A class of grp94 inhibitors with a benzamide core structure and uses thereof
A use, colitis technology, applied in the treatment of diseases mediated by Grp94, in the field of benzamide compounds, which can solve the problems that the therapeutic effect of inflammation-related diseases has not yet been studied, and the inhibitory activity and selectivity are weak
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Embodiment 1
[0040] Preparation of 4-(((1r,4r)-4-hydroxycyclohexyl)amino)-[1,1'-biphenyl]-3-carboxamide (1)
[0041]
[0042] This product is prepared by method 1, and the specific operation is as follows.
[0043] (1) Preparation of 4-fluoro-[1,1'-biphenyl]-3-benzonitrile
[0044] 5-cyano-2-fluorophenylboronic acid pinacol ester (247mg, 1.0mmol) and iodobenzene (306mg, 1.5mmol) were dissolved in dioxane, and Pd(PPh 3 ) 4 (116mg, 0.1mmol) and CsCO 3 (652mg, 2.0mmol), react overnight at 90°C under nitrogen. The reaction solution was suction-filtered with diatomaceous earth, the filtrate was spin-dried and dispersed in 20ml of ethyl acetate, washed twice with 20ml of water and sodium chloride solution, and dried over anhydrous sodium sulfate. Petroleum ether column chromatography gave 168 mg of a colorless oily substance, yield: 85.3%. 1 H NMR (300MHz, Chloroform-d) δ7.86–7.81(m,2H),7.61–7.46(m,5H),7.32(m,1H).
[0045] (2) Preparation of title compound
[0046] Dissolve the white s...
Embodiment 2
[0048] Preparation of 4-(((1r,4r)-4-hydroxycyclohexyl)amino)-2'-methyl-[1,1'-biphenyl]-3-carboxamide (2)
[0049]
[0050] The preparation method of this product is the same as in Example 1, except that iodobenzene is replaced by 2-iodotoluene (327mg, 1.5mmol). 85 mg of white solid was obtained with a total yield of 26.2%. 1 H NMR (300MHz, DMSO-d6) δ8.19 (d, J = 7.6Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 7.26–7.21 (m, 5H), 7.12 (s, 1H),6.75(d,J=8.7Hz,1H),4.60(s,1H),3.52–3.35(m,1H),3.32–3.27(m,1H),2.26(s,3H),2.01–1.98 (m,2H),1.85–1.81(m,2H),1.38–1.30(m,2H),1.26–1.15(m,2H).HRMS(ESI):calcd for C 20 h 25 N 2 o 2 [M+H] + 325.1838,found 325.1915.
Embodiment 3
[0052] Preparation of 4-(((1r,4r)-4-hydroxycyclohexyl)amino)-3'-methyl-[1,1'-biphenyl]-3-carboxamide (3)
[0053]
[0054] The preparation method of this product is the same as in Example 1, except that iodobenzene is replaced by 3-iodotoluene (327mg, 1.5mmol). 52 mg of white solid was obtained with a total yield of 16.0%. 1 H NMR (300MHz, DMSO-d6) δ8.16(d, J=7.7Hz, 1H), 8.02(s, 1H), 7.87(d, J=1.9Hz, 1H), 7.56(dd, J=8.7, 1.7Hz, 1H), 7.47(s, 1H), 7.42(d, J=8.2Hz, 1H), 7.27(t, J=7.5Hz, 1H), 7.19(s, 1H), 7.05(d, J= 7.4Hz, 1H), 6.78(d, J=8.9Hz, 1H), 4.58(d, J=4.1Hz, 1H), 3.52–3.44(m, 1H), 3.40–3.34(m, 1H), 2.35( s,3H),2.00–1.96(m,2H),1.85–1.80(m,2H),1.39–1.29(m,2H),1.27–1.14(m,2H).HRMS(ESI):calcd for C 20 h 25 N 2 o 2 [M+H] + 325.1838, found 325.1916.
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