Identification of 3-amido-4-anilinoquinolines as potent and selective inhibitors of CSF-1R kinase

Article abstract of DOI:10.1016/j.bmcl.2008.12.046

3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.

Full text of DOI:10.1016/j.bmcl.2008.12.046

Bioorganic & Medicinal Chemistry Letters 19 (2009) 697–700
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of 3-amido-4-anilinoquinolines as potent and selective
inhibitors of CSF-1R kinase
*
David A. Scott , Carrie L. Balliet, Donald J. Cook, Audrey M. Davies, Thomas W. Gero, Charles A. Omer,
Srinivasu Poondru, Maria-Elena Theoclitou, Boris Tyurin, Michael J. Zinda
Cancer Research, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and
SAR is reported, along with initial efforts to optimize the physical properties and PK through modifica-
tions at the quinoline 6- and 7-positions.
Received 15 October 2008
Revised 5 December 2008
Accepted 9 December 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
CSF-1R
Kinase inhibitor
Quinoline
Solid tumors comprise a number of cell types in addition to
malignant cells, including macrophages. These tumor-associated
macrophages (TAMs) are believed to play a number of roles to pro-
mote tumor progression and metastasis.1 Upon recruitment to the
tumor environment, macrophages release pro-angiogenic factors
such as VEGF, proteases important for invasion, and other growth
factors involved in the growth and motility of tumor cells such
as EGF. Monocyte/macrophage development and proliferation de-
pends upon the signaling pathway of the receptor tyrosine kinase
CSF-1R and its ligand CSF-1 (also known as macrophage colony
stimulatory factor, M-CSF). Inhibition of this pathway could there-
fore be expected to reduce TAM levels, leading to multiple effects
on tumor types in which macrophages have a significant presence.
Despite extensive efforts within the oncology field to develop
kinase inhibitors, uncertainty remains over the relative merits of
selective compounds versus less selective or ‘‘multi-targeted”
inhibitors.2 Targeted molecules offer the clearest indication that
in vivo effects result from the intended in vitro activity. Also, tox-
icity derived from additional activity against other kinases is likely
to be reduced.3 However, inhibition of a single kinase may not be
sufficient to achieve a clinical benefit, either through the built-in
redundancy of signaling pathways, or the ability of tumors to ac-
quire resistance.4 Inhibitors with activity against multiple kinases
may in fact be more effective, and several multi-targeted kinase
inhibitors are now commercially available. An alternative approach
to multi-targeted agents is the combination of selective ones. A
highly selective CSF-1R inhibitor would test the hypothesis of
whether reduced levels of tumor-associated macrophages could
impact tumor progression. Used alone or in combination with
other agents, such an inhibitor might offer a safe and effective ther-
apeutic option.
Screening of a subset of the AstraZeneca collection, containing
compounds known or expected to inhibit kinases, identified sev-
eral series with good activity against CSF-1R. Most of the hits were
derived from earlier AZ kinase projects, and many of these pos-
sessed poor general kinase selectivity, or belonged to a series in
which selectivity against a key enzyme such as KDR appeared dif-
ficult to achieve. The bisamide series offered a relatively selective
profile; work to optimize that series was reported recently.5
The most promising of the hit series, in terms of both CSF-1R
potency and kinase selectivity, were the 3-amido-4-anilino-6,7-
dimethoxyquinolines. One of the screening hits is shown in Fig-
ure 1 (1: IC50 = 19 nM).
Another attractive feature of the amidoquinolines was the po-
tential to optimize the physical properties and PK profile. From
Cl
F
NH
O
MeO
MeO
NH2
N
1
* Corresponding author. Tel.: +1 781 839 4343.
E-mail address: david.scott@astrazeneca.com (D.A. Scott).
Figure 1. Amidoquinoline screening hit 1.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.046

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D. A. Scott et al. / Bioorg. Med. Chem. Lett. 19 (2009) 697–700
our modeling studies, the binding of the amidoquinolines to CSF-
1R is believed to occur through the quinoline and amide nitrogens.
The 6- and 7-positions point towards the kinase solvent channel,
and are therefore available for the introduction of solubilizing
groups. Such a strategy has been widely pursued within AZ and
elsewhere, on well-known kinase inhibitor scaffolds such as the
quinazolines6 and cyanoquinolines.7
3-Amido-4-anilinoquinolines have been reported by another
group as inhibitors of CSF-1R, with modifications to the aniline
substituent and a 7-aryl group giving good cell potency and oral
PK.8 Other structural classes of CSF-1R inhibitor have also been re-
ported.9–15
The AZ collection contained a set of analogs in the dimethoxy
scaffold, and some initial aniline SAR was generated quite rapidly
(Table 1). A range of substituents are tolerated in the enzyme,
but only the most potent of these gave good activity in our cell pro-
liferation assay.16 2,3-Disubstituted anilines (13–17) typically gave
the most potent compounds, but other substitution patterns
including 3,4-Cl (24) and 2-F, 5-Me (26) also gave good cell
potency.
Compounds 1–28 were prepared from 3,4-dimethoxyaniline 30
via the route shown in Scheme 1. Preparation of the chloroester 32
has been reported via a thermal cyclization of a diethyl malonate
intermediate and subsequent chlorination step,18 but we found
that heating the malonate intermediate with POCl3 in toluene gave
the chloroester in one pot. Hydrolysis of the ester, chlorination and
then treatment with aqueous ammonia gave the chloroamide.
Most aniline additions were performed in ethanol, with the prod-
uct HCl salt readily isolated by filtration.
Solubility, plasma protein binding, and rat PK data were col-
lected for several of the dimethoxyquinolines (Table 2). The most
potent example (17, 2,3-Cl) had very poor physical properties, high
clearance and no oral exposure. The 4-F (9) and 2,4-F (18) exam-
ples were less potent in the cell assay, but had lower plasma pro-
tein binding, good bioavailability and low to moderate in vivo
clearance.
To address the low aqueous solubility of the dimethoxyquino-
line compounds, basic groups were introduced at the 6- and 7-
positions. A set of 3-Cl, 4-F anilino compounds with amine side
chains were prepared as shown in Scheme 1. 2-Methoxy-5-nitro-
phenol 29 was protected as the benzyl ether, and reduced with
Raney Ni. From aniline 31, similar chemistry previously described
for the dimethoxy scaffold generated the 3-amido-4-anilinoquin-
oline 34, with a benzyl protecting group at the 7-position. Treat-
ment with thioanisole and TFA removed the benzyl group to give
the hydroxyquinoline 35. A Mitsunobu reaction with chloroetha-
nol installed a suitable leaving group, which could be displaced
with various amines. Alternatively, final compounds could be pre-
pared by direct alkylation of the hydroxyquinoline with chloro-
alkylamines. Similar chemistry was used to install side chains at
Table 1
CSF-1R enzyme and cell activity for 1–28
R1
NH
N
O
MeO
MeO
NH2
17
Compound
R1
IC50
(l
M)
Cell (lM)
1
2
3
4
5
6
7
8
—
2-F
2-Cl
2-Br
2-Me
3-F
3-Cl
3-Me
0.200
0.009
0.022
0.036
0.052
0.033
0.018
0.038
0.030
0.031
0.046
0.100
0.026
0.013
0.031
0.029
0.006
0.025
0.010
0.018
0.052
0.028
0.016
0.009
0.015
0.013
0.100
0.022
5.6
0.45
0.7
1.8
1.8
1.2
0.42
0.62
0.97
0.53
1.1
9
4-F
4-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4-OMe
4-NMe2
2,3-F
2-F, 3-Cl
2,3-Me
2-Me, 3-Cl
2,3-Cl
2,4-F
2-F, 4-Me
2-F, 4-Cl
2,4-Cl
3,4-F
3-Cl, 4-F
3,4-Cl
2,5-F
1.5
0.49
0.12
0.27
0.25
0.09
0.40
0.25
0.59
4.0
1.4
0.33
0.23
0.43
0.21
1.2
2-F, 5-Me
3,5-F
3,5-Cl
0.36
R1
Cl
N
MeO
HO
MeO
R3
CO2Et
MeO
R3
N
N
a, b
c, d
e, f
CONH2
MeO
R3
NO2
NH2
30 R3 = OMe
31 R3 = OBn
32 R3 = OMe
29
33 R3 = OBn
1 - 28 R3 = OMe
34 R3 = OBn, R1 = 3-Cl, 4-F
Cl
Cl
F
F
X = NR'R"
or CH2NR'R"
NH
NH
CONH2
CONH2
MeO
MeO
HO
h, i
or j
g
X
N
N
O
35
Scheme 1. Preparation of examples 1–28 and 36–42. Reagents and conditions: (a) BnBr, K2CO3, DMF, rt; (b) Raney Ni, H2, EtOH; (c) diethylethoxymethylene malonate,
CH3CN, rt (R3 = Me) or diethylethoxymethylene malonate, sealed tube, 120 °C (R3 = Bn); (d) POCl3, Tol, 100 °C; (e) i—NaOH, MeOH, rt; ii—SOCl2, Tol, reflux, 2 h then acetone,
NH4OH, 0 °C; (f) aniline, cat. AcOH, EtOH, 80 °C or DMF, 100 °C (R3 = Me) or 3-Cl, 4-F-aniline, cat. AcOH, DMF, sealed tube, 120 °C (R3 = Bn); (g) thioanisole, TFA, reflux 3 h; (h)
ClCH2CH2OH, DIAD, PPh3, THF, 0–45 °C; (i) amine, cat. NaI, K2CO3, DMF, sealed tube, 100 °C; (j) chloroalkylamine, K2CO3, DMF, sealed tube, 100 °C.

D. A. Scott et al. / Bioorg. Med. Chem. Lett. 19 (2009) 697–700
699
Table 2
Enzyme and cellular potency, physical property data and rat PK upon iv (3 mpk) and po (10 mpk) dosing
R1
NH
N
O
R2
R3
NH2
Compound R1
R2
R3
IC50
M)
Cell
M)
Sol19
M)
PPB (%
free)
F
(%)
Cl (ml/min/
kg)
Vss (L/
kg)
T1/2
(h)
17
(
l
(
l
(
l
9
4-F
2-F, 3-Cl
2,3-Cl
2,4-F
2-F, 4-
Me
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
0.030
0.013
0.006
0.025
0.010
0.97
0.12
0.09
0.40
0.25
12
18
<1
54
7
6.0
2.7
<0.7
5.6
1.2
96
7
0.3
0.9
14
17
18
19
—
100
115
23
4.1
0.9
0.5
0.6
23
25
26
3-Cl, 4-F
2,5-F
2-F, 5-
Me
MeO
MeO
MeO
MeO
MeO
MeO
0.016
0.015
0.013
0.33
0.43
0.21
6
14
7
3.3
5.4
3.6
24
59
1.8
0.6
36
37
38
39
40
41
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
MeO
MeO
MeO
MeO
MeO
MeO
Me2N(CH2)2O
(CH2)2CHNH(CH2)2O
0.012
0.017
0.018
0.010
0.017
0.007
0.56
0.25
0.30
1.3
0.34
0.40
>1000
380
>1000
>1000
970
16
210
230
40
30
2.1
1.7
5.3
6.5
8.1
18
MeO(CH2)2NMe(CH2)2O
HO(CH2)2NMe(CH2)2O
1-Pyrrolidinyl-(CH2)2O
4-Me-Piperazinyl-
(CH2)3O
270
52
2.4
270
17
42
3-Cl, 4-F
MeO
4-OH-Piperidinyl-
(CH2)2O
0.080
3.8
>1000
5.5
43
44
3-Cl, 4-F
3-Cl, 4-F
1-Pyrrolidinyl-(CH2)2O
4-Me-Piperazinyl-
(CH2)3O
MeO
MeO
0.013
0.010
0.48
0.71
257
911
27
30
45
46
47
48
49
50
51
52
53
2,3-Cl
2,3-Cl
2,3-Cl
2,3-Cl
2,3-Cl
2,3-Cl
2,4-F
Me2N(CH2)2NH
1-Piperidinyl-(CH2)2NH
MeO
MeO
MeO
<0.001
0.007
0.003
0.015
0.003
0.006
0.007
0.022
0.007
0.11
0.08
0.74
0.48
0.03
0.03
0.85
0.48
0.99
340
200
300
110
280
160
>1000
>1000
160
10
5.5
2.1
0.6
4.2
78
90
8.5
19
1.6
2.4
Me2N(CH2)2NH
1-Piperidinyl-(CH2)2NH
EtO
EtO
MeO
MeO
MeO
MeO
Me2N(CH2)2NH
1-Piperidinyl-(CH2)2NH
Me2N(CH2)2NH
1-Piperidinyl-(CH2)2NH
1-Morpholinyl-
(CH2)2NH
110
220
12
36
1.6
1.9
44
20
7.8
2,4-F
2,4-F
54
2,4-F
MeO
Me2N(CH2)2NH
0.023
3.0
>1000
44
the quinoline 6-position (43, 44), starting from 2-methoxy-4-
nitrophenol.
the 7-position gave compounds with reduced cell potency (47,
48, 54). We speculated that demethylation of the 6- or 7-methoxy
groups might be one of the mechanisms of clearance, and prepared
some 7-EtO examples (49, 50). There was no obvious impact on
metabolism (50 vs 46), but cell potency was enhanced relative to
7-MeO.
As a result of its cell potency and oral PK profile, 18 was selected
for assessment in our mouse pharmacodynamic (PD) model,5 in
which inhibition of pCSF-1R was measured 2 and 6 h after oral dos-
ing. At 100 mpk,23 the compound achieved 95% inhibition of pCSF-
1R after 2 h, but this dropped off to 65% at 6 h.
All examples of this type (36–44) had excellent enzyme activity.
Most retained the cell potency of the dimethoxy compound 23, but
those with additional hydrogen bond donors (39, 42) were less ac-
tive in the cell (Table 2). These compounds were all found to have
high aqueous solubility, and reduced plasma protein binding. Rat
PK data was obtained for several examples (36, 37, 40), but the
compounds suffered from extremely high in vivo clearance and
minimal oral exposure.
Compounds with basic side chains linked through a nitrogen
atom were prepared next, with either 2,3-Cl (45–50) or 2,4-F aniline
(51–54). The synthetic route (Scheme 2) was similar to that for the
dialkoxy quinolines, but started from the appropriate bromoalkoxy
aniline 55. After preparation of the 4-chloroquinoline ester 56 and
aniline addition, the amines were introduced under Buchwald–Har-
twigcouplingconditions.20 Conversionof thevarious esters58tothe
amides was reliably achieved through treatment with formamide
and methoxide.21 7-Aminoquinoline compounds were prepared in
a similar fashion from 3-bromo-4-methoxyaniline.22
Compound 18 was screened against a panel of 150 kinases at a
concentration of 1
Apart from CSF-1R, significant activity was only observed against
GSK3
and EphB4 (Table 3).24
lM and displayed remarkable kinase selectivity.
a
In conclusion, 3-amido-4-anilinoquinolines are potent inhibi-
tors of CSF-1R with excellent kinase selectivity. Compounds from
the dimethoxy scaffold have at best moderate aqueous solubility.
Some examples showed good bioavailability in rats, and we were
able to demonstrate activity in a mouse PD model with compound
18. Efforts to optimize the physical properties and PK profile
through the introduction of basic side chains were unsuccessful.
Other approaches to optimize the PK of this attractive scaffold
are reported in the following paper.
Like the alkoxyamines, however, these compounds had high
in vivo clearance in rats (Table 2). Compounds with an amine at
the 6-position typically retained the potency of dialkoxy examples
with the corresponding aniline group, but switching the amine to

700
D. A. Scott et al. / Bioorg. Med. Chem. Lett. 19 (2009) 697–700
Cl
N
R1
R1
R1
Br
R3
CO2Et
Br
R3
NH
N
d
NH
N
e
a, b
c
NH
N
CO2Et
Br
R3
CO2Et
CONH2
R'HN
R3
R'HN
R3
NH2
56
55
57
58
Scheme 2. Preparation of examples 45–46 and 49–53. Reagents and conditions: (a) diethylethoxymethylene malonate, CH3CN, rt; (b) POCl3, Tol, 100 °C; (c) aniline, cat. AcOH,
EtOH, 80 °C or DMF, 100 °C; (d) amine, Pd2(dba)3, BINAP, Cs2CO3, Tol, 100 °C; (e) HCONH2, DMF, NaOMe, 100 °C.
11. Conway, J. G.; McDonald, B.; Parham, J.; Keith, B.; Rusnak, D. W.; Shaw, E.;
Table 3
Kinase selectivity of 18
Jansen, M.; Lin, P.; Payne, A.; Crosby, R. M.; Johnson, J. H.; Frick, L.; Lin, Min-
Hwa J.; Depee, S.; Tadepalli, S.; Votta, B.; James, I.; Fuller, K.; Chambers, T. J.;
Kull, F. C.; Chamberlain, S. D.; Hutchins, J. T. Proc. Natl. Acad. Sci. U.S.A. 2005,
102, 16078.
Kinase
CSF-1R
% Inhibition
97
87
51
28
22
20
17
17
16
15
<15
12. Irvine, K. M.; Burns, C. J.; Wilks, A. F.; Su, S.; Hume, D. A.; Sweet, M. J. FASEB J.
2006, 20, 1921.
GSK3
a
13. (a) Patch, R. J.; Brandt, B. M.; Asgari, D.; Baindur, N.; Chadha, N. K.; Georgiadis,
T.; Cheung, W. S.; Petrounia, I. P.; Donatelli, R. R.; Chaikin, M. A.; Player, M. R.
Bioorg. Med. Chem. Lett. 2007, 17, 6070; (b) Illig, C. R.; Chen, J.; Wall, M. J.;
Wilson, K. J.; Ballentine, S. K.; Rudolph, M. J.; DesJarlais, R. L.; Chen, Y.;
Schubert, C.; Petrounia, I. P.; Crysler, C. S.; Molloy, C. J.; Chaikin, M. A.;
Manthey, C. L.; Player, M. R.; Tomczuk, B. E.; Meegalla, S. K. Bioorg. Med. Chem.
Lett. 2008, 18, 1642.
14. Wall, M. J.; Chen, J.; Meegalla, S. K.; Ballentine, S. K.; Wilson, K. J.; DesJarlais, R.
L.; Schubert, C.; Chaikin, M. A.; Crysler, C. S.; Petrounia, I. P.; Donatelli, R. R.;
Yurkow, E. J.; Boczon, L.; Mazzulla, M.; Player, M. R.; Patch, R. J.; Manthey, C. L.;
Molloy, C. J.; Tomczuk, B. E.; Illig, C. R. Bioorg. Med. Chem. Lett. 2008, 18, 2097.
15. Huang, H.; Hutta, D. A.; Hu, H.; DesJarlais, R. L.; Schubert, C.; Petrounia, I. P.;
Chaikin, M. A.; Manthey, C. L.; Player, M. R. Bioorg. Med. Chem. Lett. 2008, 18,
2355.
EphB4
EphA5
MST1
MST2
Met
MKK4
JNK3
TBK1
140 kinases
Acknowledgments
16. A description of the cell assay is contained in Ref. 5.
17. Early compounds were screened in a HTRF enzyme assay, according to the
The authors thank our colleagues Yanyi Zhu and Satish Barnela
for the preparation of additional compounds in this series, Geral-
dine Bebernitz and Minwei Ye for biological data, Dominique Cus-
teau for PK studies, and Maureen Hattersley and Kirsten Bell for the
PD study.
following protocol: 5
bottom black). Twenty-five microliters substrate mix containing 120 nM poly
EY-biotin (pET-BIOT, CisBio 61GT0BLB E:Y = 4:1) substrate and 60 M ATP
lL compound is spotted into 384 well plate (Matrix flat
l
(Sigma A3377) in 1Â buffer (0.067 M Hepes, 10 mM MgCl2, 5 mM DTT, 0.005%
Triton X-100) is added to each well. The reaction is initiated by addition of 20
l
L CSF-1R enzyme mix in 1.25Â buffer (1.58 lg CSF-1R enzyme prepared from
His-tagged CSF-1R catalytic domain and expressed in Baculovirus; purified
sequentially on Qiagen Ni-NTA Superflow, Mono Q HR 10/10, and Superdex
200 SEC and stored as aliquots in 20 mM Tris, pH 7.5, 150 mM NaCl, 1.5 mM
DTT, 10% glycerol at À80 °C). The reaction is allowed to proceed at room
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