1,1-Dimethylethyl 4-(chlorosulfonyl)-1-piperidinecarboxylate

tert-Butyl 4-(N-(5-(2-methoxyphenyl)-1, 3, 4-thiadiazol-2- yl)sulfamoyl)piperidine-1-carboxylate, 128 and N-(5-(2-methoxyphenyl)-1, 3, 4- thiadiazol-2-yl)piperidine-4-sulfonamide hydrochloride, 129 a) tert- butyl 4-(N-(5-(2-methoxyphenyl)-1, 3, 4-thiadiazol-2-yl)sulfamoyl)piperidine-1- carboxylate 128 Lithium bis(trimethylsilyl)amide solution 1.0 M in THF (0.386 mL, 0.386 mmol) was added to a solution of 5-(2-methoxyphenyl)-1, 3, 4-thiadiazol-2-amine 1109 (0.040 g, 0.193 mmol) in tetrahydrofuran (1.93 mL) at -10 C and the reaction was stirred for 10 min. A solution of (R)-1-(8-(piperidin-1-yl)-2-((5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl)amino)pyrido[3, 4-d]pyrimidin-6-yl)ethyl benzoate (51 mg, 0.10 mmol) synthesized in accordance with the processes described in Examples 15 and 16 was dissolved in dichloromethane (1 mL) and triethylamine (21 muL, 0.012 mmol). tert-Butyl 4-(chlorosulfonyl)piperidine-1-carboxylate (34.1 mg, 0.12 mmol) was added to the solution at 0C. The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by LC/MS. After the completion of the reaction, the reaction was quenched by addition of a saturated aqueous sodium hydrogen carbonate solution (10 mL). The solution was extracted with dichloromethane (10 mL) three times. The extracted organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered out, and the filtrate was concentrated. The residue was roughly purified amine-modified silica gel column chromatography. The crude product was used in the subsequent reaction without further purification. The crude product thus obtained was dissolved in dichloromethane (3 mL) and TFA (1 mL). The solution was stirred at room temperature for two hours. The progress of the reaction was monitored by LC/MS. After the completion of the reaction, the reaction was quenched by addition of a saturated aqueous sodium hydrogen carbonate solution (10 mL). The solution was extracted with dichloromethane (10 mL) three times. The extracted organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered out, and the filtrate was concentrated. The residue was roughly purified amine-modified silica gel column chromatography. The crude product was used in the subsequent reaction without further purification. The crude product thus obtained was dissolved in methanol (2.0 mL) and THF (2.0 mL). Potassium carbonate (138 mg, 1.0 mmol) was added to the solution. The mixture was stirred at room temperature for five hours. The progress of the reaction was monitored by LC/MS. After the completion of the reaction, water (10 mL) was added. The solution was extracted with dichloromethane (10 mL) three times. The extracted organic phases were combined and dried over anhydrous sodium sulfate. The solid was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. The fractions containing the target product were passed through a column containing a strong cation exchange (SCX) resin to adsorb the target product onto the resin. The SCX column was washed with methanol, and the target product was eluted with ammonia (2 mol/L, methanol solution). The eluate was concentrated under reduced pressure to give the title compound (38.4 mg, yield: 70%). LC/MS:(M+H)+ = 553.3, C27H36N8O3S = 552.26 1H-NMR (DMSO-d6) delta: 10.12 (1H, s), 9.31 (1H, s), 8.27 (1H, d, J=8.2Hz), 7.63 (1H, d, J=8.7Hz), 7.25 (1H, s), 5.27 (1H, d, J=4.1Hz), 4.70-4.60 (1H, m), 4.46 (2H, s), 3.84-3.68 (4H, m), 3.64 (2H, t, J=5.9Hz), 2.99 (2H, d, J=11.9Hz), 2.87 (2H, t, J=5.5Hz), 2.50-2.39 (2H, m), 1.91-1.81 (2H, m), 1.77-1.60 (6H, m), 1.56-1.42 (2H, m), 1.38 (3H, d, J=6.9Hz).Compound 9aCHPrS46was made from Compound 6aCHPr and To a solution of To a solution of intermediate 6 (500 mg, 0.55 mmol) in DMF (10 mL) at 0C was addedTEA (0.57 mL, 1.64 mmol) and tert-butyl 4-(chlorosulfonyl)piperidine-1 -carboxylate (359mg, 0.55 mmol) and the reaction allowed to warm to it and stirred for 2h. It was thenquenched with water, diluted with EtOAc and Lid solution added. The organic layerwas separated and evaporated in vacuo to give 83 (588 mg, 70%) as a yellow powder;1H NMR (400 MHz, DMSO-d6) S ppm 9.10 (a, 1R), 8.07 (s, IH), 7.99 (d, .1=2.7 Hz, IH), 7.49 (d, J=9.2 Hz, IH), 7.15 (a, 2H), 6.74 (dd, .1=9.2, 2.7 Hz, IH), 4.05-3.97 (m, 2H), 3.49-3.42 (m, IH), 3.42-3.36 (m, 4H), 3.22-3.16 (m, 4H), 2.84-2.68 (m, 21-fl, 2.00-1.94 (m, 2H), 1.49-1.40 (m, 2H), 1.37 (s, 9H); LCMS (mlz): 613/615 [M+H].Preparation of tert-butyl 4-(N-isopropylsulfamoyl)piperidine-l- carboxylate. A mixture of tert-butyl 4-(chlorosulfonyl)piperidine-l-carboxylate (1.0137 g, 3.5723 mmol) in DCM (2 mL) was treated with pyridine (722 iL, 8.93 mmol) and propan-2- amine (460 mu^, 5.36 mmol), then stirred overnight at ambient temperature. The resulting mixture was washed with water (4x). The organic extracts were dried over anhydrous Na2S04(S), filtered, and concentrated in vacuo to afford the title compound in sufficient purity to carry into step 2 (1.09 g, quantitative yield). MS (apci) m/z = 207.2 [(M-Boc)+H].

Molecular Weight:283.77
XLogP3:1.8
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:283.0645069
Monoisotopic Mass:283.0645069
Topological Polar Surface Area:72.1
Heavy Atom Count:17
Complexity:374
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes