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WO 2013/154878 Al 17 October 2013 (17.10.2013) P O P C T

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WO 2013/154878 Al 17 October 2013 (17.10.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/154878 Al 17 October 2013 (17.10.2013) P O P C T (51) International Patent Classification: A.; 94 Jaques Street, Somerville, MA 02145 (US). C07D 401/12 (2006.01) C07D 413/12 (2006.01) TREMBLAY, Martin, R.; 47 Heywood Ave, Melrose, C07D 417/12 (2006.01) C07D 471/04 (2006.01) MA 02 176 (US). C07D 487/04 (2006.01) C07D 495/04' (2006.01) (74) Agents: INSOGNA, Anthony, M. et al; Jones Day, 222 C07D 401/14' (2006.01) A61K 31/517 (2006.01) East 41st Street, New York, NY 10017-6702 (US). C07D 217/24 (2006.01) A61P 35/00 (2006.01) C07D 403/14 (2006.01) A61P 37/00 (2006.01) (81) Designated States (unless otherwise indicated, for every 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/US20 13/035069 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 3 April 2013 (03.04.2013) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, English (25) Filing Language: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (30) Priority Data: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 61/622,259 10 April 2012 (10.04.2012) ZM, ZW. 61/713,404 12 October 20 12 ( 12.10.20 12) (84) Designated States (unless otherwise indicated, for every (71) Applicants: INFINITY PHARMACEUTICALS, INC. kind of regional protection available): ARIPO (BW, GH, [US/US]; 780 Memorial Drive, Cambridge, MA 021 39 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (US). INTELLIKINE LLC [US/US]; 1093 1 N. Torrey UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Pines Road, Suite 103, La Jolla, CA 92037 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: CASTRO, Alfredo, C ; 43 Wildwood Street, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Winchester, MA 01890 (US). CHAN, Katrina; 38835 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Hayes Street, Fremont, CA 94536 (US). EVANS, Cather¬ TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). ine, A.; 83 Jaques Street, Somerville, MA 02145 (US). JANARDANANNAIR, Somarajannair; 111 Locust St., Published: Apt. Th-78, Woburn, MA 01801 (US). LESCARBEAU, — with international search report (Art. 21(3)) Andre; 99 Porter Street #1, Somerville, MA 02143 (US). LI, Liangsheng; 8155 Cargill Avenue, Apt. 39, San Diego, — before the expiration of the time limit for amending the CA 92122 (US). LIU, Tao; 15 Sherborne Circle, Ashland, claims and to be republished in the event of receipt of MA 01721 (US). LIU, Yi; 4841 Barlow Landings Cove, amendments (Rule 48.2(h)) San Diego, CA 92 130 (US). REN, Pingda; 5534 Haven- ridge Way, San Diego, CA 92130 (US). SNYDER, Daniel, (54) Title: HETEROCYCLIC COMPOUNDS AND USES THEREOF (57) Abstract: Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and com pounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein. HETEROCYCLIC COMPOUNDS AND USES THEREOF CROSS REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 61/622,259, filed April 10, 2012, and U.S. Provisional Patent Application No. 61/713,404, filed October 12, 2012, the contents of both of which are incorporated by reference herein in their entireties. BACKGROUND [0002] The activity of cells can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction. Over the past decades, cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234). [0003] Kinases represent a class of important signaling molecules. Kinases can generally be classified into protein kinases and lipid kinases, and certain kinases exhibit dual specificities. Protein kinases are enzymes that phosphorylate other proteins and/or themselves (i.e., autophosphorylation). Protein kinases can be generally classified into three major groups based upon their substrate utilization: tyrosine kinases which predominantly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine/threonine kinases which predominantly phosphorylate substrates on serine and/or threonine residues (e.g., mTorCl, mTorC2, ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylate substrates on tyrosine, serine and/or threonine residues. [0004] Lipid kinases are enzymes that catalyze the phosphorylation of lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. Certain lipid kinases are membrane associated and they catalyze the phosphorylation of lipids contained in or associated with cell membranes. Examples of such enzymes include phosphoinositide(s) kinases (e.g., PI3-kinases, PI4-kinases), diacylglycerol kinases, and sphingosine kinases. [0005] The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is also a key factor in many other diseases in humans. PI3K signaling is involved in many disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome. [0006] PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. The class I PI3Ks (pi 10a, ρ ΐ ΐ θβ, ρ ΐ ΐ θδ, and ρ ΐ ΐ θγ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the Akt/PDKl pathway, mTOR, the Tec family kinases, and the Rho family GTPases. The class II and III PI3Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2. The PI3Ks are protein kinases that control cell growth (mTORCl) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1). [0007] The delta (δ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes. ΡΙ3Κ-δ is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. ΡΙ3Κ-δ is integrally involved in mammalian immune system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its integral role in immune system function, ΡΙ3Κ-δ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, and auto-immune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class I PI3K involved in immune system function includes ΡΙ3Κ-γ , which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus. For example, ΡΙ3Κ-γ and ΡΙ3Κ-δ are highly expressed in leukocytes and have been associated with adaptive and innate immunity; thus, these PI3K isoforms can be important mediators in inflammatory disorders and hematologic malignancies. [0008] The gamma (γ) isoform of class I PI3K consists of a catalytic subunit ρ ΐ ΐ θγ , which is associated with a plOl regulatory subunit. ΡΙ3Κ-γ is regulated by G protein-coupled receptors (GPCRs) via association with the β/γ subunits of heterotrimeric G proteins. ΡΙ3Κ-γ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function. Inhibitors of ΡΙ3Κ-γ are useful for treating a variety of inflammatory diseases, allergies, and cardiovascular diseases, among others. [0009] Unlike PI3K-5, the beta (β) isoform of class I PI3K appears to be ubiquitously expressed. ΡΙ3Κ-β has been implicated primarily in various types of cancer including PTEN-negative cancer (Edgar et al. Cancer Research (2010) 70(3):1 164-1 172), and HER2-overexpressing cancer such as breast cancer and ovarian cancer. SUMMARY [0010] Described herein are compounds capable of selectively inhibiting certain isoform(s) of class I PI3K without substantially affecting the activity of the remaining isoforms of the same class. For example, non- limiting examples of inhibitors capable of selectively inhibiting PI3K-5 and/or ΡΙ3Κ-γ, but without substantially affecting the activity of ΡΙ3Κ-β are disclosed. Such inhibitors can be effective in ameliorating disease conditions associated with ΡΙ3Κ-δ/γ activity.
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