Производные азаиндола занимают важное место в медицинской химии, потому что обладают биологической активностью. Они проявляют антионкогенную, противоопухолевую и антибактериальную активность. К сожалению, такие болезни как онкология и туберкулез остаются серьёзной проблемой здравоохранения во всем мире. Поэтому для повышения эффективности лечения этих заболеваний требуются новые лекарства и терапевтические стратегии. До сих пор ведутся активные поиски новейших, более эффективных и безопасных лекарственных веществ с азаиндолным скаффолдом [1]. На данный момент наиболее значимым противоопухолевым средством является препарат вемурафениб, продаваемый как Зельбораф[2].
На основании вышеизложенного, вполне очевидно, что синтез новых комбинаторных библиотек низкомолекулярных производных азаиндола с последующим скринингом их биологической активности является крайне актуальной задачей.
Целью настоящей работы является разработка синтетического подхода к получению полифункциональных азаиндолов в качестве ингибиторов протеинкиназ.
Для успешной реализации цели были сформулированы следующие задачи:
1. Разработать синтетическую методологию получения производных3-(1,2,3,6- тетрогидропиридин-4-ил)-1#-пирроло[2,3-й]пиридина;
2. Синтезировать библиотеку данных производных азаиндола;
3. Исследовать цитотоксичность представителей синтезированной комбинаторной библиотеки в отношении клеточной линии сверэкспресирующих EGFR киназу.
По результатам проделанной работы можно сделать следующие выводы:
1. Осуществлён синтез азаиндольного MAPK-ингибитора с хорошим выходом. Показана возможность эффективного использования оксона для оксиления пиримидинсодержащих сульфидов.
2. Посредством МТТ-теста показана высокая цитотоксичность invitro синтезированного соединения в отношении клеточных линий, сверхэкспаресирующих MCF-7, A549 и A431 в микромолярных концентрациях.
3. Показано, что высокая цитотоксичность на клеточных линиях сверэкспресирующих рецептор эпидермального фактора делает дальнейшее изучение механизма цитотоксического эффекта обусловленного мультитаргетным эффектом оправданным и актуальным.
1. Yang, S.W.Synthes isand Biological Evaluation of Analogues of Cryptolepine, an Alkaloid Isolated from the Suriname Rainforest1 / S.W. Yang, M. Abdel-Kader, S. Malone, M.C.M Werkhoven, et al. // J. Nat. Prod. - 1999. - Vol.62. - P. 976-983;
2. Jacob A. P. Dinuclear and heptanuclear complexes of copper(II) with 7-azaindole ligand:Synthesis, characterization, magnetic properties, and biological activity / A. P. Jacob, N. M. Nicole, D. A. Hadi, A. Prosviri, et al. // Journal of Inorganic Biochemistry - 2013. - Vol. 127. - P. 175-181;
3. Paulo A.New Alkaloids from Cryptolepis sanguinolenta / A. Paulo, E.T. Gomes, P.J.Houghton // J. Nat. Prod. - 1995. - Vol.58. - P. 1485-1491;
4. Ahaidar A.Total syntheses of variolin B and deoxyvariolin B / A. Ahaidar, D. Fernandez, G. Danelon, C. Cuevas, et al. // J. Org. Chem.- 2003. Vol.68. - P. 10020-10029;
5. ChoshiT.Total synthesis of grossularines-1 and -2 / T. Choshi, S. Yamada, E. Sugino, T. Kuwada, et al. // J. Org. Chem.-1995. - Vol.60. - P. 5899-5904;
6. SimoneM.Variolin B and its derivate deoxy-variolin B: New marine natural compounds with cyclin-dependent kinase inhibitor activity /M. Simone, E. Erba, G. Damia, F. Vikhanskaya, et al. // Eur. J. Cancer Oxf. Engl. 1990-2005. -Vol. 41. - P. 2366-2377;
7. Prudhomme M. Rebeccamycin analogues as anti-cancer agents / M. Prudhomme // Eur. J. Med. Chem. - 2003. - Vol. 38. - P. 123-140;
8. Zhang H.C. 3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3 / H. C. Zhang, H, Ye, B. R.Conway, C. K. Derian, et al. // Bioorg. Med. Chem. Lett.- 2004. - Vol.14. - P. 3245-3250;
9. Grant E.R.Protection against glutamate toxicity through inhibition of the p44/42 mitogen- activated protein kinase pathway in neuronally differentiated P19 cells / E. R. Grant, M.A. Errico, S.L. Emanuel, D. Benjamin, et al. // Biochem. Pharmacol.- 2001. - Vol.62. -P. 283-296;
10. Azaindole Derivatives as Inhibitors of p38 Kinase// Patent WO2004032874. 2003. /S. Dugar;
11. ShowellG.A.Binding of 2,4-disubstituted morpholines at human D4 dopamine receptors / G.A. Showell, F. Emms, R. Marwood, D. O’Connor, et al. // Bioorg. Med. Chem.- 1998. - Vol.6. - P. 1-8;
12. Kulagowski J.J.3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1 /-pyrrolo[2,3-/]pyridine:
An antagonist with high affinity and selectivity for the human dopamine D4 receptor / J.J.
Kulagowski, H.B. Broughton, N. R. Curtis, I. M. Mawer, et al. // J. Med. Chem.- 1996. - Vol.39. - P. 1941-1942;
13. Fonquerna S. Synthesis and structure-activity relationships of piperidinylpyrrolopyridine derivatives as potent and selective H1 antagonists / S. Fonquerna, M. Miralpeix, L. Pages, C. Puig, et al. // Bioorg. Med. Chem. Lett. -2005. -Vol. 15. -P. 1165-1167;
14. Gong Y. Solid-phase parallel synthesis of azarene pyrrolidinones as factor Xa inhibitors / Y. Gong, M. Becker, Y.M. Choi-Sledeski, R.S. Davis,et al. // Bioorg. Med. Chem. Lett. - 2000. - Vol. 10.- P. 1033-1036;
15. Sanderson P.E.J. Azaindoles: Moderately basic P1 groups for enhancing the selectivity of thrombin inhibitors / P.E.J. Sanderson, M.G. Stanton, B.D. Dorsey, T. Lyle, et al. // Bioorg. Med. Chem. Lett. - 2003. - Vol. 13. - P.795-798;
16. Horton D.A.The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures / D.A. Horton, G.T. Bourne, M.L. Smythe // Chem. Rev.- 2003. - Vol.103. - P. 893-930;
17. De Sa Alves F.R.From nature to drug discovery: The indole scaffold as a “privileged structure” / F. R. De Sa Alves, E.J. Barreiro, C.A.M. Fraga // Mini Rev. Med. Chem. - 2009. - Vol.9. - P. 782-793;
18. Sharma V.Biological importance of the indole nucleus in recent years: A comprehensive review / V. Sharma, P. Kumar, D. Pathak // J. Heterocycl. Chem. -2010. - Vol. 47. - P. 491-502;
19. Perry N.B.Alkaloids from the antarctic sponge Kirkpatrickia varialosa: Part 1: Variolin b, a new antitumour and antiviral compound / N.B. Perry, L. Ettouati, M. Litaudon, J. W. Blunt, et al. // Tetrahedron- 1994. - Vol. 50. - P.3987-3992;
20. Welsch M.E.Privileged scaffolds for library design and drug discovery / M.E. Welsch, S.A. Snyder, B.R. Stockwell // Curr. Opin. Chem. Biol. - 2010.- Vol.14. - P. 347-361;
21. Walker S.R.Variolins and related alkaloids. / S.R. Walker, E.J. Carter, B.C. Huff, J. C. Morris // Chem. Rev. - 2009. - Vol.109. - P. 3080-3098;
22. Li J.J. Indoles, oxindoles, and azaindoles. In Heterocyclic Chemistry in Drug Discovery /
J.J. Li // Johnwiley and Sons Inc.: Hoboken. -2013. -P. 54-118;
23. Ila H.Metalated Indoles, Indazoles, Benzimidazoles, and Azaindoles and Their Synthetic Applications / H. Ila, J. Markiewicz, V. Malakhov, P. Knochel // Synthesis. - 2013. - Vol. 45. - P. 2343-2371;
24. Mdrour J.Y.Recent advances in the synthesis and properties of 4-, 5-, 6- or 7-azaindoles / J.Y. Mdrour, S. Routier, F. Suzenet, B. Joseph // Tetrahedron- 2013. - Vol. 69. - P. 4767-4834;
25. Olgen S. Recent development of new substituted indole and azaindole derivatives as anti-HIV agents / S.Olgen // Mini Rev. Med. Chem.- 2013. - Vol. 13. - P.1700-17084;
26. Boulahjar R.Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): Potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts / R. Boulahjar , A. Ouach, C. Matteo, S. Bourg, et al. // J. Med. Chem. - 2012. - Vol.55. - P. 9589-9606;
27. Dehbi O.Synthesis and optimization of an original V-shaped collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors / O. Dehbi, A.Tikad, S. Bourg, P. Bonnet, et al. // Eur. J. Med. Chem. - 2014. - Vol. 80. - P. 352-363;
28. Kassis P.Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents / P. Kassis, J. Brzeszcz, V. Bdndteau, O. Lozach, et al. // Eur. J. Med. Chem. -2011. - Vol. 46.
- P. 5416-5434;
29. Neagoie C.Synthesis of chromeno[3,4-^]indoles as Lamellarin Danalogues: A novel DYRK1A inhibitor class / C. Neagoie, E. Vedrenne, F. Buron, J. Y. Mdrour, et al. // Eur. J. Med. Chem. - 2012. - Vol.49. - P. 379-396;
30. Lefoix M.Novel 5-azaindolocarbazoles as cytotoxic agentsand Chk1 inhibitors / M. Lefoix, G. Coudert, S. Routier, B. Pfeiffer, et al. // Bioorg. Med. Chem. - 2008. - Vol.16. - P. 5303-5321;
31. Saurat T.Design, synthesis, and biological activity ofpyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors / T. Saurat, F. Buron, N. Rodrigues, M.L. de Tauzia, et al. // J. Med. Chem. - 2014. - Vol. 57. - P. 613-631;
32. Liao J.J. Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors / J.J. Liao // J. Med. Chem. - 2007. - Vol. 50. - P. 409-424;
33. Youl E. Quercetin potentiates insulin secretion and protects INS-1 pancreatic P-cells against oxidative damage via the ERK1/2 pathway / E. Youl, G. Bardy, R. Magous, G. Cros, et al. // Br. J. Pharmacol. - 2010. - Vol. 161. - P. 799-814;
34. Gruson D. Urocortin-induced cardiomyocytes hypertrophy is associated with regulation of the GSK-3P pathway / D. Gruson, A. Ginion., N. Decroly, P. Lause, et al. // Heart Vessels
- 2012. - Vol. 27. - P. 202-207;
35. Clark J.D.Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases / J.D. Clark, M.E. Flanagan, J. B. J. Telliez // Med. Chem. - 2014. - Vol.57. - P. 5023-5038;
36. Guo M. F.The inhibition of Rho kinase blocks cell migration and accumulation possibly by challenging inflammatory cytokines and chemokines on astrocytes / M. F. Guo, J. Meng, Y.H. Li, J. Z. Yu, et al. // J. Neurol. Sci. - 2014. - Vol. 343. - P. 69-75;
37. Castanares-Zapatero D.Connection between cardiac vascular permeability, myocardial edema, and inflammation during sepsis: Role of the alAMP-activated protein kinase isoform / D. Castanares-Zapatero, C. Bouleti, C. Sommereyns, B Gerber, et al. // Crit. Care Med.- 2013. - Vol.41. - P.411-422;
38. DemeulderB.Differential regulation of eEF2 and p70S6K by AMPKalpha2 in heart /B.Demeulder, E. Zarrinpashneh, A. Ginion, B. Viollet, et al. // Biochim. Biophys. Acta -
2013. - Vol. 1832. - P. 780-790;
39. Erickson J.R. Mechanisms of CaMKII Activation in the Heart. / J. R. Erickson // Front. Pharmacol. - 2014. - Vol. 5. - P. 1-5;
40. Huynh T.N.Requirement of Mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence / T.N. Huynh, E. Santini, E. Klann // J. Neurosci.- 2014. - Vol.34. - P. 9034-9039;
41. Walker C.L.PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries / C.L. Walker, N.K. Liu, X. M. Xu // Front. Biol.- 2013. - Vol. 8. - P. 421-433;
42. De Career G.Inhibiting Cell Kinase in Cancer Therapy /G. De Career, I. Perez de Castro, M. Malumbres // Front. Med Chem.- 2012. - Vol. 6. - P. 154-188;
43. Zamecnikova A. Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer / A. Zamecnikova // Expert Opin. Drug Discov.- 2014. - Vol.9. - P. 77-92;
44. Hebert-Chatelain E. Src kinases are important regulators of mitochondrial functions / E. HHebert-Chatelain // Int. J. Biochem. Cell Biol.- 2013. - Vol. 45. - P. 90-98;
45. Pitts T.M.Targeting nuclear kinases in cancer: Development of cell cycle kinase inhibitors / T. M. Pitts, S. L. Davis, S.G. Eckhardt, E.L. Bradshaw-Pierce //Pharmacol. Ther. -2014. - Vol. 142. - P. 258-269;
46. Roskoski R. The ErbB/HER family of protein-tyrosine kinases and cancer / R. Roskoski // Pharmacol. Res.-2014. - Vol. 79. - P. 34-74;
47. Rupani A.Primary anaplastic large cell lymphoma of central nervous system-A case report / A. Rupani, C. Modi, S. Desai, J. Rege // J. Postgrad. Med.- 2005. - Vol. 51. - P. 326-327;
48. Gummadi V.R. Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode / V. R. Gummadi, S. Rajagopalan, C.Y. Looi, M. Paydar, et al. // Bioorg. Med. Chem. Lett- 2013.- Vol.23. - P. 4911-4918;
49. Pollard J.R. Discovery and development of aurora kinase inhibitors as anticancer agents / J.R. Pollard, M.J. Mortimore // Med. Chem.- 2009. - Vol. 52. - P. 2629-2651;
50. Bouloc N. Structure-based design of imidazo[1,2-a]pyrazine derivatives as selective inhibitors of Aurora-A kinase in cells / N. Bouloc, J.M. Large, M. Kosmopoulou, C. Sun, et al. // Bioorg. Med. Chem. Lett.- 2010.- Vol.20. - P. 5988-5993;
51. Bavetsias V. Aurora isoform selectivity: Design and synthesis of imidazo[4,5-^]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells // V. Bavetsias, A. Faisal, S. Crumpler, N. Brown, et al. // J. Med. Chem.- 2013. - Vol. 56. - P. 9122-9135;
52. Adams N.D. Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase / N. D. Adams, J.L. Adams, J.L. Burgess, A. M. Chaudhari, et al. // J. Med. Chem.- 2010. - Vol. 53. - P. 3973-4001;
53. Medina J.R.Discovery of a new series of Aurora inhibitors through truncation of GSK1070916 / J.R. Medina, S.W. Grant, J.M. Axten, W.H. Miller, et al. // Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 2552-2555;
54. Seefeld M. A., Preparation of Pyrrolo[2,3-^]pyridines as Inhibitors of Akt Activity / M.A. Seefeld, T. Hamajima, D.K. Jung, H. Nakamura, et al. // Patent WO 2007076423. - 2007 - № 5;
55. Hardwicke M.A.GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models / M.A. Hardwicke, C.A. Oleykowski, R. Plant, J. Wang, et al. // Mol. Cancer Ther. - 2009.- Vol. 8. - P.1808-1817;
56. Lan P.3D-QSAR and molecular docking studies of azaindole derivatives as Aurora B kinase inhibitors / P. Lan, W. N. Chen, P.H. Sun, W.M. Chen // J. Mol. Model. - 2011. - Vol.17. - P. 1191-1205;
57. Harrington P.E.The optimization of aminooxadiazoles as orally active inhibitors of Cdc7 / P.E.Harrington, M.P. Bourbeau, C. Fotsch, M. Frohn, et al. // Bioorg. Med. Chem. Lett. - 2013. - Vol. 23. - P. 6396-6400;
58. Bryan M.C. N-substituted azaindoles as potent inhibitors of Cdc7 kinase / M.C. Bryan, J.R. Falsey, M. Frohn, A. Reichelt, et al. // Bioorg. Med. Chem. Lett. - 2013. - Vol. 23. - P. 2056-2060;
59. Tong Y.Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195 / Y. Tong, K. D. Stewart, A.S. Florjancic, J. E. Harlan, et al. // ACS Med. Chem. Lett. - 2013. - Vol. 4. - P. 211-215;
60. Woods K.W. Aminopyrimidinone Cdc7 Kinase Inhibitors / K.W. Woods, C. Lai, J.M. Miyashiro, Y. Tong, et al. //Bioorg. Med. Chem. Lett. - 2012.- Vol. 22. - P. 1940-1943;
61. Ermoli A.Cell division cycle 7 kinase inhibitors: 1 Я-ругго1о[2,3-й]pyridines, synthesis and structure-activity relationships / A. Ermoli, A. Bargiotti, M.G. Brasca, A. Ciavolella, et al. // J. Med. Chem. - 2009. - Vol.52. - P. 4380-4390;
62. Koolman H. Syntheses of novel 2,3-diaryl-substituted 5-cyano-4-azaindoles exhibiting c- Met inhibition activity / H.Koolman, T. Heinrich, H. Bottcher, W. Rautenberg, W., et al. // Bioorg. Med.Chem. Lett. - 2009.- Vol.19. - P. 1879-1882;
63. Porter J.Discovery of 4-azaindoles as novel inhibitors of c-Met kinase / J. Porter, S. Lumb, R.J. Franklin, J.M. Gascon-Simorte, et al. // Bioorg. Med. Chem. Lett. - 2009. - Vol. 19. - P. 2780-2784;
64. Cai Z. W.Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors / Z. W. Cai, D. Wei, G.M. Schroeder, L.A. Cornelius, et al. // Bioorg. Med. Chem. Lett. - 2008. - Vol.18. - P. 3224-3229;
65. Williams D.K.Design, synthesis and structure-Activity relationships of novel biarylamine- based Met kinase inhibitors / D.K. Williams, X. T.Chen, C. Tarby, R. Kaltenbach, et al. // Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 2998-3002;
66. Kim K.S. Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: Synthesis, X-ray crystallographic analysis, and biological activities / K.S. Kim, L. Zhang, R. Schmidt, Z.W. Cai, et al. // J. Med. Chem. - 2008. - Vol. 51. - P. 5330-5341;
67. Becker W. Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity / W. Becker, H.G. Joost // Prog. Nucleic Acid Res. Mol. Biol. - 1999. - Vol. 62. - P. 1-17;
68. Becker W. Activation, regulation, and inhibition of DYRK1A / W. Becker, W. Sippl // FEBS J. - 2011. - Vol. 278. - P. 246-256;
69. Aranda S.DYRK family of protein kinases: Evolutionary relationships, biochemical properties, and functional roles / S. Aranda, A. Laguna, S. de la Luna // FASEB J. - 2011. - Vol. 25. - P. 449-462;
70. Hammerle B. The MNB/DYRK1A protein kinase: Neurobiological functions and Down syndrome implications / B. Hammerle, C. Elizalde, J. Galceran, W. Becker, et al. // J. Neural Transm. - 2003. - Vol. 67. - P.129-137;
71. Park J.Function and regulation of Dyrk1A: Towards understanding Down syndrome / J. Park, W. J.Song, K.C. Chung // Cell. Mol. Life Sci. CMLS-2009. - Vol. 66. - P. 3235¬3240;
72. Tejedor F.J.MNB/DYRK1A as a multiple regulator of neuronal development / F.J. Tejedor, B. Hammerle // FEBS J. - 2011. - Vol. 278. - P. 223-235;
73. Marti E. DyrklA expression pattern supports specific roles of this kinase in the adult central nervous system / E. Marti, X. Altafaj, M. Dierssen, S. de la Luna, et al. // Brain Res. - 2003. - Vol. 964. - P. 250-263;
74. Ferrer I.Constitutive DyrklA is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models / I. Ferrer, M. Barrachina, B. Puig, M. Martinez de Lagran, et al. // Neurobiol. Dis. - 2005. - Vol. 20. - P. 392-400;
75. Wegiel J. The role of DYRK1A in neurodegenerative diseases / J. Wegiel, C. X. Gong // FEBS J. - 2011. - Vol. 278. - P. 236-245;
76. Ionescu A.DYRK1A kinase inhibitors with emphasis on cancer / A. Ionescu, F. Dufrasne, M. Gelbcke, I. Jabin, et al. // Mini Rev. Med. Chem. - 2012. - Vol. 12. - P. 1315-1329;
77. Gourdain S. Development of DANDYs, new 3,5-diaryl-7-azaindoles demonstrating potent DYRK1A kinase inhibitory activity / S. Gourdain, J. Dairou, C. Denhez, L.C. Bui, et al. // J. Med. Chem. - 2013. - Vol. 56. - P.9569-9585;
78. Pin F.Synthesis and biological evaluation of 2,3-bis(het)aryl-4-azaindole derivatives as protein kinase inhibitors / F. Pin, F. Buron, F. Saab, L. Colliandre, et al. // Med. Chem. Comm . - 2011. - Vol. 2. - P. 899-903;
79. Heinrich T.Fragment-based discovery of new highly substituted 1 H-pyrrolo[2,3-b]- and 3H- imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors / T. Heinrich, J. Seenisamy, L. Emmanuvel, S.S. Kulkarni, et al. // J. Med. Chem. - 2013. - Vol. 56. - P. 1160-1170;
80. Liddle J. 4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors / J. Liddle, P. Bamborough, M.D. Barker, S. Campos, S.et al. // Bioorg. Med. Chem. Lett. - 2009. - Vol. 19. - P. 2504-2508;
81. Liddle J. 4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy / J. Lidd, P. Bamborough, M.D. Barker, S. Campos, S.et al. // Bioorg. Med. Chem. Lett.- 2012. - Vol. 22. - P. 5222-5226;
82. James C. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera / C. James, V. Ugo, J.P. le Couddic, J. Staerk, et al. // Nature - 2005. - Vol. 434. - P. 1144-1148;
83. Levine R.L. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis / R. L. Levine, M. Wadleigh, J. Cools, B.L. Ebert, et al. // Cancer Cell - 2005. - Vol.7. - P. 387-397;
84. Kralovics R. A gain-of-function mutation of JAK2 in myeloproliferative disorders / R. Kralovics, F. Passamonti, A. S. Buser, S.S. Teo, et al. // N. Engl. J. Med. - 2005. - Vol. 352. - P. 1779-1790;
85. Baxter E.J. Cancer Genome Project Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders / E.J. Baxter, L.M. Scott, P.J. Campbell, C. East, et al. //Lancet - 2005. - Vol. 365. - P. 1054-1061;
86. Zhao R. Identification of an acquired JAK2 mutation in polycythemia vera / R. Zhao, S. Xing, Z. Li, X. Fu, et al. //J. Biol. Chem. - 2005. - Vol. 280. - P. 22788-22792;
87. Tono C. JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia / C. Tono, G. Xu, T. Toki, Y. Takahashi, et al. // Leukemia - 2005. - Vol.19. - P. 1843-1844;
88. Wang T. Discovery of 3,4-ring fused 7-azaindoles and deazapurines as potent JAK2 inhibitors / T. Wang,M.W. Ledeboer, J.P. Duffy, F.G. Salituro, F.G, et al. // Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 153-156;
89. Wang T. Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole / T. Wang, J. Wang, J.P.Duffy, S. Halas, et al. // J. Med. Chem. - 2009. - Vol. 52. - P. 7938-7941;
90. Fleischmann R. Novel small-molecular therapeutics for rheumatoid arthritis/R.Fleischmann // Curr. Opin. Rheumatol. - 2012. - Vol. 24. - P. 335-341;
91. Azaindoles Useful as Inhibitors of Janus Kinases //Patent WO2007084557. №26. 2007. / L. Farmer, G. Martinez-Botella, A. Pierce, F. Salituro, et al.;
92. Zhang C. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor / C. Zhang, P. N.Ibrahim, J. Zhang, E.A. Burton, et al. // Proc. Natl. Acad. Sci. - 2013. - Vol. 110. - P. 5689-5694;
93. Tunduguru R. Signaling of the p21-activated kinase (PAK1) coordinates insulin-stimulated actin remodeling and glucose uptake in skeletal muscle cells / R. Tunduguru, T.T.Chiu, L. Ramalingam, J.S. Elmendorf, et al. // Biochem. Pharmacol. - 2014;
94. Ji X.Inhibition of p21-activated kinase 1 by IPA-3 attenuates secondary injury after traumatic brain injury in mice / X. Ji, W. Zhang, L. Zhang, L. Zhang, et al. // Brain Res. -
2014. - Vol. 1585. - P. 13-22;
95. Prudnikova T.Y. Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases / T.Y. Prudnikova, S.J. Rawat, J. Chernoff //Clin. Cancer Res. - 2014;
96. McCoull W.Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity / W. McCoull, E. J.Hennessy, K. Blades, M.R. Box, et al. // MedChemComm - 2014. - Vol.5. - P.1533-1539;
97. Young P.R. Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site / P. R. Young, M.M. McLaughlin, S. Kumar, S. Kassis, et al. // J. Biol. Chem. - 1997. - Vol. 272. - P. 12116-12121;
98. Trejo A. Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase / A. Trejo,H. Arzeno, M. Browner, S. Chanda, et al. // J. Med. Chem. - 2003. - Vol. 46. - P. 4702-4713;
99. Mavunkel B.J. Piperidine-based heterocyclic oxalyl amides as potent p38a MAP kinase inhibitors / B. J. Mavunkel, J.J. Perumattam, X. Tan, G. Luedtke, et al. // Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 1059-1062;
100. Blanco-Aparicio C. Pim kinases in cancer: Diagnostic, prognostic and treatment opportunities / C. Blanco-Aparicio, A. Carnero // Biochem. Pharmacol. -2013. - Vol.85. - P. 629-643;
101. Nakano H. Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound / H. Nakano, N. Saito, L.Parker, Y. Tada, et al. // J. Med. Chem. - 2012. - Vol. 55. - P. 5151-5164;
102. BraderS.Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis / S. Brader, S.A. Eccles // Tumori - 2004. - Vol. 90. - P. 2-8;
103. Samuels Y. High frequency of mutations of the PIK3CA gene in human cancers / Y. Samuels, Z. Wang, A. Bardelli, N. Silliman, et al. // Science - 2004. - Vol. 304. - P. 554;
104. Wymann M.P.Phosphoinositide 3-kinase in disease: Timing, location, and scaffolding / M.P. Wymann, R. Marone // Curr. Opin. Cell Biol.- 2005. - Vol. 17. - P. 141-149;
105. Parsons D.W. Colorectal cancer: Mutations in a signalling pathway / D.W. Parsons, T. L.Wang, Y. Samuels, A. Bardelli, et al. // Nature - 2005. - Vol. 436. - P. 792;
106. Kang S. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic / S. Kang, A. G. Bader, P.K.Vogt // Proc. Natl. Acad. Sci. - 2005. - Vol. 102. - P. 802-807;
107. Fan Q.W. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma / Q.W. Fan, Z.A. Knight, D.D. Goldenberg, W. Yu, et al. // Cancer Cell - 2006. - Vol. 9. - P. 341-349;
108. Jung K.H. HS-116, a novel phosphatidylinositol 3-kinase inhibitor induces apoptosis and
suppresses angiogenesis of hepatocellular carcinoma through inhibition of the
PI3K/AKT/Mtor pathway / K. H. Jung,M. Choi, S. Hong, H. Lee, et al. // Cancer Lett. - 2012. - Vol 316. - P. 187-195;
109. Hong S. Discovery of new azaindole-based PI3Ka inhibitors: Apoptotic and anti angiogenic effect on cancer cells / S. Hong, S. Lee, B. Kim, H. Lee, et al. //Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 7212-7215;
110. Tang J. Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors / J. Tang, T. Hamajima, M. Nakano, H. Sato, et al. // Bioorg. Med. Chem. Lett.- 2008. - Vol. 18. - P. 4610-4614;
111. Chowdhury S. Discovery and optimization of indoles and 7-azaindoles as Rho-kinase (ROCK) inhibitors (part-I) / S. Chowdhury, E.H. Sessions, J. Pocas, W. Grant, W., et al. //Bioorg. Med. Chem. Lett. - 2011. - Vol. 21. - P. 7107-7112;
112. Sessions E.H. Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-II) / E.H. Sessions, S. Chowdhury, Y. Yin, J. Pocas, et al. //Bioorg. Med. Chem. Lett. - 2011. - Vol. 21. - P. 7113-7118;
113. Schirok H. Improved Synthesis of the Selective Rho-Kinase Inhibitor 6-Chloro-A4-(3,5- difluoro-4-[(3-methyl-1 /-pyrrolo[2,3-/]pyridin-4 -yl)oxy]phenyl)pyrimidin-2,4-diamine / H. Schirok, H. Paulsen, W. Kroh, G. Chen, et al. // Org. Process Res. Dev. - 2010. - Vol. 14. - P. 168-173;
114. Schirok H. Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors / H. Schirok, R. Kast, S. Figueroa-Perez, S. Bennabi, et al. // ChemMedChem. - 2008. - Vol. 3. - P. 1893-1904;
115. Kast R. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase / R. Kast, H. Schirok, S. Figueroa-Perez, J. Mittendorf, et al. // Br. J. Pharmacol. - 2007. - Vol. 152. - P. 1070-1080;
116. Dahal B.K. Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension / B.K. Dahal, D. Kosanovic, K. Pamarthi, A. Sydykov, et al. // Eur. Respir. J. - 2010. - Vol. 36. - P. 808-818;
117. Zoncu R. mTOR: From growth signal integration to cancer, diabetes and ageing / R. Zoncu, A. Efeyan, M. Sabatini //Nat. Rev. Mol. Cell Biol. - 2011. - Vol. 12. - P. 21-35;
118. Tsou H. R. 4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR) / H. R.Tsou, G. MacEwan, G. Birnberg, N. Zhang, et al. // Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 2259-2263;
119. Tsou H. R. 4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR) / H. R. Tsou, G. MacEwan, G. Birnberg, N. Zhang, et al. // Bioorg. Med. Chem. Lett. - 2010. - Vol. 20. - P. 2321-2325;
120. Hong S. Design, synthesis, and evaluation of 3,5-disubstituted 7-azaindoles as Trk inhibitors with anticancer and antiangiogenic activities / S. Hong, J. Kim, J.H. Seo, K.H. Jung, et al. // J. Med. Chem. - 2012. - Vol. 55. - P.5337-5349;
121. Jiang W. G. Hepatocyte growth factor, its receptor, and their potential value in cancer
therapies / W. G. Jiang, T.A. Martin, C. Parr, G. Davies, et, al. // Crit. Rev.
Haematologica- 2005. - Vol.53. - P. 35-69;
122. Ermoli A. Cell Division Cycle 7 Kinase Inhibitors: 1 Я-Ругго1о[2,3-й]pyridines, Synthesis and Structure-Activity Relationships / A. Ermoli, A. Bargiotti, M. G. Brasca, A. Ciavolella, et al. // J. Med. Chem. - 2009. - Vol. 52. - P. 4380-4390;
123. Manning G. The protein kinase complement of the human genome / G. Manning, D. B. Whyte, R. Martinez, T. Hunter, et al. // Science - 2002. - Vol. 298. - P. 1912-1934;
124. Jeffrey P.D. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex / P.D. Jeffrey, A.A. Russo, K. Polyak, E. Gibbs, et al. // Nature - 1995. - Vol. 376.
- P. 313-320;
125. Southall N.T. Kinase patent space visualization using chemical replacements / N.T. Southall, Ajay // J. Med. Chem. - 2006. - Vol. 49. - P. 2103-2109;
126. WardR.A. Kinase Drug Discovery / R. A. Ward, F.W. Goldberg // RSC: Cambridge. - 2011;
127. Zhang J.Targeting cancer with small molecule kinase inhibitors / J. Zhang, P. L. Yang, N. S. Gray // Nat. Rev. Cancer - 2009.- Vol. 9. - P. 28-39;
128. Bollag G. Vemurafenib: The first drug approved for BRAF-mutant cancer / G. Bollag, J. Tsai, J. Zhang, C. Zhang, et al. // Nat. Rev. Drug Discov. - 2012.- Vol. 11. - P. 873-886;
129. Donald A. Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design / A. Donald,T. McHardy, M. G. Rowlands, L.Hunter, et al. // J. Med. Chem. - 2007. - Vol. 50. - P. 2289-2292;
130. Echalier A. Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): Synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex / A. Echalier,
K. Bettayeb, Y. Ferandin, O. Lozach, et al. // J. Med. Chem. - 2008. - Vol. 51. - P. 737¬751;
131. Routier S. First synthesis of symmetrical and non-symmetrical aza indolocarbazoles derivatives / S. Routier, G. Coudert, J. Mdrour, D.H. Caignard // Tetrahedron Lett. - 2002.
- Vol. 43. - P. 2561-2564;
132. RoutierS. Synthesis and biological evaluation of 7-azaindolocarbazoles / S. Routier, N. Ayerbe, J. Y. Mdrour, G. Coudert, et al. // Tetrahedron - 2002. - Vol. 58. - P. 6621-6630;
133. Messaoudi S. Synthesis and biological activities of 7-aza rebeccamycin analogues bearing the sugar moiety on the nitrogen of the pyridine ring / S. Messaoudi, F. Anizon, P. Peixoto, M. H. David-Cordonnier, et al. // Bioorg. Med. Chem. - 2006. - Vol. 14. - P. 7551-7562;
134. Ganser C. Novel 3-Azaindolyl-4-arylmaleimides exhibiting potent antiangiogenic efficacy, protein kinase inhibition, and antiproliferative activity / C. Ganser, E. Lauermann, A. Maderer, T. Stauder, et al. // J. Med. Chem. - 2012. - Vol. 55. - P. 9531-9540;
135. Faul M.M. A new one step synthesis of maleimides by condensation of glyoxylate esters with acetamides / M. M. Faul, L. L. Winneroski, C.A. Krumrich // Tetrahedron Lett. - 1999. - Vol. 40. - P. 1109-1112;
136. O’Neill D.J. Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl- maleimides as potent and selective glycogen synthase kinase-3p (GSK-3P) inhibitors / D. J. O’Neill, L. Shen, C. Prouty, B. R. Conway, et al. // Bioorg. Med. Chem. - 2004. - Vol. 12. - P. 3167-3185;
137. Maderer A. Moguntinones-New Selective Inhibitors for the Treatment of Human Colorectal Cancer / A. Maderer, S. Plutizki, J.-P. Kramb, K. Gopfert, et al. // Mol. Cancer Ther. - 2014. - Vol. 13. - P. 1399-1409;
138. Ye Q. Synthesis and biological evaluation of novel 4-azaindolyl-indolyl-maleimides as glycogen synthase kinase-3p (GSK-3P) inhibitors / Q. Ye, G. Xu, D. Lv, Z. Cheng, et al. // Bioorg. Med. Chem. - 2009. - Vol. 17. - P. 4302-4312;
139. Kuo G.H. Synthesis and discovery of macrocyclic polyoxygenated bis-7- azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3p inhibitors / G.H. Kuo, C.Prouty, A. DeAngelis, L. Shen, et al. // J. Med. Chem. - 2003. - Vol. 46. - P. 4021-4031;
140. Wang Z.H. Synthesis and CDK2 kinase inhibitory activity of 7/7'-azaindirubin derivatives / Z. H. Wang, Y. Dong, T. Wang, M.H. Shang, et al. // Chin. Chem. Lett. - 2010. - Vol. 21. P. 297-300;