Journal of Medicinal Chemistry Article Pd/C was added (gas generated). The reaction mixture was stirred for 1 h. Solid was ﬁltered oﬀ, and solvent was removed. The structure of crude compound 7b was veriﬁed by proton NMR. The product was assumed to be of 100% yield and used in the next step without further puriﬁcation. 1H NMR (400 MHz, CD3OD) δ 8.1 (s, 1H), 7.74− 7.70 (m, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.27 (m, 2H), 6.94 (d, J = 8.6 Hz, 2H), 3.91 (s, 2H), 3.80 (s, 3H), 3.79 (s, 2H), 2.87 (s, 2H), 1.61 (s, 6H). 7-(4-Methoxybenzyl)-2-(4-ﬂuorophenyl)-5,5-dimethyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazine (1.07 g, 2.93 mmol, 1.00 equiv) (7b) was added to triﬂuoroacetic acid (15 mL). The resulting solution was stirred for 2 h at 70 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 200 mL of dichloromethane. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate. 7b-1 was extracted from the aqueous layer using 3 × 100 mL of ethyl acetate. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 7b-1 (718 mg, quantitative) as a yellow solid. m/z = 246 (M + H). To a solution of 7b-1 (750 mg, 3.06 mmol, 1.00 equiv) in N,N- dimethylformamide (30 mL) were added 2-(tert-butoxycarbonyl)acetic acid (850 mg, 4.86 mmol, 1.50 equiv), HATU (1.3 g, 3.42 mmol, 1.10 equiv), and triethylamine (650 mg, 6.44 mmol, 2.00 equiv). The resulting solution was stirred overnight at rt. The residue was dissolved in ethyl acetate (200 mL). The resulting mixture was washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (4:1). This resulted in 600 mg (49%) of 7c as a pale-yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.75 (m, 2H), 7.22 (s, 1H), 7.13−7.07 (m, 2H), 4.99− 4.87 (m, 2H), 4.12 (s, 2H), 3.91 3.65 (m, 2H), 1.57 (m, 6H), 1.43 (s, 9H). To a stirred solution of compound 7b-2 (583 g, 1.45 mmol) in dichloromethane (6 mL) was added Br2 (82 μL, 1.60 mmol) in acetic acid (2 mL). The reaction mixture was stirred at rt for 30 min. Solvent was removed via rotavap at a temperature no higher than 20 °C. After neutralization, the residue was subjected to ﬂash chromatography (40 g, 0−100% ethyl acetate in hexane, 50 min, dry loading) puriﬁcation to give 628 mg (90%) of the title compound 7c as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 781−7.78 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 5.28 (s, NH), 4.84− 4.7 (m, 2H), 4.07−3.58 (m, 4H), 1.49−1.44 (m, 6H), 1.28 (s, 9H). Synthesis of 26. 2-Amino-1-(2-(4-ﬂuorophenyl)-3-(4-ﬂuoropheny- lamino)-5,5-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)- ethanone: Compound 26 was prepared from compound 7c by a Pd2(dba)3 mediated amination reaction with 4-ﬂuoroaniline followed by a TFA mediated deprotection in 46% yield over 2 steps. 1H NMR (400 MHz, CD3OD): δ 7.57 (m, 2H), 7.02 (m, 2H), 6.77 (m, 2H), 6.52 (m, 2H), 4.97−4.91 (m, 2H), 4.09−3.74 (m, 4H), 1.56 (s, 3H), 1.51 (s, 3H). m/z = 412.2 (M + 1). Synthesis of 27. 2-Amino-1-(2-(4-ﬂuorophenyl)-3-((4- ﬂuorophenyl)amino)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2- methylpropan-1-one. The synthesis has been reported in the previous communication.5 Synthesis of 28. 2-Amino-1-(2-(4-ﬂuorophenyl)-3-(4-ﬂuoropheny- lamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2- methylpropan-1-one: 4270 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273