WO 2011/002817 Al
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(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 6 January 2011 (06.01.2011) WO 2011/002817 Al (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/497 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US20 10/040486 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 29 June 2010 (29.06.2010) NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/221,430 29 June 2009 (29.06.2009) US GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/292,360 5 January 20 10 (05 .0 1.20 10) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant (for all designated States except US): AGIOS EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, PHARMACEUTICALS, INC. [US/US]; 38 Sidney LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, Street, Cambridge, MA 02139 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/Applicants (for US only): SAUNDERS, Jef¬ Declarations under Rule 4.17: frey, O. [US/US]; 117 Seymour Street, Concord, MA — as to applicant's entitlement to apply for and be granted 01742 (US). SALITURO, Francesco, G. [US/US]; 25 a patent (Rule 4.1 7(U)) Baker Drive, Marlborough, MA 01752 (US). YAN, Shunqi [US/US]; 55 Stepping Stone, Irvine, CA 92603 — as to the applicant's entitlement to claim the priority of (US). the earlier application (Rule 4.1 7(Hi)) (74) Agent: MCCARTY, Catherine, M.; Lando & Anastasi, Published: LLP, One Main Street, Eleventh Floor, Cambridge, MA — with international search report (Art. 21(3)) 02142 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: THERAPEUTIC COMPOUNDS AND COMPOSITIONS (57) Abstract: Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer. Therapeutic compounds and compositions CLAIM OF PRIORITY This application claims priority from U.S.S.N. 61/221,430, filed June 29, 2009 and U.S.S.N. 61/292,360, filed January 5, 2010, each of which is incorporated herein by reference in its entirety. BACKGROUND OF INVENTION Cancer cells rely primarily on glycolysis to generate cellular energy and biochemical intermediates for biosynthesis of lipids and nucleotides, while the majority of "normal" cells in adult tissues utilize aerobic respiration. This fundamental difference in cellular metabolism between cancer cells and normal cells, termed the Warburg Effect, has been exploited for diagnostic purposes, but has not yet been exploited for therapeutic benefit. Pyruvate kinase (PK) is a metabolic enzyme that converts phosphoenolpyruvate to pyruvate during glycolysis. Four PK isoforms exist in mammals: the L and R isoforms are expressed in liver and red blood cells, the Ml isoform is expressed in most adult tissues, and the M2 isoform is a splice variant of Ml expressed during embryonic development. All tumor cells exclusively express the embryonic M2 isoform. A well-known difference between the Ml and M2 isoforms of PK is that M2 is a low-activity enzyme that relies on allosteric activation by the upstream glycolytic intermediate, fructose- 1,6-bisphosphate (FBP), whereas Ml is a constitutively active enzyme. All tumor cells exclusively express the embryonic M2 isoform of pyruvate kinase, suggesting PKM2 as a potential target for cancer therapy. PKM2 is also expressed in adipose tissue and activated T-cells. Thus, the modulation (e.g. inhibition or activation) of PKM2 may be effective in the treatment of, e.g., obesity, diabetes, autoimmune conditions, and proliferation-dependent diseases, e.g., benign prostatic hyperplasia (BPH). Current inhibitorss of pyruvate kinase are not selective, making it difficult to treat disease related to pyruvate kinase function. Furthermore, phosphotyrosine peptide binding to PKM2 leads to a dissociation of FBP from PKM2 and conformational changes of PKM2 from an active, tetrameric form to an inactive form. Compounds that bind to PKM2 and lock the enzyme in the active confirmation will lead to the loss of allosteric control of PKM2 needed for shunting biochemical intermediates from glycolysis into biosynthesis of nucleotides and lipids. Thus, the activation of PKM2 (i.e., activators of PKM2) can also inhibit the growth and proliferation of cancer cells, activated immune cells, and fat cells. There is a continuing need for novel treatments of diseases such as cancer, diabetes, obesity, autoimmune conditions, proliferation-dependent diseases (e.g., BPH), and other diseases related to the function of pyruvate kinase (e.g., PKM2). SUMMARY OF INVENTION Described herein are compounds that modulate pyruvate kinase M2 (PKM2) and pharmaceutically acceptable salts, solvates, and hydrates thereof, for example, compounds that activate PKM2. Also provided are pharmaceutical compositions comprising a compound provided herewith and the use of such compositions in methods of treating diseases and conditions that are related to pyruvate kinase function (e.g., PKM2 function), including, e.g., cancer, diabetes, obesity, autoimmune disorders, and benign prostatic hyperplasia (BPH). In one embodiment, provided is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of formula (I): wherein: W, X, Y and Z are each independently selected from CH or N; D and D1 are independently selected from a bond or NRb; A is optionally substituted aryl or optionally substituted heteroaryl; c c c c c c L is a bond, -C(O)-, -(CR R )m-, -OC(O)-, -(CR R )m-0C(0)-, -(CR R )m- C(O)-, -NRbC(S)-, or -NRbC(0)- (wherein the point of the attachment to R1 is on the left-hand side); R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd; each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and -ORa, or two adjacent R taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl; each Rb is independently selected from hydrogen and alkyl; each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, -C(O)Ra, -OC(O)Ra, -C(O)ORa, -SRa, -NRaRb and - ORa, or two Rd taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is O, 1, 2; and g is 0, 1 or 2. In another embodiment, provided is a method for treating or preventing a disease, condition or disorder as described (e.g., treating) herein comprising administering a compound provided herein, a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. In another embodiments, provided is a method of modulating (e.g., increasing or decreasing) the level of PKM2 activity and/or glycolysis (e.g., modulating the endogenous ability of a cell in the patient to down regulate PKM2) in a patient in need thereof. The method comprises the step of administering an effective amount of a compound described herein to the patient in need thereof, thereby modulating (e.g., increasing or decreasing) the level of PKM2 activity and/or glycolysis in the patient. In some embodiments, a a compound or a composition described herein is used to maintain PKM2 in its active conformation or activate pyruvate kinase activity in proliferating cells as a means to divert glucose metabolites into catabolic rather than anabolic processes in the patient. In another embodiment, provided is a method of inhibiting cell proliferation in a patient in need thereof. The method comprises the step of administering an effective amount of a compound described herein to the patient in need thereof, thereby inhibiting cell proliferation in the patient. E.g., this method can inhibiting growth of a transformed cell, e.g., a cancer cell, or generally inhibiting growth in a PKM2- dependent cell that undergoes aerobic glycolysis. In another embodiment, provided is a method of treating a patient suffering from or susceptible to a disease or disorder associated with the function of PKM2 in a patient in need thereof. The method comprises the step of administering an effective amount of a compound described herein to the patient in need thereof, thereby treating, preventing or ameliorating the disease or disorder in the patient. In certain embodiment the modulator is provided in a pharmaceutical composition. In certain embodiment, the method includes identifying or selecting a patient who would benefit from modulation (e.g., activation) of PKM2. E.g., the patient can be identified on the basis of the level of PKM2 activity in a cell of the patient for treatment of cancer associated with PKM2 function.