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WO 2015/042414 Al 26 March 2015 (26.03.2015) P O P C T

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WO 2015/042414 Al 26 March 2015 (26.03.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/042414 Al 26 March 2015 (26.03.2015) P O P C T (51) International Patent Classification: (74) Agents: ABELLEIRA, Susan, M. et al; Hamilton, Brook, C07D 401/14 (2006.01) C07D 417/12 (2006.01) Smith & Reynolds, P.C., 530 Virginia Rd, P.O. Box 9133, C07D 213/73 (2006.01) C07D 419/12 (2006.01) Concord, MA 01742-9133 (US). C07D 401/12 (2006.01) A61K 31/433 (2006.01) (81) Designated States (unless otherwise indicated, for every C07D 413/12 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/US2014/056580 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 19 September 2014 (19.09.2014) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (25) Filing Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/880,488 20 September 2013 (20.09.2013) US (84) Designated States (unless otherwise indicated, for every 61/904,888 15 November 2013 (15. 11.2013) US kind of regional protection available): ARIPO (BW, GH, (71) Applicant: KARYOPHARM THERAPEUTICS INC. GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [US/US]; 85 Wells Avenue, Newton, MA 02459 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: BALOGLU, Erkan; 8 Benjamin Terrace, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Stoneham, MA 02180 (US). SHACHAM, Sharon; 145 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Hagen Road, Newton, MA 02459 (US). SENAPEDIS, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, William; 34 Timberline Road, Arlington, MA 02054 (US). GW, KM, ML, MR, NE, SN, TD, TG). MCCAULEY, Dilara; 49 Brantwood Road, Arlington, Declarations under Rule 4.17 : MA 02476 (US). LANDESMAN, Yosef; 260 Tappan Street, Brookline, MA 02445 (US). GOLAN, Gali; 192 — of inventorship (Rule 4.17(iv)) Har Yeela Street, 99770 Mesilat Zion (IL). KALD3, Ori; Published: Dror 30/2, 37025 Pardes Hanna (IL). SHECHTER, Shar¬ on; 18 Ivy Lane, Andover, MA 01810 (US). — with international search report (Art. 21(3)) (54) Title: MULTICYCLIC COMPOUNDS AND METHODS OF USING SAME (I) © (57) Abstract: The invention generally relates to compounds represented by Structural Formula I: or a pharmaceutically acceptable o salt thereof, wherein the variables are as defined and described herein. The invention also includes the synthesis and use of a com pound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in treatment of cancer (e.g. , mantle cell lymphoma), and other diseases and disorders (e.g., PAK-mediated, for example, PAK4 -mediated, diseases and disorders). MULTICYCLIC COMPOUNDS AND METHODS OF USING SAME RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 61/880,488, filed on September 20, 2013, and U.S. Provisional Application No. 61/904,888, filed on November 15, 2013. The entire teachings of these applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Cancer is the second most common cause of death in the United States, exceeded only by heart disease. In the United States, cancer accounts for one of every four deaths. With population growth and aging of the population, the number of new cancer patients is expected to double to 2.6 million by 2050. There is a clear need for additional drug-like compounds that are effective for the treatment of cancer. SUMMARY OF THE INVENTION [0003] The present invention relates to multicyclic compounds, or pharmaceutically acceptable salts or compositions thereof, useful as anti-cancer agents. In one embodiment of the invention, the compounds are represented by Structural Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0004] Another embodiment of the invention is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0005] Yet another embodiment of the invention is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof. [0006] Without being bound by a particular theory, it is believed that the compounds described herein can modulate (e.g. , inhibit) one or more p21 -activated kinases (PAK), for example, one or more of PAKs 1-6. More specifically, and without being bound by a particular theory, it is believed that the compounds described herein can bind to one or more PAKs and function as allosteric modulators of one or more PAKs. For example, the compounds described herein may exert their modulatory effect(s) on one or more PAKs by binding to and destabilizing one or more PAKs or contributing to the degradation of one or more PAKs, thereby modulating (e.g., inhibiting) the effect of one or more PAKs on one or more proteins downstream of the one or more PAKs, for example, growth signaling proteins such as Akt, ERK1/2, p90RSK, β-catenin, cofilin, p21 and cyclin Dl. [0007] In a particular embodiment, one or more of the Group I PAKs (e.g. , PAKl , PAK2, PAK3) is inhibited. For example, PAKl is inhibited, PAK2 is inhibited, PAK3 is inhibited or a combination of PAKl, PAK2 and PAK3, such as PAKl and PAK2, PAKl and PAK3, PAK2 and PAK3, or PAKl, PAK2 and PAK3 is inhibited. In a particular embodiment, one or more of the group II PAKs (e.g. , PAK4, PAK5, PAK6) is inhibited. For example, PAK4 is inhibited, PAK5 is inhibited, PAK6 is inhibited or a combination of PAK4, PAK5 and PAK6, such as PAK4 and PAK5, PAK4 and PAK6, PAK5 and PAK6 or PAK4, PAK5 and PAK6 is inhibited. Therefore, the compounds described herein can be useful for treating PAK- mediated disorders. [0008] As such, in another embodiment, the invention is a method of treating a PAK- mediated disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof. [0009] Another embodiment of the invention is use of a compound of the invention for treating cancer or a PAK-mediated disorder in a subject. [0010] Another embodiment of the invention is use of a compound of the invention for the manufacture of a medicament for treating cancer or a PAK-mediated disorder in a subject. [0011] Compounds of the present invention, and pharmaceutically acceptable salts and/or compositions thereof, are useful for treating a variety of cancers, such as lymphoma and, more specifically, mantle cell lymphoma. BRIEF DESCRIPTION OF THE DRAWINGS [0012] The foregoing will be apparent from the following more particular description of example embodiments of the invention. [0013] FIG. 1 is a schematic representation of a SILAC experiment and shows the experimental design. DETAILED DESCRIPTION OF THE INVENTION [0014] A description of example embodiments of the invention follows. Definitions [0015] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [001 | Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by reference herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada. [0017] Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1 190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention. [0018] "Aliphatic" means an optionally substituted, saturated or unsaturated, branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms.
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