, 234-236?C; 1 H-NMR (CDCl 3 ) ? 8.94 (s, 1H, NH), 8.40 (d, J = 9, quinazoline-2-carbimidate (12a): white solid (68 mg, 91%), mp

, 46 (s, 1H, NH), 8.57 (d, J = 8.7 Hz, 1H, H 4 ), 8.54 (s, 1H, quinazoline-2-carbimidate (12b): white solid (56.5 mg, 71%), mp. 196-198?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.7, 1111.

, 45 (s, 1H, NH), 8.59 (s, 1H, mg, 76%), mp. 168-170?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8, p.1, 1105.

, 45 (s, 1H, NH), 8.73 (s, 1H, H 7 ), 8.55 (d, J = 9, Hz, 1H, H 4 ), 7.93 (d, J = 9.0 Hz, 1H, H 5 )

, 45 (s, 1H, NH), 8.66 (s, 1H, H 7 ), 8.55 (d, J = 8.7 Hz, 1H, H 4 ), 7.91 (d, J = 8.7 Hz, 1H, H 5 )

, 46 (s, 1H, NH), 8.72 (s, 1H, H 7 ), 8.56 (d, J = 8.7 Hz, 1H, H 4 ), 7.93 (d, J = 8.7 Hz, 1H, H 5 ), vol.841, p.1, 1155.

, 45 (s, 1H, NH), 8.73 (s, 1H, H 7 ), quinazoline-2-carbimidate (12g): white powder (78 mg, 92%), mp. 246-248?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8, p.1, 1078.

, 246-248?C; 1 H-NMR (DMSO-d 6 ) ? 9, mg, 70%), mp

, 46 (s, 1H, NH), 8.57 (s, 1H, H 7 ), 8.56 (d, J = 9, mg, 80%), mp. 178-180?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.826, 1066.

, 41 (s, 1H, NH), 8.56 (s, 1H, H 7 ), 8.52 (d, J = 9, mg, 86%), mp. 190-192?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.3296, p.1, 1065.

, mg, 68%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 9

, quinazoline-2-carbimidate (12l): white solid (74.6 mg, 82%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 9.47 (s, 1H, NH), vol.8, p.61

, mg, 74%), mp > 265?C; 1 H-NMR (DMSO-d 6 ) ? 9

, 44 (s, 1H, NH), 8.62 (s, 1H, mg, 90%), mp. 244-246?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8, p.716, 1064.

, 60 (s, 1H, NH), 8.56 (d, J = 9.0 Hz, 1H, H 4 ), 8.53 (s, 1H, 7.92 (d, J = 9.0 Hz, 1H, H 5 ), 7.57-7.40 (m, 5H, Ph), 5.48 (s, 2H, CH 2 Ph

, 61 (s, 1H, NH), 8.58 (d, J = 9, 7.93 (d, J = 9.0 Hz, 1H, H 5 ), 7.56-7.38 (m, 5H, Ph), 5.47 (s, 2H, CH 2 Ph, vol.8, p.1, 1105.

, mg, 55%), mp. 168-170?C; 1 H-NMR (DMSO-d 6 ) ? 9.60 (s, 1H, NH), 8.59 (s, 1H, H 7 ), 8.57 (d, J = 9.0 Hz, 1H, H 4 ), 7.93 (d, J = 9.0 Hz, 1H, H 5 ), 7.56-7.39 (m, 5H, Ph), 5.47 (s, 1H, CH 2 Ph, vol.3078, p.837, 1050.

, quinazoline-2-carbimidate (13d): white solid (61 mg, 65%), mp. 212-214?C; 1 H-NMR (DMSO-d 6 ) ? 9.60 (s, 1H, NH), 8.72 (s, 1H, 8.56 (d, J = 8.7 Hz, 1H, H 4 ), 7.93 (d, J = 8.7 Hz, 1H, H 5 ), 7.56-7.38 (m, 5H

, quinazoline-2-carbimidate (13e): white solid (91 mg, 90%), mp. 214-216?C; 1 H-NMR (DMSO-d 6 ) ? 9.58 (s, 1H, NH), 8.65 (s, 1H, H 7 ), 8.55 (d, J = 8.7 Hz, 1H, H 4 ), 7.92 (d, J = 8.7 Hz, 1H, H 5 ), 7.57-7.39 (m, 5H, Ph), 5.47 (s, 2H, CH 2 Ph), 5.13-5.02 (m, 1H, NCH)

, 32 (s, 1H, 7.89 (d, J = 8.7 Hz, 1H, H 5 ), 7.53-7.36 (m, 5H, Ph), 5.50 (s, 2H, CH 2 Ph), 5.16-5.04 (m, 1H, NCH), 2.63 (m, 2H, 2?CH), vol.8, p.1, 1159.

, 27 (s, 1H, quinazoline-2-carbimidate (13g): white solid (59 mg, 94%), mp. 212-214?C; 1 H-NMR (CDCl 3 ) ? 9.11 (s, 1H, NH), 8.42 (d, J = 8.7 Hz, 1H, H 4 ), vol.8, p.744, 1078.

, quinazoline-2-carbimidate (13h): white solid (45 mg, 80%), mp. 190-192?C; 1 H-NMR (DMSO-d 6 ) ? 9.61 (s, 1H, NH), 8.58 (d, J = 9

C. ,

, 248-250?C; 1 H-NMR (CDCl 3 ) ? 8.94 (s, 1H, NH), 8.42 (d, J = 9.0. Hz, 1H, H 4 ), mg, 93%), mp, vol.8

, 36 (br s, 1H, NH), 8.54 (d, J = 9, mg, 76%), mp. 166-168?C, 1 H-NMR (DMSO-d 6 ) ? 9, vol.8

, 37 (s, 1H, NH), 8.59 (s, 1H, mg, 72%), mp. 172-174?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.827, p.1, 1107.

, mg, 80%), mp. 196-198?C; 1 H-NMR (DMSO-d 6 ) ? 9, vol.8

, 27 (s, 1H, H 7 ), 7.86 (d, J = 9, 0 Hz, 1H, H 5 ), 5.22 (m, 1H, NCH), 4.49 (q, J = 6.9 Hz, 2H, OCH 2 ), 2.27 (m, 2H, CH), 1.95 (m, 6H, CH), 1.48 (t, J = 6.9 Hz, vol.8, 1055.

, 34 (s, 1H, NH), 8.54 (d, J = 8.7 Hz, 1H, H 4 ), 8.53 (s, 1H, mg, 88%), mp. 228-230?C; 1 H-NMR (DMSO-d 6 ) ? 9

, 174-176?C; 1 H-NMR (DMSO-d 6 ) ? 9.34 (br s, 1H, NH), 8.56 (d, J = 9, mg, 65%), mp, vol.21

, 34 (s, 1H, NH), 8.59 (s, 1H, H 7 ), 8.55 (d, J = 9, quinazoline-2-carboximidate (15c): white solid (81 mg, 90%), mp. 162-164?C; 1 H-NMR (DMSO-d 6 ) ? 9

N. , N. , N. &. , and N. Acid, N-morpholino) propanesulfonic acid (Mops) (pH 7.2), 5 mM EGTA, 15 mM MgCl 2 , 1 mM DTT, 0.1 mM sodium vanadate. 3.3.2. Kinase Preparations and Assays Kinase activities were assayed in triplicates in buffer A or B, for 30 min. at 30?C, at a final adenosine triphosphate (ATP) concentration of 15 µM. Blank values were substracted and activities expressed in % of the maximal activity, i.e., in the absence of inhibitors. Controls were performed with appropriate dilutions of dimethylsulfoxide (DMSO). IC 50 values were calculated from dose-response curves established by Sigma-Plot graphs, EGTA), 1 mM dithiothreitol (DTT), 25 mM Tris-HCl pH 7.5, 50 µg heparin/mL, vol.25

, Its kinase activity was assayed in buffer A, with 1 mg of histone H1/mL, in the presence of 15 µM, CDK5/p25. (Human, recombinant) was prepared as previously described, vol.21

, 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 P81 phosphocellulose paper (Whatman) 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, UK) scintillation fluid. GSK-3?/?. (Porcine brain, native) was assayed, as described for CDK5/p25 but in buffer A and using a GSK-3 specific substrate

/. Ck1?, Porcine brain, native) was assayed as described for CDK5/p25 but using the CK1-specific peptide substrate RRKHAAIGpSAYSITA, vol.37

. Dyrk1a, coli as a glutathione transferase (GST) fusion protein) was purified by affinity chromatography on glutathione-agarose and assayed, as described for CDK5/p25 using Woodtide (KKISGRLSPIMTEQ) (1.5µg/assay) as a substrate. CLK1. (Human, recombinant, expressed in E. coli as GST fusion protein) was assayed in buffer A (+0.15 mg BSA/mL) with RS

, 4-f ]quinazoline derivatives 11a-c, 12a-n, 13a-h, 14a-e, 15a-c has been rapidly prepared, using microwave-assisted technology when efficient heating was needed. In order to have an efficient route to these variously 8-substituted thiazolo[5,4-f ]quinazolin-9(8H)-ones, a rational multistep synthesis of methyl 6-amino-2-cyanobenzo, Conclusions A library of thirty-three novel thiazolo, vol.5

L. Martin, X. Latypova, C. M. Wilson, A. Magnaudeix, M. Perrin et al., Tau protein kinases: Involvement in Alzheimer's disease, Ageing Res. Rev, vol.12, pp.289-309, 2013.

M. Flajolet, G. He, M. Heiman, A. Lin, A. C. Nairn et al., Regulation of Alzheimer's disease amyloid-? formation by casein kinase I, Proc. Nat. Acad. Sci, vol.104, pp.4159-4164, 2007.

H. Weinmann and R. Metternich, Drug discovery process for kinase Inhibitors, Chem. Biol. Chem, vol.6, pp.453-574, 2005.

P. Wu, T. E. Nielsen, and M. H. Clausen, Small-molecule kinase inhibitors: an analysis of FDA-approved drugs, Drug Discovery Today, vol.21, pp.5-10, 2016.

P. Wu, T. E. Nielsen, and M. H. Clausen, FDA-approved small-molecule kinase inhibitors, Trends Pharmacol. Sci, vol.36, pp.422-439, 2015.

C. S. Harris, L. Hennequin, R. Morgentin, and G. Pasquet, Synthesis and functionnalization of 4-substituted quinazolines as kinases templates, Targets in Heterocyclic Systems-Chemistry and Properties

O. A. Attanasi and D. Spinelli, , vol.14, pp.315-350, 2010.

C. Logé, A. Testard, V. Thiéry, O. Lozach, M. Blairvacq et al., Novel 9-oxo-thiazolo[5,4-f ]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: synthesis, biological evaluation and molecular modeling studies, Eur. J. Med. Chem, vol.43, pp.1469-1477, 2008.

A. Testard, C. Logé, B. Léger, J. Robert, O. Lozach et al., Thiazolo[5,4-f ]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3, Bioorg. Med. Chem. Lett, vol.16, pp.3419-3423, 2006.

Y. Loidreau, E. Deau, P. Marchand, M. Nourrisson, C. Logé et al., ] pyrimidin-4-amines as multitarget Ser/Thr kinases inhibitors, Eur. J. Med. Chem, vol.92, pp.124-134, 2015.

Y. Loidreau, P. Marchand, C. Dubouilh-benard, M. Nourrisson, M. Duflos et al., ]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases, Eur. J. Med. Chem, vol.59, pp.283-295, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00997416

Y. Loidreau, P. Marchand, C. Dubouilh-benard, M. Nourrisson, M. Duflos et al., Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors, Eur. J. Med. Chem, vol.58, pp.171-183, 2012.
URL : https://hal.archives-ouvertes.fr/hal-00997084

A. Foucourt, C. Dubouilh-benard, E. Chosson, C. Corbière, C. Buquet et al., Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent, Tetrahedron, vol.66, pp.4495-4502, 2010.
URL : https://hal.archives-ouvertes.fr/hal-01020796

A. Foucourt, D. Hédou, C. Dubouilh-benard, L. Désiré, A. Casagrande et al., Design and synthesis of thiazolo[5,4-f ]quinazolines as DYRK1A inhibitors, Part I, Molecules, vol.19, pp.15546-15571, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01109410

A. Foucourt, D. Hédou, C. Dubouilh-benard, L. Désiré, A. Casagrande et al., Design and synthesis of thiazolo[5,4-f ]quinazolines as DYRK1A inhibitors, Part II, Molecules, vol.19, pp.15411-15439, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01135223

B. Leblond, A. Casagrande, L. Désiré, A. Foucourt, and T. Besson, DYRK1 inhibitors and uses thereof WO 2013026806, Chem. Abstr, vol.158, p.390018, 2013.

R. Abbassi, T. G. Johns, M. Kassiou, and L. Munoz, DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications, Pharmacol. Ther, vol.151, pp.87-98, 2015.

F. Medda, B. Smith, V. Gokhale, A. Y. Shaw, T. Dunckley et al., Beyond secretases: Kinase inhibitors for the treatment of Alzheimer's disease, Annu. Rep. Med. Chem, vol.48, pp.57-71, 2013.

B. Smith, F. Medda, V. Gokhale, T. Dunckley, and C. Hulme, Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer's?, ACS Chem. Neurosci, vol.3, pp.857-872, 2012.

M. Varjosalo, S. Keskitalo, A. Van-drogen, H. Nurkkala, A. Vichalkovski et al., The protein interaction landscape of the human CMGC kinase group, Cell Rep, vol.3, pp.1306-1320, 2013.

C. Schmitt, P. Miralinaghi, M. Mariano, R. W. Hartmann, and M. Engel, Hydroxybenzothiophene ketones are efficient pre-mRNA splicing modulators due to dual inhibition of Dyrk1A and Clk1/4, ACS Med. Chem. Lett, vol.5, pp.963-967, 2014.

O. Dehbi, A. Tikad, S. Bourg, P. Bonnet, O. Lozach et al., Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A Inhibitors, Eur. J. Med. Chem, vol.80, pp.352-363, 2014.

M. Bajda, N. Guzior, M. Ignasik, and B. Malawska, Multi-target-directed ligands in Alzheimer's disease treatment, Curr. Med. Chem, vol.18, pp.4949-4975, 2011.

A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti et al., Multi-target-directed ligands to combat neurodegenerative diseases, J. Med. Chem, vol.51, pp.347-372, 2008.

P. A. Babu, S. Chitti, B. Rajesh, V. V. Prasanth, J. V. Kishen et al., In silico based ligand design and docking studies of GSK-3? inhibtors, Chem. Bio. Inform. J, vol.10, pp.1-10, 2010.

F. R. Alexandre, L. Domon, S. Frère, A. Testard, V. Thiéry et al., Microwaves in drug discovery and multi-step synthesis, Mol. Divers, vol.7, pp.273-280, 2003.

F. R. Alexandre, A. Berecibar, R. Wrigglesworth, and T. Besson, Efficient synthesis of thiazoloquinazolinone derivatives, Tetrahedron Lett, vol.44, pp.4455-4458, 2003.

T. Besson, J. Guillard, and C. W. Rees, Multistep synthesis of thiazoloquinazolines under microwave irradiation in solution, Tetrahedron Lett, vol.41, pp.1027-1030, 2000.

D. Hédou, M. Harari, J. Godeau, C. Dubouilh-benard, C. Fruit et al., Synthesis of polyfunctionalized benzo[d]thiazoles as novel anthranilic acid derivatives, Tetrahedron Lett, vol.56, pp.4088-4092, 2015.

D. Hédou, E. Deau, M. Harari, M. Sanselme, C. Fruit et al., Rational multistep synthesis of a novel, Tetrahedron, vol.70, pp.5541-5549, 2014.

D. Hédou, R. Guillon, C. Lecointe, C. Logé, E. Chosson et al., Novel synthesis of angular thiazolo, Tetrahedron, vol.69, pp.3182-3191, 2013.

, Methyl 2-amino-5-nitrobenzoate (2) is commercially available but quite expensive. It can be efficiently synthesized from the cheaper 5-nitro-anthranilic acid, vol.28

E. Deau, D. Hédou, E. Chosson, V. Levacher, and T. Besson, Convenient one-pot synthesis of N 3 -substituted pyrido, Tetrahedron Lett, vol.54, pp.3518-3521, 2013.
URL : https://hal.archives-ouvertes.fr/hal-01015451

F. Giraud, G. Alves, E. Debiton, L. Nauton, V. Thery et al., Synthesis, protein kinase inhibitory potencies, and in vitro antiproliferative activities of meridianin derivatives, J. Med. Chem, vol.54, pp.4474-4489, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00609975

S. Bach, M. Knockaert, J. Reinhardt, O. Lozach, S. Schmitt et al., Roscovitine targets, protein kinases and pyridoxal kinase, J. Biol. Chem, vol.280, pp.31208-31219, 2005.
URL : https://hal.archives-ouvertes.fr/hal-00018751

S. Leclerc, M. Garnier, R. Hoessel, D. Marko, J. A. Bidd et al., Indirubins inhibit glycogen synthase kinase-3? and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's Disease: A property common to most cyclin-dependent kinase inhibitors?, J. Biol. Chem, vol.276, pp.251-260, 2001.

A. Primot, B. Baratte, M. Gompel, A. Borgne, S. Liabeuf et al., Purification of GSK-3 by affinity chromatography on immobilized axin, Protein Expression Purif, vol.20, pp.394-404, 2000.

J. Reinhardt, Y. Ferandin, and L. Meijer, Purification of CK1 by affinity chromatography on immobilised axin, Protein Expression Purif, vol.54, pp.101-109, 2007.
URL : https://hal.archives-ouvertes.fr/hal-00169405

K. Patel, M. Gadewar, R. Tripathi, S. K. Prasad, and D. K. Patel, A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid, Harmine". Asian Pac. J. Trop. Biomed, vol.2, pp.660-664, 2012.

P. Jain, C. Karthikeyan, N. S. Moorthy, D. K. Waiker, A. K. Jain et al., Human CDC2-like kinase 1 (CLK1): A novel target for Alzheimer's disease, Curr. Drug Targets, vol.15, pp.539-550, 2014.

W. Becker, U. Soppa, and F. J. Tejedor, DYRK1A: A potential drug target for multiple Down Syndrome neuropathologies, CNS Neurol. Disord.-Drug Targets, vol.13, pp.26-33, 2014.

V. Tell and A. Hilgeroth, Recent developments of protein kinase inhibitors as potential AD therapeutics, Front. Cell. Neurosci, issue.7, 2013.

T. C. Coombs, C. Tanega, M. Shen, J. L. Wang, D. S. Auld et al., Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315, Bioorg. Med. Chem. Lett, vol.23, pp.3654-3661, 2013.

M. Maqbool, M. Mobashir, and N. Hoda, Pivotal role of glycogen kinase-3: A therapeutic target for Alzheimer's disease, Eur. J. Med. Chem, vol.107, pp.63-81, 2016.