Pyridine and pyridinone-based factor XIa inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.12.050

The structure-activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ra

Full text of DOI:10.1016/j.bmcl.2014.12.050

Bioorganic & Medicinal Chemistry Letters 25 (2015) 925–930
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyridine and pyridinone-based factor XIa inhibitors
⇑
James R. Corte , Tianan Fang, Jon J. Hangeland, Todd J. Friends, Alan R. Rendina, Joseph M. Luettgen,
Jeffrey M. Bozarth, Frank A. Barbera, Karen A. Rossi, Anzhi Wei, Vidhyashankar Ramamurthy,
Paul E. Morin, Dietmar A. Seiffert, Ruth R. Wexler, Mimi L. Quan
Discovery Chemistry and Cardiovascular Biology, Research and Development, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08543, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The structure–activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaf-
fold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone
( )-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between
imidazole and six-membered ring analogs.
Received 21 November 2014
Revised 10 December 2014
Accepted 12 December 2014
Available online 31 December 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Factor XIa inhibitors
FXIa
Activated partial thromboplastin time
aPTT
Thrombosis
Factor XIa (FXIa), a trypsin-like serine protease, functions early
in the intrinsic pathway of the blood coagulation cascade. It has
been demonstrated to play a key role in the amplification of throm-
bin production which leads to the growth and maturation of
thrombi.1 Based on the preclinical and genetic evidence, FXIa is a
potential target for anticoagulant therapy. FXI deficient mice are
protected in venous and arterial thrombosis models. Moreover,
they do not show an increase in bleeding relative to wild-type
mice.2 Therapeutic inhibition of FXIa by neutralizing antibodies,
antisense oligonucleotides, or small molecule inhibitors was found
to be effective in a number of animal thrombosis models with min-
imal effects on bleeding time.3–5,11
Individuals deficient in FXI have a condition known as hemo-
philia C. In contrast to the severe bleeding observed with hemo-
philia A and B, individuals with hemophilia C do not experience
spontaneous bleeding but rather injury-related bleeding which is
generally characterized as mild to moderate.6 Moreover, individu-
als with a severe FXI deficiency have shown a reduced incidence of
ischemic stroke, however they were not found to be protected
against acute myocardial infarction.7 Elevated levels of FXI are a
risk factor for acute myocardial infarction and deep vein thrombo-
sis.8 Selective FXIa inhibitors may offer an improved safety profile
by preventing thrombus formation without causing a significant
increase in bleeding.9
Several FXIa inhibitors, such as a-ketothiazole peptidomimet-
ics, boronic acid peptidomimetics, clavatadine A, and macrocyclic
indole derivatives, as well as, allosteric inhibitors have been
reported.5c,10 We have previously disclosed potent and reversible
FXIa inhibitors based on tetrahydroquinoline and indole chemo-
types.11 Recently, work from our laboratories led to the discovery
of imidazole (S)-1, a picomolar FXIa inhibitor having potent
in vivo antithrombotic efficacy in a rabbit AV-Shunt thrombosis
model (Fig. 1).12 As part of our research program to explore struc-
turally diverse FXIa inhibitors, we searched for replacements for
the imidazole ring. In this communication, we describe the SAR
of six-membered ring replacements for the imidazole ring result-
ing in the discovery of pyridine and pyridinone FXIa inhibitors.
Since one of the annular nitrogens of the imidazole ring resem-
bles the nitrogen of a pyridine ring,13 our initial ring replacements
P1'
P2'
NH2
O
N
HN
N
H
N
N
H
H2N
Cl
1
(S)-
FXIa Ki = 0.31 nM
aPTT EC2x = 1.0 µM
P1
⇑
Corresponding author. Tel.: +1 609 818 5806; fax: +1 609 818 3331.
E-mail address: james.corte@bms.com (J.R. Corte).
Figure 1. Imidazole (S)-1.
http://dx.doi.org/10.1016/j.bmcl.2014.12.050
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

926
J. R. Corte et al. / Bioorg. Med. Chem. Lett. 25 (2015) 925–930
Table 1
Table 2
Imidazole ring replacements
C5-substitution on imidazole and pyridine rings
O
O
N
H
X
N
H
X
H2N
H2N
Entry
X
FXIaa Ki (nM)
Entry
(S)-2
( )-3
( )-4
( )-5
( )-6
( )-7
X
FXIa Kia (nM)
120
N
N
N
N
(S)-2
120
HN
HN
HN
(S)-13
12
30,207
377
Cl
N
( )-4
377
320
N
N
330
( )-14
N
F
433
a
N
Ki values were obtained from purified human enzyme and were averaged from
multiple determinations (n = 2), as described in Ref. 11b.
N+
1,690
-O
N+
( )-8
( )-9
1,063
Table 3
O-
N
C6-substitution on pyridine ring
N+
2,530
O-
O
O
(S)-10
( )-11
11,423
N
H
N
H
N
H2N
N
H2N
N
O
331
936
R
N
N
20
( )-12
Entry
R
FXIaa Ki (nM)
a
Ki values were obtained from purified human enzyme and were averaged from
multiple determinations (n = 2), as described in Ref. 11b.
( )-4
H
Cl
NH2
NHMe
OH
377
206
227
860
113
949
479
( )-15
( )-16
( )-17
( )-18
( )-19
( )-20
focused on the pyridine ring system (Table 1). In order to quickly
survey a variety of six-membered rings, racemic derivatives con-
taining the simplified phenyl P2 prime group (replacing the amino
indazole moiety in (S)-1 with a phenyl) were prepared. The corre-
sponding homochiral imidazole (S)-2 is included for comparison.
Though pyridine 3 was a very weak inhibitor of FXIa, we were
pleased to discover racemic 4 had a FXIa Ki of 377 nM which was
comparable to homochiral imidazole 2 (FXIa Ki = 120 nM). The pyr-
idine nitrogen was important as oxidation to the corresponding N-
oxide 7 led to a 4-fold decrease in activity. A similar trend was
observed with the regioisomeric pyridine analogs. Pyridines 5
and 6 were equipotent to 4, where as their corresponding N-oxides
8 and 9 showed a loss in activity. Interestingly, with pyrimidine
(S)-10, containing both the nitrogens in 3 and 4, a significant loss
in activity was observed. Based on 3 and 10, a nitrogen lone pair
at the position between the substituents was deleterious for FXIa
activity. Regioisomeric pyrimidine 11 was equipotent with the pyr-
idine regioisomers 4, 5, and 6. In order to elucidate the role of the
nitrogen heteroatom on FXIa activity, the phenyl analog 12 was
prepared. The phenyl ring showed a 2- to 3-fold loss in FXIa activ-
ity (FXIa Ki = 936 nM). The pyridine (4, 5, and 6) and pyrimidine
(11) analogs proved to be good replacements for the imidazole
ring. Since the pyridines and pyrimidine exhibited similar FXIa
activity, the pyridine ring 4 was chosen for further SAR exploration
with the goal of improving potency.
OMe
N-Methyl pyridinone
a
Ki values were obtained from purified human enzyme and were averaged from
multiple determinations (n = 2), as described in Ref. 11b.
compound 14, with fluorine incorporation at the C5 position of the
pyridine, showed similar affinity as the unsubstituted pyridine 4.
Next, we explored substitution at the C6-position on the pyri-
dine ring (Table 3). The 6-chloro analog 15 showed a modest
improvement in FXIa affinity, but not as much of an improvement
as anticipated based on the chloro-imidazole (S)-13. The 2-amino
pyridine 16 showed a similar modest improvement in FXIa activity.
Methylation of the amino group (17) led to a 3.7-fold decrease in
activity. Moving to the 2-hydroxy pyridine 18, which is tautomeric
with the pyridinone, provided a 3-fold increase in FXIa affinity and
was equipotent to imidazole (S)-2. Methylation at oxygen (19) or
nitrogen (20) decreased FXIa affinity.
A variety of six-membered rings proved to be good replace-
ments for the imidazole and they are listed in order of decreasing
FXIa activity: imidazole (S)-2 ’ pyridinone 18 < pyridine regioi-
somers (4, 5, and 6) ’ pyrimidine 11 < phenyl 12. We have shown
in the imidazole series that a 40-fold increase in FXIa affinity could
be achieved by replacing the P2 prime phenyl with the amino inda-
zole moiety.12 In order to improve the affinity with the six-
membered ring scaffolds, we combined the amino indazole P2
prime moiety with the phenyl, pyridine, and pyridinone rings
(Table 4). The imidazole (S)-21 is included for comparison. Replac-
ing the P2 prime phenyl in 12, 4, and 18 with the amino indazole
moiety led to a >20-fold improvement in FXIa activity (( )-22 FXIa
Ki = 42 nM; ( )-23 FXIa Ki = 13 nM; ( )-24 FXIa Ki = 3.7 nM). The
chiral, nonracemic derivatives of 22 and 23 were prepared and FXIa
activity was found to reside in one enantiomer (compare (S)-22
Our earlier work in the imidazole series revealed that halogena-
tion (F or Cl) at the C5 position of the imidazole provided a 7.5- to
10-fold increase in FXIa activity.12 It was postulated that the
increase in activity was due to a lipophilic interaction with the ali-
phatic portion of the Lys 192 side chain of the FXIa active site. As a
result, we investigated substitution at both the C5 (Table 2) and
C6 positions (Table 3) on the pyridine ring. Imidazole (S)-2 and
chloro-imidazole (S)-13 are included for comparison. Unfortunately,

J. R. Corte et al. / Bioorg. Med. Chem. Lett. 25 (2015) 925–930
927
Table 4
primary amine can interact with three of the four possible part-
ners: a water molecule (2.7 Å), Asp189 (2.8 Å), Ala 190 (3.0 Å), or
Gly 218 (3.1 Å). The NH of the amide forms an H-bond with a
highly conserved water (3.4 Å). The carbonyl of the amide interacts
with the oxyanion hole which consists of the backbone NH’s of Ser
195 (3.3 Å), Asp 194 (3.1 Å) and Gly 193 (3.5 Å). The benzyl moiety
occupies the S1 prime pocket with an edge-on hydrophobic inter-
action between the phenyl ring and the disulfide bridge, Cys 58–
Cys 42. The pyridine nitrogen forms an H-bond to a conserved
water molecule (3.0 Å). This H-bonding does not appear to be a
key interaction for binding as the regioisomeric pyridines 5 and
6, which lack the ability to participate with the water molecule,
were equipotent to 4. In addition, the phenyl analog 12, which also
lacks the ability to H-bond with the water molecule was only mod-
estly less potent. The 3-amino indazole occupies the S2 prime
pocket and engages in a number of key H-bonds which contributes
to the 30-fold increase in FXIa activity. One of the NH bonds from
the C3-amino group forms a H-bond with the backbone carbonyl of
His 40 (3.0 Å) and the other NH forms an H-bond with the NH of
His 40 via a network of water molecules. The indazole N(1)H forms
an H-bond to Tyr 143 (3.0 Å) and the N(2) forms an H-bond
through a conserved water to Ile 151 (3.1 Å). The dihedral angle
between the pyridine scaffold and the amino indazole was 24.3°.
An overlay of pyridine (S)-23 with the X-ray structure of the
imidazole (S)-1 bound to human FXIa active site (the resolution
was 2.09 Å, the R-work was 0.179, and the R-free was 0.206) is
shown in Figure 3.12 Despite the similar binding mode, there are
two major differences in SAR between the imidazole and the six-
membered rings.15 The first difference involves the role of the het-
eroatom between the ring substituents. It is interesting to note that
the imidazole (S)-2 possesses a nitrogen atom between the ring
substituents and it was active. This was not the case for pyridine
3 or pyrimidine 10. A nitrogen atom between the ring substituents
led to a significant loss in activity. The explanation for this differ-
ence in activity may come from an interaction between the ring
atom and a conserved water molecule (orange sphere in Fig. 3).
Based on the residues of the enzyme that surround the water
and subsequent H-bonding interactions, the water molecule is ori-
ented so that the oxygen lone pair is pointing toward the ring
atom. In the case of pyridine 3 or pyrimidine 10, electrostatic
repulsion arises between the nitrogen lone pair from the ring
and the oxygen lone pair from the water, resulting in a destabiliz-
ing interaction and loss in FXIa activity.16 The imidazole ring can
avoid this electrostatic repulsion since a tautomeric form of the
Amino indazole P2 prime with phenyl, pyridine, and pyridinone rings
NH2
O
N
N
H
X
N
H
H2N
Entry
X
FXIa Kia (nM)
aPTTb EC2x
3.0
(lM)
H
N
(S)-21
3.2
N
( )-22
(S)-22
(R)-22
( )-23
(S)-23
(R)-23
42
>40
37
21
6160
13
NTc
6.0
4.5
NTc
N
N
8.4
1067
N
HN
( )-24
3.7
2.5
O
a
Ki values were obtained from purified human enzyme and were averaged from
multiple determinations (n = 2), as described in Ref. 11b.
b
aPTT (activated partial thromboplastin time) in vitro clotting assay was per-
formed in human plasma as described in Ref. 11b.
c
NT = not tested.
Figure 2. X-ray crystal of (S)-23 in factor XIa.
with (R)-22 and (S)-23 with (R)-23). As in the imidazole series, the
more active enantiomer was determined to possess the (S)-absolute
stereochemistry.12 Importantly, the pyridine and pyridinone were
single-digit nanomolar FXIa inhibitors and they exhibited in vitro
anticoagulant activity in the activated partial thromboplastin (aPTT)
clotting assay11b ((S)-23 aPTT EC2x = 4.5
EC2x = 2.5
l
M
and ( )-24 aPTT
l
M). Both the pyridine (S)-23 and the pyridinone ( )-24
were comparable to the unsubstituted imidazole (S)-21.
An X-ray structure of (S)-23 bound to human FXIa active site
(2.6 Å resolution, R-work was 0.176 and R-free was 0.226, Figure 2)
was obtained.14 The overall binding mode is similar to that
described previously for the imidazole (S)-1.12 Compound (S)-23
occupies the S1, S1 prime, and the S2 prime binding pockets and
participates in a large number of hydrogen bonding interactions.
The cyclohexyl methyl amine occupies the S1 pocket where the
Figure 3. Overlay of X-ray crystals of (S)-23 (cyan) and (S)-1 (orange) in factor XIa.

928
J. R. Corte et al. / Bioorg. Med. Chem. Lett. 25 (2015) 925–930
Table 5
The first method, used to prepare 1b, employed a modification of
the procedure described by Hart.17 In situ generation of N-trimeth-
ylsilylaldimine from 1a and lithium bis(trimethylsilyl)amide, fol-
lowed by the addition of benzyl magnesium bromide, gave after
aqueous work up, the primary amine 1b. The second approach,
used to prepare 1e, began with the carboxylic acid 1c. Negishi cou-
pling of the acid chloride, derived from 1c, and benzyl zinc chloride
afforded the ketone 1d. Condensation of ketone 1d with hydroxyl-
amine hydrochloride generated the oxime, which was reduced to
the primary amine 1e with zinc dust and TFA.18 Amide coupling
of amines 1b and 1e with N-Boc tranexamic acid provided 1f and
1h. Boc-deprotection of 1f and 1h gave the final compounds 4
and 11. The pyridine N-oxide 7 was prepared by oxidation of 1f
with mCPBA which gave 1g, followed by Boc-deprotection.
Human enzyme selectivity profile for pyridine (S)-23 compared to imidazole (S)-1
Human enzyme Kia (nM)
(S)-23
(S)-1
Factor XIa
Factor VIIa
Factor IXa
Factor Xa
Thrombin
Trypsin
Plasma kallikrein
Activated protein C
Plasmin
TPA
Urokinase
Chymotrypsin
8.4
0.31
4540
>34,900
>9000
>12,610
23
>10,890
>34,860
>9000
>12,610
64
24
4
>21,400
>22,100
>21,900
>14,060
>20,780
>31,180
8438
>21,940
15,180
>20,800
a
All Ki values in nM were obtained using human purified enzymes.
The compounds in Table
4 were prepared according to
Scheme 2. Acylation of the phenyl derivative (S)-2a provided (S)-
2b.19 Similarly, acylation of the pyridine ( )-2c followed by chiral
preparatory hplc, gave (S)-2d.20 Suzuki–Miyaura coupling of 3-
bromophenyl (S)-2b or 4-chloropyridine (S)-2d with 4-cyano-
3-fluorophenylboronic acid, followed by Boc-deprotection, gave
(S)-2e and (S)-2f. An alternative method was used to prepare the
pyridinone ( )-2j. Horner–Wadsworth–Emmons reaction of
b-ketophosphonate (S)-2g and 2-fluoro-4-formyl benzonitrile gave
imidazole can place the NH, rather than the nitrogen lone pair,
between the substituents on the ring. The imidazole NH can then
engage in a H-bond with the conserved water (2.9 Å).
The second major difference between the SAR of the imidazole
and the six-membered ring analogs involves the role of halogen on
the heterocyclic scaffold. As described, halogenation of the imidaz-
ole led to a significant increase in FXIa binding. However, haloge-
nation of the pyridine ring did not lead to this increase in
activity. The increase in binding for the imidazole was originally
attributed to a lipophilic interaction with the alkyl portion of the
Lys 192 side chain.12 Based on the overlay in Figure 3, a portion
of the pyridine ring is occupying the region of the chloro group
in the imidazole. It is possible that the pyridine ring is already pick-
ing up this lipophilic interaction which is accounted for in the
observed FXIa Ki. An alternative explanation is that halogenation
of the imidazole ring makes the imidazole NH a better H-bond
donor resulting in a stronger interaction with the conserved water
molecule and thus leading to an increase in binding for the imidaz-
ole. Since the pyridine cannot form an H-bond to the conserved
water, halogenation does not significantly help the binding affinity.
The selectivity profile of pyridine (S)-23 is compared to imidaz-
ole (S)-1 in Table 5. These compounds have >1000-fold selectivity
against many of the relevant serine proteases, except for plasma
kallikrein and trypsin.
a
,b-unsaturated ketone (S)-2h.21 Condensation of (S)-2h with 1-
(ethoxycarbonylmethyl)-pyridinium chloride or 1-(carbamoylm-
ethyl)-pyridinium chloride in the presence of ammonium acetate
in ethanol at elevated temperature afforded the racemic pyridi-
none ( )-2i.22 Boc-deprotection, amide coupling with Boc-tranex-
amic acid, followed by Boc-deprotection gave ( )-2j. Heating
(S)-2e, (S)-2f, and ( )-2j with hydrazine monohydrate in butanol
at 150 °C in a microwave afforded the aminoindazoles (S)-22,
(S)-23, and ( )-24.
In conclusion, the SAR of six-membered ring replacements for
imidazole has been described. A variety of six-membered rings
proved to be good replacements for the imidazole and they
are listed in order of decreasing FXIa activity: imidazole (S)-
2 ’ pyridinone 18 < pyridine regioisomers (4, 5, and 6) ’ pyrim-
idine 11 < phenyl 12. This work led to the discovery of the
potent and selective pyridine (S)-23 and pyridinone ( )-24 factor
XIa inhibitors. SAR and X-ray crystal structure data highlight the
key differences between the imidazole and six-membered ring
analogs. Further development on these six-membered ring
replacements for the imidazole will be reported in due course.
Representative examples of the synthesis of the compounds
listed in Tables 1–3 are described in Scheme 1. The key amine
intermediates 1b and 1e were prepared by two general methods.
OH
b, c
O
O
N
N
N
N
1c
1d
d, e
O
O
H
a
g
f
N
H
N
H
O
H
H2N
H2N
X
Z
N
X
Z
N
X
Z
Boc
1f
1a
1b
X = N; Z = CH,
4
X = N; Z = CH,
X = N; Z = CH,
h
+
-
+
-
X and Z = N, 1e
7
1g
X = N -O; Z = CH,
X = N -O ; Z = CH,
11
X and Z = N,
1h
X and Z = N,
Scheme 1. Reagents and conditions: (a) LiHMDS, THF, 0 °C, then BnMgCl, 47%; (b) thionyl chloride, cat. DMF, DCE, reflux; (c) Pd(Ph3P)4, BnZnCl, THF, ꢀ30 °C to 0 °C, 43% over
two steps; (d) hydroxylamine hydrochloride, MeOH; (e) Zn, TFA, 0 °C, 63% over two steps; (f) N-Boc-tranexamic acid, EDC, HOBt, Hunig’s base, DMF, 0 °C to rt; (g) 30% TFA
(v/v), CH2Cl2, rt, 45–67% over two steps. (h) mCPBA, CHCl3, rt.

J. R. Corte et al. / Bioorg. Med. Chem. Lett. 25 (2015) 925–930
929
CN
F
CN
a
b
OMe
OMe
Boc HN
P
BocHN
F
BocHN
O
O
HN
O
O
2h
(S)-
2g
(S)-
2i
(+)-
c, d , c
CN
O
O
f, c
d, e
R
R
N
H
F
N
H
H2N
H
N
H2N
X
X
Boc
X
R
2a
X = CH; R = Br, (S)-
2b
X = CH; R = Br, (S)-
2e
X = CH; R = H, (S)-
X = N; R = H, (S)-2f
2j
X = N; R = Cl, (+)-2c
X = N; R = Cl, (S)-2d
X = N; R = OH, (+)-
NH2
N
O
g
N
N
H
H
H2N
X
R
22
X = CH; R = H, (S)-
X = N; R = H, (S)-23
24
X = N; R = OH, (+)-
Scheme 2. Reagents and conditions: (a) 2-fluoro-4-formyl benzonitrile, K2CO3, THF, 75%; (b) 1-(ethoxycarbonylmethyl)-pyridinium chloride or 1-(carbamoylmethyl)-
pyridinium chloride, NH4OAc, EtOH, 80 °C, 60%; (c) 30% TFA (v/v), CH2Cl2, rt; (d) N-Boc-tranexamic acid, EDC, HOBt, Hunig’s base, DMF, 0 °C to rt; 66–80%; (e) chiral prep. hplc
on ( )-2d to give (S)-2d; (f) 4-cyano-3-fluorophenylboronic acid, Pd2(dba)3, tBu3PHBF4, Cs2CO3, dioxane, 90 °C; or Pd(dppf)Cl2ꢁCH2Cl2, K3PO4, DMSO, 85 °C; (g) hydrazine
monohydrate, n-BuOH, microwave, 150 °C, 10 min, 18% over three steps for phenyl (S)-22; 16% over three steps for pyridine (S)-23; 33% over four steps for pyridinone ( )-24.
7. (a) Salomon, O.; Steinberg, D. M.; Koren-Morag, N.; Tanne, D.; Seligsohn, U.
Acknowledgments
Blood 2008, 111, 4113; (b) Salomon, O.; Steinberg, D. M.; Dardik, R.; Rosenberg,
N.; Zivelin, A.; Tamarin, I.; Ravid, B.; Berliner, S.; Seligsohn, U. J. Thromb.
The authors would like to thank the Department of Discovery
Synthesis and BMS Biocon Research Center for the preparation of
an intermediate used in the synthesis of compound (S)-13 and
Dr. Steven Sheriff for deposition of the X-ray structures and data.
Haemost. 2003, 1, 658.
8. (a) Doggen, C. J. M.; Rosendaal, F. R.; Meijers, J. C. M. Blood 2006, 108, 4045; (b)
Meijers, J. C. M.; Tekelenburg, W. L. H.; Bouma, B. N.; Bertina, R. M.; Rosendaal,
F. R. N. Engl. J. Med. 2000, 342, 696.
9. Schumacher, W. A.; Luettgen, J. M.; Quan, M. L.; Seiffert, D. A. Arterioscler.
Thromb. Vasc. Biol. 2010, 30, 388.
10. (a) Deng, H.; Bannister, T. D.; Jin, L.; Babine, R. E.; Quinn, J.; Nagafuji, P.; Celatka,
C. A.; Lin, J.; Lazarova, T. I.; Rynkiewicz, M. J.; Bibbins, F.; Pandey, P.; Gorga, J.;
Meyers, H. V.; Abdel-Meguid, S. S.; Strickler, J. E. Bioorg. Med. Chem. Lett. 2006,
16, 3049; (b) Lazarova, T. I.; Jin, L.; Rynkiewicz, M.; Gorga, J. C.; Bibbins, F.;
Meyers, H. V.; Babine, R.; Strickler, J. Bioorg. Med. Chem. Lett. 2006, 16, 5022; (c)
Buchanan, M. S.; Carroll, A. R.; Wessling, D.; Jobling, M.; Avery, V. M.; Davis, R.
A.; Feng, Y.; Xue, Y.; Oster, L.; Fex, T.; Deinum, J.; Hooper, J. N. A.; Quinn, R. J. J.
Med. Chem. 2008, 51, 3583; (d) Hanessian, S.; Larsson, A.; Fex, T.; Knecht, W.;
Blomberg, N. Bioorg. Med. Chem. Lett. 2010, 20, 6925; (e) Al-Horani, R. A.; Desai,
U. R. J. Med. Chem. 2014, 57, 4805; (f) Sinha, D.; Badellino, K. O.; Marcinkiewicz,
M.; Walsh, P. N. Biochemistry 2004, 43, 7593.
11. (a) Wong, P. C.; Quan, M. L.; Watson, C.; Crain, E.; Wexler, R. R.; Seiffert, D.
Presented at the American Heart Association, Dallas, TX, Nov. 2013, APS.709.03,
Poster #7050.; (b) Quan, M. L.; Wong, P. C.; Wang, C.; Woerner, F.; Smallheer, J.
M.; Barbera, F. A.; Bozarth, J. M.; Brown, R. L.; Harpel, M. R.; Luettgen, J. M.;
Morin, P. E.; Peterson, T.; Ramamurthy, V.; Rendina, A. R.; Rossi, K. A.; Watson,
C. A.; Wei, A.; Zhang, G.; Seiffert, D.; Wexler, R. R. J. Med. Chem. 2014, 57, 955;
(c) Smallheer, J. M.; Wang, S.; Rossi, K. A.; Rendina, A.; Morin, P. E.; Wei, A.;
Zhang, G.; Wong, P. C.; Seiffert, D.; Wexler, R. R.; Quan, M. L. Presented at the
245th National Meeting of the American Chemical Society, New Orleans, LA,
April 2013; MEDI-415.
12. Hangeland, J. J.; Friends, T. J.; Rossi, K. A.; Smallheer, J. M.; Wang, C.; Sun, Z.;
Corte, J. R.; Fang, T.; Wong, P. C.; Rendina, A. R.; Barbera, F. A.; Bozarth, J. M.;
Luettgen, J. M.; Watson, C. A.; Zhang, G.; Wei, A.; Ramamurthy, V.; Morin, P. E.;
Bisacchi, G. S.; Subramaniam, S.; Arunachalam, P.; Mathur, A.; Seiffert, D. A.;
Wexler, R. R.; Quan, M. L. J. Med. Chem. 2014, 57, 9915.
13. Grimmet, M. R. Imidazoles and their Benzo Derivatives: (i) Structure In
Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and
Uses of Heterocyclic Compounds; Katritzky, A. R., Potts, K. T., Eds.; Pergamon
Press: New York, 1984; Vol. 5, pp 345–372.
References and notes
1. Emsley, J.; McEwan, P. A.; Gailani, D. Blood 2010, 115, 2569.
2. (a) Wang, X.; Smith, P. L.; Hsu, M.-Y.; Gailani, D.; Schumacher, W. A.; Ogletree,
M. L.; Seiffert, D. A. J. Thromb. Haemost. 1982, 2006, 4; (b) Wang, X.; Cheng, Q.;
Xu, L.; Feuerstein, G. Z.; Hsu, M.-Y.; Smith, P. L.; Seiffert, D. A.; Schumacher, W.
A.; Ogletree, M. L.; Gailani, D. J. Thromb. Haemost. 2005, 3, 695; (c) Rosen, E. D.;
Gailani, D.; Castellino, F. J. Thromb. Haemost. 2002, 87, 774.
3. (a) Yamashita, A.; Nishihira, K.; Kitazawa, T.; Yoshihashi, K.; Soeda, T.; Esaki, K.;
Imamura, T.; Hattori, K.; Asada, Y. J. Thromb. Haemost. 2006, 4, 1496; (b) Tucker,
E. I.; Marzec, U. M.; White, T. C.; Hurst, S.; Rugonyi, S.; McCarty, O. J. T.; Gailani,
D.; Gruber, A.; Hanson, S. R. Blood 2009, 113, 936; (c) Gruber, A.; Hanson, S. R.
Blood 2003, 102, 953.
4. (a) Crosby, J. R.; Marzec, U.; Revenko, A. S.; Zhao, C.; Gao, D.; Matafonov, A.;
Gailani, D.; MacLeod, A. R.; Tucker, E. I.; Gruber, A.; Hanson, S.; Monia, B. P.
Arterioscler. Thromb. Vasc. Biol. 2013, 33, 1670; (b) Zhang, H.; Lowenberg, E. C.;
Crosby, J. R.; MacLeod, A. R.; Zhao, C.; Gao, D.; Black, C.; Revenko, A. S.; Meijers,
J. C. M.; Stroes, E. S.; Levi, M.; Monia, B. P. Blood 2010, 116, 4684.
5. (a) Schumacher, W. A.; Seiler, S. E.; Steinbacher, T. E.; Stewart, A. B.; Bostwick, J.
S.; Hartl, K. S.; Liu, E. C.; Ogletree, M. L. Eur. J. Pharmacol. 2007, 570, 167; (b)
Wong, P. C.; Crain, E. J.; Watson, C. A.; Schumacher, W. A. J. Thromb.
Thrombolysis 2011, 32, 129; (c) Lin, J.; Deng, H.; Jin, L.; Pandey, P.; Quinn, J.;
Cantin, S.; Rynkiewicz, M. J.; Gorga, J. C.; Bibbins, F.; Celatka, C. A.; Nagafuji, P.;
Bannister, T. D.; Meyers, H. V.; Babine, R. E.; Hayward, N. J.; Weaver, D.;
Benjamin, H.; Stassen, F.; Abdel-Meguid, S. S.; Strickler, J. E. J. Med. Chem. 2006,
49, 7781.
6. (a) Seligsohn, U. J. Thromb. Haemost. 2009, 7, 84; (b) Franchini, M.; Veneri, D.;
Lippi, G. Hematology 2006, 11, 307; (c) Bolton-Maggs, P. H. B.; Patterson, D. A.;
Wensley, R. T.; Tuddenham, E. G. D. Thromb. Haemost. 1995, 73, 194.

930
J. R. Corte et al. / Bioorg. Med. Chem. Lett. 25 (2015) 925–930
14. PDB deposition number for (S)-23 is 4WXI.
19. (S)-2a was prepared from 3-bromo benzaldehyde using the procedure of Hart
15. The dihedral angle between the chloro-imidazole and the amino indazole was
21.8°. Geometries were optimized using QChem at the B3LYP/6-31G⁄⁄ level of
theory and RI-MP2/CC-PVTZ method. These studies indicated that the bioactive
conformation of the biaryl systems do not differ significantly from the lowest
energy conformation and therefore cannot explain the difference in potency.
16. A significant loss in FXIa activity is a general trend when a heteroatom,
possessing a lone pair, occupies the position between the ring substituents.
This is supported by SAR from the five-membered heterocycle ring
replacements, please see Ref. 12.
(Ref. 17). The enantiomers were separated by chiral preparatory HPLC and the
absolute stereochemistry was determined by reaction with (S)-(+)-a-
methoxyphenyl acetic acid according to Trost, B. M. et al J. Org. Chem. 1994,
59, 4202.
20. The absolute stereochemistry of (S)-2d was determined by reaction with (S)-
(+)-a-methoxyphenyl acetic acid as described in Ref. 19 and confirmed by X-
ray crystallography of (S)-23.
21. Rodriguez, A. C.; Ramos, A. P.; Hawkes, G. E.; Berti, F.; Resmini, M. Tetrahedron:
Asymmetry 1847, 2004, 15.
17. Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem. 1983, 48, 289.
18. Negi, S.; Matsukura, M.; Mizuno, M.; Miyake, K.; Minami, N. Synthesis 1996,
991.
22. (a) Krohnke, F.; Schnalke, K.-E.; Zecher, W. Chem. Ber. 1970, 103, 322; (b)
Racemization of either (S)-2h or the intermediates to the pyridinone occurred
under the reaction conditions.