Full Papers
Keywords: cancer · structure-based design · fibroblast growth
factor receptor (FGFR) · inhibitors · medicinal chemistry
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Scheme 3. a) POCl3, DMF, 608C, 26%; b) NBS, DMF, 08C; 94%; c) 89, X-Phos
precatalyst, CsF, THF, water, 608C, 51%; d) piperazinone, NaBH(OAc)3, AcOH,
MeOH, 608C, 14%.
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catalyst, gave lower yields or no conversion. The optimization
of the base was also important to prevent proto-deboronation
of 89 during the reaction. Cesium fluoride was identified as
the most suitable base for our purpose. Finally, reductive ami-
nation of aldehyde 92 with piperazine-2-one in the presence
of sodium triacetoxyborohydride as reducing agent led to ro-
garatinib (75) in 14% yield.
[7] M. Mohammadi, S. Froum, J. M. Hamby, M. C. Schroeder, R. L. Panek,
G. H. Lu, A. V. Eliseenkova, D. Green, J. Schlessinger, S. R. Hubbard,
Conclusions
Using a computational chemistry approach to generate lead
compounds, we have presented the discovery of rogaratinib
(75), a novel small-molecule inhibitor of FGFR1–4. Rogaratinib
has good DMPK properties. It demonstrated tumor growth re-
duction in pre-clinical models bearing different FGFR altera-
tions both in mono- and combination therapy.[13] Rogaratinib is
currently being evaluated in phase I clinical trials (NCT
01976741).
[10] M. A. Fabian, W. H. Biggs III, D. K. Treiber, C. E. Atteridge, M. D. Azi-
mioara, M. G. Benedetti, T. A. Carter, P. Ciceri, P. T. Edeen, M. Floyd, J. M.
Ford, M. Galvin, J. L. Gerlach, R. M. Grotzfeld, S. Herrgard, D. E. Insko,
M. A. Insko, A. G. Lai, J.-M. Lꢁlias, S. A. Mehta, Z. V. Milanov, A. M. Velas-
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[11] D. Brohm, M. Hꢁroult, M.-P. Collin, W. Hꢀbsch, M. Lobell, K. Lustig, S.
Grꢀnewald, U. Bçmer, V. Voehringer (Bayer Pharma Aktiengesellschaft),
Int. PCT Pub. No. WO2013087578, 2013.
Experimental Section
All experimental data are shown in the Supporting Information.
[13] a) M. Hꢁroult, P. Ellinghaus, C. Sieg, D. Brohm, S. Grꢀnewald, M.-P. Collin,
U. Bçmer, M. Lobell, W. Hꢀbsch, M. Ocker, S. Ince, R. Jautelat, H. Hess-
Stumpp, M. Brands, K. Ziegelbauer, American Association for Cancer Re-
search (AACR) 106th Annual Meeting, April 5–9, 2014 (San Diego, CA,
USA), Abstract 1739; b) M. Hꢁroult, M. Ocker, C. Kopitz, D. Zopf, A. Hꢅ-
gebarth, K. Ziegelbauer, S. Ince, P. Ellinghaus, American Association for
Cancer Research (AACR) 107th Annual Meeting, April 18–22, 2015 (Phil-
adelphia, PA, USA), Abstract 772; c) M.-P. Collin, M. Lobell, D. Brohm, W.
Hꢀbsch, R. Jautelat, S. Jaroch, M. Brands, M. Hꢁroult, S. Grꢀnewald, U.
Bçmer, H. Hess-Stumpp, K. Ziegelbauer, American Association for
Cancer Research (AACR) 108th Annual Meeting, April 16–20, 2016 (New
Orleans, LA, USA), Abstract 4332.
Acknowledgements
The authors thank their co-workers for their dedication and skill-
ful work. The contributions by service functions of the various in-
stitutes are also gratefully acknowledged. Furthermore, we thank
the clinical development team for continuous support of this
project.
Manuscript received: November 16, 2017
Revised manuscript received: January 20, 2018
Conflict of interest
Accepted manuscript online: && &&, 0000
Version of record online: && &&, 0000
The authors declare no conflict of interest.
ChemMedChem 2018, 13, 1 – 10
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