Sulfonamidolactam inhibitors of coagulation factor Xa

Article abstract of DOI:10.1016/j.bmcl.2008.02.054

As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally dive

Full text of DOI:10.1016/j.bmcl.2008.02.054

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2428–2433
Sulfonamidolactam inhibitors of coagulation factor Xa
Joanne M. Smallheer,* Shuaige Wang, Mia L. Laws, Suanne Nakajima, Zilun Hu,
Wei Han, Irina Jacobson, Joseph M. Luettgen, Karen A. Rossi, Alan R. Rendina,
Robert M. Knabb, Ruth R. Wexler, Patrick Y. S. Lam and Mimi L. Quan
Bristol-Myers Squibb Company, Cardiovascular Diseases Chemistry, PO Box 5400, Princeton, NJ 08543-5400, USA
Received 2 January 2008; revised 14 February 2008; accepted 21 February 2008
Available online 26 February 2008
Abstract—As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors,
the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally
diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintain-
ing good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did
introduction of alternate P4 moieties.
ꢀ 2008 Elsevier Ltd. All rights reserved.
Safer and more efficacious oral anticoagulants that elim-
inate the need for the patient monitoring remain an un-
met medical need in the treatment of thromboembolic
disorders. Therapeutic agents that target specific coagu-
lation serine proteases are a major focus of ongoing
antithrombotic drug research. In particular, selective
inhibitors of Factor Xa (fXa) have been shown in ani-
mal models to offer a greater safety margin and better
efficacy when compared with heparin, LMWH, warfa-
rin, or direct thrombin inhibitors.1 Numerous potent
and selective small molecule Factor Xa inhibitors have
been reported, several of which have progressed into hu-
man clinical trials.2
the parent series. To this end, targets were designed to
maintain the key interactions in the S1 and S4 pockets
of fXa by modifying the central scaffold, which provides
the conformational constraint necessary to present the
P1 and P4 groups in the appropriate orientation for
binding to the enzyme. Various strategies were investi-
gated for the modification and/or the removal of the
pyrazole amide linkage to eliminate the potential for
metabolic cleavage. Non-cleavable amide bond replace-
ments were prepared,6 as well as a number of alternate
CF3
NH2
N
SO2Me
N
F
Previous reports from our laboratories have described
various pyrazole-based inhibitors of fXa including clin-
ical candidates DPC423 (1)3 and razaxaban (2).4 In a
phase II clinical trial, 2 was shown to prevent deep vein
thrombosis in patients undergoing total knee replace-
ment, displaying increased efficacy, and similar safety
to the LMWH, enoxaparin.5
N
O
H
1, DPC423
CF3
NMe2
NH2
N
N
N
N
N
O
N
H
O
The identification of suitable backups for these initial
clinical candidates focused on preparing structurally di-
verse compounds that would address potential issues in
2, razaxaban
O
H2N
O
N
N
O
N
N
Keywords: Factor Xa inhibitors; Anticoagulant; Serine protease inhib-
itors; Antithrombotic.
*
Corresponding author. Tel.: +1 609 818 5332; fax: +1 609 818
3450; e-mail: joanne.smallheer@bms.com
3, apixaban
OMe
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.054

J. M. Smallheer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2428–2433
2429
scaffolds resulting from cyclization of the amide nitro-
gen back to either the central aromatic ring7 or the pyr-
azole.8 The latter strategy culminated in the design and
synthesis of apixaban (3),9 which is currently undergoing
clinical trials. In the work presented here, we incorpo-
rated the amide linkage into a monocyclic piperidone
ring and removed the pyrazole ring to give compounds
of formula 4–7 in Table 1, where X is an ether, amine,
amide, or sulfonamide linker.10 As can be seen from
the fXa Ki data for these compounds, there was a clear
difference in potency seen between the linkers, and sul-
fonamide 7 was 4- to 10-fold more potent compared
to compounds 4–6.
groups such as the N,N-(dimethylaminomethyl)-imidaz-
ole P4 group of 2 (See Table 4). Similar potency versus
fXa was observed for this analog (40) with ꢀ10-fold
improvement in PT as compared to 22. Quaternary
compounds 41 and 42 which were obtained from at-
tempted alkylation of the sulfonamide nitrogen of 40
were ꢀ10-fold more potent fXa inhibitors with similar
potency in the PT assay to 40. A loss in potency as com-
pared to the 2-methylsulfonyl-phenyl and N,N-dimeth-
ylamino-methylimidazole compounds was observed
with 4-pyridine, 43, 1-piperidine, 44, and 2-oxo-1-piper-
idine analogs, 45, although most of this potency loss
could be regained in the latter analog by the introduc-
tion of the N-methyl, N-(2-N,N-dimethylamino-
methyl)acetamide substitution on the sulfonamide
nitrogen (46). As previously observed in the pyrazole-
based series,15 the replacement of the saturated lactam
P4 group of 45 with a 2-pyridone moiety results in en-
hanced affinity for fXa. Pyridone P4 analog 47 was in-
deed the most potent in this group with fXa Ki of
0.11 nM, however, the translation to the PT assay was
poor as compared to imidazole 40. Again substitution
at the nitrogen of the sulfonamide nitrogen resulted in
a 5-fold increase in fXa potency over 47 in N-methyl,
N-(2-N,N-dimethylaminoethyl)-acetamide analog 48,
along with a 10-fold improvement in the PT assay.
The (S)-enantiomer of 4816 was evaluated in a PK study
in dogs. The compound had clearance of 1.19 L/h/kg, a
6.45 h half-life and low oral bioavailability (F% = 4%),
Further optimization of 7 via a library of P1 sulfona-
mides was therefore carried out. Among the substituted
phenyl sulfonamides, a para substituent was generally
preferred over the same substitution at the meta posi-
tion, with the p-chlorophenyl compound 10 having the
best potency at 23 nM. Both the 6-chloronapthyl (22)
and the 5-chloro-2-thienyl (25) compounds were single
digit nanomolar inhibitors of fXa. Analogs with 7-chlo-
ronaphthyl (23), 3-aminobenzisoxazolyl (24), 6-indazol-
yl (28), and 3-quinolinyl (29) P1 groups also showed
promising potency in this series.
Despite relatively good affinity for fXa, the chloronaph-
thyl compound 22 had poor potency in the prothrombin
time (PT) assay13 used for assessing the in vitro antico-
agulation efficacy of these compounds (See Table 3). In
view of the highly lipophilic nature of this compound
(clogP = 5.63), this is most likely due to high plasma
protein binding.14 Substitution of polar groups on the
sulfonamide nitrogen as a means to lower protein
binding and increase aqueous solubility was therefore
investigated. Introduction of carboxymethyl, (methoxy-
carbonyl)methyl or 3-hydroxypropyl groups in this posi-
tion provided compounds 31–33 with similar or slightly
improved fXa affinity, but did little to improve PT. In
contrast, acetamide compounds 34–39, which incorpo-
rated a terminal tertiary amine, were both 2- to 4-fold
more potent inhibitors of fXa and provided approxi-
mately 5-fold improvement in PT as compared to 22.
Table 2. P1 sulfonamide SAR
F
O O
S
N
R
N
SO2Me
H
O
Compound8
R
fXa Kia (nM)
7
8
4-MeO-phenyl
Phenyl
53
370
44.5
23
9
4-F-phenyl
4-Cl-phenyl
4-Et-phenyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
78
4-Cyanophenyl
3-Cl-phenyl
420
380
100
270
61
Further reduction in overall lipophilicity was achieved
by replacing the terminal phenylsulfone P4 group in
the parent compound with more polar heterocyclic
3-MeO-phenyl
3,4-diF-phenyl
3,4-diCl-phenyl
2,5-Cl-phenyl
3,5-diCl-phenyl
3-Pyridyl
650
730
2600
260
3200
2.2
18
Table 1. SAR of linkers
MeO
2-NH2-5-pyridinyl
Benzyl
F
N
X
SO2Me
6-Cl-naphthyl
7-Cl-naphthyl
O
3-NH2-5-benzisoxazolyl
5-Cl-2-thienyl
19
5.3
160
26
Compound11
X
O
fXa Kia (nM)
5-Cl-3-Me-2-benzothienyl
5-(3-Isoxazolyl)-2-thienyl
6-Indazolyl
4
5
6
7
200
450
560
53
NH
CONH
SO2NH
19
28
3-Quinolinyl
6-Quinolinyl
73
a Ki’s obtained from purified human enzymes and are averaged from
two experiments (n = 2).12
a Ki’s obtained from purified human enzymes and are averaged from
two experiments (n = 2).

2430
J. M. Smallheer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2428–2433
consistent with its lack of permeability in a Caco-2
assay.17
N-methylamide of compound 51, which maintained
good potency and anticoagulant activity, but still had
poor Caco-2 permeability. Removal of the o-fluoro sub-
stitution from the phenyl of 49 provided 52 with better
translation to the PT assay. Des-fluoro analog 53 with
a primary amide substituent on the sulfonamide linker
also showed good PT potency, but no Caco-2 perme-
ability. Acid 54 was similar in fXa affinity to amide 53
but had a ꢀ3-fold drop off in vitro anticoagulant actvi-
ty. Improved permeability over amides 50, 51, and 53
was achieved with methyl ester 55, which had a similar
fXa affinity and potency in the PT assay to 51. These re-
sults suggest that further optimization could provide
additional potent compounds with improved oral bio-
availability in this series. The compounds described
herein are highly selective for fXa with >10000-fold
selectivity over thrombin, trypsin, and fVIIa. Com-
pounds (S)-48 and 55, were selected for evaluation in
mechanistic studies.18 As predicted for reversible inhibi-
tors binding in the active site, both compounds were
competitive inhibitors with a chromogenic tripeptide
substrate,19 but exhibited mixed-type inhibition versus
the physiological substrate, prothrombin, which inter-
acts with FXa primarily at exosites.20 This mechanism
is advantageous since these compounds are potent
inhibitors at both low and high physiological levels of
prothrombin.
An additional improvement in potency versus fXa in
compounds with the pyridone P4 group was realized
Table 3. SAR of substituted sulfonamide analogs
O
F
O
S
N
N
SO2CH3
R
O
Cl
Compound8
R
H
fXa Kia PTb EC2x
(nM)
(lM)
22
31
32
33
34
35
36
37
2.2
1.0
0.88
2.3
2.2
102
250
89
CH2CO2H
CH2CO2Me
(CH2)3OH
CH2CONH(CH2)2NMe2
208
NDc
17
CH2CON(Me)(CH2)2NMe2 0.84
CH2CON(Me)(CH2)2NEt2
CH2CON(Me)(CH2)2OH
1.1
2.7
19.5
NDc
38
39
0.43
0.71
19.5
24.4
-CH2CON(Me)
N Me
-CH2CO N
N Me
aKis are obtained from purified human enzymes and are averaged from
two experiments (n = 2).
The racemic compounds in Tables 1–5 were synthesized
from commercially available 2-tetrahydrofuran carbox-
ylic acid as outlined in Scheme 1. The acid was
converted to the acid chloride which was coupled with
2-fluoro-4-[2-(methylsulfonyl)-phenyl]aniline3 in the
presence of DMAP to provide amide 56. Treatment of
56 with BBr3 led to the open chain bromoalcohol, which
was acetylated and then cyclized by treatment with
b PT values were measured according to Refs. 3 and 4.
c ND, not determined.
by replacing the 6-chloronaphthyl P1 with a 6-chloro-
thieno[2,3-b]pyridinyl moiety to provide the compounds
in Table 5. This allowed the replacement of the basic
sulfonamide substituent in analog 50 with the neutral
Table 4. P4 heterocycle SAR
O
F
O
S
N
N
O
P4
Cl
R
P4 groups:
Me
O
O
Me
NCH2CO2Me
NMe2
N
N
N
N
N
N
N
N
A
B
C
D
F
E
Compound
R
P4
fXa Kia (nM)
PTb EC2x (lM)
40
41
H
H
A
B
B
C
D
E
E
F
F
F
2.4
13
13
0.35
0.21
28
42
43
CH2CO2Me
12
H
H
H
NDc
NDc
NDc
12
44
45
16
10
46
47
CH2CON(Me)(CH2)2NMe2
H
1.7
0.11
0.02
0.016
35
48
(S)-48
CH2CON(Me)(CH2)2NMe2
CH2CON(Me)(CH2)2NMe2
3.3
1.7
a Kis are obtained from purified human enzymes and are averaged from two experiments (n = 2).
b PT values were measured according to Refs. 3 and 4.
c ND, not determined.

J. M. Smallheer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2428–2433
2431
Hunig’s base to give the 3-acetoxylactam. Hydrolysis of
the acetate and treatment of the resulting alcohol with
PBr3 provide the key bromolactam intermediate 57.
The bromide was displaced with p-methoxyaniline or
the corresponding phenol in the presence of sodium hy-
dride to give the N and O linked analogs 58 and 60,
respectively, or converted into the corresponding pri-
mary amine 59 by displacement with sodium azide fol-
lowed by reduction either by catalytic hydrogenation
or by triphenylphosphine in ether. Amide analogs 61
were prepared by condensation of 59 with carboxylic
acids in the presence of TBTU and TEA, and sulfon-
amide analogs 62 by reaction of 59 with the correspond-
ing sulfonylchlorides which were either commercially
available or prepared as described by Becker et al.21
Bis-sulfonylation was avoided by use of a two phase
reaction mixture consisting of 1 M K2CO3 and EtOAc,
and the excess sulfonylchloride was scavenged with
PS-trisamine resin. The sulfonamide products could
then be alkylated with the appropriate alkyl bromides
or iodides in the presence of K2CO3 in DMF to provide
compounds of formula 63. To prepare the acetamide
analogs, 62 was first alkylated using tert-butyl bromo-
acetate followed by the cleavage of the tert-butyl ester
with TFA in CH2Cl2. Amides were prepared from the
resulting acids by reaction with amines in the presence
of BOP, TEA, and DMAP at 50ꢁC. Analogs with het-
erocyclic P4 groups were similarly prepared from amine
intermediates 66, 67, and 68, which were obtained as
outlined in Scheme 2 from aryliodide intermediate 65
using copper mediated N-arylation chemistry.
A model of (S)-48 overlaid with the crystal structure of
122 is shown in Figure 1. The biaryl P4 fits as expected
into the hydrophobic box formed by residues Phe174,
Trp215, and Tyr99. The carbonyl of the central lactam
core is within H-bonding distance of the backbone
NH of Gly216. The chlorine at the 6-position of the
naphthyl P1 moiety extends deeper into the S1 pocket
to displace a structural water molecule and engage in a
hydrophobic interaction with Tyr228. Similar close
hydrophobic contact between aromatic chloride moie-
Table 5. 6-Chlorothieno[2,3-b]pyridinyl analogs
O
X
O
S
N
N
O
S
O
R
N
N
Cl
Compound
R
X
fXa Kia (nM)
PTb EC2X (lM)
Caco-2b Papp · 10ꢁ6 (cm/s)
49
50
51
52
53
54
55
H
F
0.02
0.013
0.037
0.05
0.1
32
8.3
0
CH2CON(Me)(CH2)2NMe2
CH2CONHMe
H
F
2.1
4.2
15
F
0.1
2.0
0
H
H
H
H
CH2CONH2
CH2CO2H
CH2CO2Me
4.8
16
0.13
0.043
ND
3.5
4.4
a Kis are obtained from purified human enzymes and are averaged from two experiments (n = 2).
b PT and Caco-2 values were measured according to Ref. 3 and 4.
F
H
F
N
c-g
a,b
O
N
SO2CH3
Br
SO2CH3
O
CO2H
78%
O
O
95%
56
57
j
h,i
F
72%
k
Ar
O
N
59%
N
H
60%
H2N
SO2CH3
F
O
N
F
SO2CH3
Ar
58
N
O
O
SO2CH3
59
O
l
m,n
60
30-50%
F
45-95%
N
Ar
N
O
SO2CH3
O
O
F
H
O
F
O
S
N
S
Ar
N
N
SO2CH3
Ar
N
SO2CH3
61
H
O
O
R
o-r
65-75%
62
63
Scheme 1. Reagents and conditions: (a) oxalyl chloride, DMF, CH2Cl2; (b) CH2Cl2, DMAP, 2-fluoro-4-(2-methylsulfonylphenyl)aniline; (c) BBr3,
CH2Cl2; (d) Ac2O, heptane; (e) DIPEA, DMF, reflux; (f) K2CO3, MeOH/H2O; (g) PBr3, CH2Cl2; (h) NaN3, DMF, 50 ꢁC; (i) H2, Pd/C MeOH; (j)
ArNH2, NaH, THF; (k) ArOH, NaH THF; (l) ArCO2H, TBTU, TEA, DMF; (m) ArSO2Cl, 1 M K2CO3, EtOAc; (n) PS-trisamine; (o) tert-butyl
bromoacetate, K2CO3, DMF; (p) TFA, CH2Cl2; (r) RNHR0, BOP, TEA, DMAP, DMF, 50 ꢁC.

2432
J. M. Smallheer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2428–2433
F
F
F
H
N
a,b
c-f
53%
i-l
N
N
O
H2N
HO
O
O
CO2H
96%
O
O
O
I
28%
N
I
64
65
66
F
F
h, j-l
16%
N
H2N
N
NMe2
H2N
O
g, j-l
24%
O
O
N
N
N
67
68
Scheme 2. Reagents and conditions: (a) oxalyl chloride, DMF, CH2Cl2; (b) CH2Cl2, DMAP, 2-fluoro-4-iodoaniline; (c) BBr3, CH2Cl2; (d) Ac2O,
heptane; (e) DIPA, DMF, reflux; (f) K2CO3, MeOH/H2O; (g) 2-(N,N-dimethylamino)methylimidazole, CuI, K2CO3, DMSO, 140 ꢁC, 3 h; (h)
piperidinone, K3PO4, CuI, 1,2-diaminocyclohexane, dioxane, 85 ꢁC (i) 2-hydroxypyridine, CuI, K2CO3, DMSO, 140 ꢁC, 3 h; (j) PBr3, CH2Cl2; (k)
NaN3, DMF, 50ꢁC; (l) SnCl2, MeOH.
Acknowledgment
We thank Dr. Philip Stein for providing the 6-chlorothi-
enopyridine-2-sulfonylchloride used in the synthesis of
compounds 49–55.
References and notes
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Figure 1. Model of Compound (S)-48 in white overlaid on crystal
structure of 1 (DPC423) in blue complexed with fXa (in green).
3. Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.;
Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.;
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ties and the aromatic ring of Tyr228 has been observed
in several recently reported fXa-inhibitor crystal struc-
tures.23 One of the oxygens of the sulfonamide linker
is directed toward the backbone NH of Gln192 similar
to the N2 of the pyrazole ring of 1 while the other sul-
fonamide oxygen points toward the oxyanion hole.
The N-methyl of the acetamide substituent at the sulfon-
amide nitrogen extends toward the Cys191–Cys220
disulfide bridge occupying a similar position as the tri-
fluoromethyl moiety of 1, while the basic dimethylamine
group is most likely solvent exposed.
In summary, highly potent inhibitors of fXa which com-
bine biaryl P4 groups with chloronaphthylsulfonyl and
chlorothienylpyridinesulfonyl P1 moieties linked by an
aminopiperidone conformational constraint have been
identified. Potency and molecular properties can be
fine-tuned by introduction of appropriate functionality
at the sulfonamide nitrogen in these molecules. The
best combination of fXa potency, in vitro anticoagulant
activity and permeability was obtained with compound
55.

J. M. Smallheer et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2428–2433
2433
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13. Prothrombin time assay was carried as described in Refs. 3
and 4.
14. For a discussion of the effect of plasma protein binding on
translation from fXa Ki to in vitro anticoagulant activity
see Ref. 4.
15. D.J.P. Pinto, unpublished results.
16. Single enantiomers of 48 were separated by chiral HPLC.
17. Caco-2 and dog PK parameters were measured as
described in Refs. 3 and 4.
18. Experimental details for mechanism studies are described
in a manuscript in preparation on apixaban and in
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M.; Kearney, R.; Poli, G.; Pauls, H.; Gardner, C.; Gong,
Y.; Becker, M.; Davis, R.; Spada, A.; Liang, G.; Chu, V.;
Brown, K.; Collussi, D.; Leadley, R., Jr.; Rebello, S.;
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11. All of the compounds in Tables 1–5 gave satisfactory
spectral and analytical data. Compounds 19–20, 29–30,
34–36, 38–41, 43–44, 46, 48 and 50 were isolated as TFA
salts.
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L. L.; Burdick, D.; Bruckner, R.; Chen, H.; Smallwood,
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23. (a) Maignan, S.; Guilloteau, J. P.; Choi-Sledeski, Y. M.;
Becker, M. R.; Ewing, W. R.; Pauls, H. W.; Spada, A. P.;
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Kochanny, M. J.; Ye, B.; Rumennik, G.; Light, D. R.;
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