Title of Invention

"A 4-(ARYLMETHYLOXY)-PYRIDIN-2-ONE COMPOUND"

Abstract A compound of the formula or a pharmaceutically acceptable salt thereof, wherein Rs is heteroaryl or heteroarylalkyl, wherein the heteroaryl and heteroaryl groups are optionally substituted with 1,2, 3, or 4 groups that are independently -C(O)NR6R7, -(C1-C4 alkyl)-C(O)NR6R7, -NR6R7, hydroxy(C1-C4 )alkyl, C1-C4 dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, R6R7N-(C1-C6 alkyl)-, -CO2-(C1-C6)alkyl, -N(R)C(0)NR6R7, or -N(R)C(O)-(C1-C6 )alkoxy, X1, X2, Y, Y1, Y2, Y3 and Y4 are as herein defined.
Full Text
er kinThe present invention relates to a 4-(arylmethyloxy)-pyridin-2-one compound.
Cross Reference to Related Applications
This application claims priority from U.S. Provisional Application Serial Number 60/357,029, filed February 14, 2002, and U.S. Provisional Application Serial Number 60/436,915, filed December 30, 2002, the disclosure of each of which is incorporated herein by reference in its entirety.
Background of the invention
Field of the invention
The instant invention relates to substituted pyridinones that are useful for treating diseases and conditions caused or exacerbated by unregulated p3 8 MAP kinase activity. Pharmaceutical compositions containing the pyridinone compounds, methods of preparing the pyridone compounds and methods of treatment using the compcunds are also disclosed.
Description of the Related Art
Numerous cell surface receptors use one or more of the mitogen-activated protein kinase (MAP kinase) cascades during signal transduction. MAP kinases are a family of protein-directed serine/threonine kinases that are activated by dual phosphorylation. One subgroup of the MAP kinases is p38 MAP kinase, which is activated by a variety of signals including proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as bacterial lipopolysaccharides and environmental stress such as osmotic shock and ultraviolet radiation (One, K. and J. Han, Cell Signal. 12: 1, 2000). Within the p38 kinase family, there are four distinct isozymes: p38 alpha, p38 beta, p38 gamma, and p38 delta. The p38 kinase family function downstream of an activating stimulus by phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as
ases (e.g. MAPKAP-2 and MAPKAP-3) (Trends ir. Cell
biclogy 7, 353-351, 1997/Mol Cell Biology 19, 21-30, 1399;
EMBO J 20, 466-479, 2001). Upon activation, the p33 kinase
cascade leads to the induction of gene expression of several
factors involved in inflammation and immunity including TNF,
interleukin-6, granulocyte-macrophage colony stimulating
factor (GM-CSF), and HIV long terminal repeat (Paul et al.,
Cell Signal. 9: 403-410, 1997). The products of the p38
phosphorylation stimulate the production of inflammatory
cytokines and other proteins, including TNF and IL-1, and
cyclooxygenase-2, and also possibly modulate the effects of
these cytokines on their target cells, and thus stimulate
inflammation processes (Lee, J.C. et al, Nature, 372: 376,
1994).
P38 MAP kinases have also been shown to promote apoptosis
during ischemia in cardiac myocytes, which suggests that p38
MAP kinase inhibitors can be used to treat ischemic heart
disease (J. 3iol. Chem. 274, 6272, 1999). They are also
required for T-cell HIV-1 replication and may be useful
targets for AIDS therapy. P38 pathway inhibitors have been
used to increase cancer cell sensitivity to cancer therapy
also find use in the treatment of asthma (JPET 293, 281,
2000) .
TNF is a cytokine and a potent proinflammatory mediator
implicated in inflammatory conditions such as arthritis,
asthma, septic shock, non-insulin dependent diabetes mellitus,
multiple sclerosis, asthma, and inflammatory bowel disease.
Thus inhibitors of p38 MAP kinases (required for TNF
production) may be useful for the treatment of inflammatoryconditions
resulting from excessive cytokine production such
as arthritis. (Boehm, J.C. and J.L. Adams, Exp. Opin. Ther.
Patents 10: 25, 2000, and references cited therein). TNF has
also been implicated in viral infections, such as HIV,
influenza virus, and herpes virus including herpes simplex
virus cype-i (HSV-1), herpes simplex virus type-2 (HSV-2),
cytomecaiovirus (CMV), varicella-roster virus (VZV), Epstein-
Barr virus, human herpesvirus-6 (HKV-6), human herpesvirus-7
(HHV-7), human herpesvirus-8 (HHV-6), pseudorabies and
rhinctracheitis, among others.
Excessive or unregulated TNF production has also been
shown to produce elevated levels of IL-1. Inhibition of TNF,
therefore, should reduce levels of IL-1 (European Cytokine
Netw 6, 225, 1995) and ameliorate disease states caused by
unregulated IL-1 synthesis. Such disease states include
rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,
gouty arthritis, sepsis, septic shock, endotoxic shock, gram
negative sepsis, toxic shock syndrome, adult respiratory
distress syndrome, cerebral malaria, chronic pulmonary
inflammatory disease, silicosis, pulmonary sarcosis, bone
resorption diseases, reperfusion injury, graft versus host
reaction, alallograft rejections, fever and myalgias due to
infection, cachexia secondary to infection or malignancy,
cachexia secondary to acquired immune deficiency syndrome
(AIDS), AIDS related complex (ARC), keloid formation, scar
tissue formation, Crohn's disease, ulcerative colitis, and
pyresis.
IL-1 has also been shown to mediate a. variety of
biological activities such as the activation of T-helper
cells, induction of fever, stimulation of prostaglandin or
collagenase production, neutrophil chemotaxis, and the
suppression of plasma iron levels (Rev. Infect. Disease, 6, 51
(1984)). Elevated levels of IL-1 have also been implicated in
mediating or exacerbating a number of disease states including
rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis,
gouty arthritis, inflammatory bowel disease, adult respiratory
distress syndrome (ARDS), psoriasis, Crohn's disease,
ulcerative colitis, anaphylaxis, muscle degeneration,
cachexia, Reiter's syndrome, type I and type II diabetes, bone
resorption diseases, ischemia reperfusicn injury,
arteriosclerosis, brain trauma, multiple sclerosis, sepsis,
septic shock, and toxic shock syndrome. Viruses sensitive to
TNF inhibition, such as HIV-1, HIV-2, HIV-3, are also affected
by IL-1 production. In rheumatoid arthritis, both IL-1 and
TNF induce collagenase synthesis and ultimately lead to tissue
destruction within arthritic joints (Lywphokine Cytokine Res.
(11): 253-256, (1992) and Clin. Exp. Imwunol. 989:244-250,
(1992)).
IL-6 is another pro-inflammatory cytokine, which is
associated with many conditions including inflammation.
Consequently, TNF, IL-1 and IL-6 affect a wide variety of
cells and tissues and are important inflammatory mediators of
a wide variety of disease states and conditions. The
inhibition of these cytokines by inhibition or modulation of
p38 kinase is of benefit in controlling, reducing and
alleviating many of these disease states and conditions.
Therefore, the present invention concerns finding small
molecule inhibitors or modulators of p38 kinase and the p38
kinase pathway.
Summary of the Invention
In a broad aspect, the invention provides compounds of
Formula I (Embodiment 1):
and pharmaceutical acceptable salts thereof, wherein
RI is H, halogen, N02, alkyl, carboxaldehyde, hydroxyalkyl,
dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl,
arylalkynyl, -CN, aryl, alkanoyl, alkoxy, alkoxyalkyl,
haloalkyl, haloalkoxy, carboxyl, or arylalkanoyl,
wherein the aryl portion of arylalkoxy, arylalkyl, and
arylalkanoyl is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
Ci-d alkyl, Ci-C4 alkoxy, nitro, CN, haloalkyl,
haloalkoxy or C02R;
wherein the alkyl portion of the alkyl, hydroxyalkyl,
dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl,
alkoxy, alkoxyalkyl and arylalkanoyl groups is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently halogen, Ci-C4 alkoxy, Ci-C4
alkoxycarbonyl, or C3-C7 cycloalkyl;
R2 is H, OH, halogen, -OS02-(C^-Cg) alkyl, -OSO2-aryl,
arylalkoxy, aryloxy, arylthio, arylthioalkoxy,
arylalkynyl, alkoxy, aryloxy (Cj-Cs) alkyl, alkyl, alkynyl,
-OC(0)NH(CH2)Qaryl, -OC (0)N (alkyl) (CH2)naryl, alkoxyalkoxy,
dialkylamino, alkyl, alkoxy, aryl, arylalkyl, heteroaryl, •
heteroarylalkyl, arylalkenylf heterocycloalkyl,
heterocycloalkylalkyl, alkoxyalkoxy, NR8R9, dialkylamino,
or CO2R, wherein
n is 0, 1, 2, 3, 4, 5 or 6;
each of which groups is unsubstituted or substituted with
2 A of 5 err QUIDS that are independently
halogen, - (d-Cs) alkyl-N(R)-C02R30, haloalkyl,
heteroaryl, heteroarylalkyl, -NRgRi, R0-R7N-(Ci-Cs
alkyl)-, -C(0)NR5R7, - (d-C4) alkyl-C (0) NR5R7, - (d-C4
alkyl) -NRC(0)NRiSRi7, haioalkoxy, alkyl, CN,
hydroxyalkyl, dihydroxyalkyl, alkoxy,
aikoxycarbonyl, phenyl, -S02 -phenyl wherein the
phenyl and -S02-phenyl groups are optionally
substituted with I, 2, or 3 groups that are
independently halogen or N02, or -OC(O)NR6R7, wherein
R16 and R17 are independently H or d-C6 alkyl; or
R16, Rt7 and the nitrogen to which they are attached
form a morpholinyl ring;
Rs and R7 are independently at each occurrence H,
alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy,
alkanoyl, arylalkyl, arylalkoxy,
alkoxycarbonyl, -S02-alkyl, OH, alkoxy,
alkoxyalkyl, arylalkoxycarbonyl, - (d-C4)alkyl-
C02-alkyl, heteroarylalkyl, or arylalkanoyl,
wherein each is unsubstituted or substituted
with 1, 2, or 3 groups that are independently,
halogen, OH, SH, heterocycloalkyl,
heterocycloalkylalkyl, C3-C7 cycloalkyl, alkoxy,
NH2, NH(alkyl), N (alkyl) (alkyl) , -0-alkanoyl,
alkyl, haloalkyl, carboxaldehyde, or
haioalkoxy; or
R6, R7, and the nitrogen to which they are attached
form a morpholinyl, pyrrolidinyl,
thiomorpholinyl, thiomorpholinyl S-oxide,
thiomorpholinyl S,S-dioxide, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that
are independently Ci-C4 alkyl, alkoxycarbonyl,
alkcxv, hvdroxvl, hydrcxyaj.ky_,
dihydrcxyalkyl, or halogen;
R at each occurrence is independently hydrogen or Ci-
Cs alkyl optionally substituted with 1 or 2
groucs that are independently OH, SH, halogen,
amino, monoalkylamino, dialkylaminc or C3-C6
cycloalkyl;
R30 is Ci-Cg alkyl optionally substituted with I cr 2
groups thac are independently OH, SH, halogen,
amino, monoalkylarnino, dialkylamino or C3-C5
cycloalkyl;
each Ra is independently hydrogen, alkyl, alkanoyl,
arylalkyl and arylalkanoyl, wherein each of the
above is optionally substituted with 1, 2, 3,
4, or 5 groups that are independently alkyl,
alkoxy, alkoxycarbonyl, halogen, or haloalkyl;
each R9 is hydrogen, alkyl, alkanoyl, arylalkyl,
cycloalkyl, cycloalkylalkyl, alkenyl,
heteroaryl, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, arylalkanoyl, -SOa-phenyl,
and aryl wherein each of the above is
optionally substituted with 1, 2, 3, 4, or 5
groups that are independently alkyl, alkoxy,
alkoxycarbonyl, halogen, or haloalkyl;
is H, halogen, alkoxycarbonyl, arylalkoxycarbonyl,
aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl,
arylalkoxy, -OC(0)N(alkyl) (CH2) naryl, aryloxy, arylthio,
thioalkoxy, arylthioalkoxy, alkenyl, -NR5R7, NR6R7- (Cj.-
Cs)alkyl, or alkyl, wherein
the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,
arylalkyl, -OC (0) NH (CH2) naryl, arylalkoxy,
-OC (0)N (alkyl) (CH2) naryl, and arylthioalkoxy, is
unsubstituted or substituted with 1, 2, 3, 4, cr -
groups that are independently, halogen, alkoxy,
alkyl, haloalkyl, or haloalkcxy,
wherein n is 0, 1, 2, 3, 4, 5, or 6; or
R4 is hydrogen or R4 is alkyl unsubstituted or substituted with
one or two groups that are independently CO2R, -C02- (Ci-
Cfi) alkyl, -C(0)NR6R7, -C(0)R£; -N (R30) C (O) NR15R17,
N(R30)C(0) - (Ci-Ce) alkoxy, or -NR6R7, arylalkoxy, arylalkyl,
heteroaryl, heteroarylalkyl, hydroxyalkyl,
dihydroxyalkyl, haloalkyl, R6R7N- (Ci-C6 alkyl)-, -NR6R7|
alkoxy, carboxaldehyde, -C(0)NRSR7, C02R, alkoxyalkyl, or
alkoxyalkoxy, wherein the heteroaryl or aryl portions of
is the above are unsubstituted or • substituted with 1, 2,
3, 4, or 5 groups that are independently halogen,
hydroxy, alkoxy, alkyl, -C02- (Ci-Cs) alkyl, -CONRSR7, -NR6R7,
R6R7N- (C1-C6) alkyl-, nitro, haloalkyl, or haloalkoxy; and
Rs is H, aryl, arylalkyl, arylthioalkyl, alkyl optionally
substituted with 1, 2, or 3 groups that are independently
arylalkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9,
alkoxycarbonyl, C^-Ci cycloalkyl, or alkanoyl, alkoxy,
alkoxyalkyl optionally substituted with one
trimethylsilyl group, amino, alkoxycarbonyl,
hydroxyalkyl, dihydroxyalkyl, alkynyl, -SO2-alkyl, alkoxy
optionally substituted with one trimethylsilyl group,
heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl,
alkyl-S-aryl, - alky 1-S02-aryl, heteroarylalkyl,
heterocycloalkyl, heteroaryl, or alkenyl optionally
substituted with alkoxycarbonyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, hydroxyalkyl, dihydroxyalkyl,
arylalkoxy, thioalkoxy, alkoxycarbonyl,
arylalkoxycarbonyl, C02R, CN, OH, hydroxyalkyl,
dihydroxyalkyl, amidir.ooxime, -NR5R-; -NRSK9, Re-R7N-
(d-C6 alkyl)-, carboxaldehyde; SO-alkyl, -SC:H, -
302NRSR7, aikancyi wherein the alkyl portion is
optionally substituted with OH, halogen or alkoxy, -
C(0)NRSR7, -(Ci-C alkyl) -C(0)NR6R7, amidino,
haloalkyl, - (Ci-C4 alkyl) -NR15C (0) NRloR17, - (Cj.-C4
alkyl)-NR1SC(0)R13/ -0-CH2-0, -O-CK2CK2-0-, cr
haloalkoxy; wherein
RIS is H or Ci-Cs alkyl; and
R18 is Ci-Cs alkyl optionally substituted with -0- (C2-C6
alkanoyl, Ci-Cs hydroxyalkyl, d-Cs dihydroxyalkyl,
Ci-Cs alkoxy, Ca-C6 alkoxy d-Cg alkyl; amino
alkyl, mono or dialkylamino Ci-C6 alkyl.
The invention also includes the intermediates that are
useful in making the compounds of the invention.
These compounds bind and/or interact with p38 kinase
and/or TNF. Preferably, they inhibit the activity of p38
kinase and/or TNF. They are therefore used in treating p38
map kinase or TNF mediated disorders. Preferably they are
used in treating p38 alpha or TNF mediated disorders.
The instant invention also includes pharmaceutical
compositions comprising at least one compound of formula I and
at least one pharmaceutically acceptable carrier, solvent,
adjuvant or excipient.
The instant invention also includes methods of treating a
TNF mediated disorder, a p38 kinase mediated disorder,
inflammation and/or arthritis in a subject, the method
comprising treating a subject having or susceptible to such
disorder or condition with a therapeutically-effective amount
of a compound of Formula I.
Detailed Description of the Invention
In a preferred aspect, the invention provides compounds
of formula I wherein:
when R2 is benzyloxy, R3 is H, R4 is H, and R5 is benzyl or
methyl, RI is not hydrogen;
no more than two of RI, R2, R4, and R5 are simultaneously
hydrogen;
Rs and R7 are not simultaneously OH;
when R2 is OH, R4 is methyl and R5 is phenyl, R± is not acetyl;
and
R4 and R5 are not simultaneously hydrogen.
Embodiment 2. Compounds of the formula:
and the pharmaceutically acceptable salts thereof, wherein
RI is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,
dihydroxyalkyl, arylalkoxy, arylalkyl, .alkenyl, alkynyl,
arylalkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl,
haloalkyl, carboxyl, or arylalkanoyl,
wherein the aryl portion of arylalkoxy, arylalkyl, and
arylalkanoyl is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
Ci-C4 alkyl, C1-C4 alkoxy, nitro, CN, haloalkyl,
haloalkoxy or C02R;
wherein the alkyl portion of the alkyl, hydroxyalkyl,
dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl,
alkoxy, alkoxyalkyl and arylalkanoyl groups is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently halogen, d-C4 alkoxy, Ci-C4
alkoxycarbonyl, or cyclopropyl;
is H, OK, halogen, -OS02-(C-_-C6 alkyl , -CSO2-aryl,
arylalkoxy, aryloxy, arylthioalkcxy, arylalkynyl, alkoxy,
phenyl 0x7(01-05} alkyl, -00 (0) NK (CH2) 3aryl,
-00(O)N(alkyl) (CK2) aaryl, alkyl, alkynyl, alkoxyalkoxy,
dialkylamino, heteroaryl, heterocycloalkyl, aryioxyalkyl,
or C02R, wherein
each of the above is unsubstitutsed or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
-NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl,
heteroarylalkyl, - (C1-C4) alkyl-0 (0) NRSR7, R6R7N-(C--C0-
alkyl)-, -C(0)NR6R7/ - (Ci-C* alkyl)-NRC (0) NR1SR17/ ON,
hydroxyalkyl, dihydroxyalkyl, -OC(0)NR6R7, or - (d-
Cs) alkyl-N(R)-C02R30, wherein
R1S and R17 are independently H or Cx-Cs alkyl; or
RIS, Riy and the nitrogen to which they are attached
form a morpholinyl ring;
Rs and R7 are independently at each occurrence K,
alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy,
alkoxyalkyl, alkanoyl, arylalkyl, arylalkoxy,
arylalkoxycarbonyl, or arylalkanoyl, wherein
each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, alkoxy, alkyl, OH, SH,
carboxaldehyde, haloalkyl, or haloalkoxy; or
RS, R and the nitrogen to which they are attached
£orm a morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,Sdioxide,
piperidinyl, pyrrolidinyl, or
piperazinyl ring which is optionally
substituted with 1 or 2 groups that are
independently C!-C4 alkyl, alkoxycarbonyl,
hydroxyl, hydroxyalkyl, dihydroxyalkyl, or
halogen;
n is 0, 1, 2, 3, 4, 5 or 6;
R at 'each occurrence is independently H or C^-C^ alky
optionally substituted wich 1 or 2 groups that are
independently OH, SH, halogen, ami no,
monoalkylamino, dialkylamino or C3-C6 cycloalkyl;
R30 is alkyl optionally substituted with I or 2
groups that are independently OH, SH, halogen,
amino , monoalkylamino, dialkylamino or C3-CS
cycloalkyl ;
R4 is H, alkyl optionally substituted with one or two groups
that are independently C02R, -C02alkyl, -C(0)NR6R7,
-C(0)R6/ -N(R30)C(0)NRi6Ri7, -N (R30) C (0) - (Ci-Cg) alkoxy,
or -NR6R7, arylalkoxy, heteroaryl , arylalkyl,
hydroxyalkyl, dihydroxyalkyl, haloalkyl, -NRSR7/
C(O)NR6R7, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein
the heteroaryl or aryl portions of the above are
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, hydroxy,
alkoxy, alkyl, -C02- (Ci-Cs) alkyl , -CONR6R7, -NRSR7/
RSR7N- (Ci-Cg) alkyl- , nitro, haloalkyl, or haloalkoxy;
and
R5 is H, arylalkyl, alkyl optionally substituted with 1, 2, or
3 groups that are independently arylalkoxycarbonyl ,
NR8R9/ halogen, -C(0)NR8R9, alkoxycarbonyl , or alkanoyl,
alkoxyalkyl optionally substituted with one
trimethylsilyl group, alkoxycarbonyl, . amino,
hydroxyalkyl, dihydroxyalkyl, alkenyl optionally
substituted with alkoxycarbonyl, alkynyl , -S02- alkyl,
aryl, alkoxy optionally substituted with one
trimethylsilyl group, heterocycloalkylalkyl,
heteroarylalkyl, heterocycloalkyl , or heteroaryl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkcxy, arylalkoxy, hydroxyalkyi,
dihydroxyalkyl, thioalkcxy, -SC2aikyl,
alkcxvcarhcrivi, aryialkoxycarbor.yl, C02R, CN, CH,
amidincoxime , NRSR9, R6R-N- (Cx - C; alkyl) - , - C (C} NR,-R-,
amidino, hydroxyalkyl, dihydroxyalkyl,
carboxaldehyde, -NR,;R7, haloalkyl, - (C-C4 alkyl)-
C(0)NR0-R7/ - (C:-C4 alkyl)-CO2R, - (d.-C4 alkyl)-Ci-C£
alkoxycarbonyl, - (Cl-C4i alkyl) -CN, - (C!-C4 alkyl)-
NR15C(0)R18/ -0-CK2-0-, -0-CH2CH2-0-, phenyl or
haloalkoxy;
R8 is hydrogen, alkyl, alkanoyl, arylalkyl and
arylalkanoyl;
R9 is alkyl, alkanoyl, arylalkyl, heteroaryl,
aminoalkyl, ' monoalkylaminoalkyl,
dialkylaminoalkyi, and arylalkanoyl.
Embodiment 3. Compounds according to embodiment 2
wherein
Ri is H, halogen, alkyl optionally substituted with C!-C4
alkoxycarbonyl, carboxaldehyde, hydroxyalkyl,
dihydroxyalkyl, phenyl (d-C6) alkoxy, phenyl (Ci-C6) alkyl,
CN, alkanoyl, alkoxy, C2-C4 alkynyl, C2-C6 alkenyl
optionally substituted with Ci-C4 alkoxycarbonyl,
alkoxyalkyl, haloalkyl, or phenyl (Ci-Cg) alkanoyl,
wherein the phenyl groups are unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently halogen, Ci-C4 alkyl, Ci-C4 alkoxy,
nitro, CN, CF3, OCF3 or C02R;
wherein the alkyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently halogen,
methoxy, or ethoxy;
R2 is OH, phenyl (Ci-Cg) alkoxy, phenyloxy, phenyloxy (Ci-Cg) alkyl,
phenyl (C!-C4) thioalkoxy, C±-CS alkoxy, alkoxyalkoxy, -0-
S02phenyl, alkynyl, phenyl (C2-C4) alkynyl, alkyl,
-OC(0)NK(CH2)nphenyl, -OC (0) N (alkyl) (CK2) nphenyl,
dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,
imidazolyl, pyrrolyl, tetrahvdrcquinolinyl,
tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl,
benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,
hexahydropyrimidinyl, thiazolyl, thienyl, or C02R, wherein
n is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituted or substituted with 1,
.2, 3, 4, or 5 groups that are independently halogen,
NR6R7, haloalkyl, haloalkoxy, hydroxyalkyl,
dihydroxyalkyl, alkyl, phenyl, pyridyl, piperidinyl,
piperazinyl, - (d-C6) alkyl-N(R)-C02R3o, R6R7N-(Ci-C6
alkyl)-, -C(0)NReR7, - (Ci-C4) alkyl-C (0)NR6R7, - (d-C4
alkyl) -NRC (0)NR1SR17, or -OC(0)NR6R7, wherein
R6 and R7 are independently at each occurrence H,
alkyl, (Ci-C4) hydroxyalkyl, (Ci-C4)
dihydroxyalkyl, (Ci-C4) alkoxy, (d~C4) alkoxy
(Ci-C4) alkyl, (d-d) alkanoyl, phenyl (d~d)
alkyl, phenyl (d-C4) alkoxy, phenyl (d~C4)
alkoxycarbonyl, or phenyl (d-C4) alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, OH, SH, d-C6
cycloalkyl, (d-C4) alkoxy, (d-C4) alkyl, CF3,
carboxaldehyde, NH2, NH (d-Cfi) alkyl, N(d-
alkyl (d-Cs) alkyl, OCF3; or
R6, R and the nitrogen to which they are attached
form a morpholinyl, thiomorpholinyl,
piperidinyl, pyrrolidinyl, or piperazinyl ring -
which is optionally substituted with 1 or 2
groups that are independently d-C4 alkyl,
hydroxy, hydroxy d-C4 alkyl, d-C4
dihydroxyalkyl, d~C4 alkoxycarbonyl, or
R4 is H, alkyl optionally substituted with one or two groups
chat are independently C02R, -CO-alkyl, -C(0)NRD-R7,
-C(0)R6, -N(R3o)C(C)NRlo-R17, -tf(R30)C(0) - (C,-C5} allcoxy,
or -NR5R7, -C(0)NRSR7, phenyl (d-C5) alkcxy, phenyl (d~
Cs)alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkcxy,
alkoxyalkyl, or alkoxyalkoxy, wherein
the phenyl groups are unsubstituted or substituted with
1, 2, 3, 4, or 5 groups that are independently
halogen, hydroxy, alkoxy, alkyl, nitro, CF3, OCF3 ;
R5 is phenyl (CI-GS) alkyl, (d-C6) alkyl optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently
phenyl Ci-C4 alkoxycarbonyl, -NR8R9, halogen, -C(O)NRaR9,
alkoxycarbonyl, or alkanoyl, phenyl,. alkoxy, C2-Co
alkynyl, C2-C6 alkenyl optionally substituted with
alkoxycarbonyl, indolyl, quinolinyl, isoquinolinyl,
isoindolyl, dihydroindolyl, pyrazolyl, imidazolyl,
dihydroisoindolyl, indolon-2-yl, indazolyl,
benzimidazolyl, pyridyl, imidazolidine dione,
pyrazolyl (d-Cg alkyl), imidazolyl (d-Cg alkyl),
piperidinyl (Ci-Cg) alkyl, pyrrolidinyl (d~Cg) alkyl,
imidazolidinyl (Ci-Cg) alkyl, tetrahydroisoquinolinyl (d-
Cs) alkyl, IH-indazolyl (Ci-Cg) alkyl, dihydroindolon-2-
yl(d-Cg alkyl), indolinyl(d-Cg alkyl),
dihydrobenzimidazolyl(d-C6 alkyl), or
dihydrobenzoimidazolonyl(d-Cg alkyl), pyridyl (d-Cs)
alkyl, pyridazinyl (d-C6) alkyl, pyrimidinyl (d-Cs)
alkyl, pyrazinyl (Ci-C6) alkyl, tetrahydrofuryl(Ci-
Cg) alkyl, naphthyl (Ci-Cg) alkyl, morpholinyl (Ci-Cg) alkyl,
tetrahydrofuryl (d-C6) alkyl, thienyl (Ci-C6) alkyl,
piperazinyl (Ci-Cg) alkyl, indolyl (d-C6) alkyl,
quinolinyl (d-C6) alkyl, isoquinolinyl (Cx-Cg) alkyl,
isoindolyl (Ci-C5) alkyl, dihydroir.dolyl (d-CD-) alkyl,
pyrazolyl(Ci-C4) alkyl, imidazolyl (d-Cj alkyl,
dihydroisoindolyl(Ci-Cs) alkyl, indoon-2-yl (d-Cj alkyl,
indolon-2-yl(Ci-Cg) alkyl, or morpholinyl d-Cs alkyl,
wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently d-C0- alkyl,
halogen, Ci-Cs alkoxy, phenyl d-C5 alkoxy, Ci-Cg
thioalkoxy, Ci-C6 alkoxycarbonyl, CO2R, CN, -SO2(d-
C6) alkyl, amidinooxime, NR8R9, -NR6R7, NR6R7 Ci-Cs alkyl,
-C(0)NR6R7, - (d-C4) alkyl-C (0)NRsRv, amidino, d-C4
haloalkyl, hydroxy Ci-C6 alkyl, d-C6 dihydroxyalkyl, or
Ci-C4 haloalkoxy; wherein
R8 is hydrogen, Ci-Cs alkyl, Ci-Ce alkahoyl, phenyl
Ci-Cs alkyl and phenyl d-Cs alkanoyl; and
R9 is aminoalkyl, mono Ci-C6 alkylamino Ci-Cs alkyl,
di Ci-Cs alkylamino Ci-C0- alkyl, Ci-C6 alkyl, Ci-
Cs alkanoyl, phenyl Ci-C6 alkyl, indazolyl, and
phenyl d-Cs alkanoyl.
En±)odiment 4 . Compounds according to embodiment 3,
wherein
is H, halogen, Ci-C4 alkyl optionally substituted with
alkoxycarbonyl, C2-C4 alkenyl optionally substituted with
Ci-C4 alkoxycarbonyl, C2-C4 alkynyl, or carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (Ci-Cg) alkyl, phenyl
(Ci-C4) thioalkoxy, or pyridyl; wherein each of the above
is optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently halogen, - (Ci-Cs) alkyl-N(R) -C02R30,
NRsR7, - (Ci-C4) alkyl-C(0)NRSR7, (Ci-C4) haloalkyl,
-C(0)NR6R7, - (Ci-C4 alkyl)-NRC(0)NRi6Ri7, (Ci-C4) haloalkoxy,
hydroxyalkyl, Ci-Cs dihydroxyalkyl, (Ci-Cs) alkyl, pyridyl,
or R6R7N- (Ci-Cs alkyl) - .
Embodiment 4a. Compounds according to embodiment. 4, whsrezn RI
Embodiment 4b. Compounds according to embodiment 4, wherein RI
is halogen.
Embodiment 4c. Compounds according to embodiment 4, wherein Ri
is Ci-C4 alkyl optionally substituted with Ci-C4 alkoxycarbonyl.
Embodiment 5. Compounds according to embodiment 4, wherein
R5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, pyrazolyl,
imidazolyl, furanyl, quinolinyl, ' isoquinolinyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-
yl, or pyrazinyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4 or 5 groups that are
independently Ci-C4 alkyl, halogen, CF3, OCF3, -C02CH3, Ci-
C4 hydroxyalkyl, dihydroxyalkyl, Ci-C4 alkoxy, -C02(Ci-C5
alkyl), benzyloxy, -NR6R7, - (Ca-Cj alkyl-C (0) NRSR7, -NRaR9,
NR6R7-(Ci-C4 alkyl), -C(0)NR6R7, or amidinooxime; wherein
R6 and R7 are independently at each occurrence H, Ci-C4
alkyl, Ci-C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl, Ci-C4
alkoxy, Ci-C4 alkoxy Ci-C4 alkyl, Ci-C4 alkanoyl,
phenyl Ci-C4 alkyl, phenyl Ci~C4 alkoxy, or phenyl Ci-
C4 alkanoyl, wherein each is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, OH, SH, C3-CS cycloalkyl,
aryl, C!-C4 alkoxy, Ci-C4 alkyl, OH, CF3, or OCF3; or
Rs, R and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, pyrrolidinyl, or
piperazinyl ring which is optionally substituted
with 1 or 2 groups that are independently Ci-C4
alkyl, hydroxy, hydroxy Ci-C4 alkyl, Ci-C
dihydroxyalkyl, or halogen.
Embodiment 6. Compounds according to embodiment 5,
wherein
R5 is indolyl, pyridyl, pyrimidinyl, pyrazolyl, furanyl,
indazolyl, dihydroindolyl, dihydroisoinclolyl, indolon-2-
yl, or pyrazinyl, each of which is unsubstituted or
substituted with 1, 2, 3, or 4 groups that are
independently CX-C4 alkyl, halogen, CF3, OCF3/ -C02CH3, C-.-
C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl, Ci-C4 alkoxy, -
C02(Ci-C5 alkyl), benzyloxy, -C(O)NR6R7, -NR8R9, - (Ci-
C4) alkyl-C(0)NR6R7, -NR6R7, NR6R7- (Ci-C4 alkyl)-, and
amidinooxime.
Embodiment 7. Compounds according to embodiment 6,
wherein
R5 is indolyl, pyridyl, pyrimidinyl, dihydroindolyl,
dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which
is unsubstituted or substituted with 1, 2, 3, or 4 groups
that are independently Ci-C4 alkyl, halogen, CF3, OCF3,
-C02CH3, Ci-C4 hydroxyalkyl, Cj-C4 dihydroxyalkyl, Ci-C4
alkoxy, -CO2(C-C5 alkyl), benzyloxy, -C(O)NR6R7/ NR8R9, -
(Ci-C4) alkyl -C(0)NR6R7, -NR6R7, NRSR7- 4 alkyl)-, or
amidinooxime; wherein
R6 and R7 are independently at each occurrence H, Ci-C4
alkyl, Ci-C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl, Ci-C4
alkoxy, Ci-C4 alkanoyl, Ci-C4 alkoxy Cj.-C4 alkyl, each
of which is optionally substituted with 1, 2, or 3
groups that are independently halogen, OH, SH, C3-C6
cycloalkyl, d-C4 alkoxy, Ci-C4 alkyl, OH, CF3, or
Embodiment S. Compounds according to embodiment 7,
where in
P-5 is indclyl, pyridyl, pyrimidinyi, dihydroindolyl,
dihydroisoindolyi , ' pyrazolyl, or pyrazinyl, each cf which
is unsubstitutsd or substituted with I, 2, or 3 groups
than are independently Ci-C4 alkyl, halogen, CF3, CCF3, Cj.-
C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl, Ci-C4 alkcxy,
alkyl-C(0)NRSR7, NR8R9, -NR0-R7, or NRD-R7-
(Ci-C4 alkyl)-; wherein
R6 and R7 are independently at each occurrence H, d-C4
alkyl, d-C4 hydroxyalkyl, d~C4 dihydroxyalkyl, d-d
alkanoyl, or Ci-C4 alkoxy, each of which is
optionally substituted with 1, 2, or 3 groups that
are independently halogen, OH, SH, C3-CS cycloalkyl,
C!-C4 alkoxy, C!-C4 alkyl, OH, CF3, or OCF3.
Embodiment 9. Compounds according to embodiment 4,
wherein
R5 is phenyl, phenyl (d-Cg) alkyl, or (Ci-Cs) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, benzyloxy, hydroxyalkyl,
dihydroxyalkyl, thioalkoxy, -C02(Ci-C5 alkyl), C02R,
CN, amidinooxime, -NR8R9, -NR6R7, R6R7N- (Ci-Cs alkyl)-,
-C(O)NR6R7, - (Ci-C4) alkyl-C (0)NR6R7, amidino, CF3, or
OCF3 ;
Ra is hydrogen, Ci-C6 alkyl, Ci-Cs alkanoyl, phenyl Ci-Cs
alkyl and phenyl Ci-C6 alkanoyl; and
Rg is aminoalkyl, mono Ci-Cs alkylamino Ci-Cg alkyl, di Ci-
C6 alkylamino Ci-C6 alkyl, Ci-C6 alkyl, Cx-Cg alkanoyl,
phenyl Ci-C4 alkyl, indazolyl, and phenyl Ci-C4
alkanoyl.
Embodiment 10. Compounds according to embodiment 4,
wherein
R5 is phenyl, phenyl (Ci-C6) alkyl, which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently alkyl, halogen, alkoxy, bencylcxy,
thioalkoxy, -CO2 (Ci-C5 alkyl), C02R, CN, amidinooxime,
NR8R9, -NRSR7; R6R7N-(C1-CS alkyl)-, R0-R7NC (0) - (Ci-C4 alkyl)-
R0-R7NC(0) - (Cs-Ce alkyl) -, -C(0)NR6R7/ amidino, CF3, or OCF3;
wherein
R6 and R7 are independently at each occurrence H, Ci-C4
alkyl, C1-C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl, Ci-C4
alkoxy, Ci-C4 alkoxy alkyl, Ci-C4 alkanoyl,
phenyl •C1-C4 alkyl, phenyl C1-C4 alkoxy, or phenyl Ci-
C4 alkanoyl, wherein . each is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, OH, SH, C3-C6 cycloalkyl, Cx-
C4 alkoxy, Ci-C4 alkyl, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 or 2 groups
that are independently Ci-C4 alkyl, hydroxy, hydroxy
Ca.-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen;
R8 is hydrogen, Ci-C6 alkyl, Ci-C6 alkanoyl, phenyl Ci-C6
alkyl and phenyl Ci-C6 alkanoyl; and
R9 is aminoalkyl, mono Ci-Cs alkylamino Ci-Cg alkyl, di C
Cs alkylamino Ci-C6 alkyl, C].-Cg alkyl,. Ci-Cfi
alkanoyl, phenyl C!-C4 alkyl, indazolyl, and phenyl
Ci-C4 alkanoyl.
Embodiment 11. Compounds according to embodiment 10,
wherein
R5 is phenyl, benzyl or phenethyl, wherein each is optionally
substituted with 1, 2, 3, 4, or 5 groups that are
independently Ci-Cs alkyl, -NR0-R7, -C(0)NR5R7, - (d-C4
alkyi}-C(0)NRc-R7, -NR3R9, halogen, d-C-: alkoxy, CO:R, - (d-
C4 alkyl)-C02R, CN-CD- thioalkoxy, amidinocxime, Ci-C5
alkoxycarbonyl, - (Ci-C4 alkyl)-d-Cs alkoxycarbonyi, Ci-Cnhydroxyalkyl,
Ci-Ca- dihydroxyalkyl, - (d-C4 alkyl)-CN, CN,
phenyl d-C=- alkcxy, OH, Ci-C4 haioalkyl, CL-C4 haloalkoxy,
RSR7N-(d-Cs alkyl)-, - (d-C4 alkyl)-NR15C (O) R18,
amidinooxime, -S02(C1-CD- alkyl), -0-CH2-0-, -0-CH2CH2-0-,
phenyl d-C4 alkoxy, or phenyl; wherein
Rs and R7 are independently at each occurrence H, d-C4
alkyl, d~C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl, d-C4
alkanoyl, or d-C4 alkoxy, each of which is
optionally substituted with 1, 2, or 3 groups that
are independently halogen, OH, SH, C3-CS cycloalkyl,
d-C4 alkoxy, d-C4 alkyl, OH, CF3, or OCF3.
Embodiment 12. Compounds according to embodiment 11,
wherein
R5 is phenyl, benzyl or phenethyl, each of which is
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups
that are independently CN, halogen, d-C4 alkoxy, CF3,
OCF3, d-C4 alkyl, -NR8R9, -NR0-R7, RSR7N- (d-Cs alkyl)-, or
-C(0)NRSR7, wherein
RS and R7 are independently at each occurrence H, d-C4
alkyl, Ci-C4 hydroxyalkyl, d~C4 dihydroxyalkyl, d-C4
alkanoyl, or Cj.-C4 alkoxy, each of which is
optionally substituted with 1, 2, or 3 groups that
are independently halogen, OH, SH, C3-CS cycloalkyl,
d-C4 alkoxy, d-C4 alkyl, OH, CF3, or OCF3.
Embodiment 13. Compounds according to embodiment 4,
wherein
the R5 group is of the formula:
Zi and Z2 are independently H, halogen, d-C4 alkyl, or CO?R;
and
Z is -C(0)NRSR7, - (d-C4)alkyl-C(0)NR6R7, - (d-C4 alkyl)-
NR15C(0)R18, -NRSR7, RSR7N-(d-Cs alkyl)-, -NR8R9, d-C6
hydroxyalkyl, Ci-C6 dihydroxyalkyl, d~Cs alkyl, C02R, or
halogen; wherein
Rs and R7 at each occurrence are independently H, OH, d-Cs
alkyl, amino d-C4 alkyl, NH(d-C6 alkyl) alkyl, N(d~
Cs alkyl) (Ci-Cs alkyl) d-Cfi alkyl, d-C6 "hydroxyalkyl,
Ci-Cg dihydroxyalkyl, d~Cs alkoxy d~d; alkyl, or -
S02(d-Cs alkyl) each of which is optionally
substituted with 1, 2, or 3 groups that are
independently halogen, OH, SH, C3-CS cycloalkyl, d-C4
alkoxy, d-C4 alkyl, OH, CF3, or OCF3 ;
or
R6, R and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl, thiomorpholinyl, ring optionally
substituted with 1 or 2 groups that are
independently alkyl, hydroxy, hydroxy d-C4 alkyl,
d-C4 dihydroxyalkyl, or halogen; and
R18 is Ci-Cs alkyl optionally substituted with -0- (C2-CS
alkanoyl, Ci-C6 hydroxyalkyl, d-C4 dihydroxyalkyl,
Ci-Cg alkoxy, d-C6 alkoxy d-C6 alkyl; amino Ci-C6
alkyl, mono or dialkylamino C^-Ce alkyl.
Embodiment 14. Compounds according to embodiment 4,
wherein
is pyrazclyl (d-Cs alkyl), imidazolyl (d-d alkyl),
thier.yl (d-d; alkyl), furar.yl (d-Cg alkyl), piperidinyl (d.-
Cs) alkyl, pyrrolidinyl (Cx-Cg) alkyl, imidazclidinyi (d-
Cg) aikyl, piperazinyl (C:-C5) alkyl, pyridyl (Ci-Cg) aikyl,
pyrimidyl (Ci-C5) alkyl, pyridazyl (Ci-Cg) alkyl, pyrazinyi
C5) alkyl, iscquinolinyl (Ci-Cg) alkyl,
cetrahydroisoquinolinyi (d-Cg) alkyl, indolyl (d-Cg) alkyl,
IH-indazolyl (Ci-Cg) alkyl, dihydroindolyl (d-Cg alkyl),
dihydroindolon-2-yl (Ci-Cg alkyl), indolinyl (Ci-Cg alkyl),
dihydroisoindolyl(Cx-Cg alkyl), dihydrobenzimdazolyl(Cx-C6
alkyl), or dihydrobenzoimidazolonyl(Ci-C6 aikyl), wherein
each of the above is unsubstituted or substituted with I,
2, 3, 4, or 5 groups that are independently (d~
C6) alkyl, halogen, (d-Cs) alkoxy, (d-Cs) hydroxyalkyl,
d-C6 dihydroxyalkyl, phenyl (Ci-C6) alkoxy, (d-
Ce) thioalkoxy, (Ci-Cg) alkoxycarbonyl, phenyl (d-
Cs) alkoxycarbonyl, OH, C02R, CN, amidinooxime, -NR8Rg,
-NR6R7, RSR7N- (Ci-Cg alkyl)-, -C(0)NR6R7, - (d-C4
alkyl)-C(0)NRgR7i amidino, piperazinyl, morpholinyl, -
S02 (Ci-Cg) alkyl, -S02NH2, -SO?NH (Ci-Cg) alkyl,
S02N(Ci-Cs) alkyl (d-C6) alkyl, (d-C4) haloalkyl, - (Ci-
C4 alkyl)-NR15C(0)NRlsRi7, - (C1-C4 alkyl)-NR15C (0) R18,
-0-CH2-0, -0-CH2CH2-0-, or (Ci-C4) haloalkoxy; wherein
R6 and R7 are independently at each occurrence H,
(d-Cs) alkyl, (Ci-Cg) alkoxy, (d-C6) alkoxy (Ci-
Cg) alkyl, (Cx-Cg) alkoxycarbonyl, (Ci-
C6) hydroxyalkyl, d-Cfi dihydroxyalkyl, - (Ci-
C4) alkyl-C02- (C1-C6) alkyl, (Cx-Cg) alkanoyl,
phenyl (Cx-Cg) alkyl, phenyl (d-Cs) alkoxy, or
phenyl (Cx-Cg) alkanoyl, wherein each of the above
is unsubstituted or substituted with I, 2, or 3
groups that are independently, halogen, (d-
C4) alkoxy, OH, SH, C3-C6 cycloalkyl, NH2, NH(d-
C6 alkyl) , N(C!-CS alkyl)(C1-C6 alkyl), (d-
C4)alkyl, CF3 or OCF3; or
Rs, R7, and the nitrogen to which they are attached
form a morpholinyl, thiomorpholir.yl,
piperidinyl, pyrrolidinyl, or piperazinyl ring
which is optionally substituted with 1 or 2
groups that are independently Ci-C4 alkyl,
hydroxy, hydroxy Ci-C4 alkyl, d-C4
dihydroxyalkyl, or halogen; and
RIB is GI-CS alkyl optionally substituted with -0- (C2-
C6 alkanoyl, Ci-Cs hydroxyalkyl, d-C6
dihydroxyalkyl, d-Cg alkoxy, d-C6 alkoxy Ci-C6
alkyl; amino Ci-Cg alkyl( mono or dialkylamino
Ci-Cfi alkyl.
In this embodiment, it is preferred that R6 and R7 are not
simultaneously OH; and
R6 and R7 are not simultaneously -SO2 (d-Cg alkyl) .
Embodiment 15. Compounds according to embodiment 14,
wherein
R5 is pyrazolyl (d-Cg alkyl), imidazolyl (Ci-C6 alkyl),
benzimidazolyl (d-Cs alkyl), thienyl (d-Cs alkyl),
pyrimidyl (Ci-Cs) alkyl, indolyl (Ci-Cs alkyl),
dihydroindolyl(Ci-Cs alkyl), dihydroisoindolyl(Ci-Cs
alkyl), dihydroindolon-2-yl(Ci-Cs alkyl), pyridinyl(Ci-Cs
alkyl), piperazinyl (Ci-C6 alkyl), or pyrazinyl (Ci-C6 alkyl)
each of which is optionally substituted with I, 2, or 3
groups that are independently Ci-C4 alkyl, d~C4
hydroxyalkyl, Ci-C4 dihydroxyalkyl, halogen, -C(O)NR6R7,
- (C:.-C4 alkyl)-C(0)NR6R7, Ci-Cs alkoxycarbonyl, -NR6R7, R6R7N-
(Ci-Cs alkyl)-, haloalkyl, Ci-C6 alkanoyl,
Rs and R7 at each occurrence are independently H, Ci~Cs
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl , halogen,
C3-C0- cycloalkyl, OH, SH, or C-.-C, alkcxy;
RO , R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl , piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxyalkyl , or halogen.
Embodiment 16. Compounds according to embodiment 15,
wherein
R5 is of the formula:
Z5 is Ci-C4 alkyl, C1-C4 hydroxyalkyl , Ci-C4 dihydroxyalkyl,
halogen, -C(0)NR0-R7 l - (C!-C4 alkyl) -C (0) NRb-R7, Ci-C6
alkoxycarbonyl, R6R7N- (Ci-C6 alkyl)-, -NRSR7, CF3 , or Ci-Cs
alkanoyl , wherein
R6 and R7 at each occurrence are independently H, Ci-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or d-C4 alkoxy;
or
R6, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy C!-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen.
Embodiment 17. Compounds according to embodiment 15,
wherein
R5 is of the formula:
wherein
Z5 is Ci-C4 alkyl, Ci-C4 hyciroxyalkyl, Ci-C4 dihydroxyalkyl,
halogen, -C(0)NR6R7 , - (Ci-C4 alkyl)-C (0) NRSR7, Ci-C6
alkoxycarbonyl, R6R7N-(C^-Cg alkyl)-, -NR6R7, CF3, or Ci-C6
alkanoyl, wherein
R6 and R7 at each occurrence are independently H, C^-Cg
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci~C4 alkoxy;
or
RSI R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen.
Embodiment 18. Compounds according to either embodiment
16 or 17, wherein
Z5 is Ci-C4 alkyl, d-C4 hydroxyalkyl, Ci-C4 dihydroxyalkyl,
halogen, Ci-C6 alkoxycarbonyl, CF3/ or Ci-Cfi alkanoyl.
Embodiment 19. Compounds according to either embodiment
16 or 17, wherein
Z5 is d-C4 alkyl, -C(0)NR6R7, - (Ci-C4 alkyl)-C (0) NR6R7, R6R7N- (Ci-
C6 alkyl)-, or -NR6R7, CF3, or Ci-C4 alkanoyl, wherein
RS and R7 at each occurrence are independently H, Ca-C6
alkyl optionally substituted with 1, 2, or 3 groups
-hat are independently Ci-C4 alkoxycarbonyl, halogen,
alkoxy;
or
R6, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrciidinyl , piperazinyi, or a
morpholinyl ring cctionally substituted with I or 2
groups that; are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, C].-C4 dihydroxyalkyl, or halogen.
Embodiment 20. Compounds according to embodiment 19,
wherein
Z5 is -C(0)MRSR7, - (Ci-C4 alkyl) -C(0)NRSR7, RSR7N- (Ci-Cs alkyl)-,
or -NRgR7, wherein
R6 and R7 at each occurrence are independently H, Ci-Cs
alkyl optionally substituted with I, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl , halogen,
cyclopropyl, OH, SH, or C!-C4 alkoxy.
Embodiment 21. Compounds according to embodiment 15,
wherein
Z10
R5 is of the formula: 20, wherein
Zio is H or methyl; and
Z20 is hydroxy (Ci-C4) alkyl, Ci-C4 dihydroxyalkyl, OH,
halogen, haloalkyl, (CX-C4) alkyl , OCF3 , -NR6R7, R6R7N- (CI-
alkyl)-, -(C!-C4 alkyl) -C(0)NR6R7, or -C(O)NRSR7,
wherein
R6 and R7 at each occurrence are independently H, Ci-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 22. Compounds according to embodiment 15,
wherein
R= is of the formula: wherein
ZIQ is H or methyl; and
Z20 is hydroxy (Ci-C4) alkyl, Ci-C4 dihydroxyalkyl , OH,
halogen, CF3 , (d-C4) alkyl , OCF3 , -NRSR7, R6R7N- (Ci-Cs
alkyl)-, - (C!-C4 alkyl) -C(O)NR6R7, or -C(O)NRSR7/ wherein
Rs and R7 at each occurrence are independently H, Ci-Cg
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl , halogen,
C3-C6 cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 23. Compounds according to embodiment 15,
wherein
is of the formula: N °, wherein
is H or methyl; and
Z20 is hydroxy (Ci-C4) alkyl, Ci-C4 dihydroxyalkyl, OH,
halogen, haloalkyl, (C:.-C4) alkyl, OCF3, -NR6R7, R6R-,N-(Ci-
alkyl)-, - (Ci-C4 alkyl)-C(0)NR6R7, or -C(0)NR6R7,
wherein
R6 and R7 at each occurrence are independently H, Ci-Cg
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci~C4 alkoxy.
Embodiment 24. Compounds according to embodiment 15,
Rs is of the formula: s , wherein
Zio is H or methyl; and
Z~0 is hydroxy (C:-C4) alkyl, C!-C4 dihydroxyalkyl, OH,
halogen, CF3, (Ci-C4) alkyl, OCF3, -NRSR-, RsRiN-(CL-C5
alkyl)-, -(Ci-C4 alkyl)-C(0)NRSR7, or -C(0)NR6R7, wherein
R6 and R7 at each occurrence are independently H, Ci-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or C^-C^ alkoxy.
Embodiment 25. Compounds according to embodiment 15,
wherein
R5 is of the formula:
Z10 is H or methyl; and
Z20 is hydroxy (Ci-C4) alkyl, d-C, dihydroxyalkyl, OH,
halogen, haloalkyl, (C1-C4) alkyl, OCF3, -NR6R7, R6R7N- (Ci-C6
alkyl)-, - (Ci-C4 alkyl)-C (0) NR6R7, or -C(0)NR6R7/
wherein
R6 and R7 at each occurrence are independently H, Cx-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-Cs cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 26. Compounds according to embodiment 15,
wherein
R5 is of the formula:
ZIQ is K or methyl; and
Z20 is hydroxy (C-C4) alkyl, Ci-C4 dihydroxyalkyl, OK,
halogen, CF3, (C:-C4) alkyl, OCF3, -NRfiR7, RgR7N-(d-Cs
alkyl)-, - (Ci-C4 alkyl)-C(0)NR0-R7, or -C(0)NR5R7, wherein
R6 and R7 at each occurrence are independently H, Ci~Cs
alkyl optionally substituted with 1, 2, or 3 groups
that are independently C3.-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 27. Compounds according to embodiment 15,
wherein
"7 R5 is of the formula: 20, wherein
ZIQ is H or methyl; and
Z20 is hydroxy(Ci-C4) alkyl, Ci-C4 dihydroxyalkyl, OH,
halogen, haloalkyl, (Ci-C4) alkyl , OCF3 , -NRSR7, RSR7N- (d-C6
alkyl)-, - (C!-C4 alkyl) -C(0)NRSR7, or -C(0)NR6R7,
wherein
Rs and R7 at each occurrence are independently H, Ci-Cs
alkyl optionally substituted with 1, 2, or 3 groups
that are independently C!-C4 alkoxycarbonyl, halogen,
C3-Cfi cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 28. Compounds according to embodiment 15,
wherein
R5 is of the formula:
Z10 is H or methyl; and
N
Z20 wherein
Z20 is hydroxy (d-C4 ) alkyl, Ci-C4 dihydroxyalkyl, OH,
halogen, CF3, (d-C4 ) alkyi, OCF3, -NR0-R7, R5R-N-(C:-C6
alkyl)-, - (d-C4 alkyl)-C(G)NRSR7 , or -C(0)NR5R7 , wherein
RD- and R7 at each occurrence are independently H, d-C5 alkyl
optionally substituted with 1, 2, or 3 groups that are
independently Ci-C4 alkoxycarbonyl, halogen, C3-C5 cycloalkyl,
OH, SH, or Ci-C4 alkoxy.
Embodiment 29. Compounds according to embodiment 4,
wherein
R5 is phenyl, which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently Ci-C4 alkyl, -C(0)NR6R7 ,
-(d-C4 alkyl) -C(0)NRSR7 , -NR6R7, NR6R1(Cl-C6 alkyl), d-Cs
hydroxyalkyl, dihydroxyalkyl, halogen, Ci-C4 alkoxy, CO2R,
OH, Ci-Cs alkoxycarbonyl, CF3, - (d-C4 alkyl)-
NR15C(0)NR16R17, -(Ci-C4 alkyl)-NRi5C (0) R18; wherein
RIS is H or Ci-Cg alkyl;
Ris and R17 are independently H or Ci-C6 alkyl; or
and the nitrogen to which they are attached form
a morpholinyl ring; and
RIB is Ci-Cs alkyl optionally substituted with -0- (C2-CS
alkanoyl, C^-C^ hydroxyalkyl, Ci-C6 dihydroxyalkyl,
Ci-Cg alkoxy, Ci-C6 alkoxy Ci-Cs alkyl; amino Ci-Cs
alkyl, mono or dialkylamino Ci-C6 alkyl.
Embodiment 30. Compounds according to embodiment 29,
wherein
R5 is of the formula:
(Figure Removed) Zi is K, halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4
hydroxyalkyl, Ci-C4 dihydroxyalkyl, or C^-C4 alkoxy; and
Z2 is Ci-C4 alkyl, -C(0)NRSR7 , - (Ci-C4 alkyl)-C (0) NR5R7, -NR5R-,
NR6R7 (CL-CC- alkyl), Ci-Cs hydroxyalkyl, Ci-C5
dihydroxyalkyl, halogen, Ci.-C4 alkoxy, CO-R, OH, Ci-C5
alkoxycarbonyl, or Ci-C4 haloalkyl;
Z3 is H, Ci-C4 alkyl, -C(0)NRSR7 , - (d-C4 alkyl) -C (0) NRSR7, -NR6R7,
NRSR7 (Ci-Cs alkyl), CX-C6 hydroxyalkyl, Ci-Cf i
dihydroxyalkyl, halogen, Ci-C4 alkoxy, CO2R, OH, Ci-C5
alkoxycarbonyl, or Ci-C4 haloalkyl;
and wherein
R6 and R7 at each occurrence are independently H, OH, Ci-C6
alkyl, amino Ci-C4 alkyl, NH(C1-C6 alkyl) alkyl, N(Ci-Cs
alkyl) (Ci-Cg alkyl) d-C6 alkyl, Ci-C6 hydroxyalkyl, d-C6
dihydroxyalkyl, Ci-Cs alkoxy Ci-Cs alkyl, -SO-2 (Ci-Cs alkyl),
-S02NH2, -S02NH(Ci-C6 alkyl), -S02N(Ca-C6 alkyl) (Ci-C6
alkyl), or Ci-Cs alkanoyl, each of which is optionally
substituted with 1, 2, or 3 groups that are independently
halogen, OH, SH, C3-C6 cycloalkyl, Ci-C4 alkoxy, Ci-C4
alkyl, OH, CF3, or OCF3.
In this embodiment, it is preferred that at least one of
Zi, Z2, and Z3 is not hydrogen.
Embodiment 31. Compounds according to embodiment 30,
wherein
R5 is of the formula:
wherein
Zi is H, halogen, Cj.-C4 alkyl, Ci-C4 haloalkyl, C!
hydroxyalkyl, Ci-C4 dihydroxyalkyl, or Ci-C4 alkoxy; and
Z2 is d-C4 alkyl, -C(0)NRSR7, - (Ci-C4 alkyl} -C (0) NR5R~, -FRSR7,
NRsR7(d-Cs alkyl), d-C5 hydrcxyalkyl, d-Cs
dihydrcxyalkyl, halogen, d-d alkoxy, C02R, OK, C:-C5
alkcxycarbcnyl, or Ci-C4 haloalkyl;
Z3 is H, C-C, alkyl, -C(0)NR5R7, - (d-C4 alkyl) -C (0) NR0-R~, -NR,;R-,
NR0-R7 (Ci-Cs alkyl), d-Cs hydroxyalkyl, d~d
dihydroxyalkyl, halogen, d-C4 alkoxy, C02R, OK, d~d
alkoxycarbonyl, or Ci-C4 haloalkyl, and wherein
R6 and R7 at each occurrence are independently H, OH, d~Cs
alkyl, amino Ci-C* alkyl, NH(d-Cs alkyl) alkyl, N(Ci-
C6 alkyl) (Ci-Cg alkyl) d-Cg alkyl, Ci-C6 hydroxyalkyl,
Ci-Cg dihydroxyalkyl, Ci-Cs alkoxy d-C6 alkyl,
S0:(d-Cs alkyl), -S02NH2, -S02NH(C!-Cs alkyl),
-S02N(d-C6 alkyl) (d-C5 alkyl), or d-C6' alkanoyl,
each of which is optionally substituted with 1, 2,
or 3 groups that are independently halogen, OH, SH,
C3-C6 cycloalkyl, d-C4 alkoxy, d-C4 alkyl, OH, CF3,
or OCF3.
In this embodiment, it is preferred that at least one of
Zi, Z2, and Z3 is not hydrogen.
Embodiment 32. Compounds according to embodiment 30,
wherein
R5 is of the formula:
wherein
Zi is H, halogen, d-C4 alkyl, Ci-C4 haloalkyl, Cx-C4
hydroxyalkyl, CX-C4 dihydroxyalkyl, or d-C4 alkoxy; and
Z2 is d-C4 alkyl, -C(0)NR6R7 , - (CL-C4 alkyl)-C (0) NRSR7, -NR6R7,
NRsR7(Ci-Cs alkyl), Ci-Cs hydroxyalkyl, d-C6
dihydroxyalkyl, halogen, d~C4 alkoxy, C02R, OK, d-Cs
alkoxycarbonyl, or Ci-C4 haloalkyl;
Z3 is H, Ci-C4 alkyl, -C(0)NR0-R7; - (d-C4 alkyl) -C (0) NRSR7, -NR6R7,
NR6R7(d-C6 alkyl), Ci-C0- hydroxyalkyl, d-Cfi
dihydroxyalkyl, halogen, Ci-C4 alkoxy, C02R, OH, CL-C6
alkoxycarbonyl, or C--C4 haloalkyl, and wherein
Rs and R7 at each occurrence are independently H, OH, Ci-C6
alkyl, amino d-C4 alkyl, NH(Ci-C6 alkyl) alkyl, N(d-
C6 alkyl) (GI-CS alkyl) d-Cs alkyl, d-CB- hydroxyalkyl,
d-C6 dihydroxyalkyl, d-C« alkoxy d-C6 alkyl,
S02(d-Cs alkyl), -S02NH2, -S02NH(C1-CS alkyl),
-S02N(d-C6 alkyl) (Ci-C6 alkyl), or Ci-Cfi alkanoyl,
each of which is optionally substituted with 1, 2,
or 3 groups that are independently halogen, OH, SH,
C3-CS cycloalkyl, d-C4 alkoxy, d~C4 alkyl, OH, CF3,
or OCF3 .
In this embodiment, it is preferred that at least one of
Zi, Z2, and Z3 is not hydrogen.
Embodiment 33. Compounds according to embodiment 29,
wherein
R5 is either
wherein
Zi is H, halogen, d~C4 alkyl, d-C4 haloalkyl, d~C4
hydroxyalkyl, d-C4 dihydroxyalkyl, or d-C4 alkoxy; and
Z2 is Ci-C4 alkyl, -C(0)NR6R7, - (d~C4 alkyl) -C (0) NR6R7, -NR6R7,
NRsR7(d-Cs alkyl), d-C6 hydroxyalkyl, d-Cs
dihydroxyalkyl, halogen, d~C4 alkoxy, C02R, Ci-C6
alkoxycarbonyl, - (Ci~C4 alkyl) -NRiSC (0) NRlo-R17/ or - (Cl-C4
alkyl) -NRiSC(0)Ri S ;
Z3 13 K, C-C.4 alkyl, -C(0)NRC-R7 , - (C:-C4 alkyl)-C (0) NR5R-, -NR^R-,
NR£R-(Ci-Cs alkyl), Ci-C5 hydroxyalkyl, CL-C3-
dihydrcxy alkyl, halogen, CS- alkoxy, CO:R, Ci-Cs
alkoxycarbonyl, - (Ci-C4 alkyl)-NR15c (0) NRisRi?/ °- - (Ci-C4
alkyl) -NRi SC(0)R1B;
RS , R7/ and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen;
RIS is H or Ci-Cg alkyl;
RIS and R17 are independently H or Ci-Cg alkyl; or
RIS/ Ri7, and the nitrogen to which they are attached form
a morpholinyl ring; and
RIB is Ci-Cs alkyl optionally substituted with -0-(C2-CS
alkanoyl, Ci-C6 hydroxyalkyl, Ca-C6 dihydroxyalkyl,
Ci-Cg alkoxy, Ci-Cfi alkoxy Ci-C6 alkyl; amino Ci~C6
alkyl, mono or dialkylamino Ci-Cs alkyl.
In this embodiment, it is preferred that at least one of
Zi, Z2, and Z3 is not hydrogen.
Embodiment 34. Compounds according to embodiment 33,
wherein
R5 is of the formula:
is H, halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, CX-C4
hydroxyalkyl, Ci-C4 dihydroxyalkyl, or Ci-C4 alkoxy; and
Z2 is C:-C4 alkyl, -C(0)NR5R7 , - (Ci-C4 alky!) -C (0) NR5R-, -NR5R7l
NRsR^Ci-Cs alkyl), C:-C0- hydrcxyalkyl, Ci-C6
dihydroxyalkyl, halogen, Ci-C4 alkoxy, C02R, G-.-CS
alkoxycarbonyl, - (CZ-C4 alkyl)-NR15C (0) NR16R17, or - (d-C4
alkyl) -NR15C(0)Ri a ;
Z2 is H, Ci-C4 alkyl, -C(O)NRSR7 , - (Ci-C4 alkyl) -C (0) NR6R7, -NR0-R7,
NRsR7(Ci-C6 alkyl), Ci-C6 hydroxyalkyl, C^-C6
dihydroxyalkyl, halogen, Ci-C4 alkoxy, C02R, C^Cg
alkoxycarbonyl, - (Ci-C4 alkyl)-NR15C (0) NRiSR17, or - (Ci-C4
alkyl) -NR15C(0)R18;
R6, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, •hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen;
R15 is H or Ci-Cs alkyl;
RIS and Ri7 are independently H or Ci-Cs alkyl; or
RIS/ Ri7/ and the nitrogen to which they are attached form
a morpholinyl ring; and
R18 is Ci-Cs alkyl optionally substituted with -O- (C2-C6
alkanoyl, Ci-C6 hydroxyalkyl, Ci-C6 dihydroxyalkyl,
Ci-Cs alkoxy, Ci-C6 alkoxy Ci-C6 alkyl; amino Ci-Cs
alkyl, mono or dialkylamino Ci-C6 alkyl.
In this embodiment, it is preferred that at least one of
Zi, Z2, and Z3 is not hydrogen.
Embodiment 35. Compounds according to embodiment 33,
wherein
R5 is of the formula:
wherein
Zi is K, halogen, d~C4 alkyl d-d haloalkyl, d-C4
hydroxyalkyl, d-C4 dihydrcxyalkyl, cr d-d aikoxy; and
Z2 is Ci-C4 alkyl, - C (0) NR0-R7, - (Ci-C4 alkyl) -C (0) NRC-R7, -NR5R-,
NRsR7(d-d alkyl), d-d- hydroxyalkyl, d-d
dihydroxyalkyl, halogen, d-d alkoxy, CG:R, d-d
alkoxycarbonyl, -(d-d alkyl) -NRi5C (0) NRlb-R17, or - (d-C4
alkyl) -NRlsC(0)Ria;
Z3 is H, d-C4 alkyl, -C(0)NR6R7, - (d~C4 alkyl) -C (0) NR6R7, -NRSR7/
NR6R7(Ci-Cs alkyl), CX-CS hydroxyalkyl, d-C6
dihydroxyalkyl, halogen, d~d alkoxy, C02R, d-d
alkoxycarbonyl, - (d-C4 alkyl)-NRi5C (0) NR1SR17, or - (d-C4
alkyl) -NR15C(0)R18;
R6, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring, each of which is optionally
substituted with 1 or 2 groups that are
independently alkyl, hydroxy, hydroxy d-C4 alkyl,
d-d dihydroxyalkyl, or halogen;
R15 is H or d-C6 alkyl;
RIS and R17 are independently H or Ci-C6 alkyl; or
RIS/ RIV, and the nitrogen to which they are attached form
a morpholinyl ring; and
RIB is d-Cg alkyl optionally substituted with -O-(C2-CS
alkanoyl, Ci-C6 hydroxyalkyl, d-C6 dihydroxyalkyl,
Ci-Cg alkoxy, Cx-Cg alkoxy Ci-Cg alkyl; amino Ci-C6
alkyl, mono or dialkylamino Ci-Cg alkyl.
In this embodiment, it is preferred that at least one of
Zi, Z2, and Z3 is not hydrogen.
or a pharmaceutically acceptable salt thereof, wherein
L and M are indepedently selected from -0-, -CH2-, -S-,-NR-,
N ( R ) - N ( R ) - , C ( = 0 ) - , -S02-;
Xtr Y Xd XV y Xd
R5 is Xc or Xc , wherein
Xi, X2, Xa, Xb, Xc, Xd, and Xe at are independently selected from
-C(0)NRSR7, -(Ci-C4 alkyl)-C(0)NRSR7, -NR6R7, hydroxy (d-
C4)alkyl, Ci-C4 dihydroxyalkyl, H, OH, halogen, haloalkyl,
alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C3-C7
cycloalkyl, ReR7N-(d-Cs alkyl)-, -C02- (d~C6) alkyl,
-N(R)C(0)NR6R7, -N(R)C(0) - (d-C6) alkoxy, C02R-(d-C6 alkyl )-
, or -S02NR6R7; wherein the heteroaryl and
heterocycloalkyl groups are optionally substituted with -
NR6R7, -C(0)NR6R7, R6R7N- (Ci-C6 alkyl)-, d-C6 alkyl, d-C6
alkoxy, or halogen; or
R5 is heteroaryl or heteroarylalkyl, wherein the heteroaryl and
heteroaryl groups are optionally substituted with 1,2, 3,
or 4 groups that are independently -C(0)NR6R7, - (d-C4
alkyl)-C(0)NR6R7, -NR6R7, hydroxy (d-C4) alkyl, d-C4
dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl,
haloalkoxy, RSR7N-(d-C6 alkyl)-, -C02-(d-C6) alkyl, '
-N(R)C(0)NR6R7, or -N (R) C (O) - (d-Cs) alkoxy; wherein
R6 and R7 are independently at each occurrence H, d-Cg
alkyl, d-Cs alkoxy, d-Cs alkoxy d-C6 alkyl, Ci-Cs
alkoxycarbonyl, OH, Ci-C6 hydroxyalkyl, d~C4
dihydroxyalkyl, Ci-Cs th.iohydroxya.lkyi, - (C-±-C
C02-alkyl, pyridyl Ci-C alkyl, CN-Cg aikanoyl,
benzyl, phenyl Ci-Cg alkcxy, or phenyl C-_-Cs aikanoyl,
wherein each of the above is unsubscituted cr
substituted with 1, 2, or 3 groups chat are
independently, halogen, C3-C5 cycloalkyl, Ci-Cg
alkoxy, piperidinyl Ci-C5 alkyl, morpholinyl CT.-CS
alkyl, piperazinyl Ci-C6 alkyl, OH, SH, NE2,
NH(alkyl), N(alkyl)(alkyl), -O-Ci-C4 aikanoyl, Ci-C4
alkyl, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci~C4 alkyl, Ci-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen;
R at each occurrence is independently H or Ci-Cs alkyl;
and
Y, YI, Y2, Y3; and Y4 are independently selected from H,
halogen, alkyl, carboxaldehyde, hydroxyalkyl,
dihydroxyalkyl, alkenyl, alkynyl, CN, aikanoyl, alkoxy,
alkoxyalkyl, haloalkyl, and carboxyl.
Embodiment 37. Compounds according to embodiment 36 of
the formula
Y4
or a pharmaceutically acceptable salt thereof.
Embodiment 38. Compounds according to embodiment 3'
wherein
Embodiment 39. Compounds according to embodiment 31,
wherein
Y2, Y4, and Y are independently halogen; and
Y! and Y3 are both hydrogen.
Embodiment 40. Compounds according to embodiment 39,
wherein
R5 is Xc
Xi and X2 are independently H, methyl, NR6R7, - (C1-C4 alkyl)-
C(0)NR6R7/ RSR7N-(d-C6 alkyl)-, -C(O)NR6R7/ d-Cs
hydroxyalkyl, Ci-Cs dihydroxyalkyl, or -(d-C4 alkyl)-
morpholinyl; and
Xa and Xe are independently halogen, NH2/ NH(C!-CS alkyl), N(Ci-
Cs alkyl) (Ci-Cs alkyl), methyl, or hydrogen.
In this embodiment, it is preferred that one of Xa and Xe
is not hydrogen.
Embodiment 41. Compounds according to embodiment 40,.
wherein
one of Xb and Xc is hydrogen and the other is -NR6R7, RSR7N- (Ci-
C6 alkyl)-, -C(O)NRSR7, -S02NR6R7, or halogen; where
R5 and R7 are independently at each occurrence H, Ci-C6
alkyl, Ci-Cs alkoxy, C:-C£ alkcxy Ci-C6 alkyl, C1-C6
alkoxycarbcnyl, OH, C:-Cr- hydroxyalkyl, C±-C6
dihydroxyalkyl, - (C-C.;) alkyl-C02-alkyi , pyridyl CX-CCalkyl,
C-_-C5 alkanoyl, benzyl, phenyl Ci-C5 alkcxy, or
ohenyl Ci-Cg alkanoyl, wherein each of the above is
unsubscituted or substituted with 1, 2, or 3 groups
that are independently, halogen, C3-CS cycloalkyl,
Ci-Cg alkoxy, piperidinyl Ci-Cs alkyl, morpholinyl Ci-
Cg alkyl, piperazinyl Ci-Cs alkyl, OK, SH, MK2/
NH(alkyl), N(alkyl)(alkyl), -0-Ci-C4 alkanoyl, Ci-C4
alkyl, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or" 2 groups that are
independently Ci-C4 alkyl, Ci-C4 alkoxy, hydroxy,
hydroxy C-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen.
Embodiment 42. Compounds according to embodiment 41,
wherein
R6 and R7 are independently at each occurrence H, Ci-C6 alkyl,
CI-GS alkoxy, Ci-Cg alkoxy Ci-Cs alkyl, C^-Cg
alkoxycarbonyl, OH, Ci-Cs hydroxyalkyl, C!-GS
dihydroxyalkyl, - (C1-C4) alkyl -C02- alkyl, pyridyl ^-Cg
alkyl, Ci-Cg alkanoyl, benzyl, phenyl Ci-C6 alkoxy, or
phenyl «Ci-Cs alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3 groups that
are independently, halogen, C3-Ce cycloalkyl, Ci-Cg alkoxy,
piperidinyl Ci-Cg alkyl, morpholinyl Ci-C6 alkyl,
piperazinyl Ci-Cg alkyl, OH, NH2, NH(alkyl),
N(alkyl) (alkyl) , _o-d-C4 alkanoyl, Ci-C4 alkyl, CF3, or
OCF3.
Embodiment 43. Compounds according to embodime.it 42,
wherein
Xa is hydrogen, menhyl, fluorine, or chlorine;
Xc and Xd are both hydrogen;
Xb is -NR5R7, -(Ci-C4 alkyl) -C(0)NR6-R7, R6R7N-(Ci-Cg alkyl)-,
C (0) NR0-R7; wherein
R6 and R7 are independently at each occurrence H, Ci-C5 alkyl,
Ci-Cs hydroxyalkyl, Ca-C4 dihydroxyalkyl, Ci-C6 alkoxy, GIC6
alkoxy Ci-C6 alkyl, or Ci-C6 alkanoyl, wherein each of
the above is optionally substituted with 1, 2, or 3
groups that are independently OH, SH, halogen, or C3-C6
cycloalkyl.
Embodiment 44. Compounds according to embodiment 39,
wherein
Xa is H, fluoro, chloro, or methyl;
Xe is hydrogen, halogen, or methyl; and
Xb is H;
Xd is H or halogen;
Embodiment 45. Compounds according to embodiment 44,
wherein
Xc is -S02NRSR7, or halogen; wherein
RS and R7 are independently at each occurrence H, Ci-C6
alkyl, Ci-Cs alkoxy, C^Cg alkoxy Ci-Cs alkyl, Ci-C6
alkoxycarbonyl, OH, C1-CS hydroxyalkyl, Ci-C6
dihydroxyalkyl, - (Ci-Cj alkyl-C02-alkyl, pyridyl Ci-C6
alkyl, C-_-C5 alkanoyl, benzyl, phenyl Ci-Cg alkcxy, or
phenyl Ci-C0- alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, cr 3 groups
that are independently, halogen, C3-C5 cycloalkyl,
Ci-Cg alkoxy, piperidinyl Ci-Cg alkyl, morpholinyl Ci-
C6 alkyl, pipera-inyi C:-C0- alkyl, OH, SH, NK:,
NH(alkyl), N(alkyl)(alkyl), -0-Ci-C4 alkancyi, Ci-C4
alkyl, CF3, or OCF3; or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, C].-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxya1 ky 1, or halogen;
or
Xc is fluoro, chloro, -NH2, -NH(Ci-Ce alkyl), -N(C1-C6 alkyl) (Ci-
Cg alkyl), -SO2NH2, -S02NH(C1-C6 alkyl), -S02N(C1-CS
alkyl) (Cx-Cg alkyl) , or piperazinyl, wherein the
piperazinyl group is optionally substituted with 1 or 2
groups that are independently Ci-C4 alkyl, C!-C4 alkoxy,
hydroxy, hydroxy Ci-C4 alkyl, Ci-C4 dihydroxya1ky1, or
halogen.
Embodiment 46. Compounds according to embodiment 44,
wherein
Xc is -C(0)NR6R7, -(Ci-Cg alkyl)-C (0) NR6R7, -NR6R7, or R6R7N-(Ci-C6
alkyl)-; wherein
R6 and R7 are independently at each occurrence H, Ci-Cs
alkyl, Ci-Cg alkoxy, Ci-C6 alkoxy Ci-C6 alkyl, Ci-C6
alkoxycarbonyl, OH, Ci-Cs hydroxyalky1, Ci-Cs
dihydroxyalkyl, Ci-Cg d i hydroxy a 1 ky 1, - (Ci-C4) alkyl-
C02-alkyl, pyridyl Ci-Cs alkyl, Ci-C6 alkanoyl,
benzyl, phenyl Ci-Cs alkoxy, or phenyl Ci-C6 alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, -or 3 groups that are
independently, halogen, C3-CS cycloalkyl, d-C0-
alkoxy, piperidinyl Ci-Cs alkyl, morphclinyl Ci-Cs
alkyl, piperaeinyl d-Cs alkyl, OH, -NH2, -NH(alkyl),
-N (alkyl) (alkyl) , -O-d-C4 alkanoyl, d-C4 alkyl, CF5,
or OCF3; or
RS , , and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently d-C4 alkyl, d-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen.
Embodiment 47. Compounds according to embodiment 46,
wherein
R6 is hydrogen; and
R7 is d-C6 alkyl or Ci-C6 alkanoyl, each of which is optionally
substituted with 1, 2, or 3 groups that are independently
NH2, NH(d-C6 alkyl), N(Ci-Cs alkyl) (d-Cg alkyl), OH, SH,
cyclopropyl, or d~C4 alkoxy;
Embodiment 48. Compounds according to embodiment 47,
wherein
Xc is -C(0)NRSR7.
Embodiment 49. Compounds according to embodiment 47,
wherein
Xc is NR6R7, or RSR7N-(d-Cs alkyl)-.
Embodiment 50. Compounds according to embodiment 38,
wherein
Xa is hydrogen;
two of Xb, Xc/ and Xd are hydrogen and the other is -C(0)NR6R-,
-(Ci-Cs alkyl) -C(0)NR6R7; -NR5R7, R,-R-N- (C^Cs alkyl)- or -
C02- (Ci-Cs) alkyl; wherein
Rs and R7 are independently at each occurrence K, C1-C6
alkyl, Ci-Cs alkoxy, C±-C€ alkoxy d-C6 alkyl, d-Cs
alkoxycarbonyl, OH, d-Cs hydroxyalkyl, Ci-d
dihydroxyalkyl, - (Ci-C4) alkyl-C02-alkyl, pyridyl Ci-C6
alkyl, Ci-Cs alkanoyl, benzyl, phenyl Ci-Cs alkoxy, or
phenyl Ci-C6 alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, C3-CS cycloalkyl,
Ci-Cs alkoxy, piperidinyl d-Cs alkyl, morpholinyl Ci-
Cs alkyl, piperazinyl Ci-Cs alkyl, OH, NH2, NH(alkyl),
N (alkyl) (alkyl) , -0-d-C4 alkanoyl, Ci-C4 alkyl, CF3,
or OCF3; or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, piperidinyl, pyrrolidinyl, or
piperazinyl ring which is optionally substituted
with 1 or 2 groups that are independently Ci-C4
alkyl, Ci-C4 alkoxy, hydroxy, hydroxy d-C4 alkyl, d~
C4 dihydroxyalkyl, or halogen; and
Xe is hydrogen, methyl, Ci-C2 alkoxy, or halogen.
Embodiment 51. Compounds according to embodiment 50,
wherein
Xb is -C(0)NR6R7, -(Ci-Cs alkyl)-C (0) NR6R7, -NR6R7, or R6R7N-(Ci-Cs
alkyl)- wherein
Rs is hydrogen or Ci-C4 alkyl;
R7 is OH, Ci-C6 alkyl or Ci-C6 alkanoyl, wherein the alkyl and •
alkanoyl groups substituted with 1, 2, or 3 groups that
are independently NH2, NH(d-Cs alkyl), N(C1-CS alkyl) (Ci-Cs
alkyl) , C3-C6 cycloalkyl, OH, or Ci-C4 alkoxy.
Embodiment 52. Compounds according to embodiment 38,
wherein
Xa is halogen or methyl;
Xb is H, -NR5R7, RsR7N-(Ci-C0- alkyl)-, -C(0)NRSR-, or -CO:-(CLC6)
alkyl;
Xc is -NR6R7, R6R7N-'(d-Cs alkyl)-, -C(0)NR6R7, halogen, -C02-(d-
C6) alkyl, NH2, NH(d-C6 alkyl), N(d-Cs alkyl) (d-Cs alkyl},
-S02NH2, -S02NH(Ci-Cs alkyl), -S02N(d-Cs alkyl) (CL-C6
alkyl), or piperazinyl, wherein the piperazinyl group is
optionally substituted with 1 or 2 groups that are
independently d-C4 alkyl, d-C4 alkoxy, hydroxy, hydroxy
C1-C4 alkyl, Ci-C4 dihydroxyalkyl, or halogen;
Xd is hydrogen;
Xe is H, methyl, NH2, NH(d-C6 alkyl) or N(d-C6 alkyl) (d-CB
alkyl).
Embodiment 53. Compounds according to embodiment 38,
wherein
Xi, X2, Xa, Xb, Xc, Xd, and Xe are independently selected from H,
OH, halogen, CF3, alkyl, OCF3, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,
piperidinyl, piperazinyl, or C3-C7 cycloalkyl, wherein
each of the above is optionally substituted with -NR6R7,
-C(0)NR6R7, -(Ci-Ci alkyl)-C(0)NR6R7, RSR7N-(Ci-C6 alkyl)-,
d-C6 alkyl, CI-GS alkoxy, or halogen.
Embodiment 54. Compounds according to embodiment 37,
wherein
R5 is a heteroaryl or heteroarylalkyl group, where each
heteroaryl is pyrazolyl, imidazolyl,- furanyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,
imidazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-
yl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
dihydroisoquinolinyl, or indolyl, each of which is
optionally substituted with 1, 2, 3, or 4 groups that are
independently -C(0)NRSR7, - (d-C4 alkyl)-C (0) NR,-R7, -NR5R7/
hydroxy (Ci-C4) alkyl, Ci-C4 dihydroxyalkyi, hydrogen,
hydroxy, halogen, haloalkyl, alkyl, haloalkoxy, R5R7N-(Ci-
Cs alkyl)-, -C02- (Ci-C6) alkyl, -N (R) C (O) NRD-R7, or
-N(R) C (0) - (Ci-Cs) alkoxy; wherein
Rs and R7 are independently at each occurrence H, Ci.-C6
alkyl, Ci-Cs alkoxy, d-Cfi alkoxy d-Cs alkyl, d-C6
alkoxycarbonyl, OH, Ci-C6 hydroxyalkyl, d~Cs
dihydroxyalkyi, Ci-Cs thiohydroxyalkyl, - (Ci-C4) alkyl-
C02-alkyl, pyridyl d-C6 alkyl, Ci-C6 alkanoyl,
benzyl, phenyl d~Cs alkoxy, or phenyl Ci-C6 alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, C3-C6 cycloalkyl, • d~Cs
alkoxy, piperidinyl d-C6 alkyl, morpholinyl Ci-Cs
alkyl, piperazinyl d-C6 alkyl, OH, SH, NH2,
NH (alkyl), N (alkyl) (alkyl) , -0-d-C4 alkanoyl, d-C4
alkyl, CF3, or OCF.
Embodiment 55. Compounds according to embodiment 54,
wherein
Y2, Y4, and Y are independently halogen; and
YI and Y3 are both hydrogen.
Embodiment 56. Compounds according to embodiment 55,
wherein
Xi and X2 are independently H, methyl, -NR6R7, R6R7N- (Ci-C6
alkyl)-, -C(0)NR6R7, - (d-C alkyl)-C (O) NR6R7,
hydroxyalkyl, Ci-Cs dihydroxyalkyi, or -(Ci-C4
alkyl)-morpholinyl.
Embodiment 57. Compounds according to embodiment 56,
wherein
R5 is pyridyl C-L-C6 alkyl, pyrimidinyl d-C5 alkyl, or pyrazinyl
Ci-C5 alkyl, each of which is optionally substituted with
1, 2, or 3 groups that are independently hydroxy(Ci-
C4)alkyl, Ci-C4 dihydroxyalkyl, OH, halogen, CF3, (C:-
C4) alkyl, OCF3, -NR6R7, - (d-C4 alkyl)-C (O) NR6R7, R6R7N- (d-
C6 alkyl)-, or -C(0)MR6R7.
Embodiment 58. Compounds according to embodiment 57,
wherein
R5 is of the formula:
(Figure Removed)Z5 is hydroxy (C].-C4) alkyl, d-C4 dihydroxyalkyl, OH, halogen,
CF3, (d-C4) alkyl, OCF3, -NReR7; R6R7N-(d-C6 alkyl)-, - (d-
C4 alkyl)-C(0)NR6R7, or -C(O)NR6R7, wherein
Rs and R7 at each occurrence are independently H, d-Cg
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or d-C4 alkoxy.
Embodiment 59. Compounds according to embodiment 57,
wherein
R5 is of the formula:
wherein
Z5 is hydroxy (d-C4) alkyl, Ci-C4 dihydroxyalkyl, OH, halogen,
CF3/ (d-C4) alkyl, OCF3, -NRSR7/ R6R7N-(d-Cs alkyl)-, - (d-
C4 alkyl)-c(O)NR6R7 / or -C(0)NR6R7, wherein
R6 and R7 at each occurrence are independently K, Ci~C0-
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-C5 cycloalkyl, OH, SH, or d-C4 alkoxy.
Embodiment 60. Compounds according to embodiment 57,
wherein
R5 is of the formula: N ^20; wherein
ZIQ is H or methyl; and
Z20 is - (d-d alkyl)-C(0)NR6R7, hydroxy (d-C4) alky 1, d-d
di hydroxy alkyl, OH, halogen, CF3, (Ci-C4) alkyl, OCF3,
-NRSR7, R6R7N- (Ci-Cs alkyl)-, or -C(O)NR6R7, wherein
Rs and R7 at each occurrence are independently H, d-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or d-C4 alkoxy.
Embodiment 61. Compounds according to embodiment 57,
wherein
R5 is of the formula: N Z20, wherein
ZIQ is H or methyl; and
Z20 is -(d-d alkyl)-C(0)NR6R7/ hydroxy (Ci-C4) alkyl, d-C4
dihydroxyalkyl, OH, halogen, CF3, (Ci-C4) alkyl, OCF3,
-NRSR7/ R6R7N-(Ci-Cs alkyl)-, or -C(0)NR€R7, wherein
RS and R7 at each occurrence are independently H, Ci-Cs
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 62. Compounds according to embodiment 57,
wherein
R5 is of the formula: N ^20, wherein
is H or methyl; and
Z20 is -(d-C4 alkyl) -C(0)NR6R7/ hydroxy (d-C4) alkyl , Ci-C4
dihydroxyalkyl, OH, halogen, CF3 , (d-C4) alkyl , OCF3 ,
-NR0-R7, R6R7N- (d-Cs alkyl)-, or -C(0)NReR7, wherein
R6 and R7 at each occurrence are independently H, d-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkoxycarbonyl , halogen,
C3-CS cycloalkyl, OH, SH, or d-C4 alkoxy.
Embodiment 63. Compounds according to embodiment 57,
wherein
Rs is of the formula: 20 , wherein
is H or methyl; and
Z20 is -(Ci-C4 alkyl) -C(0)NR6R7, hydroxy (d-C4) alkyl, d-C4
dihydroxyalkyl, OH, halogen, CF3, (d~C4) alkyl , OCF3,
-NR6R7, RsRvN- (d-C6 alkyl)-, or -C(0)NR6R7/ wherein
R6 and R7 at each occurrence are independently H, d-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or d-C4 alkoxy.
Embodiment 64. Compounds according to embodiment 57,
wherein
•N
R5 is of the formula: " ^20, wherein
ZIQ is H or methyl; and
Z20 is - (d-C4 alkyl)-C (0)NRSR7, hydroxy (d-Cj alkyl, d-d
dihydroxyalkyl, OH, halogen, CF3, (d-C4) alkyl, OCF3,
-NR6R7, R5R7N- (Ci-Ce alkyl)-, or -C(0)NRSR7, wherein
R6 and R7 at each occurrence are independently H, d-Cs
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment 65. Compounds according to embodiment 57,
wherein
R5 is of the formula: ~ " A20, wherein
ZIQ is H or methyl; and
Z20 is - (d-C4 alkyl)-C (0)NR6R7, hydroxy (d-C4) alkyl, d-C4
dihydroxyalkyl, OH, halogen, CF3, (d~C4) alkyl, OCF3,
-NR6R7; R6R7N-(Ci-Cs alkyl)-, or -C(0)NRSR7, wherein
Rs and R7 at each occurrence are independently H, d-Cs
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or d-C4 alkoxy.
Embodiment 66. Compounds according to embodiment
wherein
R5 is of the formula: ~ Z2°, wherein
is H or methyl; and
Z20 is -(Ci-C4 alkyl) -C(0)NR5R-, hydroxy (C-_-Ct) alkyl , d-C4
dihydroxyalkyl, OK, halogen, C?3 , (d-C4) alkyl , OCF3 ,
-NRSR7| R6R7N-(Ci-C5 alkyl)-, or -C(0)NR6R7, wherein
R0- and R7 at each occurrence are independently H, Ci-C0-
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl , halogen,
C3-CS cycloalkyl, OH, SH, or d-C., alkoxy.
Embodiment 67. Compounds according to embodiment 57,
wherein
R5 is of the formula: ^ '~20, wherein 20
Z10 is H or methyl; and
Z20 is -(Ci-C4 alkyl) -C(0)NR0-R7, hydroxy (d-C4) alkyl , CVC4
dihydroxyalkyl, OH, halogen, CF3 , (Ci-C4) alkyl , OCF3 ,
-NRB-R7, R6R7N- (Ci-Cs alkyl)-, or -C(0)NRSR7, wherein
R6 and R7 at each occurrence are independently H, Ci-Cs
alkyl optionally substituted with I, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment A7. Compounds according to embodiment 1
wherein
is H, halogen, alkyl optionally substituted with Ci-C4
alkoxycarbonyl, C2-CS alkenyl . optionally substituted with
Ci-C4 alkoxycarbonyl, C2-C4 alkynyl, Ci-C4 haloalkyl,
carboxaldehyde, Ci-C4 hydroxyalkyl, phenyl (d-Cg) alkoxy,
benzyl, phenethyl, phenpropyl, CN, or phenyl(Ci-
C6) alkanoyl,
wherein the phenyl groups are unsubstituted
substituted with 1, 2, cr 3 groups that
independently halogen, Ci-C4 alkyl, Ci-C4
nitro, CN^ CF3, OCF3 or C02H;
R: is OH, benzyloxy, phenyloxy, phenyloxy (Ci-C5) alkyl, phenyl
(d-C4) thioalkoxy, -OC (0) NK (CK:) nphenyl,
-OC (0)N (alkyl) (CH2)nphenyl, di (d-C6) alkylaminc, C;-CDalkynyl,
pyridyl, pyrimidyl, pyridazyl, pyrazolyl,
imidazolyl, pyrrolyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl,
benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,
hexahydropyrimidinyl, thiazolyl, thienyl, or C02K, wherein
n is 0, 1, 2, 3 , 4, 5 or 6;
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
NRSR7, (d-C4) haloalkyl, (Ci-C4) haloalkoxy, (Ci-C6)
alkyl, pyridyl, - (Ci-C6) alkyl-N (R)-C02R30, or NR6R7-
(Ci-Cs alkyl) -,
R4 is H, alkyl optionally substituted with one or two groups
that are independently CO2H, -C02alkyl, -C(0)NRR, -
N(R30)C(0)NRR, -N(R30)C(0) - (d-Cjalkoxy, or-NR6R7/
phenyl (Ci-Cs) alkoxy, phenyl (d-C6) alkyl, hydroxyalkyl,
wherein the phenyl groups are unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3,
or OCF3; and
R5 is phenyl (Ci-Cg) alkyl, (Ci.-C6) alkyl, phenyl, piperidinyl (d-
Cs) alkyl, thienyl (Ci-C6) alkyl, indolyl, quinolinyl,
isoquinolinyl, isoindolyl, indol-2-onyl, indazolyl,
indolyl (d-C6) alkyl, quinolinyl (d-Cs) alkyl,
isoquinolinyl (d-Cs) alkyl, isoindolyl (d-C6) alkyl, indol-
2-onyl (Ci-C6) alkyl, naphthyKCi-Cs) alkyl, pyridyl (d-
C5) alkyl, pyrimidyl (Ci-C0-) alkyl, pyrazinyl (Ci-Cj alkyl, cr
wherein
each of the above is unsubstitutea or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, benzyloxy, thioalkoxy, -C02(Ci-C5
alkyl), C02H, CN, amidinooxime, NRSR9, NR6R7-(Ci-Cs
alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3 ;
R8 is hydrogen, Ci-Cs alkyl, Ci-C6 alkanoyl, phenyl
CJ.-GS alkyl and phenyl Ci-C6 alkanoyl; and
R9 is aminoalkyl, mono Ci-C6 alkylamino C^-Cs alkyl, di Ci-
Cs alkylamino Ci-Cs alkyl, Ci-C6 alkyl, Ci-C6 alkanoyl,
phenyl Ci-C4 alkyl, indazolyl, and • phenyl Cj.-C4
alkanoyl.
In this embodiment, it is preferred that when R2 is
benzyloxy, R4 is H, and R5 is benzyl or methyl, Rj. is not
hydrogen; and
no more than two of Rlf R2, R4, and R5 are simultaneously
hydrogen.
Embodiment A8. Compounds according to embodiment A7
wherein
Ri is H, halogen, Ci-C4 alkyl optionally substituted with Ci-C4
alkoxycarbonyl, C2-C4 alkenyl optionally substituted with
Ci-C4 alkoxycarbonyl, C2-C4 alkynyl, or carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (d-C6) alkyl, phenyl
(Ci-C4) thioalkoxy, or pyridyl; wherein each of the above
is optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently halogen, - (C^-Cg) alkyl-N(R) -C02R30,
NR6R7, (Ci-C4) haloalkyl, (Ci-C4) haloalkoxy, (d-Cs) alkyl, '
pyridyl, or NRSR7- (d-C6 alkyl)-.
Embodiment A9. Compounds according to embodiment A7
wherein
R4 is H, (Ci-Cs)alkyl optionally substituted with one cr two
groups that are independently CO-H, -C02alkyl, -G(0)NRR,
-N(R3o)C(0)NRR, -N(R3o)C(0) - (Ci-Cs) alkoxy, cr -NR0-RT,
phenyi (Ci-Cs) aikcxy, or hydroxy (Ci-C6) alkyl, wherein
the phenyl groups are unsubstituted or substituted with
1, 2, or 3 groups that are independently halogen,
hydroxy, C1-C4 alkoxy, C:-C4 alkyl, nitro, CF3, OCF3;
and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (d-C6) alkyl,
phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, indolyl
(Ci-Cs) alkyl, naphthyl (Ci-Cs) alkyl, thienyl (Ci-Cs) alkyl,
pyridyl (Ci-Cg) alkyl, pyrimidyl (Ci-C6) alkyl, or
pyrazinyl (Ci-Cg) alkyl, and wherein
each of the above is unsubstituted or substituted with 1,
2, or 3 groups that are independently alkyl,
halogen, alkoxy, benzyloxy, thioalkoxy, -C02(Ci-C5
alkyl) , CF3, OCF3/ C02H, CN, amidinooxime.
In this embodiment, it is preferred that when R2 is
benzyloxy, R4 is H, and R5 is benzyl or methyl, Rx is not
hydrogen; and
no more than two of RI, R2, R4, and R5 are simultaneously
hydrogen.
Embodiment A10. Compounds according to embodiment A7,
wherein
R4 is H, (Ci-C4) alkyl optionally substituted with one or two
groups that are independently C02H, -CO2alkyl, -C(0)NRR,
-N(R30)C(0)NRR, -N(R30)C(0) - (Ci-C6) alkoxy, or -NR6R7/
phenyl (Cx-Cg) alkoxy, benzyl, phenethyl, phenpropyl, or
hydroxy (Cx-C6) alkyl, wherein
the phenyl groups are unsubstituted or substituted with
1, 2, or 3 groups that are independently halogen,
hydroxy, Ci-C4 alkoxy, Ci-C4 alkyl, nitro, CF3, CCF3;
and
R5 is indolyl, quinolinyl, iscquinolinyl, isoindolyl, indol-2-
onyl, indoiyi (Ci-Cg) alkyl, quinolinyl (C-_-C6) alkyl,
isoquinolinyl (Ci-C6) alkyl, isoindolyl (Ci-C0-) alkyl, indcl-
2-onyl (Ci-C6) alkyl, each of which is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
Ci-C4 alkyl, halogen, CF3, OCF3, -C02CH3, C^-C^
hydroxyalkyl, Ci-C4 alkoxy, -C02 (Ci-C5 alkyl), benzyloxy, -
NReRg, NR0-R7- (Ci-C6 alkyl)-, -C(0)NR6R7, or amidinooxime;
wherein
Rs and R7 are independently at each occurrence H, alkyl,
hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl,
phenylalkyl, phenylalkoxy, or phenylalkanoyl,
wherein each is unsubstituted or substituted with 1,
2, or 3 groups that are independently, halogen,
hydroxy, d-C4 alkoxy, OH, SH, C3-CS cycloalkyl, Ci-C4
alkyl, CF3, or OCF3; or
and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring which
is optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, hydroxy, hydroxy Ci-C4 alkyl, or
halogen.
Embodiment All. Compounds according to embodiment A7
wherein
RI is chloro, bromo, iodo, or H; and
RS is benzyl, phenethyl, phenpropyl, phenyl, quinolinyl,
indolyl, isoquinolinyl, isoindolyl, indol-2-onyl,
indolyl (Cx-Cs) alkyl, quinolinyl (d-C6) - alkyl,
isoquinolinyl (Ci-C6) alkyl, isoindolyl (Ci-C6) alkyl, indol-
2-onyl (Ci-Cs) alkyl, piperidinyl d-C4 alkyl, thienyl Ci-C4
alkyl, -CH2-pyridyl, or pyridyl, each of which is
unsubstituted or substituted with 1, 2, cr 3 croups that
are independently Ci-C4 alkyl, halogen, CF3, OC?3, Ci-C4
hydroxyalkyl, C:-C4 alkoxy, -C02 (Ci-C5 alkyl), benzyloxy,
NRs?-9, NR0-R7 Ci-C4 alkyl, -C(O)NR0-R7, and anidinooxime ;
wherein
Rs and R7 are independently at each occurrence K, alkyl,
hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl,
phenylalkyl, phenylalkoxy, or phenylalkanoyl,
wherein each is unsubstituted or substituted with 1,
2, or 3 groups that are independently, halogen,
hydroxy, Ci-C4 alkoxy, OH, SH, C3-C6 cycloalkyl, C^-CU
alkyl, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 or 2 groups
that are independently Ci-C4 alkyl, hydroxy, hydroxy
Ci-C4 alkyl, or halogen.
Embodiment A12. Compounds according to embodiment
All, wherein
R5 is benzyl, phenethyl, phenpropyl, or phenyl, each of which
is unsubstituted or substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkyl, halogen, CF3, OCF3, -
CO2CH3/ Ci-C4 hydroxyalkyl, Ci-C4 alkoxy, -C02(Ci-C5 alkyl),
benzyloxy, NRaRg, NR6R7 Ci-C4 alkyl, -C(0)NR6R7 , and
amidinooxime.
Embodiment A13. Compounds according to embodiment
All, wherein
R5 is quinolinyl, indolyl, isoquinolinyl, isoindolyl, indol-2-
onyl, indolyl (Ci-Cg) alkyl, quinolinyl (d-Cs) alkyl,
isoquinolinyl (Ci-Cg) alkyl, isoindolyl (Cx-Cg) alkyl, indol-
2-onyl (Ci-Cs) alkyl, piperidinyl Ci-C4 alkyl, thienyl Ci-C4
alkyl, -CH2-pyridyl, or pyridyl, each of which is
unsubstituted or substituted with 1, 2, or 3 groups chat
are independently Ci-C4 alkyl, halogen, CF3, OC?3, -C02CH3/
Ci-C4 hydroxyalkyl, Ci-C4 alkoxy, -CO-(C-Cs alkyl),
benzyloxy, NR8R5, NRSR7 Ci-C4 aikyi, -C(O)NRC-R7, and
amidinooxime.
Embodiment A14 . Compounds according to any one of
embodiments All, A12, or A13 wherein
R2 is benzyloxy, or phenethyloxy;
each of the above is unsubstituted or substituted with I,
2, or 3 , groups that are independently - (Ci-Cs) alkyl -N (R) -
C02R30, fluoro, chloro, bromo, CF3, or (C1-C4) alkyl.
Embodiment A15. Compounds according to any one of
embodiments All, A12 or A13 wherein
R2 is phenyloxy(Ci-Cs) alkyl, wherein the phenyl group is
unsubstituted or substituted with 1, 2, or 3, groups that
are independently - (d-C6) alkyl-N (R) -CO2R30, fluoro,
chloro, bromo, CF3, or (C'i-C4) alkyl.
Embodiment A16. Compounds according to embodiment Al,
wherein
Ri is H, halogen, Ci-C4 alkyl optionally substituted with Ci-C4
alkoxycarbonyl, C2-C4 alkenyl optionally substituted with
Ci-C4 alkoxycarbonyl, C2-C4 alkynyl, or carboxaldehyde.
Embodiment A17. Compounds according to embodiment
A16, wherein
R2 is benzyloxy, OH, phenyloxy, pheny 1 oxy (d-C6) alkyl, or
phenyl (d-C4) thioalkoxy, wherein each of the above is _
optionally substituted with 1, 2, 3, 4, or 5 groups that
are independently halogen, - (Ci-Cs) alkyl-N(R) -C02R30, NRSR7,
(Ci-C4) haloalkyl, (Ci-C4) halcalkoxy, (Ci-C5) alkyl,
pyriciyl, cr NRSR7-(Ci-C5 alkyl)-.
Embodiment A18. Compounds according to embodiment
A17, wherein
R4 is H, or (C1-C4) alkyl optionally substituted with one or
cwo groups that are independently C02H, -CO2alkyl,
-C(0)NRR, -N(R30)C(0)MRR, -N (R30) C (0) - (C^-Cs) alkoxy, OH,
Embodiment A19. Compounds according to embodiment A18,
wherein
R5 is phenyl, naphthyl, indolyl, pyridyl, quinolinyl,
isoquinolinyl, isoindolyl, indol-2-onyl, indolyl (d-C6)
alkyl, quinolinyl(Ci-Cs) alkyl, isoquinolinyl(Ci-C5) alkyl,
isoindolyl (Ci-C6) alkyl, indol-2 -onyl (Ci-Cs) alkyl,
pyridazinyl, pyrimidinyl, or pyrazinyl, pyridazinyl(Ci-Cs)
alkyl, pyrimidinyl (Ci-Cs) alkyl, or pyrazinyl (Ci-Cs) alkyl,
each of which is unsubstituted or substituted with 1, 2,
3, 4 or 5 groups that are independently Ci-C4 alkyl,
halogen, CF3, OCF3/ -C02CH3, Ci-C4 hydroxyalkyl, Ci-C4
alkoxy, -C02(Ci-C5 alkyl), benzyloxy, -NR8R9, -C(O)NR6R7,
NR6R7 Ci-C4 alkyl, and amidinooxime; wherein
Re and R7 are independently at each occurrence H, Ci-C4
alkyl, Ci-C4 hydroxyalkyl, Ci-C4 alkoxy, Ci-C4 alkoxy
CX-C4 alkyl, C^-C^ alkanoyl, phenyl Ca.-C4 alkyl,
phenyl Ci-C4 alkoxy, or phenyl Ci-C4 alkanoyl, wherein
each is unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, hydroxy, Ci-
C4 alkoxy, Ci-C4 alkyl, OH, SH, C3-C6 cycloalkyl, CF3,
or OCF3; or
RS, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 cr 2 groups
that are independently Ci-C4 alkyl, hydrcxy, hydroxy
Ci-C4 alkyl, or halogen.
Embodiment A20. Compounds acoording to embodiment
A19, wherein
RI is H, halogen, methyl, ethyl, C2-C4 alkenyl C2-C4 alkynyl, or
carboxaldehyde/
R2 is benzyloxy, OH, phenyloxy, phenyloxy (d-C6) alkyl, or
phenyl (Ci-C4 ) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (d-Cs) alkyl-N (R) -C02R30, NR6R7,
NR0-R7 Ci-C4 alkyl, (Ci-C4) haloalkyl, (d-C4) haloalkoxy,
(Ci-Cs) alkyl, or pyridyl; and
R4 is H, (Ci-C4 ) alkyl optionally substituted with one or two
groups that are independently C02H, -CO2alkyl, -C(0)NRR,
-N(R3 0)C(0)NRR, -N(R3 0 ) C ( 0 ) - (Ca-C6) alkoxy, OH, or -NR6R7.
Embodiment A21. Compounds according to embodiment
A20, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, Ci-Cfi alkyl,
NRioRn, Ci-C4 alkoxy, -C (0) NR10Rn, -CO2H, NRioRn Ci-C4
alkyl, Ci-Cs alkyl, Ci-C6 alkoxycarbonyl, d-Cs alkoxy,
CHO, -SO2NH2, Ci-C4 haloalkyl, d-C6 hydroxyalkyl, -Ci-C4
alkyl-NR12C(0)NR13R14, -d~C4 alkyl-NR12C (0) - (d-C4 alkyl)-
NR13R14, -d-C4 alkyl-NR12C (0) OR15, or -d-C4 alkyl-NR12C (O) -
(C1-C4 alkyl)-R15, wherein
RIO and RH at each occurrence are independently H, Ci-C6
alkyl, amino d-C4 alkyl, NH(Ci-C6 alkyl) alkyl, N(d-
C6 alkyl) (d-Cs alkyl) d-C6 alkyl, d-Cfi hydroxyalkyl,
Ci-Cs alkoxy d-Cs alkyl, OH, -S02 (d-C6 alkyl), or
Ci-Cs alkanoyl, or
RIO/ RII/ and the nitrogen to which they are attached form
a piperidir.vl, pyrrolidinyl, piperazinyl, or a
mcrphclinyl ring optionally substituted with 1 cr 2
groups that are independently alkyl or halogen,
R12 is H or Ci-C5 alkyl;
R13 and R14 are independently H or Ci-C0- alkyl; cr
R13 and R14 and the nitrogen to which they are attached
form a morpholinyl ring; and
RIS is Ci-C6 alkoxy; -OC (0) C^Cg alkyl, OH.
Embodiment A22. Compounds according to embodiment
A21, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, Ci-C6 alkyl,
NRioRii, NR10Rn Cx-Cg alkyl, Ci-C4 alkoxy, or _ -C (0) NR10Rn, -
C02H, -C!-C4 alkyl-NR10Rn, Ci-Cs alkyl, Ci-Cs
alkoxycarbonyl, Ci-C6 alkoxy, CHO, -SO2NH2, Ci-C4
haloalkyl, Ci-Cs hydroxyalkyl, -Ci-C4 alkyl-NR12C (0) NR13R14,
-C!-C4 alkyl -NR12C (0) - (C1-C4 alkyl)-NR13R14l -Ci-C* alkyl-
NR1 2C(O)ORi5, or -Ci-C4 alkyl-NR12C (0) - (d-C4 alkyl) -R15
wherein
RIO and RU at each occurrence are independently H, CJ.-GS
alkyl, amino Ci-C4 alkyl, NH(C!-C6 alkyl) alkyl, N(d-
Cs alkyl) (Ci-Cs alkyl) Ci-C6 alkyl, Cj.-C6 hydroxyalkyl,
d-Cs alkoxy Ci-C6 alkyl, OH, -S02 (Ci-C6 alkyl), or
Ci-Cs alkanoyl,
Ri2 is H or Ci-Cs alkyl;
Ri3 and Ri4 are independently H or C1-CS alkyl; or
Ri3 and R14 and the nitrogen to which they are attached
form a morpholinyl ring; and
RIS is Ci-Cs alkoxy; -OC(0)Ci-C6 alkyl, OH.
Embodiment A23 . Compounds according to embodiment
A22, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or a
groups that are independently halogen, d-C5 alkyl,
NR10Rn, NRioRn d-d alkyl, d-C4 alkoxy, -C (0) NR10Rn,
wherein
R10 and RH at each occurrence are independently H, d-Cs
alkyl, amino d-C4 alkyl, NH(d-C6 alkyl) alkyl, N(d-
C6 alkyl) (d-C6 alkyl) d-Cs alkyl, d-Cs hydroxyalkyl ,
d-d alkoxy d-C6 alkyl, OH, -S02 (d-C6 alkyl), d-C6
alkanoyl .
Embodiment A24. Compounds according to embodiment
A23, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, d-C6 alkyl,
, or d-C4 alkoxy.
Embodiment A25. Compounds according to embodiment
A23, wherein
R5 is substituted with at least one -C (0)
Embodiment A26. Compounds according to embodiment
A25, wherein
R10 and RH at each occurrence are independently H, d-Cg alkyl,
amino d-C4 alkyl, NH(C!-C6 alkyl) alkyl, N(CX-CS alkyl) (d-
C6 alkyl) Ct-Cg alkyl, Ci-C6 hydroxyalkyl, d-C6 alkoxy d-
C6 alkyl.
Embodiment 27. Compounds- according to embodiment A26,
wherein
R10 is H.
Embodiment A2S. Compounds according to embodiment
A2 5 , wherein
OH, -S02 (Ci-C0- alkyl), C:-C0- alkanoyl,
Embodiment A29. Compounds according to embodiment
A20, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, Ci-C6 alkyl, NK2,
NH(d-Cs alkyl), N(C1-C6 alkyl) (d-C6 alkyl), d-C4 alkoxy,
-C (O)NR10Rn, wherein each of the above alkyl groups is
optionally substituted with 1 or 2 groups that are
independently OH, or methoxy; wherein
RIO/ RU/ and the nitrogen to which they are attached form.
a piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl or halogen.
Embodiment A30. Compounds according to embodiment
A20, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, d-C6 alkyl, d-C4
alkoxy, -C02H, -d-C4 alkyl-NR10Rn, d-Cs alkoxycarbonyl,
d-Cs alkoxy, CHO, -S02NH2, d-C4 haloalkyl, d-C6
hydroxyalkyl, -d-C4 alkyl-NR12C (0) MR13R14, -d-C4 alkyl-
NR12C(0) - (d-C4 alkyl)-NRi3R14, -Ca-C4 alkyl-NR12C (0) OR15/ or
-d-C4 alkyl-NR12C (0) - (C--C4 alkyl) -R1S, -OC(0)d-C5 alkyl,
or OH wherein
Ri2 is H or d-C6 alkyl;
RX3 and R14 are independently H or d-Cs alkyl; or
Ria and R14 and the nitrogen to which they are
attached form a morpholinyl ring;
Ris is d-Cs alkoxy.
Embodiment A31. Compounds according to embodiment
ABO, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, Ci-C4 alkyl, CN-C4
alkoxy, -CO2H, d-C4 alkoxycarbonyl, d-C4 alkoxy, CHO, -
S02NH2; Ci-C4 haloalkyl, d-C4 hydroxyalkyl.
Embodiment A32. Compounds according to embodiment
A30, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, d-C4 alkyl, d~C4
alkoxy, -C02H, -d-C4 alkyl-NR10Rn, -Ci-C4 alkyl-
NR12C(0)NR13R14, -d-C4 alkyl-NR12C (0) - (d-C4 alkyl) -NR13R14 , -
d-C4 alkyl-NR12C(0)ORis, or -d-C4 alkyl-NRi2C (0) - (d-C4
alkyl) -Ris, or -OC(0)d-Cs alkyl, wherein
R12 is H or Ci-Cg alkyl;
Ri3 and Ri4 are independently H or d-C6 alkyl; or
R13 and R14 and the nitrogen to which they are
attached form a morpholinyl ring;
R15 is CI-GS alkoxy.
Embodiment A33. Compounds according to embodiment
A31, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, d-C4 alkyl, d-C4
alkoxy, -C02H, -d~C4 alkyl-NR10Rn, -d~C4 alkyl-
NR12C(0)NR13R14, -d-C4 alkyl-NR12C(0) - (d-C4 alkyl)-NR13R14,
wherein
Ri2 is H or Ci-Cs alkyl;
R13 and R14 are independently H or d-C6 alkyl; or
Ri3 and R14 and the nitrogen to which they are
attached form a morpholinyl ring.
Embodiment A34. Compounds according to any one or
embodiments A30, A31, A32, or A33, wherein the phenyl group is
substituted with two groups that are meta to each ctner.
Embodiment A35. Compounds according to any one c~
embodiments A30, A31, A32, or A33, wherein the phenyl group is
substituted with two groups that are para to each other.
Embodiment A3 6. Compounds according to embodiment
A20, wherein .
R5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl,
quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl,
pyridazinyl, pyrimidinyl, or pyrazinyl, , -each of which
is unsubstituted or substituted with 1, 2, 3, 4 or 5
groups that are independently C!-C4 alkyl, halogen, CF3,
OCF3, -C02CH3, C!-C4 hydroxyalkyl, Ci-C4 alkoxy, -C02(C1-C5
alkyl), benzyloxy, NR8R9, NRSR7 Ci-C4 alkyl, -C(0)NR6R7, or
amidinooxime; wherein
R5 and R7 are independently at each occurrence H, Ci-C4
alkyl, Ci-C4 hydroxyalkyl, Ci-C4 alkoxy, C].-C4 alkoxy
Ci-C4 alkyl, d-C4 alkanoyl, phenyl Ci-C4 alkyl,
phenyl Ci-C4 alkoxy, or phenyl Ci-C4 alkanoyl, wherein
each is unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, OH, SH, C3-C6
cycloalkyl, C].-C4 alkoxy, CX-C4 alkyl, OH, CF3, or
OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 or 2 groups
that are independently Ci-C4 alkyl, hydroxy, hydroxy
Ci-C4 alkyl, or halogen.
Embodiment ASS. Compounds according tc emccciment
A3 6, wherein
R3 is indolyl, pyridyl, pyrimidinyl, indazolyl, or pyrazinyl,
each of which is unsubstituted or substituted with I, 2,
3, or 4 groups that are independently d-C4 alkyl,
halogen, CF3, OCF3, -C02CH3, d-C4 hydroxyalkyl, Ci-C4
alkoxy, -C02 (d-Cs alkyl), benzyloxy, -C(O)NRb-R7, -NR8R9,
NRsR7 Ci-C4 alkyl, and amidinooxime; wherein
Rs and R7 are independently at each occurrence H, d-C4
alkyl, d-C4 hydroxyalkyl, Ci-C4 alkoxy, d-C4 alkoxy
d~C4 alkyl, d-C4 alkanoyl, phenyl CX-C4 alkyl,
phenyl Ci-C4 alkoxy, or phenyl d-C4 alkanoyl, wherein
each is unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, OH, SH, C3-C6
cycloalkyl, d-C4 alkoxy, CX-C4 alkyl, OH, CF3, or
OCF3.
Embodiment A3 9. Compounds according to embodiment
A3 8, wherein
R5 is indolyl', pyridyl, or pyrazinyl, each of which is
unsubstituted or substituted with 1, 2, 3, or 4 groups
that are independently d-C4 alkyl, halogen, CF3, OCF3/
-C02CH3/ d-C4 hydroxyalkyl, d-C4 alkoxy, -C02(C1-CS
alkyl), benzyloxy, -C(O)NR6R7, NR8R9, NR6R7-C1-C4 alkyl-,
and amidinooxime; wherein
RS and R7 are independently at each occurrence H, Ci-C4
alkyl, d-C4 hydroxyalkyl, Ci-C4 alkoxy, Ci-C4 alkoxy
d-C4 alkyl, each of which is optionally substituted'
with ._jl, 2, or 3 groups that are independently
halogen, OH, SH, C3-C6 cycloalkyl, d-C4 alkoxy, d-C4
alkyl, OH, CF3, or OCF3.
Embodiment A40, Compounds according to embodiment
A36, wherein
R5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, orpyrazinyi,
each of which is unsubstituted or substituted with I, 2,
3, 4 or 5 groups that are independently C-C4 aikyi,
halogen, C?3, OCF3; -C02CH3, d-C hydroxyalkyl, d-C4
alkoxy, -C02(Ci-C3 alkyl) , benzyloxy, -C(0)NH2, -C(0)NH(C:-
Cs alkyl} wherein the alkyl group is optionally
substituted with OH or methoxy, -C(0)N(C^-C6 alkyl) (Ci-C6
alkyl) wherein each alkyl group is independently and
optionally substituted with OH or methoxy, -C(0)NRSR7,
NR8R9, NR6R7 Ct-C4 alkyl, -Ci-C4 alkyl-NH2, -Ci-C4 alkyl-
NH(Ci-C6 alkyl) wherein each alkyl group is independently
and optionally substituted with OH or methoxy, -Ci-C4
alkyl-N (Ci-Ce alkyl) (Ci-Cs alkyl) wherein each alkyl group
is independently and optionally substituted with OH or
methoxy, and amidinooxime; wherein
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 or 2 groups
that are independently C-C4 alkyl, hydroxy, hydroxy
Ci-C4 alkyl, or halogen.
Embodiment A42. Compounds according to any one of
embodiments A37, A38, A39, or A40, , wherein
RI is H, halogen, methyl, or carboxaldehyde;
R2 is berizyloxy, phenyloxy, phenyloxy (d-Cfi) alkyl, or phenyl
(Ci-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (d-Cs) alkyl-N (R) -C02R30, NR6R7,
(Ci-C4) haloalkyl, (Ci-C4) haloalkoxy, (Ci-Cs) alkyl,
NRSR7 (Cn-Cs)alkyl, pyridyl, morpholinyl, thioraorpholinyl,
piperazinyl pyridyl (Ci-C«) alkyl, morpholinyl (Cj-Cs) alkyl,
thiomorpholinyl (d-C5) alkyl, or piperazinyl (Ci-Cs) alkyl
wherein the pyridyl, morpholinyl, thiomorphoiinyi, and
picerazinvl rings are optionally substituted with 1 or 2
qroups that are independently C-_-C4 alkyl, or halogen;
wherein
R6 and R7 are independently at each occurrence H, d-C4
alkyl optionally substituted with 1 or two groups
that are independently OH, halogen or methoxy, d-C4
hydroxyalkyl, d-C4 alkoxy, Ci-C4 alkoxy Ci-C4 alkyl,
Ci-C4 alkanoyl, benzyl, benzyloxy, or phenyl Ci-C4
alkanoyl, wherein each is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, OH, SH, C3-CS cycloalkyl, d-
C4 alkoxy, Ci-C4 alkyl, CF3, " or OCF3/ and
R4 is H, (Ci-C3) alkyl optionally substituted with one or two
groups that are independently C02H, -C02alkyl, -C(0)NRR,
-N(R30) C(0)NRR, -N(R30)C(0) - (Ci-Cs) alkoxy, -NRSR7, NR6R7C1-C4
alkyl, or hydroxy (d-C3) alkyl.
Embodiment A43.
A42, wherein
RI is H or halogen.
Compounds according to embodiment
Embodiment A44. Compounds according to embodiment
A18, wherein
R5 is phenyl (Ci-Cs) alkyl, (d-C6) alkyl, piperidinyl (Ci-Cs). alkyl,
thienyl (Ci-Cs) alkyl, indolyl (d-Cs) alkyl, naphthyl (d-
Cs) alkyl, pyridyl (d-C6) alkyl, pyrimidyl (d-C6) alkyl,
quinolinyl (Ci-Cs) alkyl, isoquinolinyl (d-C6) alkyl,
isoindolyl (Ci-Cs) alkyl, indol-2-onyl (d-C6) alkyl,
pyridazinyl(d-C6) alkyl, pyrazinyl (d-C6) alkyl, or
pyrazinyl (Ci-Cs) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4; or 5 croups that are independently a-Kyi,
halogen, alkoxy, benzyloxy, hydroxyalkyl,
thioalkcxy, -CO^C^C, alkyl), C02H, CN, amidinooxime,
NR3R9; NRD-R~- (d-C0- alkyl)-, -C(O)NRC-R7, amidino, CF3,
or OC?3;
Rs is hydrogen, d-C5 alkyl, Ci-Cs alkanoyl, phenyl
d-C6 alkyl and phenyl Ci-C6 alkanoyl; and
R9 is aminoalkyl, mono d~C6 alkylamino Ci-C5 alkyl, di Ci-
C0- alkylamino d-C6 alkyl, d-C6 alkyl, d-C5 alkanoyl,
phenyl d~C4 alkyl, indazolyl, and phenyl d-C4
alkanoyl.
In this embodiment, it is preferred that when R2 is
benzyloxy, R4 is H, and R5 is benzyl or. methyl, RI is not
hydrogen; and
no more than two of Rx, R2, R4, and R5 are simultaneously
hydrogen.
Embodiment A45. Compounds according to embodiment
A44, wherein
R5 is phenyl(Ci-C6) alkyl, which is unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently
alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -C02(d-C5
alkyl), CO2H, CN, amidinooxime, NR8Rg, NRSR7- (Ci-Cs alkyl)-,
-C(O)NR6R7, amidino, CF3, or OCF3,- wherein
Rs and R7 are independently at each occurrence H, Ci-C4
alkyl, Ci-C4 hydroxyalkyl, d-C4 alkoxy, d-C4 alkoxy
Ci-C4 alkyl, Ci-C4 alkanoyl, phenyl Ci-C4 alkyl,
phenyl Ci-C4 alkoxy, or phenyl CL-C4 alkanoyl, wherein,
each is unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, OH, SH, C3-CS
cycloalkyl, Ci-C4 alkoxy, d-C4 alkyl, CF3/ or OCF3 ;
or
RS; R7, and the nitrogen to which they are attached form a
morpholir-yl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 or 2 groups
chat are independently d-C4 alkyl, hydrcxy, hydroxy
Ci-C4 alkyl, or halogen;
Ra is hydrogen, d-C6 alkyl, d-Cs alkanoyl, phenyl Cx-Coal
kyl and phenyl Ci-C6 alkanoyl; and
R9 is aminoalkyl, mono d-C6 alkylamino d-Cs alkyl, di d-
Cs alkylamino Ci-Cs alkyl, d-Cs alkyl, d-C6
alkanoyl, phenyl Ci-C4 alkyl, indazolyl, and phenyl
d-C4 alkanoyl.
Embodiment A46. Compounds according 'to embodiment
A45, wherein
R5 is phenyl(Cx-Cg)alkyl, which is unsubstituted or substituted
with I, 2, 3, 4, or 5 groups that are independently CN,
halogen, Ci-C4 alkoxy, Ci-C4 thioalkoxy, d~C4 haloalkyl,
dC4 alkyl, d~C4 haloalkyl, d~C4 haloalkoxy, -C (0) NR20R2i,
wherein
R20 and R21 are independently H, d-C6 alkyl, Ci-C6
hydroxyalkyl, d-Cg alkoxy d-C6 alkyl, or
RSO- R2i, and the nitrogen to which they are attached form
a piperazinyl, or morpholinyl ring, each of which is
optionally substituted with 1 or 2 groups that are
independently alkyl or halogen.
Embodiment A47. Compounds according to embodiment
A46, wherein
R5 is phenyl(Ci-C4)alkyl, which is unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently CN,
halogen, d-C4 alkoxy, CX-C4 haloalkyl, d-C4 alkyl, d-C4
haloalkoxy, -C (0) NR20R2i, wherein
R20 ana R~ are independently H, Ci-Cs alkyl, Ci-C0-
hydrcxyalkyl, C-C.- alkoxy d-C5 alkyl, or
20, RZ-, and the nitrogen to which they are attached form
a piperazinyl, or morphclinyl ring, each of which is
optionally substituted with 1 or 2 groups that are
independently alkyl or halogen.
Embodiment A48. Compounds according to embodiment
A47, wherein
R5 is benzyl or phenethyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently CM, halogen, Ci-C4 alkoxy, CF3/ OCF3, C-_-C4
alkyl, -C(0)NR20R2i, wherein
R20 and R2i are independently H, d-Cs --alkyl, Ci~C6
hydroxyalkyl, CZ-C6 alkoxy Cj.-C0- alkyl, or
2o/ R2i/ and the nitrogen to which they are attached form
a piperazinyl, or morpholinyl ring, each of which is
optionally substituted with 1 or 2 groups that are
independently alkyl or halogen.
Embodiment A49. Compounds according to embodiment
A48, wherein
Rs is benzyl or phenethyl, each of which is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently halogen, methoxy, ethoxy, CF3, OCF3, methyl,
ethyl, or -C (0)NR2oR2i, wherein
R20 and R21 are independently H, C-Cg alkyl, Ci-Cs
hydroxyalkyl, d-Cs alkoxy d-Cfi alkyl,
Embodiment ABO. Compounds according to embodiment
A48, wherein
Rs is benzyl or phenethyl, each of which is unsubstituted or
substituted with I, 2, 3, 4, or 5 groups that are
•m
independently halogen, methoxy, ethoxy, C73, OCF5, methyl,
ethyl, or -C (0) NR2oRzi, wherein
R20, R21l and the nitrogen to which they are attached for
a ciperazinvl, or morpholinyl ring, each cf which is
optionally substituted with 1 or 2 groups that are
independently alkyl or halogen.
Embodiment A51. Compounds according to embodiment
A49, wherein
R5 is substituted on the phenyl ring with 1, 2, 3, 4, or 5
groups and wherein there is a group at the para position
of the phenyl.
Embodiment A52. Compounds according to . embodiment
A43, wherein
R5 is piperidinyl (d-C6) alkyl, thienyl (d-C6) alkyl, indolyl
(d-C6) alkyl, pyridyl (d-C6) alkyl, pyrimidyl (Ci-Cs) alkyl,
quinolinyl (Ci-Cg) alkyl, isoquinolinyl (d-Cs) alkyl,
isoindolyl (Ci-C6) alkyl, indol-2-onyl (Ci-C6) alkyl,
pyridazinyl (Ci-Cg) alkyl, or pyrazinyl (d-C6) alkyl, or
pyrazinyl (d-Cs) alkyl, or pyrazinyl (Ci-Cs) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently Ci-C6
alkyl, halogen, d-C6 alkoxy, d-C6 hydroxyalkyl,
benzyloxy, d-Cs thioalkoxy, -C02(d-d alkyl), C02H,
CN, amidinooxime, NR8R9, NR6R7- (d-C6 alkyl)-,
-C(0)NR6R7, amidino, CF3, or OCF3 ;
R8 is hydrogen, d-C6 alkyl, d-C6 alkanoyl, phenyl Ci-C6
alkyl and phenyl Ci-Cs alkanoyl; and
R9 is aminoalkyl, mono Ci-Cs alkylamino Ci-Cs alkyl, di d-
Cs alkylamino Ci-Cs alkyl, Ci-C6 alkyl, d-C6 alkanoyl,
phenyl d-C4 alkyl, indazolyl, and phenyl Ci-C4
alkanoyl.
In this embodiment, it is preferred that when R2 is
benzyloxy, R^ is H, and R5 is benzyl or methyl, RL is not
hydrogen; and
no mere than two of R1; R2, R4, and R5 are simultaneously
hydrogen.
Embodiment: A53 . Compounds according to embodiment
A52, wherein
Rs is piperidinyl(Ci-C4) alkyl, thienyl(Ci-C4) alkyl, indolyl
(Cx-C4) alkyl, pyridyl (d-C4) alkyl, pyrimidyl (Ci-C4) alkyl,
or pyrazinyl (Ci-C4) alkyl, each of which is unsubstituted.
Embodiment A54. Compounds according to embodiment
A52, wherein
R5 is indolyl (d-C4) alkyl, pyrimidyl (Ci-Cj alkyl, ' or
pyrazinyl (Ci-C-4) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, or 4 groups that are independently Ci-C6 alkyl,
halogen, Ci-C6 alkoxy, Ci-C6 hydroxyalkyl, benzyloxy,
Ci-Cs thioalkoxy, -C02(Ci-C5 alkyl), C02H, CN,
amidinooxime, NRaRs, NR6R7- (Ci-Cg alkyl)-, amidino,
-C(0)NR2oR2i/ CF3, or OCF3; wherein
Rs and R7 are independently at each occurrence H, Ci-C4
alkyl, Ci.-C4 hydroxyalkyl, Ci-C4 alkoxy, Ci-C4 alkoxy
Ci-C4 alkyl, Ci-C4 alkanoyl, benzyl, benzyloxy, or
phenyl Ci-C4 alkanoyl, wherein each is unsubstituted
or substituted with 1, 2, or 3 groups that are
independently, halogen, OH, SH, C3-CS cycloalkyl, Ci-
C4 alkoxy, Ci-C4 alkyl, CF3, or OCF3; or
R6, RT, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring
which is optionally substituted with 1 or 2 groups
that are independently Ci-C4 alkyl, hydroxy, hydroxy
Ci-C4 alkyl, or halogen;
Ra is hydrogen, Ci-C6 alkyl, CL-C6 alkanoyl, phenyl
Ci-C4 alkyl and phenyl C-_-C4 alkanoyl; and
R9 is aminoalkyl, mono Ci-Cs alkylamino Ci-Cs alkyl,
di Ci-Cs alkylamino Ci-Cs alkyl, C-Cs alkyl, Ci-
Cs alkanoyl, phenyl Ci-C4 alkyl, indazolyl, and
phenyl Ci-C4 alkanoyl;
R20 and R2i are independently H, C:-C6 alkyl, Ci-Cs
hydroxyalkyl, Ci-Cs alkoxy Ci-C6 alkyl, or
Rao, Rai/ and the nitrogen to which they are attached form
a piperazinyl, or morpholinyl ring, each of which is
optionally substituted with 1 or 2 groups that are
independently alkyl or halogen
Embodiment A55. Compounds according to embodiment
A54, wherein
R5 is indolyl (d.-C4) alkyl, or pyrazinyl (Ci-C4) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, or 4 groups that are independently Ci-Cs alkyl,
halogen, Ci-C6 alkoxy, Ci-Cs hydroxyalkyl, benzyloxy, Ci-C6
thioalkoxy, -C02(C1-C5 alkyl), CO2H, CN, -C (O) NR2oR2i, CF3,
or OCF3; wherein
R2o and R2i are independently H, Ci-C6 alkyl, Ci-C6
hydroxyalkyl, Ci-C6 alkoxy Ci-C6 alkyl, or
R2o/ R2i/ and the nitrogen to which they are attached form
a piperazinyl, or morpholinyl ring, each of which is
optionally substituted with 1 or 2 groups that are
independently alkyl or halogen.
Embodiment A56. Compounds according to embodiment
A52, wherein
R5 is isoquinolinvl, isoindclyl, indol-2-onyl, quir.clir.yi (d-
Cs) aikyl, isoquinolinyl (C-.-Cg) alkyl, isoindolyl (C:-C5;
alkvl, indol-2-onyl (C^-Co-) alkyl, wherein
each of the above is unsubstituted or substituted wi-ch 1,
2, 3, 4, or 5 groups that are independently d-Ccalkyl,
halogen, Ci-Cs alkoxy, d-Cs hydroxyalkyl,
benzyloxy, d-C6 thioalkoxy, -C02(C1-C5 alkyl), C02K,
CN, amidinooxime, NR8R9, NRSR7-(d-C6 alkyl)-,
-C(0)NRSR7, amidino, CF3, or OCF3.
Embodiment A57. Compounds according to embodiment Al,
wherein
R! is H, halogen, methyl, ethyl, C2-C4 alkenyl, C2-C4 alkynyl,
or carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (d.-C6) alkyl, or
phenyl (d-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (d-C6) alkyl-N (R)-C02R30, MR6R7,
(d-C4) haloalkyl, (C1-C4) haloalkoxy, (Ci-C6) alkyl,
pyridyl, or NR6R7-(d-C6 alkyl)-; and
R4 is H, (d-C4) alkyl optionally substituted with one or two
groups that are independently C02H, -C02alkyl, -C(0)NRR, -
N(R30)C(0)NRR, -N(R30)C(0) - (Ci-Cg) alkoxy, or -NR6R7, or
hydroxy (Ci - C4) alkyl ;
R5 is C3-C7 cycloalkyl or C3-C7 cycloalkylalkyl, each of which
is optionally substituted with 1 or 2 groups that are
independently alkyl, alkoxy, halogen, -NR6R7, or NR6R7- (d-
C6 alkyl)-, wherein each of the alkyl groups is optionally
substituted with 1 or 2 groups that are independently OH,
methoxy, NH2, or halogen.
Embodiment A58. Compounds according to embodiment
A57, wherein
R5 is C3-C7 cycloalkyl or C3-C7 cycloalkyl Ci-C4 alkyl, each of
which is optionally substituted with I or 2 groups that
are independently Ci-C4 alkyl, Ci-C4 alkoxy, halogen,
NI^-Rv, or NRSR7-(Ci-Cs alkyl)- wherein each of the alkyl
groups is optionally substituted with I or 2 groups chat
are independently OH, methoxy, or NH2 ;
R6 and R7 are independently at each occurrence H, Ci-C4 alkyl,
Ci-C4 hydroxyalkyl, Ci-C4 alkoxy, Cj.-C4 alkoxy Ci-C4 alkyl,,
Ci-C4 alkanoyl, benzyl, benzyloxy, or phenyl Ci-C4
alkanoyl, wherein each is unsubstituted or substituted
with 1, 2, or 3 groups that are independently, halogen,
OH, SH, C3-C6 cycloalkyl, Ci-C4 alkoxy, Ci-C4 alkyl, CF3, or
OCF3; or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, or piperazinyl ring which
is optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, hydroxy, hydroxy Ci-C4 alkyl, or
halogen.
Embodiment A59. Compounds according to embodiment
ASS, wherein
RI is H, halogen, methyl, ethyl;
R2 is benzyloxy, phenyloxy, phenyloxy (Ci-C6) alkyl, or phenyl
(Ci-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (d-Cs) alkyl-N(R) -C02R30, . amino,
mono or dialkylamino, -NRSR7, (C1-C4) haloalkyl, (CX-C4)
haloalkoxy, (Ci-Cs) alkyl, or NR€R7-(Ci-C6 alkyl)-; and
R4 is H, methyl, (Ci-C4) alkyl optionally substituted with one'
or two groups that are independently C02H, -C02alkyl,
-C(0)NRR, -N(R30)C(0)NRR, -N (R30) C (0) - (Ci-C6) alkoxy, or -
NR6R7 or hydroxy (d-C2) alkyl.
Embodiment A60. Compounds according to embodiment
A59, wherein
R2 is substituted with two halogens and is further optionally
substituted with 1 or 2 groups that are independently
halogen, - (Ci-C5) alkyl-N (R) -CO-Rso, ammo, mono or
dialkylamino, -NRQ-R7, (C^-C^) haloalkyl, (C-Cj
haloalkoxy, (Ci-Cs) alkyl, or NR6R7-(Ci-C6 alkyl).
Embodiment A61. Compounds according to embodiment Al,
wherein
R5 is H, alkyl optionally substituted with 1, 2, or 3 groups
that are independently phenylalkoxycarbonyl, -NR8R9,
halogen, -C(0)NRBR9, alkoxycarbonyl, or alkanoyl,
alkoxyalkyl optionally substituted with one
trimethylsilyl group, alkoxycarbonyl, amino,
hydroxyalkyl, alkenyl optionally substituted with
alkoxycarbonyl, alkynyl, -S02-alkyl, or alkoxy optionally
substituted with one trimethylsilyl group, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, phenylalkoxy, thioalkoxy, -SO2alkyl,
alkoxycarbonyl, phenylalkoxycarbonyl, C02H, CN, OH,
amidinooxime, NRsRs, NR6R7-(Ci-C6 alkyl)-, -C(0)NR6R7,
amidino, hydroxyalkyl, carboxaldehyde, -NR6R7,
haloalkyl, or haloalkoxy;
wherein R8 is hydrogen, alkyl, alkanoyl, phenylalkyl
and arylalkanoyl; and
wherein R9 is alkyl, alkanoyl, phenylalkyl,
heteroaryl, aminoalkyl, monoalkylaminoalkyl,-
dialkylaminoalkyl, and arylalkanoyl.
In this embodiment, it is preferred that when R2 is
benzyloxy, R4 is H, and R5 is benzyl or methyl, Rx is not
hydrogen; and
no more than two of R1( R2, R4/ and. R5 are simultaneously
hydrogen.
Embodiment A62. Compounds according to embodiment AI,
wherein
R5 is H, alkyl optionally substituted with 1, 2, or 3 groups
that are independently phenylalkoxycarbonyi, -NRaR9,
halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl,
alkoxyalkyl optionally substituted with one
trimethylsilyl group, alkoxycarbonyl, amino,
hydroxyalkyl, alkenyl optionally substituted with
alkoxycarbonyl, alkynyl, -S02-alkyl, alkoxy optionally
substituted with one trimethylsilyl group, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, phenylalkoxy, thioalkoxy, -S02alkyl,
alkoxycarbonyl, phenylalkoxycarbonyi, C02H, CN, OH,
amidinooxime, NR8R9, NRSR7- (Ci-C6 alkyl)-, -C(O)NR6R7,
amidino, hydroxyalkyl, carboxaldehyde, -NRgRv,
haloalkyl, or haloaikoxy;
wherein R8 is hydrogen, alkyl, alkanoyl, phenylalkyl
and arylalkanoyl; and
wherein R9 is alkyl, alkanoyl, phenylalkyl,
heteroaryl, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, and arylalkanoyl.
In this embodiment, it is preferred that when R2 is
benzyloxy, R4 is H, and R5 is benzyl or methyl, RI is not
hydrogen; and
no more than two of RI, R2, R4, and R5 are simultaneously
hydrogen.
Embodiment A63. Compounds according to embodiment
A62, wherein
R is H, halogen, methyl, ethyl, C2-C4 alkenyl, C:-C4 alkynyl,
or carboxaldehyde;
R- is benzyloxy, OH, phenyloxy, phenyloxy (Ci-C0-) alkyl, or
phenyl (Ci-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (C1-CD-) alkyl-N (R)-C02R30, NR^R?,
(Ci-C4) haloalkyl, (C:.-C4) haloalkoxy, (Ci-CD-) alkyl,
pyridyl, or NR6R7- (Ci-C6 alkyl)-; and
R4 is H, (Cx-Cj alkyl optionally substituted with one or two
groups that are independently C02H, -C02alkyl, -C(0)NRR, -
N(R30) C (O)NRR, -N(R3o) C(0) - (Ci-Cg) alkoxy, or -NR0-R7, or
hydroxy (C!-C4) alkyl.
Embodiment A64. Compounds according to embodiment
A63, wherein
R5 is H, alkyl optionally substituted with 1, 2, or 3 groups
that are independently phenylalkoxycarbonyl, -NRaRs,
halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl,
alkoxyalkyl optionally substituted with one
trimethylsilyl group, alkoxycarbonyl, amino,
hydroxyalkyl, alkenyl optionally substituted with
alkoxycarbonyl, alkynyl, -S02-alkyl, alkoxy optionally
substituted with one trimethylsilyl group, wherein
wherein Ra is hydrogen, Ci-C4 alkyl, Ci-C4 alkanoyl,
phenyl C1-C4 alkyl and phenyl Ci-C4 alkanoyl;
wherein R9 is Ci-C4 alkyl, Ci-C4 alkanoyl, phenyl Ci-C4
alkyl, pyridyl, aminoalkyl, monoalkylaminoalkyl,
dialkylaminoalkyl, and phenyl Ci-C4 alkanoyl.
Embodiment A65. Compounds according to embodiment
A64, wherein
R5 is CI-GS alkyl optionally substituted with 1, 2, or 3 groups
that are independently phenyl Ci-C4 alkoxycarbonyl, NH2,
mono Ci-C4 alkylamino, di Ci-C4 alkylamino, halogen,
-C(0)NK2, -C(0)NH(Ci-Cs alkyl) wherein the alkyl is
optionally substituted with OH, NE2, or methoxy, -C(Q)N
(Ci-Cs alkyl) (C±-C6 alkyl) wherein each alkyl is
optionally substituted with OH, NH2, or methoxy, Ci-C4
alkoxycarbonyl, and C^-d alkanoyl, or
R5 is Ci-C4 alkoxy Ci-C4 alkyl, C3.-C4 alkoxycarbonyl, amino, Ci-
C4 hydroxyalkyl, C2-C4 alkenyl optionally substituted with
Cx-C4 alkoxycarbonyl, C2-C4 alkynyl, -SO-- Ci-C4 alkyl, or
C1-C4 alkoxy.
Embodiment A66. A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
R! is halogen, NO2, alkyl, carboxaldehyde, hydroxyalkyl,
arylalkoxy, arylalkyl, CN, aryl, alkanoyl, alkoxy,
alkoxyalkyl, haloalkyl, or arylalkanoyl,
wherein the aryl portion of arylalkoxy, arylalkyl, and
arylalkanoyl is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
(Ci-Cj alkyl, (Ci-C4) alkoxy, nitro, CN, haloalkyl,
haloalkoxy or CO2H;
wherein the alkyl portion of the alkyl, hydroxyalkyl,
arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl
and arylalkanoyl groups is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, Ci-C4 alkoxy, Ci-C4
alkoxycarbonyl, or spirocyclopropyl;
R2 is aryl, heteroaryl, arylalkenyl, arylalkoxy, aryloxyalkyl,
arylalkyl, OH, alkynyl, aryloxy, aryloxyalkyl,
arylthioalkoxy, alkoxy, -OC (0) NH (CH:) naryl,
-CC(0)N(alkvl) (CH:)naryl, -OS02 (C^C.) alkyl, -OSC-aryl,
alkyl, alkoxyalkoxy, NRSR9, or C02H, wherein
n is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituced or substituted. 1,
2, 3, 4, or 5 groups that are independently halogen,
- (Ci-C6) alkyl-N(R)-C02R30/ alkoxy, alkoxycarbonyl, CN,
NRSR7/ haloalkyl, haloalkoxy, alkyl, heteroaryl,
heteroarylalkyl, NR0-R7- (Ci-Cs alkyl)-, phenyl, -S02-
phenyl wherein the phenyl groups are optionally
substituted with I, 2, or 3 groups that are
independently halogen or NO2; or -OC(0)NR6R7, wherein
R6 and R7 are independently at each occurrence H,
alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
SO2-alkyl, OH, hydroxyalkyl, - (d-C4) alkyl-CO2-
alkyl, heteroarylalkyl, alkanoyl, arylalkyl,
arylalkoxy, or arylalkanoyl, wherein each of
the above is unsubstituted or substituted with
1, 2, or 3 groups that are independently,
halogen, alkoxy, heterocycloalkyl, OH, SH, C3-CS
cycloalkyl, NH2, NH(alkyl), N(alkyl)(alkyl), -0-
alkanoyl, alkyl, haloalkyl, or haloalkoxy; or
R6, R-!, and the nitrogen to which they are attached
form a morpholinyl, thiomorpholinyl,
piperidinyl, pyrrolidinyl, or piperazinyl ring
which is optionally substituted with 1 or 2
groups that are independently Cx-C4 alkyl, Ci-C4
alkoxy, hydroxy, hydroxy C!-C4 alkyl, or
halogen;
R at each occurrence is independently H or Ci-C6
alkyl;
R30 is C-Cs alkyl optionally substituted with 1 or 2
groups that are independently OH, SH, halogen,
amino, moncalkylamino, dialkylamino cr C3-C0-
cycloalkyl;
R4 is.H, alkyl optionally substituted with one cr two groups
that are independently C02H, -C02alkyl, -C(0)NRR,
N(R30)C(0)NRR, -N(R30)C(0) - (Ci-Cs) alkcxy, or -NR£R7,
arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, alkoxy,
carboxaldehyde, C02H, alkoxyalkyl, or alkoxyalkoxy,
wherein
the aryl portion of arylalkoxy, arylalkyl is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, hydroxy,
alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is H, arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,
heteroarylalkyl, heterocycloalkyl, cycloalkyl,
cycloalkylalkyl, -alkyl-S-aryl, -alkyl-S02-aryl, - (C1-C4)
alkyl-C(0)-heterocycloalkyl, -S02-aryl, or heteroaryl,
wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, aryl, arylalkoxy, thioalkoxy,
alkoxycarbonyl, arylalkoxycarbonyl, OH, C02H, CN,
amidinooxime, NR8R9, NR6R7- (C^-Cg alkyl)-, -C(0)NRSR7,
- (Ci-C4 alkyl)-C(0)NRSR7, amidino, hydroxyalkyl,
SO2alkyl, -S02H, -S02NR6R7, -NR6R7, alkanoyl wherein
the alkyl portion is optionally substituted with OH,
halogen or alkoxy, haloalkyl, - (C].-C4 alkyl)-
NRi5C(0)NRlsR17, -(Ci-C4 alkyl) -NRiSC (0) R1B, -0-CH2-0, -
0-CH2CH2-0-, or haloalkoxy; wherein
R8 at each occurrence is independently hydrogen,
alkyl, alkanoyl, arylalkyl and arylalkanoyl
wherein each of the above is optionally
substituted with 1, 2, 3, 4, or 5 groups that
are independently alkyl, aikoxy,
alkoxycarbonvl, halogen, or haloalkyl; and
R9 at each occurrence is independently alkyl,
alkanovl, arvlalkyl cycloalkyl, , alkenyl,
heteroaryl, cycloalkylalkyl, arylalkancyl, -S0:-
phenvl, and aryl wherein each of the above is
optionally substituted with 1, 2, 3, 4, or 5
groups that are independently alkyl, aikoxy,
alkoxycarbonyl, halogen, or haloalkyl;
RIS is H or Ci-Cg alkyl;
R16 and R17 are independently H or Ci-Cg alkyl; or
RIS, RI?/ and the nitrogen to which they are attached
form a morpholinyl ring; and
R18 is Ci-Cg alkyl optionally substituted with -0- (C2-
C6 alkanoyl, Ci-C6 hydroxyalkyl, Ci-Cg aikoxy,'
Ci-Cg aikoxy Ci-C6 alkyl; amino Ci-C6 alkyl, mono
or dialkylamino Ci-Cg alkyl.
In this embodiment, it is preferred that:
R6 and R7 are not simultaneously OH;
RG and Rare not simultaneously -S02(Ci-C6 alkyl) ;
when R2 is OH, R4 is methyl and R5 is phenyl, R! is not acetyl ;
and
R4 and R5 are not simultaneously hydrogen.
Embodiment A71. Compounds according to
embodiment A66 wherein
RI is halogen, C^-Cg alkyl, phenyl, carboxaldehyde, Ci-C6
hydroxyalkyl, phenyl Ci-Cg aikoxy, phenyl Cx-Cg alkyl, CN,
Ci-Cs alkanoyl, d.-Cg aikoxy, Ci-C6 aikoxy C^-CS alkyl, Ci-C6
haloalkyl, or phenyl Ci~C5 alkanoyl,
wherein the above phenyl groups are unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, (d-C4) alkyl, (Ci-C4) alkoxy,
nitro, CN, Ci-C4 haloalkyl, Ci.-C4 haloalkoxy or C02H;
wherein the above alkyl groups are unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, or ethoxy,
R2 is phenylalkoxy, OH, phenyloxy, phenyloxy (Ci-Cs) alkyl,
phenylthio(Ci-C4)alkoxy, alkoxy, alkenyl, phenethyl,
-OC (0)NH(CH2)nphenyl, -OC (0) N (alkyl) (CH2) nphenyl, alkyl,
alkoxyalkoxy, NR8R9, pyridyl, pyrimidyl, pyridazyl,
pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl,
amino, tetrahydroisoquinollnyl, tetrazolyl, pyrazinyl,
benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,
hexahydropyrimidinyl, thiazolyl, thienyl, or C02H, wherein
n is 0, 1, 2, or 3;
each of the above is unsubstituted or substituted with I,
2, 3, 4, or 5 groups that are independently halogen,
- (Ci-C6) alkyl-N(R) -C02R30, haloalkyl, haloalkoxy,
alkyl, thienyl, pyridyl, or phenyl optionally
substituted with 1, 2, or 3 halogens;
R6 and R7 are independently at each occurrence H, alkyl,
alkoxy, alkoxyalkyl, hydroxyalkyl, alkoxycarbonyl, -
(Ci-C4) alkyl-CO2-alkyl, alkanoyl, phenylalkyl,
phenylalkoxy, or phenylalkanoyl, wherein each of the
above is unsubstituted or substituted with 1, 2, or
3 groups that are independently, halogen, OH, SH, Cs-
Cs cycloalkyl, alkoxy, NH2, NH (Ci-Cs alkyl) ,. N (Ci-Cs
alkyl) (Ci-Cs alkyl), alkyl, CF3 or OCF3; or
Rs, R-7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, hydroxy, hydroxy Ci-C4
alkyl, or halogen;
R4 is H, alkyl optionally substituted with one or two groups
that are independently C02K, -CO-alkyl, -C(0)NRR,
N(R30)C(0)NRR, -N(R30) C(0) - (Ci-Cs) alkoxy, or -NR6R-;
chenvlalkcxy, phenylalkyl, hydroxyalkyl, carbcxaldehyde,
haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl,
or haloalkoxy; and
R3 is benzyl, phenethyl, (Ci-Cs)alkyl, phenyl, naphthyl,
alkoxy, piperidinyl, pyrrolidinyl, imidazolidinyl,
piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl,
indolyl, IH-indazolyl, pyridyl, pyrimidyl, pyridazyl,
pyrazinyl, piperidinyl (Cj.-Cs) alkyl, pyrrolidinyl (Ci-
Cg) alkyl, imidazolidinyl (Ci-C6) alkyl, piperazinyl (Ci-
Cfi) alkyl, pyridyl (Ci-Cs) alkyl, pyrimidyl (d-C6) alkyl,
pyridazyl (Ci-Cs) alkyl, pyrazinyl (Ci-Cs) alkyl,
isoquinolinyl (Ci-C6) alkyl, tetrahydroisoquinolinyl (Ci-
C6) alkyl, indolyl (d-Cg) alkyl, or IH-indazolyl (Ci-Cs) alkyl,
and wherein
each of the above is unsubstituted or substituted with I,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, hydroxyalkyl, phenylalkoxy,
thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl,
OH, C02H, CN, amidinooxime, NR8R9, NRSR7-(Cx-Cs alkyl)-
, -C(0)NR6R7, amidino, piperazinyl, morpholinyl, -SO2
(Ci-Cg) alkyl, -S02NH2, -S02NH (Ci-Cs) alkyl, -S02N(C!-
Cs)alkyl (Ci-Cs)alkyl, haloalkyl, or haloalkoxy.
In this embodiment, it is preferred that when R2 is OH, R4
is methyl and R5 is phenyl, RI is not acetyl; and
R4 and R5 are not simultaneously hydrogen.
Embodiment A72. Conroounds accordina to embodiment A71
wh e r S1n
RJ_ is halogen, alkyl, carbcxaldehyde, hydroxyalkyl,
phenylalkoxy, phenyl, benzyl, phenethyl, phenpropyl,
phenbutyl, CN, (C2-C6)alkanoyl, haloalkyl, or phenylCO-,
phenylCH2CO- , phenylCH2CH2CO-,
wherein the above phenyl groups are unsubstituted or
substituted with I, 2, or 3 groups that are
independently halogen, (Ci-C4) alkyl, (Ci-C4) alkoxy,
nitro, CM, haloalkyl, haloalkoxy or C02H;
wherein the above alkyl groups are unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, or ethoxy,
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,
phenyloxy (Ci-C6) alkyl, phenylthio (Ci-C4) alkoxy, NR8R9, (Ci-
C6) alkyl, alkynyl, phenethyl, -OC (0)N (CH3) CH2phenyl,
alkoxyalkoxy, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,
imidazolyl, pyrrolyl, pyrazinyl, piperidinyl,
hexahydropyrimidinyl, benzimidazolyl, or thienyl, wherein
each of the above is unsubstituted or substituted with 1,
2, or 3 groups that are independently halogen, - (Ci-
C6)alkyl-N(R) -C02R3o, CF3/ OCF3, (C1-C4) alkyl, thienyl,
pyridyl, or phenyl optionally substituted with 1, 2,
or 3 halogens;
RS and R7 are independently at each occurrence H, (Ci-
Cs) alkyl, (d-Cs) alkoxy, (Ci-C6) alkoxy (Ci-Cs).alkyl,
(CI-GS) alkoxycarbonyl, hydroxy (Ci-Cg) alkyl, - (Ci-
C4) alkyl-C02-alkyl, (Cx-Cg) alkanoyl, phenyl (Ci-
Cs) alkyl, phenyl (Ci-Cg) alkoxy, or phenyl (Ci-
C6)alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, (Ci-Ce) alkoxy, NH2/
OH, SH, C3-C0- cycloalkyl, (Ci-C5) alkyl, C?3 cr OC?3 ;
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, piperidinyl, pyrrolidinyl, or
pioerazinyi ring which is optionally substituted
with 1 or 2 groups that are independently CL-C4
alkyl, hydroxy, hydroxy Ci-C4 alkyl, or halogen;
R4 is K, alkyl optionally substituted with one or two groups
that are independently C02H, -C02alkyl, -C(0)NRR,
N(R30)C(0)NRR, -N(R30)C(0) - (Ci-Cs) alkoxy, or -NR6R7,
benzyloxy, phenethyloxy^ •• phenpropyloxy, benzyl,
phenethyl, phenpropyl, hydroxyalkyl, halo(Ci-C4)alkyl,
carboxaldehyde, alkoxy, alkoxyalkyl, or' alkoxyalkoxy,
wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, hydroxy, alkoxy, alkyl, nitro, CF3 or OCF3;
and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Ci-C6) alkyl,
phenyl, piperidinyl, pyrrolidinyl, imidazolidinyl,
piperidinyl (Ci-Cs) alkyl, pyrrolidinyl (Ci-C6) alkyl,
imidazolidinyl (Ci-Cs) alkyl, pyridyl, pyrimidyl, pyridazyl,
pyrazinyl, pyridyl (Ci-C6) alkyl, pyrimidyl (Ci-Cs) alkyl,
pyridazyl (Ci-Cs) alkyl, or pyrazinyl (Ci-C6) alkyl wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, haloalkyl, NR8Rg, NRSR7- (Ci-Cs alkyl)-,
carboxaldehyde, morpholinyl, S02NH2, S02NH (alkyl) ,
S02N(alkyl)(alkyl), alkoxy, hydroxyalkyl, benzyloxy,
thioalkoxy, OH, C02H, CN, -C02 (d-C5 alkyl),
phenylalkoxycarbonyl, amidinooxime, amidino,
-C(0)NR6R7/ CF3, CF2CF3, ClCH2, or OCF3.
In this embodiment, it is preferred that when R2 is OH, R4
is methyl and R5 is phenyl, RI is net: acetyl.
Embodiment A73. Compounds according to embodiment A72
wherein
R! is halogen, alkyl, carboxaldehyde, hydroxy (C1-C4) alkyl,
phenylalkoxy, benzyl, phenethyl, -C(0)CK3, phenylCO-, or
phenyl CH2 CO-,
wherein the above phenyl groups are unsubscituted or
substituted with 1, 2, or 3 groups that are
independently halogen, (Ci-Cj alkyl, (Ci-C4) alkoxy,
nitro, CN, CF3, or OCF3;
wherein the above alkyl groups are unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,
phenyloxy (Ci-Cg) alkyl, phenethyl, NRBR9, -S-benzyl, or (Ci-
C6) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, or 3 groups that are independently halogen, -(Cj-
C6) alkyl -N (R) -CO2R30, CF3, OCF3 , alkyl, thienyl, or
pyridyl ;
Rs and R7 are independently at each occurrence H, (Cx-
C6) alkyl, (CL-CS) alkoxy, (Ci-Cg) alkoxy (Ci-C6) alkyl,
(Ci-Cs) alkoxycarbonyl, hydroxy (C^-Cs) alkyl, - (Ci-
C4) alkyl-C02-alkyl, (d-Cs) alkanoyl, phenyl (Cx-
C6) alkyl, phenyl (Ci-Cs) alkoxy, or phenyl (Ci-
C6)alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, (C^Cg) alkoxy, NH2,
OH, SH, C3-C6 cycloalkyl, (Ci-C6) alkyl, CF3 or OCF3 ;
or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, piperidinyl, pyrrolidinyl, or
piperazinyl ring which is optionally substituted
with 1 or 2 groups that are independently Ci-C4
alkyl, hydroxy, hydroxy Ci-C4 alkyl, or halogen;
R4 is H, alkyl optionally substituced with one or two groups
that are independently C02H, -C02alkyl, -C(0)NRR,
N(R30) C (O)NRR, -N(R30)C(0) - (C1-CS) alkoxy, or -NRSR7,
benzyloxy, phenechyloxy, phenpropyloxy, benzyl, or
hydroxyalkyl, wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, hydroxy, alkoxy, alkyl, nitro, CF3 or OCF3;
and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Ci-Cs)alkyl,
phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl(d~
C5) alkyl, pyrimidinyl (GX-CS) alkyl, or pyridyl (d-C4) alkyl,
wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, haloalkyl, morpholinyl, -S02 (Ci-C6) alkyl,
-S02NH2, -S02NH (Ci-Cs) , -S02N(Ci-Cs) (d-C6) , (d-
C4) alkoxy, phenyl (d-C4) alkoxy, thio (Ci-C4) alkoxy,
(Ci-C4) alkoxycarbonyl, OH, C02H, CN, amidinooxime,
amidino, NR8R9, NR6R7-(d-C6 alkyl)-, hydroxyalkyl,
CONR6R7 CF3, or OCF3.
Embodiment A74. Compounds according to embodiment A73
wherein
RI is halogen, alkyl, carboxaldehyde, or hydroxyalkyl;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy,
phenyloxy (d-C6) alkyl, phenethyl, phenylthioalkoxy, or
(Ci-Cg) alkyl, wherein
-89-
each of the above is unsubstituted or substituted with 1,
2, or 3 groups that are independently halogen, - (CT.-
Cs)alkyl-N(R) -CC:R30, CF3, OCF3, alkyl, thienyl, or
pyridyl;
R4 is H, (Ci-C4) alkyl optionally substituted with one or two
groups that are independently C02H, -CO2alkyl, -C(0)NRR,
-N(R30)C(0)NRR, -N(R3Q)C(0) - (Cl-Cs)alkoxy, or -ISTRoR?,
benzyloxy, or phenethyloxy, wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, hydroxy, (d-C4) alkoxy, (Ci-C4) alkyl, nitro,
CF3 or OCF3; and
R5 is benzyl, phenethyl, (Ci-C6) alkyl, phenyl, indazolyl, or
pyridyl, wherein each of the above is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently (Ci-C4) alkyl, halogen, OH, C02H, CN,
(Ci-C4) alkoxy, -C (0) pyrrolidine, -S02 (Ci-Cs) alkyl,
benzyloxy, -C02(Ci-C5 alkyl), amidino, thio (C!-C4) alkoxy,
amidinooxime, CF3, NR8R9, NRSR7-(Ci-C6 alkyl)-, COMRgR?, or
OCF3.
Embodiment A75. Compounds according to embodiment A74
wherein
RI is chloro, bromo, iodo, methyl, C2-C3 alkenyl, C2-C3 alkynyl;
and
R5 is benzyl, phenethyl, phenpropyl, phenyl, or pyridyl, each
of which is unsubstituted or substituted with 1, 2, or 3
groups that are independently alkyl, OH, halogen, alkoxy,
NH2, NH(Ci-C6) alkyl, N(C1-C6) alkyl (Ci-Cs) alkyl, NR8R9, NR6R7-
(Ci-C6 alkyl)-, CONRgRv, and amidinooxime; wherein
R6 and R7 are independently H, Ci-C4 alkyl, Ci-Cg alkanoyl,
wherein the alkyl and alkanoyl groups are optionally
substituted with 1, 2, or 3 groups
ir-deoenden~lv OH, halogen, or C3-C7 cyclcprcpyl.
Embodiment A76. Compounds according to embodimei
wherein
R2 is benzyloxy, phenethyl, phenyloxy (Ci-C5) alkyl, or
phenethyloxy, each of which is unsubstituted cr
substituted with 1, 2, or 3 groups that are independently
halogen, - (d-Cfi) alkyl-N(R)-C02R3o, CF3, OCF3, or
(d-Cj alkyl.
Embodiment A77. Compounds according to embodiment
A66, wherein
R5 is benzyl, phenethyl, thienyl (d-C6 alkyl), piperidinyl (d-
C6) alkyl, pyrrolidinyl (Ci-C6) alkyl, imidazolidinyl (Cx-
Cs) alkyl, piperazinyl (d-Cs) alkyl, pyridyl (Ci-C6) alkyl,
pyrimidyl (Ci-C6) alkyl, pyridazyl (d~Cs) alkyl, pyrazinyl (Cx-
Cs) alkyl, isoquinolinyl (Cx-C6) alkyl,
tetrahydroisoquinolinyl (d-C6) alkyl, indolyl (d-Cs) alkyl,
or IH-indazolyl(Cx-Cs)alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently (Cx-
Cs) alkyl, halogen, (d-Cs) alkoxy, (d-C6) hydroxyalkyl,
phenyl (Cx-Cs) alkoxy, (d-C6) thioalkoxy, (d-
C6) alkoxycarbonyl, phenyl (Ci-Cs) alkoxycarbonyl, OH,
C02H, CN, amidinooxime, NR8R9, NR6R7-(Cx-C6 alkyl)-, -
C(0)NR6R7, amidino, piperazinyl, morpholinyl, -S02
(Ci-Cs) alkyl, -S02NH2, -SO2NH (d-C6) alkyl, -S02N(Cx-
C6) alkyl (Cx-C6) alkyl, (d-C4) haloalkyl, - (d-C4
alkyl)-NRx5C(0)NR16Rx7, - (d~C4 alkyl)-NR1SC (0) R18l -0-
CH2-0, -0-CH2CH2-0-, or (d-C4) haloalkoxy; wherein
R6 and R7 are independently at each occurrence H,
alkyl, (Cx-Cs) alkoxy, (Cx-Cs) alkoxy (d-
C5)alkyl, (C:-C5) alkoxycarbonyl, (d-
C0-)hydroxyalkyl, - (d-C4) alkyl-CO2- (d-C6) alkyl,
(d-C0-) alkanoyl, phenyl (Ci-C0-) alkyl, phenyl (d.-
Cs)alkoxy, or phenyl (d-C6) alkanoyl, wherein
each of the above is unsubstituteci or
substituted with 1, 2, or 3 groups that are
independently, halogen, (Ci-C4)alkoxy, NH2, OH,
SH, C3-C5 cycloalkyl, NH(d-C6 alkyl), N(d-Cs
alkyl) (Ci-Cfi alkyl), (d-C4) alkyl, CF3 or OCF3;
or
R6, R7, and the nitrogen to which they are attached
form a morpholinyl, thiomorpholinyl,
piperidinyl, pyrrolidinyl, or piperazinyl ring
which is optionally substituted with 1 or 2
groups that are independently d-C4 alkyl,
hydroxy, hydroxy d-C4 alkyl, or halogen; and
RIB is Ci-Cg alkyl optionally substituted with -0-(C2-
C6 alkanoyl, d-Cg hydroxyalkyl, d~Cs alkoxy,
Ci-Cg alkoxy Ci-C6 alkyl; amino Ci-C6 alkyl, mono
or diaikylamino Ci-Cg alkyl.
In this embodiment, it is preferred that Rs and R7 are not
simultaneously OH; and
R6 and R7 are not simultaneously -S02(d-C6 alkyl) .
Embodiment A78. Compounds according to embodiment
A77, wherein
RI is halogen, methyl, ethyl, C2-C4 alkenyl, C2-C4 alkynyl, or
carboxaldehyde ;
R2 is benzyloxy, OH, phenyloxy, pheny 1 oxy (Ci-Cg) alkyl, or
phenyl (Ci-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (d-C6) alkyl-N (R) -C02R30, NR6R7,
(Ci-C4) haloalkyl, (Ci-C4) haloalkoxy, (Ci-C5) alkyl, or
pyridyl; and
R4 is H, (Ci-C4) alkyl optionally substituted with one cr two
groups that are independently CO:H, -C02alkyl, -C(0)NRR,
-N(R30)C(0)NRR, -N(R30)C(0) - (Ci-C6)alkoxy, or -NRC-R7, or
hydroxy (Ci-C4) alkyl.
Embodiment A79. Compounds according to embodiment
A78, wherein
R5 is benzyl, or phenethyl, wherein each is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently (Ci-C6) alkyl, halogen, (d~C6) alkoxy, (Cl-
Cs) hydroxyalkyl, phenyl (d-C6) alkoxy, (Ci-Cs) thioalkoxy,
(Ci-C6) alkoxycarbonyl, phenyl (d-Cs) alkoxycarbonyl, OH,
C02H, CN, amidinooxime, NR8R9, NR6R7- (Ci-Cs alkyl)-, ' -
C(0)NR6R7, - (d-C4 alkyl)-C (0) NR6R7amidino, piperazinyl,
morpholinyl, -S02 (Ci-C6) alkyl, -S02NH2, -S02NH(d-
C6) alkyl, -S02N(Ci-C6) alkyl (Ci-Cs) alkyl, (C1-C4) haloalkyl,
-(d-C4 alkyl)-NRiSC(0) RIB, -0-CH2-0, -0-CH2CH2-0-, or (d-
C4)haloalkoxy; wherein
R6 and R7 are independently at each occurrence H, (Ci-
C6) alkyl, (Ci-Cs) alkoxy, (d-C6) alkoxy (d-C6) alkyl,
(Ci-Cg) alkoxycarbonyl, (d-C6) hydroxyalkyl, - (d~
C4) alkyl-C02-(d-C6) alkyl, (d-C6) alkanoyl, phenyl (d-
C6) alkyl, phenyl (Ci-Cg) alkoxy, or phenyl (Ci-
)alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, (d-C4) alkoxy, NH2,
OH, SH, C3-C6 cycloalkyl, NH(d-C6 alkyl), N(d-Cs
alkyl) (Ci-Cg alkyl), (Ci-C4) alkyl, CF3 or OCF3; or
RS, R?/ and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, hydroxy, hydroxy Ci-C4
alkyl, or halogen/ and
RIB is CI-GS alkyl optionally substituted with -0- (C:-C0-
alkanoyl, Ci-Cs hydroxyalkyl, d-Cs alkoxy, Ci-Coal
koxy Ci-Cs alkyl, amino Ci-Cs alkyl, or mono or
dialkylamino Ci-C6 alkyl.
In this embodiment, it is preferred that Rs and R7 are not
simultaneously OH; and
R6 and R7 are not simultaneously -SO2 (Ci-C6 alkyl).
Embodiment A80. Compounds according to embodiment
A79, wherein
R5 is benzyl or phenethyl, wherein each is optionally
substituted with 1, 2, 3, 4, or 5 groups that- are
independently Ci-Cs alkyl, -C(0)NR6R7, - (Ci-C4 alkyl)-
C(0)NRSR7, NR8R9/ halogen, d-C6 alkoxy, C02H, - (d-C4
alkyl)-C02H, Ci-C6 thioalkoxy, amidinooxime, Ci-Cs
alkoxycarbonyl, - (d-C4 alkyl)-d-Cs alkoxycarbonyl, Ci-C6
hydroxyalkyl, -(CX-C4 alkyl)-CN, CN, phenyl Ci-C6 alkoxy,
OH, Ci-C4 haloalkyl, Ci-C4 haloalkoxy, NR6R7- (Ci-C6 alkyl)-,
-(Ci-C4 alkyl)-NRi5C(0)R13, amidinooxime, -S02 (Ci-Cs alkyl),
-O-CH2-0-, -0-CH2CH2-0-, phenyl Ci-C4 alkoxy, or phenyl;
wherein
R6 and R7 at each occurrence are independently H, OH, Ci-Cs
alkyl, amino Ci-C4 alkyl, NH(d-Cs alkyl) alkyl, N(Ci-
C6 alkyl) (Ci-Cs alkyl) d-C6 alkyl, d-C6 hydroxyalkyl,
Ci-Cg alkoxy d-C6 alkyl, -S02 (C1-C6 alkyl) each of
which is optionally substituted with 1, 2, or 3'
groups that are independently halogen, OH, SH, C3-CS
cycloalkyl, d-C4 alkoxy, d~C4 alkyl, OH, CF3, or
OCF3 ;
or
Rs/ R7, and the nitrogen to which they are attached form a
pioeridinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl, thicmorpholinyl, ring opticnaliy
substituted with 1 or 2 groups that are
independently alkyl, hydroxy, hydroxy Ci-C4 alkyl, or
halogen,
RIB is CI-GS alkyl optionally substituted with -0- (C2-C5
alkanoyl, C:-C6 hydroxyalkyl, Ci-C6 alkoxy, d-Cs
alkoxy Ci-Cs alkyl; amino d-Cs alkyl, mono or
dialkylamino Ci-Cs alkyl.
In this embodiment, it is preferred that Rs and R7 are not
simultaneously OH; and
Rs and R7 are not simultaneously -S02 (Ci~Cs alkyl) .
Embodiment A81. Compounds according to embodiment
A80, wherein
R5 is benzyl or phenethyl, wherein each is optionally
substituted with 1, 2, 3, 4, or 5 groups that are
independently Ci-Cs alkyl, -C(0)MRSR7, - (d-C4 alkyl)-
C(0)NRSR7, halogen, Ci-Cs alkoxy, C02H, - (CX-C4 alkyl) -C02H,
CI-GS thioalkoxy, amidinooxime, Ci-C6 alkoxycarbonyl, - (Ci-
C4 alkyl)-CX-GS alkoxycarbonyl, d-C6 hydroxyalkyl, - (Ci-C4
alkyl)-CN, CN, phenyl Ci-Cs alkoxy, OH, Ci-C4 haloalkyl,
Ci-C4 haloalkoxy, NR6R7- (Ci-C6 alkyl)-, NR8R9, - (Ci-C4
alkyl)-NRisC (0)Ri8, amidinooxime, -SO2 (Ci-Cs alkyl), -0-CH2-
0-, -0-CH2CH2-0-, phenyl Ci~C4 alkoxy, or phenyl; wherein
RS and R7 at each occurrence are independently H, OH, Ci-Cs
alkyl, amino Ci-C4 alkyl, NH(Ci-C6 alkyl)alkyl, N(Ci-
Cs alkyl) (Ci-Cfi alkyl) Ci-C« alkyl, d-C6 hydroxyalkyl,
Ci-Cs alkoxy Ci-C6 alkyl, -S02 (d-C6 alkyl) each of
which is optionally substituted with 1, 2, or 3
groups that are independently halogen, OH, SH, C3-C0-
cycloaikyl, d-C4 alkoxy, d-C4 alkyl, OH, CF3/ or
OCF3; and
RIB is Ci-C0- alkyl optionally substituted with -0-(C:-CS
alkanoyl, d-C0- hydroxyalkyl, d-Cs alkoxy, d-Cg
alkoxy Ci-Cs alkyl; amino Ci-C0- alkyl, mono or
dialkylamino Ci-Cs alkyl.
In this embodiment, it is preferred that Ra- and R7 are not
simultaneously OH; and
Rs and R7 are not simultaneously -S02 (d-C6 alkyl) .
Embodiment A82. Compounds according to embodiment
A81, wherein
R5 is benzyl which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently Ci-C4 alkyl, -C(0)NR6R7,
- (Ci-C4 alkyl) -C (0)NR6R7, halogen, d-C4 alkoxy, C02H, Ci-C4
thioalkoxy, d-C4 alkoxycarbonyl, d~Cg hydroxyalkyl, CN,
OH, NR6R7-(d-C6 alkyl)-, NR8R9, -S02(C1-CS alkyl), or
benzyloxy; wherein
R6 and R7 at each occurrence are independently H, OH, d-C6
alkyl, amino d-C4 alkyl, NH(d-C6 alkyl) alkyl, N(d-
C6 alkyl) (Ci-Cs alkyl) Ci-Cs alkyl, d-Cs hydroxyalkyl,
Ci-Cs alkoxy d~C6 alkyl, -S02 (Ci-Cs alkyl) each of
which is optionally substituted with 1, 2, or 3
groups that are independently halogen, OH, SH, C3-C6
cycloaikyl, d-C4 alkoxy, d-C4 alkyl, OH, CF3, or
OCF3.
In this embodiment, it is preferred that R6 and R7 are not
simultaneously OH; and
R6 and R7 are not simultaneously -SO2 (Ci-C6 alkyl).
Embodiment AS3. Compounds according to embodiment
A82, wherein
R5 is benzyl which is optionally substituted, with 1, 2, 3, 4,
or 5 groups that are independently C:-C4 alkyl, -C(C)NR0-R7/
- (Ci-C4 alkyl)-C(0)NRSR7, halogen, d-C4 alkoxy, C-_-C4
thioalkoxy, C:-C4 alkoxycarbony 1, C-_-C6 hydrcxyalkyi, CN,
NR8R9/ or NR5R7-(d-Cs alkyl)-; wherein
Rs and R7 at each occurrence are independently H, OH, d-C5
alkyl, amino d-C4 alkyl, NH(Ci-Cs alkyi) alkyl, N(Ci-
C6 alkyl) (d-Cs alkyl) d-Cg alkyl, Ci-C6 hvdroxyalkyl,
or Ci-C4 alkoxy Ci-C4 alkyl each of which is
optionally substituted with 1, 2, or 3 groups that
are independently halogen, OH, SH, C3-C6 cycloalkyl,
d-C4 alkoxy, Ci-C4 alkyl, OH, CF3, or OCF3.
In this embodiment, it is preferred that R6 and R7 are not
simultaneously OH.
Embodiment A84. Compounds according to embodiment
A83, wherein
the RS group is disubstituted with two groups that are meta to
each other.
Embodiment A86. Compounds according to embodiment
A80, wherein
R5 is benzyl which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently Cx-C4 alkyl, -C(0)NR6R7,
-(d-C4 alkyl)-C(0)NR6R7/ NRaR9, NR6R7- (Ca.-Cs alkyl)-,
halogen, C!-C4 alkoxy, C02H, - (d-C4 alkyl)-C02H, - (d-C4
alkyl)-GI-CS alkoxycarbonyl, - (d-C4 alkyl)-CN, CN, phenyl
d-C6 alkoxy, CF3, OCF3, - (d-C4 alkyl)-NR15C (0) RIB,
amidinooxime, -0-CH2-O-, -0-CH2CH2-0-, or phenyl; wherein
R6 and R7 at each occurrence are independently H, d-C4
alkyl, amino d~C4 alkyl, NH(Ci-C4 alkyl) alkyl, N(Ci-
C4 alkyl) (d-C4 alkyl) d-C4 alkyl, d-C6 hydroxyalkyl,
Ci-C4 alkoxy Ci-C4 alkyl, or OH, each of which is
optionally substituted with 1, 2, or 3 groups that
are independently halogen, OE, SH, C3-C5 cycloalkyl,
d-C4 alkoxy, Ci-C4 alkyl, OH, CF3, or CCF3; and
R-.B is C-C5 alkyl, Cl-Cs hydroxyalkyl, Ci-C5 alkoxy, O-C4
alkoxy Ci-C6 alkyl; amino Ci-C6 alkyl, mono or
dialkylamino Ci-Cs alkyl.
In this embodiment, it is preferred that Rs and R7 are not
simultaneously OH.
Embodiment A87. Compounds according to embodiment
A80, wherein
R5 is benzyl or phenethyl, wherein each is optionally
substituted with 1, 2, 3, 4, or 5 groups that are
independently Ci-C6 alkyl, -C(0)NRSR7, - (Ci-C4 alkyl)-
C(0)NR6R7, halogen, Ci-C6 alkoxy, C02H, - (d-C4 alkyl)-CO2H,
Ci-Cg thioalkoxy, amidinooxime, Ci-C6 alkoxycarbonyl, - (Ci-
C4 alkyl)-Ci-Cs alkoxycarbonyl, Ci-C6 hydroxyalkyl, - (Ci-C4
alkyl)-CN, CN, phenyl Ci-C6 alkoxy, OH, Ci-C4 haloalkyl,
Ci-C4 haloalkoxy, NR8R9, NR6R7-(Ci-Cs alkyl)-, - (C!-C4
alkyl)-NR1SC(0)R18/ amidinooxime, -S02 (d-Cg alkyl), -0-CH2-
0-, -0-CH2CH2-0-, phenyl Ci-C4 alkoxy, or phenyl; wherein
Rs, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl, thiomorpholinyl, ring optionally
substituted with 1 or 2 groups that are
independently alkyl, hydroxy, hydroxy Ci-C4 alkyl, or
halogen,
R18 is Ci-Cs alkyl optionally substituted with -0-(C2-CS
alkanoyl, Ci-C6 hydroxyalkyl, C^-C6 alkoxy, Ci-Cs
alkoxy Ci-Cs alkyl; amino Ci-Cs alkyl, mono or
dialkylamino Ci-C6 alkyl.
In this embodiment, it is preferred that R6 and R7 are not
simultaneously OH; and
R5 and R7 are not: simultaneously -S02 (Ci-C5 alkyl) .
Embodiment ASS. Compounds according to embodiment
AS 1, wherein
R5 is benzyl which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently Ci-C4 alkyl, -C(0)NR£R7,
- (d-C4alkyl) -C(0)NR6R7, halogen, Ci-C4 alkoxy, C02H, d-C4
uhioalkoxy, d-C4 alkoxycarbonyl, Ci-C6 hydroxyalkyl, CN,
OH, NR8R9, NRSR7-(d-Cg alkyl)-, -S02(d-Cs alkyl), or
ben-yloxy; and wherein
R6 and R7 at each occurrence are independently H, OH, d-C5
alkyl, amino d-C4 alkyl, NH(d-C5 alkyl) alkyl, N(Ci-
C6 alkyl) (d-Cs alkyl) d-Cs alkyl, d-Cs hydroxyalkyl,
d-C6 alkoxy d-C6 alkyl, or -SO2 (d-Cs alkyl), each of
which is optionally substituted with 1, '2, or 3
groups that are independently halogen, OH, SH, C3-CS
cycloalkyl, d-C4 alkoxy, C!-C4 alkyl, OH, CF3, or
OCF3.
In this embodiment, it is preferred that R6 and R7 are not
simultaneously OH; and
R6 and R7 are not simultaneously -S02(d-C6 alkyl).
Embodiment A89. Compounds according to embodiment
A80, wherein
R5 is benzyl which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently d-C4 alkyl, -C(O)NRSR7,
- (d-C4alkyl) -C(O)NRSR7, NRSR7- (d~Cfi alkyl)-, NR8R9,
halogen, d-C4 alkoxy, d-C4 thioalkoxy, d-C4
alkoxycarbonyl, Ci-C6 hydroxyalkyl, or CN; wherein
R6 and R7 at each occurrence are independently H, OH, d-Cs
alkyl, amino d-C4 alkyl, NH(d-C6 alkyl) alkyl, N(d-
Cs alkyl) (d-Cs alkyl) d-C6 alkyl, d-Cs hydroxyalkyl,
or Ci-C4 alkoxy Ci-C4 alkyl, each of which is
optionally substituted wiuh 1, 2, or 3 croups that
are independently halogen, OH, SH, C3-C0- cycloalkyl,
d-C4 alkoxy, Ci-C4 alkyl, OK, CF3, or OCF3.
In this embodiment, it is preferred that Rs and RT are not
simultaneously OH.
Embodiment A90. Compounds according to embodiment
A89, wherein
the Rs group is disubstituted with two groups that are meta to
each other.
Embodiment A91. Compounds according to embodiment
A78, wherein
R5 is phenyl, which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently Ci-C4 alkyl, -C(0)NRsR7,
-NR6R7, NR6R7(Ci-Cs alkyl), NR8R9, CX-C6 hydroxyalkyl,
halogen, Ci-C4 alkoxy, C02H, OH, Ci-Cs alkoxycarbonyl,
carboxaldehyde, Ci-C4 haloalkyl, - (d-C4 alkyl)-
NR15C(0)NR1SR17, - {Ci-C4 alkyl)-NRi5C (O) RIB; wherein
Rs and R7 at each occurrence are independently H, OH, Ci-C6
alkyl, amino d-C4 alkyl, NH(Ci-C6 alkyl) alkyl, N(Ct-
C6 alkyl) (Ci-Cs alkyl) d-C6 alkyl, Ci-C6 hydroxyalkyl,
Ci-Cs alkoxy Ci-C6 alkyl, -S02 (Ci-C6 alkyl), -S02NH2/
-SO2NH(C1-C6 alkyl), -S02N(C1-C6 alkyl) (d-C6 alkyl),
or Ci-Cg alkanoyl, each of which is optionally
substituted with I, 2, or 3 groups that are
independently halogen, OH, SH, C3-CS cycloalkyl, d-C4
alkoxy, d-C4 alkyl, OH, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with I or 2
groups that are independently alkyl, hydroxy,
hydroxy d-C4 alkyl, or halogen,
R1S is H cr C-Cs alkyl ;
R16 and R17 are independently H or C:-C5 alkyl; cr
R16, R17, and the nitrogen to which they are atcached form
a morpholinyl ring;
R18 is Ci-Cs alkyl optionally substituted, with -
alkanoyl, hydroxyalkyl, alkoxy,
alkoxy Ci-Cs alkyl; amino C^-Cs alkyl, mcno or
dialkylamino Ci-Cg alkyl.
In this embodiment, it is preferred that Rs and R7 are not
simultaneously OH.
Embodiment A92. Compounds according to embodiment
A91, wherein
R5 is phenyl, which is optionally substituted with 1, 2,. 3, 4,
or 5 groups that are independently Ci-C4 alkyl, - (Ci-C4
alkyl)-C(O}NR6R7 , -C(0)NR6R7 , -NRSR7, NR6R7 (Ci-C6 alkyl},
NR8R9, C1-CS hydroxyalkyl, halogen, C!-C4 alkoxy, C02H, OH,
Ci-Cs alkoxycarbonyl, carboxaldehyde, Ci-C4 haloalkyl,
(Ci-C4 alkyl) -NRl sC(0)NRi6R17/ - (C1-C4 alkyl) -NR15C (0) R18;
wherein
R6 and R7 at each occurrence are independently H, OH, Ci-C6
alkyl, amino Ci-C4 alkyl, NH(C1-CS alkyl} alkyl, N(Ci-
C6 alkyl) (Ci-Cg alkyl) Ci-C6 alkyl, Ci-C6 hydroxyalkyl,
Ct-Cs alkoxy Ci-C6 alkyl, -S02 (d-Cg alkyl), -S02ISrH2,
-SO2NH(C1-C6 alkyl), -S02N(d-C alkyl) (-Ce alkyl),
or Ci-Ce alkanoyl each of which is optionally
substituted with 1, 2, or 3 groups that are
independently halogen, OH, SH, C3-C6 cycloalkyl, Ci-C4
alkoxy, C-C4 alkyl, OH, CF3/ or OCF3;
RIS is H or Ci-C6 alkyl;
RIS and R17 are independently H or Ci-Cs alkyl; or
Ri6, RIand the nitrogen to which they are attached form
a morpholinyl ring;
Ria is CI-GS alkyl optionally substituted with -0- (C:-CDalkanoyl,
Ci-Cs hydroxyalkyl, C-±-Cs alkcxy, Ci-C0-
alkoxy Ci-Cs alkyl; amino d-Cs alkyl, mono cr
dialkylaminc Ci-CD- alkyl.
Embodiment A93. Compounds according to embodiment
A92, wherein
RI is halogen, methyl, ethyl, C2-C4 alkenyl, C2-C4 alkynyl, or
carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (Ci-C6) alkyl, or
phenyl (Ci-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (Ci-Cs) alkyl-N (R) -C02R30, NRSR7/
(d-C4) haloalkyl, (Ci-C4) haloalkoxy, (d-C6) alkyl,
pyridyl, or NRSR7-(Ci-Cs alkyl)-; and
R4 is H, (Ci-C4) alkyl optionally substituted with one or two
groups that are independently C02H, -C02alkyl, -C(0)NRR, -
N(R30)C(0)NRR, -N(R30)C(0) - (Ci-Cj alkoxy, or -NR6R7/ or
hydroxy (Ci - C4) alkyl.
Embodiment A94. Compounds according to embodiment
A93, wherein
R5 is phenyl, which is optionally substituted with 1, 2, 3, 4,
or 5 groups that are independently Ci-C4 alkyl, -C(0)NRSR7,
-(d-C4 alkyl)-C(0)NR6R7, -NR6R7, NR6R7(C1-CS alkyl), d-Cfi
hydroxyalkyl, halogen, Ci-C4 alkoxy, C02H, OH, Ci-C6
alkoxycarbonyl, carboxaldehyde, Ci-C4 haloalkyl, wherein
Rs and R7 at each occurrence are independently H, OH, Ci-C6
alkyl, amino d-C4 alkyl, NH(Ci-C6 alkyl) alkyl, N(CX-'
C6 alkyl) (Ci-Cs alkyl) Ci-Cs alkyl, C^-Cg hydroxyalkyl,
Ci-Cs alkoxy d-Cs alkyl, -S02(d-Cs alkyl), -S02NH2,
-S02NH(Ci-C6 alkyl), -SO2N(Ci-C6 alkyl) (d-Cs alkyl),
or Ci-Cs alkanoyl, each of which is optionally
substituted with 1, 2, cr 3 groups that are
independently halogen, OH, SK, C3-CS cyclcalkyl, Ci-C4
alkcxy, C-.-C4 alkyl, OH, C?3, or CC?3; .
Embodiment A101. Compounds according to embodiment
A66, wherein
R5 is thienyl (Ci-Cs alkyl), piperidinyl (d-d) alkyl,
pyrrolidinyl (Ci-Cs) alkyl, imidazolidinyl (d-d) alkyl,
piperazinyl (d-d) alkyl, pyridyl (d-d) alkyl, pyrimidyl (Ci-
Cs) alkyl, pyridazyl (Ci-Cg) alkyl, pyrazinyl (Ci-C6) alkyl,
isoquinolinyl (Ci-C6) alkyl, tetrahydroisoquinolinyl (Cj.-
Cs) alkyl, indolyl (Ci-Cg) alkyl, IH-indazolyl (d-d) alkyl,
dihydroindolonyl(Ci-Cs alkyl), indolinyl(Ci-C6 alkyl),
dihydroisoindolyl(Ci-C6 alkyl), dihydrobenzimdazolyl(Ci-Cs
alkyl), or dihydrobenzoimidazolonyl(Ci-C6 alkyl), wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently (Cx-
Cs) alkyl, halogen, (Ci-C6) alkoxy, (Ci-Cs) hydroxyalkyl,
phenyl (Ci-C6) alkoxy, (Ci-C6} thioalkoxy, (Ci-
C6) alkoxycarbonyl, phenyl (Ci-Cs) alkoxycarbonyl, OH,
C02H, CN, amidinooxime, NR8R9, NRSR7- (Ci-C6 alkyl)-, -
C(0)NRSR7, - (Ci-C4 alkyl)-C(0)NR6R7, amidino,
piperazinyl, morpholinyl, -S02 (Ci-C6) alkyl, -S02NH2,
-S02NH(Ci-C6) alkyl, -SO2N (Ci-Cs) alkyl (d-Cg) alkyl,
(Ci-C4)haloalkyl, - (d-C4 alkyl)-NRi5C (0) NRi6Ri7, •
C4 alkyl)-NRisC(O) RIB, -O-CH2-0, -0-CH2CH2-0-, or
C4)haloalkoxy; wherein
Rs and R7 are independently at each occurrence H,
(Ci-Cs) alkyl, (Ci-C6) alkoxy, (d-C6) alkoxy (Cx-
C6) alkyl, (Ci - C6) alkoxycarbonyl, (d -
C6)hydroxyalkyl, - (d-d) alkyl-C02- (d-C6) alkyl,
(Ci-Cfi) alkanoyl, phenyl (d-Cg) alkyl, phenyl (d-
Cs) alkoxy, or phenyl (d.-Cs) alkancyl, wherein
each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, (d-d) alkoxy, OH, 3H,
C3-CS cycloalkyl, NH2, NK(d-Cs alkyl), N(d-Cfi
alkyl) (d-C6 alkyl), (d-C4) alkyl, CF3 or OCF3;
or
Rs, R-T, and the nitrogen to which they are attached
form a morpholinyl, thiomorpholinyl,
piperidinyl, pyrrolidinyl, or piperazinyl ring
which is optionally substituted with 1 or 2
groups that are independently d-d alkyl,
hydroxy, hydroxy d~d alkyl, or halogen; and
RIB is Ci-C; alkyl optionally substituted with -0- (C2-
C6 alkanoyl, d-d hydroxyalkyl, Ci-C6 alkoxy,
d-d alkoxy d-d alkyl /' amino d-C6 alkyl, mono
or dialkylamino Ci-Cs alkyl.
In this embodiment, it is preferred that R6 and R7 are not
simultaneously OH; and
R6 and R7 are not simultaneously -SO2(d-C6 alkyl).
Embodiment A102. Compounds according to embodiment
A101, wherein
is halogen, methyl, ethyl, d-d alkenyl, d-d alkynyl, or
carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (d-C6) alkyl, or
phenyl (d~d) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (d-Cs) alkyl-N (R) -C02R30, NR6R-7,
(d-d) haloalkyl, (d-d) haloalkoxy, (d-Cs) alkyl,
pyridyl, or NR6R7- (d~C6 alkyl)-; and
R4 is H, (Ci-C4) alkyl optionally substituted with one or two
groups that are independently C02K, -C02alkyl/ -C(G)NR.R,
-N(R3C)C(C)NRR, -N(R30) C(0) - (Ci-C6) alkoxy, or -NR€R7, or
hydroxy (d-C4-) alkyl.
Embodiment A103. Compounds according to embodiment
A102, wherein
R5 is thienyl (d-C6 alkyl), indolyl (d-C6 alkyl), pyridinyi (Ci-C6
alkyl), piperazinyl (C!-C6 alkyl), or pyrazinyl (Ci-C6 alkyl)
each of which is optionally substituted with I, 2, or 3
groups that are independently C!-C4 alkyl, Ci-C4
hydroxyalkyl, halogen, -C(O)NR6R7, - (Ci-C4 alkyl) -C (0) NRSR7,
GI-CS alkoxycarbonyl, -NR6R7, NRSR7- (Ci-C6 alkyl)-,
haloalkyl, Ci-C6 alkanoyl,
R6 and R7 at each occurrence are independently H, Ci-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Cx-C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci-C4 alkoxy;
or
Rs, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with I or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A104. Compounds according to embodiment
A103, wherein
Rs is thienyl (Ci-Cs alkyl), indolyl (Ci-Cs alkyl), pyridinyi(Ci-Cs
alkyl), piperazinyl(Ci-C6 alkyl), or pyrazinyl(Ci-Cs
alkyl).
Embodiment A105. Compounds according to embodiment
A103, wherein
R4 is H, methyl, ethyl, or -CH2OK;
R5 is pyridinyl (d-Cs alkyl), or pyrazinyl (C-L-C6 alkyl) each of
which is optionally substituted with 1, 2, or 3 groups
that are independently d-C4 alkyl, Ci-C4 hydroxyalkyl,
halogen, -C(0)NR5R7, - (d-C4 aikyl)-C (O) NR0-R7, d-Cs
alkoxycarbonyl, -NRSR7, NR6R7- (d-Cfi alkyl)-, CF3, Ci-Cs
alkanoyl, wherein
R6 and R7 at each occurrence are independently K, C1-CS
alkyl optionally substituted with 1, 2, or 3 groups
that are independently d~C4 alkoxycarbonyl, halogen,
C3-C6 cycloalkyl, OH, SH, or Ci-C4 alkoxy;
or
R5, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A106. Compounds according to embodiment
A105, wherein
R4 is H, alkyl substituted with one or two groups that are
independently C02H, -C02-(d-C6) alkyl, -C(0)NRR,
-N(R30)C(0)NRR, -N(R30)C(0) - (d-C6) alkoxy, or -NRSR7 .
Embodiment A112. Compounds according to embodiment 16,
wherein
RI is halogen, or methyl;
R2 is benzyloxy, which is optionally substituted with 1, 2, 3,
or 4 groups that are independently halogen, - (d-Cg) alkyl-
N(R)-C02R30/ CF3, OCF3, or (d-C4) alkyl,; and
R4 is H, methyl, ethyl, -CH2OH, -CH2C02- (d-C4 alkyl), or C2
hydroxyalkyl.
Embodiment A113. Compounds according to any one of
embodiments A35, A95, A97, A98, A99, A100, 16 or 17, wherein
R: is halogen, or methyl;
R; is benzyloxy, which is optionally substituted with 1, 2, 3,
or 4 groups that are independently halogen, -(Ci-C6)alkyl-
N(R)-C02R30, CF3; OCF3, or (d-C4) alkyl,; and
R4 is alkyl substituted with one group that is C02H, -C02- (d-
Cs) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N (R30) C (0) - (d-
C6) alkoxy, or -NR6R7.
Embodiment A114. Compounds according to embodiment
A66, wherein
R5 is isoquinolinyl(d-Cs alkyl), tetrahydroisoquinolinyl (d-Cs
alkyl), IH-indazolyl (d-C6 alkyl), dihydroindolonyl(d-Cs
alkyl), indolinyl(Ci-Cg alkyl), dihydroisoindolyl(Ci-Cg
alkyl), dihydrobenzimdazolyl (Ci-C6 alkyl),
dihydrobenzoimidazolonyl (Cx-Cs alkyl), each of which is
unsubstituted or substituted with 1, 2, or 3 groups that
are independently alkyl, alkoxy, halogen, d-Cg
alkoxycarbonyl, alkanoyl optionally substituted with 1 or
2 groups that are independently selected from the group
consisting of OH, NH2, NH(d-Cs alkyl), and N(d-C6 alkyl)
(Ci-Cs alkyl), -C(0)NR6R7, - (CX-C4 alkyl)-C (O) NRSR7, NR6R7-
(Cx-Cg alkyl)-, -NR6R7, or S02H; or
piperidinyl Cx-C4 alkyl optionally substituted with 1, 2, or 3
groups that are independently Cx-C4 alkyl, Cx-C4 alkoxy,
halogen, -C(0)NRSR7, - (d-C4 alkyl)-C (O) NRSR7, NR6R7-(Cx-C6
alkyl)-, or -NR6R7/ or Cx-Cs alkoxycarbonyl.
Embodiment A115. Compounds according to embodiment
A114, wherein
R5 is isoquinolinyl (Ci-C4 alkyl), piperidinyl Ci-C4 alkyl,
tetrahyciroisoquinolinyl (Ci-C4 alkyl) , IH-indazclyl (Ci-C4
alkyl), dihydroindolonyl (Ci-C4 alkyl), indolinyl (C-C.,
alkyl), dihydroisoindolyl(Ci-C4 alkyl),
dihydrobenzimdazolyl(Ci-C4 alkyl), or
dihydrobenzoimidazolonyl(Ci-C4 alkyl).
Embodiment A116. Compounds according to embodiment
A114, wherein
R5 is piperidinyi Ci-C4 alkyl optionally substituted with 1, 2,
or 3 groups that are independently Ci-C4 alkyl, C^-C^
alkoxy, halogen, or C±-C6 alkoxycarbonyl.
Embodiment A117. Compounds according to embodiment
A66, wherein
R5 is pyrimidyl, indolinyl, indolyl, IH-isoindolyl,
isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,
dihydro-lH-benzimidazolyl, pyrrolyl, imidazolyl, or each
of which is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of
Ci-Cg alkoxycarbonyl, Ci-C4 thioalkoxy, each of which is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently -C(0)NR6R7, - (Ca-C4 alkyl)-
C(O)NR6R7, NR6R7-(Ci-C6 alkyl)-, -NRSR7, alkyl, alkoxy,
halogen, Ci-Cs alkoxycarbonyl, or alkanoyl optionally
substituted with 1 or 2 groups that are
independently selected from the group consisting of
OH, NH2, NH(Ci-Ce alkyl), and N(d-C6 alkyl) (C^-C6
alkyl), and S02H; or
pyridyl, pyrazolyl, optionally substituted with 1, 2, or
3 groups that are independently -C(0)NR6R7, - (Ci-C4
alkyl)-C(0)NR6R7, NR6R7- (C-C6 alkyl)-, -NR6R7, Ci-C4
alkyl, Ca-C4 hydroxyalkyl, halogen, C^-C6
alkoxycarbonyi, -3\TRSR7, NR£R7-(CT.-CS alkyl)-, C3, C-j.-
C0- alkanoyl. wherein
Rs and. R- at each occurrence are independently H, C-LCs
alkyl optionally substituted with 1, 2, or 3
groups that are independently Ci-C4
alkoxycarbonyl, halogen, C3-C5 oycloalkyl, OH,
SH, or Ci-C4 alkoxy;
or
Rs, RV, and the nitrogen to which they are attached
form a piperidinyl, pyrrolidinyl, piperazinyl,
or a morpholinyl ring optionally substituted
with 1 or 2 groups that are independently
alkyl, hydroxy, hydroxy Ci-C4 alkyl, or halogen.
Enibodiment A118. Compounds according to embodiment
A117, wherein
R5 is pyrimidyl, pyrrolyl, imidazolyl, or pyrazolyl, each of
which is optionally substituted with 1, 2, or 3 groups
independently selected from Ci-Ce alkoxycarbonyl, C!-C4
thioalkoxy, each of which is unsubstituted or substituted
with 1, 2, or 3 groups that are independently
alkyl, alkoxy, halogen, Ci-C6 alkoxycarbonyl, -C(0)NR6R7l
- (C!-C4 alkyl)-C(0)NRSR7; NR6R7- (C^-C6 alkyl)-, or -
NR6R7, or Ci-C4 alkanoyl optionally substituted with 1
or 2 groups that are independently selected from the
group consisting of OH, NH2, NH(Ci-C6 alkyl), and
N(Ci-Cs alkyl) (Ci-Cs alkyl), or S02H.
R
Embodiment A119. Compounds according to embodiment.
A117, wherein
is pyridyl or pyrazolyl, optionally substituted with 1, 2,
or 3 groups that are independently Ci-C4 alkyl, Ci-C4
hydroxyalkyl, halogen, -C(0)NRSR7, - (Ci-C4 alkyl) -C (0) NR6R7,
NRe-R7-(Ci-Cs alkyl)-, or -NR0-R7, Ci-C5 alkoxycarbcr.yl, -
NRSR7/ NR«R7-(Ci-Cs alkyl)-, C-Cs alkanoyl, wherein
Rs and R7 at each occurrence are independently K, C-_-C5
alkyl optionally substituted with 1, 2, or 3 groups
that are independently C-.-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or Cj.-C4 alkoxy;
or
Rs, R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A120. Compounds according to embodiment
A119, wherein
R5 is pyridyl or pyrazolyl, optionally substituted with 1, 2,
or 3 groups that are independently Ci-C4 alkyl, Ci-C4
hydroxyalkyl, halogen, -C(0)NR6R7, - (C1-C4 alkyl)-C (0) NR6R7,
NR6R7-(Ci-Cs alkyl)-, -NR6R7, Ci-Cs alkoxycarbonyl, CF3, Cx-
Cs alkanoyl, wherein
R6 and R7 at each occurrence are independently H, Ci-Cs alkyl
optionally substituted with 1, 2, or 3 groups that are
independently Ci-C4 alkoxycarbonyl, halogen, C3-C6
cycloalkyl, OH, SH, or Ci-C4 alkoxy.
Embodiment A121. Compounds according to embodiment
A119, wherein
R5 is pyridyl or pyrazolyl, optionally substituted with 1, 2,
or 3 groups that are independently CX-C4 alkyl, Ci-C4
hydroxyalkyl, halogen, -C(0)NR6R7, - (C!-C4 alkyl) -C (0).
NRSR7-(Ci-Cs alkyl)-, -NR6R7, Ci-Cs alkoxycarbonyl, CF3,
C6 alkanoyl, wherein
Rs, R7, and the nitrogen to which they are attached term apiperidinyl,
pyrrolidinyl, piperazinyi, or a
moroholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hycroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A122. Compounds according to any one of
embodiments A114, A115, A11S, or A117 wherein
R! is halogen, methyl, ethyl, C2-C4 alkenyi, C2-C4 alkynyl, or
carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (Ci-C5) alkyl, or
phenyl (C].-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (Ci-C6) alkyl-N (R) -C02R3o, NRSR?,
(Ci-C4) haloalkyl, (Ci-C4) haloalkoxy, (Ci-Cs) alkyl,
pyridyl, or NR6R7- (Ci-C6 alkyl)-; and
R4 is H, (Ci-C4) alkyl substituted with one group that is CO2H,
-C02- (Ci-Cg) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N(R30)C(0)-
(Ci-Cs) alkoxy, or -NR6R7, hydroxy (Ci-C4) alkyl.
Embodiment A123. Compounds according to embodiment
A66, wherein
R5 is Ci-Cs alkyl optionally substituted with 1 or 2, groups
that are independently Ci-C4 alkoxycarbonyl, or halogen,
or
Rs is Cx-C4 alkoxy, ethyl, methyl, cyclopropylmethyl,
cycloalkyl, or alkynyl, or
R5 is C2-CS alkenyi optionally substituted with Ci-C4
alkoxycarbonyl or cyclohexyl.
Embodiment A124. Compounds according to embodiment
A123, wherein
is halogen, methyl, ethyl, C2-C4 alkenyl, C2-C4 alkynyl, or
carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy (Ci-Cs) alkyl, or
phenyl (Ci-C4) thioalkoxy, wherein each of the above is
optionally substituted with 1, 2, 3, or 4 groups that are
independently halogen, - (Ci-C0-) alkyl-N(R) -C02R3o/
(d-C4) haloalkyl, (Ci-C4) haloalkoxy, (Ci-C6) alkyl,
pyridyl, or NRSR7- (Ci-Cs alkyl)-; and
R4 is H, (Ci-C4) alkyl substituted with one group that is C02H,
-C02- (Ci-Cs) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N(R30)C(0)-
(GI-CS) alkoxy, or -NR6R7, hydroxy (Ci-C4) alkyl; wherein
Rs and R? at each occurrence are independently H, Ci-C6
alkyl optionally substituted with 1, 2, or 3 groups
that are independently Ci-C4 alkoxycarbonyl, halogen,
C3-CS cycloalkyl, OH, SH, or Ci-C4 alkoxy;
or
Rs/ R7, and the nitrogen to which they are attached form a
piperidinyl, pyrrolidinyl, piperazinyl, or a
morpholinyl ring optionally substituted with 1 or 2
groups that are independently alkyl, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A125. Compounds according to embodiment
A124, wherein
R5 is Ci-C6 alkyl optionally substituted with 1 or 2, groups
that are independently Ci-C4 alkoxycarbonyl, or halogen,
or
R5 is Ci-C4 alkoxy, ethyl, methyl, cyclopropylmethyl,
cyclohexyl, cyclopentyl, C2-C6 alkynyl, or
R5 is C2-CS alkenyl optionally substituted with Ci-C4
alkoxycarbonyl or cyclohexyl.
mbodiment A126. Compounds according to embodiment
A66, wherein
R2 is phenylalkynyl, -OC (O)NH(CH;) naryl,
-OC(0)N(alkyl) (CH2)naryl, -OS02 (Ci-Cfi) alkyl, -OS02aryl, or
NRsRg, wherein
n is 0, 1, 2, 3, 4, 5 or 6;
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
- (Ci-C6) alkyl-N(R) -C02R30, alkoxy, alkoxycarbonyl, CN,
NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl,
heteroarylalkyl, NR6R7-(Ci-C6 alkyl)-, phenyl, -S02-
phenyl wherein the phenyl groups are optionally
substituted with 1, 2, or 3 groups that are
independently halogen or NO2; or -OC(O)NR6R7, wherein
R6 and R7 are independently at each occurrence H,
alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
S02-alkyl, OH, hydroxyalkyl, - (C!-C4) alkyl-C02-
alkyl, heteroarylalkyl, alkanoyl, arylalkyl,
arylalkoxy, or arylalkanoyl, wherein each of
the above is unsubstituted or substituted with
1, 2, or 3 groups that are independently,
halogen, alkoxy, heterocycloalkyl, OH, NH2, C3-
Cfi cycloalkyl, NH(alkyl), N(alkyl) (alkyl), -0-
alkanoyl, alkyl, Ci-C4 haloalkyl, or Ci-C4
haloalkoxy; or
R6, R7, and the nitrogen to which they are attached
form a morpholinyl, thiomorpholinyl,
piperidinyl, pyrrolidinyl, or piperazinyl ring
which is optionally substituted with 1 or 2
groups that are independently CX-C4 alkyl, Ci-C4
alkoxy, hydroxy, hydroxy C^-d alkyl, or
halogen.
Embodiment A127. Compounds according to embodiment
A126, wherein
R! is halogen, methyl, ethyl, C2-C4 alkenyl, C2-C4 alkynyl, or
carboxalde hyde; and
R4 is H, (Ci-C4) alkyl substituted with one group that is C02H,
-C02-(C1-C6)alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N(R30)C(0)-
(Ci-Cs) alkoxy, -NRSR7, NRSR?-(Ci-Cs alkyl)-, or hydroxy (Ci-
C4) alkyl.
Embodiment A128. Compounds according to embodiment
A127, wherein
Rs is phenyl, optionally substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, Ci-C4 alkyl, Ci-C4
alkoxy, CF3, OCF3, - (C1-C4 alkyl)-C (0)NR6R7, NR6R7- (Ci-Cs
alkyl)-, -NR6R7, or C(0)NR6R7, wherein
R6 and R7 are independently at each occurrence H, Ci-C6
alkyl, Ci-Cs alkoxy, Ci-Cs alkoxy Ci-C6 alkyl, Ci-C6
alkoxycarbonyl, OH, Ci-C6 hydroxyalkyl, - (Ci-
C4) alkyl -CO2- alkyl, pyridyl Ci-Cs alkyl, Ci-Cs
alkanoyl, benzyl, phenyl Ci-C6 alkoxy, or phenyl Ci-
Cs alkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, Ci-C6 alkoxy,
piperidinyl Ci-Cs alkyl, morpholinyl Ci-C6 alkyl,
piperazinyl Ci-Cs alkyl, OH, SH, C3-C6 cycloalkyl,
NH2/ NH(alkyl), N(alkyl)(alkyl), -0-Ci-C4 alkanoyl,
Ci-C4 alkyl, CF3, or OCF3; or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,'
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, C.-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen; or
R5 is benzyl optionally substituted with 1 ,2 ,3 ,4, or 5
groups that are independently halogen, CS-Cg alkyl, Ci-C6
alkoxy, CN, CF3, OCF3, - (Ci-C4 alkyl) -C (0) NR6R7, NRSR7- (C--CS
alkyl)-, -NR5R7/ or C(0)NR5R7.
Embodiment A129. Compounds according to embodiment
A128, wherein
R2 is NR8R9, or NR8R9-(C-.-C4 alkyl)-; wherein
R8 at each occurrence is independently hydrogen, Ci-Cs
alkyl, Ci-Cg alkanoyl, phenyl (Ci-C6) alkyl or
phenyl (Ci-Cs) alkanoyl wherein each of the above is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently C1-CS alkyl, GJ.-CS alkoxy, Ci-
Cs alkoxycarbonyl, halogen, or C!-C4 haloalkyl; and
R9 at each occurrence is independently Ci-Cg alkyl, Ci-Cs
alkanoyl, phenyl (C^Ce) alkyl, C3-C7 cycloalkyl, C2-CS
alkenyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, imidazolyl, C3-C7 cycloalkyl (d-C6) alkyl,
phenyl (Ci-Cg) alkanoyl, -S02-phenyl, and phenyl
wherein each of the above is optionally substituted
with 1, 2, 3, 4, or 5 groups that are independently
Ci-Cg alkyl, Ci-C€ alkoxy, Ci-Cg alkoxycarbonyl,
halogen, or Ci-C4 haloalkyl.
Embodiment A130. Compounds according to embodiment
A129, wherein
R8 is H.
Embodiment A131. Compounds according to embodiment
A130, wherein
R2 is -NH-benzyl option substituted with 1, 2, or 3 groups that
are independently halogen, Ci-C4 alkyl, Ci-C4 alkoxy, CF3,
OCF3,
R2 is -NH-C(0)phenyl, wherein the phenyl group is optionally
substituted with 1, 2, or 3 groups that are independently
halogen, Ci-C4 alkyl, or Cj.-C4 alkoxy; or
R2 is -NH-allyl.
Embodiment A132. Compounds according to embodiment
A131, wherein
RI is chloro, bromo, iodo, or methyl; and
R5 is benzyl optionally substituted with 1 ,2 ,3 ,4, or 5
groups that are independently halogen, -(Ci-C4 alkyl)-
i
C(0)NRSR7, NR6R7-(C1-CS alkyl)-, -NR6R7, Ci-Cg alkyl, C^-Cg
alkoxy, CN, CF3, OCF3, or C(O)NReR7.
Embodiment A133. Compounds according to embodiment
A131, wherein
RI is chloro, bromo, iodo, or methyl; and
R5 is phenyl, optionally substituted with 1, 2, 3, 4, or
groups that are independently halogen, -(CX-C4 alkyl)-
C(0)NR6R7, NR6R7-(Ci-Cg alkyl)-, -NR6R7, C^-d alkyl, Ci-C4
alkoxy, CF3, OCF3, or C(0)NR6R7.
Embodiment A134. A compound of the formula
or pharmaceutically acceptable salts thereof, wherein
or Xc ; wherein
X2, Xa, Xb, Xc, Xd, and Xe at are independently selected from
-C(0)NRSR7, -NRSR7, hydroxy (d-C4) alkyl, H, OH, halogen,
haloalkyl, alkyl, haloalkoxy, heteroaryl,
heterocycloalkyl, C3-C7 cycloalkyl, NR6R7- (Ci-C6 alkyl)-, -
C02- (Ci-Cs) alkyl, -N(R)C(0)NR6R7 , -N (R) C (0) - (d-C6) alkoxy,
C02H- (d-C6 alkyl)-, or -SO2NRSR7; wherein
the heteroaryl and heterocycloalkyl groups are optionally
substituted with -NR6R?, -C(0)NR6R7, NReR7- (Ci-C6 alkyl)-,
Ci-Cs alkyl, d-C6 alkoxy, or halogen;
RS and R7 are independently at each occurrence H, d-C«
alkyl,' Ci-Cs alkoxy, Ci-Cs alkoxy Ci-C6 alkyl, Ci-C6
alkoxycarbonyl, OH, Ci-Cs hydroxyalkyl, Ci-C6
thiohydroxyalkyl, - (Ci-C4) alkyl-C02-alkyl, pyridyl d-
C6 alkyl, GI-CS alkanoyl, benzyl, phenyl Ci-C6 alkoxy,
or phenyl Ci-Cs alkanoyl, wherein each of the above
is unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, C3-CS
cycloalkyl, Ci-C6 alkoxy, piperidinyl d-C6 alkyl,
morpholinyl d-C6 alkyl, piperazinyl Ci-Cs alkyl, OH,
SH, NH2, NH(alkyl), N (alkyl) (alkyl) , -O-Ci-C4 i
alkanoyl, d-C4 alkyl, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently d-C4 alkyl, d-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen;
R at each occurrence is independently H or C1-CS alkyl;
and
Y, YI, Y2, Y3, and Y4 are independently selected from H,
halogen, alkyl, carboxaldehyde, hydroxyalkyl, alkenyl,
alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl,
and carboxyl.
Embodiment A135. Compounds according to embodiment
A134, wherein
Y2, Y4, and Y are independently halogen; and
YI and Y3 are both hydrogen.
Embodiment A136. Compounds according to embodiment
A135, wherein
Xx is H, methyl, -NR6R7, NR6R7-(d-Cs alkyl)-, -C(0)NR6R7/ Ci-C6
hydroxyalkyl, or -(Ci-C4 alkyl)-morpholinyl.
Embodiment A137. Compounds according to embodiment
A136, wherein
Xa and Xe are independently halogen, is NH2/ NH(Ci-C6 alkyl),
N(C!-C6 alkyl) (C!-C6 alkyl) or methyl.
Embodiment A138. Compounds according to embodiment
A137, wherein
Xb or Xc is -NRSR7, NRSR7-(Ci-C6 alkyl)-, -C(0)NR6R7, -S02NR6R7/ or
halogen; wherein
R6 and R7 are independently at each occurrence H, Ci-Cg
alkyl, Ci-C6 alkoxy, Ci-C6 alkoxy Ci-C6 alkyl, Ci-Cs
alkoxycarbonyl, OH, Ci-C6 hydroxyalkyl, - (d-C4) alkyl-
C02-alkyl, pyridyl Ci-Cs alkyl, C!-C6 alkanoyl,,
benzyl, phenyl Ci-C6 alkoxy, or phenyl C1-C6 alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, C3-CS cycloalkyl, C-Cs
alkoxy, piperidinyl Ci-Cs alkyl, morpholinyl Ci-C6
alkyl, piperazinyl d-Cs alkyl, OH, SH, NH2,
NH(alkyl), N(alkyl) (alkyl) , -0-Ci-C4 alkanoyl, CL-C4
alkyl, CF3, or OCF3; or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, Ci-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A139. Compounds according to embodiment
A138, wherein -
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl,
or piperazinyl ring which is optionally substituted with
1 or 2 groups that are independently C].-C4 alkyl, Ci-C4
alkoxy, hydroxy, hydroxy Ci-C4 alkyl, or halogen.
Embodiment A140. Compounds according to embodiment
A138, wherein
RS, R?, and the nitrogen to which they are attached form a
piperazinyl ring which is optionally substituted with 1
or 2 groups that are independently Ci-C4 alkyl, Ci-C4
alkoxy, hydroxy, hydroxy Ci-C4 alkyl, or halogen.
Embodiment A141. Compounds according to embodiment
A138, wherein
RS and R7 are independently at each occurrence H, Ci-Cs alkyl,
Ci-Cs alkoxy, Ci-Cs alkoxy C^-Cg alkyl, Ci-Cfi
alkoxycarbonyl, OH, Ci-Cs hydroxyalkyl, - (C].-C4) alkyl-C02-
alkyl, pyridyl Cj.-Cg alkyl, Ci-C6 alkanoyl, benzyl, phenyl
GI-CS alkoxy, or phenyl Ci-C6 alkanoyl, wherein, each of the
above is unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, C3-C6 cycloalkyl,
Ci-Cs alkoxy, piperidinyl Ci-Cs alkyl, morpholinyl Ci-C6
alkyl, piperazinyl Ci-Cs alkyl, OH, NH2, NH(alkyl),
N (alkyl) (alkyl) , -0-Ci-C4 alkanoyl, d-C4 alkyl, CF3, or
OCF3.
Embodiment A142. Compounds according to embodiment
A138, wherein
Rs and R7 are independently at each occurrence H, Ci-Cs alkyl,
Ci-Cs hydroxyalkyl, Ci-Cs alkoxy, Ci-Cs alkoxy Ci-C6 alkyl,
or Ci-Cs alkanoyl, wherein each of the above is optionally
substituted with 1, 2, or 3 groups that are independently
OH, SH, halogen, or C3-CS cycloalkyl.
Embodiment A143. Compounds according to embodiment
A137, wherein
Xa and Xe are independently fluoro, chloro, or methyl; and
Xc is hydrogen or halogen.
Embodiment A144. Compounds according to embodiment
A137, wherein
Xa is halogen;
Xe is NH2, NH(Ci-Cs alkyl) or N(Ci-Cs alkyl) (d-Cg alkyl);
Xb and Xd are both hydrogen.
Embodiment A145. Compounds according to embodiment
A144, wherein
Xc is -NR6R7, NRSR7 Ci-C6 alkyl, -S02NR6R7, or halogen; wherein
R6 and R7 are independently at each occurrence H, Ci-C6
alkyl, Ci-Cg alkoxy, Ci-C« alkoxy Ci-Cs alkyl, Cj.-C«
alkoxycarbonyl, OH, Ci-Cs hydroxyalkyl, - (d-C4) alkyl-
C02-alkyl, pyridyl d-C6 alkyl, d-C6 alkanoyl,
benzyl, phenyl Ci-Cs alkoxy, or phenyl d-C0- alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, C3-C6 cycloalkyl, Ci-C5
alkoxy, piperidinyl d-Ce alkyl, morpholinyl Ci-Cs
alkyl, piperazinyl Cj.-C6 alkyl, OH, SH, NH2,
NH (alkyl), N (alkyl) (alkyl) , -0-Ci-C4 alkanoyl, d-C4
alkyl, CF3, or OCF3; or
Rs, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently d~C4 alkyl, . d-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A146. Compounds according to embodiment
A145, wherein
Xc is fluoro, chloro, NH2/ NH(C:.-C6 alkyl), N (Ci-Cs alkyl) (d-Cs
alkyl), -S02NH2/ -S02NH (d-Cs alkyl) , -SO2N(d-Cfi alkyl) (d-
C6 alkyl), or piperazinyl, wherein the piperazinyl group
is optionally substituted with 1 or 2 groups that are
independently d-d alkyl, d-C4 alkoxy, hydroxy, hydroxy
d~d alkyl, or halogen.
Embodiment A147. Compounds according to either
embodiment A137 or A144, wherein
Xc is -C(0)NR6R7, -(d-C6 alkyl)-C(0)NR6R7, NR6R7, or NR6R7-(Ci-C6
alkyl)-; wherein
Re and R7 are independently at each occurrence H, Ci-C6
alkyl, Ci-Cg alkoxy, d-C6 alkoxy d-C6 alkyl, d-Cs
alkoxycarbonyl, OH, Ci-Cs hydroxyalkyl, - (d~d) alkyl-
CO2-alkyl, pyridyl d-Cs alkyl, Ci-C6 alkanoyl,
benzyl, phenyl d-Cfi alkoxy, or phenyl Ci-Cfi alkanoyl,
wherein each of the above is unsubstituted or
substituted with I, 2, or 3 groups that are
independently, halogen, C3-CS cycloalkyl, Ci-C6
alkoxy, piperidinyl d-C6 alkyl, morpholinyl d-C«
alkyl, piperazinyl Ci-Cs alkyl, OH, NH2, NH(alkyl),
N(alkyl) (alkyl) , -0-d-C4 alkanoyl, d-C4 alkyl, CF3,
or OCF3; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, Ci-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A148. Compounds according to embodiment
A147, wherein
R6 is hydrogen; and
R7 is Ci-Cs alkyl or d-Cg alkanoyl, each of which is optionally
substituted with 1, 2, or 3 groups that are independently
NH2, NH(Ci-C6 alkyl), N(d-C6 alkyl) (d-Cs alkyl), OH, SH,
cyclopropyl, or d-C4 alkoxy.
Embodiment A148a. Compounds according to embodiment
A148, wherein
R7 is GI-CS alkanoyl optionally substituted with 1, 2, or 3
groups that are independently OH, cyclopropyl, or NH2.
Embodiment A149. Compounds according to embodiment
A135, wherein
Xa is hydrogen;
Xb, Xc, or Xd is -C(O)NR6R7, -(Ci-Cs alkyl) -C (O)NR6R7, NRSR7,
NRSR7-(Ci-Cs alkyl)- or -C02- (d-Ce) alkyl; wherein
Rs and R7 are independently at each occurrence K,
alkyl, Ci-Cs aikoxy, C-CS alkoxy O-Cg alkyl, Ci-C0-
alkoxycarbonyl, OH, Ci-Cfi hydroxyalkyl, - (C1-C4) alkyl-
C02-alkyl, pyridyl Ci-Cs alkyl, Ci-Cg alkanoyl,
benzyl, phenyl Ci-Cs alkoxy, or phenyl Ci-Cs alkancyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, C3-C6 cycloalkyl, Ci-Cs
alkoxy, piperidinyl Ci-C6 alkyl, morpholinyl Ci-C6
alkyl, piperazinyl Ci-C6 alkyl, OH, NH2, NH(alkyl),
N(alkyl) (alkyl) , -0-Ci-C4 alkanoyl, d-C4 alkyl, CF3,
or OCF3; or
RS, R7/ and the nitrogen to which they are attached form a
morpholinyl, piperidinyl, pyrrolidinyl, or
piperazinyl ring which is optionally .substituted
with 1 or 2 groups that are independently Ci-C4
alkyl, Ci-C4 alkoxy, hydroxy, hydroxy Ci-C4 alkyl, or
halogen; and
Xe is hydrogen, methyl, Ci-C2 alkoxy, or halogen.
Embodiment A150. Compounds according to embodiment
A149, wherein
Xb is NR6R7, or NR6R7- (Ci-Cs alkyl) -, -C(0)NR6R7 or -CO2- (Ci-
Cg)alkyl; wherein
Rs is hydrogen or Ci-C4 alkyl;
R7 is OH, Ci-Cs alkyl or Ci-Cs alkanoyl, wherein the alkyl and
alkanoyl groups substituted with 1, 2, or 3 groups that
are independently NH2; NH(Ci-C6 alkyl), N(Ci-C6 alkyl) (Ci-Cfi
alkyl), C3-C6 cycloalkyl, OH, or Cx-C4 alkoxy.
Embodiment A151. Compounds according to embodiment
A137, wherein
Xa is halogen;
Xb is NR6R7, NR6R7-(Ci-Cg alkyl)-, -C(0)NR6R7, or -C02-(d-
Cs) alkyl;
Xc is NRSR7, NRsR7-(Ci-Cs alkyl)-, -C(0)NR6R7, halogen, -C02-(d-
Cs) alkyl, NH2, NH(d-C6 alkyl), N(d-Cs alkyl) (Ci-Cs alkyl),
-S02NH2, -S02NH(C1-CS alkyl), -S02N(C1-C6 alkyl) (d-C6
alkyl), or piperazinyl, wherein the piperazinyl group is
optionally substituted with 1 or 2 groups that are
independently d-C4 alkyl, d-C4 alkoxy, hydroxy, hydroxy
Ci-C4 alkyl, or halogen;
Xd is hydrogen;
Xe is H, methyl, NH2, NH(d-Cs alkyl) or N(d-Cs alkyl) (-d-C
alkyl).
Embodiment A152. Compounds according to embodiment
A135, wherein
Xi, X2, Xa, Xb, Xc, Xd, and Xe are independently selected froro H,
OH, halogen, CF3/ alkyl, OCF3, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl,
piperidinyl, piperazinyl, or C3-C7 'cycloalkyl, wherein
each of the above is optionally substituted with -NR6R7;
-C(0)NR6R7/ NRfiR7-(d-C6 alkyl)-, d-Cs alkyl, d-Cs alkoxy,
or halogen.
Embodiment A153. Compounds according to embodiment
A152, wherein at least three of Xlf X2, Xa, Xb, X0, Xd, and X
are hydrogen.
Embodiment A154. A compound of the formula:
R2
or a pharmaceutically acceptable salt thereof, wherein
alkanoyl, halogen, arylalkanoyl, arylalkyl, alkoxyalkyl,
hydroxyalkyl, or carboxaldehyde, wherein
the aryl portion of arylalkyl, and arylalkanoyl is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, C:-C4 alkyl,
CL-C* alkoxy, nitro, CN, haloalkyl, haloalkoxy or
C02H;
the alkyl portion of the hydroxyalkyl, arylalkyl,
alkanoyl, alkoxyalkyl and arylalkanoyl groups are
unsubstituted or substituted with 1, 2, or 3 groups
that are independently halogen, methoxy, ethoxy or
spirocyclopropyl;
R2 is arylalkoxy, aryloxy, phenyloxy(C1-C6) alkyl, OH, halogen,
arylthioalkoxy, alkoxy, -OC (O)NH(CH2) naryl,
-OC(0)N(alkyl) (CH2) nary1, alkyl, alkoxyalkoxy,
dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl,
imidazolyl, pyrrolyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl,
benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl,
hexahydropyrimidinyl, thiazolyl, thienyl, or C02H, wherein
n is 0, 1, 2, 3, 4, 5 or 6;
the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,
-OC(O)NH(CH2)naryl, and -OC (0)N (alkyl) (CH2)naryl or
the heteroaryl and heterocycloalkyl groups is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, - (Ci-Cfi) alkyl-
N(R)-C02R3o, haloalkyl, heteroaryl, heteroarylalkyl,
NRfiR7/ NR6R7-(C1-C6 alkyl)-, -OC (0)NRSR7/ wherein
R6 and R7 are independently at each occurrence H, .
alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy,
or arylalkanoyl, wherein each of the above is
unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, OH, SH,
C3-CS cycloalkyl, alkoxy, alkyl, haloalkyl, or
haloalkoxy; or
R6, R7, and the nitrogen to which they are attached
form a morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,Sdioxide,
piperidinyl, or piperazinyl ring which
is optionally substituted with 1 or 2 groups
that are independently C!-C4 alkyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, or
halogen;
R at each occurrence is independently K or C^-Ce
alkyl;
R30 is Ci-C6 alkyl optionally substituted with 1 or 2
groups that are independently OH, SH, halogen,
amino, monoalkylamino, dialkylamino or C3-C6
cycloalkyl;
R3 is halogen, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,
-OC(0)NH(CH2)naryl, arylalkoxy, OC (0) N (alkyl) (CH2)naryl,
aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl,
NRSR7, NR6R7-(CI-GS alkyl)-, or alkyl, wherein
the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,
arylalkyl, -OC (O)NH(CH2)naryl, arylalkoxy,
-OC(0)N(alkyl) (CH2)naryl, and arylthioalkoxy, is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, alkoxy, alkyl,
haloalkyl, or haloalkoxy,
wherein n is 0, 1, 2, 3, 4, 5, or 6; or
R4 is H, alkyl substituted with one group selected from C02H, -
C02-(d-C6) alkyl, -C(0)NRR, -N (R30) C (O)NRR, -N (R30) C (0) - (Ci-
Cs) alkoxy, and -NRSR7, arylalkoxy, arylalkyl,
hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or
alkoxyalkoxy, wherein
the aryl portion of arylalkoxy, arylalkyl is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, hydroxy,
alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,
heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or
heteroaryl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, arylalkoxy, thioalkoxy,
alkoxycarbonyl, arylalkoxycarbonyl, C02H, CN,
amidinooxime, NRSR7, NR6R7-(Ci-Cs alkyl)-, -C(0)NR6R7,
amidino, haloalkyl, or haloalkoxy.
Embodiment A160. Compounds according to embodiment
A154 wherein
RI is halogen, (Ci-Ce) alkanoyl, phenyl (Ci-C6) alkanoyl,
naphthyl (d-C6) alkanoyl, naphthyl (Ci-Cs) alkyl, phenyl (Ci-
C6)alkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde,
wherein
the phenyl and naphthyl portions of the above are
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, Ci-C4 alkyl,
Ci-C4 alkoxy, nitro, CN, CF3, OCF3 or C02H;
the alkyl portion of the above groups are unsubstituted
or substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, or ethoxy.
R2 is phenylalkoxy, aryloxy, phenyloxy (C^Cg) alkyl, OH,
halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy,
-OC(0)NH(CH2)nphenyl, -OC (0)N(alkyl) (CH2)npheny 1, pyridyl,
pyrimidyl, pyridazyl, pyrazolyl, or thienyl, wherein
n is 0, 1, 2, 3, or 4, and
the above groups are ur.substituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
- (c1-C6)alkyl-N(R) -C02R30, halo (Ci-C4) alkyl, or
thienyl;
R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl,
phenyl (Ci-Cg) alkyl, phenylalkoxy, phenyloxy, phenylthio,
thioalkoxy, arylthioalkoxy, (C2-C6) alkenyl, NRSR7, NRB-R7-
(d-Cs alkyl)-, or alkyl, wherein
the phenyl, naphthyl, and aryl portions of
arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl,
-OC(O)NH (CH2)naryl, arylthioalkoxy, arylalkoxy,
and-OC (0)N (alkyl) (CH2)naryl, are unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, alkoxy, alkyl, CF3, or OCF3,
wherein n is 0, 1, 2, 3, 4, 5, or 6; or
R4 is H, (Ci-Cs) alkyl substituted with one group that is C02H,
-C02-(Ci-C6) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N(R30)C(0)-
(GI-CS) alkoxy, or -NR6R7, phenylalkoxy, phenyl (d-Cfi) alkyl,
hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy,
wherein
the phenyl portion of the above groups are unsubstituted
or substituted with 1, 2, 3, 4, or 5 groups that are
independently halogen, hydroxy, alkoxy, alkyl,
nitro, CF3, or OCF3.
R5 is phenyl (Ci-Cs) alkyl, (Ci-C6) alkyl, phenyl, naphthyl,
pyridyl, (Ci-C«) alkoxy, piperidinyl (d-C6) alkyl,
pyrrolyl (d-C6) alkyl, imidazolidinyl (d-Cs) alkyl,
pyrazolyl (d-C6) alkyl, imidazolyl (d-Cs) alkyl,
tetrahydropyridinyl (d-Cs) alkyl, thienyl (d-C6) alkyl,
phenylthio (Ci-Cs) alkyl, or pyridyl (C1-C6) alkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, or 3 groups that are independently (d-C4) alkyl,
fluoro, chloro, bromo, (d-C4) alkoxy, phenyl (C-.-C4) alkoxy,
thio(Ci-C4) alkoxy, (Ci-C4) aikoxycarbonyl, phenyl (Ci-
C4) alkoxycarbonyl, C02H, CN, amidinooxime, NRgR?, NRSR7-(Ca-
Cs alkyl)-, -C(0)NRSR7, amidino, CF3, -CF2CF3/ OCF3 or
OCF2CF3.
Embodiment A161. Compounds according to embodiment
A160 wherein
RI is halogen, (Ci-C4) alkanoyl, phenyl (Ci-C4) alkanoyl, benzyl,
phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde,
wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, Ci-C4 alkyl, Ci-C4 alkoxy, nitro, CN, CF3/
OCF3 or C02H;
the alkyl portion of the above groups are unsubstituted
or substituted with 1, 2, or 3 groups that are independently
halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy,
phenyloxy, phenyloxy (Ci-Cs) alkyl, OH, halogen,
phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, wherein
n is 0, 1, 2, 3, or 4, and
the above groups are unsubstituted or substituted with 1,
2, or 3, groups that are independently halogen, -(Ci-
C6) alkyl-N (R)-C02R30, halo (C!-C4) alkyl, or thienyl;
R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl,
phenyl (Ci-Cfi) alkyl, phenylalkoxy, phenyloxy, phenylthio,
thioalkoxy, phenyl thioalkoxy, (C2-C6) alkenyl, NR6R7, NR6R
Ci-Cs alkyl, or alkyl, wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently,
halogen, alkoxy, (CX-C4) alkyl, CF3, or OCF3/
R4 is H, (Ci-Cs) alkyl substituted with one group that is C02H,
-C0:-(d-d) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N(R30)C(0)-
(Ci-Cs) alkoxy, or -NR5R7, phenylalkoxy, benzyl, phenethyl,
hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy,
wherein
the phenyl portion of the above groups are unsubstituted
or substituted with 1, 2, or 3 groups that are
independently halogen, hydroxy, (d-C4) alkoxy, (Ci-
C4) alkyl, nitro, 'CF3, or OCF3.
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (d-Cs) alkyl,
phenyl, or pyridyl, wherein each of the above is
unsubstituted or substituted with l, 2, or 3 .groups, that
are independently (d~C4)alkyl, fluoro, chloro, bromo,
(d-C4) alkoxy, phenyl (d-C4) alkoxy, thio (d~C4) alkoxy, (Ci- '
C4) alkoxycarbonyl, C02H, CN, amidinooxime, NR6R?, NR6R7-
C6 alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3.
Embodiment A162. Compounds according to embodiment
A161 wherein
R! is bromo, phenyl (d-C4) alkanoyl, benzyl, phenethyl,
phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, d-C4 alkyl, d-C4 alkoxy, nitro, CN, CF3,
OCF3 or C02H;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy,
phenyloxy, phenyloxy (Ci-C6) alkyl, OH, halogen, or
phenylthioalkoxy, wherein
n is 0, 1, 2, 3, or 4, and
the above groups are unsubstituted or substituted with 1,
2, or 3, groups that are independently halogen, -(Ci-
C6) alkyl-N (R)-C02R30, halo (d-C4) alkyl, orthienyl;
R3 is bromo, phenylalkoxycarbonyl, phenyloxycarbonyl,
phenyl (d-Cs) alkyl, phenylalkoxy, phenyloxy, phenylthio,
thioalkoxy, phenylthioalkoxy, (C2-C0-) alkenyl, NRD-R7, NR0-R7
Ci-Cs alkyl, or alkyl, wherein
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently,
halogen, alkoxy, (d-C4) alkyl, CF3, or OCF3,
R4 is H, (Ci-Cs) alkyl substituted with one group that is C02H,
-C02-(C1-C6) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N(R30)C(0)-
(Ci-Cs) alkoxy, or -NR6R7, phenylalkoxy, benzyl, or
phenethyl, wherein
the phenyl portion of the above groups are unsubstituted
or substituted with 1, 2, or 3 groups that are
independently halogen, hydroxy, (d-C4) alkoxy, (d-
C4) alkyl, nitro, CF3, or OCF3.
RS is benzyl, phenethyl, phenpropyl, (Ci-Cs) alkyl, phenyl, or
pyridyl, wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
(Ci-C4) alkyl, fluoro, chloro, bromo, (d-C*) alkoxy, C02H,
CN, amidinooxime, amidino, CF3, OCF3, NR6R7, NR6R7- (d-C6
alkyl)-, or -C(0)NRSR7; wherein
RS and R7 are independently hydrogen, OH, Ci-C4 alkoxy, Ci-
Cs alkanoyl, or Ci-Cs alkyl, wherein each of the
above is optionally substituted with 1 or 2 groups
that are independently OH, NH2, C3-C6 cycloalkyl, or
halogen; or
RS, R7; and the nitrogen to which they are attached form a
morpholinyl, piperidinyl, pyrrolidinyl, or
piperazinyl ring which is optionally substituted
with 1 or 2 groups that are independently Ci-C4
alkyl, d-C4 alkoxy, hydroxy, hydroxy d-C4 alkyl, or
halogen.
or pharmaceutically acceptable salts thereof, wherein
RI is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,
arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl,
or arylalkanoyl,
wherein the aryl portion of arylalkoxy, arylalkyl, and
arylalkanoyl is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
d-C4 alkyl, Ci-C4 alkoxy, nitro, CN, haloalkyl,
haloalkoxy or C02H;
wherein the alkyl portion of the alkyl, hydroxyalkyl,
arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl
and arylalkanoyl groups is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, ethoxy or
spirocyclopropyl;
R2 is H, arylthio, -OC (0) NH (CH2)naryl / arylalkyl,
-OC (0)N (alkyl) (CH2)naryl, or arylthioalkoxy, wherein n is
1, 2, 3, 4, or 5; wherein the aryl groups are optionally
substituted with 1, 2, 3, 4, or 5 groups that are
independently halogen, - (d-C6) alkyl-N(R)-C02R30, Ci-C4
alkoxy, Ci-C4 alkyl, CF3, or OCF3;
R at each occurrence is independently H or Ci-Cfi alkyl;
R30 is Ci-Cs alkyl optionally substituted with 1 or 2
groups that are independently OH, SH, halogen,
amino, mono alkyl ami no, dialkylatnino or Ca-Cs
cycloalkyl;
R3 is halogen, alkoxycarbonyl, arylalkoxycarbonyl,
aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl,
arylalkoxy, -OC(O)N(alkyl)(CH2)naryl, aryloxy, arylthio,
thioalkoxy, arylthioalkoxy, alkenyl, NRSR7 d-Cs alkyl,
NRSR7 or alkyl, wherein
the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl,
arylalkyl, -OC (0)NH (CH2) naryl, arylalkoxy,
-OC(0)N (alkyl) (CH2)naryl, and arylthioalkoxy, is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, alkoxy, alkyl,
haloalkyl, or haloalkoxy,
wherein n is 0, 1, 2, 3, 4, 5, or 6; or
R4 is H, alkyl substituted with one group that is C02H, -C02-
(d-Cs) alkyl, -C(0)NRR, -N (R30) C (0) NRR, -N (R30) C (0) - (Ci-
C6) alkoxy, or -NR6R7, arylalkoxy, arylalkyl, hydroxyalkyl,
haloalkyl, alkoxy, alkpxyalkyl, or alkoxyalkoxy, wherein
the aryl portion of arylalkoxy, arylalkyl is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, hydroxy,
alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl,
heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or
heteroaryl, wherein each of the above is unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that are
independently alkyl, halogen, alkoxy, arylalkoxy,
thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO2H, CN,
amidinooxime, NR6R7, NR6R7-(Ci-Cs alkyl)-, -C(0)NR6R7,
amidino, haloalkyl, or haloalkoxy; wherein
R6 and R7 are independently at each occurrence H, Ci-Cs
alkyl, Ci-Cs alkoxy, Ci-Cfi alkoxy Ci-Cs alkyl, d-Cs
alkoxycarbony 1, OH, Ci-Cs hydroxyalkyl, - (d-C4) alkyl- •
C02-alkyl, pyridyl Ci-Cs alkyl, d-Cs alkanoyl,
benzyl, phenyl Ci-Cs alkoxy, or phenyl d-Cs alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, C3-CS cycloalkyl, C±-C€
alkoxy, piperidinyl Ci-Cs alkyl, morpholinyl Ci-C6
alkyl, piperasinyl C-^-C6 alkyl, OH, SE, NH2,
NH(alkyl), N(alkyl)(alkyl), -0-CX-C4 alkanoyl, Ci-C4
alkyl, CF3, or OCF3; or
R6; R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, Ci-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen.
Embodiment A168. Compounds according to embodiment
A163 wherein
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl,
alkoxy, pyridyl (Ci-C6) alkyl, phenyl (Ci-Cs) thioalkyl,
pyrrolyl, pyrrolyl (d-Cg) alkyl, or pyridyl, wherein each
of the above is unsubstituted or substituted with 1, 2,
or 3 groups that are independently (Ci-Ce) alkyl, halogen,
(Ci-C6) alkoxy, phenyl (Ci-Cs) alkoxy, (d-C6) thioalkoxy,
alkoxycarbonyl, C02H, CN, amidinooxime, amidino, CF3, or
OCF3.
Embodiment A169. Compounds according to embodiment A163
wherein
RI is H, Cl, Br, (Ci-C Cs) alkyl,
wherein the alkyl portion of above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, or ethoxy
R2 is H, phenylthio, -OC(0)NH(CH2)naryl/ phenylalkyl,
-OC(0)N(alkyl) (CH2)aaryl, or phenylthio (CL-Cfi) alkoxy,
wherein n is 1, 2, 3, or 4;
wherein the aryl groups are optionally substituted with
I, 2, 3, 4, or 5 groups that are independently
halogen, - (Ci-Cs) alkyl-N(R) -C02R3o, Ci-C4 alkcxy, Ci-C4
alkyl, CF3, or OCF3;
R3 is bromo, alkoxycarbonyl, phenylalkoxycarbonyl,
phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy,
phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7
or alkyl, wherein
the phenyl portion of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, (Ci-C4) alkoxy, (Ci-C4) alkyl,
halo (Ci-C4) alkyl, or halo (d-C4) alkoxy,
wherein n is 0, 1, 2, 3, or 4;
R4 is H, alkyl substituted with one group that is C02H, -C02-
(Ci-Cs) alkyl, -C(0)NRR, -N (R30) C (O)NRR, -N (R30) C (0) - (Ci-
Cs) alkoxy, or -NR6R7, phenylalkoxy, phenylalkyl,
hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or wherein
the phenyl portion of phenylalkoxy, phenylalkyl is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently halogen, hydroxy, alkoxy,
alkyl, nitro, haloalkyl, or haloalkoxy
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl,
phenyl (Ci-C6)thioalkyl, pyrrolyl, or pyridyl, wherein each
of the above is unsubstituted or substituted with 1, 2,
or 3 groups that are independently (Ci-C6) alkyl, halogen,
(CI-GS) alkoxy, benzyloxy, (Ci-C6) thioalkoxy,
alkoxycarbonyl, C02H, CN, amidinooxime, amidino, CF3,
R6 and R7 are independently hydrogen, OH, Ci-C4 alkoxy,
C6 alkanoyl, or Ci-C6 alkyl, wherein each of the
-135-
above is optionally substituted with 1 or 2 groups
that are independently OH, NH2, C3-C6. cycloalkyl, or
halogen; or
R6, R7, and the nitrogen to which they are attached form a
morpholinyl, piperidinyl, pyrrolidinyl, or
piperazinyl ring which is optionally substituted
with 1 or 2 groups that are independently C;-C4
alkyl, Ci-C4 alkoxy, hydroxy, hydroxy d-C4 alkyl, or
halogen.
Embodiment A170. Compounds according to embodiment 1
or a pharmaceutically acceptable salt thereof, wherein
RX is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,
arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl,
or arylalkanoyl,
wherein the aryl portion of arylalkoxy, arylalkyl, and
arylalkanoyl is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently halogen,
CX-C4 alkyl, Ci-C4 alkoxy, nitro, CN, haloalkyl,
haloalkoxy or CO2H;
wherein the alkyl portion of the alkyl, hydroxyalkyl,
arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl
and arylalkanoyl groups is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, methoxy, ethoxy or
spirocyclopropyl;
R2 is arylalkoxy, aryloxy, aryloxyalkyl, OH, halogen,
arylthioalkoxy, 'alkoxy, -OC (0)NH(CH2)naryl,
-OC(0)N(alkyl) (CH2)Baryl, alkyl, alkoxyaikoxy,
dialkylamino, or C02H, wherein
n is 0, 1, 2, 3, 4, 5 or 6;
the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy,
-OC(0}NK(CH2)naryl, and -OC (0)N (alkyl) (CH2) naryl or
the heteroaryl and heterocycloalkyl groups is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, - (C-C6)alkyl-
N(R)-C02R30, haloalkyl, heteroaryl, heteroarylalkyl,
NR6R7, NR«R7- (Ci-Cs alkyl} -, -OC(0)NRSR7, wherein
R6 and R7 are independently at each occurrence H, Cj-Cg
alkyl, Ci-Cg alkoxy, Ci-C alkoxy Ci-Cg alkyl, Ci-C6
alkoxycarbonyl, OH, Ci-Cg hydroxyalkyl, - (Ci-C4) alkyl-
C02-alkyl, pyridyl Ci-C« alkyl, Ci-Cfi alkanoyl,
benzyl, phenyl Ci-Cs alkoxy, or phenyl Ci-C6 alkanoyl,
wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, C3-C6 cycloalkyl, Ci-Cg
alkoxy, piperidinyl Ci-C6 alkyl, morpholinyl Ci-C6
alkyl, piperazinyl Ci-Cg alkyl, OH, SH, NH2,
NH {alkyl), N (alkyl) (alkyl) , -0-d-C4 alkanoyl, d-C4
alkyl, CF3, or OCF3; or
Rg, R7, and the nitrogen to which they are attached form a
morpholinyl, thiomorpholinyl, piperidinyl,
pyrrolidinyl, or piperazinyl ring which is
optionally substituted with 1 or 2 groups that are
independently Ci-C4 alkyl, Ci-C4 alkoxy, hydroxy,
hydroxy Ci-C4 alkyl, or halogen;
R at each occurrence is independently H or Ci-C6 alkyl;
Rao is Ci-Cg alkyl optionally substituted with 1 or 2
groups that are independently OH, SH, halogen,
amino, monoalkylamino, dialkylamino or C3-Cg
cycloalkyl;
R3 is halogen, alkoxycarbonyl, arylalkoxycarbonyl,
aryloxycarbonyl, arylalkyl, -OC (0)NH(CH2)naryl,
arylalkoxy, -OC(O)N(alkyi) (CH2)naryl, aryloxy, arylthio,
thioalkoxy, arylthioalkoxy, alkenyl, NR6R7 Ci-C6 alkyl,
NR6R7 or alkyl, wherein
the aryl portion of arylalkoxycarbonyl, aryloxycarbor.yl,
arylalkyl, -OC (0)NH (CH2) naryl, arylalkoxy,
-OC(0)N (alkyl) (CH2)naryl, and arylthioalkoxy, is
unsubstituted or substituted with 1, 2, or 3 groups
that are independently, halogen, alkoxy, alkyl,
haloalkyl, or haloalkoxy,
wherein n is 0, 1, 2, 3, 4, 5, or 6; or
R4 is H, alkyl substituted with one group that is C02H, -C02-
(Ci-C6)alkyl, -C(0)NRR, -N(R30) C (0) NRR, -N (R30) C (0) - (d-
Cs)alkoxy, or -NR6R7, arylalkoxy, arylalkyl, hydroxyalkyl,
haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein
the aryl portion of arylalkoxy, arylalkyl is
unsubstituted or substituted with 1, 2, 3, 4, or 5
groups that are independently halogen, hydroxy,
alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
RS is aryl, heterocycloalkylalkyl, heteroarylalkyl,
arylthioalkyl, heterocycloalkyl, or heteroaryl, wherein
each of the above is unsubstituted or substituted with 1,
2, 3, 4, or 5 groups that are independently alkyl,
halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl,
arylalkoxycarbonyl, C02H, CN, atnidinooxime, NR«R7f NR6R7-
(Ci-C6 alkyl)-, -C(0)NR6R7, amidino, haloalkyl, or
haloalkoxy.
Embodiment A173. Compounds according to embodiment
A170 wherein
Rl is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,
benzyloxy, phenethyloxy, phenpropyloxy, benzyl,
phenethyl, phenpropyl, CN, alkanoyl, alkoxy, or
phenylC(O)-, phenylCH2C (0) - , or phenylCH2CH:C (0) ,
wherein the above phenyl groups are unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, Ci-C4 alkyl, Ci-C4 alkoxy,
nitro, CN, CF3, OCF3 or C02H;
wherein the above alkyl groups are unsubstituted or
substituted with I, 2, or 3 groups that are
independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy,
phenyloxy (Ci-Cg) alkyl, OH, halogen, phenylthioalkoxy,
alkyl, alkoxy, -OC (0)NH(CH2) nphenyl,
OC(0)N(alkyl) (CH2)nphenyl, dialkylamino, or C02H, wherein
n is 0, 1, 2, 3, or 4;
the above aryl groups are unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently
halogen, - (Ci-C6) alkyl-N(R) -C02R30, CF3, pyridyl,
thienyl, NR6R-7, or NR6R7- (Ci-C6 alkyl)-, wherein
Rs and R? are independently at each occurrence H,
alkyl, alkanoyl, benzyl, or phenylC(O)-,
wherein the phenyl portion of the above is
unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, OH, C3-
C6 cycloalkyl, alkoxy, alkyl, CF3/ or OCF3;
Ra is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,
phenyl oxycarbonyl, phenylalkyl, -OC(0)NH(CH2)nphenyl,
phenylalkoxy, -OC(O)N(alkyl) (CH2) nphenyl, phenyloxy,
phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NRgR
or alkyl, wherein
the phenyl portion of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, alkoxy, alkyl, haloalkyl, or
haloalkoxy,
wherein n is 0, 1, 2, 3,or 4;
R4 .is H, alkyl substituted with one group that is C02H, -C02-
(Ci-C6) alkyl, -C(0)NRR, -N(R30)C(0)NRR, -N (R30) C (0) - (Ci-
Cs) alkoxy, or -NR6R7, phenylalkoxy, phenylalkyl,
hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or
alkoxyalkoxy, wherein
the phenyl • portion of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, hydroxy, alkoxy, alkyl,
nitro, haloalkyl, or haloalkoxy; and
R5 is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl
pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl,
pyrrolyl, piperidinyl, pyridyl, or thienylalkyl, wherein
each of the above is unsubstituted or substituted with 1,
2, or 3 groups that are independently alkyl, halogen,
alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl,
phenylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NR6R-
(CI-GS alkyl)-, -C(0)NR6R7, amidino, haloalkyl, or
haloalkoxy.
Embodiment A174. Compounds according to embodiment
A173 wherein
RI is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl,
benzyloxy, phenethyloxy, benzyl, phenethyl, CN, (Ci-
C6)alkanoyl, alkoxy, or phenylC(O)-, or pheny!CH2C (0) -,
wherein the above phenyl groups are unsubstituted or
substituted with 1, 2, or 3 groups that are'
independently halogen, Ci-C« alkyl, Ci-C4 alkoxy,
nitro, CN, CF3, OCF3 or CO2H;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy,
phenyloxy (d-C6) alkyl, halogen, phenyl (C1-C4) thioalkoxy,
-OC(0)NH(CH2)nphenyl, -OC(0)N(alkyl) (CH2) npher.yl, or
dialkylamino, wherein
n is 0, 1, 2, 3, or 4;
the above phenyl groups are unsubstituted or substituted
with 1, 2, or 3 groups that are independently
halogen, CF3, NR6R7, or NRSR7- (Ci-Cs alkyl)-, wherein
Rs and R7 are independently at each occurrence H,
(Ci-C6) alkyl, acetyl, benzyl, or phenylC(O)-,
wherein the phenyl portion of the above is
unsubstituted or substituted with 1, 2, or 3
groups that are independently, halogen, OK,
cyclopropyl, alkoxy, alkyl, CF3, or OCF3;
R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl,
phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy,
phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NRgR
or alkyl, wherein
the phenyl portion of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently, halogen, alkoxy, alkyl, haloalkyl, or
haloalkoxy,
wherein n is 0, 1, 2, 3,or 4;
R4 is H, alkyl substituted with one group that is C02H, -C02-
(Ci-C6)alkyl, -C(0)NRR, -N(R30) C (O)NRR, -N(R30)C(0) - (Ci-
C6)alkoxy, or -NR6R7/ phenylalkoxy, phenylalkyl,
hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or
alkoxyalkoxy, wherein
the phenyl portion of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are
independently halogen, hydroxy, alkoxy, alkyl,
nitro, haloalkyl, or haloalkoxy; and
R5 is phenyl, phenyl (Ci-C4) thioalkyl, pyridyl, or thienyl (Ci-
C4)alkyl, wherein each of the above is unsubstituted or
substituted with 1, 2, or 3 groups that are independently
(Ci-C4)alkyl, fluoro, chloro, bromo, (d-C4) alkoxy, CN,
amidinooxime, amicino, CF3, or OCF3.
Embodiment A175. Compounds according to embodiment
A174 wherein
R5 is substituted with at least one group selected from fluoro,
chloro, bromo, and methyl.
In another aspect, the invention provides pharmaceutical
compositions comprising at least one pharmaceutically
acceptable carrier, solvent, adjuvant or excipient and a
compound of formula I, embodiment A66, or embodiment A154.
The invention further provides pharmaceutical
compositions comprising at least one pharmaceutically
acceptable carrier, solvent, adjuvant or excipient and
compounds according to any of the preceding embodiments.
As noted above, the invention encompasses methods of
treating a TNF mediated disorder, a p38 kinase mediated
disorder, inflammation and/or arthritis in a subject, the
method comprising treating a subject having or susceptible to
such disorder or condition with a therapeutically-effective
amount of a compound of formula I or embodiment Al.
More specifically, the invention provides methods for
treating or preventing inflammation; arthritis, rheumatoid
arthritis, spondylarthropathies, gouty arthritis,
osteoarthritis, systemic lupus erthematosus, juvenile
arthritis, and other arthritic conditions; neuroinf lamination;
allergy, Th2 mediated diseases; pain, neuropathic pain; fever;
pulmonary disorders, lung inflammation, adult respiratory
distress syndrome, pulmonary sarcoisosis, asthma, silicosis,
chronic pulmonary inflammatory disease, and chronic
obstructive pulmonary disease (COPD); cardiovascular disease,
arteriosclerosis, myocardial infarction (including postmyocardial
infarction indications), thrombosis, congestive
heart failure, cardiac reperfusion injury, as well as
complications associated with hypertension and/or heart
failure -such as vascular organ damage, restenosis;
cardiomyopathy; stroke including ischemia and hemorrhagic
stroke; reperfusion injury; renal reperfusion injury; ischemia
including stroke and brain ischemia, and ischemia resulting
from cardiac/coronary bypass; neurotrauma and brain trauma
including closed head injury; brain edema; neurodegenerative
disorders; liver disease and nephritis; gastrointestinal
conditions, inflammatory bowel disease, Crohn's disease,
gastritis, irritable bowel syndrome, ulcerative colitis;
ulcerative diseases, gastric ulcers; ophthalmic diseases,
retinitis, retinopathies, uveitis, ocular photophobia, acute
injury to the eye tissue and ocular traumas such as posttraumatic
glaucoma, traumatic optic neuropathy, and central
retinal artery occlusion (CRAO); periodontal disease;
ophthalmological conditions, retinitis, retinopathies
(including diabetic retinopathy), uveitis, ocular photophobia,
nonglaucomatous optic nerve atrophy, and age related macular
degeneration (ARMD) (including ARMD-atrophic form), corneal
graft rejection, ocular neovascularization, retinal
neovascularization, neovascularization following injury or
infection, retrolental fibroplasias, neovascular glaucoma;
glaucoma including primary open angle glaucoma (POAG),
juvenile onset primary open-angle glaucoma, angle-closure
glaucoma, pseudoexfoliative glaucoma, anterior ischemia optic
neuropathy (AION), ocular hypertension, Reiger's syndrome,
normal tension glaucoma, neovascular glaucoma, ocular
inflammation and corticosteroid-induced glaucoma; diabetes;
diabetic nephropathy; skin-related conditions, psoriasis,
eczema, burns, dermatitis, keloid formation, scar tissue
formation, angiogenic disorders; viral and bacterial
infections, sepsis, septic shock, gram negative sepsis,
malaria, meningitis, HIV infection, opportunistic infections,
cachexia secondary to infection or malignancy, cachexia
secondary to acauired immune deficiency syndrome (AIDS), AIDS,
ARC (AIDS related complex), pneumonia, herpes virus; myalgias
due to infection; influenza; endotoxic shock; toxic shock
syndrome; autoimmune disease, graft vs. host reaction and
allograft rejections; treatment of bone resorption diseases,
osteoporosis; multiple sclerosis; disorders of the female
reproductive system, endometriosis; hemaginomas, infantile
hemagionmas, angiofibroma of the nasopharynx, avascular
necrosis of bone; benign and malignant tumors/neoplasia,
cancer, colorectal cancer, brain cancer, bone cancer,
epithelial call-derived neoplasia (epithelial carcinoma),
basal cell carcinoma, adenocarcinoma, gastrointestinal cancer,
lip cancer, mouth cancer, esophageal cancer, small bowel
cancer, stomach cancer, colon cancer, liver cancer, bladder
cancer, pancreas cancer, ovarian cancer, cervical cancer, lung
cancer, breast cancer, skin cancer, squamus cell and/or basal
cell cancers, prostate cancer, renal cell carcinoma, and other
known cancers that affect epithelial cells throughout the
body; leukemia; lymphoma; systemic lupus erthrematosis (SLE);
angiogenesis including neoplasia; metastasis; central nervous
system disorders, central nervous system disorders having an
inflammatory or apoptotic component, Alzheimer's disease,
Parkinson's disease, Huntington's disease, amyotrophic lateral
sclerosis, spinal cord injury, and peripheral neuropathy;
Canine B-Cell Lymphoma. Compounds of the invention are also
useful for preventing the production or expression of
cyclooxygenase-2, or cyclooxygenase-2 activity.
In this aspect, the invention encompasses methods of
treating a p38 kinase or TNF-alpha mediated disorder
comprising administering to a patient _u ncc^ n*^,- -
therapeutically effective amount of Compounds according to
embodiment 1 and at least one pharmaceutically acceptable
carrier, adjuvant, solvent or excipient.
Representative compounds of the invention are:
l-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H) -one;
3-bromo-l-(4-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1- (2,6-
dimethylphenyl)-6-methylpyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(1H) -
one ;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-(pyridin-
3-ylmethyl)pyridin-2(1H) -one;
4-bromo-2-(2,6-dichlorophenyl)-5-[(2,4-
difluorobenzyl)oxy}pyridazin-3(2H)-one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
3-bromo-l-(3-fluorobenzyl) -4-[(3-
methylbenzyl)oxy]pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
4-ylmethyl)pyridin-2(1H) -one;
4-(benzyloxy)-3-bromo-l-(3-fluorobenzyl)pyridin-2(1H)-
one;
l-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridin-2 (1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-
methylphenyl)-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-
fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-3-
ylmethyl)pyridin-2(1H) -one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-
methylpyridin-2(IH) -one;
4-(benzyloxy)-3-bromo-l-(4-methylbenzyl)pyridin-2(1H) -
one;
4-(benzyloxy)-3-bromo-l-(4-chlorobenzyl)pyridin-2(IH) -
one;
3-bromo-4-[(2,4-difluorobenzyl)oxy] -1-(3-
methoxybenzyl)pyridin-2(IH) -one;
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl}benzoic acid;
4- (benzyloxy)-3-bromo-l-(2-fluorobenzyl)pyridin-2(IH)-
one;
3-bromo-l-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one;
4-(benzyloxy)-3-bromo-l-[4-(methylthio)benzyl]pyridin-
2 (IH) -one;
l-benzyl-4-(benzyloxy)-3-chloropyridin-2(IH)-one;
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -yl]methyl}-
N' -hydroxybenzenecarboximidamide;
methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]methyl}benzoate;
3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(IH) -one;
3-bromo-l-(3-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(IH) -one;
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]methylJbenzonitrile;
4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6-
methylpyridin-2(IH) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-
ylmethyl)pyridin-2(IH) -one;
4- (benzyloxy)-3-bromo-l- (4-bromobenzyl)pyridin-2(IH) -one;
4-{ [3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-l(2H)-
yl]methyl}benzonitrile;
1-(3-fluorobenzyI)-4-[(4-fluorobenzyl)oxy] -3-iodopyridin
2(1H) -one;
4-bromo-2-(2,6-dichlorophenyl)-5-{[2-
(hydroxymethyl)benzyl]oxy}pyridazin-3(2H) -one;
3-bromo-4- [ (4-fluorobenzyl)oxy]-I-(pyridin-3-
ylmethyl)pyridin-2(1H)-one;
3-bromo-l-(2,4-difluorobenzyl)-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-4-t(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-2-
ylmethyl)pyridin-2(1H)-one; or a pharmaceutically acceptable
salt thereof.
Embodiment 57. Compounds according to embodiment 1 or
embodiment Al, which is
3-bromo-4-[(4-chlorobenzyl)oxy]-1- (4-
fluorobenzyl)pyridin-2(1H)-one;
l-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)
3-bromo-l-(4-chlorobenzyl)-4-[(4-
chlorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-4-[(4-chlorobenzyl)oxy]-1-[2-
(phenylthio)ethyl]pyridin-2(1H)-one;
3-bromo-4-[(4-chlorobenzyl)oxy]-1-(2-phenylethyl)pyridin-
2 (IH)-one;
3-bromo-4-hydroxy-l-(4;hydroxybenzyl)pyridin-2(1H)-one
4-(benzyloxy)-3-bromo-l-(piperidin-3-ylmethyl)pyridin-
2(lH)-one hydrochloride;
3-bromo-l-(4-methoxybenzyl)-4-phenoxypyridin-2(1H) -one;
1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3 -
carbaldehyde;
3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4 -
methoxybenzyl)pyridin-2(1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(3-
phenylpropyl)pyridin-2(1H) -one;
4-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyriain-
2 (1H) -one;
4-(benzyloxy)-3-bromo-l-[2-
(trifluoromethyl)benzyl]pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-[3-
(trifluoromethyl)benzyl]pyridin-2(1H)-one;
4- (benzyloxy) -3-brotno-l- (piperidin-4-ylmethyl)pyridin-
2 (1H) -one hydrochloride;
l-benzyl-3-bromo-4-{[2-
(trifluoromethyl)benzyl]oxy}pyridin-2(1H)-one;
l-benzyl-4- [ (2,6-dichlorobenzyl)oxy]pyridin-2 (1H) -one;
l-benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2(1H) -
one ;
1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-
2 (IH)-one;
l-benzyl-4- [ (3-chlorobenzyl) oxy] -6-tnethylpyridin-2 (1H) -
one;
1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-
2 (IH)-one;
1-benzyl-3-bromo-4- [ (2-chlorobenzyl) oxy] pyridin-2 (1H) -
one;
4- (benzyloxy) -3-bromo-l-ethylpyridin-2 (1H) -one;
4- (benzyloxy) -1- (4-bromobenzyl)pyridin-2 (1H) -one;
3-bromo-l- (4-tnethylbenzyl) -4- [ (4-
methylbenzyl)oxy]pyridin-2(1H)-one;
methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl ] methyljbenzoate;
4-(benzyloxy)-3-bromo-l-(2-thien-3-ylethyl)pyridin-2(1H)-
one;
4- (benzyloxy)-3-bromo-l-(2-thien-2-ylethyl)pyridin-2(1H)
one;
l-benzyl-4- [ (3-chlorobenzyl) oxy] pyridir.-2 (1H) -one;
3-bromo-l-(4-fluorobenzyl)-4- [ (4-
fluorobenzyl)oxy]pyridin-2(1H)-one;
4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H) -one;
4-(benzyloxy)-1-(2-fluorobenzyl)pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-methylpyridin-2(1H) -one
hydrobromide;
4- (benzyloxy) -3-bromo-l-methylpyridin-2 (1H) -one;
3-bromo-l-(3-chlorobenzyl)-4- [ (4-
chlorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(3-chlorobenzyl)-4-[ (4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l- [4-
(trifluoromethoxy)benzyl]pyridin-2 (1H) -one;
4- (benzyloxy) -3-bromo-l- (4- terc-butylbenzyl) pyridin-
2 (1H) -one;
l-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H) -one;
l-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)
one;
4-(benzyloxy)-3-bromo-l-[4-
(trifluoromethyl)benzyl]pyridin-2(1H) -one;
l-benayl-4-[(2-chlorobenzyl)oxy]pyridin-2(1H)-one;
1- (2-bromobenzyl) -3- [ (2-bromobenzyl) oxy] pyridin-2 (1H) -
one;
methyl 5-chloro-l-(4-chlorobenzyl)-6-oxo-l,6-
dihydropyridine-3-carboxylate;
3-benzyl-4-hydroxy-l-(2-phenylethyl)pyridin-2(1H) -one;
5-bromo-l-(2-chloro-6-fluorobenzyl)-3-methylpyridin-
2 (1H) -one;
-149-
1-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(IH)-
one;
l-benzyl-4-(benzyloxy)pyridin-2(IH) -one;
1-benzyl-4-(benzyloxy)-3-bromopyridin-2(IH) -one;
l-benzyl-4-(benzyloxy)-2-oxo-l,,2-dihydropyridine-3-
carbaldehyde;
l-benzyl-4-chloro-2-oxo-l,2-dihydropyridine-3-
carbaldehyde;
1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-
carbaldehyde;
l-benzyl-4-(benzyloxy}-3-methylpyridin-2(IH) -one;
4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(IH)-one;
l-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(IH) -one;
4-(benzyloxy)-3-bromo-l-[4-(methylthio)benzyl]pyridin-
2 (IH) -one;
4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(IH) -
one;
l-benzyl-4-(benzyloxy)-3-chloropyridin-2(IH)-one;
3-bromo-l-(4-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(IH)-one;
1 -benzyl -3 -bromo-2 -oxo-1,2 -dihydropyridin-4 -yl
methyl(phenyl)carbamate;
l-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(IH) -one;
1-benzyl-3-bromo-4-(3-phenylpropyl)pyridin-2(1H) -one;
1-benzyl-3-methyl-4-(2-phenylethyl)pyridin-2(IH) -one;
1-benzyl-3-methyl-4-(3-phenylpropyl)pyridin-2(IH)-one;
l-benzyl-4-(benzylthio)-3-methylpyridin-2(IH) -one;
l-benzyl-4-(benzylthio)-3-bromopyridin-2(IH)-one;
1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;
3-acetyl-4-hydroxy-6-methyl-l-[choro]phenylpyridin-2(IH)
one;
6-(benzyloxy)-l-methyl-2-oxo-l,2-dihydropyridine-3-
carbonitrile;
3-benzoyl-6-(benzyloxy)-l-methylpyridin-2(1H) -one;
3-benzyl-G-(benzyloxy)-l-methylpyridin-2(1H) -one;
l-bensyl-4-hydroxypyndin-2 (1H) -one;
l-benzyl-4-(benzylthio)pyridin-2 (1H)-one
4-amino-l-benzylpyridin-2(1H)-one;
l-benzyl-4- (benzyloxy)pyridin-2 (1H) -one,-
l-benzyl-4-hydroxypyridin-2(1H) -one;
1-benzyl-2 -oxo-1,2-dihydropyridin-4-y1
methyl(phenyl)carbamate;
or a pharmaceutically acceptable thereof.
Embodiment 58. Compounds according to embodiment 1 or
embodiment Al, which is
4-(benzyloxy)-I-(4-methylbenzyl)pyridin-2(1H) -one;
4- (benzyloxy) -3-bromopyridin-2 (IH) -one,-
methyl 4-{ [4-(benzyloxy)-2-oxopyridin-l(2H)-yl]methyl)
benzoate;
methyl-4-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl} benzoate;
4-{[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]methyl}
benzoni t ri1e;
4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2(1H) -one;
4- (benzyloxy)-1-[4-(trifluoromethyl)benzyl]pyridin-2(1H)-
one ;
4-(benzyloxy)-3-bromo-l-[4-(trifluoromethyl)
benzyl]pyridin-2(1H) -one;
4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl)
benzyl]pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl)
benzyl]pyridin-2(1H)-one;
4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-
2(1H) -one;
4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy)
benzyl]pyridin-2(1H)-one;
l-benzyl-4-hydroxy-6-methylpyridin-2(IK)-one;
l-benzyl-6-methyl-2-oxo-l,2-dihydropyridin-4-yl 4-
bromobenzenesulfonate;
l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-
2(1H)-one;
1-benzyl-6-methyl-2 -oxo-1,2-dihydropyridin-4-yl 4 -
bromobenzenesulfonate;
l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-
2(1H)-one;
l-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2 (1H)-one;
4-[(2,6-dichlororbenzyl)oxy]pyridine-1-oxide;
4-[(2,6-dichlorobenzyl)oxy]pyridine 1-oxide;
l-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-
2(1H)-one;
l-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(IE)-
one;
l-Benzyl-4-[benzylthio]-3-bromopyridin-2(1H)-one;
l-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H)-one;
1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one;
l-benzyl-4-(benzyloxy)-3-ethylpyridin-2(1H)-one;
3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-
methylpyridin-2(1H)-one;
3-acetyl-l-(2-chlorophenyl)-4-hydroxy-6-methylpyridin-
2(lH)-one;
l-benzyl-3-bromo-4-hydroxypyridin-2(1H)-one;
l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl
trifluoromethanesulfonate;
l-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-
phenylethyl)pyridin-2(1H)-one;
1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-
2(IK)-one;
3-bromo-l-(3-fluorobenzyl)-6-methyl-2-oxo-l,2-
dihydropyridin-4-yl trifluoromethanesuifonate;
3-bromo-l-(3-fluorobenzyl)-6-methyi-4-
(phenylethynyl)pyridin-2(1H)-one;
3-acetyl-l- (2,6-dichlorophenyl)-4-hydroxy-6-
methylpyridin-2(IK)-one;
1-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-
one;
4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-
2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-
2(IK)-one;
3-bromo-l-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl
trifluoromethanesuifonate;
3-bromo-l-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-
2(lH)-one;
4-(benzyloxy)-3 -ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-
one;
4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one;
4-(benzyloxy)-1-(3-fluorobenzyl)-3-
[(trimethylsilyl)ethynyl]pyridin-2(1H)-one;
4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin-2(IE)-
one;
1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one;
4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one;
or a pharmaceutically acceptable salt thereof.
Embodiment 59. Compounds according to embodiment 1 or
embodiment Al, which is
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-
fluorober.zyl) pyridin-2 (1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-1-(pyridin-3-
ylmethyl)pyridin-2(1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-4-
ylmethyl)pyridin-2(IH)-one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-
methoxybenzyl)pyridin-2 (1H) -one;
3-bromo-l-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-
methylpyridin-2(1H) -one;
3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(4-fluorobenzyl)oxy] -1-(pyridin-4-
ylmethyl)pyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-l(2H) -
yl]methyl}benzonitrile;
1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-
2 (1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy] -1-(pyridin-3-
ylmethyl)pyridin-2 (1H) -one;
3-bromo-l-(2,4-difluorobenzyl)-4-[(2,4-
dif luorobenzyl) oxy]pyridin-2(1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-2-
ylmethyl)pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
3-ylmethyl)pyridin-2(1H)-one;
3-bromo-l-(2,6-dichlorophenyl)-4- [ (2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
3-bromo-l-(3-fluorobenzyl)-4-[(3-
methylbenzyl)oxy]piperidin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
4-ylmethyl)pyridin-2(1H)-one;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-
methylphenyl)-6-methylpyridin-2(1H) -one;
or a pharmaceutically acceptable salt thereof.
Embodiment 60. Compounds according to embodiment 1, which
is
1-(l-acetyl-2,3-dihydro-lH-indol-5-yl)-3-chloro-4-[ (2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(l-glycoloyl-2,3-
dihydro-lH-indol-5-yl)-6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-[I-(2-hydroxy-2-
methylpropanoyl)-2,3-dihydro-lH-indol-5-yl] -6-methylpyridin-
2(lH)-one;
3-chloro-4- [ (2, 4-dif luorobenzyl) oxy] -6-methyl-l-
methylglycyl) -2,3-dihydro-lH-indol-5-yl]pyridin-2 (1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-
hydroxypropanoyl)-2,3-dihydro-lH-indol-5-yl] -6-methylpyridin-
2 (IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy] -1-[1-(3-hydroxy-3-
methylbutanoyl)-2,3-dihydro-lH-indol-5-yl]-6-methylpyridin-
2 (IH)-one;
5- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]indoline-1-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[1-
(methylsulfonyl)-2,3-dihydro-lH-indol-5-yl]pyridin-2(1H) -one;
1-(l-acetyl-lH-indol-5-yl)-3-chloro-4-[(2,4-
difluorobenzyDoxy] -6-methylpyridin-2 (1H) -one;
3-chloro-4-[(2,4-difluorobensyl)oxy]-1-(1-glycoloyl-lHindcl-
5-yl) -6-methylpyridin-2 (1H) -one;
3-chloro-4- [ (2,4-difluorobenzyDoxy] -1- [1- (2-hydroxy-2-
methylpropanoyl)-lH-indol-5-yl] -6-methylpyridin-2 (1H) -one;
3-chloro-4- [ (2, 4-difluorobenzyDoxy] -6-methyl-l- [1- (Nmethylglycyl)
-lH-indol-5-yl]pyridin-2 (1H) -one;
3-chloro-4- [ (2,4-difluorobenzyDoxy] -1- [1- (3-
hydroxypropanoyl)-lH-indol-5-yl] -6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-lH-indol-5-yl]-6-methylpyridin-2 (1H) -one;
5- [3-chloro-4- [ (2,4-difluorobenzyDoxy] -6-methyl-2-
oxopyridin-1(2H)-yl]-IH-indole-l-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[1-
(methylsulfonyl)-lH-indol-5-yl] pyridin-2(1H)-one;
1-(2-acetyl-2,3-dihydro-lH-isoindol-5-yl)-3-chloro-4-
[ (2,4-difluorobenzyDoxy] -6-methylpyridin-2 (1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-(2-glycoloyl-2,3-
dihydro-lH-isoindol-5-yl)-6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-[2-(2-hydroxy-2-
methylpropanoyl)-2,3-dihydro-lH-isoindol-5-yl]-6-
methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(Nmethylglycyl)-
2,3-dihydro-lH-isoindol-5-yl]pyridin-2(1H) -one;
3-chloro-4- [(2,4-difluorobenzyDoxy] -1- [2- (3-
hydroxypropanoyl)-2,3-dihydro-lH-isoindol-5-yl]-6-
methylpyridin-2(1H) -one;
3-chloro-4- [(2, 4-difluorobenzyDoxy] -1- [2- (3-hydroxy-3-
methylbutanoyl)-2,3-dihydro-1H-isoindol-5-yl]-6-methylpyridin-
2(1H) -one;
5- [3-chloro-4- [ (2, 4-difluorobenzyDoxy] -6-methyl-2-
oxopyridin-1 (2H) -yl] -1, 3-dihydro-2H-isoindole-2-carboxamide;
-156-
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2~
(methylsulfonyl)-2,3-dihydro-ltf-isoindol-5-yl]pyridin-2(IH) -
one;
1- (2-acetyl-l,2,3,4-tetrahydroisoguinolin-6-yl)-3-chloro-
4- [ (2,4-difluorobensyl)oxy]-6-methylpyridin-2(IH)-one;
4
3-chloro-4-[(2,4-difluoroben=yl)oxy]-1-(2-gIyccloyl-
1,2,3,4-tetrahydroisoquinolin-6-yl)- 6-methyIpyridin-2(IH) - one;
3-chloro-4- [ (2,4-difluorobenzyDoxy] -1- [2- (2-hydroxy-2-
methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-6-
methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2- (Wmethylglycyl)-
1,2,3, 4-tetrahydroisoquinolin-6-yl]pyridin-
2(lH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-
hydroxypropanoyl)-1,2,3,4-tetrahydroisoguinolin-€-yl]-6-
methylpyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy] -1-[2-(3-hydroxy-3-
methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-6-
methylpyridin-2(IH)-one;
6-[3-chloro-4-[(2,4-difluorobenzyl}oxy]- 6-methyl-2-
oxopyridin-1(2H) -yl] -3/4-dihydroisoquinoline-2(IH)
carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-
(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridin-
2(lH)-one;
1- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-
4- [ (2,4-difluorobenzyDoxy] -6-methylpyridin-2 (IH) -one;
3-chloro-4- [{2,4-difluorobenzyDoxy] -1- (2-glycoloyll,
2,3,4-tetrahydroisoquinolin-7-yl)-6-methylpyridin-2(lH)-one; .
3-chloro-4-[(2,4-difluorobenzyl)oxy]-i-[2-(2-hydroxy-2-
methylpropanoyl)-1,2,3,4 -tetrahydroisoquinolin-7-yl]-6-
methylpyridin-2(1H) -one;
3-chloro-4-[ (2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(Nmethylglycyl)-
1,2,3,4-tetrahydroisoquinolin-7-yl]pyridin-
2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-
hydroxypropanoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-6-
methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[2-(3-hydroxy-3-
methylbutanoyl)-l,2,3,4-tetrahydroisoquinolin-7-yl]-6-
methylpyridin-2(1H) -one;
7-[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-3,4-dihydroisoquinoline-2(1H) -
carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-
(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridin-
2 (1H) -one;
1-(l-acetyl-lH-benzimidazol-5-yl)-3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-lHbenzimidazol-
5-yl)-6-methylpyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-
methylpropanoyl)-lH-benzimidazol-5-yl]-6-methylpyridin-2(1H) -
one ;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-[1-(Nmethylglycyl)-
lH-benzimidazol-5-yl]pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-I-[I-(3-
hydroxypropanoyl)-lH-benzimidazol-5-yl]-6-methylpyridin-2(1H) -
one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-lH-benzimidazol-5-yl]-6-methylpyridin-2(1H) -
one;
5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l(2H) -yl]-IH-benzimidazole-l-carboxamide;
3-chloro-4- [ (2, 4-ciif luorobenzyl) oxy] -6-raethyl-l- [1-
(methylsulfonyl)-IH-benzimidaZol-5-yl]pyridin-2(1H)-one;
3-chloro-1-(1,3-diacetyl-2,3-dihydro-IH-benzimidazcl- 5 -
yl) -4- [ (2,4-difluorobenzyl)oxy] -6-methylpyridin-2 (IK} -one;
1-(3-acetyl-1-glycoloyl-2,3-dihydro-IH-benzimidazol- 5 -
yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2 (1H) -one;
1-[3-acetyl-l-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
1-[3-acetyl-l-(W-methylglycyl)-2,3-dihydro-1Hbenziraidazol-
5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H) -one;
1- [3-acetyl-l-(3-hydroxypropanoyl)-2,3-dihydro-1Hbenzimidazol-
5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
1-[3-acetyl-l-(3-hydroxy-3-methylbutanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
3-acetyl-5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-
methyl-2-oxopyridin-l(2H) -yl]-2,3-dihydro-lH-benziraidazole-lcarboxamide;
1-{1-acetyl-3-glycoloyl-2,3-dihydro-IH-benzimidazol- 5 -
yl)-3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methylpyridin-
2 (IK)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1,3-diglycoloyl-
2,3-dihydro-lH-benzimidazol-5-yl)-6-methylpyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(2-
hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-
6-methylpyridin-2(Itf) -one;
3-chloro-4-[{2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-1-(Nmethylglycyl)-
2,3-dihydro-lH-benzimidazol-5-yl]-6-
methylpyridin-2(IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-glyccloyl-l-(3-
hydroxypropanoyl)-2,3-dihydro-lH-bsnzimidazol-5-yl]-6-
methylpyridin-2(IH)-one;
S-[3-chloro-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-
oxopyridin-l(2H) -yl]-3-glycoloyl-2,3-dihydro-lH-benzimidazole-
1-carboxamide;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-1-[3-glycoloyl-l-(3-
hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-
methylpyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-[3-glycoloyl-l-
(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-
methylpyridin-2(IH)-one;
1- [l-acetyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl] -3-chloro-4-[(2,4-dif luorobenzyl)oxy]-6-
methylpyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-[l-glycoloyl-3-(2-
hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-
6-methylpyridin-2(IH)-one;
I-[I, 3-bis(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(2-hydroxy-2-
methylpropanoyl) -1- (J7-methylglycyl) -2,3-dihydro-lHbenzimidazol-
5-yl] -6-methylpyridin-2 (IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(2-hydroxy-2-
methylpropanoyl)-I-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]-6-methylpyridin-2(IH)-one;
5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-3-(2-hydroxy-2-methylpropanoyl)-2,3-
dihydro-lH-bensimidazole-i-carboxamide;
3-chloro-4-[(2,4-difIuorobensylJoxy]-1-[3- (2-hyaroxy-2-
methylpropanoyl)-I-(methylsulfonyl)-2, 3-dihydro-lHbenziraidazol-
5-yl]-6-methylpyridin-2(IH) -one;
1-[l-acetyl-3-(JJ-methylglycyl)-2,3-cihydro-lHbenzimidazol-
5-yl]-3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-[l-glycoloyl-3-(Nmethylglycyl)-
2,3-dihydro-lH-benzimidazol-5-yl]-6-
methylpyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-
methylpropanoyl)-3-(W-methylglycyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(IH) -one;
1- [1, 3-bis (.W-methylglycyl) -2, 3-dihydro-lH"-benzimidazol-5-
yl]-3-chloro-4-f(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2 (IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1- (3-
hydroxypropanoyl) -3- (AT-methylglycyl) -2, 3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1- (3-hydroxy-3-
methylbutanoyl) -3- (J7-methylglycyl) -2, 3-dihydro-lHbenzimidazol-
5-yl] -6-methylpyridin-2 (IH) -one;
5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -3- (JV-tnethylglycyl) -2, 3-dihydro-lHbenzimidazole-
1-carboxamide;
3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-l-[3-(Nmethylglycyl)-
1-(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-
5-yl]pyridin-2(IH)-one;
1-[l-acetyl-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy] -6-
methylpyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[l-glycoloyl-3-(3-
hydroxypropanoyl) -2,3-dihydro-lH-ben=imidazol-5-yl] -6-
methylpyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl) oxy] -1- [1-r (2-hydroxy-2-
methylpropanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl] -6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-[3- (3-
hydroxypropanoyl)-1-(W-methylglycyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(1H) -one;
1- [1,3-bis(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-3-chloro-4-[(2;4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(1H)-one;
5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-
hydroxypropanoyl)-1-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(1H)-one;
1-[l-acetyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[l-glycoloyl-3- (3-
hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-
methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-
methylbutanoyl)-l-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl] -6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-
methylbutanoyl)-l-(W-methylglycyl)-2,3-dihydro-lH-
benzimidasol-S-yl]-6-methylpyridin-2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-[3-(3-hydroxy-3-
methylbutanoyl) -1- (3-hydroxypropanoyl) -2,3-dihydro-l.nbenzimidazol-
5-yl]-6-methylpyridin-2(1H) -one;
1- [1, 3-bis (3-hydroxy-3-methylbutanoyl) -2, 3-dihydro-lf:'-
benzimidazol-5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]- 6-
methylpyridin-2(1H)-one;
5- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]-3-(3-hydroxy-3-methylbutanoyl)-2,3-
dihydro-lH-ben:imidazole-1-carboxamide;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-[3-(3-hydroxy-3-
methylbutanoyl)-1-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(1H) -one;
3-acetyl-6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl] -2,3-dihydro-lH-benzimidazole-lcarboxamide;
6-[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -3-glycoloyl-2 , 3-dihydro-liT-benzimidazole-
1-carboxamide;
6-[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]-3-(2-hydroxy-2-methylpropanoyl)-2,3-
dihydro-lH-benzimidazole-1-carboxamide;
6-[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -3- (W-methylglycyl) -2,3-dihydro-lHbenzimidazole-
1-carboxamide;
6-[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -3- (3-hydroxypropanoyl) -2,3-dihydro-lHbenzimidazole-
1 -carboxamide ;
6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l(2H) -yl]-3-(3-hydroxy-3-methylbutanoyl)-2,3-
dihydro-ltf-benzimidazole-l-carboxamide;
5-[3-chloro-4-[{2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -IH-benzimidazole-l, 3 (2H) -dicarboxamide;
6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-3-(methylsulfonyl)-2,3-dihydro-lHbencimidazole-
1 -carboxamide;
1-[l-acetyl-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[l-glycoloyl-3-
(methylsulfonyl)-2,3-dihydro-IH-benzimidazol-5-yl]-6-
methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-
methylpropanoyl)-3-(methylsulfonyl)-2,3-dihydro-1Hbenzimidazol-
5-yl]-6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[I-(Nmethylglycyl)-
3-(methylsulfonyl)-2,3-dihydro-IH-benzimidazol-
5-yl]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-
hydroxypropanoyl)-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]-6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-3-(methylsulfonyl)-2,3-dihydro-1Hbenzimidazol-
5-yl]-6-methylpyridin-2(1H) -one;
5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -3-(methylsulfonyl)-2,3-dihydro-1Hbenzimidazole-
1-carboxamide;
1-[1,3-bis(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-
yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2(lH)-one;
1-[3-acetyl-i-(methylsulfonyl)-2,3-dihydro-1Hbenzimidazol-
5-yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H) -one;
1-(l-acetyl-iH-pyrrol-3-yl)-3-chloro-4-[(2,4-
"difluorober.zyDoxy] -6-methylpyridin-2 (1H) -one;
3-chloro-4- [(2,4-difluorobenzyl)oxy] -1- (1-glycoloyl-lHpyrrol-
3-yl) -6-methylpyridin-2 (1H) -one;
3-chlcro-4- [(2,4-difluorobenzyDoxy] -1- [1- (2-hydroxy-2-
methylpropanoyl)-lH-pyrrol-3-yl]-6-methylpyridin-2(1H)-one;
3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-nethyl-l-[1-(Nmethylglycyl)-
1H-pyrrol-3-yl]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-
hydroxypropanoyl)-lH-pyrrol-3-yl]-6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-1H-pyrrol-3-yl]-6-^ethylpyriain-2(1H)-one;
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-1H-pyrrole-1-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[1-
(methylsulfonyl)-lH-pyrrol-3-yl]pyridin-2(1H) -one;
1- (l-acetyl-lH-imidazol-4-yl)-3-chloro-4-[(2,4-
dif luorobenzyl) oxy] -6-raethylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1-glycoloyl-lHimidazol-
4-yl)-6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-
methylpropanoyl)-lH-imidazol-4-yl]-6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[1-(Ntnethylglycyl)
-lH-imidazol-4-yl]pyridin-2 (1H) -one;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-1-[1-(3-
hydroxypropanoyl)-lH-imidazol-4-yl]-6-methylpyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-lH-imidazol-4-yl]-6-methylpyridin-2(1H)-one;
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l(2H)-yl] -IH-imidazole-l-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[1-
(methylsulfonyl)-lH-imidazol-4-yl]pyridin-2(1H)-one;
1- (l-acetyl-lH-pyrazol-4-yl)-3-chloro-4-t(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
3-chloro-4- [(2,4-difluoroben2yl)oxy]-1-(1-glycoloyl-lHpyrazol-
4-yl)-6-methylpyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-[1-(2-hydroxy-2-
methylpropanoyl)-lH-pyrazol-4-yl] -6-methylpyridin-2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-[1-(Wmethylglycyl)-
lH-pyrazol-4-yl]pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1- [1-(3-
hydroxypropanoyl)-lH-pyrazol-4-yl]-6-methylpyridin-2(1H) -one;
3-chloro-4-[ (2,4-difluorobenzyl)oxy]-1-[1-(3-hydroxy-3-
methylbutanoyl)-lH-pyrazol-4-yl] -6-methylpyridin-2(1H)-one;
4-[3-chloro-4-[(2,4-difluorobensyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]-IH-pyrazole-l-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-raethyl-l-[1-
(methylsulfonyl)-lH-pyrazol-4-yl]pyridin-2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-isoquinolin-7-yl-
6-methylpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(isoquinolin-6-
ylmethyl)pyridin-2(1H) -one;
5-{[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridinl(
2H)-yl]methyl}-l,3-dihydro-2H-indol-2-one;
3-chloro-4-[ (2,4-difluorobenzyl)oxy]-1-(2,3-dihydro-lHindol-
5-ylmethyl)pyridin-2(1H) -one;
1-t(l-acetyl-2,3-dihydro-lH-indol-5-yl)methyl]-3-chloro-
4-[(2,4-difluorobenzyl)oxy] pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1- [ (l-glycoloyl-2,3-
dihydro-IH-indol-5-yl)methyl]pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(2-hydroxy-2-
methylpropanoyl)-2,3-dihydro-lH-indol-5-yl]methyl}pyridin-
2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-{[1-(Nmethylglycyl)-
2,3-dihydro-lH-indol-5-yl]methyl}pyridin-2(1H) -
one;
3-chloro-4-[(2,4-difIuorobenzyl)oxy]-l-{[1-(3-
hydroxypropanoyl) -2,3-dihydro-lH-indoI-5-yl]methyl}pyridin-
2 (1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(3-hydroxy-3-
methylbutanoyl)-2,3-dihydro-lH-indol-5-yl]methyl}pyridin-
2(lH)-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}indoline-1-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-
(methylsulfonyl)-2,3-dihydro-lH-indol-5-yl]methyl}pyridin-
2 (1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,3-dihydro-lHisoindol-
5-ylmethyl)pyridin-2(1H)-one;
1- [ (2-acetyl-2,3-dihydro-lH-isoindol-5-yl)methyl]-3-
chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy] -1-t(2-glycoloyl-2,3-
dihydro-lH-isoindol-5-yl)methyl]pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyDoxy] -l-{ [2- (2-hydroxy-2-
methylpropanoyl)-2,3-dihydro-lH-isoindol-5-yl]methyl}pyridin-
2 (1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [2- (Nmethylglycyl)-
2,3-dihydro-lH-isoindol-5-yl]methyl}pyridin-
2(lH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(3-
hydroxypropanoyl) -2,3-dihydro-lH-isoindol-5-yl]methyljpyridin-
2(lH)-one;
3-chloro-4- [ (2,4-difluorobenzyDoxy] -l-{ [2- (3-hydroxy-3-
methylbutanoyl)-2,3-dihydro-lH-isoindol-5-yl]methyl}pyridin-
2 (1H) -one;
5-{ [3-chloro-4- [ (2,4-difluorobenzyDoxy] -2-oxopyridin-
1 (2H) -yl]methyl}-!, 3-dihydro-2H-isoindole-2-carboxamide;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-I-{[2-
(methylsulfonyl)-2,3-dihydro-lH-isoindol-5-yl]methyl}pyridin-
2 (IH)-one;
3-chloro-4- [(2,4-difluorobenzyl)oxy]-1-(1,2,3,4-
tetrahydroisoquinolin-6-ylmethyl)pyridin-2(1H)-one;
1-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)methyl]-
3-chloro-4- [ (2;4-difluorobenzyl)oxy]pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-[(2-glycoloyl-
1,2,3,4-tetrahydroisoquinolin-6-yl)methyl]pyridin-2(1H)-one;
3-chloro-4- [(2,4-difluorobenzyl)oxy]-l-{[2-(2-hydroxy-2-
methylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-l-{[2-(Nmethylglycyl)-
1,2,3,4-tetrahydroisoquinolin-6-
yl] methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(3-
hydroxypropanoyl)-1,2,3,4-tetrahydroisoquinolin-6-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[2-(3-hydroxy-3-
methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-6-
yl]methyl}pyridin-2(1H)-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3,4-dihydroisoquinoline-2 (1H) -carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [2-
(methylsulfonyl)-l,2,3,4-tetrahydroisoguinolin-6-
yl]methyl)pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1,2,3,4-
tetrahydroisoquinolin-5-ylmethyl)pyridin-2 (1H) -one;
1-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl)methyl]-
3-chloro-4- [ (2,4-difluorobenzyl)oxy]pyridin-2(1H) -one;
3-chloro-4- [(2,4-difluorobenzyl)oxy]-1-[(2-glycoloyl-
1,2,3,4-tetrahydroisoquinolin-5-yl)methyl]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(2-hydroxy-2-
tr.ethylpropanoyl) -1,2,3,4-tetrahydroisoquinolin-5-
yl]methyljpyridin-2 (1H) -one;
3-chloro-4- [(2,4-difluorobenzyl)oxy] -l-{ [2- (Nmethylglycyl)-
1,2,3,4-tetrahydroisoquinolin-5-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-{ [2- (3-
hydroxypropanoyl)-1,2,3,4 -1etrahydroi soquinolin-5 -
yl]methyl}pyridin-2(1H)-one;
3-chloro-4- [-(2,4-difluorobenzyl) oxy] -l-{ [2- (3-hydroxy-3-
methylbutanoyl)-1,2,3,4-tetrahydroisoquinolin-5-
yl]methyl}pyridin-2(1H) -one;
5-{[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H)-yl]methyl}-3,4-dihydroisoquinoline-2(1H)-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-
(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-
yl]methyl}pyridin-2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-(2,3-dihydro-lHbenzimidazol-
5-ylmethyl)pyridin-2(1H)-one;
1-[(l-acetyl-2,3-dihydro-lH-benzimidazol-5-yl)methyl]-3-
chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H) -one;
3-chloro-4-[ (2,4-difluorobenzyl)oxy]-1-[(l-glycoloyl-2,3-
dihydro-lH-benzimidazol-5-yl)methyl]pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(2-hydroxy-2-
methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(Ntnethylglycyl)-
2,3-dihydro-IH-benzimidazol-5-yl]methyl}pyridin-
2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-
hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl)pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(3-hydroxy-3-
methylbutanoyl)-2,3-dihydro-lH-benzimida2ol-5-
yl]methyl}pyridin-2(1H)-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin-
1 (2H) -yl]methyl} -2 , 3-dihydro-lH-ben.zimidazole-l-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-
(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H)-one;
1- [ (3-acetyl-2,3-dihydro-IH-benzimidazol-5-yl)methyl]-3-
chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one;
3-chloro-l-[(1,3-diacetyl-2,3-dihydro-lH-benzimidazol-5-
yl)methyl] -4-[(2,4-difluorobenzyl)oxy]pyridin-2 (1H) -one;
1 - [ (3 -acetyl-1-glycoloyl-2,3-dihydro-IH-benzimidazol-5 -
yl)methyl] -3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H) -
one;
l-{[3-acetyl-l-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one;
l-{[3-acetyl-l-(N-methylglycyl)-2,3-dihydro-IHbenzimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one;
l-{ [3-acetyl-l-(3-hydroxypropanoyl)-2,3-dihydro-1Hbenzimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one;
l-{[3-acetyl-l-(3-hydroxy-3-methylbutanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one;
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl]methyl}-2,3-dihydro-lH-benzimidazole-lcarboxamide;
l-{[3-acetyl-l-(methylsulfonyl)-2,3-dihydro-1Hbenzimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(3-glycoloyl-2,3-
dihydro-lH-benzimidazol-5-yl) methyl] pyridir.-2 (1H) -one;
1-[(i-acetyl-3-glycoloyl-2,3-dihydro-lH-benzimidazol-5-
yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyricin-2(IK) -
one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[(I,3-diglycoloyl-
2,3-dihydro-lH-benzimidazol-5-yl)methyl]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-glycoloyl-l-
(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4- [(2,4-difluorobenzyl)oxy]-l-{[3-glycoloyl-l-
(N-methylglycyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobennyl)oxy]-l-{[3-glycoloyl-l-
(3-hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyljpyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[3-glycoloyl-l-
(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-IH-benzimidazol- 5 -
yl]methyl}pyridin-2(1H)-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-glycoloyl-2,3-dihydro-lH-benzimidazole-lcarboxamide;
3-chloro-4- t (2,4-dif luorobenzyl) oxy] -l-{'[3-glycoloyl-l-
(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4- [(2,4-difluorobenzyl)oxy]-l-{[3-(2-hydroxy-2-
methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyljpyridin-2(1H)-one;
l-{tl-acetyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]methyl}-3-chloro-4- [ (2,4-
difluorobenzyl) oxy]pyridin-2(1H)-one;
-chloro-4-[(2,4-difluorobensyl)oxy]-l-{ [l-glycoioyl-3-
(2 -hydroxy-2 -methylpropanoyl) - 2,3 -dihyd.ro-IH-benzimidazcl- 5 -
yl] methyl}pyridin-2 (1H) -one;
l-{[1,3-bis(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1Kbenzimidazol-
5-yl]methyl)-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(2-hydroxy-2-
methylpropanoyl) -1- (W-methylglycyl) -2,3-dihydro-IHbenzimidazol
-5 -yl] methyl }pyridin-2 (1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [3-(2-hydroxy-2-
methylpropanoyl)-I-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(3-hydroxy-3-
methylbutanoyl)-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]methyl}pyridin-2(1H) -one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-
IH-benzimidazole-l-carboxamide;
3-chloro-4- [ (2, 4-dif luorobenzyl) oxy] -'!-{ [3- (2-hydroxy-2-
methylpropanoyl)-1-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(Nmethylglycyl)-
2,3-dihydro-IH-benzimidazol-5-yl]methyl}pyridin-
2(1H) -one;
l-{[l-acetyl-3-(N-methylglycyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-
dif luorobenzyl) oxy]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-
(W-methylglycyl)-2,3-dihydro-IH-benzimidazol-5-
yl] methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [1- (2-hydroxy-
methylpropanoyl) -3- (W-methylglycyl) -2, 3-dihydro-1H-
oenzimidazol-5-yl]methyl}pyridin-2 (IH) -one;
l-{ [l,3-bis(N-methylglycyl) -2,3-dihydro-lH-benzimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-
2 (IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[1-(3-
hydroxypropanoyl)-3-(W-methylglycyi)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(IH) -one;
3-chloro-4-t(2, 4-difluorobenzyl)oxy]-l-{[1-(3-hydroxy-3-
methylbutanoyl)-3-(W-methylglycyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(IH) -one;
5-{[3-chloro-4-[(2 , 4-difluorobenzyl)oxy] -2-oxopyridin-
1(2H) -yl]methyl)-3-(W-methylglycyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(Nmethylglycyl)-
1-(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-
5-yl]methyl}pyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [3- (3-
hydroxypropanoy1)-2, 3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(IH) -one;
l-{[l-acetyl-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}-3-chloro-4- [ (2,4-
difluorobenzyl)oxy]pyridin-2(IH) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-
(3-hydroxypropanoyl) -2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(IH)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(2-hydroxy-2-
methylpropanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(IH) -one;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-l-{[3-(3-
hydroxypropanoyl)-1-(W-methylglycyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(IH) -one;
l-{ [1,3-bis(3-hydroxypropanoyl)-2,3-dihydro-lH-
benzimidazol-5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
3-chloro-4- [(2,4-difluoroben=yl)oxy]-l-{[1-(3-hydroxy-3-
methylbutanoyl)-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
5-{ [3-chloro-4- [ (2,4-difluorobenzyl)oxy] -2-oxopyridin-
1 (2H)-yl]methyl}-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-{ [3- (3-
hydroxypropanoyl)-1-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
3-chloro-4- [(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-
methylbutanoyl)-2,3-dihydro-IH-benzimidazol-5 -
yl]methyl}pyridin-2(1H) -one;
l-{[l-acetyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydrolH-
benzirhidazol-5-yl] methyl}-3-chloro-4- [ (2,4-
difluorobensyl)oxy]pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-
(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-
methylbutanoyl)-1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydrolH-
benzimidazol-5-yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-
methylbutanoyl)-1-(W-methylglycyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-
methylbutanoyl)-1-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H) -one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-
IH-benzimidazole-1-carboxamide;
l-{ [1,3-bis(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lHbensimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2 (1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-
methylbutancyl)-I-(3-hydroxypropanoyl)-2,3-dihyaro-lHbenzitnidazcl-
5-yl] methyl}pyridin-2(1H)-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-2,3-dihydro-lH-benzimidazole-l-carboxamide;
3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1 (2H) -yl] methyl}-2, 3-dihydro-lH-benzimiciazole-lcarboxamide;
6-{ [3-chloro-4-t (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-glycoloyl-2,3-dihydro-lH-benzimidazole-lcarboxamide;
6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-
IH-benzimidazole-l-carboxamide/
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-(W-methylglycyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3-(3-hydroxypropanoyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1{2H) -yl]methyl)-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-
IH-benzimidazole-l-carboxamide;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-lH-benzimidazole-1,3(2H)-dicarboxamide;
6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
3-chloro-4-[(2, 4-difluorobenzyl)oxy]-l-{[3-
(methylsulfonyl)-2,3-dihydro-lH-ben2imidazol-5-
yl]methyl}pyridin-2(1H)-one;
l-{ [l-acetyl-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}-3-chloro-4- [ (2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyDoxy] -l-{ [l-glycoloyl-3-
(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-
yl]methyl}pyridin-2(1H)-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-{[1-(2-hydroxy-2-
methylpropanoyl)-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl] methyl}pyridin-2(1H)-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[1-(Nmethylglycyl)-
3-(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
3-chloro-4-[ (2,4-difluorobenzyl)oxy]-l-{[1-(3-
hydroxypropanoyl)-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H) -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-{[1-(3-hydroxy-
methylbutanoyl)-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazol-
5-yl]methyl}pyridin-2(1H)-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-(methylsulfonyl)-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
l-{[1,3-bis (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-
5-yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-
2(lH)-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin-
1(2H) -yl]methyl}-l,3-dihydro-2H-benzimidazol-2-one;
l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H) -yl]methyl}-1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridinl(
2H) -yl]methyl}-l-glycoloyl-l,3-dihydro-2H-benzimidazol-2-
one ;
5-{ [3-chloro-4- [ (2,4-difluorobensyl)oxy]-2-oxopyridin-
1 {2H) -yl] methyl}-1-(2 -hydroxy-2-methylpropanoyl}-1,3-dihydrc-
2H-benzimidazol-2-one;
5-{ [3-chloro-4- [ (2,4-difluorobenzyl}oxy] -2-oxopyridin-
1(2H) -yl]methyl}-!- UV-methylglycyl) -l,3-dihydro-2Hbensimidazol-
2 -one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-1-(3-hydroxypropanoyl)-1,3-dihydro-2Hbenzimidazol-
2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-1-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-
2H-benzimidazol- 2-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-2-oxo-2,3-dihydro-lH-benzimidazole-lcarboxamide;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-l-(methylsulfonyl)-1, 3-dihydro-2Hbenzimidazol-
2-one;
l-acetyl-6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl]methyl}-!,3-dihydro-2H-benziraidazol-2-one;
l,3-diacetyl-5-{ [3-chloro-4-[(2,4-difluorobenzyl}oxy]-2-
oxopyridin-l{2H) -yl]methyl}-!,3-dihydro-2H-benzimidazol-2-one;
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1 (2H) -yl]methyl}-l-glycoloyl-1,3-dihydro-2Hbenzimidazol-
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1 (2H) -yl]methyl}-1- (2-hydroxy-2-methylpropanoyl) -
l,3-dihydro-2H-benzimidazol-2-one;
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1 (2H) -yl]methyl}-1- (W-methylglycyl) -l,3-dihydro-2Hbenzimidazol-
2-one;
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1 (2H) -yl]methyl}-1-(3-hydroxypropanoyl)-1,3-
dihydro-2H-benzimidazol-2-one;
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl] methyl}-!-(3-hydroxy-3-methylbutanoyl)-
1,3-dihydro-2H-benzimidazol-2-one;
3-acetyl-5-{ [3-chloro-4- [-(2 ,4-dif luorobenzyl) oxy] -2-
oxopyridin-l (2H) -yl]methyl}-2-oxo-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H) -yl] methyl}-!-(methylsulfonyl)-1,3-dihydro-2Hbenzimidazol-
2-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-1-glycoloyl-l,3-dihydro-2H-benzimidazol-2-
one;
l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl ] methyl}-3-glycoloyl-1,3-dihydro-2Hbenzimidazol-
2-one ;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-!,3-diglycoloyl-l,3-dihydro-2H-benzimidazol-
2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-glycoloyl-1-(2-hydroxy-2-methylpropanoyl)-
1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-glycoloyl-l- (J^-methylglycyl) -1,3-dihydro-
2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-glycoloyl-l-(3-hydroxypropanoyl)-1,3-
dihydro-2H-benzimidazol-2-one
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-glycoloyl-l-(3-hydroxy-3-methylbutanoyl)-
1,3-dihyd.ro-2H-bensimiciazol-2-one;
5-{[3-chloro-4-[(2,4-difluoroben=yi)cxy]-2-oxopyridinl(
2H)-yl]methyl}-3-giycoloyl-2-oxc-2,3-dihydro-lHbenzimidazole-
1-carbcxamide ;
5-{[3-chloro-4-[(2,4-difIuoroben=yl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-gIycoloyl-l-(methylsulfonyl)-1,3-dihydro-
2H-benzimidazoi-2-one;
6-{ [3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-!-(2-hydroxy-2-methylpropanoyl)-1,3-dihydro-
2H-benzimida2ol-2-one;
l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-
1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-l-glycoloyl-3-(2-hydroxy-2-methylpropanoyl)-
I, 3-dihydro-2H-benzimidazol-2-orie;
5-{[3-chloro-4-[(2,4-difluorobensyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-1,3-bis(2-hydroxy-2-methylpropanoyl)-1,3-
dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-I-(Nmethylglycyl)-
1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-1-(3-
hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;
5-{ [3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-!-(3-hydroxy-3-methylbutanoyl)-3-(2-hydroxy-
2-methylpropanoyl)-l,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-3-(2-hydroxy-2-methylpropanoyl)-2-oxo-2,3-
dihydro-lH-benzimidazole-1-carboxamide;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
K2H) -yl]methyl}-3- (2-hydroxy-2-methylpropanoyl) -1-
(methylsulfonyl)-1,3-dihydro-2H-ben=imidazol-2-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-!-(N-methylglycyl)-1,3-dihydro-2Hbensimidazol-
2-one;
l-acetyl-5- { [3-chloro-4- t (2 , 4-dif luorober.zyl) oxy] -2-
oxopyridin-l(2H) -yl] methyl}-3- (N-methylglycyl) -1,3-dihydro-2Kbenzimidazol-
2-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-l-glycoloyl-3-(N-methylglycyl)-1,3-dihydro-
2H-benzimidazol-2-one;
5-{[3-chloro-4-t(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-!-(2-hydroxy-2-methylpropanoyl)-3-(Nmethylglycyl)-
1,3 -dihydro-2H-benzimidazol-2-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-1,3-bis(N-methylglycyl)-1,3-dihydro-2Hbenzimidazol-
2-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-!-(3-hydroxypropanoyl) -3-(N-methylglycyl)-
1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-!-(3-hydroxy-3-methylbutanoyl)-3- (Nmethylglycyl)-
1,3-dihydro-2H-benzimidazol-2-one;
5-{ [3-chloro-4-t(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-(N-methylglycyl) -2-oxo-2,3-dihydro-!Hbenzimidazole-
1-carboxamide;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-(N-methylglycyl)-1-(methylsulfonyl)-1,3-
dihydro-2H-benzimidazol-2-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-!-(3-hydroxypropanoyl) -1,3-dihydro-2Hbenzimidazol-
2-one;
l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridir.-l (2H) -yljmethyl)-3- (3-hydroxypropanoyl) -1,3-
dihydro-2J:f-ber.:imidazol-2-one;
5-{ [3-chloro-4- [ {2,4-difluorobensyl)oxy] -2-oxopyridin-
1 (2H) -yl] methyl}-1-glycoloyl-3- (3-hydroxypropar.oyl)~l, 3-
dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-!-(2-hydroxy-2-methylpropanoyl)-3- (3-
hydroxypropanoyl)-1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3- (3-hydroxypropanoyl} -1- (JV-methylglycyl) -
1, 3-dihyciro-2fl-benzimidazol-2-one;
5-{[3-chloro-4-[(2, 4-difluorobenzyljoxy] -2-oxopyridin-
1(2H) -yl]methyl}-1,3-bis(3-hydroxypropanoyl)-1,3-dihydro-2Hbenzimidazol-
2-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-!-(3-hydroxy-3-methylbutanoyl)-3- (3-
hydroxypropanoyl)-1,3~dihydro-2H-bensimidazol~2-one;
5-{[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3-(3-hydroxypropanoyl)-2-oxo-2,3-dihydro-1Hbenzimidazole-
1-carboxamide;
5-{[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl)-3-(3-hydroxypropanoyl)-1-(methylsulfonyl)-
1,3-dihydro-2H-benzimidazol-2-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin-
1 (2H) -yl] methyl}-l-(3-hydroxy-3-methylbutanoyl)-1,3-dihydro-
2H-benzimidazol-2-one;
l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H) -yl]methyl)-3-(3-hydroxy-3-methylbutanoyl)-
l,3-dihydro-2H-benzimidazol-2-one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy3-2-oxopyridin-
1(2H)-yl]methyl}-l-glycoloyl-3-(3-hydroxy-3-methylbutanoyl)-
1,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxyj-2-oxopyridin-
1(2H) -yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1-(2-hydrcxy-
2-methylpropanoyl)-I, 3-dihydro-2H-benzimidazol-2-one;
5-{ [3-chloro-4- [ (2,4-difluorobenzyl)oxy] -2-oxopyridin-
1(2H) -yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-1- (Wmethylglycyl)-
I,3-dihydro-2H-ben2imidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3-{3-hydroxy-3-methylbutanoyl)-1-(3-
hydroxypropanoyl)-1, 3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-1,3-bis(3-hydroxy-3-methylbutanoyl)-1,3-
dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-2-oxo-2,3-
dihydro-llf-benzimidazole-1-carboxamide;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-(3-hydroxy-3-methylbutanoyl}-1-
{methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H> -yl]methyl}-2-oxo-2,3-dihydro-lH-benzimidazole-1-
carboxamide;
3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1 (2J-T) -yl]methyl}-2-oxo-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
6-{[3-chloro-4-[{2,4-difluorobenzyl)oxy]-2-oxopyridinl(
2H)-yl]methyl}-3-glycoloyl-2-oxo-2,3-dihydro-lHbenzimidazole-
1-carboxamide;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-3-(2-hydroxy-2-methylpropanoyl>-2-oxo-2,3-
dihydro-IH-benzimidazole-1-carboxamide;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2K) -yl]methyl)-3- (.N-methylglycyl) -2-oxo-2,3-dihydro-lHbenzinudazole-
1-carboxamide;
6-{[3-chIoro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl)-3-(3-hydroxypropanoyl)-2-oxo-2,3-dihyaro-lHbenzimidazole-
1-carboxamide;
6- { [3-chloro-4- [ (2, 4-difluorobenzyl) oxy] -2-oxopyridin-
1(2H) -yl]methyl)-3-(3-hydroxy-3-methyibutanoyi)-2-oxo-2,3-
dihydro-lH-ber.zimidazole-1-carboxamide;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-2-oxo-!H-benzimidazole-l,3(2H)-dicarboxamide;
6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl)-3-(methylsulfonyl)-2-oxo-2,3-dihyaro-lHbenz
imidazole-1-carboxamide;
6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl)-!-(methylsulfonyl)-1,3-dihydro-2Hbenzimidazol-
2-one;
l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl] methyl)-3-(methylsulfonyl)-1,3-dihydro-2Hbenzimidazol-
2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin-
1 (2H) -yl]methyl)-l-glycoloyl-3-(methylsulfonyl)-1,3-dihydro-
2H-bensimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-!-(2-hydroxy-2-methylpropanoyl)-3-
(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}-!-(N-methylglycyl)-3-(methylsulfonyl)-1,3-
dihydro-2H-benzimidazol-2 -one;
5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1 (2H) -yl]methyl}-!-(3-hydroxypropanoyl)-3-(methylsulfonyl)-
l,3-dihydro-2H-benzimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl] methyl}-1-(3-hydroxy-3-methylbutanoyl)-3-
(methylsulfonyl)-l,3-dihydro-2H-bensimidazol-2-one;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl)-3-(methylsulfonyl)-2-oxo-2,3-dihydro-lKber.
zimidazole-1 - carboxamide ;
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}-1,3-bis(methylsulfonyl)-l,3-dihydro-2Hbenzimidazol-
2-one;
3-benzyl-4-hydroxy-l-(2-phenylethyl)pyridin-2(1H) -one;
l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridine-3-
carbaldehyde;
l-benzyl-4-chloro-2-oxo-l,2-dihydropyridine-3-
carbaldehyde;
methyl 5-chloro-l-(4-chlorobenzyl)-6-oxo-l,6-
dihydropyridine-3-carboxylate;
5-bromo-l-(2-chloro-6-fluorobenzyl)-3-methylpyridin-
2 (1H) -one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(4-
fluorophenyl)ethynyl]-6-methylpyridin-2(1H) -one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(4-
fluorophenyl)ethynyl]-6-methylpyridin-2(1H)-one;
methyl 3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2-oxopyridin-l(2H) -yl]benzoate;
4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)-2-oxo-l,2-
dihydropyridine-3-carbonitrile;
4- [ (2,4-dif luorobenzyl) oxy] -6- (hydroxymethyl) -I- (2., 4, 6-
trifluorophenyl)pyridin-2(1H)-one;
4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-
(trifluoromethyl)phenyl]pyridin-2(1H) -one;
3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H) -yl] benzaldehyde ;
4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-morpholin-
4-ylphenyl)-6-methylpyridin-2(1H)-one;
4- [ (2,4-difiuorobenzyl)oxy]-1-[2,6-difluoro-4-(4-
methylpiperazin-l-yDphenyl]-6-methylpyridin-2(1H) -one;
3- [3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6-methyl-2-
oxo?yridin-l(2H)-yl]benzole acid;
4- [ (2,4-difIuorobenzyl)oxy]-1-[4-(dimethylamino)-2,6-
difluorophenyl]-6-methylpyridin-2(1H)-one;
4- [ (2,4-difIuorobenzyl)oxy]-l-{2,6-difluoro-4-[(2-
hydroxyethyl) (methyl) amino]phenyl}-6-methylpyridin-2 (1H) -one;
methyl 3-[3-bromo-4- [ (2,4-difIuorobenzyl)oxy]-6-methyl-2'
oxopyridin-1(2H)-yl]ber.zoate;
3- [4- [ (2 , 4-dif Iuorobenzyl ).oxy] -6-methyl-2-oxopyridin-
1 (2H)-yl]-4-methylbenzoic acid;
4- [ (2,4-difIuorobenzyl)oxy]-1-(2, 6-difluorophenyl)-6-
(hydroxymethyl)pyridin-2(1H) -one;
3-bromo-I-{[5-(chloromethyl)pyrazin-2-yl]methyl)-4- [(2,4-
difIuorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
1-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-
difIuorobenzyl)oxy]-6-methylpyridin-2(1H)-one;
4-[(2,4-difIuorobenzyl)oxy]-1-(2,6-difluoro-4-
hydroxyphenyl)-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difIuorobenzyl)oxy] -1-[4-(hydroxymethyl)-
2-methoxyphenyl]-6-methylpyridin-2(1H)-one;
methyl 3-[3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-methylbenzoate;
3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6-methyl-l-{3-[(4-
methylpiperazin-1-yl)carbonyl]phenyl}pyridin-2(1H) -one;
3- [3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -N-[2-(dimethylamino)ethyl]benzamide;
3- [3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) benzamide,-
3- [3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -N- [2- (dimethylamino) ethyl] -N~
methylbenzamide;
3-[3-bromo-4-[(2, 4-difluorobenzyl)oxy]-o-methyl-2-
oxopyridin-l (2H) -yl] -N- (2-hydroxyethyl) -tf-methylbenzamide;
3- [3-bromo-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) -W-methylbenzamide;
4-[3-brorao-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzamide;
methyl 3-[3-chloro-4-[(2,4-difluorobenzyl}oxy]-6-methyl-
2-oxopyridin-1(2H) -yl] -4-fluorobenzoate;
4. [4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-3-methylbenzoic acid;
1-{4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
1-[(1-acetyl-lH-indol-5-yl)methyl]-3-chloro-4- [(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-
methylpyrazin-2-yl)methyl]pyridin-2(1H) -one;
methyl 2-({ [3-bromo-l-{2,6-difluorophenyl)-6-methyl-2-
oxo-1,2-dihydropyridin-4-yl]oxyjmethyl)-3,5-
difluorobenzylcarbamate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2 (1H) -one;
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] methyl}-N, W-dimethylbenzamide;
3-[3-bromo-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l (2H) -yl] -N- (2-hydroxyethyl) -4-methylbenzamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-l-{4- [{4-
methylpiperazin-1-yl)carbonyl]benzyl}pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(1H-indol-5-
ylmethyl)pyridin-2 (1H) -one;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -N-methylbensamide;
3- [3-bromo-4- [ (2, 4-dif luorober.zyl) oxy] -6-methyl-2-
oxopyridin-I(2H)-yl]benzamide;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-l-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2 (1H) -one;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyi-2-
oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) -4-methylben^amide;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]-N, 4-dimethylbenzamide;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]-N, N, 4-trimethylbenzamide;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l- [2-raethyl-
5- (morpholin-4-ylcarbonyl)phenyl]pyridin-2(1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(1-hydroxy-lmethylethyl)-
2-methylphenyl]-6-methylpyridin-2(1H) -one;
1-(2-bromobenzyl)-3- [ (2-bromobenzyl)oxy]pyridin-2(1H)-
one;
1-(2-bromobenzyl)-3- [ (2-bromobenzyl)oxy]pyridin-2(1H)-
one ;
3-bromo-l-(4-methoxybenzyl)-4-phenoxypyridin-2(1H)-one;
1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3 -
carbaldehyde;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-
dimethylaminomethyl-benzyl)-6-methyl-IH-pyridin-2-one;
N-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-
2H-pyridin-l-ylmethyl]-benzyl}-2-hydroxy-acetamide;
3-Bromo-4- (2,4-difluoro-benzyloxy)-6-methyl-l- [4-
(piperidine-1-carbonyl)-benzyl]-lH-pyridin-2-one;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-[(ethoxyamino)methyl]pyridin-2 (1H) -one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-isopropyl-benzamide;
N-(3-aminopropyl)-4-{[3-brorao-4-[(2,4-
difluorobenzyl)oxy] -6-methyl-2-oxopyridin-l (2H) -
yl]methyl}benzamide hydrochloride;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -N,4-dimethylbenzarrd.de;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl] -N,N-bis-(2-hydroxy-ethyl)-benzamide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[4-
(pyrrolidine-1-carbonyl)-benzyl]-lH-pyridin-2-one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-hydroxy-benzamide;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-methyl-benzamide;
4- [3-Bromo-4- (2 , 4-dif luoro-benzyloxy) -6-methyl-2-oxo-2Hpyridin-
1-ylmethyl] -N-(2-dimethylamino-ethyl)-benzamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(lH-indazol-5-
ylmethyl)pyridin-2(IH)-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l- [4-(4-
methyl-piperazine-1-carbonyl)-benzyl]-lH-pyridin-2-one;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl] -4-methylbenzaldehyde;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-
dimethylaminomethyl-benzyl)-6-methyl-IH-pyridin-2-one;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -N-(2-methoxyethyl)-4-methylbenzamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-(dimethylamino)-
4,6-difluorophenyl]-6-methylpyridin-2(IH) -one hydrochloride;
N- (2-aminoethyl)-4-{[3-bromo-4-t(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzamide hydrochloride;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl] -N-(2-hydroxy-ethyl)-benzamide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-hydroxymethyl-
benzyl)-6-methyl-IH-pyridin-2 -one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy] -1- [2,6-difluoro-4-
(4-methylpi?erazin-l-yl)?henyl]-6-methylpyridin-2(IK)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-(dimethylamino)-
4,6-difluorophenyl]-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-
methylpiperazin-l-yl)phenyl]-6-methylpyridin-2(1H) -one;
4- [3-3romo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-(2-methoxy-ethyl)-benzamide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-l-{4-[(2-hydroxyethylamino)-
methyl]-benzyl}-6-methyl-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2(IH)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-methyl-
5- (morpholin-4-ylcarbonyl)phenyl]pyridin-2(IH) -one;
3-3romo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(4-
methylaminomethyl-benzyl)-lH-pyridin-2-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[4-
(morpholine-4-carbonyl)-benzyl]-lH-pyridin-2-one;
'N- (2-aminoethyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]benzamide;
N- (3-aminopropyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]benzamide hydrochloride;
4- [3-Bromo-4- (2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-(2-methoxy-ethyl)-N-methyl-benzamide;
1-(4-Aminomethyl-benzyl)-3-bromo-4-(2,4-difluorobenzyl
oxy) -6-methyl-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-
(piperazin-1-ylcarbonyl)benzyl]pyridin-2(IH) -one
hydrochloride;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1- [4- (isopropylaminomethyl)-
benzyl]-6-methyl-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
dimethylphenyl)-6-methylpyridin-2(1H)-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-[(2-hydroxyethylamino)
-methyl] -benzyl}-6-raethyl-lH-pyridin-2-or.e;
1- (3-Aminomethyl-benzyl)-3-bromo-4-(2,4-difluorobenzyloxy)-
6-methyl-IH-pyridin-2-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-hydroxy-benzyl)-
6-methyl-lH-pyridin-2-one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2 (1H) -one;
N-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-
2H-pyridin-l-ylmethyl]-benzyl]-acetamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluoro-4-
[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(1H)-
one;
ethyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzoate;
1- [3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H) -one trifluoroacetate;
1-(3-{[Bis-(2-hydroxy-ethyl)-amino]-methyl)-benzyl)-3-
bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-lH-pyridin-2-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[3-(isopropylaminomethyl)-
benzyl]-6-methyl-lH-pyridin-2-one;
{3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-benzyl}-carbamic acid tert-butyl ester;
3- [3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzamide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[4-(1-hydroxy-lmethyl-
ethyl)-benzyl]-6-methyl-lH-pyridin-2-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-
dimethylaminomethyl-benzyl)-lH-pyridin-2-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-i-(3-
piperidin-1-ylmethyl-benzyl)-lH-pyridin-2-one;
3-bromo-4-[ (2,4-difluorobenzyl)oxy]-I-(2,6-
difluorophenyl)-6-{[(2-methcxyethyl)amino]methylJpyridin-
2 (IH) -one;
3-[3-bromo-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopvridin-1(2H)-yl] -W-methylbenzamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,4-difluoro-6-
t(2-hydroxyethyl) (methyl)aminojphenyl}-6-methylpyridin-2 (1H) -
one ;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(3-
morpholin-4-ylmethyl-benzyl)-lH-pyridin-2-one;
3-bromo-l-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-
trifluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(2,6-dimethylphenyl)-6-methyl-4-[{2,4,6-
trifluorobenzyl)oxy]pyridin-2(1H) -one;
1- (4-{ [Bis-(2-hydroxy-ethyl)-amino]-methyl}-benzyl)-3-
bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-I-(2, 6-difluoro-4-
morpholin-4-ylphenyl)-6-methylpyridin-2(1H)-one;
4-Benzyloxy-3-bromo-l-(4-fluoro-benzyl)-lH-pyridin-2-one;
4-[3-Chloro-4-(2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-
1-ylmethyl]-benzamide;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -W,N,4-trimethylbenzamide;
3-(3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl] -W-isopropylbenzamide;
4- [3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin~
l-ylmethyl]-benzamide;
3-[3-Bromo-4-{2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-benzonitrile;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(3-
piperazin-1-ylmethyl-benzyl)-lH-pyridin-2-one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-(2-hydroxy-ethyl)-N-methyl-benzamide;
methyl 4- [3-bromo-4- [ (2,4-difluorobenzyl)oxy] -6-methyl-2-
oxopyridin-1(2H)-yl]-3-chlorobenzoate;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[3-
(morpholine-4-carbonyl)-benzyl]-lH-pyridin-2-one;
3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N,N-bis-(2-hydroxy-ethyl)-benzamide;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-benzoic acid methyl esters'
[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-hydroxy-benzamide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-hydroxymethylbenzyl)-
6-methyl-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1- (3-
fluorobenzyl)pyridin-2(1H)-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(3-fluoro-benzyl)-
lH-pyridin-2-one;
N-(3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-
2H-pyridin-l-ylmethyl]-benzyl)-methanesulfonamide;
3-Bromo-4- (2,4-difluoro-benzyloxy)-6-methyl-l- [3-
(pyrrolidine-1-carbonyl)-benzyl]-lH-pyridin-2-one;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
3-ylmethyl)pyridin-2(1H)-one;
N-(3-aminopropyl)-3-{[3-bromo-4-[(2,4-
difluorobenzyl) oxy]-6-methyl-2-oxopyridin-1(2H) -
yl]methyl}benzamide hydrochloride;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
3-ylmethyl)pyridin-2(1H)-one;
3-Bromo-4- (2,4-difluoro-benzyloxy) -1-(3-
methylaminomethy1-benzyl) -lH-pyridin-2-one;
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
"oxopyridin-1 (2H) -yl] -3, 5-dichlorobenzenesulfonamide;
3-bromo-4- [ (2, 4-difluorober.zyl) oxy] -1- [4- (dimethylamino) -
2,6-difluorophenyl]-6-methylpyridin-2(1H)-one;
3-Bromo-4-(2,4-difiuoro-benzyloxy)-6-methyl-l-(4-
piperidin-1-yimethyl-benzyl)-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(pyridin-4-
ylmethyl)pyridin-2(1H)-one;
N-(2-aminoethyl)-3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H) -yl]methyl}benzamide hydrochloride;
3-bromo-l-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-methylpyridin-2(1H)-one;
3-chloro-l-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-
difluorobenzyl) oxy] -6-methylpyridin-2(1H) -one;
3- [3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide;
2-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2Hpyridin-
1-yimethyl]-phenyl}-acetamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-
(piperazin-1-ylcarbonyl)benzyl]pyridin-2(1H) -one
hydrochloride
3-chloro-4-[(2,4-difluorobenzyl)oxy]-I-(2,6-
difluorophenyl)-6-methylpyridin-2(1H)-one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-lylmethyl]-
benzoic acid methyl ester;
1-(3-Aminomethyl-2-fluoro-benzyl)-3-bromo-4- (2,4-
difluoro-benzyloxy)-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl) -6-.(morpholin-4-ylmethyl)pyridin-2 (1H) -one;
4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(1H)
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(iH-indol-5-
ylmethyl)pyridin-2(1H) -one;
1- [3-(aminomethy1)benzyl]-3-bromo-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one trifluoroacetate;
1- [3-(2-aminoethyl)benzyl]-3-bromo-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one trifluoroacetate;
1- [3-(aminomethyl)benzyl]-3-bromo-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(2,6-dichlorophenyl)-4-t(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-N-(2-hydroxyethyl)benzamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
4-ylmethyl)pyridin-2(1H)-one;
3-3romo-4-(2,4-difluoro-benzyloxy)-1-(4-methoxy-benzyl)-
6-methyl-IH-pyridin-2-one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl] -N,N-dimethyl-benzamide,
3-bromo-6-methyl-l-(pyridin-4-ylmethyl)-4-[(2,4,6-
trifluorobenzyl)oxy]pyridin-2(1H) -one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-lylmethyl]-
benzamide;
3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-methyl-benzamide;
{3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl] -benzyl}-carbamic acid methyl ester,-
3-bromo-4-[(2,6-difluorobenzyl}oxy]-1-(2,6-
dimethylphenyl)-6-methylpyridin-2(1H) -one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-benzonitrile;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
4-ylmethyl)pyridin-2(1H) -one;
1-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridir.-2 (1H) -one;
1-Benzyl - 4-benzyloxy-3-bromo-6-methyl - IH-pyriciir.-2 - one ;
l-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridir.-2 (l) -one;
1-Benzyl-3-bromo-4-(2,4-difluoro-benzyloxy)- 6-methyl-1Hpyridin-
2-one;
{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-
1-ylnethyl]-phenyl}-acetonitrile;
3-[3-Bromo-4- (2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-(2-hydroxy-ethyl)-benzamide;
3-Chloro-4-(2,4-difluoro-benzyloxy)-1-(3-fluoro-benzyl)-
IH-pyridin-2-one;
l-Allyl-3-chloro-4-(2,4-difluoro-benzyloxy)-6-raethyl-lHpyridin-
2-one;
3-Chloro-4-(2,4-difluoro-benzyloxy)-1-[4-(isopropylaminomethyl)-
benzyl]-lH-pyridin-2-one;
methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2-oxopyridin-l(2H) -yl]-4-methylbenzoate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-
(2,4,6-trifluorophenyl)pyridin-2(1H)-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(4-
piperazin-1-ylmethyl-benzyl)-lH-pyridin-2-one;
3-bromo-4-t(2,4-difluorobenzyl)oxy]-I-(2,6-
difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H) -one;
3- [3-Bromo-4- (2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N,N-dimethyl-benzamide;
3-bromo-l-(3-fluorobenzyl)-4-[(3-
methylbenzyl)oxy]pyridin-2(1H)-one;
3-Bromo-l-(3-fluoro-benzyl)-4-(3-methyl-benzyloxy)-1Hpyridin-
2-one;
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-1-(1,2,3,4-
tetrahydroisoquinolin-5-ylmethyl)pyridin-2(1H) -one;
3-bromo-l-(3-fluorobenzyl)-4-[(3-
methylbenzyl)oxy]pyridin-2(1H) -one;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(isoquinolin-5-
ylmethyl)pyridin-2(1H)-one trifluoroacetate;
3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-benzamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5- [ (4-
methylpiperasin-l-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-
2(lH)-one trifluoroacetate;
3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[5-(hydroxymethyl)-
2-raethylphenyl] -6-methylpyridin-2(1H)-one;
l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(pyridin-3-
ylmethyl)pyridin-2(1H) -one;
3-bromo-4-[(2f4-difluorobenzyl)oxy]-1-(2-methoxy-6-
methylphenyl) -6-methylpyridin-2 (1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-
methylphenyl)-6-methylpyridin-2(1H) -one;
3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-lylmethyl]-
benzamide;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-
(2,4,6-trifluorophenyl)pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-
(trifluoromethyl)phenyl]pyridin-2(1H)-one;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-benzoic acid;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l- (4-
morpholin-4-ylmethyl-benzyl) -lH-pyridin-2-one;
4-(2,4-Difluoro-benzyloxy)-1-(3-fluoro-benzyl)-3-iodo-lHpyridin-
2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2 (1H) -one;
3-[3-bromo-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]-N-hydroxybensamide;
3-bromo-l-(2,6-dichlorophenyl)-4- [ ( 2 , 6 -
difluorobensyljoxy] -6-methylpyridin-2 (1H) -one;
3- (4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-yImethyl}-
benzonitriie;
3-bromo-4-t(2,4-difluorobenzyl)oxy]-6-methyl-l-[3 -
(pyrrolidin-1-ylcarbonyl}phenyl]pyridin-2(1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-I-(2-
fluoroben2yl)pyridin-2(1H)-one;
4- (berzyloxy) -3-bromo-l- (4-methylbenzyl)pyridin-2 (1H) -
one;
3-{[3-chloro-4-[(2, 4-difluorobensyl)amino]-6-methyl-2-
oxopyridin-1(2H) -yl]methyl}benzonitrile;
3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-N-isopropyl-benzamide;
3-bromo-l-(4-bromo-2, 6-difluorophenyl)-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2 (1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-3-
ylmethyl)pyridin-2(1H)-one;
3-bromo-4- [ (4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-4-
ylmethyl)pyridin-2(1H)-one;
3-bromo-4- [ (4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-4-
ylmethyl)pyridin-2(1H)-one;
4- (benzyloxy) -3-bromo-l- (4-chlorobenzyl)pyridin-2 (1H) -
one;
4-Benzyloxy-3-bromo-l-(4-chloro-benzyl)-lH-pyridin-2-one;
3-bromo-l-(4-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one;
3-Bromo-l-(4-fluoro-benzyl)-4-(4-fluoro-benzyloxy)-1H-
pyridin-2-one;
methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yljbenzoate;
4- (4-Ben::yloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl) -
benzoic acid;
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1(2H) -
yl]methyl}benzole acid;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2(IH)-one;
4-(benzyloxy)-3-bromo-1-(2-fluorobenzyl)pyridin-2(IH) -
one;
3-chloro-4-[(2,4-difluorobensyl)oxy]-1-(2,6-
difluorophenyl)-6-(hydroxymethyl)pyridin-2(IH)-one;
N- (2-aminoethyl)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-1(2H) -yl]benzamide hydrochloride;
4-Benzyloxy-3-bromo-l-(4-methylsulfanyl-benzyl)-1Hpyridin-
2-one;
l-Benzyl-4-benzyloxy-3-chloro-lH-pyridin-2-one;
4-(benzyloxy)-3-bromo-l-[4-(methylthio)benzyl]pyridin-
2(lH)-one;
l-benzyl-4-(benzyloxy)-3-chloropyridin-2(IH) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{ [5-
(hydroxymethyl)pyrazin-2-yl] methyl} -6-methylpyridin-2 (IH) -one;
3-bromo-l- (2,6-dimethylphenyl) -4- [ (4-fluorobenzyl)oxy] -6-
methylpyridin-2(IH)-one;
3-bromo-l- (2,6-dimethylphenyl) -4- [ (4-fluorobenzyl)-oxy] -6-
methylpyridin-2(IH) -one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[3-(isopropylaminomethyl)-
benzyl]-lH-pyridin-2-one;
3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-2-fluoro-benzamide;
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l(2H)-yl] methyl}-N-(2,3-dihydroxypropyl)pyrazine-2-
carboxamide;
{3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2K-pyriain-
1-ylmethyl]-phenyl}-acetic acid ethyl ester;
4- (4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-Nhydroxy-
bensamidine;
4-{ [4-(benzyloxy}-3-bromo-2-oxopyridin-l(2H)-yl]methyl}-
N' -hydroxybenzenecarboximidamide;
ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2-oxopyridin-l(2H)-yl] methyl}pyra2ine-2-carboxylate;
3-Bromo-4-(2,4-difluoro-benzyloxy)-I-(3-methoxy-benzyl)-
lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobensyl)oxy]-6-methyl-l- [ (5-
methylpyrasin-2-yl)methyl]pyridin-2(1H) -one;
3-bromo-4-[(2, 4-difluorobenzyl)oxy]-1-(3-
methoxybenzyl)pyridin-2 (Iff) -one;
4- (4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-
bensoic acid methyl ester;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(4-
dimethylaminomethyl-benzyl)-lH-pyridin-2-one;
3-Chloro-4-(2,4-difluoro-benzyloxy)-1-(3-raethanesulfonylbenzyl)-
lH-pyridin-2-one;
4- (4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-
benzoic acid methyl ester;
methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]methyl}benzoate;
ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate;
4-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl}benzonitrile;
4- (4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-
benzonitrile;
(3-[3-Bromo-4-(4-fluoro-benzyloxy)-2-oxo-2H-pyridin-lylmethyl]-
benzyl}-carbamic acid tert-butylester;
3-bromo-4-[(2,4-difluorobenzyl)oxyj-1-[5-(l-hydroxy-1-
methylethyl)-2-methylphenyl]-6-methylpyridin-2(1H) -one;
4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6-
methylpyridin-2(1H) -one;
1-(3-Aminomethyl-benzyl)-4-benzyloxy-3-bromo-lK-pyridin-
2-one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-4-
ylmethyl)pyridin-2(IK) -one;
4- (benzyloxy)-3-bromo-l-(4-bromobenzyl)pyridin-2(1H)-one;
4-Benzyloxy-3-bromo-l-(4-bromo-benzyl)-lH-pyridin-2-one;
5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde;
3-chloro-4-[(2,4-difluorobensyl)oxy]-l-{[5-
(hydroxytnethyl)pyrazin-2-yl] methyl}-6-methylpyridin-2 (1H) -one;
4- (4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl) -
benzamide;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-[3-
(piperazin-l-ylcarbonyl)phenyl)pyridin-2(1H)-one
hydrochloride;
3-bromo-4- [ (2,4-difluorobenzyl)aminoJ-1-(3-
fluorobenzyl)pyridin-2(1H) -one;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-
methylpyrazin-2-yl)methyl]pyridin-2 (1H) -one;
3-chloro-4-t(2,4-difluorobenzyl)oxy]-1-[5-
(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-4- [ (4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-Bromo-l- (3-fluoro-benzyl)-4-(4-fluoro-benzyloxy) -1Hpyridin-
2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-

(morpholin-4-ylcarbonyl)phenyl]pyridin-2(IH) -one;
3-(4-Benzyloxy-3-brcmo-2-oxo-2H-pyridin-l-ylmethyl)-
benzole acid methyl ester;
3-bromo-l-(3-fluorobenzyl)-4-{[2-
(hydroxymethyl)benzyl]oxy}pyridin-2(IH) -one;
3-3romo-l-(3-fluoro-benzyl)-4-(2-hydroxymethylbenzyloxy)-
lH-pyridin-2-one;
1-Benzo[1,3]dioxol-5-ylmethyl-3-bromo-4-(2,4-difluorobenzyloxy)-
lH-pyridin-2-one;
3-bromo-4-[(2, 6-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
4-ylmethyl)pyridin-2(1H) -one;
3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(IH)-one;
3-bromo-4-[(3-chlorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(IH) -one;
3-Bromo-4-(3-chloro-benzyloxy)-1-(3-fluoro-benzyl)-1Hpyridin-
2-one;
4-(benzyloxy)-3-bromo-l-(3-fluorobensyl)pyridin-2(IH)-
one;
4-Benzyloxy-3-bromo-l-(3-fluoro-benzyl)-lH-pyridin-2-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[3-
(piperidine-1-carbonyl)-benzyl]-lH-pyridin-2-one;
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -tf,.N-dimethylbenzamide;
3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-2-fluoro-benzoic acid methyl ester;
1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-
2(lH)-one;
1-(3-Fluoro-benzyl)-4-(4-fluoro-benzyloxy)-3-iodo-lHpyridin-
2-one;
N- (3-aminopropyl)-4-[3-bromo-4-[(2,4-difluorobenzyljoxy]-
6-methyl-2-oxopyridin-l(2H) -yl]benzamide hydrochloride;
-201-
4-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-l(2H) -
yl]methyl}benzonitrile;
4-[3-Bromo-4-(4-fluoro-bensyloxy)-2-oxo-2H-pyridin-lylmethyl]-
benzonitrile;
3-Bromo-l-(3-fluoro-benzyl)-4-(2,3,4-trifluorobenzyloxy)
-lH-pyridin-2-one;
I-benzyl-4-(benzyloxy)-3-bromopyridin-2(1H)-one;
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H)-yl]methyl}-N- (2-hydroxyethyl)-Nmethylpyrazine-
2-carboxamide;
4-(4-3enzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-
benzonitrile;
3-bromo-l-(2,4-difluorobenzyl)-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
3-Bromo-l-(2,4-difluoro-benzyl)-4-(2,4-difluorobenzyloxy)-
lH-pyridin-2-one;
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l(2H) -yl]~N-(2-hydroxyethyl)benzamide;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(pyridin-3-
ylmethyl)pyridin-2(1H) -one;
l-Benzyl-4-benzyloxy-3-bromo-lH-pyridin-2-one;
3-bromo-l-(cyclopropylmethyl)-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H) -one;
1-(4-Aminomethyl-benzyl)-4-benzyloxy-3-bromo-lH-pyridin-
2-one;
3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)aminol-6-
methylpyridin-2(1H)-one;
3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]-benzoic acid methyl ester;
5-{[3-bromo-4-t(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]methyl}-W,W-dimethyIpyrazine-2-
carboxamide;
-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-2-
yltnethyl)pyridir.-2 (1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
diTnethylphenyl) -6-methylpyridin-2 (1H) -one;
3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4-
difiuorobenzyDoxy] -6-methylpyridin-2 (1H) -one;
4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(IH) -one;
3-bromo-4-hydroxy-l-(4-hydroxybenzyl)pyridin-2(IH)-one;
4-(benzyloxy)-3-bromo-l-[2-
(trifiuoromethyl)benzyl]pyridin-2(IH) -one;
1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(IH)-
one ;
4-(benzyloxy)-3-bromo-l-(piperidin-3-ylmethyl)pyridin-
2 (IH)-one hydrochloride;
1-benzyl- 3-bromo-2-oxo-1,2-dihydropyridin-4-yl
methyl(phenyl)carbamate;
4-(benzylamino)-1-(3-fluorobenzyl)-6-methyl-3-
nitropyridin-2(IH)-one;
tert-butyl 4-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-
dihydropyridin-4-yl]piperazine-1-carboxylate;
ethyl [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl ]acetate;
N- [3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-
yl]benzenesulfonamide;
3-bromo-4-[(4-tert-butylbenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(IH)-one;
N- [3-bromo-l-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-
yl]-1-phenylmethanesulfonamide;
1-(biphenyl-2-ylmethyl)-3-bromo-4-[(4-
fluorobenzyl)oxy]pyridin-2(IH)-one;
4-(biphenyl-2-ylmethoxy)-3-bromo-l-(3-
fluorobenzyl)pyridin-2(IH)-one;
3-bromo-4-[(2,4-difluorophenyl)amino]-1-(3-
fluorobensyl)pyridin-2(1H) -one;
4-anilino-3-bromo-l- (3-fluorobenzyl)pyridin-2 (IH) -one,-
methyl 4- {[3-bromo-l-(3-fluorobenzyl)-2-oxo-I,2-
dihydropyridin-4-yl]amino}benzoat e;
3-bromo-l-(3-fluorobenzyl)-4-[(3,4,5-
trimethoxyphenyl)amino]pyridin-2(IH) -one;
3-bromo-l-(3-fluorobensyl)-4-[4-(4-
fluorophenyl)piperazin-l-yl]pyridin-2(IH) -one;
3-bromo-l-(3-fluorobenzyl)-4-(4-methylpiperarin-lyl)
pyridin-2(1H)-one trifluoroacetate;
N- [3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-
yl]-2,5-difluorobenzamide/
N- [3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-
yl]-2,4-difluorobenzamide;
3-bromo-l-(eyelohexylmethyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(IH) -one;
3- [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -yl]propanoic
acid;
N- [3-bromo-l-(3-fluorobenzyl)-2-oxo-l, 2-dihydropyridin-4-
yl]-N1 -(2,4-difluorophenyl)urea;
3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]propanamide;
4-(benzyloxy)-3-bromo-l-(3-morpholin-4-yl-3-
oxopropyl)pyridin-2 (l/f) -one;
N- (3-aminopropyl)-3-[4-(benzyloxy)-3-bromo-2-oxopyridin-
1 (2H) -yl]propanamide hydrochloride;
4-(benzyloxy)-3-bromo-l-(3-oxo-3-piperazin-l~
ylpropyl)pyridin-2(IH) -one hydrochloride;
4-(benzyloxy)-3-bromo-l-(2-morpholin-4-ylethyl)pyridin-
2(lH)-one;
3-bromo-l-(3-fluorobenzyl)-4-{[4-fluoro-2-
(trifluoromethyl)benzyl]amino}pyridin-2(1H) -one;
N- (2-aminoethyl) -3- [4- (benzyloxy) -3-bromo-2-oxcpyridin-
1(2H) -yllpropanamide hydrochloride;
[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]acetic acid;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-
(tetrahydrofuran-2-ylmethyl)pyridin-2(1H) -one;
4- [(2,4-difluorobenzyl)oxy]-6-methyl-l-(tetrahydrofuran-
2-ylmethyl)pyridin-2(1H) -one;
methyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
oxopyridine-1(2H) -carboxylate;
l-allyl-3- (2,4-difluorobenzyl)-4-[ (2,4-
difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;
4-(benzyloxy)-1-(2,2-diethoxyethyl)pyridin-2(1H)-one;
methyl N-acetyl-3-[4-(benzyloxy)-2-oxcpyridin-l(2H) -
yl]alaninate;
benzyl W-acetyl-3-[4-(benzyloxy)-2-oxopyridin-l(2H) -
yl]alaninate;
benzyl N- [ (benzyloxy)carbonyl] -3-[4-(benzyloxy)-2-
oxopyridin-1(2H) -yl]alaninate;
4-(benzyloxy)-1-(2-oxopropyl)pyridin-2(1H)-one;
5-{[4-(benzyloxy)-2-oxopyridin-l(2H) -yl]methyl}-5-
methylimidazolidine-2,4-dione;
ethyl [4-(benzyloxy)-2-oxopyridin-l(2H)-yl]acetate;
2-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]acetamide;
l-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(1H) -one;
4-(benzyloxy)-l-ethylpyridin-2(1H)-one;
4-(benzyloxy)-1-(4-tert-butylbenzyl)pyridin-2 (1H) -one;
4-{ [4- (benzyloxy)-2-oxopyridin-l(2H)-
yl]methyl}benzonitrile;
tert-butyl 3-{[4-(benzyloxy)-2-oxopyridin-l (2H) -
yl]methyl}piperidine-l-carboxylate;
l,3-dibenzyl-4-hydroxy-6-methylpyridin-2(iff)-one;
1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl
methanesulfonate;
4-(benzyloxy)-1-(4-bromobenzyl)pyridin-2(Iff) -one;
4-(benzyloxy)-3-bromopyridin-2(Iff)-one;
4-(benzyloxy)-3-bromo-1-[2-
(trifluoromethyl)benzyl]pyridin-2(Iff) -one;
1-benzyl-4-(1-naphthylmethoxy)pyridin-2(iff) -one;
1-benzyl-4-(benzylthio)-3,5-dibromopyridin-2(Iff)-one;
1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(Iff)-one;
l-benzyl-3-[(benzylamino)methyl]-4-(benzyloxy)pyridin-
2(Iff)-one;
l-benzyl-4-(benzyloxy)-3-{[(2-
cyclohexylethyl)amino]methyl}pyridin-2(Iff)-one;
l-benzyl-4-(benzylthio)-5-methylpyridin-2(Iff) -one;
1-benzyl-3-bromo-6-methyl-2 -oxo-1,2-dihydropyridin-4-y1
methanesulfonate;
l-benzyl-3-bromo-6-methyl-4-{[2-
(trifluoromethyl)benzyl]oxy}pyridin-2(Iff) -one;
1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-
bromobenzenesulfonate;
l-benzyl-4-I(3-chlorobenzyl)oxy]-6-methylpyridin-2(Iff)-
one ;
1-benzyl-3-bromo-6-methyl-2-oxo-1,2-dihydropyridin-4-yl
4-bromobenzenesulfonate;
4-phenoxy-l-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-
2 (Iff) -one;
l-benzyl-4-phenoxypyridin-2(Iff)-one;
1-(4-methoxybenzyl)-4-phenoxypyridin-2(Iff) -one;
3-bromo-4-hydroxy-l-(4-hydroxybenzyl)pyridin-2(Iff)-one
hydrochloride;
4- (benzyloxy) -3-bromo-l- (piperidin-3-ylmethyDpyridin-
2 (1H) -one;
1-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(1H)-one;
1-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(IK)-one;
3-bromo-l-(3-fluorobenzyl)-4- [ (E)-2-(4-
fluorophenyl)vinyl]pyridin-2(1H) -one;
l-benzyl-4-(benzyloxy)-2-oxo-l,2-dihydropyridine-3-
carbaldehyde;
l-benzyl-4-(benzyloxy)pyridin-2(1H)-one;
l-benzyl-4-(benzyloxy)pyridin-2(1H)-one;
l-benzyl-4-(benzylthio)pyridin-2(1H) -one;
methyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-l(2H)-yl]benzoate;
benzyl (5-nitro-2,6-dioxo-3,6-dihydropyrimidin-l(2H) -
yl)acetate;
ethyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-
2H-1,2'-bipyridine-5'-carboxylate;
4-(benzyloxy)-1-(4-methylbenzyl)pyridin-2(1H) -one;
[5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridin-3-yl]methyl
carbamate;
4-(benzyloxy)-1-(4-chlorobenzyl)pyridin-2(1H) -one;
methyl (2E)-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]but-2-enoate;
4- (benzyloxy)-1-(2-fluorobenzyl)pyridin-2(1H) -one;
tert-butyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]methyl}piperidine-l-carboxylate;
4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl) -5-(1,2-dihydroxyethyl)-6-methylpyridin-2(1H) -
one;
l-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one;
4-({ [3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-
4-yl]oxyjmethyl)benzonitrile;
l-benzyl-4-(benzyloxy)-6-methylpyridin-2(IH)-one;
5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-
carbaldehyde oxime;
l-benzyl-4-(benzylthio)-3-methylpyridin-2(IH)-one;
l-benzyl-4-[ (4-methylbensyl)oxy]pyridin-2(IH) -one;
l-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2 (IH)
one;
l-benzyl-4- (benzyloxy) -3, 5-dibromo-6-methylpyridin-2 (IH)
one;
3-bromo-l-(3-fluorobenzyl)-4-(l-phenylethoxy)pyridin-
2 (IH)-one;
4-(benzyloxy)-1-[4-(trifluoromethyl)benzyl]pyridin-2(IH)
one ;
2-({[3-bromo-2-oxo-l-(pyridin-3-ylmethyl) -1,2-
dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile;
5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2 , 6-
difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-
carbonitrile;
4-(benzyloxy)-1-(3-fluorobenzyl)-3-
(trifluoromethyl)pyridin-2(IH) -one;
3-bromo-4-t(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-methyl-5-oxiran-2-ylpyridin-2(IH) -one;
l-benzyl-4- [ (3-chlorobenzyl)oxy]pyridin-2(IH) -one;
l-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(IH) -one;
5-bromo-4- [ (2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-
carbaldehyde;
tert-butyl 3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l (2H) -
yl]methyl}piperidine-l-carboxylate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-methyl-5-vinylpyridin-2(1H) -one;
4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-
2(1H) -one;
3-bromo-4-[(4-chlorobenzyl)oxy]-1- [2-
(phenylthio)ethyl]pyridin-2(1H)-one;
3-Bromo-4-(4-chioro-benzyloxy)-1-(2-phenylsulfar.ylethyl)-
lH-pyridin-2-one;
3-bromo-4-[ (2,4-difluorobenzyl)oxy]-6-methyl-l-(2-
morpholin-4-ylethyl)pyridin-2(1H)-one;
4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(pyridin-
3-ylmethyl)pyridin-2(1H)-one;
4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-brorao-l-(2,6-
difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate;'
4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2(1H) -one;
4-(benzyloxy)-1-(4-fluorobenzyl)pyridin-2 (1H) -one;
4-Benzyloxy-3-bromo-1-methanesulfonyl-IH-pyridin-2-one;
tert-butyl 4- [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]piperidine-1-carboxylate ;
1-benzyl-4-(benzyloxy)-3-vinylpyridin-2(1H)-one;
4-(benzyloxy)-1-[4-(methylthio)benzyl]pyridin-2(1H)-one;
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-(2-methyl-4-
methylamino-pyrimidin-5-ylmethyl)-iH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2(lH)-one;
1-benzyl-3-bromo-4-{ [2-
(trifluoromethyl)benzyl]oxy}pyridin-2(1H) -one;
l-benzyl-3-brotno-4-{ [2-
(trifluoromethyl)benzyl]oxy}pyridin-2 (1H) -one;
4- [ (2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-
raethylphenyl]-6-methylpyridin-2(1H)-one;
4-(benzyloxy)-1-[4-(methylsulfonyl)benzyl]pyridin-2(1H) -
one;
4-Phenoxy-lH-pyridin-2-one;
l-benzyl-4- [ (2-chlorobenzyl)oxy]pyridin-2(IH)-one;
1-benzyl-4- [ (2-chlorobenzyl)oxy]pyridin-2(1H) -one;
methyl 4-{ [4-(benzyloxy)-2-oxopyridin-l(2H) -
yl]methyl}benzoate;
4-[(2,4-difluorobenzyl) oxy]-1-(2,6-difluorophenyl)-6-
methylpyridin-2(IH)-one;
I-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(IH) -one;
4-(benzyloxy)-3-bromo-l-(piperidin-4-ylmethyl)pyridin-
2(lH)-one hydrochloride;
4-(benzyloxy)-3-bromo-l-(piperidin-4-ylmethyl)pyridin-
2(lH)-one hydrochloride;
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-[2-
(methylthio)pyrimidin-4-yl]pyridin-2(IH) -one;
4-(benzyloxy)-3-bromo-l-piperidin-4-ylpyridin-2(IH)-one
hydrochloride;
4-Benzyloxy-l-difluoromethyl-lH-pyridin-2-one;
4-Benzyloxy-3-bromo-l-(2-chloro-phenyl)- 6-methyl-1Hpyridin-
2-one;
3-Bromo-6-methyl-l-pyridin-3-ylmethyl-4-[(pyridin-3-
ylmethyl)-amino]-lH-pyridin-2-one;
1-(3,4-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (2,4-difluoro-phenyl)-amide;
1-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (2,4-difluoro-phenyl)-amide;
5-Chloro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydropyridine-
3-carboxylic acid (2,4-difluoro-phenyl)-amide;
5-Chioro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydropyridine-
3-carboxylic acid methy1-phenyl-amide;
1-(2,6-Dichloro-benzyl) -6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid benzylamide;
1-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (3-dimethylamino-propyl)-amide;
1-(2,6-Dichloro-ben=yl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
N- [5-Acetyl-l-(4-chloro-benzyl)-6-methyl-2-oxo-l,2-
dihydro-pyridin-3-yl]-4-chloro-benzamide;
I-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid N1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-
hydrazide;
N-allyl-2-[(l-benzyl-6-oxo-l,6-dihydropyridin-3-
yl)carbonyl]hydrazinecarbothioamide;
l-Benzyl-5-[5-(3,4-dichloro-benzylsulfanyl)-
[l,3,4]oxadiazol-2-yl3-lH-pyridin-2-one;
N1 -{[(l-benzyl-6-oxo-l,6-dihydropyridin-3-
yl)carbonyl]oxy}pyridine-4-carboximidamide;
1-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid 3-trifluoromethyl-benzylamide;
1-Benzyl-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid (2-
morpholin-4-yl-ethyl)-amide;
5- [4-(3-Chloro-phenyl)-piperazine-1-carbonyl]-1-(3,4-
dichloro-benzyl)-lH-pyridin-2-one;
5-Chloro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydropyridine-
3-carboxylic acid bensylamide;
1-(4-Chloro-benzyl)-5-[3-(4-chloro-phenyl)-
[1,2,4]oxadiazol-5-yl]-IH-pyridin-2-one;
1-(4-Chloro-benzyl)-5-[3-(4-chloro-phenyl)-
[l,2,4]oxadiazol-5-yl]-lH-pyridin-2-one;
2-Chloro-N-[I-(2,6-dichloro-benzyl) -6-oxo-5-
trifluoromethyl-l,6-dihydro-pyridin-3-yl] -4-fluoro-benzatnide;
N-[1-(2,6-Dichloro-benzyl)-6-oxo-5-trifluoromethyl-l,6-
dihydro-pyridin-3-yl]-4 -isopropoxy-benzamidE;
1-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (4-trifluoromethoxy-phenyl)-amide;
1-(2,6-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3 -
carboxylic acid (3-trifluoromethyl-phenyl)-amide;
5-Chloro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydropyridine-
3 -carboxylic acid (3-trifluoromethyl-phenyl)-amide;
1-(2,6-Dichloro-bensyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (4-chloro-phenyl)-amide;
1-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-
carboxylic acid (2-dimethylamino-ethyl)-amide;
5-Methyl-1-phenyl-IH-pyridin-2-one;
3-Bromo-l-(3-fluoro-benzyl)-4-(3-methoxy-phenyl)-IHpyridin-
2-one;
3-Bromo-l- (3-fluoro-benzyl)-4-(3-isopropyl-phenyl)-IHpyridin-
2-one;
3'-Bromo-1'-(3-fluoro-benzyl)-6-methoxy-l'H-
[3,4']bipyridinyl-2'-one;
4-Benzo[1,3]dioxol-5-yl-3-bromo-l-(3-fluoro-benzyl)-IHpyridin-
2-one;
3-Bromo-l-(3-fluoro-benzyl)-4-thiophen-3-yl-lH-pyridin-2-
one ;
3-Bromo-l-(3-fluoro-benzyl)-4-(3-trifluoromethyl-phenyl)-
lH-pyridin-2-one;
3-Bromo-l-(3-fluoro-benzyl)-4-naphthalen-2-yl-lH-pyridin-
2-one;
3-Bromo-l-(3-fluoro-benzyl)-4-(4-fluoro-phenyl)-1Hpyridin-
2-one;
l-Benzenesulfonyl-4-benzyloxy-3-bromo-lH-pyridin-2-one;
4- [3-Amino-l-(2,4-difluoro-phenyl)-propoxy]-3-bromo-6-
methyl-1-pyridin-3-ylmethyl-IH-pyridin-2-one;
1-(4-Bromo-2,6-difluoro-phenyl)-4-(2,4-difluorobenzyloxy)-
6-methyl-IH-pyridin-2-one;
2-[1-(4-Amino-2-methyl-pyrimidin-5-ylmethyl)-3-bromo-6-
methyl-2-oxo-1,2-dihydro-pyridin-4-yloxymethyl]-5-fluoro-
benzonitrile;
4- (2,4-Difluoro-ber.zyloxy) -6-methyl-1- (2,4, 6-trifluorophenyl)-
lH-pyridin-2-one;
1-(2-Chloro-4-hydroxy-phenyl)-4-(2,4-difluoro-benzyloxy)
6-methyl-lH-pyridin-2-one;
3- [4- (2,4-Difluorp-benzyloxy) -6-methyl-2-oxo-2H-pyridin-
1-yl]-benzole acid methyl ester;
3-Bromo-l-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-
vinyl-IH-pyridin-2-one;
3-Bromo-l-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-
styryl-lH-pyridin-2-one;
1-(2,6-Difluoro-phenyl)-4-methoxy-6-methyl-5-phenethyllH-
pyridin-2-one;
3-Bromo-l-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-
phenethyl-lH-pyridin-2-one;
1-(lH-indazol-5-yl)-4-(lH-indazol-5-ylamino)-6-
methylpyridin-2(1H)-one;
5-Bromo-4-(2,4-difluoro-benzyloxy)-1-(2,6-difluorophenyl)
-2-[2-(2,4-difluoro-phenyl)-ethyl]-6-oxo-l,6-dihydropyridine-
3-carbaldehyde;
4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-raethyl-2-oxo-2Hpyridin-
1-yl]-pyrimidine-2-carbonitrile;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-
[1,2']bipyridinyl-5'-carboxylic acid;
3-Bromo-4-(5-carboxy-pyridin-2-yloxy)-6-methyl-2-oxo-
[1,2']bipyridinyl-5'-carboxylic acid;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6,6'-dimethyl-2-oxo-
2H- [l,2']bipyridinyl-3'-carbonitrile;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Htl,
2']bipyridinyl-5'-carboxylic acid methylamide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-
[1,2'3bipyridinyl-5'-carboxylic acid (2-hydroxy-ethyl)-amide;
3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2K-
[l;2']bipyridinyl-5'-carboxylic acid (2-methoxy-ethyl)-amide;
3-Bromo-l-(2, 6-difluoro-phenyl)-4-methoxy-6-methyl-5-(4-
methyl-benzyl)-lH-pyridin-2-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-5-(1,2-dihydroxy-2-phenylethyl)-6-
methylpyridin-2(IK) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy] -5'-(l-hydroxy-1-
methylethyl)-6-methyl-2H-1,2'-bipyridin-2-one;
4-Benzyloxy-IH-pyridin-2 -one;
4-Benzyloxy-3-methyl-lH-pyridin-2-one;
2-Oxo-6-phenethyl-l,2-dihydro-pyridine-3-carbonitrile;
2-Oxo-6-phenyl-l,2-dihydro-pyridine-3-carbonitrile;
6-Oxo-l,6-dihydro-[2,3']bipyridinyl-5-carbonitrile;
6-Oxo-l,6-dihydro-[2,3']bipyridinyl-5-carboxylic acid;
3-{ [4-(bensyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]methyl}benzamide;
3-bromo-4-t(4-fluorobenzyl)oxy]-1-(4-
methoxybensyl)pyridin-2 (1H) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(4-
tnethoxybenzyl)pyridin-2 (1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy] -1-[2-fluoro-5-
(hydroxytnethyl)phenyl] -6-methylpyridin-2 (1H) -one;
3-chloro-l-(4-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-chloro-l-(4-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(3-chlorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-4-[(3,4-difluorobenzyl)oxy]-1-(3-
fluorobenzyl)pyridin-2(1H) -one;
3- [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-tnethyl-2-
oxopyridin-1(2H) -yl]-4-methylbenzoic acid;
3-bromo-l-(3-chlorobenzyl)-4- [ (4-
fluorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-l-(3-chlorobenzyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H)-one;
4-{ [3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzonitrile trifluoroacetate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(1-hydroxy-lmethylethyl)
pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one;
4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin-2(1H) •
one;
4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin-2(1H) •
2-{ [3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzonitrile;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-6-(4-
methylpiperazin-l-yl)phenyl]-6-methylpyridin-2(1H)-one
trifluoroacetate;
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-N-methyIbenzamide;
1-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-l-(4-fluorobenzyl)-4-[(4-
fluorobenzyl)oxyIpyridin-2(1H)-one;
1-[2-(aminomethyl)benzyl]-3-bromo-4- [(2,4-
dif luorobenzyl) oxy] -6-methylpyridin-2 (1H) -one,-
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-
(piperidin-l-ylcarbonyl)phenyl]pyridin-2(1H)-one;
l-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2
one;
4-[(2,4-difluorobenzyl)oxy]-1-(3-fluorobenzyl)-3-
methylpyridin-2(1H)-one;
4-(benzyloxy)-1-[4-(benzyloxy)benzyl]-3-bromopyridin-
2(1H) -one;
4-[3-bromo-4-[(2,4-difluorobensyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -N-hydroxybenzamide?
4-(benzyloxy)-3-bromo-l-[4-
(trifluoromethyl)benzyl]pyridin-2(1H)-one;
3-bromo-l-(cyclopropylmethyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(cyclopropylmethyl)-4-[(4-
fluorobenzyl)oxy]pyridin-2(1H) -one;
1-benzyl-3-bromo-4- [ (3-chlorobenzyl)oxy]-6-methylpyridin-
2(lH)-one;
1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-
2 (1H) -one;
1-benzyl-3-bromo-4- [ (3-chlorobenzyl) oxy] -6-tnethylpyridin-
2 (1H) -one;
2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}benzonitrile;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-((5-
t(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one
trifluoroacetate;
3-bromo-l-(3-fluorobenzyl)-4-[(2-
methylbenzyl)oxy]pyridin-2(1H) -one;
3-bromo-l-(3-fluorobenzyl)-4-[(2-
methylbenzyl)oxy]pyridin-2(1H) -one;
methyl 3-{[3-bromo-4- [ (2,4-difluorobenzyl)oxy]-2- .
oxopyridin-1(2H)-yl]methylJbenzoate;
3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-
phenylethyl)pyridin-2 (1H) -one;
3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-
phenylethyl)pyridin-2 (1H) -one;
1-benzyl-3-bromo-4- [ (4-methylbenzyl) oxy] pyridin-2 (1H) -
4-(benzyloxy)-1-(S-fluorobensyl)-3-iodopyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[3-
(hydroxymethyl)phenyl]-6-methylpyridin-2(1H) -one;
4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H) -one;
3-{[3-brorao-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]methyl}benzole acid;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-[2-
(hydroxymethyl)benzyl]pyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(5-{ [ (2-
hydroxyethyl)(methyl)amino]methyl}pyrazin-2-yl)methyl]-6-
methylpyridin-2(1H)-one trifluoroacetate (salt);
4-(benzyloxy)-3-bromo-l-[(6-fluoropyridin-3-
yl)methyl]pyridin-2(1H)-one;
3-bromo-4-[(4-chlorobenzyl)oxy]-1-(4-
fluorobenzyl)pyridin-2(1H)-one;
3-bromo-4-[(4-chloro-2-fluorobenzyl)amino]-1-(3-
fluorobenzyl)pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-ethylpyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-ethylpyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-ethylpyridin-2(1H)-one;
2-(2-{ [3-bromo-4-t(2,^-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]methyl}phenyl)acetamide;
l-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H) -
one;
l-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(1H) -
one;
methyl 2-{[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-
1(2H) -yl]methyl}benzoate;
3-bromo-l-(2,6-dichlorophenyl)-4-[2-(4-
fluorophenyl)ethyl]-6-methylpyridin-2(1H)-one;
3-bromo-l-(2,6-dichlorophenyl)-4-[2-(4-
fluorophenyl)ethyl]-6-methylpyridin-2(1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5-
[(isopropylamino)methyl]-2-methylphenyl}-6-methylpyriain-
2 (1H) -one hydrochloride;
3-bromo-I-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-
2(IH)-one;
AT-{3- [3-bromo-4- [ (2 ,4-dif luorobenzyl) oxy] -6-methyl-2-
oxopyridin-1(2H) -yl]benzyl}-N'-methylurea;
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-
(hydroxymethyl)phenyl]-6-methylpyridin-2(1H) -one;
3-bromo-l-(3-fluorobenzyl)-4-[(3-
fluorobenzyl)oxy]pyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-[2-(2-thienyl)ethyl]pyridin-
2 (IH)-one;
4-(benzyloxy)-3-bromo-l-[2-(2-thienyl)ethyl]pyridin-
2 (1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(2,6-
difluorophenyl)-6-methylpyridin-2(1H) -one trifluoroacetate;
3-bromo-4- [ (2,4-difluorobenzyl)amino]-1-(2,6-
di fluorophenyl) -6-tnethylpyridin-2 (1H) -one trif luoroacetate;
3-bromo-4- [ (4-chlorobenzyl)oxy]-1-(4-
methoxybenzyl)pyridin-2(1H) -one;
3-bromo-4- [ (4-chlorobenzyl)oxy]-1-(4-
methoxybenzyl)pyridin-2(1H) -one;
3-bromo-l-(4-chlorobenzyl)-4-[(4-
chlorobenzyl)oxy]pyridin-2(1H)-one;
3-bromo-l- (3-fluorobenzyl)-4-[ (4-
methoxybenzyl)oxy]pyridin-2(IH) -one;
3-bromo-l-(3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-4-
[(2,4-difluorobenzyl)oxy] -6-methylpyridin-2(1H) -one;
4-(benzyloxy)-3-bromo-l-[4-
(trifluoromethoxy)benzyl]pyridin-2(1H) -one;
4- (benzyloxy)-3-bromo-l-[4-
(trifluoromethoxy)benzyl]pyridin-2(1H) -one;
jyi _ (3. [3-bromo-4- [ (2,4-difluorobenzyl) oxy] -6-methyl-2-
oxopyridin-1 (2H) -yl]benzyl}~N,N-dimethylurea;
3-bromo-4-[(4-fluorobenzyl)oxy]-1- [4-
(trifluoromethyl)benzyl]pyridin-2(1H)-one;
2-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzamide;
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-
oxopyridin-1 (2H) -yl] benzyl}morpholine-4-carboxamide;
N-{3- [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] - 6-methyl-2-
oxopyridin-1(2H)-yl]benzyl}methanesulfonamide;
4- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] -J7-isopropylbenzamide;
4-(allylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H) -one;
4- (allylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one;
(4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]methyl}phenyl)acetic acid;
3-bromo-4-t(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-
(pyrrolidin-l-ylcarbonyl)phenyl]pyridin-2(1H) -one;
l-benzyl-4-(benzyloxy)-3-iodopyridin-2(1H) -one;
1- (biphenyl-4-ylmethyl)-3-bromo-4-[(4-
fluorobenzyl)oxy]pyridin-2 (1H) -one;
4- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzoic acid;
4-(benzyloxy)-3-bromo-l-[2-(3-thienyl)ethyl]pyridin-
2(lH)-one;
4-(benzyloxy)-3-bromo-l-[2-(3-thienyl)ethyl]pyridin-
2 (1H) -one;
3-bromo-4- [ (4-f luorobenzyl) oxy] -1- [3-
(trifluoromethyl)benzyl]pyridin-2(IK) -one;
N- [3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-
yl]-4-fluorobenzamide;
methyl 3- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
oxopyridin-1(2H) -yl]benzylcarbamate;
l-benzyl-4-(benzylthio)-3-bromopyridin-2(1H)-one;
4-(benzyloxy)-3-bromo-l-(4-tert-butylbenzyl)pyridin-
2 (1H) -one;
4-(benzyloxy)-3-bromo-l-(4-tert-butylbenzyl)pyridin-
2 (1H) -one;
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzyl}-2-methoxyacetamide;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-({5-
[(dimethylamino)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-
2(lH)-one trifluoroacetate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-
(piperazin-l-ylcarbonyl)phenyl]pyridin-2(1H) -one
hydrochloride;
4-[3-bromo-4-t(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl] -N, W-bis(2-hydroxyethyl)benzamide;
3-bromo-4-t(2,4-difluorobenzyl)oxy]-l-{5-
[(dimethylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(1H) -
one hydrochloride;
1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(1H) -one;
1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3- .
methylpyridin-2(1H)-one;
4-(benzyloxy)-1-(piperidin-3-ylmethyl)pyridin-2(1H) -one
trifluoroacetate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-
(morpholin-4-ylcarbonyDphenyl]pyridin-2 (1H) -one;
4-(benzyloxy)-1-(3-fluorobenzyl)-3-methylpyridin-2(1H)-
one;
{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzylJglycinamide hydrochloride;
3-bromo-4-t(2,4-difluorobensyl)oxy]-1-(2,6-
difluorophenyl}-5-iodo-6-methylpyridin-2(1H)-one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l- [4-
(piperidin-l-ylcarbonyl)phenyl]pyridin-2(IH) -one;
N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-
yl]-2,6-difluorobenzamide;
2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-1 (2H) -
yl]methyi}benzonitrile;
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl]methyl}-tf-methylpyrazine-2-carboxamide;
3-chloro-4-[(2,4-difluorobenzyl)amino]-1-(2,6-
difluorophenyl)-6-methylpyridin-2(1H) -one;
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzoic acid;
3-bromo-l-{3-fluorobenzyl)-4-[(3-
fluorobenzyl)amino]pyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-4-[(3-
tnethoxybenzyl) oxy]pyridin-2 (1H) -one;
3-bromo-l-(4-tert-butylbenzyl)-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one;
N- {3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzylJacetamide;
2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzyl}amino)-2-oxoethyl acetate;
l-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H) -one;
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H) -yl]benzyl}urea;
l-benzyl-4-(benzyloxy)-3-ethylpyridin-2(ifl)-one;
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzyl}-2-hydroxyacetamide;
3-bromo-4-[(4-chlorobenzyl)oxy]-1-(2-phenylethyl)pyridin-
2 (1H) -one;
3-bromo-l-(3-chlorobenzyl)-4-[(4-
chlorobenzyl)oxy]pyridin-2 (1H) -one;
1- [3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-
difluorobenzyDoxy] -6-methylpyridin-2 (1H) -one;
2-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl}benzamide;
1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(1H) -
one ;
1- [2- (aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-
2 (1H) -one;
methyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]propanoate;
l-benzyl-4-(benzyloxy)-3-methylpyridin-2(1H) -one;
4-(allylamino)-1-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one;
4-(allylamino)-1-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one;
3-bromo-l-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-
2 (1H) -one;
4- [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-
oxopyridin-1(2H)-yl] -N, W-dimethylbenzamide;
{4- [ ({4-(benzyloxy)-3-bromo-l-[4-(carboxymethyl)benzyl]-
1,2-dihydropyridin-2-yl}oxy)methylIphenyl}acetic acid;
4- (benzyloxy)-3-bromo-l-[3-
(trifluoromethyl)benzyl]pyridin-2(1H) -one;
4-(benzyloxy)-3-ethynyl-l-(3-fluorobenzyl)pyridin-2(1H) -
one,-
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{3-
[ (dimethylamino) methyl] phenyl} -6-methylpyridin-2 (1H) -one ;
4-(benzyloxy)-3-bromo-l-methylpyridin-2(1H)-one;
1-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(IH)-one;
4-(benzyloxy)-3-bromo-l-methylpyridin-2(IH) -one;
3-bromo-l-(3-fluorobenzyl)-4-{[4-
(trifluoromethyl)benzyl]oxy}pyridin-2 (IH) -one;
4-(benzylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(IH) -one;
4-[(2,4-difluorobenzyl)oxy] -1-(4-methoxybenzyl)-6-
methylpyridin-2(IH) -one;
4-(benzyloxy)-3-bromo-l-methylpyridin-2(IH) -one
hydrobromide;
4-(benzyloxy)-3-bromo-l-[4-(morpholin-4-
ylcarbonyl)phenyl]pyridin-2(IH)-one;
5-bromo-4-t(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid;
1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-
2 (IH) -one;
3- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-2-methylbenzoic acid;
4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]benzoic
acid;
ethyl N- (S-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl] methyl}-2-methylpyrimidin-
yDglycinate trifluoroacetate;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-6-methyl-5-[(E)-2-phenylvinyl]pyridin-2 (IH) -
one;
3-bromo-l-(3-fluorobenzyl)-4-{ [3-
(trifluoromethyl)benzyl] amino}pyridin-2(IH) -one;
3-bromo-4-[(4-fluorobenzyl)oxy]-1-(3-
phenylpropyl)pyridin-2(IH)-one;
3-bromo-l-(4-tert-butylbenzyl)-4- [(4-
fluorobenzyl)oxy]pyridin-2(IH)-one;
4-(allylamino)-3-bromo-l-(2,6-difluorophenyl)-6-
raethylpyridin-2(IH) -one;
l-cyclohexyl-4- [ (2,4-difluorobenzyl)oxy]-3,6-
dimethylpyridin-2(1H) -one;
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluorophenyl)-5-(hydroxymethyl)-6-methylpyridin-2(IH) -one;
l-benzyl-4-{benzyloxy)-2-oxo-l,2-dihydropyridine-3-
carbaldehyde;
4-[(2 , 4-difluorobenzyl)oxy]-6-methyl-l-prop-2-yn-lylpyridin-
2(IH)-one;
ethyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H) -
yl]propanoate;
l-benzyl-4- (benzyloxy) -3- (hydroxymethyl)pyridin-2 (IH)
one;
or a pharmaceutically acceptable salt thereof.
3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(5-methylpyrazin-
2-ylmethyl)-lH-pyridin-2-one
3-Chloro-4-(2,4-difluoro-benzyloxy) -1-(5-hydroxymethylpyrazin-
2-ylmethyl)-6-methyl-lH-pyridin-2-one
3-Bromo-4-(2,4-difluoro-benzyloxy) -1-(2,3-dihydro-lHindol-
5-ylmethyl) -IH-pyridin-2 -one
3-Bromo-4-(2,4-difluoro-benzyloxy)-1-[1-(2-hydroxyacetyl)-
2, 3-dihydro-lH-indol-5-ylmethyl]-6-methyl-lH-pyridin-
2-one
3-Bromo-4- (2,4-difluoro-benzyloxy)-6-methyl-l-(1Hpyrazol-
3-ylmethyl)-lH-pyridin-2-one
3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1 -yl] -4,N-dimethyl-benzamide
3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-yl] -4-methyl-benzamide
3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-yl] -4-fluoro-N-methyl-benzamide
4-Chloro-3- [3-chloro-4-(2,4-difluoro-benryloxy)-6-methyl-
2-oxo-2H-pyridir.-l-yl] -N-methyl-benzarr.ide
3-[3-Chloro-4-(2, 4-difluoro-benzyloxy)-6-methyl-2-cxo-2Hpyridin-
1-yl]-4-fluoro-ben2amide
4-[3-Chloro-4-(2, 4-difluoro-benzyloxy}-6-methyl-2-cxo-2Hpyridin-
1-yl]-3,N-dimethyl-benzamide
3-Chloro-4-(2,4-difluoro-benzyloxy)-1-[4-(1,2-dihydroxyethyl)
-2-methyl-phenyl]-6-methyl-lH-pyridin-2-one
N-{4-[3-Chloro-4-(2,4-difluoro-benzyloxy) -6-methyl-2-oxo-
2K-pyridin-l-ylmethyl] -phenyl}-2-hydroxy-acetamide
1-Hydroxy-cyclopropanecarboxylic acid 4-[3-chloro-4-(2,4-
difluoro-benzyloxy} -6-methyl-2-oxo-2H-pyridin-l-ylmethyl]-
benzylamide
N-{4- [3-Chloro-4-(2,4-difluoro-benzyloxy) -6-methyl-2-oxo-
2H-pyridin-l-ylmethyl] -benzyl)-2-hydroxy-acetamide
N- {4- [3-Chloro-4-(2,4-difluoro-benzyloxy) -6-methyl-2-oxo-
2K-pyridin-l-ylmethyl] -phenyl}-acetamide
{2- [3-Bromo-l-(2,6-difluoro-phenyl)-6-methyl-2-oxo-l,2-
dihydro-pyridin-4-yloxymethyl] -5-f luoro-benzyl} -carbamic acid
ethyl ester
The above names were generated using ChemDraw Ultra
version 6.0,2, which is put out by CambridgeSoft.com,
Cambridge, MA; or ACD Namepro version 5.09, which is put out
by ACDlabs.com.
Definitions
As used herein, the term "alkenyl" refers to a straight
or branched hydrocarbon of a designed number of carbon atoms
containing at least one carbon-carbon double bond. Examples
of "alkenyl" include vinyl, allyl, and 2-methyl-3-heptene.
The term "alkoxy" represents an alkyl attached to the
parent molecular moiety through an oxygen bridge. Examples of
alkoxy groups include, for example, methoxy, ethoxy, propoxy
and isopropoxy.
The term "thioalkoxy" represents an alkyl attached to the
parent molecular moiety through a sulfur atom. Examples of
thioalkoxy groups include, for example, thiomethoxy,
thioethoxy, thiopropoxy and thioisopropoxy.
As used herein, the term "alkyl" includes those alkyl
groups of a designed number of carbon atoms. Alkyl groups may
be straight or branched. Examples of "alkyl" include methyl,
ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl,
pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. "Cx-Cy
alkyl" represents an alkyl group of the specified number of
carbons. For example, Ci-C4 alkyl includes all alkyl groups
that include at least one and no more than four carbon atoms.
It also contains subgroups, such as, for example, Ca-C3 alkyl
or Ci-C3 alkyl.
The term "aryl" refers to an aromatic hydrocarbon ring
system containing at least one aromatic ring. The aromatic
ring may optionally be fused or otherwise attached to other
aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.
Examples of aryl groups include, for example, phenyl,
naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and
biphenyl. Preferred examples of aryl groups include phenyl
and naphthyl. The most preferred aryl group is phenyl. The
aryl groups herein are unsubstituted or, as specified,
substituted in one or more substitutable positions with
various groups. Thus, such aryl groups can be optionally
substituted with groups such as, for example, Ci-C« alkyl, Ci-C6
alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Ci-
C6) alkylamino, C2-C6alkenyl, C2-C6alkynyl, C^-Ce haloalkyl, Ci-C6
haloalkoxy, amino (Ci-Cfi) alkyl, mono- or di (C!-C6) alkylamino (Cj.-
C6) alkyl.
The term "arylalkyl" refers to an aryl group, as defined
above, attached to the parent molecular moiety through an
alkyl group, as defined above. Preferred arylalkyl groups
include, benzyl, phenethyl, phenpropyl, and phenbutyl. More
preferred arylalkyl groups include benzyl and phenethyl. The
most preferred arylalkyl group is benzyl. The aryl portions
of these groups are unsubstituted or, as specified,
substituted in one or more substitutable positions with
various groups. Thus, such aryl groups can be optionally
substituted with groups such as, for example, CN-Cg alkyl, Ci-C5
alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(d-
C6) alkyl amino, C2-C6alkenyl, C2-C0-alkynyl, Ci-C6 haloalkyl, Ci-C6
haloalkoxy, amino (Ca-Cg) alkyl, mono- or di (Ci-C6) alkyl amino (Ci -
Cs) alkyl.
The term "arylalkoxy" refers to an aryl group, as defined
above, attached to the parent molecular moiety through an
alkoxy group, as defined above. Preferred arylaloxy groups
include, benzyloxy, phenethyloxy, phenpropyloxy, and
phenbutyloxy. The most preferred arylalkoxy group is
benzyloxy.
The term "cycloalkyl" refers to a C3-CB cyclic
hydrocarbon. Examples of cycloalkyl include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl. More preferred cycloalkyl groups include
cyclopropyl.
The term "cycloalkylalkyl," as used herein, refers to a
C3-C8 cycloalkyl group attached to the parent molecular moiety
through an alkyl group, as defined above. Examples of
cycloalkylalkyl groups include cyclopropylmethyl and
cyclopentylethyl.
The terms "halogen" or "halo" indicate fluorine,
chlorine, bromine, or iodine.
The term "heterocycloalkyl," refers to a non-aromatic
ring system containing at least one heteroatom selected from
nitrogen, oxygen, and sulfur, wherein the non-aromatic
heterocycle is attached to the core. The heterocycloalkyl
ring may be optionally fused to or otherwise attached to other
heterocycloalkyl rings, aromatic heterocycles, aromatic
hydrocarbons and/or non-aromatic hydrocarbon rings. Preferred
heterocycloalkyl groups have from 3 to 7 members. Examples of
heterocycloalkyl groups include, for example, piperazine,
1,2,3,4-tetrahydroisoquinoline, morpholine, piperidine,
tetrahydrofuran, pyrrolidine, and pyrazole. Preferred
heterocycloalkyl groups include piperidinyl, piperazinyl,
morpholinyl, and pyrolidinyl. The heterocycloalkyl groups
herein are unsubstituted or, as specified, substituted in one
or more substitutable positions with various groups. Thus,
such heterocycloalkyl groups can be optionally substituted
with groups such as, for example, Ci-C6 alkyl, Ci-C6 alkoxy,
halogen, hydroxy, cyano, nitro, amino, mono- or di-(Ci-
C6) alkyl amino, C2-C6alkenyl, C2-C6alkynyl, Ci-C6 haloalkyl, Ci-Cg
haloalkoxy, amino (Ci-Cg) alkyl, mono- or di (Ci-Cfi) alkyl amino (Ci-
C6) alkyl.
The term "heteroaryl" refers to an aromatic ring system
containing at least one heteroatom selected from nitrogen,
oxygen, and sulfur. The heteroaryl ring may be fused or
otherwise attached to one or more heteroaryl rings, aromatic
or non-aromatic hydrocarbon rings or heterocycloalkyl. rings.
Examples of heteroaryl groups include, for example, pyridine,
furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and
pyrimidine. Preferred examples of heteroaryl groups include
thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,
pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl,
thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,
isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl,
pyrrolyl, indolyl, pyrasolyl, and benzopyrazolyl. Preferred
heteroaryl groups include pyridyl. The heteroaryl groups
herein are unsubstituted or, as specified, substituted in one
or more substitutable positions with various groups. Thus,
such heteroaryl groups can be optionally substituted with
groups such as, for example, Ci-C6 alkyl, d-CB- alkoxy, halogen,
hydroxy, cyano, nitro, amino, mono- or di-(Ci-C6) alkylamino,
C2-C6alkenyl, C2-C6alkynyl, d-C6 haloalkyl, d-C6 haloalkoxy,
amino (d-Cs) alkyl, mono- or di (Ci-C6) alkylamino (d-Cs) alkyl.
The term "heteroarylalkyl" refers to a heteroaryl group,
as defined above, attached to the parent molecular moiety
through an alkyl group, as defined above. Preferred
heteroarylalkyl groups include, pyrazolemethyl, pyrazoleethyl,
pyridylmethyl, pyridylethyl, thiazolemethyl, thiazoleethyl,
imidazolemethyl, imidazoleethyl, thienylmethyl, thienylethyl,
furanylmethyl, furanylethyl, isoxazolemethyl, isoxazoleethyl,
pyrazinemethyl and pyrazineethyl. More preferred
heteroarylalkyl groups include pyridylmethyl and pyridylethyl.
The heteroaryl portions of these groups are unsubstituted or,
as specified, substituted in one or more substitutable
positions with various groups. Thus, such heteroaryl groups
can be optionally substituted with groups such as, for
example, d-Cg alkyl, d-d alkoxy, halogen, hydroxy, cyano,
nitro, amino, mono- or di- (d-Cfi) alkylamino, C2-Csalkenyl, d-
C6alkynyl, d-C6 haloalkyl, d-C6 haloalkoxy, amino (d-C6) alkyl,
mono- or di (d-Cg) alkylamino(d-Cg) alkyl.
If two or more of the same substituents are on a common
atom, e.g., di (d-Cg) alkylamino, it is understood that the
nature of each group is independent of the other.
As used herein, the term "p38 mediated disorder" refers
to any and all disorders and disease states in which p38 plays
a role, either by control of p38 itself, or by p38 causing
another factor to be released, such as but not limited to IL-
1, IL-6 or IL-8. A disease state in which, for instance, IL-1
is a major component, and whose production or action, is
exacerbated or secreted in response to p38, would therefore be
considered a disorder mediated by p38.
As TNF-beta has close structural homology with TNF-alpha
(also known as cachectin), and since each induces similar
biologic responses and binds to the same cellular receptor,
the synthesis of both TNF-alpha and TNF-beta are inhibited by
the compounds of the present invention and thus are herein
referred to collectively as "TNF" unless specifically
delineated otherwise.
Non-toxic pharmaceutically acceptable salts include, but
are not limited to salts of inorganic acids such as
hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic,
and nitric or salts of organic acids such as formic, citric,
malic, maleic, fumaric, tartaric, succinic, acetic, lactic,
methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic,
salicylic and stearic. Similarly, pharmaceutically acceptable
cations include, but are not limited to sodium, potassium,
calcium, aluminum, lithium and ammonium. Those skilled in the
art will recognize a wide variety of non-toxic
pharmaceutically acceptable addition salts.
The compounds of this invention may contain one or more
asymmetric carbon atoms, so that the compounds can exist in
different stereoisomeric forms. These compounds can be, for
example, racemates, chiral non-racemic or diastereomers. In
these situations, the single enantiomers, i.e., optically
active forms, can be obtained by asymmetric synthesis or by
resolution of the racemates. Resolution of the racemates can
be accomplished, for example, by conventional methods such as
crystallization in the presence of a resolving agent;
chromatography, using, for example a chiral HPLC column; or
derivatizing the racemic mixture with a resolving reagent to
generate diastereomers, separating the diastereomers via
chromatography or selective crystallization, and removing the
resolving agent to generate the original compound in
er.anticnerically enriched form. Any of the above procedures
can be repeated to increase the enantiomeric purity of a
compound .
The compounds of the invention may exist as atropisomers,
i.e., chiral rotational isomers. The invention encompasses
the racemic and the resolved atropisomers . The following
illustration generically shows a compound (Z) that can exist
as atropisomers as well as its two possible atropisomers (A)
and (B) . This illustration also shows each of atropisomers
(A) and (B) in a Fischer projection. In this illustration, RI,
R2, and R4 carry the same definitions as set forth for Formula
I, RP' is a substituent within the definition of RS, and Rp is a
non-hydrogen substituent within the definition of Rs
When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless
otherwise specified, it is intended that the compounds include
the cis, trans, Z- and E- configurations. Likewise, all
tautomeric forms are also intended to be included.
The compounds of general Formula I may be administered
orally, topically, parenterally, by inhalation or spray or
rectally in dosage unit formulations containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. The term parenteral as used herein includes
percutaneous, subcutaneous, intravascular (e.g., intravenous),
intramuscular, or intrathecal injection or infusion techniques
and the like. In addition, there is provided a pharmaceutical
formulation comprising a compound of general Formula I and a
pharmaceutically acceptable carrier. One or more compounds of
general Formula I may be present in association with one or
more non-toxic pharmaceutically acceptable carriers and/or
diluents and/or adjuvants, and if desired other active
ingredients. The pharmaceutical compositions containing
compounds of general Formula I may be in a form suitable for
oral use, for example, as tablets, troches, lozenges, aqueous
or oily suspensions, dispersible powders or granules,
emulsion, hard or soft capsules, or syrups or elixirs.
For oral administration, the pharmaceutical composition
may be in the form of, for example, a tablet, hard or soft
capsule, lozenges, dispensable powders/ suspension, or liquid.
The pharmaceutical composition is preferably made in the form
of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or
capsules.
Compositions intended for oral use may be prepared
according to any method known to the art for the manufacture
of pharmaceutical compositions and such compositions may
contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preservative agents in order to provide pharmaceutically
elegant and palatable preparations. Tablets contain the
active ingredient in admixture with non-toxic pharmaceutically
acceptable excipients that are suitable for the manufacture of
tablets. These excipients may be for example, inert diluents,
such as calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating
agents, for example, corn starch, or alginic acid; binding
agents, for example starch, gelatin or acacia, and lubricating
agents, for example magnesium stearate, stearic acid or talc.
The tablets may be uncoated or they may be coated by known
techniques. In some cases such coatings may be prepared by
known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action
over a longer period. For example, a time delay material such
as glyceryl monosterate or glyceryl distearate may be
employed.
Formulations for oral use may also be presented as hard
gelatin capsules, wherein the active ingredient is mixed with
an inert solid diluent, for example, calcium carbonate,
calcium phosphate, or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil
medium, for example peanut oil, liquid paraffin or olive oil.
Formulations for oral use may also be presented as
lozenges.
Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of
aqueous suspensions. Such excipients are suspending agents,
for example sodium carboxymethylcellulose, methylcellulose,
hydropropyl-rnethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring
phosphatide, for example, lecithin, or condensation products
of an alkylene oxide with fatty acids, for example
polyoxyethylene stearate, or condensation products of ethylene
oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids
and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters
derived from fatty acids and hexitol anhydrides, for example
polyethylene sorbitan monooleate. The aqueous suspensions may
also contain one or more preservatives, for example ethyl, orn-propyl p-hydroxybenzoate, one or more coloring agents, one
or more flavoring agents, and one or more sweetening agents,
such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the
active ingredients in a vegetable oil, for example arachis
oil, olive oil, sesame oil, or coconut oil, or in a mineral
oil such as liquid paraffin. The oily suspensions may contain
a thickening agent, for example beeswax, hard paraffin, or
cetyl alcohol. Sweetening agents and flavoring agents may be
added to provide palatable oral preparations. These
compositions may be preserved by the addition of an antioxidant
such as ascorbic acid.
Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the
active ingredient in admixture with a dispersing or wetting
agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents or suspending agents are
exemplified by those already mentioned above. Additional
excipients, for example sweetening, flavoring, and coloring
agents, may also be present.
Pharmaceutical compositions of the invention may also be
the form of oil-in-water emulsions. The oily phase may be
i vegetable oil or a mineral oil or mixtures of these.
Suitable emulsifying agents may be naturally-occurring gums,
for example gum acacia or gum tragacanth, naturally-occurring
phosphatides, for example soy bean, lecithin, and esters cr
oartial esters derived from fatty acids and hexitol,
anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for
example polyoxyethylene sorbitan monooleate. The emulsions
may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening
agents, for example glycerol, propylene glycol, sorbitol,
glucose or sucrose. Such formulations may also contain a
demulcent, a preservative, and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using
those suitable dispersing or wetting agents and suspending
agents that have been mentioned above. The sterile injectable
preparation may also be a sterile injectable solution or
suspension in a non-toxic parentally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among
the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose
any bland fixed oil may be employed including synthetic monoor
diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
The compounds of general Formula I may also be
administered in the form of suppositories, e.g., for rectal
administration of the drug. These compositions can be
prepared by mixing the drug with a suitable non-irritating
excipient that is solid at ordinary temperatures but liquid at
the rectal temperature and will therefore melt in the rectum
to release the drug. Such materials include cocoa butter and
polyethylene glycols.
Compounds of general Formula I may be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as
local anesthetics, preservatives, and buffering agents can be
dissolved in the vehicle.
The active ingredient may also be administered by
injection (IV, IM, subcutaneous or jet) as a composition
wherein, for example, saline, dextrose, or water may be used
as a suitable carrier. The pH of the composition may be
adjusted, if necessary, with suitable acid, base, or buffer.
Suitable bulking, dispersing, wetting or suspending agents,
including mannitol and PEG 400, may also be included in the
composition. A suitable parenteral composition can also
include a compound formulated as a sterile solid substance,
including lyophilized powder, in injection vials. Aqueous
solution can be added to dissolve the compound prior to
injection.
For disorders of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical gel, spray, ointment or cream, or as a suppository,
containing the active ingredients in a total amount of, for
example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most
preferably 0.4 to 15% w/w. When formulated in an ointment, the
active ingredients may be employed with either paraffinic or a
water-miscible ointment base.
Alternatively, the active ingredients may be formulated
in a cream with an oil-in-water cream base. If desired, the
aqueous phase of the cream base may include, for example at
least 30% w/w of a polyhydric alcohol such as propylene
glycol, butane-l,3-diol, mannitol, sorbitol, glyceroi,
polyethylene glycol and mixtures thereof. The topical
formulation may desirably include a compound, which enhances
absorption or penetration of the active ingredient through the
skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be
administered by a transdermal device. Preferably topical
administration will be accomplished using a patch either of
the reservoir and porous membrane type or of a solid matrix
variety. In either case, the active agent is delivered
continuously from the reservoir or microcapsules through a
membrane into the active agent permeable adhesive, which is in
contact with the skin or mucosa of the recipient. If the
active agent is absorbed through the skin, a controlled and
predetermined flow of the active agent is administered to the
recipient. In the case of microcapsules, the encapsulating
agent may also function as the membrane. The transdermal patch
may include the compound in a suitable solvent system with an
adhesive system, such as an acrylic emulsion, and a polyester
patch. The oily phase of the emulsions of this invention may
be constituted from known ingredients in a known manner.
While the phase may comprise merely an emulsifier, it may
comprise a mixture of at least one emulsifier with a fat or
oil or with both a fat and an oil. Preferably, a hydrophilic
emulsifier is included together with a lipophilic emulsifier,
which acts as a stabilizer. It is also preferred to include
both an oil and a fat. Together, the emulsifier(s) with or
without stabilizer(s) make-up the so-called emulsifying wax,
and the wax together with the oil and fat make up the socalled
emulsifying ointment base, which forms the oily,
lispersed phase of the cream formulations. Emulsifiers and
5tnulsion stabilizers suitable for use in the formulation of
the present invention include Tween 60, Span 80, cetostearyl
alcohol, myristyl alcohol, glyceryl monostearate, and sodium
lauryl sulfate, among others. The choice of suitable oils or
fats for the formulation is based on achieving the desired
cosmetic properties, since the solubility of the active
compound in most oils likely to be used in pharmaceutical
emulsion formulations is very low. Thus, the cream should
preferably be a non-greasy, non-staining and washable product
with suitable consistency to avoid leakage from tubes or other
containers. Straight or branched chain, mono- or dibasic alkyl
esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate,
decyl oleate, isopropyl palmitate, butyl stearate, 2-
ethylhexyl palmitate or a blend of branched chain esters may
be used. These may be used alone or in combination depending
on the properties required. Alternatively, high melting point
lipids such as white soft paraffin and/or liquid paraffin or
other mineral oils can be used.
Formulations suitable for topical administration to the
eye also include eye drops wherein the active ingredients are
dissolved or suspended in suitable carrier, especially an
aqueous solvent for the active ingredients. The antiinflammatory
active ingredients are preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously
0.5 to 10% and particularly about 1.5% w/w. For therapeutic
purposes, the active compounds of this combination invention
are ordinarily combined with one or more adjuvants appropriate
to the indicated route of administration. If administered per
os, the compounds may be admixed with lactose, sucrose, starch
powder, cellulose esters of alkanoic acids, cellulose alkyl
esters, talc, stearic acid, magnesium stearate, magnesium
oxide, sodium and calcium salts of phosphoric and sulfuric
acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then
tableted or encapsulated for convenient administration. Such
capsules or tablets may contain a controlled-release
formulation as may be provided in a dispersion of active
compound in hydroxypropylmethyl cellulose. Formulations for
parenteral administration may be in the form of aqueous or
non-aqueous isotonic sterile injection solutions or
suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the
carriers or diluents mentioned for use in the formulations for
oral administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
The amount of therapeutically active compounds that are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this
invention depends on a variety of factors, including the age,
weight, sex and medical condition of the subject, the severity
of the inflammation or inflammation related disorder, the
route and frequency of administration, and the particular
compound employed, and thus may vary widely. The
pharmaceutical compositions may contain active ingredients in
the range of about 0.1 to 1000 mg, preferably in the range of
about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg
body weight, preferably between about 0.1 and .about 50 mg/kg
body weight and most preferably between about 0.5 to 30 mg/kg
body weight, may be appropriate. The daily dose can be
administered in one to four doses per day. In the case of skin
conditions, it may be preferable to apply a topical
preparation of compounds of this invention to the affected
area two to four times a day.
It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet,
time of administration, route of administration, and rate of
excretion, drug combination and the severity of the particular
disease undergoing therapy.
For administration to non-human animals, the composition
may also be added to the animal feed or drinking water. It may
be convenient to formulate the animal feed and drinking water
compositions so that the animal takes in a therapeutically
appropriate quantity of the composition along with its diet.
It may also be convenient to present the composition as a
premix for addition to the feed or drinking water.
The disclosures in this application of all articles and
references, including patents, are incorporated herein by
reference.
The invention is illustrated further by the following
examples, which are not to be construed as limiting the
invention in scope or spirit to the specific procedures
described in them.
The starting materials and various intermediates, may be
obtained from commercial sources, prepared from commercially
available compounds, or prepared using well-known synthetic
methods.
The compound names in this application were created using
ACD Name Pro version 5.09, or ChemDraw ultra version 6.0.2,
software.
General Synthetic Procedures
Representative procedures for the preparation of
compounds of the invention are outlined below in the Schemes
The starting materials can be purchased or prepared using
methods known to those skilled in the art. Similarly, the
preparation of the various intermediates can be achieved using
methods known in the art. The starting materials may be
varied and additional steps employed to produce compounds
encompassed by the invention, as demonstrated by the examples
below. In addition, different solvents and reagents can
typically be used to achieve the above transformations.
Protection of reactive groups may also be necessary to achieve
the above transformations. In general, the need for
protecting groups, as well as the conditions necessary to
attach and remove such groups, will be apparent to those
skilled in the art of organic synthesis. When a protecting
group is employed, deprotection will generally be required.
Suitable protecting groups and methodology for protection and
deprotection such as those described in Protecting Groups in
Organic Synthesis by Greene and Wuts are known and appreciated
in the art.
Alternatively, the compounds of the instant invention can
be prepared according to the method outlined in Scheme 2.
Scheme 2
(Figure Removed) In Scheme 2, Q at each occurrence is independently alkyl,
halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl,
arylalkoxycarbonyl, CO2H, CN, amidinooxime, NR6R7, NR6R7alkyl,
-C(0)NR6R7, amidino, haloalkyl, or haloalkoxy; and n is 0, 1,
Alternatively, compounds of the invention can be prepared
using the procedures outlined in Schemes 3-25. In Schemes
25, the X, X1, R, R1 , and R' ' substituents on groups such as
aryl, heteroaryl, amine, and alkyl, carry the same definition
described above for substituents on these groups.
(Figure Removed
The invention is illustrated further by the following
examples, which are not to be construed as limiting the
invention in scope or spirit to the specific procedures
described in them. Those having skill in the art will
recognize that the starting materials may be varied and
additional steps employed to produce compounds encompassed by
the invention, as demonstrated by the following examples.
Those skilled in the art will also recognize that it may be
necessary to utilize different solvents or reagents to achieve
some of the above transformations. In some cases, protection
of reactive functionalities may be necessary to achieve the
above transformations. In general, such need for protecting
groups, as well as the conditions necessary to attach and
remove such groups, will be apparent to those skilled in the
art of organic synthesis. When a protecting group is
employed, adeprotection step may be required. Suitable
protecting groups and methodology for protection and
deprotection such as those described in Protecting Groups in
Organic Synthesis by Greene and Wuts are well known and
appreciated in the art.
Unless otherwise specified, all reagents and solvents are
of standard commercial grade and are used without further
purification. The appropriate atmosphere to run the reaction
under, for example, air, nitrogen, hydrogen, argon and the
like, will be apparent to those skilled in the art.
Examples
Example 1
4- (benzyloxy) -1- (4-methylbenzyl)pyridin-2 (IH) -one
4-Benzyloxy-2(IH)-pyridone (3.0 g, 0.015 mol), 4-
methylbenzyl bromide (3.15 g, 0.17 mol), and potassium
carbonate (3.0 g, 0.022 mol) were heated at 80 °C for 2 hours.
Contents were allowed to cool, diluted with water and a solid
(5.52 g) was filtered. FABHRMS m/z 306.1494 (M+H, C20H2oN02
requires 306.1494). XH NMR (CDC13 /300 MHz): 7.50-7.40 (m,
5H); 7.20-7.05 (m, 5H); 6.07-6.00 (m, IH); 5.95-5.90 (m, IH) ;
5.05 (s, 2H); 5.00 (s, 2H); 2.32 (a, 3H).
Anal. Calcd for C2oHi9N02: C, 78.66; H, 6.27; N, 4.59.
Found: C, 78.54; H, 6.38; N, 4.58.
Example 2
4-(benzyloxy)-3-bromo-l-(4-methylbenzyl)pyridin-2(IH)-one
The material prepared in Example I (2.1 g, 0.007 mol) and
sodium acetate (738 mg, 0.009 mol) in glacial acetic acid (15
mL) were cooled to 15 °C. Bromine (0.412 mL, 0.008) in glacial
acetic acid (5 mL) was added dropwise. Concents were stirred
2 hours, coming to room temperature. Water (200 mL) was added
and a light yellow solid was filtered. Mp 150.4 - 151.2°C.
FABHRMS m/z 384.0599 (M+H, C20H19BrN02 requires 384.0601). :K
NMR (CDC13/300 MHz) 5: 7.42-7.30 (m, 5H) ; 7.22-7.08 (m, 5H)
6.02 (d, 1H) ; 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s, 3H).
Anal. Calcd for C20H18BrN02: C, 62.51; H, 4.72; N, 3.65.
Found: C, 62.11; H, 4.48; N, 3.54.
Examples 3-10
The compounds of Examples 3-10 are prepared essentially
according to the procedure set forth above with respect to
Example 1. Compounds wherein RI = Br are prepared essentially
according to the procedure of Example 2.
Example
No.
Ex. 3
Ex. 4
Ex. 5
Ex. 6
Ex. 7
Ex. 8
Ex. 9
RI
-H
-Br
-H
-Br
-H
-Br
-H
R2
4-Br
4-Br
4-C1
4-C1
3-F
3-F
2-F
MF
Ci9Hi6BrN02
C19HlsBr2N02
C19Hi6ClN02
C19HlsBrClN02
C19H1SFN02
Ci9H15BrFN02
C19H16FN02
M+H m/z
Requires
370.0428
447.9522
326.0948
404.0053
310.1243
310.1231
FABHRMS
m/z
370.0443
447.9548
326.0893
404.0035
310.1226
310.1243
-253-
10 -Br 2-F C19H15BrFN02 388.0348 388.0373
NMR characterization of compounds of Examples 3-10
Ex . No .
Ex. 3
Ex. 4
Ex. 5
Ex. 6
Ex. 7
Ex. 8
Ex. 9
Ex. 10
NMR Data
:H NMR (CDC13/300 MHz) 5: 7.43 {d, 2H) ; 7.40-7.33 (m, 5H)
7.07 (m, 3H) ; 6.04-6.01 (m, 1H) ; 6.00-5.92 (m, IK); 5
2H) ; 4.98 (s, 2H)
XH NMR (CDC13/300 MHz) 6: 7.50-7.15 (m, 10H) ; 6
, 2H) , 5.10 (s, 2H)
; 7.20-
03 (s,
06 (d, IK); 5.20
LH NMR (CDC13/300 MH=) 5: 7.40-7.32 (m, 5H) ; 7.24 (AB quartet,
4H) ; 7.10 (d, 1H) ; 6.03-6.00 (m, 1H) ; 5.98-5.92 (m, 1H) ; 5.03
(s, 2H) ; 4.99 (s, 2H)
XH NMR (CDC13/300 MHz) :
(s, 2H) ; 5.10 (s, 2H)
7.43-7.20 (m, 10H) ; 6. 08 (d, 1H) ; 5.20
*H NMR (CDC13/300 MHz) 5: 7.45-7.25 (m, 5H) ; 7.12 (d, 1H)
6.93 (m, 4H) ; 6.04-6.02 (m, 1H) ; 6.00-5.94 (m, 1H) ; 5.
2H) ; 5.00 (s, 2H)
08 (S,
1H NMR (CDClj/300 MHz) 5: 7.43-7.25 (m, 6H) ; 7.21 (d, 1H) ; 7.10-
6.93 (m, 3H) ; 6.08 (d, 1H) ; 5.22 (s, 2H) ; 5.12 (s, 2H)
1H NMR (CDC13/300 MHz) 8: 7.43-7.00 (m, 10H) ,- 6
5.10 (S, 2H) ; 4.99 (s, 2H)
:H NMR (CDC13/300 MHz) :
7.15-7.00 (m, 2H) ; 6.03
7.52 (d Of
(d, 1H) ; 5.20
t, 1H) ; 7.
(S, 2H) ; 5
01-5.92 (m, 2H)
44-7.26 (m, 7H)
15 (s, 2H)
Example 11
4-(benzyloxy)-3-bromopyridin-2(1H)-one
The material of Example 11 was prepared according to the
procedure of Example 2. XH NMR (CDC13/300 MHz) 5: 7.50-7.30
(m, 6H); 6.20 (d, 1H); 5.24 (s, 2H).
Anal. Calcd for Ci2H10BrNO2 (0.3H20): C, 50.48; H, 3.74; N,
4.91. Found: C, 50.79; H, 3.41; N, 4.82.
Examples 12-19
The compounds of Examples 12-19 are prepared assently
accord to the procedures set forth above for e .
compounds -herein are prepared essentially accord .o
the procedure of Example 2.
Example
No.
Ex. 12
Ex. 13
Ex. 14
Ex. 15
EX. 16
Ex. 17
Ex. 18
Ex. 19
Ri
-Br
-H
-Br
-Br
-H
-Br
-K
-Br
R2
,4-
benzyloxy
4-CO2Me
4-C02Me
4-CO2H
4-CN
4-CN
4-tButyl
4-tButyl
MF
C26H22BrN03
C2iH19N04
C2iHi6BrN04
C20H16BrN04
C20H16N202
C20H15BrN202
C23H25N02
C23H24BrN02
M-rH
Requires
476.0861
350.1392
428.0497
414.0341
317.1290
395.0395
348.1964
426.1069
1
FABHRMS
m/z
476.0854
350.1391
428.0480
414.0360
317.1270
395.0376
348.1949
426.1023
NMR characterization of compounds of Examples 12-19
Ex. No. NMR Data
Ex. 12 (CDC13/300 MHZ) =
5^00 (SL2H); 3.95 (s, 3H)
Ex. 14
Ex. 15 H NMR (DMSO-df /300 MHz): 8.00-7.80 (m, 3H); 7.53-7.27 (m, 7H);
6.50 (d, 1H); 5.32 (S, 2H); 5.20 (s, 2H)
Ex. 16
EX. 17 /300 HB.) 6: 7 61 (d, 2H), 7 48-7.30 (.. 6B), 7.23
(d. 2H); 6.12 (d. 1H); 5.22 '•- Ml. 5.20 (s, 2H)
EX. 18
2H)
(CDC13/300 MHZ) S: 7.43-7.20 (..""lOH) ; 6.02 (d, 1H) ; 5.20
(s. 2H); 5.10 (s. 2H); 1.30 (s, 9H) .
EX. 19
Example 20
4-(benzyloxy)-3-bromo-l-ethylpyridin-2(IH)-one
To 4-benzyloxy-2(IH)-pyridone (1.0 g, 0.005 mol) and
potassium carbonate (1.0 g, 0.007 mol) in DMF (10 mL) was
added bromoethane (0.82 mL, 0.011 mol). Contents were heated
at 75°C overnight. Contents were allowed to cool and
partitioned between EtOAc and water. The EtOAc layer was
dried over MgS04, filtered, and concentrated in vacuo leaving a
waxy solid, which was recrystaliized from EtOAc/hexanes to
give a white solid {720 mg) . To the white solid (700 mg,
0,003 mol} in glacial acetic acid (10 mL) , bromine (0.17 mL,
0.00325 mol) in glacial acetic acid (5 mL) was added dropwise
at 15°C. Contents were stirred one hour at room temperature
and a yellow solid (1.1 g) was filtered. The solid was
partitioned between EtOAc and 2.5N sodium hydroxide. The
EtOAc layer was dried over MgSO4, filtered, and concentrated in
vacuo leaving a colorless oil (710 mg) , which solidified.
FABHRMS m/z 310.0267 (M+H, C14H15BrN02 requires 310.0263). Hi
NMR (CDC13/300 MHz) 5: 7.45-7.30 (m, 6H) ; 7.22 (d, IH) ; 6.07
(d, IH); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H).
Anal. Calcd for Ci4Hi4BrNO2: C, 54.56; H, 4.58; N, 4.55.
Found: C, 54.21; H, 4.38; N, 4.43.
Example 21
3-bromo-4-hydroxy-l-(4-hydroxybenzyl)pyridin-2(IH)-one
The material of Example 12 (120 mg, 0.25 mmol) and 10%
palladium/carbon (30 mg) in glacial acetic acid (2 mL) were
shaken at 55 Ibs of hydrogen for 4 hours. Contents were
filtered and the filtrate was concentrated in vacuo leaving an
oil. FABHRMS m/z 295.9952 (M+H, CiaEuBrNOs requires 295.9922).
"-H NWR (DMSO-d6 /300 MHz) 5: 11.40 (br s, 1H) ; 9.40 (br s, 1H) ;
7.60 (d, 1H) ; 7.10 (d, 2H) ; 6.70 (d, 2H) ; 6.02 (d, 1H) ; 4.93
(S, 2H).
Anal. Calcd for C12H10BrN03 (1.4 H20) : C, 44.85; H, 4.02;
N, 4.36. Found: C, 45^07; H, 4.10; N, 4.35.
Example 22
4-(benzyloxy)-3-bromo-l-methylpyridin-2(1H) -one
hydrobromide
H-Br
To 4-benzyloxy-2(1H)-pyridone (1.0 g, 0.005 mol) and
potassium carbonate (760 mg, 0.0055 mol) in DMF (10 mL) was
added methyl iodide (0.342 mL, 0.0055 mol). Contents were
stirred overnight. Contents were partitioned between EtOAc
and water. The EtOAc layer was dried over MgS04/ filtered, and
concentrated in vacuo leaving a white solid (960 mg).
To the white solid (332 mg, 0.0015 mol) in glacial acetic
acid (10 mL) , bromine (256 mg, 0.0016 mol) in glacial acetic
acid (5 mL) was added dropwise at 15°C. Contents were stirred
one hour at room temperature and the desired was filtered as a
white solid, 262 mg (59% yield). mp 105.3-105.6°C. FABHRMS
m/z 296.0097 (M+H, Ci3H13BrN02 requires 296.0110). aH NMR
(CDC13/300 MHz) 8: 7.45-7.30 (m, 6H) ; 7.22 (d, 1H) ; 6.07 (d,
1H); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H).
Anal. Calcd for C13H12BrN02 (HBr, 0.3H20): C, 41.04; H,
3.60; N, 3.68. Found: C, 41.00; H, 3.87; N, 3.52.
Example 23
4-(benzyloxy)-3-bromo-l-methylpyridin-2(1H)-one
The material of Example 22 was partitioned between EtOAc
and 2.5N sodium hydroxide. The EtOAc layer was dried over
MgS04; filtered, and concentrated in vacuo leaving a red oil,
which solidified. FABHRMS m/z 294.0112 (M+H, C13Hi3BrN02
requires 294.0130). XH NMR (CDC13/300 MHz): 7.45-7.30 (m,
6H) ; 7.22 (d, 1H) ; 6.07 (d, 1H) ; 5.20 (s, 2H) ; 4.00 (q, 2H) ;
1.32 (t, 3H).
Anal. Calcd for C13Hi2BrN02: C, 53.08; H, 4.11; N, 4.76.
Found: C, 53.06; H, 4.20; N, 4.74.
Example 24
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl}-
AT1 -hydroxybenzenecarboximidamide
The material of Example 17 (500 mg, 0.00127 mol) ,
hydroxylamine hydrochloride (90 mg, 0.0013 mol) and sodium
bicarbonate (109 mg) were refluxed in ethanol (15 mL)
overnight. Contents were allowed to cool and a solid was
filtered and washed with water to give the desired as a white
solid, 447 mg, (82% yield). mp 210.2-212.2 °C FABHRMS m/z
428.0634 (M+H, C2oHi9BrN3O3 requires 428.0610). XH NMR (DMSO-d5
/ 300 MHz): 9.66 (s, 1H) ; 7.98 (d, 1H) ; 7.65 (d, 2H) ; 7.55-
7.35 (m, 5H) ; 7.30 {d, 2H) ; 6.54 (d, 1H) ; 5.82 (s, 2H) ; 5.35
( s , 2H); 5.17 (s, 2H).
Anal. Calcd for C20Hi83rN303: C, 56.09; H, 4.24; N, 9.81.
Found: C, 55.92; H, 4.01; N, 9.52.
Example 25
4-(benzyloxy)-3-bromo-l-(piperidin-4-ylmethyl)pyridin-
2 (1H) -one hydrochloride
H-CI
To the material of Example 11 (924 mg, 0.0033 mol) in DMF
(5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M
in THF, 3.6 mL). Contents were stirred one hour before adding
dropwise a solution of 4-methanesulfonyloxymethyl-1-
piperidine-1-carboxylic acid tert-butyl ester (J. Labelled
Compd, Radiopharm, 38(7), 1996, 595-606) (1.0 g, 0.0036 mol)
in DMF (5 mL) . Contents were heated at 75°C overnight.
Contents were allowed to cool and poured into water (100 mL) .
A solid was filtered and recrystallized from EtOAc to give
white crystals (546 mg) . The white crystals were refluxed in
4 N HCl/dioxane (10 mL) for 3 hours, allowed to cool and
filtered to give the desired as a white solid, 415 mg (30%
yield). mp 207. 9°C. FABHRMS m/z 377.0852 (M+H, CisaBrClNsOa
requires 377.0865). XH NMR (DMSO-dff/300 MHz) 6: 8,90 (br, 1H)
8.64 {br, 1H) ; 7.80 (d, 1H) ; 7.50-7.30 (m, 5H) ; 6.48 (d, 1H) ;
5.30 (s, 2H) ; 3.83 (d, 2H) ; 3.20 (d, 2H) ; 2.88-2.64 (m, 2H) ;
2.10-1.90 (m, 1H); 1.60 (d, 2H); 1.50-1.40 (m, 2H) .
Anal. Calcd for C18H22BrClN202 (0.3 H20) : C, 51.58; H, 5.43; N,
6.68. Found: C, 51.59; H, 5.42; N, 6.81.
Example 26
4-(benzyloxy)-I-[4-(trifluoromethyl)benzyl]pyridin-2 (IH)
one
The material of Example 26 was prepared according to the
procedure of Example 1. FABHRMS m/z 360.1213 (M+H, C2oHi7F3N02
requires 360.1211). XH NMR (CDC13/300 MHz) 5: 7.60 (d, 2H) ;
7.41-7.30 (m, 7H) ; 7.13 (d, IH) ; 6.05-6.01 (m, IH) ; 6.00-5.95
(m, IH); 5.13 (s, 2H); 5.00 (s, 2H).
Anal. Calcd for C2oHi6F3N02: C, 66.85; H, 4.49; N, 3.90.
Found: C, 66.64; H, 4.26; N, 3.93.
Example 27
4-(benzyloxy)-3-bromo-l-[4-(trifluoromethyl)
benzyl]pyridin-2(IH)-one
The material of Example 27 was prepared according to the
procedure of Example 2. FABHRMS m/z 438.0308 (M+H,
C2oH16BrF3NQ2 requires 438.0316). XH NMR (CDC13/300 MHz) 6:
7.65-7.20 (m, 10H) ; 6.13-6.03 (m, IH) ; 5.30-5.13 (m, 4H) .
Anal. Calcd for C20H15BrF3N02: C, 54.81; H, 3.45; N, 3.20.
Found: C, 54.69; H, 3.34; N, 3.19.
Example 28
4-(benzyloxy)-3-brcmo-l-(piperidin-3-ylmethyl)pyridin
2(lH)-one hydrochloride
To the material of Example 11 (3.1 g, 0.011 mol) in DMF
(20 mL) was added dropwise sodium bis (trimethylsilyl)amide (1M
in THF, 12 mL) . Contents were stirred one hour before adding
dropwise a solution of 3-methanesulfonyloxymethyl-lpiperidine-
1-carboxylic acid tert-butyl ester
(Bioorg.Med.Chem.Lett, 8(13), 1998, 1595-1600) (4.2 g, 0.015
mol) in DMF (5 mL) . Contents were heated at 75°C overnight.
Contents were allowed to cool, poured into water (100 mL) and
a solid was filtered. The solid was stirred in 4 N
HCl/dioxane (15 mL) for 3 hours and filtered to give the
desired as a white solid, 752 mg (18% yield). mp 138.1-
139.2°C. FABHRMS m/z 377.0859 (M+H, C18H22BrN202 requires
377.0865). XH NMR (DMSO-ds /300 MHz): 9.50-9.10 (br, 2H);
8.00 (d, 1H) ; 7.50-7.30 (m, 5H) ; 6.93 (d, 1H) ; 5.30 (s, 2H) ;
4.30-3.90 (m, 3H) ; 3.40-3.10 (m, 3H) ; 2.80-2.50 (m, 3H) ; 2.40-
2.00 (m, 1H) ; 1.90-1.60 (m, 4H); 1.40-1.10 (m, 1H).
Anal. Calcd for C18H21BrN2O2 (2HC1, 0.25 H20) : C, 47.55; H,
5.21; N, 6.16. Found: C, 47.48; H, 5.46; N, 6.27.
Example 29
4- (benzyloxy)-3-bromo-l-(2-thien-3-ylethyl)pyridin-2(1H)-
To the material of Example 11 (500 mg, 0.0018 mol) in DMF
(5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M
in THF, 2 mL) . Contents were stirred one hour before adding
dropwise a solution of methanesulfonic acid 2-thiophen-3-ylethyl
ester (J.A.C.S, 109(6), 1987, 1858-1859) (412 mg, 0.002
mol) in DMF (5 mL) . Contents were heated at 75°C overnight.
Contents were allowed to cool, poured into water (100 mL) , and
extracted into EtOAc, dried over MgS04, filtered, and
concentrated in vacua leaving a light yellow oil. The oil was
purified by silica gel chromatography eluting with 50%
EtOAc/hexanes to give the desired as a white solid, 199 mg
(28% yield). mp 134.0-134 . 3°C.
FABHRMS m/z 390.0144 (M+H, C18H17BrN02S requires 390.0163). XH
NMR (CDC13/300 MHz): 7.43-7.20 (m, 6H) ; 6.92-6.80 (m, 3H) ;
5.90 (d, 1H); 5.20 (s, 2H); 4.13 (t, 2H); 3.10 (t, 2H) .
Anal. Calcd for Ci8Hl6BrN02S: C, 55.39; H, 4.13; N, 3.59.
Found: C, 55.21; H, 3.87; N, 3.52.
Example 30
4- (benzyloxy)-3-bromo-l-(2-thien-2-ylethyl)pyridin-2(1H)-one
The title compound was prepared essentially according to
the procedure of Example 29. mp 128.0-129.5°C. FABHRMS
390.0160 (M+H, Ci8HnBrN02S requires 390.0163). 'H NMR
(CDC13/300 MHz) 6: 7.48-7.30 (m, 5H); 7.12 (d, IE); 6.95-6.80
(m, 2K) ; 6.75-6.68 (m IH) ; 5.95 (d, IH) ; 5.20 (s, 2H) ; 4.15
(t, 2H); 3.30 (t, 2H).
Anal. Calcd for C18HlsBrN02S: C, 55.39; H, 4.13; N, 3.59.
Found: C, 55.06; H, 4.01; N, 3.56.
Example 31
4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl)
benzylIpyridin-2(IH)-one
To the material of Example 11 (500 mg, 0.0018 mol) in DMF
(5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M
in THF, 2 mL) . Contents were stirred one hour before adding
dropwise a solution of 3-trifluoromethylbenzyl bromide (478
mg, 0.002 mol) in DMF (5 mL). Contents were heated at 75°C for
2 hours. Contents were allowed to cool, poured into water
(100 mL), and extracted with EtOAc, which was dried over MgS04,
filtered, and concentrated in vacuo leaving a white solid.
FABHRMS m/z 438.0301 (M+H, C2oHisBrF3N02 requires 438.0316).
NMR (CDC13/300 MHz): 7.60-7.20 (m, 10H) ; 6.10 (d, IH) ; 5.14
(s, 2H); 5.20 (s, 2H).
Anal. Calcd for C2oHisBrF3N02: C, 54.81; H, 3.45; N, 3.20.
i Found: C, 54.81; H, 3.36; N, 3.13.
Example 32
4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl)
benzylIpyridin-2(IH) -one
The material of Example 32 was prepared according to the
procedure of Example 31.
FABHRMS m/z 438.0280 (M+H, C2oHi6BrF3N02 requires 438.0316). 1H
NMR (CDC13/300 MHz) 6: 7.68 (d, IH) ; 7.55-7.20 (m, 8H) ; 7.15
(d, IH); 6.10 (d, IH); 5.40 (s, 2H); 5.13 (s, 2H).
Anal. Calcd for C2oHLsBrF3N02: C, 54.81; H, 3.45; N, 3.20.
Found: C, 54.48; H, 3.36; N, 3.17.
Example 33
4-(benzyloxy)-1-[4-(trifluoromethoxy)benzyl]pyridin-
2 (IH) -one
The material of Example 33 was prepared according to the
procedure of Example 1.
FABHRMS m/z 376.1158 (M+H, CjoH^FsNOs requires 376.1161). aH
NMR (CDC13/300 MHz) 8: 7.40-7.05 (m, 10H) ; 6.05-5.95 (m, 2H) ;
5.06 (S, 2H); 4.98 (s, 2H).
Anal. Calcd for C2oHi6F3N03: C, 64.00; H, 4.30; N;. 3.73.
Found: C, 63.97; H, 4.26; N, 3.57.
Example 34
4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy)
benzyl]pyridin-2(IH)-one
The material of Example 34 was prepared according to the
procedure of Example 2.
FABHRMS m/z 454.0240 (M+H, C2oHisBrF3N03 requires 454.0266). 'H
NMR (CDC13/300 MHz) 5: 7.45-7.10 (m, 10H) ; 6.08 (d, IH) ; 5.20
(s, 2H); 5.12 (s, 2H).
Anal. Calcd for C2oHiSBrF3N03: C, 52.88; H, 3.33; N, 3.08.
Found: C, 52.53; H, 3.09; N, 2.92.
Example 35
1-benzyl-4-(benzyloxy)-6-methylpyridin-2(IH)-one
Step 1: Preparation of 1-benzyl-4-hydroxy-6-
methylpyridin-2(IH)-one.
4-hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and
benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and
heated to reflux with stirring for 2 hours. After cooling to
room temperature, a light brown solid was collected by
filtration. (33.4 g, 77%): 1H NMR (DMSO-d6/300 MHz) 8: 10.5
(s, IH) , 7.4-7.1 (m, 5 H) , 5.8-5.6 (m, 2H) , 5.2 (s,2H), 5.1
(s, 2H) , 2.2 (s, 3H) . ESHRMS m/z 216.100 (M+H, C12H13NO:
requires 216.102).
Step 2: Preparation of l-benzyl-4-(benzyloxy)-6-
methylpyridin-2(IK)-one.
l-benzyl-4-hydroxy-6-r?.ethylpyridin-2 (IH)-one (10 mmol,
2.15 g) , dichloromethane (100 mL) , benzylbromide (11 mmol,
1.88 g) , sodium hydroxide (2.5 N, 20 mmol, 8 mL} , and
benzyltriethylammor.ium chloride (0.5 g) were vigorously
stirred at room temperature for 16h. Hydrochloric acid (1 N)
was added until the mixture produced an acidic reaction to pH
paper. The mixture was then extracted with ethyl acetate (3 X
50 mL) . The combined organic extracts were washed with brine,
dried over magnesium sulfate, filtered, and concentrated. The
product was obtained by flash chromatography eluting with
ethyl acetate : hexanes (1:2). The appropriate fractions were
concentrated to a clear oil. (1.3 g, 43%): XH NMR
300 MHz) 6: 7.4-7.1 (tn, 10 H) , 6.0-5.9 {m, 2H) , 5.2 (s,2H),
5,1 (s, 2H) , 2.2 (S, 3H) . ESHRMS m/Z 306.147 (M+H, C2oHisN02
requires 306.149).
Example 36
l-benzyl-4-(bensyloxy)-3-bromo-6-methylpyridin-2(IH)-one
The product from example 35, l-benzyl-4-(benzyloxy)-6-
methylpyridin-2.(lH)-one (4.2 mmol, 1.3 g) , acetic acid (50
mL) , and sodium acetate (5.0 mmol, 0.41 g) were stirred at
room temperature. Bromine (4.2 mmol, 0.67 g) was added drop
wise with stirring. After X hour, water (100 mL) was added
and the mixture was extracted with ethyl acetate (3 X 50 mL)
The combined organic extracts were washed with saturated
aqueous sodium bicarbonate solution and brine. After drying
over magnesium sulfate and concentrating, the mixture was
purified by flash column chromatography eluting with ethyl
acetate : hexanes (1 : 2) . The appropriate fractions were
concentrated to yield a light oil. (1.0 g, 62%): XH NMR
(DMSO-dg/300 MHz) 7.4-7.0 (m, 10 H), 6.5 (s, 1H), 5.29 (s,2H),
5.27 (s, 2H) , 2.2 (s, 3H) . ESHRMS m/z 384.057 (M+H, C2oH18N02Br
requires 384.060).
Example 37
l-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(1H)-
one
The product from example 35, l-benzyl-4-(benzyloxy)-6-
methylpyridin-2 (IH)-one (4.2 mmol, 1.3 g) , acetic acid (50
mL) , and sodium acetate (5.0 mmol, 0.41 g) were stirred at
room temperature. Bromine (4.2 mmol, 0.67 g) was added drop
wise with stirring. After H hour, water (100 mL) was added
and the mixture was extracted with ethyl acetate (3X50 mL) .
The combined organics were washed with saturated aqueous
sodium bicarbonate solution and brine. After drying over
magnesium sulfate and concentrating, the mixture was purified
by flash column chromatography eluting with ethyl acetate
hexanes (1 : 2) . The appropriate fractions were concentrated
to yield a white solid. (0.3 g, 15%): XH NMR (DMSO-ds/300
MHz) 7.5-7.0 (m, 10 H) , 5.42 (s,2H), 5.07 (s, 2H) , 2.45 (s,
3H) . ESHRMS m/z 463.966 (M+H, C2oHi7N02Br2 requires 463.968) .
Example 38
1-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(IH)-
one
Step 1: Preparation of 1-benzyl-6-methyl-2-oxo-1,2-
dihydropyridin-4-yl 4-bromobenzenesulfonate.
l-benzyl-4-hydroxy-6-methylpyridin-2(IH)-one (from
example 35) (10 mmol, 2.15 g), N,N' -dimethylformamide (30 mL),
potassium carbonate (20 mmol, 2.76 g) , and 4-
bromobenzenesulfonyl chloride (10 mmol, 2.55 g) were stirred
at room temperature for 16 hours. Hydrochloric acid (IN) was
added until the mixture was acidic to pH paper. Brine (50 mL)
was added and the mixture extracted with ethyl acetate (3 X 50
mL). The combined organic extracts were washed with brine and
dried over magnesium sulfate, and filtered. After
concentrating, the material was purified by flash column
chromatography eluting with ethyl acetateihexanes (1:2) . The
approoriate fractions were concentrated to a clear oil, which
solidified upon standing several days to a white solid. (3.3
g, 76%): XHNMR (DMSO-ds/400 MHz) 7.9 (m, 4H) , 7.32-7.00 (m,
5K) , 7.3 (m, 1H) , 6.12 (d, J = 2.4 Hz, 1H) , 6.02 (d, J = 2.S
Hz, 1H) , 5.20 (s, 2H) , 2.2 (s, 3H) . ESHRMS m/z 436.002 (M+H,
C19HlsN04SBr requires 436.004).
Step 2: Preparation of l-benzyl-4-[(3-chlorobenzyl)oxy]-
6-methylpyridin-2(IK)-one.
1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4 -
bromobenzenesulfonate (3.0 mmol, 1.3 g) , N,N'-
dimethylformamide (30 mL) , 3-chlorobenzyl alcohol (3.0 mmol,
0.43 g) , and sodium hydroxide (60%, 3.3 mmol, 0.13 g) were
stirred at room temperature under nitrogen for 4 hours.
Hydrochloric acid (1 N, 10 mL) was added and the mixture
extracted with ethyl acetate (3 X 25 mL) . The combined
organic extracts were washed with saturated aqueous sodium
bicarbonate solution and brine. After drying over magnesium
sulfate and concentrating, the mixture was purified by flash
column chromatography eluting with ethyl acetate:hexanes (1:1)
to obtain a light yellow oil. (14.3 g, 64%): *H NMR (DMSOds/
300 MHz) 5: 7.4-7.0 (m, 10 H), 6.0-5.8 (m, 2H) , 5.2 (s,2H),
5.0 (s, 2H) , 2.1 (s, 3H) . ESHRMS m/z 340.110 (M+H, C2oHlBNOaCl
requires 340.110).
Example 39
1-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-
2(lH)-one
The product of example 38 (SC-83316), l-benzyl-4-[(3-
chlorobensyDoxy] -6-methylpyridin-2 (IH) -one (0.91 mmol,
Mg) , acetic acid (20 mL) , and sodium acetate (0.91 mmol, 80
Mg) were stirred at room temperature when bromine (0.91 mmol,
145 Mg) was added. After stirring for one hour, the mixture
was concentrated, dissolved in ethyl acetate, and washed
successively with saturated aqueous sodium bicarbonate
solution, brine, and water. After drying over magnesium
sulfate and concentrating, the product was recrystallized from
tetrahydrofuran / hexanes to yield a white solid. (240 Mg,
63%): XH NMR (DMSO-d6/300 MHz) 7.6-7.0 (m, 10 H) , 6.5 (s,
IH) , 5.33 (s,2H), 5.33 (s, 2H) , 2.3 (s, 3H) . ESHRMS m/z
420.019 (M+H, C2oHi7N02BrCl requires 420.019).
EXAMPLE 40
l-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2 (IH)-one
The title compound was prepared essentially as described
in claim 1. mp 151.6-152.0 °C. 1H NMR (CDCl3/300MHz) 5: 7.31
(m, 8H), 7.12 (d, IH, J = 7.45 Hz), 6.13 (d, IH, J = 2.42 Ha),
5.90 (dd, IH, J = 2.62 Hz), 5.22 (s, 2H) , 5.10 (s, 2H) .
ESHRMS m/z 360.0551 (M+H Ci9Hi5Cl2NO2 requires 360.0558).
EXAMPLE 41
l-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-
2(IH)-one
l-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(IH)-one
(0.400 g, 1.11 mmol) was dissolved in acetic acid (10 mL) .
Sodium acetate (0.091 g, 1.11 mmol was added, and the mixture
was cooled to 15 °C. Bromine (0.195 g, 1.22 mmol) was added
via syringe. The reaction stirred at room temperature for 2
hours. Water (15 mL) was added, and the mixture transferred
to a separatory funnel. Ethyl acetate (50 mL) was added and
the layers were separated. The organic phase was washed with
aqueous NaHC03 (2 x 25 mL) , dried over MgS04, filtered, and
evaporated to yield a white solid. 1HNMR (CDCl3/300MHz) 5:
7.34 (m, 9H) , 6.24 (d, IH, J = 7.65 Hz), 5.37 (s, 2H) , 5.18
(s, 2H) . ESHRMS m/z 439.9646 (M+H C19Hi4BrCl2N02 requires
439.9641) .
Example 42
l-Benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described in Example 1. mp 124.6-125.0 °C. 1HNMR
(CDCl3/300MHz) 5: 7.36 (m, 9H), 7.14 (d, IH, J = 7.65 Hz), 6.04
(d, IH, J = 2.62 Hz), 5.98 (d, IH, J - 2.82 Hz), 5.10 (s, 2H),
5.09 (s, 2H) . ESHRMS m/z 326.0950 (M+H C19Hi6ClN02 requires
326.0948) .
Anal. Calc'd. for C19Hi6ClNO2: C, 70.05; H, 4.95; N, 4.30; Cl,
10.88. Found: C, 69.87; H, 4.74; N, 4.42, Cl, 11.08.
EXAMPLE 43
l-Benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described in Example 2. mp 143.3-145.5 °C. ^-HNMR
(CDCl3/300MHz) 5: 7.63 (d, 2H, J = 1.81 Hz), 7.44 (m, 9H), 6.06
(d, IH, J = 7.65 Hz), 5.29 (s, 2H), 5.17 (s, 2H). ESHRMS m/z
406. 0016. (M+H. Ci9HisBrClNOa, requires: 406.0032.) .
Anal. Calc'd. for C19H15C1 BrN02: C, 56.39; H, 3.74; N, 3.46;
Cl, 8.76. Found: C, 56.01; H, 3.38; N, 3.36, Cl, 9.01.
EXAMPLE 44
l-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2 (IH)-one
The title compound was prepared by a procedure similar to
the one described in Example 2. mp 149.0-149.7 °C. 1HNMR
(CDCl3/300MHz) 8: 7.25 (m, 10H) , 6.04 (d, IH, J = 7.65 Hz),
5.17 (s, 2H) , 5.15 (s, 2H) , 2.34 '(s, 3H) . ESHRMS m/z 386.0583
(M+H C2oHi8BrN02 requires 386.0581).
EXAMPLE 45
l-Benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described in Example 1. mp 95.5-95.7 °C. XHNMR
(CDC13/300MHZ) 8: 7.34 (m, 9H), 7.13 (d, IH, J = 7.45 Hz), 5.96
-2 731-
(m, IH), 5.95 (d, IH, J 7.45 H z ) , 5.09 (s, 2H), 4.96 (s,
2H) . . ESHRMS m/z 326.0977 (M+H Ci9H16ClN02 requires 326.0948]
EXAMPLE 46
l-Benzyl-4-[benzylthio]-3-bromopyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described in Example 2. mp 180.6-182.1 °C. 1HNMR
(CDC13/300MHZ) 8: 7.33 (m, 10H) , 7.14 (d, IH, J = 7.45 Hz),
6.08 (d, IH, J = 7.45 Hz), 5.13 (s, 2H), 4.15 (s, 2H). ESHRMS
m/z 386.0211 (M+H C19H16BrNOS requires 386.0214).
EXAMPLE 47
l-Benzyl-3-bromo-4-{[2-
(trifluoromethyl)benzyl] oxy}pyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described in Example 2. mp 133.2-133.5 °C. ^-HNMR
(CDC13 / 300MHz) 8: 7.81 (d, IH, J = 7.65 Hz), 7.68 (d, IH, J =
7.65 Hz), 7.6J1 (t, IH, J = 7.65 Hz), 7.38 (nr, 7H-) , 6. OX (d,
IH, J = 7.85 Hz), 5.39 (s, 2H) , 5.16 (s, 2H) . ESHRMS m/Z
438.0313 (M+H C2oHi5BrF3N02 requires 403.0316).
Example 48
l-benzyl-4-(benzyloxy)-3-iodopyridin-2(IH)-one
A mixture of N,0-dibenzyl-2-pyridone (2.0 g, 6.87 mmol) ,
N-iodosuccinimide (1.7 g) , dichloroacetic acid (0.15 mL) in
acetonitrile (40..0 mL) was heated at 65 °C under argon
atmosphere for 3.5 h, with constant stirring. The reaction
mixture was concentrated to dryness, and the residue was
purified by silica gel flash chromatography using EtOAc/
hexanes 1:1 v/v to give the title compound 2.3 g (80%) as a
flaky white solid: XH-NMR (CDC13) 5: 7.4 - 7.2 (m, 10 H) , 7.19
(IH, d, J = 7.6 Hz), 5.95 (d, IH, J = 7.6 Hz), 5.2 (s, IH) ,
5.15 (s, 2H) ; ER-MS m/z = 418 (MH *) ; HR-MS m/z calcd C19Hi7N02
418.0304, found 418.0277.
Example 49
l-benzyl-4-(benzyloxy)-3-vinylpyridin-2(IH)-one
A solution of l-benzyl-4-(benzyloxy)-3-iodopyridin-2(IH)-
one (1.9 g, 4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in
acetonitrile (20 0 mL) containing DMF (2.0 mL) was degassed
using house vacuum and purged with argon. Then added
PdCl2(PPh3)2 (0.3 g) and the mixture was heated at 65 °C under
argon atmosphere for 4 h, with stirring. The solvents were
distilled in vacuo, and the residue was triturated with EtOAc
and filtered through a pad of celite. The filtrate was
concentrated and the residue was purified by silica gel flash
chromatography using 25% EtOAc in hexanes to give the title
compound (0.75 g. 50%) as an orange colored solid.
XH-NMR (CDC13) 8: 7.4-7.2 (m, 10 H) , 7.14 (d, IH, J »
7.6 Hz), 7.05 (dd, IH, J = 12.0 Hz), 6.47 (dd, IH, J = 2.8
Hz), 6.07 (d, IH, J = 7.6 Hz), 5.4 (dd, IH, J - 2.8 Hz), 5.13
(s, 4H) ; ER-MS m/z = 418 (MH +) ; ER-MS m/z = 318 (MH +) ; HR-MS
m/z calcd C2iH2oN02 318.1494, found 318.1480.
Example 50
l-benzyl-4-(benzyloxy)-3-ethylpyridin-2(IH)-one
To a solution of l-benzyl-4-(benzyloxy)-3-vinylpyridin-
2(lH)-one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0
mL) was added Pd/C (10 %, 0.25 g) and stirred in an atmosphere
of hydrogen gas at 30 psi for 16 h. The catalyst was removed
by filtration, the filtrate was concentrated to dryness and
the resulting residue was purified by silica gel flash
chromatography using EtOAc/hexanes (1:1, v/v) to afford the
title compound (0.32 g, 64%) as a pale yellow powder: Hl-NMR
(CD3OD) 8: 7.52 (d, 1H, J = 7.6 Hz), 7.39 - 7.2 (m, 10 H), 6.41
(d, Ih, J = 7.6 Hz), 5.18 (s, 2H) , 5.15 (s, 2H) , 2.58 (q, 2H,
J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz) , ER-MS m/z = 320 (MH +) ;
HR-MS m/z calcd C2iH22N02 320.1651, found 320.1648.
Example 51
3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-6-
methylpyridin-2(IH)-one
Step A
Preparation of 3-acetyl-l-(2-chlorophenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one
A mixture of 2-chlorophenylisocyanate (3.0 g, 19.53
mmol), and diketene (3.3 g, 39.28 mmol) in toluene (10.0 mL)
containing triethylamine (0.05 mL) was heated to reflux for 6
h, under an atmosphere of argon. Toluene was distilled in
vacuo and the resulting residue was purified by silica gel
flash chromatography using 25 % EtOAc in hexanes as the eluent
to afford the title compound (0.85 g, see ref: Heterocycles 27
(9), 2063, 1988.) as a pale yellow solid: ^-NMR (CD3OD) 5:
7.63 (m, IH) , 7.52 (m, 2H) , 7.4 (m, IH) , 6.14 (s, IH) , 2.58
(s, 3H), and 1.95 (s, 3H); ES-MS m/z - 278 ( MH+ ) .
Step B
Preparation of ' 3-acetyl-4-(benzyloxy)-1-(2-chlorophenyl)-
6-methylpyridin-2(IH)-one
To a solution of 3-acetyl-l-(2-chlorophenyl)-4-hydroxy-6-
methylpyridin-2 (IH)-one ( 0.56 g, 2.02 mmol) in DMF (5.0 mL) ,
benzyl bromide (0.3 mL) and potassium carbonate (0.3 g, 2.16
mmol) were added. The mixture was stirred at room temperature
for 3 h, and at 65 °C for 1 h under argon atmosphere. The
reaction mixture was concentrated in vacuo and the residue was
partitioned between 5% citric acid (25 mL) and EtOAc (50.0
mL) . The organic phase was washed with brine, dried (NajSC^),
filtered, and concentrated to dryness. The resulting residue
was purified by silica gel flash chromatography using 50%
EtOAc in hexanes to afford the title compound (0.58 g, 75%) as
a pale yellow amorphous substance: ^-NMR (CD3OD) 8: 7.65 - 7.3
(m, 9H), 6.5 (s, IH), 5.31 (s, 2H), 2.42 (s, 3H), and 2.01 (s,
3H) ; ER-MS m/z = 368 (MH +) ; HR-MS m/z calcd C2iH19N03Cl
,368.1060, found 368.1053.
Example 52
l-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(IH)-one
Step A
Preparation of i-benzyl-3-bromo-4-hydroxypyridin-2(IH)-
one
A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g,
3.7 mmol) , NBS (0.7 g, 1.05 mmol) in dichloromethane was
stirred at room temperature for 1.5 h under argon atmosphere.
It was diluted with dichloromethane (25 mL), cooled and
filtered. The solids were washed with dichloromethane and
dried in vacuo. The filtrate and the washings were combined
and washed with water, dried (Na2S04) , filtered, and
concentrated to dryness. The resulting residue was washed
with EtOAc, and dried in vacuo to give a combined mass of 0.65
g of the title compound as a white powder: XH NMR (CD3OD) 8:
7.54 (d, IH, J = 7.6 Hz), 7.27 (m, 5H) , 6.12 (d, IH, J = 7.6
Hz), 5.15 (s, 2H) ; ES-MS: m/Z = 280 (MH+) .
Step B
Preparation of l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-
4-yl trifluoromethanesulfonate
To a cold (-30 °C ) suspension of l-benzyl-3-bromo-4-
hydroxypyridin-2(IH)-one (0.78 g, 2.8 mmol) in dichloromethane
(10.0 mL), was added triethylamine (0..6 mL, 4.28 mmol ),
followed by the addition of triflic anhydride (0.7 mL, 4.17
mmol) . The resulting mixture was stirred at -30 °C under
argon atmosphere for 1 h. The reaction mixture was then
poured into ice/water mixture (50 mL) and the products were
extracted with dichloromethane (2 x 25 mL) . The combined
organic extracts were washed with water (2 x 20 mL) , dried
(Na2S04) , filtered, and concentrated to dryness. The residue
was dried in vacuo to afford the desired trifluorosulfonate
(1.0 g) as a pale yellow solid which used as such in the next
Step: XH- NMR (CDC13) 8: 7.35 (m, 6H) , 6.26 (d, IH, J = 8.0
Hz); 19F- NMR (CDC13) 5: -73.73 ppm; ES-MS: m/z = 412 (MH*) .
Step C
Preparation of l-benzyl-3-bromo-4-(phenylethynyl)pyridin-
2(IH)-one.
a solution of l-benzyl-3-bromo-2-oxo-l,2-
dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g) in DMF
(5.0 mL) was added phenylacetylene (0.4 mL) and degassed using
house vacuum. The reaction flask was then purged with argon,
added diisopropylethylamine (0.53 mL) , and PdCl2(PPh3)2 (0.35
g) were added. The resulting mixture was stirred at room
temperature for 15 min and heated at 65 °C underr an-
atmosphere for 3h. The dark colored reaction mixture was
concentrated in vacuo, and the residue was partitioned between
EtOAc (50 mL) and 5% aqueous citric acid (25 mL) . The organic
extracts were washed with water, dried (Na2S04) , filtered, and
concentrated to dryness. The resulting material wa's purified
by silica gel flash chromatography using 25% EtOAc in hexanes
as the eluent . The appropriate fractions were combined,
concentrated under reduced pressure. XH NMR (CDC13) 8: 7.57 (m,
2H) , 7.38 (m, 8H) , 7.21 (d, IH, J = 6.8 Hz), 6.25 (d, IH,
6.8 Hz), and 5.16 (d, 2H) , ES-MS: m/z = 364 (MH+) ;
HR-MS m/z (MH+) calcd C20HiSNOBr 364.0337, found 364.0337.
Step D
Preparation of 1-benzyl-3-bromo-4-(2-phenylethyl)pyridin-
2(IH)-one.
A mixture of 1-benzyl-3-bromo-4-(phenylethynyl)pyridin-
2(lH)-one (0.3 g) , and platinum oxide (0.05 g) in a solvent
mixture of EtOAc (10.0 mL) and EtOH ( 10.0 mL) was stirred in
an atmosphere of hydrogen at 15 psi in a Fischer porter bottle
for 45 min. The catalyst was removed by filtration, and
filtrate was concentrated. The resulting residue was purified
by silica gel flash chromatography using 25% EtOAc in hexanes
as the eluent. The appropriate fractions (visualized under an
UV lamp) were combined and concentrated under reduced
pressure. 1H- NMR (CD3OD) 5: 7.56 (d, IH, J = 6.8 Hz), 7.31
7.17 (m, 10 H) , 6.24 (d, IH, J = 6.8 Hz), 5.19 (s, 2H.) , 2.96
(m, 2H) , and 2.91 (m, 2H) ; ES-MS m/z = 368 (MH+) ; HR-MS m/z
(MH+) calcd C20Hi9NOBr 368.0650, found 368.0630.
Example 53
3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-
phenylethyl)pyridin-2(IH)-one
The title compound was prepared essentially according to the
procedure of Example 52. XH- NMR 8: (CD3OD) 6: 7.35 (m, IH) ,
7.31-7.16 (m, 5H) , 6.99(m, IH) , 6.91 (m, IH) , 6.81 (m, IH) ,
6.20 (s, IH) , 5.41 (s, 2H) , 2.94 (m, 4H) , and 2.24 (s, 3H) ;
19F-NMR (CD3OD) 5: -IIB.OI (m) ; ES-MS, m/z = 400 (MH+) ; HR-MS
m/z calcd C2iHa0NOBrF 400.0712, found 400.0695.
Example 54
4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6-
methylpyridin-2(IH)-one
Step A
Preparation of 3-acetyl-l-(2,6-dichlorophenyl)-4-hydroxy-
6-methylpyridin-2(IH)-one
A mixture of 2,6 dichlorophenylisocyanate (4.8 g, 0.025
mol), and diketene (4.3 g, 0.05 mol) in toluene (15.0 mL) was
heated to reflux for 4 h under an atmosphere of argon. After
removal of the solvent in vacuo, the residue was purified by
silica gel flash chromatography using EtOAc/hexanes (1:3 v/v).
The appropriate fractions, as monitored by ES mass
spectrometry (MH + m/z = 312) were combined and concentrated
under reduced pressure. The resulting yellow solid (2.3 g)
was further purified by reverse-phase HPLC using 10-90%
acetonitrile/water gradient (45 min) at a flow rate of 100
mL/min. The appropriate fractions, as monitored by ES mass
spectrometry (MH + m/z = 312) were combined and concentrated to
half the volume. The solid that separated was extracted with
EtOAc ( 2 x 25 mL) . The combined extracts were washed with
water, dried (Na2S04) , filtered, and concentrated to dryness to
give the title compound (0.77 g) as a pale yellow powder: 1HNMR
(CD3OD) 5: 7.62 (m, 2H) , 7.52 (m, IH) , 6.19 (s, IH) , 2.59
(s, 3H) , and 1.96 (s, 3H) ; ES-MS m/z = 312 (MH+) ; HR-MS, m/z
calc Ci4H12N03Cl2 312.0189, found 312.0214.
Step B.
Preparation of
methylpyridin-2(IH)-one
1-(2,6-dichlorophenyl)-4-hydroxy-6-
A mixture of 3-acetyl-l-(2,6-dichlorophenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one 0.7 g (0.002mol) in n-butanol(3.0 mL)
containing sulfuric acid (1.5 mL) was heated at 120 °C for 4
h. The dark reaction mixture was cooled, added ice/water (25
mL) , and extracted with EtOAc (2 x 25 ml) . The combined
organic extracts were washed with water, dried (Na2S04) ,
filtered, concentrated under reduced pressure and the
resulting material was purified by silica gel flash
chromatography using 25% EtOAc in hexanes as the eluent to
afford the title compound (0.14 g) as a pale yellow powder: 1HNMR
(CD30D) 8: 7.6 (m, 2H) , 7.48 (m, IH) , 6.10 (dd, IH) , 5.78
(d, IH, J = 2.4 Hz), 1.91 (a, 3H) ; ES-MS m/z = 270 (MH* ); HRMS,
m/z calc Ci2H10N02Cl2 270.0083, found 270.0103.
Step C
Preparation of 4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-
methylpyridin-2(IH)-one
A mixture of 1-(2,6-dichlorophenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one (0.125 g, 0.46 mmol) and
benzylbromide (0.1 mL) in DMP (2.5 mL) was stirred at room
temperature for 16 h. The reaction mixture was diluted with
water (10.0 mL) and extracted with EtOAc (2 x 20 mL) . The
combined organic extracts were washed with water, dried
(Na2S04) , filtered, concentrated under reduced pressure and the
resulting material was purified by silica gel flash
chromatography using 25% EtOAc in hexanes to afford the title
compound (0.11 g) as a pale yellow syrup: 1E- NMR (CD3OD) 5:
7.61 (m, 2H), 7.55-7.3 (m, 6H), 6.23 (d, IH, J = 2.0 Hz), 6.01
(d, IH, J = 2.0 Hz), 5.12 (s, 2H) , and 1.93 (s, 3H) ; ES-MS
m/z=360 (MH+) ; HR-MS, m/z calc
360.0569.
360.0553, found
Step D
Preparation of 4- (benzyloxy) -3-bromo-l- (2, 6-
dichlorophenyl) -6-methylpyridin-2 (IH) -one
A mixture of 4- (benzyloxy) -1- (2, 6 -dichlorophenyl) -6-
methylpyridin-2 (IH) -one ( 0.1 £, 0.278 mmol) and Nbromosuccinimide
(0.055 g, 0.3 mmol) in dichloroethane (3.0
mL) was stirred at room temperature for 1 h, and heated at 60
°C under argon for 30 min. The reaction mixture was then
diluted with dichloroethane (15 mL) , washed with water, dried
(Na2S04) , filtered, and concentrated under reduced pressure.
XH NMR (CD3OD) 5: 7.64 (m, 2H),-7.55 (m, 3H) , 7.38 (m, 3H)
6.65 (s, IH) , 5.34 (s, 2H) , and 2.00(s, 3H) ; ES-MS m/z = 439
(MH+ ) ; HR-MS, m/z calc Ci9HiSNO2Cl2Br, 439.9635, found 439.9669.
Example 55
3-bromo-l- (3-fluorobenzyl) -4- (2-phenylethyl) pyridin-
2 (IH) -one
The title compound was prepared essentially according to
the procedure of Example 52. 1H- NMR (CD3OD) 6: 7.58 (d, IH, J
= 6.8 Hz), 7.4-7.0 (m, 9H), 6.26 (d, IH. J = 6.8 Hz), 5.19 (s,
2H) , 2.97 (m, 2H) , and 2.90 (m, 2H) ; ES-MS m/z = 386 (MH+) ; HRMS,
m/z calc C2oH18NOFBr, 386.0550, found 386.0585.
Example 56
l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl
methyl(phenyl)carbamate
Step A
Preparation of 1-benzyl-2-oxo-1, 2-dihydropyridin-4-yl
methyl(phenyl)carbamate
/
To a chilled solution of l-benzyl-4-hydroxypyridin-2(IH)-
one (0.375 g, 1.86 mmol) in anhydrous acetonitrile (10 mL) was
added triethylamine (0.206 g, 2.04 mmol) followed by N-methyl-
N-phenylcarbamoyl chloride (0.379 g, 2.24 mmol). The reaction
mixture was stirred under nitrogen atmosphere at 0°C for 30.
min then at room temperature for Ih. The reaction was
monitored by TLC (5% methanol in dichloromethane). The
solvent was removed under reduced pressure and the residue was
washed: with: l.Q% citric acid and extracted witte EtdAc-;- The*
organic extracts were combined, washed with water dried over
anhydrous Na2S04, and filtered. The solvent was removed under
reduced pressure to afford a yellow syrup. The residue was
purified by flash chromatography (silica gel) using 5% MeOH in
CH2C12 to give the desired product (0.382g, 61%) as a white
semisolid.
MS and -NMR were consistent with the desired structure.
XH-NMR (ds-DMSO, 400 MHz) 5: 7.8 (d, 1H) , 7.39 (m, 10H) , 6.19
(s, 2H) , 5.03 (s, 2H) , 3.29 (s, 3H) ; HR-MS (ES) m/z calcd for
C2oH18N203 (MH+) = 335.1396, observed 335.1418.
Step B
1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl
methyl(phenyl)carbamate
O
To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl
methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH2C12
(7 mL) was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol).
The reaction was stirred overnight at room temperature under
nitrogen atmosphere. The reaction mixture was purified by
flash chromatography (silica gel) using EtOAc/hexanes (1:1
v/v). The appropriate fractions were collected according to
ES MS (M+H 413) and concentrated. The dried product showed
about 14% of di-brominated product by analytical HPLC. The
compounds were separated by reverse phase HPLC using a 10-90%
acetonitrile in water, 30 min gradient at a 100 mL/min flow
rate, to afford (after lyophilization) the salt of the desired
compound. The salt was diluted in EtOAc and washed with
NaHC03. The organic extracts were dried over anhydrous Na2S04/
and concentrated to afford the desired compound
(0.271 g, 58%) as a beige solid.
MS and 1H-NMR were consistent with the desired structure.
XH-NMR (d6-DMSO, 400Hz) 6: 7.83 (d, IH) , 7.39 (m, 10H) , 6.48
(s, IH) , 5.12 (S,2H), 3.33 (s, 3H) ; HR-MS (ES) m/z calcd for
C2oHi703Br (MH+) = 413.0495, observed 413.0496.
Example 57
4-(benzyloxy)-3-ethynyl-l-(3-fluorobenzyl)pyridin-2(IH)
one
Step A
Preparation of
iodopyridin-2(IH)-one
4-(benzyloxy)-1-(3-fluorobenzyl)-3-
Heated a 'reaction mixture of 4-(benzyloxy)-1-(3-
fluorobenzyl)pyridin-2(IH)-one (4.83 g, 15.6 mmol) in
anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS,
3.86 g, 17.1 mmol) under nitrogen atmosphere at 65° C for 4 h.
The reaction mixture was concentrated under reduced pressure
and the residue was purified by flash chromatography (silica
gel) using EtOAc/hexanes (1:1 v:v). The appropriate fractions
were collected according to ES MS (M+H 436) and washed with
Na2SO3 to remove the color impurities. The fractions were
concentrated under reduced pressure and dried in vacuo to
afford the desired product (6.15 g, 90%) as a light yellow
solid.
MS and -"-H-NMR were consistent with the desired structure.
H-NMR (CD3OD, 400Hz) 8: 7.73 (d, 1H) , 7.47 (d, 2H) , 7.39 (m,
4H) , 7.08 (m, 3H) , 6.39 (d, 1H) , 5.29 (s, 2H) , 5.19 (s, 2H) ;
HR-MS (ES) m/z calcd for C19HiSNO2FI (MH+) = 436.0210, observed
436.0196.
Step B
Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-
[(trimethylsilyl)ethynyl]pyridin-2(1H)-one
Degassed a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-
3-iodopyridin-2 (1H)-one (2.01 g, 4.62 mtnol) in anhydrous
acetonitrile (25 mL) under argon atmosphere. Triethylamine
(1.11 g, 11 mtnol) was added and quickly degassed. The
reaction mixture was chilled in an ice bath for 15 minutes
before adding bistriphenylphosphine-palladium chloride (0.34
g, 0.48 mmol) and cuprous iodide (0.2 g) . The reaction was
stirred at room temperature for 30 min before heating at 60° C
under an atmosphere of argon for 2 h. The reaction mixture
was filtered through a bed of celite and the filtrate was
concentrated under reduced pressure. The dark brown residue
was diluted with CH2C12 (100 mL) and washed with water. The
organic extracts were combined, dried over anhydrous Na2S04,
filtered, and concentrated under reduced pressure. The dark
brown residue was purified by flash chromatography (silica
gel) using 30% EtOAc In hexane. The appropriate fractions
were combined and concentrated under reduced pressure to
afford the desired product (1.34 g, 72%) as a light yellow
solid.
MS and Hl-NMR were consistent with the desired structure.
Hl-NMR (CD3OD, 400Hz) 6: 7.74 (d, IH) , 7.47 (d, 2H) , 7.35 (m,
4H) , 7.09 (m, 3H) , 6.46 (d, IH) , 5.26 (s, 2H) , 5.13 (s, 2H) ,
0.18 (s, 9H) ; HR-MS (ES) m/z calcd for C24H24N02FSi (MH+) =
406.1638, observed 406.1610.
Step C
Preparation of 4-(benzyloxy)-3-ethynyl-l-(3-
fluorobenzyl)pyridin-2(IH)-one
To a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-
[(trimethylsilyl)ethynyl]pyridin-2(IH) -one (1.31 g, 3.2 mmol)
in anhydrous acetonitrile (25 mL) at 0° C was added
tetrabutylammonium fluoride (0.611g, 1.93 mmol). The reaction
was stirred at 0° C for 15 min then for 1 h at room
temperature. The reaction was concentrated under reduced
pressure and the residue was diluted with EtOAc and washed
with water. The organic extracts were combined, dried over
anhydrous Na2S04, filtered, and concentrated under .reduced
pressure. The residue was purified by flash chromatography
(silica gel) using EtOAc in hexanes (1:1 v/v). The
appropriate fractions were combined and concentrated under
reduced pressure to afford the desired product (0.779 g, 72%)
as a gold solid.
MS and -NMR. .were consistent with the desired structure.
Hl-NMR (CD3OD, 400HZ) 5: 7.73 (d, IH) , 7.43 (d, 2H) , 7.35
(m,4H), 7.09 (m, 3H) , 6.45 (d, IH) , 5.27 (s, 2H) , 5.13 (s,2H),
3.78 (s, IH) ; HR-MS (ES) m/z calcd for C2iHi6N02F (MH*) =
334.1243, observed 334.1234.
Example 58
4-(benzyl amirio)-3-bromo-l-(3-fluorobenzyl)pyridin-2(IH)-
one
Step A
Preparation of 1- (3-f luorobenzyl) -4-hydroxypyridin-2 (IH)
one
In a Fischer-Porter bottle, added a solution of 4-
(benzyloxy) -1- (3-f luorobenzyl )pyridin- 2 (IH) -one (4.5 g, 14.56
mmol) in absolute ethanol (20 mL) . Flushed the solution with
nitrogen then added palladium catalyst (1.05 g) . Sealed
bottle and evacuated system. The system was purged with
hydrogen gas (2 X 15 psi) to check for leaks. The reaction
was charged with hydrogen (35 psi) and stirred at room
temperature for 45 min. The system was evacuated and flushed
with nitrogen. The reaction was filtered and the catalyst was
carefully washed with fresh ethanol. The filtrate was
concentrated under reduced pressure.
MS and -NMR were consistent with the desired structure.
(CD3OD, 400Hz) 5: 7.54 (d, IH) , 7.32 (m, IH) , 7.06 (m,
3H), 6.05 (dd, IH), 5.83 (s, IH) , 5.09 (a, 2H) ; HR-MS (ES) m/z
calcd for Ci2H10N02F /MH+)= 220.0774, observed 220.0787.
Step B
Preparation of 4- (benzylamino) -1- (3-fluorobenzyl)pyridin-
2 (IH) -one
Heated a reaction mixture of 1-(3-fluorobenzyl)-4-
hydroxypyridin-2(IH)-one (1.005 g, 4.5 mmol) in benzylamine
(15 mL) at reflux (185° C) under nitrogen atmosphere for 24 h.
The reaction was monitored by ES-MS (MH+ 309) . The solvent
was removed by vacuum distillation to give a yellow residue.
MS and XH-NMR were consistent with the desired structure.
-NMR (CD3OD, 400Hz) 8: 7.31 (m, 7H) , 7.03 (m, 3H) , 5.98 (dd,
IH) , 5.45 (S, IH) , 5.00 (s, 2H) , 4-.30 (s, 2H) ; HR-MS (ES) m/Z
calcd for N2OF (MH+) - 309.J403, observed 309.1375.
Step C
Preparation of
fluorobenzyl)pyridin-2(IH)-one
4-(benzylamino)-3-bromo-l-(3-
R
To a solution of 4-(benzylamino)-1-(3-
fluorobenzyl)pyridin-2(IH)-one (C.50 g, 1.62 mmol) in
anhydrous CH2C12 (10 mL) was added N-bromosuccinimide (NBS,
0.3Q g, 1.7 mmol). The reaction was stirred, at. room
temperature under a nitrogen atmosphere for 3 h. The reaction
mixture was purified by flash chromatography (silica gel)
using EtOAc in hexanes (1:1 v/v) . The appropriate fractions
were combined and concentrated.
MS and H-NMR were consistent with the- desired structure.
Hl-NMR (CD3OD, 400Hz) 5: 7.41 (d, 1H) , 7.31 (m, 6H) , 7.04 (m,
3H) , 5.99 (d, 1H) , 5.08 (s, 2H) , 4.53 (s, 2H) ; HR-MS (ES) m/z
calcd for Ci9H16N2OFBr (MH+) = 387 . 0508 ,. observed 387.0504.
Example .59
3-Bromo-l-cyclopropylmethyl-4-(4-fluorobenzyloxy)-
IH-pyridin-2 -one
Step 1. Preparation of 4-[(4-Fluorobenzyloxy]pyridine-loxide.
To an ice-cold solution of sodium hydride (1.9 g, of a 60%
dispersion in mineral oil, 46 mmol) in DMF (39 mL) was added
4-fluorobenzyl alcohol (5.1 mL, 46 mmol). The reaction
mixture was warmed to room temperature, 4-chloropyridine-loxide1
(5.0 g, 39 mmol) was added, and the reaction mixture was
stirred for 6 h. The reaction mixture was diluted with .a 50%
aqueous solution of brine, and extracted with CHC13 (7 x 50
mL) . The combined organics were dried (MgS04) , filtered, and
concentrated under reduced pressure. Trituration with EtaO
afforded 4-[(4-fluorobenzyloxy]pyridine-1-oxide as an offwhite
solid (9.1 g, 90%), which was used in the next step
without further purification or characterization.
Step 2. Preparation of 4-(4-Fluorobenzyloxy)-lH-pyridin-2-
one.
A solution of 4-[(4-fluorobenzyloxy]pyridine-1-oxide (6.4 g,
29 mmol) in acetic anhydride (97 mL) was heated at reflux for
3 h. The reaction mixture was cooled to room temperature and
the solvent was removed under reduced pressure. The residue
was diluted with 1:1 MeOH/water (34 mL), and the mixture was
stirred at room temperature for 1 h. The solvent was removed
under reduced pressure. Trituration with Et20/hexanes afforded
4-(4-fluorobenzyloxy)-lH-pyridin-2-one as a brown solid (3.1
g, 48%): *H NMR (300 MHz, CDC13) 5 7.40-7.36 (m, 2H) , 7.22 (d,
J = 8 Hz, 1H) , 7.09 (t, J = 7 Hz, 2H), 6.03 (dd, J = 7, 3 Hz,
1H), 5.94 (d, J = 3 Hz, 1H), 4.98 (s, 2H).
Step 3. Preparation of 3-Bromo-4-(4-fluorobenzyloxy)-1Hpyridin-
2-one.
To an ice-cold solution of 4-(4-fluorobenzyloxy)pyridine-
2(lH)-one (3.1 g, 14 mmol) in AcOH (26 mL) was added a
solution of bromine (0.79 mL, 15 mmol) in AcOH (51 mL) , and
the reaction mixture was stirred at room temperature for 2 h.
The solvent was removed under reduced pressure, and
purification by flash column chromatography (silica, 1:1
Et20/hexanes) to afford 3-bromo-4-(4-fluorobenzyloxy)-1Hpyridin-
2-one as an orange solid (0.78 g, 48%): MS APCI mlz
298 [M + H] + .
Step 4. Preparation of 3-Bromo-l-cyclopropylmethyl-4-(4-
fluorobenzyloxy)-lH-pyridin-2-one.
To a solution of 3-bromo-4-(4-fluorobenzyloxy)-lH-pyridin-2-
one (0.25 g, 0.84 mmol) in DMF (13 mL) was added K2C03 (0.33 g,
1.7 mmol) and cyclopropylmethyl bromide (0.14 g, 1.0 mmol),
and the reaction mixture was stirred at 110 °C for 2 h. The
reaction mixture was cooled to room temperature, and the
solvent was removed under reduced pressure. The residue was
diluted with a 50% aqueous solution of brine, and extracted
with CHC13 (3 x 50 mL) . The combined-organics were washed with
water and then brine, dried (MgS04) , filtered, and concentrated
under reduced pressure. Purification by flash column
chromatography (silica, 1:1 EtOAc/hexanes) afforded 3-bromo-lcyclopropyl-
methyl-4-(4-fluorobenzyloxy)-lH-pyridin-2-one as a
yellow solid (0.12 g, 39%): mp 139-141 °C; *H NMR (300 MHz,
CDC13) 5 7.43-7.34 (m, 3H), 7.07 (t, J = 9 Hz, 2H), 6.06 (d, J
= 6 Hz, 1H), 5.19 (S, 2H), 3.82 (d, J = 9 Hz, 2H), 1.26-1.23
(m, 1H), 0.62-0.57 (m, 2H), 0.40-0.36 (m, 2H). ESHRMS m/z
352.0368 (M+H C16H16BrFN02 requires 352.0343)
Examples 60-69
The compounds of Examples 60-69 are prepared essentially
according to the procedures set forth above for Example 59.
Example
No.
Ex. 60
Ex. 61
Ex. 62
Ex. 63
R
pyridin-4-ylmethyl
pyridin-3-ylmethyl
4 - tert-butylbenzyl
3-trifluoromethylbenzyl
MF
C18H14BrFN202
C23H23BrFN02
C20H14BrF4N02
M+H
Requires
489.0296
444.0969
456.0217
ESHRMS
m/z
489.0281
444.0971
456.0202
Ex. 64
Ex. 65
Ex. 66
Ex. 67
Ex. 68
Ex. 69
Biphenyl-2-ylmethyl
4 -methoxybenzyl
4 - cyanobenzyl
4 - trif luoromethylbenzyl
Biphenyl-4-ylmethyl
cyclohexyl methyl
C25Hi9BrFN02
C2oHi7BrFN03
C2oHi4BrFN2O2
C2oH14BrF4NO2
C25H19BrFN02
Ci9H21BrFN02
464.0656
418.0449
413.0295
456.0217
464.0656
394.0812
464.0656
418.0457
413.0287
456.0192
464.0653
394.0797
NMR characterization of compounds of Examples 12-19
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
Ex.
No.
60
61
62
63
64
65
66
67
68
69
NMR Data
JH NMR (300 MHz, CDC13) 5 8.57 (dd, J" = 6, 3 Hz, 2H) , 7.43-7.38
(m, 2H) , 7.16 (d, J = 6 Hz, 2H) , 7.09 (t, J = 9 Hz, 2H) , 6.12
(d, J = 6 Hz, 1H) , 5.20 (s, 2H) , 5.16 (s, 2H)
H NMR (300 MHz, CDC13) 6 8.58-8.55 (m, 2H) , 7.75 (d, J = 6 Hz,
1H) , 7.41-7.37 (m, 2H) , 7.31-7.26 (m, 2H) , 7.12-7.04 (m, 2H) ,
5.17 (d, J = 6 Hz, 1H) , 5.18 (s, 2H) , 5.16 (s, 2H)
H NMR (300 MHz, MeODJ 6 7.75 (d, 1H, J = 9 Hz), 7.59 (t, J * 9
Hz, 2H) , 7.37 (d, J » 9 Hz, 2H) , 7.22 (d, J = 9 Hz, 2H) , 7.06-
6.99 (m, 2H) , 6.52 (d, J = 9 Hz, 1H) , 5.29 (s, 2H) , 5.18 (s,
2H) , 1.28 (s, 9H)
H NMR (300 MHz, CDC13) 6 7.58-7.37 (m, 5H) , 7.29-7.26 (m, 2H) ,
7.08 (t, J = 7 Hz, 2H) , 6.10 (d, J = 7 Hz, 1H) , 5.20 (s, 2H) ,
5.18 (s, 2H)
JH NMR (300 MHz, CDC13) 5 7.42-7.27 (m, 11H) , 7.07 (t, J = 6 Hz,
2H) , 6.72 (d, J - 7 Hz, 1H) , 5.88 (d, J - 9 Hz, 1H) , 5.16 (s,
2H) , 5 . 1 2 (s, 2H)
LR NMR (300 MHz, CDC13) d 7.38-7.36 (m, 2H) , 7.27-6.84 (m, 3H) ,
7.08 (3, 2H) , 6.86 (d, J = 7 Hz, 2H) , 6.01 (d, J = 6 Hz, 1H) ,
5.15 (s, 2H) , 5.09 (s, 2H) , 3.78 (s, 3H)
^H NMR (300 MHz, CDC13) d 7.64-7.61 (m, 2H) , 7.42-7.37 (m, 4H) ,
7.27-7.25 (m, 1H) , 7.12-7.06 (m, 2H) , 6.11 (d, J = 6 Hz, 1H) ,
5.19 (s, 4H)
'H NMR (300 MHz, CDC13) 6 7.59 (d, J « 6 Hz, 2H) , 7.43-7.37 (m,
4H) , 7.29-7.25 (m, 1H) , 7.08 (t, J = 6 Hz, 2H) , 6.08 (d, J - 9
Hz, 1H) , 5.20 (s, 2H) , 5.18 (s, 2H)
1H NMR (300 MHz, CDC13) 5 7.57-7.54 (m, 4H) , 7.45-7.34
(m, 7H), 7.30-7.26 (m, 1H) , 7.08 (t, J = 9 Hz, 2H) ,
6.06 '(d, J = 6 Hz, 1H) , 5.20 (s, 2H) , 5.17 (s, 2H)
H NMR (300 MHz, CDC13) 6 7.93 (d, J = 6 Hz, 1H) , 7.45-7.40 (m,
2H) , 7.29-7.26 (m, 1H) , 7.09 (t, J = 9 Hz, 2H) , 6.50 (d, J = 6
Hz, 1H) , 5.17 (s, 2H) , 4.14 (d, J = 6 Hz, 2H) , 1.90-1.74 (m, .
5H) , 1.32-1.05 (m, 5H)
Example 70
{3- [3-Bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
benzyl}carbamic acid tert-butyl ester
Step 1. Preparation of 3-Hydroxymethylbenzonitrile.
To an ice-cold solution of 3-cyanobenzaldehyde (5.0 g, 38
tnmol) in 1:1 MeOH/THF (90 mL) was added NaBH4 (1.6 g, 42 mmol),
and the reaction mixture was stirred for 3 h. The reaction
mixture was diluted with brine, and the solvent was removed
under reduced pressure. The residue was dissolved in water,
and the aqueous layer was extracted with Et20 (3 x 100 mL).
The combined organics were washed with brine, dried (MgSO4) ,
filtered, and concentrated under reduced pressure to provide
3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil,
which was used in the next step without further purification
or characterization.
Step 2. Preparation of 3-(tert-
Butyldimethylsilyloxymethyl)benzonitrile.
To an ice-cold solution of 3-hydroxymethyl benzonitrile (4.95
g, 37 mmol) in CH2C12 (47 mL) was added imidazole (5.1 g, 74
mmol), DMAP (0.45 g, 3.7 mmol), and TBSC1 (6.2 g, 41 mmol),
and the reaction mixture was stirred for 12 h. The reaction
mixture was diluted with water, and the aqueous layer was
extracted with CH2C12 (3 x 150 mL). The combined organics were
washed with brine, dried (MgS04) , filtered, and concentrated
under reduced pressure to provide 3-(tertbutyldimethylsilyloxymethyl)-
benzonitrile (9.1 g, 99%) as a
clear oil: XH NMR (300 MHz, CDC13) 6 7.51 (s, 1H), 7.42 (d, J =
6 Hz, 1H) , 7.35-7.28 (m, 1H), 4.75 (s, 2H), 0.94 (s, 9H), 0.11
(s, 6H) .
Step 3. Preparation of 3-(tert-
Butyldimethylsilyloxymethyl)benzylamine.
To an ice-cold solution of 3-(tertbutyldimethylsilyloxymethyDbenzoriitrile
(4.5 g, 18 mmol) in
THF (47 mL) was added LiAlH4 (27 mL, of a 1 M solution in THF,
27 mmol), and the reaction mixture was stirred at reflux for 3
h. The reaction mixture was cooled to 0 °C, and the reaction
was quenched with water (25 mL) and 15%NaOH in water (75 mL).
The reaction mixture was filtered, concentrated under reduced
pressure, and the residue was dissolved in EtOAc. The organic
solution was washed with water and then brine, dried (MgSO4)
filtered, and concentrated under reduced pressure to provide
3-(tert-Butyldimethylsilyloxymethyl)benzylamine (1.4 g, 30%)
as a clear oil: aH NMR (300 MHz, CDC13) 5 7.22-7.10 (m, 4H),
4.57 (s, 2H), 3.74 (s, 2H), 0.84 (s, 9H), 0.09 (s, 6H).
Step 4. Preparation of 3-(Hydroxymethyl)benzylcarbamic acid
tert-butyl ester.
To a solution of 3-(tertbutyldimethylsilyloxymethyl)
benzylamine (1.4 g, 5.5 mmol) and
Et3N (1.5 mL, 11 mmol) in CH2C12 (28 mL) was added di-tertbutyl
dicarbonate (1.3 g, 5.8 mmol), and the reaction mixture
was stirred for 12 h. The reaction mixture was diluted with
water and extracted with CH2C12 (3 x 100 mL) . The combined
organics were washed with brine, dried (MgS04) , filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, CH2C12) to afford 3-
(hydroxymethyl) berrzylcarbamic acid tert-butyl ester aa a,
HWfc (300 MHz", CDC13) 6 7.22-T.-Z&
(m, IH), 7.18 (d, J = 8 Hz, IH), 7.12 (s, IH) , 7.08-7.01 (m,
IH) , 4.60 (S, 2H)s,' 4.04 (d, J = 6 Hz, 2H) , 1.36 (s, 9H) .
Step 5. Preparation of 3-(Bromomethyl)benzylcarbamic acid
tert-butyl ester.
To an ice-cold solution of 3-
(hydroxymethylbenzyl)carbamic acid tert-butyl ester (0.7 g,
3.0 mmol) and CBr4 (1,. 0 g, 3.1 mmol) in THF (14 mL) was added
Ph3P (0.81 g, 3.1 mmol), and the reaction mixture was stirred
for 18 h. The reaction mixture was filtered, and concentrated
under reduced pressure. Purification by flash column
chromatography (silica, eluent 5:95 to!5:85 EtOAc/hexanes) to
afford the 3-(bromomethyl)benzyl-carbamic acid tert-butyl
ester as a white solid (0.42 g, 51%): XH NMR (300 MHz, MeOD) 5
7.55 (s, IH), 7.32-7.27 (m, 2H), 7.21-7.19 (m, IH), 4.54 (s,
2H), 4.21 (s, 2H), 1.28 (s, 9H).
Step 6. Preparation of l{3-[3-Bromo-4-(4-fluorobenzyloxy)-2-
oxo-2H-pyridin-l-ylmethyl]benzyl}carbamic acid tert-butyl
ester.
To a solution of 3-bromo-4- (4-fluorobenzyloxy)pyridine-2(IH) -
one (from Step 3, synthesis EXAMPLE 59 ) (0.2 g, 0.67 mmol) in
DMF (11 mL) was added K2C03 (0.26 g, 1.3 mmol) and 3-
(bromomethyl)benzylcarbamic acid tert-butyl ester (0.23 g,
0.80 mmol), and the reaction mixture was stirred at 80 °C for
3 hours. The reaction mixture was cooled to room temperature,
and concentrated under reduced pressure. The residue was
diluted with a 50% aqueous solution of brine (24 mL), and
extracted with CHC13 (4 x 50 mL) . The combined organics was
washed water and then brine, dried (MgS04) , filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, 3:7 EtO&c/hexanes-) and
reczgrsta-llizatiorr fronr MeQHTa-f.fordeds-{3- [3;-brQmo=4- (4-
fluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzylJcarbamic
acid tert-butyl ester as an off-white solid (0.07 g, 20%): mp
136-138 °C; XH NMR (300 MHz, CDC13) § 7.42-7.37 (m, 2H), 7.30-
7.20 (m, 5H), 7.08 (t, J = 9 H z , 2H), 6.04 (d, J = 9 H z , 1H),
5.16 (s, 2H) , 5.14 (s, 2H), 4.28 (d, J = 6 Hz, 1H), 1.44 (s,
9H) . ESHRMS m/z 517.1124 (M+H C25H27BrFN204 requires 517.1133)
Example 71
1- (3-Aminomethylbenzyl) -3-bromo-4- (4-fluorobenzyloxy) -1Hpyridin-
2-one
To an ice-cold solution of 1-[3-{N-tert-
Butoxycarbonyljaminomethylbenzyl]-3-bromo-4-(4-
fluorobenzyloxy)pyridine-2(1H)-one (Example 69) (0.05 g, 0.1
mmol) in CH2C12 (2 tnL) was added TFA (2 mL) , and the reaction
mixture was stirred for 1 h. The solvent was removed under
reduced pressure to provide 1-(3-aminomethylbenzyl)-3-bromo-4-
(4-fluorobenzyloxy)-lH-pyridin-2-one as a tan solid (0.049 g,
100%), as the TFA salt: mp 127-139 °C; XH NMR (300 MHz, DMSOd
6 8.13 (br s, 2H) , 7.94 (d, J « 6 Hz, 1H) , 7.52-7.47 (m,
2H), 7.44-7.37 (m, 2H), 7.27 (t, J = 8 Hz, 3H), 6.53 (d, J = 8
Hz, 1H), 5.30 (s, 2H), 5.14 (s, 2H), 4.01 (d, J « 6 Hz, 2H),
3.39 (br s,,2H); Anal. Calcd for C2oH17BrF2N202»l. 125 TFA: C,
48.99; H, 3.53; N, 5.13. Found: C, 48.80; H, 3.43; N, 4.75.
ESHRMS m/z 417.0608 (M+H C20H19BrFN202 requires 417.0609).

Example 72
COMc
Methyl 2-[3-Br9mo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
benzoate
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 59 (0.36 g, 48%): mp 161-165 °C; *H
NMR (300 MHz, CDC13) 6 7.98 (d, J = 6 Hz, 1H), 7.51-7.26 (m,
6H), 7.11-7.05 (m, 2H), 6.05 (d, J = 8 Hz, 1H), 5.60 (s, 2H),
5.18 (s, 2H), 3.93 (s, 3H). ESHRMS m/z 446.0430 (M+H
C2iH1BBrFNO4 requires 418.0398)
Example 73
3-Bromo-4-(4-fluorobenzyloxy)-1-(2-hydroxymethylbenzyl)-
lH-pyridin-2-one
To an ice-cold solution of 3-bromo-4-(4-fluorobenzyloxy)-1-(2-
hydroxymethylbenzyl)-lH-pyridin-2-one (Example 72) (0.25 g,
0.56 mmol) in THF (1 mL) was added LiBH4 (2.0 M solution in
THF, 0.56 mmol), and the reaction mixture was stirred at 40 °C
for 6 hours. The reaction mixture was cooled to room
temperature, the solvent was removed under reduced pressure,
and the residue was dissolved in EtOAc. The organic solution
was washed with brine, dried (MgSO4) , filtered, and
concemtrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6)
6 7.82 (d, J - 8 Hz, 1H), 7.54-7.49 (m, 2H), 7.41 (d, J - 7
Hz, 1H), 7.29-7.21 (m, 4H), 6.81 (d, J « 7 Hz, 1H), 6.53 (d, J
= 8 Hz, 1H), 5.30-5.25 (m, 3H), 5.18 (s, 2H), 4.60 (d, J. 7
Hz, 2H) . ESHRMS m/z 418.0437 (M+H C2oHi8BrFNO3 requires
418.0449)
Example 74
3-Bromo-4-(2,4-difluorobenzyloxy)-1-[(4-
dimethylaminomethyl)benzyl]-lH-pyridin-2-one
Step 1. Preparation of 4-(2,4-Difluorobenzyloxy)pyridine-1-
oxide.
To an ice-cold solution of sodium hydride (1.2 g of a 60%
dispersion in mineral oil, 51 tnmol) in DMF (43 mL) was added
2,4-difluorobenzyl alcohol (5.7 mL, 51 mmol). The reaction
mixture was warmed to room temperature, 4-chloropyridine-loxide1
(5.5 g, 43 mmol) was added, and the reaction mixture was
stirred for 6 h. The reaction mixture was diluted with a 50%
aqueous solution of brine, and extracted with CHC13 (7 x 50
mL) . The combined organics were dried (MgS04) , filtered, and
the solvent was removed under reduced pressure. Trituration
with Et20 afforded 4-(2,4-difluorobenzyloxy)pyridine-1-oxide as
an off-white solid (9.1 g, 90%): 1H NMR (300 MHz, CDC13) 6
8.16-8.08 (m, 1H), 7.47-7.36 (m, 1H), 6.97-6.81 (m, 1H) , 5.09
(d, J = 8 Hz, 1H).
Step 2. Preparation of 4-(2,4-Difluorobenzyloxy)-IH-pyridin-
2-one.
A solution of 4-(2,4-difluorobenzyloxy)pyridine-l-oxide (13.4
g, 57 tnmol) in acetic anhydride (30 mL) was stirred at reflux
for 4 h. The solvent was removed under reduced pressure, the
residue was diluted with 1:1 MeOH/water (60 mL), and the
mixture was stirred at room temperature for 1 h. The solvent
was removed under reduced pressure. Purification by flash
column chromatography (silica, eluent methylene chloride to
9:1 methylene chloride/methanol) provided 4- (2,4-
difluorobenzyloxy) -lH-pyridin-2-one as a light brown solid
(4.2 g, 31%): aH NMR (300 MHz, CDC13) 5 7.43 (q, J = 8 Hz, 1H),
7.23 (d, J = 7 Hz, 1H), 6.91-6.87 (m, 2H), 6.02 (dd, J = 8, 2
Hz, 1H), 5.97 (d, J = 2 Hz, 1H), 5.03 (s, 2H).
Step 3. Preparation of 3-Bromo-4-(2,4-difluorobenzyloxy)-1Hpyridin-
2-one.
To an ice-cold solution of 4-(2,4-difluorobenzyloxy)-1Hpyridin-
2-one (0.75 g, 3.1 mmol) in AcOH (12 mL) was added a
solution of bromine (0.2 mL, 3.5 mmol) in AcOH (6 mL), and the
reaction mixture was stirred 10 min. The solvent was removed
under reduced pressure to afford 3-bromo-4-(2,4-
difluorobenzyloxy)-IH-pyridin-2-one as a white solid (1.0 g,
100%): ESI MS m/z 299 [M + H]+.
Step 4. Preparation of 3-Bromo-l-(4-chloromethylbenzyl)-4-
(2,4-difluorobenzyloxy)-IH-pyridin-2-one.
To a solution of 3-bromo-4-(2, 4-difluorobenzyloxy)-IH-pyridin-
2-one (0.60 g, 2.5 mmol) in DMF (40 mL) was added K2C03 (0.70
g, 5.1 mmol) and ct,a' -dichloro-p-xylene (0.53 g, 3.0 mmol), and
the reaction mixture was stirred at 110 °C for 2 h. The
reaction mixture was cooled to room temperature, diluted with
brine, and extracted with CHC13 (4 x 100 mL) . The combined
organics were washed water and then brine, dried (Na2S04) ,
filtered, and concentrated under reduced pressure to afford 3-
bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluorobenzyloxy)-IHpyridin-
2-one as an off-white solid (0.49 g, 43%): XH NMR (300
MHz, CDC13) 5 7.54 (app q, J = 8 Hz, 1H) , 7.38-7.28 (m, 5H)
6.94 (td, J = 8, 2 Hz, 1H), 6.85 (td, J = 8, 2 Hz, 1H), 6.10
(d, J = 9 Hz, 1H), 5.21 (s, 2H), 5/16 (s, 2H), 4.56 (a, 2H).
Step 5. Preparation of 3-Bromo-4-(2,4-difluorobenzyloxy)-1-
[(4-dimethylaminomethyl) benzyl]-lH-pyridin-2-one.
To a sealed tube containing 3-bromo-l-(4-chloromethylbenzyl)-
4-(2,4-difluoro-benzyloxy)-lH-pyridin-2-one (0.49 g, 1.1 mmol)
was added a solution of dimethylamine (5.5 mL of a 2.0 M
solution in THF, 11 mmol), and the reaction mixture was
stirred for 15 h. The solvent was removed under reduced
pressure. Purification by flash column chromatography
(silica, eluent methylene chloride to 92:7.2:0.8 methylene
chloride/methanol/ammonia) provided 3-bromo-4-(2,4-
difluorobenzyloxy)-1-(4-dimethylaminomethylbenzyl)-IH-pyridin-
2-one as a light yellow solid (0.23 g, 46%): mp 111-113 °C;
NMR (500MHz, CDC13) 6 7.50-7.49 (m, 1H) , 7.26-7.22 (m, 5H) ,
6.90-6.88 (m, 1H), 6.82-6.78 (m, 1H) , 6.04 (d, J = 6 Hz, 1H),
5.16 (s, 2H), 5.11 (s, 2H), 3.37 (s, 2H), 2.19 (s, 6H). ESHRMS
m/z 463.0782 (M+H C22H22BrF2N202 requires 463.0827)
Example 75
3-Bromo-4- (2, 4-dif luorobenzyloxy) -1- [3-
(isopropylarainomethyl)benzyl]-lH-pyridin-2-one
The title compound was prepared by a procedure similar to
the one described for Example 74 (0.06 g, 35%): mp 109-110 °C;
XH NMR (300 MHz, CDC13) 5 7.54 (d, J= 6 Hz, 1H) , 7.33-7.20 (m,
5H), 6.94-6.81 (m, 2H), 6.10 (d, J = 6 Hz, 1H), 5.20 (s, 2H),
5.14 (s, 2H), 3.77 (s, 2H), 2.88 (t, J = 6 Hz, 1H), 1.13 (d, J
- 6 Hz, 6H) . ESHRMS m/z 477.0955 (M+H C23H24BrF2N2O2 requires
477.0984)
Example 76
3-Bromo-4- (2 , 4 -dif luorobenzyloxy) -1- [ (3-
dimethylaminomethyl) benzyl] -lH-pyridin-2-one
The title compound was prepared by a procedure similar to
the one described for Example 74 (0.06 g, 25%): mp 103-107 °C;
XH NMR (300 MHz; CDC13) d 7.52 (d, J » 8 Hz, 1H) , 7.32-7.24 (m,
5H) , 6.94 (td, J = 9, 3 Hz, 1H) , 6.84 (td, J - 9, 3 Hz, 1H) ,
6.08 (d, J = 8 Hz, 1H) , 5.20 (s, 2H) , 5.16 (s, 2H) , 3.44 (s,
2H) , 2.24 (s, 6H) . ESHRMS m/Z 463.0801 (M+H
requires 463.0827).
Example 77
3-Bromo-4-(2,4-difluorobenzyloxy)-1- [ (3-
methylaminomethyl)benzyl]-lfl-pyridin-2-one
The title compound was prepared by a procedure similar to
the one described for Example 74 (0.05 g, 16%) : mp 107-111 °C;
XH NMR (300 MHz, CDC13) 5H), 6.94-6.81 (m, 2H), 6.09 (d, J = 6 Hz, 1H), 5.20 (s, 2H),
5.14 (s, 2H), 3.73 (s, 2H), 2.45 (s, 1H). ESHRMS m/z 449.0652
(M+H C2iH2oBrF2N202 requires 449.0671)
Example 78
(3- [3-Bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-lylmethyl]
benzyl) carbamic acid tert-butyl ester
The title compound was prepared essentially according to the
procedure described in Example 70. mp 80-84 °C; *H NMR (300
MHz, DMSO-ds) 5 7.60-7.50 (m, 1H) , 7.33-7.21 (m, 5H) , 6.97-6.81
(m, 2H) , 6.10 (dd, J = 8 , 2 Hz, 1H) , 5.20 (s, 2H) , 5.15 (s,
2H) , 4.87 (br s, 2H) , 4.30 (s , 2H) 1.45 (s, 9H) . ESHRMS m/z
535.1019 (M+H CssHggBrFsCU requires 535.1039)
1- [(3-Aminomethyl)benzyl] -3-bromo-4- (2,4-difluorobenzyloxy) -
lH-pyridin-2-one
Step 1. Preparation of 1-[(3-Aminomethyl)benzyl]-3-bromo-4-
(2,4-di fluorobenzyloxy)-IH-pyridin-2-one.
To an ice-cold, solution of {3-[3-Bromo-4-(2,4-
difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzyl}carbamic
acid tert-butyl ester (Example 78) (0.05 g, 0.1 mmol) in CH2C12
(2 mL) was added TFA (2 mL), and the reaction mixture was
stirred for 1 hour. The solvent was removed under reduced
pressure to provide I-[(3-aminomethyl)benzyl]-3-bromo-4-(2,4-
difluorobenzyloxy)-lH-pyridin-2-one as a tan solid (0.049 g,
100%), as the TFA salt: mp 80-84 °C; XH NMR (300 MHz, DMSO-d6)
5 8.15 (br s, 3H) , 7.97 (d, J - 8 Hz, 1H), 7.79-7.60 (m, 1H),
7.44-7.30 (m, 4H), 7.20-7.15 (m, 1H), 6.61 (d, J = 6 Hz, 1H),
5.31 (s, 2H), 5.16 (s, 2H), 4.03 (s, 2H) ; 19F NMR (282 MHz,
DMSO-ds) 5 -74.56 (4. 8F) , -109.63 (IF), -113.61 (IF). ESHRMS
m/z 435.0540 (M+H C2oHi8BrF2N202 requires 435.0515)
Example 80
3-Chloro-4-(2,4-difluorobenzyloxy)-1-[4-
(isopropylaminomethyl)benzyl] -l.ff-pyridin-2-one
Step 1. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-IHpyridin-
2-one.
To a solution of 4-[(4-fluorobenzyl)oxy]pyridine-2(1H) -
one (from Step 2, Example 74) (1.4 g, 5.9 mmol) in AcOH (25
mL) was added N-chlorosuccinimide (0.95 g, 7.1 mmol) and the
reaction mixture was heated at reflux for 2 h. The solvent
was removed under reduced pressure. XH NMR (300 MHz, MeOD) 6
7.63-7.55 (m, 1H), 7.45(d, J = 8 Hz, 1H) , 7.07-7.00 (m, 2H),
6.58 (d, J - 8 Hz, 1H), 5.31 (d, J = 8 Hz, 1H).
Step 2. Preparation of 3-Chloro-l-(4-chloromethylbenzyl)-4-
(2,4-difluorobenzyloxy)-lH-pyridin-2-one.
3-Chloro-l- (4-chloromethylbenzyl)-4-(2,4-
difluorobenzyloxy)-lH-pyridin-2-one was prepared by procedure
similar to the one described for 3-bromo-1-(4-chloromethylbenzyl)
-4- (2, 4-dif luorobenzyloxy) -lH-pyridin-2-one (Step 3, )
as white solid (0.24 g, 34%): aH NMR (300 MHz, CDC13) 6 7.53
(app g, J = 9 Hz, 1H) , 7.34 (app q, J = 9 Hz, 1H) , 7.23 (d, J
= 8 Hz, 1H), 6.94 (td, J = 10, 2 Hz, 1H), 6.85 (td, J = 10, 2
Hz, 1H), 6.14 (d, J = 8 Hz, 1H), 5.20 (s, 2H), 5.16 (s, 2H),
4.56 (s, 2H) .
Step 3. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-1-
[4-(isopropylamino-methyl)benzyl]-lH-pyridin-2-one.
The title compound was prepared by a procedure similar to
the one described for Example 74 (0.17 g, 69 %): mp 146-151
°C; XH NMR (300 MHz, CDC13) 5 7.52 (app g, J = 9 Hz, 1H), 7.35-
7.21 (m, 5H), 6.94 (td, J m 8, 2 Hz, 1H), 6.85 (td, J = 8, 2
Hz, 1H), 6.18 (d, J = 8 Hz, 1H), 5.22 (s, 2H), 5.08 (s, 2H),
3.81 (S, 2H), 2.98 (br s, 1H), 1.20 (s, 6H). ESHRMSm/2
requires 433.1489)
Example 81
3-Chloro-4-(2,4-difluorobenzyloxy)-1- [ (3-
methanesulfonyl)benzyl]-lH-pyridin-2-one
Step 1. Preparation of (3-Methanesulfonyl)phenyl methanol.
To an ice-cold solution of 3-(methylsulfonyl)benzoic acid (1.4
g, 7.1 mmol) in 2:1 Et2O/THF (60 mL) was added LiAlH4 (8.5 mL
of 1.0 M solution in THF, 8.5 mmol), and the reaction mixture
was heated at reflux for 1 h. The reaction mixture was cooled
to 0 °C, and the reaction was quenched with water (15 mL) and
15%NaOH in water (35 mL). The reaction mixture was filtered,
concentrated under reduced pressure, and the residue was
dissolved in EtOAc. The organic solution was washed with
water and then brine, dried (MgS04) , filtered, and concentrated
under reduced pressure. Purification by flash column
chromatography (silica, eluent 1:2 to 3:1 EtOAc/hexanes)
provided (3-methanesulfonyl)phenyl methanol as a clear oil
(0.56 g, 42%): XH NMR (300 MHz, CDC13) 5 7.93 (s, 1H), 7.83 (d,
J = 7 Hz, 1H), 7.64 (d, J = 7 Hz, 1H), 7.53 (t, J = 1 Hz, 1H),
4.78 (d, J = 6 Hz, 2H), 3.05 (s, 3H), 2.61 (brs, 1H).
Step 2. Preparation of l-Chloromethyl-3-
methanesulfonylbenzene.
A solution of (3-methanesulfonyl)phenyl methanol (0.21 g, 1.1
mmol) in thionyl chloride (3 mL) was heated at 80 °C for 3 h.
The reaction mixture was cooled to room temperature, and the
-309-
solvent was removed under reduced pressure to provide 1-
chloromethyl-3-methanesulfonylbenzene as a yellow oil (0.23 g,
95%): XH NMR (300MHz, CDC13) 8 7.98 (a, 1H) , 7.90 (d, J = 8
Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.59 (t, J = 8 Hz, IE), 4.65
(s, 2H), 3.08 (s, 3H) .
Step 3. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-1-
[(3-methanesulfonyl)-benzyl]-lH-pyridin-2-one.
The title compound was prepared by a procedure similar to the
one described for Example 80 (0.14 g, 78%): mp 155-157 °C; XH
NMR (300 MHz, CDC13) 6 7.88 (d, J = 8 Hz, 1H) , 7.83 (m, 1H) ,
7.67 (d, J = 8 Hz, 1H), 7.58-7.48 (m, 2H), 7.31 (d, J= 8 Hz,
1H) , 6.95-6.83 (m, 2H) , 6.22 (d, J = 8 Hz, 1H), 5.22 (s, 4H),
3.08 (s, 3H) . ESHRMS m/z 440.0525 (M+H C2oH17ClF2NO4S requires
440.0529)
Example 82
3-Chloro-4-(2,4-difluorobenzyloxy)-1-[ (4-
methanesulfonyl)benzyl]-lH-pyridin-2-one
The title compound was prepared by a procedure similar to the
one described for Example 81 (0.08 g, 73%): mp 223-225 °C; XH
NMR (300 MHz, CDC13) 6 7.91 (d, J = 8 Hz, 2H), 7.53-7.47 (m,
3H) , 7.30-7.26 (m, 1H) , 6.94-6.86 (m, 2H), 6.22 (d, J= 8 Hz,
1H), 5.23 (s, 4H), 3.03 (s, 3H). ESHRMS m/z 440.0512 (M+H
C2oHi7ClF2NO4S requires 440.0529)
4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
benzamide
Step 1. Preparation of Methyl 4-[3-chloro-4-(2,4-
difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzoate.
Methyl 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]benzoate was prepared by a procedure similar to the
one described for Example 81 (0.14 g, 60%): XH NMR (300 MHz,
CDC13) 5 8.01 (dd, J= 8, 2 Hz, 1H), 7.52 (app q, J = 8 Hz,
1H), 7.36 (d, J = 9 Hz, 2H), 7.26-7.22 (m, 2H), 6.94 (td, J
8, 2 Hz, 1H), 6.85 (td, J = 8, 2 Hz, 1H), 6.16 (d, J = 9 Hz,
1H), 5.21 (s, 4H), 3.92 (s, 3H).
Step 2. Preparation of 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-
2-oxo-2H-pyridin-l-ylmethyl]benzamide.
A sealed tube containing a solution of 4-[3-Chloro-4-(2,4-
difluorobsnzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzole acid
methyl ester (0.25 g, 0.60 mmol) and NH3 (20 mL of a 7 N
solution in MeOH, 140 mmol) was heated at 75 °C for 16 h. The
reaction mixture was cooled to room temperature and the
solvent was removed under reduced pressure. Trituration with
Et20/MeOH afforded 4- [3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-
2H-pyridin-l-ylmethyl]benzamide as a white solid (0.14 g,
60%): mp 235-238 °C; XH NMR (500 MHz, DMSO-ds) d 7.93 (d, J = 8
Hz, 2H), 7.79 (d, J = 8 Hz, 2H), 7.60 (app q, J = 8 Hz, 1H),
7.35-7.27 (m, 4H) , 7.20-7.10 (m, 1H) , 6.61 (d, J = 8 Hz, 1H),
5.28 (S, 2H) , 5.14 (s, 2H) . ESHRMS- m/z. 4-05,.-Q-7a& (M-+Hrequi
r es: 405.0812):
-31LExample
3-Chloro-4-(2,4-difluorobenzyloxy)-l-isoquinolin-5-ylmethyllH-
pyridin-2-one
Step 1. Preparation of Isoquinolin-5-ylmethanol.
To an ice-cold solution of isoquinoline-5-carbaldehyde2 (0.68
g, 4.3 mmol) in MeOH (15 mL) was added NaBH4 (0.17 g, 4.6
mmol), and the reaction mixture was stirred for 15 min. The
reaction was quenched with brine, the solvent was removed
under reduced pressure, and the residue was dissolved in
EtOAc. The organic solution was washed with water and then
brine, dried (Na2S04) , filtered, and concentrated under reduced
pressure to afford isoquinolin-5-ylmethanol as a brown solid
(0.63 g, 93%): XH NMR (300 MHz, DMSO-ds) 5 9.87(3, 1H) , 8.82
(d, J = 6 Hz, 1H), 8.57 (d, J- 6 Hz, 1H), 8.47 (d, J = 9 Hz,
1H) , 8.30 (d, J = 6 Hz, 1H) , 7.95 (t, J" = 9 Hz, 1H) , 5.34 (s,
2H) .
Step 2. Preparation of 5-Bromomethylisoquinoline.
To a solution of isoquinolin-5-ylmethanol (0.63 g, 3.9 mmol)
in AcOH (3.3 mL) was added HBr (6.6 mL, a 30% w/w solution in
AcOH, 24 mmol), and the reaction mixture was stirred at 75 °C
for 45 min. The reaction mixture was cooled to room
temperature, and the precipitate was collected to provide the
5-bromomethylisoquinoline hydrobromide acid salt as a brown
solid (1.1 g, 871): XH NMR (300 MHz, CDC13) 5 9.22 (a, IE),
8.58 (d, J = 6 Hz, 1H) , 7.95-7.89 (m, 2H) , 7.76 (d, J =9 Hz,
1H), 7.59 (dd, J = 9, 6 Hz, 1H), 5.16 (s, 2H).
Step 3. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-1-
isoquinol in- 5 -ylmethyl - IH-pyr idin- 2 -one.
The title compound was prepared by a procedure similar to the
one described for Example 81, as the TFA salt (0.13 g, 33%):
mp 235-238 °C; ^ NMR (300 MHz, DMSO-d6) 6 9.55 (s, 1H), 8.66
(d, J - 6 Hz, 1H), 8.29 (d, J = 6 Hz, 1H), 8.22 (d, J = 8 Hz,
1H), 7.91 (d, J = 8 Hz, 1H), 7.77 (t, J = 8 Hz, 1H), 7.65-7.63
(m, 1H), 7.53 (d, J = 7 Hz, 1H), 7.35-7.25 (m, 1H), 7.20-7.10
(m, 1H), 6.68 (d, J= 8 Hz, 1H), 5.67 (s, 2H), 5.32 (s, 2H) ;
19F NMR (282 MHz, DMSO-d6) 5 -74.79 (3F) , -109.43 (IF), -113.62
(IF). ESHRMS m/z 413.0868 (M+H C22H16C1F2N203 requires 413.0863)
Example 85
0
3-Chloro-4-(2, 4-difluorobenzyloxy)-1-(1,2,3,4-
tetrahydroisoquinolin-5-ylmethyl)-IH-pyridin-2-one
Step 1. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-1-
(1,2,3,4-tetrahydro-isoquinolin-5-ylmethyl)-lH-pyridin-2-one.
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-
isoquinolin-5-ylmethyl-lH-pyridin-2-one (Example 84) (0.14 g,
0.34 mmol) in AcOH (1.3 mL) was added NaCNBH3 (0.09 g, 1.4
mmol) , and the reaction mixture was stirred for 2 h. The
-313.-
reaction mixture was cooled to 0 °C, and diluted with water(10
mL) and 40% aqueous NaOH (10 mL), and the aqueous layer was
washed with EtOAc (3 x 50 mL). The combined organics were
washed with brine, (Na2S04) , filtered, and concentrated
under reduced pressure. Purification by flash column
chromatography (silica, eluent 98:1.8:0.2 to 88:10.8:1.2
CH2Cl2/MeOH/NH3) provided 3-chloro-4-(2,4-difluoro-benzyloxy)-
1-(1,2,3,4-tetrahydroisoquinolin-5-ylmethyl)-lH-pyridin-
as a white solid (0.13 g, 92%): mp 180-184 °C; XH NMR (300 MHz,
MeOD) 3 7.65-7.55 (nt, 2H) , 7.16-7.00 (m, 4H) , 6.90-6.80 (m,
IE), 6.60 (d, J = 8 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 4.06
(s, 2H), 3.21 (t, J = 6 Hz, 2H), 2.82 (t, J = 6 Hz, 2H).
ESHRMS m/z 417.1173 (M+H C22H2oClF2N202 requires 417.1176)
Example 86
3-Chloro-4-(2,4-difluorobenzyloxy)-1-(lH-indol-5-ylmethyl)-1Hpyridin-
2-one
Step 1. Preparation of 5-(Carboxymethyl)-indole-1-carbamic
acid tert-butyl ester.
To a solution of methyl indole-5-carboxylate (6.9 g, 39 mmol)
and Et3N (6.0 mL, 43 mmol) in CH2C12 (150 mL) was added ditert-
butyl dicarbonate (19 g, 86 mmol), and the reaction
mixture was stirred for 14 h. The reaction mixture was
diluted with CH2C12, washed with water and then brine, dried
(Na2SO4) , filtered, and the solvent was removed under reduced
pressure. Purification by flash column chromatography
(silica, 3:7 EtOAc/hexanes) provided 5-(Carboxymethyl) -indole-
1-carbamic acid tert-butyl ester as a light yellow oil (11 g,
100%): XH NMR (300MHz, CDC13) 5 8.29 (a, 1H) , 8.15 (d, J = 9
Hz, 1H) , 7.93 (d, 17 - 9 Hz, 1H) , 7.78 (d, J- 3 Hz, 1H) , 6.85
(d, J = 3 Hz, 1H), 3.91 (s, 3H), 1.68 (a, 9H).
Step 2. Preparation of 5-Hydroxymethylindole-l-carbamic acid
tert-butyl ester:,
To a -78 °C solution of 5-(carboxymethyl)-indole-1-carbamic
acid tert-butyl ester (10.8 g, 39 mmol) in THF (180 mL) was
added DIBAL (127 mL of a 1 M solution in THF, 127 mmol), and
the reaction mixture was stirred for 2.5 h. The reaction was
quenched with 1:1 1 N HCl/MeOH (100 mL), the reaction mixture
was warmed to room temperature, diluted with CH2C12 (100 mL)
and separated. The organic solution was washed with saturated
Rochelle salt, dried (Na2S04) , filtered, and concentrated under
reduced pressure. Purification by flash column chromatography
(silica, 1:1 EtOAc/hexanes) provided 5-hydroxymethylindole-lcarbamic
acid tert-butyl ester as a yellow oil (6.5 g, 68%): 1H
NMR (300 MHz, CDC13) 5 8.07 (d, J = 9 Hz, 1H), 7.59 (d, J - Hz, 1H), 7.54 (s, 1H), 7.28 (d, J = 9 'Hz, 1H), 6.58 (d, J = 6
Hz, 1H), 4.73 (3, 2H), 1.97 (s, 9H).
Step 3. Preparation of 5-Bromomethylindole-1-carbamic acid
tert-butyl ester.
To an ice-cold solution of 5-hydroxymethylindole-l-carbamic
acid tert-butyl ester (0.51 g, 2.1 mmol) in 4:1 Et20/CH2Cl2 (4
mL) was added PBr3 (0.2 tuL, 2.2 mmol), and the reaction mixture
was stirred for 40 min. The reaction mixture was diluted with
CH2C12, washed a saturated solution of NaHC03 (3 x 10 mL) ,
dried (Na2S04) , filtered, and the solvent was removed under
reduced pressure to provide 5-bromomethyl-indole-1-carbamic
acid tert-butyl ester as a yellow solid (0.59 g, 93%). *H NMR
(300 MHz, CDC13) 5 8.07 (d, J = 9 Hz, 1H) , 7.68-7.62 (m, 2H) ,
7.33 (d, J = 9 Hz, 1H), 6.60 (s, 1H), 4.68 (s, 2H), 1.67 (a,
9H) .
Step 4. Preparation of 5- [3-Chloro-4-(2,4-difluorobenzyloxy)-
2-oxo-2H-pyridin-l-ylmethyl]indole-1-carbamic acid tert-butyl
ester. ;
5- [3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
indole-1-carbamic acid tert-butyl ester was prepared
by a procedure similar to the one described for Example 81 as
an off-white solid (0.54 g, 67%).: XH NMR (300 MHz, CDC13) 6
8.10 (d, J" = 8 Hz, 1H) , 7.60 (d, J = 3 Hz, 2H) , 7.52 (m, 1H) ,
7.26 (m, 1H), 6.94 (td, J = 9, 2 Hz, 1H), 6.84 (td, J = 9, 2
Hz, 1H) 6.53 (d, J = 2 Hz, 1H), 6.08 (d, J = 8 Hz, 1H), 5.25
(s, 2H), 5.18 (s, 2H), 1.66 (s, 9H).
Step 5. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-1-
(lH-indol-5-ylmethyl)-lH-pyridin-2-one.
A flask containing 5-[3-chloro-4-(2,4-difluorobenzyloxy)-2-
oxo-2H-pyridin-l-ylmethyl]indole-1-carbamic acid tert-butyl
ester (0.48 g, 0.96 mmol) was heated at 150 °C for 4 h. The
reaction mixture was cooled to room temperature, and
purification by preparatory HPLC (Phenomenex Luna C18(2)
column, 250 x 21.20 mm, 10 }i
Solvent A: 0.05% TFA in 95:5 H20/CH3CN; Solvent B: 0.05% TFA in
95:5 CH3CN/H20
Eluent: 30-95% B over 20 min; flow 20.0 mL/min; UV Detector:
254 nm; Retention Time: 15.6 min) provided 3-chloro-4-(2,4-
difluorobenzyloxy)-1-(lH-indol-5-ylmethyl)-lH-pyridin-2-one as
an off-white solid (0.14 g, 36%): mp 152-153 °C; *H NMR (300
MHz, DMSO-dg) 5 11.11 (br s, 1H) , 7.91 (d, J = 8 Hz, 1H), 7.61
(app q, J = 8 Hz, 1H, 7.51 (s, 1H), 7.36-7.33 (m, 3H), 7.16
(td, J = 8, 2 Hz, 1H), 7.09 (dd, J= 8, 2 Hz, 1H), 6.57 (d, J
- 8 Hz, 1H), 6.40 (br S, 1H), 5.28 (s, 2H), 5.16 (a, 2H)
ESHRMS m/z 401.0845 (M+H C2iHi6ClF2N202 requires 401.0863),
i
Example 87
1- (1-Acetyl-lH- indol-5-ylmethyl) -3-chloro-4- (2,4
difluorobenzyloxy) -lH-pyridin-2-one
To a solution of 3-chloro-4- (2,4-difluorobenzyloxy) -1- (1Hindol-
5-ylmethyl) -lH-pyridin-2-one (Step 5, synthesis of
Example 86 ) (0.22 g, 0.57 mmol) in CH3CN (10 mL) was added
acetic anhydride (0.06 mL, 0.58 mmol) and Et3N (2 mL) , and the
reaction mixture was stirred at 86 °C for 6 h. The reaction
mixture was cooled to room temperature, and partitioned
between 1 N HC1 and EtOAc. The organic solution was
separated, washed with brine, dried (Na2S04) , filtered, and
concentrated under reduced pressure. 1H NMR (300 MHz, MeOD)
8.35 (d, J = 9 Hz, 1H) , 7.77 (d, J = 9 Hz, 1H) , 7.70 (d, J = 3
Hz, 1H) , 7.54 (s, 2H) , 7.31 (d, J = 9 Hz, 1H) , 7.01-6.99 (ra,
2H) , 6.66 (d, J = 3 Hz, 1H) , 6.59 (d, J = 9 Hz, 1H) , 5.29 (s,
4H) , 2.63 (s, 3H) . ESHRMS m/Z 443.0965 (M+H
requires 443.0969).
Example 88
3-Chloro-4-(2, 4-difluorobenzyloxy)-1-(2,3-dihydro-lH-indol-5-
ylmethyl)-lH-pyridin-2-one
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-1-(1Hindol-
5-ylmethyl)-lH-pyridin-2-one (Step 5, synthesis of
Example 86 ) (0.24 g, 0.60 mmol) in AcOH (5 mL) was added
NaCNBH3 (0.06 g, 1.0 mmol), and the reaction mixture was
stirred for 1 h. The reaction mixture was partitioned between
water and EtOAc, and the precipitate was collected by
filtration. Trituration with CH2C12 afforded 3-Chloro-4-(2,4-
dif luorobenzyl-oxy) -1-(2,3-dihydro-lH-indol-5-ylmethyl)-IHpyridin-
2-one as a white solid (0.2 g, 81%): mp 137-139 °C; XH
NMR (300 MHz, CDC13) 6 7.51 (app q, J = 9 Hz, 1H), 7.21 (d, J =
6 Hz, 1H) , 7.11 (s, 1H) , 6.99-6.80 (m, 3H), 6.57 (d, J = 9 H z ,
1H), 6.08 (d, J - 9 Hz, 1H), 5.18 (s, 2H), 5.02 (s, 2H), 3.83
(br s, 1H), 3.55 (t, J - 9 Hz, 2H), 2.99 (t, J » 9 Hz, 2H).
ESHRMS m/z 403.1022 (M+H C2iHi8ClF2N202 requires 403.1019).
The following example compounds were prepared by procedures
similar to that described for Example 74. The yields and the
analytical data of the title compounds are reported below.
Examples 89-101.
compounds of Examples 89-101 are prepared essentially
according to the procedures set forth above for Example 74.
The yield (Y) , molecular formula (MF) and analytical data for
these compounds are shown below.
Example
No.
Ex. 89
Ex. 90
Ex. 91
Ex. 92
Ex. 93
Ex. 94
Ex. 95
R
pyridin-3-ylmethyl
pyr idin- 4 -ylme thyl
pyridin-2-ylmethyl
4 - tert-butyl ) benzyl
3 -methoxybenzyl
Benzo [ I , 3]dioxol-5-
yl me thyl
2-f luorobenzyl
Y
25
6
56
32
50
35
42
MF
C18Hi3BrF2N202
C18Hi3BrF2N202
Ci8Hi3BrF2N202
C23H22BrF2N02
C20Hi6BrF2N03
C2oHi4BrF2N04
Ci9H14BrF3N02
M+H
Requires
407.0202
407.0202
407.0201
462.0875
436.0354
450.0147
424.0155
ESHRMS
m/z
407.0197
407.0189
407.0184
462.0863
436.0353
450.0136
424.0143
%) : mp 179-182 °C; XH NMR (300 MHz, CDC13) 6 7.58-7.53 (m, 3H)',
7.33-7.26 (m, 1H) , 7.14-7.02 (m, 2H) , 6.96-6.82 (m, 2H), 6.11
(d, J. 9 Hz, 1H), 5.20 (s, 2H), 5.18 (a, 2H). ESHRMS m/z
(M+H requires).
Example 96
3-Bromo-4-(2,4-difluorobenzyloxy)-1-(2,4-difluorobenzyl)-1Hpyridin-
2-one
Step 1. Preparation of 4-(2,4-Difluorobenzyloxy)-1-(2,4-
difluorobenzyl) -lH-pyridin-2-one.
To a solution of 2,4-dihydroxypyridine (0.35 g, 3.2 mmol) in
DMF (50 mL) was added K2C03 (2.5 g, 13 mmol) and 2,4-
difluorobenzyl bromide (1.0 mL, 7.6 mmol), and the reaction
mixture was stirred at 110 °C for 4 h. The reaction mixture
was cooled to room temperature, diluted with brine, and
extracted with CHCla (4 x 100 mL) . The combined organics were
washed with water and then brine, dried (Na2S04) , filtered, and
concentrated under reduced pressure. 1H NMR (300 MHz, CDC13) 5
7.54 (app q, J = 8 Hz, 1H), 7.38-7.28 (m, 5H), 6.94 (td, J =
8, 2 Hz, 1H), 6.85 (td, J « 8, 2 Hz, 1H), 6.10 (d, J = 9 Hz,
1H), 5.21 (s, 2H), 5.16 (a, 2H), 4.56 (s, 2H).
Step 2. Preparation of 3-Bromo-4-(2,4-difluorobenzyloxy)-1-
(2,4-fluorobenzyl)-lH-pyridin-2-one.
To an ice-cold solution of 4-(2,4-difluorobenzyloxy)-1-(2, 4-
difluorobenzyl)-lH-pyridin-2-one (0.72 g, 2.0 mmol) in AcOH
(4.0 mL) was added a solution of bromine (0.11 mL, 2.2 mmol)
in AcOH (7.2 mL), and the reaction mixture was stirred for 40
min. The solvent was removed under reduced pressure. *H NMR
(300 MHz, CDC13) 5 7.63-7.45 (m, 2H) , 7.42 (d, J = 6 Hz, 1H),
6.93-6.77 (m, 4H), 6.12 (d, J = 6 Hz, 1H), 5.20 (s, 2H) , 5.12
(s, 2H). ERMS m/z M+H 442.
-320-
Example 97
{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2tf-pyridin-lylmethyl]-
phenyl}acetonitrile
Step 1. Preparation of Methyl 3-cyanomethylbenzoate.
To an ice-cold solution of methyl 3-bromotnethylbenzoate (9.1
g, 40 mmol) in CH3CN (108 mL) was added tetrabutylammonium
fluoride (17.3 mL, 60 mmol) and trimethylsilylcyanide (8.0 mL,
60 mmol), and the reaction mixture was heated at reflux for 20
h. The reaction mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. Purification
by flash column chromatography (silica, 1:1 EtOAc/hexanes)
provided methyl 3-cyanomethylbenzoate as a clear oil (3.0 g,
43%): XH NMR (300 MHz, DMSO-d6) 6 7.97 (s, IE), 7.92 (d, J = 8
Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 4.16
(s, 2H), 3.87 (s, 3H).
Step 2. Preparation of (3-Hydroxymethylphenyl)acetonitrile.
To an ice-cold solution of methyl 3-cyanomethylbenzoate (2.8
g, 18 mmol) in THF (23 mL) was added LiBH4 (8.8 mL of a 2 M
solution in THP, 18 mmol), and the reaction mixture was heated
at reflux for 4 h. The reaction mixture was cooled to room
temperature, the reaction was quenched with 1:1 water/1 N HCl,
and the aqueous layer was washed with EtOAc (3 x 150 mL). The
combined organics were washed with brine, dried (MgS04) ,
filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica, 2:1
EtOAc/hexanes) provided (3-hydroxymethylphenyl)-acetonitrile
as a clear oil (0.97 g, 41%); XH NMR (300 MHz, MeOD) 6 8.15-
8.08 (m, 1H) , 7.47-7.34 (m, 1H) , 7.27 (s, 1H) , 6.97-6.82 (m,
1H), 4.87 (s, 2H), 3.91 (s, 2H)
Step 3. Preparation of (3-Bromomethylphenyl)acetonitrile.
To an ice-cold solution of (3-hydroxymethylphenyl)acetonitrile
(0.97 g, 7.3 mmol) in THF (35 mL) was added CBr4 (2.5 g, 7.7
mmol) and Ph3P (2.0 g, 7.7 mmol), and the reaction mixture was
stirred for 3 h. The reaction mixture was filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, eluent 1:9 to 1:4
EtOAc/hexanes) provided (3-bromomethylphenyl)acetonitrile as a
clear oil (0.89 g, 58%): XH NMR (300 MHz, MeOD) 5 7.47-7.29 (m,
1H) , 7.27 (s, 1H) , 6.97-6.82 (m, 1H) , 4.87 (s, 2H) , 3.91 (s,
2H) .
Step 4. Preparation of (3-[3-Bromo-4-(2,4-difluorobenzyloxy)-
2-oxo-2H-pyridin-l-ylmethyl]phenyl}acetonitrile.
The title compound was prepared by a procedure similar to the
one described for Example 74 (0.07 g, 10%): mp 120-121 °C;
NMR (300 MHz, CDC13) 5 7.60-7.50 (m, 1H), 7.37-7.27 (m, 5H),
6.96 (td, J = 9,. 3 Hz, 1H) , 6.82 (td, J = 9, 3 Hz, 1H) , 6.13
(d, J= 8 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H). ESHRMS m/z
445.0381 (M+H C2iHlsBrF2N202 requires 445.0358).
Example 98
-322-
2-[3-Brorao-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
benzonitrile
The title compound was prepared by a procedure similar to the
one described for Example 74 (0.13 g, 47%): mp 194-197 °C;
NMR (300 MHz, CDC13) 5 1.15 (d, J = 9 Hz, 1H), 7.69-7.49 (m,
4H), 7.42 (t, J = 8 Hz, 1H), 6.96-6.73 (m, 2H), 6.18 (d, J = 8
Hz, H), 6.17 (s, 2H), 5.30 (s, 2H). ESHRMS m/z 431.0210 (M+H
C2oHi4BrF2N2O2 requires 431.0201.
1- [ (2-Aminomethyl)benzyl) ] -3-bromo-4- (2,4-difluorobenzyloxy) -
IH-pyridin-2 -one
To a solution of 2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-
2H-pyridin-l-ylmethyl]-benzonitrile (0.11 g, 0.25 mmol) in THF
(3 mL) was added BH3-DMS (0.25 mL of a 2.0 M solution in THF,
0.5 mmol), and the reaction mixture was stirred at 70 °C for 1
h. The reaction mixture was cooled to 0 °C, and the reaction
was quenched, with MeOH. The solvent was removed under reduced
pressure, and the residue was partitioned between 2N NaOH and
EtOAc. The organic solution was washed with brine, dried
(MgS04) , filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica, eluent
methylene chloride to 90:9:1 methylene
chloride/methanol/ammonia) provided 1- [ (2 -aminomethyl) benzyl] -
3-bromo-4- (2, 4-dif luorobenzyloxy) -lH-pyridin-2-one as a white
solid (0.15 g, 48%): *H NMR (300 MHz, CDC13) 6 7.55 (app q, J =
8 Hz, 1H) , 7.40-7.26 (m, 4H) , 7.14 (d, J = 8 Hz, 1H) , 6.94
(td, J = 8, 2 Hz, 1H) , 6.85 (td, J= 8, 2 Hz, 1H) , 6.08 (d, J
= 8 Hz, 1H) , 5.31 (a, 2H) , 5.21 (s, 2H) 4.03 (s, 2H) . ESHRMS
m/z 435.0517 (M+H CaoHiaB^^C^ requires 435.0514).
Example 100
Methyl 3-[3-Bromo-4-(2, 4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl] benzoate
The title compound was prepared by a procedure similar to the
one described for Example 74 (0.05 g, 11%): mp 115-117
NMR (300 MHz, CDC13) 5 8.15-7.95 (m, 2H) , 7.65-7.50 (m, 2H) ,
7.45-7.40 (m, 1H) , 7.32 (d, J" = 6 Hz, 1H) , 7.00-6.80 (m, 2H) ,
6.12 (d, J = 9 Hz, 1H), 5.21 (s, 2H), 5.20 (s, 2H), 3.92 (s,
3H).. ESHRMS m/z 464.0292 (M+H C2iH17BrF2NO4 requires 464.0303).
Example 101
Methyl 4-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-benzoate
The title compound was prepared by a procedure similar to the
one described for Example 74 (0.17 g, 46%): mp!36-139 °C; XH
NMR (300 MHz, CDC13) 5 8.01 (d, J - 8 Hz, 2H), 7.60-7.51 (ra,
1H), 7.37 (d, J = 8 Hz, 2H), 7.29-7.26 (m, 1H), 6.93 (td, J =
9, 2 Hz, 1H), 6.84 (td, J = 9, 2 Hz, 1H), 6.13 (d, J = 8 Hz,
1H), 5.23 (s, 4H), 3.91 (s, 3H). ESHRMS m/z 464.0306 (M+H
C2iH17BrF2N02 requires 464.0304).
Example 102
O O
3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
benzamide
A sealed tube containing a solution of methyl 3- [3-bromo-4-
(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoate
(0.1 g, 0.21 mmol) and NH3 (3 mL of a 7 N solution in MeOH, 21
mmol) was heated at 75 °C for 16 h. The reaction mixture was
cooled to room temperature and the solvent was removed under
reduced-pressure. Trituration with Et20/MeQK a£fordedi a white?
solid (0.06 g, 64%): mp 198-201 °C; XH NMR (300 MHz, DMSO-ds) 6
8 . 0 2 - 8 . 0 0 (m, 2H), 7.85-7.75 (m, 2H), 7.70-7.60 (m, 1H), 7.45-
7.30 (m, 4H) , 7.17 (t, J = 3 Hz, 1H), 6.60 (d, J = 9 Hz, 1H),
5.32 (S, 2H) , 5.18 (s, 2H). ESHRMS m/Z 449.0295 (M+H
C2oH16BrF2N203 requires 449.0307).
Example 103
4- [3-Bromo-4- (2,4-difluorobenzyloxy) -2~oxo-2H-pyridin-l
The title compound was prepared by a procedure similar to the
one described for Example 102 from Example 101 (0.04 g,
12%): mp 235-238 °C; XH NMR (300 MHz, DMSO-d6) d 8.00 (d, J = 8
Hz, 1H) , 7.94 (br s, 1H) , 7.78 (d, J = 8 Hz, 1H) , 7.64 (app q,
J = 8 Hz, 1H) , 7.38-7.30(m, 4H) , 7.17 (td, J = 6 , 2 Hz, 1H) ,
6.60 (d, J = 9 Hz,. 1H) , 5.27 (s, 2H) , 5.14 (s, 2H) . ESHRMS
m/z 449.0291 (M+H requires 449.0307).
Example 104
O F
1-(3-Aminomethyl-2-fluorobenzyl)-3-bromo-4-(2,4-
difluorobenzyloxy) -lH-pyridin-2-one
Step 1. Preparation of 3-Bromo-l-(3-bromomethyl-2-
fluorobenzyl)-4- (2,4-difluoro-benzyloxy)-lH-pyridin-2-one.
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-IH-pyridin-
2-one (from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF
mL) was added K2C03 (0.26 g, 1.9 mmol) and 2,6-
bis(bromomethyl)fluorobenzene (1.6 g, 5.7 mmol), and the
reaction mixture was stirred at 110 °C for 3 h. The reaction
mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was diluted with
a 50% aqueous solution of brine, and the aqueous layer was
extracted with EtOAc (3 x 50 mL). The combined organics were
washed with water, dried (Na2SO4) , filtered, and the solvent
was removed under reduced pressure. Purification by flash
column chromatography (silica, eluent 99:1 to 95:5 methylene
chloride/methanol) afforded 3-bromo-l-(3-bromomethyl-2-
fluorobenzyl)-4- (2,4-difluorobenzyloxy)-lH-pyridin-2-one as an
off-white solid (0.24 g, 49%): XH NMR (300 MHz, CDC13) 6 7.55-
7.40 (m, 3H) , 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80
(m, 2H), 6.14 (d, J = 6 Hz, 1H), 5.22 (B, 2H) , 5.19 (s, 2H),
4.50 (s, 2H).
Step 2. Preparation of 1-(3-Aminomethyl-2-fluorobenzyl)-3-
bromo-4-(2,4-difluoro-benzyloxy)-lH-pyridin-2-one.
A sealed tube containing a solution of 3-bromo-l-(3-
bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1Hpyridin-
2-one (0.24 g, 0.45 mmol) and NH3 (24 mL of a 7 N
solution in MeOH, 168 mmol) was heated at 80 °C for 1 h. The
reaction mixture was cooled to room temperature and the
solvent was removed under reduced pressure. Purification by
flash column chromatography (silica, eluent 99.5:0.5 to 96:4
methylene chloride/methanol) afforded a white solid (0.12 g,
60% ): mp 160-163 °C; H NMR (300 MHz, CDC13) 5 7.46-7.45 (m,
1H), 7.44-7.35 (m, 2H) , 7.34-7.26 (m, 1 H), 7.15-7.05 (m, 1H) ,
6.95-6.80 (m, 2H), 6.11 (d, J - 9 Hz, 1H), 5.21 (s, 2H), 5,19
(S, 2H) , 3.90 (s, 2H). ESHRMS m/z 453.0442 (M+H CaoHi7BrF3N3Oa
requires 453.0420) .
Example 105
6 F O
Methyl 3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-2-fluoro-benzoate
Step 1. Preparation of Methyl 2-fluoro-3-methylbenzoate.
To a solution of 2-fluoro-3-methyl benzoic acid (3.57 g, 23
mmol) in MeOH (40 mL) was added concentrated sulfuric acid
(2.3 mL), and the reaction mixture was heated at reflux for 12
h. The reaction mixture was cooled, the solvent was removed
under reduced pressure, and the residue was dissolved in
EtOAc. The organic solution was washed with a saturated
solution of NaHC03 and then brine, dried (Na2S04) , filtered and
concentrated under reduced pressure to afford methyl 2-fluoro-
3-methylbenzoate as a yellow oil (3.2 g, 82%): XH NMR (300 MHz,
CDC13) 5 7.76-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.08 (t, J- 8
Hz, 1H) , 3.98 (s, 3H), 2.31 (d, J = 3 Hz, 3H) .
Step 2. Preparation of Methyl 3-bromomethyl-2-fluorobenzoate.
To a mixture of methyl 2-fluoro-3-methylbenzoate (1.5 g, 8.9
mmol) and N-bromosuccinimide (1.67 g, 9.4 mmol) was added
carbon tetrachloride (24 mL) and benzoyl peroxide (5 mg) , and
the mixture was heated at reflux for 16 h. The reaction
mixture was cooled, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography
(silica, eluent 5:95 to 60:40 EtOAc/hexanes) afforded methyl
3-bromomethyl-2-fluorobenzoate as a light yellow solid (0.91
g, 41% ): XH NMR (300 MHz, CDC13) § 7.93-7.88 (m, 1H), 7.61-
7.56 (m, 1H), 7.20 (t, J = 8 Hz, 1H), 4.53 (d, J = 3 Hz, 2H),
3.94 (s, 3H) .
Step 3. Preparation of Methyl 3-[3-chloro-4-(2,4-
difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-2-
fluorobenzoate.
Methyl 3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-2-fluorobenzoate was prepared by a procedure
similar to the one described for Example 81 (0.33 g, 69%): mp
171-174 °C; XH NMR (300 MHz, CDC13) d 7.89-7.84 (m, 2H), 7.60-
7.45 (m, 2H), 7.25-7.15 (m, 1H), 7.00-6.80 (m, 2H), 6.17 (d, J
= 6.0 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.93 (s, 3H).
ESHRMS m/z 438.0747 (M+H C2iHi6ClF3N04 requires 438.0714).
Example 106
O F O
3-[3-Chloro-4-(2 , 4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]-
2-fluoro-benzamide
The title compound was prepared by a procedure similar to the
one described for Example 99 (0.15 g, 62%): mp 252-254 °C; XH
NMR (300 MHz, DMSO-d6) 5 8.04 (d, J = 8 Hz, 1H) , 7.92 (br s,
1H), 7.79-7.65 (m, 3H), 7.49-7.48 (m, 1H), 7.37-7.31 (m, 3H),
.80 (d, J - 8 Hz, I E ) , 5.46 (s, 2H) , 5.33 (s, 2H). ESHRMS
m/z 423.0710 (M+H C2oHisClF3N203 requires 423.0718).
Example 107
3-Bromo-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl) -IHpyridin-
2-one
Step 1. Preparation of 4-Benzyloxy-1-(3-fluorobenzyl)-1Hpyridin-
2-one.
To a solution of 4-benzyloxy-lH-pyridin-2-one (1.0 g, 5 mmol)
and K2C03 (2.0 g, 9.9 mmol) in DMF (30 mL) was added 3-
fluorobenzyl bromide (1.4 g, 7.5 mmol), and the reaction
mixture was heated to 110 °C for 3 h. The reaction mixture
was cooled to room temperature, and partitioned between EtOAc
and water. The organic solution was washed with water and
then brine, dried (Na2S04) , filtered and concentrated under
reduced pressure. Purification by flash column chromatography
(silica, eluent 97:3 to 93:7 methylene chloride /methanol)
afforded 4-benzyloxy-1-(3-fluorobenzyl)-lH-pyridin-2-one (1.04
g, 67% ): XH NMR (300 MHz, CDC13) 5 7.45-7.25 (m, 5H), 7.13 (d,
J= 8 Hz, 1H), 7.10-6.90 (m, 3H) , 6.10-5.95 (m, 2H), 5.07 (s,
2H), 5.00 (s, 2H).
Step 2. Preparation of 1-(3-Fluorobenzyl)-4-hydroxy-lHpyr
idin-2-one.
-330-
To a solution of 4-benzyloxy-l-(3-fluorobenzyl)-IH-pyridin-2-
one (1.79 g, 5.8 mmol) in EtOH (50 mL) was added 10% Pd/C
(0.4 g), and reaction mixture was stirred under a hydrogen
atmosphere for 1.5 h. The reaction mixture was filtered
through diatomaceous earth and concentrated under reduced
pressure to give.1-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one
(0.92 g, 72% ): XH NMR (300 MHz, CDC13) 6 7.55 (d, J = 6 Hz,
1H), 7.40-7.30 (m, 1H), 7.10-6.95 (m, 3H), 6.07 (dd, J = 6 , 3
Hz, 1H), 5.85 (d, J = 3 Hz, 1H), 5.11 (s, 2H).
Step 3. Preparation of 3-Bromo-l-(3-fluorobenzyl)-4-hydroxylH-
pyridin-2-one.
To an ice-cold solution of 1-(3-fluorobenzyl)-4-hydroxy-lHpyridin-
2-one (0.67 g, 3.1 mmol) in AcOH (5.7 mL) was added a
solution of bromine (0.52 g, 3.24 mmol) in AcOH (10.8 mL), and
the reaction mixture was stirred for 5 min. The reaction
mixture was warmed to room temperature and concentrated under
reduced pressure to afford 3-bromo-l-(3-fluorobenzyl)-4-
hydroxy-lH-pyridin-2-one as a yellow solid (1.07 g, crude):
NMR (500 MHz, MeOD) 6 7.64 (d, J = 8 Hz, 1H), 7.35-7.30 (m,
1H) , 7.05-6.90 (m, 3H) , 6.20 (d, J = 8 Hz, 1H) , 5.18 (s, 2H) .
Step 4. Preparation of 3-Bromo-4-(2,4-difluorobenzyloxy)-1-
(3 -fluorobenzyl)-IH-pyridin-2 -one.
To a solution of 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-lHpyridin-
2-one (0.20 g, 0.67) and K2C03 (0.27 g, 1.34 mmol) in
acetone (10 mL) was added 2,4-difluorobenzyl bromide (0.16 g,
0.8 mmol), and the reaction mixture was heated at reflux for 1
h. The reaction mixture was cooled to room temperature,
concentrated under reduced pressure, and the residue was
dissolved*in EtOAc. The organic solution was washed with
water and then brine, dried (Na2S04) , filtered and concentrated
under, reduced pressure. XH NMR (300 MHz., CDC13) 5 7.65--7.5.S
(m, 1H), 7.40-7.25 (m, 2H), 7.15-6.80 (m, 5H) , 6.14 (d, J- 8
Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMSm/z 424.0159 (M+H
Ci9Hi4BrF3N02 requires 424.0155).
Example 108
3-Bromo-l-(3-fluorobenzyl)-4-(2,3,4-trifluorobenzyloxy)-1Hpyridin-
2-one
The title compound was prepared by a procedure similar to the
one described for Example 107 (0.09 g, 39%): mp 176-178 °C; X
NMR (300 MHz, CDC13) 5 7.40-7.25 (m, 4H) , 7.11-6.98 (m, 4H) ,
6.11 (d, J = 9 Hz, 1H), 5.23 (s, 2H), 5.16 (s, 2H). ESHRMS
m/z 442.0060 (M+H C19H13BrF4N02 requires 442.0061)..
Example 109
1-[3-(2-Aminoethyl) benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)
lH-pyridin-2-one
The title compound was prepared from compound of Example 97 by
a procedure similar to the one described for Example 99, as
the TFA salt (0.13 g, 33%): mp 70-74 °C; XH NMR (300 MHz, DMSOds)
6 8.21 (br s, 1H) , 6.60-6.50 (m, 1H) , 7.52 (d, J= 6 Hz,
1H) , 7.30-7.10 (m, 3H) , 7.01 (d, J » 9 Hz, 1H) , 6.94-6.85 (m,
2H) , 6.20 (d, J = 6 Hz, 1H) , 5.20 {s, 2H) , 5.05 (s, 2H) , 3.23
(br s, 2H) , 2.97 (t, J = 8 Hz, 2H) , 2.05 (br s, 2H) . ESHRMS
m/z 449.0698 (M+H C2iH2oBrF2N202 requires 449.0671) .
Example 110
3-Chloro-4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1Hpyridin-
2 -one
Step 1. Preparation of 4-(2,4-difluorobenzyloxy)-1-(3-
fluorobenzyl)-lH-pyridin-2-one.
To a solution of 1-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one
(from Step 2 EXAMPLE 107) (0.92 g, 4.2 mtnol) and K2C03 (1.2 g,
8.4 mmol) in acetone (62 mL) was added 2,4-difluorobenzyl
bromide (1.3 g, 6.3 mmol), and the reaction mixture was heated
at reflux for 3 h. The reaction mixture was cooled room
temperature, concentrated under reduced pressure, and the
residue was partitioned between water and EtOAc. The organic
solution was washed with brine, dried (Na2S04) , filtered, and
concentrated under reduced pressure. Purification by flash
-333-
column chromatography (silica, eluent methylene chloride to
95:5 methylene chloride/methanol) to provide 4-(2,4-
difluorobenzyloxy)-1-(3-fluorobenzyl)-lH-pyridin-2-one as a
white solid (1.2-1 g, 84%): XH NMR (300 MHz, CDC13) 6 7.45-7.20
(m, 2H), 7.14 (d, J= 8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J
= 3 Hz, 1H), 5.95.(dd, J = 5, 3 Hz, 1H), 5.08 (s, 2H), 5.00
(s, 2H).
Step 2. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-1-
(3 -fluorobenzyl)-IH-pyridin-2-one.
To a solution of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-
lH-pyridin-2-one (0.15 g, 0.4 mmol) in AcOH (3 mL) was added
N-chlorosuccinimide (70 mg, 0.5 mmol), and the reaction
mixture was heated at reflux for 10 min. The reaction mixture
was cooled room temperature and the solvent was removed under
reduced pressure. XH NMR (300 MHz, CDC13) 6 7.60-7.50 (m, 1H) ,
7.45-7.20 (m, 2H) , 7.10-6.80 (m, 5H) , 6.16 (d, J = 8 Hz, 1H) ,
5.21 (s, 2H), 5.15 (S, 2H). ESHRMS m/z 380.0641 (M+H
Ci9Hi4ClF3N02 requires 480.0660).
Examples 111-123
The following example compounds were prepared by procedures
similar to that described for Example 107. The yields and the
analytical data are described below.
Example 111
3-Bromo-4-(3-chlorobenzyloxy)-1-(3-fluorobenzyl)-lH-pyridin-2-
one
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 107 (0.12 g, 42%): mp 149-153 °C; XH
NMR (300 MHz, CDC13) 6 7.40-7.23 (m, 6H) , 7.09 (d, J = 8 Hz,
1H), 7.05-6.95 (m, 2H), 6.05 (d, J = 8 Hz, 1H), 5.19 (s, 2H),
5.14 (s, 2H). ESMS ra/z M+H 442.
Example 112
3-Bromo-4-(3,4-difluorobenzyloxy)-1- (3-fluorobenzyl)-1Hpyridin-
2 -one
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 107 (0.08 g, 48%): mp 172-174 °C; XH
NMR (300 MHz, CDC13) 5 7.40-6.95 (m, 8H) , 6.05 (d, J= 6 Hz,
1H) , 5.16 (s, 4H) . ESHRMS ra/z 424.0111 (M+H C19H14BrF3NO2
requires 424.0155).
Example 113
3-Bromo-l-(3-fluorobenzyl)-4-(4-fluorobenzyloxy)-lH-pyridin-2-
one
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 107 (0.07 g, 35%): mp 180-183 °C; XH
NMR (300 MHz, CDC13) 6 7.50-7.25 (m, 5H) , 7.15-7.00 (m, 4H),
6.07 (d, J= 8 Hz, 1H), 5.18 (s, 2H), 5.14 (s, 2H). ESHRMS
m/z 406.0258 (M+H C19Hi5BrF2N02 requires 406.0249).
Example 114
3-Bromo-l-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-lH-pyridin-2-
one
To an ice-cold solution of 1-(3-fluorobenzyl)-4-(3-
f luorobenzyloxy) -IJf-pyridin-Z-one (0. l*g, 0.43 rnracrl,)
(2 inL) was addeci: a. scrlutioa; of~ bromiiae?-(72? mgf, 0:. 4^=. mmoU'
AcOH (1 mL), and the reaction mixture was stirred for 5 min.
The reaction mixture was warmed to room temperature and the
solvent was removed under reduced pressure. XH NMR (300 MHz,
CDC13) 5 7.45-6.95 (m, 9H), 6.05 (d, J = 8 H z , 1H), 5.21 (a,
2H) , 5.14 (a, 2H) . ESHRMS m/z 406.0254 (M+H Ci9Hi5BrF2N02
requires 406.0249).
Examples 115-123
The compounds of Examples 115-123 are prepared essentially
according to the procedures set forth above for Example 107:
XH NMR (300 MHz, CDC13) 5 7.35-7.20 (m, 4H) , 7.15-6.85 (m, 5H) ,
6 . 0 7 - C d , LT = 8 Hs, 1H) , 5.21 (s , 2H) , 5.13 (s , 2H) , 3.82 (B,
3H)
1H NMR (300 MHz, CDC13) 6 7.45-7.20 (m, 4H) , 7.10-6.95 (m, 3H) ,
6.11 (d, J = 8 Hz, 1H) , 5.19 (s, 2H) , 5.14 (s, 2H) , 1.32 ( a ,
9H)
XH NMR (300 MHz, CDC13) 5 7.40-6.90 (m, 9H) , 6.08 (d, J = 8 Hz, .
1H) , 5.19 (s, 2H) , 5.14 (s , 2H) , 2.37 ( s , 3H)
XH NMR (300 MHz, CDC13) 6 7.67-7.53 (m, 4H) , 7.31-724 (m, 2H) ,
7.09-6.98 (m, 3H) , 6.04 (d, J = 8 Hz, 1H) , 5.26 (s, 2H) , 5.14
(s, 2H)
XH NMR (300 MHz, CDC13) 6 7.71 (dd, J = 8, 2 Hz, 2H) , 7.58-7.55
(m, 2H), 7.29-7.25 (m, 2H) , 7.09 (d, J = 8 Hz, 1H) , 7.03-6.98
(m, 2H) , 6.03 (dd, J = 8, 2 Hz, 1H) , 5.26 ( a , 2H) , 5.15 (s, 2H)
H NMR (300 MHz, CDC13) 5 7.45-6.90 (m, 9H) , 6.15-6.10 (m, 1H) ,
5.18 (s, 2H) , 5.15 (s, 2H) , 2.38 (s, 3H)
1H NMR (300 MHz, CDC13) 6 7.70-7.65 (m, 1H) , 7.55-7.25 (m, 9H)
7.14 (d, . 7 = 8 Hz, 1H) , 7.10-6.95 (m, 3H) , 5.81 (d, J = 8 Hz,
1H) , 5.12 (s, 2H) , 5.08 (s, 2H)
1H NMR (300 MHz, CDC13) 6 7.40-7.25 (m, 3H) , 7.15-6.90 (m, 6H) ,
6.15-6.10 (m, 1H) , 5.16 (s, 2H) , 5.14 (s, 2H) , 3.82 (s, 3H)
H NMR (3od MHz, CDC13) 6 8.06 (dd, J « 8, 1 Hz, 1H) , 7.87 (d, J
= 8 Hz, 1H) , 7.70-7.60- (m, 1H) , 7.50-7.25 (m, 3H) , 7.09 (d, J
= 8 Hz, 1H) , 7.05-6.95 (m, 2H) , 6.19 (d, J •= 8 Hz, 1H) , 5.65
(s, 2H) , 5.16 (s, 2H), 3.91 (s, 3H)
Example 124
3-Bromo-l-(3-fluorobenzyl)-4-(2-hydroxymethylbenzyloxy)-1Hpyridin-
2-one
Step 1. Preparation of 3-Bromo-l-(3-fluorobenzyl)-4-(2-
hydroxymethylbenzyloxy)-lH-pyridin-2-one.
To an ice-cold solution of methyl 2-[3-bromo-l-(3-
fluorobenzyl)-2-oxo-l,2-dihydro-pyridin-4-yloxymethyl]benzoate
(0.12 g, 0.28 mmol) in THF (5 mL) was added LiBH4 (0.15 mL of a
2.0 M solution in THF, 0.30 mmol), and the reaction mixture
heated at reflux for 5 hours. The reaction mixture was cooled
to room temperature, the solvent was removed under reduced
pressure, and the residue dissolved in EtOAc. The organic
solution was washed with brine, dried (Na2S04) , filtered, and
concentrated under reduced pressure. XH NMR (300 MHz, DMSO-d6)
d 7.98 (d, J= 8 Hz, 1H), 7.46-7.28 (m, 5H), 7.15-7.10 (m,
3H), 6.56 (d, J = 8 Hz, 1H), 5.35 (a, 2H), 5.25 (brs, 1H),
5.14 (s, 2H) . ESHRMS m/z 418.0453 (M+H C2oHi8BrFNO3 requires
418.0449).
Example 126
2-{2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]-
phenyl}acetamide
Step 1. Preparation of (2-Bromomethylphenyl)acetic acid.
A solution of isochroman-3-one (1.5 g, 10 mmol) in 30% HBr in
acetic acid (13 mL) was stirred at room temperature for 2 h,
and 70 °C for 1 h. The reaction mixture was cooled to room
temperature, and poured into ice-water. The precipitate was
collected to afford (2-bromomethylphenyl)acetic acid as an
off-white solid (2.15 g, 93%): XH NMR (300 MHz, DMSO-ds) 5
7.45-7.23 (m, 4H), 4.73 (s, 2H), 3.73 (s, 2H).
Step 2. Preparation of Methyl (2-Bromomethylphenyl)acetate,
-339-
To an ice-cold solution of (2-bromomethylphenyl)acetic acid (1
g, 4.4 mmol) in THF (2.4 mL) was added
trimethylsilyldiazomethane (3 mL of a 2 M solution in hexanes,
6 mmol), and the reaction mixture was stirred for 14 h. The
reaction was quenched with AcOH, and the solvent was removed
under reduced pressure. Purification by flash column
chromatography (silica, eluent 98:2 to 94:6 methylene
chloride/hexanes) afforded methyl (2-bromomethylphenyl)acetate
as a light yellow solid (0.34 g, 32%): *H NMR (300 MHz, CDC13)
5 7.40-7.20 (m, 4H), 4.59 (s, 2H), 3.81 (s 2H), 3.71 (s, 3H).
Step 3. Preparation of Methyl {2-[3-bromo-4-(2,4-
difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]phenyl}acetate.
Methyl {2-[3-bromo-4-(2, 4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]-phenyl}acetate was prepared by a procedure similar
to the one described for EXAMPLE 74 (0.41 g, 68%) : *H NMR (300
MHz, CDC13) a 7.55-6.81 (m, 8 H), 6.10 (d, J= 6 Hz, 1H), 5.20
(S, 4 H), 3.78 (s, 2H), 3.60 (s, 3H).
Step 4. Preparation of 2-{2-[3-Bromo-4-(2,4-
difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
phenyl}acetamide.
2-(2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
phenyl}-acetamide was prepared by a procedure similar
to the one described for Example 102 (0.07 g, 72%): mp 178-
183 °C; '•H NMR. (300 MHz, DMSO-ds) 5 7.89 (d, J = 8 Hz, 1H)
7.66 (d, J m 9 Hz, 1 H), 7.54 (brs, 1H), 7.35 (brs, 1H),
7.30-7.15 (m, 4H), 6.98 (brs, 1H), 6.85 (d, J = 7 Hz, 1H),
6.60 (d, J = 8 Hz, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 3.62 (s,
2H) . ESHRMS m/z 463.0442 (M+H C2iH1BBrF2N203 requires 463.0463).
Example 127
-340-
Ethyl (3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl] -phenyl}acetate
Step 1. Preparation of Ethyl (3-bromomethylphenyl) acetate.
To a mixture of m-tolylacetic acid ethyl ester (3.0 g, 16.8
mmol) and N-bromosuccinimide (3.0 g, 16.8 mmol) was added
carbon tetrachloride (45 mL), followed by benzoyl peroxide (5
mg), and the reaction mixture was heated at reflux for 16 h.
The reaction mixture was cooled to room temperature, filtered,
and concentrated under reduced pressure. Purification by
flash column chromatography (silica, eluent 5:95 to 2:3
EtOAc/hexanes) afforded ethyl (3-bromomethylphenyl) acetate as
an off-white solid (0.89 g, 21% ): XH NMR (300 MHz, CDC13) 5
7.32-7.21 (m, 4H), 4.48 (s, 2H), 4.16 (q, J = 6 Hz, 2H), 3.63,
(s, 2H), 1.27 (t, J = 6 Hz, 3H).
Step 2. Preparation of Ethyl (3-[3-Bromo-4-(2,4-
difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]phenyl}acetate.
Ethyl {3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-
1-ylmethyl]phenyl}-acetate was prepared by a procedure similar
to the one described for EXAMPLE 74 (0.27 g, 69%): mp 95-98
°C; XH NMR (300 MHz, CDC13) 6 7.65-7.55 (m, 1H) , 7.40-7.20 (m,
5H) , 7.00-6.80 (m, 2H), 6.09 (d, J = 9 Hz, 1H), 5.21 (s, 2H),
5.16 (S, 2H), 4.14 (q, J = 6 Hz, 2H), 3.60 (s, 2H), 1.25 (t, J
= 6 Hz, 3H) . ESHRMS m/z 492.0655 (M+H C23H2iBrF2NO4 requires
435.0617).
Example 128
0
2-{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-lylmethyl]
phenyl} acetamide
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 102 (0.07 g, 28%): mp 164-167 °C; ^
NMR (300 MHz, DMSO-d6) 5 7.96 (d, J= 9 Hz, 1H), 7.70-7.60 (m,
1H), 7.60 (br 3, 1H), 7.50-7.10 (m, 6H), 6.89 (br s, 1H), 6.58
(d, J= 9 Hz, 1H), 5.31 (s, 2H), 5.12 (s, 2H), 3.32 (s, 2H).
ESHRMS m/z 463.0485 (M+H C21Hi8BrF2N203 requires 463.0464).
Example 129
F O
4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-3-methyl-1Hpyridin-
2-one
Preparation of 4- (2,4-Difluorobenzyloxy) -1- (3-
fluorobenzyl)-3-methyl-lH-pyridin-2-one.
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1-(3-
fluorobenzyl)-lH-pyridin-2-one (EXAMPLE 107) (0.14 g, 0.32
mmol) , K2C03 (88 mg, 0.64 mmol) and Cs2C03 (0.10 g, 0.32 mmol)
in dioxane (2 mL) was added Pd(PPh3)4 (18 mg, 0.12 mmol),
followed by trimethylboroxine (40 mg, 0.32 mmol). The
reaction mixture was degassed, purged with argon, and heated
at reflux for 4 h. The reaction mixture was cooled to room
temperature, and partitioned between water and EtOAc. The
organic solution was washed with brine, dried (Na2S04) ,
filtered and concentrated under reduced pressure. Purification
by flash column chromatography (silica, eluent methylene
chloride to 97:3 methylene chloride/MeOH) afforded 4-(2,4-
difluorobenzyloxy)-1-(3-fluorobenzyl)-3-methyl-lH-pyridin-2-
one as a white solid (0.09 g, 79% ): mp 127-129 °C; 1H NMR (300
MHz, CDC13) 5 7.50-7.40 (m, 1H) , 7.35-7.25 (m, 1H) , 7.17 (d, J
= 9 Hz, 1H), 7.06 (d( J = 6 Hz, 1H), 7.00-6.80 (m, 4H), 6.12
(d, J = 9 Hz, 1H), 5.12 (s, 4H), 2.07 (s, 3H). ESHRMS m/z
360.1180 (M+H C2oHi6F3N02 requires 360.1206).
Example 130
4- (2 ,4 -Difluorobenzyloxy) -1- (3-fluorobenzyl) -3-iodo-lHpyridin-
2-one
Step 1. Preparation of 4- (2, 4-Dif luorobenzyloxy) -1- (3-
To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one
(from Step 1, EXAMPLE 110) (0.92 g, 4.2 mmol) and K2C03 (1.15
g, 8.4 mmol) in acetone (62 mL) was added 2,4-difluorobenzyl
bromide (1.3 g, 6;3 mmol), and the reaction mixture was heated
at reflux for 3 h. The reaction mixture was cooled to room
temperature, concentrated under reduced pressure, and the
residue was dissolved in EtOAc. The organic solution was
washed with water and then brine, dried (Na2SO4) , filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, eluent methylene chloride to
95:5 methylene chloride/methanol) provided 4-(2,4-
difluorobenzyloxy)-1-(3-fluorobenzyl)-lH-pyridin-2-one as a
white solid (1.21 g, 84%): XH NMR (300 MHz, CDC13) 6 7.45-7.20
(m, 2H), 7.14 (d, J = 8 Hz, 1H), 7.05-6.75 (m, 5H) , 6.05 (d, J
= 3 Hz, 1H), 5.95 (dd, J = 5, 3 Hz, 1H), 5.08 (s, 2H), 5.00
(s, 2H).
Step 2. Preparation of 4-(2,4-Difluorobenzyloxy)-1-(3-
fluorobenzyl)-3 -iodo-IH-pyridin-2-one.
To a mixture of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-
lH-pyridin-2-one (0.15 g, 0.43 mmol) and N-iodosuccinimide
(0.10 g, 0.46 mmol) in CH3CN (3 mL) was added dichloroacetic
acid (13 mg, 0.10 mmol), and the reaction mixture was heated
to 60 °C for 4 h. The reaction mixture was cooled to room
temperature,, concentrated under reduced pressure, and the
residue was dissolved in methylene chloride. The organic
solution was washed with a saturated solution of NaHCO3 and
then brine, dried (Na2S04) , filtered and concentrated under
reduced pressure. Purification by flash column chromatography
(silica, eluent 90:10 methylene chloride/hexanes to 99:1
methylene chloride/methanol) provided 4-(2,4-
difluorobenzyloxy)-1-(3-fluorobenzyl)-3-iodo-lH-pyridin-2-one
as a white solid (0.15 g, 77%): mp 164-167 °C; 1K NMR (300 MHz,
CDC13) 6 7.65-7.55 (m, 1H) , 7.35-7.26 (m, 2H) 7.15-6.80 (m,
5H), 6.05 (d, J = 6 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H).
ESHRMS m/z 472.0033 (M+H C19Hi4F3IN02 requires 472.0018).
Example 131
NC 6It
4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-2-oxo-l,2-
dihydropyridine-3 -carbonitrile
Step 1. Preparation of 4-Methoxy-2-oxo-l,2-dihydropyridine-3-
carbonitrile.
A solution of 2- (ditnethylaminoethoxymethylene)malononitrile
(1.97 g) in concentrated sulfuric acid (7.0 mL) was stirred at
room temperature for 6.5 h. The reaction mixture was poured
into water, and the precipitate was collected by filtration.
XH NMR (300 MHz, DMSO-ds) 5 12.14 (br s, 1H) , 7.79 (d, J = 9
Hz, 1H), 6.35 (d, J = 9 Hz, 1H), 3.98 (s, 3H).
Step 2. Preparation of 1-(3-Fluorobenzyl)-4-methoxy-2-oxol,
2-dihydro-pyridine-3-carbonitrile.
1-(3-Fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydro-pyridine-3-
carbonitrile was prepared by a procedure similar to the one
described for EXAMPLE 74 (0.56 g, 93%): 1H NMR (300 MHz, CDC13)
57.48 (d, J = 9 Hz, 1H), 7.40-7.27 (m, 1H), 7.00-6.95 (m,
2H), 6.08 (d, J = 9 Hz, 1H), 5.10 (s, 2H), 4.00 (s, 3H).
Step 3. Preparation of 1-(3-Fluorobenzyl)-4-hydroxy-2-oxol,
2-dihydropyridine-3-carbonitrile.
To a solution of sodium hydride (92 mg of a 60% dispersion in
mineral oil, 2.3 mmol) in DMF (7 mL) was added ethanethiol
(0.14 g, 2.2 mmol), followed by a solution of l-(3-
fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydropyridine-3-
carbonitrile (0.23 g, 0.89 mmol) in DMF (2 mL), and the
reaction mixture was heated to 100 °C. The reaction mixture
was cooled to room temperature, acidified with 3 N HC1, and
washed with EtOAc. The organic solution was washed with
brine, dried (Na2S04) , filtered and concentrated under reduced
pressure to give 1-(3-fluorobenzyl)-4-hydroxy-2-oxo-1,2-
dihydro-pyridine-3-carbonitrile as an off-white solid (0.20 g,
91%): aH NMR (300 MHz, MeOD) 5 8.00 (s, 1H), 7.82 (d, J= 8 Hz,
1H) , 7.40-7.3.0 (m, 1H) , 7.15-7.00 (m, 2H) , 6.13 (d, J= 8 Hz,
1H), 5.11 (s, 2H).
Step 4. Preparation of 4-(2,4-Difluorobenzyloxy)-1-(3-
fluorobenzyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile.
4-(2,4-Difluorobenzyloxy)-1-(3-fluorobenzyl)-2-oxo-l,2-
dihydro-pyridine-3-carbonitrile was prepared by a procedure
similar to the one described for EXAMPLE 107 (0.09 g, 30%): mp
187-190 °C; XH NMR (300 MHz, CDC13) 6 7.60-7.45 (m, 2H), 7.40-
7.30 (m, 1H), 7.10-6.50 (m, 5H), 6.13 (d, J= 9 Hz, 1H), 5.27
(s, 2H), 5.10 (s, 2H).
Example 132
-346-
1-Cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl-1Hpyridin-
2-one
Step 1. Preparation of Methyl 1-cyclohexyl-4-hydroxy-2,5-
dimethyl- 6 -oxo-1,6-dihydro-pyridine- 3 -carboxylate.
To a solution of 3-cyclohexylaminobut-2-enoic acid methyl
ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) was added 2-
methylmalonic acid bis-(2,4,6-trichloro-phenyl) ester (2.71 g,
5.72 mmol) and the reaction mixture was heated at 170 °C for 3
h. The reaction mixture was cooled to room temperature, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, eluent methylene chloride to
94:6 methylene chloride/MeOH) and recrystallization from hot
MeOH provided methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-
oxo-1,6-dihydropyridine-3-carboxylate as pale yellow crystals
(0.34 g, 21%): *H NMR (500 MHz, DMSO-ds) 5 9.82 (s, 1H), 4.00-
3.90 (m, 1H), 3.76 (s,.3H), 2.75-2.60 (m, 2H), 2.31 (s, 3H),
1.81 (s, 3H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 3H), 1.40-1.20
(m, 2H), 1.15-1.05 (m, 1H).
Step 2. Preparation of l-Cyclohexyl-4-hydroxy-2,5-dimethyl-6-
oxo-1,6-dihydro-pyridine-3-carboxylic acid.
A solution of methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-
oxo-1,6-dihydro-pyridine-3-carboxylate (0.35 g, 1.25 mmol) in
2 N NaOH (5 mL) was heated at reflux for 3.5 h. The reaction
mixture was cooled room temperature, acidified to pH 1-2.with
1 N HCl, and washed with EtOAc. The organic solution was
washed with brine, dried (MgS04) , filtered and concentrated
under reduced pressure to afford 1-cyclohexyl-4-hydroxy-2,5-
dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid as a
white solid (0.31 g, 94%): ^ NMR (300 MHz, MeOD) 5 4.30-4.00
(br s, 1H), 2.76 (br s, 5H), 1.90 (s, 3H), 1.90-1.80 (m, 2H),
1.75-1.60 (m, 3 H), 1.50-1.15 (m, 3H).
-347-
Step 3. Preparation of l-Cyclohexyl-4-hydroxy-3,6-dimethyllH-
pyridin-2-one.
A solution of l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-
dihydropyridine-3-carboxylic acid (0.15 g, 0.57 mmol) in
concentrated HCl (5 mL) was heated at reflux for 4 h. The
reaction mixture was cooled to room temperature, diluted with
water and washed with EtOAc. The organic solution was washed
with brine, dried (MgS04) , filtered and concentrated under
reduced pressure to give l-cyclohexyl-4-hydroxy-3,6-dimethyllH-
pyridin-2-one as a white solid (0.2 g, 77%); XH NMR (300
MHz, DMSO-dg) 6 9.81 (a, 1H) , 5.73 (s, 1H) , 3.95-3.75 (m, 1H) ,
2.80-2.55 (m, 2H), 2.25 (s, 3H), 1.85-1.40 (m, 5H), 1.72 (s,
3H), 1.38-1.05 (m, 3H).
Step 4. Preparation of 1-Cyclohexyl-4-(2,4-
difluorobenzyloxy) -3,6-dimethyl-IH-pyridin-2-one.
l-Cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl-1Hpyridin-
2-one was prepared by a procedure similar to the one
described for EXAMPLE 107 (0.05 g, 16%): mp 118-120 °C; 1H NMR
(300 MHz, CDC13) 6 7.48-7.41 (m, 1H), 6.95-6.81 (m, 2H), 5.87
(s, 1H) , 5.07 (s, 2'H) , 4.05-3.85 (m, 1H) , 3.00-2.80 (m, 2H) ,
2.35 (s, 3H), 1.98 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.55 (m,
3H), 1.40-1.20 (m, 3H).
Example 133
3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(lH-pyrasol-4-
ylmethyl) -lH-pyridin-2-one
Step 1. Preparation of 4-Methylpyrazole-l-carboxylic acid
tert-butyl ester.
To a solution of 4-methyl-IH-pyrazole (1 g, 12 mmol) and DMAP
(0.15 g, 1.2 mmol) in CH3CN (20 mL) was added di-tert-butyl
dicarbonate (2.8 g, 13 mmol), and the reaction mixture was
stirred for 1 h. The reaction mixture was concentrated under
reduced pressure, and the residue dissolved in EtOAc. The
organic solution was washed with 1 N HC1, water and then
brine, dried (MgSO4) , filtered, and concentrated under reduced
pressure to provide 4-methyl-pyrazole-l-carboxylic acid tertbutyl
ester as a light yellow oil (2.2 g, 100%) : XH NMR (300
MHz, CDC13) 5 7.83- (s, 1H) , 7.53 (s, 1H) , 2.09 (s, 3H) , 1.64
(s, 9H).
Step 2. Preparation of 4-Bromomethylpyrazole-l-carboxylic
acid tert-butyl ester.
To a solution of 4-methylpyrazole-l-carboxylic acid tert-butyl
ester (1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL) was
added N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl
peroxide (50 mg), and the reaction mixture was heated at
reflux for 16 h. The reaction mixture was cooled to room
temperature, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography
(silica, 1:4 EtOAc/hexanes) provided 4-bromomethylpyrazole-lcarboxylic
acid tert-butyl ester as a light yellow oil (0.42
g, 30%): 1H NMR (300 MHz, CDC13) 5 8.10 (s, 1H), 7.74 (s, 1H),
4.39 (s, 2H), 1.65 (s, 9H).
-34-9t~
Step 3. Preparation of 4- [3-Chloro-4-(2,4-difluorobenzyloxy)-
6-methyl-2-oxo-2H-pyridin-l-ylmethyl]pyrazole-l-carboxylic
acid tert-butyl ester.
4-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2Hpyridin-
l-ylmethyl]pyrazole-l-carboxylic acid tert-butyl ester
was prepared by a procedure similar to the one described for
EXAMPLE 632: XH NMR (300 MHz, CDC13) 3 8.09 (a, 1H) , 7.72 (s,
IE) , 7.53 (app q, J = 6 Hz, IE), 6.97-6.82 (m, 2H) , 6.00 (s,
1H), 5.19 (S, 2H), 5.13 (s, 2H), 2.43 (s,,3H), 1.63 (s, 9H).
Step 4. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-6-
methyl-1-(IH-pyrazol-4-ylmethyl)-lH-pyridin-2-one.
4- [3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2Hpyridin-
1-ylmethyl]pyrazole-1-carboxylic acid tert-butyl ester
(0.16 g, 0.34 mmol) was heated to 140 °C for 16 h. The
reaction mixture was cooled to room temperature. XH NMR (300
MHz, CDC13) 6 8.33 (s, 2H), 7.68 (d, J= 6 Hz, 1H), 7.52 (app
q, J = 6 Hz, 1H), 6.93-6.83 (m, 2H), 6.47 68 (d, J = 9 Hz,
1H), 5.19 (S, 2H), 5.24 (s, 2H), 5.20(s, 2H).
Example 134
4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methylJbenzonitrile
Preparation of 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyljbenzonitrile. 3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methylpyridin-2(1H)-one(1.0 g, 3.6 tranol) was dissolved in
N,N-dimethyIformamide (5 raL) . a-Bromo-p-tolunitrile (0.85g,
4.3 mmol) was added followed by K2CO3 (0.59 g, 4.3 mmol) . The
resulting mixture was heated to 80 °C for 16 h. The reaction
was concentrated to an oil that was partitioned between water
and ethyl acetate and extracted with ethyl acetate (3 x 100
ml). The organic extracts were combined, washed with brine,
dried over Na2S04, and filtered. The filtrate was concentrated
to an oil, and purified by chromatography (silica gel,
hexane/ethyl acetate) to yield a white solid (0.65 g, 46%). 1H
NMR (400 MHz, CDC13) $ 7.62 (d, J = 8.4 Hz, 2H) , 7.41-7.31 (m,
7H), 7.23 (d, J = 7.6 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 5.24
(s, 2H) , 5.18 (s, 2H) . ES HRMS m/z 395.0404 (M+H C2oHi5BrN202
requires 395.0390).
Example 135
3-{ [4- (benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyljbenzonitrile
The title- compound was prepared by a procedure essentially as
described in example 134. XH NMR (400 MHz, CDC13) 5 7.62-7.54
(m, 3H), 7.45 (d, J = 7.6Hz, 1H), 7.43-7.31 (m, 5H), 7.26 (d,
J = 1.6 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 5.24 (s, 2H), 5.15
(s, 2H) . ES HRMS m/z 395.0420 (M+H C2oHi5BrN202 requires
395.0390) .
Example 136
2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)
yl] methylJbenzonitrile
The title compound was prepared by a procedure essentially as
described in example 134. XH NMR (400 MHz, CDC13) 5 7.74 (d, J
= 8.4 Hz, IH) ; 7.63 (dd, J = 1.2, 8.0 Hz, IH) , 7.57 (dt, J =
1.2, 8.4 Hz, IH), 7.55 (d, J=8.0Hz, IH); 7.43-7.30 (m, 6H),
6.13 (d, J = 8.0 Hz, IH,), 5.33 (s, 2H), 5.23 (s, 2H). ES
HRMS m/z 395.0398 (M+H C2oHi5BrN202 requires 395.0390).
Example 137
1-[4-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(IH)-
one
Preparation of 1-[4-(aminomethyl)benzyl]-4-(benzyloxy)-3-
bromopyridin-2(IH)-one. EXAMPLE 134 (100 mg, 0.25 mmol) was
dissolved in tetrahydrofuran (2 mL) under N2. Borane
-352-
dimethylsulfide complex (0.25 rnL, O.Smmol, 2M in
tetrahydrofuran) was added. The reaction was then heated to
70'C and shaken overnight. The mixture was cooled and all
the solvent was distilled under vacuum. The resulting residue
was partitioned between ethyl acetate and 0.2 N NaOH, and
extracted with ethyl acetate (3 x 10 mL). The organic
extracts were combined, washed with brine, dried over Na2S04,
and filtered. The filtrate was concentrated to an oil, and
triturated with dichloromethane and hexane to give an offwhite
solid. (80 mg, 80%) . XH NMR (400 MHz, dgDMSO) 8 7.90 (d,
•J - 7.6HZ,'1H); 7.43-7.21 (m, 9H), 6.70 (d, J=7.6Ez, 1H),
5.29 (s, 2H), 5.08 (s, 2H), 3.71 (s, 2H). ES HRMS m/z
399.0721 (M+H C2oHi9BrN202 requires 399.0703).
Example 138
1-[3-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(1H)
one
The title compound was prepared by a procedure essentially as
described in Example 137 using the title compound of Example
135 as starting material. XH NMR (400 MHz, d6DMSO) 5 7.90 (d,
J=7.6Hz, 1H), 7.44-7.22 (m, 9H), 6.50 (d, J=7.6Hz, 1H),
5.30 (s, 2H), 5.12 (s, 2H), 3.88 (s, 2H). ES HRMS m/z
399.0730 (M+H C2oH19BrN2O2 requires 399.0703).
Example 139
1-[2-(arainomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(IH)-
one
The title compound was prepared by a procedure essentially as
described in Example 137 using the title compound of Example
136 as starting material. XH NMR (400 MHz, d6DMSO) 5 7.88 (d, J
= 8.0 Hz, IH); 7.45-7.34 (m, 5H), 7.26- 7.21 (m, 3H); 6.85 (d,
Js'7.2 Hz, IH) , 6.53 (d, J=7.6 Hz, IH) , 5.32 (s, 2H) , 5.12 (s,
2H) , 3.90 (s, 2H) . ES HRMS m/z 399.0699 (M+H C20H19BrN202
requires 399.0703).
Example 140
4-{ [4- (benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methylJbenzamide
Preparation of 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl}benzamide. EXAMPLE 134 (100 mg, 0.25 mmol) was added
to a suspension of potassium fluoride (40% on alumina) in tbutyl
alcohol, heated to 85*C, and stirred for 2Oh. The
alumina was removed by filtration and washed with
dichloromethane and water. The resulting filtrate was
separated and the aqueous layer was extracted with
dichloromethane (2 x 20 mL) . The organic extracts were
combined, dried over Na2SO4/ and filtered. The filtrate was
concentrated to an oil . Trituration with dichloromethane and
hexane gave a solid (11.5 mg, 11%). XH NMR (400 MHz, dgDMSO) 5
7.94 (d, J = 8.0 Hz, 1H) , 7.80 (d, J = 8.4 Hz, 2H) ; 7.43-7.29
(m, 7H) , 6.51 (d, J=7.6 Hz, 1H) , 5.31 (s, 2H) , 5.16 (s, 2H) .
ES HRMS m/z 413.0541 (M+H CsoH^BrNzC^ requires 413.0495).
Example 141
3-{ [4- (benzyloxy) -3-bromo-2-oxopyridin-l (2H) -
yl] methyl} benzamide
The title compound was prepared by a procedure
essentially as described in Example 140 using the title
compound of Example 135 as starting material. XH NMR (400 MHz,
d6DMSO) 6 7.95 (d, J = 7.6 Hz, 2H), 7.76 (m, 2H); 7.43-7.26 (m,
8H), 6.51 (d, J=7.6 Hz, 1H), 5.31 (s, 2H), 5.15 (s, 2H).
ESHRMS m/z 413.0497 (M+H C2oHi7BrN203 requires 413.0495).
Example 142
2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl}benzamide
The title compound was prepared by a procedure
essentially as described in Example 140 using the title
compound of Example 136 as starting material. XH NMR (400 MHz,
d6DMSO) 5 7.78 (d, J = 7.6 Hz, 1H), 7.54 (dd, J = 1.6, 7.6 Hz,
1H); 7.45 (d, J=7.6Hz, 2H); 7.44-7.32 (m, 5H), 7.15 (d, J=7.6
Hz, 1H), 6.49 (d, J=7.6 Hz, 1H), 5.39 (s, 2H), 5.30 (s, 2H).
ES HRMS m/z 4413.0506 (M+H C2oH17BrN203 requires 413.0495).
Example 143
Methyl 3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl'] methyl} benzoate
Preparation of Methyl 3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-
K2H) -yl] methyl Jbenzoate. EXAMPLE 134 (100 rag, 0.25 mmol) was
suspended in methanol and cooled to O'C. HCl (g) was bubbled
through the mixture until saturated (-30 minutes). The
reaction was warmed to ambient temperature and stirred for 4
hours. HCl and methanol were removed in vacua, yielding an
oil, that was purified by chromatography (silica gel,
hexane/ethyl acetate) to yield a white solid (3 mg, 3%). 1H NMR
(400 MHz, CD3OD) 6 7.98 (app d, «7 = 8.0 Hz, 2H) , 7.77 (app d, J
= 8.0 Hz, 1H); 7.55 (app d, J = 8.0 Hz, 2H); 7.41-7.35 (m,
5H), 6.52 (d, J = 7.6 Hz, 1H), 5.31 (a, 2H), 5.27 (s, 2H);
3.88, (s, 3H) . API-ES MS m/z 429.0 (M+H C2iHi8BrN04 requires
428,0492).
Example 144
Methyl 4-{ [4- (benzyloxy) -3-bromo-2-oxopyridin-l (2H) -
yl]methyl}benzoate
The title compound was prepared by a procedure essentially as
described in Example 143 using the title compound of Example
134 as starting material. *H NMR (400 MHz, CD3OD) 6 7.94 (app
d, J = 8.4 Hz, 2H), 7.76 (app d, J = 7.6 Hz, 1H); 7.46 (app d,
J= 8.0 Hz, 2H) ; 7.39-7.35 (m, 5H) , 6.51 (d, J=7 . 6 Hz, 1H) ,
5.31 (S, 2H), 5.26 (s, 2H); 3.88, (s, 3H). ES HRMS m/z
428.0492 (M+H C2iH1BBrN04 requires 428.0492).
Example 145
4- [4- (benzyloxy) -3-bromo-2-oxopyridin-l (2H) -yl]benzonitrile
Preparation of 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-l (2H) -
yl]benzonitrile 3-bromo-4- [ (2, 4-dif luorobenzyl) oxy] -6-
methylpyridin-2 (1H) -one (100 mg, 0.36 tnmol) was suspended in
dimethylsulfoxide (5 mL) , cesium carbonate (375 mg, 1.15 mmol)
was added and the reaction was shaken for 5 minutes. 4-
Fluorobenzonitrile (52 mg, 0.43 mmol was then added, the
reaction was heated to 80' C, and stirred. Reaction was
monitored by LC/MS, and after 4h was heated to 100'C and
stirred for 16 hours. Reaction mixture was partitioned
between water and ethyl acetate and extracted with ethyl
acetate (5 x 50 mL) . The organic extracts were combined,
washed with brine, dried over Na2SO4, and filtered. The
filtrate was concentrated to an oil, and purified by
chromatography (silica gel, hexane/ethyl acetate) to yield a
white solid (40 mg, 29%). XH NMR (400 MHz, CDC13) 6 7.77 (d,
= 8.4 Hz, 2H) , 7.52 (d, J=8.8Hz, 2H) , 7.44-7.42 (m, 4H) ,
7.28 (d, J m 7.6 Hz, 1H) , 7.26 (s, 1H) , 6.24 (d, J = 7.6 Hz,
1H) ; 5.31, (s, 2H) . ES HRMS m/z 381.0230 (M+H C19Hi3BrN202
requires 381.0233) .
Example 146
2- [4- (benzyloxy) -3-bromo-2-oxopyridin-l (2H) -yljbenzonitrile
-358-
Preparation of 2-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]benzonitrile 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2 (IH) -one (100 mg, 0.36 mmol) was suspended in
dimethylsulfoxide (5 mL), cesium carbonate (375 mg, 1.15 mmol)
was added and the reaction was shaken for 5 minutes. 4-
Fluorobenzonitrile (52 mg, 0.43 mmol) was then added and the
reaction was heated to 80*C with stirring. Reaction was
monitored by LC/MS, and after 4h was heated to 100'C and
stirred for 16 hours. The reaction mixture was partitioned
between water and ethyl acetate and extracted with ethyl
acetate (5 x 50 mL). The organic extracts were combined,
washed with brine, dried over Na2S04, and filtered. The
filtrate was concentrated to an oil, and purified by
chromatography (silica gel, hexane/ethyl acetate) to yield a
white solid (18 mg, 13%) . *H NMR (400 MHz, CDC13) 6 7.81 (dd, J
=1.2, 8.4 Hz, IH), 7.73 (dt, J = 1.2, 8.0 Hz, IH), 7.57 (dt,
J = 0.8, 8.0 Hz, IH), 7.50-7.36 (m, 6H), 7.27 (d, J = 8.0
IH), 6.28 (d, J = 8.0 Hz, IH); 5.31 (s, 2H). ES HRMS m/z
381.0249 (M+H Ci9Hi3BrN2O2 requires 381. 0233) .Example 147
(4-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]methyl}phenyl)acetic acid
-359-
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(IH)-
one(0.5g, I.IB ramol) was dissolved in AT,.N-dimethylformamide (5
mL) . 4-(Bromomethyl)phenylacetic acid (0.5 g, 2.14 mmol) was
added followed by K2C03 (0.3 g, 2.14 ramol). The reaction was
heated to 80"C and shaken for 16 hours, then heated to 100'C
and shaken for 16 hours more. The reaction mixture was
partitioned between water and ethyl acetate and extracted with
ethyl acetate (2 x 50 mL). The aqueous layer was acidified
(pH 2) with IN HC1 and extracted with ethyl acetate (3 x 50
ml). The organic extracts were combined, washed with brine,
dried over Na2S04, and filtered. The filtrate was concentrated
to an oil, and purified by chromatography (silica gel,
hexane/ethyl acetate) followed by reversed phase
chromatography (Cia, 0.1% aqueous trifluoroacetic acid
/acetonitrile) to yield a white solid (25 mg, 3%). 1H NMR (400
MHz, CDC13) 6 7.40-7.38 (m, 3H) , 7.25-7.20 (m, 7H) , 6.05 (d, J
= 8.0 Hz, IH), 5.21 (s, 2H); 5.13, (s, 2H); 3.62, (s, 2H).
ES HRMS m/z 428.0510 (M+H C2iH18BrN04 requires 428.0492).
Example 148
{4-[(4-(benzyloxy)-3-bromo-2-{[4-(carboxymethyl)benzyl]oxy}-
llambdas-pyridin-l-yl)methyl]phenyljacetic acid
-360-
Preparation of (4-[(4-(benzyloxy)-3-bromo-2-{[4-
(carboxymethyl) benzyl] oxy} -llambdas-pyridin-lyl)
methyl]phenyl]acetic acid. The desired product was isolated
by reversed phase chromatography (Ci8, 0.1% aqueous
trifluoroacetic acid/acetonitrile) using the preparation of
Example 147 yielding a white solid (53 mg, 5%). XH NMR (400
MHz, CDC13) a 7.40-7.38 (m, 3H) , 7.27-7.24 (m, 6H) , 7.20 (d, J
= 7.6 Hz, IH), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.4 Hz,
IH), 6.06 (d, J = 7.6 Hz, IH), 5.21 (s, 2H); 5.11 (s, 2H) ;
5.11 (s, 2H); 3.63 (s, 2H); 3.58 (s, 2H). ES HRMS m/z
576.1009 (M+H C3oH28BrN06 requires 576.1016).
Example 149
2-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyl}benzonitrile
Preparation of 2-{[3-bromo-4-[ (2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl] methyl}benzonitrile. 3-bromo-4-
(2,4-difluorophenoxy)-6-methylpyridin-2(IH)-one (50 mg, 0.15
mmol) was dissolved in tetrahydrofuran (2 mL). a-Bromo-otolunitrile
(44 mg, 0.23 mmol) was added followed by sodium
hydride (7.2 mg, 0.18 mmol, 60% in mineral oil) and sodium
iodide (56 mg, 0.38 mmol). The reaction was heated to 50'C
and stirred for 16 hours. The reaction was filtered through
Celite and the filtrate was concentrated to an oil that was
partitioned between water and ethyl acetate and extracted with
-361-
ethyl acetate (4 x 10 mL). The organic extracts were
combined, washed with brine, dried over MgS04, and filtered.
The filtrate was concentrated to an oil, and purified by
chromatography (silica gel, hexane/ethyl acetate) to yield a
white solid (25 mg, 37%). XH NMR (400 MHz, CDC13) 5 7.68 (dd, J
- 8.0, 1.2 Hz, 1H); 7.58 (app q, J - 8.8 Hz, 1H); 7.52 (dt, J
= 8.0 & 1.2 Hz, in), 7.38 (t, J = 7.6 Hz, 1H); 7.08 (d, J =
8.8 Hz, 1H), 7.00-6.93 (m, 1H); 6.89-6.84 (m, 1H); 6.05 (s,
1H) , 5.57 (s, 2H) , .5.22 (s, 2H) ; 2.28, (s, 3H) . ES HRMS m/z
445.0335 (M+H C2iHisBrF2N202 requires 445.0358).
Example 150
3-{[3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methylJbenzonitrile
The title compound was prepared by a procedure essentially as
described in Example 149 using 3-bromo-4-(2,4-
difluorophenoxy)-6-methylpyridin-2(1H)-one (1 g, 3.0 mmol) as
starting material. *H NMR (CDC13, 400 MHz) 6 7.61-7.55 (m,
2H) ; 7.45-7.41 (m, 3H); 6.98-6.94 (m, 1H) ; 6.89-6.84 (m, • 1H) ;
6.03 (s, 1H), 5.36 (s, 2H), 5.22 (s, 2H); 2.30, (s, 3H). ES
HRMS m/z 445.0349 (M+H C2iHi5BrF2N202 requires 445.0358)
Example 151
4-{ [3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridinl(
2H)-yl]methyl}benzonitrile
The title compound was prepared by a procedure essentially as
described in Example 149 using 3-bromo-4-(2,4-
difluorophenoxy)-6-methylpyridin-2(IH)-one (1 g, 3.0 mmol) as
starting material. *H NMR (400 MHz, CDC13) 6 7.61 (d, J = 8.4
Hz, 2H); 7.62-7.56 (m, IH); 7.27 (d, J = 8.8 Hz, 2H); 6.95
(app t, J = 8.4 Hz, IH) , 6.88-6.83 (m, IH) ; 6.03 (s, IH) , 5.39
(s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 445.0359
(M+H C21HiSBrF2N202 requires 445.0358).
Example 152
4-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyljbenzamide
EXAMPLE 151 (50 mg, 0.11 mmol) was added to a suspension or
potassium. fLuojride (4-0-% on alumina) in t-butyl alcohol. The-
reaction was heated to 90'C and stirred for 20 hours.
Alumina was removed by filtration and washed with
dichloromethane and water. The resulting filtrate was
separated and the aqueous layer was extracted with
dichloromethane (2 x 20 mL). The organic extracts were
combined, dried over Na2S04 and filtered. The filtrate was
concentrated to an oil which was purified by chromatography
(silica gel, hexane/ethyl acetate) to yield a white solid,
yielding the product (13 mg, 25%) . *H NMR (400 MHz, CDC13) 5
7.75 (app d, J = 8.4 Hz, 2H), 7.58 (app q, J = 8.4 Hz, 1H);
7.24 (d, J = 8.4 Hz, 2H); 6.98-6.94 (m, 1H) , 6.89-6.83 (m, 1H)
6.01 (s, 1H); 5.40 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES
HRMS m/z 463.0486 (M+H C2iHi7BrF2N203 .requires 463.0463).
Example 153
Methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzoate
EXAMPLE 151 (50 mg, 0.11 mmol) was suspended in methanol and
cooled to O'C. HC1 (g) was bubbled through the mixture until
saturated (-30 minutes). Reaction was sealed, warmed to
ambient temperature, and stirred for 2 hours. HCl and
methanol were removed in vacuo, yielding an oil, that was
purified by chromatography (silica gel, hexane/ethyl acetate)
to yield a white solid (19 mg, 36%) . XH NMR (400 MHz, CDC13) 5
7.97 (app d, J = 8.4 Hz, 2H), 7.58 (app q, J = 8.0 Hz, 1H);
7.22 (d, J=8.4Hz, 2H); 6.95 (appdt, J-1.5, 9.6Hz, 1H),
6.89-6.83 (m, 1H) , 6.00 (a, 1H); 5.41 (s, 2H), 5.21 (a, 2H);
3.90, (s, 3H); 2.27 (a, 3H). ES HRMS m/z 478.0461 (M+H
C22HiBBrN04 requires 478.0460).
Example 154
Methyl 3-{ [3-bromo-4- t:(2 , 4-dif luorobenzyl) oxy] -6-methyl-2-
oxopyridin-1(2H)-yl]methyljbenzoate
The title compound was prepared by a procedure essentially as
described in Example 149 using the title compound of Example
150 as starting material. XH NMR (400 MHz, CDC13) 6 7.95-7.92
(m, 1H) ; 7.84 (bs, 1H) ; 7.58 (app q, J = 8.0 Hz, 1H); 7.39-
7.37 (m, 2H); 6.95 (app dt, J = 1.6, 8.4 Hz, 1H), 6.88-6.83
(m, 1H), 6.00 (S, 1H); 5.40 (s, 2H), 5.21 (s, 2H); 3.90, (s,
3H) ; 2.30 (s, 3H) . ES HRMS m/Z 478.0449 (M+H C22H18BrN04
requires 478.0460).
Example 155
3-{ [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-
1(2H) -yl]methyl}benzamide
The title compound was prepared by a procedure essentially as
described in Example 152 using the title compound of Example
150 as starting material. 1U NMR (400 MHz, CDC13) 5 7.68-7.66
(m, 2H), 7.57 (app q, J = 8.4 Hz, 1H); 7.42-7.34 (m, 2H);
6.98-6.92 (m, 1H), 6.89-6.83 (m, 1H) 6.01 (s, 1H); 5.39 (s,
2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 463.0461 (M+H
C2iHi7BrF2N203 requires 463.0463).
Example 156
2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyl}benzamide
The title compound was prepared by a procedure essentially as
described in Example 152 using the title compound of Example
149 as starting material. XH NMR (400 MHz, CDC13) 5 7.68-7.66
(m, 2H), 7.57 (app q, J = 8.4 Hz, 1H); 7.42-7.34 (m, 2H);
6.98-6.92 (m, 1H), 6.89-6.83 (m, 1H) 6.01 (s, 1H); 5.39 (s,
2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 463.0461 (M+H
C2iH17BrF2N203 requires 463.0463). XH NMR (400 MHz, CDC13) 5
7.56-7.55 (m, 2H) ; 7.32-7.25 (m, 2H) ; 7.00-6.94 (m, IH) , 6.88-
6.84 (m, IH) ; 6.81-6.79 (m, IH) 6.11 (s, IH) ; 5.51 (s, 2H) ,
5.24 (3, 2H) ; 2.43 (s, 3H) . ESHRMS tn/z 463.0467 (M+H
requires. 463.0463) .
Example 157
1- [2- (aminomethyl) benzyl] -3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy]
6-methylpyridin-2 (IH) -one
EXAMPLE 149 (50 mg, 0.11 mmol) was dissolved in
tetrahydrofuran (2 mL) under N2. Borane-methyl sulfide complex
(0.11 mL, 0.22 mmol, 2M in tetrahydrofuran) was added. The
reaction was then heated to 70"C and shaken overnight. After
cooling to ambient temperature, all the solvent was distilled
under vacuum. The resulting residue was partitioned between
ethyl acetate and 0.2 N NaOH, and extracted with ethyl acetate
(3 x'20 mL). The organic extracts were combined, washed with
brine, and dried over Na2S04, and filtered. The filtrate was
concentrated to an oil, and purified by chromatography
(silica gel, hexane/ethyl acetate) to yield a white solid, to
give product (19 mg, 39%). XH NMR (400 MHz, CDC13) 5 7.56-7.55
(m, 2H); 7.32-7.25 (m, 2H); 7.00-6.94 (m, IH), 6.88-6.84 (m,
IH) ; 6.81-6.79 (m, IH) ; 6.11 (s, IH) ; 5.44 (s, 2H) , 5.17 (s,
; 4.59 (s, 2H); 2.18 (s, 3H). ESHRMS m/z 449.0692 (M+H
requires 449.0671).
-367-
Example 158
3-bromo-l- [3- (bromomethyl) benzyl] -4- [ (2,4-difluorobenzyl) oxy]
6-methylpyridin-2 (IH) -one
Preparation of 3-bromo-l- [3- (bromomethyl) benzyl] -4- [ (2, 4-
difluorobenzyDoxy] -6-methylpyridin-2 (IH) -one.
3-bromo-4- [ (2, 4-difluorobenzyl) oxy] -6-methylpyridin-
2(lH)-one (2 g, 6.06 mmol) was suspended in 1,4-dioxane (250
mL) . a, oc' -Dibromo-.m-xylene (8 g, 30.3 mmol) was added
followed by sodium hydride (0.3 g, 7.5 mmol, 60% in mineral
oil) . The reaction was heated to 60 "C and stirred for 16
hours. The reaction was filtered through Celite and the
filtrate was concentrated to an oil that was partitioned
between water and dichloromethane and extracted with
dichloromethane (4 x 250 mL) . The organic extracts were
combined, washed with brine, dried over Na2S04, and filtered.
The filtrate was concentrated to an oil, and purified by
chromatography (silica gel, hexane/ethyl acetate) to yield a
white solid (1.2g, 38%). XH NMR (400 MHz, CDC13) 5 7.57 (app q,
J = 7.6 Hz, IH) ; 7.28-7.25 (m, 2H) ; 7.17 (s, IH) ; 7.08 (m, IH) ;
6.94 (app dt, J - 1.2, 9.6 Hz, IH) , 6.87-6.82 (m, IH) ; 5.99
(s, IH) , 5.34 (s, 2H) , 5.20 (s, 2H) ; 4.43 (s, 2H) ; 2.29 .(s,
3H) . ES HRMS m/z 511.9672 (M+H C2iH17Br2F2NO2 requires
511.9667) .
-368-
Example 159
3-bromo-l- [4-(bromomethyl)benzyl]-4-[(2,4-difluorobenzyl)oxy]
6-methylpyridin-2(IH)-one
The title compound was prepared by a procedure essentially as
described in Example 158. XH NMR (400 MHz, CDC13) 6 7.68-7.66
(m, 2H), 7.57 (app q, J = 8.4 Hz, IH); 7,42-7.34 (m, 2H) ;
6.98-6.92 (m, IH), 6.89-6.83 (m, IH) 6.01 (s, IH); 5.39 (s,
2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 463.0461 (M+H
C2iH17BrF2N203 requires 463.0463) .1H NMR (400 MHz, CDC13) 8 7.56
(app q, J = 7.6 Hz, IH); 7.32(d, J = 8.0 Hz, 2H); 7.14 (d, J =
8.0 Hz, 2H) ; 6.94 (app t, J = 8.4 Hz, IH), 6.87-6.82 (m, IH) ;
5.98 (s, IH), 5.33 (s, 2H), 5.19 (s, 2H); 4.44 (s, 2H); 2.29
(s, 3H) . ES HRMS m/z 511.9683 (M+H C2iHi7Br2F2N02 requires
511.9667) .
Example 160
1-[4-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methylpyridin-2(IH)-one
Br
Example 159 (200 mg, 0.39 mmol) was suspended in methanol (3
mL) and cooled to -78 "C. Ammonia (g) was bubbled through the
mixture for 30 minutest Thet reaction, vessel was. sealed,
allowed to reach ambient temperature, and stirred for 4 hours.
The solvent and ammonia were removed from the reaction in
vacua with stirring and the resulting oil was triturated with
ether to yield a solid (174 mg, 99%). XH NMR (400 MHz, CD3OD)
5 7.61 (q, J = 7.6 Hz, 1H); 7.40 (d, J = 8.0 Hz, 2H); 7.20 (d,
J = 8.0 Hz, 2H); 7.03 (app t, J = 8.8 Hz, 2H), 6.51 (s, 1H),
5.43 (s, 2H), 5.29 (s, 2H); 4.07 (s, 2H); 2.36 (s, 3H). ES
HRMS m/z 449.0673 (C2iHi9BrF2N202 requires 449.0671).
Examples 161-168
The compounds of Examples 161-168 are prepared essentially
according to the procedures set forth above for Examples
160 or by using the compound of Example 158:
Potassium trimethylsilanolate (80 mg, 0.62 mmol) was added and
the reaction was stirred at ambient temperature for 4 hours.
The reaction mixture was concentrated to an oil that was
partitioned between water and ethyl acetate and extracted with
ethyl acetate. The organic extracts were combined, washed
with brine, dried over Na2S04, and filtered. The filtrate was
concentrated to an oil and purified by reversed phase
chromatography (C18, 0.1% aqueous trifluoroacetic
acid/acetonitrile) to yield the product (64 mg, 44%) XH NMR
(400 MHz, CD3OD) 6 7.92 (app d, J = 8.0 Hz, 1H); 7.78 (a, IE);
7.62 (app q, J = 8.0 Hz, 1H) ; 7.44 (t, i7 = 7.6 Hz, 1H) ; 7.36
(app d, J = 8.0 Hz, 1H) ; 7.02 (app 't, J=7.6Hz, 2H) ; 6.51
(s, 1H), 5.48 (S, 2H), 5.30 (a, 2H); 2.37 (s, 3H). ES HRMS
m/z 464.0328 (C2iHiSBrF2N04 requires 464.0304).
Examples 170-174
The compounds of Examples 170-174 are prepared using the
compound of Example 159 or 161:
Example
No.
Ex. 170
Ex. 171
Ex. 172
Ex. 173
Ex. 174
R
-C(0)CH3
-C(0)OCH3
-S02CH3
-C(0)CH2OH
-C(0)NH2
MF
C23H2iBrF2N2O3
C23H2iBrF2N204
C22H21BrF2N204S
C23H2iBrF2N204
C22H20BrF2N303
M+H
Requires
491.0776
507.0726
527.0446
507.0726
492.0729
ESHRMS
m/z
491.0772
507.0731
527.0430
507.0712
492.0751
NMR" characterization of compounds of Examples 170-174
Ex. No. NMR Data
Ex. 170 JH NMR (400 MHz, CD3OD) 6 7.61 (app q, J = 8.0 Hz,
t, J = 8.0, 1H) , 7.18 (app d, J = 8.0 Hz, 1H) ,
4H) ; 6.49 (s, 1H) , 5.41 (s, 2H) , 5.29 (s, 2H) ;
1.94 (s, 3H) '
1H); 7.28 (app
7.05-7.00 (m,
2.37 (s, 3H) ;
EX. 171 *H NMR (400 MHz, CDC13) 6 7.57 (app q, J = 7.6 Hz,
t, J = 8.0, 1H) , 7.17 (app d, J = 8.0 Hz, 1H) ,
2H) ; 6.97-6.91 (m, 1H) ; 6.87-6.82 (m, 1H) , 5.98
(s, 2H) , 5.19 (S, 2H) ; 4.30 (d, J - 6.0 Hz, 2H) ;
2.28 (s, 3H)
1H); 7.25 (app
7.06-7.02 (m,
(s, 1H) , 5.33
3.67 (S, 3H) ;
EX. 172
XH NMR (400 MHz, CD3CN) 5 7.58 (app q, J = 7.6 Hz,
t, J = 8.0, 1H) , 7.24 (app d, J = 8.0 Hz, 1H) ,
7.05-7.00 (m, 3H) ; 6.32 (s, 1H) , 6.06 (bs, 1H) ,
5.23 (s, 2H) ,- 4.17 (d, J = 6.4 Hz, 2H) ; 2.78 (s,
3H)
1H); 7.31 (app
7.11 (s, 1H) ;
5.31 (s, 2H) ,
3H); 2.28 (s,
Ex. 173
1H NMR (400 MHz, CDC13) 6 7.55 (app q, J = 6.0 Hz,
t, J = 7.6, 1H) , 7.15 (app d, J = 7.2 Hz, 1H) ,
3H); 6.94 (app dt, J = 1.2, 8.8 Hz, 1H) ; 6.88-6.81
(s, 1H) , 5.27 (s, 2H) , 5.19 (s, 2H) ; 4.39 (d, J--
4.05 (s, 2H) , 2.31 (s, 3H)
1H) ; 7.23 (app
7.05-7.00 (m,
(m, 1H); 6.03
= 6.4 Hz, 2H);
EX. 174 H NMR (400 MHz, CD3OD) 6 7.62 (app q, J = 8.0 Hz,
t, J = 8.0, 1H) , 7.19 (app d, J = 8.0 Hz, 1H) ,
4H); 6.49 (s, 1H) , 5.41 (s, 2H) , 5.29 (s, 2H) ;
2.35 (S, 3H)
1H); 7.28 (app
7.05-6.96 (m,
4.25 (s, 2H) ;
Examples 175-185
The compounds of Examples 175-175 are prepared using the
compounds of Examples 159 or 160:
Example
No.
Ex. 175
Ex. 176
Ex. 177
Ex. 178
R
-CH2NHCH(CH3)2
morphol in- 4 -ylmethyl
-CH2N(CH3)2
piper idin- 1 -ylmethyl
MF
C24H25BrF2N202
C25H25BrF2N203
C23H23BrF2N202
C26H27BrF2N202
M+H
Requires
491.1140
519.1089
'477.0984
517.1297
ESHRMS
m/z
491.1143
519.1062
477.0931
517.1258
Ex. 179
Ex. 180
Ex. 181
Ex. 182
Ex. 183
Ex. 184
Ex. 185
[bis (2-
hydroxyethyl) amino] m
ehtyl
-CH2NHCH2CH2OH
piperazin-1-
ylmethyl
-CH2NHC(0)pCH3
-CH2NHC(0)CH3
-CH2NHS02CH3
-CH2NHC(0)NH2
C25H27BrF2N204
C23H23BrF2N203
C2SH26BrF2N302
C23H2iBrF2N204
C23H2iBrF2N203
C22H2iBrF2N204S
C22H20BrF2N303
537.1195
493.0933
518.1249
507.0726
491.0776
527.0446
492.0729
537.1181
493.0907
518.1213
507.0752
491.0793
527.0431
492.0720
NMR characterization of compounds of Examples 175-185
Ex. No. NMR Data
XH NMR (400 MHz, CDC13) 6 7.56 (app q, J = 8.0 Hz, IH) ; 7.20 (d,
J = 8.0 Hz, IH) , 7.13 (d, J = 8.0 Hz, 2H) , 6.94 (app dt, J *
1.2, 8.0 Hz, IH) , 6.87-6.81 (m, 2H) ; 5.97 (s, IH) , 5.32 (s, 2H) ,
5.19 (s, 2H) ; 4.31 (d, J = 6.0 Hz, 2H) ; 3.68 (s, 3H) ; 2.28 (s,
3H)
Ex. 182
Ex. 183 *H NMR (400 MHz, CDC13) d 7.61 (app q, J = 8.0 Hz, IH); 7.23 (d,
J = 8.0 Hz, 2H) , 7.08 (d, J = 8.0 Hz, 2H) , 7.04-6.99 (m, 2H) ;
6.47 (S, IH) , 5.39 (s, 2H) , 5.28 (s, 2H) ; 4.30 (s, 2H) ; 2.34 (s,
3H); 1.95 ( s , 3H)
Ex. 184 ^H NMR (400 MHz, CD3OD) 6 7.62 (app q, J = 8.0 Hz, IH) ; 7.34 (d,
J = 8.4 Hz, 2H) , 7.11 (d, J = 8.4 Hz, 2H) , 7.02 (app t, J = 8.8
Hz, 2H) , 6.48 (s, IH), 5.42 (s, 2H), 5.28 (s, 2H); 4.21 (s, 2H) ;
2.82 (s, 3H); 2.35 ( s , 3H)
Ex. 185 XH NMR (400 MHz, d,DMP) 6 7.76 (app q, J 8.0 Hz, IH) ; 7.28 (d,
J = 8.0 Hz, ;) , 7.14 (d, J = 8.0 Hz, 2H) , 7.34-7.26 (m, IH) ;
7.22-7.14 (m, IH) ; 6.62 (s, IH) , 5.65 (s, 2H) , 5.39 (s, 2H) ,
5.37 (S, 2H); 4.26 (d, J - 6.0 Hz, 2H); 2.40 (s, 3H)
Example 186
4- (4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzoyl)piperazine-l-carboxamide
3-bromo-4-(2,4-difluorophenoxy)-6-methyl-l- [4-(piperazin-
1-ylcarbonyl)benzyl]pyridin-2(IH)-one (300 mg, 0.54 mmol) was
dissolved in J\T,W-dimethylacetamide (5 mL) . Trimethylsilyl
isocyanate (0.15 mL, 1.08 mmol) was added followed by N,Ndiisopropylethylamine
(0.23 mL, 1.3 mmol) and the reaction was
stirred for 1 hour at ambient temperature. The reaction was
then diluted with tetrahydrofuran (40 mL) and polyamine resin
(1.3 g, 2.81 mmol/g) and methylisocyanate functionalized
polystyrene (1 g, 1.38 mmol/g) were added. The mixture was
shaken for 6 hours, filtered, and the resulting filtrate was
concentrated to a white solid (279 mg, 90%) . XH NMR (400 MHz,
CD3OD) 5 7.61 (app g, J = 8.0 Hz, IH); 7.41 (d, J = 8.0 Hz,
2H), 7.23 (d, J = 8.0 Hz, 2H), 7.03 (app t, J = 8.8 Hz, 2H);
6.51 (s, IH) , S.4r6Ms% 2ff) , 5-..3.0. (a, 2H) , 3.75-3.35 (m, 8B) ;
2.37 (s, 3H) . ES HRMS m/z 575.1104 (026^58^2^04 requires
575.1100).
Example 187
N- (4- { [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-2-
oxopyridin-1 (2H) -yl] methyl} benzyl) -2-methoxyacetamide
O
Polymer bound carbodiimide resin (2.3 g, 1.18 meq/g, 2.7
mmol) was suspended in JV/W-dimethylf ormamide. Acetoxyacetic
acid (120 mg, 1.33 mmol) was added, followed by 1-
hydroxybenzotriazole (1M in N,N- dimethyl f ormamide, 0.165 mL)
and AT/W-diisopropylethylamine (0.3 mL, 2.0 mmol). The
reaction was shaken for 1 hour when EXAMPLE 159 (300 mg, 0.67
mmol) was added. The reaction was shaken for 16 hours and
then diluted with tetrahydrofuran. Polyamine resin (1 g, 2.81
mmol/g) and methylisocyanate functionalized polystyrene (2 g,
1.38 mmol/g) were added and the mixture was shaken for 72
hours, filtered and the resulting filtrate concentrated.
Trituration with water followed by trituration with ether
yielded a white solid (125 mg, 36%) . XH NMR (400 MHz, CDC13)
5 7.56 (app q, J - 8.0 Hz, 1H) ; 7.21 (d, J = 8.0 Hz, 2H) , 7.13
(d, J=8.0Hz, 2H) , 6.94 (app t, J=8.8Hz, 1H) , 6.88-6.81
(m, 1H) ; 5.97(s, 1H) , 5.33 (s, 2H), 5.19 (s, 2H) ; 4.43 (.d, J =
6.0 Hz, 2H) ; 3.92 (s, 2H) ; 3.39 (s, 3H) ; 2.29 (s, 3H) . ES
HRMS m/z 521.0882 requires 521.0882).
Examples 188-193
By following the general method for the preparation of Example
187 and substituting the appropriate carboxylic acid for
acetoxyacetic acid, the compounds of Examples 188-193 are
prepared. These compounds were triturated with water and
again with ether and purified by chromatography (silica gel,
hexane/ethyl acetate) as appropriate to yield off-white
solids. Example 191 was prepared from its W-t-butoxycarbonyl
protected intermediate. Deprotection was accomplished with 4N
HC1 in dioxane to afford the title compound as its
hydrochloride salt (86 mg, 24%). Deprotection of the methyl
ester from Ex. 188 was accomplished with K2C03 in
methanol/water to yield Ex. 192 as a white solid. The yields
and analytical data are shown below.
Compound
No.
Ex. 188
Ex. 189
Ex. 190
Ex. 191
Ex. 192
Ex. 193
R
CH2OCOCH3
C(CH3)2OH
C(-CH2CH2-
)OH
CH2NH2
CH2OH
CH2NHCOCH3
%
Yield
49
13
33
24
25
81
MF
C25H23BrF2N205
C25H25BrF2N204
C25H23BrF2N204
C23H22BrF2N303
C23H21BrF2N204
C25H24BrF2N303
M+H
Requires
549.0831
535.1039
535.0865
533 .0882
507.0726
548.0991
ESHRMS
m/z
549.0849
535.1035
535.0876
533.0899
507.0730
548.1000
Example 194
1_{4-[(4-acetylpiperazin-l-yl)carbonyl]benzyl}-3-bromo-4-
[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one
Fx
0
3-bromo-4- (2 , 4-difluorophenoxy) -6-methyl-l- [4- (piperazin-
1 -yl carbonyl) benzyl ]pyridin- 2 (1H) -one (200 mg, 0.36 mmol) was
dissolved in W,W-dimethylformamide (5 mL) . N,NDiisopropylethylamine
(0.25 mL, 1.44 mmol) was added followed
by acetic anhydride (0.10 mL, 1.06 mmol). The reaction was
stirred for 2 hours at ambient temperature, and concentrated
to an oil that was triturated in ether and again in water to
yield an off-white solid (131 mg, 63%) XH NMR (400 MHz, CD3OD)
6 7.62 (app q, J = 8.0 Hz, 1H) ; 7.42 (d, J - 8 . 0 Hz, 2H) 7.23
(d, J = 8.0 Hz, 2H) , 7.62-7.02 (m, 1H) ; 7.02 (app t, J=8.0
Hz, 1 H) ; 6.52 (s, 1H) , 5.46 (s, 2H) , 5.30 (s, 2H) ; 3.80-3.65
(m, 8H) ; 2.37 (s, 3H) ; 2.11 (s, 3H) . ES HRMS m/z 574.1150
requires 574.1148).
Example 195
3-bromo-4- [ (2, 4-difluorobenzyl) oxy] -6-methyl-l- (4-{ [4-
(methylsulfonyl)piperazin-l-yl] carbonyl } benzyl ) pyridin-2 (1H)
one
3-bromo-4-(2, 4-difluorophenoxy)-6-methyl-l-[4-(piperazin-1-
ylcarbonyl)benzyl]pyridin-2(IH)-one (300 mg, 0.54 mmol) was
dissolved in N, W-dimethylformamide (5 mL) . 4-Methylmorpholine
(0.23 mL, 2.2 ramol) was added followed by methanesulfonyl
chloride (0.10 mL, 1.33 mmol) and the reaction was stirred for
2 h. The reaction was then diluted with tetrahydrofuran (40
mL) and polyamine resin (1.3 g, 2.81 mmol/g) and
methylisocyanate functionalized polystyrene (1 g, 1.38 mmol/g)
were added. The mixture was shaken for 16 hours, filtered,
and the resulting filtrate concentrated to an oil that was
triturated with water. The resulting white solid was
collected, washed with ether and dried (172 mg, 52%). 1H NMR
(400 MHz, CDC13) 6 7.57 (app q, J = 8.2 Hz, IH); 7.34 (d, J =
8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.02 (app dt, J = 1.2,
8.8 Hz, IH), 6.88-6.82 (m, IH); 6.02 (s, IH), 5.37 (s, 2H),
5.21 (s, 2H); 3.80-3.20 (m, 8H); 2.79 (s, 3H); 2.30 (s, 3H).
ES HRMS m/z 610.0851 (C26H26BrF2N305S requires 610.0817).
Example 196
Methyl-4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l (2H)-
yl]benzoate.
Step 1. Preparation of 4-[4-(benzyloxy)-2-oxopyridin-l(2H) -
yl]benzonitrile.
4-benzyloxy-2(1H)-pyridone (12.00 g, 59.63 mmol) was dissolved
in dimethyl sulfoxide (100 mL). Potassium carbonate (10.99 g,
79.50 mmol) was added, followed by 4-fluorobenzonitrile (4.81
g, 39.75 mmol). The reaction was stirred at 100 °C for 18
hours. After cooling to room temperature the reaction was
diluted with H20 (150 mL) and the solids were collected by
filtration washing with diethyl ether. Chromatography (silica
gel, hexanes/ethyl acetate) provided an off-white solid (7.78
g, 65%). XH NMR (300 MHz, CDC13) 67.79 (d, J=8.3Hz, 2H) ,
7.54 (d, Jr=8.5Hz, 2H) , 7.44-7.41 (m, 5H) , 7.22 (d, J =
13.3, 1H), 6.13 (dd, J = 2.6, 7.7 Hz, 1H), 6.06 (d, J= 2.6
Hz, 1H), 5.07 (s, 2H).
Step 2. Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-
1(2H)-yl]benzonitrile
4-[4-(benzyloxy) -2-oxopyridin-l(2H)-yl]benzonitrile (Step 1)
(2.76 g, 9.13 mmol) was suspended in acetonitrile (50 mL) and
cooled in an ice-bath. W-bromosuccinimide (1.71 g, 9.54 mmol)
was added. Once the addition was complete the cooling bath
was removed. After stirring for 45 minutes the reaction was
:- with, a^etDjaiteiLe:, and solids were collected by
filtration to give a white solid (3.13 g, 90%). ^H NMR (300
MHz, DMSO-dg) .6 8.00 (d, J = 8.5 Hz, 2H) , 7.84 (d, J = 7.9 Hz,
1H) , 1.66 (d, J = 8.5, 2H), 7.50-7.37 (m, 5H) , 6.63 (d, J.
7.9 Hz, 1H), 5.41 (s, 2H).
Step 3. Preparation of methyl-4-[4-(benzyl)oxy-3-bromo-2-
oxopyridin-1(2H)-yl]benzoate. 4-[4-(benzyloxy)-3-bromo-2-
oxopyridin-l(2H)-yl]benzonitrile (Step 2) (1.50 g, 3.93 mmol)
suspended in methanol (50 mL) was cooled in an ice-bath. HCl
(g) was then bubbled through the mixture for 5 minutes. The
reaction was then stirred at room temperature overnight, at
which time the reaction mixture was concentrated. The residue
was suspended in 6N HCl (60 mL) and heated at reflux for 1.5
hours. After cooling to room temperature the solids were
collected by filtration. Chromatography (silica gel,
hexanes/ethyl acetate) provided an off-white shiny solid
(0.540 g, 61%). XH NMR (400 MHz, DMSO-d6) 5 8.04 (d, J = 8.5
Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H),
7.47-7.39 (m, 5H), 6.57 (d, J = 7.9 Hz, 1H), 5.38 (s, 2H),
3.86 (s, 3H) . ES-HRMS m/z 416.0355 (M+H caldc for CaoHi6BrN04
requires 414.0341).
Example 197
4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]benzole acid.
Preparation of 4- [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]benzole acid. EXAMPLE 196 (0.460 g, 1.11 mmol) was
dissolved in tetrahydrofuran (5.0 tnL) . Potassium
trimethylsilanolate (0.285 g, 2.22 mmol) was added. The
reaction was stirred at room temperature for 3 hours at which
time H2O (10 mL) was added. The aqueous reaction mixture was
acidified (pH-3) with IN HCl. The tetrahydrofuran was
evaporated, additional H20 (50 mL) was added and the aqueous
layer was extracted with ethyl acetate (2 x 50 mL). The
combined organic layers were washed with brine (50 mL), dried
over Na2SO4/ filtered and evaporated to provide a rust colored
solid (0.444 g, 100%). *H NMR (400 MHz, DMSO-d6) 68.02 (d, J
= 8.6 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.6 Hz,
2H), 7.50-7.34 (m, 5H), 6.57 (d, J = 7.9 Hz, 1H), 5.38 (s,
2H) . ES-HRMS m/z 400.0191 (M+H calcd for C19Hi4BrN04 requires
400.0184).
Example 198
4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yllbenzamide.
Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yllbenzamide. STEP 2, EXAMPLE 196 (0.238 g, 0.624 mmol) was
suspended in tert-butyl alcohol (3.0 mL). KF on 40 wt % A1203
(0.453 g, 3.12 mmol) was added. The reaction mixture was
heated at reflux for 5 days. Additional KF on 40 wt % A12O3
(0.453 g, 3.12 mmol) was added and heating was continued at
reflux overnight. After cooling to room temperature
chloroform and methanol were added and the solids were
collected by filtration. Chromatography (reverse-phase,
acetonitrile/H20) provided a tan solid (0.073 g, 30%). *H NMR
(400 MHz, DMSO-d6) 68.07 (s, IH) , 7.95 (d, J - 8.6 Hz, 2H)
7.79 (d, J = 7.8 Hz, IH), 7.47-7.34 (m, 7H), 6.56 (d, J = 7 . 9
Hz, IH), 5.38 (s, 2H). ES-HRMS m/z 399.0372 (M+H calcd for
C19HiSBrN203 requires 399.0344).
Example 199
1-[4-(aminomethyl)phenylj-4-(benzyloxy)-3-bromopyridin-2(IH)-
one.
Preparation of 1- [4- (aminomethyl)phenyl]-4-(benzyloxy)-3-
bromopyridin-2(1H)-one. STEP 2, EXAMPLE 196 (1.25 g, 3.28
mmol) was dissolved in tetrahydrofuran (15 mL). Boranedimethylsulfide
(3.44 mL, 6.89 mmol, 2.0 M in tetrahydrofuran)
was added and the mixture heated at reflux. After 14.5 hours
the solvent was evaporated. 0.5M NaOH (50 mL) was added
followed by ethyl acetate. The aqueous layer was neutralized
with IN HCl. Methanol saturated with HCl was added and the
mixture was heated at reflux for 5 hours. After cooling to
room temperature, diethyl ether was added and the solids were
collected by filtration. The solids were treated with 4JV HCl
in dixoane (5 mL) and methanol (1 mL) at room temperature for
1 hour, at which time diethyl ether was added and the solids
were collected by filtration to give a tan solid (0.920 g,
6 7 % ) . XH NMR (300 MHz, DMSO-ds) 68.67 (br s, 2H) , 7.76 (d, J
= 7 . 6 Hz, IH) , 7.64 (d, J = 8.3 Hz, 2H) , 7.50-7.37 (m, 7H) ,
6.56 (d, J = 7.6 Hz, IH), 5.41 (s, 2H), 4.09 (bra, 2H). ESHRMS
m/z 385.0555 (M+H calcd for Ci9Hi7BrN2O2 requires
385.0552) .
Example 200
Methyl-4- [3-chloro-4-[(2,4-diflurobenzyl)oxy]-2-oxypyridin-
1(2H)-yl]benzoate.
Step 1. Preparation of 4-[4-(benzyloxy)-2-oxopyridin-l(2H)
yl]benzonitrile.
4-benzyloxy-2(IH)-pyridone (50.0 g, 248.47 mmol) was dissolved
in dimethyl sulfoxide (300 mL) . Potassium carbonate (68.68 g,
496.94 mmol) was added, followed by 4-fluorobenzonitrile
(31.60 g, 260.89 mmol). The reaction was stirred at 100 °C for
20 hours. After cooling to room temperature the reaction was
diluted with H20 (600 mL) and the solids were collected by
filtration washing with diethyl ether. The solids were then
washed with hot methanol to provide a tan solid (55.6 g, 74%).
XH NMR (300 MHz, CDC13) 5 7.79 (d, J = 8.3 Hz, 2H) , 7.54 (d,
8.5 Hz, 2H) , 7.44-7.41 (tn, 5H) , 7.22 (d, J = 13.3, IH) , 6.13
(dd, J = 2.6, 7.7 Hz, IH), 6.06 (d, J = 2.6 Hz, IH), 5.07 (s,
2H) .
Step 2. Preparation of 1-[4-nitrilephenyl]-4-hydroxy-2(IH)-
pyridinone.
4-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]benzonitrile (Step 1)
(20.0 g, 66.15 mmol) was dissolved in methanol (300 mL).
Ammonium formate (8.34 g, 132.3 mmol) was added followed by 5%
Pd/C (6.62 g) . The resulting mixture was heated at reflux for
20 minutes at which time the reaction began to exotherm. The
reaction was allowed to cool to room temperature at which time
it was filtered through a pad of Celite® washing with
methanol. The filtrate was evaporated to provide a pale
yellow solid (16.2 g, >100%) . XH NMR (300 MHz, CDC13) 68.46
(s, IH), 7,95 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H),
7.47 (d, J = 7.7 Hz, IH), 5.98 (dd, J - 2.6, 7.7 Hz, IH), 5.54
(d, J = 2.4 Hz, IH).
Step 3. Preparation of 4-[4-[(2,4-difluorobenzyloxy) ] -2-
oxopyridin-1(2H)-yljbenzonitrile.
-385-
1- [4-Nitrilephenyl]-4-hydroxy-2(1H)-pyridinone (Step 2) (16.2
g) was dissolved in W/W-dimethylformamide (100 mL). Potassium
carbonate (10.06 g, 72.77 mtnol) was added followed by a-bromo-
2,4-difluorotoluene (8.91 mL, 69.46 mmol). The resulting
mixture was heated to 65°C for 1 hour. Additional a-bromo-2,4-
difluorotoluene (4.25 mL, 33.08 mmol) was added. The
resulting mixture was heated to 65°C for 5 hours. Additional
a-bromo-2,4-difluorotoluene (2.12 mL, 16.54 mmol) was added.
After stirring at 65°C overnight the reaction was allowed to
cool to room temperature. H20 (300 mL) was added and the solid
was collected by filtration. A portion (8.0 g) of the solids
were washed with hot methanol to give a pale yellow solid
(6.22 g, 78%). *H NMR (300 MHz, CDC13) 68.00 (d, J- 8.5 Hz,
2H) , 7.72-7.64 (m, 2H) , 7.66 (d, J = 8.5 Hz, 2H) , 7.40-7.32
(m, 1H) , 7.22-7.16 (m, 1H), 6.17-6.11 (m, 2H), 5.17 (s, 2H)
Step 4. Preparation of methyl-4-[4-[(2,4-difluorobenzyl)oxy]-
2-oxopyridin-l(2H)-yl]benzoate.
4-[4-[(2,4-difluorobenzyloxy)]-2-oxopyridin-l(2H)-
yl]benzonitrile (Step 3) (2.00 g, 5.91 mmol) suspended in
methanol (20 mL) and H2O (5 mL) was cooled in an ice-bath. HCl
(g) was bubbled through the mixture until most of the solids
dissolved. The resulting mixture was then heated at reflux
for_ 3 haurs. reaction was; then- retooled in an ice=~bafch.
and HC1 was bubbled through the mixture for 5 minutes. The
mixture was heated at reflux for 2 hours and then the methanol
was evaporated. Additional H20 (50 mL) was added and the
aqueous reaction mixture was extracted with ethyl acetate (50
mL) and tetrahydrofuran (50 mL). The combined organic layers
were washed with brine (50 mL) , dried over Na2S04/ filtered and
evaporated. Chromatography (silica gel, hexanes/ethyl acetate
with 10% methanol) gave an off-white solid (0.630 g, 29%).
NMR (300 MHz, DMF-d€) 88.15 (d, J = 8.5 Hz, 2H) , 7.80 (app q,
J = 7.9 Hz, 1H), 7.74-7.67 (m, 1H), 7.68 (d, J = 8.5 Hz, 2H) ,
7.42-7.34 (app dt, J - 2.4, 9.0 Hz, 1H), 7.28-7.22 (m, 1H),
6.20 (dd, J = 2.6, 7.6 HZ, 1H), 6.15 (d, J = 2.4 Hz, 1H), 5.28
(S, 2H), 3.98 (s, 3H).
Step 5. Preparation of methyl-4-[3-chloro-4-[(2,4-
diflurobenzyl)oxy]-2-oxypyridin-l(2H)-yl]benzoate. Methyl-4-
[4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]benzoate
(Step 4) (0.520 g, 1.40 mmolj was suspended in acetonitrile
(10.0 mL) . W-chlorosuccinimide (0.196 g, 1.47 mmol) was added
followed by several drops of dichloroacetic acid. The
resulting mixture was heated at reflux overnight. After
cooling to room temperature additional acetonitrile was added
and the precipitate was collected by filtration to give an
off-white solid (0.331 g, 58%). XH NMR (300 MHz, DMF-d6)
58.34 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 7.9 Hz, 1H), 8.04-7.96
(m, 1H) , 7.88 (d, J = 8.5 Hz, 2H) , 7.59-7.53 (m, 1H), 7.52-
7.41 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 5.70 (s, 2H), 4.15 (s,
3H) . ES-HRMS m/z 406.0644 (M-t-H calcd for C2oHi4ClF2N04
requires 406.0652).
Example 201
- 3 ST3-
Bromo-4-[(2,4-diflurorbenzyl)oxy]-1-[3-
(hydroxymethyl)phenyl]-6-methylpyridin-2(IH)-one,
Step 1. Preparation of 4-Hydroxy-l-[3-
(hydroxymethyl)phenyl]6-methylpyridin-2(IH)-one.
4-hydroxy-6-methyl-2-pyrone (10.0 g, 79-.3 mmol) and 3-
aminobenzyl alcohol (9.77g, 79.3 mmol) were combined in H2O
(100 mL) and heat at reflux. After 48 hours at reflux the
reaction mixture was concentrated. The residue was treated
with methanol and the precipitate was collected by filtration
to give a pale yellow solid (3.04 g, 17%) . XH NMR (300 MHz,
DMSO-ds) d 10.6 (br s, IH), 7.46-7.35 (m, 2H) , 7.09-7.03 (m,
2H), 5.88 (d, J = 1.6 Hz, IH), 5.55 (d, J = 2.6 Hz, IH), 4.54
(d, J = 4.2 Hz, 2H), 1.83 (s, 3H).
Step 2. Preparation of 1-[3-(hydroxymethyl)phenyl]-4-[ (2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one.
4-Hydroxy-l- [3- (hydrgxymethyDphenyl] 6-methylpyridin-2 (1H) -one
(Step 1) (0.674 g, 2.91 tnmol) was suspended in acetone (10
mL). Cesium carbonate (1.04 g, 3.21 mmol) was added followed
by a-bromo-2,4-difluorotoluene (0.392 mL, 3.06 mmol). After
stirring at'room temperature for 2 days the reaction was
concentrated. The residue was portioned between H20 (30 mL)
and ethyl acetate (30 mL). The aqueous layer was further
extracted with ethyl acetate (30 mL). The combined organic
layers were washed with brine (30 mL) , dried over Na2SO4;
filtered and concentrated. Chromatography (on silica,
hexanes/ethyl acetate with 10% methanol) provided a white
solid (0.531 g, 51%). 1H NMR (300 MHz, CDC13) 5 7.51-7.39 (tn,
3H), 7.82 (s, 1H) , 7.16 (d, J =• 26.8 Hz, 1H), 7.08-6.86 (m,
2H), 6.00 (d, J = 2.6 Hz, 1H), 5.92 (d, J = 2.6 Hz, 1H), 5.05
(s, 2H), 4.68 (s, 2H), 1.93 (s, 3H). ES-HRMS m/z 358.1256
(M+H calcd for CaoHr^NOs requires 358.1249) .
Step 3. Preparation of 3-bromo-4-[(2,4-diflurorbenzyl)oxy]-1-
[3-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-one . l-[3-
(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one (Step 2) (0.460 g, 1.29 mmol) was
suspended in acetonitrile (5.0 mL) and cooled in an ice-bath.
W-bromosuccinimide (0.241 g, 1.35 mmol) was added. Once the
addition was complete the cooling bath was removed. After
stirring for 1.5 hours the reaction was diluted with
acetonitrile and solids were collected by filtration to give a
white solid (0.385 g, 68%). XH NMR (300 MHz, DMSO-d6) d 7.70
(app q, J = 7.9 Hz, 1H), 7.49-7.32 (m, 3H), 7.24-7.10 (m, 3H),
6.66 (s, 1H), 5.35 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 1.95 (s,
3H) . ES-HRMS m/z 436.0384 (M+H calcd for C2oHi6BrF2N03
requires 436.0354).
Example 202
Methyl-4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzoate.
Step 1. Preparation of Methyl 4-(4-hydroxy-6-methyl-2-
oxypyridin-1(2H)-yl)benzoate.
O
4-hydroxy-6-methyl-2-pyrone (21.00 g, 166.70 mmol) and 4-
methylaminobenzoate (25.20 g, 166.70 mmol) were combined in
1,2-dichlorobenzene (50 mL) and rapidly heated to 160 °C.
After 15 minutes at 160 °C the reaction was allowed to cool to
room temperature. The reaction was diluted with
dichloromethane (50 mL) and extracted with saturated Na2.C03 (2
x 100 mL). The combined aqueous layers were acidified (pH-2)
with concentrated HC1. The precipitate was collected by
filtration and washed with diethyl ether to give a
yellow/orange solid (10.9 g, 25%). XH NMR (300 MHz, DMSO-ds) 5
10.8 ( s, 1H) , 8.07 (d, J - 8.5 Hz, 2H) , 7.40 (d, J = 8.5 Hz,
2H), 5.95 (d, J=2.4.Hz, 1H), 5.61 (d, J=2.4, 1H), 3.91 (S/
3H) , 1.85 (S,, 3H) .
Step 2. Preparation of Methyl-4-[4-[(difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]bensoate.
Methyl 4- (4-hydroxy-6-methyl-2-oxypyridin-l (2H) -yDbenzoate
(Step 1) (10.90 g, 42.04 mmol) was dissolved in N,Ndimethylformamide
(100 mL). Potassium carbonate (6.97 g,
50.45 mmol) was added, followed by 2,4-difluorobenzyl bromide
(5.66 mL, 44.14 mmol). The reaction was stirred at room
temperature for 3 days then diluted with H20 (100 mL). The
reaction mixture was extracted into ethyl acetate and
tetrahydrofuran (2 x 100 mL). The precipitate was collected
by filtration and the organic filtrate was washed with brine
(50 mL) , dried over Na2SO4, filtered and evaporated- The
resulting solid was combined with the precipitate to provide a
pale pink solid (6.77 g, 42%) . 1E NMR (300 MHz, DMSO-ds)
58.01 (d, J = 8.3 Hz, 2H) , 7.67 (q, J = 7.9 Hz, 1H) , 7.43 (d,
J = 8.3 Hz, 2H) , 7.35 (m, 1H) , 7.18 (app dt, J = 1.6, 8.5 Hz,
1H), 6.08 (d, J = 1.8 Hz, 1H), 5.98 (d, J - 2.4 Hz, 1H), 5.14
(s, 2H), 3.91 (s, 3H), 1.87 (s, 3H).
Step 3. Preparation of methyl-4-[3-bromo-4-
[ (difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoate
Methyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)
yl]benzoate (Step 2) (6.74 g, 17.49 mtnol) suspended in
acetonitrile (100 mL) was cooled in an ice-bath. Nbromosuccinimide
(3.27 g, 18.36 mmol) was added. After 1 hour
the ice-bath was removed and after an additional 30 minutes
the reaction was diluted with acetonitrile (20 mL). The
precipitate was collected by filtration to provide the title
compound as an off-white solid (6.94 g, 85%). XH NMR (300
MHz, CDC13) 68.20 I'd, J = 8.7 Hz, 2H) , 7.61 (q, J = 7.9 Hz,
1H) , 7.30 (d, J = 8.7 Hz, 2H) , 7.02-6.96 (m, 1H) , 6.90 (app
dt, J = 2.4, 9.5 Hz, 1H), 6.14 (s, 1H), 5.28 (s, 2H), 3.98 (s,
3H), 2.00 (s, 3H). ES-HRMS m/z 464.0304 (M+H calcd for
C21Hi6BrF2NO4 requires 464.0301).
Example 203
4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]benzoic acid.
EXAMPLE 202 (7.43 g, 16.00 mmol) was dissolved in
tetrahydrofuran (40 mL). Potassium trimethylsilanolate (4.10
g, 32.00 mmol) was added and the reaction mixture was stirred
at room temperature for 22 hours. The tetrahydrofuran was
evaporated and H20 (50 mL) was added. The aqueous reaction
mixture was acidified with IN HC1 and the precipitate was
collected by filtration. The solids were washed with boiling
methanol to give an off-white solid (5.05 g, 70%). 1H NMR
(300 MHZ, DMSO-dg) 8 13,2 (br s, IE) , 8.10 (d, J = 8.5 Hz, 2H) ,
7.72 (q, J = 7.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 (app
dt, J = 2.4, 9.9 Hz, 1H), 7.23 (app dt, J = 1.8, 8.5 Hz, 1H),
6.72 (s, 1H), 5.37 (s, 2H), 1.97 (s, 3H). ES-HRMS m/z
450.0154 (M+H calcd for C2oHi4BrF2N04 requires 450.0147).
Example 204
4-(Benzyloxy)-1-(3-fluorobenzyl)-3-(trifluoromethyl)pyridin-
2(1H)-one.
-F
The starting material (0.250 g, 0.591 mmol) was dissolved in
1-methyl-2-pyrrolidinone (5.0 mL). Trifluoroacetic acid,
sodium salt (0.322 g, 2.36 mmol) was added, followed by
copper(I)iodide (0.225 g, 1.18 mmol). The resulting mixture
was heated to 180°C for 5 hours and then allowed to cool to
room temperature. The reaction was diluted with H2O (50 mL)
and brine (50 mL), then extracted into ethyl acetate (2 x 50
mL). The combined organic layers were washed with brine (50
mL) , dried over Na2S04, filtered and evaporated.
Chromatography (reverse-phase, acetonitrile/H20) provided an
off-white solid (0.050 g, 22%). 1H NMR (400 MHz, CDC13) 5
7.40-7.27 (m, 8H), 7.06 (d, J=7.7Hz, 1H), 6.97 (d, J = 9.0
Hz, 1H), 6.07 (d, J = 7.7 Hz, 1H), 5.20 (s, 2H), 5.06 (s, 2H).
ES-HRMS m/z 378.1097 (M+H calcd for C2oHi5F4NO2 requires
378.1112) .
Example 205
4-{ [3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H) -yl] methyl Jb'enzoic acid
EXAMPLE 153 (50.0 g, 104.54 mmol) was dissolved in methanol
(500 mL) and dioxane (100 mL). IN NaOH (130 mL, 130 mmol) was
added. The resulting mixture was heated to 50 °C for 5.5
hours. The reaction was partially concentrated and the
heterogenous mixture was acidified (pH 2) with IN HC1. The
precipitate was collected by filtration to afford a white
solid (49.2 g, 100 %) . XH NMR (300 MHz, DMSO-ds) 6 7.94 (d, J
=8.3 Hz, 2H), 7.70 (app q, J = 7.9 Hz, IH), 7.35 (dt, J =
2.2, 9.9 Hz, IH), 7.18 (app d, J=8.3Hz, 2H), 7.17-7.12 (m,
IH), 6.64 (s, IH), 5.41 (s, 2H), 5.33 (a, 2H), 2.32 (s, 3H).
ES-HRMS m/z 464.0327 (M+H calcd for C2iHifiBrF2N04 requires
464.0304).
Example 206
3-Bromo-4-[(2,4-diflurobenzyl)oxy]-1-[4-
(hydroxymethyl)benzyl]-6-methylpyridin-2(IH)-one.
Example 205 (40.0 g, 86.16 mmol) suspended in tetrahydrofuran
(300 mL) was cooled in an ice-bath. Borane dimethylsulfide
(129.2 mL, 258.48 mmol, 2.0 M in tetrahydrofuran) was slowly
added. The resulting mixture was slowly allowed to warm to
room temperature overnight. The mixture was recooled in an
ice-bath and quenched by the addition of small pieces of ice.
After the evolution of gas ceased additional ice-water was
added. The flask was fitted with a distillation apparatus and
the dimethylsulfide was removed. After the reaction was
cooled to room temperature, H20 (300 mL) , ethyl acetate (200
mL) and tetrahydrofuran (300 mL) were added. The precipitate
that formed was collected by filtration and the filtrate was
placed in a separator/ funnel. The aqueous layer was further
extracted with ethyl acetate (300 mL). The combined organic
layers were washed with brine (300 mL). The organic phase was
dried over Na2S04 and evaporated which was combined with the
precipitate to yield an off-white solid (37.8 g, 97%). XH NMR
(400 MHz, CDC13) 5 7.47 (app q, J = 7.7 Hz, 1H) , 7.23 (d, J =
7.9 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.86 (app dt, J = 2.3,
8.6 Hz, 1H) , 6.79 (app dt, J = 2.4, 8.4 Hz, 1H) , 6.00 (s, 1H) ,
5.28 (s, 2H),-5.16 (s, 2H), 4.57 (s, 2H), 2.25 (s, 3H). ESHRMS
m/z 450.0512 (M+H calcd for C2iHi8BrF2N03 requires
450.0511).
Example 207
Bromo-4-[(2,4-diflurobenzyl)oxy]-1-[4-(1-hydroxy-lmethylethyl)
benzyl]-6-methylpyridin-2(1H)-one.
Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-1-[4-(1-
hydroxy-1-methylethyl)benzyl]-6-methylpyridin-2(1H)-one.
EXAMPLE 153 (2.00 g, 4.18 mmol) suspended in tetrahydrofuran
(20 mL) was cooled in the dry ice/acetone bath. Methyl
magnesium bromide (4.32 mL, 12.96 mmol, 3.0 M in diethyl
ether) was slowly added. The reaction was slowly allowed to
warm to room temperature overnight. The reaction was then
cooled in an ice bath and quenched by the addition of
saturated NH4C1 (50 mL) . H20 was added and the reaction was
extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over Na2S04, filerted and
evaporated. The residue was subjected to chromatography
(silica gel, hexanes/ethyl acetate with 10% methanol) to
provide an off-white foam. The foam was dissolved in
acetonitrile and cooled in an ice bath. AT-bromosuccinimide
(0.057 g, 0.320 mmol) was added. Once the addition was
complete the cooling bath was removed. After 2.5 hours at
room temperature the reaction was concentrated. Purification
by chromatography (silica gel, hexanes/ethyl acetate with 10%
methanol) provided a white foam. XH NMR (400 MHz, CDC13) 8
7.56 fapp q, J = 7.7 Hz, 1H ), 7.39 (d, J = 78.3 Hz, 2H), 7.11
(d, J = 8.2 Hz, 2H) , 6.92 (app dt, J" = 1.7, 8.4 Hz, 1H) , 6.86-
6.81 (m, 1H), 5.97 (s, 1H), 5.31 (s, 2H), 5.18 (s, 2H), 2.29
(s, 3H) , 1.52 (a-, 6H) . ES-HRMS tn/z 478.0811 (M+H C23H22BrF2N03
requires 4 7 8 . 0 8 2 4 ).
Example 208
3-bromo-4- [ (2,4-diflurobenzyl)oxy]- 6-methyl-l-{4-
[(methylamino)methyl]benzylJpyridin-2(IH)-one.
Step 1. Preparation of 4-{[3-bromo-4-[(2,4-
dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-l(2H)
yl]methyl}benzaldehyde.
EXAMPLE 206 (1.30 g, 2.89 mmol) was suspended in acetonitrile
(10 mL) and cooled in an ice-bath. 1-hydroxy-l,3-dihydro-3,3-
bis(trifluoromethyl)-1,2-benziodoxole 1-oxide (0.580 g, 1.44
mmol) was added and the reaction mixture was stirred at room
temperature overnight. Diethyl ether was added and the solid
was collected by filtration to give a white solid (1.14 g,
88%). XH NMR (400 MHz, CDC13) 8 9.96 (a, IE), 7.80 (d, J =
8.2 Hz, 2H), 7.56 (app q, J = 7.7 Hz, IH), 7.30 (d, J = 8.2
Hz, 2H) , 6.93 (app dt, J = 1.6, 8.3 Hz, IH), 6.87-6.82 (m,
IH), 6.02 (s, IH), 5.41 (s, 2H), 5.20 (s, 2H), 2.27 (s, 3H).
Step 2. 3-bromo-4-[(2,4-diflurobenzyl)oxy] - 6-methyl-l-(4-
[(methylamino)methyl]benzyl}pyridin-2(1H)-one. 4-{ [3-Bromo-4-
[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}benzaldehyde (Step 1) (1.53 g, 3.41 mmol) of step 1
was dissolved in W,W-dimethylformamie (5.0 mL). Methylamine
(3.41 mL, 6.83 mmol, 2.0 M in tetrahydrofuran) was added
followed by NaHB(OAc) 3 (2.17 g, 10.23 mmol) in N,Ndimethylformamide
(8.0 mL) and acetic acid (2.0 mL). The
reaction was stirred at room temperature overnight at which
time IN NaOH (50 mL) was added and then extracted with ethyl
acetate (2 x 50 mL). The organic layers were washed with
brine (25 mL) , dried over Na2S04 and evaporated.
Chromatography ( on silica, ethyl acetate with 5% methanolic
ammonia/hexanes) afforded a tan solid (0.810 g, 53%). !E NMR
(400 MHz, CDC13) 8 7.55 (appq, J = 7.8 Hz, IH) , 7.22 (d, J
8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.92 (app dt, J = 2.4,
8.3 Hz, IH), 6.90-6.80 (m, IH), 5.95 (s, IH), 5.32 (s, 2H),
5.17 (s, 2H), 3.68 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H). ESHRMS
m/z 463.0838 (M+H calcd for C22H2iBrF2N2O4 requires
463.0827).
Example 209
4-t (2,4-diflurobenzyl)oxy]-1-(4-methoxybenzyl)-6-
methylpyridin-2-(IH)-one.
Step 1. Preparation of 1-(4-methoxybenzyl)-4-hydroxy-6-
methylpyridin-2(1H)-one.
HO,
O-
4-Hydroxy-6-methyl-2-pyrone (4.60 g, 36.45 mmol) and 4-
methoxybenzylamine (5.00 g, 36.45 mmol) in H20 (100 mL) were
heated to reflux. After 15 hours at reflux the reaction was
allowed to cool , to room temperature. The precipitate was
collected by filtration washing with H20 to give a pale yellow
solid (8.00 g, 89 %) . XH NMR (400 MHz, DMSO-d6) 5 7.2 (d, J =
8.7 Hz, 2H) , 6.85 (d, J = 8.7 Hz, 2H) , 5.74 (d, J = 2.0 Hz,
1H) , 5.56 (d, J=2.5HZ, 1H) , 5.08 (s, 2H) , 3.68 (s, 3H) ,
2.14 (s, 3H) .
Step 2. Preparation of 4- [ (2,4-diflurobenzyl) oxy] -1- (4--
methoxybenzyl) -6-methylpyridin-2 (1H) -one. l-(4-
methoxybenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (Step 1)
(7.97 g, 32.49 mmol) was dissolved in N, W-dimethylformamide
(60 mL) . Potassium carbonate (4.94 g, 35.74 mmol) was added,
followed by cc-bromo-2, 4-dif luorotoluene (4.38 mL, 34.11 mmol).
The reaction was stirred at room temperature for 20 hours at
which time the* mixture was filtered through a pad of Celite®
washing with acetonitrile and the filtrate was evaporated.
The residue was dissolved in H20 (150 mL) and extracted into
ethyl acetate (2 x 100 mL). The organic phase was washed with
brine (100 mL), dried over Na2S04/ filtered and evaporated.
Chromatography (on silica, hexanes/ethyl acetate with 10%
methanol) yielded an off-white solid (3.64 g, 30%). XH NMR
(300 MHz CDC13) 8 7.42 (app q, J = 7.7 Hz, IH) , 7.13 (d, J =
8.5 Hz, 2H), 6.96-6.84 (m 2H) , 6.85 (app'd, J=8.7Hz, 2H) ,
6.01 (d, J = 2.6 Hz, 'IH) , 5.82 (d, J = 2.8 Hz, IH) , 5.23 (s,
2H), 5.02 (s, 2H), 3.79 (s, 3H), 2.25 (s, 3H). ES-HRMSm/z
372.1412 (M+H CziHigFjNOa requires 372.1417).
Example 210
3-bromo-4-[(2,4-diflurobenzyl)oxy]-1-(4-methoxybenzyl)-6-
methylpyridin-2(IH)-one
O-
Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-1-(4-
methoxybenzyl)-6-methylpyridin-2(IH)-one. EXAMPLE 209 (0.200
g, 0.538 mmol) suspended in acetonitrile (3 mL) was cooled in
an ice-bath. W-bromosuccinimide (0.101 g, 0.565 mmol) was
added. Once the addition was complete the cooling bath was
removed. After 1 hour the reaction was concentrated,
purification by chromatography (silica gel, hexanes/ethyl
acetate) provided a white solid (0.240 g, 99%). XH NMR (300
MHz, CDCL3) 5 7.59 (app, J =- 7.8 Hz:, IH) , 7.16 (d, J" = 8. T
HZ, 2Jftf 6n97=' (app?.dtr - J-W2..4'., 8.6-Hz:,; IH) , 6:._9L-6.83_ (mT
100--

IH) , 6.85 (app d, i7 = 8.7 Hz, 2H) , 5.98 (s, IH) , 5.31 (s, 2H) ,
5.21 (s, 2H) , 3..V9 (s, 3H) , 2.34 (s, 3H) . ES-HRMS m/z
450.0491 (M+H C2iHiBBrF2NO3 requires 450.0511).
Example 211
3-bromo-4-[(2,4-diflurobenzyl)oxy]-1-(4-hydroxybenzyl)-6-
methylpyridin-2(IH)-one
Preparation.of 3-bromo-4-[(2,4-diflurobenzy1)oxy]-1-(4-
hydroxybenzyl)-6-methylpyridin-2(IH)-one. EXAMPLE 210 (0.235
g, 0.522 mmol) was suspended in acetonitrile (3 mL) .. Cerric
ammonium nitrate (1.14 g, 2.09 mmol) dissolved in H20 (1 mL)
was added. The reaction was stirred at room temperature for 1
hour and then diluted with dichloromethane (25 mL). The
reaction was then washed with H20 (10 mL) . The aqueous phase
was back extracted with dichloromethane (20 mL). The combined
organic layers were dried over Na2S04, filtered and evaporated.
The residue was washed with hot ethyl acetate to give an offwhite
solid (0.134 g, 59%). XH NMR (300 MHz, DMSO-ds) §7.75
(app q, J = 7.9 Hz, IH), 7.65 (s, IH), 7.45-7.36 (m, IH), 7.36
(d, J = 10.1HZ, 2H) , 7.27-7.20 (m, IH), 6.49 (d, J = 10.1 Hz,
2H), 5.60 (s, 2H), 5.07 (s, 2H), 2.63 (s, 3H). ES-HRMS m/z
436.0187 (M+H C20HisBrF2N03 requires 436.0354).
Example 2.12
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l{4-[(4-hydroxy-4-
methylpiperidin-1-yl)carbonyl]benzyl}-6-methylpyridin-2(IH)
one.
Step 1. Preparation of 4-hydroxy-4-methylpiperidine
hydrochloride .
tert-Butyl -4 -oxo- l-piperidine (10.0 g, 50.19 mmol) dissolved
in diethyl ether (100 mL) was cooled in an ice-bath. Methyl
magnesium bromide (18.40 mL, 55.21 mmol, 3.0 M in diethyl
ether) was added. After slowly warming to room temperature
the reaction was recooled in an ice-bath and quenched by the
addition of saturated NH4C1 (75 mL) . Additional H20 was added
and the organic layer was removed. The aqueous layer was
further extracted with diethyl ether (50 mL) . The combined
organic layers were washed with brine, dried over Na2S04,
filtered and concentrated. Chromatography ( silica gel,
hexanes/ethyl acetate) provided a clear oil. The resulting
oil was dissolved in diethyl ether (10 mL) and treated with
HCl/dioxane (32.61 mL, 130.43 mmol). After stirring at room
temperature for 1 hour the reaction mixture was concentrated
to give a pale yellow solid (5.05 g, 100%) .
Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-
l{4- [ (4-hydroxy-4-methylpiperidin-l-yl)carbonyl]benzyl}-6-
methylpyridin-2 (1H)-one. THE ACID (0.300 g, 0.646 nunol) was
suspended in dichloromethane (6.0 mL). 1-hydroxybenzotriazole
(0.044 g, 0.323 mmol) was added followed by 3-(lcyclohexylcarbodiitnide)
propyl-functionalized silica gel (2.02
g, 1.29 mmol, loading = 0.64 mmol/g), 3-(l-morpholine)propyl
functionalized silica gel (1.84 g, 1.29 mmol, loading =0.7
mmol/g) and dichloromethane (2 mL). After stirring at room
temperature for 15 minutes, 4-hydroxy-4-methylpiperidine
hydrochloride (0.147 g, 0.969 mmol) was added. The resulting
mixture was stirred at room temperature overnight, at which
time dimethylamine-3-functionalized silica gel (1.7 g, 2.58
mmol, loading = 1.5 mmol/g) was added followed by isocyanate-
3-functionalized silica gel (1.3 g, 1.62 mmol, loading = 1.22
mmol/g). The resulting mixture was stirred at room
temperature for 3 hours. The reaction mixture was then
filtered and concentrated. Chromatography' (silica gel,
hexanes/ethyl acetate with 10% methanol) provided a white foam
(0.200 g, 55%). XH NMR (300 MHz, CDC13) 5 7.58 (app q, J =
7.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz,
2H) , 6.96 (app t, J" = 8.3 Hz, 1H) , 6.87 (app dt, J = 2.0, 9.5
Hz, 1H) , 6.06 (s, 1H) , 5.38 (s, 2H) , 5.22 (s, 2H) , 4.27 (Jbr m,
1H) , 3.41 (Jbr m, 3H), 2.30 (s, 3H) , 2.06 (s, 1H) , 1.60 (Jbr m,
4H) , 1.28 (s, 3H) . ES-HRMS m/z 561.1173 (M+H
requires 561.1195).
Example 213
4-{[3-bromo-4- [ (2,4-difluorobenzyl)oxy]- 6-methyl-2
oxypyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-
methylpropyl)benzamide.
The title compound was by a procedure, essentially as in
Example 212 using l-amino-2-methyl-2-propanol hydrochloride as
starting material.
aH NMR (400 MHz, CDC13) 5 7.70 (d, J = 8.3 Hz, 2H) , 7.53 (app
q, J = 7.8 Hz, IH) , 7.33 (t, J = 5.8 Hz, IH) , 7.06 (d, J - 8 . 3
Hz, 2H) , 6.95-6.90 (m, IH) , 6.86-6.81 (m, IH) , 6.04 (s, IH) ,
5.30 (s, 2H), 5.19 (s, 2H) , 3.40 (d, J = 5.9 Hz, 2H) , 2.98 (br
a, IH) , 2.24 (s,.'3H), 1.21 (s, 6H) . ES-HRMS m/z 535.1012 (M+H
requires 535.1039).
Example 214
3-bromo-4- [ (2,4-dif luorobenzyl) oxy] -l{4- [ (4-hydroxypiperidin
1 -yl ) carbonyl ] benzyl } - 6 -methylpyridin- 2 ( IH) -one .
The title compound was produced essentially as in Example 212
using 4-hydroxypiperidine as starting material. 1H NMR (400
MHz, CDC13) 5 7.55 (app q, J = 7.7 Hz, 1H) , 7.30 (d, J = 8.2
Hz, 2H) , 7.15 (d, J" - 8.3 Hz, 2H) , 6.94 (appdt, J-2.4, 8.4
Hz, 1H) , 6.84 (app ddd, J-2.6, 8.9, 10. 3 Hz, 1H) , 6.01 (s,
1H) , 5.36 (s, 2H) , 5.19 (s, 2H) , 4.12-4.07 (m, 1H) , 3.96-3.90
(m, 1H) , 3.60 (£>r s, 1H) , 3.33 (brs, 1H) , 3.13 (jbr s, 1H) ,
2.27 (s, 3H) , 1.91 (brs, 3H) , 1.77 (brs, 1H) , 1.57 (brs,
1H) , 1.44 (br s, 1H) . ES-HRMS m/z 547.1006 (M+H
requires 547.1039).
Example 215
4-{ [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-2-oxopyridin
1 (2H) -yl]methyl}-N- (2-hydroxyethyl)benzatnide .
Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
raethyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2-
hydroxyethyl)benzamide. To a reaction vessel (borosilicate
culture tube) was added EXAMPLE 205 (0.300 g, 0.646 mmol). A
stock -solution of 1-hydroxybensotriazole in N,Ndimethylformamide
(3 mL, 0.11 M) was added to the reaction
vessel followed by approximately 1.10 g of the polymer bound
carbodiimide resin (1.8 mmol/g). Additional N,Ndimethylformamide
(2 mL) was then added to the reaction
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 15 minutes. Ethanolamine (0.06
mL, 0.994 mmol) was then added to the reaction vessel and the
reaction apparatus was orbitally shaken at room temperature
overnight. At this time the reaction was diluted with
tetrahydrofuran (20 mL) and treated with approximately 2.0 g
of polyamine resin (2.63 mmol/g) and approximately 2.6 g of
methylisocyanate functionalized polystyrene (1.10 mmol/g) and
the orbital shaking was continued at 200 RPM at room
temperature for 3 hours. The reaction vessel was then opened
and the solution phase product was separated from the
insoluble quenched byproducts by filtration and collection
into a vial. After partially evaporation the insoluble
byproducts were rinsed further with tetrahydrofuran (2 x 10
mL) and combined with the partially reduced filtrate. The
resulting filtrate was concentrated by blowing N2 over the vial
while heating (60 °C) in a reaction block (KEM-Lab Parallel
Reactor) to give an off-white solid. (0.111 g, 34%) XH NMR
(400 MHz, DMF-dg) 5 8.45 (t, J = 5.4 Hz, 1H) , 7.94 (d, J = 8.2
Hz, 2H) , 7.76 (app q, J = 7.9 Hz, 1H) , 7.33-7.27 (m, 1H), 7.27
(app d, J = 7.9 Hz, 2H), 7.20 (app dt, J = 2.4, 8.6 Hz, 1H),
6.65 (s, 1H), 5.47 (s, 2H), 5.38 (s, 2H), 4.83 (br s, 1H),
-406-
3.64-3.60 (m, 2H), 2.47-3.42 (m, 2H) , 2.40 (s, 3H). ES-HRMS
m/z 507.0742 (M+H C23H2iBrF2N204 requires 507.0726) .
Example 216-231
Preparation of 3-bromo-4-(2,4-difluorophenoxy)-6-methyl-l-[4
(aminocarbonyl)benzyl]pyridin-2(IH)-one compounds
By following the method of Example 215 and substituting
the appropriate amine, the compounds of Examples 216-231 are
prepared. The deprotection of the protected intermediates was
accomplished with 4N HCl in dioxane to afford the compounds as
hydrochloride salts.
Compound
No.
Ex. 216
EX. 217
EX. 218
EX. 219
EX. 220
EX. 221
EX. 222
EX. 223
EX. 224
EX. 225
Ri
CH2CH2NHH
H
H
H
CH3
CH2CH2OCH2CH2OH
CH2CH2CH2-
H
R2
CH2CH2NHCH2CH2NH2
CH2CH2CH2NH2
OH
CH3
CH3
CH2CH20-
CH2CH2OH
CH2CH2CH2-
CH(CH3)2
%
Yield
73
49
31
53
59
51
61
69
66
50
MF
C25H24BrF2N304
C23H22BrF2N303
C24H24BrF2N303
C21H17BrF2N204
C22Hi9BrF2N204
C23H2iBrF2N203
C25H23BrF2N204
C2SH25BrF2N205
C2SH25BrF2N203
C24H23BrF2N203
M+H
Requires
532.1042
506.0885
520.1042
479.0413
477.0620
491.0776
533.0882
551.0988
531.1084
505.0933
ESHRMS
m/z
532.102
506.088
520.104
479.042
477. 06C
491. 07S
533. 09C
551. 09"
531. 10E
505. 09C
Ex. 226
Ex. 227
Ex. 228
Ex. 229
Ex. 230
EX. 231
CH2CH2-
CH2CH2N(CH3) -
H
H
CH3
CH3
CH2CH2-
CH2CH2N(CH3)-
CH2CH2N(CH3)2
CH2CH2OCH3
CH2CH2OH
CH2CH2OCH3
71
83
81
79
36
82
C2sH23BrF2N203
C26H26BrF2N303
C2SH26BrF2N303
C24H23BrF2N204
C24H23BrF2N204
C2SH25BrF2N204
517.0933
546.1198
534.1198
521.0882
521.0882
535.1039
517.0908
546.1215
534.1197
521.0861
521.0893
535.1028
Example 232
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]- N-(2-hydroxyethyl)benzamide.
Preparation of 4-{[3-bromo-4-[ (2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]- N-(2-hydroxyethyl)benzamide. To
a reaction vessel (borosilicate culture tube) was added
ihydroxybenzotriazole
in N/W-dimethylformamide (3 mL, 0.11 M)
was added to the reaction vessel followed by approximately
1.13 g of the polymer bound carbodiimide resin (1.8 mmol/g).
Additional N,N-dimethylformamide (2 mL) was then added to the
reaction vessel. The parallel reaction apparatus was then
orbitally shaken (Labline Benchtop Orbital Shaker) at
approximately 200 RPM at room temperature for 15 minutes.
Ethanolamine (0.06 mL, 0.994 mmol) was then added to the
reaction vessel and the reaction apparatus was orbitally
shaken at room temperature overnight. At this time the
reaction waff diluted wi±Jt toefcEahydroturaa (2,0 mL.) and- treated
with approximately 2.0 g of polyamine resin (2.63 mmol/g) and
approximately 2.7 g of methylisocyanate functionalized
polystyrene (1.10 mmol/g) and the orbital shaking was
continued at 200 RPM at room temperature for 3 hours. The
reaction vessel was then opened and the solution phase
products were separated from the insoluble quenched byproducts
by filtration and collection into a vial. After partially
evaporation the insoluble byproducts were rinsed further with
tetrahydrofuran (2 x 10 mL) and combined with the partially
reduced filtrate. The resulting filtrate was concentrated by
blowing N2 over the vial while heating (60 °C) in a reaction
block (KEM-Lab Parallel Reactor). Purification by
chromatography (silica gel) provided an off-white solid (0.155
g, 47%). XH NMR (400 MHz, DMF-dg) 8 8.58 (t, J = 5.5 Hz, 1H) ,
8.10 (d, J = 8.3 Hz, 2H), 7.79 (app q, J = 7.9 Hz, 1H), 7.47
(d, J = 8.3 Hz, 2H) , 7.36-7.30 (m, 1H), 7.21 (app dt, J=2.4,
8.5 Hz, 1H), 6.73 (s, 1H), 5.43 (s, 2H), 3.68 (appt, J = 5.9
Hz, 2H) , 3.52-3.49 (m, 2H), 2.03 (s, 3H) . ES-HRMS m/z
493.0597 (M+H C22H19BrF2N204 requires 493.0569).
Examples 233-243
By following the method of Example 232 and substituting
ethanolamine for the appropriate amine, the compounds of
Examples 233-243 are prepared. The deprotection of the
protected intermediates was accomplished with 4I\T HCl in
dioxane to afford the compounds as hydrochloride salts.
Compound
No.
Ex. 233
Ex. 234
Ex. 235
Ex. 236
Ex. 237
Ex. 238
Ex. 239
Ex. 240
Ex. 241
Ex. 242
Ex. 243
Ri
CH2CH2NHH
H
H
H
CH3
CH2CH20-
CH2CH2OH
CH2CH2CH2-
H
CH2CH2-
R2
CH2CH2NHCH2CH2NH2
CH2CH2CH2NH2
OH
CH3
CH3
CH2CH20-
CH2CH2OH
CH2CH2CH2-
CH(CH3)2
CH2CH2-
%
Yield
40.3
57.1
21.5
33.9
20.7
22.3
84.4
46.6
76.5
52.6
47.2
MF
C24H22BrF2N303
C22H20BrF2N303
C23H22BrF2N303
C2oHi5BrF2N204
C21Hi7BrF2N2O3
C22H19BrF2N203
C24H21BrF2N204
C24H23BrF2N2Os
C2SH23BrF2N203
C23H21BrF2N203
C24H21BrF2N204
M+H
Requires
518.0885
492.0729
506.0885
465.0256
463.0463
477.0620
519.0726
537.0831
517.0933
491.0776
503.0776
ESHRMS
m/z
518.0866
492.0748
506.0915
465.0259
463.0479
477.0643
519.0723
537.0854
517.0892
491.0781
503.0791
Ex. 244
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin
1(2H)-yl]benzamide.
Preparation of 4- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]benzamide. EXAMPLE 203 (0.500 g,
1.11 mmol) was suspended in tetrahydrofuran. (5.0 inL) . 2-
Chloro-4,6-dimethoxy-l,3/5-triazine (0.234 g, 1.33 mmol) was
added followed by 4-methylmorBhnline (0.366 mL-,- 3._3.1 mmol) .
Thar resulting mixtuEfe Qont. temperature fcrc t5T
hours at which time NH4OH (2.5 mL) was added. The resulting
mixture was stirred at room temperature overnight. H2O (25 mL)
and tetrahydrofuran (25 mL) was added. The aqueous layer was
further extracted with ethyl acetate (25 mL). The combined
organic layers were washed with saturated sodium carbonate
solution (25 mL) , LW HCl (25 mL), brine (25 mL), dried over
Na2SO4, filtered and concentrated to provide a pale yellow
solid (0.500 g, 100 %) . XH NMR (400 MHz, DMF-ds) 6 8.13 (s,
IH), 8.02 (d, J = 8.5 Hz, 2H), 7.70 (app q, J » 7.9 Hz, IH),
7.40 (d, J - 8.5 Hz, 2H) , 7.41-7.34 (m, IH) , 7.22 (app dt, J =
1.8, 8.5 Hz, IH), 6.71 (s, IH), 5.37 (s, 2H), 1.97 (s, 3H).
ES-HRMS m/z 449.0281 (M+H C2oH15BrF2N203 requires 449.0307).
Ex. 245
4- (Benzyloxy)-3-bromo-l-[4-(morpholin-4-
ylcarbonyl)phenyl]pyridin-2(IH)-one.
Preparation of 4-(Benzyloxy)-3-bromo-l-[4-(morpholin-4-
ylcarbonyl)phenyl]pyridin-2(IH)-one. To a reaction vessel
(borosilicate culture tube) was added EXAMPLE 197 (0.100 g,
0.250 tnmol) which was dissolved in N,N-dimethylformamide (2.0
mL). 1-Hydroxybenzotriazole (0.017 g, 0.125 mmol) was added
to the reaction vessel followed by approximately 0.423 g of
the polymer bound carbodiimide resin (1.8 mmol/g). Additional
N/N-dimethylformamide (2 mL) was then added to the reaction
-411.-
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 15 minutes. Morpholine (0.033 g,
0.0.375 mmol) dissolved in tf,.N-dimethlyformamide (0.5 mL) was
then added to the reaction vessel and the reaction apparatus
was orbitally shaken at room temperature overnight. At this
time the reaction was diluted with W/W-dimethylformamide (2.0
mL) and dichloromethane (4.0 mL) and treated with
approximately 0.770 g of polyamine resin (2.63 mmol/g) and
approximately 1.0 g of methylisocyanate functionalized
polystyrene (1.10 mmol/g) and the orbital shaking was
continued at 200 RPM at room temperature for 3 hours. The
reaction vessel was then opened and the solution phase product
was separated from the insoluble quenched byproducts by
filtration and collection into a vial. After partially
evaporation the insoluble byproducts were rinsed with
dichloromethane (2 x 10 mL). The filtrate was evaporated by
blowing N2 over the vial while heating (60 °C) in a reaction
block (KEM-Lab Parallel Reactor) to give an off-white solid
(0.092 g, 79%).
XH NMR (400 MHz, CDC13) 5 7.50 (d, J = 8.5 Hz, 2H) , 7.48-7.33
(m, 7H), 7.27 (d, J = 7.8 Hz, IH), 6.19 (d, J = 7.8 Hz, IH),
5.29 (s, 2H), 3.76-3.47 (br m, 8H). ES-HRMS m/z 469.0733 (M+H
C23H2iBrN204 requires 469.0757).
Ex. 246
4-(Benzyloxy)-3-bromo-l-[4- (piperazin-1-
ylcarbonyl)phenyl]pyridin-2(IH)-one hydrochloride.
Preparation of 4- (benzyloxy) -3-bromo-l- [4- (piperazin-1-
ylcarbonyl ) phenyl] pyridin-2 ( IH) -one hydrochloride . By
following the method of Ex. 245 and substituting .N- tert- butyl
carboxylate piperazine (0.070 g, 0.375 mmol) for morpholine
the title compound was prepared as the N- t-butoxycarbonyl
protected compound. .The deprotection of the N-tbutoxycarbonyl
intermediate was accomplished with 4W HCI in
dioxane to afford the title compound as its hydrochloride salt
(0.112 g, 100%) . 1H NMR (400 MHz, DMSO-dg) 8 9.55 (Jbr s, 2H) ,
7.78 (d, J = 7.8 Hz, IH) , 7.58 (d, J - 8.5 Hz, 2H) , 7.48-7.33
(m, 7H) , 6.57 (d, J = 7.8 Hz, IH) , 5.38 (s, 2H) , 3.79-3.36 (Jbr
m, 4H) , 3.30-3.14 (Jbr s, 4H) . ES-HRMS m/z 468.0940 (M+H
requires 468.0917).
Ex. 247
4- [4- (Benzyloxy) -3-bromo-2-oxopyridin-l (2H) -yl] -Nhydoxybenzamide.
Preparation of 4-[4-(Benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]-N-hydoxybenzamide. By following the method of EXAMPLE 245
and substituting 0-(tetrahydro-2H-pyranyl-2yl) hydroxylamine
(0.044 g, 0.375 mmol) for morpholine the title compound was
prepared as the tetrahydropyranly protected compound. The
deprotection of the tetrahydropyranly intermediate was
accomplished with 4.N HC1 in dioxane to afford the title
compound (0.056 g, >71%) . *H NMR (400 MHz, DMSO-ds) 6 11.03
(br S,1H), 7.83 (d, J - 8.6 Hz, 2H), 7.78 (d, J • 7.8 Hz, 1H),
7.48-7.35 (m, 7H) , 6.55 (d, J> 7.8 Hz, 1H) . 5.37 (s, 2H) .
ES-HRMS m/z 415.0278 (M+H Ca9Hi5BrN204 requires 415.0288).
Ex. 248
Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl] methyl Jbenzoate.
Step 1. Preparation of 3-chloro-4-[ (2,4-difluorobenzyl)oxy]
6-methylpridin-2(1H)-one .
(5.00 g, 19.90 mmol) was suspended in 1,2-dichloroethane (100
tnL). Dichloroacetic acid (0.082 mL, 0.995 mmol) was added,
followed by W-chlorosuccinimide (3.19 g, 23..88 mmol). The
reaction mixture was heated at 80 °C for 15.5 hours. The 1,2-
dichloroethane was evaporated and the remaining solids were
washed with acetonitrile to provide a tan solid (4.97 g, 88%).
Step 2. Preparation of methyl-4-{[3-chloro-4-[ (2,4-
dif luorobenzyl) oxy]-6-methyl-2-oxopyridin-l (2H)-
yl]methyl}benzoate. 3-Chloro-4-[(2,4-difluorobenzyl)oxy] -6-
methylpridin-2(1H)-one (Step 1) (4.97 g, 17.40 mmol) suspended
in tetrahydrofuran (50 inL) was cooled in an ice-bath. Methyl
4-(bromomethyl)benzoate (5.98 g, 26.10 mmol) was added,
followed by sodium hydride (0.835 g, 20.88 mmol, 60%
dispersion in mineral oil). Once the addition was complete
the cooling bath was removed in the mixture was heated to 50 °C
for 19 hours. After cooling to room temperature saturated
NH4C1 (50 mL) was added. Ethyl acetate was added and the
precipitate was collected by filtration. The filtrate was
further extracted with ethyl acetate. The combined organic
layers were washed with brine (50 mL), dried over Na2S04,
filtered and evaporated. The resulting solid was combined
with the precipitate and washed with hot ethyl acetate to give
an off-white solid (5.24 g, 69%). XH NMR (400 MHz, DMSO-ds) 8
7.90 (d, J = 8.5 Hz, 2H), 7.63 (app q, J - 7.9 Hz, 1H), 7.31
(app dt, J = 2.4, 9.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H) , 7.17-
7.13 (m, 1H), 6.60 (s, 1H), 5.36 (s, 2H), 5.27 (s, 2H), 3.81
(s, 3H) , 2.27 (s, 3H) . ES-HRMS m/z 434.0931 (M+H C22H18BrF2N04
requires 434.0965).
Example 249
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyl}-N- methylbenzamide
To a reaction vessel (borosilicate culture tube) was added
EXAMPLE 169 (0.300 g, 0.646 mmol). A stock solution of 1-
hydroxybenzotriazole in W,J7-dimethylformamide (3 mL, 0.11 M)
was added followed by approximately 1.10 g of the polymer
bound carbodiimide resin (1.8 mmol/g). Additional NtNdimethylformamide
(2 mL) was then added to the reaction
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 15 minutes. N-Methylamine (0.50
mL, 0.999 mmol) was then added to the reaction vessel and the
reaction apparatus was orbitally shaken at room temperature
overnight. At this time the reaction was diluted with
tetrahydrofuran (35 mL) and treated with approximately 2.0 g
of polyamine resin (2.63 mmol/g) and approximately 2.6 g of
methylisocyanate functionalized polystyrene (1.50 mmol/g) and
the orbital shaking was continued at 200 RPM at room
temperature for 4 hours. The reaction vessel was then opened
and the solution phase products were separated from the
insoluble quenched byproducts by filtration and collection
into a vial. After partial evaporation the insoluble
byproducts were rinsed^ witir trefcratiyetoyfi.!rare. (2, x 10 mL.) . The
filtrate was evaporated by blowing N2 over the vial while
heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor).
Chromatography (C-18, acetonitrile/H20 with 0.1%
trifluoroacetic acid) afforded a white solid (0.178 g, 58%).
XH NMR (400 MHz, DMF-dg) 8 7.65-7.53 (m, 3H) , 7.37-7.28 (m,
2H) , 6.97-6.82 (m, 2H) , 6.00 (a, 1H) , 5.36 (a, 2H) , 5.19 (a,
3H) , 2.96 (t, J = 4.83 Hz, 3H) , 2.29 (s, 3H) . ES-HRMS m/Z
477.0635 (M+H C22Hi9BrF2N203 requires 477.0620).
Preparation of Examples 250- 261
By following the method of Example 249 and replacing Nmethylamine
with the appropriate amine, the compounds of
Examples 250-261 are prepared. The deprotection of the
protected intermediates was accomplished with 4W HCl in
dioxane to afford the compounds as hydrochloride salts.
Compound
No.
Ex. 250
Ex. 251
Ex. 252
Ex. 253
Ex. 254
Ri
CH2CH2NHH
H
H
CH3
R2
CH2CH2NHCH2CH2NH2
CH2CH2CH2NH2
OH
CH3
%
Yield
89
75
84
45
69
MF
C25H24BrF2N304
C23H22BrF2N3O3
C24H24BrF2N303
C2iH17BrF2N204
C23H2iBrF2N2O3
M+H
Requires
532.1042
506.0885
520.1042
479.0413
491.0776
ES-HRMS
nt/z
532.1067
506.0900
520.1000
479.0394
491.0731
Ex. 255
Ex. 25S
Ex. 257
Ex. 258
Ex. 259
Ex. 260
Ex. 261
H
CH2CH20-
H
CH2CH2OH
CH2CH2CH2-
H
CH2CH2-
CH3
CH2CH20-
CH2CH2OH
CH2CH2OH
CH2CH2CH2-
CH(CH3)2
CH2CH2-
58
69
51
25
62
46
60
C22H19BrF2N2O3
C25H23BrF2N204
C23H21BrF2N204
C2SH25BrF2N2Os
C26H2SBrF2N203
C24H23BrF2N203
C25H23BrF2N203
479.0602
533.0882
507.0726
551.0988
531.1089
505.0933
517.0933
479.0598
533.0857
507.0698
551.0972
531.1088
505.0918
517.0950
Example 262
N- (3-{ [3-bromo-4- [ (2, 4-dif luorobenzyl) oxy] -6-methyl-2-
oxopyridin-1 (2H) -yl]methyl}benzyl) -2-methoxyacetamide
To a reaction vessel (borosilicate culture tube) was added
methoxyacetic acid (0.09 g, 1.00 mmol) . A stock solution of
1-hydroxybenzotriazole (3 mL, 0.16 M) and W-methylmorpholine
(3 mL, 0.43 M) in tf,W-dimethylformamide were added to the
reaction vessel followed by approximately 0.97 g of the
polymer bound carbodiimide resin (1.38 mmol/g). Additional
N',W-dimethylformamide (3 mL) was then added to the reaction
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 4 hours. l-[3-
(aminomethyl)benzyl] -3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one (EXAMPLE 161) (0.30 g, 0.668 mmol) was
then added to the reaction vessel followed by additional N,Ndimethylformamide
(5.0 mL) and the reaction apparatus was
orbitally shaken at room temperature overnight. At this time
the reaction was diluted with tetrahydrofuran (20 mL) and
treated with approximately 2.06 g of polyamine resin (2.63
mmol/g) and approximately 2.67 g of methylisocyanate
functional!zed polystyrene (1.10 mmol/g). and the orbital
shaking was continued at 200 RPM at room temperature for 4
hours. The reaction vessel was then opened and the solution
phase products were separated from the insoluble quenched
byproducts by filtration and collection into a vial. After
partial evaporation the insoluble byproducts were rinsed with
tetrahydrofuran (2 x 10 mL) . The filtrate was evaporated by
blowing N2 over the vial while heating (60 °C) in a reaction
block (KEM-Lab Parallel Reactor) afforded a tan solid (0.321
g, 89.4%). H NMR (400 MHz, DMF-dg) 5 8.33 (br s, IH) , 7.81
(app q, 7 - 7.85 Hz, IH), 7.40-7.23 (m, 5H), 7.09 (d, J = 7.25
Hz, IH) , 6.68 (s, IH) , 5.46 (s, 2H) , 5.42 (s, 2H) , 4.45 (d, J
= 6.24 Hz, 2H), 3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ESHRMS
m/z 521.0891 (M+H C24H23BrF2N2O4 requires 521.0882).
Preparation of Example 263-265
By following the method of Example 262 and replacing
methoxyacetic acid with the appropriate acid, the compounds of
Examples 263-265 are prepared. The deprotection of the
protected intermediates was accomplished with 4.W HCl in
dioxane to afford the compounds as hydrochloride salts.
Compound
No.
Ex. 263
Ex. 264
Ex. 265
R
CH2NH2
CH2NHCOCH3
CH2OCOCH3
%
Yield
46.1
70.4
42.7
MF
C23H23BrF2N303
C2sH24BrF2N304
C23H2iBrF2N204
M+H
Requires
506.0885
548.0991
549.0831
ES-HRMS
m/z
506.0870
548.1007
549.0837
Example 266
Br
N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzyl)-2-hydroxy-2-
methylpropanami de
1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methylpyridin-2(lH)-one (EXAMPLE 161) (0.300 g, 0.668 mmol),
1-hydroxyisobutyric acid (0.215 g, 2.064 mmol), 1-
hydroxybenzotriazole (0.112 g, 0.826 mmol), and l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.185
g, 0.963 mmol) were dissolved in -W,tf-dimethylacetamide (3 mL) .
W-methylmorpholine (0.209 g, 2.064 mmol) was added, and the
reaction stirred for 1 hour at room temperature. The reaction
was diluted with H20 (50 mL) and the aqueous layer extracted
with ethyl acetate (3 x 25 mL) . The combined organics were
then washed with 1W HC1 (25 mL) , saturated Na2C03 (25 mL) ,
brine (25 mL) , dried over Na2S04/ and concentrated to yield an
off-white solid (0.235 g, 64%). XH NMR (400 MHz, DMF-d6) 8
8.25 (br s, 1H) , 7.81 (app q, J = 7.92 Hz, 1H) , 7.40-7.21 (m,
5H) , 7.09 (d, J = 6.84 Hz, 1H) , 6.67 (s, 1H) , 5.46 (s, 2H) ,
5.42 (s, 2H) , 4.42 (d, J = 6.24 Hz, 2H) , 2.44 (s, 3H) , 1.38
(s, 6H) . ES-HRMS m/z 535.1024 (M+H €25^58^2^04 requires
535.1039).
Example 267
N- (3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzyl)-1-
hydroxycyc1opropanecarboxami de
By following the method of Example 266 and substituting 1-
hydroxy-1-cyclopropane-carboxylic acid for 1-hydroxyisobutyric
acid, the title compound was prepared (0.352 g, 96%) . XH NMR
(400 MHz., DMF-dfr) 8 8.46 (app t, J = 6.24 Hz, 1H) , 7.81 (app q,
-421-
J - 7.92 Hz, 1H) , 7.40-7.22 (m, 5H) , 7.06 (d, J - 7.05 Hz,
1H) , 6.67 (s, 1H) , 5.45 (s, 2H) , 5.42 (s, 2H) , 4.46 (d, J =
6.44 Hz, 2H), 2.45 (s, 3H) , 1.17-1.12 (m, 2H) , 0.93 (app q, J
3.82 Hz, 2H) . ES-HRMS m/z 533.0861 (M+H
requires 533.0882).
Example 267
Br
N1-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzyl)-N,N-dimethylurea
Step 1: Preparation of 4-nitrophenyl 3-{[3-bromo-4-[(2,4'
difluorobenzyDoxy] -6-methyl-2-oxopyridin-1 (2H) -
yl]methyl}benzylcarbamate .
1 - [3 - (aminomethyL) benzyLJ -3 -bxomrir4 [
was suspended in dichloromethane (15 mL) . Pyridine was added
(0.43 mL, 5.34 trimol) After stirring for 10 minutes at room
temperature, a stock solution of 4-nitrophenyl chloroformate
(10.0 mL, 0.50 M) in dichloromethane was added dropwise.
After stirring for 4.5 hours at room temperature, a stock
solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in
dichloromethane was again added dropwise and stirring
continued at 40 °C overnight. The reaction mixture was
concentrated and subjected to chromatography (silica gel,
ethyl acetate with 10% methanol/hexanes) to afford a yellow
solid (1.11 g, 66%). 1H NMR (400 MHz, DMSO-d6) 8 8.56 (app t,
J = 6.10 Hz, 1H), 8.24-8.21 (m, 2H), 7.62 (app q, J=7.88Hz,
1H) , 7.40-7.27 (m, 7H) , 6.98 (d, J = 7.52 Hz, 1H) , 6.54 (s,
1H) , 5.30 (s, 2H) , 5.24 (s, 2H) , 4.25 (d, J = 6.18 Hz, 2H) ,
2.30 (s, 3H) . ES-HRMS m/z 614.0753 (M+H C2eH22BrF2N306 requires
614.0733).
Step 2: Preparation of N1-(3-{[3-bromo-4-1(2,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -
yl] methyl}benzyl) -N,N-dimethylurea . To a reaction vessel
(borosilicate culture tube) was added 4-nitrophenyl 3-{ [3-
bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}benzylcarbamate (from step 1) (0.350 g, 0.570 mmol)
dissolved in dichloromethane (6.0 mL) . The parallel reaction
apparatus was then orbitally shaken (Labline Benchtop Orbital
Shaker) at approximately 200 RPM at room temperature for 15
minutes. A stock solution of W/W-dimethylamine in
tetrahydorfuran (0.427 mL, 2.0 M) was then added to the
reaction vessel and the reaction apparatus was orbitally
shaken at room temperature overnight. The reaction mixture
was concentrated and subjected to chromatography (silica gel,
e-thyl acetate with 10% methanol/hexanes) which afforded an off
white solid (0.226 g, 63.3%). XH NMR (400 MHz, DMF-dg) 5 7.81
(app q, J = 7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d, J - 7.45
Hz, 1H), 6.88 (app t, J = 5.84 Hz, 1H), 6.68 (s, 1H) , 5.45 (s,
2H) , 5.42 (s, 1H) , 4.35 (d, J = 5.84 Hz, 1H) , 2.92 (s, 6H) ,
2.44 (s, 3H) . ES-HRMS m/z 520.1065 (M+H C24H24BrF2N303 requires
520.1042) .
Preparation of. Example 268-270
By following the method of Example 267 and replacing N,Ndimethylamine
with the appropriate amine, the compounds of
Examples 268-270 are prepared. The deprotection of the
protected intermediates was accomplished with 4.N HCl in
dioxane to afford the compounds as hydrochloride salts.
Compound % M+H ES-HRMS
Ri R2 MF
No. Yield Requires
Ex. 268 CH2CH2N-CH2CH2N- 66.6 C26H27BrF2N403561.1307561.1309
Ex. 269 H CH3 27 . 0 C23H22BrF2N303 506 . 0885506 . 0898
Ex. 270 CH2CH20-CH2CH20- 64.4 C2sH26BrF2N304 562 .1148562 .1137
Example 271
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H)-yl]benzole acid.
Step 1: Preparation of methyl 3-(4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)benzoate .
Methyl 3-aminobenzoate (75.00 g, 496.13 mmol) and 4-hydroxy-6-
methyl-2-pyrone (62.57 g, 496.13 mmol) were suspended in 1,2-
dichlorobenzene (150 mL) and heated to 165 °C for 15 minutes.
The reaction was cooled to room temperature and extracted with
0.54M K2C03 (4 x 250 mL) . The aqueous layers were acidified
(pH 2) with 4N HCl. The precipitate was collected by
filtration to afford a yellow-orange solid (20.24 g, 16%).
The resulting filtrate was extracted with ethyl acetate (3x1
L). The organic layers were washed with brine (500 mL), dried
over MgS04 and evaporated. The resulting solid was washed with
hot H20 to afford a yellow-orange solid (3.84 g, 3%). The two
solids were then combined. 1H NMR (400 MHz, DMSO-d6) 8 7.98
(dt, J = 1.31, 7.79 Hz, 1H) , 7.69 (app t, J = 1.78 Hz, 1H) ,
7.62 (t, J = 7.78 Hz, 1H) 7.49 (ddd, J = 1.07, 1.07, 7.85 Hz,
1H) , 5.89 (dd, J = 0.87, 2.48 Hz, 1H) , 5.55 (app d, J = 0.94
Hz, 1H) , 3.83 (s, 3H) , 1.80 (s, 3H) . ES-HRMS m/z 260.0895
(M+H Ci4H13N04 requires 260.0917).
Step 2: Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-1(2H)-yl]benzoate .
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l (2H)-yDbenzoate (
from step 1) (24.00 g, 92.57 mmol) and K2C03 (15.35 g, 111.08
mmol) were dissolved in W,N-dimethylformamide (220 mL) .
Difluorobenzyl bromide (20.12 g, 97.20 mmol) was then added
and the reaction mixture stirred for 48 hours at room
temperature. The reaction mixture was diluted with H20 (1 L)
and the precipitate collected by filtration to afford a white
solid (4.08 g, 11%). The resulting oil was purified by
chromatography (silica gel, ethyl acetate with 10%
methanol/hexanes) to afford an off white solid (11.88 g, 33%).
The two solids were combined. 1H NMR (400 MHz, CDCls) 5 8.11
(dt, J - 1.41, 7.79 Hz, 1H) , 7.87 (app t, J = 1.78 Hz, 1H) ,
7.58 (app t, J = 7.69 Hz, 1H) 7.45-7.38 (m, 2H), 6.94-6.84 (m,
2H) , 5.97 (d, J = 2.68 Hz, 1H) , 5.90 (ddd, J = 0.94, 1.74,
1.74 Hz, 1H) , 5.97 (s, 1H) , 3.90 (s, 3H) , 1.89 (s, 3H) . ESHRMS
m/z 386.1179 (M+H C2iH17F2N04 requires 386.1198).
Step 3: Preparation of methyl 3-[3-bromo-4-[(2,4-
difluorobenzyl)oxy] -6-methyl-2-oxopyridin-l (2H) -yDbenzoate .
Methyl 3- [4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]benzoate ( from step 2) (15.85 g, 41.130 mmol)
suspended in acetonitrile (165 tnL) was cooled in an ice-bath.
AT-bromosuccinimide (7.687 g, 43.186 mmol) was added and the
ice-bath was removed. The reaction mixture was stirred for
1.5 hours at room temperature. Reaction was concentrated and
subjected to chromatography (silica gel, ethyl acetate with
10% methanol/hexanes) afforded an off white solid (17.63 g,
92%). XH NMR (400 MHz, CDC13) 5 8.17 (dt, J = 1.41, 7.85 Hz,
1H) , 7.90 (t, J - 1.81 Hz, 1H) , 7.67-7.41 (m, 3H) , 7.05-6.88
(m, 2H) , 6.13 (s, 1H) , 5.30 (a, 2H) , 3.95 (s, 1H) , 2.01 (a,
3H) . ES-HRMS m/z 464.0286 (M+H C2iH16BrF2N04 requires
464.0304) .
Step 4: Preparation of the title compound . Methyl 3-[3-
bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]benzoate ( from step 3) (10.0 g, 21.539 mmol) was dissolved
in methanol (36 mL) and tetrahydrofuran (14 mL) . 42V NaOH
(13.5 mL, 53.847 mmol) was added. The resulting mixture was
stirred for 1.5 hours at room temperature. The reaction was
acidified (pH 2) with 4J7 HCl. The precipitate was collected
by filtration to afford an off white solid (7.83 g, 81%) XH
NMR (400 MHz, DMSO-ds) 6 8.01 (dt, J = 1.41, 7.65 Hz, 1H) ,
7.76 (app t, J = 1.78 Hz, 1H) , 7.76-7.15 (m, 5H) , 6.66 (s,
1H) , 5.32 (s, 2H) , 1.92 (s, 3H) . ES-HRMS m/z 450.0134 (M+H
4-5-0-. Ql^) .
-4-2-7-
Example 272
Ethyl 3- [3-bromo-4- [ (2, 4-dif luorobenzyljoxy] -6-methyl-2-
oxopyridin-1 (2H) -yl] benzoate
By following the method of Example 271 and substituting ethyl
3-aminobenzoate for methyl 3-aminobenzoate, the title compound
was prepared (2.66 g, 79%). *H NMR (400 MHz, CDC13) 6 8.13 (dt,
J = 1.41, 7.85 Hz, 1H) , 7.84 (t, J = 1.88 Hz, 1H) , 7.62-7.55
(m, 2H) , 7.36 (app dq, J = 1.07, 7.85 Hz, 1H) , 6.96 (app dt, J
= 2.55, 8.35 Hz, 1H) , 6.88-6.84 (m, 1H) , 6.08 (s, 1H) , 5.25
(S, 2H) , 4.42-4.30 (m, 2H) , 1.96 (s, 3H) , 1.36 (t, J = 7.12
Hz, 3H) . ES-HRMS m/z 478.0482 (M+H C^HisB^NCU requires
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridinl
(2H) -yll -tf-methylbenzemcfccfe
To a reaction vessel (borosilicate culture tube) was added
EXAMPLE 271 (0.300 g, 0.666 mmol). A stock solution of 1-
hydroxybenzotriazole in N,.N-dimethylformamide (3 mL, 0.11 M)
was added to the reaction vessel followed by approximately
0.97 g of the polymer bound carbodiimide resin (1.38 mmol/g).
Additional W,W-dimethylformamide (2 mL) was then added to the
reaction vessel. The parallel reaction apparatus was then
orbitally shaken (Labline Benchtop Orbital Shaker) at
approximately 200 RPM at room temperature for 15 minutes. NMethylamine
in tetrahydrofuran (0.50 mL, 0.999 mmol) was then
added to the reaction vessel and the reaction apparatus was
orbitally shaken at room temperature overnight. At this time
the reaction was diluted with tetrahydrofuran (30 mL) and
treated with approximately 2.0 g of polyamine resin (2.63
mmol/g) and approximately 3.6 g of methylisocyanate
functionalized polystyrene (1.10 mmol/g) and the orbital
shaking was continued at 200 RPM at room temperature for
hours. The reaction vessel was then opened and the solution
phase products were separated from the insoluble quenched
byproducts by filtration and collection into a vial. After
partial evaporation the insoluble byproducts were rinsed with
tetrahydrofuran (2 x 10 mL) . The filtrate was evaporated by
blowing N2 over the vial while heating (60 °C) in a reaction
block (KEM-Lab Parallel Reactor) to give an off-white solid
(0.189 g, 61%). XH NMR (400 MHz, DMF-d6) 6 8.56 (br d, J =
4.16 Hz, 1H) , 8.05-7.76 (m, 3H) , 7.66 (t, J = 7.79 Hz, 1H) ,
7.56-7.19 (m, 3H) , 6.74 (a, 1H) , 5.43 (s, 2H) , 3.46 (a, 3H) ,
2.03 (s, 3H) . ES-HRMS m/z 463.0476 (M+H C2iHi7BrF2N203 requires
463.0463).
Preparation of Example 274-289
By following the method of Example 273 and replacing Nmethylamine
with the appropriate amine, the compounds of
Examples 274-289 are prepared. The deprotection of the
protected intermediates was accomplished with 4W HCl in
dioxane to afford the compounds as their hydrochloride salts.
Compound
No.
Ex. 274
Ex. 275
Ex. 276
Ex. 277
Ex. 278
Ex. 279
Ex. 280
Ex. 281
Ex. 282
Ex. 283
Ex. 284
Ex. 285
Ex. 286
Ex. 287
Ex. 288
Ex. 289
Rl
CH2CH2NHH
H
H
CH3
CH2CH20-
H
CH2CH2CH2-
H
CH2CH2-
CH2CH2N(CH3)-
H
H
CH3
CH3
CH3
R2
CH2CH2NHCH2CH2NH2
CH2CH2CH2NH2
OH
CH3
CH2CH20-
CH2CH20H
CH2CH2CH2-
CH(CH3)2
CH2CH2-
CH2CH2N(CH3)-
CH2CH2N(CH3)2
CH2CH20CH3
CH2CH2N(CH3)2
CH2CH20H
CH2CH20CH3
%
Yield
92.8
95.7
97.8
91.0
67.7
86.7
78.3
87.9
80.6
87.9
75.8
86.1
90.2
60.0
81.6
94.4
MF
C2«H22BrF2N303
C22H20BrF2N303
C23H22BrF2N303
C2oH15BrF2N204
C22H19BrF2N203
C24H21BrF2N204
C22Hl9BrF2N204
C25H23BrF2N203
C23H31BrF2N203
C24H21BrF2N204
C25H24BrF2N303
C24H24BrF2N303
C23H21BrF2N204
C2SH2fiBrF2N303
C23H21BrF2N204
C24H23BrF2N204
M+H
Requires
518.0885
492.0729
506.0885
465.0256
477.0620
519.0726
493.0569
517.0933
491.0776
503.0776
532.1042
520.1042
507.0726
534.1198
507.0726
521.0882
ES-HRMS
m/z
518.0865
492.0711
506-.0889
465.0278
477.0626
519.0696
493.0575
517.0918
491.0797
503.0732
532.1038
520.1030
507.0680
534.1155
507.0694
521.0862
-430-
Example 290
3-[3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]benzamide
EXAMPLE 271 (2.00 g, 4.44 mmol) and 2-chloro-4,6-dimethoxy-
1,3,5-triazine (0.94 g, 5.33 mmol) were suspended in
tetrahydrofuran (20 mL) . 4-Methylmorpholine (1.5 mL, 13.32
mmol) was added. The resulting mixture was stirred for 1.5
hours at room temperature. NH4OH (10 mL, 148.00 mmol) was
added and the reaction was stirred for 0.5 hours at room
temperature. H20 (50 mL) and tetrahydrofuran (50 mL) were
added and the organic layer was separated. The aqueous phase
was extracted with ethyl acetate (75 mL) and the combined
organics were washed with saturated Na2C03 (50 mL) , 1W HCl (50
mL) , and brine (50 mL) . The organic phase was dried over
Na2SO4 and evaporated. The resulting solid was washed with
diethyl ether to give a white solid (1.86 g, 93%) . 1H NMR (400
MHz, DMF-dg) 8 8.20 (br s, 1H) , 8.10-8.07 (m, 1H) , 7.79 (a,
1H) , 7.79 (app q, J » 7.83 Hz, 1H) , 7.66 (app t, J = 7.79 Hz,
1H) , 7.57-7.54 (m, 1H) , 7.46 (br s, 1H) , 7.36-7.19 (m, 2H) ,
6.74 (s, 1H) , 5.43 (s, 2H) , 2.04 (s, 3H) . ES-HRMS m/z
449.0307 (M+H C2oH15BrF2N2O3 requires 449.0307).
Example 291
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl] benzole acid
Step 1: Preparation of methyl 3-[3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoate
The product from step 2, Example 271 (4.54 g, 11.78 mmol) and
W-chlorosuccinimide (1.65 g, 12.37 mmol) were suspended in
dichloromethane (12 mL) . Dichloroacetic acid (0.10 ml, 1.22
mmol) was added and the reaction mixture was stirred overnight
at 40 °C. The reaction was cooled to room temperature and a
precipitate formed. The precipitate was collected by
filtration and washed with dichloromethane (3 x 10 mL) to
afford a white solid (1.75 g, 35%) . The filtrate was
concentrated and subjected to chromatography (silica gel,
ethyl acetate with 10% methanol/hexanes) to afforded an off
white solid (1.29 g, 26%). The two solids were then combined.
XH NMR (400 MHz, CDC13) 6 8.12 (dt, J - 1.38, 7.83 Hz, 1H) ,
7.85 (t, i7 - 1.74 Hz, 1H) , 7.60-7.52 (m, 2H) , 7.37 (dq, J
0.92, 7.92 Hz, 2H) , 6.95 (app dt, J 2.55, 8.32 Hz, 1H) ,
6.89-6.83 (m, 1H) , 6.11 (s, 1H) , 5.24 (s, 2H) , 3.90 (s, 3H) ,
1.96 (s, 3H) . ES-HRMS m/z 420.0783 (M+H C21HisClF2N04 requires
420.0809).
Step 2: Methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yllbenzoate ( from step 1) (2.90 g,
6.91 mmol) was dissolved in methanol (5 mL) and
tetrahydrofuran (12 mL) . 4N NaOH (4.3 mL, 17.27 mmol) was
added. The resulting mixture was stirred for 1.5 hours at
room temperature. The reaction was acidified (pH-2) with 4W
HC1. The precipitate was collected by filtration to afford an
off white solid (2.36 g, 84%). *H NMR (400 MHz, DMSO-ds ) 8
8.01 (dt, J = 1.41, 7.65 Hz, 1H) , 7.76 (app t, J = 1.68 Hz,
1H) , 7.69-7.53 (m, 3H) , 7.36-7.14 (m, 2H) , 6.69 (s, 1H) , 5.32
(s, 2H) , 1.93 (s, 3H) . ES-HRMS m/z 406.0662 (M+H C2oHi4ClF2N04
requires 406.0652).
Example 292
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-[3-
'(hydroxymethyl)phenyl] -6-methylpyridin-2 (1H) -one
The starting material (0.550 g, 1.540 mmol) and Nchlorosuccinimide
(0.214 g, 1.602 mmol) were suspended in
dichloromethane (15 mL) . Dichloroacetic acid (0.01 ml, 0.154
tnmol) was added and the reaction mixture heated to 40 °C for 9
hours. The reaction was cooled to room temperature and a
precipitate formed. The precipitate was collected by
filtration and washed with dichloromethane (3 x 10 mL) to
afford a white solid (0.286 g, 47%). XH NMR (400 MHz, DMSO-ds)
8 7.38 (app q, J = 7.35 Hz, IH), 7.30-7.24 (m, 2H), 7.00 (br s,
IH) , 6.85 (app dt, J = 2.37, 6.24 Hz, IH) , 6.82-6.67 (m, 2H) ,
6.01 (s, IH) , 5.07 (s, 2H) , 4.48 (d, J = 5.24 Hz, 2H) , 1.81
(app d, J = 0.40 Hz, 3H) . ES-HRMS m/z 392.0885 (M+H
C2oHi6ClF2N03 requires 392.0860).
Example 293
1-[3-(aminomethyl)phenyl]-3-bromo-4-t(2,4-difluorobenzyl)oxy]-
6-methylpyridin-2(IH)-one
Step 1: Preparation of 1- [3- (chloromethyDphenyl] -4- [ (2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one.
2,4,6-Trichloro-[1,3,5]-triazine (3.09 g, 16.78 mmol) was
dissolved in W/W-dimethylformamide (45 mL) . The reaction
mixture was stirred at room temperature for 1 hour and then
dichloromethane (90 mL) was added. The alcohol (5.72 g, 15.99
mmol) was then added. The reaction mixture was stirred at
room temperature for 1 hour. The reaction mixture was diluted
with dichloromethane (200 mL) and the organic phase was washed
with H20 (200 mL) , saturated Na2CO3 (200 mL) , Itf HCl (200 mL) ,
and brine (200 mL). The organic phase was dried over MgSO and
evaporated to give an orange solid (5.95 g, 99%).
Step 2: Preparation of 1-[3-(aminomethyl)phenyl]-4-[(2,4-
difluorobenzyl)oxy]-6- methylpyridin-2(1H)-one.
1- [3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy] -6-
methylpyridin-2(1H)-one from step 1 (1.00 g, 2.66 mmol) was
suspended in methanol (5 mL) . The suspension was then brought
to -78 °C and NH3 was bubbled through the reaction mixture for
10 minutes. The reaction was then slowly allowed to warm to
room temperature and stirred at room temperature for 4 days.
The reaction was concentrated and the residue taken up in
CH2C12 and filtered to remove excess salt. The filtrate was
concentrated to afford a tan solid (0.94 g, 99%).
Step 3: Preparation of title compound . l-[3-
(atninofflgthyl) ptieiiyi ] -4- [ (2, €-difluorobetTZyl) oxyi - 6-
methylpyridin-2(IH)-one from step 3 (3.89 g, 10.93 mmol)
suspended in acetonitrile (42 mL) was cooled in an ice-bath.
N-bromosuccinimide (2.04 g, 11.47 mmol) was added and the icebath
was removed. The reaction mixture was stirred for 1.5
hours at room temperature. The reaction was diluted with
acetonitrile (100 mL) and the precipitate that formed was
collected by filtration and washed with acetonitrile (3 x 30
mL) to afford an off-white solid (2.74 g, 58%). XH NMR (400
MHz, DMSO-d6) 8 7.67-7.59 (m, 3H), 7.34-7.31 (m, 2H), 7.04 (app
t, J = 8.72 Hz, 2H), 7.05-6.88 (m, 2H), 6.13 (s, IH), 5.30 (s,
2H) , 3.95 (S, IH) , 2.01 (s, 3H) . ES-HRMS m/z 435.0538 (M+H
C2oH17BrF2N202 requires 435.0514).
Example 294
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzyl}methanesulfonamide
To a reaction vessel (borosilicate culture tube) was added
EXAMPLE 293 (0.200 g, 0.459 mmol) and J7,W-dimethylformamide (4
mL) . A stock solution of 4-methylmorpholine in N,Ndimethylformamide
(1.8 mL, 1.0 M) was added to the reaction
vessel and the parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
REM. a±x room temperature for 10 minutes. A. stock- so-lutdort- of5
me thane sulfonyl chloride in AT,.N-dimethylformamide (4.50 mL,
0.15 M) was then added to the reaction vessel and the reaction
apparatus was orbitally shaken at room temperature for 2
hours. At this time the reaction was diluted with
dichloromethane (4 mL) and treated with approximately 2.1 g of
polyamine resin (2.63 mmol/g) and approximately 0.8 g of
methylisocyanate functionalized polystyrene (1.7 mmol/g) and
the orbital shaking was continued at 200 RPM at room
temperature overnight. The reaction vessel was then opened
and the solution phase products ' were separated from the
insoluble quenched byproducts by filtration and collection
into a vial. After partial evaporation the insoluble
byproducts were rinsed with dichloromethane ( 2 x 5 mL). The
filtrate was evaporated by blowing N2 over the vial while
heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor)
to give a yellow solid (0.190 g, 81%). ^ NMR (400 MHz, CD3OD)
8 7.63 (app q, J - 7.00 Hz, 1H) , 7.56-7.50 (m, 2H) , 7.25 (m,
1H) , 7.16 (dt, J = 1.94, 7.25 H=, 1H) , 7.04 (app t, J - 8.59
Hz, 2H) , 6.58 (s, 1H) , 5.34 (s, 2H) , 4.30 (s, 2H) , 2.87 (s,
3H) , 2.03 (s, 3H) . ES-HRMS m/z 513.0313 (M+H C21Hi9BrF2N204S
requires 513.0290).
Preparation of Example 295-296
By following the method of Example 294 and replacing
methanesulfonyl chloride with the appropriate acid chloride,
the compounds of Examples 295-296 are prepared.
Compound
No.
Ex. 295
Ex. 296
R
CH3
OCH3
%
Yield
78.0
84.0
MF
C22H19BrF2N203
C22H19BrF2N204
M+H
Requires
477.0620
493.0569
ES-HRMS
m/z
477.0640
493.0591
Example 297
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzyl}-2-methoxyacetamide
To a reaction vessel (borosilicate culture tube) was added
approximately 2.87 g of polymer bound carbodiimide resin (0.96
mmol/g) followed by a stock solution of methoxyacetic acid
(8.0 mL, 0.10 M) in N,W-dimethylacetamide. A stock solution
of 1-hydroxybenzotriazole in N,j\7-dimethylacetamide (3.0 mL,
0.10 M) and W-methylmorpholine (6.0 mL, 0.10 M) in 1,2-'
dichloroethane were added to the reaction vessel. The
parallel reaction apparatus was then orbitally shaken (Labline
Benchtop Orbital Shaker) at approximately 200 RPM at room
temperature for 4 hours. A stock solution of EXAMPLE 293 in
W,W-dimethylacetamide (5.0 tnL, 0.10 M) was then added to the
reaction vessel and the reaction apparatus was orbitally
shaken at room temperature overnight. At this time the
reaction was diluted with 1,2-dichloroethane (10 mL) and
treated with approximately 1.70 g of polyamine resin (2.63
mmol/g) and approximately 0.84 g of methylisocyanate
functional! zed polystyrene (1.50 mmol/g) and the orbital
shaking was continued at 200 RPM at room temperature for 4
hours. The reaction vessel was then opened and the solution
phase products were separated from the insoluble quenched
byproducts by filtration and collection into a vial . After
partial evaporation the insoluble byproducts were rinsed with
W,W-dimethylacetamide (2x5 mL) . The filtrate was evaporated
by blowing N2 over the vial while heating (60 °C) in a reaction
block (KEM-Lab Parallel Reactor) and subjected to
chromatography (silica gel, ethyl acetate with 10%
me t hano I/ hexane s) afforded an off white solid (0.081 g, 28%).
H NMR (400 MHz, DMF-ds) 6 7.59 (q, J = 7.65 Hz, 1H) , 7.46 (app
t, J = 7.55 Hz, 1H) , 7.40-7.37 (m, 1H) , 7.11-7.07 (m, 2H) ,
7.00 (t, J = 8.56 Hz, 2H) , 6.54 (s, 1H) , 5.30 (s, 2H) , 4.43
(s, 2H) , 3.88 (s, 2H) , 3.35 (app d, J = 0.80 Hz, 2H) , 1.97 (s,
3H) . ES-HRMS m/z 507.0699 (M+H CiaHziBrFsNaO* requires
507.0726) .
Preparation of Examples 298-300
HN R
By following the method of and replacing methoxyacetic acid
with the appropriate acid, the compounds of Examples 298-300
are prepared. The deprotection of the protected intermediates
was accomplished with 4.N HCl in dioxane or 1 M K2COs in
methanol to afford the compounds as hydrochloride salts.
MF
Compound %
R
No. Yield
Ex. 298 CH2OCOCH3 35.5
Ex. 299 CH2NH2 32 . 6 C22H2oBrF2N3O3 492 . 0729492 . 0744
M+H ES-HRMS
Requires m/z
535 . 0675 535 . 0686
Ex. 300
CH2OH 33.4 C22H19BrF2N2O4493. 0569493.0578
Example 301
N'-{3-[3-bromo-4-[ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H) -yl]benzyl}-N,N-dimethylurea
Step 1: Preparation of 4-nitrophenyl 3-[3-bromo-4-[(2,4'
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -
yl]benzylcarbamate.
1- [3- (aminomethyl)phenyl3 -3-bromo-4- [ (2,4-difluorobenzyl) oxy3 -
6-methylpyridin-2 (IH) -one (1.08 g, 2.48 mmol) was suspended in
dichloromethane (7.5 mL) . Pyridine was added (0.222 mL, 2.74
mmol) . After stirring for 10 minutes at room temperature, a
stock solution of 4-nitrophenyl chloroformate (5.0 mL, 0.50 M)
in dichloromethane was added dropwise. After stirring for 4.5
hours at room temperature, a stock solution of 4-nitrophenyl
chloroformate (2.5 mL, 0.50 M) in dichloromethane was again
added dropwise and stirring continued at room temperature
overnight. The reaction mixture was concentrated and
subjected to chromatography (silica gel, ethyl acetate with
10% methanol/hexanes) afforded a yellow solid (0.85 g, 57%).
Step 2: Preparation of title compound . To a reaction vessel
(borosilicate culture tube) was added 4-nitrophenyl 3-[3-
bromo-4-[(2,4-difluorobenzyl)oxy3-6-methyl-2-oxopyridin-l(2H)-
yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and
dichloromethane (2.5 mL) . The parallel reaction apparatus was
then orbitally shaken (Labline Benchtop Orbital Shaker) .at
approximately 200 RPM at room temperature for 15 minutes. A
stock solution of N,N-dimethylamine in tetrahydorfuran (0.15
mL, 2.0 M) was then added to the reaction vessel and the
reaction apparatus was orbitally shaken at room temperature
overnight. The reaction mixture was concentrated and
subjected to chromatography (silica gel, ethyl acetate with
1G%? mstibtaissU'h.exaiires:) wtticir afforded;, an. whiter soLicL (Q
g, 51%). XH NMR (400 MHz, DMF-dg) 6 7.58 (app q, J - 7.79 Hz,
1H) , 7.42 (app t, J = 7.65 Hz, 1H) , 7.37 (app d, J = 7.79 Hz,
1H) , 7.08 (s, 1H) , 7.03 (app dt, J - 1.58, 5.37 Hz, 1H) , 6.96
(app dt, J = 2.55, 8.39 Hz, 1H) , 6.88-6.83 (m, 1H) , 6.06 (s,
1H) , 5.24 (s, 2H), 4.95 (app t, J - 5.57 Hz, 1H) , 4.42 (app
dddd, J = 5.10, 5.71, 10.20, 15.17 Hz, 2H) , 2.90 (s, 6H) , 1.96
(s, 3H) . ES-HRMS m/z 506.0848 (M+H C23H22BrF2N303 requires
506.0885).
Preparation of Examples 302-303
By following the method of Example 301 and substituting N,Ndimethylamine
with the appropriate amine, the compounds of
Examples 302-303 are prepared.
Compound
No.
Ex. 302
Ex. 303
Ri
H
CH2CH20-
R2
CH3
CH2CH20-
%
Yield
52.3
50.7
MF
C22H20BrF2N303
C25H24BrF2N304
M+H
Requires
492.0729
548.0991
ES-HRMS
m/z
492.0737
548.0962
Example 304
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzyl}urea
To a reaction vessel (borosilicate culture tube) was added
EXAMPLE 293 (0.200 g, 0.459 mmol) and tetrahydrofuran (4.0
raL). A stock solution of 4-methylmorpholine in
tetrahydrofuran (1.8 mL, 1.0 M) Was added to the reaction
vessel and the parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 10 minutes. A stock solution of
trimethylsilyl isocyanate in tetrahydrofuran (4.0 mL, 0.2 M)
was then added to the reaction .vessel and the reaction
apparatus was orbitally shaken at room temperature for two
hours. At this time the reaction was diluted with
tetrahydrofuran (4.0 mL) and the resulting precipitate
collected by filtration. The solid was then washed with
tetrahydrofuran ( 3 x 5 mL) to afford a white solid (0.214 g,
97%). XH NMR (400 MHz, CD3OD) d 7 .12 (app q, J = 7.83 Hz, 1H) ,
7.55 (app t, J = 8.06 Hz, 1H) , 7.46 (d, J = 7.52 Hz, 1H) ,
7.25-7.14 (m, 4H) , 6.65 (s, 1H) , 5.65 (app t, J = 0.80 Hz,
1H) , 5.40 (s, 2H) , 4.38 (s, 2H) , 2.05 (s, 3H) . ES-HRMS m/z
478.0594 (M+H C2iHi8BrF2N3O3 requires 478.0572).
Example 305
3-bromo-4- [ (2,4-dif luorobenzyDoxy] -l-{3-
[(dimethylamino)methyl]phenyl}-6-methylpyridin-2(IH)-one
Step 1: Preparation of 4-[ (2,4-difluorobenzyDoxy]-1-{3-
[ (dimethylamino)methyl]phenyl
}-6-methylpyridin-2(IH)-one.
1- [3- (chloromethyl)phenyl] -4- [ (2,4-difluorobenzyDoxy] -6-
methylpyridin-2(IH)-one (from step 1 of the synthesis of
EXAMPLE 293) (0.500 g, 1.330 mmol) was suspended in a stock
solution of J7,N-dimethylamine in methanol (2.0 mL, 2.0 M) and
stirred overnight at room temperature. Reaction was
concentrated and the residue partitioned between H20 (25 mL)
and ethyl acetate (25 mL) . The aqueous layer was furtherextracted
with ethyl acetate (2 x 30 mL) , and the combined
organics were washed with brine (30 mL), dried over MgS04, and
concentrated to afford an off-white solid (0.508 g, 99%).
Step 2: Preparation of the title compound . 4-[(2,4-
dif luorobenzyl) oxy] -1- {3- [ (dimethylamino) methyl ]phenyl } -6-
methylpyridin-2 (1H) -one from step 1 (0.200 g, 0.521 mmol) was
suspended in acetonitrile (2.5 mL) and cooled in an ice-bath.
W-bromosuccinimide (0.097 g, 0.547 mmol) was added and the
ice-bath was removed. The reaction mixture was stirred for
1.5 hours at room temperature. The reaction was diluted with
acetonitrile (100 mL) . The precipitate that formed was
collected by filtration and washed with acetonitrile (3 x 15
mL) to afford a yellow solid (0.160 g, 66%). Chromatography
(C-18, acetonitrile/H20 with 0.1% trifluoroacetic acid,
followed by chroma tography silica gel, ethyl acetate with 10%
methanol/hexanes) afforded an off-white solid (0.024 g, 10%).
H NMR (400 MHz, CD3OD) 6 7.68 (app q, J - 7.85 Hz, 1H) , 7.58
(app t, J m 7.65 Hz, 1H) , 7.50 (app d, J » 7.85 Hz, 1H) , 7.25-
7.05 (m, 4H) , 6.63 (s, 1H) , 5.39 (s, 2H) , 3.61 (app q, J =
12.08 Hz, 2H) , 2.32 (s, 6H) , 2.08 (s, 3H) . ES-HRMS m/z
463.0782 (M+H CaalfciBrFaNaOi requires 463.0827).
Example 306
N-{4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)
yl]benzyl}acetamide
1-[4- (aminomethyl)phenyl-4-(benzyloxy)-3-bromopyridin-2(IH)-
one hydrochloride (0.150 g, 0.389 mtnol) was dissolved in N,Ndimethylformamide
(3.5 mL) . A stock solution of 4-
methylmorpholine in N,N-dimethylformamide (1.5 mL, 1.0 M) was
added and the reaction stirred at room temperature for 10
minutes. A stock solution of acetyl chloride in N,Ndimethylformamide
(3.0 mL, 0.2 M) was then added to the
reaction vessel and the reaction apparatus was orbitally
shaken at 200 RPM for 2 hours at room temperature. At this
time the reaction was diluted with di chl orome thane (4 mL) and
treated with approximately 1.8 g of polyamine resin (2.63
mmol/g) and approximately 0.8 g of methylisocyanate
functionalized polystyrene (1.7 mmol/g) and the orbital
shaking was continued at 200 RPM at room temperature
overnight. The reaction vessel was then opened and the
solution phase products were separated from the insoluble
quenched byproducts by filtration and collection into a vial,
After partial evaporation the insoluble byproducts were
further rinsed with dichloromethane ( 3 x 5 mL) and combined
with the partially concentrated filtrate. The resulting
filtrate was concentrated by blowing N2 over the vial while
heating (60.°C) in a reaction block (KEM-Lab Parallel Reactor)
to give an off-white solid (0.083 g, 50%). XH NMR (400 MHz,
CD3OD) 87.59 (d, J = 7.79 Hz, IH), 7.48-7.29 (m, 9H), 6.55 (d,
J - 7.79 Hz, IH) , 5.35 (s, 2H) , 4.39 (s, 2H) , 1.98 (s, 3H) .
ES-HRMS m/z 427.0625 (M+H C2iHi9BrN203 requires 427.0652).'
Example 307
N-{4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]benzyl}-2-
hydroxyacetamide
To a reaction vessel (borosilicate culture tube) was
added approximately 1.95 g of polymer bound carbodiimide resin
(0.96 mmol/g) followed by a stock solution of glycolic acid
(5.8 mL, 0.10 M) in N,W-dimethylacetamide. A stock solution
of 1-hydroxybenzotriazole in 2\T,W-dimethylacetamide (0.4 mL,
0.10 M) and W-methylmorpholine in 1,2-dichloroethane (3.9 mL,
0.10 M) were added to the reaction vessel. The parallel
reaction apparatus was then orbitally shaken (Labline Benchtop
Orbital Shaker) at approximately 200 RPM at room temperature
for 2 hours. A stock solution of 1-[4-(aminomethyl)phenyl]-4-
(benzyloxy)-3-bromopyridin-2(1H)-one hydrochloride in W/Wdimethylacetamide
(0.05 M, 7.8 mL) was then added to the
reaction vessel and the reaction apparatus was orbitally
shaken at room temperature overnight. At this time the
reaction was diluted with 1,2-dichloroethane (8 mL) and
treated with approximately 1.17 g of polyamine resin (2.63
mmol/g) and approximately 0.58 g of methyl isocyanate
functional!zed polystyrene (1.50 mmol/g) and the orbital
shaking was continued at 200 RPM at room temperature for 4
hours. The reaction vessel was then opened and the solution
phase products were- separated from the insoluble quenched
fii»UiEaeiait »rn* collection, inta aw vial. After
.44,7-
partial evaporation the insoluble byproducts were rinsed with
Jf,.f7-dimethylacetamide (2 x 5 mL) and combined with the
partially concentrated filtrate. The filtrate was
concentrated by blowing N2 over the vial while heating (60 °C)
in a reaction block (KEM-Lab Parallel Reactor) and subjected
to chromatography (silica gel, ethyl acetate with 10%
methanol/hexanes) which afforded an off white solid (0.081 g,
21%). XH NMR (400 MHz, CD3OD) 8 7.55-7.30 (m, 10H) , 6.51 (d, J
= 7.85 Hz, IH), 5.37 (a, 2H), 4.52 (s, 2H), 4.08 (s, 2H). ESHRMS
m/z 443.0605 (M+H C2iHi9BrN204 requires 443.0601).
Example 308
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-morpholin-4-
ylethyl)pyridin-2(IH)-one
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2 (IH)-one
(0.100 g, 0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol),
and 4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were
suspended in acetonitrile (4 mL) . The reaction was stirred at
60 °C overnight. H20 (25 mL) was added and the resulting
precipitate was collected by filtration. The solid was
subjected to chromatography (silica gel, ethyl acetate with
ta%"- methanoll. afforded, an off-white solid; (a.atft gv,.3.0%*).. IH
NMR (400 MHz, CDC13) 6 7.55 (app q, J = 7.92 Hz, 1H) , 6.93 (app
t, J = 8.39 Hz, 1H) , 6.84 (app t, J - 9.40 Hz, 1H) , 5.95 (s,
1H) , 5.18 (s, 2H) , 4.16 (app t, J = 6.78 Hz, 2H) , 3.68 (s,
4H) , 2.65 (app t, J = 6.38 Hz, 2H) , 2.54 (s, 4H) , 2.43 (s,
3H) . ES-HRMS m/z 443.0743 (M+H Ci9H2iBrF2N203 requires
443.0776).
Example 309
ethyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-
yl]propanoate
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2(lH)-one (0.50 g, 1.78 mmol) and cesium fluoride (0.0027 g,
0.178 mmol) were suspended in tetrahydrofuran (10 mL) followed
by dropwise addition of tetraethylortho silicate (0.37 g, 1.78
mmol) at room temperature. After stirring for 10 minutes at
room temperature, ethyl acrylate (0.23 g, 2.32 mmol) was added
dropwise and the reaction stirred at room temperature
overnight. The reaction mixture was filtered through a pad of
Celite®. The filtrate was concentrated and the resulting
residue subjected to chromatography (silica gel, ethyl acetate
with 10% methanol/hexanes) to afford a white solid (0.62 g,
92%). *H NMR (400 MHz, CDC13) S 7.42 (d, J = 7.79 Hz, 1H) ,
7.41-7.29 (m, 5H) , 6.03 (d, J = 7.65 Hz, 1H) , 5.20 (s, 2H) ,
4.17 (t, J = 5.98 Hz, 2H), 4.07 (q, J = 7.16 Hz, 2H), 2.83
J . 5.98 Hz, 2H) , 1.19 (t, J = 7.18 Hz, 3H) . ES-HRMS m/z
380.0523 (M+H Ci7Hi8BrN04 requires 380.0492).
Example 310
methyl 3- [4- (benzyloxy) -3-bromo-2-oxopyridin-l (2H) -
yl]propanoate
3-bromo-4- [ (2,4-difluorobenzyl) oxy] -6-methylpyridin-
2(lH)-one (5.00 g, 17.85 mmol) and cesium fluoride (0.27 g,
1.78 mmol) were suspended in tetrahydrofuran (50 mL) followed
by dropwise addition of tetramethylortho silicate (2.70 g,
17.85 mmol) at room temperature. After stirring for 10
minutes at room temperature, methyl acrylate (2.00 g, 23.20
mmol) was added dropwise and the reaction stirred at room
temperature for 48 hours. The reaction mixture was filtered
through a pad of Celite®. The filtrate was concentrated and
the resulting residue subjected to chromatography (silica gel,
ethyl acetate with 10% methanol/hexanes) to afford a white
solid (6.10 g, 93%) . XH NMR (400 MHz, CDC13) 8 7.42 (d, J =
7.65 Hz, 1H) , 7.41-7.29 (m, 5H) , 6.04 (d, J - 7.65 Hz, 1H) ,
5.20 (s, 2H) , 4.17 (t, J = 5.91 Hz, 2H) , 3.63 (s, 3H) , 2.85
(t, J = 5.91 Hz, 2H) . ES-HRMS m/z 366.0350 (M+H Ci6HisBrN04
requires 366.0335).
Example 311
F'
N- [3-bromo-l- (3-fluorobenzyl) -2-oxo-l,2-'dihydropyridin-4-yl] -
2,6-difluorobenzamide
Step 1: Preparation of 3,4-dibromo-l-(3-fluorobenzyl)pyridin-
2 (1H)-one.
3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl
trifluoromethanesulfonate (2.00 g, 4.65 mmol) , KBr (5.53 g,
46.49 mmol), and 18-Crown-6 (0.10 g, 0.38 mmol) were dissolved
in W/W-dimethylacetamide (26 mL) . The reaction mixture was
then heated at reflux for 16 hours. The reaction was
concentrated and the resulting residue was partition between
water (50 mL) and ethyl acetate (3 X 50 mL) . The combined
organics were washed with HzO (2 X 30 mL) , brine (50 mL), dried
over MgSO4, concentrated, and subjected to chromatography
(silica gel, ethyl acetate with 10% methanol/hexane) to afford
a brown solid (0.850 g, 51%).
Step 2: Preparation of 4-asido-3-bromo-l-(3
fluorobenzyl)pyridin-2(IH)-one.
Sodium azide (1.08 g, 16.62 mmol) was suspended in N,Ndimethylformamide
(10 mL) and a stock solution of 3,4-
dibrotno-1-(3-fluorobenzyl)pyridin-2 (IH)-one (from step 1) in
N, .W-dimethylformamide (33.0 mL, 0.33 M) was added and the
resulting mixture was heated to 60 °C for 4 hours. Ice water
(30 mL) was added and the aqueous layer was extracted with
ethyl acetate (4 X 50 mL) . The combined organics were washed
with H20 (3 X 50 mL) , brine (2 X 25 mL) , dried over MgS04,
concentrated, and subjected to chromatography (silica gel,
ethyl acetate with 10% methanol/hexane) to afford an off-white
solid (3.50 g, 98%) .
Step 3: Preparation of 4-amino-3-bromo-l-(3-
fluorobenzyl)pyridin-2(IH)-one hydrochloride
4-azido-3-bromo-l-(3-fluorobenzyl)pyridin-2(IH)-one (from step
2) (4.00 g, 12.38 mmol) was suspended in ethyl acetate (300
mLi. drift,, Es. C2J1X 5,- 3T.14. mtnol) was added.. A. stock solution
of NHtCl in H20 (300 mL, 0.2 M) was added and the reaction
mixture was stirred at room temperature for 36 hours. The
reaction was filtered through a pad of Celite® and
concentrated. The resulting solid was dissolved in ethyl
acetate (150 mL) and washed with water (3 X 50 mL) , brine (50
mL) , dried over MgS04, and concentrated. XH NMR (400 MHz,
CD3OD) 8 7.38-7.29 (m, 2H), 7.05 (d, J - 7.79 Hz, 1H), 6.99 (d,
J = 8.99 Hz, 2H), 6.03 (d, J = 7.39 Hz 1H), 5.09 (a, 2H). ESHRMS
m/z 297.0023 (M+H C2oHr7BrF2N202 requires 297.0033) .
Step 4: Preparation of the title compound . 4-amino-3-bromo-
1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 3) (0.30 g,
1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol)
were suspended in acetonitrile (5 mL) followed by dropwise
addition of triethylamine (0.2 mL, 1.41 mmol). This reaction
mixture was stirred for 10 minutes at room temperature before
being cooled to 0 °C. 2,6-difluorobenzoyl chloride (0.37 g,
2.12 mmol) was added dropwise and the reaction was heated at
reflux overnight. The reaction was cooled to room temperature
and 1JV NaOH (10 mL) was added. The reaction was then stirred
for 45 minutes at room temperature. The reaction mixture was
extracted with ethyl acetate (3 x 25 mL) and the organic layer
washed with IN NaOH (2 X 25 mL) , H20 (until pH neutral), brine
(50 mL) , dried over MgS04, concentrated, and subjected to
chromatography (on C-18, acetonitrile/ H2O with 0.1%
trifluoracetic acid) to afford a white solid (0.19 g, 43%). ^
NMR (400 MHz, CDC13) 8 8.42 (br s, 1H) , 7.67 (d, J = 7.65 Hz,
1H) , 7.49 (app tt, J = 6.31, 8.60 Hz, 1H) , 7.33-28 (m, 2H) ,
7.10-6.97 (m, 5H) , 5.17 (s, 2H) . ES-HRMS m/z 437.0083 (M+H
C19Hi2BrF3N202 requires 437.0107).
Ex. 312.
3-bromo-l- (4-bromo-2, 6-difluorophenyl) -4- [(2,4-
dif luorobenzyl) oxy] -6-methylpyridin-2 (IH) -one
Step 1: Preparation of 1- (4 -bromo-2, 6-difluorophenyl) -4'
hydroxy-6-methylpyridin-2 (IH) -one .
4 -Hydroxy- 6 -methyl -2 -pyrone (30.0 g, 238 mmol) and 4-bromo-
2, 6-difluoroaniline (49.5 g, 238 mmol) were suspended in 50 ml
of 1,2-dichlorobenzene in a 250 ml, 3 -necked, round bottom
flask equipped with a J-Kem temperature controller probe, a
Dean-Stark trap, and a heating mantle. The reaction was
heated to 165°C for 15 minutes, during which, water and some
1,2-dichlorobenzene was collected in the Dean-Stark trap. The
reaction was allowed to cool to about 80°C. The flask was
placed in an ice bath and about 25 ml of toluene was added and
stirred. After about 10 minutes, a precipitate formed. The
precipitate was filtered and washed 3 times with toluene, 3
times with hot water to remove excess pyrone, and dried in
vacuo to give a tan solid (22.1 g, 29%). 1H NMR (400 MHz,
DMSO-dg) 6 11.00 (br s, IH) , 7.71 (d, J = 6.98 Hz, 2H) , 5.97
(t, J = 0.88 Hz, IH), 5.55 (d, J = 2. 25. Hz^ l®.r L.9JL -ts 2KK
-45.Cminutes
at 1 ml/min with detection 254 nm, at 50°C) . ES-MS m/z
316 (M+H). ES-HRMS m/z 315.9779 (M+H calcd for C12H8BrF2N02
requires 315.9779).
Step 2: Preparation of 1-(4-bromo-2,6-difluorophenyl)-4-
[ (2,4-difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one
1-(4-brorao-2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-
2(lH)-one ( from Step 1) (5.0 g, 15.8 mmol) was stirred
briskly at room temperature with 2,4-difluorobenzyl bromide
(2.23 ml, 17.4 mmol) and K2C03 (3.27 g, 23.7 mmol) in 50 ml of
dimethylformamide. After stirring overnight, the reaction was
poured quickly into 900 ml of cold water. The resulting
precipitate was filtered and washed with water and hexane.
The product was purified using a Biotage silica chromatography
system using 20% ethyl acetate/hexanes to give a beige solid
(4.32 g, 62%). XH NMR (400 MHz, CDC13) 5 7.41 (app q, J - 6.31
Hz, IH) , 7.25 (dd, J = 8.33, 1.74 Hz, 2H) , 6.91 (dt, J - 9.2,
0.8 Hz, IH), 6.86 (dt, J-9.2, 0.8 Hz, IH), 5.95 (d, J=2.56
Hz, IH) , 5.92 (dd, J « 2.56, 0.94 Hz, IH) , 5.01 (s, 2H) , 1.98
(s, 3H). LC/MS, tr = 3.04 minutes (5 to 95% acetonitrile/water
over 5 minutes at 1 ml/min with detection 254 nm, at 50°C) . ESMS
m/z 442 (M+H). ES-HRMS m/z 442.0057 (M+H calcd for
C19Hi2BrF4N02 requires 442.0060).
Step 3: Preparation of the title compound . 1-(4-bromo-2,6-
difluorophenyl) -4-L(2,,4-di£luorobenzyl) oxyl -6-methylpyridin-
2(lH)-one ( from Step 2) (500 mg, 1.13 mmol) was stirred at
room temperature with iv-bromosuccinimide (221 mg, 1.24 mmol)
in 5 ml of CH2C12 for 1.5 hours. The reaction was evaporated
on a rotary evaporator and the resulting solid was washed 4
times with acetonitrile and dried in vacua to yield a white
solid (478 mg, 92%). XH NMR (300 MHz, CDC13) 6 7.62 (app q, J
- 6.64 Hz, IH) , 7.31 (d, J = 6.85 Hz, 2H) , 7.01 (app t, J
8.36 Hz, IH) , 6.96 (dt, J - 9.46, 2.21 Hz, IH) , 6.19 (s, IH) ,
5.30 (s, 2H), 2.10 (s, 3H); LC/MS, tr = 3.17 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 520 (M+H) . ES-HRMS m/z 521.9134
(M+H calcd for Ci9HnBr2F4N02 requires 521.9146).
Ex. 313
3-bromo-4- [ (2,4-difluorobenzyl) oxy] -6-methyl-l- (2,4,6-
trifluorophenyl)pyridin-2(IH)-one
The title compound was produced essentially as in Example 313,
using 2,4,6-trifluoroaniline instead of 4-bromo-2,6-
difluoroaniline. 1E NMR (300 MHz, CDC13) 8 7.62 (app q, J =
7.79 Hz, IH) , 7.01 (app dt, J - 8.26, 2.01 Hz, IH) , 6.95 -
6.85 (m, 3H), 6.19 (s, IH), 5.30 (s, 2H), 2.11 (s, 3H); LC/MS,
tr = 2.81 minutes (5 to 95% acetonitrile/water over 5 minutes
at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 460 (M+H) . ES-HRMS
m/z 459.9954 (M+H calcd for Ci9HuBrF5N02 requires 459.9966).
Ex. 314
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2(IH)-one
4-[(2,4-difluorobenzyl)oxy] -6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2 (IH)-one (350 mg, 0.92 mmol) was
refluxed with N-chlorosuccinimide (147 mg, 1.1 mmol) and
dichloroacetic acid (0.038 ml, 0.46 mmol) in 5 ml of CH2C12
overnight. The reaction was evaporated on a rotary evaporator
and the resulting solid was washed 4 times with acetonitrile
and dried in vacua to yield a white solid (217 mg, 57%) . XH
NMR (300 MHz, CDC13) 5 7.60 (app q, J = 7.75 Hz, IH) , 7.00 (app
dt, J = 8.23, 2.05 Hz, IH), 6.93 - 6.86 (m, 3H), 6.22 (s, IH),
5.30 (s, 2H), 2.12 (s, 3H); LC/MS, tr = 2.78 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 416 (M+H) . ES-HRMS m/z 416.0472 (M+H calcd
for Ci9HiiClF5NO2 requires 416.0471) .
Ex. 315
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-
(2,4,6-
trifluorophenyl)pyridin-2(IH)-one
Step 1: Preparation of 4-[ (2,4-difluorobenzyl)oxy]-6-
(hydroxymethyl)-1-(2,4,6-trifluorophenyl)pyridin-2(IH)-one
4- [(2,4-Difluorobenzyl)oxy]-6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2(IH)-one (9.0 g, 23.6 mmol) was
heated to 135°C overnight with Se02 (13.1 g, 118 mmol) in 75 ml
of 1,4-dioxane in a 350 ml sealed glass pressure vessel. The
reaction mixture was cooled and placed on a plug of silica gel
and washed with 5% methanol in CH2C12. The filtrate was
evaporated and the resulting solid was washed with diethyl
ether and dissolved in hot ethyl acetate. The insoluble Se
salts were filtered off and the organic layer was evaporated.
7.01g (17.6 mmol) of a 3:1 ratio of aldehyde to desired
alcohol was isolated. The mixture was stirred with NaBH4 (802
mg, 21.2 mmol) in 30 ml of methanol at room temperature for 1
hour. The reaction was evaporated and CH2C12 and acetonitrile
were used to dissolve the bulk of the solid. The remaining
insoluble solid was filtered off. The organic layer was
washed 3 times with NH4C1, dried over MgS04 and evaporated.
The resulting solid was washed 3 times with diethyl ether and
dried in vacuo to yield a light orange solid (4.35 g, 46%). XH
NMR (300 MHz, DMSO-d6) 8 7.68 (app q, J = 7.92 Hz, IH) , 7.47
(app t, J - 8.57 Hz, 2H), 7.35 (dt, J = 9.87, 2.42 Hz, IH),
7.18 (dt, J = 8.31, 1.71 Hz, IH), 6.21 (d, J=2.42Hz, IH),
6.07 (d J - 2.62 Hr, IH), 5.67 (br s, IH), 5.18 (s, 2H), 3.98
(s, 2H) ; LC/MS, tr 2.31 minutes (5 to 95% acetonitrile/water
'over 5 minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 398
(M+H).
Step 2:' Preparation of the title compound . 4-[(2,4-
Difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(2,4,6-
trifluorophenyl)pyridin-2(1H)-one ( from step 1) (2.1 g, 5.28
mmol) was stirred at room temperature with Jtf-bromosuccinimide
(1.13 g, 6.34 mmol) in 5 ml CH2C12 for 2 hours. The reaction
was evaporated on a rotary evaporator and the resulting solid
was washed 4 times with acetonitrile and dried in vacua to
yield a white solid (1.35 g, 54%). XH NMR (300 MHz, CD3OD) d
7.69 (app q, J = 6.65 Hz, 1H), 7.20 (app t, J = 8.36 Hz, 2H),
7.09 (app t, J = 8.46 Hz, 2H), 6.88 (s, 1H), 5.46 (s, 2H),
4.21 (s, 2H) ; LC/MS, tr = 2.48 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C), ES-MS m/z 476 (M+H). ES-HRMS m/z 475.9907 (M+H calcd
for Ci9HiiBrF5N03 requires 475.9915).
Ex. 316
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-
(2,4,6-
trifluorophenyl)pyridin-2(1H)-one
4-[(2,4-Difluorobenzyl)oxy]-6-(hydroxymethyl)-1- (2,4,6-
trifluorophenyl)pyridin-2(1H)-one (2.1 g, 5.28 mmol) was
refluxed with N-chlorosuccinimide (846 mg, 6.34 mmol) and
dichloroacetic acid (0.87 ml, 10.56 mmol) in 5 ml CH2C12
overnight. The reaction was evaporated on a rotary evaporator
and the resulting oil was triturated with diethyl ether to
obtain a solid. The solid was washed 4 times with
acetonitrile. Chroma tography was done using a Biotage silica
gel system with 60% ethyl acetate/hexanes . The recovery was
poor from the column to give a white solid (109 mg, 5%) . XH
NMR (300 MHz, CD3OD) 6 7.67 (app q, J = 7.85 Hz, IH) , 7.24 -
7.06 (m, 4H) , 6.90 (s, IH) , 5.45 (s, 2H) , 4.22 (s, 2H) LC/MS,
2.71 minutes (5 to 95% acetonitrile/water over 5 minutes
at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 432 (M+H) . ES-HRMS
m/z 432.0413 (M+H calcd for Ci^uClFsNCfe requires 432.0420).
Ex. 317
3-bromo-4-[(2,4-difluorobenzyl) oxy] -I-(2,6-difluoro-4-
morpholin-4-ylphenyl)-6-methylpyridin-2(IH)-one
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-
difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2 (IH)-one
4- [ (2,4-Difluorobenzyl)oxy] -6-methyl-l- (2,4,6-
trifluorophenyl)pyridin-2(1H)-one (870 mg, 2.28 mmol) was
heated to 100°C with K2CO3 (630 rag, 4.56 mmol) in 5 ml of
morpholine for 36 hours. The reaction was added to 200 ml of
cold water and the resulting solid was washed with water and
50:50 diethyl ether/hexanes and dried in vacua to give a beige
solid (738 mg, 72%). XH NMR (400 MHz, CDC13) 8 7.41 (app q,
= 7.70 Hz, 1H), 6.93 - 6.85 (m, 2H), 6.49 (d, J = 10.47 Hz,
2H), 5.96 (d, J = 2.41 Hz, 1H), 5.89 (d, J « 1.75 Hz, 1H),
5.00 (s, 2H), 3.83 (t, J = 4.83 Hz, 4H), 3.19 (t, J = 4.84 Hz,
4H), 1.99 (s, 3H); LC/MS, tr = 3.09 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C), ES-MS m/z 449 (M+H). ES-HR/MS m/z 449.1485 (M+H calcd
for C23H2oF4N2O3 requires 449.1483) .
Step 2: Preparation of the title compound . 4-[(2,4-
DifluorobenzyDoxy] -1- (2, 6-difluoro-4-morpholin-4-ylphenyl) -6-
methylpyridin-2(1H)-one ( from step 1) (500 mg, 1.12 mmol) was
stirred at room temperature with W-bromosuccinimide (236 mg,
1.33 mmol) in 5 ml of CH2C12 for 2 hours. The reaction was
evaporated on a rotary evaporator and the resulting oil was
triturated with diethyl ether to obtain a solid. The solid
was washed 4 times with acetonitrile and dried in vacua to
yield a white solid (171 mg, 29%) . XH NMR (400 MHz, CDC13) 8
7.58 (app q, J = 7.74 Hz, 1H) , 6.96 (app t, J"=8.39Hz, 1H)
6.86 (dt, J = 9.46, 2.28 Hz, 1H) , 6.50 (d, J = 10.74 Hz,. 2H) ,
6.09 (s, 1H), 5.24 (s, 2H), 3.84 (t, J=4.84Hz, 4H), 3.20
(t, J = 4.83 Hz, 4H) , 2.07 (s, 3H) ; LC/MS, tr = 3.18 minutes (5
to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254
nm, at 50°C), ES-MS m/z 527 (M+H). ES-HRMS m/z 527.0570 (M+H
calcd for C23Hi9BrF4N203 requires 527.0588).
Ex. 318
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2,6-difluoro-4-(4-
methylpiperazin-l-yl)phenyl] -6-methylpyridin-2(IH)-one
The title compound was prepared essentially as in Example 317,
using 1-methylpiperazine instead of morpholine. 1H NMR (400
MHz, CDC13) 6 7.57 (app g, J = 7.79 Hz, IH), 6.96 (dt, J -
8.19, 1.88 Hz, IH) , 6.86 (appdt, J = 9.44, 2.48 Hz, IH) , 6.52
(d, J - 10.61 Hz, 2H), 6.14 (s, IH), 5.24 (s, 2H), 3.72 (br s,
4H), 3.51 (d, J - 11.27 Hz, 2H), 3.07 (brs, 2H), 2.85 (d, J -
4.29 Hz, -3H) , 2.06 (s, 3H) ; LC/MS, tr = 2.50 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS jn/z 540 (M+H). ES-HRMS m/z 540.0930 (M+H calcd
for Cj4H2aBrF4N3O2 requires 540.0904).
Ex. 320
3-chloro-4- [ (2,4-dif luorobenzyDoxy] -1- [2, 6-difluoro-4- (4-
methylpiperazin-l-yl)phenyl]-6-methylpyridin-2(IH)-one
4- [(2,4-DifluorobenzyDoxy] -1- [2,6-difluoro-4- (4-
methylpiperazin-l-yl)phenyl]-6-methylpyridin-2(IH)-one (1.3 g,
2.82 mmol) was stirred at reflux with N-chlorosuccinimide (451
mg, 3.38 mmol) and dichloroacetic acid (0.17 ml, 1.41 mmol) in
6 ml CH2C12 overnight. LC-MS showed 33% completion. More Nchlorosuccinimide
(271 mg, 2.23 mmol) was added and refluxed
overnight. The reaction was evaporated on a rotary evaporator
and the resulting oil was triturated with ethyl acetate to
obtain a solid. The solid was washed 4 times with ethyl
acetate and with diethyl ether and dried in vacuo to obtain a
white solid (606 mg, 43%). *H NMR (400 MHz, DMSO-d6) 5 7.66
(br q, J = 7.74 Hz, IH), 7.33 (br t, J = 9.00 Hz, IH), 7.16
(br t, J" = 7.65 Hz, IH) , 6.96 (d, J = 11.81 Hz, 2H) , 6.79 (s,
IH), 5.33 (s, 2H), 3.61 (br m, 4H), 3.25 (br m, 4H), 3.21 (br
3, 3H) , 2.04 (s, 3H) ; LC/MS, tr = 2.45 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C), ES-MS m/z 496 (M+H). ES-HRMS m/z 496.1400 (M+H calcd
for C24H22C1F4N3O2 requires 496.1409).
Example 321
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[4-(dimethylamino)-2,6-
difluorophenyl]-6-methylpyridin-2(IH)-one
-463-
The title compound was'prepared essentially as described in
Example 317, using dimethylamine instead of morpholine. XH NMR
(400 MHz, CDC13) 8 7.59 (q, J = 7.74 Hz, IH) , 6.95 (dt, J =
8.32, 1.61 HZ, IH), 6.85 (app dt, J = 9.54, 2.41 Hz, IH), 6.27
(d, J - 11.01 Hz, 2H), 6.08 (s, IH), 5.23 (s, 2H), 2.98 (s,
3H) , 2.07 (s, 3H); LC/MS, tr » 3.35 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C), ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0447 (M+H calcd
for C2iHi7BrF4N2O2 requires 485.0482).
Example 322
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-{2,6-difluoro-4-[(2-
hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(IH)-one
The title compound was prepared essentially as in Example 317,
using 2-(methylamino)ethanol instead of morpholine.
XH NMR (400 MHz, CDC13) 8 7.58 (q, J = 7.74 Hz, IH) , 6.95 (dt,
J - 8.24, 1.66 HZ, IH), 6.85 (app dt, J=9.49, 2.37 Hz; IH),
6.35 (d, J = 11.01 Hz, 2H), 6.10 (s, IH), 5.23 (s, 2H), 3.77
(t, J = 5.77 Hz, 2H), 3.45 (t, J - 5.78 Hz, 2H), 2.99 (s, 3H),
2.08 (s, 3H); LC/MS, tr = 2.96 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 515 (M+H). ES-HRMS m/z 515.0576 (M+H calcd
for CzSisBrJUNjOa requires 515.0588) .
Example 323
Br
3-bromo-l-(3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-1-(2, 6-
difluoro-4-hydroxyphenyl)-6-methylpyridin-2(IH)-one .
4- [ (2,4-Difluorobenzyl)oxy]-6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2(IH)-one (step 2 above) (10.0 g, 26.2
mtnol) was heated to 45°C with KOSiMe3 (10.08 g, 78.6 mmol) in
50 ml of tetrahydrofuran for 4 days. The reaction was diluted
with 30 ml of ethyl acetate and washed with IN HCl and water,
dried over MgSO4, and evaporated to give an orange solid. The
solid was stirred in hot 60% ethyl acetate/hexanes and
filtered to give a white solid, which was dried in vacuo to
obtain a white solid (3.79 g, 38%). The filtrate was found to
contain a mixture of desired product and the ortho substituted
regioisomer. XH NMR (400 MHz, CDC13) 5 7.42 (app q, J = 7.70
Hz, IH), 6.95 - 6.83 (m, 2H), 6.34 (d, J = 9.40 Hz, 2H) , 6.05
(app s, 2H), 5.06 (s, 2H), 2.01 (s, 3H); LC/MS, tr = 2.80
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min, at 254 nm, at 50°C) , ES-MS m/z 380 (M+H) . ES-HRMS m/z
380.0926 (M+H calcd for Ci9H13F4N03 requires 380.0904).
Step 2: Preparation of the title compound . 4- [(2,4-
DifluorobenzyDoxy] -1- (2,6-difluoro-4-hydroxyphenyl) -6-
methylpyridin-2 (IH) -one ( from step 1) (3.73 g, 8.14 mmol) was
stirred as a suspension at room temperature with Nbromosuccinimide
(1.52 g, 8.55 mmol) in 30 ml CH2C12 overnight .
LC-MS showed a 60% starting material. The solid was filtered
off, dissolved in 30 ml of CHjC^/W/.N-dimethylformamide and
stirred with more J7-bromosuccinimide (0.76 g, 4.28 mmol)
overnight. LC-MS showed the tri-brominated product as the
major product. The reaction was poured into water and
extracted with n-butanol. The combined organic layers were
evaporated on a rotary evaporator and the resulting solid was
washed with diethyl ether and dried in vacuo to yield a white
solid (873 mg, 17%). XH NMR (400 MHz, CDC13) 8 7.67 (app q, J
= 7.80 Hz, IH) , 7.32 (dt, J = 4.86, 2.11 Hz, IH) , 7.16 (dt, J
= 8.48, 1.84 Hz, IH) , 6.79 (s, IH) , 5.35 (s, 2H) , 2.08 (a,
3H) ; LC/MS, tr = 3.26 minutes (5 to 95% acetonitrile/water over
5 minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 616
(M+H). ES-HRMS n/z 615.8234 (M+H calcd for
requires 615.8200) .
Example 324
2-{4- [3-bromo-4- [ (2,4-difluorobenzyl) oxy] -6-methyl-2-
oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}acetamide
Step 1: Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy]-1-
(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(IH)-one .
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-
trifluorophenyl)pyridin-2 (IH)-one ( above) (7.5 g, 16.3 mmol)
was heated to 45°C with KOSiMe3 (10.08 g, 78.6 mmol) in 50 ml
of tetrahydrofuran for 48 hours. The reaction was diluted
with 30 ml of ethyl acetate and washed with IN HCl and water,
dried over MgS04, and evaporated to give a black oil. The oil
was dissolved in ethyl acetate. A precipitate formed upon
standing, which was filtered, washed with ethyl acetate and
dried in vacuo to obtain a white solid (2.80 g, 37%). The
filtrate showed the presence of desired product and the ortho
substituted regioisomer. XH NMR (400 MHz, DMSO-dfi) 8 7.66 (q,
J = 7.92 Hz, IH) , 7.32 (dt, J = 8.77, 2.19 Hz, IH) , 7.15 (m,
IH) , 6.73 (s, IH) , 6.67 (d, J = 9.66 Hz, 2H) , 5.33 (a, 2H) ,
2.03 (s, 3H) ; LC/MS, tr = 2.92 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 458 (M+H) . ES-HRMS m/z 457.9995 (M+H calcd
for C19H12BrF4N03 requires 458.0009) .
Step 2: Preparation of the title compound . 3-Bromo-4-[(2,4-
difluorobenzyl) oxy] -1- (2,6-difluoro-4-hydroxyphenyl)-6-
tnethylpyridin--Z(lB9kraofifev( fear step* I) (5W mg> L..QSL wass
stirred briskly with 2-bromoacetamide (196 mg, 1.43 tnmol) and
K2C03 (282 mg, 2.05 mmol) in 5 ml of tf,.W-dimethylformamide at
room temperature for 24 hours. The reaction was poured
quickly into cold water and the resulting solid was filtered,
washed with water, acetonitrile, and diethyl ether, and dried
in vacua to give a white solid (289 mg, 51%). XH NMR (400 MHz,
DMSO-dg) 6 7.66 (q, J- 7.92 Hz, 1H), 7.61 (br s, 1H), 7.45 (br
S, 1H) , 7.33 (dt, J = 10.07, 2.15 Hz, 1H) , 7.16 (dt, J = 8.53,
1.88 Hz, 1H) , 6.99 (d, J = 9.54 Hz, 2H) , 6.76 (s, 1H) , 5.34
(s, 2H) , 2.03 (s, 3H) ; LC/MS, tr - 2.70 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 515 (M+H) . ES-HRMS m/z 515.0245 (M-fH calcd
for C21HisBrF4N204 requires 515.0224).
Example 325
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1- [2,6-difluoro-4-(2-
hydroxyethoxy)phenyl]-6-methylpyridin-2(1H)-one
The title compound was prepared by a procedure similar to the
one described for Example 324. XH NMR (400 MHz, DMSO-ds) 8
7.66 (q, J » 7.92 Hz, 1H) , 7.33 (dt, J = 10.04, 2.19 Hz, 1H) ,
7.17 (dt, J = 8.68, 1.84 Hz, 1H) , 6.99 (d, J = 9.67 Hz, 2H)
6.75 .(s, 1H) , 5.34 (s, 2H) , 4.92 (t, J = 4.86 Hz, 1H) , 4.07-
(t, J = 4.77 Hz, 2H), 3.70 (t, J = 4.83 Hz, 2H), 2.03 (s, 3H) ;
LC/MS, tr = 2.81 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 502 (M+H).
ES-HRMS m/z 502.0291 (M+H calcd for C2iHi6BrF4N04 requires
502.0272)
Example 326
3-bromo-l-(2,6-difluorophenyl)-4-{[4-fluoro-2-
(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(IH)-one
Step 1: Preparation of 1-(2,6-difluorophenyl)-4-{[4-fluoro-2-
(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(IH)-one .
1-(2, 6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2(IH)-one
(step 1) (3.0 g, 12.65 mmol) was dissolved in N,Ndimethylformamide
and cooled to 0°C. Triphenylphosphine (3.98
g, 15.18 mmol) and diethyl azodicarboxylate (2.39 ml, 15.18
mmol) were added and stirred for 10 minutes. 1,2-
Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was
added and stirred at 0°C for 1 hour, then allowed to warm to
room temperature and stirred overnight. LC-MS showed only 1
product, not a mixture of regioisomers, as expected. The
reaction was added to water and extracted 3 times with ethyl
acetate. The combined organic layers were dried over MgS04 and
evaporated. A Biotage silica column was done using 60% ethyl
acetate/hexanes as an eluent. Desired product, with a
substantial impurity was obtained. Another Biotage silica
column was ran using 30% ethyl acetate/hexanes to obtain pure
product. The resulting oil was triturated with diethyl ether
to obtain a white solid (720 rag, 15%) . XH NMR (300 MHz, CDC13)
8 7.51 - 7.39 (m, 2H) , 7.26 (dd, J = 9.62, 2.51 Hz, IH) , 7.13 -
7.01 (m, 3H) , 6.03 (d, J = 2.42 Hz, IH) , 5.96 (d, J = 2.41 Hz,
IH) , 5.06 (s, 2H) , 4.73 (s, 2H) , 2.81 (br s, IH) , 2.02 (s,
3H) ; LC/MS, tr = 2.37 minutes (5 to 95% acetonitrile/water over
5 minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z
(M+H) . ES-HR/MS m/z 376.1181 (M+H calcd for C2oHi6F3N03
requires 376.1155) . Identity of the positional isomer was
determined from hmbc, 2-D NMR experiments using H to C 2- and
3- bond coupling.
Step 2: Preparation of the title compound . l-(2,6-
Difluorophenyl) -4-{ [4-fluoro-2- (hydroxymethyl) benzyl ]oxy} -6-
methylpyridin-2 (IH) -one ( from step 1) (350 mg, 0.93 mmol) was
stirred at room temperature with W-bromosuccinimide (199 mg,
1.12 mmol) in 1.5 ml CH2C12 for 1.5 hours. The reaction was
evaporated on a rotary evaporator and the resulting solid was
washed 4 times with acetonitrile and dried in vacua to yield a
white solid (197 mg, 47%). *H NMR (300 MHz, CDC13) 8 7.53 -
7.43 (m, 2H) , 7.25 (dd, J = 9.46, 2.62 Hz, IH) , 7.11 - 7.03
(m, 3H) , 6.25 (s, IH) , 5.31 (s, 2H) , 4.81 (s, 2H) , 2.28 (br s,
IH) , 2.10 (s, 3H) ; LC/MS, tr = 2.38 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0247 (M+H calcd
for CjoHisBrFaNOs requires 454.0260).
Example 327
3-chloro-l-(2,6-difluorophenyl)-4-{[4-fluoro-2-
(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(IH)-one
1-(2,6-Difluorophenyl)-4-{[4-fluoro-2-
(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(IH)-one (step 1
above) (275 mg, 0.73 mmol) was stirred at reflux with Nchlorosuccinimide
(117 mg, 0.88 mmol) and dichloroacetic acid
(0.03 ml, 0.36 mmol) in 1.5 ml CH2Cl2 overnight. The reaction
was evaporated on a rotary evaporator and the resulting solid
was washed 4 times with ethyl acetate and with diethyl ether
and dried 112 vacuo to obtain a white solid (65.5 mg, 22%) . XH
NMR (300 MHz, CDC13) 6 7.52 - 7.43 (m, 2H), 7.26 (dd, J = 9.38,
2.52 Hz, IH), 7.12 - 7.04 (m, 3H), 6.27 (s, IH), 5.32 (s, 2H),
4.82 (s, 2H) , 2.29 (br s, IH) , 2.11 (s, 3H) ; LC/MS, tr = 2.32
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min, at 254 nm, at 50°C) , ES-MS m/z 410 (M+H) . ES-HRMS m/z
410.0755 (M+H calcd for C2oH15ClF3NO3 requires 410.0765).
Example 328
3-[3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-2-methyl-N-(2-morpholin-4-ylethyl)benzamide
Step 1: Preparation of methyl 3-(4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)-2-methylbenzoate .
4-Hydroxy-6-methyl-2-pyrone (72.6 g, 576 mmol) and methyl-3-
amino-2-methylbenzoate (100 g, 605 mmol) were suspended in 75
ml of 1,2-dichlorobenzene in a 500 ml, 3-necked round bottom
flask equipped with a J-Kem temperature controller probe, a
Dean-Stark trap, and a heating mantle. The reaction was
heated to 165°C for 15 minutes, during which, water and some
1,2-dichlorobenzene was collected in the Dean-Stark trap. The
reaction was allowed to cool to about 80°C. The flask was
placed in an ice bath and about 300 ml of toluene was added
and stirred. After about 30 minutes, a precipitate formed.
The precipitate was filtered and washed 3 times with toluene,
3 times with hot water to remove excess pyrone, and dried in
vacua to give a tan solid (44.6 g, 28% yield). XH NMR (400
MHz, DMSO-ds) 8 10.66 (br s, 1H) , 7.80 (dd, J « 7.72, 1.28 Hz,
1H) , 7.33 (dd, J = 7.78, 1.34 Hz, 1H) , 5.91 (dd, J - 2.41,
0.69 Hz, 1H) , 5.55 (d, J = 2.42 Hz, 1H) , 3.82 (s, 3H) , 2.06
(s, 3H) , 1.73 (s, 3H) ; LC/MS, tr - 1.85 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1078 (M+H calcd
for C15Hi5N04 requires 274.1074).
Step 2: Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]-2-methylbenzoate .
Methyl-3- (4-hydroxy-6-methyl-2-oxopyridin-l (2H) -yl) -2-
methylbenzoate { from Step 1) (42.0 g, 154 tranol) was stirred
briskly at room temperature with 2,4-difluorobenzyl bromide
(19.7 ml, 154 mmol) and K2C03 (31.8 g, 231 mmol) in 250 ml of
W,W-dimethylformamide. After stirring overnight, the reaction
was poured into 1 L of cold water. The solution was extracted
3 times with ethyl acetate and the organic layers were dried
over MgS04, and evaporated. The product was carried on to the
next step as a crude oil (60.4 g, 85%) . XH NMR (400 MHz,
CDC13) 8 7.96 (dd, J = 7.85, 1.28 Hz, 1H), 7.45 - 7.34 (m, 2H),
7.27 - 7.23 (m, 1H) , 6.94 - 6.84 (m, 2H) , 5.98 (d, J - 2.68
Hz, 1H) , 5.92 (dd, J = 2.69, 0.81 Hz, 1H) , 5.01 (s, 2H) , 3.88
(s, 3H) , 2.28 (s, 3H) , 1.81 (s, 3H) ; LC/MS, tr = 2.96 minutes
(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at
254 nm, at 50°C) , ES-MS m/z 400 (M+H) . ES-HRMS m/z 400.1341
(M+H calcd for C22H19F2N04 requires 400.1355).
Step 3: Preparation of 3-[4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]-2-methylbenzoic acid .
Methyl 3-[4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin-
1 (2H)-yl]-2-methylbenzoate ( from Step 2) (60.0 mg, 150 mmol)
was stirred with 2.5 N NaOH (120 ml, 300 mmol) in 375 ml of
tetrahydrofuran and 75 ml of water at room temperature
overnight. The reaction was acidified with 1 N HC1, 350 ml of
water was added and the solution was extracted 3 times with
ethyl acetate. The. combined, organic layers were dried over
MgS04, filtered and evaporated. The resulting solid was
filtered, washed with ethyl acetate and dried in vacua to
yield a white solid 33.8 g, 58%). XH NMR (400 MHz, CDC13) 6
7.98 (dd, J * 7.92, 1.20 Hz, 1H) , 7.43 (app q, J = 7.70 Hz,
1H) , 7.38 (t, J - 7.72 Hz, 1H) , 7.35 (dd, J - 7.81, 1.21 Hz,
1H), 6.92 - 6.84 (m, 2H) , 6.17 (d, J - 2.56 Hz, 1H), 6.00 (dd,
J m 2.55, 0.81 Hz, 1H) , 5.05 (s, 2H) , 2.30 (s, 3H) , 1.84 (s,
3H) ; LC/MS, tr = 2.61 minutes (5 to 95% acetonitrile/water over
5 minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 386
(M+H) . ES-HR/MS m/z 386.1228 (M+H calcd for C2iH17F2N04
requires 386.1198).
Step 4: Preparation of 3-[3-bromo-4-[(2,4-
dif luorobenzyl) oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-
methylbenzoic acid .
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]-2-methylbenzoic acid ( from Step 3) (23.0 g, 59.7 mmol)
was stirred at room temperature with N-bromosuccinimide (12.74
g, 71.6 mmol) in 120 ml of CH2C12 for 2 hours. The reaction
was evaporated on a rotary evaporator and the resulting solid
was stirred in acetonitrile for 1 hour, washed 7 times with
acetonitrile and dried in vacuo to yield a white solid (19.14.
g, 69%). XH NMR (400 MHz, DMSO-ds) 8 7.87 (dd, J = 7.52, 1.61
Hz, 1H) , 7.67 (app q, J = 7.92 Hz, 1H) , 7.45 - 7.37 (m, 2H) ,
7.33 (dt, J = 9.87, 2.54 Hz, 1H) , 7.17 (dt, J = 8.50, 1.67 Hz,
1H) , 6.71 (s, IK), 5-. 32. (s:,. 2H)., 2..0a (a, 3.H) , 1.86 (s-,. 3H) r
LC/MS, tr = 2.69 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 464 (M+H) .
ES-HRMS m/z 464.0284' (M+H calcd for C2iHi6BrF2N04 requires
464.0304) .
Step 5: Preparation of the title compound . 3-[3-Bromo-4-
[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)-yl]-2-
methylbenzoic acid ( from Step 4 above) (500 mg, 1.08 mmol)
was dissolved in 5 ml of CH2C12. 4-(2-Aminoethyl)morpholine
(170 |il, 1.29 mmol) was added, followed, in order, by EDCI (247
mg, 1.29 mmol)/ 1-hydroxybenzotriazole (174 mg, 1.29 mmol) and
triethylamine (301 \il, 2.16 mmol). The reaction was stirred at
room temperature overnight. The reaction was quenched with
NH4C1 and extracted 3 times with ethyl acetate. The combined
organic layer was dried over MgS04 and evaporated. The
resulting oil was triturated with diethyl ether/hexane to
obtain a solid, which was dried in vacua to give a white solid
(472 mg, 76%). XH NMR (400 MHz., DMSO-d6) 6 7.64 (app q, J =
7.79 Hz, 1H) , 7.47 (dd, J » 7.65, 1.01 Hz, 1H) , 7.39 (t, J =
7.75 Hz, 1H) , 7.17 (dd, J = 7.65, 0.81 Hz, 1H) , 7.01 (dt, J -
8.26, 1.61 Hz, 1H), 6.91 (dt, J = 9.42, 2.32 Hz, 1H), 6.49 (t,
J = 5.04 Hz, 1H) , 6.18 (s, 1H) , 5.30 (s, 2H) , 3.73 (t, .7 -
4.53 Hz, 4H) , 3.68 - 3.47 (m, 2H) , 2.59 (t, J = 5.94 Hz, 2H),
2.51 (t, J = 4.33 Hz, 4H), 2.15 (s, 3H), 1.98 (s, 3H); LC/MS,
tr = 2.27 minutes (5 to 95% acetonitrile/water over 5 minutes
at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 576 (M+H) . .ES-HRMS
m/z 576.1313 (M+H calcd for C27H2BBrF2N3O4 requires 576.1304).
Examples 329-337
The following compounds are prepared essentially according to
the procedure set forth for Example 328:
Example
No.
Ex. 329
Ex. 330
Ex. 331
Ex. 332
EX. 333
Ex. 334
EX. 335
Ex. 336
Ex. 337
-NHCH2CH2OCH3
-N(CH3)2
-NHCH2CH2OH
-NHCH3
-N(CH3)CH2CH2OH
4-
methylpiperazin-
morpholin-4-yl
-N(CH3)CH2CH2OCH3
-NH2
MF
C24H22BrF2N204
C23H20BrF2N203
C23H20BrF2N204
C22Hi8BrF2N203
C24H22BrF2N204
C26H25BrF2N303
C2SH22BrF2N204
C2SH24BrF2N204
C21H16BrF2N203
M+H ESHRMS
Requires m/z
521.0882 521.0906
491.0776491.0752
507.0726507.0689
477.0620477.0585
521.0882 521.0890
546.1198546.1187
533.0882 533.0856
535.1039535.1055
463.0463 463.0492
NMR characterization of compounds of Examples 329-337
Example
No.
Ex. 329
Ex. 330
Ex. 331
NMR Data
XH NMR (400 MHz, CDC13) 6 7.59 (app q, J - 7.79 Hz, 1H) , 7.47
(dd, J-7.65, 1.08 Hz, 1H) , 7.34 (t, J- 7. 72 Hz, 1H) , 7.12
(dd, J = 7.78, 0.94 Hz, 1H) , 6.96 (app dt, J - 7.92, 2.27 Hz,
1H) , 6.87 (dt, J = 9.46, 2.55 Hz, 1H) , 6.29 (m, 1H) , 6.12 (s,
1H) , 5.25 (s, 2H) , 3 . 7 3 - 3 . 6 5 (m/ 1H) , 3.56 - 3.48 (m, 3H) ,
3.35 (d, J m 3.09 Hz, 3H) , 2.09 (s, 3H) , 1.93 (s, 3H)
*H NMR (400 MHz, CDC13) 8 7.59 (app q, J » 7.79 Hz, 1H) ,
7.34 (t, J = 7.66 Hz, 1H) , 7.28 (dd, J = 7.66, 1.21 Hz,
1H) , 7.07 (dd, J = 7.65, 1.08 Hz, 1H) , 6.96 (app dt, J =
8.52, 2.02 Hz, 1H) , 6.87 (dt, J - 9.46, 2. 55 Hz, 1H) ,
6.29 (m, 1H) , 6.12 (s, 1H) , 5.25 (s, 2H) , 3.11 (s, 3H) ,
2.82 (s, 3H) , 1.96 (s, 3H) , 1.95 (a, 3H)
XH NMR (400 MHz, CDClj) 8 7.59 (app q, J - 7.74 Hz, 1H) , 7.46
(d, J - 6.71 Hz, 1H) , 7.32 (t, J « 7.72 Hz, 1H) , 7.07 (d, J -
6.85 Hz, 1H) , 6.98 (m, 2H) , S.87 (dt, J = 9.47, 2.41 Hz, 1H) ,
6.15 S, IH), 5.26 (S, 2H), 3.71 (t, J = 4.97 Hz, 2H), 3.60 -
3.45 (m, 2H), 2.06 (s, 3H), 1.95 (s, 3H)
Ex. 332 H NMR (400 MHz, CDC13) 6 7.59 (app q, J = 7.79 Hz, IH) , 7.42
(dd, J = 7.66, 0.94 Hz, IH), 7.31 (t, J = 7.72 H=, IH), 7.09
(dd, J « 7.79, 0.94 Hz, IH), 6.96 (appdt, J = 8 . 2 6 , 1.61 Hz,
IH), 6.87 (dt, J = 9.44, 2.49 Hz, IH), 6.12 (s, IH) , 5.25 (s,
2H), 2.96 (d, J - 4.83 Hz, 3H), 2.07 (s, 3H), 1.93 (s, 3H)
Ex. 333 JH NMR (300 MHz, DMSO-d«) 8 7.73 (q, J* 7.92 Hz, IH) , 7.44 -
7.20 (m, 5H), 6.75 (s, IH), 5.37 (s, 2H), 4.83 (br s, IH), 3.65
(br s, 2H), 3.45 - 3.33 (m, 2H), 2.81 (s, 3H), 1.93 (d, J -
3.42 Hz, 3H), 1.85 (d, J - 8.06 Hz, 3H)
Ex. 334 H NMR (300 MHz, DMSO-ds) 5 7.67 (app g, J = 7.92 Hz, IH) , 7.40
(t, J = 7.78 Hz, IH), 7.34 (dt, J - 9 . 8 7 , 2.55HZ, IH), 7.27
(d, J - 7.52 Hz, IH) , 7.24 (d, J - 7.79 Hz, IH) , 7.17 (dt, J -
8.41, 1.97 Hz, IH), 6.71 (s, IH), 5.32 (s, 2H), 3.63 (m, 2H),
3.29 (br s, IH), 3.09 (br s, 2H), 2.34 (t, J = 4 . 5 7 H z , 2H),
2.16 (s, 3H) , 1.88 (d, i 7 - 8 . 8 6 H z , 3H) 2.20 (br s, 2H) , , 1.80
(d, J - 4.83 Hz, 3H)
Ex. 335 H NMR (300 MHz, CDC13) 8 7.64 (app q, J = 7.79 Hz, IH) , 7.42
(t, J - 7.65 Hz, IH) , 7.33 (d, J » 7.66 Hz, IH) , 7.14 (d, J «
7.65 Hz, IH), 7.00 (dt, J - 8.76, 2.21 Hz, IH), 6.91 (dt, J =
9.47, 2.42 Hz, IH), 6.17 (s, IH), 5.29 (s, 2H), 3.98 - 3.92 (m,
IH), 3.80 - 3.77 (m, 3H), 3.59 (br s, 2H), 3.29 (t, J - 4.43
Hz, 2H), 2.04 (s, 3H), 2.00 (s, 3H)
EX. 336 1H NMR (300 MHz, CDC13) 5 7.65 (app q, J - 7.79 Hz, IH) , 7.43
7.32 (m, 2H), 7.12 (dd, J - 7.66, 1.21 Hz, IH), 7.00 (dt, J =
9.06, 1.51 Hz, IH), 6.92 (dt, J- 9.42, 2.52 Hz, IH), 6.16 (s,
IH), 5.30 (s, 2H), 3.69 (t, J - 5.04 Hz, 2H), 3.39 (s, 3H),
3.26 (S, IH), 3.19 (s, IH), 2.91 (s, 3H) , 2.04 (s, 3H), 2.00
(S, 3H)
Ex. 337 *H NMR (300 MHz, DMSO-ds) 8 7.91 (br s, IH) , 7.73 (app q, J =
7.85 Hz, IH) , 7.53 - 7.20 (m, 5H) , 6.74 (s, IH) , 5.37 (s, 2H) ,
1.99 (s, 3H), 1.92 (s, 3H)
Example 338
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-1-[3-(hydroxymethyl)-2-
methylphenyl]-6-methylpyridin-2(IH)-one
3- [3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H)-yl]-2-raethylbenzoic acid (Step 4 above) (2.0 g, 4.31
mmol) was cooled to 0°C -in 10 ml of tetrahydrofuran. 19.5 ml
of 1M BHa'THF in tetrahydrofuran was added and stirred
overnight, allowing the temperature to rise to room
temperature. The reaction was cooled back down to 0°C and ice
chips were added to quench the reaction. The slurry was
extracted 3 times with an ethyl acetate/tetrahydrofuran
mixture. The combined organic layers were washed with .brine,
dried over MgS04/ filtered and evaporated to give a white solid
(1.73 g, 89%). XH NMR (400 MHz, DMSO-dg) 8 7.67 (app q, J -
7.92 Hz, 1H) , 7.46 (d, J = 7.52 Hz, 1H) , 7.32 (dt, J - 10.74,
2.42 Hz, 1H) , 7.30 (t, J = 7.72 Hz, 1H) , 7.17 (dt, J = 8.46,
1.88 Hz, 1H) , 7.03 (d, J = 7.38 Hz, 1H) , 6.68 (a, 1H) , 5.32
(s, 2H) , 4.51 (s, 2H) , 3.29 (d, J = 9.40 Hz, 1H) , 1.85 (s,
3H) , 1.81 (s, 3H) , LC/MS, tr = 2.64 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at
50°C) , ES-MS m/z 450 (M+H) . ES-HRMS m/z 450.0480 (M+H calcd
for CjiHiBBrF2N03 requires 450.0511).
Example 339
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H)-yl]-N-(2-methoxyethyl)-2-methylbenzamide
Step 1: Preparation of 3-[3-chloro-4-[(2,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -yl] -2-
methylbenzoic acid .
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]-2-methylbenzoic acid (Step 3 above) (10.0 g, 25.9 mmol)
was refluxed with N-chlorosuccinimide (4.15 g, 31.1 mmol) and
dichloroacetic acid (1.06 ml, 12.9 mmol) in 50 ml of CH2C12
overnight. The reaction was evaporated on a rotary evaporator
and the resulting solid was stirred in acetonitrile for 30
minutes, washed 4 times with acetonitrile and dried in vacuo
to yield a white solid (8.3 g, 78%). XH NMR (300 MHz, DMSO-dg)
8 7.93 (dd, J = 7.15, 1.92 Hz, 1H) , 7.72 (app q, J = 7.92 Hz,
1H) , 7.52 - 7.35 (m, 3H) , 7.22 (dt, J = 8.47, 2.01 Hz, 1H) ,
6.80 (s, 1H), 5.38 (s, 2H), 2.14 (s, 3H) , 1.93 (s, 3H) ; LC/MS,
tr = 2.64 minutes (5 to 95% acetonitrile/water over 5 minutes
at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 420 (M+H) . ES-HRMS
m/z 420.0806 (M+H calcd for C2iH16ClF2N04 requires 420.0809).
Step 5: Preparation of the title compound . 3-[3-Chloro-
(2,4-difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -yl] -2-
methylbenzoic acid ( from Step 1 above) (500 mg, 1.19 mmol)
was dissolved in 5 ml of CH2C12. 2-Methoxyethylamine (129 ]il,
1.49 mmol) was added, followed, in order, by EDCI (286 mg,
1.49 mmol), 1-hydroxybenzotriazole (202 mg, 1.49 mmol) and
triethylamine (332 /il, 2.38 mmol). The reaction was stirred
at room temperature overnight. The reaction was quenched with
NH4C1 and extracted 3 times with ethyl acetate. The combined
organic layer was dried over MgS04 and evaporated. The
resulting solid was dried in vacuo to give a white solid
-, 7L%) . *!£ HHEr CCdtT MHz.,, CDCl^ S 7.55 (ap^ q^ JC = 7VT4. Hz,
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-N,2-dimethylbenzamide
The title compound was prepared by a procedure similar to the
one described for Example 337, where methylamine was used as
the amine and the product was obtained in 73% yield. ^ NMR
(300 MHz, DMSO-dg) 8 8.37 (app d, J = 4.64 Hz, 1H) , 7.72 (app
q, J - 7.92 Hz, 1H) , 7.44 - 7.35 (m, 4H) , 7.22 (dt, J = 8.54,
1.61 Hz, 1H) , 6.78 (s, 1H) , 5.37 (s, 2H) , 2.79 (d, J = 4.43
Hz, 3H) , 1.95 (s, 3H) , 1.94 (s, 3H) ; LC/MS, tr - 2.46 minutes
(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at
254 nm, at 50°C) , ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1163
(M+H calcd for C22Hi9ClF2N2O3 requires 433.1125).
Example 341
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-N-(2-hydroxyethyl)-2-methylbenzaraide
The title compound was prepared by a procedure similar to the
one described for , where ethanolamine was used as the amine
and the product was obtained in 65% yield. XH NMR (400 MHz,
DMSO-d6) 8 8.39 (t, J = 5.51 Hz, 1H), 7.67 (app q, J= 7.88 Hz,
1H) , 7.43 - 7.33 (m, 3H) , 7.23 (d, J* 7.25 Hz, 1H) , 7.17 (dt,
J = 8.39, 1.66 Hz, 1H) , 6.74 (a, 1H) , 5.32 (s, 2H) , 3.48 (br
s, 2H) , 3.31 - 3.26 (m, 2H) , 1.90 (s, 3H) , 1.89 (s, 3H) ;
LC/MS, tr = 2.34 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 463 (M+H) .
ES-HRMS m/z 463.1220 (M+H calcd for C23H2iClF2N204 requires
463.1231).
Example 342
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-2-methylbenzamide
3- [3-Chloro-4- [ (2,4-difluorobenzyDoxy] -6-methyl-2-oxopyridin-
1 (2H)-yl]-2-methylbenzoic acid (Step 1 above) (500 mg, 1.19
mmol) was stirred with 2-chloro-4,6-dimethoxy-l,3,5-triazine
(251 mg, 1.43 mmol) and W-methylmorpholine (392 nl, 3.57 mmol)
in 5 ml of tetrahydrofuran at room temperature for 2 hours.
2.5 ml of NH4OH was added and stirred at room temperature for
2.5 hours. The reaction was diluted with tetrahydrofuran and
ethyl acetate and extracted. The combined organic layers were
washed with NaHC03, 1 N HCl, and brine, dried over MgS04,
filtered and evaporated. The resulting solid was dried in
vacuo to obtain a white solid (313 mg, 63%). XH NMR (400 MHz,
DMSO-dg) 6 7.87 (br s, 1H) , 7.66 (q, J = 7.83 Hz, 1H) , 7.48 -
7.30 (m, 3H), 7.23 (d, J = 7.52 Hz, 1H), 7.17 (t, J = 7.65 Hz,
1H) , 6.73 (s, 1H) , 5.32 (s, 2H) , 1.94 (s, 3H) , 1.88 (s, 3H) ;
LC/MS, tr = 2.44 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min, at 254 nm, at 50°C) , ES-MS m/z 419 (M+H) .
ES-HRMS m/z 419.0963 (M+H calcd for C2iHi7ClF2N203 requires
419.0969).
Example 343
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)
yl]-3,5-difluorobenzonitrile
-482-
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]pyridine 1-
oxide .
2, 4-difluorobenzyl alcohol (100. g, 0.694 mol) and 4-
nitropyridine N-oxide (98. g, 0.700 mol)are combined with 250
g Cs2CC>3 (1.1 eq) in 2.5 L anhydrous dimethylformamide and
heated to 80°C with stirring. The reaction was followed by
19F-NMR (crude reaction mixture with external D20 reference)
and complete after 40 h. The mixture was filtered hot;
product crystallized out on cooling. 90.21 g (55%) of white
plates were collected by filtration and washed with diethyl
ether. The mother liquor was diluted with 2.5 L diethyl ether
and stored in the freezer overnight, yielding a second crop
68.76 g (41%, combined yield 96%). ^-NMR (400 MHz, DMSO-dg) 8
8.06 (m, 2 H), 7.61 (quartet, J = 8.45 Hz, 1H), 7.30 (t, J =
10.37 Hz,lH), 7.12, (t, J = 8.45 Hz, 1H), 7.09 (d, J = 5.06
Hz, 2H) , 5.14 (s, 2H) . 19F-NMR (400 MHz, DMSO-d6) 8 -109.43
(quintet, J = 7.78 Hz, IF), -113.82 (quartet, J = 9.55 Hz,
IF). LC/MS tr = 3.90 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 238 (M+H).
Step 2:f Preparation of 4- [ (2,4-difluorobenzyl)oxy]-pyridin-
2(IH)-one (7).
4- [ (2 ,4 -dif luorobenzyl) oxy] pyridine 1-oxide ( from Step 1)
(30.0 g , 0.127 mol) , anhydrous potassium acetate (25 g, 0.25
mol) , acetic anydride (25 g, 0.25 mol), and 10 ml acetic acid
were combined in a 250-ml round-bottomed flask with overhead
stirring and heated to 130°C for 4 hours. The mixture was
concentrated under vacuum, the solids dissolved in 95 ml
acetonitrile: 5 ml water, filtered through charcoal and poured
into 600 ml ice with stirring. The mixture was allowed to
stand overnight at room temperature, then 9.62 g (30%) product
collected by filtration as a medium brown solid (adequate for
the next step without purification) . 'H-NMR (400 MHz, DMSO-dg)
5 11.10 (B, IH) , 7.59 (quartet, J - 9.91 Hz, IH) , 7.29 (t, J=
10.36 Hz, IH), 7.21 (d, J = 8.20 Hz, IH) , 7.11 (t, J=8.48
Hz, IH) , 5.83 (m, 2H) , 5.02 (s, 2H) . 19F-NMR (400 MHz, DMSOd6)
8 -109. 57 (quintet, J = 7.66 Hz, IF) -113.88 (quartet, J =
8.93 Hz, IF). LC/MS tr = 4.29 minutes (0-95% '
acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes
at 1 ml/min with detection at 254 nm, at 50°C) ES-MS m/z 238
Step 3: Preparation of 3-chloro-4- [ (2,4-
dif luorobenzyl) oxy] pyridin-2 (IH) -one .
4-[ (2,4-difluorobenzyDoxy]-pyridin-2 (IH)-one ( from Step 2)
(8.60 g, 36.3 mmol) was stirred in 150 ml dimethylformamide
and treated with N-chlorosuccinimide (5.4 g, 39.9 mmol).
After 15 hours, the precipitate was collected by filtration
(5.11 g, 52%) yeilding a lustrous white solid. The mother
liquor was diluted to 500 ml with diethyl ether, providing
2.47 g (25%) in a second crop. ^-NMR (400 MHz, DMSO-dfi) 6
11.87 (s, IH) , 7.60 (quartet, J = 6.34 Hz, IH) , 7.43 (d, J =
7.58 Hz, IH), 7.31 (dt, J = 10.08, 2.21 Hz, IH), 7.14 (dt, J =
8.65, 1.79 Hz, IH), 6.44 (d,' J - 7.49 Hz, IH), 5.28 (s, IH) .
19F-NMR (400 MHz, DMSO-ds) 5 -109.58 (quintet, J- 7.75 Hz, IF),
-113.68 (quartet, J = 8.68 Hz, IF). LC/MS tr = 4.47 minutes
(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes at 1 ml/tnin with detection at 254 nm, at 50°C) ES-MS
m/z 272, 274 3:1 (M+H).
Step 4: Preparation of the title compound .
3-chloro-4- [ (2,4-dif luorobenzyDoxy]pyridin-2 (IH) -one ( from
step 3) (3.25 g, 11.9 mmol) was combined with Cs2C03 (3.93 g,
12.1 mmol) in 50 ml dimethyl formamide and heated to 70°C,
stirring under nitrogen. 3,4,5-trifluorobenzonitrile (1.83 g,
11.9 mmol) was added. After 4 hours, the mixture was
filtered, concentrated in vacuo, washed thrice with hot
cyclohexane, dissolved in tetrahydrofuran, treated with MgSO4
and charcoal, and filtered. The solution was evaporated
leaving a fine white solid (3.99 g, 82%). ^-NMR (400 MHz,
DMSO-d6) 6 8.12 (d, J = 7.59 Hz, 2H) , 7.92 (d, J = 8.31 Hz,
IH) , 7.65 (quartet, J = 6.77, IH) , 7.34 (dt, J = 9.81, 2.71
Hz, IH) , 7.16 (dt, J m 8.59, 2.50 Hz, IH) , 6.87 (d, J = 8.01
Hz, IH) , 5.39 (s, 2H) . 19F-NMR (400 MHz, DMSO-ds) 8 -109.17
(quintet, J = 8.97 Hz, IF), -113.51 (quartet, J = 9.53 Hz,
IE) f -Llfi.22. (dr J . 7.69 Hz,, 2F) . LC/MS tr -. 5.51 minutes (0-
95% acetonitrile/water, 0.05% trifluoroacetic acid, over
minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS
m/z 409 (M+H). ES-HRMS m/z 409.0351 (M+H calcd for
C19H1oClF4N202 requires 409.0361) .
Example 344
1- [4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-
dif luorobenzyl) oxy] pyridin-2(IH)-one hydrochloride
Step 1: Preparation of tert-butyl 4-[3-chloro-4-[(2,4-
dif luorobenzyl) oxy] -2-oxopyridin-l(2H)-yl]-3,5-
difluorobenzylcarbamate .
4- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-
yl]-3,5-difluorobenzonitrile (2.84 g, 6.95 mmol), di-t-butyl--
dicarbonate (3.18 g, 14.6 mmol), and nickel(II) chloride
(0.90 g, 6.95 mmol) were combined with 40 ml methanol and 40
ml tetrahydrofuran and cooled to 0°C stirring in an ice bath.
Sodium boronydrxdist. (i..33".g-) was: added, in.
portions over 10 minutes to control foaming, and the reaction
was stirred 1 hour. Additional sodium borohydride (0.50 g,
13.2 mmol) was required to force the reaction to completion by
LC. A color change from yellow to black persisted on
completion. The mixture was filtered through a bed of
charcoal layered on anhydrous MgS04 and evaporated to dryness.
Excess dicarbonate and byproduct t-butanol were
removed by repeated heating with water to 80°C in vacuo,
giving the product as a fine white powder (3.11 g, 87%). XHNMR
(400 MHz, DMSO-dg) 8 7.89 (d, J = 8.04 Hz, 1H) , 7.65
(quartet, J = 6.73 Hz, 1H) , 7.55 (t, J = 6.73 Hz.lH), 7.34,
(dt, J = 10.05, 2.51 Hz, 1H), 7.16 (m, 3H), 6.77 (d, J = 8.18
Hz, 1H) , 5.34 (s, 2H) , 4.18 (d, J * 5.68 Hz, 2H) , 1.34 (s,
9H) . 19F-NMR (400 MHz, DMSO-d6) 5 -109.26 (quintet, J = 6.91
Hz, IF), -113.53 (quartet, J = 7.73 Hz, IF), -120.32 (d, J =
8.91 Hz, 2F). LC/MS tr = 5.90 minutes (0-95%
acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes
at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 513
(M+H) . ES-HRMS m/z 513.1164 (M+H calcd for Cz^ClF*^*^
requires 513.1199).
Step 2: Preparation of the title compound .
tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-l(2H)-yl]-3,5-difluorobenzylcarbamate ( from step
3) (1.39 g, 2.71 mmol) was dissolved in 20 ml tetrahydrofuran
and treated with 4 ml concentrated hydrochloric acid. The
solution was evaporated and dried in vacuo to a fine white
solid (1.20 g, 99%). XH-NMR (400 MHz, DMSO-ds) 8 8.54 (m,
2H) , 7.86 (d, J = 7.57 Hz, 1H) , 7.65 (quartet, J = 7.62, 1H),
7.50 (d, J = 9.25 Hz, 2H), 7.34 (dt, J = 10.50, 2.45 Hz, 1H) ,
7.16 (dt, J = 8.38, 2.55 Hz, 1H) , 6.78 (d, J = 7.86 Hz, 1H) ,
5.37 (s, 2H) , 4.10 (br s, 2H) , 4.97-1.1,4 (v bar s> 3-HT.
-48-J(
400 MHz, DMSO-dg) 5 -109.21 (quintet, J = 7.77 Hz, IF), •-
113. 51 (quartet, J - 8.95 Hz, IF), -119.56 (d, J = 9.44 Hz,
2F) . LC/MS tr = 4.33 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes at 1 ml/min with
detection at 215 nm, at 50 °C) ES-MS m/z 413 (M+H) . ES-HRMS
m/z 413.0712 (M+H calcd for Ci9UnClF^202 requires 413.0674).
Example 345
NH-HCI
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-
[ (methylamino)methyl]phenylJpyridin-2(IH)-one hydrochloride
Step 1: Preparation of tert-butyl 4-[3-chloro-4-[(2,4-
difluorobenzyl)oxy]-2-oxopyridin-1(2H) -yl] -3,5-
difluorobenzyl(methyl)carbamate
tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2--
oxopyridin-l (2H)-yl]-3, 5-difluorobenzylcarbamate ( from Step
1) (252 mg, 0.491 mmol) and iodomethane (75 mg, 0.528 mmol)
are combined in a ml anhydrous dimethylformamide. Sodium
hydride 60% in mineral oil (30 mg, 0.75 mmol) was added and
-48athe
mixture stirred under nitrogen at room temperaure for 1
hour. Saturated aqueous NH4Cl was added (4 ml) followed by 20
ml water and the product was extracted into ethyl acetate,
washed with brine, dried over MgS04/ filtered, and evaporated
to give the product as a white powder (208 mg, 80%) . ^-NMR
(400 MHz, DMSO-ds) 5 7.87 (d, J - 7.85 Hz, 1H) , 7.64 (quartet,
J = 6.66 Hz, 1H) , 7.32, (dt, J = 9.39, 3.29 Hz, 1H) , 7.13 (m,
3H) , 6.77 (d, J = 7.94 Hs, 1) , 5.38 (s, 2H) , 4.43 (s, 2H) ,
2.90 (s, 3H) , 1.40 (br m, 9H) . 19F-NMR (400 MHz., DMSO-d6) 6 -
109.25 (quintet, J = 8.93 Hz, IF), -113.53 (quartet, J = 9.73
Hz, IF), -119.89(d, J = 9.35 Hz, 2F) . LC/MS tr • 6.16 minutes
(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 527 (M+H) . ES-HRMS
m/z 527.1338 (M+H calcd for C^-jClF*^* requires 527.1355).
Step 2 : Preparation of the title compound .
tert-butyl 4- [3-chloro-4- [ ( 2, 4 -dif luorobenzyl ) oxy] -2-
oxopyridin-1 (2H) -yl] -3 , 5-dif luorobenzyl (methyl) carbamate (
from step 1) (188 mg, 0.357 mmol) was subjected to the
conditions of Step 2, yielding a fine white solid (165 mg,
100%). XH-NMR (400 MHz, DMSO-d6) 5 9.30 (br s, 2H) , 7.89 (d,
J = 7.99 Hz, 1H) , 7.65 (quartet, J = 7.64, 1H) , 7.55 (d, J =
8.66 Hz, 2H) , 7.34 (dt, J = 9.93, 2.57 Hz, 1H) , 7.17 (dt, J =
8.49, 2.48 Hz, 1H) , 6.81 (d, J = 8.01 Hz, 1H) , 5.39 (s, 2H) ,
4.21 (s, 2H) , 2.56 (s, 3H) . 19F-NMR (400 MHz, DMSO-'dg) 6 -
109.20 (quintet, J - 7.56 Hz, IF), -113 . 52 (quartet, J - 9.67
Hz, IF), -119.21 (d, J = 8.79 Hz, 2F) . LC/MS tr = 4.30 minutes
(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes at 1 ml/min with detection at 215 nm, at 50 °C) ES-MS
m/z 427 (M+H) . ES-HRMS m/z 427.0816 (M+H calcd for
C2oHi6ClF4N202 requires 427.0831).
Example 346
NH-HCI
3-chloro-l-(4-{[ (cyclopropylmethyl)amino]methyl}-2, 6-
difluorophenyl)-4- [ (2,4-difluorobenzyl)oxy]pyridin-2(IH)-one
hydrochloride
The title compound was prepared by direct 'analogy with ,
replacing iodomethane with bromocyclopropylmethane and
extending the reaction time to 6 hours in Step 1.
Step 1:
1 tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-
oxopyridin-1(2H)-yl]-3,5-
difluorobenzyl(eyelopropylmethyl)carbamate
XH-NMR (400 MHz, DMSO-dg) 5 7.89 (d, J = 7.91 Hz, IH) , 7.65
(quartet, J = 6.81 Hz, IH) , 7.33, (dt, J = 9.90, 2.26 Hz, IH) ,
7.17 (m, 3H), 6.77 (d, J - 7.90 Hz, 1), 5.38 (s, 2H) , 4.51 (s,
2H) , 3.10 (br s, 2H) , 1.36 (m, 9H) , 0.97 (br s, IH) , 0.38 (m,
2S.I, CF.lffi (nr, 2H) . 19F-NHE (40.CT MHz., DMSO-dg) 5 -109.25
(quintet, J = 7.77 Hz, IF), -113.54 (quartet, J = 9.02 Hz,
IF), -120. 24 (m, 2F) . LC/MS tr = 5.99 minutes (0-95%
acet oni trile/water, 0.05% trifluoroacetic acid, over 6
minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 567 (M+H) . ES-HRMS
m/z 567.1653 (M+H calcd for C28H28C1F4N204 requires 567.1668).
Step 2 : Title compound .
-NMR (400 MHz, DMSO-d6) 5 9.51 (br s, 2H) , 7.87 (d, J = 7.96
Hz, 1H) , 7.63 (m, 3H) , 7.33 (dt, J = 9.93, 2.65 Hz, 1H) , 7.16
(dt, J = 8.36, 2.32 Hz, 1H) , 6.81 (d, J = 7.92 Hz, 1H) , 5.38
(s, 2H) , 4.22 (br s, 2H) , 2.82 (br s, 2H) , 1.10 (m, 1H) , 0.57
(m, 2H) , 0.36 (m, 2H) . 19F-NMR (400 MHz, DMSO-d6) 8 -109.25
(quintet, J = 7.69 Hz, IF), -113 .54 (quartet, J = 9.35 Hz,
IF), -120.24 (m, 2F) . LC/MS tr = 4.55 minutes (0-95%
acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes
at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 467
(M+H). ES-HRMS m/z 467.1119 (M+H calcd for C23H2oClF4N202
requires 467.1144) .
Example 347
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)
yl]-3,5-difluoroimetJay.
Ifeeozamide
Step 1: Preparation of 4-[3-chloro-4-[(2,4-
difluorobenzyDoxy] -2-oxopyridin-l (2H) -yl] -3,5-
difluorobenzamide .
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H) -
yl]-3,5-difluorobenzonitrile (540 mg, 1.32 tnmol) and
potassium trimethylsilonate 90% (375 mg, 2.63 mmol) are
combined in 8 ml anhydrous toluene and heated to reflux with
stirring. After 10 minutes, the mixture allowed to cool then
partitioned between saturated aqueous ammonium chloride and
ethyl acetate. The aqueous layer is extracted twice with
ethyl acetate, the combined organics are washed with brine,
dried over MgS04, and evaporated in vacua. The crude product
is taken up in tetrahydrofuran and filtered through charcoal
layered over silica gel, and the solution evaporated in vacua
to give the product' as a white powder (468 mg, 83%) . ^-NMR
(400 MHz, DMSO-ds) 5 8.22 (br s, 2H) , 7.92 (d, J = 7.84 Hz,
1H) , 7.78 (d, J = 8.45, 2H) , 7.65 (quartet, J = 8.40 Hz, 1H) ,
7.34, (dt, J m 10.09, 2.58 Hz, 1H) , 7.17 (dt, J = 8.72, 2.30
Hz, 1H) , 6.83 (d, ,7= 7.91 Hz, 1H) , 5.39 (s, 2H) . 19F-NMR (400
MHz, DMSO-d6) 6 -1.09.21 (quintet, J = 7.43 Hz, IF), -113.52
(quartet, J = 9.62 Hz, IF), -118.74 (d, J = 8.88 Hz, 2F) .
LC/MS tr = 4.67 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes, then 95% acetonitrile
for 2 minutea,. at r ntL/min. with detection at 215 nm,. at, 5ia°O.
ES-MS m/z 427 (M+H). ES-HRMS m/z 427.0454 (M+H calcd for
requires 427.0467).
Step 2 : Preparation of the title compound .
4- [3-chloro-4- [ (2, 4-difluorobenzyl) oxy] -2-oxopyridin-l (2H) -
yl ] -3, 5-dif luorobenzamide ( from step 1) (243 mg, 0.357 mmol)
was subjected to the conditions of Step 1, with the exception
that two equivalents of sodium hydride 60% in mineral oil and
iodomethane were used instead of one (46 mg, 0.69 mmol and 103
mg, 0.724 mmol respectively). ^-NMR (400 MHz, DMSO-dg) 8
7.92 (d, J = 7.76 Hz, 1H) , 7.66 (quartet, J = 7.33, 1H) , 7.44
(d, J = 7.59 HZ, 2H) , 7.34 (dt, J = 9.88, 2.63 Hz, 1H) , 7.17
(dt, J = 8.35, 2.06 Hz, 1H) , 6.83 (d, J = 7.55 Hz, 1H) , 5.39
(s, 2H) , 2.98 (S, 3H) , 2.91 (s, 3H) . 19F-NMR (400 MHz, DMSOdfi)
8 -109.22 (quintet, J = 8.10 Hz, IF), -113 . 53 (quartet, J -
9.18 Hz, IF), -118.88 (d, J = 7.77 Hz, 2F) . LC/MS tr = 5.13
minutes (0-95% acetonitrile/water, 0.05% trif luoroacetic acid,
over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C)
ES-MS m/z 455 (M+H). ES-HRMS m/z 455.0791 (M+H calcd for
C2iH16ClF4N2O3 requires 455.0780).
Example 348
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-
yl]-3-fluoro-5-
me t hoxybenzoni.tr ile
Step 1: Preparation of 4-[3-chloro-4-[(2,4-
difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3-fluoro-5-
hydroxybenzonitrile .
4-[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-
yl]-3,5-difluorobenzonitrile (522 mg, 1.28 mmol) and
potassium trimethylsilonate 90% (655 mg, 4.60 mmol) are
combined in 8 ml anhydrous tetrahydrofuran and stirred under
nitrogen at room temperature for 2 hours. The precipitated
potassium salt of was collected by filtration, washed with a
minimum of tetrahydofuran, and dried in vacua. A portion of
this salt (275 mg, 0.618 mmol) was dissolved in 5 ml water,
the pH was adjusted below 6 with concentrated hydrochloric
acid, the product collected by filtration, washed with water,
sucked dry under a blanket of dry nitrogen, and dried further
in vacua overnight (251 mg, 100%, 98% overall) . XH-NMR (400
MHz, DMSO-de) 6 11.46 (br s, 1H) , 7.74 (d, J = 7.81 Hz, 1H) ,
7.67 (quartet, J = 6.76 Hz, 1H) , 7.52 (d, J = 8.76, 1H) ,
7.364, (dt, J = 10.18, 2.37 Hz, 1H), 7.24 (br s, 1H), 7.17 (br
t, J = 8.75, 1H) , 6.74 (d, J = 8.04 Hz, 1H) , 5.39 (s, 2H) .
"F-NMR (400 MHz, DMSO-d6) 8 -109.26 (quintet, J = 8.50 Hz, IF),
-113.52 (quartet, J = 9.29 Hz, IF), -118.06 (d, J = 9.38 Hz,
IF). LC/MS tr = 5.13 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes, then 95% acetonitrile
for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C)
ES-MS m/z 407 (M+H). ES-HRMS m/z 407.0381 (M+H calcd for
Ci9HiiClF3N203 requires 407.0405).
Step 2: Preparation of the title compound .
The potassium salt of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-
2-oxopyridin-l(2H)-yl]-3-fluoro-5-hydroxybenzonitrile ( from
Step 1) (273 mg, 0.614 mmol) was stirred in 5 ml anhydrous
dimethylformamide under nitrogen. lodomethane (93 mg, 0.66
mmol) was added, and stirring continued for 2 hr. The mixture
was diluted to 50 ml with ice-cold water, and the white
precipitate collected by filtration. The precipitate was
washed thrice with water, sucked dry under a blanket of
nitrogen, and dried further in vacuo overnight (242 mg, 87%) NMR (400 MHz, DMSO-dg) 5 7.73 (m, 2H) , 7.65 (m, 2H) , 7.34
(dt, J = 9.90, 2.39 Hz, 1H), 7.17 (dt, J « 8.75, 2.47 Hz, 1H) ,
6.75 (d, J= 7.97 Hz, 1H), 5.37 (s, 2H), 3.84 (a, 3H).
(400 MHz, DMSO-d6) 5 -109.24 (quintet, J = 7.85 Hz, IF),
113.54 (quartet, J = 9.83 Hz, IF), -118.33 (d, J = 7.77 Hz,
IF). LC/MS tr = 5.40 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 421 (M+H) . ES-HRMS
m/z 421.0522 (M+H calcd for C2oHi3ClF3N203 requires 421.0561).
Example 349
J7-{4- [3-chloro-4- [ (2,4-difluorobenzyl)oxy] -2-oxopyridin-l (2H) -
yl]-3, 5-difluorobenzyl}urea
Step 1: Preparation of the title compound
1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(IH)-one hydrochloride (162 mg,
0.361 mmol) is dissolved in 4 ml 50% aqueous acetic acid and
treated with potassium cyanate (59 mg, 0.72 mmol). The
mixture was stirred 2 hr, then the mixture was diluted to 50
ml with cold water, and the crude product, contaminated with
the acetamide, was purified by silica gel chromatography,
eluting first with 20% ethanol in hexane then 40% ethanol in
hexane. The 50% fractions were pooled by TLC and evaporated,
giving the product as a fine white powder (65 mg, 40%). XH-NMR
(400 MHz, DMSO-de) 5 7.87 (d, J = 8.07 Hz, IH) , 7.64 (quartet,
J = 6.53 Hz, IH) , 7.33, (dt, J - 9.47, 1.99 Hz, IH) , 7.15 (m,
3H), 6.76 (d, J = 7.97 Hz, IH), 6.59 (m, IH), 5.65 (br a, 2H),
5.38 (s, 2H) , 4.22 (m, 2H) . 19F-NMR (400 MHz, DMSO-dg) 8 -
109.22 (quintet, J = 7.86 Hz, IF), -113.51 (quartet, J - 9.40
IF), -120.65 (d, J m 8.75 Hz, 2). LC/MS tr - 4.85 minutes (0-
95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS
m/z 456 (M+H).
Example 350
4-[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-
1(2H)-yl]-3,5-difluorobenzyl}amino)-1,1-dimethyl-2-oxoethyl
acetate
Step 1: Preparation of the title compound
1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one hydrochloride (225 mg,
0.501 mmol) is dissolved in a solution of 10 ml
tetrahydrofuran and triethylamine (111 mg, 1.10 mmol). 2-
acetoxy-2-methyl-propionyl chloride (85 mg, 0.516 mmol) is
added, and the mixture stirred for 30 minutes before
partitioning between saturated aqueous ammoniom chloride and
ethyl acetate. The layers are seperated, and the aqueous
phase extracted twice with ethyl acetate. The combined
organics are washed with water and brine, then dried over
MgS04, filtered, and evaporated in vacuo, giving the product
as a fine white powder (254 mg, 94%). ^-NMR (400 MHz, DMSOds)
5 8.47 (t, J = 6.16 Hz, 1H) , 7.88 (d, J = 7.71 Hz, 1H) ,
7.65 (quartet, J = 7.24 Hz, 1H), 7.34, (dt, J = 10.04, 2.49
Hz, 1H), 7.16 (m, 3H), 6.77 (d, J = 7.18 Hz, 1H), 5.38 (s,
2H), 4.32 (d, J= 5.93 2H), 2.02 (s, 3H), 1.48(s, 6H). 19FNMR
(400 MHz, DMSO-d6) 8 -109.26 (quintet, J = 9.00 Hz, IF),, -
113.52 (quartet, J = 9.52 Hz, IF), -120.62 (d, J = 9.09 Hz,
2F). LC/MS tr = 5.43 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 541 (M+H). ES-HRMS
m/z 541.1128 (M+H calcd for C25H22C1F4N205 requires 541.1148) .
Example 351
- [3-chloro-4- [ (2 , 4-dif luorobenzyl) oxy] -2-oxopyridin-l (2H)
yl] -3, 5 -dif luorobenzyl }acet amide
The compound was prepared in the following the produre for
Example 350, substituting acetyl chloride (24 mg, 0.30 mmol)
for 2-acetoxy-2-methyl-propionyl chloride. (128 mg, 96%) . 1HNMR
(400 MHz, DMSO-ds) 8 8.48 ( br S, 1H) , 7.87 (d, J- 7.28
Hz, 1H) , 7.64 (quartet, J - 8.01 Hz, 1H) , 7.33, (dt, J = 9.87,
2.25 Hz, 1H) , 7.17 (m, 3H) , 6.76 (d, J « 8.25 Hz, 1H) , 5.38
(s, 2H) , 4.30 (m, 2H) , 1.88(8, 3H) . 19F-NMR (400 MHz, DMSO-dg)
5 -109.22 (quintet, J= 8.04 Hz, IF), -113.52 (quartet, J =
9.91 Hz, IF), -120.43 (d,. J - 8.77 Hz, 2F) . LC/MS tr = 5 . 04
minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid,
over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C)
ES-MS m/z 555 (M+H) . ES-HRMS m/z 455.0824 (M+H calcd for
requires 455.0780).
Example 352
NH
N-{4- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-
yl]-3,5-difluorobenzyl}-2-methoxyacetamide
The compound was prepared in the following the produre for
EXAMPLE 350, substituting 2-methoxy-acetyl chloride (45 mg,
0.415 mmol) for 2-acetoxy-2-methyl-propionyl chloride. (124
mg, 78%). ^-NMR (400 MHz, DMSO-d6) 5 8.56 (t, J = 6.77 Hz,
1H), 7.90 (d, J = 7.85 Hz, 1H), 7.67 (quartet, J=7.67Hz,
1H), 7.36, (dt, J = 10.03, 2.36 Hz, 1H), 7.20 (m, 3H), 6.79
(d, J - 8.07 Hz, 1H), 5.40 (s, 2H), 4.37 (d, J = 6.28 Hz,
2H) , 3.91(S, 2H) , 3.35 (s, 3 H) . 19F-NMR (400 MHz, DMSO-ds) 6
109.23 (quintet, J = 8.29 Hz, IF), -113.50 (quartet, J= 9.36
Hz, IF), -120.43 (d, J = 9.07 Hz, 2F). LC/MS tr = 5.13
miinutes (0-95% acetonitrile/water, 0.05% trifluoroacetic
acid, over 6 minutes at 1 ml/min with detection at 215 nm, at
50°C) ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0856 (M+H calcd
for C22Hi8ClF4N204 requires 485.0886).
Example 353
IV- {4- [3-chloro-4- [ (2, 4-dif luorobenzyl) oxy] -2-oxopyridin-l (2H)
yl] -3, 5 -dif luorobenzyl} -2 -furamide
The compound was prepared in the following the produre for
EXAMPLE 350, substituting furoyl chloride (62 mg, 0.48 mmol)
for 2 -acetoxy-2 -methyl -propionyl chloride. Yield: 142 mg, 85%.
NMR (400 MHz, DMSO-ds) 6 9.07 (t, J= 6.14 Hz, 1H) , 7.90 (d,
J = 7.88 Hz, 1H) , 7.87 (dd, J"=1.69, 0.80 Hz, 1H) , 7.67 (td,
J =• - &_4&, 6,aO Hz, LH) , 7.35, (dt, J^IO.OO, 2,.ai Hi, 1H.) ,
V 2B) , 7. IS (ddfe^ JL =-- - &^S8^ 2.^3.0 r L..Q7
-49-9-
1H) , 7.16 (dd, J = 3.52, 0.77 HZ, 1H) , 6.79 (d, J=8.07Hz,
1H) , 6.64 (dd, J- 3.16, 1.73 Hz, 1H) , 5.40 (s, 2H) , 4.49 (d,
J= 6.13 Hz, 2H) . 19F-NMR (400 MHz, DMSO-dg) 6 -109.23
(quintet, J. 7.65 Hz, IF), -113.50 (quartet, J- 9.84 Hz,
IF), -120.29 (d, J = 9.41 Hz, 2F) . LC/MS tr = 5.32 minutes
(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes at 1 ml/min with detection at 215 nm, at 50 °C) ES-MS
m/z 507 (M+H) . ES-HRMS m/z 507.0716 (M+H calcd for
requires 507.0729).
Example 354
N-{4- [3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-
yl]-3,5-difluorobenzyl}-lH-imidazole-4-carboxamide
Step 1: Preparation of the title compound
1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-
difluorobenzyl)oxy]pyridin-2(1H)-one hydrochloride (150 mg,
0.334 mmol) is dissolved in a solution of 4 ml tetrahydrofuran
and triethylamine (35 mg, 0.35 mmol). 4-imidazolecarboxylic
acid (62 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (90
mg, 0.67 mmol), 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (128 mg, 0.668 mmol), and
triethylamine (100. mg, 0.989 mmol) were combined in 5 ml
tetrahydrofuran and stirred under nitrogen. The solution
containing 1- [4- (aminomethyl) -2, 6-difluorophenyl] -3-chloro-4-
[ (2,4-difluorobenzyl)oxy]pyridin-2(IH)-one hydrochloride was
added in one portion, rinsing with 2 ml tetrahydrofuran.
Stirring was continued at room temperature overnight, then the
reaction was poured into 90 ml of icewater, and the product
collected by filtration and dired in vacuo (254 mg, 94%) .
(400 MHz, DMSO-d6) 8 12.55 (br S, IH) , 8.73 (t, J = 6.57
Hz, IH), 7.90 (d, J = 7.87 Hz, IH), 7.75 (s, IH), 7.67 (m,
2H), 7.35, (dt, J - 10.04, 2.54 Hz, IH), 7.21 (m, 3H), 6.78
(d, J=8.04Hz, IH), 5.39 (s, 2H), 4.47 (m, 2H). 19F-NMR
(400 MHz, DMSO-dg) 6 -109.26 (quintet, J. 7.87 Hz, IF), -
113.52 (quartet, J - 9.30 Hz, IF), -120.59 (d, J = 9.21 Hz,
2F). LC/MS tr = 4.48 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 507 (M+H). ES-HRMS
m/z 507.0818 (M+H calcd for C23Hi6ClF4N403 requires 507.0842).
Example 355
N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)
yl]-3,5-difluorobenzyl}-5-oxoprolinamide
Step 1: Preparation of the title compound
The compound was prepared following the procedure for Example
354, substituting 2-pyrrolidone-5-carboxylic acid for 4-
imidazolecarboxylic acid. -NMR (400 MHz, DMSO-d6) 5 8.67 (t,
J" - 6.08 Hz, 1H) , 7.88 (m, 1H) , 7.65 (qr, J- 7.57, 1H) , 7.34,
(dt, J- 9.32, 2.63 Hz, 1H) , 7.22 (d, J- 9.36, 2H) , 7.17 (dt,
J m 8.51, 2.55 Hz, 1H) , 6.77 (d, J=7.66Hz, 1H) , 5.73 (a,
1H) , 5.38 (s, 2H), 4.35 (d, J - 5.74, 2H) , 4.05 (m, 1H) , 2.15
(m, 2H) , 1.90 (m, 2H) . 19F-NMR (400 MHz, DMSO-d6) 8 -109.25
(quintet, J= 7.72 Hz, IF), -113.52 (quartet, J= 8.94 Hz,
IF), -120.39 (d, J = 9.11 Hz, 2F) . LC/MS tr » 4.81 minutes
(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS
m/z 524 (M+H) . ES-HRMS m/z 524.0998 (M+H calcd for
requires 524.0995).
Example 356
#-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)
yl]-3,5-difluorobenzyl}-3-hydroxy-3-methylbutanamide
Step 1: Preparation of the title compound
The compound was prepared following the procedure for , '
substituting 2-hydroxy-2-methyl butyric acid for 4-
imidazolecarboxylic acid. XH-NMR (400 MHz, DMSO-dg) 8 8.43 (t,
J - 6.04 Hz, 1H), 7.88 (d, J = 8.01, 1H), 7.65 (qr, J - 6.84,
1H) , 7.34, (dt, .7=10.13, 2.55 Hz, 1H) , 7.22 (d, J=8.74,
2H) , 7.16 (dt, J = 8.57, 2.45 Hz, 1H) , 6.77 (d, .7 =7.89 Hz,
1H) , 5.38 (s, 2H) , 4.75. (s, 0. 5H (OH)), 4.35 (d, J » 6.48,
2H), 2.28 (s, 2H) , 1.47 (s, 0.5H(OH)), 1.16 (s, 6H) . 19F-NMR
(400 MHz, DMSO-d6) 8 -109.26 (quintet, J = 7.79 Hz, IF),
113.53 (quartet, J = 9.23 Hz, IF), -120.49 (d, J = 9.39 Hz,
2F). LC/MS tr = 5.08 minutes (0-95% acetonitrile/water, 0.05%
trifluoroacetic acid, over 6 minutes at 1 ml/min with
detection at 215 nm, at 50°C) ES-MS m/z 513 (M+H). ES-HRMS
m/z 513.1177 (M+H calcd for C24H22C1F4N204 requires 513.1199).
Example 357
N- (4-[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)
yl]-3,5-difluorobenzyl}-1-hydroxycyclopropanecarboxamide
Step 1: Preparation of the title compound
The compound was prepared following the procedure for ,
substituting 1-hydroxy-l-cyclopropanecarboxylic acid for
imidazolecarboxylic acid. XH-NMR (400 MHz, DMSO-ds) 5 8.70 (t,
J = 6.26 Hz, 1H), 7.89 (d, J = 6.31, 1H), 7.65 (qr, J = 6.83,
1H) , 7.34 (t, J = 10.58 Hz, 1H) , 7.19 (m, 3H) , 6.77 (d, J" =
7.70 Hz, 1H), 5.38 (s, 2H), 4.35 (d, J. 5.66, 2H) , 1.14 (s,
1H) , 1.02 (m, 2H) , 0.84 (m, 2H) . 19F-NMR (400 MHz, DMSO-d6) 5
-109.25 (quintet, J = 8.05 Hz, IF), -113.53 (quartet, J- 8.27
Hz, IF), -120.59 (d, J = 8.99 Hz, 2F). LC/MS tr = 5.01
minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid,
over 6 minuteat 1 ml/min with detection at 215 nm, at 50°C)
ES-MS m/z 497 (M+H). ES-HRMS m/z 497.0873 (M+H calcd for
requires 497.0886).
Example 358
N-(4- [3-chloro-4- [ (2, 4 -dif luorobenzyl )oxy] -2-oxopyridin-l (2H) -
yl] -3 , 5-dif luorobenzyl} -2-hydroxy-2-methylpropanamide
Step 1: Preparation of the title compound
The compound was prepared following the procedure for ,
substituting 2-hydroxyisobutyric acid for 4-
imidazolecarboxylic acid. XH-NMR (400 MHz, DMSO-d6) 8 8.48 (t,
J = 6.41 Hz, 1H) , 7.89 (d, J = 7 .78, 1H) , 7.65 (qr, J = 9.10,
1H) , 7.33 (dt, Jm 10.12, 2.41 Hz, 1H) , 7.17 (m, 3H) , 6.77 (d,
J = 7.69 Hz, 1H) , 5.38 (s, 2H) , 4.31 (d, « J = 6 . 5 0 , 2H) , 1.41
(s, IH) , 1.33 (s, 6H) . "F-NMR (400 MHZ, DMSO-dg) S -109.25
(quintet, J - 7.49 Hz, IF), -113.53 (quartet, J = 9.64 Hz,
IF), -120.59 (d, J = 8.68 Hz, 2F) . LC/MS tr = 5.05 minutes
(0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
minutes at 1 ml/min with detection at 215 nm, at 50 °C) ES-MS
m/z 499 (M+H). ES-HRMS m/z 499.1020 (M+H calcd for
requires 499.1042).
Example 359
4- [3-bromo-4- [ (2,4-dif luorobenzyl) oxy] -2-oxopyridin-l (2H) -yl]
3 , 5-dif luorobenzonitrile
Step 1: Preparation of 3 -bromo-4 -[ (2,4-
dif luorobenzyl) oxy] pyridin-2 (IH) -one .
The compound was prepared in the following the produre for 3-
chloro-4- [ (2,4-dif luorobenzyl) oxy] pyridin-2 (IH) -one (, Step
3), substituting W-brotnosuccinimide for AT-chlorosuccinimide.
-NMR (400 MHz, DMSO-d6) 5 11.85 (br s, IH) , 7.61 (m, IH) ,
7.46 (d, J = 7.36 Hz, IH) , 7.30, (m, IH) , 7.14 (m, IH) , 6.40
(d, J = 7.71 Hz, IH) , 5.26 (s, 2H) . 19F-NMR (400 MHz, DMSOd6)
6 -109.69 (quintet, J = 7.93 Hz, IF), -113.63 (quartet, J =
9.55 Hz, IF). LC/MS tr = 4.48 minutes (0-95%
acetonitrile/water, 0.05% trif luoroacetic acid, over 6 minutes
at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 316
(M+H) .
Step 2: Preparation of the title compound .
The compound was prepared following the procedure for 4-[3-
chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3,5-
difluorobenzonitrile (, Step 4), substituting 3-bromo-4- [ (2,4-
difJLuorobenzyl) oxy] pyridin-2 (IH)-onet, ( frnrar stepr L) (1.92 g,
6.06 mmol) for 3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-
2(lH)-one (, from Step 3). ^-NMR (400 MHz, DMSO-dg) 8 8.13 (
d, J » 7.24 Hz, 2H), 7.95 (d, J - 7.76 Hz, IH), 7.66 (quartet,
J» 8.71 Hz, IH) , 7.34, (dt, J = 9.94, 2.53 Hz, IH) , 7.17 (dt,
J = 8.64, 2.33 Hz, IH) , 6.82 (d, J = 7.77 Hz, IH) , 5.39 (s,
2H) . 19F-NMR (400 MHz, DMSO-ds) 5 -109.28 (quintet, J = 7.98
Hz, IF), -113.45 (quartet, J = 9.29 Hz, IF), -116.30 (d, J =
7.44 Hz, 2F) . LC/MS tr = 5.48 minutes (0-95%
acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes
at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 453
(M+H) . ES-HRMS m/z 452.9836 (M+H calcd for
requires 452.9856).
Example 360
F
3-Bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-
2(lH)-one
Step 1: Preparation of 1-(3-fluorobenzyl)-4-hydroxy-6-
methylpyridin-2(IH)-one
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol)
and 3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15
mL) was heated to reflux for 16 h under argon atmosphere.
Butanol wad distilled in vacuo, the residue was triturated
with EtOAc, cooled and filterd the precipitate. It was
washed with cold EtOAc, and dried to give 0.86 g of the title
compound as a pale yellow powder: 1H- NMR (CD30D/400 MHz) 5
7.31 (m, 1H), 7.0 - 6.85 (m, 2H), 6.83 (d, 1H, J = 9.6 Hz),
5.96 (d, 1H, j - 2.0 Hz) , 5.80 (d, • 1H, J = 2.0 Hz), 5.30 (s,
2H), and 2,24 (s, 3H); ESMS m/z - 234 ( MH+).
Step 2: Preparation of 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-
6-methylpyridin-2(1H)-one
A mixture of 1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-
2(1H)-one ( 0.8 g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in
dichloromethane (15.0 mL) was stirred at room temperature,
under argon atmosphere. After 1.5 h, the reaction mixture was
diluted with dichloromethane (15.0 mL), cooled and filterd the
solids. The residue was washed with dichloromethane and dried
in vacuo to give 0.93 g of the title compound as a white
powder: 1H- NMR (CD30D/400 MHz) 6 . 7.33 (m, 1H), 7.2 - 6.8
(m, 3H), 6.07 (s, 1H), 5.34 (s, 2H), 2.26 (s, 3H); ESHRMS m/z
312.0016 (M+H C13H12N02BrF requires 312.0035).
Step 3: Preparation of 3-bromo-l-(3-fluorobenzyl)-6-methyl-2-
oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate
To a suspension of 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-6-
methylpyridin-2(IH)-one
(0.86 g, 0.0028 mol) in dichloromethane (15.0 mL) cooled to
30 °C, triethyl amine (0.5 mL, 0.004 mol) and trflic anhydride
(0.7 mL, 0.0042 mol) were added and stirred for 1 h. The
resulting orange solution was poured into ice cold water (25
mL) and extracted with dichloromethane ( 2 x 25 mL) The
combined organic extracts were washed with water, dried
(Na2S04) and concentrated under reduced pressure. The
resulting residue was purified by silica gel flash
chromatography using 1:1 EtOAc/hexane v/v to afford
1.0 g (85%) the title compound as a light brown solid: 1H- NMR
(CDC13/400 MHz) 8
7.32 (m,lH), 7.0 - 6.85 (m, 3H), 6.18 (s, IH), 5.32 (s, 2H),
and 2.34 (s, 3H); ESHRMS m/z 443.9492 (M+H C14HllN04BrF4S
requires 443.9528).
Step 4: Preparation of 3-bromo-l-(3-fluorobenzyl)-6-methyl-
(phenylethynyl)pyridin-2(IH)-one
A solution of 3-bromo-l-(3-fluorobenzyl)-6-methyl-2-oxo-l,2-
dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0022
mol) and phenylacetylene (0.3 mL, 0.0029 mol) in DMF (5.0 mL)
was degassed using house vacuum, and purged with argon (3
cycles).
Then added diisopropylethylamine, (0.5 mL) followed by the
addition of PdCl2(PPh3)2 (0.36 g) . The reaction mixture was
heated at 65 °C for 1.5 h under argon atmosphere. The solvents
were distilled in vacuo, and the residue was purified by
silica gel flash chromatography using EtOAc/hexane (2:3 v/v)
to afford 0.65 g (70%) of the title compound as a brown
colored amorphous solid: XH- NMR (CD30D/400 MHz). 87.59 (m,
2H), 7.45 - 7.3 (m, 4H), 7.05 - 6.85 (m, 3H), 6.44 (s, 1H) ,
5.41 (s, 2H) , and. 2.31 (s, 3H) ; 19F-NMR (CD30D/400 MHz) 5 -
116.33 (m ); ESHRMS m/z 396.0373 (M+H C21H16NOBrF 396.0399).
Step 5: Preparation of 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-
(2-phenylethyl)pyridin-2(1H)-one
To a solution of 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-
(phenylethynyl)pyridin-2(1H)-one (0.55 g, 0.0014 mol) in
EtOAc (10.0 mL) and EtOH (10.0 mL) was added Pt02 (O.OSg) and
stirred in an atmosphere of hydrogen gas at 15 psi for 30 min.
The catalyst was removed by filtration, the filtrate was
concentrated and the residue was purified by silica gel flash
chromatography using 25% EtOAc in hexane as the eluent.
The appropriate fractions were combined (visualized under UV)
and concentrated to dryness. 1H- NMR (CD30D/400 MHz) 5 7.35 (m,
1H), 7.31 - 7.16 (m, 5H) , 6.99(m, 1H), 6.91 (m, 1H), 6.81 (m,
1H), 6.20 (s, 1H), 5.41 (s, 2H), 2.94 (m, 4H), and 2.24 (s,
3H) ; 19F-NMR (CD30D/400 MHz) 6 -115.01 (m ) ; ESHRMS m/z
400.0695 (M+H C21H20NOBrF 400.0712).
Example 361
F
3-bromo-l-(3-fluorobenzyl)-4-(l-phenylethoxy)pyridin-2(IH)-
one
A mixture of 3-bromo-l-(3-fluorobenzyl)-4-hydroxypyridin-
2(IH)-one (0.2 g, 0.72mmol), potassium carbonate (0.1 g, 0.72
mmol) and (1-bromoethyl)benzene (0.19 g, 1 mmol) in DMF (3.0
mL) was stirred at room temperature for 16 h. DMF was
distilled in vacuo, and the residue was purified by flash
chromatography (EtOAc in hexane (1:3 v/v) to give pale yellow
syrup. This material was further purified by reverse-phase
HPLC using 10 - 90% acetonitrile/water gradient (30 min), at
flow rate of 100 mL/min. The appropriate fractions were
combined, concentrated to a small volume (20 mL), added EtOAc
(25 mL) and washed successively with satd. sod. bicarbonate,
water, and dried (Na2S04) . EtOAc was removed under reduced
pressure and residue was dried in vacuo to afford the title
compound (0.15 g, 52%) as an amorphous substance: XH NMR
(CD3OD/ 400 MHz) 5 7.56 (d, IH, J = 7.6 Hz), 7.4 - 7.2 (m, 5H),
7.0 (m, 3H), 6.28 (d, IH, J = 1.6 Hz), 5.65 (m, IH), 5.19 (d x
d, 2H, J = 14.8 Hz), and 1.64 (d, 3H, J - 6.4 Hz), ES-HRMS
m/z 402.0492 (M+H C2oHiBN02Br/ requires 402.0499).
Example 362
3-bromo-l-(3-fluorobenzyl)-4-[(E)-2-(4-
fluorophenyl)ethenyl]pyridin-2(IH)-one
A mixture of 3-bromo-l-(3-fluorobenzyl)-2-oxo-l, 2-
dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0023
mol), and 4-fluorostyrene (0.33 mL,, 0.0028 mol) in degassed
DMF (10 0 ml) containing diisopropyl ethyl amine (0.37 g,
0.0029 mol) was treated with PdCl2(PPh3)2 (0.32 g, 0.46 mmol)
and heated at 65 °C under argon atmosphere for 16 h. DMF was
distilled in vacuo, and the residue was purified by flash
chromatography (EtOAc/ hexane 1:4 v/v) to afford a yellow
substance which was further purified by by reverse-phase HPLC
using 10 - 90% acetonitrile/water gradient (30 min), at flow
rate of 100 mL/min. The appropriate fractions were combined,
concentrated to a small volume (20 mL), added EtOAc (25 mL)
and washed successively with satd. sod. bicarbonate, water,
and dried (Na2SO4) . EtOAc was removed under reduced pressure
and residue was dried in vacuo to afford the title compound
(0.06 g, 6%) as yellow powder: XH NMR (CD3OD/ 400 MHz) 8 7.68
(m, 3H), 7.39 (m, 3H), 7.2 - 7.0 (m, 5H), 6.82 (d, IH, J =
7.2 Hz), and 5.22 (s, 2H) ; 19F NMR(CD3OD/ 400 MHz) 8 -113.9 (m)
and -115 (m) ; ES-HRMS m/z 402.0305 (M+HC2oHi5NOF2Br, requires
402.0300).
Example 363
4-(Benzyloxy)-3-bromo-l-[(6-fluoropyridin-3-
yl)methyl]pyridin-2(IH)-one
A mixture of 4-(benzyloxy)-3-bromopyridin-2(IH)-one (0.2 g,
0.00076 mol), 5-bromomethyl-2-fluoropyridine (0.25 g, 0.0013
mol) and pot. Carbonate (0.15 g, 0.0011 mol) in DMF (3.0 ml)
was stirred at room temperature for 16 h under argon
atmosphere. DMF was distilled in vacuo and the residue was
partitioned between water (15 ml) and EtOAc (25 mL). The
organic phase was washed with water, dried (Na2S04) and
concentrated under reduced pressure. XH NMR (CD3OD/ 400
MHz) 8 8.22 (m, IH, 2.4 Hz), 7.92(m, IH), 7.82 (d, IH, J =
7.6 Hz), 7.44 - 7.31 (m 5H), 7.03( m, IH) 6.49 (d, IH, J =
7.6 Hz) ,5.29 (s, 2H) , and 5.20 (s, 2H) ; 19F NMR(CD3OD/ 400
MHz) 8 -72.30 (d, J = 6.0 Hz) and -115 (m); ES-HRMS m/z
389.0295 (M+H C18HiSN202FBr, requires 389.0309).
Example 364
3-Bromo-4- [ (2,4-difluorobenzyl)oxy]-1-(2,6-
dimethylphenyl)-6-methylpyridin-2(IH) -one
STEP1
Preparation of
1-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin-2(IH)-
one
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol),
2,6 dimethylaniline (2.4 g, 0.02 mol), and p-toluenesulfonic
acid (0.2 g) as heated at 140 °C for 3 h under nitrogen
atmosphere. The reaction mixture was cooled, triturated
with acetonitrile , cooled and filtered the solids.
XH NMR (CD3OD/ 400 MHz) 6 7.22 (m, 3H ) , 6.12 (d, IH, J - 1.6
Hz), 5.83 (d, IH, J = 1.8 Hz), 2.00 (s, 6H) , and 1.82 (s,
3H); ESMS m/z 229 (M+H).
Step 2
Preparation of
3-Bromo-l-(2,6-dimethylphenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one
A mixture of 1-(2,6-dimethylphenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one (0.4g, 0.00175 mol), and NBS (0.35
g, 0.0019 mol) in dichloromethane (10.0 ml) was stirred at
room temperature under nitrogen atmosphere. After 1 h, the.
solids were filtered, washed with dicholoromethane to give
0.42 g (78%) of the title compd as a pale yellow powder: XH
NMR (CD3OD/ 400 MHz) 6 7.22 (m, 3H ), 6.21 (a, IE), 1.99 (s,
6H), and 1.82 (s, 3H); ESMS m/z 308/310 (M+H).
Step 3
A mixture of 3-Bromo-l-(2,6-dimethylphenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one (O.lSg, 0.00049 mol), 2,4
difluorobenzyl bromide (0.12 g, 0.00058 mol) and potassium
carbonate (0.075 g, 0.00054 mol) in DMF 3.00 mL) was stirred
at room temperature uder argon atmosphere for 2h. It was
then heated at 60 °C for 30 min and concentrated in vacuo.
The residue was purified by flash chromatography. XH NMR
(CD3OD/ 400 MHz) S 7.62 (m, IH), 7.28 ( m,3H), 7.04 (m, 2H),
6.68 (s, IH), 5.35 (m, IH), 1.98 (s, 6H), and 1.92 (s, 3H);
ES-HRMS m/z 434.0574 (M+H C2iH19N02F2Br, requires 434. 0562) .
Example 365
3-Bromo-l-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy] -6-
methylpyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described for Example 364. ^ NMR (CD3OD/ 400 MHz) 6
7.58 (m, 2H), 7.23 (m, 3H), 7.15 (m, 2H), 6.62 (s, IH), 5.32
(s, 2H), 1.98 (m, 6H), and 1.91 (s, 3H); ES-HRMS m/z 416.0670
(M+H C2iH2oN02FBr; requires 416.0656).
Example 366
3-Bromo-l-(2,6-dimethylphenyl)-6-methyl-4- [(2,4,6-
trifluorobenzyl)oxy]pyridin-2(IH)-one
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 364. XH NMR (CD3OD/ 400 MHz) 8 7.19
(m, 3H), 6.95 (m, 2H), 6.69 (s, IH), 5.29 (s, 2H), 1.95 (s,
6H) , andl.90 (s, 3H) ; ES-HRMS m/z 452.0471. (M+H C21Hi8N02F3Br,
requires 452.0468).
Example 367
3-Bromo-4-[(2,6-difluorobenzyl)oxy]-1-(2,6-dimethylphenyl)-6-
methylpyridin-2(IH)-one.
The title compound was prepared by a procedure similar to
the one described for EXAMPLE 364. XH NMR (CD3OD/ 400 'MHz) 5
7.46 (m, IH), 7.24 (m, 3H) , 7.08 (m, 2H) , 6.74 (s, IH) , 5.38
(s, 2H), 1.99 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z 434.0589
(M+H C2iHi9NO2F2Br, requires 434.0562).
Example 368
\ /
3-Bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one
Step 1
Preparation of 1-(2,6-dichlorophenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one
This compound was prepared by a procedure similar to the one
described in step 1 for EXAMPLE 364. Yield: 28%, 1H NMR (CD30D)
57.6(m,2H), 7.48 (m, IH), 6.10 (dd, IH) , 5.78 (d, IH, J = 2.4 Hz),
1.91 (s, 3H); ( ES-MS m/z = 270 (MH+ );
Step 2
Preparation of 3-bromo-l-(2,6-dichlorophenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one
This compound was prepared by a procedure similar to the one
described in step 2 for EXAMPLE 364. Yield: 78%, 1H NMR (400
MHz) CD3OD 5 7.61 (m, 2H), 7.49 (m, IH), 6.2 (a, IH), and 1.91
(s, 3H); ES-MS, m/z = 348 (MH+ ).
Step 3
This compound was prepared by a procedure similar to the one
described in step 3 for EXAMPLE 364. Yield: 44%, 1H NMR (CD3OD)
67.62(d,2H, J = 8.0 Hz), 7.51 (m, 3H) , 7.15 (m, 2H) , 6.64 (s,
IH) , 5.33 (s, 2H) , and 2.0 (s, 3H) ; 19F NMR (CD3OD) 5 -166.21
(m);ES-HRMS m/z 455.9541(M+H C19Hi4N02Cl2BrF, requires 455.9564).
Example 369
3-Bromo-l-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy] -6-
methylpyridin-2(IH)-one
This compound was prepared by a procedure similar to the one
described for EXAMPLE 368.
Yield: 64%, XH NMR (CD3OD/400 MHz 8 7.62 (m, 3H), 7.48 (m, IH), 7 . 05 (m,
2H) , 6.70 (S, IH) , 5.36 (s, 2H) , and 2 . 02 (s, 3H) , 19F NMR
(CD3OD) 5 -111.43 (m) and
-115.89 (m) ; ES-HRMS m/z 473.9450 (M+H ClsH13NO2Cl2BrF2,
requires 473.9469).
Example 370
Cl
3-Bromo-l-(2,6-dichlorophenyl)-4-t(2,6-difluorobenzyl)oxy]-
6-methylpyridin-2(IH)-one
This compound was prepared by a procedure similar to the one
described for EXAMPLE 368. Yield: 78%, XH NMR (CD3OD/400 MHz)
57.62(d,2H,J = 8.0Hz),7.52 (m, 2H) , 7.1 (m, 2H) , 6.77 (s, IH) ,
and 2.04 (s, 3H) ; 19F NMR (CD3OD) 5 -117.04 (m) ; ES-HRMS m/z
473.9468 (M+H Ci9H13N02Cl2BrF2, requires 473 .9469) .
Example 371
3-Bromo-4-t(2,4-difluorobenzyl)oxy]-1-(2-methoxy-6-
methylphenyl)-6-methylpyridin-2(IH)-one
Step 1
Preparation of 4-hydroxy-l-(2-methoxy-6-methylphenyl)-6-
methylpyridin-2(IH)-one
This compound was prepared by a procedure similar to the one
described in step 1 for EXAMPLE 368. Yield: 21%, XH NMR
{CD3OD/400 MHz) 5 7.31 (m, IH), 6.94 (m, 2H), 6.05 (d,. IH, J = 2.4 Hz),
5.78 (d, IH, J * 2.4 Hz), 3.76 (s, 3H), 2.00 (s, 3H), and 1.83
(s, 3H) ; ES-HRMS m/z 246.1092 (M+H Ci4Hi6N03, requires
246.1123).
Step 2
Preparation of 3-bromo-4-hydroxy-l-(2-methoxy-6-
methylphenyl)-6-methylpyridin-2(IH)-one
This compound was prepared by a procedure similar to the one
described in step 2 for EXAMPLE 368. Yield: 58%, XH NMR
(CD3OD/400 MHz) 6 7.34 (m, IH), 6.96 m (2H) , 6.15 (s, IH) , 3.76 (s,
3H), 1.99 (s, 3H), and 1.83 (s, 3H); ESMS m/z 324 (M+H).
Step 3
This compound was prepared by a procedure similar to the one
described for EXAMPLE 368. Yield: 60%, XH NMR (CD3OD/400MHz)
87.63 (m, IH), 7.36 (m, IH) , 7.01 (m, 4H) , 6.61 (s, IH) , 5.33 (s,
2H) , 3.76 (s, 3H , 1.99(s, 3H) , and 1.95 (s, 3H) ; 19F NMR
(CD3OD/400 MHz) 6 -111.64 (m) , and -116.03 (m) ; ES-HRMS m/z
450.0532 (M+H C2iH19NO3Cl2BrF2, requires 450.0511).
Example 372
4- [3-bromo-4- [ (2,4-difluorobenzyl)oxy] -6-methyl-2-
oxopyridin-1(2H)-yl]-3,5-dichlorobenzenesulfonamide
Step 1
Preparation of 3, 5-dichloro-4-(4-hydroxy-6-methyl-2-
oxopyridin-1 (2H) -yDbenzenesulfonamide
A mixture of 4-hydroxy-6-methylpyrone ((1.2 g, 0.0095 mol),
and 2,6-dichlorosulphanilamide (2.4 g, 0.0099 mol) was heated
at 170 °C under argon for 20 min. The resulting dark colored
melt: was cooled and the crude material was first purified by
flash chromatography (EtOAc) to give partially purified
material which contained the desired product. This was
further purified by reverse-phase HPLC using 10 - 90%
CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min.
The appropriate fractions (m/z = 349 )were combined and freeze
dried to afford 0.19 g of 3,5-dichloro-4- (4-hydroxy-6-methyl-
2 -oxopyridin-l(2H) -yDbenzenesulfonatnide as pale yellow solid:
XH NMR (CD3OD/400 MHz) 88.06(s, 2H) , 6.13 (d, 1H, J = 1.6 Hz),
5.78 (d, 1H, J = 1.6 Hz), and 1.94 (s, 3H) ) ; ES-HRMS m/z
348.9819 (M+H requires 348.9811).
Step 2
A mixture of 3, 5-dichloro-4- (4-hydroxy-6-methyl-2-oxopyridin-
1 (2H) -yDbenzenesulfonamide (0.18 g, 0.0005 mol) , Nbromosuccinimide
(0.1 g, 0.00056 mol) in acetici acid (2.0 mL)
was stirred at room temperature under argon atmosphere for 1
h. Acetic acid was removed in vacuo, the residue was
dissolved in DMF (2.0 mL) , and added 2,4 dif luorobenzyl
bromide (0.128 g, 0.0006 mol), potassium carbonate (0.1 g,
0.0007 mol). The resulting mixture was stirred at room
temperature for 1 h. The solvents were distilled in vacuo,
and the residue was purified by flash chroma tography (EtOAc/
hexane 1: 3 v/v) to give 0.14 g of partially purified product.
This was further purified by reverse-phase HPLC using 10 - 90%
CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min.
The appropriate fractions (m/z = 553 ) were combined and
freeze dried to afford 0.045 g of pale yellow powder. This
was partitioned between EtOAc (25 ml) and 5% sod. bicarbonate.
The organic phase was washed with water, dried (Na2S04) and
concentrated under reduced pressure. This material was dried
invacuo to afford the title compound (0.033 g) as a white
amorphous substance :
*H NMR (CDC13/400 MHz) 57.99(s, 2H) , 7.59 (m, 1H) , 6.98 (m, 1H) ,
6.85 (m, 1H) , 6.23 (s, 1H) , 5.69 (s, 2H) , 5.28 (s, 2H) , 1.97
(s, 3H) , and 1,76 (br, 2H) ; ES-HRMS m/z 552.7214 (M+H
requires 552.9197).
Example 373
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)
6-methylpyridin-2(1H)-one
Step I
Preparation of 1-(2,6-difluorophenyl)-4-hydroxy-6-
methylpyridin-2(1H)-one
A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol)
and 2,6 difluoroaniline (9.5 g, 0.073 mol) was heated at 170
°C under argon atmosphere for 20 min. The water formed was
removed using a Dean-stark apparatus. The melt was cooled,
the dark solid was tritutrated with EtOAc., and filtered. This
material was washed thoroughly with EtOAc to afford the
desired product 1-(2,6-difluorophenyl)-4-hydroxy-6-
methylpyridin-2(1H)-one 6.5 g (35%) as a light brown solid: *H
NMR (CD3OD/400 MHz) 57.56 (m, 1H) , 7.19 (m, 2H) , 6.09 (m, 1H ),
5.77 (d, 1H, J « 2.4 Hz), and 1.99 (s, 3H); ES-HRMS ra/z
238.0679 (M+H Ci2H10N02F2 requires 238.0674).
-522TPreparation
of 3-bromo-l-(2,6-difluorophenyl)-4-hydroxy-6-
methylpyridin-2 ClH)-one '
The title compound was prepared by a procedure described in
Step2 for EXAMPLE 364.
Yield: 79%, XH NMR (CD3OD/400 MHz) 87.58 (m, IH) , 7.21 (m, 2H) ,
6.19 (d, IH, J - 0.8 Hz), 1.99 (s, 3H); ES-HRMS m/z 315.9811
(M+H C12H9N02F2Br requires 315.9779).
Step 3
This compound was prepared by a procedure described in step 3
for EXAMPLE 364.
Yield : 63%, XH NMR (CD3OD) 5 7.58 (m, 2H) , 7.23 (m, 2H) , 7,06
(m, 2H) , 6.68 (s, IH) , 5.36 (s, 2H) , and 2.10 (s, 3H) ; 19F NMR
(CD3OD) 5 -111.50(m) , -115.96 (m), and -121.93 (m) ; ES-HRMS m/z
442.0061 (M+H Ci9Hi3N02F4Br requires 442.0060).
Example 374
3-Bromo-4- [(2,4-difluorobenzyDoxy] -1- (2,6-difluorophenyl) -5-
iodo-6-methylpyridin-2 (IH) -one
A solution of 3-Bromo-4- [ (2 , 4-difluorobenzyl) oxy] -1- (2,6-
difluorophenyl) -6-methylpyridin-2 (IH) -one (0.3 g, 0.00068 mol)
and N-iodosuccinimide (0.22 g, 0.00098 mol) in dichloroethane
, containing dichloroacetic acid (0.1 mL) was heated to reflux
for 6 h under argon atmosphere. After the removal of the
solvents under reduced pressure, the residue was partitioned
between, dichloromethane (20 mL) and 5% sod. sulphite (10 mL) .
The organic phase was washed with water, dried (Na2S04) , and
concentrated under reduced pressure. The residue was purified
by flash chromatography (25% EtOAc in hexane) to afford the
title compound (0.125 g, 32 %) as a pale yellow powder: XH NMR
(CDC13/400 MHz) 5 7.68 (m, IH) , 7.46 (m, IH) , 7.11 (m, 2H) , 6.95
(m, IH) , 6.85 (m, IH) , 5.23 (s, 2H) , and 2. 38 (s, 3H) ; 19F NMR
(CDC13) 6-109.15(m), -112.95 (m) , -118.50 (m) ; ES-HRMSm/z
567.9014 (M+H CisHijNC^Brl requires 567.9027).
Example 375
3-Bromo-4- [ (2,4-difluorobenzyl) oxy] -1- [2- (dimethylamino) -4,6'
difluorophenyl]-6-methylpyridin-2(IH)-one
Step 1
3,5-difluoro-N~l~,N~l~-dimethylbenzene-l,2-diamine
To a solution of 2,4,6-trifluoronitrobenzene (2.58 g, 0.0145
mol) in THF (20.0 ml) was added a solution of N,Ndimethylamine
in THF (8.5 mL of 2M soln) and stirred for 45
min at 0 °C. It was then stirred at room temperature for 30
min and concentrated to dryness. The resulting material was
dissolved in EtOH (25 mL), added Pd/C (10%, 0.6 g) and
hydrogenated at 50 psi for 4 h. The catalyst was removed by
filtration, and the filtrate was concentrated to dryness under
reducued pressure. Te residue was partitioned between sod.
bicarbonate (10%, 25 mL) and EtOAc (30 mL). The organic phase
was washed with water, dried (Na2S04) , and concentrated to
dryness to afford the title compound (1.3 g, 50%) as a dark
colored solid: XH NMR (CDC13/400 MHz) 56.52(m, 2H) , 3.64 ( br,
2H), and 2.65 (a, 6H); ES-HRMS m/z 172.0772 (M+
requires 172.0810).
Step 2
1- [2-(dimethylamino)-4,6-difluorophenyl]-4-hydroxy-6-
methylpyridin-2(IH)-one
An intimate mixture of 4-hydroxy-6-methyl-2-pyrone (1.3 g,
0.0103 mol) , and 3,5- difluoro-N,N-dimethylbenzene-l, 2-
diamine (1.4 g, 0.008 mol) was heated at 160 °C under argon
for 15 min. The dark colored reaction mixture was cooled,
triturated with EtOAc (15 ml), and filtered. The solids were
washed with warm EtOAc, followed by hexane and dried to give
the title compound as a light blue solid (0.4 g, 14 %).
Analalytically pure sample was prepared by reverse-phase HPLC
purification using 10 -90% CH3CN/Water (30 min gradient) at a
flow rate of 100 mL/min. The appropriate fractions were
combined and freeze-dried to give the title compound: XH NMR
(CD3OD/400 MHz) 8 6.61 (m, 2H) , 6.08 (d, 1H, J « 2.0 Hz), 6.78 (d,
1H, J = 2.0 Hz), 2.69 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z
281.1084 (M+H C14H1SN202F2 requires 281.1096).
Step 2
Preparation of
3-bromo-l- [2- (dimethylamino) -4, 6-difluorophenyl] -4-hydroxy-
6-methylpyridin-2 (1H) -one
The title compound was prepared by a procedure described in
step2 for EXAMPLE 364. Yield: 71%, XH NMR (CD3OD/400 MHz)
86.62(m, 2H) , 6.17 (s, IE) , 2.67 (s, 6H) , and 1.94 (a, 3H) ; ESHRMS
m/z 359.0188 requires 359.0201).
Step 3
This compound was prepared by a procedure described in step 3
for EXAMPLE 364.
Yield : 34%, XH NMR (CDC13/400 MHz) 6 7.62 (m, IH) , 6.98 (m, IH) ,
6.85 (m, IH), 6.46 (m, 2H) , 6.11(s, IH), 5.24 (a, 2H), 2.66
(s, 6H) , and 1.98 (a, 3H) ; 19F NMR (CDC13/400 MHz) 5 -108.06
(m) , -109.60 (m) , - 115.02 (m), and -116.01 (m) ; ES-HRMS m/z
485.0451 (M+H C2iHi8N202F4Br requires 485.0482).
The title compound was prepared by stirring a suspension of
thet product of step 3, above, (0.14 g) with 4N HCl in
dioxane (0.7 mL) at room temperature for 30 min. The mixture
was concentrated to dryness. XH NMR (CD3OD/400 MHz) 87.62 (m,
IH), 7.02 (m, 2H), 6.65 (m, 3H), 5.34 (s, 2H), 2.66 (s, 6H) ,
and 2.05 (s, 3H); ESMS m/z = 485.
Example 376
3-Bromo-4-[(2,4-difluorobennyl)oxy]-1-{2,4-difluoro-6-[(2-
hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(IH)-one
The title compound was prepared by a similar procedure
described for EXAMPLE 375, replacing N,N-dimethyl group by NMethyl-
amirioethanol. *H NMR (CDC13/400 MHz) 87.59(m, IH) , 6.98
(m, IH), 6.85 (m, IH), 6.61(m, IH), 6.52 (m, IH), 6.17 (m,
IH), 5.25 (s, 2H), 3.63 (m, IH), 3.53 (m, IH), 3.26 (m, IH)
3.0 (m, 1H), 2.66 (3, 6H), and 2.09 (s, 3H); ES-HRMS m/z
515.0512 (M+H C22H2oN203F4Br requires 515.0588).
Example 377
2-({ [3-Bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2-
dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile
Step 1
2-(Bromomethyl)-5-fluorobenzonitrile
A mixture of 5-fluoro-2-methylbenzonitrile ( 2.0 g, 0.015
mol), NBS (3.2 g, 0.018 mol) and benzoylperoxide (0.25 g) in
carbontetrachloride (25.0 ml) was heated to reflux for
6 h, under argon atmosphere. The reaction mixture was cooled
and filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by flash chromatography
(5% EtOAc in hexane ) to afford 2-(Bromomethyl)-5-
fluorobenzonitrile
(1.9 g, 60%) as a colorless liquid: *H NMR (CDC13/400 MHz)
5 7.59 (m) 7.58 (m, 1H) , 7.38 (m, 1H) , and 7.25 (m, 1H)
A mixture of 3-bromo-l-(2,6-difluorophenyl)-4-hydroxy-6-
1.0 g, 0.0032 mol) , potassium carbonate (0.65 g, 0.0047 mol)
and 2- (Bromomethyl)
5-fluorobenzonitrile (0.95 g, 0.0045 mol) in dimethylacetamide
(15.0 ml) was stirred at room temperature under argon
atmosphere. After Ih, dimethylacetamide was distilled in vacuo
and the residue was partitioned between dichl or ome thane (50
ml) and 55 citric acid (15 mL) . The organic phase was washed
with water, dried (Na2S04) , and concentrated to dryness . The
resulting material was triturated with EtOAc, filtered, washed
with EtOAc and dried to afford the title compound (0.86 g,
60%) as a white powder: XH NMR (DMSO-ds/400 MHz) 87.95 (m, IH) ,
7.81 (m, IH) , 7.68 (m, 2H) , 7.37 (m, 2H) , 6.79(s, IH) , 5.45
(s, 2H) , and 2.03 (a, 3H) ; 19F- NMR (DMSO-ds) 6 -111.31 (m) , -
120.34 (m);ES-HRMS m/z 449.0094 (M+H CjoHuNaOzFaBr requires
449.0107) .
Example 378
4-{[2- (Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-l-(2,6-
difluorophenyl)-6-methylpyridin-2(IH)-one trifluoroacetate
To a cold suspension of 2-({[3-Bromo-l-(2,6-difluorophenyl) -
6-methyl-2-oxo-.l, 2-dihydropyridin-4-yl] oxy}methyl)
fluorobenzonitrile (0.3 g, 0.00066 mol) in THF (3.0 mL), was
added BH3.THF (l.o miL) . After stirring at room temperature for
15 min, the reaction, mixture was heated to reflux for 30 min
argon atmosphere. The resulting clear solution cooled,
added MeOH (2.0 mL) , concentrated under reduced pressure, and
the residue was purified by reverse-phase HPLC purification
using 10 -90% CH3CN/Water (30 min gradient) at a flow rate of
100 mL/min. The appropriate fractions (m/z= 453 M+H) were
combined and freeze-dried to give the title compound (0.16 g,
43%) as its trifluoroacetate salt: XH NMR (DMSO-cU/400 MHz)
(br, 3H) , 7.65 (m, 2H) , 7.37 (m, 4H) , 6.78 (s, 1H) , 5.42
(s, 2H) , 4.21 (br, 2H), and 2.04 (s, 3H) ; 19F NMR (DMSO-d6/400
MHz) 8 -112.96 (m), and -120.41 (m) ; ES-HRMS m/z 453.0387 (M+H
CaoHi7N303F3Br requires 453.0420).
Example 379
N- [2- ({ [3-bromo-l- (2 , 6-dif luorophenyl) -6-methyl-2-oxo-l,2-
dihydropyridin-4-yl] oxyjmethyl) -5-f luorobenzyl] urea
To a suspension of 4- { [2- (aminomethyl) -4-f luorobenzyl] oxy} -3-
bromo-1- (2 , 6-dif luorophenyl) -6-methylpyridin-2 (1H) -one
trifluoroacetate (0.13g, 0.00023 mol) in THF (3.0 mL) , was
added triethyl amine (0.07 mL, 0.0005 mol) followed by the
addition of trimethylsilylisocyanate (0.066 mL) . The
reaction mixture was stirred at room temperature for 1 h, and
the desired product was isolated by reverse -phase HPLC
purification using 10 -90% CH3CN/Water (30 min gradient) at a
flow rate of
100 mL/min. The appropriate fractions (m/z= 496 M+H) were
combined and freeze -dried,. was, partitioned
mL). The organic phase was washed with water, dried (Na2S04)
and concentrated to dryness voider reduced pressure, to afford
the title compound as a white amorphous powder (0.065 g ) : H
NMR (DMSO-d6/400 MHz) 57.62 (m, IH) , 7.52 (m, IH) , 7.35 (m,
2H), 7.09 (m, 2H), 6.77 (s, IH), 6.51 (t, IH), 5.61 (s, 2H),
5.38 (s. 2H) , 4.28 (d, 2H, J = 6.0 Hz), and 2.02 (s, 3H) ; 19F
NMR (DMSO-ds/400 MHz) 8-114.044 (m) , and -120.31 (m) ; ES-HRMS
m/z 496.0460 (M+H CziHisNaOaFaBr requires 496.0478).
Example 380
Methyl 2- ({ [3-bromo-l- (2, 6-difluorophenyl) -6-methyl-2-oxol,
2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
To solution of 4-{ [2-(aminomethyl)-4-fluorobenzyl]oxy}-3-
bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(IH)-one
trifluoroacetate (0.12g, 0.00021 mol) in dimethylacetamide
(2.0 mL) at 0 °C, was added triethylamine (0.06 mL, 0.00043
mol) followed by the addition of methy1chioroformate (0.05
mL). The reaction mixture was stirred at room temperature for
30 min under argon atmosphere. Dimethylacetamide was
distilled in vacuo and the residue was partitioned between
dichloromethane (10 mL) and 5% citric acid (10 mL). The
organic phase was washed with water, dried (Na2S04) and
concentrated to dryness. The resulting residue was purified
by flash chromatography (60%EtOAc in hexane) to afford the
title, compound (O.Q9 g.r 75A)L.. asu-avdaifest.amorphous, powder.:. 1H
7.38 (m, 2H), 7.115 (m, 2H), 6.78 (s, IH), 5.38 (s, 2H) , 4.31
(d, 2H, J = 6.0 Hz), 3.53 (s, 3H) , and 2.03(s, 3H) ; 19F NMR
(DMSO-dg/400 MHz) 5 -113.77 (m) , and -120.33 (m) ; ES-HRMS m/z
511.0508 (M+H C22Hi9N204F3Br requires 511.0475).
Example 381
N- [2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2-
dihydropyridin-4-yl]oxyjmethyl)-5-fluorobenzyl]-2-
hydroxyacetamide
To a suspension of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-
bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(IH)-one
trifluoroacetate (0.12g, 0.00021 mol) in
THF (2.0 mL) at 5 °C, was added triethyl amine (0.036 g,
0.00035 mol) followed by the addition of acetoxyacetyl
chloride (0.05 mL) . The mixture was stirred at room
temperature for 30 min, diluted with cold water (10 mL), and
extracted the products with dichloromethane ( 2 x 10 mL). The
combined organic extracts were washed with water, dried
(Na2S04) and concentrated to dryness. The residue was
dissolved in ethanol (0.5 mL), added IN NaoH (0.5 mL)and
stirred at room temperature for 1 h. The resulting solution
was diluted with water (15 mL), and extracted with
dichloromethane (2 x 10 mL). The combined dichloromethane
extracts were washed with water, dried (Na2S04) and
concentrated to dryness. The residue was purified by flash
chromatography (1% MeOH in EtOAc) to afford the title compound
(0.032 g, 30 %) as a white amorphous powder: XH NMR (CDC13/400
Hz) 87.45 (m, 2H) , 7.18 (m, IH) , 7.05 (m, 3H) , 6.23 (s, IH) ,
5.24 (s, 2H) , 4.56 (d, .2H, J = 6.4 Hz), 4.08 (d, 2H, J = 5.2
Hz), 2.79 (t, IH), and 2.08 (s, 3H;) 19F NMR (CDC13/400 MHz)
5-111.88 (m) , and -118.62 (m) ; ES-HRMS m/z 511.0482 (M+H
requires 511.0475).
Example 382
Ethyl 2-({[3-chloro-l-(2,6-difluorophenyl)-6-methyl-2-oxo-
1,2-dihydropyridin-4-yl]oxyjmethyl)-5-fluorobenzylcarbamate
To solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-
chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(IH)-one
trifluoroacetate (0.3g, 0.00057 mol) in dimethylacetamide (3.0
mL) was added N-methymorpholine (0.064 g, 0.00064 mol),
followed by addition of ethylchloroformate (0.06 mL) and
stirred at - 10 °C, for 30 min. The solvents were distilled
in vacuo and the residue was purified by reverse-phase HPLC
purification using 10 -90% CH3CN/Water (30 min gradient) at a
flow rate of 100 mL/min. The appropriate fractions (m/z= 481
M+H) were combined and freeze-dried, and the residue was
partitioned between 5% sod. bicarbonate (20 mL) and
dichloromethane (20 mL) . The organic phase was washed with
water, dried (Na2S04) and concentrated to dryness under reduced
pressure, to afford the title compound as a white amorphous
powder (0.15 g, 55%): XH NMR (CD3OD/400MHz) 57.61 (m, IH) ,
(m, 1H), 7.26 (-t, 2H, J - 8.4 Hz), 7.12 (dd, 1H), 7.05 (3d,
1H, J = 2.4 Hz), 6.74 (s, 1H), 5.40 (s, 2H), 4.42 (s, 2H),
4.05 (q, 2H, J = 7.2 Hz), 2.12 (s, 3H), and 1.21 (t, 3H, J =
7.2 Hz ) ; ES-HRMS m/z 481.1118 (M+H C23H2iN204F3Cl requires
481.1136).
Example 383
F
Isobutyl 2- ({ [3-chloro-l- (2, 6-dif luorophenyl) -6-methyl-
2 -oxo- 1,2 -dihydropyridin-4 -yl] oxy} methyl) -5-
f luorobenzylcarbamate
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 382. Yield 57 %; *H NMR (CD3OD/400
MHz) 57.61 (m, 1H) , 7.51 (m, 1H) , 7.24 (~t, 2H, J = 8.0 Hz),
7.18 (m, 1H) , 7.06 (m, 1H) , 6.74 (s, 1H) , 5.40 (s, 2H) , 4.21
(s, 2H) , 3.79 (d. 2H, J = 6.8 Hz), 2.12 (a, 3H) , 1.85 (m, 1H) ,
and 0.91 (d, 6H, J « 6.4 Hz); ES-HRMS m/z 509.1422 (M+H
requires 509.1449)
Example 384
-534-
F
Cyclopropylmethyl 2- ({ [3-chloro-l- (2, 6-difluorophenyl) -6-
rnethyl-2-oxo-l, 2-dihydropyridin-4-yl] oxyjmethyl) -5-
f luorobenzy 1 carbama t e
The title compound was prepared by a procedure similar to the
one described for EXAMPLE 382. Yield 46%; *H NMR (CD3OD/400 Hz)
57.61 (m, IH) , 7.55 (m, IH) , 7.24 (- t, 2H, J = 7.6 Hz), 7.18
(m, IH) , 7.05 (m, IH) , 6.73 (s, IH) , 5.40 (s, 2H) , 4.42 (s,
2H) , 3.83 (d, 2H, J = 7.2 Hz), 2.12 (s, 3H) , 1.1 (br, IH) ,
0.58 (-d, 2H) , and 0.22 (- d, 2H) ; ES-HRMS m/z 507.1316 (M+H
requires 507.1293).
Example 385
CF3COOH
1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one trifluoroacetate
Step 1
1- [ (4-amino-2-methylpyrimidin-5-yl) methyl] -4-hydroxy-6-
methylpyridin-2 (1H) -one
A mixture of 4-hydroxy-6-methyl-2-pyrone (0.9 g, 0.007 mol)
and 4-amino-5-aminomethyl-2-methylpyrimidine (1.0 g, 0.007
mol) in water (10.0 ml) was heated at 100 °C for 1 h under
argon atmosphere. The reaction mixture was cooled, and
filtered the yellow precipitate. It was washed successively
with cold water, ethanol, and dried in vacuo to afford the
title compound (I. 01 g, 51%) as a pale yellow powder: *H NMR
(DMSO-dg/400 MHz) 87.62 (s, 1H) , 7.04 (s, 1H) , 5.83 (d, 1H, J =
2.0 Hz), 5.58 (d, 1H, J = 2.0 Hz), 4.92 (s, 2H) , 2.24 (s, 3H) ,
and 2.22 (s, 3H) ; ES-HRMS m/z 325.0304 (M+H Ci2Hi4N402Br requires
325.0295) .
Step 2
1- [ (4-amino-2-methylpyrimidin-5-yl)methyl] -3-bromo-4-
hydroxy-6-methylpyridin-2(1H)-one
A mixture of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl] -4-
hydroxy-6-methylpyridin-2(lH)-one ( 0 . 5 g , 0.002 mol), and NBS
(0.4, g-, a.002. raol.) ia.glacial acetic actct (5.Q mil
at room temperature for 1 h under argon atmosphere. Acetic
acid was removed in vacuo, residue was triturated with EtOAc
containing 10 % EtOH, and filtered. The pale yellow
precipitate was washed with EtOAc containing 10% EtOH and
dried in vacuo to afford the title compound (0.47 g, 725) as
a pale yellow powder:
*H NMR (CD3OD/400 MHz) 67.62(s, 1H) , 6.09 (s, 1H) , 5.15 (s, 2H) ,
2.42 (s, 3H) , and 2.33 (a, 3H) ; ES-HRMS m/z 247.li60 (M+H
requires 247.1190).
Step 3
To suspension of 1- [ (4 -amino-2-methylpyrimidin-5-yl) methyl] -3-
bromo-4-hydroxy-6-methylpyridin-2 (1H) -one (1.0 g, 0.0031 mol)
and potassium carbonate (0.0 g, 0.004 mol) in
dimethylacetamide (10.0 mL) was added 2,4 difluorobenzyl
bromide (0.62 mL, 0.0048 mol) and stirred at room temperature
for 2 hours. Dimethylacetamide was distilled in vacuo and the
residue was purified by reverse -phase HPLC using 10 - 90%
CHaCN/Water (30 min gradient) at a flow rate of 100 mL/min.
The appropriate fractions (m/z = 566 )were combined and freeze
dried to afford 0.65 g (37 %) of the title compound as its
trifluoroacetate salt: XH NMR (CD3OD/400 MHz) 5 7.65 (s, 1H) , 7.58
(m, 1H) , 7.05 (m, 2H) , 6.61 (s , 1H) , 5.31 (s, 2H) , 5.18 (s,
2H) , 2.51 (s. 3H) , and 2.46 (s, 3H) ; 1H NMR (CD3OD/400 MHz)
5-111.39 (m ), and -115.98 (m) ; ES-HRMS m/z 451.0590 (M+H
C19H18N402BrF2 requires 451.0576).
Example 386
1- [ (4-amino-2-methylpyrimidin-5-yl)methyl] -3-bromo-4- [ (2,4-
dif luorobenzyl) oxy] -6-methylpyridin-2 (IH) -one hydrochloride
Ion exchange (25g) BioRad AG 2X8 resin (200-400 mesh chloride
form) was washed with 1M HCI (150 mL) , and equilibrated for
2.5 h. This resin was loaded onto a column, and added a
solution of Example 385 (3.3 g, 5.8 mmol) in water/CH3CN
(1:1) . The column was eluted slowly over 1 h, fractions were
collected, and freeze dried to afford the desired HCI salt
(2.2 g, 72%) as a white solid: Hl-NMR (CD3OD, 400Hz) 5 7.60 (m,
2H) , 7.21 (m, 2H) , 6.62 (s, IH) , 5.31 (s , 2H) , 5.18 (s, 2H) ,
2.52 (s, 3H) , 2.47 (s,3H); ES-HRMS m/Z 451.0544/453.0577 (M+H
requires 451.0581/453.0563).
Example 387
1- [(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[ (2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one trifluoroacetate
Step 1. Preparation of 1-[(4-amino-2-methylpyrimidin-5-
yl)methyl]-3-chloro-4-hydroxy-6-methylpyridin-2(IH)-one
1H NMR (CD3OD, 400Hz) 8 7.62 (m, IH) , 6.11 (s, IH) , 5.13 (s,
2H), 2.66 (S, 3H), 2.42 (s,3H); ES-HRMS m/z 281.0793 (M+H
C12Hi3N402Cl requires 281.0800).
Step 2. Preparation of 1- [ (4-amino-2-methylpyrimidin-5-
yl)methyl]-3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one trifluoroacetate
The title compound was prepared by a procedure similar to the
one described for Example 385 step 2. XH NMR (CD3OD, 400Hz) 5
7.59 (m, 2H), 7.03 (m, 2H), 6.63 (s, IH), 5.31 (s, 2H) , 5.17
(s, 2H), 2.48 (s, 3H) , 2.46 (s, 3H); ES-HRMS m/z 407.1097
(M+H C19Hi7N402ClF2 requires 407.1081) .
Example 388
1- [(4-amino-2-methylpyrimidin-5-yl)methyl] -3-chloro-4- [ ( 2 , 4 -
difluorobenzyDoxy] -6-methylpyridin-2 (IH) -one hydrochloride
Ion exchange (12.Sg) BioRad AG 2X8 resin (200-400 mesh
chloride form) was washed with 1M HCI (150 mL), and
equilibrated for 2.5 h. This resin was loaded onto a column,
and added a solution of EXAMPLE 387 (1.2 g, 2.4 mmol) in
water/CH3CN (1:1) . The column was eluted slowly over 1 h,
fractions were collected,and freeze dried to afford the
desired HC1 salt (1.03 g, 97%) as a white solid: 1H NMR (CD3OD,
400Hz) 5 7.60 (m, 2H) , 7.04 (m, 2H), 6.64 (a, IH), 5.31 (a,
2H), 5.17 (s, 2H), 2.50 (a, 3H) , 2.47 (a, 3H); ES-HRMS m/z
407.1079 (M+H C19Hi7N402ClF2 requires 407.1081).
Example 389
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(lH-indazol-5-
ylmethyl)-6-methylpyridin-2(IH)-one trifluoroacetate
To a mixture of 3-bromo-4-[ (2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one (0.55 g, 0.0017 mol) and 5-
(bromomethyl)-l-tetrahydro-2H-pyran-2-yl-lH-indazole (0.5 g,
0.0017 mol) in THF (10.0 mL) was added NaH (0.045 g, 0.0019
mOl) and heated at
60 °C for 16 h under argon atmosphere. THF was distilled under
reduced pressure, and the residue was suspended in EtOAc,
added acetic acid (0.5 mL) and the product was purified by
flash chromatography (80% EtOAc in hexane). The appropriate
fractions were combined and concentrated to give an amorphous
substance (0.31 g). This was stirred with trifluoroacetic
(0.5 mL) for 30 min, the solution was diluted with
ace.t.Qffitrile (5 mL) and the product was isolated by reverse-
phase HPLC using 10 - 90% CH3CN/Water (30 min gradient) at a
flow rate of 100 mL/min. The appropriate fractions (m/z = 460
) were combined and freeze dried to afford 0.14 g (52%) of
the title compound as its trifluoroacetate salt: 1H NMR
(CD3OD/400 MHz) 5 7.97 (s, IH) , 7.62 (m, IH) , 7.51 (m, IH) , 7.45
(s, IH), 7.25 (m, IH), 7.03 (t, 2H) , 6.49 (s, IH) , 5.53 (s,
2H) , 5.29 (s, 2H), and 2.40 (s, 3H) ; 19F NMR (CD3OD/400 MHz) 5 -
111.69 (m) , -116.09 (m) ; ES-HRMS m/z 460.0432 (M+H
requires 460.0467).
Example 390
N-l~-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}-2-methylpyrimidin-4-yl)glycinamide
trifluoroacetate
To a solution of BOC-Gly-OH (0.19 g, 0.0011 mol) inrDMF (2.0
mL), was added N-methylmorpholine (0.14 mL, 0.0011 mol),
followed by the addition of isobutylchloroformate (0.15 mL,
0.0011 mol) and stirred at -10 °C for 15 min. Then added a
solution of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-
bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one
trifluoroacetate (0/125 g, 0.00022 mol) in DMF (2,0 mL)
containing diisopropylethylamine (0.1 g, 0.006 mL) and the
resulting mixture was stirred for 16 h, at room temperature.
The solvents were distilled in vacuo and the residue was
purified by by reverse-phase HPLC using 10 - 90% CH3CN/Water
(30 min gradient) at a flow rate of 100 mL/min. The
appropriate fractions (m/z = 608/610) were combined and freeze
dried to afford 0.025 g of white powder. This was stirred
with trifluoroacetic acid (0.5 mL) for 1 h and product was
isolated by reverse-phase HPLC using 10 - 90% CH3CN/Water
min gradient) at a flow rate of 100 mL/min. The appropriate
fractions (m/z = 508/510) were combined and freeze dried to
afford the title compound (0.02 g) as a white powder: XH NMR
(CD3OD/400 MHz) S8.18(s, IH) , 7.61 (m, IH) , 7.02 (m, 2H) , 6.59
(a, IH), 5.30 (s, 4H), 4.23 (s, 2H) , 2.60 (s, 3H), and 2.47
(S, 3H) ; ES-HRMS m/z 508.0797 (M+H C2iH2iNs03BrF2 requires
508.0790).
Example 391
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-
(methylthio)pyrimidin-4-yl]methyl}pyridin-2(IH)-one
Step 1
Br
4- (Bromomethyl) -2- (methylthio)pyrimidine
To a solution of 4-methyl-2-methylthiopyrimiaine (12.6 g, 0.09
mol) in acetic acid (50.0 mL) was added bromine (3.5 mL, C.1I
mol) and heated at 80 °C under argon atmosphere for 2 h.
Acetic acid was distilled in vacuo, the residue was triturated
with dichloromethane (100.0 mL) and poured into satd.
sod.bicarbonate solution (200.0 mL) . Additional
dichloromethane (100.0 ml) was added and stirred for 15 min.
The organic phase was washed with water ( 3 x 1 0 0 mL), dried
(Na2S04) , and concentrated under reduced pressure. The dark
colored residue was purified by flash chromatography
(EtOAc/hexane 1:4 v/v) to afford 4-(bromomethyl)-2-
(methylthio)pyrimidine (10.9 g, 55%) as a dark colored liquid:
1H NMR (CDC13/400 MHz) 5 8.50 (d, 1H, J = 4.8 Hz), 7.09 (d, 1H, J
= 4.8 Hz), 4.34 (s, 2H) , and 2.56 (s, 3H); ESMS m/z 219 (M+H).
Step 2
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one 5.0 g, 0.015 mol) and 4-
(Bromomethyl)-2- (methylthio)pyrimidine (4.0 g, 0.018 mol) in
THF (50.0 mL) was added NaH (0.4 g, 0.0017) and stirred at 55
°C under argon for 16 h. The reaction mixture was
concentrated under reduced pressure and the residue was
partitioned between 5% citric acid (25 mL) and EtOAc (50 mL).
A precipitate was formed, it was filtered, washed with water,
EtOAc, and dried in vacuo to afford the title compound
(4.2 g, 59 %) as a light brown powder, 1E NMR (CD3OD/400 MHz)
6 8.45 (d, 1H, J = 5.2 Hz), 7.6 (m, IE), 7.06 (d over m, 2H, J =
5.2 Hz), 6.54 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s,
3H) , 2.33 (s, 3H) ; ES-HRMS m/z 468.0173 (M+H C19H17N302BrSF2
requires 468.0187).
Example 392
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{ [2-
(methylsulfonyl)pyrimidin-4-yl]methyl}pyridin-2 (IH) -one
*'-«
A suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy}-6-methyll-{
[2-(methylthio)pyrimidin-4-yl] methyl}pyridin-2 (IH)-one 0.28
g, 0.0006 mol), and magnesium monoperoxyphthalate hexahydrate
90.6 g, 0.0012 mol) in acetonitrile (8.0 ml) and water (2.0
ml) was stirred at room temperature for 16 h. The resulting
clear solution was concentrated under reduced pressure, and
the residue was partitioned between dichloromethane (30 mL)
and water (20 mL). The organic phase was washed with water,
dried (Na2S04) and concentrated to afford the title compound
(0.27 g, 90%) as a pale yellow substance: XH NMR (CD3OD/400
MHz) 58.91 (d, IH, J = 5.2 Hz), 7.63 (d over m, 2H, J = 5.2
Hz), 7.03 (m, 2H), 6.58 (a, IH), 5.54 (s, 2H), 5.33 (s, 2H),
3.28 (s, 3H) , and 2.49 (s, 3H) ; 19F NMR (CD3OD/400 MHz) 5-111.58
(m ), -115.98 (m);ES-HRMS m/z 500.0113 (M+H C19H17N304BrSF2
requires 500.0086).
Example 393
CF3COOH
4-{ [3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitrile
trifluoroacetate
A mixture of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-
{ [2- (methylsulfonyl)pyrimidin-4-yl]methylJpyridin-2(IE)-one
(1.0 g, 0.002 mol ) and NaCN (0 .,15 g, 0.0031 mol) in DMF (5.0
mL) was stirred at room temperature for 2 h under argon
atmosphere. DMF was distilled in vacuo, the residue was
triturated with acetonitrile (10 mL) and water (10 mL), and
filtered the red colored precipitate. It was washed with
acetonitrile and dried to afford the title compound (0.26 g)
The washings and the fitrate were combined and purified by
reverse-phase HPLC using 10 - 90% acetonitrile/water gradient
(30 min.) at a flow rate of 100 mL/min to give an additional
0.5 g of the title compound: XH NMR (CD3OD/400 MHz) 88.83 (d,
1H, J = 5.2 Hz), 7.62 (d over m, 2H, J = 5.2 Hz), 7.00 (m,
2H), 6.58 (s, 1H), 5.46 (a, 2H), 5.33 (s, 2H), and 2.47 (s,
3H) ; 19F NMR (CD3OD/400 MHz) 5 - 111.64 (m) , -116.03 (m) ; ES-HRMS
m/z 447.0278 (M+H C19H14N402BrF2 requires 447.0263).
Example 394
CF3COOH
4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-1-(2,6-
difluorophenyl)-6-methylpyridin-2(IH)-one trifluoroacetate
To a solution of 4-{ [3-3romo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitrile
trifluoroacetate (0.3 g. o;oo066mol) in a solvent mixture of
EtOAc (15.0 mL) and acetic acid (5.0 mL), was added Pd/C (10
% , 0.18 g) and stirred in an atmosphere of-hydrogen at 15. psi
for 2 h. The catalyst was removed by filtration . The
filtrate was concentrated to dryness and the residue was
residue was purified by reverse-phase HPLC using 10 - 90%
acetonitrile/water gradient (30 min) at a flow rate of 100
mL/min. The appropriate fractions (m/z = 451) were combined
and freeze dried to afford (0.32 g, 645) of the title compound
as its trif luoroacetate salt: XH NMR (DMSO-d6/400 mHz) 58.78 (d,
IH, J = 5.2 Hz), 8.28 (br, 2H), 7.62 (m, IH), 7.38 (m, IH),
7.25 (d, IH, J = 5.2 Hz), 7.18 (m IH), 6.62 (s, IH), 5.32 (s,
2H) , 5.29 (s, 2H) , 4.24 (s, 2H) , and 2.46 (s, 3H) ; 19F NMR
(DMSO-d6/400 MHz) 5 - 109.59 (m) , -113.67 (m) ; ES-HRMSm/z
451.0530 (M+H C19H18N402BrF2 requires 451.0576).
Example 395
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(2-methoxypyrimidin-4-
yl)methyl]-6-methylpyridin-2(IH)-one trifluoroacetate
A solution of 4- { [3 -3romo-4- [ (2 , 4-dif luorobenzyl} oxy] -6-
methyl-2-oxopyridin-l (2H) -yl]methyl}pyr'imidine-2-carbonitrile
trifluoroacetate (0.13 g, 0.00023 mol) in MeOH (2.0 mL) was
treated with IN NaOH (0.5 mL). After stirring at room
temperature for 3h, it was heated at 60 °C for ap^additional
3 h and left overnight room temperature. The resulting
solution was diluted with acetonitrile, and purified by
reverse-phase HPLC using 10 - 90% acetonitrile/water gradient
(30 min) at a flow rate of 100 mL/min. The appropriate
fractions (m/z = 452 ) were combined and freeze dried to
afford the title compound ( 0.015 g) as a white powder: ^H
NMR (CD3OD) 88.84 (d, IH, J = 5.2 Hz)
7.62 (d, IH, J = 5.2 Hz), 7.05 (m, 2H), 6.57 (s, IH), 5.49 (s,
2H) , 5.32 (s, 2H) , 3.96 (s, 3H), and 2.49 (s, 3H) ; ES-HRMS m/z
452.0440 (M+H C19H17N303BrF2 requires 452.0416).
Example 396
Methyl 4-{[3-bromo-4-[(2,4-difluorobenryl)oxy]-6-methyl-
2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carboxylate
trifluoroacetate
The title compound was obtained as a second product in the
formation of 3-Bromo-4- [ (2, 4-dif luorobenzyl) oxy]--l- [ (2-
methoxypyrimidin-4-yl)methyl]-6-methylpyridin-2(1H)-one
trifluoroacetate. XH NMR (CD3OD/400 MHz) 88.46 (d, 1H, J » 5.2
Hz), 7.62 (m, 1H), 7.00 (m 2H), 6.93 (d, 1H, J=5.2Hz), 6.55
(s, 1H), 5.39 (s, 2H), 5.32 (a, 2H), 3.85 (s, 3H), and 2.44
(s, 3H) ; ES-HRMS tn/z 480.0340 (M+H C2oHi7N3O4BrF2 requires
480.0365).
Example 397
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(2-hydroxypyrimidin-4-
yl)methyl]-6-methylpyridin-2(1H)-one trifluoroacetate
A mixture of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]methyl}pyrimidine-2-carbonitrile
trifluoroacetate (0.2 g, 0.00035 mol) potassium fluoride on
aluminum oxide (0.25 g) in t-butand (5.0 mL) was refluxed for
4 h under argon atmosphere. The reaction mixture was cooled,
filtered the precipitate and washed with ethanol. The
combined filtrate and washings were concentrated to dryness
and the residue was purified by reverse-phase HPLC using 10 -
90% acetonitrile/water gradient (30 min) at a flow rate of 100
mL/min. The appropriate fractions (m/z = 452) were combined
and freeze dried to afford the title compound ( 0.05 g) as a
white powder:
-E NMR (DMSO-ds/400 Mz) 57.85 (d, 1H J = 6.4 Kz) , 7.64 (m, 1H) ,
7.30 (m 1H), 7.15 (m 1H), 6.55 (s, 1H), 6.22 (d, 1H, J = 6.4
Hz), 5.28 (s, 2H) , 5.12 (d, 2H) , and 2.29 (s, 3H) ; 19F- NMR
(DMSO-d6/400 MHz) 5 - 109.69 (m) , and -113 .67 ' (m) ; ES-HRMS m/z
438.0228 (M+H C1BH15N303BrF2* requires 438.0259).
Example 398
4-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H)-yl]methyl}pyrimidine-2-carboxamide trifluoroacetate
The title compound was obtained by a procedure described for
Example 397. XH NMR (DMSO-ds/400 MHz) 58.82 (d, 1H J = 5.2 Hz),
8.01 (br, 1H), 7.79 (br 1H), 7.64 (m, 1H), 7.34 (m , 2H), 7.16
(m 1H), 6.62 (s, 1H) , 5.36 (s, 2H), 5.30 (s, 2H), and 2.38 (s,
3H) ; 19F NMR (DMSO-d€/400 MHz) 5 - 109.64 (m) , and -113.66 (m) ;
ES-HRMS m/z 465.0385 (M+H requires 465.0368).
Example 399 N NHCOOMe
Methyl (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-
oxopyridin-1(2H)-yl]methylJpyrimidin-2-yl)methylcarbamate
To a solution of 4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-
bromo-1-(2,6-difluorophenyl)-6-methylpyridin-2(IH)-one
trifluoroacetate (0.13 g, 0.00023 mol) in dimethylacetamide
(1.0 mL), was added triethylamine (0.04 mL, 0.0003 mol),
followed by the addition of methylchloroformate (0.05 .mL) 'and
stirred at 0 °C for 30 min under argon atmosphere. The
reaction mixture was diluted with water (10 mL) and extracted
with EtOAc (2 x 20 mL), The combined organic extracts were
washed with water, dried (Na2S04) and concentrated to dryness.
The resulting residue was purified by flash chromatography (5%
MeOH in EtOAc) to afford the title compound (0.055 g, 37%) as
pale yellow powder: XH NMR (DMSO-ds/400 MHz) 68.65 (d, IH J =
5.6 Hz), 7.63 (IH), 7.5 (m, IH), 7.28 (m IH), 7.13 (m, 2H),
6.59 (s, IH), 5.28 (s, 4H), 5.26 (d, 2H, J = 6.0 Hz), and 2.46
(S, 3H) ; 19F NMR (DMSO-ds/400 MHz) 5 - 109.64 (m) , and -113.71
(m) ; ES-HRMS m/z 509.0621 (M+H C21H2oN404BrF2 requires 509.0630).
Example 400
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-
methylpyrazin-2-yl)methyi]pyridin-2(1H)-one
Stet) 1
4-hydroxy-6-methyl-l-[(5-methylpyrazin-2-yl)methyl]pyridin-
2(1H)-one
A mixture of 4-hydroxy-6-methyl-2-pyrone (5.0 g, 0.04 mol) and
5-aminomethyl-2-methylpyrazine (5.0 g, 0.041 mol) in water
(25.0 ml) was heated at 100 °C for 1 h under argon atmosphere.
The reaction mixture was cooled, and filtered the yellow
precipitate. It was washed with ethanol, and dried in vacuo
to afford the title compound (5.8 g, 63%) as a pale yellow
powder: XH NMR (DMSO-d6/400 MHz) 510.43 (br, 1H) , 8.38(d, 2H, J
= 5.2 Hz), 5.77 (d, 1H, J = 2.0 Hz), 5.58 (d, 1H, J = 2.0 Hz),
4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ESMS m/z 232
(M+H).
Step 2
3-Bromo-4-hydroxy-6-methyl-I-[(5-methylpyrazin-2-
yl)methyl]pyridin-2(IH)-one
The title compound was prepared by a procedure described in
step 2 for Example 385.
Yield: 64%, XH NMR (CD3OD/400 MHz) 58.47 (s, 1 H ) , ' 8 . 4 2 (s, IH) ,
6.07 (s, IH) , 5.38 (s, 2H) , 2.51 (s, 3H) , and 2 . 4 4 (s, 3H) ,
ESMS m/z 310 and 312 (M+H).
Step 3
To a mixture of 3-Bromo-4-hydroxy-6-methyl-l-[ (5-
methylpyrazin-2-yl)methyl]pyridin-2(IH)-one (0.45 g, 0.0015
mol), and potassium carbonate (0.25 g, 0.0018 mol) in
dimethylacetamide (5.0 mL) was added 2,4 difluorobenzyl
bromide (0.25 mL. 0.0019 mol)and stirred at room temperature
under argon for 1 h. Dimethylacetamide was distilled in
vacuo and the residue was partitioned between CH2C12 (20 mL)
and water (20 mL) . The organic phase was washed with water,
dried (Na2S04) and concentrated under reduced pressure. The
resulting material was purified by flash chromatography
(EtOAc/hexane 4:1 v/v) as the eluent. The appropriate
fractions (m/z = 451/453) were combined and concentrated under
reduced pressure to give a white (0.25 g, 38% )solid. XH NMR
(CD3OD/400 MHz) 58.49 (s, IH) , 8.40 (s, IH) , 7.60 (m, IH) , 6.99
(m, 2H) , 6.51 (s, IH) , 5.42 (s, 2H) , 5.29 (s, 2H) , 2.54 (s,
3H) , and 2.50 (s, 3H) ; 19F NMR (CD3OD/400 MHz) 6-117.70 (m) , and -
116.09 (m) ; ES-HRMS m/s 436.0435 (M+H C:sH17N30;ErF2 requires
436 .0467) .
Examole 401
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyrazin-2-
ylmethyl)pyridin-2(1H)-one
2- Chloromethylpyrazine
A mixture of 2-methylpyrazine (3.5 g, 0.037 mol), NCS (6.3 g,
0.047 mol) and benzoyl peroxide (0.05 g) was heated to reflux
for 16 h under argon atmosphere. It was filtered and the
filtrate was concentrated to dryness. The resulting residue
was purified by flash chromatography using 30 % EtOAc in
hexane to afford 2-chloromethylpyrazine as a dark colored
liquid (1.7 g, 36 5): XH NMR (CD3OD/400 MHz) 88.75 (d, 1H, J =
1.2 Hz), 8.58 (m, 1H), 8.56 (m, 1H), and 4.75 (s, 2H) ; ESMS
tn/z = 129 (M+H) .
Step 2
3-Bromo-4-[(2, 4-difluorcbenzyl) oxy] -6-methylpyridin-2(IH)-one
(1.8 g, 0.0055 mol) and 2- chloropyrazine (0.8 g, 0.00625)
were suspended in THF (25 mL), then added NaH (0.15 g, 0.0062
mol), KI (0.1 g) and the mixture was heated at 65 °C under
argon atmosphere for 16 h. The reaction mixture was cooled,
added acetic acid (0.5 mL) and concentrated to dryness under
reduced pressure. The residue was stirred with a mixture of
water (50 mL) and EtoAc (25 mL) and filtered the precipitate.
It was washed with water, and acetonitrile an dried in vacuo
to afford 1.7 g of light brown powder. ^E NMR (CD3OD/400 MHz)
58.65 (d, IH) , 8.49 (m, IH), 8.47 9m, IH) , 7.61 (~q, IH) , 7.02
(m, 2H), 6.52 ^(s, IH), 5.47 (s, 2H), 5.23 (s, 2H), and 2.53
(s, 3H);
F NMR (CD3OD/400 MHz) 5-111.72 (m), and -116.0.7 (m.) ; ES-HRMS rn/z
422.0283 (M+H CiaHisNsOaBrFa requires 422.0310) .
Example 402
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(IH)-one
Step 1
N. N
Ethyl 5-methylpyrazine-2-carboxylate
A solution of 5-methylpyrazine-2-carboxylic acid =; n
0.109 mol) in euhancl (70.0 mL) containing (1.5 g, 0.0079 mcl)
was heated to reflux for 4 h under argon atmosphere. The dark
colored solution was cooled, added sod.bicarbonate (1.0 g) and
concentrated under reduced pressure. The residue was
partitioned between water (50 mL) and EtOAc (100 mL). The
organic layer was washed with water (2 x 25 mL), dried
(Na2S04) , and concentrated under reduced pressure to afford
ethyl 5-methylpyrazine-2-carboxylate (12.05 g, 67%) as an
orange colored liquid: XH NMR (CD3OD/400 MHz) S9.1 (d. 1H, J =
1.2 Hz), 8.62 (d, 1H, J = 1.2 Hz), 4.45 (q, 2H, J. = 7.2 Hz),
2.63 (s, 3H), and 1,41 (t, 3H, J = 7.2 Hz); ESMS m/z 167
(M-fH) .
Step 2
Ethyl 5-(bromomethyl)pyrazine-2-carboxylate
A solution of ethyl 5-methylpyrazine-2-carboxylate (12.0 g,
0.072 mol) in glacial acetic acid (60 mL) containing bromine
(4.0 mL) was heated at 80 °C under anhydrous conditions for 45
min. After the removal of acetic acid in vacuo, the residue
was partitioned between saturated, bicarbonate (100 mL) and
EtOAc (3x30 mL). The combined EtOAc extracts were washed
with water (2 x 25 mL) , dried (Na2SO4) , and concentrated under
reduced pressure. The resulting liquid was purified by flash
chromatography (20 %EtOAc in hexane) to afford ethyl-
(Sbromomethylpyrazine-2-carboxylate (7.7 g, 44%) as an orange
colored liquid: XK NMR (CD3OD/400 MHz) 59.18 (d. IK, J = 1.2 H z ) ,
8.85 (d, 1H, J = 1.2 H z ) , 4.71 (d, 2H), 4.47 (q, 2H, J = 7.2
H z ) , and 1.42 (t, 3H, J = 7.2 Hz); ES-HRMS m/z 244.9942 (M+K
CBKioN202Br requires 244.9920).
Step 3
Ethyl 5-{[3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methylJpyrazine-2-carboxylate
To a mixture of 3-bromo-4-[(2 , 4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one (6.0 g, 0.018 mol) and ethyl 5-
(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02 mol) in THF
(50.0 mL) was added NaH (0.5 g) and heated at 55 °C under
argon atmosphere for 3 h. The reaction mixture was cooled ,
added acetic acid (1.2 ml)and concentrated under reduced
pressure. The residue was triturated with water and filtered
the solid. It was washed with water, followed by ethanol and
dried in vacuo to afford the title compound (3.0 g, 78% )as
alight brown powder: 1H NMR (CD3OD/400 MHz) 89.10 (d. 1H, J = 1.2
Hz), 8.77 (d, 1H, J - 1.2 Hz), 7.61 (m, 1H), 7.01 (ra 2H), 6.54
(a, 1H), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J = 6.8 Hz),
2.52 (s, 3H) , and 1,39 (t, 3H, J = 6.8 Hz); 19F NMR (CD3OD/400
MHz) 5-111.64 (m), and -116.04 (m) ; ES-HRMS m/z 494.0482 (M+H
C21Hi9N304BrF2 requires 494.0522).
Tc a suspension of ethyl 5- { [3-fcrcmo-4- [ (2, 4-
difluorober-zyDoxy] -6-methyl-2-oxopyridin-i (2K) -
yl]methyl}pyra2ine-2 -carboxylate (2.0 g, 0.004 mol) in tbutanol
(15,0 mL and TH? (5.0 mL) was added NaBH4 (0.13 g,
0.0047 mol) and the mixture was stirred at room temperature
for 16 h under argon atmosphere. It was cooled, added MeOH
(5.0 mL) and acetic acid {1.0 mL) and concentrated to dryness
The residue was triturated with water and filtered. It was
washed with water, dried in vacuo and purified by flash
chromatography (1% MeOH in EtOAc to afford the title compound
(0.75 g, 41%) as a pale yellow powder: XH NMR (CD3OD/400 MHz)
6 8.58 (d. 1H, J = 1.6 Hz) , 8.56 (d, 1H, J = 1.6 Hz) , 7.6 (m,
1H) , 7.01(m, 2H) , 6.52 (a, 1H) , 5.46. (s, 2H) , 5.29 (s, 2H) ,
4.71 (s, 2H) , and 2.54 (s, 3H} ; 19F NMR (CD3OD/400 MHz)
5 -111.70 (m), and -116.06 (m) ; ES-HRMS m/z 452.0394 (M+H
requires 452.0416).
Example 403
CF3COOH
3-Brorao-4-[(2,4-difluorobenzyl)oxy]-1-({5-
[(dimethylamino) methyl]pyrazin-2-yl}methyl)-6-methylpyridin-
2(1H)-one trifluoroacetate
3-Bromo-l-{ [5-(chloromethyl)pyrazin-2-yl] methyl}-4- [(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one
Cyanurylchloride (0.42g, 0.0023 mol) was added to DMF (0.52
mL) and stirred at room temperature for 15 min. Then added
dichloromethane (15 mL) followed by the addition of 3-Bromo-4-
['(2, 4-dif luorobenzyl) oxy] -l-{ [5- (hydroxymethyl) pyrazin-2-
yl]methyl}-6-methylpyridin-2(IH)-one 1.0 g, 0.0022 mol) and
reaction mixture was stirred at room temperature under argon
atmosphere. After 1 h, an additional 1.0 mL of DMF was added
and the reaction was allowed to proceed for another hour, when
a clear solution was obtained. The solution was diluted with
dichloromethane (20 mL) and washed with water, dried (Na2S04) ,
and concentrated to dryness under reduced pressure. The
residue was triturated with EtOAc, filtered, washed with EtOAc
and dried to afford 0.79 g ( 77%) of the title compound as a
pale yellow powder: 1E NMR (CD3OD/400MHz) 5 8.66 (s, 2H) , 7.73
(m, IH), 7.05 (m, 2H), 6.56 (s, IH), 5.52 (s, 2H), 5.33 (s,
2H), 4.74 (s, 2H), and 2.57 (s, 3H); ES-HRMS m/z 470.0051 (M+H
Ci9Hi6N302BrClF2 requires 470.0077).
Step 2
A suspension of 3-Bromo-1-{[5-(chloromethyl)pyrazin-2-
yl]methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(IH)-
one (0.25 g, 0.00053 mol) in TH-F (1.0 mL) was treated with N,
N, -dimethyl amir.e (1.0 mL of 2M soln in THF) and stirred a~
room temperature for 16 h. The reaction mixture was
concentrated and the title compound was isolated by reverse -
phase HPLC using 10 - 90% acetonitrile/water gradient (30 min)
at a flow rate of 100 mL/min. The appropriate fractions (m/z
= 479) were combined and freeze dried to afford the title
compound (0.27 g, 87%) as a white powder: XH NMR
(CD3OD/400MHz) 58.78(d. IE, J Hz), 8.56 (d, IH, J = 1.2 Hz),
7.61 (m IH) , 7.01 (m, 2H) , 6.55 (s, IH) , 5.49 (s, 2H) , 5.30, 4.52 (s, 2H) , 2.94 (s, 6H) and 2.57 (s, 3H) ; 19F NMR
(CD3OD) = 5-111.56 (m) and -116.02 (m) ; ES-HRMS m/z 479.0885 (M+H
requires 479.0889).
Example 404
Me
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-[(5-{[(2-
hydroxyethyl)(methyl)amino]-methyl}pyrazin-2-yl)methyl]-6-
methylpyridin-2(IH)-one trifluoroacetate
The title compound was prepared in a similar manner as
described for Example 403, substituting N-methylaminoethanol
for N, N-dimethylamine. Yield = 78%,
XH NMR (CD3OD/400MHz) 8 8.78 (d. IH, J Hz) , 8.59 (d. IH, J =
1.2 Hz), 7.6 (m, IH), 7.01 (m, 2H) , 6.55 (s, IH), 5.49 (s,
2K) , 5.30 (s, 2H), 3.89 (~t, 2H), 2.97 (s, 3H), and 2.57 (s,
3H) ; 19F NMR (CD3OD/400 MHz) = 8-111.56 (m) and -116.04 (m) ; ESHRMS
m/z 509.0964 (M+H 022^4^0361-?: requires 509.0994).
Example 405
3-Bromo-4- [ (2,4-difluorobenzyl) oxy] -6-methyl'-l- ({5- [.(4-
methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-
2(1H)-one trifluoroacetate
Step 1
5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-
oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid
A suspension of ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyrazine-2-carboxylate
(0.18 g, 0.002 mol) and IN NaOH (0.6 mL in 1:1 v/v EtOH/Water)
was stirred at room temperature for 1.5 h. The reaction
mixture was acidified with 5% citric acid and filtered the
precipitate. It was washed with water, followed by ethanol
and dried in vacua to afford the title compound (0.14 5, 77%)
as a light brown powder: "'H NMR (CD3OD/400 MKz) = S 9.03 (s. 1H) ,
8.SO (s, 1H), 7.61 (m.lH), 7.00 (ra, 2H), 6.52 (s, IK), 5.51
(s, 2H) , 5.30 (s. 2H) , and 2.52 (s, 3H) ; 1SF NMR CD3OD/400
MHz) = 5-111.75 (m) and -116.06 (m) ; ES-HRMS m/z 456.0209 (M+K
C:9H15N403BrF2 requires 466.0209).
Step 2
To a solution of 5-{ [3-Bromo-4-t(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid
(0.28 g, 0.0006 mol) in DMF (3.0 mL), at -15 °C, was added
isobutylchloroformate (0.082g, 0.0006 mol), followed by the
addition of N-methylmorpholine (0.06 g, 0.00063 mol) and
stirred under argon for 15 min. N-methylpiperazine (0.072 g,
0.00072 mol) in DMF (2,0 mL) was then added to the reaction
and the mixture was stirred at room temperature for 3 h.
After the removal of the solvents in vacuo, the residue was
purified by reverse-phase HPLC using 10 - 90%
acetonitrile/water gradient {30 min) at a flow rate of 100
mL/min. The appropriate fractions (m/z = 548) were combined
and freeze dried to afford the title compound ( 0.32 g, 80%)
as a white powder: aH NMR (CD3OD/400 MHz) 58.89 (d. 1H, J =
1.6 Hz), 8.73 (d, 1H, J = 1.6 Hz), 7.61 (m, 1H), 7.01
(m,2H), 6.56 (s, IE), 5.50 (s, 2H), 5.30 (s, 2H), 2.9 (s, 3H),
and 2.57 (s, 3H) ; 19F NMR (CD3OD/400 MHz) = 5 - 109.36 (m) and -
114.91 (m); ES-HRMS m/z 548.1090 (M+H C2tE2SN503B2:F2 requires
548.1103).
Example 406
3-3romo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5-[(4-
methylpiperazin-1-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-
2(1H)-one
A solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-
({5- [ (4-methylpiperazin-l-yl)carbonyl]pyrazin-2-
yl}methyl)pyridin-2(IE)-one trifluoroacetate (0.17 g, 0.00026
mol) in 0.IN NaOH (25 mL) was stirred at room temperature for
15 min. and extracted the product in ethyl acetate (2 x 20
mL). The combined organic extracts were washed with water (2
x 20 mL) , dried (Na2SO4) and concentrated to dryness. The
residue was dried in vacuo to afford the title product (0.09
g, 64%) as a white powder: XH NMR (CD3OD/400 MHz) 58.69 (d. 1H, J
= 1.2 Hz), 8.67 (d, 1H, J = 1.2 Hz), 7.60 (m, 1H), 7.00 (m,
2H), 6.54 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 3.78 (t, 2H, J
= 4.8 Hz), 3.58 (t, 2H, J = 4.8 Hz), 2.526 (s, 3H), 2.53 (t,
2H, J = 4.8 Hz), 2.44 (t, 2H, J = 4.8 Hz), and 2.31 (s, 3H)
19F NMR (CD3OD/400 MHz) = 8-111.65 (m) and -116.06 (m); ES-HRMS
m/z 548.1123 (M+H C24H2SN503BrF2 requires 548.1103).
Example 407
-OH
5-{[3-Bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxyethyl)-Nmethylpyrazine-
2 -carboxamide
The title compound was prepared in a similar manner as
described for Example 405 , substituting N.-methylpiperazine by
N-methylethanolamine. Yield = 60%,
XH NMR (CD3OD/400 MHz) 5 8.69 (d. 1H, J = 1.2 Hz), - 8.64 (d. 1H,
J = 1.2 Hz), 7.61 (m, 1H) , 7.00 (m, 2H), 6.54 (s, 1H), 5.49
(a, 2H), 5.30 (s, 2H), 3.81 (~ t, 1H), 3.66 (m, 2H), 3.56 (t,
1H, J = 5.2 Hz), 3.12 (d, 3H J = 7.6 Hz), 2.56 (s, 3H); 19F NMR
(CD3OD/400 MHz) 5-109.64 (m) and -113.66 ( m ) ; ES-HRMS tn/z 523.0743
(M+H C22H22N404BrF2 requires 523.0797).
Example 408
5-{ [3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}-N-(2,3-dihydroxypropyl)p:
carboxamide
The title compound was prepared in a similar manner as
described for EXAMPLE 405, substituting N-methylpiperazine by
3-amino-l,2-propanediol. Yield = 56%; "H NMR (CD3OD/400 MHz)
59.09 (d. 1H, J = 1.2 Hz), 8.70 (d. 1H, J = 1.2 Hz), 7.60
(m,lH), 7.00 (m, 2H) , 6.54 (s, 1H) , 5.53 (s. 2H) , 5.30 (s,
2H) , 3.80 (m, 1H) , 3.61 (dd, 1H), 5.53 (d, 2H) , J=5.2Hz),
3.42 (dd, 1H) , and 2.55 (s, 3H) ; 19F NMR (CD3OD/400 MHz)
6-109.65 (m), and -113. 67 (m); ES-HRMS m/z 539.0703 (M+H
requires 539.0736). ' "
Example 409
5-{ [3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-
1(2H) -yl]methyl}-N-(2-hydroxyethyl)pyrazine-2-carboxamide
The title compound was prepared in a similar manner as
described for EXAMPLE 405, substituting N-methylpiperazine by
2-aminoethanol. Yield = 46%; XH NMR (CD3OD/400 Hz) 5 9.08 (d. 1H,
J = 1.2 Hz), 8.70 (d, 1H, J = 1.2 Hz), 7.601 (m, 1H) , 7.01
(m, 2H) , 6.54 (s, 1H), 5.53 (s, 2H), 5.30 (s, 2H) , 3.69 (t,
2H, J = 6.0 Hz), 3.53 (t, 2H, J = 6.0 Hz), 2.55 (s, 3H); ) ; 19F
NMR (CD3OD/400 Hz) 6-111-67 (m) and -116.07(m); r;S-ERMS m/:
509.0616 (M+H C2iH2oN404BrF2 requires 509.0630).
Example 410
3-Bromo-4-.[ (2 , 4-dif luorobenzyl) qxy] -l-{ [5- . '
(methoxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(IHJ-one
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{ [5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one
(0.35 g, 0.00078 mol) in DMF at 0 °C, was added NaH (0.022 g,
0.00092 mol) and stirred for.10 man. lodomethane (0.05 mL)
was added to the reaction and the mixture was stirred at 10 °C
for 3 h. DMF was distilled in vacuo and the residue was
partitioned between 5% citric acid and EtOAc (15,0 mL). The
organic phase was washed with water, dried (Na2SO4) and
concentrated to dryness. The residue was purified by flash
chromatography (EtOAc), and the appropriate fractions were
combined and concentrated to a pale yellow powder.
XH NMR (CD3OD/400 MHz) 5 8.59 (a) , 8.55 (a, IE), 7.60 (m,
6.99 (m, 2H), 6.52 (s, 1H), 5.47 (s, 2H), 5.30 (s, 2H), 4.57
(s, 2H), 3.44 (s, 2H), and 2.54 {s, 3H); 19F NMR (CD3OD/400 Hz)
5-111.69 (m) and -116. 09 Cm); ES-HRMS m/z 466.0577 (M+H
C2iH19N303BrF2 requires 466.0572).
Example 411
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-((5-[ (2-
methoxyethoxy)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-
2(lH)-one
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridiir-2 (IH) -one
(0.25 g, 0.00055 mol) in dimethyl acetamide at
0 °C, was added NaH (0.016 g, 0.00067 mol) and stirred for 15
min. 2-Methoxyethyl bromide (0.09 g, 0.00-65 mol) was then
added , and the mixture was stirred at room temperature for 6
h. Dimethylacetamide was distilled in vacuo and the product
was purified by reverse-phase HPLC using 10 - 90%
acetonitrile/water gradient (30 min) at a flow rate of 100
mL/min. The appropriate fractions (m/z = 510) were combined
and freeze dried to afford the title compound (0.32 g, 80%) as
a white powder:
1E NMR (CD3OD/400 Hz) 68.59 (a. IH) , 8.58 (s, IH) , 7.60 (m , IH) ,
7.02 (m, 2H), 6.52 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H), 4.67
(s, 2H) , 3.71 (~t, 2H, ), 3.57 (~t, 2H) , 3.34 (s, 3H)-, and
2.54 (s, 3H) ; ES-HRMS m/z 510.0852 (M+H C2oHiaN404BrF2 requires
510.0835).
Example 412
(5-{ [3-3romo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}pyrazin-2-yl)methyl carbamate
To a suspension of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl]-6-methylpyridin-2(1H)-one -
(0.21 g, 0.00055 mol) in THF (5.0 tnL) and DMF (2.0 mL) , was
added 4-nitrophenylchlorof ormate (0.1 g, 0 . QQQ5 .fflol). and"
cooled to 0 °C. Triethylamine (0.052g, 0.0005 mol) was then
added, stirred at room temperature for I h, and at 65 °C for
an additional In. It was cooled in an ice bath and added 2M
ammonia in propanol (1.0 mL) and stirred at room temperature
for 2 h. After the removal of the solvents under reduced
pressure, the residue was partitioned between 5% sod.
bicarbonate, and EtOAc (25 mL). The organic phase was washed
with 5% sod. bicarbonate, (3 x 25 mL), water (3 x 25 mL),
dried (Na2S04) and concentrated under reduced pressure. The
resulting substance was purified by isolated by reverse-phase
HPLC using 10 -90% CH3CN/Water (30 min gradient) at a flow rate
of 100 mL/min. The appropriate fractions (m/z= 495 M+H) were
combined and freeze-dried, and the residue was partitioned
between 5% sod. bicarbonate (20 mL) and EtOAc (25 mL). The
organic phase was washed with water, dried (Na2S04) and
concentrated to dryness under reduced pressure, to afford the
title compound as a white powder (0.065 g) :
-H NMR (CD3OD/400 MHz) 5 8.61 (br s, IH) , 8.54 (br s, IK), 7.60
)mlH), 7.02 (m, 2H) , 6.52 (s, IH) , 5.47 (s, 2H) , 5.29 (s,
2H) , 5.15 (s, 2H) , and 2.54 (s, 3H) : 19FNMR (CD3CD) 5 -111.70
(m) , and -115.09 (m) ; ES-HRMS m/z 495.0449 (M+H C20HigN404BrF:
requires 495.0474).
Exanrole 413
l-benzyl- 3-bromo-2-oxo-1,2-dihydropyridin-4-yl
methyl(phenyl)carbamate
Step 1. Preparation of l-benzyl-2-oxo-l,2-dihydropyridin-4-yl
methyl(phenyl)carbamate
To a chilled solution of l-benzyl-4-hydroxypyridin-2(IH)-
one (0.375 g, 1.86 mmol) in anhydrous acetonitrile (10 mL) was
added triethylamine (0.206 g, 2.04 mmol) followed by N-methyl-
N-phenylcarbamoyl chloride (0.379 g, 2.24 mmol). The reaction
mixture was stirred under nitrogen atmosphere at 0° C for 30
minutes then at room temperature for Ihour. The reaction was
monitored by TLC (5% methanol in dichloromethane). The
solvent was removed under reduced pressure and the residue was
washed with 10% citric acid and extracted with ethyl acetate.
The organic extracts were combined, washed with water and
dried over anhydrous Na2S04. The solvent was removed under
reduced pressure to afford a. yellow syrup. The residue was
purified by flash chromatography (silica gel) using 5% MeOH i
CH2C12 to give the desired product (0.382g, 61%) as a whice
semisolid. -NMR (d0--DMSO, 400 MHz) 67.8 (d, 1H, u = 7.2 Ez]
7.39 (m, 10K) , 6.19 (s, 2H) , 5.03 (s, 2H) , 3.29 (s, 3H) ; E3-
HRMS m/z 335.1396 (M+H calculated for C2oHlsN203 requires
335.1418).
Step 2. Preparation of l-benzyl-3-bromo-2-oxo-l,2 -
dihydropyridin-4-yl methyl(phenyl)carbamate
To a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl
methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous
(7 mL) was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol).
The reaction was stirred overnight at room temperature under
nitrogen atmosphere. The reaction mixture was purified by
flash chromatography (silica gel) using ethyl acetate/hexane
(1:1 v/v). The appropriate fractions were collected according
to ES MS (M+H 413) and concentrated. The dried product showed
about 14% of di-bromonated product by analytical HPLC. The
compounds were separated by reverse phase HPLC using a 10-90%
acetonitrile in water (30 minute gradient) at a 100 mL/min
flow rate to afford (after lyophilization) the salt of the
desired compound. The salt was diluted in ethyl acetate and
washed with NaHC03. The organic extracts were dried over
anhydrous Na2S04 and concentrated to afford the desired
compound (0.271 g, 58%) as a beige solid. Hi-NMR (d6-DMSO,
400 MHz) 67.94 (d, 1H, J= 7.2 Hz), 7.29 (m, 10H) , 6.48 (s, 1H) ,
5.12 (s, 2H), 3.33 (s, 3H); ES-HRMS m/z 413.0495 (M+H
calculated for C20E1B03Br requires 413.0496) .
Example 414
4-(benzyloxy)-3-ethynyl-l-(3-fluorobenzyl)pyridin-2(1H)-one
Step 1. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-
iodopyridin-2(1H)-one
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-
2(lH)-one {4.83 g, 15.6 mmol) in anhydrous acetonitrile (55
mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated
at 65° C under nitrogen for 4 hours. The reaction mixture was
concentrated under reduced pressure and the residue was
purified by flash chromatography (silica gel) using ethyl
acetate/hexane (1:1 v:v). The appropriate fractions were
collected according to ES MS (M+H 436) and washed with Na2S03
to remove the color impurities. The fractions were
concentrated under reduced pressure and dried in vacuo to
afford the desired product (6.15 g, 90%) as a light yellow
solid. ^-NMR (CE3OD, 400 MHz) 67.73 (d, 1H, J= 7.6 Hz), 7.47
(d, 2H, J= 7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H,
-570-
J= 8.0 Hs), 5.29 (s, 2H), 5.19 (s, 2H); ES-ERMS m/z 436-0210
(M+H calculated for Ci9HlsN02FI requires 436.0196).
Step 2. Preparation of 4-(benzyloxy)-1-(S-fluorobensyl)-3-
[(trimethylsilyl)ethynyl]pyridin-2(IH)-one
Degassed a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-
3-iodopyridin-2(IH)-one (2.01 g, 4.62 mmol) in anhydrous
acetonitrile (25 tnL) under argon atmosphere. Triethylamine
(l.ll g, 11 mmol) was added,and quickly degassed. The
reaction mixture was chilled in an ice bath for 15 minutes
before adding bistriphenylphosphine-palladium chloride (0.34
g, 0.48 mmol) and cuprous iodide (0.2 g) . The reaction was
stirred at room temperature for 30 minutes before heating at
60° C under an atmosphere of argon for 2 hours. The reaction
mixture was filtered through a bed of celite and the filtrate
was concentrated under reduced pressure. The dark brown
residue was diluted with CH2C12 (100 mL) and washed with water.
The organic extracts were combined, dried over anhydrous
Na2S04, and concentrated under reduced pressure. The dark
brown residue was purified by flash chromatography using 30%
ethyl acetate in hexane. The appropriate fractions were
combined and concentrated under reduced pressure to afford the
desired product (1.34 g, 72%) as a light yellow solid. '"H-NMR
(CD3OD, 400 MHz) 5" -4 (d, IH, J« 7.6 Hz), 7.47 (d, 2H, J= 7.6
Hz), 7.35 (m, 4H) 09 (m, 3H), 6.46 (d, IH, J= 7.6 Hz), 5.26
(s, 2H), 5.13 (s, *H) , 0.18 (s, 9H); ES-HRMS m/z 406.1638 (M+H
calculated for C24H2sNO2FSi requires 406.1610).
Step 3. Preparation of 4-(benzyloxy)-3-ethynyl-l- (3-
fluorobenzyl)pyridin-2(IH)-one
To a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-
[(trimethylsilyl)ethynyl]pyridin-2(IH) -one (1.31 g, 3.2 mmol)
in anhydrous acetonitrile (25 mL) at 0° C was added
tetrabutylammoniun fluoride (0.611g, 1.93 mmol). The reaction
was stirred at 0° C for 15 minutes then for 1 hour at room
temperature. The reaction was concentrated under reduced
pressure and the residue was diluted with ethyl acetate and
washed with water. The organic extracts were combined, dried
over anhydrous Na2S04 and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel)
using ethyl acetate in hexane (1:1 v/v) . The appropriate
fractions were combined and concentrated under reduced
pressure to afford the desired product (0.779 g, 72%) as a
gold solid. JH-NMR (CD3OD, 400 MHz) 57.73 (d, IH, J= 7.6 Hz), .
7.43 (d, 2H, J= 7.2 Hz), 7.35 (m, 4H) , 7.09 (m, 3H), 6.45 (d,
IH, J= 7.6 Hz), 5.27 (s, 2H), 5.13 (s,2H), 3.78 (s, IH); ESHRMS
m/z 334.1243 (M+H calculated for C2iH17N02F requires
334 .1234) .
Example 415
4-(benzylamino)-3-bromo-l-(3-f luorober.zyl) pyridin-2(IK)-one
Step 1. Preparation of l-(3-fluorobenzyl)-4-hydroxypyridin-
2(IH)-one
In a Fischer-Porter bottle, added a solution of 4-
(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(IH)-one (4.5 g, 14.56
mmol) in absolute ethanol (20 mL). Flushed the solution with
nitrogen then added palladium catalyst (1.05 g, 10% P"d;AC)
»
Sealed bottle and evacuated system. The system was purged
with hydrogen gas (2 X 15 psi) to check for leaks. The
reaction was charged with hydrogen (35 psi) and stirred at
room temperature for 45 minutes. The system was evacuated and
flushed with nitrogen. The reaction was filtered and the
catalyst was carefully washed with fresh ethanol. The
filtrate was concentrated under reduced pressure. 1H-NMR
(CD3OD, 400 MHz) 87.54 (d, IH, J= 7.6 Hz), 7.32 (m, IH), 7.06
(d, IH, J= 7.6 Hz), 6.99 (m, 2H), 6.05 (dd, IH, J= 2.4 Hz, 2.8
Hz), 5.83 (d, IH, J= 2.4 Hz), 5.09 (s, 2H); ES-HRMS m/z
220.0774 (M+H calculated for C12HUN02F requires 220.0787).
Step 2. Preparation of 4-(benzylamino)-1-(3-
fluorobenzyl)pyridin-2(IH)-one
A mixture of 1- (3-fluorobenzvl)-4-hydroxypyridin-2(IH)-
one (1.005 g, 4.5 mmol) in benzylamine (15 mL) was heated ac
reflux (185° C) under nitrogen atmosphere for 24 hours. The
reaction was monitored by ES-MS (MH+ 309) . The solvent was
removed by vacuum distillation to give a yellow residue. 1HNMR
(CD3OD, 400 MHz) 67.31 (m, 7H), 7.03 (m, 3K), 5.98 (d, IH,
J= 7.2 Hz), 5.45 (s, IH), 5.00 (s, 2H), 4.30 (s, 2H); ES-HRMS
m/z 309.1403 (M+H calculated for Ci9Hi8N2OF requires 309.1375).
Step 3. Preparation of 4- (benzylamino)-3-bromo-1- (3-
fluorobenzyl)pyridin-2(IH)-one
To a solution of 4-(benzylamino) -1-(3-
fluorobenzyl)pyridin-2(IH)-one (0.50 g, 1.62 mmol) in
anhydrous CH2C12 (10 mL) was added N-bromosuccinimide (NBS,
0.30 g, 1.7 mmol). The reaction was stirred at room
temperature under a nitrogen atmosphere for 3 hours. The
reaction mixture was purified by flash chromatography (silica
gel) using ethyl acetate in hexane (1:1 v/v). The
appropriate fractions were combined and concentrated. ^-NMR
(CD3OD, 400 MHz) 57.41 (d, IH, J= 7.6 Hz), 7.31 (m, 6H),
(m, 3H), 5.99 (d, IH, J= 7.6 Hz), 5.08 (s, 2H), 4.53 (s, 2H);
ES-HRMS m/z 387.0508 (M+H calculated for CigHi7N2OBrF requires
387.0504) .
Example 416
4- (benzyloxy) -1- (3-fluorobenzyl) -3-methylpyridir.-2 (1H) -ens
Step 1. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-
iodopyridin-2(1H)-one
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-
2 (1H)-one (4.83 g, 15.6 mmol) and N-iodosuccinimi.de (NIS, 3.86
g, 17.1 mmol) in anhydrous acetonitrile (55 mL) was heated at
65° C for 4 hours under nitrogen atmosphere. The reaction
mixture was concentrated under reduced pressure and the
residue was purified by flash chromatography (ethyl
acetate/hexane 1:1 v/v). The appropriate fractions were
collected according to ES MS (M+H 436) and washed with Na2S03
to remove the color impurities. The fractions were
concentrated under reduced pressure and dried in vacuo to
afford the desired product (6.15 g, 90%) as a light yellow
solid. 'H-NMR (CD3OD, 400 MHz) 67.73 (d, IE, J= 7.6 Hz), 7.36
(m, 6H) , 7.08 (m, 3H), 6.39 (d, 1H, J= 8.0 Hz), 5.28 (s, 2H) ,
5.19 (s, 2H); ES-HRMS m/z 436.0196 (M+H calculated for
C19Hi6N02FI requires 436.0210) .
Step 2. Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-
methylpyridin-2(1H)-one
a degassed solution of 4-(benzyloxy)-i-(3-
fluorobenzyl)-3-iodopyridin-2(1H)-one (1.03 g, 2.36 mmol) in
anhydrous DMF (15 mL) under argon atmosphere was added
triethylamine (1.11 g, 11 mmol). The reaction mixture was
chilled in an ice bath for 15 minutes before adding
tetramethyl tin (2.10 g, 11.75 mmol) followed by
bistriphenylphosphine-palladium chloride (0.166 g, 0.24 mmol).
The reaction was stirred at room temperature for 30 minutes
before heating at 95° C under an atmosphere of argon for 3
hours. The reaction mixture was filtered through a bed of
celite and the filtrate was concentrated under reduced
pressure. The dark brown residue was diluted with ethyl
acetate (100 mL) and washed with water. The organic extracts
were combined, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The dark brown residue was purified
by flash chromatography (30% ethyl acetate in hexane). The
appropriate fractions were combined and concentrated under
reduced pressure to afford the desired product (0.1758 g, 22%)
as a light yellow solid. The product was further purified by
reverse phase HPLC using a 10-90% acetonitrile/water (30
minute gradient) at a 100 mL/min flow rate, to afford a
cleaner product as a light yellow solid (0.0975g, 8%). ^-H-NMR
(CD3OD, 400 MHz) 87.58 (d, 1H, J= 7.6 Hz)), 7.35 (m, 6H), 6.98
(m, 3H), 6.46 (d, 1H, J= 7.6 Hz), 5.19 (s, 2H), 5.15 (s, 2H),
2.0 (s, 3H) ; ES-HRMS m/z 324.1366 (M+H calculated for C2oHi9N02F
requires 324.1394).
Example 417
1- (3-fluorobenzyl)-4- [ (4-fluorobenzyl)oxy]-3-iodopyridin-
2(IH)-one
Step 1: Preparation of 1-(3-fluorobenzyl)-4-hydroxy-3-
iodopyridin-2(IH) -one
To a mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-
2(lH)-one (1.1 g, 5 mmol) in acetonitrile (15 mL) was added Niodosuccinimide
(1.1 g, 5.5 mmol) along with a ca. amount of
dichloroacetic acid (0.1 mL). The reaction mixture stirred at
room temperature for 1 hour under nitrogen. The mixture was
chilled in an ice bath and filtered cold with fresh MeCl2. The
beige solid was dried to afford the desired iodinated
intermediate (1.21g, 69%). ES-LRMS m/z 346.
Step 2: Preparation of 1-(3-fluorobenzyl)-4-[(4-
fluorobenzyl) oxy] -3-iodopyridin-2(IH)-one
To a mixture of 1-(3-fluorobenzyl)-4-hydroxy-3-
iodopyridin-2(IH)-one (0.5g, 1.44 mmol) in DMF (5 mL) was
added K2C03 (0.199g, 1.44 mmol) followed by the addition of 4-
fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction
aixture stirred at room temperature for 30 minutes, The
nixture was diluted with ethyl acetate (50 mL) and washed with
vater. The organic extracts were dried over anhydrous Na2S04
and concentrated to dryness. ^H-NMR (CD3OB, 400 MHz) 57.75 (d,
IH, J= 7.6 Hz), 7.49 (q, 2H), 7.34 (q, IE), 7.11(m, 5H), 6.40
(d, IH, J= 7.6 Hz), 5.26 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z
454.0098 (M+H calculated for C19H15N02F2l requires 454.0110).
Example 418
1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-methylpyridin-
2(lH)-one
To a degassed solution of 1-(3-fluorobenzyl)-4-[(4-
fluorobenzyl)oxy]-3-iodopyridin-2(IH)-one (0.804g, 1.7 mmol)
in DMF (10 mL) and LiCl (0.25g, 5.9 mmol) was added
tetramethyltin (0.49 mL, 3.54 mmol) followed by
bistriphenylphosphine-palladium chloride catalyst (0.124g,
0.177 mmol)'. The reaction mixture was heated in an oil bath
(85°-90° C) under nitrogen for 3 hours. The solvent was
concentrated and the residue was diluted with ethyl acetate
and washed with water. The organic extracts were dried over
anhydrous Na2S04 and concentrated to dryness. The residue was
purified by flash column chromatography (20% ethyl acetate in
hexane) . The appropriate fractions were concentrated. ^-H-NMR
(CD3OD, 400 MHz) 5 7.59 (d, IH, J=7.6 Hz), 7.46 (m, 2H), 7.34
(m, IH) , 7.10 (m, 4H) , 6.46 (d, IH, J=7.6 Hz), 5.17 (s, 2H) ,
5.15 (S, 2K), 1,99 (s, 3-d}; ES-ERMS m/z 342.1314 (Mcalculated
for C2oHigN02F: requires 342.1300} .
Example 419
benzyl-3-bromo-4-[(2,4-difluorobenzvl)oxy]-6-methylpyridin-
2(lH)-one
To a degassed cold solution of DMF (10 mL) and. PPh3
(resin, 0.93 g, 2.75 mmol) was added DEAD (0.44 mL, 2.75
mmol). The reaction mixture stirred at -10°C for 20 minutes
under nitrogen. A solution of l-benzyl-3-bromo-4_-hydroxy-6-
methylpyridin-2(1H)-one (0.62 g, 2.1 mmol) and 2,4-
difluorobenzylalcohol (0.283 mL, 2.5 mmol) in DMF (10 mL) was
added to the resin suspension. The reaction mixture stirred
at -10° C for 30 minutes and then allowed to stir at room
temperature for 1 hour. The resin was filtered and rinsed
with fresh MeOH and the filtrate was concentrated. The residue
was dissolved in ethyl acetate and purified by flash column
chromatography (ethyl acetate/hexane 1:1 v/v). The
appropriate fractions were concentrated. aH-NMR (CD3OD, 400
MHz) 6 7.62 (m, 1H), 7.31 (m, 3H), 7.1 (d, 2H, J= 7.2 Hz), 7.02
(t, 2H, J= 8.6 Hz), 6.48 (s, 1H), 5.42 (s, 2H), 5.28 (s, 2H),
2.34 (s, 3H); ES-HRMS m/z 420.0399/422.0380 (M+H calculated
for C2oHi7N02F2Br requires 420 . 0405/422 ..0387) .
Example 420
-579-
N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl]
4 -fluorobenzamide
Step 1. Preparation of 4-amino-l-(3-fluorobenzyl)pyridin-
2(1H)-one
In a Fischer-Porter bottle, added a solution of 4-
(benzylamino) -1-(3-fluorobenzyl)pyridin-2(1H)-one (2.5g, 8.11
mmol) in glacial acetic acid (20 mL). After the solution was
flushed with nitrogen, catalyst was added (10%Pd/C, 2.0g).
The vessel was sealed, evacuated, and purged with hydrogen
gas. The system was charged with hydrogen gas (50psi) and the
mixture stirred at room temperature for 4 hours. The system
was evacuated and flushed with nitrogen. The reaction mixture
was filtered through a bed of celite and washed with fresh
ethanol. The filtrate was concentrated under reduced pressure
and the residue was purified by flash column chromatography
(hexane/ethyl acetate 3:4 v/v). The filtrate was
concentrated. ^-NMR (CD3OD, 400 MHz) 8 7.32 (q, 1H) , 7.02
(m, 3H), 5.93 (dd, 1H, J= 2.4 Hz, 2.8 Hz), 5.58 (d, 1H, J= 2.4
Hz); ES-HRMS m/z 219.0966 (M+H calculated for C12H12N2OF
requires 219.0928).
Step 2. Preparation of 4-fluoro-N-[1-(3-flucroben-yi)-2-cxo-
1,2-dihydropyriqin-4-yl]benzamide
To a solution of 4-amino-l-(3-fluorobenzyl)pyridin-2(IK)-
one (0.263 g, 1.2 mmol) in acetonitrile (7 mL) was added a
DMA (ca.), triethylamine (0.25 mL, 1.8 mmol) and 4-
fluorobenzoyl chloride (0.213 mL, 1.8 mmol). The reaction
mixture stirred at 0° C for 25 minutes and then filtered. The
solid was washed with 10% citric acid and water to afford the
desired compound (0.326 g, 79%) after drying. -NMR (dsDMSO,
400 MHz) 5 7.98 (m, 2H) , 7.71 (d, 1H, J= 7.6 Hz), 7.35 (tn, 3H)
7.08 (m, 3H), 6.98 (d, 1H, J= 2.4 Hz), 6.61 (dd, 1H, J= 2.4
Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMS m/s 341.1.
Step3. Preparation of N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-
1,2-dihydropyridin-4-yl] -4-fluorobenzamide
To a mixture of 4-fluoro-N-[1-(3-fluorobenzyl)-2-oxo-l,2-
dihydropyridin-4-yl]benzamide (0.305g, 0.89 mmol) in
acetonitrile (7 mL) was added NBS (0.159g, 0.89 mmol). The
reaction mixture stirred at room temperature for 1.5 hours.
The filtrate was removed under reduced pressure and the
residue was purified by flash column chromatography (ethyl
acetate/hexane 1:1 v/v). The fractions were concentrated. 1HNMR
(CD3OD, 400 MHz) 5 8.03 (m, 2H), 7.79 (d, 1H, J« 7.6 Hz),
7.47 (d, 1H, J= 8.0 Hz), 7.28 (m, 3H), 7.12 (m, 3H), 5.23 (s,
2H); ES-HRMS m/z 419.0202/421.0191 (M+H calculated for
requires 419.0201/421.0183).
-581-
Sxanrole 421
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6
methylpyridin-2(IH)-one
Step 1. Preparation of 3-chloro-l-(2,6-difluorophenyl)-4-
hydroxy-6-methylpyridin-2(IH)-one
To a mixture of 1-(2,6-difluorophenyl)-4-hydroxy-6-
methylpyridin-2(IH)-one (0.30 g, 1.26 mmol) in dichloromethane
(5 mL) was added NCS (2.52 g, 1.90 mmol). The reaction
mixture stirred at room temperature under nitrogen for 4.5
hours. The suspension was cooled in ice bath, filtered, and
the solid was rinsed with fresh dichloromethane to afford the
desired product (0.271 g, 79%) as a white solid. ^-NMR
(CD3OD, 400 MHz) 8 7.58 (m, IH), 7.22 (m, 2H), 6.20 (s IH),
2.00 (s, 3H) ; ES-HRMS m/z 272.0287 (M+H calculated for
Ci2H9N02F2Cl requires 272.0290).
Step 2. Preparation of 3-chloro-4-[ (2,4-difluorobenzyl)oxy]-
1-(2,6-difluorophenyl)-6-methylpyridin-2(IH)-one
To a solution of 3-chloro-l-(2,6-difluorophenyl)-4-
hydroxy-6-methylpyridin-2(IH)-one (0.27 g, 1.00 mmol) in DMA
(5 mL) was added K2C03 followed by the addition of 2,4-
difluorobenzyl bromide (0.128 mL, 1 mrr.cl) . The reaction
mixture stirred at room temperature for 2 hours and then was
diluted in water. The reaction mixture was extracted wich
ethvl acetate, the organic extracts were dried over Na2S04 and
the filtrate was concentrated. The resulting residue was
purified by flash column chromatography (ethyl acetate/hexane
3:4 v/v) to afford the desired product. -H-NMR (CD3OD, 400
MHz) 5 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 6.71 (s, IH),
5.36 (s, 2H) , 2.11 (s, 3H) ; ES-HRMS tn/s 398.0551 (M+H
calculated for Ci9H13NO2F4Cl requires 398.0571).
Example 422
3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-
methylpyridin-2(IH)-one
Step 1: Preparation of 1-(4-fluorobenzyl)-4- [ (4-
fluorobenzyl)amino]-6-methylpyridin-2(IH)-one
A mixture of 4-hydroxy-6-methylpyrone (5.0 g, 0.04 mol)
and 4-fluorobenzylamine (10.0 g. 0.08 mol) in n-butanol (25.0
mL) was heated to reflux for 24 hours under argon atmosphere.
The resulting solution was concentrated to dryness under
reduced pressure. The residue was triturated with ethyl
acetate and filtered. It was thoroughly washed with ethyl
acetate and dried to afford the title compound as a pale
yellow powder (4.1 g. 30%). -NMR (CD3OD, 400 MHz) 5 7.33 (q,
2H), 7.04 (m, 5H), 5.85 (d, IE, J= 2.0 Hz), 5.44 (d, 2H, J=
2.4 Hz), 5.20 (s, IE), 4.29 (s, 2H), 2.17 (s, 3H); ES-HRMS m/=
341.1488 (M+H calculated for C20H19N;OF2 requires 341.1460).
Step 2: Preparation of 3-bromo-l-(4-fluorobenzyl)-4 - [ (4-
fluorobenzyl)amino]-6-methylpyridin-2(IH)-one
To a solution of 1-(4-fluorobenzyl)-4- [ (4-
fluorobenzyl)amino]-6-methylpyridin-2(IH)-one (0.2857 g, 0.84
mmol) in MeCl2 was added NBS (0.156 g, 0.88 mmol) . The
reaction stirred at room temperature under nitrogen for 45
minutes. The reaction mixture was diluted with MeCl2 and
washed with NaHCO3. The organic extracts were washed with
water, dried over Na2S04, and concentrated to afford the
desired product (0.3242 g, 92%) as a yellow solid. ^H-NMR
(CD3OD, 400 MHz) 5 7.32 (q, 2H), 7.04 (m, 6H), 5.91 (s, IH),
5.28 (s, 2H), 4.50 (s, 2H), 2.17 (s, 3H); ES-HRMS m/2
419.0549/421.0537 (M+H calculated for C20HiaN2OBrF2 requires
419.0565/421.0547).
Example 423
3-bromo-l-(cyclopropylmethyl)-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(IH)-one
To a mixture of 3-bromo-l-(cyclopropylmethyl)-4-hydroxy-
6-methyl?yridin-2(IH)-one (0.276 g, 1.C7 mmcl) and K2C03 (0.14S
g, 1.07 mmol) in DMA (4 mL) was added 2, 4-difluorcbenzyl
bromide (0.14 ml, 1.07 mmol). The mixture snirrea at room
temperature for 1.5 hours. The reaction mixture was diluted
in water and extracted with ethyl acetate. The organic
extracts were dried over Na2S04 and concentrated. The residue
was purified by flash column chromatography (ethyl
acetate/hexane 1:1 v/v). The appropriate fractions were
combined, and concentrated. 1H-NMR (CD3OD, 400 MHz) 5 7.60 (q,
IH) , 7.04 (m, 2H) , 6.42 (s, IK), 5.26 (s, 2H) , 4.06 (s, IH) ,
4.04 (s, IH), 2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H]; ESHRMS
m/z 384.0392 (M+H calculated for C17Hi7N2OBrF2 requires
384.0405).
Example 424
H3C
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-4-
ylmethyl)pyridin-2(IH)-one
Step 1. Preparation of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-
Commercially available 4-hydroxy-6-methyl pyrone (10 g,
79.3 rnmcl) was condensed with commercially available 4-
(aminomethyl) pyridine (8 mL, 79.3 mmol) in water (SCmL) . The
mixture was heated in an oil bath at reflux for 1 hour under
nitroqen. The solvent was evaporated. MS and I-NMR were
consistent with the desired desbrominated structure. -NMR
(CD3OD, 400 MHz) 5 8.45 (dd, 2H, J= 1.6 Hz, 1.6 Hz) , 7.15 (d,
2H, J= 6.0 Hz), 6.00 (d, IH, J= 2 . 0 Hz), 5.80 (d, IH, J= 2
Hz), 5.34 (s, 2H) , 2.23 (s, 3H) ; ES-LRMS (M+H) tn/z 217.
To a suspension of the above compound (0.801 g, 3.7 mmol)
in MeCl2 (10 mL) was added NBS (0.725 g, 4.07 mmol) . The
reaction mixture stirred at room temperature for 30 minutes
under nitrogen. The suspension was chilled in an ice bath and
filtered. The solid was washed with fresh MeCl2 and dried to
afford a beige solid (0.9663 g, 88%) after drying. XH-NMR :
(CD3OD, 400 MHz) 58.47 (d, 2H, J= 5.2 Hz), 7.16 (d, 2H, J= 6.0
Hz), 6.09 (s, IH) , 5.40 (s, 2H) , 2.24 (s, 3H) ; ES-LRMS (M+H)
m/z 295/297.
Step 2. Preparation of 3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-
methyl-1- (pyridin-4-ylmethyl) pyridin-2 (IH) -one
To a cold solution of 2, 4-difluorobenzylalcohol (0.569
mL, 5.1 mmol) in THF (5 mL) was added PPh3 (resin, 2.55 g, 7.65
mmol) followed by the addition of DIAD (1.48 mL, 7.65 mmol).
The reaction mixture stirred at -10°C for 15 minutes under
nitrogen. A solution of 3-bromo-4-hydroxy-6-methyl-l-
( pyridin-4-ylmethyl) pyridin-2 (IH) -one (1.0 g, 3.4 mmol), in
DMF (10 mL) was added to the resin suspension. The reaction
mixture stirred at 0° C for 1.5 hours and then allowed to sti:
at room temperature overnight. The resin was filtered and
rinsed with fresh MeOH and the filtrate was concentrated. The
residue was dissolved in ethyl acetate and purified by flash
column chromatography (ethyl acetate) . The appropriate
fractions were concentrated. ^-NMR {CD3OD, 400 MHz) 5 8.47
(d, 2H, J= 5.6 Kz), 7.63 (q, IH), 7.15 (d, IH, J= 5.6 Hz),
7.05 (m, 2H), 6.55 (s, IH) , 5.45 (s, 2H), 5.31 (s, 2H), 2.35
(s, 3H); ES-HRMS m/z 421.0366/423.0355 (M+H calculated for
C19Hi6N202F2Br requires 421.0358/423.0339).
Example 428
3-bromo-4- [ (2, 4-dif luorober.zyl) oxy] -6-methyl-1- (pyridin-3-
Step 1. Preparation of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-
3-ylmethyl)pyridin-2(IH)-one
OH
Br
Commercially available 4-hydroxy-6-methyl pyrone (15 g,
119.0 mmol) was condensed with commercially available 3-
(aminomethyl) pyridine (12.10 mL, 119.0 mmol) in water (75
mL) The mixture was heated iu an oil bath at reflux for 1
hour under nitrogen. The solvent was evaporated. "H-NMR
(CD3OD, 400 MHz) 5 8.43 (d, IH, J= 4.8 Hz), 8.38 (s, IK), 7.60
(d, IH, J= 8.0 Hz), 7.39 (dd, IH, J= 4.8 Hz, 4.8 Hz), 5.97 (d,
IH, J= 2.0 Hz), 5.79 (d, IH, J= 2.4 Hz), 5.33 (s, 2H), 2.28
(s, 3H); ES-LRMS (M+H) m/z 217.
To a suspension of the above compound (5.01 g, 23.1 mmol)
in MeCl2 (50 mL) was added NBS (4.53 g, 25.4 mmol). The
reaction mixture stirred at room temperature for 30 minutes
under nitrogen. The suspension was chilled in an ice bath and
filtered. The solid was washed with fresh MeCl2 and dried to
afford a beige solid (7.89 g, 114%) after drying. ^-NMR
(CD3OD, 400 MHz) 5 8.44 (d, IH, J= 4.4 Hz), 8.39 (s, IH), 7.62
(d, IH, J» 7.6 Hz), 7.39 (dd, IH, J= 5.2, Hz, 4.4 Hz) ;•-€•. 07 '(s,
IH) , 5.39 (s, 2H) , 2.29 (s, 3H) ; ES-LRMS (M+H) m/z 295/2*97. ,
Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-1-(pyridin-3-ylmethyl)pyridin-2(IH)-one
The compound was prepared essentially as described in Step 2
of example 424 using 3-bromo-4-hydroxy-6-methyl-l-(pyridin-3-
ylmethyl)pyridin-2 (IH)-one. ^-H-NMR (CD3OD, 400 MHz) 8 8.45 (d,
IH, J= 4.4 Hz), 8.41 (S, IH), 7.63 (m, 2H), 7.41 (dd, IH, J=
5.2 Hz, 4.8 Hz), 7.02 (m, 2H), 6.52 (s, IH), 5.44 (s, 2H),
5.29 (s, 2H), 2.40 (s, 3H); ES-HRMSm/z 421.0355/423.0358
(M+H calculated for C19HlsN202F2Br requires 421.0358/423.0339),
Example 435
3-bromo-4-[(2 , 4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-2-
ylmethyl)pyridin-2(IH)-one
Step 1. Preparation of 3-bromo-4-hydroxy-6-methyl-1-(pyridin-
2-ylmethyl)pyridin-2(IH)-one
OH
Commercially available 4-hydroxy-6-methyl pyrone (5 g,
39.6 mmol) was condensed with commercially available 2-
(aminomethyl) pyridine (4.03 mL, 39.6 mmol) in water (25 mL).
The mixture was heated in an oil bath at reflux for 1.5 hour
under nitrogen. The solvent was evaporated. MS and ^-NMR
were consistent with the desired desbromonated structure. 1HNMR
(CD3OD, 400 MHz) §8.47 (d, IH, J= 4.8 Hz), 7.75 (ddd, IH,
J= 2.0 Hz,'1.6 Hz, 1.6 Hz), 7.28 (dd, IH, J= 4.8 Hz, 4.8 Hz),
7.11{d, IH, J= 7.6 Hz), 5.98 (d, IH, J= 2.4 Hz), 5.77 {d, IH,
J= 2.4 Hz), 5.35 (s, 2H), 2.28 (s, 3H); ES-LRMS (M+H) m/z 217.
To a suspension of the above compound (3.0 g, 13.8 mmol)
in MeCl2 (30 mL) was added NBS (2.71 g, 15.18 mmol). The
reaction mixture stirred at room temperature for 2.5 hours
under nitrogen. The suspension was chilled in an ice bath and
filtered. The solid was washed with fresh MeCl2 and dried to
afford a beige solid (3.18 g, 77%) after drying. LH-NMR
(CD3OD, 400 MHz) 6 8.46 (d, 1H, J= 4.8 Hz) , 7.76 (ddd, 1H, J=
2.0 Hz, 1.6 Hz, 1.6 Hz), 7.29 (dd, IE, J= 5.2 Hz, 5.2 Hz),
7.17 (d, 1H, J= 8.0 Hz), 6.07 (s, 1H), 5.40 (s, 2H), 2.30 (s,
3H); ES-LRMS (M+H) m/z 295/297.
Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-1-(pyridin-2-ylmethyl)pyridin-2(1H) one
The compound was prepared essentially as described in
Step 2 of example 424 using 3-bromo-4-hydroxy-6-methyl-1-
(pyridin-2-ylmethyl)pyridin-2(1H)-one ^-NMR (CD3OD, 400 MHz) 6
8.45 (d, 1H, J= 4.4 Hz), 7.76 (ddd, 1H, J= 2.0 Hz, 2.0 Hz, 1.6
Hz), 7.62 (q, 1H), 7.29 (dd, 1H, J= 5.2 Hz, 5.6 Hz), 7.21 (d,
1H, J= 8.0 Hz), 7.04 (m, 2H) , 6.51 (s, 1H) , 5.45 (s, 2H) , 5.29
(S, 2H), 2.42 (s, 3H); ES-HRMSm/z 421.0354/423.0332 (M+H
calculated for Ci3Ei6N202F2Er requires 421.0358/423.0339).
Examples 425-427, 429-435, 436-437
The following compounds were prepared essentially according to
the procedures set forth above for Example 424, using the
products of Step 1 of Examples 424, 428, or 435.
Ex . No .
425
426
427
429
430
431
432
433
434
435
436
437
438
Ri
H
F
F
H
F
F
F
F
Cl
F
H
F
F
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
R3
F
F
H
F
F
H
F
Cl
F
H
F
F
F
R4
K
H
H
H
H
H
F
H
H
H
H
H
F
R=-
H
F
F
H
F
H
H
H
H
F
H
F
H
X
N
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
Y
CH
CH
CH
N
N
N
N
N
N
N
CH
CH
CH
Z
CK
CH
CH
CK
CH
CH
CH
CH
CH
CH
N
N
N
MF
C19HlsN202FBr
C19H14N202F3Br
Ci9H15N202F2Br
ClsHlsN202FBr
Ci9H14N202F3Br
C19HlsN202FBr-'
C19Hi4N2O2F;3Br
C19H15N202FClBr
Ci3H15N202FClBr
Ci9HiSN202F2Br
Ci9HlsN202FBr
Ci9H14N202F3Br
C19H14N202F3Br
M+H m/z
required
403 .0452/
405.0434
439.0264/
441.0245
421.0358/
423 .0339
403 .0487/
405.0438
439.0264/
441.0245
403.0452/
405.0434
439.0264/
441.0245
437.0062/
439.0041
437.0062/
439.0041
421.0358/
423.0339
403.0452/
405.0434
439.0264/
441.0245
439.0264/
441.0245
SS-.-Ms
rn/z
403 . 0 4 4
405.04I-:
4 3 9 . 0 2 7C
441.0274
421.037J
4 2 3 . 0 3 S E
403 .048":
4 0 5 . 0 4 3 E
439.026:
441.0243
403.048i
405.0474
439.0266
441.0233
437.0066
439.004]
437.004f
439.004:
421.037."
423.033
403.045-;
405.0375
439.026
441.024;
439.026'
441.024:
NMR characterization of compounds of Examples 425-427, 429-
435, 436-437
Ex.No, NMR Data
425 (CD3OD, 400 MHz) 6 8.47 (d, 2H, J» 5.6 Hz), 7.50 7.14 (m, 4H), 6.49 (s, 1H), 5.44 (s, 2H), 5.27 (s, 2H), 2.32 (s,
3H
426 :H-NMR (CD3OD, 400 MHz) 5 8.48 (dd, 2H, J= 1.6 Hz), 7.15 (d, 2H, J=
6.0 Hz), 6.98 (t, 2H, J= 1.2 Hz), 6.60 (s, 1H), 5.45 (s, 2H) S.29
_(s, 2H) , 2.36 (s, 3H)
427
429
430
431
432
433
434
435
436
437
438
:E NMR (CD-.OD, 400 MHz) 5 8 . 47 (d, 2K, J = 1 . 6 Hz), 7.45 (IT., J.H) ,
7.15 (d, 2K, J = 5.6 Hz) , 7.06 (t, 2H, J = 8.4 Hz) , 6.52 (S, IH) ,
5 46 (s, 2H) , 5.34 (s, 2H) , and 2.37 (s, 3H)
! :E-NMR (CD3OD, 400 MHz) S 8.45 (d, IE, J = 4 . 4 Hz), 8.40 ( S , IH! ,
7.62 (d, IH, J= 8.0 Hz), 7.49 (q, 2H) , 7.41 (dd, IH, J= 4.8 Hz,
4.8 Hz), 7.14 (t, 2H, J= 8.8 Ez) , 6.46 (s, IH) , 5.43 (s, 2H) , 5.26
(s, 2H) , 2.38 (S, 3H)
'-H-NMR (CD3OD, 400 MHz) 5 8.45 (d, IH, J= 3.6 Hz), 8.42 (d, IH, J=
1.2 Hz), 7.60 (d, IH, J= 8.4 Hz), 7.41 (dd, IH, J= 5.2 Hz, 4.8
Hz), 6.97 (m, 2H) , 6.57 (s, IH) , 5.45 (s, 2H) , 5.27 (s, 2H) , 2.42
(s, 3H)
-NMR (CD3OD, 400 MHz) 8 8.45 (d, IH, J= 4.4 Hz), 8.41 (d, IH, J=
1.6 Hz), 7.58 (m, 2H) , 7.41 (m, 2H) , 7.22 (m, 2H) , 6.51 (s, IH) ,
5.44 (s, 2H) , 5.34 (s, 2H) , 2.39 (s, 3H)
'H-NMR (CD3OD, 400 MHz) 6 8.45 (d, IH, J= 4.0 Hz), 8.41 (d, IH,
J=1.6 Hz), 7.63 (d, IH, J= 7.6 Hz), 7.53 (m, IH) , 7.41 (dd, IH, J=
5.6 Hz, 5.2 Hz), 7.26 (m, IH) , 6.51 (s, IH) , 5.45 (s, 2H) , 5.29
(s, 2H) , 2.40 (s, 3H)
XH-NMR (CD3OD, 400 MHz.) 5 8.45 (d, IH, J= 4.0 Hz), 8.41 (d, IH, J=
1.6 Hz), 7.60 (m, 2H) , 7.39 (dd, IH, J= 5.2 Hz), 7.28 (s, IH) ,
7.26 {s, IH) , 6.50 (S, IH) , 5.44 (s, 2H) , 5.31 (s, 2H) , 2.40 (s,
3H) '
:H-NMR (CD3OD, 400 MHz) 5 8.45. (d, IH, J= 4.0 Hz), 8.41 (d, IH, J=
1.6 Hz), 7.68 (m, 2H) , 7.39 (dd, IH, J= 4 . 8 Hz , 4 . 8 Hz) , 7.31 (dd,
IH, J= 2.4 Hz, 2.8 Hz), 7.16 (ddd, IH, J= 2.8 Hz, 2.8 Hz, 2.8 Hz),
6.50 (s, IH) , 5.45 (s, 2H) , 5.32 (s, 2H) , 2.41 (s, 3H)
^-NMR (OD3OD, 400 MHz) 5 8.45 (d, IH, J= 4.0 Hz), 8.42 (s, IH) ,
7.60 (d, IH, J= 8.0 Hz), 7.47 (m, IH) , 7.40 (dd, IH, J= 5.2 Hz,
4.8 Hz), 7.07 (m, 2H) , 6.59 (s, IH) , 5.45 (s, 2H) , 5.32 (s, 2H) ,
2.41 (s, 3H)
1H-NMR (CD3OD, 400 MHz) 5 8.45 (d, IH, J= 4.8 Hz), 7.76 (ddd, IH,
J= 2.0 Hz, 1.6 Hz, 1.6 Hz), 7.51 (q, 2H) , 7.30 (dd, IH, J= 5 . 2
Hz), 7.19 (d, IH, J= 7.6 Hz), 7.14 (t, 2H, J= 8.8 Hz), 6.46 (s,
IH) , 5.44 (s, 2H) , 5.26 (s, 2H) , 2.40 (s, 3H)
'H-NMR (CD3OD, 400 MHz) 8 8.46 (d, IH, J= 4.8 Hz), 7.76 (ddd, IH,
J=2.0 Hz, 1.6 Hz, 1.6 Hz), 7.29 (dd, IH, J= 4.8 Hz, 5.2 Hz), 7.21
(d, IH, J= 7.6 Hz), 6.69 (dd, 2H, J= 8.0 Hz, 7.6 Hz), 6.57 (s,
IH) , 5.46 (s, 2H) , 5.28 (s, 2H) , 2.43 (s, 3H)
'H-NMR (CD3OD, 400 MHz) 5 8.45 (d, IH, J= 4.4 Hz), 7.76 (ddd, IH,
J= 2.0 Hz, 1.6 Hz, 1.6 Hz), 7.55 (m, IH) , 7.26 (m, 3H) , 6.50 (s,
IH) , 5.46 (s, 2H) , 5.29 (s, 2H) , 2.42 (s, 3H)
Example 439
3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-l-(pyridin-
3-ylmethyl)pyridin-2(IH)-one
Step 1. Preparation of 3-bromo-6-methyl-2-cxo-l-(pyridin-3-
ylmethyl)-l/2-dihydropyridin-4-yl trifluoromethanesulfonste
a chilled suspension (-30° C) of 3-bromo-4-hydroxy-6-
methyl-l-(pyridin-3-yltnethyl)pyridin-2 (IH) -one (0.481g, 1.63
mmol) in dichloromethane (6 mL) was .added triethylamine (0.28
mL, 2.04 mmol), followed by the addition of a solution of
trifluoromethanesulfonic anhydride (0.4 mL, 2.44 mmol) in
dichloromethane (3 mL). The reaction mixture stirred at -30°
C under nitrogen for 1 hour. The reaction mixture was diluted
with dichloromethane and washed with cold NaHC03/water. The
organic extracts were dried over Na2S04 and the filtrate was
concentrated under reduced pressure to afford the desired
compound as a yellow semisolid (0.6675 g, 95%) after drying,
ES-LRMS (M+H) m/z 427.1/429.1.
Step 2. Preparation of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6-
methyl-1-(pyridin-3-ylraethyl)pyridin-2(IH)-one
To a degassed solution of 3-bromo-6-methyl-2-oxo-l-
(pyridin-3-ylmethyl)-1,2-dihydropyridin-4-yl
trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL),
DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.225 mL,
1.95 mmol) and PdCl2(?Ph3)2 (O.llg) were added. The reaction
mixture stirred at room temperature under nitrogen for 1 hour
arid then heated in an oil bath (S5°C) under nitrogen
overnight. The solvents were distilled in vacuo and the
residue was purified by flash column chromatography (5%
methanol in ethyl acetate). The extracts were concentrated to
afford the desired compound (0.432 g, 69%) after drying. ""HNMR
(CD3OD, 400 MHz) 6 8.45 (s, 2H), 7.96 (s, IH), 7.64 (m,
3H), 7.41 (dd, IH, J= 4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J= 8.8
Hz), 6.46 (s, IH), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z
397.0361/399.0310 (M+H calculated for C2oHi$N2OFBr requires
397.0346/399.0328).
Step 3. Preparation of 3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-
methyl-1-(pyridin-3-ylmethyl)pyridin-2(IH)-one
A suspension of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6-
methyl-1-(pyridin-3-ylmethyl)pyridin-2(IH)-one (0.430g, 1.01
mmol) in Ethyl acetate (5 mL) and EtOH (5 mL), containing PtG>2
(0.015 g) was stirred in an atmosphere of hydrogen (15 psi)
in a Fischer- Porter bottle for 2 hours. The reaction mixture
was filtered and the filtrate was concentrated to reduce
volume. The material was purified by flash column
chromatography (ethyl acetate). The appropriate fractions
were combined and concentrated under reduced pressure to
afford the desired product (0.0943 g, 22 %) as a sticky
semisolid after drying. -NMR (CD3OD, 400 MHz) 8 8.46 (d,
2H, J= 26.4 Ez) , 7.60 (d, 1H, J= 8 .0 H z ) , 7.41 (dd, 1H, J= 4 . 3
Hz, 4.8 H z ) , 7.21 (m, 2H) , 6.97 (t, 2H, J= 8.8 H z ) , 6.24 (s,
IE), 5.43 (s, 2H) , 2.93 (m, 4H) , 2.31 (s, 3H) ; ES-HRMS m/z
401.0645/403.0603 (M+H calculated for C2oK-_sN:OFEr requires
401.0659/403.0641).
Example 440
3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-1-(pyridin-
4-ylmethyl)pyridin-2(1H)-one
The title compound was prepared by a procedure similar to
the one described for step 1 to step3 (0.374 g, 2.5%). MS and
1H-NMR for step 1 were consistent with the desired structure.
XH-NMR (CD3OD, 400 MHz) 6 8.80 (d, 2H, J= 6.8 Hz), 7.89 (d, 2H,
J= 6.8 Hz), 6.61 (s, 1H), 5.66 (s, 2H), 2.45 (s, 3H); ES-HRMS
m/z 427.9645/429.9625 (M+H calculated for C13HiaN2O4SF3Br
requires 427.9599/429.9578).
MS and 1H-NMR for step 3 were consistent with the desired
structure. XH-NMR (CD3OD, 400 MHz) 5 8.48 (d, 2H, J= 5.2 Hz),
7.21 (m, 2H), 7.13 (d, 2H, J= 5.2 Hz), 6.98 (t, 2H, J= 9.0
Hz), 6.26 (s, 1H), 5.43 (s, 2H), 2.95 (m, 4H), 2.25 (s, 3H);
ES-HRMS m/z 401.0682/403.0636 (M+H calculated for C2oH19N2OFBr
requires 401.0659/403.0641).
Example 441
3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-
3-ylmethyl) pyridin-2 (IH) -one
Step 1. Preparation of 3-chloro-4-hydroxy-6-methyl-l-
(pyridin-3-ylmethyl)pyridin-2(IH) -one
To a suspension of 4-hydroxy-6-methyl-l-(pyridin-3-
ylmethyl)pyridin-2(IH)-one (1.016 g, 4.7 mmol) in MeCl2 (10 mL)
was added NCS (1.21 g, 1.78 mmol). The reaction mixture
stirred at room temperature for 24 hours under nitrogen. The
suspension was chilled in an ice bath and filtered. The solid
was washed with fresh MeCl2 and dried to afford a yellow solid
(1.00 g, 85%) after drying. hl-NMR (CD3OD, 400 MHz) 5 8.54
(m, 2H) , 7.85 (d, IH, J=l.6 Hz), 7.61 (m, IH), 6.10 (s, IH),
5.41 (s, 2H), 2.33 (s, 3H); ES-LRMS (M+H) m/z 251/253.
Step 2. Preparation of 3 -chloro-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-l-(pyridin-3-ylmethyl)pyridin-2(IH)-one
To a degassed cold solution of DMF (10 mL) and ?Ph3
(resin, 2.2 g, 6.6 mmol) was added DEAD (1.03S mL, 6.6 mmcl).
The reaction mixture stirred at -10° C for 20 minutes under
nitrogen. A solution of 3-chloro-4-hydroxy-6-methyl-I-
(pyridin-3-ylmethyl)pyridin-2(IH)-one (1.00 g, 4.0 mmol) and
2,4-diflucrobenzylalcohol (0.66 mL, 6.0 mmol) in DM? (10 mL)
was added to the resin suspension. The reaction mixture
stirred at -10° C for 30 minutes and then allowed to stir at
room temperature for 1 hour. The resin was filtered and
rinsed with fresh MeOH and the filtrate concentrated. The
residue was dissolved in ethyl acetate and purified by flash
column chromatography (5% methanol in ethyl acetate). The
appropriate fractions were concentrated. -NMR (CD3OD, 400
MHc) 8 8.45 (ddd, 2H, J= l.SHz, 1.6 Hz, 1.6 Hz), 7.61 (m," 2H) ,
7.41 (dd, IH, J= 4'.4 Hz, 4.8 Hz), 7.02 (m, '2'H) , 6.55 (s, IH) ,
5.43 (s, 2H), 5.29 (s, 2H), 2.41 (s, 3H); ES-HRMS m/z
377.0882/379.0840 (M+H calculated for C19HisN202F2Cl requires
377.0863/379.0840) .
Example 442
1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-6-
methyl-4-[(2,4,6-trifluorobenzyl)oxy] pyridin-2(IH)-one
trifluoroacetate
The title compound was prepared by a procedure similar to
the one described for Example 385, step 2 (0.142 g, 9%) . 1H
NMR (CD3OD, 400 MHz) S 7.64 (s, IH) , 7.00 (m, 2H) , 6.66 (s,
1H) , 5.29 (S, 2E) , 5.18 (s, 2H) , 2.50 (S, 3H) , 2.47 (s, 3H) ;
ES-KRMS m/z 469.0488/471.0464 (M+H calculated for CigHi-N^O-F
requires 469.0481/471.0463).
Example 443
3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] - 6 -methyl - 1- { [2-methyl-4-
( methylamino) pyrimidin-5-yl] methyl }pyridin- 2 (1H) -one
trif luoroacetate
To a solution of 1- [ (4-amino-2-methylpyrimidin-5-
yl) methyl] -3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-
methylpyridin-2 (1H) -one hydrochloride (0.15 g, 0.3 mmol) in
DMF (3 mL) was added DBU (0.09 mL, 0.6 mmol). The solution
was cooled in an ice bath and iodomethane (0.019 mL, 0.3 mmol)
was added. The reaction mixture stirred at room temperature
under nitrogen for 2 hours. The reaction was purified by
reverse phase HPLC 10-90% CH3CN/water (30 minute gradient) at
a flow rate of 100 mL/min. The appropriate fractions (m/z=
465 M+H) were combined and freeze dried to afford the desired
product (0.036 g, 25%) as a white powder. XH NMR (CD3OD, 400
MHz) 5 7.72 (s, 1H) , 7.60 (m, 1H) , 7.03 (m, 2H) , 6.62 (s, 1H) ,
5.31 (s, 2H) , 5.16 (s, 2H) , 3.77 (s, 3H) , 2.60 (s, 3H) , 2.47
(s, 3H) ; ES-HRMS m/z 465.0717/467.0712 (M+H calculated for
requires 465.0732/467.0714).
Example 444
ethyl N-(5-{[3-bromo-4-[(2,4-difluorobensyl)cxy]-6-methyl-2-
oxopyridin-1(2K)-yl]methyl}-2-methylpyrimidin-4-yl)glycinate
trifluoroacetate
The title compound was prepared by a procedure similar to
the one described for Example 442 with the exception that the
reaction mixture had to be heated at oil bath temperature 70°
C for 2 days (0.1384 g, 51 %) . 1H NMR (CD3OD, 400 MHz) 6 7.78
(s, 1H), 7.61 (m, 1H), 7.03 (m, _2H), 6.61 (a, IE), 5.30 (s,
2H) , 5.18 (s, 2H) , 5.03 (s, 2H) , 4.27 (q, 2H) , 2.55-(s, 3H) ,
2.46 (s, 3H), 1.28 (t, 3H, J= 7.0 Hz); ES-HRMS m/z
537 .0936/539.0932 (M+H calculated for C23H24N404F2Br requires
537.0943/539.0926)
Example 445
N-(5-{[3-chloro-4-[(2 , 4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]methyl}-2-methylpyrimidin-4-yl)-
2-hydroxyacetamide trifluoroacetate
To a chilled solution of 1-[(4-amino-2-methylpyrimidin-5-
yDmethyl] -3-chloro-4- [ (2,4-difluorobenzyl) oxy] -6-
methylpyridin-2(1H)-one trifluoroacetate (0.200 g, 0.38 mmol)
in DMF (20 mL) and a catalytic amount of DMA? was added
triethylamine (0.064 mL, 0.38 mmol). The reaction stirred at -
20° C and acetoxyacetyl chloride (0.082 mL, 0.76 mrr.ol) was
added. The reaction stirred cold for 15 minuues and then
allowed to warm up to room temperature for 3 hours. The
reaction was monitored by LR-ESMS m/z = 466. The reaction was
incomlete after 3 hours. Added acetoxyacetyl chloride (0.05
mL, 0.466 mmol) , and triethylamine (0.2 mL, 1.43 tnmol) to the
reaction mixture and continued to stir overnight at room
temperature. The next morning the reaction heated at 65° C
for 3 hours. The solvent was removed in vacuo and IN LiOH
(2.5 mL) was added to the residue. The reaction was heated at
60° C for 5 hours. The reaction was diluted with acetonitrile
and water (1:1) and purified by reverse phase HPLC in 10-90%
CH3CN/water (30 minute -gradient) at a flow. .rate, of 50.mL/min.
The appropriate fractions were freeze dried to afford the
desired product (0.020 g, 9%). 1E NMR (CD3OD, 400 MHz) 5 8.04
(s, IH) , 7.6 (m, IH) , 7.02 (m, IH) , 6.59 (s, IH) , 5.30 (s,
2H), 5.24 (s, 2H), 4.26 (s, IH), 2.60 (s, 3H), 2.43 (s, 3H) ;
ES-HRMS m/z 465.1161 (M+H calculated for
requires 465.1136).
Example 446
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-
methylpyrazin-2-yl)methyl]pyridin-2(IH)-one
fStep 1. Preparation of 3-chloro-4-hydroxy-6-methyl-l-[(5-
methylpyrazin-2-yl)methyl]pyridin-2(IH)-one

OH
To a solution of 4-hydroxy-6-methyl-l-[(5-methylpyrazin-
2-yl)methyl]pyridin-2(1H)-one (l.OOg, 4.3 mmol) in glacial
acetic acid (10 mL) was added NCS (0.79 g, 5.94 mmol). The
reaction mixture stirred at 60° C for 6 hours. The solvent
was removed under reduced pressure and the resulting residue
was triturated with ethyl acetate. The desired product was
filtered and dried (0.80 g, 69%). XH NMR 8.47 (s, IH) , 8.42 (a, IH) , 6.08 (s, IH) , 5 ..36 (s, 2H) , 2.50
(s, 3H) , 2.43 (s, 3H) ; ES-HRMS m/z 266.0691 (M+H calculated
for Ca2Hi3N302Cl requires 266.0691).
Step 2. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-l-[(5-methylpyrazin-2-yl)methyl]pyridin-2(IH)-one
To a solution of 3-chloro-4-hydroxy-6-methyl-l-[(5-
methylpyrazin-2-yl)methyl]pyridin-2(IH)-one (2.48 g, 9.3 mmol)
in DMA (7 mL)was added K2C03 (1.54 g, 11.0 mmol) followed by
2,4-difluorobenzyl bromide (1.2 mL, 9.3 mmol). The reaction
mixture stirred at room temperature under nitrogen for 1.5
hours. The solvent was distilled in vacuo. The resulting
residue was diluted in dichloromethane and washed with water.
The organic extracts were concentrated and the resulting
residue was purified by flash column chromatography (ethyl
acetate). The appropriate fractions were combined, and
concentrated. XH NMR (CD3OD, 400 MHz) 8 8.49 (d, IH, J=1.2
Hz), 8.40 (s, IH), 7.59 (m, IH), 7.04 (m, 2H), 6.54 (s, IH),
5.41 (3, 2H), 5.28 (s, 2H), 2.54 (s, 3K), 2 . 4 0 (s, 3H); ESHRMS
m/z 392.1014 (M+H calculated for C19K17N30:C1F: requires
392 .0972) .
Example 447
3-bromo-4-t(2,4-difluorobenzyl)oxy]-6-methyl-l-({5-
[ (methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(IH)-one
trifluoroacetate
To a suspension of 3-bromo-l- { [5- (chloromethyl) pyr.azin-2-
yl] methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(IH)
one (0.25 g, 0.53 mmol) in THF was added methylamine (1 mL,
2.1 mmol). The reaction was sealed and stirred at room
temperature overnight. The reaction mixture was diluted in
water:acetonitrile (1:1) and purified by reverse phase HPLC
10-90% CH3CN/water (30 minute gradient) at a flow rate of 70
mL/min. The appropriate fractions were combined and freeze
dried to afford the desired product (0.22 g, 71%) as an
amorphous solid. XH NMR (CD3OD, 400 MHz) 6 8.73 (s, IH) , 8.55
(s, IH), 7.6 (m, 2H), 7.02 (m, IH), 6.54 (s, IH), 5.47 (s,
2H), S.29 (s, 2 H), 4.37 (s, 2 H), 2.78 (s, 3H), 2.56 (s, 3H).
ES-HRMS m/z 465.0732/467.0709 (M+H calculated for C2oH2oN402BrF2
requires 465.0732/467.0714).
Example 448
Ethyl 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2-oxopyridin-l(2H)-
yl]methyl}pyrazine-2-carboxylate
To a mixture of 3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one (0.59g, 2.07
mmol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (0.62 g,
2.4 mmol) in THF (15 mL) was added NaH (0.06 g, 2.4 mmol).
The reaction stirred at 60° C for 3.5 hours. The solvent was
removed under reduced pressure and the residue was partitioned
over dichloromethane and citric acid (5%) . The organic
extracts were washed with water and dried over Na2S04
(anhydrous). The organic extracts were concentrated and the
residue was purified by flash column chromatography (100 %
ethyl acetate). The appropriate fractions were combined and
concentrated under reduced pressure to remove solvent. 1H NMR
(CD3OD, 400 MHz) 6 9.11 (d, IH, J= 1.6 Hz), 8.77 (a, IH), 7.52
(m, IH), 7.02 (m, 2H), 6.57 (s, IH), 5.53 (s, 2H), 5.30 (s,
2H), 4.49 (q, 2H), 2.52 (s, 3H), 1.39 (t, 3H, J= 7.2 Hz); ESHRMS
m/z 450.1045 (M+H calculated for C2iH19N304ClF2 requires
450.01027).
Example 449
-chloro-4-[(2,4-difluorobenzyl)oxy]-1-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl)-6-methylpyridin-2(1H) -one
To a suspension of ethyl 5-{ [3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}pyrazine-2-carboxylate (4.0 g, 8.9 mmol) in THF:tbutanol
(1:1) (10 mL) was added NaBH4 (0.46 g, 12.4 mmol) . The
reaction stirred at room temperature under argon overnight.
The reaction mixture was quenched with acetic acid (2 mL) and
the solvent was removed in vacuo. The residue was triturated
with water and filtered. The solid was washed with fresh
water followed by ethanol. The solid was purified by flash
column chromatography (100% ethyl acetate). The appropriate
fractions were combined and concentrated under reduced
pressure to afford the desired compound (1.58 g, 44%) as a
white solid. ^ NMR (CD3OD, 400 MHz) 8 8.59 (s, 1H) , 8.56 (s,
1H), 7.52 (m, 1H) , 7.01 (m, 2H), 6.55 (m, 1H), 5.45 (s, 2H),
5.29 (s, 2H) , 4.71 (2H) , 2.54 (s, 3H) ; ES-HRMSm/Z 408.0940
(M+H calculated for Ci9Hi7N303ClF2 requires 408.0921) .
Example 450
-604-
5-{ [3-bromo-4-[(2,4-difluorobenzyl}oxy] -6-methyl-2-cxopyridin-
1 (2H) -yl] methyl }-N,N-diniethylpyrazine-2-carboxamide
To a cold solution of 5-{ [3-bromo-4-[(2,4-
difluorobenzyl)oxy]-6-rnethyl-2-cxopyridin-i(2K)-
yl]methyl}pyrazine-2-carboxylic acid {0.175 g, 0.37 rrunol) in
DMF (5 mL, -10° C) was added IBC? (0.046 mL, 0.35 mmol)
followed by NMM (0.041 mL 0.37 mmol). The reaction was
activated for 20 minutes at -15° C after which dimethylamine
(0.375 mL, 0.74 mmol} was added. The reaction stirred at -10°
C to room temperature for 45 minutes. The solvent was removed
in vacuo and the residue was purified by reverse phase HPLC
10-90% CH3CN/water (30 minute gradient) at a flow rate of 70
mL/min. The appropriate fractions were combined and freeze
dried to afford the desired product (0.140g, 75%.) as "a white
solid. 1R NMR (CD3OD, 400 MHz) 5 8.68 (s, 1H) , 8:67 (s, 1H) ,
7.52 (m, 1H) , 7.02 (m, 2H) , 6.54 (s, 1H) , 5.50 (s, 2H), 5.30
(s, 2H) , 3.11 (s, 3 H) , 3.07 (s, 3H) , 2.55 (s, 3H) ; ES-HRMS
m/z 493.0680/495.0657 (M+H calculated for C2iH2oN403BrF2
requires 493,0680/495.0657} .
Example 451
5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin-
1 (2H) -yl] methyl}-N-methylpyrazine-2-carboxamide
The title compound was prepared essentially as in Ex. 450,
substituting dimethylamine with methylamine. XH NMR (CD3OD, 400
MHz) 8 9.07 (s, 1H) , 8.68 (s, 1H) , 7.54 (m, 1H) , 7.02 (m, 2H) ,
6.54 (S, 1H), 5.52 (s, 2H), 5.30 (s, 2H), 2.94 (s, 3E), 2.54
(s, 3H) ; ES-KRMS m/z 479.0542/481.0518 (M-rH calculated for
C2oKi8N403BrF2 requires 479.0525, 481.0507).
Example 452
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(1-hydroxy-lmethylethyl)
pyrazin-2-yl]methyl}-6-methylpyridin-2 (IH).-one
To a cold flask of MeMgBr (1.59 mL, 1.0 mmol) was added a
suspension of ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate
(0.5 g, 1.0 mmol) in THF (20 mL). The reaction stirred at 0°
C for 1.5 hours and then at room temperature overnight. The
reaction was quenched with cold citric acid (25 mL, 5%) and
extracted with ethyl acetate (2 X 100 mL). The organic
extracts were washed with fresh water. The organic extracts
were concentrated and purified by reverse phase HPLC 10-90%
CH3CN/water (30 minute gradient) at a flow rate of 70 mL/min.
The appropriate fractions were combined and freeze dried to
afford the desired product (29.9 mg, 6%). XH NMR (CD3OD, 400
MHz) 5 8.76 (d, 1H, J= 1.6 Hz), 8.54 (d, 1H, J= 1.2 Hz), 7.52
(m, 1H), 7.02 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2H) , 5.29 (s,
2H), 2.55 (s, 3H), 1.52 (s, 6H); ES-HRMS m/z
480.0745/482.0722 (M+H calculated for C2iH2iN303BrF2 requires
480.0729/482.0711) .
Example 453
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyl}-N-(2-methoxyethyl)pyrazine-2-carboxamide
The title compound was prepared essentially as in Ex. 450,
substituting dimethylamine with 2-methoxyethylamine. 1H NMR
(CD3OD, 400 MHz) 5 9.08 (d, IH, J= 1.2 Ez), 8.70 (d, IH, J= 1.2
Hz), 7.61 (m, IH) , 7.04 (m, 2H), 6.54 (s, IH), 5.53 (s, 2H),
5.30 (s, 2H) , 3.56 (m , 4H) , 3.30 (s, 3H) , 2'.54 (s, 3H) ; ESHRMS
m/z 523.0822/525.0810 (M+H calculated for
requires 523.0787/525.0770).'
Example 454
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{ [5- (morpholin-
4-ylcarbonyl)pyrazin-2-yl]methyl}pyridin-2(IH)-one
The title compound was prepared essentially as in Ex.
450, substituting dimethylamine with morpholine. XH NMR
(CD3OD, 400 MHz) 5 8.77 (d, IH, J= 1.6 Hz), 8.67 (s, IH), 7.54
(m, IH) , 7.02 (m, 2H) , 6.54 (s, IH) , 5.50 (s, 2H) , 5.30 (s,
2H), 3.75 (S, 4H), 3.59 (dd, 4H, J= 5.6 Rz, 5.2 Hz), 2.5o (s,
3H); ES-HRMS m/2 535.0816/537.0817 (M+H calculated fcr
requires 535.0787/537.0770).
Examole 455
3-chloro-4-[(2,4-difluorobenzyl)oxy]-1-({5-[(4-
hydroxypiperidin-1-yl)carbonyl]pyrazin-2-yl}methyl)-6-
methylpyridin-2(IH)-one
Step I. Preparation of 5-{[3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}pyrazine-2-carboxylic acid
A mixture of ethyl 5-{ [3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}pyrazine-2-carboxylate (1.03g, 2.3 mmol) in IN NaOH
(3.4 ml, 3.45 mmol, EtOH/water 1:1 v/v) stirred at room
temperature for 2 hours. The reaction mixture was quenched
with 5% citric acid and filtered. The solid was washed with
water and dried to afford the desired product (1.011 g, 100%)
as a white solid. XH NMR (CD3OD, 400 MHz) 5 9.02 (s, IH) ,
8.60 (s, IH), 7.60 (m, IH), 7.04 (m, 2H), 6.55 (s, IH), 5.50
-60S(
s, 2H) , 5.30 (s, 2H) , 2.52 (s, 3H) ; ES-HRMS m/z 422.0732
(M+H calculated for C-_ir,l5N3O^ClF2 requires 422.0714).
Step 2. Preparation of 3 -chloro-4 -[ (2 , 4-dif luorobenzyl} cxy] -
1- ( (5- [ (4 -hydroxypiperidin-1-yl) carbonyl] pyrazin-2-yl}mechyl) -
6-methylpyridin-2 (IK) -one
The title compound was prepared by a procedure similar to
the one described for Example 453 (0.1396 g, 47%) . XH NMR
(CD3OD, 400 MHz) 5 8.67 (s, 2H) , 7.59 (m, 1H) , 7.02 (m, 2H) ,
6.57 (s, 1H) , 5.49 (s, 2H) , 5.30 (s, 2H) , 4.16 (m, 1H) , 3.89
(septet, 1H) , 3.72 (m, 1H) , 3.38 (m, 2H) , 2.56 (s, 3H) , 1.93
(m, IE) , 1.83 (m, 1H) , 1.45 (m, 2H) ; ES-HRMS. m/z 505.1485 (M+H
calculated for C24H24N404C1F2 requires 505.1449).
Example 456
5-{[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-S-methyl-2-
oxopyridin-1(2H)-yl]methyl}-N-(3-hydroxy-2,2-
dimethyIpropyl)pyrazine-2-carboxamide
The title compound was prepared by a procedure similar to
the one described for Example 455 (0.215 g, 71%). XH NMR
(CD3OD, 400 MHz) 5 9.08 (d, 1H, J= 1.2 Hz), 8.71 (d, 1H, J= 1.6
Hz), 7.58 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 5.52 (s, 1H),
5.30 (s, 1H), 3.31 (s, 4H), 2.55 (s, 3H), 0.912 (s, 6H); ESHRMS
m/z 507.1630 {M+H calculated for Cz^eN^ClFa requires
507.1605).
Example 457
5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrazine-
2 -carboxamide
The title compound was prepared by a procedure similar to the
one described for Example 455 except no purification was
required, only a NaHC03/ethyl acetate extraction was -needed,
(0.2176 g, 73%). XH NMR (CD3OD, 400 MHz) 5 9.11 (d, IH, J=
1.6Hz), 8.73 (d, IH, J= 1.3 Hz), 7.59 (m, IH) , 7.02 (m, 2H) ,
6.57 (s, IH), 5.53 (a, 2H), 5.30 (s, 2H), 4.01 (q, 2H) , 2.54
(s, 3H) ; ES-HRMS m/z 503.0930 (M+H calculated for
C2iHi7N403ClF5 requires 503.0904).
l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-tnethylpyridin-
2(IH)-one
Step 1: l-allyl-4-hydroxy-6-methylpyridin-2(IH)-one. 4-
hydroxy-6-methyl-2-pyrone (2g, 16 mmol) was stirred in water
(25 mL). Allylamine (1.2 ml, 16mmol) was added to the
-610-
reaction. The reaction was then heated to 100 °C at which
point the reaction became homogeneous. The reaction was
stirred at 100 °C for 2h. The reaction was then allowed to
cool to rt after which a white precipitate formed. The
precipitate was isolated by suction filtration. After
additional washing with water, 1. 8g (69%) of an off-white
solid was obtained.
Step 2: l-allyl-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2(lH)-one. To a stirred solution of the above pyrone(4.0g, 24
mmol) in DMF(75ml) was added Cs2CO3 (7.8g, 24mmol) followed by
addition of 2,4-diflurorbenzyl bromide(3.4 mmol, 26.4 mmol).
The resulting mixture was stirred at rt for 2h. Additional
Cs2C03 (Ig) and bromide (1 ml) was added and the reaction was
stirred for an additional 2h. The Cs2C03 was removed by
suction filtration. The DMF was removed under vacuum and the"
crude material was purified by flash chromatography. Elution
with ethyl acetate-hexanes (2:1 to 1:1) afforded 1.5 g (21%)
of the desired compound.
Step 3: l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one. To a stirred suspension of the above
pyridinone (Ig, 3.4 mmol) in CH3CN (10 ml) was added nbromosuccinimide
(670 mg, 3.8 mmol). The reaction mixture was
stirred, at rt, for 3h. The product was obtained by
filtration of the reaction mixture and washing of the solid
with diethyl ether. Hl-NMR (DMSOd6/400 MHz) 8 7.62 (app q, J =
8.8 hz, 1H) , 7.31 (ddd, J = 12.0, 9.6, 2.8 hz, 1H); 7.15 (app
dtd, J = 8.4, 2.4, 0.8 Hz, 1H) ; 6.50 (s, 1H) ; 5.87 (ddt, J =
12.4, 10.4, 5.6 Hz, 1H) , 5.30 (s, 2H) , 5.10 (dd, J = 10, 1.6
Hz, 1H), 4.87 (dd, J = 17.6, 1.6 Hz, 1H), 4.64 (m, 2H), 2.34
(s, 3H) ; 19F-NMR (DMSOd6/282.2 MHz) -109.68 (quin, J = 1H) , -
113.66(quar, J = 1H); KRMS m/z 370.0255 (M + H calcd for
C16HlsBrF2N02 = 3 7 0 . 0 2 4 6 ) .
Example 459
l-allyl-3-chloro-4- [ (2,4-difluorobenzyl) oxy] -6 -methylpyr idin-
2(lH)-one
Step 1: l-allyl-3-chloro-4-hydroxy-6-methylpyridin-2 (1H) -one.
To a stirred solution of l-allyl-4-hydroxy-6-methylpyridin-
2(lH)-one (500 mg, 3.0 mmol) in CH3CN(10 ml), .at rt,.was added
sequentially n-bromosuccinimide (440 mg, 3.3 mmol) and
dichloroacetic acid (546 p.1 , 6.62 mmol). The resulting mixture
was stirred for 2h. The heterogeneous mixture was filtered
and the solid was washed with additional CH3CN to give 350 mg
(59%) of the desired product as a tan solid. '"H-NMR (DMSOd6/300
MHz) 8 11.16 (s, 1H) , 5.98-5.86 (m, 2H) , 5.12 (dd, J = 10.5,
1.5 Hz, 1H) , 4.89 (dd, J = 17.1, 1.5 Hz, 1H) , 4.63-4.61 (m,
2H) , 2.29 (s, 3H) . ES-HRMS m/z 200.050 (M + H calcd for
- 200.0470)
Step 2: l-allyl-3-chloro-4-[ (2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one. The title compound was prepared by
the procedure outline in the synthesis of Example 458, step 3
1H-NMR (DMSOds/300 MHz) 8 7.67 (app q, J = 8.4 hz, 1H) , 7.36
(app dt, J = 10.2, 2.7 hz, 1H) ; 7.15 (m, 1H); 6.58 (s, 1H) ;
5.93 (ddt, J = 15.3, 9.6, 4.8 Hz, 1H), 5.30 (s, 2H) 5.15 (dd,
J = 10.2, 1.2 Hz, 1H), 4.92 (dd, J = 17.4, 1.2 Hz, 1H), 4.69-
4.67 (m, 2H), 2.41 (s, 3H). ES-HHMS m/z 32S.07SO (M + H calcd
for Ci6HiSClF2N02 = 325.0730).
Exaorole 460
Methyl (2E)-4-[3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]but-2-enoate
To a stirred suspension of NaH (277 mg, 11 mmol) in anhydrous
THF (30 ml), which was cooled to 0°C, was slowly-added 3-bromo-
4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one (3.3g,
10 mmol). The resulting slurry was stirred for 15 min, after
which methyl 4-bromocrotonate (1.4 ml, 12 mmol) was added to
the reaction. The ice bath was removed and the reaction was
heated to reflux for 16h. The reaction was quenched by the
addition of IN NEUCl. The layers were separated and the
aqueous layer was extracted with CH2C12 (5x) . The organics
were combined, dried, and concentrated in vacuo. The crude
yellowish material was then triturated with Et20 to give, after
filtration and drying, 1.8g (43%) of a white solid. ^-NMR
(DMSOds/300 MHz) § 7.65 (app q, J = 8.7 hz, IH), 7.36 (app dt,
J = 12.0, 3.0 hz, IH); 7.17 (dt, J = 8.4, 1.8 Hz, IH); 6.94
(dt, J = 15.9, 4.5 HZ, IH) ; 6.57 (a, IH) , 5.52 (d, J = 15.9
Hz, IH), 5.29 (a, 2H), 4.84 (m, 2H), 3.63 (s, 3H), 2.33 (s,
3H) . ES-HRMS m/z 428.0301 (M + H calcd for CiaH17BrF2N04 =
428.0310) .
Example 461
3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-l-prop-2-
ynylpyridin-2 (1H) -one.
Stepl : 4- [ (2 , 4-dif luorobenzyl) oxy] - 6 -methyl -1 -prop- 2-
ynylpyridin-2 (1H) -one. The title compound was prepared by
alkylation of 4- [ (2 , 4-dif luorobenzyl) oxy] -6-methylpyridin-
2(lH)-one (2: 5g, 10 mmol) with propargyl bromide .,(1 . 3 ml, 11.0
mmol) as described above to give 1'. 3g (44%) of the desired
product. 1H- NMR (DMSOds/300 MHz) 8 7.60 (app q, J = 8.4 hz,
1H) , 7.35-7.27 (m, 1H) ; 7.16-7.10 (m, 1H) ; 5.94 (d, J = 2.1
Hz, 1H) , 5.88 (d, J = 3.0 Hz, 1H) , 5.03 (s, 2H) , 4.76 (d, J =
2.4, Hz, 2H) , 3,31 (s, 3H) , 3.24 (t, J - 2.4 Hz, 1H) , 2.39 (s,
3H) ; ES-HRMS m/z 290.0994 (M + H calcd for C1SH14F2N02 =
290.0993) .
Step 2: Bromination of 4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-lprop-
2-ynylpyridin-2 (1H) -one (500 mg, 1.67 mmol) with NBS (300
rag, 1.67 mmol) was carried out in the manner described above
to give 350 mg (57%) of the desired compound. ^-NMR
(DMSOds/300 MHz) 5 7.67 (app q, J = 9.0 hz, 1H) , 7.36 (app dt ,
J = 10.5, 2.4 hz, 1H) ; 7.23-7.16 (m, 1H) ; 6.60 (s, 1H) , 5.29
(s, 2H) , 4.90 (d, J = 2.4, Hz, 1H) , 3.35 (s, 3H) , 3.32 (s,
1H) , 2.53 (s, 3H) ; ES-HRMS m/z 368.0107 (M + H calcd for
CiSH13BrF2N02 368.0098).
Example 462
4- [ (2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-1-(pyridin-
3-ylmethyl)pyridin-2(IH)-one.
Stepl: To a suspension of (4-[(2,4-difluorobenzyl)oxy]-
6-methyl-l-(pyridin-3-ylmethyl)pyridin-2(IH)-one) (710 mg, 2
mmol) in dioxane (10 mL) was added selenium dioxide (l.lg 10
mmol). The resulting mixture was heated to 160 °C in a.125 mL
sealed tube for Ih. The reaction was filtered through a
fritted funnel. The filtrate was washed with (10:1) CH2C12-
MeOH. The organics were combined and concentrated in vacuo.
The crude material was purified by flash chromatography.
Elution with (50:50 -> 0:100)hexanes yielded 450 mg (63%) of
the aldehyde. XH-NMR (DMSOd6/400 MHz). 59.48 (s, IH, CHO) .
Step 2: The aldehyde (350 mg, 1 mmol) was dissolved in MeOH
(4 mL) and cooled to 0 °C . To this mixture was added NaBH4
(28 mg, 1 mmol) in one portion. After 30 min, additional NaBH4
(20 mg) was added to the reaction. The MeOH was then removed
under vacuum. The residue was diluted with IN NH4C1 and then
extracted with CH2C12(4X). The organics were combined, dried,
and concentrated in vacuo. The yellowish crude product was
then taken up in (1:1) CH2Cl2-Et20. After sitting for a period
of time a white precipitate resulted. Filtration and washing
with additional Et20 yielded, after drying, 250 mg (55%) of the
desired alcohol. -NMR (DMSOd6/400 MHz). 58.42 (dd, J = 4.4,
1.6 Hz, 1H) 8.37 (d, J = 1.6 Hz, 1H), 7.61 (app q, J = 8.0 Hz,
IK), 7.45 (d, J = 8.0 Hz, 1H) , 7.32-7.27(M, 2H) , 7.12 (dt, J =
8.4, 1.6 Hz, IK), 6.07 (d, J = 2.8 Hz, 1H) , 5.99 (d, J = 12.3
Hz, 1H), 5.63 (br s, 1H), 5.18 (s, 2H), 5.09 (s, 2H), 4.29 (s,
2H). LC/MS, t- = 1.19 minutes (5 to 95% acetonitrile/water over
5 minutes at 1 ml/min with detection 254 nm, at 50°C) . ES-MS
m/z 359.1 (M+H)
Example 463
3-Bromo-4- [ (2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)1-
(pyridin-3-ylmethyl)pyridin-2 (1H)-one.
The title compound was prepared by bromination of as
described above to give a 60% yield. 1H-NMR (DMSOds/300 MHz)
6 7.93 (d, J = 7.8 Hz, 1H), 7.73-7.65 (m, 3H), 7.38 (dt, J =
10.2, 2.4 Hz, 1H), 7.21 (app t, J = 8.7 Hz, 2H), 6.74 (s, 1H),
5.38.-5.36 (m, 4H), 4.50 (s, 2H) ; ES-HRMS m/z 437.0311 (M +
cacld for Ci9H16BrF2N202 = 437.0313).
Example 464
3-bromo-4-[ (2,4-difluorobensyl)oxy]-6-
[ (diraethylamino)methyl]-I-(pyridin-3-ylmethyi)pyridin-2(IK)-
one.
The title compound was prepared in a similar manner to the
procedure outlined below for 3-bromo-4- [ (2,4-
difluorobenzyl)oxy]-I-(2,6-difluorophenyl)-6-[(dimethylamino)-
methyl]pyridin-2(1H)-one using the aldehyde (300 mg, 0.85
mmol) described above and 2.0 N THF solution of dimethylamine
(500 ]iL, 1 mmol) to give 110 mg (34%) of a colorless oil. The
oil was then dissolved in MeOH (1 mL) and stirred with fumaric
acid (25 mg) for Ih. The resulting precipitate was filtered,
washed with diethyl ether, and dried to give the pure product
as its fumurate salt. -NMR (DMSOd6/400~ MHz) . 5 8 .43-8 .41 (m,
IH) , 8.35 (s, IH), 7.67-7.61 (m, IH), 7.44-7.40 (m, IH), 7.35-
7.29 (m, 2H) , 7.17-7.12 (m, IH} , 6.62 (s, IH) , 6.60 (s, IH) ,
5.41 (s, 2H) , 5.32 (s, 2H) , 3.13 (s, 2H) , 2.12 (s, 6H) .
LC/MS, tr = 1.55 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z
464 (M+H).
Example 465
3-bromo-4- [(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
(hydroxymethyl)pyridin-2(IK)-one
Stepl: 4- [ (2,4-difluorobenzyl)oxy]-I-(2,6-difluorophenyl)-6-
oxo-1,6-dihydropyridine- 2 -carbaldehyde.
F
In a 300 ml high-pressure glass reaction vessel "(16.3 g,
45 mmol) was dissolved in 1,4-dioxane (90 mL). The reaction
vessel was sealed and immersed in a preheated oil bath at 170 °
C. The reaction was heated at 170° C (165 -170 °C) for 1.5
hours and then cooled to room temperature. The reaction was
worked up by filtering the reaction mixture through a plug of
celite and silica gel. The plug was then washed with 500 ml
of methanol-CH2Cl2 mixture (1:5). The filtrate was evaporated
to give 14.2 g of the desired crude aldehyde.
Step 2: Preparation of 4-[(2,4-difluorobenzyl)oxy]-1- (2,6-
difluorophenyl)-6-(hydroxymethyl)pyridin-2(IE)-one.
In a 500 ml three neck round bottom flask equipped with a stir
bar of 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
oxo-1,6-dihydropyridine-2-carbaldehyde (14.2 g, 37.7 mmol) was
dissolved in methanol (200 mL). The reaction mixture was
cooled to 0 °C and to this was added sodium borohydride (2.13g,
56.30 mmol) in a slow portion-wise fashion. The reaction was
stirred at 0 °C for 2 hour. Excess amount of sodium
borohydride was added to drive the reaction to completion.
After stirring for approximately 2.5 hours, the reaction was
allowed to warm to room temperature and then concentrated to
dryness. The residue was taken up in ethyl acetate (100 mL)
and washed with dilute HC1 (pH of aqueous layer was
approximately 4). Organic extracts were washed with brine (IX
50 ml) , dried over MgS04, and concentrated in vacuo. The crude
product was recrystallized from ethyl acetate and hexane to
yield 7.56 g (44% yield-starting from step 1) of the desired
alcohol.
Step 3: Preparation of the title compound.
In a 100 ml round bottom flask of 4-[(2,4-difluorobenzyl)oxy]-
1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(IH)-one
(2.49 g, 6.56 mmol), from step 2, was dissolved in
acetonitrile (35 mL). The reaction mixture was cooled to 0
in ice bath for 10 min. and then charged with Nbomosuccinamide
(1.17g, 6.6 mmol) . The mixture was allowed
-619-
to stir, at 0 °C, under nitrogen atmosphere for 2 hours. The
reaction was the worked up by removing the acetonitrile under
vacuum. The resulting residue was then filtered, with washing
from a small amount of acetonitrile, to give a yellow solid. 1P.
NMR (400 MHz, DMSO-ds) 5 7.695 - 7.588 (m, 2H), 7.368-7.314
3H), 7.175 (dt, J = 8.5, 2.5, Hz, IH), 6.760 (s, IH), 5.712
(t, J = 5.674 Hz, IH), 5.384 (s, 2H), 4.004-3.990 (m, 2H); 5SHRMS
m/z 458.0013 (M+H-calcd for Ci9H13BrF4N03, requires
458.0013).
Example 466
3-chloro-4- [ (2, 4-difluorobenzyDoxy] -1- (2, 6-difluorophenyl) -6-
(hydroxymethyl)pyridin-2(IH)-one
The title compound was prepared by taking 4-[(2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
(hydroxymethyl)pyridin-2(IH)-one (1.5g, 3.9 mmol) in
acetonitrile (15 tnL) and adding to that N-chlorosuccinimide
(580 mg, 4.3 mmol) . The reaction was stirred at rt for 3h
afterwhich a small amount of additional N-chlorosuccinimide
(50 mg, 0.4 mmol) was added to the reaction. Stirring was
continued for Ih. The reaction mixture was filtered through a
fritted funnel to obtain the crude material. *H NMR (400 MHz,
DMSO-d6) 8 7.69 - 7.61 (m, 2H) , 7.37-7.31 (m, 3H) , 7.17 (dt, J
= 8.8, 2.0 Hz, 1H), 6.80 (s, IK), 5.70 (t, J = 6.0 Hz, IK),
5.38 (S, 2H), 4.01 (d, J = 6.0 Hz, 2H); ES-HRMS m/= 414.0515
(M-fH calcd for C19H13C1F4N03, requires 414.0520).
Exarrrole 467
5-bromo-4-[(2,4-difluorobenzyl)oxy]
-1-(2,6-difluorophenyl) -6-oxo-l,6-dihydropyridine-2-
carbaldehyde
Preparation of the title compound. In a 50 ml one neck round
bottom flask 4-[(2,4-difluorobenzyl)oxy]-1- (2,6-
difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde (0.36
g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The
reaction mixture was cooled to 0 °C in ice bath and charged
with N-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was
allowed to stir at 0 °C for 2 hours under nitrogen atmosphere
After 2 hours, the solvent was evaporated under vacuum. XH
(400 MHz, DMSO-dg) 5 9.53 (s, 1H) , 7.73 - 7.67 (m, 2H) , 7.62-
7.54 (m, 1H), 7.35 (dt, J = 10.40, 2.56 Hz, 1H), 7.27 (t,
J=8.35 Hz, 2H), 7.19 (dt, J =8.60, 2.44 Hz, 1H), 5.72 (s, 1H),
5.50 (s, 2H) ; ES-MS m/z 455.9836 (M+H calcd for Ci9HuBrF4N03,
requires 455.9859).
Example 468
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
[(dimethylamino)methyl]pyridin-2(IH)-one
In a 50 ml round bottom flask 5-bromo-4-[(2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-l,6-. _
dihydropyr idine-2 -carbaldehyde (0.456 gmy-^l.O mmol) was
stirred in dichloromethane (5 mL). To this mixture was added
a 2M THF solution of dimethyl amine (1.25ml, 2.5 mmol ). The
mixture was allowed to stir under nitrogen atmosphere and at
room temperature for 2 hours. To this mixture was then added
triacetoxy sodium borohydride (0.37 g, 1.75 mmol) followed by
two to three drops of acetic acid. The mixture was then
stirred at rt overnight. The solvents were then removed by
evaporation and the residue was taken up in ethyl acetate (30
ml) and washed with aqueous sodium bicarbonate and brine. The
organics were then combined, dried over MgS04, and concentrated
in vacuo. The crude product was purified by flash column
chromatography using a solvent gradient of (3:1) ethyl
acetate-hexane to (0:100) ethyl acetate to give 0,14 g (30 %
yield) of the desired product. XH NMR (300 MHz, DMSO-ds) B
7.73-7.58 (m, 2H), 7.42-7.30 (m, 3H), 7.22 (dt, J=8.73, 2.60
Hz, IH) , 6.81 (s, IH) , 5.44 (s, 2H) , 3.04 (s, 2H) , 1.96 (s,
6H) ; ES-MS m/z 485.0 (M+H) . ES-HRMS m/z 485.0457 (M+H calcd
for C2iH1BBrF4N202, requires 485.0489).
Exanrole 469
3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -1- (2, 6-difluorophenyl) -6-
(morpholin-4-ylmethyl)pyridin-2 (1H) -one
The title compound was prepared by reacting 5-bromo-4-
[ (2 , 4-difluorobenzyl) oxy] -I- (2, 6-difluorophenyl) -6-oxo-l, 6-
dihydropyridine- 2 -carbaldehyde (0.456 g, Immol ) with
morpholine (0.13 ml, 1.5 mmol) and triacetoxy sodium
borohydride (0,42 g, 2.0 mmol) in dichlorome thane (7 mL) by
using a similar procedure to the one described for Example
468. The crude product was purified by flash column
chromatography. Elution with (50:50 ~» 0:100) hexanes-ethyl
acetate to give 0.15 g (29% yield) of the desired product. XH
NMR (300 MHz, DMSO-ds) 5 7.75- 7.57 (m, 2H) , 7.43-7.31 (m, 3H) ,
7.20 (dt, J=8.64, 2.48 Hz, 2H) , 6.85 (s, IE) , 5.44 (s, 2H)
3.37 (app t, J=4.37 Hz, 4H) , 3.13 (s,2H), 2.08 (t, J=4.19 Hz,
4H) ; ES-HRMS m/z 527.0600 {M+H calcd for C23H2oBrF4N203 requires
527.0594) .
Example 470
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
{[(2-methoxyethyl)amino]methyl}pyridin-2(1H)-one
The title compound was prepared by reacting 5-bromo-4-
[ (2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-oxo-l,6-
dihydropyridine-2-carbaldehyde -(0.319 g, 0.7 mmol) with 2-
methoxy ethylamine (0.086 ml, 1.0 mmol) and tri-acetoxy sodium
borohydride (0.42 g, 2.0 mmol) in dichloromethane (4 mL)by
using a procedure, similar to the one described for Example
468. The crude product was purified by flash column
chromatography. Elution with (50:50 -> 0:100) hexanes-ethyl
acetate to give 0.13 g of the desired product.
XH NMR (400 MHz, CDC13) 6 7.54 (q, J=6.89 Hz, 1H) , 7.41 - 7.33
(m, 1H), 7.19 (s, 1H), 6.99 (t, J = 7.90 Hz, 2H), 6.90 (dt,
J=7.90, 2.78, Hz, 1H), 6.80 (dt, J = 10.60, 2.34 Hz, 1H), 6.51
(s,lH), 5.24 (s,2H), 3.33 (t, J=4.69 Hz,1H), 3.30 (s, 3H),
2.57(t, J= 4.86 Hz, 2H), 1.53 (s,2H); ES-HRMS m/z 515.0548
(M+H calcd for C^oB^NjOa, requires 515.0594).
Example 471
5-bromo-4-[(2,4-difluorobenzyl)oxy]-I-(2,6-difluorophenyl)-6-
oxo-I,6-dihydropyridine-2-carboxylic acid
In a 100 ml round bottom flask, 3-bromo-4- [(2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6 •
(hydroxymethyl)pyridin-2(1H)-one (1.70 g, 3.7 mmol)-was
dissolved in acetone (10-mL) and cooled to 0 ° C in-ice bath.
To the reaction was added 1M acetone solution of Jones (5 ml,
excess amount) . Additional Jones reagent was added over time
(approximately 6 hours) until the reaction was complete. The
reaction was then concentrated down to dryness. The residue
was then taken up in ethyl acetate (10 mL) and washed with
brine. The dark yellow to brown colored crude product was
purified by dissolving in IN aqueous NaOH. The remaining
organic impurities were removed by extracting with diethyl
ether. The organic layers were discarded and the aqueous
layer was acidified with dilute HC1 (til PH app 1) to
precipitate the pure acid which was then filtered and
triturated with ether to obtain 1.17 g (65%) of the desired
product. ^-H NMR (400 MHz, DMSO-d6) 5 7.66 (q, J= 9.41 Hz, 1H) ,
7.57- 7.50 (m, 1H), 7.34 (dt, J= 10.11, 2.78 Hz, 1H), 7.28-
7.23 (m, 3H) , 7.18 (dt, 8.90, 2.42 Hz, 1H) , 5.47 (s, 2H) . ESHRMS
m/z 471.9814 (M+H calcd for Ci9H11BrF4N04, requires
471.9808)
Exairrole 472
Methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2 -
oxopyridin-1(2H)-yl]-3-methylbenzoate
Stepl: Preparation of methyl 4-(4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)-3-methylbenzoate .
In a 50 ml one neck round bottom flask equipped with a
stir bar, Dean Stark trap, and condenser 4-amino-2-methylmethylbenzoate
(1.19g, 11.63 mmol) and 4-hydroxy-6-methyl-2Hpyran-
2-one (l.Sllg, 12.78 mmol) were mixed together and
dissolved in 1,2-dichlorobenzene (5 tnL) . The mixture was
vigorously stirred and then placed in a preheated oil bath at
165 0 °C. The reaction was maintained at 165 0 °C for 1.5
hour and cooled to room temperature. The reaction was worked
up by diluting with toluene (10 mL) and then stirring at room
temperature for 2 hours. A light brown precipitate resulted.
The crude product was isolated by filtration and then
zriturated with ether. 1H NMR ( 4 0 0 MHz, DMSO-d5) 5 10.64 (s,
IE), 7.93 (S,1H), 7.85 (dd, 8.46 Hz, 1H), 7.26 (d , J= S.12
Hz, 1H), 5.91 (d, J= 2.32 Hz, 1H), 5.54 (d, u=2.32 Hz, IH) ,
3.84 (s, 3K), 1.99 (s, 3H), 1.73 (s,3E). SS-HRMS m/z 272.0SSO
(M-H calcd for C15Hi4N04, requires 272.1001).
Step 3: Preparation of Methyl 4-(3~bromc-4-hydrcxv-6-
methyl-2-oxopyridin-l (2H)-yl)-3-methylbenzoate
Methyl 4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-
yl)-3-methylbenzoate was prepared by reacting - methyl 4-(4-
hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-3-methylbenzoate with
N-bomosuccinamide in acetonitrile by following a procedure,
similar to the one described in Example 465- step 3. 1H NMR
(400 MHz, DMSO-d6) 5 7.95 (s, IH) , 7.87 (dd, J = 7.76, 2.02 Hz,
IH) , 7.31 (d, J=8.54, IH), 6.09 (s,lH), 3.85 (s, 3H) , 1.99
(s,3H), 1.74 (s, IH). ES-HRMS m/z 352.0195 (M+H calcd for
Ci5Hi4BrNO4, requires 352.0185)
Step 4: The title compound was prepared by taking methyl 4-
(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-3-
methylbenzoate (0.92 g, 2.61 mmol) and dissolving in dry DMF
(5 mL). Potassium carbonate (0.432 g, 3.13 mmol) and 2,4
Difluuorobenzyl bromide (0.335 ml, 2.61 mmol) were then added.
The mixture was allowed to stir at room temperature for 2
hours.
The reaction was then worked up by pouring it into 100 ml of
ice-water which resulted in a precipitate forming which was
isolated by filtering through a fritted funnel. The crude
product was washed with ether and dried in vacuum to give O.S5
g (76.20%) of pure product. LH NMR (400 MHc, DMSO-d0-) 6 7 . 98
(d, J = 1.6 Hz, IE), 7.88 (dd, J =8.04, 2.0 Hz, IK), 7.69 (q,
J = 8.6 Hz, 1H), 7.36-7.30 (m, 2H), 7.17 (dt, J = 8.7, 2.3 Hz,
1H), 6.71 (s,!H), 5.32 (s,2H), 3.86 (s,3K), 2.00 (s,3H), 1.86
(s, 3H) . ES-HRMS m/z 478.0459 (M+H calcd for C22H19BrF2N04
requires 478.0466).
Examples 473-476
The compounds of Examples 473-476 are prepared by derivitazion
of the compounds of Example 472.
Compound
No.
Ex. 473
Ex. 474
Ex. 475
Ex. 476
R
-C02H
-CH2OH
C(O)NH(CH2)2OCH3
C(0)NHCH3
MF
C21HlsBrF2N04
C21H18BrF2N03
C24H22BrF2N204
C22H20BrF2N203
M+H
Requires
464.0310
450.0500
521.0888
477.0626
ESHRMS
m/z
464.0324
450.0517
521.0865
477.0609
NMR characterization of Examples 473-475
Ex.No. NMR Data
473 :H-NMR (400 MHz, DMSO-d5) 5 13.11 ( s , IH) , 7.95 (d, J = 1-70 Ks,
IH) , 7.86 (dd, J=7.88, 1.91 Hs, IH) , 7.67 (dg, J = 8.47, 1,39 H=,
IH), 7.35-7.30 (m, 2H) , 7.17 (dt, J = 8 . S 4 r 2.48 Hz, 1H), S.71
(S,1H), 5.32 ( s , 2 H ) , 1.99 (s, 3H? , 1.87 (s, 3H)
474 :H NMR (400 MHz, DMSO-as) 5 7.S7 (q, J =8.5 Hz,IE), 7.34 (dd, J
= 10.04, 2.77 Hz, IH), 7.32 (s, IH) , 7.24 (dd, J = 8.39,1.47 Hz,
IH), 7.17 (dt, J = 8 . 8 4 , 2 . 6 Hz, IH), 7.08(d, J = 7.94 Hz, 1 H ) ,
6.66 (S,1H), 5.30 (S, 2H), 5.25 (t, J = S.01 H2, IH), 4.5 (d, J
=6.68 Hz, 2H), 1.91 (s, 3H ), 1.86 (s,3H)
475 1H NMR (400 MHz, DMSO-ds) 5 8.58 (app t, J =5.4 Hz,IK), 7.84
(S,1H), 7.76 (dd, J= 8.06, 1.63 Hz, IH) , 7.68 (dq, J= 8.77, 2.04
Hz, IH) , 7.33 (dt, J=9.76, 2.03 Hz, IH) , 7.27 (d, J=8.34 Hz,lH),
7.17 (ddt, J=8.51, 2.63, 0.91 Hz, IH), 6.70 (s, IH), 5.31 ( s , 2 H ) ,
4.50 (t, J=5.6 Hz , IH), 3.47-3.36 (m, 4H), 3.24 (s, 3H), 1.97
( s , 3 H ) , 1.87 (s,3H)
476 1H NMR {400 MHz,"DKSO-dJ S 8.50-8,'43 (m, IH) , 7.82 (s, IH) , 7.74
(dd, J=8.22, 1.79 Hz, IH) , 7.69 (q, J=-6^.75 Hz, IH) , 7.33 (dt, J=
9.88, 2.57 Hz, IH) , 7.26(d, J=8.52 Hz, IH) , 7.17(dt, J= 8.93, 2.16
Hz, IH) , 6 . 6 9 ' ( s , IH) , 5.31 (s, 2H) , '2.77 (d, J = 4 . 5 8 H s , 3H) ,
1.97 (s, 3H), 1.86 (s, 3H)
Example 477
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-4'
vinylphenyl)pyrxdin-2(IH)-one
Step 1- Preparation of -1-(4-bromo-2-methylphenyl)-4-
hydroxy-6-methylpyridin-2(IH)-one
The title compound was prepared in a similar manner to the
procedure outlined above for 4-(4-hydroxy-6-methyl-2-
oxopyridin-l(2H) -yl) -3-methylbenzoate. XH NMR (400 MHz, DMSOd6)
6 10.61 (s, 1H) , 7.59 (d, J= 2.84 Hz, 1H) , 7.45 (dd, J=
8.39, 2.44 Hz, 1H), 7.06 (d, J= 7.44, 1H), 5.89 (d, J=2.73 Hz,
1H), 5.53(d, J=2.30, 1H), 1.91 (s, 3H), 1.75 (s, 3H). ESHRMS
m/Z- 294.0127 (M+H calcd for C13H13BrN03, requires
294.0130).
Step 2- Preparation of - 1-(4-bromo-2-methylphenyl)-4- [ (2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one
1-(4-bromo-2-methylphenyl)-4-hydroxy-6-methylpyridin-2
(1H)-one (7.35 g, 25.0 mmol) was dissolved in DMF (15 mL) and
stirred with potassium carbonate (4.14 g, 30.0 mmol) and 2,4
difluorobenzyl bromide (3.21 ml (25.0 mmol) at room
temperature for 2 hours. The reaction was worked up by pouring
in to 300 ml ice water under continuous stirring. A white
precipitate was obtained which was isolated by filtering and
further purified by triturating with ether to give 3.06 g
(29%) of the desired product. 'E NMR (400 MKz, DMS-dD-) 5 7.65-
7.59 (m, 2H) , 7.49 (dd, J=S.45, 2.22 Hz, IK), 7.31 (dt, J=
9.79, 2.22 Hz, 1H) , 7.16- 7.08 (m, 2H) , 6.05 (d, J= 2.58 Hz,
1H) , 5.93 (d, J= 2.66 Hz, 1H), 5.08 (s, 2H), 1.93 (s, 3H),
1.77 (s, 3H) . ES-HRMS m/z 420.0390 (M+H calcd for C2oHi73r?2NOrequires
420.0411) .
Step 3: Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-
1-(2-methyl-4-vinylphenyl)pyridin-2(1H)-one.
F
In a 50 ml round bottom flask previously evacuated and filled
with nitrogen, 1-(4-bromo-2-methylphenyl)-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2 (1H)-one (0.420 g, 1.0
mmol) was dissolved in dry THF (10 mL) . To this mixture was
added Pd (PPh3)4 (0.173 g, 0.15 mmol). The reaction flask was
sealed with a rubber septum, evacuated and filled with
nitrogen. Under a nitrogen atmosphere, tributyl(vinyl)tin
(0.35 ml, 1.2 mmol) was added to the sealed reaction mixture
and stirred overnight at 50 °C.
The reaction was worked up by quenching with water and
extraction of the product with ethyl acetate. The crude
product was purified by column chromatography. Elution with
ethyl acetate-hexanes (50:50 -> 0:100) gave 0.32 g (69%) of the
desired product.
Step 4: The title compound was prepared by reacting
4- [ (2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-4-
vinylphenyl)pyridin-2(IH)-one (0.64 g, 1.74 mmol) with Nbromosuccinamide
(0.325 g, 1.83 mmol) in acetonitrile (9 mL)
at 0°C using a similar procedure as described in step 3 of
Example 465, to give 0.423 g (54.5 % after recrystallization)
of the desired product. XH NMR (400 MHz, DMSO-d6) 5 7.67(app
q, J= 7.59 Hz, IH), 7.48(s,lH), 7.42(dd, J=8.21,1.98 Hz,lH),
7.33(dt, J-10.00, 2.27 Hz, IH), 7.17(dt, J=8.51, 2.44 Hz, IH),
7.13(d, J=7.88 Hz, IH) 6.74(dd, J=11.29,. 6.34 Hz, IH) , 6.67
(s,lH), 5.88(d, J= 17.85, IH) , 5.32-5.30 (m, 2H) , 1.92 (s,
3H), 1.88 (s,3H). ES-HRMS m/z 446.0579 (M+H calcd for
C22H19BrF2N02, requires 446.0568).
Example 478
3-bromo-4-[(2,4-difluorobenzyl)oxy] -1-[4-(1,2-dihydroxyethyl)
2-methylphenyl]-6-methylpyridin-2(IH) -one
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-
4-vinylphenyl)pyridin-2(IH)-one (0.126 g, 0.28 mmol) was
dissolved in a mixture of acetone (3 mL) and water (1 mL). To
this was added 4-methylmorphclir.e N-oxide (0.032 g, 0.2S ramcl)
and catalytic amount (approximately 5 mgs) of osrr.ium tecroxide
was added, and stirred under nitrogen atmosphere. After
approximately 2 hours, the reaction was worked up by
evaporation of the acetone. The product was extracted into
ethyl acetate and concentrated to give a dark colored solid
which was further purified by column chromatography to give
0.049 g (37 % yield)of charcoal colored solid. 1H NMR (400
MH2, DMSO-ds) 5 7.67 (q, J=8.24 Hz, 1H) , 7.37-7.23 (m, 3H)
7.17 (dt, J= 8.62, 2.62 Hz, 1H) , 7.07 (dd, J=9.36, 2.24 Hz,
1H), 6.65(s,lH), 5.30 (s, 2H), 4.74(t, J=6.16Hz, 1H), 4.57-
4.50 (m, 1H), 3.45(app t, J=6.12 Hz, 2H), 3.41- 3.37 (m, 1H),
1.91(s,3H), 1.85 (s, 3H) . ES-HRMS m/z 480.0625 (M+H, calcd for
C22H2iBrF2N04, requires 480.0S23).
Example 479
methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)
oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-chlorobenzoate
Step 1: Preparation of methyl 4-chloro-3-(4-hydroxy-6-
methyl-2-oxopyridin-1 (2H) -yDbenzoate.
A condensation reaction with methyl 3-amino-4-chlorobenzoate
(14.5g, 78.2 mmol) and 4-hydroxy-6-methyl pyranone under
reaction condition similar to the one described in Example
465- step 3 gave 12.32 (53.8%) of desired product.
Step-3- Preparation of methyl-4-chloro-3-[4 -[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoate.
In a 250ml round bottom flask, methyl 4-chloro-3-(4-
hydroxy-6-methyl-2-oxopyridin-l (2H)-yDbenzoate (5.28 g, 18.0
mmol) from stepl was reacted with 2,4-difluoro-benzylbromide
(3.72 g, 18.0 mmol) in DMF using similar procedure as in
Example 472 step 3. After aqueous work up and chromatographic
purification, 2.3 g (30%) pure product was obtained.
Step 4: methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoate was prepared
by reacting methyl-4-chloro-3-[4-[(2,4-difluorobenzyl) oxy]-6-
methyl-2-oxopyridin-1 (2H)-yl]benzoate (2.3 g, 5.47 mmol) with
N-bromcsuccinamide ( 0 . 9 7 g, 5.47 mraol) in acetonitrile (10 nL)
at 0°C, using a similar procedure as described in step 3 of
Example 465, to give l.SOg (66.2 %) of the desired product.
2JMR (400 MHz, DMSO-ds) 5 8.06-8.03 (m, 2H) , 7.35 (d, J-9.7C
Hz, 1H) , 7.63 (q, J- 7.62, 1H) , 7.34(dt, J=10.07, 2.46 Hz,
I E ) , 7.17 (dt,J 8.72, 2.90 Hz, IK), 6.73 ( s , I H ) , 5.33 (s,
2H), 3.85 (s, 3H), 1.91 (s, 3H). ES-MSm/Z 495.9757 (M-H calcd
for C21H14BrClF2N04, requires 495.9795).
3- [3-bromo-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-4-chlorobenzoic acid
In a 50 ml round bottom flask, methyl-4-chloro-3- [4-
[ {2,4-difluoroben2yl)oxy] -6-raethyl-2-oxopyridin-l (2H) -
yljbenzoate {0.450 g, 0.90 iranol) was stirred in THF (5 mL).
To this mixture was added NaOH (0.120 g, 3.0 mmol ) as a
solution in water (1.5 mL). The reaction mixture was stirred
at room temperature overnight. The THF was evaporated and the
residue was acidified with dilute HCl. A white precipitate
was obtained. The product was filtered, washed with water and
dried in vacuum to give 0.375 g (86 % yield ) of the desired
product. XH NMR (400 MHz, DMSO-ds) 5 7.89 (dd, J=7.78, 1.73
Hz, 1H) , 7.71-7.65 (m, 2H), 7.53 (d, J=9.08Hz, 1H), 7.33 (dt,
J=9.95, 2.59 Hz, 1H), 7.17 (dt, J=8.22, 2.59 He, IK), £.63 (s,
1H), 5 . 3 2 ( s , 2K), 1.89 ( s , 3 K ) . ES-M5 m/s 481.95S5 (M-H calcd
for C:0 H123rClF2N04, requires 481.9601).
Example 481
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-
methylphenyl]-6-methylpyridin-2(1H)-one
Step 1: Preparation of 4-hydroxy-l-[5-(hydroxymethyl)-2-
methylphenyl]-6-methyl pyridin-2(1H)-one .
4-Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) and 3-Amino-
4-methylbenzyl alcohol (25.0 g, 182.2 mmol) were taken up in
25 ml of 1,2-dichlorobenzene. The solution was heated to 165°C
in a 250 ml round bottom flask equipped with a J-Kem
temperature controller probe, and a heating mantle. In a
separate 250 ml round bottom flask 4-Hydroxy-6-methyl-2-pyrone
(23.0 g, 182.2 mmol) was suspended in 25 ml of 1,2-
dichlorobenzene and also heated to 165°C. The pyrone solution
was poured into the flask containing the aniline and the
reaction stirred at 165°C for 20 minutes. The reaction was
allowed to cool to room temperature. Reaction contents were
washed with saturated NaHC03 (aq.). Separated the organic and
aqueous layers. Aqueous layer was made acidic with drcpwise
addition of concentrated HCl. The product was extracted from
the acidic aqueous layer with n-BuOK. N-BuOK removed in vacuo
to produce a reddish brown oil. (S.5 g, 19%). Contents
carried forward to next reaction with no further purification.
XH NMR (300 MHz, CC3OD) 5 7.35 (m, 2H) , 7.08 (s, IH) , 6.08 (br
s, IH) , 5.81 (br s, IH) , 4.60 (s, 2H) , 2.01 (s, 3H) , 1.87 (s,
3H). LC/MS, tr = 1.42 minutes (5 to 95% acetonitrile/water over
5 minutes at 1 ml/min with detection 254 nm, at 50°C) . ES-
m/z 246.1131 (M+H). ES-HRMS m/z 246.1107 (M+H calcd for
C14Hi6N03 requires 246.1125).
Step 2: 4-[(2,4~difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-
methylphenyl] -6-methyl-pyridin-2(IH) -one .
4-hydroxy-l-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl
pyridin-2 (IH)-one ( from Step 1) (8.0 g, 32.6 mmol) was
stirred briskly at room temperature with 2,4-difluorobenzyl
bromide (4.2 ml, 32.6 mmol) and K2CO3 (4.5 g, 32.6 mmol) in 50
ml of dimethylformamide. After stirring for 8 hours, H20 (100
ml) was added to reaction mixture. The product was extracted
with ethyl acetate. Ethyl acetate layer was separated and
dried over Na2S04. Ethyl acetate was removed in vacuo. A
yellow oil was obtained. The oil was passed through a plug of
silica gel first eluting with 500 ml of ethyl acetate/hexane
(1:1). This eluent was set aside. Next, ethyl acetate (100%)
was passed through the plug until desired produce was
completely flushed from silica (3 liters). Solvent was
removed in vacuo. Light yellow oil obtained (7.5 g, 62%) . "H
NMR (300 MHz, CD3OD) 5 7.60 (app q, J = 6-44 Hz, IH) , 7.42 (d,
J = .81 Hz, 2H) , 7.15 (s, IH) , 7.06 (m, 2H) , 6.21 (dd, J =
1.61, 1.00 Hz, IH) , 6.12 (d, J = 2.62 Hz, IH) , 5.16 (s, 2H) ,
4.65 (s, 2H) , 2.07 (s, 3H) , 1.93 (s, 3H) ; LC/MS, tr = 2.38
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 372 (M+H) .
Step 3: Preparation of the title compound . 4-[(2,4-
difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-methylphenyl]-6-
methyl-pyridin-2 (IH)-one ( from Step 2) (4.0,9,- 10.8 mmol) was
stirred at room temperature with N-bromosuccinimide (2.1 g,
11.9 mmol) in 100 ml of CH2C12 for 2.0 hours. The reaction was
evaporated on a rotary evaporator and the resulting solid was
washed with acetonitrile and dried in vacuo to yield a white
solid (3.9 g, 80%). 1H NMR (300 MHz, CDC13) 5 7.67 (app q, J =
6.24 Hz, IH) , 7.35 (d, J = 1.01 Hz, 2H) , 7.10 (s, IH) , 7.04
(m, IH) , 6.91 (ddd, J « 11.08, 8.66, 2.42 Hz, IH) , 6.15 (d, J
= 0.63 Hz, 2H), 5.29 (s, 2H), 4.66 (s, 2H), 2.08 (s, 3H), 1.97
(s, 3H); ES-MS m/z 450 (M+H). ES-HRMS m/z 450.0467 (M+H calcd
for C2iHi9BrF2NO3 requires 450.0511).
Example 482
3-chloro-4- [ (2,4-diflucrcbenzyl)oxy]-1-[5-(hydroxymethyl)-
methylphenyl]-S-methyLpyridin-2(IH)-one
The title compound was prepared by a procedure similar to
the one described for Example 481, except that the product
from Step 2, Example 481 was chlorinated instead of being
brominated. The procedure is as follows: 4-[(2,4-
difluorobenzyl)oxy]-1-[S-(hydroxymethyl)-2-methylphenyl]-6-
methyl-pyridin-2(IH)-one (from Step 2, Example 481 above) (7.0
g, 18.8 mmol) was refluxed with N-chlorosuccinimide (2.5 g,
18.8 mmol) in 50 ml of CH2C12 overnight. The reaction was
evaporated on a rotary evaporator and the resulting solid was
stirred in MeOH. The precipitate was collected on a filter
pad, washed with MeOH and dried in vacuo to yield a white
solid (1.6 g, 21%). Hi NMR (300 MHz, DMF-d7) 5 7.85 (app q, J
= 6.44 Hz, IH) , 7.43 (d, J = 0.81, IH) , 7.42 - 7.23 '(m, 3H) ,
6.84 (s, IH) , 5.48 (s, 2H) , 4.67 (s, 2H) , 2.05 (s, 3H) , 2.03
(s, 3H); ES-MS m/z 406 (M+H). . ES-HRMS m/z 406.1033 (M+H calcd
for C2iHi6ClF2N04 requires 406.1016).
Example 483
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-
methylphenyl]-6-methylpyridin-2(IH)-one
Step 1: Preparation of 3-amino-4-chloro-benzyl alcohol .
HO
3-Nitro-4-chloro-benzyl alcohol (23.0 g, 122.6 mmol) is
taken up in isopropyl alcohol (175 ml) and water (35 ml) .
Iron powder (10 micron) (68.0 g, 1.2 moles) and NK4Cl (56.0 g,
1.2 moles) are added. The suspension is stirred overhead at
70°C in a three neck round bottom flask equipped with a heating
mantle and a J-Kem temperature controller probe. After 4
hours, isopropyl alcohol was removed in vacuo. Water (100 ml)
and concentrated HCl (10 ml) was added to mixture. Contents
are transferred to a separtory funnel and ethyl acetate is
used to extract the aqueous layer of impurities. The aqueous
layer was then basified with 50% aqueous NaOH. The product
was extracted from the basic aqueous layer with ethyl acetate.
The ethyl acetate layer was dried over Na2S04 and then removed
in vacuo. The remaining residue was taken up in 50% ethyl
acetate/hexane and the precipitate was collected on a filter
pad. Precipitate was washed with 50% ethyl acetate/hexane to
yield a flocculent brown solid (8.4 g, 44%). ^R NMR (300 MHz,
CD3OD) 5 7.17 (d, J = 8.26 Hz, IH), 6.86 (d, J = 2.01 Hz, IH),
6.66 (dd, J = 2.01, 0.61 Hz, IH) , 4.51 (s, 2H) ; LC/MS, tr =
0.32 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) ; ES-MS m/z 158 (M+H)
Step 2: 1-[2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-
methylpyridin-2(IH)-one .
HO.
3-amino-4-chloro-benzyl alcohol (8.0g, 51.0 mmol) and 4-
hydroxy-6-methyl-2-pyrone (6.4 g, Sl.Ommol) were taken up in
1,2-dichlorobenzene (50 ml). The mixture was plunged into a
165°C oil bath where it stirred for 20 minutes. The reaction
was cooled to room temperature and the reaction was worked up
by washing with saturated NaHC03 (aq.) and extracting
impurities with ethyl acetate. The product remained in the
aqueous layer. The basic aqueous layer was made acidic with
concentrated HCl. The product was extracted from the acidic
aqueous layer with ethyl acetate. The ethyl acetate layer was
dried over Na2SO4 and the solvent removed in vacuo. The
product was obtained as a yellow oil in a 26% yield and was
carried through to the next step with no further purification.
XH NMR (300 MHz, CD3OD) 8 7.62 (d, J = 8.26 Hz, 2H) , 7.51 (dd,
J = 8.46, 2.22 Hz, 1H) , 7.36 (d, J = 2.01 Hz, 1H) , 6.13 (br s,
1H) , 5.84 (d, J = 2.42 Hz, 1H) , 4.68 (s, 2H) , 1.97 (s, 3H) ;
LC/MS, tr = 0.25 minutes and 1.41 minutes (tautomer) , (5 to
95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-MS m/z 266 (M+H) .
Step 3: 1-[2-chloro-5-(hydroxymethyl)phenyl]-4- [ (2,4-
dif luorobenzyl) oxy] -6-tnethylpyridin-2 (1H) -one .
1- [2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-
methylpyridin-2 (1H)-one ( from step 2) (3.5g, 13.2 mmol) was
taken up in DMF (10 ml) and cooled to 0°C. 2,4-Dif luorobenzyl
bromide (1.7 ml, 13.2 mmol) and K2C03 (1.8 g, 13.2 mmol) were
added and the reaction stirred for 6 hours. The reaction was
worked up by adding saturated NaKC03 (aq.) and extracting with
ethyl acetate. The ethyl acetate extraction was washed with
wa~er, and the aqueous layer was extracted with ethyl acetate.
The organic layers were combined and dried over Na2S04,
filtered, and the solvent removed in vacuo. The product was
obtained in 83% crude yield and carried through to the next
step as a brown oil. LC/MS, tr = 2.48 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 392 (M+H) . ES-HRMS m/z 392.0853
(M+H calcd for C2oH17ClF2NO3 requires 392.0860).
Step 4: The title compound was prepared from 1- [2-chloro-5-
(hydroxymethyl)phenyl]-4- [ (2,4-difluorobenzyl)oxy]-6-
methylpyridin-2 (IH) -one (from step 3) (1.8g, 4.6 mmol) and Nbromosuccinimide
(0.82 g, 4.6 mmol) by dissolving them in
CH2C12 (10 ml) and stirring for 2 hours at room temperature.
The solvent was removed in vacuo and the residue was taken up
in CH3CN. The precipitate was collected on a filter pad and
rinsed with CH3CN to yield a white solid (370 mg, 17%) . XH
NMR (300 MHz, CDC13) 5 7.65 (app q, J = 6.24 Hz, IH), 7.52 (d,
J = 8.26 Hz, IH), 7.40 (dd, J = 8.26, 2.01 Hz IH), 7.26 (d, J
= 0.81 Hz, IH) , 7.03 (m, IH) , 6.91 (ddd, J = 11.08, 8.66, 2.42
Hz, IH) , 6.17 (d, J = 0.81 IH) , 5.29 (s, 2H) , 4.63 (s, 2H) ,
2.02 (s, 3H) ; ES-MS m/z 471 (M+H). ES-HRMS m/z 471.9953 (M+H
calcd for C2oHi6BrClF2NO3 requires 471.9944).
Example 484
3-chloro-4-[(2,4-diflucrcbenryl)oxy]-I-[5-(hydroxymethyl)-2-
methylphenyl] -6-methylpyridir.-2 (IH) -one
The title compound was prepared from 1-[2-chloro-5-
(hydroxymethy1)phenyl]-4-[(2 , 4-difluorobenzyl)oxy]-6-
methylpyridin-2 (1H)-one (2.4 g, 6.1 mmol) and NC5 (815.0 mg,
6.1 mmol) in 65°C dichloroethane (20 ml). A catalytic amour:c
of dichloroacetic acid (2 drops) was added. After two hours
the solvent was removed in vacuo and the residue was taken up
in diethyl ether. The precipitate was collected on a filter
pad and then taken up in 50% ethyl acetate/hexanes to remove
residual succinimide. The precipitate was collected on a
filter pad and then dried in vacuo to produce a white powder
(180 mg, 6.9%). . XH NMR (300 MHz, CDC13) 5 7.61 (app q, J =
6.44 Hz, IH) , 7.52 (d, J = 8.26 Hz, IH) , 7.40 (dd, J = 8.26,
2.01 Hz IH) , 7.27 (d, J = 2.01 Hz, IH) , 7.00 (m, IH) , 6.91
(m, IH) , 6.20(s, IH) , 5.29 (s, 2H) , 4.65 (s, 2H) , 2.03 (s,
3H); ES-MS m/z 426 (M+H). ES-HRMS m/z 426.0453 (M+H calcd for
C2oHlsCl2F2N03 requires 426.0470).
Example 485
HC1
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5-
[(dimethylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(IH)
one hydrochloride
ctep i: Preparation of 3- [3-bromo-4- [ ( 2 , 4 -
difluorobenzyl)oxy] -6-methyI-2-oxopyridin-l (2H) -yl] -4-
methylberizaldehyde .
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[5-(hydroxymethyl)-2-
methylphenyl]-6-methylpyridin-2(1H)-one (1.5g, 3.33 mmol) was
dissolved in 75% CH3CN/CH2C12 (20ml) and cooled to 0°C. Dess-
Martin Periodinane(2 .8 g, 6.66 mmol) .was added and the
reaction stirred for four hours. At this time, the reaction
was quenched with 5% sodium bisulfite (aq.). The product was
extracted with ethyl acetate. The combined organic extracts
were then washed with saturated NaHC03 (aq.). The aqueous
layer was extracted with ethyl acetate. The combined organic
extracts were dried over Na2S04, filtered, and concentrated.
The resulting residue was taken up in diethyl ether and the
precipitate was collected on a filter pad and washed with more
diethyl ether to yield a white solid (1.35 g, 91%). 1H NMR
(300 MHz, CDC13) 5 10.00 (s, 1H) , 7.91 (dd, J = 7.65, 1.61 Hz,
1H) , 7.65 (m, 2H) , 7.57 (d, J = 7.85 Hz, 1H) , 7.03 (m, 1H) ,
6.95 (ddd, J = 12.69, 8.86, 2.62 Hz, 1H) , 6.19 (s, 1H) , 5.31
(s, 2H), 2.20 (s, 3H), 1.96 (s, 3H); ES-MS m/z 448 (M+H). ESHRMS
m/z 448.0347 (M+H calcd for C2iHi7BrF2NO3 requires
448.0354) .
Step 2: Preparation of the title compound . 3-[3-bromo-4-
[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-
methylbenzaldehyde ( from step 1) (0.50 g, 1.11 mmol) was
dissolved in CH2C12 ( 10 ml). N,N-dimethylamine (2.0 M in THF)
(1.11 ml, 2.22 mmol) was added. This mixture stirred for a
room temerature for 12 hours. Next, sodium
acetoxyborohydride (0.47 g, 2.22 mmol) was added and the
reaction stirred for two more hours. The reaction was washed
with 1 N NaOK (aq.) and then extracted with CH2C1;. The
combined organic extracts were washed with water. The aqueous
layer was separated and extracted with CHaClz . The combined
organic extracts were dried over Na2S04, filtered and
concentrated in vacuo . The resulting residue was taken up in
diethyl ether. 1M HCl in diethyl ether (5 ml) was added and
the precipitate was collected on a filter pad. This
precipitate was hygroscopic. The hygroscopic solid was then
taken up in hot ethyl acetate. Hexane was added until a
precipitate crashed out . The precipitate was collected on a
filter pad to yield a white solid (150 mg, 26%). XH NMR (400
MHz, D20) 8 7.42 (m, 3H) , 7.17 (s,lH), 6.86 (m, 2H) ,
1H) , 5.20(s, 2H) , 4.18(s, 1H) , 2.72(s, 6H) , 1.85(s, 3H) ,"
1.82(s, 3H) ; ES-MS m/z 477 (M+H) . ES-HRMS m/z 477.0955 (M+H
calcd for C23H24BrF2N2O2 requires 477.0984).
Example 486 HCl
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5-
[(isopropylamino)methyl]-2-methylphenyl}-6-methylpyridin-
2(1H)-one hydrochloride
The title compound was prepared by reductive amination of
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H) -yl] -4-methylbenzaldehyde ( from step 1) (0.50 g, 1.11
mmol) with iso-propyl amine (0.13 g, 2.22} according to the
procedure described above for Example 485 (Step 2) to give the
desired compound (0.49g, 84%). 1H NMR (400 MHz, CD3OD) 5 7.54
(app quartet, J = 6.58 Hz, 1H) , 7.53 (m, 2H) , 7.29(br s, 1H) ,
7.03(m, 1H) , 6.68 (s, 1H) , 5.36 (s, 2H) , 4.22(s, 2H) , 3.46(m,
1H) , 2.06 (s, 3H) , 2.01 (s, 3H) , 1.37 (d, J = 6.58 Hz, 6H) ;
ES-MS m/z 491 (M+H) . ES-HRMS m/z 491.1107 (M+H calcd for
2 requires 491.1140).
Example 487
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide
cr ocH3
Step 1: Preparation of methyl 3-(4-hydroxy-6-methyl-2
oxopyridin-1(2H)-yl)-4-methylbenzoate .
4-Hydroxy-6-methyl-2-pyrone (22.9 g, 181.6 mmol) and
methyl-3-amino-2-methylbenzoate (25 g, 151.3 mmol) were
suspended in 50 ml of 1,2-dichlorobenzene in a 250 ml, 3-
necked round bottom flask equipped with a J-Kem temperature
controller probe, a Dean-Stark trap, and a heating mantle.
The reaction was heated to 165°C for 15 minutes, during which,
water and some 1,2-dichIorober.zer.e was collected in the Dean-
Stark trao. The reaction was allowed to cool to about 110"C.
At this point, 200 ml of toluene was added. The flask was
plunged into a 0°C ice bath while stirring. "Oiling out"
occurred. Perhaps too much toluene was added so some of the
solvent was removed in vacuo . The oil went back into solution
and a light brown precipitate remained. The toluene mixture
was allowed to stir for 72 hours at room temperature. A
precipitate was collected on a filter pad. The precipitate
was filtered and washed 3 times with toluene, 3 times with
50°C. water to remove excess pyrone, and dried in vacuo to give
a tan solid (16.5 g, 40% yield). aH NMR (300 -MHz, CD3OD) 8
8.06 (dd, J = 8.06, 1.61 Hz, 1H) , 7.80 (d, J = 1.61 Hz, 1H) ,
7.56 (d, J = 8.06, Hz, 1H) , 6.15 (dd, J = 2.42, 0.81" Hz, 1H) ,
5.86 (d, J = 2.42 1H) , 3.94 (s, 3H) , 2.15 (a, 3H) , 1.91 (a,
3H) / ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1066 (M+H calcd for
C15H16N04 requires 274.1074).
Step 2: Preparation of methyl 3- [4- [ (2,4-dif luorobenzyl) oxy]
6-methyl-2-oxopyridin-l (2H) -yl] -4-methylbenzoate .
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H) -yl) -4-
methylbenzoate ( from Step 1) (16.5 g, 60.4 mmol) 2,4-
dif luorobenzyl bromide (7.8 ml, 60.4 mmol) were taken up in
250 ml of N,N-dimethyl formamide and the mixture was cooled to
0°C. K2C03 (8.3g, 60,4 mmol) was added and reaction stirred
for 12 hours during which time the reaction was allowed to
warm to room temperature. LC/MS indicated the presence of
starting material after 12 hours. An excess of K2C03 was added
at room temperature along with 0.50 ml of 2,4-difluorobenzyl
bromide. The reaction stirred for an additional two hours.
Saturated NaHC03 (aq.) was poured into reaction vessel. The
solution was extracted with ethyl acetate and the organic
layers were combined then washed with water. The organic
layer was separated and the aqueous layer was extracted with
ethyl acetate. The organic layers were combined and dried
over Na2S04, and evaporated. The product was carried on to the
next step as a crude oil (24.1 g, quantitative yield). 1H NMR
(300 MHz, CDC13) 8 8.06 (dd, J = 7.85, 1.61 Hz, "1H), 7.82 (d, J
= 1.61, 1H), 7.52-7.44 (m, 2H) , 7.01 - 6.88 (m, 2H) , 6.05 (d,
J = 2.62 Hz, 1H) , 5.97 (dd, J = 2.62, 0.81 Hs, 1H) , 5.08 .(s,
2H) , 3.93 (s, 3H) , 2.20 (s, 3H) , 1.89 (s, 3H) ; ES-MS. m/z 400
(M+H) . ES-HRMS m/z 400.1374 (M+H calcd for C22H2oF2N04 requires
400.1355).
Step 3: Preparation of 3-[4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid .
Methyl 3-[4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-methylbenzoate (14g, 35.0 mmol)(from
step 2) was taken up in THF (25 ml) and H20. 2.5 N NaOH (aq.)
was added and the reaction stirred for 30 minutes at room
temperature. The reaction was made acidic via the addition of
concentrated HC1. The product was extracted with ethyl
acetate. The ethyl acetate extraction was dried over Na2S04,
filtered, and the solvent removed in vacuo. Upon vacuum
removal of the solvent, the product crashed out of the ethyl
acetate. This precipitate was collected on a filter pad and
washed with a 50 ethyl acetate/hexanes to yield a white powder
(9g, 7%). 1H NMR (300 MHz, CDC13) 6 8.01 (dd, J = , 1.61 Hz,
1H) , 7.84 (d, J = 1.61 Hz, 1H) , 7.52 - 7.47 (app q, J = 8.26,
1H) , 7.43 (d, J = 8.06 Hz, 1H) , 7.00 - 6.88 (m, 2H) , 6.19 (d,
J = 2.62 Hz, 1H) , 6.05 (dd, J = 2.62, 1.81 Hz, 1H) , 5.17 (s,
2H) , 2.19 (s, 3H) , 1.90 (s, 3H) ; ES-HR/MS m/z 386.12 (M+H
calcd for C2iHisF2N04 requires 386.1198).
Step 4: Preparation of 3-[3-bromo-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-
methylbenzoic acid .
3- [4- [ (2, 4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-
1 (2H)-yl]-4-methylbenzoic acid (5.9 g, 15.2 mmol) (from step
3 above) was taken up in dichloromethane (25 ml) . NBromosuccinimide
was added and the reaction stirred for 14
hours. The dichloromethane was removed in vacuo and the
residue was taken up in acetonitrile. The precipitate was
collected on a filter pad and rinsed with acetonitrile to
yield the desired product as a white solid (5.2 g, 74%) . XH
NMR (300 MHz, CD3OD) 8 7.87 (dd, J = 7.85, 1.61,Hz, 1H) ,
(d, J = 1.81 Hz, 1H), 7.69 (app q, J = 8.06 Hz 1H), 7.57 (d, J
= 8.06 Hz, 1H) , 7.09 (dt, J = 8.66, 2.22 Hz, 1H) , 6.70 (s,
1H) , 5.40 (s, 2H) , 2.14 (s, 3H) , 2.02 (s, 3H) ; ES-MS m/z 464
(M+H) . ES-HRMS m/z 464.0275 (M+H calcd for C21Ki7Br?;N04
requires 464.0304).
Step 5: Preparation of the title compound. 3-[3-bromc-4-
[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-
methylbenzoic acid (from Step 4 above) (1.9g, 4.10 mmol) was
dissolved in 20 ml of CH2C12. Ethanolamine (297 (il, 4.92 mmol)
was added, followed, in order, by EDCI (0.764 g, 4.92 mmol),
1-hydroxybenzotriazole (0.665g, 4.92 mmol) and triethylamine
(1.14 ml, 8.20 mmol). The reaction was stirred at room
temperature overnight. The reaction was quenched with NH4C1
and extracted 3 times with ethyl acetate. The combined
organic layer was then washed with saturated NaHCO3 (aq.) and
extracted 3 times with ethyl acetate. The organic layers were
combined and washed with H20 and extracted 3 times with ethyl
acetate. The organic layers were combined and dried over
Na2S04 and evaporated. The resulting residue was triturated
with diethyl ether/hexane to obtain a solid, which was dried
in vacuo to give a white solid (1.5g, 72%). XH NMR (300 MHz,
CDC13) 6 7.93 (dd, J = 7.85, 1.61 Hz, 1H) , 7.65 (d, J = 1.61
Hz, 1H), 7.62 (app q, J = 8.26 Hz, 1H) , 7.40 (d, J = 8.06 Hz,
1H) , 7.39 - 7.30 (m, 1H) , 7.03 - 6.97 (m, 1H) , 6.88 - 6.81
(m, 1H) , 6.25 (s, 1H) , 5.20 (s, 2H) , 3.70 - 3.52 (m, 1H) , 3.16
- 3.12 (m, 2H) , 2.10 (s, 3H) , 1.98 (s, 3H) ; ES-MS m/z 507
(M+H). ES-HRMS m/z 507.0719 (M+H calcd for
requires 507.0726).
Examples 488-491
The compounds of Examples 488-491-47S are prepared essentially
according to the procedures set forth for Example 487.
Compound
No.
Ex. 488
Ex. 489
Ex. 490
Ex. 491
R
-NH(CH2)2OCH3
-NHCH3
-N(CH3 ) 2
-morpholine
%
Yield
84
79
54
65
MF
C24H24BrF2N204
C22H2oBrF2N2O3
C23H22BrF2N203
C25H24BrF2N204
M+H
Requires
528.0882
477.0620
491.0776
533.0858
ESHRMS
m/z
521.0868
477.0602
491.0753
533. -0882
Example 492
3-bromo-4-[(2,4-difluorobenzyl)oxyj-1- [5- (1-hydroxy-lmethylethyl)-
2-methylphenyl]-6-methylpyridin-2(IH)-one
Step 1: Preparation of methyl 3-[3-bromo-4-[( 2 ,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -yl] -4-
raethylbenzoate .
Methyl 3-[4-[(2,4-difiuorobenzyl)oxy]-S-methyl-2-
oxopyridin-1(2H)-yl]-4-methylbenzoate ( as prepared above)
(1.8g, 4.51 mmol) was taken up in CH2C12 (10 ml). Nbromosuccinimide
(0.80 g, 4.51 mmol) was added and the mixture
stirred at room temperature for two hours. The CH2Cl2 is
removed in vacuo and the residue is taken up in CH3CN. The
resulting precipitate is collected on a filter pad and washed
with CH3CN to yield a white solid (0.30 g, 14%, first crop).
XH NMR (3.00 MHz, CDC13) 8 8.06 (dd, J = 8.06, 1.61 Hz, 1H) ,
7.80 (d, J = 1.61 Hz, 2H), 7.65 (app q, J = 8.46 Hz, 1H), 7.48
(d, J = 8.06, 1H) , 7.05 - 6.99 (m, 1H) , 6.96 - 6.89 (m, 1H) ,
6.16 (s, 1H) , 5.31 (s, 2H) , 3.93 (s, 3H) , 2.17 (s, 3H) , 1.96
(s, 3H) . ES-HRMS m/z 478.0476 (M+H calcd for C22Hi9BrF2N04
requires 478.0476).
Step 2: Preparation of the title compound. Methyl 3-[3-
bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin-l(2H)-
yl]-4-methylbenzoate (0.22 g, 0.46 mmol) was taken up in THF
and cooled to 0°C. MeMgCl (3.0 M in THF) (0.73 ml, 2.2 mmol)
was slowly added to the 0°C solution. The reaction was allowed
to proceed without maintaining the 0°C bath temperature. The
reaction was complete within two hours. At this time the
mixture was quenched with saturated NH4C1 (aq.) and extracted
with ethyl acetate. The organic layers were combined, washed
with H20, and extracted with ethyl acetate. The organic layers
were combined and dried over Na2S04, filtered, and evaporated.
The residue was taken up in 50% ethyl acetate/hexanes. The
precipitate was collected on a filter pad arid washed with 50%
ethyl acetate/hexanes to yield a white solid {0.10 g, 45%).
:K NMR (300 MHz, CD3OD) 5 7.70 (app q, J = 8.26, Ez, 1H) , 7.54
(dd, J = 8.06, 2.01 Hz, IE), 7.40 (d, J = 1.81 Hz, IK}, 7.12 -
7.06 (m, 2H} , 6.68 (s, 1H) , 5.40 (s, 2K) , 2.05 (s, 3K) , 2.02
(s, 3H) , 1.57 (s, 6H) . ES-KRMS m/z 478.0785 (M+H calcd for
requires 478.0824).
Example 493
OCH3
methyl 3- [3-chloro-4- [ (2, 4-difluorobenzyl) oxy] -.6-methyl-2-
oxopyridin-1(2H)-yl]-4-methylbenzoate
The title compound was prepared by taking up methyl 3-[4-
[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-
methylbenzoate (1.46g, 3.66 mmol) in dichloroethane (25 ml)
and adding N-chlorosuccinimide (0.49g, 3.66 mmol),
dichloroacetic acid (catalytic), and heating to 50°C for 6
hours. At this time, the solvent was removed in vacuo and the
residue taken up in diethyl ether. The precipitate was
collected on a filter pad. XH NMR (300 MHz, CDC13) 5 8.07 (dd,
J = 7.85, 1.61 Hz, 1H) , 7.80 (d, J = 1.81 Hz, 2H) , 7.62 (app
q, J = 8.46 Hz, 1H) , 7.48 (d, J = 7.85, IK), 7.05 - 6.95 (m,
1H) , 6.93 - 6.89 (m, 1H) , 6.19 (s, 1H) , 5.30 (s, 2H) , 3.93
(s, 3H) , 2.17 (s, 3H) , 1.97 (s, 3H) . ES-HRMS tn/z 434.0932 (M+H
calcd for C22H19ClF2N04 requires 434.0965).
Example 494
methyl 4-[3-bromo-4-[(2,4-difluorobencyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-3-chlorobenzoate
Step 1: Preparation of methyl 3-chloro-4-(4-hydroxy-6-methyl-
2-oxopyridin-1 (2H) -yDbenzoate .
OCH3
4-Hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) and
methyl-3-amino-2-chlorobenzoate (30 g, 161.6 mmol) were
suspended in 75 ml of 1,2-dichlorobenzene in a 250 ml, 3-
necked round bottom flask equipped with a J-Kem temperature
controller probe, a Dean-Stark trap, and a heating mantle.
The reaction was heated to 175°C for 20 minutes, during which,
water and some 1,2-dichlorobenzene was collected in the Dean-
Stark trap. The reaction was allowed to cool to about 110°C.
At this point, 200 ml of toluene was added. The toluene
mixture was allowed to stir for 72 hours at room temperature.
A precipitate was collected on a filter pad. The precipitate
was filtered and washed 3 times with toluene, 3 times with
50°C. water to remove excess pyrone, and dried in vacuo to give
a tan solid (13.0 g, 27% yield). 1H NMR (300 MHz, CD3OD) 5
8.26 (d, J = 1.81 Hz, 1H) , 8.14 (dd, J = 8.26, 1.81 Hz, 1H)
7.54 (d, J = 8.26, Hz, 1H) , 6.14(dd, J = 2.42, 1.0 Hz, IK),
5.83 (d, J = 2.42 IE), 4.QQ (s, 3H) , 1.96 (s, 3K) ; LC/MS, tr =
1.81 minutes (5 to 95% acetor.itrile/watsr over 5 minutes at '-
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 294 (M+H) .
Stec 2: Preparation of methyl 3-chioro-4-[4-[(2,4-
difluorobenzyl)oxy] -6-methyl-2-oxopyridin-l(2H)-yljbenzoate .
R.
Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-
yDbenzoate ( from Step 1) (2.4g, 8.17 mmol) was taken- up in
DMF (10 ml). 2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol)
and K2C03 (1.13 g, 8.17 mmol) were added. The reaction stirred
for 6 hours at room temperature. At this time, the reaction
was poured into water (200 ml) and extracted with ethyl
acetate. The ethyl acetate layer was dried over Na2S04,
filtered, and the solvent removed in vacuo to give amber oil
(2.62 g, 77% crude yield). LC/MS, tr = 2.79 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C). ES-MS m/z 294 (M+H).
Step 3: Preparation of the title compound . Methyl 3-chloro-
4- [4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]benzoate ( from step 2) (2.60g, 6.21 mmol) was taken up in
CH2C12 (20 ml). N-bromosuccinimide (l.llg, 6.21 mmol) was
added and the mixture stirred at room temperature for 4 hours.
The CH2C12 is removed in vacuo and the residue is taken up in
CH3CN. The resulting precipitate is collected on a filter pad
and washed with CH3CN to yield a white solid (0.75 g, 24%). XH
NMR (300 MHz, CDC13) 5 8.22 (d; u = 1.88 Ez, IH) , 8.06 (dd, J =
8.19, 1.75 Hz, IH), 7.59 (app q, J = 8.46 Hz, IH), 7.33 (d, J
= 8.19, IH) , 6.96 (dt, J = 8.06, 1.21 Hz, IH) , 6-89 - 6.84
(m, IH) , 6.13 (s, IH) , 5.26 (s, 2H) , 3.95 (s, 3H) , 1.95 (s,
3H) . ES-HRMS m/z 497.9892 (M+H calcd for C22H16BrCl?:N04
requires 497.9914).
Example 495
3-bromo-4-[(2,4-difluorobenzyl)amino]-1-(3-
fluorobenzyl)pyridin-2(IH)-one
Step 1
Preparation of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(IH)
one
OBn
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with 4-benzyloxy-2(IH)-pyridinone
(20 g, 99.6 mmol) and N,N-dimethyl formamide (50 mL). K2C03
(13.7 g, 99.6 mmol) and KI ( 1.6 g, 9.6 mmol) were added
followed by 3-fluorobenzyl bromide (14.6 mL, 119.4 mmol). The
reaction mixture was heated,for 18 h at 80 C. The reaction
mixture was concentrated in vacuo and treated with hot ethyl
acetate. The solids were filtered off, the filtrate was
coured into water and was extracted with ethyl'acetate. The
organic extract was washed with brine, dried with' anhydrous
Na2SO4, and concentrated in vacuo. The residue was dissolved
in hot ethyl acetate and precipitated with hexanes to give the
title compound (10 g, 33%). XH NMR (400 MKz, CD3OD) 6 7.57 (d,
J = 8.4 Hz, IK), 7.37 (m, 5H) , 7.07 (d, J = 8.4 Hz, 1H), 7.01
(app d, J = 8.4 Hz, 2H), 6.17 (d, J = 2.68 and 7.6 Hz, 1H),
6.04 (d, J = 2.68 Hz, 1H), 5.10 (a, 2H), 5.08 (s, 2H) ppm. 19
F NMR (400 MHz, CD3OD) 5 -114.88 (1 F) ppm. ES-HRMS tn/z
310.1271 (M+H calcd for C19H17FN02 requires 310.1238).
Step 2
Preparation of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one
F
A small Parr bottle was charged with SC-82484 (10 g, 32.3
mmol), ethanol (175 mL) andlO% Pd/C (0.5 g) . The system was
flushed twice with both nitrogen and hydrogen. The reaction
mixture was hydrogenated at 30 psi until no starting material
was visible by LC-MS. The reaction mixture was slurried with
Celite and then was filtered through a pad of celite. The
filtrate and ensuing ethanol washes were concentrated in vacuo
to give a beige solid. 1H NMR (400 MHz, CD3OD) 5 7.53 (d, J =
7.67 Hz, 1H) , 7.32 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H) , 6.98 (d,
J = 8.4 Hz, 2H), 6.05 (dd, J = 2.58 and 7.67 Hz, 1H), 5.83 (d,
-657-
J = 2.0 Hz, 2H) , 5.10 (s, 2H) ppm. 19 F NMR (400 MHz, CD3OD) 6
-115.33 (1 ?) ppm. ES-HRMS m/z 218.0641 (M+H calcd for
C-_2HiiFN02 requires. 218.0612) .
Step 3
Preparation of 4-[ (2,4-difluorobenzyl)amino]-1-(3-
fluorobenzyl)pyridin-2(IH)-one
F .
The product from Step 2 (0.5 g, 2.28-mmol) and 2,4-
difluoro benzylamine (4 mL, 33.6 mmol) were combined in a
nitrogen flushed culture tube. The tube was capped and heated
at 180 C for 24 h. The excess amine was distilled in vacuo
and the residue was chromatographed on silica (95:5 ethyl
acetate: methanol) . The final compound was isolated as a
light yellow solid (0.16 g, 36%). XH NMR (400 MHz, CD3OD) 6
7.33 (m, 3H) , 7.03 (d, J = 8 Hz, IH) , 6.96 (m, 3H) , 6.95 (m,
IH) , 5.97 (dd, J = 3.2 and 8.0 Hz, 1 H) , 5.48 (d, J = 2.56 Hz,
IH) , 5.02 (s, 2H) , 4.33 (s, 2H) ppm. 19 F NMR (400 MHz, CD3OD)
5 -113.88 (1 F) , -115.33 (IF), -116.78 (IF) ppm. ES-HRMS
345.1221 (M+H calcd for CigH^Fa^O requires 345.1209).
Step 4 Preparation of 3 -bromo-4 -[ (2, 4-dif luorobenzyl) amino] -1-
( 3 -f luorobenzyl )pyridin-2 (IH) -one
N-Bromo succinimide (81 mg, 0.46 mmol) was added to a
solution of the product from Step 3 (0.15 g, 0.44 mmol) in
methylene chloride (10 mL). After stirring at 25 C for 1 h,
the reaction was complete by LC-MS. The reaction mixture was
poured into saturated aqueous NaHCOa. The aqueous mixture was
extracted with ethyl acetate. The organic layer was washed
with brine, dried with anhydrous MgS04, and concentrated in
vacuo. 1H NMR (400 MHz, CDC13) 5 7.3-7.2- Cm, 4H) , 7.07 (app t,
J = 7.6 Hz, 2H) , 6.97 (m, 2H), 6.80 (m, 2H) ," 5.78• (d, J = 7.6
Hz, IH), 5.30 (br s, IH), 5.08 (s, 2H), 4.46 (d, J = 6 Hz, 2H)
ppm. 19 F NMR (400 MHz, CDC13) 6 -110.64 (1 F) , -112.75 (IF), -
114.79 (IF) ppm. ES-HRMS m/z 423.0275 (M+H calcd for
C19H15BrF3N20 requires 423.0314).
Example 496
3-bromo-l-(3-fluorobenzyl)-4-{[3-
(trifluoromethyl)bensyl]amino}pyridin-2(IH)-one
The title compound was prepared essentially as in Example
495. XH NMR (400 MHz, CDC13) 5 7.54 (m, 2H) , 7. 43 (m, 2H) ,
7 .27 (q, J = 3 .1, 9.0 Hz, IH) , 6.96 (app t, J = 3.8 Hz, 2H) ,
5.71 (d, J = 7.6 Hz, IH) , 5.4 (br m, IH) , 5.08 (s, 2H) , 4.52
(d, J = 5.6 Hz, 2H) ppm. 19 F NMR (400 MHz, CDC13) 5 -63 (3 F) ,
-112 (1 F) ppm. ES-HRMS m/z 455.0388 (M-rH calcd for
requires 455.0377).
Example 497
F
3-bromo-l-(3-fluorobenzyl)-4-{[4-fluoro-2-
(trifluoromethyl)benzyl]amino}pyridin-2(IH)-one
The title compound was prepared essentially as in
Example 495. 1H NMR (400 MHz, CDC13) 5 7.43 (m, 2H) , 7.27 (m,
3H}, 7.07 (m, 2H), 6.99 (m, 2H), 5.65 (d, J = lOHz, IH), 5.46
(br s, IH) , 5.09 (s, 2H) , 4.64 (s, 2H) ppm. 19 F NMR (400 MHz,
CDC13) 5 -61.31 (3 F) , -112.69 (1 F) , 112.97 (IF) ppm. ES-HRMS
m/z 473.0246 (M+H calcd for C2oHlsBrF5N20 requires 473.0282).
Example 498
Preparation of -bromo-4- [ (4-chloro-2-fluorobenzyl)aminc]-1 - ( 3 -
fluorobenzyl)pyridin-2(IH)-one
The title compound was prepared essentially as in Example
495. XH NMR (400 MHz, CDC13) 5 7.27 (m, IH) , 7.19 (app t, J =
8.8 Hz, IH) , 7.10 (m, 4H), 6.95 (app t, J = 8.8 Hz, 2H) , 5.74
(d, J = 8 Hz, IH) , 5.40 (br s, IH) , 5.08 (a-, 2H) , 4.47 (d J =
6 Hz, 2H) pprn. 19 F NMR (400 MHz, CDC13) 5 -112.67 (1 F) , . -
116.39 (1 F) ppm. ES-HRMS m/z 439.0047 (M+H calcd for
ClsHisClBrF2N20 requires 439.0019) .
Example 499
The title compound was prepared essentially as in Example
495. XH NMR (400 MHz, CDC13) 5 7.35- 7.2 (m, 1H) , 7.27 (dd, J =
2.5 and 8 Hz, IH), 7.05 (app d, J = 7.2 Hz, 3H), 6.97 (m, 4H),
5.72 (d, J = 7.6 Hz, IH), 5.41 (br s, IH), 5.08 (s, 2H), 4.46
(d, J = 6.4 Hz, 2H) ppm. 19 F NMR (400 MHz, CDC13) 8 -112.5 (1
F), -113 (1 F) ppm. ES-HRMS m/z 405.0431 (M+H calcd for
aO requires 405.0409) .
-661-
Example 500
Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl
1-(pyridin-4-ylmethyl)pyridin-2(IH)-one
Step 1 Preparation of 4-[(2,4-difluorobenzyl)amino]-6-methyl-
1-(pyridin-4-ylmethyl)pyridin-2(IH)-one
(0.3 g, 1.39 mmol) and 2,4-difluoro benzylamine (1 mL,
8.4 mmol) were combined in a nitrogen flushed culture tube.
The tube was capped and heated at 180 C for 24 h. The excess
amine was distilled in vacuo. XH NMR (400 MHz, CD3OD) 5 8.44
(dd, J - 1.7 and 4.8Hz, 2H), 7.38 (q, J = 10 and 15 Hz, IH),
7.14 (d, J - 4.8 Hz, 2H), 6.95 (m, 2H), 5.90 (dd, J = 1 and
2.5HZ, IH), 5.47 (d, J = 2, IH), 5.28 (s, 2H), 4.33 (s, 2H),
2.27 (s, 3H) ppm. " F NMR (400 MHz, CD3OD) 8 -113.73 (IF), -
116.66 (1 F) ppm. ES-HRMS m/z 342.1422 (M+H calcd for
requires 342.1418).
Step 2 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-6
methyl-1-(pyridin-4-ylmethyl)pyridin-2(IH)-one
-Bromo succiniraide (77 mg, 0.43 ramol) was added to a
solution of the product of Step 1 (0.14 g, 0.41 mmol) in
methylene chloride (10 mL). After stirring at 25 C for 1 h,
the reaction was complete by LC-MS. The reaction mixture was
poured into saturated aqueous NaHCO3. The aqueous mixture was
extracted with ethyl acetate. The organic layer was washed
with brine, dried with anhydrous Na2SO4/ filtered and
concentrated in vacuo. The residue was triturated with
hexanes to give the title compound as a yellow solid (81 mg,
47 %) . XH NMR (400 MHz, CDC13) 8 8.47 (dd, J = 1.6 and 4.8HS,
2H), 7.24 (q, J = 6.4 and 13.6 Hz, IH), 7.01 (d, J = 6.4 Hz,
2H) , 6.83 (m, 2H) , 5.68 (s, IH) , 5.25 (s, 2H), 4.45 (d, J =
6.4HZ, 2H) , 2.12 (s, 3H) ppm. 19 F NMR (400 MHz, CDC13) 5 -
110.51 (m, 1 F), -114.66 (m, 1 F) ppm. ES-HRMS m/z 420.0524
(M+H calcd for C19H17BrF2N30 requires 420.0523).
Example 501
Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-
1-(pyridin-3-ylmethyl)pyridin-2(IH)-one
The title compound was prepared essentially as in example 500.
:H NMR (400 MHz, CDC13) 5 8.45 (d, J = 4.8E3, 2H) , 7.55
(app t, J = 6 Hz, IH), 7.21 (m, 2H), 6.83 (m, 2H), 5.55 (s,
IH), 5.34 (d, J = 5.2HZ, IH), 5.27 ( s , 2H), 4.45 (s, 2H), 2.10
(d, J = 4.8HZ, 3H) ppm. 19 F NMR (400 MHz, CDC13) 5 -110.74 (1
F ) , -114.86 (1 F) ppm. ES-HRMS m/~ 420.0533 (M+H calcd for
C19H17BrF2N30 requires 420.0523).
Example 502
Preparation of 3-bromo-4-[ (2,4-difluorobenzyl)amino]-1-(2,6-
difluorophenyl)-6-methylpyridin-2(IH) -one
Step 1 Preparation of 4- [ (2,4-difluorobenzyl)amino]-1-(2,6-
dif luorophenyl) -6-methylpyridin-2 (IH) -one
F
1-(2, 6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(IH)-
one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (ImL, 8.4
mmol) were combined in a nitrogen flushed culture tube. The
tube was capped and heated at 180 C for 24 h. The excess
amine was distilled in vacuo and the residue was
-664-
chromatographed on silica (1:1 hexanes: ethyl acetate). The
compound was approximately 50% pure and was carried on without
further purification (0.633 g) . aK NMR (40C MH=, CD3OD) 6 7.53
(m, IH) , 7.41 (m, IH) , 7.16 (t, J = S.SHz, 2H) , 6.93 (m, 2H) ,
6.00 (s, IH), 5.42 (s, IH), 5.42 (s, 1H), 4.37 (s, 2H), 1.93
(s, 3H) ppm. LC/MS, tr = 4.65 minutes (5 to 95%
acetonitrile/water over 8 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 363 (M+H) .
Step 2 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-1-
(2,6-difluorophenyl)-6-methylpyridin-2(IH)-one
N-Bromo succinimide (168 mg, 0.945 mtnol) was added to a
solution of the product of Step 1 (0.633 g) in methylene
chloride (10 mL). After stirring at 25 C for 1 h, the
reaction was 50 % complete by LC-MS. Additional N-bromo
succinimide (150 mg) was added and the reaction was stirred at
25 C for 12 h. The reaction mixture was poured into saturated
aqueous NaHC03. The aqueous mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried with
anhydrous Na2S04, and concentrated in vacuo. The residue was
purified by reverse phase chromatography (60:40 Acetonitrile:
water with 0.05% trifluoroacetic acid). The title compound
was isolated as the TFA salt (O.lSlg, 23%). *H JSMR (400 MHz,
CD3OD) 5 7.53 (m, IH) , 7.35 (q, J = 8, 15.6HZ, IH) , 7.16 (t, J
= 8 Hz, 2H), 6.96 (app q, J = 8, 16.4Hz, 2H), 6.12 (s, IH) ,
4.86 (s, 2H) , 1.94 (s, 3H) ppm. " F NMR (400 MHz, CD3OD) 5 -
77.33 (1 F ) , -113.60 (1 F ) , -116.63 (IF), -121.50 (IF) ppm.
SS-HRMS m/z 441.0231 (M+H calcd for CisHi4BrF4N20 requires
441.0220) .
Example 503
Preparation of 3-chloro-4-[(2,4-difluorobenzyl)amino]-1-(2,6-
difluorophenyl)-6-methylpyridin-2(IH)-one
1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(IH)-
one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (ImL, 84
mmol) were combined in an nitrogen flushed culture tube. The
tube was capped and heated at 180 C for 24 h. The excess
amine was distilled in vacuo and the residue was used without
further purification. N-Chloro succinimide (168 mg, 1.26
mmol) was added to a solution of the residue in methylene
chloride (10 mL). After stirring at 25 C for 1 h, the
reaction mixture was poured into saturated aqueous NaHCCb. The
aqueous mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried with anhydrous Na2S04, and
concentrated in vacuo. The residue was chromatographed on
silica (25:75 hexanes: ethyl acetate) to give the title
compound (32 mg, 6%). XH NMR (400 MHz, CD3OD) 6 7.55 (m, IH) ,
7.36 (q, J = 9.2 and 15.2Hz, IH) , 7.18 (t, J = 7.6Hz, 2H),
6.98 (m, 2H), 6.15 (s, IH), 4.62 (s, 2H), 1.96 (s, 3H) ppm. 19
F NMR (400 MHz, CD3OD) 5 -113.78 (1 F), -116.72 (1 F), -121.57
-666-
(IF) ppm. ES-HRMS m/z 397.0752 (M+H calcd for C19Hi4ClF4N:0
reouires 397.0725).
Example 504
Preparation of 3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6
methyl-2-oxopyridin-l(2H)-yl]methyl}benzonitrile
Step 1 Preparation of 3-phthalimidomethyl-benzonitrile
3-Phthalimidomethyl-benzonitrile was prepared as described in
the literature. (Bookser, B.C.; Bruice, T.C. J. Am. Chem.
Soc. 1991, 113, 4208-18.)
Step 2 Preparation of 3-(aminomethyl)benzonitrile
^NH2
3-(Aminomethyl)benzonitrile was prepared as described in the
literature. (Bookser, B.C.; Bruice, T.C. J. Am. Chem. Soc.
1991, 113, 4208-18.)
Step 3 Preparation of 3-[(4-hydroxy-6-methyl-2-oxopyridin-
1(2H)-yl)methyl]benzonitrile
A nitrogen flushed pyrex reaction tube was charged with
3- (aminomethyDbenzonitrile (1 g, 7.9 mmol), 4-hydroxy-6-
methyl- 2 -pyrone (1 g, 7.9 mmol) and water (20 mL) . The tube
was capped and was heated to reflux. After 1.5 h, the product
precipitated from solution. The reaction mixture was cooled
to room temperature, filtered and washed with water. The
product was used without further purification (1.67g, 88 %) .
XH NMR (400 MHz, dmso-d6) 5 10.53 (s, 1H) , 7.61 (d, J = 8Hz,
1H) , 7.52 (t, J = 8Hz, 2H) , 7.38 (d, J = 8 Hz, 1H) , 5.79 (dd,
J = 1 and 2.5 Hz, 1H) , 5.56 (d, J = 2.7 Hz, 1H) , 5.18 -(s, -
2H) , 2.14 (s, 3H) ppm. ES-HRMS m/z 241.0968 (M+H calcd for
requires 241.0972) .
Step 5 Preparation of 3- { [4- [ (2 , 4-dif luorobenzyl) amino] -6-
methyl- 2-oxopyridin-l (2H) -yl] methyl }benzonitrile
The product from Step 4 (0.5 g, 2.08 mmol} and 2,4-difluoro
benzylamine (2mL, 16.8 mmol) were combined in.a nitrogen
flushed culture tube. The tube was capped and heated at 180 C
for 24 h. The excess amine was distilled in vacuo and the
residue was triturated with ethyl acetate/ hexanes to
precipitate the starting materials. The residue was
chroraatographed on reverse phase (1:1 water: acetonitrile with
0.05% trifluoroacetic acid ). The product of Step 5 was
isolated as a white' semi-soizd (0.125g, 15%). XH NMR (400 mz,
CD3OD) 6 7.61(d, J = BEz, IK), 7.49 (t, J = 8 Ez, IK), 7.41 (m,
3H) , 6.94 (m, 2H) , 5.89 (dd, J = 0.8 and 2.1Ez, 1H) , 5.47 (d,
J = 2.8K2, 1H) , 5.27 (s, 2H), 4.34 (s, 2H), 2.IS (s, 3H) p?m.
LC/MS, tr = 4.87 minutes (5 to 95% acetonitrile/water over S
minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z
366 (M+H).
Step 6 Preparation of 3 -{ [3-chloro-4-[(2,4-
difluorobenzyl)amino]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}benzonitrile
N-Chloro succinimide (36 mg, 0.27 mmol) was added to a
solution of the product of Step 5 (0.125 g, 0.26 mmol) in
methylene chloride (10 mL). After stirring at 25 C for 2 h,
the reaction was complete by LC-MS. The reaction mixture was
poured into saturated aqueous NaHCO3. The aqueous mixture was
extracted with ethyl acetate. The organic layer was washed
with brine, dried with anhydrous Na2SO4, and concentrated in
vacuo. The residue was triturated with acetonitrile to give
the title compound as a tan solid (20 mg, 13%). aH NMR
MHz, CD3OD) 5 7.61 (d, J = 8.4 Hz, 1H), 7.49 (m, 2H), 7.40 (d,
J = 8.4 Hz, 1H), 7.33 (q, J = 8.4 and 14.8 Hz, 1H), 6.94 (m,
2H), 6.00 (s, 1H), 5.34 (s, 2H), 4.56 (s, 2H), 2.21 (s, 3H)
ppm. 19 F NMR (400 MHz, CD3OD) 6 -114.00 (1 F) , -116.89 (1 F)
ppm. LC/MS, tr = 5.49 minutes (5 to 95% acetonitriie/water
over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ESVIS
m/z 400 (M+H) .
Examcle 505
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-
methyl-2-oxopyridin-l(2H)-yl]methyljbenzonitrile
The title compound was prepared essentially as -in Example-
504. 1H NMR (400 MHz, CD3OD) 8 7 . 66 (d, J = 8 Hz, 2H) , 7 .33
(q, J =8 and 15.2 Hz, IH), 7.25 (d, J = 8 Hz, 2H), 6.94 (m,
2H), 6.01 (s, IH), 5.36 (s, 2H), 4.55 (s, 2H), 2.19 (s, 3H)
ppm. 19 P NMR (400 MHz, CD3OD) 5 -77.52 (IF), -113.89 (IF), -
116.71 (1 F) ppm. LC/MS, tr = 5.49 minutes (5 to 95%
acetonitrile/water over 8 minutes at I ml/min with detection
254 nm, at 50°C) . ES-MS m/z 400 (M+H) .
Example 506
Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-[2-
fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(IH)-one
Preparation of (3-amino-4-fluorophenyl)methanol
NH2
A flask equipped with overhead stirrer was charged with
4-fluoro-3-nitrobenzyl alcohol (20g, 0.117 mol) and 200 mL of
5:1 isopropanol: water. Ammonium chloride (62 g, 1.17 mol)
was added followed by iron filings (S5g, 1.17 mol). The
mixture was stirred at 70 C for 1.5 H when it was shown to be
complete by LC-MS. The liquid was. decanted and the solids
were washed with additional isopropanol: water. The
isopropanol was removed and the residue was diluted with 0.5 N
HCl and was extracted with ethyl acetate. The aqueous layer
was brought to pH 12-14 with 2.5 N NaOH and was extracted with
ethyl acetate. The organic layer was dried with anhydrous
Na2S04 and concentrated in vacuo. 3-Amino-4-fluorophenyl
methanol was isolated as a brown solid (4.5g, 27%) and was
used without further purification. LC/MS, tr = 2.40 minutes (5
to 95% acetonitrile/water over 8 minutes at 1 ml/tnin with
detection 254 nm, at 50°C) . ES-MS m/z 142 (M+H) .
ES-HRMS m/z 142.0692 (M+H calcd for C7H8FNO requires 142.0663) .
Step 2 Preparation of 1-[2-fluoro-5-(hydroxymethyl)phenyl]-4-
hydroxy-6-methylpyridin-2(1H)-one
OH
A 100 mL round bottomed flask equipped with stirbar,
Dean-Stark trap and reflux condenser was charged with (3-
amino-4-fluorcphenyi)methanoi (4.5 g, 31.9 mmol),
4-hydroxy-6-methyl-2-pyrone (4 g, 31.9 mmol) and odichlorobenzene
(5 mL). The system was immersed in a 170 C
oil bath for 10 minutes. The solvent was removed in vacuc and
the residue was chromatographed on reverse phase (75:25
water:acetonitrile with 0.05% TFA). The product contained
some starting materials after purification and was used
without further purification (1.27g, 15%) . XH NMR (400 MKz,
dmso-ds) 8 7.39 (m, IH), 7.20 (dd, J = 2.2 and 7.6 Hz, IH),
6.74 (dd, J = 2.7 and 9.6 Hz, IH), 5.93 (dd, J = 1.2 and 2.2
Hz, IH) , 5.22 (dd, J = 0.4 and 2..2, Hz, IH) , 2.12 (s, 3H) ppm.
ES-HRMS m/z 250.0662 (M+H- calcd for C13Hi3FNO3 requires
250 .0874) .
Step 3 Preparation of 4-[(2,4-difluorobenzyl)oxy]-1-[2-fluoro-
5-(hydroxymethyl)phenyl]-6-methylpyridin-2(IH)-one
F
A 100 mL roundbottomed flask (nitrogen purged) was
charged with 1-[2-fluoro-5-(hydroxymethyl)phenyl]-4-hydroxy-6
methylpyridin-2(IH)-one (1.2g, 4.82 mmol) and N,N-dimethyl
formamide (10 mL). Potassium carbonate (0.6g, 4.4 mmol) and
2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) was added and
the reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with saturated
aqueous NaHCO3 and extracted with ethyl acetate. The organic
layer was concentrated in vacuo and the residue was
chromatographed on silica (9:1 methylene chloride: ethanol).
The impure oil (0.3g, 17%) was carried on without further
purification. LH NMR (400 MHz, CD3OD) 5 7.54 (m, 2H) , 7.30 (m,
2H) , 7.02 (m, 2H), 6.17 (dd, J = 1 and 2.8 Hz, 1H), 6.03 (d, J
=2.8 Hz, 1H), 5.14 (s, 2H), 4.62 (s, 2H), 2.14 (s, 3H) ppm.
19 F NMR (400 MHz, CD3OD) 5 -111.35 (IF), -115.97 (1 F) , -127.31
(1 F) ppm. LC/MS, tr = 5.05 minutes (5 to 95%
acetonitrile/water over 8 minutes at 1 ml/min with detection
254 nm, at 50°C). ES-MS m/z 375 (M+H).
Step 4 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-
[2-fluoro-5-(hydroxymethyl)phenyl]-6-methylpyridin-2(1H)-
N-Bromo succinimide (50 mg, 0.3 mmol) was added to a
solution of the product of Step 3 (0.12 g, 0.32 mmol) in N,Ndimethyl
formamide (4 mL) . After stirring at 25 C for 2 h,
trifluoroacetic acid (50 |iL) was added. After 1 h, additional
N-Bromo succinimide (30 mg) was added. After 1 h, the
reaction was complete by LC-MS. The reaction mixture was
poured into brine and was extracted with ethyl acetate. The
organic layer was washed with brine, dried with anhydrous
Na2S04, and concentrated in vacuo. The residue was
chromatographed on reverse phase (95:5 methylene chloride:
ethanol). The title compound was isolated as the TFA salt (38
mg, 26 %). aH NMR (400 MHz, CD3OD) 8 7.64 (q, J = 7.6 and 14.8
Hz, 1H), 7.51 (m, 1H), 7.31 (app t, J = 8.4 Hz, 1H), 7.04 (t,
j = 8.4 Hz, 2H), 6.63 (s, IH), 5.34 (s, 2H) , 4.62 (s, 2H),
2 . 0 6 (s, 3H) ppm. -5 F NMR (400 MHz, CD3OD) 5 -111.48 (IF), -
115.92 (1 F) , -127.23 (1 F) ppm. ES-HRMS m/z 454.0223 (M-fH
calcd for C2oHi6BrF3N03 requires 454.0260) .
Example 507
Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid
Step 1 Preparation of methyl 4-fluoro-3-nitrobenzoate
A I L 3-necked round bottomed flask equipped with a
nitrogen inlet, stirbar, addition funnel and thermocouple was
charged with 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) and
methanol (300 mL). The system was cooled to 0 C and acetyl
choride (27 mL, 0.37 mol) was added dropwise. The system was
warmed to room temperature, the addition funnel was replaced
with a reflux condenser, and was heated to reflux for 1.5 h.
The reaction mixture was cooled to room temperature, quenched
with saturated aqueous NaHC03/ and extracted with ethyl
acetate. The organic extract was washed with brine, dried
with Na2SO4 and concentrated in vacuo to give methyl 4-f luoro-
3-nitrobenzoate as an orange solid (40.6 g, 75%). XH NMR (400
MHz, CD3OD) 8 8.67 ((dd, J = 2.2 and 6.8 Hz, IH), 8.34 (dddd, J
= 2.2, 4.4, 6.4 and 8.8 Hz, IK), 7.55 (dd, J = 8.8 and 10.3
Hz, IK), 3.94 (s, 3H) ppm. ES-HRMS m/z 200.02446 (M-i-K calcd
for CgH7FN04 requires 200.0354).
Steo 2 Preparation of methyl 3-amino-4-fluorobenzoate
A Parr bottle was charged with the product of Step 1 (40
g, 0.2 mol), ethanol (400 mL) andlO% Pd/C (1 g g). The system
was flushed twice with nitrogen and hydrogen. The reaction
mixture was hydrogenated at 40 psi until no starting material
was visible by LC-MS. The reaction mixture was slurried with
Celite and then was filtered through a pad of celite. The
filtrate and ensuing ethanol washes were concentrated in vacuo
to give methyl 3-amino-4-fluorobenzoate as an orange solid
(30.6 g, 91%) . XH NMR (400 MHz, CD3OD) 5 7.54 (d, J = 8.7 Hz,
1H) , 7.35 (m, 1H) , 7.06 (t, J = 8.7 Hz, 1H) , 3.09 (s, 3H) ppm.
F NMR (400 MHz, CD3OD) 5 -131.02 (IF) ppm. ES-HRMS m/z
199.0281 (M+H calcd for C8H7FN04 requires 199.02).
Step 3 Preparation of methyl 4-fluoro-3-(4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)benzoate
A 250 mL round bottomed flask equipped with stirbar,
Dean-Stark trap and reflux condenser was charged with the
product of Step 3 (30 g, 0.18 mol), 4-hydroxy-6-methyl-2-
pyrone (22.6 g, 0.18 mol), and o-dichlorobenzene (90 mL). The
system was immersed in a 170 C oil bath for 30 minutes and was
then cooled to room temperature. The reaction mixture was
washed with aqueous Na2C03 (38 g, 0.36 mol, 300 mL water). The
acrueous layer was washed with ethyl acetate and then was
acidified to uH 1-2 with concentrated HCI. This was extracted
with ethyl acetate, which was then dried with MgS04 and
concentrated in vacuo. The viscous orange oil was used
without further purification (14.4 g, 28%). "~H NMR (400 MHz,
CD3OD) 8 8.18 (dddd, J = 2.3, 5.2, 7.2 and 8.8 Hz, 1H), 7.97
(dd, J = 2 and 7.2 Hz, 1H), 7.44 (t, J = 8.8 Hz, 1H), 6.09 (d,
J = 1.8 Hz, 1H), 5.78 (d, J = 2.4 Hz, 1H), 3.9 (s, 3H), 2.14
(S, 3H) ppm. 19 F NMR (400 MHz, CD3OD) 8 -117.29 (IF) ppm.
ES-HRMS m/z 278.0796 (M+H calcd for Ci4H13FN04 requires
278.0823) .
Step 4 Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoate
F
CO2Me
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with the product of Step 3 (14.4 g,
51.9 mmol) and N,N-dimethyl formamide (40 mL). 1,8-
diazabicyclo[5.4.0]undec-7-ene (10.9 mL, 72.8 mmol) was added
followed by 2,4-difluorobenzyl bromide (9.3 mL, 72.8 mmol).
The reaction mixture was stirred at 65 C for 18 h, was poured
into saturated aqueous NaHC03 and was extracted with ethyl
acetate. The organic layer was washed with brine, dried with
Na2S04 and concentrated in vacuo to give the title product, as
an orange oil (21.Sg), which was carried on to the next
reaction without further purification. 1H NMR (400 MHz, CD3CB)
5 8.20 (dddd, J = 2.2, 4.8, 7.2 and 8.8 Hz, IE), 8.00 (dd, J =
2.2 and 7.2 Hz, IK), 7.56 (td, J = 2.4, 6.4 and 9.2 Hz, IK),
7.46 (t, J = 9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J = 0.8 and
2.6 Hz, 1H), 6.04 (d, J = 2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s,
3H) , 1.98 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) 5 -111.34
(IF), -116.00 (1 F), -117.35 (1 F) ppm. ES-HRMS m/z 404.1104
(M+H calcd for C2iHi7F3N04 requires 404.1104).
Step 5 Preparation of methyl 3-[3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-
fluorobenzoate
A 250 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with the product of Step 4 (21 g,
52 mmol) and N-methyl-2-pyrrolidine (100 mL). N-Chloro
succinimide (8.3 g, 62 mmol) was added and the reaction
mixture was stirred at 65 C for 2 h. The mixture was then
cooled to room temperature, poured into saturated aqueous
NaHC03 and extracted with ethyl acetate. The organic layer was
washed with brine, dried with Na2S04, and concentrated in
vacuo. The residue was triturated with diethyl ether and
filtered to give the title compound, as a white powder (5.9 g,
25%). XH NMR (400 MHz, CD3OD) 6 8.22 (dddd, J = 2, 4.8, 6.8
and 8.8 Hz, 1H), 8.03 (dd, J = 2 and 7.2 Hz, 1H), 7.62 (q, J =
8.4 and!4.8 Hz, 1H), 7.48 (t, J = 14 Hz, 1H), 7.04 (m, 2H),
6.69 (s, 1H), 5.36 (a, 2H), 3.91 (a, 3H), 2.03 (s, 3H) ppm.
19 F NMR (400 MHz, CD3OD) 5 -111.38 (IF), -115.97 (1 F) , -117.43
(1 F) ppm. ES-HRMS m/z 438.0723 (M+K calcd for C2iKiSCl?3N04
requires 438.0714).
Step 6 Preparation of 3 -[3-chloro-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoic acid
F
C02H
A 100 mL round bottomed flask was charged with the
product of Step 5 (2.5 g, 5.72 mmol), tetrahvdrofuran (40 mL) ,
methanol (10 mL), and water (10 mL). To this slurry was added
2.5 N NaOH (4.6 mL, 11.4 mmol). The reaction mixture became
clear after 5 minutes and the reaction was complete in 35
minutes by LC-MS. The organics were removed on the rotary
evaporator and the remaining solution was acidified to pH 3
with 6N HCl. The desired compound was precipitated by the
addition of diethyl ether and subsequent filtration. The
title compound was isolated as a white powder (2.5 g, 98%). XH
NMR (400 MHz, dmso-d€) 6 8.10 (dddd, J = 2.1, 4.8, 7.2 and 8.4
Hz, 1H), 8.00 (dd, J = 2.1 and 7.6 Hz, 1H), 7.66 (q, J = 9.2
and 15.6 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1H), 7.34 (td, J = 2.4
and 10.4 Hz, 1H), 7.17 (tdd, J = 1, 2.7 and 8.4 Hz, 1H), 6.76
(s, 1H) , 5.33 (s, 2H) , 1.98 (s, 3H) ppm. 19 F NMR (400 MHz,
dmso-ds) 5 -109.32 (IF), -113.64 (1 F) , -117.22 (1 F) ppm.
ES-HRMS m/z 424.0575 (M+H calcd for C2oHi4ClF3N04 requires
424.0558).
Example 508
O
Preparation of 3-[3-chloro-4-[(2, 4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-fluoro-N-methylbenzaraide
To a reaction vessel (borosilicate culture tube) was
added 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-l(2H)-yl]-4-fluorobenzoic acid (0.300 g, 0.708
mmol) and 1-hydroxybenzotriazole (0.048 g, 0.45 mmol) . N,NDimethylformamide
(3 mL) was added to the reaction vessel
followed by approximately 1.2 g of the polymer bound
carbodiimide resin (1.38 mmol/g). Additional N,Ndimethylformamide
(2 mL) was then added to the reaction
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 15 minutes. N-Methyl amine (1
mL, 2 mmol) was then added to the reaction vessel and the
reaction apparatus was orbitally shaken at room temperature
overnight. At this time the reaction was diluted with
tetrahydrofuran (20 mL) and treated with approximately 2.17 g
of polyamine resin (2.63 mmol/g) and approximately 2.8 g of
methylisocyanate functional!zed polystyrene (1.5 mmol/g) and
the orbital shaking was continued at 200 RPM at room
temperature for 3 hours. The reaction vessel was then opened
and the solution phase product was separated from the
insoluble quenched byproducts by filtration and collection
into a vial. After partially evaporation the insoluble
byproducts were rinsed with tetrahydrofuran (2 x 10 tnL) . Tne
filtrate was evaporated by blowing N2 over the vial and the
resulting solid was triturated with diethyl ether to give an
off-white solid. (0.168 g, 59%)
XH NMR (400 MHz, CD3OD) 6 8.02 (dddd, J = 2, 4.4, 7.2 and 8.4
Hz, 1H), 7.80 (dd, J = 2 and 6.8 Hz, 1H), 7.62 (q, J = 8 and
14.4 Hz, 1H), 7.34 (t, J - 8.8 Hz, 1H), 7.04 (m, 2H), 6.69 (s,
1H) , 5.36 (s, 2H) , 3.29 (s, 3H) , 1.98 (s, 3H) ppm. 19 F NMR
(400 MHz, CD3OD) 8 -108.94 (IF), -113.55 (1 F) , -117.76 (1 F)
ppm. ES-HRMS m/z 437.0861 (M+H calcd for C21H17ClF3N203 requires
437.0874) .
Examples 509-518 ,
By following the method of Example 508 and replacing Nmethylatnine
with the appropriate amine, the compounds of
Examples 509-518 are prepared.
'-'
Example
No.
Ex. 509
Ex. 510
Ex. 511
Ex. 512
Ex. 513
•~
Ri
CH3
--
H
CH2CH2N(C
H3)-
CH2CH20-
H
R2
CH3
CH2CH2OH
CH2CH2N(C
H3)-
CH2CH20-
CH2CH2OCH3
%
Yield
59
70
70
19
59
L MF
222Hi9ClF3N203
C22Hi9ClF3N204
C25H24C1F3N303
C24H2iClF3N204
C23H21C1F3N204
M+H
Requires
451.1031
467.0980
506.1453
493.1101
481.1136
ESHRMS
m/z
451.1016
467.0985
506.1447
493.1136
481.1136
Ex. 514
Ex. 515
Ex. 516
Ex. 517
Ex. 518
CH3
H
H
H
CH2CH2NHCH2CH2OH
CH2CH2CH20
H
CH2CH (OH)
CH2OH
C(CH3)2CH2
OHCH2CH2NH-
63
51
64
54
34
C23H2iClF3N2O4
C23H21C1F3N204
C23H21C1F3N205
C24H23C1F3N204
C23H22C1F3N303
481.1136
481.1136
497.1086
495.1293
491.89
481.1131
481.1121
497.1102
495.1303
Example 519
CO2H
Preparation of 3- [3-bromo-4- [ (2 , 4-difluorobenzyl) oxy] -
methyl-2-oxopyridin-l(2H) -yl] -4-fluorobenzoic acid
Stepl Preparation of methyl 3-[3-bromo-4-[ (2,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -yl] -4-
fluorobenzoate
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with methyl 3-[4-[(2,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -yl] -4-
fluorobenzoate (7.3 g, 18 mmol) and N-methyl-2-pyrrolidine
(20 mL) . N-Bromo succinimide (3.5 g, 19.8 mmol) was added and
the reaction mixture was stirred at room temperature for 30
minutes. The mixture poured into saturated aqueous NaHCCh and
extracted with ethyl acetate. The organic layer was washed
with brine, dried with Na2S04, and concentrated in vacuo. The
residue was triturated with diethyl ether and filtered to give
the title compound as a white powder (3.49 g) . ^ NMR (400
MHz, CD3OD) 5 8.16 (qd, J = 3, 6.8 and 15.6 Hz, 1H), 7.84 (d, J
= 2.12 Hz, 1H), 7.64 (q, J = 8.4 and!4.8 Hz, 1H), 7.29 (d, J =
8.4 Hz, 1H) , 7.04 (m, 2H), 6.60 (s, 1H), 5.34 (s, 2H) , 3.87
(s, 3H) , 2.00 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) 8 -111.51
(IF), -115.98 (IF), -117.43 (IF) ppm. ES-HRMSm/z
494. 0387 (M+H calcd for C22Hi9BrF2NOs requires 494.0409).
Step 2 Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoic acid
F
A 100 mL round bottomed flask was charged with the
product of Step 2 (3.4 g, 7.05 mmol), tetrahydrofuran (40 mL),
methanol (10 mL), and water (10 mL) . To this slurry was added
2.5 N NaOH (5.6 mL, 14.1 mmol). The reaction mixture became
clear after 5 minutes and the reaction was complete in 1 h by
LC-MS. The organics were removed on the rotary evaporator and
the remaining solution was acidified to pH 1-2 with 6N HC1.
The desired compound was precipitated by the addition of water
and diethyl ether and subsequent filtration. The title
compound was isolated as a white powder (2.64 g, 80%). XH NMR
(400 MHz, CD3OD) 6 8.21 (dddd, J = 2.4, 5.2, 7.2 and 9.2 Hz,
1H) , 8.00 (dd, J = 2.0 and 7.2 Hz, 1H) , 7.65 (q, J = 8.4 and
14.8 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.04 (appt, J = 9.6
Hz, 1H), 6.65 (s, 1H), 5.36 (s, 2H), 2.07 (s, 3H) ppm. 19 F
NMR (400 MHz, CD3OD) 8 -111.40 (IP), -116.00 (1 F ) , -118.36 (1
F) ppm. ES-HRMS m/z 480.0259 (M+H calcd for C2iH17BrF2N05
requires 480.0253).
Example 520
'CO2H
Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-methoxybenzoic acid
Step 1 Preparation of methyl 3-amino-4-methoxybenzoate
A I L 3-necked round bottomed flask equipped with a
nitrogen inlet, stirbar, addition funnel and thermocouple was
charged with 3-amino-4-methoxy benzoic acid (50 g, 0.299 mol)
and methanol (300 mL). The system was cooled to 0 C and
acetyl choride (30 mL, 0.42 mol) was added dropwise. The
system was warmed to room temperature, the addition funnel was
replaced with a reflux condensor, and was heated to reflux for
1.5 h. The reaction mixture was cooled to room temperature,
quenched with saturated aqueous NaHC03/ and extracted with
ethyl acetate. The organic extract was washed with brine,
dried with Na2S04 and concentrated in vacuo to give methyl 3-
amino-4-methoxybenzoate as a dark solid (47.9 g, 88%), XH NMR
(400 MHz, CD3OD) 6 7.40 (t, J = 2 68 Hz, 1H) , 7.37 (t, J = 2.0
Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H)
ppm. ES-HRMS m/z 182.0826 (M+H calcd for C9Hi2ClN03 requires
182.0812) .
Step 2 Preparation of methyl 3-(4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)-4-methoxybenzoate
A 250 mL round bottomed flask equipped with stirbar,
Dean-Stark trap and reflux condenser was charged with the
product of Step 1 (23.5 g, 0.129 mol), 4-hydroxy-6-methyl-2-
pyrone (17.8 g, 0.14 mol), and o-dichlorobenzene (200 mL).
The system was immersed in a 170 C oil bath for 2 h and was
then cooled to room temperature. The reaction mixture was
washed with aqueous Na2CO3 (28 g, 0.26 mol, 500 mL water). The
aqueous layer was washed with ethyl acetate and then was
acidified to pH 1-2 with concentrated HCl. This was extracted
with ethyl acetate, which was then dried with Na2S04 and
concentrated in vacuo. The viscous orange oil was triturated
with MeOH to give the title compound as a yellow solid (1.61
g, 4%). 1H NMR (400 MHz, CD3OD) 5 8.14 (dd, J = 2.2 and 8.8
Hz, 1H) , 7.79 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H),
6.05 (d, J = 2.3 Hz, 1H), 5.77 (d, J = 2.3 Hz, 1H), 3.88 (s,
-684-
3H 3.87 {s, 3H) , 1.90 (s , 3H) ppm. ES-HRMS m/z 290.0997
(M+H calcd for CiSHaeN05 requires 290.1023).
Step 3 Preparation of methyl 3- [4- [ (2 ,4-difluorobensyl) oxy] -6
methyl-2-oxopyridin-l(2H) -yl] -4-methoxybenzoate
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet .was charged with the product of Step 2 (1.6 g,
5.5 mmol) and N,N-dimethyl formamide (10 mL) . 1,8-
diazabicyclo [5 .4 . 0]undec-7-ene (0.91 mL, 6 mmol) was added
followed by 2 , 4-dif luorobenzyl bromide (0.77 mL, 6 mmol) . The
reaction mixture was stirred at 60 C for 4 h, was poured into
saturated aqueous NaHCO3 and was extracted with ethyl acetate.
The organic layer was washed with brine, dried with Na2S04 and
concentrated in vacuo to give the title compound as an orange
foam (2.13g, 93%), which was carried on to the next reaction
without further purification. XH NMR (400 MHz, CD3OD) 6 8 . 17
(dd, J = 2.64 and 11.6 Hz, 1H) , 7.82 (td, J - 2.7 and 6.8 Hz,
1H) , 7.57 (m, 1H) , 7.29 (d, J = 11.6 Hz, 1H) , 7.02 (m, 2H) ,
6.16 (m, 1H) , 6.03 (d, J = 3.5 Hz, 1H) , 5.14 (s, 2H) , 3.89 (s,
6H) , 1.93 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) 8 -
111. 43 (IF), -116.04 (1 F) ppm. ES-HRMS m/z 416.1310 (M+H
calcd for C22H2oF2N05 requires 416.1304).
Step 4 Preparation of methyl 3- [3-bromo-4- t (2,4-
dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-l (2H) -yl] -4-
methoxybenzoate
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with the product of Step 3 (2.1 g,
5.06 mmol) and N-methyl-2-pyrrolidine (10 mL) . N-Bromo
succinimide (1 g, 5.56 mmol) was added and the reaction
mixture was stirred at room temperature for 1 h. The mixture
poured into saturated aqueous NaHC03 and extracted with ethyl
acetate. The organic layer was washed'with brine, dried with
Na2S04/ and concentrated in vacuo. The residue was
chromatographed on silica (1:1 hexanes: ethyl acetate) to give
the title compound as an orange oil (0.77 g, 31%) . 1H NMR (400
MHz, CD3OD) 8 8.16 (app qd, J = 2.5 and 7.2 Hz, 1H), 7.84 (d, J
= 2.6 Hz, 1H) , 7.64 (m, 1H) , 7.30 (d, J = 9.2 Hz, 1H), 7.04
(appt, J = 8.4 Hz, 2H)-, 6.60 (s, 1H) , 5.33 (s, 2H) , 3.80 (a,
6H) , 1.99 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) 6 -111.56
(IF), -116.00 (1 F) ppm. ES-HRMS m/z 494.0398 (M+H calcd for
C22Hi9BrF2NOs requires 494.0409).
Step 5 Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-1 (2H)-yl]-4-methoxybenzoic acid
A 100 mL round bottomed flask was charged with the
product of Step 4 (0.77 g, 1.55 mmol), tetrahydrofuran (10
mL) , methanol (5 mL), and water (5 mL) . To this slurry was
added 2.5 N NaOH (1.2 mL, 3.1 mmol). The reaction mixture
became clear after 30 minutes and the reaction was complete in
1 h by LC-MS. The organics were removed on the rotary
evaporator and the remaining solution was acidified to pH 2-3
with 6N HC1. The desired compound was precipitated by the
addition of water and diethyl ether and subsequent filtration.
The title compound was isolated as a white powder (0.60 g,
81%). XH NMR (400 MHz, CD3OD) 6 8.17 (dd, J - 2.2 and 8.8 Hz,
1H), 7.82 (d, J = 2.2 Hz, 1H), 7.64 (q, 1H), 7.29 (d, J = 8.8
Hz, 1H), 7.34 (t, J = 8.8 Hz, 2H), 6.60 (s, 1H), 5.34 (s,
2H), 3.87 (s, 3H), 2.01 (s, 3H) ppm. ES-HRMS m/z 480.0259
(M+H calcd for C2iHi7BrF2NO5 requires 480.0253).
Example 521
Br
Preparation of 3- [3-bromo-4-f(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l (2H) -yl] -4-methoxy-N-methylbenzamide
Step 1
To a reaction vessel (borosilicate culture tube) was added
Example 520 (0.300 g, 0.624 mmol) and 1-hydroxybenzotriazole
(0.042 g, 0.31 mmol). N,N-Dimethylformamide (3 mL) was added
to the reaction vessel followed by approximately 1.06 g of the
polymer bound carbodiimide resin (1.38 mmol/g), Additional
N,N-dimethylformamide (2 mL) was then added to the reaction
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 15 minutes. N-Methyl amine (2
mL, 4 mmol) was then added to the reaction vessel and the
reaction apparatus was orbitally shaken at room temperature
overnight. At this time the reaction was diluted with
tetrahydrofuran (20 mL) and treated with approximately 2 g of
polyamine resin (2.63 mmol/g) and approximately 2.5 g of
methylisocyanate functionalized polystyrene (1.5 mmol/g) and
the orbital shaking was continued at 200 RPM at room
temperature for 3 hours. The reaction vessel was then opened
and the solution phase product was separated from the
insoluble quenched byproducts by filtration and collection
into a vial. After partially evaporation the insoluble
byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The
filtrate was evaporated by blowing N2 over the vial and the
resulting solid was triturated with diethyl ether to give the
desired product as an off-white solid (0.094 g, 31%). XH NMR
(400 MHz, CD3OD) 8 7.98 (dd, J = 2.2 and 8.8 Hz, 1H) , 7.64 (m,
2H), 7.28 (d, J = 9.2 Hz, 1H), 7.04 (t, J = 9.2 Hz, 2H), 6.60
(s, 1H) , 5.34 (s, 2H), 3.86 (s, 3H), 2.88 (s, 3H), 2.01 (a,
3H) ppm. 19 F NMR (400 MHz, CD3OD) 5 -111.59 (IF), -116.01 (1
F) ppm. ES-HRMS m/z 493.0593 (M+H calcd for C22H2oBrF2N204
requires 493.0569).
Example 522
Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-methoxy-N,N-dimethylbenzamide
The title compound was prepared essentially as in Example 521.
1E NMR (400 MHz, CD3OD) b 7.64 {m, IH) , 7.61 (dd, J = 2 and
8.8 Hz, IH), 7.33 (d, J = 2.2 Hz, IH), 7.27 (d, J = 8 Hz, IH),
7.04 (t, J = 8 Hz, 2H), 6.59 (s, IH), 5.33 (a, 2H) , 3.85 (a,
3H) , 3.07 (S, 6H) , 2.02 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD)
8 -111.60 (IF), -116.01 (1 F) ppm. ES-HRMS m/z 507.0716 (M+H
calcd for C23H22BrF2N204 requires 507.0726).
Example 523
1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4- [ (2,4-
difluorobenzyl) oxy] -6-methylpyridin-2(IH)-one hydrochloride
Step 1
Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzamide
A 250 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with 3-[3-chloro-4-[(2,4-
dif luorobenzyl) oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-
fluorobenzoic acid (2.58g, 6.1 mmol), 4-methylmorpholine (2.0
mL, 18.3 mmol), 2-chloro-4,6-dimethoxy-l,3,5-triazine (1.28g,
7.3 mmol) and tetrahydrofuran (30 mL) . After stirring the
mixture for 30 min at 25° C, NH4OH (15.0 mL) was added. The
mixture was stirred for 30 min and diluted with water. The
product precipitated from solution. The precipitated was
filtered and washed with water and diethyl ether to give the
title compound (2.55g, 78%) as a white solid. XH NMR (400 MHz,
(CD3)2SO) 8 8.10 (m, IH) , 7.9 (dd, J = 2.1 and 5.2 Hz, IH) ,
7.65 (q, 6.7 and 8.5 Hz, IH), 7.56 (t, J = 9.1 Hz, IH), 7.35
(td, J = 2.4 and 8.2 Hz, IH) 7.17 (td, J = 2 and 6.6 Hz, IH)
6.78 (s, IH), 5.36 (a, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 423.
0719 (M+H calcd for C2oHi5ClF3N203 requires 423.0718).
Step 2
Preparation of 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-
[ (2,4 difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one
hydrochloride
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with the product from step 1 (1.5
g, 3.5 mmol) , BH3»THF complex (7.4 mL, 7.4 mmol) , and
tetrahydrofuran (15 mL). The mixture was refluxed for 6 h,
allowed to cool to room temperature and quenched with HCl 6N.
The organics were evaporated and the remaining aqueous
solution was saturated with NaOH 2.5N and extracted with
di chl or ome thane. The organic phase was dried with Na2S04 and
concentrated in vacuo. HCl 6N was added, and concentrated in
vacuo. aH NMR (400 MHz, (CD3)2SO) 6 8.2 (m, 1H) , 7.6 (m, 1H)
7.5 (m, 1H), 7.3 (t, J = 9.8 Hz, 1H), 7.16 (t, J = 8.6 Hz, 1H)
6.78 (s, 1H), 5.36 (s, 2H), 4.05 (d, J = 5.8 Hz, 2H), 2 (s,
3H) ppm. ES-HRMS m/z 409. 0940 (M+H calcd for C2oH17ClF3N202
requires 409.0925).
Example 524
3-[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-4-fluoro-N-[2-hydroxy-l-
(hydroxymethyl)ethyl] benzamide
Preparation of 3- [3-chloro-4- [ (2,4-dif luorobenzyl) oxy] -6-
methyl- 2 -oxopyridin-1 (2H) -yl] -4-f luoro-N- [2-hydroxy-l-
( hydroxymethyl) ethyl] benzamide
The title compound was prepared essentially as in Example
521. XH NMR (400 MHz, CD3OD) 8 8.1 (m, 1H) , 7.8 (dd, J = 2.3
and 5.1 Hz, 1H) , 7.6 (q, J = 7.4 and 7.0 Hz, 1H) , 7.41 (t , J =
8.9 Hz, 1H) , 7.04 (m, 2H) 6.7 (s, 1H) , 5.36 (s, 2H) , 4.1 (t, J
= 5.8 Hz, 1H) , 3.7 (d, J = 5.1 Hz, 4H) 2.1 (s, 3H) ppm. ESHRMS
m/z 497. 1045 (M+H calcd for C^^iCIF 3N205 requires
497.1086) .
Examples 525-528
The compounds of Examples 525-528 are prepared by derivitazion
of Example 523. The analytical data are shown below.
Ex . No . R MF M+H ESHRMS
Ex. 525
Ex. 526
Ex. 527
Ex. 528
-C(0)CH3
-C(0)CH2OCH3
- S02CH3
-C(0)NH2
C22H18C1F3N203
C23H2oClF3N204
C2iH18ClF3N204S
C2iHi6ClF3N303
Requires
451.1031
481.1136
487.0701
452.0983
tn/z
451.1010
481.1132
487.0679
452.0987
NMR characterization of compounds of Examples 525-528
Ex.No. NMR Data
525 H NMR (400 MHz, CD3OD) 8 7.6 (q, J = 7.8 and 7.0 Hz, 1H) , 7.5 (m,
1H), 7.3 (t, J = 9.0 Hz, 1H), 7.2 (dd, J = 1.9 and 5.1 Hz, 1H),
7.05 (m, 2H), 6.65 (s, 1H) , 5.36 (s, 2H), 4.39 (s, 2H), 2,1 (s,
3 H ) , 1 . 9 8 (s, 3H) ppm
526 TH NMR (400 MHz, CD3C13) 8 7.45 (q, J = 8.6 and 6.2 Hz, 1H), 7.3
(m, 1H), 7.1 (m, 2H), 6.85 (q, J = 6.5 and 1.9 Hz, 1H), 6.78 (td,
J = 2.7 and 7.8 Hz, 1H), 6.2 (s, 1H), 5.2 (s, 2H), 4.39 (d, J =
6.2 Hz, 2H), 4.0 (S, 3H) 2.3 (s, 2H), 2.0 (s, 3H), 1.98 (s, 3H)
527 H NMR (400 MHz, CD3OD) S 7.49 (q, J = 8.2 and 6.3 Hz, 1H) , 7.33
(m, 1H) , 7.23(m, 1H), 7.1 (t, J = 8.9, 1H), 6.9 (td, J = 0.78 and
6.6 1H), 6.8 (td, J = 2.7 and 6.25 Hz, 1H), 6.2 (s, 1H), 5.2 (s,
2H), 4.2 (s, 2H), 2.8 (s, 3H) 2.0 (s, 3H) ppm
528 XH NMR (400 MHz, (CD3)2SO) 8 7.61 (q, J = 8.9 and 6.6 Hz, 1H),
7.38(d, J = 7.8 Hz, 1H), 7.3 (d, J = 10.2 HZ, 1H) 7.21 (d, J = 7.4
Hz, 1H), 7.1 (t, J = 8.6 Hz, 1H), 6.71 (s, 1H), 6.5 (t, J = 5.8
H2, 1H), 5.56 (s, 2H), 5.3 (s, 2H), 4.18 (d, J = 6.25 H2, 2H),
3.61 (s, 1H), 1.98 (s, 3H) ppm
Example 529
2-({[3-chloro-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2-
dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile
-693-
2-(bromomethyl)-5-fluorobenzonitrile (3.47 g, 16.2 mmoi;, Jchloro-
1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(IH)-
one (3.15 g, 11.6 mmol) , K2CO3 (2.56 g, 18.6 mmol), and 18-
crown-6 (0.15 g) were dissolved in N,N-dimethylacetamide (25
mL) . Reaction mixture stirred on 60°C oil bath for 4 hours.
Solvent removed by distillation. Reaction neutralized with 5%
citric acid. The solid product was washed with hexane
followed by 30% EtOAc/hexane. Filtered a brown solid (5.2 g,
79% yield).
XH NMR (CD3OD / 400MHz) 57.82 (m, 2H), 7.61 (m, 4H), 6.75 (s,
IH), 5.49 (s, 2H), 2.13 (s, 3H). ESHRMS m/z 405.0616 (M+H
requires 405.0612).
Example 530
4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-l-(2,6-
difluorophenyl)-6-methylpyridin-2(IH)-one trifluoroacetate
BH3THF (17.8 mL, 17.8 mmol) was added dropwise to a
chilled (0°C) solution of 2-({[3-chloro-l-(2,6-difluorophenyl)-
6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl) - 5 -
fluorobenzonitrile (3.61 g, 8.92 mmol) in THF (30 mL).
Following the addition, the reaction was heated at 60°C for 1.5
hours. The reaction was quenched with MeOH, the solvent
evaporated, and the crude product purified by prep HPLC. The
product was isolated by freeze-drying and evaporation of the
solvent to give a white solid (1.52 g, 32.6%). XH NMR (CD3OD/
400MHz) 87.62 (m, 2H), 7.32 (m, 1H) , 7.25 (tr, 2H, J = 8.00
Hz), 7.18 (m, 1H), 6.78 (s, 1H), 5.43 (s, 1H), 4.22 (s, 1H),
2.14 (s, 3H) . ESHRMS tn/z 409.0900 (M+H C^H^C^C! requires
409.0925) .
Examples 531-551
The compounds of Examples 531-551 are prepared by derivitazion
of Example 530. The analytical data are shown below.
Compound
No.
Ex. 531
Ex. 532
Ex. 533
Ex. 534
Ex. 535
Ex. 536
Ex. 537
Ex. 538
Ex. 539
Ex. 540
EX. 541
R
-OCH3
-CF3
-0-isopropyl
-NH-CH2CH3
-Cite
t r ahy dr o fur an -
3-yl
-0-propyl
-0-CH2CH=CH2
-0-CH2C=CH
-0-tButyl
-NH-t Butyl
-S02CH2CH2CH3
MF
C22H18C1F3N204
C22H15C1F6N203
C24H22C1F3N204
C23H21C1F3N303
C25H22C1F3N205
C24H22C1F3N204
C24H20C1F3N204
C24H18C1F3N204
C25H24C1F3N204
C2SH25C1F3N303
C23H22C1F3N204S
M+H
Requires
467.0980
505.0748
495.1293
480.1296
523.1242
495.1293
493.1136
491.0980
509.1449
508.1609
515.1014
ESHRMS
m/z
467.0985
505.0754
495.1304
480.1277
523.1282
495.1338
493.1116
491.0961
509.1436
508.1574
515.0979
Ex. 542
Ex. 543
Ex. 544
Ex. 545
Ex. 546
Ex. 547
Ex. 548
Ex. 549
Ex. 550
Ex. 551
-S02CH2CH3
-NH-isopropyl
-CH2OCH3
-NHCH3
-N(CH3) (tButyl)
-NH (cyclopropyl)
-NHCH2CF3
NHCH2 (cyclopropyl)
-NHCH2 (tButyl)
-N(CH3)2
C24H23C1F3N303
C23H20C1F3N204
C22H20C1F3N303
C26H27C1F3N303
C24H21C1F3N303
C23H17C1F6N303
C25-H23C1F3N303
C26H27C1F3N303
C23H22C1F3N303
494.1453
481.1136
466.1140
522.1766
492.1296
534.1014
506.1453
522.1766
480.1296
494.1456
481.1174
466.1141
522.1737
492.1285
534.1005
506.1432
522.1740
480.1307
NMR characterization of compounds of Examples 531-551
Ex. No.
531
532
533
534
535
536
537
538
NMR data
H NMR (CD3OD / 400MHz) 67.61 (m, 1H) , 7.53 (m, 1H) , 7.24 (t, 2H,
J = S.OOHz), 7.14 (m, 1H) , 7.05 (m, 1H) , 6.74 (s, 1H) , 5.40 (s,
2H) , 4.42 (s, 2H) , 3.63 (s, 3H) , 2.12 (s, 3H)
1H NMR (CD3OD / 400MHz) 87.59 (m, 2H) , 7.24 (t, 2H, J = 8.00 Hz),
7.11 (m, 2H) , 6.73 (s, 1H) , 5.43 (s, 2H) , 4.62 (s, 2H) , 2.12 (s,
3H)
H NMR (CD3OD / 400MHz) 87.61 (m, 1H) , 7.53 (m, 1H) , 7.24 (t, 2H,
J 7. 60 Hz), 7.13 (m, 1H), 7.05 (m, 1H) , 6.74 (s, 1H) , 5.40 (s,
2H) , 4.81 (m, 1H) , 4.41 (s, 2H) , 2.12 (s, 3H) , 1.21 (d, 6H, J =
6.00 Hz)
XH NMR (CD3OD / 400MHz) 87.61 (m, 1H) , 7.52 (m, 1H) , 7.24 (t, 2H,
J = 0.80 Hz), 7.13 (m, 1H) , 7.03 (m, 1H) , 6.73 (s, 1H) , 5.39 (s,
2H) , 4.44 (s, 2H), 3.12 (q, 2H, J = 7.20 Hz), 2.12 (s, 3H) , 1.08
(t, 3H, J 7.20 Hz)
XH NMR (CD3OD / 300MHz) 87.62 (m, 1H) , 7.54 (m, 1H) , 7.25 (t, 2H,
J » 8. 4 Hz), 7.15 (m, 1H) , 7.07 (m, 1H) , 6.75 (s, 1H) , 5.41 (s,
2H) , 5.15 (s br, 1H) , 4.44 (s, 2H) , 3.82 (m, 4H) , 2.13 (s, 4H) ,
2.03 (s br, 1H)
H NMR (CD3OD / 300MHz) 87.62 (m, 1H) , 7.54 (m, 1H) , 7.25 (t, 2H,
J = 8.1 Hz), 7.15 (m, 1H) , 7.06 (m, 1H) , 6.74 (s, 1H) , 5.41 (s,
2H) , 4.43 (s, 2H) , 3.98 (t, 2H, J = 6.6 Hz), 2.13 (s, 3H) , 1.63
(m, 2H) , 0.94 (t, 3H, J = 7.2 Hz)
XH NMR (CD3OD / 300MHz) 87.62 (m, 1H) , 7.54 (m, 1H) , 7.25 (t, 2H,
J * 8.4 Hz), 7.14 (m, 1H) , 7.07 (m, 1H) , 6.74 (s, 1H) , 5.92 (m
br, 1H) , 5.41 (s, 2H) , 5.29 (d, 1H, J = 17.7 Hz), 5.17 (d, 1H, J
= 10.5 Hz), 4.63 (s, 1H) , 4.53 (d, 2H, J = 5.4 Hz), 4.44 (s,
2H) , 2.13 (s, 3H)
XH NMR (CD3OD / 400MHz) 87.61 (m, 1H) , 7.53 (m, 1H) , 7.24 (t, 2H,
J = 7.6 Hz), 7.14 (m, 1H) , 7.06 (m, 1H) , 6.74 (s, 1H) , 5.41 (s,
2H) , 4.65 (d, 2H, J = 2.4 Hz), 4.44 (s, 2H) , 2.86 (t, 1H, J =
-L6B-
8.7 Hz), 7.15 (m, IH) , 7.05 (m, IH), 6.75 (s, IH), 5.42 (s,
2H), 4.47 (s, 2H), 2.70 (s, 3H), 2.14 (s, 3H). ESHRMS m/z
466.1141 (M+H C22H2oClF3N303 requires 466.1140).
Example 552
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(1-hydroxy-lmethylethyl)
pyridin-2-yl]methyl}-6-methylpyridin-2(IH)-one
Step 1: Preparation of methyl 6-methylnicotinate 1-oxide ,
Methyl 6-methylnicotinate (6.0 g, 39.7 mmol) was added
into dichloromethane (100 mL) in the round bottom flask under
nitrogen. 3-chloroperoxybenzoic acid (10.0 g, 57.9 mmol) was
then added into the flask and stirred for 5 hour. Saturated
sodium bicarbonate solution (100 ml) was added into the
reaction and the mixture was transferred to separatory funnel.
Additional 200mL of dichloromethane was added into the funnel
and obtained the organic layer. The organic layer was washed
with water (150 mL) and dried over anhydrous magnesium
sulfate. The resulting solution was evaporated to yield white
solid (6 g, 90 %) . LC/MS, tr = 0.33 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 168 (M+H) . ES-HRMS m/z 168.0628
(M+H calcd for C8H10N03 requires 168.0655).
Step 2: Preparation of methyl 6- (chloromethyDnicotinate .
0
Methyl 6-methylnicotinate 1-oxide ( from Step 1) (6.0 g,
35.9 mmol) was was added into the p-toluenesulfonyl chloride
(10 g, 52.4 mmol) in 100 mL of 1,4- dioxane. The mixture was
heated to reflux for 20 hours. Saturated sodium bicarbonate
solution (200 ml) was added into the reaction and the mixture
was transferred to separatory funnel. The compound was
extracted using ethyl acetate (300ml x 2) and the combined
ethyl acetate solution was dried over magnesium sulfate and
evaporated to black solid (5.2 g, 78%). LC/MS, tr = 1.52
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 186 (M+H)
ES-HRMS m/z 186.0314 (M+H calcd for C8H9C1NO2 requires
186.0316).
Step 3: Preparation of methyl 6-{ [4-[ (2,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -
yl]methyl}nicotinate .
Methyl 6-(chloromethyl)nicotinate ( from step 2). (2 g,
10.8 mmol) was added into 4-[(2,4-difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one in 20 mL of dimethyl formamide
followed by addition of cesium carbonate (5g, 15.3 mmol). The
mixture was heated to 100 C for 20 hours. It was cooled to
room temperature and added 400 mL of water. Brown precipitate
came out of from solution. It was filtered and rinsed with
water (200 mL x 3) and dried to obtain 4 g of solid. The
product was purified using a' Gilson Reversed Phase preparative
chromatography to obtain white solid (1.4 g, 32%) . *H NMR (400
MHz, CDC13) 5 9.09 (d, J =1.48 Hz, 1H) , 8.19 (dd, J = 6.04,
2.15 Hz, 1H), 7.37 (app q, J = 8.32 Hz, 1H), 7.25 (d, J = 8.33
Hz, 1H) , 6.84 (m, 2H) , 5.94 (d, J = 2.82HZ, 1H) , 5.83 (d, J =
2.15HZ, 1H) , 5.36 (s, 2H) , 4.97 (s, 2H) , 3.90 (s, 3H) , 2.27(s,
3H) ; LC/MS, tr = 2.30 minutes (5 to 95% acetonitrile/water over
5 minutes at 1 ml/min with detection 254 nm, at 50°C) . ES-MS
m/z 401 (M+H) . ES-HRMS m/z 401.1307 (M+H calcd for C2iHi9F2N204
requires 401.1307).
Step 4: Preparation of the title compound .
3 molar solution of methyl magnesium bromide in ether
(5mL, ISmmol) was added into 5 ml of anhydrous tetrahydrofuran
in the round bottom flaks under nitrogen. The mixture was
cooled to 0°C. Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]methyl}nicotinate ( from Step 3)
(300mg, 0.75mmol)was dissolved in 5 ml of anhydrous
tetrahydrofuran in dropper funnel and the solution was slowly
added into cold methyl magnesium bromide solution in the round
bottom flask. After the addition, the mixture was continue
stirring at 0 C for 30 minute and cold solution of saturated
ammonium chloride (100 ml) was added slowly into the reaction
mixture. The mixture was transferred to separatory funnel and
the product was extracted with ethyl acetate (200ml x2). The
combined ethyl acetate solution was dried over anhydrous
magnesium sulfate and evaporated to dryness. The resulting
residue (220 mg) was added into 10 ml of dichloromethane

followed by addition of N-bromo succinimide (100 mg, 0.56
mmol) , The solution was stirred at room temperature for 3
hours. Saturated sodium bicarbonate solution (100 ml) was
added into the reaction mixture and it was transferred to
separatory funnel. The product was extracted with ethyl
acetate (200ml x2) . The combined ethyl acetate solution was
dried over anhydrous magnesium sulfate and evaporated to
dryness .
XH NMR (400 MHz, CDC13) 8 8.61 (d, J =1.88 Hz, IH) , 7.73 (dd, J
= 5.77, 2.42 Hz, IH) , 7.55 (app q, J = 6.31 Hz, IH) , 7.30 (d,
J - 8.19b Hz, IH) , 6.93 (m, IH) , 6.84 (m, IH) , 6.00 (s, IH) ,
5.37 (s, 2H) , 5.19 (s, 2E) , 2.48 (s, 3H) , 1.56 (s, 6H) ; LC/MS,
tr = 2.29 minutes (5 to 95% acetonitrile/water over 5 minutes
at 1 ml/min with detection 254 nm, at 50°C) . ES-MS m/z 479
(M+H) . ES-HRMS m/z 479.0791 (M+H calcd for
requires 479.0776).
Example 553
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-
(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(IH)-one
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxyj-l-{[5-
(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(IH)-one
O
Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyljnicotinate ( from preparation of
step 3) (350 mg, 0.87 ramol) was added into anhydrous
tetrahydrofuran (15 ml) and the solution was cooled to -78 C.
Into the cold solution, was added lithium aluminum hydride
(100 mg, 2.6 mmol). After the addition, the reaction mixture
was warm to 0 C and continue stirring for one additional hour.
Potassium hydrogen sulfate (1 N solution, 150 ml) was added
slowly into the reaction mixture to quench the reaction. The
resulting mixture was transferred to a separatory funnel and
the product was extracted with ethyl acetate (200ml x 2).
The combine ethyl acetate solution was dried over anhydrous
magnesium sulfate and evaporated to dryness. LC/MS, tr = 1.88
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 373 (M+H)
Step 2: Preparation of the title compound .
4-[ (2,4-difluorobenzyl)oxy]-l-{ [5-(hydroxymethyl)pyridin-2-
yl]methyl}-6-methylpyridin-2(IH)-one ( from step 1) . (230 mg,
0.62 mmol) was added into 10 ml of dichloromethane followed by
addition of N-bromo succinimide (110 mg, 0.62 mmol). The
solution was stirred at room temperature for 3 hours.
Saturated sodium bicarbonate solution (100 ml) was added into
the reaction mixture and it was transferred to a separatory
funnel. The product was extracted with ethyl acetate (200ml
x2). The combined ethyl acetate solution was dried over
anhydrous magnesium sulfate and evaporated' to dryness. 1H NMR
(400 MHz, CDC13) 8 8.47 (app s, IH), 7.64 (dd, J = 5.77, 2.29
HZ, 1H), 7.55 (app q, J = 6.45 Hz, 1H), 7.33 (d, J = 6.05 Hz,
1H) , 6.93 (m, 1H)', 6.84 (m, 1H) , 6.00 (s, 1H) , 5.39 (s, 2H) ,
5.19 (s, 2H), 4.68 (s, 2H), 2.46 (s, 3H); LC/MS, tr = 2.01
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C). ES-MS m/z 451 (M+H)
Example 554
6-{ [3-bromo-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylnicotinamide
Step 1: Preparation of methyl 6-{[3-bromo-4-[(2, 4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}nicotinate .
Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}nicotinate (350 mg, 0.87 mmol) (1.0
g, 2.5 mmol) was added into 150 ml of dichloromethane followed
by addition of N-bromo succinimide (500 mg, 2.8 mmol). The
solution was stirred at room temperature for 3 hours.
Saturated sodium bicarbonate solution (300 ml) was added into
the reaction mixture and it was transferred to a separatory
funnel. The product was extracted with ethyl acetate (500ml
x2) . The combined ethyl acetate solution was dried over
anhydrous magnesium sulfate and evaporated to dryness. 1H NMR
(400 MHz, CDC13) 8 9.08 (app d, J = 2.15 Hz, 1H) , 8.21 (dd, J =
6.04, 2.15 Hz, 1H) , 7.55 (app qt , J = 6.31 Hz, 1H) , 7.41 (d, J
= 6.31 Hz, 1H) , 6.91 (m, 1H) , 6.84 (m, 1H) , 6.02 (s, 1H) , 5.42
(s, 2H) , 5.19 (s, 2H) , 3.91 (s, 3H) , 2.45 (s, 3H) ; LC/MS, tr =
2.85 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 479 (M+H) .
ES-HRMS m/z 479.0415 (M+H calcd for C2iH18BrP2N2O4 requires
479.0413) .
Step 2: Preparation of 6- { [3-bromo-4- [ (2 , 4-
dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-l (2H) -
yl] methyl }nicotinic acid .
O
Methyl 6-{ [3-bromo-4- [ (2 , 4 -dif luorobenzyl) oxy] - 6 -methyl -
2-oxopyridin-l (2H) - yl] methyl }nicotinate ( from step 1) (1.0
g, 2.1 mmol) was added into the mixture of 100 ml
tetrahydrofuran and 10 ml of methanol followed by addition of
2.5 N sodium hydroxide (0.85 ml, 2.1 mmol). The solution was
heated to 50 C for 2 hours. After the solution was cooled to
room temperature and evaporate to completely dried residue.
The residue was added into 50 ml of tetrahydrofuran and 4 N
HCl in 1,4-dioxane (0.52 ml, 2.1 mmol) and stirred the mixture
for 30 minute. The mixture was evaporate to dryness. The
residue was added 20 ml water and the aqueous solution was
neutralized to exactly ph 7 by addition of saturated sodium
bicarbonate solution drop wise. The resulting heterogeneous
mixture was left standed for 20 hours. Filtered, rinsed with
water (30 ml x 3) and dried over high vacuum oven to afford
white solid ( 950 mg, 97%) .
H NMR (400 MHz, CDC13 and CD3OD) 5 8.98 (app br s, 1H), 8.15
(dd, J = 6.17, 2.02 Hz, 1H), 7.45 (app q, J = 6.58 Hz, 1H),
7.21 (d, J = 8.19 Hz, 1H), 6.84 (m, 1H), 6.76 (m, 1H), 6.04
(s, 1H) , 5.35 (s, 2H), 5.12 (s, 2H), 2.32 (s, 3H); LC/MS, tr =
2.48 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 465 (M+H) .
ES-HRMS m/z 465.0254 (M+H calcd for C2oHi6BrF2N204 requires
465.0256).
Step 3: Preparation of the title compound .
6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}nicotinic acid ( from step 2)(230
mg, 0.5 mmol) was added into the 1-hydroxybenzotriazole
(lOlmg, 0.75 mmol) in 5 ml of N,N-dimethyIforamide. 4 -methyl
morpholine (0.16 ml, 1.5 mmol) was added into the mixture
followed by addition of 1-(3-(dimethylamino) propyl-3-
ethylcarbodiimide hydrochloride (143 mg, 0.75 mmol). Stirred
the mixture for 30 minute to become homogenous solution. To
that homogenous solution, was added 2-(methylamino)
ethanol(0.06 ml, 0.75 mmol) and the mixture was stirred for 20
hours. Water (150 ml) was added into the reaction mixture
and the product was extracted using ethyl acetate (400ml x2).
The combined ethyl acetate solution was dried over anhydrous
magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz,
DMSO-d6) 8 8.47 (app br s, 1H), 7.80 (br d, J = 7.92 Hz, 1H),
7.64 (app q, J = 6.58 Hz, 1H), 7.30 (m, 2H), 7.15 (m, 1H),
6.56 (s, 1H), 5.39 (s, 2H), 5.28 (s, 2H), 3.46 (m, 2H), 3.23
(m, 2H) 2.93 (m, 3H), 2.36 (s, 3H); LC/MS, tr = 2.29 minutes (5
to 95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C). ES-HRMS m/z 522.0850 (M+H calcd
for HaaBrFzNaCu requires 522.0835).
Example 555
0
Br
6- { [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-
1 (2H) -yl ] methyl } -N- (2-hydroxyethyl) nicotinamide
Following the method of Example 554 (step 3) and
substituting 2- (methylamino) ethanol for the ethanolamine
obtained the title compound as a white solid (79% yield) . XH
NMR (400 MHz, CD3OD) 6 8.93 (d, J = 2.01 Hz, 1H) , 8.21 (dd, J =
6.04, 2.21 Hz, 1H) , 7.67 (app q, J = 6.44 Hz, 1H) , 7.39 (d, J
= 8.06 Hz, 1H) , 7.08 (m, 2H) , 6.58 (s, 1H) , 5.55 (s, 2H) , 5.35
(s, 2H) , 3.74 (app t, J - 5.73HZ, 2H) , 3.53 (app t, J =
5.73HZ, 2H) , 2.49 (s, 3H) ; LC/MS, tr = 2.26 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-HRMS m/z 508.0673 (M+H calcd for
requires 508.0678).
Example 556
6-{ [3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-
1 (2H) -yl] methyl}-N,N-dimethylnicotinamide
Following the method of Example 554 (step 3) and substituting
dimethylamine for the ethanolamine obtained the title compound
as a white solid (75% yield). *H NMR (400 MHz, CDC13) 8 8.55
(d, J = 1.62 Hz, 1H), 7.68 (dd, J = 5.77, 2.15 Hz, 1H), 7.55
(app q, J = 6.45 Hz, IH), 7.37 (d, J = 8.06 Hz, IH), 6.93 ^m,
IH), 6.84 (m, IH), 6.02(8, IH), 5.40 (s, 2H), 5.20 (s, 2H),
3.09 (s, 3H), 2.97 (s, 3H), 2.45 (s, 3H); LC/MS, tr = 2.45
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-HRMS m/z 492.0710
(M+H calcd for C22H2iBrF2N303 requires 492.0729).
Example 557
3-bromo-4-[(2, 4-difluorobenzyl)oxy]-6-methyl-l- [2-
(trifluoromethyl)phenyl]pyridin-2(IH)-one
Step 1: Preparation of 4-hydroxy-6-methyl-l-[2-
(trifluoromethyl)phenyl]pyridin-2(IH)-one .
roxy-6-methyl-2-pyrone (lOg, 79.3 mmol) was added
into the 2-(trifluoromethyl) aniline (14 ml, 111.3 mmol) in 10
ml of 1,2-dichlorobenzene in a round bottom flask. The
mixture was then placed in a pre-heated oil bath at 165 C.
After 30 minute of heating, the mixture was cooled to room
temperature and added 250 ml of saturated sodium bicarbonate
solution. The mixture was stirred at room temperature for
minutes and transferred to a separatory funnel. Ethyl acetate
(300ml) was added into the separatory funnel and partitions
the layers. The aqueous layer was obtained and the organic
layer was added 200 ml of saturated sodium bicarbonate
solution. The aqueous layer was obtained again and the
combined aqueous solution was neutralized with HC1 solution.
Upon neutralization, white solid precipitated out of the
solution. Filtered the solid, rinsed with water (100 ml x5)
and dried over high vacuum oven to obtain the white solid g, 35.5%). LC/MS, tr = 1.77 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C). ES-MS m/z 270 (M+H).
Step 2: Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-
1-[2-(trifluoromethyl)phenyl]pyridin-2(IH)-one .
4-hydroxy-6-methyl-l-[2-(trifluoromethyl)phenyl]pyridin-2(IH)-
one ( from Step 1) (7.3 g, 27.1 mmol) was added into 3,4-
difluorobenzyl bromide (5.5 g, 26.5 mmol) in 60 ml of dimethyl
formamide. The mixture was cooled to 0 C and cesium
carbonate (20g, 61.3 mmol) was added into the mixture. After
the addition, the mixture was warmed to room temperature and
stirred for 4 hours. Water (500ml) was added into the
reaction mixture. Yellow solid came out of solution.
Filtered and rinsed with water (200ml x 2) to obtain the
yellow solid. Dissolved the solid in ethyl acetate (500 ml)
and water (300 ml) and transfer to a separatory funnel and
obtained the organic layer. The organic layer was washed
again with water (200ml) and dried over anhydrous magnesium
sulfate. The organic solution was evaporated to dryness. 1H
NMR (400 MHz, CDC13) 8 7.82 (d, J =7.65 Hz, IH) , 7.7 (t, J =
7.52 Hz, IH), 7.58 (t, J = 7.65 Hz, IH), 7.42 (q, J = 6.45 Hz,
IH), 7.27 (d, J = 7.78 Hz, 2H), 6.89 (m, 2H), 5.95 (app d, J =
2.42HZ, IH), 5.90 (app d, J = 2.42HZ, IH), 5.01 (app d, J =
2.94 Hz, 2H) , 1.86 (s, 3H) ; LC/MS, tr = 2.74 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 396 (M+H)
Step 3: Preparation of the title compound.
N-bromosuccinimide (0.24g, 1.36 mmol) was added into 4-[(2,4-
difluorobenzyDoxy] -6-methyl-l- [2-
(trifluoromethyl)phenyl]pyridin-2(IH)-one (0.54g, 1.36 mmol)
in 20 ml of dichloromethane. The mixture was stirred at room
temperature for 2 hours. Saturated sodium bicarbonate
solution (150 ml) was added into the reaction mixture and the
combine solution was transferred to a separatory funnel. The
product was extracted with ethyl acetate (250ml). The ethyl
acetate solution was dried over anhydrous magnesium sulfate
and evaporated to dryness. XH NMR (400 MHz, CDC13) 6 7.82 (d,
J =7.25 Hz, IH), 7.7 (app t, J = 7.66 Hz, IH), 7.60 (m, 2H),
7.26 (a, IH), 6.97 (m, IH), 6.87 (m, IH), 6.09 (s, IH), 5.25
(app d, J = 3.35HZ, 2H) , 1.94 (s, 3H) ; LC/MS, tr = 2.84 minutes
(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-HRMS m/z 474.0113 (M+H calcd
for C2oHa4BrFsN02 requires 474.0123).
Example 558
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
methyl-5-vinylpyridin-2(IH)-one
Step 1: To a room temperature solution of 3-bromo-4- [ (2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one (1.00 g, 1.76 mmol) in anhydrous THF
(12 mL) was added, sequentially, tributyl(vinyl)tin (1.21 g,
3.81 mmol) and tetrakis(triphenylphosphine)palladium (236 mg,
0.204 mmol) under an argon stream. The reaction vessel was
then equipped with a reflux condenser and the reaction system
purged with an argon flow. The resulting yellow solution was
heated to 68 °C and stirred under a positive pressure of argon
for 12.0 hours until complete disappearance of starting
material by LCMS analysis. The reaction mixture was
concentrated in vacuo and the resulting dark residue was
subjected to Si02 chromatography with ethyl acetate/hexanes
(3:7) to furnish a reddish solid. XH NMR (400 MHz, CDC13) 8
7.62 (app q, J = 7.8 Hz, 1H), 7.45 (app tt, J = 8.4, 6.2, 1H),
7.09 (app t, J = 8.8 Hz, 2H) , 6.90 (app t, J = 8.0 Hz, 1H) ,
6.83 (app dt, J - 6.8, 2.5 Hz, 1H) , 6.51 (dd, J = 17.7, 11.4
Hz, 1H) , 5.53 (dd, J = 11.4, 1.5 Hz, 1H) , 5.41 (dd, J = 17.8,
1.5 Hz, 1H) , 5.09 (br s, 2H) , 2.09 (s, 3H) ; LC/MS C-18
column, tr = 3.20 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min with detection 254 nm, at 50°C) . ES-MS m/z
468 (M+H) . ES-HRMS m/z 468.0210 (M+H calcd for
requires 468.0217).
Example 560
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-
(1,2-dihydroxyethyl)-6-methylpyridin-2(1H)-one
Step 1: To a room temperature solution of 3-bromo-4-[(2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-
vinylpyridin-2(1H)-one (0.970 g, 2.07 mmol) in water/acetone
1:3 (8.7 mL) was added, sequentially, osmium tetroxide (0.110
g, 0.433 mmol) and N-methyl morpholine oxide (1.32 g, 11.2
mmol) . The resulting solution was stirred for one hour until
complete consumption of starting material by LCMS analysis,
and the reaction was concentrated in vacuo. The resulting dark
residue was subjected to SiO2 chromatography with ethyl
acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz,
CDC13) 5 7.59 (app q, J = 8.2 Hz, 1H) , 7.45 (ddd, J = 14.7,
8.5, 6.8 Hz, 1H), 7.08 (app t, J = 8.5 Hz, 2H), 6.94 (app t, J
= 8.2 Hz, 1H) , 6.88 (app t, J = 8.5 Hz, 1H) , 5.31 (AB-q, J =
10.6 Hz, A= 38.3 Hz, 2H) , 5.07 (dd, J = 9.1, 3.8 Hz, 1H), 3.83
(t, J = 10.8 Hz, 1H) , 3.60 (dd, J = 11.4, 3.9 Hz, 1H) , 2.94
(br s, 1H) , 2.16 (s, 3H); LC/MS C-18 column, tr = 2.26 minutes
(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-MS m/z 502 (M-t-H) . ES-HRMS m/z
502.0276 (M+H calcd for C2iHi7BrF4N04 requires 502.0272).
Example 561
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-
(hydroxymethyl)-6-methylpyridin-2(1H)-one
Step 1: To a -20 °C solution of 5-bromo-4-[(2,4-
difluorobenzyDoxy] -1- (2, 6-difluorophenyl) -2-methyl-6-oxo-l, 6-
dihydropyridine-3-carbaldehyde (0.659 g, 1.40 mmol) in
methanol (10 mL) was added, portionwise, solid sodium
borohyride (3.6 g, 96 mmol) over one hour until complete
consumption of starting material by LCMS analysis. Next, the
reaction mixture was diluted with 500 mL of ethyl acetate and
washed with 3 X 200 mL of water. The resulting organic extract
was Na2S04 dried, filtered, and concentrated in vacuo to
approximately 100 mL volume. The resulting liquid was diluted
with hexanes (100 mL) to furnish an amorphous solid that was
collected and dried at 1 mm Hg vacuum to furnish (620 mg, 94
%) of the desired product. 1H NMR (400 MHz, d4-MeOH) 6 7.70
(app q, J = 8.3 Hz, 1H) , 7.62 (app tt, J = 10.4, 6.3 Hz, 1H) ,
7.25 (app t, J = 8.6 Hz, 2H) , 7.03 (app t, J = 8.6 Hz, 1H) ,
6.88 (app t, J = 8.5 Hz, 1H) , 5.31 (s, 2H), 4.58 (s, 2H) , 2.17
(s, 3H) ; LC/MS C-18 column, tr = 2.49. minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 tnl/min with detection
254 nm, at 50°C) . ES-MS m/z 472 (M+H) . ES-HRMS m/z 472.0152
(M+H calcd for C2oHisBrF4N03 requires 472.0166).
Example 562
4- (benzyloxy)-3-bromo-l-(2,6-difluorophenyl)-6-methylpyridin-
2(1H)-one
Step 1: Preparation of 4-(benzyloxy)-1-(2,6-difluorophenyl)-
6-methylpyridin-2(1H)-one .
F'
To a briskly stirred room temperature solution of l-(2,6-
difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (1.43 g,
6.03 mmol) in dimethyl formamide (4.6 mL) was added
sequentially K2C03 (2.01 g, 14.5 mmol) and benzyl bromide
(2.40 mL, 20.2 mmol). The resulting suspension was stirred
for 6.5 hours until complete consumption of starting material
by LCMS analysis. The reaction was then diluted with ethyl
acetate (200 mL) and brine washed (3 X 200 mL). The resulting
organic extract was Na2SO4 dried, filtered, and concentrated in
vacuo to approximately 100 mL volume. The resulting mother
liquor rapidly precipitated and furnished an amorphous solid
that was collected and dried at 1 mm Hg vacuum to provide a
solid (1.62 g, 82 %) . *H NMR (300 MHz, d4-MeOH) 6 7.62 (app
tt, J = 8.6, 6.4 Hz, 1H) , 7.52-7.32 (m, 4H) , 7.30-7.12 (m,
3H), 6.27 (d, J = 1.6 Hz, 1H), 6.04 (d, J = 2.6 Hz, 1H), 5.18
(s, 2H), 2.06 (s, 3H). LC/MS C-18 column, tr = 2.51 minutes (5
to 95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-MS m/z 328 (M+H) . ES-HRMS m/z
328.1179 (M+H calcd for Ci9H16F2N02 requires 328.1144).
Step 2: To a room temperature solution of 4-(benzyloxy)-1-
(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one (1.52 g, 4.64
mmol) in methyl ene chloride (15 mL) was added solid Nbromosuccinimide
(2.01 g, 11.3 mmol) and the resulting reddish
solution was stirred for 4.0 hours. At this time the
reaction was diluted with ethyl acetate (400 mL) and washed
with sodium sulfite (5 % aqueous solution, 100 mL) and brine
(3 X 200 roL) . The resulting organic extracts were Na2S04 dried,
filtered, and concentrated in vacuo to approximately 60 mL
volume. The resulting mother liquor rapidly precipitated and
furnished an amorphous solid that was collected and dried at 1
mm Hg vacuum to provide a solid (1.70 g, 91 %) . XH NMR (300
MHz, d4-MeOH) 6 7.64 (app tt, J = 8.6, 6.4 Hz, 1H), 7.57 (br d,
J = 7.1 Hz, 1H) , 7.50-7.34 (m, 4H) , 7.27 (app t, J = 8.0 Hz,
1H) , 7.26-7.21 (m, 1H) , 6.66 (s, 1H) , 5.40 (s, 2H) , 2.12 (s,
3H); LC/MS C-18 column, tr = 2.63 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 406 (M+H) . ES-HRMS m/z 406.0228
(M+H calcd for C19Hi5BrF2N02 requires 406.0249) .
Example 563
5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-
methyl-6-oxo-l,6-dihydropyridin-3-yl]methyl carbamate
Step 1: To a room temperature solution of 3-bromo-4-t(2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(hydroxymethyl)-
6-methylpyridin-2(1H)-one (76.2 mg, 0.161mmol) in methylene
chloride (0.4 mL) was added a solution of trichloroacetyl
isocyanate (toluene, 0.60 M, 0.5 mL, 0.30 mmol) . The resulting
solution was stirred for one hour until complete consumption
of starting material by LCMS analysis. The reaction mixture
was then directly applied to A12O3 (0.5 g of Broeckman-activity
type I) and the slurry was matured for three hours. At this
time, the A12O3 plug was flushed with ethyl acetate/methanol
(95:5) and the resulting mother liquor was concentrated to a
residue that was subjected to Si02 chromatography using ethyl
acetate/hexanes (1:1) to furnish a white solid (71.0 mg, 85
%) . XH NMR (400 MHz, d4-MeOH) 5 7.71-7.59 (m, 2H) , 7.26 (app t,
J = 8.5 Hz, 2H) , 7.02 (app t, J = 9.2 Hz, 2H) , 5.32 (s, 2H) ,
5.02 (s, 2H) , 2.15 (s, 3H) ; LC/MS C-18 column, tr = 2.35
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 515 (M+H) .
ES-HRMS m/z 515.0188 (M+H calcd for C2iH16BrF4N204 requires
515.0224) .
Example 564
5-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2, 6-difluorophenyl)-2-
methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde
Step 1: To a room temperature solution of 3-bromo-4-[(2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-5-(1,2-
dihydroxyethyl)- 6-methylpyridin-2(1H)-one (550 mg, 1.10
mmol) in toluene (10.0 mL) was added lead(IV) acetate (810 mg,
1.82 mmol). The resulting dark brown solution was stirred for
two hours until complete consumption of starting material by
LCMS analysis. The reaction mixture was then diluted with
ethyl acetate (400 mL) , water washed (3 X 100 mL) , and brine
washed (3 X 300 mL) . The resulting organic extract was
separated, Na2S04 dried, and concentrated. The resulting dark
residue was subjected to Si02 chromatography with ethyl
hexanes (1:1) to furnish a light yellow solid (321
rag, 62 %). XH NMR (400 MHz, CDC13) 6 10.08 (s, 1H), 7.56-7.48
(m, 2H) , 7.12 (app t, J = 7.3 Hz, 2H) , 6.94 (app t, J = 8.5
Hz, 1H) , 6.88 (app t, J = 8.7 Hz, 1H) , 5.33 (s, 2H) , 2.45 (s,
3H) ; LC/MS C-18 column, tr = 2.94 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 470 (M+H) . ES-HRMS m/z 469.9996
(M+H calcd for C2oHi3BrF4N03 requires 470.0009).
Example 565
5-bromo-4- [ (2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-
methyl-6-oxo-l,6-dihydropyridine-3-carbaldehyde oxime
Step 1: To a room temperature solution of 5-bromo-4- [ (2,4--
dif luorobenzyl) oxy] -1-(2,6-difluorophenyl)-2-methyl-6-oxo-l,6-
dihydropyridine-3-carbaldehyde (316.5 mg, 0.673 mmol) in
methanol (10.0 mL) was added solid NH2OH»H20(300.0 mg, 4.32
mmol) and sodium acetate (480.0 mg, 5.85 mmol). The resulting
suspension was stirred for 1.5 hours until complete
consumption of starting material by LCMS analysis. The
reaction mixture was then concentrated in vacuo and the
resulting residue was diluted with methylene chloride (300 mL)
and water washed (2 X 100 mL). The resulting organic extract
was separated, Na2S04 dried, and concentrated to furnish a
light yellow solid (390 mg, 99 %) . XH NMR (400 MHz, d4-MeOH
with CDC13) 8 8.06 (s, 1H), 7.51-7.40 (m, 2H), 7.06 (app dd, J
= 8.6, 7.4 Hz, 2H) , 6.88 (app dt, J = 8.3, 2.4 Hz, 1H) , 6.83
(app dt, J = 9.2, 2.4 Hz, 1H) , 5.13 (s, 2H) , 2.76 (a, 3H) ;
LC/MS C-18 column, tr = 2.61 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 485 (M+H) . ES-HRMS m/z 485.0093
(M+H calcd for C2oHi4BrF4N203 requires 485.0118).
Example 566
5-bromo-4-[ (2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-2-
methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile
Step 1: To a room temperature solution of 5-bromo-4-[(2,4-
dif luorobenzyl) oxy] -1- (2 , 6-dif luorophenyl) -2-methyl-6-oxo-l, 6-
dihydropyridine-3-carbaldehyde oxime (340.0 mg, 0.701mmol)
in methylene chloride (8.0 mL) was added solid 1,1' carbonyl
diimidazole (290.0 mg, 1.79 mmol) and sodium acetate (480.0
mg, 5.85 mmol). The resulting solution was stirred for 1.5
hours until complete consumption of starting material by LCMS
analysis. The reaction mixture was then concentrated in vacuo
and the resulting residue was directly applied to SiO2
chromatography with ethyl acetate/hexanes (3:7) to furnish a
white solid (262 mg, 90 %) . ^ NMR (400 MHz, CDC13) 8 7.61
(app q, J = 7.4 Hz, 1H) , 7.52 (app tt, J = 8.4, 6.3 Hz, 1H) ,
7.14 (app dd, J = 8.6, 7.4 Hz, 2H), 6.94 (app dt, J = 8.5, 2.5
Hz, 1H) , 6.88 (app dt, J = 8.5, 2.4 Hz, 1H) , 5.43 (s, 2H) ,
.32 (s, 3H) ; LC/MS C-18 column, tr = 2.95 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 tnl/min with detection
254 nm, at 50°C) . IR (neat) 3111, 3067, 3032, 2914, 2840, 2215
(nitrile stretch), 1678, 1587, 1470 cm"1; ES-MS m/z 467 (M+H).
ES-HRMS m/z 467.0037 (M+H calcd for C2oHi2BrF4N202 requires
467.0013).
Example 567
F
4-(benzyloxy)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one
Step 1: A solution of 4-(benzyloxy)-3-bromo-l-(2,6-
difluorophenyl)-6-methylpyridin-2 (1H)-one (1.42 g, 3.50 mmol)
in 1,2 dichloroethane (18 mL) was treated with solid Niodosuccinimide
(1.59 g, 7.06 mmol) and dichloroacetic acid
(0.260 g, 2.01 mmol). The resulting solution was stirred and
heated to 50 °C for 2.5 hours until complete consumption of
starting material by LCMS. At this time the reaction was
diluted with ethyl acetate (400 mL) and washed with sodium
sulfite (5 % aqueous solution, 100 mL) and brine (3 X 200 mL).
The resulting organic extracts were NajSO* dried, filtered, and
concentrated in vacuo to approximately 30 mL volume. The
resulting mother liquor rapidly precipitated and furnished an
amorphous solid that was collected and dried at 1 mm Hg vacuum
to provide a solid (1.49 g, 82 %) . 1H NMR (400 MHz, CDC13) 8
7.62 (app d, .J = 6.8 Hz, 2H) , 7.51-7.38 (m, 4H) , 7.09 (app t,
J = 8.0 Hz, 2H) , 5.20 (s, 2H) , 2.39 (s, 3H) ; LC/MS C-18
column, tr = 3.28 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min with detection 254 nm, at 50°C) . ES-MS m/z
532 (M+H) . ES-HRMS m/z 531.9196 (M+H calcd for
requires 531.9215) .
Example 568
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-
methyl-5-oxiran-2-ylpyridin-2(IH)-one
Step 1: A sample of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-
(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one (10.0
mg, 0.0214 mmol) was treated with a solution of dimethyl
dioxirane in acetone (approx. 0.1 M, 5 mL, 0.5 mmpl) . The
reaction vessel was capped and sealed, and the resulting
solution was stirred 6.0 hours. At this time the reaction was
concentrated in vacuo and the resulting residue was subjected
to Si02 chromatography with ethyl acetate/hexanes (4:6) to
furnish a semi-solid (5.0 mg, 48 %) . XH NMR (400 MHz, CDC13) 8
7.57 (app q, J = 7.4 Hz, IH) , 7.46 (app tt, J = 8.5, 6.2, IH) ,
7.11 (app t, J = 8.0 Hz, 2H) , 6.94 (app t, J = 8.2 Hz, IH)
6.83 (app t, J = 9.2 Hz, IH) , 5.31 (AB-q, J = 10.9 Hz, A= 29.0
Hz, 2H), 3.63 (app t, J = 3.5 Hz, IH), 3.03 (dd, J = 9.4, 5.0,
IH) , 2.85 (dd, J = 5.2, 2.7, IH) , 2.14 (s, 3H) ; LC/MS C-18
column, tf - 2.26 minutes (5 to 95% acetonitrile/water over 5
minutes at 1 ml/min with detection 254 nm, at 50°C) . ES-MS m/z
484 (M+H) and 502 (M+H30) . ES-HRMS m/z 502.0273 (M+H3O calcd
for C2iH17BrF4NO4 requires 502.0272).
Example 569
4- (benzylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one
Step 1: A slurry of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-
(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one (80.0
mg, 0.141 mmol) and benzyl amine (300 mg, 2.80 ramol) was
heated to 63 °C and stirred for 1.0 hours until complete
disappearance of starting material by LCMS analysis. The
reaction mixture was then diluted with ethyl acetate (300 mL)
and brine washed (3 X 200 mL). The resulting organic extracts
were Na2S04 dried, filtered, and concentrated in vacuo to a
residue that was then subjected to SiOa chromatography with
ethyl acetate/hexanes (3:7) to furnish a brown solid (60.0
mg, 81 %) . *H NMR (400 MHz, CDC13) 8 7.43-7.22 (m, 6H) , 7.04
(app t, J = 8.4 Hz, 2H) , 5.02 (br t, J = 1.6 Hz, 1H) , 4.86
(d, J = 5.5 Hz, 2H), 2.37 (s, 3H); LC/MS C-18 column, tr = 3.02
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 531 (M+H)
ES-HRMS m/z 530.9344 (M+H calcd for Ci9H15BrF2lN20 requires
530.9375).
Example 570
3-bromo-4- [ (2 , 4-dif luorobenzyl) oxy] -1- (2 , 6-dif luorophenyl) -6-
methyl-5- [ (E) -2-phenylethenyl] pyridin-2 (IH) -one
Step 1: To an anhydrous -78 °C solution of p-bromostyrene
(1.80 g, 10.0 mmol) in ether (18 mL) was added sequentially
a solution of zinc chloride (10.0 mL, 1.0 M ether, 10.0 mmol)
over 1.0 minute and a solution of tert-butyl lithium (15.0 mL,
1.6 M pentanes, 24.0 mmol) over 8.0 minutes. The resulting
solution became cloudy and the reaction mixture was allowed to
warm to room temperature on its own accord (over 30 minutes)
After an additional 1.0 hour, the suspension was transferred
by syringe directly to a separate vessel containing a solution
of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-I-(2,6-difluorophenyl)-
5-iodo-6-methylpyridin-2(IH)-one (1.50 g, 2.64 mmol) and
tetrakis (tripheylphosphine)palladium (294 mg, 0.254 mmol) in
anhydrous THF (4 mL) . This resulting suspension was heated to
55 °C for 40 minutes and cooled to room temperature, whereby it
was stirred under a positive pressure of argon for an
additional 4.0 hours until complete disappearance of starting
material by LCMS analysis. The reaction suspension was
subsequently treated with NaHCO3 and brine (100 and 200 mL,
respectively). The resulting emulsion was extracted with ethyl
acetate (3 X 300 mL) and the organic extracts were Na2S04
dried, filtered, and concentrated in vacuo to a residue that
was then subjected to Si02 chromatography with ethyl
cetate/hexanes (3:7) to furnish a reddish solid (1.25 g, 86
%) . XH NMR (400 MHz, CDC13) 6 7.51-7.39 (m, 2H) , 7.38-7.24 (m,
5H) , 7.10 (app t, J = 8.5 Hz, 2H) , 6.84 (d, J = 17.2 Hz, 1H) ,
6.82-6.75 (m, 1H) , 6.74-6.68 (m, 1H) , 6.69 (d, J = 17.2, 1H) ,
5.11 (br s, 2H) , 2.15 (s, 3H) ; LC/MS C-18 column, tr = 3.74
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 544 (M+H) .
ES-HRMS m/z 544.0565 (M+H calcd for C27Hi9BrF4N02 requires
544.0530).
Example 574
4-(allylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-
methylpyridin-2(1H)-one
Step 1: A slurry of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-
(2, 6-difluorophenyl)-5-iodo-6-methylpyridin-2(1H)-one (1.40
g, 2.46 mmol) and allyl amine (1.98 mg, 34.6 mmol) was heated
to 50 °C and stirred for 1.0 hours until complete disappearance
of starting material by LCMS analysis. The reaction mixture
was then concentrated in vacuo (1.0 mm Hg) for 2 days at 50 °C
to furnish a brown solid (1.18 g, 99 %) . XH NMR (300 MHz,
CDC13) 5 7.43 (app tt, J = 8.4, 6.2, 1H) , 7.09 (app t, J = 8.4
Hz, 2H) , 6.02 (app dq, J = 11.0, 6.2 Hz, 1H) , 5.39 (dd, J =
16.9, 1.8 Hz, 1H) , 5.30 (dd, J = 11.0, 1.8 Hz, 1H) , 4.84 (br
s, 1H) , 4.35 (br s, 2H), 2.42 (s, 3H) ; LC/MS C-18 column, tr =
2.71 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 481 (M+H) .
ES-HRMS m/2 480.9261 (M+H calcd for Ci5Hi3BrF2IN20 requires
480.9219)
Example 575
4-(allylamino)-I-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-
2(IH)-one
Step 1: A solution of 4-(allylamino)-3-bromo-l-(2,6-
difluorophenyl)-5-iodo-6-methylpyridin-2(IH)-one (1.00 g,
2.07 mmol) and tetrakis(tripheylphosphine)palladium (420 mg,
0.363 mmol) in anhydrous THF (10 mL) under an argon stream was
heated to 64 °C and stirred for 12 hours until complete
disappearance of starting material by LCMS analysis. The
reaction suspension was subsequently treated with brine (600
mL). The resulting emulsion was extracted with ethyl acetate
(3 X 400 mL) and the organic extracts were anhy. Na2S04 dried,
filtered, and concentrated in vacuo to a residue that was then
subjected to SiO2 chromatography with ethyl acetate/hexanes
(gradient 3:7) to furnish a solid (376 mg, 45 %). 1H NMR (400
MHz, d4-MeOH) 8 7.55 (app tt, J = 8.7, 6.3, IH), 7.18 (app t, J
= 7.6 Hz, 2H), 5.89 (app ddd, J = 15.4, 10.3, 5.1 Hz, IH),
5.01 (app d, J = 17.0, Hz, IH), 5.50 (s, IH), 5.22 (app d, J =
11.0 Hz, IH), 4.35 (app d, J = 5.0 Hz , 2H), 2.36 (s, 3H);
LC/MS C-18 column, tr 2.33 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 run, at 50°C) . ES-MS m/z 403 (M+H) . ES-HRMS m/z 403.0133
(M+H calcd for Ci5Hi4F2IN20 requires 403.0113).
Example 576
4-(allylamino)-I-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-
2(IH)-one
Step 1: A solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy] -1-
(2,6-difluorophenyl)-6-methylpyridin-2(IH)- one (197 mg,
0.445 mrnol) and allyl amine (1.32 mg, 23.1 romol) in THF (6.0
mL) was heated to 68 °C and stirred for 74.0 hours. The
reaction mixture was then concentrated in vacuo (30 mm Hg) to
furnish a residue that was subjected to Si02 chromatography
with ethyl acetate/hexanes (3:7) to furnish a solid (36.0 mg,
23 %) . XH NMR (400 MHz, d4-MeOH) 6 7.55 (app tt, J = 8.5, 6.5,
IH) , 7.18 (app t, J = 8.5 HZ, 2H), 6.14 (a, IH), 5.91 (app dq,
J = 11.5, 6.4 Hz, IH) , 5.23 (dd, J = 17.0, 1.5 Hz, IH) , 5.19
(dd, J = 11.0, 1.6 Hz, IH), 4.00 (app d, J = 4.7 Hz , 2H),
1.98 (s, 3H); LC/MS C-18 column, tr = 2.24 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 355 (M+H). ES-HRMS m/z 355.0257
(M+H calcd for Ci5Hi4F2BrF2N2O requires 355.0252).
Example 577
ethyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-
1,2 '-bipyridine-5'-carboxylate
Step 1: To a room temperature suspension of 3-bromo-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one (500.0 mg, 1.51
mmol) and Cs2C03 (1.50 g, 4.60mmol) in 1-methyl-2-pyrrolidinone
(3.0 mL) was added ethyl 6-chloronicotinate (900 mg, 4.85
mmol) . The resulting suspension was stirred and heated to 106
°C for 36 hours until complete consumption of starting material
by LCMS analysis. The reaction mixture was then diluted with
ethyl acetate (400 mL) , water washed (3 X 200 mL) . The
resulting organic extract was separated, Na2S04 dried, and
concentrated. The resulting dark residue was subjected to SiO2
chromatography with ethyl acetate/hexanes (3:7) to furnish a
solid. XH NMR (400 MHz, d4-MeOH) 8 8.68 (app d, J = 2.5 Hz,
IH) , 8.39 (dd, J = 8.7, 2.3 Hz, IH), 7.62 (app q, J = 8.2 Hz,
IH) , 7.15 (d, J = 8.6 Hz, IH) , 7.08 (s, IH) , 7.08-6.99 (m,
2H) , 5.31 (s, 2H) , 4.37 (q, J = 7.1 Hz, 2H) , 2.43 (s, 3H) ,
1.37 (t, J = 7.1 Hz, 3H) ; LC/MS C-18 column, tr = 3.44 minutes
(5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-MS m/z 479 (M+H) . ES-HRMS m/z
479.0401 (M+H calcd for C2iH18BrF2N204 requires 479.0431)
Example 578
OH
3-bromo-4- [ (2,4-difluorobenzyl)oxy]-5'-(1-hydroxy-lmethylethyl)-
6-methyl-2H-1,2'-bipyridin-2-one
Step 1: To a 0 °C solution of methyl magnesium bromide (3.0 M,
3.5 mL, 10.5 mmol) was added dropwise over 15 minutes a
solution of ethyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxo-2H-l,2'-bipyridine-5'-carboxylate (500.0 mg,
1.05 mmol) in THF (4.0 mL). The internal temperature of the
reaction was never allowed to exceed 0 °C. The resulting
solution was maintained for 30 minutes until complete
consumption of starting material by LCMS analysis. Next, a
solution of ammonium chloride (saturated aqueous, 160 mL) was
added. The reaction mixture was extracted with ethyl acetate
(3 X 100 mL) and the resulting organic extracts were
separated, Na2S04 dried, and concentrated in vacuo to a residue
that was subjected to Si02 chromatography with ethyl
acetate/hexanes (gradient 3:7 to 6:4) to furnish a solid (386
mg, 79 %) . XH NMR (400 MHz, d»-MeOH) 8 8.23 (app d, J = 2.8
Hz, 1H) , 7.97 (dd, J - 8.6, 2.3 Hz, 1H), 7.61 (app q, J = 8.2
Hz, 1H) , 7.06-7.00 (m, 3H), 7.00 (s, 1H), 5.30 (s, 2H) , 2.38
(s, 3H), 1.54 (s, 6H); LC/MS C-18 column, tr = 2.75 minutes (5
to 95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-MS m/z 465 (M+H) . ES-HRMS
m/z 465.0615 (M+H calcd for C21H20BrF2N203 requires 465.0620).
IR(neat) 3366, 3030, 2974, 1600, 1507, 1362, 1232 cm ~1. 13C NMR
(400 MHz, d4-MeOH, visible peaks with carbon fluorine coupling
present) 6 164.4, 160.7, 158.9, 157.6, 143.6, 141.6, 137.5,
131.61, 131.56, 131.51, 131.46, 119.29, 119.25, 119.15,
119.11, 112.23, 111.55, 111.52, 111.33, 111.29, 106.0, 103.9,
103.7, 103.4, 96.8, 70.3, 64.9, 64.8, 30.5, 22.6.
Example 579
3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2-furylmethyl)-6-
methylpyridin-2(IH)-one
Step 1: Preparation of the title compound . To a room
temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methylpyridin-2 (IH) -one (330.0 mg, 1.00 mmol) ) and NaH
(48.0 mg, 2.0 mmol) in THF (3.0 mL) was added 2-
(chloromethyl)furan (461 mg, 3.97 mmol). The resulting
suspension was stirred and heated to 68 °C for 9 hours until
complete consumption of starting material by LCMS analysis.
The reaction mixture was then diluted with ethyl acetate (400
mL) , water washed (3 X 200 mL) . The resulting organic extract
was separated, Na2S04 dried, and concentrated. The resulting
dark residue was subjected to Si02 chromatography with ethyl
acetate/hexanes (4:6) to furnish a solid. 1H NMR (300 MHz, d4-
MeOH) 8 7.62 (app q, J = 8.4 Hz, IH), 7.46 (s, IH), 7.06 (app
t, J = 8.7 Hz, 2H), 6.51 (s, IH), 6.41-6.37 (m, 2H), 5.37 (s,
2H), 5.32 (s, 2H), 2.61 (s, 3H); LC/MS C-18 column, tr = 2.63
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 410 (M+H) .
ES-HRMS m/z 410.0177 (M+H calcd for C18Hi5BrF2N03 requires
410.0198).
Example 580
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(thien-2-
ylmethyl)pyridin-2(IH)-one
Step 1: To a room temperature suspension of 3-bromo-4-[(2,4-
difluorobenzyl)oxy]-6-methylpyridin-2(IH)-one (330.0 mg, 1.00
mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added
2-(chloromethyl)thiophene (461 mg, 3.97 mmol). The resulting
suspension was stirred and heated to 68 °C for 12 hours until
complete consumption of starting material by LCMS analysis.
The reaction mixture was then diluted with ethyl acetate (400
mL) , water washed (3 X 200 mL) . The resulting organic extract
was separated, Na2SO4 dried, and concentrated. The resulting
dark residue was subjected to Si02 chromatography with ethyl
acetate/hexanes (4:6) to furnish a solid. ^U NMR (400 MHz, d4-
MeOH) 8 7.58 (app q, J = 8.2 Hz, IH) , 7.30 (app dd, J = 5.1,
1.2 Hz, IH) , 7.05 (d, J = 2.6 Hz, IH) , 7.01 (app t, J = 8.1
Hz, 2H) , 6.93 (dd, J = 5.1, 3.4 Hz, IH) , 6.43 (s, IH) , 5.49
(s, 2H) , 5.25 (s, 2H) , 2.51 (s, 3H) ; LC/MS C-18 column, tr =
2.74 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 426 (M+H) .
ES-HRMS m/z 425.9936 (M+H calcd for C1BHiSBrF2N02S requires
425.9969) .
Example 581
3-bromo-l- (2, 6-dif luorophenyl) -4- (2-furylmethoxy) -6-
methylpyridin-2 (IH) -one
Step 1: To a suspension of 3-bromo-4-[ (2,4-
difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-
2(1H)- one (250 mg, 0.445 mmol) and furfuryl alcohol (198 mg,
2.0 mmol) in THF (2.5 mL) was added solid NaH (46.0 mg, 1.92
mmol). Following the evolution of gas, the resulting
suspension laws heated to 60 °C and stirred for 3.5 hours until
complete consumption of starting material by LCMS analysis.
The reaction mixture was then diluted with ammonium chloride
(saturated aqueous, 100 mL) and extracted with ethyl acetate
(3 X 100 mL) . The resulting organic extracts were separated,
Na2S04 dried, and concentrated to provide a residue that was
subjected to Si02 chromatography with ethyl acetate/hexanes
(3:7) to furnish a solid (110.0 mg, 49 %) . XH NMR (400 MHz,
d4-MeOH) 5 7.63 (app tt, J - 8.5, 6.2, IH), 7.62-7.61 (m, IH),
7.28 (app t, J = 8.5 Hz, 2H), 6.77 (s, IH), 6.68 (d, J = 4.1
Hz, IH), 6.51(dd, J = 4.2, 3.9 Hz, IH) , 5.34 (s, 2H), 2.15 (s,
3H) ; LC/MS C-18 column, tr = 2.43 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 396 (M+H). ES-HRMS m/z 396.0044
(M+H calcd for C17Hi3BrF2NO3 requires 396.0041) .
Example 582
3-bromo-l-[2-fluoro-6-(3-furylmethoxy)phenyl]-4- (3-
furylmethoxy)-6-methylpyridin-2(IE)-one
By following the method of preparation of 3-bromo-l-(2,6-
difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2 (IH)-one
(Example 581) and substituting 3-furylmethanol for furfuryl
alcohol, the title compound was prepared in 55 % chemical
yield. *H NMR (400 .MHz, d4-MeOH) 8 7.64 (s, IH) , 7.55-7.42 (m,
3H), 7.40 (app t, J = 1.4 Hz, IH), 7.12 (d, J = 9.0 Hz, IH),
6.92 (app t, J = 8.4 Hz, IH), 6.58 (s, 2H), 6.34 (br s, IH),
5.21 (s, 2H), 5.03 (AB-q, J = 14.0 Hz, A= 58.0 Hz, 2H), 1.99
(s, 3H) ; LC/MS C-18 column, tr = 2.67 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 run, at 50°C) . ES-MS m/z 474 (M+H) . ES-HRMS m/z 474.0346
(M+H calcd for C22Hi8BrFN05 requires 474.0347).
Example 583
3-bromo-l-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]-6-methyl-4-
(thien-3-ylmethoxy)pyridin-2(IH)-one
By following the method of preparation of 3-bromo-l-(2,6-
difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2(IH)-one
Example 581 and substituting thien-3-ylmethanol for furfuryl
alcohol, the title compound was prepared in 38 % chemical
yield. *H NMR (400 MHz, d4-MeOH) 6 7.50-7.42 (m, 3H) , 7.33
(dd, J = 5,0, 3.0 Hz, IH) , 7.26 (br d, J = 2.0 Hz, IH) , 7.19
(dd, J = 5.0, 1.2 Hz, IH), 7.09 (d, J = 8.6 Hs, IH), 6.98 (dd,
J = 14.9, 1.3 Hz, IH) , 6.93 (dt, J = 8.7, 1.0 Hz, IH) , 6.53
(br s, IH), 5.33 (s, 2H), 5.14 (AB-q, J = 12.1 Hz, A= 50.0 Hz,
2H) , 1.97 (s, 3H) ; LC/MS C-18 column, tr = 2.93 minutes (5 to
95% acetonitrile/water over 5 minutes at 1 ml/min with
detection 254 nm, at 50°C) . ES-MS m/z 506 (M+H) . ES-HRMS m/z
505.9881 (M+H calcd for C22Hi8BrFN03S2 requires 505.9890).
Example 584
:thyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-[(methylamino)carbonyllbenzoate
Step 1: Preparation of 3-(4-hydroxy-6-methyl-2-oxopyridinl(
2H)-yl)-4-(methoxycarbonyl)benzoic acid .
4 -Hydroxy- 6 -methyl -2 -pyrone (75.0 g, 595 mmol) and 3-
amino-4-(methoxycarbonyl)benzole acid (40.0 g, 0.205 mmol}
were suspended in 56 ml of 1,2-dichlorobenzene in a 500 ml, 3-
necked, round bottom flask equipped with a J-Kem temperature
controller probe, a Dean-Stark trap, and a heating mantle.
The reaction was heated to 180 °C over a period of 26 minutes
during which time all solids dissolved. Upon reaching an
internal temperature of 180 °C, the reaction was allowed to
maintain this temperature for an additional 25.0 minutes
during which time the evolution of water from the reaction
mixture was evident. Next, the heating apparatus was removed
and the reaction was allowed to cool on its own accord to
about 100 °C. The reaction was then diluted with 160 ml of
toluene and stirred. After about 10 minutes, the reaction
reached room temperature and a gummy solid had formed. The
precipitate was filtered, washed with EtOAc (400 mL) and water
(200 mL, 55 °C) , and dried in vacuo to give a tan solid (30.5
g, 49%). XH NMR (400 MHz, d4-MeOH) 5 8.20-8.09 (m, 2H) , 7.84
(s, 1H) , 6.08 (app d, J = 1.0 Hz, 1H) , 5.76 (app d, J = 2.3
Hz, 1H) , 3.76 (s, 3H) , 1.91 (s, 3H) . LC/MS, C-18 column, tr =
1.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50 °C) . ES-MS m/z 304 (M+H) .
ES-HRMS m/z 304.0803 (M+H calcd for C15Hi4NO6 requires
304.0816) .
Step 2: Preparation of methyl 2-(4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]bensoate .
OH
O
To a solution of 3-(4-hydroxy-6-methyl-2-oxopyridin-
1 (2H)-yl)-4-(methoxycarbonyl) benzoic acid ( from Step 1) (1.00
g, 3.30 mmol) in dimethylformamide (10 mL) and THF (10 mL) was
added cyclohexylcarbodiimide-derivatized silica gel (a product
of Silicycle chemical division Quebec, Canada) with a loading
of 0.60 mmol/g (15.2 g, 9.73 mmol). After stirring for 30
minutes, a solution of methylamine (2.0 M, THF, 2.9 mL, 5.8
mmol) was added followed by the addition of 1-hydroxybenzotriazole
(20.0 mg, 0.15 mmol). The reaction suspension
was allowed to stir for 24 hours until the complete
disappearance of starting material by LCMS analysis. The
silica suspension was filtered and washed with 300 mL ethyl
acetate/methanol (9:1) and 300 mL ethyl acetate/methanol
(1:1). The resulting mother liquor was concentrated to furnish
a brown semi-solid (898 mg, 86 %) . ^ NMR (300 MHz, d4-MeOH)
8 8.22 (d, J = 8.0 Hz, 1H) , 8.04 (dd, J = 8.3, 1.9 Hz, 1H)
7.73 (d, J = 1.6 Hz, 1H) , 6.13 (d, J = 1.5, Hz, 1H) , 5.80 (d,
J - 2.2 Hz, 1H) , 3.80 (s, 3H) , 3.03 (s, 3H) , 1.97 (s, 3H)
LC/MS, C-18 column, tr = 1.31 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 317 (M+H). ES-HRMS m/z 317.1142
(M+H calcd for Ci6Hi7N2Os requires 317.1132) .
Step 3: Preparation of methyl 2- (3-bromo-4-hydroxy-6-methyl-
2-oxopyridin-l(2H)-yl)-4- [(methylamino)carbonyl]benzoate
To a room temperature suspension of methyl 2-(4-hydroxy-
6-methyl-2-oxopyridin-l(2H)-yl)-4-
[ (methylamino)carbonyl]benzoate ( from Step 2) (406.0 mg,
1.28 mmol) in CH2C12 (8 mL) was added solid N-bromosuccinimide
(251 mg, 1.41 mmol) and stirred for 10 minutes until complete
consumption of starting material by LCMS analysis. The
reaction was next diluted with CH2C12 (5 mL) , ethyl acetate (5
mL), and hexanes (1 mL). After approximately 30 minutes the
resulting white precipitate was filtered and washed with
ethyl acetate (5 mL) to furnish a solid (298 mg, 62%) . 1H
NMR (400 MHz, d4-MeOH) 8 8.20 (d, J = 8.2 Hz, 1H) , 8.01 (d,
8.1 Hz, 1H), 7.69 (s, 1H), 6.18 (s 1H), 3.75 (a, 3H), 2.91 (s,
3H) , 1.91 (s, 3H) ; LC/MS, tr = 1.27 'minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 395 (M+H) . ES-HRMS m/z 395.0237
(M+H calcd for C16Hi6BrN2Os requires 395.0237).
Step 4: Preparation of the title compound .
To a solution of methyl 2-(3-bromo-4-hydroxy-6-methyl-2-
oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]benzoate ( from
Step 3) (241 mg, 0.610 mmol) in dimethylformamide (0.5 mL) was
added sequentially K2C03 (240 mg, 1.73 mmol) and 2,4
difluorobensyl bromide (0.085 mL, 0.66 mmol). The resulting
suspension was stirred for 6.5 hours until complete
consumption of starting material by LCMS analysis. The
reaction was then diluted with ethyl acetate (200 mL) and
brine washed (3 X 200 mL) . The resulting organic extract was
Na2S04 dried, filtered, and concentrated in vacuo to
approximately 5 mL volume. The resulting mother liquor rapidly
precipitated and furnished an amorphous solid that was
collected. ^E NMR (400 MHz, d4-MeOH) 5 8.22 (d, J = 8.2 Hz,
1H), 8.03 (dd, J = 8.2, 1.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H),
7.67 (app q, J = 8.3 Hz, 1H) , 7.05 (app t, J = 8.6 Hz, 2H) ,
6.64 (s, 1H) , 5.37 (s, 2H) , 3.74 (s, 3H) , 2.90 (s, 3H) , 2.01
(s, 3H) . LC/MS C-18 column, tr = 2.87 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 521 (M+H) . ES-HRMS m/z 521.0491
(M+H calcd for CzaHaoBrFz^Os requires 521.0518).
Example 585
3- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-4-(1-hydroxy-l-methylethyl)-N-methylbenzamide
Step 1: To a -10 °C solution of methyl magnesium bromide (3.0
M, 0.60 mL, 1.8 mmol) was added dropwise over 10 minutes a
solution of methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]-4-
t (methylamino)carbonyl]benzoate (85.0 mg, 0.163 mmol) in THF
(1.0 mL). The internal temperature of the reaction was never
allowed to exceed 0 °C. The resulting solution was maintained
for 10 minutes. Next, a solution of ammonium chloride
(saturated aqueous, 100 mL) was added. The reaction mixture
was removed from the bath and resulting emulsion was extracted
with ethyl acetate (3 X 100 mL) and the resulting organic
extracts were separated, Na2S04 dried, and concentrated in
vacuo to a residue that was subjected to Si02 chromatography
with ethyl acetate/hexanes (gradient 3:7 to 6:4) to furnish a
solid (16 mg, 19 %) . 1H NMR (400 MHz, d4-MeOH) 5 7.89 (d, J =
8.5 Hz, 1H) , 7.78 (d, J = 8.4 Hz, 1H) , 7.61 (app q, J = 8.2
Hz, 1H), 7.41 (S, 1H), 7.03-6.99 (m, 2H), 6.57 (s, 1H), 5.30
(s, 2H), 2.83 (S, 3H), 2.05 (s, 3H), 1.51 (s, 3H), 1.39 (s,
3H) ; LC/MS C-18 column, tr = 2.28 minutes (5 to 95%
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 nm, at 50°C) . ES-MS m/z 521 (M+H) . ES-HRMS m/z 521.0860
(M+H calcd for C24H24BrF2N204 requires 521.0882) .
Example 586
3-bromo-l-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]- 6-methyl-4-
(thien-3-ylmethoxy)pyridin-2(IH)-one
By following the method of preparation of 3-bromo-l-(2,6-
difluorophenyl)-4-(2-furylmethoxy)-6-methylpyridin-2 (IH)-one
Example 581 and substituting 4-{[3-bromo-4-[(2,4-
dif luorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -
yl]methyl}benzamide for 3-bromo-4-[(2 , 4-difluorobenzyl)oxy]-
1-(2,6-difluorophenyl)-6-methylpyridin-2(IH)- one , the title
compound was prepared in 76 % chemical yield. """H NMR (400
MHz, d4-MeOH) 6 7.83 (d, J = 8.1 Hz, 2H), 7.54 (app d, J = 1.1
Hz, IH) , 7.19 (d, J = 8.1 Hz, 2H) , 6.57 (d, J = 3.2 Hz, IH) ,
6.53 (s, IH), 6.43 (dd, J = 3.1, 1.8 Hz, IH), 5.45 (br s, 2H),
5.22 (s, 2H) , 2:34 (s, 3H) ; LC/MS C-18 column, tr = 1.98
minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm,. at 50°C) . ES-MS m/z 417 (M+H) .
ES-HRMS m/z 417.0469 (M+H calcd for dsHiaBr^CU requires
417.0444) .
Example 587
(-)-3- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-N,4-dimethylbenzamide
Example 489 (1.78 g, 4.36 tnmol) were separated using a Chiral
Technologies Chiralpak AD column {21 mm x 250 mm, 20 /im)
eluting with 100% ethanol (isocratic, 20 ml/min), loading 10
mg per injection. Fractions of the early-eluting atropisomer
were pooled and concentrated in vacuo to the title compound
(718 mg, 80%). Analytical chiral LC (Chiralpak AD, 4.6 mm x
50 mm, 10/itn particle size, 0.5 ml/min ethanol) Retention time:
1.70 min, ee 94%. [a]D = -23.8° (5 mg/ml DMSO, 22 °C) . XH NMR
(400 MHz, DMSO-ds) 8 8.42 (br qr, J = 4.51 Hz, 1H) , 7.82 (dd, J
= 7.92, 1.70 Hz, 1H) , 7.68 (dt, J = 8.24, 6.58 Hz, 1H) , 7.58
(d, J = 1.59 Hz, 1H), 7.48 (d, J = 7.98 Hz, 1H), 7.34 (dt, J =
9.90, 2.50 Hz, 1H), 7.18 (dt, J = 8.53, 2.57 Hz, 1H), 6.71 (s,
1H) , 5.33 (s, 2H) , 2.74 (s, 3H) , 1.98 (s, 3H) , 1.88 (s, 3H) .
19F-NMR (400 MHz, DMSO-d6) 6 -109.58 (quintet, J = 7.49 Hz, IF),
-113.65 (quartet, J = 9.11 Hz, IF). ES-HRMS m/z 477.0612 (M+H
calcd for C22H2oBrF2N2O3 requires 477.0620) .
Example 588
( + )-3-[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-
oxopyridin-1(2H)-yl] -N,4-dimethylbenzamide
The title compound was prepared as in Example 587 ,
pooling the late-eluting atropisomer (722 mg, 81%).
Analytical chiral LC (Chiralpak AD, 4.6 mm x 50 mm, 10/xm
particle size, 0.5 ml/min ethanol) Retention time: 2.00 min,
ee 98%. [o]D = +28.2° (5 mg/ml DMSO, 22 °C) . XH NMR (400 MHz,
DMSO-dg) 8 8.42 (br qr, J = 4.51 Hz, 1H) , 7.82 (dd, J = 7.92,
1.70 Hz, 1H), 7.68 (dt, J = 8.24, 6.58 Hz, 1H), 7.58 (d, J =
1.59 Hz, 1H) , 7.48 (d, J = 7.98 Hz, 1H) , 7.34 (dt, J = 9.90,
2.50 Hz, 1H), 7.18 (dt, J = 8.53, 2.57 Hz, 1H), 6.71 (s, 1H),
5.33 (S, 2H) , 2.74 (s, 3H) , 1.98 (s, 3H) , 1.88 (s, 3H) . 19F-NMR
(400 MHz, DMSO-ds) 8 -109.58 (quintet, J = 7.49 Hz, IF), -
113.65 (quartet, J - 9.11 Hz, IF). ES-HRMS m/z 477.0614 (M+H
calcd for C22H2oBrF2N2O3 requires 477.0620) .
Example 589
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin-
1(2H)-yl]-3-chlorobenzamide
Step 1: Preparation of methyl 3-chloro-4-(4-hydroxy-6-methyl-
2-oxopyridin-l(2H)-yl)benzoate .
4-Hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) and
methyl-3-amino-2-chlorobenzoate (30 g, 161.6 mmol) were
suspended in 75 ml of 1,2-dichlorobenzene in a 250 ml, 3-
necked round bottom flask equipped with a J-Kem temperature
controller probe, a Dean-Stark trap, and a heating mantle.
The reaction was heated to 175°C for 20 minutes, during which,
water and some 1,2-dichlorobenzene was collected in the Dean-
Stark trap. The reaction was allowed to cool to about 110°C.
At this point, 200 ml of toluene was added. The toluene
mixture was allowed to stir for 72 hours at room temperature.
A precipitate was collected on a filter pad. The precipitate
was filtered and washed 3 times with toluene, 3 times with
50°C. water to remove excess pyrone, and dried in vacuo to give
a tan solid (13.0 g, 27% yield). XH NMR (300 MHz, CD3OD) 8
8.26 (d, J = 1.81 Hz, 1H) , 8.14 (dd, J = 8.26, 1.81 Hz, 1H)
7.54 (d, J = 8.26, Hz, 1H) , 6.14(dd, J = 2.42, 1.0 Hz, 1H) ,
5.83 (d, J = 2.42 1H) , 4.00 (s, 3H) , 1.96 (s, 3H) ; LC/MS, tr =
1.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1
ml/min with detection 254 nm, at 50°C) . ES-MS m/z 294 (M+H) .
Step 2: Preparation of methyl 3-chloro-4-[4-[ (2, 4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoate .
Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-
yDbenzoate ( from Step 1) (2.4g, 8.17 mmol) was taken up in
DMF (10 ml). 2,4-difluorobenzylbrond.de (1.05 ml, 8.17 mmol)
and K2C03 (1.13 g, 8.17 mmol) were added. The reaction stirred
for 6 hours at room temperature. At this time, the reaction
was poured into water (200 ml) and extracted with ethyl
acetate. The ethyl acetate layer was dried over Na2S04,
filtered, and the solvent removed in vacuo to give amber oil
(2.62 g, 77% crude yield). LC/MS, tr = 2.79 minutes (5 to 95%'
acetonitrile/water over 5 minutes at 1 ml/min with detection
254 ntn, at 50°C) . ES-MS m/z 294 (M+H) .
Step 3: Preparation of methyl 4-[3-bromo-4-[(2,4-
dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-l(2H)-yl]-3-
chlorobenzoate .
Methyl 3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2-oxopyridin-l (2H)-yllbenzoate ( .from step 2) (2.60g, 6.21
mmol) was taken up in CH2C12 (20 ml) . N-bromosuccinimide
(l.llg, 6.21 mmol) was added and the mixture stirred at room
temperature for 4 hours. The CH2C12 is removed in vacuo and
the residue is taken up in CH3CN. The resulting precipitate is
collected on a filter pad and washed with CH3CN to yield a
white solid (0.75 g, 24%). XH NMR (300 MHz, CDC13) 5 8.22 (d,
J = 1.88 Ez, IE), 8.06 (dd, J = 8.19, 1.75 Hz, 1H) , 7.59 (app
q, J = 8.46 Hz, 1H) , 7.33 (d, J = 8.19, 1H) , 6.96 (dt, J =
8.06, 1.21 Hz, 1H), 6.89 - 6.84 (m, 1H) , 6.13 (s, 1H) , 5.26
(s, 2H), 3.95 (s, 3H), 1.95 (s, 3H); ES-MS m/z 478 (M+H). ESHRMS
m/z 497.9892 (M+H calcd for C22Hi6BrClF2N04 requires
497.9914).
Step 4: Preparation of 4-[3-bromo-4-[(2,4-
dif luorobenzyDoxy] -6-methyl-2-oxopyridin-1(2H)-yl]-3-
chlorobenzoic acid .
Cl
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1 (2H)-yl]-3-chlorobenzoate (2.30g, 4.61 tnmol) was
taken up in THF (20 ml) and H2O (4 ml) . 2.5 N NAOH (9.2 ml)
was added to the vessel and the reaction stirred overnight to
completion. Concentrated HCl was added dropwise until
reaction was made acidic (pH = 1) . H2O (100 ml) and THF (100
ml) were added to the mixture. The contents were poured into
a separatory funnel and the aqueous layer was extracted with
ethyl acetate. The organic layer was dried over Na2S04, the
solvent removed in vacuo, and the residue was taken up in a
50% mixture of ethyl acetate/hexane. The precipitate was
collected on a filter pad to yield a white powder (1.5g, 67%).
H NMR (300 MHz, DMSO) 8 13.59 (1H), 8.16 (d, J = 1.81 Hz, 1H),
8.06 (dd, J = 6.24, 1.81 Hz, 1H) , 7.73 (app q, J = 8.46, 1H) ,
7.68 (d, J = 8.26 Hz, 1H) , 7.38 (dt, J = 9.48, 2.62 Hz, 1H)
7.26 - 7.18 (m, 1H), 6.80 (s, 1H) , 5.39 (a, 2H), 3.93 (s, 3H) ,
1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749 (M+H
calcd for C2oHi4BrClF2N04 requires 483.9757).
Step 5: 4-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-3-chlorobenzoic acid (0.5 g, 1.03 mmol)
was taken up in THF (10 ml). 2-Chloro-4, 6-dimethoxy-1,3,5-
triazine (0.22 g, 1.24 mmol) and N-methyl morpholine (0.34 ml,
3.09 mmol) were added. The mixture stirred at room
temperature for 1 hour. At this time, NH4OH (2.5 ml) was added
and the reaction stirred at room temperature for one more
hour. To the reaction mixture was added more THF (50 ml) and
water (200 ml). The mixture was extracted with ethyl acetate.
The ethyl acetate extraction was washed with saturated brine
solution. The brine layer was extracted with ethyl acetate.
The organic layers were combined, dried over Na2SO4/ filtered
and the solvent was removed in vacuo. The'residue was taken up
in ethyl acetate and the resulting precipitate was collected
on a filter pad to yield a white powder (0.38 g, 76%) ^H NMR
(300 MHz, CD3OD) 5 8.18 (d, J = 1.81 Hz, 1H) , 8.02 (dd, J =
8.26, 2.01 Hz, 1H) , 7.69 (app q, J = 8.26 Hz, 1H), 7.55 (d, J
= 8.06 Hz, 1 H) 7.12 - 7.06 (m, 2H) , 6.71 (s, 1H) , 5.40 (s,
2H), 2.07 (s, 3H). ES-MS m/z 482 (M+H). ES-HRMS m/z 482.9919
(M+H calcd for C2oH15BrClF2N203 requires 482.9917) .
Example 590
3-[3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(H)-yl]-4-methylbenzamide
Stepl: Preparation of 3-[3-chloro-4-[ (2, 4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-l (2H) -yl] -4-
methylbenzoic acid .
3- [4- [ (2,4-Difluorobenzyl)oxy] -6-methyl-2-oxopyridin-
1(2H)-yl]-4-methylbenzoic acid ( from above) (7.5g,19.4 mmol)
and NCS (2.6 g, 19.4 mmol) were taken up in 65°C dichloroethane
(100 ml) . A catalytic amount of dichloroacetic acid (2 drops)
was added. After two hours the solvent was removed in vacuo
and the residue was taken up in diethyl ether. The
precipitate was collected on a filter pad and then taken up in
50% ethyl acetate/hexanes to remove residual succinimide. The
precipitate was collected on a filter pad and then dried in
vacuo to produce a white powder (4.2 g, 52%). XH NMR (300 MHz,
CD3OD) 8 8.10 (dd, J = 7.85, 1.81 Hz, 1H) , 7.83 (d, J = 8.26,
1.81 Hz, 1H), 7.40 (app q, J = 8.26 Hz, 1H), 7.58 (d, J = 7.85
Hz, 1H), 7.13 - 7.06 (m, 2H), 6.74 (s, 1H), 5.40 (a, 2H), 2.14
(s, 3H) , 2.04 (s, 3H) ; ES-MS m/z 420 (M+H) . ES-HRMS m/z
420.0786 (M+H calcd for C2iHi7ClF2NO4 requires 420.0809).
Step 2: 3- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-methylbensoic acid ( 1.5g, 3.57 mmol)
was taken up in THF (30 ml). 2-Chloro-4,6-dimethoxy-1,3,5-
triazine (0.75 g, 4.28 mmol) and N-methyl morpholine (1.18 ml,
10.72 mmol) were added. The mixture stirred at room
temperature for 1 hour. At this time, NH4OH (7.5 ml) was added
and the reaction stirred at room temperature for one more
hour. To the reaction mixture was added more THF (100 ml) and
water (150 ml). The mixture was extracted with ethyl acetate.
The ethyl acetate extraction was washed with saturated brine
solution. The brine layer was extracted • with ethyl acetate.
The organic layers were combined, dried over Na2S04, filtered
and the solvent was removed in vacuo. The residue was taken up
in ethyl acetate and the resulting precipitate was collected
on a filter pad to yield a white powder (1.32 g, 88%) LH NMR
(300 MHz, CD3OD) 8 7.96 (dd, J = 7.85, 1.81 Hz, 1H) , 7.71 (d, J
= 1.81 Hz, 1H) , 7.67 (app q, J = 8.06 Hz, 1H) , 7.56 (d, J =
8.06 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H),
2.13 (s, 3H) 2.05 (S, 3H). ES-MS m/z 419 (M+H). ES-HRMS m/z
419.0979 (M+H calcd for C2iH18ClF2N203 requires 419.0969).
Example 591
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-N,4-dimethylbenzamide
The title compound was prepared from 3- [3-chloro-4- [ (2, 4--
dif luorobenzyl) oxy] -6-methyl-2-oxopyridin-l(2H)-yl]-4-
methylbenzoic acid ( from step 1 above) (1.5 g, 3.57 mmol) in
dichloromethane (35 ml). To this mixture, 2.0 M methyl amine
in THF (3.6 ml, 7.14 mmol) was added, followed, in order, by
EDCI (0.67 g, 4.28 mmol), 1-hydroxybenzotriazole (0.58 g, 4.28
mmol) and tri ~hylamine (0.99 ml, 7.14 mmol) . The reaction
was stirred at room temperature overnight. The reaction was
quenched with NH4C1 and extracted 3 times with ethyl acetate.
The combined organic layer was then washed with saturated
NaHCO3 (aq.) and extracted 3 times with ethyl acetate. The
organic layers were combined and washed with H20 and extracted
3 times with ethyl acetate. The organic layers were combined
and dried over Na2S04 and evaporated. The resulting residue
was triturated with diethyl ether/hexane to obtain a solid,
which was dried in vacuo to give a white solid (1.5g, 72%). 1H
NMR (300 MHz, CD3OD) 6 7.90 (dd, J = 8.06, 1.81 Hz, 1H) , 7.67
(app q, J = 6.44 Hz, 1H) , 7.55 (d, J = 8.06 Hz, 1H) , 7.13 -
7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.93 (s, 3H), 2.13
(s, 3H) , 2.04 (s, 3H) ES-MS m/z 433 (M+H) . ES-HRMS m/z
433.1153 (M+H calcd for C22H2oClF2N203 requires 433.1125).
Example 592
N-(3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-fluorobenzyl}propanamide
A 10 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with 1-[5-(aminomethyl)-2-
fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-
methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol),
propionyl chloride (49 uL, 0.56 mmol), triethylamine (195 uL,
1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C
for 5 min the reaction was completed by LC-MS. The reaction
mixture was poured into a saturated aqueous NH4C1 solution.
The aqueous mixture was extracted with ethyl acetate. The
organic phase was dried with Na2S04 and concentrated in vacuo
to obtain (240 mg, 91%) as a yellow solid. 1H NMR (400 MHz,
(CD3)2SO) 8 8.3 (t, J = 5.8 Hz, 1H), 7.6 (q, J = 8.7 and 6.58
Hz, 1H), 7.38 (d, J = 7.78 Hz, 1H), 7.3 (dd, J = 2.6 and 7.6
Hz, 1H), 7.22 (d, J = 7.51 Hz, 1H), 7.12 (td, J = 2.0 and 6.5
Hz, 1H), 6.65 (s, 1H), 5.3 (s, 2H), 4.23 (d, J = 3.6 Hz, 2H),
2.1 (q, J = 7.7 Hz 2H) , 1.98 (s, 3H) , 0.98 (t, J = 7.5 Hz, 3H)
ppm. ES-HRMS m/z 465.1203 (M+H calcd for Caa^iClFs^Oa requires
465.1187).
Example 593
N-{3- [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-fluorobenzyl} dimethylurea
A 10 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with 1-[5-(aminomethyl)-2-
fluorophenyl]-3-chloro-4-[(2,4 difluoroberizyl)oxy]-6-
methylpyridin-2(1H)-one hydrochloride (250 mg, 0.56 mmol),
dimethylcarbamyl chloride (52 ^iL, 0.56 mmol), triethylamine
(195 \iL, 1.4 mmol) and tetrahydrofuran (4.0 mL) . After stirring
at 25° C for 5 min the reaction was completed by LC-MS. The
reaction mixture was poured into a saturated aqueous NH4C1
solution. The aqueous mixture was extracted with ethyl
acetate. The organic phase was dried with Na2SO4 and
concentrated in vacuo to obtain the desired product (245 mg,
86%) as a white solid. 1E NMR (400 MHz, (CD3OD) 6 7.61 (q, J =
7.9 and 6.7 Hz, 1H), 7.4(m, 1H) , 7.3 (d, J = 9.3 Hz, 1H), 7.21
(m, 1H), 7.1 (m, 2H), 6.65 (a, 1H), 5.35 (s, 2H), 4.38 (s,
2H) , 2.9 (s, 6H), 2.1 (s, 3H) ppm. ES-HRMS m/z 480.1269 (M+H
calcd for C23H22C1F3N303 requires 480.1296) .
Example 594
N-{3- [3-chloro-4- [ (2, 4-dif luorobenzyl) oxy] -6-methyJ.-2-
oxopyridin-1(2H)-yl]-4-fluorobenzyl}-2-hydroxyacetamide
A 10 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with 1-[5-(aminomethyl)-2-
fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-
methylpyridin-2 (1H)-one hydrochloride (250 tng, 0.56 mmol) ,
acetoxyacetyl chloride (66 \iL, 0.62 mmol), triethylamine (195
|j,L, 1.4 mmol) and tetrahydrofuran (4.0 mL) . After stirring at
25° C for 5 min the reaction was completed by LC-MS. NaOH
(2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0mL) was added and
stirred for 10 min to give the title compound. The reaction
mixture was acidified with concentrated HC1 and extracted with
ethyl. The organic phase was dried with Na2S04 and
concentrated in vacuo to obtain (217 mg, 78%) of the desired
product as a yellow solid. XH NMR (400 MHz, (CD3OD) 87.6 (q, J
= 7.6 and 6.9 Hz, 1H), 7.44 (m, 1H), 7.34 (m, 2H), 7.22 (m,
2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.41 (s, 2H), 4.0 (a, 2H),
2.05 (s, 3H) ppm. ES-HRMS m/z 467.0957 (M+H calcd for
requires 467.0980) .
Example 595
N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-fluorobenzyl}-2-hydroxy-2-
methylpropanamide
The title compound was prepared essentially as described in
Example 594, with 1-chlorocarbonyl-l-methylethyl acetate
substituting acetoxyacetyl chloride aH NMR (400 MHz, (CDC13) b
9.9 (q, J = 8.2 and 6.5 Hz, 1H), 9.7 (t, J = 2.6 Hz, 1H), 9.5
(t, J = 8.9 Hz, 2H), 9.3 (m, 1H), 9.2 (m, 1H), 8.6 (s, 1H) 7.6
(s, 2H), 6.8 (d, J = 15 Hz, 1H), 6.63 (d, J = 15 Hz, 1H), 4.42
(d, J = 3.2 Hz, 6H), 3.99 (s, 3H) ppm. ES-HRMS m/z 495.1271
(M+H calcd for Ca^zaClFaNzO* requires 495.1293).
Example 596
N1- [3-chloro-4- [ (2,4-difluorobenzyl) oxy] - 6 -methyl -2-
oxopyridin-1 (2H) -yl] -4-f luorobenzyl}glycinamide hydrochloride
A 25 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with boc-glycine (105 mg, 0.6 mmol)
and 8 mL of DMF. The mixture was cooled to 0° C and
isboutylchloroformate (77.5 |J.L, 0.6 mmol) was added and stirred
for 20 min. 1- [5- (aminomethyl) -2-fluorophenyl] -3 -chloro
[ (2,4 difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one
hydrochloride (250 mg, 0.6 mmol) was added and stirred for 3h.
After completion of the reaction by LC-MS, concentrated HC1 (2
mL) and 2 mL of methanol was added to remove the boc group.
The reaction was stirred for 24 h, neutralized with 2M NaOH
and extracted with, ethyl acetate. The organic phase was dried
with Na2S04 and concentrated in vacuo to obtain (196 mg, 66%)
of the desired product as a the HCl salt. XH NMR (400 MHz,
(CD3OD) 8 7.6 (q, J = 8 and 6.5 Hz, 1H) , 7.5 (m, 1H) , 7.3 (m,
2H) , 7.0 (m, 2H) , 6.63 (s , 1H) , 5.35 (s, 2H) , 4.4 (q, J = 15
and 13.6 Hz, 2H) , 3.7 (s, 2H) , 2.05 (s, 3H) ppm. ES-HRMS m/z
466.1157 (M+H calcd for CazHaoClFaNaOa requires 466.1140).
Example 597
3- [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin-
1(2H)-yl]-4-fluorobenzamide
A 250 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with 3-[3-bromo-4-[(2,4-
difluorobenzyDoxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-
fluorobenzoic acid (3.65g, 7.8 mmol), 4-methylmorpholine (2.6
mL, 23.4 mmol), 2-chloro-4,6-dimethoxy-l,3,5-triazine (1.64g,
9.36 mmol) and tetrahydrofuran (40 mL). After stirring the
mixture for 30 min at 25° C, NH4OH (20.0 mL) was added. The
mixture was stirred for 30 min and diluted with water. The
product precipitated from solution. The precipitated was
filtered and washed with water and diethyl ether to give the
title compound (2.37g, 65%) as a white solid. XH NMR (400 MHz,
(CD3)2SO) 8 7.9 (d, J = 7.3 Hz, 1H) , 7.61 (q, J = 8.6 and 6.7
Hz, 1H), 7.5 (m, 2H), 7.3 (t, J = 9.6 Hz, 1H), 7.15 (t, J =
8.7 Hz, 1H), 6.7 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ESHRMS
m/z 469.0172 (M+H calcd for CaoHisBrFaNaOa requires
469.0195) .
Example 598
3- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-4-fluoro-N-methylbenzamide
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1
mmol) in N,N-dimethylformamide (20 mL) was cooled to -10 C.
isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl
morpholine (0.23 mL, 2.1 mmol) were added to the reaction
vessel. After stirring at -10 C for 20 minutes, a solution of
N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and
the reaction mixture was warmed to room temperature as it
stirred for 18 hours. The reaction mixture was concentrated
in vacuo, suspended in water, filtered and washed with water,
ethyl acetate and diethyl ether. 1H NMR (400 MHz, CD3OD) 6
8.03 (dddd, J = 3.0, 6.4, 9.2 and 11.6 Hz, 1H) , 7.81 (dd, J =
3.0 and (.2 Hz, 1H) , 7.66 (q, J = 10.4 Hz, 1H) , 7.47 (t, J =
12 Hz, 1H) , 7.06 (t, J » 12 Hz, 2H) , 6.67 (s, 1H) , 5.38 (s,
2H) , 2.91 (s, 3H) , 2.10 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD)
5 -111.50 (IF), -115.97 (1 F) , -120.16 ppm. ES-HRMS m/z
481.0346 (M+H calcd for CziH^BrFa^Oa requires 481.0369).
Example 599
3- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]-4-fluoro-N,N-dimethylbenzamide
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1
mmol) in N,N-dimethylformamide (20 mL) was cooled to -10 C.
Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl
morpholine (0.23 mL, 2.1 mmol) were added to the reaction
vessel. After stirring at -10 C for 20 minutes, a solution of
N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and
the reaction mixture was warmed to room temperature as it
stirred for 18 hours. The reaction mixture was concentrated
in vacuo and partitioned between water and ethyl acetate. The
organic layer was washed with brine and concentrated in vacuo.
The solid was chromatographed on silica (95:5 methylene
chloride : isopropyl alcohol) to give the desired product as a
white powder (0.31 g, 30 %) . XH NMR (400 MHz, CD3OD) 8 7.64
(m, 1H), 7.50 (dd, J = 2.4 and 7.2 Hz, IH), 7.45 (t, J = 9.6
Hz, IH), 7.04 (t, J - 9.2 Hz, 2H), 6.65 (s, IH), 5.36 (a, 2H),
3.09 (s, 3H) , 3.05 (s, 3H) , 2.10 (s, 3H) ppm. 1S F NMR (400
MHz, CD3OD) 5 -111.51 (IF), -115.88 (1 F) , -121.90 (IF) ppm.
ES-HRMS m/z 495.0508 (M+H calcd for €22^96^3^03 requires
495.0526).
Example 600
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2-fluoro-5-[(4-
methylpiperazin-1-yl)carbonyl]phenyl}-6-methylpyridin-2(IH)
one
Step 1 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-
{2-fluoro-5- [ (4-methylpiperazin-l-yl)carbonyl]phenyl}-6-
methylpyridin-2(IH)-one
To a reaction vessel (borosilicate culture tube) was
added 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (0.300 g, 0.623
mrnol) and 1-hydroxybenzotriazole (0.042 g, 0.45 mmol) . N,NDimethylformamide
(3 mL) was added to the reaction vessel
followed by approximately 1.1 g of the polymer bound
carbodiimide resin (1.38 mmol/g). Additional N,Ndimethylformamide
(2 mL) was then added to the reaction
vessel. The parallel reaction apparatus was then orbitally
shaken (Labline Benchtop Orbital Shaker) at approximately 200
RPM at room temperature for 15 minutes. N-Methyl amine (1
mL, 2 mmol) was then added to the reaction'vessel and the
reaction apparatus was orbitally shaken at room temperature
overnight. At this time the reaction was diluted with
tetrahydrofuran (20 mL) and treated with approximately 2.0 g
of polyamine resin (2.63 mmol/g) and approximately 2.5 g of
methylisocyanate functionalized polystyrene (1.5 mmol/g) and
the orbital shaking was continued at 200 RPM at room
temperature for 3 hours. The reaction vessel was then opened
and the solution phase product was separated from the
insoluble quenched byproducts by filtration and collection
into a vial. After partially evaporation the insoluble
byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The
filtrate was evaporated by blowing N2 over the vial and the
resulting solid was triturated with diethyl ether to give an
off-white solid. (0.14g, 41%)
XH NMR (400 MHz, CD3OD) 5 7.63 (m, 1H) , 7.51 (dd, J = 2.2 and
7.2 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.03 (m, 2H), 6.65 (s,
1H) , 5.34 ( S , 2H) , 3.74 (s, 2H) , 3.51 (s, 2H) , 2.80 (s, 4H) ,
2.08 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) 5 -111.31 (IP), -
115.72 (1 F), -121.41 (1 F) ppm. ES-HRMS m/z 550.0946 (M+H
calcd for C25H24C1F3N303 requires 550.0948) .
Example 601-603
By following the method of Example 600 and replacing Nmethylamine
with the appropriate amine, the compounds of
Examples 601-603 are prepared.
Compound % . M+H ESHRMS
No. RI R2 Yield MF Requires m/z
EX. 601 CH2CH2O- CH2CH2- 99 C24H21BrF3N204 537.0631 537.0620
Ex. 602 CH3 CH2CH2OH 43 C23H21BrF3N204 525.0631 525.0618
EX. 603 H CH2C(CH3)2O
H 65 C24H23BrF3N204 539.0783 539.0788
Example 604
methyl 4- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]-3-fluorobenzoate
Step 1 Preparation of 4-amino-3-fluorobenzoic acid
NH2
CO2H
3-Fluoro-4-aminobenzoic acid was prepared as described in the
literature. (Schmelkes, F.C.; Rubin, M. J. Am. Chem. Soc.
1944, 66, 1631-2-)
Step 2 Preparation of methyl 4-amino-3-fluorobenzoate
NH2
CO2Me
A 250 mL 3-necked round bottomed flask equipped with a
nitrogen inlet, stirbar, addition funnel and thermocouple was
charged with 4-amino-3-fluorobenzoic acid (11.8 g, 76 mol) and
methanol (100 mL). The system was cooled to 0 C and acetyl
choride (7.6 mL, 107 mol) was added dropwise. The system was
warmed to room temperature, the addition funnel was replaced
with a reflux condensor, and was heated to reflux for 6 h.
The reaction mixture was cooled to room temperature, quenched
with saturated aqueous NaHC03, and extracted with ethyl
acetate. The organic extract was washed with brine and
concentrated in vacuo to give methyl methyl 4-amino-3-
fluorobenzoate as an tan solid (8.2 g, 64%). aH NMR (400 MHz,
CD3OD) 6 7.56 (dd, J = 1.6 and 8.0 Hz, 1H), 7.52 (dd, J = 1.9
and 12 Hz, 1H), 6.76 (t, J = 8.4 Hz, 1H), 3.81 (s, 3H) ppm.
19F NMR (400 MHz, CD3OD) 8 -139.05 (IF) ppm. ES-HRMS m/z
170.0565 (M+H calcd for C8H9FN02 requires 170.0612).
Step 3 Preparation of methyl 3-fluoro-4-(4-hydroxy-6-methyl-
2-oxopyridin-l (2H) -yDbenzoate
A 250 mL round bottomed flask equipped with stirbar, Dean-
Stark trap and reflux condenser was charged with the product
of Step 2 (8 g, 47.3 mmol), 4-hydroxy-6-methyl-2-pyrone (12 g,
84.6 mmol), and N-methyl-2-pyrrolidine (8 mL). The system was
immersed in a 150 C oil bath for 2 hours and was then cooled
to room temperature. The reaction mixture was washed with
aqueous K2CO3 (8.5 g, 200 mL water) . The aqueous layer was
washed with ethyl acetate and then was acidified to pH 4-5
with glacial HOAc. This was extracted with ethyl acetate,
which was then concentrated in vacuo. The viscous oil was
triturated with acetonitrile and filtered to the title
compound as a tan solid (2.3 g, 17%). JH NMR (400 MHz, CD3OD)
5 7.98 (dd, J = 1.8 and 8.0 Hz, 1H), 7.91 (dd, J = 1.7 and 10
Hz, 1H), 7.46 (t, J = 8Hz, 1H), 6.09 (dd, J = 0.9 and 2.4 Hz,
1H), 5.77 (d, J = 2.7 Hz, 1H), 3.94 (s, 3H), 1.97 (s, 3H) ppm.
15 F NMR (400 MHz, CD3OD) 5 -123.00 (IF) ppm. ES-HRMS tn/z
278.0781 (M+H calcd for Ci4Hi3FN04 requires 278.0823).
Step 4 Preparation of methyl 4- [4-[(2,4-difluorobenzyl)oxy]
6-methyl-2-oxopyridin-l(2H)-yl]-3-fluorobenzoate
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with the product of Step 4 (2.3 g,
8.3 mmol) and N,N-dimethyl formamide (20 mL) . 1,8-
diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.1 mmol) was added
followed by 2,4-difluorobenzyl bromide (1.2 mL, 9.1 mmol).
The reaction mixture was stirred at 60 C for 3 h, was poured
into saturated aqueous NaHCO3 and was extracted with ethyl
acetate. The organic layer was washed with brine and
concentrated in vacuo. The solid was triturated with
acetonitrile and filtered to give the title compound (2.15 g,
64%). XH NMR (400 MHz, CD3OD) 6 7.99 (dd, J = 1.7 and 8.4 Hz,
1H), 7.93 (dd, J = 1.8 and 10.4 Hz, 1H), 7.55 (m, 1H), 7.48
(t, J = 6.8 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J = 1.3 and 2.76
Hz, 1H), 6.02 (d, J = 2.7 Hz, 1H), 5.14 (s, 2H), 3.94 (s, 3H),
1.98 (s, 3H) ppm. " F NMR (400 MHz, CD3OD) 6 -111.34 (IF), -
115.97 (1 F), -122.98 (1 F) ppm. ES-HRMS m/z 404.1133 (M+H
calcd for C2iHi7F3NO4 requires 404.1104).
-759-
Step 5 Preparation of methyl 4-[3-bromo-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-
fluorobenzoate
A 100 mL round bottomed flask equipped with stirbar and
nitrogen inlet was charged with the product of Step 4 (2.15 g,
5.3 mmol) and N-methyl-2-pyrrolidine (15 mL). After cooling
to 0 C, a solution of N-bromo succinimide (1.03 g, 5.8 mmol)
in 10 mL of N-methyl-2-pyrrolidine was added over 15 minutes.
After 15 additional minutes, the reaction mixture was warmed
to room temperature and was stirred for 1 hour. The mixture
was then poured into saturated aqueous NaHC03 and extracted
with ethyl acetate. The organic layer was washed with brine
and concentrated in vacuo. The residue was triturated with
acetonitrile and filtered to give the title compound as a
white powder (1.5 g, 59%). 1R NMR (400 MHz, CD3OD) 5 8.00 (dd,
J = 2.0 and 8.4 Hz, 1H), 7.95 (dd, J = 1.7 and 10 Hz, 1H),
7.64 (q, J = 8.8 and 14.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H),
7.04 (t, J = 8.4 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 3.95 (s,
3H) , 2.01 (s, 3H) ppm. " F NMR (400 MHz, CD3OD) 5 -111.50
(IF), -115.97 (1 F), -123.01 (1 F) ppm. ES-HRMS m/z 484.0169
(M+H calcd for C2iHieBrF3N04 requires 484.0192).
Example 605
4-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyljbenzoic acid.
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid. Methyl-4-
{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyljbenzoate (30.4 g, 70.1 mmol) was suspended in
methanol (150 mL) and dioxane (150 mL). 2.5N NaOH (30.8 mL,
77.08 mmol) was added. The resulting mixture was heated to 50
C for 8.0 hours. The reaction was partially concentrated and
the heterogenous mixture was acidified (pH 2) with IN HCl.
The precipitate was collected by filtration washing with H20
and diethyl ether to afford a white solid (29.2 g, 99 %). 1H
NMR (400 MHz, DMSO-d6) 8 7.88 (d, J = 8.3 Hz, 2H) , 7.63 (app q,
J = 7.9 Hz, 1H), 7.31 (dt, J = 2.4, 9.9 Hz, 1H), 7.18 (app d,
J = 8.3 Hz, 2H), 7.17-7.12 (m, 1H), 6.60 (s, 1H), 5.35 (s,
2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/Z 420.0821 (M+H
calcd for C2iHi7ClF2N04 requires 420.0809) .
Example 606
4-{ [3-chloro-4- [ (2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}benzamide
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl] methyl}benzamide. 4-{ [3-
chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1(2H)-yl]methyl}benzoic acid (12.0 g, 28.58 mmol) was
suspended in tetrahydrofuran (100 mL). 2-Chloro-4,6-
dimethoxy-1,3,5-triazine (6.02 g, 34.3 mmol) was added
followed by 4-methylmorpholine (9.43 mL, 85.74 mmol). The
resulting mixture was stirred at room temperature for 1.5
hours at which time NH4OH (50.0 mL) was added. The resulting
mixture was stirred at room temperature for 1 hour and then
partially concentrated. The precipitate was collected by
filtration washing with H20 and diethyl ether to provide an
off-white solid (12.11 g, 100 %). XH NMR (400 MHz, DMSO-d6) 6
7.91 (br s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.63 (app q, J =
7.9 Hz, 1H), 7.31 (dt, J = 2.6, 10.5 Hz, 1H), 7.17-7.12 (m,
1H) , 7.13 (app d, J = 8.3 Hz, 2H) , 6.59 (s, 1H) , 5.32 (s, 2H) ,
5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 419.0968 (M+H calcd
for C2iH18ClF2N203 requires 419.0969) .
Example 607
4-{ [3-chloro-4- [ (2,4-difluorobenzyl)oxy] -6-methyl-2-
oxopyridin-1 (2H) -yl] methyl) -N,N-dimethylbenzamide
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]methyl}}-N,N-dimethylbenzamide.
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyljbenzoic acid (2.00 g, 4.76 mmol)
was suspended in N,N-dimethylformamide (20 mL). 1-
Hydroxybenzotriazole (0.773 g, 5.72 mmol) was added followed
by 4-methylmorpholine (1.57mL, 14.28 mmol), dimethylamine
(7.14 mL, 2.0 M in tetrahydrofuran, 14.28 mmol) and then 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28
g, 6.66 mmol). The resulting mixture was stirred at room
temperature for 3 hours at which time the reaction was diluted
with H2O (75 mL) . The reaction mixture was then extracted with
ethyl acetate. The combined organic extracts were washed with
saturated NaHC03, brine, dried over Na2S04/ filtered and
concentrated. The resulting solid was washed with ethyl
acetate to provide the title compound as a white solid (1.67
g, 78%) . XH NMR (400 MHz, CDC13) 8 7.53 (app q, J = 7.8 Hz,
1H) , 7.33 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H),
6.95-6.90 (m, 1H), 6.84 (app dt, J = 2.5, 9.4 Hz, 1H), 6.02
(s, 1H), 5.35 (s, 2H), 5.19 (s, 2H), 2.97-2.93 (br m, 6H),
2.26 (s, 3H) . ES-HRMS m/z 447.1246 (M+H calcd for
requires 447.1282).
Example 608
4-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]methyl}-N-(2-hydroxy-2-
methylpropyl)benzamide
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-
methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2-hydroxy-2-
methylpropyl)benzamide. 4-{[3-chloro-4-[(2,4-
difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-
yl]methyl}benzoic acid (2.00 g, 4.76 mmol) was suspended in
N,N-dimethyIformamide (10 mL). 1-Hydroxybenzotriazole (0.772
g, 5.71 mmol) was added followed by 4-methylmorpholine
(1.57mL, 14.28 mmol), l-amino-2-methyl-2-propanol
hydrochloride (1.49 g, 11.90 mmol) and then 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28
g, 6.66 mmol). The resulting mixture was stirred at room
temperature for 2 days at which time the reaction was diluted
with H20 (50 mL), The reaction mixture was then extracted with
ethyl acetate. The combined organic extracts were washed with
saturated NaHC03, brine, dried over Na2S04, filtered and
concentrated. The resulting solid was washed with diethyl
ether to provide the title compound as a tan solid (2.08 g,
89%). 1H NMR (400 MHz, CDC13) 5 7.72 (d, J = 8.2 Hz, 2H) ,
7.51 (app q, J = 7.7 Hz, IH), 7.25-7.21 (m, IH) , 7.10 (d, J =
8.2 Hz, 2H), 6.93 (app dt, J = 1.6, 8.3, 9.4 Hz, IH), 6.87-
6.82 (m, IH), 6.01 (s, IH), 5.32 (s, 2H), 5.19 (s, 2H), 3.42
(d, J = 5.9 Hz, 2H), 2.26 (s, 3H), 1.23 (s, 6H). ES-HRMS m/z
491.1522 (M+H calcd for CasH^ClFa^Cu requires 491.1544).
Example 609
N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin-1(2H)-yl]benzyl)-2-hydroxyacetamide.
Step 1. Preparation of 1-[4-(aminomethyl)phenyl]-3-bromo-4-
[ (2,4-difluoroben