Design, synthesis, and activity of a novel series of factor Xa inhibitors: Optimization of arylamidine groups

Article abstract of DOI:10.1021/jm0200660

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine grou

Full text of DOI:10.1021/jm0200660

2484
J . Med. Chem. 2002, 45, 2484-2493
Design , Syn th esis, a n d Activity of a Novel Ser ies of F a ctor Xa In h ibitor s:
Op tim iza tion of Ar yla m id in e Gr ou p s1,2
Gary Phillips, William J . Guilford,* Brad O. Buckman, David D. Davey, Keith A. Eagen, Sunil Koovakkat,
Amy Liang, Meg McCarrick, Raju Mohan, Howard P. Ng, Michael Pinkerton, Babu Subramanyam, Elena Ho,
Lan Trinh, Marc Whitlow, Shung Wu, Wei Xu, and Michael M. Morrissey
Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, P.O. Box 4099, Richmond, California 94804-0099
Received February 8, 2002
A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa)
inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an
additional interaction and a replacement for the distal amidine group that binds in the S3/S4
pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases
the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to
Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives
for the second amidine. These substitutions have increased the selectivity vs the related serine
proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of
binding to fXa based on trypsin crystallographic data are outlined.
In tr od u ction
equivalents of phenol and the reaction temperature and
using sequential addition.
Factor Xa (fXa) plays a strategic role in the coagula-
tion pathway at the juncture of the intrinsic and
extrinsic pathways. The discovery of a novel class of
potent, selective fXa inhibitors provides the opportunity
to develop a new anticoagulant with greatly reduced
bleeding risk.3,4 An early lead structure in our fXa
inhibitors program, 1, bears two arylamidine groups,
which have been associated with poor oral bioavailabil-
ity. Therefore, the next phase of our drug discovery
effort was focused on modifying one of the arylamidine
groups. We had evidence from earlier studies that at
least one amidine is necessary for activity, and we
expected potency to decrease significantly on replace-
ment of one of the amidines. For that reason, we
expected that once a monoamidine was found, an
additional binding site would be required to regain the
lost potency. Herein, we report on the results of those
studies that conclude with potent, selective, and novel
monoamidine inhibitors of fXa.
Compounds substituted on the dimethylbenzamide,
5a -l, or dimethyl aniline, 4 cc and 5m -r were pre-
pared in a similar manner, with a series of appropriately
substituted phenols added to give 2. Compounds sub-
stituted on the benzamidine aromatic moiety, 6a -p ,
were prepared in a similar manner, with a series of
appropriately substituted cyanophenols added to the
monoaddition product. Hydroxy compounds were pre-
pared as the appropriate methoxy compound and depro-
tected with boron tribromide. Typically, the amino-
substituted compounds were prepared from the cor-
responding nitro compounds by reduction. The 6-amino-
substituted compounds (6g,m ) were purified by high-
performance liquid chromatography (HPLC) after the
final step and were found to isomerize on reapplication
to the reaction conditions (see Figure 1). Compounds
7a -n bearing a carboxylic acid group at C-4 were
prepared typically by addition of phenols to 2,6-dichlo-
ropyridine-4-carboxylic acid using higher temperatures
and longer reaction times.
Resu lts a n d Discu ssion
The screening tree to determine the best inhibitors
began with the potency determination against human
fXa. Subsequent screening against human thrombin
(fIIa) for selectivity within the coagulation cascade and
bovine trypsin for general specificity against serine
proteases was carried out for the more potent inhibitors
(fXa, Ki < 1 µM).
A series of diaryloxypyridines bearing an arylamidine
group and a 3-substituted aromatic group were prepared
to explore the structure-activity relationships (SAR) for
fXa binding (Table 1). The importance of the distal
amidine group to binding to fXa can be seen in the loss
of potency by replacing the amidine, 1, with hydrogen,
4a . The difficulty in identifying a significant interaction
between the S3/S4 pocket of fXa and the ligand is
Ch em istr y
Compounds were prepared as previously described1-3,5
and as outlined in Scheme 1. Unsymmetrical bisary-
loxypyridines were prepared by reaction of 1 equiv of a
3-cyanophenol with 2,3,5,6-tetrafluoro-4-methylpyridine
to give the desired monoaddition adduct 3. Addition of
a second phenol using higher temperatures in dimethyl
sulfoxide (DMSO) gave compounds 4a -ss after conver-
sion of the nitrile to the amidine under standard Pinner
conditions.6 Both phenol additions could be carried out
in a single reaction vessel by controlling the number of
10.1021/jm0200660 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/02/2002

Novel Series of Factor Xa Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2485
Sch em e 1
demonstrated by the fact that most of the modifications
showed a greater than 2 orders of magnitude loss in
activity. Acidic functional groups as in analogues 4d and
4q were not tolerated by any of the proteases assayed.
However, three substituents, the weak bases dimethy-
laniline (4cc) and imidazole (4k k ) and the neutral
dimethylamide (4f), showed interesting activity.
A SAR was developed around the most potent ana-
logue in the series, dimethylcarboxamide-bearing in-
hibitor 4f. The slightly larger diethylcarboxamide ana-
logue, 4g, is 8-fold less potent than the dimethyl
analogue indicating that the amide binding site may be
limited in size. Removal of the methyl groups from the
amide resulted in inhibitors that were 15- and 3-fold
less potent against fXa 4b and 4e, respectively. A
similar steric trend is observed with the cyclic amides;
the smaller 4i is more potent than 4j-l. Systematic SAR
efforts also revealed the important components of the
amide functional group. As shown in Table 1, a decrease
in potency is observed upon removal of the carbonyl
group, 4n n , just the carbonyl oxygen, 4y,z, or removal
of the nitrogen, 4v or 4w . Substitution of the amide for
a sulfonamide, 4x, also resulted in a decrease in potency
against fXa. Introduction of a methylene carbon between
the aromatic and the amide groups resulted in a 3-fold
decrease in activity in the dimethylcarboxamide series,
4f vs 4n , but had little effect on the unsubstituted
amide, 4b vs 4o. With the introduction of a two carbon
linker, 4t vs 4u , potency decreased about 10-fold from
4f. A similar result was seen upon introduction of a
hydroxymethylene group, 4r ,s, with the dimethylcar-
boxamide about 6-fold less active than the unsubstituted
amide and 27-fold less potent than 4f. We hypothesized
that the potency of the dimethylcarboxamide analogues
is due to the amide adopting a nonplanar configuration
with respect to the phenyl ring rather than the planar
configuration predicted for less potent inhibitors such
as the unsubstituted amide (4b) and N-methylamide
(4e).
4cc the most potent compound of the series (4bb-ff,jj).
Substitution of the aniline to give a sulfonamide, amide,
or urea (4gg-ii) caused at least a 20-fold decrease in
activity. The imidazole, 4k k , also showed interesting
potency, and further elaboration of the imidazole will
be discussed in a later series. The binding of these
compounds within the S3/S4 pocket is consistent with
the increase in potency with increased tendency for
adopting a nonplanar configuration with respect to the
phenyl ring.
Additional substitutions on the phenyl rings were
made in the hope of regaining the potency lost upon
replacing the second amidine functionality. Initially,
substitutions were made on the distal phenyl ring, using
4f or 4cc as parents from the most potent monoamidines
found (Table 2). No improvements in activity were found
with any substitution. Substitution at the 6-position of
the aromatic ring decreased potency (5e-f,j-l,o-r ) in
both the aniline and the dimethylcarboxamide series.
Similar loss in potency was seen upon substitution in
the 2- and 4-position in the dimethylaniline series
(5m ,n ) and in the dimethylcarboxamide series (5a -d ).
Substitution at the 5-position was tolerated in the
dimethylcarboxamide series (5g,i) by fXa and selective
against other proteases. However, the selectivity was
reversed with the 5-hydroxy analogue, 5h , which was
at least 8-fold more potent against thrombin and trypsin
than fXa.
Substitutions on the amidine-bearing phenyl ring
yielded more interesting results. To make proper com-
parisons, the distal phenyl group was kept constant with
a dimethylcarboxamide or dimethylaniline as in 4f,cc
(Table 3). One of the first compounds prepared in this
series was the para-amino analogue, 6m , which was
2-3-fold more potent than unsubstituted 4cc. The
enhanced potency of a para-aminobenzamidine over
para-hydroxybenzamidine and benzamidine had been
observed previously against trypsin and fXa.7 In con-
trast to the simple substituted benzamidine case, in our
series, the para-hydroxy analogue, 6o, was about 20-
fold more potent than the corresponding amino ana-
In the base-substituted analogue series, anilines have
a similar SAR to the amides, with the dimethylaniline
F igu r e 1. N and O Interconversion.

2486 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Ta ble 1. Activity of Analogues of 1 Containing One Amidine
Phillips et al.
Ta ble 2. Activity of Compounds Substituted on the Distal
S3/S4 Binding Ring
Ki (nM)
no.
X
Xa
13
IIa
trypsin
1
C(NH)NH2
H
22 000
>5000
>5000
>5000
>5000
810
>5000
>5000
>5000
>5000
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
4z
4a a
4bb
4cc
4d d
4ee
4ff
4gg
4h h
4ii
4jj
4k k
4ll
4m m
4n n
4oo
4p p
4qq
4r r
4ss
>5000
Ki (nM)
IIa
CONH2
CO2Et
COOH
280
no.
X
Y
Xa
80
4500
2400
2000
1400
>5000
>5000
160
trypsin
2700
5200
5000
1200
80
690
2400
220
1400
820
>5000
>5000
460
4f
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
H
>5000
CONHMe
CONMe2
CONEt2
CONMeBn
COPyrrolidine
COMorpholine
COPiperidine
COPiperazineMe
CONHPh
CH2CONMe2
CH2CONH2
CH2COOEt
CH2COOH
CHOHCONMe2
CHOHCONH2
(CH2)2CONMe2
(CH2)2CONH2
COMe
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
4cc
5m
5n
5o
5p
5q
5r
2-OH
2-OMe
4-OH
4-OMe
5,6-OH
5,6-OMe
5-CONMe2
5-OH
5-OMe
6-Me
6-OH
6-OMe
H
2-Me
>5000
2700
3000
>5000
450
3400
>5000
>5000
>5000
2800
>5000
3000
>5000
740
>5000
1600
1900
750
>5000
>5000
>5000
>5000
>5000
>5000
>5000
140
4200
>5000
>5000
>5000
3300
>5000
>5000
>5000
160
320
500
>5000
2400
280
810
>5000
>5000
2600
950
5300
3700
2100
1900
5000
1000
>5000
2200
370
1300
700
1400
2100
720
1400
640
2500
3300
160
530
400
4-Cl
>5000
4900
>5000
6-COOEt
6-COOH
6-Me
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
2200
>5000
>5000
COCHMe2
SONMe2
CH2NH2
CH2NMe2
NO2
3800
2400
2900
6-OMe
Ta ble 3. Activity of Compounds Substituted on the Proximal
or S1 Binding Ring and Substitution on the Distal Aromatic
Ring
>5000
>5000
2600
>5000
>5000
1900
2700
2100
NH2
NMe2
NHEt
NEt2
>5000
730
NHPh
1800
3804
5800
4000
650
3800
4900
>5000
1900
NHSO2Me
NHAc
NHCONH2
Morpholine
Imidazole
OMe
>5000
>5000
>5000
1800
>5000
5300
>5000
2000
4800
125
1350
1800
620
3200
1700
5000
1600
1300
OCF3
>5000
2900
OCHMe2
F
Ki (nM)
Cl
OH
CF3
CH2OH
>5000
>5000
no.
A
X
Xa
80
>5000
>5000
23
180
160
2700
14
IIa
trypsin
4f
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
CONMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
H
2-OH
>5000
>5000
>5000
1200
>5000
>5000
2700
>5000
>5000
1100
>5000
>5000
6a
6b
6c
6d
6e
6f
6g
6h
6i
2-OH-5-OMe
5,6-OH
5,6-OMe
5-OH-6-OMe
5-OMe
6-NH2
6-NHSO2CF3
6-OH
logue, 6m , and about 50-fold more potent than the
unsubstituted analogue, 4cc.2,3 A similar difference in
potency was seen in the dimethylcarboxamide series of
analogues, 4f and 6g,i. Since our first report on the
enhanced potency of the para-hydroxybenzamidine group,
researchers at Aventis have reported a 20-fold increase
in potency upon introduction of a para-hydroxyl group
on their pyrrolidinone template.8 In addition, we have
reported an 8-fold increase in potency for a similar
change to the N-propenylbenzamidine-aminophenol tem-
plate9 and a 4-fold decrease in potency in the N-
propenylbenzamidine-benzimidazole template.10 These
results suggest that there is an optimum binding
orientation for a para-hydroxybenzamidine substituent
in the S1 pocket. The corresponding methoxy-containing
compounds, 6d -f,j-k ,p , which are hydrogen bond
2300
550
>5000
1.8
1100
>5000
2600
1100
4300
1900
6j
6-OMe
720
160
4cc
6k
6l
6m
6n
6o
6p
H
2,6-OMe
6-Me
6-NH2
6-NHSO2Me
6-OH
6-OMe
>5000
1200
64
5500
3
300
>5000
190
400
>5000
1000
1400
acceptors and electron-donating substituents, were over
9-fold less active than the unsubstituted analogue.
Similarly, sulfonamides 6h ,n , which are hydrogen bond

Novel Series of Factor Xa Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2487
Ta ble 4. Activity of Compounds Substituted on the Distal or
S3/S4 Binding Ring
optimized dimethylcarboxamide (7d ) or a dimethy-
lamine (7e) substitutent and a carboxylic acid group
were potent inhibitors of fXa. In contrast to the amide
and amine series, the SAR in the imidazole series had
not yet been explored fully and was examined with a
carboxylic acid at C-4.
In general agreement with observations in the amide
and amine series (Table 1), substitution of the imidazole
at C-2 with a methyl caused a 3-fold increase in potency
over the unsubstituted compound (7f vs 7g). Reversal
of the point of attachment and the methyl subsituent
did not affect potency but did decrease selectivity vs
thrombin (7g vs 7i). Partial saturation of the N-methyl
imidazole to the N-methyl-imidazoline ring produced
one of the most potent compounds in this series, 7l. In
general agreement with observations in the amide,
amino, and imidazole series (Tables 1 and 4), a methyl
group dramatically increased the potency of the ana-
logue (7l vs 7k ), which can be explained by the preferred
out-of-plane orientation of the phenyl and imidazoline
rings mentioned earlier. Additional SAR evidence for
the importance of the methyl substituent on the orien-
tation of the phenyl ring and the substituent is the loss
of potency seen in the dimethyl substitution at C-4 (7m ).
In the trypsin crystal structure of 7k (Figure 2),11 the
imidazoline ring is in the plane of the phenyl, but in
the trypsin crystal structure of 7l, the ring is forced out
of the plane of the phenyl ring by the methyl group.13
A parallel activity to the search for positive interac-
tions between the inhibitor and fXa is the development
of a SAR for negative interactions with thrombin (fIIa)
and trypsin. The active sites of serine proteases have
distinct differences,12 which we were only partially
successful in exploiting. Compound 1 has excellent
selectivity vs thrombin and good selectivity vs trypsin.
However, replacement of the distal or S3/S4 binding
amidine group resulted in reduced selectivity for both
thrombin and trypsin (Table 1). The failure to identify
an additional interaction for the distal ring with fXa
(Table 2) also failed to provide a negative interaction
with thrombin or trypsin. The influence of the basic
amidine replacements described in Table 4 is seen in
the 30-fold variation in the selectivity ratio of fXa to
thrombin (7e-l) and the 8-fold variation in the corre-
sponding ratio of fXa vs trypsin (7h vs 7l). The increase
in selectivity is due to methyl substituent and partial
saturation of the imidazole ring but is limited by steric
bulk as in 7m .
donors and electron-donating substituents, were over
30-fold less active than the unsubstituted analogue. The
methyl-containing compound, 6l, which has a similar
steric bulk and weak electron-donating properties, is
7-fold less active. Other substituents caused no increase
in potency. On the basis of these results, we concluded
that potency against fXa can be dramatically increased
with a small electron-donating substituent at C-6
capable of forming a hydrogen bond with the serine of
the catalytic triad.
The SAR for the substituents on the distal ring in the
4-carboxylic acid series of analogues was explored as
shown in Table 4. Interestingly, the hydroxy substituent
does not have as large an effect on the bisamidine (7b
vs 7a ) as it does on the monoamidine (7d vs 7c)
resulting in the monoamidine having similar potency
to the bisamidine (7d vs 7b). Analogues bearing the
The crystal structure of bovine trypsin complexed
with 7k has been refined at 1.8 Å to an R factor of 15.5%
and a Rfree of 21.7% in space group P3121. The inhibitor
is bound at the active site of trypsin in an L-shaped
conformation similar to the binding mode of an earlier
inhibitor from the same series (Figure 2)11 and is similar
to the binding of a pyrrolidinone inhibitor to Trypsin8
and fXa.14 The proximal benzamidine ring is bound in
the S1 pocket, with the amidine making hydrogen bonds
to Asp189, Ser190, Gly218, and a water molecule. The
hydroxyl group para to the amidine is also hydrogen-
bonded to a water molecule, which in turn is hydrogen-
bonded to the hydroxyl of the catalytic triad Ser195. The
pyridine ring has no interactions with the primary
trypsin molecule. The imidazoline moiety binds in the
S3/S4 pocket in an extended conformation. One of the

2488 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Phillips et al.
F igu r e 2. Crystal structure of 7k in bovine trypsin. The carbon atoms of the inhibitor are colored green. Carbon atoms of specific
residues have been colored. Asp189 at the bottom of the S1 pocket is blue. The catalytic triad Ser195, His57, and Asp102 is
orange. Residues that form the S4 pocket, Thr98, Leu99, Gln175, and Trp215, are purple. Hydrogen bonds are depicted as dashed
lines.
imidazoline nitrogens makes a long hydrogen bond to
the carbonyl oxygen on Asn97. The C-4 carboxylate is
solvent-exposed and makes no interactions with trypsin.
Selectivity vs the serine proteases, thrombin and
trypsin, is strongly affected by the introduction of the
6-hydroxyl group on the proximal or S1 binding amidine
group (6i,o vs 4f,cc). This increase in potency against
fXa and selectivity vs thrombin and trypsin is thought
to be the result of variation in the binding of ligand to
the serine proteases, rather than the introduction of
selective negative interactions. The differential interac-
tion of the 6-hydroxyl group on the proximal ring and
with different proteases is at least partly explained by
a hydrogen bond to the Oγ Ser195 of the catalytic triad.
The distance between the 6-hydroxyl group of 7k and
the Ser195 in trypsin (Figure 2) is 3.61 Å, which
requires a bridging water molecule to form a hydrogen
bond. The corresponding distance between the 6-hy-
droxyl group of a closely related analogue of 7k and fXa
is 2.4 Å, which allows for a stronger direct hydrogen
bond.13
at 30 min (rat, 1 mg/kg, n ) 3). Replacement of the
amidine group with an imidazoline group, as in 7k ,
further increased the comparable plasma concentration
at 30 min to 3.0 µM with a 1.4 µM concentration at 1 h.
Unfortunately, introduction of the N-methyl group on
7k to give the more potent 7l resulted in a 3-fold
decrease in plasma concentrations after intravenous
administration to the rat with 1.1 µM at 30 min and
0.4 µM at 60 min. The pharmacokinetic profile of 7l was
expanded to include oral dosing in the rat at 10 mg/kg.
Plasma concentrations of 1.4, 0.2, and 0.1 µM were
measured at 1, 2, and 4 h, respectively. Although the
4-carboxylic acid group was able to improve the phar-
macokinetic profile of the pyridine-based fXa inhibitors,
alternative substitutents at C-4 of the pyridine ring
were explored to improve the profile.3
Con clu sion
A novel series of potent inhibitors of human fXa have
been designed and prepared with low nanomolar poten-
cies and 400-fold selectivity over the related serine
protease human fIIa and 100-fold selectivity over bovine
trypsin. The second amidine of the original inhibitors
has been replaced with less basic or neutral substitu-
ents. An additional binding site has been identified
between Ser195 of the catalytic triad and a hydroxy
group on the amidine-bearing ring via a bridging water
molecule. Future papers will describe the exploration
of substitution on the 4-position of the pyridine and the
In addition to potency and selectivity, we evaluated
the pharmacokinetic profile of our inhibitors in the rat.
The plasma concentrations after intravenous adminis-
tration (1 mg/kg, n ) 3) for 1 at 30 min was 0.1 µM as
compared to a concentration of 0.8 µM for 7a . The
pharmacokinetic profile of the inhibitors was further
improved with the introduction of the para-hydroxy
group, 7b, which gave a plasma concentration of 1.9 µM

Novel Series of Factor Xa Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2489
a pressure tube for 15 min. The tube was sealed and allowed
to warm to room temperature overnight. The tube was opened,
and the imidate was precipitated by addition of ether and
hexanes. The precipitate was collected and dissolved in etha-
nol. Hydrogen chloride gas was bubbled through the solution
at 0 °C in a pressure tube for 15 min. The tube was sealed
and heated at 65 °C for 2.5 h. The solution was evaporated in
vacuo, and the residue was heated in 8 mL of 6 N HCl for 1 h.
The reaction mixture was purified by reversed-phase prepara-
effect of those substitutents on potency, selectivity, and
oral bioavailability.15
Exp er im en ta l Section
All starting materials not described below were purchased
from commercial sources. All reagents and solvents were used
as received from commercial sources without additional pu-
rification. Elemental analyses were performed by Robertson
Microlit Laboratories, Madison, NJ , and results were within
(0.4% of the calculated values. Nuclear magnetic resonance
(NMR) spectra were recorded with a Varian XL-300 spectrom-
eter and were consistent with the assigned structures. HPLC
was performed with a Rainin SD-1 Dynamax system and a
C-18 reverse phase Dynamax 60A column using a gradient of
acetonitrile (0.1% trifluoroacetyl (TFA)) in water (0.1% TFA).
Human FXa and human fIIa were from Enzyme Research
Lab., South Bend, IN, and bovine trypsin was from Boehringer
Mannheim Corp., Indianapolis, IN. All peptide-p-nitroanilide
substrates were purchased from Pharmacia Hepar Inc., Fran-
klin, OH. TrisHCl, NaCl, and CaCl2 were from J . T. Baker
Inc., J ackson, TN, and poly(ethylene glycol) 6000 was from
BDH Laboratory Supplies, Poole, England.
2,6-Dich lor op yr id in e-4-ca r boxylic Acid , Eth yl Ester .
To a solution of 2,6-dichloropyridine-4-carbonyl chloride (8.19
g, 38.09 mmol, 1 equiv) in 70 mL of methylene chloride at 0
°C was added triethylamine (7 mL, 50.6 mmol, 1.3 equiv)
followed by ethanol (3.0 mL, 50.6 mmol, 1.3 equiv). The
reaction was allowed to warm to room temperature overnight.
The reaction was diluted with water, and the layers were
separated. The organic layer was washed with water, satu-
rated sodium bicarbonate, and 10% aqueous HCl and then
dried over anhydrous Na2SO4 and evaporated in vacuo to
afford the ester (8.1 g, 95%) as a yellow solid. 1H NMR
(CDCl3): 1.41 (t, 3), 4.42 (q, 2), 7.80 (s, 2) ppm.
1
tive HPLC to afford 174 mg of pure 7l. H NMR (DMSO-d6):
10.35 (br s, 1), 9.05 (br s, 2), 8.83 (br s, 2), 7.40-7.71 (m, 6),
7.07 (m, 3), 3.82-4.20 (m, 4), 3.00 (s, 3). Anal. C, H, N.
3-[(3,5-Diflu or o-4-m eth yl-6-p h en oxyp yr id in -2-yl)oxy]-
ben zen eca r boxim id a m id e, Acetic Acid Sa lt (4a ). 1H NMR
(300 MHz, DMSO): δ 10.3 (br s, 4H), 7.5 (m, 4H), 7.3 (m, 2H),
7.1 (m, 3H), 2.4 (s, 3 H), 1.75 (s, 3 H). Anal. (C19H15F2N3O2‚
C2H4O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben za m id e, 1.1 Tr iflu or oa cetic
Acid (4b). NMR (DMSO-d6): δ 9.3 (s, 2H), 9.05 (s, 2H), 8.0
(s, 1H), 7.5 (m, 6 H), 7.42 (t, 1H), 7.22 (d, 2H), 2.4 (m, 3H).
Anal. (C20H16N4O3F2‚1.1TFA) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zoic Acid Eth yl Ester , Acetic
Acid Sa lt (4c). NMR (DMSO-d6): δ 10.2 (br, 4 H), 7.75 (d, 1
H), 7.7 (s, 1 H), 7.5 (m, 6 H), 4.35 (q, 2 H), 2.4 (s, 3 H), 1.75 (s,
3 H), 1.35 (t, 3 H). Anal. (C22H19F2N3O4‚C2H4O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zoic Acid , 0.25 Hyd r a te (4d ).
NMR (DMSO-d6): δ 9.3 (s, 2H), 9.1 (s, 2 H), 7.75 (d, 1 H), 7.5
(m, 7 H), 2.4 (s, 3 H). Anal. (C20H15F2N3O4‚0.25H2O) C, H, N.
3-[[6-[3-Am in o(im in o)m eth yl]p h en oxy]3,5-d iflu or o-4-
m eth ylpyr idin -2-yl]oxy]n -m eth yl-ben zam ide, Acetic Acid
Sa lt, 0.2 Hyd r a te (4e). NMR (DMSO-d6): δ 10.3 (br, 4H), 8.5
(m, 1H), 7.6 (m, 1 H), 7.58 (m, 3 H), 7.4 (m, 4 H), 7.3 (m, 1 H),
2.8 (d, 3 H), 2.4 (s, 3H), 1.75 (s, 3 H). Anal. (C21H18F2N4O3‚
C2H4O2‚0.2H2O) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]-N,N-d im eth ylben za m id e, Acetic
Acid Sa lt, Hem ih yd r a te (4f). NMR (DMSO-d6): δ 10.3 (br,
4 H), 7.5 (m, 5 H), 7.2 (m, 3 H), 3.0 (s, 3 H), 2.8 (s, 3 H), 2.4 (s,
3 H), 1.75 (s, 3 H). Anal. (C22H20F2N4O3‚0.5H2O‚C2H4O2) C,
H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]-N,N-d ieth ylben za m id e, Acetic
Acid Sa lt, Hem ih yd r a te (4g). NMR (DMSO-d6): δ 10.1 (br,
4 H), 7.5 (m, 3 H), 7.4 (m, 2 H), 7.2 (d, 1H), 7.1 (m, 4 H), 3.4
(br, 2 H), 3.0 (br, 2 H), 2.4 (s, 3 H), 1.75 (s, 3 H), 1.15 (br, 3 H),
0.95 (br, 3 H). Anal. (C24H24F2N4O3‚C2H4O2‚0.5H2O) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-n -m et h yl-n -p h en ylm et h ylb en -
zam ide, Acetic Acid Salt, Hem ih ydr ate (4h ). NMR (DMSO-
d6): δ (mixture of rotamers) 10.1 (br, 4 H), 7.6 (m, 3 H), 7-7.6
(m, 13), 4.6 and 4.25 (2s, 2 H), 2.85 and 2.65 (2s, 3H), 2.4 (s,
3 H), 1.75 (s, 3 H). Anal. (C28H24F2N4O3‚C2H4O2‚0.5H2O) C,
H, N.
2-Ch lor o-6-(5-cya n o-2-ben zyloxyp h en oxy)p yr id in e-4-
ca r boxylic Acid , Eth yl Ester . To a solution of 2,6-dichloro-
pyridine-4-carboxylic acid, ethyl ester (6.35 g, 28.9 mmol 1
equiv) in 300 mL of DMSO were added cesium carbonate (12.2
g, 37.5 mmol, 1.3 equiv) and 5-cyano-2-benzyloxyphenol (6.5
g, 28.9 mmol, 1 equiv). The reaction was allowed to stir
overnight at room temperature. The reaction was poured into
water (1 L) and adjusted to pH 7 with 10% HCl. The resultant
mixture was extracted into ethyl acetate (3 × 300 mL), and
the combined organic layers were washed with 10% HCl,
water, and brine. After it was dried over anhydrous Na2SO4,
the solution was evaporated in vacuo to afford crude material
(13.1 g). Purification by flash chromatography through silica
gel with 2/1 hexanes-ethyl acetate as eluent afforded pure
1
ether (7.6 g 64%) as a white solid. H NMR (CDCl3): 1.40 (t,
2), 4.41 (q, 2), 5.10 (s, 2), 7.00 (m, 1), 7.15 (m, 2), 7.28 (m, 3),
7.40-7.58 (m, 4) ppm.
2-(5-Cya n o-2-b en zyloxyp h en oxy)-6-[3-(4,5-d ih yd r o-1-
m eth yl-1H-im id a zol-2-yl)p h en oxy]p yr id in e-4-ca r boxyl-
ic Acid , Eth yl Ester . To a solution of 2-chloro-6-(5-cyano-2-
benzyloxyphenoxy)pyridine-4-carboxylic acid, ethyl ester (1.60
g, 3.9 mmol, 1 equiv) in 40 mL of DMSO were added cesium
carbonate (1.65 g, 5.1 mmol, 1.3 equiv), imidazoline phenol
(1.3 g, 3.9 mmol, 1 equiv), and potassium fluoride (0.23 g, 3.9
mmol, 1 equiv). The reaction was heated at 100 °C for 19 h.
The mixture was diluted with 0.1 N NaOH (120 mL) and ethyl
acetate (120 mL). The layers were separated, and the aqueous
layer was extracted with ethyl acetate (3 × 100 mL). The
combined organic layers were washed with 10% HCl, water,
and brine, dried over anhydrous Na2SO4, and evaporated in
vacuo. Purification by flash chromatography through silica gel
with 20:1:0.1 methylene chloride:methanol:ammonium hy-
droxide afforded pure ether (131 mg, 6%). 1H NMR (CDCl3):
1.18 (t, 3), 2.64 (s, 3), 3.40 (t, 2), 3.81 (t, 2), 4.39 (q, 2), 495 (s,
2), 6.93-7.40 (m, 14) ppm.
1-[3-[[6-[3-[Am in o(im in o)m eth yl]ph en oxy]-3,5-diflu or o-
4-m eth ylpyr idin -2-yl]oxy]ben zoyl]pyr r olidin e, Acetic Acid
Sa lt, 0.9 Hyd r a te (4i). NMR (DMSO-d6): δ 10.3 (br, 4 H),
7.3-7.6 (m, 5 H), 7.2 (m, 3 H), 3.4 (t, 2 H), 3.2 (t, 2 H), 2.4 (s,
3 H), 2.1 (s, 6 H), 1.8 (m, 4 H), 1.75 (s, 3 H). Anal.
(C24H22F2N4O3‚C2H4O2‚0.9H2O) C, H, N.
4-[3-[[6-[3-[Am in o(im in o)m eth yl]ph en oxy]-3,5-diflu or o-
4-m et h ylp yr id in -2-yl]oxy]b en zoyl]m or p h olin e, Acet ic
Acid Sa lt (4j). NMR (DMSO-d6): δ 10.1 (br, 4 H), 7.3-7.6
(m, 5 H), 7.2 (m, 3 H), 3.1-3.8 (m, 8 H), 2.4 (s, 3 H), 1.75 (s,
3 H). Anal. (C24H22F2N4O4‚C2H4O2) C, H, N.
1-[3-[[6-[3-[Am in o(im in o)m eth yl]ph en oxy]-3,5-diflu or o-
4-m eth ylpyr edin -2-yl]oxy]ben zoyl]piper idin e, Acetic Acid
Sa lt, 0.75 Hyd r a te (4k ). NMR (DMSO-d6): δ 10.25 (br, 4H),
7.6 (m, 3 H), 7.4 (m, 2 H), 7.2 (m, 1 H), 7.15 (m, 2 H), 3.45 (br,
2 H), 3.15 (br, 2 H), 2.4 (s, 3H), 1.8 (s, 3 H), 1.3-1.6 (m, 6 H).
Anal. (C25H24F2N4O3‚C2H4O2‚0.75H2O) C, H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
(4,5-dih ydr o-1-m eth yl-1H-im idazol-2-yl)ph en oxy]pyr idin e-
4-ca r boxylic Acid , 2.2 Tr iflu or oa cetic Acid Sa lt, 0.9
Hyd r a te (7l). Hydrogen chloride gas was bubbled through a
solution of 3 (340 mg, 0.62 mol) in 5 mL of ethanol at 0 °C in

2490 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Phillips et al.
1-[3-[[6-[3-[Am in o(im in o)m eth yl]ph en oxy]-3,5-diflu or o-
4-m e t h y lp y r id in -2-y l]o x y ]b e n zo y l]-4-m e t h y lp ip e r a -
zin e, Acetic Acid Sa lt, Hyd r a te (4l). NMR (DMSO-d6): δ
10.5 (br, 4H), 7.6 (m, 3 H), 7.4 (m, 2 H), 7.2 (m, 1 H), 7.15 (m,
2 H), 3.17-3.7 (m, 4 H), 2.4 (s, 3H), 2.4 (m, 4 H), 2.2 (s, 3 H),
1.8 (s, 3 H). Anal. (C25H25F2N5O3‚C2H4O2‚H2O) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]3,5-d iflu or o-4-
m eth ylpyr idin -2-yl]oxy]-N-ph en ylben zam ide, Acetic Acid
Sa lt (4m ). NMR (DMSO-d6): δ 10.3 (br, 4 H), 7.8 (m, 4 H),
7.3-7.6 (m, 8 H), 7.15 (t, 1 H), 2.4 (s, 3 H), 1.75 (s, 3 H). Anal.
(C26H20F2N4O3‚C2H4O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zen ea ceta m id e, 0.1 Hyd r a te,
1.6 Tr iflu or oa cet ic Acid Sa lt (4n ). NMR (300 MHz,
DMSO): δ 7.52 (m, 2H), 7.25 (m, 2H), 6.95 (m, 4H), 3.64 (s,
2H), 2.95 (s, 3H), 2.75 (s, 3H), 2.37 (s, 3H). Anal. (C23H22F2N4O3‚
0.1H2O‚1.6C2HF3O2) C, H, N, F.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylpyr idin -2-yl]oxy]ben zen eacetam ide, 1.25 Hydr ate,
1.12 Tr iflu or oa cetic Acid Sa lt (4o). NMR (300 MHz,
DMSO): δ 9.36 (s, 2H), 9.2 (s, 2H), 7.58 (m, 4H), 7.25 (m, 1H),
6.95 (m, 3H), 3.64 (s, 2H), 2.37 (s, 3H). Anal. (C21H18F2N4O3‚
1.25H2O‚1.12C2HF3O2) C, H, N, F.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zen ea cetic Acid Eth yl Ester ,
Acetic Acid Sa lt (4p ). NMR (300 MHz, DMSO): δ 7.58 (m,
4H), 7.25 (m, 1H), 6.95 (m, 3H), 4.1 (q, 2H), 3.64 (s, 2H), 2.37
(s, 3H), 1.2 (t, 3H). Anal. (C23H21F2N3O4‚C2H4O2) C, H, N, F.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zen ea cetic Acid , 1.1 Hyd r a te,
Tr iflu or oa cetic Acid Sa lt (4q). NMR (300 MHz, DMSO): δ
9.36 (s, 2H), 9.2 (s, 2H), 7.58 (m, 4H), 7.25 (m, 1H), 6.95 (m,
3H), 3.4 (s, 2H), 2.37 (s, 3H). Anal. (C21H17F2N3O4‚1.1H2O‚C2-
HF3O2) C, H, N, F.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-N,N-d im et h yl-a -h yd r oxy-b en -
zen ea ceta m id e, Acetic Acid Sa lt, 0.5 Hyd r a te (4r ). NMR
(300 MHz, DMSO): δ 7.5 (m, 4H), 7.19 (t, 1H), 7.09 (m, 3H),
5.35 (m, 1H), 2.82 (s, 6H), 2.37 (s, 3H). Anal. (C23H21F2N4O4‚
0.5H2O‚C2H4O2) C, H, N, F.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-r-m et h oxyb en zen ea cet a m id e,
Acet ic Acid Sa lt , 0.5 H yd r a t e (4s). NMR (300 MHz,
DMSO): δ 7.5 (m, 4H), 7.25 (m, 1H), 7.09 (m, 3H), 4.55 (m,
1H), 3.25 (s, 3H), 2.37 (s, 3H). Anal. (C22H20F2N4O4‚0.5H2O‚
C2H4O2) C, H, N.
3-[[6-[3-(Am in om et h yl)p h en oxy]-3,5-d iflu or o-4-m et h -
ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, 2 Tr iflu o-
r oa cetic Acid Sa lt (4y). NMR (300 MHz, DMSO): δ 9.03 (s,
2H), 8.25 (br s, 2H), 7.6 (m, 4H), 7.3 (m, 1H), 7.2 (m, 3H), 4.05
(s, 2H), 2.37 (s, 3H). Anal. (C20H18F2N4O2‚0.5H2O‚0.2C2HF3O2)
C, H, N, F.
3-[3,5-Diflu or o-6-[3-(d im eth yla m in om eth y)p h en oxy]-
4-m eth ylpyr idin -2-yl]oxy]ben zen ecar boxim idam ide, Ace-
tic Acid Sa lt, 0.5 Hyd r a te (4z). NMR (DMSO): δ 10.4 (br, 4
H), 7.5 (m, 4 H), 7.25 (t, 1 H), 7.0 (m, 3 H), 3.3 (s, 2 H), 2.4 (s,
3 H), 2.1 (s, 6 H), 1.75 (s, 3 H). Anal. (C22H22F2N4O2‚C2H4O2‚
0.5H2O) C, H, N.
3-[3,5-Diflu or o-6-(3-n itr op h en oxy)-4-m eth ylp yr id in -2-
yl]oxy]ben zen eca r boxim id a m id e, Acetic Acid Sa lt, 0.9
Hyd r a te (4a a ). NMR (DMSO-d6): δ 10.1 (br, 4 H), 8.05 (m, 2
H), 7.65 (m, 2 H), 7.55 (m, 2 H), 7.45 (m, 2 H), 2.4 (s, 3 H),
1.75 (s, 3 H). Anal. (C19H14F2N4O4‚C2H4O2‚0.9H2O) C, H, N.
3-[[6-(3-Am in op h en oxy)-3,5-d iflu or o-4-m eth ylp yr id in -
2-yl]oxy]ben xen eca r boxim id a m id e, 0.7 Hyd r a te, 2 Tr i-
flu or oa cetic Acid Sa lt (4bb). NMR (DMSO-d6): δ 9.3 (s, 2
H), 9.2 (s, 2 H), 7.8 (m, 3 H), 7.75 (m, 1 H), 7.0 (t, 1 H), 6.4 (d,
1 H), 6.3 (m, 2 H), 2.4 (s, 3 H). Anal. (C19H16F2N4O2‚0.7H2O‚2C2-
HF3O2) C, H, N.
3-[[3,5-D iflu o r o -6-[3-(d im e t h y la m in o )p h e n o x y ]-4-
m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, Ace-
1
tic Acid Sa lt (4cc). H NMR (300 MHz, DMSO): δ 10.3 (br
s, 4H), 7.5 (m, 4H), 7.1 (t, 1H), 6.45 (d, 1H), 6.40 (s, 1H), 6.3
(d, 1 H), 2.85 (s, 6 H), 2.4 (s, 3 H), 1.75 (s, 3 H). Anal.
(C21H20F2N4O2‚C2H4O2) C, H, N.
3-[[3,5-Diflu or o-6-[3-(eth ylam in o)ph en oxy]-4-m eth ylpy-
r idin -2-yl]oxy]ben zen ecar boxim idam ide, Acetic Acid Salt,
0.3 Hyd r a te (4d d ). NMR (DMSO-d6): δ 10.2 (br, 4 H), 7.5
(m, 4 H), 7.0 (t, 1 H), 6.35 (d, 1 H), 6.2 (m, 2 H), 5.7 (s, 1 H),
3.0 (m, 2 H), 2.4 (s, 3 H), 1.8 (s, 3 H), 1.15 (t, 3 H). Anal.
(C21H20F2N4O2‚0.3H2O‚C2H4O2) C, H, N.
3-[[6-[-3-(Dim e t h yla m in o)p h e n oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, Ace-
tic Acid Sa lt (4ee). NMR (DMSO-d6): δ 10.2 (br, 4 H), 7.5
(m, 4 H), 7.1 (t, 1 H), 6.4 (d, 1 H), 6.35 (s, 1 H), 6.25 (d, 1 H),
3.25 (q, 4 H), 2.4 (s, 3 H), 1.75 (s, 3 H), 1.0 (t, 6 H). Anal.
(C23H24F2N4O3‚C2H4O2) C, H, N.
3-[[3,5-Diflu or o-4-m eth yl-6-[3-(p h en yla m in o)p h en oxy]-
p yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, 0.6 Acetic
Acid Sa lt, 0.5 Hyd r a te, 0.4 Hyd r och lor id e (4ff). NMR
(DMSO-d6): δ 10 (br, 4H), 8.4 (s, 1H), 7.5 (m, 4 H), 7.25 (t,
2H), 7.15 (m, 3 H), 6.9 (m, 2 H), 6.8 (s, 1 H), 6.55 (d, 1H), 2.4
(s, 3H), 1.8 (s, 1.8 H). Anal. (C25H20F2N4O3‚0.6C2H4O2‚0.5H2O‚
0.4HCl) C, H, N.
3-[[3,5-Diflu or o-6-[3-(m eth ylsu lfon yla m in o)p h en oxy]-
4-m eth ylpyr idin -2-yl]oxy]ben zen ecar boxim idam ide, Ace-
tic Acid Sa lt (4gg). NMR (DMSO-d6): δ 10.2 (br, 4 H), 7.5
(m, 3 H), 7.40 (dt, 1 H), 7.15 (t, 1 H), 6.85 (dd, 1 H), 6.80 (t,
1H), 6.66 (dd, 1 H), 2.83 (s, 3 H), 2.36 (s, 3 H), 1.74 (s, 3 H).
Anal. (C20H18F2N4O4S‚C2H4O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3, 5-d iflu or o-
4-m eth ylp yr id in -2-yl]oxy]-N,N-d im eth ylben zen ep r op a n -
a m id e, 1.8 Tr iflu or oa cetic Acid Sa lt (4t). NMR (300 MHz,
DMSO): δ 9.33 (d, 2H), 7.56 (m, 4H), 7.23 (m, 1H), 6.9 (m,
3H), 2.95 (s, 3H), 2.85 (s, 3H), 2.75 (t, 2H), 2.53 (t, 2H), 2.37
(s, 3H). Anal. (C24H24F2N4O3‚1.8C2HF3O2) C, H, N, F.
3-[[6-[3[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zen ep r op a n a m id e, 0.5 Hy-
d r a te, 1.5 Tr iflu or oa cetic Acid Sa lt (4u ). NMR (300 MHz,
DMSO): δ 9.33 (s, 2H), 9.14 (s, 2H), 7.6 (m, 3H), 7.34 (s, 1H),
7.2 (m, 1H), 6.95 (m, 2H), 6.85 (s, 1H), 2.8 (t, 2H), 2.37 (s, 3H),
2.3 (t, 2H). Anal. (C22H20F2N4O3‚0.5H2O‚1.5C2HF3O2) C, H, N,
F.
N-[3-[[6-[3-[Am in o(im in o)m eth yl]ph en oxy]3,5-diflu or o-
4-m et h ylp yr id in -2-yl]oxy]p h en yl]a cet a m id e, 0.25 H y-
d r a te, Acetic Acid Sa lt (4h h ). NMR (DMSO-d6): δ 10.3 (br,
4 H), 10.1 (s, 1 H), 7.5 (m, 5 H), 7.2 (m, 2 H), 6.8 (m, 1 H), 2.4
(s, 3 H), 2.05 (s, 3 H), 1.75 (s, 3 H). Anal. (C21H18F2N4O3‚
C2H4O2‚0.25H2O) C, H, N.
3-[[6-(3-Actylp h en oxy)-3,5-d iflu or o-4-m eth ylp yr id in -2-
yl]oxy]ben zen eca r boxim id a m id e, Acetic Acid Sa lt (4v).
NMR (300 MHz, DMSO): δ 7.5 (m, 8H), 2.41 (s, 3H), 1.72 (s,
3H). Anal. (C21H17F2N3O3‚C2H4O2) C, H, N, F.
3-[[3,5-Diflu or o-4-m eth yl-6-[3-(2-m eth yl-1-oxop r op yl)-
p h en oxy]p yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, 0.9
Acetic Acid Sa lt, Hyd r och lor id e (4w ). NMR (300 MHz,
DMSO): δ 10.4 (br, 4H), 7.5 (m. 8H), 2.5 (s, 6H), 2.4 (s, 3H),
1.75 (s, 3H). Anal. (C23H21F2N5O3‚HCl‚0.9C2H4O2) C, H, N, F.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-N,N-d im et h ylb en zen esu lfon a -
m id e, Acetic Acid Sa lt, 0.5 Hyd r a te (4x). NMR (300 MHz,
DMSO): δ 7.5 (m, 8H), 3.42 (m, 1H), 2.37 (s, 3H), 1.14 (d, 6H).
Anal. (C21H20F2N4O4S‚C2H4O2‚0.5H2O) C, H, N.
1-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]p h en yl]u r ea , 0.1 Am m on iu m
Ch lor id e, Hyd r och lor id e (4ii). NMR (DMSO-d6): δ 9.4 (s,
2 H), 9.2 (s, 2 H), 9.1 (s, 1 H), 7.6 (m, 4 H), 7.4 (s, 1 H), 7.15 (t,
1 H), 7.0 (d, 1 H), 6.65 (d, 1 H), 6.1 (s, 2 H), 2.4 (s, 3 H). Anal.
(C20H16F2O3N5‚0.1NH4Cl‚HCl) C, H, N.
3-[3,5-D iflu o r o -6-[3-(m o r p h o lin e -4-y l)p h e n o x y ]-4-
m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, Ace-
tic Acid , 0.6 Hyd r a te (4jj). NMR (DMSO-d6): δ 10.2 (br, 4
H), 7.3-7.6 (m, 4 H), 7.15 (t, 1 H), 6.7 (m, 2 H), 6.5 (d, 1 H),
3.7 (s, 4 H), 3.0 (s, 4H), 2.4 (s, 3 H), 1.75 (s, 3 H). Anal.
(C23H22N4F2O3‚C2H4O2‚0.6H2O) C, H, N.
3-[[3,5-Diflu or o-6-[3-(1H -im id a zol-1-yl)p h e n oxy]-4-
m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, Hy-

Novel Series of Factor Xa Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2491
d r och lor id e, 0.9 Hyd r a te (4k k ). NMR (DMSO-d6): δ 9.9 (br,
4 H), 8.3 (s, 1 H), 7.8 (s, 1 H), 7.5 (m, 6 H), 7.3 (t, 1 H), 7.15
(m, 2 H), 2.4 (s, 3 H). Anal. (C22H17F2N5O2‚HCl‚0.9H2O) C, H,
N.
3-[[3,5-Diflu or o-4-m eth yl-6-[3-(tr iflu or om eth yl)ph en oxy]-
p yr ed in -2-yl]oxy]ben zen eca r boxim id a m id e, Acetic Acid
Sa lt (4ll). NMR (300 MHz, DMSO): δ 10.1 (br. s, 4H), 7.61-
7.55 (m, 2H), 7.51 (m, 1H), 7.46 (m, 1H), 7.23 (m, 1H), 6.74-
6.65 (m, 3H), 3.71 (s, 3H), 2.39 (s, 3H). Anal. (C20H17F2N3O3‚
0.7C2H4O2‚0.1C4H10O‚0.6HCl) C, H, N.
3-[[6-[(3-Tr iflu or om et h oxy)p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, Ace-
tic Acid Sa lt (4m m ). NMR (300 MHz, DMSO): δ 2.37 (s, 3H),
7.15 (m, 3H), 7.55 (m, 5H). Anal. (C20H14F5N3O3‚C2H4O2) C,
H, N, F.
Acid Sa lt (5e). NMR (DMSO-d6): δ 9.3 (s, 2), 9.0 (s, 2), 7.4
(m, 4), 6.7 (s, 1), 6.5 (s, 1), 2.8 (br s, 6), 2.4 (s, 3). Anal.
(C22H20F2N4O4‚2.0C2HF3O2‚0.9NH4Cl) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-4,5-d im et h oxy-N,N-d im et h yl-
ben za m id e, 1.2 Hyd r a te, Tr iflu or oa cetic Acid Sa lt (5f).
NMR (DMSO-d6): δ 9.3 (s, 2), 9.1 (s, 2), 7.9 (s, 1), 7.4 (m, 7),
3.9 (s, 3), 3.6 (s, 3), 2.4 (s, 3). Anal. (C22H20F2N4O5‚C2HF3O2‚
1.2H2O) C, H, N.
5-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]-N,N,N′,N′-tetr a m eth ylben zen e-
1,3-d ica r boxa m id e, 1.75 Tr iflu or oa cetic Acid Sa lt (5g).
NMR (DMSO-d6): δ 9.3 (s, 2), 9.1 (s, 2), 7.5 (m, 4), 7.25 (s, 2),
7.15 (s, 1), 3.0 (br s, 6), 2.8 (br s, 6), 2.4 (s, 3). Anal.
(C25H25F2N5O4‚1.75C2HF3O2) C, H, N.
3-[[[6-[3-(Meth yleth oxy)p h en oxy]-3,5-d iflu or o-4-m eth -
yl-pyr idin -2-yl]oxy]ben zen ecar boxim idam ide, Acetic Acid
Sa lt (4n n ). NMR (300 MHz, DMSO): δ 7.58 (m, 4H), 7.19 (t,
1H), 6.65 (m, 3H), 4.52 (m, 1H), 2.37 (s, 3H), 1.21 (d, 6H). Anal.
(C22H21F2N3O3‚C2HF3O2) C, H, N, F.
3-[[3,5-Diflu or o-6-(3-flu or op h en oxy)-4-m eth ylp yr id in -
2-yl]oxy]ben zen eca r boxim id a m id e, 1.1 Acetic Acid Sa lt
(4oo). NMR (300 MHz, DMSO): δ 10.4 (br. s, 4H), 7.59-7.48
(m, 3H), 7.44 (m, 1H), 7.34 (m, 1H), 7.06 (d, 1H), 7.00-6.94
(m, 2H), 2.38 (s, 3H). Anal. (C19H14F3N3O2‚1.1C2H4O2) C, H,
N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-5-h yd r oxy-N,N-d im et h ylb en z-
a m id e, 1.6 Tr iflu or oa cetic Acid Sa lt (5h ). NMR (DMSO-
d6): δ 9.3 (s, 2), 9.0 (s, 2), 7.5 (m, 4), 6.5 (m, 3), 2.9 (s, 3), 2.7
(s, 3), 2.4 (s, 3). Anal. (C22H20F2N4O4‚1.41C2HF3O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-5-m et h oxy-N,N-d im et h ylb en z-
a m id e, 1.1 Tr iflu or oa cetic Acid Sa lt (5i). NMR (DMSO-
d6): δ 9.3 (s, 2), 9.1 (s, 2), 7.6 (m, 4), 6.8 (s, 1), 6.7 (d, 2), 3.7 (s,
3), 2.9 (s, 3), 2.8 (s, 3), 2.4 (s, 3). Anal. (C23H22F2N4O4‚1.1C2-
HF3O2) C, H, N.
3-[[6-(3-Ch lor op h en oxy)-3,5-d iflu or o-4-m eth ylp yr ed in -
6-yl]oxy]ben zen eca r boxim id a m id e, 1.25 Acetic Acid Sa lt
(4p p ). NMR (300 MHz, DMSO): δ 10.4 (br. s, 4H), 7.62-7.47
(m, 4H), 7.35 (t, 1H), 7.31 (t, 1H), 7.21 (dd, 1H), 7.12 (dd, 1H),
2.40 (s, 3H). Anal. (C19H14ClF2N3O2‚1.25C2H4O2) C, H, N.
3-[[3,5-Diflu or o-6-(3-h ydr oxyph en oxy)-4-m eth ylpyr idin -
2-yl]oxy]ben zen eca r boxim id a m id e, Acetic Acid Sa lt, Di-
eth yl eth er (4qq). NMR (300 MHz, DMSO): δ 7.58 (m, 4H),
2.37 (s, 3H), 7.1 (m, 1H), 6.55 (m, 3H). Anal. (C19H15F2N3O3‚
C2H4O2‚C4H10O) C, H, N, F.
3-[[3,5-Diflu or o-4-m eth yl-6-[3-(tr iflu or om eth yl)ph en oxy]-
p yr ed in -2-yl]oxy]ben zen eca r boxim id a m id e, Acetic Acid
Sa lt (4r r ). NMR (300 MHz, DMSO): δ 10.4 (br. s, 4H), 7.59-
7.53 (m, 5H), 7.5-7.4 (m, 3H), 2.41 (s, 3H). Anal. (C20H14F5N3O2‚
1.0C2H4O2) C, H, N.
3-[[3,5-D iflu o r o -6-[3-(h y d r o x y m e t h y l)p h e n o x y ]-4-
m eth ylpyr idin -2-yl]oxy]ben zen ecar boxim idam ide, 0.4 Hy-
d r a te, 1.1 Tr iflu or oa cetic Acid Sa lt (4ss). NMR (300 MHz,
DMSO): δ 9.33 (s, 2H), 7.56 (m, 4H), 7.23 (m, 1H), 7.02 (m,
3H), 4.45 (s, 2H), 2.37 (s, 3H). Anal. (C20H17F2N3O3‚0.4H2O‚
1.1C2HF3O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]-2-h yd r oxy-N,N-d im eth ylben za -
m id e, 1.5 Tr iflu or oa cetic Acid Sa lt (5a ). NMR (DMSO-
d6): δ 9.6 (s, 1), 9.2 (s, 2), 9.0 (s, 2), 7.5 (m, 3), 7.4 (d, 1), 7.1 (d,
1), 6.9 (d, 1), 6.8 (t, 1), 3.7 (br s, 6), 2.4 (s, 3). Anal.
(C22H20F2N4O4‚1.5C2HF3O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]-2-m eth oxy-N,N-d im eth ylben za -
m id e, 1.35 Tr iflu or oa cetic Acid Sa lt (5b). NMR (DMSO-
d6): δ 9.2 (s, 2), 9.0 (s, 2), 7.5 (dd, 3), 7.4 (d, 1), 7.2 (d, 1), 7.1
(t, 1), 7.0 (d, 1), 3.5 (br s, 6), 3.0 (s, 3), 2.4 (s, 3). Anal.
(C23H22F2N4O4‚1.35C2HF3O2) C, H, N.
5-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-N,N-d im et h yl-2-m et h oxyb en -
zen eca r boxa m id e, Hyd r a te, 1.2 Tr iflu or oa cetic Acid Sa lt
(5c). NMR (DMSO-d6): δ 9.8 (br s, 1), 9.3 (s, 2), 9.2 (s, 2), 7.5
(m, 4), 7.0 (dd, 1), 6.9 (s, 1), 6.8 (d, 1), 2.9 (br s, 3), 2.7 (br s, 3),
2.4 (s, 3). Anal. (C22H20F2N4O4‚1.2C2HF3O2‚1.0H2O) C, H, N.
5-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-N,N-d im et h yl-2-m et h oxyb en -
zen eca r boxa m id e, Hyd r a te, 1.25 Tr iflu or oa cetic Acid
Sa lt (5d ). NMR (DMSO-d6): δ 9.3 (s, 2), 9.0 (s, 2), 7.5 (m, 3),
7.4 (d, 1), 7.1 (d, 1), 6.9 (m, 2), 3.7 (s, 3), 2.9 (s, 3), 2.6 (s, 3),
2.4 (s, 3). Anal. (C23H22F2N4O4‚1.25C2HF3O2‚1.0H2O) C, H, N.
5-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylpyr idin -2-yl]oxy]-3,4-dih ydr oxy-N,N-dim eth ylben -
za m id e, 0.9 Am m on iu m Ch lor id e, 2.0 Tr iflu or oa cet ic
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m e t h ylp yr id in -2-yl]oxy]-N ,N -d im e t h yl-4-m e t h ylb e n z-
a m id e, 1.65 Tr iflu or oa cetic Acid Sa lt (5j). NMR (DMSO-
d6): δ 9.3 (s, 2), 9.1 (s, 2), 7.5 (m, 4), 7.3 (d, 1), 7.1 (m, 2), 2.9
(br s, 3), 2.7 (br s, 3), 2.4 (s, 3), 2.1 (s, 3). Anal. (C23H22F2N4O3‚
1.65C2HF3O2) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-4-h yd r oxy-N,N-d im et h ylb en z-
a m id e, 1.2 Tr iflu or oa cetic Acid Sa lt, 0.5 Hyd r a te (5k ).
NMR (DMSO-d6): δ 9.2 (s, 2), 8.9 (s, 2), 7.4 (m, 4), 7.0 (m, 2),
6.9 (d, 1), 2.8 (br s, 6), 2.4 (s, 3). Anal. (C22H20F2N4O4‚1.2C2-
HF3O2‚0.5H2O) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]3,5-d iflu or o-4-
m et h ylp yr id in -2-yl]oxy]-4-m et h oxy-N,N-d im et h ylb en z-
a m id e, 1.55 Tr iflu or oa cetic Acid Sa lt (5l). NMR (DMSO-
d6): δ 9.3 (s, 2), 9.1 (s, 2), 7.5 (m, 3), 7.3 (d, 1), 7.2 (m, 2), 7.1
(d, 1), 3.8 (s, 3), 2.9 (br s, 3), 2.8 (br s, 3), 2.4 (s, 3). Anal.
(C23H22F2N4O4‚1.55C2HF3O2) C, H, N.
3-[[3,5-Diflu or o-6-(3-(d im e t h yla m in o)-2-m e t h ylp h e -
n oxy)-4-m e t h ylp yr id in -2-yl]oxy]b e n ze n e ca r b oxim id -
a m id e, 1.75 Hyd r a te, 2 Tr iflu or oa cetic Acid Sa lt (5m ).
NMR (DMSO-d6): δ 9.3 (s, 2H), 9.2 (s, 2H), 7.55 (m, 3 H), 7.4
(d, 1H), 7.1 (t, 1H), 6.9 (d, 1H), 6.75 (d, 1H), 2.65 (s, 6H), 2.4
(s, 3H), 2.05 (s, 3H). Anal. (C22H22F2N4O2‚1.75H2O‚2C2HF3O2)
C, H, N.
3-[[6-(4-Ch lor o-3-d im eth yla m in oph en oxy)-3,5-d iflu or o-
4-m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, Hy-
d r a te, 2.2 Tr iflu or oa cetic Acid Sa lt (5n ). NMR (DMSO-
d6): δ 9.3 (s, 2H), 9.14 (s, 2H), 7.6 (m, 3H), 7.5 (m, 1 H), 7.28
(d, 1H), 6.88 (d, 1H), 6.74 (dd, 1H), 2.65 (s, 6H), 2.4 (m, 3H).
Anal. (C22H19ClF2N4O‚2.2C2HF3O2‚H2O) C, H, N.
2-[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]-4-d im eth yla m in oben zen eca r boxyl-
ic Acid , Eth yl Ester , Acetic Acid Sa lt, 1.1 Hyd r a te (5o).
NMR (DMSO-d6): δ 9.2 (s, 2H), 8.95 (s, 2H), 7.67 (d, 1 H),
7.46 (d, 3H), 7.35 (m, 2H), 7.15 (d, 1H), 6.48 (d,1H), 6.35 (s,
1H), 4.0 (q, 2H), 2.95 (s, 6H), 2.35 (s, 3H), 1.85 (s, 3H), 1.05 (t,
3H). Anal. (C26H28F2N4O6‚1.1H2O) C, H, N.
2-[[6-[3-[Am in o(im in o)m eth yl]p h en oxy]-3,5-d iflu or o-4-
m eth ylp yr id in -2-yl]oxy]-4-d im eth yla m in oben zoic Acid ,
1.5 Tr iflu or oa cetic Acid Sa lt (5p ). NMR (DMSO-d6): δ 9.25
(s, 2H), 9.0 (s, 2H), 7.68 (d, 1 H), 7.45 (m, 3H), 7.22 (d, 1H),
6.5 (d, 1H), 6.4 (m, 1H), 3.05 (s, 6H), 2.4 (s, 3H). Anal.
(C22H20F2N4O4‚1.5C2HF3O2) C, H, N.
3-[[3,5-Diflu or o-6-[5-(d im e t h yla m in o)-2-m e t h ylp h e -
n oxy]-4-m e t h ylp yr id in -2-yl]oxy]b e n ze n e ca r b oxim id -
a m id e, 1.2 Hyd r a te, 2 Tr iflu or oa cetic Acid Sa lt (5q).
NMR (DMSO-d6): δ 9.2 (s, 2H), 9.05 (s, 2H), 7.45 (m, 3 H),

2492 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12
Phillips et al.
7.3 (m, 4H), 3.05 (s, 6H), 2.35 (s, 3H), 2.05 (s, 3H). Anal.
(C22H22F2N4O2‚1.2H2O‚2C2HF3O2) C, H, N.
2H), 7.3 (m, 2H), 7.1 (m, 3H), 2.95 (s, 3H), 2.75 (s, 3H), 2.37
(s, 3H). Anal. (C23H22F2N4O4‚0.5H2O‚1.5C2HF3O2) C, H, N, F.
2,4-Dim et h oxy-3-[[3,5-d iflu or o-6-[3-(d im et h yla m in o)-
p h en oxy]-4-m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim i-
d a m id e, 0.6 Acetic Acid Sa lt, 2 Hyd r a te, 0.1 Tr iflu or o-
a cetic (6k ). NMR (300 MHz, DMSO): δ 7.45 (d, 1H), 7.07 (m,
2H), 6.44 (d, 1H), 6.24 (s, 1H), 6.05 (d, 1H), 3.78 (s, 6H), 2.85
(s, 6H), 2.37 (s, 3H). Anal. (C23H24F2N4O4‚0.6C2H4O2‚0.2H2O‚
0.1C2HF3O2) C, H, N, F.
3-[[3,5-D iflu o r o -6-[3-(d im e t h y la m in o )p h e n o x y ]-4-
m e t h y lp y r id in e -2-y l]o x y ]-4-m e t h y lb e n ze n e c a r b o x -
im id a m id e, 0.95 Acetic Acid Sa lt, 0.3 Hyd r a te, 0.05 Tr i-
flu or oa cetic Acid Sa lt (6l). NMR (300 MHz, DMSO): δ 10.1
(br. s, 4H), 7.55 (d, 1H), 7.48 (d, 1H), 7.42 (d, 1H), 7.02 (t, 1H),
6.43 (dd, 1H), 6.30 (t, 1H), 6.22 (dd, 1H), 2.81 (s, 6H), 2.37 (s,
3H), 2.19 (s, 3H). Anal. (C22H22N4O2F2‚0.95C2H4O2‚0.05C2-
HF3O2‚0.3H2O) C, H, N.
4-Am in o-3-[[3,5-diflu or o-6-[3-(dim eth ylam in o)ph en oxy]-
4-m eth ylp yr id in -2-yl]oxy]ben zen eca r boxim id a m id e, 1.5
Hyd r a te, 0.18 Tr iflu or oa cetic Acid Sa lt, 0.8 Acetic Acid
Sa lt (6m ). NMR (300 MHz, DMSO): δ 12.0 (br. s, 1H), 8.78
(br. s, 2H), 8.63 (br. s, 2H), 7.49 (dd, 1H), 7.48 (s, 1H), 7.00 (t,
1H), 6.78 (d, 1H), 6.41 (dd, 1H), 6.30 (t, 1H), 6.25 (dd, 1H),
6.22 (br. s, 2H), 2.81 (s, 6H), 2.36 (s, 3H). Anal. (C21H21F2N5O2‚
0.8C2H4O2‚0.18C2HF3O2‚1.5H2O) C, H, N.
3-[[[3,5-D iflu o r o -6-(3-d im e t h y la m in o )p h e n o x y ]-4-
m eth ylpyr idin -2-yl]oxy]-4-(m eth ylsu lfon ylam in o)ben zen e-
ca r boxim id a m id e, 1.5 Hyd r a te, 0.1 Tr iflu or oa cetic Acid
Sa lt, 0.8 Acetic Acid Sa lt (6n ). NMR (300 MHz, DMSO): δ
9.3 (br. s, 4H), 7.50 (d, 1H), 7.21 (t, 1H), 7.15-7.12 (m, 2H),
6.60 (dd, 1H), 6.53-6.47 (m, 2H), 3.00 (s, 3H), 2.90 (s, 6H),
2.21 (s, 3H). Anal. (C22H23F2N5O4S‚0.8C2H4O2‚0.1C2HF3O2‚
1.5H2O) C, H, N.
3-[[[3,5-D iflu o r o -6-(3-d im e t h y la m in o )p h e n o x y ]-4-
m eth ylp yr id in -2-yl]oxy]-4-h yd r oxyben zen eca r boxim id -
a m id e, 2.2 Tr iflu or oa cetic Acid Sa lt, 0.2 Hyd r ogen Br o-
m id e (6o). NMR (300 MHz, DMSO): δ 11 (br s, 1H), 9.07 (s,
2H), 8.75 (s, 2H), 7.65 (s, 1H), 7.57 (d, 1H), 7.08 (d, 1H), 6.95
(t, 1H), 6.4 (d, 1H), 6.27 (s, 1H), 6.15 (d, 1H), 2.85 (s, 6H), 2.37
(s, 3H). Anal. (C21H20F2N4O3‚2.2C2HF3O2‚0.2HBr) C, H, N, F.
3-[[3,5-Diflu or o-6-[3(d im eth yla m in o)p h en oxy]-4-m eth -
ylp yr id in -2-yl]oxy]-4-m e t h oxyb e n ze n e ca r b oxim id a -
m id e, 0.5 Acetic Acid Sa lt, 0.2 Meth ylen e Ch lor id e,
Hyd r a te (6p ). NMR (300 MHz, DMSO): δ 7.75 (d, 1H), 7.7
(s, 1H), 7.28 (d, 1H), 7.05 (t, 1H), 6.45 (d, 1H), 6.3 (s, 1H), 6.15
(d, 1H), 2.85 (s, 6H), 2.37 (s, 3H). Anal. (C22H22F2N4O3‚H2O‚
0.5C2HF3O2‚0.2CH2Cl2) C, H, N, F.
2-[3-[Am in o(im in o)m eth yl]p h en oxy]-6-[5-[a m in o(im i-
n o)m eth yl]-2-h ydr oxyph en oxy]pyr idin e-4-car boxylic Acid,
Dih yd r a te, 3.2 Tr iflu or oa cetic Acid Sa lt (7b). NMR (300
MHz, DMSO): δ 11.17 (s, 1H), 9.38 (s, 2H), 9.23 (s, 2H), 9.14
(s, 2H), 8.95 (s, 2H), 7.65 (m, 5H), 7.1 (m, 4H). Anal.
(C20H17N5O5‚2H2O‚3.2C2HF3O2) C, H, N.
3-[[3,5-Diflu or o-6-(5-(d im et h yla m in o)-2-m et h oxyp h e-
n oxy)-4-m e t h ylp yr id in -2-yl]oxy]b e n ze n e ca r b oxim id -
a m id e, Acetic Acid Sa lt, 0.2 Hyd r a te (5r ). NMR (DMSO-
d6): δ 9.25 (s, 2H), 9.05 (s, 2H), 7.5 (m, 2 H), 7.45 (m, 3H),
7.25 (d, 1H), 7.1 (d, 1H), 3.65 (s, 3H), 3.05 (s, 6H), 2.35 (s, 3H),
1.95 (s, 3H). Anal. (C22H22F2N4O3‚C2H4O2‚0.2H2O) C, H, N.
3-[[6-[3-[Am in o(im in o)m eth yl]-2-h yd r oxyp h en oxy]-3,5-
d iflu or o-4-m et h ylp yr id in -2-yl]oxy]-N,N-d im et h ylb en z-
a m id e, Hyd r a te, Tr iflu or oa cetic Acid (6a ). NMR (300
MHz, DMSO): δ 9.03 (s, 2H), 8.75 (s, 2H), 7.5 (m, 1H), 7.3 (m,
5H), 2.97 (s, 3H), 2.92 (s, 3H), 2.37 (s, 3H). Anal. (C22H20F2N4O4‚
H2O‚C2HF3O2) C, H, N, F.
3-[[3,5-D iflu o r o -6-[3-(d im e t h y la m in o )p h e n o x y ]-4-
m eth ylp yr id in -2-yl]oxy]-2-h yd r oxy-4-m eth oxyben zen e-
ca r boxim id a m id e, 1.2 Hyd r a te, 2 Tr iflu or oa cetic Acid
Sa lt (6b). NMR (300 MHz, DMSO): δ 8.88 (s, 2H), 8.67 (s,
2H), 7.45 (d, 1H), 7.02 (t, 1H), 6.75 (d, 1H), 6.41 (d, 1H), 6.24
(s, 1H), 6.02 (d, 1H), 2.85 (s, 6H), 2.37 (s, 3H).
(6b): Anal. (C21H20F2N4O4‚1.2H2O‚2C2HF3O2) C, H, N, F.
3-[[6-[5-[Am in o(im in o)m eth yl]-2,3-dih ydr oxyph en oxy]-
3,5-d iflu or o-4-m eth ylp yr id in -2-yl]oxy]-N,N-d im eth ylben -
za m id e, Hyd r a te, 1.5 Tr iflu or oa cetic Acid Sa lt (6c). NMR
(300 MHz, DMSO): δ 10.2 (br s, 2H), 9.03 (s, 2H), 8.75 (s, 2H),
7.3 (m, 1H), 7.1 (m, 5H), 2.95 (s, 3H), 2.75 (s, 3H), 2.37 (s,
3H). Anal. (C22H20F2N4O5‚H2O‚1.5C2HF3O2) C, H, N, F.
3-[[6-[5-[Am in o(im in o)m eth yl]-2,3-dim eth oxyph en oxy]-
3,5-d iflu or o-4-m eth ylp yr id in -2-yl]oxy]-N,N-d im eth ylben -
za m id e, 0.3 Hyd r ogen Br om id e, 1.3 Tr iflu or oa cetic Acid
Sa lt (6d ). NMR (300 MHz, DMSO): δ 9.19 (s, 4H), 9.07 (s,
4H), 7.3 (m, 3H), 7.1 (m, 3H), 3.89 (s, 3H), 3.65 (s, 3H), 2.95
(s, 3H), 2.75 (s, 3H), 2.37 (s, 3H). Anal. (C24H24F2N4O5‚0.3HBr‚
1.3C2HF3O2) C, H, N, F.
3-[[6-[5-[Am in o(im in o)m eth yl]-3-h yd r oxy-2-m eth oxy-
p h en oxy]-3,5-d iflu or o-4-m eth ylp yr id in -2-yl]oxy]-N,N-d i-
m eth ylben za m id e, 0.1 Hyd r ogen Br om id e, 1.15 Tr iflu o-
r oa cetic Acid Sa lt (6e). NMR (300 MHz, DMSO): δ 10.3 (s,
1H), 9.03 (s, 2H), 8.75 (s, 2H), 7.3 (m, 3H), 7.1 (m, 3H), 3.89
(s, 3H), 2.95 (s, 3H), 2.75 (s, 3H), 2.37 (s, 3H). Anal.
(C23H22F2N4O5‚0.1HBr‚1.15C2HF3O2) C, H, N, F.
3-[[6-[5-[Am in o(im in o)m eth yl]-3-m eth oxyph en oxy]-3,5-
d iflu or o-4-m et h ylp yr id in -2-yl]oxy]-N,N-d im et h ylb en z-
a m id e, 2 Tr iflu or oa cetic Acid Sa lt (6f). NMR (300 MHz,
DMSO): δ 9.25 (s, 2 H), 9.2 (s, 2H), 7.4 (t, 1 H), 7.2 (m, 6H),
3.8 (s, 3H), 2.95 (s, 3H), 2.75 (s, 3 H), 2.4 (s, 3 H) ppm. Anal.
(C23H22F2N4O4‚2C2HF3O2) C, H, N.
3-[[6-[2-Am in o-5-[a m in o(im in o)m et h yl]p h en oxy]-3,5-
d iflu or o-4-m et h ylp yr id in -2-yl]oxy]-N,N-d im et h ylb en z-
a m id e, 1.6 Hyd r a te, 0.17 Tr iflu or oa cetic Acid Sa lt, 0.8
Acetic Acid Sa lt (6g). NMR (300 MHz, DMSO): δ 8.8 (s, 4H),
7.49 (dd, 1H), 7.47 (s, 1H), 7.33 (t, 1H), 7.16-7.11 (m, 2H),
7.06 (s, 1H), 6.76 (d, 1H), 6.19 (s, 2H), 2.98 (s, 3H), 2.79 (s,
3H), 2.40 (s, 3H). Anal. (C22H21F2N5O3‚1.6H2O‚0.8C2H4O2‚0.17C2-
HF3O2) C, H, N.
3-[[6-[[5-[Am in o(im in o)m et h yl]-2-t r iflu or om et h ylsu l-
fon yla m in o]p h en oxy]-3,5-d iflu or o-4-m eth ylp yr id in -2-yl]-
oxy]-N,N-d im eth ylben za m id e, 0.2 Hyd r och lor id e (6h ).
NMR (300 MHz, DMSO): δ 8.93 (s, 2H), 8.52(s, 2H), 7.49-
7.47 (m, 3H), 7.26 (t, 1H), 7.10-7.03 (m, 2H), 6.98 (m, 1H),
2.95 (s, 3H), 2.78 (s, 3H), 2.34 (s, 3H). Anal. (C23H20F5N5O5S‚
0.2HCl) C, H, N.
3-[[6-[5-[Am in o(im in o)m eth yl]-2-h yd r oxyp h en oxy]-3,5-
d iflu or o-4-m et h ylp yr id in -2-yl]oxy]-N,N-d im et h ylb en z-
a m id e, 0.1 Hyd r a te, 0.9 Tr iflu or oa cetic Acid Sa lt, 0.76
Acetic Acid Sa lt (6i). NMR (300 MHz, DMSO): δ 9.03 (s,
2H), 8.75 (s, 2H), 7.6 (m, 2H), 7.3 (m, 1H), 7.1 (m, 4H), 2.95 (s,
3H), 2.75 (s, 3H), 2.37 (s, 3H). Anal. (C22H20F2N4O4‚0.1H2O‚
0.9C2HF3O2‚0.76C2H4O2) C, H, N, F.
3-[[6-[5-[Am in o(im in o)m eth yl]-2-m eth oxyph en oxy]-3,5-
d iflu or o-4-m et h ylp yr id in -2-yl]oxy]-N,N-d im et h ylb en z-
a m id e, 0.5 Hyd r a te, 1.5 Tr iflu or oa cetic Acid Sa lt (6j).
NMR (300 MHz, DMSO): δ 9.10 (s, 4H), 8.94 (s, 4H), 7.7 (m,
2-[5-[Am in o(im in o)m e t h yl]p h e n oxy]-6-[3-[(d im e t h -
yla m in o)ca r bon yl]p h en oxy]p yr id in e-4-ca r boxylic Acid ,
4 Hyd r a te, 3 Hyd r och lor ic Acid Sa lt (7c). NMR (300 MHz,
DMSO): δ 9.35 (s, 2H), 9.2 (s, 2H), 8.5 (br, 1H), 7-7.8 (m.
10H), 3.0 (s, 3H), 2.8 (s, 3H). Anal. (C22H20N4O5‚4H2O‚3HCl)
C, H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
[(d im eth yla m in o)ca r bon yl]p h en oxy]p yr id in e-4-ca r boxy-
lic Acid , 0.9 Hyd r a te, 1.3 Tr iflu or oa cetic Acid Sa lt (7d ).
NMR (300 MHz, DMSO): δ 11.21 (s, 1H), 9.16 (s, 2H), 9.04 (s,
2H), 7.7 (m, 2H), 7.43 (m, 1H), 7.1 (m, 6H), 3.05 (s, 3H), 2.85
(s, 3H). Anal. (C22H20N4O6‚0.9H2O‚1.3C2HF3O2) C, H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
(dim eth ylam in o)ph en oxy]pyr idin e-4-car boxylic Acid, 0.5
Hyd r a te, 2.2 Tr iflu or oa cetic Acid Sa lt (7e). NMR (DMSO-
d6): δ 9.1 (s, 2), 8.8 (s, 2), 7.6 (m, 2), 7.4 (t, 1), 7.0 (m, 6), 3.0
(s, 6). Anal. (C21H20N4O5‚2.2C2HF3O2‚0.5H2O) C, H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
(1H-im id a zol-1-yl)p h en oxy]p yr id in e-4-ca r boxylic Acid ,
Hyd r a te, 2.1 Tr iflu or oa cetic Acid Sa lt (7f). NMR (DMSO-
d6): δ 9.7 (s, 1), 9.0 (s, 2), 8.7 (s, 2), 8.2 (s, 1), 7.9 (s, 1), 7.6 (m,

Novel Series of Factor Xa Inhibitors
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 12 2493
of the S1-binding moiety in the 2,6-diphenoxypyridine series.
Book of Abstracts, 215th American Chemical Society National
Meeting, Dallas, TX, March 29-April 2 1998; American Chemi-
cal Society: Washington, DC; MEDI-123.
3), 7.3 (d, 1), 7.1 (s, 1), 7.0 (d, 1). Anal. (C22H17N5O5‚2.1C2-
HF3O2‚H2O) C, H, N.
2-[5-[Am in o(im in o)m eth yl]-2-h yd r oxyp h en oxy]-6-[3-(2-
m eth yl-1H-im id a zol-1-yl)p h en oxy]p yr id in e-4-ca r boxyl-
ic Acid , 2.5 Tr iflu or oa cetic Acid Sa lt, 1.5 Hyd r a te (7g).
NMR (300 MHz, DMSO): δ 9.02 (br s, 2), 8.78 (br s, 2), 7.80
(d, 1), 7.72 (d, 1), 7.52-7.64 (m, 3), 7.31-7.46 (m, 3), 7.09 (d,
2), 7.0 (d, 1), 2.46 (s, 3). Anal. (C23H19N5O5‚1.9H2O‚1.8C2HF3O2)
C, H, N.
(3) A communication introducing this material has been published.
Phillips, G. P.; Buckman, B. O.; Davey, D. D.; Eagen, K. A.;
Guilford, W. J .; Hinchman, J .; Ho, E.; Koovakkat, S.; Liang, A.;
Light, D. R.; Mohan, R.; Ng, H. P.; Post, J .; Smith, D.; Subra-
manyam, B.; Sullivan, M. E.; Trinh, L.; Vergona, R.; Walters,
J .; White, K.; Whitlow, M.; Wu, S.; Xu, W.; Morrissey, M. M.
The discovery of ZK807191: A potent, selective and orally active
inhibitor of factor Xa. J . Med. Chem. 1998, 41, 3557-3562.
(4) Light, D. R.; Guilford, W. J . Discovery of the Factor Xa Inhibitor,
ZK 807834 (CI 1031). Curr. Top. Med. Chem. 2001, 1, 121-136.
(5) Guilford, W. J .; Dallas, J .; Arnaiz, D. Synthesis of 13C3, 15N4-
labeled Factor Xa Inhibitor. J . Labelled Compd. Radiopharm.
2001, 44, 247-256.
2-[5-[Am in o(im in o)m eth yl]-2-h yd r oxyp h en oxy]-6-[3-(4-
m eth yl-1H-im id a zol-1-yl)p h en oxy]p yr id in e-4-ca r boxyl-
ic Acid , 3 Hyd r a te, 1.9 Tr iflu or oa cetic Acid Sa lt (7h ).
NMR (300 MHz, DMSO): δ 2.10 (s, 3), 6.93 (d, 1), 7.08 (m, 2),
7.23 (m, 1), 7.30-7.60 (m, 6), 7.85 (s, 3), 8.70 (br s, 2), 8.95 (br
s, 2). Anal. (C23H19N5O5‚3H2O‚1.9C2HF3O2) C, H, N.
2-[5-[Am in o(im in o)m eth yl]-2-h yd r oxyp h en oxy]-6-[3-(1-
m eth yl-1H-im id a zol-2-yl)p h en oxy]p yr id in e-4-ca r boxyl-
ic Acid , 2.1 Tr iflu or oa cetic Acid Sa lt, 0.9 Hyd r a te (7i).
NMR (300 MHz, DMSO): δ 3.79 (s, 3), 6.90 (d, 1), 7.08 (m, 2),
7.36-7.42 (m, 1), 7.46-7.62(m, 5), 7.68 (d, 1), 7.73 (d, 1), 8.63
(br s, 2), 8.95 (br s, 2). Anal. (C23H19N5O5‚0.9H2O‚2.1C2HF3O2)
C, H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
(2,4-d im eth yl-1H-im id a zol-1-yl)p h en oxy]p yr id in e-4-ca r -
boxylic Acid , 1.5 Tr iflu or oa cetic Acid Sa lt, 2.5 Hyd r a te
(7j). NMR (300 MHz, DMSO): δ 2.21 (s, 3), 2.40 (s, 3), 6.95
(d, 1), 7.08 (s, 2), 7.20-7.34 (m, 4), 7.41-7.60 (m, 3), 8.15 (br
s, 2), 8.90 (br s, 2). Anal. (C24H19N5O5‚2.5H2O‚1.5C2HF3O2) C,
H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
(4,5-d ih yd r o-1H -im id a zol-2-yl)p h en oxy]p yr id in e-4-ca r -
boxylic Acid , 1.7 Tr iflu or oa cetic Acid Sa lt, 2.6 Hyd r a te
(7k ). NMR (300 MHz, DMSO): δ 3.95 (br s, 4), 7.05 (d, 2),
7.08 (d, 2), 7.40-7.75 (m, 7), 8.80 (br s, 2), 9.03 (br s, 2), 10.50
(br s, 2). Anal. (C22H18N5O5‚2.6H2O‚1.7C2HF3O2) C, H, N, F.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
(4,5-d ih yd r o-4,4-d im eth yl-1H-im id a zol-2-yl)p h en oxy]p y-
r id in e-4-ca r boxylic Acid , 2 Tr iflu or oa cetic Acid Sa lt,
Hyd r a te (7m ). NMR (300 MHz, DMSO): δ 1.40 (s, 6), 3.75
(s, 2), 7.04-7.09 (m, 3), 7.46-7.76 (m, 6), 8.80 (br s,2), 9.05
(br s, 2), 10.45 (br s, 1), 10.75 (br s, 1). Anal. (C24H23N5O5‚
1.1H2O‚2C2HF3O2) C, H, N.
2-[5-[Am in o(im in o)m et h yl]-2-h yd r oxyp h en oxy]-6-[3-
[(2-a m in oet h yl)a m in o]p h en oxy]p yr id in e-4-ca r b oxylic
Acid , 1.5 Tr iflu or oa cetic Acid Sa lt (7n ). NMR (300 MHz,
DMSO): δ 2.95 (m, 2), 3.31 (m, 2), 6.32-6.42 (m, 2), 6.46-
6.56 (m, 1), 6.80 (s, 1), 6.90 (s, 1), 7.06-7.18 (m, 2), 7.61-7.90
(m, 4), 8.78 (br s, 2), 9.10 (br s, 2). Anal. (C21H21N5O5‚2H2O‚
1.5C2HF3O2) C, H, N.
(6) Pinner, A.; Klein. F. Ber. 1883, 16, 1643.
(7) (a) Mares-Guia, M.; Shaw, E. Studies on the Active Center of
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J .; Markwardt, F.; Walsmann, P. Synthetic Inhibitors of Serine
Proteinases. XIV Inhibition of Factor Xa by Derivatives of
Benzamidine. Thromb. Res. 1976, 9, 637-646. (c) Walsmann,
P. Inhibition of serine proteinases by benzamidine derivatives.
Acta Biol. Med. Germ. 1977, 36, 1931-1937.
(8) Choi-Sledeski, Y. M.; McGarry, D. G.; Green, D. M.; Mason, H.
J .; Becker, M. R.; Davis, R. S.; Ewing, W. R.; Dankulich, W. P.;
Manetta, V. E.; Morris, R. L.; Spada, A. P.; Cheney, D. L.; Brown,
K. D.; Colussi, D. J .; Chu, V.; Heran, C. L.; Morgan, S. R.;
Bentley, R. G.; Leadley, R. J .; Maignan, S.; Guilloteau, J .-P.;
Dunwiddie, C. T.; Pauls, H. W. Sulfonamidopyrrolidinone Factor
Xa Inhibitors: Potency and Selectivity Enhancements via P-1
and P-4 Optimization. J . Med. Chem. 1999, 42, 3572-3587.
(9) Shaw, K. J .; Guilford, W. J .; Griedel, B.; Sakata, S.; Trinh, L.;
Wu, S.; Xu, W.; Zhao, Z.; Morrissey, M. M. Benzimidazole-Based
fXa Inhibitors with Improved Thrombin and Trypsin Selectivity.
Bioorg. Med. Chem. Lett. 2002, 12, 1311-1314.
(10) Wu, S.; Guilford, W. J .; Chou, Y.-L.; Griedel, B.; Liang, A.;
Sakata, S.; Shaw, K. J .; Trinh, L.; Xu, W.; Zhao, Z.; Morrissey,
M. M. Design and Synthesis of Aminophenol-Based Factor Xa
Inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 1307-1310.
(11) Whitlow, M.; Arnaiz, D.; Buckman, B. O.; Davey, D. D.; Griedel,
B.; Guilford, W. J .; Koovakkat, S. K.; Liang, A.; Mohan, R.;
Phillips, G. P.; Seto, M.; Shaw, K. J .; Xu, W.; Zhao, Z.; Light, D.
R.; Morrissey, M. M. Crystallographic Analysis of potent and
selective factor Xa Inhibitors complexed to bovine trypsin. Acta
Crystallogr. 1999, D55, 1395-1404.
(12) Renatus, M.; Bode, W.; Huber, R.; Sturzebecher, J .; Stubbe, M.
T. Structural and Functional Analyses of Benzamidine-based
Inhibitors in Complex with Trypsin: Implications for the Inhibi-
tion of Factor Xa, tPA, and Urokinase. J . Med. Chem. 1998, 41,
5445-5456.
(13) Adler, M.; Davey, D. D.; Phillips, G. B.; Kim, S. H.; J ancarik, J .;
Rumennik, G.; Light, D. R.; Whitlow, M. Preparation, Charac-
terization, and the Crystal Structure of the Inhibitor ZK-807834
(CI-1031) Complexed with Factor Xa. Biochemistry 2000, 12534-
12542.
(14) Maignan, S.; Guilloteau, J . P.; Pouzieux, S.; Choi-Sedeski, Y.
M.; Becker, M. R.; Klein, S. I.; Ewing, W. R.; Pauls, H. W.; Spada,
A. P.; Mikol, V. Crystal Structures of Human Factor Xa Com-
plexed with Potent Inhibitors. J . Med. Chem. 2000, 43, 3226-
3232.
(15) Ng, H. N.; Buckman, B. O.; Eagen, K. A.; Guilford, W. J .;
Kochanny, M. J .; Mohan, R.; Shaw, K. J .; Wu, S. C.; Lentz, D.;
Liang, A.; Trinh, L.; Ho, E.; Smith, D.; Subramanyam, B.;
Vergona, R.; Walters, J .; White, K. A.; Sullivan, M. E.; Morrissey,
M. M. Phillips, G. B. Design, Synthesis and Biological Activity
of Novel Factor Xa Inhibitors. 4-Aryloxy Substituents of 2,6-
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Refer en ces
(1) Phillips, G. B.; Davey, D. D.; Eagen, K. A.; Koovakkat, S.; Liang,
A.; Ng, H. P.; Pinkerton, M.; Trinh, L.; Whitlow, M.; Beatty, A.
M.; Morrissey, M. M. Design, Synthesis, and Activity of a Novel
Series of Factor Xa Inhibitors. J . Med. Chem. 1999, 42, 1749-
1756.
(2) Some of these data have been previously reported. Xu, W.;
Davey, D. D.; Eagen, K.; Guilford, W. J .; Ng, H.; Phillips, G. B.;
Pinkerton, M.; Wu, S. C.; Liang, A.; Trinh, L.; Hinchman, J .;
Post, J .; Sullivan, M. E.; Morrissey, M. M. Design, synthesis and
biological activity of novel factor Xa inhibitors. 3. Optimization
J M0200660