Supporting Information. Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine- 3-carboxamides as New Anti-tuberculosis Agents

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1 Supporting Information Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine- 3-carboxamides as New Anti-tuberculosis Agents Zhaoyang Wu, Yu Lu, Linhu Li, Rui Zhao, Bin Wang, Kai Lv, Mingliang Liu, * and Xuefu You * TABLE OF CONTENTS 1. Chemistry section 2. General procedure for the preparation of 3a-n 3. General procedure for the synthesis of 6, 7 4. General procedure for the synthesis of 8, 9 5. General procedure for the synthesis of 10a-n and 11a-m 6. Procedure for the synthesis of Copies of spectrums of representative compound 10j 1. Chemistry section All commercially available solvents and reagents were obtained from commercial suppliers and used without further purification. All reactions involving reactants, reagents or intermediates sensitive to air or moisture were performed under an inert atmosphere of nitrogen. Melting points were determined in open capillaries and uncorrected. 1 H NMR and 13 C NMR spectra were determined on a Varian Mercury- 400/500/600 spectrometer in DMSO-d 6 or CDCl 3 using tetramethylsilane (TMS) as an internal standard. Electrospray ionization (ESI) mass spectra and high resolution mass spectra (HRMS) were obtained on an MDSSCIEX Q-Tap mass spectrometer. The reagents were all of analytical grade or chemically pure. TLC was performed on silica gel plates (Merck, ART F254). Compound purity was determined by HPLC using an HPLC system (Agilent 1260) equipped with a quaternary pump, auto sampling injector, and UV detector. HPLC analysis conditions were as follows: RP column 5 µm Agilent C-18 ( mm); flow rate 1.0 ml/min; UV detection at 254 nm; 100% water (0.1% Ammonium acetate) was maintained from 0 to 7 min followed by a constant concentration of 70% methanol in water for 25 min; All evaluated compounds were 95% pure. S2

2 2. General procedure for the preparation of 3a-n To a solution of phenols 1a-n (20 mmol), N-(2-Hydroxyethyl)phthalimide (3.83 g, 20 mmol) and PPh 3 (7.87 g, 30 mmol) in THF (30 ml) was added dropwise a solution of DEAD (4.7 ml, 30 mmol) in THF (10 ml) at 0-5 over 20 min. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted in diethyl ether and stirred at -5~0 for 30 min and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel) eluting with petroleum ether (PE) and ethyl acetate (EtOAc) (6:1, v/v) to give 2a-n. A solution of 2a-n (3 mmol) and 85% hydrazine hydrate (0.19 ml, 3.3 mmol) in ethanol (30 ml) was stirred at 50 for 4h, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the title compounds 3a-n, which were used directly without further purification. 3. General procedure for the synthesis of 6, 7 To a stirred mixture of 2-aminopyridines 4, 5 (5.41 g, 50 mmol), triethylamine (7.0 ml, 50 mmol) and acetonitrile (20 ml) was added dropwise a solution of ethyl 2- chloroacetoacetate (6.9 ml, 50 mmol) in acetonitrile (10 ml) over a period of 10 min. The reaction mixture was stirred for 10h at reflux, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel), eluting with PE and EtOAc (3:1, v/v) to give 6, 7 as white solids Ethyl 2, 6-dimethylimidazo[1,2-a]pyridine-3-carboxylate 6. The title compound 6 was obtained from 4 and ethyl 2-chloroacetoacetate (69.8 %), mp : H NMR (500 MHz, CDCl 3 ) δ (ppm) 9.12 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 9.0, 1.7 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H, O-CH 2 CH 3 ), 2.69 (s, 3H, CH 3 ), 2.37 (s, 3H, CH 3 ), 1.43 (t, J = 7.1 Hz, 3H, O-CH 2 CH 3 ). MS-ESI (m/z): (M+H) Ethyl 2, 7-dimethylimidazo[1,2-a]pyridine-3-carboxylate 7. The title compound 7 was obtained from 5 and ethyl 2-chloroacetoacetate (72.3 %), mp : H NMR (400 MHz, CDCl 3 ) δ (ppm) 9.15 (d, J = 7.1 Hz, 1H), 7.36 (s, 1H), 6.79 (dd, J = 7.1, 1.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H, O-CH 2 CH 3 ), 2.69 (s, 3H, CH 3 ), 2.43 (s, 3H, CH 3 ), 1.42 (t, J = 7.1 Hz, 3H, O-CH 2 CH 3 ). MS-ESI (m/z): (M+H) General procedure for the synthesis of 8, 9 To a solution of 6, 7 (50 mmol) in ethanol (150 ml) was added a solution of LiOH (60 mmol) in water (10 ml) at room temperature. The reaction mixture was stirred at the same

3 temperature for 24h and concentrated under reduced pressure. The residue was dissolved in water (50 ml) and washed with ethyl acetate (3 30 ml). The aqueous layer was adjusted to ph with 2N HCl at 0~5 and then stirred at the same temperature for 20 min. The precipitate was collected by filtration and washed with water to give 8, 9 as white solids ,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid 8 The title compound 8 was obtained from 6 (75.6 %), mp : H NMR (500 MHz, DMSO-d 6 ) δ (ppm) (s, 1H, COOH), 9.08 (s, 1H), 7.55 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 1.6 Hz, 1H), 2.57 (s, 3H, CH 3 ), 2.35 (s, 3H, CH 3 ). MS-ESI (m/z): (M+H) ,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid 9 The title compound 9 was obtained from 7 (73.8 %), mp : H NMR (400 MHz, DMSO-d 6 ) δ (ppm) (s, 1H, COOH), 9.12 (d, J = 7.1 Hz, 1H), (m, 1H), 6.98 (dd, J = 7.1, 1.7 Hz, 1H), 2.56 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ). MS-ESI (m/z): (M+H) General procedure for the synthesis of 10a-n and 11a-m To a stirred mixture of imidazo[1,2-a]pyridine-3-carboxylic acids 8, 9 (0.13 g, 0.7 mmol), EDCI (0.16 g, 0.84 mmol) and HOBT (0.11 g, 0.84 mmol) in methylene chloride (10 ml) was added 2-phenoxyethanamines 3a-n (1.05 mmol) at room temperature and then stirred for 10h at the same temperature and filtered. The filtrate was washed with saturated NaHCO 3 solution (3 3 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel), eluting with PE and EtOAc (1:3, v/v) to give 10a-n and 11a-m ,6-Dimethyl-N-(2-phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamide 10a The title compound 10a was obtained from 3a and 8 (59.9 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.19 (s, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), 6.32 (s, 1H), (m, 2H), (m, 2H), 2.68 (s, 3H), 2.34 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 66.83, 38.88, 18.47, 16.70; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 20 N 3 O 2 (M+H) + : ; Found: ,6-Dimethyl-N-(2-(2-tolyloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxamide 10b The title compound 10b was obtained from 3b and 8 (62.34 %), mp : H

4 NMR (500MHz, CDCl 3, δ, ppm): 9.23 (s, 1H), 7.50 (d, J = 9.1Hz, 1H), 7.20 (d, J = 9.0, 1.2Hz, 1H), (m, 2H), (m, 1H), 6.84 (d, J = 8.5Hz, 1H), 6.35 (s, 1H), 4.20 (t, J = 5.1Hz, 2H), (m, 2H), 2.70 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , 66.88, 39.06, 18.51, 16.48, 16.40; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 2 (M+H) + : ; Found: , 6-Dimethyl-N-(2-(3-tolyloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxamide 10c The title compound 10c was obtained from 3c and 8 (54.89 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.20 (s, 1H), 7.47 (d, J = 9.0Hz, 1H), (m, 2H), 6.79 (d, J = 7.5Hz, 1H), (m, 2H), 6.31 (s, 1H), 4.17 (t, J = 5.1Hz, 2H), (m, 2H), 2.69 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H). 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 66.78, 38.93, 21.64, 18.48, 16.64; MS-ESI (m/z): (M + H) +, (M + Na) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 2 (M+H) + : ; Found: , 6-Dimethyl-N-(2-(4-tolyloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxamide 10d The title compound 10d was obtained from 3d and 8 (60.73 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.21 (s, 1H), 7.52 (d, J = 9.0Hz, 1H), 7.21 (d, J = 9.0Hz, 1H), 7.10 (d, J = 8.5Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.36 (s, 1H), 4.17 (t, J = 5.1Hz, 2H), (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , 67.03, 38.93, 20.60, 18.50, 16.72; MS-ESI (m/z): (M + H) +, (M + Na) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 2 (M+H) + : ; Found: , 6-Dimethyl-N-(2-(2-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10e The title compound 10e was obtained from 3e and 8 (62.81 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.20 (s, 1H), 7.47 (d, J = 9.1Hz, 1H), 7.17 (dd, J = 9.1, 1.4Hz, 1H), (m, 2H), (m, 2H), 6.55 (s, 1H), 4.22 (t, J = 5.1Hz, 2H), 3.91 (m, 2H), 3.82 (s, 3H), 2.71 (s, 3H), 2.35 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 68.63, 55.72,

5 38.82, 18.47, 16.30; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 3 (M+H) + : ; Found: , 6-Dimethyl-N-(2-(3-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10f The title compound 10f was obtained from 3f and 8 (55.69 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.20 (s, 1H), 7.49 (d, J = 9.0Hz, 1H), (m, 2H), (m, 2H), 6.49 (m, 1H), 6.32 (s, 1H), 4.18 (t, J = 5.1Hz, 2H), (m, 2H), 3.79 (s, 3H), 2.70 (s, 3H), 2.36 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 66.94, 55.46, 38.91, 18.50, 16.57; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 3 (M+H) + : ; Found: , 6-Dimethyl-N-(2-(4-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10g The title compound 10g was obtained from 3g and 8 (59.74 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.21 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), (m, 4H), 6.33 (s, 1H), 4.14 (t, J = 5.1Hz, 2H), (m, 2H), 3.77 (s, 3H), 2.71 (s, 3H), 2.36 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.61, 55.86, 38.97, 38.85, 18.48, 16.66; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 3 (M+H) + : ; Found: , 6-Dimethyl-N-(2-(4-fluorophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10h The title compound 10h was obtained from 3h and 8 (65.96 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.18 (s, 1H), 7.46 (d, J = 9.1Hz, 1H), 7.16 (dd, J = 9.1, 1.3Hz, 1H), (m, 2H), (m, 2H), 6.29 (s, 1H), 4.13 (t, J = 5.1Hz, 2H), (m, 2H), 2.68 (s, 3H), 2.34 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , , , 67.58, 38.87, 18.47, 16.69; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 FN 3 O 2 (M+H) + : ; Found:

6 5.9. 2,6-Dimethyl-N-(2-(4-chlorophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10i The title compound 10i was obtained from 3i and 8 (63.46 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.19 (s, 1H), 7.50 (d, J = 9.0Hz, 1H), 7.25 (m, 1H); (m, 1H), 7.20 (dd, J = 9.1, 1.2Hz, 1H), (m, 2H), 6.32 (s, 1H), 4.16 (t, J = 5.1Hz, 2H), (m, 2H), 2.70 (s, 3H), 2.36 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , 67.27, 66.94, 55.45, 38.90, 18.50, 16.61; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 ClN 3 O 2 (M+H) + : ; Found: ,6-Dimethyl-N-(2-(4-bromophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10j The title compound 10j was obtained from 3j and 8 (67.58 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.19 (s, 1H), 7.48 (d, J = 9.0Hz, 1H), 7.39 (d, J = 8.7Hz, 2H), 7.19 (d, J = 9.0Hz, 1H), 6.81 (d, J = 8.7Hz, 2H), 6.29 (s, 1H), 4.15 (t, J = 5.0Hz, 2H), (m, 2H), 2.69 (s, 3H), 2.36 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.21, 38.80, 18.49, 16.68; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 BrN 3 O 2 (M+H) + : ; Found: ,6-Dimethyl-N-(2-(2-nitrophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10k The title compound 10k was obtained from 3k and 8 (54.27 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.20 (s, 1H), 7.87 (dd, J = 8.1,1.7Hz, 1H), (m, 1H), 7.46 (d, J = 9.1Hz, 1H), 7.16 (dd, J = 9.1, 1.6Hz, 1H), (m, 2H), (m, 1H), 4.31 (t, J = 4.9Hz, 2H), (m, 2H), 2.74 (s, 3H), 2.34 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 68.87, 38.51, 18.49, 16.64; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 N 4 O 4 (M+H) + : ; Found: ,6-Dimethyl-N-(2-(4-nitrophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10l The title compound 10l was obtained from 3l and 8 (55.49 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.18 (s, 1H), (m, 2H), 7.48 (d, J = 9.0Hz, 1H),

7 7.20 (dd, J = 9.1, 1.4Hz, 1H), (m, 2H), 6.30 (s, 1H), 4.29 (t, J = 5.2Hz, 2H), (m, 2H), 2.70 (s, 3H), 2.36 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.74, 38.70, 18.50, 16.71; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 N 4 O 4 (M+H) + : ; Found: ,6-Dimethyl-N-(2-(biphenyl-4-yloxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 10m The title compound 10m was obtained from 3m and 8 (52.62 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.21 (s, 1H), (m, 4H), 7.47 (d, J = 9.0Hz, 1H), (m, 2H), (m, 1H), 7.17 (dd, J = 9.1, 1.6Hz, 1H), (m, 2H), 6.33 (s, 1H), 4.23 (t, J = 5.1Hz, 2H), (m, 2H), 2.71 (s, 3H), 2.35 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , , , 67.06, 38.91, 18.49, 16.74; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 24 H 24 N 3 O 2 (M+H) + : ; Found: ,7-Dimethyl-N-(2-phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamide 11a The title compound 11a was obtained from 3a and 9 (62.5 %), mp : H NMR (400MHz, CDCl 3, δ, ppm): 9.26 (d, J = 7.1Hz, 1H), (m, 3H), 6.97 (t, J = 7.4Hz, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 6.74 (dd, J = 7.1, 1.6Hz, 1H), 6.30 (s, 1H), 4.18 (t, J = 5.1Hz, 2H), (m, 2H), 2.68 (s, 3H), 2.41 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 66.86, 38.85, 21.46, 16.70; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 20 N 3 O 2 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(2-tolyloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxamide 11b The title compound 11b was obtained from 3b and 9 (60.34 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.30 (d, J = 7.1Hz, 1H), 7.45 (s, 1H), (m, 1H), (m, 1H), (m, 2H), 6.43 (s, 1H), 4.20 (t, J = 5.0Hz, 2H), (m, 2H), 2.73 (s, 3H), 2.45 (s, 3H), 2.25 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , 66.92, 39.00, 21.48, 16.60, 16.39; MS-ESI (m/z): (M + H) + ;

8 HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 2 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(3-tolyloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxamide 11c The title compound 11c was obtained from 3c and 9 (64.47 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.28 (d, J = 7.1Hz, 1H), 7.37 (s, 1H), (m, 1H), (m, 2H), (m, 2H), 6.31 (s, 1H), 4.17 (t, J = 5.0Hz, 2H), 3.91 (m, 2H), 2.71 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 66.83, 38.89, 21.63, 21.45, 16.71; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 2 (M+H) + : ; Found: , 7-Dimethyl-N-(2-(4-tolyloxy)ethyl)imidazo[1,2-a]pyridine-3-carboxamide 11d The title compound 11d was obtained from 3d and 9 (63.45 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.26 (d, J = 7.1Hz, 1H), 7.32 (s, 1H), 7.09 (d, J = 8.4Hz, 2H), 6.82 (d, J = 8.5Hz, 2H), 6.74 (dd, J = 7.1, 1.6Hz, 1H), 6.29 (s, 1H), 4.15 (t, J = 5.1Hz, 2H), (m, 2H), 2.68 (s, 3H), 2.28 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.04, 38.89, 21.46, 20.59, 16.63; MS-ESI (m/z): (M + H) +, (M + Na) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 2 (M+H) + : ; Found: , 7-Dimethyl-N-(2-(2-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11e The title compound 11e was obtained from 3e and 9 (60.68 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.27 (d, J = 7.1Hz, 1H), 7.32 (s, 1H), (m, 2H), (m, 2H), 6.74 (dd, J = 7.1, 1.6Hz, 1H), 6.53 (s, 1H), 4.22 (t, J = 5.1Hz, 2H), (m, 2H), 3.83 (s, 3H), 2.71 (s, 3H), 2.41 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , 68.67, 55.74, 38.79, 21.45, 16.45; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 3 (M+H) + : ; Found: , 7-Dimethyl-N-(2-(3-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11f The title compound 11f was obtained from 3f and 9 (54.46 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.27 (d, J = 7.1Hz, 1H), 7.42 (s, 1H), (m, 1H), 6.82 (d, J = 7.0Hz, 1H), (m, 2H), (m, 1H), 6.38 (s, 1H), 4.18 (t, J =

9 5.1Hz, 2H), (m, 2H), 3.79 (s, 3H), 2.72 (s, 3H), 2.44 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , 66.97, 55.45, 38.86, 38.74, 21.48, 16.59; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 3 (M+H) + : ; Found: , 7-Dimethyl-N-(2-(4-methoxyphenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11g The title compound 11g was obtained from 3g and 9 (58.57 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.27 (d, J = 7.1Hz, 1H), 7.33 (s, 1H), (m, 4H), 6.76 (dd, J = 7.1, 1.3Hz, 1H), 6.29 (s, 1H), 4.13 (t, J = 5.1Hz, 2H), (m, 2H), 3.77 (s, 3H), 2.69 (s, 3H), 2.42 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.67, 55.87, 38.93, 21.46, 16.73; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 19 H 22 N 3 O 3 (M+H) + : ; Found: , 7-Dimethyl-N-(2-(4-fluorophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11h The title compound 11h was obtained from 3h and 9 (54.44 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.26 (d, J = 7.1Hz, 1H), 7.32 (s, 1H), 7.32 (s, 1H), (m, 2H), (m, 2H), 6.75 (dd, J= 7.1, 1.5Hz, 1H), 6.26 (s, 1H), 4.14 (t, J = 5.1Hz, 2H), (m, 2H), 2.69 (s, 3H), 2.41 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 67.64, 38.86, 21.47, 16.71; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 FN 3 O 2 (M+H) + : ; Found: , 7-Dimethyl-N-(2-(4-chlorophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11i The title compound 11i was obtained from 3i and 9 (60.21 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.26 (d, J = 7.1Hz, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 7.24 (s, 1H), (m, 2H), 6.76 (d, J = 7.1Hz, 1H), 6.25 (s, 1H), 4.15 (t, J = 5.1Hz, 2H), (m, 2H), 2.69 (s, 3H), 2.42 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.33, 38.80, 21.48, 16.69;

10 MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 ClN 3 O 2 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(4-bromophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11j The title compound 11j was obtained from 3j and 9 (56.49 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.25 (d, J = 7.1Hz, 1H), (m, 2H), 7.33 (s, 1H), (m, 2H), 6.76 (dd, J = 7.1, 1.4Hz, 1H), 6.25 (s, 1H), 4.15 (t, J = 5.1Hz, 2H), (m, 2H), 2.68 (s, 3H), 2.42 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , 19, 67.26, 38.78, 21.48, 16.65; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 BrN 3 O 2 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(2-nitrophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11k The title compound 11k was obtained from 3k and 9 (55.34 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.24 (d, J = 7.1Hz, 1H), 7.85 (dd, J = 8.1, 1.6Hz, 1H), (m, 1H), 7.29 (s, 1H), (m, 2H), 6.72 (dd, J = 7.1, 1.6Hz, 1H), (m, 1H), 4.29 (t, J = 4.9Hz, 2H), (m, 2H), 2.72 (s, 3H), 2.39 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 68.85, 38.44, 21.40, 16.62; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 N 4 O 4 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(4-nitrophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11l The title compound 11l was obtained from 3l and 9 (58.84 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.26 (d, J = 7.1Hz, 1H), (m, 2H), 7.34 (s, 1H), (m, 2H), (m, 1H), 6.20 (s, 1H), 4.29 (t, J = 5.2Hz, 2H), (m, 2H), 2.70 (s, 3H), 2.43 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , 67.81, 38.67, 21.49, 16.76; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 N 4 O 4 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(biphenyl-4-yloxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11m The title compound 11m was obtained from 3m and 9 (53.32 %), mp : 194-

11 H NMR (500MHz, CDCl 3, δ, ppm): 9.28 (d, J = 7.1Hz, 1H), (m, 4H), (m, 2H), (m, 2H), (m, 2H), (m, 1H), 6.32 (s, 1H), 4.23 (t, J = 5.1Hz, 2H), (m, 2H), 2.71 (s, 3H), 2.42 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , , , , 67.09, 38.89, 21.48, 16.69; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 24 H 24 N 3 O 2 (M+H) + : ; Found: ,7-Dimethyl-N-(2-(3-nitrophenoxy)ethyl)imidazo[1,2-a]pyridine-3- carboxamide 11n The title compound 11n was obtained from 3n and 9 (59.69 %), mp : H NMR (500MHz, CDCl 3, δ, ppm): 9.26 (d, J = 8.2Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 7.32 (s, 1H), (m, 1H), 6.76 (dd, J = 7.1, 1.7Hz, 1H), 6.25 (s, 1H), 4.27 (t, J = 5.2Hz, 2H), (m, 2H), 2.70 (s, 3H), 2.42 (s, 3H); 13 C NMR (125MHz, CDCl 3, δ, ppm): , , , , , , , , , , , , , , 67.76, 38.71, 21.48, 16.78; MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 19 N 4 O 4 (M+H) + : ; Found: Procedure for the synthesis of 14 A mixture of 2-bromoethylamine hydrobromide (1.58g, 7.83mmol) and 4-bromoaniline 12 (4.00g, 23.5 mmol) in toluene (40 ml) was refluxed for 5h. The precipitate was filtered and treated with 20% aq NaOH (30 ml) and the mixture was extracted with CH 2 Cl 2 (3 50 ml). The organic phases were combined, washed with brine, dried and filtered. The organic layer was concentrated under reduced pressure to give the title compounds 13, which were used directly without further purification. To a stirred mixture of imidazo[1,2-a]pyridine-3-carboxylic acids 8 (0.13 g, 0.7 mmol), EDCI (0.16 g, 0.84 mmol) and HOBT (0.11 g, 0.84 mmol) in methylene chloride (10 ml) was added crude product of compounds 13 (0.30g) at room temperature and then stirred for 10h at the same temperature and filtered. The filtrate was washed with saturated NaHCO 3 solution (3 5 ml) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel), eluting with MeOH and DCM (1:30, v/v) to give 14 as white powder (68mg, 29.0%). 1 H NMR (500 MHz, CDCl 3 ) δ 9.20 (s, 1H), 7.48 (d, J = 9.0Hz, 1H), (m,

12 1H), (m, 1H), 7.20 (dd, J = 9.1, 1.6Hz, 1H), (m, 2H), 6.15 (s, 1H), 4.24 (s, 1H), (m, 2H), (m, 2H), 2.64 (s, 3H), 2.37 (s, 3H); 13 C NMR (150 MHz, DMSO-d 6 ) δ , , , , , , , , , , , , 42.26, 38.11, 17.79, MS-ESI (m/z): (M + H) + ; HRMS-ESI (m/z): Calcd. for C 18 H 20 BrN 4 O(M+H) + : ; Found: Copies of spectrums of representative target compound 10j Copy of H 1 -NMR spectrum of 10j

13 Copy of C 13 -NMR spectrum of 10j Copy of MS spectrum of 10j Copy of HRMS spectrum of 10j