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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (20 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z 401.4 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s, 3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H), 2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H), 3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s., 2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H). washed with saturated NaHCO3(aq) (20 mL) The organic phase was separated the aqueous phase was re-extracted with DCM (20 mL) The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue The crude material was purified by mass the product containing fractions The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL) The MeOH/NH3 was removed in vacuo

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

Procedure: A stirred solution of 2-bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole (600 mg, 1.49 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (377 mg, 2.99 mmol) in NMP (4 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was cooled to room temperature then saturated NaHCO3(aq) (30 mL) was added. The resulting suspension was left to slurry for 1 hour before filtering under vacuum to afford the title compound as a pale brown solid which was used in the next step without further purification. LC-MS: Rt 1.06 min; MS m/z 446.8 [M]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.77-7.86 (m, 2H), 3.71 (t, J=8.84 Hz, 2H), 3.36 (br. s., 2H), 2.97 (br. s., 2H), 2.40-2.54 (m, 4H), 2.22 (s, 3H). The resulting suspension was left before filtering under vacuum

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

Procedure: A stirred solution of 2-bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole (600 mg, 1.49 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (377 mg, 2.99 mmol) in NMP (4 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was cooled to room temperature then saturated NaHCO3(aq) (30 mL) was added. The resulting suspension was left to slurry for 1 hour before filtering under vacuum to afford the title compound as a pale brown solid which was used in the next step without further purification. LC-MS: Rt 1.06 min; MS m/z 446.8 [M]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.77-7.86 (m, 2H), 3.71 (t, J=8.84 Hz, 2H), 3.36 (br. s., 2H), 2.97 (br. s., 2H), 2.40-2.54 (m, 4H), 2.22 (s, 3H). The resulting suspension was left before filtering under vacuum

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

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (90 mg, 0.468 mmol) and HOBT (21.09 mg, 0.156 mmol) in DMF (0.8 mL) and added N-ethyl-N-isopropylpropan-2-amine (0.056 mL, 0.468 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (79 mg, 0.624 mmol). After 17 hours, the reaction mixture was diluted with DMSO (100 uL) and purified by preparative HPLC (ACN/water with formic acid) to give the title compound as a 0.63 formic acid salt (60 mg, 0.131 mmol, 84%) as a tan solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H) 2.48 (s, 3 H) 2.77 (br. s., 2 H) 2.91 (br. s., 4 H) 3.43 (br. s., 2 H) 3.67 (dd, J=11.5, 6.4 Hz, 2H) 7.43-7.49 (m, 1 H) 7.51 (s, 1 H) 7.87 (s, 1 H) 7.94 (dd, J=8.7, 2.4 Hz, 1 H) 8.02 (d, J=8.1 Hz, 1 H) 8.41 (d, J=8.6 Hz, 1 H) 8.49 (d, J=1.8 Hz, 1 H) 11.91 (br. s., 1 H). purified by preparative HPLC (ACN/water with formic acid)

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

Procedure: 2-Amino-4,6-dichloropyrimidine (1.64 g, 10 mmol) was added portionwise to a stirred solution (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (1.6 g, 12.5 mmol) in absolute EtOH (10 mL) followed by TEA (1.8 mL, 12.5 mmol) dropwise at ambient temperature. The resulting suspension was warmed to reflux (initially a clear solution was observed on warming) and resulted in the gradual formation of a tan coloured precipitate. The mixture was refluxed for a total of 3 hours. The mixture was allowed to cool, EtOH (30 mL) was added to the mixture and heated to give a solution and was left to cool to ambient temperature. The resulting solid was collected by filtration, washed with cold EtOH (50 mL) and dried under suction to yield the title compound as a solid (2.07 g, 82%). The resulting suspension was warmed to reflux (initially a clear solution on warming) and resulted in the gradual formation of a tan coloured precipitate The mixture was refluxed for a total of 3 hours to cool heated to give a solution was left The resulting solid was collected by filtration washed with cold EtOH (50 mL) dried under suction

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

Procedure: A solution of {3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (20.0 g, 43.2 mmol) in DMF (150 mL) was treated with DIPEA (6.7 g, 5.2 mmol), cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (6.27 g, 49.7 mmol) and HATU (18.9 g, 49.7 mmol) and the mixture left to stir at room temperature for 1 hour. The reaction mixture was diluted with 0.5M aqueous K2CO3 solution and extracted with ethyl acetate (×2). The combined organic extract was washed with water (×2) and brine, dried (Na2SO4) and evaporated to afford a solid. The resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave the title compound as a cream solid (17.1 g, 69%). LCMS (Method 5) [M+H]+=570.9, RT=2.82. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.70 (s, 1H), 9.30 (dd, 1H, J=7.0, 1.6 Hz), 8.62-8.63 (m, 2H), 8.27 (s, 1H), 7.59 (dd, 1H, J=8.8, 2.7 Hz), 7.52 (d, 1H, J=2.7 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=7.0, 4.2 Hz), 7.11 (t, 1H, J=73.3 Hz), 5.07 (d, 2H, J=5.9 Hz), 3.69 (dd, 1H, J=10.8, 8.6 Hz), 3.56 (dd, 1H, J=12.2, 8.8 Hz), 3.36 (dd, 1H, J=10.8, 4.4 Hz), 3.22 (dd, 1H, J=12.3, 4.5 Hz), 2.45-2.46 (m, 3H), 2.37-2.39 (m, 3H), 2.17 (s, 3H). the mixture left extracted with ethyl acetate (×2) The combined organic extract was washed with water (×2) and brine dried (Na2SO4) evaporated to afford a solid The resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM Collecting appropriate fractions followed by evaporation

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

Procedure: A solution of {3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (20.0 g, 43.2 mmol) in DMF (150 mL) was treated with DIPEA (6.7 g, 5.2 mmol), cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (6.27 g, 49.7 mmol) and HATU (18.9 g, 49.7 mmol) and the mixture left to stir at room temperature for 1 hour. The reaction mixture was diluted with 0.5M aqueous K2CO3 solution and extracted with ethyl acetate (×2). The combined organic extract was washed with water (×2) and brine, dried (Na2SO4) and evaporated to afford a solid. The resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave the title compound as a cream solid (17.1 g, 69%). LCMS (Method 5) [M+H]+=570.9, RT=2.82. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.70 (s, 1H), 9.30 (dd, 1H, J=7.0, 1.6 Hz), 8.62-8.63 (m, 2H), 8.27 (s, 1H), 7.59 (dd, 1H, J=8.8, 2.7 Hz), 7.52 (d, 1H, J=2.7 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=7.0, 4.2 Hz), 7.11 (t, 1H, J=73.3 Hz), 5.07 (d, 2H, J=5.9 Hz), 3.69 (dd, 1H, J=10.8, 8.6 Hz), 3.56 (dd, 1H, J=12.2, 8.8 Hz), 3.36 (dd, 1H, J=10.8, 4.4 Hz), 3.22 (dd, 1H, J=12.3, 4.5 Hz), 2.45-2.46 (m, 3H), 2.37-2.39 (m, 3H), 2.17 (s, 3H). the mixture left extracted with ethyl acetate (×2) The combined organic extract was washed with water (×2) and brine dried (Na2SO4) evaporated to afford a solid The resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM Collecting appropriate fractions followed by evaporation

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

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (90 mg, 0.468 mmol) and HOBT (21.09 mg, 0.156 mmol) in DMF (0.8 mL) and added N-ethyl-N-isopropylpropan-2-amine (0.056 mL, 0.468 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (79 mg, 0.624 mmol). After 17 hours, the reaction mixture was diluted with DMSO (100 uL) and purified by preparative HPLC (ACN/water with formic acid) to give the title compound as a 0.63 formic acid salt (60 mg, 0.131 mmol, 84%) as a tan solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H) 2.48 (s, 3H) 2.77 (br. s., 2H) 2.91 (br. s., 4H) 3.43 (br. s., 2H) 3.67 (dd, J=11.5, 6.4 Hz, 2H) 7.43-7.49 (m, 1H) 7.51 (s, 1H) 7.87 (s, 1H) 7.94 (dd, J=8.7, 2.4 Hz, 1H) 8.02 (d, J=8.1 Hz, 1H) 8.41 (d, J=8.6 Hz, 1H) 8.49 (d, J=1.8 Hz, 1H) 11.91 (br. s., 1H). purified by preparative HPLC (ACN/water with formic acid)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (20 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z 401.4 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s, 3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H), 2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H), 3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s., 2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H). washed with saturated NaHCO3(aq) (20 mL) The organic phase was separated the aqueous phase was re-extracted with DCM (20 mL) The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue The crude material was purified by mass the product containing fractions The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL) The MeOH/NH3 was removed in vacuo

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

Procedure: A stirred solution of 2-bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole (600 mg, 1.49 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (377 mg, 2.99 mmol) in NMP (4 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was cooled to room temperature then saturated NaHCO3(aq) (30 mL) was added. The resulting suspension was left to slurry for 1 hour before filtering under vacuum to afford the title compound as a pale brown solid which was used in the next step without further purification. LC-MS: Rt 1.06 min; MS m/z 446.8 [M]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.77-7.86 (m, 2H), 3.71 (t, J=8.84 Hz, 2H), 3.36 (br. s., 2H), 2.97 (br. s., 2H), 2.40-2.54 (m, 4H), 2.22 (s, 3H). The resulting suspension was left before filtering under vacuum

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

Procedure: Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (90 mg, 0.468 mmol) and HOBT (21.09 mg, 0.156 mmol) in DMF (0.8 mL) and added N-ethyl-N-isopropylpropan-2-amine (0.056 mL, 0.468 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (79 mg, 0.624 mmol). After 17 hours, the reaction mixture was diluted with DMSO (100 uL) and purified by preparative HPLC (ACN/water with formic acid) to give the title compound as a 0.63 formic acid salt (60 mg, 0.131 mmol, 84%) as a tan solid. MS: 429 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3 H) 2.48 (s, 3 H) 2.77 (br. s., 2 H) 2.91 (br. s., 4 H) 3.43 (br. s., 2 H) 3.67 (dd, J=11.5, 6.4 Hz, 2H) 7.43-7.49 (m, 1 H) 7.51 (s, 1 H) 7.87 (s, 1 H) 7.94 (dd, J=8.7, 2.4 Hz, 1 H) 8.02 (d, J=8.1 Hz, 1 H) 8.41 (d, J=8.6 Hz, 1 H) 8.49 (d, J=1.8 Hz, 1 H) 11.91 (br. s., 1 H). purified by preparative HPLC (ACN/water with formic acid)

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

Procedure: 2-Amino-4,6-dichloropyrimidine (1.64 g, 10 mmol) was added portionwise to a stirred solution (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (1.6 g, 12.5 mmol) in absolute EtOH (10 mL) followed by TEA (1.8 mL, 12.5 mmol) dropwise at ambient temperature. The resulting suspension was warmed to reflux (initially a clear solution was observed on warming) and resulted in the gradual formation of a tan coloured precipitate. The mixture was refluxed for a total of 3 hours. The mixture was allowed to cool, EtOH (30 mL) was added to the mixture and heated to give a solution and was left to cool to ambient temperature. The resulting solid was collected by filtration, washed with cold EtOH (50 mL) and dried under suction to yield the title compound as a solid (2.07 g, 82%). The resulting suspension was warmed to reflux (initially a clear solution on warming) and resulted in the gradual formation of a tan coloured precipitate The mixture was refluxed for a total of 3 hours to cool heated to give a solution was left The resulting solid was collected by filtration washed with cold EtOH (50 mL) dried under suction