Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase

Article abstract of DOI:10.1016/j.bmcl.2015.09.058

To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC₅₀ = 7.68-13.70 nM) and p38α MAP kinase (IC₅₀ = 1240-3370 nM). Among them, 19j inhibited ALK5 with IC₅₀ value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.

Full text of DOI:10.1016/j.bmcl.2015.09.058

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of 5-(fluoro-substituted-6-
methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles
as inhibitors of transforming growth factor-b type I receptor kinase
y
⇑
Maddeboina Krishnaiah, Cheng Hua Jin , Yhun Yhong Sheen, Dae-Kee Kim
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-
methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a–l have been synthesized and
Received 6 July 2015
Revised 21 September 2015
Accepted 24 September 2015
Available online xxxx
evaluated for their TGF-b type I receptor kinase (ALK5) and p38
a MAP kinase inhibitory activity in an
enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-
imidazoles 19h–l displayed the similar level of potency to that of 5 against both ALK5 (IC50 = 7.68–
13.70 nM) and p38a MAP kinase (IC50 = 1240–3370 nM). Among them, 19j inhibited ALK5 with IC50 value
of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.
Keywords:
TGF-b
ALK5 inhibitor
Fibrosis
Ó 2015 Elsevier Ltd. All rights reserved.
Cancer
Kinase assay
The transforming growth factor-b (TGF-b) is a member of a
large family of dimeric polypeptide growth factors that include
TGF-bs (TGF-b1, TGF-b2, TGF-b3), activins, inhibins, and bone mor-
phogenetic proteins. TGF-b signals through heteromeric complexes
of type I and type II TGF-b receptors (TbR-I and TbR-II, respec-
tively). The signaling cascade is initiated by the binding of ligand
to the constitutively active type II receptor. Successively, the type
I receptor (ALK5) is phosphorylated in the juxtamembrane GS
domain, stimulating its kinase activity. The activated ALK5 propa-
gates the signals through phosphorylation of the receptor-regu-
lated Smads, Smad2 and Smad3 that in turn form complexes
with the common mediator Smad, Smad4. These Smad complexes,
when translocated into the nucleus, regulate the expression of sev-
eral hundred genes involved in cell proliferation, differentiation,
growth, migration, adhesion, immune response, apoptosis, and
extracellular matrix production.1–3 TGF-b plays an essential role
in the initiation and progression of fibrosis in various organ sys-
tems such as liver,4 lung,5 kidney,6 and heart.7 Deregulation of
TGF-b signaling has been implicated in various human diseases,
including cancer,8 pancreatic diseases,9 and hematological
malignancies.10
Current studies have shown that blocking the TGF-b signaling
pathway with several small-molecule ATP-competitive ALK5
inhibitors such as 1 (SB-505124),11 2 (SD-208),12 3 (GW6604),13
4 (LY-2157299),14 and 5 (EW-7197)15 inhibited autophosphoryla-
tion of ALK5 and TGF-b-induced transcription of matrix genes in
reporter assays at sub-micromolar concentrations. Among them,
4 and 5 have progressed to phase II and phase I clinical trials for
cancer, respectively.
Previously, we reported a number of the 2-pyridyl-substituted
triazoles,16 thiazoles,17 pyrazoles,18–20 and imidazoles21,22 as poten-
tial ALK5 inhibitors. Very recently, we have prepared a series of
2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methyl-
pyridin-2-yl)imidazoles and found that 5 is a highly potent, selec-
tive, and orally bioavailable ALK5 inhibitor.15 The
5 has
demonstrated its pronounced anticancer and antifibrotic efficacy
in various animal models.23–25
Recently, Bonafoux et al. reported a series of 2-aminoimidazoles
as ALK5 inhibitors that possessing a F substituent at the 5-position
of the 6-methyl-2-pyridyl moiety.26 They showed that a 5-fluoro-
substituted compound 6 was 1.5-fold more inhibitory in TGF-b-in-
duced PAI-luciferase assay and 2.1-fold less inhibitory in p38
a
MAP kinase assay compared to a parent compound, indicating
improved selectivity profile (Fig. 1).
On the basis of this finding, we decided to further investigate
the effect of a F substituent at the three different positions (3, 4,
or 5) of the 6-methyl-2-pyridyl moiety in 5 and its analogues on
ALK5 inhibitory activity and selectivity. The target compounds
⇑
Corresponding author. Tel.: +82 2 3277 3025; fax: +82 2 3277 2467.
E-mail address: dkkim@ewha.ac.kr (D.-K. Kim).
Present address: College of Pharmacy, Yanbian University, No. 977 Park Road,
y
Yanji, Jilin 133002, China.
http://dx.doi.org/10.1016/j.bmcl.2015.09.058
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
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2
M. Krishnaiah et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
N
O
HN
N
N
O
N
N
F
N
H
NH
N
N
N
N
N
Cl
1
(SB-505124)
O
3 (GW6604)
2 (SD-208)
NH2
N
N
F
N
N
H
N
N
N
N
N
NH2
N
N
H
N
H
N
N
N
F
N
5
(EW-7197)
6
4 (LY-2157299)
Figure 1. ALK5 inhibitors under development.
b
in 83% yield, which was subsequently converted to the aldehyde
12 in 70% yield by reaction with i-PrMgCl (2.0 M in THF) in CH2Cl2
and followed by treatment with anhydrous DMF (Scheme 2).
a
R
Br
R
Br
R
N
N
N
CHO
7a
: R = 3-NH2
7b: R = 4-NH2
9a
: R = 3-F (74%)
9b: R = 4-F (64%)
8a
: R = 3-F (38%)
8b: R = 4-F (44%)
A
series of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-
([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a–l was prepared
as shown in Scheme 3. The aldehydes 9a, 9b, and 12 were treated
with aniline and diphenyl phosphite in i-PrOH at room tempera-
ture to give the (phenylamino)methylphosphonates 13a–c in
65–97% yields. Coupling of the 13a–c with [1,2,4]triazolo[1,5-a]
pyridine-6-carbaldehyde28 in a mixture of THF and i-PrOH (4:1)
at room temperature in the presence of Cs2CO3 and followed by
hydrolysis with 3 N HCl gave the corresponding monoketones
14a–c in 66–87% yields.
Scheme 1. Reagents and conditions: (a) (i) concn HCl, NaNO2, 0 °C, 10 min; (ii) 65%
HPF6 in H2O, 100 °C, 10 min; (b) n-BuLi (1.6 M in hexane), anhydrous DMF, toluene,
ꢀ78 °C, 2 h.
F
F
F
a
b
N
CHO
N
I
N
Br
Oxidation of the 14a–c with 48% HBr in DMSO at either 40 °C
(for 15b) or 70 °C (for 15a and 15c) afforded the diketones 15a–c
in 31–91% yields. It was found that the 4-fluoro atom in the pyri-
dine ring was rather labile in this strong acidic condition, thus
affording the 15b in much lower yield compared to the 15a and
15c even at a lower reaction temperature. The condensation of
the diketones 15a–c with 60% 2,2-dimethoxyacetaldehyde and
NH4OAc in a mixture of t-BuOMe and MeOH (2:1) at room temper-
ature produced the imidazoles 16a–c in good yields. The acetal
protecting group of the 16a and 16c was cleaved in 1 N HCl solu-
tion at 70 °C to give the imidazole-2-carboxaldehydes 17a and
17c in 92% and 90% yields, respectively. But, in the same reaction
condition, the 16b gave the 17b along with the inseparable mix-
ture of by-products as major products in which a F atom in the
17b was replaced with a Cl atom or a OH group (determined by
HRMS). Thus, deprotection of the acetal group in the 16b was
accomplished in a mild condition with p-toluenesulfonic acid
monohydrate in anhydrous DMF at 50 °C to give the 17b in 61%
yield. Coupling of the 17a–c with appropriately substituted
anilines 18a–d in 1,2-dichloroethane in the presence of AcOH
and followed by reduction of the resulting imines with NaBH4 in
a mixture of THF and MeOH (1:3) gave the target compounds
19a–c, 19e–j, and 19l in good yields (77–90%). Conversion of the
nitrile functionality in compounds 19c and 19j to the correspond-
ing carboxamide was achieved by treatment with 34.5% H2O2 and
1 N NaOH in EtOH to afford the 19d and 19k in 61% and 47% yields,
respectively.
10
11 (83%)
12 (70%)
Scheme 2. Reagents and conditions: (a) TMSCl, NaI, CH3 CN, 90 °C, 2 d; (b) i-PrMgCl
(2.0 M in THF), CH2Cl2, anhydrous DMF, rt, overnight.
19b–e, 19g, and 19i–l possess a substituent, either o-F, m-CN,
m-CONH2, or m-CH@CH2 in a phenyl ring because they were found
to be the most beneficial to the ALK5 inhibitory activity and selec-
tivity in a previous study.15
The requisite 3-, 4-, and 5-fluoro-6-methyl-2-pyridinecarbox-
aldehydes 9a, 9b, and 12 were prepared as shown in Schemes 1
and 2. Treatment of commercially available 3-amino-2-bromo-6-
methylpyridine (7a) and 4-amino-2-bromo-6-methylpyridine
(7b)27 with aqueous NaNO2 at 0 °C in the presence of concn HCl
and followed by fluorination with 65% aqueous HPF6 solution gave
the corresponding fluoro compounds 8a and 8b in 38% and 44%
yields, respectively. Lithiation of 8a and 8b with n-BuLi at ꢀ78 °C
in toluene followed by treatment with anhydrous N,N-dimethylfor-
mamide gave the aldehydes 9a and 9b in 74% and 64% yields,
respectively (Scheme 1).
The attempted conversion of the commercially available 2-
bromo-5-fluoro-6-methylpyridine (10) to the aldehyde 12 under
the similar reaction condition for the 9a and 9b shown in Scheme 1
was failed. Thus, alternatively, the bromo atom of the 10 was
exchanged to the iodo atom with NaI in the presence of
chlorotrimethylsilane (TMSCl) in CH3CN at 90 °C to afford the 11
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M. Krishnaiah et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
ALK5 and p38
R1
N
N
a
inhibitory activity of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-
O
P
N
OPh
OPh
([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a–l in kinase assay
N
b
a
N
N
R2
O
9a, 9b, 12
R1
HN
N
N
HN
N
13a: R1 = 3-F (97%)
13b: R1 = 4-F (90%)
13c: R1 = 5-F (88%)
14a: R1 = 3-F (80%)
14b: R1 = 4-F (96%)
14c: R1 = 5-F (87%)
N
H
R1
N
N
N
N
N
19a-l
N
O
N
OCH3
OCH3
N
c
d
Compd
R1
R2
IC50 (nM)
ALK5a p38ab
Selectivity indexc
N
H
R1
O
N
R1
N
19a
19b
19c
19d
19e
19f
19g
19h
19i
19j
19k
19l
3-F
3-F
3-F
3-F
3-F
4-F
4-F
5-F
5-F
5-F
5-F
5-F
H
o-F
m-CN
m-CONH2
m-CH@CH2
H
o-F
H
o-F
m-CN
m-CONH2
m-CH@CH2
9.76
12.10
9.23
11.00
9.81
72.50
41.90
9.23
12.50
7.68
10.80
13.70
34.90
69.40
9.67
399
766
209
251
171
41
63
23
23
17
>137
>238
221
267
161
137
132
19
16a: R1 = 3-F (79%)
16b: R1 = 4-F (87%)
16c: R1 = 5-F (78%)
15a: R1 = 3-F (87%)
15b: R1 = 4-F (31%)
15c: R1 = 5-F (91%)
>10000
>10000
2040
3370
1240
1480
1810
668
NH2
N
R2
N
N
N
e
CHO
f
N
H
R1
: R2 = H
18a
18b
18c
N
: R2 = o-F
2
1 (SB-505124)
4 (LY-2157299)
5 (EW-7197)
: R = m-CN
17a: R1 = 3-F (92%)
17b: R1 = 4-F (61%)
17c: R1 = 5-F (90%)
405
2180
6
225
18d: R2 = m-CH=CH2
a
ALK5 was expressed in Sf9 insect cells as human recombinant GST-fusion
protein by means of the vaculovirus expression system. A proprietary radioisotopic
N
R2
protein kinase assay (33PanQinaseÒ Activity Assay) was performed at ProQinase
N
GmbH (Freiburg, Germany) using casein as a substrate.
HN
N
N
b
p38a MAP kinase was expressed as untagged human recombinant protein in
N
H
E. coli. The enzyme was purified by Ni–NTH–agarose (Qiagen).
A proprietary
R1
radioisotopic protein kinase assay (33PanQinaseÒ Activity Assay) was performed at
N
ProQinase GmbH (Freiburg, Germany) using ATF2 as a substrate.
c
IC50 of p38a/IC50 of ALK5.
19a: R1 = 3-F, R2 = H
19b: R1 = 3-F, R2 = o-F
(84%)
(82%)
(89%)
19c: R1 = 3-F, R2 = m-CN
g
g
Table 2
ALK5 inhibitory activity of 19j, 1, 4, and 5 in luciferase assay
1
: R = 3-F, R2 = m-CONH2 (61%)
19d
19e
19f
: R1 = 3-F, R2 = m-CH=CH2 (90%)
Compd
p3TP-luciferase activitya,b (% control)
: R1 = 4-F, R2 = H
(85%)
(77%)
(88%)
(89%)
(81%)
Mockc
3
0.3
19g: R1 = 4-F, R2 = o-F
19h: R1 = 5-F, R2 = H
19i: R1 = 5-F, R2 = o-F
19j: R1 = 5-F, R2 = m-CN
TGF-b
19j
1 (SB-505124)
4 (LY-2157299)
5 (EW-7197)
100 10.3
18 4.3
45 1.3
140 3.8
35 4.5
: R1 = 5-F, R2 = m-CONH2 (47%)
: R1 = 5-F, R2 = m-CH=CH2 (82%)
19k
19l
a
Luciferase activity was determined at a concentration of 100 nM of inhibitor.
Activity is given as the mean SD of three independent experiments run in
b
Scheme 3. Reagents and conditions: (a) aniline, diphenyl phosphite, i-PrOH, rt,
12–19 h; (b) (i) [1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde, Cs2CO3, THF/i-PrOH
(4:1), rt, 24 h; (ii) 3 N HCl, rt, 1 h; (c) 48% HBr in H2O, DMSO, 40 °C (for 15b), 1.5 h or
70 °C (for 15a and 15c), 2 h; (d) 60% 2,2-dimethoxyacetaldehyde in H2O, NH4OAc,
t-BuOMe/MeOH (2:1), rt, 4–6 h; (e) 1 N HCl, 70 °C, 2 h (for 17a and 17c) or
PTSAꢁH2O, anhydrous DMF, 50 °C, 24 h (for 17b); (f) (i) 18a–d, AcOH, 1,2-
dichloroethane, reflux, 3–12 h; (ii) NaBH4, MeOH/THF (3:1), rt, 0.5–4 h; (g) 34.5%
H2O2, 1 N NaOH, EtOH, rt, 2.5–4 h.
triplicate relative to control incubations without DMSO vehicle.
c
Luciferase activity was determined without treatment of TGF-b and inhibitor.
p38a MAP kinase inhibition than 5 (IC50 = 2180 nM), thus showing
that the selectivity indices of the former (17–63) were much lower
than that of the latter (225). Introduction of a fluoro-substituent at
the 4-position in the pyridine ring had negative impact on ALK5
inhibition, thus, 19f (R2 = H, IC50 = 72.50 nM) and 19g (R2 = o-F,
IC50 = 41.90 nM) displayed 7.5- and 4.3-fold lower ALK5 inhibitory
To evaluate whether these potential inhibitors 19a–l could inhi-
bit ALK5, a kinase assay was performed using the purified human
ALK5 kinase domain produced in Sf9 insect cells and casein as a
activity than 5, respectively. They also did not inhibit p38
a MAP
kinase up to a concentration of 10 M. The imidazoles having a
l
substrate (Table 1). Because the kinase domain of p38
a
MAP kinase
fluoro-substituent at the 5-position in the pyridine ring, 19h–l dis-
played the similar level of potency to that of 5 against both ALK5
is known to be one of the most homologous to that of ALK5,29 it
was also chosen for a kinase assay to study the selectivity profile
of this series of compounds.
(IC50 = 7.68–13.70 nM) and p38
a MAP kinase (IC50 = 1240–
3370 nM) regardless of R2 substituent. Consequently, the selectiv-
ity indices of the compounds (132–267) were comparable to that
of 5. All the 3- and 5-fluoro-substituted compounds were more
potent in ALK5 inhibition than the competitors 1 (IC50 = 34.90 nM)
and 4 (IC50 = 69.40 nM). And, the 4- and 5-fluoro-substituted
All the imidazoles having a fluoro-substituent at the 3-position
in the pyridine ring, 19a–e (IC50 = 9.23–12.10 nM) showed the sim-
ilar level of potency against ALK5 to that of 5 (IC50 = 9.67 nM). But,
19a–e (IC50 = 171–766 nM) were 2.8–12.7-fold more potent in
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4
M. Krishnaiah et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
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compounds showed much higher selectivity indices against p38
MAP kinase than 1 (19) and 4 (6).
a
Because 19j showed slightly higher level of potency in ALK5
inhibition in a kinase assay (IC50 = 7.68 nM) than 5, a cell-based
luciferase assay was performed using HaCaT cells permanently
transfected with p3TP-luciferase reporter construct30 at a concen-
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(82% inhibition) was more inhibitory than 1 (55% inhibition), 4
(no inhibition), and 5 (65% inhibition) in a cell-based luciferase
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In this letter, we have synthesized and evaluated a series of
5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]-
triazolo[1,5-a]pyridin-6-yl)imidazoles 19a–l to further optimize an
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less selective against p38
tuted compounds were chemically rather unstable and displayed
much lower ALK5 and p38 MAP kinase inhibitory activity than
5. The 5-fluoro-substituted compounds displayed the similar level
of potency to that of 5 against both ALK5 and p38 MAP kinase.
a MAP kinase than 5. The 4-fluoro-substi-
a
a
One of the 5-fluoro-substituted compounds, 19j was found to be
more inhibitory than the parent compound 5 in ALK5 inhibition
in both kinase assay and cell-based luciferase assay with a high
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selectivity index of 161 against p38a.
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Acknowledgment
This work was supported by a Grant from Ministry of Education,
Science and Technology, Republic of Korea (20100029596).
Supplementary data
Supplementary data (synthetic procedures and analytical data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2015.09.058.
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Please cite this article in press as: Krishnaiah, M.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.09.058