1-N,1-N,2-trimethylpropane-1,2-diamine

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

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

Procedure: To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added N1,N1,2-trimethylpropane-1,2-diamine (100 mg, 0.86 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of methanol and THF (1:3, v/v) to give N-(1-(dimethylamino)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 16.5%) as a yellow solid. MS: (M+H)+=392; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.90 (brs, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=8.4 Hz), 8.37 (s, 1H), 7.97 (s, 1 h), 7.45 (s, 1H), 7.10 (d, 1H, J=8.4 Hz), 2.74 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H). filtered the filter cake was purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of methanol and THF (1:3

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

Procedure: To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added N1,N1,2-trimethylpropane-1,2-diamine (100 mg, 0.86 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of methanol and THF (1:3, v/v) to give N-(1-(dimethylamino)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 16.5%) as a yellow solid. MS: (M+H)+=392; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.90 (brs, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=8.4 Hz), 8.37 (s, 1H), 7.97 (s, 1 h), 7.45 (s, 1H), 7.10 (d, 1H, J=8.4 Hz), 2.74 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H). filtered the filter cake was purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of methanol and THF (1:3

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

Procedure: A mixture of 1 g of the compound obtained in EXAMPLE 13, 1 g of 2-dimethylamino -1,1- dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 10-12), 1 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 16 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of NaOH, extracted with a 6N solution of HCl, washed with AcOEt, the acidic aqueous phase is rendered alkaline by the addition of 2N NaOH, extracted with AcOEt and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.65 g of the expected product after crystallization from iso ether. M.p.=161° C. The reaction mixture is evaporated under vacuum the residue is extracted with AcOEt washed with a 1N solution of NaOH extracted with a 6N solution of HCl washed with AcOEt by the addition of 2N NaOH extracted with AcOEt dried over Na2SO4 the solvent is evaporated off under vacuum The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent

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

Procedure: To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added N1,N1,2-trimethylpropane-1,2-diamine (100 mg, 0.86 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of methanol and THF (1:3, v/v) to give N-(1-(dimethylamino)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 16.5%) as a yellow solid. MS: (M+H)+=392; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.90 (brs, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=8.4 Hz), 8.37 (s, 1H), 7.97 (s, 1 h), 7.45 (s, 1H), 7.10 (d, 1H, J=8.4 Hz), 2.74 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H). filtered the filter cake was purified by column chromatography (silica gel, 200-300 mesh eluting with a mixture of methanol and THF (1:3

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

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

Procedure: A mixture of 1.5 g of the compound obtained in Example 15 Step B, 1 g of 2-dimethylamino-1,1-dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 12-14), 1.6 g of BOP and 2 g of DIPEA in 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/MeOH mixture (98/2; v/v). 0.15 g of the expected product is obtained after crystallization from iso ether, mp=161° C. is left The reaction mixture is concentrated under vacuum the residue is extracted with EtOAc the organic phase is washed with 1N NaOH solution, with water dried over Na2SO4 the solvent is evaporated off under vacuum The residue is chromatographed on silica eluting with a DCM/MeOH mixture (98/2; v/v)

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

Procedure: A mixture of 1.5 g of the compound obtained in Example 15 Step B, 1 g of 2-dimethylamino-1,1-dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 12-14), 1.6 g of BOP and 2 g of DIPEA in 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/MeOH mixture (98/2; v/v). 0.15 g of the expected product is obtained after crystallization from iso ether, mp=161° C. is left The reaction mixture is concentrated under vacuum the residue is extracted with EtOAc the organic phase is washed with 1N NaOH solution, with water dried over Na2SO4 the solvent is evaporated off under vacuum The residue is chromatographed on silica eluting with a DCM/MeOH mixture (98/2; v/v)

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

Procedure: A mixture of 1.5 g of the compound obtained in Example 15 Step B, 1 g of 2-dimethylamino-1,1-dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 12-14), 1.6 g of BOP and 2 g of DIPEA in 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/MeOH mixture (98/2; v/v). 0.15 g of the expected product is obtained after crystallization from iso ether, mp=161° C. is left The reaction mixture is concentrated under vacuum the residue is extracted with EtOAc the organic phase is washed with 1N NaOH solution, with water dried over Na2SO4 the solvent is evaporated off under vacuum The residue is chromatographed on silica eluting with a DCM/MeOH mixture (98/2; v/v)

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

Procedure: The title compound was prepared in a manner analogous to Step 3 of Method A, from 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and 2,N1,N1-trimethyl-propane-1,2-diamine (Tsuji, et al Chem. Pharm. Bull. Vol. 12, pp. 946-950 (1964)). Radial chromatography with 0.5% (58% NH4OH)/5%MeOH/CHCl3 gave a yellow oil, which was placed in CHCl3, treated with 4M HCl in dioxane (2.2 equiv), and azeotroped from CHCl3 in succession to provide 100 mg of yellow powder in 23% yield, mp 275-290° C. (decomp).

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

Procedure: N1,N1,2-Trimethylpropane-1,2-diamine (5.68 g, 48.8 mmol) was dissolved into isopropanol/water (1:1, 150 mL). To this solution was added CbzOSu (12.2 g, 1 equiv, 48.8 mmol) in one portion. The reaction was left to stir at room temperature overnight for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (300 mL) and water (100 mL). The layers were separated and the organic layer extracted with water (2×100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to an oil. The crude oil was purified on an ISCO purification system with gradient elution from 2% methanol in DCM to 30% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (8.95 g, yield: 73.2%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI+) for C14H22N2O2 (250.2); Found: 251 (MH+). The reaction was left The solvent was removed the residue was taken up in a mixture of ethyl acetate (300 mL) and water (100 mL) The layers were separated the organic layer extracted with water (2×100 mL) The organic layer was dried over anhydrous MgSO4 filtered concentrated to an oil The crude oil was purified on an ISCO purification system with gradient elution from 2% methanol in DCM to 30% methanol in DCM The desired fraction was collected concentrated

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

Procedure: A mixture of 1 g of the compound obtained in EXAMPLE 13, 1 g of 2-dimethylamino -1,1- dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 10-12), 1 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 16 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of NaOH, extracted with a 6N solution of HCl, washed with AcOEt, the acidic aqueous phase is rendered alkaline by the addition of 2N NaOH, extracted with AcOEt and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.65 g of the expected product after crystallization from iso ether. M.p.=161° C. The reaction mixture is evaporated under vacuum the residue is extracted with AcOEt washed with a 1N solution of NaOH extracted with a 6N solution of HCl washed with AcOEt by the addition of 2N NaOH extracted with AcOEt dried over Na2SO4 the solvent is evaporated off under vacuum The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent