(1S,2R)-cyclohexane-1,2-diamine

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

Procedure: Diisopropylethylamine (7.5 ml) and cis-cyclohexane-1,2-diamine (5.0 g) were added to an N-methylpyrrolidone (50 ml) solution containing methyl 2-benzylamino-6-chloronicotinate (6.0 g), followed by stirring at 120° C. for 11 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. Di-tert-butyl dicarbonate (4.7 g) was added to a tetrahydrofuran (50 ml) solution containing the obtained residue and the resulting mixture was left at rest at room temperature for 3 days. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel:silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=3:1), and a light yellow solid of methyl 2-benzylamino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)nicotinate (7.7 g) was thus obtained. The reaction mixture was cooled to room temperature The organic layer was collected washed with saturated saline dried over anhydrous sodium sulfate the solvent was distilled away under reduced pressure Di-tert-butyl dicarbonate (4.7 g) was added to a tetrahydrofuran (50 ml) solution containing the obtained residue the resulting mixture was left at rest at room temperature for 3 days The solvent was distilled away under reduced pressure The obtained residue was purified by silica gel column chromatography (silica gel:silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=3:1)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-(1H-indazol-5-ylamino)-5-chloropyrazine-2-carboxamide (˜100 mg) in ˜3 mL NMP was added 6 equivalents of DIEA and 20 equivalents of racemic cis-1,2-cyclohexanediamine. The mixture was heated at 150° C. in a sealed tube overnight. The reaction mixture was cooled, acidified with TFA, diluted with water and prepped via rpHPLC to give the title compound. MS found for C18H22N8O as (M+H)+ 367.2. The reaction mixture was cooled

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 16×100 mm screw cap test tube were added HATU (80.5 mg, 212 μmol.20) and (1R,2S)-cyclohexane-1,2-diamine (20.1 mg, 176 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 176 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give the desired N-((1R,2S)-2-aminocyclohexyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 38.2 μmol, 21.7%). MS (M+H)+=550 (>90% purity); 1H NMR (CDCl3) δ: 9.02 (s, 1H), 8.51 (s, 1H), 7.51 (s, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.22 (dd, J=9.3, 2.1 Hz, 1H), 5.61-5.84 (m, 2H), 4.78 (br. s., 1H), 4.18 (s, 3H), 4.02 (t, J=3.2 Hz, 1H), 3.91 (s, 3H), 3.76 (br. s., 1H), 3.62-3.71 (m, 2H), 2.09 (br. s., 2H), 2.03 (s, 2H), 1.80-1.98 (m, 4H), 1.52-1.78 (m, 4H), 0.98 (dd, J=9.3, 7.4 Hz, 2H), 0.00 (s, 9H). In a 16×100 mm screw cap test tube was added to give a light yellow solution which immediately formed a white precipitated solvents evaporated residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 16×100 mm screw cap test tube were added HATU (80.5 mg, 212 μmol.20) and (1R,2S)-cyclohexane-1,2-diamine (20.1 mg, 176 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 176 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give the desired N-((1R,2S)-2-aminocyclohexyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 38.2 μmol, 21.7%). MS (M+H)+=550 (>90% purity); 1H NMR (CDCl3) δ: 9.02 (s, 1H), 8.51 (s, 1H), 7.51 (s, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.22 (dd, J=9.3, 2.1 Hz, 1H), 5.61-5.84 (m, 2H), 4.78 (br. s., 1H), 4.18 (s, 3H), 4.02 (t, J=3.2 Hz, 1H), 3.91 (s, 3H), 3.76 (br. s., 1H), 3.62-3.71 (m, 2H), 2.09 (br. s., 2H), 2.03 (s, 2H), 1.80-1.98 (m, 4H), 1.52-1.78 (m, 4H), 0.98 (dd, J=9.3, 7.4 Hz, 2H), 0.00 (s, 9H). In a 16×100 mm screw cap test tube was added to give a light yellow solution which immediately formed a white precipitated solvents evaporated residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane

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

Procedure: A mixture of 2.53 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 4.6 g of cis-1,2-diaminocyclohexane in 10 ml of pyridine was heated as described in Example 1 giving 2.4 g of the desired product, m.p. 225°-227°C. was heated

Conditions: temp:115.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.33 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.73 g of cis-1,2-diaminocyclohexane in 10 ml of pyridine was heated in an oil bath of 115° C. for 1 hour then filtered while hot. Cooling the filtrate afforded 1.09 g of the desired product, m.p. 270°-274° C. then filtered while hot Cooling the filtrate

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

Procedure: Part A. 1-(4-Chlorocarbonyl-phenyl)-cyclopropanecarboxylic acid methyl ester (0.66 g, 2.77 mmol) was stirred in CH2Cl2 (10 mL) at rt under N2. 1,2-Cis-diamino-cyclohexane (0.66 mL, 2.0 eq) was added as one portion. The mixture was stirred for 10 min. Diluted HCl was added. The mixture was extracted with EtOAc (2×). The aqueous layer was basified with conc. NaOH, extracted with EtOAc (2×). The organic layers were washed with H2O and brine, dried over MgSO4, filtered, and concentrated to afford 1-[4-(2-amino-cyclohexylcarbamoyl)-phenyl]-cyclopropanecarboxylic acid methyl ester (0.35 g, yield: 39.8%). LC/MS (ESI+) 317.4 (M+H). The mixture was extracted with EtOAc (2×) extracted with EtOAc (2×) The organic layers were washed with H2O and brine dried over MgSO4 filtered concentrated

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

Procedure: cis-Cyclohexane-1,2-diamine (5.00 g, 43.9 mmol, 1.00 eq) was charged to a 250 ml, three-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Ethanol (50 mL) was added and the solution was cooled to <0° C. using an ice-brine bath. A solution of ethyl trifluoroacetate (6.23 g, 1.00 eq) in EtOH (25 mL) was added via a syringe pump over a one hour period. Once the addition was complete, the cooling bath was removed and the solution was slowly warmed to RT and stirred for 3.5 hours to afford the title compound in EtOH. Half (41 mL, about 21.9 mmol) of the total solution (about 82 mL) was carried into the next step. equipped with an overhead stirrer the solution was cooled to <0° C. Once the addition the cooling bath was removed

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

Procedure: cis-Cyclohexane-1,2-diamine (5.00 g, 43.9 mmol, 1.00 eq) was charged to a 250 ml, three-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Ethanol (50 mL) was added and the solution was cooled to <0° C. using an ice-brine bath. A solution of ethyl trifluoroacetate (6.23 g, 1.00 eq) in EtOH (25 mL) was added via a syringe pump over a one hour period. Once the addition was complete, the cooling bath was removed and the solution was slowly warmed to RT and stirred for 3.5 hours to afford the title compound in EtOH. Half (41 mL, about 21.9 mmol) of the total solution (about 82 mL) was carried into the next step. equipped with an overhead stirrer the solution was cooled to <0° C. Once the addition the cooling bath was removed

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

Procedure: The title compound, yellow solid, MS: m/e=327.2 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).

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

Procedure: The title compound, yellow foam, MS: m/e=385.1 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).

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

Procedure: The title compound, yellow foam, MS: m/e=385.1 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).