Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives as novel c-Met kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.08.067

We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein

Full text of DOI:10.1016/j.bmcl.2014.08.067

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5093–5097
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives
as novel c-Met kinase inhibitors
Seung-Tae Kang b, Eun-Young Kim b, Raghavendra Archary c, Heejung Jung a,c, Chi Hoon Park a,c
,
Chang-Soo Yun a,c, Jong Yeon Hwang a,c, Sang Un Choi a, Chonghak Chae a, Chong Ock Lee a,
b
a,c,
Hyoung Rae Kim a, Jae Du Ha a, , Dohyun Ryu , Sung Yun Cho
⇑
⇑
a Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600, Republic of Korea
b Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Republic of Korea
c Department of Medicinal and Pharmaceutical Chemistry, University of Science & Technology, Daejeon 305-550, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The
SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met
driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification
of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine
substituents.
Received 29 April 2014
Revised 18 August 2014
Accepted 29 August 2014
Available online 16 September 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cancer
c-Met inhibitor
Pyridazin-3-one
O
Cl
c-Met (mesenchymal epithelial transition factor) is the proto-
typic member of a subfamily of receptor tyrosine kinases and its
ligand HGF (hepatocyte growth factor) have been received consid-
erable attention and studied extensively as attractive therapeutic
cancer targets.1 c-Met and HGF are highly overexpressed in various
cancer tissues, such as lung, gastric, renal, ovarian, prostate, and
liver cancers.2 Upon binding of HGF, c-Met dimerizes, trans-
phosphorylates, and activates the signaling cascades for recruiting
adaptor proteins, such as growth factor-bound protein 2 (Grb2),
Cl
Cl
HN
N
N
N
ii
i
N
N
R2
R2
2
1
Scheme 1. Reagents and conditions: (i) PhB(OH)2, Pd(dppf)2Cl2, K2CO3, 90 °C, 3 h,
81%; (ii) AcOH, H2O, 120 °C, 4 h, 83%.
Grb2-associated-binding protein
1
(Gab1), PLC and SRC.3
Constitutive activation of c-Met has been severely implicated in
tumorigenic invasive growth, migration, proliferation, survival,
angiogenesis, and metastasis by downstream signal transducers,
such as MAPK, PIP3K, and STAT pathways.4 In addition, the
aberrant HGF/MET signaling cascade by activating mutations, gene
rearrangements, bypass mechanisms, and interactions with other
receptor families confers major key factors for acquiring resistance
to EGFR and BRAF kinase inhibitors.5 Overexpression of Met is
strongly correlated with a metastatic activation of tumors and poor
prognosis in a number of human cancers.6
O
OH
OH
O
N
H
i, ii
+
Cl
N
Ph
iii
3
O
Indeed, the regulation of c-Met activities in physiological
conditions provides strong rational for targeting c-Met in cancer
OH
N
H
4
Scheme 2. Reagents and conditions: (i) H2O/iPrOH, rt, 13 h; (ii) NH4OH, rt, 3 h, 50%
(2 steps); (iii) Pd/C, H2, MeOH, 98%.
⇑
Corresponding authors. Tel.: +82 42 860 7072 (J.D.H.), +82 42 860 7077 (S.Y.C.).
E-mail addresses: jdha@krict.re.kr (J.D. Ha), sycho@krict.re.kr (S.Y. Cho).
http://dx.doi.org/10.1016/j.bmcl.2014.08.067
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

5094
S.-T. Kang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5093–5097
Br
Br
N
N
O
Br
OH
ii
N
i
N
N
OTs
+
N
N
OH
N
H
O
N
Br
N
O
5
6
4
iii
O
B
Br
N
O
HO
O
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
O
iv
v
O
O
R
2
R2
R2
7
8
9
Scheme 3. Reagents and conditions: (i) iPr2NH, EtOH, rt, 13 h, 87%; (ii) TsCl, DMAP, Et3N, CH2Cl2, rt, 2 h, 99%; (iii) 2, Cs2CO3, 50 °C, 13 h, 60%; (iv) 4,4,40,40,5,5,50,50-octamethyl-
2,20-bis(1,3,2-dioxaborolane), KOAc, dppf, dioxane, 80 °C, 13 h, 70%; (v) NaBO3, H2O, THF, 30%, (2 steps).
2-(benzylamino)ethan-1-ol and epichlorohydrin to afford (S)-(4-
HO
O
OTs
N
O
N
O
benzylmorpholin-2-yl)methanol 3. (S)-morpholin-2-ylmethanol 4
was obtained by simple deprotection of benzyl functionality of 3
(Scheme 2). Treatment of 4 with 2,5-dibromopyrimidine in the pres-
ence of diisopropylamine led to the intermediate 5.
Versatile intermediate 7 was easily furnished by treatment of 6
with suitable precursor 2, which was derived from 5 by simple
tosylation.
N
N
N
N
i, ii, iii
N
N
N
N
+
O
O
N
N
Boc
R2
R2
11
10
9
Scheme 4. Reagents and conditions: (i) K2CO3, DMF, 95 °C, 13 h, 50%; (ii) TFA, rt,
13 h, 52%; (iii) HCHO (35%), HCO2H, 95 °C, 13 h, 61%.
Successive treatment of bromide 7 to afford pinacolborane
derivative 8 was accomplished by palladium-catalyzed cross cou-
pling of bis(pinacolato) diboron compound as shown in Scheme 3.
Hydroxyl group was introduced by NaBO3 oxidation of 8 to afford
9. The preparation of final N-methylpiperidine attached pyridazi-
none derivative 11 was outlined in Scheme 4. 5-Pyrimidinol was
reacted with appropriate piperidine 10 followed by deprotection
of Boc group, and subsequently the resulting piperidine was
reacted with formaldehyde in the presence of formic acid to afford
compound 11. A variety of aromatic groups were introduced by
cross-coupling of suitable aromatic borolane 12 to afford com-
pound 13, and subsequent treatment of 2-bromoethanol and form-
aldehyde afforded 14 and 15, respectively (Scheme 5). A series of
tetrahydropyridine derivatives was prepared from the appropriate
alkylation of tetrahydropyridine 16 either in methylation condition
or alkylation condition to afford 17 and 18, respectively (Scheme 6).
A series of pyridine and phenyl coupled compounds 19, 20 and 21
varying in the side chain portion of pyridine and phenyl was
treatments. A number of c-Met kinase inhibitors have been
reported and some of them reached the clinical trial.7
Recently, we have reported c-Met inhibitors and presented their
biological activities.8 In our efforts to discover novel c-Met kinase
inhibitors, a class of compounds based (S)-2-((4-(5-bromopyrimi-
din-2-yl)morpholin-2-yl)methyl)-6-phenylpyridazin-3(2H)-one
were synthesized and their biological activity was evaluated.
Described herein is a series of novel pyridazinone-based inhibitors
of c-Met kinases, which were substituted with morpholino-
pyrimidines.
The synthesis of phenyl substituted pyridazinones 2 is outlined
in Scheme 1 by convenient synthesis from commercially available
2,5-dichloropyridazine followed by palladium catalyzed cross-cou-
pling reaction of the corresponding aromatic compounds. 2-
Hydroxyethylmorpholine 4 can be easily furnished by starting with
N
Br
O
B
N
N
O
HN
O
N
O
N
N
N
N
i, ii
N
N
N
N
N
+
O
N
N
O
R2
R2
13
Boc
12
7
iv
iii
N
N
N
N
N
N
N
O
N
O
OH
N
N
N
N
N
N
N
N
O
O
R2
R2
15
14
Scheme 5. Reagents and conditions: (i) Pd(PPh3)2Cl2, CH2Cl2, DME/H2O (3:1), 80 °C, 3 h, 64%; (ii) 4 M HCl in 1,4-dioxane, CH2Cl2, rt, 1 h, 90%; (iii) HCHO (35%), HCO2H, 95 °C,
13 h, 60%; (iv) bromoethanol, K2CO3, DMF, 60 °C, 4 h, 55%.

S.-T. Kang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5093–5097
5095
N
N
O
HN
N
N
N
N
Br
O
N
O
iii
N
O
i, ii
N
N
N
N
N
N
N
N
R2
17
O
O
HO
N
R2
R2
iv
N
O
7
16
N
N
N
N
O
R2
18
Scheme 6. Reagents and conditions: (i) N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, Pd(dppf)2Cl2, K2CO3, dioxane/H2O (4: 1), 85 °C, 3 h, 90%; (ii) 4 M HCl/
dioxane, CH2Cl2, rt, 4 h, 94%; (iii) HCO2H, HCHO (35%), 95 °C, 13 h, 71%; (iv) 2-bromoethanol, K2CO3, 60 °C, 3 h, 77%.
prepared from bromopyridine 7 with the appropriate boronic acid
O
N
Br
or boronic ester also by use of methods (vide supra, Scheme 7).
The in vitro c-Met kinase inhibitory activities toward substitu-
ents effect on R1 and R2 position of phenyl compartment were
tested and the results are summarized in Table 1. To understand
substituent effect of pyrimidine compartment, introduction of pyr-
azole and its derivatives (12a, 12b, 12c) were investigated on R2 of
phenyl substituents.
N
O
O
iv
N
O
N
N
N
N
N
N
N
N
O
O
R2
7
R2
19
i, ii
Me
N
i
F
In cell cytotoxicity assay of N-methyl pyrazole moiety, one-digit
micromolar range of inhibitory activity was observed in Hs746T,
H1993, H3122 and U87MG cell lines (negative cell line) (7a).
Subsequently, substitution of piperidine in place of methyl
significantly improved in vitro enzyme inhibitory activities and cell
proliferation inhibitory activities in Hs746T and H1993 cell lines
(13d, 13e). Of the phenyl substituents, 3-Cl, 3-CN, 4-F and 3-CF3,
3,4,5-trifluorophenyl significantly improved in vitro enzyme
inhibitory activities (13a, 13f). In case of methyl substituent in
place of hydrogen in piperidine, 3-F (15a) and 3-Cl, 4-F (15d)
displayed potent c-Met enzyme inhibitory activities and cell
proliferation inhibitory activities. Introduction of hydroxyethyl
N
N
N
N
O
N
O
N
N
N
N
N
N
N
N
O
O
R2
R2
21
20
Scheme 7. Reagents and conditions (i) Pd(dppf)2Cl2, Cs2CO3, 6-fluoropyridin-3-yl
boronic acid, 80 °C, 4 h, 70%; (ii) 1-methylpiperazinen, DIPEA, NMP, 150 °C, 13 h,
43%; (iii) morpholinoethanol, NaH, THF, rt, 3 h, 50%; (iv) 4-(2-(4-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl) morpholine, Cs2CO3, PdCl2, dime-
thoxyethane/H2O (3:1), 80 °C, 2 h, 76%.
Table 1
SAR of substituent of R1 and R2 on pyridazinones11
R1
N
N
R2
N
N
N
O
O
Entry
R1
R2
c-Met IC50
0.72
(lM)
Hs746T IC50
3.02
(
lM)
H1993 IC50
4.1
(lM)
H3122 IC50
>10
(l
M)
U87MG IC50
7.6
(lM)
N
N
Me
)
7a
4-OCH2Ph
N
N
NH
13a
3-CN
0.005
0.0012
0.11
>10
>10
12a
(
13b
13c
13d
13e
13f
12a
12a
12a
12a
12a
12a
3,5-Difluoro
3-Cl
3-Cl, 4-F
3-CF3
3,4,5-Trifluoro
3-F
0.027
0.055
0.011
0.021
0.016
0.010
0.45
0.75
0.071
0.084
0.23
0.22
1.6
3.4
0.79
1.3
1.2
3.5
1.9
>10
1.7
1.4
1.5
7.5
3.2
9.9
1.2
2.5
1.5
4.9
13g
N
N
N
14a
3-F
0.007
0.46
3.2
3.8
3.3
3.4
N
N
OH
12b
(
)
14b
14c
12b
12b
4-F
0.020
0.003
0.28
0.19
>10
>10
>10
4.07
3,4,5-Trifluoro
N
Me
15a
3-F
0.007
0.46
3.2
3.3
3.4
12c
(
)
15b
15c
15d
12c
12c
12c
3,4,5-Trifluoro
4,5-Difluoro
3-Cl, 4-F
0.019
0.021
0.009
0.48
0.94
0.014
3.6
5.7
1.2
7.6
>10
1.4
9.1
>10
1.5

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S.-T. Kang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5093–5097
Table 2
SAR of substituent of R1 on 3-cyanophenyl pyridazinones11
R1
N
N
N
N
N
CN
O
O
No
7b
R1
c-Met IC50
0.004
(lM)
Hs746T IC50
0.0007
(l
M)
H1993 IC50
0.01
(l
M)
H3122 IC50
>1.0
(
lM)
U87MG IC50
>1.0
(lM)
N
N
N
N
O
O
7c
0.021
0.46
2.6
>10
>10
OH
N
7d
11
0.008
0.013
0.18
0.43
1.5
2.4
>10
>10
>10
>10
N
N
O
NH
N
13h
14d
0.006
0.004
0.039
0.68
2.1
>10
>10
>10
>10
N
N
N
OH
N
0.0034
NH
N
16
17
0.040
0.010
0.74
1.2
3.8
4.1
>10
>10
9.7
Me
>10
OH
18
0.002
0.028
0.21
0.41
2.5
1.8
>10
>10
>10
3.4
N
O
O
N
N
19a
O
O
19b
0.090
1.42
1.2
>10
1.4
Cl
F
20a
20b
0.11
7.146
0.65
7.4
1.3
>10
1.4
>10
1.6
N
N
0.012
N
O
N
N
Me
O
N
20c
20d
0.035
0.005
0.74
3.7
9.8
nd
N
N
O
0.013
0.23
>10
>10
N
moiety in place of methyl of piperidine displayed potent c-Met
enzyme inhibitory activities and moderate cell proliferation inhib-
itory activities (14a, 14b).
sion (SP) options.9 The crystal structure of c-Met (PDB code:
2RFS) was used with structural defects fixed by the Protein Prepa-
ration Wizard module.10 The bound conformation of co-crystal
ligand was generated with a good root mean square displacement
(RMSD) of 0.2 A, showing the robustness of the docking protocols.
Analysis of c-Met residues interacting with compounds reveals
information valuable for the evaluation of binding affinity. The
strong interaction of pyridazinones with c-Met is attributed to
the strong hydrogen bonds between the pyrimidine moiety and
the main chain NH of Met1160 hinge residue, and between pyrid-
azinone and Asp1222. C2 atom of morpholine ring makes weak
hydrogen bonding with Pro1158. In addition, hydrophobic interac-
tions are also important for ligand binding. Pyrimidine ring posi-
tions at the narrow groove formed by Ile1084 and Met1160 of
hinge region. And phenyl-pyridazinone group sandwiches between
Met1211 and Tyr1230, making strong ring stacking interaction to
Tyr1230. The potency of piperidine-containing compounds may
be attributed to the hydrogen bonding with O atom of Val1083.
The relative low binding affinity of compound 1 would be due to
the lack of this hydrogen bonding. The 3-CN group may have
To understand the SAR of pyrimidine substituents at 5-position
of pyrimidine, we investigated substituents with other functional
groups, such as extended piperidines (11, 16, 17, 18), pyrazoles
(7c, 7d, 13h, 14d, 20d), phenyls (19a, 19b), and pyridines (20a,
20b, 20c) in Table 2. Of the piperidine substituents, hydroxyethyl
substituted tetrahydro-pyridine (18) exhibited highly potent in c-
Met enzyme activity with moderate cell based activity in either
Hs746T or H193 cell lines. Introduction of substituted pyrazoles
exhibited potent enzyme inhibitory activities and cell base activity
toward Hs746T and H1993 cell lines. In the initial assessment of
the substituent effect of pyrazole, micromolar range of inhibitory
activity was observed with methyl substituted pyrazole or R1 and
R2 of benzyloxy substituted phenyl (11).
In particular, 4-tetrahydropyran substituted pyrazole (20d) dis-
played potent enzyme and cell based activities in both cell lines.
Molecular docking studies were performed using the Glide soft-
ware contained in the Maestro 9.5 software with standard-preci-

S.-T. Kang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5093–5097
5097
Figure 1. Binding model of compound 14a in the c-Met pocket.
Iafrate, A. J.; Lee, C.; Christensen, J. G.; Engelman, J. A.; Jänne, P. A. Cancer Cell
2010, 17, 77; (c) Engelman, J. A.; Zejnullahu, K.; Mitsudomi, T.; Song, Y.; Hyland,
C.; Park, J. O.; Lindeman, N.; Gale, C. M.; Zhao, X.; Christensen, J.; Kosaka, T.;
Holmes, A. J.; Rogers, A. M.; Cappuzzo, F.; Mok, T.; Lee, C.; Johnson, B. E.;
Cantley, L. C.; Jänne, P. A. Science 2007, 1039, 316.
water-bridged ionic interactions with Asp1164 and Asp1231
(Fig. 1).
In summary, we have identified a series of pyridazinones with a
substituted morpholine as potent c-Met kinase inhibitors. This ser-
ies of compounds exhibited potent cell based activities in Hs746T
and H1993 cell lines. Further studies for improving pharmacoki-
netic properties of pyridazinone derivatives in order to improve
oral bioavailability and potent in vivo xenograft anti-tumor activity
are underway in our research group.
6. (a) Drebber, U.; Baldus, S. E.; Nolden, B.; Grass, G.; Bollschweiler, E.; Dienes, H.
P.; Hölscher, A. H.; Mönig, S. P. Oncol. Rep. 2008, 19, 1477; (b) Sawada, K.;
Radjabi, A. E.; Shinomiya, N.; Kistner, E.; Kenny, H.; Becker, A. R.; Turkyilmaz,
M. A.; Salgia, R.; Yamada, S. D.; Vande Woude, G. F.; Tretiakova, M. S.; Lengyel,
E. Cancer Res. 2007, 67, 1670; (c) Lo Muzio, L.; Farina, A.; Rubini, C.; Coccia, E.;
Capogreco, M.; Colella, G.; Leonardi, R.; Campisi, G.; Carinci, F. Tumor Biol. 2006,
27, 116; (d) Lengyel, E.; Prechtel, D.; Resau, J. H.; Gauger, K.; Welk, A.;
Lindemann, K.; Alanti, G.; Richter, T.; Knudsen, B.; Vande Woude, G. F.;
Harneck, N. Int. J. Cancer 2005, 113, 678; (e) Cheng, H.-L.; Trink, B.; Tzai, T.-S.;
Liu, H.-S.; Chan, S.-H.; Ho, C.-L.; Sidransky, D.; Chow, N.-H. J. Clin. Oncol. 2002,
20, 1544.
Acknowledgments
This work was supported by a grant from the Korea Research
Institute of Chemical Technology (KRICT) and the chemical library
used in this study was kindly provided by the Korea Chemical Bank
of Korea Research Institute of Chemical Technology.
7. Cui, J. J. J. Med. Chem. 2014. http://dx.doi.org/10.1021/jm500342d. ASAP.
8. (a) Cho, S. Y.; Han, S. Y.; Ha, J. D.; Ryu, J. W.; Lee, J. O.; Jung, H.; Kang, N. S.; Kim,
H. R.; Koh, J. S.; Lee, J. Bioorg. Med. Chem. Lett. 2010, 20, 4223; (b) Han, S.-Y.; Lee,
J. O.; Ahn, S.-H.; Lee, M.-O.; Kang, S.-Y.; Cha, H.-J.; Cho, S. Y.; Ha, J. D.; Ryu, J. W.;
Jung, H. J.; Kim, H. R.; Koh, J. S.; Lee, J. Invest. New Drugs 2012, 30, 518; (c) Lee, J.
K.; Han, S.-Y.; Jung, H.; Yang, J.; Choi, J.-W.; Chae, J. H.; Park, J. H.; Choi, S. U.;
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Supplementary data
9. [glide] Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.;
Mainz, D. T. J. Med. Chem. 2004, 47, 1739.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
08.067.
10. [2RFS] Bellon, S. F.; Kaplan-Lefko, P.; Yang, Y.; Zhang, Y.; Moriguchi, J.; Rex, K.;
Johnson, C. W.; Rose, P. E.; Long, A. M.; O’Connor, A. B.; Gu, Y.; Coxon, A.; Kim, T.
S.; Tasker, A.; Burgess, T. L.; Dussault, I. J. Biol. Chem. 2008, 283, 2675.
11. c-Met kinase assay: Inhibition of kinase activity against recombinant c-Met
protein was measured using homogeneous time-resolved fluorescence (HTRF)
assays. Recombinant proteins containing c-Met kinase domain were purchased
from Millipore. Optimal enzyme, ATP, and substrate concentrations were
established using HTRF KinEASE kit (Cisbio) according to the manufacturer’s
instructions. Assays are composed of the c-Met enzyme mixed with serially
diluted compounds and peptide substrates in a kinase reaction buffer (250 mM
HEPES (pH 7.0), 0.5 mM orthovanadate, 0.05% BSA, 0.1% NaN3, 5 mM MgCl2,
1 mM DTT). Following the addition of reagents for detection, the Time
Resolved-Fluorescence Resonance Energy Transfer (TRFRET) signal was
measured using an EnVision multi-label reader (Perkin Elmer). Dose–
response curves were generated to determine IC50 using Prism version 5.01
(GraphPad). Flt3 kinase assay was performed as described above using
recombinant Flt3 protein in kinase reaction buffer (250 mM HEPES (pH 7.0),
0.5 mM orthovanadate, 0.05% BSA, 0.1% NaN3, 5 mM MgCl2, 1 mM MnCl2,
1 mM DTT). Reference compounds were included in each assay for plate
uniformity (crizotinib) and select compounds were subjected to repeat
experiments.⁄Proliferation assay: Cells were plated in 96-well plates (10,000
cells per well) and serial dilutions of compounds were added. At the end of the
incubation period (72 h), cell viability was measured by a tetrazolium dye
assay using WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-
disulfophenyl)-2H-tetrazolium, monosodium salt] (Dojindo, Japan). IC50 was
calculated by a nonlinear regression using Prism version 5.01.
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