ANTI-VIRAL COMPOUNDS

COMPOSES ANTI-VIRAUX

English Abstract

Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") or
other viruses are disclosed. This
invention is also directed to compositions comprising such compounds, co-
formulation or co-administration of such compounds
with other anti-viral or therapeutic agents, processes and intermediates for
the syntheses of such compounds, and methods of using
such compounds for the treatment of HCV or other viral infections.

French Abstract

L'invention concerne des composés efficaces pour inhiber la réplication du virus de l'hépatite C (« VHC ») ou d'autres virus. Cette invention concerne également des compositions comprenant de tels composés, la coformulation ou la coadministration de tels composés avec d'autres agents thérapeutiques ou anti-viraux, des procédés et des intermédiaires pour la synthèse de tels composés, et des procédés d'utilisation de tels composés pour le traitement du VHC ou d'autres infections virales.

Claims

CLAIMS

What is claimed is:


1. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula I,


Image

wherein:
A and B are each independently selected from carbocyclyl or heterocyclyl, and
are each
independently optionally substituted with one or more R18, wherein R18 is
independently
selected at each occurrence from the group consisting of halogen, oxo, thioxo,
hydroxy,
mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl,
alkenyl, alkynyl,
carbocyclyl, heterocyclyl, -L S-O-R S, -L S-S-R S, -L S-C(O)R S, -L S-OC(O)R
S, -L S-C(O)OR S,
-L S-N(R S R S'), -L S-C(=NR S)R S', -L S-S(O)R S, -L S-SO2R S, L S-C(O)N(R S
R S'), -L S-
N(R S)C(O)R S', -L S-C(=NR S)N(R S'R S"), -L S-N(R S')C(=NR S)R S", -L S-N(R
S)C(O)N(R S'R S"),
-L S-N(R S)SO2R S', -L S-SO2N(R S R S'), and -L S-N(R S)SO2N(R S'R S");
W1 and W2 are each independently selected from N or C(R33);
Z is a bond, -CR41R41'- or -NR41-, wherein R41 and R41' are each independently
selected from the
group consisting of hydrogen, alkyl, alkenyl and alkynyl;
R10 and R33 are each independently selected at each occurrence from the group
consisting of
hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino,
carboxy, formyl,
phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,-L S-O-R
S, -L S-S-R S, -
L S-C(O)R S, -L S-OC(O)R S, -L S-C(O)OR S, -L S-N(R S R S'), L S-C(=NR S)R S',
-L S-S(O)R S, -
L S-SO2R S, -L S-C(O)N(R S R S'), -L S-N(R S)C(O)R S', -L S-C(=NR S)N(R S'R
S"), -L S-
N(R S')C(=NR S)R S", -L S-N(R S)C(O)N(R S'R S"), -L S-N(R S)SO2R S', -L S-
SO2N(R S R S'), -L S-
N(R S)SO2N(R S'R S"), -L E-Q-L E'-(C3-C18carbocyclyl) and -L E-Q-L E'-(M3-
M18heterocyclyl);

201



X is selected from the group consisting of a bond, -L S-O-, -L S-S-, -L S-C(O)-
, -L S-N(R S)-, -
L S-N(R S)C(O)-, -L S-C(O)N(R S)-, -L S-N(R S)C(O)O-, -L S-OC(O)N(R S)-, -L S-
N(R S)C(O)N(R S')-, -L S-C(=NR S)N(R S')-, -L S-N(R S')C(=NR S)-, -L S-S(O)-, -
L S-SO2-, -
L S-C(O)O- and -L S-OC(O)-;
R22 is carbocyclyl or heterocyclyl, and is optionally substituted with one or
more R26, wherein R26
is independently selected at each occurrence from the group consisting of
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, alkyl,
alkenyl, alkynyl, -L S-O-R S, -L S-S-R S, -L S-C(O)R S, -L S-OC(O)R S, -L S-
C(O)OR S, -L S-
N(R S R S'), -L S-C(=NR S)R S', -L S-S(O)R S, -L S-SO2R S, -L S-C(O)N(R S R
S'), -L S-
N(R S)C(O)R S', -L S-C(=NR S)N(R S'R S"), -L S-N(R S')C(=NR S)R S", -L S-N(R
S)C(O)N(R S'R S"),
-L S-N=C(NR S R S')(NR S R S'), -L S-N(R S)SO2R S', -L S-SO2N(R S R S'), -L S-
N(R S)SO2N(R S'R S"),
-L E-Q-L E'-(C3-C18carbocyclyl) and -L S-Q-L E'-(M3-M18heterocyclyl); or R22
is alkyl,
alkenyl or alkynyl, and is optionally substituted with one or more R26; or R22
is hydrogen;
Y is selected from the group consisting of a bond, -L S-O-, -L S-C(O)-, -L S-
S(O)2-, -L S-S(O)-,
-L S-OS(O)2-, -L S-OS(O)-, -L S-C(O)O-, -L S-OC(O)-, -L S-OC(O)O-, -L S-
C(O)N(R15)-, -
L S-N(R15)C(O)-, -L S-C(O)N(R15)O-, -L S-N(R15)C(O)O-, -L S-C(O)N(R15)N(R15')-
, -L S-S-
, -L S-C(S)-, -L S-C(S)O-, -L S-OC(S)-, -L S-N(R15)-, -L S-C(S)N(R15)-, -L S-
N(R15)C(S)-, -
L S-N(R15)S(O)-, -L S-N(R15)S(O)2-, -L S-S(O)2N(R15)-, -L S-S(O)N(R15)-, -L S-
C(S)N(R15)O-, and -L S-C(S)N(R15)N(R15')-, wherein R15 and R15' are each
independently
selected at each occurrence from the group consisting of hydrogen, alkyl,
alkenyl and alkynyl;
R50 is -L1-A1, wherein A1 is selected from the group consisting of
carbocyclyl, heterocyclyl,
alkyl, alkenyl and alkynyl, and L1 is selected from the group consisting of a
bond, alkylene,
alkenylene and alkynylene, wherein A1 is optionally substituted with one or
more R30, and R30
is independently selected at each occurrence from the group consisting of
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, alkyl,
alkenyl, alkynyl, -L S-O-R S, -L S-S-R S, -L S-C(O)R S, -L S-OC(O)R S, -L S-
C(O)OR S, -L S-
N(R S R S'), -L S-C(=NR S)R S', -L S-S(O)R S, -L S-SO2R S, -L S-C(O)N(R S R
S'), -L S-
N(R S)C(O)R S', -L S-C(=NR S)N(R S'R S"), -L S-N(R S')C(=NR S)R S", -L S-N(R
S)C(O)N(R S'R S"),
-L S-N(R S)SO2R S', -L S-SO2N(R S R S'), -L S-N(R S)SO2N(R S'R S"), -L E-Q-L
E'-(C3-
C18carbocyclyl) and -L E-Q-L E'-(M3-M18heterocyclyl), and wherein L1 is
optionally
substituted with one or more R38, and R38 is independently selected at each
occurrence from
the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano,
amino,
carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy, alkylcarbonyl,
alkoxycarbonyl,
alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -L S-O-R S, -L S-S-R S, -L
S-C(O)R S, -
L S-OC(O)R S, -L S-C(O)OR S, -L S-N(R S R S'), -L S-C(=NR S)R S', -L S-S(O)R
S, -L S-SO2R S, -
L S-C(O)N(R S R S'), -L S-N(R S)C(O)R S', -L S-C(=NR S)N(R S'R S"), -L S-N(R
S')C(=NR S)R S", -

202



L S-N(R S)C(O)N(R S,R S"), -L S-N(R S)SO2R S', -L S-SO2N(R S R S'), -L s-N(R
s)SO2N(R s'R s"),
carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -L E-Q-L E'-
(C3-
C18carbocyclyl) and -L E-Q-L E'-(M3-M18heterocyclyl);
L S is independently selected at each occurrence from the group consisting of
a bond, alkylene,
alkenylene and alkynylene;
R S, R S' and R S" are each independently selected at each occurrence from the
group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl,
alkoxyalkoxyalkyl,
thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl,
alkoxycarbonylamino, and alkoxycarbonylaminoalkyl;
L E and L E' are each independently selected at each occurrence from the group
consisting of a
bond, alkylene, alkenylene and alkynylene;
Q is independently selected at each occurrence from the group consisting of a
bond, alkylene,
alkenylene, alkynylene, -S-, -O-, -C(O)-, N(R S)-, N(R S)C(O)-, -C(O)N(R S)-, -

N(R S)C(O)O-, -OC(O)N(R S)-, N(R S)C(O)N(R S')-, -C(=NR S)N(R S')-, -N(R
S')C(=NR S)-, -
S(O)-, -SO2-, -O-SO2-, -SO2-O-, -O-S(O)-, -S(O)-O-, -C(O)O- and -OC(O)-;
R10, R15, R15', R18, R26, R30, R33, R38, R41, and R41' are each independently
optionally substituted at
each occurrence with at least one substituent selected from the group
consisting of halogen,
oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl,
phosphate and azido;
and
each C3-C18carbocyclyl and M3-M18heterocyclyl moiety in -L E-Q-L E'-(C3-
C18carbocyclyl) and -
L E-Q-L E'-(M3-M18heterocyclyl) is independently optionally substituted at
each occurrence
with at least one substituent selected from the group consisting of hydrogen,
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, alkyl,
alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl,
alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino, and
alkoxycarbonylaminoalkyl.


2. The compound, tautomer or salt of claim 1, wherein:
A and B are each independently selected from C4-C11 carbocyclyl or M4-
M11heterocyclyl, and are
each independently optionally substituted with one or more R18, wherein R18 is
independently
selected at each occurrence from the group consisting of halogen, oxo, thioxo,
hydroxy,
mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6alkyl,
C2-C6alkenyl,
C2-C6alkynyl, C3-C6carbocyclyl, M3-M6heterocyclyl, -L S-O-R S, -L S-S-R S, -L
S-C(O)R S, -
L S-OC(O)R S, -L S-C(O)OR S, -L S-N(R S R S'), -L S-C(=NR S)R S', -L S-S(O)R
S, -L S-SO2R S, -

203



L S-C(O)N(R S R S'), -L S-N(R S)C(O)R S', -L S-C(=NR S)N(R S,R S"), -L S-N(R
S')C(=NR S)R S", -
L S-N(R S)C(O)N(R S'R S"), -L S-N(R S)SO2S', -L S-SO2N(R S R S'), and -L S-
N(R S)SO2N(R S'R S");
W1 and W2 are each independently selected from N or C(R33);
Z is a bond, -CR41R41'- or NR41-, wherein R41 and R41' are each independently
selected from the
group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl and C2-C6alkynyl;
R10 and R33 are each independently selected at each occurrence from the group
consisting of
hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino,
carboxy, formyl,
phosphate, azido, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, M3-

M6heterocyclyl, -L S-O-R S, -L S-S-R S, -L S-C(O)R S, -L S-OC(O)R S, -L S-
C(O)OR S, -L S-
N(R S R S,), -L S-C(=NR S)R S', -L S-S(O)R S, -L S-SO2R S, -L S-C(O)N(R SR
S'), -L S-
N(R S)C(O)R S', -L S-C(=NR S)N(R S'R S"), -L S-N(R S')C(=NR S)R S", -L S-N(R
S)C(O)N(R S'R S"),
-L S-N(R S)SO2R S', -L S-SO2N(R S R S'), -L-S-N(R S)SO2N(R S'R S"), -L E-Q-L
E'-(C3-
C18carbocyclyl) and -L E-Q-L E'-(M3-M18heterocyclyl);
X is selected from the group consisting of a bond, -L S-O-, -L S-S-, -L S-C(O)-
, -L S-N(R S)-, -
L S-N(R S)C(O)-, -L S-C(O)N(R S)-, -L S-N(R S)C(O)O-, -L S-OC(O)N(R S)-, -L S-
N(R S)C(O)N(R S')-, -L S-C(=NR S)N(R S,)-, -L S-N(R S')C(=NR S)-, -L S-S(O)-, -
L S-SO2-, -
L S-C(O)O- and -L-S-OC(O)-;
R22 is C4-C11carbocyclyl or M4-M11heterocyclyl, and is optionally substituted
with one or more
R26, wherein R26 is independently selected at each occurrence from the group
consisting of
halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl,
phosphate,
azido, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -L-S-O-R S, -L S-S-R S, -L S-
C(O)R S, -L S-
OC(O)R S, -L S-C(O)OR S, -L S-N(R S R S')2 -L S-C(=NR S)R S', -L S-S(O)R S, -L
S-SO2R S, -L S-
C(O)N(R S R S'),-L S-N(R S)C(O)R S', -L S-C(=NR S)N(R S'R S"), -L S-N(R
S')C(=NR S)R S", -L S-
N=C(NR S R S')(NR S R S'), L S-N(R S)C(O)N(R S'R S"), L S-N(R S)SO2R S', -L S-
SO2N(R SR S'), -
L S-N(R S)SO2N(R S'R S"), -L E-Q-L E'-(C3-C18carbocyclyl) and -L E-Q-L E'-(M3-
M18heterocyclyl); or R22 is C1-C6alkyl, C1-C6alkenyl or C1-C6alkynyl, and is
optionally
substituted with one or more R26; or R22 is hydrogen;
Y is selected from the group consisting of a bond, -L S-O-, -L S-C(O)-, -L S-
S(O)2-, -L S-S(O)-,
-L S-OS(O)2-, -L S-OS(O)-, -L S-C(O)O-, -L S-OC(O)-, -L S-OC(O)O-, -L S-
C(O)N(R15)-, -
L S-N(R15C(O)-, -L S-C(O)N(R15)O-, L S-N(R15)C(O)O-, -L S-C(O)N(R15)N(R15')-, -
L S-S-
, -L S-C(S)-, -L S-C(S)O-, -L S-OC(S)-, -L S-N(R15)-, -L S-C(S)N(R15)-, -L S-
N(R15)C(S)-, -
L S-N(R15)S(O)-, -L S-N(R15)S(O)2-, -L S-S(O)2N(R15)-, -L S-S(O)N(R15)-, L S-
C(S)N(R15)O-, and -L S-C(S)N(R15)N(R15')-, wherein R15 and R15' are each
independently
selected at each occurrence from the group consisting of hydrogen, C1-C6alkyl,
C2-C6alkenyl
and C2-C6alkynyl;


204



R50 is -L1-A1, wherein A1 is selected from the group consisting of C4-
C11carbocyclyl, M4-
M11heterocyclyl, C1-C6alkyl, C2-C6alkenyl and C2-C6alkynyl, and L1 is selected
from the
group consisting of a bond, C1-C6alkylene, C2-C6alkenylene and C2-
C6alkynylene, wherein A1
is optionally substituted with one or more R30, and R30 is independently
selected at each
occurrence from the group consisting of halogen, oxo, thioxo, hydroxy,
mercapto, nitro,
cyano, amino, carboxy, formyl, phosphate, azido, C1-C6alkyl, C2-C6alkenyl, C2-
C6alkynyl, -
L S-O-R S, -L S-S-R S, -L S-C(O)R S, -L S-OC(O)R S, -L S-C(O)OR S, -L S-N(R S
R S'), -L S-
C(=NR S)R S', -L S-S(O)R S, -L S-SO2R S, -L S-C(O)N(R S R S'), L S-N(R S)C(O)R
S', -L S-
C(=NR S)N(R S' R S"), -L S-N(R S')C(=NR S)R S", -L S-N(R S)C(O)N(R S'R S"), -L
S-N(R S)SO2R S', -
L S-SO2N(R S R S'), -L S-N(R S)SO2N(R S'R S"), -L E-Q-L E'-(C3-C18carbocyclyl)
and -L E-Q-L E'-
(M3-M18heterocyclyl), and wherein L1 is optionally substituted with one or
more R38, and R38
is independently selected at each occurrence from the group consisting of
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, C1-
C6alkoxy, C1-C6thioalkoxy, C1-C6alkylcarbonyl, C1-C6alkoxycarbonyl, C1-
C6alkylcarbonyloxy, C1-C6alkylamino, C1-C6alkoxycarbonylamino, -L S-O-R S, -L
S-S R S', -
L S-C(O)R S, -L S-OC(O)R S, -L S-C(O)OR S, -L S-N(R SR S'); -L S-C(=NR S)R S',
-L S-S(O)R S, -
L S-SO2R S, -L S-C(O)N(R S R S'), L S-N(R S)C(O)R S', -L S-C(=NR S)N(R S'R
S"), -L S-
N(R S')C(=NR S)R S", -L S-N(R S)C(O)N(R S'R S"), L S-N(R S)SO2R S', -L S-
SO2N(R S R S'), -L S-
N(R S)SO2N(R S'R S"), carbocyclyl, heterocyclyl, carbocyclylC1-C6alkyl,
heterocyclylC1-
C6alkyl, -L E-Q-L E'-(C3-C18carbocyclyl) and -L E-Q-L E',-(M3-
M18heterocyclyl);
L S is independently selected at each occurrence from the group consisting of
a bond, Cl-
C6alkylene, C2-C6alkenylene and C2-C6alkynylene;
R S, R S' and R S" are each independently selected at each occurrence from the
group consisting of
hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-
C6thioalkoxy, C1-
C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxyC1-C6alkyl, C1-C6thioalkoxyC1-
C6alkyl, C1-
C6alkylcarbonyl, C1-C6alkylcarbonylC1-C6alkyl, C1-C6alkoxycarbonyl, C1-
C6alkoxycarbonylC1-C6alkyl, C1-C6alkylcarbonyloxy, C1-C6alkylcarbonyloxyC1-
C6alkyl, C1-
C6alkylamino, C1-C6alkylaminoC1-C6alkyl, C1-C6alkoxycarbonylamino, and C1-
C6alkoxycarbonylaminoC1-C6alkyl;
L E and L E' are each independently selected at each occurrence from the group
consisting of a
bond, C1-C6alkylene, C2-C6alkenylene and C2-C6alkynylene;
Q is independently selected at each occurrence from the group consisting of a
bond, C1-
C6alkylene, C2-C6alkenylene, C2-C6alkynylene, -S-, -O-, -C(O)-, N(R S)-, N(R
S)C(O)-, -
C(O)N(R S)-, N(R S)C(O)O-, -OC(O)N(R S)-, N(R S)C(O)N(R S')-, -C(=NR S)N(R S')-
, -
N(R S')C(=NR S)-, -S(O)-, -SO2-, -O-SO2-, -SO2-O-, -O-S(O)-, -S(O)-O-, -C(O)O-
and
-OC(O)-;


205



R10, R15, R15', R18, R26, R30 R33, R38, R41, and R41' are each independently
optionally substituted at
each occurrence with at least one substituent selected from the group
consisting of halogen,
oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl,
phosphate, and azido;
and
each C3-C18carbocyclyl and M3-M18heterocyclyl moiety in -L E-Q-L E,-(C3-
C18carbocyclyl) and -
L E-Q-L E'-(M3-M18heterocyclyl) is independently optionally substituted at
each occurrence
with at least one substituent selected from the group consisting of halogen,
oxo, thioxo,
hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-
C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6thioalkoxy, C1-C6alkoxyC1-C6alkyl,
C1-
C6thioalkoxyC1-C6alkyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonylC1-C6alkyl, C1-
C6alkoxycarbonyl, C1-C6alkoxycarbonylC1-C6alkyl, C1-C6alkylcarbonyloxy, C1-
C6alkylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6alkylaminoC1-C6alkyl, C1-
C6alkoxycarbonylamino, and C1-C6alkoxycarbonylaminoC1-C6alkyl.


3. The compound, tautomer or salt according to one of claims 1-2, wherein:
Y is -L S-O-, -L S-S- or -L S-N(R15)-; and
A1 is C4-C11carbocyclyl or M4-M11heterocyclyl and is optionally substituted
with one or more R30.

4. The compound, tautomer or salt according to one of claims 1-3, wherein A
and B are each
independently selected from C5-C6carbocyclyl or M5-M6heterocyclyl and are each
independently
optionally substituted with one or more R18.


5. The compound, tautomer or salt according to one of claims 1-4, wherein W1
and W2 are N, and Z
is NR41-.


6. The compound, tautomer or salt according to one of claims 1-5, wherein X is
-O- or -S-, and R22
is C5-C6carbocyclyl or M5-M6heterocyclyl and is optionally substituted with
one or more R26.


7. The compound, tautomer or salt according to one of claims 1-6, wherein the
moiety

Image is selected from the group consisting of Image



206


Image

wherein Q is N or
C(R33), and wherein R10, R17, R33 and R35 are each independently selected at
each occurrence from the
group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro,
cyano, amino, carboxy,
formyl, phosphate, azido, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-
C6carbocyclyl, M3-
M6heterocyclyl, -L s-O-R s, -L s-S-R s, -L s-C(O)R s, -LOC(O)R s,-L s-C(O)OR
s, -L s-N(R s R s'), -
L s-C(=NR s)R s', -L s-S(O)R s, -L s-SO2R s, -L s-C(O)N(R s R s'), -L s-N(R
s)C(O)R s', -L s-
C(=NR s)N(R s'R s".), -L s-N(R s')C(=NR s)R s", -L s-N(R s)C(O)N(R s'R s"), L
s-N(R s)SO2R s', -L s-
SO2N(R s R s'), -L s-N(R s)SO2N(R s'R s"), -L E-Q-L E'-(C3-C18carbocyclyl) and
-L E-Q-L E'-(M3-
M18heterocyclyl).

8. The compound, tautomer or salt according to one of claims 1-7, wherein R22
is
Image
and is optionally substituted with one or
more R26, and wherein R48 is hydroxy, amino, C1-C6alkylamino, C1-C6alkoxy, C1-
C6alkoxycarbonylamino or C1-C6alkylcarbonyloxy.

9. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula II:

Image
wherein:
R6 is selected from the group consisting of hydrogen and cyano;
207


R8 is selected from the group consisting of hydrogen and arylalkyl;
R25 is selected from the group consisting of hydrogen and alkyl;
R37 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl,
and cycloalkyl;
R42 is selected from the group consisting of arylsulfanyl, heteroarylsulfanyl,
and aryloxy;
wherein R42 is optionally substituted with one or more substituents
independently selected from R46;
R46 is one or more substituents selected from the group consisting of
hydrogen, hydroxy,
amino, halogen, dialkylamino, and alkoxycarbonylamino;
R70 is selected from the group consisting of aryl, and heterocyclo; wherein
R70 is optionally
substituted with R75;
R75 is one or more substituents independently selected from the group
consisting of hydrogen,
halogen, alkoxy, cyano, alkyl, haloalkyl, and aryl.

10. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula III:

Image
wherein R80 is selected from the group consisting of hydrogen, alkylcarbonyl,
and haloaryl.
11. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula IV,

208


Image
wherein:
Q is selected from the group consisting of N and CH;
R1 is selected from the group consisting of alkylsulfanyl, cyanoalkylsulfanyl,
and alkyl;
R19 is selected from the group consisting of alkyl and haloarylalkoxy;
R56 is selected from the group consisting of hydrogen, hydroxy, alkyl, and
alkylcarbonylamino.

12. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula V:

Image
wherein:
R5 is selected from the group consisting of hydrogen and alkylsulfanyl;
R29 is selected from the group consisting of alkyl, arylalkoxy, halogen, and
haloarylalkoxy;
R47 is selected from the group consisting of alkyl, haloalkyl, alkylsulfanyl,
arylalkylsulfanyl,
and heterocyclo;
R4 is selected from the group consisting of hydrogen, alkoxy, and alkyl;
209


R66 is selected from the group consisting of hydrogen, hydroxy, aryloxy,
alkylsulfonyloxy,
alkylcarbonylaminoarylsulfonoyloxy, haloarylsulfonyloxy, cyano, arylalkoxy,
alkylcarbonylamino,
halogen, and alkyl;
R81 is selected from the group consisting of hydrogen, alkoxy, and carbonyl.

13. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula VI:

Image
wherein:
R73 is alkyl;
R76 is selected from the group consisting of hydroxy, alkylaminocarbonyl, and
alkylcarbonylamino.

14. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula VII:

Image
wherein:
210


A is selected from the group consisting of O and S;
R21 is selected from the group consisting of hydrogen and hydroxy;
or R21 taken together with R39 form a 5-12 membered heterocycle containing at
least two
heteroatoms selected from the group consisting of O, N, and S; wherein the
heterocycle is optionally
substituted aryl or halogen; or
R39 is selected from the group consisting of hydrogen, alkyl, arylalkenyl,
dialkylamino,
heteroaryl, haloheteroaryl, haloarylaminosulfonyl, arylsulfonyloxy,
alkylcarbonyloxy,
cycloalkylaminocarbonyl, arylalkoxycarbonylamino, haloheteroaryl,
alkoxycarbonyl, and NH-R99;
R99 is selected from the group consisting of hydrogen, arylalkyl,
cycloalkylalkyl, aryl,
heteroaryl, haloarylalkylamino, arylalkylamino, and alkylheteroaryl;
R67 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and
alkylcycloalkyl;
R96 is selected from the group consisting of hydrogen, hydroxy, amino, alkoxy,

arylsulfonyloxy, alkylcarbonylamino, alkoxy, halogen, alkoxycarbonyloxy,
haloalkoxycarbonylamino, and arylalkoxy.

15. A compound, a tautomer of the compound, or a pharmaceutically acceptable
salt of the compound
or tautomer, wherein the compound has Formula VIII:

Image
wherein:
R23 is selected from the group consisting of hydrogen, alkoxyaryl,
alkoxyarylsulfanyl,
hydroxyarylsulfanyl, haloarylalkoxy, cyanoarylalkoxy, and arylalkoxy;
R31 is selected from the group consisting of hydrogen and halogen;
R49 is selected from the group consisting of hydrogen, arylalkoxy,
haloarylcarbonylamino,
alkoxyarylcarbonylamino, arylalkenyl, arylalkyl, halogen, cyano,
haloaryloxyalkyl, alkyl,
alkoxyarylsulfanyl, haloheteroaryl, and alkoxycarbonyl;

211


R52 is selected from the group consisting of hydrogen, halogen, alkyl,
hydroxyaryloxy,
aryloxy, hydroxyalkylaryloxy, alkoxyarylalkyl, alkoxyaryloxy,
alkylarylalkoxyarylamino, arylalkyl,
heteroaryl, and aminoaryloxy;
R77 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

16. A pharmaceutical composition comprising a compound, tautomer or salt
according to one of
claims 1-15.

17. A method of inhibiting HCV virus replication, comprising contacting HCV
virus with an
effective amount of a compound, tautomer or salt according to one of claims 1-
15, thereby inhibiting
replication of said virus.

18. A method of treating HCV infection, comprising administering an effective
amount of a
compound, tautomer or salt according to one of claims 1-15 to an HCV patient,
thereby reducing
HCV viral level in the blood or liver of the patient.

19. Use of a compound, tautomer or salt according to one of claims 1-15 for
the manufacture of a
medicament for the treatment of HCV infection or inhibiting HIV replication.

20. A process of making a compound according to one of claims 1-15, comprising
the steps
described in one of schemes 1-8.

212

Description

CA 02633752 2008-06-18
WO 2007/081517 PCT/US2006/048685
ANTI-VD.2AL COMPOUNDS

[0001] This application claims the benefit and incorporates herein by
references the entire
content of U.S. Provisional Application No. 60/752,473, filed December 21,
2005.

FTELD
[0002] The present invention relates to compounds effective in inhibiting
replication of
Hepatitis C virus ("HCV"). The present invention also relates to methods of
making such
compounds, compositions comprising such compounds, intermediates for the
syntheses of such
compounds, and methods of using such compounds/compositions for the treatment
of HCV infection
or conditions/symptoms associated therewith. In addition, the present
invention relates to use of such
compounds for the manufacture of medicaments for the treatment of HCV
infection.

BACKGROUND
[0003] HCV, a human pathogen, is an RNA virus belonging to the Hepacivirus
genus in the
Flaviviridae family. As is characteristic with all other members of the
Flaviviridae family, HCV has
enveloped virions that contain a positive stranded RNA genome encoding all
known virus-specific
proteins in one single, uninterrupted, open reading frame. The open reading
frame comprises
approximately 9500 nucleotides encoding a single large polyprotein of about
3000 amino acids. The
polyprotein comprises a core protein, envelope proteins El and E2, a membrane
bound protein p7,
and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. A
cellular protease
cleaves the viral protein at the NS2-NS3 junction allowing a viral protease
(NS3 protease) to mediate
subsequent cleavages. The NS3 protein also exhibits nucleoside triphosphatase
and RNA helicase
activities. NS2 and NS4A may, too, be involved in proteolytic activity. NSSA
is a phosphoprotein
involved in replication_ NS5B is a RNA-dependent RNA polymerase. U.S. Patent
Pub. No.
2004/0265792, published 30 December 2004, mentions that inhibition of the
aforementioned non-
structural proteins may inhibit HCV replication.
[0004] HCV infection is associated with progressive liver pathology, including
cirrhosis and
hepatocellular carcinoma. HCV-associated end-stage liver disease is the most
frequent indication for
liver transplantation among adults. Chronic hepatitis C may be treated with a
once-weekly injection
of peginterferon-alpha in combination with daily ribavarin. Peginterferon-
alpha is interferon-alpha
attached to polyethylene glycol to slow elimination of the drug from the body.
This results in
enhanced compliance and clinically superior anti-viral activity when compared
to treatments of
interferon-alpha daily injections. Substantial limitations to efficacy and
tolerability remain as many
users suffer from side effects and viral elimination from the body is often
inadequate.

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[0005] Attempts have been made to design drugs that specifically inhibit
functions of the
hepatitis C virus. Boehringer Ingelheim U.S. Patent No. 6,323,180 mentions tri-
peptide compounds
as HCV serine protease inhibitors proposed for treatment of HCV infection.
[0006] Another approach is ISIS-14803 (Isis Pharmaceuticals), an antisense
inhibitor
complementary to a conserved sequence of the hepatitis C virus RNA. This
molecule binds to the
viral RNA and inhibits the expression of proteins required for replication.
[0007] Inhibition of HCV translation, by a yeast RNA that binds to cellular
polypeptides and
prevents their interaction with the viral internal ribosome entry site (IRES),
is described in Das el al,
J. VIROLOGY, 72(7):5638-5647 (1998).
[0008] Fused-bicyclic heterocyclic compounds have been proposed for diverse
life-science-
related uses. Examples of such heterocyclic compounds include naphthyridine,
pyridopyrirnidine,
pyrimidopyrimidine, pyrazolopyrimidine and thiazolo/thienopyrimidine
compounds.
[0009] Naphthyridine-type fused-bicyclic compounds have been investigated for
disease-
treatment uses. For example, Boots WO 93/13097, published 8 July 1993,
mentions
[1,8]naphthyridine compounds, such as ethyl 4-(4-methoxyanilino)-6-ethoxy-7-
methyl-l,8-
naphthyridine-3-carboxylate hydrochloride, proposed for use as anti-rheumatic
agents. Boots WO
95/00511, published 5 January 1995, mentions substituted ring-fused 4-
aminopyridines, such as 3-
ethoxy-5-(2-ethoxy-5-pyridylamino) -2-methyl-1,8-naphthyridine, proposed for
use as anti-rheumatic
agents. Zeneca WO 98/13350, published 2 April 1998, mentions
[1,8]naphthyridine compounds, such
as 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylanilino)-1,8-naphthyridine
hydrochloride, proposed as
anti-angiogenic agents. Neurogen WO 2004/055004, published 1 July 2004,
mentions naphthyridine
compounds as capsaicin-receptor modulators, specific compounds being 5-(4-
trifluoromethyl-
phenylamino) -2-(3-trifluoromethyl-pyridin-2-yl)-[1,6] naphthyridine-7-
carboxylic acid, and 2-
methoxymethyl-4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-
yl)-[ 1, 8]
naphthyridine-3-carboxylic acid.
[0010] Pyridopyrimidine-type fused-bicyclic compounds have been investigated
for various
disease-treatment uses. For example, Pfizer WO 98/05661, published 12 February
1998, mentions
substituted pyridopyrimidine compounds, such as [8-(1-ethyl-propyl)-2-methyl-
5,6,7,8-tetrahydro-
pyrido(2,3-d)pyrimidin-4y1]-(2,4,6-trimethyl-phenyl)-amine, as corticotrophin
releasing factor
(hormone) CRF (CRH) antagonists proposed for treatment of Alzheimer's Disease
and obesity. Pfizer
WO 98/23613, published 4 June 1998, mentions fused-bicyclic pyrimidine
compounds, including
pyridopyrimidinyl-aminophenyl compounds, such as (3-ethynyl-phenyl)-pyrido[3,4-
d]pyrimidin-4-
yl-amine, proposed for treatment of hyperproliferative diseases such as
cancer. Glaxo Wellcome U.S.
Patent No. 6,169,091, issued 2 January 2001, mentions bicyclic heteroaromatic
compounds, such as 4-
(4-benzyloxyanilino)pyrido[2,3-d]-pyrimidine, as tyrosine Idnase inhibitors
proposed for treatment of
fibrosis, inflammation, nervous system diseases and cancer. Eli Lilly WO
01/32632, published 10
2


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May 2001, mentions 4-substitutcd pyrimidine compounds, including 2-
trifluoromethyl-4-[2-(2-(2-
chlorophenyl)ethylamino]pyrido-[2,3-d]pyrimidine hydrochloride, as mGluRl
antagonists proposed
for treatxnent of neurological disorders associated with glutamate dysfunction
such as convulsions,
migraine, psychosis, anxiety and pain. Abbott Laboratories WO 01/57040
published 9 August 2001,
mentions 6, 7-disubstituted-4-aminopyrido [2,3-d] pyrimidine compounds, such
as 4-amino-6-(4-
rnethylphenyl)-7-(4 bromophenyl)pyrido[2,3-d]pyrimidine, as adenosine ldnase
inhibitors proposed
for treatment of pain and inflammation. Neurogen WO 2004/055004, published 1
July 2004,
mentions pyridopyrrnidinyl-aminophenyl compounds, such as 2-methyl-2-{4-[2-
methyl-7-(3-methyl-
pyridin-2-yl)-pyrido[2,3-d]pyrirnidin-4-ylamino]-phenyl}-propionic acid, as
capsaicin-receptor
modulators. Pfizer U.S. Patent No. 6,395,733, issued 28 May 2002, mentions
heterocyclic ring-fused
pyrimidine compounds, such as 3-chloro-phenyl-pyrido[2,3-d]pyrimidin-4-yl-
amine, proposed for
treatment of hyper-proliferative disease, such as cancer.
[0011] Pyrimidopyrimidine-type fused bicyclic compounds have been investigated
for both
pest-control and disease-treatment uses. For example, Dow Elanco U.S. Patent
No. 5,350,749, issued
27 September 1994, mentions 4-substituted-pyrimido [2,3-d] pyrimidine
compounds proposed for use
as fungicides, insecticides and miticides. Warner-Lambert WO 95/19774,
published 27 July 1995,
mentions pyrimidopyrimidine compounds, such as 4-benzylamino-7-
methylaminopyrimido[4,5-
d]pyrimidine, as tyrosine kinase inhibitors proposed for treatment of cancer,
vascular restenosis and
psoriasis.
[0012] Thienopyrimidine-type fused-bicyclic compounds have been investigated
for various
disease-treatment uses. For example, Warner-Lambert WO 95/19774, published 27
July 1995,
mentions fused heterocyclic pyrimidine compounds, including 4-(3-
bromoanilino)thieno[2,3-
d]pyrimidine, as tyrosine Icinase inhibitors proposed for treatment of cancer,
vascular restenosis and
psoriasis. Glaxo Wellcome U.S. Patent No. 6,169,091, issued 2 January 2001,
mentions bicyclic
heteroaromatic compounds, such as 5-methyl-4-(4-phenoxyanilino)thieno[2,3-
d]pyrimidine
hydrochloride as tyrosine lcinase inhibitors, proposed for treatment of
fibrosis, inflammation, nervous
system diseases and cancer. Eli Lilly WO 01/32632, published 10 May 2001,
mentions 4-substituted-
pyrimidine compounds, such as 6-methyl-4-[2,6-
dichlorobenzylthio)ethylamino]thieno[2,3-
d]pyrimidine hydrochloride, as mGluRl antagonists proposed for treatment of
neurological disorders
associated with glutamate dysfunction such as convulsions, migraine,
psychosis, anxiety and pain.
[0013] Bristol-Myers Squibb WO 2004/014852, published 19 February 2004,
mentions
iminothiazolidinones, including fused-bicyclic derivatives of 2-(4-
aminophenyl)-5H-thiazolo[2,3-
6]quinazolin-3-one, as NS5A protein-inhibitors proposed to prevent HCV
replication.
[0014] Bristol-Myers Squibb WO 2004/014313, published 19 February 2004,
mentions
combination therapies for treatment of viral diseases, including
iminothiazolidinone NS5A-protein-
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WO 2007/081517 PCT/US2006/048685
inhibiting anti-HCV compounds in combination with other agents capable of
interfering with HCV
function.

SUMMARY
[0015] The present invention features compounds having I, II, III, IV, V, VI,
~VII or VIII,
tautomers of these compounds, and pharmaceutically acceptable salts of these
compounds or
tautomers. These compounds, tautomers or salts can be used, either
individually or in combination
with other drugs or agents, to inhibit the replication of HCV or other
viruses. These compounds,
tautomers or salts can also be used, either individually or in combination
with other drugs or agents, to
disrupt functions of HCV or other viruses.
[0016] The present invention also features compositions that comprise the
compounds,
tautomers or salts of the present invention. A composition of the present
invention can include one or
more compounds, tautomers or salts of the present invention. A composition of
the present invention
can also include one or more other antiviral or therapeutic agents.
[0017] In addition, the present invention features methods of using the
compounds,
tautomers or salts of the present invention, or compositions comprising the
same, to inhibit the
replication of HCV or other viruses. These methods comprise contacting HCV or
another virus, or
cells infected with HCV or said another virus, with an effective amount of a
compound, tautomer or
salt of the present invention, thereby inhibiting the replication of HCV or
said another virus.
[0018] The present invention further features methods of using the compounds,
tautomers or
salts of the present invention, or compositions comprising the same, to
inhibit the proliferation or
transmission of HCV or other viruses. These methods comprise contacting HCV or
another virus, or
contacting cells infected with HCV or another virus, with an effective amount
of a compound,
tautomer or salt of the present invention, thereby inhibiting the
proliferation or transmission of HCV
or said another virus.
[0019] Moreover, the present invention features methods of using the
compounds, tautomers
or salts of the present invention, or compositions comprising the same, to
treat HCV or other viral
infections. These methods comprise administering to a patient in need of such
treatment an effective
amount of a compound, tautomer or salt of the present invention, thereby
reducing the blood or tissue
level of HCV or other viruses in the patient.
[0020] The present invention also features use of the compounds, tautomers or
salts of the
present invention for the manufacture of medicaments for the treatment of HCV
or other viral
infections.
[0021] Furthermore, the present invention features processes of malcing the
compounds,
tautomers or salts of the present invention, and intermediates employed in
these processes.

4


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[0022] Other features, objects, and advantages of the present invention are
apparent in the
detailed description that follows. It should be understood, however, that the
detailed description,
while indicating preferred embodiments of the invention, are given by way of
illustration only, not
limitation. Various changes and modifications within the scope of the
invention will become apparent
to those skilled in the art from the detailed description.

. DETAILED DESCRIPTION
[0023] The following description is exemplary in nature and is not intended to
limit the
present disclosure, application, or uses.

Compounds
[0024] The present invention features compounds having Formula I, tautomers
thereof, and
pharmaceutically acceptable salts of the compounds or tautomers,
Rso
A
z Rz2
B W,

W2 Rio
I
wherein:
A and B are each independently selected from carbocycly] or heterocyclyl, and
are each
independently optionally substituted with one or more R18, wherein R'$ is
independently
selected at each occurrence from the group consisting of halogen, oxo, thioxo,
hydroxy,
mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl,
alkenyl, alkynyl,
carbocyclyl, heterocyclyl, -LS-O-Rs, -Ls-S-Rs, -Ls-C(O)Rs, -Ls7-OC(O)RS, -Ls-
C(O)ORS,
-Ls-N(RsRs-), -Ls-C(=NRs)Rs., -Ls-S(O)Rs, -Ls-SO2R,s, -Ls--C(O)N(RsRs,), -Ls-
N(Rs)C(O)Rs=. Ls-C(--NRs)N(Rs.Rs..), Ls-N(Rs-)C(=NRs)Rs-=, -Ls--
N(Rs)c(O)N(Rs.RS.=),
-Ls--N(RS)SO2Rs,, -Ls--SO2N(RsRs,), and -Ls-N(Rs)SO2N(Rs.Rs,=);
Wl and W2 are each independently selected from N or C(R3),
,


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WO 2007/081517 PCT/US2006/048685

Z is a bond, -CRa'R4"- or NR41-, wherein R41 and R4" are each independently
selected from the
group consisting of hydrogen, alkyl, alkenyl and alkynyl;
R10 and R33 are each independently selected at each occurrence from the group
consisting of
hydrogen; halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, arnino,
carboxy, formyl,
phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -Ls-O-
Rs, -Ls-S-Rs, -
Ls-C(O)R,s, -Ls-OC(O)Rs, -Ls-C(O)ORs, -Ls-N(RsRs,), -Ls-C(=Nlts)Rs', -Ls-
S(O)Rs, -
Ls-SO2Rs, -Ls-C(O)N(RsRs.), -Ls-N(Rs)C(O)Rs.. I-s-C(=NRs)N(Rs-Rs..), -I,,s--
N(Rs.)C(=NRs)Rs,,, -Ls-N(Rs)C(O)N(I?tis,Rs..), -Ls-N(Rs)SOZRs., -Ls-
SO2N(RsRs=), -Ls-
N(Rs)SO2N(Rs.Rs,.), -LE--Q-LE'-(C3-Clscarbocyclyl) and -La-Q-LV-(M3-
Mj$heterocyclyl);
X is selected from the group consisting of a bond, -Ls--O-, -Ls-S-, -Ls-C(O)-,
-Ls-N(Rs)-, -
Ls-N(Rs)C(O)-, -Ls-C(O)N(Rs)-, -Ls-N(Rs)C(O)O-, -LS-OC(O)N(Rs)-, -Ls-
N(Rs)C(O)N(Rs,)-, I-s--C( NRs)N(Rs.)-, I-s-N(Rs,)C(=NRs)-, I-s-S(O)-, -Ls-SOz-
, -
LS--C(O)O- and -Ls-OC(O)-;
Rz2 is carbocyclyl or heterocyclyl, and is optionally substituted with oine or
more R26, wherein Rz6
is independently selected at each occurrence from the group consisting of
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, alkyl,
alkenyl, alkynyl, -Ls-O-Rs, -Ls-S-Rs, -Ls-C(O)Rs, -Ls-OC(O)Rs, -LS-C(O)ORs, -
Ls-
N(RsRs=), Ls-C(=NRs)Rs,, -Ls-S(O)Rs, -Ls--S02Rs> Ls-C(O)N(RsRs-), -Ls-
N(Rs)C(O)Rs,, -Ls--C(=NRs)N(Rs.Rs,.), -Ls-N(Rs,)C(=NRs)Rs,,, -Ls-
N(Rs)C(O)N(Rs,Rs,.)>
-Ls--N=C(NRsRs')(NRsRs'), -Ls-N(Rs)S02RS', -LS--SO2N(RsRs,), -Ls-
N(Rs)SO2N(Rs,Rsõ),
-LF-Q-LE'-(C3-CI$carbocyclyl) and -LE-Q-LE,-(M3-Ml$heterocyclyl); or R22 is
alkyl,
alkenyl or alkynyl, and is optionally substituted with one or more R26; or R22
is hydrogen;
Y is selected from the group consisting of a bond, -Ls-O-, -Ls-C(O)--, -
L~S(O)Z-, -Ls-S(O)-,
-Ls-OS(O)Z-, -Ls-OS(O)-, -Ls-C(O)O-, -Ls-OC(O)--, -Ls-OC(O)O-, -Ls--C(O)N(R15)-
, -
Ls--N(R's)C(O)--, -Ls--C(O)N(R15)O-, -Ls-N(R's)C(O)O-, Ls-C(O)N(R15)N(R'5')-, -
Ls-S-
, -Ls-C(S)-, -Ls-C(S)O-, -Ls-OC(S)-, -Ls--N(Rts)_, _LS_C(S)N(Rl s)-, _Ls-
N(R1s)C(S)-, _
Ls-N(R's)S(O)-, -LS_N(R's)S(O)z-a I-s-S(O)2N(R'S)-: Ls-S(O)N(R15)-, -Ls-
C(S)N(R15)O-, and -Ls-C(S)N(R)5)N(R15')-, wherein R15 and R!5' are each
independently
selected at each occurrence from the group consisting of hydrogen, alkyl,
alkenyl and alkynyl;
R50 is -L? A', wherein A' is selected from the group consisting of
carbocyclyl, heterocyclyl,
alkyl, alkenyl and alkynyl, and L' is selected from the group consisting of a
bond, alkylene,
alkenylene and alkynylene, wherein A' is optionally substituted with one or
more R30, and R30
is independently selected at each occurrence from the group consisting of
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, alkyl,
alkenyl, alkynyl, Ls-O-Rs, -L~S-Rs, -Ls-C(O)Rs, -Ls-OC(O)RS, -Ls-C(O)ORS, -Ls-
N(RsRs.), -Ls-C(=NRs)Rss: -Ls-S(O)Rs, -Ls-S02Rs, -Ls-C(O)N(RsRs,), -Ls-
6


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N(Rs)C(O)Rs., -Ls-C(=NRs)N(Rs,Rs~), -Ls-N(Rs.)C(=NRs)Rs.., -Ls-N(Rs)C(O)N(Rs-
Rs..),
-Ls-N(Rs)SO2Rs., -Ls-SOxN(RsRs,), -Ls-N(Rs)SO2N(Rs=Rs.,), -LS-Q--LE,-(C3-
C18carbocyclyl) and -LE-Q-LE.-(M3-MlBheterocyclyl), and wherein L' is
optionally
'substituted with one or more R38, and =R38 is independently selected at each
occurrence from
the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano,
amino,
carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy, alkylcarbonyl,
alkoxycarbonyl,
alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -Ls-O-Rs, -Ls-S Rs, -LS-
C(O)Rs, -
Ls-OC(O)Rs, Ls-C(O)ORs, -Ls-N(RsRs=), -Ls-C(=NRs)Rs=, -Ls-S(O)R.s, -Ls-SO2Rs, -

Ls-C(O)N(RsRs.), -Ls-N(Rs)C(O)Rs., -Ls-C(=NR.s)N(Rs.Rs..), -Ls-
N(Rs.)C(=NRs)Rs.=, -
Ls-N(Rs)C(O)N(Rs.Rs,.), -Ls-N(R.s)S02Rs., -Ls-SO2N(R.sRs,), -Ls-
N(Rs)SO2N(Rs.Rs..),
carbocyclyl, heterocyclyl, " carbocyclylalkyl, heterocyclylalkyl, -LF-Q-LE.-
(C3-
C18carbocyclyl) and -LE-Q-LE.-(M3-M,$heterocyclyl);
Ls is independently selected at each occurrence from the group consisting of a
bond, alkylene,
alkenylene and alkynylene;
Rs, Rs. and Rs., are each independently selected at each occurrence from the
group consisting of
hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl,
alkoxyalkoxyalkyl,
thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylan-iinoalkyl,
alkoxycarbonylamino, and alkoxycarbonylanunoalkyl;
LE and L. are each independently selected at each occurrence from the group
consisting of a
bond, alkylene, alkenylene and alkynylene;
Q is independently selected at each occurrence from the group consisting of a
bond, alkylene,
alkenylene, alkynylene, -S-, -0-, -C(O)--, N(Rs)-, N(Rs)C(O)-, -C(O)N(R.s)--, -

N(R$)C(O)0--, -OC(O)N(Rs)-, =N(Rs)C(O)N(Rs,)-, -C(=NRs)N(Rs.)--, N(Rs.)C(=NRs)-
, -
S(O)-, -SOz-, -O-SOZ-, -SO2-0-, -O-S(O)-, -S(O)-O-, -C( )O- and -OC(O)-;
Rlo, R's, R'ss, R's> Rae> R30, R33>R38> R41> and R 1' are each independently
optionally substituted at
each occurrence with at least one substituent selected from the group
consisting of halogen,
oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl,
phosphate and azido;
and
each C3-Cjgcarbocyclyl and M3-M18heterocyclyl moiety in -LE-Q-LE.-(C3-
C18carbocyclyl) and -
LE-Q-LE.-(M3-M1eheterocyclyl) is independently optionally substituted at each
occurrence
with at least one substituent selected from the group consisting of hydrogen,
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, anzino, carboxy, formyl, phosphate,
azido, alkyl,
alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl,
alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy,
7


CA 02633752 2008-06-18
WO 2007/081517 PCT/US2006/048685
alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino, and
alkoxycarbonylaminoalkyl.
[0025] In one embodiment, the present invention features compounds having
Forrnula I,
tautomers thereof, and pharmaceutically acceptable salts of the compounds or
tautomers, wherein:
A and B are each independently selected from C4-CI 1 carbocyclyl or M4-MI
Iheterocyclyl, and are
each independently optionally substituted with one or more R78, wherein R'$ is
independently
selected at each occurrence from the group consisting of halogen, oxo, thioxo,
hydroxy,
mercapto, nitro, cyano, amino, carboxy, fonnyl, phosphate, azido, CI-C6alkyl,
C2-C6alkenyl,
CZ-C6alkynyl, C3-C6carbocyclyl, M3-M6heterocyclyl, -Ls--O--Rs, -Ls-S-Rs, -Ls-
C(O)Rs, -
Ls-OC(O)Rs, -LS-C(O)ORs, -Ls-N(RsRs.), -Ls-C(=NRs)Rs=, -Ls7-S(O)Rs, -Ls--
SOZRs, -
Ls-C(O)N(RsRs,), -Ls-N(Rs)C(O)Rs,. -Ls--C(=NRs)N(Rs,Rsõ), -Ls-
N(Rs=)C(=NRs)Rs,., -
Ls-N(Rs)C(O)N(Rs,Rs..), -Ls-N(Rs)SOzRs., -Ls--SO2N(RsRs,), and -Ls-
N(Rs)SO2N(Rs,Rs,.);
Wi and W2 are each independently selected from N or C(R33);
Z is a bond, -CR41W"- or NR41-, wherein R4' and R4" are each independently
selected from the
group consisting of hydrogen, Cl-C6alkyl, C2-C6alkenyl and C2-C6alkynyl;
R10 and R33 are each independently selected at each -occurrence from the group
consisting of
hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino,
carboxy, formyl,
phosphate, azido, Ct-Cgalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, M3-

M6heterocyclyl, -Ls-O-Rs, -Ls--S-Rs, -Ls-C(O)Rs, -Ls-OC(O)Rs, -Ls-C(O)ORs, -Ls-

N(RsRs,), -Ls-C(=NRs)RS', -Ls-S(O)Rs, -Ls-S02Rs, -Ls-C(O)N(RsRs,)a -Ls-
N(Rs)C(O)Rss. Ls-C(=NRs)N(Rs.Rs.,), -LS-N(Rs=)C(=NRs)Rs,., -Ls-
N(Rs)C(O)N(Rs.Rs..),
-Ls-N(Rs)SOZRs=, -Ls--SOZN(RsRs'): -Ls-N(Rs)SO2N(Rs.Rs.,), -LE-Q-Ls.--(C3-
CiBcarbocyclyl) and -LE-Q-LE.-(M3-M,gheterocyclyl);
X is selected from the group consisting of a bond, -Ls-O-, -Ls-S-, -LS7-C(O)-,
-Ls-N(Rs)-, -
I.s-N(Rs)C(O)-, -Ls-C(O)N(Rs)-, -Ls-N(Rs)C(O)0--, Ls-OC(O)N(Rs)-, -Ls-
N(Rs)C(O)N(Rs,)-, -Ls-C{=NRs)N(Rs=)-, -Ls-N('Rs,)C(=NRs)-, -Ls-S(O)-, -Ls-SO2-
, -
Ls--C(O)O- and -Ls-OC(O)-;
R22 is C4-C,lcarbocyclyl or M4-Mllheterocyclyl, and is optionally substituted
with one or more
R26, wherein R26 is independently selected at each occurrence from the group
consisting of
halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl,
phosphate,
azido, CI-C6alkyl, C2-C6alkenyl, CZ-C6alkynyl, -Ls-O--Rs, -Ls-S-Rs, -Ls--
C(O)Rs, -Ls-
OC(O)Rs, -Ls-C(O)ORs, -LS-N(RsRs')a -Ls-C(=NRs)RS=, -Ls-S(O)RS, -Ls-S02Rs, -Ls-

C(O)N(RsRs,), Ls-N(Rs)C(O)Rs,, Ls-C(=NRs)N~s,Rs..), -Ls-N(Rs.)C(=NRs)I~,,, -Ls-

N=CQ4RsRs=)(NRsRs,), Ls-N(Rs)C(O)N(Rs,Rs,.), -Ls-N(Rs)S02Rs', -Ls--
SO2N(RsRs=), -
Ls-N(Rss)SOzN(Rs,Rs.=), -LE-Q-LE-(C3-Cj$carbocyclyl) and LE-Q-LE=-(Ma-
S


CA 02633752 2008-06-18
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M,sheterocyclyl); or R22 is C,-C6alkyl, C,-C6alkenyl or C,-C6alkynyl, and is
optionally
substituted with one or more R26; or R22 is hydrogen;
Y is selected from the group consisting of a bond, -Ls-O-, -Ls-C(O)-, -Ls-
S(O)Z-, -Ls--S(O)-,
-LS-OS(O)2-, -Ls--OS(O)-, -Ls-C(O)O-, -Ls-OC(O)-, -LsOC(O)O-, -Ls-C(O)N(R's)-,
-
Ls--N(R's)C(O)-, -Ls-C(O)N(R.15)0-, -Ls-N(R's)C(O)O-, -Ls-C(O)N(R's)N(R's')--,
-Ls-S-
, -Ls-C(S)-, -Ls-C(S)O-, -Ls-OC(S)--, -Ls-N(R's)-, -Ls-C(S)N(R's)-, -Ls-
N(R's)C(S)-, -
Ls-N(R's)S(O)-, -LS_-N(R's)S(O)Z-, -Ls-S(O)2N(R15)_, -Ls-S(O)N(R~s)-, -Ls-
C(S)N(R's)O-, and -Ls-C(S)N(R's)N(R's')--, wherein R's and R's' are each
independently
selected at each occurrence from the group consisting of hydrogen, C,-C6alkyl,
C2-C6a]kenyl
and C2-C6alkynyl;
R5D is -L'-A', wherein A' is selected from the group consisting of C4-
Cõcarbocyclyl, M4-
Mõheterocyclyl, C,-C6alkyl, C2-C6alkenyl and Ca-C6alkynyl, and L' is selected
from the
group consisting of a bond, C,-C6alkylene, C2-C6alkenylene and C2-
C6alkynylene, wherein A'
is optionally substituted with one or more R30, and R30 is independently
selected at each
occurrence from the group consisting of halogen, oxo, thioxo, hydroxy,
mercapto, nitro,
cyano, amino, carboxy, formyl, phosphate, azido, C,-C6alkyl, C2-C6alkenyl, C2-
C6alkynyl, -
Ls-O-Rs, -Ls-S-Rs, -Ls-C(O)Rs, -Ls-OC(O)Rs, -Ls-C(O)ORs, -Ls-N(RsRss), -Ls-
C(=NRs)Rs., I-s-S(O)Rs, -Ls-S02RS, -Ls-C(O)N(RsRs=), -Ls-N(Rs)C(O)Rs., Ls-
C(=NRs)N(Rs,Rsõ), Ls-N(Rs=)C(=NRs)Rs~, -I-s-N(Rs)C(O)N(Rs,Rsõ), -Ls-
N(Rs)S02Rs., -
Ls-SOZN(RsRs=), -Ls-N(Rs)SO2N(Rs.Rs.=), -LE-Q--LE.-(C3-C,gcarbocyclyl) and -LE-
-Q-LE=-
(M3-M,sheterocyclyl), and wherein Ll is optionally substituted with one or
more R38, and R38
is independently selected at each occurrence from the group consisting of
halogen, oxo,
thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate,
azido, C,-
C6alkoxy, C,-C6thioalkoxy, C,-C6alkylcarbonyl, C,-C6alkoxycarbonyl, C,-
C6alkylcarbonyloxy, Cy-C6alkylamino, C,-C6alkoxycarbonylamino, -Ls-O-Rs, -Ls--
S-Rs, -
Ls-C(O)Rs, -Ls-OC(O)Rs, -Ls-C(O)ORs, -LS-N(RsRs=), -Ls-C(=NRs)Rs., Ls-S(O)Rs, -

Ls-S02Rs, -Ls-C(O)N(RsRs.), -Ls-N(Rs)C(O)Rs., -Ls-C(=NRs)N(Rs.Rsõ), -.Ls-
N(Rs=)C(=NRs)Rs==, -Ls-N(Rs)C(O)N(Rs=Rs,.), -Ls-N(Rs)S02Rs=, -Ls-SOaN(RsRs.), -
Ls-
N(Rs)SO2N(Rs.Rs..), carbocyclyl, heterocyclyl, carbocyclylC,-C6alkyl,
heterocyclylC,-
C6alkyl, -LF-Q-LE.-(C3-C18carbocyclyl) and -LE-Q-LE=-(M3-M, 8heterocyclyl);
Ls is independently selected at each occurrence from the group consisting of a
bond, C,-
C6alkylene, C2-C6alkenylene and C2-C6alkynylene;
Rs, Rs. and Rs,. are each independently selected at each occurrence from the
group consisting of
hydrogen, C,-C6alkyl, Ca-C6alkenyl, C2-C6alkynyl, C,-Cbalkoxy, C,-
C6thioalkoxy, C,-
C6alkoxyC,-Cbalkyl, C,-C6alkoxyC,-C6alkoxyC,-C6alkyl, CI-C6thioalkoxyC,-
C6alkyl, C,-
C6alkylcarbonyl, C,-C6alkylcarbonylC,-C6alkyl, C,-C6alkoxycarbonyl, C,-
9


CA 02633752 2008-06-18
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C6alkoxycarbonylCj-C6alkyl, Cl-C6alkylcarbonyloxy, Ci-C6alkylcarbonyloxyC,-
C6alkyl, Cl-
C6alkylamino, C,-C6alkylaminoCj-C6alkyl, Cl-C6alkoxycarbonylamino, and Cl-
C6alkoxycarbonylaminoC,-C6alkyl;
LE and LE, are each independently selected at each occurrence from the group
consisting of a
bond, C,-C6alkylene, C2-C6alkenylene and C2-C6allcynylene;
Q is independently selected at each occurrence from the group consisting of a
bond, C,-
C6alkylene, C2-C6alkenylene, C2-C6alkynylene, -S-, -0-, -C(O)-, N(Rs)-,
N(Rs)C(O)-, -
C(O)N(Rs)-, N(Rs)C(O)O-, -OC(O)N(Rs)-, N(Rs)C(O)N(Rs.)-, -C(=NRs)N(Rsl)-, -
N(Rs,)C(=NRs)-, -S(O)-, -SO2-, -O-SOZ-, -SOz-O-, -O-S(O)-, -S(O)-O-, -C(O)O-
and
-0C(O)-;
R10, R'5, R'S', R'8, R26, R.3 R33, R38, R47, and R4" are each independently
optionally substituted at
each occurrence with at least one substituent selected from the group
consisting of halogen,
oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl,
phosphate, and azido;
and
each C3-C,acarbocyclyl and M3-M18heterocyclyl moiety in -LE-Q-LE'-(C3-
C,gcarbocyclyl) and -
LE-Q-LE-(M3 M,8heterocyclyl) is independently optionally substituted at each
occurrence
with at least one substituent selected from the group consisting of halogen,
oxo, thioxo,
hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C,-
C6alkyl, C2-
C6alkenyl, C2-C6alkynyl, C,-C6alkoxy, Cl-C6thioalkoxy, C,-C6alkoxyC,-C6alkyl,
Cl-
C6thioalkoxyC,-C6alkyl, C,-C6alkylcarbonyl, C,-C6a1ky1carbonylC,-C6alkyl, C,-
C6alkoxycarbonyl, C,-C6alkoxycarbonylC1-C6alkyl, C,-C6alkylcarbonyloxy, C,-
C6alkylcarbonyloxyC,-C6alkyl, C,-C6alkylamino, Cl-C6alkylaminoCI-C6alkyl, C,-
C6alkoxycarbonylamino, and Cl-C6alkoxycarbonylaminoC,-C6alkyl.
[00261 In one example of this embodiment, Y is -LS-O-, -Ls-S- or -Ls-N(R15)-,
and R50 is
-L'-A',' wherein L' is a bond, C,-C6alkylene, C2-C6alkenylene or C2-
C6alkynylene and is optionally
substituted with one or more R38, and A' is C4-C,Icarbocyclyl or M4-
M,lheterocyclyl and is optionally
substituted with one or more R3o
[00271 In another example of this embodiment, Y is a bond, and R50 is L'-A',
wherein L' is
a bond, C,-C6alkylene, C2-C6alkenylene or C2-C6alkynylene and is optionally
substituted with one or
more R38, and A' is C4-Cõcarbocyclyl or 1V1a-Mõheterocyclyl and is optionally
substituted with one or
more R3o.

[00281 In still another example of this embodiment, Y is a bond, and R50 is -
L'-A', wherein
L' is selected from the group consisting of a bond, Cl-C6alkylene, C2-
C6alkenylene and C2-
C6alkynylene and is optionally substituted with one or more R38, and A' is
hydrogen or R'8.
[0029] In yet another example of this embodiment, Y is selected from the group
consisting of
-LS-S(O)2N(R15)-, -Ls-OS(O)2-, -I.s-OC(O)-, -Ls-C(0)0--, I.s--C(O)- and
N(R.'s)C(O)O-.

1.0


CA 02633752 2008-06-18
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[0030] In still yet another example of this embodiment, A and B are each
independently
selected from CS-C6carbocyclyl or MS-M6heterocyclyl and are each independently
optionally
substituted with one or more R'$.
[0031] In still another example of this embodiment, Wi and W2 are N, and Z is
NR"-.
[00321 In yet another example of this embodiment, X is -0- or -S-, and R22 is
CS-
C6carbocyclyl or MS-M6heterocyclyl and is optionally substituted with one or
more RZ6.

.r
vtõll
B
Z
[0033] In yet another example of this embodiment, the moiety w2 R1D is
R35 ~n

~ \ \ w, = .
R17 W3 W2 RtO, wherein:
Wi, W2, W3 and W4 are each independently selected from N or C(R3); and
R'o, R", R33 and R35 are each independently selected at each occurrence from
the group consisting
of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino,
carboxy, formyl,
phosphate, azido, Cl-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, M3-

M6heterocyclyl, -Ls-O-Rs, -Ls--S-RS, -Ls-C(O)Rs, -Ls-OC(O)Rs, -Ls-C(O)ORs, -Ls-
=
N(RsRs.), -Ls-C(=NRs)Rs,, -Ls-S(O)RS, -Ls-S02Rg, -Ls-C(O)N(RsRs.), -Ls-
N(Rs)C(O)Rs., -Ls-C(=NRs)N(Rs,Rsõ), -Ls--N(Rs,)C(=NRs)Rs,,, -Ls-
N(Rs)C(O)N(Rs=Rs~),
-Ls-N(Rs)SO2Rs,, -Ls-SO2N(RsRs'), I-s-N(Rs)SOxN(Rs'Rs~), -Ls--Q-La.-(C3-
Clscarbocyclyl) and -LE-Q-LE.-(M3-M78heterocyclyl).

B w,
[0034] In yet another example of this embodiment, the moiety W2 R10 is

R35 R35
~v,~ , .J1J1M
R33
I ~ \N i

selected f r f ? m the group consisting Of R'7 N N RtO, R17N N~Rlo.,
R35
1
N ~1'L!1l1f~
~ ~ =
N N
Rn--
,.N N R~0 /
R" , and S N R'o, wherein:
Q is N or C(R33); and

11


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R10, R", R33 and R35 are each independently selected at each occurrence from
the group consisting
of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino,
carboxy, formyl,
phosphate, azido, CI-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6carbocyclyl, M3-

M6heterocyclyl, -Ls-O-Rs, -Ls-S-Rs, -LS-C(O)Rs, -Ls--OC(O)Rs, -Ls-C(O)ORs, -LS-

N(RsRs.), -Ls-C(=NRs)Rs., -Ls-S(O)Rs, -L~S02Rs, -Ls--C(O)N(RsRs,)~ -LS-
N(Rs)C(O)RS., -Ls-C(=NRs)N(Rs,Rsõ), -Ls-N(Rs.)C(=NRs)RS.., -Ls-
N(Rs)C(O)N(Rs,Rsõ),
-Ls-N(Rs)SOZRS., -Ls--SO2N(RsRs.), -Ls-N(Rs)SO2N(Rs,Rs,.), LE-Q--LE=-(C3-
Cl$carbocyclyl) and -LE-Q-LE.-(M3 M18heterocyclyl).
[00351 In a further example of this embodiment, A and B are each independently
selected
from CS-C6carbocyclyl or M5-M6heterocyclyl and are each independently
optionally substituted with
one or more R'$, wherein:
W, andW2 are N;
Z is NR.41-;
Xis-0-or-S-;
RZa is C5-C6carbocyclyl or M5-M6heterocyclyl and is optionally substituted
with one or more R26
Y is a bond, -Ls-O-, -Ls-S- or -Ls--N(R15)-; and
A' is C5-Clocarbocyclyl or M$-Mloheterocyclyl and is optionally substituted
with one or more R3o
[0036] In another example of this embodiment, A and B are each independently
selected
from C5-Cgcarbocyclyl or MS-M6heterocyclyl and are each independently
optionally substituted with
one or more R18, wherein:
W, and W2 are N;
Z is NR41-;
X is -O- or -S-;
R48
R22 i +aR48 48 .
s or , wherein Ris hydroxy, amino,
Ci-C6alkyIarnino, C,-C6alkoxy, Cl-Cbalkoxycarbonylamino or Cl-
C6alkylcarbonyloxy, and
R22 (e.g., R48 or the phenyl ring in R22) is optionally substituted with one
or more RZ6;
Y is a bond, -Ls--O-, -LS--S- or -Ls--N(R'5)-; and
A' is CS-Clocarbocyclyl or MS-M10heterocyclyl and is optionally substituted
with one or more R3o
12


CA 02633752 2008-06-18
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W,
B

[0037] In still another example of this embodiment, the moiety W2 R7D is
R35 R35
vv~.nr 'n~'~r =
R~ ~ ~N N N

, N NRlo
the OUp consisting of R77 I N~ N';~R10
selected from tn
,
R35
,nrvtr ~
Jtn.rv~
N I I N ~ N

\ %\ Ry7
N N Rto
R"~ , and s N R10, wherein:
Q is N or C(R33);
R10, R", R33 and R35 are each independently selected at each occurrence from
the group consisting
of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino,
carboxy, formyl,
phosphate, azido, Cl-C6alkyl, CZ-C6alkenyl, C2-Csalkynyl, C3-C6carbocyclyl, M3-

M6heterocyclyl, -Ls-O-Rs, -LS-S-Rs, -Ls-C(O)Rs, -L$-OC(O)Rs, -Ls-C(O)ORS, -Ls--

N(RsRs,), -Ls-C(=NRs)Rs., -Ls-S(O)Rs, -Ls-SO2Rs, -LS-C(O)N(RsRs.), Ls-
N(Rs)C(O)Rs=. -Ls-C(=NRs)N(Rs,Rsõ), -Ls-N(Rs.)C(=NRS)Rs,., -Ls-
N(Rs)C(O)N(Rs,Rsõ),
-Ls-N(RS)SOZRs=, -LS-=SO2N(RsRs=), -Ls-N(RS)SO2N(RS=RS.=), -LE-Q-LE'-(C3-
C18carbocyclyl) and -LE--Q--LE,-(M3-M, 8heterocyclyl);
A is C5-C6carbocyclyl or MS-M6heterocyclyl and is optionally substituted with
one or more R'B,
Z is NR41-;
Xis-O-or-S-;

R4e az is or +aR48 a$ =
R , wherein R is hydroxy, amino,
Ci-C6alkylamino, Cl-C6alkoxy, CI-C6alkoxycarbonylamino or CI-
C6alkylcarbonyloxy, and
R22 (e.g., R48 or the phenyl ring in Ra2) is optionally substituted with one
or more RZ6;
Y is a bond, -Ls-O-, -Ls-S- or -LS-N(R15)-; and
A' is C5-Cl carbocyclyl or MS-M10heterocyclyl and is optionally substituted
with one or more R30.
[0038] In another embodiment, the present invention features a family of
pyridopyrimidinyl-
aminophenyl ether compounds, tautomers of the compounds, or pharmaceutically
acceptable salts of
the compounds or tautomers, wherein the compounds of this family correspond in
structure to
Formula II:

13


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R25
O R7o

R8
\N \
R6 Ra2

3 ~
R~ N N
II
wherein:
R6 is selected from the group consisting of hydrogen and cyano;
R$ is selected from the group consisting of hydrogen and arylalkyl;
R25 is selected from the group consisting of hydrogen and alkyl;
R37 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl,
and cycloalkyl;
R42 is selected from the group consisting of arylsulfanyl, heteroarylsulfanyl,
and aryloxy;
wherein R42 is optionally substituted with one or more substituents
independently selected from Ra6;
R46 is one or more substituents selected from the group consisting of
hydrogen, hydroxy,
amino, halogen, dialkylamino, and alkoxycarbonylamino;
R70 is selected from the group consisting of aryl, and heterocyclo; wherein
R70 is optionally
substituted with R75;
R75 is one or more substituents independently selected from the group
consisting of hydrogen,
halogen, alkoxy, cyano, alkyl, haloalkyl, and aryl.
[0039] In a subset family of this embodiment within Formula II, R6 is selected
from the
group consisting of hydrogen and cyano;
R8 is selected from the group consisting of hydrogen and phenylmethyl;
R25 is selected from the group consisting of hydrogen and methyl;
R37 is selected from the group consisting of hydrogen, methyl, ethyl, t-butyl,
isopropyl,
hydroxymethylethyl, and cyclohexyl;
R42 is selected from the group consisting of phenylsulfanyl, phenoxy, and
pyrimidinylsulfanyl;
R46 is selected from the group consisting of hydrogen, hydroxy, amino, N,N-
dimethylamino,
and t-butoxycarbonylamino;

14


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R70 is selected from the group consisting of phenyl, thiazolyl, pyridinyl,
tetrahydrofuranyl,
naphthyl, quinolinyl, and thienyl;
R75 is one or more substituents selected from the group consisting of
hydrogen, methyl, butyl,
hydroxy, methoxy, bromo, chloro, fluoro, cyano, trifluoromethyl, and phenyl.
[0040] In still another embodiment, the present invention features a family of
pyridopyrimidinyl-aminophenyl alkyl ether compounds, tautomers of the
compounds, or
pharmaceutically acceptable salts of the compounds or tautomers, wherein the
compounds of this
family correspond in structure to Formula IIl:

O-Rso
HN

S
CH3 N N OH
CH3

ffi
wherein R80 is selected from the group consisting of hydrogen, alkylcarbonyl,
and haloaryl.
[0041] In a subset family of this embodiment within Formula III, R80 is
selected from the
group consisting of hydrogen, methylcarbonyl, and bromophenyl.
[0042] In yet another embodiment, the present invention features a family of
thiazolopyrimidinyl-aminophenyl and thienopyrimidinyl-aminophenyl compounds,
tautomers of the
compounds, or pharmaceutically acceptable salts of the compounds or tautomers,
wherein the
compounds of this family correspond in structure to Formula N:



CA 02633752 2008-06-18
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R19
HN

S
Ri-~' N
S
N R56
N
wherein:
Q is selected from the group consisting of N and CH;
R' is selected from the group consisting of alkylsulfanyl, cyanoalkylsulfanyl,
and alkyl;
R19 is selected from the group consisting of alkyl and haloarylalkoxy;
R56 is selected from the group consisting of hydrogen, hydroxy, alkyl, and
alkylcarbonylamino.
[0043] In a subset family of this embodiment within Formula N, R' is selected
from the
group consisting of methylsulfanyl, cyanomethylsulfanyl, propyl, and butyl;
R19 is selected from the group consisting of methyl and bromophenylmethoxy;
R56 is selected from the group consisting of hydrogen, hydroxy, methyl, and
methyloarbonylamino.
[0044] In a fiirther embodiment, the present invention features a family of
pyrimidopyrimidinyl-aminophenyl compounds, tautomers of the compounds, or
pharmaceutically
acceptable salts of the compounds or tautomers, wherein the compounds of this
family correspond in
structure to Formula V:

R29
Rg1 I
R5 N

N ~ ~N LRM
I ~
47~ N N ~ R66
R

V
16


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wherein:
R5 is selected from the group consisting of hydrogen and alkylsulfanyl;
R29 is selected from the group consisting of alkyl, arylalkoxy, halogen, and
haloarylalkoxy;
R47 is selected from the group consisting of alkyl, haloalkyl, alkylsulfanyl,
arylalkylsulfanyl,
and heterocyclo;
is selected from the group consisting of hydrogen, alkoxy, and alkyl;
R66 is selected from the group consisting of hydrogen, hydroxy, aryloxy,
alkylsulfonyloxy,
alkylcarbonylaminoarylsulfonoyloxy, haloarylsulfonyloxy, cyano, arylalkoxy,
alkylcarbonylamino,
halogen, and alkyl;
R81 is selected from the group consisting of hydrogen, alkoxy, and carbonyI.
[0045] In a subset family of this embodiment within Formula V, RS is selected
from the
group consisting of hydrogen and methylsulfanyl;
R29 is selected from the group consisting of methyl, ethyl, fluoro,
phenylmethoxy, and
bromophenylmethoxy;
R47 is selected from the group consisting of hydrogen, propyl, isopropyl,
ethylsulfanyl,
piperidinyl, morpholinyl, heptafluororpropyl, and phenylmethylsulfanyl;
R64 is selected from the group consisting of hydrogen, methoxy, hydroxy, and
methoxy;
R66 is selected from the group consisting of hydrogen, methyl, hydroxy,
methoxy, phenoxy,
phenylmethoxy, phenylsulfanyloxy, isopropylsulfonyloxy,
methylcarbonylaminophenylsulfonyloxy,
bromophenylsulfanyloxy, cyano, methylcarbonylamino, and fluoro;
R$' is selected from the group consisting of hydrogen, t-butoxy, and carbonyl.
[0046] In another embodiment, the present invention features a family of
pyrazolopyrimidinyl-aminophenyl compounds, tautomers of the compounds, or
pharmaceutically
acceptable salts of the compounds or tautomers, wherein the compounds of this
family correspond in
structure to Formula VI:
CH3

I
HN

S ak76
NN R731--~ N

17


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VI
wherein:
R73 is alkyl;
R76 is selected from the group consisting of hydroxy, alkylaminocarbonyl, and
alkylcarbonylamino.
[0047] In a subset family of this embodiment within Formula VI, R73 is
selected from the
group consisting of methyl and butyl;
R76 is selected from the group consisting of hydroxy, methylaminocarbonyt, and
methylcarbonylamino.
[0048] In still yet another embodiment, the present invention features a
family of
pyridopyrimidinyl-aminophenyl compounds, tautomers of the compounds, or
pharmaceutically
acceptable salts of the compounds or tautomers, wherein the compounds of this
family correspond in
structure to Formula=VII:
R39

R21
HN
N
A
1 I
~
R67 N N R96
VII
wherein:
A is selected from the group consisting of 0 and S;
R21 is selected from the group consisting of hydrogen and hydroxy;
or Ral taken together with R39 form a 5-12 membered heterocycle containing at
least two
heteroatoms selected from the group consisting of 0, N, and S; wherein the
heterocycle is optionally
substituted aryl or halogen; or
e is selected from the group consisting of hydrogen, alkyl, arylalkenyl,
dialkylamino,
heteroaryl, haloheteroaryl, haloarylaminosulfonyl, arylsulfonyloxy,
alkylcarbonyloxy,
cycloalkylaminocarbonyl, arylalkoxycarbonylamino, haloheteroaryl,
alkoxycarbonyl, and NH-R99;
R99 is selected from the group consisting of hydrogen, arylalkyl,
cycloalkylalkyl, aryl,
heteroaryl, haloarylalkylamino, arylalkylamino, and alkylheteroaryl;
R67 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and
alkylcycloalkyl;
18


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R96 is ' selected from the group consisting of hydrogen, hydroxy, amino,
alkoxy,
arylsulfonyloxy, alkylcarbonylamino, alkoxy, halogen, alkoxycarbonyloxy,
haloalkoxycarbonylamino, and arylalkoxy.
100491 In a subset family of this embodiment within Formula VII, RZ' is
selected from the
group consisting of hydrogen and hydroxy, or when taken together with R39 form
benzooxazoly]
optionally substituted with phenyl or bromo; or
R39 is selected from the group consisting of hydrogen, methyl, phenylethenyl,
N,N-
dipropylamino, pyrrolyl, bromophenylaminosulfonyl, phenylsulfonyloxy, t-
butylcarbonyloxy, N-
cyclohexylaminocarbonyl, N-cyclopentylaminocarbonyl,
phenylmethoxycarbonylamino,
methoxycarbonylamino, methoxycarbonyl and bromobenzimidazolyl;
R67 is selected from the group consisting of hydrogen, methyl, ethyl,
isopropyl, t-butyl, sec-
butyl, cyclopropyl, cyclobutyl, and methylcyclopropyl;
R96 is selected from the group consisting of hydrogen, hydroxy, amino,
phenylsulfonyloxy,
methylcarbonylamino, methoxy, fluoro, t-butoxycarbonylamino,
trichloroethoxycarbonylamino, and
phenylmethoxy;
Rgg is selected from the group consisting of hydrogen, phenylmethyl,
phenylethyl,
cyclopentylmethyl, furanyl, thienyl, naphthayl, bromophenylmethylamino,
phenylmethylamino, and
methylpyrido[2,3-d]pyrimidinyl.
[00501 In yet another embodiment, the present invention features a family of
pyridopyrimidinyl-aminophenyl compounds, tautomers of the compounds, or
pharmaceutically
acceptable salts of the compounds or tautomers; wherein the compounds of this
family correspond in
structure to Formula VIII:
R49

R31
~ I

HN R23
R52
N

( / /J
77
R N N
VIII
wherein:
Ra3 is selected from the group consisting of hydrogen, alkoxyaryl,
alkoxyarylsulfanyl,
hydroxyarylsulfanyl, haloarylalkoxy, cyanoarylalkoxy, and arylalkoxy;
R31 is selected from the group consisting of hydrogen and halogen;
19


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R49 is selected from the group consisting of hydrogen, arylalkoxy,
haloarylcarbonylamino,
alkoxyarylcarbonylamino, arylalkenyl, arylalkyl, halogen, cyano,
haloaryloxyalkyl, alkyl,
alkoxyarylsulfanyl, haloheteroaryl, and alkoxycarbonyl;
RSZ is selected from the group consisting of hydrogen, halogen, alkyl,
hydroxyaryloxy,
aryloxy, hydroxyalkylaryloxy, alkoxyarylalkyl, alkoxyaryloxy,
alkylarylalkoxyarylamino, arylalkyl,
heteroaryl, and aminoaryloxy;
R 77 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
[0051] In a subset family of this embodiment within Formula VIII, RZ' is
selected from the
group consisting of hydrogen, methoxyphenyl, methoxyphenylsulfanyl,
hydroxyphenylsulfanyl,
fluorophenylmethoxy, difluorophenylmethoxy, cyanophenylmethoxy, phenylmethoxy,
bromophenylmethoxy, and methoxyphenylmethoxy;
R31 is selected from the group consisting of hydrogen, chloro, and fluoro;
R49 is selected from the group consisting of hydrogen, methyl, phenylmethoxy,
bromophenylcarbonylamino, chlorophenylcarbonylamino,
methoxyphenylcarbonylamino,
fluorophenylcarbonylamino, phenylethenyl, phenylethyl, chloro, fluoro, bromo,
cyano,
bromophenoxymethyl, and hydroxyphenylsulfanyl.
R52 is selected from the group consisting of hydrogen, fluoro, bromo, methyl,
phenoxy,
hydroxyphenoxy, hydroxyethylphenoxy, methoxyphenylethyl, methoxyphenoxy, N-
methyl-N-4-
phenylmethoxyjphenylamino, phenylmethyl, and thiazolylbenzimidazolyl;
R" is selected from the group consisting of hydrogen, methyl, and isopropyl.
Salts of the Compounds of this Invention
[0052] The compounds of the present invention, or tautomers thereof, can be
used in the
form of salts. Depending on the particular compound, a salt of the compound
may be advantageous
due to one or more of the salt's physical properties, such as enhanced
pharmaceutical stability in
differing temperatures and humidities, or a desirable solubility in water or
oil. In some instances, a
salt of a compound also may be used as an aid in the isolation, purification,
and/or resolution of the
compound.
[0053] Where a salt is intended to be administered to a patient, the salt
preferably is
pharmaceutically acceptable. Pharmaceutically acceptable salts include, but
are not limited to, salts
commonly used to form alkali metal salts and/or to form addition salts of free
acids or free bases. In
general, these salts typically may be prepared by conventional means with a
compound of this
invention by reacting, for example, the appropriate acid or base with the
compound. .
[0054] Pharmaceutically acceptable acid addition salts of the compounds of
this invention
may be prepared from an inorganic or organic acid. Examples of suitable
inorganic acids include
hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and
phosphoric acid. Suitable


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organic acids generally include, for example, aliphatic, cycloaliphatic,
aromatic, araliphatic,
heterocyclyl, carboxyic, and sulfonic classes of organic acids. Specific
examples of suitable organic
acids include acetate, trifluoroacetate, formate, propionate, succinate,
glycolate, gluconate,
digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate,
maleate, fumarate, pyruvate,
aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate,
salicylate, p-hydroxybenzoate,
phenylacetate, mandelate, embonate (pamoate), methanesulfonate,
ethanesulfonate, benzenesulfonate,
pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,
cyclohexylaminosulfonate,
algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate,
alginate, bisulfate, butyrate,
camphorate, camphorsulfonate, cyclopentanepropionate, , dodecylsulfate,
glycoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-
naphthalesulfonate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate, picrate; pivalate,
thiocyanate, tosylate, and
undecanoate.
[0055] Pharmaceutically acceptable base addition salts of the compounds of
this invention
include, for example, metallic salts and organic salts: Preferred metallic
salts include, but are not
limited to, alkali metal (group Ia) salts, alkaline earth metal (group Ila)
salts, and other physiological
acceptable metal salts. Such salts may be made from aluminum, calcium,
lithium, magnesium,
potassium, sodium, and zinc. Non-limiting examples of preferred organic salts
can be made from
tertiary amines and quatemary amine salts, such as trometharnine,
diethylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
ethylenediamine,
meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups
can be quatemized
.with agents such as lower alkyl (C1-C6) halides (e.g., methyl, ethyl, propyl,
and butyl chlorides,
bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl,
and diamyl sulfates), long
chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides,
and iodides), aralkyl
halides (e.g., benzyl and phenethyl bromides), and others.

Solvates, Prodrugs, and Isomers
[0056] The compounds of the present invention, tautomers thereof, and their
salts, may also
exist in the form of solvates with water, for example hydrates, or with
organic solvents such as
methanol, ethanol or acetonitrile to form, respectively, a methanolate,
ethanolate or acetonitrilate. The
compounds of the present invention may exist in each form of solvate or
mixtures thereof.
[0057] In one aspect, the compounds, tautomers or salts of the present
invention may be in
the form of prodrugs. Some are aliphatic or aromatic esters derived from
acidic groups on compounds
of this invention. Others are aliphatic or aromatic esters of hydroxyl or
amino groups on compounds
of this invention. The present invention also features phosphate prodrugs of
hydroxyl groups on the
compounds of this invention.

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[0058] The compounds of the invention may comprise asymmetrically substituted
carbon
atoms known as chiral centers. These chiral centers are designated as "R" or
"S" depending on the
configuration of substituents around the chiral carbon atom. The terms "R" and
"S" used herein are
configurations as defined in Nomenclature of Organic Chemistry, Section E:
Stereochemistry,
Recommendations 1974, PURE APPL. CHEM., 45:11-30 (1976). The compounds of this
invention
may exist, without limitation, as single stereoisomers (e.g., single
enantiomers or single
diastereomer), mixtures of stereoisomers (e.g. any mixture of enantiomers or
diastereomers), or
racemic mixtures. All such single stereoisomers, mixtures and racemates are
encompassed within the
scope of the invention. Compounds identified herein as single stereoisomers
are meant to describe
compounds that are present in a form that is substantially free from other
stereoisomers (e.g., other
enantiomers or diastereomers). By "substantially free," it means that at least
80% of the compound in
a composition is the desired stereoisomer; preferably, at least 90% of the
compound in a composition
is the desired stereoisomer; and more preferably, at least 95%, 96%, 97%, 98%
or 99% of the
compound in a composition is the desired stereoisomer. Where the
stereochemistry of the chiral
carbon(s) present in a chemical structure is not specified, the chemical
structure is intended to
encompass compounds containing either stereoisomer of each chiral center
present in the chemical
structure.
[0059] Individual stereoisomers of the compounds of this invention can be
prepared using
many methods known in the art. These methods include, but are not limited to,
stereospecific
synthesis, chromatographic separation of diastereomers, chromatographic
resolution of enantiomers,
conversion of enantiomers in an enantiomeric mixture to diastereomers followed
by
chromatographically separation of the diastereomers and regeneration of the
individual enantiomers,
and enzymatic resolution.
[0060] Stereospecific synthesis typically involves the use of appropriate
optically pure
(enantiomerically pure) or substantial optically pure materials and synthetic
reactions that do not
cause racemization or inversion of stereochemistry at the chiral centers.
Mixtures of stereoisomers of
compounds, including racemic mixtures, resulting from a synthetic reaction may
be separated, for
example, by chromatographic techniques as appreciated by those of ordinary
skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral
chromatography resins,
many of which are commercially available. In a non-limiting example, racemate
is placed in solution
and loaded onto the column containing a chiral stationary phase. Enantiomers
can then be separated
by HPLC.
[0061] Resolution of enantiomers can also be accomplished by converting
enantiomers in a
mixture to diastereomers by reaction with chiral auxiliaries. The resulting
diastereomers can be
separated by column chromatography or crystallization/re-crystallization. This
technique is useful
when the compounds to be separated contain a carboxyl, anuno or hydroxyl grbup
that will form a salt
22


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or covalent bond with the chiral auxiliary. Non-limiting examples of suitable
chiral auxiliaries
include chirally pure amino acids, organic carboxylic acids or organosulfonic
acids. Once the
diastereomers are separated by chromatography, the individual enantiomers can
be regenerated.
Frequently, the chiral auxiliary can be recovered and used again.
[0062] Enzymes, such as esterases, phosphatases or lipases, can be useful for
the resolution
of derivatives of enantiomers in an enantiomeric mixture. For example, an
ester derivative of a
carboxyl group in the compounds to be separated can be treated with an enzyme
which selectively
hydrolyzes only one of the enantiomers in the mixture. The resulting
enantiomerically pure acid can
then be separated from the unhydrolyzed ester.
[0063] Alternatively, salts of enantiomers in a mixture can be prepared using
any method
known in the art, including treatment of the carboxylic acid with a suitable
optically pure base such as
alkaloids or phenethylamine, followed by precipitation or crystallization/re-
crystallization of the
enantiomerically pure salts. Methods suitable for the resolution/separation of
a mixture of
stereoisomers, including racemic mixtures, can be found in ENANTIOMERS,
RACEMATES, AND
RESOLUTIONS (Jacques et al., 1981, John Wiley and Sons, New York, Nl').
[0064] A compound of this invention may possess one or more unsaturated carbon-
carbon
double bonds. All double bond isomers, such as the cis (Z) and trans (E)
isomers, and mixtures
thereof are intended to be encompassed within the scope of a recited compound
unless otherwise
specified. In addition, where a compound exists in various tautomeric forms, a
recited compound is
not limited to any one specific tautomer, but rather is intended to encompass
all tautomeric forms.
100651 Certain compounds of the invention may exist in different stable
conformational
forms which may be separable. Torsional asymmetry due to restricted rotations
about an asymmetric
single bond, for example because of steric hindrance or ring strain, may
permit separation of different
conformers. The compounds of the invention includes each conformational isomer
of these
compounds and mixtures thereof.
[0066] Certain compounds of the invention may also exist in zwitterionic form
and the
invention includes each zwitterionic form of these compounds and mixtures
thereof.

Definitions
[0067] The compounds of the present invention are generally described herein
using standard
nomenclature. For a recited compound having asymmetric center(s), it should be
understood that all
of the stereoisomers of the compound and mixtures thereof are encompassed in
the present invention
unless otherwise specified. Non-limiting examples of stereoisomers include
enantiomers,
diastereomers, and cis-transisomers. Where a recited compound exists in
various tautomeric forms,
the compound is intended to encompass all tautomeric forms. Certain compounds
are described
herein using general formulas that include variables (e.g., R30, Wi, A, L', X,
or Y). Unless otherwise
23


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specified, each variable within such a formula is defined independetly of any
other variable, and any
variable that occurs more than one time in a formula is defined independently
at each occurrence. If
substituents are described as being "independently selected" from a group,
each substituent is selected
independently from the other. Each substituent therefore can be identical to
or different from the
other substituent(s). '
[0068] . The number of carbon atoms in a hydrocarbyl substituent can be
indicated by the
prefix "C.-Cy," where x is the minimum and y is the maximum number of carbon
atoms in the
substituent. Thus, for example, "C,-C6alkyl" refers to an alkyl substituent
containing from 1 to 6
carbon atoms. Illustrating further, C3-C6cycloalkyl means a saturated
hydrocarbyl ring containing
from 3 to 6 carbon ring atoms. A prefix attached to a multiple-component
substituent only applies to
the first component that immediately follows the prefix. To illustrate, the
term "alkylaryl" contains
two components: alkyl and aryl. Thus, for example, Cl-C6alkylaryl refers to a
Cl-C6all.yl appended to
the parent molecular moiety through an aryl group. Likewise, alkylC6-Cloaryl
refers to an alkyl group
appended to the parent molecular moiety through a C6-C,oaryl group. Similarly,
the prefix "halo" on
haloalkoxyalkyl indicates that the alkoxy component is substituted with one or
more halogen radicals,
while the prefix "halo" on alkoxyhaloalkyl indicates that the alkyl component
is substituted with one
or more halogen radicals.
[0069] When words are used to describe a linking element between two other
elements of a
depicted chemical structure, the leftmost-described component of the linking
element is the
component that is bound to the left element in the depicted structure. To
illustrate, if the chemical
structure is X-L-Y and L is described as methylarylethyl, then the chemical
would be X-methyl-aryl-
ethyl-Y.
[0070] If a linking element in a depicted structure is a bond, then the left
element in the
depicted structure is bound directly to the right element in the depicted
structure. For example, if a
chemical structure is depicted as X-L-Y and L is selected as a bond, then the
chemical structure
would be X-Y. For another example, if a chemical moiety is depicted as -IrX
and L is selected as a
bond, then the chemical moiety would be X. For yet another example, if a
chemical structure is
depicted as X-L1-L2-Y, X-LI-I.2-L3-Y or X-L,-LZ-. ..-LI.,-Y, and LI, L2, L3,
... LN are selected as
bonds, then the chemical structure would be X-Y.
[0071] When a chemical formula is used to describe a substituent, the dash on
the right (or
left) side of the formula indicates the portion of the substituent that has
the free valence(s).
[0072] If a substituent is described as being "substituted," a non-hydrogen
radical is in the
place of one or more hydrogen radials on a carbon, nitrogen or oxygen of the
substituent. Thus, for
example, a substituted alkyl substituent is an alkyl substituent wherein at
least one non-hydrogen
radical is in the place of a hydrogen radical(s) on the alkyl substituent. To
illustrate, monofluoroalkyl
is alkyl substituted with one fluoro radical, and difluoroalkyl is alkyl
substituted with two fluoro
24


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radicals. It should be recognized that if there are two or more substitutions
on a substituent, each of
the non-hydrogen radicals may be Identical or different unless otherwise
stated.
[0073] A substituent is "substitutable" if it comprises at least one carbon,
nitrogen or oxygen
atom that is bonded to one or more hydrogen atoms.
[0074] If a substituent is described as being "optionally substituted", the
substituent may be
either substituted or not substituted. If a substituent is described as being
optionally substituted with
up to a particular number of non-hydrogen radicals, that substituent may be
either not substituted, or
substituted by up to that particular number of non-hydrogen radicals or by up
to the maximum number
of substitutable positions on the substituent, whichever is less. Thus, for
example, if a substituent is
described as a heteroaryl optionally substituted with up to three non-hydrogen
radicals, then any
heteroaryl with less than three substitutable positions would be optionally
substituted by up to only as
many non-hydrogen radicals as the heteroaryl has substitutable positions. To
illustrate, tetrazolyl
(which has only one substitutable position) would be optionally substituted
with up to one non-
hydrogen radical. To illustrate further, if an amino nitrogen is described as
being optionally
substituted with up to two non-hydrogen radicals, then a primary amino
nitrogen will be optionally
substituted with up to two non-hydrogen radicals, whereas a secondary amino
nitrogen will be
optionally substituted with up to only one non-hydrogen radical.
[0075] The term "alkenyl" (alone or in combination with another term(s)) means
a straight-
or branched-chain hydrocarbyl substituent containing one or more double bonds
and typically from 2
to 20 carbon atoms, more typically from 2 to 8 carbon atoms, and even more
typically from 2 to 6
carbon atoms. Each carbon-carbon double bond may have either cis or trans
geometry within the
alkenyl moiety, relative to groups substituted on the double bond carbons. Non-
limiting examples of
such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-
pentadienyl, 1,4-butadienyl,
1-butenyl, 2-butenyl, and 3-butenyl.
[0076] The term "alkenylene" (alone or in combination with another term(s))
refers to a
divalent unsaturated hydrocarbyl group which may be linear or branched and
which has at least one
carbon-carbon double bond. An alkenylene group typically contains 2 to 20
carbon atoms, more
typically from 2 to 8 carbon atoms, and even more typically from 2 to 6 carbon
atoms. Non-limiting
examples of alkenylene groups include -C(H)=C(H)-, -C(H)=C(H)-CHZ-,
-C(H)=C(H)-CH2--CH2-, -CHZ-C(H)=C(H}-CHa-, -C(H)=C(H}-CH(CH3)-, and
-CH2-C(H)=C(H)-CH(CH2CH3)-.
[0077] The term "alkoxy" (alone or in combination with another term(s)) refers
to an alkyl
group appended to the parent molecular moiety through an oxy moiety (i.e., -0-
alkyl). Non-limiting
examples of such a substituent include methoxy (-O-CH3), ethoxy, n-propoxy,
isopropoxy, n-butoxy,
iso-butoxy, sec-butoxy, and tert-butoxy.



CA 02633752 2008-06-18
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[0078] The term "alkoxyalkyl" (alone or in combination with another term(s))
refers to an
alkoxy group appended to the parent molecular moiety through an alkylene
group. Non-limiting
examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2-
methoxyethyl, and
methoxymethyl.
[0079] The term "alkoxycarbonyl" (alone or in combination with another
term(s)) refers to
an alkoxy group appended to the parent molecular moiety through a carbonyl
group (i.e.,
-C(O)--O-alkyl). Representative examples of alkoxycarbonyl include, but are
not limited to,
0

methoxycarbonyl, ethoxycarbonyl ( 77 ), and tert-butoxycarbonyl.
[0080] The term "alkoxycarbonylamino" (alone or in combination with another
term(s))
refers to N(RARB)-, where RA is alkyl-(}-C(O)--, and RB is alkyl-O-C(O)- or
hydrogen. RA and
RB maybe identical or different.
[0081] The term "alkoxycarbonylaminoalkyl" (alone or in combination with
another term(s))
refers to N(R.ARB)-alkylene-, where RA is alkyl-O-C(O)-, and RB is alkyl-O-
C(O)-- or
hydrogen. RA and RB may be identical or different.
[0082] The term "alkoxycarbonylalkyl" (alone or in combination with another
term(s)) refers
to an alkoxycarbonyl group appended to the parent molecular moiety through an
alkylene group.
Representative examples of alkoxycarbonylalkyl include, but are not limited
to, 2-methoxy-2-
oxoethyl, 2-ethoxy-2-oxoethyl, 3-methoxy-3-oxopropyl, 3-ethoxy-3-oxopropyl, 4-
ethoxy-2-
(ethoxycarbonyl)-44-oxobutyl, 5-methoxy-5-oxopentyl, and 6-methoxy-6-oxohexyl.
[0083] The term "alkyl" (alone or in combination with another term(s)) means a
straight-or
branched-chain saturated hydrocarbyl substituent typically containing from 1
to 20 carbon atoms,
more typically from 1 to 8 carbon atoms, and even more typically from 1 to 6
carbon atoms. Non-
limiting= examples of such substituents include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl, pentyl, iso-amyl, hexyl, and octyl.
[0084] The term "alkylamino" (alone or in combination with another term(s))
refers to -
NRARB, wherein RA is alkyl, and R$ is hydrogen or alkyl. RA and RB may be
identical or different.
For instance, CI-C6alkylarnino refers to NR.ARB, wherein RA is Cl-C6alkyl, and
RB is hydrogen or
CI-C6alkyl.
[0085] The terrn "alkylaminoalkyl" (alone or in combination with another
term(s)) refers to
N(RARB)-alkylene-, wherein RA is alkyl, and Rg is hydrogen or allcyl. RA and
RB may be identical
or different. Thus, CI-C6alkylaminoC,-C6alky refers to N(RARB)-C,-C6alkylene-,
wherein RA is C,-
C6alkyl, and RB is hydrogen or C1-C6alkyl.
[0086] The term "alkylcarbonyl" (alone or in combination with another term(s))
refers to an
alkyl group appended to the parent molecular moiety through a carbonyl group
(i.e., -C(O)-alkyl).
26


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Representative examples of alkylcarbonyl include, but are not limited to,
acetyl, ethylcarbonyl
0

z~CH3 ( ), 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
[0087] The term "alkylcarbonylalkyl" (alone or in combination with another
term(s)) refers
to an alkylcarbonyl group appended to the parent molecular moiety through an
alkylene group.
Representative examples of alkylcarbonylalkyl include, but are not liinited
to, 2-oxopropyl, 3,3-
dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
[0088] The term "alkylcarbonyloxy" (alone or in combination with another
term(s)) refers to
an a9lkylcarbonyl group appended to the parent molecular moiety through an oxy
moiety.
Representative examples of alkylcarbonyloxy include, but , are not limited to,
acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy.
[0089] The term ' alkylcarbonyloxyalkyl' (alone or in combination with
another term(s))
refers to an alkylcarbonyloxy group appended to the parent molecular moiety
through an alkylene
moiety. Representative examples of alkylcarbonyloxyalkyl include, but are not
limited to, 2-
(acetyloxy)ethyl, 3-(acetyloxy)propyl, and 3-(propionyloxy)propyl.
[0090] The terms "alkylene" or "alkylenyl" (alone or in combination with
another term(s))
denote a divalent group derived from a straight or branched saturated
hydrocarbyl chain typically
containing from I to 20 carbon atoms, more typically from 1 to 8 carbon atoms,
and even more
typically from 1 to 6 carbon atoms. Representative examples of alkylene
include, but are not limited
to, -CH2-, -CHZCHZ-, -CH2CH2CH2-, -CHaCH2CHzCH2-, and -CH2CH(CH3)CH2-.
[0091] The term "alkynyl" (alone or in combination with another term(s)) means
a straight-
or branched-chain hydrocarbyl substituent containing one or more triple bonds
and typically from 2 to
20 carbon atoms, more typically from 2 to 8 carbon atoms, and even more
typically from 2 to 6
carbon atoms. Non-limiting examples of such substituents include ethynyl, 1-
propynyl, 2-propynyl,
3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
[0092] The terms "alkynylene" (alone or in combination with another term(s))
refers to a
divalent unsaturated hydrocarbon group which may be linear or branched and
which has at least one
carbon-carbon triple bonds. Representative alkynylene groups include, by way
of example, -C C-, -
C=C-CHZ-, -C=C-CH2-CH2-, -CHz-C C-CHa-, -C=-C-CH(CH3)-, and -CH2-C C-
CH(CH2CH3)-.
[0093] The term "amino" (alone or iri combination with another term(s)) means -
NH2. The
term "monosubstituted amino" (alone or in combination with another term(s))
means an amino
substituent wherein one of the hydrogen radicals is replaced by a non-hydrogen
substituent. The term
"disubstituted amino" (alone or in combination with another term(s)) means an
amino substituent
wherein both of the hydrogen atoms are replaced by non-hydrogen substituents,
which may be
identical or different.

27


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[0094] The term "aminocarbonyl" (alone or in combination with another term(s))
means
-C(O)-NFTa, which also may be depicted as:

NHi
[0095] The term "aminoalkyl" (alone or in combination with another term(s))
means
-alkylene--NH2.
[0096] The term "aminoalkylcarbonyl" (alone or in combination with another
term(s)) means
-C(O)--a.lkyIene--NH2. For example, "aminomethylcarbonyl" may be depicted as:
0
NHZ
[0097] The term "aminosulfonyl" (alone or in combination with another term(s))
means
-S(O)Z-NH2, which also may be depicted as:
\/ 0
V NHZ

[0098] The term "aryl" (alone or in combination with another term(s)) refers
to an aromatic
carbocyclyl containing from 6 to 14 carbon ring atoms. Non-limiting examples
of aryls include
phenyl, naphthalenyl, anthracenyl, and indenyl. An aryl group can be connected
to the parent
molecular moiety through any substitutable carbon atom of the group.
[0099] The term "arylalkyl" (alone or in combination with another term(s))
refers to an aryl
group appended to the parent molecular moiety through an alkylene group.
Representative examples
of substituted/unsubstituted arylalkyl include, but are not limited to,
benzyl, 4-(benzyloxy)benzyl, 4-
methoxybenzyl, 4-hydroxybenzyl, 3-(1,3-benzodioxol-5-yl)-2-rnethylpropyl, 3-
(phenoxy)benzy], 3-
(1,3-benzodioxol-5-yl)propyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylmethyl,
3,5-ditert-butyl-2-
hydroxybenzyl, 3-methoxybenzyl, 3,4-dimethoxybenzyl, 4-(dimethylamino)benzyl,
4-[3-_
(dimethylamino)propoxy]benzyl, (6-methoxy-2-naphthyl)methyl, and 2-naphth-2-
ylethyl.
[0100] The term "arylalkylcarbonyl" (alone or in combination with another
term(s)) refers to
an arylalkyl group appended to the parent molecular moiety through a carbonyl
group (i.e.,
arylallcyl-C(O)-). Representative examples of arylalkylcarbonyl include, but
are not limited to, 2-
naphthylacetyl and phenylacetyl.
[0101] The term "arylalkoxy" (alone or in combination with another term(s))
refers to an
arylalkyl group appended to the parent molecular moiety through an oxy moiety
(i.e., arylalkyl-O-).
Representative examples of arylalkoxy include, but are not limited to, 2-
phenylethoxy, 3-naphth-2-
ylpropoxy, and 5-phenylpentyloxy.

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[0102] The term "arylalkoxyalkyl" (alone or in combination with another
term(s)) refers to
an arylalkoxy group appended to the parent molecular moiety through an
alkylene group.
Representative examples of arylalkoxyalkyl include, but are not limited to,
benzyloxymethyl, 2-
(benzyloxy)ethyl, and (2-phenylethoxy)methyl.
[0103] The term "arylalkoxycarbonyl" (alone or in combination with another
term(s)) refers
to an arylalkoxy group appended to the parent molecular moiety through a
carbonyl group.
Representative examples of arylalkoxycarbonyl include, but are not limited to,
benzyloxycarbonyl,
and naphth-2-ylmethoxycarbonyl.
[0104] The term "arylcarbonyl" (alone or in combination with another term(s))
refers to an
aryl group appended to the parent molecular moiety through a carbonyl group.
Representative
examples of arylcarbonyl include, but are not limited to, benzoyl and
naphthoyl.
[0105] The term "aryloxy" (alone or in combination with another term(s))
refers to an aryl
group appended to the parent molecular moiety through an oxy moiety.
Representative examples of
substituted/unsubstituted aryloxy include, but are not limited to, phenoxy,
naphthyloxy, 3-
bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.
[0106] The term "aryloxyalkyl" (alone or in combination with another term(s))
refers to an
aryloxy group appended to the parent molecular moiety through an alkylene
group. Representative
examples of aryloxyalkyl include, but are not limited to, 2 phenoxyethyl, 3-
naphth-2-yloxypropyl,
and phenoxymethyl.
[0107] The term "aryloxycarbonyl" (alone or in combination with another
term(s)) refers to
an aryloxy group appended to the parent molecular moiety through a carbonyl
group.
[0108] The term "arylthio" (alone or in combination with another term(s))
refers to an aryl
group appended to the parent molecular moiety through a sulfur atom (i.e.,.
ary1-S ). Representative
examples of arylthio include, but are not limited to, phenylthio, naphthalen-l-
ylthio, and naphthalen-
2-ylthio.
[0109] The term "arylthioalkyl" (alone or in combination with another term(s))
refers to
aryl-S-alkylene-. Representative examples of arylthioalkyl include, but are
not limited to,
(phenylthio)methyl, 2-(phenylthio)ethyl, and 3-(phenylthio)propyl.
[0110] The term "arylthioalkoxy" (alone or in combination with another
term(s)) refers to an
arylthioalkyl group appended to the parent molecular moiety through an oxy
group.
[0111] The term "arylthioalkoxyalkyl" (alone or in combination with another
term(s)) refers
to an arylthioalkoxy group appended to the parent molecular moiety through an
alkylene group.
[0112] The terms "carbocycle" or "carbocyclic" or " carbocyclyl" (alone or in
combination
with another term(s)) refer to a saturated (e.g., "cycloalkyl"), partially
saturated (e.g., "cycloalkenyl"
or "cycloalkynyl") or completely unsaturated (e.g., "aryl") ring system
containing zero heteroatom
ring atom and typically from 3 to 18 carbon ring atoms. "Ring atoms" or "ring
members" are the
29


CA 02633752 2008-06-18
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atoms bound together to form the ring or rings of a cyclic substituent. A
carbocyclyl may be, without
limitation, a single ring, or two or more fused rings, or bridged or spiro
rings. A carbocyclyl may
contain from 3 to 14 ring members (i.e., C3-C14carbocyclyl, such as C3-
C14cycloalkyl), from 3 to 10
ring members (i.e., C3-C,ocarbocyclyl, such as C3-C,ocycloalkyl), from 3 to 8
ring members (i.e., C3-
C$carbocycIyl, such as C3-Cacycloalkyl), from 3 to 6 ring members (i.e., C3-
C6carbocyclyl, such as
C3-C6cycloalkyl), from 4 to 10 ring members (i.e., C4-Clocarbocyclyl, such as
C4-C,acycloalkyl and
C4-Clocycloalkenyl), from 4 to 8 ring members (i.e., C4-C8carbocyclyl, such as
C4-C$cycloalkyl and
C4-C8cycloalkenyl), or from 5 to 7 ring members (i.e., CS-C7carbocyclyl, such
as CS-C,cycloalkyl, CS-
C7cycloalkenyl and phenyl). A substituted carbocyclyl may have either cis or
trans geometry.
Representative examples of carbocyclyl groups include, but are not limited to,
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,
cyclopentadienyl,
cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl,
cyclohexenyl, phenyl,
naphthyl, fluorenyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl,
isoindenyl, bicyclodecanyl,
anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"),
decalinyl, and norpinanyl.
A carbocyclyl group can be attached to the parent molecular moiety through any
substitutable carbon
atom of the group.
[0113] The term "carbocyclylalkyl" (alone or in combination with another
term(s)) refers to
a carbocyclyl group appended to the parent molecular moiety through an
alkylene group. For
instance, C3-C,ocarbocyclylC,-C6alkyl refers to a C3-C,ocarbocyclyl group
appended to the parent
molecular moiety through Cl-C6alkylene. Likewise, CS-C7carbocyclylC,-C6alkyl
refers to a C5-
C7carbocyclyl group appended to the parent molecular moiety through C,-
Cralkylene.
[0114] The term "carbocyclylalkoxy" (alone or in combination with another
term(s)) refers
to a carbocyclylalkyl group appended to the parent molecular moiety through an
oxy group (i.e.,
carbocyclyl-alkylene--O-). For instance, C3-C10carbocyclylC1-C6alkoxy refers
to a C3-
CIocarbocyclylC,-C6alkyl group appended to the parent molecular moiety through
an oxy group.
Likewise, a CS-C7carbocyclylC,-Cbalkoxy group refers to a Cs-C7carbocyclylC,-
C6alkyl group
appended to the parent molecular moiety through an oxy group.
[0115] The term "carbocyclylalkoxyalkyl" (alone or in combination with another
term(s))
refers to a carbocyelylalkoxy group appended to the parent molecular moiety
through an alkylene
group (i.e., carbocyclyl---alkylene-O-alkylene-). For instance, C3-
C,ocarbocyclylC,-C6alkoxyC,-
C6alkyl refers to C3-CiOcarbocyclylC,-C6alkoxy group appended to the parent
molecular moiety
through a Cl-C6alkylene group.
[0116] The term "carbocyclylalkoxycarbonyl" (alone or in combination with
another
term(s)) refers to a carbocyclylalkoxy group appended to the parent molecular
moiety through a
carbonyl group (i.e., --C(O)-O-alkylene-carbocyclyl). For instance, C3-
ClocarbocyclylCt-
C6alkoxycarbonyl refers to a C3-C1ocarbocyclylC,-C6alkoxy group appended to
the parent molecular


CA 02633752 2008-06-18
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moiety through a carbonyl group. As a non-limiting example,
"phenylethoxycarbonyl" may be
depicted as:

o
[0117] The term "carbocyclylalkylcarbonyl" (alone or in combination with
another term(s))
refers to a carbocyclylalkyl group appended to the parent molecular moiety
through a carbonyl group
(i.e., -C(O)-alkylene-carbocyclyl). For example, "phenylethylcarbonyl" may be
depicted as:
0
[0118] The term "carbocyclylcarbonyl" (alone or in combination with another
term(s)) refers
to a carbocyclyl group appended to the parent molecular moiety through a
carbonyl group (i.e.,
carbocyclyl-C(O)-). For example, "phenylcarbonyl" may be depicted as:
0
[0119] The term "carbocyclyloxy" (alone or in combination with another
term(s)) refers to a
carbocyclyl group appended to the parent molecular moiety through an oxy
moiety (i.e.,
carbocyclyl-O$-).
[0120] The term "carbocyclyloxyalkyl" (alone or in combination with another
term(s)) refers
to a carbocyclyloxy group appended to the parent molecular moiety through an
alkylene group (i.e.,
carbocyolyl--O-alkylene-).
[0121] The term "carbocyclyloxycarbonyl" (alone or in combination with another
term(s))
refers to a carbocyclyloxy group appended to the parent molecular moiety
through a carbonyl group
(i.e., --C(O)-(}-carbocyclyl). ' For example, "phenyloxycarbonyl" may be
depicted as:

O
[0122] The term "carbocyclylthio" (alone or in combination with another
term(s)) refers to a
carbocyclyl group appended to the parent molecular moiety through a sulfur
atom (i.e.,
carbocyclyl-S-).
[0123] The term "carbocyclylthioalkoxy" (alone or in combination with another
term(s))
refers to carbocyclyl-alkylene-S-.
[0124] The term "carbocyclylthioalkoxyalkyl" (alone or in combination with
another
term(s)) refers to carbocyclyl-alkylene-S-alkylene-
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[0125] The term "carbocyclylthioalkyP" (alone or in combination with another
term(s)) refers
to a carbocyclylthio group appended to the parent molecular moiety through an
alkylene group (i.e.,
carbocyclyl-S-alkylene-).
[0126] The term "carbocyclylcarbocyclyl" (alone or in combination with another
term(s))
refers to a carbocyclyl group appended to the parent molecular moiety through
another carbocyclyl
group (i.e., carbocyclyl-carbocyclyl-). For instance, C3-Clacarbocyc1y1C5-
C7carbocyclyl refers to a
C3-C,acarbocyclyl group appended to the parent molecular moiety through a C5-
C7carbocyclyl group
(i.e., C3-C,ocarbocyclyl-C$-C7carbocyclyl-).
[0127] The term "carbocyclylcarbocyclylalkyl" (alone or in combiriation with
another
term(s)) refers to a carbocyclylcarbocyclyl group appended to the parent
molecular moiety through an
alkylene group.
[0128] The term "carbocyclylalkoxycarbocyclylalkyl" (alone or in combination
with another
term(s)) refers to carbocyclyl-alkylene--O--carbocyclyl-alkylene-. For
instance, C3-
CiocarbocyclylC1-C6alkoxyCS-C7carbocyc1y1C3-C4alkyl. refers to C3-
Clocarbocyclyl--Cl-
C6alkylene-O-C5-C7carbocyclyl-C3-C4alkylene=.
[0129] The term "(carbocyclylalkyl)carbocyclylalkyl" (alone or in combination
with another
term(s)) refers to carbocyclyl--alkylene--carbocyclyl-alkylene-. For instance,
C3-ClocarbocyclylCl-
C6alkylC5-C7carbocyclylC3-C4alkyl refers to C3-C,ocarbocyclyl-Cl-C6alkylene--
C5-
C7carbocyclyl-C3-C4alkylene--.
[0130] The term "carbocyclylalkoxyheterocycloalkyl" (alone or in combination
with another
term(s)) refers to carbocyclyl-alkylene-O--heterocyclyt-alkylene-.
[0131] The term "carbocyclylcarbonylheterocycloalkyl" (alone or in combination
with
another term(s)) refers to carbocyclyl-C(O)--heterocyclyl-alkylene--.
[0132] The term "carbocyclylheterocycloalkyl" (alone or in combination with
another
term(s)) refers to carbocyclyl-heterocyclyl-alkylene-.
[0133] The term "carbocyclylcarbonylcarbocyclylalkyl" (alone or in combination
with
another term(s)) refers to carbocyclyl--C(O)-carbocyclyl-alkylene-. For
instance, C3-
ClocarbocyclylcarbonylC4-C8carbocyclylC,-C6alkyl refers to C3-Cjocarbocyclyl--
C(O)-C4-
Cscarbocyclyl--C j-C6alkylene-.
[0134] The term "(carbocyclylalkyl)heterocycloalkyl" (alone or in combination
with another
term(s)) refers to carbocyclyl-alkylene-heterocyclyl-alkylene.
[0135] The tenm "carbonyl" (alone or in combination with another term(s))
refers to -C(O)-,
which also may be depicted as:
0
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[0136] The term "carboxy" (alone or in combination with another term(s)) means
-C(O)-OH,
which also may be depicted as:
0

OH
[0137] The term "carboxyalkyl" (alone or in combination with another term(s))
refers to a
carboxy group appended to the parent molecular moiety through an alkylene
group. Representative examples of carboxyalkyl include, but are not limited
to, carboxymethyl, 2-carboxyethyl, and 3-

carboxypropyl.
[0138] The term "cyclic amino" (alone or in combination with another term(s))
means a
heterocyclyl moiety comprising at least one nitrogen ring atom, with the
remaining ring atoms being
carbon and optionally nitrogen or sulfur. Non-limiting examples of such
moieties include piperidinyl,
piperazinyl, and thiazine groups.
[0139] The term "cycloalkenyl" (alone or in combination with another term(s))
refers to a
non-aromatic, partially unsaturated carbocyclyl substituent having zero
heteroatom ring member and
typically from 4 to 18 carbon ring members. Representative examples of
cycloalkenyl groups
include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl,
and
octahydronaphthalenyl.
[0140] The term "cycloalkyl" (alone or in combination with another term(s))
refers to a
saturated carbocyclyl group containing zero heteroatom ring member and
typically from 3 to 18
carbon ring members. Non-limiting examples of cycloalkyls include cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.
[0141] The term "cycloalkylcarbonyl" (alone or in combination with another
term(s)) refers
to a cycloalkyl group appended to the parent molecular moiety through a
carbonyl group.
[0142] The term "cyano" (alone or in combination with another term(s)) means -
CN, which
N
III
C
also may be depicted as ~~L . -
[0143] The term "dialkylamino" (alone or in combination with another term(s))
refers to -
NRARB, wherein RA and RS are independently selected from alkyl groups.
[0144] The term "dialkylaminocarbonyl" (alone or in combination with another
term(s))
refers to a dialkylamino group appended to the parent molecular moiety through
a carbonyl group
(i.e., N(RARB)-C(O)-, wherein RA and RB are independently selected from alkyl
groups).
[0145] The term "formyl" (alone or in combination with another term(s)) refers
to a -C(O)H
group.

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[0146] The term "halogen" or "halo"(alone or in combination with another
term(s)) means a
fluorine radical (which may be depicted as -F), chlorine radical (which may be
depicted as -Cl),
bromine radical (which may be depicted as -Br), or iodine radical (which may
be depicted as -1).
[0147] The prefix "halo" indicates that the substituent to which the prefix is
attached is
substituted with one or more independently selected halogen radicals. For
example, "haloalkyl"
(alone or in combination with another tenn(s)) means an alkyl substituent
wherein at least one
hydrogen radical is replaced with a halogen radical. Norn-limiting examples of
haloalkyls include
chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and
1,1,1-trifluoroethyl.
111ustrating further, "haloalkoxy" (alone or in combination with another
term(s)) means an alkoxy
substituent wherein at least one hydrogen radical is replaced by a halogen
radical. Non-limiting
examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy,
fluoromethoxy,
difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and
1,1,1,-trifluoroethoxy.
.It should be recognized that if a substituent is substituted by more than one
halogen radical, those
halogen radicals may be identical or different (unless otherwise stated).
[0148] The prefix "perhalo" indicates that every hydrogen radical on the
substituent to which
the prefix is attached is replaced with independently selected halogen
radicals, i.e., each hydrogen
radical on the substituent is replaced with a halogen radical. If all the
halogen radicals are identical,
the prefix typically will identify the halogen radical. Thus, for example, the
term "perfluoro" means
that every hydrogen radical on the substituent to which the prefix is attached
is substituted with a
fluorine radical. To illustrate, the term "perfluoroalkyl" means an alkyl
substituent wherein a fluorine
radical is in the place of each hydrogen radical. Non-limiting examples of
perfluoroalkyl substituents
include trifluoromethyl (-CF3), perfluoroisopropyl, perfluorobutyl,
perfluorodecyl, and
perfluorododecyl. To illustrate further, the term "perfluoroalkoxy" means an
alkoxy substituent
wherein each hydrogen radical is replaced with a fluorine radical. Non-
limiting examples of
perfluoroalkoxy substituents include trifluoromethoxy (-O-CF3),
perfluoroisopropoxy,
perfluorobutoxy, perfluorodecoxy, and perfluorododecoxy.
[0149] The terms "heterocycle" or "heterocyclo" or "heterocyclyl" (alone or in
combination
with another term(s)) refer to a saturated (e.g., "heterocycloalkyl"),
partially unsaturated (e.g.,
"heterocycloalkenyl" or "heterocycloalkynyP") or completely unsaturated (e.g.,
"heteroaryl") ring
system typically containing from 3 to 18 ring atoms, where at least one of the
ring atoms is a
heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms
being independently
selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A
heterocyclyl group can
be linked to the parent molecular moiety via any substitutable carbon or
nitrogen atom in the group,
provided that a stable molecule results.
[0150] A heterocyclyl may be, without limitation, a single ring, which
typically contains
from 3 to 14 ring atoms (i.e., M3-M,4heterocyclyl), from 3 to 8 ring atoms
(i.e., M3-Msheterocyclyl),
34


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from 3 to 6 ring atoms (i.e., M3-M6heterocyclyl), or from 5 to 6 ring atoms
(i.e., MS-M6heterocyclyl).
Non-limiting examples of single-ring heterocyclyls include furanyl,
dihydrofuranyl,
tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl,
imidazolyl, isoimidazolyl,
imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,
triazolyl, tetrazolyl, dithiolyl,
oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,
isothiazolinyl, thiazolidinyl,
isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-
oxadiazolyl,
1,2,4-oxadiazolyl (also known as "azoximyl"), 1,2,5-oxadiazolyl (also known as
"furazanyl"), and
1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-
oxatriazolyl), dioxazolyl
(including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, and 1,3,4-
dioxazolyl), oxathiolanyl,
pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, -pyridinyl,
piperidinyl, diazinyl
(including pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known
as "1,3-diazinyl"),
and pyrazinyl (also known as "1,4-diazinyl")), piperazinyl, triazinyl
(including s-triazinyl (also known
as "1,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-
triazinyl (also known as
' 1,2,3-triazinyl, oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-
oxazinyl (also known as
"pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o-
isoxazinyl and
p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-
oxathiazinyl or
1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-
oxadiazinyl), morpholinyl,
azepinyl, oxepinyl, thiepinyl, and diazepinyl.
[0151] A heterocyclyl may also include, without limitation, two or more rings
fused together,
such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and
[1,6] naphthyridinyl),
thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl,
pyrazolopyrimidinyl,
indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,
pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-
pyridinyl), pyridopyrimidine, and
pteridinyl. Other non-limiting examples of fused-ring heterocyclyls include
benzo-fused
heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as
"pseudoindolyl"), isoindazolyl
(also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known
as "1-benzazinyl")
and isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl,
benzodiazinyl
(including cinnolinyl (also known as "1,2-benzodiazinyl") and quinazolinyl
(also known as
"1,3 benzodiazinyl")), benzopyranyl (including "chromenyl" and
"isochromenyl"), benzothiopyranyl
(also known as "thiochromenyl"), benzoxazolyl, indoxazinyl (also known as
"benzisoxazolyl"),
anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also
known as
"coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl",
"thionaphthenyl",
and "benzothiofuranyl"), isobenzothienyl (also Iazown as "isobenzothiophenyl",
"isothionaphthenyl",
and "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl,
benzotriazolyl,
benzoxazinyl (including 1,3,2 benzoxaziny), 1,4,2 benzoxazinyl, 2,3,1-
benzoxazinyl, and


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3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-
benzisoxazinyl),
tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl.
[0152] The term "two-fused-ring" heterocyclyl (alone or in combination with
another
term(s)) means a saturated, partially saturated, or aromatic heterocyclyl
containing two fused rings.
Non-limiting examples of two-fused-ring heterocyclyls include naphthyridinyl
(including [1,8]
naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl,
thienopyrimidinyl,
pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl,
pyrindinyl,
pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl, pteridinyl,
indolyl, isoindolyl, indoleninyl,
isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl,
benzodiazinyl, benzopyranyl,
benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl,
benzodioxanyl,
benzoxadiazolyl, benzofuranyl, isobenzofuranyl; benzothienyl, isobenzothienyl,
benzothiazolyl,
benzothiadiazolyl, benzoimidazolyl, benzotriazolyl, benzoxazinyl,
benzoisoxazinyl, and
tetrahydroisoquinolinyl.
[0153] A heterocyclyl may comprise one or more sulfur atoms as ring members;
and in some
cases, the sulfur atom(s) is oxidized to SO or SOa. The nitrogen heteroatom(s)
in a heterocyclyl may
or may not be quaternized, and may or may not be oxidized to N-oxide. In
addition, the nitrogen
heteroatom(s) may or may not be N-protected.
[0154] As used herein, the number of ring atoms in a heterocyclyl moiety can
be identified
by the prefix "Mx M,,, where x is the minimum and y is the maximum number of
ring atoms in the
heterocyclyl moiety.
[0155] The term "heterocycloalkoxy" (alone or in combination with another
term(s)) refers
to a heterocycloalkyl group appended to the parent molecular moiety through an
oxy group.
[0156] The term "heterocycloalkoxyalkyl" (alone or in combination with another
term(s))
refers to a heterocycloalkoxy group appended to the parent molecular moiety
through an alkylene
group (i.e., heterocyclyl-alkylene-O-alkylene-).
[0157] The term "heterocycloalkoxycarbonyl" (alone or in combination with
another
term(s)) refers to a heterocycloalkoxy group appended to the parent molecular
moiety through a
carbonyl group (i.e., heterocyclyl-alkylene-O-C(O)-).
[0158] The term "heterocycloalkyl" (alone or in combination with another
term(s)) refers to
a heterocyclyl appended to the parent molecular moiety through an alkylene
group (e.g.,
heterocycloCz -C6alkyl).
[0159] The term "heterocycloalkylcarbonyl" (alone or in combination with
another term(s))
refers to a heterocycloalkyl group appended to the parent molecular moiety
through a carbonyl group
(i.e., -C(O)-alkylene-heterocyclyl).

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[0160] The term "heterocyclocarbonyl" (alone or in combination with another
term(s)) refers
to a heterocyclyl appended to the parent molecular moiety through a carbonyl
group (i.e.,
-C(O)-heterocyclyl).
[0161] The terms "heterocyclyloxy" or "(heterocyclo)oxy" (alone or in
combination with
another term(s)) refers to a heterocyclyl group appended to the parent
molecular moiety through an
oxy moiety.
[0162] The term "(heterocyclyo)oxyalkyl" (alone or in combination with another
term(s))
refers to a heterocyclyloxy group appended to the parent molecular moiety
through an alkylene group
(i.e., heterocyclyl-O-alkylene--).
[0163] The term "(heterocyclo)oxycarbonyl" (alone or in combination with
another term(s))
refers to a (heterocyclo)oxy group appended to the parent molecular moiety
through a carbonyl group
(i.e., heterocyclyl-O-C(O)-).
[0164] The term "heterocyclothio" (alone or in combination with another
term(s)) refers to a
heterocyclyl appended to the parent molecular moiety through -S-.
[0165] The term "heterocyclothioalkoxy" (alone or in combination with another
term(s))
refers to heterocyclyl-alkylene-S-.
[0166] The term "heterocyclothioalkoxyalkyl" (alone or in combination with
another
term(s)) refers to heterocyclyl-alkylene-S-alkylene-.
[0167] The term "heterocyclothioalkyl" (alone or in combination with another
term(s)) refers
to a heterocyclothio group appended to the parent molecular moiety through an
alkylene group (i.e.,
heterocyclyl-S-alkylene-).
[0168] The term "heterocyclocarbocyclyl" (alone or in combination with another
term(s))
refers to a heterocyclyl appended to the parent molecular moiety through a
carbocyclyl group (i.e.,
heterocyclo-carbocyclyl-).
[0169] The term 'heterocyclocarbocyclylalkyl" (alone or in combination with
another
term(s)) refers to a heterocyclocarbocyclyl group appended to the parent
molecular moiety through an
alkylene group (i.e., heterocyclyl-carbocyclyl-alkylene-).
[0170] The term "(heterocyclo)alkoxycarbocyclylalkyl" (alone or in combination
with
another term(s)) refers to heterocyclo--alkylene-0--carbocyclyl-alkylene-.
[0171] The term "(heterocyclo)carbonylcarbocyclylalkyl" (alone or in
combination with
another term(s)) refers to heterocyclo--C(O)--carbocyclyl-alkylene-.
[0172] The term "(heterocyclo)heterocycloalkyl" (alone or in combination with
another
term(s)) refers to heterocyclo-heterocyclo-alkylene-.
[0173] The term "(heterocyclo)alkoxyheterocycloalkyl" (alone or in combination
with
another term(s)) refers to heterocyclo-alkylene--O-heterocyclo-alkylene-.

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[0174] The term "(heterocyclo)carbonylheterocycloalkyl" (alone or in
combination with
another term(s)) refers to heterocyclo-C(O)--heterocyclo--alkylene--.
[0175] The term "(heterocycloalkyl)carbocyclylalkyP" (alone or in combination
with another
term(s)) refers to heterocyclo--alkylene--carbocyclyl-alkylene--.
[0176] The term "(heterocycloalkyl)heterocycloalkyl" (alone or in combination
with another
term(s)) refers to heterocyclo-alkylene-heterocyclo--alkylene-. Thus, for
example, (M3-
M,oheterocycloC,-C6alkyl)MS-M6heterocycloC,-C3alkyl means M3-M,oheterocyclo-C,-

C6alkylene---MS-M6heterocyelo--C2-C3alkylene-.
[0177] The term "heteroaryl" (alone or in combination with another term(s))
means an
aromatic heterocyclyl typically containing from 5 to 18 ring atoms. A
heteroaryl may be a single ring,
or two or more fused rings. Non-limiting examples of five-membered heteroaryls
include imidazolyl;
furanyl; thiophenyl (or thienyl or thiofuranyl); pyrazolyl; oxazolyl;
isoxazolyl; thiazolyl; 1,2,3-,
1,2,4-, 1,2,5-, and 1,3,4-oxadiazolyl; and isothiazolyl. Non-limiting examples
of six-membered
heteroaryls include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; and 1,3,5-
, 1,2,4-, and
1,2,3-triazinyl. Non-limiting examples of 6/5-membered fused ring heteroaryls
include
benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl,
and anthranilyl. Non-
limiting examples of 6/6-membered fused ring heteroaryls include quinolinyl;
isoquinolinyl; and
benzoxazinyl (including cinnolinyl and quinazolinyl).
[0178] The term "heteroarylalkoxy" (alone or in combination with another
term(s)) refers to
a heteroarylalkyl appended to the parent molecular moiety through an oxy group
(i.e.,
heteroaryl-alkylene--O-). Representative examples of heteroarylaikoxy include,
but are not limited
to, 2-pyridin-3-ylethoxy, 1,3-thiazol-5-ylmethoxy, 3-quinolin-3-ylpropoxy, and
5-pyridin-4-
ylpentyloxy.
[0179] The term "heteroarylalkoxyalkyl" (alone or in combination with another
term(s))
refers to a heteroarylalkoxy group apperided to the parent molecular moiety
through an alkylene group
(i.e., heteroaryl-alkylene-O-alkylene-). Representative examples of
heteroarylalkoxyalkyl include,
but are not limited to, (2-pyridin-3-ylethoxy)methyl, (3-quinolin-3-
ylpropoxy)methyl, (1,3-thiazol-5-
ylmethoxy)methyl, and 2-(S pyridin-4-ylpentyloxy)ethyl.
[0180] The term "heteroarylalkoxycarbonyl" (alone or in combination with
another term(s))
refers to a heteroarylalkoxy group appended to the parent molecularmoiety
through a carbonyl group
(i.e., heteroaryl-alkylene--O--C(O)--). Representative examples of
heteroarylalkoxycarbonyl
include, but are not limited to, (2-pyridin-3-ylethoxy)carbonyl, (3-quinolin-3-
ylpropoxy)carbonyl, 2-
(1,3-thiazol-5-ylmethoxy)carbonyl, and (5-pyridin-4-ylpentyloxy)carbonyl.
[0181] The term "heteroarylalkyl" (alone or in combination with another
term(s)) refers to a
heteroaryl group appended to the parent molecular moiety through an alkylene
group. Representative
examples of heteroarylalkyl include, but are not limited to, 3-
quinolinylmethyl, 3-pyridinylmethyl, 4-
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pyridinylmethyl, IH-imidazol-4-ylmethyl, 1H-pyrrol-2-ylmethyl, pyridin-3-
ylmethyl, and 2-
pyrimidin-2-ylpropyl.
[0182] The term "heteroarylalkylcarbonyl" (alone or in combination with
another term(s))
refers to a heteroarylalkyl group appended to the parent molecular moiety
through a carbonyl group
(i.e., heteroaryl-alkylene--C(O)-).
[0183] The term "heteroarylcarbonyl" (alone or in combination with another
term(s)) refers
to a heteroaryl group appended to the parent molecular moiety through a
carbonyl group.
Representative examples of heteroarylcarbonyl include, but are not limited to,
pyridin-3-ylcarbonyl,
(1,3-thiazol-5-yl)carbonyl, and quinolin-3-ylcarbonyl.
[01841 The term "heteroaryloxy" (alone or in combination with another term(s))
refers to a
heteroaryl group appended to the parent molecular moiety through an oxy
moiety. Representative
examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy,
and quinolin-3-yloxy. *
[0185J The term "heteroaryloxyalkyl" (alone or in combination with another
term(s)) refers
to a heteroaryloxy group appended to the parent molecular moiety through an
alkylene group (i.e.,
heteroaryl-O--alkylene-).
[0186] The term "heteroaryloxycarbonyl" (alone or in combination with another
term(s))
refers to a heteroaryloxy group appended to the parent molecular moiety
through a carbonyl group
(i.e., heteroaryl-O-C(O)-).
[0187] The term "heteroarylthio" (alone or in combination with another
term(s)) refers to a
heteroaryl group appended to the parent molecular moiety through -S-.
[01881 The term "heteroarylthioalkoxy" (alone or in combination with another
term(s)) refers
to heteroaryl-alkylene-S-.
[0189] The term "heteroarylthioalkoxyalkyl" (alone or in combination with
another term(s))
refers to heteroaryl-alkylene-S-alkylene-.
[0190] The term "heteroarylthioalkyl" (alone or in combination with another
term(s)) refers
to a heteroarylthio group appended to the parent molecular moiety through an
alkylene group (i.e.,
heteroaryl-S-alkylene-).
[0191] The term "hydrogen" (alone or in combination with another term(s))
refers to a
hydrogen radical, and may be depicted as -H.
[0192] The term "hydroxy" (alone or in combination with another term(s))
refers to -OH.
[0193] The term "hydroxyalkyl" (alone or in combination with another term(s))
refers to an
alkyl substituent wherein one or more hydrogen radicals are replaced with -OH.
Representative
examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-
hydroxyethyl, 3-
hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.
[0194] The term "keto" (alone or in combination with another term(s)) means an
oxo radical,
and may be depicted as =O.

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[0195] The term "iminoalkyl" (alone or in combination with another term(s))
refers to a
-~4
~rH, radical of the forrnul.a wherein the H may be optionally substituted with
alkyl or hydroxy, in
which case the substituent would be alkyliminoalkyl or hydroxyiminoalkyl
respectively.
[0196] The term "nitro" (alone or in combination with another term(s)) means
NOZ.
[0197] The term "oxo" (alone or in combination with another term(s)) refers to
a =0 moiety
(i.e., ~ ) ..

[0198] The term "oxy" (alone or in combination with another term(s)) means -0-
.
[0199] The term "propargyl" (alone or in combination with another term(s))
means the
monovalent radical depicted as: -CHZ-CH=CH.
[0200] . The term "sulfonyl" (alone or in combination with another term(s))
means -S(O)z-,
which also may be depicted as:

\s~/
[0201] The term "sulfinyl" (alone or in combination with another term(s))
means -S(O)-,
which also may be depicted as:
0
11
10202] The term "thio" or "thia" (alone or in combination with another
term(s)) means -S-.
[0203] The term "thiol," "mercapto" or "sulfhydryl" (alone or in combination
with another
term(s)) means a sulfhydryl substituent, (i.e., -SH). Thus, for example,
thiolalkyl means an alkyl
substituent wherein one or more hydrogen radicals are replaced with -SH, while
alkylthio means
alkyl-S-.
[0204] The term "thioalkoxy" (alone or in combination with another term(s))
refers to an
alkyl group appended to the parent molecular moiety through -S-.
Representative examples of
thioalkoxy include, but are not limited to, methylthio, ethylthio, and
butylthio.
[0205] The term "thioalkoxyalkyl" (alone or in combination with another
term(s)) refers to a
thioalkoxy group appended to the parent molecular moiety through an alkylene
group (i.e.,
alkyl-S-alkylene-).
[0206] The term "thiocarbonyl" (alone or in combination with another term(s))
means a
carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a
substituent may be
depicted as -C(S)-, and also may be depicted as:



CA 02633752 2008-06-18
WO 2007/081517 PCT/US2006/048685
s
'2.. ~
[0207] The term "pharmaceutically acceptable" is used adjectivally to mean
that the
modified noun is appropriate for use as a pharmaceutical product or as a part
of a pharmaceutical
produbt.
[0208] The term "therapeutically effective amount" refers to the total amount
of each active
substance that is sufficient to show a meaningful patient benefit, e.g. a
reduction in viral load.
[0209] The term "prodrug" refers to derivatives of the compounds of the
invention which
have chemically or metabolically cleavable groups and become, by solvolysis or
under physiological
conditions, the compounds of the invention which are pharmaceutically active
in vivo. A prodrug of a
compound may be formed in a conventional manner by reaction of a functional
group of the
compound (such as an amino, hydroxy or carboxy group). The prodrug derivative
form often offers
advantages of solubility, tissue compatibility, or delayed release in a
mammalian organism (see,
Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
Prodrugs include
acid derivatives well known to practitioners of the art, such as, for example,
esters prepared by
reaction of the parent acidic compound with a suitable alcohol, or amides
prepared by reaction of the
parent acid compound with a suitable amine. Examples of prodrugs include, but
are not limited to,
acetate, formate, benzoate or other acylated derivatives of alcohol or amine
functional groups within
the compounds of the invention.
[0210] The term "solvate'=' refers to the physical association of a compound
of this invention
with one or more solvent molecules, whether organic or inorganic. This
physical association often
includes hydrogen bonding. In certain instances the solvate will be capable of
isolation, for example
when one or more solvent molecules are incorporated in the crystal lattice of
the crystalline solid.
"Solvate" encompasses both solution-phase and isolable solvates. Exemplary
solvates include, but
are not limited to, hydrates, ethanolates, and methanolates.
[0211] The term "chiral" refers to molecules that do not have a plane of
symmetry and are
therefore not superimposable on their mirror image. A chiral molecule may
exists in two forms, one
right-handed and one left-handed. 1
[0212] The term "stereoisomer" refers to isomers that have their atoms
connected in the
same order but have different three-dimensional arrangements. The term
stereoisomer includes, for
example, enantiomers and diastereomers.
[0213] The term "cis-trans isomer" refers to stereoisomers that differ in
their stereochemistry
about a double bond or ring. Cis-trans isomers are also called geometric
isomers.
[0214] The term "enantiomer" refers to stereoisomers of a chiral substance
that have a
mirror-image relationship.

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[02151 The term "diastereomer" refers to stereoisomers that are not
enantiomers, or mirror
images of each other.
[0216] The term "racemic mixture" refers to a mixture consisting of equal
parts (+) and (-)
enantiomers of a chiral substance. Even though the individual molecules are
chiral, racemic mixtures
are optically inactive.
[02171 The term "tautomer" refers to isomers that are interconvertable. For
example, enols
and ketones are tautomers because they are interconverted by treatment with
either acid or base.
[0218] The term "position isomer" refers to any of two or more constitutional
isomers that
differ in the position of a particular substituent or group. Functional groups
can be attached at
structurally nonequivalent positions on a carbon skeleton. For example, [1,3]
imidazole, depicted as
HN--7 HN-N

<
, and [1,4] imidazole, depicted as are position isomers.
[02191 The term "N-protecting group" or "N-protected" refers to those groups
capable of
protecting an amino group against undesirable reactions. Commonly used N-
protecting groups are
described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3'd
ed., John Wiley &
Sons, NY (1999), which is incorporate herein by reference in its entirety. Non-
limiting examples of
N-protecting groups include acyl groups such as.formyl, acetyl, propionyl,
pivaloyl, t-butylacetyl, 2-
chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-
nitrophenoxyacetyl, benzoyl,
4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as
benzenesulfonyl or p-
toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or
triphenylmethylsulfenyl
(trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-
S(O)-) or t-butylsulfinyl
(t-Bu-S(O)-); carbamate forming groups such as benzyloxycarbonyl, p-
chlorobenzyloxycarbonyl, p-
methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
p-
bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-
dimethoxybenzyloxycarbonyl, 2,4-
dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-
dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-
biphenylyl)-i-
methylethoxycarbonyl, dimethyl-3,5-dimethoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-
butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,
ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl,
phenoxycarbonyl, 4-nitro-
phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl,
cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl groups such as benzyl, p-
methoxybenzyl,
triphenylmethyl, or benzyloxymethyl; p-methoxyphenyl; and silyl groups such as
trimethylsilyl.
Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-
butylacetyl, phenylsulfonyl,
benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
[02201 The following abbreviations are used in the General Synthetic Methods
and Examples
described below:
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AcOH = acetic acid
atm = atmospheres
Boc = N-t-butoxycarbonyl (protecting group)
CDI = 1,1'-carbonyldiimidazole
CH2CI2 = methylene chloride (dichloromethane)
CuI = cuprous iodide [copper (1) iodide]
DCE = 1,2-dichloroethane
DEAD = diethyl azodicarboxylate
DMA = N-N-dimethylacetamide
DMAP = 4-dimethylaminopyridine
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide
EDCI = (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
EMME = 2-ethoxymethylene-malonic acid diethyl ester
Et3N = triethylamine
Ether = diethyl ether
EtI = ethyl iodide
EtOAc = ethyl acetate
EtOH = ethanol
Fe = iron
Fe(AcAc)3 = Iron(IlI)-acetylacetonate
Fmoc chloride = 9-fluorenylmethyl chloroformate
HOBt = N-Hydroxybenzotriazole
Hunig's base = N,N-diisopropylethylamine
IPA = isopropyl alcohol
K2C03 = potassiurn carbonate
KOH = potassium hydroxide
LDA = lithium diisopropylamine
MeOH = methanol
MsCI = methanesulfonyl chloride
NaH = sodium hydride
NH2OH=HC1= hydroxylamine hydrochloride
NMP = 1-methyl-2 pyrrolidinone
MgaSO4 = magnesium sulfate
Na2SO4 = sodium sulfate
NH3 = ammonia

43


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NH4C1= ammonium chloride
NHaOH = amrnonium hydroxide
PG = protecting group such as Boc- or Troc-
POC13 = phosphorous oxy chloride
R-MgC1= Grignard reagent
R-I = alkyl iodide or substituted alkyl iodide
SnC12 = Stannous chloride (Tin (11) chloride)
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
Triflic Anhydride = trifluoromethanesulfonic anhydride
Troc = 2,2,2-trichloroethoxycarbonyl- (protecting group)
General Synt/a.etic Metlzods and Examples
[0221] The following synthetic methods and schemes illustrate the general
methods by
which the compounds of the present invention can be prepared. Starting
materials can be obtained
from commercial sources or prepared using methods well known to those of
ordinary skill in the art.
By way of example, synthetic routes similar to those shown hereinbelow may be
used, together with
synthetic methods known in the art of synthetic organic chemistry, or
variations thereon, as
appreciated by those skilled in the art_
(0222] The present invention is intended to encompass compounds prepared by
either
synthetic processes or metabolic processes. Metabolic processes include those
occurring in the
human or animal body (in vivo), or those occurring in vitro.
[0223] If a substituent described herein is not compatible with the synthetic
methods of this
invention, the substituent may be protected with a suitable protecting group
that is stable to the
reaction conditions used in these methods. The protecting group may be removed
at a suitable point
in the reaction sequence to provide a desired intermediate or target compound.
Suitable protecting
groups and methods for protecting or deprotecting substituents are well know
in the art, examples of
which can be found in Greene and Wuts, supra_

Preparation of Compounds of Formulae I-VIII

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K
W
t
[0224] Compounds of Formula I can be synthesized by reacting W2 R10 with
r

H2N x~R22, wherein W,, WZ, A, B, X, Y, R10, R22, and R50 have the meanings as
set forth in
the above embodiments or examples, and K is Cl or another halogen. Likewise,
compounds of
K
K
RB I ~
\ \ \N
{ N CH3 ~
N N'~)
Formulae II-VIII can be prepared by reacting R3' N N , CH3 5 K

R K K
K

N R~
N N N
N , \ \~ I J I \ \
~ J\~ N
S N , R47 N N , R73 R67 N N , or
O-R9o

R25 R19
Rso

K H2N H2N ~ \N I \
~
R42 S
~ OH, s
R'7 N N with H2N
R58,
R2g R39
CH3
R21
R49
I \ Rat
H2N \ R64 H2N HzN
S SI\ AI\
~\ H2N R~

/ Rce, R76, Rs , or R52
respectively.



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[0225) The synthesis of compounds of Formulae I-VIII is exemplified in Schemes
1-8.
.ivinr R35
NNV\Wi ~ N
B I
~
Representative compounds of Formula I, wherein 'Nz R10 is R" N N R'0,
R10, R" and R35 are as defined hereinabove, and Z is NR4', can be prepared
u'sing the procedure as
outlined in Scheme 1.

Scheme 1
Y-Rso
Ra1
~
R Y,--Rso R35 \ N X-R~
r-N =N
+ / t2tt N~N Ra'HN X-R~ R17~N N

(1) ' (2) (3)

[02261 Amines of fonnula (2) wherein R41 is hydrogen can be treated with N,N-
dimethylformamidine compounds of formula (1) in the presence of an acid such
as, but not limited to,
acetic acid, at elevated temperature (for example, from about 80 C to about
150 C), thereby
producing compounds of formula (3). The acetic acid can function as a solvent.
Other suitable
solvents can also be used in the reaction.
[0227] N alkylation of compounds of formula (2) wherein R41 is hydrogen
provides formula
(2) or (3) wherein Ra' is alkyl. This process can be facilitated with an
alkylating reagent of formula
Ra'X', wherein X' is halogen, tosylate, triflate or mesylate, in the presence
of a base such as, but not
limited to, an organic base such as triethylamine or diisopropylamine, or an
inorganic base such as
sodium, cesium or potassium carbonate, in a suitable solvent, 'and at a
temperature ranging from about
room temperature to about 100 C.

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Scheme 2
O R35 N R17
OII _R'38 AI/~ \ ~N
R17k + R3 ~Oalkyl R~~"~O.M HZN N ~" R1r
(5) (6) RJS N OH
(4)
(7a) (7b)
R~
R35 N R35 N "' N
(7a) -- ~ ~ ~ ~ ~
R17 N ?C2 R~r N NH2 R~~ N N
(1) N
(8) (9)

[0228] Preparation of the N,N-dimethylformamidine compounds of formula (1) can
be
accomplished as described in Scheme 2. Ketones of formula (4) and esters of
formula (5), in the
presence of a base such as, but not limited to, sodium or potassium hydride
(or sodium metal) at about
0 C in a suitable solvent such as, but not limited to, diethyl ether, provide
a salt of formula (6)
wherein M is potassium or sodium. Treatment of formula (6) with 2-
cyanoacetamide in the presence
of piperidine acetate, at about reflux gives nitriles of formula (7a) and
(7b). The regioisomers (7a)
and (7b) can be separated at this point or later in the synthetic route, using
purification techniques
known to those sldlled in the art. Compounds of formula (7a) can either be
converted to compounds
of formula (8) wherein X2 is Cl by treatment with phosphorous oxychloride or
to compounds of
formula (8) wherein X2 is Br by treatment with tetrabutylammonium bromide and
phosphorous
pentoxide in a suitable solvent, at reflux. A solution of compounds of formula
(8) wherein X2 is Cl or
Br and liquid ammonia are reacted in a sealed high pressure vessel at elevated
temperature, for
example, at about 130 C to provide compounds of formula (9). Compounds of
formula (9) and N,N-
dimethylformamide dimethyl acetal in a solvent such as, but not limited to,
toluene, at reflux yield the
N,N-dimethylformamidine compounds of formula (1).

Scheme 3
G G G
-- ~~
G2N R101 GzN X-R22 R41HN X_R22

(10) (11) (2)
G

H2N Rzo,
(12)
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[0229] Compounds of formula (2) wherein R41 is hydrogen and X is 0 or S, can
be prepared
from compounds of formula (10) according to Scheme 3, wherein Rlol is a
leaving group such as, but
not limited to, halogen, triflate or mesylate (the latter two can be prepared
from the corresponding
alcohol using methodologies known to one skilled in the art), via a two-step
synthesis, namely,
reduction of the nitro group followed by displacement of RIo,, or displacement
of RIo, followed by.
reduction of the nitro group.
[0230] Displacement of Rlo, with RZZXH wherein X is 0 or S can be facilitated
in the
presence of a suitable base such as, but not limited to, potassium, cesium or
sodium carbonate or
bicarbonate, or sodium or potassium hydride, and optionally in the presence of
18-crown-6, at
elevated temperature. The reaction can generally be performed in a solvent
such as, but not limited to,
N,N-dimethylformamide or dimethylsulfoxide, at a temperature from about room
temperature to
about 180 C. The reaction can generally be performed in a solvent such as,
but not limited to, N,N-
dimethylformamide or dimethylsulfoxide, at a temperature from about room
temperature to about 180
C. The reaction can also be conducted in a microwave oven. It is appreciated
compounds of formula
(11) can also be obtained from the reaction of formula (10) wherein R,o, is -X-
H with compounds of
formula R22X3 wherein X3 is a leaving group such as, but not limited to,
halogen, triflate or mesylate,
using the aforementioned reaction conditions. The displacement reactions can
also be effected in the
presence of a metal catalyst such as, but not limited to, copper metal, CuI,
or palladium acetate,
optionally in the presence of a ligand such as, but not limited to, 2,2'-
bis(diphenylphosphino)-1,1'-
binaphthyl or tri-tert-butylphosphine, and optionally in the presence of a
base such as, but not limited
to, pyridine, triethylamine, sodium tert-butoxide, cesium carbonate, or sodium
hydride. The reaction
is generally performed at a temperature from about room temperature to about
180 C, in a solvent
such as, but not limited to, toluene or N,N-dimethylformamide.
102311 Reduction of the nitro group can be accomplished by treatment of nitro
compound
with a reducing agent such as, but not limited to, iron powder/ammonium
chloride or tin(II) chloride,
in a suitable solvent.
[0232] It is also appreciated that compounds of formula (10) can also be
converted to
compounds of formula (2) by first reducing the nitro functionality, followed
by the displacement
reaction, using reaction conditions as described hereinabove.

Preparation of Aminophenyl CouplingAgents (10, 11 and 12)
[0233] A wide variety of aminophenyl coupling agents are possible. The agents
in Scheme 4
are exemplary of this variety.
[0234] In a typical preparation, a substituted 2-chloro-nitrobenzene compound
in
dimethylformamide (DMF) is treated with a sodium thiophenolate at about 50 C
for about 2 hours, is
cooled and diluted with methylene chloride, washed with water, dried over
sodium sulfate, filtered
48


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and concentrated under vacuum to give the substituted-2-phenylsulfanyl-
nitrobenzene compound.
This nitrobenzene compound is then reduced with stannous chloride (SnC12) or
iron (Fe) in ethanol.
The reaction mixture is adjusted to pH 12 with 1 N sodium hydroxide, extracted
with ethyl acetate,
dried over sodium sulfate, filtered and concentrated under vacuum giving the
substituted-2-
phenylsulfanyl-aminobenzene compound 10.
[0235] Similarly, the corresponding substituted-2-hydroxy-nitrobenzene
compound is
dissolved in dimethylformamide reacted with a sodium phenoxide solution,
stirred and heated to
100 C for about 5 days. The reaction mixture is cooled and diluted with
methylene chloride, washed
with water, dried over sodium sulfate, filtered and concentrated under vacuum
to give the substituted-
2-phenoxy-nitrobenzene compound. This nitrobenzene compound is then reduced
with stannous
chloride (SnC12) and iron (Fe) in ethanol. The reaction mixture is adjusted to
pH 12 with 1 N sodium
hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered
and concentrated under
vacuum giving the substituted-2-phenoxy-aminobenzene compound 12.
[0236] Similarly, either compound 10 where R9 is hydroxy- or protected
hydroxyl- can be
further modified by alkylating the hydroxy- group using a substituted benzyl
bromide to give the
corresponding 5-substituted-phenoxy-2-substituted-phenylsulfanyl-aminobenzene
compound 11.

49


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Scheme 4

R9 R9 R9
K2C03 SnCl2 EtOH
-~ ~
I \ I ~
OZN DMF 02N or HZN

Ci xsH S Fe NH4CI s ~ ~ MeOH/7HF/ H2O 10 1:>x
=
DMF X

K2C03 X \ /SW Br R=OH
R9 R9 DMF
triflic anhydride KZC03
/ I
R
= J ~ -~-
\ 02N
02N
OH O-SO2CF3
I / R
R9 DMF R9 R9 H~IV
K~C03 SnCl2 EtOH S

OZN O2N or H2N \ I/ X
Br O Fe NH4CI O
x ~~ oH MeOH/THF/ H20 = ~, 11
x x
R9 is defined above; 12
X is OH, NH2, NHR, halo, alkyl,=or alkoxy
R is alkyl, alkoxy, bromo, fluoro, chloro, or cyano

Preparation of?-Substituted-4 Aminophenyl-substituted pyrido[2,3-dJpyrimidine
Compounds
[0237] A typical preparation of 7-substituted-4-aminophenyl-substituted-
pyrido[2,3-
d]pyrimidine compounds (Scheme 6) involves the coupling reaction of a
substituted aminophenyl
coupling agent (described in Scheme 4) with a 6-substituted-2-amidino-3-
cyanopyridine compound 9
(Scheme 5).
[00100] As described in Scheme 4, a wide variety of aminophenyl coupling
agents are
possible.
[0238] Preparation of the 7-substituted-4-aminophenyl-substituted-pyrido[2,3-
d]pyrimidines
can be accomplished by coupling a N,N-dimethylformamidino compound 9 with a
variety of coupling
agents some of which are described in Scheme 4.
[0239] Preparation of the N,N-dimethylformamidine compounds 9 can be
accomplished as
described in Scheme 5. A substituted alkyl methyl ketone and ethyl formate are
added to a diethyl
ether solution of sodium hydride (or sodium metal) at about 0 C for about 2
hours. After the addition


CA 02633752 2008-06-18
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the reaction is allowed to stir at room temperature overnight. Additional
diethyl ether is added and the
precipitate is quicldy isolated by vacuum filtration died in a vacuum
desiccator. This material was
dissolved in water with 2-cyanoacetamide. A piperidine acetate solution is
added and the resulting
solution is heated at reflux for about 2 hours. The mixture is cooled to room
temperature and adjusted
to pH 4 with glacial acetic acid. The resulting solid is isolated by vacuum
filtration rinsed with water
and dried and identified as the 6-substituted-2-oxo-1,2-dihydropyridine-3-
carbonitrile 24. Compound
24 can either be converted to the 2-chloro-pyridine with phosphorous
oxychloride (as shown in
Scheme 5) or the 2 bromopyridine. The 2-bromoyridine is prepared by taking a
toluene solution of
compound 24 and reacting with tetrabutylammonium bromide and phosphorous
pentoxide at reflux
for about 5 hours. The reaction mixture is cooled, water added and the mixture
stirred for about 2
hours at room temperature. The reaction mixture was diluted with toluene, the
organic layer separated,
washed with brine and dried over magnesium sulfate, filtered and concentrated
under vacuum to give
the 2-bromopyridine. An ethanol solution of either the 2-chloropyridine or the
2-bromopyridine and
liquid ammonia are reacted in a sealed high pressure vessel at about 130 C for
about 20 hours. The
reaction mixture is concentrated under vacuum and the residue washed with
water and dried to give
the 6-substituted-2-amino-nicotinonitrile 25.'Compound 25 and N,N-
dimethylformamide dimethyl
acetal is dissolved in toluene and heated to reflux for about 3 hours. The
resulting solution is cooled to
room temperature and concentrated under vacuum to give the 6-substituted-3-
cyano-pyridin-2-yl-
N,N-dimethylformamidine 9.
Spheme 5.

~ N
'\ NaH 7 H2N N ,
+ ~
R7 H O R ~ O,Na R7N OH
2g
~N
I\ ~ POCIg I\ ~ NH3 I~ /
R7 N OH Rr N CI Rr N~ NH2
2~

DMF-DMA
~
Rr N~
N
ii! I

R7 is selected from the group consisting of hydrogen, alkyl, haloalkyl,
alkoxy, cycloalkyl, alkoxycarbonylalkyl,
alkoxycarbonylalkylamino, cyanoalkoxycarbonylalkyl, cyanoalkyl, hydtoxyalkyl,
morpholino, hydrazino,
alkylaminoalkoxy, alkoxyalkylamino, and aryl

[0240] As described above, the preparation of 7-substituted-4-aminophenyl-
substituted-
pyrido[2,3-d]pyrimidines can be accomplished by coupling the substituted 6-
substituted-3-cyano-
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pyridin-2-yl-N,N-dimethylformamidine 9 as shown in Scheme 5 with a variety of
coupling agents
some of which are described in Scheme 4. This coupling reaction is described
in Scheme 6.
[0241] In a typical preparation, compound 9 and an aminophenyl coupling agent
similar to
those described in Scheme 4 are dissolved in acetic acid and stirred at about
130 C for about 15
minutes. The mixture is cooled to room temperature, the acetic acid removed
under vacuum and the
resulting residue purified by reverse phase chromatography. At this point any
functional protecting
group such as the Boc, Troc or other group can be removed by known methods to
give the final
products.
Scheme 6
iN
f R R
R 7 N
2N HN
H N~ .\ ~

s 1:1X NS Rr N N x

11

N
R9 R9
H N N HN
z o 0
, - J ~
x R N N 1C
.1,3.
R7, R9 ,?C and R are as defined above

,ivirtir
W
,
[0242] Representative compounds of Formula 1, wherein the ring B of 2 R'O
is a five-membered ring heterocycle and W, is CH, R10; R'7 and R35 are as
defined hereinabove, and Z
is NR41, can be prepared using the procedure as outlined in Scheme 7 and
consists of reacting an
alkylamino-substituted heterocycles such as 13 with Meldrum's acid and
triethylorthoformate and
heating to about 100 C. The reaction mixture is concentrated and purified by
chromatography to give
the aminomethylene malonic acid ester 14. Compound 14 is then dissolved in
diphenylether and the
resulting solution heated to 250 C for about 30 minutes. giving 15. A mixture
of compound 15 is
mixed with phosphorous oxychloride (POC13) and heated to about 50 C with
stirring for 6 hours,
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cooled quenched by pouring unto ice. It is cooled then adjusted to pH 10 with
concentrated
ammonium hydroxide and extracted with methylene chloride, dried over anhydrous
sodium sulfate,
filtered and concentrated under vacuum giving 16. . In a typical preparation,
compounds 16 and an
aminophenyl coupling agent similar to those described in Scheme 4 are coupled
with 2,8,9-triisobutyl-
2,5,8,9-tetraaza-l-phospha-bicyclo[3.3.3]undecane tris(dibenzylideneacetone)-
dipalladium, and
sodium tert-butoxide in a solvent typically toluene and the like to provide
21.

Scheme 7
O~O
O O Meldrurn's acid Z__
z triethy lorthofonnate R7X NH2
R7 XN
H 13
14 O R
250 C O R
diphenylether HZN

O CI S HN
POCI
3 S
~i ~ ~ -- ii ~ ~ ii
? r Y.J
R X N R X N R~ X N X
H

15 16 21

/wv~W
,
[0243J Representative compounds of Formula I, wherein the ring B of Wz Rla
is a five-membered ring heterocycle and Wl is N, R'0, Rt7 and R35 are as
defmed hereinabove, and Z is
NR41, can be prepared using the procedure as outlined in Scheme 8 and consists
of reacting an
alkylamino-substituted heterocycles such as 17 with formamide at reflux. The
pyrimidine product 18
is then reacted with phosphorous oxychloride (POC13) to give the coupling
partner 19. In a typical
preparation, compounds 19 and an aminophenyl coupling agent similar to those
described in Scheme
4 are.dissolved in ethanol and heated to reflux for 12 hours to provide 20.

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Scheme 8
0
OH CI
OR POCI3
z I Z ~N Z N
Rr~~~X NH~ formarnide r,
R Y~X NJ Rr,Y'X NJ
17 18 19
Ethanol reflux
O
R
O R

H2N
HN s ~ S \ I /
Z I N X
R7 Y~t N~ X 11


ru,,,r
/
aW2 W,
[0244J Representative compounds of Formula I, wherein the ring B of R10
is a five-membered ring heterocycle and W1 is N or CII, R10, R17 and R35 are
as defined
hereinabove, and Z is NR41, can be prepared
[02451 Optimum reaction conditions and reaction times for each individual step
may vary
depending on the particular reactants employed and substituents present in the
reactants used. Unless
otherwise specified, solvents, temperatures and other reaction conditions may
be readily selected by
one of ordinary slcill in the art. Reactions may be worked up in the
convention manner, e.g. by
eliminating the solvent from the residue and further purified according to
methodologies generally
known in the art such as, but not limited to, crystallization, distillation,
extraction, trituration and
chromatography.
[02461 It should be understood that the above-described embodiments and
schemes and the
following examples are given by way of illustration, not limitation. Vari.ous
changes and
modifications within the scope of the present invention will become apparent
to those skilled in the art
from the present description.

Example 1
4-Amino N-[2-(4-hydroxy-phenylsulfanyl)-5-methyl-phenyl]-2-(2-methoxy-
ethylamino)-pyrimidine-
5-carboxamidine
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[0247] The product from Example 156 (42 mg, 0.1 mmol) in 2-methoxy-ethylamine
(1mL)
was heated at 180 C for 2 hours in a microwave reactor. The solvent was
evaporated and the residue
was purified by HPLC with TFA method to give the title compound as a
trifluoroacetic acid salt (15
mg, 28 %). 'H NMR (300 MHz, DMSO-d6) S ppm: 2.31 (s, 3 H) 3.28 (s, 3 H) 3.49
(m, 4 H) 6.86 (m,
3 H) 7.28 (m, 4 H) 8.17 (s, br, 3 H) 8.73 (s, br, 1 H) 9.75 (s, br, 2 H) 11.33
(s, br, 1 H); MS (ESI+)
m/z 425 (M+H)+.

Example 2
4-Amino-2-butylamino-N-[2-(4-hydroxy-phenylsulfanyl)-5-methyl-phenyl]-
pyrimidine-5-
carboxamidine

[02481 The product frorri Example 156 (42 mg, 0.1 mmol) in butylamine (lml)
was heated at
180 C for 2 hours in a microwave reactor. The solvent was evaporated and the
residue was purified
HPLC with TFA method to give the title compound as the trifluoroacetic acid
salt (13 mg, 24%). 'H
NMR (300 MHz, DMSO-d6) S ppm: 0.90 (t, J=7.35 Hz, 3 H) 1.29 (m, 2 H) 1.51 (m,
2 H) 2.30 (s, 3 H)
3.32 (m, 2 H) 6.85 (m, 3 H) 7.27 (m, 4 H) 8.15 (s, br, 3 H) 8.71 (s, br, 1 H)
9.55 (s, br, 1 H) 9.92 (s,
br, 1 H) 11.23 (s, br, 1 H); MS (ESI+) m/z 423 (M+H)+.

Example 3
N- {4-[4-Methyl-2-(6-propyl-thieno[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenyl} -acetamide
Example 3a
ethyl 2-amino-5-propylthiophene-3-carboxylate

[0249] A solution of equimolar amounts of ethyl cyanoacetate and sulfur in
dimethylformamide at ambient temperature was treated with triethylamine (0.5
equivalent) then upon
warming to 50oC , valeraldehyde (1 equivalent) was added dropwise. After 3
hours the reaction was
quenched with water and extracted with ethyl acetate. The organic layer was
concentrated to provide
the title compound.

Example 3b
6-propylthieno[2,3-d]pyrimidin-4-ol
[02501 The product of example 3a was reacted with excess formamide at reflux
for 3 hours.
The reaction mixture was quenched with water and the resulting precipitate was
collected by filtration
and washed with water and dried under vaucuum to provide the title compound.

Example 3c
4-chloro-6-propylthieno[2,3-d]pyrimidine
[02511 The product of Example 3b was reacted with excess POC13 at reflux for
3h then at
room temperature for 16h. The reaction was poured over ice and partitioned
between water and ethyl
acetate. The organic layer was concentrated to provide the title compound.



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Example 3d
N- {4-[4-Methyl-2 -(6-propyl-thieno [2,3 -d] pyrimidin-4-ylamino)-phenylsul
fanyl] -phenyl } -acetarnide
[0252] The product of Example 3c was reacted with the product of Example 7b
were reacted
in ethanol at reflux for 16 hours. The reaction was concentrated to produce
the title compound.
Example 4
(6-Butyl-thieno [2,3 -d]pyrimidin-4-yl)-(5 -methyl-2-phenylsulfanyl-phenyl)-
amine

[0253] The title compound was prepared according to the procedures of Example
3
substituting hexanal for valeraldehyde in Example 3a.

Example 5
(5-Methyl-2-phenylsulfanyl-phenyl)-(2-propyl-thiazolo[5,4-b]pyridin-7-yl)-
amine
Example 5A
Butyrylamino-acetic acid methyl ester

[02541 A suspension of glycine hydrochloride (1.00 g, 7.964 mmol) in methylene
chloride
(40 mL), cooled to 0 under a nitrogen atmosphere, was treated with
triethylamine (4.44 mL, 31.86
mmol) and butyryl chloride (0.93 mL, 8.76 mmol), and the mixture stirred at
room temperature for 2.5
hours. The reaction was washed with saturated aqueous sodium bicarbonate (50
mL), water (50 mL)
and brine. The organic phase was dried over anhydrous sodium sulfate, filtered
and concentrated
under vacuum giving the title compound. Purification by silica gel flash
chromatography with 25%
ethyl acetate/methylene chloride afforded the title compound as a colorless
oil (0.776 g, 4.88 mmol,
61%).

Example 5B
Thiobutyrylamino-acetic acid methyl ester

[0255] A solution of the product of Example 5A (0.774 g, 4.862 mmol) in
anhydrous THF
(50 mL) was treated with Lawesson reagent (1.338 g, 3.209 mmol), then heated
at reflux under a
nitrogen atmosphere for 30 minutes. The reaction was cooled to 0 and a
saturated aqueous sodium
bicarbonate solution (40 mL) was slowly added dropwise. The mixture was
stirred at room
temperature for 15 minutes, and then extracted with ethyl acetate (100 mL),
and the organic extract
washed with saturated aqueous sodium bicarbonate (50 mL), water (2 x 25 mL),
and brine. Dried the
organic phase over anhydrous-sodium sulfate, filtered, and concentrated under
vacuum giving the title
compound. Purification by silica gel flash chromatography with 1% ethyl
acetate/methylene chloride
afforded the title compound as a colorless oil (0.790 g, 4.508 mmol, 93%).

Example 5C
2-Thiobutyrylamino-acetamide
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[0256] A solution of the product of Example 5B (0.788 g, 4.496 mmol) in
methanol (30 mL)
was saturated with ammonia gas and the reaction was stirred in a stoppered
flask at room temperature
for 17 hours. The solvent was concentrated under vacuum giving the title
compound and the solid
purified by silica gel flash chromatography with 10% methanol/methylene
chloride to give the title
compound as a white solid (500 mg, 3.12 mmol, 69%).

Example 5D
2-Propyl-thiazol-5-ylamine
[0257] A solution of the product of Example 5C (395 mg, 2.465 mmol) in
anhydrous ethyl
acetate (12 mL) was treated with phosphorous tribromide (0.189 mL, 1.972 mmol)
under a nitrogen
atmosphere and stirred at room temperature for 20 minutes. Added additional
phosphorous
tribromide (0.050 mL) and let stir for 5 minutes. The reaction mixture was
diluted with ethyl acetate
(50 mL) and washed with saturated aqueous sodium bicarbonate (25 mL). The
aqueous wash was
extracted with ethyl acetate (2 x 50 mL), and the organic extracts were
combined and washed with
brine, dried over anhydrous sodium sulfate, filtered and concentrated under
vacuum giving the title
compound. Purification by silica gel flash chromatography with 3%
methanol/methylene afforded the
title product (175 mg, 1.23 mmol, 50%).

Example 5E
2,2-Dimethyl-5-[(2-propyl-thiazol-5-ylamino)-methylene]-[ 1,3]dioxane-4, 6-
dione

[0258) A solution of the product of Example 5D (212.7 mg, 1.496 mmol) in
anhydrous
ethanol (5 mL) was treated with Meldrum's acid (237 mg, 1.645 mmol) and
triethylorthofromate
(0.25 mL, 1.496 mmol) at room temperature, and the reaction was heated in a
preheated 100 oil bath.
After 15 minutes, the reaction was ccioled to room temperature and the solvent
removed by rotary
evaporation under vacuum. Purification by silica gel flash chromatography with
a gradient of 10% to
20% ethyl acetate/methylene chloride afforded the title compound as an off-
white solid (240 mg,
0.8099 rnmol, 54%).

Example 5F
2-Propyl-4H-thiazolo[5,4-b]pyridin-7-one
[0259] The product of Example 5E (230 mg, 0.7781 mmol) was added to refluxing
diphenyl
ether (5 mI.) under a nitrogen atmosphere. After refluxing for 5 minutes, the
solution was cooled in
an ice bath and diluted with hexanes (50 mL). The resulting golden solid was
collected by vacuum
filtration and thoroughly washed with hexanes to give the title compound (125
mg, 0.644 mmol,
83%).

Example 5G
7-Chloro 2-propyl-thiazolo[5,4-b]pyridine
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[02601 The product of Example SF (123 mg, 0.6332 mmol) and phosphorous
oxychloride (2
mL) were refluxed for 1 hour under a nitrogen atmosphere. The solution was
cooled in an ice bath,
treated with ice, and the pH adjusted to 7 with 6N aqueous sodium hydroxide.
Extracted with
methylene chloride (3 x 50 mL) and dried the combined organic extracts over
anhydrous sodium
sulfate, filtered and concentrated under vacuum giving the title compound as a
brown oil (120 mg,
0.564 mmol, 89%).
Example 5H
4-Methyl-2-nitro-l-phenylsulfanyl-benzene
[0261] A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 mL of DMF
was heated
at 50 C with 4-chloro-3-nitrotoluene (2.65 mL, 20 mmol) with stirring for 2
days. Cooled to room
temperature and diluted with CHZCIZ: Washed with water and dried the organic
layer over Na2 SO4.
Filtered and concentrated under vacuum giving the title compound (4.29 g, 87%)
'H NMR (300 MHz,
CDC13) S ppm: 2.36 (s, 3 H) 6.76 (d, J=8.09 Hz, 1 H) 7.16 (d, J=8.46 Hz, 1H)
7.45 (m, 3 H) 7.58 (m,
2 H) 8.03 (s, 1 H).

Example 51
5-Methyl-2-phenylsulfanyl-phenylamine
[0262] A solution of the product from Example 5H (1.17 g, 7.0 mmol) in 25 mL
of absolute
EtOH and SnC12 (3.58 g, 29.8 mmol) was stirred at room temperature for 16 h.
Adjusted to pH 12 with
1N NaOH and extracted with EtOAc. Dried over Na2SO4, filtered and concentrated
under vacuum
giving the title compound (835 mg, 82%) 'H NMR (300 MHz, CDC13) S ppm: 2.30
(2, 3 H) 6.62 (d,
J=8.83 Hz, 1 H) 6.69 (s, 1 H) 7.10(m, 3 H) 7.21 (m, 2 H) 7.54 (d, J=7.72 Hz, 2
H).

Example 5J
(5-Methyl-2-phenylsulfanyl-phenyl)-(2-propyl-thiazolo[5,4-b]pyridin-7-yl)-
amine
[0263] A dry nitrogen-purged flask was charged with 2,8,9-triisobutyl-2,5,8,9-
tetraaza-l-
phospha-bicyclo[3.3.3]undecane (38 mg, 0.111 mmol), tris(dibenzylideneacetone)-
dipalladium (25.4
mg, 0.0277 mmol), and sodium tert-butoxide (82.4 mg, 0.8322 mmol). A solution
of the product of
Example 5G (118 mg, 0.5548 mmol) in anhydrous toluene (2 mL) and a solution of
the product from
Example 51 (107.5 mg, 0.4993 mmol) in toluene (3 inL) were added via syringe.
The reaction was
heated at reflux in a preheated 120 oil bath for 18 hours, cooled to room
temperature, treated with
additional tris(dibenzylideneacetone)dipalladium (25.4 mg), and heated at
reflux for an additiona12.5
hours. The reaction was cooled to room temperature and the solvent removed by
rotary evaporation
in vacuo. Purification by silica gel flash chromatography with a gradient of
1% to 3% ethyl
acetate/methylene chloride afforded the title compound (29 mg, 0.074 mmol,
15%). 'H NMR (300
MHz, DMSO-D6) S ppm: 1.00 (t, J=7.35 Hz, 3 H) 1.71 - 1.90 (m, 2 H) 2.38 (s, 3
H) 3.05 (t, J=7.35

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Hz, 2 H) 6.87 (d, J=5.52 Hz, 1 H) 7.07 (dd, J-7.91, 1.29 Hz, 1 H) 7.12 - 7.31
(m, 5 H) 7.37 - 7.46 (m,
2 H) 8.15 (d, J=5.52 Hz, 1 H) 8.52 (s, 1 H); MS (DCUNH3) xn/z 392 (1VI+H)+.

Example 6
4-[4-Methyl-2-(2-propyl-thiazolo[5,4-b]pyridin-7-ylamino)-phenyl sul fanyl]-
phenol
Example 6a
Trifluoro-methanesulfonic acid 4-methyl-2-nitro-phenyl ester

[0264] A solution of the 4-methyl-2-nitro phenol (6.0 g, 39.1 mmol) and Et3N
(16.38 mL,
117.5 mmol) in 100 mL of CH2CIZ under a N2 atmosphere was treated with
trifluoromethanesulfonic
anhydride (7.25 mL, 43.1 mmol) at 0 C for 30 min. Quenched by addition of
MeOH. Washed
sequentially with 10% citric acid, 0.5 m KOH and water. Dried over MgSO4,
filtered and concentrated
under vacuum giving the title compound which was purified by silica gel column
chromatography
eluting with CH2ClZ giving an amber oil (11.22 g, 100%).

Example 6b
4-(4-Methyl-2-nitro-phenylsulfanyl)-phenol
[0265] The product from Example 6a (11.22 g, 39.3 mmol) and 4-mercaptophenol
(4.96 g,
39.3 mmol) in 100 mL of EtOH'was treated with NaZCO3 and heated overnight
under efflux. Cooled
to room temperature and quenched with water. Extracted with EtOAc. Dried over
MgSO4, filtered and
concentrated under vacuum giving the title compound, which was purified by
silica gel column
chromatography eluting with 25% EtOAc/hexane giving a red oil (8.65 g, 85%).

Example 6c
4-(2-Amino-4-rnethyl-phenylsulfanyl)-phenol
[0266] The product from Example 6b (8.65 g, 31.3 mmol) was reduced with SnCI2
following
the procedure from Example 51 giving the title compound as a white solid (8.51
g, 100%).

Example 6d
4-(4-methyl-2-(2-propylthiazolo[5,4-b]pyridin-7-ylamino)phenylthio)phenol
[0267] A dry nitrogen-purged flask was charged with 2,8,9-triisobutyl-2,5,8,9-
tetraaza-l-
phospha bicyclo[3.3.3]undecane (40.4 mg, 0.118 mmol),
tris(dibenzylideneacetone)-dipalladium (27
mg, 0.0295 mmol), and sodium tert-butoxide (87.7 mg, 0.885 mmol). A solution
of the product of
Example 5G (125.5 mg, 0.590 mmol) in anhydrous toluene (5 mL) was added via
syringe, followed
by the product from Example 6c (136 mg, 0.590 mmol). The reaction was heated
at reflux in a
preheated 110 oil bath for 14 hours, cooled to room temperature, treated with
additional 2,8,9-
triisobuiyl-2,5,8,9-tetraaza-l-phospha-bicyclo[3.3.3]undecane (40.4 mg) and
tris(dibenzylideneacetone)dipalladium (27 mg), and heated at reflux for an
additional 7 hours. The
reaction was cooled to room temperature and the solvent removed by rotary
evaporation in vacuo.
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Purification by silica gel flash chromatography with a gradient of 15% to 30%
ethyl
acetate/methylene chloride gave impure material. Purification by silica gel
flash chromatography
with a gradient of 1% to 2% methanol/methylene chloride afforded the desired
title compound as a
light yellow solid (20 mg, 0.049 mmol, 8%). 'H NMR (300 MHz, DMSO-D6) S ppm:
1.03 (t, J=7.35
Hz,3H)1.76-1.94(m,2H)2.31(s,3H)3.10(t,J7.35Hz,2H)5.76(s,IH)6.67-6.73(rn,2H)
6.96 - 7.04 (m, 1 H) 7.08 - 7.14 (m, I H) 7.20 (d, J-8.46- Hz, 2 H) 7.29 (s, 1
H) 8.14 (d, J=5.52 Hz, 1
H) 8.55 (s, 1 H) 9.73 (s, 1 H); MS (DCI/NH3) m/z 408 (M+H)

Example 7
N- {4-[4-Methyl-2-(2-propyl-thiazolo [5,4-b]pyridin-7-ylamino)-phenylsulfanyl]-
phenyl } -acetamide
Example 7a
N-[4-(4-Methyl-2-nitro phenylsulfanyl) phenyl]-acetamide

[0268] The product from Example 6a (1 g, 3.51 nunol) was reacted with N-(4-
mercapto-
phenyl)-acetamide (0.65 g, 351 mmol) for 18 h following the procedure from
Example 6b giving the
title compound (1.04 g, 98 %).

Example 7b
N-[4-(2-Amino-4-methyl-phenylsulfanyl)-phenyl]-acetamide
[0269] The product from Example 7a (0.30 gm, 1 mmol) was reacted with SnCla as
described in Example 51 to give the,title compound (0.27 gm, 100%) as an amber
oil which was used
without further purification.

Example 7c
N-(4-(4-methyl-2-(2-propylthiazolo[5,4 b]pyridin-7-
ylamino)phenylthio)phenyl)acetamide
[0270] A dry nitrogen-purged flask was charged with 2,8,9-triisobutyl-2,5,8,9-
tetraaza-l-
phospha-bicyclo[3.3.3]undecane (38.6 mg, 0.1128 mmol),
tris(dibenzylideneacetone)-dipalladium
(25.8 mg, 0.0282 mmol), and sodium tert-butoxide (83.8 mg, 0.8463 mmol). A
solution of the
product of Example 5G (120 mg, 0.5642 mmol) in anhydrous toluene (5 mL) was
added via syringe,
followed by the product from Example 7b (130 mg, 0.4773 mmol). The reaction
was heated in a
preheated 100 C oil bath for 2.5 hours, cooled to room temperature, treated
with additional 2,8,9-
triisobutyl-2,5,8,9-tetraaza-1 phospha-bicyclo[3.3.3]undecane (38.6 mg),
tris(dibenzylideneacetone)dipalladium (25.8 mg) and starting aniline (130 mg),
and heated at 100 C
for an additional 18 hours. The reaction was cooled to room temperature and
the solvent removed by
rotary evaporation in vacuo. Purification by silica gel flash chromatography
with a gradient of 40% to
60% ethyl acetate/rnethylene chloride gave the desired title compound as a tan
foam (26 mg, 10%).
'H NMR (300 MHz, DMSO-d6) S ppm: 1.01 (t, J=7.35 Hz, 3= H) 1.73 - 1.91 (m, 2
H) 2.01 (s, 3 H)
2.34 (s, 3 H) 3.07 (t, J-7.54 Hz, 2 H) 6.78 (d, J=5.52 Hz, 1 H) 6.97 - 7.09
(m, 1 H) 7.16 - 7.30 (m, 3



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H) 7.36 (s, 1 H) 7.51 (d, J=8.82 Hz, 2 H) 8.15 (d, J=5.52 Hz, I H) 8.53 (s, 1
H) 9.99 (s, I H); MS
(DCI/NH3) m/z 449 (M+H)+.

Example 8
N- { 4-[4-Methyl=2-(2 -methyl-2H-pyrazol o[3,4-b]pyridin-4-ylarni no)-phenyl s
ul fanyl] -phenyl }-
acetamide
Example 8a
2,2-Dimethyl-5-[(1-methyl-lH-pyrazol-3-ylamino)-methylene]-[ 1,3]dioxane-4,6-
dione

[02711 A mixture of 1-methyl-lH-pyrazol-3-ylamine (1.05 g, 10.8 mmol), 2,2-
dimethyl-
[1,3]dioxane-4,6-dione (1.71 g, 11.9 mmol), and triethylorthoformate (1.60 g,
10.8 mmol,) in a 25 niL
round bottomed flask was heated in a 100 C oil bath for 15 min. The mixture
was cooled to room
temperature and EtOH (10 mL) was added. The reaction mixture was heated to
dissolve all solids and
then cooled back to room temperature. The solid that was formed was isolated
by filtration, rinsed
with ethanol, and dried to provide the title compound (1.81 g, 66 % yield).

Example 8b
2-Methyl-2,7-dihydro-pyrazolo[3,4 b]pyridin-4-one

[0272] A mixture of the product of Example 8a (1.50 g, 5.97 mmol) and diphenyl
ether (25
mL) was heated under reflux for lh, with removal of the resultant acetone by
distillation. The solvent
was then decanted, and the remaining solid residue was dissolved in
dichloromethane (5 mL) and
purified by chromatography on silica gel, eluting with a 0-10% MeOH/CH2C12
gradient, to provide
the title compound (0.360 g, 40% yield).

Example 8c
4-Chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine
[02731 A mixture of the product of Example 8b (0.177 g, 1.19 mmol) and
phosphorus
oxychloride (3 mL) was heated under reflux for 30 min and then cooled to room
temperature. The
reaction mixture was poured over ice, taken to pH 8 by the addition of IN
aqueous sodium hydroxide
solution, and extracted with dichloromethane (3 x 30 mL). The combined organic
phase was dried
over anhydrous magnesium sulfate, filtered, and evaporated under reduced
pressure to provide the
title compound (0.170 g, 88% yield).

Example 8d
N-{4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ylamino)-
phenylsulfanyl] phenyl}-
acetamide

[0274] A mixture of the product of Example 8c (47.3 mg, 0.282 mmol), the
product of
Example 7b (84.6 mg, 0.3 10 mmol), Pd2(dba)3 (12.9 mg, 0.0141 mmol), sodium t-
butoxide (67.8 mg,
0.706 mmol), and 2,8,9-triisobuiyl-2,5,8,9-tetraaza-l-
phosphabicycl[3,3,3]undecane (19.3 mg, 0.0564
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mmol) in toluene (4 mL) was degassed, left under a positive pressure of
nitrogen, and heated under
reflux for 2 h. Additional amounts of Pd2(dba)3 (4.0 mg, 0.0044 mrnol) and PN3
(4.5 mg, 0.013
mmol) were added the reaction mixture was heated under reflux for an addition
2 h. The mixture was
then cooled to room temperature and partitioned between ethyl acetate (30 mL)
and water (30 mL).
The aqueous phase was extracted with ethyl acetate and the combined organic
phase was dried over
anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure.
The residue was
purified by chromatography on silica gel, eluting with 5% MeOH/CH2CI2, to
provide the title
compound (0.0195 g, 17% yield). 'H NMR (3001VIHz, DMSO-d6) S ppm: 2.03 (s, 3
H), 2.29 (s, 3 H),
4.11 (s, 3 H), 5.97 (d, J-5.15 Hz, 1 H), 6.94 - 7.00 (m, 1 H), 7.05 (dd, J--
8.09, 1.47 Hz, 1 H), 7.19 (s,
1 H), 7.26 (d, J-8.82 Hz, 2 H), 7.56 (d, J=8.82 Hz, 2 H), 8.09 (d, J--5.15 Hz,
1 H), 8.20 (s, 1 H), 8.80
(s, I H), 10.04 (s, 1 H); MS (ESr) m/z 404.1(M+H)+.

Example 9
4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-ylamino)-phenylsulfanyl]-
phenol
[0275J A mixture of the product of Example 8c (62.1 mg, 0.371 znmol), the
product of
Example 6c (85.7 mg, 0.371 mmol), Pd2(dba)3 (16.9 mg, 0.0185 mmol), sodium t-
butoxide (89.0 mg,
0.926 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-l-
phosphabicycl[3,3,3]undecane (25.4 mg, 0.0741
mmol) in toluene (3 mL) was degassed, left under a positive pressure of
nitrogen, and heated under
reflux for 2 h. Additional amounts of Pd2(dba)3 (7.0 mg, 0.0076 mmol) and
2,8,9-triisobutyl-2,5,8,9-
tetraaza-1-phosphabicycl[3,3,3]undecane (15 mg, 0.044 mmol) were added the
reaction mixture was
heated under reflux for an addition 2 h. The mixture was then cooled to room
temperature and
partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous phase
was extracted with
ethyl acetate and the combined organic phase was washed with brine, dried over
anhydrous
magnesium sulfate, filtered, and evaporated under reduced pressure. The
residue was purified by
chromatography on silica gel, eluting with a 2-5% MeOH/CH2C12a gradient to
provide the title
compound (0.0279 g, 21 % yield). 'H NMR (300 MHz, DMSO-d6) S ppm: 2.27 (s, 3
H), 4.11 (s, 3 H),
5.92 (d, J=5.15 Hz, I H), 6.75 - 6.85 (m, 3 H), 7.02 (dd, J=8.27, 0.92 Hz, 1
H), 7.14 (s, 1 H), 7.18 -
7.27 (m, 2 H), 8.09 (d, J=5.15 Hz, I H), 8.20 (s, 1 H), 8.77 (s, 1 H), 9.82
(s, 1 H); MS (ESr') m/z
363.0 (M+H)+ (ESI") m/z 360.9 (M-H)".

Example 10
4-[4-(4-Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenoi
Example l0A
2-Amino-6-methyl-ni cotinonitrile

[0276] 2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia
(250 mL) in 500
mL of ethanol were reacted in a sealed high-pressure vessel at 130 C for 20
hours. The reaction
mixture was concentrated under vacuum and the residue washed with water (2 x
50 mL) then dried in
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a vacuum oven for 24 hours to provide the title compound as a light yellow
solid (18 g, 82%). 'H
NMR (300 MHz, DMSO-d6) S ppm:2.30 (s, 3H), 6.52 (d, J= 7.7 Hz, 1H), 6.78 (s,
2H), 7.73 (d, J= 7.7
Hz, 1H).

Example lOB
N'-(3-Cyano-6-methyl pyridin-2-yl)-N,N-dimethyl-formamidine

[0277] A solution of the product of Example 10A (10 g, 75.19 mmol) and N,N-
Dimethylformamide dimethyl acetal (11 mL, 82.71 mmol) in toluene (100 mL) was
heated at reflux
for 6 hours. After cooling to room temperature, the solution was concentrated
under vacuum to
provide the title compound as a yellow solid (13.78 g, 98%). 'H NMR (300 MHz,
DMSO-d6) S ppm:
2.41 (s, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 6.87 (d, J= 7.7 Hz, 1H), 7.89 (d, J=
8.1 Hz, 1H), 8.59 (s, IH).
Example lOC
1-Chloro-4-(4-methoxy-benzyloxy)-2-nitro-benzene
[0278] A solution of 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1-
chloromethyl-4-methoxy-
benzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8.64 mmol) and
tetrabutylammonium
iodide (0.005 g, 0.0135 mmol) in N,N-dimethylformamide (5 ml) was stirred at
room temperature for
16 hours. Afterwards ice water (10 mL) was added to the solution and the.
resultant solid was
collected by filtration and dried in a vacuum oven to provide the title
compound (0.812 g, 96%).

Example 10D
4-[4-(4-Methoxy-benzyloxy)-2-nitro-phenylsulfanyl]-phenol
[0279] A solution of the product of Example 10C (0.812 g, 2.76 mmol), 4-
hydroxythiophenol
(0.419, 3.32 mmol) and cesium carbonate (2.16 g, 6.64 mmol) in N,N-
dimethylformamide (5 mL) was
heated to 100 C for 16 hours. After cooling to room temperature the mixture
was poured into ice
water (20 mL) and the resultant solution acidified with 1N aqueous
hydrochloric acid. The solution
was then extracted with ethyl acetate (3 x 10 mL), the combined extracts dried
over magnesium
sulfate, filtered and concentrated under vacuum to provide the title compound
(1.06 g, 100%).

Example 10E
4-[2-Amino-4-(4-methoxy-benzyloxy)-phenylsulfanyl]-phenol
[0280] A solution of the product of Example 10D (1.06 g, 2.76 mmol), iron
powder (0.63 g, 11.04
mmol) and ammonium chloride (0.18 g, 3.31 mmol) in a methanol (18 mL),
tetrahydrofuran (18 mL),
and water (6 mL) solution was heated to reflux for 3 hours. The resultant
mixture was diluted with
methanol (50 mL) and filtered through a pad of celite. The filtrate was
concentrated under vacuum to
a volume of 10 mL, the solution diluted with water (50 mL). and extracted with
ethyl acetate (2 x 50
mL). The combined extracts were dried over magnesium sulfate, filtered and
concentrated under
vacuum to provide the title compound (0.99 g, 100%).
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Example IOF
4-[4-(4-Methoxy benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)
phenylsulfanyl]-phenol
[0281] A solution of the product of Example lOB (28.4 mg, 0.151 mmol), and the
product of
Example 10E (53.3 mg, 0.151 mmol) in acetic acid (1 mL) was stirred in an oil
bath preheated to
130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue triturated with methanol to provide
the title compound as a
tan solid (26.5 mg, 35%). 'H NMR (300 MHz, DMSO-d6) S ppm: 9.92 (s, 1 H), 9.63
(s, I H), 8.70 (d,
J=8.09 Hz, 1 H), 8.55 (s, 1 H), 7.52 (d, J=8.46 Hz, 1 H), 7.38 (d, J=8.82 Hz,
2 H), 7.27 (s, 1 H), 7.06 -
7.18 (m, 3 H), 6.94 (d, J=8.46 Hz, 3 H), 6.61 - 6.72 (m, 2 H), 5.02 (s, 2 H),
3.75 (s, 3 H), 2.66 (s, 3 H);
MS (ESI+) m/z 497.2 (M+H)+, (ESI-) m/z 495.3 (M-H)-.

Example 11
3-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-rnethyl-pyrido[2,3-d]pyrirnidin-4-
ylamino)-phenoxymethyl]-
benzonitrile
Example 11 A
3-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitril e

[0282] A solution of 4-chloro-3 -nitro -phenol was reacted with 3-bromomethyl
benzonitrile using
the conditions described in Example IOC to provide 3-(4-chloro-3-nitro-
phenoxymethyl)-benzonitrile
which was treated sequentially using the procedures from Examples 10D and l0E
to provide the title
product.

Example I1B
3-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxymethyl]-
benzonitrile

[0283] The product of Example 11A was reacted with the product of Example lOB
using the
procedure of Example 1OF substituting the product of Example 11A for the
product of Example IOE
to provide the crude title compound which was purified by reverse phase
preparative HPLC on a
Waters Symmetry C8 column (25mm x 100mm, 71im particle size) using a gradient
of 10% to 100%
acetonitrile/0. 1% trifluoroacetic acid in water over 8 minutes (10 minutes
run time) at a flow rate of
40n:iL/min to provide the title compound as a trifluoroacetic acid salt (20
mg, 23%). 1H N1VIR (300
MHz, DMSO-d6) S ppm: 11.39 (s, 1 H), 9.70 (s, I H), 8.89 (d, J=8.46 Hz, 1 H),
8.77 (s, 1 H), 7.92 (s,
I H), 7.75 - 7.86 (m, 3 H), 7.62 (t, J=7.72 Hz, 1 H), 7.18 - 7.29 (m, 2 H),
7.03 - 7.14 (m, 3 H), 6.55 -
6.69 (m, 2 H), 5.18 (s, 2 H), 2.74 (s, 3 H); MS (ESI+) m/z 492.1 (M+H)+ (ESI-)
m/z 490.2 (M-H)-.

Example 12
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(pyridin-2-ylmethoxy)
phenylsulfanyl]-phenol
Example 12A
4-[2-Amino-4-(pyridin-2-ylmethoxy)-phenylsulfanyl]-phenol
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[0284] A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-
pyridine
hydrobromide salt using the conditions described in Example 10C to provide 2-
(4-Chloro-3-nitro-
phenoxymethyl)-pyridine which was treated sequentially using the procedures
from Examples 10D
and l0E to provide the title product.

Example 12B
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(pyridin-2-ylmethoxy)-
phenylsulfanyl]-phenol
[0285] The product of Example 12A was reacted with the product of Example lOB
using the
procedure of Example 10F substituting the product of Example 12A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (15 mg, 17%). 1H N1VIR (300 MHz, DMSO-
D6) S ppm 2.76
(s, 3 H) 5.19 (s, 2 H) 6.63 (d, J=8.82 Hz, 2 H) 6.98 - 7.17 (m, 3 H) 7.20 (d,
J=2.57 Hz, 1 H) 7.22 -
7.30 (m, I H) 7.38 (dd, J=6.43, 4.96 Hz, 1 H) 7.53 (d, J=7.72 Hz, 1 H) 7.71 -
7.94 (m, 2 H) 8.58 (d,
J=4.04 Hz, 1 H) 8.82 (s, 1 H) 8.93 (d, J=7.72 Hz, I H) 9.71 (br s, 1 H) 11.66
(br s, 1 H); MS (ESI+)
ni/z 468(M+H)+.

Example 13
4-[4-(4-tert-Butyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol

Example 13A
4-[2-Amino-4-(4-tertbutyl-benzyloxy)-phenylsulfanyl]-phenol
102861 A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-
tert-butyl-
benzene using the conditions described in Example 10C to provide 4-(4-tert-
Butyl-benzyloxy)-1-
chloro-2-nitro-benzene which was treated sequentially using the procedures
from Examples lOD and
10E to provide the title product.

Example 13B
4-[4-(4-tert-Butyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol

[0287] The product of Example 13A was reacted with the product of Example lOB
using the
procedure of Example 10F substituting the product of Example 13A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (52 mg, 36%). 1H NIvIR (300 MHz, DMSO-
D6) S ppm: 1.28
(s,9H)2.74(s,3H)5.06(s,2H)6.63(d,J=8.46Hz,2H)7.00-7.12(m,3H)7.15-7.27(m,2H)
7.30 - 7.47 (m, 5 H) 7.79 (d, J=8.46 Hz, 1 H) 8.77 (s, I H) 8.89 (d, J=8.46
Hz, 1 H) 9.69 (s, 1 H); MS
(ESI+) m/z 523 (M+H)+.

Example 14


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4-[4-(2-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 14A
4-[2-Amino-4-(2-bromo-benzyloxy)-phenylsulfanyl]-phenol
[0288] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-2-
bromomethyl-benzene
using the conditions described in Example lOC to provide 4-(2 Bromo benzyloxy)-
1-chloro-2-nitro-
benzene which was treated sequentially using the procedures from Examples 10D
and l0E to provide
the title product.

Example 14B
4-[4-(2-Bromo benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0289] The product of Example 14A was reacted with the product of Example lOB
using the
procedure of Example 10F substituting the product of Example 14A for the
product of Example 1 E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid saIt (42 mg, 39%). IH NMR (300 MHz; DMSO-
D6) S ppm: 2.68
(s, 3 H) 5.13 (s, 2 H) 6.67 (m, 2 H) 6.96 (d, J=7.68 Hz,
1H)7.14(m,3H)7.30(m,2H)7.44(m, 1 H)
7.59 (m, 2 H) 7.68 (d, J=7.68 Hz, 1 H) 8.59 (s, 1 H) 8.73 (d, J=8.09 Hz, 1 H)
9.66 (s, 1 H) 10.27 (s, I
H); MS (ESI+) m/z 545, 547 (M+H)+.

Example 15
4-[4-(3-Bromo-benzyloxy)-2-(7-methyl-pyrido [2,3 -d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 15A
4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol
[0290] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-3-
bromomethyl-benzene
using the conditions described in Example 10C to provide 4-(3-Bromo-benzyloxy)-
1-chloro-2-nitro-
benzene which was treated sequentially using the procedures from Examples 10D
and IOE to provide
the title product.

Example 15B
4-[4-(3-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylarnino)-
phenylsulfanyl]-phenol
[0291] The product of Example 15A was reacted with the product of Example lOB
using the
procedure of Example l OF substituting the product of Example 15A for the
product of Example I OE
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (25 mg, 23%). 1H 1VNIIt (300 MHz, DMSO-
D6) S ppm: 2.72
(s, 3 H) 5.13 (s, 2 H) 6.65 (m, 2 H) 7.11 (m, 5 H) 7.40 (m, 2 H) 7.54 (d,
J=7.72 Hz, I H) 7.66 (s, 1 H)
7.72 (d, J=8.82 Hz, I H) 8.71 (s, 1 H) 8.84 (d, J=8.09 Hz, 1 H) 9.68 (s, 1 H),
11.04 (m, 1 H); MS
(ESI+) m/z 545, 547 (M+H)+.

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Example 16
4-[4-(4-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol

Example 16A
4-[2-Amino-4-(4-bromo-benzyloxy)-phenylsulfanyl]-phenol
[0292] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-4-
bromomethyl-benzene
using the conditions described in Example l OC to provide 4-(4-Bromo-
benzyloxy)-1-chloro-2-nitro-
benzene which was treated sequentially using the procedures from Examples 10D
and l0E to provide
the title product.

Example 16B
4-[4-(4-Bromo-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[02931 The product of Example 16A was reacted with the product of Example lOB
using the
procedure of Example 10F substituting the product of Example 16A for the
product of Example IOE
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (19 mg, 17%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.72
(s, 3 H) 5.13 (s, 2 H) 6.63 (m, 2 H) 7.03 (dd, J=8.82, 2.57 Hz, I H) 7.10 (m,
2 H) 7.21 (d, J=8.46 Hz,
2 H) 7.40 (m, 2 H) 7.54 (d, J=8.09 Hz, 1 H) 7.66 (s, 1 H) 7.73 (d, J=8.46 Hz,
I H) 8.72 (s, I H) 8.84
(d, J=8.46 Hz, 1 H) 9.69 (s, 1 H) 11.08 (m, 1 H); MS (ESI+) m/z 545, 547
(M+H)+.

Example 17
4-[4-(2-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylarnino)-
phenylsulfanyl]-phenol
Example 17A
4-[2-Amino-4-(2-methyl-benzyloxy)-phenylsulfanyl]-phenol
[02941 A solution of 4-chloro-3-nitro-phenol was reacted with 1 Bromomethyl-2-
methyl benzene
using the conditions described in Example 10C to provide 1-Chloro-4-(2-methyl-
benzyloxy)-2-nitro-
benzene which was treated sequentially using the procedures from Examples IOD
and 10E to provide
the title product.

Example 17B
4-[4-(2-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0295] The product of Example 17A was reacted with the product of Example IOB
using the
procedure of Example IOF substituting the product of Example 17A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (35 mg, 36%). 1H NMR (300 MHz, DMSO-
D6) 8 ppm: 2.32
(s, 3 H) 2.71 (s, 3 H) 5.09 (s, 2 H) 6.65 (m, 2 H) 7.03 (dd, J=8.82, 2.57 Hz,
I H) 7.11 (m, 2 H) 7.24
(m, 5 H) 7.41 (d, J=6.99 Hz, 1 H) 7.69 (d, 1=8.46 Hz, 1 H) 8.69 (s, 1 H) 8.82
(d, J=8.82 Hz, 1 H) 9.67
(s, 1 H) 10.84 (s, 1 H); MS (ESI+) m/z 481 (M+H)+.

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Example 18
4-[4-(3-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol

Example 18A
4-[2-Amino-4-(3-methyl-benzyloxy) phenylsulfanyl]-phenol

[0296] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-3-
methyl-benzene
using the conditions described in Example IOC to provide 1-Chloro-4-(3-methyl-
benzyloxy)-2-nitro-
benzene which was treated sequentially using the procedures from Examples I OD
and l0E to provide
the title product.

Example 18B
4-[4-(3-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylarnino)
phenylsulfanyl]-phenol
[0297] The product of Example 18A was reacted with the product of Example IOB
using the
procedure of Example 10F substituting the product of Example 18A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (37 mg, 39%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.31
(s, 3 H) 2.73 (s, 3 H) 5.07 (s, 2 H) 6.64 (m, 2 H) 7.16 (m, 9 H) 7.75 (d,
J=8.46 Hz, I H) 8.73 (s, 1 H)
8.86 (d, J=8.46 Hz, 1 H) 9.69 (s, 1 H) 11.16 (s, 1 H); MS (ESI+) m/z 481
(M+H)+_

Example 19
4-[4-(4-Methyl-benzyloxy)-2-(7-rnethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 19A
4-[2-Amino-4-(4-methyl-benzyloxy)-phenylsulfanyl] -phenol

[0298] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Brornomethyl-4-
methyl-benzene
using the conditions described in Example 10C to provide 1-Chloro-4-(4-methyl-
benzyloxy)-2-nitro-
benzene which was treated sequentially using the procedures from Examples lOD
and l0E to provide
the title product.

Example 19B
4-[4-(4-Methyl-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0299] The product of Example 19A was reacted with the product of Example lOB
using the
procedure of Example lOF substituting the product of Example 19A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (29 mg, 30%). 1H NNHZ (300 MHz, DMSO-
D6) S ppm: 2.30
(s, 3 H) 2.67 (s, 3 H) 5.05 (s, 2 H) 6.64 (m, 2 H) 6.94 (d, J=7.38 Hz, 1 H)
7.17 (m, 6 H) 7.33 (d,
J=8.09 Hz, 2 H) 7.56 (d, J=8.46 Hz, 1 H) 8.57 (s, 1 H) 8.72 (d, J=8.09 Hz, 1
H) 9.63 (s, 1 H) 10.12 (s,
1 H); MS (ESI+) m/z 481 (M+H)+.

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Example 20
2-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxymethyl]-
benzonitrile
Example 20A
2-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile

[03001 A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-
benzonitrile using
the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-
phenoxymethyl)-benzonitrile
which was treated sequentially using the procedures from Examples 10D and l0E
to provide the title
product.

Example 20B
2-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-rnethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxymethyl]-
benzonitrile

[0301] The product of Example 20A was reacted with the product of Example 10B
using the
procedure of Example 10F substituting the product of Example 20A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (21 mg, 16%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 9.93
(s, I H), 9.63 (s, 1 H), 8.75 (d, J=8.46 Hz, 1 H), 8.57 (s, 1 H), 7.60 (d,
J=8.09 Hz, 1 H), 7.38 (d,
J=8.46 Hz, 2 H), 7.27 (s, 1 H), 7.05 - 7.19 (m, 3 H), 6.85 - 7.00 (m, 3 H),
6.67 (d, J=8.82 Hz, 2 H),
5.02 (s, 2 H), 3.75 (s, 3 H), 3.14 - 3.28 (m, 1 H), 1.32 (d, J=6.62 Hz, 6 H);
MS (ESI+) m/z 492.2
(Ivi+H)+ (ESI-) m/z 490.2 (M-H)-.

Example 21
4-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxymethyl]-
benzonitrile
Example 21A
4-[3 -Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile

[0302] A solution of 4-chloro-3-nitro-phenol was reacted with 4-Bromomethyl-
benzonitrile using
the conditions described in Example 10C to provide 4-(4-Chloro-3-nitro-
phenoxymethyl)-benzonitrile
which was treated sequentially using the procedures from Examples 10D and 10E
to provide the title
product.

Example 21B
4-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxymethyl]-
benzonitrile

[0303] The product of Example 21A was reacted with the product of Example lOB
using the
procedure of Example lOF substituting the product of Example 21A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (15 mg, 14%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 11.69
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(s, 1 H), 9.72 (s, I H), 8.94 (d, J=8.46 Hz, 1 H), 8.83 (s, I H), 7.78 - 7.96
(m, 3 H), 7.63 (d, J=8.46 Hz,
2 H), 7.22 - 7.27 (m, 1 H), 7.18 (d, J=2.57 Hz, I H), 7.06 - 7.13 (m, 3 H),
6.59 - 6.66 (m, 2 H), 5.23 (s,
2 H), 2.76 (s, 3 H); MS (ESI+) m/z 492.1 (M+H)+ (ESI-) m/z 490.1 (M-H)-.

Example 22
4-[4-[ 1-(4-Bromo-phenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl]-
phenol
Example 22A
1-Bromo-4-(1-bromo-ethyl)-benzene
[0304] A solution of 1-(4-bromo-phenyl)-ethanol (4.21 g, 20.9 mmol) in 15 mL
of CH2C12 was
reacted with 15 mL of 1.OM PBr3 in CH2Cl2 at room temperature for 4 h.
Quenched by pouring into
ice and adjusted to pH 9 with 5% aqueous NaHCO3. Extracted with CHaCIa and
dried over Na2SO4,
filtered and concentrated under vacuum giving the title compound (4.1 g, 75%).

Example 22B
4-[ 1-(4-Bromo-phenyl)-ethoxy]-1-chloro-2-nitro-benzene

[0305] The product from Example 22A (995 mg, 3.77 mmol) was reacted with 4-
chloro-3-nitro-
phenol (650 mg, 3.77 mmol) in 15 mL of DMF with K2C03 (10.4 g, 3.77 mmol) at
80 C for 3 h.
Cooled to room temperature and diluted with water. Extracted with CH2C12a
washed four times with
water. Dried over Na2SO4, filtered and concentrated under vacuum giving the
title compound (1.24 g,
92%).

Example 22C
4- {4-[ 1-(4-Brorno-phenyl)-ethoxy]-2-nitro-phenylsulfanyl } -phenol

[03.06] The product from Example 22B (1.15 g, 3.22 mmol) was reacted with 4-
mercapto-phenol
(403 mg, 3.22 mmol) and K2C03 (890 mg, 6.44 mmol) in 25 mL of DMF at 80 C for
18 h. Cooled to
room temperature and poured into water. Extracted with CH2C12 and washed
several times with water.
Dried over NaZSO4, filtered and concentrated under vacuum giving the title
compound (980 mg, 68
%).

Example 22D
4-[2-Amino-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenol
[0307] The product from Example 22C (560 mg, 1.25 mmol) was reacted with Fe
(279 mg, 5.0
mmol) and NH4CI (76 mg, 1.40 mmol) in 5 mL MeOH/ 5 mL TBF/ 2.5 mL water
following the
procedure from Example l0E giving the title compound as a solid (439 mg, 84%).

Example 22E
4-[4-[1-(4-Bromo phenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin--4-
ylamino)-phenylsulfanyl]-
phenol


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[0308] The product from Example 22D (204 mg, 0.49 mmol) was reacted with the
product from
Example lOB (93 mg, 0.49 mmol) following the procedure from Example lOF to
provide the crude
title compound which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (38 mg, 12%). 1H NMR (300 MHz, DMSO-d6) S ppm: 11.24
(br s,1H) 9.70
(s,IH) 8.83 (d, J=8.09 Hz, 1H) 8.74 (s, 1H) 7.76 (d, J=8.45 Hz, 1H) 7.55 (d,
J=8.46 Hz, 2H) 7.37 (d,
J= 8.46 Hz, 2H) 7.09 (m, 4H) 6.93 (dd, J= 6.62 Hz, J= 2.20 Hz, 1H) 6.63 (d,
J=8.82 Hz, 2H) 5.51 (q,
J=6.25 Hz, 2H) 2.73 (s, 3H), 1.53 (d, J=6.25 Hz, 3H); MS (ESI+) m/z,559, 561
(M+H-TFA)+; (ESI-)
m/z, 557, 559 (M-H-TFA)-.

Example 23
4-[4-[ 1-(4-Fluoro-phenyl)-ethoxy]-2-(7-methyl-pyrido [2,3-d]pyrimi din-4-
ylamino)-phenylsulfanyl]-
phenol
Example 23A
4- {2-Amino-4-[ 1-(4-fluoro-phenyl)-ethoxy]-phenyl sulfanyl } -phenol

[0309] A solution of 1-(4-fluoro-phenyl)-ethanol was converted tol-(1-Bromo-
ethyl)-4-fluoro-
benzene using the conditions described in Example 22A which was treated
sequentially using the
procedures from Examples 22B-22D to provide the title product.

Example 23B
4-[4-[1-(4-Fluoro-phenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino) phenylsulfanyl]-
phenol

[03101 The product from Example 23A (207 mg, 0.584 mmol) was reacted with the
product from
Example lOB (110 mg, 0.584 mmol) following the procedure from Example lOF to
provide the crude
title compound which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (30 mg, 35%). 1H NMM (300 MHz, DMSO-d6) S ppm: 1.54
(d, J=6.25 Hz, 3
H) 2.73 (s, 3 H) 5.53 (q, J=6.13 Hz, 1 H) 6.63 (d, J=8.82 Hz, 2 H) 6.93 (dd,
J=8.82, 2.57 Hz, 1 H)
7.05 - 7.14 (m, 4 H) 7.18 (t, J=9.01 Hz, 2 H) 7.41 - 7.49 (m, 2 H) 7.76 (d,
J=8.46 Hz, 1 H) 8.73 (s, I
H) 8.84 (d, J=8.46 Hz, 1 H) 9.71 (s, 1 H); MS (ESI+) m/z 497 (MH)-.

Example 24
4-[4-[ 1-(3-Fluoro-phenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl]-
phenol
Example 24A
4-{2-Amino-4-[1-(3-fluoro-phenyl)-ethoxy]-phenylsulfanyl} -phenol

[0311] A solution of 1-(3-fluoro-phenyl)-ethanol was converted tol-(1-Bromo-
ethyl)-3-fluoro-
benzene using the conditions described in Example 22A which was treated
sequentially using the
procedures from Examples 22B-22D to provide the title product.

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Example 24B
4-[4-[ 1-(3-Fluoro-phenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl]-
phenol
[03121 The product from Example 24A (226 mg, 0.637 mmol) was reacted with the
product from
Example lOB (120 mg, 0.637 mmol) following the procedure from Example 10F to
provide the crude
title compound which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (87 mg, 22%). 1H NMR (300 MHz, DMSO-D6) S ppm: 1.55
(d, J=6.62 Hz, 3
H) 2.72 (s, 3 H) 5.54 (q, J--6.13 Hz, 1 H) 6.64 (d, J--8.46 Hz, 2 H) 6.91 (dd,
J=8.82, 2.57 Hz, I H)
7.06 - 7.15 (m, 5 H) 7.20 - 7.28 (m, 2 H) 7.35 - 7.44 (m, I H) 7_70 (d, J=8.46
Hz, 1 H) 8.68 (s, I H)
8.81 (d, J=8.46 Hz, 1 H) 9.73 (s, 1 H); MS (ESI+) rnlz 499 (IVI+H)+.

Example 25
4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl]-phenol

Example 25A
4-[2-Amino-4-(2-chloro-thiazol-5-ylmethoxy)-phenylsulfanyl] phenol

[0313] A solution of 4-chloro-3-nitro-phenol was reacted with 5-Bromomethyl-2-
chloro-thiazole
(prepared according to the method of Kim, H.-J., Liu, S., Keum, Y.-S., Qing,
X. J. Agric. Food Chem.
2003, 51, 1823-1830) using the conditions described in Example lOC to provide
2-Chloro-5-(4-
chloro-3-nitro-phenoxymethyl)-thiazole which was treated sequentially using
the procedures from
Examples 10D and l0E to provide the title product.

Example 25B
4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
ph enyl s ul fanyl ]-ph en ol

[0314] The product of Example 25A was reacted with the product of Example lOB
using the
procedure of Example IOF substituting the product of Example 25A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt. IH NMR (300 MHz, DMSO-D6) S ppm: 2.71
(s, 3 H) 5.34
(s, 2 H) 6.66 (d, J=8.46 Hz, 2 H) 7.01 (dd, J=8.64, 2.02 Hz, 1 H) 7.06 - 7.28
(m, 4 H) 7.68 (d, J=8.46
Hz, 1 H) 7.80 (s, I H) 8.67 (s, 1 H) 8.82 (d, J=8.46 Hz, 1 H) 9.70 (s, 1 H),
10.81 (bs, 1 H); MS (ESI+)
m/z 508 (M+H)+.

Example 26
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-trifluoromethyl-
benzyloxy)-phenylsulfanyl]-
phenol

Example 26A
4-[2-Amino-4-(3-trifluoromethyl-benzyloxy)-phenylsulfanyl]-phenol
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[0315] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chlorornethyl-
3-trifluoromethyl-
benzene using the conditions described in Example lOC to provide I-Chloro-2-
nitro-4-(3-
trifluoromethyl-benzyloxy)-benzene which was treated sequentially using the
procedures from
Examples 10D and 10E to provide the title product.

Example 26B
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(3-trifluoromethyl-benzyl
oxy)-phenylsulfanyl]-
phenol

[0316] The product of Example 26A was reacted with the product of Example 10B
using the
procedure of Example 10F substituting the product of Example 26A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (9.9 mg, 9%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.74
(s, 3 H), 5.22 (s, 2 H), 6.64 (d, J=8.46 Hz, 2 H), 7.10 (d, J=8.82 Hz, 3 H),
7.19 - 7.30 (m, 2 H), 7.62 -
7.72 (m, J=7.35 Hz, 2 H), 7.72 - 7.84 (m, 4 H), 8.75 (s, 1 H), 8.88 (d, J=7.35
Hz, I H), 9.69 (s, 1 H);
MS ESI+ m/z 535 (M+H)+,ESI- m/z 533 (M-H)-.

Example 27
4-[4-Benzyloxy-2-(7-methyl-pyrido [2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
Example 27A
4-(2-Amino-4-benzyloxy-phenylsulfanyl)-phenol

[0317] A solution of 4-chloro-3-nitro-phenol was reacted with Bromomethyl-
benzene using the
conditions described in Example IOC to provide 4-Benzyloxy-l-chloro-2-nitro-
benzene which was
treated sequentially using the procedures from Examples 10D and 10E to provide
the title product.

Example 27B
4-[4-Benzyloxy-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[0318] The product of Example 27A was reacted with the product of Example lOB
using the
procedure of Example lOF substituting the product of Example 27A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (73 mg, 25%). 'H NMR (300 MHz, DMSO-
D6) S ppm: 2.70
(s, 3 H) 5.11 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.98 (d, J=7.72 Hz, 1 H) 7.10
(d, J=8.46 Hz, 2 H) 7.18
(d, J=8.46 Hz, 1 H) 7.24 (s, 1 H) 7.28 - 7.51 (m, 5 H) 7.63 (d, J=8.82 Hz, 1
H) 8.64 (s, 1 H) 8.78 (d,
J=8.82 Hz, I H) 9.65 (s, 1 H) 10.56 (br s, 1 H); MS (ESI+) m/z 467(M+H)+.

Example 28
4-[4-(3-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 28A
4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol
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[0319] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-3-
fluoro-benzene
using the conditions described in Example IOC to provide 1-Chloro-4-(3-fluoro-
benzyloxy)-2-nitro-
benzene which was treated sequentially using the procedures from Examples l OD
and 10E to provide
the title product.

Example 28B
4-[4-(3-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl] -phenol
[0320] The product of Example 28A was reacted with the product of Example lOB
using the
procedure of Example 1 F substituting the product of Example 28A for the
product of Example l0E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (41 mg, 42%). 1H NMR (300 MHz, DMSO-
D6) 8 ppm: 2.72
(s, 3 H) 5.14 (s, 2 H) 6.65 (m, 2 H) 7.02 (dd, J=8.64, 2.76 Hz, 1 H) 7.10 (m,
2 H) 7.23 (m, 5 H) 7.44
(m, 1 H) 7.71 (d, J=8.46 Hz, 1 H) 8.69 (s, I H) 8.83 (d, J=8.46 Hz, 1 H) 9.69
(s, 1 H) 10.96 (s, 1 H);
MS (ESI+) m/z 485 (M+H)+.

Example 29
4-[2-(7-Methyl-pyrido [2,3 -d]pyrimidin-4-ylamino)-4-(tetrahydro-fiuan-2-
ylmethoxy)-
phenylsulfanyl]-phenol
Example 29A
4-[2-Amino-4-(tetrahydro-furan-2-ylmethoxy)-phenylsulfanyl]-pbenol
[0321] A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-
tetrahydro-furan
using the conditions described in Example IOC to provide 2-(4-Chloro-3-nitro-
phenoxymethyl)-
tetrahydro-furan which was treated sequentially using the procedures from
Examples lOD and IOE to
provide the title product.

Example 29B
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(tetrahydro-furan-2-
ylmethoxy)-
phenylsulfanyl]-phenol

[0322] The product of Example 29A was reacted with the product of Example lOB
using the
procedure of Example lOF substituting the product of Example 29A for the
product of Example IOE
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (29 mg, 17%). 1H NMR (300 MHz, DMSO-
D6) S ppm:1.55 -
1.84 (m, 1 H) 1.84 - 2.07 (m, 1 H) 2.67 (s, 3 H) 3.59 - 3.71 (m, 2 H) 3.73 -
3.83 (m, 1 H) 3.85 - 4.02
(m, 2 H) 4.15 (dd, J=6.43, 4.23 Hz, 2 H) 6.66 (d, J=8.46 Hz, 2 H) 6.87 (dd,
J=8.64, 2.76 Hz, I H)
7.02 - 7.15 (ni, 2 H) 7.12 - 7.24 (m, 2 H) 7.53 (d, J=8.46 Hz, 1 H) 8.56 (s, 1
H) 8.71 (d, J=8.46 Hz, 1
H) 9.62 (s, I H) 9.92 (s, 1 H); MS (ESI+) m/z 461 (M+H)+.

Example 30
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4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylarnino)-4-(naphthalen-l-ylmethoxy)-
phenylsulfanyl]-
phenol

Example 30A
4-[2-Amino-4-(naphthalen-1-ylmethoxy)-phenylsulfanyll-phenol
[0323] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-
naphthalene using
the conditions described in Example l OC to provide 1-(4-Chloro-3-nitro-
phenoxymethyl)-naphthalene
which was treated sequentially using the procedures from Examples 10D and l0E
to provide the title
product.

Example 30B
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(naphthalen-l-ylmethoxy)-
phenylsulfanyl]-
phenol

[03241 The product of Example 30A was reacted with the product of Example lOB
using the
procedure of Example IOF substituting the product of Example 30A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (31 mg, 25%). 1H NMR (300 MHz, DMSO-
D6) 8 ppm: 2.68
(s,3H)5.56(s,2H)6.67(d,J=8.82Hz,2H)7.01-7.16(m,3H)7.16-7.24(m,1H)7.35(s,1H)
7.45 - 7.64 (m, 4 H) 7.69 (d, J=6.62 Hz, I H) 7.87 - 8.02 (m, 2 H) 8.05 - 8.14
(m, 1 H) 8.59 (s, 1 H)
8.74 (d, J=8.46 Hz, 1 H) 9.65 (s, 1 H) 10.23 (s, 1 H); MS (ESI+) 517(M+H)+.

Example 31
4-[4-(3 -Methoxy-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 31 A
4-[2-Amino-4-(3-methoxy-benzyloxy)-phenylsulfanyl]-phenol

[0325] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Chloromethyl-3-
methoxy-
benzene using the conditions described in Example IOC to provide 1-Chloro-4-(3-
methoxy-
benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures
from Examples lOD
and l0E to provide the title product.

Example 31B
4-[4-(3-Methoxy-benzyloxy)-2-(7-methyl pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0326] The product of Example 31A was reacted with the product of Example lOB
using the
procedure of Example 10F substituting the product of Example 31A for the
product of Example l0E
to provide a solid which was triturated with methanol to provide the title
compound (24 mg, 26%). 'H
NMR (300 MHz, DMSO-D6) S ppm 9.93 (s, 1 H), 9.63 (s, 1 H), 8.71 (d, J=8.09 Hz,
1 H), 8.55 (s, 1
H), 7.53 (d, J=8.09 Hz, 1 H), 7.26 - 7.35 (m, 2 H), 7.15 (d, J=8.46 Hz, I H),
7.07 - 7.13 (m, 2 H), 6.98
- 7.04 (m, J=5.15 Hz, 2 H), 6.96 (s, 1 H), 6.90 (dd, J=8.09, 2.57 Hz, I H),
6.62 - 6.71 (m, 2 H), 5.08
(s, 2 H), 3.75 (s, 3 H), 2.67 (s, 3 H); MS (ESI+) m/z 497.2 (M+H)+ (ESI-) m/z
495.2(1VI-H)-.


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Example 32
4-[2-(7-Methyl-pyrido [2,3-d]pyrimidin-4-ylamino)-4-(quinolin-2-ylmethoxy)-
phenylsulfanyl] -phenol
Example 32A
4-[2-Amino-4-(quinolin-2-ylmethoxy)-phenylsulfanyl]-phenol

[0327] A solution of 4-chloro-3-nitro-phenol was reacted with 2-Chioromethyl-
quinoline
hydrochloride salt using the conditions described in Example lOC to provide 2-
(4-Chloro-3-nitro-. ,
phenoxymethyl)-quinoline which was treated sequentially using the procedures
from Examples lOD
and 1 E to provide the title product.

Example 32B
4-[2-(7-Methyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-4-(quinolin-2-ylmethoxy)-
phenylsulfanyl] -phenol
[03281 The product of Example 32A was reacted with the product of Example lOB
using the
procedure of Example IOF substituting the product of Example 32A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (13 mg, 27%). 1H NMR (500 MHz, DMSO-
D6) S ppm: 2.75
(s, 3 H) 5.39 (s, 2 H) 6.62 (d, J=8.54 Hz, 2 H) 7.09 (d, J=8.54 Hz, 2 H) 7.14
(dd, J=8.54, 2.44 Hz, 1
H) 7.22 - 7.28 (m, 2 H) 7.63 (t, J=7.93 Hz, 1 H) 7.68 (d, J=8.54 Hz, 1 H) 7.74
- 7.81 (m, 1 H) 7.83 (d,
J=8.54 Hz, I H) 8.00 (t, J=7.93 Hz, 2 H) 8.44 (d, J=8.54 Hz, 1 H) 8.76 (s, 1
H) 8.92 (d, J=8.54 Hz, 1
H) 9.68 (s, 1 H) 11.64 (br s, 1 H); MS (ESI+) 518(M+H)+.

Example 33
4-[4-(Biphenyl-4-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0329] The product of Example 16B (free salt form, 0.055 g, 0.1 mmol),
phenylboronic acid
(0.017 g, 0.14 mmol), cesium carbonate (0.05 g, 0.15 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (0.007 g, 0.01 mmol) were
combined in N,N-
dimethylformamide (1 mL) and heated to 100 C for 24 hours. After cooling to
room temperature the
mixture was poured into ice water (20 mL) and the resultant solution acidified
with 1N aqueous
hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10
mL), the combined
extracts dried over sodium sulfate, filtered and concentrated under vacuum. .
The crude product was
purified by HPLC with TFA to provide the title compound as a trifluoroacetic
acid salt (10 mg, 15%).
IH NMR (300 MHz, DMSO-D6) S ppm: 2.67 (s, 3 H), 5.16 (s, 2 H), 6.60 - 6.72 (m,
2 H), 6.98 (d,
J=8.09 Hz, 1 H), 7.06 - 7.22 (m, 3 H), 7.27 - 7.41 (m, 2 H), 7.47 (t, J=7.54
Hz, 2 H), 7.54 (d, J=8.46
Hz, 3 H), 7.60 - 7.73 (m, 4 H), 8.58 (s, 1 H), 8.72 (d, J=8.09 Hz, 1 H), 9.64
(s, 1 H), 10.08 (s, 1 H);
MS (ESI +) m/z 543 (M+H+)+.

Example 34
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4-[4-(5-Chloro-thiophen-2-ylmethoxy)-2-(7-methyl-pyrido[2,3 -d]pyrimidin-4-yl
amino)-
phenylsulfanyl]-phenol

Example 34A
4-[2-Amino-4-(5-chloro-thiophen-2-ylmethoxy)-phenylsulfanyl] phenol

[0330] A solution of 4-chloro-3-nitro-phenol was reacted with 2-Chloro-5-
chloromethyl-
thiophene using the conditions described in Example 10C to provide 2-Chloro-5-
(4-chloro-3-nitro-
phenoxyrnethyl)-thiophene which was treated sequentially using the procedures
from Examples 10D
and 10E to provide the title product.

Example 34B
4-[4-(5 -Chloro-thiophen-2-ylmethoxy)-2-(7-methyt-pyrido[2,3 -d] pyrimidin-4-
ylamino) -
phenylsulfanyl]-phenolphenylsulfanyl]-phenol
[03311 The product of Example 34A was reacted with the product of Example lOB
using the
procedure of Example lOF substituting the product of Example 34A for the
product of Example 10E
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (6.6 mg, 10%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.72
(s, 3 H) 5.25 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.97 - 7.14 (m, 4 H) 7.19 (d,
J=8.46 Hz, 2 H) 7.72 (d,
J=8.09 Hz, 1 H) 8.71 (s, I H) 8.84 (d, J=8.46 Hz, 1 H) 9.69 (s, 1 H) 11.01 (br
s, 1 H); MS (ESI+) m/z
543 (IvI+H)+.

Example 35
4-[4-(4-Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)
phenylsulfanyl]-phenol
Example 35A
4-[2-Amino-4-(4-fluoro benzyloxy)-phenylsulfanyl]-phenol

[03321 A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-
fluoro-benzene
using the conditions described in Example lOC to provide 1-Chloro-4-(4-fluoro-
benzyloxy)-2-nitro-
benzene which was treated sequentially using the procedures from Examples 10D
and 10E to provide
the title product.

Example 35B
4-[4-(4 Fluoro-benzyloxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[03331 The product of Example 35A was reacted with the product of Example 10B
using the
procedure of Example l OF substituting the product of Example 35A for the
product of Example IOE
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (40 mg, 41%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.69
(s,3H)5.09(s,2H)6.65(m,2H)6.97(dd,J=8.64,2.39Hz, I H)7.09(m,2H)7.21
(m,4H)7.50,
(m, 2 H) 7.61 (d, J=8.46 Hz, I H) 8.61 (s, 1 H) 8.75 (d, J=8.46 Hz, 1 H) 9.65
(s, 1 H) 10.41 (s, 1 H);
MS (ESI---) m/z 485 (M+H)+.
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Example 36
3-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenoxymethyl]-benzonitrile
Example 36A
4-Methyl-3-oxo-pentanal, sodium salt

[0334] A flame-dried 100-mL flask equipped with a 25-niL addition funnel was
purged with
nitrogen gas and charged with anhydrous diethyl ether (40 mL) followed by the
addition of sodium
slivers (1.65 g, 0.0725 mol). The reaction mixture was cooled to ice/water
bath temperature and a
solution of methyl isopropyl ketone (6.244 g, 0.0725 mol) and ethyl formate
(5.481 g, 0.0725 mol) in
anhydrous diethyl ethei- (5 mL) was added slowly dropwise over 1.5 hours, at 0
C. After the addition
was complete the cooling bath was removed and the 'reaction mixture stirred at
room temperature
overnight. Additional ether (10 mL) was then added to break up the resulting
precipitate, and the
solid was isolated quickly by vacuum filtration. The solid was rinsed with
small amounts of ether and
then dried in a vacuum desiccator for one hour to provide the title product as
an off-white solid (5.35
g, 54% yield). This material was used in the next step without further
purification.

Example 36B
6-Isopropyl-2-oxo 1,2-dihydro-pyridine-3-carbonitrile

[0335] To a solution of the product of Example 36A (5.35 g, 0.0393 mol) and 2-
cyanoacetamide
(3.47 g, 0.0413 mol) in water (35 mL) was stirred at room temperature for 10
minutes. To this
mixture was added 2.5 mL of a stock piperidine acetate solution (prepared from
9.8 mL of piperidine,
6 rnL of acetic acid and 10 mL of water), and the solution was heated under
reflux for 2 hours. The
mixture was then cooled to room temperature and taken to pH 4 by the addition
of glacial acetic acid.
The resulting light yellow solid was isolated by vacuum filtration, rinsed
with water (2 x 30 mL), and
dried under vacuum to provide the title product (4.36 g, 68%).

Example 36C
2-Bromo-6-isopropyl-nicotinonitrile
[03361 To a solution of the product of Example 36B (4.35 g, 0.0269 mol),
tertrabutylammonium
bromide (10.4 g, 0.0323 mol) and phosphorous pentoxide (8.01 g, 1.05 mol) in
toluene (80 mL) was
heated under reflux for 5 hours. The reaction mixture was then cooled to room
temperature, water (80
mL) was added, and the mixture was stirred for 2 h at room temperature. The
reaction mixture was
diluted with toluene (20 mL) and the organic layer separated. The aqueous
layer was washed with
toluene (50 mL) and the combined organic layers were washed with brine (50
mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated under vacuum to
provide the title product as
a yellow oil (5.64 g, 93 Jo).

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Example 36D
2-Amino-6-isopropyl-nicotinonitrile
[0337] To a solution of the product of Example 36C (21 g, 0.093 mol) and
liquid ammonia (250
mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 130
C for 20 hours. The
reaction mixture was concentrated under vacuum and the residue ground to a
fine powder then
washed with water (2 x 50 mL) and dried in a vacuum oven for 24 hours to
provide the title
compound as a beige solid (14 g, 93%).

Example 36E
N'-(3-Cyano-6-isopropyl-pyridin-2-yl) TI-1V-dimethyl-formamidine

[0338] To a solution of the product of Example 36D (7.1g, 0.044 mol) and N,N-
Dimethylformatnide dimethyl acetal (6.44 mL, 0.0484 mol) in toluene (100 mL)
was heated at reflux
for 3 hours. The resulting solution was cooled to room temperature and
concentrated under vacuum
to provide the title compound (9.5 g, 100%) as a thick brown oil that
solidified upon standing.
Although this material appears to be pure by NMR, it contains small amounts of
highly colored
impurities. It can be chromatographed on silica gel (ethyl acetate/hexane
gradient) to provide a
slightly yellow oil that solidifies upon standing (about 70% recovery from
chromatography).

Example 36F
3-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile
[0339] The title compound was prepared according to the procedure of Example
10C substituting
3-bromomethyl-benzonitrile for 1-chloromethyl-4-methoxy-benzene (0.813 g,
98%).

Example 36G
3-[4-(4-Hydroxy-phenylsulfanyl)-3-nitro-phenoxymethyl]-benzonitrile
[0340] The title compound was prepared according to the procedure of Example l
OD substituting
3-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile for 1-Chloro-4-(4-methoxy-
benzyloxy)-2-nitro-
benzene (1.07 g, 100%).

Example 36H
3-[3-Amino-4-(4-hydroxy-phenylsulfanyl)-phenoxymethyl]-benzonitrile
[0341] The title compound was prepared according to the procedure of Example
10E substituting
3-[4-(4-Hydroxy-phenylsulfanyl)-3-nitro phenoxymethyl]-benzonitrile for 4-[4-
(4-Methoxy-
benzyloxy)-2-nitro-phenylsulfanyl]-phenol (0.97 g, 98%).

Example 361
3-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenoxymethyl]-beinzonitrile

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[0342] A solution of the product of Example 36E (47.4 mg, 0.219 mmol), and the
product of
Example 36H (76.3 rng, 0.219 mmol) in acetic acid (I mL) was stirred in an oil
bath preheated to
130 C for 15 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue purified by reverse phase preparative
HPLC on a Waters
Symmetry C8 column (25mm x 100mm, 7 m particle size) using a gradient of 10%
to 100%
acetonitrile/0.1% trifluoroacetic acid in water over 8 minutes (10 minutes run
time) at a flow rate of
40mL/rnin to provide the title compound as a trifluoroacetic acid salt (14 mg,
10%). iH NMR (300
MHz, DMSO-d6) S ppm: 10.94 (s, 1 H), 9.69 (s, I H), 8.88 (d, J=8.46 Hz, 1 H),
8.70 (s, 1 H), 7.92 (s,
I H), 7.72 - 7.87 (m, 3 H), 7.62 (t, J=7.72 Hz, 1 H), 7.15 - 7.28 (m, J=8.82
Hz, 2 H), 7.08 - 7.15 (m,
2 H), 6.99 - 7.06 (m, I H), 6.61 - 6.72 (m, 2 H), 5.18 (s, 2 H), 3.19 - 3.30
(m, I H), 1.34 (d, J=6.99
Hz, 6 H); MS(ESl) m/z 520.3 (M+H)+, (ESI-) m/z 518.3 (M-H)-.

Example 37
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(2-methoxy-benzyl oxy)-
phenylsulfanyl]-
phenol

Example 37A
4-[2-Amino-4-(2-methoxy benzyloxy)-phenylsulfanyl]-phenol

[0343] A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-2-
methyl-benzene
using the conditions described in Example lOC to provide 1-Chloro-4-(2-methyl-
benzyloxy)-2-nitro-
benzene which was treated sequentially using the procedures from Examples IOD
and 10E to provide
the title product.

Example 37B
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(2-methoxy-benzyloxy)-
phenylsulfanyl)-
phenol

[0344] The product of Example 37A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 37A for the
product of Example 36H
to provide a solid which was triturated with methanol to provide the title
compound (31 mg, 31%).
1H NMR (500 MHz, DMSO-D6) S ppm: 9.88 (s, I H), 9.57 (s, 1 H), 8.73 (d, J=5.49
Hz, I H), 8.56 (s,
I H), 7.58 (d, J=7.32 Hz, 1 H), 7.40 (dd, J=7.63, 1.53 Hz, 1 H), 7.31 - 7.37
(m, 1 H), 7.30 (s, I H),
7.18 (d, J=6.10 Hz, I H), 7.11 (d, J=8.54 Hz, 2 H), 7.05 (d, J=7.93 Hz, 1 H),
6.97 (t, J=7.32 Hz, 1 H),
6.93 (s, 1 H), 6.67 (d, J=8.54 Hz, 2 H), 5.06 (s, 2 H), 3.80 (s, 3 H), 3.16 -
3.25 (m, 1 H), 1.33 (d,
J=6.71 Hz, 6 H); MS (ESI+) mlz 525.2 (M+H)+ (ESI-) m/z 523.2 (M-H)-.

Example 38
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-(4-methoxy-benzyloxy)-
phenylsulfanyl]-
phenol



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[0345] The product from Example IOE was reacted with the product of Example
36E following
the procedure of Example 361 substituting the product of Example 10E for the
product of Example
36H to provide a solid which was triturated with methanol to provide the title
compound (43 mg,
49%). IH NMR (300 MHz, DMSO-D6) S ppm: 9.93 (s, 1 H), 9.63 (s, 1 H), 8.75 (d,
J=8.46 Hz, I H),
8.57 (s, 1 H), 7.60 (d, J=8.09 Hz, I H), 7.38 (d, J=8.46 Hz, 2 H), 7.27 (s, 1
H), 7.05 - 7.19 (m, 3 H),
6.85 - 7.00 (m, 3 H), 6.67 (d, J=8.82 Hz, 2 H), 5.02 (s, 2 H), 3.75 (s, 3 H),
3.14 - 3.28 (m, I H), 1.32
(d, J=6.62 Hz, 6 H); MS (ESI+) m/z 525.3 (M+H)+ (ESI-) m/z 523.3 (M-H)-.

Example 39
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl amino)-4-(1-phenyl-ethoxy)-
phenylsulfanyl]-phenol
Example 39A
4-[2-Amuno-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenol
[0346] A solution of 1-(3-fluoro-phenyl)-ethanol was converted to 1-(1-Bromo-
ethyl)-3-fluoro-
benzene using the conditions described in Example 22A which was treated
sequentially using the
procedures from Examples 22B-22D to provide the title product.

Example 39B
4-[2-(7-Isopropyl-pyrido [2,3-d]pyrimidin-4-ylamino)-4-(1-phenyl-ethoxy)-
phenylsulfanyl]-phenol
[0347] The product from Example 39A was reacted with the product from Example
36E
following the procedure from Example 3 61 substituting the product of Example
39A for the product of
Example 36H to provide the crude title compound which was purified by HPLC
with TFA to provide
the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S
ppm: 1.34 (d,
J=6.99 Hz, 6 H) 1.55 (d, J=6.25 Hz, 3 H) 3.14 - 3.29 (m, 1 H) 5.49 (q, J=6.37
Hz, 1 H) 6.63 (d, =J=8.82
Hz, 2 H) 6.89 (dd, J=8.82, 2.57 Hz, 1 H) 7.09 (dd, J=9.01, 2.76 Hz, 3 H) 7.19 -
7.48 (m, 6 H) 7.75 (d,
J--8.82 Hz, 1 H) 8.67 (s, 1 H) 8.83 (d,_ J=8.46 Hz, 1 H) 9.67 (s, 1 H) 10.85
(s, I H); MS ESI+ (m/z)
509, ESI- (m/z) 507.

Example 40
4-[4-[ 1-(4-Bromo-phenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl]-phenol
[0348] The product from Example 22D (211 mg, 0.506 mrnol) was reacted with the
product from
Example 36E (109 mg, 0.506 mmol) following the procedure from Example 361
substituting the
product of Example 22D for the product of Example 36H to provide the crude
title compound which
was purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt =(150 mg,
42%). 1H NMR (300 MHz, DMSO d6) 8 ppm: 10.87 (br s,IH) 9.68 (s,1H) 8.83 (d,
J=8.45 Hz, 1H)
8.67 (s, 1H) 7.75 (d, J=7.72 Hz, 1H) 7.55d, J=8.46 Hz, 2H) 7.37 (d, J=8.46 Hz,
2H) 7.09 (m, 4H) 6.89
(dd, J=8.46 Hz, J=2.20 Hz, 1H) 6.66 (d, J=8.82 Hz, 2H) 5.50 (q, J=6.25 Hz, 2H)
3.25 (sept, J=6.99

81


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Hz, 1H) 1.53 (d, J=6.25 Hz, 3H) 1.34 (d, J=6.99 Hz, 611). MS (ESI+) m1z 587,
589 (M+H-TFA)+;
(ESI-) mlz 585, 587 (M-H-TFA)-.

Example 41
4-[4-[ 1-(3-Fluoro-phenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanylj-phenol
[0349] The product from Example 24A (197 mg, 0.555 mmol) was reacted with the
product from
Example 36E (120 mg, 0.555 mmol) following the procedure from Example 361
substituting the
product of Example 24A for the product of Example 36H to provide the crude
title compound which
was purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt (100 mg,
28%). 1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.34 (d, J=6.99 Hz, 6 H) 1.55 (d,
J=6.62 Hz, 3 H) 3.19
- 3.32 (m, J=13.70, 6.94, 6.94 Hz, 1 H) 5.53 (q, J=6.62 Hz, 1 H) 6.64 (d,
J=8.46 Hz, 2 H) 6.91 (dd,
.I--8.82, 2.57 Hz, 1 H) 7.09 (d, J=8.46 Hz, 5 H) 7.19 - 7.29 (m, 2 H) 7.39
(dd, J=8.09, 5.88 Hz, 1 H)
7.78 (d, J=8.46 Hz, I H) 8.68 (s, I H) 8.85 (d, J=8.46 Hz, 1 H) 9.70 (s, 1 H);
MS (ESI+) m/z 527
(1vI+H)+.

Example 42
4-[2-(7-Isopropyl-pyrido[2,3-d)pyrimidin-4-ylamino)-4-(3 -trifluoromethyl-
benzyloxy)-
phenylsulfanyl)-phenol

[0350] The product from Example 26A was reacted with the product from Example
36E
following the procedure from Example 361 substituting the product of Example
26A for the product of
Example 36H to provide the crude title compound which was purified by HPLC
with TFA to provide
the title compound as a trifluoroacetic acid salt (22 mg, 21%). 1H NMR (300
MHz, DMSO-D6) 8
ppm: 1.34 (d, J=6.99 Hz, 6 H), 5.22 (s, 2 H), 6.65 (d, J=8.46 Hz, 2 H), 7.01 -
7.13 (m, 3 H), 7.20 (d,
J=8.82 Hz, 2 H), 7.66 (d, J=7.35 Hz, 1 H), 7.70 - 7.82 (m, 4 H), 8.68 (s, 1
H), 8.87 (d, J=8.46 Hz, 1
H), 9.68 (s, 1 H); MS ESI+ m/z 563 (M+H)+,ESI- m/z 561 (M-H)-.

Example 43
4-[4-(3 -Fluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenyl sul fanyl)-phenol
[03511 The product from Example 57D was reacted with the product from Example
36E
following the procedure of Example 361 substituting the product of Example 57D
for the product of
Example 36H to provide the crude title compound which was purified by HPLC
with TFA to provide
the title compound as a trifluoroacetic acid salt (26 mg, 51%). IH NMR (300
MHz, DMSO-D6) 8
ppm: 1.35 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 5.14 (s, 2 H) 6.65 (m, 2 H) 7.16
(m, 8 H) 7.44 (m, I H)
7.81 (d, J=8.46 Hz, 1 H) 8.73 (s, I H) 8.90 (d, J=8.46 Hz, 1 H) 9.69 (s, 1 H)
11.08 (s, 1 H); MS
(ESI+) rn/z 513 (M+H)+.

Example 44
4-[4-(4 Fluoro-benzyloxy)-2-(7-isopropyl pyrido[2,3-djpyrimidin-4 ylamino)-
phenylsulfanylj-phenol
82 .


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[0352] The product of Example 35A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 35A for the
product of Example 36H
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (23 mg, 45%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 1.35
(d, J=6.99 Hz, 6 H) 3.26 (m, 1 H) 5.09(s,2H)6.62 (m,2H)7.14(m, 7 H) 7.48 (m, 2
H) 7.81 (d,
J=8.46 Hz, 1 H) 8.73 (s, 1 H) 8.90 (d, J=8.46 Hz, I H) 9.68 (s, 1 H) 11.12 (s,
1 H); MS (ESI+) m/z
513 (M+H)+.

Example 45
4-[4-[ 1-(4-Fluoro-phenyl)-ethoxy]-2-(7-isopropyl-pyrido[2,3-d]pyrimi din-4-yl
amino)-
phenylsulfanyl) -phenol

[03531 The product from Example 23A (180 mg, 0.5 10 mmol) was reacted with the
product from
Example 36E (110 mg, 0.510 mmol) following the procedure from Example 361
substituting the
product of Example 23A for the product of Example 36H to provide the crude
title compound which
was purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt (35 mg,
12%). 1H NMR (300 MHz, DMSO-D6) S ppm: 1.35 (d, J=6.99 Hz, 6 H) 1.54 (d,
J=6.62 Hz, 3 H)
3.23 - 3.34 (m, 1 H) 5.52 (q, J=5.88 Hz, 1 H) 6.63 (d, J=8.82 Hz, 2 H) 6.94
(dd, J=8.82, 2.57 Hz, 1 H)
7.08 (m, J=8.82 Hz, 4 H) 7.14 (d, J=4.78 Hz, 1 H) 7.17 - 7.21 (m, I H) 7.41 -
7.49 (m, 2 H) 7.86 (d,
J=8.82 Hz, 1 H) 8.76 (s, 1 H)=8.91 (d, J=8.46 Hz, 1 H); MS (ESI+) rn/z 527
(M+H)+.

Example 46
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4 ylamino)-4-(3-methoxy-benzyloxy)-
phenylsulfanyl]-
phenol

[0354] The product of Example 31A was reacted with the product of Example 3 6E
using the
procedure of Example 361 substituting the product of Example 31A for the
product of Example 36H
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (23 ing, 45%). 1H NMR (300 MHz, DMSO-
D6) 8 ppm: 10.98
(s, I H), 9.67 (s, 1 H), 8.88 (d, J=8.09 Hz, 1 H), 8.70 (s, 1 H), 7.78 (d,
J=8.09 Hz, I H), 7.31 (t, J=8.09
Hz, 1 H), 7.15 - 7.24 (m, J=8.82 Hz, 2 H), 7.06 - 7.15 (m, 2 H), 6.95 - 7.05
(m, J=6.62 Hz, 3 H), 6.90
(dd, J=7.72, 2.21 Hz, 1 H), 6.54 - 6.73 (m, 2 H), 5.09 (s, 2 H), 3.75 (s, 3
H), 3.19 - 3.28 (m, I H), 1.34
(d, J=6.99 Hz, 6 H); MS (BSI+) m/z 525.2 (M+H)+ (ESI-) mfz 523.2(M-H)-.

Example 47
4-[4-(3-Bromo benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl)-phenol
[03551 The product of Example 15A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 15A for the
product of Example 36H
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
83


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compound as, a trifluoroacetic acid salt (16 mg, 28%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 1.33
(d, J=6.62 Hz, 6 H) 3.21 (m, 1 H) 5.13 (s, 2 H) 6.68 (d, J=8.82 Hz, 2 H) 6.95
(dd, J=8.64, 2.76 Hz, I
H) 7.12 (m, 3 H) 7.34 (m, 2 H) 7.50 (m, 2 H) 7.60 (d, J=8.82 Hz, 1 H) (s, I H)
8.57 (s, 1 H) 8.76 (d,
J=8.46 Hz, 1 H) 9.65 (s, 1 H) 9.95 (s, 1 H); MS (ESI+) m/z 573, 575 (M+H)+.

Example 48
4-[4-(4 Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0356] The product of Example 16A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 16A for the
product of Example 36H
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (28 mg, 49%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 1.32
(d, J=6.99 Hz, 6 H) 3.22 (m, 1 H) 5.10 (s, 2 H) 6.67 (d, J=8.46 Hz, 2 H) 6.94
(dd, J=8.82, 2.57 Hz, 1
H) 7.12 (m, 3 H) 7.28 (d, J=2.57 Hz, 1 H) 7.41 (d, J=8.46 Hz, 2 H) 7.59 (m, 3
H) 8.56 (s, 1 H) 8.75 (d,
J=8.46 Hz, 1 H) 9.65 (s, 1 H) 9.94 (s, I H); MS (ESI+) m/z 573, 575 (M+H)+.

Example 49
4-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenoxymethyl]-benzonitrile

[0357] The product of Example 21A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 21A for the
product of Example 36H
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (32 mg, 26%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 10.91
(s, I H), 9.69 (s, 1 H), 8.87 (d, J=9.19 Hz, 1 H), 8.69 (s, I H), 7.88 (d,
J=8.09 Hz, 2 H), 7.77 (d,
J=8.46 Hz, 1 H), 7.64 (d, J=8.46 Hz, 2 H), 7.15 - 7.26 (m, J=8.82 Hz, 2 H),
7.08 - 7.15 (m, 2 H), 7.01
(d, J=8.82 Hz, 1 H), 6.58 - 6.72 (m, 2 H), 5.23 (s, 2 H), 3.20 - 3.31 (m, 1
H), 1.34 (d, J=6.99 Hz, 6 H);
MS (ESI+) m/z 520.2 (M+H)+ (ESI-) m/z 518.2 (M-H)-.

Example 50
2-[4-(4-Hydroxy-phenylsulfanyl)-3 -(7-isopropyl-pyrido [2,3 -d]pyrimidin-4-
ylamino)-
phenoxymethyl] benzonitiile

[0358] The product of Example 20A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 20A for the
product of Example 36H
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (11 mg, 9%). 1H NMR (300 MHz, DMSO-D6)
5 ppm: 11.30
(s, 1 H), 9.71 (s, I H), 8.93 (d, J=8.82 Hz, 1 H), 8.76 (s, 1 H), 7.92 (d,
J=7.35 Hz, 1 H), 7.84 (d,
J=8.82 Hz, 1 IT), 7.72 - 7.80 (m, 2 H), 7.59 (ddd, J=7.72, 6.25, 2.58 Hz, 1
H), 7.19 - 7.28 (m, 2 H),
7.06 - 7.17 (m, 3 H), 6.64 - 6.69 (m, 2 H), 5.25 (s, 2 H), 3.22 - 3.33 (m, 1
H), 1.35 (d, J=6.99 Hz, 6
H); MS (ESI+) m/z 520.2 (M+H)+ (ESI-) m/z 518.2 (M-H)-.

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Example 51
4-[4-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol

[0359] The product of Example 27A was reacted with the product of Example 36E
using the
procedure of Example 361 substituting the product of Example 27A for the
product of Example 36H
to provide a solid which was triturated with methanol to provide the title
compound. 1H NMR (300
MHz, DMSO-D6) S ppm: 1.32 (d, J=6.62 Hz, 6 H) 3.10 - 3.30 (m, 1 H) 5.11 (s, 2
H) 6.67 (d, J=8.82
Hz,2H)6.90-6.99(m,1H)7.07-7.19(m,1H)7.11(d,J=8.82Hz,2H)7.23-7.52(m,6H)7.59
(d, J=8.09 Hz, 1 H) 8.56 (s, 1 H) 8.75 (d, J=8.09 Hz, 1 H) 9.64 (s, 1 H) 9.95
(s; 1 H); MS (DCI/NH3)
m/z 495 (M+H)+.

Example 52
3-[3-[7-(1-Hydroxy-l-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(4-
hydroxy-
phenylsulfanyl)-phenoxymethyl]-benzonitrile

The product from Example 36E (45.9 mg, 0.212 mmol) and the product from
Example 36H (73.5 mg,
0.212 mmol) in acetic acid (1 mL) was gradually heated form room temperature
to 130 C in an oil
bath over a 15 minute time period, followed by heating at 130 C for an
additional 1.5 hours. The
mixture was then cooled to room temperature, concentrated under vacuum to
provide the crude title
compound which was purified by reverse phase preparative HPLC on a Waters
Symmetry C8 column
(25rnm x 100mm, 7 m particle size) using a gradient of 10% to 100%
acetonitrile/0.1 fo
trifluoroacetic acid in water over 8 minutes (10 minutes run time) at a flow
rate of 40rnL/min to
provide the title compound as the trifluoroacetic acid salt (22 mg, 20%). 'H
NMR (300 MHz, DMSO-
d6) S ppm: 11.76 (s, 1 H), 9.72 (s, I H), 9.06 (d, J=8.09 Hz, 1 H), 8.83 (s, 1
H), 8.20 (d, J=8.46 Hz, 1
H), 7.92 (s, I H), 7.75 - 7.88 (m, 2 H), 7.63 (t, J=7.72 Hz, 1 H), 7.21 - 7.26
(m, 1 H), 7.19 (d, J=2.57
Hz, 1 H), 7.07 - 7.15 (m, 3 H), 6.64 (d, J=8.46 Hz, 2 H), 5.18 (s, 2 H), 1.56
(s, 6 H); MS (ESI) M/z
536.2 (M+H)+, (ESI-) m/z 534.2 (M-H)-.

Example 53
2-[3-[7-(1-Hydroxy-l-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(4-
hydroxy-
phenylsulfanyl)-phenoxymethyl] benzonitrile

[0360] The product of Example 20A was reacted with the product of Example 36E
using the
procedure of Example 52 substituting the product of Example 20A for the
product of Example 36H to
provide the crude title compound which was purified by.HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (11 mg, 11%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 11.73
(s, 1 H), 9.75 (s, 1 H), 9.05 (d, J=8.46 Hz, 1 H), 8.84 (s, 1 H), 8.20 (d,
J=8.82 Hz, 1 H), 7.92 (d,
J=7.35 Hz, 1 H), 7.69 - 7.84 (m, 2 H), 7.54 - 7.64 (m, 1 H), 7.23 - 7.27 (m, 1
H), 7.21 (d, J=2.57 Hz, I


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H), 7.10 - 7.17 (m, 3 H), 6.64 - 6.69 (m, 2 H), 5.25 (s, 2 H), 1.56 (s, 6 H);
MS (ESI+) m/z 536.2
(M+H)+ (ESI-) m/z 534.3 (M-H).

Example 54
4-[3-[7-(1-Hydroxy-l-methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(4-
hydroxy-
phenylsulfanyl)-phenoxymethyl] benzonitrile

[03611 The product of Example 21A was reacted with the product of Example 36E
using the
procedure of Example 52 substituting the product of Example 21A for the
product of Example 36H to
provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (10 mg, 10%). 1H NMR (300 MHz, DMSO-
D6) 6 ppm: 11.64
(s, 1 H), 9.73 (s, 1 H), 9.05 (s, 1 H), 8.82 (s, I H), 8.19 (d, J=8.82 Hz, I
H), 7.88 (d, J=8.09 Hz, 2 H),
7.64 (d, J=8.46 Hz, 2 H), 7.23 (d, J=8.82 Hz, 1 H), 7.18 (d, J=2.57 Hz, 1 H),
7.04 - 7.15 (m, 3 H), 6.62
- 6.69 (m, 2 H), 5.23 (s, 2 H), 2.54 (s, 1 H), 1.56 (s, 6 H); MS (ESI+) m/z
536.2 (M+H)+ (ESI-) m/z
534.2 (M-H)-.

Example 55
4-[2-[7-(1-Hydroxy-I -methyl-ethyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-4-(2-
methoxy-benzyloxy)-
phenylsulfanyl]-phenol
[0362] The product of Example 37A was reacted with the product of Example 36E
using the
procedure of Example 52 substituting the product of Example 37A for the
product of Example 36H to
provide a solid which was triturated with methanol to provide the title
compound (8 mg, 8%). 1H
NMR (300 MHz, DMSO-D6) S ppm: 11.81 (s, 1 H), 9.40 - 9.95 (m, 1 H), 9.06 (d,
J=8.46 Hz, 1 H),
8.85 (s, 1 H), 8.21 (d, J=8.46 Hz, 1 H), 7.31 - 7.44 (m, 2 H), 7.25 (d, J=8.46
Hz, 1 H), 7.15 (d, J=2.57
Hz, 1 H), 7.02 - 7.14 (m, 4 H), 6.97 (t, J=7.54 Hz, 1 H), 6.61 - 6.67 (m, 2
H), 5.05 (s, 2 H), 3.80 (s, 3
H), 2.54 (s, 1 H), 1.56 (s, 6 H); MS (ESI+) m/z 541.2 (M+H)+ (ESI-) m/z 539.2
(M-H)-.

Example 56
4- {4-(4-Bromo-benzyloxy)-2-[7-(1-hydroxy-l-m.ethyl-ethyl)-pyrido[2,3-
d]pyrimidin-4-ylamino]-
phenylsulfanyl} -phenol

[0363] The product of Example 16A was reacted with the product of Example 36E
using the
procedure of Example 52 substituting the product of Example 16A for the
product of Example 36H to
provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (8 mg, 13%). IH NMR (300 MHz, DMSO-D6)
S ppm: 1.55
(s, 6 H) 2.08 (s, 1H)5.10(s,2H)6.65(d,J=8.46Hz,2H)7.13(m,5H)7.41
(d,J=8.46Hz,2H)
7.60 (d, J=8.09 Hz, 2 H) 8.15 (d, J=8.46 Hz, 1 H) 8.77 (s, 1 H) 9.00 (d,
J=8.46 Hz, l H) 9.70 (s, I H)
11.43 (s, 1 H); MS (ESI+) m/z 589, 591 (M+H)+.

Example 57
4-[4-(3-Fluoro-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylarnino)-
phenylsulfanyl] phenol
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Example 57A
N'-(3-Cyano-pyridin-2-yl)-N,N-dimethyl-formamidine

[0364] A solution of 2-Amino-nicotinonitrile (5 g, 42 mmol) and N,N-
Dimethylformamide
dimethyl acetal (6.13 mL, 46.2 mmol) in toluene (20 mL) was heated at reflux
for 3 hours. After
cooling to room temperature, the solution was concentrated under vacuum to
provide the title
compound (7.3 g, 100%). =

Example 57B
1 -Chloro-4-(3 -fluorobenzyloxy)-2-nitro-benzene

[0365] The title compound was prepared according to the procedure of Example
lOC substituting
1-Bromomethyl-3-fluoro-benzene for 1-chloromethyl-4-methoxy-benzene (0.56 g,
100%).

Example 57C
4-[4-(3 Fluoro-benzyloxy)-2-nitro phenylsulfanyl]-phenol

[03661. The title compound was prepared according to the procedure of Example
I OD substituting
l -Chloro-4-(3-fluoro-benzyloxy)-2-nitro-benzene for 1-Chloro-4-(4-methoxy-
benzyloxy)-2-nitro-
benzene (0.57 g, 77%).

Example 57D
4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol
[0367] The title compound was prepared according to the procedure of Example
10E substituting
4-[4-(3-Fluoro-benzyloxy)-2-nitro-phenylsulfanyl]-phenol for 4-[4-(4-Methoxy-
benzyloxy)-2-nitro-
phenylsulfanyl]-phenol (0.501 g, 96%).

Example 57E
4-[4-(3-Fluoro benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino) phenylsulfanyl)-
phenol

[0368] A solution of the product from Example 57A (35 mg, 0.2 mmol) and the
product from
Example 57D (68 mg, 0.2 mmol) in acetic acid (1 mL) was gradually heated form
room temperature
to 130 C in an oil bath over a 15 minute time period, followed by heating at
130 C for an additional
1.5 hours. The mixture was then cooled to room temperature, concentrated under
vacuum to provide
the crude title compound which was purified by reverse phase preparative HPLC
on a Waters
Symmetry C8 column (25mm x 100mm, 71im particle size) using a gradient of 10%
to 100%
acetonitrile/0.1% trifluoroacetic acid in water over 8 minutes (10 minutes run
time) at a flow rate of
40mL/min to provide the title compound as the trifluoroacetic acid salt (28
mg, 30%). 'H NMR (300
MHz, DMSO-d6) S ppm: 5.14 (s, 2 H) 6.65 (m, 2 H) 7.14 (m, 8 H) 7.49 (m, 1 H)
7.66 (m, I H) 8.61
(s, 1 H) 8.88 (d, J=7.47 Hz, 1 H) 9.07 (s, 1 H) 9.65 (s, 1 H) 10.34 (s, 1 H);
MS (ESI) m/z 471
(M+H)+.
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Example 58
4-[4-(2-Methyl-benzyl oxy)-2-(pyrido[2,3-d]pyrimi din-4-ylamino)-phenylsul
fanyl]-phenol
[0369] The product of Example 17A was reacted with the product of Example 57A
using the
procedure of Example 57E substituting the product of Example 17A for the
product of Example 57D
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (50 mg, 54%). 1 H NMR (300 MHz, DMSO-
D6) S ppm: 2.31
(s, 3 H) 5.09 (s, 2 H) 6.66 (m, 2 H) 7.01 (in, I H) 7.19 (m, 7 H) 7.42 (d,
J=6.99 Hz, 1 H) 7.71 (dd,
J=7.91, 4.23 Hz, I H) 8.63 (s, I H) 8.89 (d, J=7.35 Hz, 1 H) 9.09 (s, 1 H)
9.66 (s, 1 H) 10.50 (s, 1 H);
MS (ESI+) m/z 467 (M+H)+.

Example 59
4-[4-(4-Methyl-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[0370] The product of Example 19A was reacted with the product of Example 57A
using the
procedure of Example 57E substituting the product of Example 19A for the
product of Example 57D
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (45 mg, 48%). 1H NNHZ. (300 MHz, DMSO-
D6) S ppm: 2.30
(s, 3 H) 5.05 (s, 2 H) 6.65 (m, 2 H) 7.10 (m, 7 H) 7.33 (d, J=8.07 Hz, 2 H)
7.69 (dd, J=8.27, 4.23 Hz,
1 H) 8.62 (s, 1 H) 8.87 (d, J=7.72 Hz, I H) 9.07 (s, 1 H) 9.64 (s, 1 H) 10.42
(s, 1 H); MS (ESI+) mlz
467 (M+H)+.

Example 60
4-[4-(2-Bromo-benzyloxy)-2-(pyrido [2,3-d]pyrimidin-4-yl amino)-
phenylsulfanyl]-phenol
[0371] The product of Example 14A was reacted with the product of Example 57A
using the
procedure of Example 57E substituting the product of Example 14A for the
product of Example 57D
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (40 mg, 38%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 5.13
(s, 2 H) 6.66 (m, 2 H) 6.99 (d, J=8.43 Hz, 1 H) 7.15 (m,3H)7.35 (m,3H)7.64(m,3
H) 8.60 (s, 1 H)
8.85 (d, J=7.32 Hz, I H) 9.07 (s, I H) 9.66 (s, 1 H) 10.28 (s, 1 H); MS (ESI+)
m/z 531, 533 (M+H)+.
Example 61
3-[4-(4-Hydroxy phenylsulfanyl)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxymethyl]-benzonitrile
[0372] The product from Example 36H and the product from Example 57A were
reacted
according to the procedure in Example 57E substituting the product of Example
36H for the product
of Example 57D to provide a solid which was triturated with methanol to
provide the title compound
(44 mg, 44%). 1H NMR (300 MHz, DMSO-D6) 8 ppm: 10.08 (s, I H), 9.65 (s, 1 H),
9.06 (s, 1 H),
8.86 (s, I H), 8.58 (s, 1 H), 7.92 (s, I H), 7.77 - 7.86 (m, 2 H), 7.54 - 7.70
(m, J=7.72, 7.72 Hz, 2 H),
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7.28 (s, 1 H), 7.07 - 7.19 (m, 3 H), 6.97 (s, 1 H), 6.63 - 6.72 (m, 2 H), 5.18
(s, 2 H); MS (ESI+) m/z
478.2 (M+H)+, (ESI-) rn/z 476.1 (M-H)-.

Example 62
4-[4-(3-Methyl-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[0373] The product of Example 18A was reacted with the product of Example 57A
using the
procedure of Example 57E substituting the product of Example 18A for the
product of Example 57D
to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (50 mg, 54%). 1H NMR (300 MHz, DMSO-
D6) 5 ppm: 2.31
(s, 3 H) 5.07 (s, 2 H) 6.65 (m, 2 H) 7.12 (m, 9 H) 7.78 (dd, J=8.10 Hz, 4.77
Hz, 1 H) 8.72 (s, I H)
8.94 (d, J=7.47 Hz, I H) 9.12 (d, J=3.15 Hz, 1 H) 9.67 (s, 1 H) 11.03 (s, I
H); MS (ESI+) m/z 467
(M+H)+.

Example 63
4-[4-(4-Methoxy-benzyloxy)-2-(pyrido[2,3 -d]pyrimidin-4-ylamino)-phenylsul
fanyl]-phenol
[03741 The product from Example 10E and the product from Example 57A were
reacted
according to the procedure in Example 57E substituting the product of Example
10E for the product
of Example 57D to provide a solid which was triturated with methanol to
provide the title compound
(49 mg, 55%). 1H NMR (300 MHz, DMSO-D6) S ppm: 10.07 (s, 1 H), 9.63 (s, I H),
9.05 (s, I H),
8.83 (s, 1 H), 8.58 (s, I H), 7.64 (s, I H), 7.38 (d, J=8.46 Hz, 2 H), 7.20 -
7.29 (m, 1 H), 7.12 - 7.18
(m, I H), 7.06 - 7.12 (m, 2 H), 6.90 - 6.99 (m, 3 H), 6.62 - 6.69 (m, 2 H),
5.02 (s, 2 H), 3.75 (s, 3 H);
MS (ESI+) m/z 483.2 (M+H)+, (ESI-) m/z 481.2 (M-H)-.

Example 64
4-[4-(2-Methoxy benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[03751 The product of Example 37A was reacted with the product of Example 57A
using the
procedure of Example 57E substituting the product of Example 37A for the
product of Example 57D
to provide a solid which was triturated with methanol to provide the title
compound (47 mg, 56%).
IH NMR (300 MHz, DMSO-D6) S ppm: 10.08 (s, I H), 9.63 (s, I H), 9.07 (s, 1 H),
8.85 (d, J=6.62
Hz, I H), 8.59 (s, 1 H), 7.64 (s, 1 H), 7.41.(dd, J=7.35, 1.47 Hz, 1 H), 7.30 -
7.38 (m, 1 H), 7.24 (s, 1
H), 7.16 (d, J=8.46 Hz, I H), 7.08 - 7.14 (m, 2 H), 7.05 (d, J=8.09 Hz, 1 H),
6.89 - 7.01 (m, J=7.54,
7.54 Hz, 2 H), 6.61 - 6.71 (m, 2 H), 5.05 (s, 2 H), 3.80 (s, 3 H); MS (ESI+)
m/z 483.2 (M+H)+,
(ESI-) m/z 481.2 (M-H)-.

Example 65
4-[4-(4-Hydroxy-phenylsulfanyl)-3-(pyrido[2,3-d]pyrimi din-4-ylamino)-
phenoxymcthyl]-benzonitrile
[03761 The product of Example 21A was reacted with the product of Example 57A
using the
procedure of Example 57E substituting the product of Example 21A for the
product of Example 57D
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to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (6 mg, 6%). IH NMR (300 MHz, DMSO-D6)
S ppm: 11.17
(s, I H), 9.69 (s, 1 H), 9.09 - 9.20 (m, J=3.68 Hz, 1 H), 8.97 (d, J=8.82 Hz,
1 H), 8.74 (s, 1 H), 7.78 -
7.96 (m, 3 H), 7.64 (d, J=8.46 Hz, 2 H), 7.20 (d, J=8.46 Hz, 2 H), 7.07 - 7.16
(m, 2 H), 7.03 (d, J=6.25
Hz, I H), 6.57 - 6.70 (m, 2 H), 5.23 (s, 2 H); MS (ESI+) m/z 478.2 (M+H)+,
(ESI-) m/z 476.2 (M-
H)-.

Example 66
4-[4-(3-1Vlethoxy-benzyloxy)-2-(pyrido [2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[03771 The product from Example 31A and the product from Example 57A were
reacted
according to the procedure in Example 57E substituting the product of Example
31A for the product
of Example 57D to provide a solid which was triturated with methanol to
provide the title compound
(38 mg, 45%). 1H NMR (300 MHz, DMSO-D6) S ppm: 10.07 (s, I H), 9.63 (s, 1 H),
9.07 (s, 1 H),
8.86 (d, J=7.72 Hz, i H), 8.59 (s, 1 H), 7.64 (s, 1 H), 7.23 - 7.36 (m, 2 H),
7.16 (dd, J=8.64, 1.65 Hz, I
H), 7.07 - 7.13 (m, 2 H), 6.93 - 7.05 (m, 3 H), 6.89 (dd, J=8.27, 2.02 Hz, 1
H), 6.61 - 6.71 (m, 2 H),
5.08 (s, 2 H), 3.75 (s, 3 H); MS (ESI+) m/z 483.2 (M+H)+, (ESI-) m/z 481.2 (M-
H)-.

Example 67
4-[4-(4-Bromo-benzyloxy)-2-(pyrido[2,3-d]pyrirnidin-4-ylamino)-phenylsulfanyl]-
phenol
[0378] The product from Example 16A and the product from Example 57A were
reacted
according to the procedure in Example 57E substituting the product of Example
16A for the product
of Example 57D to provide the crude title compound which was purified by HPLC
with TFA to
provide the title compound as a trifluoroacetic acid salt (11 mg, 16%). IH NMR
(300 MHz, DMSO-
D6) S ppm: 5.09 (s, 2 H), 6.66 (d, J=8.46 Hz, 2 H), 6.94 (s, 1 H), 7.11 (d,
J=8.46 Hz, 3 H), 7.25 (s, 1
H), 7.41 (d, J=8.09 Hz, 2 H), 7.57 - 7.69 (m, 3 H), 8.59 (s, 1 H), 8.84 (s, I
H), 9.06 (s, 1 H), 9.64 (s, 1
H), 10.07 (s, I H); MS ESI+ m/z 531 (M+H)+, ESI- m/z 529 (M-H)-.

Example 68
4-[4-(3-Bromo benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]
phenol

[0379] The product from Example 15A and the product from Example 57A were
reacted
according to the procedure in Example 57E substituting the product of Example
15A for the product
of Example 57D to provide the crude title compound which was purified by HPLC
with TFA to
provide the title compound as a trifluoroacetic acid salt (40 mg, 16%). 1H NMR
(300 MHz, DMSO-
D6) S ppm: 5.12 (s, 2 H), 6.67 (d, J=8.46 Hz, 2 H), 6.94 (s, 1 H), 7.12 (d,
J=8.46 Hz, 3 H), 7.26 (s, I
H), 7.36 (t, J=7.72 Hz, 1 H), 7.45 (s, I H), 7.54 (d, J=6.62 Hz, 1 H), 7.66
(s, 2 H), 8.57 (s, 1 H), 8.83
(s, 1 H), 9.04 (s, 1 H), 9.64 (s, 1 H), 10.08 (s, 1 H); MS ESI+ m/z 531
(M+H)+, ESI- m/z 529 (M-H)-.
Example 69


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4-[4-Benzyloxy-2-(pyrido[2,3-d]pyrimidin-4-yl amino)-phenylsulfanyl]-phenoI

[03801 The product from Example 27A and the product from Example 57A were
reacted
according to the procedure in Example 57E substituting the product of Example
27A for the product
of Example 57D to provide the title compound which was isolated as the acetic
acid salt (79 mg,
48%). 1H NMR (300 MHz, DMSO-D6) S ppm: 5.10 (s, 3 H), 6.61 - 6.72 (m, 2 H),
6.93 (d, J=9.56
Hz, 1 H), 7.11 (d, J=8.46 Hz, 4 H), 7.24 (s, 1 H), 7.32 - 7.47 (m, 5 H), 7.59 -
7.68 (m, I H), 8.54 (s, 1
H), 8.83 (d, J=9.56 Hz, 1 H), 9.04 (s, 1 H); ESI+ m/z 453 (M+H)+, ESI- m/z 451
(M-H)-.

Example 70
4-[4-[ 1-(4-Bromo-phenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0381] The product from Example 22D (153 mg, 0.367 mmol) was reacted with the
product from
Example 57A (63 mg, 0.367 mmol) following the procedure from Example 57E to
provide the crude
title compound which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (97 mg, 40%). 1H NMR (300 MHz, DMSO-d6) S ppm: 10.60
(br s, 1H) 9.67
(s, 1H) 9.09 (s, 1H) 8.88 (d, J=8.46 Hz, IH) 8.64 (s, 1H) 7.73 (m, J=3.31 Hz,
1H) 7.54 (d, J=8.46 Hz,
2H) 7.36 (d, J=8.46 Hz, 2H) 7.11 (m, 4H) 6.86 (d, J=9.19 Hz, 1H) 6.64 (d, J=
8.46 Hz, 2H) 5.51 (q,
J=6.62 Hz, 1H) 1.53 (d, J=6.62 Ha, 3H); MS (ESI+) m/z, 545, 547 (M+H-TFA)+;
(ESI-) m/z, 543,
545 (M-H-TFA)-.

Example 71
4-[4-[ 1-(4-Fluoro-phenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0382] The product from Example 23A (180 mg, 0.803 mmol) was reacted with the
product from
Example 57A (140 mg, 0.803 =mmol) following the procedure from Example 57E to
provide the crude
title compound which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (60 mg, 12%). 1H NMR (500 MHz, DMSO-D6) S ppm: 1.53
(d,.J=6.35 Hz, 3
H) 5.51 (q, 1 H) 6.61 (d, J=8.79 Hz, 2 H) 6.74 - 6.82 (m, I H) 6.93 (dd,
'J=8.79, 2.44 Hz, I H) 7.06 -
7.09 (m, 3 H) 7.11 - 7.19 (m, 2 H) 7.44 (dd, J=8.54, 5.62 Hz, 2 H) 7.83 - 7.86
(m, J=8.54, 5.13 Hz, 1
H) 8.75 (s, 1 H) 8.96 (d, J=7.32 Hz, 1 H) 9.14 (d, J=2.93 Hz, 1 H); MS (ESI+)
m/z 485.

Example 72
4-[4-[ 1-(3-FIuoro-phenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0383] The product from Example 24A (285 mg, 0.80 mmol) was reacted with the
product from
Example 57A (140 mg, 0.803 nunol) following the procedure from Example 57E to
provide the crude
title compound which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (150 mg, 31 fo). IH NivIlt. (300 MHz, DMSO-D6) S
ppm: 1.55 (d, J=6.25 Hz,
3 H) 5.53 (q, .T=6.13 Hz, I H) 6.65 (d, J--8.46 Hz, 2 H) 6.85 (d, J=6.99 Hz, 1
H) 7.03 - 7.18 (m, 4 H)
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7.21 - 7.29 (m, 2 H) 7.37 - 7.45 (m, 1 H) 7.67 (dd, J-8.09, 4.41 Hz, 1 H) 8.57
(s, IH) 8.81 (s, I H)
9.06 (s, 1 H) 9.66 (s, 1 H); MS (ESI+) m/z 485 (M+H)+.

Example 73
(5-Benzyloxy-4-chloro-2-fluoro phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
arnine
Example 73A
Carbonic acid 2-chloro-4-fluoro-phenyl ester ethyl ester

[0384] To a solution of 2-chloro-4-fluoro-phenol (0.8 mL, 7.64 rnmol) and
triethylamine (1.3 mL,
9.16 mmol) in dichloromethane (10 mL) at 0 C was added ethyl chloroformate
(0.9 mL, 9.16 mmol)
dropwise. The ice bath was removed and the solution was allowed to warm to
room temperature and
stirred for an additional 16 hours. Afterwards dichloromethane (20 mL) was
added to the mixture, the
organic solution was washed with brine (50 mL), dried over anhydrous magnesium
sulfate, filtered,
and concentrated under vacuum to provide the title product as an oil (1.65 g,
100%).

Example 73B
Carbonic acid 2-chloro-4-fluoro-5-nitro-phenyl ester ethyl ester

[0385] A solution of the product from Example 73A (0.88 g, 4.03 mmol) in
concentrated sulfuric
acid (2 mL) cooled in an ice bath was added fuming nitric acid (0.27 mL, 6.45
mmol) slowly to
maintain the temperature at 0 C. The mixture was stirred for an additional 2
hours, then_ice water (10
rnL) was added to the solution and the resultant solid was collected by
filtration washed with water
and dried in a vacuum oven to provide the title compound (0.87 g, 82%).

Example 73C
2-Chloro-4-fluoro-5-nitro-phenol
[0386] To a solution of the product from Example 73B (0.87 g, 3.30 mmol) in
methanol (20 mL)
and water (1 mL) was added sodium bicarbonate (2.22 g, 26.4 mmol) and the
mixture stirred at room
temperature for 16 hours. The methanol was then removed under vacuum,
dichloromethane (20 mL)
was added to the mixture, the organic solution was washed with brine (50 mL),
dried over anhydrous
magnesium sulfate, filtered, and concentrated under vacutim to provide the
title product (0.62 g,
98%).

Example 73D
1-Benzyl oxy-2-chloro-4-fluoro-5-nitro-benzene

[0387] The title compound was prepared according to the procedure of Example I
OC substituting
benzyl bromide and the product'from Example 73C for 1-chloromethyl-4-methoxy-
benzene and 4-
chloro-3-nitro phenol (0.72 g, 79 1 ).

Example 73E
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5-Benzyloxy-4-chloro-2-fluoro-phenylamine
[0388] The title compound was prepared according to the procedure of Example
lOD substituting
the product from Example 73D for 1-Chloro-4-(4-methoxy-benzyloxy)-2-nitro-
benzene (77 mg,
100%).

Example 73F
(5-B enzyloxy-4-chloro-2-fluoro-phenyl)-(7-rnethyl-pyrido[2,3-d]pyrimidin-4-
yl)-amine

[0389J A solution of the product of Example lOB (17 mg, 0.0927 mnnol), and the
product of
Example 73E (28 mg, 0.111 mmol) in acetic acid (1 mi.) was stirred in an oil
bath preheated to 130 C
for 15 minutes. The mixture was then cooled to room temperature, the acetic
acid removed under
vacuum, and the resultant residue was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt (8.1 mg, 17%). 1H NMR (300 MHz, DMSO-d6) S ppm: 2.72
(s, 3 H), 5.19 (s,
2 H), 7.28 - 7.53 (m, 6 H), 7.66 (d, J=9.56 Hz, 1 H), 7.70 (d, J=8.82 Hz, 1
H), 8.73 (s, 1 H), 8.84 (d,
J=8.09 Hz, I H), 10.85 (s, I H); MS(ESI) m/z 395 (M+H)+.

Example 74
(5-Benzyloxy-4-chloro-2-fluoro-phenyl)-pyrido [2,3-d]pyrimidin-4-yl-amine

[03901 The title compound was prepared according to the procedure of Example
73F substituting
the product from Example 57A for the product from Example lOB (7.9 mg, 19%).
'H NMR (300
MHz, DMSO-d6) S ppm: 5.19 (s, 2 H), 7.20 - 7.54 (m, 6 H), 7.65 (d, J=9.56 Hz,
1 H), 7.78 (dd,
J=8.27, 4.60 Hz, 1 H), 8.73 (s, 1 H), 8.95 (d, J=8.09 Hz, I H), 9.12 (d,
J=3.31 Hz, I H), 10.82 (s, 1 H);
MS (ESI+) m/z 381 (M+H)+.

Example 75
(5-Benzyloxy-2,4-difluoro-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
Example 75A
Carbonic acid 2,4-difluoro-phenyl ester ethyl ester

[03911 The title compound was prepared according to the procedure of Example
73A substituting
2,4-Difluoro-phenol for 2-chloro-4-fluoro-phenol (1.48 g, 96%).

Example 75B
Carbonic acid 2,4-difluoro-5-nitro-phenyl ester ethyl ester

[03921 The title compound was prepared according to the procedure of Example
73B.
Example 75C
2,4-Difluoro-5-nitro-phenol
[03931 The title compound was prepared according to the procedure of Example
73C substituting
the product from Example 73B for the product of 313B (0.59 g, 89%).
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Example 75D
1-Benzyloxy-2,4-difluoro-5-niiro-benzene

[0394] The title compound was prepared according to the procedure of Example
73D substituting
the product from Example 75C for the product of 313C (0.56 g, 63%).

Example 75E
5-Benzyloxy-2,4-difluoro-phenylamine
[0395] The title compound was prepared according to the procedure of Example
73E substituting
the product from Example 75D for the product of 313D (89 mg, 100%).

Example 75F
(5-Benzyloxy-2,4-difluoro-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
[0396] The title compound was prepared according to the procedure of Example
73F substituting
the product from Example 75E for the product of Example 73E. The resultant
residue was purified by
HPLC with TFA to provide the title compound as a trifluoroacetic acid salt
(7.4 mg, 16%). 'H NMR
(300 MHz, DMSO-d6) S ppm: 2.72 (s, 3 H), 5.17 (s, 2 H), 7.19-7.60 (m, 7 H),
7.71 (d, J=8.46 Hz, I
H), 8.75 (s, I. H), 8.85 (d, J=8.46 Hz, I H), 10.84 (s, I H); MS(ESl) m/z 379
(M+H)+.

Example 76
(5-B enzyloxy-2,4-difluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine

[0397] A solution of the product of Example 57A (17 mg, 0.099 mmol), and the
product of
Example 73E (28 mg, 0.119 mmol) in acetic acid (1 mL) was stirred in an oil
bath preheated to 130 C
for 15 minutes. The mixture was then cooled to room temperature, the acetic
acid removed under
vacuum, and the resultant residue was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt (21_4 mg, 45%). 1H NMR (300 MHz, DMSO-D6) S ppm:
5.17 (s, 2 H) 7.19 -
7.61 (m, 7 H) 7.80 (dd, J=8.09, 4.41 Hz, I H) 8.77 (s, 1 H) 8.97 (d, J=7.35
Hz, 1 H) 9.14 (d, J=2.94
Hz, 1 H) 10.88 (s, 1 H); MS (ESI+) m/z 365 (M+H)+.

Example 77
4- {2-[Benzyl-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amino]-4-benzyloxy-
phenylsulfanyl} -phenol
[0398] To a solution of the product of Example 27 (26.3 mg, 0.062 mmol),
benzyl bromide
(0.0075 mL, 0.062 mmol) and potassium carbonate (8.6 mg, 0.062 mmol) in N,N-
dimethylformamide
(0.5 mL) was stirred at room temperature for 16 hours. Afterwards, the mixture
was poured into ice
water (10 mL) and the resultant solution acidified with 1N aqueous
hydrochloric acid. The solution
was then extracted with ethyl acetate (3 x 10 mL), the combined extracts dried
over magnesium
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sulfate, filtered and concentrated under vacuum to provide the crude title
compound which was
purified by HPLC with TFA to provide the title compound as a trifluoroacetic
acid salt (6.7 mg, 18%).
1H NMR (300 MHz, DMSO-D6) S ppm: 2.74 (s, 3 H) 5.10 (s, 2 H) 5.69 (s, 1 H)
6.65 (d, J=8.82 Hz, 2
H) 7.02 - 7.18 (m, 2 H) 7.14 - 7.26 (m, I H) 7.26 - 7.58 (m, 12 H) 7.86 (s, I
H) 8.93 (s, 1 H) 9.23 (s, I
H) 9.73 (s, I H) 12.09 (s, I H); MS (ESI+) m/z 557 (M+H)+.

Example 78
(5-Benzyloxy-2-bromo-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yt)-arnine
Example 78A
5-Benzyloxy-2-brorno phenylamine

[0399] The title compound was made according to the method of Boger, D.L.,
Wysocld,
R.J., Ishizaki, T. J. Am. Chem. Soc., 112, 1990, p. 5230-5240. The amount
obtained was 4.58g, 48%.
Example 78B
(5-Benzyloxy-2-bromo-phenyl)-(7-methyl-pyrido [2,3-d]pyrimidin-4-yl)-amine

[04001 . The product from Example 78A (2.0 g, 7.19 mmol) and the product from
Example
lOB (1.35 g, 7.19 mmol) in acetic acid (15 mL) was gradually heated form room
temperature to 130
C in an oil bath over a 15 minute time period, followed by heating at 130 C
for an additional 1.5
hours. The mixture was then cooled to room temperature, concentrated under
vacuum to provide the
crude title compound (3.4 g of a sticky red syrup, 100%) a portion of which
was purified by HPLC
with TFA to provide the title compound as the trifluoroacetic acid salt (81
mg). 'H NMR (300 MHz,
DMSO-d6) 8 ppm: 2.74 (s, 3H), 5.14 (s, 2H), 7.06 (dd, J=8.8, 2.9 Hz, 1H), 7.23
(m, 1H), 7.41 (m,
5H), 7.70 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 8.79 (s, 11-1), 8.91 (d,
J=8.8 Hz, 1H), 11.40 (bs,
111); MS (ESI+) m/z 421/423 (M+H)+,

Example 79
2-Chloro-N-[3-(pyrido[2,3-d]pyrirnidin-4-ylamino)-phenyl]-benzamide
Example 79A
N-(3-Amino phenyl)-2-chloro-benzamide

[0401] The title compound was prepared according to the procedure of Example
254A
substituting 2-chloro-benzoyl chloride for 4-bromo-benzoyl chloride followed
by reduction of the
nitro group using the procedure from Example 255B to provide the title
product.

Example 79B
2-Chloro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
[0402] The product from Example 79A was reacted with the product from Example
57A
using the procedure from Example 254C substituting the product from Example
79A for the product
from Example 254B to provide the crude product which was purified by HPLC with
TFA to provide


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the title compound as a trifluoroacetic acid salt (18 mg, 22%). 1H NMR (300
MHz, DMSO-D6) 6
ppm: 7.45 - 7.54 (m, 4 H), 7.56 - 7.62 (m, 3 H), 7.83 - 7.90 (m, 1 H), 8.25 -
8.29 (m, 1 H), 8.93 (s, 1
H), 9.12 - 9.18 (m, 2 H), 1Ø70 (s, I H), 11.23 (s, 1 H); MS ESI+ m/z 376
(M+H)+, ESI- m/z 374 (M-
H)-.

Example 80
2-Bromo-N-[3-(pyrido [2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
Example 80A
N-(3-Amino-phenyl)-2-bromo-benzamide

[0403] The title compound was prepared according to the procedure of Example
254A
substituting 2-bromo-benzoyl chloride for 4-bromo-benzoyl chloride followed by
reduction of the
nitro group using the procedure from Example 255B to provide the title
product.

Example 80B
2-Bromo-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzami de

[0404] The product from Example 80A was reacted with the product from Example
57A
using the procedure from Example 254C substituting the product from Example
80A for the product
from Example 254B to provide the crude product which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (18 mg, 22%). 1H NMR (300
MHz, DMSO-D6) S
ppm: 7.44 - 7.54 (m, 4 H), 7.56 - 7.60 (m, 2 H), 7.74 (dd, J=7.91, 0.92 Hz, I
H), 7.82 - 7.89 (m, 1 H),
8.27 (s, 1 H), 8.92 (s, 1 H), 9.11 - 9.19 (m, 2 H), 10.68 (s, 1 H), 11.20 (s,
1 H); MS ESI+ m/z 420
(M+H)+, ESI- m/z 418 (M-H)-.

Example 81
2-Methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
Example 81A
N-(3-Amino-phenyl)-2-methoxy benzamide

[0405] The title compound was prepared according to the procedure of Example
254A
substituting 2-methoxy-benzoyl chloride for 4-bromo-benzoyl chloride followed
by reduction of the
nitro group using the procedure from Example 255B to provide the title
product.

Example 81B
2-Methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
[0406] The product from Example 81A was reacted with the product from Example
57A
using the procedure from Example 254C substituting the product from Example 8
1A for the product
from Example 254B to provide the crude product which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (26 mg, 33%). 1H NMR (300
MHz, DMSO-D6) S
ppm: 3.90 (s, 3 H), 7.08 (t, J=6.99 Hz, 1 H), 7.20 (d, J=8.46 Hz, 1 H), 7.41 -
7.56 (m, 4 H), 7.62 (dd,
=96


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J=7.54, 1.65 Hz, 1 H), 7.88 (dt, 1 H), 8.28 (s, I H), 8.94 (s, 1 H), 9.12 -
9.19 (m, 2 H), 10.30 (s, I H),
11.30 (s, 1 H); MS ESI+ m/z 372 (M+H)+, ESI- m/z 370 (M-H)-.

Example 82
3-Methoxy-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
Example 82A
N-(3-Amino-phenyl)-3-methoxy-benzamide
[0407] The title compound was prepared according to the procedure of Example
254A
substituting 3-methoxy-benzoyl chloride for 4-bromo-benzoyl chloride followed
by reduction of'the
nitro group using the procedure from Example 255B to provide the title
product.

Example 82B
3-Methoxy-N-[3-(pyrido[2,3-djpyrimidin-4-ylamino)-phenyl]-benzamide
[0408] The product from Example 82A was reacted with the product from Example
57A
using the procedure from Example 254C substituting the product from Example
82A for the product
from Example 254B to provide the crude product which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (35 mg, 45%). IH NMR (300
MHz, DMSO-D6) 8
ppm: 3.85 (s, 3 H), 7.18 (dd, J-7.54, 2.02 Hz, I H), 7.42 - 7.51 (m, 3 H),
7.53 - 7.61 (m, 3 H), 7.82
(dd, J=7.72, 5.15 Hz, 1 H), 8.32 (t, J=1.84 Hz, 1 H), 8.89 (s, I H), 9.09 -
9.17 (m, 2 H), 10.38 (s, 1 H),
10.99 (s, 1 H); MS ESI+ m/z 372 (M+H)+, ESI- m/z 370 (M+H)-.

Example 83
3-Fluoro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
Example 83A
N-(3-Amino-phenyl)-3-fluoro-benzamide
[0409] The title compound was prepared according to the procedure of Example
254A
substituting 3-fluoro-benzoyl chloride for 4-bromo-benzoyl chloride followed
by reduction of the
nitro group using the procedure from Example 255B to provide the title
product.

Example 83B
3-Fluoro-N-[3-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl]-benzamide
[0410] The product from Example 83A was reacted with the product from Example
57A
using the procedure from Example 254C substituting the product from Example
83A for the product
from Example 254B to provide the crude product which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (21 mg, 28%). 1H NMR (300
MHz, DMSO-D6) 6
ppm: 7.41 - 7.53 (m, 2 H), 7.54 - 7.65 (m, 3 H), 7.77 - 7.86 (m, 3 H), 8.33
(s, 1 H), 8.89 (s, I H), 9.10
- 9.16 (m, 2 H), 10.48 (s, 1 H), 10.97 (s, 1 H); MS ESI+ m/z 360 (IvM+H)+, ESI-
m/z 358 (M-H)-.

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Example 84
4-[4-Benzylamino-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol

Example 84A
4-(4-Amino-2-nitro-phenylsulfanyl)-phenol
[04111 A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-
hydroxykhiophenol (0.75
g, 6.00 mmol), cesium carbonate (3.9 g, 12 mmol) in dimethylsulfoxide (10 ml)
was heated'at 100 C
for 16 hours. Afterwards ice water (50 mL) was added to the solution and the
resultant slurry was
treated with ethyl acetate (100 ml). The layers were separated and the organic
layer was washed with
10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous
sodium sulfate. The
drying agent was filtered and solvent was removed under vacuum leaving a red
solid as the title
compound, (1.45 g, 92%).

Example 84B
4-(4-B enzyl amino-2-nitro-phenylsulfanyl)-phenol

[0412] A solution of the product of Example 84A (0.63 g, 2.4 mmol),
benzaldehyde (0.24 g,
2.3 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) in methanol (10 mL)
containing 1%
acetic acid was stirred at room temperature for 16 hours. The reaction mixture
was quenched with
water (20 mL) and the resultant solution was concentrated under vacuum to a
yellow solid. The solid
was dissolved in ethyl acetate (50 mL), and washed with water, 10% sodium
bicarbonate and 10%
sodium chloride. The organic layer was dried over anhydrous sodium sulfate,
filtered and solvent
removed under vacuum leaving a light yellow oil. The oil was purified by
silica gel chromatography
eluting with 1% methanol in methylene chloride to provide the title compound
(0.63 g, 77%).

Example 84C
4-(2-Amino-4-benzylamino-phenylsulfanyl)-phenol
[04131 A solution of the product of Example 84B (0.5 g, 1.4 mmol), iron powder
(0.49 g,
8.74 mmol) and ammonium chloride (0.50 g, 9.3 mmol) in a methanol (10 mL),
tetrahydrofuran (10
mL.), and water (5 mL) soliution was heated to reflux for 1.5 hours. The
resultant mixture was diluted
with methanol (50 mL) and filtered through a pad of celite. The filtrate was
concentrated under
vacuum to a volume of 10 mL, the solution diluted with water -(50 mL) and
extracted witli ethyl
acetate (2 x 50 niL). The combined extracts were washed with 10% sodium
chloride then dried over
magnesium sulfate, filtered and concentrated under vacuum to provide the title
compound (0.30 g,
66%).

Example 84D
4-[4-Benzylamino-2-(7-methyl-pyrido [2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
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[0414] A solution of the product from Example lOB (30 mg, 0.159 mmol), and the
product
from Example 84C (56.5 mg, 0.17 mmol) in acetic acid (2 mL) was stirred in an
oil bath preheated to
130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue purified by HPLC with TFA to provide
the title compound as
a trifluoroacetic acid salt (12 mg, 10%). 1H NMR (300 MHz, DMSO-D6) 8 ppm:
2.71 (s, 3 H), 4.50
(s, 2 H), 6.60 - 6.69 (m, 2 H), 6.73 - 6.85 (m, 2 H), 7.04 - 7.29 (m, 6 H),
7.31 - 7.40 (m, 2 H), 7.46 (d,
J=7.35 Hz, 2 H), 8.54 (s, I H), 8.75 (s, 1 H), 9.74 (s, 1 H); MS(ESI) m/z 466
(M+H)+, (ESI-) m/z
464 (M-H)-.

Example 85
N 1-Benzyl-4-(4-benzyloxy-phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-
4-yl)-benzene-1,3-
diamine
Example 85A
4-(2-Amino-4-nitro-phenylsulfanyl)-phenol
[0415] A solution of 2-Chloro-5-nitroaniline (3 g, 17.4 mmole), 4-
hydroxythiophenol (2.4 g,
19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 ml)
was heated at 100
C for 16 hours. Afterwards. ice water (200 mL) was added to the solution and
to the resultant slurry
was added ethyl acetate (200 ml). The layers were separated and the organic
layer was washed with
10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium
sulfate. The drying
agent was filtered and solvent was removed under vacuum leaving a yellow oil.
The oil was purified
by silica gel chromatography eluting with methylene chloride/methanol (97:3),
to provide a yellow
solid as the title compound (2.1g, 46%).

Example 85B
2-(4-Benzyloxy-phenylsulfanyl)-5-nitro-phenylamine
[0416] A slurry containing of the product from Example 85A (0.2 g, 0.763
mmole) and
cesium carbonate (0.25 g, 0.763 mmole) in dimethylformamide (5 ml) was treated
with benzyl
bromide (0.091 ml, 0.763 mmole) and the resulting slurry was stirred 18 hours
at room temperature.
Afterwards ice water (50 mL) was added to the solution and to the resultant
slurry was added ethyl
acetate (50 ml). The layers were separated and the organic layer was washed
with 10% sodium
bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The
drying agent was
filtered and solvent was removed under vacuum leaving a yellow solid as the
title compound (0.24 g,
89%).

Example 85C
[2-(4-B enzyloxy-phenylsulfanyl)-5-nitro-phenyl]-(7-methyl-pyrido[2,3-
d)pyrimidin-4-yl)-amine
[0417] A solution of the product from Example lOB (62 mg, 0.331 mmol), and the
product
of Example 85B (120 mg, 0.331 mmol) in acetic acid (1 mL) was stirred in an
oil bath preheated to
99


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130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum leaving a brown oil as the title compound (0.15 g, 92%). The
compound was used
without purification in the next step.

Example 85D
4-(4-Benzyloxy-phenylsulfanyl)-N3 -(7-methyl-pyrido[2, 3-d]pyrimidin-4-yl)-
benzene-1,3-diamine
[0418] A solution of the product from Example 85C (0.150 g, 0.303 mmole), iron
powder
(0.10 g, 1.86 mmol) and ammonium chloride (0.10 g, 1.98 mmol) in a methanol (2
mL),
tetrahydrofuran (2 mL), and water (1 mL) solution was heated to reflux for 1.5
hours. The resultant
mixture was diluted with methanol (50 mL) and filtered through a pad of
celite. The filtrate was
' concentrated under vacuum to a volume of 10 mL, the solution diluted with
water (50 mL) and
extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed
with 10% sodium
chloride then dried over magnesium sulfate, filtered and concentrated under
vacuum to provide the
title compound (0.06 g, 42%).

Example 85E
Nl -Benzyl-4-(4-benzyloxy-phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-
4-yl)-benzene-l,3-
diamine
[0419] A mixture of the compound prepared in Example 85D (0.06 g, 0.130
mmole),
benzaldehyde (0.013g, 0.130 mmole) and sodium cyanoborohydride (0.0081 g, 0.13
mmole) in
methanol (1 ml) containing 1 drop acetic acid was stirred 18 hr at room
temperature. The solvent was
removed under vacuum and the resultant residue purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (12 mg, 17%). 1H NMR (300 MHz, DMSO-
D6) 8 ppm: 2.69
(s, 3 H), 4.30 (s, 2 H), 4.96 (s, 2 H), 6.60 (dd, J=8.46, 2.57 Hz, 1 H), 6.72 -
6.89 (m, 3 H), 6.94 - 7.09
(m, 2 H), 7.19 - 7.29 (m, 1 H), 7.29 - 7.46 (m, 11 H), 7.63 (d, J=8.46 Hz, 1
H), 8.61 (s, 1 H), 8.71 (d,
J=8.82 Hz, I H), 10.69 (s, 1 H).

Example 86
4-[4-[(Furan-3-ylmethyl)-amino]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylanuno)-
phenylsulfanyl]-
phenol

Example 86A
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-nitro-phenylsulfanyl]-
phenol
[04201 A solution of the product from Example lOB (340 mg, 1.80 mmol), and the
product
of Example 85A (480 mg, 1.80 mmol) in acetic acid (10 rnL) was stirred in an
oil bath preheated to
130 C for 30 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum leaving a brown oil as the title compound (0.65 g, 89%).

Example 86B
4-[4-Amino-2-(7-methyl pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
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[0421] A slurry of the product from Example 86A (0.19 g, 0.469 mmol) and 10%
Pd/C
(0.025 g) in acetic acid (3 ml) was placed under a hydrogen atmosphere with
stirring for 2 hr at room
temperature. The slurry was filtered and the solvent removed under vacuum
leaving a brown solid as
an acetate salt of the title compound (0.21 g, 91%).

Example 86C
4-[4-[(Furan-3-ylmethyl)-amino]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol

[0422] A solution of the product from Example 86B (69.7 mg, 0.141 mmol), 3-
furaldehyde
(13.5 mg, 0.141 mmol) and sodium cyainoborohydride (8.7 mg, 0.141 mmol) in 2
ml methanol was
stirred 18 hr at room temperature. The solvent was evaporated under vacuum and
the resultant
residue purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt (16
mg, 14%). 1H NMR (300 MHz, DMSO-D6) S ppm: 2.75 (s, 3 H), 3.85 (s, 1 H), 4.09
(s, 2 H), 6.47 (s,
I H), 6.53 (d, J=8.82 Hz, 2 H), 6.62 - 6.75 (m, 2 H), 6.94 (d, J=8.46 Hz, 3
H), 7.21 - 7.32 (m, 1 H),
7.61 (s, 1 H), 7.83 (d, J=8.46 Hz, 1 H), 8.77 (s, I H), 8.88 (s, I H), 9.51
(s, 1 H), 11.68 (s, 1 H).

Example 87
4-{2-(7-Methyl-pyrido [2,3-d]pyrimidin-4-ylan'iino)-4-[(thiophen-3-ylmethyl)-
amino]-
phenylsulfanyl } -phenol

[04231 A solution of the product from Example 86B and 3-thiophene
carboxaldehyde were
reacted according to the procedure from Example 86C substituting 3-thiophene
carboxaldehyde for 3-
furaldehyde to provide the crude product which was purified by HPLC with TFA
to provide the title
compound as a trifluoroacetic acid salt (26 mg, 37%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.74
(s, 3 H), 3.74 (s, I H), 4.26 (s, 2 H), 6.52 (d, J=8.82 Hz, 3H), 6.64 - 6.76
(m, 1 H), 6.86 - 6.99 (m, 3
H), 7.02 - 7.14 (m, 1 H), 7.19 - 7.34 (m, 1 H), 7.42 - 7.54 (m, 1 H), 7.82 (d,
1=8.09 Hz, 1 H), 8.76 (s, 1
H), 8.90 (s, 1 H), 9.51 (s, 1 H), 11.65 (s, 1 H).

Example 88
4- {2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-[(naphthalen-1-ylmethyl)-
amino]-
phenylsulfanyl } -phenol

[0424] A solution of the product from Example 86B and 1-naphthaldehyde were
reacted
according to the procedure from Example 86C substituting 1-naphthaldehyde for
3-furaldehyde to
provide the crude product which was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt (18 mg, 12%). 1H NMR (300 MHz, DMSO-D6) S ppm: 2.73
(s, 3 H), 4.73 (s,
1H),6.39(s, 1H),6.45-6.60(m,2H),6.67-6.80(m, 1 H), 6.88 - 6.98 (m, 2 H), 7.17 -
7.34 (m, 1
H), 7.43 - 7.54 (m, 1 H), 7.51 - 7.71 (m, 4 H), 7.71 - 7.83 (m, 1 H), 7.83 (d,
J=8.82 Hz, 1 H), 7.95 -
8.09 (m, 2 H), 8.10 - 8.18 (m, 1 H), 8.22 (d, J=8.09 Hz, 1 H), 8.76 (s, 1 H),
8_82 - 8.89 (m, 1 H), 9.51
(s, I H), 11.64 (s, 1 H).
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Example 89
4-[4-[(Furan-2-ylmethyl)-amino]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsul fanyl]-
phenol
[0425] A solution of the product from Example 86B and 2-furaldehyde were
reacted
according to the procedure from Example 86C substituting 2-furaldehyde for 3-
furaldehyde to provide
the crude product which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (18 mg, 16%). IH NMR (300 MHz, DMSO-D6) S ppm: 2.69 -
2.81 (m, 3 H),
4.26 (s, 2 H), 6.27 - 6.44 (m, I H), 6.45 - 6.59 (m, 2 H), 6.46 - 6.60 (m, 3
H), 6.68 - 6.78 (m, 2 H),
6.89 - 7.00 (m, 2 H), 7.20 - 7.33 (m, I H), 7.59 (s, 1 H), 7.84 (d, J=8.09 Hz,
I H), 8.77 (s, I H), 8.89
(s, I H), 11.73 (s, 1 H).

Example 90
4-{2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-[(thiophen-2-ylmethyl)-
amino]-
phenylsulfanyl } -phenol

[0426] A solution of the product from Example 86B and 2-thiophene
carboxaldehyde were
reacted according to the procedure from Example 86C substituting 2-thiophene
carboxaldehyde for 3-
furaldehyde to provide the crude product which was purified by HPLC with TFA
to provide the title
compound as a trifluoroacetic acid salt (11 mg, 16%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.64 -
2.86 (m, 3 H), 4.47 (s, 2 H), 6.46 - 6.57 (m, 2 H), 6.64 - 6.78 (m, 3 H), 6.87
- 7.00 (m, 3 H), 7.02 -
7.13 (m, 2 H), 7.19 - 7.31 (m, 2 H), 7.32 - 7.48 (m, 1 H), 7.82 (d, J=8.82 Hz,
1 H), 8.77 (s, 1 H), 8.89
(s, 1 H), 9.50 (s, 1 H), 11.68 (s, I H).

Example 91
4-i4-(4-Bromo-benzylamino)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 91 A
4-[4-(4-Bromo benzylamino)-2-nitro-phenylsulfanyl]-phenol

[0427] A solution of the product from Example 84A and 4-Bromobenzaldehyde were
reacted
according to the procedure from Example 84B substituting 4-Bromobenzaldehyde
for the product
from Example 84A to provide the crude product which was purified by silica gel
chromatography
eluting with 2% methanol in methylene chloride to provide the title compound
as a yellow solid
(0.l lg, 73%).

Example 91B
4-[2-Amino-4-(4-bromo-benzylamino) phenylsulfanyl]-phenol

[0428] A solution of the product from Example 91 A was reacted according to
the procedure
from Example 84C to provide the title compound (0.17 g, 76%).

Example 91C
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4-[4-(4-Bromo-benzylamino)-2-(7-methyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-
phenylsulfanyl] -phenol
[0429] A solution of the product of Example 10B (50 mg, 0.266 mmol), and the
product of
Example 91B (110 mg, 0.266 mmol) in acetic acid (2 mL) was stirred in an oil
bath preheated to
130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue purified by HPLC with TFA to provide
the title compound as
a trifluoroacetic acid salt (22 mg, 15%). 1H NMR (300 MHz, DMSO-D6) 8 ppm:
2.73 (s, 3 H), 4.26
(s, 2 H), 6.53 (d, J=8.46 Hz, 2 H), 6.54 - 6.69 (m, 2 H), 6.85 - 7.03 (m, 2
H), 7.23 (d, J=8.46 Hz, I H),
7.30 (d, J=8.46 Hz, 3 H), 7.46 - 7.61 (m, 2 H), 7.78 (d, J=8.46 Hz, 1 H), 8.73
(s, I H), 8.89 (d,
J=19.12 Hz, I H), 9.51 (s, I H), 11.46 (s, I H).

Example 92
N1-Benzyl-4-(4-methoxy phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-
yl)-benzene-1,3-
diamine
4-(4-Methoxy-phenylsulfanyl)-3-nitro-phenylamine
Example 92A
[0430] A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-
methoxythiophenol (0.84
g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10
rnl) was heated at
100 C for 16 hours. Afterwards ice water (50 mL) was added to the solution
and the resultant slurry
was treated with ethyl acetate (100 ml). The layers were separated and the
organic layer was washed
with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous
sodium sulfate.
The drying agent was filtered and solvent was removed under vacuum leaving a
red solid as the title
compound (1.5 g, 94%).

Example 92B
Benzyl-[4-(4-methoxy phenylsulfanyl)-3-nitro-phenyl]-amine

[0431] A solution of the product of Example 92A (0.50 g, 1.81 mmol),
benzaldehyde (0.19 g,
1.81 mmol) and sodium cyanoborohydride (0.11 g, 1.8 mmol) in methanol (10 mL)
containing 1 !
acetic acid was stirred at room temperature for 16 hours. The reaction mixture
was quenched with
water (20 mL) and the resultant solution was concentrated under vacuum to a
yellow solid. The solid
was dissolved in ethyl acetate (50 mL), and washed with water, 10% sodium
bicarbonate and 10%
sodium chloride. The organic layer was dried over anhydrous sodium sulfate,
filtered and solvent
removed under vacuum leaving a light yellow oil. The oil was pufified by
silica gel chromatography
eluting with 1% methanol in methylene chloride to provide the title compound
as a brick red solid
(0.62 g, 91 f ).

Example 92C
Ni -Benzyl-4-(4-methoxy-phenylsulfanyl)-benzene-1,3-diamine
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[0432] A solution of the product of Example 92B was reacted according to the
procedure
from Example 84C to provide the title compound (0.49 g, 89%).

Example 92D
N 1-Benzyl-4-(4-methoxy-phenylsulfanyl)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-
yl)-benzene-1,3 -
diamine
[0433] - A solution of the product of Example 10B (27.8 mg, 0.148 mmol), and
the product of
Example 92C (49 mg, 0.148 mmol) in acetic acid (2 mL) was stirred in an oil
bath preheated to 130 C
for 20 minutes. The mixture was then cooled to room temperature, the acetic
acid removed under
vacuum, and the resultant residue purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt (15 mg, 14%). 1H NMR (300 MHz, DMSO-D6) S ppm: 2.64 -
2.81, (m, 3 H)
3.56 - 3.71, (m, 3 H) 4.29 (s, 2 H),6.61 - 6.75 (m, 3 H), 6.95 - 7.07 (m, 2
H), 7.16 - 7.45 (m, 8 H), 7.76
(d, J=8.46 Hz, 1 H), 8.69 (s, 1 H), 8.80 (d, 1H), 11.34 (s, 1 H).

Example 93
N 1-B enzyl-4-(4-methoxy-phenoxy)-N3 -(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
benzene-1,3 -diamine
Example 93A
4-(4-Methoxy-phenoxy)-3-nitro-phenylamine

[0434] A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-
methoxyphenol (0.74 g,
6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 ml)
was heated at 100
C for 16 hours. Afterwards ice water (50 mL) was added to the solution and the
resultant slurry was
treated with ethyl acetate (100 ml). The layers were separated and the organic
layer was washed with
10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous
sodium sulfate. The
drying agent was filtered and solvent was removed under vacuum leaving a red
solid as the title
compound (1.1 g, 73%).

Example 93B
N1-Benzyl-4-(4-methoxy-phenoxy)-benzene-1, 3 -diamine

[0435] A solution of the product from Example 93A was reacted according to the
procedure
from Example 92B substituting the product from Example 93A for the product
from Example 92A
which was reduced according to the procedure from Example 84C to provide the
title compound (0.05
g, 12%).

Example 93C
N 1-Benzyl-4-(4-methoxy-phenoxy)-N3-(7-methyl-pyrido [2,3 -d]pyrimidin-4-y1)-
benzene-1,3-diamine
[0436] A solution of the product of Example lOB and the product from Example
93B was
reacted according to the procedure from Example 92D substituting the product
from Example 93B for
the product from Example 92C which was purified by HPLC with TFA to provide
the title compound
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as a trifluoroacetic acid salt (8 mg, 18%). 1H NMR (300 MHz, DMSO-D6) 8 ppm:
2.55 - 2.68 (m, 3
H), 3.61 (s, 3 H), 4.26 (d,J=5.88 Hz, 2 H), 6.27 (t, J=5.88 Hz, 1 H), 6.50
(dd, J=8.64, 2.76 Hz, I H),
6.64 - 6.87 (m, 6 H), 7.18 - 7.45 (m, 6 H), 8.48 (s, 1 H), 8.57 (d, J=8.46 Hz,
I H), 9.59 (s, I H).

Example 94
N 1-Benzyl-4-(4-benzyloxy-phenoxy)-N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
benzene-1,3-
diamine
Example 94A
4-(4 Benzyloxy-phenoxy)-3-nitro-phenylamine

[04371 A solution of 4-chloro-3-nitro aniline (2.0 g, 11.16 mmol), 4-
benzyloxyphenol (2.55*
g, 12.76mmol), powdered potassium hydroxide (0.94 g, 16.80 mmol) in
dimethylformamide (15 ml)
was heated at 120 C for 20 hours. Afterwards ice water (50 mL) was added to
the solution and the
resultant slurry was treated with ethyl acetate (100 ml). The layers were
separated and the organic
layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then
dried over anhydrous
sodium sulfate. The drying agent was filtered and solvent was removed under
vacuum leaving a dark
red solid as the title compound, (2.07 g, 53%).

Example 94BNl -Benzyl-4-(4-benzyloxy-phenoxy)-benzene-1,3-diamine

[0438] A solution of the product from Example 94A was reacted according to the
procedure
from Example 92B substituting the product from Example 94A for the product
from Example 92A
which was reduced according to the procedure from Example 84C to provide the
title compound (0.6
g, 91%).

Example 94C
N1-Benzyl-4-(4-benzyloxy-phenoxy) N3-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
benzene-1,3-
diamine
[04391 A solution of the product of Example lOB and the product from Example
94B was
reacted according to the procedure from Example 92D substituting the product
from Example 94B for
the product from Example 92C which was purified by HPLC with TFA to provide
the title compound
as a trifluoroacetic acid salt (12 mg, 10%). 1H NMR (300 MHz, DMSO-D6) 8 ppm:
2.70 (s, 3 H),
4.27 (s, 2 H), 4.94 (s, 2 H), 4.99 - 5.12 (m, 1 H), 6.64 (dd, J=8.82, 2.94 Hz,
1 H), 6.70 - 6.92 (m, 9 H),
6.90 - 7.00 (m, 1 H), 7.16 - 7.29 (m, 1 H), 7.31 - 7.42 (m, 5 H), 7.70 (d,
J=8.46 Hz, 1 H), 8.67 - 8.86
(m, 2 H), 11.22 (s, 1 H).

Example 95
4-j4 Arnino-2-(7-isopropyl pyrido[2,3-d]pyrimidin-4 ylamino)phenylsulfanyl]
phenol
Example 95A
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-nitro-phenylsulfanyl]-
phenol
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[0440] A solution of the product from Example lOB (340 mg, 2.31 mmol), and the
product
of Example 85A (610 mg, 2.30 mmol) in acetic acid (10 mL) was stirred in an
oil bath preheated to
130 C for 10 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum providing a brown oil as the title compound (0.92 g, 92%).

Example 95B
4-[4-Amino-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[0441] A slurry of the compound prepared in Example 95A (0.7 g, 1.73 mmol) and
10%
Pd/C (100 mg) in acetic acid (10 ml) and methanol (10 mL) was placed under a
hydrogen balloon
atmosphere with stirring for 20 hours at room temperature. The slurry was
filtered and the solvent
removed under vacuum to provide the title compound as an acetic acid salt (540
mg, 63%). 1H NMR
(300 MHz, DMSO-D6) S ppm: - 1.35 (d, J = 7.0 Hz, 6H),.=1.91 (s, 6H), 3.27 (m,
1H), 6.55 (d, J= 8.8
Hz, 2H), 6.62 (m, 1H), 6.69 (m, 1H), 6.95 (d, J= 8.8 Hz, 2H), 7.20 (d, J= 8.5
Hz, 1H), 7.87 (d, J=
8.5 Hz, 1H), 7.95 (s, 1H), 8.75 (s, 1H), 8.99 (m, IH), 9.52 (s, 1H), 11.57
(bs, 1H); MS (ESI+) rn/z 404
(M+H)+.

Example 96
4-[2-(7-Isopropyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-4-phenethylamino-
phenylsulfanyl] -phenol
[0442] A solution containing the product from Example 95B (65 mg, 0.124
mmole),
phenylacetaldehyde (15 mg, 0.124 mmole) and sodium cyanoborohydride (10 mg,
0.199 mmole) in 2
ml methanol was stirred 18 hr at room temperature. The solvent was evaporated
under vacuum and
the resultant residue purified by HPLC with TFA to provide the title compound
as a trifluoroacetic
acid salt (25 mg, 32%). 1H NMR (300 MHz, DMSO-D6) S ppm: 1.28 (d, 6 H), 2.31 -
2.48 (nz, 1 H),
2.78 - 2.93 (m, 2 H), 3.16 - 3.35 (m,2H),4.17-4.36(m,2H),4.73-4.91 (m,
1H),6.47-6.59(m,2
H), 6.61 - 6.74 (m, I H), 6.86 - 7.01 (m, 2 H), 7.10 (d, J=6.99 Hz, 1 H), 7.15
- 7.27 (m, 1 H), 7.19 -
7.39 (m, 6 H), 7.89 (d, J=8.46 Hz, 1 H), 8.77 (s, I H), 8.96 (s, I H), 9.50
(s, 114), 11.61 (s, 1 H).

Example 97
4-[4-(Cyclopentylmethyl-amino)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl]-
phenol

[0443) A solution containing the product from Example 95B was reacted with
cyclopentanecarbaldehyde according to the procedure from Example 96
substituting
cyclopentanecarbaldehyde for phenylacetaldehyde which was purified by HPLC
with TFA to provide
the title compound as a trifluoroacetic acid salt (11 mg, 9%). 1H NMR (300
MHz, DMSO-D6) S ppm:
1.26 - 1.43 (m, 6 H), 1.53 (s, 4 H), 1.75 (d, J=3.31 Hz, 4 H), 2.01 - 2.19 (m,
1 H), 2.92 (d, J=6.99 Hz,
2H),3.20-3.36(m, 1H),6.53(d,J=8.82Hz,2H),6.58-6.73(m, 1H),6.87-
7.00(in,2H),6.98-
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7.13 (m, I H), 7.17 - 7.36 (m, 1 H), 7.89 (s, 1 H), 8.15 (s, 1 H), 8.77 (s, 1
H), 8.95 (s, 1 H), 9.49 (s, 1
H), 10.98 (s, I H), 11.68 (s, I H).

Example 98
N1-Benzyl-N3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-4-(4-methoxy-
phenylsulfanyl)-benzene-
1,3-diamine

[0444] A solution of the product from Example 36E (40.4 mg, 0.187 mmol) and
the product
of Example 92C (62.8 mg, 0.187 mmol) in acetic acid (2 mL) was stirred in an
oil bath preheated to
140 C for 45 minutes. The reaction was cooled to room temperature, diluted
with hexanes (50 mL),
concentrated by rotary evaporation, and co-evaporated with methylene
chloride/hexanes (4x). The
residue was dried on under vacuum, then purified by silica gel flash
chromatography with a gradient
of 15% to 20% ethyl acetate/methylene chloride as eluent to afford the title
compound as a yellow
solid (29.6 mg, 31 fo). 'H NMR (300 MHz, DMSO-D6) S ppm: 1.31 (d, J=6.99 Hz, 6
H) 3.11 - 3.26
(m, 1 H) 3.64 (s, 3 H) 4.30 (d, J=5.88 Hz, 2 H) 6.53 (dd, J=8.46, 2.57 Hz, 1
H) 6.66 - 6.78 (m, 3 H)
6.95 (d, J=2.21 Hz, 1 H) 7.03 (d, J=8.82 Hz, 2 H) 7.12 - 7.28 (m, 2 H) 7.28 -
7.44 (m, 4 H) 7.54 (d,
J=8.46 Hz, I H) 8.50 (s, I H) 8.65 (d, .1=8.46 Hz, 1 H) 9.75 (s, 1 H); MS
(DCUNH3) m/z 508 (M+H)+.
Example 99
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-pyrrol-1-yl-phenylsulfanyl]-
phenol
[0445] To a solution of the product from Example 86B (50 mg, 0.101 mmol) and
succinic
dialdehyde (40% in water solution) (0.065 mL, 0.303 mmol) in toluene (5 mL)
and methanol (3 mL)
was added 4A molecular sieves (100 mg). The mixture was then heated to 60 C
for 7 hours, cooled
to room temperature, the solvent removed under vacuum, a solution of 0.1 N
aqueous hydrochloric
acid (20 mL) added and the mixture extracted with dichloromethane (2 x 25 mL)
and dioxane (25
mL). The combined organic extracts were dried and concentrated under vacuum
then the resultant
residue purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt (14
mg, 26%). 'H NMR (300 MHz, DMSO-D6) S ppm: 2.68 (s, 3H), 6.26 (m, 2H), 6.77
(d, J = 8.5 Hz,
2H), 7.05 (d, J= 8.5 Hz, 1H), 7.24 (d, J= 8.5 Hz, 2H), 7.37 (m 2H), 7.48 (dd,
J= 8.6, 2.4 Hz, 1H),
7.57 (d, J= 8.5 Hz, 1H), 7.73 (d, J= 2.6 Hz, 1H), 8.57 (s, 1 H), 8.80 (d, J=
8.4 Hz, 1 H), 9.81 (s, 1H),
10.11 (s, 1H); MS (ESI+) m/z 426 (M+H)+.

Example 100
4-[2,4-Bis-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenol
[0446] To a solution of the product from Example 86B (50 mg, 0.101 mmol) and
the product
from Example lOB (19 mg, 0.101 mmol) in acetic acid (1 mL) was heated to 120
C for 2 hours.
After cooling to room temperature, the solvent was removed under vacuum and
methanol (2 mL) was
added. The resultant solid was collected and triturated with methanol to
provide the title compound as
a light brown solid (12 mg, 23%). 'H NMR (300 MHz, DMSO-D6) S ppm: 2.67 (s,
3H), 2.68 (m,
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3H), 6.75 (d, J = 8.8 Hz, 2H), 6.83 (m, 1H), 7.12 (m, 1H), 7.21 (d, J= 8.8 Hz,
2H), 7.34 (m, 1H), 7.58
(m, J= 8.8 Hz, 2H), 8.73 (s, 1H), 8.81 (m, IH), 8.88 (m, IH), 9.76 (s, IH),
10.13 (s, 1H), 11.95 (bs,
1H); MS (ESI+) m/z 519 (M+H)+.

Example 101
4-[4-(4-Bromo-benzylamino)-2-(7-isopropyl-pyrido[2,3-d]pyrirnidin-4-ylamino)-
phenylsulfanyl]-
phenol

[0447] A solution containing the product from Example 95B was reacted with 4-
Bromo-
benzaldehyde according to the procedure from Example 96 substituting 4-Bromo-
benzaldehyde for
phenylacetaldehyde which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (7 mg, 3%). 1H NMR (300 MHz, DMSO-D6) S ppm: 1.35
(d, J 6.6 Hz, 6H),
3.30 (m, IH), 6.55 (d, J = 8.5 Hz, 2H), 6.68 (m, 1H), 6.76 (d, J = 8.8 Hz,
2H), 6.91 (m, 1H), 6.98 (d, J
= 8.5 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.32 (m, 1H), 7.56 (m, 2H), 8.78 (s,
IH), 9.53 (m, 1H); MS
(ESI+) m/z 574 (M+H)+.

Example 102
4-[4-Methyl-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]
phenol

[0448] To a solution of the product from Example lOB (100 mg, 0.575 mmol) and
the
product from Example 6c (146 mg, 0.632 mmol) in acetic acid (1 mL) was heated
at 130 C for I
hour. The mixture was then allowed to cool to room temperature, then methanol
(5 mL) added to the
solution and the resulting solid collected and washed with methanol to provide
the title compound
(120 mg, 56%). IH NMR (300 MHz, DMSO-D6) S ppm: 2.29 (s, 3H), 2.66 (s, 3H),
6.73 (d, J = 8.8
Hz, 2H), 6.93 (m, 1H), 7.03 (m, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.26, (s, 1H),
7.53 (d, J = 8.5 Hz, 1H),
8.53 (s, 1H), 8.77 (m, 1H), 9.76 (bs, 1H), 9.96 (bs, 1H); MS (ESI)+m/z 375
(M+H)+.

Example 103
(5-Methyl-2 phenylsulfanyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
amine

[04491 To a solution of the product from Example l OB (90 mg, 0.517 mmol) and
the product
from Example 51 (122 mg, 0.569 mmol) in acetic acid (1 mL) was heated at 130
C for 1 hour. The
mixture was then allowed to cool to room temperature, the resulting solid
collected and washed with
methanol, then dissolved 50 mg of the material in dioxane (2 mL) and added
hydrochloric acid
followed by removal of the solvent under vacuum to provide the title compound
as a hydrochloride
salt. 1H NMR (300 MHz, DMSO-D6) 6 ppm: 2.37 (s, 3H), 2.74 (s, 3H), 7.18 (m,
5H), 7.24 (m, 1H),
7.37 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 8.80 (s, 1H), 8.99 (d, J= 8.5 Hz, 1H),
11.82 (bs, 1H); MS
(ESI)+ m/z 359 (M+H)+.
Example 104
[3-(3-Bromo-phenoxymethyl)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
amine
Example 104A
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1-Nitro-3 -(3 -bromo-phenoxymethyl)-benzene

[0450] To a solution of 3-nitrobenzyl chloride (1.0 g, 5.83 mmol), 3-
bromophenol (1.01 g,
5.83 mmol) and potassium carbonate (806 mg, 5.83 mmol) in acetone (25 mL) was
heatedto reflux for
23 hours. After cooling the solid was filtered off and the filtrate was
concentrated under vacuum to a
yellow residue which was dissolved in ethyl acetate (50 mL) and washed with 1N
aqueous sodium
hydroxide solution (25 mL) and water (25 mL) then dried and concentrated under
vacuum to the title
compound as a white solid (1.64 g, 91%).

Example 104B
3-(3-Bromo-phenoxymethyl)-phenylamine
[0451] To a solution of the product from Example 104A (1.64 g, 5.32 mmol),
iron powder
(1.49 g, 26.62 mmol) and ammonium chloride (430 mg, 7.98 mmol) in a mixture of
tetrahydrofuran
(20 mL), water (6 mL) and ethanol (20 mL) was heated to reflux for 3 hours.
The mixture was cooled
to room temperature, filtered through a pad of celite, which was washed with
ethanol and the resultant
filtrate concentrated under vacuum. The material was then dissolved in water
(50 mL) and extracted
with ethyl acetate (50 mL), the organic layer dried and concentrated under
vacuum to provide the title
compound as a yellow oil (1.43 g, 97%).

Example 104C
[3-(3 Bromo-phenoxymethyl)-phenyl]-(7-rnethyl pyrido[2,3-d]pyrimidin-4-yl)-
amine

[0452] To a solution of the product from Example 10C (50 mg, 0.266 mmol) and
the product
from Example 104B (74 mg, 0.266 mol) in acetic acid (3 mL) was heated to 130
C for 30 minutes.
After cooling to room temperature the solution was concentrated under vacuum
and purified by HPLC
with TFA to provide the title compound as a trifluoroacetic acid salt (62 mg,
44%). IH NMR (300
MHz, DMSO-D6) 8 ppm: 2.71 (s, 3H), 5.20 (s, 2H), 7.05 (m, 1H), 7.16 (m, 1H),
7.24 (m, 2H), 7.33
(m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.70 (d, J= 8.5 Hz, 1H), 7.79 (m, 1H), 7.84
(s, 1H), 8.83 (s, 1H),
8.96 (d, J= 8.4 Hz, 1H), 10.75 (bs, 1H); MS (ES1)+ m/z 421/423 (M+H)+.

Example 105
(3'-Methoxy-5-methyl-biphenyl-3 -yl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
amine
Example 105A
3-Bromo-5-methyl-phenylamine
[0453] The title compound was prepared from 3-Bromo-5-nitrotoluene (1.08 g,
5.0 mmol)
using the conditions from Example 104B to provide the title compound as an
orange oil (0.8 g, 86%).
Example 105B
(3-Bromo-5-methyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
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[0454] The product from Example 105A (0.8 g, 4.3 mmol) was reacted with the
product
from Example 10C using the procedure from Example 104C substituting the
product from Example
105A for the product from Example 104B to provide the crude residue which was
purified by
chromatography on silica eluting with 99:1 dichloromethane/methanol to provide
the title compound
as a yellow powder (1.1 g, 77%).

Example 105C
(3'-Methoxy-5-methyl-biphenyl-3-yl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-y1)-
amine
[0455] The product of Example 105B (0066 g, 0.2 mmol), 3-Methoxy phenylboronic
acid
(0.043 g, 0.28 mmol), cesium carbonate (0.1 g, 0.3 mmol) and
dichlorobis(triphenylphosphine)palladium(lI) (0.014 g, 0.02 mmol) were
combined in N,N-
dimethylformamide (1 mL) and heated to 100 C for 24 hours. After cooling to
room temperature the
mixture was poured into ice water (20 mL) and the resultant solution acidified
with IN aqueous
hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10
mL), the combined
extracts dried over sodium sulfate, filtered and concentrated under vacuum.
The crude product was
purified by HPLC with TFA to provide the title compound as a trifluoroacetic
acid salt (12 mg, 13%).
1H NMR (300 MHz, DMSO-D6) S ppm: 2.45 (s, 3 H), 2.75 (s, 3 H), 3.83 (s, 3 H),
6.98 (dd, J=7.72,
2.21 Hz, 1 H), 7.20 (d, J=2.21 Hz, 1 H), 7.25 (d, J=8.09 Hz, 1 H), 7.41 (t,
J=7.91 Hz, 1 H), 7.48 (s, 1
H), 7.56 (s, 1 H), 7.82 (d, J=5.15 Hz, 1 H), 7.83 (d, J=3.31 Hz, 1 H), 8.96
(s, 1 H), 9.03 (d, J=8.46 Hz,
1 H), 11.34 (s, I H); MS (ESI)+ m/z 357 (M+H)+.

Example 106
{ 2-2-(4-Methoxy-phenyl)-ethyl]-5-methyl-phenyl } -(7-methyl-pyrido [2,3-
et]pyrimidin-4-yl)amine
Example 106A
1-[2-(4-Methoxy-phenyl)-vinyl-4-methyl-2 nitro-benzene

[0456] To a solution of 1-Bromo-4-methyl-2-nitro-benzene (0.76g, 3.5 mmol), 1-
methoxy-4-
vinyl benzene (0.59 g, 4.4 mmol), triethylamine (0.88 g, 8.8 mmol), tri-o-
tolylphosphine (0.022 g)
and palladium acetate (0.008g) in NN-dimethylformamide (7 mL) was placed in a
high-pressure tube
and purged with nitrogen for 10 mins. The tube was sealed and heated at 120 C
for 16 hours. The
mixture was partitioned with water and ethyl acetate adjusting the pH to 3.
The organic layer was
washed with brine, dried (sodium sulfate) and filtered through a plug of
silica. The filtrate was
evaporated under vacuum and the residue was triturated with hexane/ethyl
acetate (9:1) to provide the
title compound (0.55 g, 58%).

Example 106B
2-[2-(4-Methoxy-phenyl)-ethyl]-5-methyl-phenylamine
110


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[0457] To a solution of the product from Example 106A (164 mg, 0.6 mmol) and
10%
palladium on charcoal (50 mg) in ethanol (20 ml) was hydrogenated with a
hydrogen balloon for three
days. The solvent was filtered through celite, washed with ethanol and
evaporated under vacuum to
provide the title compound (140 mg, 97%).

Example 106C
{2-2-(4-Methoxy-phenyl)-ethyl]-5-methyl-phenyl }-(7-methyl-pyrido[2,3-
d]pyrimidin-4-yl)amine
[0458] The product from Example 106B was reacted with the product from Example
lOC
using the procedure from Example 104C substituting the product from Example
106B for the product
from Example 104B to provide the crude residue which was purified by
chromatography on silica
eluting with 99:1 dichloromethane/methanol to provide the title compound (53
mg, 69%). IH NMR
(300 MHz, DMSO-D6) 8 ppm: 2.30.(s, 3 H), 2.69 (m, 7 H), 3.64 (s, 3 H), 6.69
(d, J = 8.8 Hz, 2 H),
6.89 (d, J= 8.8 Hz, 2 H), 7.08 (d, J= 7.7 Hz, 1 H), 7.13 (s, 1 H), 7.22 (d, J=
7.7 Hz, 1 H), 7.53 (d, J=
8.5 Hz, 1 H), 8.50 (s, 1 H), 8.79 (d, J= 8.5 Hz, 1 H), 9.83 (s, I H); (ESI+)
m/z 385 (M+H)+.

Example 107
4-[4-Methyl-2-(pyrido [2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenol

[0459] The product from Example 6c was reacted with the product from Example
57A using
the procedure from Example IOF substituting the product from Example 6c for
the product from
Example l0E and substituting the product from Example 57A for the product from
Example 10B to
provide the crude residue which was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) 6 ppm: 2.31 (s, 3 H),
6.61 - 6.78 (m, 2 H),
7.02 (d, J= 8.09 Hz, 1 H), 7.11 - 7.20 (m, 3 H), 7.24 (s, 1 H), 7.87 (dd, J=
8.46, 4.41 Hz, 1 H), 8.79
(s, 1 H), 9.03 (d, J= 8.46 Hz, I H), 9.14 - 9.19 (m, I H), 9.79 (s, I H); MS
(ESI+) m/z 361 (M+H)+.
Example 108
(5-Methyl-2-phenylsulfanyl-phenyl)-pyrido [2,3 -d]pyrimidin-4-yl-amine

[0460] The product from Example SI was reacted with the product from Example
57A using
the procedure from Example IOF substituting the product from Example 51 for
the product from
Example 10E and substituting the product from Example 57A for the product from
Example lOB to
provide the crude residue which was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt. IH NMR (300 MHz, DMSO-D6) 8 ppm: 2.37 (s, 3 H),
7.09 - 7.27 (m, 6 H),
7.35 (d, J= 7.72 Hz, 2 H), 7.83 (dd, J= 8.09, 4.41 Hz, 1 H), 8.75 (s, 1 H),
8.96 (d, J = 7.72 Hz, 1 H),
9.13 (d, J= 3.31 Hz, 1 H); MS (ESI+) m1z 345 (M+H)+.

Example 109
N-{4-[4-Methyl-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl] phenyl}-
acetamide
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[04611 The product from Example 7b was reacted with the product from Example
57A using
the procedure from Example lOF substituting the product from Example 7b for
the product from
Example l0E and substituting the product from Example 57A for the product from
Example 10B to
provide the crude residue which was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 2.02 (s, 3 H),
2.34 (s, 3 H), 7.13 -
7.35 (m, 5 H), 7.46 (d, J 8.46 Hz, 2 H), 7.87 (dd, J = 8.09, 4.41 Hz, 1 H),
8.80 (s, 1 H), 9.01 (d, J
8.09 Hz, I H), 9.15 (d, J 3.31 Hz, 1 H), 9.99 (s, 1 H); MS (ESI+) m/z 402
(M+H)+.

Example 110
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]
phenol

[0462] The product from Example 6c was reacted with the product from Example
36E using
the procedure from Example 361 substituting the product from Example 6c for
the product from
Example 36H to provide the crude residue which was purified by HPLC with TFA
to provide the title
compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.35
(d, J = 6.62
Hz, 6 H), 2.31 (s, 3 H), 3.29 (t, J = 6.89 Hz, 1 H), 6.70 (d, J = 8.82 Hz, 2
H), 7.01 (d, J = 8.09 Hz, 1
H), 7.17 (d, J = 8.82 Hz, 2 H), 7.13 - 7.22 (m, 2 H), 7.23 (s, 1 H), 7.87 (d,
J = 8.82 Hz, 1 H), 8.79 (s, 1
H), 8.97 (d, J = 8.82 Hz, 1 H), 9.80 (s, 1 H), 11.42 (s, 1 H); MS (ESI+) m/z
403 (IVI+H)+.

Example 111
2-Chloro-4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl -
phenylsulfanyl]-phenol
[0463] To a solution of the product from Example 110 (50 mg, 0.124 mmol) in
acetic acid
(1.5 mL) was added sulfuryl chloride (0.01 mL, 0.124 mmol) dropwise at room
temperature. The
mixture was stirred for an additional 30 minutes then was concentrated under
vacuum and purified by
HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (19
mg, 28%). 1H NMR
(300 MHz, DMSO-D6) 8 ppm: 1.35 (d, J= 6.6 HZ, 6H), 2.34 (s, 3H), 3.30 (m, 1H),
6.82 (d, J= 8.5
Hz, 1 H), 7.08 (dd, J = 8.5, 2.2 Hz, 1 H), 7.17 (m, 1 H), 7.24 (m, 3H), 8.74
(s, 1 H), 8.94 (d, J = 8.5 Hz,
1H), 10.50 (s, 1H), 11.42 (bs, 1H); MS (ESI+) m/z 437 (M+H)+.

Example 112
2,6-Dichloro-4-[2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenol
104641 To a solution of the product from Example 110 (50 mg, 0.124 mmol) in
acetic acid
(1.5 mL) was added sulfuryl chloride (0.02 mL, 0.248 mmol) dropwise at room
temperature. The
mixture was stirred for an additiona130 minutes then was concentrated under
vacuum and purified by
HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (17
mg, 23%). 1H NMR
(300 MHz, DMSO-D6) 8 ppm: 1.35 (d, J = 6.6 Hz, 6H), 2.37 (s, 3H), 3.28 (m,
1H), 7.12 (s, 1H), 7.28
(m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 8.70 (s, 1H),
8.88 (d, J = 8.8 Hz, IH),
10.38 (s, 1H), 11.22 (bs, 1H); MS (ESI+) m/z 472 (M+H)+.

112


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Example 113
4-[4-Hydroxymethyl-2-(7-i sopropyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-
phenylsulfanyl] -phenol
Example 113A
4-(4-Hydroxy-phenylsulfanyl)-3-nitro-benzoic acid methyl ester

[0465] A solution of 4-Chloro-3-nitro-benzoic acid methyl ester (4.0 g, 18.55
mmol) in
anhydrous N,N-dimethylformamide (25 mL) was treated with 4-mercaptophenol
(2.34 g, 18.55 mmol)
and cesium carbonate (9.07 g, 27.83 mmol) at room temperature for 23 hours.
The solvent was then
removed by rotary evaporation under vacuum, the residue taken up in water (100
mL) and the pH
adjusted to 3 with 1N aqueous HCI. The aqueous solution was extracted with
ethyl acetate (2 x 100
mL), and the combined organic extracts washed with brine (50 mL). The organic
layer was dried over
magnesium sulfate, filtered, and concentrated by rotary evaporation to provide
the product as an
orange oil contaminated with N,N-dimethylformamide (7.28 g).

Example 113B
3-Amino-4-(4-hydroxy-phenylsulfanyl)-benzoic acid methyl ester

[0466] A suspension of the product of Example 113A (as a mono DMF adduct)(7.25
g, 19.23
mmol) ammonium chloride (1.54 g, 28.8 mmol) and iron powder (5.37 g, 96.15
mmol) in
tetrahydrofuran (75 rnL), water (25 mL) and ethanol (75 mL) was heated at
reflux for 3 hours. The
reaction was cooled to room temperature, and the mixture was filtered through
a pad of celite, which
was then washed with methanol, and the filtrate concentrated to a solid under
vacuum. The residue
was then dissolved in water (100 mL) and extracted with dichloromethane (2 x
50 mL). The
combined organic extracts were washed with brine (25 mL), dried over magnesium
sulfate, filtered,
and concentrated under vacuum to provide the title compound as a white solid
(4.2 g, 79%).

Example 113C
4-(2-Amino-4-hydroxymethyl ghenylsulfanyl)-phenol

[04671 To the product from Example 113B (500 mg, 1.82 mmol) in tetrahydrofuran
(50 mL)
was added a solution of lithium aluminum hydride (1.OM in THF, 1.8 mL, 1.82
mmol) dropwise at
room temperature followed by heating the mixture to 70 C for 4 hours. Water
(25 mL) was then
carefully added to the solution and the organic layer separated, dried and
concentrated under vacuum
to provide the title compound (295 mg, 66%).

Example 113D
4-[4-Hydroxymethyl-2-(7-isopropyl-pyrido[2,3-d]pyrinzidin-4-ylamino)-
phenylsulfanyl]-phenol
104681 The product from Example .1 13C was reacted with the product from
Example 36E
using the procedure from Example 361 substituting the product from Example
113C for the product
from Example 36H to provide the crude residue which was purified by HPLC with
TFA to provide
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the title compound as a trifluoroacetic acid salt (30 mg, 31%). 1H NMR (300
MHz, DMSO-D6) S
ppm: 1.36 (d, J = 7.0 Hz, 6H), 3.30 (m, 1H), 4.50 (s, 2H), 6.72 (d, J = 8.5
Hz, 2H), 7.05 (d, J= 8.1
Hz, 1H), 7.19 (d, J= 8.5 Hz, 2H), 7.27 (m, 1H), 7.35 (s, 1H), 7.87 (d, J= 8.5
Hz, 1H), 8.79 (s, 1H),
8.98 (m, IH), 9.82 (s, 11-1), 11.43 (bs, 1H); MS (ESI+) m/z 419 (M+H)+.

Example 114
Acetic acid 4-(4-hydroxy-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-
4-ylamino)-benzyl
ester
[0469] The product from Example 113C was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
113C for the product
from Example 36H to provide the crude residue which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (12 mg,,11%). 1H NMR (300
MHz, DMSO-D6) S
ppm: 1.36 (d, J= 6.6 Hz, 611), 2.05 (s, 3H), 3.30 (m, 1H), 5.07 (s, 2H), 6.71
(d, J= 8.5 Hz, 2H), 7.03
(d, J= 8.1 Hz, 1 H), 7.19 (d, J = 8.5 Hz, 2H), 7.27 (m, 1 H), 7.40 (m, 1 H),
7.95 (d, J= 8.8 Hz, 1 H),
8.89 (s, iH), 9.02 (d, J= 8.8 Hz, IH), 9.75 (bs, 1H), 11.79 (bs, 1H); MS
(ESI+) rn/z 461 (M+H)+.

Example 115
N- {4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenyl} -
acetamide
[0470] The product from Example 7b was reacted with the product from Example
36E using
the procedure from Example 361 substituting the product from Example 7b for
the product from
Example 36H to provide the crude residue which was purified by HPLC with TFA
to provide the title
compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.35
(d, J = 6.99
Hz, 6 H), 2.02 (s, 3 H), 2.33 (s, 3 H), 3.28 (t, J= 6.89 Hz, I H), 7.18 (s, I
H), 7.20 (d, J= 8.46 Hz, 2
H), 7.28 (s, 1 H), 7.46 (d, J= 8.46 Hz, 2 H), 7.86 (d, J= 8.46 Hz, 1 H,) 8.79
(s, 1 H), 8.93 (d, J= 8.82
Hz, 1 H), 9.99 (s, 1 H), 11.46 (s, 1 H); MS (ESI+) m/z 444 (M+H)+.

Example 116
(7-Isopropyl-pyrido [2,3 -d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5 -methyl-
phenyl]-amine
Example 116A
1-(4-Methoxy-phenoxy)-4-methyl-2-nitro-benzene

[0471] 4-Methoxy-phenol was reacted with 1-fluoro-4-methyl-2-nitrobenzene
according to
the procedure from Example 122a substituting 4-methoxy-phenol for hydroquinone
to provide the
title compound.

Example 116B
2-(4-Methoxy-phenoxy)-5-methyl-phenylamine
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[0472] The product from Example 11 6A was reduced according to the procedure
of Example
104B substituting the product from Example 116A for the product from Example
104A to provide the
title compound.

Example 116C
(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5-methyl-
phenyl]-amine
[0473] The product from Example 116B was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
116B for the product
from Example 36H to provide the crude residue which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S
ppm: 1.33 (d, J
6.99 Hz, 6 H), 2.33 (s, 3 H), 3.26 (dt, J= 13.74, 6.85 Hz, 1 H), 3.67 (s, 3
H), 6.77 - 6.96 (m, 5 H),
7.18 (dd, J= 8.46, 2.21 Hz, I H), 7.33 (d, J= 1.84 Hz, I H), 7.83 (d, J= 8.46
Hz, I H), 8.84 (s, 1 H),
8.91 (d, J= 8.82 Hz, 1 H), 11.33 (s, 1 H); MS (ESI)+ rn/z 401 (M+H)+.

Example 117
4-[2-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenoxy]-phenol
[0474] The product from Example 122b was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
122b for the product
from Example 36H to provide the crude residue which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) 8
ppm: 1.33 (d, J=
6.99Hz,6H),2.32(s,3H),3.27(t,J=6.89Hz,1H),6.67(m,2H),6.75-6.85(m,3H),7.16(dd,J
= 8.46, 1.84 Hz, 1 H), 7.31 (d, J= 1.47 Hz, 1 H), 7.84 (d, J= 8.46 Hz, I H),
8.85 (s, 1 H), 8.94 (d, J=
8.46 Hz, 1 H), 9.28 (s, 1 H); MS (ESI)+ m/z 387 (M+H)+.

Example 118
(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenylsulfanyl)-5 -
methyl-phenyl]-amine
[0475] The product from Example 6a (5.0 g, 175 mmol) was reacted with 4-
methoxy-
benzenethiol (2.45 g, 175 mmol) for 18 h following the procedure from Example
6b giving 1-(4-
methoxy-phenylsulfanyl)-4-methyl-2-nitro-benzen, which was reduced with SnC12
following the
procedure from Example 51 giving 2-(4-Methoxy-phenylsulfanyl)-5-methyl-
phenylamine.
[0476] 2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine was reacted with the
product
from Example 36E using the procedure from Example 3 61 substituting 2-(4-
methoxy-phenylsulfanyl)-
5-methyl-phenylamine for the product from Example 36H to provide the crude
residue which was
purified by HPLC with TFA to provide the title compound as a trifluoroacetic
acid salt. 1H NMR
(300 MHz, DMSO-D6) S ppm: 1.35 (d, J= 6.62 Hz, 6 H), 2.33 (s, 3 H), 3.28 (t,
J= 6.89 Hz, 1 H),
3.69 (s, 3 H), 6.81 (d, J= 9.19 Hz, 2 H), 7.06 - 7.20 (m, 2 H), 7.23 (d, J=
8.82 Hz, 2 H), 7.26 (s, I H),
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7.85 (d, J = 8.46 Hz, 1 H), 8.76 (s, I H), 8.94 (d, J = 8.46 Hz, 1 H), 11.36
(s, 1 H); MS (ESI)+ m/z 417
(M+H)+.

Example 119
(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylsul fanyl-
phenyl)-amine
Example 119A
N'-(3-Cyano-6-cyclopropyl pyridin-2-yl)-N,N-dimethyl-formamidine

[0477] Cyclopropyl methyl ketone was reacted according to the procedures
described in
Examples 36A-36E to provide the title compound.

Example 119B
(7-Cyclopropyl-pyrido [2, 3-d]pyrimidin-4-yl)-(5-methyl-2-phenylsuifanyl-
phenyl)-amine

[0478] The product from Example 51 was reacted with= the product from Example
119A
using the procedure from Example 102 substituting the product from Example 51
for the product from
Example 6c and substituting the product from Example 119A for the product from
Example lOB to
provide the crude residue which was purified by trituration with methanol to
provide the title
compound. IH NMR (300 MHz, DMSO-D6) S ppm: 1.05 - 1.19 (m, 4 H), 2.22 - 2.41
(m, I H), 2.35
(s, 3 H), 7.05 - 7.31 (m, 7 H), 7.37 (s, 1 H), 7.58 (d, J = 8.46 Hz, 1 H),
8.50 (s, 1 H), 8.65 (d, J= 8.46
Hz, I H), 10.21 (s, 1 H); MS (ESI)+ m/z 385 (M+H)+.

Example 120
4-[2-(7-Cyclopropyl-pyrido[2,3-d]pyrimi din-4-ylamino)-4-methyl-
phenylsulfanyl)-phenol
[0479] The product from Example 6c was reacted with the product from Example
119A
using the procedure from Example 102 substituting the product from Example
119A for the product
from Example lOB to provide the crude residue which was purified by
trituration with methanol to
provide the title compound. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.05 - 1.22 (m,
J= 1.84 Hz, 4
H), 2.24 - 2.39 (m, I H), 2.29 (s, 3 H), 6.73 (d, J= 8.82 Hz, 2 H), 6.91 (d,
J= 8.09 Hz, I H), 7.04 (dd,
J= 8.09, 1.47 Hz, 1 H), 7.17 (d, J= 8.82 Hz, 2 H), 7.25 (s, 1 H), 7.57 (d, J
8.82 Hz, 1 H), 8.49 (s, 1
H), 8.71 (d, J= 8.46 Hz, 1 H), 9.74 (s, 1 H), 9.92 (s, 1 H); MS (ESI)+ m/z.401
(M+H)+.

Example 121
N- {4-[2-(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenyl} -
acetamide
[0480] The product from Example 7b was reacted with the product from Example
119A
using the procedure from Example 102 substituting the product from Example 7b
fqr the product from
Example 6c and substituting the product from Example 119A for the product from
Example lOB to
provide the crude residue which was purified by trituration with methanol to
provide the title
compound. IH NMR (300 MHz, DMSO-D6) S ppm: 1.13 (d, J= 6.25 Hz, 4 H), 2.02 (s,
3 H), 2.22 -
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2.38 (m, 1 H), 2.31 (s, 3 H), 7.07 (s, 2 H), 7.20 (d, J = 8.82 Hz, 2 H), 7.30
(s, I H), 7.50 (d, J= 8.82
Hz, 2 H), 7.56 (d, J= 8.46 Hz, I H), 8.49 (s, 1 H), 8.68 (d, J = 8.82 Hz, 1
H), 9.99 (s, 2 H); MS (ESI+)
m/z 442 (M+H)+.

Example 122
4-[2-(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenoxy]-phenol
Example 122a
4-(4-methyl-2-nitrophenoxy)phenol
[0481] A solution of hydroquinone (3.2 g, 29.0 mmol) and K2C03 (8.0 g, 54.0
mmol) in 40
niL of DMF was heated at 100 C with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g,
19.3 mmol) with
stirring for 24 hours. Cooled to room temperature and diluted with EtOAc.
Washed with water and
dried the organic layer over MgSO4. Filtered and concentrated under vacuum
giving the title
compound, which was purified by silica gel column chromatography eluting with
5% EtOAc/hexane
giving an orange oil (1.89 g, 40%).

Example 122b
4-(2-arnino-4-methylphenoxy)phenol
[0482] The product from Example 122a (1.89 g, 7.71 mmol) was reduced with
SnCIZ
following the procedure from Example 51 giving the title compound as a white
solid (1.42 g, 86%).
Example 122c
4-(2-(7-cyclopropylpyrido[2,3-d]pyrimidin-4-ylamino)-4-methylphenoxy)phenol
[04831 The product from Example 122b was reacted with the product from Example
119A
using the procedure from Example 102 substituting the product from Example
122b for the product
from Example 6c and substituting the product from Example 11 9A for the
product from Example lOB
to provide the crude residue which was purified by trituration with methanol
to provide the title
compound. 1H NNMR (300 MHz, DMSO-D6) S ppm: 1.03 - 1.18 (m, J = 6.25 Hz, 4 H),
2.20 - 2.35
(m, 1 H), 2.30 (s, 3 H), 6.57 - 6.85 (m, 5 H), 7.03 (dd, J= 8.27, 1.65 Hz, 1
H), 7.36 (d, J= 1.84 Hz, 1
H), 7.52 (d, J= 8.46 Hz, I H), 8.50 (s, 1 H), 8.65 (d, J= 8.46 Hz, I H), 9.18
(s, 1 H), 9.70 (s, 1 H);
MS (ESI)+ m/z 385 (M+H)+.

Example 123
(7-Cyclopropyl-pyrido [2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5 -methyl-
phenyl]-amine
[0484] The product from Example 11 6B was reacted with the product from
Example 119A
using the procedure from Example 102 substituting the product from Example
116B for the product
from Example 6c and substituting the product from Example 119A for the product
from Example 10B
to provide the crude residue which was purified by trituration with methanol
to provide the title
compound. IH NMR (300 MHz, DMSO-D6) S ppm: 1.02 - 1.20 (m, J= 6.25 Hz, 4 H),
2.21 - 2.37
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(m, I H), 2.31 (s, 3 H), 3.66 (s, 3 H), 6.75 - 6.92 (m, 5 H), 7.06 (dd, J=
8.64, 0.92 Hz, 1 H), 7.37 (s, 1
H), 7.51 (d, J= 8.46 Hz, 1 H), 8.49 (s, 1 H), 8.63 (d, J= 8.82 Hz, 1 H), 9.74
(s, 1 H); MS (ESI)+ m/z
399 (M+H)+.

Example 124
(7-Cyclopropyl -pyrido[2,3-d]pyrirnidin-4-yl)-[2-(4-fluoro-phenylsulfanyl)-5-
methyl-phenyl]-amine
[04851 The product from Example 6a (5.00 g, 17.53 mmol) was reacted with 4-
fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol following the
procedure from Example
5H for 18 h giving 1-(4-Fluoro-phenylsulfanyl)-4-methyl-2-nitro-benzene which
was purified by
silica gel column chromatography eluting with 5 % EtOAc /hexane providing a
solid (3.39 g, 74 %).
1-(4-Fluoro-phenylsulfanyl)-4-methyl-2-nitro-benzene was reduced with SnC12
following the
procedure from Example 51 giving 2-(4-Fluoro-phenylsulfanyl)-5-methyl-
phenylaniine.
[0486] 2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine was reacted with the
product
from Example 119A using the procedure from Example 102 substituting 2-(4-
Fluoro-phenylsulfanyl)-
5-methyl-phenylamine for the product from Example 6c and substituting the
product from Example
119A for the product from Example 10B to provide the crude residue which was
purified by
trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-
D6) 8 ppm:
0.96 - 1.19 (m, J= 6.25 Hz, 4 H), 2.22 - 2.42 (m, 1 H), 2.33 (s, 3 H), 7.02 -
7.28 (m, 6 H), 7.33 (s, I
H), 7.56 (d, J = 8.46 Hz, 1 H), 8.46 (s, 1 H), 8.66 (d, J= 8.09 Hz, I H),
10.03 (s, 1 H); MS (ESI)+ m/z
403 (M+H)+.

Example 125
(7-Cyclopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[2-(4-methoxy-phenylsulfanyl)-5 -
methyl-phenyl]-amine
[0487] 2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine (Example 118) was
reacted
with the product from Example 119A using the procedure from Example 102
substituting 2-(4-
Methoxy-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c
and substituting
the product from Example 119A for the product from Example lOB to provide the
crude residue
which was purified by trituration with methanol to provide the title compound.
1H NMR (3001VIHz,
DMSO-D6) 8 ppm: 0.96 - 1.30 (m, J= 5.52 Hz, 4 H), 2.21 - 2.42 (m, * 1 H), 2.31
(s, 3 H), 3.71 (s, 3
H), 6.85 (d, J= 8.82 Hz, 2 H), 6.99 - 7_12 (m, 2 H), 7.24 (d, J= 8.82 Hz, 2
H), 7.63 (d, J= 8.46 Hz, 1
H), 8.53 (s, 1 H), 8.72 (d, J= 8.46 Hz, 1 H), 10.33 (s, 1 H); MS (ESI)+ m/z
415 (M+H)+.

Example 126
[2-(4-Methoxy phenoxy)-5-methyl-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
amine
[04881 The product from Example 116B was reacted with the product from Example
lOC
using the procedure from Example 104C substituting the product from Example I
I6B for the product
from Example 104B to provide the crude residue which was purified by HPLC with
TFA to provide
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the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S
ppm: 2.33 (s, 3
H), 2.72 (s, 3 H), 3.68 (s, 3 H), 6.80 - 6.95 (m, 5 H), 7.18 (dd, J = 8.46,
2.21 Hz, 1H),7.34(d,J=
1.84 Hz, 1 H), 7.76 (d, J = 8.46 Hz, 1 H), 8.85 (s, 2 H), 11.32 (s, I H).

Example 127
4-[2-(7-tert-Butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-
phenol
Example 127A
N'-(6-tert-Butyl-3 -cyano-pyridin-2-yl)-N,N-dimethyl-formamidine

[04891 3,3-Dimethyl-2-butanone was reacted according to the procedures
described in
Examples 36A-36E to provide the title compound.

Example 127B
4-[2-(7-tert-Butyl-pyri do [2,3-d]pyrimidin-4-ylamino)-4-methyl-phenyl
sulfanyl]-phen ol

[0490] The product from Example 6c was reacted with the product from Example
127A
using the procedure from Example 361 substituting the product from Example 6c
for the product from
Example 36H and substituting the product from Example 127A for the product
from 276E to provide
the crude residue which was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (40 mg, 29%). 1 H NMR (300 MHz, DMSO-D6) S ppm: 1.44
(s, 9H), 2.31 (s,
3H), 6.71 (d, J 8.5 Hz, 214), 7.00 (d, J= 8.1 Hz, 1H), 7.16 (m, 1H), 7.18 (d,
J= 8.8 Hz, 2H), 7.23 (s,
1H), 8.01 d, J= 7.6 Hz, 1H), 8.75 (s, 1H), 8.97 (d, J= 8.8 Hz, 1H), 9.79 (s,
1H), 11.22 (bs, 1H); MS
(ESI)+ m/z 417 (M+H)+.

Example 128
(5-Methyl-2-phenylsulfanyl-phenyl) -(7-propyl-pyrido[2,3 -d]pyrimidin-4-yl)-
amine

[0491] The product was prepared using the procedure from Example 36A
substituting 2-
pentanone for methyl isopropyl ketone to give the intermediate that was then
reacted according to the
sequential procedures from Examples 36A-36E.

Example 128A
N'-(3-Cyano-6-propyl pyridin-2-yl)-N,N-dimethyl-formamidine

[0492] The product was prepared using the procedure from Example 36A
substituting 2-
pentanone for methyl isopropyl ketone to give the intermediate that was then
reacted according to the'
sequential procedures from Examples 36A-36E.

Example 128B
(5-Methyl-2-phenylsulfanyl-phenyl)-(7-propyl pyrido[2,3-d]pyrimidin-4-yl)-
amine

[0493] The product from Example 51 (49 mg 0.231 mmol) and the product from
Example
128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to
130 C for 1.5 hours.
119

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After cooling to room temperature a solid in the acetic acid solvent appeared
which was collected by
filtration to provide the title compound as an acetic acid salt (68 mg, 62%).
1H NMR (300 MHz,
DMSO-D6) S ppm: 0.94 (t, J = 7.4 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.35 (s,
3H), 2.88 (t, J = 7.6
Hz, 2H), 7.18 (m, 5H), 7.23 (m, 2H), 7.37 (s, 1H), 7.51 (d, J= 8.1 Hz, 1H),
8.48 (s, 1H), 8.69 (d, J=
8.5 Hz, 1H); MS (ESI)+ m/z 387 (M+H)+.

Example 129
3-[4-Methyl-2-(7-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[04941 The product from Example 6a (10.14 g, 35.6 mmol) was reacted with 3-(4-
methyl-2-
nitro-phenylsulfanyl)-phenol (4.48 g, 35.6 mmol) for 18 h following the
procedure from Example 6b
giving 3-(4-Methyl-2-nitro-phenylsulfanyl)-phenol (7.88 g, 85 %), which was
reduced with SnC12
following the procedure from Example 51 giving 3-(2-amino-4-methyl-
phenylsulfanyl)-phenol.
[0495] 3-(2-amino-4-methyl-phenylsulfanyl)-phenol (49 mg 0.231 rnmol) and the
product
from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and
heated to 130 C
for 1.5 hours. After cooling to room temperature a solid in the acetic acid
solvent appeared which was
collected by filtration to provide the title compound as an acetic acid salt
(78 mg, 68%). IH NMR
(300 MHz, DMSO-D6) S ppm: 0.95 (t, J= 7.3 Hz, 3H), 1.79 (m, 211), 1.88 (s,
6H), 2.40 (s, 311), 2.88
(t, J= 7.6 Hz, 2H), 6.57 (m, 3H), 7.00 (t, J= 7.7 Hz, 1H), 7.13 (m, IH), 7.26
(d, J= 7.7 Hz, 1H), 7.38
(s, 1H), 7.51 (d, J= 8.5 Hz, 1H), 8.50 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H); MS
(ESI)+ m/z 403 (M+H)+.
Example 130
N- {4-[4-Methyl-2-(7-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl sul
fanyl]-phenyl ) -acetami de
[04961 The product from Example 7b (49 mg 0.231 mmol) and the product from
Example
128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to
130 C for 1.5 hours.
After cooling to room temperature and removal of the acetic acid solvent under
vacuum methanol (3
mL) was added to the oil which caused a solid to form which was triturated
with methanol to provide
the title compound 80 mg, 78%). 1H NMR (300 MHz, DMSO-D6) S ppm: 0.95 (t, J=
7.4 Hz, 3H),
1.89 (m, 2H), 2.02 (s, 311), 2.32 (s, 3H), 2.89 (t, J= 7.5 Hz, 211), 7.06 (s,
2H), 7.21 (t, J 8.5 Hz, 2H),
7.30 (s, 1H), 7.50 (d, J= 8.8 Hz, 2H), 7.52 (m, 1H), 8.52 (s, 1H), 8.74 (d, J
= 7.7 Hz, 1H), 10.00 (s,
1H); MS (ESI)+ m/z 444 (M+H)+.

Example 131
4-[4-Methyl-2-(7-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[0497] The product from Example 6c (49 mg 0.231 mmol) and the product from
Example
128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to
130 C for 1.5 hours.
After cooling to room temperature a solid in the acetic acid solvent appeared
which was collected by
filtration to provide the title compound as an acetic acid salt (77 mg, 68%).
1H NMR (300 MHz,

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DMSO-D6) S ppm: 0.96 (t, J= 7.4 Hz, 3H), 1.80 (m, 2H), 1.88 (s, 6H), 2.40 (s,
3H), 2.90 (t, J= 7.6
Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.90 (d, J= 8.1 Hz, 1H), 7.03 (m, IH), 7.18
(d, J= 8.8 Hz, 2H),
7.22 (s, 1H), 7.54 (d, J= 8.1 Hz, 114), 8.53 (s, 1H), 8.78 (d, J= 8.5 Hz, 1H);
MS (EST)+ m/z 403
(M+H)+.

Example 132
N- {4-[5-Hydroxy-2-(7-isopropyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-
phenyl} -acetamide

[0498] A mixture of 2-methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-
Acetamido
thiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF
(10 mL) was heated
2.5 h at 100 'C. The mixture was cooled, diluted with ethyl acetate (100 rnL)
and the organic layer
was washed with water and aqueous 10% sodium chloride solution, then, dried
over anhydrous
sodium sulfate. The drying agent was filtered and the solvent removed under
vacuum leaving N-[4-
(5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl)-phenyl]-acetamide as a solid (2.5
g, 81 %). A solution
of N-[4-(5-Hydroxy-4-methyl-2-nitro phenylsulfanyl)-phenyl]-acetamide (2.5 g,
6.45 mmol), iron
powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in a
methanol (10 mL),
tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for
1.5 hours. The resultant
mixture was diluted with methanol (50 mL) and filtered through a pad of
celite. The filtrate was
concentrated under vacuum to a volume of 10 mL, the solution diluted with
water (50 mL) and
extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed
with 10% sodium
chloride then dried over magnesium sulfate, filtered and concentrated under
vacuum to provide N-[4-
(2-Amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetarnide (1.7g, 91%).
[0499] N-[4-(2-Amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide was
reacted
with the product from Example 36E using the procedure from Example 361
substituting N-[4-(2-
amino-5-hydroxy-4-methyl-phenylsulfanyl)-phenyl]-acetamide for the product
from Example 36H to
provide the crude residue which was purified by HPLC with TFA to provide the
title compound as a
trifluoroacetio acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.34 (d, J=6.99
Hz, 6 H), 2.03 (s, 3
H), 2.11 (s, 3 H), 3.27 (s, 1 H), 6.63 (s, 1 H), 7.12 (s, I H), 7.25 (d,
J=8.82 Hz, 2 H), 7.51 (d, J=8.82
Hz, 2 H), 7.85 (d, J=8.46 Hz, 1 H), 8.80 (s, 1 H), 8.94 (d, J=8.46 Hz, 1 H),
9.75 (s, I H), 10.02 (s, 1
H), 11.36 (s, 1 H); MS (ESI)+ m1z 460 (M+H)+.

Example 133
N'-(4-Benzyloxy-phenyl)-NZ-(7-isopropyl-pyrido [2,3-d]pyrimidin-4-yl)-4,N'-
dimethyl-benzene-l,2-
diamine

Example 133A
(4-Benzyloxy-phenyl)-(4-methyl-2-nitro-phenyl)-amine
[05001 A mixture of 4-methyl-2-nitroaniline (1.006 g, 6.612 mmol), 4-
benzyloxybromobenzene (5.794 g, 22.02 mmol), cuprous iodide (62.9 mg, 0.3306
mmol), potassium
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carbonate (0.914 g, 6.612 mmol) and anhydrous o-xylene (18 mL) was heated at
1500 for 24 hours.
Added additional cuprous iodide (30 mg) and heated an additional 6 hours at
160 . The reaction was
cooled to room temperature and the solvent removed by rotary evaporation under
vacuum. The
residue was purified by silica gel flash chromatography using 1:1 methylene
chloride/hexanes as
eluent to afford the title compound as a red oil which slowly crystallized
(1.23 g, 56%).

Example 133B
(4-Benzyloxy-phenyl)-methyl-(4-methyl-2-nitro phenyl)-amine

[0501] A solution of the product from Example 133A (229.4 mg, 0.6861 mmol) in
anhydrous N,N-dimethylformamide (3 mL) was added to a suspension of sodium
hydride (60%
dispersion in mineral oil, 55 mg, 1.372 mmol) in N,N-dimethylformamide (3 mL)
at room
temperature under a nitrogen atmosphere. The reaction was stirred at room
temperature for 1 hour,
then added methyl iodide (0.171 mL, 2.744 mmol) and let stir at room
temperature for 2 hours. The
solvent was removed by rotary evaporation under vacuum. The residue was taken
up in water (30
mL) and extracted with methylene chloride (50 mL). The organic phase was
washed with water (30
mL), dried over anhydrous magnesium sulfate, filtered, and concentrated by
rotary evaporation under
vacuum to afford the title compound as a maroon-colored solid (239 mg, 100%).

Example 133C
(4-Benzyloxy-phenyl)-methyl-(4-methyl-2-amino-phenyl)-amine
[0502] A mixture of the product from Example 133B (129.4 mg, 0.3714 mmol),
iron powder
(128 mg, 2.284 mmol), ammonium chloride (130 mg, 2.433 mmol) in water (1 mL)
and ethanol (2
mL) was heated at 70 under a nitrogen atmosphere for 1 hour. The reaction was
cooled to room
temperature and vacuum filtered, washing the residue with methanol. The
filtrate was concentrated
under vacuum and azeotroped with toluene (50 niL). The residue was purified by
silica gel flash
chromatography using methylene chloride as eluent to provide the title
compound as a waxy solid (85
mg, 72%).

Example 133D
N'-(4-B enzyloxy-phenyl)-N2-(7-isopropyl-pyrido [2,3-a'lpyrirnidin-4-yl)-4,1V'
-dimethyl-benzene-1,2-
diamine
[0503] A solution of the product from Example 36E (28 mg, 0.1297 mmol) and the
product
from Example 133C (41.3 mg, 0.1297 mmol) in acetic acid (1 mL) was stirred in
an oil bath preheated
to 140 C for 1 hour. The reaction was cooled to room temperature, diluted with
hexanes (50 mL),
concentrated by rotary evaporation under vacuum, and co-evaporated with
methylene
chloride/hexanes (4x). The residue was dried, then purified by silica gel
flash chromatography using
20% ethyl acetate/methylene chloride as eluent to afford the title compound as
a yellow solid (35 mg,
55%). 'H NMR (300 MHz, DMSO-D6) 5 ppm: 1.27 (d, J= 6.62 Hz, 6 H), 2.34 (s, 3
H), 3.08 (s, 3
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H), 3.06 - 3.22 (m, I
H),4.79(s,2H),6.50(d,J=9.19Hz,2H),6.60(d,J=8.82Hz,2H),7.05-
7.17 (m, 2 H), 7.25 - 7.37 (m, 5 H), 7.41 (d, J= 8.46 Hz, 1 H), 7.47 (s, 1 H),
8.42 (d, J=8.46 Hz, I H),
8.52 (s, I H), 9.33 (s, I H); MS (DCI/NH3) m/z 490 (M+H)+.

Example 134
(2-Benzyl-5-methyl-phenyl)-(7-isopropyl-pyrido[2,3 -d]pyrimidin-4-yl)-amine
Example 134A
2-B enzyl-5 -methyl-phenyl arnine

[0504] A solution of lithium alu.minum hydride in tetrahydrofuran (1.0 M, 2.54
mL, 2.54
mmol) was added via syringe to a flask containing aluminum chloride (534 mg,
4.005 mmol) under a
nitrogen atmosphere and cooled in a 0 bath. After letting the mixture cool
for 5 minutes, a solution
of 2-amino-4-methylbenzophenone (200 mg, 0.9467 mmol) in tetrahydrofuran (4
mL) was added
slowly dropwise at 0 . The reaction was then heated at 50 for 30 minutes. The
reaction was cooled
to room temperature and moist ethyl ether (5 mL) was added. The reaction was
carefully poured into
water (20 mL) and extracted with ethyl ether (2 x 50 mI,). The combined
ethereal extracts were
washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated by rotary
evaporation under vacuum. Purification by silica gel flash chromatography
using 40:60
hexanes/methylene chloride as eluent provided the title compound as an oil (94
mg, 50%).

Example 134B
(2-B enzyl-5-methyl-phenyl)-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine

[0505] A solution of the product from Example 36E (34.6 mg, 0.160 mmol) and
the product
from Example 134A (31.6 mg, 0.160 mmol) in acetic acid (1 niL) was stirred in
an oil bath preheated
to 140 C for 1 hour. The reaction was cooled to room temperature, diluted with
hexanes (50 mL),
concentrated by rotary evaporation under vacuum, and co-evaporated with
methylene
chioride/hexanes (4x). The residue was dried, then purified by silica gel
flash chromatography using
2% methanol/methylene chloride as eluent to provide the title compound as a
light yellow solid (50
mg, 85%). 'H NMR (300 MHz, DMSO-D6) S ppm: 1.32 (d, J=6.99 Hz, 6 H) 2.30 (s, 3
H) 3.12 - 3.28
(m, 1 H) 3.87 (s, 2 H) 6.95 - 7.20 (m, 8 H) 7.57 (s, 1 H) 8.47 (s, I H) 8.74
(d, J=8.46 Hz, I H) 9.81 (s,
1 H); MS (DCI/NH3) m/z 369 (M+H)+.

Example 135
(7-Cyclohexyl-pyrido [2, 3 -d]pyrimidin-4-yl)-(5-methyl-2-phenylsulfanyl-
phenyl)-amine
Example 135A
N'-(3-Cyano-6-cyclohexyl-pyridin-2-yl)-N,N-dimethyl-formamidine

[0506] 1-Cyclohexyl-ethanone was reacted according to the procedures described
in
Examples 36A-36E to provide the title compound.

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Example 135B
(7-Cyclohexyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylsulfanyl-phenyl)-
amine

[0507] To a solution of the product from Example 135A (56.0 mg, 0.2322 mmol)
in acetic
acid (4 mL) was added the product from Example 51 (50.0 mg, 0.2322 mmol) and
the mixture stirred
in an oil bath preheated to 130 C for 15 minutes. The mixture was then cooled
to room temperature,
the acetic acid removed under vacuum, and the resultant residue purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt (20 mg, 20%). 1H NMR
(300 MHz, DMSO-
D6) S ppm: 1.38 - 1.51 (m, 2 H), 1.57 - 1.69 (m, 2 H), 1.70 - 1.80 (m, 2 H),
1.80 - 1.99 (m, 6 H), 2.33
- 2.40 (m, 3 H), 7.12 - 7.17 (m, 1 H), 7.12 - 7.26 (m, 3 H), 7.30 - 7.33 (m, 1
H), 7.33 - 7.38 (m, 2 H),
8.68 - 8.75 (m, 1 H), 8.82 - 8.90 (m, 1 H); MS (DCI/NH3) m/z 427 (M+H)+.

Example 136
4-[2-(7-Cyclohexyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-
phenol
[0508] The product from Example 135A was reacted with the product from Example
6c
according to the procedure from Example 135B substituting the product from
Example 6c for the
product from Example 51 to provide the title compound as a trifluoroacetic
acid salt (20 mg, 20%).
1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.38 - 1.52 (m, 2 H), 1.55 - 1.80 (m, 3 H),
1.80 - 1.91 (m, 2
H), 1.91 - 2.03 (m, 3 H), 2.30 (s, 3 H), 3.26 - 3.47 (m, 1 H), 6.66 - 6.74 (m,
2 H), 6.74 - 6.81 (m, 1 H),
6.96 - 7.03 (m, 1 H), 7.10 - 7.14 (m, I H), 7.14 - 7.21 (m, 3 H), 7.21 - 7.26
(m, 1 H), 8.72 - 8.80 (m, I
H), 8.90 - 8.97 (m, 1 H), 9.78 (s, 1 H); MS (DCUNH3) mlz 443 (1VI+H)+.

Example 137
N-{4-[2-(7-Cyclohexyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl] phenyl}-
acetamide

[0509] The product from Example 135A was reacted with the product from Example
7b
according to the procedure from Example 135B substituting the product from
Example 7b for the
product from Example 51 to provide the title compound as a trifluoroacetic
acid salt (21 mg, 25%). 1H
NMR (300 MHz, DMSO-D6) S ppm: 1.28 - 1.52 (m, 3 H), 1.53 - 1.79 (m, 3 H), 1.79
- 1.97 (m, 4 H),
2.02 (s, 3 H), 2.32 (s, 3 H), 2.79 - 2.94 (m, I H), 7.03 - 7.12 (m, 1 H), 7.20
(d, J= 8.46 Hz, 2 H), 7.31
(s, 1 H), 7.50 (d, J = 8.82 Hz, 2 H), 7.56 (d, J = 8.46 Hz, 1 H), 8.54 (s, 1
H), 8.76 (d, J = 8.82 Hz, I
H), 9.99 (s, 2 IT); MS (DCI/NH3) m/z 484 (M+H)+.

Example 138
N- {4-[2-(7-Cyclobutyl-pyrido [2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenyl } -
acetamide
Example 138A
N'-(3-Cyano-6-cyclobutyl-pyridin-2-yl)-N,N-dimethyl-formamidine
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[0510] 1-Cyclobutyl-ethanone was reacted according to the procedures described
in
Examples 36A-36E to provide the title compound.

Example 138B
N- {4-[2-(7-Cyclobutyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenyl}-
acetarnide
[0511] The product from Example 138A was reacted with the product from Example
7b
according to the procedure from Example 135B substituting the product from
Example 7b for the
product from Example 51 and substituting the product from Example 138A for the
product from
Example 135A to provide the title compound as a trifluoroacetic acid salt (30
mg, 36% yield). 1H
NMR (500 MHz, DMSO-D6) S ppm: 0.86 (t, J = 7.02 Hz, 1 H), 1.86 - 1.98 (m, 1
H), 2.02 (s, 3 H),
2.06 - 2.18 (m, I H), 2.34 (s, 3 H), 2.37 - 2.47 (m, 4 H), 3.80 - 4.02 (m, I
H), 7.13 - 7.25 (m, 4 H),
7.29 (s, I H), 7.45 (d, J= 8.54 Hz, 2 H), 7.78 (d, J= 8.54 Hz, 1 H), 8.80 (s,
1 H), 8.92 (d, J= 8.54 Hz,
I H), 9.98 (s, I H); MS (DCI/NH4) m/z 456 (M+H)+.

Example 139
4-[2-(7-Cyclobutyl-pyrido [2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-
phenol

[0512] The product from Example 138A was reacted with the product from=Example
6c
according to the procedure from Example 135B substituting the product from
Example 6c for the
product from Example 51 and substituting the product from Example 138A for the
product from
Example 135A to provide the title compound as a trifluoroacetic acid salt (30
mg, 33%). 1H NMR
(300 MHz, DMSO-D6) S ppm: 1.85 - 2.01 (m, I H), 2.03 - 2.24 (m, 1 H), 2.31 (s,
3 H), 2.36 - 2.46
(m,4H),3.81-4.13(m,2H),6.70(d,J=8.46Hz,2H),7.02(d,J=8.09Hz,1H),7.17(d,J=8.46
Hz, 3 H), 7.24 (s, 1 H), 7.82 (d, J= 8.46 Hz, 1 H), 8.82 (s, 1 H), 9.97 (d, J=
8.46 Hz, 1 H), 9.72 - 9.93
(m, 1 H); MS (DCI/NH4) m/z 415 (M+H)+.

Example 140
(7-sec-Butyl-pyrido[2,3-d]pyrimidin-4-y1)-(5-methyl-2-phenylsulfanyl-phenyl)-
amine
Example 140A
N'-(6-sec-Butyl-3-cyano-pyridin-2-yl)-N,N-dimethyl-formamidine
[0513] 3-Methyl-pentan-2-one was reacted according to the procedures described
in
Examples 36A-36E to provide the title compound.

Example 140B
(7-sec-Butyl-pyrido[2,3-d]pyrimidin-4-y1)-(5-methyl-2-phenylsulfanyl-phenyl)-
amine
[0514] The product from Example 140A was reacted with the product from Example
51
according to the procedure from Example 135B substituting the product from
Example 140A for the
product from Example 135A to provide the title compound as a trifluoroacetic
acid salt. 1H NMR

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(300 MHz, DMSO-D6) S ppm: 0.83 (t, J= 7.35 Hz, 3 H), 1.32 (d, J= 6.99 Hz, 3
H), 1.59 - 1.75 (m, 1
H), 1.75 - 1.95 (m, I H), 2.37 (s, 3 H), 2.95 - 3.12 (m, 2 H), 7.11 - 7.22 (m,
5 H), 7.25 (d, J= 6.62 Hz,
1 H), 7.31 - 7.46 (m, 2 H), 7.81 (d, J= 8.82 Hz, 1 H), 8.76 (s, 1 H), 8.91 (d,
J= 8.46 Hz, I H); MS
(DCI/NH4) M/Z 401 (M+H)+.

Example 141
N- {4-[2-(7-sec-Butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenyl } -
acetamide
[0515] The product from Example 140A was reacted with the product from Example
7b
according to the procedure from Example 135B substituting the product from
Example 7b for the
product from Example 51 and substituting the product from Example 140A for the
product from
Example 135A to provide the title compound as a trifluoroacetic acid salt (37
mg, 45%). 1H NMR
(500 MHz, DMSO-D6) 8 ppm: 0.84 (t, J= 7.32 Hz, 3 H), 1.33 (d, J= 6.71 Hz, 3
H), 1.62 - 1.76 (m, 1
H), 1.77 - 1.91 (m, 1 H), 2.34 (s, 3 H), 2.49 (s, 3 H), 2.96 - 3.14 (m, 1 H),
7.11 - 7.25 (m, 4 H), 7.28
(s, 1 H), 7.46 (d, J= 9.16 Hz, 2 H), 7.83 (d, J= 8.54 Hz, 1 H), 8.79 (s, I H),
8.94 (d, J= 7.93 Hz, 1
H), 9.97 (s, 1 H), 11.31 - 11.69 (m, I H); MS (DCI/NH4) m/z 458 (M+H)+.

Example 142
N-(4- {4-Methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3 -d]pyrirnidin-4-
ylamino] -phenylsulfanyl } -
phenyl)-acetarnide
Example 142A
N'-[3-Cyano-6-(1-methyl-cyclopropyl)-pyridin-2-yl]-N,N-dirnethyl-formamidine

[05161 1-(1-Methyl-cyclopropyl)-ethanone was reacted according to the
procedures
described in Examples 36A-36E to provide the title compound.

Example 142B
N-(4-{4-Methyl-2-[7-(1-methyl-cyclopropyl) pyrido[2,3-d]pyrimidin-4 ylamino]-
phenylsulfanyl}-
phenyl)-acetamide

[05171 The product from Example 142A was reacted with the product from Example
7b
according to the procedure from Example 135B substituting the product from
Example 7b for the
product from Example 51 and substituting the product from Example 142A for the
product from
Example 135A to provide the title compound as a trifluoroacetic acid salt (30
mg, 50%). IH NMR
(300 MHz, DMSO-D6) 8 ppm: 0.79 - 0.91 (m, 1 H), 1.08 - 1.19 (m, 2 H), 1.19 -
1.30 (m, 1 H), 1.37 -
1.50 (m, 2 H), 1.61 (s, 3 H), 2.02 (s, 1 H), 2.33 (s, 3 H), 7.10 - 7.24 (m, 4
H), 7.28 (s, I H), 7.45 (d, J
= 8.82 Hz, 2 H), 7.85 (d, J= 8.46 Hz, 1 H), 8.78 (s, I H), 8.89 (d, J= 9.19
Hz, I H), 9.99 (s, 1 H); MS
(DCUNHa) m/z 456 (M+H)+.

Example 143
4-{4-Methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3-d]pyrimidin-4-ylamino]
phenylsulfanyl}-phenol
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[0518] The product from Example 142A was reacted with the product from Example
6c
according to the procedure from Example 135B substituting the product from
Example 6c for the
product from Example 51 and substituting the product from Example 142A for the
product from
Example 135A to provide the title compound as a trifluoroacetic acid salt (20
mg, 37%). IH NMR
(300 MHz, DMSO-D6) S ppm: 0.77 - 0.91 (m, 1 H), 1.07 - 1.18 (m, 2 H), 1.38 -
1.52 (m, 2 H), 1.61
(s; 3 H), 2.31 (s, 3 H), 6.70 (d, J= 8.46 Hz, 2 H), 7.02 (d, J= 8.09 Hz, 1 H),
7.10 - 7.21 (m, J= 8.46
Hz, 3 H), 7.23 (s, 1 H), 7.86 (d, J= 8.82 Hz, 1 H), 8.78 (s, 1 H), 8.93 (d, J=
8.82 Hz, I H), 9.82 (s, I
H); MS (DCUNH4) m/z 415 (M+H)+.

Example 144
3- {4-Methyl-2-[7-(1-methyl-cyclopropyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-
phenylsulfanyl } -phenol
[0519] The product from Example 142A was reacted with 3-(2-amino-4-methyl-
phenylsulfanyl)-phenol (Example 129) according to the procedure from Example
135B substituting 3-
(2-amino-4-methyl-phenylsulfanyl)-phenol for the product from Example 51 and
substituting the
product from Example 142A for the product from Example 135A to provide the
title compound as a
trifluoroacetic acid salt (20 mg, 37%). 1H NMR (300 MHz, DMSO-D6) S ppm: 0.77 -
0.92 (m, 1 H),
1.35 - 1.48 (m, 2 H), 1.60 (s, 3 H), 2.36 (s, 3 H), 6.41 - 6.68 (m, 3 H), 6.90
- 7.05 (m, I H), 7.23 (d, J
= 6.62 Hz, 1 H), 7.29 - 7.42 (m, 2 H), 7.77 (d, J= 9.56 Hz, 1 H), 8.68 (s, I
H), 8.82 (d, J= 7.72 Hz, 1
H), 9.52 (s, 1 H); MS (DCUNH4) m/z 415 (M+H)+.

Example 145
(7-Ethyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylsulfanyl-phenyl)-amine
Example 145A
N'-(3-Cyano-6-ethyl-pyridin-2-yl) N,N-dimethyl-formamidine

[0520] A solution of the product from Example lOB (0.942 g, 5.0 mmol) in
anhydrous
tetrahydrofuran (50 mL) was cooled to -78 C under a nitrogen atmosphere. To
this solution was
added slowly dropwise a solution of lithium diisopropylamide (3.0 mL of a 2.0
M solution in
toluene/hexane/heptane, 6.0 mmol, 1.2 eq). After the addition was complete the
reaction mixture was
stirred at -78 C for lh, and then methyl iodide (1.42 g, 10.0 mmol, 2.0 eq)
was added dropwise. The
reaction mixture was stirred for an additional 1.5 h at -78 C, during which
time all solids dissolved.
The reaction flask was then removed from the cooling bath and saturated
aqueous ammonium
chloride (25 mL) and water (25 mL) was added. The reaction -mixture was
extracted with ethyl
acetate (3 x 100 mL) and the combined organic layers were washed with brine,
dried over anhydrous
magnesium sulfate, filtered, and evaporated under vacuum. The residue was
purified by
chromatography on silica gel, eluting with a 3/2 hexane:ethyl acetate to
provide the title compound
(0.87 g, 86% yield).

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Example 145B
(7-Ethyl-pyrido[2,3-d]pyrimidin-4-yl)-(5-methyl-2-phenylsulfanyl-phenyl)-amine

[0521] The product from Example 145A was reacted with the product from Example
5I
according to the procedure from Example 135B substituting the product from
Example 145A for the
product from Example 135A to provide the title compound as a trifluoroacetic
acid salt (20 mg, 33%).
1H NMR (500 MHz, DMSO-D6) 5 ppm: 1.34 (t, J=7.93 Hz, 3 H), 2.35 (s, 3 H), 3.01
(q, J = 7.93 Hz,
2 H), 7.09 - 7.29 (m, 6 H), 7.3 6(s, 1 H), 7.78 (d, J= 8.54 Hz, 1 H), 8.75 (s,
1 H), 8.88 (d, J= 8.54 Hz,
1 H); MS (DCT/NH4) m/z 373 (M+H)+.

Example 146
N- {4-[2-(7-Ethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-
phenyl } -acetamide
[0522] The product from Example= 145A was reacted with the product from
Example 7b
according to the procedure from Example 135B substituting the product from
Example 7b for the
product from Example 51 and substituting the product from Example 145A for the
product from
Example 135A to provide the title compound as a trifluoroacetic acid salt (20
mg, 29%). 1H NMR
(500 MHz, DMSO-D6) S ppm: 1.34 (m, 3 H), 2.37 (s, 3 H), 3.01 (q, J= 7.93 Hz, 2
H), 7.12 - 7.28 (m,
H), 7.35 (s, 1 H), 7.36 (s, I H), 7.78 (d, J= 8.54 Hz, I H), 8.75 (s, 1 H),
8.88 (d, J= 8.54 Hz, 1 H);
MS (DCUNH4) m/z 430 (IVI+H)+.

Example 147
4-[4-(6-Bromo-1 H-benzoimidazol-2-yl)-2-(7-isopropyl-pyrido[2, 3 -d]pyrimidin-
4-ylamino)-phenoxy]-
phenol
Example 147A
4-(4-Benzyloxy-phenoxy)-3-nitro-benzaldehyde
[0523] A mixture of 4-chloro-3-nitrobenzaldehyde (1.00 g, 5.389 mmol), 4-
(benzyloxy)phenol (1.187 g, 5.928 mmol), and potassium carbonate (0.744 g,
5.389 mmol) in
anhydrous pyridine (10 mL) was heated at reflux under a nitrogen atmosphere
for 30 minutes. The
reaction was cooled to room temperature and the solvent removed by rotary
evaporation under
vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with 1N
aqueous
hydrochloric acid (2 x 50 mL), water (50 mL), and brine (50 mL). The organic
phase was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
Purification by silica gel flash
chromatography using methylene chloride as eluent provided the title compound
as a yellow solid
(1.625 g, 86%).

Example 147B
2-[4-(4-Benzyloxy-phenoxy)-3-nitro-phenyl]-6-bromo-1H benzoimidazole
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[0524] A solution of 4-brorno-1,2-benzenediamine (214 mg, 1.145 mmol) in N,N-
dimethylformamide (12 mL) containing water (0.4 mL) was treated with the
product of Example
147A (400 mg, 1.145 rnmmol) and OXONE (458 mg, 0.7443 mmol), and the reaction
stirred at room
temperature for 30 minutes. Water (40 mL) was then added and the reaction
stirred for 10 minutes.
The mixture was vacuum filtered and the solid washed with water, then dried
under vacuum.
Purification by silica gel chromatography using a gradient of 3% to 4% ethyl
acetate/methylene
chloride as eluent provided the title compound as a yellow solid (305 mg,
51%).

Example 147C
2-(4-Benzyloxy-phenoxy)-5-(6-bromo-1 H-benzoimidazol-2-yl)-phenylamine

(0525] The product of Example 147B (374 mg, 0.723 mmol), iron powder (248 mg,
4.45
mmol), and ammonium chloride (253 mg, 4.74 mmol) in water (5 mL) and ethanol
(10 mL) were
heated at 80 for 45 minutes. The reaction mixture was cooled to room
temperature, diluted with
ethyl acetate (100 mL), and washed with water (2 x 50 mL) and brine (50 mL).
The organic phase
was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary
evaporation under
vacuum provided the title compound as a golden solid (327 mg, 93%).

Example 147D
[2-(4-B enzyloxy-phenoxy)-5-(6-bromo-lH-benzoimidazol-2-yl)-phenyl]-(7-
isopropyl-pyrido[2,3-
d]pyrimi din-4-yl)-amine

[0526] A solution of the product from Example 36E (26.7 mg, 0.123 mmol) and
the product
of Example 147C (60 mg, 0.123 mmol) in acetic acid (2 mL) was stirred in an
oil bath preheated to
140 C for 30 minutes. The reaction was cooled to room temperature, diluted
with hexanes (50 mL),
concentrated by rotary evaporation under vacuum, and co-evaporated with
methylene
chloride/hexanes (4x). The residue was dried under vacuum, then purified by
silica gel
chromatography using 3% methanol/methylene chloride as eluent to provide the
title cornpound as an
off-white solid (59 mg, 73%).

Example 147E
4-[4-(6-Bromo-lH-benzoimidazol-2-yl)-2-(7-isopropyl pyrido[2,3-d]pyrimidin--4-
ylamino)-phenoxy)-
phenol

[0527] A solution of the product from Example 147D (38.8 mg, 0.059 mmol) and
pentamethylbenzene (87 mg, 0.5901 mmol) in trifluoroacetic acid (5 mL) was
stirred at room
temperature for 2 hours. The solvent was removed by rotary evaporation under
vacuum and co-
evaporated with methylene chloride/hexanes (2x). The resulting solid was
triturated with hexanes
(3x) and purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt (22
mg, 47%). 'H NMR (300 MHz, DMSO-D6) S ppm: 1.36 (d, J= 6.99 Hz, 6 H), 3.20 -
3.39 (m, 1 H), .
6.78 (d, J= 8.82 Hz, 2 H), 6.95 (d, J= 9.19 Hz, 2 H), 7.02 (d, .T = 8.82 Hz, 1
H), 7.36 (dd, J= 8.64,
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2.02 Hz, I H), 7.55 (d, J= 8.46 Hz, 1 H), 7.78 (d, J= 1.47 Hz, I H), 7.91 (d,
J= 8.82 Hz, 1 H), 8.11
(dd, J = 8.64, 2.02 Hz, 1 H), 8.35 (d, J =1.84 Hz, 1 H), 8.94 (s, 1 H), 9.03
(d, J = 8.82 Hz, 1 H), 9.46
(br s, 1 H), 11.63 (br s, 1 H); MS (APCI+) m/z 567/569 (M+H)+.

Example 148
4-[4-(6-Brorno-1 H-benzoimidazol-2-yl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenoxy]-phenol
[0528] The product from Example 147C was reacted with the product from Example
lOB
using the procedure described in Example 147D substituting the product from
Example lOB for the
product from Example 36E to provide [2-(4-Benzyloxy phenoxy)-5-(6-bromo-lH-
benzoimidazol-2-
yl)-phenyl]-(7-rnethyl-pyrido[2,3-d]pyrimidin-4-yl)-amine which was
debenzylated according to the
procedure described in Example 147E to provide the crude product which was
purified by HPLC with
TFA to provide the title compound as a trifluoroacetic acid salt. 'H NMR (300
MHz, DMSO-D6) 8
ppm: 2.74 (s, 3 H), 6.77 (d, J= 9.19 Hz, 2 H), 6.95 (d, J= 8.82 Hz, 2 H), 7.01
(d, J= 8.82 Hz, 1 H),
7.35 (dd, J= 8.46, 1.84 Hz, I H), 7.54 (d, J= 8.82 Hz, 1 H), 7.74 - 7.85 (m, 2
H), 8.10 (dd, J= 8.82,
2.21 Hz, 1 H), 8.36 (d, J= 2.21 Hz, 1 H), 8.90 (s, 1 H), 8.95 (d, J= 8.46 Hz,
I H), 9.45 (bs, 1 H),
11.35 (bs, 1 H); MS (ESI+) m/z 539/541 (M+Fi)+.

Example 149
4-(4-Amino-phenylsulfanyl)-N-(4-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3 -
d]pyrimidin-4-ylamino)-
benzenesulfonamide

Example 149A
N-(4-Bromo-phenyl)-4-chloro-3-nitro-benzenesulfonamide
[0529] A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.561 g, 10
mmol) in acetic
acid (20 mL) was treated with 4-bromoaniline (1.72 g, 10 mmol) and anhydrous
sodium acetate (1.23
g, 15 mmol), then heated at 100 for 30 minutes. The reaction was cooled to
room temperature and
the acetic acid removed by rotary evaporation under vacuum. The residue was
taken up in ethyl
acetate (100 mL) and washed with water (2 x 25 mL) and brine (25 mL). The
organic phase was
dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum,
co-evaporating the oil
with methylene chloride/hexanes. Purification by silica gel chromatography
using methylene chloride
followed by 5% ethyl acetate/methylene chloride as eluent provided the title
compound as a yellow
solid (2.038 g, 52%).

Example 149B
4-(4-Amino-phenylsulfanyl)-N-(4-bromo-phenyl)-3-nitro-benzenesulfonamide
[0530] A mixture of the product of Example 149A (500 mg, 1.277 mmol), 4-
aminothiophenol (240 mg, 1.915 mmol) and anhydrous sodium acetate (524 mg,
6.384 mmol) in
anhydrous ethanol (9 mL) was heated at reflux under a nitrogen atmosphere for
1 hour. The reaction

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was cooled to room temperature and the ethanol removed by rotary evaporation
under vacuum. 'Fhe
residue was taken up in ethyl acetate (100 mL) and washed with water (2 x 50
mL) and brine (50 mL).
The organic phase was dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum,
co-evaporating the oil with methylene chloride/hexanes to obtain the title
compound as an orange
foam (613 mg, 100%).

Example 149C
{4-[4-(4-Bromo-phenylsulfamoyl)-2-nitro-phenylsulfanyl]-phenyl}-carbamic acid
tert-butyl ester
[05311 A solution of the product of Example 149B (613 mg, 1.277 mmol) in
anhydrous 1,4-
dioxane (10 mL) was treated with di-tert-butyl dicarbonate (418 mg, 1.92 mmol)
at room temperature,
then the reaction was heated at reflux under a nitrogen atmosphere for 3
hours. The reaction was
cooled to room temperature, additional di-tert-butyl dicarbonate (500 mg) was
added, and the reaction
refluxed for 17 hours. The reaction was cooled to room temperature and the
solvent removed by
rotary evaporation under vacuum. Purification of the residue by silica gel
chromatography using 3%
ethyl acetate/methylene chloride as eluent provided the title compound as a
yellow solid (512 mg,
69%).

Example 149D
{4-[2-Amino-4-(4-bromo-phenylsuifamoyl)-phenylsulfanyl]-phenyl}-carbarnic acid
tert-butyl ester
[0532] The product of Example 149C (510 mg, 0.879 mmol), iron powder (302 mg,
5.40
mmol), and ammonium chloride (308 mg, 5.76 mmol) in water (4 mL) and ethanol
(8 mL) were
heated at 80 for 40 minutes. The reaction was cooled to room temperature,
diluted with ethyl acetate
(100 mL), and washed with water (2 x 50 mL) and brine (50 mL). The organic
phase was dried over
anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation
under vacuum to provide
the title compound as a white foam (436 mg, 90%).

Example 149E
{4-[4-(4-Bromo-phenylsulfamoyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester

105331 A solution of the product from Example 36E (59 mg, 0.2725 mmol) and the
product
from Example 149D (150 mg, 0.2725 mmol) in acetic acid (4 mL) was stirred in
an oil bath preheated
to 140 C for 25 minutes. The reaction was cooled to room temperature, diluted
with hexanes (100
mL), concentrated by rotary evaporation under vacuum, and co-evaporated with
methylene
chloride/hexanes (4x). The residue was dried under vacuum, then purified by
silica gel
chromatography using 4% methanol/methylene chloride as eluent to provide the
title compound as a
tan solid (67 mg, 34%).

Example 149F
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4-(4-Amino-phenylsulfanyl) N-(4-bromo-phenyl)-3-(7-isopropyl-pyrido[2,3-
d]pyrimidin-4-ylamino)-
benzenesulfonamide

[0534] The product from Example 149E (44 mg, 0.061 mmol) was treated with
trifluoroacetic acid (2 mL) in methylene chloride (2 mL) at room temperature
for 30 minutes. The
solvents were removed by rotary evaporation under vacuum and the residual oil
dried under hi-
vacuum. Purification by silica gel chromatography using 5% methanol/methylene
chloride as eluent
provided the title compound as a trifluoroacetic acid salt (25 mg, 48%). 'H
NMR (300 MHz, DMSO-
D6) 5 ppm: 1.35 (d, J= 6.62 Hz, 6 H), 3.13 - 3.38 (m, 1 H), 6.63 (d, J = 8.46
Hz,= 2 H), 6.87 (d, J=
7.72 Hz, 1 H), 7.01 - 7.09 (d, J= 8.82 Hz, 2 H), 7.12 (d, J= 8.46 Hz, 2 H),
7.44 (d, J= 8.82 Hz, 2 H),
7.61 (dd, J= 7.72, 1.47 Hz, 1 H), 7.71 (s, I H), 7.81 (dd, J= 6.62, 1.47 Hz, 1
H), 8.66 - 8.80 (m, I H),
8.90 (d, J= 6.99 Hz, 1 H), 10.55 (s, 1 H); MS (ESI+) m/z 621/623 (M+H)+.

Example 150
4-(4-Amino-phenylsulfanyl)-N-(4-bromo-phenyl)-3-(7-methyl-pyrido[2,3-
d]pyrimidin-4-ylamino)-
benzenesulfonamide

[0535] The product from Example 149D was reacted with the product from Example
10B
using the procedure described in Example 149E substituting the product from
Example l0B for the
product from Example 36E to provide {4-[4-(4-Bromo-phenylsulfamoyl)-2-(7-
methyl-pyrido[2,3-
d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester
which was
deprotected according to the procedure described in Example 149F, followed by
silica gel
chromatography provided the title compound as a trifluoroacetic acid salt. 'H
NMR (300 MHz,
DMSO-D6) S ppm: 2.74 (s, 3 H), 6.64 (d, J= 8_46 Hz, 2 H), 6.89 (d, J= 8.09 Hz,
1 H), 7.05 (d, J=
9.19 Hz, 2 H), 7.12 (d, J= 8.82 Hz, 2 H), 7.44 (d, J= 8.82 Hz, 2 H), 7.63 (dd,
J= 7.72, 0.74 Hz, 1 H),
7.74 (s, 1 H), 7.79 (dd, J= 7.72, 1.10 Hz, 1 H), 8.70 - 8.83 (m, 1 H), 8.88
(d, J= 8.09 Hz, 1 H), 10.55
(s, 1 H); MS (ESI+) mlz 593/595 (M+H)+.

Example 151
4-[4-Chloro-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol
Example 151A
4-(4-Chloro-2-nitro-phenoxy)-phenol
[0536] A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide
(0.894 g,
0.0159 mol) in anhydrous dimethylsulfoxide (7 mL) was heated at 120 for 30
minutes under a
nitrogen atmosphere. A solution of 2,5-dichloronitrobenzene (1.90 g, 0.0099
mol) in
dimethylsulfoxide (3 mL) was added dropwise over a 30 minute period at 120'
then let the reaction
stir for 1 hour at the same temperature. The reaction was then cooled in an
ice bath and poured into
30 mL of ice water. The mixture was acidified with concentrated hydrochloric
acid to pH 1 and
extracted with ethyl ether (2 x 50 mL). The combined ethereal extracts were
washed with water (3 x
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150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by
rotary evaporation under
vacuum. Purification of the residue by silica gel chromatography using
methylene chloride as eluent
provided the product as a tan solid (1.34 g, 51%). '

Example 151 B
4-(2-Amino-4-chloro-phenoxy)-phenol
[0537] A mixture of the product of Example 151A (400 mg, 1.506 mmol) and iron
powder
(336 mg, 6.02 mmol) in acetic acid (10 mL) and ethanol (10 mL) was heated at
reflux under a
nitrogen atmosphere for 25 minutes. The reaction was cooled to room
temperature, diluted with water
(50 mL), and treated with solid sodium carbonate until the pH was 6. Extracted
with ethyl acetate (2
x 50 mL) and washed the organic with brine (50 mL), dried over anhydrous
sodium sulfate, filtered,
and concentrated by rotary evaporation under vacuum. Co-evaporating the
resulting oil with
methylene chloride/hexanes provided the title compound as a tan solid (355 mg,
100%).

Example 151 C
4-[4-Chloro-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-phenol
[0538] A solution of the product from Example 36E (38 mg, 0.177 mmol) and the
product
from Example 151B (42 mg, 0.177 mmol) in acetic acid (2 mL) was stirred in an
oil bath preheated to
140 C for 1.5 hour. The reaction was cooled to room temperature, diluted with
hexanes (100 mL),
concentrated by rotary evaporation under vacuum, and co-evaporated with
methylene
chloride/hexanes (4x). The residue was dried under hi-vacuum, then purified by
triturating with 40%
ethyl acetate/methylene chloride to provide the title compound as a beige
solid (49 mg, 65%). tH
NIVIIZ (300 MHz, DMSO-D6) S ppm: 1.31 (d, J= 6.99 Hz, 6 H), 3.10 - 3.29 (m, 1
H), 6.70 (d, J=
8.82 Hz, 2 H), 6.76 - 6.90 (m, 3 H), 7.24 (dd, J= 8.64, 2.39 Hz, I H), 7.55
(d, J= 8.82 Hz, I H), 7.71
(bs, 1 H), 8.59 (bs, 1 H), 8.73 (d, J= 8.09 Hz, 1 H), 9.31 (bs, 1 H), 9.89
(bs, I H); MS (DCIlNH3) mlz
407 (M+H)+.

Example 152
4-(4-Hydroxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
benzonitrile
Example 152A
4-(4-Hydroxy-phenoxy)-3-nitro-benzonitrile
[0539] A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide
(0.894 g,
0.0159 mol) in anhydrous dimethylsulfoxide (8 mL,) was heated at 90 C for 30
minutes under a
nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzonitrile (1.806 g,
0.0099 mol) in
dimethylsulfoxide (8 mL) was added dropwise over a 30 minute period at 90 ,
then let the reaction stir
for 1 hour at the same temperature. The reaction was then cooled in an ice
bath and poured into 30
mL of ice-water. The mixture was acidified with concentrated hydrochloric acid
to pH 3 and
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extracted with ethyl ether (3 x 100 mL). The combined ethereal extracts were
washed with water (3 x
150 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated by rotary
evaporation under vacuum. Purification by silica gel chromatography using 4%
ethyl
acetate/methylene chloride as eluent provided the product as an orange solid
(0.984 g, 39%).

Example 152B
3-Amino-4-(4-hydroxy-phenoxy)-benzonitrile
105401 The product of Example 152A (500 mg, 1.952 mmol) was hydrogenated in
methanol
(20 mL) with hydrogen (1 atmosphere, balloon) and 10% palladium on carbon (50
mg) for 30
minutes. The reaction was vacuum filtered through a 0.450 PTFE membrane and
the catalyst washed
with methanol. The filtrate was concentrated by rotary evaporation under
vacuum to provide the title
compound as a pinkish-beige solid (437 mg, 99%).

Example 152C
4-(4-Hydroxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
benzonitrile
[05411 A solution of the product from Example 36E (41 mg, 0.1896 mmol) and the
product
from Example 152B (42.9 mg, 0.1896 mmol) in acetic acid (2 mL) was stirred in
an oil bath preheated
to 140 C for 1.5 hour. The reaction was cooled to room temperature, diluted
with hexanes (100 mL),
concentrated by rotary evaporation under vacuum, and co-evaporated with
methylene
chloride/hexanes (4x). The residue was dried under hi-vacuum. Purification by
silica gel
chromatography using 30 / ethyl acetate/methylene chloride as eluent provided
the title compound as
an white solid (16 mg, 21%). 'H NMR (300 MHz, DMSO-D6) 8 ppm: 1.31 (d, J= 6.99
Hz, 6 H),
3.11 - 3.28 (m, 1 H), 6.77 (d, J= 8.82 Hz, 2 H), 6.85 (d, J= 8.46 Hz, I H),
6.93 (d, J= 8.46 Hz, 2 H),
7.64 (dd, J= 17.28, 8.46 Hz, 2 H), 8.12 (s, 1 H), 8.66 (s, I H), 8.81 (d, J=
8.09 Hz, 1 H), 9.47 (s, I
H), 9.99 (s, 1 H); MS (DCUrdH3) m/z 398 (M+H)+.

Example 153
(5-Bromo-2-phenoxy-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
[0542] 5-bromo-2-phenoxybenzenamine was reacted with the product from Example
57A
using the procedure described in Example 57E substituting 5-bromo-2-
phenoxybenzenamine for the
product from Example 57D to provide the brude product which was purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz,
DMSO-D6) 6 ppm:
6.94 - 7.03 (m, J = 8.09, 5.88 Hz, 3 H), 7.07 (t, J = 7.35 Hz, 1 H), 7.24 -
7.36 (m, 2 H), 7.54 (dd, J=
8.82, 2.21 Hz, I H), 7.77 (dd, J= 8.46, 4.41 Hz, 1 H), 7.83 (d, J= 2.21 Hz, 1
H), 8.82 (s, 1 H), 8.89
(d, J= 7.35 Hz, 1 H), 9.10 (d, J= 2.57 Hz, I H); MS (ESI)+ m/z 394 (M+2)+.

Example 154
(5-Chloro-2-phenoxy-phenyl)-pyrido[2,3-d]pyrimidin-4-yl-amine
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[05431 5-Chloro-2-phenoxy-phenylamine was reacted with the product from
Example 57A
using the procedure described in Example 57E substituting 5-chloro-2-phenoxy-
phenylamine for the
product from Example 57D to provide the crude product which was purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz,
DMSO-D6) S ppm:
6.97 (d, J = 7.72 Hz, 2 H), 7.00 - 7.11 (m, 2 H), 7.24 - 7.34 (m, J 8.09, 8.09
Hz, 2 H), 7.41 (dd, J =
8.82, 2.57 Hz, 1 H), 7.69 - 7.77 (m, 2 H), 8.77 (s, I H), 8.85 (d, J= 8.46 Hz,
1 H), 9.08 (d, J=3.31 Hz,
I H); MS (ESI)+ m/z 349 (M+H)+.

Example 155
1-{3-[4-Chloro-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-
phenyl } -ethanol
[0544] 1-[4-(2-Amino-4-chloro-phenoxy)-phenyl]-ethanol was reacted with the
product from
Example 36E according to the procedure from Example 152C substituting 1-[4-(2-
Amino-4-chloro-
phenoxy)-phenyl]-ethanol for the product from Example 152B to provide the
crude product which
was purified by HPLC with TFA to provide the title compound as a trifluoro
acetic acid salt. 1H
NMR (300 MHz, DMSO-D6) S ppm: 1.16 (d, J=6.62 Hz, 3H), 1.31 (d, J=6.99 Hz,
6H), 3.17 - 3.28
(m, IH), 4.60 (q, 1H), 6.81 (m, 1H), 6.94 (s, 1H), 7.01 (d, J--7.72 Hz, 1H),
7.06 (d, J=8.82 Hz, 1H),
7.23 (t, J=7.91 Hz, 1H), 7.43 (dd, J=8.82, 2.57 Hz, IH), 7.72 (m, IH), 7.76
(s, 1H), 8.79 (s, 1H), 8.82
(s, 1H); MS (ESI-) m/z 433 (M-H)-.

Example 156
4-[2-(7-Ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenol
Example 156A
4-Amino-2-ethylsulfanyl-pyrimidine-5-carbonitrile
[0545] A solution of 2-Ethyl-2-thiopsuedourea hydrobromide (1.52 g, 8.19
mmol),
(Ethoxymethylene)malononitrile (1.0 g, 8.19 mmol) and N,N-
diisopropylethylamine (3.57 mL, 20.05
mmol) in ethanol (20 mL) was stirred at room temperature for 3.5 hours. The
resultant solid was
collected, washed with ethanol, and the dried under vacuum to provide the
title compound as a light
yellow solid (580 mg, 39%).

Example 156B
N'-(5-Cyano-2-ethylsulfanyl-pyrimidin-4-yl) N,N-dimethyl-formamidine

[0546] A solution of the product from Example 156A (200 mg, 1.11 mmol) and N,N-

dimethylformamide dimethyl acetal (0.15 mL, 1.11 mmol) in toluene (10 mL) was
refluxed for 2.5
hours. After cooling to room temperature the solution was concentrated under
vacuum to provide the
title compound as a colorless solid (260 mg, 100%).

Example 156C
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4-[2-(7-Ethylsulfanyl-pyrimido[4, 5-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenol
[0547] A solution of the product from Example 6c (54 mg, 0.234 mmol) and the
product
from Example 156B (50 mg, 0.213 mmol) in acetic acid (2 mL) was heated at 130
C for 1.5 hours.
The solution was then allowed to cool to room temperature, the acetic acid
removed under vacuum
and the resultant residue purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (51 mg, 45%). 'H NMR (300 MHz, DMSO-d6) S ppm: 1.38
(t, J = 7.4 Hz,
3H), 2.30 (s, 3H), 3.23 (q, J= 7.3 Hz, 2H), 6.72 (d, J= 8.8 Hz, 2H), 6.98 (d,
J = 8.1 Hz, 1H), 7.10 (m,
lH), 7.18 (d, J= 8.7 Hz, 2H), 7.21 (s, 1H), 8.62 (s, 1H), 9.70 (s, 1H), 9.78
(bs, 1H), 10.85 (s, 1H); MS
(ESI)+ m/z 422 (M+H)+.

Example 157
(7-Ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[5 -methyl-2-(4-phenoxy-
phenylsulfanyl)-phenyl]-
amine

Example 157a
5-Methyl-2-(4-phenoxy-phenylsulfanyl)-phenylamine
[0548] The product from Example 6c (0.500 g, 1.91mmol) was dissolved in CH2CI2
along
with phenyl boronic acid (0.701 g, 5.74 mmol), copper(II) acetate (0.659 g,
3.83mmol), and
triethylamine (0.387 g, 3.83mmol). Stirred at room temperature for 48 h, at
which time 2 more
equivalents of each reagent was added. Stirred at room temperature for another
16 h at which time
another 2eq of each reagent was added. Stirred at room temperature for another
16h. The reaction was
diluted with water and extracted with ethyl acetate Dried over Na2SO4i
filtered and concentrated under
vacuum giving the crude product which was purified silica =gel column
chromatography eluting with
20 % EtOAc/hexane (0.100 g, 15%). The product was reduced with SnC1z following
the procedure
from Example 51 to give the title compound (90 mg, 98%).

Example 157b
7-(ethylthio) N-(5-methyl-2-(4-phenoxyphenylthio)phenyl)pyrimido[4,5-
d]pyrimidin-4-amine
[0549] A solution of the product from Example 156B and the product from
Example 157a
was reacted according to the procedure from Example 156C substituting the
product from Example
157a for the product from Example 6c to provide the crude product which was
purified by HPLC with
TFA to provide the title compound as a trifluoroacetic acid salt (16 mg, 21%).
1H NMR (300 MHz,
DMSO-D6) S ppm: 1.37 (t, J= 7.35 Hz, 3H), 2.34 (s, 3H), 3.22 (q, J= 7.35 Hz,
2H), 6.82 (m, 2H),
6.93 (m, 211), 7.29 (m, 8H), 8.57 (s, IH), 9.64 (s, 1H), 10.66 (s, 1H); MS
(ESI+) m/z 498 (M+H)+.

Example 158
4-[4-Methyl-2-(7-piperidin-l-yl-pyrimido[4,5-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
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[0550] To a solution of the product from Example 156C (42 mg, 0.1 mmol) in
piperidine
(lml) was microwaved (CEM Discover microwave) at 180 C for 2 hours. The
solution was
concentrated under vacuum and the residue was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (17 mg, 38%). IH NMR (300 MHz, DMSO-
D6) S ppm: 1.64
(m, 6H), 2.30 (s, 3H), 3.96 (m, 4H), 6.72 (m, 2H), 7.01 (d, J = 7.72 Hz, 1H),
7.17 (m, 4H), 8.59 (s,
1H), 9.53 (s, 11-1), 9.83 (s, 1H), 11.43 (s, 1H); (ESI+) rn/z 445 (M+H)+.

Example 159
Propane-2-sulfonic acid 4-[2-(7-ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-
ylamino)-4-methyl-
phenylsulfanyl] phenyl ester

[0551] The product from Example 156C (0.042 g, 0.1 mmol), isopropyl sulfonyl
chloride
(Q.014 g, 0.105 mmol), 4-dimethylaminopyridine (0.002 g, 0.01 mmol) and
diisopropylethylamine
(0.04 g, 0.3 mmol) in 1,2-dichloroethane (2.0 mL) was stirred for 1 hour,
poured into water (20 mL)
and extracted with ethyl acetate (3 x 10 mL). The combined extracts were dried
over sodium sulfate,
filtered and concentrated under vacuum. The crude product was purified by HPLC
with TFA to
provide the title compound as a trifluoroacetic acid salt (15 mg, 23%). 1H
N1VIR (300 MHz, DMSO-
D6) S ppm: 1.27 - 1.46 (m, 9 H), 2.37 (s, 3 H), 3.20 (q, J=7.35 Hz, 2 H), 3.56
- 3.70 (m, I H), 7.09 -
7.20 (m, 2 H), 7.19 - 7.29 (m, 3 H), 7.34 (s, 1 H), 7.39 (d, J=8.09 Hz, 2 H),
8.56 (s, 1 H), 9.61 (s, 1 H),
10.72 (s, 1 H); MS (ESI)+ m/z 528 (M+H)+.

Example 160
4-Acetylamino-benzenesulfonic acid 4-[2-(7-ethylsulfanyl-pyrimido[4,5-
d]pyrimidin-4-ylamino)-4-
methyl phenylsulfanyl]-phenyl ester

[0552] The product from Example 156C was reacted with 4-Acetylamino-
benzenesulfonyl
chloride according to the procedure from Example 159 substituting 4-
Acetylamino-benzenesulfonyl
chloride for isopropyl sulfonyl chloride to provide the crude product which
was purified by HPLC
with TFA to provide the title compound as a trifluoroacetic acid salt (31 mg,
50 fo). IH NMR (300
MHz,DMSO-D6)Sppm: 1.36(t,J=7.35Hz,3H),2.10(s,3H),2.35(s,3H),3.20(q,J=7.35Hz,
2H), 6.85 (d, J = 8.82 Hz, 2H), 7.13 (d, J = 8.82 Hz, 2H), 7.26 (m, 3H), 7.71
(m, 2H), 7.81 (m, 2H),
8.52 (s, 1H), 9.59 (s, 1H), 10.48 (s, IH), 10.71 (s, 1H); MS (ESI+) m/z 619
(M+H)+.

Example 161
4-[4-Methyl-2-(7-morpholin-4-yl-pyrimido [4, 5-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0553] To a solution of the product from Example 156C in morpholine (lml) was
microwaved (CEM Discover microwave) at 180 C for 2 hours. The solution was
concentrated under
vacuum and the residue was purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (29 mg, 65%). 1H NMR (300 MHz, DMSO-D6) S ppm: 2.30
(s, 3H), 3.73 (t,

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J = 4.41 Hz, 4H), 3.94 (bs, 4H), 6.72 (d, J = 8.82 Hz, 2H), 7.02 (d, J= 8.09
Hz, 111), 7.18 (m, 4H),
8.61 (s, 1H), 9.57 (s, IH), 9.85 (s, 1H), 11.47 (s, 111); MS (ESI+) m/z 447
(M+H)+.

Example 162
Benzenesulfonic acid 4-[2-(7-ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-
4-methyl-
phenylsulfanyl]-phenyl ester

[0554] The product from Example ' 156C was reacted with benzenesulfonyl
chloride
according to the procedure from Example 159 substituting benzenesulfonyl
chloride for isopropyl
sulfonyl chloride to provide the crude product which was purified by HPLC with
TFA to provide the
title compound as a trifluoroacetic acid salt (27 mg, 48%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
1.36 (t, J= 7.35 Hz, 3H), 2.36 (s, 311), 3.20 (q, J= 7.35 Hz, 214), 6.85 (ni,
2H), 7.11 (m, 2H), 7.20 (d,
J= 7.72 Hz, 1H), 7.35 (ni, 2H), 7.65 (ni, 211), 7.86 (m, 311), 8.51 (s, 1H),
9.58 (s, 1H), 10.65 (s, 1H);
MS (ESI+) 562 (M+H)+.

Example 163
4-Bromo-benzenesulfonic acid 4-[2-(7-ethylsulfanyl-pyrimido[4,5-djpyrimidin-4-
ylamino)-4-rnethyl-
phenylsulfanyl)-phenyl ester

[0555] The product from Example 156C was reacted with 4-bromo-benzenesulfonyl
chloride
according to the procedure from Example 159 substituting 4-bromo-
benzenesulfonyl chloride for
isopropyl sulfonyl chloride to provide the crude product which was purified by
FIl'LC with TFA to
provide the title compound as a trifluoroacetic acid salt. IH NMR (300 MHz,
DMSO-D6) S ppm:
1.36 (t, J= 7.35 Hz, 3H), 2.37 (s, 3H), 3.20 (q, J= 7.35 Hz, 211), 6.87 (m,
211), 7.12 (m, 2H), 7.19 (d,
J= 7.05 Hz, 1H), 7.36 (m, 2H), 7.71 (m, 214), 7.87 (m, 2H), 8.51 (s, 1H), 9.60
(s, 1H), 10.61 (s, 1H);
MS (ESI+) m/z 640/642 (M+H)+.

Example 164
(7-Ethylsulfanyl-pyrimido[4,5-djpyrimidin-4-yl)-[2-(4-hydroxy-phenylsulfanyl)-
5-methyl-phenyl]-
carbamic acid tert-butyl ester

[0556] The product of Example 156C was reacted with Di-tert butyl dicarbonate
and triethyl
amine in tetrahydrofuran at room temperature for 16 hours. Afterwards, the
mixture was poured into
water (10 mL) and the resultant solution extracted with ethyl acetate (3 x 10
mL), the combined
extracts dried over magnesium sulfate, filtered and concentrated under vacuum
to provide the title
-compound. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.52 (t, J= 7.35 Hz, 3H), 1.62 (s,
91-1), 2.50 (s,
3H), 3.35 (q, J= 7.35 Hz, 2H), 7.21 (d, J= 8.46 Hz, 2H), 7.41 (m, 5H), 8.71
(s, 1H), 9.80 (s, 1H),
10.72 (s, 1H); MS (ESI+) m/z 522 (M+M+.

Example 165
{4-[2-(7-Ethylsulfanyl pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenoxy}-
acetonitile
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[0557] The product from Example 164 (52 mg, 0.1 mmol), bromo-acetonitrile
(0.008 ml,
0.12 mmol), cesium carbonate (0.065 g, 0.2 mmol) and tetrabutylammonium iodide
(0.001 g) in N,N-
dimethylformamide (2 nil) was stirred at room temperature for 2 hours. The
mixture was partitioned
between water and ethyl acetate. The organic layer was washed with brine,
dried (sodium sulfate),
filtered and evaporated under vacuum. To the residue was added dichloromethane
(2.5 ml) and
trifluoroacetic acid (2.5 ml) then stirred at room temperature for 1 hour. The
solvent was evaporated
under vacuum and the residue was purified by HPLC with TFA to provide the
title compound (9 mg,
20%). 1H NMR (300 MHz, DMSO-D6) S ppm: 1.42 (t, J = 7.35 Hz, 3H), 2.24 (s,
3H), 3.29 (q, J=
7.35 Hz, 2H), 5.25=(s, 2H), 6.81 (m, 5H), 7.20 (d, J= 8.46 Hz, 2H), 8.34 (s,
1H), 9.25 (s, 1H), 9.75 (s,
111); MS (ESI+) In/z 461 (M+H)+.

Example 166
[2-(4-Benzyloxy-phenylsulfanyl)-5-methyl-phenyl]-(7-ethylsul fanyl-
pyrimido[4,5-d]pyrimidin-4-yl)-
amine

[0558] The product from Example 164 was reacted with benzyl bromide according
to the
procedure from Example 165 substituting benzyl bromide for bromo-acetonitrile
to provide the crude
product which was purified by silica gel chromatography using 98/2
dichloromethane/methanol as
eluent to provide the title compound (15 mg, 29%). 1H N1VIR. (300 MHz, DMSO-
D6) 8 ppm: 1.20 (t, J
= 7.35 Hz, 3H), 2.27 (s, 31-1), 3.08 (q, J = 7.35 Hz, 2H), 5.44 (s, 2H), 6.74
(d, J= 8.46 Hz, 2H), 6.95
(m, 3H), 7.20 (d, J= 8.46 Hz, 2H), 7.35 (m, 5H), 8.77 (s, 1H), 9.42 (s, 1H),
9.81 (s, 1H); MS (ESI+)
m/z 512 (M+H)+.

Example 167
4-[4-(3-Bromo-benzyloxy)-2-(2-methylsulfanyl-thiazolo[4,5-d]pyrimidiin-7-
ylamino)-
phenylsulfanyl] phenol

Example 167A
N'-(5-Cyano-2-methylsulfanyl-thiazol-4-yl) N,N-dimethyl-formamidine

[0559] The title compound was prepared from the reaction of 4-Amino-2-
methylsulfanyl-
thiazole-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the
procedure from
Example 156B to provide the title compound as a white foam (0.132, g, 99%).

Example 167B
4-[4-(3-Bromo-benzyloxy)-2-(2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-
ylamino)-
phenylsulfanyl]-phenol

[0560] A solution of the product from Example 167A (66.0 mg, 0.29 mmol) and
the product
from Example 15A (118 mg, 0.29 mmol) in acetic acid (1 mL) was stirred in a
preheated 140 C oil
bath for 20 niinutes. The mixture was cooled and concentrated under vacuum.
The resultant residue
was then purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt (34
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mg, 17%). IH NMR (300 MHz, DMSO-D6) S ppm: 2.75 (s, 3H), 5.12 (s, 2H), 6.70
(d, J = 8.82 Hz,
1H), 6.96 - 7.05 (m, 2H), 7.07 - 7.16 (m, 3H), 7.33 (t, J = 7.72 Hz, IH), 7.41
- 7.46 (m, 1H), 7.51 (d, J
= 7.72 Hz, 1H), 7.63 (s, 1H), 8.47 (s, 1H), 9.73 (s, 2H); MS (ESI)+ m/z
583/585 (M+H)+.

Example 168
4-[4-(4-Bromo-benzyloxy)-2-(2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-
ylamino)-
phenylsulfanyl]-phenol

[0561] A solution of the product from Example 167A and the product from
Example 16A
were reacted according to the procedure from Example 167B substituting the
product from Example
16A for the product from Example 15A to provide the crude material which was
purified by
trituration with methanol to provide the title compound as a white solid (46
mg, 27%). 1H NMR (300
MHz, DMSO-D6) S ppm: 2.76 (s, 3H), 5.09 (s, 2H), 6.70 (d, J= 8.46 Hz, 2H),
6.91 - 7.24 (m, 5H),
7.38 (d, J = 8.09 Hz, 2H), 7.56 (d, J= 8.09 Hz, 2H), 8.46 (s, 1H), 9.71 (s,
211); MS (ESI)+ m/z
583/585 (M+H)+.

Example 169
4-[4-Methyl-2-(2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-ylamino)
phenylsulfanyl]-phenol
[0562] A solution of the product from Example 167A and the product from
Example 6c were
reacted according to the procedure from Example 167B substituting the product
from Example 6c for
the product from Example 15A to provide the crude material which was purified
by HPLC with TFA
to provide the title compound as a trifluoroacetic acid salt (17 mg, 11%). IH
NMR (300 MHz,
DMSO-D6) S ppm: 2.27 (s, 3H), 2.76 (s, 3H), 6.76 (d, J= 8.46 Hz, 2H), 6.82 (d,
J = 8.09 Hz, l H),
7.06 - 7.22 (m, 4H), 8.49 (s, 1H), 9.86 (s, 2H); MS (ESI)+ m/z 413 (M+H)+.

Example 170
N- {4-[4-Methyl-2-(2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-ylamino)-
phenylsulfanyl]-phenyl} -
ace#amide
[0563] A solution of the product from Example 167A and the product from
Example 7b were
reacted according to the procedure from Example 167B substituting the product
from Example 7b for
the product from Example 15A to provide the crude material which was purified
by trituration with
methanol to provide the title compound (110 mg, 83%). 1H NMR (300 MHz, DMSO-
D6) S ppm:
2.03 (s, 3H), 2.29 (s, 3H), 2.76 (s, 3H), 6.96 (d, J= 8.09 Hz, 1H), 7.14 (d,
J= 8.09 Hz, 111), 7.18 -
7.26 (m, J= 8.82 Hz, 311), 7.54 (d, J = 8.46 Hz, 2H), 8.45 (s, 1H), 9.74 (s,
1H), 10.04 (s, 1H); MS
(ESI)+ m/z 454 (M+H)+.

Example 171
N- {4-[2-(1-tert-Butyl-1 H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenyl } -
acetamide
Example 171A
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N'-(2-tert-Butyl-4-cyano-2H-pyrazol-3 -yl)-N,N-dimethyl-formami dine
[0564] The title compound was prepared from the reaction of 5-Amino-l-tert-
butyl-lH-
pyrazole-4-carbonitrile with N,N-dimethylformamide dimethyl acetal using the
procedure from
Example 156B to provide the title compound.

Example 171B
N- {4-[2-(1-tert-Butyl-1 H-pyrazolo [3,4-d]pyrimidin-4-ylamino)-4-methyl-
phenyl sulfanyl)-phenyl } -
acetamide
[0565] A solution of the product from Example 171A and the product from
Example 7b were
reacted according to the procedure from Example 167B substituting the product
from Example 7b for
the product from Example 15A and substituting the product from Example 171A
for the product from
Example 167A to provide the crude material which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt (54 mg, 32%). 1H NMR (300 MHz,
DMSO-D6) 5 ppm:
1.74 (s, 9H), 2.03 (s, 3H), 2.41 (s, 3H), 7.13 (d, J = 8.82 Hz, 211), 7.49 (m,
4H), 7.62 (s, 1H), 8.41 (s,
IH), 8.47 (s, 1H), 8.76 (s, 1H), 10.06 (s, 1H), 10.39 (s, 1H); MS (ESI+) m/z
447 (M+H)+.

Example 172
4-[2-(l -tert-Butyl-lH-pyrazolo[3,4-d]pyrimidin-4-ylamino)-4-methyl-
phenylsulfanyl]-phenol
[0566] A solution of the product from Example 171A and the product from
Example 6c were
reacted according to the procedure from Example 167B substituting the product
from Example 6c for
the product from Example 15A and substituting the product from Example 171A
for the product from
Example 167A to provide the crude material which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt (40 mg, 25%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
1.76 (s, 911), 2.38 (s, 3H), 6.67 (d, J = 8.82 Hz, 211), 7.07 (d, J= 8.82 Hz,
211), 7.34 (d, J = 8.09 Hz,
1 H), 7.50 (d, J = 8.09 Hz, IH), 7.5 8(s, IH), 8.43 (s, 1 H), 8.49 (s, 1 H),
8.75 (s, 1 H), 9.91 (s, 1 H),
10.40 (s, 1 H); MS (ESI+) m/z 406 (M+H)+.

Example 173
4-[2-(7-Isopropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-
phenol
Example 173A
N'-(5 -Cyano-2-isopropyl-pyrimidin-4-yl)-N,N-dimethyl-formamidine

[0567] The title compound was prepared from the reaction of 4-Amino-2-
isopropyl-
pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the
procedure from
Example 156B to provide the title compound.

Example 173B
4-[2-(7-Isopropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl-phenylsulfanyl]-
phenol
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[0568] A solution of the product from Example 173A and the product from
Example 6c were
reacted according to the procedure from Example 167B substituting the product
from Example 6c for
the product from Example 15A and substituting the product from Example 173A
for the product from
Example 167A to provide the crude material which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt (39 mg, 38 / ). 1H NMR (300 MHz,
DMSO-D6) 8 ppm:
1.36 (d, J= 6.62 Hz, 6H), 2.30 (s, 3H), 3.29 (m, I.H), 6.70 (d, J= 8.46 Hz,
2H), 6.98 (d, J = 8.09 Hz,
IH), 7.17 (m, 4H), 8.72 (s, 1H), 9.76 (s, IH), 9.90 (s, IH), 11.13 (s, 1H); MS
(ESI+) m/z 404
(1''t+H)-f-=

Example 174
4-[4-Benzyloxy-2-(7-isopropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0569] A solution of the product from Example 173A and the product, from
Example 27A
were reacted according to the procedure from Example 167B substituting the
product from Example
27A for the product from Example 15A and substituting the product from Example
173A for the
product from Example 167A to provide the crude material which was purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt (10 mg, 20%). 1H NMR
(300 MHz, DMSO-
D6) S ppm: 1.35 (d, J = 6.99 Hz, 6H), 3.27 (m, 1H), 5.11 (s, 2H), 6.64 (d, J =
8.46 Hz, 2H), 7.06 (m,
5H), 7.40 (m, 5H), 8.64 (s, 1H), 9.65 (s, 1H), 9.84 (s, 1H), 10.88 (s, IH); MS
(ESI+) m/z 496
(M+H)+.

Example 175
N- {4-[2-(7-Ethylsulfanyl-5-methylsulfanyl-pyrimido[4,5-djpyrimidin-4-ylamino)-
4-methyl-
phenylsulfanyl] -phenyl } -acetamide

Example 175A
N'-(5-Cyano-2-ethyIsulfanyl-6-methylsulfanyl-pyrimddin-4-yl)-N,N-dimethyl-
formamidine
[0570] The title compound was prepared from the reaction of 4-Amino-2-
ethylsulfanyl-6-
methylsulfanyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl
acetal using the
procedure from Example 156B to provide the title compound.

Example I75B
N- {4-[2-(7-Ethylsulfanyl-5-rnethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-
ylamino)-4-methyl-
phenylsulfanyl]-phenyl} -acetamide

[0571] A solution of the product from Example 175A and the product from
Example 7b were
reacted according to the procedure from Example 167B substituting the product
from Example 7b for
the product from Example 15A and substituting the product from Example 175A
for the product from
Example 167A to provide the crude material which was purified by. HPLC with
TFA to provide the
title compound as a trifluoroacetic acid salt (23 mg, 35%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
1.36 (t, J = 7.35 Hz, 3H), 2.03 (s, 3H), 2.24 (s, 3H), 2.40 (s, 3H), 3.18 (q,
J = 7.35 Hz, 2H), 6.84 (m,
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3H), 7.19 (d, J = 8.46 Hz, 2H), 7.49 (d, J = 8.46 Hz, 2H), 7.82 (s, 1H), 9.97
(s, 1H), 12.25 (s, 114); MS
(ESI+) m/z 509 (M+H)+.

Example 176
4-[2-(7-Ethylsulfanyl-5 -methylsulfanyl-pyrimido [4,5-d]pyrimidin-4-ylamino)-4-
methyl-
phenylsulfanyl] phenol

[05721 A solution of the product from Example 175A and the product from
Example 6c were
reacted according to the procedure from Example 167B substituting the product
from Example 6c for
the product from Example 15A and substituting the product from Example 175A
for the product from
Example 167A to provide the crude material which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt (19 mg, 31%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
1.36 (t, J = 7.35 Hz, 3H), 2.21 (s, 3H), 2.44 (s, 3H), 3.19 (q, J= 7.11 Hz,
2H), 6.70 (m, 5H), 7.18 (d, J
= 8.46 Hz, 2H), 7.84 (s, 1H), 9.67 (s, 1H), 12.24 (s, I H); MS (ESI+) m/z 468
(M+H)+.

Example 177
N- {4-[2-(2-Cyanomethylsulfanyl-thiazolo[4,5-d]pyrimidin-7-ylamino)-4-methyl-
phenylsulfanyl]!
phenyl } -acetamide

Example 177A
N'-(5-Cyano-2-cyanomethylsulfanyl-thiazol-4-yl) N,N-dimethyl-formamidine

[05731 The title compound was prepared from the reaction of 4-Amino-2-
cyanomethylsulfanyl-thiazole-5-carbonitrile with N,N-dimethylformamide
dimethyl acetal using the
procedure from Example 156B to provide the title compound.

Example 177B
N-{4-[2-(2-Cyanomethylsulfanyl-thiazolo[4,5-d]pyrimi din-7-ylamino)-4-methyl-
phenylsulfanyl]-
phenyl} -acetamide

[0574] A solution of the product from Example 177A and the product from
Example 7b were
reacted according to the procedure from Example 167B substituting the product
from Example 7b for
the product from Example 15A and substituting the product from Example 177A
for the product from
Example 167A to provide the crude material which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt (64 mg, 52%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
2.03 (s, 3H), 2.30 (s, 331), 4.54 (s, 2H), 6.95 (d, J= 8.09 Hz, 111), 7.15 (d,
J= 8.09 Hz, 1H), 7.23 (m,
3H), 7.55 (d, J = 8.46 Hz, 2I-1), 8.51 (s, 1H), 9.91 (s, 1H), 10.04 (s, 1M; MS
(ESI+) m/z 479 (M+H)+.
Example 178
{7-[2-(4-Hydroxy-phenylsulfanyl)-5-methyl-phenylamino]-thiazolo[4,5-
d]pyrirnidin-2-ylsulfanyl} -
acetonitrile
[0575] A solution of the product from Example 177A and the product from
Example 6c were
reacted according to the procedure from Example 167B substituting the product
from Example 6c for

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the product from Example 15A and substituting the product from Example 177A
for the product from
Example 167A to provide the crude material which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt (62 mg, 56%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
2.27 (s, 3H), 4.54 (s, 2H), 6.77 (m, 3H), 7.18 (m, 4H), 8.53 (s, 1H), 9.85 (s,
11-1), 9.97 (s, 1H); MS
(ESI+) m/z 438 (M+H)+.

Example 179
4-[4-Benzyloxy-2-(7-heptafluoropropyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-
phenylsulfanyl J-phenol
Example 179A
N'-(5-Cyano-2-heptafluoropropyl-pyrimidin-4-yl)-N,N-dimethyl-formamidine
[0576] The title compound was prepared from the reaction of 4-Amino-2-
heptafluoropropyl-
pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the
procedure from
Example 156B to provide the title compound.

Example 179B
4-[4-Benzyloxy-2-(7-heptafluoropropyI-pyrimido[4,5-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0577] A solution of the product from Example 179A and the product from
Example 27A
were reacted according to the procedure from Example 167B substituting the
product from Example
27A for the product from Example 15A and substituting the product from Example
179A for the
product from Example 167A to provide the crude material which was purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt (24 mg, 39%). IH NMR
(300 MHz, DMSO-
D6) S ppm: 5.11 (s, 2H), 6.61 (d, J = 8.46 Hz, 2H), 7.04 (dd, J= 8.82, 2.57
Hz, 1H), 7.10 (d, J= 8.46
Hz, 2H), 7,17 (d, J = 2.57 Hz, 1H), 7.23 (d, J= 8.82 Hz, IH), 7.40 (m, 5H),
8.79 (s, 1H), 9.63 (s, 1H),
10.12 (s, 1H), 11.01 (s, 1 A); MS (ESI+) m/z 622 (M+H)+.

Example 180
(7-Isopropyl-pyrimido[4,5-d]pyrimidin-4-yl)-[5-methyl-2-(4-phenoxy-
phenylsulfanyl)-phenyl]-amine
[0578] A solution of the product from Example 173A and the product from
Example 157a
were reacted according to the procedure from Example 167B substituting the
product from Example
157a for the product from Example 15A and substituting the product from
Example 173A for the
product from Example 167A to provide the crude material which was purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz,
DMSO-D6) S ppm:
1.34 (d, J= 6.99 Hz, 6H), 2.34 (s, 3H), 3.24 (m, IH), 6.81 (d, J = 8.82 Hz,
2H), 6.94 (d, J = 7.72 Hz,
2H), 7.28 (m, 8H), 8.63 (s, 1H), 9.83 (s, 114), 10.78 (s, 1H); MS (ESI+) m/z
480 (M+H)+.

Example 181
(7-Ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(4-methoxy phenylsulfanyl)-
5-methyl-phenyl]-
amine

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Example 181 A
1-(4-Methoxy-phenylsulfanyl)-3-methyl-5-nitro benzene

[0579] Cuprous 4-methoxy thiophenolate (0.94 g, 4.63 mmol), which was prepared
by
refluxing excess 4-rnethoxythiophenol with copper oxide in ethyl alcohol
overnight and isolating the
desired product by filtration, and 3-bromo-5-nitrotoluene (1.0 g, 4.63 mmol),
prepared in two steps
from 3-nitro-4-aminotoluene as described in J. Am. Chem. Soc. Vol. 78, pp
1992, 1956, were heated
to 165 C in a mixture of quinoline (5 mL) and pyridine (1 mL) for 2 hours.
After quenching with
aqueous HCl the desired.product was isolated by chromatography on silica using
ethyl acetate/hexane
as eluent to provide the title compound (0.96 g, 75%).

Example 181 B
3-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine
[0580] The product from Example 181A was reduced according to the procedure
from
Example 147C substituting the product from Example 181A for the product from
Example 147B to
provide the title compound.

Example 181C
(7-Ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylsulfanyl)-
5-methyl-phenyl]-
amine

[0581] The product from Example 181B was reacted with the product from Example
156B
according to the procedure from Example 156C substituting the product from
Example 181B for the
product from Example 6c to provide the crude product which was purified by
Hl'LC with TFA to
provide the title compound as a trifluoroacetic acid salt. IH NMR (500 MHz,
DMSO-D6) S ppm:
1.37 (t, J = 7.32 Hz, 3H), 2.28 (s, 3H), 3.21 (q, J = 7.32 Hz, 2H), 3.79 (s,
3H), 6.83 (s, 1H), 7.03 (d, J
= 9.16 Hz, 2H), 7.42 - 7.53 (m, 4H), 8.71 (s, 1H), 9.72 (s, 1H), 10.39 (s,
111); MS (ESI+) m/z 436
(M+H)+.

Example 182
(7-Ethylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[3 -(3-methoxy-phenylsulfanyl)-
5-methyl-phenyl]-
amine

Example 182A
3-(3-Methoxy-phenylsulfanyl)-5-methyl-phenylamine
[0582] Cuprous 3-methoxy thiophenolate was reacted with 3-bromo-5-nitrotoluene
according to the procedure from Example 181A substituting cuprous 3-methoxy
thiophenolate for
cuprous 4-methoxy thiophenolate to provide 1-(3-Methoxy-phenylsulfanyl)-3-
methyl-5-nitro-benzene
which was reduced according to the procedure from Example 181B to provide the
title compound.

Example 182B
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(7-Ethylsulfanyl-pyrimi do[4,5-d]pyrimi din-4-yl)-[3 -(3 -methoxy-phenyl sul
fanyl)-5-methyl-phenyl)-
amine

[0583] The product from Example 182A was reacted with the product from Example
156B
according to the procedure from Example 156C substituting the product from
Example 182A for the
product from Example 6c to provide the crude product which was purified by
HPLC with TFA to
provide the title compound as a trifluoroacetic acid salt. IH NMR (300 MHz,
DMSO-D6) S ppm:
1.37 (t, J= 7.35 Hz, 3H), 2.33 (s, 3H), 3.21 (q, J = 7.11 Hz, 211), 3.74 (s,
3H), 6.84 - 6.96 (m, J= 1.10
Hz, 3H), 7.05 (s, 1H), 7.32 (dd, J= 9.01, 7.17 Hz, 1H), 7.60 (s, 1H), 7.65 (s,
1H), 8.74 (s, 1H), 9.74
(s, 1H), 10.47 (s, IH); MS (ESI+) rn/z 436 (M+H)+.

Example 183
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-(5-ethyl-2-phenylsulfanyl-
phenyl)-amine
Example 183A
5-Ethyl-2-phenylsulfanyl-phenylamine
[0584] Sodium thiophenolate was reacted with 1-Chloro-4-ethyl-2-nitro-benzene
according
to the procedure from Example 5H substituting 1-Chloro-4-ethyl-2-nitro-benzene
for 4-chloro-3-
nitrotoluene to provide 4-Ethyl-2-nitro-l-phenylsulfanyl-benzene which was
reduced according to the
procedure from Example 51 to provide the title compound.

Example 183B
4-Amino-2-benzyl sulfanyl-pyrimidine-5 -carbonitrile

[0585] A solution of 2-Benzyl-2-thiopsuedourea hydrochloride (5.0 g, 24.67
mmol),
(Ethoxymethylene)malononitrile (3.01 g, 24.67 mmol) and N,N-
diisopropylethylamine (10.75 mL,
61.68 mmol) in ethanol (50 mL) was stirred at room temperature for 18 hours.
The resultant solid
was collected, washed with ethanol, and the dried under vacuum to provide the
title compound (2.69
g, 45%).

Example 183C
N'-(2-Benzylsulfanyl-5-cyano-pyrimidin-4-yl) N,N-dimethyl-formamidine

[05861 A solution of the product from Example 183B was reacted with N,N-
dimethylformamide dimethyl acetal according to the procedure from Example 156B
substituting the
product from Example 183B for the product from Example 156B to provide the
title compound.

Example 183D
(7 Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-(5-ethyl-2-phenylsulfanyl-
phenyl)-amine
[05871 The product from Example 183A was reacted with the product from Example
183C
according to the procedure from Example 156C substituting the product from
Example 183A for the
product from Example 6c and substituting the product from Example 183C for the
product from
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Example 156B to provide the crude product which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt. MS (ESI+) m/z 482 (M+H)+.

Example 184
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-methoxy-phenylsulfanyl)-
5-methyl-phenyl]-
amine

[0588] The product from Example 183C was reacted with 2-(4-Methoxy-
phenylsulfanyl)-5-
methyl-phenylamine (Example 118) according to the procedure from Example 156C
substituting 2-(4-
Methoxy-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c
and substituting
the product from Example 183C for the product from Example 156B to provide the
crude product
which was purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt.
MS (ESI+) m/z 498 (M+H)+,

Example 185
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-(5 -fluoro-2-phenylsulfanyl-
phenyl)-amine
Example 185A
5-Fluoro-2-phenylsulfanyl-phenylamine
[0589] 4-Fluoro-2-nitrophenol was reacted according to procedures similar to
those
described in Examples 6a, 6b, and 6c substituting benzenethiol for 4-
mercaptophenol and 4-fluoro-2-
nitrophenol for 4-methyl-2-nitro phenol to provide the title compound.

Example 185B
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-(5-fluoro-2-phenylsulfanyl-
phenyl)-amine
[0590] The product from Example 185A was reacted with the product from Example
203A
according to the procedure from Example 156C substituting the product from
Example 203A for the
product from Example 6c and substituting the product from Example 185A for the
product from
Example 156B to provide the crude product which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt. MS (ESI+) zn/z 472 (M+H)+.

Example 186
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-fluoro-phenyisulfanyl)-
5-methyl-phenyl]-
amine

[0591] The product from Example 183C was reacted with 2-(4-Fluoro-
phenylsulfanyl)-5-
methyl-phenylamine (Example 124) according to the procedure from Example 156C
substituting 2-(4-
Fluoro-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c
and substituting the
product from Example 183C for the product from Example 156B to provide the
crude product which
was purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt. MS
(ESI+) m/z 486 (M+H)+.

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Example 187
(7-Benzylsulfanyl-pyrimido [4,5-d]pyrimidin-4-yl)-(5-methyl-2-m-tolylsulfanyl-
phenyl)-amine
[0592] The product from Example 183C was reacted with 5-Methyl-2-m-
tolylsulfanyl-
phenylamine according to the procedure from Example 156C substituting 5-Methyl-
2-m-
tolylsulfanyl-phenylamine for the product from Example 6c and substituting the
product from
Example 183C for the product from Example 156B to provide the crude product
which was purified
by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt.
MS (ESI+) m/z 482
(M+H)+.

Example 188
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-(5-methyl-2-phenylsulfanyl-
phenyl)-amine
[05931 The product from Example 183C was reacted with the product from Example
51
according to the procedure from Example 156C substituting the product from
Example 51 for the
product from Example 6c and substituting the product from Example 183C for the
product from
Example 156B to provide the crude product which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt. MS (ESI+) m/z 468 (M+H)+.

Example 189
3-[2-(7 Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-ylamino)-4-methyl
phenylsulfanyl]-phenol
[0594] The product from Example 183C was reacted with 3-(2-amino-4-methyl-
phenylsulfanyl)-phenol (Example 129) according to the procedure from Example
156C substituting 3-
(2-amino-4-methyl-phenylsulfanyl) phenol for the product from Example 6c and
substituting the
product from Example 183C for the product from Example 156B to provide the
crude product which
was purified by HPLC with TFA to provide the title compound as a
trifluoroacetic acid salt. MS
(ESI+) m/z 484 (M+H)+.

Example 190
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(3-methoxy-phenylsulfanyl)-
5-methyl-phenyl]-
amine

[0595] The product from Example 183C was reacted with the product from Example
182A
according to the procedure from Example 156C substituting the product from
Example 182A for the
product from Example 6c and substituting the product from Example 183C for the
product from
Example 156B to provide the crude product which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S
ppm: 2.34 (s, 3H),
3.74 (s, 3H), 4.52 (s, 2H), 6.84 - 6.97 (m, J= 1.10 Hz, 3H), 7.05 (s, 1H),
7.21 - 7.39 (m, 4H), 7.46 -
7.53 (m, 211), 7.61 (s, 1H), 7.66 (s, 1H), 8.76 (s, 1H), 9.77 (s, 111), 10.47
(s, 111); MS (ESI+) m/z=
498 (M+H)+.

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Example 191
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylsulfanyl)-
5-methyl-phenyl]-
amine
[0596] The product from Example 183C was reacted with the product from Example
181 B
according to the procedure from Example 156C substituting the product from
Example 181B for the
product from Example 6c and substituting the product from Example 183C for the
product from
Example 156B to provide the crude product which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S
ppm: 2.28 (s, 3H),
3.79 (s, 3H), 4.52 (s, 211), 6.83 (s, 1H), 7.04 (d, J= 8.82 Hz, 2H), 7.19 -
7.38 (m, 2H), 7.41 - 7.55 (m,
5H), 8.74 (s, 11-1), 9.75 (s, IH), 10.42 (s, 111); MS (ESI+) m/z 497 (M+H)+.

Example 192
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-[2-(4-methoxy-phenoxy)-5-
methyl-phenyl]-amine
[0597] The product from Example 183C was reacted with the product from Example
116B
according to the procedure from Example 156C substituting the product from
Example 116B for the
product from Example 6c and substituting the product from Example 183C for the
product from
Example 156B to provide the crude product which was purified by HPLC with TFA
to provide the
title compound as a trifluoroacetic acid salt. MS (ESI+) m/z 482 (M+H)+.

Example 193
(7-Benzylsulfanyl-pyrimido[4,5-d]pyrimidin-4-yl)-(5-methyl-2-p-tolylsulfanyl-
phenyl)-amine
[0598] The product from Example 183C was reacted with. 5-methyl-2-p-
tolylsulfanyl-
phenylamine according to the procedure from Example 156C substituting 5-methyl-
2-p-tolylsulfanyl-
phenylamine for the product from Example 6c and substituting the product from
Example 183C for
the product from Example 156B to provide the crude product which was purified
by HPLC with TFA
to provide the title compound as a trifluoroacetic acid salt. MS (ESI+) rn/z
482 (M+H)+.

Example 194
4-[4-(3-Bromo-benzyloxy)-2-(pyrimido[4,5-d]pyrimidin-4-ylamino)-
phenylsulfanyl] -phenol
Example 194A
N'-(5-Cyano-pyrimidin-4-yl)-N,N-dimethyl-formamidine
[0599] The title compound was prepared from the reaction of 4-Amino-5-
pyrimidinecarbonitrile (Aldrich) with N,N-dimethylformamide dimethyl acetal
using the procedure
from Example 156B to provide the title compound.

Example 194B
4-[4-(3-Bromo benzyloxy)-2-(pyrimido[4,5-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
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[06001 The product from Example 194A was reacted with the product from Example
15A
according to the procedure from Example 156C substituting the product from
Example I SA for the
product from Example 6c and substituting the product from Example 194A for the
product from
Example 156B to provide the crude product whioh was purified by HPLC with
NH4OAc to provide
the title compound. 1H NMR (300 MHz, DMSO-D6) S ppm: 5.12 (s, 2H), 6.64 (d, J
= 8.82 Hz, 2H),
6.93 - 7.04 (m, 1H), 7.10 (d, J = 8.82 Hz, 2H), 7.14 - 7.23 (m, 2H), 7.36 (t,
J = 7.72 Hz, 1H), 7.43 -
7.49 (m, 1H), 7.54 (dt, J = 7.81, 1.61 Hz, 1H), 7.65 (d, J= 1.47 Hz, 1H), 9.04
(m, 1H), 9.63 (s, 1H),
10.29 (m, IH); MS (ESI-) m/z 531 (M-H)-.

Example 195
4-[4-Benzyloxy-2-(pyrimido[4,5-d]pyrimidin-4-ylarnino) phenylsulfanyl]-phenol

[0601] The product from Example 194A was reacted with the product from Example
27A
according to the procedure from Example 156C substituting the product from
Example 27A for the
product from Example 6c and substituting the product from Example 194A for the
product from
Example 156B to provide the= crude product which was purified by HPLC with
NH4OAc to provide
the title compound. 1H NMR (300 IvlEiz, DMSO-D6) S ppm: 5.10 (s, 2H), 6.63 (d,
J = 8.46 Hz, 2H),
6.94 - 7.05 (m, 1H), 7.10 (d, J= 8.82 Hz, 2H), 7.18 (d, J= 7.72 Hz, 2H), 7.29 -
7.51 (m, 5H), 9.05 (m,
1H), 9.63 (s, 1H), 9.92 (s, 1H), 10.66 (s, 1H); MS (ESI-) m/z 452 (M-H)-.

Example 196
(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[3-(4-methoxy-phenylsulfanyl)-5-
methyl-phenyl]-amine
[06021 The product from Example 181B was reacted with the product from Example
36E
using the procedure from Example 3 61 substituting the product from Example
181B for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt. 1H N1VIl2 (500 MHz, DMSO-
D6) S ppm: 1.33 (d, J =
6.71 Hz, 6H), 2.29 (s, 3H) 3.25 (qq, J= 7.02, 6.90 Hz, 1H), 3.79 (s, 3H), 6.88
(s, 1H), 7.03 (d, J =
9.16 Hz, 2H), 7.42 (d, J = 7.93 Hz, 2H), 7.45 (d, J= 8.54 Hz, 2H), 7.77 (d, J
= 8.54 Hz, 1H), 8.81 (s,
1H), 8.95 (d, J = 8.54 Hz, 11-1), 10.74 (s, 1H); MS (ESI+) m/z 417 (M+H)+.

Example 197
4-[3-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-5-methyl-phenylsulfanyl]-
phenol
Example 197A
4-(3-Amino-5-methyl-phenylsulfanyl)-phenol
[06031 To the product from Example 181B (0.5 g, 2.0 mmol) in dichloromethane
was treated
with boron tribromide (10 mmol) at room temperature for 1 hour. The solution
was the extracted with
water, then the organic solution dried and concentrated to provide the title
compound.

Example 197B
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4-[3-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-S-methyl-phenylsulfanyl]-
phenol
[0604] The product from Example 197A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
197A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) 6
ppm: 1.35 (s,
3H), 1.33 (s, 3H), 2.28 (s, 3H), 3.27 (qq, J = 6.86 Hz, 1H), 6.79 - 6.91 (m,
1H), 6.86 (d, J= 8.82 Hz,
2H), 7.30 (s, 1H), 7.36 (d, J = 8.46 Hz, 2H), 7.35 (s, 1H), 7.83 (d, J = 8.46
Hz, IH), 8.87 (s, IH), 8.98
(d, J= 8.82 Hz, 1H), 9.92 (s, 1H), 11.06 (s, 1H); MS (ESI-) m/z 403 (M+H)+.

Example 198
4-[5 -(3 -Fluoro-benzyloxy)-2-(4-hydroxy-phenylsul fanyl)-phenylamino]-7-
methyl-pyrido [2,3-
d] pyrimidine-6-carboni tril e

Example 198A
N'-(3,5-Dicyano-6-methyl-pyridin-2-yI)-N,N-dimethyl-formamidine
[06051 A solution of 2-Amino-6-methyl-pyridine-3,5-dicarbonitrile (0.158 g,
1.0 mmol) and
N,N-Dimethylformamide dimethyl acetal (0.119 g, 1.0 mmol) in toluene (10 mL)
was heated at reflux
for 6 hours. After cooling to room temperature, the solution was concentrated
under vacuum to
provide the title compound as a brown solid (0.2 g, 94%).

Example 198B
4-[5-(3-Fluoro-benzyloxy)-2-(4-hydroxy-phenylsulfanyl)-phenylamino]-7-methyl-
pyrido[2,3-
d]pyrimi dine-6-carbonitrile

[06061 The product of Example 198A was reacted with the product of Example lOB
using
the procedure of Example 1OF substituting the product of Example 198A for the
product of Example
l0E to provide the crude material which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (18 mg, 29%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.82
(s, 3H), 5.13 (s, 211), 6.64 (d, J = 8.46 Hz, 2H), 6.99 (d, J= 9.56 Hz, 1H),
7.09 (d, J= 8.82 Hz, 2H),
7.12 - 7.21 (m, 3H), 7.29 (d, J= 7.72 Hz, 2H), 7.39 - 7.53 (m, 1H), 8:63 (s,
1H), 9.36 (s, 1H), 9.64 (s,
1H), 10.33 (s, 1H).

Example 199
[3-(3-Fluoro benzyloxy)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
Example 199A
(3 -Fluoro-benzyloxy)-3 -nitro-b enzene

[0607] A solution of 3-nitro-phenol (0.278 g, 2.0 mmol), 1-bromomethyl-3-
fluoro-benzene
(0.258 ml, 2.1 mmol), potassium carbonate (0.553 g, 4.0 mmol) and
tetrabutylammonium iodide
(0.001 g) in N,N-dimethylformarnide (5 ml) was stirred at room temperature for
16 hours.
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Afterwards, ice water (10, mL) was added to the solution and the resultant
solid was collected by
filtration and dried in a vacuum oven to provide the title compound in
quantitative yield.

Example 199B
(3-Fluoro-benzyloxy)-3-amino-benzene
[0608] To a solution of the product from Example 199A (0.494 g, 2.0 mmol),
iron powder
(0.56 g, 10.0 mmol) and ammonium chloride (0.54 g, 10.0 mmol) in a methanol
(20 mL),
tetrahydrofuran (20 mL), and water (10 mL) solution was heated to reflux for 2
hours. The resultant
mixture was filtered through a pad of celite, and the filtrate was
concentrated. Then ethyl acetate was
added, stirred for 30 minutes, filtered and concentrated under vacuum to
provide the title compound
(0.405 g, 93%).

Example 199C
[3-(3-Fluoro-benzyloxy) phenyl]-(7-methyl pyrido[2,3-d]pyrimidin-4-yl)-amine

[0609] The product of Example 199B was reacted with the product of Example lOB
using
the procedure of Example l OF substituting the product of Example 199B for the
product of Example
l0E to provide the crude material which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (32 mg, 89%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 2.74
(s, 3H), 5.18 (s, 2H), 6.98 (m, 1H), 7.18 (m, 1H), 7.42 (m, 6H), 7.79 (d, J=
8.46 Hz, IH), 8.92 (s,
1H), 9.00 (d, J = 8.82 Hz, 1H), 11.16 (s, 1H); MS (ESI+) m/z 361 (M+H)+.

Example 200
[3-(3-Fluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido [2,3-d]pyrimidin-4-y1)-
amine

[0610] The product from Example 199B was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
199B for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S
ppm: 1.34 (d, J=
6.99 Hz, 6H), 3.26 (m, 1H), 5.18 (s, 2H), 6.93 (m, IH), 7.17 (m, 1H), 7.42 (m,
6H), 7.79 (d, J= 8.46
Hz, 1H), 8.8 (s, 1H), 9.00 (d, J= 8.46 Hz, 1H), 10.76 (s, 1H); MS (ESI+) m/z
389 (M+H)+.

Example 201
[3-(3-Fluoro-benzyloxy)-phenyl] pyrido[2,3-d]pyrimidin-4-yl-amine

[0611] The product of Example 199B was reacted with the product of Example 57A
using
the procedure of Example 57E substituting the product of Example 199B for the
product of Example
57D to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 5.18
(s, 2H), 6.98
(m, 1H), 7.18 (m, 1H), 7.42 (m, 6H), 7.87 (dd, J= 8.27, 4.60 Hz, 1H), 8.93 (s,
1H), 9.14 (m, 2H),
11.12 (s, 1H); MS (ESI+) m/z 347 (M+H)+.
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Example 202
[3-(4-Fluoro-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine

Example 202A
3-(4-Fluoro-benzyloxy)-phenylamine
[06121 3-Nitro-phenol was reacted with 1-bromomethyl-4-fluoro-benzene
according to the
procedure from Example 199A substituting 1-bromomethyl-4-fluoro-benzene for 1-
bromomethyl-3-
fluoro-benzene then reduced according to the procedure from Example 199B to
provide the title
compound.

Example 202B
[3-(4-Fluoro-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine
[0613] The product of Example 202A was reacted with the product of Example 57A
using
the procedure of Example 57E substituting the product of Example 202A for the
product of Example
57D to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt (20 mg, 58%). 1H NMR (300 MHz, DMSO-
D6) S ppm: 5.13
(s, 2H), 6.92 (m, 111), 7.24 (m, 211), 7.38 (m, 211), 7.55 (m, 3H), 7.80 (dd,
J = 8.27, 4.60 Hz, 111), 8.87
(s, 1H), 9.07 (dd, J = 8.27, 1.65 Hz, 1H), 9.12 (dd, J = 4.41, 1.84 Hz, 1H),
10.69 (s, 1H); MS (ESI+)
m/z 347 (M+H)+.

Example 203
[3-(3,5 -Difluoro-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-
amine
Example 203A
3-(3,5 -Difluoro-benzyloxy)-phenylamine

[0614] 3-Nitro-phenol was reacted with 1-bromomethyl-3,5-difluoro-benzene
according to
the procedure from Example 199A substituting 1-bromomethyl-3,5-difluoro-
benzene for 1-
bromomethyl-3-fluoro-benzene then reduced according to the procedure from
Example 199B to
provide the title compound.

Example 203B
[3-(3,5-Difluoro benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-y1)-
amine

[0615] The product from Example 203A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
203A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (26 mg, 67%). 1H NMR (300
MHz, DMSO-D6) S
ppm: 1.35 (d, J= 6.99 Hz, 6H), 3.26 (m, 1H), 5.19 (s, 2H), 6.95 (m, IH), 7.20
(m, 3H), 7.38 (m, 211),
7.54 (s, 1H), 7.82 (d, J= 8.46 Hz, 111), 8.86 (s, 1H), 9.02 (d, J= 8.46 Hz, 11-
1), 10.89 (s, 111); MS
(ESI+) m/z 407 (M+H)+.
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Example 204
[3-(3,5-Difluoro-benzyloxy)-phenyl]-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-
amine

[0616j The product of Example 203A was reacted with the product of Example 10B
using
the procedure of Example 1OF substituting the product of Example 203A for the
product of Example
10E to provide the crude material which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 2.73
(s, 3H), 5.19
(s, 2H), 6.95 (m, 1H), 7.21 (m, 3H), 7.38 (m, 2H), 7.55 (s, IH), 7.75 (d, 3=
8.46 Hz, 1H), 8.87 (s,
IH), 8.98 (d, J= 8.46 Hz, 1H), 10.90 (s, 1H); MS (ESI+) rn/z 379 (M+H)+.

Example 205
[3-(3,5-Difluoro-benzyloxy)-phenyI]-pyrido[2,3-d]pyrimidin-4-yl-amine
[0617] The product of Example 203A was reacted with the product of Example 57A
using
the procedure of Example 57E substituting the product of Example 203A for the
product of Example
57D to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 5.19
(s, 2H), 6.94
(m, 11-1), 7.21 (m, 3H), 7.39 (d, J= 5.15 Hz, 2H), 7.58 (s, 1H), 7.81 (dd, J=
8.09, 4.41 Hz, 1H), 8.87
(s, 1H), 9.10 (m, 2H), 10.79 (s, 1H); MS (ESI+) m/z 365 (M+H)+.

Example 206
4-[3 -(7-Methyl-pyri do[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl] -
benzonitrile
Example 206A
4-(3-Amino-phenoxymethyl)-benzonitrile

[0618] 3-Nitro-phenol was reacted with 4-bromomethyl-benzonitrile according to
the
procedure from Example 199A substituting 4-bromomethyl-benzonitrilefor 1-
bromomethyl-3-fluoro-
benzene then reduced according to the procedure from Example 199B to provide
the title compound.
Example 206B
4-[3-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile
[0619] The product of Example 206A was reacted with the product of Example lOB
using
the procedure of Example IOF substituting the product of Example 206A for the
product of Example
IOE to provide the crude material which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 2.71
(s, 3H), 5.27
(s, 2H), 6.92 (m, 1H), 7.38 (m, 2H), 7.59 (s, 1H), 7.68 (m, 3H), 7.89 (d, J=
8.46 Hz, 21-1), 8.83 (s,
1H), 8.95 (d, 3= 8.82 Hz, 1H), 10.64 (s, 1H); MS (ESI+) m/z 368 (1Vl+H)+.

Example 207
4-[3 -(Pyrido [2,3-d]pyrimidin-4-yl amino)-phenoxymethyl] -benzonitrile
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106201 The product of Example 206A was reacted with the product of Example 57A
using
the procedure of Example 57E substituting the product of Example 206A for the
product of Example
57D to provide the crude title compound which was purified by HPLC with TFA to
provide the title
compound as a trifluoroacetic acid salt. IH NMR (300 MHz, DMSO-D6) 8 ppm: 5.27
(s, 211), 6.93
(m, 1H), 7.38 (m, 2H) 7.60 (s, IH), 7.67 (d, J = 8.46 Hz, 2H), 7.80 (dd, J=
8.46, 4.41 Hz, 1H), 7.90
(d, J= 8.46 Hz, 2H), 8.86 (s, 1H), 9.07 (dd, J = 8.46, 1.65 Hz, 1H), 9.13 (dd,
J= 4.41, 1.65 Hz, 1H),
10.72 (s, 1H); MS (ESI+) rn/z 354 (M+H)+.

Example 208
3-[3-(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-
benzonitrile
Example 208A
3 -(3 Amino-phenoxymethyl) benzonitrile

[0621] 3-Nitro-phenol was reacted with 3-bromomethyl-benzonitrile acaording to
the
procedure from Example 199A substituting 3-bromomethyl-benzonitrilefor 1-
bromomethyl-3-fluoro-
benzene then reduced according to the procedure from Example 199B to provide
the title compound.

Example 208B
3 -[3 -(7-Isopropyl-pyri do [2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-
benzonitrile

[0622] The product from Example 208A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
208A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (22 mg, 56%). 1H NMR. (300
MHz, DMSO-D6) 5
ppm: 1.34 (d, J= 6.99 Hz, 6H), 3.26 (m, 1H), 5.22 (s, 2H), 6.93 (m, 1H), 7.38
(m, 2H), 7.62 (m, 2H),
7.77 (d, J= 8.46 Hz, 1H), 7.84 (m, 2H), 7.95 (s, 1H), 8.83 (s, 1H), 8.99 (d,
J= 8.46 Hz, 1H), 10.67 (s,
1H); MS (ESI+) m/z 396 (M+H)+.

Example 209
2-[3-(Pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxymethyl)-benzonitrile
Example 209A
2-(3-Amino-phenoxymethyl)-benzonitrile
[0623] 3-Nitro-phenol was reacted with 2-bromomethyl-benzonitrile according to
the
procedure from Example 199A substituting 2-bromomethyl-benzonitrile for 1-
bromomethyl-3-fluoro-
benzene then reduced according to the procedure from Example 199B to provide
the title compound.
Example 209B
2-[3 -(Pyrido [2,3-d]pyrimidin-4-ylamino)-phenoxymethyl]-benzonitrile

[0624] The product from Example 209A was reacted with the product from Example
36E
using the procedure frorn Example 361 substituting the product from Example
209A for the product
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from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) 8
ppm: 5.30 (s,
2H), 7.02 (m, 1H), 7.42 (m, 2H), 7.59 (m, 2H), 7.78 (m, 2H), 7.85 (dd, J=
8.46, 4.41 Hz, 1H), 7.94
(d, J = 7.72 Hz, IH), 8.92 (s, 1H), 9.14 (m, 2H), 11.03 (s, 111); MS (ESI+)
m/z 354 (M+H)+.

Example 210
(3-Benzyloxy-phenyl)-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
Example 210A
3-Benzyloxy-phenylamine
[0625] 3-Nitro-phenol was reacted with bromomethyl-benzene according to the
procedure
from Example 199A substituting bromomethyl-benzene for 1-bromomethyl-3-fluoro-
benzene then
reduced according to the procedure from Example 199B to provide the title
compound.

Example 210B
(3 -Benzyloxy-phenyl)-(7-isopropyl-pyrido [2,3-d]pyrimidin-4-yl)-arnine

[06261 The product from Example 210A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
210A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (5 mg, 10%). 1H NMR (500
MHz, DMSO-D6) 8
ppm: 1.33 (d, J= 6.84 Hz, 6H), 3.25 (qt, J= 6.84 Hz, 1H), 5.13 (s, 2H), 6.89 -
6.94 (m, J= 2.20, 2.20
Hz, 1I1), 7.33 - 7.41 (m, 511), 7.45 - 7.48 (m, J= 7.32 Hz, 211), 7.54 - 7.58
(m, J = 2.44, 2.44 Hz, 1H),
7.76 (d, J = 8.30 Hz, 111), 8.84 (s, IH), 9.02 (d, J= 8.30 Hz, 1H); MS ESI+
m/z 371 (M+H)+, ESI-
m/z 369 (M-H)-.

Example 211
[3-(3-Bromo-benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
Example 211 A
3 -(3 -Bromo-benzyloxy)-phenylamine

[0627] 3-Nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene according
to the
procedure from Example 199A substituting 1-bromo-3-bromomethyl-benzene for 1-
bromomethyl-3-
fluoro-benzene then reduced according to the procedure from Example 199B to
provide the title
compound.

Example 211B
[3-(3-Bromo benzyloxy)-phenyl]-(7-isopropyl-pyrido[2,3-d]pyximidin-4-yl)-
arnine

[0628] The product from Example 211A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example 21
1A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
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the title compound as a trifluoroacetic acid salt (1 mg, 1%). 1H NMR (300 MHz,
DMSO-D6) S ppm:
1.34 (d, J = 6.99 Hz, 6H), 5.16 (s, 211), 6.94 (td, J= 4.50, 2.39 Hz, 1H),
7.39 (td, J = 7.63, 3.86 Hz,
3H), 7.46 - 7.51 (m, 1H), 7.53 - 7.57 (m, 2H), 7.69 (s, 1H), 7.80 (d, J= 8.46
Hz, 1H), 8.86 (s, IH),
9.01 (d, J = 8.46 Hz, 1H), 10.84 (s, 1H); MS ESI+ m/z 451 (M+H)+, ESI- m/z 449
(M-H)-.

Example 212
(7-Isopropyl-pyrido[2,3-d]pyrirnidin-4-yl)-[3-(3-methoxy-benzyloxy)-phenyl]-
amine
Example 212A
3-(3 -Methoxy-benzyloxy)-phenylamine

[0629] 3-Nitro-phenol was reacted with 1-Bromomethyl-3-methoxy-benzene
according to
the procedure from Example 199A substituting 1-Bromomethyl-3-methoxy-benzene
for 1-
bromomethyl-3-fluoro-benzene then reduced according to the procedure from
Example 199B to
provide the title compound.

Example 212B
(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-[3 -(3-methoxy-benzyloxy)-phenyl]-
amine

[0630] The product from Example 212A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
212A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
the title compound as a trifluoroacetic acid salt (8 mg, 9%). 1H NMR (300 MHz,
DMSO-D6) 8 ppm:
1.35 (d, J= 6.99 Hz, 6H), 3.76 (s, 3H), 5.12 (s, 2H), 6.87 - 6_98 (m, 2H),
7.00 - 7.06 (m, 2H), 7.36 (dt,
J= 19.85, 8.09 Hz, 3H), 7.52 (s, 1H), 7.82 (d, J= 8.82 Hz, 1H), 8.88 (s, 1H),
9.02 (d, J= 8.46 Hz,
1H), 10.94 (s, 1H); MS ESI+ m/z 401 (M+H)+, ESI- m/z 399 (M-H)-.

Example 213
[3-(4-Bromo-benzyloxy)-phenyl]-pyrido[2,3-d]pyrimidin-4-yl-amine
Example 213A
3-(4-Brorno-benzyloxy)~phenylamine
[0631] 3-Nitro-phenol was reacted with 1-bromo-4-bromomethyl-benzene according
to the
procedure from Example 199A substituting 1-bromo-4-bromomethyl-benzene for 1
bromomethyl-3-
fluoro-benzene then reduced according to the procedure from Example 199B to
provide the title
compound.

Example 213B
[3-(4-Bromo-benzyloxy)-phenyl] pyrido[2,3-d]pyrirnidin-4-yl-amine

[0632] The product from Example 213A was reacted with the product from Example
36E
using the procedure from Example 361 substituting the product from Example
213A for the product
from Example 36H to provide the crude material which was purified by HPLC with
TFA to provide
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the title compound as a trifluoroacetic acid salt. IH NMR (300 MHz, DMSO-D6) 8
ppm: 5.13 (s,
2H), 6.82 (dd, J= 8.09, 1.84 Hz, 1H), 7.32 (t, J= 8.09 Hz, 1H), 7.45 (d, J=
8.46 Hz, 3H), 7.61 (d, J=
8.46 Hz, 2H), 7.64 - 7.71 (m, 2H), 9.01 (dd, J= 8.46, 1.84 Hz, 1H), 9.08 (dd,
J= 4.23, 1.65 Hz, 1H),
10.01 (s, 1H); MS ESI+ m/z 407 (M+H)+, ESI+ m/z 429 (M+Na)+, ESI- m/z 405 (M-
H)-.

Example 214
[2-(4-Amino-phenylsulfanyl)-5-benzyloxy-phenyl]-(7-methyl-pyrido[2,3-
d]pyrimidin-4-yl)-amine
Example 214A
4-Benzyloxy-l-chloro-2-nitro-benzene
[0633] A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromomethyl-
benzene
(2.01 g, 11.5 mmol), potassium carbonate (1.65 g, 12.0 mmol) and
tetrabutylammonium iodide (0.005
g, 0.0135 mmol) in N,1V dimethylfonmamide (5 ml) was stirred at room
temperature for 16 hours.
Afterwards, ice water (10 mL) was added to the solution and the resultant
solid was collected by
filtration and dried in a vacuum oven to provide the title compound (3.0 g,
99%).

Example 214B
4-(4-Benzyloxy-2-nitro-phenylsulfanyl)-phenylamine
[06341 A solution of the compound prepared in Example 214A (1.0 g, 3.80 mmol),
4-
aminothiophenol (0.5 g, 4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in
dimethylformamide (10 ml)
was heated at 40 C for 16 hours. Afterwards, ice water (50 mL) was added to
the solution and the
resultant slurry was treated with ethyl acetate (100 ml). The layers were
separated and the organic
layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then
dried over anhydrous
sodium sulfate. The drying agent was filtered and solvent was removed under
vacuum leaving an
orange oil as the title compound, (1.1 g, 83%).

Example 214C
[4-(4-Benzyloxy-2-nitro-phenylsuifanyl) phenyl]-carbamic acid tert-butyl ester

[0635] A solution of the compound from Example 214B (1.1 g, 3.1 mmole) was
treated with
Boc anhydride (0.9 g, 4.00 mmole) in dioxane (15 ml) and heated at reflux
hours. The next day, the
solvent was removed under vacuum leaving the title compound as a light tan oil
(1.4 g, 100%).

Example 214D
[4-(2-Amino-4-benzyloxy-phenylsulfanyl)-phenyl]-carbamic acid tert-butyl ester

[0636] A solution of the product of Example 214C (1.4 g, 3.09 mmol), iron
powder (0.70 g,
12 mmol) and ammonium chloride (0.18 g, 3.41 mmol) in a methanol (10 mL),
tetrahydrofuran (10
mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The
resultant mixture was diluted
with methanol (50 mL) and filtered through a pad of celite. The filtrate was
concentrated under
vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and
extracted with ethyl
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acetate (2 x 50 mL). The combined extracts were washed with 10% sodium
chloride then dried over
magnesium sulfate, filtered and concentrated under vacuum to provide the title
compound (1.1 g,
90%).

Example 214E
[2-(4-Amino-phenylsulfanyl)-5-benzyloxy-phenyl]-(7-methyl pyrido[2,3-
d]pyrimidin-4-yl)-arnine
[0637] A solution of the product from Example lOB (67 mg, 0.355 mmol), and the
product
from Example 214D (150 mg, 0.355 mmol) in acetic acid (I mL) was stirred in an
oil bath preheated
to 130 C for 10 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue was treated with 50% TFA in CH2C12 (2
ml) for 30 minutes at
room temperature. The solvent was evaporated under vacuum and the resultant
residue was purified
by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt
(25 mg, 12%). 1H
NMR (300 MHz, DMSO-D6) S ppm: 2.76 (s, 3H), 5.10 (s, 2H), 6.46 - 6.61 (m, 2H),
6.97 - 7.12 (m,
31-1), 7.10 - 7.22 (m, 2H), 7.29 - 7.51 (m, 6H), 7.85 (d, J = 8.46 Hz, 1H),
8.80 - 8.90 (m, 2H), 8.95 (d, J
= 8:46 Hz, 1 H), 11.70 (s, 1 H).

Example 215
[2-(4-Amino-phenylsulfanyl)-5-benzyloxy-phenyl]-(7-isopropyl-pyrido[2,3-
d]pyrimidin-4-yl)-amine
[0638] A solution of the product from Example 36E (80 mg, 0.368 mmol), and the
product
from Example 214D (160 mg, 0.368 mmol) in acetic acid (2 mL) was stirred in an
oil bath preheated
to 130 C for 10 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum and the residue was treated with 50% TFA in CH2C12 (2 ml) for 30
minutes at room
temperature. The solvent was evaporated under vacuum and the resultant residue
was purified by
HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (22
mg, 10%). IH NMR
(300 MHz, DMSO-D6) S ppm: 1.36 (d, J= 6.62 Hz, 6H), 3.19 - 3.38 (m, 1H), 5.10
(s, 2H), 6.41 -
6.61 (m, 2H), 6.92 - 7.18 (m, 5H), 7.27 - 7.52 (m, 6H), 7.91 (d, J = 8.46 Hz,
1H), 8.84 (s, IH), 9.01 (s,
lH), 11.64 (s, 2H).

Example 216
[2-(4-Amino-phenylsulfanyl)-5-(1-phenyl-ethoxy)-phenyl]-(7-isopropyl-
pyrido[2,3-d]pyrimidin-4-
yl)-amine

Example 216A
1-Chloro-2-nitro-4-(1-phenyl-ethoxy)-benzer)e
[0639] A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromoethyl-
benzene (3.2
g, 17.3 mmol), sodium carbonate (1.80 g, 17.0 mmol) in acetone (20 ml) was
heated at reflux for 18
hours. The reaction mixture was cooled, the solids filtered off and the
filtrate concentrated to a thick
syrup under vacuum. The residue was dissolved in ether (80 ml) and washed with
water (20 ml) and

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30% KOH solution (2 X 20 ml) and the solvent is concentrated under vacuum
leaving an oily residue
as the title compound (3.01 g, 94%).

Example 216B
4-[2-Nitro-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenylamine
[0640] A solution of the compound from Example 216A (1.86 g, 6.95 mmol), 4-
aminothiophenol (0.88 g, 7.00 mmol), cesium carbonate (2.3 g, 7.00 mmol) in
dimethylformamide
(10 ml) was heated at 40 C for 16 hours. Afterwards ice water (50 mL) was
added to the solution and
the resultant slurry was treated with ethyl acetate (100 ml). The layers were
separated and the organic
layer was washed with 10% sodium bicarbonate and 10% sodium chloride, and
dried over anhydrous
sodium sulfate. The drying agent was filtered and solvent was removed under
vacuum leaving an
orange oil as the title compound, (2.35 g, 92%).

Example 216C
{4-[2-Nitro-4-(1-phenyl-ethoxy)-phenylsulfanyl]-phenyl}-carbamic acid tert-
butyl ester

[0641] A solution of the compound from Example 216B (2.35 g, 6.4 mmole) was
treated
with Boc anhydride (1.7 g, 7.70 mmole) in dioxane (20 ml) and heated at reflux
for 18 hours. The
next day, the solvent was removed under vacuum leaving the title compound as a
light tan oil (1.78 g,
60%).

Example 216D
{4-[2-Amino-4-(1-pheny]-ethoxy)-phenylsulfanyl]-phenyl}-carbamic acid tert-
butyl ester
[0642] A solution of the product from Example 216C (1.78 g, 3.80 mmol), iron
powder (0.85
g, 15.3 mmol) and ammonium chloride (0.25 g, 4.57 mmol) in a methanol (10 mL),
tetrahydrofuran
(10 rnL), and water (5 mL) solution was heated to reflux for 1.5 hours. The
resultant mixture was
diluted with methanol (50 mL) and filtered through a pad of celite. The
filtrate was concentrated
under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and
extracted with ethyl
acetate (2 x 50 mL). The combined extracts were washed with 10% sodium
chloride then dried over
magnesium sulfate, filtered and concentrated under vacuum to provide the title
compound (0.53 g,
32%).

Example 216E
[2-(4-Amino-phenylsulfanyl)-5-(1-phenyl-ethoxy) phenyl]-(7-isopropyl-
pyrido[2,3-d]pyrimidin-4-
yl)-amine

[0643] A solution of the product from Example 36E (57 mg, 0.265 mmol), and the
product
from Example 216D (116 mg, 0.265 mmol) in acetic acid (2 mL) was stirred in an
oil bath preheated
to 130 C for 10 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum and the residue was treated with 50% TFA in CH2C12 (2 ml) for 30
minutes at room
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temperature. The solvent was evaporated under vacuum and the resultant residue
was purified by
HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (18
mg, 11%). 1H NMR
(300 MHz, DMSO-D6) S ppm: 1.30 (m, 3H), 1.31 (d, 614), 3.18 - 3.34 (m, IH),
5.48 (s, 11-1), 6.50 (s,
IH), 6.86 - 7.08 (m, 311), 7.10 (d, J= 5.15 Hz, 211), 7.22 - 7.50 (m, 5H),
7.86 (s, 1H), 8.37 (s, 1H),
8.48 (s, 1H), 8.78 (s;'1H), 8.94 (s, 1H), 11.19 (s, 1H).

Example 217
[2-(2-Amino-6-chloro-pyrimidin-4-ylsulfanyl)-5-benzyloxy-phenyl]-(7-methyl-
pyrido[2,3-
d]pyrimidin-4-yl)-amine

Example 217A
4-Benzyloxy-2-nitro-phenylamine
[0644] A solution containing 4-amino-3-nitro phenol (1.09 g, 7.07 mmole),
benzylbromide
(1.28 g, 7.5 mmole and cesium carbonate (2.43 g, 7.5 mmole) were stirred for 4
days at room
temperature. After the reaction was complete, the reaction mixture was poured
into ice water (500
ml), stirred 1 hour, and the resultant solid was filtered and dried under
vacuum to provide the title
compound (1.1 g, 64%).

Example 217B
4-benzyloxy-2-nitrobenzenediazoniumLtetrafluoroborate
[0645] The product from Example 217A (0.5 g, 2.05 mmole) was dissolved in TBF
(10 ml)
and added dropwise to a cold (-20 C) solution containing boron trifluoride
etherate (1.1 ml, 8.20
mmole), and tert-butyl nitrite (0.6 ml, 4.92 mmole) over a 5 min period. The
resultant mixture was
stirred for 10 minutes at -20 C, then 2 hr at 10 C. The reaction mixture was
then poured into hexane
(100 ml) and the solid was filtered, washed with ether and dried under vacuum
to provide the title
compound (0.61 g, 87%).

Example 217C
4-(4-Benzyloxy-2-nitro-phenylsulfanyl)-6-chloro-pyrimidin-2-ylamine
106461 A solution of the product from Example 217B (0.1 g, 0.290 mmol) in
dimethylsulfoxide (1 ml) was added dropwise to a solution containing potassium
thioacetate (0.04g,
0.350 mrnol) in dimethylsulfoxide (1 ml). The reaction mixture immediately
began bubbling. The
mixture was stirred 90 minutes at room temperature when the bubbling had
subsided. The resultant
dark green mixture was then treated with an aqueous 3M potassium hydroxide
solution (0.1 ml) and
stirred an additional 80 minutes, whereupon, solid 4,6 dichloro-2-
aminopyrimidine was added and the
mixture stirred an additiona160 minutes. The reaction mixture was diluted with
ethyl acetate (50 ml),
washed with water (20 ml), 10% sodium bicarbonate and 10% sodium chloride
solution, dried over
sodium sulfate, filtered and the solvent removed under vacuum to provide a tan
solid as the title
compound (0.1 g, 88%).
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Example 217D
4-(2-Amino-4-benzyloxy-phenylsulfanyl)-6-chloro-pyrimidin-2-ylamine

[06471 A solution of the product from Example 217C (0.1 g, 0.257 mmol), iron
powder
(0.058 g, 1.03 mmol) and ammonium chloride (0.017 g, 0.310 mmol) in a methanol
(5 mL),
tetrahydrofuran (5 mL), and water (2 mL) solution was heated to reflux for 1.5
hours. The resultant
mixture was diluted with methanol (50 mL) and filtered through a pad of
celite. The filtrate was
concentrated under vacuum to a volume of 10 mL, the solution diluted with
water (50 mL) and
extracted with ethyl acetate (2 x 50 mL). The combined extracts were washed
with 10% sodium
chloride then dried over magnesium sulfate, filtered and concentrated under
vacuum to provide the
title compound (0.04 g, 43%).

Example 217E
[2-(2-Amino-6-chloro-pyrimidin-4-ylsulfanyl)-5-benzyloxy-phenyl]-(7-methyl-
pyrido[2, 3-
d]pyrimidin.-4-yl)-amine

[0648] A solution of the product from Example lOB (21 mg, 0.112 mmol), and the
product
from Example 217D (40 mg, 0.112 mmol) in acetic acid (1 mL) was stirred in an
oil bath preheated to
130 C for 10 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue was treated with 50% TFA in CH2ClZ (2
ml) for 30 minutes at
room temperature. The solvent was evaporated under vacuum and the resultant
residue was purified
by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt
(5 mg, 7%). IH NMR
(300 MHz, DMSO-D6) S ppm: 2.66 (s, J = 6.25 Hz, 311), 5.21 (s, 2H), 6.53 (s,
1H), 7.07 (s, 1H), 7.14
(dd, J= 8.64, 2.76 Hz, 1H), 7.25 - 7.61 (m, 6H), 7.62 - 7.72 (m, 1H), 8.52 (s,
1H), 8.66 (d, J = 8.82
Hz, 1H), 8.71 (s, 1H), 8.88 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H).

Example 218
4-[4-(3-Bromo-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenoxy]-phenol
Example 218A
4-[4-(3-Bromo-benzyloxy)-2-nitro-phenoxy]-phenol
[0649] A solution of hydroquinone (276.4 mg, 2.510 mmol) in anhydrous 3.64
mmol) and
heated under a nitrogen atmosphere at 120 for 30 minutes. A solution of 4-(3-
Bromo-benzyloxy)-1-
chloro-2-nitro-benzene (from Example 15A) (774 mg, 2.259 mmol) in
dimethylsulfoxide (4 mL) was
added dropwise from an addition funnel over a period of 30 minutes at 120 ,
the mixture was then
stirred at this temperature for 1 hour. The reaction was cooled in an ice
bath, then poured into ice
water (20 mL) and adjusted the pH to 2 with concentrated hydrochloric acid.
The mixture was
extracted with ethyl ether (3 x 100 mL), the combined ethereal extracts were
washed with water (3 x
100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated by rotary
evaporation under vacuum. Purification of the residue by silica gel flash
chromatography using 3%
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ethyl acetate/methylene chloride as eluent afforded the title compound as a
dark yellow solid (386 mg,
0.927 mmol, 41 %).

Example 218B
4-[2-Amino-4-(3-bromo-benzyloxy)-phenoxy]-phenol
[0650] A mixture of the product from Example 218A (384.6 mg, 0.924 mmol), iron
powder
(317.4 mg, 5.683 mmol), and ammonium chloride (323.7 mg, 6.052 mmol) in water
(3 mL) and
ethanol (6 mL) was heated at 700 under a nitrogen atmosphere for 1 hour. The
reaction was cooled to
room temperature and vacuum filtered, washing the residue with methanol. The
filtrate was
concentrated under vacuum and azeotroped with toluene (50 mL). The residue was
purified by silica
gel flash chromatography using a gradient of 7% to 10% ethyl acetate/methylene
chloride as eluent to
provide the title compound as a beige solid (272 mg, 0.704 mmol, 76%).

Example 218C
4-[4-(3-Bromo benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)
phenoxy]-phenol
[0651] A solution of the product from Example 36E (25 mg, 0.116 mmol) and the
product
from Example 218B (44.6 mg, 0.116 mmol) in acetic acid (1 mI.,) was stirred in
an oil bath preheated
to 140 C for 1 hour. The reaction was cooled to room temperature, diluted with
hexanes (50 mL),
concentrated by rotary evaporation, and co-evaporated with methylene
chloride/hexanes (4x). The
residue was dried under hi-vacuum overnight, then purified by silica gel flash
chromatography using
3% methanol/methylene chloride as eluent to provide the title compound as a
light yellow solid (34
mg, 0.0613 mmol, 53%). 1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.30 (d, J=6.62 Hz,
6H), 3.09 -
3.28 (1n, 1H), 5.12 (s, 2H), 6.62 (d, J=9.20 Hz, 2H), 6.76 (d, J=8.82 Hz, 2H),
6.82 - 6.97 (m, 2H),
7.32 - 7.36 (m, 1H), 7.39 (d, J=7.72 Hz, IH), 7.45 - 7.58 (m, 3H), 7.68 (s,
1H), 8.57 (s, 1H), 8.72 (d,
J-8.82 Hz, 1H), 9.14 (s, 1H), 9.75 (s, 1H); MS (ESI+) m/z 557/559 (M+H)+.

Example 219
4-[4-(4-Bromo benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylarnino)-
phenoxy]-phenol
Example 219A
4-[2-Amino-4-(4-bromo-benzyloxy)-phenoxy]-phenol

[0652] 4-(4-Bromo-benzyloxy)-1-chloro-2-riitro-benzene (from Example 16A) was
reacted
with hydroquinone according to the procedure from Example 39A and reduced
according to the
procedure from Example 39B to provide the title product.

Example 219B
4-[4-(4-Bromo-benzyloxy)-2-(7-isopropyl pyrido[2,3-d]pyrimidin-4-ylamino)
phenoxy]-phenol
[0653] The product from Example 219A was reacted with the product from Example
36E
according to the procedure from Example 39C substituting the product from
Example 219A for the
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product from Example 218B to provide the title compound after silica gel
chromatography (38 mg,
59%). 1H NMR (300 MHz, DMSO-D6) 6 ppm: 1.30 (d, J=6.99 Hz, 6H), 3.10 - 3.27
(m, 1H), 5.09
(s, 2H), 6.56 - 6.66 (m, 2H), 6.70 - 6.79 (m, 2H), 6.81 - 6.97 (m, 211), 7.32
(d, J=2.57 Hz, 1H), 7.43
(d, J=8.46 Hz, 2H), 7.53 (d, J=8.46 Hz, 1H), 7.60 (d, J=8.46 Hz, 2H), 8.57 (s,
1H), 8.72 (d, J=8.46
Hz, 1H), 9.14 (s, 1 H), 9.74 (s, 1H); MS (ESI+) m/z 557/559 (M+H)+.

Exarnple 220
4-[4-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-
phenol
Example 220A
4-(2-Amino-4-benzyloxy phenoxy)-phenol

[0654] 4-Benzyloxy-l-chloro-2-nitro-benzene (from Example 27A) was reacted
with
hydroquinone according to the procedure from Example 39A and reduced according
to the procedure
from Example 39B to provide the title product.

Example 220B
4-[4-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenoxy]-
phenol
[0655] The product from Example 220A was reacted with the product from Example
36E
according to the procedure from Example 39C substituting the product from
Example 220A for the
product from Example 218B to provide the title compound after silica gel
chromatography (58 mg,
65%). 1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.30 (d, J=6.99 Hz, 6H), 3.08 - 3.27
(m, 1H), 5.10 (s,
2H), 6.62 (d, J=9.2 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.81 - 6.98 (m, 2H), 7.26
- 7.61 (m, 7H), 8.57 (s,
114), 8.72 (d, J=8.46 Hz, 1H), 9.13 (s, 111), 9.75 (s, 1H); MS (DCT/NH3) m/z
479 (M+H)+.

Example 221
4-[4-Benzyloxy-2-(7-ethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-
phenol
[06561 The product from Example 27A was reacted with the product from Example
145A
using the procedure from Example IOF substituting the product from Example 27A
for the product
from Example l0E and substituting the product from Example 145A for the
product from Example
lOB to provide the title product. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.32 (t,
J=7.72 Hz, 311),
2.95 (q, J=7.72 Hz, 2H), 5.11 (s, 2H), 6.65 (d, J=8.82 Hz, 2H), 6.91 - 7.05
(m, 1H), 7.10 (d, J=8.46
Hz, 2H), 7.32 - 7.50 (m, 6H), 8.12 (d, J=6.99 Hz, 1H), 8.66 - 8.77 (m, 1H),
9.04 (d, J=8.82 Hz, 1H),
9.63 (s, IH), 10.28 (s, 1H); MS (APCI) m/z 481 (M+H)+.

Example 222
4-[4-Benzyloxy-2-(7-cyclohexyl-pyrido[2,3-d]pyrirnidin-4-ylamino)-
phenylsulfanyl]-phenol
[0657] The product from Example 27A was reacted with the product from Example
135A
using the procedure from Example I OF substituting the product from Example
27A for the product
from Example IOE and substituting the product from Example 135A for the
product from Example
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lOB to provide the title product. 1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.23 - 1.51
(m, 4H), 1.53 -
1.79 (m, 4H), 1.80 - 2.00 (m, 2H), 2.77 - 3.02 (m, 1H), 5.10 (s, 2H), 6.67 (d,
J=8.46 Hz, 2H), 6.88 -
7.01 (m, 1H), 7.11 (d, J=8.82 Hz, 2H), 7.22 - 7.31 (m, 1H), 7.32 - 7.49 (m,
6H), 7.56 (d, J=7.72 Hz,
1H), 8.55 (s, 1H), 8.73 (d, J=8.09 Hz, 1H), 9.94 (s, 1H); MS (APCI) m/z 535
(M+H)+.

Example 223
4-[4-Benzyloxy-2-(7-sec-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[06581 The product from Example 27A was reacted with the product from Example
140A
using the procedure from Example lOF substituting the product from Example 27A
for the product
from Example IOE and substituting the product from Example 140A for the
product from Example
lOB to provide the title product. 1H NMR (300 MHz, DMSO-D6) 8 ppm: 0.82 (t,
J=7.35 Hz, 3H),
1.30 (d, J=6.62 Hz, 3H), 1.58 = 1.73 (m, 1H), 1.75 - 1.87 (m, 1H), 2.89 - 3.08
(m,.1H), 5.11 (s, 2H),
6.67 (d, J=8.82 Hz, 2H), 6.85 - 7.03 (m, 1H), 7.11 (d, J=8.46 Hz, 2H), 7.30 -
7.50 (m, 6H), 7.56 (d,
J=8.82 Hz, 1H), 8.56 (s, 1H), 8.75 (d, J=8.46 Hz, 1H), 9.64 (s, 1H), 9.95 (s,
I H); MS (APCI) m/z

Example 224
4-[4-(2-Chloro-thiazol-5 -ylmethoxy)-2-(7-isopropyl-pyrido [2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl]-phenol
Example 224 A
4-[2-Arnino-4-(2-chloro-thia.zol-5-ylmethoxy)-phenylsulfanyl]-phenol
[0659] The title compound was prepared as described in Example 16A
substituting benzyl
bromide with 2-chloro-5-bromomethyl thiazole to provide the title compound
(0.38 g, 64

Example 224b
4-[4-(2-Chloro-thiazol-5-ylmethoxy)-2-(7-isopropyl-pyrido [2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl]-phenol

[0660] A solution of the product of Example 36E (40.4 mg, 0.187 mmol), and the
product of
Example 224A (68 mg, 0.187 mmol) in acetic acid (1 mL) was stirred in an oil
bath preheated to 130
C for 10 minutes. The mixture was then cooled to room temperature, the acetic
acid removed under
vacuum, and the resultant residue purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt (31 mg, 30%). 'H NMR (300 MHz, DMSO-d6) 8 ppm: 1.35
(d, J=6.99 Hz, 6
H) 3.17 - 3.36 (m, 1 H) 5.35 (s, 2 H) 6.55 (d, J=7.72 Hz, 1 H) 6.58 - 6.74 (m,
2 H) 7.00 - 7.30 (m, 4
H) 7.68 - 7.95 (m, 2 H) 8.76 (s, 1 H) 8.94 (d, J=8.46 Hz, I H) 9.73 (s, 1 H)
11.34 (s, 1 H); MS (ESI+)
rn/z 536 (M+H)+, (ESI-) m/z 534 (M-H)-.

Example 225
4-[4-(6-Chloro-pyridin-2-ylmethoxy)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl]-phenol

Example 225a
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4-[2-Amino-4-(6-chloro-pyridin-2-ylznethoxy)-phenylsulfanyl]-phenol
[0661] The title compound was prepared as described in Example 16A
substituting benzyl
bromide with 2-chloro-5-bromomethyl pyridine to provide the title compound
(0.63 g, 73 %).

Example 225b
4-[4-(6-Chloro-pyridin-2-ylmethoxy)-2-(7-rnethyl-pyrido [2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl]-phenol

[0662] A solution of the product of Example I OB (37 mg, 0.197 mmol), and the
product of
Example 225a (70.7 mg, 0.197 mmol) in acetic acid (2 mL) was stirred in an oil
bath preheated to
130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue puri,fied by HPLC with TFA to provide
the title compound as
a trifluoroacetic acid salt (20 mg, 20%). 'H NIvIlZ (300 MHz, DMSO-d6) S ppm:
2.70 (s, 3 H) 5.18 (s,
2 H) 6.65 (d, J=8.82 Hz, 2 H) 7.02 (d, J=8.09 Hz, 1 H) 7.11 (d, J=8.82 Hz, 2
R) 7.19 (d, J=8.82 Hz, 1
H) 7.25 (s, 1 H) 7.52 (dd, J=13.60, 7.72 Hz, 2 H) 7.67 (d, J=8.09 Hz, 1 H)
7.93 (t, J=7.72 Hz, 2 H)
8.65 (s, 1 H) 8.80 (d, J=8.09 Hz, I H) 9.68 (s, I H); MS (ESI+) rn/z 502
(M+H)+, (ESI-)m/z 500 (M-
H)-.

Example 226
4-[4-(6-Chloro-pyridin-2-ylmethoxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl]-phenol

[0663] A solution of the product of Example 36E (36 mg, 0.168 mmol), and the
product of
Example 225a (60 mg, 0.168 xnmol) in acetic acid (1 mL) was stirred in an oil
bath preheated to 130
C for 10 minutes. The mixture was then cooled to room temperature, the acetic
acid removed under
vacuum, and the resultant residue purified by HPLC with TFA to provide the
title compound as a
trifluoroacetic acid salt (31 mg, 30%). 'H NMR (300 MHz, DMSO-d6) S ppm: 1.16
(d, J=6.99 Hz, 3
H) 1.36 (d, J=6.62 Hz, 3 H) 3.20 - 3.40 (m, 1 H) 5.18 (s, 1 H) 6.55 (d, 1=7.72
Hz, 1 H) 6.64 (d, J=8.82
Hz,2H)6.77(s,1H)7.04-7.18(m,2H)7.15-7.29(m,2H)7.52(dd,J=10.48,7.91Hz,2H)7.77
(d, J=7.72 Hz, 1 H) 7.93 (t, J=7.72 Hz, 2 H) 8.82 (s, 1 H) 8.97 (s, 1 H) 9.72
(s, I H) 11.66 (s, 1 H);
MS (ESI+) m/z 530 (M+H)+, (ESI-) m/z 528 (M-H)-.

Example 227
4-[2-(7-tert-Butyl pyrido[2,3-d]pyrimidin-4 ylamino)-4-(3-fluoro-benzyloxy)-
phenylsulfanyl]-phenol
[0664] The product from Example 127A (110 mg, 0.478 mmol) was reacted with the
product
from Example 28A (164 mg, 0.48 mmol) in 1 mL of glacial acetic acid was heated
at 120 C for13
min. Cooled to room temperature and removed the acetic acid under vacuum. The
crude product was
purified by HPLC with TFA to give the title compound as a trifluoroacetic acid
salt (134 mg, 44 %).
'H NMR (300 MHz, DMSO-d6) 6 ppm: 1.43 (s, 9 H) 5.14 (s, 2 H) 6.65 (d, J=8.45
Hz, 2 H) 7.17 (m, 4
H) 7.29 (d, J=8.45 Hz, 2 H) 7.44 (d, J=8.45 Hz, 2 H) 7.99 (d, J=7.80 Hz, IH)
8.72 (s, I H) 8.93 (d,
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J=8.45 Hz, 1 H) 9.68 (s, 1 H) 10.90 (br s, 1 H); MS (ESI+) m/z, 527 (M+H-
TFA)+; (ESI-) m/z, 525
(M-H-TFA)-.

Example 228
4-[4-[ 1-(3-Bromo-phenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
Example 228a
1 -( l -Bromo-ethyl)-4-fluoro-benzene

[06651 To a solution of 1-(3-Bromo-phenyl)-ethanol (7.0 g, 34.0 mmol) in
dichloromethane
(40 mL) was added drop wise phosphorus tribromide (77 g, 34.0 mmol) The
mixture was stirred at
room temperature for 16 h. The reaction was poured onto ice/water. The aqueous
phase was made
basic with sodium bicarbonate. The aqueous phase was extracted with
dichloromethane. The organic
phase was washed with water, brine, and dried over sodium sulfate, filtered
and concentrated under
vacuum giving the title compound (7.8 g, 80 %).

Example 228b
4-[ 1-(3-Bromo-phenyl)-ethoxy]-1-chloro-2-nitro-benzene

[0666] To Example 228a (7.8 g, 30 mmol) in DMF (50 mL) was added 4-chloro-3
nitro-
phenol (5.14 g, 30.0 mmol), and K2CO3 (8.18 g, 60 mmol). The mixture was
heated at 80 C for 16 hr.
The reaction was cooled and poured into water. The aqueous phase was extracted
with ethyl acetate
(2x) and the combined phases were washed with water, brine, and dried over
sodium sulfate. The
organic phase was concentrated under reduced pressure. The residue was
purified by silica gel
chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title
compound (7.0 g, 66 %).

Example 228c
4-{4-[1-(3-Bromo-phenyl)-ethoxy]-2-nitro-phenylsulfanyl}-phenol
[06671 To Example 228b (5.0 g, 14.0 mmol) in DMF (50 mL) was added 4-
mercaptophenol
(1.7 g, 14.0 mmol), and KZCO3 (3.8 g, 28 mmol). The mixture was heated at 80
C for 16 hr. The
reaction was cooled and poured into water. The aqueous phase was extracted
with ethyl acetate (2x)
and the combined phases were washed with water, brine, and dried over sodium
sulfate. The organic
phase was concentrated under reduced pressure. The residue was purified by
silica gel
chromatography eluting with (hexanes/ethyl acetate/methano175:15:5) to give
the title compound (5.2
g, 83 %).

Example 228d
4- {2-Amino-4-[ 1-(3 -bromo-phenyl )-ethoxy]-phenylsulfanyl } -phenol

[0668] The product from Example 228c (5.4 g, 12.2 mmol) was reacted with Fe
and NH4CI
as described in Example l0E to give the title compound (3.6 g, 76 %).

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Example 228e
4-[4-[ 1-(3-Bromo phenyl)-ethoxy]-2-(pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanylJ-phenol
[0669] The product from Example 57A (125 mg, 0.72 mmol) was reacted with
Example
228d (298 mg, 0.72 mmol) in acetic acid (10 mL) at 125 C in a sealed tube for
5 minute giving the
crude title compound which was purified by HPLC with TFA providing the product
as the
trifluoroacetic acid (120 mg, 31 %). 'H NMR (300 MHz, DMSO-d6) fi ppm: 1.54
(d, J=6.25 Hz, 3 H)
5.52 (q, J 6.25 Hz, 1 H) 6.66 (d, J=8.82 Hz, 2 H) 6.85 (s, 1 H) 7.07 - 7.12
(m, 3 H) 7.19 (s, 1 H) 7.32
(t, J=7.72 Hz, 1 H) 7.39 -7.49 (m, 2 H) 7.61 (s, 2 H) 8.57 (s, 1H) 8.80 (s, 1
H) 9.06 (s, -1 H) 9.65 (s, 1
H); MS (ESI.-) m/z 545 (M-H)-.

Example 229
4-[4-[ 1-(3 -Bromo-phenyl)-ethoxy]-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-phenylsulfanyl] -
phenol
[0670] The product from Example lOB (110 mg, 0.58 mmol) was reacted with
Example
228d (243mg, 0.58 mmol) in acetic acid (10 mL) at 125 'C in a sealed tube for
5 minute giving the
crude title compound which was purified by. HPLC with TFA providing the
product as the
trifluoroacetic acid (100 mg, 30 %). 'H NMR (300 MHz, I?MSO-d6) S ppm: 1.33
(d, J=6.25 Hz, 3 H)
2.53 (s, 3H) 5.31 (q, J-6.43 Hz, 1 H) 6.44 (d, J=8.82 Hz, 2 H) 6.68 (dd,
J=8.82, 2.57 Hz, 1 H) 6.85 -
6.92 (m, 3 H) 6.95 (d, J-2.57 Hz, 1 H) 7.11 (t, J=7.72 Hz, 1 H) 7.19 - 7.27
(in, 2 H) 7.40 (s, 1 H) 7.44
(d, .J-8.46 Hz, I H) 8.44 (s, I H) 8.56 (d, J=8.46 Hz, 1 H); MS (ESI +) m/z
560 (M+H)+.

Example 230
4-[4-[1-(3-Bromo-phenyl)-ethoxy]-2-(7-isopropyl pyrido[2,3-d]pyrirnidin-4-
ylamino)-
phenylsulfanyl]-phenol

[0671] The product from Example 36E (130 mg, 0.60 mmol) was reacted with
Example
228d (250 mg, 0.60 mmol) in acetic acid (10 mL) at 125 C in a sealed tube for
5 minute giving the
crude title compound which was purified by HPLC with TFA providing the product
as the
trifluoroacetic acid (140 mg, 39 lo).'H NMR (300 MHz, DMSO-d6) S ppm: 1.34
(d,.I-6.99 Hz, 6 H)
1.54 (d, J=6.25 Hz, 3 H) 3.26 (q, 1 H) 5.52 (q, J-6.62 Hz, 1 H) 6.65 (d, J-
8.46 Hz, 2 H) 6.92 (dd,
T-8.82, 2.94 Hz, 1 H) 7.10 (m, 4 H) 7.32 (t, J=7.72 Hz, 1 H) 7.39 - 7.50 (m, 2
H) 7.60 (s, I H) 7.79
(d, J=8.46 Hz, 1 H) 8.70 (s, 1 H) 8.86 (d, J=8.46 Hz, 1 H) 9.72 (s, 1 H); MS
(ESI+) m/z 588 (M+H)+.
Example 231
4-[4-(3-Bromo-benzyloxy)-2-(7-tert-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[06721 The product from Example 127A (147 mg, 0.63 mmol) and the product from
Example 15A (256 mg, 0.63 mmol) were heated in 2 mL of glacial acetic acid at
120 C for 15 min.
Cooled to room temperature and the acetic acid was removed under vacuum. The
crude product was
purified by HPLC with TFA to provide the title compound as a trifluoroacetic
acid salt 45 mg, 10 %).
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'H NMR (300 MHz, DMSO-d6) 8 ppni: 1.43 (s, 9 H) 5.13 9 (s, 2 H) 6.66 (d,
J=8.83 Hz, 2 H) 7.01 (d,
J=6.62 Hz, I H) 7.11(d, J=8.83 Hz, 2 H) 7.19 (m, 1 H) 7.37 (m, 1 H) 7.46 (d,
J=7.72 Hz, 1 H) 7.54
(D, J=6.62 Hz, I H) 7.66 (s, 1 H) 7.95 (d, J=8.09 Hz, I H) 8.69 (s, I H) 8.88
(D, J=8.83 Hz; 1 H) 9.68
(s, i H); MS (ESI+) m/z, 587, 589 (M+H-TFA)+; (ESI-) rn/z, 585, 587 (M-H-TFA)-
.

Example 232
4-[4-(3-Bromo phenoxymethyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol
Example 232A
4-[2-Amino-4-(3-bromo-phenoxymethyl)-phenylsulfanyl]-phenol
106731 A solution of 4-[4-(3-Bromo-phenoxymethyl)-2-nitro-phenylsulfanyl]-
phenol (325
mg, 0.752 mmol), iron dust (210 mg, 3.76 mmol) and ammonium chloride (60 mg,
1.13 mmol) in
tetrahydrofuran (5 rnL), water (1.5 mL) and ethanol (5 mL) was heated at
reflux for 2.5 hours. After
cooling to room temperature, the solution was filtered through a pad of
celite, which was washed with
methanol. The filtrate was then concentrated under vacuum, then dissolved in
water (20 mL) and
extracted with ethyl acetate (2 x 20 mL). The organic extracts were dried and
concentrated under
vacuum to provide the title compound as a light yellow solid (240 mg, 79 oo).

Example 232B
4-[4-(3-Bromo-phenoxymethyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol

[0674] A solution of the product from Example 232A (85 mg, 0.211 mmol) and the
product
from Example 36E (46 mg, 0.211 mmol) in acetic acid (3 mL) was heated at 130
C for 15 minutes.
The solution was then allowed to cool to room temperature, the acetic acid
removed under vacuum
and the resultant residue purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (63 mg, 43%). 'H NMR (300 MHz, DMSO-d6) S ppm: 1.35
(d, J= 7.0 Hz,
6H), 3.25 (m, 1H), 5.13 (s, 2H), 6.77 (d; J= 8.8 Hz, 2H), 7.02 (d, J= 8.1 Hz,
2H), 7.15 (m, 1H), 7.23
(m, 4H), 7.36 (m 1H), 7.46 (s, 111), 7.83 (d, J= 8.8 Hz, 1H), 8.76 (s, 1H),
8.95 (d, J= 8.8 Hz, IH),
9.88 (s, 1H), 11.22 (bs, 1H); MS (ESI)+ m/z 573/575 (M+H)+.

Example 233
4-[4-(3-Bromo-phenoxymethyl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol

[0675] A solution of the product from Example 232A (60 mg, 0.149 mmol) and the
product
from Example 10B (28 mg, 0.149 mmol) in acetic acid (3 mL) was heated at 130
C for 15 minutes.
The solution was then allowed to cool to room temperature, the acetic acid
removed under vacuum
and the resultant residue purified by HPLC with TFA to provide the title
compound as a
trifluoroacetic acid salt (46 mg, 47%). 'H NMR (300 MHz, DMSO-d6) S ppm: 2.72
(s, 3H), 5.12 (s,
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2H), 6.77 (d, J= 8.5 Hz, 2H), 7.02 (m, 2H), 7.16 (m, 1H), 7.23 (m, 4H), 7.36
(m 1H), 7.47 (s, 1H),
7.70 (d, J= 8.8 Hz, 1H), 8.70 (s, 1H), 8.86 (d, J= 8.5 Hz, 1H), 9.87 (s, IH),
10.95 (bs, 1H); MS
(ESl)+ m/z 545/547 (M+H)+.

Example 234
4-[4-(2,5 -Di fluoro-benzyloxy)-2-(pyrido [2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl] -phenol
Example 234a
2-Bromomethyl-1,4-difluoro-benzene
[0676] To a solution of (2,5-difluoro-phenyl)-methanol (4.8 g, 33.6 mmol) in
dichloromethane (40 mL) was added drop wise phosphorus tribromide (94 g, 33.6
mmol) The
mixture was stirred at room temperature for 16 h. The reaction was poured onto
ice/water. The
aqueous phase was made basic with sodium bicarbonate. The aqueous phase was
extracted with
dichloromethane. The organic phase was concentrated under reduced pressure.
The residue was
purified by silica gel chromatography eluting with (hexanes/ethyl acetate
90:10) to give the title
compound (3.5g, 50 %).

Example 234b
1-Chloro-4-(2,5-fluoro-benzyloxy)-2-nitro-benzene
[0677] To Example 234a (2.2 g, 10.4 mmol) in DMF (50 mL) was added 4-chloro-3-
nitro-
phenol (1.8 g, 10.4 mmol), and K2C03 (2.87 g, 20.8 mmol). The mixture was
heated at 80 C for 16 h.
The reaction was cooled and poured into water. The aqueous phase was extracted
with ethyl acetate
(2x) and the combined phases were washed with water, brine, and dried over
sodium sulfate. The
organic phase was concentrated under reduced pressure. The residue was
purified by silica gel
chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title
compound (2.48 g, 66 %).

Example 234c
4-[4-(2,5-Difluoro-benzyloxy)-2-nitro phenylsulfanyl]-phenol

[0678] To Example 234b (2.5 g, 8.3 mmol) in DMF (50 mL) was added 4-
mercaptophenol
(1.0 g, 8.3 mmol), and K2CO3 (2.3 g, 16.5 mmol). The mixture was heated at 80
C for 16 h. The
reaction was cooled and poured into water. The aqueous phase was extracted
with ethyl acetate (2X)
and the combined phases were washed with water, brine, and dried over sodium
sulfate. The organic
phase was concentrated under reduced pressure. The residue was purified by
flash chromatography
eluting with (hexanes/ethyl acetate/methano175:15:5) to give the title
compound (1.7 g, 52 %).

Example 234d
4-[2-Amino-4-(2,5-difluoro-benzyloxy)-phenylsulfanyl]-phenol
[06791 The product from Example 234c (1.70 g, 4.2 mmol) was reacted with Fe
and NH4Cl
as described in Example 10E to give the title compound (1.3 g, 84 %).
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Example 234e
4-[4-(2,5-Difluoro-benzyloxy)-2-(pyrido[2,3-d]pyrimidin-4-ylarnino)-
phenylsulfanyl]-phenol

[0680] The product from Example 57A (100 mg, 0.57 mmol) was reacted with
Example
234d (206 mg, 0.57 mmol) in acetic acid (10 mL) at 125 C in a sealed tube for
5 minute giving the
crude title compound which was purified by HPLC with TFA providing the product
as the
trifluoroacetic acid (140 mg, 39 %). 'H NMR (300 MHz, DMSO-d6) S ppm: 5.13 (s,
2 H) 6.67 (d,
J=8.46 Hz, 2 H) 6.93 - 7.01 (m, I H) 7.10 - 7.16 (m, 3 H) 7.22 - 7.37 (m, 4 H)
7.41 - 7.52 (m, J-5.79,
5.79, 2.76 Hz, 1 H) 7.64 (dd, J 8.09, 4.41 Hz, 1 H) 8.53 (s, 1 H) 8.84
(d,1=7.72 Hz, 1 H) 9.05 (s, 1
H); MS (ESI+) m/z 489 (M+H)+.

Example 235
4-[4-(2,5-Difluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-
phenol

[06811 The product from Example 36E (100 mg, 0.46 mmol) was reacted with
Example
234d (206 mg, 0.46 mmol) in acetic acid (10 mI,) at 125 C in a sealed tube
for 5 minute giving the
crude title compound which was purified by HPLC with TFA providing the product
as the
trifluoroacetic acid (140 mg, 39 %). 'H NMR (300 MHz, DMSO=d6) S ppm: 1.34 (d,
J-6.62 Hz, 6 H)
5.14 (s, 2 H) 6.66 (d, J=8.46 Hz, 2 H) 7.06 (d, J 2.57 Hz, 1 H) 7.12 (d,
J=8.46 Hz, 2 H) 7.21 - 7.35
(m, 4 H) 7.44 (s, 1 H) 7.77 (d, J-8.46 Hz, 1 H) 8.69 (s, 1 H) 8.88 (d, J=8.46
Hz, I H) 9.70 (s, I H);
MS (ESI+) m/z 531 (M+H)+.

Example 236
4-[4-(2-Chloro-5-fluoro-benzyloxy)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-
ylamino)-
phenylsulfanyl] phenol

Example 236a
2-Bromomethyl-l-chloro-4-fluoro-benzene
[06821 To a solution of (2-chloro-5-fluoro-phenyl)-methanol (5.0 g, -31.1
mmol) in
dichloromethane (40 mL) was added drop wise phosphorus tribromide (87 g, 31.1
mmol) .The
mixture was stirred at room temperature for 16 h. The reaction was poured onto
ice/water. The
aqueous phase was made basic with sodium bicarbonate. The aqueous phase was
extracted with
dichloromethane. The organic phase was concentrated under reduced pressure.
The residue was
purified by silica gel chromatography eluting with (hexanes/ethyl acetate
90:10) to give the title
compound (5.75 g, 82.5 %).

Example 236b
1-Chloro-4-(2-chloro-50flouro-benzyloxy)-2-nitro-benzene
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[06831 To Example 236a (5.7 g, 25.7 mmol) in DMF (50 mL) was added 4-chloro-3-
nitro-
phenol (4.46 g, 25.7 mmol), and K2CO3 (7.10 g, 51.4 mmol). The mixture was
heated at 80 C for 16
h. The reaction was cooled and poured into water. The aqueous phase was
extracted with ethyl acetate
(2x) and the combined phases were washed with water, brine, and dried over
sodium sulfate. The
organic phase was concentrated under reduced pressure. The residue was
purified by silica gel
chromatography eluting with (hexanes/ethyl acetate 90:10) to give the title
compound (7.0 g, 86 %).

Example 236c
4-[4-(2-Chloro-5-fluoro-benzyloxy)-2-nitro-phenylsulfanyl]-phenol
[0684] To Example 236b (2.5 g, 8.3 mmol) in DMF (50 mL) was added 4-
mercaptophenol
(1.0 g, 8.3 mmol), and K2C03 (2.3 g, 16.5 mmol). The mixture was heated at 80
C for 16 h. The
reaction was cooled and poured into water. The aqueous phase was extracted
with ethyl acetate (2X)
and the combined phases were washed with water, brine, -and dried over sodium
sulfate. The organic
phase was concentrated under reduced pressure. The residue was purified by
silica gel
chromatography eluting with (hexanes/ethyl acetate/methanol (70:25:5) to give
the= title compound
(5.0 g, 78 %).

Example 236d 4-[2-Amino-4-(2-chloro-5-fluoro-benzyloxy)-phenylsulfanyl]-phenol

[0685] The product from Example 236c (4.2g, 10.2 mmol) was reacted with Fe and
NH4CI
as described in Example l0E to give the title compound (3.0 g, 77

Example 236e
4-[4-(2-Chloro-5 -fluoro-benzyl oxy)-2-(7-isopropyl-pyrido [2,3-d]pyrimidin-4-
yl amino)-
phenylsulfanyl] -phenol

[06861 The product from Example 36E (125 mg, 0.72 mmol) was reacted with
Example
236d (298 mg, 0.72 mmol) in acetic acid (10 mL) at 125 C in a sealed tube for
5 minute giving the
crude title compound which was purified by adding ethyl ether to the residue
providing the desired
product as the acetic acid (225 mg, 66 %). 'H NMR (300 MHz, DMSO-d6) S ppm:
1.32 (d, J=6.99 Hz,
6 H) 3.21 (q, 1 H) 5.15 (s, 2 H) 6.69 (d, J=8.46 Hz, 2 H) 6.99 (dd, I H) 7.13
(d, .1=8.46 Hz, 4 H) 7.25
- 7.35 (m, 2 H) 7.49 (dd, J=9.38, 3.13 Hz, I H) 7.54 - 7.62 (m, J=8.82, 5.15
Hz, 3 H) 8.55(1H, s) ( 1
8.74 (s, I H) 9.66 (s, 1 H) 9.98 (s, 1 H); MS (ESI -) m/z 547 (M+H)+.

Example 237
4-[5 Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl)-phenol
Example 237A
4-Benzyloxy-2-fluoro-l-nitro benzene
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[06871 A mixture of 3-fluoro-4 nitrophenol (0.30 g, 1.91 mmol), benzyl bromide
(0.36 g,
2.10 mmol, 1.1 eq), potassium carbonate (0.792 g, 5.73 mmol, 3.0 eq) and
tetrabutylammonium
iodide (5.0 mg, 0.0 14 mmol, 0.007 eq) in dimethylformamide (5 mL) was stirred
at room temperature
for 16 h. Water (20 mL) was added to the reaction mixture and the resulting
solid precipitate was
isolated by vacuum filtration and dried to provide the title compound (0.455
g, 96%) as a yellow
solid.

Example 237B
4-(5-Benzyloxy-2-nitro-phenylsulfanyl)-phenol
[0688] The product of Example 237A (0.301 g, 1.22 mmol), 4-mercaptophenol
(0.184 g,
1.46 mmol, 1.2 eq) and cesium carbonate (0.952 g, 2.92 mmol, 2.4 eq) in
dimethylformamide (10 rnL)
was heated in a 100 C oil bath for 3 hours and then cooled to room
temperature. Water (20 mL) was
added and the mixture was stirred at room temperature for 2 hours, and the
resulting solid was
isolated by vacuum filtration and dried to provide the title compound (0.405
g, 94%) as a yellow
solid.

Example 237C
4-(2-Amino-5-benzyloxy-phenylsulfanyl)-phenol
[0689] The product of Example 237B (0.390 g, 1.10 mmol), iron powder (0.248 g,
4.41
mmol, 4.0 eq) and ammonium chloride (0.071 g, 1.32 mmol, 1.2 eq) in
tetrahydrofuran (6 mL),
methanol (6 mL) and water (2 mL) was heated under reflux for 16 hours and then
cooled to room
temperature. The reaction mixture was filtered through Celite, rinsing with
methanol, and the filtrate
was evaporated under reduced pressure to provide the title compound (0.340 g,
95%) as a gray
powder that was used in subsequent reactions without further purification.

Example 237D
4-[5-Benzyloxy-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)
phenylsulfanyl]-phenol
[06901 The product of Example 237C (0.0908 g, 0.281 mmol) and the product of
Example
36E (0.0607 g, 0.281 mmol) in glacial acetic acid (2 mL) was heated in a 140 C
oil bath for 10 min,
cooled to room temperature, and evaporated under reduced pressure. The residue
was purified by
column chromatography on silica gel eluting with 5% methanol/dichloromethane
to provide the title
compound (0.0368 g, 27%) as a tan solid. 1H NMR (300 MHz, DMSO-D6) S ppm: 9.88
(s, 2 H),
8.82 (d, J-8.46 Hz, 1H), 8.52 (s, IH), 7.58 (d, J=8.46 Hz, 1H), 7.28 - 7.42
(m, 5H), 7.19 - 7.28 (m,
3H), 6.87 (dd, ./--8.64, 2.76 Hz, 1H), 6.75 - 6.84 (m, 2H), 6.38 (d, J-2.57
Hz, 1H), 4.99 (s, 2H), 3.14 -
3.27 (m, 1H), 1.32 (d, J=6.99 Hz, 6H); MS (ESI) m/z 495.2 (M+Id)+, (ESI) m/z
493.2 (M-H)-.

Example 238
4-[2-(7-Methyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-4-styryl-phenylsulfanyl] -
phenol
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Example 238A
4-(4-Bromo-2-nitro-phenylsulfanyl)-phenol

[0691] A mixture of 4 bromo-l-fluoro-2=nitrobenzene (0.44 g, 2.0 mmol), 4-
mercaptophenol
(0.303 g, 2.4 mmol), and cesium carbonate (1.56 g, 4.8 mmol, 2.4 eq) in
dimethylformainide (10 mL)
was heated in a 100 C oil bath for 3 hours and then cooled to room
temperature. The reaction mixture
was poured over ice water (50 mL), adjusted to pH 3 by the addition of IN
aqueous hydrochloric acid,
and extracted with ethyl acetate (3 x 100 mL). The combined organic layers
were dried over
anhydrous magnesium sulfate, filtered and evaporated to provide the title
compound as a thick yellow
oil (0.70 g, >100%) that was utilized without further purification.

Example 238B
4-(2-Amino-4-bromo-phenylsulfanyl)-phenol
[0692] A mixture of the product from Example 238A (0.302 g, 0.926 mmol), iron
powder
(0.208 g, 3.7 mmol, 4.0 eq) and ammonium chloride (0.059 g, 1.11 mmol, 1.2 eq)
in a mixture of
methanol (6 mL), tetrahydrofuran (6. mL), and water (2 mL) was heated under
reflux for 5 hours and
then cooled to room temperature. The reaction mixture was filtered through
Celite and the filter pad
was rinsed with methanol (25 mL). The filtrate was evaporated under reduced
pressure to leave a
brown glassy solid (0.27 g, 99%) that was utilized without further
purification.

Example 23 8C
4-[4-Bromo-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenyl sulfanyl]-
phenol

[0693] A mixture of the product from Example 238B (0.158 g, 0.533 mmol) and
the product
from Example lOB (0.100 g, 0.533 mmol) in glacial acetic acid (2 mL) was
heated in a 130 C oil bath
for 30 min. An additional amount of the product from Example lOB (0.060 g,
0.319 mmol) was
added and the reaction mixture was heated for an additional 30 min at 130 C.
The reaction mixture
was then cooled to room temperature and the solvent evaporated under reduced
pressure. The residue
was triturated with 2-propanol, and the resulting solid isolated by vacuum
filtration and dried to
provide the title compound (0.083 g, 36% yield) as a beige solid.

Example 238D
4-[2-(7-Methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-4-styryl phenylsulfanyl]-
phenol

10694] A mixture of the product from Example 238C (0.0791 g, 0.180 mmol),
styrene (0.176
g, 1.69 mmol, 9.4 eq), palladium(II) acetate (6.2 mg, 0.0276 mmol, 0.15 eq),
tri-o-tolylphosphine
(13.3 mg, 0.0437 mmol, 0.24 eq), and di-isopropyl ethylamine (0.697 g, 0.539
mmol, 3.0 eq) in
dimethylformamide (2 mL) was heated in a 130 C oil bath for 98 hours. The
mixture was then cooled
to room temperature and the solvent evaporated under a stream of nitrogen gas.
The residue was
partitioned between ethyl acetate and water and the aqueous layer further
extracted with ethyl acetate.
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The combined organic layers were dried over anhydrous magnesium sulfate,
filtered and evaporated.
The residue was purified by HPLC wiyh TFA to provide the title compound as a
trifluoroacetic acid
salt (6.1 mg, 10% yield). 1H NMR (300 MHz, DMSO-D6) 6 ppm: 11.27 (s, 1H), 9.89
(s, 1H), 8.93
(d, J=8.09 Hz, 1H), 8.79 (s, 1H), 7.78 (d, J=8.82 Hz, 1H), 7.66 (s, 1H), 7.58
(d, J=7.35 Hz, 2H), 7.52
(dd, J=8.09, 1.47 Hz, 1H), 7.37 (t, J=7.35 Hz, 2H), 7.19 - 7.31 (m, 5H), 7.00
(d, J--8.09 Hz, 1H), 6.73
- 6.81 (m, 2H), 2.75 (s, 3H).

Example 239
(7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-(2-phenylsulfanyl-5-styryl-phenyl)-
amine
Example 239A
(5-Bromo-2-phenylsulfanyl-phenyl)-(7-methyl-pyrido [2, 3--d]pyrimidin-4-yl)-
amine

[06951 5-bromo-2-(phenylthio)benzenamine was prepared according to procedures
similar to
those described'in Examples 6a, 6b, and 6c substituting benzenethiol for 4-
mercaptophenol and 4-
bromo-2-nitrophenol for 4-methyl-2-nitro phenol.
[0696] A mixture of the product from Example lOB (0.188 g, 1.0 mmol) and 5-
bromo-2-
(phenylthio)benzenamine (0.280 g, 1.0 mrnol) in glacial acetic acid (2 mL) was
heated in a 130 C oil
bath for 30 min. The reaction mixture was then cooled to room temperature and
the solvent
evaporated under reduced pressure. The residue was triturated with methanol,
and the resulting solid
isolated by vacuum filtration and dried to provide the title compound (0.276
g, 65% yield) as a beige
solid.

Example 239B
(7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-(2-phenylsulfanyl-5-styryl-phenyl)-
amine
[06971 A mixture of the product from Example 239A (0.127 g, 0.30 mmol),
styrene (0.133 g,
1.27 mmol, 4.3 eq), palladium(LI) acetate (5.3 mg, 0.0236 mmol, 0.08 eq), tri-
o-tolylphosphine (17.7
mg, 0.058 mmol, 0.19 eq), and triethylamine (0.0913 g, 0.90 mmol, 3.0 eq) in
dimethylformamide (3
mL) was heated in a 130 C oil bath for 98 hours. The mixture was then cooled
to room temperature
and the solvent evaporated under a stream of nitrogen gas. The residue was
partitioned between ethyl
acetate and water and the aqueous layer further extracted with ethyl acetate.
The combined organic
layers were dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was
purified by HPLC -with TFA to provide the title compound as a trifluoroacetic
acid salt (4.0 mg,
2.4%). IH NMR (300 MHz, DMSO-D6) S ppm: 11.21 (s, 1H), 8.85 (d, J=8.46 Hz,
1H), 8.74 (s, 1H),
7.68-7.78 (m, 2H), 7.55-7.65 (m, J=7.35 Hz, 3H), 7.19 - 7.46 (m, 11H), 2.72
(s, 3H); MS (ESI') m/z
447.2 (M+H)+, (ESt) m/z 445.2 (M-H)".

Example 240
(7-Methyl-pyrido [2,3 -d]pyrimidin-4-yl)-(3-styryl-phenyl)-amine
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Example 240A
(3-Bromo-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine

[0698] A mixture of the product from Example lOB (0.206 g, 1.09 mmol) and 3-
bromoamiline (0.188 g, 1.09 mmol) in glacial acetic acid (1 mL) was heated in
a 130 C oil bath for 15
min. The reaction mixture was then cooled to room temperature and the solvent
evaporated under
reduced pressure. The residue was triturated with methanol, and the resulting
solid isolated by
vacuum filtration and dried to provide the title conipound (0.126 g, 37%) as a
beige solid.

Example 240B
(7-Methyl-pyrido[2,3-d]pyrimidin-4-yl)-(3-styryl-phenyl)-arnine
[0699] A mixture of the product from Example 240A (0.063 g, 0.20 mmol),
styrene (0.0412
g, 0.40 mmol, 2.0 eq), palladium(II) acetate (0.9 mg, 0.004 mmol, 0.02 eq),
tri-o-tolylphosphine (2.4
mg, 0.008 mmol, 0.04 eq), and triethylamine (0.0607 g, 0.60 mmol, 3.0 eq) in
dimethylformamide (2
mL) was heated in a 120 C oil bath for 4 hours. The mixture was then cooled to
room temperature
and the solvent evaporated under a stream of nitrogen gas. The residue was
partitioned between ethyl
acetate and water and the aqueous layer further extracted with ethyl acetate.'
The combined organic
layers were dried over anhydrous magnesium sulfate, filtered and evaporated.
The residue was
recrystallized from methanol and dried to provide the title compound as yellow
crystals (11.8 mg,
17%). 1H N1VIIZ. (300 MHz, DMSO-D6) S ppm: 10.01 (s, 1H), 8.89 (d, J=8.46 Hz,
1H), 8.72 (s, 111),
8.03 (s, 1 H), 7.72 - 7.85 (m, J=6.07, 2.76 Hz, 1 H), 7.64 (d, J=6.99 Hz,
211), 7.57 (d, J=8.82 Hz, 1 H),
7.35 - 7.49 (m, 4H), 7.24 - 7.35 (m, 3H), 2.63 - 2.74 (m, 3H); MS (ESr) m/z
339.1 (M+H), (EST)
m/z 337.1 (M-H)".

Example 241
(2-Methyl-5-phenethyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-y1)-amine
Example 241A
1-Methyl-2-nitro-4-styryI-benzene
[0700] A mixture of 4-bromo-2-nitrotoluene (0.432 g, 2.0 mmol), styrene (0.250
g, 2.40
mmol, 1.2 eq), palladium(lI) acetate (4.5 mg, 0.020 mmol, 0.01 eq), tri-o-
tolylphosphine (12.2 mg,
0.04 mmol, 0.02 eq), and triethylamine (0.405 g, 4.0 mmol, 2.0 eq) in
dimethylformamide (2 mL) was
heated in a 120 C oil bath for 4 hours. The mixture was then cooled to room
temperature and the
solvent evaporated under a stream of nitrogen gas. The residue was partitioned
between ethyl acetate
and water and the aqueous layer further extracted with ethyl acetate. The
combined organic layers
were dried over anhydrous magnesium sulfate, filtered and evaporated. The
residue was purified by
chromatography on silica gel, eluting with a hexane/ethyl acetate gradient to
provide the title
compound as a yellow solid (166 mg, 35% yield).

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Example 241 B
2-Methyl-5-phenethyl-phenylamine
[0701] A mixture of the product from Example 241A (0.166 g, 0.694 mmol) and
10%
palladium on charcoal (18.4 mg, 0.025 eq), in ethanol (10 mL) was stirred
under one atmosphere of
hydrogen for 16 hours. The reaction mixture was then filtered through Celite
and the solvent
evaporated under reduced pressure to provide the title compound as a slightly
red oil (0.141 g, 96%
yield).

Example 241C
(2-Methyl-5-phenethyl-phenyl)-(7-methyl-pyrido[2,3-d]pyrimidin-4-yl)-amine
[0702] A mixture of the product from Example lOB (0.041 g, 0.22 mmol) and the
product
from Example 241B (0.046 g, 0.22 mmol) in glacial acetic acid (1 rnL) was
heated in a 130 C oil bath
for 15 min. The reaction mixture was then cooled to room temperature and the
solvent evaporated
under reduced pressure. The residue was triturated with methanol, and the
resulting solid isolated by
vacuum filtration and dried to provide the title compound (0.0121 g, 16%
yield) as a slightly orange
solid. 1H NMR (300 MHz, CHCl3-d) 6 ppm: 8.84 (s, IH), 8.23 (d, J=8.46 Hz, 1H),
7.44 (s, 1H),
7.15 - 7.37 (m, 8H), 7.07 (dd, J=7.72, 1.47 Hz, 1H), 2.93 (s, 4H), 2.78 (s,
3H), 2.28 (s, 3H); MS
(ESI') m/z 355.3 (M+H)*, (ESI') m/z 353.2 (M-H)'.

Example 242
(7-Isopropyl-pyrido[2,3-d]pyrimidin-4-yl)-(2-methyl-5-phenethyl-phenyl)-amine
[0703] A mixture of the product from Example 241 B (46.2 mg, 0.219 mmol) and
the product
from Example 36E (47.3 mg, 0.219 mmol) in glacial acetic acid (1 mL) was
heated in a 130 C oil bath
for 15 min. The reaction mixture was then cooled to room temperature and the
solvent evaporated
under reduced pressure. The residue was purified by HPLC with TFA to provide
the title compound
as a trifluoroacetic acid salt (0.0131 g, 10 %). 1H NMR (300 MHz, DMSO-D6) S
ppm: 11.09 (s,
IH), 8.94 (d, J=8.46 Hz, 1H), 8.74 (s, 1H), 7.82 (d, J=8.46 Hz, 1H), 7.12 -
7.35 (m, 8H), 3.21 - 3.33
(m, 1H), 2.89 (s, 4H), 2.15 (s, 3H), 1.35 (d, J=6.62 Hz, 6H); MS (ESI}) m/z
383.2 (M+H)+, (ESI") m/z
381.3 (M-H)".

Example 243
(5-Methyl-2 phenylsulfanyl-phenyl)-(7-propyl-pteridin-4-yl)-amine
Example 243A
N'-(3-Cyano-6-propylpyrazin-2-yI) N,N-dimethylformamidine

[0704] A mixture of 3-amino-5-propylpyrazine-2-carbonitrile (0.140 g, 0.863
mmol)
(prepared according to the method of Taylor and LaMattina, JOC 1977, 47, 1523)
and
dimethylformamide dimethylacetal (0.123 g, 1.04 mmol, 1.2 eq) in toluene (10
mL) was heated under
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reflux for 2 h. The mixture was cooled to room temperature and the solvent
evaporated under reduced
pressure to provide the title compound (0.188 mg, 100%) as a thick oil.

Example 243B
(5-Methyl-2-phenylsulfanyl-phenyl)-(7-propyl-pteridin-4-yI)-amine
[0705] A mixture of the product from Example 243A (38.2 mg, 0.176 mmol) and
the product
of Example 51 (41.6 mg, 0.193 mmol, 1.1 eq) in acetic acid (1 mL) was heated
under reflux for 1.5 h.
The reaction mixture was cooled to room temperature and the solvent evaporated
under reduced
pressure. The resulting residue was triturated with methanol to provide the
title compound (19 mg,
28% yield) as a beige solid. 1H NMR (300 MHz, DMSO-D6) 8 ppm: 0.97 (t, J=7.35
Hz, 3 H), 1.76-
1.90 (m, 2 H), 2.42 (s, 3 H); 2.94 - 3.05 (m, 2 H), 7.08 - 7.28 (m, 6 H), 7.55
(d, J=8.09 Hz, 1 H), 8.45
(s, 1 H), 8.81 (s, 1 H), 8.89 (s, I H), 10.32 (s, I H). MS (ESI') m/z 388.1
(M+H)+ (ESI") m/z 386.1
(M-HY

Example 244
4-[4-Benzyloxy-2-(7-isopropyl-pteridin-4-ylamino)-phenylsulfanyl]-phenol
Example 244A
3-Amino-5-isopropyl-4-oxy-pyrazine-2-carbonitrile
[0706] A mixture of 2-hydroxyimino-3-methylbutyraldehyde (1.93 g, 16.8 mmol)(
prepared
by the procedure of Nakamura, Agric. Biol. Chem. 1961, 25, 665-670) and 2-
aminomalononitrile
tosylate (4.25 g, 16.8 mmol) in i-propanol (40 mL) was stirred at room
temperature for 18 h. The
resulting solid was isolated by vacuum filtration and rinsed with i-propanol
and air dried to provide
the title compound (0.525 g, 18% yield) as a white solid.

Example 244B
3-Amino-5-isopropyl-pyrazine-2-carbonitrile
[0707] A solution of the product from Example 244A (0.525 g, 2.95 mmol) in
tetrahydrofuran (30 mL) was stirred at ice water bath temperature. To this
solution was added quialcly
dropwise phosphorus trichloride (4.0 g, 2.6 mL, 29.5 mmol, 10 eq). The
reaction mixture was stirred
at room temperature for 16 h and then the solvent and excess reagent was
evaporated. The resulting
residue was partitioned between ethyl acetate and half-saturated aqueous
sodium bicarbonate. The
aqueous phase was extracted with ethyl acetate (3 x 100 mL) and the combined
organic layers dried
over anhydrous magnesium sulfate, filtered, and evaporated to provide the
title compound (0.370 g,
77% yield) as a light brown solid.

Example 244C
N'-(3-Cyano-6-isopropyl-pyrazin-2-yl)-N,N-dimethyl-fonmamidine
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107081 A mixture of the product from Example 244B (0.37 g, 2.28 mmol) and
dimethylformamide dimethylacetal (0.30 g, 2.5 mmol, 1.1 eq) in toluene (25 mL)
was heated under
reflux for 1.75 h. The reaction mixture was then cooled to room temperature
and the solvent
evaporated under reduced pressure to provide the title compound (0.50 g, 100%)
as a thick red/brown
oil that was used in subsequent reactions without fiu-ther purification.

Example 244D
4-[4-Benzyloxy-2-(7-isopropyl-pteridin-4-ylamino)-phenylsulfanyl]-phenol
[0709] A mixture of the product from Example 244C (56.2 mg, 0.259 mmol) and
the product
from Example 27A in acetic acid (1 mL) was heated under reflux for 2 h. The
reaction mixture was
cooled to room temperature and evaporated under reduced pressure: The
resulting residue was
triturated with methanol to provide the title compound (55.5 mg, 53% yield) as
a beige solid. 1H
NN.iR (300 MHz, DMSO-D6) 8 ppm: 10.37 (s, I H), 9.65 (s, 1 H), 9.03 (s, 1 H),
8.80 (s, 1 H), 8.31 (s,
1 H), 7.38 (d, J=8.09 Hz, 1 H), 7.21 (d, .T=8.82 Hz, 2 H), 7.03 (dd, J=8.09,
1_47 Hz, 1 H), 6.68 (d,
J=8.82 Hz, 2 H), 3.35 - 3.46 (m, 1 H), 2.37 (s, 3 H), 1.38 (d, J=6.62 Hz, 6
H). MS (ESIF) m/z 404.2
(Iv1+H)+ (ESI") m/z 402.3 (M-H)".

Example 245
[2-(4-Amino-phenoxy)-5-(6-bromo-1H benzoimidazol-2-yl)-phenyl]-(7-isopropyl-
pyrido[2,3-
d]pyrimidin-4-yl)-amine
Example 245A
[4-(4-Formyl-2-nitro phenoxy) phenyl]-carbamic acid tert-butyl ester

[0710] A mixture of 4-chloro-3-nitrobenzaldehyde and (4-Hydroxy-phenyl)-
carbamic acid
tert-butyl ester were reacted together in DMSO with addition of KOH to provide
the title product.
Example 245B
{4-[2-Amino-4-(6-bromo-lH-benzoimidazol-2-yl)-phenoxy]-phenyl}-carbamic acid
tert-butyl ester
[0711] The product from Example 245A was reacted according to the procedures
from
Examples 147B and 147C to provide the title product.

Example 245C
[2-(4-Amino-phenoxy)-5-(6-bromo-1 H-benzoimidazol-2-yl)-phenyl ]-(7-isopropyl-
pyri do[2,3-
d]pyrimidin-4-yl)-aniine
[0712] The product from Example 245B was reacted with the product from Example
36E in
HOAc and placed in a preheated 120 C oil bath. The solvent was removed under
a stream of N2.
The product was deprotected by dissolving in a 1:1 mixture of TFA in DCM and
stirred at room
temperature. The crude material was purified by HPLC with TFA to provide the
title product as a
trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.35 (d, J=6.99
Hz, 6 H) 3.21 - 3_39

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(m, 1 H) 6.87 - 7.04 (m, 4 H) 7.09 (d, J=8.46 Hz, 1 H) 7.36 (dd, J=8.82, 1.84
Hz, 1 H) 7.56 (d, J=8.46
Hz, 1 H) 7.78 (d, J=1.47 Hz, 1 H) 7.89 (d, J=8.46 Hz, 1 H) 8.14 (dd, J=8.82,
1.84 Hz, 1 H) 8.37 (d,
J=1.84 Hz, I H) 8.90 (s, 1 H) 9.00 (d, J=8.09 Hz, 1 H); MS (ESI+) m/z 568.2
(M+H)+.

Example 246
4-[4-Benzyloxy-2-(7-tert-butyl-pyrido[2,3-d]pyrimidin-4-ylamino)-
phenylsulfanyl]-phenol
[0713] The product from Example 27A was heated at 130 C in acetic acid with
the product
from Example 127A for 15 minutes, the mixture was then cooled to room
temperature, the solvent
removed and the residue purified by column chromatography on silica gel to
provide the title product.
IH IVIVIIt (300 MHz, DMSO-D6) S ppm: 1.38 (s, 9 H) 5.1I (s, 2 H) 6.60 - 6.74
(m, 2 H) 6.94 (d,
J=7.35 Hz, 1 H) 7.06 - 7.19 (m, 3 H) 7.27 - 7.50 (m, 6 H) 7.78 (d, J=8.09 Hz,
1 H) 8.56 (s, 1 H) 8.75
(s, 1 H) 9.64 (s, I H) 9.95 (s, 1 H); MS (ESI+) m/z 509 (M+H)+.

Example 247
2-(4-Amino-phenylsulfanyl)-5-(2-chloro-thiazol-5-ylmethoxy)-phenyl]-(7-
isopropyl-pyrido[2, 3-
d]pyrirnidin-4-yl)-amine

Example 247A
{4-[2-Amino-4-(2-chloro-thiazol-5-ylmethoxy)-phenylsulfanyl]-phenyl}-carbamic
acid tert-butyl
ester

[0714] 2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole (from Example 25A)
was
reacted with 4-aminothiophenol in anhydrous ethanol and at reflux under a
nitrogen atmosphere. The
reaction was cooled to room temperature and the ethanol removed by rotary
evaporation. The residue
was taken up in water and extracted with ethyl acetate. The combined organic
extracts were washed
with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo. Trituration of
the solid with 4% ethyl acetate/methylene chloride afforded 4-(4-((2-
chlorothiazol-5-yl)methoxy)-2-
nitrophenylthio)aniline. A mixture of 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-
nitrophenylthio)aniline
and di-tert-butyl dicarbonate in 1,4-dioxane was heated at reflux under a
nitrogen atmosphere, and
then additional Boc anhydride was added and the reaction allowed to reflux.
The reaction was cooled
to room temperature and the solvent removed by rotary evaporation in vacuo.
The resulting solid was
triturated. with 2.5% ethyl acetate/methylene chloride to obtain tert-butyl 4-
(4-((2-chlorothiazol-5-
yl)methoxy)-2-nitrophenylthio)phenylcarbamate. A suspension of 4-(4-((2-
chlorothiazol-5-
yl)methoxy)-2-nitrophenylthio)phenylcarbamate, iron powder, and ammonium
chloride in water and
ethanol was heated. The reaction was cooled to room temperature. The mixture
was diluted with
ethyl acetate and washed with water and brine. The organic phase was dried,
filtered, and
concentrated under vacuum to provide the title compound.

Example 247B
[2-(4-Amino-phenylsulfanyl)-5-(2-chloro-thiazol-5-ylmethoxy)-phenyl]-(7-
isopropyl-pyrido[2,3-
d]pyrimidin-4-yl)-amine
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[0715] The product from Example 247A was heated at 130 C in acetic acid with
the product
from Example 36E for 15 minutes, the mixture was then cooled to room
temperature, the solvent
removed under vacuum and a mixture of dichloromethane/trifluoroacetic acid 1/1
was added and the
residue then stirred at room temperatue for 2 hours followed by removal of the
solvent under vacuum
and the residue purified by HPLC with TFA to provide the title product as a
trifluoroacetic acid salt.
1H NMR (300 MHz, DMSO-D6) S ppm: 1.36 (d, J=6.99 Hz, 6 H) 3.20 - 3.37 (m, 1 H)
3.75 (s, 2 H)
5.33 (s, 2 H) 6.53 (d, J=8.46 Hz, 2 H) 6.99 - 7.12 (m, 5 H) 7.14 (s, 1 H) 7.80
(s, 1 H) 7.92 (d, J=8.82
Hz, I H) 8.83 (s, I H) 9.01 (s, 1 H) 11.62 (s, 1 H); MS (ESI+) m/z 535 (M+H)+.

Example 248
{4-[2-(7-tert-Butyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-4-(2-chloro-thiazol-5-
ylmethoxy)-
phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester

[0716] The product from Example 247A was heated at 130 C in acetic acid with
the product
from Example 127A for 15 minutes, the mixture was then cooled to room
temperature, the solvent
removed and the residue purified by HPLC with TFA to provide the title product
as a trifluoroacetic
acid salt. 1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.43 (d, J=l 1.40 Hz, 15 H) 2.73
(s, I H) 5.36 (s, 2
H) 7.00 (d, 1 H) 7.13 (d, J=8.46 Hz, 2 H) 7.25 (d, 1 H) 7.33 (d, J=8.46 Hz, 3
H) 7.81 (s, 2 H) 8.62 (s,
I H) 8.78 (s, 1 H) 9.39 (s, 1 H) 10.49 (bs, 1H); MS (ESI+) m/z 649 (M+H)+.

Example 249
[2-(4-Amino-phenylsulfanyl)-5-(2-chloro-thiazol-5-ylmethoxy) phenyl]-(7-tert-
butyl-pyrido[2,3-
d]pyrimidin-4-yl)-amine

[07171 The product from Example 248 was added to a mixture of
dichloromethane/trifluoroacetic acid 1/1 and the solution stirred at room
temperature for 2 hours
followed by removal of the solvent under vacuum and the resultant residue was
purified by HPLC
with TFA to provide the title product as a trifluoroacetic acid salt. 1H
NNNIIt (300 MHz, DMSO-D6) S
ppm: 1.44 (s, 6 H) 2.51 - 2.59 (m, 1 H) 3.72 (s, 2 H) 5.33 (s, 2 H) 6.24 (dd,
J=8.82, 2.94 Hz, I H) 6.42
(d, J=2.94 Hz, 1 H) 6.53 (d, J=8.46 Hz, 2 H) 6.98 - 7.12 (m, 3 H) 7.14 (s, 1
H) 7.74 - 7.85 (m, 1 H)
8.09 (d, J=8.46 Hz, 1 H) 8.83 (s, 1 H) 9.03 (s, 1 H) 11.65 (s, 1 H); MS (ESI+)
m/z 549 (M+H)+.

Example 250
[2-(4-Amino-phenylsulfanyl)-5-(6-bromo-1 H-benzoimidazol-2-yl)-phenyl]-(7-
isopropyl-pyrido[2,3-
d]pyrimidin-4-yl)-amine

Example 250A
[4-(4-Formyl-2 nitro phenylsulfanyl)-phenyl]-carbamic acid tert-butyl ester

[0718] A mixture of 4-chloro-3-nitrobenzaldehyde and 4-aminothiophenol were
reacted
together according to the procedure of Example 216B substituting 4-chloro-3-
nitrobenzaldehyde for
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the product from Example 216A which was then subjected to the conditions from
Example 216C to
provide the title product.

Example 250B
[2-(4-Amino-phenylsulfanyl)-5-(6-bromo-1 H-benzoimidazol-2-yl)-phenyl]-(7-
isopropyl-pyrido[2,3-
d]pyrimidin-4-yl)-amine

[07191 The product from Example 250A was reacted according to the procedures
from
Examples 147B, 147C and 147C to provide a crude residue which was purified by
HPLC with TFA to
provide the title product as a trifluoroacetic acid salt. 1H 1VMR (300 MHz,
DMSO-D6) S ppm: 1.38
(d, J=6.62 Hz, 6 H) 3.26 - 3.40 (m, 1 H) 6.64 (d, J=8.46 Hz, 2 H) 7.03 (d,
J=8.46 Hz, 1 H) 7.17 (d,
J=8.46 Hz, 2 H) 7.35 (dd, J=8.46, 1.84 Hz, 1 H) 7.54 (d, J=8.82 Hz, 1 H) 7.77
(d, J=1.84 Hz, 1 H)
7.94 (d, J=8.46 Hz, 1 H) 8.03 (dd, J=8.46, 1.84 Hz, 1 H) 8.18 (s, 1 H) 8.89
(s, 1 H) 9.05 (d, J=8.82 Hz,
1 H); MS (ESI+) m/z 584 (M+H)+.

Example 251
[2-(4-Amino-phenylsulfanyl)-5-(3-fluoro-benzyloxy)-phenyl]-(7-isopropyl-
pyrido[2,3-d]pyrimidin-4-
yl)-amine

Example 251 A
{4-[2-Amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenyl}-carbamic acid tert-
butyl ester
[07201 The product from Example 57B was reacted with 4-aminothiophenol
according to the
procedure from Example 214B followed by reaction according to the procedures
from Examples
214C and 214D to provide the title product.

Example 251B
[2-(4-Amino-phenylsulfanyl)-5-(3-fluoro-benzyloxy)-phenyl)-(7-isopropyl-pyrido
[2, 3 -d]pyrimidin-4-
yl)-amine

[07211 The product from Example 251A was heated at 130 C in acetic acid with
the product
from Example 36E for 15 minutes, the mixture was then cooled to room
temperature, the solvent
removed under vacuum and a mixture of dichloromethane/trifluoroacetic acid 1/1
was added and the
residue then stirred at room temperatue for 2 hours followed by removal of the
solvent under vacuum
and the residue purified by column chromatography on silica gel to provide the
title product. 1H
NMR (300 MHz, DMSO-D6) 8 ppm: 1.26 - 1.44 (d, 6 H) 3.23 - 3.37 (m, 1 H) 5.13
(s, 2 H) 6.44 -
6.61 (m,2H)6.96-7.10(m,3H)7.10-7.22(m,2H)7.24-7.35(m,3H)7.35(d,J=6.25Hz, I H)
7.43 (dd, J=7.91, 5.70 Hz, 2 H) 7.92 (s, 1 H) 8.18 (d, J=8.82 Hz, 1 H) 8.83
(s, 1 H) 9.03 (s, 1 H); MS
(ESI+) mlz 512 (M+H)+.

Example 252
[2-(4-Amino-phenylsulfanyl)-5-(3 -fluoro-benzyloxy)-phenyl]-(7-tert-butyl-
pyrido[2,3-d]pyrimidin-4-
yl)-amine
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[0722] The product from Example 251A was heated at 130 C in acetic acid with
the product
from Example 127A for 15 minutes, the mixture was then cooled to room
temperature, the solvent
removed under vacuum and a mixture of dichloromethane/trifluoroacetic acid 1/1
was added and the
residue then stirred at room temperatue for 2 hours followed by removal of the
solvent under vacuum
and the residue purified by HPLC with TFA to provide the title product as a
trifluoroacetic acid salt.
1H NMR (300 MHz, DMSO-D6) 8 ppm: 1.38 - 1.50 (m, 9 H) 5.12 (s, 2 H) 6.44 -
6.61 (m, 3 H) 6.96 -
7.12 (in, 3 H) 7.19 (s, 3 H) 7.23 - 7.33 (m, 3 H) 7.38 - 7.50 (m, 2 H) 8.00
(s, 1 H) 8.76 (s, I H) 8.96 (s,
I H); MS (ESI+) m/z 526 (M+H)+.

Example 253
[5-Benzyloxy-2-(4-dimethylamino-phenylsulfanyl)-phenyl]-(7-isopropyl-
pyrido[2,3-d]pyrimidin-4-
yl)-amine

Example 253A
5-Benzyloxy-2-(4-dimethylamino-phenylsulfanyl)-phenylamine
[0723] The product from Example 214B (1.0g, 0.284 mmol) was placed in a tube
along with
formic acid (5 mL), dioxane (5 mL), and 37% aqueous formaldehyde (5 mL). The
tube was sealed
and heated to 110 C for 20 minutes. The mixture was cooled to room
temperature, the solvent
removed and the resultant residue purified with column chromatography on
silica gel followed by
reduction of the nitro group according to the procedure of Example 214D to
provide the title product
(411 mg, 43%).

Example 253B
[5-Benzyloxy-2-(4-dimethylamino-phenyl sulfanyl)-phenyl]-(7-isopropyl-
pyrido[2,3-d]pyrimidin-4-
yl)-amine

[0724] A mixture of the product from Example 253A and the product from Example
36E in
glacial acetic acid was heated in a preheated 130 C oil bath for 20 min. The
reaction mixture was
then cooled to room temperature and the. solvent evaporated under vacuum to
provide the title
compound as an acetic acid salt. 1H NMR (300 MHz, DMSO-D6) S ppm: 1.36 (d,
J=7.0Hz, 6H),
2.81 (s, 611), 3.30 (m, 1H), 5.10 (s, 2H), 6.45 (d, J=9.2Hz, 2H), 7.07 (d,
J=8.8Hz, 211), 7.12 (m, 211),
7.25 (d, J=8.8Hz, 1H), 7.40 (m, 5H), 7.94 (m, 1H), 8.78 (s, 111), 8.99 (m,
1H), 11.70 (bs, 1H); MS
(ESI) m/z 522 (M+H)+.

Example 254
4-Brorno-N-[3-(pyrido[2,3-d]pyrirnidin-4-ylamino)-phenyl]-benzamide
Example 254A
4-Bromo-N-(3-nitro-phenyl)-benzamide
183
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[0725] The title compound was prepared according to the procedure of Example
255A
substituting 3-nitro-phenylamine for 4-Fluoro-3-nitro-aninline and
substituting 4-bromo-benzoyl
chloride for 3-Trifluoromethyl-benzoyl chloride to provide the title product
(3.373 g, 90%).

Example 254B
4-Bromo-N-(3 -amino-phenyl)-benzamide

[0726] The title compound was prepared according to the procedure of Example
255B
substituting the product from Example 254A for the product from Example 255A
to provide the title
product (1.8 g, 80%).

Example 254C
4-Bromo-N-[3-(pyrido[2,3-d]pyrimidin-4 ylamino)-phenyl]-benzamide

[0727] A solution of the product from Example 57A (40.0 mg, 0.212 mmol), and
the product
of Example 254B (61.6 mg, 0.212 mmol) in acetic acid (1 mL) was stirred in an
oil bath preheated to
130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue purified by HPLC with TFA to provide
the title compound as
a fxifluoroacetic acid salt (25.0 mg, 30%). 1H NMR (300 MHz, DMSO-D6) S ppm:
7.45 (t, J=8.09
Hz, 1 H), 7.52 - 7.61 '(m, 2 H), 7.74 - 7.86 (m, 3 H), 7.94 (d, J=8.82 Hz, 2
H), 8.33 (t, .F=1.84 Hz, I
H), 8.88 (s, I H), 9.09 - 9.17 (m, 2 H), 10.48 (s, 1 H), 10.94 (s, I H); MS
(ESI+) m/z 420 (M+H)+,
(ESI-) m/z 417 (M-H)-.

Example 255
N-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl pyrido[2,3-d]pyrimidin-4-ylamino)-
phenyl]-3-
trifluoromethyl-benzamide

Example 255A
N-(4-Fluoro-3-nitro-phenyl)-3-trifluoromethyl-benzamide
[0728] A solution of 4-Fluoro-3-nitro-aniline (2.00g, 12.8mmol), 3-
Trifluoromethyl-benzoyl
chloride (I.895mL, 12.8mmo1), Hunig's base (4.463mL, 25.6mmol) in
tetrahydrofuran (50m1) was
stirred at room temperature for 1 hour. Afterwards water (450 mL) was added to
the solution and the
resultant solid was collected by filtration and dried in a vacuum oven to
provide the title compound
(3.311 g, 97%).

Example 255B
N-[4-(4-Hydroxy-phenylsulfanyl)-3-nitro-phenyl]-3-trifluoromethyl-benzamide
[0729] A solution of the product of Example 255A (2.00 g, 5.80mmo1), 4-
hydroxythiophenol
(0.732g, 5.80 mmol) and potassium carbonate (1.604 g, 1 I.6mmo1) in N,N-
dimethylformamide (40
mL) was heated to 80 C for 2 hours. After cooling to room temperature the
mixture was poured into
ice water (100 mL). The solution was then extracted with ethyl acetate (3 x
150 mL), the combined

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extracts dried over magnesium sulfate, filtered and concentrated under vacuum
to provide the title
compound (2.52 g, 100%).

Example 255C
N-[3 -Amino-4-(4-hydroxy-phenylsulfanyl)-phenyl]-3-tri fluoromethyl-benzamide

[07301 A solution of the product of Example 255B (0.660 g, 1.52 mmol), iron
powder (0.339
g, 6.07 mmol) and ammonium chloride (0.099 g, 1.82 mmol), tetrahydrofuran (18
mL), and water (6
mL) solution was heated to reflux for 3 hours. The resultant mixture was
diluted with methanol (50
mL) and filtered through a pad of celite. The filtrate was diluted with water
(50 mL) and extracted
with dichlorornethane (2 x 100 mL). The combined extracts were dried over
magnesium sulfate,
filtered and concentrated under vacuum to provide the title compound (0.60 g,
97%).

Example 255D
N-[4-(4-Hydroxy-phenylsulfanyl)-3-(7-methyl-pyrido[2,3 -d]pyrimidin-4-ylamino)-
phenyl]-3-
trifluoromethyl-benzamide

[0731] A solution of the product from Example lOB (40.0 mg, 0.212 mmol), and
the product
from Example 255C (86.0 mg, 0.212 mmol) in acetic acid (1 mL) was stirred in
an oil bath preheated
to 130 C for 20 minutes. The mixture was then cooled to room temperature, the
acetic acid removed
under vacuum, and the resultant residue purified by HPLC with TFA to provide
the title compound as
a trifluoroacetic acid salt (11 mg, 10%). 'H NMR (300 MHz, DMSO-D6) S ppm:
2.74 (s, 3 H), 6.70
(d, J=8.82 Hz, 2 H), 7.18 (d, J=8.46 Hz, 3 H), 7.64 (dd, J=8..46, 2.21 Hz, 1
H), 7.79 (t, J=7.72 Hz, 2
H), 7.93 - 8.07 (m, J=6.62 Hz, 2 H), 8.21 - 8.30 (m, 2 H), 8.78 (s, 1 H), 8.92
(d, J--7.72 Hz, 1 H), 9.79
(s, 1 H), 10.67 (s, I H), 11.17 - 11.50 (m, 1 H) MS (ESI+) m/z 548.2(M+H)+,
(ESI-) m/z 546.2 (M-
H)--

Biol gical Evaluation
[0732) Representative compounds of the invention were analyzed according to
the assays
described below.
[0733] The following acronyms are used herein:
ICSa 50% inhibitory concentration
TC50 50% toxicity concentration
DMEM Dulbecco's Modified Essential MediumTM
RNA ribonucleic acid
RT-PCR reverse transcriptase polymerase chain reaction
SEAP secreted alkaline phosphatase

[07341 The hepatitis C virus genome encodes a large polyprotein, which after
processing
produces the necessary functional components to synthesize progeny RNA.
Selectable cell lines that
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CA 02633752 2008-06-18
WO 2007/081517 PCT/US2006/048685
produce high and sustained levels of subgenomic HCV RNA (replicons) have been
derived from
human hepatoma cells (Huh7) as described in Ikeda et al., J. VIROLOGY,
76(6):2997-3006 (2002), and
Blight et al., SCIENCE, 290:1972-1974 (2000). The mechanism of RNA replication
in these cell lines
is considered to be identical to the replication of full length HCV RNA in
infected hepatocytes. The
compounds of this invention are inhibitors of HCV RNA replication in the
replicon assay systems
described below.

Evaluation of the HCV lnhibitors in HCVReplicon

[0735] Representative compounds of the invention were evaluated for their
inhibitory effect
on HCV genotype la and lb replicons. They were also evaluated by MTT assay for
cytotoxicity to
the host cells. The cell lines were maintained according.to the methods
described by Yi et al.,
VIROLOGY, 304(2):197-210 (2002).

A. RNA assay and SEAP Assay

[0736] The purpose of these assays was to evaluate the efficacy of the
compounds in
inhibiting the replication of HCV genotype la and lb replicons in vitro.
[0737] Genotype la and/or lb replicon cells were plated at 3-5 x103 cells per
well in 96-well
plate in DMEM medium containing 5% fetal calf serum. The next day, the culture
medium was
removed and replaced with fresh medium containing eight serial dilutions of
compound. The
untreated control culture was treated in an identical manner except no
inhibitor was added to the
medium. Plates were incubated in a COZ incubator at 37 C. On day 4, 100 gl
lysis buffer (RTL)
(Qiagen) was added to each well after removal of culture medium. RNA was
purified according to
manufacturer's recommendations (Qiagen RNAeasy) and eluted in 200 gl of water.
The HCV RNA
level was quantified from a portion (5 gl out of 200 gl) of the purified RNA
by real-time RT-PCR
method. The primers and probe were derived from specific sequence in the 5'-
Untranslated Region
(5'UTR). RT-PCR reaction was performed at 48 C for 30 min, followed by 40
cycles set to 95 C, 15
s; 54 C, 30 s; and 72 C, 40 s. Alternatively, the activity of SEAP was
measured in each culture
supematant after four days incubation with compound according to the
manufacturer's instructions.
The percentage reduction of HCV RNA or SEAP in the presence of compound was
calculated and the
50% inhibitory concentration (IC50) was calculated by non-linear regression
analysis using the Prism
program (version 4.0, GraphPad software, San Diego, CA).
[0738] When tested using the above method, representative compounds of the
present
invention inhibited HCV replicon replication with IC50 values in the range of
from about 0.3 nM to
about 100 M.

B. Cy+totoxicity assay
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[0739] The purpose of this assay was to determine the toxicity of the
compounds on viral
host cells in vitro.
[0740] Cytotoxicity of the compounds was measured using a mitochondrial enzyme-
based
cell proliferation/viability assay in replicon cells. Briefly, HCV replicon
cells were plated at 3-5 x 103
cells per we1l in 96-well plate in DMEM medium containing 5% FCS. At day 1,
culture medium was
removed and replaced with fresh medium containing eight serial dilutions of
compound. The
untreated control culture was treated in an identical manner except no
inhibitor was added to the
medium. Plates were incubated in a COa incubator at 37 C. On day 4, stock
solution of the
tetrazolium salt, MTT (4 mg/ml in PBS, Sigma cat.# M 2128) was added to each
well at 25 I per
well. Plates were further incubated for 4 hours, treated with 20% SDS plus
0.02 N HCl at 50 l per
well to lyse the cells. After an overnight incubation, optical density was
measured by reading the
plates at 570/650 nm wavelengths. The percent reduction of formazan blue color
formed relative to
control was calculated and the 50% toxicity concentration (TCso) was
calculated by non-linear
regression analysis using the Prism program (version 4.0, GraphPad software,
San Diego, CA).
[0741] When tested using the above method, the TC50 values of representative
compounds of
the present invention were greater than the corresponding IC50 values of these
compounds.
Pharmaceutical Compositions and Uses
[0742] The present invention features pharmaceutical compositions comprising
the
compounds of the invention. As a non-limiting example, a pharmaceutical
composition of the present
invention comprises one or more compounds of this invention, wherein each
compound is
independently selected from Formulae I, II, III, N, V, VI, VII or VIII.
Preferably, each compound is
independently selected from Examples 1-255.
[0743] The present invention also features pharmaceutical compositions
comprising
pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of
this invention.
Pharmaceutically acceptable salts can be. zwitterions or derived from
pharmaceutically acceptable
inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable
salt of a compound of
the invention retains the biological effectiveness of the free acid or base of
the compound without
undue toxicity, irritation, or allergic response, has a reasonable
benefit/risk ratio, and is effective for
their intended use and not biologically or otherwise undesirable. Non-limiting
examples of
pharmaceutically acceptable 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-hydroxy-ethanesulfonate (isethionate), lactate,
maleate,
methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,
pectinate, persulfate, 3-
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CA 02633752 2008-06-18
WO 2007/081517 PCT/US2006/048685
phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
thiocyanate, p-toluenesulfonate and
undecanoate. The basic nitrogen-containing groups can also be quaternized with
such agents as
loweralkyl halides (e.g., methyl, ethyl, propyl or butyl chlorides, bromides
or iodides), dialkyl sulfates
(e.g., dimethyl, diethyl, dibutyl or diamyl sulfates), long chain halides
(e.g., decyl, lauryl, myristyl or
stearyl chlorides, bromides or iodides), aralkyl halides (e.g., benzyl or
phenethyl bromides). Other
salts that can be used in the present invention include salts with alkali or
alkaline earth metals, such as
sodium, potassium, calcium or magnesium, or with organic bases. Examples of
acids which can be
used to form pharmaceutically acceptable acid addition salts include, but are
not limited to,
hydrochloric acid, sulphuric acid, phosphoric acid, oxalic acid, maleic acid,
succinic acid, citric acid,
or other suitable inorganic or organic acids.
[0744] The present invention further features pharmaceutical compositions
comprising a
compound of the invention (or a salt, solvate or prodrug thereof) and another
therapeutic agent. In a
non-limiting example, a pharmaceutical composition of the present invention
includes 1, 2, 3 or more
compounds of the invention (or salts, solvates or prodrugs thereof), and 1, 2,
3 or more other
therapeutic agents. By way of illustration not limitation, these other
therapeutic agents can be
selected from antiviral agents (e.g., anti-HIV agents or other anti-HCV
agents), immunomodulators,
anti-cancer or chemotherapeutic agents, or anti-inflammation agents. Specific
examples of these other
therapeutic agents include, but are not limited to, ribavirin; interferons
(e.g., IFN alpha 2a or 2b);
protease inhibitors; immunosuppressants; antibodies (e.g., therapeutic
monoclonal or chimeric
antibodies); antisense or siRNA; HIV inhibitors; hepatitis B (HBV) inhibitors;
agents for treating
cirrhosis and inflammation of the liver; Omega IFN (BioMedicines Inc.,
Emeryville, CA); BILN-2061
serine protease inhibitor (Boehringer Ingelheim Pharma KG, Ingelheim,
Germany); Summetrel
antiviral (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-
alpha 2a (F.
Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-alpha 2a (F.
Hoffmann-La
Roche LTD, Basel, Switzerland); Pegasys and Ribavirin PEGylated IFN-alpha
2a/ribavirin (F.
Hoffmann-La Roche LTD, Basel, Switzerland); CellCept HCV IgG immunosuppressant
(F.
Hoffmann-La Roche LTD, Basel, Switzerland); Wellferon lymphoblastoid IFN-alpha
nl
(GlaxoSmithKline plc, Uxbridge, UK); Albuferon-alpha albumin IFN-alpha 2b
(Human Genome
Sciences Inc., Rockville, MD); Levovirin ribavirin (ICN Pharmaceuticals, Costa
Mesa, CA); IDN-
6556 caspase inhibitor (Idun Pharmaceuticals Inc., San Diego, CA); IP-501
antifibrotic (Indevus
Pharmaceuticals Inc., Lexington, MA); Actimmune INF-gamma (InterMune Inc.,
Brisbane, CA);
Infergen A IFN alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS
14803 antisense
(ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., New York,
NY); JTK-003 RdRp
inhibitor (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated
IFN-alpha 2a/immune
tnodulator (Maxim Pharmaceuticals inc., San Diego, CA); Ceplene immune
modulator (Maxim
Pharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressant (Nabi
188


CA 02633752 2008-06-18
WO 2007/081517 PCT/US2006/048685
Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-alpha
2b/alpha 1-thymosin
(RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc.,
San Mateo, CA);
Levovirin I1ViP'DH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine
IMPDH inhibitor
(Ribapharm Inc., Costa Mesa, CA); Heptazyme ribozyme (Ribozyme Pharmaceuticals
Inc., Boulder,
CO); Intron A IFN-alpha 2b (Schering-Plough Corporation, Kenilworth, NJ); PEG-
Intron PEGylated
IFN-alpha 2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron IFN-alpha
2b/ribavirin
(Schering-Plough Corporation, Kenilworth, NJ); Ribavirin (Schering-Plough
Corporation,
Kenilworth, NJ); PEG-Intron/Ribavirin PEGylated IFN-alpha 2b/ribavirin
(Schering-Plough
Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone
Pharmaceuticals Inc., San
Mateo, CA); Rebif IFN-beta la (Serono, Geneva, Switzerland); IFN-beta and
EMZ701 IFN-beta and
EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67 beta-tubulin
inhibitor (Tularik Inc.,
South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex Pharmaceuticals Inc.,
Cambridge, MA);
VX-950/LY-570310 serine protease inhibitor (Vertex Pharmaceuticals Inc.,
Cambridge, MA/Eli Lilly
and Co., Inc., Indianapolis, IN); Omniferon natural IFN-alpha (Viragen Inc.,
Plantation, FL); XTL-
!
t~~'ttQJt N ~'N~N~
a H O
002 monoclonal antibody (XTL Biopharmaceuticals); o~ 0 (hereinafter
,,L

HN" 'N N~J,NHa
H f'~ _ iT
O O
compound VX-950, Vertex Pharmaceuticals Inc.); (hereinafter
F O
CI
I \ I ~ OH
Q N
I H
compound SCH503034, Schering-Plough Co.); and .r ~a (hereinafter compound
GS9137, Gilead Sciences, Inc., Foster City, CA). Any other desirable
therapeutic agent(s) can also be
included in a pharmaceutical composition of the present invention.
[07451 In one embodiment, a pharmaceutical composition of the present
invention comprises
one or more compounds of the present invention (or salts, solvates or prodrugs
thereof), and one or
more other antiviral agents.
[07461 In another embodiment, a pharmaceutical composition of the present
invention
comprises one or more compounds of the present invention (or salts, solvates
or prodrugs thereof),
and one or more other anti-HCV agents. In one example, each of the compounds
of the present
invention is independently selected from Formulae I, H, III, IV, V, VI, VII or
VIII, or Examples 1-
255, and each of the other anti-HCV agents is independently selected from HCV
RNA dependent
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RNA polymerase inhibitors (e.g., nucleoside or non-nucleoside type polymerase
inhibitors), HCV
protease inhibitors, or HCV belicase inhibitors.
[0747] In a further embodiment, a pharmaceutical composition of the present
invention
comprises one or more 'compounds of the present invention (or salts, solvates
or prodrugs thereof),
and two or more other anti-HCV inhibitors. Preferably, each compound of the
present invention is
independently selected from Formulae I, II, III, IV, V, VI, VII or VIII, or
from Examples 1-255. The
other anti-HCV inhibitors can be selected from the same inhibitor class (e.g.,
all of them are selected
from HCV RNA dependent RNA polymerase inhibitors, or from HCV protease
inhibitors), or selected
from different inhibitor classes (e.g., one or more are selected from HCV RNA
dependent RNA
polymerase inhibitor and the other or others are selected from HCV protease
inhibitors).
[0748] In still another embodiment, a pharmaceutical composition of the
present invention
comprises at least one compound of the present invention (or a salt, solvate
or prodrug thereof), and at
least one HCV RNA dependent RNA polymerase inhibitor. Preferably, each
compound of the present
invention is independently selected from Formulae I, II, III, IV, V, VI, VII
or VIII, or Examples 1-
255.
[0749] In another embodiment, a pharmaceutical composition of the present
invention
comprises at least one compound of the present invention (or a salt, solvate
or prodrug thereof), and at
least one HCV protease inhibitor. Preferably, the compound of the present
invention is selected from
Formulae I, II, III, N, V, VI, VII or VIII, or Examples 1-255.
[0750] In yet another embodiment, a pharmaceutical composition of the present
invention
comprises at least one compound of the present invention (or a salt, solvate
or prodrug thereof), at
least one HCV RNA dependent RNA polymerase inhibitor, and at least one HCV
protease inhibitor.
Preferably, the compound of the present invention is selected from Formulae I,
II, III, IV, V, VI, VII
or VIII, or Examples 1-255.
[0751] In still yet another embodiment, a pharmaceutical composition of the
present
invention comprises at least one compound of the present invention (or a salt,
solvate or prodrug
thereof), and two or more anti-HCV agents each of which is independently
selected from HCV RNA
dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably,
'the compound of the
present invention is selected from Formulae I, II, III, N, V, VI, VII or VIII,
or Examples 1-255.
[0752] In still another embodiment, a pharmaceutical composition of the
present invention
comprises at least one compound of the present invention (or a salt, solvate
or prodrug thereof), and
three or more other anti-HCV agents each of which is independently selected
from HCV RNA
dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably,
the compound of the
present invention is selected from Formulae I, II, III, N, V, VI, VII or VIII,
or Examples 1-255.
[0753] Non-limiting examples of HCV RNA dependent RNA polymerase inhibitors
include
those described in W00190121(A2), US6348587B1, W00160315, W00132153,
EP1162196A1 and
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W00204425. Non-limiting examples of HCV protease inhibitors include BILN-2061,
VX-950, and
SCH503034.
[0754] In another embodiment, a pharmaceutical composition of the present
invention
comprises at least one compound of the present invention (or a salt, solvate
or prodrug thereof), and
one or more other antiviral agents, such as anti-HBV or anti-HIV agents. Non-
limiting examples of
anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting
examples of anti-HIV
drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir,
amprenavir, atazanavir, tipranavir,
TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,
tenofovir, zalcitabine,
abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360,
enfuvirtide, T-1249, and
other HIV protease, reverse transcriptase, integrase or fusion inhibitors.
Other desirable antiviral
agents can also be included in a pharmaceutical composition of the present
invention, as appreciated
by those skilled in the art.
[0755] In one embodiment, a pharmaceutical composition of the present
invention comprises
at least one compound of the present invention selected from Formulae I, II,
III, IV, V, VI, VII or VIII
or from Examples 1-255, or a salt, solvate or prodrug thereof, and at least
one anti-HBV agent. In
another embodiment, a pharmaceutical composition of the present invention
comprises at least one
compound of the present invention selected from Formulae I, II, III, IV, V,
VI, VII or Vlii or from
Examples 1-255, or a salt, solvate or prodrug thereof, and at least one anti-
HIV agent. In yet another
embodiment, a pharmaceutical composition of the present invention comprises at
least one compound
of the present invention selected from Formulae I; II, III, IV, V, VI, VII or
VIII or from Examples 1-
255, or a salt, solvate or prodrug thereof, and at least one anti-hepatitis A,
anti-hepatitis D, anti-
hepatitis E or anti-hepatitis G agent.
[0756] In still yet another embodiment, a pharmaceutical composition of the
present
invention comprises at least one compound of the present invention selected
from Formulae I, II, III,
IV, V, VI, VII or VIII or from Examples 1-255, or a salt, solvate or prodrug
thereof, and at least one
agent suitable for treating liver inflammation.
[0757] A pharmaceutical composition of the present invention typically
includes a
pharmaceutically acceptable carrier or excipient. Non-limiting examples of
suitable pharmaceutically
acceptable carriers/excipients include sugars (e.g., lactose, glucose or
sucrose), starches (e.g., corn
starch or potato starch), cellulose or its derivatives (e.g., sodium
carboxymethyl cellulose, ethyl
cellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil,
corn oil or soybean oil), glycols (e.g., propylene glycol), buffering agents
(e.g., magnesium hydroxide
or aluminum hydroxide), agar, alginic acid, powdered lragacanth, malt,
gelatin, talc, cocoa butter,
pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or phosphate
buffer solutions.
Lubricants, coloring agents, releasing agents, coating agents, sweetening,
flavoring or perfuming
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agents, preservatives, or antioxidants can also be included in a
pharmaceutical composition of the
present invention, as appreciated by those of ordinary sldll in the art.
[07581 A pharmaceutical composition of the present invention can be
administered to a
patient in need thereof via a variety of routes, such as orally, parenterally,
sublingually, rectally,
topically or by inhalation spray. Topical administration may involve the use
of transdermal
administration such as transdermal patches or iontophoresis devices.
Parenteral administration
includes, but is not limited to, subcutaneous, intravenous, intramuscular or
intrasternal injections, and
infusion techniques.
[0759] The pharmaceutical compositions of the present invention can be
formulated based on
their routes of administration using methods well known in the art. For
example, a sterile injectable
preparation can be prepared as a sterile injectable aqueous or oleagenous
suspension using suitable
dispersing or wetting agents and suspending agents. Suppositories for rectal
administration can be
prepared by mixing drugs with a suitable nonirritating excipient such as cocoa
butter or polyethylene
glycols which are solid at ordinary temperatures but liquid at the rectal
temperature and will therefore
melt in the rectum and release the drugs. Solid dosage forms for oral
administration can be capsules,
tablets, pills, powders or granules. In such solid dosage forms, the active
compounds can be admixed
with at least one inert diluent such as sucrose lactose or starch. Solid
dosage forms may also comprise
other substances in addition to inert diluents, such as lubricating agents. 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 can
include pharmaceutically acceptable emulsions, solutions, suspensions, syrups
or elixirs containing
inert diluents commonly used in the art. Liquid dosage forms may also comprise
wetting,
emulsifying, suspending, sweetening, flavoring, or perfuming agents. The
pharmaceutical
compositions of the present invention can also be administered in the form of
liposomes, as described
in U.S. Patent No. 6,703,403. Formulation of drugs that are applicable to the
present invention is
generally discussed in, for example, Hoover, John E., REMINGTON'S
PHARMACEUTICAL SCIENCES
(Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL
DOSAGE FOI2MS
(Marcel Decker, New York, N.Y., 1980).
[0760] The present invention further features methods of using the compounds
of the present
invention (or salts, solvates or prodrugs thereof) to inhibit HCV replication.
In one embodiment, the
methods comprise contacting HCV virus with an effective amount of a compound
of the present
invention (or a salt, solvate or prodrug thereof), thereby inhibiting the
replication of the HCV virus.
In another embodiment, the methods comprise contacting cells infected with HCV
virus with an
effective amount of a compound of the present invention (or a salt, solvate or
prodrug thereof),
thereby inhibiting the replication of the HCV virus in the cells. In still
another embodiment, the
methods comprise contacting HCV virus or infected cells with an effective
amount of two or more
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compounds of the present invention (or salts, solvates or prodrugs thereof),
thereby inhibiting the
replication of the HCV virus. As used herein, "inhibiting" means significantly
reducing, or
abolishing, the activity being inhibited (e.g., viral replication). In many
cases, representative
compounds of the present invention can reduce the replication of HCV virus
(e.g., in HCV replicon
assays as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,
90%, 95% or
more.
[0761] . The compounds of the present invention may inhibit all HCV subtypes.
Examples of
HCV subtypes that are amenable to the present invention include, but are not
be limited to, HCV
genotypes 1, 2, 3, 4; 5 and 6, including HCV genotypes la, Ib, 2a, 2b, 2c or
3a. In one embodiment, a
compound or compounds of the present invention (or salts, solvates or prodrugs
thereof) are used to
inhibit the replication of HCV genotype Ia. In another embodiment, a compound
or compounds of
the present invention (or salts, solvates or prodrugs thereof) are used to
inhibit the replication of HCV
genotype lb. In still another embodiment, a compound or compounds of the
present invention (or
salts, solvates or prodrugs thereof) are used to inhibit the replication of
both HCV genotypes la and
lb.
[0762] The present invention also features methods of using the compounds of
the present
invention (or salts, solvates or prodrugs thereof) to treat HCV infection.
These methods typically
comprise administering a therapeutic effective amount of a compound of the
present invention (or a
salt, solvate or prodrug thereof) to an HCV patient, thereby reducing the HCV
viral level in the blood
or liver of the patient. As used herein, the term "treating" refers to
reversing, alleviating, inhibiting
the progress of, or preventing the disorder or condition, or one or more
symptoms of such disorder or
condition to which such term applies. The term "treatment" refers to the act
of treating. In one
embodiment, the methods comprise administering a therapeutic effective amount
of two or more
compounds of the present invention (or salts, solvates or prodrugs thereof) to
an HCV patient, thereby
reducing the HCV viral level in the blood or liver of the patient. Preferably,
the compound(s)
employed in these methods has Formulae I, II, III, IV, V, VI, VII or VIII or
is selected from Examples
1-255, or is a salt, solvate or prodrug thereof.
[0763] In another aspect, the present invention features methods of using a
pharmaceutical
composition of the present invention to treat HCV infection. Any
pharmaceutical composition
described herein can be used for this purpose. These methods typically
comprise administering a
therapeutic effective amount of a phannaceutical composition of the present
invention to an HCV
patient, thereby reducing the HCV viral level in the blood or liver of the
patient. Where the
pharmaceutical composition includes other therapeutic agent(s), it may also
treat other diseases,
disorders or conditions in the patient.
107641 In one embodiment, the pharmaceutical composition being administered
comprises at
least one compound of the present invention selected from Formulae I, II, III,
IV, V, VI, VII or VIII
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or from Examples 1-255, or a salt, solvate or prodrug thereof, and at least
another anti-HCV agent
selected from HCV RNA dependent RNA polymerase inhibitors, HCV protease
inhibitors or HCV
helicase inhibitors. In another embodiment, the pharmaceutical composition
being administered
comprises at least one compound of the present invention selected from
Formulae I, II, III, IV, V, VI,
VII or VIII or from Examples 1-255, or a salt, solvate or prodrug thereof, and
at least two other anti-
HCV agents each of which is independently selected from HCV RNA dependent RNA
polymerase
inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In still
another embodiment, the
pharmaceutical composition being administered comprises at least one compound
of the present
invention selected from Formulae 1,.11, ITI, IV, V, VI, VII or VIII or from
Examples 1-255, or a salt,
solvate or prodrug thereof, and 1, 2 or more HCV RNA dependent RNA polymerase
inhibitors (e.g.,
those described in W00190121(A2), US6348587B1, W00160315, W00132153,
EP1162196A1 and
W00204425). In yet another embodiment, the pharmaceutical composition being
administered
comprises at least one compound of the present invention selected from
Formulae I, II, III, IV, V, VI,
VII or VIII or from Examples 1-255, or a salt, solvate or prodrug thereof, and
1, 2 or more HCV
protease inhibitors (e.g., BILN-2061, VX-950, and SCH503034).
[0765] In a further embodiment, the pharmaceutical composition being
administered
comprises at least one compound of the present invention selected from
Formulae I, II, lII, IV, V, VI,
VII or VIII or from Examples 1-255, or a salt, solvate or prodrug thereof, and
at least one antiviral
agent selected from anti-HIV agents, anti-HBV agents, anti-hepatitis A agents,
anti-hepatitis D agents,
anti-hepatitis E agents, or anti-hepatitis G agents.
[0766] In yet another aspect, the present invention provides methods of using
a compound(s)
of the present invention and another therapeutic agent(s) to treat HCV
infection. The methods
comprise administering a therapeutic effective amount of a compound(s) of the
present invention and
another therapeutic agent(s) to an HCV patient, thereby reducing the HCV viral
level in the blood or
liver of the patient. Each compound of the present invention (or a salt,
solvate or prodrug thereof) and
the other therapeutic agent(s) can be combined in a single formulation and
administered
simultaneously to the patient. They can also be administered simultaneously
but in different
formulations. In addition, they can be administered sequentially.
[0767] In one embodiment, the compound(s) of the present invention being
administered
includes one or more compounds selected from Formulae I, II, III, IV, V, VI,
VII or VIII or from
Examples 1-255, or salts, solvates or prodrugs thereof, and the other
therapeutic agent(s) being
administered includes one or more agents selected from HCV RNA dependent RNA
polymerase
inhibitors, HCV protease inhibitors or HCV helicase inhibitors. In another
embodiment, the
compound(s) of the present invention being administered includes one or more
compounds selected
from Formulae I, II, III, IV, V, VI, VII or VIII or from Examples 1-255, or
salts, solvates or prodrugs
thereof, and the other therapeutic agent(s) being administered includes two or
more agents selected
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from HCV RNA dependent RNA polymerase inhibitors, HCV protease inhibitors or
HCV helicase
inhibitors. In yet another embodiment, the compound(s) of the present
invention being administered
includes one or more compounds selected from Formulae I, II, III, IV, V, VI,
VII or VIII or from
Examples 1-255, or salts, solvates or prodrugs thereof, and the other
therapeutic agent(s) being
administered includes one, two or more HCV RNA dependent RNA polymerase
inhibitors (e.g., those
described in W00190121(A2), US6348587B1, W00160315, W00132153, EP1162196A1 and
W00204425). In still yet another embodiment, the compound(s) of the present
invention being
administered includes one or more compounds selected from Formulae I, II, IIT,
IV, V, VI, VII or VIII
or from Examples 1-255, or salts, solvates or prodrugs thereof, and the other
therapeutic agent(s)
being administered includes one, two or more HCV protease inhibitors (e.g.,
BILN-2061, VX-950,
and SCH503034).
[0768] A compound of the present invention (or a salt, solvate or prodrug
thereof) can also
be coadministered with other desired drugs, such as anti-HN agents, anti-HBV
agents, anti-hepatitis
A agents, anti-hepatitis D agents, anti-hepatitis E agents, anti-hepatitis G
agents, or other antiviral
drugs.
[0769] A compound of the present invention (or a salt, solvent or prodrug
thereof) can be
administered to a patient in a single dose or divided doses. A typical daily
dosage can range, without
limitation, from 0.1 to 200 mg/kg body weight, such as from 0.25 to 100 mg/lcg
body weight. Single
dose compositions can contain these amounts or submultiples thereof to make up
the daily dose.
Preferably, each dosage contains a sufficient amount of a compound of the
present invention that is
effective in reducing the HCV viral load in the blood or liver of the patient.
The amount of the active.
ingredient, or the active ingredients that are combined, to produce a single
dosage form may vary
depending upon the host treated and the particular mode of administration. It
will be understood that
the specific dose level for any particular patient will depend upon a variety
of factors including the
activity of the specific compound employed, the age, body weight, general
health, sex, diet, time of
administration, route of administration, rate of excretion, drug combination,
and the severity of the
particular disease undergoing therapy.
[0770] In still another aspect, the compounds of Formulae I, II, III, IV, V,
VI, VII or VIII, or
their pharmaceutically acceptable salts, stereoisomers or tautomers, can be
administered as the sole
active pharmaceutical agent, or used in combination with one or more other
agents, to treat infections
or symptoms associated with other RNA-containing viruses.
[0771] Treatment or prevention of infection caused by RNA-containing viruses
can be
provided by a combination therapy comprising a therapeutically effective
amount of a first anti-viral
agent provided by one or more compounds, or salts thereof, of Formulae I, II,
III, N, V, VI, VII or
VIII, along with a therapeutically-effective amount of a second agent provided
by one or more
compounds selected from the group consisting of another anti-viral agent; a
host immune modulator;
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interferon derivative, such as interferon-alpha, pegylated-interferon-alpha,
interferon-beta, and
interferon-gamma; a cytoldne; a vaccine; a nucleoside analog; inhibitors of
key enzymes which result
in HCV dysfunction, examples of such enzymes being HCV metalloprotease, HCV
serine protease,
inosine monophosphate dehydrogenase (IMPDH), and HCV helicase; inhibitors of
viral particle
proteins such as HCV NS4B protein, and HCV NS5a protein; and agents which
inhibit HCV function,
such as HCV entry, HCV assembly, and HCV egress. Also included are vaccines
comprising HCV
antigens or antigen adjuvant combinations directed against HCV. Further
included are agents that
interact with host cellular components to block viral protein synthesis by
inhibiting the internal
ribosome entry site (IRES) initiated translation step of HCV viral replication
or to block viral particle
maturation and release with agents targeted toward the viroporin family of
membrane proteins such
as, for example, HCV P7.
10772] In one embodiment, the present invention is directed to a method of
treating or
preventing infection caused by an RNA-containing virus comprising
administering to a patient in need
of such treatment a therapeutically effective amount of a compound of Formulae
I, II, III, IV, V, VI,
VII or VIII, or a pharmaceutically acceptable salt thereof.
[0773] In another embodiment, the present invention is directed to a method of
treating or
preventing infection caused by an RNA-containing virus comprising co-
administering to a patient in
need of such treatment one or more agents selected from the group consisting
of a host immune
modulator and a second antiviral agent, or a combination thereof, with a
therapeutically effective
amount of a compound of Formulae I, II, III, IV, V, VI, VII or VIII, or a
pharmaceutically acceptable
salt thereof.
[0774] In yet another embodiment, the present invention is directed to a
method of treating
or preventing infection caused by an RNA-containing virus comprising co-
administering to a patient
in need of such treatment one or more agents selected from the group
consisting of interferon-alpha,
pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a
vaccine, and a vaccine
comprising an antigen and an adjuvant, and a second antiviral agent, or a
combination thereof, with a
therapeutically effective amount of a compound of Formulae I, II, III, N, V,
VI, VII or VIII, or a
pharmaceutically acceptable salt thereof.
[0775] In still another embodiment, the present invention provides a method of
treating or
preventing infection caused by an RNA-containing virus comprising co-
administering to a patient in
need of such treatment one or more agents selected from the group consisting
of a host immune
modulator and a second antiviral agent which inhibits replication of HCV by
inhibiting host cellular
functions associated with viral replication, or a combination thereof, with a
therapeutically effective
amount of a compound of Formulae I, II, III, N, V, VI, VII or VIII, or a
pharmaceutically acceptable
salt thereof.

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[0776] In a further embodiment, the present invention provides a method of
treating or
preventing infection caused by an RNA-containing virus comprising co-
administering to a patient in
need of such treatment an agent or combination of agents that treat or
alleviate symptoms of HCV
infection including cirrhosis and inflammation of the liver, with a
therapeutically effective amount of
a compound of Formulae I, II, III, N, V, VI, VII or VIII, or a
pharmaceutically acceptable salt
thereof.
[0777] In another embodiment, the present invention provides a method of
treating or
preventing infection caused by an RNA-containing virus comprising co-
administering to a patient in
need of such treatment one or more agents that treat patients for disease
caused by hepatitis B(HBV)
infection, with a therapeutically effective amount of a compound of Formulae
I, II, III; IV, V, VI, VII
or VIII, or a pharmaceutically acceptable salt thereof.
[0778] In yet another embodiment, the present invention provides a method of
treating or
preventing infection caused by an RNA-containing virus comprising co-
administering to a patient in
need of such treatment one or more agents that treat patients for disease
caused by human
immunodeficiency virus (HN) infection, with a therapeutically effective amount
of a compound of
Formulae I, II, III, N, V, VI, VII or VIII, or a pharmaceutically acceptable
salt thereof.
[0779] The phrase "combination therapy" (or "co-therapy"), is intended to
embrace
administration of each agent in a sequential manner in a regimen that will
provide beneficial effects of
the drug combination, and is intended as well to embrace co-administration of
these agents in a
substantially simultaneous manner, such as by oral ingestion or a single
capsule having a fixed ratio of
these active agents or ingestion of multiple, separate capsules for each
agent. "Combination therapy"
will also include simultaneous or sequential administration by oral,
intravenous, intramuscular or
other parenteral routes into the body, including direct absorption through
mucous membrane tissues,
as found in the sinus passages. Sequential administration also includes drug
combinations where the
individual agents may be administered at different times and/or by different
routes but which act in
combination to provide a beneficial effect, for example, by co-action of
pharmacolcinetic or
pharmacodynamic effects of each agent.
[0780] The present invention also features use of the compounds of the
invention, or
pharmaceutically acceptable salts, solvates or prodrugs thereof, for the
manufacture of medicaments
for the treatment of HCV or other viral infections. In one embodiment, the
present invention features
the use of a compound of the present invention selected from Formulae I, II,
III, N, V, VI, VII or
VIII, or a salt, solvate or prodrug thereof, for the manufacture of a
medicament for the treatment of
HCV infection. In another embodiment, the present invention features the use
of two or more
compounds of the present invention (or salts, solvates or prodrugs thereof)
for the manufacture of a
medicament for the treatment of HCV infection, wherein each of the two or more
compounds is
independently selected from Formulae I, II, III, IV, V, VI, VII or VIII.

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[0781] In still another embodiment, the present invention features the use of
at least one
compound of the present invention (or a salt, solvate or prodrug thereof) and
at least one additional
therapeutic agent for the manufacture of a medicament for the treatment of HCV
infection.
Preferably, the compound(s) of the present invention is selected from Formulae
I, II, III, N, V, VI,
VII or VIII, and the additional therapeutic agent(s) can be selected, by way
of illustration not
limitation, from antiviral agents (e.g., anti-HN agents or other anti-HCV
agents), immunomodulators,
anti-cancer or chemotherapeutic agents, and anti-inflammation agents. Specific
examples of
additional therapeutic agents include, but are not limited to, ribavirin;
interferons (e.g., IFN alpha 2a
or 2b); protease inhibitors; immunosuppressants; antibodies (e.g., therapeutic
monoclonal or chimeric
antibodies); antisense or siRNA; HIV inhibitors; hepatitis B (HBV) inhibitors;
agents for treating
cirrhosis and inflammation of the liver; Omega IFN (BioMedicines Inc.,
Emeryville, CA); BILN-2061
serine protease inhibitor (Boebringer Ingelheim Pharma KG, Ingelheim,
Germany); Summetrel
antiviral (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-
alpha 2a (F.
Hoffinann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-alpha 2a
(F. Hoffmann-La
Roche LTD, Basel, Switzerland); Pegasys and Ribavirin PEGylated IFN-alpha
2a/ribavirin (F.
Hoffmann-La Roche LTD, Basel, Switzerland); CellCept HCV IgG immunosuppressant
(F.
Hoffmann-La Roche LTD, Basel, Switzerland); Wellferon lymphoblastoid IFN-alpha
nl
(GlaxoSmithKline plc, Uxbridge, UK); Albuferon-alpha albumin IFN-alpha 2b
(Human Genome
Sciences Inc., Rockville, MD); Levovirin ribavirin (ICN Pharmaceuticals, Costa
Mesa, CA); IDN-
6556 caspase inhibitor (Idun Pharmaceuticals Inc., San Diego, CA); IP-501
antifibrotic (Indevus
Pharmaceuticals Inc., Lexington, MA); Actimmu.ne INF-gamma (InterMune Inc.,
Brisbane, CA);
Infergen A IFN alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS
14803 antisense
(ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., New York,
NY); JTK-003 RdRp
inhibitor (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated
IFN-alpha 2a/immune
modulator (Maxim Pharmaceuticals inc., San Diego, CA); Ceplene immune
modulator (Maxim
Pharmaceuticals Inc., San Diego, CA); Civacir HCV IgG immunosuppressant (Nabi
Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-alpha
2b/alpha 1-thymosin
(RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc.,
San Mateo, CA);
Levovirin IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); Viramidine IlVIPDH
inhibitor
(Ribapharm Inc., Costa Mesa, CA); Heptazyme ribozyme (Ribozyme Pharmaceuticals
Inc., Boulder,
CO); Intron A IFN-alpha 2b (Schering-Plough Corporation, Kenilworth, NJ); PEG-
Intron PEGylated
IFN-alpha 2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron IFN-alpha
2b/ribavirin
(Schering-Plough Corporation, Kenilworth, NJ); Ribavirin (Schering-Plough
Corporation,
Kenilworth, NJ); PEG-Intron/Ribavirin PEGylated IFN-alpha 2b/ribavirin
(Schering-Plough
Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone
Pharmaceuticals Inc., San
Mateo, CA); Rebif IFN-beta la (Serono, Geneva, Switzerland); IFN-beta and
EMZ701 IFN-beta and
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E1VIZ701 (Transition Therapeutics Inc., Ontario, Canada); T67 beta-tubulin
inhibitor (Tularik Inc.,
South San Francisco, CA); VX-497 IMPDH inhibitor (Vertex Pharmaceuticals Inc.,
Cambridge, MA);
VX-950/LY-570310 serine protease inhibitor (Vertex Pharmaceuticals Inc.,
Cambridge, MA/Eli Lilly
and Co., Inc., Indianapolis, IN); Omniferon natural IFN-alpha (Viragen Inc.,
Plantation, FL); XTL-
002 monoclonal antibody (XTL Biopharmaceuticals); compound VX-950 (Vertex
Pharmaceuticals
Inc.); compound SCH503034 (Schering-Plough Co.); and compound GS9137 (Gilead
Sciences, Inc.,
Foster City, CA).
[0782] In yet another embodiment, the present invention features the use of at
least one
compound of the present invention (or a salt, solvate or prodrug thereof) and
at least one additional
anti-viral agent for the manufacture of a medicament for the treatment of
viral infection. Preferably,
the compound(s) of the present invention is selected from Formulae I, II, III,
IV, V, VI, VII or VIII,
and the additional anti-viral agent(s) can be selected, without limitation,
from anti-HCV or anti-HIV
agents. In one example, the present invention features the use of at least one
compound of the present
invention selected from Formulae I, II, III, IV, V, VI, VII or VIII (or a
salt, solvate or prodrug
thereof), and at least one additional anti-HCV agent for the manufacture of a
medicament for the
treatment of HCV infection. Non-limiting examples of anti-HCV agents include
HCV RNA
dependent RNA polymerase inhibitors (e.g., nucleoside or non-nucleoside type
polymerase inhibitors)
or HCV protease inhibitors. In another example, the present invention features
the use of at least one
compound of the present invention selected from Formulae I, II, III, IV, V,
VI, VII or VIII (or a salt,
solvate or prodrug thereof), and at least two or more additional anti-HCV
agents for the manufacture
of a medicament for the treatment of HCV infection. Each of the additional
anti-HCV agents can be
independently selected from HCV RNA dependent RNA polymerase inhibitors or HCV
protease
inhibitors.
[0783] In still another embodiment, the present invention features the use of
at least one
compound of the present invention selected from Formulae I, II, III, IV, V,
VI, VII or VIII (or a salt,
solvate or prodrug thereof), and at least one anti-HIV agent for the
manufacture of a medicament for
the treatment of HIV or HCV infection. In still yet another embodiment, the
present invention
features the use of at least one compound of the present invention selected
from Formulae I, II, III,
IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least
one anti-hepatitis A, anti-
hepatitis B, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agent for
the manufacture of a
medicament for the treatment of viral hepatitis. In a further embodiment, the
present invention
features the use of at least one compound of the present invention selected
from Formulae I, II, III,
IV, V, VI, VII or VIII (or a salt, solvate or prodrug thereof), and at least
one agent for treating liver
inflammation, for the manufacture of a medicament for the treatment of
Hepatitis C.
[0784] The foregoing description of the present invention provides
illustration and
description, but is not intended to be exhaustive or to limit the invention to
the precise one disclosed.
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Modifications and variations are possible in light of the above teachings or
may be acquired from
practice of the invention. Thus, it is noted that the scope of the invention
is defined by the claims and
their equivalents.

200