Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) Inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.01.079

Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline

Full text of DOI:10.1016/j.bmcl.2011.01.079

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1719–1723
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun
N-terminal kinase (JNK) Inhibitors
Yuanjun He, Theodore M. Kamenecka, Youseung Shin, Xinyi Song, Rong Jiang, Romain Noel, Derek Duckett,
⇑
⇑
Weimin Chen, Yuan Yuan Ling, Michael D. Cameron, Li Lin, Susan Khan, Marcel Koenig , Philip V. LoGrasso
Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain pene-
tration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the bio-
chemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3
inhibitor (IC50 = 40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration
properties. With these properties, 13a is considered a potential candidate for in vivo evaluation.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 December 2010
Revised 14 January 2011
Accepted 19 January 2011
Available online 22 January 2011
Keywords:
JNK
Quinazoline
Inhibitors
c-Jun-N-terminal Kinase (JNK) was discovered in the early-mid
1990s1–4 and is a member of the mitogen activated protein kinase
(MAP) family. In the nearly two decades of work on JNK, the
enzyme has been implicated in numerous diseases ranging from
cardiovascular disease,5 to metabolic disorders6 and neurodegen-
eration.7–11 There are three isoforms of JNK. JNK1 and JNK2 are
ubiquitously expressed, whereas JNK3 is expressed primarily in
the brain with lower levels of expression in the heart and testis.12
Because of the numerous potential clinical applications for JNK,
many small molecule inhibitor programs have developed over the
past five years. Compound classes that have shown nice JNK selec-
tivity include: aminopyrazoles,13 aminopyridines,14,15 pyridine
carboxamides,15,16 benzothien-2-yl-amides and benzothiazol-2-yl
acetonitriles,17,18 quinoline derivatives,19 and aminopyrimi-
dines.20–22 For a recent review of all these classes see LoGrasso
and Kamenecka.23 Most of these classes of compounds did not
demonstrate good brain penetration, although Kamenecka et al. re-
cently reported aminopyrimidines showing excellent brain pene-
tration properties.22
p38), while also incorporating good brain penetration (brain/plas-
ma ratio of 0.8:1) in mouse, and excellent pharmacokinetics in rat.
With these properties, 13a is an attractive candidate for in vivo
evaluation in CNS efficacy models.
The JNK inhibitors 1a,b and 2 (Fig. 1) were described in the pat-
ent and primary literature,22,24 with JNK3 IC50 = 90 nM for 1b and
IC50 = 180 nM for 2, respectively.22,25 The isoquinoline 1b was only
moderately potent in cells however (inhibition of c-jun phosphor-
ylation = 1.0 lM). Compounds 1b and 2 were found to have good
brain penetration and PK properties.22,24 As a strategy to design a
novel structural class with improved JNK3 potency and similar or
improved PK and brain penetration properties, we decided to com-
bine the amino isoquinoline of compound 1 and the amino pyrim-
idine scaffolds (compound 2). With this in mind we designed
quinazoline 3 (Fig. 1). We found that quinazoline 3 was a potent
JNK inhibitor with good brain penetration (Table 1). To establish
an SAR on the quinazoline ring, we first modified the 7-position
(Table 1). The synthesis is outlined in Scheme 1. For the syntheses
of the 2-chloro quinazolines from the corresponding fluoro alde-
hydes we followed the procedure described by Patel et al.26 A ser-
ies of pyrazole, isoxazole, morpholino, and pyridyl substitutions
were assessed at the 7-position on the quinazoline ring (com-
pounds 3–8f, Table 1). Pyrazole substitutions (compounds 3, 8a,
8g, 8h) had the lowest JNK3 IC50 values, suggesting preference
for pyrazole at the 7-position (Table 1). Despite the approximate
three-fold improvement in cell-based potency of 8a over 3, the
higher polar surface area of 8a caused a significant decrease in
brain penetration (Table 1). The available space for modifications
in this position appeared to be very limited and we concluded that
the N-methyl-pyrazole moiety was optimal in terms of overall
In the current work we present a series of novel quinazolines
which were potent JNK inhibitors with >2200-fold selectivity over
p38 (compound 14d). Moreover, a systematic SAR approach utiliz-
ing biochemical and cell-based assays, along with mouse and rat
pharmacokinetics enabled us to develop compounds (e.g., 13a)
which maintained their potency and selectivity (>500-fold over
⇑
Corresponding author. Tel.: +1 561 228 2230; fax: +1 561 228 3081 (P.V.L.);
tel.: +1 561 228 2212 (M.K.).
E-mail addresses: marcelk@scripps.edu (M. Koenig), lograsso@scripps.edu (P.V.
LoGrasso).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.079

1720
Y. He et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1719–1723
R
N
N
O
N
N
O
O
N
F
N
N
N
N
N
N
N
N
OMe
N
O
N
N
H
N
N
H
N
N
H
N
3
1a:
R = H
2
1b: R = CH3
Figure 1. JNK3 inhibitors.
Table 1
Biochemical and cell-based IC50 values, and mouse plasma and brain levels for a series of 2,7-substituted quinazolinesa
R'
7
6
8
R
5
1
N
4
2
N
N
H
3
Compound
R0
R
JNK3
JNK1
c-Jun
IC50 (lm)
Mouseb
Plasma
(lm)
IC50
(
lm)
IC50
(
lm)
Brain
7.17
N
N
N N
N
O
N
3
0.09
0.05
0.31
17.8
HN N
N
N
N
N
N
N
N
N
N
O
O
O
8a
8b
0.05
0.7
0.04
nt
0.12
nt
42.9
nt
1.31
nt
N
N
N
O
N
O
8c
4.4
nt
nt
nt
nt
nt
nt
N
N
N
N
N
N
N
N
N
O
O
8d
0.21
26.7
8.1
N
N
8e
0.73
nt
nt
nt
nt
N
N
N
O
8f
>20
nt
nt
nt
nt
nt
nt
nt
N
HN N
N
N
N
N
N
8g
0.05
0.04
N
N
N
N
N
8h
0.06
0.1
0.29
13.1
1.37
nt = not tested.
a
JNK3 biochemical IC50 values are the averages of four or more experiments, and the JNK1 and cell-based IC50 values are the averages of two or more experiments. All
standard deviations are 644% for the biochemical and 681% for the cell-based assays.
b
10 mg/kg ip 2 h.
R'
Br
Br
R
a
R
b
N
N
N
N
N
H
N
N
H
N
Cl
7-Br
5: 8-Br
4:
8:
6:
7-Br
9: 8-Br
7-Br
7: 8-Br
Scheme 1. Reagents and conditions: (a) HCI in EtOH, n-BuOH, 120 °C, 2–24 h; (b) Boronic acid, Pd(PPh3)4, Na2CO3, dioxane/water, 120 °C, 30’, lW.

Y. He et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1719–1723
1721
Table 2
Biochemical and cell-based IC50 values, and mouse plasma and brain levels for a series of 2,8-substituted quinazolinesa
7
R'
6
8
5
R
N 1
N
2N
H
4
3
Compound
R0
R
JNK3
IC50
JNK1
c-Jun
Mouseb
Plasma
(l
m)
Brain
(lm)
IC50
0.02
0.01
(
lm)
IC50
0.02
0.33
(lm)
N
N
N
N
N
O
O
O
9a
9b
0.03
0.02
2.7
2.2
0.15
0.23
N
N
N
N
N
N
N
N
N
OMe
F
9c
0.07
0.09
0.25
6.1
1.5
N
N
N
N
N
O
O
9d
9e
0.007
0.06
0.03
0.05
3.0
1.4
nt
nt
N
N
N
S
N
N
5.2
10.3
5.0
12.7
7.6
4.5
nt
N
N
OMe
F
9f
0.08
0.02
0.09
nt
0.5
0.2
5.1
N
N
N
9g
9h
0.01
nt
N
N
S
N
N
OMe
F
N
nt
N
nt = not tested.
a
JNK3 biochemical IC50 values are the averages of four or more experiments, and the JNK1 and cell-based IC50 values are the averages of two or more experiments. All
standard deviations are 644% for the biochemical and 681% for the cell-based assays.
b
10 mg/kg ip 2 h.
properties. Replacement of the 3-morpholino on the 1,2,4-triazole
(8a) with 3-p-methyl-pyridyl on the 1,2,4-triazole (8g) decreased
the cell-based IC50 by three-fold to 40 nM. However, this substitu-
tion caused brain penetration to be quite poor (8h) (Table 1), espe-
cially when compared to compound 3. Attempts to improve the
potency and maintain the good pharmacological profile by replac-
ing the morpholino-triazolo aniline moiety were unsuccessful
(data not shown).
We next investigated the 8-position on the quinazoline ring
(Table 2). We found a number of different substitutions that
improved the biochemical potency. Compound 9a showed good
cellular potency but unfortunately the brain penetration was poor
low presumably due to high clearance. Furthermore, the good
biochemical potency did not translate into good cellular potency
(Table 3). Despite extensive synthetic efforts we were unable to
achieve the good PK and brain penetration properties we had with
quinazoline 3 by modifying the 2-, 7- and 8- positions. Generally,
the 8-substituted quinazolines led to more potent compounds
but poorer PK properties. A contributing factor may be the signifi-
cantly shorter half lives in microsomes as compared to the
7-substituted analogs. It became apparent that compounds with
the N-methyl pyrazole group in the 7-position led to compounds
with good pharmacological properties and substitutions in the
8-position improved the potency. We should also note that substi-
tutions in the 5- and 6-positions were generally not well tolerated
(data not shown). We therefore focused on the synthesis of analogs
bearing the N-methyl pyrazole group in the 7-position and differ-
ent substitutions in the 8-position (Table 4). All compounds shown
in Table 4 were synthesized as outlined in Scheme 2, except for
compounds 14b and 14f, which were made in five steps starting
from formylation of 3-fluoro-2-(trifluoromethyl)bromobenzene
and 2-bromo-6-fluoroanisole, respectively. Compound 14d showed
(Table 2). Similarly, the thiazole replacement at position
8
improved the JNK3 potency by four-fold (compare 9d to 9a), but
the cell-based IC50 for 9d was 150-fold less potent than 9a suggest-
ing decreased cell penetration for 9d. By replacing the methyl
pyridine group with phenyl groups and thus reducing the polar
surface area we indeed did achieve much improved brain penetra-
tion (compounds 9e/f), but unfortunately these compounds were
only modestly active in cells (Table 2). Compound 9g did have both
good brain penetration and potency (Table 2); however the PK
properties were poor (data not shown).
the best JNK3 potency with IC50 = 9 nM and cell-based IC50
=
40 nM, and had great selectivity over p38 (IC50 >20 M), but
l
In an effort to improve the brain penetration and also PK
properties of 9a we further explored the effect of substitutions in
the 2-position (Table 3). We hypothesized that by introducing
groups in the 2-position that would reduce the polar surface area
and molecular weight we would improve the brain penetration.
Compound 10b indeed showed much improved brain to plasma
ratio compared to 9a; however the plasma concentration was
unfortunately had very poor brain penetration (Table 4). The great
selectivity of compound 14d for JNK3 over p38 can potentially be
attributed to a better fit in the smaller active site for JNK3 and/or
a planar structure to the molecule. Compound 14f was found to
be very potent (IC50 = 4 nM vs JNK3) with good brain penetration;
however its oral bio-availability was low (%F = 8) and therefore not
a good candidate for further advancement. The same was true for

1722
Y. He et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1719–1723
Table 3
Table 4
Biochemical and cell-based IC50 values, and mouse plasma and brain concentrations
for 2-position substitutions designed to reduce polar surface area and molecular
weighta
Biochemical and cell-based IC50 values, and mouse plasma and brain levels for a series
of 2,7,8-substituted quinazolinesa
R'
N N
N
O
7
8
6
N
N
7
8
R
6
5
N
N
5
1
N
2
1
R
N
2
4
N
H
3
4
N
3
N
H
Compound R
JNK3 c-Jun Polar
IC50 IC50 surface
m)
m) areab
Mousec
Plasma Brain
(lm)
Compound
R
R0
JNK3
c-Jun
IC50 (lm)
Mouseb
Plasma
10.4
(lm)
(l
(l
IC50
(
lm)
Brain
8.3
N
13a
13b
Cl
Cl
CH3
0.04
0.10
0.62
N
N
N
O
9a
0.03 0.02 90
2.72
2.31
0.15
0.23
N
0.063
4.3
7.2
14a
14b
CH3
CF3
CH3
CH3
0.01
0.19
0.16
nt
7.4
8.3
7.6
5.6
N
10a
0.03 nt
77
N
14c
CH3
0.02
0.13
10.6
5.0
N
O
N
14d
CH3
0.009
0.04
6.3
0.22
O
F
10b
10c
10d
10e
10f
0.06 0.63 68
0.78
nt
1.06
nt
14e
14f
CH3
CH3
0.01
0.04
0.05
6.4
9.4
1.1
4.9
0.17 nt
0.09 nt
49
79
OMe
0.004
nt = not tested.
O
a
The JNK3 biochemical IC50 values are the averages of four or more experiments,
the JNK1 and cell-based IC50 values are the averages of two or more experiments.
All standard deviations are 644% for the biochemical and 681% for the cell-based
assays.
0
0
N
O
OH
b
0.05 0.93 69
nt
nt
10 mg/kg ip 2 h.
O
0.03 3.0
69
nt
nt
N
excellent brain penetration and good PK properties as well (Tables
4 and 5). Moreover, the compound had >500-fold selectivity over
p38. Compound 13b had a superior brain/plasma ratio of 1.7:1
compared to 13a, but suffered from a six-fold less potent cell-
based activity compared to 13a (Table 4). The PK properties of
compounds 3 and 13a are summarized in Table 5. Compound
13a is currently under further investigation in animal models.
In summary, we discovered a series of novel quinazoline com-
pounds as JNK inhibitors with good potency in biochemical and
cellular assays. Compound 13 improved upon compound 3 by
three-fold in cell potency and had 80% brain penetration compared
to 40% for compound 3. In contrast, compound 3 had a greater
a
JNK3 biochemical IC50 values are the averages of four or more experiments, and
the JNK1 and cell-based IC50 values are the averages of two or more experiments.
All standard deviations are 644% for the biochemical and 681% for the cell-based
assays.
b
Polar surface area calculated by ChemBioDraw Ultra 11.0.
10 mg/kg ip 2 h.
c
many of the other compounds with good brain penetration in the
14 series. We decided to introduce a chloro substitution at position
8 on the quinazoline ring and identified compound 13a, which had
R'
R'
N N
N N
O
O
O
Br
N
N
N
N
Br
N
N
Cl
R
Cl
N
Cl
N
N
N
N
N
N
N
a
b
c
N
N
N
N
H
N
N
H
N
N
H
N
Cl
11
12
13
14
W; (c) boronic acid, Pd(PPh3)4,
Scheme 2. Reagents and conditions: (a) HCI in EtOH, n-BuOH, 120 °C, 2–24 h; (b) boronic acid, Pd(PPh3)4, Na2CO3, dioxane/water, 120 °C, 30’,
l
Na2CO3, dioxane/water, 100–140 °C, 12–16 h, lW.
Table 5
PK properties of the two lead compounds
Compound
Clp (mL/min/kg)
Rat pka
Oral AUC (
Mꢀh)
Mouseb
Plasma
(
l
m)
t1/2 (h)
Vd (L)
l
Oral Cmax
(l
M)
%F
Brain
3
13a
3
6
3
3
0.8
1.4
6.3
2.3
0.7
0.3
28
19
17.8
10.4
7.2
8.3
a
1 mg/kg IV, 2 mg/kg po.
10 mg/kg ip 2 h.
b

Y. He et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1719–1723
1723
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pound 3 may be preferred for non-central nervous system (CNS)
indications and compound 13 may be preferred for CNS
indications.
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Acknowledgement
This work was supported by NIH Grant U01NS057153 awarded
to P.L.
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