1. Hz, 1. Hz, and 1. , s, 2H, CH 2 ), 3.66 (s, 3H, NMe Phthal ), 3.54 (s, 3H, NMe, ), 2.29 (t, J = 7.5 Hz, 2H, CH 2 CO) 13 C NMR (100 MHz, DMSO-d 6 ) ? 171.5 (CONH) IV ), 152.5 (C IV-C=N ), pp.28-32

2. Hz, 8 Hz, 2H, 2 x H ar ), 4.50 (s, 2H (s, 3H, NMe Phthal ), 3.56 (s, 3H, NMe), 3.15 (t, 2H, SCH 2 ) 2H, CH 2 CO), p.7830

C. Iv-), CH ar )133.4 (CH ar-Phthal )

. Nme, HRMS (MALDI: DHB, PEG 600): calcd

. Phthal, 71 (m, 2H, 2 x H ar-Phthal ), 7.41 (d, J = 9, 79 (d, J = 9.0 Hz, 2H, 2 x H ar ), 4.46 (s, 2H, pp.80-87

D. Meoh, 1. Phthald, 1. , and 1. , 21 (m, 1H, H ar-Phthal ), 7.75 (m, 2H, 2 x H ar-Phthal ), 77.65 (bs, 3.79 (s, 3H, NMe Phthal ), 3.53 (s, 3H, NMe), 3.17 (t, J = 7.3 Hz, 2H, SCH 2 ), 2.41 (t, J = 7.4 Hz, 2H, CH 2 CO), 1.70 (m, 4H, 2 x CH 2 ), 1.32 (m, 12H, 6 x CH 2 ). 13 C NMR (75 MHz, CDCl 3 ) ? 171, p.35

. Mhz, CDCl 3 ) ? 171, pp.140-148

1. Hz, 57 (m, 3H, 2 x H ar-Phthal and H ar, pp.86-736

1. Hz and 1. , 49 (s, 2H, CH 2 ), 3.82 (s, 3H, NMe Phthal ), 3.19 (t, ), 2.41 (t, J = 7.4 Hz, 2H, CH 2 CO), 1.79-1.69 (m, 4H, 2 x CH 2 13 C NMR (100 MHz, CDCl 3 ) ? 171.3 (CONH), pp.62-92

J. D. Watson, D. M. Anderson, J. G. Giri, and C. K. Goldman, Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor, Science, vol.264, issue.2, pp.965-968, 1994.

J. Brennan, E. Roessler, and T. A. Waldmann, A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells, Proc. Natl. Acad. Sci. U

S. A. Kirman, I. Nielsen, and O. , Increased numbers of interleukin-15-expressing cells in active ulcerative colitis, Am. J. Gastroenterol. Ruckert, R.; Asadullah, K.; Seifert, M.; Budagian, V. M. C, vol.91, issue.914, pp.4935-4939, 1994.

R. Paus and S. Bulfone-paus, Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis?, J. Immunol, vol.165, pp.2240-2250, 2000.

. Leuk, I. B. Lymphoma-mcinnes, F. Liew, and T. Strom, Interleukin 15: a proinflammatory role in rheumatoid arthritis synovitis, Immunol. Today Pavlakis, M.; Strehlau, J.; Lipman, M, vol.35, issue.197, pp.37-45, 1998.

R. C. Manfro and P. Roy-chaudhury, Intragraft IL-15 transcripts are increased in human renal allograft rejection, Transplantation, vol.62, issue.8, pp.543-545, 1996.

W. Maslinski and T. B. Strom, Interleukin-15 gene transcripts are present in rejecting islet allografts, Liew, F. Y. Soluble IL-15, pp.1077-1078, 1997.

W. W. Hancock, W. Maslinski, X. C. Li, T. B. Strom, T. Moll et al., Targeting IL-15 receptorbearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis Interleukin-15 receptor-directed immunotoxins atteunuate disease severity in rat adjuvant arthritis, J. Immunol. Mol. Immunol, vol.173, issue.4712, pp.5818-5826, 2004.

R. Li, H. Cen, H. F. Pan, and D. Ye, Therapeutic potential of IL-15 in rheumatoid arthritis

C. Sheng, G. Dong, Z. Miao, W. Zhang, and W. Wang, State-of-the-art strategies for targeting protein?protein interactions by small-molecule inhibitors, Chem. Soc. Rev., vol.6, issue.22, pp.812-818, 2015.
DOI : 10.1371/journal.pcbi.1000695

D. Lagorce, O. Sperandio, and M. A. Miteva, Drug-Like Protein-Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology, Mol. Inform. M, vol.2014, issue.3315, pp.414-437

N. D. Waal, J. Wilkinson, C. H. Yu, M. R. Arkin, S. Kalsoom et al., Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: an approach for inhibiting protein-protein interactions In vitro and in silico exploration of IL-2 inhibition by small drug-like molecules Systemic delivery of small interfering RNA targeting the interleukin-2/15 receptor ? chain prevents disease progression in experimental arthritis Structure-function studies of interleukin 15 using site-specific mutagenesis, polyethylene glycol conjugation, and homology modeling, J. Med. Chem. Med. Chem. Res. PLoS One J. Biol. Chem. J. C E, vol.47, issue.272, pp.3111-3130, 1997.

C. Pulliam, S. R. Uzhachenko, R. V. Adunyah, S. E. Shanker, and A. , Common gamma chain cytokines in combinatorial immune strategies against cancer, Immunology Letters, vol.169, issue.169, pp.24313-24322, 2004.
DOI : 10.1016/j.imlet.2015.11.007
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710466

S. J. Davis and S. Ikemizu, Crystal structure of the IL-15-IL-15R? complex, a cytokine-receptor unit presented in trans, Nat. Immunol. N, vol.8, issue.22, pp.1001-1007, 2007.

J. Hoskings, mutein exhibits potent antitumor activity and is well tolerated in vivo, Nat. Biotechnol, vol.18, issue.223, pp.1197-1202, 2000.

W. C. Greene, V. Toome, and G. Ju, Identification of specific residues of human interleukin 2

. U. Sci, X. Wang, M. Rickert, and K. C. Garcia, Structure of the quaternary complex of interleukin-2 with its ?, ?, and ?c receptors, Science, vol.85, issue.31025, pp.7709-7713, 1988.

P. Li, I. Moraga, R. Spolski, E. Ozkan, W. J. Leonard et al., Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15, Nat. Immunol. J, vol.13, issue.26, pp.1187-1195, 2012.

Y. Jacques, Soluble interleukin-15 receptor ? (IL-15R?)-sushi as a selective and potent agonist of IL-15 action through IL-15R?/?. Hyperagonist IL-15 x IL-15R? fusion proteins, J

B. Trucchi, T. O-'brien, A. Isacchi, D. Donati, and R. D-'alessio, Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosine containing protein inhibitors. Synthesis and structure-activity relationships, 29) Carpino, L. A.; El-Faham, pp.437-450, 2013.

G. D. Cuny, L. Hedstrom, A. M. Sridhara, K. R. Reddy, J. Keshavayya et al., Synthesis and antimicrobial activity of 2-substituted [4- (1,3,4-oxadiazol-2-yl methyl)] phthalazin-1(2H)-one derivatives Synthesis, characterization and preliminary anticonvulsant evaluation of some 4-alkyl-1, 34) Sridhara, A. M.; Venugopala, K. R.; Keshavayya, pp.1004-1007, 2010.

S. K. Peethambar, Synthesis and antimicrobial studies of some new 3-isoxazoline substituted phthalazine methylsulfonyl oxadiazoles, E-Journal of Chemistry, vol.8, pp.1022-1029, 2011.

M. R. Shaker, H. C. Kolb, and K. B. Sharpless, The chemistry of mercapto-and thione-substituted 1,2,4-triazoles and their utility in heterocyclic synthesis The growing impact of click chemistry on drug discovery, ARKIVOC Drug Discovery Today, vol.8, issue.36, pp.59-112, 2003.

V. V. Rostovtsev, L. G. Green, V. V. Fokin, and K. B. Sharpless, A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective ???Ligation??? of Azides and Terminal Alkynes, Angewandte Chemie International Edition, vol.20, issue.14, pp.2596-2599, 2002.
DOI : 10.1016/0040-4039(95)00987-N

M. Vincent, G. Teppaz, L. Lajoie, V. Sole, and S. Loisel, Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency, International Journal of Cancer, vol.11, issue.3, pp.757-765, 2013.
DOI : 10.1158/1535-7163.MCT-12-0019

J. W. Highly-potent-anti-cd20-rli-immunocytokine-tilley, L. Chen, D. C. Fry, S. D. Emerson, G. D. Powers et al., targeting established human B lymphoma in SCID mouse, MAbs, vol.6, issue.40, pp.1026-1037, 2014.

J. Liu, C. Palermo, R. Ju, G. Geng, B. Fleming et al., Identification of a small molecule inhibitor of the IL-2/IL- 2R? receptor interaction which binds to IL-2 The synthesis and selective IL-2 inhibitory activity of bis piperazine-phenol Mannich adducts, 42) Waldmann, T. A. Targeting the interleukin-15/interleukin-15 receptor system in inflammatory autoimmune diseases, pp.7589-7590, 1997.

T. A. Waldmann, Targeting the interleukin-15 system in rheumatoid arthritis Arthritis Rheum, C, vol.52, issue.43, pp.2585-2588, 2005.

M. D. Crittenden, G. L. Parenteau, F. M. Dirbas, and M. Tsudo, Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival, J. Immunol. N, vol.153, issue.45, pp.4330-4338, 1994.

Y. Tagaya, Targeting the binding interface on a shared receptor subunit of a cytokine family enables the inhibition of multiple member cytokines with selectable target spectrum, J. Biol

D. K. Gehlhaar, G. M. Verkhivker, P. A. Rejto, C. J. Sherman, D. B. Fogel et al., Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming (48) Muegge, I.; Martin, Y. C. A general and fast scoring function for protein-ligand interactions: a simplified potential approach LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays, LigScore: a novel scoring function for predicting binding affinities, pp.395-407, 1995.