NVP-BSK805

To a solution of tert-butyl 7-(4-((7-chloro-4-hydroxy-4-methylhept-2-yn- 1 -yl)oxy)- 1, 3 - dioxoisoindolin-2-yl)-4, 6-dioxo-5-azaspiro[2. 5]octane-5-carboxylate (1 equiv.) in acetone is added NaT (5 equiv.). The reaction mixture is stirred at reflux temperature for 24 h, then the solvent is removed under vacuum and crude product is dissolved in EtOAc and an aqueous solution ofNa2SO3 (10percent). Organic layer is separated, washed with water, dried (Na2SO4) and evaporated under vacuum. Crude iodo product is used in the next step without any further purification.To a solution of 4-(2, 6-difluoro-4-(3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxalin-5- yl)benzyl)morpholine (1 equiv.) and DIEA (2.5 equiv.) in DMF is added crude iodo intermediate (1 equiv.) and the resulting solution is stirred at rt for 16 h. The solvent is evaporated and theresidue is dissolved in dioxane. HC1 (4N in dioxane) is added and the solution stirred at room temperature for 12 hours. The solvent is then evaporated under reduced pressure and the crude product is purified by flash column chromatography on silica gel to provide 4-((7-(4-(4-(8-(3, 5- difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl)-4-hydroxy-4-methylhept-2-yn-1-yl)oxy)-2-(4, 6-dioxo-5-azaspiro[2. 5]octan-7-yl)isoindoline-1, 3-dione.A reaction vessel is charged with 4-(2, 6-difluoro-4-(3-(1-(piperidin-4-yl)-1H-pyrazol-4- yl)quinoxalin-5-yl)benzyl)morpholine (1 equiv.) and DMF (0.3 M) then cooled to 0 °C. Sodium hydride (60percent dispersion in mineral oil, 1.1 equiv.) is added and the reaction is warmed to ambient temperature and mixed for 1 hour. The reaction is cooled to 0 °C then tert-butyl 3-(3-(4-((7-chloro- 4-hydroxy-4-methylhept-2-yn-1-yl)oxy)phenyl)-2-oxoimidazolidin-1-yl)-2, 6-dioxopiperidine-1- carboxylate (1.1 equiv.) is added and the reaction is mixed at ambient temperature overnight. DMF is removed by rotary evaporation. The crude material is then dissolved in dioxane. HCl (4N in dioxane) is added and the solution stirred at room temperature for 12 hours. The solvent is then evaporated under reduced pressure and the crude product is purified on silica.A reaction vessel is charged with 4-(2, 6-difluoro-4-(3-(1-(piperidin-4-yl)-1H-pyrazol-4- yl)quinoxalin-5-yl)benzyl)morpholine (1 equiv.) and DMF (0.3 M) then cooled to 0 °C. Sodium hydride (60percent dispersion in mineral oil, 1.1 equiv.) is added and the reaction is warmed to ambient temperature and mixed for 1 hour. The reaction is cooled to 0 °C then tert-butyl 2-(4-((7-chloro- 4-hydroxy-4-methylhept-2-yn-1-yl)oxy)phenyl)-3, 6, 8-trioxo-2, 7-diazaspiro[4.5]decane-7- carboxylate (1.1 equiv.) is added and the reaction is mixed at ambient temperature overnight. DMF is removed by rotary evaporation. The crude material is then dissolved in dioxane. HCl (4N in dioxane) is added and the solution stirred at room temperature for 12 hours. The solvent is then evaporated under reduced pressure and the crude product is purified on silica.Dimethyldicarbonate (27 mul, 0.245 mmol) is added dropwise, under stirring at O0C, to a solution of 8-(3, 5-Difluoro-4-morpho.in-4-ylmethyl-phenyl)-2-(1-piperidin-4-yl-1 H-pyrazol-4- yl)-quinoxaline (as obtained in example 98, 120 mg, 0.245 mmol) in THF. The cooling bath is then removed and the reaction mixture stirred at RT for an additional 30 min. The mixture is then diluted with de-ionized water and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with CH2CI2. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2CI2 and purified by chromatography on a 12 g silica gel column on a Combiflash Companion.(TM). (Isco Inc.) apparatus (gradient CH2CI2/ (CH2CI2: EtOH: NH3 90:9:1.1) from 1 :0 => 1 :9) to afford the title compound as a pale yellow foam. Rt =0.865 min (Acquity UPLC BEH C18, 2.1x50mm, 2-chloroethylmethyl ether (13.5 mul, 0.143 mmol) is added dropwise to a solution of 8-(3, 5- Difluoro-4-rnorpholin-4-ylmethyl-phenyl)-2-(1 -piperidin-4-yl-1 H-pyrazol-4-yl)-quinoxaline (as obtained in example 98, 67 mg, 0.137 mmol), Cs2CO3 (24 mg, 0.075 mmol) in DMF (0.5 ml). The resulting mixture is heated under Ar at 950C for 17h. Two products are formed in a ratio 1 :1 , as identified by example 122 and example 123. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 40 g silica gel column on a Combiflash Companion.(TM). (Isco Inc.) apparatus ( gradient CH2CI2/ (CH2CI2: EtOH: NH3 90:9:1) from 1 :0 => 0:1) to afford example 122 and example 123.Cyclopropanecarbonyl chloride (23 mul, 0.245 mmol) is added dropwise, under stirring at 00C, to a solution of 8-(3, 5-Difluoro-4-morpholin-4-ylmethyl-phenyl)-2-(1-pipehdin-4-yl-1H-pyrazol-

Molecular Weight:490.5
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:8
Rotatable Bond Count:5
Exact Mass:490.22926586
Monoisotopic Mass:490.22926586
Topological Polar Surface Area:68.1
Heavy Atom Count:36
Complexity:696
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes