(E)-4-(dimethylamino)but-2-enoic acid

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

Procedure: To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (42 mg, 0.25 mmol), DIEA (150 μL, 0.84 mmol) and then PyBOP (88 mg, 0.17 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (94) as an HCl salt (29 mg). MS found for C28H38N8O4 as (M+H)+ 551.3, (M−H)− 549.3. UV: λ=274, 281, 313, 344, 369 nm. quenched with TFA (0.2 mL) diluted with 2 mL water

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

Procedure: To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide HCl salt (47 mg, 0.10 mmol) in NMP (4 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.30 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (104 mg, 0.20 mmol). The mixture was stirred at RT for 2 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (80) as an HCl salt (32 mg). MS found for C26H35N9O4 as (M+H)+ 538.2, (M−H)− 536.3. UV: λ=246 nm. quenched with TFA (0.2 mL) diluted with 2 mL water

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

Procedure: To a solution of (R)-5-(4-(morpholine-4-carbonyl)phenylamino)-3-(piperidin-3-ylamino)-1,2,4-triazine-6-carboxamide HCl salt (47 mg, 0.10 mmol) in NMP (4 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.30 mmol), DIEA (180 μL, 1.0 mmol) and then PyBOP (104 mg, 0.20 mmol). The mixture was stirred at RT for 2 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (80) as an HCl salt (32 mg). MS found for C26H35N9O4 as (M+H)+ 538.2, (M−H)− 536.3. UV: λ=246 nm. quenched with TFA (0.2 mL) diluted with 2 mL water

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

Procedure: This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide (intermediate 20) and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (18.9 mg, 29.7%). Data: UPLC (C) Rt: 1.38 min; m/z 517.3 (M+H)+. This compound was prepared, in an analogous manner

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

Procedure: This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (11.8 mg, 46.6%). Data: UPLC (C) Rt: 1.29 min; m/z 511.0 (M+H)+. This compound was prepared, in an analogous manner

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

Procedure: This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (11.8 mg, 46.6%). Data: UPLC (C) Rt: 1.29 min; m/z 511.0 (M+H)+. This compound was prepared, in an analogous manner

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

Procedure: (E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid using Method E (29% yield). HPLC: 99%, RT=3.448 min. MS: m/z=482 [M+H]+, RT=3.40 min. 1H-NMR (DMSO-d6) δ 10.30 (s, 1H), 8.02 (s, 1H), 7.62 (d, 2H), 7.43-7.38 (m, 4H), 7.15 (tt, 1H), 7.10-7.01 (m, 6H), 6.73 (m, 1H), 6.49 (broad s, 2H), 6.44 (d, 1H), 3.93 (m, 2H), 2.80 (s, 6H).

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

Procedure: (E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-4-(dimethylamino)but-2-enoic acid using Method E (35% yield). HPLC: 99%, RT=3.399 min. MS: m/z=466 [M+H]+, RT=3.37 min. 1H-NMR (DMSO-d6) δ 10.52 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H), 8.04 (s, 1H), 7.74 (d, 1H), 7.48 (t, 1H), 7.43-7.38 (m, 3H), 7.29-7.26 (d, 2H), 7.17-7.12 (m, 3H), 7.05-6.99 (m, 3H), 6.74 (m, 1H), 6.48 (d, 1H), 3.94 (d, 2H), 2.79 (s, 6H).

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

Procedure: (R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D and E. HPLC purity: 100%. MS: m/z=473 [M+H]+.

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

Procedure: (R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D and E. HPLC purity: 99%. MS: m/z=459 [M+H]+.

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

Procedure: (E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-(dimethylamino)but-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, (4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D, and E. HPLC purity: 100%. MS: m/z=513 [M+H]+.

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

Procedure: A solution of 211 ml of dimethylamine (2M in tetrahydrofuran, 0.422 moles) is added dropwise to a solution of 50 g trimethylsilyl-4-bromocrotonate (0.211 moles, 75.9% by GC-MS) in 250 ml of tetrahydrofuran at 0–5° C. under N2. The reaction mixture is stirred at room temperature for 30 minutes. A white solid by-product is removed by filtering and 2 ml water is added to the filtrate followed by seeding. The crystals formed are filtered and washed with ether to give 18.3 g (from two crops) of the desired product as off-white solid. Yield is 67.2% (98% purity by GC-MS, NMR is consistent with the expected structure). A white solid by-product is removed by filtering 2 ml water is added to the filtrate The crystals formed are filtered washed with ether