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United States Patent (10) Patent No.: US 9,724,354 B2 Brake Et Al

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United States Patent (10) Patent No.: US 9,724,354 B2 Brake Et Al USOO9724354B2 (12) United States Patent (10) Patent No.: US 9,724,354 B2 Brake et al. (45) Date of Patent: Aug. 8, 2017 (54) COMBINATION OF CATALYTIC MTORC1/2 6,727.251 B2 4/2004 Bebbington et al. INHIBITORS AND SELECTIVE INHIBITORS g: R 1939: Shano et al. O OF AURORAAKNASE 7,049,116 B2 5, 2006 Shokat 7,148,228 B2 12/2006 Kasibhatla et al. (71) Applicant: Millennium Pharmaceuticals, Inc., 7,271,262 B2 9, 2007 tty al Cambridge, MA (US) 7,572,784 B2 8/2009 Claiborne et al. 8,026,246 B2 9, 2011 Claiborne et al. (72) Inventors: Rachael L. Brake, Natick, MA (US); 8,399.659 B2 3/2013 Claiborne et al. Huifeng Niu, Cambridge, MA (US) 9,102,678 B2 8, 2015 Claiborne et al. g Nu, 2C, 2001/0024.833 A1 9, 2001 Laborde et al. 2002fOO16976 A1 2/2002 Shokat (73) Assignee: Millennium Pharmaceuticals, Inc., 2002fO156081 A1 10, 2002 Hirst et al. Cambridge, MA (US) 2003/0022885 A1 1/2003 Bebbington et al. 2003/0055068 A1 3/2003 Bebbington et al. c - r 2003. O180924 A1 9, 2003 DeSimone (*) Notice: Sibi tO E. site th still 2003/0187001 A1 10, 2003 Calderwood et al. patent 1s extended or adjusted under 2005/0085472 A1 4/2005 Tanaka et al. U.S.C. 154(b) by 0 days. 2005. O197340 A1 9, 2005 Arora et al. 2006,0074074 A1 4/2006 Ohtsuka et al. (21) Appl. No.: 14/777,888 2006/0235031 A1 10, 2006 Arnold et al. 2006/0246551 A1 11/2006 Stack et al. 1-1. 2007/00549.15 A1 3/2007 Arora et al. (22) PCT Filed: Mar. 21, 2014 2007/007 2897 A1 3/2007 Mahaney et al. 2007/00998.71 A1 5/2007 Davis et al. (86). PCT No.: PCT/US2O14/0314.42 2007/O112005 A1 5, 2007 Chen et al. S 371 (c)(1) 2007/O149521 A1 6/2007 Crew et al. 2) D e s S 17, 2015 2007/O185087 A1 8, 2007 Claiborne et al. (2) Date: ep. f, (Continued) (87) PCT Pub. No.: WO2014/153509 FOREIGN PATENT DOCUMENTS PCT Pub. Date: Sep. 25, 2014 CN 1224424 A 7, 1999 (65) Prior Publication Data CN iro,d Ont1nue12.o US 2016/0271140 A1 Sep. 22, 2016 Related U.S. Application Data OTHER PUBLICATIONS (60) Provisional application No. 61/804,314, filed on Mar. Savannah et al. 'Dual Targeting of mTOR and Aurora-A Kinase for 22, 2013. the Treatment of Uterine 1-8 Leiomyosarcoma, Clin Cancer Res., 2012, vol. 18, pp. 4633-4645.* (51) Int. Cl. Abdel-Mohsen. Synthesis, Reactions and Antimicrobial Activity of AOIN 43/00 (2006.01) 2-Amin-4-(8quiNliN 1-5-ye-1-(p-tolyl)-pyrrole-3-carbonitrile. Bull. Korean Chem. Soc. 2005:26(5):719-728. 3. 2. R Apsel, et al. Targeted polypharmacology: discovery of dual inhibi ( .01) tors of tyrosine and phosphoiNsitide kinases. Nat Chem Biol. 2008 A6 IK 45/06 (2006.01) Nv;4(11):691-9. (52) U.S. Cl. Berdnik, D. et al., Drosophila aurora-A is required for centrosome CPC ............ A61 K3I/55 (2013.01); A61K 3 1/519 maturation and actin-dependent asymmetirc protein localization (2013.01); A61K 45/06 (2013.01) during mitosis, Current Biology, 12:640-647 (2002). (58) Field of Classification Search (Continued) CPC ...................................................... A61K 3.1A55 USPC .......................................................... 514/215 See application file for complete search history. Primary Examiner — Nizal Chandrakumar (74) Attorney, Agent, or Firm — Brenda Herschbach (56) References Cited Jarrell; Choate, Hall & Stewart LLP U.S. PATENT DOCUMENTS 57 ABSTRACT 4,099,012 A 7, 1978 Gschwend (57) is: A 2.8. Egelski 1 Disclosed are methods for the treatment of proliferative 5.66,151 A 1/1993 Edie al disorders. Disclosed in particular, are methods for treatment 520,082 A 5/1993 Bockefall of proliferative disorders such as cancer, by administering an 5,593,997 A 1/1997 Dow et al. mTORC1/2 inhibitor in combination with a selective inhibi 5,747,487 A 5/1998 Albright et al. tor of Aurora A kinase. Preferred MTORC1/2 inhibitors 3.75. f 39. E. et al 1 include MLNO128 and the preferred Aurora Akinase inhibi 6,390.82 Bi 5, 2002 SE" C. a. tor of the combination is MLN8237. 6,521,417 B1 2/2003 Shokat 6,552,192 B1 4/2003 Hanus et al. 6,624,119 B1 9, 2003 Reinhard et al. 2 Claims, 5 Drawing Sheets US 9,724,354 B2 Page 2 (56) References Cited WO WO-2007 126841 A2 11/2007 WO WO-2007 134828 A1 11/2007 U.S. PATENT DOCUMENTS WO WO-2008/005266 A2 1, 2008 WO WO-2008/O11154 A2 1, 2008 2007/0203143 A1 8/2007 Sheppard et al. WO WO-2008/021038 A2 2/2008 2007/0213355 A1 9/2007 Capraro et al. WO WO-2008O31594 A1 3f2008 2007/0224672 A1 9, 2007 Leban et al. WO WO-2008/O548O8 A2 5, 2008 2007/0249598 A1 10/2007 Wang et al. WO WO-2008/063525 A1 5, 2008 2007,0254883 A1 11, 2007 Crew et al. WO WO-2008O8307O A1 T 2008 2007/0293516 A1 12/2007 Knight et al. WO WO-2008, 118331 A2 10, 2008 2008/0032960 A1 2/2008 Knight et al. WO WO-20081272.26 A2 10, 2008 2008.0167292 A1 7/2008 Claiborne et al. WO WO-2009021990 A1 2/2009 2010.0004235 A1 1/2010 Schirok et al. WO WO-20090648O2 A2 5, 2009 2010, O184760 A1 7, 2010 Ren et al. WO WO-2009,070652 A1 6, 2009 2010/0310651 A1 12, 2010 Mittal WO WO-2009088.986 A1 T 2009 2010/0317680 A1 12/2010 Curtin et al. WO WO-2009088990 A1 T 2009 2011/0312942 A1 12/2011 Claiborne et al. WO WO-2009 11487O A2 9, 2009 2011/0312943 A1 12/2011 Claiborne et al. WO WO-2009 114874 A2 9, 2009 2012/0010230 A1 1/2012 MacDougall et al. WO WO-2009/158687 A1 12/2009 2015, 0166545 A1 6, 2015 Claiborne et al. WO WO-2010.006072 A2 1/2010 2016,0185782 A1 6, 2016 Claiborne et al. WO WO-2010.006086 A2 1/2010 WO WO-2010036380 A1 4/2010 WO WO-2010, 129816 A2 11/2010 FOREIGN PATENT DOCUMENTS WO WO-2011/014248 A1 2/2011 WO WO-2012/151562 A1 11, 2012 CN 1486.310 A 3, 2004 EP OO14470 A2 8, 1980 EP O273697 A2 T 1988 OTHER PUBLICATIONS EP O773O23 A1 5, 1997 JP 2001-507349 A 6, 2001 Bhat, et al. Pyrazolopyrimidine nucleosides. 12. Synthesis and JP 2003-528141 A 9, 2003 biological activity of certain pyrazolo 3,4-dipyrimidine nucleosides JP 2004-533999 A 11, 2004 related to adeNsine. J Med Chem. Oct. 1981:24(10): 1165-72. JP 2005-529163 A 9, 2005 Bischoff, J.R. et al., a homologue of Drosophila aurora kinase is JP 2007-522217 A 8, 2007 oncogenic and amplified in human colorectal cancers, European JP 2009-544617. A 12/2009 Molecular Biology Organization, 17:3062-3065 (1998). WO WO-94.17803 A1 8, 1994 Bishop, A.C. et al. "Generation of moNspecific naNmolar tyrosine WO WO-96,3151.0 A1 10, 1996 kinase inhibitors via a chemical genetic approach”, Journal of the WO WO-96, 40706 A1 12, 1996 WO WO-97.15658 A1 5, 1997 American Chemical Society, American Chemical Society, Wash WO WO-97, 19065 A1 5, 1997 ington, DC, US, vol. 121, N. 4, 1999, pp. 627-31. WO WO-97,32883 A1 9, 1997 Cancer Prevention Overview, http://www.cancer.gov/cancertopics/ WO WO-98/14450 A1 4f1998 pdq/prevention? overview?patient, National Cancer Institute, (2009). WO WO-98.28281 A1 7, 1998 Cantor, E.H. et al., Interaction of calcium channel blockers with WO WO-98.58926 A1 12, 1998 non-neuronal benzodiazepine binding sites, Proceedings of the WO WO-00, 42042 A2 T 2000 National Academy of Sciences, 81:1549-1552 (1984). WO WO-OOf 67754 A1 11, 2000 Carmena, M. et. al., The Cellular Geography of Aurora Kinases, WO WO-01/10462 A1 2, 2001 Nature, 4.842-854 (2003). WO WO-01 (19829 A2 3, 2001 Carvajal, R. et al., Aurora kinases: new targets for cancer therapy, WO WO-01 72300 A1 10, 2001 Clinical Cancer Research 12(23):6869-6875 (2006). WO WO-O2,226O7 A1 3, 2002 C WO WO-02/066461 A1 8, 2002 ervantes, A. et al., Pharmacokinetic (PK) and pharmacodynamic WO WO-02/068415 A1 9, 2002 (PD) results from 2 phase 1 studies of the investigational selective WO WO-O2/O72O73 A2 9, 2002 Aurora AAkinase (AAK) inhibitor MLN8237: Exposure-dependent WO WO-02/076986 A1 10, 2002 AAK inhibition in human tumors, American Society of Clinical WO WO-02/094834 A1 11, 2002 Oncology, 1 (2010). WO WO-03/000187 A2 1, 2003 Cervantes, A. et al., Phase 1 Pharmacokinetic and WO WO-03/O13545 A1 2, 2003 Pharmacodynamic Study of MLN8237, a Novel, Selective Aurora A WO WO-03/103.687 A1 12/2003 Kinase Inhibitor, in Patients with Advanced Solid Tumors, Ameri WO WO-2005/037843 A1 4/2005 can Society of Clinical Oncology, 1 (2009). WO WO-2005/044181 A2 5, 2005 Dees, C.E. et al., Phase 1 study of the investigational drug WO WO-2005/047289 A1 5, 2005 MLN8237, an oral Aurora Akinase inhibitor, in patients with solid WO WO-2005, O74603 A2 8, 2005 WO WO-2005, O76987 A2 8, 2005 tumors, American Society of Clinical Oncology, 1 (2010). WO WO-2005/085248 A1 9, 2005 Development Pipeline Presentations: Abstract Compendium, WO WO-2005/0978OO A1 10, 2005 American Society of Clinical Oncology, (2013).
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