Modulators of indoleamine 2,3-dioxygenase
A technology of SO2 and alkyl, which is applied in the field of preventing and/or treating HIV compounds and preparing such compounds, and can solve the problems of unclear single-drug activity and other issues
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Embodiment 1
[0161] Example 1: tert-butyl 4-(2-(5-ethylthiophene-2-carboxamido)-2-phenylethyl)piperidine-1-carboxylate
[0162]
[0163] To tert-butyl 4-(2-amino-2-phenylethyl)piperidine-1-carboxylate (50.0 mg, 0.164 mmol), 5-ethylthiophene-2-carboxylic acid (28.2 mg, 0.181 mmol) and DIEA To a stirred solution of (86 uL mL, 0.49 mmol) in DMF (2 mL) was added HATU (94 mg, 0.25 mmol). The resulting solution was stirred at room temperature. After 18 h, the solution was treated with 2M ammonia / MeOH (3 mL). After stirring at room temperature for another 1 h, the solution was partitioned between EtOAc and brine and the phases were separated. The EtOAc solution was washed with 10% aqueous citric acid (2x), saturated NaHCO 3 aqueous solution (2x), washed with Na 2 SO 4 Dry and concentrate to dryness under reduced pressure. The residue was subjected to flash chromatography (silica gel, 0-100% EtOAc / hexanes, gradient elution) to give the title compound (54 mg, 74% yield) as a white solid. ...
Embodiment 2
[0164] Example 2: tert-butyl 4-(2-(5-bromothiophene-2-carboxamido)-2-phenylethyl)piperidine-1-carboxylate
[0165]
[0166] As described herein for the preparation of tert-butyl 4-(2-(5-ethylthiophene-2-carboxamido)-2-phenylethyl)piperidine-1-carboxylate, from 4-(2- The title compound was prepared from tert-butyl amino-2-phenylethyl)piperidine-1-carboxylate and 5-bromothiophene-2-carboxylic acid in 77% yield. LCMS (ESI) m / z C 23 h 29 BrN 2 o 3 Calculated value of S: 492.1. Measured value: 493.2 (M+1) + . 1 HNMR (400 MHz, CDCl 3 ) δ 7.27 - 7.40 (m, 5H), 7.20 (d, J = 3.9 Hz, 1H), 7.01(d, J = 3.9 Hz, 1H), 6.01 (d,J = 8.2 Hz, 1H), 5.22 (q, J = 8.2 Hz, 1H), 3.95- 4.10 (m, 2H), 2.61 (t, J = 12.3 Hz, 2H), 1.65 - 1.94 (m, 4H), 1.35 - 1.50(m, 10H), 1.01 - 1.30 (m, 2H).
Embodiment 3
[0167] Example 3: tert-butyl 4-(2-(5-chlorothiophene-2-carboxamido)-2-phenylethyl)piperidine-1-carboxylate
[0168]
[0169] To a stirred solution of tert-butyl 4-(2-amino-2-phenylethyl)piperidine-1-carboxylate (0.785 g, 2.58 mmol) in DMF (30 mL) was added COMU (1.63 g, 3.81 mmol) , followed by the addition of DIEA (1.36 mL, 7.79 mmol), and then 5-chlorothiophene-2-carboxylic acid (0.544 g, 3.35 mmol). After stirring at room temperature for 2 h, the solution was quenched with water and dissolved in DCM and saturated Na 2 CO 3 Partition between aqueous solutions. The phases were separated and the aqueous phase was extracted with DCM (2x). The combined DCM solution was concentrated to dryness under reduced pressure and the residue was purified by reverse phase HPLC (C18, MeCN / water with ammonium carbonate modifier) to give the title compound. LCMS (ESI) m / z C 23 h 29 ClN 2 o 3 Calculated value of S: 448.1. Measured value: 449.1 (M+1) + . 1 H NMR (400 MHz, CDCl 3 ...
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