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(12) United States Patent (10) Patent No.: US 8,962,619 B2 Ashwell Et Al

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(12) United States Patent (10) Patent No.: US 8,962,619 B2 Ashwell Et Al USOO8962619B2 (12) United States Patent (10) Patent No.: US 8,962,619 B2 Ashwell et al. (45) Date of Patent: *Feb. 24, 2015 (54) SUBSTITUTED (58) Field of Classification Search MIDAZOPYRIDINYL-AMNOPYRIDINE None COMPOUNDS See application file for complete search history. (71) Applicant: ArCule, Inc., Woburn, MA (US) (56) References Cited U.S. PATENT DOCUMENTS (72) Inventors: Mark A. Ashwell, Carlisle, MA (US); Chris Brassard, Somerville, MA (US); 4,522,811 A 6/1985 Eppstein et al. Anton Filikov, Rockville, MD (US); 33. R: ck 3. RileyShWell f et alal. ............... 514,303 ason Hill. Auburndale, MA (US); Steffi 8,609.688 B2 * 12/2013 Ashwell et al. ............... 514,303 Koerner, Medford, MA (US); 2002/0151549 A1 10/2002 Hayakawa et al. Jean-Marc Lapierre, Pelham, NH (US); 2006/0035921 A1 2/2006 Castelhano et al. Yanbin Liu, Acton, MA (US); Nivedita 2007. O142369 A1 6/2007 van Heek et al. 2007,0254.868 A1 11/2007 Lauffer et al. Namdev, Westford, MA (US); Robert 2009/0253734 A1 10/2009 Kelly, III et al. Nicewonger, Tyngsboro, MA (US); 2011/0059936 A1 3/2011 Lauffer et al. Rocio Palma, North Andover, MA (US); 2011/0172203 A1 7, 2011 Ashwell et al. Manish Tandon, Framingham, MA 2012/0329793 A1* 12/2012 Ashwell et al. ............ 514,234.2 (US); David Vensel, Brookline, MA (US); Akihisa Matsuda, Tokyo (JP); FOREIGN PATENT DOCUMENTS Shin Iimura, Tokyo (JP); Kenichi CN 1824665 A 8, 2006 Yoshida, Tokyo (JP); Takanori DE 3722.992 A1 1, 1989 Yamazaki, Tokyo (JP); Takahiro P 12: A. 3. E. Kitamura, Tokyo (JP); Takeshi JP 200034.4780 A 12/2000 Isoyama, Tokyo (JP) KR 20090007347 U 7, 2009 WO WO-96.19991 A1 T 1996 (73) Assignee: ArCule, Inc., Woburn, MA (US) WO WO-99.57 103 A1 11, 1999 WO WO-03.08.0125 A2 10/2003 (*) Notice: Subject to any disclaimer, the term of this WO WO-03080610 A1 10, 2003 WO WO-03O88967 A1 10, 2003 patent is extended or adjusted under 35 WO WO-20050117OO A1 2/2005 U.S.C. 154(b) by 0 days. WO WO-2007056155 A1 5, 2007 Thiis patenttent iis subjectbiect tot a terminalt inal didis WOwo WO-2007wo.-2008.007900 111904 A2A1 10/20071/2008 claimer. WO WO-2008108958 A2 9, 2008 (21) Appl. No.: 14/075,505 (Continued) OTHER PUBLICATIONS (22) Filed: Nov. 8, 2013 Bukowski et al. “Imidazo[4,5-b]pyridine Derivatives of Potential (65) Prior Publication Data Tuberculostatic Activity.” Archie der Pharmazie. 324.2(1991): 121 127. US 2014/0073635 A1 Mar. 13, 2014 CAS Registry No. 134330-74-8, retrieved Oct. 21, 2011. CAS Registry No. 135286-66-7, retrieved Oct. 21, 2011. CAS Registry No. 95 1258-58-5, retrieved Oct. 21, 2011. Related U.S. ApplicationO O Data CAS Registry No. 95.1258-60-9,95 1258-59-6, retrieved Oct. 21, 2011. (63) Continuation of application No. 13/529,459, filed on AS E. N. 2: ES t : 38: Jun. 21, 2012, now Pat. No. 8,609,688. CAS Registryegistry No. 95 1258-63-2,-oz-1, retrievedretrieve Oct.C. 21, 2011. (60) Provisional application No. 61/500,889, filed on Jun. (Continued) 24, 2011. (51) Int. Cl Primary Examiner — Anna Pagonakis A6 IK3I/437 (2006.01) Etc."gent or Firm — Cooley LLP. Ivor R. Elrifi: CO7D 47L/04 (2006.01) A 6LX3/5377 (2006.01) (57) ABSTRACT A 6LX3L/2197 (2006.01) - 0 A6 IK3I/506 (2006.01) The present invention relates to substituted imidazopyridinyl aminopyridine compounds and methods of synthesizing CO7D 49.8/08 (2006.01) these compounds. The present invention also relates to phar CO7D 49/08451/02 (2006.01) maceuticalical compositions containing Substitutedbstituted imid1m1 azopy ridinyl-aminopyridine compounds and methods of treating (52) U.S. Cl. cell proliferative disorders, such as cancer, by administering CPC ............ C07D 471/04 (2013.01); C07D498/08 these compounds and pharmaceutical compositions to Sub (2013.01); C07D 451/02 (2013.01); C07D jects in need thereof. 491/08 (2013.01) USPC ........................................ 514/234.2:544/127 6 Claims, No Drawings US 8,962,619 B2 Page 2 (56) References Cited CAS Registry No. 95 1258-69-8, retrieved Oct. 21, 2011. CAS Registry No. 95 1258-70-1, retrieved Oct. 21, 2011. CAS Registry No. 95 1258-71-2, retrieved Oct. 21, 2011. FOREIGN PATENT DOCUMENTS CAS Registry No. 95 1258-72-3, retrieved Oct. 21, 2011. WO WO-2009000413 A1 12/2008 CAS Registry No. 95 1258-73-4, retrieved Oct. 21, 2011. WO WO-2009051454 A2 4/2009 CAS Registry No. 95 1258-74-5, retrieved Oct. 21, 2011. WO WO-2011082270 A2 T 2011 CAS Registry No. 95 1258-79-0, retrieved Oct. 21, 2011. WO WO-2012.177852 A1 12/2012 CAS Registry No. 95 1259-09-9, retrieved Oct. 21, 2011. OTHER PUBLICATIONS CAS Registry No. 95.1259-10-2, retrieved Oct. 21, 2011. CAS Registry No. 95.1258-64-3, retrieved Oct. 21, 2011. CAS Registry No. 95.1259-11-3, retrieved Oct 21, 2011. CAS Registry No. 95.1258-65-4, retrieved Oct. 21, 2011. Tóth etal. "Nitrogen Bridgehead Compounds.”.J. Heterocyclic Chem CAS Registry No. 95.1258-66-5, retrieved Oct. 21, 2011. 28.2(1991);497-501. CAS Registry No. 95.1258-67-6, retrieved Oct. 21, 2011. CAS Registry No. 95.1258-68-7, retrieved Oct. 21, 2011. * cited by examiner US 8,962,619 B2 1. 2 SUBSTITUTED The AKT family regulates cellular survival and metabo MIDAZOPYRIDINYL-AMINOPYRONE lism by binding and regulating many downstream effectors, COMPOUNDS e.g. Nuclear Factor-KB, Bcl-2 family proteins and murine double minute 2 (MDM2). Akt1 is known to play a role in the cell cycle. Moreover, activated Akt1 may enable proliferation CROSS-REFERENCE TO RELATED and survival of cells that have sustained a potentially APPLICATIONS mutagenic impact and, therefore, may contribute to acquisi tion of mutations in other genes. Akt1 has also been impli This application is a continuation of U.S. Ser. No. 13/529, cated in angiogenesis and tumor development. Studies have 459, filed Jun. 21, 2012, which claims priority to, and the shown that deficiency of Akt1 enhanced pathological angio benefit of, U.S. Ser. No. 61/500,889, filed Jun. 24, 2011. The genesis and tumor growth associated with matrix abnormali contents of each of these applications are incorporated herein ties in skin and blood vessels. Since it can block apoptosis, by reference in their entirety. and thereby promote cell survival, Akt1 is a major factor in many types of cancer. BACKGROUND OF THE INVENTION Accordingly, new compounds and methods for modulating 15 AKT genes, proteins and treating proliferation disorders, Cancer is the second leading cause of death in the United including cancer, are needed. The present invention addresses States, exceeded only by heart disease. (Cancer Facts and these needs. Figures 2004, American Cancer Society, Inc.). Despite recent SUMMARY OF THE INVENTION advances in cancer diagnosis and treatment, Surgery and radiotherapy may be curative if a cancer is found early, but The present invention provides, in part, Substituted imida current drug therapies for metastatic disease are mostly pal Zopyridinyl-aminopyridine compounds of formula I or II, and liative and seldom offer a long-term cure. Even with new methods of preparing the compounds of formula I or II: chemotherapies entering the market, the need continues for new drugs effective in monotherapy or in combination with 25 (I) existing agents as first line therapy, and as second and third HN line therapies in treatment of resistant tumors. Cancer cells are by definition heterogeneous. For example, N EN within a single tissue or cell type, multiple mutational "mechanisms' may lead to the development of cancer. As 30 X CO)4. N () Such, heterogeneity frequently exists between cancer cells taken from tumors of the same tissue and same type that have O originated in different individuals. Frequently observed mutational "mechanisms' associated with some cancers may differ between one tissue type and another (e.g., frequently 35 observed mutational "mechanisms' leading to colon cancer HN may differ from frequently observed “mechanisms' leading to leukemias). It is therefore often difficult to predict whether a particular cancer will respond to a particular chemothera peutic agent (Cancer Medicine, 5' edition, Bast et al., B.C. 40 Decker Inc., Hamilton, Ontario). Components of cellular signal transduction pathways that (II) regulate the growth and differentiation of normal cells can, HN when dysregulated, lead to the development of cellular pro N N liferative disorders and cancer. Mutations in cellular signal 45 rN-y ing proteins may cause Such proteins to become expressed or activated at inappropriate levels or at inappropriate times elN/ \ / during the cell cycle, which in turn may lead to uncontrolled cellular growth or changes in cell-cell attachment properties. For example, dysregulation of receptor tyrosine kinases by 50 mutation, gene rearrangement, gene amplification, and over NRR' expression of both receptor and ligand has been implicated in the development and progression of human cancers. HN AKT protein family, which members are also called pro tein kinases B (PKB) plays an important role in mammalian 55 cellular signaling. In humans, there are three genes in the AKT family: Akt1, Akt2, and Akt3. These genes code for wherein: enzymes that are members of the serine/threonine-specific X is NRR, OR, SRs or protein kinase family. Akt1 is involved in cellular survival pathways, by inhibitingapoptotic processes. Akt1 is also able 60 to induce protein synthesis pathways, and is therefore a key :::::: signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Akt2 is an important signaling molecule in the Insulin signaling path way and is required to induce glucose transport.
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