2-amidothiazole derivatives and its preparation method and use

[0221] Example 1 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-cyclohexyl-1,2,3,6-tetrahydropyridin-4-yl )thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (compound L1)

[0222]

[0223] Step 1: Synthesis of 4-[2-amino-4-(4-chlorothiophen-2-yl)thiazol-5-yl]-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0224] 5-Bromo-4-(4-chlorothiophen-2-yl)-2-amino-thiazole (900mg, 3.1mmol), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4 - pinacol borate (960mg, 3.1mmol), anhydrous sodium carbonate (920mg, 7.3mmol) and tetrakistriphenylphosphine palladium (180mg, 0.2mmol), dissolved in a mixed solvent of ethylene glycol dimethyl ether and water Medium (45mL, V:V=2:1). Reacted at 70°C for 1.5h under the protection of nitrogen. Cool down to room temperature, filter, and concentrate the filtrate to obtain a crude product, which is purified by silica gel column chromatography to obtain 1.1 g of the title compound.

[0225] ESI-MS(m / z): 398.2[M+H] +

[022

[0242] Example 2 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl )thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (compound L2)

[0243]

[0244] Using a method similar to Example 1, but in the first step, replace N- Starting from tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (960 mg, 3.1 mmol), the title was prepared by substituting paraformaldehyde for cyclohexanone in the fifth step Trifluoroacetate salt of compound, 32 mg.

[0245] 1 H NMR (400MHz, DMSO-d 6 )δ12.73(s, 1H), 12.31(s, 1H), 9.26(s, 1H), 8.84(d, J=2.1Hz, 1H), 8.40(d, J=2.1Hz, 1H), 7.62( d, J=1.5Hz, 1H), 7.52(d, J=1.5Hz, 1H), 6.29(s, 1H), 4.00-3.97(d, J=13.1Hz, 2H), 3.68(s, 1H), 3.60-3.52(m, 1H), 3.46(d, J=11.6Hz, 2H), 3.07-3.01(m, 2H), 2.93(d, J=12.1Hz, 2H), 2.82(d, J=3.9Hz , 3H), 2.56-2.54 (m, 1H), 1.95 (d, J=10.5Hz, 2H), 1.72-1.63 (m, 2H), 1.38 (s, 3H), 1.31-1.18 (m, 2H).

[0246] ESI-MS(m / z): 578.2[M+H] + .

[0247] Example 3 1-(3-chloro-5-{[4-(4-chlorothien-2-yl)-5-(1-cyclohexyl-1,2,5,6-tetrahydropyridin-3-yl )thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid (compound L3)

[0248]

[0249] Using a method similar to Example 1, but in the first step, replace N- 32 mg of the trifluoroacetic acid salt of the title compound were prepared from tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (960 mg, 3.1 mmol).

[0250] 1 H NMR (400MHz, DMSO-d 6 )δ12.89(s, 1H), 12.26(s, 1H), 9.80(s, 1H), 8.85(d, J=2.1Hz, 1H), 8.42(d, J=2.1Hz, 1H), 7.63( s, 1H), 7.42(s, 1H), 6.30(s, 1H), 4.00-3.97(m, 3H), 3.82(d, J=15.4Hz, 1H), 3.62(s, 1H), 3.29-3.24 (m, 1H), 3.07-3.01(t, J=11.9Hz, 2H), 2.93(d, J=12.1Hz, 2H), 2.69-2.53(m, 2H), 2.09-1.93(m, 4H), 1.82 (d, J=10.4Hz, 2H), 1.71-1.59 (m, 3H), 1.48-1.39 (m, 2H), 1.32-1.23 (s, 3H), 1.14-1.05 (m, 2H).

[0251] ESI-MS(m / z): 646.2[M+H] + .