Triazolo and imidazo dihydropyrazolopyrimidine potassium channel antagonists

Article abstract of DOI:10.1016/j.bmcl.2013.01.064

Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of I_Kur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective K_v1.5 inhibitor with an acceptable PK and liability profile.

Full text of DOI:10.1016/j.bmcl.2013.01.064

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1743–1747
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triazolo and imidazo dihydropyrazolopyrimidine potassium channel
antagonists
Heather J. Finlay a, , Ji Jiang a, Yolanda Caringal a, Alexander Kover a, Mary Lee Conder b, Dezhi Xing b,
⇑
Paul Levesque b, Timothy Harper c, Mei Mann Hsueh c, Karnail Atwal a, Michael Blanar b, Ruth Wexler a,
John Lloyd a
a Department of Discovery Chemistry, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, United States
b Department of Discovery Biology, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, United States
c Department of Discovery Preclinical Candidate Optimization, Bristol-Myers Squibb, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective
blockers of IKur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series
are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and
selective Kv1.5 inhibitor with an acceptable PK and liability profile.
Received 2 October 2012
Revised 10 January 2013
Accepted 16 January 2013
Available online 26 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Atrial fibrillation
Potassium channel
Kv1.5
IKur
Dihydropyrazolopyrimidine
Atrial fibrillation (AF) is the most common form of sustained
cardiac arrhythmia.1 AF is characterized by rapid and irregular si-
nus rhythm, which can lead to blood stasis and a significantly high-
er incidence of thromboembolism.2 Reversion to normal sinus
rhythm may be achieved through ablation,3 pacemaker insertion4
or the use of antiarrhythmic drugs.5 Antiarrythmic drugs which
target ion channels expressed in cardiac myocytes prolong the
effective refractory period (ERP) and convert an atrial arrhythmia
back to normal sinus rhythm.6 Current clinically approved Class
III agents target ion channels which are expressed in atrium and
of concept.11–23 In a recent disclosure, the preclinical and clinical
profile of MK-0448 was described.24 In a small cohort of normal
healthy volunteers, MK-0448 did not demonstrate atrial ERP in-
crease at projected efficacious plasma exposures and further vali-
dation of the target is required.
In previous publications, we have described multiple chemical
series25–27 including the discovery and optimization of potent
and selective dihydropyrazolopyrimidine based inhibitors of the
IKur potassium current encoded by the hKv1.5 gene in humans.28
Early optimization of this series focused on C7 aryl substitution
as well as C2, C3 and C5 substituents.29 Additionally, the
stereochemistry preference at position C7 was established.28 C6
substituents were also explored and the C6 amide and
the ventricle, for example, D,L-sotalol, amiodarone, dofetilide and
ibutilide and have the potential liability of fatal ventricular
arrhythmias such as torsades de pointe.7
IKur is a delayed rectifier repolarization current which is function-
ally expressed in the human atrium and not in the ventricle.8 Inhibi-
tion of IKur leads to prolongation of ERP and restoration of normal
sinus rhythm.9 The current body of data suggests that drugs which
selectively target inhibition of IKur may be safer since they should
prolong atrial ERP without being proarrhythmic in the ventricle.10
Selective inhibition of IKur with small molecule antagonists has
been a long standing target with extensive effort to identify and
advance potential drug candidates and demonstrate clinical proof
Cl
Cl
Cl
N
F
Cl
O
C7
N
N
N
N
N
N
C6
C2
N
N
H
N
H
C3
O
F
2
1
⇑
Corresponding author.
E-mail address: heather.finlay@bms.com (H.J. Finlay).
Figure
1. Previously
disclosed
C6
amido
and
benzimidazolo
dihydropyrazolopyrimidines.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.064

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H. J. Finlay et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1743–1747
Table 1
Cl
O
C6 N(1) aryl triazolodihydropyrazolopyrimidines
R1
Cl
N
N
H
Cl
NH
Cl
N
O
Cl
a), b), c), d), e)
R1
NH2
O
Cl
N
NH2
N
O
N
2
C2
R1
N
BoC
N
N
O
R
N
H
3a R1 = H
3b R1 = CH3
Compound
R1
R2
Kv1.5, L-929 cells (IC50, lM)
3c R1 = CF3
Cl
5
6
7
8
9
10
H
H
H
H
H
CH3
4-Fluoro-phenyl
3-Fluoro-phenyl
2-Fluoro-phenyl
2-Methoxy-phenyl
4-Methyl-phenyl
4-Methyl-phenyl
0.115
0.097
0.074
0.116
0.080
25%b
Cl
Cl
Cl
f), g)
N
h)
N
N
2
N
N2
N1
N
C2
N
N
N
N
R1
N
R1
R
2
R
a Inhibition is measured in triplicate at 3 concentrations and the mean values used
N
BoC
N
H
to calculate IC50 values.
b
% Inhibition of current in L-929 cells at 0.3
l
M, 2–4 point determinations.
5 -10 and 17 -46
4
Scheme 1. Reagents and conditions for R1 = H, R1 = CH3, R1 = CF3: (a) DMF, NaHCO3,
75 °C, 24 h (R1 = H, 55%) or heptane, THF catalytic piperidine, 75 °C, 24 h (R1 = H,
50%, R1 = CH3, 76%, R1 = CF3, 52%); (b) di t-butyl carbonate, THF, DMAP, RT (R1 = H,
89%, R1 = CH3, 100%, R1 = CF3, 100%); (c) chiral separation; (d) LiOH, THF; (e) EDCI,
HOBt NH4Cl, TEA, DCM (R1 = H, 66%, R1 = CH3, 86%, R1 = CF3, 94%, 2 steps); (f) DMF,
DMA, RT; (g) AcOH, R2NHNH2, 60 °C, 2 h; (h) 50% TFA, DCM (range in yield 13–70%,
3 steps).
Cl
Cl
Cl
Cl
O
N2
N
a), b), c), d)
R3
N
N
N
N
NH2
N
N
N1
benzimidazole series were optimized.30 In an effort to improve the
PK profile of our initial lead compounds, (Fig. 1, compounds 1 and
2) additional amide isosteres at the C6 position were explored,
leading to the identification of a potent series of substituted C6 tri-
azoles and imidazoles described in this Letter.
N
BoC
N
H
11 - 16
3b
Scheme 2. Reagents and conditions: (a) DMF/DMA, RT 2 h; (b) hydrazine, AcOH
60 °C, 2 h; 30%, 2 steps; (c) arylboronic acid, anhydrous pyridine, DCM, Cu(OAc)2 RT,
24 h; (d) 50% TFA/DCM (range in yield 35–47%, 2 steps).
Initially we explored a series of N(1) aryl substituted triazoles
which yielded our first potent Kv1.5 inhibitors in the triazole series.
Using a general sequence which included a 3 component, 1 pot
Biginelli reaction (Scheme 1), the core pyrazolo dihydropyrimidine
C6 ester was synthesized as a racemate. The BoC protected race-
mate was separated under chiral HPLC conditions and the enanti-
omers taken on to the corresponding C6 amide (3).31 The BoC
protected N(1) aryl substituted triazoles were obtained from 3 by
reaction with commercially available aryl hydrazines32 as the sin-
gle regioisomer at position N(1) (shown in Scheme 1). We have
previously disclosed that in the C6 amide series, a substituent
was required at either C2 or C3 to prevent the formation of reactive
metabolites in vivo.29 Intial examples were prepared without C2 or
C3 substituents, but second generation compounds in all C6 tria-
zoles included either a C2 methyl or trifluoromethyl group to ad-
dress this potential issue. Compounds 5–10 and 17–46 (Table 1)
were prepared in the N(1) aryl series.
Table 2
C6 N(2) aryl triazolo dihydropyrimidines
Cl
Cl
N2
N
R3
N
N
N
N
N1
N
H
Compound
R3
Kv 1.5, L-929 cells (IC50, lM)
11
12
13
14
15
16
2-Fluoro-phenyl
4-Methyl-phenyl
2-Methyl-phenyl
2-Methoxy-phenyl
3-Methoxy-phenyl
4-Methoxy-phenyl
23%a
14%a
0.722
4%a
N(2) aryl substituted triazoles were subsequently targeted and
we utilized the Chan–Lam cross coupling conditions33,34
(Scheme 2). Example compounds in this series 11–16 are included
in Table 2.
14%a
5%a
a
% Inhibition of current in L-929 cells at 0.3 lM, 2–4 point determinations.
Additional N(1) alkyl substituted triazoles and N(1) heterocycle
triazoles were subsequently prepared as shown in Scheme 1 from
the corresponding custom hydrazines. Due to the limited commer-
cial availability of alkyl and heterocycle hydrazines, alkyl hydra-
zines were prepared conveniently from the corresponding
aldehydes and ketones via reduction of the intermediate hydra-
zones35 and pyridyl hydrazines from direct halide displacement
with hydrazine.36
N(1) alkyl and cycloalkyl triazoles 17–37 are shown in Table 3.
Using methyl hydrazine, a mixture of N(1) and N(2) methyl tria-
zoles was obtained. The mixture was separated and the regiochem-
istry determined by NMR. Both N(1) and N(2) methyltriazoles
larger alkyl and cycloalkyl groups at N(1) to increase potency. All
subsequent alkyl hydrazines explored yielded exclusively N(1)
substituted triazoles under these conditions, the structures of
which were also confirmed by NMR. Pyridyl triazoles 38–46 (Ta-
ble 4) were also obtained as the single N(1) regioisomer.
To further extend the SAR in the N(1) alkyl and cycloalkyl C6 tri-
azole series, C6 imidazo dihydropyrazolopyrimides were synthe-
sized via the corresponding 1-(1-alkyl-1H-imidazol-2-yl)propan-
2-one intermediate (e.g., 47) as shown in Scheme 3 for the synthe-
sis of compound 48.36 An alternate route to install the imidazole
from common intermediate 3c proved unsuccessful since we could
demonstrated <10% Kv1.5 inhibition at 0.3 lM and we focused on

H. J. Finlay et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1743–1747
1745
Table 3
Table 4
C6 N(1) unsubstituted and alkyl triazolo dihydropyrimidines
C6 N(1) triazolo-2-pyridyl substituted dihydropyrimidines
Cl
Cl
Cl
Cl
N
N
N
N
N
N
N
N
N
N
R1
2
F3C
R
N
N
H
N
H
Compound R1
R2
Kv1.5, L-929 cells
(IC50 M)
Inhibition of
hERG current
Y
,
l
Compound
Y
Kv1.5, L-929 cells IC50
,
l
M
PXR (EC20, lM)
17
18
19
20
21
22
23
24
25
26
H
H
H
H
H
H
H
H
H
H
Benzyl
H
Ethyl
n-Propyl
i-Propyl
Cyclohexyl
t-Butyl
Cyclopentyl
Cyclobutyl
Cyclopropyl
methyl
4-Cyclohexyl 0.068
methyl
0.135
8%a
ND
ND
ND
ND
38
39
40
41
42
43
44
45
46
H
6-F
6-CF3
6-Cl
4-CH3
5-CH3
6-CH3
6-OCH3
6-O CH2CH3
11%a
ND
0.256
0.096
0.190
0.410
0.389
0.211
0.087
0.223
0.07
0.14
ND
0.44
ND
0.44
0.96
1.1
0.191
0.102
0.089
0.059
0.223
0.037
0.048
0.229
26% at 10
87% at 10
ND
l
l
M
M
6.0
ND
ND
lM
a
% Inhibition of current in L-929 cells at 0.3
l
M, 2–4 point determinations.
27
H
3.2
lM
28
29
H
H
CH2CF3
Tetrahydro
pyran
(CH2) 2CF3
(CH2) 3CF3
(CH2) 2OH
Cyclobutyl
Cyclohexyl
Cyclobutyl
Cyclobutyl
0.200
ND
ND
15%a
O
N
a), b), c), d), e)
O
30
31
32
33
34
35
36
37
H
H
H
CH3
CH3
tBu
CF3
0.151
0.103
6%a
0.094
0.127
0.283
0.165
25%a
ND
ND
ND
40% at 10
ND
ND
ND
ND
O
O
N
OEt
47
lM
Cl
Cl
N
N
CH2OCH3 Cyclobutyl
f), g),h)
a
N
N
% Inhibition of current in L-929 cells at 0.3 lM, 2–4 point determinations.
F3C
N
H
48
not prepare the prerequisite C6 aldehyde directly and could not
convert the intermediate C6 ester or primary amide into the alde-
hyde, without loss of the N-Boc protecting group. The sequence
employed resulted in racemic imidazoles which were resolved
using Chiral OD HPLC separation conditions. Example imidazoles
48, 49 and 50 (Table 5) were prepared via this route.
Scheme 3. Reagents and conditions: (a) LAH, ether 0 °C–rt 2 h; (b) swern oxidation
(74%, 2 steps); (c) glyoxal trimer, MeOH/7 N NH3 rt 16 h; (d) EtI, NaH, DMF rt 4 h;
(e) HCl aq, THF rt 16 h (29%, 3 steps); (f) dichlorobenzaldehyde, dioxane 160 °C
microwave 10 min; (g) trifluoroaminopyrazole, dioxane 160 °C microwave 10 min
(13%, 2 steps); (h) chiral HPLC OD separation.
All compounds synthesized by the methods described above
were assayed for block of IKur current in patch clamped mammalian
L929 cells expressing human Kv1.5 mRNA and stably express the
IKur protein.37 The initial N(1) aryl C6 triazolo dihydropyrazolopyr-
imidines compounds 5–9 were identified as potent inhibitors of
Kv1.5 (Table 1). Compound 10 bearing a C2 methyl is significantly
less potent than compound 9 which is unsubstituted at the C2
position.
Extending the SAR to N(2) aryl substituted triazoles, provided
compounds 11–16, which were significantly less potent than the
corresponding N(1) analogs for Kv1.5 inhibition (Table 2). There-
fore, further optimization of this series was focused on extending
SAR in the N(1) triazole position.
(e.g., 29 and 32). Generally the C3–C6 cycloalkyl analogs were more
potent compared to the corresponding linear alkyl analogs, (e.g.,
22, 24 and 25 vs 19, 20). Cyclobutyl triazole, 33, had an acceptable
in vitro liability profile and was progressed to a coarse rat PK
study.38 This compound, however, demonstrated rapid clearance
in rats (Table 7).
As shown in Table 4, substituted pyridyl triazoles maintained
Kv1.5 potency, but also demonstrated significant hERG inhibition
and PXR transactivation which was not attenuated by substitution
on the pyridine. The most potent pyridine, compound 45, demon-
strated 98% inhibition of hERG current at 10 l
M39 which precluded
the compound from further in vivo evaluation.
To reduce lipophilicity in the N(1) aryl series, aliphatic and het-
erocyclic groups were subsequently targeted. These compounds
were found to maintain potent Kv1.5 inhibition, (Tables 3 and 4).
As shown in Table 3, cycloalkyl N(1) triazole derivatives were
potent Kv1.5 inhibitors. These compounds also demonstrated sig-
nificant selectivity with respect to hERG channel inhibition, for
example compound 33 showed only 40% inhibition of hERG cur-
Direct C6 imidazolo analogs were within two to threefold po-
tency of the corresponding N(1) triazoles (e.g., 48 vs 19 and 49
vs 21). However, the C2 substituted analogs also demonstrated po-
tent in vitro PXR transactivation and rapid clearance in rats (e.g., 49
and 50 Tables 5 and 7).
Lead N(1) cyclobutyl C6 triazolo 33 was further profiled in the
in vitro microsomal incubation study. The principal sites of
metabolism were identified as the C2 methyl group and oxidation
of the pendant N(1) cyclobutyl group. To block both sites of metabo-
lism, C2 trifluoromethyl and C40 trifluoromethyl substituted cyclo-
hexyl analogs compounds 51 (isomer 1) and 52 (isomer 2) were
synthesized.
rent at 10 lM. Substitution at position C2 to address the potential
issue of reactive intermediate formation29 led to a loss in potency
consistent with previous work in the C6 amide series (e.g., 25 vs
33, 36 and 22 vs 34). Efforts to reduce lipophilicity further by
incorporating polar groups resulted in reduced Kv1.5 activity,

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H. J. Finlay et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1743–1747
Table 5
had an improved in vitro and in vivo profile compared to the C6
imidazoles and optimized the N(1) substituent to improve the
selectivity profile versus hERG. We subsequently identified the
sites of oxidative metabolism and improved the PK profile by
blocking the N(1) cycloalkyl portion and at the C2 position of the
dihydropyrimidine core. Compound 51, (R)-7-(3,4-dichloro-
phenyl)-5-methyl-2-(trifluoromethyl)-6-(1-(4-(trifluoro-
Example C6 N substituted alkyl imidazo dihydropyrimidines
Cl
Cl
N
N
N
N
F3C
2
R
methyl)cyclohexyl)-1H-1,2,4-triazol-5-yl)-4,7-dihydropyrazol-
N
H
o[1,5-a]pyrimidine was identified as
a potent and selective
inhibitor of IKur with an acceptable in vitro liability profile and an
acceptable in vivo rat PK profile. However 51 demonstrated signif-
icant hypotension in the rat in vivo PD model precluding further
evaluation of this compound.
Compound R2
Kv1.5, L-929 cells (IC50
,
l
M) PXR (EC20
,
l
M)
48
49
50
Ethyl
i-Propyl
(CH2)2
0.128
0.204
0.098
0.11
0.11
0.64
OCH2CH3
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.01.
064.
Table 6
Lead C6 N(1) triazolo dihydropyrimidine example 51
Cl
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PXR
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2C19, 2D6, 3A4)
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51
52
0.133
0.607
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Compound 51, (R)-7-(3,4-dichlorophenyl)-5-methyl-2-(trifluo-
romethyl)-6-(1-(4-(trifluoromethyl)cyclohexyl)-1H-1,2,4-triazol-
5-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine was identified as a po-
tent and selective IKur inhibitor with an acceptable in vitro liability
profile as shown in Table 6. Compound 51 demonstrated an im-
proved rat PK profile as shown in Table 7 and was advanced to
the rat PD model. Compound 51 was administered to rats at
0.3 mpk by IV infusion. A significant decrease in BP (ꢀ28 7%), a
compensatory increase in HR (6 1%), a decrease in QT (ꢀ8 4%)
and a decrease in VERP (ꢀ25 6%) were observed at plasma con-
centration 1.6
L-type Ca channel inhibition in the flux assays, (IC50 46 and
5.2 M, respectively). The mechanism for observed hypotension
lM. Compound 51 did not have significant Na and
l
in rats is not clearly understood at this time.
In summary, the first C6 triazolo and imidazolo substituted
dihydropyrimidines have been synthesized and identified as po-
tent inhibitors of Kv1.5. We focused on the C6 triazoles which
31. Representative synthetic procedures and separation conditions are included in
the Supplementary data.

H. J. Finlay et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1743–1747
1747
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34. Representative synthetic procedures and regiochemical assignments are
included in the Supplementary data.
36. Representative synthetic procedures are included in the Supplementary data.
37. Snyders, D. J.; Tamkun, M. N.; Bennett, P. B. J. Gen. Physiol. 1993, 101, 513.
38. Protocols for PK experiments are included in the Supplementary data.
39. Zhou, Z.; Vorperian, V. R.; Gong, Q.; Zhang, S.; January, C. T. J. Cardiovasc.
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