2-bromo-1-chloro-4-(trifluoromethyl)benzene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-1-chloro-4-(trifluoromethyl)benzene (26 mg, 0.0001 mol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.000002 mol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (5 mg, 0.00001 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) was stirred under N2 (g) for 20 min. To this mixture were added (5S)-2-{trans-4-[(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decan-1-one (30 mg, 0.00008 mol) and sodium tert-butoxide (11.8 mg, 0.000123 mol), and the resulting mixture was degassed and stirred at 100° C. for 16 h. At this time 1M TBAF (tetra-n-butylammonium fluoride) in THF (0.3 mL) was added dropwise to the reaction mixture and the solution was stirred at rt for 1 h. The volatiles were removed in-vacuo and the residue was purified by prep-HPLC to afford the desired product. LC-MS: 431.1 (M+H)+. the resulting mixture was degassed stirred at 100° C. for 16 h At this time 1M TBAF (tetra-n-butylammonium fluoride) in THF (0.3 mL) was added dropwise to the reaction mixture the solution was stirred at rt for 1 h The volatiles were removed in-vacuo the residue was purified by prep-HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR(CDCl3, 300 MHz) δ 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 (s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS (ES)+: 440 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR (CDCl3, 300 MHz) 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS ES)+: 440 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR(CDCl3, 300 MHz) δ 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 (s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS (ES)+: 440 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR (CDCl3, 300 MHz) 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS ES)+: 440 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 17, Parts B and C, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±) -cis-N-[2-chloro-5-(trifluoromethyl)phenyl]-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (c18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 114 as the free base. LRMS (ES)+: 394.4 (M+H)+. after HPLC purification ( c18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) extracted with chloroform washed with brine dried (K2CO3) concentrated to the title compound of EXAMPLE 114 as the free base

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (100 mg, 0.304 mmol), sodium tert-butoxide (58 mg, 0.608 mmol), and 3-bromo-4-chlorobenzotrifluoride (95 mg, 0.365 mmol) in anhydrous toluene (6 mL) were degassed with argon at 85° C. for 15 min. The solution was cooled slightly, and a mixture of solid Pd2(dba)3 (5.6 mg, 6.1 μmol) and solid BINAP (11 mg, μmol) were added to the solution. The flask was capped under a positive pressure of Ar and heating was continued at 85° C. overnight. After the reaction was complete as evidenced by the lack of starting aniline by TLC analysis, the solution was cooled and diluted with ether. The red slurry was filtered through Celite 521® and concentrated under reduced pressure to give crude N-Boc protected biarylamine as a red oil (101 mg). The crude product was purified by silica gel chromatography on the Isco Combi-flash unit using a 10-g RediSep cartridge and a gradient elution of ethyl acetate in hexanes from 5% to 75%. A CH2Cl2 (4 mL) solution of the N-Boc protected product was cooled to 0° C. and treated with trifluoroacetic acid (TFA) (250 μL). The disappearance of N-Boc protected material was followed by TLC analysis (1:1 hexanes:EtOAc) over 8 h. The TFA solution was then basified with 3 N NaOH to pH >12 and extracted with CH2Cl2. Evaporations of the extracts gave 21 mg of the title compound of EXAMPLE 72 as an off-white powder. 1H NMR (500 MHz, CDCl3) δ 1.26 (br s, 1H), 1.95 (m, 1H), 2.0 (m, 1H), 2.15 (m, 1H), 2.74 (m, 4H), 2.90 (t, 1H, J=1.9 Hz), 3.29 (m, 1H), 3.33 (m, 4H), 3.51 (t, 1H, J=1.9 Hz), 5.96 (s, 1H), 6.52 (s, 1H), 6.69 (s, 1H), 6.86 (m, 1H), 7.07 (s, 1H), 7.34 (m, 1H). LRMS (ES)+: 408 (M+H)+. The solution was cooled slightly were added to the solution The flask was capped under a positive pressure of Ar heating the solution was cooled The red slurry was filtered through Celite 521® concentrated under reduced pressure to give crude N-Boc The crude product was purified by silica gel chromatography on the Isco Combi-flash unit a gradient elution of ethyl acetate in hexanes from 5% to 75% treated with trifluoroacetic acid (TFA) (250 μL) The disappearance of N-Boc protected material was followed by TLC analysis (1:1 hexanes:EtOAc) over 8 h extracted with CH2Cl2

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-1-chloro-4-(trifluoromethyl)benzene (26 mg, 0.0001 mol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.000002 mol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (5 mg, 0.00001 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) was stirred under N2 (g) for 20 min. To this mixture were added (5S)-2-{trans-4-[(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decan-1-one (30 mg, 0.00008 mol) and sodium tert-butoxide (11.8 mg, 0.000123 mol), and the resulting mixture was degassed and stirred at 100° C. for 16 h. At this time 1M TBAF (tetra-n-butylammonium fluoride) in THF (0.3 mL) was added dropwise to the reaction mixture and the solution was stirred at rt for 1 h. The volatiles were removed in-vacuo and the residue was purified by prep-HPLC to afford the desired product. LC-MS: 431.1 (M+H)+. the resulting mixture was degassed stirred at 100° C. for 16 h At this time 1M TBAF (tetra-n-butylammonium fluoride) in THF (0.3 mL) was added dropwise to the reaction mixture the solution was stirred at rt for 1 h The volatiles were removed in-vacuo the residue was purified by prep-HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in a manner similar to that described in Example 838 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromo-1-chloro-4-(trifluoromethyl)benzene in Step A and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine in Step B. MS (ESI): mass calcd. for C21H14F4N6, 426.12; m/z found, 427.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.36 (dd, J=2.1, 1.5, 1H), 8.10 (s, 2H), 8.05 (d, J=1.5, 1H), 7.90-7.85 (m, 1H), 7.81-7.77 (m, 1H), 7.74 (d, J=1.8, 1H), 7.66 (d, J=8.0, 1H), 7.13 (dd, J=2.6, 1.7, 1H), 7.11 (dd, J=6.5, 1.6, 1H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-chloro-5-trifluoromethylbenzene was used instead of 1-bromotoluene in Step 1 thereof, 123 mg of the titled compound was prepared.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-chloro-5-trifluoromethylbenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 222 mg of the titled compound was prepared

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-bromo-4-chlorobenzotrifluoride (1.50 g), 1-fluoro-2-fluoromethyl-3-buten-2-ol (0.80 g), potassium carbonate (2.10 g), tetrabutylammonium bromide (325 mg), palladium acetate (56 mg) and N,N-dimethylacetamide (10 ml) was stirred under a nitrogen atmosphere at 80° C. for 14 hours. To the reaction mixture, 1 N HCl was added followed by extraction with a hexane/ethyl acetate mixed (1/1) solvent; the resulting organic layers were combined and washed with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride; the mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=10/1) to give 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-trans-buten-2-ol (1.53 g) having a melting point of 61-62° C. followed by extraction with a hexane/ethyl acetate mixed (1/1) solvent washed with a saturated aqueous solution of sodium thiosulfate the mixture was dried with anhydrous sodium sulfate concentrated under reduced pressure