5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-methyl-3,7-diazabicyclo[3.3.0]octane (297 mg, 2.36 mmol; see Example 54C), 2,7-dibromofluoren-9-one (680 g, 2.01 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium (0) (Pd2 dba3; 37 mg, 0.040 mmol; Alfa), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 63 mg, 0.10 mmol; Strem) and sodium tert-butoxide (270 mg, 2.81 mmol; Acros) in 10 mL toluene was warmed to 90° C. and stirred for 16 h. The reaction mixture was cooled to ambient temperature and filtered through Celite, rinsing with CH2Cl2. After concentrating the solution under reduced pressure, the residue was purified by flash chromatography (120 g silica gel, 1-20% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to give the crude product. This material was purified further by flash chromatography (40 g Analogix NH2 column, 10-100% EtOAc in hexanes) to afford the title compound as a reddish solid (335 mg, 0.875 mmol; 44% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.64 (d, J=2 Hz, 1H), 7.49 (dd, J=8, 2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.64 (dd, J=8, 2 Hz, 1H), 3.42-3.53 (m, 2H), 3.29 (dd, J=10, 3 Hz, 2H), 2.99-3.13 (m, 2H), 2.75-2.94 (m, 2H), 2.56 (dd, J=9, 3 Hz, 2H), 2.41 (s, 3H); MS (ESI): m/z 383 (M+1)+, 385 (M+3)+. The reaction mixture was cooled to ambient temperature filtered through Celite rinsing with CH2Cl2 After concentrating the solution under reduced pressure the residue was purified by flash chromatography (120 g silica gel, 1-20% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to give the crude product This material was purified further by flash chromatography (40 g Analogix NH2 column, 10-100% EtOAc in hexanes)

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (200 mg, 0.4 mmol), 2-methyl-octahydro-pyrrolo[3,4-c]pyrrole (70 mg, 0.56 mmol), Herrmann's catalyst (4.5 mg, 0.0048 mmol), tri-tert-butyl phosphine hydrofluoroborate (3.5 mg, 0.011 mmol), molybdenum hexacarbonyl (53 mg, 0.2 mmol) and DBU (40 μl, 0.27 mmol) were dissolved in THF (2 ml) and heated in a microwave at 125° C. for 15 mins. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by HPLC (MDAP, Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a pale yellow solid (18 mg, 8%). LCMS (Method 5) [M+H]+=574.1, RT=3.06 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.88 (s, 1H), 9.42 (dd, 1H, J=1.6, 7.0 Hz), 8.81 (s, 1H), 8.61 (dd, 1H, J=1.5, 4.3 Hz), 7.84 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=2.6, 8.8 Hz), 7.54 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.3, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz), 4.24 (dd, 1H, J=8.6, 12.3 Hz), 4.09 (dd, 1H, J=3.9, 12.3 Hz), 3.80 (dd, 1H, J=8.9, 12.6 Hz), 3.59-3.47 (m, 1H), 3.02-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.65-2.48 (m, 4H), 2.29 (s, 3H). After flushing with MeOH the product was eluted with 2M ammonia in MeOH The resulting yellow glass was purified by HPLC (MDAP, Method 1) evaporated to afford a yellow solid After flushing with MeOH the product was eluted with 2M ammonia in MeOH

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (200 mg, 0.4 mmol), 2-methyl-octahydro-pyrrolo[3,4-c]pyrrole (70 mg, 0.56 mmol), Herrmann's catalyst (4.5 mg, 0.0048 mmol), tri-tert-butyl phosphine hydrofluoroborate (3.5 mg, 0.011 mmol), molybdenum hexacarbonyl (53 mg, 0.2 mmol) and DBU (40 μl, 0.27 mmol) were dissolved in THF (2 ml) and heated in a microwave at 125° C. for 15 mins. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by HPLC (MDAP, Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a pale yellow solid (18 mg, 8%). LCMS (Method 5) [M+H]+=574.1, RT=3.06 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.88 (s, 1H), 9.42 (dd, 1H, J=1.6, 7.0 Hz), 8.81 (s, 1H), 8.61 (dd, 1H, J=1.5, 4.3 Hz), 7.84 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=2.6, 8.8 Hz), 7.54 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.3, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz), 4.24 (dd, 1H, J=8.6, 12.3 Hz), 4.09 (dd, 1H, J=3.9, 12.3 Hz), 3.80 (dd, 1H, J=8.9, 12.6 Hz), 3.59-3.47 (m, 1H), 3.02-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.65-2.48 (m, 4H), 2.29 (s, 3H). After flushing with MeOH the product was eluted with 2M ammonia in MeOH The resulting yellow glass was purified by HPLC (MDAP, Method 1) evaporated to afford a yellow solid After flushing with MeOH the product was eluted with 2M ammonia in MeOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step FG (1): The title compound (80 mg) was prepared in 46% yield via Ullman type coupling of (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (TFA salt of Example 68) and 2-methyloctahydropyrrolo[3,4-c]pyrrole by following a procedure analogous to Step FF (1). LC/MS (M+H)+ 581.43. 1H NMR (400 MHz, CD3OD) δ ppm 1.27 (s, 2H) 1.49 (s, 1H) 1.98-2.06 (m, 2H) 2.23-2.35 (m, 5H) 2.38 (s, 2H) 2.54 (s, 1H) 2.58-2.69 (m, 2H) 2.75 (s, 1H) 2.92 (d, J=12.09 Hz, 4H) 2.99-3.11 (m, 2H) 3.18 (s, 1H) 3.55 (d, J=10.83 Hz, 1H) 3.83 (m, 2H) 3.88-3.98 (m, 2H) 4.05 (d, J=14.10 Hz, 1H) 4.30 (m, 1H) 4.65 (m, 1H) 5.42-5.54 (m, 2H) 6.70-6.77 (m, 5H) 7.19 (t, J=7.43 Hz, 2H). CD3OD

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-methyl-3,7-diazabicyclo-[3.3.0]octane in a yield of 13% of theory. Colourless crystals of m.p. 220°-222° C. (ethanol).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.9 g (18 mmoles) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2.3 g of 3- methyl-3,7-diazabicyclo[3.3.0]octane in 75 ml of dry dimethylformamide was stirred for 20 hours at ambient temperature. The reaction mixture was concentrated in vacuo, the residue was divided between 1N hydrochloric acid and methylene chloride. The organic phase was washed two further times using 1N hydrochloric acid and once using water. The combined aqueous phases were rendered basic using potassium carbonate and extracted using methylene chloride (3×150 ml). The combined methylene chloride phases were dried over magnesium sulphate, concentrated and the crude material was recrystallised from acetonitrile. 2.9 g (41% of theory) of colourless crystals of m.p. 157°-159° C. were obtained. The reaction mixture was concentrated in vacuo The organic phase was washed two further times extracted The combined methylene chloride phases were dried over magnesium sulphate concentrated the crude material was recrystallised from acetonitrile 2.9 g (41% of theory) of colourless crystals of m.p. 157°-159° C. were obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-benzyl-5-methyloctahydropyrrolo[3,4-c]pyrrole (2.4 g) in methanol (60 ml) was mixed with ammonium formate (2.1 g) and palladium on carbon (5%, 0.12 g), and the mixture was refluxed for 8 hours. After cooling, the reaction solution was filtered and concentrated. The crude product could be directly reacted further. The product with the molecular weight of 126.20 (C7H14N2); MS (ESI): 127 (M+H+) was obtained in this way. the mixture was refluxed for 8 hours After cooling the reaction solution was filtered concentrated The crude product could be directly reacted further MS (ESI): 127 (M+H+) was obtained in this way

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-methyl-3,7-diazabicyclo[3.3.0]octane (297 mg, 2.36 mmol; see Example 54C), 2,7-dibromofluoren-9-one (680 g, 2.01 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium (0) (Pd2 dba3; 37 mg, 0.040 mmol; Alfa), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 63 mg, 0.10 mmol; Strem) and sodium tert-butoxide (270 mg, 2.81 mmol; Acros) in 10 mL toluene was warmed to 90° C. and stirred for 16 h. The reaction mixture was cooled to ambient temperature and filtered through Celite, rinsing with CH2Cl2. After concentrating the solution under reduced pressure, the residue was purified by flash chromatography (120 g silica gel, 1-20% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to give the crude product. This material was purified further by flash chromatography (40 g Analogix NH2 column, 10-100% EtOAc in hexanes) to afford the title compound as a reddish solid (335 mg, 0.875 mmol; 44% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.64 (d, J=2 Hz, 1H), 7.49 (dd, J=8, 2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.64 (dd, J=8, 2 Hz, 1H), 3.42-3.53 (m, 2H), 3.29 (dd, J=10, 3 Hz, 2H), 2.99-3.13 (m, 2H), 2.75-2.94 (m, 2H), 2.56 (dd, J=9, 3 Hz, 2H), 2.41 (s, 3H); MS (ESI): m/z 383 (M+1)+, 385 (M+3)+. The reaction mixture was cooled to ambient temperature filtered through Celite rinsing with CH2Cl2 After concentrating the solution under reduced pressure the residue was purified by flash chromatography (120 g silica gel, 1-20% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to give the crude product This material was purified further by flash chromatography (40 g Analogix NH2 column, 10-100% EtOAc in hexanes)

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide (200 mg, 0.4 mmol), 2-methyl-octahydro-pyrrolo[3,4-c]pyrrole (70 mg, 0.56 mmol), Herrmann's catalyst (4.5 mg, 0.0048 mmol), tri-tert-butyl phosphine hydrofluoroborate (3.5 mg, 0.011 mmol), molybdenum hexacarbonyl (53 mg, 0.2 mmol) and DBU (40 μl, 0.27 mmol) were dissolved in THF (2 ml) and heated in a microwave at 125° C. for 15 mins. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The resulting yellow glass was purified by HPLC (MDAP, Method 1). Appropriate fractions were combined and evaporated to afford a yellow solid. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH to give the title compound as a pale yellow solid (18 mg, 8%). LCMS (Method 5) [M+H]+=574.1, RT=3.06 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.88 (s, 1H), 9.42 (dd, 1H, J=1.6, 7.0 Hz), 8.81 (s, 1H), 8.61 (dd, 1H, J=1.5, 4.3 Hz), 7.84 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=2.6, 8.8 Hz), 7.54 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.3, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz), 4.24 (dd, 1H, J=8.6, 12.3 Hz), 4.09 (dd, 1H, J=3.9, 12.3 Hz), 3.80 (dd, 1H, J=8.9, 12.6 Hz), 3.59-3.47 (m, 1H), 3.02-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.65-2.48 (m, 4H), 2.29 (s, 3H). After flushing with MeOH the product was eluted with 2M ammonia in MeOH The resulting yellow glass was purified by HPLC (MDAP, Method 1) evaporated to afford a yellow solid After flushing with MeOH the product was eluted with 2M ammonia in MeOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step FG (1): The title compound (80 mg) was prepared in 46% yield via Ullman type coupling of (1S,4R,5S,15R)-19-bromo-5-(3,5-difluoro-benzyl)-4-hydroxy-14-oxa-2,6-diaza-tricyclo[13.6.1.016,21]docosa-11,16(21),17,19-tetraen-7-one (TFA salt of Example 68) and 2-methyloctahydropyrrolo[3,4-c]pyrrole by following a procedure analogous to Step FF (1). LC/MS (M+H)+ 581.43. 1H NMR (400 MHz, CD3OD) δ ppm 1.27 (s, 2H) 1.49 (s, 1H) 1.98-2.06 (m, 2H) 2.23-2.35 (m, 5H) 2.38 (s, 2H) 2.54 (s, 1H) 2.58-2.69 (m, 2H) 2.75 (s, 1H) 2.92 (d, J=12.09 Hz, 4H) 2.99-3.11 (m, 2H) 3.18 (s, 1H) 3.55 (d, J=10.83 Hz, 1H) 3.83 (m, 2H) 3.88-3.98 (m, 2H) 4.05 (d, J=14.10 Hz, 1H) 4.30 (m, 1H) 4.65 (m, 1H) 5.42-5.54 (m, 2H) 6.70-6.77 (m, 5H) 7.19 (t, J=7.43 Hz, 2H). CD3OD