Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine-3-carboxamide derivatives

Article abstract of DOI:10.1016/j.ejmech.2017.05.044

We report herein the design and synthesis of “novel imidazo [1,2-a]pyridine-3-carboxamides (IPAs)” bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results reveal that 2,6-dimethyl-N-[2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041–2.64 μM) against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv with the SI values of 4395 and 1405, respectively. Moreover, N-[2-(piperazin-1-yl)ethyl] moiety was also identified as a potentially alternative linker (compound 31), opening a new direction for further SAR studies.

Full text of DOI:10.1016/j.ejmech.2017.05.044

European Journal of Medicinal Chemistry 137 (2017) 117e125
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Design, synthesis and antimycobacterial activity of novel imidazo[1,2-
a]pyridine-3-carboxamide derivatives
,
Kai Lv a, Linhu Li a, Bo Wang a, Mingliang Liu a *, Bin Wang b, Weiyi Shen c, Huiyuan Guo a,
,
**
Yu Lu b
a Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
b Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research
Institute, Beijing ChestHospital, Capital Medical University, Beijing 101149, China
c Zhejiang Starry Pharmaceutical Co. Ltd., Xianju 317300, China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the design and synthesis of “novel imidazo [1,2-a]pyridine-3-carboxamides (IPAs)”
bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results
reveal that 2,6-dimethyl-N-[2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene
Received 1 December 2016
Received in revised form
15 May 2017
Accepted 20 May 2017
Available online 27 May 2017
ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041e2.64
mM)
against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv
with the SI values of 4395 and 1405, respectively. Moreover, N-[2-(piperazin-1-yl)ethyl] moiety was also
identified as a potentially alternative linker (compound 31), opening a new direction for further SAR
studies.
Keywords:
Imidazo[1,2-a]pyridine
Design
© 2017 Elsevier Masson SAS. All rights reserved.
Synthesis
Antimycobacterial activity
1. Introduction
(Fig. 1) [7,8] and ND09759 (Fig. 1) [9,10] were reported to have
strong inhibitory potency against drug-sensitive, MDR and XDR
Tuberculosis (TB) is a chronic infectious disease caused mainly
by Mycobacterium tuberculosis (MTB). The World Health Organi-
zation (WHO) 2015 TB report estimated that approximately one-
third of the world population is infected with MTB, and 9.6
million people were infected and 1.5 million died from TB world-
wide in 2014 [1]. The high prevalence of multidrug-resistant MTB
(MDR-MTB) and the emergence of extensively drug-resistant MTB
(XDR-MTB), together with coinfection with Human Immunodefi-
ciency Virus (HIV), have intensified the need for new anti-TB drugs
[2e4]. Bedaquiline (an ATP synthase inhibitor) was, for the first
time since 1970s, approved by the US FDA for clinical management
of MDR-TB in 2012 [5], but some adverse events have been noted
[6]. Therefore, it is urgent to identify new molecules with alterna-
tive scaffolds as effective anti-TB drug candidates.
strains by targeting the QcrB subunit of the menaquinol cyto-
chrome c oxidoreductase (bc1 complex) [8,11]. Structureeactivity
relationship (SAR) studies of IPAs demonstrated that the carbox-
amide linker with the N-benzylic group is critical for anti-
mycobacterial activity [7]. However, many 2,6-dimethyl IPAs
bearing a N-(2-phenoxy)ethyl moiety were also found to demon-
strate highly potent activity (MIC: 0.025e0.054 mg/mL) against both
drug-sensitive MTB and MDR-MTB strains in our lab. Among them,
IMB-1402 (Fig. 1) displays acceptable safety and pharmacokinetic
properties [12]. This suggests that other 3-carboxamide linkers
between the imidazo[1,2-a]pyridine core and the benzene ring
would be tolerated within the SAR of this IPA series. Accordingly, a
series of novel 2,6-/2,7-dimethyl IPAs bearing a variety of different
linkers were designed and synthesized as new anti-TB agents in
this study (Scheme 2). Our primary objective was to identify
alternative linkers with potent antimycobacterial activity. A pre-
liminary SAR study was also explored to facilitate the further
development of IPAs.
Recently, imidazo[1,2-a]pyridine-3-carboxamides (IPAs) as TB
antibiotics have garnered great interest. Two candidates Q203
* Corresponding author.
** Corresponding author.
E-mail addresses: lmllyx@126.com (M. Liu), luyu4876@hotmail.com (Y. Lu).
http://dx.doi.org/10.1016/j.ejmech.2017.05.044
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.

118
K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
Fig. 1. Structures of Q203, ND-09759 and IMB-1402.
2. Results and discussion
piperazines 22a, b and 4-(4-fluorophenyl) piperidine 23 in the
presence of Bis-(2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl)
2.1. Chemistry
and triethylamine (Et3N) gave target compounds 24-33 (Scheme 2).
Detailed synthetic pathways to amine derivatives 3, 4, 8a-l, 9a-
d, 13a-b, 14a-b, 16a-i, and 18 which are commercially unavailable
are depicted in Scheme 1. Coupling of 4-bromophenol with hydroxy
phthalimide 1, 2 in the presence of diethyl azodicarboxylate (DEAD)
and PPh3 followed by treatment with hydrazine hydrate in ethanol
yielded amine 3, 4. Treatment of anilines 5a-l with compounds 6, 7
in toluene under reflux condition gave the desired 1, 2-diamines
8a-l and 1,3-diamines 9a-d. Nucleophilic substitution of benzyl
bromides 10 a, b with compounds 11, 12 followed by deprotection
the Boc-group furnished N-benzylethane-1,2-diamines 13a, b and
2-(benzyloxy)ethan-1-amines 14a,b. Buchwald-Hartwig coupling
of bromobenzenes 15a-i with piperazine in toluene afforded
compounds 16a-i. Condensation of compound 16a with N-(2-
bormoethyl)phthalimide 17, and then treatment of the resulting
condensate with hydrazine hydrate in ethanol yielded 2-(4-
phenylpiperazin-1-yl)ethan-1-amine 18.
2.2. Pharmacology
The target compounds 24-33 were initially screened for in vitro
activity against MTB H37Rv ATCC 27294 strain using the Microplate
Alamar Blue Assay (MABA) [14,15]. The minimum inhibitory con-
centration (MIC) is defined as the lowest concentration effecting a
reduction in fluorescence of >90% relative to the mean of replicate
bacterium-only controls. The MIC values of the compounds along
with isoniazid (INH) and rifampicin (RFP) for comparison are pre-
sented in Table 1.
Synthesized compound 25 exhibits significantly reduced activ-
ity (MIC: 0.62
mM) compared to IMB-1402 (24, MIC: 0.038 mM),
suggesting that ethyl seems to be more favorable for activity than
propyl. Therefore, structural modifications were focused on the N-
(2-phenoxy)ethyl linker in this study. First, the linker was replaced
by the isostere N-(2-phenylamino)ethyl one giving compounds
26a-k, and SAR of the substitution on the benzene ring was
investigated. It is clear that the anti-MTB potency is visibly influ-
enced by the nature and position of the substitution on the benzene
ring. For example, introduction of one or two halogen atoms on the
Core acids 21a, b were obtained from 2-aminopyridines 19a, b in
two steps using our published procedures [13]. Direct amidation of
the acids 21a, b with the above amines 3, 4, 8a-l, 9a-d,13a, b, 14a, b,
16a-i, 18 and commercially available 1-(pyridine-2/4-yl)
Scheme 1. Synthesis of compounds 3, 4, 8a-l, 9a-d, 13a-b, 14a-b, 16a-i, and 18.

K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
119
Scheme 2. Synthesis of target compounds 24e31.
benzene ring does not much affect the activity (26b-e vs 26a). The
presence of electron-donating groups leads to obviously enhanced
potency. Compounds with a methoxyl group 26g or a tert-butyl one
26h at the para-position demonstrate the strongest activity with
nitrogen of the piperazine ring. The activity of the molecule (31)
could be enhanced through introduction of various groups on the
benzene ring, extensive SAR studies are currently carried out in our
lab and the study results will be reported in due course.
the MIC values of 0.044
pound 26f with two methyl groups at the para- and meta-positions
shows also potent activity (MIC: 0.18 M). Conversely, introduction
m
M and 0.041
m
M, respectively, and com-
Compounds 24, 26g and 26h were further evaluated against two
clinical isolated 11168 and 9160 MDR strains resistant to both of
INH and RFP. It is shown that the MIC values of compounds 26g and
m
of an electron-withdrawing group is detrimental. For instance,
when a trifluoromethyl group is merged to the meta-position, the
26h are much higher than 24 (MIC: <0.041e0.20
two MDR strains, but both of them display good activity (MIC:
0.57e2.64 M). The cytotoxic potential of compounds 26g and 26h
mM) against these
resulting compound 26k (MIC: 5.31
mM) is 6-fold less potent than
m
26a, and introduction of a nitro group (26i) or a trifluoromethyl one
(26j) at the para-position leads to complete loss of activity. These
results indicate that electron-donating groups are preferred over
electron-withdrawing ones or halogens.
was also investigated in a mammalian Vero cell line. The results are
shown in Table 2. Neither of the tested compounds is toxic in the
cell line, and they have acceptable safety indices against MTB
H37Rv with the SI values of 4395 and 1405, respectively.
Secondly, compounds with a N-(3-phenylamino)propyl moiety
27a-d were designed and synthesized. As expected, compounds
27a and 27c are significantly less active than the corresponding N-
2-(phenylamino)ethyl ones 26a and 26h, respectively, and com-
pound 27d is inactive. And, surprise, compound 27b displays
3. Conclusion
In conclusion, we have rediscovered 2,6-dimethyl-N-(2-
phenylamino)ethyl IPA with an electron-donating group on the
benzene ring as a potent scaffold. Compounds 26g and 26h display
slightly better activity (MIC: 1.47
mM) than 26b (MIC: 1.53 mM).
Moreover, the impact of the position of the methyl group on the
pyridine ring of the cores was also investigated and the 6-position
was identified to be optimal for substitution (26g vs 26l, 27a vs 27e,
27c vs 27f). In further modifications, it is shown that replacement of
the phenyl moiety with the corresponding benzyl one significantly
decreases the activity by 15e60-fold (28a vs 26a, 28b vs 26d, 29b vs
24).
excellent to good activity (MIC: 0.041e2.64 mM) against both drug-
sensitive MTB strain H37Rv and drug-resistant clinical isolates.
Moreover, N-[2-(piperazin-1-yl)]ethyl moiety was also identified as
a potentially alternative linker between the IPA core and the ben-
zene ring, and extensive SAR studies of compound 31 (MIC: 0.66 mM
against MTB H37Rv) having the advantage of improving the
aqueous solubility are currently carried out in our lab.
Finally, the N-2-(phenylamino)ethyl linker was replaced by
phenyl/pyridyl heterocyclic amines (piperazine, piperidine) and
none of the resulting compounds 30a-i, 32a,b and 33 demonstrate
4. Experimental protocols
any inhibition (MIC: 43.47 - > 90
Interestingly, replacement of the anilino group of 26a by 4-
phenylpiperazinyl one (31) remains good activity (MIC: 0.66 M).
It is clear that compound 31 has the advantage of improving the
aqueous solubility through protonation of the tertiary amino
mM).
4.1. Chemistry
m
Melting points were determined in open capillaries and are
uncorrected. 1H NMR spectra were determined on a Varian
Mercury-400 spectrometer in DMSO-d6 or CDCl3 using

120
K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
Table 1
Table 2
Structures and in vitro activity of 24e33 against MTB H37Rv ATCC 27294.
In vitro activity against MDR-MTB strains, and cytotoxicity of selected compounds.
SIc
b
Compd.
MIC (
m
M)
CC50
(
m
M)
MDR-MTB11168a
MDR-MTB9160a
24
<0.041
1.47
1.37
>291
>57
0.20
2.64
0.57
>291
>57
NT
e
26g
26h
INH
RFP
193.38 18.01
57.63 1.54
NT
NT
4395
1405
e
Compd.
W
MIC (
m
M) Compd.
W
MIC (mM)
e
24
0.038
27f
10.58
INH: isoniazid; RFP: rifampicin; NT: not tested.
(IMB-1402)
a
MDR-MTB11168 and MDR-MTB9160 were isolated from patients in Beijing
ChestHospital.
25
0.62
27g
>87
b
c
CC50: 50% cytotoxic concentration on Vero cell line.
SI: selectivity index for MTB H37Rv ATCC 27294.
26a
26b
0.81
1.53
28a
28b
49.61
9.97
4.2. Synthesis
4.2.1. General synthesis procedure for the synthesis of compound 3,
4
To a stirred solution of 4-bromophenol (3.46 g, 20 mmol), Ph3P
(7.86 g, 30 mmol) and compound 1, 2 (20 mmol) in anhydrous THF
(50 mL) was added dropwise DEAD (4.7 mL, 30 mmol) at 0 ꢀC over
15 min. The mixture was stirred overnight and concentrated. The
26c
26d
26e
26f
26g
26h
26i
0.76
0.64
1.39
0.18
0.044
0.041
>90
29a
29b
30a
30b
30c
30d
30e
1.93
0.62
95.42
90.35
>90
residue
was
purified
by
column
chromatography
(hexane:EtOAc ¼ 3: 1) to give a white solid (22e34%).
To a stirred solution of above solide (5 mmol) in ethanol (20 mL)
was added hydrazine hydrate (0.6 mL, 85%, 10 mmol) at room
temperature. The mixture was refluxed for 3 h, cooled to room
temperature and filtered. The filtrate was poured into DCM
(100 mL) and washed by saturated brine (50 mL), dried over
anhydrous MgSO4, filtered, and concentrated to give the crude
compounds 3, 4 (yield 70e80%) as brown oils which were used
directly in the next step.
43.47
>77
26j
42.55
30f
>86
4.2.2. General synthesis procedure for the synthesis of compounds
8a-l and 9a-d
26k
26l
5.31
30g
30h
45.98
To a stirred solution of 5a-l (21 mmol) in anhydrous toluene
(40 mL) was added compounds 6, 7 (7 mmol) at room temperature.
The mixture was refluxed for 5 h, cooled to room temperature and
filtered. The filtered solid was treated with NaOH solution (1 M,
50 mL) and extracted by DCM (50 mL ꢁ 3). The combined extraction
was dried over anhydrous MgSO4 and filtered. The filtration was
concentrated to yield the crude compounds 8a-l, 9a-d which were
not further purified and used directly for the next step.
47.31
>87
27a
27b
6.21
1.47
30i
31
84.43
0.66
27c
27d
1.32
32a
32b
95.04
4.2.3. General synthesis procedure for compounds 13a-b and 14a-b
To a stirred solution of compounds 11, 12 in acetonitrile was
added potassium carbonate and benzyl bromides 10a, b. The
mixture was refluxed for 3 h, cooled to room temperature and
concentrated. The residue was treated with EtOAc, washed with
water and saturated brine, dried over anhydrous MgSO4, filtered
and concentrated. The residue was purified by silica gel column
(DCM: MeOH ¼ 50: 1) to yield oils.
>87
>95
27e
RIP
12.43
0.071
33
90.33
0.36
/
INH
/
INH: isoniazid; RFP: rifampicin.
To a solution of above oils in DCM was added TFA at room
temperature. The mixture was concentrated to afford the crude
compounds 13a-b, 14a-b which were not further purified and used
directly for the next step.
tetramethylsilane as an internal standard. Electrospray ionization
(ESI) mass spectra and high resolution mass spectra (HRMS) were
obtained on an MDSSCIEX Q-Tap mass spectrometer. Fast Atom
Bombardment (FAB) mass spectra and high resolution mass spectra
(HRMS) were obtained on a MICROMASS AutoSpec Ultima-TOF
mass spectrometer. The reagents were all of analytical grade or
chemically pure. TLC was performed on silica gel plates (Merck,
ART5554 60F254).
4.2.4. General synthesis procedure for compounds 16a-i
To a stirred solution of piperazine and t-BuONa in anhydrous
toluene was added Pd(OAc)2 and BINAP in anhydrous toluene un-
der argon at room temperature, and the resulting mixture was
stirred for 15 min at the same temperature. To the reaction was
added bromobenzenes 15a-i, and the mixture was refluxed for 20 h.

K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
121
The mixture was cooled to room temperature, filtered through
celite. The filtrate was concentrated. The residue was treated with
EtOAc, extracted by HCl solution (1 N, 20 mL ꢁ 2). The water phase
was adjusted to pH 7 by NaOH solution (1 N) at 0 ꢀC, extracted by
EtOAc. The combined organic phase was washed by water and
saturated brine, dried over anhydrous MgSO4, and filtered. The
filtrate was concentrated to yield compounds 16a-i as yellow oils
which were not further purified and used directly for the next step.
111.82, 65.77, 35.95, 28.90, 17.77, 15.60; MS-ESI (m/z): 402.1, 404.1
(M þ H)þ.
4.2.6.3. 2,6-dimethyl-N-(2-(phenylamino)ethyl)imidazo [1,2-a]pyri-
dine-3- carboxamide 26a. According to the general procedure,
employing compound 21a and 8a afforded compound 26a as a
white solid (45%), mp: 127e129 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d
8.86 (s, 1H), 7.83e7.79 (m, 1H), 7.47 (d, J ¼ 9.0 Hz, 1H), 7.23 (dd,
J ¼ 9.0, 1.5 Hz, 1H), 7.10e7.06 (m, 2H), 6.65e6.61 (m, 2H), 6.53 (t,
J ¼ 7.2 Hz, 1H), 5.73 (s, 1H), 3.51e3.46 (m, 2H), 3.28e3.23 (m, 2H),
4.2.5. Synthesis of compound 18
2.54 (s, 3H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 162.29,147.97,
To a stirred solution of compound 16a (638 mg, 3.94 mmol) in
acetonitrile (20 mL) was added potassium carbonate (545 mg,
3.94 mmol) and compound 17 (1.0 g, 3.94 mmol). The mixture was
refluxed for 3 h, cooled to room temperature and concentrated. The
residue was treated with EtOAc, washed with water and saturated
brine, dried over anhydrous MgSO4, filtered and concentrated. The
residue was treated with EtOH (10 mL) to yield a yellow solid
(1.06 g, 80%) which was not further purified and used directly for
the next step.
To a stirred solution of above solid (1.06 g, 3.15 mmol) in ethanol
(20 mL) was added hydrazine hydrate (0.6 mL, 85%, 10 mmol) at
room temperature. The mixture was refluxed for 3 h, cooled to
room temperature and filtered. The filtrate was poured into DCM
(50 mL) and washed by saturated brine, dried over anhydrous
MgSO4, filtered, and concentrated to give the title compound 18
(210 mg, 32%) as a white solid. 1H NMR (500 MHz, DMSO-d6)
145.32, 145.11, 130.17, 129.51, 126.03, 123.17, 118.03, 115.76, 115.16,
113.01, 44.16, 39.22, 18.50, 16.72; MS-ESI (m/z): 309.20 (M þ H)þ.
4.2.6.4. N-(2-((4-fluorophenyl)amino)ethyl)-2,6-dimethylimidazo
[1,2-a]pyridine-3- carboxamide 26b. According to the general pro-
cedure, employing compound 21a and 8b afforded compound 26b
as a white solid (20.2%), mp: 138e140 ꢀC; 1H NMR (400 MHz,
DMSO-d6)
d
8.86 (s, 1H), 7.83 (t, J ¼ 5.6 Hz, 1H), 7.48 (d, J ¼ 9.2 Hz,
1H), 7.25 (dd, J ¼ 9.2, 1.2 Hz, 1H), 6.93 (t, J ¼ 8.8 Hz, 2H), 6.72e6.56
(m, 2H), 3.48 (dd, J ¼ 12.8, 6.4 Hz, 2H), 3.23 (t, J ¼ 6.4 Hz, 2H), 2.54
(s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 161.13, 154.10
(d, J ¼ 229 Hz) 145.40, 144.73, 143.76, 129.29, 124.78, 122.04, 115.65,
115.30 (d, J ¼ 87.2 Hz), 112.61, 112.54, 42.87, 38.26, 17.78, 15.61; MS-
ESI (m/z): 327.14 (M þ H)þ.
d
7.21e7.15 (m, 2H), 6.90e6.85 (m, 2H), 6.75e6.73 (m, 1H), 3.39 (s,
4.2.6.5. N-(2-((2-fluorophenyl)amino)ethyl)-2,6-dimethylimidazo
[1,2-a]pyridine-3- carboxamide 26c. According to the general pro-
cedure, employing compound 21a and 8c afforded compound 26c
as a white solid (26%),mp: 118e120 ꢀC; 1H NMR (500 MHz, CDCl3)
8H), 3.06e2.88 (m, 2H), 2.50e2.38 (m, 2H), 1.80 (m, 2H); MS-ESI
(m/z):206.2 (M þ H)þ.
4.2.6. General procedure for the synthesis of target compounds (24,
25, 26a-l, 27a-g, 28a,b, 29a,b, 30a-i, 31, 32a,b, 33)
d
9.16 (s, 1H), 7.51 (d, J ¼ 9.0 Hz, 1H), 7.27e7.20 (m, 2H), 6.92 (d,
J ¼ 7.6 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J ¼ 8.2 Hz, 1H), 6.19 (s, 1H), 4.49
To a stirred solution of compounds 21a, b (0.5 mmol) in anhy-
drous DCM (20 mL) was added BOP-Cl (0.6 mmol), Et3N (1.5 mmol)
and the amino parts (3, 4, 8a-l, 9a-d, 13a,b, 14a,b, 16a-i, 18, 22a,b
and 23) at room temperature. The mixture was stirred overnight at
the same temperature, and washed by H3PO4 solution (1%), satu-
rated NaHCO3 solution and brine, dried over anhydrous MgSO4,
filtered, and concentrated. The residue was purified by Flash col-
umn chromatography (DCM/MeOH, 0e10%) to afford the crude
target compounds as yellow solids. The solid was further purified
by treating with EtOAc and hexane (11 mL, 1: 10) to yield the target
compounds (24, 25, 26a-l, 27a-g, 28a,b, 29a,b, 30a-i, 31, 32a,b, 33).
(s, 1H), 3.68e3.63 (m, 2H), 3.33e3.29 (m, 2H), 2.68 (s, 3H), 2.37 (s,
3H); 13C NMR (100 MHz, DMSO-d6)
d 161.17, 155.37, 153.08, 145.39,
144.87, 143.84, 129.18, 124.76, 121.96, 115.63, 115.47, 115.42, 115.20,
112.61, 112.54, 42.88, 38.26, 17.78, 15.67; MS-ESI (m/z): 327.13
(M þ H)þ.
4.2.6.6. N-(2-((4-bromophenyl)amino)ethyl)-2,6-dimethylimidazo
[1,2-a]pyridine-3- carboxamide 26d. According to the general pro-
cedure, employing compound 21a and 8d afforded compound 26d
as a white solid (25%), mp: 164e167 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.20 (s, 1H), 7.48 (d, J ¼ 9.0 Hz, 1H), 7.28e7.26 (m, 1H), 7.25e7.23
(m, 1H), 7.20 (dd, J ¼ 9.1, 1.6 Hz, 1H), 6.57e6.53 (m, 2H), 6.15 (s, 1H),
4.2.6.1. N-(2-(4-bromophenoxy)ethyl)-2,6-dimethylimidazo [1,2-a]
pyridine-3- carboxamide 24. According to the general procedure,
employing compound 21a and 3 afforded compound 24 as a white
4.24 (s, 1H), 3.77e3.73 (m, 2H), 3.42e3.38 (m, 2H), 2.64 (s, 3H), 2.37
(s, 3H); 13C NMR (150 MHz, DMSO-d6)
d 161.17, 147.94, 144.88,
solid (26.9%),mp: 170e172 ꢀC; 1H NMR (600 MHz, CDCl3)
d 9.19 (s,
143.84, 131.42, 129.16, 124.76, 121.93, 115.60, 115.44, 113.80, 106.15,
42.26, 38.11, 17.79, 15.68; MS-ESI (m/z): 387.09 (M þ H)þ; HRMS-ESI
1H), 7.48 (t, J ¼ 4.8 Hz, 1H), 7.17 (dd, J ¼ 14.4, 9.0 Hz, 2H), 6.79 (d,
(m/z): Calcd. for
387.0814.
C
18H20BrN4O (M
þ
H)þ: 387.0815; Found:
J ¼ 9.0 Hz, 1H), 4.16 (t, J ¼ 6.0 Hz, 2H), 3.92 (dd, J ¼ 12.6, 6.6 Hz, 2H),
2.69 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 161.78,157.66,
145.35, 145.13, 132.60, 130.26, 126.06, 123.26, 116.36, 115.81, 115.17,
113.68, 67.21, 38.80, 18.49, 16.68; MS-ESI (m/z): 388.22 (M þ H)þ;
HRMS-ESI (m/z): Calcd. for C18H19BrN3O2 (M þ H)þ: 388.06552;
Found: 388.06665.
4.2.6.7. N-(2-((4-chloro-3-fluorophenyl)amino)ethyl)-2,6-
dimethylimidazo [1,2-a] pyridine-3-carboxamide 26e.
According to the general procedure, employing compound 21a and
8e afforded compound 26e as white solid (40.0%),mp:
180e183 ꢀC; 1H NMR (500 MHz, CDCl3)
9.26 (d, J ¼ 7.0 Hz, 1H),
a
4.2.6.2. N-(3-(4-bromophenoxy)propyl)-2,6-dimethylimidazo [1,2-a]
pyridine-3- carboxamide 25. According to the general procedure,
employing compound 21a and 4 afforded compound 25 as a white
d
7.32 (s, 1H), 6.96e6.92 (m, 1H), 6.77 (d, J ¼ 6.8 Hz, 1H), 6.66e6.62
(m, 1H), 6.50e6.45 (m, 1H), 6.12 (s, 1H), 4.26 (s, 1H), 3.77e3.72 (m,
2H), 3.38e3.33 (m, 2H), 2.64 (s, 3H), 2.42 (s, 3H); 13C NMR
solid (30%), mp: 195e197 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d 8.77
(s, 1H), 7.87 (t, J ¼ 5.6 Hz, 1H), 7.46 (d, J ¼ 8.4 Hz, 2H), 7.43 (d,
J ¼ 9.2 Hz, 1H), 7.31 (d, J ¼ 8.4 Hz, 2H), 6.90 (dd, J ¼ 9.2, 1.6 Hz, 1H),
4.06 (s, 2H), 3.47 (t, J ¼ 5.6 Hz, 2H), 2.51 (s, 3H), 2.29 (s, 3H),
(100 MHz, DMSO-d6)
d
161.21, 148.97 (d, J ¼ 232 Hz), 146.28, 144.89,
143.86, 129.18, 124.77, 121.94, 119.56, 119.38, 117.05, 116.84, 115.61,
115.46,111.92,111.65,111.59, 42.49, 38.11,17.79,15.67; MS-ESI (m/z):
361.04 (M þ H)þ; HRMS-ESI (m/z): Calcd. for C18H19FClN4O
(M þ H)þ: 361.1225; Found: 361.1223.
2.03e198 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 161.78, 157.66,
144.61, 143.76, 132.09, 129.08, 124.62, 121.88, 116.71, 115.76, 115.45,

122
K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
4.2.6.8. N-(2-((3,4-dimethylphenyl)amino)ethyl)-2,6-
dimethylimidazo [1,2-a] pyridine-3-carboxamide 26f. According to
the general procedure, employing compound 21a and 8f afforded
compound 26f as a white solid (23.8%),mp: 147e149 ꢀC; 1H NMR
general procedure, employing compound 21a and 8k afforded
compound 26k as a white solid (19.8%), mp: 169e170 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
9.16 (s,1H), 7.51 (d, J ¼ 9.1 Hz,1H), 7.27e7.20 (m,
2H), 6.92 (d, J ¼ 7.6 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J ¼ 8.2 Hz, 1H), 6.19
(500 MHz, CDCl3)
d
9.18 (s, 1H), 7.52 (d, J ¼ 9.0 Hz, 1H), 7.21 (dd,
(s, 1H), 4.49 (s, 1H), 3.68e3.63 (m, 2H), 3.33e3.29 (m, 2H), 2.68 (s,
J ¼ 9.1, 1.5 Hz, 1H), 6.95 (d, J ¼ 8.1 Hz, 1H), 6.52 (d, J ¼ 2.3 Hz, 1H),
6.49e6.45 (m, 2H), 3.77e3.72 (m, 2H), 3.46e3.42 (m, 2H), 2.64 (s,
3H), 2.37 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H); 13C NMR (125 MHz, CDCl3)
3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 162.27,147.94,145.29,
145.14, 130.04, 129.39, 125.96, 124.77, 123.03, 117.98, 115.71, 115.14,
112.88, 44.15, 39.19, 18.48, 16.69; MS-ESI (m/z): 377.08 (M þ H)þ;
HRMS-ESI (m/z): Calcd. for C19H20F3N4O (M þ H)þ: 377.15837;
Found: 377.15815.
d
162.20, 146.07, 145.31, 145.09, 137.63, 130.51, 130.10, 126.24,
126.05, 123.10, 115.76, 115.20, 115.07, 110.59, 44.38, 39.31, 20.15,
18.81, 18.50, 16.72; MS-ESI (m/z): 337.10 (M þ H)þ; HRMS-ESI (m/z):
Calcd. for C20H25N4O (M þ H)þ: 337.20229; Found: 337.20186.
4. 2 . 6 .14 . N- (2- ((4 -m et hox y phe nyl )a m ino )e t hyl )- 2, 6 -
dimethylimidazo [1,2-a] pyridine-3-carboxamide 26l. According to
the general procedure, employing compound 21b and 8g afforded
compound 26l as a white solid (26.9%),mp: 147e149 ꢀC; 1H NMR
4.2.6.9. N-(2-((4-methoxyphenyl)amino)ethyl)-2,6-dimethylimidazo
[1,2-a] pyridine-3-carboxamide 26g. According to the general pro-
cedure, employing compound 21a and 8g afforded compound 26g
as a white solid (33.9%), mp: 119e122 ꢀC; 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
9.20 (s, 1H), 7.48 (d, J ¼ 9.0 Hz, 1H), 7.19 (d,
J ¼ 8.6 Hz, 2H), 7.18 (dd, J ¼ 9.1, 1.3 Hz, 1H), 6.79 (d, J ¼ 8.6 Hz, 2H),
6.69 (d, J ¼ 8.6 Hz, 2H), 6.25 (brs, 1H), 3.76 (s, 3H), 3.76e3.73 (m,
2H), 3.41e3.39 (m, 2H), 2.61 (s, 3H), 2.36 (s, 3H); 13C NMR
d
9.21 (s, 1H), 7.47 (d, J ¼ 9.1 Hz, 1H), 7.18 (dd, J ¼ 9.1, 1.5 Hz, 1H),
6.81e6.76 (m, 2H), 6.68e6.63 (m, 2H), 6.22 (s, 1H), 3.75e3.72 (m,
5H), 3.42e3.38 (m, 2H), 2.63 (s, 3H), 2.36 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) d 161.15, 150.72, 144.84, 143.83, 142.94, 129.16,
(100 MHz, DMSO-d6)
d
161.15, 150.71, 144.83, 143.83, 142.93, 129.16,
124.77, 121.95, 115.68, 115.45, 114.69, 112.99, 55.31, 43.30, 38.45,
124.76, 121.95, 115.68, 115.46, 114.69, 112.99, 55.31, 43.29, 38.44,
17.78, 15.67; MS-ESI (m/z): 339.07 (M þ H)þ; HRMS-ESI (m/z):
Calcd. for C19H23N4O2 (M þ H)þ: 339.18155; Found: 339.18121.
17.78, 15.67; MS-ESI (m/z): 339.1 (M þ H)þ.
4.2.6.15. 2,6-dimethyl-N-(3-(phenylamino)propyl)imidazo
[1,2-a]
pyridine-3- carboxamide 27a. According to the general procedure,
employing compound 21a and 9a afforded compound 27a as a
white solid (20.2%), mp: 156e158 ꢀC; 1H NMR (400 MHz, DMSO-d6)
4.2.6.10. N-(2-((4-(tert-butyl)phenyl)amino)ethyl)-2,6-
dimethylimidazo
According to the general procedure, employing compound 21a and
8h afforded compound 26h as white solid (26.9%),mp:
147e149 ꢀC; 1H NMR (500 MHz, CDCl3)
9.21 (s, 1H), 7.47 (d,
J ¼ 9.0 Hz, 1H), 7.22 (d, J ¼ 8.6 Hz, 2H), 7.18 (dd, J ¼ 9.1, 1.3 Hz, 1H),
6.65 (d, J ¼ 8.6 Hz, 2H), 6.18 (s, 1H), 3.76e3.73 (m, 2H), 3.46e3.42
(m, 2H), 2.1 (s, 3H), 2.36 (s, 3H), 1.27 (s, 9H); 13C NMR (100 MHz,
[1,2-a]
pyridine-3-carboxamide
26h.
d
8.78 (s, 1H), 7.85 (t, J ¼ 5.6 Hz,1H), 7.46 (d, J ¼ 9.2 Hz,1H), 7.22 (dd,
a
J ¼ 9.2, 1.6 Hz, 1H), 6.55e6.58 (d, J ¼ 9.5 Hz, 2H), 6.51 (t, J ¼ 9.0 Hz,
1H), 5.58 (t, J ¼ 5.6 Hz, 1H), 3.43e3.88 (m, 2H), 3.12e3.07 (m, 2H),
2.53 (s, 3H), 2.29 (s, 3H), 1.87e1.80 (m, 2H); 13C NMR (100 MHz,
d
DMSO-d6)
d 161.01, 148.91, 144.57, 143.54, 129.07, 128.88, 124.59,
121.89, 115.85, 115.48, 111.97, 40.58, 36.94, 28.77, 17.78, 15.57; MS-
DMSO-d6)
d
161.17, 146.28, 144.86, 143.84, 137.86, 129.12, 125.51,
ESI (m/z): 323.2 (M þ H) þ
.
124.77, 121.91, 115.66, 115.45, 111.67, 42.66, 38.42, 33.40, 31.46,
17.78, 15.68; MS-ESI (m/z): 365.09 (M þ H)þ; HRMS-ESI (m/z):
Calcd. for C22H29N4O (M þ H)þ: 365.23359; Found: 365.23341.
4.2.6.16. N-(3-((4-fluorophenyl)amino)propyl)-2,6-dimethylimidazo
[1,2-a]pyridine -3-carboxamide 27b. According to the general pro-
cedure, employing compound 21a and 9b afforded compound 27b
as a white solid (20.2%), mp: 170e172 ꢀC; 1H NMR (400 MHz,
4.2.6.11. 2,6-dimethyl-N-(2-((4-nitrophenyl)amino)ethyl)imidazo
[1,2-a]pyridine -3-carboxamide 26i. According to the general pro-
cedure, employing compound 21a and 8i afforded compound 26i as
a white solid (42.7%),mp: 238e240 ꢀC; 1H NMR (500 MHz, CDCl3)
DMSO-d6)
d
8.78 (s, 1H), 7.84 (t, J ¼ 5.6 Hz, 1H), 7.46 (d, J ¼ 9.2 Hz,
1H), 7.23 (d, J ¼ 1.6 Hz, 1H), 7.21 (dd, J ¼ 9.2, 1.6 Hz, 1H), 6.58e6.53
(m, 2H), 5.53 (s, 1H), 3.43e3.38 (m, 2H), 3.07 (t, J ¼ 5.2 Hz, 2H), 2.53
(s, 3H), 2.30 (s, 3H), 1.87e1.79 (m, 2H); 13C NMR (100 MHz, DMSO-
d
9.19 (s, 1H), 8.08 (d, J ¼ 9.1 Hz, 2H), 7.53 (d, J ¼ 9.0 Hz, 1H), 6.60 (d,
J ¼ 9.2 Hz, 2H), 6.43 (s, 1H), 5.75 (s, 1H), 5.30 (s, 1H), 3.86e3.81 (m,
d6) d 161.00, 155.30, 153.00, 145.66, 144.53, 143.74, 129.09, 124.59,
2H), 3.53e3.47 (m, 2H), 2.70 (s, 3H), 2.41 (s, 3H); 13C NMR
121.90, 115.84, 115.48, 115.33, 115.11, 112.69, 112.62, 41.26, 36.94,
þ
(100 MHz, DMSO)
d
161.76, 155.06, 145.43, 144.35, 136.19, 129.71,
28.72, 17.77, 15.57; MS-ESI (m/z): 341.2 (M þ H)
.
126.73, 125.22, 122.45, 115.97, 42.22, 38.52, 18.24, 16.14; MS-ESI (m/
z): 354.06 (M þ H)þ; HRMS-ESI (m/z): Calcd. for C18H20N5O3
(MþH)þ: 354.15607; Found: 354.15589.
4.2.6.17. N-(3-((4-(tert-butyl)phenyl)amino)propyl)-2,6-
dimethylimidazo [1,2-a] pyridine-3-carboxamide 27c.
According to the general procedure, employing compound 21a and
9c afforded compound 27c as white solid (26.9%), mp:
115e117 ꢀC; 1H NMR (400 MHz, DMSO-d6)
8.79 (s, 1H), 7.84 (t,
4.2.6.12. 2,6-dimethyl-N-(2-((4-(trifluoromethyl)phenyl)amino)
ethyl)imidazo [1,2-a]pyridine-3-carboxamide 26j. According to the
general procedure, employing compound 21a and 8j afforded
compound 26j as a white solid (19.8%),mp: 155e158 ꢀC; 1H NMR
a
d
J ¼ 5.6 Hz, 1H), 7.46 (d, J ¼ 9.2 Hz, 1H), 7.23 (dd, J ¼ 9.2, 1.6 Hz, 1H),
7.08 (d, J ¼ 8.4 Hz, 2H), 6.51 (d, J ¼ 8.4 Hz, 2H), 5.41 (s, 1H),
3.43e3.38 (m, 2H), 3.10e3.06 (m, 2H), 2.54 (s, 3H), 2.29 (s, 3H),
1.86e1.79 (m, 2H), 1.20 (s, 9H); 13C NMR (100 MHz, DMSO-d6)
(400 MHz, DMSO-d6)
d
8.85 (s, 1H), 7.83 (t, J ¼ 5.6 Hz, 1H), 7.47 (d,
J ¼ 9.2 Hz, 1H), 7.38 (d, J ¼ 8.4 Hz, 2H), 7.24 (dd, J ¼ 9.2, 1.7 Hz, 1H),
6.74 (d, J ¼ 8.4 Hz, 2H), 6.54 (t, J ¼ 6.4 Hz, 1H), 3.48 (dt, J ¼ 14.4,
7.2 Hz, 2H), 3.39e3.29 (m, 3H), 2.53 (s, 3H), 2.31 (s, 3H); 13C NMR
d
160.99, 146.51, 144.54, 143.75, 137.71, 129.06, 125.45, 124.60,
121.89, 115.84, 115.48, 111.77, 40.79, 39.94, 33.40, 31.48, 28.84, 17.77,
(100 MHz, DMSO-d6)
d
161.22,151.67,144.92,143.85,130.69,129.23,
15.58; MS-ESI (m/z): 379.1 (M þ H)þ.
126.31, 126.27, 124.77, 121.98, 115.59, 115.48, 111.22, 41.78, 38.04,
17.78,15.65; MS-ESI (m/z): 377.08 (M þ H)þ; HRMS-ESI (m/z): Calcd.
for C19H20F3N4O (M þ H)þ: 377.15837; Found: 377.15813.
4.2.6.18. 2,6-dimethyl-N-(3-((4-nitrophenyl)amino)propyl)imidazo
[1,2-a]pyridine -3-carboxamide 27d. According to the general pro-
cedure, employing compound 21a and 9d afforded compound 27d
as a white solid (42.7%),mp: 225e228 ꢀC; 1H NMR (400 MHz,
4.2.6.13. 2,6-dimethyl-N-(2-((3-(trifluoromethyl)phenyl)amino)
ethyl)imidazo [1,2-a]pyridine-3-carboxamide 26k. According to the
DMSO-d6)
d
8.77 (s, 1H), 7.98 (d, J ¼ 9.3 Hz, 2H), 7.85 (t, J ¼ 5.5 Hz,

K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
123
1H), 7.47 (s, 1H), 7.34 (t, J ¼ 5.4 Hz, 1H), 7.22 (dd, J ¼ 9.1, 1.6 Hz, 1H),
6.65 (d, J ¼ 9.3 Hz, 2H), 3.42 (q, J ¼ 6.6 Hz, 2H), 3.26 (dd, J ¼ 12.7,
6.7 Hz, 2H), 2.54 (s, 3H), 2.29 (s, 3H), 1.88 (p, J ¼ 6.8 Hz, 2H); 13C
4.2.6.24. N-(2-(benzyloxy)ethyl)-2,6-dimethylimidazo
[1,2-a]pyri-
dine-3- carboxamide 29a. According to the general procedure,
employing compound 21a and 14a afforded compound 29a as a
NMR (100 MHz, DMSO-d6)
d
161.07, 154.53, 144.63, 143.78, 135.54,
white solid (24.8%), mp: 86e87 ꢀC, 1H NMR (500 MHz, CDCl3)
d 9.17
129.10, 126.26, 124.60, 121.91, 115.78, 115.48, 40.22, 36.74, 28.44,
(s, 1H), 7.46 (d, J ¼ 9.0 Hz, 1H), 7.35e7.27 (m, 5H), 7.16 (d, J ¼ 9.0 Hz,
17.76, 15.62; MS-ESI (m/z): 368.1 (M þ H)þ.
J ¼ 1.0 Hz, 1H), 6.24 (s, 1H), 4.56 (s, 2H), 3.72e3.68 (m, 4H), 2.64 (s,
3H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 161.7, 145.16, 144.98,
137.80, 130.06, 128.64, 127.97, 126.05, 123.05, 115.71, 115.29, 77.41,
4.2.6.19. 2,7-dimethyl-N-(3-(phenylamino)propyl)imidazo
[1,2-a]
77.16, 76.91, 73.45, 68.90, 40.54, 39.21, 18.47, 16.60; MS-ESI (m/z):
pyridine-3- carboxamide 27e. According to the general procedure,
employing compound 21b and 9a afforded compound 27e as a
white solid (20.2%), mp: 156e158 ꢀC; 1H NMR (400 MHz, DMSO-d6)
324.20 (M þ H) þ
.
4.2.6.25. N-(2-((4-bromobenzyl)oxy)ethyl)-2,6-dimethylimidazo
[1,2-a]pyridine-3- carboxamide 29b. According to the general pro-
cedure, employing compound 21a and 14b afforded compound 29b
as a white solid (26.9%), mp: 112e114 ꢀC; 1H NMR (400 MHz,
d
8.78 (s, 1H), 7.85 (t, J ¼ 5.6 Hz,1H), 7.46 (d, J ¼ 9.2 Hz, 1H), 7.22 (dd,
J ¼ 9.2, 1.6 Hz, 1H), 6.55e6.58 (d, J ¼ 9.5 Hz, 2H), 6.51 (t, J ¼ 9.0 Hz,
1H), 5.58 (t, J ¼ 5.6 Hz, 1H), 3.43e3.88 (m, 2H), 3.12e3.07 (m, 2H),
2.53 (s, 3H), 2.29 (s, 3H), 1.87e1.80 (m, 2H); 13C NMR (100 MHz,
DMSO-d6)
d
8.77 (s, 1H), 7.84 (t, J ¼ 5.6 Hz, 1H), 7.52 (d, J ¼ 8.4 Hz,
DMSO-d6)
d 161.01, 148.91, 144.57, 143.54, 129.07, 128.88, 124.59,
2H), 7.47 (d, J ¼ 9.2 Hz, 1H), 7.31 (d, J ¼ 8.4 Hz, 2H), 7.24 (dd, J ¼ 9.2,
1.6 Hz, 1H), 4.51 (s, 2H), 3.61 (t, J ¼ 5.6 Hz, 2H), 3.52 (q, J ¼ 5.6 Hz,
2H), 3.32 (s, 1H), 2.51 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz,
121.89, 115.85, 115.48, 111.97, 40.58, 36.94, 28.77, 17.78, 15.57; MS-
ESI (m/z): 323.2 (M þ H) þ
.
DMSO-d6)
d 160.94, 144.71, 143.76, 137.94, 131.12, 129.64, 129.21,
4.2.6.20. N-(3-((4-(tert-butyl)phenyl)amino)propyl)-2,7-
dimethylimidazo [1,2-a] pyridine-3-carboxamide 27f. According to
the general procedure, employing compound 21b and 9c afforded
compound 27f as a white solid (26.9%),mp: 115e117 ꢀC; 1H NMR
124.61, 121.99, 120.45, 115.71, 115.46, 70.99, 68.45, 38.57, 17.77,
15.48; MS-ESI (m/z): 402.1, 404.0 (M þ H) þ
.
4.2.6.26. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-
phenylpiperazin-1-yl) methanone 30a. According to the general
procedure, employing compound 21a and 16a afforded compound
30a as a white solid (23.8%), mp: 120e123 ꢀC; 1H NMR (500 MHz,
DMSO-d6)
6.96e6.93 (m, 2H), 6.83e6.79 (m, 1H), 3.69 (s, 4H), 3.19 (s, 4H), 2.38
(s, 3H), 2.28 (s, 3H); 13C NMR (126 MHz, CDCl3)
162.80, 150.93,
145.45, 144.19, 129.54, 129.37, 124.48, 122.66, 120.84, 116.87, 115.99,
114.97, 63.81, 50.12, 18.34, 15.43; MS-ESI (m/z): 335.20 (M þ H)þ;
HRMS-ESI (m/z): Calcd. for C21H25N4O (MþH)þ: 335.18664; Found:
335.18631.
(400 MHz, DMSO-d6)
d
8.79 (s, 1H), 7.84 (t, J ¼ 5.6 Hz, 1H), 7.46 (d,
J ¼ 9.2 Hz, 1H), 7.23 (dd, J ¼ 9.2, 1.6 Hz, 1H), 7.08 (d, J ¼ 8.4 Hz, 2H),
6.51 (d, J ¼ 8.4 Hz, 2H), 5.41 (s, 1H), 3.43e3.38 (m, 2H), 3.10e3.06
(m, 2H), 2.54 (s, 3H), 2.29 (s, 3H), 1.86e1.79 (m, 2H), 1.20 (s, 9H); 13
C
d
8.28 (s, 1H), 7.46 (d, J ¼ 9.1 Hz, 1H), 7.25e7.18 (m, 3H),
NMR (125 MHz, DMSO-d6)
d 160.99, 146.51, 144.54, 143.75, 137.71,
129.06, 125.45, 124.60, 121.89, 115.84, 115.48, 111.77, 40.79, 39.94,
d
33.40, 31.48, 28.84, 17.77, 15.58; MS-ESI (m/z): 379.1 (M þ H)þ.
4.2.6.21. 2,7-dimethyl-N-(3-((4-nitrophenyl)amino)propyl)imidazo
[1,2-a]pyridine-3- carboxamide 27g. According to the general pro-
cedure, employing compound 21b and 9d afforded compound 27b
as a white solid (42.7%),mp: 225e228 ꢀC; 1H NMR (400 MHz,
4.2.6.27. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(4-
fluorophenyl)piperazin-1-yl) methanone 30b. According to the
general procedure, employing compound 21a and 16b afforded
compound 30b as a white solid (26.5%), mp: 110e112 ꢀC; 1H NMR
DMSO-d6)
d
8.79 (s, 1H), 7.98 (d, J ¼ 5.6 Hz, 2H), 7.79 (t, J ¼ 5.6 Hz,
1H), 7.35e7.32 (m, 2H), 6.84 (d, J ¼ 8.4 Hz, 2H), 6.64 (d, J ¼ 8.4 Hz,
2H), 3.43e3.38 (m, 2H), 3.29e3.23 (m, 2H), 2.54 (s, 3H), 2.29 (s, 3H),
1.86e1.79 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
d 161.08, 154.53,
(500 MHz, DMSO-d6)
d
8.27 (s, 1H), 7.46 (d, J ¼ 9.1 Hz, 1H), 7.19 (dd,
J ¼ 9.1, 1.2 Hz, 1H), 7.09e7.03 (m, 2H), 7.00e6.94 (m, 2H), 3.69 (s,
145.22, 144.86, 137.04, 135.54, 126.28, 115.46, 115.11, 114.52, 110.70,
4H), 3.13 (s, 4H), 2.38 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz,
40.22, 36.73, 28.48, 20.69, 15.67; MS-ESI (m/z): 368.1 (M þ H)þ.
DMSO-d6)
d 161.41, 157.52, 155.18, 147.67, 144.11, 143.11, 129.05,
124.21, 121.89, 117.91, 117.84, 115.48, 115.27, 114.94, 49.60, 45.55,
4.2.6.22. N-(2-(benzylamino)ethyl)-2,6-dimethylimidazo [1,2-a]pyri-
dine-3- carboxamide 28a. According to the general procedure,
employing compound 21a and 13a afforded compound 28a as a
white solid (13.6%),mp:149e151 ꢀC. 1H NMR (400 MHz, DMSO-d6)
44.47, 17.60, 14.78, 8.53; MS-ESI (m/z): 353.2 (M þ H)þ.
4.2.6.28. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(2-
fluorophenyl)piperazin-1-yl) methanone 30c. According to the gen-
eral procedure, employing compound 21a and 16c afforded com-
pound 30c as a white solid (46.1%), mp: 135e138 ꢀC; 1H NMR
d
8.42 (s, 1H), 7.46 (s, 1H), 7.04 (d, J ¼ 5.6 Hz, 2H), 6.88 (m, 4H), 3.54
(s, 2H), 3.13 (d, J ¼ 5.6 Hz, 3H), 2.14 (s, 3H), 2.08 (s, 1H), 1.88 (s, 3H);
13C NMR (100 MHz, DMSO-d6)
161.71, 145.48, 144.33, 129.68,
d
(500 MHz, CDCl3)
d
8.33 (s, 1H), 7.50 (d, J ¼ 9.1 Hz, 1H), 7.16 (dd,
129.37, 128.79, 128.08, 125.26, 122.40, 115.99, 51.87, 47.73, 37.72,
J ¼ 9.1, 1.4 Hz, 1H), 7.10e7.03 (m, 2H), 7.01e6.93 (m, 2H), 3.87 (s,
18.28, 16.25; MS-ESI (m/z): 323.2 (M þ H)þ.
4H), 3.15 (s, 4H), 2.51 (s, 3H), 2.34 (s, 3H); 13C NMR (126 MHz,
CDCl3)
d 162.79, 149.47, 145.54, 144.32, 129.68, 129.22, 125.74,
4.2.6.23. N-(2-((4-bromobenzyl)amino)ethyl)-2,6-dimethylimidazo
[1,2-a]pyridine-3- carboxamide 28b. According to the general pro-
cedure, employing compound 21a and 13b afforded compound 28b
as a white solid (26.9%),mp: 112e114 ꢀC. 1H NMR (600 MHz, DMSO-
124.53, 122.62, 120.16, 118.04, 116.53, 115.93, 114.86, 51.20, 45.43,
18.35, 15.52; MS-ESI (m/z):353.2 (M þ H)þ.
4.2.6.29. (4-(4-chlorophenyl)piperazin-1-yl)(2,6-dimethylimidazo
[1,2-a]pyridin-3-yl) methanone 30d. According to the general pro-
cedure, employing compound 21a and 16d afforded compound 30d
as a white solid (36.5%), mp: 179e181 ꢀC; 1H NMR (500 MHz,
d6)
d
8.79 (s, 1H), 7.59 (t, J ¼ 5.4 Hz, 1H), 7.47 (d, J ¼ 9.0 Hz, 1H), 7.44
(d, J ¼ 8.4 Hz, 4H), 7.31 (d, J ¼ 8.4 Hz, 4H), 7.23 (dd, J ¼ 9.0, 1.2 Hz,
1H), 3.57 (s, 4.8H), 3.45 (dd, J ¼ 12.6, 6.6 Hz, 2H), 3.34 (s, 3H), 2.59 (t,
J ¼ 6.6 Hz, 2H), 2.29 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
d
160.85,
DMSO-d6) d 8.29e8.26 (m, 1H), 8.20e8.17 (m, 2H), 7.47 (d,
144.60, 143.82, 138.67, 131.00, 130.72, 129.15, 124.70, 121.93, 119.87,
J ¼ 9.1 Hz, 1H), 7.22 (dd, J ¼ 9.2, 1.6 Hz, 1H), 6.86e6.83 (m, 2H), 3.67
115.55, 115.47, 56.83, 52.60, 36.65, 17.84, 15.74; MS-ESI (m/z): 401.1,
(s, 4H), 3.44 (s, 4H), 2.37 (s, 3H), 2.29 (s, 3H); 13C NMR (126 MHz,
403.0 (M þ H) þ
.
CDCl3) d 162.88, 149.58, 145.55, 144.33, 129.61, 129.25, 125.75,

124
K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
124.52, 122.71, 118.10, 116.05, 114.90, 50.11, 45.23, 18.36, 15.50; MS-
ESI (m/z): 369.2 (M þ H)þ; HRMS-ESI (m/z): Calcd. for C20H22ClN4O
(MþH)þ: 369.14767; Found: 369.14734.
ESI (m/z):380.2(M þ H)þ; HRMS-ESI (m/z): Calcd. for C20H22N5O3
(M þ H)þ: 380.17172; Found: 380.17136.
4.2.6.35. 2,6-dimethyl-N-(2-(4-phenylpiperazin-1-yl)ethyl)imidazo
[1,2-a]pyridine-3- carboxamide 31. According to the general pro-
cedure, employing compound 21a and 18 afforded compound 31 as
a white solid (28.4%), mp: 138e140 ꢀC; 1H NMR (500 MHz, CDCl3)
4.2.6.30. (4-(4-bromophenyl)piperazin-1-yl)(2,6-dimethylimidazo
[1,2-a]pyridin-3-yl) methanone 30e. According to the general pro-
cedure, employing compound 21a and 16e afforded compound 30e
as a white solid (36.9%), 1H NMR (500 MHz, DMSO-d6)
d
8.28 (s, 1H),
d
9.26 (s, 1H), 7.46 (d, J ¼ 9.1 Hz, 1H), 7.31e7.26 (m, 2H), 7.16 (dd,
7.46 (d, J ¼ 9.1 Hz, 1H), 7.17 (dd, J ¼ 9.1, 1.2 Hz, 1H), 7.13e7.09 (m,
J ¼ 9.1, 1.7 Hz, 1H), 6.97e6.92 (m, 2H), 6.88 (t, J ¼ 7.3 Hz, 1H), 6.70 (s,
1H), 3.66e3.61 (m, 2H), 3.24e3.22 (m, 2H), 2.78e2.66 (m, 11H),
2H), 6.90e6.86 (m, 2H), 3.80 (s, 4H), 3.23 (s, 4H), 2.42 (s, 3H), 2.31
(s, 3H); 13C NMR (125 MHz, CDCl3)
d
162.83, 149.52, 145.45, 144.29,
2.35 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 161.65, 151.15, 145.25,
129.72, 129.30, 125.76, 124.49, 122.64, 117.06, 115.88, 114.76, 50.41,
45.36, 18.40, 15.52; MS-ESI (m/z): 413.2415.1(M þ H)þ; HRMS-ESI
(m/z): Calcd. for C20H22BrN4O (MþH)þ: 413.09715; Found:
413.09687.
145.03, 129.87, 129.27, 126.07, 122.95, 120.08, 116.18, 115.77, 115.33,
56.25, 52.87, 49.46, 35.66, 18.49, 16.96; MS-ESI (m/z): 378.37
(M þ H)þ; HRMS-ESI (m/z): Calcd. for C22H28N5O (M þ H)þ:
378.22884; Found: 378.22857.
4.2.6.31. (4-(2,4-difluorophenyl)piperazin-1-yl)(2,6-dimethylimidazo
[1,2-a] pyridin-3-yl)methanone 30f. According to the general pro-
cedure, employing compound 21a and 16f afforded compound 30f
as a white solid (46.5%), mp: 126e128 ꢀC; 1H NMR (500 MHz,
4.2.6.36. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(pyridin-4-yl)
piperazin-1-yl) methanone 32a. According to the general proced-
ure, employing compound 21a and 22a (commercial available)
afforded compound 32a as a white solid (52.3%).mp: 99e101 ꢀC; 1H
CDCl3)
1H), 6.94e6.88 (m, 1H), 6.85e6.79 (m, 2H), 3.88 (s, 4H), 3.07 (s, 4H),
2.49 (s, 3H), 2.33 (s, 3H); 13C NMR (100 MHz, DMSO)
161.44,
d
8.32 (s, 1H), 7.46 (d, J ¼ 9.1 Hz, 1H), 7.13 (dd, J ¼ 9.1, 1.6 Hz,
NMR (500 MHz, DMSO-d6)
d
8.27 (s,1H), 8.19 (d, J ¼ 5.4 Hz, 2H), 7.47
(d, J ¼ 9.1 Hz, 1H), 7.21 (d, J ¼ 9.1 Hz, 1H), 6.84 (d, J ¼ 5.2 Hz, 2H),
d
3.67 (s, 4H), 3.44 (s, 4H), 2.37 (s, 3H), 2.29 (s, 3H); 13C NMR
158.50 (d, J ¼ 47.6 Hz), 156.11 (d, J ¼ 48.0 Hz), 155.89 (d, J ¼ 37.2 Hz),
153.65 (d, J ¼ 48.8 Hz), 144.20, 143.30, 136.37 (d, J ¼ 12.8 Hz),
128.96, 124.18, 121.83, 120.54, 115.53, 114.86, 111.08, 104.95, 104.69,
104.44, 63.79, 50.82, 44.66, 17.61, 14.84; MS-ESI (m/z):371.2
(M þ H)þ; HRMS-ESI (m/z): Calcd. for C20H21F2N4O (MþH)þ:
371.16779; Found: 371.16746.
(125 MHz, CDCl3) d 162.81, 151.02, 145.48, 144.26, 129.64, 129.33,
124.43, 122.69, 122.62,117.75, 116.20, 54.08, 49.73, 18.39,15.52; MS-
ESI (m/z):336.2(M þ H)þ; HRMS-ESI (m/z): Calcd. for C19H22N5O
(M þ H)þ: 336.18189; Found: 336.18157.
4.2.6.37. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(pyridin-2-yl)
piperazin-1-yl) methanone 32b. According to the general proced-
ure, employing compound 21a and 22b (commercial available)
afforded compound 32b as a white solid (52.3%), mp: 99e101 ꢀC;
4.2.6.32. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(p-tolyl)piper-
azin-1-yl) methanone 30g. According to the general procedure,
employing compound 21a and 16g afforded compound 30g as a
white solid (36.7%), mp: 160e163 ꢀC; 1H NMR (500 MHz, CDCl3)
Mp: 141e144 ꢀC, 1H NMR (500 MHz, DMSO-d6)
d8.27 (s,1H), 8.13 (d,
J ¼ 3.5 Hz, 1H), 7.59e7.52 (m, 1H), 7.46 (d, J ¼ 9.1 Hz, 1H), 7.20 (d,
J ¼ 9.1 Hz,1H), 6.85 (d, J ¼ 8.6 Hz,1H), 6.68e6.65 (m,1H), 3.68e3.56
(m, 8H), 2.37 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d
8.31 (s, 1H), 7.48 (d, J ¼ 9.1 Hz, 1H), 7.14 (dd, J ¼ 9.1, 1.5 Hz, 1H),
7.12e7.08 (m, 2H), 6.88e6.85 (m, 2H), 3.84 (s, 4H), 3.19 (s, 4H), 2.50
(s, 3H), 2.33 (s, 3H), 2.28 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 161.59, 158.69, 147.58, 144.17, 143.23, 137.65, 128.91, 124.21, 121.76,
d
162.83, 149.32, 145.50, 144.24, 129.49, 129.30, 124.66, 124.69,
115.50, 114.98, 113.36, 107.34, 44.88, 44.29, 17.58, 14.82; MS-ESI (m/
z): 336.2 (M þ H)þ; HRMS-ESI (m/z): Calcd. for C19H22N5O
(M þ H)þ: 336.18189; Found: 336.18154.
120.78, 117.62, 116.12, 114.94, 58.27, 48.34, 20.20, 18.34, 15.49; MS-
ESI (m/z): 349.2 (M þ H)þ; HRMS-ESI (m/z): Calcd. for C21H25N4O
(M þ H)þ: 349.20229; Found: 349.20195.
4.2.6.38. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(4-
fluorophenyl)piperidin-1-yl) methanone 33. According to the gen-
eral procedure, employing compound 21a and 23 (commercial
available) afforded compound 33 as a white solid (16.5%), mp:
4.2.6.33. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(4-
methoxyphenyl) piperazin-1-yl)methanone 30h. According to the
general procedure, employing compound 21a and 16h afforded
compound 30h as a white solid (41.0%),mp: 213e215 ꢀC; 1H NMR
117e119 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 8.28 (s, 1H), 7.46 (d,
(500 MHz, CDCl3)
d
8.31 (s, 1H), 7.47 (d, J ¼ 9.1 Hz, 1H), 7.14 (dd,
J ¼ 9.0 Hz, 1H), 7.32e7.30 (m, 2H), 7.19 (dd, J ¼ 9.0, 1.5 Hz, 1H),
7.14e7.10 (m, 2H), 4.15e4.10 (m, 2H), 3.09e3.07 (m, 2H), 2.87e2.82
(m, 1H), 2.37 (s, 3H), 2.30 (s, 3H),1.83e1.81 (m, 2H),1.61e1.58 (m,
J ¼ 9.1, 1.6 Hz, 1H), 6.94e6.89 (m, 2H), 6.88e6.83 (m, 2H), 3.84 (s,
4H), 3.77 (s, 3H), 3.12 (s, 4H), 2.50 (s, 3H), 2.33 (s, 3H); 13C NMR
(100 MHz, DMSO-d6)
d
161.60, 154.26, 149.78, 144.20, 143.32,
2H); 13C NMR (125 MHz, DMSO-d6)
d 161.74, 159.82, 144.06, 142.99,
128.99, 124.25, 121.79, 115.51, 114.86, 108.53, 45.62, 44.75, 43.97,
17.60, 14.82; HRMS-ESI (m/z): Calcd. for C21H25N4O2 (M þ H)þ:
365.19720; Found: 365.19687.
141.69, 128.81, 128.61, 128.55, 124.22, 121.72, 115.53, 115.28, 115.14,
114.98, 40.99, 17.66, 14.81; MS-ESI (m/z): 353.2 (M þ H)þ.
4.3. MIC determination
4.2.6.34. (2,6-dimethylimidazo [1,2-a]pyridin-3-yl)(4-(4-
nitrophenyl)piperazin-1-yl) methanone 30i. According to the gen-
eral procedure, employing compound 21a and 16i afforded com-
pound 30i as a white solid (25.2%), mp: 218e220 ꢀC; 1H NMR
MICs against replicating M. tuberculosis were determined by the
microplate Alamar blue assay (MABA). RIF and INH were included
as positive controls. M. tuberculosis H37Rv and clinical isolate
strains was grown to late log phase (70e100 Klett units) in Difco
Middlebrook 7H9 Broth (catalog no. 271310) supplemented with
0.2% (vol/vol) glycerol, 0.05% Tween 80, and 10% (vol/vol) albumin-
dextrosecatalase (BBL Middlebrook ADC Enrichment, catalog no.
212352) (7H9-ADCTG). Cultures were centrifuged, washed twice,
(500 MHz, CDCl3)
d 8.34 (s, 1H), 8.17e8.13 (m, 2H), 7.47 (d,
J ¼ 9.1 Hz, 1H), 7.15 (dd, J ¼ 9.1, 1.6 Hz, 1H), 6.89e6.85 (m, 2H), 3.87
(s, 4H), 3.51 (s, 4H), 2.50 (s, 3H), 2.33 (s, 3H); 13C NMR (126 MHz,
CDCl3)
d 162.95, 150.27, 145.68, 144.59, 129.64, 129.31, 125.77,
124.59, 122.89, 118.87, 116.76, 115.22, 50.24, 45.29, 18.41, 15.57; MS-

K. Lv et al. / European Journal of Medicinal Chemistry 137 (2017) 117e125
125
and then suspended in phosphate phosphate-buffered saline.
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4
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Notes
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2017.05.044.