* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Step 3: spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride 16.4 g (42.4 mmol) benzyl 7'-chloro-2'-oxo-1'.2'-dihydrospiro[piperidine-4,4'-pyrido[2,3d][1,3]oxazine]-1-carboxylate and 2.00 g palladium(Pd/C 10percent) in 500 mL EtOH were hydrogenated in a hydrogen atmosphere for 6 h at RT. Then another 1.0 g palladium (Pd/C 10percent) were added the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried. Yield: 5.40 g (50percent of theoretical) ESI-MS: m/z=220 (M+H)+ Rt(HPLC): 0.90 min (method C)
50%
With hydrogen In ethanol at 20℃; for 9 h;
Step 3: spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride 16.40 g (0.04 mol) benzyl 7'-chloro-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3d]-[1,3]oxazine]-1-carboxylate and 2.00 g palladium(Pd/C 10percent) in 500 mL EtOH were hydrogenated for 6 h at RT in a hydrogen atmosphere. Then 1 g of palladium (Pd/C 10percent) were additionally added and the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried in the drying cupboard for 3 h at 50° C.Yield: 5.40 g (50percent of theoretical)ESI-MS: m/z=220 (M+H)+ Rt(HPLC): 0.90 min (method C)
EXAMPLE 4A^-rcyig^^-Chloro-S-oxo-P^^^-trifluoroethylVS.J.S^.lO-hexahvdroazepinofSLambda-elindazol-?- yl]-2'-oxo-r.2'-dihydro-lH-spiro[piperidine-4,4'-pyrido[2,3-</][l,3]oxa2ine]-l-carboxamideTo a solution of (7i?)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10- tetrahydroazepino[3,4-e]indazol-8(3H)-one (100 mg, 0.3 mmol) [Chaturvedula et al. WO 2006/052378],and triethylamine (120 uL, 0.9 mmole) is added ^-nitrophenyl chloroformate (60 mg, 0.3 mmmol) and stirred at 0 0C for 1 hr. Spiro[piperidine-4,4'-pyrido[2,3-c/][l,3]oxazin]- 2'(l'H)-one hydrochloride [Burgey et al. WO 2006/044504], (77'mg, 0.3mmole is then added with triethylamine (120 uL, 0.675 mmol) and the reaction mixture is stirred at ambient temperature for 16 hrs. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3 * 25 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (3 x), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography, eluting with a gradient of CHCl3 :MeOEta - 100:0 to 90:10, provides the title compound.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 39 1-(6-(5-fluoroindoline-1-carbonyl)pyrimidin-4-yl)spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one 0.10 g (0.36 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone were added to 92 mg (0.36 mmol) spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one-hydrochloride and 146 muL (0.84 mmol) DIPEA in 1.8 mL DMF. The reaction mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and lyophilised. Yield: 120 mg (72% of theory) ESI-MS: m/z=461 (M+H)+ Rt (HPLC-MS): 2.90 min (method E)
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 9h;
Step 3: spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride 16.4 g (42.4 mmol) benzyl 7'-chloro-2'-oxo-1'.2'-dihydrospiro[piperidine-4,4'-pyrido[2,3d][1,3]oxazine]-1-carboxylate and 2.00 g palladium(Pd/C 10%) in 500 mL EtOH were hydrogenated in a hydrogen atmosphere for 6 h at RT. Then another 1.0 g palladium (Pd/C 10%) were added the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried. Yield: 5.40 g (50% of theoretical) ESI-MS: m/z=220 (M+H)+ Rt(HPLC): 0.90 min (method C)
50%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 9h;
Step 3: spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride 16.40 g (0.04 mol) benzyl 7'-chloro-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3d]-[1,3]oxazine]-1-carboxylate and 2.00 g palladium(Pd/C 10%) in 500 mL EtOH were hydrogenated for 6 h at RT in a hydrogen atmosphere. Then 1 g of palladium (Pd/C 10%) were additionally added and the mixture was hydrogenated for a further 3 h at RT in a hydrogen atmosphere. After filtration of the reaction mixture the solvent was eliminated in vacuo. The residue was triturated with EtOH, the precipitate formed was suction filtered, washed with EtOH and dried in the drying cupboard for 3 h at 50 C.Yield: 5.40 g (50% of theoretical)ESI-MS: m/z=220 (M+H)+ Rt(HPLC): 0.90 min (method C)
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 130℃;
Example 44 1-(4-(4,5-difluoroindoline-1-carbonyl)pyridin-2-yl)spiro[piperidine-4,4'-pyrido[2,3-d][1,3]-oxazin]-2'(1'H)-one 0.23 g (0.78 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone were added to 0.20 g (0.78 mmol) spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one-hydrochloride and 0.11 g (0.78 mmol) potassium carbonate in 3.0 mL NMP. The reaction mixture was first of all stirred for 10 h at 130 C., then cooled to RT and then stirred overnight at RT. The crude product was combined with water/acetonitrile and purified by preparative HPLC-MS. The product fractions were combined and evaporated down. The residue was triturated with diisopropylether, suction filtered and dried in the air. Yield: 50 mg (13% of theory) ESI-MS: m/z=478 (M+H)+ Rt (HPLC-MS): 3.00 min (method E)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 231-(6-(4-methyl-2-oxo-2,3-dihydrobenz-[d]oxazol-6-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1.3]oxazin]-2'(1'H)-one; 20 mg (0.078 mol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 20 mg (0.072 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.57 mmol) DIPEA were combined in 1.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.Yield: 3 mg (9% of theory)ESI-MS: m/z=461 (M+H)+ Rt (HPLC): 1.24 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 50℃;
Example 301-(6-(2,4-dimethyl-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)spiro[piperidine-4,4'-pyrido-[2,3-d][1,3]oxazin]-2'(1'H)-one; 0.15 g (0.59 mmol) <strong>[1038866-44-2]spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.31 mL (1.8 mmol) DIPEA were combined in 1.5 mL DMF and stirred first of all overnight at RT then for 2 h at 50 C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.Yield: 130 mg (48% of theory)ESI-MS: m/z=458 (M+H)+ Rt(HPLC): 0.96 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃;
Example 391-{6-[2-(methoxymethyl)-4-methyl-1H-benzo[d]imidazol-6-yloxy]pyrimidin-4-yl}spiro-(piperidin-4,4'-pyrido[2,3-d][1,3]oxazin)-2'(1'H)-one; 49 mg (0.19 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 50 mg (0.16 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(methoxymethyl)-4-methyl-1H-benzo-[d]imidazole and 0.10 mL (0.57 mmol) DIPEA in 2.0 mL DMF were stirred at 40 C. over the weekend. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.Yield: 37 mg (40% of theory)ESI-MS: m/z=488 (M+H)+ Rt (HPLC): 0.99 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 3h;
Example 411-[2-methoxy-6-(4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)pyrimidin-4-yl]spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 58 mg (0.23 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.20 mmol) 6-(6-chloro-2-methoxypyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 0.10 mL DIPEA (0.57 mmol) in 1.0 mL DMF were stirred for 3 h at 90 C. The reaction mixture was mixed with water, the precipitate w suction filtered, washed and dried. The residue was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.Yield: 45 mg (43% of theory)ESI-MS: m/z=491 (M+H)+ Rt (HPLC): 1.26 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃;
Example 441-(6-(2-cyclopropyl-4-methyl-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 41 mg (0.16 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 40 mg (0.13 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-cyclopropyl-4-methyl-1H-benzo[d]-imidazole and 0.08 mL (0.48 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.Yield: 30 mg (39% of theory)ESI-MS: m/z=484 (M+H)+ Rt (HPLC): 1.04 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 40℃; for 7h;
Example 511-(6-(7-chloro-2-methyl-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 110 mg (0.37 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and 4 h at 40 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.Yield: 50 mg (30% of theory)ESI-MS: m/z=478/480 (Cl) (M+H)+ Rt (HPLC): 1.07 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃;
Example 54(S)-1-(6-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 59 mg (0.23 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.21 mmol) (S)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 0.12 mL (0.70 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 40 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with 4M sodium hydroxide solution. The precipitate formed was suction filtered, washed and dried.Yield: 21 mg (18% of theory)ESI-MS: m/z=514 (M+H)+ Rt (HPLC): 1.09 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 695-methyl-7-(6-(2'-oxo-1'.2'-dihydrospiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)-pyrimidin-4-yloxy)-2H-benzo[b][1.4]oxazin-3(4H)-one; 72 mg (0.28 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.22 mmol) 7-(6-chloropyrimidin-4-yloxy)-5-methyl-2H-benzo[b][1.4]oxazin-3(4H)-one and 100 muL (0.58 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was combined with methanol and water. The precipitate formed was suction filtered, washed with methanol and dried.Yield: 75 mg (73% of theory)ESI-MS: m/z=475 (M+H)+ Rt(HPLC): 1.18 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 611-(6-(7-chloro-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 36 mg (0.14 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 50 mg (0.14 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 50 muL (0.30 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by chromatography. The fractions containing product were combined and lyophilised.Yield: 38 mg (51% of theory)ESI-MS: m/z=534 (M+H)+ Rt(HPLC): 1.04 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 40℃; for 6h;
Example 621-(6-(7-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 49 mg (0.19 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 70 mg (0.19 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 muL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 3 h at 40 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.Yield: 8 mg (8% of theory)ESI-MS: m/z=548 (M+H)+ Rt(HPLC): 1.07 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 14h;
Example 641-(6-(4-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 105 mg (0.36 mmol) 6-(6-chloropyrimidin-4-yloxy)-4-methylbenzo[d]thiazol-2(3H)-one and 200 muL (1.16 mmol) DIPEA in 2.0 mL DMF were stirred for 14 h at 60 C. The reaction mixture was cooled, mixed with water and stirred for 30 min. The precipitate formed was suction filtered, stirred with methanol, suction filtered again and dried.Yield: 120 mg (72% of theory)ESI-MS: m/z=477 (M+H)+ Rt(HPLC): 3.25 min (method C)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃;
Example 651-(6-(7-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 33 mg (0.13 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 40 mg (0.12 mmol) 7-methyl-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 muL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60 C. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered. The precipitate was dissolved and then purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.Yield: 35 mg (51% of theory)ESI-MS: m/z=528 (M+H)+ Rt(HPLC): 0.96 min (method B)
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 14h;
Example 741-(6-(4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 125 mg (0.36 mmol) 6-(6-chloro-2-trifluoromethyl-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.20 mL (1.16 mmol) DIPEA in 2.0 mL NMP were stirred for 14 h at 60 C. After cooling the reaction mixture was mixed with water and stirred for 30 min. The precipitate formed was suction filtered and dried.Yield: 0.18 mg (97% of theory)ESI-MS: m/z=529 (M+H)+ Rt(HPLC): 1.40 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;
Example 661-(6-(2-(2-methoxyethyl)-4-methyl-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 29 mg (0.11 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 29 mg (0.09 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(2-methoxyethyl)-4-methyl-1H-benzo-[d]imidazole and 50 muL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 50 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.Yield: 55 mg (51% of theory)ESI-MS: m/z=502 (M+H)+ Rt(HPLC): 2.72 min (method C)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Example 681-(6-(7-methyl-1H-indazol-5-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d]-[1,3]oxazin]-2'(1'H)-one; 60 mg (0.23 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 60 mg (0.23 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-1H-indazole and 100 muL (0.58 mmol) DIPEA in 0.8 mL DMF were stirred at RT over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous saturated NaHCO3 solution. The precipitate formed was suction filtered and dried.Yield: 40 mg (38% of theory)ESI-MS: m/z=444 (M+H)+ Rt(HPLC): 3.06 min (method C)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;
Example 70(R)-1-(6-(4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-6-yloxy)pyrimidin-4-yl)-spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 166 mg (0.65 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 205 mg (0.62 mmol) (R)-6-(6-chloropyrimidin-4-yloxy)-4-methyl-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole and 320 muL (1.86 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 50 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution. The precipitate formed was suction filtered, washed and dried.Yield: 110 mg (35% of theory)ESI-MS: m/z=514 (M+H)+ Rt(HPLC): 0.98 min (method B)
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h;
Example 754-(4-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yloxy)-6-(2'-oxo-1'.2'-dihydrospiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)nicotinonitrile; 40 mg (0.16 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 40 mg (0.12 mmol) 6-chloro-4-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yloxy)-nicotino-nitrile and 0.08 mL (0.47 mmol) DIPEA in 0.80 mL NMP were stirred for 1 h at 140 C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. and neutralised with aqueous NaHCO3 solution. The precipitate formed was suction filtered and dried.Yield: 47 mg (36% of theory)ESI-MS: m/z=485 (M+H)+ Rt(HPLC): 1.34 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 60℃;
Example 714-methyl-6-(2-methyl-6-(2'-oxo-1'.2'-dihydrospiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2(3H)-one; 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 90 mg (0.31 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 200 muL (1.16 mmol) DIPEA in 1.5 mL DMF were stirred overnight at RT. Another 90 mg (0.35 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong> and 200 muL (1.16 mmol) DIPEA were added and the mixture was stirred for 8 h at 60 C. The reaction mixture was mixed with water and stirred overnight. Then DCM was added and the mixture was stirred for a further 30 min. DCM was removed and the aqueous phase was suction filtered. The precipitate was washed with EtOH and dried.Yield: 100 mg (68% of theory)ESI-MS: m/z=475 (M+H)+ Rt(HPLC): 1.04 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃;
Example 581-(6-(7-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 138 mg (0.54 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 180 mg (0.54 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 280 muL (1.62 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 60 C. The reaction mixture was combined with ice water. The precipitate formed was suction filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.Yield: 50 mg (18% of theory)ESI-MS: m/z=514 (M+H)+ Rt(HPLC): 2.88 min (method L)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃;
Example 631-(6-(7-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro-[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 21 mg (0.08 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 22 mg (0.07 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(trifluoromethyl)-1H-benzo[d]-imidazole and 40 muL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred at 50 C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.Yield: 18 mg (44% of theory)ESI-MS: m/z=512 (M+H)+ Rt(HPLC): 1.30 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃;
Example 671-(6-(2-methoxy-7-methyl-1H-benzo[d]imidazol-5-yloxy)pyrimidin-4-yl)spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one; 64 mg (0.25 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 57 mg (0.20 mmol) 5-(6-chloropyrimidin-4-yloxy)-2-methoxy-7-methyl)-1H-benzo[d]-imidazole and 130 muL (0.75 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 60 C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.Yield: 20 mg (17% of theory)ESI-MS: m/z=474 (M+H)+ Rt(HPLC): 1.10 min (method B)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 10h;
Example 781-{1-[6-(2.7-dimethyl-3H-benzimidazol-5-yloxy)-pyrimidin-4-yl]-spiro[piperidin-4,4'-pyrido-[2,3-d][1,3]oxazin]-2'(1'H)-one; 128 mg (0.500 mmol) <strong>[1038866-44-2]spiro[piperidin-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'H)-one hydrochloride</strong>, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.Yield: 65 mg (25% of theory)ESI-MS: m/z=512 (M+H)+ Rt (HPLC): 3.0 min (method C)
To a solution of (7lambda)-4-chloro-10-[l-(trifluoromethyl)cyclopropyl]-3,6,7,12- tetrahydroimidazo[r,2':l,7]azepino[3,4-e]indazol-7-amine (100 mg, 0.3 mmol)],and triethylamine (120 uL, 0.9 mmole) is added p-nitrophenyl chloroformate (60 mg, 0.3 mmmol) and stirred at 0C for 1 hr. Spiro[piperidine-4,4'-pyrido[2,3-d][l,3]oxazin]-2'(1'H)-one hydrochloride [Burgey et ah WO 2006/044504], (77 mg, 0.3mmole is then added with triethylamine (120 uL, 0.675 mmol) and the reaction mixture is stirred at ambient temperature for 16 hrs. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3 * 25 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (3 x), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane ? 93% dichloromethane/ methanol] gives the title compound
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