Synthesis and characterization
The NMR spectra were recorded on a Bruker AV-500 spectrometer (Bruker, Karlsruhe, Germany) with TMS as an internal standard. HRESIMS was measured by a Shimazu LC-20AD AB SCIEX triple TOF 5600 + MS spectrometer (Shimadzu Corporation, Tokyo, Japan). The synthesis pathway of title compounds was shown in Scheme 1 and the general synthesis method was described as follow. Column chromatography was performed using 200–300 mesh silica gels. The solvents and reagents were dried prior to use. Each target compound was identified and verified by 1H NMR, 13C NMR, and HRESIMS.
Synthesis of 4-(chloromethyl)-2-methylthiazole (2a) and its analogues (2b-2e).
A solution of thioacetamide (3.75 g, 50 mmol) and 1,3-dichloroacetone (6.35 g, 50 mmol) in anhydrous 100 mL EtOH was stirred at reflux temperature for 4 h. Then the solvent was removed under reduced pressure and extracted with ethyl acetate (EA) and saturated NaHCO3 solution. The organic layer was washed twice with 50 mL saturated sodium chloride solution and dried over MgSO4 and evaporated. The residue was purified by chromatography on a silica gel column to afford 1a as a white powder (6.9 g, 95% yield). The analogues (1b-1e) could be synthesized by the method similar to that described in the synthesis of 2a.
4-(chloromethyl)-2-methylthiazole (2a): 95% yield; brown oil; 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 4.66 (s, 2H), 2.74 (s, 3H).
4-(chloromethyl)-2-isopropylthiazole (2b): 92% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 0.8 Hz, 1H), 4.67 (s, 2H), 3.36 − 3.29(m, 1H), 1.40 (d, J = 6.9 Hz, 6H).
2-(tert-butyl)-4-(chloromethyl)thiazole (2c): 91% yield; yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.13 (s, 1H), 4.66 (s, 2H), 1.42 (s, 9H).
4-(chloromethyl)-2-phenylthiazole (2d): White solid; yield 75%; 1H NMR (500 MHz, CDCl3) δ 7.92 − 7.90 (m, 2H), 7.41 − 7.38 (m, 3H), 7.24 (s, 1H), 4.71 (s, 2H)
4-(chloromethyl)-2-(4-(trifluoromethyl)phenyl)thiazole (2e): White solid; yield 71%; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 4.76 (s, 2H)
Synthesis of (2-methylthiazol-4-yl)methyl benzoate (3a) and its analogues (3b and 3c).
A solution of 2a (4.3 g, 33 mmol) and sodium benzoate (5.3 g, 36 mmol) in anhydrous 50 mL DMF was stirred at reflux temperature. When disappearance of starting material was observed in thin layer chromatography (TLC), the mixture was cooled to room tempurature, poured it into saturated NaCl solution and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by chromatography on a silica gel column using petroleum ether (PE) and EA (v/v: 3/1) as the eluents to obtain 3a as white solid (7.06g, 96% yield). The analogous (3b and 3c) could be synthesized in a similar method with the exception of replacing identical equivalent weigh 2b or 2c instead of 2a.
Synthesis of (2-methylthiazol-4-yl)methyl benzoate (3a)
96% yield; yellow oil;1H NMR (400 MHz, CDCl3) δ 8.11–8.04 (m, 2H), 7.60–7.53 (m, 1H), 7.46–7.40 (m, 2H), 7.21 (s, 1H), 5.43 (d, J = 0.8 Hz, 2H), 2.73 (s, 3H).
(2-isopropylthiazol-4-yl)methyl benzoate (3b)
88% yield; brown oil; 1H NMR (400 MHz, CDCl3) δ 8.18–8.00 (m, 2H), 7.65–7.52 (m, 1H), 7.49–7.38 (m, 2H), 7.22 (s, 1H), 5.45 (s, 2H), 3.39 − 3.32 (m, 1H), 1.42 (d, J = 6.9 Hz, 6H).
(2-(tert-butyl)thiazol-4-yl)methyl benzoate (3c)
83% yield; brown oil; 1H NMR (400 MHz, CDCl3) δ 8.11–8.06 (m, 2H), 7.61–7.52 (m, 1H), 7.44 (dd, J = 8.3, 7.1 Hz, 2H), 7.20 (s, 1H), 5.46 (s, 2H), 1.45 (s, 9H).
Synthesis of ((2-phenylthiazol-4-yl)methyl benzoate (3d) and (2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methyl benzoate (3e).
A solution of 2d (4.18g, 20 mmol) and sodium benzoate (3.24 g, 22 mmol) in anhydrous 50 mL DMF was stirred at reflux temperature. When disappearance of starting material was observed in TLC, the mixture was cooled to room tempurature, poured it into saturated NaCl solution and kept stirring intensely for 20min. When large amounts of solid was precipitated, the solid was collected by filtration then purified by chromatography on a silica gel column using PE and EA (v/v: 3/1) as the eluents to obtain 3d as white solid (5.37g, 91% yield). Compound 3e could be synthesized in a similar method with the exception of replacing identical equivalent weigh 2e instead of 2d.
(2-phenylthiazol-4-yl)methyl benzoate (3d)
91% yield; yellow oily liquid; 1H NMR (500 MHz, CDCl3) δ 8.13–8.07 (m, 2H), 8.00–7.92 (m, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.50–7.39 (m, 5H), 7.36 (s, 1H), 5.53 (s, 2H).
(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methyl benzoate (3e)
93% yield; black solid; 1H NMR (500 MHz, CDCl3) δ 8.14–8.09 (m, 2H), 8.08 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.61–7.55 (m, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.45 (s, 1H), 5.55 (d, J = 0.7 Hz, 2H).
Synthesis of (2-methylthiazol-4-yl)methanol (4a) and its analogues (4b–4e).
To a solution of 3a (7.06 g, 30.3 mmol) in 100 mL methanol, 1.8g (45 mmol) NaOH was added and kept stirring at room temperature. When disappearance of 3a was observed in TLC, the solution was adjusted to neutral by 1M HCl. Then the solvent was evaporated and the residue was purified by chromatography on a silica gel column using PE and acetone (v/v: 1/1) as the eluents to afford 4a as white solid (3.4 g, 88% yield). The analogous (4b–4e) could be synthesized in a similar method with the exception of replacing identical equivalent weigh 3b–3e instead of 3a.
(2-methylthiazol-4-yl)methanol (4a)
88% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.00 (t, J = 0.9 Hz, 1H), 4.68 (d, J = 0.9 Hz, 2H), 2.66 (s, 3H).
(2-isopropylthiazol-4-yl)methanol (4b)
82% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 0.8 Hz, 1H), 4.73 (d, J = 0.8 Hz, 2H), 3.33 − 3.27 (m, 1H), 1.38 (d, J = 6.9 Hz, 6H).
(2-(tert-butyl)thiazol-4-yl)methanol (4c): 71% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.02 (t, J = 0.9 Hz, 1H), 4.73 (d, J = 0.9 Hz, 2H), 1.43 (s, 9H).
(2-phenylthiazol-4-yl)methanol (4d): 85% yield; brown oil; 1H NMR (500 MHz, CDCl3) δ 7.97–7.86 (m, 2H), 7.47–7.38 (m, 3H), 7.16 (s, 1H), 4.80 (d, J = 0.9 Hz, 2H), 3.08(s, 1H).
(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methanol (4e)
70% yield; yellow solid; 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.27 (s, 1H), 4.85 (d, J = 0.9 Hz, 2H).
Synthesis of 2-methylthiazole-4-carbaldehyde (5a) and its analogues (5b–5e).
To a suspension of MnO2 (17.4g, 200 mmol) in 100 mL DCM, 4a (1.29 g, 10 mmol) was added and kept stirring at room temperature. When disappearance of 4a was observed in TLC, the insoluble substance was filtered out and washed with DCM twice. The filtrate was evaporated under reduce pressure to remove solvent to give 5a (1.1g, 85% yield) as a white solid. Without further purification, the product was used in the next reaction. The analogues (5b–5e) could be synthesized by the method similar to that described in the synthesis of 5a.
2-methylthiazole-4-carbaldehyde (5a)
85% yield; yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.04 (s, 1H), 2.78 (s, 3H).
2-isopropylthiazole-4-carbaldehyde (5b)
82% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.06 (s, 1H), 3.47–3.26 (m, 1H), 3.44 − 3.37 (m, 1H), 1.44 (d, J = 6.9 Hz, 6H).
2-(tert-butyl)thiazole-4-carbaldehyde (5c)
91% yield; yellow oil; 1H NMR (400 MHz, Chloroform-d) δ 10.01 (s, 1H), 8.06 (s, 1H), 1.48 (s, 9H).
2-phenylthiazole-4-carbaldehyde (5d)
90% yield; yellow oil; 1H NMR (500 MHz, CDCl3) δ 10.10 (s, 1H), 8.17 (s, 1H), 8.08–7.97 (s, 2H), 7.52–7.47 (s, 3H).
2-(4-(trifluoromethyl)phenyl)thiazole-4-carbaldehyde(5e)
93% yield; brown solid; 1H NMR (500 MHz, CDCl3) δ 10.12 (s, 1H), 8.24 (s, 1H), 8.13 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H).
Synthesis of (E)-3-((2-methylthiazol-4-yl)methylene)indolin-2-one (LJ1)
To a solution of 5a (12.7 mg, 0.1 mmol) in 3 mL ethanol, 6a (13.3mg, 0.1 mmol) and piperidine (34 mg, 0.4 mmol) were added and kept refluxing. When disappearance of 5a was observed in TLC, the solvent was evaporated and the residue was purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 40/60, flow rate: 3 mL/min tR = 23.3 min) to yield compound LJ1 (21.8 mg, 90% yield) as yellow solid. Melting point 220–222 ℃; 1H NMR (500 MHz, Acetone-d6) δ 9.53 (s, 1H), 9.17 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.53 (s, 1H), 7.24 (td, J = 7.6, 1.3 Hz, 1H), 7.03 (td, J = 7.6, 1.1 Hz, 1H), 6.94 (dd, J = 15.0, 7.7 Hz, 1H), 2.88 (s, 3H).13C NMR (125 MHz, Acetone-d6) δ 166.8, 166.2, 151.6, 143.0, 129.6, 128.3, 127.4, 126.0, 125.6, 122.2, 121.3, 109.3, 18.6. HR-MS (ESI) m/z: calcd for C13H10N2OS [M + H]+ 243.0587, found 243.0573.
Synthesis of (E)-3-((2-isopropylthiazol-4-yl)methylene)indolin-2-one (LJ2):
Following the similar synthesis procedure of LJ1, compound LJ2 (24.8 mg, 92% yield) was obtained as yellow solid by replacing identical equivalent weigh 5b instead of 5a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 30/70, flow rate: 3 mL/min tR = 28.1 min). Melting point 182 ℃; 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.51 (s, 1H), 7.24 (td, J = 7.6, 1.3 Hz, 1H), 6.99 (td, J = 7.6, 1.1 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.51–3.41 (m, 1H), 1.46 (d, J = 6.9 Hz, 6H).13C NMR (100 MHz, DMSO-d6) δ 178.4, 170.1, 151.0, 143.4, 130.2, 128.6, 127.9, 126.8, 125.5, 122.1, 121.5, 110.0, 33.2, 23.1. HR-MS (ESI) m/z: calcd for C15H14N2OS [M + H]+ 271.0900, found 271.0886.
Synthesis of (E)-3-((2-(tert-butyl)thiazol-4-yl)methylene)indolin-2-one (LJ3)
Following the similar synthesis procedure of LJ1, compound LJ3 (25 mg, 88% yield) was obtained as yellow solid by replacing identical equivalent weigh 5c instead of 6a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 23.1 min). Melting point 211–212 ℃; 1H NMR (500 MHz, Acetone-d6) δ 9.57 (s, 1H), 9.24 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.55 (s, 1H), 7.25 (td, J = 7.6, 1.3 Hz, 1H), 7.04 (td, J = 7.6, 1.1 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 1.57 (s, 9H).13C NMR (125 MHz, Acetone-d6) δ 181.8, 169.7, 151.4, 143.0, 129.6, 128.1, 126.8, 126.2, 125.6, 122.3, 121.1, 109.3, 38.0, 30.2. HR-MS (ESI) m/z: calcd for C16H16N2OS [M + H] + 285.1056, found 285.1043.
Synthesis of (E)-3-((2-phenylthiazol-4-yl)methylene)indolin-2-one (LJ4)
Following the similar synthesis procedure of LJ1, compound LJ4 (28.9 mg, 95% yield) was obtained as yellow solid by replacing identical equivalent weigh 5d instead of 5a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 16.7 min). Melting point 262–263℃; 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.12 (d, J = 7.7 Hz, 1H), 8.51 (s, 1H), 8.10–8.08 (m, 2H), 7.65–7.58 (m, 4H), 7.29 (td, J = 7.6, 1.4 Hz, 1H), 7.09 (td, J = 7.7, 1.1 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H).13C NMR (150 MHz, DMSO-d6) δ 170.0, 168.6, 152.5, 143.5, 133.1, 131.5, 130.5, 130.1, 129.8, 127.5, 126.8, 126.5, 126.1, 122.1, 121.7, 110.1.HR-MS (ESI) m/z: calcd for C18H12N2OS [M + H] + 305.0743, found 305.0741.
Synthesis of (E)-5-methoxy-3-((2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methylene)indolin-2-one (LJ5)
Following the similar synthesis procedure of LJ1, compound LJ5 (33.4 mg, 90% yield) was obtained as yellow solid by replacing identical equivalent weigh 5e instead of 5a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 15/85, flow rate: 3 mL/min tR = 12.0 min). Melting point 277–278 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.05 (d, J = 7.7 Hz, 1H), 8.60 (s, 1H), 8.29 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.60 (s, 1H), 7.30 (td, J = 7.6, 1.3 Hz, 1H), 7.11 (td, J = 7.7, 1.1 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H). 13C NMR (125 MHz, DMSO-d6) δ 170.0, 166.8, 152.8, 143.6, 136.6, 131.0 (d, J = 32.0 Hz), 130.7, 130.6, 127.6, 127.4, 127.1 (q, J = 3.8 Hz), 126.5, 126.2, 125.5 (d, J = 271.4 Hz), 122.0, 121.8, 110.2, 93.4. HR-MS (ESI) m/z: calcd for C19H11F3N2OS [M + H]+ 373.0617, found 373.0621.
Synthesis of (E)-5-methyl-3-((2-methylthiazol-4-yl)methylene)indolin-2-one (LJ6)
Following the similar synthesis procedure of LJ1, compound LJ6 (24.8 mg, 97% yield) was obtained as yellow solid by replacing identical equivalent weigh 6b instead of 6a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 30/70, flow rate: 3 mL/min tR = 15.4 min). Melting point 218 ℃; 1H NMR (500 MHz, Acetone-d6) δ 9.43 (s, 1H), 9.05 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.06 (dd, J = 7.8, 0.9 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 2.89 (s, 3H), 2.35 (s, 3H). 13C NMR (125 MHz, Acetone-d6) δ 169.7, 166.6, 151.6, 140.6, 130.2, 129.9, 128.9, 127.1, 125.9, 125.7, 122.2, 108.9, 20.5, 18.6. HR-MS (ESI) m/z: calcd for C14H12N2OS [M + H]+ 257.0743, found 257.0737.
Synthesis of (E)-3-((2-isopropylthiazol-4-yl)methylene)-5-methylindolin-2-one (LJ7)
Following the similar synthesis procedure of LJ1, compound LJ7 (27.5 mg, 97% yield) was obtained as yellow solid by replacing identical equivalent weigh 5b and 6b instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 24.5 min). Melting point 194 ℃; 1H NMR (500 MHz, Acetone-d6) δ 9.42 (s, 1H), 9.12 (s, 1H), 8.08 (s, 1H), 7.51 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 3.55–3.46 (m, 1H), 2.35 (s, 3H), 1.56 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, Acetone-d6) δ 183.6, 177.9, 151.5, 140.7, 130.2, 129.9, 129.2, 128.7, 126.6, 125.9, 122.4, 109.0, 33.3, 22.3, 20.4. HR-MS (ESI) m/z: calcd for C16H16N2OS [M + H]+ 285.1056, found 285.1041.
Synthesis of (E)-3-((2-(tert-butyl)thiazol-4-yl)methylene)-5-methylindolin-2-one (LJ8)
Following the similar synthesis procedure of LJ1, compound LJ8 (25.3 mg, 86% yield) was obtained as red solid by replacing identical equivalent weigh 5c and 6b instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 19.3 min). Melting point 215–217 ℃; 1H NMR (500 MHz, Acetone-d6) δ 9.13 (s, 1H), 8.09 (s, 1H), 7.51 (s, 1H), 7.07 (dd, J = 7.8, 0.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 2.35 (s, 3H), 1.60 (s, 9H). 13C NMR (125 MHz, Acetone-d6) δ 181.7, 169.8, 151.4, 140.7, 130.1, 129.9, 128.6, 126.7, 125.9, 125.8, 122.4, 108.9, 38.1, 30.3, 20.3. HR-MS (ESI) m/z: calcd for C17H18N2OS [M + H]+ 299.1213, found 261.1204.
Synthesis of (E)-5-methyl-3-((2-phenylthiazol-4-yl)methylene)indolin-2-one (LJ9)
Following the similar synthesis procedure of LJ1, compound LJ9 (29.6 mg, 93% yield) was obtained as yellow solid by replacing identical equivalent weigh 5d and 6b instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 23.7 min). Melting point 250–250 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.07 (s, 1H), 8.48 (s, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.62–7.60 (m, 3H), 7.54 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 2.36 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 170.1, 168.4, 152.5, 141.2, 133.2, 131.5, 130.7, 130.1, 130.0, 129.5, 128.4, 126.8, 126.4, 126.1, 122.2, 109.7, 21.4. HR-MS (ESI) m/z: calcd for C19H14N2OS [M + H]+ 319.0900, found 319.0894.
Synthesis of (E)-5-hydroxy-3-((2-methylthiazol-4-yl)methylene)indolin-2-one (LJ10)
Following the similar synthesis procedure of LJ1, compound LJ10 (25.2 mg, 98% yield) was obtained as red solid by replacing identical equivalent weigh 6c instead of 6c and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 50/50, flow rate: 3 mL/min tR = 13.0 min). Melting point 264 ℃; 1H NMR (600 MHz, Acetone-d6) δ 9.23 (s, 1H), 8.82 (s, 1H), 8.04 (s, 1H), 7.49 (s, 1H), 6.76 (s, 1H), 6.74 (d, J = 1.1 Hz, 1H), 2.89 (s, 3H). 13C NMR (125 MHz, Acetone-d6) δ 169.9, 166.8, 152.3, 151.6, 135.8, 127.1, 126.3, 125.9, 123.0, 116.2, 115.8, 109.5, 18.6. HR-MS (ESI) m/z: calcd for C13H10N2O2S [M + H]+ 259.0536, found 259.0533.
Synthesis of (E)-5-hydroxy-3-((2-isopropylthiazol-4-yl)methylene)indolin-2-one (LJ11)
Following the similar synthesis procedure of LJ1, compound LJ11 (25.4 mg, 89% yield) was obtained as red solid by replacing identical equivalent weigh 5b and 6c instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 40/60, flow rate: 3 mL/min tR = 19.2 min). Melting point 228 ℃; 1H NMR (600 MHz, Acetone-d6) δ 9.22 (s, 1H), 8.84 (d, J = 2.5 Hz, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.50 (s, 1H), 6.76 (dd, J = 8.2, 2.5 Hz, 1H), 6.73 (dd, J = 8.3, 0.6 Hz, 1H), 3.54 (p, J = 6.9 Hz, 1H), 1.52 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, Acetone-d6) δ 178.3, 169.8, 152.3, 151.5, 135.9, 126.4, 126.3, 126.0, 123.2, 116.1, 109.3, 109.3, 33.4, 22.4. HR-MS (ESI) m/z: calcd for C15H14N2O2S [M + H]+ 287.0849, found 287.0842.
Synthesis of (E)-3-((2-(tert-butyl)thiazol-4-yl)methylene)-5-hydroxyindolin-2-one (LJ12)
Following the similar synthesis procedure of LJ1, compound LJ12 (27.3 mg, 91% yield) was obtained as red solid by replacing identical equivalent weigh 5c and 6c instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 35/65, flow rate: 3 mL/min tR = 15.6 min). Melting point 234 ℃; 1H NMR (600 MHz, Acetone-d6) δ 9.22 (s, 1H), 8.83 (d, J = 2.5 Hz, 1H), 8.08 (s, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 6.77 (dd, J = 8.2, 2.6 Hz, 1H), 6.72 (dd, J = 8.2, 0.6 Hz, 1H), 1.58 (s, 9H).13C NMR (125 MHz, Acetone-d6) δ 181.8, 169.8, 152.3, 151.4, 135.9, 126.5, 126.3, 126.1, 123.3, 116.3, 116.1, 109.2, 38.0, 30.3. HR-MS (ESI) m/z: calcd for C16H16N2O2S [M + H]+ 301.1005, found 301.0996.
Synthesis of (E)-5-hydroxy-3-((2-phenylthiazol-4-yl)methylene)indolin-2-one (LJ13)
Following the similar synthesis procedure of LJ1, compound LJ13 (30.7 mg, 96% yield) was obtained as red solid by replacing identical equivalent weigh 5d and 6c instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 35/65, flow rate: 3 mL/min tR = 18.1 min). Melting point 198 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.97 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.13–8.12 (m, 2H), 7.60–7.59 (m, 3H), 7.53 (s, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H).13C NMR (125 MHz, DMSO-d6)) δ 170.1, 168.6, 152.5, 152.5, 136.0, 133.1, 131.4, 130.0, 129.3, 128.8, 127.0, 126.2, 122.9, 117.0, 115.6, 110.1. HR-MS (ESI) m/z: calcd for C18H12N2O2S [M + H] + 321.0692, found 321.0690.
Synthesis of (E)-5-hydroxy-3-((2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methylene)indolin-2-one (LJ14)
Following the similar synthesis procedure of LJ1, compound LJ14 (33.3 mg, 86% yield) was obtained as red solid by replacing identical equivalent weigh 5e and 6c instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 13.1 min). Melting point 293–294 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.96 (s, 1H), 8.57 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H), 6.76 (dd, J = 8.3, 2.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 169.5, 166.3, 152.4, 152.0, 136.2, 135.6, 130.5 (d, J = 31.9 Hz), 129.8, 127.3, 127.0, 126.41 (q, J = 3.6 Hz), 125.5, 123.9 (d, J = 272.3 Hz), 122.3, 116.8, 114.9, 109.8. HR-MS (ESI) m/z: calcd for C19H11F3N2O2S [M + H]+ 389.0566, found 389.0559.
Synthesis of (E)-5-methoxy-3-((2-methylthiazol-4-yl)methylene)indolin-2-one (LJ15)
Following the similar synthesis procedure of LJ1, compound LJ15 (24.2 mg, 89% yield) was obtained as red solid by replacing identical equivalent weigh 6d instead 6a, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 40/60, flow rate: 3 mL/min tR = 22.2 min). Melting point 199–200 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.89 (d, J = 2.7 Hz, 1H), 8.29 (s, 1H), 7.48 (s, 1H), 6.83 (dd, J = 8.4, 2.7 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 2.83 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 170.2, 167.2, 154.8, 151.2, 137.0, 129.5, 126.6, 126.0, 122.8, 116.4, 113.4, 110.3, 55.7, 19.7. HR-MS (ESI) m/z: calcd for C14H12N2O2S [M + H]+ 273.0692, found 273.0691.
Synthesis of (E)-3-((2-isopropylthiazol-4-yl)methylene)-5-methoxyindolin-2-one (LJ16):
Following the similar synthesis procedure of LJ1, compound LJ16 (26.1 mg, 87% yield) was obtained as red solid by replacing identical equivalent weigh 5b and 6d instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 30/70, flow rate: 3 mL/min tR = 23.6 min). Melting point 171 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.80 (d, J = 2.7 Hz, 1H), 8.33 (s, 1H), 7.50 (s, 1H), 6.85 (dd, J = 8.4, 2.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 3.49–3.41 (m, 1H), 1.45 (d, J = 6.9 Hz, 6H). 13C NMR (150 MHz, DMSO-d6) δ 178.7, 170.2, 154.9, 151.2, 137.1, 128.8, 126.9, 125.9, 122.9, 115.6, 114.4, 110.1, 56.1, 33.4, 23.2. HR-MS (ESI) m/z: calcd for C16H16N2O2S [M + H]+ 301.1005, found 301.0997.
Synthesis of (E)-3-((2-(tert-butyl)thiazol-4-yl)methylene)-5-methoxyindolin-2-one (LJ17)
Following the similar synthesis procedure of LJ1, compound LJ17 (29.8 mg, 95% yield) was obtained as yellow solid by replacing identical equivalent weigh 5c and 6d instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 18.9 min). Melting point 218 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.72 (d, J = 2.6 Hz, 1H), 8.34 (s, 1H), 7.50 (s, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 1.51 (s, 9H).13C NMR (100 MHz, DMSO-d6) δ 182.2, 170.1, 155.0, 151.2, 137.2, 128.9, 127.1, 125.7, 123.1, 115.3, 115.0, 110.0, 56.5, 38.2, 31.0. HR-MS (ESI) m/z: calcd for C17H18N2O2S [M + H]+ 315.1162, found 315.1144.
Synthesis of (E)-5-methoxy-3-((2-phenylthiazol-4-yl)methylene)indolin-2-one (LJ18)
Following the similar synthesis procedure of LJ1, compound LJ18 (30.7 mg, 92% yield) was obtained as red solid by replacing identical equivalent weigh 5d and 6d instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 24.1 min). Melting point 227–228 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.82 (d, J = 2.6 Hz, 1H), 8.54 (s, 1H), 8.11 (dd, J = 6.6, 2.8 Hz, 2H), 7.61–7.59 (m, 4H), 6.89 (dd, J = 8.4, 2.7 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 170.1, 168.7, 154.9, 152.5, 137.3, 133.1, 131.5, 130.1, 129.9, 127.0, 126.6, 126.6, 122.8, 116.2, 113.8, 110.4, 56.2.HR-MS (ESI) m/z: calcd for C19H14N2O2S [M + H] + 335.0849, found 335.0836.
Synthesis of (E)-5-methyl-3-((2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methylene)indolin-2-one (LJ19)
Following the similar synthesis procedure of LJ1, compound LJ19 (34.1 mg, 85% yield) was obtained as red solid by replacing identical equivalent weigh 5e and 6d instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 20.0 min). Melting point 243–244 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.62 (s, 1H), 8.30 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 169.5, 166.5, 154.5, 152.3, 136.9, 136.2, 130.7 (d, J = 31.8 Hz), 130.6, 127.3, 126.5, 126.4 (q, J = 3.9 Hz), 125.9, 123.93 (d, J = 272.4 Hz), 122.2, 115.9, 113.1, 110.0, 55.7. HR-MS (ESI) m/z: calcd for C20H13F3N2O2S [M + H]+ 403.0723, found 403.0726.
Synthesis of (E)-5-fluoro-3-((2-methylthiazol-4-yl)methylene)indolin-2-one (LJ20)
Following the similar synthesis procedure of LJ1, compound LJ20 (24.7 mg, 95% yield) was obtained as yellow solid by replacing identical equivalent weigh 6e instead of 6a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 30/70, flow rate: 3 mL/min tR = 13.3 min). Melting point 239–241 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.94 (dd, J = 10.4, 2.8 Hz, 1H), 8.36 (s, 1H), 7.55 (s, 1H), 7.09 (td, J = 8.9, 2.8 Hz, 1H), 6.84 (dd, J = 8.5, 4.7 Hz, 1H), 2.84 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 170.1, 167.7, 157.96 (d, J = 233.3 Hz), 150.9, 139.65–139.58 (m), 130.6, 128.0, 125.00 (d, J = 2.8 Hz), 123.17 (d, J = 10.2 Hz), 116.30 (d, J = 23.9 Hz), 115.00 (d, J = 27.5 Hz), 110.45 (d, J = 8.4 Hz), 19.7. HR-MS (ESI) m/z: calcd for C13H9FN2OS [M + H]+ 261.0492, found 261.0480.
Synthesis of (E)-5-fluoro-3-((2-isopropylthiazol-4-yl)methylene)indolin-2-one (LJ21)
Following the similar synthesis procedure of LJ1, compound LJ21 (25.6 mg, 89% yield) was obtained as yellow solid by replacing identical equivalent weigh 5b and 6e instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 19.4 min). Melting point 203 ℃; 1H NMR (600 MHz, Acetone-d6) δ 9.53 (s, 1H), 9.18 (dd, J = 10.5, 2.8 Hz, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.03 (td, J = 8.8, 2.8 Hz, 1H), 6.91 (dd, J = 8.5, 4.6 Hz, 1H), 3.52 (p, J = 6.9 Hz, 1H), 1.55 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, Acetone-d6) δ 178.5, 168.8, 158.31 (d, J = 233.9 Hz), 151.2, 139.16 (d, J = 1.9 Hz), 127.9, 127.4, 125.23 (d, J = 3.7 Hz), 123.42 (d, J = 10.2 Hz), 115.57 (d, J = 24.2 Hz), 115.16 (d, J = 27.7 Hz), 109.74 (d, J = 8.2 Hz), 33.4, 22.2. HR-MS (ESI) m/z: calcd for C15H13FN2OS [M + H]+ 289.0805, found 289.0801.
Synthesis of (E)-3-((2-(tert-butyl)thiazol-4-yl)methylene)-5-fluoroindolin-2-one (LJ22)
Following the similar synthesis procedure of LJ1, compound LJ22 (26.8 mg, 89% yield) was obtained as yellow solid by replacing identical equivalent weigh 5c and 6e instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 16.9 min). Melting point 207–208 ℃; 1H NMR (600 MHz, Acetone-d6) δ 9.51 (s, 1H), 9.2 (dd, J = 10.5, 2.8 Hz, 1H), 8.20 (s, 1H), 7.58 (s, 1H), 7.04 (td, J = 8.8, 2.8 Hz, 1H), 6.91 (dd, J = 8.5, 4.6 Hz, 1H), 1.59 (s, 9H).13C NMR (125 MHz, Acetone-d6) δ 182.2, 169.7, 158.32 (d, J = 233.7 Hz), 151.1, 139.15 (d, J = 1.9 Hz), 128.0, 127.5, 125.16 (d, J = 2.7 Hz), 123.43 (d, J = 10.4 Hz), 115.56 (d, J = 24.2 Hz), 115.12 (d, J = 27.7 Hz), 109.74 (d, J = 8.2 Hz), 38.1, 30.2. HR-MS (ESI) m/z: calcd for C16H15FN2OS [M + H]+ 303.0962, found 303.0952.
Synthesis of (E)-5-fluoro-3-((2-phenylthiazol-4-yl)methylene)indolin-2-one (LJ23)
Following the similar synthesis procedure of LJ1, compound LJ23 (30.2 mg, 94% yield) was obtained as yellow solid by replacing identical equivalent weigh 5e and 6e instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 16.0 min). Melting point 291–292 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.08 (dd, J = 10.4, 2.8 Hz, 1H), 8.59 (s, 1H), 8.08 (dd, J = 7.7, 1.8 Hz, 2H), 7.64–7.60 (m, 4H), 7.13 (td, J = 8.8, 2.8 Hz, 1H), 6.87 (dd, J = 8.5, 4.7 Hz, 1H).13C NMR (125 MHz, DMSO-d6) δ 170.0, 168.9, 158.91 (d, J = 1.9 Hz), 152.2, 139.76 (d, J = 1.8 Hz), 133.0, 131.6, 131.0, 130.1, 127.7, 126.8, 125.71 (d, J = 2.9 Hz), 123.12 (d, J = 2.5 Hz), 116.59 (d, J = 24.0 Hz), 114.54 (d, J = 25.6 Hz), 110.65 (d, J = 8.4 Hz). HR-MS (ESI) m/z: calcd for C18H11FN2OS [M + H]+ 323.0649, found 323.0640.
Synthesis of (E)-5-fluoro-3-((2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)methylene)indolin-2-one (LJ24):
Following the similar synthesis procedure of LJ1, compound LJ24 (35.1 mg, 90% yield) was obtained as yellow solid by replacing identical equivalent weigh 5f and 6e instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 26.8 min). Melting point 274 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.96 (dd, J = 10.3, 2.8 Hz, 1H), 8.67 (s, 1H), 8.26 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.65 (s, 1H), 7.14 (td, J = 8.8, 2.8 Hz, 1H), 6.88 (dd, J = 8.5, 4.6 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) δ 169.5, 166.7, 158.3, 156.8, 152.1, 139.4, 136.2, 131.5, 130.18 (d, J = 146.7 Hz), 127.12 (d, J = 6.0 Hz), 126.62 (q, J = 38.1, 4.2 Hz), 125.66 (d, J = 4.0 Hz), 123.93 (d, J = 272.5 Hz), 122.59 (d, J = 10.0 Hz), 116.35 (d, J = 23.8 Hz), 1 113.95 (d, J = 27.5 Hz), 110.32 (d, J = 8.0 Hz). HR-MS (ESI) m/z: calcd for C19H10F4N2OS [M + H]+ 391.0523, found 391.0518.
Synthesis of (E )-5-chloro-3-((2-methylthiazol-4-yl)methylene)indolin-2-one (LJ25): Following the similar synthesis procedure of LJ1, compound LJ25 (22.6 mg, 82% yield) was obtained as yellow solid by replacing identical equivalent weigh 6f instead of 6a and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 30/70, flow rate: 3 mL/min tR = 21.5 min). Melting point 258 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.20 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 7.55 (s, 1H), 7.28 (dd, J = 8.3, 2.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 2.84 (s, 3H).13C NMR (100 MHz, DMSO-d6) δ 169.9, 167.6, 150.8, 142.0, 130.7, 129.5, 128.1, 127.8, 125.6, 124.4, 123.7, 111.2, 19.7. HR-MS (ESI) m/z: calcd for C13H9ClN2OS [M + H]+ 277.0197, found 277.0191.
Synthesis of (E)-5-chloro-3-((2-isopropylthiazol-4-yl)methylene)indolin-2-one (LJ26)
Following the similar synthesis procedure of LJ1, compound LJ26 (27.3 mg, 90% yield) was obtained as yellow solid by replacing identical equivalent weigh 5b and 6f instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 25/75, flow rate: 3 mL/min tR = 30.0 min). Melting point 189 ℃; 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.31 (d, J = 2.3 Hz, 1H), 8.40 (s, 1H), 7.56 (s, 1H), 7.28 (dd, J = 8.3, 2.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.49–3.41 (m, 1H), 1.49 (d, J = 6.9 Hz, 6H).13C NMR (100 MHz, DMSO-d6) δ 178.6, 169.9, 150.8, 142.0, 130.1, 129.5, 128.2, 127.7, 125.7, 124.4, 123.7, 111.2, 33.2, 23.0. HR-MS (ESI) m/z: calcd for C15H13ClN2OS [M + H]+ 305.0510, found 305.0504.
Synthesis of (E)-3-((2-(tert-butyl)thiazol-4-yl)methylene)-5-chloroindolin-2-one (LJ27):
Following the similar synthesis procedure of LJ1, compound LJ27 (28.6 mg, 90% yield) was obtained as yellow solid by replacing identical equivalent weigh 5c and 6f instead of 5a and 6a respectively, and purified by semi-preparative HPLC (water/methanol containing 0.05% TFA = 20/80, flow rate: 3 mL/min tR = 22.1 min). yellow solid; Melting point 205.9-206.8℃; 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.32 (s, 1H), 8.41 (s, 1H), 7.56 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 1.52 (s, 9H).13C NMR (100 MHz, DMSO-d6) δ 182.4, 169.8, 150.7, 142.0, 130.0, 129.5, 128.3, 127.6, 125.7, 124.5, 123.7, 111.2, 38.3, 31.0. HR-MS (ESI) m/z: calcd for C16H15ClN2OS [M + H]+ 319.0666, found 319.0661.