Journal of Medicinal Chemistry Compound 32 was synthesized from compound 7 (R1 = R2 = H) Pd2(dba)3 mediated coupling reaction with p-toluidine. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.77−7.75 (m, 2H), 7.26−7.14 (m, 4H), 7.01−6.95 (m, 2H), 6.53 (m, 1H), 4.53 (m, 2H), 4.22 (m, 2H), 2.17 (s, 3H). m/z = 337.2 (M + 1). Synthesis of 33. 2-(4-Fluorophenyl)-8,8-dimethyl-3-(p-tolylamino)-7, 8-dihydroimidazo[1,2-a]pyrazin-6(5H)-one: Compound 33a was prepared from 7 by the following way: To a stirred solution of compound 7 (390 mg, 1.51 mmol, 1.00 equiv) in dichloromethane (20 mL) was added NBS (0.28 g, 1.00 equiv). The resulting solution was stirred for 2 h at rt. The solid was ﬁltered out, and the mixture was washed with a saturated solution of Na2S2O3 and dried over Na2SO4. The mixture was concentrated under vacuum. The solids was puriﬁed by silica gel chromatography (petroleum ether/EtOAc = 1:2) to result in 432 mg (85%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.94−7.89 (m, 2H), 7.31−7.25 (m, 2H), 4.57 (s, 2H), 1.56 (s, 6H). m/z = 338 (M + 1). Compound 33 was prepared from compound 33a by a Pd2(dba)3 mediated amination reaction with p-toluidine. 1H NMR (MeOH-d4, 400 Hz) δ 7.62−7.58 (m, 2H), 7.05 (t, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 4.42 (s, 2H), 2.12 (s, 3H), 1.71 (s, 6H). m/z = 365.2 (M + 1). Synthesis of 34. 3-(4-Chloro-3-ﬂuorophenylamino)-2-(4-ﬂuoro- phenyl)-8,8-dimethyl-7,8-dihydro imidazo[1,2-a]pyrazin-6(5H)-one: Compound 34 was prepared from compound 7b by a Pd2(dba)3 mediated amination reaction with 4-chloro-3-ﬂuoroaniline. 1H NMR (MeOH-d4, 400 Hz) δ 7.74−7.70 (m, 2H), 7.21 (t, J = 8.4 Hz, 1H), 7.08 (m, 2H), 6.49−6.40 (m, 2H), 4.43 (s, 2H), 1.72 (s, 6H). m/z = 403.1 (M + 1). Synthesis of 35. 2-(4-Fluorophenyl)-8,8-dimethyl-N-p-tolyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-amine: Compound 35 was prepared from compound 35-1 (shown below and prepared by analogy to compound 9 and using Cbz-glycine) by a Pd2(dba)3 mediated amination reaction with p-toluidine followed by a 6N HCl mediated hydrolysis. 1H NMR (MeOH-d4, 400 Hz) δ 7.78− 7.75 (m, 2H), 7.06−6.97 (m, 4H), 6.56 (d, J = 8.4 Hz, 2H), 5.16 (s, NH), 4.33 (t, J = 4.8 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 2.29 (s, 3H), 1.95 (s, 6H). m/z = 436.2 (M + 1). Synthesis of 36. N,2-Bis(4-ﬂuorophenyl)-8,8-dimethyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-amine: Compound 36 was prepared from compound 35-1 by a Pd2(dba)3 mediated amination reaction with 4-ﬂuoroaniline followed by a 6N HCl mediated hydrolysis. 1H NMR (400 MHz, MeOH-d4) δ 7.62− 7.58 (m, 2H), 7.12−7.08 (m, 2H), 6.68−6.63 (m, 2H), 6.67 (m, 2H), 4.16 (m, 2H), 3.78 (m, 2H), 1.92 (s, 6H). m/z = 355.1 (M + 1). ■ ASSOCIATED CONTENT AUTHOR INFORMATION *S Supporting Information In vitro ADME of selected analogues; PAMPA vs Log P; Caco- 2 (A−B) vs Log P; Caco-2 A−B/B−A ratio vs Log P; Caco-2 (B−A) vs Log P. This material is available free of charge via the Internet at http://pubs.acs.org. ■ Corresponding Author *Phone: 858-332-4751. E-mail: akc@gnf.org. Author Contributions #Equal contribution to this work Notes ACKNOWLEDGMENTS The authors declare no competing ﬁnancial interest. ■ This work was supported by a translational research grant (WT078285) from the Wellcome Trust and a grant from the Medicines for Malaria Venture to the Novartis Institute for Article ■ Tropical Diseases, the Genomics Institute of the Novartis Research Foundation, and the Swiss Tropical Institute REFERENCES (1) (a) Rottmann, M.; McNamara, C.; Yeung, B. K.; Lee, M. C.; Zou, B.; Russell, B.; Seitz, P.; Plouﬀe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H. P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Spiroindolones, a potent compound class for the treatment of malaria. Science 2010, 329 (5996), 1175− 1180. (b) Wu, T.; Nagle, A. S.; Chatterjee, A. K. 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