2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2014.04.011

Blockade of the P2Y₁ receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y ₁₂ receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y ₁ receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC₅₀ less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher C_trough, lower Cl, smaller V_dss, and similar bioavailability compared with 3.

Full text of DOI:10.1016/j.bmcl.2014.04.011

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2481–2485
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl
spiropiperidine indolinyl series as potent P2Y1 receptor antagonists
⇑
⇑
Carol H. Hu , Jennifer X. Qiao , Ying Han, Tammy C. Wang, Ji Hua, Laura A. Price, Qimin Wu, Hong Shen,
Christine S. Huang, Robert Rehfuss, Ruth R. Wexler, Patrick Y. S. Lam
Medicinal Chemistry, Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved
safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates
of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl
spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the
Received 13 January 2014
Revised 1 April 2014
Accepted 4 April 2014
Available online 13 April 2014
most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5
lM with
10 M ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharma-
cokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.
l
Keywords:
P2Y1 receptor antagonist
Antiplatelet
Ó 2014 Elsevier Ltd. All rights reserved.
Urea mimetics
2-Amino-1,3,4-thiadiazoles
Structure–activity relationship (SAR)
Adenosine-50-diphosphate (ADP) plays a pivotal role in platelet
aggregation and thrombus formation. Two G-protein coupled recep-
tors from the P2 nucleotide receptor family, P2Y1 and P2Y12, are both
required for full ADP-induced platelet aggregation. But each plays a
different role in this process. P2Y1 triggers a rapid and transient intra-
cellular calcium increase which leads to platelet shape change and
initiates the process of platelet activation. P2Y12 mediates a slower
and more sustained decrease of cyclic adenosine monophosphate
(cAMP) level which amplifies and stabilizes platelet activation.
Blockade of either P2Y1 or P2Y12 receptor has been shown to
significantly repress platelet aggregation, which is very important
in the treatment of thrombosis.1,2 P2Y12 receptor antagonists are
well-established antiplatelet drugs, such as the irreversible antag-
onists clopidogrel (PlavixÒ)3 and prasugrel (EffientÒ),4 as well as
the more recently developed reversible antagonist ticagrelor
(BrilintaÒ).5 Recent studies have shown that mice dosed with
selective P2Y1 antagonist, MRS2179, demonstrated a complete
blockade of ADP-induced platelet aggregation, and strong efficacy
in a ferric chloride (FeCl3) induced model of thrombosis with a
mild prolongation of bleeding time.6 These studies suggest that
P2Y1 antagonists could be a potential treatment for a variety of
thrombotic disorders and may have improved safety margins
relative to P2Y12 antagonists.
We previously disclosed a series of non-nucleotide P2Y1 recep-
tor antagonists, t-butylphenoxypyridinyl ureas with a general
structure of 1 (Fig. 1).7 Replacement of the urea group in 1 with
aminoheterocycles led to several series of P2Y1 antagonists includ-
ing compounds containing 2-amino-1,3,4-thiadiazoles or 2-amino-
thiazoles as urea surrogates.8 Compounds 2a and 2b were the most
potent examples in the respective series, and both showed good
P2Y1 binding but relatively moderate antiplatelet activity in the
platelet aggregation (PA) assay. Extensive SAR studies8 in the
t-butylphenoxy chemotype revealed that the aminoheterocycle
urea mimetics were generally less active in the PA assay compared
with the corresponding ureas, which could be attributed to the
increased hydrophobicity of the heterocycle analogs.
Furthermore, we recently reported that structural modifications
of the aforementioned t-butylphenoxypyridinyl urea series led to a
series of N-neopentyl spiropiperidine indolinyl diaryl ureas as
potent P2Y1 antagonists with improved antiplatelet activity.9 Fur-
ther SAR including addition of a hydroxyl group at the 7-position
of the indolinyl ring led to the discovery of compound 3, an
advanced lead with much improved antiplatelet activity (PA
IC50 = 0.13 lM with 10 l
M of ADP).10
We aimed to further explore the structural diversity of the urea
region by using the more active 7-hydroxy spiropiperidine indoli-
nyl chemotype 3 as the template to identify non-urea analogs with
in vitro antiplatelet activity and pharmacokinetic profiles similar
to those of the urea lead 3. In this paper, we will first describe
the initial SAR of several different aminoheteroaryl containing
⇑
Corresponding authors. Tel.: +1 609 818 5708/5298; fax: +1 609 818 6810.
E-mail addresses: carol.hu@bms.com (C.H. Hu), jennifer.qiao@bms.com
(J.X. Qiao).
http://dx.doi.org/10.1016/j.bmcl.2014.04.011
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

2482
C. H. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2481–2485
Table 1
(a)
SAR of 2-aminoheteroaryl analogs 4a–i
H
N
H
N
R
R =
O
OH
R'
A
N
O
OCF3
R
N
H
N
1
P2Y1 Ki = 6 nM
PA IC50 = 2.1 µM [2.5 µM ADP]
PA IC50 = 11 µM [10 µM ADP]
N
N
O
4
(A = 5 or 6-membered
heteroaryl rings)
S
S
N
CF3
c
Entry
#
R0
–NH-A-R
P2Y1 Kia
(nM)
P2Y1 FLIPR
IC50 (nM)
PA IC50
M)
N
N
b
(l
CF3
2b
P2Y1 Ki = 12 nM
PA IC50 = 5.2 µM [2.5 µM ADP]
PA IC50 = 57 µM [10 µM ADP]
2a
P2Y1 Ki = 7 nM
PA IC50 = 7.5 µM [2.5 µM ADP]
N
N
4a
4b
CF3
Cl
9.6
6.0
0.19
6.4
0.99
5.4
N
H
Ph
S
Ph
N
(b)
N
N
S
H
N
N
O
OH
OH
N
4c
Cl
Cl
6.2
66
49
>10
9.0
N
H
A
N
R
N
H
Ph
Ph
O
N
Cl
N
H
N
H
N
S
N
O
4d
NTd
N
H
Cl
R'
N
N
Ph
N
4e
Cl
20
54
>10
N
H
S
3
4-6
N
P2Y1 Ki = 8 nM
P2Y1 FLIPR IC50 = 0.12 nM
PA IC50 = 0.13 µM [10 µM ADP]
A = 5 or 6-membered
heteroaryl rings
4f
Cl
Cl
17
2.3
3.7
N
H
Ph
p-Tol
S
N
4g
343
NTd
>10
N
H
Figure 1. (a) The diaryl urea lead 1 and related urea mimetic series exemplified by
compound 2a and 2b in the t-butylphenoxy chemotype; (b) N-neopentyl spiropi-
peridine indolinyl diaryl urea lead 3 and general structures 4–6 of urea mimetics in
the later series.
N
N
Ph
Ph
4h
4i
Cl
Cl
511
49
NTd
NTd
>40
>40
N
H
N
compounds designed to mimic the biological conformation of the
urea group (Table 1). We will then present the lead optimization
of the most potent 2-amino-1,3,4-thiadiazole series (Table 2 and
Fig. 2). Finally we will discuss the pharmacokinetic profile of
selected 2-amino-1,3,4-thiadiazole analogs in comparison to com-
pound 3 (Table 3).
N
N
H
a
SPA beads (LEADseeker™, Amersham Biosciences) were used in 384-well assay
plate for P2Y1 membrane binding assay, n = 1.
b
FLIPR was tested with 1
l
M of 2-methylthio-ADP, and IC50 values are reported
as the mean, n = 2.
c
PA IC50 was tested at 10
l
M of ADP,9 n = 1.
d
In search of potent urea mimetics, we compared several five-,
and six-membered ring systems. Table 1 outlines representative
compounds from each ring type. Compounds were evaluated for
in vitro potency in the P2Y1 binding assay, P2Y1 FLIPR assay, and
PA activity assay.7–10 P2Y1 binding assay identified inhibitors of
NT: not tested.
terms of in vitro inhibition of platelet aggregation (PA IC50 = 0.99
at 10
more active than the 1,3,4-thiadiazole analog 2a (PA IC50 = 7.5
at 2.5 M ADP) in the t-butylphenoxy series.
l
M
l
M ADP) among all the ring systems studied and was much
lM
[
33P]2MeS-ADP binding to the cloned human P2Y1 receptor stably
expressed in a HEK293 cell line.7 FLIPR assay measured the activa-
tion of the calcium signal transduction pathway by P2Y1 in washed
human platelets using the endogenously expressed receptor.9,11 PA
activity assay tested the ability of P2Y1 antagonists to inhibit plate-
l
We selected the most potent 2-amino-1,3,4-thiadiazole 4a to
study the substitutions on the indoline (R0) and the terminal phe-
nyl ring (R) as illustrated in Table 2. Based on key SAR of compound
3 in the urea series, we picked small electron-withdrawing R
groups such as CF3, Cl, F, CN, and CO2Me to substitute at the 4-
position of the indoline ring to increase antiplatelet activity and
to potentially reduce reactive intermediate formation.10 Com-
pounds 5a–5f which also contain a hydrophobic R group such as
CF3, tBu, and OCF3 were among the most potent analogs made in
the series, having similar antiplatelet activity (PA IC50 ca. 1
Among them 5a was the most potent and was the first non-urea
compound synthesized with a PA IC50 less than 0.5 M, which
was four-fold less potent than urea analog 3. On the other hand,
5g with an o-Cl R substitution, showed similar activity in the bind-
ing assay as the corresponding m-Cl or p-Cl analogs 5h or 5i, but
surprisingly, was much less potent in the functional assays.
let aggregation induced by 2.5 or 10 lM ADP using human platelet-
rich plasma (PRP).9 Despite showing similar potency in the binding
assay, 4a was significantly more potent than the corresponding
5-amino-1,2,4-thiadiazole analog 4b and 2-amino-1,3,4-oxadiaz-
ole analog 4c in both the P2Y1 FLIPR and PA assays. The two regio-
isomeric thiazoles 4e and 4f showed similar affinity in the P2Y1
receptor binding assay; however, the 5-phenyl isomer 4f was more
potent than the 4-phenyl isomer 4e in the FLIPR and the PA
assays. The P2Y1 binding affinity was much decreased for the six-
membered aminopyridine 4g and aminopyridazine 4h. While the
aminopyrazine 4i had similar binding activity as the isoxazole
analog 4d, 4i was much less active than 4d in the PA assay.
2-Amino-1,3,4-thiadiazole analog 4a showed the best profile in
lM).
l

C. H. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2481–2485
2483
Table 2
showed high protein binding and low aqueous solubility similar
to compound 310 (human: 99.3% bound and less than 1
g/mL at
SAR of 2-amino-1,3,4-thiadiazole analogs 4a, 5a–i
l
pH 6.5). However, due to relatively low metabolic stability (%
remaining after 10 min of rat liver microsomal incubation for 6a
was 37% and for 6b was 75%), PK studies were not carried out with
these two compounds.
N
N
OH
R'
N
H
N
S
Based on the in vitro potency in the antiplatelet assays and the
favorable metabolic stability profile (liver microsomes), 2-
amino-1,3,4-thiadiazole analogs 5a, 5b, and 5f were selected for
pharmacokinetic studies in rats. Table 3 summarizes the pharmaco-
kinetic profile of these three compounds in comparison to the urea
lead 3. These compounds all showed very good liver microsomal sta-
bility in rats and humans. All three thiadiazole analogs gave higher
exposure and Ctrough than compound 3 following both iv and p.o.
administration in rats. Since P2Y1 is distributed widely in the body
and we were targeting P2Y1 in the plasma, we believe that it is pref-
erable to have compounds with small Vdss so that the drug stays in
the plasma, thus potentially reducing off-target adverse effects.
2-Amino-1,3,4-thiadiazole analogs 5b and 5f both showed three-
to four-fold smaller Vdss compared with compound 3. Compound
5f had the best overall PK profile with a p.o. trough concentration
of 30 nM at 24 h, Cl of 2.1 mL/min/kg, Vdss of 2.1 L/kg, half-life of
12 h, and oral bioavailability of 28%.
Scheme 1 illustrates an efficient transformation of spiropiperid-
inyl indoline intermediate 710 to various aminoheterocycle urea
mimetics using compounds 4e and 4g–i as examples. Indoline 7
coupled with 1,2-dibromobenzene by Buchwald–Hartwig reaction
in the presence of Pd2(dba)3, rac-BINAP, and Cs2CO3 in toluene and
afforded the key bromo intermediate 8 in 64% yield. A second
Buchwald–Hartwig reaction of 8 with various heteroaryl amines
gave the corresponding aminoheterocycles 9e and 9g–i. Demethyl-
ation of 9e and 9g–i occurred smoothly with 5 equiv of boron tri-
chloride and 6 equiv of tetrabutylammonium iodide (TBAI) in dry
dichloromethane at ꢀ50 °C followed by gradually warming to
room temperature to afford the corresponding 7-hydroxy com-
pounds 4e and 4g–i in moderate yields. In the presence of TBAI,
boron trichloride can remove aryl methyl groups efficiently at
low temperature.12 However, due to the chelation ability of boron
trichloride to Lewis bases, 5-6 equiv of boron trichloride and TBAI
are required to remove the methyl groups for heteroaryls such as
4e and 4g–i. The two sequential Buchwald-Hartwig reactions fol-
lowed by deprotection allowed us to quickly screen the activity
of a variety of aminoheteroaryl analogs. The second Buchwald–
Hartwig coupling reaction did not work when efforts were made
to couple 2-amino-5-phenylthiazole with 8. The 2-amino-thiazole
analog 4f was consequently synthesized via a different route as
indicated in Scheme 2.
R
N
a SPA beads (LEADseeker™, Amersham Biosciences) were used in 384-well assay
plate for P2Y1 membrane binding assay, n = 1.
b FLIPR was tested with 1
the mean, n = 2.
l
M of 2-methylthio-ADP, and IC50 values are reported as
c PA IC50 was tested at 10
l
M of ADP,9 n = 1.
6a: R" =
N
N
N
N
OH
N
P2Y1 Ki = 6.5 nM
P2Y1 FLIPR IC50 = 1.5 nM
PA IC50 = 0.93 µM [10 µM ADP]
N
H
R"
S
Cl
N
6b: R" =
N
N
P2Y1 Ki = 6.6 nM
P2Y1 FLIPR IC50 = 0.20 nM
PA IC50 = 0.90 M [10 M ADP]
µ
µ
Figure 2. Pyrazine analog 6a and pyrazole analog 6b.
In an attempt to reduce lipophilicity, analogs with heteroaryl
substitution, such as pyrazines, pyrazoles, pyridines, and tetrahy-
dropyran, on the 2-amino-1,3,4-thiadiazole ring were synthesized.
Among them, pyrazine 6a and pyrazole 6b showed the best
potency in the binding assay7 and functional assays having PA
1 lM (see Fig. 2). The clogP values for 6a
(clogP = 5.2) and 6b (clogP = 5.7) were reduced several log units
compared with 5a (clogP = 8.2) and 5f (clogP = 8.6). Pyrazole 6b
The syntheses of 5-amino-1,2,4-thiadiazole, 2-amino-1,3,4-oxa-
diazole, aminothiazole and aminoisoxazole are depicted in
Scheme 2.8a The aniline intermediate 1010 reacted with 1,10-thi-
ocarbonyldipyridin-2(1H)-one in dichloromethane at 0 °C to give
the isothiocyanate 11, the key intermediate used for the synthesis
of all the four aminoheterocycles in Scheme 2, in 91% yield.
IC50 less than
Table 3
Pharmacokinetic profile of selected 2-amino-1,3,4-thiadiazole analogs 5a, 5b, 5f compared to urea lead 3 in ratsa,b
Entry #
Cl (mL/min/kg)
Vdss (L/kg)
t1/2 (h)
iv AUC tot (nM*h)
iv Ctrough c(nM)
p.o. Ctrough c(nM)
F%
RLMd
HLMd
3
10
5.4
6.0
1.2
2.1
9.9
24
13
12
1328
4627
6960
6213
10
46
54
95
4.1
12
3.6
30
36
22
14
28
86
87
84
94
100
86
82
5a
5b
5f
4.0
1.8
2.1
99
a
b
c
Dose: 0.5 mg/kg (iv)/0.5 mg/kg (p.o.); Formulation: 70% water, 10% ethanol, 10% cremophor, 10% N,N-dimethylacetamide.
Cassette PK.
Ctrough values were measured at 24 h after iv and p.o. administration.
Percentage remaining after 10 min incubation with 0.5 lM rat or human liver microsome (LM).
d

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C. H. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2481–2485
was simply reacted with hydroxylamine in ethanol then cyclized
at 85 °C and deprotected to provide aminoisoxazole 4d. Intermedi-
ate 11 was coupled with 2-amino-1-phenylethanone, followed by
cyclization in concentrated sulfuric acid and demethylation to pro-
vide 2-amino-4-thiazole 4f.
OMe
Cl
OMe
Cl
H
N
Br
N
a
b
Scheme 3 describes the general syntheses of compounds in the
lead 2-amino-1,3,4-thiadiazole series. Treatment of intermediate
1210 with 1,10-thiocarbonyldipyridin-2(1H)-one gave the isothio-
cyanate 13 in 96% yield. Compound 13 was then coupled with an
aryl or heteroaryl hydrazide, followed by acid-catalyzed cycliza-
tion in one-pot. Demethylation afforded the desired 7-OH spiropi-
peridine indolinyl compounds 4a, 5a–b, 5e–f, and 6a–b. On the
other hand, the anionically-activated aromatic CF3 group in 5b
can be converted to the nitrile or methyl ester under mild basic
aqueous conditions by the methodology we reported earlier13 to
provide compounds 5c and 5d, respectively.
A parallel synthesis route for 2-amino-1,3,4-thiadiazole analogs
was also developed from the common intermediate hydra-
zinecarbothioamide 14 as illustrated in Scheme 4. Aniline 1010
reacted with 1,10-thiocarbonyldipyridin-2(1H)-one in dichloro-
methane at 0 °C, followed by Boc-protected pivalohydrazide and
removal of the Boc group to provide 14 for parallel synthesis in
good yields for multi-gram scale reactions. Key intermediate 14
then coupled with various commercially available arylcarbonyl
chlorides, followed by cyclization with 98% sulfuric acid and
demethylation to give an array of 2-amino-1,3,4-thiadiazoles, such
as 5g–i.
N
N
7
8
OH
Cl
OMe
HetAr
HetAr
N
H
N
H
N
N
c
Cl
N
N
9e,g,h,i
4e,g,h,i
Ph
N
Tol
N
Ph
N
Ph
HetAr =
N
N
S
4e
N
4g
4h
4i
Scheme 1. Reagents and conditions: (a) 1,2-dibromobenzene, Pd2(dba)3, rac-BINAP,
Cs2CO3, toluene, 110 °C, 16 h, 64%; (b) NH2-HetAr, Pd2(dba)3, Xanthphos or rac-
BINAP, Na2CO3 or NaOtBu, toluene, 110 °C, 16 h, 9e, 15%; 9g, 74%; 9h, 78%; 9i, 85%;
(c) BCl3 (5 equiv) TBAI (6 equiv), CH2Cl2, ꢀ50 °C to rt, 16 h, 4e, 39%; 4g, 51%; 4h,
46%; 4i, 30%.
In summary, we identified a series of novel aminoheterocycle
urea surrogates in the 7-hydroxy-N-neopentyl spiropiperidine
indolinyl series which are potent small molecule P2Y1 antago-
nists. Among all the urea mimetics studied, the 2-amino-1,3,4-
thiadiazole series was the most potent. Extensive SAR studies
enhanced by parallel synthesis led to the discovery of compound
5a, the most potent non-urea compound evaluated with PA IC50
The reaction of 11 with benzamidine provided the intermediate
carbamothioylbenzamidine, which was oxidatively cyclized by
directly adding diethyl azodicarboxylate (DEAD) in one pot, fol-
lowed by demethylation to afford 5-amino-1,2,4-thiadiazole 4b.8a
Intermediate 11 was reacted with benzohydrazide, followed by
cyclization in the presence of tosyl chloride/pyridine at 70 °C,
and removal of the methyl group to give 2-amino-1,3,4-oxadiazole
4c. Acetophenone anion generated from acetophenone and sodium
hydride in DMF was reacted with 11, followed by methylation with
iodomethane to offer the intermediate Michael acceptor, which
less than 0.5 lM. Several 2-amino-1,3,4-thiadiazole analogs such
as 5a, 5b, and 5f showed good liver microsomal stability, among
which compound 5f demonstrated the best overall pharmacoki-
netic profile.
Ph
S
OMe
Cl
OMe
OH
N
C
N
NH2
N
N
N
N
l,m,n
H
a
S
Cl
Cl
N
N
N
10
4f
h,i,j,k
11
b,c,d
e,f,g
Ph
Ph
Ph
O
N
OH
OH
Cl
OH
Cl
N
H
O
N
H
N
N
H
N
N
N
N
N
N
S
Cl
N
N
N
4b
4c
4d
Scheme 2. Reagents and conditions: (a) 1,10-thiocarbonyldipyridin-2(1H)-one (1 equiv), CH2Cl2, rt, 2 h, 91%; (b) benzimidamide, DMF, rt, 16 h; (c) DEAD (2 equiv), 30 min,
40% for 2 steps; (d) BCl3 (5 equiv), TBAI (6 equiv), CH2Cl2, ꢀ50 °C to rt, 16 h, 26%; (e) benzohydrazide, THF, rt, 16 h; (f) TosCl (1.2 equiv), pyridine (2.1 equiv), 70 °C, 16 h; (g)
BCl3 (5 equiv), TBAI (6 equiv), CH2Cl2, ꢀ50 °C to rt, 16 h, 54% for 3 steps; (h) acetophenone, NaH, 0 °C, DMF, 16 h; (i) MeI, rt, 16 h, 83%; (j) hydroxylamine (4 equiv), EtOH, 16 h,
rt, 85 °C; (k) BCl3 (5 equiv), TBAI (6 equiv), CH2Cl2, ꢀ50 °C to rt, 16 h, 10% for 2 steps; (l) 2-amino-1-phenylethanone, CH2Cl2, rt, 16 h; (m) 98% H2SO4 (20 equiv), rt, 1 h, 53% for
2 steps; (n) BCl3 (5 equiv), TBAI (6 equiv), CH2Cl2, ꢀ50 °C to rt, 16 h, 18%.

C. H. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2481–2485
2485
Ar
S
OH
R'
OMe
R'
OMe
R'
N
N
H
N
NH2
N
N
N
N
a
C
b,c
S
N
N
N
13
12
4a,5a-b, R' = CF3
5e,
R' = F
5f,6a-b, R' = Cl
S
S
OH
OH
R'
N
N
H
N
N
H
N
N
N
d
N
CF3
N
N
5b
5c, R' = CN
5d,
R' = CO2Me
Scheme 3. Reagents and conditions: (a) 1,10-thiocarbonyldipyridin-2(1H)-one, CH2Cl2, rt, 5 h, 91–96%; (b) arylcarbohydrazide NH2NHCOAr, CH2Cl2, rt, 16 h; then 98% H2SO4,
rt, 30 min, 54–86% for 2 steps; (c) BCl3 (5 equiv), TBAI (6 equiv), CH2Cl2, ꢀ50 °C to rt, 16 h, 14–46%; (d) 5c: 1 N NaOH, NH4OH, rt, 72 h, 76%; 5d: 1 N NaOH, MeOH, 40 °C, 1 h,
29%.
410; (d) Hechler, B.; Nonne, C.; Roh, E. J.; Cattaneo, M.; Cazenave, J.-P.; Lanza,
F.; Jacobson, K. A.; Gachet, C. J. Pharmacol. Exp. Ther. 2006, 316, 556.
3. For recent reviews on P2Y12 drugs, see: (a) Yousuf, O.; Bhatt, D. L. Nat. Rev.
S
OMe
Cl
OMe
Cl
Cardiol. 2011, 8, 547; (b) Dorsam, R. T.; Murugappan, S.; Ding, Z.; Kunapuli, S. P.
Hematology (Abingdon, United Kingdom) 2003, 8, 359; (c) Escolar, G.; Heras, M.
Drugs Today 2000, 36, 187; (d) Herbert, J. M.; Frehel, D.; Vallee, E.; Kieffer, G.;
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1993, 11, 180.
NH2
N
H
NH2
N
N
a,b,c
N
H
4. (a) Angiolillo, D. J.; Suryadevara, S.; Capranzano, P.; Bass, T. A. Expert Opin.
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N
N
14
10
Ar
S
N
OH
Cl
N
H
N
N
d,e,f
Library Synthesis
N
7. Chao, H.; Turdi, H.; Herpin, T. F.; Roberge, J. Y.; Liu, Y.; Schnur, D. M.; Poss, M. A.;
Rehfuss, R.; Hua, J.; Wu, Q.; Price, L. A.; Abell, L. M.; Schumacher, W. A.;
Bostwick, J. S.; Steinbacher, T. E.; Ogletree, M. L.; Huang, C. S.; Chang, M.;
Cacace, A. M.; Arcuri, M. J.; Celani, D.; Wexler, R. R.; Lawrence, R. M. J. Med.
Chem. 2013, 56, 1704.
8. (a) Ruel, R.; L’Heureux, A.; Thibeault, C.; Daris, J.-P.; Martel, A.; Price, L. A.; Wu,
Q.; Hua, J.; Wexler, R. R.; Rehfuss, R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2013,
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Lett. 2013, 23, 4206.
5g-i
Scheme 4. Reagents and conditions: (a) 1,1-thiocarbonyldipyridin-2(1H)-one,
CH2Cl2, 0 °C, 30 min; (b) pivalohydrazide, CH2Cl2, rt, 16 h, 71% for 2 steps; (c) TFA,
CH2Cl2, 1 h, 86%; (d) arylcarbonyl chloride, CH2Cl2, rt, 2 h; (e) 98% H2SO4, rt, 16 h; (f)
BCl3 (5 equiv), TBAI (6 equiv), CH2Cl2, ꢀ78 °C to rt, 16 h.
9. Qiao, J. X.; Wang, T. C.; Ruel, R.; Thibeault, C.; L’Heureux, A.; Schumacher, W. A.;
Spronk, S. A.; Hiebert, S.; Bouthillier, G.; Lloyd, J.; Pi, Z.; Schnur, D.; Abell, L. M.;
Price, L. A.; Liu, F.; Wu, Q.; Steinbacher, T. E.; Bostwick, J. S.; Chang, M.; Zheng,
J.; Gao, Q.; Ma, B.; McDonnell, P. A.; Huang, C. S.; Rehfuss, R.; Wexler, R. R.; Lam,
P. Y. S. J. Med. Chem. 2013, 56, 9275.
10. Jeon, Y. T.; Yang, W.; Qiao, J. X.; Li, L.; Ruel, R.; Thibeault, C.; Hiebert, S.; Wang,
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B.-C.; Mathur, A.; Chacko, S.; Malley, M.; Chen, X.-Q.; Shen, H.; Huang, C. S.;
Schumacher, W. A.; Bostwick, J. S.; Stewart, A. B.; Price, L. A.; Hua, J.; Li, D.;
Levesque, P. C.; Rehfuss, R.; Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett.
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References and notes
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Morrow, D. M.; Senadhi, S.; Thaljil, R. K.; Zhao, S.; Burns-Kurtis, C. L.; Marino, J.-
P. Bioorg. Med. Chem. Lett. 2008, 18, 6222; (c) Houston, D.; Costanzi, S.;
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