Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

Article abstract of DOI:10.1016/j.bmcl.2009.11.061

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3β and tumor growth in a BT474 tumor xenograft model in mice.

Full text of DOI:10.1016/j.bmcl.2009.11.061

Bioorganic & Medicinal Chemistry Letters 20 (2010) 684–688
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced
CYP450 and hERG inhibition of aminopyridines
a
a
a
a
a
a
Hong Lin a, , Dennis S. Yamashita , Ren Xie , Jin Zeng , Wenyong Wang , Jack Leber , Igor G. Safonov ,
Sharad Verma a, Mei Li a, Louis LaFrance a, Joseph Venslavsky a, Dennis Takata a, Juan I. Luengo a,
Jason A. Kahana b, Shuyun Zhang b, Kimberly A. Robell b, Dana Levy b, Rakesh Kumar b,
Anthony E. Choudhry b, Michael Schaber b, Zhihong Lai b, Barry S. Brown b, Brian T. Donovan b,
Elisabeth A. Minthorn c, Kristin K. Brown d, Dirk A. Heerding a
*
a Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States
b Oncology Biology, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States
c Oncology Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States
d Molecular Discovery Research, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge bind-
ers, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that
demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of
previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phos-
phorylation of GSK3b and tumor growth in a BT474 tumor xenograft model in mice.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 September 2009
Revised 11 November 2009
Accepted 16 November 2009
Keywords:
AKT kinase inhibitors
Aminopyridines
In the preceding communications,1,2 we disclosed the develop-
ment of a potent and selective series of AKT inhibitors based on a
trisubstituted pyridine core and novel azaindazole hinge binders.
Our efforts culminated in the identification of compound 1a
(Fig. 1), which displayed improved kinase selectivity and drug-like
properties with respect to its indazole analog.2 However, com-
pound 1a was observed to be a sub-micromolar CYP3A4 inhibitor,
and its methyl analog 1b was found to be a potent hERG channel
developability profile, and achieved a robust pharmacodynamic ef-
fect and tumor growth inhibition in BT474 tumor xenograft model
in mice. Herein, we wish to report the synthesis and evaluation of
compound 14c and related tetrasubstituted pyridine analogs.
The synthesis of tetrasubstituted pyridines 14a–c commenced
from compound 2 and proceeded via pyridine N-oxide 3, a versatile
intermediate for subsequent introduction of small groups adjacent
to the ring nitrogen atom.4 Taking advantage of this, compound 3
was subjected to Mitsunobu coupling conditions to generate inter-
mediate 5, which was converted to tetrasubstituted aminopyridine
6a with tosylsulfonyl chloride (TsCl), pyridine and ethanolamine.5,6
inhibitor when tested in a functional assay (IC50 = 1.4 lM, see
Fig. 1).3 Despite efforts to reduce lipophilicity of the trisubstituted
pyridine derivatives by replacing indazole with azaindazoles,2 po-
tent CYP3A4 inhibition persisted and this remained a daunting
problem. We attempted to replace the pyridine core with pyrida-
zine or pyrazine, but this only led to inactive compounds (data
not shown). We then turned our attention to introducing small
groups next to the pyridine nitrogen atom to increase steric bulk-
iness, which we believed might help to reduce the CYP450 liability.
Introduction of an amino group onto the pyridine core led to
appreciably reduced CYP450 and hERG inhibition relative to the
parent trisubstituted pyridine series. Our efforts resulted in the
identification of compound 14c, which demonstrated an improved
O
H
N
N
N
R
N
N
H
N
NH2
O
1a, R = H
1b, R = Me
* Corresponding author.
E-mail address: hong.2.lin@gsk.com (H. Lin).
Figure 1. Trisubstituted pyridines as AKT inhibitors.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.061

H. Lin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 684–688
685
A Suzuki coupling reaction of 6a with indazole boronate ester 7a
afforded compound 8a and a second Suzuki coupling reaction of
8a with 2-methyl-furanylboronate ester 91 afforded 10a. Boc
deprotection under standard conditions furnished the target mole-
cules 14a. 7-Azaindazole 14b was prepared in a similar manner as
that of 14a. For the Suzuki coupling reactions, it was found that the
use of a bi-dentate ligand on the catalyst, such as Pd(dppf)Cl2,
worked better for these aminopyridine substrates.
For the synthesis of 4,7-diazaindazole derivative 14c, a modified
approach was applied since preparation of the corresponding bor-
onate ester of 12 was not successful and the corresponding stann-
ane reagent could not be conveniently prepared on large scale with
sufficient purity. Thus, tetrasubstituted aminopyridine 6a was
converted to boronate ester 11, which was used as a crude reaction
mixture without purification since it was prone to proteo-deboro-
nation. A Suzuki coupling reaction of compound 11 and 5-bromo-
4,7-diazaindazole 122 afforded a mixture of Boc-protected 13a and
deprotected 13b under these basic conditions.7 This mixture was
subjected to a subsequent Suzuki reaction with compound 9, fol-
lowed by Boc deprotection to afford target molecule 14c.
The cyano and methyl group were introduced at the 6-position
of the pyridine core via N-oxide 5 according to the literature pro-
cedures8,9 and the targeted molecules (i.e., compound 15 and 16
in Table 1) were prepared following the route depicted in
Scheme 1.
The 6-amino group was also introduced by regio-selective
nitration of compound 2. This alternative synthetic route produced
a number of analogs, such as 6-azaindazole 14d exemplified in
Scheme 2. The pyridine alcohol 2 was first nitrated at the 6-posi-
tion using standard conditions, followed by reduction of the nitro
group with iron in acetic acid to furnish compound 17 in good
overall yield. Boc protection of the 6-amino group followed by a
Mitsunobu reaction with N-Boc protected amino alcohol 4 fur-
nished compound 18 in excellent yields. Conversion of compound
18 to the corresponding boronate ester 19 was performed under
similar conditions to those described for preparing 11. Subsequent
introduction of the 6-azaindazole 2010 under Suzuki conditions
furnished the elaborated compound 21 in moderate to good yields.
A final Suzuki coupling between compound 21 and boronate ester
9, followed by deprotection of the benzenesulfonyl and Boc pro-
tecting groups using standard methods, furnished compound 14d
in good overall yields.
treatment with LDA at low temperature. This process was conve-
niently facilitated by the directing effect of the neighboring ben-
zenesulfonamide group.11 Quenching the anion derived from 22
with benzenesulfonyl chloride or iodine then led to 23a and 23b,
respectively. The latter was then converted to nitrile 23c with
Zn(CN)2 under microwave irradiation conditions in the presence
of Fu’s catalyst.12 Deprotection of the acetonide under acidic condi-
tions also removed the Boc protecting group, which was put back
on with Boc2O to give 24a or 24b. These two chiral aminoalcohols
were subjected to the chemistry highlighted in Scheme 2 to afford
the final products 25a and 25b. The cyano group of 25b was par-
tially hydrolyzed to give carboxamide 25c.
The effects of small substitution adjacent to the pyridine nitro-
gen atom on CYP450 inhibition and potency are summarized in Ta-
ble 1. In general, introduction of an amino group maintained or
slightly increased the enzymatic potency against all three AKT iso-
forms, as well as cellular potency in both anti-proliferation and
mechanistic assays (14a, 14b, 14c).13 The amino group also helped
to reduce CYP450 3A4 inhibition by about eightfold (1b and 14c).
Compound 14c demonstrated reduced hERG channel inhibitory
potency (IC50 = 10.4 lM, see Fig. 2) in comparison to compound
1b.3 The analogs containing either a cyano or methyl group at
the 6-position of the core pyridine did not demonstrate cellular po-
tency even though these analogs were potent AKT inhibitors in
enzymatic assays. Furthermore, these compounds did not appre-
ciably reduce CYP450 inhibition.
O
H
A
B
N
R'
X
N
N
R
H
N
O
NH2
Encouraged by the tolerability of this amino group and the
advantage it brought to reduce CYP450 inhibition, substituted
amine analogs at the 6-position of the core pyridine were prepared
through standard reductive amination reactions. Unfortunately,
this position did not tolerate any steric bulkiness, as even the sim-
ple ethylamine analog 26b lost about 100-fold potency (Table 2).
Alternatively, substitution of small group at the 2-position of the
indole ring seems to be well tolerated as compounds 25a–c were
potent AKT inhibitors in enzymatic assays. However, cyano analog
25b and carboxamide analog 25c seemed to lose cellular potency.
Furthermore, they were observed to have similar potency against
p450 3A4 compared to compound 14c.
We also prepared tetrasubstituted pyridine analogs with the
substituents at the 2-position of the indole to evaluate the impact
of such a modification on AKT activity and CYP450 inhibition (com-
pounds 25a–c in Table 2).
Synthesis of requisite side chains 24a and 24b is depicted in
Scheme 3. Following efficient conversion of tryptophanol 4 to the
fully protected derivative 22, regio-controlled lithiation/deproto-
nation of the 2-position of the indole ring became possible upon
Table 1
Tetrasubstituted pyridine analogs with indazole and azaindazole hinge binders
Compd
A
B
X
R
R0
AKT1/2/3a IC50
(
lM)
BT474b IC50
(l
M)
p-GSK3b BT474c IC50
(l
M)
CYP450 3A4 IC50 (lM)
1b
N
CH
N
N
CH
N
N
CH
CH
CH
CH
N
H
Me
Me
Me
Me
Me
H
0.001/0.025/ND
0.29
0.20
0.47
0.31
0.30
ND
0.21
0.22
0.47
0.56
0.68
>10
0.63
0.10
1.0
5.0
1.3
14a
14b
14c
14d
15
CH
CH
N
CH
N
NH2
NH2
NH2
NH2
CN
0.003/0.015/0.001
0.001/0.015/0.002
0.001/0.019/0.002
0.001/0.013/0.003
0.010/0.25/0.019
0.003/0.063/0.010
CH
CH
0.79
0.63
16
N
N
Me
H
1.26
0.28
a
b
c
n P 2.
Inhibition of cell proliferation.
Inhibition of phosphorylation of GSK3b.

686
H. Lin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 684–688
Cl
O
O
Br
N
Cl
Cl
a
b
c
Br
O
Br
N
6
N
R
OH
Boc
OH
OH
NHBoc
HN
N
2
3
5
4
O
Boc
O
Cl
A
A
A
N
N
N
Cl
N
Br
1R
N
N
O
N
B
O
B
N
N
O
O
2R
H2N
R
H2N
R
O
7a, A=CH;
7b, A=N
O
O
9
R
NHBoc
NHBoc
NHBoc
d
6a, 2R=NH2, 1R=H
e
6b, 2R=Cl, 1R=H
8a, A=CH
8b, A=N
10a, A=CH
10b, A=N
6c, 2R=H, 1R=NH2
g
f
3R
O
Boc
N
A
B
N
N
N
Cl
O
O
B
Cl
N
N
N
N
N
N
O
Br
N
N
N
12
e,f
H2N
R
H2N
H2N
O
O
h
R
R
NHBoc
11
NHBoc
NH2
13a, 3R=Boc
13b, 3R=H
14a, A=B=CH
14b, A=N, B=CH
14c, A=B=N
*
R =
N
Scheme 1. Synthesis of tetrasubstituted pyridine analogs via pyridine N-oxide intermediates. Reagents and conditions: (a) TFAA, ureaꢀH2O2 (UHP), DCM, 0 °C to rt, 2 h, 88%;
(b) Ph3P, DEAD, THF/DMF (6:1); (c) TsCl, pyridine, ethanolamine; (d) Pd(Ph3P)4, 2 N Na2CO3 aq, 90 °C, 4 h; (e) Pd(dppf)Cl2ꢀCH2Cl2, 5 mol %, 2 N Na2CO3, 110 °C, 4 h; (f) TFA,
DCM, RP-HPLC purification; (g) 5,5,50,50-tetramethyl-2,20-bi-1,3,2-dioxaborinane, Pd(dppf)Cl2ꢀCH2Cl2, KOAc, dioxane, 80 °C, 16 h; (h) Pd(Ph3P)4, 2 N Na2CO3 aq, 90 °C, 4 h.
Cl
O
B
Cl
Br
Cl
Cl
N
N
O
Br
Br
c,d
Boc
e
a,b
N
6
N
Boc
N
H
N
H
H
O
H
N
H2N
O
N
OH
2
OH
17
NHBoc
NHBoc
18
19
SO2Ph
O
N
SO2Ph
N
N
N
N
N
N
N
Cl
N
Br
N
N
20
g,h,i
Boc
N
H
H2N
f
H
H
N
O
O
N
NHBoc
NH2
21
14d
Scheme 2. Synthesis of tetrasubstituted aminopyridine analog via regio-selective nitration. Reagents and conditions: (a) HNO3/H2SO4, 0 °C to rt, 16 h, 65%; (b) Fe, acetic acid,
5 °C, 1.5 h, 97%; (c) NaHMDS, (Boc)2O, THF, ꢁ78 °C to rt, 3 h, 79%; (d) 4, DIAD, PPh3, DMF/THF (10:1), 0 °C to rt, 4 h, 92–100%; (e) Pd(dppf)Cl2, KOAc, THF, reflux, 7 h, 83–87%;
(f) Pd(dppf)Cl2, 2 N aq Na2CO3, THF, reflux, 2 h, 48–71%; (g) 9, Pd(PPh3)4, 2 N aq Na2CO3, THF, reflux, overnight, 47–82%; (h) 6 N NaOH, THF/isopropanol (1:2), rt to 60 °C, 1 h;
(i) TFA, CH2Cl2, rt, 2 h, 54–81% overall.

H. Lin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 684–688
687
Table 2
SAR of aminopyridine 4,7-diazaindazole analogs
Compd
R
R0
R00
H
AKT1/2/3a IC50
(
lM)
BT474b IC50
0.58
(lM)
p-GSK3b BT474c IC50
(l
M)
P450 3A4 IC50
3.2
(lM)
*
*
26a
Me
0.006/0.13/0.006
0.50/6.3/0.50
0.28
26b
25a
H
Et
H
3.9
>10
5.0
H
N
Cl
Me
0.001/0.012/0.002
0.001/0.007/0.001
0.001/0.015/0.001
0.15
0.30
0.50
*
H
N
CN
25b
Me
Me
H
H
2.8
>30
>30
1.6
4.0
*
H
N
CONH2
25c
>10
*
a
b
c
n P 2.
Inhibition of cell proliferation.
Inhibition of phosphorylation of GSK3b.
Compound 14c was then evaluated in mice using BT474 tumor
xenograft model. As shown in Figure 3A, compound 14c demon-
strated a significant pharmacodynamic effect in a dose dependent
manner. To further establish the anti-tumor activity in vivo, com-
pound 14c was dosed intraperitoneally (ip) for 21 days (QD) in
the same xenograft model (Fig. 4B). Dose-dependent inhibition of
O
H
N
N
N
R'
N
N
R''
N
H
O
R
NH2
100
75
50
25
0
IC50 = 1.4 µM
Hill slope = 0.93
max. inhibition = 83.4%
n = 8
Despite the introduction of an amino group adjacent to the core
pyrinde nitrogen atom, compound 14c maintained selectivity
when compared to the corresponding trisubstituted analog 1b.
As shown in Figure 3, compound 14c displays greater than 1000-
fold selectivity over representative kinases from many different
families except for PAK1. However, achieving selectivity over
PKA, a very close relative of AKT in AGC superfamily, remains
challenging.
The pharmacokinetic profile of compound 14c was evaluated in
mouse, rat, dog and monkey (see Table 3). Higher exposure and
lower clearance in all species were observed with 14c upon intra-
venous (iv) or intraperitoneal (ip) administration. Like 1a, this
compound was not observed to be orally available.
IC50 = 10.4 µM
Hill slope = 1.02
max. inhibition = 95.0%
n = 14
compound 1b
compound 14c
0.01
0.1
1
10
[µM]
100
1000
Figure 2. Compound 1b and 14c mediated block of hERG current.
OH
Boc
a,b
c
O
O
N
N
Boc
HN
N
H
N
N
R
Boc
22
PhSO2
PhSO2
d
4
23a, R=Cl
23b, R=I
23c, R=CN
OH
boc
e,f
HN
N
R
PhSO2
24a, R=Cl
24b, R=CN
Scheme 3. Synthesis of the substituted tryptophanols with small groups at 2-position of the indole ring. Reagents and conditions: (a) 2,2-bis(methyloxy)propane, DMF,
TsOHꢀH2O, rt, 3 h, 74%; (b) NaH, PhSO2Cl, DMF, 0 °C, 70%; (c) LDA, THF, ꢁ78 °C, PhSO2Cl (23a, 79%) or I2 (23b, quantitative); (d) Zn(CN)2, Pd(tBu3P)2, DMF, microwave
irradiation, 150 °C, 30 min, 85%; (e) 1 N HCl (aq)/MeOH/THF 3:2:1 v/v/v, 80 °C; (f) Boc2O, NaHCO3 (satd aq), DCM, 82% over two steps.

688
H. Lin et al. / Bioorg. Med. Chem. Lett. 20 (2010) 684–688
Compound 1b
Compound 14c
100000
10000
1000
100
10
1
Figure 3. Comparison of the kinase selectivity between compound 1b and aminopyridine analog 14c.
Table 3
model. Furthermore, compound 14c displayed much reduced
CYP450 inhibition, hERG channel inhibition, and improved phar-
macokinetic properties compared to the previously described tri-
substituted pyridines. Therefore, compound 14c has a suitable
profile to warrant further evaluation as an iv clinical development
candidate.
Pharmacokinectic profiles of compounds 1a and 14c
Compound
Species
Admin.
Dose mg
DNAUC(0-t)
Cl
nga h/mL/mg
mL/min/kg
1a
14c
1a
14c
1a
14c
1a
Mouse
Rat
ipa
iva
ivb
ivb
ivb
ivb
ivb
ivb
9.6
2.2
10.6
2.4
2.4
3.1
96
170
301
303
425
630
386
853
ND
98.9
53.2
46.0
34.4
25.3
39.1
22.3
Acknowledgements
Dog
Monkey
3.1
3.0
The authors thank Dr. Arthur Shu for preparing compound 14c
in large scale, and thank Dr. Karl Erhard for the final purification of
compound 14c to support preclinical toxicity study.
14c
a
Bolus.
Infusion.
b
References and notes
80
60
40
20
0
1. Lin, H.; Yamashita, D. S.; Zeng, J.; Xie, R.; Wang, W.; Nidarmarthy S.; Luengo, J.
I.; Rhodes, N.; Knick, V. B.; Kumar, J.; Choudhry, A. E.; Lai, Z.; Minthorn, E. A.;
Strum, S. L.; Wood, E. R.; Elkins, P. A.; Concha, N. O.; Heerding, D. A. Bioorg. Med.
Chem Lett. 2009. doi:10.1016/j.bmcl.2009.11.064.
2. Lin, H.; Yamashita, D. S.; Zeng, J.; Xie, R.; Luengo, J. I.; Rhodes, N.; Zhang, S.-Y.;
Robell, K. A.; Levy, D.; Kumar, J.; Choudhry, A. E.; Lai, Z.; Minthorn, E. A.;
Koretke, K. K. Heerding, D. A. Bioorg. Med. Chem Lett. 2009. doi:10.1016/
j.bmcl.2009.11.060.
A
Vehicle
50mg
25mg
12.5mg
6.25mg
3. Data obtained in PatchXpress assay in HEK293 cells. For hERG estimation
through PatchXpress, see: Ly, J. Q.; Shyy, G.; Misner, D. L. Clin. Lab. Med. 2007,
27(1), 201.
2500
2000
1500
1000
500
B
Vehicle Control
Compound 14c 30mg/kg, IP , QDx21
Compound 14c 20mg/kg, IP , QDx21
Compound 14c 10mg/kg, IP , QDx21
D14%TGI
4. Nicholas, K. S. Pyridine N-Oxide e-EROS Encyclopedia of Reagents for Organic
Synthesis, 2001.
5. (a) Lam, P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M. J.; Galemmo, R. A.;
Fevig, J. M.; Teleha, C. A.; Alexander, R. S.; Smallwood, A. M.; Rossi, K. A.;
Wright, M. R.; Bai, S. A.; He, K.; Luettgen, J. M.; Wong, P. C.; Knabb, R. M.;
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A. V.; Solov’eva, N. P.; Anisimova, O. S.; Granik, V. G. Tetrahedron 1998, 54(21),
5775.
6. Cl by-product 6b and the regio isomer 6c were also formed in this reaction, but
were easily separable from 6a by trituration since they were more soluble in
MeOH or EtOH.
39%
41%
59%
7. Tosylsulfonyl protecting group was used to avoid the formation of the mixture,
but a deprotection step under basic conditions was added.
8. Fyfe, M. C. T.; Thomas, G. H.; Gardner, L. S.; Bradley, S. E.; Gattrell, W.;
Rasamison, C. M.; Shah, V. K. PCT Int. Appl. WO 2006067532A1 20060629,
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17
21
25
29
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DAYS
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Figure 4. (A) Effect of compound 14c (IP) on GSK3b phosphorylation in BT474
tumor xenograft mouse model. (B) Effect of compound 14c on BT474 tumor growth
in xenograft mouse model.
12. Pd(Ph3 P)4 or PddppfCl2 did not give any product 23c.
13. The observed activity of both compound 1b and 14c approached to the
detection limit in the standard AKT1 enzymatic assay. Hence, the empirical pKiꢂ
values of 9.30 for compound 1b and 9.63 for compound 14c represent a more
accurate measure of enzyme potency. For details of the assay conditions, see:
Heerding, D. A.; Rhodes, N.; Leber, J. D.; Clark, T. J.; Keenan, R. M.; Lafrance, L.
V.; Li, M.; Safonov, I. G.; Takata, D. T.; Venslavsky, J. W.; Yamashita, D. S.;
Choudhry, A. E.; Copeland, R. A.; Lai, Z.; Schaber, M. D.; Tummino, P. J.; Strum, S.
L.; Wood, E. R.; Duckett, D. R.; Eberwein, D.; Knick, V. B.; Lansing, T. J.;
McConnell, R. T.; Zhang, S.-Y.; Minthorn, E. A.; Concha, N. O.; Warren, G. L.;
Kumar, R. J. Med. Chem. 2008, 51, 5663.
BT-474 tumor growth was observed, wherein a 59% reduction in
tumor volume, relative to the control group, was observed at
30 mg/kg dose level.
In summary, we have identified the novel tetrasubstituted ami-
nopyridine 14c as a potent and selective AKT inhibitor. Compound
14c demonstrated a robust in vivo pharmacodynamic effect and
dose-dependent inhibition of tumor growth in a BT474 xenograft