Discovery of 1-(2-Aminomethylphenyl)-3-trifluoromethyl-N-[3-fluoro-2′ -(aminosulfonyl)[1,1′-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor

Article abstract of DOI:10.1021/jm030212h

Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recentl

Full text of DOI:10.1021/jm030212h

5298
J . Med. Chem. 2003, 46, 5298-5315
Articles
Discover y of 1-(2-Am in om eth ylp h en yl)-3-tr iflu or om eth yl-N-
[3-flu or o-2′-(a m in osu lfon yl)[1,1′-bip h en yl)]-4-yl]-1H-p yr a zole-5-ca r boxya m id e
(DP C602), a P oten t, Selective, a n d Or a lly Bioa va ila ble F a ctor Xa In h ibitor 1
J ames R. Pruitt,† Donald J . P. Pinto,* Robert A. Galemmo, J r.,‡ Richard S. Alexander, Karen A. Rossi,
Brian L. Wells, Spencer Drummond, Lori L. Bostrom, Debra Burdick, Robert Bruckner, Haiying Chen,
Angela Smallwood, Pancras C. Wong, Matthew R. Wright, Steven Bai, J oseph M. Luettgen, Robert M. Knabb,
Patrick Y. S. Lam, and Ruth R. Wexler
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, 31 Pennington-Rocky Hill Road,
Pennington, New J ersey 08534
Received April 30, 2003
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic
pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective
treatment for both venous and arterial thrombosis. We recently described a series of meta-
substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor
Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of
our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole
derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor
Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds
are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this
series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue,
as a highly potent, selective, and orally bioavailable factor Xa inhibitor.
In tr od u ction
Two classes of antithrombotic agents are used in the
treatment and prevention of thromboembolic diseases,
antiplatelet agents and anticoagulants. Antiplatelet
agents block platelet activation and aggregation. Anti-
coagulants inhibit thrombin generation and fibrin for-
mation. The limitations of current anticoagulant thera-
pies, such as unfractionated heparin, warfarin, and low-
molecular weight heparins, have led to the research and
development of new anticoagulants.2 Warfarin, the only
marketed oral anticoagulant, is prescribed for a growing
number of indications but takes several days to reach
therapeutic levels and has a narrow therapeutic index.3
It has been our desire to develop safe and efficacious
orally active anticoagulants that require less rigorous
patient monitoring.
The coagulation cascade provides many opportunities
to intervene and therefore expand current anticoagulant
therapies. Factor Xa, a trypsin-like serine protease, is
situated at the critical juncture between the intrinsic
and extrinsic pathways, catalyzing the conversion of
prothrombin to thrombin, and hence plays a pivotal role
in the final common pathway of the cascade4 and has
become an important target in the discovery and
development of new anticoagulants. As factor Xa (fXa)
F igu r e 1. Structural scaffold for SAR.
precedes thrombin in the coagulation cascade, inhibitors
of fXa could be more effective in attenuating thrombotic
disorders. Additionally, since fXa inhibitors affect co-
agulation specifically, but not platelet function, this
mechanism should have less propensity to increase
abnormal bleeding.5
Selectivity has been one of the key issues in the design
of small molecule inhibitors of serine proteases. Histori-
cally, the substrate specificity of the S1 subsite of the
trypsin-like serine proteases of the coagulation cascade
for the cationic arginine has presented a significant
problem for the development of therapeutically useful
inhibitors of this class of enzyme.6 In addition, the early
cationic inhibitors had poor oral absorption and rela-
tively short duration of action.7 The effort to develop
selective thrombin and fXa inhibitors with good oral
bioavailability and useful duration of action in vivo has
evolved from the use of charged compounds incorporat-
ing cationic guanidine and amidine functionality as
ligands to compounds using neutral or less basic aryl
or heteroaryl functionality at P1.8,9 Initial success at
replacing the benzamidine with a benzylamine, while
* To whom correspondence should be addressed. Tel.: (609) 818-
5295. Fax: (609) 818-3460. E-mail: Donald.Pinto@bms.com.
† Current address: Incyte Corporation, Newark, DE.
‡ Current address: R. W. J ohnson Pharmaceutical Research Insti-
tute, Spring House, PA.
10.1021/jm030212h CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/29/2003

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5299
Sch em e 1. Synthesis of the 1-(Methoxyphenyl)-3-methylpyrazole Analoguesa
a
Reagents: (a) AcOH, reflux; (b) Al(Me)3/CH2Cl2; (c) TFA, reflux; (d) BBr3/CH2Cl2.
Sch em e 2. Synthesis of the
maintaining fXa potency and enhancing the PK profile,
was accomplished in our laboratories with DPC423.10
Our laboratories10,11 and others12 have reported on less
basic surrogates for benzamidines such as 2-aminoiso-
quinoline and 3-aminobenzisoxazole and neutral inhibi-
tors13,14 of fXa. In this paper we report on our continuing
efforts to discover benzamidine surrogates with im-
proved selectivity over trypsin and other serine pro-
teases and with good ADME properties. Specifically as
shown in Figure 1, we sought to build on the structural-
activity relationships already discovered with the
DPC423 scaffold10 and scan for non-amidino P1 groups.
This work resulted in the discovery of DPC602, a
2-(aminomethyl)phenylpyrazole analogue as, a potent,
selective and orally bioavailable inhibitor of factor Xa.
1-(4-Methoxyphenyl)-3-(trifluoromethyl)Pyrazole
Analoguesa
Ch em istr y
The required ethyl-1-phenyl-3-methyl-5-carboxypyra-
zoles (3, Scheme 1) were prepared regioselectively from
a condensation of the appropriate phenylhydrazine 1
and ethyl 2-(N-methoxyimino)-4-oxopentanoate 2.10,15
Coupling of ester 3 with the known amines 4 by
pretreatment of 4 with trimethylaluminum16 and heat-
ing the mixture in toluene gave good yields of the amide
5. Deprotection of the tert-butylsulfonamide moiety, by
treatment with trifluoroacetic acid, afforded compounds
6a -f. Treatment of the methoxy-substituted precursor
compounds 6b-d with excess boron tribromide17 af-
forded the phenolic analogues 7a -c.
The 3-trifluoromethylpyrazole analogues 13a -c were
prepared by the method outlined in Scheme 2. Conden-
sation of 4-methoxyphenylhydrazine 8 with 1,1,1-tri-
fluoro-2,4-pentanedione 910 in refluxing methoxyethanol
afforded the 5-methylpyrazole 10. The 5-methyl group
was oxidized in four steps to the corresponding carbox-
a
Reagents: (a) MeOCH2CH2OH, AcOH, reflux; (b) NBS, ben-
zoyl peroxide, CCl4; (c) KOAc, 18-crown-6, MeCN; (d) IR400 resin,
MeOH; (e) NaIO4, cat. RuCl3, MeCN, 0 °C; (f) oxalyl chloride; (g)
cat. DMAP, pyridine, CH2Cl2; (h) TFA, reflux.
ylic acid. This was achieved via a NBS-mediated bro-
mination to the bromomethyl group, followed by trans-
formation to the O-acetyl derivative by displacement of
the bromine with potassium acetate (activated by 18-
crown-6) in acetonitrile. Conversion of the acetate
derivative to the alcohol with acidic resin followed by

5300 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Pruitt et al.
Sch em e 3. Synthesis of the 1-[3-(Aminomethyl)-4-methoxyphenyl]-3-methylpyrazole 18a
a
Reagents: (a) AcOH, H2O, reflux; (b) iBuOCOCl, NMM, THF; (c) NaBH4, THF, H2O; (d) MsCl, Et3N, CHCl3; (e) NaN3, DMSO; (f) 50%
aq NaOH, EtOH, H2O; (g) oxalyl chloride; (h) cat. DMAP, Et3N, CHCl3; (i) SnCl2 dihydrate, MeOH; (j) TFA, reflux.
oxidation with ruthenium chloride/sodium periodate
afforded the carboxylic acid derivative 11. Compound
11 was converted to the acyl chloride by treatment with
oxalyl chloride and coupled with amines 4a -d in the
presence of N,N-dimethylaminopyridine and pyridine in
dichloromethane to afford compounds 12a -d . Further
treatment of 12a -c with trifluoroacetic acid provided
sulfonamide compounds 13a -c.
Compound 18 was prepared by the reaction of 3-car-
boxy-4-methoxyphenylhydrazine 14 with ethyl 2-(N-
methoxyimino)-4-oxopentanoate 2 to afford the carboxy-
functionalized phenylpyrazole ester 15 (Scheme 3).
Transformation of this benzoic acid to the benzylic azide
16 was accomplished by sequential sodium borohydride
reduction of the mixed anhydride and mesylation of the
resulting alcohol with methansulfonyl chloride followed
by treatment with sodium azide. Pyrazole ester saponi-
fication, acid chloride formation, and subsequent cou-
pling to biphenylamine 4a afforded compound 17.
Reduction of the benzylic azide 17 with stannous
chloride18 and final deprotection of the tert-butyl-
sulfonamide with trifluoroacetic acid provided com-
pound 18.
Refluxing a mixture of the 2-carboxy-4-methoxy-
phenylhydrazine 19 with ethyl 2-(N-methoxyimino)-4-
oxopentanoate 2 in a mixture of acetonitrile and acetic
acid afforded a mixture (1:1) of pyrazole derivatives 20
and 21 (Scheme 4). Formation of the mixed anhydrides
of compounds 20 and 21, followed by sodium boro-
hydride reduction, afforded the benzylic alcohols com-
pounds 22 and 23. A small amount (10%) of the ring-
closed lactone derivative 24 was also isolated. The
desired phenyl pyrazole 22 was isolated by flash chro-
matography and then transformed to a benzylic azide
by mesylation of the alcohol and azide displacement.
Saponification of the pyrazole ester afforded compound
25, which was transformed to the acid chloride and
coupled with the phenyl aniline derivative 4a to afford
compound 26. The azide functionality of 26 was reduced
to the benzylic amine with tin(II) chloride dihydrate and
then refluxed with TFA to afford sulfonamide compound
27.
Analogues 33a ,b and 34a ,b were prepared according
to the route outlined in Scheme 5. A mixture of 5-meth-
oxy-2-hydrazinobenzoic acid 19 and 1,1,1-trifluoro-4-
(furan-2-yl)-2,4-butanedione 28 was heated at reflux in
acetic acid to afford the 5-furanylpyrazole compound
29a in good yield. The benzoic acid functionality from
compound 29a was transformed to the benzylic azide
compound 30a . Oxidation of the furan moiety of com-
pound 30a to the carboxylic acid, followed by the acid
chloride formation and coupling with the appropriate
biphenylamine 4a ,c-e afforded the azide compounds
32a -d . Subsequent reduction with tin(II) chloride af-
forded compounds 33a ,b. The sulfonamide analogues
32c,d were similarly reduced and deprotected with TFA
to afford compounds 34a ,b.
DP C 602 was also synthesized via the methodology
outlined in Scheme 5. Other analogues lacking the
4-methoxyphenyl P1 substituent were similarly synthe-
sized via a modified approach outlined in Scheme 6.
2-Hydrazinobenzoic acid compound 35 and 1,1,1-tri-
fluoro-4-(furan-2-yl)-2,4-butanedione 28 were condensed
at reflux in acetic acid. The resulting carboxylic acid was
transformed into the acyl chloride and quenched with
aqueous ammonia to afford amide derivative 36. Dehy-
dration of 36 with trichloroacetyl chloride in the pres-
ence of excess triethylamine afforded the nitrile inter-
mediate, which was reduced to the amine with cobalt(II)
chloride and sodium borohydride,19 and protected to
afford compound 37. The furan moiety of compound 37
was oxidized with potassium permanganate20a,b to afford

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5301
Sch em e 4. Synthesis of the 1-[2-(Aminomethyl)-4-methoxyphenyl]-3-methylpyrazole 27a
a
i
Reagents: (a) AcOH, MeCN, reflux; (b) BuOCOCl, NMM, THF; (c) NaBH4, THF, H2O; (d) MsCl, Et3N, CHCl3; (e) NaN3, DMSO; (f)
50% aq. NaOH, EtOH, H2O; (g) oxalyl chloride; (h) cat. DMAP, Et3N, CHCl3; (i) SnCl2 dihydrate, MeOH; (j) TFA, reflux.
the carboxylic acid derivative 38. Subsequent acyl
chloride formation and coupling with amines 4a ,c-e
and deprotection with TFA afforded the desired benzyl-
amine analogues 40a -d .
To prepare the two-carbon homologue side chain
(Scheme 8), the mixed anhydride of carboxylic acid 41
was reduced to the alcohol, converted to the mesylate,
and displaced with cyanide to give the nitrile 47. The
furan moiety of 47 was oxidized to the carboxylic acid
with buffered sodium chlorite, converted to the acyl
chloride, and coupled with amine 4d to afford compound
48. Catalytic reduction of the nitrile of 48 gave the
desired amine analogue 49.
The alkylated benzylamine analogues 45a -d were
prepared following the sequence outlined in Scheme 7.
The 2-(2-methoxycarbonyl-phenyl)-5-trifluoromethyl-
2H-pyrazole-3-carboxylic acid (42) was obtained via a
sequence of reactions as described previously for inter-
mediate 36 (Scheme 5). In this particular case 2-hy-
drazinobenzoic acid was condensed with trifluoromethyl
intermediate 28 to afford the pyrazolyl intermediate 41
which was immediately converted to the ester via the
acid chloride/methanol methodology. Oxidation of the
furyl functonality as previously described afforded the
desired carboxylic derivative 42. This was then was
coupled to the biphenylamine 4d via the acyl chloride
to afford the compound 43. Saponification of the ester
moiety, mixed anhydride formation, reduction to the
benzylic alcohol, and subsequent MnO2 oxidation af-
forded key aldehyde intermediate 44. The alkylated
amines 45a -d , were obtained via the reductive ami-
nation of 44 with methylamine, dimethylamine, iso-
propylamine, or benzylamine. A Horner-Emmons reac-
tion of 44 with diethylphosphonoacetonitrile followed by
hydrogenation of the acrylonitrile side chain in the
presence of TFA afforded the propylamine compound 46.
Resu lts a n d Discu ssion
The discovery of DPC423 (fXa Ki ) 0.15 nM) from
these laboratories had successfully shown that it was
possible to replace the more polar meta-benzamidine
(pKa ∼ 10.7) with a less basic meta-benzylamine (pKa
∼ 8.8) in the P1 position. Although DPC423 was
selective (>1000-fold) against thrombin and other serine
proteases, the selectivity against trypsin was only 400-
fold (DPC423 trypsin Ki ) 60 nM). While this was not
a concern for us in the development of DPC423, the
potential concern about long-term inhibition of trypsin
made it necessary for us to identify a DPC423 follow-
on with a much improved trypsin selectivity profile. To
achieve greater fXa selectivity while maintaining a good
pharmacokinetic profile, we chose to modify the P1
moiety of our existing series of 1-phenylpyrazole-5-
carboxamides. As a starting point, in these modifications

5302 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Pruitt et al.
Sch em e 5. Synthesis of the 1-[2-(Aminomethyl)-phenyl-3-(trifluoromethyl)Pyrazole Analogue. Synthesis of DPC602a
a
Reagents: (a) AcOH, reflux; (b) iBuOCOCl, NMM, THF; (c) NaBH4, THF, H2O; (d) MsCl, Et3N, CHCl3; (e) NaN3, DMSO; (f) KMnO4,
H2O, acetone; (g) oxalyl chloride; (h) cat. DMAP, Et3N, CH2Cl2; (i) SnCl2 dihydrate, MeOH; (j) TFA, reflux; (k) 10%Pd/C, MeOH, HCl.
we compared the fXa bound X-ray structures of DPC423
with TAP (tick anticoagulant protein, Figure 2). The
TAP structure reveals a hydrogen bond interaction of
the tyrosyl (hydroxyl) moiety of TAP with Asp189 of
fXa.21 In contrast, the highly optimized DPC423 has the
benzylamine P1 substituent interacting with Asp189 in
fXa, just as we had previously seen in the trypsin bound
complex,10 and the benzylamine is within hydrogen
bonding distance with the carbonyl of Gly218. Both
compounds are potent inhibitors of factor Xa. Intrigued
by the differences in binding modes for these two
different, yet potent fXa molecules, we reasoned that
either replacing our benzylamine with a 4-methoxy- or
4-hydroxyphenylpyrazole substituent or repositioning of
the methylamine P1 moiety might afford potent factor
Xa inhibitor. To test the first part of this hypothesis,
we incorporated a hydroxyl or a methoxyl functionality
on the P1 phenyl ring of the pyrazole template and
compared it with the highly potent benzamidine ana-
logues SN429 and DPC423 (Table 1).
compound when compared to other methoxyphenyl P1
regioisomers. Additionally, these compounds are weak
inhibitors of serine protease enzymes thrombin and
trypsin. Compound 6d is a considerably weaker inhibi-
tor of fXa (Ki ) 11 nM) when compared to the benz-
amidine compound SN429 (fXa Ki ) 0.01 nM) and the
m-benzylamine compound DPC423 (fXa Ki ) 0.15 nM).
The loss in fXa potency for 6d relative to SN429 and
DPC423 may be due to a weak hydrogen bond interac-
tion of the 4-methoxy functionality of 6d with Asp189.
The importance of the 4-methoxy moiety is further
evident by the significant loss in fXa potency for the
unsubstituted phenylpyrazole compound 6a (fXa Ki )
198 nM). While compound 6a is not as potent as
compound 6d , it still elicits binding affinity to the fXa
enzyme. This result is a further illustration of the
optimized conformation of our rigid pyrazole molecules
in the fXa enzyme active site. Also in contrast to
compound 6d , the other methoxyphenyl regioisomers,
compounds 6b (fXa Ki > 30 000 nM) and 6c (fXa Ki )
110 nM), along with the 2-hydroxyphenyl analogue 7a
(fXa Ki ) 1200 nM), the 3-hydroxyphenyl analogue 7b
The data in Table 1 shows the 4-methoxyphenyl P1
analogue 6d (fXa Ki ) 11 nM) as the most potent

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5303
Sch em e 6. Synthesis of the 1-[2-(aminomethyl)Phenyl]-3-(trifluoromethyl)Pyrazole Analoguesa
a
Reagents: (a) AcOH, reflux; (b) SOCl2; (c) aq. NH3; (d) Cl3CCOCl, Et3N, CH2Cl2; (e) NaBH4, CoCl2; (f) aq HCl; (g) Boc2O; (h) KMnO4;
(i) oxalyl chloride; (j) DMAP; (k) TFA.
Sch em e 7. Synthesis of the Alkylated 2-(Aminoalkyl) Analoguesa
a
Reagents: (a) oxalyl chloride; (b) MeOH; (c) KMnO4, H2O, acetone; (d) oxalyl chloride; (e) cat. DMAP, Et3N, CH2Cl2; (f) NaOH, MeOH;
(g) iBuOCOCl, NMM, THF; (h) NaBH4, H2O; (i) MnO2, CH2Cl2; (j) HNR2, MeOH; (k) NaBH4, MeOH; (l) NaH, EtO2P(O)CH2CN, DMF; (m)
H2, 10% Pd-C, 2% TFA, MeOH.
(fXa Ki ) 164 nM), and 4-hydroxyphenyl analogue 7c
(fXa Ki ) 900 nM), are weak inhibitors of fXa. This
suggests that these weak inhibitors do not effectively
interact with Asp189 but maintain other important
interactions with the protein.
To further optimize compound 6d , we employed the
strategy of modifications on the pyrazole template and
the biphenyl portion of the compound, that was suc-
cessfully used to identify our earlier compound DPC42310
(Table 2). As we had previously observed with the meta-

5304 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Sch em e 8. Synthesis of the 2-(aminoethyl) Analog 49a
Pruitt et al.
a
Reagents: (a) iBuOCOCl, NMM, THF; (b) NaBH4, MeOH; (c) MsCl, Et3N, CH2Cl2; (d) KCN, Et4NBr, H2O, toluene; (e) NaClO2, NaH2PO4,
MeCN, H2O; (f) oxalyl chloride; (g) cat. DMAP, Et3N, CH2Cl2; (h) H2, 10% Pd-C, 2% TFA, MeOH.
F igu r e 2. X-ray structure of N-terminal tripeptide sequence of Tick Anticoagulant Protein (orange) in fXa with an overlay of a
structure of DPC423 (magenta).
benzylamine series of DPC423, incremental fXa potency
increases was seen in the p-methoxyphenyl P1 pyrazole
series in going from the C-3 methyl analogue 6d to the
C-3 trifluoromethylpyrazole analogue 13a . In the case
of the P4 substitution, compound 6f showed a 2-fold
improvement over 6d . However in the C-3 trifluoro-
methylpyrazole series, the changes in the P4 substituent
did not further improve binding affinity. In addition,
in the clotting assay (APTT, activated partial throm-
boplastin time), compounds 13a (IC2x ) 103.7 µM), 13b
(IC2x ) 18.8 µM) and 12d (IC2x ) 64.9 µM) were poor
when compared to SN429 (IC2x ) 0.44 µM) and DPC423
(IC2x ) 4.86 µM). This may be attributable to the high
protein binding (>98%) exhibited by these molecules.
The above not withstanding, we evaluated the phar-
macokinetics for a select set of neutral compounds
(Table 3). The data shows an overall improvement in
pharmacokinetics for the neutral compounds when
compared to highly basic benzamidine SN429 (pKa ∼
10.7). The hallmark feature for compounds 6d and 6e
was the decreased clearance (Cl) and low volume of
distribution (Vdss). In addition, the good Caco-2 perme-
ability for neutral compound 6d (Papp ) 51 × 10-6 cm/
s) was predictive of its good oral bioavailability (F )
48%). In terms of half-life, compound 13b was best;
however, the oral bioavailability for this compound was
not determined but was expected to be poor based on
its low Caco-2 Papp value.
In the SAR development of the m-benzylamine pyra-
zole series which led to the clinical compound DPC423,10
we had previously found that the 3-aminomethyl-
phenylpyrazole P1 substituent was an effective ligand
for S1 binding interaction with Asp189.10 This is exem-
plified by the fXa activity for compound 51 (Table 4, fXa
Ki ) 2.7 nM). In our desire to achieve further enhance-
ment of fXa potency in our p-methoxyphenyl pyrazole

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5305
Ta ble 1. In Vitro fXa Activity of Substituted Phenyl P1 Pyrazole Analogues
human fXaa
human thrombina
human trypsina
compd
6a
6b
6c
6d
7a
7b
7c
R
Ki (nM)
Ki (nM)
Ki (nM)
H
198
>30000
110
11
1200
164
900
0.15
0.013
>21000
>21000
>21000
>21000
>21000
>21000
>21000
6000
>1500
>1500
>1500
>1500
>1500
>1500
>1500
60
2-OMe
3-OMe
4-OMe
2-OH
3-OH
4-OH
-
DPC423
SN429
3-(CdN)NH2
300
16
a
Human purified enzymes were used. Ki values are averaged from multiple determinations (n ) 2), and the standard deviations are
<30% of the mean. Ki’s were measured as in refs 10 and 22.
Ta ble 2. In Vitro Factor Xa Activity of p-Methoxyphenyl Pyrazole Analogues
human fXaa
human thrombina
human trypsina
human APTTb
compd
R
X
Y
Ki (nM)
Ki (nM)
Ki (nM)
IC2x (µM)
6d
6e
6f
13a
13b
13c
12a
CH3
CH3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
C-H
N
C-F
C-H
N
C-F
C-F
C-H
C-F
NH2
NH2
NH2
NH2
NH2
NH2
CH3
NH2
CH3
11
16
>21000
>21000
>21000
>21000
>21000
>21000
>21000
300
>1500
>1500
>1500
>1500
>1600
NT
>2500
16
60
NT
NT
NT
103.7
18.8
NT
64.9
0.44
4.86
5.3
3.5
2.8
4.2
3.6
0.013
0.15
SN429 (amidine)
DPC423 (benzylamine)
6000
a
Human purified enzymes were used. Ki values are averaged from multiple determinations (n ) 2) and the standard deviations are
b
<30% of the mean. Ki’s were measured as in refs 10 and 22. APTT measurements were performed as in ref 26a,b. NT ) not tested.
Ta ble 3. In Vivo Dog Pharmacokinetics of Neutral and Basic
phenyl ring. Compound 27 produced a 3-fold improve-
Factor Xa Inhibitors
ment in fXa Ki (Ki ) 3.8 nM) when compared to
Cla
(L/h/kg)
iv
t1/2
Cmax
Vdss
Caco-2c
a
a
a
compound 6d and a 70-fold improvement over its
regioisomer 18. The high serine protease selectivity was
also maintained. A further benefit was also evident in
the improved in vitro potency in the clotting assay
(APTT IC2x ) 12 µM).
The discovery of the 2-aminomethyl-4-methoxyphenyl
P1 group, allowed us to explore C-3 modifications on
the pyrazole core and the P4 biphenyl group in an effort
to further improve potency (Table 5). Incremental
improvements in binding affinity were observed for
changes made with the trifluoromethyl group at R1,
compound 34a ; the addition of a fluorine atom at R3,
compound 34b; and the choice of an o-sulfonylmethyl-
phenyl P4 substituent (compound 33a ). Combining the
best features from these compounds produced sub-
nanomolar inhibtors 34b (fXa Ki ) 0.88 nM) and 33b
(fXa Ki ) 0.54 nM) with good overall selectivity for fXa.
(h)
iv
(µM) (L/kg) Papp × 10-6 %Fb
compd
iv
iv
cm/s
po
48
ND
ND
4.4
6d
6e
13b
SN429
0.09
0.08
0.12
0.67d
4.46
4.33
6.0
3.86
3.96
0.73
2.9d
0.52
0.4
51
1.1
< 0.1
0.3
1.8
0.82d
0.29d
a
b
IV dose 1 mg/kg/h. Oral dose 4 mg/kg. IV dose 0.5 mg/kg/hr.
ND ) not determined. c Caco-2 was measured as in ref 27.
Reference 10.
d
series, we sought to combine the P1 phenyl substituents
from 6d and 51 into a molecule such as compound 18.
Unfortunately, compound 18 was found to be a consid-
erably weaker inhibitor (fXa Ki ) 270 nM). With this
result, we reasoned that an internal H-bond between
the vicinal 3-aminomethyl moiety and the oxygen atom
of the 4-methoxyphenyl substituent precluded an effec-
tive interaction of the P1 with Asp 189 in the S1 pocket.
This hypothesis was confirmed by the repositioning of
the aminomethyl P1 moiety to the 2-position of the P1
Noteworthy is the data for pyrazole analogues 40a -d
lacking the p-methoxy substituent which were shown

5306 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Ta ble 4. In Vitro fXa Activity of Benzylamine P1 Analogues
Pruitt et al.
amine inhibitors of factor Xa, we compared the X-ray
structure of compound 40c complexed to human factor
Xa to that of DPC423 in fXa (Figure 3). The crystal
structure of DPC423 in fXa was resolved to a 2.15 Å
resolution with a crystallographic R-factor of 0.222. The
crystal structure of 40c in fXa was resolved to a 1.9 Å
resolution with a crystallographic R-factor of 0.224. The
overall binding mode of the inhibitors was quite similar
to the mode observed in trypsin pyrazole-based inhibitor
complexes that were studied previously.10 Outside of the
S1 pocket, the interactions between DPC423 and those
of 40c and factor Xa are essentially identical. For the
pyrazole template, a close contact is observed between
the N2 nitrogen on the pyrazole ring and the backbone
amide nitrogen of Gln192. This pyrazole nitrogen is also
in close proximity to the disulfide bond between residues
191 and 220. In the linker region, the amide carbonyl
interacts with Gly216 directly and also through a water
molecule. The amide proton interacts in a similar
manner with Gly218. The biphenyl P4 moieties of both
these inhibitors are neatly tucked between Tyr99,
Phe174, and Trp215 in the S4 region. No direct interac-
tion is observed between the inhibitor and Ser195 of the
catalytic triad.
a
Human purified enzymes were used. Ki values are averaged
from multiple determinations (n ) 2) and the standard deviations
are <30% of the mean. Ki’s were measured as in refs 10 and 22.
b
APTT measurements were performed as in ref 26a,b. NT ) not
tested.
to be equipotent with analogous compounds 33a and
34a ,b which contain the 4-methoxy moiety. These data
suggest that the 2-aminomethyl P1 ligand binds strongly
to the S1 region of the enzyme, essentially negating the
contribution from the 4-methoxyl substituent. We were
gratified to observe that for compounds 40a -d , high
selectivity for fXa relative to trypsin was maintained.
Although 3-fold less potent than DPC423, the selectivity
of compounds 40a -d was viewed as an asset. Extension
of the 2-aminoalkyl moiety as in 46 and 49 (Table 6)
significantly decreased the fXa potency. Alkylamino
compounds 45a -d were less active. It therefore appears
that the 2-aminomethylphenyl P1 pyrazole substitution
was optimal for binding to factor Xa.
Although the benzylamine P1 of both inhibitors
interacts with the carboxylate of Asp189, they do so in
a slightly different manner. A small rotation is observed
for the phenyl ring in compound 40c. The P1 o-
aminomethyl moiety in compound 40c fits in the S1
pocket and interacts with Asp189. The carbon of the
aminomethyl moiety is close to the wall of the S1 pocket
near residue Gly218. In contrast, the m-benzylamine
binds with the carbon of the aminomethyl moiety near
the center of the S1 pocket. The trajectory of the
m-benzylamine P1 substituent shows a water molecule
interacting with the benzylamine nitrogen and the
second side-chain oxygen of Asp189. The benzylamine
moieties of both inhibitors interact via hydrogen bonds
with the carbonyl of the Gly218 backbone.
To better understand the differences in binding
interactions of the o-benzylamine and the m-benzyl-
Ta ble 5. In Vitro fXa Activity of Benzylamine P1 Analogues with Varied P4 Substituents 27
human
thrombina
Ki (nM)
human
trypsina
Ki (nM)
human
APTTb
rabbit
fXaa
rabbit
rabbit
A-V shunt
human fXaa
Ki (nM)
APTTb
compd
27
34a
33a
34b
33b
40a
40b
R1
R2
R3
R4
IC2x (µM) Ki(nM) IC2x (µM) ID50c (µmol/ kg/h)
CH3 OMe
H
H
H
F
SO2NH2
SO2NH2
SO2CH3
SO2NH2
SO2CH3
SO2NH2
SO2CH3
SO2NH2
SO2CH3
-
3.8
2.4
1.7
0.88
0.54
1.8
>21000
14000
9100
15000
6500
4100
1400
3600
1500
>1600
>1600
>1600
>1600
>1600
>1600
>1600
3500
12
NT
NT
NT
NT
NT
4.6
2.6
2.9
4.3
0.3
NT
NT
NT
4.4
3.4
4.8
2.6
10.6
6.6
1.7
NT
NT
NT
3.4
5.5
NT
NT
4.2
3.2
1.1
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
-
OMe
OMe
OMe
OMe
H
H
H
H
-
14.5
7.3
6.4
2.4
7.1
3.8
4.8
26
F
H
H
F
F
-
1.0
40c
40d
DPC423
0.91
0.46
0.15
>2500
60
6000
4.9
a
Human purified enzymes were used. Ki values are averaged from multiple determinations (n ) 2) and the standard deviations are
<30% of the mean. Ki’s were measured as in refs 10 and 22. APTT measurements were performed as in ref 26a,b. c AV-shunt
measurements were done as in refs 10 and 22.
b

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5307
F igu r e 3. Superposition of the coordinates of DPC423(purple) from the DPC423-factor Xa complex on the coordinates of the
40c-factor Xa complex.
Ta ble 6. In Vitro Factor Xa Activity of 2-(Aminoalkyl)phenyl
Ta ble 7. In Vivo Dog Pharmacokinetics and Cell Permeability
P1 Pyrazole Derivatives
of Aminomethyl P1 Analogues
human
protein
a
b
Cla
Vdss
t1/2
Caco-2c
(L/h/kg) (L/kg) (h) F %b Papp × 10-6 bindingd
compd
33a
33b
40c
iv
iv
iv
po
cm/s
NT
NT
6.5 ( 0.4
4.9 ( 0.3
(% bound)
1.29
1.51
0.14
0.24
8.0
5.4
1.2
0.9
6
NT
NT
98
89
89
2.84 NT
7.1
7.5
100
57
DPC423
human
fXaa
Ki (nM)
human
thrombina
Ki (nM)
human
trypsina
Ki (nM)
a
b
IV dose 0.5 mg/kg. Oral dose 0.2 mg/kg. c Reference 27.
d
Reference 28.
compd
R1
NH2
NH2
NH2
NHMe
NMe2
NHiPr
NHCH2Ph
n
40d
49
46
45a
45b
45c
45d
1
2
3
1
1
1
1
0.46
110
600
28
800
38
1500
>2500
>2500
NT
>2500
NT
nected to the femoral artery and vein. Inside the Tygon
shunt, a silk thread induces formation of a thrombus.
After 40 min the thrombus is recovered and weighed.
The dose required to reduce the thrombus weight by
50% is designated the ID50.10 Compounds 33b, 34b, 40c,
and 40d (Table 5) show good potency in the rabbit AV-
shunt thrombosis model.
On the basis of the excellent in vitro and in-vivo
efficacy profile of the 4-methoxy-2-(aminomethyl)phenyl
compounds 33a and 33b, and with 2-(aminomethyl)-
phenyl pyrazole compound 40c (Table 7), we evaluated
their pharmacokinetics in dog. Upon intravenous ad-
ministration in beagle dogs, moderately high clearance
and volumes of distribution were observed for com-
pounds 33a and 33b. The best overall PK profile was
achieved with compound 40c, which showed 10-fold
lower clearance and a long terminal half-life (T1/2).
Excellent oral bioavailability (F% ) 100) was observed
for compound 40c which was consistent with the high
Caco-2 permeability observed for this compound. The
human plasma protein binding via equilibrium dialysis
for 40c was 89%. The selectivity profile for compound
40c (Table 8) was excellent except for plasma kallikrein
(>60-fold). This profile compared favorably to that
>21000
>21000
>21000
>21000
>21000
>21000
>2500
NT
61
a
Human purified enzymes were used. Ki values are averaged
from multiple determinations (n ) 2) and the standard deviations
are <30% of the mean. Ki’s were measured as in refs 10 and 22.
In the human APTT in vitro clotting assay, the potent
p-methoxy analogue 33b was ∼2-fold better when
compared to DPC423. With the exception of compound
33b, the p-methoxy compounds (27, 33a , 34a , and 34b)
shown in Table 5 were slightly weaker than DPC423
in the clotting APTT assay. The compounds lacking the
p-methoxy functionality (40a -c) were comparable to
DPC423 in the same assay. Interestingly, the more
potent compound 40d (APTT IC2x ) 26 µM) was
considerably weaker than its counterpart 33b (APTT
IC2x ) 2.4 µM) and DPC423 (APTT IC2x ) 4.9 µM). To
get a full understanding of the in vivo efficacy for these
compounds, we examined them in the rabbit arterio-
venous shunt (AV-shunt) thrombosis model. In that
model, anesthetized rabbits have a shunt device con-

5308 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Pruitt et al.
Ta ble 8. Selectivity Profile of 40c versus DPC423
Ki (nM)
drops were microseeded with a crushed crystal from a previous
crystal growth.
For the 40c structure, preexisting crystals of factor Xa were
soaked in 5 mM 40c, 22% PEG 6000, 200 mM Na acetate pH
5.5 and 5% DMSO for 17 days at 4 °C to replace a 15 nM
proprietary inhibitor.
human enzymes
40c
DPC423
factor Xa
0.91
0.15
60
trypsin
3500
thrombin
3600
58
4600
>12000
>15000
6800
>13000
>15000
>33000
6000
61
1800
2200
>15000
>17000
>19000
>35000
>45000
For both factor Xa inhibitor crystals, cryoprotectant was
introduced to the factor Xa crystals by first transferring the
crystals to a 2 µL drop of the soaking solution. This drop was
then bridged into a 20 µL drop of a solution of 22% PEG 6000,
200 mM Na acetate pH 5.5, and 20% ethylene glycol. After
about 1 min, the crystals were frozen.
plasma kallikrein
activated protein C
factor IXa
factor VIIa
chymotrypsin
urokinase
plasmin
Data for the fXa DPC423 complex were collected at the DND
beamline 4 ID at the Advanced Photon Source using a
MARCCD detector. Data were collected at 100 K using an
Oxford cryosystems cooling device with a wavelength of 1.0
Å. Data frames of one degree rotation were collected. Data
were 99% complete. Data for the fXa-40c complex were
collected at the IMCA beamline 17 ID at the Advanced Photon
Source using a MARCCD detector. Data were collected at 100
K using an Oxford cryosystems cooling device with a wave-
length of 1.0 Å. Data frames of 1° rotation were collected. Data
were 99% complete. Raw data was processed with the program
Denzo.23 The program EPMR24 was used to determine the
initial model for refinement using the pdb coordinates 1fjs
(minus the inhibitor and solvent molecules) as the search
model. The CNX (Accelerys) program was used for crystal-
lographic refinement. Simulated annealing (at a maximum
temperature of 3000°) was followed by B-factor refine-
ment. The inhibitors were built with the program QUANTA
(Accelerys). Peaks in the difference electron density map which
were greater than 3σ which were less than 4 Å away from the
protein were built in as solvent molecules. No major adjust-
ments to the protein model were needed during the course of
the refinements. Final R-factors as well as other relevant data
collection statistics are found in the supporting data. Coordi-
nates for all enzyme inhibitor structures will be deposited with
the Protein Data bank.25
Eth yl 2-N-(Meth oxyim in o)-4-oxop en ta n oa te (2). Ethyl
2,4-dioxopentanoate (39.5 g, 250 mmol) and N-methoxylamine
hydrochloride (13.9 g, 167 mmol) in EtOH (150 mL) was left
to stand over molecular sieves (3 Å, 100 g) for 18 h. CH2Cl2
(100 mL) was added, the sieves were removed by filtration,
and the solvent was evaporated. The crude product was
applied to a column of flash silica gel and eluted with 20:1
hexane:EtOAc. There was obtained 12.3 g of ethyl 2-(N-
methoxyimino)-4-oxopentanoate (66.2 mmol, 40%). 1H NMR
(CDCl3) δ: 4.3 (q, J ) 8 Hz, 2H), 4.0 (s, 3H), 3.65 (s, 2H), 2.2
(s, 3H) and 1.3 (t, J ) 8 Hz, 3H) ppm; LRMS (M + H)+ m/z:
187.
Eth yl 3-Meth yl-1-p h en yl-1H-p yr a zoleca r boxyla te (3a ).
Ethyl 2-(N-methoxyimino)-4-oxopentanoate (0.5 g, 2.67 mmol)
and phenylhydrazine (0.58 g, 5.35 mmol) in acetic acid (10 mL)
and 2-methoxyethanol (5 mL) were heated at 105 °C for 5 h.
The reaction was evaporated, dissolved in ethyl acetate, and
washed with 0.2 N HCl and then water. The solution was dried
(Na2SO4) and evaporated and the residue applied to a silica
gel column. Elution with a gradient of 10:1 to 5:1 hexane:ethyl
acetate gave 160 mg (26%) of ethyl 3-methyl-1-phenyl-1H-
pyrazolecarboxylate. 1H NMR (CDCl3) δ: 7.5-7.3 (m, 5H), 6.8
(s, 1H), 4.2 (q, J ) 7 Hz, 2H), 2.35 (s, 3H), 1.25 (t, J ) 3 Hz,
3H) ppm; LRMS (M + H)+ m/z: 231.
3-Met h yl-1-p h en yl-1H -p yr a zole-5-(N-(2′-N-ter t-b u t yl-
a m in osu lfon yl-[1,1′]-bip h en -4-yl))ca r boxa m id e (5a ). To a
solution of 4-(2-N-tert-butylaminosulfonyl)phenyl)aniline22a,b
(0.22 g, 0.73 mmol) in dichloromethane (10 mL) at 0 °C was
added a solution of trimethylaluminum (2.0 M in hexane, 5
equiv, 1.75 mL). This mixture was stirred for 15 min, and then
ethyl 3-methyl-1-phenyl-1H-pyrazolecarboxylate (0.16 g, 0.69
mmol) in dichloromethane (5 mL) was added. The reaction was
allowed to warm to ambient temperature and stirred for 18 h.
This mixture was carefully quenched with water and then
diluted with ethyl acetate, and the layers were separated,
dried, and evaporated. The residue was applied to a silica gel
tPA
previously determined for DPC423.10 Thus combining
the in vitro and in vivo efficacy and the excellent in vivo
pharmacokinetic profile, compound 40c emerged as a
leading candidate for further evaluation. DP C602, the
crystalline hydrochloride salt form of 40c, was selected
for preclinical development.
Con clu sion s
Optimization of the substituents on the P1 phenyl-
pyrazole portion of our fXa inhibitors led to a potent
and selective p-methoxy analogue 27. Further optimiza-
tion led to potent, selective o-aminomethyl pyrazole
derivatives. By careful selection of appropriate substit-
uents on the pyrazole core and the biphenyl P4 region
of the molecule, a highly potent, selective, and orally
active bioavailable fXa inhibitor compound 40c was
discovered. On the basis of a balanced review of the
selectivity, in vitro potency, antithrombotic properties,
and pharmacokinetic profile, DP C602, a crystalline
hydrochloride salt form of 40c, was selected for further
preclinical evaluation.
Exp er im en ta l Section
All reactions were run under an atmosphere of dry nitrogen
or argon. All solvents were used without purification as
acquired from commercial sources. NMR spectra were obtained
with a Varian VXR-300a spectrometer. Microanalyses were
performed by Quantitative Technologies Inc. and were within
0.4% of the calculated values. Mass spectra were obtained on
a HP 5988A MS/HP particle beam interface. Flash chroma-
tography was done using EM Science silica gel 60. HPLC
purifications were done on a Rainin Dynamax SD200 or an
Agilent 1100 instrument using a C18 reverse phase column
with acetonitrile/water (containing 0.05% TFA) as a mobile
phase. HPLC purity in most cases was >95%. Various P4
starting materials such as 4′-amino[1,1′-biphenyl]-2-tert-butyl-
sulfonamide, 4′-amino-3′-fluoro[1,1′-biphenyl]-2-tert-butyl-
sulfonamide, 3-fluoro-2′-(methylsulfonyl)[1,1′-biphenyl]-4-amine,
and 2-(6-amino-3-pyridinyl)benzene-tert-butylsulfonamide sub-
stituted aminobiaryls and aminopyridylphenylsulfonamides
were obtained as per procedures described by Quan et al.22a,b
The DPC423 factor Xa crystals were obtained from GLA-
Domainless â-Factor Xa (Haematologic Technologies) that had
been fractionated on a Pharmacia mono Q 10/10 column
equilibrated with 50 mM Tris pH 8.0, 100 mM NaCl, and 1
mM CaCl2 and eluted with a 20 bed volume, 0 to 500 mM NaCl
gradient. Inhibitor was added to the fractions as they were
collected. The protein eluted at about 100 mM NaCl. This
solution was incubated overnight and concentrated to 6 mg/
mL using a Vivaspin 6 mL concentrator with a 5000 MWCO
membrane. The crystals were grown using hanging drop vapor
diffusion, at 4 °C, with from 14% to 24% PEG 6000 buffered
with 100 mM Na phosphate in the reservoir. The drops contain
4 µL of protein solution and 4 µL of reservoir solution. The

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5309
column and the title compound isolated by gradient elution
with mixture of 3:1 to 1:1 hexane:ethyl acetate. There was
obtained 150 mg (44%) of 3-methyl-1-phenyl-1H-pyrazole-5-
(N-(4-(2′-N-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)carbox-
amide. 1H NMR (CDCl3) δ: 8.15, (d, J ) 7 Hz, 1H), 7.75 (s,
1H), 7.6-7.4 (m, 12H), 6.75 (s, 1H), 2.4 (s, 3H), 1.0 (s, 9H)
ppm; HRMS (M + H)+ for C27H28N4O3S, calcd m/z: 489.196038,
obs: 489.194346.
3-Meth yl-1-ph en yl-1H-pyr azole-5-(N-(2′-am in osu lfon yl-
[1,1′]-b ip h en -4-yl))ca r b oxa m id e (6a ). A solution of 150
mg of 3-methyl-1-phenyl-1H-pyrazole-5-(N-(4-(2′-N-tert-butyl-
aminosulfonyl-[1,1′]-biphen-4-yl)carboxamide in trifluoroacetic
acid (15 mL) was heated at reflux for 1 h. The reaction was
evaporated, taken up in ethyl acetate and washed with 1 N
sodium hydroxide solution. The organic solution was dried and
evaporated to give 140 mg of product. Further purification of
3-methyl-1-phenyl-1H-pyrazole-5-(N-(4-(2′-aminosulfonyl-[1,1′]-
biphen-4-yl)carboxamide was effected by hplc utilizing gradient
elution with a mixture of water: acetonitrile with 0.05%
trifluoroacetic acid on a reverse phase C18 (60 Å) column gave
130 mg (98%) of a white solid. mp: > 260 °C (decomposes).
1H NMR (CD3OD) δ: 8.1 (d, J ) 7.7 Hz, 1H), 7.7-7.3 (m, 13H),
6.8 (s, 1H), 2.15 (s, 3H) ppm; HRMS (M + H)+ for C23H20N4O3S,
calcd m/z: 433.133438, obs: 433.131005.
a sunlamp and heated at reflux for 18 h. The reaction mixture
was filtered through Celite to remove solid impurity and
washed with carbon tetrachloride (200 mL) and evaporated
1
to give 28.5 g of product [partial H NMR (CDCl3) δ: 4.4 ppm
(s, CH2Br, 2H)] with some unreacted starting material re-
maining. This material was treated with potassium acetate
(0.134 mol, 13.2 g) and 18-crown-6 (3.0 g) in acetonitrile (400
mL) at ambient temperature for 18 h. The reaction mixture
was evaporated, filtered, dissolved in EtOAc (500 mL), and
washed with water (3 × 200 mL). The solution was dried and
1
evaporated to give 17.4 g of the acetate. H NMR (CDCl3) δ:
7.4 (d, J ) 9 Hz, 2H), 7.0 (d, J ) 9 Hz, 2H), 6.75 (s, 1H), 5.05
(s, 2H), 3.85 (s, 3H), 2.1 (s, 3H) ppm. The acetate from above
was dissolved in MeOH (250 mL), and IR400 (OH-) resin (17.7
g) was added. After 3 h at ambient temperature, the reaction
was filtered and evaporated to give 16.43 g of product.
Recrystallization from a mixture of benzene:hexane gave an
analytically pure sample; mp: 79.0 °C. 1H NMR (CDCl3) δ:
7.5 (d. J ) 9 Hz, 2H), 7.1 (d. J ) 9 Hz, 2H), 6.05 (s, 1H), 4.6
(d, J ) 7 Hz, 2H), 3.85 (s, 3H), 2.0 (broad, 1H) ppm. To the
solution of 5-hydroxymethyl-1-(4-methoxyphenyl)-3-trifluoro-
methyl-1H-pyrazole (22.7 mmol, 6.2 g) in acetonitrile (100 mL)
at 0 °C were added sodium periodate (47.6 mmol, 10.2 g) and
several crystals of ruthenium(III) chloride. This reaction
mixture was stirred at ambient temperature for 18 h. The
reaction mixture was filtered through Celite to remove white
solid impurity and the filter cake washed with 1:1 acetonitrile:
water. The filtrate was evaporated in vacuo, and the residue
was taken up in water and made basic with 1 N NaOH (30
mL, pH ) 10). The basic aqueous solution was washed with
Et2O (3 × 50 mL). The aqueous solution was made acidic (pH
3) by the dropwise addition of concentrated HCl at 0 °C and
then extracted with ethyl acetate (3×); the ethyl acetate
extracts were washed with brine, dried (MgSO4), and evapo-
rated to give 3.03 g of product (48%). This material was used
3-Met h yl-1-(4-m et h oxyp h en yl)-1H -p yr a zole-5-(N-(2′-
a m in osu lfon yl-[1,1′]-bip h en -4-yl))ca r boxa m id e (6d ). This
compound was prepared by the same methodology described
for 6a with 4-methoxyphenyl hydrazine‚HCl substituted for
phenyl hydrazine. There was obtained 750 mg (84%) of
3-methyl-1-(2-methoxyphenyl)-1H-pyrazole-5-(N-(2′-amino-
1
sulfonyl-[1,1′]-biphen-4-yl)carboxamide. mp: 116-122 °C. H
NMR (CD3OD) δ: 8.0 (d, J ) 7.2 Hz, 1H), 7.6-7.2 (m, 9H),
6.9 (d, J ) 8.7 Hz, 2H), 6.7 (s, 1H), 3.75 (s, 3H), 2.3 (s, 3H)
ppm; HRMS (M + H)+ for C24H22N4O4S, calcd m/z: 463.144002,
obs: 463.141980. Anal. Calcd for C24H22N4O4S‚0.5H2O: C,
61.13, H, 4.92, N, 11.88; found, C, 61.56, H, 4.88, N, 11.80.
1
without further purification. H NMR (CDCl3) δ: 7.4 (d, J )
9.1 Hz, 2H), 7.3 (s, 1H), 7.0 (d, J ) 9.1 Hz, 2H), 3.9 (s, 3H)
3-Meth yl-1-(2-h ydr oxyph en yl)-1H-pyr azole-5-(N-(2′-am i-
n osu lfon yl-[1,1′]-b ip h en -4-yl))ca r b oxa m id e (7a ). Com-
pound 6b (0.245 g, 0.53 mmol) in dichloromethane (20 mL)
was cooled to 0 °C, and a solution of boron tribromide in
dichloromethane (1.0 M, 6 equiv, 3.2 mL) was added. The
reaction was allowed to warm to ambient temperature and
stirred for 18h. The reaction was evaporated and the residue
applied to a small plug of silica gel and eluted with ethyl
acetate. The ethyl acetate solution was dried and evaporated.
This material was purified by hplc utilizing gradient elution
with a mixture of water:acetonitrile with 0.05% trifluoroacetic
acid on a reverse phase C18 (60 Å) column to give the 103 mg
ppm.
1-(4-Meth oxyp h en yl)-3-tr iflu or om eth yl-1H-p yr a zole-5-
(N-(2′-am in osu lfon yl-[1,1′]-biph en -4-yl)car boxam ide (13a).
To 300 mg of 1-(4-methoxyphenyl)-3-trifluoromethyl-1H-pyra-
zole-5-carboxylic acid (1.05 mmol) in dichloromethane (10 mL)
at 0 °C was added a solution of oxalyl chloride in dichloro-
methane (2 M, 1.5 equiv, 1.58 mmol, 0.8 mL) and a drop of
dimethylformamide. After 4 h the reaction was complete, the
solvent was evaporated and the acid chloride carried on to the
next reaction. The acyl chloride was dissolved in dichloro-
methane (20 mL) and then added over a period of 15-20 min
to a 0 °C solution of 4-(2-N-tert-butylaminosulfonyl)phenyl)-
aniline (1.2 equiv, 1.25 mmol, 0.365 g), pyridine (10 equiv, 12.5
mmol, 0.99 g, 1.0 mL) and N,N-dimethylaminopyridine (1.2
equiv, 1.25 mmol, 0.155 g) in dichloromethane (20 mL). The
reaction was maintained at 0 °C until thin-layer chromatog-
raphy indicated that all of the starting acid chloride was
consumed. The reaction was evaporated and then the residue
suspended in 1 N hydrochloric acid solution. The suspension
was extracted with ethyl acetate; the extracts were washed
with 1 N hydrochloric acid solution twice and then dried and
evaporated. There was obtained 660 mg of the desired
product.1H NMR (CDCl3) δ: 8.2-8.1 (m, 2H), 7.7-7.4, (m, 9H),
7.3 (d, J ) 1 Hz, 1H), 7.2 (s, 1H), 7.0 (d, J ) 9 Hz, 2H), 3.85
(s, 3H), 1.0 (s, 9H) ppm; LRMS (M + Na)+ m/z: 594.5. 1-(4-
methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-(N-(2′-N-tert-
butylaminosulfonyl-[1,1′]-biphen-4-yl)carboxamide (0.66 g) was
dissolved in trifluoroacetic acid (20 mL) and heated at reflux
for 30 min. The reaction was evaporated and then dissolved
in ethyl acetate and washed with 1 N sodium hydroxide
solution twice and brine. This solution was dried and evapo-
rated to 0.48 g of crude product. This material was made
analytically pure by first subjecting it to flash chromatography
with a 200 g column of silica gel and elution with 2:1 hexane:
ethyl acetate and finally recrystallizing the homogeneous
chromatography product from chloroform. There was obtained
1
(43%) of title compound. mp: 207-210 °C. H NMR (DMSO-
d6) δ: 10.4 (s, 1H), 10.0 (s, 1H), 8.0 (d, J ) 7.5 Hz, 1H), 7.7 (d,
J ) 10 Hz, 2H), 7.65-7.5 (m, 2H), 7.4-7.3 (m, 6H), 7.2 (t, J )
10 Hz, 1H), 6.9 (t, J ) 7.5 Hz, 2H), 6.8 (s, 1H), 2.2 (s, 3H)
ppm; HRMS (M + H)+ for C23H20N4O4S, calcd m/z: 449.128352,
obs: 449.129006.
5-Met h yl-1-(4-m et h oxyp h en yl)-3-t r iflu or om et h yl-1H -
p yr a zole (10). A mixture of 1,1,1-trifluoro-2,4-pentanedione
9 (0.08 mol, 9.8 mL) and 4-methoxyphenylhydrazine‚HCl 8
(0.09 mol, 16.3 g, 1.1 equiv) in 2-methoxyethanol (50 mL) and
acetic acid (100 mL) was refluxed for 18 h. The reaction
mixture was evaporated and then poured into 10% NaOH (300
mL). The product was extracted with CH2Cl2 (3 × 200 mL),
dried, and evaporated to give 18.8 g of crude product. This
was filtered through a plug column of flash silica gel (500 g)
by eluting with 5:1 hexane:ethyl acetate in three 1 L fractions.
These fractions were combined and evaporated to give to give
17.3 g of product (84%) with the 2-phenyl isomer as a minor
1
contaminant (<10:1). H NMR (CDCl3) δ: 7.35 (d, J ) 9 Hz,
2H), 7.05 (d, J ) 9 Hz, 2H), 6.4 (s, 1H), 3.85 (s, 3H), 2.3 (s,
3H) ppm.
1-(4-Meth oxyp h en yl)-3-tr iflu or om eth yl-1H-p yr a zole-5-
ca r boxylic Acid (11). A mixture of 5-methyl-1-(4-methoxy-
phenyl)-3-trifluoromethyl-1H-pyrazole (0.067 mol, 17.3 g),
N-bromosuccinimide (14.4 g, 0.081 mol.), and benzoyl peroxide
(0.4 g) in carbon tetrachloride (500 mL) was illuminated with
1
0.262 g (48%) of the title compound. mp: 237.3 °C. H NMR

5310 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Pruitt et al.
1
(DMSO-d6) δ: 10.8 (s, 1H), 8.0 (d, J ) 7 Hz, 1H), 7.7-7.2 (m,
12 H), 7.1 (d, J ) 9 Hz, 2H), 3.8 (s, 3H) ppm; HRMS (M + H)+
for C24H19F3N4O2S, calcd m/z: 517.116712, obs: 517.115737.
Anal. Calcd for C24H19F3N4O2S: C, 55.81, H, 3.72, F, 11.03,
N, 10.85, S, 6.22; found, C, 56.02, H, 3.77, F, 11.29, N, 10.51,
S, 5.84.
0.6 mmol). H NMR (CDCl3) δ: 7.3 (t, J ) 7.5 Hz, 1H), 7.0-
6.9 (m, 2H), 6.85 (d, J ) 7.5 Hz, 1H), 4.85 (s, 2H), 3.8 (s, 3H)
ppm; LRMS (M + H)+ m/z: 245. The second product isolated
was the desired material, 22 (0.18 g, 0.62 mmol) as determined
1
by proton NMR NOE experiments. H NMR (CDCl3) δ: 7.15
(d, J ) 7.5 Hz, aromatic H6), 7.05 (d, J ) 1 Hz, aromatic H3),
6.85 (dd, J ) 7.5 and 1 Hz, aromatic H5), 6.8 (s, pyrazole H,
NOE), 4.3 (s, benzylic H), 4.2 (q, J ) 7.5 Hz, -OCH2CH3), 3.85
(s, -OCH3), 2.35 (s, pyrazole -CH3, NOE), 1.25 (t, J ) 7.5
Hz, -OCH2CH3) ppm; LRMS (M + H)+ m/z: 291. The third
product to elute was the regioisomer 23 (0.14 g, 0.5 mmol). 1H
NMR (CDCl3) δ: 7.18 (d, J ) 7.5 Hz, aromatic H6, NOE), 7.1
(d, J ) 1 Hz, aromatic H3), 6.9 (dd, J ) 7.5 and 1 Hz, aromatic
H5), 6.9 (s, pyrazole H, NOE), 4.4 (q, J ) 7.5 Hz, OCH2CH3),
4.25 (s, benzylic H), 3.85 (s, OCH3), 2.2 (s, pyrazole CH3, NOE),
1.38 (t, J ) 7.5 Hz, OCH2CH3) ppm; LRMS (M + H)+ m/z: 291.
1-(4-Meth oxyp h en yl)-3-tr iflu or om eth yl-1H-p yr a zole-5-
(N-(3-flu or o-2′-m et h a n esu lfon yl-[1,1′]-b ip h en -4-yl)ca r -
boxa m id e (12c). This material was prepared according to the
methods described for 13a with the exception that during the
coupling step 3-fluoro-4-(2-methanesulfonyl)phenyl)aniline was
substituted for 4-(2-N-tert-butylaminosulfonyl)phenyl)aniline.
The subsequent trifluoroacetic acid cleavage step was omitted.
Purification of the final product by HPLC utilizing gradient
elution with a mixture of water:acetonitrile with 0.05% tri-
fluoroacetic acid on a reverse phase C18 (60 Å) column gave
1
155 mg (47%) of the title compound. mp: 242.3 °C. H NMR
1-(2-Azid om eth yl-4-m eth oxyp h en yl)-3-m eth yl-1H-p yr -
a zole-5-ca r boxylic a cid (25). Ethyl 1-(2-hydroxymethyl-4-
methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylate (0.18 g,
0.62 mmol) was dissolved in chloroform (20 mL) and then
methanesulfonyl chloride (0.3 g, 2.6 mmol) and triethylamine
(0.26 g, 2.6 mmol) were added. The reaction was complete in
6 h; it was evaporated, dissolved in ethyl acetate (100 mL),
washed with 1 N hydrochloric acid (50 mL) and brine (50 mL),
dried, and evaporated to give 0.22 g of product (0.6 mmol, 97%).
The resulting mesylate and sodium azide (0.12 g, 1.8 mmol)
were dissolved in dimethylformamide (15 mL) and heated for
1.5 h at 60 °C and then diluted with brine (50 mL), extracted
with ethyl acetate (100 mL), dried, and evaporated. There was
obtained 0.11 g of ethyl 1-(2-azidomethyl-4-methoxyphenyl)-
3-methyl-1H-pyrazole-5-carboxylate (0.35 mmol, 58%). 1H
NMR (CDCl3) δ: 7.2 (d, J ) 7.5 Hz, 1H), 7.0 (d, J ) 1 Hz, 1H),
6.9 (dd, J ) 7.5 and 1 Hz, 1H), 6.8 (s, 1H), 4.2 (q, J ) 7.5 Hz,
2H), 4.1 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H), 1.2 (t, J ) 7.5 Hz,
3H) ppm; LRMS (M + H)+ m/z: 316. The ester (0.11 g, 0.35
mmol) in ethanol (2 mL) and water (2 mL) was stirred with
50% sodium hydroxide (3 drops) at 45 °C and followed by TLC
(1:1 hexane:ethyl acetate). When all of the ester was consumed,
the reaction was cooled, diluted with brine, and washed with
ethyl ether (25 mL). The aqueous layer was acidified with 1
N hydrochloric acid (pH ) 1), extracted with ethyl acetate
(2 × 30 mL), dried, and evaporated. There was obtained
3-methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-
carboxylic acid (0.06 g). LRMS (M - H)-: 285 m/z.
(DMSO-d6) δ: 10.7 (s, 1H), 8.1 (dd, J ) 7 and 1 Hz, 1H), 7.8-
7.5 (m, 4H), 7.5-7.3 (m, 4H), 7.2 (dd, J ) 9 and 1.5 Hz, 1H),
7.05 (d, J ) 9 Hz, 2H), 3.8 (s, 3H) and 2.9(s, 3H) ppm; HRMS
(M + H)+ for C25H19F4N3O4S, calcd m/z: 534.1111, obs:
534.1114. Anal. Calcd for C25H19F4N3O4S‚0.5 H2O: C, 55.35,
H, 3.72, N, 7.75; found, C, 55.66, H, 3.33, N, 7.52.
E t h yl 1-(2-ca r b oxy-4-m et h oxyp h en yl)-3-m et h yl-1H -
p yr a zole-5-ca r boxyla te (20) a n d Eth yl 1-(2-Ca r boxy-4-
m eth oxyph en yl)-5-m eth yl-1H-pyr azole-3-car boxylate (21).
2-Amino-5-methoxybenzoic acid (4.2 g, 25.1 mmol) in concen-
trated hydrochloric acid (50 mL) was cooled to 0 °C, and
sodium nitrite (2.08 g, 30.2 mmol) in cold water (20 mL) was
added dropwise. This mixture was stirred at 0 °C for 30 min
and then tin(II)chloride dihydrate (17.0 g, 75.4 mmol) in cold
concentrated hydrochloric acid (25 mL) was added dropwise.
This mixture was allowed to thaw to ambient temperature over
3 h and then filtered and air-dried overnight. The filter cake
was broken up and dried further in a vacuum oven at 60 °C
overnight. There was obtained 8.76 g of 2-carboxy-4-methoxy-
phenylhydrazine 19 contaminated with tin salts. Ethyl 2-(N-
methoxyimino)-4-oxopentanoate 2 (1.0 g, 5.35 mmol) and crude
2-carboxy-4-methoxyphenylhydrazine 19 (2.33 g, ca. 10.7
mmol) in acetonitrile (40 mL) and acetic acid (5 mL) were
stirred at ambient temperature for 3 h and then heated at
reflux for an additional 3 h. The reaction was cooled to ambient
temperature, diluted with methylene chloride (150 mL), and
filtered. The filtrate was evaporated and the product isolated
by flash chromatography by elution with 10% methanol in
chloroform. This material (1.28 g, 4.2 mmol, 79%) coeluted as
a mixture of regiosiomers as evident by proton NMR. 1H NMR
(CDCl3) δ: 7.7 (broad d, J ) 7 Hz, 1H), 7.65-7.5 (m), 7.4-
7.25 (m), 7.2-7.1 (m), 6.8 (s, major regioisomer), 5.3 (s, minor
regioisomer), 4.35 (broad q, J ) 7 Hz, minor regioisomer), 4.15
(q, J ) 8 Hz, major regioisomer), 3.9 (s, major regioisomer),
3.85 (s, minor regioisomer), 2.35 (s, minor regioisomer), 2.1
(s, major regioisomer), 1.35 (broad t, J ) 7 Hz, minor
regioisomer), 1.2 (t, J ) 8 Hz, major regioisomer) ppm; LRMS
(M + H)+ m/z: 306.
Eth yl 1-(2-Hyd r oxym eth yl-4-m eth oxyp h en yl)-3-m eth -
yl-1H-p yr a zole-5-ca r boxyla te (22) a n d Eth yl 1-(2-Hy-
d r oxym eth yl-4-m eth oxyp h en yl)-5-m eth yl-1H-p yr a zole-3-
ca r boxyla te (23). A mixture compounds 20 and 21 (1.28 g,
4.2 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled
to 0 °C. To the cold solution were added N-methylmorpholine
(0.42 g, 4.2 mmol) and isobutyl chloroformate (0.57 g, 4.2
mmol). The reaction was stirred for 30 min at 0 °C, the
precipitate removed by filtration, and the cold solution poured
immediately into a cold (5 °C) solution of sodium borohydride
(0.48 g, 12.6 mmol) in water (20 mL) and tetrahydrofuran (20
mL). The reaction was allowed to thaw to room temperature
over 18 h. The reaction mixture was evaporated, partitioned
between ethyl acetate (100 mL) and 1 N hydrochloric acid (50
mL) and then washed with 5% sodium bicarbonate (50 mL)
and brine (50 mL). The organic layer was dried and evapo-
rated; three products were isolated by elution of the crude
mixture from a silica gel column with 2:1 hexane:ethyl acetate.
The first product to elute was a ring closed lactone 24 (0.14 g,
3-Meth yl-1-(2-a zid om eth yl-4-m eth oxyp h en yl)-1H-p yr -
a zole-5-(N-(4-(2-N-ter t-b u t ylsu lfa m id o)p h en yl)p h en yl)-
ca r b oxa m id e (26). 3-Methyl-1-(2-azidomethyl-4-methoxy-
phenyl)-1H-pyrazole-5-carboxylic acid (0.60 g, 0.21 mmol) in
dichloromethane (5 mL) was cooled to 0 °C, and oxalyl chloride
(0.21 mL of a 2 M solution in dichloromethane) and dimethyl-
formamide (1 drop) were added. The reaction was complete
inside of 1 h; it was evaporated to remove residual HCl. The
acid chloride (0.17 g, 0.50 mmol) in dichloromethane (3 mL)
was added dropwise to an ice-cold solution of 4-(2-N-tert-
butylsulfonamido)phenylaniline 4a (0.15 g, 0.51 mmol), pyri-
dine (0.39 g, 4.4 mmol), and 4,4-(dimethylamino)pyridine (0.09
g, 0.7 mmol) in dichloromethane (15 mL). The reaction was
allowed to warm to ambient temperature over 18 h and then
evaporated, dissolved in ethyl acetate (30 mL), washed with
1 N hydrochloric acid (20 mL), and dried. Silica gel flash
chromatography, eluting with a gradient of 2:1 to 1:1 hexane:
ethyl acetate, gave 0.09 g of the title compound (0.16 mmol,
1
76%). H NMR (CDCl3) δ: 8.15 (d, J ) 9 Hz, 1H), 7.78 (broad
s, 1H), 7.6-7.4 (m, 6H), 7.35-7.2 (m, 2H), 7.05 (d, J ) 1 Hz,
1H), 6.92 (dd, J ) 7.5 and 1 Hz, 1H), 6.75 (s, 1H), 4.3 (s, 2H),
3.85 (s, 3H), 3.55 (s, 1H), 2.4 (s, 3H), 1.0 (s, 9H) ppm; LRMS
(M - H)-: 572 m/z.
1-(2-Am in om eth yl-4-m eth oxyph en yl)-3-m eth yl-1H-p yr -
a zole-5-(N-(2′-a m in osu lfon yl-[1,1′]-b ip h en -4-yl))ca r b ox-
a m id e, Tr iflu or oa cetic Acid Sa lt (27). 1-(2-Azidomethyl-
4-methoxyphenyl)-3-methyl-1H-pyrazole-5-(N-(2′-N-tert-butyl-
aminosulfonyl-[1,1′]-biphen-4-yl))carboxamide (0.09 g, 0.16
mmol) was stirred with tin(II) chloride dihydrate (0.11 g, 0.47
mmol) in methanol (10 mL). When the reaction was complete

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5311
by TLC (1:1 hexane:ethyl acetate), it was evaporated to give a
crude mixture of the aminomethyl product and tin salts
weighing 0.39 g. The material was heated at reflux in trifluoro-
acetic acid (10 mL) for 45 min and then evaporated. The
residue was partitioned between 1 N sodium hydroxide (30
mL) and ethyl acetate (30 mL). The ethyl acetate solution was
dried and evaporated to give 0.04 g of crude product. This
material was purified further by HPLC utilizing gradient
elution with a mixture of water:acetonitrile with 0.05% tri-
fluoroacetic acid on a reverse phase C18 (60 Å) column to give
0.010 g of the title compound (0.02 mmol, 13%). mp 184.3 °C.
1H NMR (DMSO-d6) δ: 10.55 (s, 1H), 8.2 (broad s, 2H), 8.0
(dd, J ) 9 and 1 Hz, 1H), 7.7-7.5 (m, 4H), 7.4-7.1(m, 6H),
7.0 (m, 2H), 3.85 (s, 3H), 3.8 (m, 2H), 2.3 (s, 3H) ppm; HRMS
(M + H)+ calcd m/z: 492.170551, obsd m/z: 492.17155
1-(2-Ca r b oxy-4-m et h oxyp h en yl)-3-t r iflu or om et h yl-5-
(fu r a n -2-yl)-1H-p yr a zole (29a ). Crude 2-carboxy-4-methoxy-
phenylhydrazine 19 (8.88 g, ca. 23.9 mmol) and 4,4,4-trifluoro-
1-(2-furyl)-1,3-butanedione 28 (7.4 g, 35.9 mmol) in acetic acid
(150 mL) was heated at 100 °C for 4 h. The hot reaction
mixture was evaporated and the residue stirred in a biphasic
mixture of water (150 mL) and chloroform (150 mL). The layers
were filtered, separated, the solid precipitate was washed
several times with additional chloroform (3 × 50 mL), and the
chloroform layer and washings were combined, dried, and
evaporated. There was obtained 3.55 g of 3-trifluoromethyl-
1-(2-carboxy-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole;
LRMS (M - H)- m/z: 351.
potassium permanganate (5.0 g, 27.5 mmol) in water (60 mL).
The reaction was heated at 60 °C for 3 h and then cooled to
ambient temperature, and isopropyl alcohol (60 mL) was
added. This mixture was stirred for 18 h and then filtered
through a Celite pad and washed with copious amounts of
isopropyl alcohol. The combined filtrates were evaporated, and
the residue was dissolved in 1 N NaOH (50 mL) and washed
with ethyl ether (2 × 50 mL). The basic layer was acidified
with 1 N HCl (75 mL) and solid NaCl added. The suspension
was extracted with EtOAc (3 × 100 mL), and the extracts were
dried and evaporated. There was obtained 0.91 g (68%) of
3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyr-
1
azole-5-carboxylic acid. H NMR (CDCl3) δ: 7.3 (s, 1H), 7.25
(d, J ) 8 Hz, 1H), 7.1-7.0 (broad, 1H), 7.05 (d, J ) 1 Hz, 1H),
6.95 (dd, J ) 8 and 1 Hz, 1H),4.05 (broad s, 2H), 3.9 (s, 3H)
ppm; LRMS (M - H)- m/z: 340.
1-(2-Azidom eth yl-4-m eth oxyph en yl)-3-tr iflu or om eth yl-
1H -p yr a zole-5-(N-(2-flu or o-4-(2-N-ter t-b u t yla m in osu l-
fon yl-[1,1]-b ip h en -4-yl))ca r b oxa m id e (32d ). 1-(2-Azido-
methyl-4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-car-
boxylic acid (1.09 g, 3.2 mmol) in dichloromethane (50 mL)
was stirred at 0 °C with oxalyl chloride from 3.2 mL of a 2 M
dichloromethane solution of the reagent and a catalytic
amount of DMF (3 drops). The reaction was complete in 3 h
and then evaporated to remove residual reagent. There was
obtained 1.04 g (2.9 mmol) of the acid chloride. A portion of
the acyl chloride (0.52 g, 1.45 mmol) in dichloromethane (10
mL) was added dropwise to an ice-cold solution of 2-fluoro-4-
(2-N-tert-butylsulfonamido)phenylaniline (0.56 g, 1.74 mmol),
pyridine (1.14 g, 14.5 mmol), and 4,4- (dimethylamino)pyridine
(0.21 g, 1.74 mmol) in dichloromethane (30 mL). The reaction
was allowed to warm to ambient temperature over 18 h and
then evaporated, dissolved in ethyl acetate (100 mL), washed
with 1 N hydrochloric acid (50 mL), and dried. Silica gel flash
chromatography, eluting with 4:1 hexane:ethyl acetate, gave
0.28 g (30%) of the title compound. 1H NMR (CDCl3) δ: 8.5 (t,
J ) 8 Hz, 1H), 8.3 (t, J ) 11.3 Hz, 1H), 8.25 (s, 1H), 8.15 (t, J
) 11.3 Hz, 2H), 7.95 (s, 1H), 7.6-6.9 (m, 6H), 4.25 (s, 2H), 3.9
(s, 3H), 1.05 (s, 9H) ppm; HRMS (M + Na)+ calcd m/z:
668.167907, obsd m/z: 668.166000.
1-(2-Azid o-4-m e t h oxyp h e n yl)-3-t r iflu or om e t h yl-5-
(fu r a n -2-yl)-1H-p yr a zole (30a ). Compound 29 (3.55 g, 10.1
mmol) was dissolved in tetrahydrofuran (100 mL) and cooled
to 0 °C. N-Methylmorpholine (1.02 g, 10.1 mmol) and isobutyl
chloroformate (1.38 g, 10.1 mmol) were added. The reaction
mixture was stirred for 30 min at 0 °C, filtered, and added
immediately to a cold solution of sodium borohydride (1.15 g,
30.2 mmol) in water (50 mL) and tetrahydrofuran (50 mL).
The reaction mixture was evaporated, partitioned between
ethyl acetate (100 mL) and 1 N hydrochloric acid (50 mL) and
then washed with 5% sodium bicarbonate (50 mL) and brine
(50 mL). The organic layer was dried and evaporated and then
purified further by flash chromatography using 4:1 hexane:
ethyl acetate as the eluent. There was obtained 1.5 g of 1-(2-
hydroxymethyl-4-methoxyphenyl)-3-trifluoromethyl-5-(furan-
1-(2-Am in om eth yl-4-m eth oxyph en yl)-3-tr iflu or om eth yl-
1H-p yr a zole-5-(N-(2′-m eth ylsu lfon yl-[1,1]-bip h en -4-yl))-
ca r b oxa m id e, Tr iflu or oa cet ic Acid Sa lt (33a ). 1-(2-
Azidomethyl-4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-
5-carboxylic acid chloride and 4-(2-methylsulfonylphenyl)aniline
were treated in the manner described for 33b to give 98 mg
1
2-yl)-1H-pyrazole. H NMR (CDCl3) δ: 7.4 (d, J ) 1 Hz, 1H),
7.25 (d, J ) 8 Hz, 1H), 7.18 (d, J ) 1,5 Hz, 1H), 6.95 (s, 1H),
6.9 (dd, J ) 8 and 1 Hz, 1H), 6.3 (m, 1H), 5.75 (d, J ) 1.5 Hz,
1H), 4.3 (broad s, 2H), 3.9 (s, 3H) ppm; LRMS (M + H)+ m/z:
339. To a cooled chloroform (50 mL) solution of 1-(2-hydroxy-
methyl-4-methoxyphenyl)-3-trifluoromethyl-5-(furan-2-yl)-1H-
pyrazole (1.5 g, 4.44 mmol) and triethylamine (1.79 g, 17.7
mmol) was added a chloroform solution (10 mL) of methane-
sulfonyl chloride (2.03 g, 17.7 mmol). The reaction was
complete in 4 h. It was evaporated and dissolved in ethyl
acetate (100 mL), and the ethyl acetate solution was washed
with cold 5% NaHSO4 (50 mL) and cold saturated NaHCO3
(50 mL). The organic layer was dried and evaporated to give
2.1 g of the mesylate which was used immediately in the next
reaction; LRMS (M + H)+ m/z: 417.
1
(42%) of the title compound. mp 133 °C. H NMR (CD3OD) δ:
8.15 (dd, J ) 11 and 1 Hz, 1H), 7.8-7.65 (3H, m), 7.6 (t, J )
11 Hz), 7.45 (s, 1H), 7.4-7.3 (4H, m), 7.25 (d, J ) 1.2 Hz, 1H),
7.1 (dd, J ) 11 and 1.2 Hz, 1H), 3.95 (s, 2H), 3.9 (s, 3H), 2.7
(s, 3H) ppm; HRMS (M + H)+ for C26H23F3N4O4S, calcd
m/z: 545.147037, obsd m/z: 545.145700. Anal. Calcd for
C
26H23F3N4O4S‚1.3 C2HF3O2: C, 49.58, H, 3.54, N, 8.09; found,
C, 49.72, H, 3.39, N, 7.65.
1-(2-Am in om eth yl-4-m eth oxyph en yl)-3-tr iflu or om eth yl-
1H -p yr a zole-5-(N-(3-flu or o-4-(2-a m in osu lfon yl-[1,1]-b i-
p h en -4-yl))ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (34b).
Compound 32d (0.28 g, 0.43 mmol) and tin(II) chloride
dihydrate (0.29 g, 1.3 mmol) was stirred in methanol (30 mL)
for 18 h. The reaction was evaporated, and the reduction
product (0.60 g) was refluxed in trifluoroacetic acid (20 mL)
for 30 min and then evaporated. The residue was suspended
in 1 N NaOH (30 mL), extracted with EtOAc (3 × 50 mL),
dried, and evaporated. This material was purified further by
A mixture of the mesylate prepared above (2.1 g, 5.05 mmol)
and sodium azide (0.98 g, 15.1 mmol) in dimethylformamide
(40 mL) was heated at 60 °C for 2 h. The reaction mixture
was cooled, diluted with brine (100 mL), and extracted with
ethyl acetate (100 mL). The ethyl acetate extract was washed
with water (5 × 50 mL) and then dried and evaporated. There
was obtained 1.43 g (78%) of 3-trifluoromethyl-1-(2-azido-
methyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole. 1H NMR
(CDCl3) δ: 7.4 (d, J ) 1 Hz, 1H), 7.3 (d, J ) 8 Hz, 1H), 7.1 (d,
J ) 1.5 Hz, 1H), 6.95 (dd, J ) 8 and 1 Hz, 1H), 6.3 (m, 1H),
5.7 (d, J ) 1.5 Hz, 1H), 4.1 (broad s, 2H), 3.9 (s, 3H) ppm;
LRMS (M + H)+ m/z: 364.
hplc utilizing gradient elution with
a mixture of water:
acetonitrile with 0.05% trifluoroacetic acid on a reverse phase
C18 (60 Å) column to give 0.18 g (80%) of the title compound.
mp 103.2 °C. 1H NMR (DMSO-d6) δ: 10.7 (s, 1H), 8.0 (dd, J )
7.5 and 1 Hz, 1H), 7.8 (s, 1H), 7.7-7.55 (m, 3H), 7.45 (d, J )
1 Hz, 1H), 7.4 (s, 1H), 7.35-7.25 (m, 3H), 7.2 (dd, J ) 7.5 and
1 Hz, 1H), 7.05 (dd, J ) 9 and 1.5 Hz, 1H), 3.85 (s, 3H), 3.75
(broad s, 2H) ppm; HRMS (M + H)+ for C25H21F4N5O4S, calcd
m/z: 564.132864, obsd m/z: 564.131700. Anal. Calcd for
1-(2-Azidom eth yl-4-m eth oxyph en yl)-3-tr iflu or om eth yl-
1H-p yr a zole-5-ca r boxylic Acid (31a ). To 1.43 g of 1-(2-
azidomethyl-4-methoxyphenyl)-3-trifluoromethyl-5-(furan-2-
yl)-1H-pyrazole (3.9 mmol) in acetone (60 mL) was added

5312 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Pruitt et al.
C
25H21F4N5O4S‚C2HF3O2: C, 47.86, H, 3.27, N, 10.34; found,
at 100 °C for 1 h. The hot reaction was stirred at for another
1 h and then diluted with 1-chlorobutane (300 mL) and water
(300 mL). The layers were separated, and the water layer was
extracted with 1-chlorobutane (6 × 50 mL). The combined
organic layers were extracted with water (4 × 100 mL) and
then the product was extracted into a solution of saturated
NaHCO3 (5 × 100 mL). The combined basic extracts were
acidified with concentrated HCl (pH ca. 2), and the resulting
gum was isolated by decanting off the aqueous layer. This
material was purified by trituration with benzene to give 16.2
C, 47.98, H, 3.22, N, 10.20.
1-(2-Am in om eth yl-4-m eth oxyph en yl)-3-tr iflu or om eth yl-
1H-pyr azole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-biph en -
4-yl))ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (33b). 1-(2-
Azidomethyl-4-methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-
5-carboxylic acid chloride (0.52 g, 1.45 mmol) in dichloromethane
(10 mL) was added dropwise to an ice-cold solution of 2-fluoro-
4-(2-methylsulfonylphenyl)aniline (0.52 g, 1.74 mmol), pyridine
(1.14 g, 14.5 mmol), and 4,4- (dimethylamino)pyridine (0.21
g, 1.74 mmol) in dichloromethane (30 mL). The reaction was
allowed to warm to ambient temperature over 18 h and then
evaporated, dissolved in ethyl acetate (100 mL), washed with
1 N hydrochloric acid (50 mL), and dried. Silica gel flash
chromatography, eluting with a gradient of 5:1 to 1:1 hexane:
ethyl acetate, gave 0.46 g (0.78 mmol, 54%) of the desired
amide. LRMS (M + H)+ m/z: 587. This azide (0.46 g, 0.78
mmol) and tin(II) chloride dihydrate (0.53 g, 2.35 mmol) was
stirred in methanol (25 mL) for 18 h. The reaction was
evaporated, and the residue was suspended in 1 N NaOH (50
mL), extracted with EtOAc (3 × 100 mL), dried, and evapo-
rated to give 0.29 g of crude product. The crude product was
purified further by HPLC utilizing gradient elution with a
mixture of water:acetonitrile with 0.05% trifluoroacetic acid
on a reverse phase C18 (60 Å) column to give 157 mg (36%) of
the title compound. mp 101.5 °C. 1H NMR (600 MHz, CD3OD)
δ: 8.15 (dd, J ) 8 and 1 Hz, 1H), 7.78 (m, 1H), 7.73 (m, 1H),
7.65 (m, 1H), 7.45 (s, 1H), 7.39 (m, 1H), 7.31 (m, 2H), 7.2
(m, 2H), 7.04 (m, 1H), 3.89 (s, 3H), 3.76 (broad s, 2H), 2.76 (s,
1
g (50.3 mmol, 76%) of product. H NMR (CDCl3) δ: 8.15 (dd,
J ) 7.7 and 1.8 Hz, 1H), 7.74 (td, J ) 7.7 and 2.2 Hz, 1H),
7.65 (td, J ) 7.7 and 2.2 Hz, 1H), 7.5 (dd, J ) 7.7 and 1.1 Hz,
1H), 7.3 (d, J ) 1.4 Hz, 1H), 6.9 (s, 1H), 6.3 (m, 1H), 5.75 (d,
J ) 3.7 Hz, 1H) ppm.
2-(2-Met h oxyca r b on ylp h en yl)-5-t r iflu or om et h yl-2H -
p yr a zole-3-ca r boxylic Acid (42). Compound 41 (16.1 g, 50
mmol) in CH2Cl2 (160 mL) was stirred with oxalyl chloride
(7.61 g, 60 mmol) and 5 drops of DMF for 4 h. The mixture
was evaporated to give a solid which was redissolved in MeOH,
and this was stirred at ambient temperature for 2 h and then
evaporated. There was obtained 16.65 g (50 mmol, 100%) of
1
the desired product as a syrup. H NMR (CDCl3) δ: 8.15 (dd,
J ) 7.3 and 1.5 Hz, 1H), 7.8-7.6 (m, 2H), 7.5 (dd, J ) 8.1 and
2.2 Hz, 1H), 7.4 (d, J ) 1.1 Hz, 1H), 6.9 (s, 1H), 6.3 (m, 1H),
5.77 (d, J ) 3.3 Hz, 1H), 3.6 (s, 3H) ppm.
To 2-(5-furan-2-yl-3-trifluoromethyl-pyrazol-1-yl)benzoic acid
methyl ester (16.65 g, 50 mmol) in acetone (1200 mL) was
added 40 g of KMnO4 in 800 mL of water dropwise over 1 h.
This mixture was heated at reflux for 4 h and then cooled to
ambient temperature. To this solution was added isopropyl
alcohol (263 mL), and the mixture was stirred at ambient
temperature for 18 h. This material was filtered through a
pad of Celite and washed with acetone and the acetone
removed by evaporation. The aqueous suspension was acidified
with concentrated H2SO4 (pH 2) and then extracted with
EtOAc (2 × 200 mL), dried (MgSO4), and evaporated. There
was obtained 17 g of crude material as a syrup. Trituration
with 1-chlorobutane gave the title compound (5.45 g, 17.35
3H) ppm; HRMS (M
m/z: 563.137615, obsd m/z: 563.138100. Anal. Calcd for
C
+
H)+ for C26H22F4N4O4S, calcd
26H22F4N4O4S‚1.5C2HF3O2: C, 47.48, H, 3.23, N, 7.64; found,
C, 47.71, H, 3.06, N, 7.65.
1-(2-(Am in om eth yl)p h en yl)-3-tr iflu or om eth yl-1H-p yr -
a zole-5-(N-(3-flu or o-2′-a m in osu lfon yl-[1,1′]-bip h en -4-yl))-
ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (40c). Oxalyl
chloride (300 µl, 3.4 mmol) and DMF (3 drops) were added to
compound 38 (888 mg, 2.3 mmol) in CH2Cl2 (30 mL), and the
resulting solution was stirred for 65 min at room temperature.
The solvents were evaporated, and the resulting compound
was placed briefly under high vacuum before redissolving in
CH2Cl2 (30 mL). 4-Amino-3-fluoro-2′-(tert-butylamino)sulfonyl-
[1,1′]-biphenyl (890 mg, 2.8 mmol), and 4-(dimethylamino)-
pyridine (420 mg, 3.4 mmol) were added, and the resulting
solution was stirred for 22 h at room temperature. The reaction
was concentrated and chromatographed on silica gel (20-30%
EtOAc/hexanes). The fractions containing product were com-
bined and concentrated to half the original volume and then
extracted 3× with ice-cooled 1 M HCl, 2× with room temper-
ature 1 M HCl, sat. NaHCO3, 2 M HCl, and sat. NaHCO3. The
organic layer was dried over Na2SO4, filtered, and evaporated
to yield the desired product (600 mg, 38%). TFA (9 mL) was
added to {2-[5-(3-fluoro-2′-N-tert-butylaminosulfonyl-biphenyl-
4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]benzylcarbam-
ic acid tert-butyl ester (600 mg, 0.87 mmol) in CH2Cl2 (3 mL)
and stirred at room temperature for 18 h. The reaction was
evaporated and purified by reverse phase prep HPLC (10-
70% MeCN/H2O/0.5% TFA) to yield impure product (349 mg).
This material was again purified by reverse phase HPLC (5-
70% MeCN/H2O/0.5% TFA) to yield clean product (162 mg,
35%). Any impure fractions containing product were combined
and purified by reverse phase HPLC (20-60% MeCN/H2O/
0.5% TFA) to yield additional product (119 mg, 26%). 1H NMR
(DMSO-d6) δ 8.25 (bs, 2H), 7.85 (s, 1H), 7.67 (dd, 2H, J ) 7.0,
J ′ ) 2.2), 7.68-7.55 (m, 4H), 7.51 (s, 2H), 7.41 (s, 2H), 7.33-
7.28(m, 2H), 7.21 (dd, 1H, J ) 8.4, J ′ ) 2.1), 3.81 (s, 2H) ppm;
19F NMR (DMSO-d6 δ -61.26, -74.29, -122.79 ppm; HRMS
calcd C24H20F4N5O3S: 534.1223; found, 534.1216. Anal. Calcd
for C24H20F4N5O3S‚C2HF3O2: C, 48.15, H, 3.26, N, 10.80; found,
C, 48.01, H, 3.02, N, 10.68.
1
mmol, 35%) as a white solid. H NMR (CDCl3) δ: 8.12 (dd, J
) 7.7 and 1.4 Hz, 1H), 7.75-7.6 (m, 3H), 7.42 (dd, J ) 7.7 and
1.1 Hz, 1H), 7.2 (s, 1H), 7-6.7 (broad, 1H), 3.7 (s, 3H) ppm.
1-(2-Met h oxyca r bon yl-p h en yl)-3-t r iflu or om et h yl-1H-
p yr a zole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-bip h en -4-
yl))ca r boxa m id e (43). To compound 42 (2.7 g, 8.9 mmol) in
CH2Cl2 (25 mL) were added oxalyl chloride (1.24 g, 9.8 mmol)
and 4 drops of DMF. The reaction was stirred at ambient
temperature for 2 h and then evaporated and placed under
high vacuum. This material was combined with 2-fluoro-4-(2-
methylsulfonylphenyl)aniline 4d (2.97 g, 9.8 mmol) and DMAP
(3.6 g, 29.4 mmol) in CH2Cl2 (25 mL) and stirred at ambient
temperature for 18 h. The reaction was evaporated, dissolved
in EtOAc (120 mL), washed with 1 N HCl (3 × 50 mL) and
then dried (MgSO4) and evaporated. This material was tri-
turated with 1-chlorobutane and there was obtained 3.34 g of
product (6 mmol, 67%) with a purity of 97% by HPLC. 1H NMR
(CDCl3) δ: 8.3 (t, J ) 8.4 Hz, 1H), 8.2 (dd, J ) 7.7 and 1.7 Hz,
1H), 8.18 (broad s, 1H), 8.1 (dd, J ) 7.7 and 1.8 Hz, 1H), 7.8-
7.5 (m, 5H)7.35-7.25 (m, 2H), 7.17 (s, 1H), 3.8 (s, 3H), 2.7 (s,
3H) ppm; LRMS (M + NH4)+: 579 m/z.
3-Tr iflu or om eth yl-1-(2-for m ylp h en yl)-1H-p yr a zole-5-
(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-bip h en -4-yl))ca r box-
a m id e (44). Compound 43 (3.5 g, 6.2 mmol) in MeOH (30 mL)
was stirred with water (4 mL) and 50% NaOH (2 mL) at
ambient temperature for 5 h. The basic mixture was diluted
with water (100 mL) and concentrated HCl added until acidic
(pH 1). The product was isolated by filtration, air-dried, and
triturated with 1-chlorobutane to give the carboxylic acid (3
1
g, 5.5 mmol, 89%). H NMR (CDCl3) δ: 8.3-8.1 (m, 4H), 7.8-
7.5 (m, 5H), 7.3 (m, 1H), 7.2-7.1 (m, 2H) and 2.7 ppm (s, 3H)
ppm; LRMS (M-H)-: 546.1 m/z. The carboxylic acid (1.66 g,
3.0 mmol) and NMM (0.37 g, 3.66 mmol) in THF (10 mL) was
cooled to -10 °C (MeOH/ice bath). To the cold solution, isobutyl
chloroformate (0.5 g, 3.66 mmol) was added. The reaction was
2-(5-F u r a n -2-yl-3-t r iflu or om et h yl-p yr a zol-1-yl)b en z-
oic Acid (41). 2-Hydrazinobenzoic acid (12.5 g, 66.3 mmol)
and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (13.65 g, 66.3
mmol) in acetic acid (100 mL) and water (30 mL) were heated

New Orally Bioavailable Factor Xa Inhibitor
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25 5313
7H), 7.22 (dd, J ) 8.1 and 1.5 Hz, 1H), 4.25 (broad s, 2H),
stirred for 1 h at -10 °C. The solution was filtered then added
to a 0 °C solution of NaBH4 (0.17 g, 4.57 mmol) in 1:1 THF:
water (6 mL: 6 mL). The reaction was left to thaw to ambient
temperature and stirred 18 h. The reaction was quenched by
the addition of 1 N HCl (18 mL), and EtOAc (30 mL) was
added. The solution washed with 5% NaHCO3 and brine and
then dried (MgSO4) and evaporated. Chromatography on a
column of flash silica with a mixture of EtOAc:hexane as the
elutent gave the desired product (0.56 g, 1.1 mmol, 37%). mp:
3.72 (s, 2H), 2.93 (s, 3H) ppm; HRMS (M + H)+ for C32H27
F4N4O3S, calcd m/z: 622.1662, obsd m/z: 622.1659.
-
1-(2-(3-Am in opr opyl)ph en yl)-3-tr iflu or om eth yl-1H-pyr -
azole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1′]-biph en -4-yl))-
ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (46). To a solution
of diethyl (cyanomethyl)phosphonate (0.123 g, 0.7 mmol) in
DMF (10 mL) was added NaH (25 mg of 60% suspension in
mineral oil). This mixture was stirred for 30 min and then
cooled to 0 °C, and a solution of 3-trifluoromethyl-1-(2-
formylphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-
[1,1]-biphen-4-yl))carboxamide 44 (prepared in SZ738, 0.71 g,
0.63 mmol) in DMF (10 mL) was added dropwise. The reaction
was stirred for 30 min with cooling and then the ice bath was
removed and the reaction stirred for 3 h at ambient temper-
ature. After this time, 1 N HCl (20 mL) and water (20 mL)
were added. This mixture was extracted with EtOAc (3 × 10
mL), and the EtOAc extract was washed with water (4 × 10
mL) and brine (15 mL) and then dried (MgSO4) and evaporated
to give 588 mg of the crude unsaturated nitrile. This material
was then taken up in MeOH (50 mL) with TFA (1 mL) and
placed in a Parr bottle, and 10% Pd-C catalyst (300 mg) was
added under a N2 blanket. The suspension was shaken on a
Parr apparatus under 50 psi of H2 gas for 18 h. The catalyst
was removed by filtration through a pad of Celite under a N2
blanket. The product was isolated by HPLC utilizing gradient
elution with a mixture of water:acetonitrile with 0.05% tri-
fluoroacetic acid on a reverse phase C18 (60 Å) column to give
the title compound as 71 mg of a white solid (0.13 mmol, 21%);
mp 102.1 °C. 1H NMR (CD3OD) δ: 8.14 (dd, J ) 8 and 1.4 Hz,
1H), 7.8-7.6 (m, 3H), 7.58-7.45 (m, 3H), 7.4-7.25 (m, 4H),
7.2 (dd, J ) 7.3 and 1.1 Hz, 1H) 2.81 (broad t, J ) 7.9 Hz,
2H), 2.76 (s, 3H), 2.57 (broad t, J ) 8 Hz, 2H) and 1.88 (5 line
pattern, J ) 7.7 Hz, 2H) ppm; HRMS (M + H)+ for C27H24N4O3-
SF4, calcd m/z: 561.1584, obsd m/z: 561.1590.
1
101.5 °C. H NMR (CDCl3) δ: 8.33 (broad s, 1H), 8.26 (t, J )
8 Hz, 1H), 8.2 (dd, J ) 7.7 and 1.4 Hz, 1H), 7.7-7.5 (m, 4H),
7.45 (td, J ) 7.3 and 1.8 Hz, 1H), 7.4-7.22 (m, 3H), 7.2 (s,
1H), 7.14 (d, J ) 8.4 Hz, 1H), 4.55 (d, J ) 4.1 Hz, 2H), 2.7 (s,
3H) ppm; LRMS (M + Na)+: 556.1 m/z. 1-(2-Hydroxymethyl-
phenyl)-3-trifluoromethyl-1H-pyrazole-5-(N-(3-fluoro-2′-methyl-
sulfonyl-[1,1]-biphen-4-yl))carboxamide (0.88 g, 1.65 mmol) and
MnO2 (activated, 2.5 g, 28.8 mmol) in CHCl3 was stirred at
ambient temperature for 48 h. The reaction was filtered
through a pad of Celite, washed with chloroform then evapo-
1
rated to give 0.711 g of the aldehyde 44 (1.34 mmol, 81%). H
NMR (CDCl3) δ: 9.3 (s, 1H), 8.4-8.0 (m, 3H), 7.8-7.3 (m, 8H),
7.2 (s, 1H), 2.7 (s, 3H) ppm.
1-(2-Meth ylam in om eth ylph en yl)-3-tr iflu or om eth yl-1H-
p yr a zole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-bip h en -4-
yl))ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (45a ). Com-
pound 44 (0.025 g, 0.05 mmol) was stirred in THF (3 mL) with
40% methylamine in water (2 mL) for 18 h. This was
evaporated and added to NaBH4 (0.2 mmol, 0.008 g) in MeOH
(2 mL). After 18 h, the reaction was evaporated and the
product purified by HPLC utilizing gradient elution with a
mixture of water:acetonitrile with 0.05% trifluoroacetic acid
on a reverse phase C18 (60 Å) column to give the title
compound as 10 mg of a colorless syrup (0.018 mmol, 36%).
mp 100.8 °C. 1H NMR (DMSO-d6) δ: 10.6 (s, 1H), 8.8-8.7
(broad, 1H), 8.1 (dd, J ) 7.7 and 1.4 Hz, 1H), 7.81 (s, 1H),
7.8-7.5 (m, 7H), 7.48 (d, J ) 8 Hz, 1H), 7.42-7.3 (m, 2H),
7.21 (dd, J ) 7.7 and 1.4 Hz, 1H), 3.95 (broad, 2H), 2.9 (s, 3H)
ppm; HRMS (M + H)+ for C26H22N4O3SF4, calcd m/z: 547.1427,
obsd m/z: 547.1441.
Ack n ow led gm en t. The authors would like to thank
Celia Dominguez, Maria Park, and Eugene Amparo for
their synthetic support. Portions of this work were
collected at beamline 17-BM in the facilities of the
Industrial Macromolecular Crystallography Association
Collaborative Access Team (IMCA-CAT) at the Ad-
vanced Photon Source. These facilities are supported by
the companies of the Industrial Macromolecular Crys-
tallography Association through a contract with Illinois
Institute of Technology (IIT), executed through IIT's
Center for Synchrotron Radiation Research and Instru-
mentation. Use of the Advanced Photon Source was
supported by the U.S. Department of Energy, Basic
Energy Sciences, Office of Energy Research, under
Contract No. W-31-102-Eng-38.
1-(2-Dim eth yla m in om eth ylp h en yl)-3-tr iflu or om eth yl-
1H-pyr azole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-biph en -
4-yl))ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (45b). Pre-
pared from compound 44 (100 mg, 0.19 mmol) by the method
reported for 45a with 40% dimethylamine in water substituted
for 40% methylamine solution. The product was a white solid
1
(35 mg, 0.063 mmol, 33%). mp 136.7 °C. H NMR (DMSO-d6)
δ: 10.7 (s, 1H), 8.1 (dd, J ) 7.7 and 1.4 Hz, 1H), 7.85 (broad
s, 1H), 7.82-7.64 (m, 4H), 7.62-7.58 (m, 2H), 7.5 (d, J ) 8
Hz., 1H), 7.43-7.3 (m, 2H), 7.22 (dd, J ) 8.3 and 1.4 Hz, 1H),
4.18 (broad s, 2H), 2.92 (s, 3H), 2.7 (broad s, 6H) H ppm; RMS
(M + H)+ for C27H24N4O3SF4, calcd m/z: 561.1584, obsd m/z:
561.1584.
1-(2-Isop r op yla m in om eth ylp h en yl)-3-tr iflu or om eth yl-
1H-pyr azole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-biph en -
4-yl))ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (45c). Pre-
pared from compound 44 (100 mg, 0.19 mmol) by the method
reported for 45a with isopropylamine substituted for 40%
methylamine solution. The product was a white solid (42 mg,
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental details. This material is available free of charge via
the Internet at http://pubs.acs.org.
Note Ad d ed a fter ASAP P ostin g
1
The supporting Information paragraph omitted in the
manuscript posted October 29, 2003, was added and the
manuscript reposted November 17, 2003.
0.073 mmol, 38%). H NMR (DMSO-d6) δ: 10.73 (s, 1H), 8.15
(dd, J ) 7.8 and 1.5 Hz, 1H), 7.93 (broad s, 1H), 7.80-7.68
(m, 4H), 7.63-7.57 (m, 2H), 7.45 (d, J ) 8 Hz., 1H), 7.43-
7.25 (m, 2H), 7.20 (dd, J ) 8 and 1.5 Hz, 1H), 4.31 (broad s,
2H), 2.92 (s, 3H), 2.78 (m, 1H), 2.06 (d, J ) 8 Hz, 6H) ppm;
HRMS (M + H)+ for C28H27F4N4O3S, calcd m/z: 574.1662, obsd
m/z: 574.1666.
Refer en ces
(1) This work was presented in part by (a) Galemmo, R. A. J r.;
Pruitt, J . R.; Lam, P. Y.; Pinto, D. J .; Dominguez, C.; Alexander,
R. S.; Rossi, K. A.; Wells, B. L.; Drummond, S.; Bostrom, L. L.;
Wong, P. C.; Wright, M. R.; Bai, S.; Knabb, R. M.; and Wexler,
R. R. New Functional Groups for the Interaction with the S1
Pocket of Factor Xa; the Discovery of (4-methoxyphenyl)pyrazole
and (2-(aminomethyl)phenyl)pyrazole Inhibitors. Abstr. Pap. Am.
Chem. Soc. 2001, 221, MEDI-015. (b) Pruitt, J . R.; Galemmo, R.
A. J r.; Bostrom, L. L.; Wong, P. C.; Wright, M. R.; Bai, S.; Knabb,
R. M.; and Wexler, R. R. Discovery of DPC602: Ortho-
substituted Phenylpyrazoles as Potent, Orally Bioavailable
Inhibitors of Factor Xa. Abstr. Pap. Am. Chem. Soc. 2001, 221,
MEDI-049.
1-(2-Ben zyla m in om eth ylp h en yl)-3-tr iflu or om eth yl-1H-
p yr a zole-5-(N-(3-flu or o-2′-m eth ylsu lfon yl-[1,1]-bip h en -4-
yl))ca r boxa m id e, Tr iflu or oa cetic Acid Sa lt (45d ). Pre-
pared from compound 44 (100 mg, 0.19 mmol) by the method
reported for 45a with benzylamine substituted for 40% methyl-
amine solution. The product was a white solid (45 mg, 0.072
1
mmol, 38%). H NMR (DMSO-d6) δ: 10.80 (s, 1H), 8.12 (dd, J
) 7.7 and 1.5 Hz, 1H), 7.90 (broad s, 1H), 7.82-7.67 (m, 4H),
7.65-7.60 (m, 2H), 7.52 (d, J ) 7.9 Hz., 1H), 7.43-7.25 (m,

5314 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 25
Pruitt et al.
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