3-(dimethylamino)propanoic acid

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

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

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

Procedure: The title compound was prepared by the method of Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], 3-(dimethylamino)propanoic acid [Papapoulos, et al, WO 9619998A1], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-[3-(dimethylamino)propanoyl]oxy-2-piperidinecarboximidamide as an oil.

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

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

Procedure: The title compound was prepared by the method of Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], 3-(dimethylamino)propanoic acid [Papapoulos, et al, WO 9619998A1], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-[3-(dimethylamino)propanoyl]oxy-2-piperidinecarboximidamide as an oil.

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

Procedure: To a solution of 3-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (42 mg, 0.109 mmol) in dioxane (2 mL) was added 3-chlorophenol (28 mg, 0.218 mmol), CuI (6 mg, 0.0327 mmol), Cs2CO3 (71 mg, 0.218 mmol) and 3-(dimethylamino)propanoic acid (3 mg, 0.0327 mmol). The reaction was stirred at 130° C. (MW) for 2 h, cooled to RT then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 15.5% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 7.02-7.00 (m, 1H), 6.93 (dd, J=8.0, 2.4 Hz, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.00 (t, J=7.2 Hz, 2H), 3.58 (s, 3H), 3.45-3.50 (m, 2H), 3.15-3.10 (m, 2H), 1.77-1.72 (m, 2H), 1.57-1.52 (m, 1H), 1.23-1.34 (m, 2H), 0.82 (d, J=6.8 Hz, 6H). LCMS: MH+ 432 and TR=3.366 min. The organic layer was dried over Na2SO4 concentrated to a residue which was purified by Prep HPLC

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

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

Procedure: To a solution of 3-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (42 mg, 0.109 mmol) in dioxane (2 mL) was added 3-chlorophenol (28 mg, 0.218 mmol), CuI (6 mg, 0.0327 mmol), Cs2CO3 (71 mg, 0.218 mmol) and 3-(dimethylamino)propanoic acid (3 mg, 0.0327 mmol). The reaction was stirred at 130° C. (MW) for 2 h, cooled to RT then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 15.5% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 7.02-7.00 (m, 1H), 6.93 (dd, J=8.0, 2.4 Hz, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.00 (t, J=7.2 Hz, 2H), 3.58 (s, 3H), 3.45-3.50 (m, 2H), 3.15-3.10 (m, 2H), 1.77-1.72 (m, 2H), 1.57-1.52 (m, 1H), 1.23-1.34 (m, 2H), 0.82 (d, J=6.8 Hz, 6H). LCMS: MH+ 432 and TR=3.366 min. The organic layer was dried over Na2SO4 concentrated to a residue which was purified by Prep HPLC

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

Procedure: 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N4-isopropylpyrimidine-4,5-diamine 3-(dimethylamino)propanoate (48, 0.500 g, 1.68 mmoles) was dissolved in dimethylformamide and 3-dimethylaminopropionic acid (0.310 g, 2.02 mmoles) and isobutyl 2-isobutoxyquinoline-1(2H)-carboxylate (IIDQ, 0.699 mL, 2.35 mmoles) were added. The reaction mixture was allowed to stir at room temperature for 18 hours, concentrated, and purified by silica gel column chromatography (5-10% ethanol in dichloromethane) to provide N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-6-(isopropylamino)pyrimidin-5-yl)-3-(dimethylamino)propanamide (49) as a tan solid. Yield: 0.350 g (53%). LCMS (Waters walk-on); 2.43 min., 397.2, M+H. concentrated purified by silica gel column chromatography (5-10% ethanol in dichloromethane)

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

Procedure: Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-dimethylamino propionic acid to yield (3aR,4S,7aR)-4-(3-dimethylamino-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 413; RT 4.968 min; LC-MS Method ii

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

Procedure: BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), N,N-dimethyl-beta-alanine (0.016 g, 0.103 mmol) and diisopropylethylamine (0.11 mL, 0.617 mmol) in DMF (1 mL). the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give a white solid. Purification by reverse phase HPLC (acetonitrile:water with 0.1% TFA) gave the title compound (0.024 g, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 10.04 (s, 1H), 9.17-9.45 (m, 1H), 8.96 (t, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.42-7.50 (m, 2H), 7.29-7.40 (m, 2H), 7.23 (d, 1H), 7.08 (s, 1H), 4.53 (d, 2H), 3.31-3.39 (m, 2H), 2.71-2.82 (m, 8H). ES MS: m/z 568 (M+1). The organic layer was washed with water dried over sodium sulfate concentrated The residue was triturated with methanol to give a white solid Purification by reverse phase HPLC (acetonitrile:water with 0.1% TFA)

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

Procedure: 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(dimethylamino)propan-1-one was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate and 3-(dimethylamino)propanoic acid with method S1, S2, S3, S4A. Yield 17.3%. 1H NMR (CD3OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H), 3.89 (m, 1H), 3.66 (m, 1H), 3.28 (m, 1H), 3.01 (m, 1H), 2.61 (m, 4H), 2.44 (t, 1H), 2.25 (s, 6H), 1.75 (m, 2H), 1.20 (m, 1H). HPLC PURITY: 92%, MS: m/z=491 [M+H]+