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( 12 ) United States Patent US010155768B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 155 , 768 B2 Miyazaki et al. (45 ) Date of Patent: Dec . 18 , 2018 ( 54 ) FUSED PYRIMIDINE COMPOUND OR SALTWO 2004056830 Al 7 / 2004 wo 2005047289 A1 5 / 2005 THEREOF WO 2005062795 A2 7 / 2005 WO 2006017443 A2 2 / 2006 (71 ) Applicant : TAIHO PHARMACEUTICAL CO . , WO 2007067781 A2 6 / 2007 LTD . , Tokyo (JP ) WO 2011018894 A1 2 / 2011 WO 2013114113 Al 8 / 2013 (72 ) Inventors : Isao Miyazaki, Tsukuba ( JP ) ; Tadashi WO 2014184069 Al 11/ 2014 wo 2015022926 A1 2 / 2015 Shimamura , Tsukuba ( JP ) ; Masanori WO 2015078417 A1 6 / 2015 Kato , Tsukaba (JP ); Hidenori Fujita , wo 2017 / 043550 A1 3 / 2017 Tsukuba ( JP ); Satoru Iguchi, Tsukuba WO 2017038838 A1 3 / 2017 ( JP ) (73 ) Assignee : Taiho Pharmaceutical Co ., Ltd . , OTHER PUBLICATIONS Tokyo ( JP ) Extended European Search Report dated Jan . 12 , 2018 , cited in the related European application No . 17756554 . 6 , 6 pages . ( * ) Notice : Subject to any disclaimer, the term of this Mulligan , “ RET revisited : expanding the oncogenic portfolio ” , patent is extended or adjusted under 35 Nature Reviews, 14 ( 3 ) :pp . 173 - 186 , ( 2014 ) . Ibanez , “ Structure and Physiology of the RET Receptor Tyrosine U . S . C . 154 (b ) by 0 days . Kinase ” , Cold Spring Harbor Perspectives in Biology , 5 ( 2 ) a009134 :pp . 1 - 10 , ( 2013 ) . ( 21) Appl. No. : 15 /708 ,917 Kohno et al. , “ KIF5B -RET fusions in lung adenocarcinoma” , Nature Medicine , 18 ( 3 ) :pp . 375 -377 , (2012 ) . ( 22 ) Filed : Sep . 19 , 2017 Santoro et al , “ RET/ PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture ” , European Jour Prior Publication Data nal of Endocrinology , 155 :pp . 645 -653 , ( 2006 ) . (65 ) Yeganeh et al, “ RET Prato Oncogene Mutation Detection and US 2018 /0009818 A1 Jan . 11 , 2018 Medullary Thyroid Carcinoma Prevention " , Asian Pacific Journal of Cancer Prevention , 16 (6 ): pp . 2107 -2117 , ( 2015 ) . Related U . S . Application Data Gattelli et al ., " Ret inhibition decreases growth and metastatic potential of estrogen receptor positive breast cancer cells ” , EMBO (63 ) Continuation of application No. Molecular Medicine, 5 : pp . 1335 - 1350 , (2013 ) . PCT/ JP2017 /006672 , filed on Feb . 22 , 2017 . Ito et al . , “ Expression of glial cell line - derived neurotrophic factor family members and their receptors in pancreatic cancers ” , Surgery , ( 30 ) Foreign Application Priority Data 138 ( 4 ): pp . 788 -794 , (2005 ) . Dawson et al ., " Altered Expression of RET Proto -oncogene Product Feb . 23, 2016 ( JP ) .. .. .. .. .. .. 2016 -031919 in Prostatic Intraepithelial Neoplasia and Prostate Cancer ” , Journal Jul. 15 , 2016 ( JP ) . .. .. .. .. .. .. .. .. .. .. .. 2016 - 140801 of the National Cancer Institute , 90 ( 7 ) :pp . 519 - 523 , ( 1998 ) . (Continued ) (51 ) Int . CI. A61K 31 /519 ( 2006 .01 ) Primary Examiner — Jeffrey H Murray CO7D 487 /04 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Rothwell, Figg , Ernst & A61P 35 /00 ( 2006 . 01 ) Manbeck , P . C . (52 ) U .S . CI. CPC .. .. .. .. C07D 487 /04 (2013 .01 ) ; A61K 31/ 519 (57 ) ABSTRACT ( 2013 .01 ) ; A61P 35 / 00 ( 2018 .01 ) The problem to be solved by the present invention is to (58 ) Field of Classification Search provide a novel compound having RET inhibitory activity . ??? . .. A61K 31/ 519 ; CO7D 487/ 04 The present invention also provides a pharmaceutical prepa USPC .. .. .. .. 514 / 262 . 1 , 265 . 1 ; 544 / 262 , 280 ration that is useful for the prevention and /or treatment of See application file for complete search history . RET- related diseases , particularly cancer , based on RET inhibitory activity . The present invention provides a com (56 ) References Cited pound represented by Formula ( 1 ) : U . S . PATENT DOCUMENTS 5 ,665 , 721 A 9 / 1997 Bhagwat et al . 2006 /0211678 AL 9 / 2006 Ahmed et al. 2007 /0135387 A 6 / 2007 Michaelides et al. - NH 2014 / 0108453 A1 4 / 2014 Venkataraman et al. 2016 /0115168 A1 4 / 2016 Iguchi et al . 2017 /0217970 A1 8 / 2017 Kawai et al . 2018 /0009817 A1 1/ 2018 Miyazaki et al . 1 FOREIGN PATENT DOCUMENTS 2007 - 521334 A 8 / 2007 JP 2008 -508358 A 3 / 2008 wherein A , R2, and X are as defined in the specification ; or JP 2009 -518434 A 5 / 2009 a salt thereof. JP 2015505555 A 2 / 2015 wo 96 / 40686 Al 12 / 1996 9 Claims, 2 Drawing Sheets US 10 ,155 ,768 B2 Page 2 (56 ) References Cited Warmuth et al. , “ Dual -specific Src and Abl kinase inhibitors, PP1 and CGP76030 , inhibit growth and survival of cells expressing imatinib mesylate - resistant Ber - Abl kinases ” , Blood , 101( 2 ) :pp . 664 -672 , ( 2003 ) . OTHER PUBLICATIONS Lowe et al. , “ Osteopetrosis in Src - deficient mice is due to an Cai et al. , “ KIF5B - RET Fusions in Chinese Patients with Non autonomous defect of osteoclasts ” , Proceedings of the National Academy of Sciences of the United States of America , 90 ( 10 ) :pp . Small Cell Lung Cancer ” , Cancer, 119 :pp . 1486 - 1494 , ( 2013 ) . 4485 - 4489 , ( 1993 ) . Elisei et al . , “ Prognostic Significance of Somatic RET Oncogene Molina et al. , " Profound block in thymocyte development in mice Mutations in Sporadic Medullary Thyroid Cancer : A 10 - Year Follow lacking p56 ” , Nature , 357 (6374 ): pp . 161- 164, ( 1992 ) . Up Study ” , The Journal of Clinical Endocrinology & Metabolism , McClellan et al ., “ Discovery of potent and selective thienopyrimidine 93 ( 3 ): pp . 682 -687 , (2008 ) . inhibitors of Aurora kinases" . Bioorganic & Medicinal Chemistry Zeng et al. , “ The Relationship between Over -expression of Glial Letters 21, 2011 , pp . 5620 - 5624 . Cell -derived Neurotrophic Factor and Its RET Receptor with Pro Bavetsias et al . , “ Aurora Kinase Inhibitors : Current Status and Outlook ” , Frontiers in Oncology , 2015 , vol. 5 , Art .278 . gression and Prognosis of Human Pancreatic Cancer ” , The Journal Keefe et al. , “ Tumor control versus adverse events with targeted of International Medical Research , 36 : pp . 656 - 664 , ( 2008 ) . anticancer therapies” Nature Reviews Clinical Oncology , 2012 , vol. Carlomagno et al, “ The Kinase Inhibitor PP1 Blocks Tumorigenesis 9 , No . 2 , pp . 98 - 109 . Induced by RET Oncogenes 1 ” Cancer Research , 62 ( 4 ) :pp . 1077 International Search Report cited in PCT/ JP2017 / 006672 dated Apr. 1082 , ( 2002 ) . 25 , 2017 , 2 pages . Waltenberger et al , “ A Dual Inhibitor of Platelet- Derived Growth U . S . Appl. No . 15 /700 ,800 , filed Sep . 11, 2017 . Factor b - Receptor and Src Kinase Activity Potently Interferes With F . Hidenori et al ., “ 4784 / 13 – TAS0286 /HM05 , A Novel Highly Motogenic and Mitogenic Responses to PDGF in Vascular Smooth Selective RET Inhibitor , Prominently Inhibits Various RET Defec Muscle Cells a Novel candidate for Prevention of Vascular Remod tive Tumor Growth ” , AACR Annual Meeting 2018 Online Proceed eling ” , Circulation Research , 85 ( 1 ) :pp . 12 - 22 , ( 1999 ) . ings and Itinerary Planner Home, Abstract , Apr. 17 , 2018 , 1 page . Tatton et al ., “ The Src - selective Kinase Inhibitor PP1 Also Inhibits F . Hidenori et al. , “ TAS0286 /HMO5 , A Novel Highly Selective Kit and Ber - Abl Tyrosine Kinases * ” , The Journal of Biological RET Inhibitor, Prominently Inhibits Various RET Defective Tumor Chemistry , 278 ( 7 ): pp . 4847 -4853 , (2003 ) . Growth ” , 4784 Abstract , Mar. 14 , 2018 , 1 page . U . S . Patent Dec. 18, 2018 Sheet 1 of 2 US 10 , 155 , 768 B2 Fig . 1 Control 17h. *4 Example 85 100 mg/ kg /day > TIERT - - - 1 - - - - wysymyWNW ti XATIRLAYIR . * . - - . - . A I . A S . " A . 1 . A . Relativetumorvolume(RTV) $<* *MAX&ADAM . - . MAAVAARAWATIKUWAVUKAVARNAHESA tiM*$45aix40 VYNY YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY : v - . - : ES. - - - - - . - - . - - - 1 3 . - - - . - . - - - . WARAWA M . .. K A.XX AINHAYAMOSAI- . > 11 / 1 AA S IALAISAIA , , AYA Y . * . + , AAAFRASSO MAS .XXXAxir - - - - ** " 75 " " 7773 6 Days Fig . 2 1 . * Control * Example 90 50 mg/ kg /day Example 89 150 mg/ kg /day Prover Example 87 50 mg/ kg /day .. .. .. .. Relativetumorvolume(RTV) . - - - - - - - - - - - - - - - - - - . .. .. TYL. - INTL . - - . 4 . LAYU . SILA V . 17. I 1944 * What 3 5 7Days 9 11 13 15 U . S . Patent Dec. 18, 2018 Sheet 2 of 2 US 10 ,155 ,768 B2 Fig . 3 meisiekstuk kotoisis de la bodabei eisiada batutat einen seks butalaisiminde debut akan amint ke balance in bed shoá sin indeholder en min beskriminin de kunstenaariadode su adeco bebe des adminis in de bubuloksianish deb betoneis back teksteisininko dukket olvisinde bulabai risinde - Control . - - - - - - - - - - - . - - . - - - - . - - - - - - 4xww Example 85 100 mg/ kg /day . SAS . AYANIHAN . YAANIAYAT AY717 * * * * ** * * * * * * * . VAYA AYLANAS W Bodyweightchange(%fromDayO) *WWv. *X94XXXXwX974 . - - . - . - . - . - . - A th A + + * * * + * * * * + + + ** * * * * * * * * * * SYY - TRY . AYA . YA . RA Days Fig . 4 wWMWWWWWWWWWWWWWWWWWWWWMA hWwWwwWw k Methith MAWAWM Control Example 90 50 mg/ kg /day . Example 89 150 mg/ kg / day Example 87 50 mg/kg / day - - - - - . - Bodyweightchange(%fromDay1) . - - - . - - . - . - - . - . - . - . - . - . - . - - . - - - - - . - . - - . - - . - - - - - - - * * * * * * * * * * * * * * - - . * - * - * = . - - . - . - . - 20 . 0 . .. i S v2 " . .. À Days 9 11 13 15 US 10 , 155 ,768 B2 FUSED PYRIMIDINE COMPOUND OR SALT tions , the inhibitors raise concerns about possible various THEREOF side effects , which may require dose reduction and / or drug holidays , thus leading to insufficient RET inhibitory activity. CROSS -REFERENCE TO RELATED PATENT
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