2-Acetylamino-4-methyl-thiazole-5-carboxylic acid

To a suspension of 6 (500mg, 3.20mmol) in tetrahydrofuran (20mL) were added pyridine (1.30mL, 16.0mmol) and acetyl chloride (0.60ml, 7.90mmol) at 0°C, and the reaction mixture was stirred for 21h at room temperature. After the volatiles of the mixture were removed in vacuo, water was poured into the residue, and the suspension was stirred for 1h. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to yield 7 (585mg, 91percent) as a colorless powder. To a suspension of 6 (500mg, 3.20mmol) in tetrahydrofuran (20mL) were added pyridine (1.30mL, 16.0mmol) and acetyl chloride (0.60ml, 7.90mmol) at 0°C, and the reaction mixture was stirred for 21h at room temperature. After the volatiles of the mixture were removed in vacuo, water was poured into the residue, and the suspension was stirred for 1h. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to yield 7 (585mg, 91percent) as a colorless powder. To a suspension of 6-(2-amino-5-chlorothiazol-4-yl)-3, 4-dihydroquinolin-2(1H)-one (0.110 g, 0.45 mmol) and 37mg (0.29 mmol) Thiazole-5-carboxylic acid, 83 p1(0.48 mmol) DIPEA and 154 mg(0.481 mmol) TBTU in 0.5 mL DMF are stirred for 10 mm at r.t. Then 80 mg (0.24 mmol) (S)-1 -[4-(5-methoxy-3, 4-dihydro-1 H-isoquinolin-2-ylmethyl)-phenyl]-eth ylamine hydrochloride (example XXXIII.2) in 1.0 mL DMF and 102 p1(0.601 mmol) DIPEA are added and the resulting mixture is stirred at r.t. for 2 h . After that time, the reaction is quenched by the addition of 200 iL water and purified by H PLC.General procedure: 14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 mul (0.51 mmol) DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for 10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (ACN/H2O/TFA).For the examples 2.26-2.28 TEA is used as base.Example 2.1 (general route) /V-((S)-1-(4-((R)-1 -(2-((2, 2-difluoroethyl)(methyl)amino)pyrimidin-4-yl)pyi 14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 muIota (0.51 mmol) DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for 10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (ACN/H20/TFA). C23H29F2N5O2 (M= 445.5 g/mol) ESI-MS: 446 [M+H]+ Rt (HPLC):0.99 min (method E) For the examples where 1 -chloro-N, N-2-trimethylpropenylamine is used, the reagent is added to the mixture of the appropiate acid in DCM and stirred at r.t. for 30 min.For the examples 2.25 - 2.34 THF is used as solvent For the examples 2.26 - 2.28 TEA is used as base.For the examples where 1 -chloro-N, N-2-trimethylpropenylamine is used, the reagent is added to the mixture of the appropiate acid in DCM and stirred at r.t. for 30 min.General procedure: 14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 mul (0.51 mmol) DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for 10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (ACN/H2O/TFA).For the examples 2.8-2.11, 2.13-2.14 and 2.16 the reaction time is 1 h.Example 2.1 (general route) /V-((S)-1-(4-((R)-1 -(2-((2, 2-difluoroethyl)(methyl)amino)pyrimidin-4-yl)pyi 14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 muIota (0.51 mmol) DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for 10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (ACN/H20/TFA). C23H29F2N5O2 (M= 445.5 g/mol) ESI-MS: 446 [M+H]+ Rt (HPLC):0.99 min (method E) For the examples 2.8 - 2.11 , 2.13 - 2.14 and 2.16 the reaction time is 1 h.General procedure: 14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 mul (0.51 mmol) DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for 10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and the resulting mixture is stirred at r.t. over night. Afterwards the mixture is directly purified by HPLC (ACN/H2O/TFA).C23H29F2N5O2 (M=445.5 g/mol)ESI-MS: 446 [M+H]+Rt (HPLC): 0.99 min (method E)2-Acetamido-N-((1S)-1-(4-((3R)-1-(5-((2, 2-difluorocyclopropyl)methoxy)pyrid rrolidin-3-yloxy)phenyl)ethyl)-4-methylthiazole-5-carboxamide 25.7 mg (0.13 mmol) 2-Acetamido-N-((1S)-1-(4-((3R)-1-(5-((2, 2-difluorocyclopropyl)methoxy)pyridin-2-yl)pyrrolidin-3-yloxy)phenyl)ethyl)-4-methylthiazole-5-carboxamide 25.7 mg (0.13 mmol) 25.7 mg (0.13 mmol) 56.8 mg (0.28 mmol) General procedure: Example 2.1 (general route) 2-Acetamido-N-((S)-1 -(4-((f?)-1 -(4-(cvclopropylmethoxy)phenyl)pyrrolidin-3- yloxy)phenyl)ethyl)-4-methylthiazole-5-carboxamide 56.8 mg (0.28 mmol) A mixture of 10j (0.23g, 1.14mmol), 7 (0.23g, 1.14mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) (0.26g, 1.37mmol) in dimethylformamide (3mL) was stirred at room temperature for 15h. The reaction mixture was then allowed to heat at 100C for 3h and was evaporated in vacuo. The residue was purified using silica gel column chromatography (methanol/chloroform) to yield 13 (69.0mg, 17%) as a yellow oil.

Molecular Weight:200.22
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:200.02556330
Monoisotopic Mass:200.02556330
Topological Polar Surface Area:108
Heavy Atom Count:13
Complexity:234
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes