Imidazo heteroaryl derivative as well as preparation method and medical application thereof
A heteroaryl and aryl technology, which is applied in the direction of pharmaceutical formulations, drug combinations, medical preparations containing active ingredients, etc., can solve the problems of poor oral bioavailability and inconvenient administration
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Embodiment 1
[0226] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]3,6-dihydro-2H-pyridin-1-yl]methyl ]-1[[(2S)-oxetan-2-yl]methyl]thieno[2,3-d]imidazole-5-carboxylic acid 1
[0227]
[0228] first step
[0229] Methyl 5-nitro-4-[[(2S)-oxetan-2-yl]methylamino]thiophene-2carboxylate 1c
[0230] Compound 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester 1a (305mg, 1.15mmol, prepared by the method disclosed in Example 114 Intermediate C on page 124 of the specification in patent application WO200399805A1), compound ( S)-Oxetan-2-ylmethylamine 1b (100mg, 1.15mmol, Nanjing Yaoshi Technology Co., Ltd.), triethylamine (580mg, 5.73mmol) was dissolved in tetrahydrofuran (10mL), stirred at 80°C for 16 Hour. Cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (310 mg, yield: 90.1%).
[0231] MS m / z (ESI): 273.1 [M+1].
[0232] 1 H NMR (500MHz, DMSO-d 6 )δ8.64(t,1H)...
Embodiment 2
[0265] 2-((4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6- Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-thieno[2,3-d]imidazole- 5-Carboxylic acid 2
[0266]
[0267] first step
[0268] 4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6- Tetrahydropyridine 4-toluenesulfonate 2b
[0269] Compound 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxin-4-yl)-5,6-dihydropyridine-1 (2H)-tert-butyl carboxylate 2a (111mg, 0.25mmol, prepared by the method disclosed in intermediate C5 on page 32 of the specification in the patent application US20190382384A1), p-toluenesulfonic acid monohydrate (237mg, 1.24mmol) Dissolve in ethyl acetate (10 mL), and stir at 60°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the title compound 2b (129 mg, p-toluenesulfonate), which was directly used in the next reaction without purification. MS m / z (ESI):...
Embodiment 3
[0280] 2-((4-((S or R)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl )piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid 3
[0281]
[0282]
[0283] first step
[0284] (S)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6- tert-butyl dihydropyridine-1(2H)-carboxylate 3b
[0285] (R)-4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6- tert-butyl dihydropyridine-1(2H)-carboxylate 3c
[0286] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6-dihydropyridine - 1(2H)-tert-butyl carboxylate 3a (6.52g, 14.62mmol, prepared by the method disclosed in the example intermediate C3 on page 54 of the patent application WO2019239319A1 specification) was subjected to chiral separation (separation condition: Superchiral S-AD chiral preparative column, 2.1cm I.D×25cm L; mobile phase: Hexane / IPA=95 / 5 (V / V), flow rate: 16mL / min), the corresponding components were c...
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