2,2-二甲基吡咯烷

反应条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (150 mg, 0.54 mmol), N,N-diisopropylethylamine (188 μL, 1.08 mmol) and 2,2-dimethyl-pyrrolidine (131 mg, 1.08 mmol) in NMP (0.5 mL) was heated at 180° C. in the microwave (Smith Personal Synthesiser) for 600 seconds. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2×15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 98:2:0.2 to 95:5:0.5 to give the title compound as a brown oil (31 mg, 17%). 1H NMR (400 MHz, CDCl3) δ7.38 (d, 2H), 6.90 (d, 2H), 4.04 (t, 2H), 2.78 (t, 2H), 2.54 (t, 2H), 2.16-2.12 (m, 2H), 1.94 (pentet, 2H), 1.90-1.64 (m, 11H), 1.20-1.34 (m, 1H), 0.98 (s, 6H); HRMS (ESI+) 341.2588 (M+H)+. The reaction mixture was quenched with water (15 mL) extracted with ethyl acetate (2×15 mL) dried over Na2SO4 filtered concentrated in vacuo The compound was purified by column chromatography on Biotage® silica gel eluting with dichloromethane

反应条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (150 mg, 0.54 mmol), N,N-diisopropylethylamine (188 μL, 1.08 mmol) and 2,2-dimethyl-pyrrolidine (131 mg, 1.08 mmol) in NMP (0.5 mL) was heated at 180° C. in the microwave (Smith Personal Synthesiser) for 600 seconds. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2×15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 98:2:0.2 to 95:5:0.5 to give the title compound as a brown oil (31 mg, 17%). 1H NMR (400 MHz, CDCl3) δ7.38 (d, 2H), 6.90 (d, 2H), 4.04 (t, 2H), 2.78 (t, 2H), 2.54 (t, 2H), 2.16-2.12 (m, 2H), 1.94 (pentet, 2H), 1.90-1.64 (m, 11H), 1.20-1.34 (m, 1H), 0.98 (s, 6H); HRMS (ESI+) 341.2588 (M+H)+. The reaction mixture was quenched with water (15 mL) extracted with ethyl acetate (2×15 mL) dried over Na2SO4 filtered concentrated in vacuo The compound was purified by column chromatography on Biotage® silica gel eluting with dichloromethane

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 82 mg, 0.290 mmol) and 2,2-dimethylpyrrolidine (57.6 mg, 0.581 mmol; ChemBridge, San Diego, Calif.) and heating at 100° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(3-(diethylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (s, 6H) 1.96-2.06 (m, 4H) 2.87 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.85, 2.35 Hz, 2H) 3.78 (t, J=6.16 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.66 (dd, J=8.02, 1.17 Hz, 1H) 7.89-7.94 (m, 1H) 8.62 (s, 1H) 11.99 (br. s., 1H). MS (ESI, pos. ion) m/z: 362.1 (M+1). Prepared similarly to that Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethylchloroacetate (0.15 ml, 1.37 mmol), potassium carbonate (416 mg, 1.5 mmol) and 2,2-dimethyl-pyrolidine (0.280 mg, 2.06 mmol) were suspended in ethanol (3 ml) and subjected to microwave irradiation at 120° C. for 45 min. The resultant mixture was suspended in diethyl ether (30 ml), extracted with 2M hydrochloric acid (30 ml) and the organic layer discarded. The aqueous layer was treated with a slight excess of 4N sodium hydroxide solution and extracted with diethyl ether (3×30 ml). The organic layers were combined, dried over sodium sulfate, filtered and solvent removed under reduced pressure to afford (2,2-dimethyl-pyrrolidin-1-yl)-acetic acid ethyl ester (156 mg). irradiation at 120° C. for 45 min extracted with 2M hydrochloric acid (30 ml) The aqueous layer was treated with a slight excess of 4N sodium hydroxide solution extracted with diethyl ether (3×30 ml) dried over sodium sulfate filtered solvent removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (40 mg, 129 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6; 18 μL, 141 μmol) as starting materials and isolated (41 mg, 81%) as light-brown oil; LC-MS (UV peak area, ESI) 100%, 393.1611 [MH+]. isolated (41 mg, 81%) as light-brown oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (40 mg, 129 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6; 18 μL, 141 μmol) as starting materials and isolated (41 mg, 81%) as light-brown oil; LC-MS (UV peak area, ESI) 100%, 393.1611 [MH+]. isolated (41 mg, 81%) as light-brown oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a, 50 mg, 180 μmol) was dissolved in DMF (2 mL). TBTU (63.7 mg, 198 μmol), DIEA (154 μl, 902 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6, 24 μl, 198 μmol) were added and the reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (3 mL) and 1 N sodium hydroxide solution (2 mL) were added; the mixture was dried by passage through ChemElut® and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (17 mg, 31%) as off-white wax; LC-MS (UV peak area, ESI) 97%, 309.1367 [MH+]. the mixture was dried by passage through ChemElut® concentrated in vacuo The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=365.5 [MH+].

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=366.4 [MH+].

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: According to the general method described in step 3 of example 53, reaction of 2,2-dimethylpyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (23%) as sticky yellow solid.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: According to the general method described in step 3 of example 53, reaction of 2,2-dimethylpyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (23%) as sticky yellow solid.