Design, synthesis and RON receptor tyrosine kinase inhibitory activity of new head groups analogs of LCRF-0004

Article abstract of DOI:10.1016/j.bmcl.2015.07.080

New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase with various level of selectivity for c-Met RTK were obtained.

Full text of DOI:10.1016/j.bmcl.2015.07.080

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and RON receptor tyrosine kinase inhibitory
activity of new head groups analogs of LCRF-0004
⇑
Franck Raeppel, Stéphane L. Raeppel , Eric Therrien
Laboratoires ChemRF Inc./ChemRF Laboratories Inc., 3194 rue Claude-Jodoin, Montréal, QC H1Y 3M2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
New heteroarylcarboxamide head groups substituted with two aromatic rings analogs of thieno[3,2-
b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON
tyrosine kinase with various level of selectivity for c-Met RTK were obtained.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 19 June 2015
Revised 21 July 2015
Accepted 23 July 2015
Available online xxxx
Keywords:
RON
c-Met
RTK inhibitors
Head group
Molecular docking
RON homology model
Oncology
RON (Récepteur d’Origine Nantais, also known as human
MST1R, for macrophage stimulating 1 receptor) is the transmem-
brane receptor tyrosine kinase (RTK) for its endogenous ligand
MSP (for macrophage stimulating protein, also known as HGFL,
for hepatocyte growth factor-like).1 RON RTK belongs to the MET
proto-oncogene family, one of the three protein families of the
semaphorin superfamily. RON RTK shares significant structural
and functional homology with c-Met RTK, and is normally
expressed at low level in most epithelial cells. Activation of RON
RTK by MSP triggers downstream signaling pathways (b-catenin,
in tumor tissues correlates with increased metastasis and poor
prognosis in human cancer patients.
As part of our internal research program dedicated to the dis-
covery of novel therapeutic agents to eradicate and/or control the
proliferation of metastatic cancers and metastases we have shown
in a recent study that it was possible to replace the pyrazole head
group of LCRF-0004,7 known to be a potent and selective RON RTK
inhibitor, by different five-membered heterocycles such as pyrrole,
imidazole and triazole (Fig. 1, structure A)8 without loss of RON
enzyme inhibitory activity. In a second study, we have disclosed
that it was also possible to replace 1-phenyl-5-(trifluoromethyl)-
1H-pyrazole-4-carboxamide head group of LCRF-0004 by a fused
bicyclic lactam head group (Fig. 1, structure B)9 as mimetic of its
potential bioactive conformation.
PI3K/Akt, MAPK, NF-jB and STAT3) which mediate a number of
biological events including macrophage activity and tissue repair,
and epithelial cell behavior (cell growth, motility, and epithelial
to mesenchymal transition). Aberrant activity of RON has been
described in numerous types of cancers including colorectal,2
breast,3 lung,4 pancreas5 and prostate6 and occurs mainly through
wild type receptor overexpression or expression of isoform vari-
ants harboring different truncations within the extracellular
domain, leading to enhanced and uncontrolled tyrosine kinase
activity suggesting their potential interest as promising therapeu-
tic targets for cancer therapy. Importantly, overexpression of RON
In our first study,8 our design was guided by molecular docking
study using an X-ray crystal structure of c-Met kinase domain
(PDB: 3U6I)10 which shares a high sequence homology with RON.
The docking of LCRF-0004 using the Fitted program11 revealed a
class II extended conformation with the head group deeply
engaged in the hydrophobic back pocket of the enzyme. A probable
intramolecular hydrogen bond between a fluorine atom from the
trifluoromethyl group and the NH-acidic carboxamide seems to
rigidify the head group in the desired bioactive conformation
(Fig. 2). By scrutinizing carefully this predicted binding mode we
deemed it possible to replace the trifluoromethyl substituent from
the pyrazole head group by something bulkier and potentially with
a modulated electrostatic environment. In order to validate this
⇑
Corresponding author at present address: SagitheR Consulting, 2620 rue de
l’Étrier, Saint-Lazare, QC J7T 3L8, Canada.
E-mail address: stephane.raeppel@gmail.com (S.L. Raeppel).
Present address: Molecular Forecaster Inc., 969 rue Marc-Aurèle Fortin, Laval, QC
H7L 6H9, Canada.
http://dx.doi.org/10.1016/j.bmcl.2015.07.080
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Raeppel, F.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.07.080

2
F. Raeppel et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
X2
X3
X1
CF3
H
N
Ar
F
O
3
X4
X
O
N
N
X2
Ar2
H
N
H
N
Previous
studies
Present
study
N
S
F
F
X1
Structure A
Ar1
N
CF3
O
O
N
O
O
Z
Y
N
N
S
N
N
S
LCRF-0004
Structure C
n
Ar
X1
X2
X3
N
N
F
N
X4
O
O
N
N
S
Structure B
N
Figure 1. Structure of LCRF-0004 and generic structures for new analogs (A, B and C).
hydrazine with acetophenone to produce hydrazone 6 followed
by a Vilsmeier–Haack reaction gave rise to 1,3-diphenyl-1H-pyra-
zole-4-carbaldehyde 7.13 Oxidation of the formyl substituent of
compound 7 by potassium permanganate under aqueous alkaline
conditions14 provided carboxylic acid 8. Amide coupling between
intermediates 4 and 8 afforded compound 9 having a 1,3-diphe-
nyl-1H-pyrazole-4-carboxamide head group. Compound 13 was
obtained in four steps from ethyl 3-oxo-3-phenylpropanoate and
intermediate 4 (Scheme 3). Ethyl 3-oxo-3-phenylpropanoate was
first transformed into the activated tosyloxy derivative 10 by the
action of Koser’s reagent (HITB), then treated with thiobenzamide,
under Hantzsch conditions, to afford thiazole 1115 and finally
saponified to afford 2,4-diphenylthiazole-5-carboxylic acid 12.
Figure 2. Docking pose of LCRF-0004 in c-Met kinase domain.
Amide coupling between intermediates
compound 13 having a 2,4-diphenylthiazole-5-carboxamide head
group. Compound 19 was obtained in six steps from
4 and 12 provided
hypothesis, we describe herein our efforts in the design and syn-
thesis of small molecules with new heteroarylcarboxamide head
groups substituted with two aromatic rings (Fig. 1, structure C)
as analogs of LCRF-0004. These new compounds demonstrated
high potency for the inhibition of RON tyrosine kinase with various
levels of selectivity for c-Met RTK.
The synthesis of new analogs is described as follows: compound
5 was prepared in ten steps from commercially available starting
materials (Scheme 1). 1,5-Diphenyl-1H-pyrazole-4-carboxylic acid
3 was first prepared in three steps from ethyl 3-oxo-3-phenyl-
propanoate by an enamine formation, followed by a condensation
with phenyl hydrazine and a saponification reaction. After acid
chloride formation of intermediate 3 and amide coupling with
known aniline 4,12 the desired final compound 5 was obtained
2-bromo-1-phenylethanone and intermediate
4 (Scheme 4).
2-Bromo-1-phenylethanone was first alkylated by potassium 2-
cyano-1-ethoxyethenolate formed in situ, cyclized under acidic
conditions to form the pyrrole ring and submitted to a palla-
dium-catalyzed dehalogenation reaction under hydrogen atmo-
sphere to provide ethyl 5-phenyl-1H-pyrrole-3-carboxylate 16.16
After copper-catalyzed N-arylation17 of pyrrole 16 and a saponifi-
cation reaction, 1,5-diphenyl-1H-pyrrole-3-carboxylic acid 18
was obtained. Amide coupling between intermediates 4 and 18
provided the final compound 19 having a 1,5-diphenyl-1H-pyr-
role-3-carboxamide head group.
Compounds having a 1,5-bis-aryl-1H-pyrazole-4-carboxamide
head group were prepared using the following general synthesis18
(Scheme 5). Methyl or ethyl aryl ester was reacted with lithium
with
a 1,5-diphenyl-1H-pyrazole-4-carboxamide head group.
Compound 9 was obtained in four steps from acetophenone and
intermediate
4
(Scheme 2). Thus, condensation of phenyl
H
N
NMe2
NH2
N
O
O
MeO
OMe
O
O
N
4M NaOH/water
EtO
OEt
NMe2
OEt
N
toluene
60oC
O
AcOH
THF/MeOH
rt to reflux
MeOH
reflux
2
1
N
N
H
N
F
N
1) (COCl)2, DMF cat, DCM, rt
HO
O
O
O
2)
F
NH2
N
S
5
3
4
N
O
N
DIPEA
DMF
N
S
rt to 50oC
N
N
Scheme 1. Synthesis of compound 5.
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F. Raeppel et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
H
N
NH2
POCl3
KMnO4
O
H
N
N
N
DMF
2M KOH/water
N
N
N
H
0oC to rt
HO
1,4-dioxane
rt
AcOH
EtOH
reflux
O
O
7
6
8
N
N
Cpd 4
H
N
HATU reagent
DIPEA
F
O
O
N
DMF
rt to 50oC
N
S
9
N
Scheme 2. Synthesis of compound 9.
OH
S
I
OTs
NH2
O
O
O
O
N
S
2M NaOH/water
OEt
OEt
EtO
THF/MeOH
rt
MeCN
75oC
OTs
DMF
60oC
O
11
10
N
H
N
Cpd 4
F
S
HATU reagent
DIPEA
N
O
O
HO
S
DMF
N
S
rt to 90oC
13
O
N
12
N
Scheme 3. Synthesis of compound 13.
H2
O
CN
HCl in
1) K2CO3, 45oC
O
10% Pd/C
1,4-dioxane
OEt
CN
NH
16
O
EtO
0oC to rt
MeOH
rt
NH
Cl
2)
EtO
EtO
O
Br
14
O
O
acetone, rt
15
NHMe
NHMe
I
Cpd 4
HATU reagent
DIPEA
4M NaOH/water
N
DMF
rt
THF/MeOH
rt to reflux
HO
N
17
CuI
EtO
K2CO3
toluene
reflux
O
O
18
H
N
N
F
O
O
N
N
S
19
N
Scheme 4. Synthesis of compound 19.
1-tert-butoxyethenolate prepared in situ, followed by the enamine
formation and a condensation reaction with phenyl hydrazine.
After acidic tert-butyl ester hydrolysis and amide coupling with ani-
line 4, final compounds 24–31 were isolated in pure form after flash
chromatography purification under normal and/or reverse phases.
An alternative synthesis is described below which was used for
the preparation of new analogs featuring an acid sensitive 1,
Methyl or ethyl aryl ester was reacted with lithium 1-
ethoxyethenolate prepared in situ, followed by the enamine forma-
tion and a condensation reaction with phenyl hydrazine. After
saponification and amide coupling with aniline 4, final compounds
35–40 were isolated in pure form after flash chromatography
purification under normal and/or reverse phases.
In this present study, our design was guided by molecular
docking studies using an homology model of RON kinase domain
built from the X-ray crystal structure of c-Met kinase domain
(PDB: 3U6I)10 (Fig. 3). The docking using the Fitted program11 of
5-bis-aryl-1H-pyrazole-4-carboxylic
acid
23
such
as
Ar1 = 2-thienyl, 3-thienyl, 2-furyl, 5-methylisoxazol-3-yl, 4-nitro-
phenyl, and 4-acetamidophenyl, and Ar2 = phenyl (Scheme 6).
Please cite this article in press as: Raeppel, F.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.07.080

4
F. Raeppel et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
O
NMe2
H
N
N
O
O
O
Ar2
NH2
Ar2
N
MeO
OMe
O
LiHMDS
O
O
O
Ar1
Ar1
O
Ar1
22
Ar1
O
AcOH
MeOH
reflux
THF
O
OR
DCM
70oC
-78oC to rt
NMe2
20
21
R = Me or Et
TFA
N
Ar2
Cpd 4
HATU reagent
DIPEA
H
N
N
F
N
Ar1
N
Ar2
HO
O
O
DMF
DCM
rt
Ar1
O
N
S
rt to 50oC
24-31
23
N
N
Scheme 5. General synthesis of compounds 24–31.
O
NMe2
H
N
OEt
O
N
O
Ar2
NH2
MeO
OMe
Ar2
N
O
O
O
LiHMDS
EtO
Ar1
Ar1
OEt
NMe2
Ar1
OEt
Ar2
Ar1
OR
THF
DCM
70oC
O
AcOH
MeOH
reflux
-78oC to rt
32
33
34
R = Me or Et
N
Ar2
H
Cpd 4
N
F
N
HATU reagent
DIPEA
N
N
NaOH/water
Ar1
O
HO
O
Ar1
THF/MeOH
rt to reflux
DMF
O
N
S
rt to 50oC
35-40
N
23
N
Scheme 6. Alternative synthesis of compound 35–40.
Figure 3. Docking poses in RON kinase domain homology model. (a) LCRF-0004; (b) compound 5; (c) compound 9; (d) compound 28.
LCRF-0004 in the model of the active site of RON showed a pre-
dicted docking score of À24.6 versus À23.1 for compound 5.
Predicted docking scores for compounds 9 and 28 were À22.4
and À22.6, respectively.
kinase when compared to LCRF-0004, this compound turned out
to be more active for the inhibition of phospho-c-Met in MKN-45
gastric cancer cells (c-Met RTK is present in full-length and is over-
expressed). On the other hand, moving the phenyl substituent on
position 3 instead of position 5 on the pyrazole ring of compound
5, such as in compound 9, starts to be detrimental for RON inhibi-
tion. Likewise, replacing the pyrazole by a thiazole ring, such as in
compound 13 or moving the phenyl substituent on position 2, such
as in pyrrole 19, reinforces this trend, probably due to steric hin-
drances. Thus, the three substituents on the heteroaryl head group
shall be contiguous in order to respect the 5-atom linker character-
istic19 and based on this exploratory work we decided to further
investigate close analogs of compound 5.
As previously disclosed, the presence of both trifluoromethyl
and phenyl substituents on the pyrazole head group of LCRF-
0004 is essential for the inhibition of RON activity.7 In the present
study, we decided to explore the replacement of the bulky and
electro-negative trifluoromethyl moiety by a phenyl ring and to
study its influence when transposed around the heteroaryl head
group as well. At first, to verify our hypothesis compound 5 was
prepared as a prototype in this new chemical series (Table 1).
Although twice less active against the inhibition of RON tyrosine
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F. Raeppel et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
Table 1
Enzymatic and cellular inhibitory activities of LCRF-0004 and bis-aryl compounds
Table 2
Enzymatic and cellular inhibitory activities of new bis-aryl compounds
F
HG
F
HG
O
O
N
S
N
S
N
N
N
N
Compds
LCRF-0004
5
Head group (HG)
RON (h) kinase
Phospho-c-Met
in MKN-45
IC50 (lM)
Compds Head group (HG)
RON (h) kinase Phospho-c-Met in
IC50
(l
M)
IC50
(lM)
MKN-45 IC50
(lM)
N
H
N
N
N
H
N
N
5
0.023
0.025
n.a.
0.74
0.012
0.023
6.87
O
CF3
O
N 2
N1
5
3
N
H
N
H
N
4
N
0.74
24
1.09
0.35
1.23
F
O
O
N
H
N
N
N
N
25
2.07*
2.26*
OMe
9
0.032
0.045
H
N
O
O
O
O
O
N
N
H
N
26
27
28
0.023
N
N
13
H
N
S
N
N
H
N
0.027
0.014
0.30
0.23
19
0.101
4.84*
OMe
H
N
N
N
N
H
N
O
*
‘Plateau’ was observed.
O
O
N
N
N
H
N
As shown in Table 2, substituents in ortho or meta positions on
the phenyl ring or heteroaryls (Ar1) are well accepted and have only
a slight impact on the inhibition of RON tyrosine kinase. Indeed,
compound 28 having a 3-pyridinyl ring as a replacement of the tri-
fluoromethyl substituent is equipotent to LCRF-0004. Moreover,
compound 28 is a highly potent inhibitor of c-Met (h) kinase
29
30
n.a.
n.a.
0.19
>10
F
N
N
H
N
domain with an IC50 = 0.010
the inhibition of phospho-c-Met in MKN-45 cell-based assay with
an IC50 = 0.23 M. Likewise, compound 27 showed a high potency
against c-Met (h) kinase domain with an IC50 = 0.007 M. In addi-
lM. This result was translated into
O
l
l
tion, compounds 27 and 28 exhibit good inhibitory activity against
the phosphorylation of RON in HT29 colon cancer cells (preliminary
data). Although, compound 29 (Ar1 = 4-fluorophenyl) and com-
pound 36 (Ar1 = 3-thienyl, as bio-isostere of phenyl ring) proved
to be quite potent in our phospho-c-Met cell-based assay, com-
pounds 30 and 31 turned out to be inactive. This result could be
explained by a possible clash between the para-methoxy sub-
stituent of 30 and an electrostatic repulsion between 4-pyridinyl
of 31 in the active site of c-Met kinase domain, respectively.
In conclusion, we have designed and synthesized new potent
inhibitors of RON based on LCRF-0004 by replacing its trifluo-
romethyl substituent with an aromatic ring. Furthermore, this
new search allowed us to study the effect of various heteroarylcar-
boxamide head groups20 substituted with two aromatic rings on
the RON inhibitory activity and selectivity over c-Met. Thus, potent
dual RON/c-Met inhibitors were discovered, and these new chem-
ical agents may be preferable over specific agents, especially when
OMe
N
H
N
N
31
36
n.a.
n.a.
>10
O
O
N
N
N
H
N
0.34
S
n.a. (data not available).
both RTKs are co- and overexpressed in cancer patients. Future
works will optimize these new head groups and explore the other
parts of LCRF-0004 as well, which should allow us to further mod-
ulate and optimize the in vitro and in vivo activities and DMPK
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6
F. Raeppel et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
S. F.; Whittington, D. A.; Harmange, J.-C.; Dominguez, C.; Kim, T.-S.; Dussault, I.
J. Med. Chem. 2012, 55, 1868.
11. (a) Corbeil, C. R.; Englebienne, P.; Moitessier, N. J. Chem. Inf. Model. 2007, 47,
435; (b) Corbeil, C. R.; Moitessier, N. J. Chem. Inf. Model. 2009, 49, 997.
12. Compound 4 was prepared in five steps according to WO 2006/010264 A1.
profile of our inhibitors. More studies from our academic collabo-
rators using LCRF-0004 as a pharmacological tool for the drug tar-
get validation of RON will be also disclosed soon.21
13. Compound
7 was prepared according to Youssef, A. M.; White, M. S.;
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F
NH2
O
N
N
N
Ar2
H
N
N
S
F
4
Ar1
N
O
N
O
41
+
N
S
O
O
20 : R = t-Bu
or
N
N
Ar1
OR
32 : R = Et
N
N
Ar2
N
HO
+
42
Ar1
O
B(OH)2
Ar2
A. R.; Maroun, C.; Besterman, J. M.; Vaisburg, A. Bioorg. Med. Chem. Lett. 2010,
20, 2745; LCRF-0004 refers to compound 4 in this publication. LCRF-0004 is an
internal identification number at Laboratoires ChemRF Inc./ChemRF
Laboratories Inc.
During this study, we have also prepared compounds of generic structure C
(Fig. 1) in which Ar1 = hydroxyarene (e.g., phenol, pyridone, hydroxypyridine,
a demethylation reaction of the corresponding
methoxy substituent using BBr3 reagent. See one example illustrated below:
etc.) and Ar2 = phenyl by
N
N
H
N
H
N
F
N
F
N
BBr3
O
O
O
O
DCM
0oC to rt
N
S
OH
OMe
N
S
N
27
N
43
N
N
8. Raeppel, S. L.; Raeppel, F.; Therrien, E. Bioorg. Med. Chem. Lett. 2015, 25, 2527.
9. Raeppel, S. L.; Therrien, E.; Raeppel, F. Bioorg. Med. Chem. Lett. 2015, 25.
accepted.
21. Baird, A.-M.; O’Byrne, K.; Easty, D.; Shiels, L.; Byrne, A.; Raeppel, S.; Soltermann,
A.; Nonaka, D.; Fennell, D.; Mutti, L.; Pass, H.; Opitz, I.; Gray, S. Lung Cancer
2014, 83, S29.
10. Liu, L.; Norman, M. H.; Lee, M.; Xi, N.; Siegmund, A.; Boezio, A. A.; Booker, S.;
Choquette, D.; D’Angelo, N. D.; Germain, J.; Yang, K.; Yang, Y.; Zhang, Y.; Bellon,
Please cite this article in press as: Raeppel, F.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.07.080