Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

An Update on JAK Inhibitors

Author(s): Francesca Musumeci*, Chiara Greco, Ilaria Giacchello, Anna Lucia Fallacara, Munjed M. Ibrahim, Giancarlo Grossi, Chiara Brullo and Silvia Schenone

Volume 26, Issue 10, 2019

Page: [1806 - 1832] Pages: 27

DOI: 10.2174/0929867325666180327093502

Price: $65

conference banner
Abstract

Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors. These efforts recently afforded to the market approval of four JAK inhibitors. Despite the fact that all these drugs are pyrrolo[2,3-d]pyrimidine derivatives, many compounds endowed with different heterocyclic scaffolds have been reported in the literature as selective or multi-JAK inhibitors, and a number of them is currently being evaluated in clinical trials. In this review we will report many representative compounds that have been published in articles or patents in the last five years (period 2013-2017). The inhibitors will be classified on the basis of their chemical structure, focusing, when possible, on their structure activity relationships, selectivity and biological activity. For every class of derivatives, compounds disclosed before 2013 that have entered clinical trials will also be briefly reported, to underline the importance of a particular chemical scaffold in the search for new inhibitors.

Keywords: JAK inhibitors, patents, anticancer agents, inflammatory diseases, autoimmune diseases, heterocyclic compounds, covalent inhibitors.

[1]
Babon, J.J.; Lucet, I.S.; Murphy, J.M.; Nicola, N.A.; Varghese, L.N. The molecular regulation of Janus kinase (JAK) activation. Biochem. J., 2014, 462, 1-13.
[2]
Menet, C.J.; Mammoliti, O.; López-Ramos, M. Progress toward JAK1-selective inhibitors. Future Med. Chem., 2015, 7, 203-235.
[3]
Roskoski, R., Jr Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol. Res., 2016, 111, 784-803.
[4]
Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V.E., III; Silvennoinen, O.; O’Shea, J.J. The Janus kinases (Jaks). Genome Biol., 2004, 5, 253.
[5]
Darnell, J.E., Jr; Kerr, I.M.; Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264, 1415-1421.
[6]
Jones, A.V.; Kreil, S.; Zoi, K.; Waghorn, K.; Curtis, C.; Zhang, L.; Score, J.; Seear, R.; Chase, A.J.; Grand, F.H.; White, H.; Zoi, C.; Loukopoulos, D.; Terpos, E.; Vervessou, E.C.; Schultheis, B.; Emig, M.; Ernst, T.; Lengfelder, E.; Hehlmann, R.; Hochhaus, A.; Oscier, D.; Silver, R.T.; Reiter, A.; Cross, N.C. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood, 2005, 106, 2162-2168.
[7]
Quintás-Cardama, A.; Verstovsek, S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin. Cancer Res., 2013, 19, 1933-1940.
[8]
Ghoreschi, K.; Laurence, A.; O’Shea, J.J. Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat. Immunol., 2009, 10, 356-360.
[9]
Ghoreschi, K.; Gadina, M. Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp. Dermatol., 2014, 23, 7-11.
[10]
Saeed, I.; McLornan, D.; Harrison, C.N. Managing side effects of JAK inhibitors for myelofibrosis in clinical practice. Expert Rev. Hematol., 2017, 10, 617-625.
[11]
Deisseroth, A.; Kaminskas, E.; Grillo, J.; Chen, W.; Saber, H.; Lu, H.L.; Rothmann, M.D.; Brar, S.; Wang, J.; Garnett, C.; Bullock, J.; Burke, L.B.; Rahman, A.; Sridhara, R.; Farrell, A.; Pazdur, R.U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin. Cancer Res., 2012, 18, 3212-3217.
[12]
Barosi, G.; Rosti, V.; Gale, R.P. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis. OncoTargets Ther., 2015, 18, 1091-1102.
[13]
van Vollenhoven, R.F. Rheumatoid arthritis in 2012: Progress in RA genetics, pathology and therapy. Nat. Rev. Rheumatol., 2013, 9, 70-72.
[14]
Gonzales, A.J.; Bowman, J.W.; Fici, G.J.; Zhang, M.; Mann, D.W.; Mitton-Fry, M. Oclacitinib (APOQUEL(®)) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J. Vet. Pharmacol. Ther., 2014, 37, 317-324.
[15]
Markham, A. Baricitinib: First global approval. Drugs, 2017, 77, 697-704.
[16]
Williams, N.K.; Bamert, R.S.; Patel, O.; Wang, C.; Walden, P.M.; Wilks, A.F.; Fantino, E.; Rossjohn, J.; Lucet, I.S. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J. Mol. Biol., 2009, 387, 219-232.
[17]
Musumeci, F.; Sanna, M.; Grossi, G.; Brullo, C.; Fallacara, A.L.; Schenone, S. Pyrrolo [2,3-d]pyrimidines as kinase inhibitors. Curr. Med. Chem., 2017, 24, 2059-2085.
[18]
Nerviano Medical Sciences, S.R.L. Substituted pyrroles as kinase inhibitors and their preparation. WO 2014019908, 2014.
[19]
Nerviano Medical Sciences, S.R.L. Preparation of pyrimidinylpyrrole derivatives for use as kinase inhibitors. WO 2012143248, 2012.
[20]
Brasca, M.G.; Nesi, M.; Avanzi, N.; Ballinari, D.; Bandiera, T.; Bertrand, J.; Bindi, S.; Canevari, G.; Carenzi, D.; Casero, D.; Ceriani, L.; Ciomei, M.; Cirla, A.; Colombo, M.; Cribioli, S.; Cristiani, C.; Della Vedova, F.; Fachin, G.; Fasolini, M.; Felder, E.R.; Galvani, A.; Isacchi, A.; Mirizzi, D.; Motto, I.; Panzeri, A.; Pesenti, E.; Vianello, P.; Gnocchi, P.; Donati, D. Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors. Bioorg. Med. Chem., 2014, 22, 4998-5012.
[21]
Merck Sharp & Dohme Corp. Cycloalkylnitrile pyrazole carboxamides as Janus kinase inhibitors. WO 2013040863, 2013.
[22]
Merck Sharp & Dohme Corp. Pyrazole carboxamides as Janus kinase inhibitors. WO 2013041042, 2013.
[23]
Merck Sharp & Dohme Corp. Cyanomethylpyrazole carboxamides as Janus kinase inhibitors. WO 2013043962, 2013.
[24]
Merck Sharp & Dohme Corp. Acyclic cyanoethylpyrazoles as Janus kinase inhibitors. WO 2013043964, 2013.
[25]
Incyte Corporation. Preparation of bipyrazole derivatives as JAK kinase inhibitors. WO 2014186706, 2014.
[26]
Liang, X.; Huang, Y.; Zang, J.; Gao, Q.; Wang, B.; Xu, W.; Zhang, Y. Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors. Bioorg. Med. Chem., 2016, 24, 2660-2672.
[27]
Liang, X.; Zang, J.; Zhu, M.; Gao, Q.; Wang, B.; Xu, W.; Zhang, Y. Design, synthesis, and antitumor evaluation of 4-amino-(1H)-pyrazole derivatives as JAKs inhibitors. ACS Med. Chem. Lett., 2016, 7, 950-955.
[28]
Sang, Y-L.; Duan, Y-T.; Qiu, H-Y.; Wang, P-F.; Makawana, J.A.; Wang, Z-C.; Zhu, H-L.; He, Z-X. Design, synthesis, biological evaluation and molecular docking of novel metronidazole derivatives as selective and potent JAK3 inhibitors. RSC Advances, 2014, 4, 16694-16704.
[29]
Exelixis Inc. 4-Aryl-2-amino-pyrimidines or 4-aryl-2- aminoalkyl-pyrimidines as JAK-2 modulators and methods of use. WO 2007089768, 2007.
[30]
Targegen Inc. Bi-aryl meta-pyrimidine inhibitors of kinases. WO 2007053452, 2007.
[31]
Cytopia RES Pty Ltd. Phenyl amino pyrimidine compounds and uses thereof. WO 2008109943, 2008.
[32]
YM Biosciences Australia Pty Ltd. Preparation of phenyl amino pyrimidine bicyclic compounds useful as protein kinase inhibitors. WO 2014000032, 2014.
[33]
Calitor Sciences LLC, Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use. WO 2015094803, 2015.
[34]
Dana-Faber Cancer Institute, Inc. Janus kinase inhibitors and uses thereof. WO 2015164614, 2015.
[35]
Joshi, M.; Rizvi, S.M.; Belani, C.P. Afatinib for the treatment of metastatic non-small cell lung cancer. Cancer Manag. Res., 2015, 7, 75-82.
[36]
de Claro, R.A.; McGinn, K.M.; Verdun, N.; Lee, S.L.; Chiu, H.J.; Saber, H.; Brower, M.E.; Chang, C.J.; Pfuma, E.; Habtemariam, B.; Bullock, J.; Wang, Y.; Nie, L.; Chen, X.H.; Lu, D.R.; Al-Hakim, A.; Kane, R.C.; Kaminskas, E.; Justice, R.; Farrell, A.T.; Pazdur, R. FDA approval: Ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin. Cancer Res., 2015, 21, 3586-3590.
[37]
Tan, L.; Akahane, K.; McNally, R.; Reyskens, K.M.; Ficarro, S.B.; Liu, S.; Herter-Sprie, G.S.; Koyama, S.; Pattison, M.J.; Labella, K.; Johannessen, L.; Akbay, E.A.; Wong, K.K.; Frank, D.A.; Marto, J.A.; Look, T.A.; Arthur, J.S.; Eck, M.J.; Gray, N.S. Development of selective covalent Janus kinase 3 inhibitors. J. Med. Chem., 2015, 58, 6589-6606.
[38]
Almirall, S.A. Pyrazolopyrimidin-2-yl derivatives as JAK inhibitors. WO 2015086693, 2015.
[39]
Almirall, S.A. Imidazolopyrimidin-2-yl derivatives as JAK inhibitors. WO 2015091531, 2015.
[40]
Almirall, S.A. Preparation of 2-(pyrazolopyridin-3-yl) pyrimidine derivatives as JAK inhibitors. WO 2016198663, 2016.
[41]
Portola Pharmaceuticals, Inc. Pyridazine compounds as JAK inhibitors. WO 2015123453, 2015.
[42]
Vertex Pharmaceuticals Inc. Azaindoles useful as inhibitors of Janus kinases. WO 2007084557, 2007.
[43]
Astellas Pharma Inc. Heterocyclic Janus kinase 3 inhibitors. WO 2007077949, 2007.
[44]
Farmer, L.J.; Ledeboer, M.W.; Hoock, T.; Arnost, M.J.; Bethiel, R.S.; Bennani, Y.L.; Black, J.J.; Brummel, C.L.; Chakilam, A.; Dorsch, W.A.; Fan, B.; Cochran, J.E.; Halas, S.; Harrington, E.M.; Hogan, J.K.; Howe, D.; Huang, H.; Jacobs, D.H.; Laitinen, L.M.; Liao, S.; Mahajan, S.; Marone, V.; Martinez-Botella, G.; McCarthy, P.; Messersmith, D.; Namchuk, M.; Oh, L.; Penney, M.S.; Pierce, A.C.; Raybuck, S.A.; Rugg, A.; Salituro, F.G.; Saxena, K.; Shannon, D.; Shlyakter, D.; Swenson, L.; Tian, S.K.; Town, C.; Wang, J.; Wang, T.; Wannamaker, M.W.; Winquist, R.J.; Zuccola, H.J. Discovery of VX-509 (Decernotinib): a potent and selective Janus kinase 3 inhibitor for the treatment of autoimmune diseases. J. Med. Chem., 2015, 58, 7195-7216.
[45]
Iwata, S.; Tanaka, Y. Progress in understanding the safety and efficacy of Janus kinase inhibitors for treatment of rheumatoid arthritis. Expert Rev. Clin. Immunol., 2016, 12, 1047-1057.
[46]
Merck Sharp & Dohme Corp. Azaindoles as Janus kinase inhibitors. WO 2013052355, 2013.
[47]
Nakajima, Y.; Inoue, T.; Nakai, K.; Mukoyoshi, K.; Hamaguchi, H.; Hatanaka, K.; Sasaki, H.; Tanaka, A.; Takahashi, F.; Kunikawa, S.; Usuda, H.; Moritomo, A.; Higashi, Y.; Inami, M.; Shirakami, S. Synthesis and evaluation of novel 1H-pyrrolo [2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3. Bioorg. Med. Chem., 2015, 23, 4871-4883.
[48]
Astellas Pharma Inc. Condensed pyridine compounds. WO 2008084861, 2008.
[49]
Novartis Tiergesundheit AG. Preparation of heterocyclylsubstituted aminosulfonylmethyl cyclohexanes as Janus kinase inhibitors. WO 2015144773, 2015.
[50]
Incyte Corporation. Preparation of piperidin-4-yl azetidine derivatives as JAK1 inhibitors. WO 2011112662, 2011.
[51]
Clinicaltrials.gov. 20 Studies found for: INCB039110. Available at: https://clinicaltrials.gov/ct2/results?term=INCB039110&Search=Search [Accessed: November 24, 2017].
[52]
Bissonnette, R.; Luchi, M.; Fidelus-Gort, R.; Jackson, S.; Zhang, H.; Flores, R.; Newton, R.; Scherle, P.; Yeleswaram, S.; Chen, X.; Menter, A. A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral Janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis. J. Dermatolog. Treat., 2016, 27, 332-338.
[53]
Mascarenhas, J.O.; Talpaz, M.; Gupta, V.; Foltz, L.M.; Savona, M.R.; Paquette, R.; Turner, A.R.; Coughlin, P.; Winton, E.; Burn, T.C.; O’Neill, P.; Clark, J.; Hunter, D.; Assad, A.; Hoffman, R.; Verstovsek, S. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica, 2017, 102, 327-335.
[54]
Incyte Corporation. Cyclohexyl azetidine derivatives as JAK inhibitors. WO 2013026025, 2013.
[55]
Incyte Corporation. Piperidinylcylobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors. WO 2013173720, 2013.
[56]
Merck Sharp & Dohme Corp. Preparation of pyrrolopyrimidines as Janus kinase inhibitors. WO 2013085802, 2013.
[57]
Elwood, F.; Witter, D.J.; Piesvaux, J.; Kraybill, B.; Bays, N.; Alpert, C.; Goldenblatt, P.; Qu, Y.; Ivanovska, I.; Lee, H.H.; Chiu, C.S.; Tang, H.; Scott, M.E.; Deshmukh, S.V.; Zielstorff, M.; Byford, A.; Chakravarthy, K.; Dorosh, L.; Rivkin, A.; Klappenbach, J.; Pan, B.S.; Kariv, I.; Dinsmore, C.; Slipetz, D.; Dandliker, P.J. Evaluation of JAK3 biology in autoimmune disease using a highly selective, irreversible JAK3 inhibitor. J. Pharmacol. Exp. Ther., 2017, 361, 229-244.
[58]
Pfizer Inc. Pyrrolo[2,3-d]pyrimidine derivative as inhibitors of Janus-related kinases (JAK) and their preparation. WO 2014128591, 2014.
[59]
Pfizer Inc. Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b] pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides as JAK inhibitor and their preparation. WO 2015083028, 2015.
[60]
Pfizer Inc. Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b] pyrazinyl, pyrrolo[2,3-b]pyridinyl acrylamides and epoxides thereof. WO 2016178110, 2016.
[61]
Thorarensen, A.; Dowty, M.E.; Banker, M.E.; Juba, B.; Jussif, J.; Lin, T.; Vincent, F.; Czerwinski, R.M.; Casimiro-Garcia, A.; Unwalla, R.; Trujillo, J.I.; Liang, S.; Balbo, P.; Che, Y.; Gilbert, A.M.; Brown, M.F.; Hayward, M.; Montgomery, J.; Leung, L.; Yang, X.; Soucy, S.; Hegen, M.; Coe, J.; Langille, J.; Vajdos, F.; Chrencik, J.; Telliez, J.B. Design of a Janus kinase 3 (JAK3) specific inhibitor 1-((2S,5R)-5-((7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) allowing for the interrogation of JAK3 signaling in humans. J. Med. Chem., 2017, 60, 1971-1993.
[62]
Telliez, J.B.; Dowty, M.E.; Wang, L.; Jussif, J.; Lin, T.; Li, L.; Moy, E.; Balbo, P.; Li, W.; Zhao, Y.; Crouse, K.; Dickinson, C.; Symanowicz, P.; Hegen, M.; Banker, M.E.; Vincent, F.; Unwalla, R.; Liang, S.; Gilbert, A.M.; Brown, M.F.; Hayward, M.; Montgomery, J.; Yang, X.; Bauman, J.; Trujillo, J.I.; Casimiro-Garcia, A.; Vajdos, F.F.; Leung, L.; Geoghegan, K.F.; Quazi, A.; Xuan, D.; Jones, L.; Hett, E.; Wright, K.; Clark, J.D.; Thorarensen, A. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol., 2016, 11, 3442-3451.
[63]
Clinicaltrials.gov. 6 Studies found for: PF-06651600. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=PF-06651600&cntry1=&state1=&recrs= [Accessed: November 24, 2017].
[64]
Wang, T.; Liu, X.; Hao, M.; Qiao, J.; Ju, C.; Xue, L.; Zhang, C. Design, synthesis and evaluation of pyrrolo [2,3-d]pyrimidine-phenylamide hybrids as potent Janus kinase 2 inhibitors. Bioorg. Med. Chem. Lett., 2016, 26, 2936-2941.
[65]
Lee, S.M.; Yoon, K.B.; Lee, H.J.; Kim, J.; Chung, Y.K.; Cho, W.J.; Mukai, C.; Choi, S.; Kang, K.W.; Han, S.Y.; Ko, H.; Kim, Y.C. The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3. Bioorg. Med. Chem., 2016, 24, 5036-5046.
[66]
Soth, M.; Hermann, J.C.; Yee, C.; Alam, M.; Barnett, J.W.; Berry, P.; Browner, M.F.; Frank, K.; Frauchiger, S.; Harris, S.; He, Y.; Hekmat-Nejad, M.; Hendricks, T.; Henningsen, R.; Hilgenkamp, R.; Ho, H.; Hoffman, A.; Hsu, P.Y.; Hu, D.Q.; Itano, A.; Jaime-Figueroa, S.; Jahangir, A.; Jin, S.; Kuglstatter, A.; Kutach, A.K.; Liao, C.; Lynch, S.; Menke, J.; Niu, L.; Patel, V.; Railkar, A.; Roy, D.; Shao, A.; Shaw, D.; Steiner, S.; Sun, Y.; Tan, S.L.; Wang, S.; Vu, M.D. 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. J. Med. Chem., 2013, 56, 345-356.
[67]
Jaime-Figueroa, S.; De Vicente, J.; Hermann, J.; Jahangir, A.; Jin, S.; Kuglstatter, A.; Lynch, S.M.; Menke, J.; Niu, L.; Patel, V.; Shao, A.; Soth, M.; Vu, M.D.; Yee, C. Discovery of a series of novel 5H-pyrrolo [2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 2522-2526.
[68]
de Vicente, J.; Lemoine, R.; Bartlett, M.; Hermann, J.C.; Hekmat-Nejad, M.; Henningsen, R.; Jin, S.; Kuglstatter, A.; Li, H.; Lovey, A.J.; Menke, J.; Niu, L.; Patel, V.; Petersen, A.; Setti, L.; Shao, A.; Tivitmahaisoon, P.; Vu, M.D.; Soth, M. Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines. Bioorg. Med. Chem. Lett., 2014, 24, 4969-4975.
[69]
Duan, J.J.; Lu, Z.; Jiang, B.; Yang, B.V.; Doweyko, L.M.; Nirschl, D.S.; Haque, L.E.; Lin, S.; Brown, G.; Hynes, J., Jr; Tokarski, J.S.; Sack, J.S.; Khan, J.; Lippy, J.S.; Zhang, R.F.; Pitt, S.; Shen, G.; Pitts, W.J.; Carter, P.H.; Barrish, J.C.; Nadler, S.G.; Salter-Cid, L.M.; McKinnon, M.; Fura, A.; Schieven, G.L.; Wrobleski, S.T. Discovery of pyrrolo [1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors. Bioorg. Med. Chem. Lett., 2014, 24, 5721-5726.
[70]
Bristol-Myers Squibb Co. Pyrrolopyridazine Jak3 inhibitors and their use for the treatment of inflammatory and autoimmune diseases. WO 2012125886, 2012.
[71]
Pfizer Ltd. Indazoles. WO 2013014567, 2013.
[72]
Jones, P.; Storer, R.I.; Sabnis, Y.A.; Wakenhut, F.M.; Whitlock, G.A.; England, K.S.; Mukaiyama, T.; Dehnhardt, C.M.; Coe, J.W.; Kortum, S.W.; Chrencik, J.E.; Brown, D.G.; Jones, R.M.; Murphy, J.R.; Yeoh, T.; Morgan, P.; Kilty, I. Design and synthesis of a pan-Janus kinase inhibitor clinical candidate (PF-06263276) suitable for inhaled and topical delivery for the treatment of inflammatory diseases of the lungs and skin. J. Med. Chem., 2017, 60, 767-786.
[73]
Topivert Pharma Ltd. Preparation of 4,5,6,7-tetrahydro-1Himidazo[ 4,5-c]pyridine and 1,4,5,6,7,8-hexahydro-1Himidazo[ 4,5-d]diazepine derivatives as Janus kinase inhibitors. WO 2017077283, 2017.
[74]
Topivert Pharma Ltd. Preparation of 4,5,6,7-tetrahydro-1Himidazo[ 4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo [4,5-d]azepine derivatives as Janus kinase inhibitors. WO 2017077288, 2017.
[75]
Ritzén, A.; Sørensen, M.D.; Dack, K.N.; Greve, D.R.; Jerre, A.; Carnerup, M.A.; Rytved, K.A.; Bagger-Bahnsen, J. Fragment-based discovery of 6-arylindazole JAK inhibitors. ACS Med. Chem. Lett., 2016, 7, 641-646.
[76]
Cellzome Ltd. Pyrazolo[4,3-c]pyridine derivatives as Jak inhibitors. WO 2013017479, 2013.
[77]
Cellzome Ltd. Pyrazolo[4,3-c]pyridine derivatives as Jak inhibitors. WO 2013017480, 2013.
[78]
Merck Sharp & Dohme Corp. Cycloalkyl nitrile pyrazolo pyridones as Janus kinase inhibitors. WO 2014146246, 2014.
[79]
Merck Sharp & Dohme Corp. Geminally substituted cyanoethylpyrazolo pyridones as Janus kinase inhibitors. WO 2014146249, 2014.
[80]
Merck Sharp & Dohme Corp. N-(2-cyano heterocyclyl) pyrazolo pyridones as Janus kinase inhibitors. WO 2014146492, 2014.
[81]
Merck Sharp & Dohme Corp. Acyclic cyanoethylpypyrazolo pyridones as Janus kinase inhibitors. WO 2014146493, 2014.
[82]
Merck Sharp & Dohme Corp. Ethyl N-Boc piperidinyl pyrazolo pyridones as Janus kinase inhibitors. 2016 WO 2016064935, 2016.
[83]
Merck Sharp & Dohme Corp. Ethyl N-Boc piperidinyl pyrazolo pyridones as Janus kinase inhibitors. WO 2016061751, 2016.
[84]
Pfizer Inc. Pyrazolopyridines and pyrazolopyrimidines as JAK inhibitors and their preparation. WO 2015173683, 2015.
[85]
Calitor Sciences LLC, Sunshine Lake Pharma Co., Ltd. Preparation of substituted pyrazolo[1,5-a]pyrimidine-3- carboxamide derivatives as JAK kinase inhibitors. WO 2015073267, 2015.
[86]
Celon Pharma S.A. Pyrazolo[1,5-a]pyrimidine derivatives as kinase JAK-2 inhibitors. WO 2015118434, 2015.
[87]
F. Hoffmann-La Roche AG. 5-Chloro-2- difluoromethoxyphenyl pyrazolopyrimidine compounds which are JAK inhibitors. WO 2015177326, 2015.
[88]
Array Biopharma Inc. 4,6-Disubstituted-pyrazolo[1,5- a]pyrazines as Janus kinase inhibitors and their preparation. WO 2016090285, 2016.
[89]
Meyer, S.C.; Keller, M.D.; Chiu, S.; Koppikar, P.; Guryanova, O.A.; Rapaport, F.; Xu, K.; Manova, K.; Pankov, D.; O’Reilly, R.J.; Kleppe, M.; McKenney, A.S.; Shih, A.H.; Shank, K.; Ahn, J.; Papalexi, E.; Spitzer, B.; Socci, N.; Viale, A.; Mandon, E.; Ebel, N.; Andraos, R.; Rubert, J.; Dammassa, E.; Romanet, V.; Dölemeyer, A.; Zender, M.; Heinlein, M.; Rampal, R.; Weinberg, R.S.; Hoffman, R.; Sellers, W.R.; Hofmann, F.; Murakami, M.; Baffert, F.; Gaul, C.; Radimerski, T.; Levine, R.L. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell, 2015, 28, 15-28.
[90]
Wu, S.C.; Li, L.S.; Kopp, N.; Montero, J.; Chapuy, B.; Yoda, A.; Christie, A.L.; Liu, H.; Christodoulou, A.; van Bodegom, D.; van der Zwet, J.; Layer, J.V.; Tivey, T.; Lane, A.A.; Ryan, J.A.; Ng, S.Y.; DeAngelo, D.J.; Stone, R.M.; Steensma, D.; Wadleigh, M.; Harris, M.; Mandon, E.; Ebel, N.; Andraos, R.; Romanet, V.; Dölemeyer, A.; Sterker, D.; Zender, M.; Rodig, S.J.; Murakami, M.; Hofmann, F.; Kuo, F.; Eck, M.J.; Silverman, L.B.; Sallan, S.E.; Letai, A.; Baffert, F.; Vangrevelinghe, E.; Radimerski, T.; Gaul, C.; Weinstock, D.M. Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia. Cancer Cell, 2015, 28, 29-41.
[91]
Kim, M.K.; Shin, H.; Park, K.S.; Kim, H.; Park, J.; Kim, K.; Nam, J.; Choo, H.; Chong, Y. Benzimidazole derivatives as potent JAK1-selective inhibitors. J. Med. Chem., 2015, 58, 7596-7602.
[92]
Simov, V.; Deshmuckh, S.V.; Dinsmore, C.J.; Elwood, F.; Fernandez, R.B.; Garcia, Y.; Gibeau, C.; Gunaydin, H.; Jung, J.; Katz, J.D.; Kraybill, B.; Lapointe, B.; Patel, S.B.; Siu, T.; Su, H.; Young, J.R. Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors. Bioorg. Med. Chem. Lett., 2016, 26, 1803-1808.
[93]
JN Therapeutics. Preparation of substituted imidazo[1,2- a]pyridin-2-ylamine compounds for treating, preventing, or ameliorating one or more symptoms of a Janus kinasemediated disease. WO 2016119700, 2016.
[94]
Vasbinder, M.M.; Alimzhanov, M.; Augustin, M.; Bebernitz, G.; Bell, K.; Chuaqui, C.; Deegan, T.; Ferguson, A.D.; Goodwin, K.; Huszar, D.; Kawatkar, A.; Kawatkar, S.; Read, J.; Shi, J.; Steinbacher, S.; Steuber, H.; Su, Q.; Toader, D.; Wang, H.; Woessner, R.; Wu, A.; Ye, M.; Zinda, M. Identification of azabenzimidazoles as potent JAK1 selective inhibitors. Bioorg. Med. Chem. Lett., 2016, 26, 60-67.
[95]
Galapagos NV. Imidazo[4,5-c]pyridine derivatives as JAK kinase inhibitors useful for the treatment of degenerative and inflammatory diseases and their preparation. WO 2013117645, 2013.
[96]
Galapagos NV. Preparation of N-[4-ethyl-6-[1- (methylsulfonyl)-3-azetidinyl]-3-pyridinyl]-N,1-dimethyl- 1H-imidazo[4,5-c]pyridin-6-amine as JAK inhibitor useful for the treatment of degenerative and inflammatory diseases. WO 2014111380, 2014.
[97]
Galapagos NV. Imidazo[4,5-c]pyridine derivatives useful for the treatment of degenerative and inflammatory diseases. WO 2013117645, 2013.
[98]
Galapagos NV. Novel compound useful for the treatment of degenerative and inflammatory diseases. WO 2013117646, 2013.
[99]
Galapagos NV. Imidazo[4,5-c]pyridine derivatives as JAK kinase inhibitors useful for the treatment of degenerative and inflammatory diseases and their preparation WO 2013117649, 2013.
[100]
Galapagos NV. Preparation of pyridoimidazoles and pharmaceutical compositions thereof for the treatment of inflammatory disorders. WO 2017012647, 2017.
[101]
Eli-Lilly & Co. Amino pyrazole compounds. WO 2010074947, 2010.
[102]
Ma, L.; Clayton, J.R.; Walgren, R.A.; Zhao, B.; Evans, R.J.; Smith, M.C.; Heinz-Taheny, K.M.; Kreklau, E.L.; Bloem, L.; Pitou, C.; Shen, W.; Strelow, J.M.; Halstead, C.; Rempala, M.E.; Parthasarathy, S.; Gillig, J.R.; Heinz, L.J.; Pei, H.; Wang, Y.; Stancato, L.F.; Dowless, M.S.; Iversen, P.W.; Burkholder, T.P. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J., 2013, 3e109
[103]
Clinicaltrials.gov. 4 Studies found for: LY2784544. https://clinicaltrials.gov/ct2/results?cond=&term=LY2784544&cntry1=&state1=&Search=Search (Accessed November 24, 2017).
[104]
Celon Pharma S.A. Preparation of imidazo[1,2-b]pyridazin- 6-amine derivatives as JAK2 inhibitors. WO 2014020531, 2014.
[105]
Array Biopharma Inc. Preparation of imidazopyrimidine derivatives for use as Jak kinase inhibitors. WO 2013055645, 2013.
[106]
Ligand Pharmaceuticals Inc. Janus kinase inhibitor compounds and methods. WO 2013025628, 2013.
[107]
Galapagos NV. Novel compounds useful for the treatment of degenerative and inflammatory diseases. WO 2010010190, 2010.
[108]
Menet, C.J.; Fletcher, S.R.; Van Lommen, G.; Geney, R.; Blanc, J.; Smits, K.; Jouannigot, N.; Deprez, P.; van der Aar, E.M.; Clement-Lacroix, P.; Lepescheux, L.; Galien, R.; Vayssiere, B.; Nelles, L.; Christophe, T.; Brys, R.; Uhring, M.; Ciesielski, F.; Van Rompaey, L. Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634. J. Med. Chem., 2014, 57, 9323-9342.
[109]
Danese, S.; Fiorino, G.; Peyrin-Biroulet, L. Filgotinib in Crohn’s disease: JAK is back. Gastroenterology, 2017, 153, 603-605.
[110]
Taylor, P.C.; Abdul Azeez, M.; Kiriakidis, S. Filgotinib for the treatment of rheumatoid arthritis. Expert Opin. Investig. Drugs, 2017, 26, 1181-1187.
[111]
Clinicaltrials.gov. 20 Studies found for: filgotinib. https://clinicaltrials.gov/ct2/results?cond=&term=filgotinib&cntry1=&state1=&recrs (Accessed November 24, 2017).
[112]
Galapagos NV. Aminotriazolopyridine for use in the treatment of inflammation, and pharmaceutical compositions thereof. WO 2013189771, 2013.
[113]
F. Hoffmann-La Roche AG. Preparation of triazolopyridine compounds as Janus kinase inhibitors and methods of use thereof. WO 2016139212, 2016.
[114]
Labadie, S.; Barrett, K.; Blair, W.S.; Chang, C.; Deshmukh, G.; Eigenbrot, C.; Gibbons, P.; Johnson, A.; Kenny, J.R.; Kohli, P.B.; Liimatta, M.; Lupardus, P.J.; Shia, S.; Steffek, M.; Ubhayakar, S.; van Abbema, A.; Zak, M. Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 5923-5930.
[115]
Theravance Biopharma R&D IP, LLC. Naphthyridine compounds as Jak kinase inhibitors. WO 2016191524 2016.
[116]
Jiangsu Simcere Pharmaceutical Co., Ltd. Pyrimidine compounds and use thereof. WO 2014075318, 2014.
[117]
Wang, Y.; Huang, W.; Xin, M.; Chen, P.; Gui, L.; Zhao, X.; Tang, F.; Wang, J.; Liu, F. Identification of 4-(2-furanyl)pyrimidin-2-amines as Janus kinase 2 inhibitors. Bioorg. Med. Chem., 2017, 25, 75-83.
[118]
Gehringer, M.; Pfaffenrot, E.; Bauer, S.; Laufer, S.A. Design and synthesis of tricyclic JAK3 inhibitors with picomolar affinities as novel molecular probes. ChemMedChem, 2014, 9, 277-281.
[119]
Astellas Pharma Inc. Fused pyrrolopyridine derivative. WO 2010119875, 2010.
[120]
Nakamura, K.; Inami, M.; Morio, H.; Okuma, K.; Ito, M.; Noto, T.; Shirakami, S.; Hirose, J.; Morokata, T. AS2553627, a novel JAK inhibitor, prevents chronic rejection in rat cardiac allografts. Eur. J. Pharmacol., 2017, 796, 69-75.
[121]
Bristol-Myers Squibb Co. JAK2 inhibitors and their use for the treatment of myeloproliferative diseases and cancer. WO 2011028864, 2011.
[122]
Wan, H.; Schroeder, G.M.; Hart, A.C.; Inghrim, J.; Grebinski, J.; Tokarski, J.S.; Lorenzi, M.V.; You, D.; Mcdevitt, T.; Penhallow, B.; Vuppugalla, R.; Zhang, Y.; Gu, X.; Iyer, R.; Lombardo, L.J.; Trainor, G.L.; Ruepp, S.; Lippy, J.; Blat, Y.; Sack, J.S.; Khan, J.A.; Stefanski, K.; Sleczka, B.; Mathur, A.; Sun, J.H.; Wong, M.K.; Wu, D.R.; Li, P.; Gupta, A.; Arunachalam, P.N.; Pragalathan, B.; Narayanan, S.; Nanjundaswamy, K.C.; Kuppusamy, P.; Purandare, A.V. Discovery of a highly selective JAK2 Inhibitor, BMS-911543, for the treatment of myeloproliferative neoplasms. ACS Med. Chem. Lett., 2015, 6, 850-855.
[123]
Mace, T.A.; Shakya, R.; Elnaggar, O.; Wilson, K.; Komar, H.M.; Yang, J.; Pitarresi, J.R.; Young, G.S.; Ostrowski, M.C.; Ludwig, T.; Bekaii-Saab, T.; Bloomston, M.; Lesinski, G.B. Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer. Oncotarget, 2015, 6, 44509-44522.
[124]
Pomicter, A.D.; Eiring, A.M.; Senina, A.V.; Zabriskie, M.S.; Marvin, J.E.; Prchal, J.T.; O’Hare, T.; Deininger, M.W. Limited efficacy of BMS-911543 in a murine model of Janus kinase 2 V617F myeloproliferative neoplasm. Exp. Hematol., 2015, 43, 537-545.
[125]
Hart, A.C.; Schroeder, G.M.; Wan, H.; Grebinski, J.; Inghrim, J.; Kempson, J.; Guo, J.; Pitts, W.J.; Tokarski, J.S.; Sack, J.S.; Khan, J.A.; Lippy, J.; Lorenzi, M.V.; You, D.; McDevitt, T.; Vuppugalla, R.; Zhang, Y.; Lombardo, L.J.; Trainor, G.L.; Purandare, A.V. Structure-based design of selective Janus kinase 2 imidazo [4,5-d]pyrrolo [2,3-b]pyridine inhibitors. ACS Med. Chem. Lett., 2015, 6, 845-849.
[126]
Gehringer, M.; Forster, M.; Pfaffenrot, E.; Bauer, S.M.; Laufer, S.A. Novel hinge-binding motifs for Janus kinase 3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres. ChemMedChem, 2014, 9, 2516-2527.
[127]
F. Hoffmann-La Roche AG. Fused tricyclic compounds for use as inhibitors of Janus kinases and their preparation. WO 2013007765, 2013.
[128]
Goedken, E.R.; Argiriadi, M.A.; Banach, D.L.; Fiamengo, B.A.; Foley, S.E.; Frank, K.E.; George, J.S.; Harris, C.M.; Hobson, A.D.; Ihle, D.C.; Marcotte, D.; Merta, P.J.; Michalak, M.E.; Murdock, S.E.; Tomlinson, M.J.; Voss, J.W. Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. J. Biol. Chem., 2015, 290, 4573-4589.
[129]
Yamagishi, H.; Shirakami, S.; Nakajima, Y.; Tanaka, A.; Takahashi, F.; Hamaguchi, H.; Hatanaka, K.; Moritomo, A.; Inami, M.; Higashi, Y.; Inoue, T. Discovery of 3,6-dihydroimidazo [4,5-d]pyrrolo [2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors. Bioorg. Med. Chem., 2015, 23, 4846-4859.
[130]
Forster, M.; Chaikuad, A.; Bauer, S.M.; Holstein, J.; Robers, M.B.; Corona, C.R.; Gehringer, M.; Pfaffenrot, E.; Ghoreschi, K.; Knapp, S.; Laufer, S.A. Sselective Jak3 inhibitors with a covalent reversible binding mode targeting a new induced fit binding pocket. Cell Chem. Biol., 2016, 23, 1335-1340.
[131]
Hurley, C.A.; Blair, W.S.; Bull, R.J.; Chang, C.; Crackett, P.H.; Deshmukh, G.; Dyke, H.J.; Fong, R.; Ghilardi, N.; Gibbons, P.; Hewitt, P.R.; Johnson, A.; Johnson, T.; Kenny, J.R.; Kohli, P.B.; Kulagowski, J.J.; Liimatta, M.; Lupardus, P.J.; Maxey, R.J.; Mendonca, R.; Narukulla, R.; Pulk, R.; Ubhayakar, S.; van Abbema, A.; Ward, S.I.; Waszkowycz, B.; Zak, M. Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1. Bioorg. Med. Chem. Lett., 2013, 23, 3592-3598.
[132]
Friedman, M.; Frank, K.E.; Aguirre, A.; Argiriadi, M.A.; Davis, H.; Edmunds, J.J.; George, D.M.; George, J.S.; Goedken, E.; Fiamengo, B.; Hyland, D.; Li, B.; Murtaza, A.; Morytko, M.; Somal, G.; Stewart, K.; Tarcsa, E.; Van Epps, S.; Voss, J.; Wang, L.; Woller, K.; Wishart, N. Structure activity optimization of 6H-pyrrolo [2,3-e][1,2,4]triazolo [4,3-a]pyrazines as Jak1 kinase inhibitors. Bioorg. Med. Chem. Lett., 2015, 25, 4399-4404.
[133]
F. Hoffmann-La Roche AG. Tricyclic heterocyclic compounds, compositions and methods of use thereof as Jak inhibitors. WO 2013007768, 2013.
[134]
Siu, T.; Kumarasinghe, S.E.; Altman, M.D.; Katcher, M.; Northrup, A.; White, C.; Rosenstein, C.; Mathur, A.; Xu, L.; Chan, G.; Bachman, E.; Bouthillette, M.; Dinsmore, C.J.; Marshall, C.G.; Young, J.R. The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization. Bioorg. Med. Chem. Lett., 2014, 24, 1466-1471.
[135]
Zimmermann, K.; Sang, X.; Mastalerz, H.A.; Johnson, W.L.; Zhang, G.; Liu, Q.; Batt, D.; Lombardo, L.J.; Vyas, D.; Trainor, G.L.; Tokarski, J.S.; Lorenzi, M.V.; You, D.; Gottardis, M.M.; Lippy, J.; Khan, J.; Sack, J.S.; Purandare, A.V. 9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors. Bioorg. Med. Chem. Lett., 2015, 25, 2809-2812.
[136]
Bristol-Myers Squibb Co. Carbazole and carboline kinase inhibitors. WO 2010080474, 2010.
[137]
Gigante, M.; Pontrelli, P.; Herr, W.; Gigante, M.; D’Avenia, M.; Zaza, G.; Cavalcanti, E.; Accetturo, M.; Lucarelli, G.; Carrieri, G.; Battaglia, M.; Storkus, W.J.; Gesualdo, L.; Ranieri, E. miR-29b and miR-198 overexpression in CD8+ T cells of renal cell carcinoma patients down-modulates JAK3 and MCL-1 leading to immune dysfunction. J. Transl. Med., 2016, 14, 84.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy