Journal of Medicinal Chemistry HPLC/MS test showed that desired product (II) was the only peak. Solvent was removed via rotavap at a temperature no higher than 20 °C. After neutralization, white solid (3.60 g) was obtained. The product was conﬁrmed by 400 MHz proton NMR to be the title compound 10. The product was used in the next step without further puriﬁcation and exhibited quantitative mass recovery. LC-MS: (ES, m/z) [M + H]+ calcd for C21H27BrFN4O3, 482; found, 482. 1H NMR (MeOH-d4, 400 Hz) δ 7.84−7.81 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.09−4.01 (m, 4H), 3.81 (t, J = 4.8 Hz, 2H), 1.89 (s, 6H), 1.46 (s, 9H). Synthesis of 17. (S)-2-Amino-1-(3-(4-chloro-3-ﬂuorophenylami- no)-2-(4-ﬂuorophenyl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl)ethanone: Compound 17 was prepared from compound 10 (R1 = Me, R2 = H) by a Pd2(dba)3 mediated amination reaction with 4-chloro-3- ﬂuoroaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. 1H NMR (MeOH-d4, 400 MHz) δ 7.61−7.58 (m, 2H), 7.16−7.12 (m, 1H), 7.07−7.02 (m, 2H), 6.47−6.42 (m, 2H), 5.74 (m, 1H), 4.07−3.68 (m, 6H), 1.56 (d, J = 6.8 Hz, 3H). m/z = 432.0 (M + 1). Synthesis of 18. (R)-2-Amino-1-(3-(4-chloro-3-ﬂuorophenylami- no)-2-(4-ﬂuorophenyl)-8-methyl-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl)ethanone: Compound 18 was prepared from compound 10 (R1 = Me, R2 = H) by a Pd2(dba)3 mediated amination reaction with 4-chloro-3- ﬂuoroaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. m/z = 432.2 (M + 1). Synthesis of 19. (S)-2-Amino-1-(3-(4-chloro-3-ﬂuorophenylami- no)-2-(4-ﬂuorophenyl)-8-isopropyl-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl)ethanone: Compound 19 was prepared from compound 10 (R1 = isopropyl, R2 = H) by a Pd2(dba)3 mediated amination reaction with 4- chloro-3-ﬂuoroaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. 1H NMR (MeOH-d4, 400 MHz) δ7.61−7.58 (m, 2H), 7.26−7.20 (m, 3H), 6.45−6.38 (m, 2H), 5.5 (d, J = 7.9 Hz, 1H), 4.11−3.75 (m, 6H), 2.36−2.31 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). m/z = 460.2 (M + 1). Article Synthesis of 20. (R)-2-Amino-1-(3-(4-chloro-3-ﬂuorophenylami- no)-2-(4-ﬂuorophenyl)-8-isopropyl-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl)ethanone: Compound 20 was prepared from compound 10 (R1 = isopropyl, R2 = H) by a Pd2(dba)3 mediated amination reaction with 4-chloro-3- ﬂuoroaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. 1H NMR (MeOH-d4, 400 MHz) δ 7.69− 7.67 (m, 2H), 7.27−7.20 (m, 3H), 6.68−6.65 (dd, J = 2.5 Hz, J = 11.0 Hz, 1H), 6.60−6.55 (dd, J = 2.25 Hz, J = 8.7 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 4.42−4.02 (m, 4H), 3.94−3.87 (m, 2H), 2.55 (m,1H), 1.24(d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H). m/z = 460.2 (M + 1). Synthesis of 21. 2-Amino-1-(3-(4-chloro-3-ﬂuorophenylamino)-2- (4-ﬂuorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)-yl)ethanone: Compound 21 was prepared from compound 10 (R1 = Me, R2 = Me) by a Pd2(dba)3 mediated amination reaction with 4-chloro-3- ﬂuoroaniline followed by a TFA mediated deprotection in a protocol similar to compound 22. 1H NMR (MeOH-d4, 400 MHz) δ 7.59−7.55 (m, 2H), 7.20−7.13 (m, 3H), 6.60 (dd, J = 11.2, 10.8 Hz), 1H), 6.53 (dd, J = 2.4, 0.8 Hz, 1H), 4.0 (m, 4H), 3.78 (m, 2H), 2.00 (s, 6H). m/z = 446.0 (M + 1). Elemental analysis (compound + 2.0 HCl + 2.0 H2O): % C, 47.62; % H, 5.09; %N, 12.62; (calc). %C = 47.54/47.38; %N = 12.44/12.46; % H = 4.62/4.57 (experimental). LC/MS major mass 446.2. Synthesis of 22 (Analogue of Compound 12 in Scheme 2 where R1R2Me). 2-Amino-1-(2-(4-ﬂuorophenyl)-3-(4-ﬂuorophenylamino)- 8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethanone: In a glass vial, Cs2CO3, 4F-aniline (0.462 g, 4.1 mmol, 2.0 equiv), Pd2(dba)3 (0.095 g, 0.104 mmol, 0.05 equiv), xantphos (0.120 g, 0.208 mmol, 0.1 equiv), and dioxane were stirred for 5 min at rt. Compound 10 (1 g, 2.08 mmol, 1.0 equiv) was added to the reaction mixture, after which the reaction mixture was degassed for 15 min and then stirred at 120 °C under N2 for 8 h. HPLC/MS test showed that the starting material compound 10 was consumed and desired product was formed predominantly along with some 9. The reaction was ﬁltered to remove solids. The reaction mixture was concentrated and then puriﬁed by normal phase column chromatography (silica gel 80 g) using a gradient of 100−0% to 0−100% hexane:EtOAc. The desired product eluted at 60:40 EtOAc:hexanes. The organic layer was concentrated at reduced pressure to yield the Boc derivative (950 mg, 89%) yield. 4253 dx.doi.org/10.1021/jm300041e | J. Med. Chem. 2012, 55, 4244−4273