Substituted pyrazolopyrimidines and substituted purines and their use as ubiquitin-specific-processing protease 1 (USP1) inhibitors
A solvate, C1-C2 technology for substituted pyrazolopyrimidines and substituted purines and their use as ubiquitin-specific processing protease 1 (USP1) inhibitors to address targeted deubiquitination The safe and effective treatment of nephrase is unclear and not commercially available
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[0559] This disclosure encompasses the preparation and use of salts of the disclosed compounds, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium, potassium, cesium, and the like; alkaline earth metal salts, such as calcium, magnesium, and the like; organic amine salts, such as triethylamine, Pyridinium, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,N'-benzhydrylethylenediamine and similar salts; inorganic acid salts, such as hydrochloride, hydrobromic acid Salt, phosphate, sulfate and similar salts; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate , trifluoroacetate, oxalate, formate, and similar salts; sulfonates, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and...
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[0651] General Synthesis Method
[0652] Compounds of the disclosure are prepared from the present disclosure using methods known to those skilled in the art, or by the illustrative methods shown in the following general schemes. In any of the general schemes described, suitable protecting groups may be employed in the synthesis. (See Wuts, P.G.M.; Greene, T.W., "Greene's Protective Groups in Organic Synthesis", 4th ed., J. Wiley & Sons, NY, 2007).
[0653] All reagents were used without further purification unless otherwise indicated. 1 H NMR spectra were at room temperature on a Bruker 300 MHz instrument in DMSO-d 6 or CD 3 Obtained in OD. When more than one conformational isomer was detected, the chemical shift of the most abundant conformational isomer was reported. 1 Chemical shifts in H NMR spectra are reported in parts per million (ppm) on a delta scale relative to an internal standard of residual solvent. The splitting pattern is designed as s, that is, singlet...
preparation example 1
[1538]
[1539] At 100°C, 6-chloro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3 ,4-d]pyrimidine (100mg, 0.25mmol), K 3 PO 4 .3H 2 O (208mg, 0.78mmol), (2-isopropylphenyl)boronic acid (84mg, 0.51mmol) and Pd(PPh 3 ) 4 (30mg, 0.025mmol) in 1,4-dioxane (4ml) and water (0.3ml) was stirred for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EA (20 mL x 2). The combined organic layers were washed with Na 2 SO 4 (10 g) was dried, filtered and concentrated to dryness. The concentrated residue was purified by silica gel chromatography (PE:EA=30:1 to 5:1) followed by preparative HPLC to afford 62 mg of the title compound. LC-MS (Method A) (ESI+): m / z 477 (M+H) + ; 1 H-NMR (300MHz, CDCl 3 )δ9.30(s,1H),8.20(s,1H),7.72(d,J=7.2Hz,1H),7.59(d,J=8.1Hz,2H),7.44-7.51(m,4H), 7.26-7.35 (m, 2H), 5.75 (s, 2H), 3.73 (s, 3H), 3.56 (m, 1H), 1.27 (d, J=6.9Hz, 6H).
[1540] The following compounds were obtained according to gen...
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