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Mai Mult a Tinktu U U Utora MAIMULT A TINKTUUS010000511B2 U U UTORA (12 ) United States Patent ( 10 ) Patent No. : US 10 , 000 ,511 B2 Walensky et al. (45 ) Date of Patent: Jun . 19 , 2018 (54 ) SMALL MOLECULES FOR THE ( 2013. 01 ) ; CO7D 249/ 12 ( 2013 .01 ) ; CO7D MODULATION OF MCL - 1 AND METHODS 277 / 34 ( 2013 .01 ) ; C07D 279 /06 ( 2013 .01 ) ; OF MODULATING CELL DEATH , CELL C07D 307 /54 ( 2013 . 01 ) ; C07D 327/ 04 DIVISION , CELL DIFFERENTIATION AND (2013 .01 ) ; C07D 401/ 12 ( 2013 .01 ) ; C07D METHODS OF TREATING DISORDERS 403 /04 (2013 .01 ) ; C07D 403 / 06 (2013 . 01 ) ; CO7D 403 /08 ( 2013 .01 ) ; C07D 405/ 12 ( 71 ) Applicant: Dana - Farber Cancer Institute , Inc . , (2013 . 01 ) ; C07D 405 / 14 ( 2013 .01 ) ; C07D Boston , MA (US ) 409 / 06 ( 2013 .01 ) ; CO7D 409 / 12 ( 2013 . 01 ) ; ( 72 ) Inventors : Loren D . Walensky , Newton Centre , C07D 409 / 14 ( 2013 .01 ) ; C07D 413 / 06 MA (US ) ; Michelle L . Stewart , ( 2013 . 01 ) ; C07D 413 / 14 ( 2013 . 01 ) ; C07D 417 /04 ( 2013 .01 ) ; C07D 417 / 14 ( 2013 .01 ) ; Brookline , MA (US ) ; Nicole Cohen , C07C 2602/ 10 ( 2017 . 05 ) Newton , MA (US ) ( 58 ) Field of Classification Search ( 73 ) Assignee : Dana -Farber Cancer Institute , Inc. , CPC .. CO7D 513 / 04 ; CO7D 249/ 12 ; C07D 401/ 12 ; Boston , MA (US ) CO7D 413 / 14 ( * ) Notice: Subject to any disclaimer , the term of this USPC .. .. .. 514 /370 ; 544 / 54 patent is extended or adjusted under 35 See application file for complete search history . U . S . C . 154 ( b ) by 0 days . days . (21 ) Appl. No. : 14 /705 , 764 ( 56 ) References Cited ( 22 ) Filed : May 6 , 2015 U . S . PATENT DOCUMENTS 2004 /0002117 AL 1 /2004 Hogan et al . (65 ) Prior Publication Data 2004 / 0157883 Al 8 / 2004 Chen et al. US 2015 /0315211 A1 Nov. 5 , 2015 2004 /0191328 Al 9 /2004 Warrell , Jr. et al. 2007 / 0203236 A1 8 / 2007 Smith et al . 2009 / 0054402 A1 2 / 2009 Wang et al. Related U . S . Application Data 2009 / 0069324 A1 3 / 2009 Reed et al . (62 ) Division of application No. 13 /576 , 116 , filed as 2009/ 0124616 A1 5 /2009 Song et al. application No. PCT/ US2011 /023220 on Jan . 31 , 2009 /0163545 A1 6 / 2009 Goldfarb 2010 /0004324 A11 /2010 Skaar et al . 2011, now abandoned . 2010 /0234456 AL 9 / 2010 Wendt et al . 2011/ 0077250 A1* 3 / 2011 Ryder .. .. .. .. .. .. .. A61K 31/ 70 (60 ) Provisional application No . 61/ 299 , 803, filed on Jan . 514 /236 . 8 29, 2010 . 2012 /0142917 AL 6 /2012 Lawrence et al. (51 ) Int. Ci. FOREIGN PATENT DOCUMENTS C07D 513 /04 ( 2006 . 01 ) C07D 249 / 12 ( 2006 .01 ) EP 1475372 11/ 2004 C07D 401/ 12 ( 2006 .01 ) 2004 /099518 A 4 /2004 2006516383 7 / 2006 C07D 413 / 14 ( 2006 . 01 ) JP 2007084494 4 / 2007 C07D 409 / 12 ( 2006 . 01 ) WO 2004 /069200 A2 8 / 2004 C07C 311 / 20 ( 2006 .01 ) (Continued ) C07D 409 / 14 ( 2006 . 01 ) CO7D 405 / 14 ( 2006 .01 ) C07D 417 / 14 ( 2006 . 01 ) OTHER PUBLICATIONS CO7D 307/ 54 ( 2006 . 01 ) ZINC 15913384 , PubChem SID 59797118 , PubChem CID : 6848561 CO7D 405 / 12 ( 2006 .01 ) (509102 -00 - 5 ) , Available Date: May 28 , 2009 . http :/ /pubchem .ncbi . C07D 409 / 06 ( 2006 . 01 ) nlm .nih . gov / substance /59797118 /version / 1. * C07D 413 /06 ( 2006 .01 ) (Continued ) CO7D 279 / 06 ( 2006 .01 ) C07D 327 / 04 ( 2006 .01 ) Primary Examiner — Yih -Horng Shiao CO7D 239 /60 ( 2006 .01 ) ( 74) Attorney , Agent , or Firm — Fish & Richardson P. C . C07D 403 / 06 ( 2006 . 01 ) CO7D 27734 (2006 .01 ) ( 57 ) ABSTRACT CO7D 417 /04 ( 2006 . 01 ) This invention relates to compounds which selectively bind C07C 337 / 08 ( 2006 . 01 ) to the survival protein MCL - 1 with high affinity and selec C07C 251/ 20 ( 2006 .01 ) tivity , pharmaceutical compositions containing such com C07C 251/ 84 ( 2006 . 01 ) pounds and the use of those compounds or compositions for C07C 335 / 16 (2006 .01 ) modulating MCL - 1 activity and for treating hyperprolifera C07D 403 / 04 ( 2006 .01 ) tive disorders , angiogenesis disorders , cell cycle regulation CO7D 403 /08 (2006 . 01) disorders , autophagy regulation disorders , inflammatory dis (52 ) U . S . CI. orders , and / or infectious disorders and /or for enhancing CPC . .. .. .. C07D 513 / 04 ( 2013 .01 ) ; C07C 251 /20 cellular engraftment and / or wound repair , as a sole agent or ( 2013 .01 ) ; C07C 251/ 84 ( 2013 .01 ) ; C07C in combination with other active ingredients . 311/ 20 ( 2013 .01 ) ; C07C 335 / 16 ( 2013 .01 ) ; C07C 337/ 08 (2013 . 01 ) ; C07D 239 /60 17 Claims, 19 Drawing Sheets US 10 ,000 , 511 B2 Page 2 References Cited Database PubChem Compound [Online ], NCBI; May 30 , 2009 , ( 56 ) Database accession No . CID 42504827 . Registry ( STN ) [online ], Dec . 8 , 2004 , [ searching date Oct . 27 , FOREIGN PATENT DOCUMENTS 2014 ], CAS registration No . 794552 -61 - 7 . WO WO 2008 / 131000 10 / 2008 Registry ( STN ) [online ] , Dec . 8 , 2004 , [searching date Oct . 27 , WO WO 2008 / 156676 12 / 2008 2014 ] , CAS registration No. 794552 -60 - 6 . WO WO 2009 /023773 2 / 2009 Registry ( STN ) [online ] , Jan . 22, 2001, [searching date Oct. 27 , WO WO 2010 / 005534 A2 1 / 2010 2014 ] , CAS registration No . 315698 -78 - 3 . WO WO 2010 / 102286 9 / 2010 Office Action issued in EP Patent Application No. 11737834 . 9 wo WO 2010 / 151799 A2 12 / 2010 1462, dated Sep . 30 , 2014 . WO WO 2011 - 094708 A2 8 / 2011 Office Action issued in JP Patent Application No . 2012 -551374 , dated Nov. 11 , 2014 . European Search Report for Application No . EP 11737834 . 9 OTHER PUBLICATIONS 1452 / 2528893 , dated Jun . 25 , 2013 . Armstrong , S . A . , et al. , Inhibition of FLT3 in MLL . Validation of a STN CAPLUS 2010 : 1626364 / AN WO 2010151799 /US therapeutic target identified by gene expression based classification , 20110077250 , Priority date : US 2009 -61220988 filed on Jun . 26 , Cancer Cell 3 ( 2 ) : 173 - 183 (2003 ) . 2009 . * Bakhshi, A ., et al. , Cloning the chromosomal breakpoint oft ( 14 : 18 ) MLS000774515 , National Center for Biotechnology Information . human lymphomas : clustering around JH on chromosome 14 and PubChem Compound Database ; CID = 5894545 , https: / /pubchem . near a transcriptional unit on 18 , Cell 41( 3 ) :899 - 906 ( 1985 ) . ncbi. nlm .nih . gov / compound / 5894545 ( accessed Oct . 21 , 2016 ). * Bird , G . H . , et al ., Chapter 22 Synthesis and Biophysical Charac 509102 - 00 - 5 , National Center for Biotechnology Information . terization of Stabilized alpha - Helices ofBCL - 2 Domains , Methods PubChem Compound Database ; CID = 6848561 , https : / /pubchem . Enzymol 446 : 369 - 386 ( 2008 ) . ncbi. nlm .nih . gov / compound /6848561 (accessed Oct . 21 , 2016 ). * Boisvert - Adamo , K ., et al. , Mcl - 1 is required for melanoma cell Barret et al. , " Preparation of Quinone - Imide Ketals From Amides resistance to anoikis , Mol Cancer Res 7 ( 4 ) :549 -556 ( 2009 ) . with Hyper valent Organo - Iodine Compounds ” , Tetrahedron Letts . , Chen , et al. , Differential targeting of prosurvival Bcl- 2 proteins by 32 ( 19 ) :2133 - 2134 ( 1991) . their BH3- only ligands allows complementary apoptotic function , Bukhtoyarova et al ., “ Synthesis and Spectral Properties of N - Aryl Mol Cell, 17 ( 3 ) : 393 - 403 ( 2005 ) . 5 -hydroxy - 1 , 4 - naphthoquinone 4 - Imines” , Russian J . Organ . 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