1-METHYL-4-(6-AMINOPYRIDIN-3-YL)PIPERAZINE

1-Methyl-4-(6-nitro-pyridin-3-yl)-piperazine (1.11 g, 5.02 mmol) and 10percent Pd/C (110 mg) in MeOH (15 mL) were stirred for 5 h and filtered. [1-METHYL-4-(6-NITRO-PYRIDIN-3-YL)-PIPERAZINE (L. LLG, ] 5.02 mmol) and 10percent [PD/C] (110 mg) in [MEOH] (15 mL) were stirred for 5 h and filtered. The filtrate was concentrated to give 951 mg (99percent yield) of a yellow solid that was used without further purification. 'H NMR [(CDC13)] : [8] 7. 78 (d, 1H, J = 3.0 Hz), 7.18 (dd, 1H, J = 3.0, 8.9 Hz), 6.48 (d, 1H, [J] = 8.9 Hz), 3.08 (dd, 4H, J = 4.9, 4.9 Hz), 2.61 (dd, 4H, J = 4.9, 4.9 Hz), 2. 37 (s, 3H).General procedure: 4.1.42. Tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (11a); A suspension of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (15.4 g, 50 mmol) in CHTo a solution of compound 5-7 (3 g, 13.5 mmol) in MeOH (300 ml) was added Pd/C (3 g). The atmosphere in the vessel was replaced by hydrogen for several times, and then the reaction solution was reacted under a hydrogen pressure of 30 Psi at r.t. for 16 h. The reaction was monitored by TLC until the completion of reaction. The reaction solution was filtered and concentrated to remove solvent, therefore obtaining compound 5-8 (2.8 g, Yield 98.5percent). 1-methylpiperazine (3.00g, 29.6mmol), potassium carbonate ([K5 g of compound 42, Was added to a 250 mL reaction flask, To the flask was added 80 mL of methanol, Then add 10percent palladium carbon 0.5g, Through the hydrogen, room temperature reaction 16h, The reaction was terminated, the palladium-carbon was removed by filtration, The filtrate was concentrated, The resulting residue was beaten with methyl t-butyl ether, To give light purple solid compound 7-13 4.05g, Yield 93.6percent.The suspension of l-methyl-4-(6-nitropyridin-3-yl)piperazine (5 g, 22.5 mmol), NH4C1 (12 g, 225 mmol), and Fe (5 g, 5 mmol) was stirred in EtOH/H20 (1 : 1) (100 mL) at 80 °C for 3 h. TLC showed starting material l-methyl-4-(6-nitropyridin-3-yl)piperazine disappeared. After filtration on a pad of Celite, the solvent was removed under vacuum. EA and brine were added into the mixture and the organic layer was separated, dried over Na2S04 and concentrated at reduced pressure to give 2.5 g of 5-(4-methylpiperazin-l- yl)pyridin-2-amine (yield 60percent). LCMS: (M+H)General procedure: A mixture of compounds 8c-8e (26.0 mmol) in acetic acid(10 mL) and methyl alcohol (40 mL) was refluxed, iron (78.0 mmol)was added. The reaction mixture was heated at 60 °C for 2 h. Thereaction mixture was poured into saturated aqueous sodium carbonate(100 mL) and extracted with ethyl acetate (3 x 50 mL), thendried over sodium sulfate, filtered and concentrated. The crudeproduct was purified via column chromatography to afford compounds9c-9e.5-(4-methylpiperazin-1-yl)pyridin-2-amine A solution of l-methyl-4-(6-nitro-pyridin-3-yl) piperazine (1.5 g, 6.83 mmol) in MeOH (75 mL) was hydrogenated in the presence of 10percent Pd/C (0.3 g) using an H2 balloon. After 12 h, the reaction mixture was filtered through a pad of Celite and rinsed with MeOH (2 x 15 mL). The filtrate was concentrated and purified by triturating in n-pentane to afford the title compound (1.0 g) as a brown solid. 1H NMR (400 MHz, CDC1A suspension of l-methyl-4-(6-nitro-pyridin-3-yl)-piperazine (2 g, 9 mmol) and wet Pd / C (0.5 g ) in MeOH (200 mL) was hydrogenated under HExample 10 Synthesis of 5-(4-methylpiperazin-l-yl)pyridin-2-amine, Compound 10 To l-methyl-4-(6-nitro-3-pyridyl)piperazine (3.4 g) in ethyl acetate (100 mL) and ethanol (100 mL) was added 10percent> Pd/C (400 mg) and then the reaction was stirred under hydrogen (10 psi) overnight. After filtration through CELITE™, the solvents were evaporated and the crude product was purified by silica gel column chromatography using DCM/ 7N ammonia in MeOH (0- 5percent) to afford 5-(4-methylpiperazin-l-yl)pyridin-2-amine (2.2 g). To l-methyl-4-(6-nitro-3-pyridyl)piperazine (3.4 g) in ethyl acetate (100 mL) and ethanol (100 mL) was added 10percent Pd/C (400 mg) and then the reaction was stirred under hydrogen (10 psi) overnight. After nitration through CELITE™, the solvents were evaporated and the crude product was purified by silica gel column chromatography using DCM/ 7N ammonia in MeOH (0- 5percent) to afford 5-(4-methylpiperazin-l-yl)pyridin-2-amine (2.2 g). To 1 -methyl-4-(6-nitro-3 -pyridyl)piperazine (3.4 g) in ethyl acetate (100 mL) and ethanol (100 mL) was added 10percent Pd/C (400 mg) and then the reaction was stirred under hydrogen (10psi) overnight. After filtration through CELITETM, the solvents were evaporated and the crude product was purified by silica gel column chromatography using DCM/ 7N ammonia in MeOH (0- 5percent) to afford 5-(4-methylpiperazin-1-yl)pyridin-2-amine (2.2 g). ‘HNMR (d6-DMSO) ö ppm 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10percent Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through Celite®, the solvents were evaporated and the cmdeproduct was purified over silica gel using DCM/ 7N Ammonia in MeOH (0- 5percent) to afford 5- (4-methylpiperazin- 1 -yl)pyridin-2-amine (2.2 g).‘HNMR (DMSO- d6) 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10percent Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through Celite®, the solvents were evaporated and the crudeproduct was purified over silica gel using DCM/ 7N Ammonia in MeOH (0- 5percent) to afford 5- (4-methylpiperazin- 1 -yl)pyridin-2-amine (2.2 g).‘HNMR (DMSO- d6) 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).To l-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10percent Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through Celite®, the solvents were evaporated and the crude product was purified over silica gel using DCM/ 7N Ammonia in MeOH (0- 5percent) to afford 5- (4-methylpiperazin-l -yl)pyridin-2-amine (2.2 g). (0499) 1HNMR (DMSO- de) δ 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).At room temperature, hydrogen gas, add Pd/C (0.194 g) to a solution of 1-methyl-4-(6-nitropyridine-3-yl)piperazine (1.940 g) in THF (25 mL) stir at room temperature for 2 hours. The filtrate was collected by filtration and then concentrated to give 1.481 g of 5-(4-methylpiperazin-1-yl)pyridin-2-amine.9a (30 mg, 0.11 mmol) and 10b (42.2 mg, 0.22 mmol) were suspended in xylene (0.3 mL), and the atmosphere was replaced by argon for 3 times. The mixture was heated to 150 C, and reacted overnight with stirring. After the mixture was cooled to room temperature, ethyl acetate (0.3 mL) was added, and the stirring was continued for about 2 hours. The mixture was filtered, and the filter residue was washed with ethyl acetate to afford a yellow solid as the title compound I-2 (13 mg, 32.5 mummol, 29.5%). 1H NMR (600 MHz, chloroform-d, ppm) delta 9.17 (s, 1H), 8.32 (brs, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J = 3.0 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 9.0, 3.0 Hz, 1H), 6.07 (p, J = 6.8 Hz, 1H), 3.22 (t, J = 5.0 Hz, 4H), 2.63 (t, J = 4.9 Hz, 4H), 2.38 (s, 3H), 1.73 (d, J = 6.8 Hz, 6H).2-chloro-8-tert-butyl-6-hydroxypteridine-7 (8H) -one (2.1 mmol) was dissolved in DMSO (10 mL), Then add 2-amino-5- (N-methylpiperazinyl) pyridine (2.8mmol)), potassium carbonate (0.52g, 3.8mmol), Potassium fluoride (44 mg, 0.76 mmol). The temperature was raised to 120 C. and the reaction was heated for 8 h.The reaction was detected by TLC. After cooling to room temperature, solids precipitated, filtered with suction, and the filter cake was rinsed with water.After drying, it was mixed with phosphorus oxychloride (5 mL) and heated to 60 C. for 4 h.The reaction was completed. The reaction solution was cooled to room temperature, and added dropwise to ice water, and a solid precipitated.After sufficiently stirring for 30 minutes, suction filtration was performed, and the filter cake was dried to obtain yellow solid I-4 (yield 69.8%).General procedure: Dry tetrahydrofuran (THF, 60 mL) was added to a round bottomflask containing compound 2 (3.00 g, 6.04 mmol), cesium carbonate(2.76 g, 8.46 mmol), palladium (II) acetate (0.06 g, 0.30 mmol) andBINAP (0.30 g, 0.48 mmol). A solution of aromatic amine(6.04 mmol) in THF (20 mL) was added under a nitrogen atmosphereand heated at 66 C for 8 h. The mixturewas filtered throughCelite and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography withpetroleum ether (60e90 C fraction):EtOAc (3:1e1:5, v/v) as eluentto afford compounds 3a-3d (77e93%).5-(6-[[5-(4-methylpiperazin-l-yl)pyridin-2-yl]amino]pyrimidin-4-yl)-2-[(l- methylpyrrolidin-3-yl)oxy]benzonitrile: The title compound was prepared from 5-(6- chloropyrimidin-4-yl)-2-fluorobenzonitrile, 5-(4-methylpiperazin-l-yl)pyridin-2-amine and 1- methylpyrrolidin-3-ol using Method 28 and E. The final product was purified by prep-HPLC under the following conditions: column, XBridge Prep C18 OBD Column, 150 x 19 mm, 5 um; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1 % NH3.H2O), 25 % to 41 % gradient in 7 min; detector, UV 254 nm. 5-(6-[[5-(4-methylpiperazin-l-yl)pyridin-2- yl]amino]pyrimidin-4-yl)-2-[(l-methylpyrrolidin-3-yl)oxy]benzonitrile was obtained as yellow solid (23 mg, 6.7 % for 2 steps). HPLC: 97.3 % purity, RT = 0.77 min. MS: m/z = 471.2 [M+H]+. lH NMR (300 MHz, DMSO-d6) delta 10.02 (s, 1 H), 8.70 (s, 1 H), 8.34-8.20 (m, 2 H), 8.08-7.97 (m, 2 H), 7.72-7.62 (m, 1 H), 7.51-7.40 (m, 1 H), 7.39-7.29 (m, 1 H), 5.16-5.07 (m, 1 H), 3.18-3.08 (m, 4 H), 2.87-2.65 (m, 3 H), 2.51-2.39 (m, 4 H), 2.44-2.31 (m, 2 H), 2.28 (s, 3 H), 2.22 (s, 3 H), 1.92-1.75 (m, 1 H).5-(6-[[5-(4-methylpiperazin-l-yl)pyridin-2-yl]amino]pyrimidin-4-yl)-2-(oxan-4- yloxy)benzonitrile: 5-(6-[[5-(4-methylpiperazin- l-yl)pyridin-2-yl]amino]pyrimidin-4-yl)-2- (oxan-4-yloxy)benzonitrile was prepared from 5-(6-chloropyrimidin-4-yl)-2-(oxan-4- yloxy)benzonitrile and 5-(4-methylpiperazin-l-yl)pyridin-2-amine using Method 28. The final product was purified by prep-HPLC under the following conditions: column, XB ridge Prep C18 OBD Column, 150 x 19 mm, 5 um; mobile phase, acetonitrile in water (with 0.05% NH3.H20), 30% to 60% gradient in 8 min; detector, UV 254 nm. 5-(6-[[5-(4-methylpiperazin- l-yl)pyridin- 2-yl]amino]pyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile was obtained as light yellow solid (59 mg, 44% for 2 steps). HPLC: 98.1% purity, RT = 2.51 min. MS: m/z = 472.3 [M+H]+. lH NMR (400 MHz, DMSO-/delta) delta 10.01 (s, 1 H), 8.69 (s, 1 H), 8.34-8.21 (m, 2 H), 8.04-8.01 (m, 2 H), 7.99 (s, 1 H), 7.70-7.63 (m, 1 H), 7.55-7.48 (m, 1 H), 7.48-7.40 (m, 1 H), 4.96-4.85 (m, 1 H), 3.91-3.81 (m, 2 H), 3.59-3.48 (m, 2 H), 3.15-3.08 (m, 4 H), 2.49-2.41 (m, 4 H), 2.21 (s, 3 H), 2.10- 1.95 (m, 2 H), 1.74- 1.61 (m, 2 H). Example 30: 6-([6-[3-cyano-4-(oxan-4-yloxy)phenyl]pyrimidin-4-yl]amino)-N, N- dimethylpyridine-3-carboxamideGeneral procedure: To the solution of Acid SM-IX (750 mg, 2.i8 mmol, iOO mol-%) in dry DCM (iO ml) under nitrogen atmosphere was added 3-amino-5- methylisoxazole (427 mg, 4.36 mmol, 200 mol-%) and pyridine (526 p1, 6.53mmol, 300 mol-%). T3P (50 w-% in EtOAc) (2.6 ml, 4.36 mmol, 200 mol-%) was added dropwise and the reaction mixture stirred at rt for four hours. DCM (i 0 ml) and i 0 % NaH 003 (30 ml) were added. The water phase was extracted twice with DCM (2 x iO ml). The organic phases were combined and washed with 0.i N HCI solution (3 x 30 ml), water (3 x 30 ml) and finally withbrine (3 x 30 ml) and dried with sodium sulfate. The crude yield of compound i was 95 % (875 mg).1H NMR (200 MHz, DMSO-d6): 0.97 (5, 3 H), i.24 -2.46 (m, i6 H), 2.37 (5, 3H), 2.58 - 3.Oi (m, 2 H), 6.64 (5, i H), 6.88-7.06 (m, i H), 7.07 - 7.25 (m, 2 H), iO.88 (5, i H).To the solution of Acid SM-IX (750 mg, 2.i8 mmol, iOO mol-%) in dry DCM (iO ml) under nitrogen atmosphere was added 3-amino-5- methylisoxazole (427 mg, 4.36 mmol, 200 mol-%) and pyridine (526 p1, 6.53mmol, 300 mol-%). T3P (50 w-% in EtOAc) (2.6 ml, 4.36 mmol, 200 mol-%) was added dropwise and the reaction mixture stirred at rt for four hours. DCM (i 0 ml) and i 0 % NaH 003 (30 ml) were added. The water phase was extracted twice with DCM (2 x iO ml). The organic phases were combined and washed with 0.i N HCI solution (3 x 30 ml), water (3 x 30 ml) and finally withbrine (3 x 30 ml) and dried with sodium sulfate. The crude yield of compound i was 95 % (875 mg).1H NMR (200 MHz, DMSO-d6): 0.97 (5, 3 H), i.24 -2.46 (m, i6 H), 2.37 (5, 3H), 2.58 - 3.Oi (m, 2 H), 6.64 (5, i H), 6.88-7.06 (m, i H), 7.07 - 7.25 (m, 2 H), iO.88 (5, i H).

Molecular Weight:192.26
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:192.137496527
Monoisotopic Mass:192.137496527
Topological Polar Surface Area:45.4
Heavy Atom Count:14
Complexity:177
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes