Therapeutic compounds
A technology of compounds and analogs, applied in the field of therapeutic compounds
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[0422] The following are examples of methods and compositions of the present disclosure. It should be understood that various other embodiments may be practiced given the general description provided above. The present disclosure will be understood in more detail with reference to the following examples. However, the claims should not be construed as limiting the scope of the embodiments.
[0423] Intermediate A
[0424] 2-Bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-7(4H )-ketone preparation
[0425] The general reaction scheme is as follows:
[0426]
[0427] Step 1: Ethyl 3-(4-cyclohexylphenyl)-3-oxopropanoate
[0428]
[0429] To a solution of 1-(4-cyclohexylphenyl)ethanone (40 g, 197 mmol) in THF (400 mL) at 0 °C was added NaH (60% in mineral oil, 17.4 g, 435 mmol) followed by slow addition of dicarbonate Ethyl ester (70 g, 593 mmol) and stirred for 5 h. The reaction solution was replaced with saturated NH 4 ...
example 1
[0621] 5-(4-Cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-di Preparation of Hydropyrazolo[1,5-a]pyrimidine-2-carboxamide
[0622]
[0623] To 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1, 5-a]pyrimidine-2-carboxylic acid (Intermediate B, 40 mg, 0.09 mmol), N,N-dimethylamine hydrochloride (18 mg, 0.22 mmol) and DIPEA (0.12 mL, 0.74 mmol) in DMF (3 mL) To the solution in HATU (50 mg, 0.13 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc (40 mL) and washed with water (50 mL x 2). The organic layer was passed through Na 2 SO 4 Dry, filter, and concentrate in vacuo. The crude product was purified by preparative HPLC (acetonitrile 0-45 / 0.1% FA in water, Xtimate C18 150 x 40 mm x 10 μm) to give the title compound (8.4 mg, 20%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ): δ12.06(s, 1H), 7.73(d, J=8.4Hz, 2H), 7.45(d, J=8.4Hz, 2H), 6...
example 2
[0625] 5-(4-(Cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo- Preparation of 4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide
[0626] The general reaction scheme is as follows:
[0627]
[0628] Step 1: 5-(4-(Cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-di Hydropyrazolo[1,5-a]pyrimidine-2-carboxamide
[0629]
[0630] The title compound (35 mg, 38%) was provided as a brown solid. It was prepared from 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine following the procedure outlined for Intermediate B, Step 1 Alk-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.21 mmol) was prepared. LCMS(ESI): m / z 452.2(M+H) + .
[0631] Step 2: 5-(4-(Cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-di Hydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid
[0632]
[0633] The title compound (30 mg, 85%) was provided as a white solid. It was prepared from...
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