, Yield: 14%; 14 mg; Yellow solid, 8H)-one (4a), vol.3068, pp.699-700, 1346.

H. , H Ar ), 3.73 (3H, s, CH 3 ), CDCl 3 , 25 ? C, 300 MHz): ? H 9.39 (1H, br s, H Ar ), 8.73 (1H, d, J = 4.8 Hz, H Ar ), 8.58-8.36 (2H, m, H Ar + H 4 ), 8.19 (1H, s, H 7 ), vol.7, pp.129-154

, 95:5; v/v); mp 202-205 ? C; IR (neat) ? max 3540, HRMS (ESI + ): Calcd for C 15 H 10 N 4 OS, pp.34-37

, 8H)-one (4c or FC162) [34]: yield: 69%; 91 mg

, CDCl 3 , 25 ? C, 300 MHz): ? H 9.41 (d, J = 2.3 Hz, 1H, H Ar ), 8.75 (d, J = 4.9 Hz, 1H, H Ar ), 8.54-8.38 (m, 2H, H Ar + H 4 ), 8.26 (s, 1H, H 7 ), 7.88 (d, J = 8.7 Hz, 1H, H 5 ), vol.3012, pp.151-160, 1024.

, Cyclobutyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (4d): Yield: 57%; 64 mg

, 39 (1H, br s, H Ar ), 8.72 (1H, d, J = 4.8, H Ar ), 8.45-8.29 (2H, m, H Ar + H 4 ), 8.30 (1H, s, H 7, CDCl 3 + D 2 O, 25 ? C, 300 MHz): ? H 9, vol.7, pp.848-849, 1347.

D. Meoh, 95:5; v/v); mp 212-215 ? C; IR (neat) ? max 3064, 3964, 2872; 1902, 1645, 1584, 1451, 828 cm ?1 ; 1 H-NMR (CDCl 3 , 25 ? C, 300 MHz): ? H 9.40 (1H, br s, H Ar )

. Mhz, 5 (CH), 148.4 (CH), 146.3, 144.1 (CH), ? C 168.0 (C), 159.8 (C), vol.152, p.151

H. , Calcd for C 19 H 16 N 4 OS

D. Meoh, CDCl 3 , 25 ? C, 300 MHz): ? H 9.38 (1H, br s, H Ar ), 8.72 (1H, br s, H Ar ), 2H, m, H Ar + H 4 ), 8.25 (1H, s, H 7 ), 7.84 (1H, d, J = 8.7 Hz, H 4, vol.3146, pp.2181-2194, 1076.

, × CH 2 ), 25.2 (CH 2 ). HRMS (ESI + ): Calcd for, vol.54

, In Vitro Kinase Preparation and Assays

, Homogenization buffer: 25 mM MOPS; 15 mM EGTA; 15 mM MgCl 2 ; 60 mM ?-glycerophosphate

, Buffer A: 10 mM MgCl 2 ; 1 mM EGTA; 1 mM DTT; 25 mM Tris/HCl, and 50 µg/mL heparin. Buffer B: 60 mM ?-glycerophosphate; 30 mM p-nitrophenylphosphate; 25 mM MOPS pH 7.0; sodium vanadate. All chemicals were purchased from Sigma-Aldrich, vol.2, p.15

, Kinase Preparations and Assays Kinase activities were assayed in triplicates, in buffer A or B, at 30 ? C, at a final adenosine triphosphate (ATP) concentration of 15 µmol/L. Blank values were subtracted, and activities were expressed in percent (%) of the maximal activity

, Ci/mmol; 10 mCi/mL) in a final volume of 30 µL. After 30 min incubation at 30 ? C, 25 µL aliquots of supernatant were spotted onto sheets of Whatman P81 phosphocellulose paper, and 20 s later, the filters were washed eight times (for at least 5 min each time) in a solution of 10 mL phosphoric acid/L of water. The wet filters were counted in the presence of 1 mL ACS (Amersham) scintillation fluid. GSK-3?/? (porcine brain, native) was assayed, in buffer A, with 0.5 mg BSA/mL + 1 mM DTT, using GS-1 (YRRAAVPPSPSLSRHSSPHQSpEDEEE) (pS stands for phosphorylated serine), a GSK-3 specific substrate, Its kinase activity was assayed in buffer A, with 1 mg of histone H1/mL, in the presence of 15 µM

, native) was assayed as described for CDK1, but in buffer B, and using 25 µM CKS peptide (RRKHAAIGpSAYSITA), a CK1-specific substrate, vol.39

, DYRK1A (Human, recombinant, expressed in E. coli as GST fusion proteins) was purified by affinity chromatography on glutathione-agarose and assayed as described for CDK1/cyclin B, with with 0.5 mg BSA/mL + 1 mM DTT and using Woodtide (KKISGRLSPIMTEQ) (1.5 µg/assay) as a substrate

, Conclusions This work demonstrates the efficacy of synthetic methodologies, such as C-H arylation of arenes and hetero-arenes for SAR studies. The application of this powerful tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potential active compounds generated through this strategy, vol.162

, Supplementary Materials: The following are available online. 1 H-NMR and 13 C-NMR spectra of new compounds 8a-f and 4a-f

T. B. and C. F. , conceived the project and designed the experiments. F.C. and M.H. performed the experimental work

M. , designed and supervised the biological experiments. T.B. wrote the manuscript with the cooperation of C.F. All authors discussed the results and commented on the manuscript

F. C. , M. H. , C. D. , L. B. , E. P. et al., thank the LABEX SynOrg (ANR-11-LABX-0029) for financial support. This research was supported by grants from the, Fonds Unique Interministériel" (FUI) TRIAD project and Conseil Régional de Bretagne (L.M.) and the "Fondation Jérôme Lejeune

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, Sample Availability: Samples of compound FC162 (4c) are available from the authors for academic studies with Material Transfer Agreement (MTA)