Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents

Article abstract of DOI:10.1016/j.ejmech.2019.06.038

A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.

Full text of DOI:10.1016/j.ejmech.2019.06.038

Accepted Manuscript
Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-
a]pyridine-3-carboxamides as new antitubercular agents
Wang Apeng, Kai Lv, Linhu Li, Hongtao Liu, Zeyu Tao, Bin Wang, Mingliang Liu,
Chao Ma, Xican Ma, Bing Han, Aoyu Wang, Yu Lu
PII:
S0223-5234(19)30565-3
DOI:
https://doi.org/10.1016/j.ejmech.2019.06.038
EJMECH 11441
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 29 March 2019
Revised Date: 13 June 2019
Accepted Date: 13 June 2019
Please cite this article as: W. Apeng, K. Lv, L. Li, H. Liu, Z. Tao, B. Wang, M. Liu, C. Ma, X. Ma, B. Han,
A. Wang, Y. Lu, Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-
carboxamides as new antitubercular agents, European Journal of Medicinal Chemistry (2019), doi:
https://doi.org/10.1016/j.ejmech.2019.06.038.
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ACCEPTED MANUSCRIPT
Graphic Abstract
WZY02, a new antitubercular lead discovered by our lab. In this study, multi-series of
WZY02 derivatives were designed, synthesized and evaluated. Compounds 15b and 15d
were found to have excellent activity against both drug-sensitive MTB and MDR-MTB
strains, good safety and pharmacokinetic profiles.

ACCEPTED MANUSCRIPT
Design, synthesis and biological activity of N-(2-phenoxy)ethyl
imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents
Apeng Wang,a, 1 Kai Lv,a, 1 Linhu Li,a Hongtao Liu,a,b Zeyu Tao,a Bin Wang,c
Mingliang Liu,a, * Chao Ma,a Xican Ma,a Bing Han,a Aoyu Wang,a Yu Luc, *
aInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing 100050, China
bDepartment of Pharmacy, Hebei General Hospital, Hebei, Shijiazhuang 050051,
China
cBeijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of
Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing
Chest Hospital, Capital Medical University, Beijing 100149, China
1These authors contributed equally to this work.
*Corresponding author: lmllyx@126.com, 86-010-63030965 (M.L. Liu);
luyu4876@hotmail.com, 86-010-89509357 (Y. Lu)
Abstract
A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs),
based on the structure of WZY02 discovered in our lab, were designed and
synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent
in vitro inhibitory activity with low nanomolar MIC values against both
drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds
15b and 15d display good safety and pharmacokinetic profiles, suggesting their
promising potential to be lead compounds for future antitubercular drug discovery.
KEYWORDS: imidazo[1,2-a]pyridine, design, synthesis, antimycobacterial activity
1. Introduction
Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (MTB), is one of
the top 10 causes of death worldwide.[1] Global TB reported that there were
approximately 10.0 million new TB cases and 1.6 million TB-related deaths
worldwide in 2017.[2] The prevalence of multidrug-resistant (MDR) TB and the
emergence of extensively drug-resistant (XDR) TB, together with coinfection with
Human Immunodeficiency Virus (HIV), has created an urgent demand for the
discovery and development of novel TB drugs to improve the treatment outcomes.[3-6]
[7]
[8]
Although bedaquiline
and delamanid
have been approved for the treatment of
MDR-TB, some adverse events have been noted.[9] Therefore, the unmet medical need
for safer and more effective agents with novel mechanisms of action for the treatment

ACCEPTED MANUSCRIPT
of TB cannot be overemphasized due to the high attrition rate in new drug
development. [10]
Q203 (Fig. 1), an imidazo[1,2-a]pyridine-3-carboxamides (IPA) candidate in phase
II clinical trials at present [2], was reported to have strong inhibitory potency against
drug-sensitive, MDR and XDR strains [11]. As a novel class of anti-TB agents
targeting QcrB [12], IPAs have garnered great interest recently, and many series of new
IPAs were reported to have potent antimycobacterial activity [13-19]. Structure-activity
relationship (SAR) studies of IPAs demonstrated that the carboxamide linker with the
N-benzylic group is critical for antimycobacterial activity [20]. A variety of different
linkers between the IPA core and the benzene ring were investigated, and some
2,6-dimethyl IPAs bearing a N-(2-phenoxy)ethyl moiety, exampled by WZY02 (Fig.
1), were also found to demonstrate excellent activity against both drug-sensitive MTB
and MDR-MTB strains in our lab[17, 18]. However, given that only 2,6-
/2,7-dimethyl-N-(2-phenoxy)ethyl IPAs were explored in our previous work [18], we
intended to make additional structural modifications on the C2 and C5-8 positions of
the IPA core, and then para-position on the benzene ring of WZY02. Thus, a series of
novel N-(2-phenoxy)ethyl IPAs with halogen, electron-withdrawing and
electron-donating groups on the C2 and C5-8 positions of the IPA core, as well as
halogen and electron-donating groups on the para-position of the benzene ring were
designed and synthesized in this study. Our primary objective was to identify
optimized N-(2-phenoxy)ethyl IPA scaffolds with potent antimycobacterial activity
and lay a good foundation for further structural modification in the future. A
preliminary SAR study was also explored to facilitate the further development of
these compounds.
Fig. 1. Structures of Q203 and WZY02, and design of new IPA derivatives
2. Results and discussion
2.1. Chemistry
Detailed synthetic pathway to target compounds 6-9 was shown in Scheme 1.
Microwave assistant cyclization of esters 1 and pyridine-amines 2 formed imidazo[1,
2-a]pyridine 3a-y according to our published procedures.[21] Hydrolysis of 3a-y with
LiOH gave acids 4a-y. Amidation of the acids 4a-y with amines 5 using
Bis(2-Oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) furnished IPAs 6-9.

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O
O
OEt
R2
OH
R2
W
Y
N
R1
O
N
R1
N
i
R1
ii
NH2
N
N
O
NH
R2
2
3a-y
4a-y
iii
N
R1
O
O
O
N
NH2
6a-y, 7a-g, 8a-c, 9a-b
R2
OEt
Y
W
X
5
1 X = Cl, Br
Reagents and conditions: i: MW, 120 oC, EtOH; ii: LiOH, THF, H2O, 0-5 oC; iii: BOP-Cl, Et3N, DCM, rt.
Scheme 1. Synthesis of target compounds 6a-y, 7a-g, 8a-c and 9a-b.
The synthesis of targets 15a-k with alkaline moieties was shown in scheme 2.
Commercially available 2-(4-bromophenoxy)tetrahydro-2H-pyran 10 was employed
as starting material. Buchwald-Hartwig amination of 10 with amines, followed by
removal of THP (tetrahydro-2H-pyran) group yielded 12b-f. Nucleophilic substitution
of 12b-f or commercially available 12a with bromoacetonitrile gave compounds
13a-f, which upon LiAlH4 mediated reduction yielded amines 14a-f. Coupling of
IPAs acid 4 with amines 14a-f achieved IPAs 15a-k.
Scheme 2. Synthesis of target compounds 15a-k
2.2. In-vitro anti-MTB activity
The target compounds 6-9 were initially screened for in vitro activity against MTB
[22]
H37Rv ATCC 27294 strain using the Microplate Alamar Blue Assay (MABA)
.
The minimum inhibitory concentration (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), rifampicin (RFP) and the lead compound WZY02 (6a) for comparison are
presented in Table 1.
The data revealed that many of them have considerable potency against this strain
(MIC: < 1 µg/mL). Six compounds 6f, 6l, 6n, 7d, 8b and 8c (MIC: 0.023-0.029
µg/mL) were found to be more active than INH, RFP and WZY02 (MIC: 0.031-0.050

ACCEPTED MANUSCRIPT
µg/mL). An electron-withdrawing (NO2) or a halogen atom (F, Cl, Br) as the R1 group
on the C-6 position of the IPA core instead of the methyl group of WZY02 leads to
decreased activity (6a vs 6b-e), but the presence of another electron-donating alkoxy
group (OMe) is acceptable (6a vs 6f). On the other hand, the position of the R1 group
on the IPA core affects the anti-MTB activity significantly. Methyl or halogen (Cl) on
the C-6 position of the core is preferred over the same group on the C-5, C-7 or C-8
position (6a vs 6g vs 6i, 6d vs 6h vs 6j vs 6k).
Next, the optimization was focused on R2 modifications (Table 1). An ethyl and a
chlorine atom were introduced on the C-2 and C-6 positions of WZY02, respectively,
and the resulting compound 6l with the same core of Q203, shows excellent potency
(MIC: 0.023 µg/mL). Interestingly, replacement of the chlorine atom of 6l with
fluorine leads obviously reduced activity (6l vs 6m) potentially due
to the electron-withdrawing property of the fluorine atom, but the presence of a
bromine atom in compound 6n (MIC: 0.025 µg/mL) remains about the same potency
(6l vs 6n). As expected, shift of the same group on the C-6 position to the
corresponding C-7 or C-8 position leads to significantly decreased activity (6l vs 6o vs
6p). For 6-methyl series, the anti-MTB activity decreases with the alkyl groups (R2)
of the core (6a vs 6q vs 6r), but replacement of the n-propyl (n-Pr) of 6r with
cycloalkyl (c-Pr) results in increased activity (6r vs 6s). This conclusion is true for
6-F series (6t vs 6u). For the compounds with the same R2 group (n-Pr or c-Pr),
similar to the previously mentioned SAR, 6-Cl or 6-Me is much more active than the
corresponding 7-Cl or 7-Me (6w vs 6x, 6s vs 6y), and 6-Cl than the corresponding 6-F
(6w vs 6u).
The last round of modifications was to investigate the role of the groups on the
para-position of the benzene ring (W). As expected, 4-chlorophenyl analogues show
similar potency to the corresponding 4-bromophenyl ones (6r vs 7a, 6c vs 7b, 6o vs
7c, 6l vs 7d, 6v vs 7e, 6t vs 7f, 6x vs 7g). It is gratifying to note that the three new
compounds with an electron-donating group (OMe) on the para-position of the
benzene ring (8a-c) demonstrate potent activity (MIC: 0.023-0.056 µg/mL),
suggesting that other groups besides halogens could also be suitable for this position.
In fact, the SAR of 2,6-disubstituted N-(2-phenoxy)ethyl IPAs containing various
groups on the different positions is being explored in our lab. Interestingly,
replacement of the benzene ring with pyridine in compounds 9a, b leads to a complete
loss of activity, indicating that the benzene ring could be indispensable to anti-MTB
potency. Overall, the above results indicate that anti-MTB activity of these
compounds is related to R1 and R2 of the IPA core as well as W on the para-position
of the benzene ring.
Table 1. Structures and activity of compounds 6-9 against MTB H37Rv

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Compd.
R1
R2
W
MIC
Compd. R1
R2
W
MIC
(µg/mL)
(µg/mL)
6a
6b
6c
6d
6e
6f
6-Me
Me
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
0.031
1.280
1.208
0.488
0.358
0.028
0.463
2.682
13.925
0.505
2.524
0.023
0.202
0.025
6.354
17.524
0.275
0.415
0.052
2.682
6u
6v
6-F
c-Pr Br
n-Pr Br
c-Pr Br
c-Pr Br
c-Pr Br
n-Pr Cl
0.928
0.054
0.098
32
6-NO2 Me
6-Cl
6-Cl
7-Cl
7-Me
6-Me
6-F
6-F
Me
Me
Me
6w
6x
6-Cl
6-Br
6y
5.004
0.631
3.841
5.862
0.029
0.631
1.141
32
6-OMe Me
7a
6g
6h
6i
7-Me
7-Cl
8-Me
8-Cl
5-Cl
6-Cl
6-F
Me
Me
Me
Me
Me
Et
7b
7c
Me
Et
Cl
Cl
Cl
7-Cl
6-Cl
6-Cl
6-F
7d
7e
Et
6j
n-Pr Cl
n-Pr Cl
c-Pr Cl
6k
6l
7f
7g
7-Cl
6-Cl
6-Me
6-Me
Cl
6m
6n
6o
6p
6q
6r
6s
6t
Et
8a
Et
OMe 0.056
6-Br
7-Cl
8-Cl
6-Me
6-Me
6-Me
6-F
Et
8b
8c
c-Pr OMe 0.027
Et
Et
OMe 0.023
>32
Et
9a
Et
Et
9b
RFP
INH
Me
Me
>32
n-Pr
c-Pr
n-Pr
0.050
0.049
RFP: rifampicin; INH: isoniazid.
Six compounds 6f, 6l, 6n, 7d, 8b and 8c with the best activity (MIC: 0.023-0.029
µg/mL) were further evaluated for their metabolic stability. To our delight, all but 8b
of them exhibit superior stability in human hepatocyte with much longer t1/2
(12.9-54.2 min) compared to the lead compound 6a (6.5 min) (Table 2).
Table 2. Metabolic stability of selected compounds in human hepatocyte

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Compd.
6a
6f
6l
6n
7d
8b
8c
T1/2 (min)
6.5
54.2
35.2
15.8
12.9
7.8
19.5
Based on the strong in vitro anti-MTB activity and good metabolic stability,
6-methyl-2-ethyl, 6-chloro-2-ethyl, 6-bromo-2-ethyl and 6-methoxy-2-methyl IPAs
were identified as the best cores. Meanwhile, in consideration of the potent activity of
compounds (8a-c) with OMe group on the para-position of the benzene ring, the
effect of various electron-donating amino groups at the same position of the four best
IPA cores was further investigated. With a few exceptions (15f, 15i, 15k), as showed
in Table 3, these compounds show the same excellent activity (MIC: 0.0625 µg/mL)
as Q203 and PBTZ169 (a novel clinical drug candidate targeting DprE1, currently in
Phase II clinical trials), and more active than the lead WZY02. It is clear that these
new W groups exception for N-methylpiperazin-1-yl, are acceptable.
Table 3. Structures and activity of compounds 15a-k against MTB H37Rv
Compd. R1
R2
W
MIC
Compd.
R1
R2
W
MIC
(µg/mL)
(µg/mL)
6a
Me
Cl
Cl
Br
Br
Br
Br
Me -Br 0.125
15g
OMe Me
OMe Me
OMe Me
C
D
F
0.0625
0.0625
0.5
15a
15b
15c
15d
15e
15f
Et
Et
Et
Et
Et
Et
A
E
B
C
D
F
0.0625
0.0625
0.0625
0.0625
0.0625
1
15h
15i
15j
Me
Me
Et
Et
D
F
0.0625
4
15k
Q203
PBTZ169
0.0625
0.0625
Encouraged by their excellent potency against drug sensitive MTB H37Rv strain,
fourteen compounds 6f, 6l, 6n, 7d, 8b, 8c, 15a-e, 15g, 15h and 15j were evaluated
against two clinical isolated MTB-MDR (11168 and 9160) strains resistant to both
INH and RFP. As shown in Table 4, compounds 15a-e, 15g, 15h and 15j exhibit
better activity (MIC: < 0.016–0.225 µg/mL) against both the two strains than
PBTZ169, suggesting their promising potential for both drug-sensitive and resistant

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MTB strains (Tables 1 and 2). What's even more exciting was that five compounds
(15b, 15c, 15e, 15h, 15j) also show potent MIC values of < 0.016–0.032 µg/mL
which are not greater than Q203 (MIC: < 0.016–0.057 µg/mL).
Based on the measured activity levels against all of the tested strains, compounds
15a-e, 15g, 15h and 15j were further tested for in vivo tolerability by recording the
number of survivors after a single oral dose in ICR mouse of 500 mg/kg, followed by
a 7-day observation. As shown in Table 4, compounds 15a-d and 15g show very low
oral acute lethal toxicity. Interestingly, the compounds containing an
octahydro-1H-isoindone moiety display some toxicity: 6-bromo-2-ethyl (15e) has the
lowest toxicity, followed by 6-methoxy-2-methyl (15h) and then 6-methyl-2-ethyl
IPA (15j).
Table 4. Anti-MDR-MTB activity and acute toxicity of selected compounds
MIC (µg/mL)
Acute
MIC (µg/mL)
Acute
Compd MDR-MT
MDR-MT toxicity Compd.
MDR-MT
B 11168a
MDR-MT toxicity
b
b
.
B 11168a
B 9160a
B 9160a
6f
0.125
0.500
0.311
0.449
1.000
0.429
0.394
NT
NT
NT
NT
NT
NT
5/5
15d
15e
<0.016
<0.016
<0.016
<0.016
<0.016
<0.016
0.130
0.032
0.111
<0.016
0.024
0.057
5/5
3/5
5/5
1/5
0/5
NT
NT
6l
0.063
6n
7d
8b
8c
15a
0.125
15g
15h
15j
0.25
<0.016
<0.016
Q203
PBTZ16
9
<0.016
0.225
0.116
0.232
15b
15c
<0.016
<0.016
0.016
5/5
5/5
RFP
INH
36.889
>40
38.647
>40
NT
NT
<0.016
a MDR-MTB 11168 and MDR-MTB 9160 were isolated from patients in Beijing Chest Hospital.
bNo. of animals that survived/total no. of animals. NT: not tested.
2.3. In vivo pharmacokinetic profiles
The in vivo pharmacokinetic (PK) profiles of compounds 15a-d and 15g with low
oral acute lethal toxicity, were evaluated in ICR mouse after a single oral
administration of 50 mg/kg. Compared with 15a, 15c and 15g, as shown in Table 5,
compounds 15b and 15d display significantly higher Cmax (3332 and 5079 ng/mL,
respectively) and AUC0-∞ (11071 and 7116 h.ng/mL, respectively), and longer T1/2
(4.41 and 4.71h, respectively).
Table 5. In vivo PK profiles of selected compounds dosed orally in ICR mouse at 50 mg/kg (n =
3)

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Compd.
MRT (h)
1.64±0.063
3.56±0.90
2.82±2.45
1.88±0.495
1.07±0.158
T1/2 (h)
Tmax (h)
0.25±0
Cmax (ng/mL)
2123±156
3332±269
983±509
AUC0-∞ (h.ng/mL)
3338±297
15a
15b
15c
15d
15g
2.70±0.094
4.41±0.329
4.19±1.23
4.71±0.791
0.916±0.349
1.333±0.577
0.25±0
11071±2358
818±105
0.75±0.43
0.33±0.14
5079±2690
638±826
7116±3285
754±966
3. Conclusion
In conclusion, a series of novel N-(2-phenoxy)ethyl IPAs were designed and
synthesized as new anti-TB agents. Structural modifications on the C2 and C5-8
positions of the IPA core, and then para-position on the benzene ring of WZY02
discovered in our lab were made in this study. Many of them exhibit excellent in vitro
inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB
strain H37Rv and drug-resistant clinical isolates. Particularly, compounds 15b and
15d display good safety and PK properties, suggesting they may serve as new and
promising candidates for further study. Studies to determine in vivo efficacy of 15b
and 15d will begin soon.
4. Experimental protocols
4.1. Chemistry
Melting points were determined in open capillaries and are uncorrected. 1H NMR and
13C NMR spectra were determined on a Varian Mercury-500, 600 spectrometer in
DMSO-d6 or CDCl3 using 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 Synthesis
4.2.1. General procedure for the synthesis of compounds 6-9
[21]
To a solution of 4a-z (0.5 mmol)
in DCM (10 mL) was added amines 5 (0.5
mmol), BopCl (152.7 mg, 0.6 mmol), and triethylamine (121.4 mg, 1.2 mmol) at
room temperature, and stirred overnight at the same temperature. The mixture was
washed by H3PO4 solution (1%), saturated NaHCO3 solution and brine, dried over
anhydrous MgSO4, filtered, and concentrated. The residue was purified by Flash
column chromatography (DCM/MeOH, 0-10%) to afford the crude target compounds
as yellow solids. The solid was further treated with EtOAc and hexane (11 mL, 1: 10)
to yield the target compounds 6-9.

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4.2.1.1.
N-(2-(4-bromophenoxy)ethyl)-2-methyl-6-nitroimidazo[1,2-a]pyridine-3-carboxa
mide (6b)
According
to
above
general
procedure,
acid
employing
and
2-methyl-6-nitroimidazo[1,2-a]pyridine-3-carboxylic
4b
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6b as a yellow solid，35.5%
1
yield, mp: 157-159 ℃; H NMR (600MHz, DMSO-d6) δ 9.43 (s, 1H), 8.58 (s, 1H),
7.99 (d, J = 9.0Hz, 1H), 7.70 (d, J = 9.0Hz, 1H), 7.41 (d, J = 8.4Hz, 2H), 6.92 (d, J =
8.4Hz, 2H), 4.09 (t, J = 6.0Hz, 2H), 3.64-3.61 (m, 2H), 2.85 (s, 3H); 13C NMR
(150MHz, DMSO-d6) δ 162.75, 157.65, 142.36, 136.94, 136.49, 132.14, 126.87,
126.63, 119.48, 116.95, 116.80, 112.02, 66.24, 37.78, 8.86; HRMS-ESI (m/z): Calcd.
for C17H16BrN4O4 (M+H)+: 419.0349; Found: 419.0352.
4.2.1.2.
N-(2-(4-bromophenoxy)ethyl)-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (6c)
According
to
above
general
procedure,
acid
employing
and
6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4c
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6c as a yellow solid，56.9%
yield, mp: 176-178℃; 1H NMR (500MHz, CDCl3) δ 9.41 (dd, J = 2.5 Hz, J = 5.0 Hz
1H), 7.55-7.52 (m, 1H), 7.38 (d, J = 9.0 Hz, 2H), 7.27-7.23 (m, 1H), 6.80 (dd, J = 8.7
13
Hz, 2H), 6.30 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.93-3.89 (m, 2H), 2.70 (s, 3H); C
NMR (125MHz, CDCl3) δ 161.26, 157.46, 153.51 (d, J = 237.58 Hz), 146.34, 143.54,
132.51, 118.91, 118.71, 116.68, 116.61, 116.19, 115.53, 115.19, 113.61, 66.98, 38.69,
16.71; HRMS-ESI (m/z): Calcd. for C17H16BrFN3O2 (M+H)+: 392.0404; Found:
392.0409.
4.2.1.3.
N-(2-(4-bromophenoxy)ethyl)-6-chloro-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (6d)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4d
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6d as a yellow solid，35.5%
yield, mp: 179-181℃; 1H NMR (500MHz, CDCl3) δ 9.50 (d, J = 2.5Hz 1H), 7.55 (d,
J = 9.0Hz, 2H), 7.41-7.38 (m, 2H), 7.35-7.33 (m, 1H), 6.83-6.79 (m, 2H), 6.36 (s, 1H),
4.16 (t, J = 5.0Hz, 2H), 3.94-3.90 (m, 2H), 2.72 (s, 3H); 13C NMR (125MHz, CDCl3)
δ 161.24, 157.57, 146.01, 144.29, 132.63, 128.72, 126.24, 121.91, 116.75, 116.45,
116.30, 116.26, 115.86, 113.75, 67.05, 38.86, 16.64 ; HRMS-ESI (m/z): Calcd. for
C17H16BrClN3O2 (M+H)+: 408.0109; Found: 408.0112.
4.2.1.4.
6-bromo-N-(2-(4-bromophenoxy)ethyl)-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (6e)
According
to
above
general
procedure,
acid
employing
and
6-bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4e

ACCEPTED MANUSCRIPT
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6e as a yellow solid，35.5%
yield, mp: 156-158℃; 1H NMR (600MHz, DMSO-d6) δ 9.15 (s, 1H), 8.10 (brs, 1H),
7.57 (d, J = 9.6 Hz, 1H), 7.52 (d, J = 9.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 6.96 (d, J
13
= 8.4 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.70-3.68 (m, 2H), 2.54 (s, 3H); C NMR
(150 MHz, DMSO-d6) δ 160.69, 157.69, 150.93, 143.41, 132.14, 129.35, 126.70,
117.18, 116.79, 116.24, 112.06, 106.46, 66.28, 38.32, 9.32. HRMS-ESI (m/z): Calcd.
for C17H16Br2N3O2 (M+H)+: 451.9604; Found: 451.9609.
4.2.1.5. N-(2-(4-bromophenoxy)ethyl)-6-methoxy-2-methylimidazo[1,2-a]pyri-
dine-3-carboxamide (6f)
According
to
above
general
procedure,
acid
employing
4f and
6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6f as a yellow solid，35.5%
yield, mp: 163-164℃; 1H NMR (500MHz, DMSO-d6) δ 8.68 (d, J = 1.5Hz, 1H), 7.94
(s, 1H), 7.50 (d, J = 4.5Hz, 1H), 7.46 (d, J = 9.0Hz, 2H), 6.87-6.83 (m, 2H), 7.20-7.17
(m, 1H), 6.96 (d, J = 8.5Hz, 2H), 4.16 (t, J = 5.5Hz, 2H), 3.79 (s, 3H), 3.72-3.69 (m,
13
2H), 2.53 (s, 3H); C NMR (125MHz, DMSO-d6) δ 161.21, 157.77, 148.66, 145.11,
141.84, 162.22, 120.75, 116.85, 116.77, 116.45, 116.39, 112.11, 109.21, 66.42, 55.96,
39.02, 15.67; HRMS-ESI (m/z): Calcd. for C18H19BrN3O3 (M+H)+: 404.0604; Found:
404.0611.
4.2.1.6. N-(2-(4-bromophenoxy)ethyl)-2,7-dimethylimidazo[1,2-a]pyridine-3-car-
boxamide (6g)
According
to
above
general
procedure,
acid
employing
and
2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylic
4g
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6g as a yellow solid，35.5%
yield, 1H NMR (500MHz, CDCl3) δ 9.25 (d, J = 7.1Hz, 1H), 7.42-7.35 (m, 2H), 7.33
(s, 1H), 6.83-6.78 (m, 2H), 6.76 (dd, J = 7.1, 1.4Hz, 1H), 6.25 (s, 1H), 4.15 (t, J =
5.1Hz, 2H), 3.93-3.88 (m, 2H), 2.68 (s, 3H), 2.42 (s, 3H); 13C NMR (125MHz, CDCl3)
δ 161.71, 157.68, 146.53, 145.47, 138.72, 132.61, 127.37, 116.37, 116.04, 115.15,
115.00, 19, 67.26, 38.78, 21.48, 16.65; MS-ESI (m/z): 388.22 (M + H)+; HRMS-ESI
(m/z): Calcd. for C18H19BrN3O2 (M+H)+: 388.0655; Found: 388.0667.
4.2.1.7.
N-(2-(4-bromophenoxy)ethyl)-7-chloro-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (6h)
According
to
above
general
procedure,
acid
employing
and
7-chloro-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4h
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6h as a yellow solid，35.5%
1
yield, mp: 172-174℃; H NMR (600MHz, DMSO-d6) δ 9.27 (dd, J = 7.2Hz, J =
1.8Hz, 1H), 8.58 (dd, J = 4.2Hz, J = 1.8Hz, 1H), 8.27 (d, J = 5.4Hz, 1H), 7.45 (d, J
=7.5Hz, 2H), 7.14-7.13 (m, 1H), 6.95 (d, J =7.5Hz, 2H), 4.17 (t, J = 5.0Hz, 2H),
3.72-3.69 (m, 2H), 2.50 (s, 3H); 13C NMR (150MHz, DMSO-d6) δ 160.53, 157.70,
151.80, 151.40, 147.98, 135.14, 132.15, 116.80, 114.21, 112.06, 109.28, 66.29, 38.31,

ACCEPTED MANUSCRIPT
9.54; HRMS-ESI (m/z): Calcd. for C17H16BrClN3O2 (M+H)+: 408.0109; Found:
408.0114.
4.2.1.8. N-(2-(4-bromophenoxy)ethyl)-2,8-dimethylimidazo[1,2-a]pyridine-3-car-
boxamide (6i)
According
to
above
general
procedure,
acid
employing
and
2,8-dimethylimidazo[1,2-a]pyridine-3-carboxylic
4i
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6i as a yellow solid，35.5%
yield, mp: 151-163℃; 1H NMR (500MHz, CDCl3) δ 9.26 (d, J = 7.0 Hz, 1H), 7.33 (s,
1H), 7.26 (s, 1H), 7.24 (s, 1H), 6.87-6.83 (m, 2H), 6.76 (d, J = 7.5 Hz, 1H), 6.25 (s,
13
1H), 4.15 (t, J = 5.1Hz, 2H), 3.93-3.88 (m, 2H), 2.69 (s, 3H), 2.42 (s, 3H); C NMR
(125MHz, CDCl3) δ 161.74, 157.18, 146.59, 145.54, 138.66, 129.67, 127.37, 126.42,
116.01, 115.86, 115.18, 114.99, 67.33, 38.80, 21.48, 16.69; HRMS-ESI (m/z): Calcd.
for C18H19BrN3O2 (M+H)+: 388.0655; Found: 388.0657.
4.2.1.9.
N-(2-(4-bromophenoxy)ethyl)-8-chloro-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (6j)
According
to
above
general
procedure,
acid
employing
and
8-chloro-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4j
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6j as a yellow solid，25.0%
yield, mp: 158-161℃; 1H NMR (500MHz, CDCl3) δ 9.51 (s, 1H), 7.55 (d, J = 5.0 Hz,
1H),7.41-7.26 (m, 3H), 6.82-6.79 (m, 1H), 6.37 (brs, 1H), 4.16 (t, J = 5.5 Hz, 2H),
3.91 (q, J = 5.0 Hz, 2H), 2.72 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 160.69,
157.68, 150.93, 143.41, 132.13, 129.35, 126.70, 117.18, 116.79, 116.24, 112.46, 66.27,
38.32, 9.32; HRMS-ESI (m/z): Calcd. for C17H16BrClN3O2 (M+H)+: 408.0109; Found:
408.0113.
4.2.1.10.
N-(2-(4-bromophenoxy)ethyl)-5-chloro-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (6k)
According
to
above
general
procedure,
acid
employing
and
5-chloro-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4k
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6k as a yellow solid，46.9%
yield, mp: 133-135℃; 1H NMR (500MHz, CDCl3) δ 9.50 (d, J = 2.5 Hz 1H), 7.38 (d,
J = 9.0 Hz, 1H), 7.41-7.38 (m, 2H), 7.35-7.33 (m, 1H), 6.83-6.79 (m, 2H), 6.36 (s,
13
1H), 4.16 (t, J = 5.0 Hz, 2H), 3.94-3.90 (m, 2H), 2.72 (s, 3H); C NMR (125 MHz,
CDCl3) δ 161.24, 157.57, 146.01, 144.29, 132.63, 128.72, 126.24, 121.91, 116.75,
116.45, 116.30, 116.26, 115.86, 113.75, 67.05, 38.83, 16.64 ; HRMS-ESI (m/z): Calcd.
for C17H16BrClN3O2 (M+H)+: 408.0109; Found: 408.0113.
4.2.1.11.
N-(2-(4-bromophenoxy)ethyl)-6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxa
mide (6l)
According
to
above
general
procedure,
employing

ACCEPTED MANUSCRIPT
6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
acid
4l
and
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6l as a yellow solid，55.5%
yield, mp: 173-175℃; 1H NMR (500MHz, CDCl3) δ 9.47 (dd, J = 1.0 Hz, J = 2.0 Hz,
1H), 7.55 (d, J = 9.5 Hz, 1H), 7.40-7.37 (m, 2H), 7.31 (dd, J = 2.0 Hz, J =9.5 Hz, 1H),
6.82-6.78 (m, 2H), 6.37 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.92 (q, J = 5.0 Hz, 2H),
3.00 (q, J = 7.5 Hz, 2H), 1.42 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
161.13, 157.40, 151.58, 144.41, 132.49, 128.29, 126.06, 121.57, 121.57, 116.85,
116.11, 115.06, 113.58, 66.90, 38.69, 38.37, 23.45, 13.33; HRMS-ESI (m/z): Calcd.
for C18H18BrClN3O2 (M+H)+: 422.0265; Found: 422.0270.
4.2.1.12.
N-(2-(4-bromophenoxy)ethyl)-2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxa
mide (6m)
According
to
above
general
procedure,
acid
employing
and
2-ethyl-6-fluoroimidazo[1,2-a]pyridine-3-carboxylic
4m
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6m as a yellow solid，35.5%
1
yield, mp: 165-167℃; H NMR (500MHz, CDCl3) δ 9.40-9.38 (m, 1H), 7.56 (d, J =
9.0 Hz, 1H), 7.39 (dd, J = 2.0 Hz, J =9.0 Hz, 2H), 7.25-7.22 (m, 1H), 6.81-6.78 (m,
2H), 6.34 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.92 (q, J = 5.0 Hz, 2H), 3.00 (q, J = 7.5
Hz, 2H), 1.42 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.79, 157.74,
152.64 (d, J = 231.25 Hz), 151.39, 142.62, 132.19, 117.98, 117.78, 117.09, 117.02,
116.84, 116.48, 114.13, 113.79, 112.10, 66.33, 38.28, 21.89, 13.12; MS-ESI (m/z):
406.1 (M + H)+. HRMS-ESI (m/z): Calcd. for C18H18BrFN3O2 (M+H)+: 406.0561;
Found: 406.0569.
4.2.1.13.
6-bromo-N-(2-(4-bromophenoxy)ethyl)-2-ethylimidazo[1,2-a]pyridine-3-carboxa
mide (6n)
According
to
above
general
procedure,
acid
employing
and
6-bromo-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4n
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6n as a yellow solid，60.0%
yield, mp: 161-163℃; 1H NMR (500MHz, CDCl3) δ 9.56 (s, 1H), 7.48 (d, J = 9.5 Hz,
1H), 7.39-7.37 (m, 3H), 6.80-6.78 (m,2H), 6.32 (s, 1H), 4.15 (brs, 2H), 3.91(brs, 2H),
3.01-2.97 (m, 2H), 1.43-1.39 (m, 3H); 13C NMR (150 MHz, DMSO-d6) δ 160.65,
157.68, 150.89, 143.28, 132.13, 129.09, 126.82, 117.41, 116.78, 115.65, 112.05,
106.63, 66.27, 38.29, 21.73, 13.01; HRMS-ESI (m/z): Calcd. for C18H18Br2N3O2
(M+H)+: 465.9760; Found: 465.9766.
4.2.1.14.
N-(2-(4-bromophenoxy)ethyl)-7-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxa
mide (6o)
According to above general procedure, employing 7-chloro-2-ethylimidazo-
[1,2-a]pyridine-3-carboxylic acid (4o) and 2-(4-bromophenoxy)ethan-1-amine 5a
1
afforded compound 6o as a yellow solid，53.2% yield, mp: 144-146℃; H NMR
(500MHz, CDCl3) δ 7.62 (d, J = 1.5Hz, 1H), 7.40-7.38 (m, 2H), 6.92 (d, J = 2.5Hz,

ACCEPTED MANUSCRIPT
1H), 6.81-6.79 (m, 2H), 6.37 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.92 (q, J = 5.5 Hz, 2H),
13
3.00 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ
161.26, 157.53, 151.79, 146.07, 133.90, 132.63, 128.84, 128.51, 116.53, 116.23,
115.73, 114.96, 114.92, 113.74, 67.03, 38.79, 23.54, 13.50; HRMS-ESI (m/z): Calcd.
for C18H18BrClN3O2 (M+H)+: 422.0265; Found: 422.0268.
4.2.1.15.
N-(2-(4-bromophenoxy)ethyl)-8-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxa
mide (6p)
According
to
above
general
procedure,
acid
employing
and
8-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4p
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6p as a yellow solid，35.5%
yield, mp: 143-145℃; 1H NMR (500MHz, CDCl3) δ 9.30-9.29 (m, 1H), 7.41-7.38 (m,
2H), 6.87-7.84 (m, 1H), 6.80 (dd, J = 7.0 Hz, J = 2.0 Hz, 2H), 6.44 (brs, 1H), 4.16 (t,
J = 5.0 Hz, 2H), 3.92 (q, J = 5.0 Hz, 2H), 3.06 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.5Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 161.27, 153.86, 151.89, 144.51, 130.54, 128.37,
128.07, 126.27, 122.86, 122.23, 121.65, 116.95, 115.16, 113.49, 67.98, 38.68, 23.60,
13.32. HRMS-ESI (m/z): Calcd. for C18H18BrClN3O2 (M+H)+: 422.0265; Found:
422.0268.
4.2.1.16.
N-(2-(4-bromophenoxy)ethyl)-2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxa
mide (6q)
According
to
above
general
procedure,
acid
employing
and
2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic
4q
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6q as a yellow solid，60.9%
1
yield, mp: 139-141℃; H NMR (500MHz, CDCl3) δ 9.16-9.15 (m, 1H), 7.51 (d, J =
9.0 Hz, 1H), 7.40-7.37 (m, 2H), 7.18 (dd, J = 1.5 Hz, J = 9.0 Hz, 1H), 6.82-6.78 (m,
2H), 6.33 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.93-3.90 (m, 2H), 3.00 (q, J = 2.5 Hz, 2H),
13
2.35 (d, J = 0.5 Hz, 3H), 1.41 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ
161.64, 157.48, 150.81, 145.12, 132.47, 130.04, 125.88, 123.08, 116.15, 114.15,
113.53, 67.02, 38.63, 23.44, 18.41, 13.50; MS-ESI (m/z): 402.1 (M + H)+. HRMS-ESI
(m/z): Calcd. for C19H21BrN3O2 (M+H)+: 402.0812; Found: 402.0820.
4.2.1.17.
N-(2-(4-bromophenoxy)ethyl)-6-methyl-2-propylimidazo[1,2-a]pyridine-3-carbox
amide (6r)
According
to
above
general
procedure,
acid
employing
and
6-methyl-2-propylimidazo[1,2-a]pyridine-3-carboxylic
4r
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6r as a yellow solid，35.5%
yield, mp: 147-149℃; 1H NMR (500MHz, CDCl3) δ 9.13 (s, 1H), 7.51 (d, J = 9.0 Hz,
1H), 7.39 (dd, J = 2.0 Hz, J =7.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 6.80 (dd, J = 2.0
Hz, J = 7.0 Hz, 1H), 6.38 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.94-3.90 (q, J = 5.5 Hz,
2H), 2.94 (t, J = 5.5 Hz, 2H), 2.35 (s, 3H), 1.89-1.81 (m, 2H), 0.99 (t, J = 7.0 Hz, 3H);

ACCEPTED MANUSCRIPT
13C NMR (125 MHz, CDCl3) δ 161.67, 157.47, 149.69,145.18,132.46, 129.94, 125.85，
122.93, 116.12, 115.89, 114.78, 113.52, 67.05, 38.60, 32.23, 22.68, 18.39, 14.19;
HRMS-ESI (m/z): Calcd. for C20H23BrN3O2 (M+H)+: 416.0968; Found: 416.0966.
4.2.1.18. N-(2-(4-bromophenoxy)ethyl)-2-cyclopropyl-6-methylimidazo[1,2-a]-
pyridine-3-carboxamide (6s)
According
to
above
general
procedure,
acid
employing
4s and
2-cyclopropyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6s as a yellow solid，89.0%
yield, mp: 166-168℃; 1H NMR (500MHz, CDCl3) δ 9.26 (s, 1H), 7.49 (d, J = 9.5 Hz,
1H), 7.39 (dd, J = 2.0 Hz, J = 7.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 5.5
Hz, 1H) 6.80 (dd, J = 2.0Hz, J = 7.0Hz, 1H), 4.16 (t, J = 5.0Hz, 2H), 3.94 (q, J = 5.5
13
Hz, 2H), 2.35 (s, 3H), 2.17-2.14 (m, 1H), 1.18-1.17 (m, 2H), 1.11-1.08 (m, 2H); C
NMR (125 MHz, CDCl3) δ 161.69, 157.52, 147.56,144.56,132.52, 130.30, 126.63,
125.83, 124.39, 116.08, 116.03, 67.17, 38.57, 18.42, 10.39, 7.57; HRMS-ESI (m/z):
Calcd. for C20H21BrN3O2 (M+H)+: 414.0812; Found: 414.0818.
4.2.1.19. N-(2-(4-bromophenoxy)ethyl)-2-propyl-6-fluoroimidazo[1,2-a]-
pyridine-3-carboxamide (6t)
According
to
above
general
procedure,
acid
employing
and
6-fluoro-2-propylimidazo[1,2-a]pyridine-3-carboxylic
4t
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6t as a yellow solid，31.0%
yield, mp: 153-155℃; 1H NMR (500MHz, CDCl3) δ 9.40 (brs, 1H), 7.59 (dd, J = 9.5
Hz, J = 5.0 Hz,1H), 7.28 (d, J = 8.5 Hz, 2H), 6.86 (dd, J = 8.5 Hz, 2H), 6.68 (brs, 1H),
6.39 (brs, 1H), 4.17 (t, J = 5.0 Hz, 2H), 3.94 (q, J = 5.5 Hz, 2H), 2.97 (t, J = 7.5 Hz,
2H), 1.87 (q, J = 7.5 Hz, 2H), 1.02 (t, J = 7.0 Hz, 3H); 13C NMR (125MHz, CDCl3) δ
161.26, 157.46, 154.46, 152.57, 146.34, 143.54, 132.51, 118.91, 118.71, 116.68,
116.61, 116.19, 115.53, 115.19, 113.61, 67.05, 38.60, 32.23, 22.68, 14.18; MS-ESI
(m/z): 420.0 (M + H)+. HRMS-ESI (m/z): Calcd. for C19H20BrFN3O2 (M+H)+:
420.0717; Found: 420.0719.
4.2.1.20. N-(2-(4-bromophenoxy)ethyl)-2-cyclopropyl-6-fluoroimidazo[1,2-a]-
pyridine-3-carboxamide (6u)
According
to
above
general
procedure,
acid
employing
4u and
6-fluoro-2-cyclopropylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6u as a yellow solid，31.0%
yield, mp: 153-155℃; 1H NMR (500MHz, CDCl3) δ 9.54 (d, J = 1.5 Hz, 1H), 7.34 (d,
J = 9.5 Hz, 1H), 7.29-7.27 (m, 3H), 6.99 (t, J = 5.0 Hz, 2H), 6.69-6.66 (m, 2H), 4.05 (t,
J = 5.0 Hz, 2H), 3.84 (q, J = 5.5 Hz, 2H), 2.07-2.02 (m, 2H), 1.09-1.06 (m, 2H),
1.05-0.98 (m, 2H); 13C NMR (125MHz, CDCl3) δ 160.69, 157.69, 150.93, 143.41,

ACCEPTED MANUSCRIPT
132.14, 129.35, 126.70, 117.18, 116.79, 116.24, 112.06, 106.46, 66.27, 38.32, 9.32,
9.22; MS-ESI (m/z): 418.0 (M + H)+. HRMS-ESI (m/z): Calcd. for C19H18BrFN3O2
(M+H)+: 418.0561; Found: 418.0565.
4.2.1.21.
N-(2-(4-bromophenoxy)ethyl)-6-chloro-2-propylimidazo[1,2-a]pyridine-3-carbox
amide (6v)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-propylimidazo[1,2-a]pyridine-3-carboxylic
4v
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6v as a yellow solid, 54.5%
yield, mp: 176-177℃; 1H NMR (500MHz, CDCl3) δ 9.45 (dd, J = 0.5 Hz, J = 1.5 Hz,
1H), 7.62 (d, J = 8.5 Hz, 1H), 7.41-7.35 (m, 3H), 6.81 (dd, J = 2.0 Hz, J =9.0 Hz, 2H),
6.50 (s, 1H), 4.16 (t, J = 5.0 Hz, 2H), 3.93 (q, J = 5.0 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H),
13
1.87 (q, J = 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ
161.25, 157.51, 150.46, 144.49, 132.62, 128.46, 126.21, 121.67, 116.95, 115.60,
113.74, 67.05, 38.78, 21.27, 22.66, 14.26; HRMS-ESI (m/z): Calcd. for
C19H20BrClN3O2 (M+H)+: 436.0422; Found: 436.0426.
4.2.1.22. N-(2-(4-bromophenoxy)ethyl)-6-chloro-2-cyclopropylimidazo[1,2-a]-
pyridine-3-carboxamide (6w)
According
to
above
general
procedure,
acid
employing
4w and
6-chloro-2-cyclopropylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6w as a yellow solid，68.3%
yield, mp: 163-165℃; 1H NMR (500MHz, CDCl3) δ 9.23 (s, 1H), 7.44 (d, J = 9.0 Hz,
1H),7.35 (dd, J = 7.0 Hz, J = 2.0 Hz, 2H), 7.14 (dd, J = 9.0 Hz, J = 2.0 Hz, 1H), 7.09
(t, J = 5.0 Hz, 1H), 6.78-6.74 (m, 2H), 4.13 (t, J = 5.0 Hz, 2H), 3.91 (q, J = 5.0 Hz,
13
2H), 2.15-2.12 (m, 1H), 1.16-1.13 (m, 2H), 1.07-1.03 (m, 2H); C NMR (125 MHz,
CDCl3) δ 161.19, 157.45, 132.55, 128.72, 128.62, 125.96, 121.89, 116.74, 116.27,
116.06, 113.60, 67.05, 38.63, 10.31, 7.72; MS-ESI (m/z): 434.0 (M + H)+. HRMS-ESI
(m/z): Calcd. for C19H18BrClN3O2 (M+H)+: 434.0265; Found: 434.0270.
4.2.1.23. N-(2-(4-bromophenoxy)ethyl)-7-chloro-2-cyclopropylimidazo[1,2-a]-
pyridine-3-carboxamide (6x)
According
to
above
general
procedure,
acid
employing
4x and
7-chloro-2-cyclopropylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6x as a yellow solid，35.5%
yield, mp: 146-147 ℃; 1H NMR (500MHz, CDCl3) δ 9.39 (d, J = 7.5 Hz, 1H), 7.55 (d,
J = 2.0 Hz, 1H),7.39 (dd, J = 2.0 Hz, J = 7.0 Hz, 2H), 7.09 (t, J = 5.0 Hz, 1H), 6.90
(dd, J = 2.5 Hz, J = 7.5 Hz, 1H), 6.78 (dd, J = 2.0 Hz, J = 7.0 Hz, 2H), 4.15 (t, J = 5.0
Hz, 2H), 3.93 (q, J = 5.0 Hz, 2H), 2.18-2.12 (m, 1H), 1.18-1.59 (m, 2H), 1.13-1.09 (m,
2H); 13C NMR (150MHz, DMSO-d6) δ 160.71, 157.69, 151.10, 144.82, 132.13,

ACCEPTED MANUSCRIPT
131.64, 127.81, 116.76, 116.15, 114.89, 113.64, 112.06, 66.29, 38.30, 9.37, 9.17;
HRMS-ESI (m/z): Calcd. for C19H18BrClN3O2 (M+H)+: 434.0265; Found: 434.0267.
4.2.1.24. N-(2-(4-bromophenoxy)ethyl)-2-cyclopropyl-7-methylimidazo[1,2-a]-
pyridine-3-carboxamide (6y)
According
to
above
general
procedure,
acid
employing
4y and
2-cyclopropyl-7-methylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-bromophenoxy)ethan-1-amine 5a afforded compound 6y as a yellow solid，35.5%
1
yield, mp: 142-145℃; H NMR (500 MHz, CDCl3) δ 9.31 (d, J = 7.0 Hz, 1H),
7.41-7.36 (m, 2H), 7.31 (s, 1H), 7.08 (t, J = 5.0 Hz, 1H), 6.81-6.77 (m, 2H), 6.74 (dd,
J = 7.0 Hz, J = 1.5 Hz, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.93 (dd, J = 10.4 Hz, J = 5.4 Hz,
2H), 2.40 (s, 3H), 2.39-2.12 (m, 1H), 1.28-1.14 (m, 2H), 1.09-1.01 (m, 2H); 13C NMR
(150MHz, DMSO-d6) δ161.09, 157.71, 150.17, 145.40, 137.26, 132.14, 126.19,
116.76, 115.33, 115.00, 114.58 , 112.04, 66.39, 38.21, 20.69, 9.41, 8.86; HRMS-ESI
(m/z): Calcd. for C20H21BrN3O2 (M+H)+: 414.0812; Found: 414.0814.
4.2.1.25.
N-(2-(4-chlorophenoxy)ethyl)-6-methyl-2-propylimidazo[1,2-a]pyridine-3-carbox
amide (7a)
According
to
above
general
procedure,
acid
employing
and
6-methyl-2-propylimidazo[1,2-a]pyridine-3-carboxylic
4r
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7a as a yellow solid，57.6%
yield, mp: 159-161℃; 1H NMR (600 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.04 (t, J = 5.5
Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.22 (dd, J = 9.1, 1.3 Hz, 1H),
7.06 - 6.87 (m, 2H), 4.15 (t, J = 5.6 Hz, 2H), 3.68 (q, J = 5.6 Hz, 2H), 2.86 (t, J = 7.6
Hz, 2H), 2.29 (s, 3H), 1.76-1.57 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H); 13C NMR (150
MHz, DMSO-d6) δ 161.06, 157.29, 148.76, 143.81, 129.24, 128.99, 124.53, 124.32,
121.87, 116.19, 115.66, 115.54, 66.50, 38.22, 30.48, 21.77, 17.75, 13.85; HRMS-ESI
(m/z): Calcd. for C20H23ClN3O2 (M+H)+: 372.1473; Found: 372.1475.
4.2.1.26.
N-(2-(4-chlorophenoxy)ethyl)-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carbox
amide (7b)
According
to
above
general
procedure,
acid
employing
and
6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylic
4c
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7b as a yellow solid，57.6%
yield, 1H NMR (600 MHz, DMSO-d6) δ 9.07 (dd, J = 2.4 Hz, J = 4.8 Hz, 1H), 8.16 (t,
J = 5.4 Hz, 1H), 7.70 (dd, J = 5.4 Hz, J = 8.0 Hz, 1H), 7.59-7.56 (m, 1H), 7.34-7.31
(m, 2H), 7.02-6.99 (m, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.70 (dd, J = 5.4 Hz, 11.4 Hz,
13
2H), 2.57 (s, 3H); C NMR (150MHz, DMSO-d6) δ 160.41, 157.26, 152.84 (d, J =

ACCEPTED MANUSCRIPT
234.3 Hz), 144.90, 141.69, 129.25, 124.39, 119.04, 118.87, 117.12, 116.27, 114.46,
114.17, 66.35, 38.31, 14.98; HRMS-ESI (m/z): Calcd. for C17H16ClFN3O2 (M+H)+:
348.0910; Found: 348.0915.
4.2.1.27.
7-chloro-N-(2-(4-chlorophenoxy)ethyl)-2-ethylimidazo[1,2-a]pyridine-3-carboxa
mide (7c)
According
to
above
general
procedure,
acid
employing
and
7-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4o
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7c as a yellow solid，35.5%
yield, mp: 147-149℃; 1H NMR (500 MHz, CDCl3) δ 9.30 (d, J = 7.5 Hz, 1H), 7.61 (s,
1H), 7.25 (d, J = 9.0 Hz, 2H), 6.91 (dd, J = 7.5, 1.5 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H),
6.37 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.91 (d, J = 5.0 Hz, 2H), 3.01 (q, J = 7.5 Hz,
2H), 1.40 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, DMSO) δ 160.72, 157.30, 156.59,
151.13, 144.72, 131.43, 129.33, 128.02, 124.39, 116.28, 115.63, 115.19, 113.91, 66.38,
38.32, 21.78, 13.12; HRMS-ESI (m/z): Calcd. for C18H18Cl2N3O2 (M+H)+: 378.0711;
Found: 378.0715.
4.2.1.28.
6-chloro-N-(2-(4-chlorophenoxy)ethyl)-2-ethylimidazo[1,2-a]pyridine-3-carboxa
mide (7d)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4l
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7d as a yellow solid，35.5%
yield, mp: 175-178℃; 1H NMR (500MHz, CDCl3) δ 9.49 (s, 1H), 7.55 (d, J = 5.0 Hz,
1H), 7.29 (d, J = 7.0Hz, 1H), 7.20-6.92 (m, 4H), 6.48 (brs, 1H), 4.24 (t, J = 5.0 Hz,
13
2H), 3.95 (q, J = 5.0 Hz, 2H), 3.05 (q, J = 7.5 Hz, 2H), 1.43 (t, J = 7.5Hz, 3H); C
NMR (125 MHz, CDCl3) δ 161.26, 153.86, 151.90, 146.42, 144.50, 128.43, 126.27,
124.63, 122.19, 116.94, 116.47, 115.38, 68.43, 38.80, 23.50, 13.32; HRMS-ESI (m/z):
Calcd. for C18H18Cl2N3O2 (M+H)+: 378.0711; Found: 378.0713.
4.2.1.29.
6-chloro-N-(2-(4-chlorophenoxy)ethyl)-2-propylimidazo[1,2-a]pyridine-3-carbox
amide (7e)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-propylimidazo[1,2-a]pyridine-3-carboxylic
4v
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7e as a yellow solid，39.4%
yield, mp: 173-173 ℃; 1H NMR (500MHz, CDCl3) δ 9.43 (d, J = 1.5Hz, 1H), 7.53 (d,
J = 9.5Hz, 1H), 7.28 (dd, J = 2.0Hz, J =9.5Hz, 1H), 7.24 (d, J =9.0Hz, 2H), 6.84 (d, J
=9.0Hz, 2H), 6.37 (s, 1H), 4.14 (t, J = 5.0Hz, 2H), 3.91 (q, J = 5.0Hz, 2H), 2.93 (t, J =
13
7.5Hz, 2H), 1.84 (q, J = 7.5Hz, 2H), 0.99 (t, J = 7.5Hz, 3H); C NMR (125 MHz,
CDCl3) δ 161.14, 157.41, 150.35, 144.39, 132.51, 128.36, 126.10, 121.57, 116.85,
116.12, 115.50, 113.63, 66.94, 38.68, 32.16, 22.55, 14.16; HRMS-ESI (m/z): Calcd.
for C19H20Cl2N3O2 (M+H)+: 392.0927; Found: 392.0930.

ACCEPTED MANUSCRIPT
4.2.1.30.
N-(2-(4-chlorophenoxy)ethyl)-6-fluoro-2-propylimidazo[1,2-a]pyridine-3-carboxa
mide (7f)
According
to
above
general
procedure,
acid
employing
and
6-fluoro-2-propylimidazo[1,2-a]pyridine-3-carboxylic
4t
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7f as a yellow solid，35.5%
yield, mp: 161-163℃; 1H NMR (500MHz, CDCl3) δ 9.38-9.35 (m, 1H), 7.56 (dd, J =
5.0Hz, J = 9.5Hz, 1H), 7.25-7.23 (m, 3H), 6.37 (s, 1H), 4.14 (t, J = 5.0Hz, 2H), 3.91
(q, J = 5.0Hz, 2H), 2.96-2.92 (m, 2H), 1.90-1.80 (m, 2H), 0.99 (t, J = 7.5Hz, 3H); 13C
NMR (125 MHz, DMSO) δ 160.78, 157.32, 156.59, 153.56, 151.70, 150.13, 142.59,
129.32, 124.38, 117.97, 117.76, 117.01, 116.23, 114.26, 113.76, 66.46, 60.49, 38.30,
30.55, 21.74, 14.58, 13.89; HRMS-ESI (m/z): Calcd. for C19H20ClFN3O2 (M+H)+:
376.1223; Found: 376.1225.
4.2.1.31. 7-chloro-N-(2-(4-chlorophenoxy)ethyl)-2-cyclopropylimidazo[1,2-a]-
pyridine-3-carboxamide (7g)
According
to
above
general
procedure,
acid
employing
4x and
7-chloro-2-cyclopropylimidazo[1,2-a]pyridine-3-carboxylic
2-(4-chlorophenoxy)ethan-1-amine 5b afforded compound 7g as a yellow solid，35.5%
1
yield, mp: 163-165℃; H NMR (600 MHz, DMSO-d6) δ 8.94 (d, J = 7.5 Hz, 1H),
8.23 (t, J = 5.5 Hz, 1H), 7.71 (s, 1H), 7.32 (d, J = 9.0 Hz, 2H), 7.07 (dd, J = 7.5, 2.5
Hz, 1H), 6.99 (d, J = 9.0 Hz, 2H), 4.17 (t, J = 5.8 Hz, 2H), 3.70 (q, J = 5.7 Hz, 2H),
2.43-2.19 (m, 1H), 0.98 (d, J = 6.6 Hz, 4H); 13C NMR (150 MHz, DMSO-d6) δ
160.71, 157.26, 156.53, 151.09, 144.83, 131.67, 129.26, 127.83, 124.36, 116.25,
116.18, 114.90, 113.68, 66.36, 60.43, 38.32, 14.52, 9.36, 9.18; MS-ESI (m/z): 390.0
(M + H)+. HRMS-ESI (m/z): Calcd. for C19H18Cl2N3O2 (M+H)+: 390.0771; Found:
390.0777.
4.2.1.32.
6-chloro-2-ethyl-N-(2-(4-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3-carbox
amide (8a)
According
to
above
general
procedure,
acid 4l
employing
and 2-(4-
6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
methoxyphenoxy)ethan-1-amine 5c afforded compound 8a as a yellow solid，35.5%
yield, mp: 143-146℃; 1H NMR (500 MHz, CDCl3) δ 9.48 (d, J = 1.5 Hz, 1H), 7.54 (d,
J = 9.0 Hz, 1H), 7.29 (dd, J = 9.5, 2.0 Hz, 1H), 6.87-6.84 (m, 4H), 6.38 (s, 1H), 4.14
(t, J = 5.0 Hz, 2H), 3.70 (q, J = 5.0 Hz, 2H), 3.76 (s, 3H), 3.01 (q, J = 7.5 Hz, 2H),
1.42 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 160.99, 154.30, 152.38,
151.11, 144.07, 128.60, 126.17, 121.81, 116.69, 115.36, 115.24, 114.81, 67.23, 55.74,
38.78, 23.27, 13.38; MS-ESI (m/z): 374.1 (M + H)+. HRMS-ESI (m/z): Calcd. for
C19H21ClN3O3 (M+H)+: 374.1266; Found: 374.1270.

ACCEPTED MANUSCRIPT
4.2.1.33. 2-cyclopropyl-N-(2-(4-methoxyphenoxy)ethyl)-6-methylimidazo[1,2-a]-
pyridine-3-carboxamide (8b)
According
to
above
general
procedure,
employing
2-cyclopropyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic acid 4s and 2-(4-
methoxyphenoxy)ethan-1-amine 5c afforded compound 8b as a yellow solid，35.5%
yield, mp: 171-173℃; 1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 7.48 (d, J = 9.0 Hz,
1H), 7.17 (dd, J = 9.0, 1.5 Hz, 1H), 7.13 (s, 1H), 6.84 (m, 4H), 4.14 (t, J = 5.0 Hz,
2H), 3.92 (dd, J = 10.0 Hz, J = 5.5 Hz, 2H), 2.35 (s, 3H), 2.16-2.18 (m, 1H),
1.19-1.17 (m, 2H), 1.10-1.08 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 161.89, 154.32,
152.61, 150.09, 144.86, 130.09, 125.92, 123.19, 115.98, 115.77, 115.37, 114.91, 67.60,
55.84, 38.83, 18.51, 10.58, 7.59; HRMS-ESI (m/z): Calcd. for C21H24N3O3 (M+H)+:
366.1812; Found: 366.1814.
4.2.1.34.
2-ethyl-N-(2-(4-methoxyphenoxy)ethyl)-6-methylimidazo[1,2-a]pyridine-3-carbo
xamide (8c)
According
to
above
general
procedure,
acid 4q
employing
and 2-(4-
2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic
methoxyphenoxy)ethan-1-amine 5c afforded compound 8c as a yellow solid，35.5%
1
yield, mp: 163-165℃; H NMR (500 MHz, CDCl3) δ 9.16 (dd, J = 1.5 Hz, J = 0.5
Hz,1H), 7.50 (d, J = 9.5 Hz, 1H), 7.15 (d, J = 9.5 Hz, 1H), 6.85-6.83 (m, 4H), 6.35
(brs, 1H), 4.14-4.12 (m, 2H), 3.91-3.87 (m, 2H), 3.76 (s, 3H), 3.00 (q, J = 7.5 Hz, 2H),
2.34 (s, 3H), 1.41 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.63, 154.24,
152.46, 150.79, 145.10, 129.95, 125.92, 123.00, 115.87, 115.36, 114.78, 114.48, 67.39,
55.73, 38.80, 23.43, 18.40, 13.53; MS-ESI (m/z): 354.2 (M + H)+. HRMS-ESI (m/z):
Calcd. for C20H24N3O3 (M+H)+: 354.1812; Found: 354.1814.
4.2.1.35.
6-chloro-2-ethyl-N-(2-(pyridin-4-yloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxami
de (9a)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4l
2-(pyridin-4-yloxy)ethan-1-amine 5d afforded compound 9a as a yellow solid，45.1%
yield, mp: 212-214℃; 1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.53 (t, J = 9.5
Hz, 1H), 7.29 (d, J = 9.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 9.0 Hz, 1H),
6.34 (brs, 1H), 4.17 (t, J = 5.0 Hz, 2H), 3.92 (q, J = 5.0 Hz, 2H), 3.01 (q, J = 7.5 Hz,
2H), 1.42 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.27, 156.91, 151.71,
144.56, 143.29, 128.42, 126.21, 122.79, 121.71, 116.99, 115.24, 67.24, 38.84, 23.60,
13.43.; MS-ESI (m/z): 345.2 (M + H)+. HRMS-ESI (m/z): Calcd. for C17H18ClN4O2
(M+H)+: 345.1113; Found: 345.1115.

ACCEPTED MANUSCRIPT
4.2.1.36. 2,6-dimethyl-N-(2-(pyridin-4-yloxy)ethyl)imidazo[1,2-a]pyridine-3-
carboxamide (9b)
According
to
above
general
procedure,
acid
employing
and
2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic
4a
2-(pyridin-4-yloxy)ethan-1-amine 5d afforded compound 9b as a yellow solid，35.5%
1
yield, mp: 210-212℃; H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.92-7.90 (m,
1H), 7.63 (dd, J = 7.5 Hz, J = 8.0 Hz, 2H), 7.46 (d, J = 9.0 Hz, 1H), 7.24-7.22 (m, 1H),
6.03 (dd, J = 7.5 Hz, J = 8.0 Hz, 2H), 4.05-4.02 (m, 2H), 3.63 (9, J = 5.5 Hz, 2H),
2.46 (s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 177.27, 161.32, 144.95,
143.92, 141.20, 129.35, 124.76, 122.05, 117.35, 115.50, 115.40, 54.73, 17.82, 15.61.
HRMS-ESI (m/z): Calcd. for C17H19N4O2 (M+H)+: 311.1503; Found: 311.1505.
4.2.1. General procedure for the synthesis of compounds 15a-k
To a stirred solution of heterocyclic amines (2 mmol) and compound 10 (514.2
mg, 2 mmol) in anhydrous toluene (10 mL) was added Cs2CO3 (977.5 mg, 3 mmol),
(±)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene (124.5 mg, 0.2 mmol) and
Palladium(II) acetate (44.9 mg, 0.2 mmol) at room temperature under argon. The
mixture was refluxed for 5 hours, cooled to room temperature, and quenched by H2O
(10 mL). The mixture was extracted by EtOAc (15 mL × 3). The organic layer was
washed by saturated sodium chloride solution, and dried over anhydrous MgSO4,
filtered and concentrated. The residue was purified by Flash column chromatography
(DCM/MeOH, 0-10%) to afford the crude target compounds 11b-f (70-94% yield).
To a stirred solution of 11b-f (1.8 mmol) in anhydrous EtOH was added
4-methylbenzenesulfonate,pyridin-1-ium (PPTS) (150.8 mg, 0.6 mmol), and refluxed
for a day. The mixture was concentrated to gave crude 12b-f which was used for the
next step directly without further purification.
To a stirred solution of 12a (commercially available, 236.1 mg, 1.8 mmol) or
12b-f (1.8 mmol) in DMSO (5 mL) was added bromoacetonitrile (300.0 mg, 2.5
mmol), K2CO3 (556.8 mg, 4 mmol) at room temperature. The mixture was stirred for
3 hours at room temperature, quenched by H2O (30 mL), and extracted by EtOAc (30
mL × 2). The organic layer was washed by saturated sodium chloride solution, and
dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by
Flash column chromatography (DCM/MeOH, 0-10%) to afford the crude target
compounds 13a-f (15-30% yield for two steps).
To a stirred solution of 13a-f (0.3 mmol) in anhydrous THF (5 mL) was added
LiAlH4 (1 M solution in THF, 1 mL) at room temperature, and refluxed for 1 hour.
The mixture was cooled under ice bath, and slowly quenched by H2O (0.5 mL). The
mixture was diluted by Et2O (15 mL), and filtered over celite. The mixture was
washed by saturated Na2CO3 solution (10 mL). The aqueous layer was extracted by
EtOAc (15 mL × 3). The combined organic layer was concentrated to give the crude
mixture 14a-f which was used for the next step directly without further purification.

ACCEPTED MANUSCRIPT
To a solution of 4 (0.5 mmol) in DCM (10 mL) was added amines 14a-f (0.5
mmol), BopCl (152.7 mg, 0.6 mmol), and triethylamine (121.4 mg, 1.2 mmol) at
room temperature, and stirred overnight at the same temperature. The mixture was
washed by H3PO4 solution (1%), saturated NaHCO3 solution and brine, dried over
anhydrous MgSO4, filtered, and concentrated. The residue was purified by Flash
column chromatography (DCM/MeOH, 0-10%) to afford the crude target compounds
as yellow solids. The solid was further treated with EtOAc and hexane (11 mL, 1: 10)
to yield the target compounds 15a-k.
4.2.1.1. 6-chloro-N-(2-(4-(dimethylamino)phenoxy)ethyl)-2-ethylimidazo[1,2-a]-
pyridine-3-carboxamide (15a)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4l
4-(dimethylamino)phenol 12a afforded target compound 15a as a yellow solid, 22.0%
1
yield for two steps, mp: 185-187 ℃; H NMR (500 MHz, DMSO-d6) δ 9.03 (d, J =
1.5 Hz, 1H), 8.15 (t, J = 5.5 Hz, 1H), 7.66 (dd, J = 9.5 Hz, J = 0.5 Hz, 1H), 7.45 (dd, J
= 9.5 Hz, J = 2.0 Hz, 1H), 7.07 – 6.82 (m, 2H), 6.75 – 6.64 (m, 2H), 4.06 (t, J = 6.0
Hz, 2H), 3.65 (q, J = 5.7 Hz, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.78 (s, 6H), 1.24 (t, J =
7.5 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 160.59, 151.05, 150.25, 145.61,
143.20, 126.96, 124.76, 119.61, 117.14, 115.88, 115.37, 114.19, 66.51, 41.07, 38.57,
21.76, 13.03; HRMS-ESI (m/z): Calcd. for C20H24ClN4O2 (M+H)+: 387.1582; Found:
387.1588.
4.2.1.2. 6-chloro-2-ethyl-N-(2-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenoxy)-
ethyl)imidazo[1,2-a]pyridine-3-carboxamide (15b)
According
to
above
general
procedure,
acid
employing
and
6-chloro-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4l
1-(4-fluorophenyl)piperazine as amine afforded target compound 15b as a yellow
solid, 32.5% yield, mp: 175-177℃; 1H NMR (500 MHz, DMSO-d6) δ 9.03 (d, J = 1.5
Hz, 1H), 8.16 (t, J = 5.5 Hz, 1H), 7.66 (d, J = 9.5 Hz, 1H), 7.45 (dd, J = 9.5, 2.0 Hz,
1H), 7.07 (t, J = 9.0 Hz, 2H), 7.01 (dd, J = 9.0, 4.5 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H),
6.90 (d, J = 9.0 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.67 (q, J = 6.0 Hz, 2H), 3.24 – 3.18
(m, 4H), 3.16 – 3.12 (m, 4H), 2.96 (q, J = 7.5 Hz, 2H), 1.24 (dd, J = 9.0 Hz, J = 6.0
13
Hz, 3H); C NMR (125 MHz, DMSO-d6) δ 161.10, 152.66 , 151.56, 148.35, 144.81
(d, J = 277.5 Hz), 127.51, 125.94, 125.27, 120.12, 118.09, 117.89, 117.83, 117.66,
116.37, 115.87, 115.70, 115.59, 66.75, 64.60, 50.14, 49.68, 38.99, 22.24, 13.55 ;
MS-ESI (m/z): 522.2 (M + H)+. HRMS-ESI (m/z): Calcd. for C28H30ClFN5O2 (M+H)+:
522.2067; Found: 522.2070.
4.2.1.3. 6-chloro-2-ethyl-N-(2-(4-(piperidin-1-yl)phenoxy)ethyl)imidazo[1,2-a]-
pyridine-3-carboxamide (15c)

ACCEPTED MANUSCRIPT
According
to
above
general
procedure,
employing
6-
bromo-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid 4n and piperidine as amine
1
afforded target compound 15c as a yellow solid, 22.1% yield, mp: 153-155℃; H
NMR (500 MHz, CDCl3) δ 9.58 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H), 7.38 (dd,
J = 9.5 Hz, J = 2.0 Hz, 1H), 6.87 (m, 4H), 6.37 (s, 1H), 4.14 (t, J = 5.0 Hz, 2H), 3.90
(dd, J = 10.2 Hz, J = 5.4 Hz, 2H), 3.01-2.96 (m, 6H), 1.72 (brs, 4H), 1.54 (brs, 2H),
1.42 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.26, 152.12, 151.61 ,
144.66, 130.41, 128.37, 118.81, 117.31, 115.14, 108.15, 67.15, 52.19, 38.99, 26.17,
24.26, 23.56, 13.49; HRMS-ESI (m/z): Calcd. for C23H28BrN4O2 (M+H)+: 471.1390;
Found: 471.1396.
4.2.1.4. 6-bromo-2-ethyl-N-(2-(4-(4-(trifluoromethyl)piperidin-1-yl)phenoxy)-
ethyl)imidazo[1,2-a]pyridine-3-carboxamide (15d)
According
to
above
general
procedure,
acid
employing
6-
and
bromo-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4n
4-(trifluoromethyl)piperidine as amine afforded target compound 15d as a yellow
1
solid，35.5% yield, mp: 231-234℃; H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H),
8.12 (t, J = 5.4 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.51 (dd, J = 9.6, 1.8 Hz, 1H), 6.91
(d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.66 (q, J = 6.0
Hz, 2H), 3.58 (d, J = 12.0 Hz, 2H), 2.95 (q, J = 7.8 Hz, 2H), 2.60 (dd, J = 12.0 Hz, J
= 10.2 Hz, 2H), 2.41 (ddd, J = 16.2 Hz, J = 8.4 Hz, J = 4.2 Hz, 1H), 1.86 (d, J = 12.0
13
Hz, 2H), 1.56 (qd, J = 12.0 Hz, J = 3.6 Hz, 2H), 1.24 (t, J = 7.8 Hz, 3H); C NMR
(150 MHz, DMSO-d6) δ 160.61, 152.11, 150.86, 145.48, 143.27, 129.09, 128.77,
126.82, 118.15, 117.43, 115.70, 115.09, 109.53, 106.63, 66.27, 48.88, 40.06, 38.87,
38.70, 38.52, 24.08, 21.73, 13.02; MS-ESI (m/z): 539.2 (M + H)+. HRMS-ESI (m/z):
Calcd. for C24H27BrF3N4O2 (M+H)+: 539.1264; Found: 539.1266.
4.2.1.5. 6-bromo-2-ethyl-N-(2-(4-(octahydro-2H-isoindol-2-yl)phenoxy)ethyl-
)imidazo[1,2-a]pyridine-3-carboxamide (15e)
According
to
above
general
procedure,
acid
employing
and
6-bromo-2-ethylimidazo[1,2-a]pyridine-3-carboxylic
4n
octahydro-1H-isoindole as amine afforded target compound 15e as a yellow solid，
1
17.5% yield, mp: 204-206℃; H NMR (500 MHz, DMSO-d6) δ 9.10 (d, J = 1.0 Hz,
1H), 8.13 (t, J = 6.5 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.53-7.50 (m, 1H), 6.83 (d, J =
9.0 Hz, 2H), 6.40 (d, J = 8.5 Hz, 2H), 4.04-4.02 (m, 2H), 3.66-3.63 (m, 2H),
3.17-3.05 (m, 4H), 2.95 (q, J = 7.5 Hz, 2H), 2.47-2.27 (m, 2H), 1.53- 1.30 (m, 8H),
13
1.24 (t, J = 7.5 Hz, 3H); C NMR (125 MHz, DMSO-d6) δ 160.62, 150.82, 148.93,
143.28, 143.17, 129.19, 126.88, 117.46, 115.93, 115.78, 115.55, 106.72, 86.83, 51.79,
38.65, 26.09, 22.72, 21.75, 13.09; MS-ESI (m/z): 511.3 (M + H)+. HRMS-ESI (m/z):
Calcd. for C26H32BrN4O2 (M+H)+: 511.1703; Found: 511.1706.

ACCEPTED MANUSCRIPT
4.2.1.6. 6-bromo-2-ethyl-N-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)-
imidazo[1,2-a]pyridine-3-carboxamide (15f)
According
to
above
general
procedure,
employing
6-bromo-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid 4n and 4-methylpiperazine
1
afforded target compound 15f as a yellow solid，35.5% yield, mp: 188-189℃; H
NMR (500 MHz, DMSO-d6) δ 9.10 (d, J = 1.2 Hz, 1H), 8.15 (t, J = 5.5 Hz, 1H), 7.60
(dd, J = 9.5 Hz, J = 1.2 Hz, 1H), 7.51 (dd, J = 9.5 Hz, J = 2.0 Hz, 1H), 6.99 – 6.76 (m,
4H), 4.08 (t, J = 5.5 Hz, 2H), 3.65 (q, J = 5.5 Hz, 2H), 3.04 – 2.99 (m, 4H), 2.95 (q, J
13
= 7.5 Hz, 2H), 2.46 (s, 4H), 2.22 (s, 3H), 1.24 (t, J = 7.5 Hz, 3H); C NMR (125
MHz, DMSO-d6) δ 160.66, 151.92, 150.90, 145.57, 143.31, 129.16, 126.87, 117.48,
117.25, 115.75, 115.10, 106.70, 66.30, 54.68, 49.24, 45.65, 38.55, 21.77, 13.09;
MS-ESI (m/z): 486.1 (M + H)+. HRMS-ESI (m/z): Calcd. for C23H29BrN5O2 (M+H)+:
486.1499; Found: 486.1497.
4.2.1.7. 6-methoxy-2-methyl-N-(2-(4-(4-(trifluoromethyl)piperidin-1-yl)phenoxy)-
ethyl)imidazo[1,2-a]pyridine-3-carboxamide (15g)
According
to
above
general
procedure,
employing
6-methoxyl-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid 4f and afforded target
compound 15g as a yellow solid，35.5% yield, mp: 230-232℃; 1H NMR (600 MHz,
DMSO-d6) δ 8.69 (d, J = 2.2 Hz, 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.49 (d, J = 9.6 Hz,
1H), 7.18 (dd, J = 9.6 Hz, J = 2.5 Hz, 1H), 6.95 – 6.83 (m, 4H), 4.08 (t, J = 5.9 Hz,
2H), 3.78 (s, 3H), 3.66 (q, J = 5.7 Hz, 2H), 3.58 (d, J = 12.3 Hz, 2H), 2.59 (td, J =
12.2 Hz, J = 1.8 Hz, 2H), 2.53 (s, 3H), 2.40 (ddd, J = 12.2 Hz, J = 10.4 Hz, J = 6.2 Hz,
1H), 1.86 (d, J = 12.4 Hz, 2H), 1.56 (qd, J = 12.5 Hz, J = 4.0 Hz, 2H); 13C NMR (150
MHz, DMSO-d6) δ 161.56, 152.60, 149.05, 145.93, 145.46, 142.22, 128.29 (q, J =
277.50 Hz), 121.08, 118.61, 116.88, 116.76, 115.55, 115.38, 109.69, 66.86, 56.39,
49.33, 40.50, 39.32, 39.14, 38.86, 24.52, 16.07; MS-ESI (m/z): 477.2 (M + H)+.
HRMS-ESI (m/z): Calcd. for C24H28F3N4O3 (M+H)+: 477.2108; Found: 477.2110.
4.2.1.8. 6-methoxy-2-methyl-N-(2-(4-(octahydro-2H-isoindol-2-yl)phenoxy)ethyl)-
imidazo[1,2-a]pyridine-3-carboxamide (15h)
According
to
above
general
procedure,
acid
employing
4f and
6-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylic
octahydro-1H-isoindole as amine afforded target compound 15a as a yellow solid，
35.5% yield, mp: 203-205℃; 1H NMR (600 MHz, CDCl3) δ 9.11 (d, J = 1.8 Hz, 1H),
7.47 (d, J = 9.6 Hz, 1H), 7.11 (dd, J = 9.6, 2.4 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.45
(d, J = 9.0 Hz, 2H), 6.37 (s, 1H), 4.13 (t, J = 4.8 Hz, 2H), 3.90 – 3.85 (m, 5H), 3.30 –
3.22 (m, 2H), 3.14-3.11 (m, 2H), 2.70 (s, 3H), 2.31 – 2.30 (m, 2H), 1.66 – 1.59 (m,
2H), 1.52-1.49 (m, 4H), 1.42 – 1.37 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 161.82,
149.85, 148.95, 145.12, 144.04, 142.82, 122.06, 116.40, 116.36, 116.16, 111.76,
110.29, 68.13, 56.31, 52.30, 39.09, 37.56, 26.63, 23.27, 16.78; MS-ESI (m/z): 449.0
(M + H)+. HRMS-ESI (m/z): Calcd. for C26H33N4O3 (M+H)+: 449.2547; Found:

ACCEPTED MANUSCRIPT
449.2549.
4.2.1.9. 6-methoxy-2-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)-
imidazo[1,2-a]pyridine-3-carboxamide (15i)
According to above general procedure, employing 6-methoxy-2-methyl
imidazo[1,2-a]pyridine-3-carboxylic acid 4f and 4-methylpiperazine as amine
1
afforded target compound 15i as a yellow solid，35.5% yield, mp: 173-176℃; H
NMR (500 MHz, CDCl3) δ 9.11 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 9.5 Hz, 1H), 7.13 (dd,
J = 9.5, 2.5 Hz, 1H), 6.96 – 6.91 (m, 2H), 6.91 – 6.86 (m, 2H), 6.35 (t, J = 5.5 Hz,
1H), 4.17 (t, J = 5.0 Hz, 2H), 3.92 (dd, J = 10.5, 5.5 Hz, 2H), 3.88 (s, 3H), 3.23 (brs,
4H), 2.78 (brs, 4H), 2.72 (s, 3H), 2.49 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.90,
152.91, 149.78, 145.43, 143.05, 121.95, 118.69, 116.56, 116.01, 115.52, 115.34,
110.16, 67.31, 56.26, 54.99, 49.97, 45.66, 38.89, 16.95; MS-ESI (m/z): 424.1 (M +
H)+. HRMS-ESI (m/z): Calcd. for C23H30N5O3 (M+H)+: 424.2343; Found: 424.2345.
4.2.1.10. 2-ethyl-6-methyl-N-(2-(4-(octahydro-2H-isoindol-2-yl)phenoxy)ethyl)-
imidazo[1,2-a]pyridine-3-carboxamide (15j)
According to above general procedure, employing 2-ethyl-6-methyl
imidazo[1,2-a]pyridine-3-carboxylic acid 4q and octahydro-1H-isoindole as aine
1
afforded target compound 15j as a yellow solid，17.1% yield, mp: 204-206℃; H
NMR (600 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.99 (t, J = 5.4 Hz, 1H), 7.51 (d, J = 9.0
Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H),
4.03 (s, 2H), 3.64 (q, J = 6.0 Hz, 2H), 3.18 (s, 2H), 3.05 (s, 2H), 2.94 (q, J = 7.2 Hz,
2H), 2.30 (s, 3H), 2.27 (s, 2H), 1.58-1.49 (m, 2H), 1.55 – 1.46 (m, 2H), 1.44 – 1.38
(m, 2H), 1.38 – 1.30 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
DMSO-d6) δ 160.90, 149.67, 148.91, 143.66, 143.15, 129.21, 124.63, 122.07, 115.88,
115.54, 115.13, 114.44, 111.52, 66.93, 51.75, 38.54, 36.74, 26.33, 26.04, 22.67, 21.69 ,
17.76, 13.18; MS-ESI (m/z): 447.2 (M + H)+. HRMS-ESI (m/z): Calcd. for
C27H35N4O2 (M+H)+: 447.2755; Found: 447.2757.
4.2.1.11. 2-ethyl-6-methyl-N-(2-(4-(4-methylpiperazin-1-yl)phenoxy)ethyl)-
imidazo[1,2-a]pyridine-3-carboxamide (15k)
According
to
above
general
procedure,
employing
2-ethyl-6-methylimidazo[1,2-a]pyridine-3-carboxylic acid 4q and 4-methylpiperazine
1
afforded target compound 15a as a yellow solid，35.5% yield, mp: 199-201℃; H
NMR (500 MHz, CDCl3) δ 9.17 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 9.0 Hz,
J = 1.5 Hz, 1H), 6.92-6.85 (m, 4H), 6.36 (d, J = 5.5 Hz, 1H), 4.14 (t, J = 5.0 Hz, 2H),
3.90 (dd, J = 10.5 Hz, J = 5.5 Hz, 2H), 3.24 (brs, 5H), 3.01 (q, J = 7.5 Hz, 2H),
2.78-2.51 (m, 6H), 2.35 (s, 3H), 1.41 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 161.65, 149.52, 145.17, 142.79, 121.70, 118.44, 116.30, 115.08, 109.91, 67.05,

ACCEPTED MANUSCRIPT
56.01, 54.74, 49.71, 38.64, 16.69. MS-ESI (m/z): 422.1 (M + H)+. HRMS-ESI (m/z):
Calcd. for C24H32N5O2 (M+H)+: 422.2551; Found: 422.2557.
4.3. MIC determination.
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（ATCC27294） and clinical isolate strains were grown to late log
phase (70 to 100 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, and then suspended in
phosphate phosphate-buffered saline. Suspensions were then passed through an 8
µm-pore-size filter to remove clumps, and aliquots were frozen at -80 °C. Two fold
dilutions of test compounds and positive controls were prepared in 7H9-ADC-TG in a
volume of 100 µl in 96-well, black, clear-bottom microplates (BD Biosciences,
Franklin Lakes, NJ). M. tuberculosis (100 µl containing 2 × 105 CFU) was added,
yielding a final testing volume of 200 µl. The plates were incubated at 37°C; on day 7
of incubation, 12.5 µl of 20% Tween 80 and 20 µl of Alamar blue were added to all
wells. After incubation at 37 °C for 16 to 24 h, the fluorescence was read at an
excitation of 530 nm and an emission of 590 nm. The MIC was defined as the lowest
concentration effecting a reduction in fluorescence of ≥90% relative to the mean of
replicate bacterium-only controls.
4.4. Acute toxicity determination.
The toxicity study was carried out using female ICR mice weighting 18-22 g each.
The animals were randomly distributed to control group and treated groups,
containing five animals per group. They were maintained on animal cubes, provided
with water and foods. After depriving the animals’ food overnight, the control group
received 5% CMC solution orally (0.5 mL), whereas each treated group received
orally the agents suspended in 5% CMC solution (500 mg/kg). The animals were
observed continuously for the first 4 hours and then each hour for the next 24 h and at
8 hourly intervals for the following 7 days after administering, to observe any death or
changes.
4.5. Pharmacokinetic Profiles determination.
SPF female ICR mice weighing 18–22ꢀg were used in the pharmacokinetic study.
The ICR mice were fasted overnight before dosing. Every treatment group contain 3
rats. Mice were dosed with the tested compounds suspension at 50ꢀmg/kg (p.o.).
Compounds were suspended in 0.5% CMC for oral administration. Blood was
collected from the jugular vein of each animal at the following times after
administration of drugs: 0.25, 0.5, 1, 2, 4, 6, 8 and 24ꢀh after a single oral dosing. All
blood samples were centrifuged at 3000ꢀr/min for 10ꢀmin to obtain serum which was
then stored at −20ꢀ°C. 150ꢀµL of the serum was added to 500ꢀµL of acetonitrile and the
mixture was centrifuged at 13000ꢀr/min for 10ꢀmin to remove protein. The supernatant
was dried and dissolve in 100ꢀµL of acetonitrile, the solution was centrifuged at

ACCEPTED MANUSCRIPT
13000ꢀr/min for 10ꢀmin. The supernatant was moved to a sample bottle for HPLC
analysis. Total area under the concentration time curve (AUC), the elimination
half-time (t1/2), the peak concentration (Cmax) and the time to reach peak concentration
(Tmax) of samples were determined directly from the experimental data using
WinNonlin V6.2.1.
Ethical statement
All animal experiments were carried out in accordance with the guidelines of the
Chinese Association for Laboratory Animal Sciences, and approved by the
institutional ethical committee (IEC) of Peking Union Medical College.
Funding sources
This work is supported by the CAMS Innovation Fund for Medical Science
(CAMS-2017-I2M-1-011), National Mega-project for Innovative Drugs
(2015ZX09102007-008; 2018ZX09721001-004-007; 2018ZX09711001-007-002),
NSFC-81872753.
Notes
The authors declare no competing financial interest.
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