Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors

Accepted Manuscript

Design and biological evaluation of novel 4-(2-fluorophenoxy) quinoline de-

rivatives bearing an imidazolone moiety as c-Met kinase inhibitors

Weike Liao, Gang Hu, Zhuang Guo, Deyu Sun, Lixia Zhang, Yanxin Bu,

Yingxiu Li, Yajing Liu, Ping Gong

PII:

S0968-0896(15)00520-9

DOI:

http://dx.doi.org/10.1016/j.bmc.2015.06.026

BMC 12382

Reference:

Bioorganic & Medicinal Chemistry

To appear in:

Received Date:

Revised Date:

Accepted Date:

8 May 2015

8 June 2015

9 June 2015

Please cite this article as: Liao, W., Hu, G., Guo, Z., Sun, D., Zhang, L., Bu, Y., Li, Y., Liu, Y., Gong, P., Design

and biological evaluation of novel 4-(2-fluorophenoxy) quinoline derivatives bearing an imidazolone moiety as c-

Met kinase inhibitors, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.2015.06.026

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Design and biological evaluation of novel 4-(2-fluorophenoxy) quinoline derivatives bearing an

imidazolone moiety as c-Met kinase inhibitors

Weike Liao,^aGang Hu,^aZhuang Guo,^aDeyu Sun,^bLixia Zhang,^aYanxin Bu,^aYingxiu Li,^aYajing Liu,^a*Ping

Gong^a**

^aKey Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103

Wenhua Road, Shenhe District, Shenyang 110016, P. R. China.

^bLiaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District.

Abstract

A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed,

synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines

(A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and

cellular assays. The most promising analog, 58 (c-Met IC₅₀= 1.42 nM), displayed 2.1-, 8.6-, fold increase against

H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure-activity relationships

revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for

antitumor activity.

Keywords: c-Met; antitumor activity; quinoline derivatives; imidazolone-4-carboxamide.

1. Introduction

Mesenchymal–epithelial transition factor (c-Met), a member of a structurally distinct family of receptor

tyrosine kinases (RTK), is a proto-oncogene encoding the high affinity receptor for hepatocyte growth factor

(HGF).^1,2The c-Met/HGF signaling pathway plays important roles during normal development, organogenesis, and

homeostasis. After activation by HGF, c-Met induces an invasive program consisting of cell proliferation, migration,

invasion, and survival that is essential during normal processes, such as morphogenesis and wound healing.³

Aberrant HGF/c-Met signaling has been identified in a wide range of human malignancies, including breast, gastric,

liver, lung cancers and so on.^4-6Furthermore, overexpression of c-Met and HGF was demonstrated to correlate with

poor prognosis or metastatic progression in a number of major human cancers.⁷For these reasons, c-Met and its

ligand HGF are emerging as attractive targets for targeted cancer therapies.

Among current approaches for targeting the c-Met signaling pathway, small-molecule inhibitors directed

against the ATP binding site of c-Met have been considered the most successful strategy. Over the last decade, a

number of c-Met inhibitors have been reported, such as Bristol-Myers Squibb’s BMS777607 1,⁸Kirin Brewery’s

acylthiourea 2,⁹Amgen 3,¹⁰AM 7 4,¹¹cabozantinib 5 ¹²and foretinib 6 (Figure 1).¹³Among them, 6,7-disubstituted

quinoline derivatives have been most extensively investigated. Of these reported quinoline-based inhibitors,

principal modification usually occurs at the 7-position of quinoline and the “5 atoms linker” section between

moiety A and B. The crystal structure of foretinib (PDB: 3LQ8) and Met kinase complex revealed that the amide

linker assumed a pseudocyclic conformation which formed three hydrogen bonds with c-Met.¹⁴Therefore,

on the premise of “5 atoms regulation”, we postulated various rings can be used to replace the amide linker

between moiety A and B via cyclization strategy. Based on this hypothesis, we previously designed a series of

6,7-disubstituted-4-phenoxyquinoline-based c-Met inhibitors exemplified by compounds 7–11 (Figure 2),¹⁵which

* Corresponding author. Tel./fax: +86 24 2398 6426. E-mail address: lyjpharm@126.com; (Y. Liu).

** Corresponding author. Tel./fax: +86 24 2398 6429. E-mail address: gongpinggp@126.com (P. Gong).

1

bear

2-arylquinoline-4-carboxamide,

4-oxo-1-phenyl-1,4-dihydrocinnoline-3-carboxamide,

1,2,3-triazole-4-carboxamide and

4-arylpyridine-4-carboxamide,

4-methyl-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide. However, despite these motivating factors, most

of the clinically investigated class II c-Met inhibitors also possess essential activity on other RTK targets. Therefore,

novel c-Met inhibitors with improved selectivity profiles, particularly to VEGFR-2, and minimal side effects should

be developed.

(Figure 1. should be listed here)

(Figure 2. should be listed here)

Imidazolone-backbone scaffold-containing molecules are among the vast array of compounds found active as

anti-cancer agents presumably because of its ability to form hydrogen-bonding interactions with drug targets

(12–14, Figure 3).¹⁶Considering its potency and conformation to “5 atoms regulation”, we replaced the

cyclopropane-1,1-

dicarboxamide

fragment

of

foretinib

with

2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide scaffold. We assumed that the carbonyl groups and the

NH groups of 2-imidazolone ring and carboxamide may function as potential H-bond acceptors or donors to retain

interactions with key residues in the binding pocket. In addition, different tertiary amines were introduced at the

7-position of quinolines as polar and hydrophilic fragments. The outcome of this exercise was shown in Figure 4,

and their structure-activity relationships (SARs) were further explored.

(Figure 3. should be listed here)

(Figure 4. should be listed here)

All target compounds were evaluated for their inhibition toward c-Met kinase and antiproliferative activities in

vitro against HT-29 (human colon cancer), H460 (human lung cancer), A549 (human lung adenocarcinoma) and

MKN-45 (human gastric cancer), and most of them showed promising inhibition. Furthermore, the inhibitory

activities of the most potent compound 58 against five other RTK kinases were also investigated, the results are

illustrated in Table 1 and Table 2.

2. Chemistry

The synthesis of the key intermediates of 6,7-disubstituted-4-phenoxyquinolines 22a-e was achieved in 8 steps

from commercially available 1-(4-hydroxy-3-methoxyphenyl)ethanone as shown in Scheme 1, which was

illustrated in detail in our previous study.¹⁵

(Scheme 1. should be listed here)

The target compounds 28–58 were prepared as illustrated in Scheme 2. Condensation of substituted anilines

with sodium cyanate in AcOH/H₂O at 50 °C resulted in high yield of intermediates 23a-m. The rhodium-catalyzed

N-H insertion reaction of primary ureas with ethyl 2-diazo-3-oxobutanoate gave the corresponding ethyl

3-oxo-2-(3-phenylureido)butanoate, which were converted into the corresponding imidazolones 24a-m by TFA-

catalyzed cyclodehydration.¹⁷Subsequent methylation with methyl iodide in DMF provided the desired

N-methylimidazolones 25a-m in nearly quantitative yield, which were then converted to acids 26a-m using sodium

hydroxide solution at 40 °C for 10 h. The intermediate 26n was obtained via the N-H insertion reaction of primary

ureas with tert-butyl 2-diazo-3-oxobutanoate and subsequent TFA-induced cyclodehydration as well as

deprotection. Finally, intermediates 26a-n were refluxed in toluene and SOCl₂for 5 h to afford acyl chlorides 27a-n,

which were condensed with intermediates 22a-e in the presence of sodium carbonate in dichloromethane at room

temperature overnight to obtain the target compounds 28–58, respectively.

(Scheme 2. should be listed here)

2

3. Biology

3.1. HTRF kinase assay

The c-Met kinase activity was evaluated using homogeneous time-resolved fluorescence (HTRF) assays as

previously reported.^18,19In addition, the most promising compound 58 was further evaluated against other five

tyrosine kinase (VEGFR-2, c-Kit, Flt-3, EGFR and Ron) using the same screening method. Briefly, 20 µg/mL poly

(Glu, Tyr) 4:1 (Sigma) was preloaded as a substrate in 384-well plates. Then 50 µL of 10 mM ATP (Invitrogen)

solution diluted in kinase reaction buffer (50 mM HEPES, Ph 7.0, 1 M DTT, 1 M MgCl₂, 1 M MnCl₂, and 0.1%

NaN₃) was added to each well. Various concentrations of compounds diluted in 10 µL of 1% DMSO (v/v) used as

the negative control. The kinase reaction was initiated by the addition of purified tyrosine kinase proteins diluted in

39 µL of kinase reaction buffer solution. The incubation time for the reactions was 30 min at 25 °C and the

reactions were stopped by the addition of 5 µL of Streptavidin-XL 665 and 5 µL Tk Antibody Cryptate working

solution to all of wells. The plate was read using Envision (Perkin Elmer) at 320 nm and 615 nm. The inhibition

rate (%) was calculated using the following equation: % inhibition = 100 – [(Activity of enzyme with tested

compounds – Min)/(Max – Min)] × 100 (Max: the observed enzyme activity measured in the presence of enzyme,

substrates, and cofactors; Min: the observed enzyme activity in the presence of substrates, cofactors and in the

absence of enzyme). IC₅₀values were calculated from the inhibition curves.

3.2. Cell proliferation assay

The anti-proliferative activities of compounds 28–58 were evaluated against four c-Met-dependent cancer cell

lines (A549, H460, HT-29 and MKN-45) using the standard MTT assay in vitro, with foretinib as the positive

control.^20,21The cancer cell lines were cultured in minimum essential medium (MEM) supplement with 10% fetal

bovine serum (FBS). Approximate 4 × 10³cells, suspended in MEM medium, were plated onto each well of a

96-well plate and incubated in 5% CO₂at 37 °C for 24 h. The tested compounds at the indicated final

concentrations were added to the culture medium and the cell cultures were continued for 72 h. Fresh MTT was

added to each well at a terminal concentration of 5 µg/mL, and incubated with cells at 37 °C for 4 h. The formazan

crystals were dissolved in 100 µL DMSO each well, and the absorbency at 492 nm (for absorbance of MTT

formazan) and 630 nm (for the reference wavelength) was measured with an ELISA reader. All compounds were

tested three times in each of the cell lines. The results expressed as IC₅₀(inhibitory concentration 50%) were the

averages of three determinations and calculated by using the Bacus Laboratories Incorporated Slide Scanner (Bliss)

software.

4. Results and discussion

4.1. In vitro assays and SARs

All the target compounds were evaluated for their inhibitory activities against c-Met kinase as well as

antitumor activities against A549, H460, HT-29 and MKN-45 cancer cell lines. The results expressed as IC₅₀values

are shown in Table 1 as the mean values of triplicate experiments. As illustrated in Table 1, all the tested

compounds displayed potent c-Met enzymatic activity with IC₅₀values ranging from 1.42 to 35.68 nM, which

validated our hypothesis that the replacement of the cyclopropane-1,1- dicarboxamide framework in foretinib with

2-imidazolone-4-carboxamide moiety maintained the c-Met inhibitory efficacy.

The SARs was commenced by the introduction of a three carbon tether that contains different tertiary amines

at the 7-position of the quinoline ring. Of all the amines, the 4-methyl piperidinyl 31 and the 4-methylpiperazinyl

32 afforded greater activities towards morpholinyl 28 ， pyrrolidinyl 29 and piperidinyl 30. Accordingly,

4-methylpiperidinyl and 4-methylpiperazinyl derivatives were further studied in our work.

Comprehensive 4-methylpiperidinyl and 4-methylpiperazinyl analogs with diverse R₂groups were examined

3

for potency. The SARs based on IC₅₀values (Table 1) revealed that variations in the R₂groups markedly affect

their enzyme activities. Primarily, mono-electron-donating groups (EDGs) such as 4-methyl 34 and 4-methoxy 36

were introduced; a decrease against c-Met enzyme and cellular activities was observed compared to 32, which had

no substituent on the phenyl ring. Incorporation of double-EDGs (3,4-dimethoxy) lowered the efficiency even

further (the data not shown). In view of this, the use of EDGs was not pursued.

Halogen groups were subsequently introduced at the para position of the phenyl ring with the hope of

increased potency. Gratifyingly, the data in Table 1 showed that halogen made a good contribution to enzyme

activity, with following rank order: H<Br<F<Cl. Incorporating a 3,4-dihalogened group in the form of

3,4-difluoro 45 or 3-chloro-4-fluoro 47 afforded compound that, while still potent in the c-Met kinase essay,

exhibited somewhat a decreased cellular activity, compared to 38, which indicates mono-substitution of phenyl is

more preferred.

Different electron-withdrawing groups (EWGs) were also investigated, the para-substituted trifluoromethyl

and trifluoromethoxyl atom allowed us to slightly improve c-Met inhibitory activity (49, 51 vs 32, ranging from 1.2

to 2.3-fold increase). In addition, moving the para-trifluoromethyl group 51 to the ortho position 55 is

advantageous to potency while the meta position 53 is not well tolerated, which could be further confirmed by

2-chloro analog 57 vs 4-chloro analog 40. Our final modification focused on the R₃group of the imidazolone motif.

To our delight, the 2-chloro analog 58, which is a demethylated version of compound 57, had the most promising

potency towards both cellular and enzyme activities.

(Table 1. should be listed here)

4.2. Enzymatic selectivity assays

The inhibitory activity of the most potent compounds 58 against VEGFR-2, c-Kit, Flt-3, EGFR and Ron

kinase were also assayed using the homogeneous time resolved fluorescence (HTRF) method (Table 2). Compound

58 demonstrated selectivity against VEGFR-2, c-Kit, Flt-3, Ron and EGFR kinase (65-fold, 27-fold, 94-fold,

190-fold and >10000 fold).

(Table 2. should be listed here)

5. Binding model analysis

To further elucidate the binding mode of compounds, a detail docking analysis was performed. In our study,

the co-crystal structure of foretinib (GSK1363089) with c-Met was selected as the docking model (PDB ID code:

3LQ8). The docking simulation was conducted using Glide XP (Schrödinger 2014), since Glide uses a hierarchical

series of filters to search for possible locations of the ligand in the active-site region of the receptor. The shape and

properties of the receptor are represented on a grid by several different sets of fields that provide progressively

more accurate scoring of the ligand poses. The image files were generated using Accelrys DS visualizer 4.0 system.

The binding model was exemplified by the interaction of compound 58 with c-Met. As shown in Figure 5, the

protonated nitrogen atom of 4-methylpiperazinyl, nitrogen atom of the quinoline and the

2-imidazolone-4-carboxamide moiety formed five hydrogen-bonding interactions with Asp1222, Met1160 and

Tyr1159, respectively.

(Figure 5. should be listed here)

6. Conclusions

In summary, we designed and synthesized novel c-Met receptor tyrosine kinase inhibitors based upon

6,7-disubstitued quinoline and imidazolone scaffolds. c-Met kinase and four human cancer cell lines (HT-29, H460,

MKN-45 and A549) were used to evaluate the potency of the synthesized compounds. The results revealed that

4

most of the tested compounds were potent c-Met inhibitors (c-Met IC₅₀=1.42 to 35.68 nM). Compared with

foretinib, one compound showed higher c-Met kinase inhibitory activity, and 12 were more potent against one or

more cell lines. The analysis of SARs indicated that the replacement of the cyclopropane-1,1-dicarboxamide

framework in foretinib with the 2-imidazole-4-carboxamide scaffold maintained the potent efficiency. The

preference for a 2-chloro substituted phenyl ring in moiety B as well as an N-unsubstituted imidazolone linker was

observed. Moreover, the three-carbon tether containing 4-methylpiperazinyl (R₁) in the 7-position of quinolines is

advantageous. To our delight, the most promising compound 58, showed excellent inhibition of c-Met kinase (IC₅₀

= 1.42 nM) compared to five other kinases screened in this report, as well as 2.1- and 8.6-fold increase against

H460 and MKN-45 cell lines compared to foretinib, respectively. The druggability of 58 is currently evaluated and

this compound is also optimized. Research progress will be reported in due course.

7. Experimental

Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further

purification. Reactions’ time and purity of the products were monitored by TLC on FLUKA silica gel aluminum

cards (0.2 mm thickness) with fluorescent indicator 254 nm. Column chromatography was run on silica gel

(200–300 mesh) from Qingdao Ocean Chemicals (Qingdao, Shandong, China). All melting points were obtained on

a Büchi Melting Point B-540 apparatus (Büchi Labortechnik, Flawil, Switzerland) and were uncorrected. Mass

spectra (MS) were taken in ESI mode on Agilent 1100 LC–MS (Agilent, Palo Alto, CA, USA). H NMR and ¹³

1

C

NMR spectra were recorded on Bruker ARX-400, 400 MHz; or Bruker ARX-600, 600 MHz spectrometers (Bruker

Bioscience, Billerica, MA, USA) with TMS as an internal standard. The IR spectra were recorded by means of the

KBr pellet technique on a Bruker FTS 135 spectrometer. Elemental analysis was determined on a Carlo-Erba 1106

Elemental analysis instrument (Carlo Erba, Milan, Italy).(In the mode of measurement C, H, and N, the sample into

the combustion tube in pure oxygen atmosphere static combustion and products by a specific reagent after

formation of CO₂, H₂O, N₂and nitrogen oxides, uniform mixing under the atmospheric pressure. The thermal

conductivity detector is used for determining the content of C, H and N from mixed gases.).

7.1. General procedure for preparation of 3-fluoro-4-(6,7-disubstituted quinolin-4-yloxy)anilines (22a–e)

The preparation of the key intermediates 22a–e has been illustrated in detail in our laboratory previous study,

so the synthesis method would not be listed here.¹⁵

7.1.1.

3-Fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)aniline (22a)

White solid; Yield: 81.8%; M.p.: 217–218 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.47 (d, J = 5.2 Hz, 1H), 7.58 (s,

1H), 7.44 (s, 1H), 7.04 (t, J = 8.7 Hz, 1H), 6.57 (dd, J = 11.9, 2.6 Hz, 1H), 6.50 (m, 1H), 6.41 (d, J = 5.3 Hz, 1H),

4.27 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.82 (s, 2H), 3.74 (m, 4H), 2.60 (t, J = 7.1 Hz, 2H), 2.51 (d, J = 4.2 Hz, 4H),

2.13 (m, 2H); MS (ESI) m/z (%): 428.2 [M+H]⁺, 450.1 [M+Na]⁺.

7.1.2.

3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)aniline (22b)

Gray solid; Yield: 85.5%; M.p.:208–209 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (d, J = 5.2 Hz, 1H), 7.55

(s, 1H), 7.44 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.57 (d, J = 14.1 Hz, 1H), 6.46 (m, J = 12.8, 7.1 Hz, 2H), 4.28 (t, J =

5.7 Hz, 2H), 3.96 (s, 3H), 3.59 (s, 2H), 3.35 (m, 4H), 3.04 (s, 2H), 2.28 (m, 2H), 1.96 (d, J = 28.0 Hz, 4H); MS

(ESI) m/z (%): 412.5 [M+H]⁺.

7.1.3.

3-Fluoro-4-(6-methoxy-7-(3-(piperdine-1-yl)propoxy)quinolin-4-yloxy)aniline (22c)

Gray solid; Yield: 85.5%; M.p.:196–197 °C; IR (KBr) cm^-1: 3482.2, 3387.0, 2946.5, 2835.1, 2788.1, 1621.1,

1587.8, 1512.8, 1483.4, 1252.9, 1215.4, 853.5; ¹H NMR (300 MHz, CDCl₃) δ 8.46 (d, J = 5.3 Hz, 1H), 7.58 (s, 1H),

7.41 (s, 1H), 7.03 (t, J = 8.7 Hz, 1H), 6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (m, 1H), 6.39 (dd, J = 5.3, 1.1 Hz, 1H),

4.24 (t, J = 6.8 Hz, 2H), 4.04 (s, 3H), 3.81 (s, 2H), 2.54 (m, 2H), 2.43 (s, 4H), 2.14 (m, 2H), 1.60 (m, 4H), 1.55 (m,

2H); MS (ESI) m/z (%): 426.3 [M+H]⁺.

5

7.1.4.

3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperdine-1-yl)propoxy)quinolin-4-yl-oxy)aniline (22d)

White solid; Yield: 77.4%; M.p.:193–194 °C;¹H NMR (300 MHz, CDCl₃) δ 8.46 (d, J = 5.3 Hz, 1H), 7.58 (s,

1H), 7.41 (s, 1H), 7.03 (t, J = 8.7 Hz, 1H), 6.56 (dd, J = 11.8, 2.6 Hz, 1H), 6.50 (dd, J = 9.0, 2.9 Hz, 1H), 6.39 (dd,

J = 5.3, 0.8 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.03 (s, 3H), 3.82 (s, 2H), 2.94 (d, J = 11.5 Hz, 2H), 2.57 (m, 2H),

2.15 (m, 2H), 1.98 (t, J = 10.9 Hz, 2H), 1.63 (d, J = 10.4 Hz, 2H), 1.28 (m, 3H), 0.93 (d, J = 6.0 Hz, 3H); MS (ESI)

m/z (%): 440.3 [M+H]⁺.

7.1.5.

3-Fluoro-4-(6-methoxy-7-(3-(4-methylpiperazine-1-yl)propoxy)quinolin-4-yl-oxy)aniline (22e)

White solid; yield: 77%; M.p.:201–202 °C ¹H NMR (300 MHz,CDCl₃) δ 8.48 (d, J = 5.3 Hz, 1H), 7.61 (s, 1H),

7.41 (s, 1H), 7.06 (t, J =8.7 Hz, 1H), 6.58 (dd, J =11.8, 2.6 Hz, 1H), 6.54 (dd, J =9.0, 2.9 Hz,1H), 6.41 (dd, J =5.3,

0.8 Hz, 1H), 4.28 (t, J =6.7 Hz, 2H), 4.06 (s, 3H),3.84 (s, 2H), 2.64 – 2.51 (m, 8H), 2.18 (s, 3H), 2.11 (t, J =10.9 Hz,

2H), 1.88(m, 2H); MS (ESI) m/z (%): 441.4 [M+H]⁺, 463.3 [M +Na]⁺.

7.2.General procedure for preparation of ureas (23a–m)

To a solution of substituted aniline (0.1 mol) dissolved in 48 mL glacial acetic acid and 96 mL H₂O, sodium

cyanate (13 g, 0.2 mol) in warm water (90 mL) was added with continuous stirring. The mixture was warmed to 50

°C for 2 h and then cooled in ice, The crude solid, thus obtained was filtered, dried, and recrystallized with boiling

water.

7.2.1.

phenylurea (23a).

White solid, yield: 90.2%; M.p.:145–147 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.47 (s, 1H), 7.38 (dd, J = 8.4

Hz, 0.9 Hz, 2H), 7.2 (t, J = 7.6 Hz, 2H), 6.88 (t, J = 7.6 Hz, 1H), 5.81 (brs, 2H). MS (ESI) m/z (%): 137.1 [M+H]⁺.

7.2.2.

White solid, yield: 81.1%; M.p.:178–179 °C. MS (ESI) m/z (%): 173.1 [M+Na]⁺.

7.2.3. 4-methoxyphenylurea (23c).

4-methylphenylurea (23b).

1

White solid, yield: 76.5%; M.p.:165–166 °C. H NMR (400 MHz, DMSO-d₆) δ: 8.31 (s, 1H), 7.28 (d, J = 6.8

Hz, 2H), 6.80 (d, J = 6.8 Hz, 2H), 5.73 (s, 2H), 3.68 (s, 3H). MS (ESI) m/z (%): 189.1 [M+Na]⁺.

7.2.4.

4-fluorophenylurea (23d).

White solid, yield: 80.6%; M.p.:178–180 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.54 (s, 1H), 7.39 (dd, J = 9.1,

5.0 Hz, 2H), 7.04 (t, J = 8.9 Hz, 2H), 5.83 (s, 2H). MS (ESI) m/z (%): 177.2 [M+Na]⁺.

7.2.5.

4-chlorophenylurea (23e).

White solid, yield: 84.8%; M.p.:206–208 °C. MS (ESI) m/z (%): 193.2 [M+Na]⁺.

7.2.6.

4-bromophenylurea (23f).

White solid, yield: 78.8%; M.p.:224–226 °C. MS (ESI) m/z (%): 215.1 [M+H]⁺.

7.2.7.

3,4-difluorophenylurea (23g).

White solid, yield: 76.8%; M.p.:182–184 °C. MS (ESI) m/z (%): 172.9 [M+H]⁺.

7.2.8.

3-chloro-4-fluorophenylurea (23h).

White solid, yield: 75.4%; M.p.:186–188 °C. MS (ESI) m/z (%): 189.1 [M+H]⁺.

7.2.9.

4-(trifluoromethoxy)phenyl)urea (23i).

White solid, yield: 74.2%; M.p.:135–139 °C. MS (ESI) m/z (%): 221.2 [M+H]⁺.

7.2.10. 4-(trifluoromethyl)phenylurea (23j).

White solid, yield: 79.6%; M.p.:140–142 °C. MS (ESI) m/z (%): 205.1 [M+H]⁺.

7.2.11. 3-(trifluoromethyl)phenylurea (23k).

White solid, yield: 75.4%; M.p.:102–105 °C. MS (ESI) m/z (%): 205.2 [M+H]⁺.

7.2.12. 2-(trifluoromethyl)phenylurea (23l).

White solid, yield: 80.6%; M.p.:154–158 °C. MS (ESI) m/z (%): 205.0 [M+H]⁺.

7.2.13. 2-chlorophenylurea (23m).

6

White solid, yield: 84.8%; M.p.:152–153 °C. MS (ESI) m/z (%): 193.1 [M+Na]⁺.

7.3. General procedure for the synthesis of 2-imidazolones (24a–m)

To a vigorously stirred suspension of ethyl 2-diazo-3-oxobutanoate (14 mmol) and finely powdered urea 23

(408 mg, 18 mmol) in toluene-1,2-dichloroethane (1:1, 140 mL) was heated to 80 °C and a suspension of Rh₂Oct₄

(217 mg, 0.28 mmol) in toluene (28 mL) was added over 60 min. The mixture was then stirred for an additional 30

min. After cooling to room temperature, TFA (16.8 mL) was added dropwisely, the solution was then stirred for 30

min, after removal of solvent under reduced pressure, the residue was dissolved in 150 mL CH₂Cl₂, washed with

6N HCl (3 × 30 mL), and then brine before being dried. The organic layer was concentrated, triturated with ether to

obtain the imidazolone as a white solid.

7.3.1.

ethyl 5-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (24a)

1

White solid, yield: 80.7%; M.p.:173–175 °C. H NMR (400 MHz, CDCl₃) δ 8.29 (brs, 1H), 7.54 – 7.39 (m,

3H), 7.33 – 7.27 (m, 2H), 4.32 (q, J = 7.4 Hz, 2H), 2.26 (s, 3H), 1.34 (t, J = 7.4 Hz, 3H). MS (ESI) m/z (%): 246.9

[M+H]⁺, 514.8 [2M+Na]⁺.

7.3.2.

ethyl 5-methyl-2-oxo-1-(p-tolyl)-2,3-dihydro-1H-imidazole-4-carboxylate (24b)

White solid, yield: 71.0%; M.p.:211–212 °C. MS (ESI) m/z (%): 261.1 [M+H]⁺, 521.2 [2M+H]⁺.

7.3.3.

ethyl 1-(4-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24c)

White solid, yield: 73.8%; M.p.:201–203 °C. MS (ESI) m/z (%): 277.2 [M+H]⁺, 575.4 [2M+Na]⁺.

7.3.4.

ethyl 1-(4-fluorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24d)

White solid, yield: 78.6%; M.p.:202–204 °C. MS (ESI) m/z (%): 264.8 [M+H]⁺, 550.6 [2M+Na]⁺.

7.3.5.

ethyl 1-(4-chlorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24e)

White solid, yield: 81.8%; M.p.:219–220 °C. MS (ESI) m/z (%): 281.0 [M+H]⁺, 560.9 [2M+H]⁺.

7.3.6.

ethyl 1-(4-bromophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24f)

White solid, yield: 75.2%; M.p.:232–233 °C. MS (ESI) m/z (%): 324.9 [M+H]⁺, 672.9 [2M+Na]⁺.

7.3.7.

ethyl 1-(3,4-difluorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24g)

White solid, yield: 83.2%; M.p.:213–215 °C. MS (ESI) m/z (%): 304.9 [M+Na]⁺, 586.4 [2M+Na]⁺.

7.3.8.

ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24h)

White solid, yield: 72.4%; M.p.:217–219 °C. MS (ESI) m/z (%): 299.0 [M+H]⁺, 597.2 [2M+H]⁺.

7.3.9.

ethyl 5-methyl-2-oxo-1-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate(24i)

White solid, yield: 84.3%; M.p.:146–147 °C. MS (ESI) m/z (%): 331.0 [M+H]⁺, 683.0 [2M+Na]⁺.

7.3.10. ethyl 5-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate (24j)

White solid, yield: 81.7%; M.p.:170–173 °C. MS (ESI) m/z (%): 337.1 [M+Na]⁺, 651.2 [2M+Na]⁺.

7.3.11. ethyl 5-methyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate (24k)

White solid, yield: 79.5%; M.p.:158–161 °C. MS (ESI) m/z (%): 314.2 [M+H]⁺, 626.7 [2M+H]⁺.

7.3.12. ethyl 5-methyl-2-oxo-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate (24l)

White solid, yield: 78.9%; M.p.:196–198 °C. MS (ESI) m/z (%): 336.9 [M+Na]⁺, 628.8 [2M+H]⁺.

7.3.13. ethyl 1-(2-chlorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (24m)

White solid, yield: 74.9%; M.p.:205–207 °C. MS (ESI) m/z (%): 280.9 [M+H]⁺.

7.4. General procedure for the synthesis of N-methyl-2-imidazolones (25a–m)

To a vigorously stirred mixture of 2-imidazolones 24 (3 mmol) and K₂CO₃(828 mg, 6 mmol) in DMF (10 mL)

was added methyl iodide (6 mmol) at room temperature, and the resulting suspension was stirred for 3 h. After

completion of the reaction, the mixture was poured into ice-water, the precipitate was filtered and dried under

vacuum to obtain the compound as a white solid.

7.4.1.

ethyl 3,5-dimethyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (25a)

7

White solid, yield: 89.5%; M.p.:89–92 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.55 – 7.38 (m, 3H), 7.32 – 7.21 (m,

2H), 4.32 (q, J = 7.0 Hz, 2H), 3.54 (s, 3H), 2.26 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI) m/z (%): 261.1 [M+H]⁺.

7.4.2.

ethyl 3,5-dimethyl-2-oxo-1-(p-tolyl)-2,3-dihydro-1H-imidazole-4-carboxylate (25b)

White solid, yield: 88.1%; M.p.:112–113 °C. MS (ESI) m/z (%): 313.3 [M+K]⁺.

7.4.3.

ethyl 1-(4-methoxyphenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25c)

White solid, yield: 86.3%; M.p.:108–109 °C. MS (ESI) m/z (%): 290.9 [M+H]⁺, 602.8 [2M+Na]⁺.

7.4.4.

ethyl 1-(4-fluorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25d)

White solid, yield: 92.4%; M.p.:162–163 °C. MS (ESI) m/z (%): 300.9 [M+Na]⁺.

7.4.5.

ethyl 1-(4-chlorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25e)

White solid, yield: 88.8%; M.p.:116–117 °C. MS (ESI) m/z (%): 295.1 [M+H]⁺.

7.4.6.

ethyl 1-(4-bromophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25f)

White solid, yield: 90.3%; M.p.:119–122 °C. MS (ESI) m/z (%): 377.1 [M+K]⁺.

7.4.7.

ethyl 1-(3,4-difluorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25g)

White solid, yield: 93.0%; M.p.:111–112 °C. MS (ESI) m/z (%): 297.1 [M+H]⁺, 318.4 [M+Na]⁺.

ethyl 1-(3-chloro-4-fluorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25h)

7.4.8.

White solid, yield: 90.7%; M.p.:114–116 °C. MS (ESI) m/z (%): 312.6 [M+H]⁺, 645.6 [2M+H]⁺.

7.4.9. ethyl 3,5-dimethyl-2-oxo-1-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate

(25i)

White solid, yield: 91.7%; M.p.:86–88 °C. MS (ESI) m/z (%): 383.1 [M+K]⁺.

7.4.10. ethyl 3,5-dimethyl-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate

(25j)

White solid, yield: 86.6%; M.p.:93–95 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.4 Hz, 2H), 7.56 (d, J =

8.3 Hz, 2H), 4.30 (q, J = 7.0 Hz, 2H), 3.52 (s, 3H), 2.24 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). MS (ESI) m/z (%): 351.1

[M+Na]⁺.

7.4.11. ethyl

(25k)

3,5-dimethyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate

White solid, yield: 89.2%; M.p.:88–89 °C. MS (ESI) m/z (%): 328.9 [M+H]⁺.

7.4.12. ethyl 3,5-dimethyl-2-oxo-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylate

(25l)

White solid, yield: 85.1%; M.p.:103–105 °C. MS (ESI) m/z (%): 329.1 [M+H]⁺.

7.4.13. ethyl 1-(2-chlorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (25m)

White solid, yield: 81.5%; M.p.:102–103 °C. MS (ESI) m/z (%): 294.8 [M+H]⁺.

7.5. General procedure for the synthesis of 2-imidazolone acid (26a–n)

To a stirred mixture of 2-imidazolone ester (1 mmol) in dioxane/EtOH (9 mL, 7:2) is added 5 eq of NaOH in 1

mL water at room temperature, and the resulting suspension was stirred for 10 h at 40 °C. After removal of solvent

under reduced pressure, the residue was dissolved in water, acidified with glacial acetic acid to provide the

2-imidazolone acid as a white solid.

7.5.1.

3,5-dimethyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid (26a)

White solid, yield: 80.5%; M.p.:182–185 °C. MS (ESI) m/z (%): 232.9 [M+H]⁺.

7.5.2.

3,5-dimethyl-2-oxo-1-(p-tolyl)-2,3-dihydro-1H-imidazole-4-carboxylic acid (26b)

White solid, yield: 74.0%; M.p.:212–215 °C. MS (ESI) m/z (%): 246.9 [M+H]⁺.

7.5.3.

1-(4-methoxyphenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26c)

White solid, yield: 72.5%; M.p.:197–199 °C. MS (ESI) m/z (%): 262.9 [M+H]⁺.

7.5.4.

1-(4-fluorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26d)

8

White solid, yield: 79.7%; M.p.:219–223 °C. MS (ESI) m/z (%): 250.9 [M+H]⁺.

7.5.5.

1-(4-chlorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26e)

White solid, yield: 76.6%; M.p.:224–225 °C. MS (ESI) m/z (%): 266.9 [M+H]⁺.

7.5.6.

1-(4-bromophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26f)

White solid, yield: 72.9%; M.p.:225–227 °C. MS (ESI) m/z (%): 310.9 [M+H]⁺.

7.5.7.

1-(3,4-difluorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26g)

White solid, yield: 82.5%; M.p.:191–193 °C. MS (ESI) m/z (%): 268.9 [M+H]⁺.

7.5.8.

1-(3-chloro-4-fluorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26h)

White solid, yield: 76.9%; M.p.:196–198 °C. MS (ESI) m/z (%): 285.0 [M+H]⁺.

7.5.9.

(26i)

3,5-dimethyl-2-oxo-1-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic

acid

White solid, yield: 78.8%; M.p.:190–192 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (d, J = 8.1 Hz, 2H), 7.56

(d, J = 8.4 Hz, 2H), 3.40 (s, 3H), 2.21 (s, 3H). MS (ESI) m/z (%): 317.0 [M+H]⁺.

7.5.10. 3,5-dimethyl-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic acid (26j)

White solid, yield: 83.5%; M.p.:187–188 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J = 8.4 Hz, 2H), 7.58

(d, J = 8.4 Hz, 2H), 3.41 (s, 3H), 2.25 (s, 3H). MS (ESI) m/z (%): 322.8 [M+Na]⁺.

7.5.11. 3,5-dimethyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic acid (26k)

White solid, yield: 77.1%; M.p.:157–158 °C. MS (ESI) m/z (%): 300.8 [M+H]⁺, 323.0 [M+Na]⁺.

7.5.12. 3,5-dimethyl-2-oxo-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxylic acid (26l)

White solid, yield: 78.9%; M.p.:195–197 °C. MS (ESI) m/z (%): 300.9 [M+H]⁺.

7.5.13. 1-(2-chlorophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26m)

White solid, yield: 74.5%; M.p.:231–132 °C. MS (ESI) m/z (%): 301.0 [M+H]⁺.

7.5.14. 1-(2-chlorophenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (26n)

To a vigorously stirred suspension of tert-butyl 2-diazo-3-oxobutanoate 1 (14 mmol) and finely powdered

urea 23m (408 mg, 18 mmol) in toluene-1,2-dichloroethane (1:1, 140 mL) was heated to 80 °C and a suspension of

Rh₂Oct₄(217 mg, 0.28 mmol) in toluene (28 mL) was added over 60 min. The mixture was then stirred for an

additional 30 min. After cooling to room temperature, TFA (16.8 mL) was added dropwisely, the solution was then

stirred for 3 h, after removal of solvent under reduced pressure, the residue was dissolved in 150 mL CH₂Cl₂,

washed with 6N HCl (3 × 30 mL), and then brine before being dried. The organic layer was concentrated, triturated

with ether to obtain the imidazolone-4-carboxylic acid 26n as a white solid. Yield: 88.2%; M.p.:207–209 °C. MS

(ESI) m/z (%): 252.9 [M+H]⁺.

7.6. General procedure for Preparation of the target Compounds (28–58)

A mixture of the corresponding acid 26a-n (0.486 mmol), toluene (5 mL), and SOCl₂(2.5 mL) was heated at

reflux for 5 h. Upon cooling to room temperature, the solvent was evaporated in vacuum. The residue was

redissolved in dried CH₂Cl₂(5 mL) and drop-wise added to a mixture of the corresponding aniline 22a-e (0.243

mmol), Na₂CO₃(0.486 mmol) and CH₂Cl₂(5 mL) in an ice bath, which was then removed to raise the temperature

to room temperature and stirred overnight. The resulting mixture was sequentially washed with 20% K₂CO₃(10 mL

× 2) and then brine (20 mL × 2), the organic phase was separated, dried, and evaporated. The crude product

obtained was purified by silica gel chromatography using a mixture of CH₂Cl₂/MeOH to afford 28-58 as white

solids.

7.6.1.

N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-3,5-dimethyl-2-oxo-

1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide (28)

Yield: 74.4%; M.p.:151–153 °C; IR (KBr) cm^-1: 3427.7, 2955.1, 2853.7, 1698.0, 1668.3, 1597.3, 1507.2,

1

1480.6, 1431.3, 1350.2, 1305.5, 1251.2, 1211.3, 1155.3, 1143.2, 1012.2, 854.9; H NMR (600 MHz, DMSO-d₆) δ

9

10.86 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.98 (dd, J = 13.0, 2.3 Hz, 1H), 7.66 (dd, J = 8.8 Hz,1.2 Hz, 1H), 7.56 (t, J

= 7.7 Hz, 2H), 7.54 (s, 1H), 7.50 – 7.44 (m, 2H), 7.41 (s, 1H), 7.38 – 7.34 (m, 2H), 6.46 (d, J = 5.2 Hz, 1H), 4.21 (t,

J = 6.4 Hz, 2H), 3.96 (s, 3H), 3.59 (t, J = 4.4 Hz, 3H), 3.36 (s, 3H), 2.47 (t, J = 7.1 Hz, 3H), 2.44 – 2.34 (m, 4H),

2.14 (s, 3H), 2.02 – 1.94 (m, 2H). MS (ESI) m/z (%): 663.8 [M+Na]⁺; Anal. calcd. for C₃₅H₃₆FN₅O₆(%): C, 65.51;

H, 5.65; N, 10.91; Found (%): C, 65.54; H, 5.69; N, 10. 96.

7.6.2.

N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dimethyl-2-

oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide (29)

Yield: 67.6%; M.p.:120–121 °C; IR (KBr) cm^-1: 3425.0, 2929.8, 2795.5, 1690.1, 1669.1, 1597.4, 1506.8,

1

1480.0, 1431.3, 1349.5, 1305.5, 1249.8, 1210.9, 1166.5, 1138.1, 971.4, 853.2; H NMR (600 MHz, CDCl₃) δ 8.48

(d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.72 (dd, J = 11.6, 1.6 Hz, 1H), 7.57 (s, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.44 (t, J =

7.4 Hz, 2H), 7.30 (dd, J = 9.0, 2.1 Hz, 1H), 7.28 – 7.23 (m, 2H), 7.24 – 7.19 (t, J = 8.6 Hz, 1H), 6.39 (d, J = 5.1 Hz,

1H), 4.27 (t, J = 6.6 Hz, 2H), 4.05 (s, 3H), 3.51 (s, 3H), 2.69 (t, J = 7.3 Hz, 2H), 2.59 – 2.51 (m, 4H), 2.25 (s, 3H),

2.21 – 2.13 (m, 2H), 1.84 – 1.76 (m, 4H). MS (ESI) m/z (%): 626.1 [M+H]⁺; Anal. calcd. for C₃₅H₃₆FN₅O₅(%): C,

67.19; H, 5.80; N, 11.19; Found (%): C, 67.24; H, 5.89; N, 11. 23.

7.6.3.

N-(3-fluoro-4-((6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dimethyl-2-o

xo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide (30)

1

Yield: 64.9%; M.p.:126–128 °C; H NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H),

7.95 (dd, J = 12.3, 2.3 Hz, 1H), 7.66 – 7.56 (m, 2H), 7.55 (s, 1H), 7.53 – 7.43 (m, 3H), 7.42 (s, 1H), 7.40 – 7.29 (m,

2H), 6.47 (d, J = 5.2 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 3.97 (s, 3H), 3.33 (s, 3H), 2.79 – 2.55 (m, 6H), 2.14 (s, 3H),

2.13 – 2.02 (m, 2H), 1.63 – 1.53 (m, 4H), 1.44 (m, 2H). MS (ESI) m/z (%): 640.0 [M+H]⁺; Anal. calcd. for

C₃₆H₃₈FN₅O₅(%): C, 67.59; H, 5.99; N, 10.95; Found (%): C, 67.64; H, 6.09; N, 10. 98.

7.6.4.

N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide (31)

Yield: 73.6%; M.p.:113–114 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 7.71 (dd,

J = 11.9, 2.4 Hz, 1H), 7.57 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.44 – 7.38 (m, 2H), 7.32 (dd, J = 8.6, 1.2 Hz, 1H),

7.25 – 7.22 (m, 2H), 7.19 (t, J = 8.7 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 4.24 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.49 (s,

3H), 2.94 (d, J = 10.9 Hz, 2H), 2.57 (t, J = 7.3 Hz, 2H), 2.23 (s, 3H), 2.20 – 2.09 (m, 2H), 1.98 (t, J = 10.7 Hz, 2H),

1.63 (d, J = 12.2 Hz, 2H), 1.42 – 1.32 (m, 1H), 1.32 – 1.22 (m, 2H), 0.93 (d, J = 6.3 Hz, 3H). MS (ESI) m/z (%):

653.9[M+H]⁺; Anal. calcd. for C₃₇H₄₀FN₅O₅(%): C, 67.98; H, 6.17; N, 10.71; Found (%): C, 67.99; H, 6.02; N, 10.

99.

7.6.5.

N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide (32)

Yield: 71.2%; M.p.:115–118 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.74 (dd,

J = 11.8, 2.3 Hz, 1H), 7.58 (s, 1H), 7.55 – 7.48 (m, J = 7.5 Hz, 3H), 7.47 – 7.41 (m, 1H), 7.32 – 7.28 (m, 3H), 7.26

– 7.21 (m, 1H), 6.41 (d, J = 5.3 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.52 (s, 3H), 2.70 – 2.35 (m, 10H),

2.31 (s, 3H), 2.27 (s, 3H), 2.20 – 2.10 (m, 2H). ¹³C NMR (101 MHz, DMSO) δ 159.77, 159.03, 155.13, 152.69,

152.41, 152.35, 150.04, 149.32, 146.84, 138.34, 136.30, 136.18, 134.66, 129.85 (2C), 128.81, 128.31 (2C), 124.65,

124.25, 116.97, 116.41, 114.88, 108.89, 102.46, 99.46, 67.20, 56.26, 55.26 (2C), 54.83, 53.22 (2C), 46.24, 29.37,

26.52. MS (ESI) m/z (%): 654.8 [M+H]⁺; Anal. calcd. for C₃₆H₃₉FN₆O₅(%): C, 66.04; H, 6.00; N, 12.84; Found

(%): C, 66.19; H, 6.06; N, 12. 79.

7.6.6.

N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(p-tolyl)-2,3-dihydro-1H-imidazole-4-carboxamide (33)

1

Yield: 65.8%; M.p.:131–132 °C; H NMR (600 MHz, CDCl₃) δ 8.48 (d, J = 5.3 Hz, 1H), 8.07 (s, 1H), 7.69

(dd, J = 11.8, 2.4 Hz, 1H), 7.57 (s, 1H), 7.43 (d, J = 7.1 Hz, 1H), 7.30 – 7.27 (m, 3H), 7.21 (t, J = 8.6 Hz, 1H), 7.13

10

(d, J = 8.2 Hz, 2H), 6.39 (d, J = 5.1 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.50 (s, 3H), 2.95 (d, J = 10.2

Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 2.16 (dt, J = 13.8, 6.8 Hz, 2H), 2.02 – 1.96 (m, 2H),

1.63 (d, J = 12.7 Hz, 2H), 1.37 (s, 1H), 1.32 – 1.23 (m, 2H), 0.93 (d, J = 6.4 Hz, 3H). MS (ESI) m/z (%): 667.9

[M+H]⁺; Anal. calcd. for C₃₈H₄₂FN₅O₅(%): C, 68.35; H, 6.34; N, 10.49; Found (%): C, 68.28; H, 6.32; N, 10.51.

7.6.7.

N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(p-tolyl)-2,3-dihydro-1H-imidazole-4-carboxamide (34)

Yield: 66.2%; M.p.:114–116 °C; IR (KBr) cm^-1: 3419.0, 3250.6, 2935.3, 2796.7, 1694.1, 1620.6, 1580.0,

1511.2, 1479.5, 1431.1, 1348.5, 1249.6, 1210.1, 1164.0, 1096.4, 1011.4, 840.7; ¹H NMR (400 MHz, CDCl₃) δ 8.49

(d, J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.68 (dd, J = 12.0, 2.1 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.36 – 7.27 (m, 3H),

7.22 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 5.5 Hz, 2H), 6.40 (d, J = 5.1 Hz, 1H), 4.27 (t, J = 6.5 Hz, 2H), 4.06 (s, 3H),

3.50 (s, 3H), 2.86 – 2.42 (m, 10H), 2.39 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.20 – 2.05 (m, 2H). MS (ESI) m/z (%):

668.9 [M+H]⁺; Anal. calcd. for C₃₇H₄₁FN₆O₅(%): C, 66.45; H, 6.18; N, 12.57; Found (%): C, 66.28; H, 6.32; N,

12.51.

7.6.8.

N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(4-me

thoxyphenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (35)

1

Yield: 67.3%; M.p.:121–124 °C; H NMR (400 MHz, CDCl₃) δ 8.49 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.70

(dd, J = 12.0, 2.2 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.30 (m, 1H), 7.23 (m, 1H), 7.17 (d, J = 8.1 Hz, 2H), 6.99 (d,

J = 7.9 Hz, 2H), 6.40 (d, J = 5.2 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.06 (s, 3H), 3.83 (s, 3H), 3.51 (s, 3H), 2.93 (d, J

= 9.9 Hz, 2H), 2.60 – 2.45 (m, 2H), 2.25 (s, 3H), 2.22 – 2.08 (m, 2H), 1.96 (t, J = 10.9 Hz, 2H), 1.64 (d, J = 12.1

Hz, 2H), 1.32 – 1.18 (m, 1H), 1.27 (t, J = 11.1 Hz, 2H), 0.94 (d, J = 4.7 Hz, 3H). MS (ESI) m/z (%): 683.9 [M+H]⁺;

Anal. calcd. for C₃₈H₄₂FN₅O₆(%): C, 66.75; H, 6.19; N, 10.24; Found (%): C, 66.78; H, 6.22; N, 10.31.

7.6.9.

N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(4-me

thoxyphenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (36)

1

Yield: 65.8%; M.p.:131–133 °C; H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.47 (s, J = 5.3 Hz, 1H),

7.96 (dd, J = 12.9, 2.1 Hz, 1H), 7.69 – 7.59 (m, 1H), 7.54 (s, 1H), 7.46 (t, J = 7.8 Hz 1H), 7.39 (s, 1H), 7.27 (d, J =

6.7 Hz, 2H), 7.09 (d, J = 6.5 Hz, 2H), 6.46 (d, J = 5.2 Hz, 1H), 4.19 (t, J = 6.5 Hz, 2H), 3.96 (s, 3H), 3.82 (s, 3H),

3.37 (s, 3H), 2.48 – 2.23 (m, 10H), 2.15 (s, 3H), 2.11 (s, 3H), 2.04 – 1.85 (m, 2H). MS (ESI) m/z (%): 684.8

[M+H]⁺; Anal. calcd. for C₃₇H₄₁FN₆O₆(%): C, 64.90; H, 6.04; N, 12.27; Found (%): C, 64.88; H, 6.02; N, 12.34.

7.6.10. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(4-flu

orophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (37)

1

Yield: 62.9%; M.p.:101–103 °C; H NMR (400 MHz, CDCl₃) δ 8.47 (d, J = 5.3 Hz, 1H), 8.44 (s, 1H), 7.72

(dd, J = 11.9, 2.4 Hz, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.20 (t, J =

2.5 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 5.2 Hz, 1H), 4.24 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), 3.48 (s, 3H),

2.95 (d, J = 11.0 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.21 (s, 3H), 2.19 – 2.10 (m, 2H), 1.99 (t, J = 10.7 Hz, 2H), 1.63

(d, J = 11.3 Hz, 2H), 1.44 – 1.34 (m, 1H), 1.32 – 1.28 (m, 2H), 0.92 (d, J = 6.2 Hz, 3H). MS (ESI) m/z (%): 671.9

[M+H]⁺; Anal. calcd. for C₃₇H₃₉F₂N₅O₅(%): C, 66.16; H, 5.85; N, 10.43; Found (%): C, 66.29; H, 5.66; N, 10.69.

7.6.11. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-1-(4-flu

orophenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (38)

Yield: 69.1%; M.p.:108–110 °C; IR (KBr) cm^-1: 3421.7, 3251.7, 2935.3, 2879.4, 2796.3, 1694.2, 1620.6,

1580.0, 1511.3, 1479.5, 1431.1, 1348.1, 1348.5, 1249.6, 1210.2, 1164.0, 1096.4, 1011.4，951.6，892.8，840.6; ¹H

NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 5.3 Hz, 1H), 7.99 (s, 1H), 7.67 (dd, J = 11.8, 2.3 Hz, 1H), 7.51 (s, 1H), 7.37

(s, 1H), 7.25 (dd, J = 8.8, 1.6 Hz, 1H), 7.20 – 7.16 (m, 3H), 7.13 (d, J = 8.1, 2H), 6.34 (d, J = 5.1 Hz, 1H), 4.20 (t, J

= 6.7 Hz, 2H), 3.99 (s, 3H), 3.46 (s, 3H), 2.73 – 2.31 (m, 10H), 2.25 (s, 3H), 2.18 (s, 3H), 2.13 – 2.00 (m, 2H). MS

(ESI) m/z (%): 672.9 [M+H]⁺; Anal. calcd. for C₃₆H₃₈F₂N₆O₅(%): C, 64.27; H, 5.69; N, 12.49; Found (%): C,

11

64.36; H, 5.66; N, 12.35.

7.6.12. 1-(4-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)o

xy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (39)

Yield: 69.2%; M.p.:115–117 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J = 5.3 Hz, 1H), 7.95 (s, 1H), 7.74 (dd,

J = 11.8, 2.3 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.43 (s, 1H), 7.30 (dd, J = 9.0, 2.1 Hz, 1H), 7.25 (t, J =

8.4 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.23 – 7.20 (m, 1H), 6.41 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.05 (s,

3H), 3.50 (s, 3H), 2.92 (d, J = 11.4 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 2.19 – 2.10 (m, 2H), 1.96 (t, J =

10.9 Hz, 2H), 1.63 (d, J = 12.0 Hz, 2H), 1.40 – 1.33 (m, 1H), 1.30 – 1.21 (m, 2H), 0.93 (d, J = 6.3 Hz, 3H). MS

(ESI) m/z (%): 687.8 [M+H]⁺; Anal. calcd. for C₃₇H₃₉ClFN₅O₅(%): C, 64.58; H, 5.71; N, 10.18; Found (%): C,

64.39; H, 5.66; N, 10.33.

7.6.13. 1-(4-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)o

xy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (40)

Yield: 70.4%; M.p.:121–123 °C; IR (KBr) cm^-1: 3420.8, 2935.2, 2796.4, 1695.0, 1668.8, 1579.5, 1508.3,

1

1479.4, 1431.0, 1348.7, 1249.8, 1164.9, 1091.2, 1011.3, 833.4; H NMR (400 MHz, CDCl₃) δ 8.49 (d, J = 5.2 Hz,

1H), 7.86 (s, 1H), 7.75 (dd, J = 11.8, 2.2 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.44 (s, 1H), 7.30 (dd, J =

8.9, 2.2 Hz, 1H), 7.25 (d, J = 4.5 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.27 (t, J = 6.6 Hz,

2H), 4.05 (s, 3H), 3.51 (s, 3H), 2.75 – 2.35 (m, 10H), 2.31 (s, 3H), 2.27 (s, 3H), 2.15 (dt, J = 13.7, 6.7 Hz, 2H). ¹³

C

NMR (101 MHz, DMSO) δ159.76, 158.94, 152.69, 152.41, 152.19, 150.03, 149.31, 146.85, 138.35, 136.34, 136.17,

133.55, 133.28, 130.06 (2C), 129.87 (2C), 124.63, 124.00, 116.98, 116.63, 114.88, 108.96, 108.85, 99.45, 67.19,

56.25, 55.26 (2C), 54.83, 53.22 (2C), 46.23, 29.38, 26.53, 11.61. MS (ESI) m/z (%): 711.0 [M+Na]⁺; Anal. calcd.

for C₃₆H₃₈ClFN₆O₅(%): C, 62.74; H, 5.56; N, 12.19; Found (%): C, 62.59; H, 5.46; N, 12.35.

7.6.14. 1-(4-bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)o

xy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (41)

1

Yield: 71.5%; M.p.:131–132 °C; H NMR (400 MHz, CDCl₃) δ 8.48 (d, J = 5.3 Hz, 1H), 7.81 (s, 1H), 7.74

(dd, J = 11.8, 2.1 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.57 (s, 1H), 7.43 (s, 1H), 7.31 – 7.27 (m, 1H), 7.26 – 7.22 (m,

1H), 7.16 (d, J = 8.6 Hz, 2H), 6.41 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.50 (s, 3H), 2.95 –

2.87 (m, 2H), 2.58 – 2.50 (m, 2H), 2.26 (s, 3H), 2.19 – 2.07 (m, 2H), 1.95 (t, J = 10.7 Hz, 2H), 1.63 (d, J = 12.2 Hz,

2H), 1.42 – 1.29 (m, 1H), 1.30 – 1.17 (m, 2H), 0.92 (d, J = 6.3 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ159.79,

159.03, 152.68, 152.43, 152.15, 150.03, 149.30, 146.84, 136.22, 136.11, 133.99, 132.81 (2C), 130.35(2C), 124.58,

123.81, 121.72, 117.09, 116.80, 114.87, 108.94, 108.90, 102.43, 99.46, 67.29, 56.25, 55.21, 54.00 (2C), 34.52 (2C),

30.92, 29.41, 26.72, 22.33, 11.59. MS (ESI) m/z (%): 731.9 [M+H]⁺; Anal. calcd. for C₃₇H₃₉BrFN₅O₅(%):C, 60.66;

H, 5.37; N, 9.56; Found (%): C, 60.69; H, 5.28; N, 9.63.

7.6.15. 1-(4-bromophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)

oxy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (42)

1

Yield: 66.7%; M.p.:133–135 °C; H NMR (400 MHz, CDCl₃) δ 8.48 (d, J = 5.2 Hz, 1H), 8.07 (s, 1H), 7.77

(dd, J = 11.9, 2.3 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.57 (s, 1H), 7.43 (s, 1H), 7.37 – 7.30 (m, 1H), 7.23 (t, J = 8.6

Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.42 (d, J = 5.2 Hz, 1H), 4.26 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 3.50 (s, 3H), 2.86

– 2.45 (m, 10H), 2.42 (s, 3H), 2.26 (s, 3H), 2.19 – 2.09 (m, 2H). MS (ESI) m/z (%): 734.7 [M+H]⁺; Anal. calcd. for

C₃₆H₃₈BrFN₅O₅(%): C, 58.94; H, 5.22; N, 11.46; Found (%): C, 58.99; H, 5.28; N, 11.61.

7.6.16. 1-(3,4-difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)pheny

l)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (43)

1

Yield: 64.5%; M.p.:118–122 °C; H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H),

7.96 (dd, J = 12.3, 2.5 Hz, 1H), 7.70 – 7.56 (m, 3H), 7.53 (s, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.40 (s, 1H), 7.27 (m,

1H), 6.46 (d, J = 5.0 Hz, 1H), 4.20 (t, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.59 (m, 4H), 3.34 (s, 3H), 2.47 (t, J = 7.0 Hz,

12

2H), 2.39 (m, 4H), 2.16 (s, 3H), 2.04 – 1.93 (m, 2H). MS (ESI) m/z (%): 678.0 [M+H]⁺; Anal. calcd. for

C₃₅H₃₄F₃N₅O₆(%):C, 62.03; H, 5.06; N, 10.33; Found (%): C, 62.35; H, 5.08; N, 10.11.

7.6.17. 1-(3,4-difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-

yl)oxy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (44)

Yield: 64.9%; M.p.:109–111 °C; ¹H NMR (600 MHz, CDCl₃) δ 8.47 (d, J = 5.1 Hz, 1H), 7.94 (s, 1H), 7.75 (dd,

J = 10.5, 2.1 Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.30 (t, J = 9.0 Hz, 2H), 7.25 (m, 1H), 7.17 – 7.08 (m, 1H), 7.03 (d,

J = 8.1 Hz, 1H), 6.40 (d, J = 5.0 Hz, 1H), 4.24 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 3.49 (s, 3H), 2.91 (d, J = 10.7 Hz,

2H), 2.54 (t, J = 7.2 Hz, 2H), 2.25 (s, 3H), 2.18 – 2.08 (m, 2H), 1.94 (t, J = 11.3 Hz, 2H), 1.62 (d, J = 12.1 Hz, 2H),

1.40 – 1.31 (m, 1H), 1.24 (d, J = 10.2 Hz, 2H), 0.92 (d, J = 6.3 Hz, 3H). MS (ESI) m/z (%): 690.0 [M+H]⁺; Anal.

calcd. for C₃₇H₃₈F₃N₅O₅(%): C, 64.43; H, 5.55; N, 10.15; Found (%): C, 64.49; H, 5.45; N, 10.21.

7.6.18. 1-(3,4-difluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-

yl)oxy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (45)

Yield: 68.8%; M.p.:118–120 °C; IR (KBr) cm^-1: 3418.6, 2935.0, 2801.7, 2320.3, 1698.2, 1670.3, 1580.6,

1508.6, 1480.0, 1431.7, 1349.3, 1304.8, 1249.8, 1211.2, 1164.6, 1120.6, 1096.1，949.9, 853.6，779.7; ¹H NMR (600

MHz, CDCl₃) δ 8.45 (d, J = 5.0 Hz, 1H), 7.92 (s, 1H), 7.73 (dd, J = 11.8, 2.2 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 1H),

7.29 (t, J = 9.0 Hz, 2H), 7.24 (m, 1H), 7.15 – 7.07 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.41 (d, J = 5.1 Hz, 1H), 4.23

(t, J = 6.5 Hz, 2H), 4.02 (s, 3H), 3.49 (s, 3H), 2.78 – 2.35 (m, 10H), 2.38 (s, 3H), 2.26 (s, 3H), 2.19 – 2.08 (m, 2H).

MS (ESI) m/z (%): 690.8 [M+H]⁺; Anal. calcd. for C₃₆H₃₇F₃N₆O₅(%): C, 62.60; H, 5.40; N, 12.17; Found (%): C,

62.49; H, 5.45; N, 12.21.

7.6.19. 1-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quino

lin-4-yl)oxy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (46)

1

Yield: 65.9%; M.p.:117–119 °C; H NMR (400 MHz, CDCl₃) δ 8.50 (d, J = 5.3 Hz, 1H), 7.78 (dd, J = 10.5,

2.0 Hz, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.45 (s, 1H), 7.40 (dd, J = 6.5, 2.3 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.26 – 7.24

(m, 1H), 7.23 – 7.17 (m, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 4.07 (s, 3H), 3.53 (s, 3H), 2.94 (d, J

= 11.2 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H), 2.29 (s, 3H), 2.22 – 2.10 (m, 2H), 1.97 (t, J = 10.8 Hz, 2H), 1.65 (d, J =

12.6 Hz, 2H), 1.43 – 1.31 (m, 1H), 1.30 – 1.19 (m, 2H), 0.94 (d, J = 6.3 Hz, 3H). MS (ESI) m/z (%): 705.8 [M+H]⁺;

Anal. calcd. for C₃₇H₃₈ClF₂N₅O₅(%): C, 62.93; H, 5.42; N, 9.92; Found (%): C, 62.98; H, 5.35; N, 10.01.

7.6.20. 1-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinli

n-4-yl)oxy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (47)

Yield: 66.4%; M.p.:131–133 °C; IR (KBr) cm^-1: 3422.0, 2936.3, 2879.6, 2797.7, 1698.2, 1669.8, 1620.2,

1504.5, 1479.4, 1431.1, 1348.6, 1283.2, 1250.0, 1210.7, 1164.4, 1122.1, 1097.8, 871.8; ¹H NMR (400 MHz, CDCl₃)

δ 8.49 (d, J = 5.3 Hz, 1H), 7.83 (s, 1H), 7.75 (dd, J = 11.8, 2.2 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.36 (dd, J = 6.3,

2.5 Hz, 1H), 7.32 – 7.28 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 7.20 – 7.14 (m, 1H), 6.41 (d, J = 4.8 Hz, 1H), 4.26 (t, J

= 6.7 Hz, 2H), 4.05 (s, 3H), 3.51 (s, 3H), 2.70 – 2.31 (m, 10H), 2.30 (s, 3H), 2.27 (s, 3H), 2.19 – 2.08 (m, 2H). ¹³

C

NMR (101 MHz, DMSO) δ 159.78, 158.99, 158.53, 156.07, 155.12, 152.68, 152.41, 152.23, 150.03, 149.31,

146.85, 131.72, 129.34, 124.59, 123.92, 120.61, 120.43, 118.11, 117.90, 117.11, 116.77, 114.88, 109.16, 108.96,

99.46, 67.19, 56.25, 55.26 (2C), 54.83, 53.22 (2C), 46.23, 29.45, 26.53, 11.51. MS (ESI) m/z (%): 707.0 [M+H]⁺;

Anal. calcd. for C₃₆H₃₇ClF₂N₆O₅(%): C, 61.14; H, 5.27; N, 11.88; Found (%): C, 61.18; H, 5.32; N, 12.01.

7.6.21. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (48)

1

Yield: 72.8%; M.p.:134–135 °C; H NMR (400 MHz, CDCl₃) δ 8.48 (d, J = 5.1 Hz, 1H), 7.77 (dd, J = 11.4,

2.1 Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.40 – 7.31 (m, 4H), 7.29 (dd, J = 8.7, 2.1 Hz, 1H), 7.26(m,

1H), 6.41 (d, J = 5.2 Hz, 1H), δ 4.25 (t, J = 6.8 Hz, 2H), 4.05 (s, 3H), 3.53 (s, 3H), 3.03 (d, J = 9.8 Hz, 2H), 2.75 –

2.61 (m, 2H), 2.29 (s, 3H), 2.26 – 2.15 (m, 2H), 2.12 – 1.98 (m, 2H), 1.65 (d, J = 11.2 Hz 2H), 1.48 – 1.29 (m, 3H),

13

0.92 (d, J = 5.3 Hz, 3H). MS (ESI) m/z (%): 637.8 [M+H]⁺; Anal. calcd. for C₃₈H₃₉F₄N₅O₆(%): C, 61.87; H, 5.33;

N, 9.49; Found (%): C, 61.92; H, 5.27; N, 9.42.

7.6.22. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(4-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (49)

1

Yield: 74.2%; M.p.:138–140 °C; H NMR (600 MHz, CDCl₃) δ 8.48 (d, J = 5.2 Hz, 1H), 7.75 (dd, J = 11.7,

2.2 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.38 – 7.32 (m, 4H), 7.29 (dd, J = 8.8, 2.2 Hz, 1H), 7.24 (m,

1H), 6.40 (d, J = 5.1 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.52 (s, 3H), 2.84 – 2.36 (m, 10H), 2.29 (s, 3H),

2.28 (s, 3H), 2.17 – 2.10 (m, 2H). MS (ESI) m/z (%): 738.8 [M+H]⁺; Anal. calcd. for C₃₇H₃₈F₄N₆O₆(%): C, 60.16;

H, 5.19; N, 11.38; Found (%): C, 60.22; H, 5.27; N, 9.42.

7.6.23. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (50)

1

Yield: 72.0%; M.p.:124–126 °C; H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H),

8.04 – 7.85 (m, 3H), 7.64 (d, J = 7.5 Hz, 2H), 7.59 (m, 1H), 7.53 (s, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.39 (s, 1H), 6.46

(d, J = 5.1 Hz, 1H), 4.18 (t, J = 6.7 Hz, 2H), 3.96 (s, 3H), 3.34 (s, 3H), 2.85 (d, J = 9.8 Hz, 2H), 2.48 – 2.36 (m,

2H), 2.19 (s, 3H), 2.05 – 1.92 (m, 2H), 1.57 (d, J = 11.0 Hz, 2H), 1.36 – 1.08 (m, 5H), 0.89 (d, J = 5.3 Hz, 3H). MS

(ESI) m/z (%): 722.4 [M+H]⁺; Anal. calcd. for C₃₈H₃₉F₄N₅O₅(%): C, 63.24; H, 5.45; N, 9.70; Found (%): C, 63.32;

H, 5.47; N, 9.76.

7.6.24. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (51)

Yield: 73.8%; M.p.:128–129 °C; ¹H NMR (600 MHz, CDCl₃) δ 8.48 (d, J = 5.2 Hz, 1H), 7.80 – 7.73 (m, 4H),

7.57 (s, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.43 (s, 1H), 7.30 (dd, J = 8.8, 1.9 Hz, 1H), 7.25 (t, J = 8.7 Hz, 1H), 6.41 (d,

J = 5.1 Hz, 1H), 4.26 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.52 (s, 3H), 2.75 – 2.33 (m, 10H), 2.30 (s, 6H), 2.17 – 2.09

(m, 2H). MS (ESI) m/z (%): 722.9 [M+H]⁺; Anal. calcd. for C₃₇H₃₈F₄N₆O₅(%): C, 61.49; H, 5.30; N, 11.63; Found

(%): C, 61.32; H, 5.45; N, 11.56.

7.6.25. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (52)

Yield: 65.9%; M.p.:116–118 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J = 5.3 Hz, 1H), 7.81 (s, 1H), 7.77 (dd,

J = 11.6, 2.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.58 – 7.51 (m, 2H), 7.45 (s,

1H), 7.33 – 7.28 (m, 1H), 7.26 – 7.23 (m, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 4.07 (s, 3H), 3.54

(s, 3H), 2.94 (d, J = 11.3 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.23 – 2.07 (m, 2H), 1.97 (t, J = 10.9 Hz,

2H), 1.64 (d, J = 12.4 Hz, 2H), 1.43 – 1.32 (m, 1H), 1.32 – 1.22 (m, 2H), 0.94 (d, J = 6.3 Hz, 3H). MS (ESI) m/z

(%): 721.8 [M+H]⁺; Anal. calcd. for C₃₈H₃₉F₄N₅O₅(%): C, 63.24; H, 5.45; N, 9.70; Found (%): C, 63.34; H, 5.53;

N, 9.56.

7.6.26. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (53)

1

Yield: 66.5%; M.p.:117–120 °C; H NMR (600 MHz, CDCl₃) δ 8.41 (d, J = 5.3 Hz, 1H), 7.69 (dd, J = 11.8,

2.4 Hz, 1H), 7.67 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.49 – 7.48 (m, 1H), 7.45

(d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.23 – 7.21 (m, 1H), 7.21 – 7.20 (m, J = 2.9 Hz, 1H), 6.34 (d, J = 4.9 Hz, 1H),

4.19 (t, J = 6.7 Hz, 2H), 3.98 (s, 3H), 3.45 (s, 3H), 2.63 – 2.28 (m, 10H), 2.23 (s, 3H), 2.22 (s, 3H), 2.10 – 2.02 (m,

2H). MS (ESI) m/z (%): 723.0 [M+H]⁺; Anal. calcd. for C₃₇H₃₈F₄N₆O₅(%): C, 61.49; H, 5.30; N, 11.63; Found

(%): C, 61.64; H, 5.33; N, 11.51.

7.6.27. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (54)

Yield: 67.1%; M.p.:109–111 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J = 5.3 Hz, 1H), 7.93 (s, 1H), 7.86 (dd,

14

J = 7.5, 2.1 Hz, 1H), 7.80 – 7.69 (m, 2H), 7.65 (t, J = 7.7 Hz, 1H), 7.57 (s, J = 4.1 Hz, 1H), 7.42 (s, J = 6.7 Hz, 1H),

7.36 – 7.29 (m, 2H), 7.24 (t, J = 8.5 Hz, 1H), 6.41 (d, J = 5.2 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H), 3.53 (s,

3H), 2.93 (d, J = 11.3 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.25 – 2.14 (m, 2H), 2.14 (s, 3H), 1.97 (t, J = 10.9 Hz, 2H),

1.64 (d, J = 12.6 Hz, 2H), 1.44 – 1.32 (m, 1H), 1.31 – 1.19 (m, 2H), 0.93 (d, J = 6.3 Hz, 3H). MS (ESI) m/z (%):

721.8 [M+H]⁺; Anal. calcd. for C₃₈H₃₉F₄N₅O₅(%): C, 63.24; H, 5.45; N, 9.70; Found (%): C, 63.34; H, 5.37; N,

9.74.

7.6.28. N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-3,5-dim

ethyl-2-oxo-1-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1H-imidazole-4-carboxamide (55)

Yield: 67.6%; M.p.:118–120 °C; IR (KBr) cm^-1: 3426.2, 2935.7, 2879.4, 2797.2, 1699.7, 1669.6, 1607.6,

1508.3, 1480.0, 1431.7, 1349.2, 1304.7, 1210.9, 1164.6, 1132.8, 1011.7, 852.4, 739.2; ¹H NMR (400 MHz, CDCl₃)

δ 8.42 (d, J = 5.3 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.70 – 7.63 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.51

(s, 1H), 7.37 (s, 1H), 7.29 – 7.23 (m, 2H), 7.17 (t, J = 8.6 Hz, 1H), 6.34 (d, J = 5.2 Hz, 1H), 4.20 (t, J = 6.7 Hz, 2H),

3.99 (s, 3H), 3.46 (s, 3H), 2.67 – 2.27 (m, 10H), 2.23 (s, 3H), 2.13 – 2.07 (m, 2H), 2.07 (s, 3H). MS (ESI) m/z (%):

722.9 [M+H]⁺; Anal. calcd. for C₃₇H₃₈F₄N₆O₅(%): C, 61.49; H, 5.30; N, 11.63; Found (%): C, 61.58; H, 5.35; N,

11.42.

7.6.29. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yl)o

xy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (56)

1

Yield: 69.2%; M.p.:125–128 °C; H NMR (400 MHz, CDCl₃) δ 8.50 (d, J = 5.3 Hz, 1H), 7.89 (s, 1H), 7.75

(dd, J = 11.8, 2.4 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.49 – 7.41 (m, 3H), 7.39 – 7.34 (m, 1H), 7.34 (dd, J = 9.1, 1.7 Hz ,

1H), 7.25 (t, J = 8.5 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.27 (t, J = 6.7 Hz, 2H), 4.06 (s, 3H), 3.56 (s, 3H), 2.99 (d, J

= 11.4 Hz, 2H), 2.66 – 2.57 (m, 2H), 2.20 (s, 3H), 2.16 (m, 2H), 2.03 (t, J = 10.9 Hz, 2H), 1.66 (d, J = 12.1 Hz, 2H),

1.46 – 1.36 (m, 1H), 1.35 – 1.26 (m, 2H), 0.95 (d, J = 6.2 Hz, 3H). MS (ESI) m/z (%): 688.1 [M+H]⁺; Anal. calcd.

for C₃₇H₃₉ClFN₅O₅(%): C, 64.58; H, 5.71; N, 10.18; Found (%): C, 64.45; H, 5.56; N, 10.37.

7.6.30. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)o

xy)phenyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (57)

Yield: 70.4%; M.p.:135–136 °C; IR (KBr) cm^-1: 3424.1, 3252.1, 2946.6, 2921.9, 2769.8, 1695.5, 1669.5,

1578.8, 1507.9, 1479.8, 1430.4, 1348.2, 1248.7, 1209.9, 1164.8, 1098.6, 1011.2, 852.9; ¹H NMR (400 MHz, CDCl₃)

δ 8.50 (d, J = 5.3 Hz, 1H), 7.88 (s, 1H), 7.74 (dd, J = 11.8, 2.4 Hz, 1H), 7.60 – 7.55 (m, 2H), 7.48 – 7.39 (m, 3H),

7.35 (dt, J = 7.6, 3.2 Hz, 1H), 7.31 (dd, J = 9.0, 1.5 Hz, 1H), 7.24 (t, J = 8.6 Hz, 1H), 6.41 (d, J = 5.2 Hz, 1H), 4.27

(t, J = 6.7 Hz, 2H), 4.06 (s, 3H), 3.55 (s, 3H), 2.77 – 2.35 (m, 10H), 2.31 (s, 3H), 2.19 (s, 3H), 2.17 – 2.08 (m, 2H).

¹³C NMR (101 MHz, DMSO) δ 159.80, 158.95, 155.13, 152.69, 152.45, 151.89, 150.07, 149.33, 146.89, 138.44,

136.38, 133.23, 132.29, 131.97, 131.65, 130.76, 129.02, 124.61, 117.15, 116.56, 114.93, 109.25, 109.01, 102.50,

99.51, 67.23, 56.28, 55.07 (2C), 54.86, 53.25 (2C), 46.26, 29.52, 26.56, 11.12. MS (ESI) m/z (%): 710.8 [M+Na]⁺;

Anal. calcd. for C₃₆H₃₈ClFN₆O₅(%): C, 62.74; H, 5.56; N, 12.19; Found (%): C, 62.59; H, 5.46; N, 12.33.

7.6.31. 1-(2-chlorophenyl)-N-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)o

xy)phenyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (58)

1

Yield: 62.1%; M.p.:121–122 °C; H NMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.60

(dd, J = 12.9, 2.0 Hz, 2H), 7.58 (s, 1H), 7.45 (m, 4H), 7.38 (d, J = 8.6 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 6.38 (d, J =

5.2 Hz, 1H), 4.27 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 2.78 – 2.47 (m, 10H), 2.44 (s, 3H), 2.32 (s, 3H), 2.19 – 2.08 (m,

2H). MS (ESI) m/z (%): 675.3 [M+H]⁺; Anal. calcd. for C₃₅H₃₆ClFN₆O₅(%): C, 62.26; H, 5.37; N, 12.45; Found

(%): C, 62.29; H, 5.46; N, 12.20.

15

References and notes

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16

Legends

Figure 1. Structures of small-molecule c-Met inhibitors

Figure 2. Our previous work on small-molecule c-Met kinase inhibitors

Figure 3. Anticancer agents bearing imidazolone moiety

Figure 4. General structure of the target compounds

Scheme 1. Reagents and conditions: (i) Br(CH₂)₃Cl, acetone, 0 °C, 30 min, rt., 12 h; (ii) 98%HNO₃, CH₂Cl₂, 0 °C,

4 h; (iii) DMF-DMA, toluene, 110 °C, 10 h; (iv) Fe powder, HOAc, rt., 30 min, 80 °C, 2 h; (v) secondary amines,

CH₃CN, 85 °C, 10 h; (vi) POCl₃, 85 °C, 6 h; (vii) 2-fluoro-4-nitrophenol, PhCl, 140 °C, 30 h; (viii) Fe powder,

NH₄Cl (cat.), EtOH/H₂O, reflux, 5 h.

Scheme 2. Reagents and conditions: (i) NaOCN, AcOH/H₂O, 50 °C, 2 h; (ii) (a) Rh₂Oct₄(2 mol %), ethyl

2-diazo-3-oxobutanoate, 1:1 toluene/DCE, 80 °C, 30 min. (b) 10% TFA, rt, 30 min; (iii) CH₃I (3 equiv), K₂CO₃(3

equiv) DMF, 3 h; (iv) NaOH (5 equiv), 1,4-dioxane/EtOH, 40 °C, 10 h; (v) (a) Rh₂Oct₄(2 mol %), tert-butyl

2-diazo-3-oxobutanoate, 1:1 toluene/DCE, 80 °C, 30 min. (b) 10% TFA, rt, 3 h; (vi) PhMe, SOCl₂, reflux, 5 h; (vii)

appropriate aniline, Na₂CO₃, CH₂Cl₂.

Table 1

SARs of quinoline derivatives.

Table 2

kinase selectivity profile of compound 58 and foretinib

Figure 5. The c-Met active site in complex with compound 58, Compound 58 was shown in colored sticks (green:

carbon atom, blue: nitrogen atom, red: oxygen atom, yellow: chlorine atom, cyan: fluorine atom). The conventional

H-bond interaction was shown in green dotted line.

17

Table 1

SAR of quinoline derivatives.

IC₅₀(μM)^a

Compd.

R₁

R₂

R₃

c-Met IC₅₀(nM)

A549

H460

HT-29

MKN-45

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

Foretinib^b

morpholinyl

H

CH₃

H

0.98 ±0.14

1.46 ±0.18

0.79 ±0.09

0.66 ±0.08

0.60 ±0.08

1.12 ±0.14

0.83 ±0.08

1.04 ±0.20

0.96 ±0.12

0.52 ±0.04

0.43 ±0.06

0.42 ±0.04

0.36 ±0.03

0.68 ±0.07

0.48 ±0.06

0.62 ±0.09

0.53 ±0.08

0.40 ±0.05

0.43 ±0.04

0.38 ±0.03

0.62 ±0.09

0.44 ±0.04

0.54 ±0.06

0.50 ±0.05

0.88 ±0.10

0.77 ±0.06

0.45 ±0.03

0.37 ±0.03

0.32 ±0.05

0.31 ±0.04

0.25 ±0.02

0.19 ± 0.02

0.79 ±0.09

1.03 ±0.19

0.65 ±0.06

0.59 ±0.05

0.42 ±0.04

0.94 ±0.10

0.51 ±0.04

0.94 ±0.08

0.69 ±0.06

0.25 ±0.04

0.26 ±0.03

0.20 ±0.02

0.17 ±0.02

0.55 ±0.06

0.36 ±0.04

0.54 ±0.05

0.23 ±0.02

0.24 ±0.03

0.25 ±0.04

0.21 ±0.02

0.59 ±0.05

0.34 ±0.02

0.41 ±0.04

0.36 ±0.02

0.58 ±0.04

0.57 ±0.03

0.22 ±0.02

0.19 ±0.01

0.18 ±0.02

0.13 ±0.01

0.10 ±0.008

0.21 ± 0.03

0.74 ±0.08

0.32 ±0.03

0.51 ±0.07

0.24 ±0.04

0.21 ±0.04

0.19 ±0.02

0.43 ±0.07

0.36 ±0.03

0.49 ±0.06

0.44 ±0.05

0.084 ±0.007

0.067 ±0.005

0.062 ±0.006

0.058 ±0.003

0.16 ±0.04

0.12 ±0.03

0.17 ±0.04

0.095 ±0.006

0.086 ±0.005

0.089 ±0.007

0.073 ±0.008

0.14 ±0.04

0.12 ±0.04

0.13 ±0.02

0.098 ±0.008

0.32 ±0.03

0.20 ±0.01

0.081 ±0.004

0.069 ±0.007

0.043 ±0.005

0.037 ±0.006

0.014 ±0.004

0.12 ±0.03

35.68 ±2.54

ND

pyrrolidinyl

H

0.94 ±0.09

0.56 ±0.03

0.36 ±0.03

0.30 ±0.02

0.79 ±0.09

0.49 ±0.03

0.79 ±0.08

0.56 ±0.02

0.24 ±0.03

0.19 ±0.04

0.17 ±0.03

0.14 ±0.02

0.28 ±0.02

0.29 ±0.05

0.39 ±0.06

0.23 ±0.04

0.18 ±0.02

0.20 ±0.03

0.14 ±0.02

0.40 ±0.04

0.27 ±0.02

0.36 ±0.01

0.26 ±0.03

0.52 ±0.06

0.43 ±0.07

0.14 ±0.01

0.13 ±0.02

0.15 ±0.01

0.12 ±0.01

0.086 ±0.005

0.032 ± 0.005

piperidinyl

H

31.20 ±2.32

28.54 ±2.86

23.86 ±2.11

ND

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

morpholinyl

H

4-CH₃

4-OCH₃

4-F

24.25 ±2.10

ND

27.30 ±2.14

6.26 ±0.41

5.41 ±0.32

5.64 ±0.36

4.36 ±0.38

18.44 ±2.46

13.3 ±0.96

18.6 ±1.40

7.43 ±0.46

5.80 ±0.24

6.67 ±0.32

5.16 ±0.20

25.49 ±2.69

20.54 ±2.81

14.68 ±2.36

10.64 ±2.23

26.18 ±2.52

19.22±1.24

10.86 ±1.50

8.10 ±1.32

4.16 ±0.28

2.90 ±0.23

1.42 ±0.14

1.64 ±0.10

4-F

4-Cl

4-Br

3,4-2F

3-Cl-4-F

4-OCF₃

4-CF₃

3-CF₃

2-CF₃

2-Cl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

4-methylpiperidinyl

4-methylpiperazinyl

2-Cl

-

Bold values show the IC₅₀values of the target compounds lower than the values of the positive control. ND: Not

determined.

^aIC₅₀: concentration of the compound (μM) producing 50% cell growth inhibition after 72 h of drug exposure,

as determined by the MTT assay. Each experiment was carried out in triplicate.

^bUsed as a positive control.

Table 2

kinase selectivity profile of compound 58 and foretinib

Enzyme

Enzyme IC₅₀(nM)

foretinib

58

92.6

VEGFR-2

c-kit

4.86

6.72

5.58

3.43

2990

38.2

Flt-3

134

Ron

270

EGFR

>100,000

Figure(1)

Figure(2)

Figure(3)

Figure(4)

Scheme 1

Scheme 2

Figure(5)

Graphical abstract

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing imidazolone moiety designed, synthesized

and evaluated for their enzymatic assays, cytotoxicity and docking analysis.

18

Article Doi

Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors

DOI: 10.1016/j.bmc.2015.06.026

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.bmc.2015.06.026

Full text of DOI:10.1016/j.bmc.2015.06.026

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