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(12) United States Patent (10) Patent No.: US 8.263,610 B2 Ali Et Al

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(12) United States Patent (10) Patent No.: US 8.263,610 B2 Ali Et Al US008263610B2 (12) United States Patent (10) Patent No.: US 8.263,610 B2 Ali et al. (45) Date of Patent: Sep. 11, 2012 (54) SUBSTITUTED (56) References Cited IMIDAZOLYL-5,6-DIHYDROBENZONISO QUINOLINE COMPOUNDS U.S. PATENT DOCUMENTS 4,522,811 A 6/1985 Eppstein et al. (75) Inventors: Syed M. Ali, North Andoyer, MA (US); 2005/01434424,612,318 AA1 * 9/19866/2005 WintersHudkins et........................ al. 514,293 Mark A. Ashwell, Carlisle, MA (US); 2008.0160028 A1 7/2008 Reicheltet al. Chris Brassard, Somerville, MA (US); Audra Dalton, Revere, MA (US); Anton FOREIGN PATENT DOCUMENTS Filikov, Stoneham, MA (US); Jason EP 104522 A2 4, 1984 Hill, Auburndale, MA (US); Nivedita EP 1238979 A1 9, 2002 Namdev, Westford, MA (US); Rocio E. A. is: Palma, North Andover, MA (US); SU 1626648 A1 9, 1995 Manish Tandon, Framingham, MA WO WO-O 144244 A1 6, 2001 (US); David Vensel, Boston, MA (US); WO WO-2005OO9389 A2 2/2005 JianqiangWang, Acton, MA (US); Neil WO WO-2006010567 A1 2/2006 Westlund, Groton, MA (US) WO WO-2007095628 A1 8, 2007 s s OTHER PUBLICATIONS (73) Assignee: ArCule, Inc., Woburn, MA (US) Diaz-ortizDaz-Ortiz etet al.,al., “Synthesis Tetrahedron, of Pyrazolo56(2000), 3,4-bipyridines pp. 1569-1577. by Cycload (*) b discl h f thi dition Reactions under Microwave Irradiation', Tetrahedron, Notice: Subject to any disclaimer, the term of this 56(11): 1569-1577 (2000). patent is extended or adjusted under 35 International Search Report and Written Opinion for PCT/US2009/ U.S.C. 154(b) by 165 days. 069821, mailed on Apr. 27, 2010. Paronikyan et al. “Synthesis and Anticonvulsant Activity of Pyrazolo 3,4-bipyrano (thiopyrano04,3-dipyridine and (21) Appl. No.: 12/649,762 pyrazolo 3,4-c isoquinoline Derivatives.” Pharm. Chem. J. 35.1(2001):8-10. Paronikyan et al. “Synthesis and Some Conversions of Partially (22) Filed: Dec. 30, 2009 Hydrogenated 1-Aminopyrano(thiopyrano)4,3-dipyrazolo 3,4- bipyridines and pyrazolo 3,4-c isoquinolines.” Chemistry of H ereocycticlic CUompounas. ds. 39.3(2003):374-378: (65) Prior Publication Data Sharlow et al. “Development and Implementation of a Miniaturized US 2010/O239526A1 Sep. 23, 2010 High-Throughput Time-Resolved Fluorescence Energy Transfer Assay to Identify Small Molecule Inhibitors of Polo-Like Kinase 1.” O O ASSAY and Drug Development Technologies. 5.6(2007):723-726. Related U.S. Application Data Winters et al. “Easy Synthesis of New Ring-Fused Pyridones from (60) Provisional application No. 61/141,371, filed on Dec. Heteroaromatic B-vinylamines.” Synthesis. 12(1984): 1052-1054. 30, 2008. * cited by examiner Primary Examiner — Niloofar Rahmani (51) Int. Cl. (74) Attorney, Agent, or Firm — Mintz Levin Cohn Ferris AOIN 43/42 (2006.01) Glovsky and Popeo, P.C.: Ivor R. Elrifi; Matthew Pavao, J.D. A6 IK3I/44 (2006.01) (57) ABSTRACT CO7D 47L/00 (2006.01) The present invention relates to substituted imidazolyl-5,6- CO7D 49/00 (2006.01) dihydrobenzonisoquinoline compounds and methods of CO7D 49.8/00 (2006.01) synthesizing these compounds. The present invention also CO7D 53/00 (2006.01) relates to pharmaceutical compositions containing Substi C07D 515/00 (2006.01) tuted imidazolyl-5,6-dihydrobenzonisoquinoline com (52) U.S. Cl. .......................................... 514/293; 546/82 pounds and methods of treating cell proliferative disorders, (58) Field of Classification Search 546/82 Such as cancer, by administering these compounds and phar - - - - - - - - - - - - - - - - - - - - 5141293 maceutical compositions to Subjects in need thereof. See application file for complete search history. 21 Claims, No Drawings US 8,263,610 B2 1. 2 SUBSTITUTED is abnormally active (overexpressed) in certain types of stom IMIDAZOLYL-5,6-DIHYDROBENZONISO ach cancers, and this amplification is associated with a poorer QUINOLINE COMPOUNDS prognosis and response to standard clinical methods. Abnor mal expression of FGFR2 is also found in patients with pros CROSS-REFERENCE TO RELATED tate cancer. More than 60 percent of women with breast APPLICATIONS cancer in the United States carry at least a single mutation in this gene as well. The present application claims priority to, and the benefit of, U.S. Provisional Application No. 61/141,371, filed Dec. Accordingly, new compounds and methods for modulating 30, 2008. The contents of this application is herein incorpo 10 FGFR2 and treating proliferation disorders, including cancer, rated by reference in its entirety. are needed. The present invention addresses these needs. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION Cancer is the second leading cause of death in the United 15 States, exceeded only by heart disease. (Cancer Facts and The present invention provides, in part, Substituted imida Figures 2004, American Cancer Society, Inc.). Despite recent Zolyl-5,6-dihydrobenzonisoquinoline compounds of For advances in cancer diagnosis and treatment, Surgery and mula I, II, III or IV and methods of preparing the compounds radiotherapy may be curative if a cancer is found early, but of Formula I, II, III or IV: current drug therapies for metastatic disease are mostly pal liative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for (I) new drugs effective in monotherapy or in combination with Rc2 existing agents as first line therapy, and as second and third N-N^ line therapies in treatment of resistant tumors. 25 W Cancer cells are by definition heterogeneous. For example, Rel a NN within a single tissue or cell type, multiple mutational "mechanisms' may lead to the development of cancer. As Rc4 S Such, heterogeneity frequently exists between cancer cells taken from tumors of the same tissue and same type that have 30 X originated in different individuals. Frequently observed R1 Nx1 mutational "mechanisms' associated with some cancers may (II) differ between one tissue type and another (e.g., frequently observed mutational "mechanisms' leading to colon cancer may differ from frequently observed “mechanisms' leading 35 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. Decker Inc., Hamilton, Ontario). Components of cellular signal transduction pathways that 40 regulate the growth and differentiation of normal cells can, when dysregulated, lead to the development of cellular pro (III) liferative disorders and cancer. Mutations in cellular signal Rc2 ing proteins may cause Such proteins to become expressed or N-N? activated at inappropriate levels or at inappropriate times 45 W during the cell cycle, which in turn may lead to uncontrolled Rel 21 NN cellular growth or changes in cell-cell attachment properties. For example, dysregulation of receptor tyrosine kinases by mutation, gene rearrangement, gene amplification, and over N expression of both receptor and ligand has been implicated in 50 the development and progression of human cancers. Rc6, FGFR2 is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved Rc5 between members and throughout evolution. FGFR family members differ from one another in their ligandaffinities and 55 tissue distribution. A full-length representative protein con (IV) sists of an extracellular region, composed of three immuno Rc2 globulin-like domains, a single hydrophobic membrane N-N? spanning segment and a cytoplasmic tyrosine kinase domain. W The extracellular portion of the protein interacts with fibro 60 Rel 21 NN blast growth factors, setting downstream signals, ultimately influencing mitogenesis and differentiation. Rc4 N Alterations in the activity (expression) of the FGFR2 gene are associated with certain cancers. The altered gene expres sion may enhance several cancer-related events such as cell 65 R Y Rc6, proliferation, cell movement, and the development of new blood vessels that nourish a growing tumor. The FGFR2 gene US 8,263,610 B2 3 4 or a salt, Solvate, hydrate or prodrug thereof, wherein: the atom they attach to, form a 5-, 6- or 7-member ring which comprises 1-4 heteroatoms selected from N, O and S and is optionally substituted; R, is H, unsubstituted or substituted Co-Co aryl, unsub stituted or substituted heteroaryl comprising one or two 5- or O 6-member ring and 1-4 heteroatoms selected from N, O and S. unsubstituted or Substituted C-Cs carbocycle, unsubstituted is a 5- or 6-member ring which optionally comprises 1-4 or Substituted heterocycle comprising one or two 5- or heteroatoms selected from N, O and S, and is optionally 6-member ring and 1-4 heteroatoms selected from N, O and S. substituted; 10 - NRR', NR"C(O)NR'R'', NR"C(O)R - NR"C R is H. halogen, unsubstituted or Substituted C-C alkyl, (O)OR - NR"S(O).R., or—C(O)NR'R'; unsubstituted or substituted phenyl, or unsubstituted or sub Rs and Rs' are each independently H, or-T'-Q,"; stituted heteroaryl comprising one or two 5- or 6-member ring R" is H, or unsubstituted or substituted C-C alkyl; and 1-4 heteroatoms selected from N, O and S; 15 T.T., and Ts are each independently a bond, or unsub R is H, or unsubstituted or substituted C-C alkyl: stituted or substituted C-C alkyl linker; R. and Ra are each independently H, unsubstituted or Q, is H, unsubstituted or substituted Co-Co aryl, unsub Substituted C-C alkyl, or R and Ra, together with the stituted or substituted heteroaryl comprising one or two 5- or atoms they attach to, form a 5-, 6- or 7-member ring which 6-member ring and 1-4 heteroatoms selected from N, O and S. optionally comprises 1-4 heteroatoms selected from N, O and unsubstituted or Substituted C-Cs carbocycle, unsubstituted Sand is optionally substituted; or Substituted heterocycle comprising one or two 5- or Rs and R are each independently H, unsubstituted or 6-member ring and 1-4 heteroatoms selected from N, O and S.
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