
phenyl-propyl
2-thiophene 2-(N-methylamino)-3-
phenyl-propyl
3-thiophene 2-(N-methylamino)-3-
phenyl-propyl
3-aminophenyl 2-(N-methylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N-methylamino)-3-
phenyl-propyl
Example 61
The compounds in table VII can be prepared using
the appropriate starting materials and procedures as
described above.
TABLE VII
N
i
4 0 I R21
Rll R'21
3,5-dichlorophenyl 2(S)-amino-3-phenyl-propyl
4-methoxyphenyl 2(S)-amino-3-phenyl-propyl
3-tolyl 2(S)-amino-3-phenyl-propyl

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3-chlorophenyl 2(S)-amino-3-phenyl-pro 1
pY
4-fluorophenyl 2(S)-amino-3-phenyl-propyl
2-naphthyl 2(S)-amino-3-phenyl-propyl
n-butyl 2(S)-amino-3-phenyl-propyl
2-thiophene 2(S)-amino-3-phenyl-propyl
3-thiophene 2(S)-amino-3-phenyl-propyl
3-aminophenyl 2(S)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(S)-amino-3-phenyl-propyl
3-isopropylphenyl 3-phenylpropyl
3-tolyl 3-phenylpropyl
3-chlorophenyl 3-phenylpropyl
3-chloro-4-fluorophenyl 3-phenylpropyl
3,5-Ditrifluoromethylphenyl 3-phenylpropyl
4-fluorophenyl 3-phenylpropyl
3,4-dichlorophenyl 3-phenylpropyl
1-naphthyl 3-phenylpropyl
3-fluorophenyl 3-phenylpropyl
2-naphthyl 3-phenylpropyl
n-butyl 3-phenylpropyl
2-thiophene 3-phenylpropyl
3-thiophene 3-phenylpropyl
3-aminophenyl 3-phenylpropyl
2-t5-chlorothiophene) 3-phenylpropyl
3,5-dichlorophenyl 3-methyl-3-phenyl-propyl
4-tolyl 3-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-methoxyphenyl 3-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
3-isopropylphenyl 3-methyl-3-phenyl-propyl
3-tolyl 3-methyl-3-phenyl-propyl
3-chlorophenyl 3-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-fluorophenyl 3-methyl-3-phenyl-propyl
3,4-dichlorophenyl 3-methyl-3-phenyl-propyl
2-naphthyl 3-methyl-3-phenyl-propyl
n-butyl 3-methyl-3-phenyl-propyl
2-thiophene 3-methyl-3-phenyl-propyl
3-thiophene 3-methyl-3-phenyl-propyl
3-aminophenyl 3-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 3-methyl-3-phenyl-propyl
3,5-dichlorophenyl 3-amino-3-phenyl-propyl
4-tolyl 3-amino-3-phenyl-propyl
3-trifluoromethylphenyl 3-amino-3-phenyl-propyl
4-methoxyphenyl 3-amino-3-phenyl-propyl
4-trifluoromethylphenyl 3-amino-3-phenyl-propyl
3-isopropylphenyl 3-amino-3-phenyl-propyl
3-tolyl 3-amino-3-phenyl-propyl
3-chlorophenyl 3-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-amino-3-phenyl-propyl
4-fluorophenyl 3-amino-3-phenyl-propyl
3,4-dichlorophenyl 3-amino-3-phenyl-propyl
1-naphthyl 3-amino-3-phenyl-propyl
3-fluorophenyl 3-amino-3-phenyl-propyl
2-naphthyl 3-amino-3-phenyl-propyl

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n-butyl 3-amino-3-phenyl-propyl
2-thiophene 3-amino-3-phenyl-propyl
3-thiophene 3-amino-3-phenyl-propyl
3-aminophenyl 3-amino-3-phenyl-propyl
2-(5-chlorothiophene) 3-amino-3-phenyl-propyl
3,5-dichlorophenyl 2(R)-amino-3-phenyl-propyl
4-tolyl 2(R)-amino-3-phenyl-propyl
3-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-methoxyphenyl 2(R)-amino-3-phenyl-propyl
4-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
3-isopropylphenyl 2(R)-amino-3-phenyl-propyl
3-tolyl 2(R)-amino-3-phenyl-propyl
3-chlorophenyl 2(R)-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,4-dichlorophenyl 2(R)-amino-3-phenyl-propyl
1-naphthyl 2(R)-amino-3-phenyl-propyl
3-fluorophenyl 2(R)-amino-3-phenyl-propyl
2-naphthyl 2(R)-amino-3-phenyl-propyl
n-butyl 2(R)-amino-3-phenyl-propyl
2-thiophene 2(R)-amino-3-phenyl-propyl
3-thiophene 2(R)-amino-3-phenyl-propyl
3-aminophenyl 2(R)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(R)-amino-3-phenyl-propyl
3,5-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
4-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-methoxyphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-isopropylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-chlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3-chloro-4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,5-Ditrifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,4-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
1-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
3-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-naphthyl 2-methyl-2-amino-3-phenyl-
propyl

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n-butyl 2-methyl-2-amino-3-phenyl-
propyl
2-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-aminophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-(5-chlorothiophene) 2-methyl-2-amino-3-phenyl-
propyl
3,5-dichlorophenyl 2-methyl-3-phenyl-propyl
4-tolyl 2-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-methoxyphenyl 2-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
3-isopropylphenyl 2-methyl-3-phenyl-propyl
3-tolyl 2-meth 1-3
propyl
y
P
y
3-chlorophenyl 2-meth
l-3
hen
l
Y -P y -propyl
3-chloro-4-fluorophenyl 2-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-fluorophenyl 2-methyl-3-phenyl-propyl
3,4-dichlorophenyl 2-methyl-3-phenyl-propyl
1-naphthyl 2-meth 1-3
y -Ph~Yl-propyl
3-fluoro hen 1 2-methyl-3-phenyl-propyl
P Y
2-naphthyl 2-methyl-3-phenyl-propyl
n-butyl 2-methyl-3-phenyl-propyl
2-thiophene 2-meth 1-3
propyl
y
p
y
3-thiophene 2-meth
l-3
hen
l
Y -p y -propyl
3-aminophenyl 2-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 2-methyl-3-phenyl-propyl
3,5-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-tolyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-methoxyphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-isopropylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-tolyl 2-(N,N-dimethylamino)-3-
h
3-chlorophenyl p
(NyN-dimethylamino)-3-
phenyl-propyl
3-chloro-4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
4-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
1-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl

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3-fluorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
n-butyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-thiophene 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-thiophene 2-(N,N-dimethylamino)-3-
phenyl-propyl
3-aminophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N,N-dimethylamino)-3-
phenyl-propyl
3,5-dichlorophenyl 2-(N-methylamino)-3-
phenyl-propyl
4-tolyl 2-(N-methylamino)-3-
phenyl-propyl
3-trifluoromethylphenyl 2-(N-methylamino)-3-
phenyl-propyl
4-methoxyphenyl 2-(N-methylamino)-3-
phenyl-propyl
4-trifluoromethylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3-isopropylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3-tolyl 2-(N-methylamino)-3-
phenyl-propyl-
3-chlorophenyl 2-(N-methylamino)-3-
phen 1
y -propyl
3-chloro-4-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N-methylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N-methylamino)-3-
phenyl-propyl
4-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
1-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
3-fluorophenyl 2-(N-methylamino)-3-
phenyl-propyl
2-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
n-butyl 2-(N-methylamino)-3-
phenyl-propyl
2-thiophene 2-(N-methylamino)-3-
phenyl-propyl
3-thiophene 2-(N-methylamino)-3-
phenyl-propyl
3-aminophenyl 2-(N-methylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N-methylamino)-3-
phenyl-propyl

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Example 62
Using the corresponding starting materials, the
following compounds of Table VIII may be prepared using
the procedure for 3-methyl-2-(2(S)-amino-3-
phenylpropylamino)-5-(3-trifluoromethylphenyl)-6-(4-
pyridyl)-4{3H)-pyrimidinone.
TABLE VIII
3
/ NHR21
Rii Rzl
3,5-dichlorophenyl 2(S)-amino-3-phenyl-propyl
4-methoxyphenyl 2(S)-amino-3-phenyl-propyl
3-tolyl 2(S)-amino-3-phenyl-propyl
3-chlorophenyl 2(S)-amino-3-phenyl-propyl
4-fluorophenyl 2(S)-amino-3-phenyl-propyl
2-naphthyl 2(S)-amino-3-phenyl-propyl
n-butyl 2(S)-amino-3-phenyl-propyl
2-thiophene
2(S)-amino-3-phenyl-propyl
3-thiophene
2(S)-amino-3-phenyl-propyl
3-aminophenyl
2(S)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(S)-amino-3-phenyl-propyl
3-isopropylphenyl 3-phenylpropyl
3-tolyl 3-phenylpropyl
3-chlorophenyl 3-phenylpropyl
3-chloro-4-fluorophenyl 3-phenylpropyl
3,5-Ditrifluoromethylphenyl 3-phenylpropyl
4-fluorophenyl 3-phenylpropyl
3,4-dichlorophenyl 3-phenylpropyl
1-naphthyl 3-phenylpropyl
3-fluorophenyl 3-phenylpropyl
_
2-naphthyl 3-phenylpropyl
n-butyl 3-phenylpropyl
2-thiophene 3-phenylpropyl
3-thiophene 3-phenylpropyl
3-aminophenyl 3-phenylpropyl
2-(5-chlorothiophene) 3-phenylpropyl
3,5-dichlorophenyl 3-methyl-3-phenyl-propyl
4-tolyl 3-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-methoxyphenyl 3-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 3-methyl-3-phenyl-propyl
3-isopropylphenyl 3-methyl-3-phenyl-propyl
3-tolyl 3-methyl-3-phenyl-propyl
3-chlorophenyl
3-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-methyl-3-phenyl-propyl

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3,5-Ditrifluoromethylphenyl 3-methyl-3-phenyl-propyl
4-fluorophenyl 3-methyl-3-phenyl-propyl
3,4-dichlorophenyl 3-methyl-3-phenyl-propyl
2-naphthyl 3-methyl-3-phenyl-propyl
n-butyl 3-methyl-3-phenyl-propyl
2-thiophene 3-methyl-3-phenyl-propyl
3-thiophene 3-methyl-3-phenyl-propyl
3-aminophenyl 3-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 3-methyl-3-phenyl-propyl
3,5-dichlorophenyl 3-amino-3-phenyl-propyl
4-tolyl 3-amino-3-phenyl-propyl
3-trifluoromethylphenyl 3-amino-3-phenyl-propyl
4-methoxyphenyl 3-amino-3-phenyl-propyl
4-trifluoromethylphenyl 3-amino-3-phenyl-propyl
3-isopropylphenyl 3-amino-3-phenyl-propyl
3-tolyl 3-amino-3-phenyl-propyl
3-chlorophenyl 3-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 3-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 3-amino-3-phenyl-propyl
4-fluorophenyl 3-amino-3-phenyl-propyl
3,4-dichlorophenyl 3-amino-3-phenyl-propyl
1-naphthyl 3-amino-3-phenyl-propyl
3-fluorophenyl 3-amino-3-phenyl-propyl
2-naphthyl 3-amino-3-phenyl-propyl
n-butyl 3-amino-3-phenyl-propyl
2-thiophene 3-amino-3-phenyl-propyl
3-thiophene 3-amino-3-phenyl-propyl
3-aminophenyl 3-amino-3-phenyl-propyl
2-(5-chlorothiophene) 3-amino-3-phenyl-propyl
3,5-dichlorophenyl 2(R)-amino-3-phenyl-propyl
4-tolyl 2(R)-amino-3-phenyl-propyl
3-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-methoxyphenyl 2(R)-amino-3-phenyl-propyl
4-trifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
3-isopropylphenyl 2(R)-amino-3-phenyl-propyl
?-tolyl 2(R)-amino-3-phenyl-propyl
~-chlorophenyl 2(R)-amino-3-phenyl-propyl
3-chloro-4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2(R)-amino-3-phenyl-propyl
4-fluorophenyl 2(R)-amino-3-phenyl-propyl
3,4-dichlorophenyl 2(R)-amino-3-phenyl-propyl
1-naphthyl 2(R)-amino-3-phenyl-propyl
3-fluorophenyl 2(R)-amino-3-phenyl-propyl
2-naphthyl 2(R)-amino-3-phenyl-propyl
n-butyl 2(R)-amino-3-phenyl-propyl
2-thiophene 2(R)-amino-3-phenyl-propyl
3-thiophene 2(R)-amino-3-phenyl-propyl
3-aminophenyl 2(R)-amino-3-phenyl-propyl
2-(5-chlorothiophene) 2(R)-amino-3-phenyl-propyl
3,5-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
4-tolyl 2-methyl-2-amino-3-phenyl-
propyl
3-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl

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4-methoxyphenyl 2-methyl-2-amino-_3-phenyl-
propyl
4-trifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-isopropylphenyl 2-methyl-2-amino-3-phenyl-
propyl
3-tolyl 2-methyl-2-amino-3-phen 1
Y _
propyl
3-chlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3-chloro-4-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
3,5-Ditrifluoromethylphenyl 2-methyl-2-amino-3-phenyl-
propyl
4-fluorophenyl 2-methyl-2-amino-3-phenyl=
propyl
3,4-dichlorophenyl 2-methyl-2-amino-3-phenyl-
propyl
1-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
3-fluorophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-naphthyl 2-methyl-2-amino-3-phenyl-
propyl
n-butyl 2-methyl-2-amino-3-phenyl-
propyl
2-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-thiophene 2-methyl-2-amino-3-phenyl-
propyl
3-aminophenyl 2-methyl-2-amino-3-phenyl-
propyl
2-(5-chlorothiophene) 2-methyl-2-amino-3-phenyl-
propyl
3,5-dichlorophenyl 2-methyl-3-phenyl-propyl
4-tolyl 2-methyl-3-phenyl-propyl
3-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-methoxyphenyl 2-methyl-3-phenyl-propyl
4-trifluoromethylphenyl 2-methyl-3-phenyl-propyl
3-isopropylphenyl 2-methyl-3-phenyl-propyl
3-tolyl 2-methyl-3-phenyl-propyl
3-chlorophenyl 2-methyl-3-phenyl-propyl
3-chloro-4-fluorophenyl 2-methyl-3-phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-methyl-3-phenyl-propyl
4-fluorophenyl 2-methyl-3-phenyl-propyl
3,4-dichlorophenyl 2-methyl-3-phenyl-propyl
1-naphthyl 2-methyl-3-phenyl-propyl
3-fluorophenyl 2-methyl-3-phenyl-propyl
2-naphthyl 2-methyl-3-phenyl-propyl
n-butyl 2-methyl-3-phenyl-propyl
2-thiophene 2-methyl-3-phenyl-propyl
3-thiophene 2-methyl-3-phenyl-propyl
3-aminophenyl 2-methyl-3-phenyl-propyl
2-(5-chlorothiophene) 2-methyl-3-phenyl-propyl
3,5-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl

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4-tolyl 2-(N,N-dimethylamino)-3-
h
3-trifluoromethylphenyl 2
(NyN-dimethylamino)-3-
h
4-methoxyphenyl p
(NyN-dimethylamino)-3-
h
4-trifluoromethylphenyl 2
(NyN-dimethylamino)-3-
h
3-isopropylphenyl 2
(NYN-dimethylamino)-3-
phenyl-propyl
3-tolyl 2-(N,N-dimethyla
mino)-3-
_
phenyl-propyl
3-chlorophenyl 2-(N,N-dimethylamino)-3-
h
3-chloro-4-fluorophenyl 2
(NyN-dimethylamino)-3-
phenyl-propyl
3,5-Ditrifluoromethylphenyl 2-(N,N-dimethylamino)-3-
h
4-fluorophenyl p
(NyN-dimethylamino)-3-
phenyl-propyl
3,4-dichlorophenyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
1-naphthyl 2-(N,N-dimethylamino)-3-
h
3-fluorophenyl p
(NyN-dimethylamino)-3-
phenyl-propyl
2-naphthyl 2-(N,N-dimethylamino)-3-
phenyl-propyl
n-butyl 2-(N,N-dimethylamino)-3-
h
2-thiophene p
(NyN-dimethylamino)-3-
h
3-thiophene p
(NYN-dimethylamino)-3-
h
3-aminophenyl p
(NyN-dimethylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N,N-dimethylamino)-3-
h
y
3,5-dichlorophenyl p
(N
mephylamino)-3-
~ phenyl-propyl
4-tolyl 2-(N-methylamino)-3-
h
Y
3-trifluoromethylphenyl 2
(N
methylamino)-3-
h
Y
4-methoxyphenyl 2
(N
methylamino)-3-
h
y
4-trifluoromethylphenyl 2
(N
methylamino)-3-
h
y
- 3-isopropylphenyl 2
(N
methylamino)-3-
phenyl-propyl
3-tolyl 2-(N-methylamino)-3-
phenyl-propyl
3-chlorophenyl 2-(N-methylamino)-3-
h
y
3-chloro-4-fluorophenyl 2
(N
methylamino)-3-
phenyl-propyl

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3,5-Ditrifluoromethylphenyl 2-(N-methylamino)-3-
ph
y
3,4-dichlorophenyl 2
(N
methylamino)-3-
h
y
4-fluorophenyl p
(N
mephylamino)-3-
h
y
1-naphthyl 2
(N
mephypamino)-3-
h
y
3-fluorophenyl p
(N
mephypamino)-3-
phenyl-propyl
2-naphthyl 2-(N-methylamino)-3-
phenyl-propyl
n-butyl 2-(N-methylamino)-3-
h
Y
2-thiophene p
(N
methylamino)-3-
phenyl-propyl
3-thiophene 2-(N-methylamino)-3-
h
y
3-aminophenyl 2
(N
mephylamino)-3-
phenyl-propyl
2-(5-chlorothiophene) 2-(N-methylamino)-3-
phenyl-propyl
Example 63
Procedure for the preparation of 2-((2-(3-
trifluoromethylphenyl)phenylmethyl)amino)-3-methyl-5-(4-
fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone
F
3
NCH-
.
N
H
Step A. 2-((2-bromophenylmethyl)amino)-5-(4-
fluorophenyl)-6-(4-pyridvl)-3-methvl-4(3H)-pvrimidinone:
The compound, 3-methyl-5-(4-fluorophenyl)-6-(4-pyridyl)-
2-thiomethyl-4(3H)-pyrimidinone (470 mg, 1.44 mmol) was
dissolved-in methanol:water mixture(1.8:1, 40m1 and
22.5m1). Potasssium peroxymonosulfate (OXONE Aldrich
Chem Co., 2.5g 4.1 mmol) was added to a cooled (4°C)
reaction mixture and then the reaction was continued for
16h at room-temperature. The reaction mixture was
concentrated and extracted with dichloromethane and the
organic layer was washed with water, dried over NaZSOd
and was concentrated. The residue (500mg) and o-

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bromobenzylamine were mixed in 1,4-dioxane (20 ml). The
clear solution was heated at 85°C for 18 h and progress
of the reaction monitored by TLC. The reaction mixture
was concentrated and chromatographed on a silica gel
column to obtain the titled compound. MS(m/z): 466.9
CZ,HIpBrFN,O requirs: 465.33 1H-NMR (CDC1~) :d 8.49 (dd, 2H,
pyridyl), 7.67-6.81 (m, 12H, Ph and pyridyl), 5.44 (t,
1H, NH), 4.92 (d 2H, CHZ-Ph), 3.6 (s, 3H, N-CH3).
Step A. 2-((2-(3-trifluoromethylphenyl)phenylmethyl)
amino)-3-methyl-5-(4-fluorophenyl)-6-(4-pvridvl)-4(3H)-
pyrimidinone: 2-((2-bromophenylmethyl)amino)-5-(4-
fluorophenyl)-6-(4-pyridyl)-3-methyl-4(3H)-pyrimidinone
(175 mg, 0.38 mmol) was dipersed in 2M sodium carbonate
solution (12 ml) and 3-trifluromethylbenzene- boronic
acid (170 mg, 0.89 mmol), toluene (l2ml) were added to
the above mixture and the reaction mixture was degassed
and catalyst tetrakistriphenylphosphine Pd(0) (50 mg)
was added. The reaction mixture was refluxed for 16 h.
The formation of the product was monitored by TLC. Then
it was cooled, diluted with toluene (12 ml) and washed
with water. The organic layer was dried over sodium
sulfate, concentrated and the product was purified by
silica gel chromatgraphy to give the title compound.
MS ( m/ z ) : 531 . 1 C~aH2zF4Na0 requir . 53 0 . 53 ; 1H-NMR ( CDC13 ) : d
8.43 (m, 2H, pyridyl), 7.69-7.12 (m,8H, Ph), 7.11-6.88
(m, 6H, pyridyl and Ph-CF,), 4.85 (m, 3H, CHZ-Ph and NH),
3 . 3 2 ( N-CH3 ) .
Example 64
Using the corresponding starting materials, the
following compounds of Table IX may be prepared using
the procedure for 2-((2-(3-trifluoromethylphenyl)
phenylmethyl)amino)-3-methyl-5-(4-fluorophenyl)-6-(4-
' pyridyl)-4(3H)-pyrimidinone.
- 35

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TABLE IX
R11
NCH3 R40
N~N
N J H
Rii Rso
4-fluorophenyl 3,5-dichlorophenyl -
4-fluorophenyl 4-tolyl
4-fluorophenyl 4-methoxyphenyl
4-fluorophenyl 4-trifluoromethylphenyl
4-fluorophenyl 3-isopropylphenyl
4-fluorophenyl 3-tolyl
4-fluorophenyl 3-chlorophenyl
4-fluorophenyl 3-chloro-4-fluorophenyl
4-fluorophenyl 3,5-Ditrifluoromethylphenyl
4-fluorophenyl 4-fluorophenyl
4-fluorophenyl 3,4-dichlorophenyl
4-fluorophenyl 1-naphthyl
4-fluorophenyl 3-fluorophenyl
4-fluorophenyl 2-naphthyl
4-fluorophenyl n-butyl
4-fluorophenyl 2-thiophene
4-fluorophenyl 3-thiophene
4-fluorophenyl 3-aminophenyl
4-fluorophenyl 2-(5-chlorothiophene)
3-trifluoromethylphenyl 3,5-dichlorophenyl
3-trifluoromethylphenyl 4-tolyl
3-trifluoromethylphenyl 3-trifluoromethylphenyl
3-trifluoromethylphenyl 4-methoxyphenyl
3-trifluoromethylphenyl 4-trifluoromethylphenyl
3-trifluoromethylphenyl 3-isopropylphenyl
3-trifluoromethylphenyl 3-tolyl
3-trifluoromethylphenyl 3-chlorophenyl
3-trifluoromethylphenyl 3-chloro-4-fluorophenyl
- .3-trifluoromethylphenyl 3,5-Ditrifluoromethylphenyl
3-trifluoromethylphenyl 4-fluorophenyl
3-trifluoromethylphenyl 3,4-dichlorophenyl
3-trifluoromethylphenyl 1-naphthyl
3-trifluoromethylphenyl 3-fluorophenyl
3-trifluoromethylphenyl 2-naphthyl
3-trifluoromethylphenyl n-butyl
3-trifluoromethylphenyl 2-thiophene
3-trifluoromethylphenyl 3-thiophene
- 3-trifluoromethylphenyl 3-aminophenyl
3-trifluoromethylphenyl 2-(5-chlorothiophene)
Example 65
Using the corresponding starting materials, the
following compounds of Table X may be prepared using the

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procedure for 2-((2-(3-trifluoromethylphenyl)
phenylmethyl)amino)-3-methyl-5-(4-fluorophenyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone.
TABLE X
O
NCH3
\ N i 'N
NJ H ~ /
Rll Rao
4-fluorophenyl 3,5-dichlorophenyl
4-fluorophenyl 4-tolyl
4-fluorophenyl 4-methoxyphenyl
4-fluorophenyl 4-trifluoromethylphenyl
4-fluorophenyl 3-isopropylphenyl
4-fluorophenyl 3-tolyl
4-fluorophenyl 3-chlorophenyl
4-fluorophenyl 3-chloro-4-fluorophenyl
4-fluorophenyl 3,5-Ditrifluoromethylphenyl
4-fluorophenyl 4-fluorophenyl
4-fluorophenyl 3,4-dichlorophenyl
4-fluorophenyl 1-naphthyl
4-fluorophenyl 3-fluorophenyl
4-fluorophenyl 2-naphthyl
4-fluorophenyl n-butyl
4-fluorophenyl 2-thiophene
4-fluorophenyl 3-thiophene
4-fluorophenyl 3-aminophenyl
4-fluorophenyl 2-(5-chlorothiophene)
3-trifluoromethylphenyl 3,5-dichlorophenyl
3-trifluoromethylphenyl 4-tolyl
3-trifluoromethylphenyl 3-trifluoromethylphenyl
3-trifluoromethylphenyl 4-methoxyphenyl
3-trifluoromethylphenyl 4-trifluoromethylphenyl
3-trifluoromethylphenyl 3-isopropylphenyl
3-trifluoromethylphenyl 3-tolyl
3-trifluoromethylphenyl 3-chlorophenyl
3-trifluoromethylphenyl 3-chloro-4-fluorophenyl
3-trifluoromethylphenyl 3,5-Ditrifluoromethylphenyl
3-trifluoromethylphenyl 4-fluorophenyl
3-trifluoromethylphenyl 3,4-dichlorophenyl
3-trifluoromethylphenyl 1-naphthyl
3-trifluoromethylphenyl 3-fluorophenyl
3-trifluoromethylphenyl 2-naphthyl
3-trifluoromethylphenyl n-butyl
3-trifluoromethylphenyl 2-thiophene
3-trifluoromethylphenyl 3-thiophene
3-trifluoromethylphenyl 3-aminophenyl
3-trifluoromethylphenyl 2-(5-chlorothiophene)

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8xample 66
Using the corresponding starting materials, the
following compounds of Table XI may be prepared using
the procedure for 2-((2-(3-trifluoromethylphenyl)
phenylmethyl)amino)-3-methyl-5-(4-fluorophenyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone.
TABLE XI
O
R11 NCH3
i
N~N
NJ H ~ /
R4o
R" Ra o
4-fluorophenyl 3,5-dichlorophenyl
4-fluorophenyl 4-tolyl
9-fluorophenyl 4-methoxyphenyl
4-fluorophenyl 4-trifluoromethylphenyl
4-fluorophenyl 3-isopropylphenyl
4-fluorophenyl 3-tolyl
4-fluorophenyl 3-chlorophenyl
4-fluorophenyl 3-chloro-4-fluorophenyl
4-fluorophenyl 3,5-Ditrifluoromethylphenyl
4-fluorophenyl 4-fluorophenyl
4-fluorophenyl 3,4-dichlorophenyl
4-fluorophenyl 1-naphthyl
4-fluorophenyl 3-fluorophenyl
4-fluorophenyl 2-naphthyl
4-fluorophenyl n-butyl
4-fluorophenyl 2-thiophene
4-fluorophenyl 3-thiophene
4-fluorophenyl 3-aminophenyl
4-fluorophenyl 2-(5-chlorothiophene)
3-trifluoromethylphenyl 3,5-dichlorophenyl
3-trifluoromethylphenyl 4-tolyl
3-trifluoromethylphenyl 3-trifluoromethylphenyl
3-trifluoromethylphenyl 4-methoxyphenyl
3-trifluoromethylphenyl 4-trifluoromethylphenyl
3-trifluoromethylphenyl 3-isopropylphenyl
3-trifluoromethylphenyl 3-tolyl
3-trifluoromethylphenyl 3-chlorophenyl
3-trifluoromethylphenyl 3-chloro-4-fluorophenyl
3-trifluoromethylphenyl 3,5-Ditrifluoromethylphenyl
3-trifluoromethylphenyl 4-fluorophenyl
3-trifluoromethylphenyl 3,4-dichlorophenyl
3-trifluoromethylphenyl 1-naphthyl
3=trifluoromethylphenyl 3-fluorophenyl
3-trifluoromethylphenyl 2-naphthyl
3-trifluoromethylphenyl n-butyl
3-trifluoromethylphenyl 2-thiophene

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3-trifluoromethylphenyl 3-thiophene
3-trifluoromethylphenyl 3-arninophenyl
3-trifluoromethylphenyl 2-(5-chlorothiophene)
ale 67
Biological Assays
The following assays were used to characterize the
ability of compounds of the invention to inhibit the
production of TNF-a and IL-1-(3. The second assay
measured the inhibition of TNF-a and/or IL-1-~i in mice
after oral administration of the test compounds. The
third assay, a glucagon binding inhibition in vitro
assay, can be used to characterize the ability of
compounds of the invention to inhibit glucagon binding.
The fourth assay, a Cyclooxygenase enzyme (COX-1 and
COX-2) inhibition activity in vitro assay, can be used
to characterize the ability of compounds of the
invention to inhibit COX-1 and/or COX-2.
Lipopolysaccharide-activated moaocyte TNF production
assay
Isolation of monocytes
Test compounds were evaluated in vitro for the
ability to inhibit the production of TNF by monocytes
activated with bacterial lipopolysaccharide (LPS).
Fresh residual source leukocytes (a byproduct of
plateletpheresis) were obtained from a local blood bank,
and peripheral blood mononuclear cells (PBMCs) were
isolated by density gradient centrifugation on Ficol-
Paque~'Plus (Pharmacia). PBMCs were suspended at 2 x
106/ml in DMEM supplemented to contain 2$ FCS, 10 mM,
0.3 mg/ml glutamate, 100 U/ml penicillin G and 100 mg/ml
streptomycin sulfate (complete media). Cells were
plated into Falcon*flat bottom, 96 well culture plates
(200 ul/well) and cultured overnight at 37°C and 6~ COz.
Non-adherent cells were removed by washing with 200 -
ul/well of fresh medium. Wells containing adherent
cells (~70~ monocytes) were replenished with I00 ul of
fresh medium.
*Trade-mark

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Preparation of test compound stock solutions
Test compounds were dissolved in DMZ. Compound
stock solutions were prepared to an initial
concentration of 10 - 50 uM. Stocks were diluted
initially to 20 - 200 uNi in complete media. Nine two-
fold serial dilutions of each compound were then
prepared in complete medium.
Treatment of cells with test compounds and activation of
TNF production with 3ipopolysaccharide
One hundred microliters of each test compound
dilution were added to microtiter wells containing
adherent monocytes and 100 ul complete medium.
Monocytes were cultured with test compounds for 60 min
at which time 25 ul of complete medium containing 30
ng/ml lipopolysaccharide from E. coli K532 were added to
each well. Cells were cultured an additional 4 hrs.
Culture supernatants were then removed and TNF presence
in the supernatants was quantified using an ELISA.
TNF ELISA
Flat bottom, 96 well Corning High Binding ELISA
plates were coated overnight (4°C) with 150 uL/well of 3
ug/ml murine anti-human TNF-a MAb (R&D Systems #MAB210).
Wells were then blocked for 1 hr at room temperature
with 200 uL/well of CaClz-free ELISA buffer supplemented
to contain 20 mg/ml BSA (standard ELISA buffer: 20 mM,
°1,50 mM NaCl, 2 mM CaCl2, O.I5 mM thimerosal~, pH 7.4).
Plates were washed and replenished with 100 ul of test
supernatants (diluted 1:3) or standards. Standards
consisted of eleven 1.5-fold serial dilutions from a
stock of 1 ng/ml recombinant human TNF (R&D Systems).
Plates were incubated at room temperature for 1 hr on
- orbital shaker (300 rpm), washed and replenished with
100 ul/well of 0.5 ug/ml goat anti-human TNF-a (R&D
systems #AB-210-NA) biotinylated at a 4:1 ratio. Plates
were incubated for 40 min, washed and replenished with
100 ul/well of alkaline phosphatase-conjugated
*Trade-mark

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streptavidin (Jackson ImmunoResearch #016-050-084) at
0.02 ~,zg/ml. Plates were incubated 30 min, washed and
- replenished with 200 ul/well of 1 mg/ml of p-nitrophenyl
phosphate. After 30 min, plates were read at 405 nm on
a V~ plate reader.
Data analysis
Standard curve data were fit to a second order
polynomial and unknown TNF-a concentrations determined
from their OD by solving this equation for
concentration. TNF concentrations were then plotted vs.
test compound concentration using a second order
polynomial. This equation was then used to calculate
the concentration of test compounds causing a 50~
reduction in TNF production.
Compounds of the invention can also be shown to
inhibit LPS-induced release of IL-1(3, IL-6 and/or IL-8
from monocytes by measuring concentrations of IL-l~i, IL-
6 and/or IL-8 by methods well known to those-skilled in
the art. In a similar manner to the above described
assay involving the LPS induced release of TNF-a from
monocytes, compounds of this invention can also be shown
to inhibit LPS induced release of IL-1(3, IL-6 and/or IL-
8 from monocytes by measuring concentrations of IL-1(3,
IL-6 and/or IL-8 by methods well known to those skilled
in the art. Thus, the compounds of the invention may
lower elevated levels of TNF-a, IL-1, IL-6, and IL-8
levels. Reducing elevated levels of these inflammatory
cytokines to basal levels or below is favorable in
controlling, slowing progression, and alleviating many
disease states. All of the compounds are useful in the
methods of treating disease states in which TNF-a, IL-
1(3, IL-6, and IL-8 play a role to the full extent of the
definition of TNF-a-mediated diseases described herein.
Inhibition of LPS-Induced TNF-a production in mice

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Male DBA/1LACJ mice were dosed with vehicle or test
compounds in a vehicle (the vehicle consisting of 0.5~
tragacanth in 0.03 N HC1) 30 minutes prior to
lipopolysaccharide (2 mg/kg, I.V.) injection. Ninety
minutes after LPS injection, blood was collected and the
serum was analyzed by ELISA for TNF levels.
The following compounds exhibit activities in the
monocyte assay (LPS induced TNF release) with ICSO values
of 20 ~1M or less:
2-(2,6-Dichlorobenzyl)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone
2-(Butylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone
2-(Benzylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-((R-1-phenylethyl)amino)-(4-
pyridyl)-4(3H)-pyrimidinone
2-(2-(2-Chlorophenyl)-ethylamino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-(2-(4-fluorophenyl)-ethylamino)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-((2-hydroxy-2-phenyl)-ethylamino)-
3-methyl-6-(4-pyridyl)-4(3H}-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-amino)-
6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((1-methyl-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((R-1-methyl-3-
phenylpropyl)-amino}-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((2-phenylaminoethyl}-
amino)-6-(4-pyridyl)-4{3H)-pyrimidinone
5-(4-Fluorophenyl)-2-((3-imidazolylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-{4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-(3-
(pyrrolidin-1-yl)-propylamino)-4(3H)-pyrimidinone
3,6-biphenyl=4-(4-pyridyl)-2{1H)-pyridone
6-(4-Methylphenyl)-3-phenyl-4-(4-pyridyl)-2(2H)-pyridone
6-(4-Ethylphenyl)-3-phenyl-4-(4-pyridyl}-2(1H)-pyridone
6-(2,4-Dimethylphenyl)-3-phenyl-4=(4-pyridyl)-2{1H)-
pyridone
3-Phenyl-4-{4-pyridyl)-6-{2-thienyl)-2(1H)-pyridone
6-(2-Furyl)-3-phenyl-4-(4-pyridyl)-2(1H)-pyridone

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2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4- _
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((R)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((S)-2-N-Ethyl-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((2-Amino-2-methy-3-phenylpropyl)amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((2-Aminomethy-3-phenylpropyl)-amino)-5-(4-
fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((3-Amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-(3-(2-
methylphenyl)propyl)-amino)-6-(4-pyridyl)-4(3H)-
pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((R,S)-2-amino-3-(2'-
fluorophenyl)-propyl-amino)-6-(4-pyridyl)-4(3H)-
pyrimidinone
2-(((S)-2-Acetamido-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl}-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone
2-(((S)-2-N-n-Butylamino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-ethyl-5-(4-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Ethyl-5-(4-fluorophenyl)-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((2-(3-trifluoromethylphenyl)phenylmethyl)amino)-3-
methyl-5-(4-fluorophenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(4-tolyl)-
6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(4-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
isopropylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-chloro-
4-fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone

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3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3,5-
bis(trifluoromethyl)phenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3,4-
dichlorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-{1-
naphthyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(3,5-dichlorophenyl)-
6-(4-pyridyl)-4(3H}-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(4-tolyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylaminoj-5-(3-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-{4-methoxyphenyl)-6-
(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(4-
trifluoromethylphenyl)-6-(4-pyridyl}-4(3H)-pyrimidinone
3-Methyl-2-(2-methyl-3-phenylpropylamino)-5-(3-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2-methyl-3-phenylpropylamino)-5-(1-
naphthyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-({(S)-2-N-glycylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N-Glycylamino-3-phenylpropyl)-amino)-3-methyl-
5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-(((S)-2-hydroxyacetamido-3-
phenylpropyl)-amino)-3-methyl-6-{4-pyridyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-2-(((S)-2-pyrrolidinyl-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-((S)-3-Benzylpiperazinyl)-5-(4-fluorophenyl)-3-methyl-
6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-methylphenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-3-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((R)-3-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone

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2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone
2-(((R)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4--(3H)-pyrimidinone
2-((3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-methylphenyl)propyl)-amino)-3-methyl-6-
(4-pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-6-
(4-pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone
2-((3-Amino-3-phenylpropyl)-amino}-3-methyl-5-(3-
methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-chlorophenyl)propyl)-amino)-3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3,4-dimethylphenyl)-4-(3H)-pyrimidinone
2-(((2R,3R)-3-Amino-2-methyl-3-phenylpropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((2S,3S)-3-Amino-2-methyl-3-phenylpropyl)-amino}-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-2-(((S)-3-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
3G 5-(4-Fluorophenyl)-2-(((R)-3-N-isopropylamino-3-
phenyipropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)- ----
pyrimidinone
5-(4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone
3-Methyl-6-(4-pyridyl)-2-((S)-tetrahydroisoquinol-3-
ylmethylenamino)- 5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone
3-Methyl-5-(3-methylphenyl)-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone
3-Methyl-5-(4-methylthiophenyl)-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone

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5-(4-Fluorophenyl)-2-((3-hydroxy-3-phenylpropyl)-amino)-
3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-6-{4-pyridyl)-4-(3H)-pyrimidinone
2-(((S}-2-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-Amino-3-(4-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-Amino-3-(2-chlorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-({(S)-2-N-Isopropylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4-(3H)=
pyrimidinone
2-(((S)-2-N-Isopropylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone
5-(3-Chlorophenyl-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S}-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-chlorophenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-5-(3-trifluorophenyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-(((S)-2-N-methylamino-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4-(3H)-pyrimidinone.
The following compounds exhibit activities in the
monocyte assay (LPS induced TNF release) with ICSO values
of 5 ~,4M or less
2-(2,6-Dichlorobenzyl)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone
2-(Benzylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-
pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-((R-1-phenylethyl)amino)-(4-
pyridyl)-4(3H}-pyrimidinone
2-(2-(2-Chlorophenyl)-ethylamino)-5-(4-fluorophenyl}-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-(2-(4-fluorophenyl}-ethylamino)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((3-phenylpropyl)-amino)-
6-(4-pyridyl)-4(3H)-pyrimidinone

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5-(4-Fluorophenyl)-3-methyl-2-((1-methyl-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((R-1-methyl-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((2-phenylaminoethyl)-
amino)-6-(4-pyridyl)-4(3X)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-(3-
(pyrrolidin-1-yl)-propylamino)-4(3H)-pyrimidinone
6-(4-Ethylphenyl)-3-phenyl-4-(4-pyridyl)-2(1H)-pyridone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((R)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((S)-2-N-Ethyl-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((2-Amino-2-methy-3-phenylpropyl) amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((2-Aminomethy-3-phenylpropyl)-amino)-5-(4-
fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((3-Amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-
methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-(3-(2-
methylphenyl)propyl)-amino)-6-(4-pyridyl)-4(3H)-
pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((R,S)-2-amino-3-(2'-
fluorophenyl)-propyl-amino)-6-(4-pyridyl)-4(3H)-
pyrimidinone
2-(((S)-2-Acetamido-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)-
pyrimidinone
2-(((S)-2-N-n-Butylamino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-ethyl-5-(4-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
_ 3-Ethyl-5-(4-fluorophenyl)-2-((2-methy-3-phenylpropyl)
amino)-6-(4-pyridyl)-4(3H)-pyrimidinone
2-((2-(3-trifluoromethylphenyl)phenylmethyl)amino)-3-
methyl-5-(4-fluorophenyl)-6-(4-pyridyl)-4(3H)-
pyrimidinone

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3-Methyl-2-(2{S)-amino-3-phenylpropylamino)-5-(4-tolyl)-
6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(4-
trifluoromethylphenyl)-6-{4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3=phenylpropylamino)-5-(3-
isopropylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-{2(S)-amino-3-phenylpropylamino)-5-(3-chloro-
4-fluorophenyl)-6-{4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3,5-
bis{trifluoromethyl)phenyl)-6-(4-pyridyl)-4(3H~-
pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3,4-
dichlorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2{S)-amino-3-phenylpropylamino)-5-(1-
naphthyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)=amino-3-phenylpropylamino)-5-(3-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(3,5-dichlorophenyl)-
6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(4-tolyl)-6-(4-
pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(3-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(4-methoxyphenyl)-6-
(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(3-phenylpropylamino)-5-(4-
trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2-methyl-3-phenylpropylamino)-5-(3-
fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
3-Methyl-2-(2-methyl-3-phenylpropylamino)-5-(1-
'naphthyl)-6-(4-pyridyl)-4(3H)-pyrimidinone
5-{4-Fluorophenyl)-2-(((S)-2-N-glycylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N-Glycylamino-3-phenylpropyl)-amino)-3-methyl-
5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-(((S)-2-hydroxyacetamido-3-
- 40 phenylpropyl)-amino)-3-methyl-6-{4-pyridyl)-4-(3H)-
pyrimidinone
5-{4-Fluorophenyl)-2-(((S)-2-pyrrolidinyl-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-{3H)-
pyrimidinone
2-((S)-3-Benzylpiperazinyl)-5-(4-fluorophenyl)-3-methyl-
6-(4-pyridyl)-4-(3H)-pyrimidinone

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2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-methylphenyl)propyl)-amino)-5-(4-
fluorophenyl}-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-3-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl}-4-(3H)-pyrimidinone
2-(((R)-3-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-{3H)-pyrimidinone
2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone
2-(((R)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-methylphenyl)propyl)-amino)-3-methyl-6-
(4-pyridyl)5-(3-trifluoromethylphenyl)-4-(3H}-
pyrimidinone
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-6-
(4-pyridyl)5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone
2-((3-Amino-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl}-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-((3-Amino-3-(2-chlorophenyl)propyl)-amino)-3-methyl-5-
(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-
pyridyl)5-(3,4-dimethylphenyl)-4-{3H)-pyrimidinone
2-(((2R,3R)-3-Amino-2-methyl-3-phenylpropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((2S,3S)-3-Amino-2-methyl-3-phenylpropyl)-amino)-5-
(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-2-(((S)-3-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-{4-pyridyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-2-(((R)-3-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone
3-Methyl-6-(4-pyridyl)-2-((S)-tetrahydroisoquinol-3-
ylmethylenamino)- 5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone

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3-Methyl-5-(3-methylphenyl)-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino)-4-(3H)-
pyrimidinone
3-Methyl-5-(4-methylthiophenyl)-6-(4-pyridyl)-2-((S)-
tetrahydroisoquinol-3-ylmethylenamino}-4-(3H)-
pyrimidinone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-3-methyl-5-(3-
methylphenyl}-6-(4-pyridyl)-4-(3H)-pyrimidinone
5-(4-Fluorophenyl)-2-((3-hydroxy-3-phenylpropyl)-amino)-
3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4-
fluorophenyl)-6-(4-pyridyl)-4-{3H)-pyrimidinone
2-(((S)-2-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-Amino-3-(4-fluorophenyl)propyl)-amino}-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-Amino-3-(2-chlorophenyl)propyl)-amino)-5-(4-
fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)-pyrimidinone
2-(((S)-2-N-Isopropylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-5-(3-trifluoromethylphenyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N-Isopropylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone
S-(3-Chlorophenyl-2-(((S)-2-N-isopropylamino-3-
phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl}-amino)-3-
methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-5-(3-chlorophenyl)-6-(4-pyridyl)-4-(3H)-
pyrimidinone
2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-
methyl-6-(4-pyridyl)-5-(3-trifluorophenyl)-4-(3H)-
pyrimidinone
5-(4-Fluorophenyl)-3-methyl-2-(((S)-2-N-methylamino-3-
phenylpropyl)-amino)-6-(4-pyridyl)-4-(3H)-pyrimidinone
- 40 Compounds of the invention may be shown to have
anti-inflammatory properties in animal models of
inflammation, including carageenan paw edema, collagen
induced arthritis and adjuvant arthritis, such as the
carageenan paw edema model (C. A. Winter et al Proc.
Soc. Exp. Biol. Med. (1962) vol 111, p 544; K. F.

CA 02274093 2003-02-20
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211
Swingle, in R. A. Scherrer and M. W. Whitehouse, Eds.,
Antiinflammatory Agents, Chemistry and Pharmacology,
Vol. 13-II, Academic, New York, 1974, p. 33) and
collagen induced arthritis (D. E. Trentham et al J. Exp.
Med. (1977) vol. 146, p 857; J. S. Courtenay, Nature
(New Biol.) (1980), Vol 283, p 666).
~"I-Glucagon Handing Screen with CSO/hGLUR Cells
The assay is described in WO 97/16442.
Reagents
The reagents can be prepared as follows: (a)
prepare fresh 1M o-Phenanthroline (Aldrich) (198.2 mg/ml
ethanol); (b) prepare fresh 0.5M DTT (Sigma); (c)
Protease Inhibitor Mix (1000X): 5 mg leupeptin, 10 mg
benzamidine, 40 mg bacitracin and 5 mg soybean trypsin
inhibitor per ml DMSO and store aliquots at -20°C; (d)
250 E1M human glucagon (Peninsula): solubilize 0.5 mg
vial in 575 ~.1 O.1N acetic acid (1 ~.1 yields 1 ).tM final
concentration in assay for non-specific binding) and
store in aliquots at -20°C; (e) Assay Buffer: 20mM Tris
(pH 7.8), 1 mM DTT and 3 mM o-phenanthroline; (f) Assay
Buffer with 0.1~ BSA (for dilution of label only; 0.01
final in assay): 10 ~.ll 10~ BSA (heat-inactivated) and
990 ail Assay Buffer; (g) 1~SI-Glucagon (NF.N, receptor-
grade, 2200 Ci/m~nol) : dilute to 50, 000 cpml25 ~,1 in
assay buffer with BSA (about 50pM final concentration in
assay).
Harvestincr of CHO/hGLUR Cells for Assav
1. Remove media from confluent flask then rinse
once each with PBS (Ca, Mg-free) and Enzyme-free
Dissociation Fluid (Specialty Media, Inc.).
2. Add 10 ml Enzyme-free Dissoc. Fluid and hold
for about 4 min. at 37°C.

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3. Gently tap cells free, triturate, take aliquot
for counting and centrifuge remainder for 5 min. at 1000
rpm.
4. Resuspend pellet in Assay Buffer at 75000 cells
per 100 ~1.
Membrane preparations of CHO/hGLUR cells can be
used in place of whole cells at the same assay volume.
Final protein concentration of a membrane preparation is
determined on a per batch basis.
Assay
The determination of inhibition of glucagon binding
can be carried out by measuring the reduction of I125-
glucagon binding in the presence of compounds of Formula
I. The reagents are combined as follows:
Compound/ 250 ).l.M 125I- CHO/hGLUR
Vehicle Glucagon Glucagon Cells
Total --/5 ~,l -- 25 ~,l 100 ~.1
Binding
5 ~,l/-- '- 25 ~,1 100 ~,1
Compound
Nonspecif I --/5 ~.~,1 1 ~,1 25 )..1,1 100 ~.1
1C
Binding
The mixture is incubated for 60 min. at 22°C on a shaker
at 275 rpm. The mixture is filtered over pre-soaked
(0.5~ polyethylimine (PEI)) GF/C filtermat using an
Innotech Harvester or Tomtec Harvester with four washes
of ice-cold 20mM Tris buffer (pH 7.8). The
radioactivity in the filters is determined by a gamma-
scintillation counter.
Thus, compounds of the invention may also be shown
to inhibit the binding of glucagon to glucagon
receptors.
Cyclooxygeaase Enzyme Activity Assay

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The human monocytic leukemia cell line, THP-1,
differentiated by exposure to phorbol esters expresses
only COX-1; the human osteosarcoma cell line 143B
expresses predominantly COX-2. THP-1 cells are
routinely cultured in RPMI complete media supplemented
with 10o FBS and human osteosarcoma cells (HOSC) are
cultured in minimal essential media supplemented with
10~ fetal bovine serum (MEM-10~FBS); all cell
incubations are at 37°C in a humidified environment
containing 5~ COz.
COX-1 Assay
In preparation for the COX-1 assay, THP-1 cells are
grown to confluency, split 1:3 into RPMI containing 2~
FBS and 10 mM pr~orbol 12-myristate 13-acetate (TPA), and
incubated for 48 hours on a shaker to prevent
attachment. Cells are pelleted and resuspended in
Hank's Buffered Saline (HBS) at a concentration of 2.5 x
106 cells/mL and plated in 96-well culture plates at a
density of 5 x 105 cells/mL. Test compounds are diluted
in HBS and added to the desired final concentration and
the cells are incubated for an additional 4 hours.
Arachidonic acid is added to a final concentration of 30
mM, the cells incubated for 20 minutes at 37°C, and
enzyme activity determined as described below.
COX-2 Assav
For the COX-2 assay, subconfluent HOSC are
trypsinized and resuspended at 3 x 106 cells/mL in MEM-
FBS containing 1 ng human IL-1b/mL, plated in 96-well
tissue culture plates at a density of 3 x 10' cells per
well, incubated on a shaker for 1 hour to evenly
_ distribute cells, followed by an additional 2 hour
static incubation to allow attachment. The media is
then replaced with MEM containing 2~ FBS (MEM-2~FBS) and
1 ng human IL-1b/mL, and the cells incubated for 18-22

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hours. Following replacement of media with 190 mL MEM,
mL of test compound diluted in HBS is added to
achieve the desired concentration and the cells
incubated for 4 hours. The supernatants are removed and
5 replaced with MEM containing 30 mM arachidonic acid, the
cells incubated for 20 minutes at 37°C, and enzyme
activity determined as described below.
COX Activity Determined
10 After incubation with arachidonic acid, the
reactions are stopped by the addition of 1 N HC1,
followed by neutralization with 1 N NaOH and
centrifugation to pellet cell debris. Cyclooxygenase
enzyme activity in both HOSC and THP-1 cell supernatants
is determined by measuring the concentration of PGE2
using a commercially available ELISA (Neogen #404110).
A standard curve.of PGEZ is used for calibration, and
commercially available COX-1 and COX-2 inhibitors are
included as standard controls.
Accordingly, the compounds of the invention or a
pharmaceutical composition thereof are useful for
prophylaxis and treatment of rheumatoid arthritis;
Pagets disease; osteophorosis; multiple myeloma;
uveititis; acute and chronic myelogenous leukemia;
pancreatic i~ cell destruction; osteoarthritis;
rheumatoid spondylitis; gouty arthritis; inflammatory
bowel disease; adult respiratory distress syndrome
CARDS); psoriasis; Crohn's disease; allergic rhinitis;
ulcerative colitis; anaphylaxis; contact dermatitis;
asthma; muscle degeneration; cachexia; Reiter's
syndrome; type I and type II diabetes; bone resorption
diseases; graft vs. host reaction; ischemia reperfusion
injury; atherosclerosis; brain trauma; Alzheimer's
disease; stroke; myocardial infarction; multiple
sclerosis; cerebral malaria; sepsis; septic shock; toxic
shock syndrome; fever, and myalgias due to infection.
HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,

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adenovirus, the herpes viruses (including HSV-1, HSV-2),
and herpes zoster, all of which are sensitive to TNF-oc
and/or IL-1 inhibition or glucagon antagonism, will also
be positively effected by the compounds and methods of
the invention.
The compounds of the present invention also may
possess analgesic properties and may be useful for the
treatment of pain disorders, such as hyperalgesia due to
excessive IL-1. The compounds of the present invention
may also prevent the production of prostaglandins by
inhibition of enzymes in the human arachidonic
acid/prostaglandin pathway, including cyclooxygenase (WO
96/0338T~.
Because of their ability to lower TNF-a and IL-1
concentrations or inhibit glucagon binding to its
receptor, the compounds of the invention are also useful
research tools for studying the physiology associated
with blocking these effects.
The methods of the invention comprise administering
an effective dose of a compound of the invention, a
pharmaceutical salt thereof, or a pharmaceutical
composition of either, to a subject (i.e., an animal,
preferably a mammal, most preferably a human) in need of
a reduction in the level of TNF-a, TL-1, IL-6, and/or
IL-8 levels and/or reduction in plasma glucose levels
and/or which subject may be suffering from rheumatoid
arthritis; Pagets disease; osteophorosis; multiple
myeloma; uveititis; acute and chronic myelogeno s
leukemia; pancreatic Q cell destruction; osteoarthritis;
rheumatoid spondylitis; gouty arthritis; inflammatory
bowel disease; adult respiratory distress syndrome
(ARDS)~; psoriasis; Crohn's disease; allergic rhinitis;
ulcerative colitis; anaphylaxis; contact dermatitis;
asthma; muscle degeneration; cachexia; Reiter~s
syndrome; type I and type II diabetes; bone resorption
diseases; graft vs. host reaction; Alzheimer's disease;

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216 '
stroke; myocardial infarction; ischemia reperfusion
injury; atherosclerosis; brain trauma; multiple
sclerosis; cerebral malaria; sepsis; septic shock; toxic
shock syndrome; fever, and myalgias due to infection, or
which subject is infected by HIV-1, HIV-2, HIV-3,
cytomegalovirus (CMV), influenza, adenovirus, the herpes
viruses (including HSV-1, HSV-2), or herpes zoster.
In another aspect, this invention comprises the use
of a compound of the invention, or pharmaceutically
acceptable salts thereof, in the manufacture of a
medicament for the treatment either acutely or
chronically of a TNF-oc, IL-1(3, IL-6, and/or IL-8 mediated
disease state, including those described previously.
Also, the compounds of this invention are useful in the
manufacture of a analgesic medicament and a medicament
for treating pain disorders, such as hyperalgesia. The
compounds of the present invention also are useful in the
manufacture of a medicament to prevent the production of
prostaglandins by inhibition of enzymes in the human
arachidonic acid/prostaglandin pathway.
In still another aspect, this invention provides a
pharmaceutical composition comprising an effective TNF-
oc, IL-l~i, IL-6, and/or IL-8 lowering amount and/or
effective plasma glucose level lowering amount of a
compound of the invention and a pharmaceutically
acceptable carrier or diluent, and if desired other
"active ingredients. The compounds of the invention are
administered by any suitable route, preferably in the
form of a pharmaceutical composition adapted to such a
route, and in a dose effective for the treatment
intended. Therapeutically effective doses of the
compounds of the present invention required to arrest
the progress or prevent tissue damage associated with
the disease are readily ascertained by one of ordinary
skill in the art using standard methods.
For the treatment of TNF-OC, IL-1~3, IL-6, and IL-8
mediated diseases and/or hyperglycemia, the compounds of

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217
the present invention may be administered orally,
parentally, by inhalation spray, rectally, or topically
in dosage unit formulations containing conventional
pharmaceutically acceptable carriers, adjuvants, and
vehicles. The term parenteral as used herein includes,
subcutaneous, intravenous, intramuscular, intrasternal,
infusion techniques or intraperitoneally.
The dosage regimen for treating a TNF-OC, IL-1, IL
6, and IL-8 mediated diseases and/or hyperglycemia with
the compounds of this invention and/or compositions of
this invention is based on a variety of factors,
including the type of disease, the age, weight, sex,
medical condition of the patient, the severity of the
condition, the route of administration, and the
particular compound employed. Thus, the dosage regimen
may vary widely, but can be determined routinely using
standard methods. Dosage levels of the order from about
0.01 mg to 30 mg per kilogram of body weight per day,
preferably from about 0.1 mg to 10 mg/kg, more
preferably from about 0.25 mg to 1 mg/kg are useful for
all methods of use disclosed herein.
The pharmaceutically active compounds of this
invention can be processed in accordance with
conventional methods of pharmacy to produce medicinal
agents for administration to patients, including humans
and other mammals .
For oral administration, the pharmaceutical
composition may be in the form of, for example, a
capsule, a tablet, a suspension, or liquid. The
pharmaceutical composition is preferably made in the
form of a dosage unit containing a given amount of the
active ingredient. For example, these may contain an
amount of active ingredient from about 1 to 2000 mg,
- preferably from about 1 to 500 mg, more preferably from
about 5 to 150 mg. A suitable daily dose for a human or
other mammal may vary widely depending on the condition

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- . 218
of the patient and other factors, but, once again, can
be determined using routine methods.
The active ingredient may also be administered by
injection as a composition with suitable carriers
including saline, dextrose, or water. The daily
parenteral dosage regimen will be from about 0.1 to
about 30 mg/kg of total body weight, preferably from
about 0.1 to about 10 mg/kg, and more preferably from
about 0.25 mg to 1 mg/kg.
Injectable preparations, such as sterile injectabl~
aqueous or oleaginous suspensions, may be formulated
according to the known are using suitable dispersing or
wetting agents and suspending agents. The sterile
injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution
in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including
synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
Suppositories for rectal administration of the drug
can be prepared by mixing the drug with a suitable non-
irritating excipient such as cocoa butter and
polyethylene glycQls that are solid at ordinary
temperatures but liquid at the rectal temperature and
will therefore melt in the rectum and release the drug.
A suitable topical dose of active ingredient of a
compound of the invention is 0.1 mg to 150 mg
administered one to four, preferably one or two times
daily. For topical administration, the active
ingredient may comprise from 0.001 to 10~ w/w, e.g.,
from 1~ to 2~ by weight of the formulation, although it

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219
may comprise as much as 10~ w/w, but preferably not more
than 5~ w/w, and more preferably from 0.1~ to 1~ of the
- formulation.
Formulations suitable for topical administration
. 5 include liquid or semi-liquid preparations suitable for
penetration through the skin (e. g., liniments, lotions,
ointments, creams, or pastes) and drops suitable for
administration to the eye, ear, or nose.
For administration, the compounds of this invention
are ordinarily combined with one or more adjuvants
appropriate for the indicated route of administration.
The compounds may be admixed with lactose, sucrose,
starch powder, cellulose esters of alkanoic acids,
stearic acid, talc, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulphuric
acids, acacia, gelatin, sodium alginate, polyvinyl-
pyrrolidine, and/or polyvinyl alcohol, and tableted or
encapsulated for conventional administration.
Alternatively, the compounds of this invention may be
dissolved in saline, water, polyethylene glycol,
propylene glycol, ethanol, corn oil, peanut oil,
cottonseed oil, sesame oil, tragacanth gum, and/or
various buffers. Other adjuvants and modes of
administration are well known in the pharmaceutical art.
The carrier or diluent may include time delay material,
such as glyceryl monostearate or glyceryl distearate
-.alone or with a wax, or other materials well known in
the art.
The pharmaceutical compositions may be made up in a
solid form (including granules, powders or suppositories)
or in a liquid form (e.g., solutions, suspensions, or
emulsions). The pharmaceutical compositions may be
w subjected to conventional pharmaceutical operations such
- as sterilization and/or may contain conventional
adjuvants, such as preservatives, stabilizers, wetting
agents, emulsifiers, buffers etc.

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Solid dosage forms for oral administration may
include capsules, tablets, pills, powders, and granules.
In such solid dosage forms, the active compound may be
admixed with at least one inert diluent such as sucrose,
lactose, or starch. Such dosage forms may also
comprise, as in normal practice, additional substances
other than inert diluents, e.g., lubricating agents such
as magnesium stearate. In the case of capsules,
tablets, and pills, the dosage forms may also comprise
buffering agents. Tablets and pills can additionally be
prepared with enteric coatings.
Liquid dosage forms for oral administration may
include pharmaceutically acceptable emulsions,
solutions, suspensions, syrups, and elixirs containing
inert diluents commonly used in the art, such as water.
Such compositions may also comprise adjuvants, such as
wetting, sweetening, flavoring, and perfuming agents.
Compounds of the present invention can possess one
or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the
form of racemic or non-racemic mixtures thereof. The
optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes,
e.g., by formation of diastereoisomeric salts, by
=. treatment with an optically active acid or base.
Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric,
and camphorsulfonic acid and then separation of the
mixture of diastereoisomers by crystallization followed
by liberation of the optically active bases from these
salts. A different process for separation of optical
isomers involves the use of a chiral chromatography
column optimally chosen to maximize the separation of the
enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by
reacting compounds of the invention with an optically
pure acid in an activated form or an optically pure

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isocyanate. The synthesized diastereoisomers can be
separated by conventional means such as chromatography,
distillation, crystallization or sublimation, and then
hydrolyzed to deliver the enantiomerically pure compound.
The optically active compounds of the invention can
likewise be obtained by using active starting materials.
These isomers may be in the form of a free acid, a free
base, an ester or a salt.
The compounds of the present invention can be used
in the form of salts derived from inorganic or organic
acids. The salts include, but are not limited to, the
following: acetate, adipate, alginate, citrate,
aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride,
hydrobromide, hydroiodide, 2-hyroxy-ethanesulfonate,
lactate, maleate, methansulfonate, nicotinate, 2-
naphthalenesulfonate, oxalate, palmoate, pectinate,
persulfate, 2-phenylpropionate, picrate, pivalate,
propionate, succinate, tartrate, thiocyanate, tosylate,
mesylate, and undecanoate. Also, the basic nitrogen-
containing groups can be quaternized with such agents as
lower alkyl halides, such as methyl, ethyl, propyl, and
butyl chloride, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl, and diamyl sulfates,
long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides
like benzyl and phenethyl bromides, and others. Water or
oil-soluble-or dispersible products are thereby obtained.
Examples of acids that may be employed to from
pharmaceutically acceptable acid addition salts include
such inorganic acids as hydrochloric acid, sulphuric
acid and phosphoric acid and such organic acids as
oxalic acid, malefic acid, succinic acid and citric acid.
Other examples include salts with alkali metals or

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alkaline earth metals, such as sodium, potassium,
calcium or magnesium or with organic bases.
While the compounds of the invention can be
administered as the sole. active pharmaceutical agent,
they can also be used in combination with one or more
compounds of the invention or other agents. When
administered as a combination, the therapeutic agents
can be formulated as separate compositions that are
given at the same time or different times, or the
therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the
invention and is not intended to limit the invention to
the disclosed compounds. Variations and changes which
are obvious to one skilled in the art are intended to be
within the scope and nature of the invention which are
defined in the appended claims.
From the foregoing description, one skilled in the
art can easily ascertain the essential characteristics
of this invention, and without departing from the spirit
and scope thereof, can make various changes and
modifications of the invention to adapt it to various
usages and conditions.

Representative Drawing